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Chemoenzymatic approach to the synthesis of the morphinan skeleton via a Claisen rearrangement approach

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Chemoenzymatic approach to the synthesis of the morphinan skeleton via a Claisen rearrangement approach
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Oppong, Kofi A., 1969-
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English
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vii, 188 leaves : ill. ; 29 cm.

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Subjects / Keywords:
Acetates ( jstor )
Alcohols ( jstor )
Esters ( jstor )
Ethers ( jstor )
Morphinans ( jstor )
Morphine ( jstor )
Numberings ( jstor )
Silica gel ( jstor )
Skeleton ( jstor )
Solvents ( jstor )
Chemistry thesis, Ph. D ( lcsh )
Claisen condensation ( lcsh )
Dissertations, Academic -- Chemistry -- UF ( lcsh )
Morphine ( lcsh )
Organic compounds -- Synthesis ( lcsh )
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bibliography ( marcgt )
theses ( marcgt )
non-fiction ( marcgt )

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Thesis:
Thesis (Ph. D.)--University of Florida, 2001.
Bibliography:
Includes bibliographical references (leaves 127-133).
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Also available online.
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Printout.
General Note:
Vita.
Statement of Responsibility:
by Kofi A. Oppong.

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CHEMOENZYMATIC APPROACH TO THE SYNTHESIS OF THE
MORPHINAN SKELETON VIA A CLAISEN REARRANGEMENT APPROACH













By

KOFI A. OPPONG











A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT
OF THE REQUIREMENTS FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2001





























Dedicated to



Nana Akua and Akwasi














ACKNOWLEDGMENTS


I would like to take this opportunity to express gratitude to a number of people who had a positive influence on my life in the last 5 years. First I would like to thank my research advisor Dr. Tomas Hudlicky for his support and guidance over the years. I have come to appreciate the impact and the importance of the training I received from Dr. Hudlicky. Being associated with his group has been one of the landmark experiences in my life, something I will not forget.

I also wish to show my appreciation to members of my committee (Dr. Merle Battiste, Dr. William Dolbier, Dr. Dennis Wright, Dr. Vanecia Young and Dr. Howard Johnson) for the help they rendered to me during my time here. I give special thanks to Dr. Battiste and Dr. Dolbier, who as committee members had a direct impact on my development as a student. I also want to acknowledge Dr. Dolbier because he played a huge role in my obtaining admission to this graduate school. I extend thanks to Dr. James Deyrup, Donna Balkom and Lori Clark for their assistance with all the administrative aspects of my stay at the University of Florida. Since joining the faculty of the University of Florida, Dr. Dennis Wright has been a tremendous asset to me personally and to all the students in the Hudlicky group in general. I would like to acknowledge Dr. Dennis Wright for all his chemistry suggestions, discussions and contributions, all of which added to my growth as a chemist.

I extend my gratitude to all the members of the Hudlicky research group who in one way or another helped to nurture me over the years. I would like to iii








recognize Dr. Yan Fengyan and Dr. Ba Nguyen with whom I collaborated on the fluoroinositol project; and Dr. Larry Brammer, who was instrumental in my training during my first year in graduate school. I thank Dr. David Gonzalez and Dr. Bennett Novak for their advice and chemistry discussions. Dr David Gonzalez was instrumental in my advancement in laboratory techniques and for that I am indebted. The fermentation team also deserves acknowledgment: Dr. Bennett Novak, Dr. Mary Ann Endoma, Vu Bui and Natalia Korkina. I also acknowledge Dr. Caimin Duan who has been a model of hard work for me. I am indebted to Nora Restrepo, Stephan Schilling, Jennifer Lombardi and Jerremy Willis for their friendship and advice in chemistry and other matters.

I am grateful to those people with whom I worked together on the morphine project; I thank Dr. David Gonzalez, Charles Stanton and Elizabeth Hobbs for their contribution to the morphine project. Recently it has been my pleasure to work with Dr. Lucillia Santos and Lukaz Koroniak who contributed immensely to the progress of the morphine project. We owe our progress to Vu Bui who kept a constant stream of diol flowing our way.

I am also thankful for all the help received from the analytical services department, especially Dr. Ion Ghiriviga, Dr. Khalil Abboud and Lidia Madveeva.

I would also like to thank Dupont-NOBCChE and the Shell Fellowships for their support of my education. I give special thanks to Dr. Hollinsed for all his assistance.

I want to acknowledge Dr. Josie Reed for the many chemistry/administrative problems that she solved for me and for the entire Hudlicky group. During my time here she has served as an excellent mother figure for me. All her efforts are appreciated and did not go unnoticed.




iv








I would like to thank some of the friends I have made in Gainesville: Tahra Edwards, Gabriela Feldberg, Jacinth McKenzie and Michael Mosi, Jerremey Willis, and Nadia Kunan who made my stay here a great experience and gave me reason to persevere and to finish.














TABLE OF CONTENTS


page
ACKNOWLEDGMENT............................................................111i
ABSTRACT ......................................................................vii

CHAPTERS

1. INTRODUCTION................................................................ 1

2. HISTORICAL BACKGROUND ................................................. 3
Introduction .................................................................... 3
Morphine Biosynthesis..........................................................5
Total and Formal Syntheses of Morphine ....................................... 8
Morphine Syntheses via Sigmatropic Rearrangements ........................... 21
Recent Related Developments................................................... 29
Chelated Enolate Claisen Rearrangement ......................................41

3. RESULTS AND DISCUSSION................................................... 55
Introduction ................................................................... 55
First Generation Synthesis: Control of C9 and C14 Stereocenters................. 61
Claisen I-First Attempt of Kazmaier Claisen on Morphine Precursor........... 64
Friedel Craft-Attempt at C 10O-Cl 1 Closure ................................... 69
Claisen il-keland Claisen on Phthaloyl Ester................................. 71
Claisen llI-Kazmaier Claisen of Glycinate, of Cyclohexadiene Diol........... 73
Synthesis of Matrix Metalloproteinase Inhibitors (MMP's) ....................
Second Generation Synthesis: Overman's Intermediate via Claisen
Rearrangement................................................................. 81
Alternative Methods to Setting the C 13 Quaternary Center ...................... 89

4. CONCLUSION .................................................................. 97

5. EXPERIMENTAL SECTION ...................................................102
General Procedure ............................................................. 102
Experimental Procedures ....................................................... 103

LIST OF REFERENCES........................................................... 127

APPENDIX: SELECTED SPECTRA............................................... 134

BIOGRAPHICAL SKETCH........................................................ 186



Vi














ABSTRACT

Abstract of Dissertation Presented to the Graduate School
of the University of Florida in Partial fulfillment of the Requirements for the Degree of Doctor of Philosophy CHEMOENZYMATIC APPROACH TO THE SYNTHESIS OF THE

MORPHINAN SKELETON VIA A CLAISEN REARRANGEMENT APPROACH By

Kofi Oppong

August 2001


Chairman: Dr. Tomas Hudlicky Major Department: Chemistry HO JARO Br
"-___ RO COOH HO,
01 f14 M D9 e 14 9NH, HO'


HO HO


An approach to the morphinan skeleton with complete control of the C9 and C14 stereocenters is described. The first generation of the synthesis of the A and C rings of morphine are discussed. Also described are attempts at establishing the C 13 quaternary center with emphasis on construction of the D-ring. The use of precursors from the enzymatic biooxidation of aromatic compounds in the construction of the morphinan skeleton through various chemical modifications is reported.





Vii














CHAPTER 1
INTRODUCTION


Morphine (1), one of the world's oldest drugs, is consumed to the tune of one hundred metric tons in the United States alone annually.'-4 Its main legal uses is for pain relief in cases of severe trauma (caused by the agonist binding to the [i- receptors in the HO 2


4 15 10 16
0
D
13 9 NMe
S14
C
,%%
HO


central nervous system). These receptors are responsible for analgesia, euphoria, addiction and respiratory depression. In recent years morphine has been used in high doses as an anaesthetic in open-heart surgery due to its ability to slow down respiratory activity without affecting cardiac function.

Morphine is the major component (20%) of the opium of the poppy, Paperver somniferum, 4and its documented use dates back to 1500 BC5 and its impact on society has been quite remarkable. On average 20 people per day die of drug abuse across Europe. In 1999 alone the opium harvest in Afghanistan, a country illegally harvesting morphine, was 4581 metric tons. Legally opium is harvested in India (the only legal producer) on a multi-ton scale. The alkaloid constituent of the opium poppy is about





2


25%; of this, two of the important alkaloids, morphine (1) and codeine (2), constitute approximately 1 7%.6

Although morphine is quite abundant from the isolation of the natural resource, it still remains a viable synthetic target to various research groups around the world. The focus is not only to find an efficient synthesis of morphine but more importantly to arrive at a more practical synthesis of the morphinan skeleton, which would allow for a more competent route to some the important derivatives of morphine.

Of the twenty-one formal synthesis of morphine only three syntheses have used sigmatropic rearrangements as key steps. Interestingly, the rearrangements were all used to install the quaternary center at C13. None of the above approaches used the rearrangement to transfer stereochemnistry inherent in the molecule to another site with the result of correctly setting two important stereocenters in one transformation.

This thesis describes a Claisen rearrangement approach to the synthesis of the morphinan skeleton. Control of the stereo centers C9 and C 14 are discussed and recent advances in the synthesis of the morphinan skeleton are also reported.














CHAPTER 2
HISTORICAL BACKGROUND


Introduction

According to the available records, the relationship between opium and human beings started in ancient Middle Eastern civilizations about 3500 years ago.6 Since then the potent bioactivity of morphine and its derivatives was an important issue that has crossed the frontiers of medicine and become a socio-political factor. In the sixteenth century, Parcellus popularized the use of opium as an analgesic when he introduced various preparations and named it "laudanum" which is derived from the latin word meaning to praise.

Although opium had been used for centuries, morphine was not isolated as a crystalline material until 1803 as reported by Derosne. Three years later in 1806, Seguin presented a description of the isolation of morphine to the Institute of France,'0 and later in the same year, Serturner was finally credited with the first isolation of crystalline morphine."1 A century later in 1925, Sir Robert Robinson postulated the correct structure of morphine including relative stereochemistry.' 2 This was later confirmed by X-ray crystallographic analysis in combination with other analytical techniques.13,14 After its isolation morphine 1 was introduced into medical practice and used extensively to treat ailments such as diarrhea, asthma, diabetes, ulcers and pain relief. Bayer at the end of the ninteenth century was marketing diacetyl morphine





3





4


(Diamorphine). 14 It was nicknamed heroin because it was considered a "heroic" drug. Heroin 3 has the same physiological effects as morphine (because of rapid hydrolysis to morphine, most of its actions are due to morphine itself) except that it acts faster and is more potent. However there are appropriate differences. Heroin is lipid soluble and rapidly enters the brain. Morphine is not as lipophilic and hence its passage to MeO AcO


010

H~h Me NMe

2 3
Codeine Heroin
Scheme 2

the brain occurs at a much slower rate. Codeine 2 is approximately one-sixth as effective as morphine as an analgesic. It is best administered orally and acts as a good cough suppressant.

In 1952, Gates achieved the first total synthesis of morphine'5,16 and confirmed the structure of morphine as proposed by Robinson. Since Gates historic synthesis, about 20 formal syntheses of morphine have been reported. In spite of these reports and 150 years of effort since its discovery, a truly practical synthesis, which would compete economically with the isolation of morphine directly from the opium poppy, Papever somniferum, has not yet been achieved.

Astonishingly, of all the reported formal synthesis of (-)-morphine to date only three have used some sort of sigmatropic rearrangement. Only the syntheses of Rapoport,

1,8Parsons, 1,0and Mulzer 21-25 have relied on these types of reactions. Interestingly, the three syntheses made use of the rearrangement for the same purpose: to install the





5


quaternary center at Cl13 (morphine numbering, while transferring the stereochemistry already present in the starting material to that position.



Morphine Biosynthesis

It is interesting to note that Robert Robinson, who proposed that morphine

consisted of a twisted benzylisoquinoline skeleton, made one of the most important

O 02H N HO N
HO -~ NH2 H NH2 NH2
4 HO CHO
4 ii5 6
SCO2H iv H

-0 0
HO HO 0
7 8 v


MeO MeO HO

HO NMe vii HO NH A N
HOI ,N HO HO
H H H
11N N
HO HO HO
11 10 9

viii

MeO NMeO

HO NMe ix HO.-HONMe
HO HO
HO N HO H

HO MeO
12 13


Scheme 3

Enzymes: i)L-tyrosine decarboxylase; ii) phenolase; iii) L-tyrosine transaminase; iv) phydroxyphenylpyruvate decarboxylate; v) (S)-norcoclaurine synthase; vi) norcoclaurine6-O-methyltransferase; vii) tetrahydrobenzylisoquinoline-N-methyltransferase; viii) phenolase; ix) 3'-hydroxy-N-methyl (S)-coclaurine-4'-O-methyltransferase.





6


observations that eventually led to the elucidation of the structure of morphine.12,26 Studies conducted on the biosynthesis of morphine indicate that the morphinan alkaloids are formed by a series of benzylisoquinoline intermediates (Scheme 3) which eventually forms (R)-reticuline 14 (Scheme 4). 27,28

MeO MeO MeO
NMe/
HO ....... HO HO
HO
HO NMe NMe
HOI H +
MeO MeO MeO
OH OH
13 13 14
MeO MeO MeO

HO HO HO


MeO MeO MeO
R H 0 OH
17 R = H 16 15
18 R = Ac

MeO MeO MeO


M NMe ONMe NMe

MeO O1 1
19 20 21
Scheme 4

The benzylisoquinoline skeleton is derived from two molecules of L-tyrosine (4), which is converted into a molecule each of dopamine 6 and 4-hydroxy phenylacetaldehyde 8 through the intermediacy of tyramine 5 and 4-hydroxyphenyacetic acid 7 respectively (Scheme 3). Condensation of these two derivatives of L-tyrosine is catalyzed in a stereospecific manner by (S)-norcoclaurine synthase, which results in the





7


formation of (S)-norcoclaurine 9, which serves as the skeletal foundation of most of the benzylisoquinoline alkaloids. The next three steps can be summarized as two enzymecatalyzed methylations and an aromatic hydroxylation to afford (S)-reticuline 13, that possesses the opposite configuration to the compound found in the biosynthesis of morphine (what would be the C9 center of morphine has the opposite stereochemistry). Inversion to the correct intermediate is effected in two steps through the intermediate imine dehydroreticuline 14 (Scheme 4) by a highly stereospecific and NADPH/NADPH' dependent reductase to afford (R)-reticuline 15.29,30 It is likely that the mechanism involves the formation of two phenolate radicals and their subsequent coupling. The next step in the biosynthesis is the conversion of (R)-reticuline into salutaridine 16 by a membrane-bound cyctochrome P-450 enzyme whose catalytic action is strictly dependent on NADPH and molecular oxygen. After the formation of salutaridine 16, the ketone moiety is reduced by an NADPH-dependent oxidoreductase to afford salutaridinol 17,31 which then undergoes enzyme-catalyzed acetyl CoA dependent acetylation to yield the acetate 18.32 The next intermediate formed is thebaine 19, which results from ring closure at slightly basic pH. Failure to find a specific enzyme for this step has led to the conclusion that this step is spontaneous. Neopinone 20 is formed by the demethylation of thebaine to form the ketone, which is in chemical equilibrium with codeinone 21. The final steps in the morphine biosynthesis are the conversion of codeinone to codeine (2) and a final demethylation of codeine to afford morphine (1). An alternate pathway to morphine has also been proposed and it involves arriving at the target first by demethylation of thebaine to obtain the intermediate alcohol 22, then conversion to the enone 23 whose reduction by codeinone reductase affords morphine 1 (Scheme 5). 33, 34





8


MeO MeO MeO


O1, O O
NMe K NMe NMe
MeO MeO
19 22 23
Scheme 5



Total and Formal Synthesis of Morphine

Gates landmark synthesis of morphine in 1952 started from naphthalene

HO MeO MeO

7 steps \/ MeO 0
SNC4 o OH
NC CN OH 0
23 24 25

Scheme 6

diol 23, which was subsequently converted over seven steps to the substituted naphtoquinone 24 (Scheme 6).15,16 The [4+2] cycloaddition of 24 with 1,3-butadiene under thermal conditions afforded the phenanthrene 25. Phenanthrene 25 was subjected to hydrogenation in the presence of copper chromite which led to an unexpected cyclization affording tetracyclic amide 26. Although the stereochemistry at C9 (morphine numbering) was set correctly during the cyclization, it was necessary to epimerize the C14 (morphine numbering) center (Scheme 7). Gates, while attempting to close the furan ring via alpha bromination of the corresponding ketone, achieved this epimerization with dinitroarylhydrazone 27, the most commonly intercepted intermediate in subsequent formal morphine syntheses. The furan ring was then closed to afford pentacycle 29 and





9


MeO MeO MeO Br
/OeOO

MeO 0 MeO 0O HO
S CNIH,/CuCrO" ( se' N 'I
SCuCrO 8 steps
OH O NH NCH
CN H



SArHNArHNN
2825 29




Scheme 7


completed the construction of the morphine skeleton. Finally, hydrolysis, lithium aluminum hydride reduction, and demethylation completed the first total synthesis of morphine 1.

Shortly after Gates' historic synthesis, Ginsburg completed a formal synthesis by synthesizing dihydrothebainone 35 in 1954.3 In Ginsburg's synthesis, condensation of
MeO Br MeO Br MeO


2stes steps 3 steps 1
NCH O NCH e



























3031 32 53
O ArHNN
28 29














Scheme 7


veratrompleed 31 via ortho-lithiaruction to cyclohexan morphine 3 skeleton. Finally, hydrolysis, lithiumrst step (Scheme 8). aluminum hydride reduction, and demethylation completed the first total synthesis of morphine 1.

Shortly after Gates' historic synthesis, Ginsburg completed a formal synthesis by synthesizing dihydrothebainone 35 in 1954."~ In Ginsburg's synthesis, condensation of MeO MeO

MOMeO MeO 0
5 steps ,4 steps MeO

30 31 32 33
MeO MeO
/OI
5 steps ~MeO O 8 steps, HO~
ONH- JcA NMe

0
34 35
Scheme 8

veratrole 31 via ortho-lithiation to cyclohexanone 30 served as the first step (Scheme 8).





10


The coupled product was dehydrated and then converted to enone 32. Michael addition with dibenzyl malonate, followed by decarboxylation and a Friedel-Crafts annulation resulted in the formation of the phenanthrenone 33. Finally the D ring was installed using a series of steps culminating in the spontaneous formation of the ethylamine bridge accompanied with cleavage of the C4 methyl ether and formation of the tetracyclic amide 34. An additional 8 steps followed by d-tartaric acid resolution yielded (-)dihydrothebainone 35, and consequently, the first of many formal synthesis of morphine.

Nine years later, Barton presented a biomimetic synthesis of a radio labeled thebaine 38 (Scheme 9).36 Starting from tritium labeled reticuline 36 he performed an MnO2 promoted oxidative coupling to construct the phenanthrene core. However this step

MeO MeO MeO

HO HO 2 steps O
SNCH NCH\ NCH
I II H
MeO MeO MeO
OH 0
36 37 38
Scheme 9


proceeded in a poor yield and after two additional steps a radioisotope dilution study of the final thebaine 38 was performed to establish a 0.012% conversion of tritium labeled salutaridine 37.

Simultaneous reports presented in 1967 by Grewe37-38 and Morrison, Waite and Shavel40 collectively, established a successful path for the coupling of rings A and C (Scheme 10).








MeO
MeOMeO NH

MeO
39 CO2H 40

4 steps

MeO N MeO

HO H+ HO
N NCH3 NCH3

MeO NOK
41 35
Scheme 10



Substituted benzyltetrahyroisoquinoline 41 was readily obtained after a Birch reduction of the coupled product of compounds 39 and 40. Grewe then used phosphoric acid, while Morrison, Waite and Shavel were successful with 10% aqueous HCI, to render the ortho coupled product in 3% yield. The para product was obtained in 37% yield. This process resulted in the formation of dihydrothebainone 35.

Other research groups later improved the ortho selectivity of the Grewe cyclization, and this disconnection is found in several of the following formal synthesis. Kametani41 utilized a Pschorr type cyclization in his approach to thebaine 19 to maximize the ortho- para selectivity (Scheme 11). Diazotization of 2-aminobenzyl tetrahydroisoquinoline 42 followed by thermal decomposition yielded racemic salutaridine 16 in a yield of 1.1%, however no ortho-ortho products were observed.





12


MeO

BnO 1. NaNO2, H2SO4/ AcOH MeO
NH2 2.70 oC HO
CH3 NCH3
MeO MeO
OMe 0
42 22
2 steps
MeO


NCH3

MeO
19
Scheme 11



Schwartz, 42,43 in a biosynthetically designed synthesis, used thallium (I) trifluoroacetate to effect the ortho-para coupling of N-acylnorreticuline 43, affording the corresponding salutaridine derivative 44 (Scheme 12). Reduction of this intermediate with LiAlH4 followed by O-ring closure with HCI resulted in the formation of thebaine and resulting in a formal total synthesis. MeO MeO

HO HO
HO TI(TFA). HO 2 steps. 19
NR I eq. NR thebaine

MeO MeO
OH OH
43 44

Scheme 12





13


Beyerman" used a Grewe type cyclization with a symmetric arene to overcome selectivity problems (Scheme 13). The N-methylation of benzyl protected phenol 45, PhNN,
OBn OH 0 N
MeO eO MeO .
I. HCI
BnO 2 steps HO Grewe reaction, HO
N 2. 5-chloro-1HO NH NCH3 phenyltetrazole, NCH3
MeO MeO K2C3, DMF O
45 46 47

SH2, Pd-C

35

Scheme 13


followed by hydrogenation and finally a Birch reduction rendered tricycle 46, which readily cyclized in the presence of HCI to 47. Fortunately, the additional hydroxyl group at C2 in 47 was selectively removed by conversion to the corresponding tetrazole ether followed by hydrogenolysis, which afforded dihydrothebainone 35 and formalized Beyerman's synthesis.

Rice45 is given credit for the most practical synthesis of morphine to date, with an overall yield of 29%. Using starting materials similar to those used by Grewe and Morrison, Rice was able to synthesize amine 50 by coupling of acid 48 and amine 49. In 3 steps Rice was able to synthesize bromide 51 using a strategy similar to that of Beyerman. This was a key intermediate because it possessed a well placed bromine substituent, which blocked para cyclization. Bromonordihydrothebaine 52 was formed in 60% yield, and was eventually converted to dihydrocodienone 53 (Scheme 14). Overall





14


the whole synthesis required isolation of only six intermediates, obtained in sufficiently pure form to continue with the synthesis. It still remains the most practical synthesis to date.

MeO NMeO N NH2 MeO N
HC COOH + 3steps,.HO): ". HO
48 49 N NH

MeON
50

4 steps

Me rMeO N Br MeO N Br
I 14% NH4.HF
0 steps HO __CF3SO3H, 00C HO

05 NF ] NCHO 05 NCHO
"r
53 52 51

Scheme 14


In 1983, Evans46 used the ortho lithiated veratrole 54 in an initial coupling reaction with piperidone 55 in his approach (Scheme 15). After the coupling, dehydration afforded alkene 56, which was further coupled with dibromide 57. Isoquinoline 58 was then converted to the aziridinium salt 59, which was then opened, oxidized to an aldehyde and finally treated with Lewis acid to form the morphinan 60. Removal of the CIO hydroxyl group followed by oxidation afforded ketone 61, which is one of Gates' intermediates hence resulting in a formal synthesis.






15


MeO MeO MeO

MeO < MeO + Y~rMeO)IQ
Li 2step Br2 steps.

K) 57 NCH3

01:)N"CHCH3
55 H3 56 steps


MeO MeO Me


MeO~> MeO 2sesMeO'Q
-3 steps tp Q
NCH3 %NCH +C14

]S H H 3 N% CH3
61 60 59
Scheme 15

A third report in 1983 by White 47 described an oxidative coupling approach to () codeine 2 (Scheme 16). After protection and bromination, (-)-Norreticuline 62,

MeO MeO Br Me Br


HO 3 Hse O
H ts op 3 steps 0
NE NCOCF3 "%NMe
MeO MeO$ MeO1%
OH 0
62 63 64

12steps

MeO ~ Meo B
1e~ L0iAIH,

0 0


HO*'&t 0
2 65


Scheme 16





16


underwent successful and selective para-para coupling to afford salutaridine analogue 63, which was further manipulated to bromothebaine 64. Simple hydrolysis followed by double bond migration afforded the Gates intermediate 65 which on treatment with LiAlH4 gave (-)-codeine 2.

In 1986, Schafer48 reported another oxidative coupling approach to salutaridine (Scheme 17). Formamidine 67 was coupled with bromide 66 and the product

MeO OMe
OTBS
MeO Me MeO

Br TBSO HO
66 2 steps 2 steps
Me NMe o NMe
YY>,:: NN)II
SMeO MeO
BnO OBn O

67 N'tBu 68 16
Scheme 17



reductively cleaved to afford the cyclization precursor 68. Cyclization was achieved using TiCl4 and subsequent rearomatization of the A-ring using DDQ afforded salutaridine 16 in 3% overall yield in 15 steps.

In 1987, Fuchs49 reported a total synthesis of morphine using a tandem coupling reaction to construct the morphinan skeleton. His approach to the morphinan skeleton used an intramolecular conjugate addition/alkylation sequence in which connections C12C13 and C9-C14 were formed as a result of one-tandem process. Coupling of aryl 69 to alcohol 70 under Mistunobu conditions followed by deprotection and an oxidation/reduction sequence afforded ether 71 with the desired cis stereochemistry (Scheme 18). The tandem cyclization was achieved by treatment of ether





17


MeO
MeO MeO MeO
HO Br Br
Br 4steps O nBuLi O
69 \Br
OH q 0P 0P
TBSO HO' HO 72
SO27 72
71
70 S02Ph 7
7 steps

MeO MeO H MeO H
NTEOC NTEOC
0N 2 steos 2 steps 0
NCH3
O O MeO
75 74 73
Scheme 18



71 with n-BuLi, which led to the closure of the C12- C13, bond and subsequently underwent alkylative closure of the final ring to yield the tetracycle 72. After oxidative cleavage of the olefin to the corresponding aldehyde the nitrogen was introduced by reductive amination and protected as the trimethylsilylethoxycarbonyl ester, and finally oxidation followed by enol ether formation afforded 73. Base catalyzed elimination of the sulfonyl group followed by oxidation with DDQ gave dienone 74. Upon removal of the protecting group, a 1,6-Michael type addition afforded codeinone 21 as well as the nonconjugated neopinone, which could be readily isomerized to codeinone under conditions reported by Rapoport and Barber.50 Fuchs completed his total synthesis by converting codeinone to racemic morphine with reduction and final demethylation.





18


In 1992, Tius51 used an intermolecular Diels-Alder reaction as an early step in his formal synthesis. Quinone 75, which was prepared in 7 steps from 3-methoxy-2-hydroxy

o OO0
MeO
+ toluene EtO2CHN

E H 1000 C O
OEtO,C

MeO O
75 76 77

MeO
several MeO
steps I
HO
NMe

78
Scheme 19



benzaldehyde, was heated with diene 76, prepared in 2 steps from 1,4-cyclohexanedione monoethylene ketal, to construct phenanthrene 77 (Scheme 19). After several subsequent steps Tius completed his synthesis by constructing thebainone 78, thus intercepting Gates' approach.

Parker and Fokas52 accomplished a well designed formal synthesis of morphine in 1993. Their approach hinged on an efficient radical cascade which in one step led to the construction of a morphinan complete with the A, B, C and O-rings of morphine (Scheme 20). To be able to take advantage of this tandem cyclization strategy, they had to first construct aryl ether 82, through an eight-step sequence starting from m-methoxy phenethylamine 79 and culminating in a Mitsunobu coupling of the resultant alcohol 80 with phenol 81. With the aryl ether in hand the ortho allyloxy aryl radical 83 was generated using tributyltin hydride/ AIBN. Tandem closure led to isolation of





19


NH2 NMeTs MeO MeO

HO
HO
Br SPh O Br SPh
MeO7 steps 8 NMeTs
mitsunobu MeTs
79 80
MeO R = TBDMS RO 82

I
O ~
NMeTs

RO
86


MeO MeO MeO


0NMeTs NMeTs SPh
SPh SPh NMeTs
RO RO '~NMeTs

RO
S85 84 83 8

Scheme 20


tetracycle 86 in 35% yield by initial attack of the radical on the proximal but more substituted end of the cyclohexyl ring double bond to establish the furan ring with the correct stereochemistry at Cl13. The radical generated in the formation of the furan

MeO MeO MeO


OO Swern O
NMeTs '/ R 0 NMe ------. 0NMe


RO RO 0
86 87 88

Scheme 21





20


ring then attacked the P-carbon of the styrene double bond to give rise to the resonance stabilized radical of 85 with the correct stereochemistry at C14. Final elimination of the phenylthio group from 85 led to formation of styrene 86. Dihydroisocodeine was formed when the tosylamide 86 was treated with Li/NH3 at -780 C. Swern oxidation of dihydroisocodeinone 87 afforded dihydrocodeinone 88, which then completed her approach.

The crucial step in Overman's53 approach was essentially a Grewe type disconnection, but involved an intramolecular Heck reaction to complete the construction of the B-ring. The synthesis started with enantioselective reduction reduction of 2-allyl cyclohexenone 89 which would introduce chirality into the synthesis. Condensation of the resultant S-alcohol 90 with phenylisocyanate, oxidation of the side chain olefin with osmium tetraoxide and acetonide protection afforded 91 (Scheme 22).

0 OH QCHNHPh

Do 2 steps

89 90 91



MeO N DBSN MeO SiMe2Ph

BnO TBO+ NHDBS
I CHO
94 93 92

Scheme 22

A copper catalyzed suprafacial SN2' displacement of the allyl carbamate with lithium dimethylphenyl silane, deprotection and diol cleavage yielded an intermediate aldehyde, which then underwent reductive amination with dibenzosuberyl amine to afford 92.





21


Condensation of allylsilane 92 with iodide 93 (prepared in 7 steps from isovanillin in an overall 62% yield) at 60 'C in the presence of ZnI2 followed by iminium ion-allylsilane cyclization yielded the isoquinoline intermediate 94. Palladium mediated coupling led to the formation of the C12-C13 bond and morphinan 95 (Scheme 23) with the correct stereochemistry at C9, C13, and C14. Liberation of the phenolic oxygen and (-face epoxidation of the C6-C7 double bond and subsequent intramolecular ring-opening by the phenolic hydroxyl completed the dihydrofuran ring. Oxidation followed by reductive DBS cleavage in the presence of formaldehyde yielded (-)- dihydrocodeinone 88.

MeO MeO
MeO~
MeG N DBSN
BnO H0 NBnO NDBS ON 5 NDB
H NDB NDBS
HO
94 95 96

1

MeO MeO



NMe NDBS
H H
88 97
Scheme 23



Morphine Syntheses via Sigmatropic Rearrangements

Although a wide variety of synthetic approaches have been applied to the morphine problem, sigmatropic rearrangements have rarely been elicited as synthetic tools. Of the more than twenty formal syntheses only three, namely those of Rapoport, 50





22


Parsons20 and recently Mulzer2125 were able to utilize sigmatropic rearrangements as key steps in their approaches to morphine.

Interestingly, all three approaches used the sigmatropic rearrangement for the same purpose, to install the quaternary center at C13 (morphine numbering) while transferring the stereochemistry already present in the starting material to that position.

Rapoports' synthesis began with the conversion of ortho-vanillin 98 to amino acid 99 in twelve steps (Scheme 24). The amino acid then underwent rearrangement in the MeO MeO MeO
HO-~I H
O- 12 steps MeO MeO MeO
S CHO C02H$ OH


98 N 0 N O
Me Me Me
99 100 101

MeO, MeO MeO
MeO- -- Me MeO- ok OHO [


Me MeO MeO
O OMe OH








O~~e (Evans, 6 steps) MeO
Me Me e
In




104 103 102





Scheme 24
6 steps e


( 1; OMe
1 0 (Evans, 6 steps) MeO
;OMe

'Me O HNMe 105 106

Scheme 24





23


presence of acetic anhydride to afford lactam 100. Benzylic oxidation followed by reaction with formic acid yielded, after allylic migration and hydrolysis, alcohol 102. Condensation of the alcohol with trimethyl orthoacetate produced acetal 103, which subsequently underwent rearrangement to afford the methyl ester 104. This compound contained the required quaternary center at C1 3 as well as the complete C ring with an adequate pattern of substitution. Ring B was emergent in this structure but required more steps to develop.

After several attempts, Rapoport decided to intercept the advanced Evans intermediate 105 from which Evans was able to synthesize one of Gates advanced intermediates (106) in six additional steps.

Parsons, in 1984 reported the synthesis of the precursor 113, through an interesting sequence. Their synthesis started with the 1,2 addition of the Grignard


I OMe

MgBr Luche.0 OH
107 109 110



DMADA0
PhMe, A
N N"NMe2 ONeNMe2
111 112
Scheme 25



compound 107, to ketone 108. After hydrolysis, the product 109 was reduced using Luche condition to obtain the alcohol 110, which was condensed with dimethylacetamide





24


dimethyl acetal to form the acetamido acetal 111. Concomitant rearrangement of 111 via an Eschenmoser-Claisen rearrangement gave the amide 112 (Scheme 25). Using this series of transformations, Parsons and Chandler were able to set the stereochemistry at C 13 correctly.

Closure of ring B was achieved starting with the ozonolysis of 112 which resulted in the aldehyde 113, which was consequently treated with N-methyl hydroxylamine


o0 0 0 0~
< < KI <
O O, 0 O CHNHOH 0 0
PhH, A + NMe2
NMe NMe2 N'CH
BnO 2 BnO 2 nO N OCH3
112 113 114


0 0 0 A 0
NMe NMe2
N.Me 2 NHMe Ne
BnO e

115 116 117
Scheme 26



to yield the intermediate 114. The intermediate then accordingly rearranged to produce the isoxazolidine 115 through an intramolecular cycloaddition with an overall 72% yield. The cycloaddition product possessed the correct stereochemistry at C14 but was epimeric at C9. The resultant epimers were separated using chromatography and the N-O bond of the morphine-like isomer was cleaved by hydrogenolysis to produce the amino alcohol 116. The morphinan 117 (Scheme 26) was obtained by heating the resulting hydrochloride salt of 116 under vacuum followed by LAH reduction of the resulting hydroxy amide produced the morphinan 117 with an overall yield of 2.1%.





25


In Mulzer's21-25 synthesis of morphine, a creative approach towards the morphine skeleton was employed. In the first generation of the synthesis he used a model study to explore the possibility of establishing the important benzylic quaternary stereogenic center (C 13) via either conjugate addition of a cuprate to an unsaturated ketone or [3,3]sigmatropic rearrangement.

Starting from alcohol 118 Mulzer and co-workers attempted an EschenmoserMeO MeO

MeO MeC(OMe),NMe2 MeO
Xylenes, A NMe2

O -0 0
118 119
NaBH4
MeOH MeO MeO
I i, H2C=CHMgCI,
MeO 5% CuBr-SMe,,TMSCI MeO
02 ii, 2N HCI

0 O
120 121
Scheme 27


Claisen rearrangement to obtain amide 119 in only 21% yield. With this unsatisfactory result they tried both the Ireland and the Johnson variants of the Claisen rearrangement on the alcohol 120 that was obtained after reduction of the enone, both failed completely. An explanation for this might be strong conjugation of the double bond (C5-C13 morphine numbering) to the aromatic ring. Since Claisen rearrangements and 1,4additions of vinyl cuprates are complementary to each other, the latter was attempted on the enone 120 with positive results, leading to the formation ketone 121 in 87% yield over 2 steps.





26


Another interesting discovery was made during this model study. After preparing a more elaborate substrate 124 from the addition of ortholithiated veratrole to the vinylogous ester 122 followed by hydrolysis and dehydration. Enone 123 after reduction was subjected to Eschenmoser-Claisen rearrangement conditions. The results were similar, even though rearranged product was obtained the yields were low. More interestingly after cleavage of the terminal double bond of amide 125 (Scheme 28) to obtain the aldehyde 126, all attempts at closing the B- ring failed completely. Mulzer explained these results using the theory that repulsive interactions between the orthomethoxy group and the substituents a-to the C13 carbon (morphine numbering) on the cyclohexyl ring. This steric interaction causes the aromatic ring to twist out of conjugation with the double bond in the cyclohexyl ring. This assumption had merit because H- NMR of the allylic alcohol clearly showed the two rotomers reminiscent

0 Li ,OMe OMe
.,tOMe OMe

Oi- OMe. OMe NaBH OMe
Et20 / MeOH
2. NH4CI(aq) 0 OH
122 123 124

S1OOMe MeO MeO
L0 A4e, NMO
MeC(OMe)2NMe2 OMe Acetone, MO MeO
Xvylenes, 24% 2. NaIOA, EtOU MeO HO
NMe2 NMe2 NMe2
O O O
125 126 127

Scheme 28

of the known atropisomerism found in biphenyls. The result is a highly adverse steric influence at the benzylic sp2 -hybridized carbon by the aromatic ring. The apparent





27


solution to this setback was to restrict the conformational flexibility of the aromatic ring by means of a tether, which would also provide the two-carbon fragment for the B-ring. This idea led to the synthetic pathway that would eventually result in the synthesis of the morphine skeleton by way of phenanthrone 129. Starting from enantiomerically pure phenanthrone 129, which was synthesized in 3 steps from acid 128, conjugate addition with a variety of funtionalized organocuprates provided good yields of the olefin 130. Mulzer and co-workers discovered that the substitution pattern on the aromatic ring was critical in obtaining clean 1,4-adducts. With olefin 130 in hand they were able to effect Ering closure using a clever "umpolong" strategy. After trapping the ketone as the silyl enol ether, bromination with NBS in THF at low temperature yielded bromoketone 131 as a 3:1 isomeric mixture. The undesirable isomer could however be recycled by way of reductive removal of bromide with zinc and concomitant silylation of the resultant enolate. When ao-bromoketone 131 was heated in DMF at 1400C the dihydrofuran was obtained in 20 minutes in quantitative yield. The next stage in the synthesis involved the introduction of the nitrogen functionality at C9 (morphine numbering). Ketone 132 was subjected to a three step sequence that resulted in a) protection as the ethylene ketal b) hydroboration of the vinyl group with BH3.SMe2 followed by oxidation and c) removal of the chloro substituent by catalytic hydrogenation to render alcohol 133. The alcohol was then converted to the benzene sulfonamide derivative 134 using a variation of the Mistunobu protocol which uses N-methylbenzene sulfonamide, 1,1 'azodicarbonylpiperidine (ADDP) and Bu3P. The next step was to introduce a double bond by benzylic radical bromination followed by debromination. Hence exposure of 134





28


to NBS and catalytic amount of dibenzoyl peroxide in refluxing cabon tetrachloride

MeO Cl MeO Cl MeO Cl
128 t-..ICOH "MeO~o
MeO v MeO MeO
128 COOH H H


129 130
MeO Cl MeO C MeO


Br H 0 H
BrOH
OO
0,0

O OO
131 132 133
MeO MeO


O H 01 HI
O NSO22 NSO Ph
o o
NSO2Ph 0 oPh

135
0 134 135

MeO MeO MeO

S1 I

O N CH3 CH3

136 0 7 HO" 1
Scheme 29


afforded the morphimethine". Treatment of the styrene 135 under reductive conditions (Li/NH3/THF) yielded the desired heterocyclization product, (-)-dihydrocodeinone 88 after hydrolysis of the ketal 136 using 3N HC1. Unfortunately attempts to convert dihydrocodeinone to morphine failed probably because of competing oxidation of the tertiary amine followed by polymerization. In 13 steps and an overall 11.5 % this make Mulzers' synthesis one of the most practical of all attempts at morphine synthesis.





29


Recent Related Developments

In addition to the Claisen approach to the morphine skeleton, the Hudlicky group is actively pursuing two other approaches toward the morphinan skeleton namely an intramolecular Diels-Alder approach and a Heck coupling cascade approach.

Hudlicky, Boros and Boros54 were able to synthesize the B-, C-, and O- rings using a combination of three important transformations, microbial oxidation, intramolecular Diels-Alder cycloaddition and a Cope rearrangement. Starting from toluene, which was subjected to microbial oxidation to yield diol 138, protection of the distal hydroxyl group afforded the thexyldimethylsilyl ether 139. Alkylation of the proximal hydroxyl group with sorbyl bromide rendered the tetraene 140. The substrate was now ready for an intramolecular Diels-Alder reaction. The Diels-Alder

M / \n

HO HO. 0. k
HO" TDSO" TDSO
137 138 TDSO 139 TDSO 140

1d
/'- \ ~/ \*O


1124OTDS
144 142 143 141
C9 (morphine numbering)

Scheme 30 Conditions: a) Toluene dioxygenase; b) THSC1, imidazole, DMF; c) NaH, sorbyl bromide, THF, 00 C to rt., 30h.; d) CCl4, 770 C, 7h.; e) nBu4NF-3H20, THF; f) PCC, CH2Cl2, rt.; g) xylenes, sealed tube, 2500 C, 22h.; h) NaBH4, CeC13-7H20, MeOH, rt., 15 min.

reaction could possibly take two reaction pathways namely, diene k, I with dienophile m (Scheme 30) or diene m, n with dienophile k. The latter reaction pathway involving diene





30


m,n and dienophile k was observed to yield furan 141. Attempts to induce Cope rearrangement to form the desired tricyclic compound 142 were unsuccessful. To supply some driving force for the Cope rearrangement, the THS-ether was converted in two steps into the ketone by first fluoride deprotection of the silyl group followed by PCC oxidation to afford ketone 143. The ketone successfully underwent the rearrangement to afford enone 142. Reduction using Luche conditions produced compound 144 that possesses the carbon skeleton for the lower half of morphine with all the stereocenters correctly set with the exception of what would be C9 (morphine numbering).

Hudlicky and Gum55 published a second generation intramolecular DielsN3//
HO. NO O

TDSO TDSO N3 TDSO -".NH,
145 146 147



c

0"
TDSO'I NH~c
O dO
TDSO* NHAc TDSO NHAc
149 148

Scheme 31 Conditions: a) NaH, sorbyl bromide; b) PPh3, THF; c) Ac20, pyridine; d)2300 C, PhMe.


Alder approach towards the morphine skeleton in 1998. Unlike the first generation attempt, provisions were made for eventual closure of the D-ring by appending a nitrogen functionality from the quaternary carbon of the tricycle 149 (Scheme 31). During the cyclization of the triene, it was discovered that the stereochemistry of the methyl group at what would be C9 (morphine numbering) was indeed 3-faced instead of (x-faced as had





31


been reported earlier. This led to the conclusion that the intramolecular Diels-Alder proceeded through an exo transition state.

In 1998, Hudlicky56 and coworkers published a radical cyclization approach to the morphinan skeleton that represents the most advanced morphinan synthesized in the Hudlicky group. In the first generation of this radical approach, the focus was to Br
[ OH RO

HO d, HO OMe

TDSO TDSO Br
137 151 152 R = TDS ']
TDSO
153
BzO BzO HO

00 h 0
Br Br

TDSO TDSO TDSO
156 155 154

Scheme 32 Conditions: a) JM109 (pDTG601); b) PAD, HOAc; c) THSC1, imidazole, DMF; d) BzOH, Bu3P, DEAD, THF; e) NaOMe, MeOH; f) 150, Bu3P, DEAD, THF; g) H30+; h) benzyl bromide, K2CO3, acetone; i) Bu3SnH, AIBN, toluene reflux.


achieve a tandem radical cyclization that would lead to the construction of the A, C, D, and O-rings of morphine (Scheme 32) with the correct stereochemistry at the chiral centers in a manner analogous to the Parker52 synthesis but with different connectivity at the C9, C10 and C I carbon atoms. The first step was to validate the tandem process with simple model studies. The initial model examined the feasibility of constructing the C12Cl13 bond through a radical closure. To this regard bromoguiacol 150 was synthesized in 4 steps starting from an enzymatic transformation with P. putida TGO2C and used as a nucleophile in the second Mitsunobu inversion of the alcohol 152 also obtained through





32


an initial enzymatic step (Scheme 32). With ether 153 in hand the next steps involved protection of the phenol as the benzoate after cleavage of the labile thexyl group. Under radical conditions generated by Bu3SnH and AIBN ether 155 was transformed to the tricycle 156 with three of the five stereo centers in morphine set correctly.

A second model study (Scheme 33) to provide information about the relative
0

Br ;1I~Br NA0
HO. a- d 0 /

HO HO e
157 158



0 0
0 >__>O 0 .=0
N N

TDSO TDSO
159b 159a

Scheme 33 Conditions: a) PAD, HOAc; b) TBSOTf; c) o-bromophenol, Bu3P, DEAD, THF; d) NaH, 2-oxazolidone; e) Bu3SnH, AIBN, toluene reflux. stereochemistry of the C9-C14 bond was designed using diene 157, which was functionalized effectively in four steps into the oxazolone 158. Under radical conditions pentacycle 159 was obtained in approximately 10% yield. 'H NMR analysis confirmed a trans relationship between the protons at C9 and C14 but it was difficult to ascertain the configuration of these chiral centers relative to C5 or C6 and so the product was assigned either as 159a or 159b.

With these two promising results Hudlicky and coworkers then focused on constructing the entire morphine skeleton. In the second-generation synthesis, o-bromo-





33


fl-bromoethylbenzene 160 was subjected to enzymatic conditions with the expectation that the larger bromoethyl group would direct the cis-dihydroxylation. This assumption proved to be correct because diol 161 was isolated from the fermentation broth using E. coli JM 109 (pDTG601A). Diimide reduction of 161 followed by acetonide protection of the cis-diol moiety provided the dibromide 162. Introduction of


OH o
HO.": rr0
Br Br Br O Br
Br Br
160 161 162

d




H N O N O Br N 0

O 0
164a 164b 163


Scheme 34 Conditions: a) JMO109 (pDTG601); b) PAD, HOAc; c) DMP, pTSA; d) 2oxazolidone, NaH; e) Bu3SnH, AIBN, benzene reflux. the oxazolidone gave 163, which upon exposure to radical conditions gave a 2:1 mixture of octahydroisoquinolones 164a and 164b in favor of the isomer with an epi-C9 configuration (Scheme 34). The lack of stereo control was attributed to the negligible steric effect of the acetonide. Since the epi-isomer was in greater availability the decision was made to pursue the synthesis of ent-morphine. Mitsunobu inversion with bromoguiacol generated the precursor for the second radical cyclization, ether 166. Treatment with Bu3SnH/AIBN gave pentacycle 167. To complete the synthesis of the ent-morphinan, the silyl-protecting group was removed followed by reduction of the





34

oxazolidone to yield the alcohol 168. A double Swern oxidation was utilized to convert 168 into the rather unstable ketoaldehyde 169, which upon exposure to trifluoromethanesulfonic acid led to the formation of alcohol 170, which contains the complete morphinan skeleton.

MeO
I MeO

aNb 000 0
0I
H.. N B o O; Os~:
HO. \ N O --N
6 H a. b 0
TBSO H HO'
165 HO 166 167

d
MeO MeO MeO

OH f O OH
O ~ e Of o
0 0 0
--N.... --N..'..--N-...

O 0 Ho
170 169 168

Scheme 35 Conditions: a) 150, Bu3P, DEAD, THF; b) TBAF, THF; c) Bu3SnH, AIBN, benzene reflux; d) DIBAL-H, CH2CI2; e) oxalyl chloride, DMSO, Et3N, CH2C12; f) TFA.


Currently57' 58 a third generation approach using intramolecular Diels-Alder is being developed (Scheme 36). The major improvement in the third generation is the use of a (E, Z)-diene system as seen in 171 which will invariably lead to an inversion at the C9 (morphine numbering) stereocenter preceding the formation of compounds of the type 173. Using a nucleophilic displacement by the nitrogen tether onto the leaving group would form B-, C-, D-, and O- rings with correct stereochemistry in 174.





35


I

o o

TDSO' N3 TDSO'* NHAc
171 172






R X
TDSO' TDSO' NHAc
174 173
Scheme 36



Another noteworthy approach to the morphinan skeleton was recently published by Hudlicky and coworkers.59 It involves a rare Heck cyclization to yield an advanced pentacyclic precursor of morphine. Biooxidation of (2-bromoethyl)-benzene 157, with Escherichia coli JM109 (pDT601) followed by reduction of the less hindered double bond with diimide yielded diol 175 in 80% yield (Scheme 37). The next step involved protection of the two diol moieties as the benzoate. This was followed by displacement of the bromine by oxazolidine-2,4-dione to afford the dibenzoate 176. After reduction of the more reactive amide carbonyl with NaBH4, N-acyliminium ion-olefin cyclization and subsequent elimination of the alkyl chloride afforded the tricycle 177. This was followed by deprotection of the benzoate groups and subsequent selective protection of the





36


homoallylic hydroxyl group as the TBDMS ether. Using Mitsunobu protocol the

O
Br Br N 0
HO. HO. b, HO. O
a bc '_\O
HO HO HO d, e, f
157 175 176

OH OBz
0 RO., BzO.,
Br

RO.' i 'r g, h '
h N

O 0 0

179 178 177
j R = TBDMS




0
RO.,

/ N

0
O
180

Scheme 37 Conditions: a) E. coli JMIO9 (pDTG601); b) PAD, AcOH, MeOH; c) PhCO2H, DCC, DMAP, CH2CI2; d) Oxazolidine, tetramethylguanidine, THF, reflux; e) NABH4, MeOH; f) AlCl3, CH2CI2; g) DBU, DMSO, reflux; h) LiOH, MeOH; i) TBDMSOTf, imidazole, DMF; j) Bu3P, DEAD, bromoguiacol, THF; k) Pd(PPh3)4, proton sponge, toluene, reflux.


unprotected alcohol was converted into the bromoguaiacol derivative to give intermediate 179. Heck cyclization of the tetrasubstituted olefin yielded the tetracycle 180 as the only identifiable product.

In a recent publication in Organic Letters,60 Ogasawara and co-worker undertook a rather elaborate approach to the morphine skeleton that deserves mention because of their clever approach to the construction of the C14 stereocenter correctly and also their





37

construction of the C9-C10 bridge. Starting from a mixture of the alcohol 181 they MeO MeO MeO

MeO MeO MeO
a
OH IkOAc + OH


181 K2C03 (+)-(R)-182 (-)-(S)-184
MeOH (47%: >99% ee) (48%: 97% ee)
82% L(+).(R)-183

Scheme 38 Conditions: a) vinyl acetate, lipase PS, ButOme, 37 oC. are able to obtain the pure S-isomer through an optimized pathway61 (Scheme 38) using vinyl acetate. Even though this synthesis was undertaken with the racemic mixture, the use of isomer 184 is projected for a future synthesis of natural morphine. Starting from the mixture of alcohols 181 they synthesized the bromoacetal 185 as a mixture by utilizing ethyl vinyl ether in the presence of NBS (Scheme 39). Under radical cyclization conditions, they were able to obtain the cyclized product in moderate yields. The authors attributed this to the steric hindrance caused by the methoxy group in the 2-position of the aromatic ring. The cyclized product 186 was converted in 3 steps into the ketone 190. Reduction of the ketone with NaBH4 yielded the alcohol 191 diastereoselectively. This result might be due to prior coordination of the borohydride reagent to the pivaloyl moiety, which results in hydride delivery to the P3-face of the molecule. The xanthate 192 (Scheme 39) obtained from the alcohol 191 was then thermolyzed to afford the cyclohexene derivative 193 in 81% yield. Allylic oxidation of 193 using chromium





38


trioxide and 3,5-dimethylpyrazole complex in CH2C12 afforded the enone 194. Using

MeO MeO MeO N
I Br
MeO MeO OEt MeO 0
161 a O OEt O O !


185 186 187

MeO I MeO MeO NP
Meo' Oiv .o

MeO OPiv MeO OPiv4e MeO OH

1 1 90OH OH
190
189 188
MeO 1 MeO MeO

MeO OPiv hMeO OPiv
MeO OPiv
-OH -OC(S)SMe


191 192 193
MeO

MeO OPiv




0
194

Scheme 39 Conditions: a) EVE, NBS, Et20. b) Bu3SnH, AIBN (cat.), benzene. c) mCPBA, BF3.OEt2. d) LiAlH4, THF. e) Piv-Cl, pyridine. f) PDC, CH2CI2. g) NaBH4, iPrOH. h) Mel, CS2, NaH. i) o-C6H4C12, reflux. j) CrO3 3,5-(Me)2pyrazole.


Sakurai conditions allyl functionality was introduced at the C14 center (morphine numbering) by treatment of 194 with allytrimethylsilane (Scheme 40) in the presence of titanium (IV) chloride. Ketone 195 was then transformed into the ketal 196 followed by





39


MeO MeO MeO
MeO

MeO MeO Meo OPiv
OPiv OPiv

H H
00
o o \194 195 196

MeO T
\ MeO N
MeO/ OPiv
MeO OPiv
-0
H H
00 0 0

198 197

Scheme 40 Conditions: a) allylTMS, TiCl4, CH2CI2, -780 C. b) (CH2OH)2, p-TsOH, benzene, reflux. c) OsO4 (cat.), NaIO4. d) (CH2OH)2, p-TsOH, benzene, reflux.


reductive cleavage of the olefin in 196 to afford the aldehyde 197. Upon reflux in benzene in the presence of ethylene glycol and catalytic amounts of p-toluenesulfonic acid, the hydrophenanthrene 198 was obtained in 85% yield. Construction of the D-ring was achieved using Parker conditions, which involved deprotection of the pivaloyl group followed by Mitsunobu (Scheme 41) coupling of the free alcohol 199 with N-methyl-ptoulenesulfonylamide to give the tosylate 200. Treatment of the tosylate with sodium naphthalenide afforded the morphinan 201 in 89% yield via concomitant detosylation followed by regioselective cyclization. Morphinan 201 was then converted in 3 steps to the morphinan 202, which is the O-methylated analogue of dihydrothebainone 35 (page 14).





40


MeO MeO MeO

MeO OH MeO MeO
NMeTs NMe
H H H
0 0 0 0 0 0

199 200 201


MeO

MeO
NMe
H
O
202

Scheme 41 Conditions: a) LiAlH4, MeNHTs, Bu3P, DPAP. b) Sodium naphthalenide, THF, -300 C.


Chelated Enolate Claisen Rearrangements

In 1977 Wolfgang Steglich62, 63 reported the synthesis of a series of amino acids utilizing a Claisen rearrangement. This was the first time the Claisen rearrangement had been extended to the synthesis of this important class of compounds. Steglich and coworkers first synthesized N-benzoyl c-amino acid esters with a general structure such as 205. After transesterification with the allyl alcohol 206, they then observed that under dehydration conditions oxazoles were formed. The oxazoles thus formed concomitantly rearranged without isolation to form oxazolones 209 (Scheme 41). Under conditions of hydrolysis they observed the formation of P-amino acid with the general structure of 210 in yields up to 95%. The oxazole intermediate 208 can be seen as a trapped enolate





41


whose geometry is fixed by virtue of being in the five membered oxazole ring. This

0
"' OH I HO,
N204 0 206
H 2N 011 Na ()A N
O [-H20] NaH H O
O H 4A Mol. Sieves O
O
207
203 205 207
COCI2 or
PPh3/CCI4,
SEt3N/CH3CN



hydrolysis N 0 [3.3]

rl N N
H


210 209 208

Scheme 41


important aspect of the reaction meant that the sigmatropic rearrangement could proceed with stereoselectivity. Unfortunately when the substituent a- to the nitrogen is hydrogen there is epimerization at that center leading to a non-stereoselective rearrangement.

Paul Bartlett64 in 1982 decided to investigate the work done earlier by Steglich. His goal was to compare these conditions to the Ireland Claisen65 rearrangement conditions. Also important was the utilization of this reaction in the synthesis of y,8unsaturated amino acids. He also wanted to study the stereochemical influence, if any of the a-substituent in the Claisen rearrangement. Deprotonation Conditions: Bartlett and coworkers used 2.1 equivalents of LDA to effect enolization. The found that shorter (2.5 min) or longer (40 min) enolate generation times had no significant influence on yield or





42


stereoselectivity. Also the use of TBDMS chloride instead TMS chloride as the silylating agent did not increase yield or stereoselectivity. Reaction in a less polar solvent (ether) proceeded with a slight increase the stereoselectivity but led to a decreased yield. Table 1. Influence of Conditions on Rearrangement of Amino Esters.

00 0
BocNH. BcINH BocNH O

H H
211 212 213

Conditions Yield/ % Ratio 212/213
*Standard 60-65 9
Ether 45 10
20% HMPT/THF solvent 51 4
KDA 0
1.1 equiv of MgC2 42 10


*Deprotonation at -750C with 2.1 equiv. of lithium isopropylcyclohexylamide or lithium diisopropyl amide; silylation with Me3SiCl after 10 min; warming to reflux for lh; hydrolysis of silyl ester.


Contrastingly the use of HMPA and TMEDA, which are highly dissociating systems as co-solvents resulted in both lower yield and lower stereoselectivity (Table 1). The use of a lewis acid (MgCI2) also slightly increased stereoselectivity but led to a lower overall yield. The result of this study is in concurrence with the accepted principle of an Eenolate geometry and a chair-like transition state for aliphatic substrates. He proposed that coordination of the counter ion between the carbonyl oxygen and the nitrogen anion is at least partly responsible for the E-enolate geometry.

Influence of N-Protecting Groups: A variety of N-protecting groups were explored (Table 2) with varying yields and stereoselectivity. Overall the Boc- protecting





43




Table 2. Effect of N-Protecting Groups on Rearrangement of trans ButenalGlycinates

00 0
R=N H OH R=N OH
I_ O H 7 OHR =H


H H
214 215 216

R yield/ % Ratio 215/216

1. Boc 60-65 9

2. Cbz 65 4

3. Bz 65 5.4

4. CF3CO 58 1.5

5. Phthaloyl 0

6. Et2 0



group gave the best results. The reduced stereoselectivity with the trifluoroacetyl derivative (Entry 4) was explained by reduced importance of the chelation effect due to the increased acidity of the nitrogen. The inability to obtain products in the case of the Nphthaloyl and N, N-diethyl analogues was attributed to the lack of an extended conjugated system for nitrogen-substituted enolate stabilization.

Uli Kazmaier6677 in 1994 published an article about a remarkable variation to the classical enolate Claisen rearrangement that would revolutionalize the synthesis of both natural and unnatural amino acids. It had already been established by Steglich62. 63 that enolizable amino acids could undergo rearrangement with moderate to good stereoselectivity if the enolate geometry was fixed either in the form of an oxazole ring or





44


constricted due to chelation with the counter ion. While Bartlett64 had always converted the enolate into the silylketene acetal, Kazmaier discovered that by allowing the chelated enolates (Figure 1) to simply warm up from -780 C to about -150 C resulted in

OR

M: metal
YN\M Y: protecting group

217

Figure 1. Nature of Chelated Enolate in Kazmaier Claisen Rearrangement. rearranged products in excellent yields and also high diastereoselectivity. The chelated enolates had several advantages. Since the chelated enolates are significantly more stable than the corresponding non-chelated lithium enolates, they can be warmed to room temperature without decomposition and side reactions such as ketene formation via elimination can be suppressed. Secondly because of the fixed enolate geometry due to
9
chelation, the reactions proceed with high diastereoselectivity. Due to the inherent flexibility of this chemistry, many variations of protective groups Y (Figure 1) can be used. Varying the metal M used can also modify the selectivity and reactivity of the reaction. Since the coordination sphere of a metal ion is not saturated in a bidentate enolate system, this allows for additional coordination with external ligands. Lastly transformation of the high-energy ester enolate into a chelate-bridged stabilized carboxylate provides a good driving force for the reaction.

When this reaction was applied to acyclic allylic esters the results obtained confirmed a preferred chair-like transition state. Even though different Lewis acids were utilized, ZnCI2 produced the best results (Scheme 42). The formation of the syn product





45




2.2 eqLDA F
BocH~ND 1.2 eq ZnCIJ 0oHN'
Boo-'y ,.oq o2 BocN'^
0 L ZnO JBocHN COOH
218 219 220
Scheme 42

is explained by a preferential rearrangement through the chair-like transition state (Figure 2), which avoids the steric interactions between the pseudoaxial hydrogen and

H
Ao0


0 NYNY


Zn ZnS
S S S
Chair Boat

Figure 2. Chair vs boat transition states in the Kazmaier Claisen Rearrangement of acyclic substrates.


the chelate complex in the boat transition state. The results obtained in the acyclic series of experiments are summarized in Table 3, which details the influence of substituents at the double bond, the olefin configuration and the different nitrogen-protecting groups as related to the yield and diastereoselectivity of the rearrangement products. All the substituted allyl esters displayed high diastereoselectivity where the formation of syn products from trans substituted esters and anti products from cis substituted esters were favored.





46


Table 3. Results from Acyclic Kazmaier Claisen Rearrangement


R3 R2 R2 R2 R2

R4 R2.2 eq LDA R R 3 R1 R42 Ri
_)-. R[ I-'
ORR
XHN '- 1.2 eq ZnCl2 XHN "
,XHN COOH XHN COOH
O Zn-O
221 222 223 224

X [a] RI R2 R3 R4 [b] Yield Diastereomer ratio
(+)-223:(+)-224
1 Z H H H H 88
2 Z H CH3 H H 78
3 Z H H C3H, H 76 95:5
4 Z CH3 H CH3 H 88 93:7
5 Z C2H5 H CH3 H 98 95:5
6 Z C2H5 H H C4H9 73 95:5
7 Boc CH3 H CH3 H 84 96:4
8 Boc H H C3H, H 78 96:4
9 TFA H H C3H, H 79 95:5
10 TFA C2H5 H H C4H9 65 94:6
11 Z H H H D 75 98.5:1.5

[a] Z= benzyloxycarbonyl, Boc = tert-butoxycarbonyl, TFA =trifluoroacetyl
[b] D = tert-butyldiphenylsilyl




Due to the excellent results obtained with the acyclic substrates, the chemistry

was applied to cycloalkenyl glycinates (Scheme 43). These substrates were of particular

interest because their rearrangement would yield y,8-unsaturated amino acids, a class of

compounds with high activity as enzyme inhibitors. Indeed it had been previously

postulated that cyclic allylic esters prefer to rearrange via a boat-like transition state.

Kazmaier and coworkers investigated the effect of ring size as well as the metal salt used

for chelation of the ester enolate (Table 4). As predicted, with the cyclic allylic esters the

syn-product is preferred and the best results with respect to yield and stereoselectivity





47



I1)n 1) 2.5 eg LDA
1.2 eq MX7
BocHN 2) CHN BocHN COOMe BocHN COOMe
0
BcN 'O 2) CHzN,

225 226 227
Scheme 43


are obtained with cyclohexenyl glycinates (n = 2). All the metal salts used gave good product yields in the cyclohexenyl case (n = 2). The crude amino acids obtained were directly converted into the corresponding methyl esters using diazomethane. The best results were obtained with zinc chloride and are summarized in Table 4. Table 4. Results from Rearrangement with Zinc Chloride.

n % Yield Ratio
226:227

1 79 80:20

2 83 90:10
3 73 92:8

4 57 86:14



It was noted during this study that homologous cycloheptenyl substrates (n = 3) showed similar degrees of diastereoselectivity as in the cyclohexenyl case. However increase in ring size to the more flexible cyclooctenyl case (n = 4) resulted in decrease in selectivity. Also noteworthy was the fact that diastereoselectivity in the cyclopentenyl case (n = 1) was lower than that observed for the cyclohexenyl and cycloheptenyl cases respectively. The product formation as well as the diastereoselectivities observed for the six and seven membered esters were explained by rearrangement through a boat-like transition state, 67





48


which minimizes the steric interactions between the cycloalkenyl ring and the solvated chelating metal (Figure 3).




S I-N N S Y= Boc
M O -0 0 S = Solvent
S OM = Zn R = TDS
chair Boat

Figure 3. Chair vs boat transition states in the Kazmaier Claisen Rearrangement of cyclic substrates.


In summary Kazmaier has successfully demonstrated the utility of his variation of the classic enolate Claisen rearrangement. The chelated ester enolate rearrangement is not partial to acyclic substrates but can also be practical for cyclic substrates. High diastereoselectivity and excellent yields are observed for the rearrangements, which proceed via a boat-like transition state for cyclic esters and a chair-like transition state for acyclic esters.

In 1997 Hudlicky78 and coworkers applied the Kazmaier chelated enolate rearrangement to their chemoenzymatic approach to morphine. Model studies to obtain optimum reaction conditions were undertaken on compounds of type 232. These glycinates were obtained first by direct oxidation of the aromatic precursor by either the mutant strain Psuedomonas putida F39/D or the more potent recombinant organism Escherichia coli JM 109(pDTG601A) to render the diene-diols of type 229. After diimide (potassium azodicarboxylate) reduction of the less hindered double bond, the distal





49


R R R R
OH b OH C OH

OH OH OTDS
228 229 230 231
d

R 0
R O ,NHBoc

R = Me, CI, Ph, 2-MeOPh C OTDS
232
Scheme 44. Conditions: a) Toluene dioxygenase expressed in Pseudomonas putida F39/D (R = Me; 3.5 g/L) or Escherichia coli JM109 (pDT601A) (R = Cl; 10.0 g/L), (R = Ph; 3.0 g/L), (R= MeOPh; 2.5 g/L). b) PAD, HOAc, MeOH, 00C -rt, 12h., 85 95%. c) TDSCI, imidazole, DMF, 50 C, 8h., 80 90%. d) Boc-Gly, DCC, DMAP, CH2C12, 24 48h., 75 90%.


hydroxyl group was then protected as the THS-ether. DCC coupling protocol was used to convert the proximal hydroxyl group into the Boc- protected glycyl derivative 232 (Scheme 44).

The glycinates (R = Me, Cl, Ph, 2-MeOPh) served as the substrates for the first Claisen study. The results obtained were quite promising in term of yield. All the glycinates underwent rearrangement under the Kazmaier conditions with yields ranging from 25 90%. Surprisingly the configuration of the major product of the rearrangement was opposite to that expected (Table 5). Due to the fixed enolate geometry, which is a result of the formation of the chelate, the only variable would be the predominance of one transition state over the other. In this case the chair transition state clearly predominates leading to the product ratios observed.





50


Table 5. Ratio of C9 Epimers for Kazmaier Claisen Rearrangement of glycinates.

0 R R OOH R COOH
NHBoc %O LDA (2.2 eq.)
ZnCI, (1.2 eq. 14 9 NHBoc 14 9 NHBoc
TDSO TDSO TDSO
232 233 234


R 233 234 Overall yield
Ph 75% 25% 80%

CH3 75% 25% 90%

Cl 90% 10% 25%

2-MeOPh 50% 50% 75%



Due to the lack of control of stereoselectivity, the authors considered epimerization of the lactones resultant from treatment of the epimeric amino acids with tosic acid (Scheme 45). They reasoned that since the bulky protected amino acid was

R OOH TsOH, R
/ NHBoc CH,CI 0
TDSO
TDSO 233 235 NHBoc
23323
DBU/THF
R OOH R
NHBoc TsOH,
CHC1I O
TDSO TDSO
NHBoc
234 236
Scheme 45


more accessible in the wrong isomer (situated on the concave face of the bicyclic molecule), it could be effectively epimerized to the more stable isomer. Hence after treatment with DBU in THF for 37h they were able to achieve an 80% epimerization of





51


235 to give the isomer with correct stereochemistry at C9 and C14 (morphine numbering).

Inspired by the work of Kazmaier and the subsequent application of this chemistry by Hudlicky and co-workers78'79 in their approach to the morphine skeleton, Percy79 and co-workers investigated the possibility of generating y-oxo-P,P-difluorinated amino acids by chelated [3.3]-sigmatropic rearrangement of protected glycinate esters of readily available difluoroallylic alcohols. This type of rearrangement had the potential to produce amino acids having a CF2 center a to a carbonyl functionality through release of the masked carbonyl group (Scheme 46).

HO ,NHX
"1 239 MEM
OMEM 1.3 eqiuv. LDA OMEM 239 MEM
THF, -780C F H EDC, DMAp F H
2. HCHO F OH CH2C'2 F O- NHX
0
237 238 240

1. 3 equiv. LDA
THF, -780C
2. ZnC!2


OMEM
FH
F
BocHN COH
241
Scheme 46


The synthesis started with difluoroallylic alcohol 238, which was converted into the glycyl ester 240 under DCC coupling conditions. The glycinate was then subjected to modified Kazmaier Claisen condition which involves the use of 3 equivalents of LDA added in a reverse addition order to that proposed by Kazmaier (the Lewis acid is added





52


after generation of the enolate with LDA). After acidic workup the only isolated product was the rearranged acid 241.

In summary the synthesis of morphine has resulted in ingenious strategies by different research groups over the years to tackle this small yet challenging molecule. While the focus of the various syntheses has been synthesis of the target, the chemistry generated by this pursuit and its application to alkaloid chemistry is the legacy of morphine synthesis. Starting from Gates' 15, 16 synthesis to the latest synthesis by Mulzer21-25 it is fascinating to see the many different synthetic pathways that have been employed in morphine synthesis. Sigmatropic rearrangements have played a small yet important role in morphine synthesis. The syntheses by Parsons, 20 Rapoport5o and Mulzer21-25 effectively used sigmatropic rearrangements to establish the C13 quaternary center of morphine

The chelated enolate Claisen Rearrangement had modest beginnings from Steglich62, 63 and coworkers and later Bartlett64 and coworkers. The idea was greatly improved by Kazmaier 66-77 and coworkers who have developed it into one of the more powerful tools in amino acid chemistry.

The next chapter of this dissertation will discuss a chemoenzymatic approach to the synthesis of the morphine skeleton. This approach uses a disconnection of the morphine molecule that is unlike any of the preceding syntheses. More importantly, it utilizes a sigmatropic rearrangement, the Chelated Enolate Claisen rearrangement (Kazmaier Claisen) to establish control of C9 and C14 stereocenters of morphine in addition to attempting to establish the C13 quaternary center. Additionally the synthesis uses an enzymatic step, which is capable of converting cheap readily available aromatic





53


precursors into either catechols (A-ring of morphine) or cyclohexadiene diols (C-ring of morphine). With all these factors combined, the chemoenzymatic approach becomes an attractive route to the morphinan skeleton.

In 1968 as a result of studies conducted by David T. Gibson87 on the microbial oxidation of aromatic hydrocarbons by soil bacteria, the first stable cis-diol was isolated. The organism responsible for this transformation was a mutant strain of the bacteria Pseudomonas putida (F1l) and was designated Pseudomonas putida (F39/D). This strain was devoid of the cis-diol dehydrogenase enzyme hence only produced the cis-diene diol. The use of these diols as synthons was initiated in the late 1980's with work done by Ley and coworkers who achieved a racemic synthesis of pinitol from meso-cis-diols derived from benzene. Since then, one of the leading researchers in this area of chemistry has been Hudlicky who has been able to utilize the cis-diene-diols as chiral synthons86 in the synthesis of a wide variety of compounds.

In 1988, in the first publication by Hudlicky and co-workers in this area, the idea of Claisen rearrangements of the allylic alcohol unit of the cis-diols was proposed. This idea was actually reduced to practice in 1997 and thus began the initial studies that featured the Claisen rearrangement as a key step in the chemoenzymatic approach to the morphine skeleton.86

In the -first generation of this approach, conditions for a suitable Claisen rearrangement that would lead to the transfer of stereochemical information inherent in the cyclohexadiene-diols were investigated. The Kazmaier-Claisen rearrangement offered the best conditions for this purpose. The goal was to synthesize P3-amino acids of different complexity bearing chiral side chains. Eventually such compounds would





54


contain the correct stereochemistry at the C9 and C14 (morphine numbering) centers of morphine.

In the initial model studies, as reviewed in the historical chapter it was discovered that even though the Claisen rearrangements proceeded with low stereoselectivity, there was the potential to achieve complete control of the C9, C14 stereocenters through equilibration of isomers. Efforts in the initial stages of this approach were also directed at finding efficient ways of obtaining the bicyclic skeleton One of the opportunities for construction of this bicycle was through direct enzymatic dihydroxylation of substituted biphenyls. Indeed when selected biphenyls were subjected to biooxidation conditions, the 78
resultant diene diols were obtained. Unfortunately it became apparent that as the degree of oxidation in the substrate increased, the yield for the enzymatic process decreased considerably probably as a result of poisoning of the bacteria by the oxygenated substrate.

This dissertation will focus on the progress made in the second generation of the chemoenzymatic approach to morphine. The discussion will address how control of the C9 and C14 centers of morphine was achieved through the use of the Kazmaier-Claisen rearrangement and epimerization. It will also give an account of the progress made toward a formal total synthesis of morphine via Overman's intermediate. In addition some applications in the field of matrix metallo proteinase inhibitors, compounds that are connected to morphinan intermediates through common structural elements will be discussed. Finally recent advances in the chemoenzymatic approach to morphine will also be discussed.





55








CHAPTER 3
RESULTS AND DISCUSSION


Introduction


The structural complexity of the morphine molecule has prompted many

innovative routes to the morphinan skeleton as was detailed in the first chapter. The

synthetic design utilized in the chemoenzymatic synthesis of the morphinan skeleton,

makes it a very attractive route to the morphine molecule. Retrosynthetically, the

approach is directed toward the target through the intermediate (3-cyclohexenyl amino

acid 242. The amino acid could be obtained through a Claisen rearrangement of the Xxx

Scheme 47
HO RO RO

RO OOH RO
O 1 D 9 C H fo>kc O110
9NMe 9NH2 N
C 114 2
-0 6
HO HO S- HO
1 242 S 243
S = solvent
M = Zn R

RO

RO RO RO
B(OH)2 RO RO
246
Br Br ~ HO
HO. HO,
diimide HO
HO HO
248 247 244 245





56

glycinate ester 243 which could be synthesized from the biphenyl diol derivative 244. This synthon is available either from direct biooxidation of the biphenyl precursor 245 or through the coupling reaction between the aromatic boronic acid 246 and diol 247 derived from diimide reduction of the cis-diene diol 248 (Scheme 47).

The retrosynthetic strategy outlined above uses remarkable design elements that deserve mention. 1) The C-ring of morphine can essentially be described as a cyclohexenyl cis-diol unit. This moiety can be recognized in the structure of the chiral HO '

Br Br B
OH N HMe

6OH HO' 6 HO'"
248 248 1


Scheme 48

cis-cyclohexadiene diol 248 with the correct absolute stereochemistry at C5 and C6 set as a result of the enzymatic transformation (Scheme 48). 2) The approach capitalizes on the recognition that the main backbone of the morphine skeleton consists of an oxidized biphenyl unit 252 (Figure 4). This structural component, namely 244 (Scheme 47), is also present in various alkaloids like pancratistatin the synthesis of which is being pursued in the Hudlicky group. This unit could be obtained as outlined above either through direct biooxidation of a biphenyl precursor or through the coupling of an aromatic boronic acid with cis-cyclohexadiene diol (Scheme 47). 3) The allylic alcohol unit present in diol 244 (Scheme 47) allows for the introduction of the amino acid side chain into the molecule through a Claisen rearrangement. 4) Finally the C 13 quaternary center could be





57


O-\ O-\ R 0 R 0
RO

HN, OH HN ,
NMe
11' HO OH HO OH
RO OH OH
249 250 251
morphine pancratistatin narciclasine
codeine 7-deoxypancratistatin lycoricidine



OR
OR
OR
OH

OH
252

Figure 4. Synthetic targets with oxidized biphenyl unit.



established by utilizing the allylic alcohol moiety present in intermediate 254 via a

HO RO RO
A A
0 RO B RO COOH

C N W R NHR 14 9 NHR
HO O RO
1 253 24


RO RO

RO RO OOH

N '1 9 NH

HO 6 HO
S 243 242
S = solvent
Scheme 49 M=Zn





58


second Claisen rearrangement. The amino acid 254 is also set up for closure of the C10C II using a Friedel-Craft reaction after conversion of the acid into the aldehyde or the acid chloride. Before the discussion proceeds into the actual execution of the approach, a brief history about the development of the chemistry of enzymatic dihydroxylations would be in order.

In 1968 as a result of studies conducted by David T. Gibson87 on the microbial oxidation of aromatic hydrocarbons by soil bacteria, the first stable cis-diol 256 was wild strain of P. putida Fl
I

CH3 CH3 CH3
OH q OH
P. putida FI P. putida FI
toluene 1- OH cathechol OH acetate
C dehydrogenase dehydrogenase
Cl Cl Cl
255 256 257



P. putida F39/D
Scheme 50


isolated. The organism responsible for this transformation was a mutant strain of the bacteria Pseudomonas putida (Fl) and was designated Pseudomonas putida (F39/D). This strain was devoid of the cis-diol dehydrogenase enzyme hence only produced the cis-diene diol 256 (Scheme 50). The use of these diols as synthons was initiated in the late 1980's with work done by Ley88 and coworkers who achieved a racemic synthesis of pinitol from meso-cis-diols derived from benzene. Since then, one of the leading researchers in this area of chemistry has been Hudlicky who has been able to utilize the cis-diene-diols as chiral synthons6 in the synthesis of a wide variety of compounds (Figure 5).





59


In 1988, in the first publication by Hudlicky and co-workers in this area, the idea

of Claisen rearrangements of the allylic alcohol unit of the cis-diols was proposed. This

idea was actually reduced to practice in 1997 (pg 49-52, historical section) and thus

began the initial studies that featured the Claisen rearrangement as a key step in the

OH
HOOH HO .-OH OH

HO HO C13H27
HO OH N HONH
OH
D-chiro-inositol (-)-trihydroxyheliotridane D-erythro-spingosine
258 259 262
OH
OH
OOH OOOH
O OH O / OH HO O
0 H 0 N H 1H

R O R O HO OH
OH
pancratistatin R = OH narciclasine R = OH amino-inositol dimer
7-deoxypancratistatin R = H lycoricidine R = H 263
263
250 251 O
MeON

M OH -N-H OH OEt
O N HO
NMe OjO:
OH
O OH OH HO OEt
ent-morphinan kifunensine specionin
260 261 264

Figure 5. (Examples of Targets Synthesized from cis-diols)


chemoenzymatic approach to the morphine skeleton.86

In the first generation of this approach, conditions for a suitable Claisen

rearrangement that would lead to the transfer of stereochemical information inherent in

the cyclohexadiene-diols were investigated. The Kazmaier-Claisen rearrangement offered

the best conditions for this purpose. The goal was to synthesize P-amino acids of





60


different complexity bearing chiral side chains. Eventually such compounds would contain the correct stereochemistry at the C9 and C14 (morphine numbering) centers of morphine.

In the initial model studies, as reviewed in the historical chapter (pages 49-51), it was discovered that even though the Claisen rearrangements proceeded with low stereoselectivity, there was the potential to achieve complete control of the C9, C14 stereocenters through equilibration of isomers. Efforts in the initial stages of this approach were also directed at finding efficient ways of obtaining the bicyclic skeleton 252 (Figure 4). One of the opportunities for construction of this bicycle was through direct enzymatic dihydroxylation of substituted biphenyls. Indeed when selected biphenyls were subjected to biooxidation conditions, the resultant diene diols were obtained.78 Unfortunately it became apparent that as the degree of oxidation in the substrate increased, the yield for the enzymatic process decreased considerably probably Table 6. Results from Biooxidation of substituted biphenyls.

R1 R2

R2 R2
E. coli JM109 (pDTG601A) OH


Z:" OH
265 R1 = H, R2= H 268 R1 = H, R2 = H

266 R1 = H, R2 = OMe 269 R1 = H, R2 = OMe

267 R 1 = OMe, R2 = OMe 270 R 1 = OMe, R2 = OMe


Subtrate Yield (gil)
265 3.0
266 2.5
267 0.8





61


as a result of poisoning of the bacteria by the oxygenated substrate (Table 6). The low yields that accompanied the biooxidation of 267 to diol 270 the morphine precursor prompted us to seek other ways of constructing this bicyclic skeleton with the intent of functionalizing it appropriately into the morphinan skeleton.

This dissertation will focus on the progress made in the second generation of the chemoenzymatic approach to morphine. The discussion will address how control of the C9 and C 14 centers of morphine was achieved through the use of the Kazmaier-Claisen rearrangement and epimerization. It will also give an account of the progress made toward a formal total synthesis of morphine via Overman's intermediate. In addition some applications in the field of matrix metallo proteinase inhibitors, compounds that are connected to morphinan intermediates through common structural elements will be discussed. Finally recent advances in the chemoenzymatic approach to morphine will also be discussed.


First Generation Synthesis- Control of C9 and C14 Stereocenters of Morphine

The first few steps in the synthesis focused on the Suzuki Coupling protocol in the synthesis of biphenyl diol derivative 270 (Table 6) which would then be functionalized into a glycinate ester. Starting from guaiacol (271), a known compound, which is not commercially available, we employed a procedure used by Hoshino83 and coworkers in their synthesis of lycoramine. It involves first, the generation of a tert- butylamine bromine complex by addition of bromine to the amine at -680 C for a 24 48 hour period. After formation of the complex, which is the actual brominating agent, the reaction mixture is cooled back to -780 C at which time a solution of guaiacol dissolved in minimum amount of methylene chloride is added dropwise (Scheme 51). The reaction





62


typically gives a 50-60 % yield of bromogiuacol (150) in addition to two other Br Br
OH OH b OMe

OMe OMe OMe
271 150 272

d c

B(OH)2
OMe

OMe
273

Scheme 51. Conditions: a) Br2, tert-butylamine, toluene, -780 C, 60-62 %; b) Mel, K2CO3, Acetone, rt., 90-94 %; c) Mg, 12 (cat.), B(OEt)3, NH4CI (sat'd), 80-85 %; d) tBuLi, B(OEt)3, NH4CI (sat'd), 77-80 %.


regioisomers. Isolation of bromogiuacol from the reaction mixture is achieved by Kugelroh distillation. The next step involved methylation of the phenol with methyl iodide in acetone, employing potassium carbonate as the base. These reactions typically gave a 90-94 % yield of the dimethyl bromocatechol. In the next step the 1,2dimethoxybromobenzene (272) was converted into the corresponding boronic acid (273). The boronic acid was obtained by using either Grignard conditions or lithium halogen exchange with t-butyllithium. The Grignard conditions gave better overall yields.

The other coupling partner became available from diimide reduction of the chiral cyclohexadiene diol 248, with potassium azodicarboxylate (PAD). This procedure, which has been optimized in the Hudlicky group, typically gives about 90-95 % of the reduced product 247 (Scheme 52). We also synthesized the boronic acid derived from vinyl bromide 247 with the intent of coupling it with 1,2-dimethoxybromobenzene 272 (Scheme 52). Conversion of acetonide 274 to the boronic acid 275 proceeded with low





63


yields (45-50 %) hence making this route to the coupled product unfavorable.

Br Br Br

OH OH
O:: a O:: b 40 6 O
248 247 274

Ic

B(OH)2



275

Scheme 52. Conditions: a) PAD, HOAc, MeOH, 00 C-rt., 14 h, 90 %; b) DMP, Acetone, TsOH, 95%; t-BuLi, B(OEt)3, -780C, NH4CI (sat'd), 45-50 %.


We now turned our attention to the Suzuki Coupling81,82 step, a technique which has become one of the more efficient methods of bond formation between an aromatic ring and an sp2 center. In our hands typical conditions involved the use of tetrakis triphenylphosphine palladium (Pd(PPh3)4) as the catalyst and a benzene/ ethanol solvent system with 2M Na2CO3 as the base. The reactions were normally complete after three hours under reflux conditions. Yields were in the 75-80 % range and this was very crucial since the Suzuki coupling was one of the key steps in our synthesis (Scheme 53).

MeO
MeO B(OH)2
a MeO b. c O
MeO OH
B(OH)2 O
273 270 OH 275

Scheme 53. Conditions: a) 0.03 % eq. Pd(PPh3)4, 2M Na2CO3, 247, PhH-EtOH, reflux; b) 0.03 % eq. Pd(PPh3)4, 2M Na2CO3, 274, PhH-EtOH, reflux; c) H', THF.





64


Claisen I-First attempt of Kazmaier Claisen on Morphine Precursor

To perform the Claisen rearrangement, we planned to take advantage of the remaining allylic alcohol unit in the bicyclic intermediate 270. In order to ensure selective conversion of the proximal hydroxyl group into the glycinate ester we first had to protect the distal hydroxyl group as its silyl ether. The thexyldimethylsilyl (TDS) group was well suited for our substrate because its bulky nature ensures the protection of the least hindered hydroxyl group, which in this case is the distal hydroxyl. Yields for the step are typically around 90% for TDS-ether 276. Less bulky silylating groups like TMS-Cl tend to lead to a large percentage of product resulting from lack of selectivity in the protection of the distal and the proximal hydroxyl groups. The reaction involves first, generating the imidazole-TDS complex at -12' C followed by addition of the diol (270) to the reaction mixture. Our efforts led to isolation of silyl ether 276 (Scheme 54). The next stage in the synthesis required the functionalization the proximal hydroxyl group as a glycinate ester,

MeO MeO
MeO MeO

OH THS-CI, Imidazole OH
DMF -O
DMF Gly-Boc, DCC,
OH OTHS DMAP, CH2Cl2
270 276


MeO

MeO O
OkQ-NHBoc

OTHS
277
Scheme 54





65


the Claisen rearrangement precursor. One of the standard procedures for achieving this type of transformation involves a DCC coupling.75 In our hands the DCC coupling conditions worked well with Boc-glycine, DCC and catalytic DMAP. Yields ranged from 70-85%. Careful workup of the reaction mixture, which requires removal of the reaction solvent (CH2CI2) followed by precipitation of the dicyclohexylurea by-product with diethyl ether a procedure which usually removes about 80 85% of the dicyclohexyl urea (DCU) by-product. Column chromatography is then used to purify the crude mixture. With the glycinate ester 277 in hand we were ready to perform what would be the key step in our approach to morphine. A [3.3] sigmatropic rearrangement to establish the chiral centers at C9 and C14 (morphine numbering). As previously discussed, the Kazmaier-Claisen rearrangement provided the best opportunity to perform this transformation. The conditions involve the addition of Lewis acid (usually ZnCI2) to a /OMe

0 OMe LDA (2.2 eq.)
BocH- OZnCl, (1.2 eq.)

THSO
277
MeO MeO

MeO 0 OH MeO 0~ OH

9'NHBoc -' 9 NHBoc
THSO' THSO* H
278a 278b

70 : 30
Scheme 55


solution of the glycinate ester in THF. After about 15 minutes of stirring the reaction mixture is cooled to -78' C and the base (usually LDA) is added. The reaction mixture





66


then allowed to warm slowly to room temperature over 36-48h. According to Kazmaier, the rearrangement usually occurs between -10' 0' C. In our hands we observed very good conversion of starting material to products, with yields of rearranged acids averaging between 75 85% but there were two significant problems. 1) The ratio of the rearranged products 278a and 278b were opposite to that expected. We anticipated the product with a syn relationship between the proton at C14 and the nitrogen at C9 to be the major product. 2) The two rearranged acids possessed very similar spectroscopic properties so initially it was difficult to ascertain the identity of the isomers. 3) These compounds were virtually inseparable using standard chromatographic techniques even after their derivatization into the corresponding methyl esters.

The fixed enolate geometry that results from chelate formation in the KazmaierClaisen rearrangement causes the stereochemical outcome of the rearrangement to be a function of the transition state that the reaction proceeds through. For cyclohexyl substrates the unfavorable steric interactions in the chair transition state (Figure 3)



r f/

Y N Y= Boc
,M S = Solvent
S M=Zn
R' = TDS
chair Boat
R = 2,3-dimethoxyphenyl

Figure 6. Chair vs boat transition states in the Kazmaier Claisen Rearrangement of morphinan intermediates.


the cyclohexyl ring and the metal chelate, causes this transition state to be less preferred to the boat transition state, which is devoid of such interactions. It is very important to





67


note that Robert Ireland 89,9 who performed rearrangements on silyl ketene acetal analogues of these compounds, observed that both transition states could operate depending on the size and position of the substituents on the cyclohexyl ring. The effect of the large THS group can be neglected, but considerations of the dimethoxy phenyl substituent, which is in the a-position to the allylic carbon, reveals that in the boat transition state this substituent might have an unfavorable steric interaction with the solvated metal (Figure 6). This leads to two steric arguments; 1) in the chair transition state there is an unfavorable interaction between the solvated metal and the cyclohexyl ring, 2) in the boat transition state the steric interactions are between the aromatic ring substituent and the solvated metal. As a result of these opposing steric interactions, the energy difference between the two transition states is very small, leading to product formation from both pathways. In our case the chair transition state is favored resulting in 70: 30 ratio of products.

As previously stated the rearranged acids 278a and 278b had similar spectroscopic properties, and they were virtually inseparable by standard chromatographic techniques. One of the options we explored to obtain pure samples of each was to derivatize these acids into the corresponding lactones, which would offer a more rigid structure with the anticipation that this might help in the identification of the acids. This transformation was achieved with tosic acid in anhydrous methylene chloride resulting in the formation of the corresponding lactones from the mixture of the epimeric acids (Scheme 56). Even though two possible lactones could have been obtained from this reaction we only observed the lactone derived from the trapping of the benzylic carbocation. Indeed in this way we were able to obtain dimethoxy phenyl lactone 279 in





68


pure form and were able to obtain spectral data for the compound. Lactone 280 was also Scheme 56

MeO MeO

N. + MeO 0 OH

14HNHBoc 14 ~ o
144 H
THSO. THSO.
278a 278b
I TsOH,
CH2CI2 anh.

MeO MeO

eO MeO
M 00 0 1- 09

9 k
H NHBoc H NHBoc H NHBoc
280 279 281


isolated and easily converted to lactone 279 through an epimerization reaction with DBU. The data obtained was compared to phenyl lactone 281 which had been synthesized earlier and whose identity had been confirmed by X-ray crystallography. Friedel Craft-Attempt at C I0-C 11 Closure


Even though we were unable to separate the two epimeric acids 279a and 279b we saw an opportunity to study the feasibility of the C10-CI1 bond (morphine numbering) closure, through a Friedel-Craft type reaction. We had conflicting literature precedence for this transformation. Ginsburg35 was able to close the C IO-Cl 1 bond under acid conditions from the intermediate acid 282. Although Ginsburg's intermediate contains the same bicyclic skeleton as in our example, his compound is much simpler and essentially has only one more functional group, the ketone at C5 (morphine numbering).





69


MeO MeO

/~ 0
MeO OOH MeO
O 0 Ginsburg


282 33

MeO MeO

MeO HO MeO Mulzer
I~HO ~ MeO O
NMe2 NMe,

0 0
126 127

Scheme 57


Using hydrofluoric acid he was able to achieve the Friedel-Craft annulation, to obtain the desired diketone 33. Mulzer,21-25 in his morphine synthesis, made intermediate 126 which also contained the bicyclic unit comprising the A and C-rings of morphine and essentially resembles that of Ginsburg, with the exception of the presence of the dimethylamido group resulting from a prior Eschenmoser-Claisen rearrangement step. Mulzer was not able to achieve annulation of the B-ring on the aldehyde upon treatment with various Lewis acids (Scheme 57). With these two contrasting results it was difficult to make any predictions as to the outcome of our attempts at B-ring closure. Starting from acid 278, we derivatized it as the acid chloride using three different conditions.

MeO MeO

MeO OOH SOBnO
NHBoc Lewis acid NHBoc
PhH
THSO THSO"
278 283

Scheme 58





70


Initially we used thionyl chloride as the reagent for this transformation. We realized that these conditions (Scheme 58) were too harsh because we observed cleavage of the thexyl and Boc- protecting groups and or decomposition of the starting material even before addition of the Lewis acid. We saw no evidence of cyclized product (283) in the reaction mixtures and hence decided to resort to milder conditions for synthesizing the intermediate acid chloride. The conditions that we decided to work with involved either making the acid chloride by using oxalyl chloride/DMF or PPh3/CCI4 using conditions analogous to that used by Rapoport91 in his synthesis of tylophorine. Starting from acid 278, we used a combination of oxalyl chloride and DMF to generate the acid chloride. Typically after four to six hours, we observed disappearance of the OH-stretch of the acid and appearance of a strong signal at 1780 corresponding to the acid chloride. At this point the Lewis acid was added and the reaction refluxed overnight. The various Lewis acids employed were AICI3, Me2AIC1, ZnCI2 and SnCI4. The reactions typically after workup led to recovery (Scheme 59) of starting material and a small percentage of by-product due to cleavage of the Boc-protecting group. The results from the triphenyl phosphine/carbon tetrachloride reaction were similar to the oxalyl chloride/ DMF reaction, here too no product from closure of the C 10- C 1 1 bond was isolated. Mulzer25 in his discussion of his attempt at the Friedel-Craft reaction suggested that there might be a phenomenon similar to that of atropoisomerism of biphenyl compounds present in these types of substrates. This being the case our A-ring may be twisted out of conjugation with the cyclohexenyl ring making a Friedel-Craft type closure very difficult. The solution to this problem will be to either make the furan ring of morphine or to establish the nitrogen bridge first. This might help to hold the aromatic ring in a more preferable conformation that would allow





71


for a successful Friedel-Craft closure. MeO MeO

MeO 02H aorb MeO OH

NHBoc NHBoc
THSO THSO
278 284

C
MeO

MeO 0
TO NHBoc

THSO'
283

Scheme 59. Conditions: a) Oxalyl chloride, DMF, CH2C12; b) PPh3, CCl4, THF; c) Lewis acid (AICl3, Me2AlCI, ZnCI2 and SnCl4). Claisen IH-Ireland Claisen on Phthaloyl Ester

Our goal still remained to improve the selectivity of the Kazmaier Claisen rearrangement. One of the options we had not explored was a sigmatropic rearrangement under Ireland65,89,90 conditions, which we hoped might lead to an improvement in the ratio of rearranged epimeric acids. To attempt the Ireland-Claisen rearrangement, we first functionalized the silyl ether 276 into the phthaloylester 285 (Scheme 60). Under Ireland conditions, we observed good conversion of starting ester to products but the product ratio again favored the undesirable epimer 286a. More importantly, the epimers were also difficult to separate by column chromatography.






72


MeO MeO

MeO ~ Phthaloyl-gly MeO 0"
OH DCCDMAP )QN "~/LDA,
CH2C12 RTMSCI,
0 THF. 80%
26OTHS 25OTHS 2. CH2N.,



MeO MeO0 e

Me-0 0 0
0' OMe MeO


rl14 1 9N

THSO* 0 / THSO" 0
286b 286a

20 80
Scheme 60



At this point we reevaluated our synthetic approach to alleviate the

stereoselectivity problem in the Kazmaier-Claisen rearrangement. We rationalized

R0


HO RO""R~ 246
B(OH)2

RO OOMe Br OOMe
0 -eNHBoc NHBoc
1 H14 H 14 H
HO THSO THSO
1 287 288


Br Br OOMe
Boc Br NHBoc
___ __ ~ Y14 H
&OH RO SO-5H
OH" Ro THO
S- 1
248 S 290 289b


Scheme 61





73

that the source of the problem might be adverse steric interactions between the aromatic substituent and the metal chelate (Figure 6, pg 67). Our immediate solution to this problem was to attempt the Kazmaier-Claisen on the cyclohexenyl gylcinate ester 290, which has a bromine substituent in the a-position to the allylic carbon. Such a substrate would posses a much minor steric interaction in the boat transition state between the solvated metal and the ring substituent (as discussed on pg 67) leading to a much improved product ratio. This also meant that the Suzuki Coupling step, which had previously preceeded the Claisen rearrangement, would now be performed after the rearrangement. Our new general retrosynthetic scheme would be as represented by Scheme 61.


Claisen lI-Kazmaier Claisen of Glycinate of Cyclohexadiene Diol

Starting from diol 247 we were able to protect the distal hydroxy group as the thexyldimethylsilyl ether 291. Using DCC coupling protocol we obtained the glycinate ester 292. We were now in a position to perform the Kazmaier Claisen on the precursor

Br Br Br O
OH THS-C1, Imid. OH Gly-Boc, DCC O NHBoc
THS-CI, Imid. DMAP

OH DMF, -8 o C OTHS CH2Cl2 OTHS
247 291 292

Scheme 62


292. Using 2.2 equivalents of LDA and 1.4 equivalents of ZnCl2 we were able to obtain rearranged product epimeric at C9. We observed the yields for the transformation increase from 75% to 80-85%; the ratio of the rearranged acids epimeric at C9 also decreased slightly from a 70: 30 ratio to a 60: 40 ratio in our favor. But the best aspect of





74

this reaction was the fact that these epimeric acids, converted to their corresponding methyl esters could be separated by silica gel column chromatography. More importantly the faster-eluting major isomer 289a could be equilibrated to the -isomer (the desired epimer for our morphine synthesis) by an epimerization reaction with DBU. Starting from isomer 289a, we are able to obtain a 1: 1 mixture of epimers after 96 hours in refluxing THF. Similar epimerization reactions with TFA and NaOMe gave a 4: 1 and 5: 1 ratio of epimers respectively. Even though the reaction is still non-stereoselective, we had found a way to obtain the epimer with the correct stereochemistry at C9 and C14. This was a huge breakthrough in our synthetic approach because it meant that we now had the opportunity to carry out an enantioselective synthesis of morphine.

Br 0 Br CO2Me Br CO2Me
O-J NHBoc 9NHBoc + 4 NHBoc
OTHS THSO H THSO H
292 289a 289b
60 : 40



C

Scheme 63. Conditions: a) LDA (2.2 eq.), ZnCI2 (1.4 eq.), THF, -780 C, 80%; b) CH2N2, Et20, 90%; c) DBU, THF, reflux, 65%.


We had also achieved control of the C9 and C14 (morphine numbering) stereocenters, which is very crucial to a successful morphine synthesis.

During this period of time we entered into a collaborative project with scientists at Procter and Gamble Pharmaceuticals who were interested in compounds to be used as scaffolds in their matrix metallo proteinase (MMP) inhibitors studies. Dr. Hudlicky recognized structural similarities between their targets (hydroxamic acids with an R-





75


configuration at the a-center of the amino acid) and some of the compounds synthesized from the Kazmaier Claisen rearrangement during the morphine synthesis model study.


C O2Me


-~NHBoc
TDSO
293

Figure 7. Structure of morphine precursor used in initial MMP screen.


To our surprise, ester 293 as a mixture of R and S-isomers at a-center of the amino acid side chain showed MMP inhibition. This led to the initiation of the collaborative project with Proctor and Gamble Pharmaceuticals where the goal was to synthesize esters of the type 293 to be evaluated for biological activity as MMP inhibitors. This was a great opportunity because it gave us the occasion to apply our chemistry to industrial scale projects. The next section will describe some of the efforts made in the synthesis of matrix metallo proteinase inhibitors in a collaborative effort with researchers at Procter and Gamble Pharmaceuticals.



Synthesis of Matrix Metalloproteinase Inhibitors (MMP's)

Researchers at Procter and Gamble have been exploring the synthesis of unnatural amino acids to be used as scaffolds in the preparation of potent matrix metalloproteinase inhibitors (MMP's).9295 MMP inhibitors have shown activity as antagonists of various diseases where tissue remodeling plays a key role,96 including osteoarthritis,97'98 rheumatoid arthritis,99 tumor metastasis,10 multiple sclerosis'0' and conjective heart failure. 02 The structural features of their target, resembled ester 289a which interestingly





76


was the undesired isomer from the Kazmaier Claisen rearrangement (Scheme 63).

Br CO2Me O2Me

OH HNHBoc MeNHBoc
____H H*I:: Me
OH HO'[ HO

248 296 303

Scheme 64


We prepared a series of cyclohexylglycine and cyclohexylalanine derivatives of the type 296 and 303 (Scheme 64) to be utilized as intermediates for the synthesis of MMP inhibitors. Also as part of the collaborative project, the absolute stereochemistry of ester 289a was determined unambiguously by X-ray crystallography (Figure 7). Esters 296 and 303 were synthesized using similar protocol as has been described earlier in the chapter. Approaches to compounds of this type through enolate alkylation or aldol type condensations are quite difficult, hence the Kazmaier Claisen provides a direct route to these unnatural amino acids with control of stereoselectivity and respectable yields.

Starting from the diol 247, a two step sequence involving protection of the distal hydroxyl group as the TBS-ether, followed by esterification of the proximal hydroxyl group by DCC coupling rendered gylcinate ester 292 (Scheme 65). We achieved the rearrangement to the corresponding acids via Kazmaier Claisen conditions. Diazomethane was then utilized in the conversion of the acids to the methyl ester derivatives. The next step involved reduction of the vinyl bromide with Adam's catalyst at 40 psi with triethylamine as the proton scavenger. Finally tetrabutyl ammonium fluoride mediated deprotection of the TBS group rendered the alcohol 296 which





77


underwent other proprietary transformations before being used in MMP testing. Because

Br Br O Br O OMe
OH 0__0J NHBoc
a Oc,d "NHBoc
OH OTBS TBSO'
247 292 293



O OMe O OMe /

NHBoc g NHBoc 0 OMe

Ho TBSO .16/ NHBoc
296 295
TBSO
steps 294
0O OMe
R" =Alkyl
*NHR' 0
R
R"O'" I I
R"OR
297

Scheme 65. Conditions: a) TBS-CI, imidazole, DMF, -12' C, 85%; b) DCC, DMAP, NBoc-glycine or N-Boc-alanine, CH2Cl2, 80%; c) ZnCl2, LDA, THF, -780 C, 75%; d) CH2N2, Et20, 90%; e) H2/PtO2 (40 psi), Et3N, MeOH, 75%; f) nBu3SnH, AIBN, PhH.g) TBAF, THF, 80%.


of the success of the Claisen with the glycine ester, we planned to prepare sulfonamide

299 through a DCC coupling reaction with TBS-ether 298 and the alanine moiety already

functionalized as the sulfonamide. This reaction proved unsuccessful, hence we prepared

ester 301 and following the removal of the Boc protection group, were able install the

sulfonamide to obtain 299. The Kazmaier Claisen rearrangement of 299 to 300 worked

smoothly as in the case of the glycine ester (Scheme 66) even though yields were lower

probably due to the lower chelating potential of the sulfonamide as compared to the

carbamate in structure 292. The synthesis of 300 also did not proceed with the same





78


diastereoselectivity as in the earlier cases presumably because of the increased size of the

sulfonamide functionality leading to a decrease in preference for the chair transition
B OH Br 0 Br0 OH
Br O Br
OO ONHRBr
aV O NHR e M NHR
/M\ Me Me
298 OTBS 299 OTBS TBSO 300

b td f-h
28299 300



Br O Br 0 O OMe
O yNHBoc & O NH2
Me -S. Me NHR
MeBSMe
OTBe ct, OTBS HO. Me

301 302 303
0
R=-S -x/ \ _/\
R


Scheme 66. Conditions: a) alanine N-sulfonamide, DCC; b) N-Boc alanine, DCC; c) TFA, CH2Cl2; d) 4-methoxy-l,l '-biphenylsulfonyl chloride, Et3N, THF; e) ZnCl2, LDA, THF, -780 C; f) CH2N2, Et20; g) H2 (40 psi), PtO2, Et3N, MeOH; h) TBAF, THF.


state. Even so, acids 300 were converted over three steps to methyl esters 303, the

precursors for MMP inhibitors. One of the more difficult steps in this project was the last

SO OMe 0 OMe
Br

INHR a NHR
THSO
293 304
b

O OMe R = Boc

NHR
THSO
295

Scheme 66. Conditions: a) H2 (40 psi), 5% or 10% Pd-C, MeOH; b) H2 (40 psi), PtO2, Et3N, MeOH.





79


step involving the removal of the vinyl bromide through hydrogenation. Initial attempts at this transformation utilized 10% and 5% Palladium on Carbon (Pd/C) at 40 psi in methanol. Even though this resulted in the removal of the vinyl bromide it also resulted in hydrogenolysis of the silyl ether leading to the isolation of ester 304. Even though ester 304 was devoid of the hydroxyl group, the hydroxamic acid derivative this compound surprisingly showed some activity as an MMP inhibitor. After investigating several other conditions we discovered that using Adam's catalyst (PtO2) in methanol at 40 psi with Table 7. MMP inhibition activity for glycine and alanine analogs.


0 OH 0 OH Br O OH O OH

/ ~NHR HMNHR
NHR NHR HMeN
HH,
HO' HO'" HO HO

IC50 (nM)a
305 306 307 308

MMP-2 12 20 38 251

MMP-3 1,220 2,490 3,795 6,150

MMP-13 30 176 131 338

0
R=S / /
0


triethylamine as a proton sponge works nicely leading to isolation of the silyl ether 295 in 89% yield.

With the completion of the collaborative project, we turned our attention back to morphine synthesis; we now had a stereospecific way of obtaining the methyl ester 289b






80






























L) K D C.) U)











0


BD




Figure 8





81


(Scheme 60). The next step involved the coupling of the methyl ester with an aromatic boronic acid to obtain our crucial bicyclic intermediate 242 using the Suzuki conditions that by now had been optimized for the morphine project (Scheme 49, pg 57).


Second Generation Synthesis- Overman's Intermediate via Claisen Rearrangement

In this section the efforts towards synthesizing the Overman53 intermediate 95 (pg 21-22, Chapter 1) are described. The target was chosen for two main reasons, first the synthesis of the Overman intermediate would allow us to achieve a formal total synthesis of morphine since dihydrocodeinone (88) was synthesized in three steps from the Overman intermediate. Also, after coupling ester 289b with an appropriate aromatic piece this bicycle would possess all the functionality needed to achieve the synthesis of the Overman intermediate. Retrosynthetically our goal was to arrive at the Overman intermediate through a Friedel-Craft102,103 reaction on acid 309. Even though our earlier






95 309 310


MeO 4
MeO MeO
B nO B OC O eB O0 M
313 B(OH)2 BnO COOMe 2
Br O2Me 9 NHR y NHBoc
6
-~ NHBoc THSO' HO'
THSO 312 311
289b


Scheme 68





82


attempts at the Friedel-Craft reaction were unsuccessful we were hopeful that with the construction of the nitrogen bridge, this precursor would have a more rigid structure with the aromatic ring in a favorable position to effect cyclization (path y, Scheme 68). The key step in this synthesis would be the setting of the C13 quaternary center by a [3,3]sigmatropic rearrangement. The options available were an Ortho-ester Claisen104,105 rearrangement or an Eschenmoser 6,107 type Claisen rearrangement using the allylic alcohol moiety in precursor 310 (path x, Scheme 68). Alcohol 310 could in turn be synthesized through a Mitsunobu108' reaction of alcohol 311. Compound 311 could be achieved from a two-step sequence involving a Suzuki reaction to couple the methyl ester and the aromatic boronic acid followed by a fluoride deprotection of the silyl ether. Boronic acid 313 was synthesized (Scheme 69) using the same protocol that was used for the synthesis of the dimethoxy boronic acid 273 (pg 61) with similar results in terms of yield. With boronic acid 313 in hand we were able to achieve coupling with ester Br Br
OH OH OBn

OMe OMe OMe
271 150 314

d C

B(OH)2
OBn

OMe
313

Scheme 69. Conditions: a) Br2, tert-butylamine, toluene, -780 C, 60-62 %; b) BnBr, K2CO3, Acetone, rt., 90-94 %; c) Mg, I2 (cat.), B(OEt)3, NH4CI (sat'd), 82-86 %; d) tBuLi, B(OEt)3, NH4CI (sat'd), 75-80 %.





83


289b to obtain the bicycle 312. The following reactions were performed on the 2,3dimethoxyphenyl and 2-benzyloxy-3-methoxyphenyl analogs as shown in Scheme 70 but

the description of the process will focus on the benzyl-protected analog. To ensure the

correct regio-chemistry of the Claisen rearrangement we proceeded to invert the alcohol

at C6 (morphine numbering). This process began with a tetrabutyl ammonium fluoride

MeO
MeO
RO P Br CO2Me B(OH) RO COOMe
313 R = Bn 9 NHR
NHBoc 273 R = Me NHR b
a 6
THSO' THSO
289b 312 R = Bn
316 R = Me
MeO
MeO MeO MeO

/ RO CcMe c BnO CO2Me
RO CORMe- CO, MeONH-oc

/7 NHBoc H NHBoc
NRH
O XO 314 X = Bz, R = Bn 311 R = Bn
315 R = Bn 318 X = Bz, R =Me 317 R = Me
320 R =Me d
320 R = Me d 310 X = H. R = Bn 319 X = H, R = Me

MeO

x
RONMe


x
95 R = Bn 321 R = Me

Scheme 70. Conditions: a) 0.03 % eq. Pd(PPh3)4, 2M Na2CO3, 313, PhH-EtOH, reflux; b) TBAF, THF; c) DEAD, PBu3, BzOH, THF, -10 oC rt; d) K2CO3, MeOH.



(TBAF) deprotection of the thexyldimethylsilyl group to give alcohol 311. The free Oafaced alcohol was then inverted with a Mitsunobu108,109 reaction (Scheme 70) using





84


tributylphosphine, benzoic acid and DEAD (diethylazodicarboxylate). The benzoate thus formed was hydrolysed easily with K2CO3/ MeOH to obtain the inverted free alcohol 310. With alcohol 310 in hand the next step was to attempt the Orthoester Claisen rearrangement. Typical conditions involve in-situ formation of the orthoester followed by subsequent acid catalyzed rearrangement at temperatures ranging from 160 oC to 180 oC. Using a combination of triethyl orthoacetate and catalytic amounts of propionic acid we attempted the Orthoester Claisen using three different solvent systems (Scheme 71). The reactions were run either in neat triethyl orthoacetate, xylenes or in toluene. The results obtained were quite consisitent in all three solvents. The product of the attempted orthoester-Claisen rearrangement was a compound resulting from cleavage of the ortho ester intermediate and subsequent trapping of the resultant allylic cation by our amine


MeO MeO

MeO CO2Me MeO CO 2Me
a 30
NHBoc 32 NH
HO
319 322
'322

MeO MeO MeO

MeO CO2Me MeO CO2Me MeO CO2Me
NHBoc ONHBoc INH2
OEt2
0 +
OEt
323 324 325

Scheme 71. Conditions: a) i) triethylorthoacetate, propionic acid (cat.) 1600C-1800C; ii) triethylorthoacetate, propionic acid (cat.), xylenes, 1600C-1800C; iii) triethylorthoacetate, propionic acid (cat.), toluene, 1600C-1800C.





85


functionality. We suspect that thermal and/or acid catalyzed decomposition of the carbamate protecting group leads to the free amine, which then traps the allylic cation. In the first generation synthesis (pg 68) we used the cleavage of the C-O bond (at C6 morphine numbering) to our advantage in determining the identity of our rearranged acids through a lactonization reaction. Unfortunately in this case it was a significant problem because cleavage of the ortho ester always occurred before any potential rearrangement and so we were unable to proceed further with this route towards Overman's intermediate. The identity of the orthoester-Claisen product was obtained using NMR experiments namely GHMQC and HETCOR. The sequence 5-6-7-8-14-9

6.88
.2702
3.88 0 124.1
56.0 153.1
.81
3,82 146.9 0 0 .O 3.75
60.733 .5 172.3 51.9
4.06
6.57
130.5 [' 3.29 NH 38.9
4,91 1.99
45.9 1.72
1.51 18.9
2.22
(morphine 25.8


Figure 9. Assignment of Orthoester Claisen product.


numbering) was seen by the DQCOSY spectrum (HI- HI correlation) as CH-CH-CH2CH2-CH-CH-. The aryl group was confirmed to be in position 13 by the long range couplings H(1 1)-C(13) and H(5)-C(12) as seen in the GHMBC spectrum. The methyl ester was confirmed to be in position 9 by the cross-peak H(9)-C(CO). With these correlational experiments the molecule was assembled with the exception of the two open valencies at C6 and C9. The carbon chemical shifts of the atoms suggest that they are





86


bonded to the nitrogen atom. This molecular formula was further confirmed by HRMS. From these correlation experiments the proton and carbon signals were correctly assigned as shown in Figure 9. From long range coupling experiments, the connectivity of our molecule was confirmed when we observed a long range coupling between the proton at C6 (morphine numbering) whose signal appears at 4.91 ppm and the proton on the oacenter of the amino acid (C9 morphine numbering) whose signal appears at 4.06 ppm. This was further confirmed by a long-range 'H- 13C coupling between the proton signal at 4.91 ppm and the carbon signal at 59.6 ppm, which belongs to the carbon at the ar-center (C9 morphine numbering).


Since we now had alcohol 311 in our possession, we reasoned that we could still establish the C13 quaternary center by employing a conjugate addition of an MeO MeO MeO _./
BnO COMe BnO 0 BnO 02,Me
C2M aO, Me OM


HO' NHBoc a 1 NHBoc HO NHBoc
HO 0 HO

311 326 327


Scheme 72. Conditions: a) PCC, CH2C2; b) (H2C=CH)2CuMgCI, THF, -78C. organocuprate with the enone obtained from oxidation of the alcohol. Alcohol 311 was subjected to PCC oxidation conditions to obtain enone 326. Upon addition of a vinyl cuprate, no 1,4 addition product was isolated. The major product of the reaction was the





87


1,2-addition adduct 327. It is our suspicion that because this bicyclic compound RO 0 O99

RO O


NHBoc
HO


Figure 10. Possible atropoisomerism of morphinan intermediates exhibits atropoisomerism, the aromatic ring is twisted out of conjugation with the cyclohexenyl ring (Figure 10). This probably causes the aromatic ring to be perpendicular to the cyclohexyl ring so any substituent in the 2-position of the aromatic ring (benzyl in this case) sterically hinders any attack to the C 13 center.

In summary our attempt at the Overman intermediate failed because of two main problems. The first problem, which was encountered in the orthoester-Claisen, is a trend that we had observed earlier in the synthesis (Scheme 56, pg 68) and used to our advantage. The C6 (morphine numbering) position easily ionizes if any good leaving groups are present because of the stability of the resultant allylic carbocation which is resonance stabilized by the aromatic ring. Under catalytic or stoichiometric acid conditions, the orthoester intermediates are cleaved either through an SNI or an SN2 mechanism to yield products of the type 322. The second problem is of a steric nature, cuprate addition to the Cl 3 (morphine numbering) center led to recovery of 1,2-addition products exclusively. Mulzer25 in his synthesis of morphine encountered the same problem in his attempt at conjugate addition to a similar substrate (Scheme 73). Initial model studies were successful at establishing what would be the C13 center by cuprate addition. When the same reaction was applied to more advanced intermediates 123 and





88


329 the conjugate addition yielded only 1,2-adducts. 'H-NMR spectra of Mulzer's intermediates demonstrated the presence of atropoisomers and this led to his assumption that these intermediates exhibited atropoisomerism. In our case high temperature IHNMR experiments were inconclusive because even though we observed the presence of two isomers it was impossible to determine whether the isomerism was from the carbamate moiety or due to atropoisomerism. The result of the atropoisomerism is that

MeO MeO
I i, H2C=CHMgC1,
MeO 5% CuBr-SMe,,TMSCI MeO
ii, 2N HCI

O 0
120 121

MeO
MeO
MeO i, H2C=CHMgCI, MeO
MeO 5% CuBr-SMe2,TMSCI
) -..V ii, 2N HCI /
HO
O N
123 328
MeO MeO

MeO i, H2C=CHMgCI, MeO
5% CuBr-SMe2,TMSC1
ii, 2N HCI
O HO
329 330

the aromatic Scheme 73


residue becomes more or less pependicular to the double bond hindering any attack on the benzylic sp2-hybridized carbon.





89


Alternative methods to Setting the C13 quaternary center.

At this point we had to assess the route to establishing the C 13 quaternary center. We still had a couple of options available to achieve this task. The first option was to take advantage of some of the inherent properties in intermediate 311 to establish the C 13 center. If indeed our assumption was correct and alcohol 311 (Scheme 70) was prone to exhibit atropoisomerism, then a tether at the 2-position of the aromatic ring becomes a very important group. The effect of the atropoisomerism would essentially position the tether at the 2-position of the aromatic ring in a desirable position to effect either radical or nucleophilic attack of the C13 carbon. If the attack at C13 comes from the 0-face of the molecule, this synthesis would eventually lead to morphine. An attack

MeO MeO
ORO. ,2Me

HO 02 Me ____ ,)-m
~NHR b
RO
THSO c N
331

(b(a) [ (b) (c)

MeO radical cyclization Pd cat. closure Claisen

BnO MeO Meo MeO

MeHO OMe HO O.Me HO 0O Me

Overman's intermediate R R NHR
95 R0'"g O MeO2C 0 CO.Me
332 333 334
Figure 10. Strategy for establishment of C 13 quaternary center.





90


from the ox-face would lead to ent-morpnine. The second option would be to attempt the C13 attack from the amino ester side chain either through a palladium catalyzed SN2 reaction or a radical type attack.

Before applying the alternate routes to the establishment of the C 13 center to the morphinan intermediates we decided that a quick model study to ascertain the feasibility of these reactions would be in order. We prepared enone 340 and silyl ether 343 as shown in Scheme 74 from phenol and 1,3-cyclohexadione (337). Cleavage of the MOM


aO
HO MOMO MOM 1
335 336 MOMO e
O c O
0 0 Br 02

b] Io o
O EtO 339 340
337 338

o
0
0
0 0
341


0 0
MOMO hi MOMO e,f g

2Br
0 TDSO TDSO TDSO
339 342 343 344

Scheme 74. Conditions: a) MOM-Cl, Nail, THF; b) EtOH, pTsOH, Phil; c) t-BuLi, THF; e) H /THF; f) Bromoacetylbromide, DMAP, CH2CI2; g) nBu3SnH, AIBN, Phil; h) NaBH4, MeOH; i) TDS-Cl, imidazole, DMF.





91


protecting group from the bicycle 339 afforded the intermediate alcohol, which was converted to the bromoacetate 340 the radical cyclization precursor. Silyl ether 343 was obtained from intermediate 342 after cleavage of the MOM-protecting group and subsequent appendage of the bromoacetate. The two bromoacetates were then subjected to radical conditions using a protocol previously used by Ogasawara6o and coworker in their synthesis of 3,4-dimethoxy-7-morphinanone (pg 39, Ch. 1). The radical reaction failed to produce any cyclized product in the case of silyl ether 343. Instead we observed the formation of the reduced product exclusively. This was not unexpected due to the fact that for that cyclization to work the reaction had to proceed from a stablilized ester radical to an unstable radical. On the other hand enone 340 subjected to the same conditions yielded the cyclized product 341 in 66% yield with recovery of about 15% of reduced product. With the success of the model study our attention focused on its application to the morphine synthesis.

Our goal was to achieve the synthesis of intermediates of the type 345 or 347

MeO MeO

0 CO2Me 0 02Me
Br NHBoc 0 NHBoc
THSOMeO
THSO 345 THSO' 346 Mo
345 346
HO CO2Me

MeO MeO e
o ...... o 4
THSO
O CO2Me -- CO2Me 349
Br 01 NHBoc 0 NHBoc

OO
347 348

Scheme 75





92


(Scheme 75) in order to apply our model study to real morphinan intermediates. A successful radical closure would lead to the establishment of the C13 quaternary center; this would be followed by a translactamization reaction after deprotection of the Bocgroup to establish the nitrogen bridge as shown in Scheme 75.

The first order of business was to redesign our aromatic ring with a protecting group in the 2-position that could be cleaved readily to allow for the appendage of the bromoacetyl group. The first protecting group we worked with was the TBS-group. Bromoguaiacol 150 was readily converted to the TBS ether using triethylamine, DMAP and TBS-CI. Unfortunately in the next step that involved the lithium halogen exchange and alkylation using triisopropyl borate, we realized that the TBS-group was too bulky

Br Br
OH a 5 OTBS b OTBS

(Me (Me -OMe
150 350 351

Scheme 76. Conditions: a) TBS-CI, Et3N, DMAP, CH2Cl2; b) B(Oipr)3, H' hence preventing the subsequent alkylation step. The only material isolated from the reaction was starting material and the reduced product 351 (Scheme 76). We were able to confirm the formation of the anion using deuterium exchange experiments. So we realized that the problem lay in the alkylation step. The next protecting group considered was the paramethoxybenzyl group (PMB). This was in theory an ideal protecting group for our synthesis because we had prior experience (in our approach to the Overman intermediate, Scheme 69, pg 83) on the synthesis of the benzyl protected boronic acid and reasoned that the synthesis of the PMB boronic acid would be analogous. Most importantly this group could be cleaved with DDQ, which in our estimation would not





93


affect any of our chiral centers or other protecting groups. Using K2CO3 and acetone we protected bromoguaiacol as the PMB ether. In the subsequent step we successfully synthesized the boronic acid 353 using n-BuLi and triisopropyl borate.

Br Br B(OH)2
OH OPMB b OPMB

OMe OMe OMe
150 352 353

c

MeO MeO

HO CO Me d PMBO O2Me

9- NHBoc NHBoc

THSO" THSO"
355 354

Scheme 77. Conditions: a) PMB-Br, K2CO3, Acetone; b) n-Buli, B(oipr)3, H'; c) 0.03 % eq. Pd(PPh3)4, 2M Na2CO3, 289b, PhH-EtOH, reflux; d) DDQ, H20, CH2CI2. The Suzuki coupling of the boronic acid with methyl ester 289b (Scheme 77) worked quite well to afford PMB ether 346. At this point we attempted cleavage of the PMB group in order to append the bromoacetyl group on the phenol. Unfortunately this step led mostly to decomposition of our starting material. With the failure of the PMB route

Br
OH OH

OMe OMe
150 271

Scheme 78. Conditions: a) n-Buli, B(oipr)3, H+;




Full Text
29
Recent Related Developments
In addition to the Claisen approach to the morphine skeleton, the Hudlicky group
is actively pursuing two other approaches toward the morphinan skeleton namely an
intramolecular Diels-Alder approach and a Heck coupling cascade approach.
Hudlicky, Boros and Boros54 were able to synthesize the B-, C-, and O- rings
using a combination of three important transformations, microbial oxidation,
intramolecular Diels-Alder cycloaddition and a Cope rearrangement. Starting from
toluene, which was subjected to microbial oxidation to yield diol 138, protection of the
distal hydroxyl group afforded the thexyldimethylsilyl ether 139. Alkylation of the
proximal hydroxyl group with sorbyl bromide rendered the tetraene 140. The substrate
was now ready for an intramolecular Diels-Alder reaction. The Diels-Alder
* C9 (morphine numbering)
Scheme 30 Conditions: a) Toluene dioxygenase; b) THSC1, imidazole, DMF; c) NaH,
sorbyl bromide, THF, 0 C to rt., 30h.; d) CC14, 77 C, 7h.; e) nBu4NF-3H20, THF; f)
PCC, CH2C12, rt.; g) xylenes, sealed tube, 250 C, 22h.; h) NaBH4, CeCl3-7H20, MeOH,
rt., 15 min.
reaction could possibly take two reaction pathways namely, diene k, 1 with dienophile m
(Scheme 30) or diene m, n with dienophile k. The latter reaction pathway involving diene


MeO
PULSE SCQUtNCE
Pul* 31.1 degrees
Acq. tl* 0.500 *9C
Width 15751.7 HZ
1024 repetition*
053ERVE CIS, 75.4542017 MHZ
OECOUPLE Hi, 300.0750122 MHZ
Power 30 d6
continuously on
WALTZ*15 BOduleted
OATA PROCESSING
Un broadening 3.5 Hz
FT *1Z* 32755
Total t1 1 in, 4 sec
MoO
NHBoc
OTDS


26
Another interesting discovery was made during this model study. After preparing
a more elaborate substrate 124 from the addition of ortholithiated veratrole to the
vinylogous ester 122 followed by hydrolysis and dehydration. Enone 123 after reduction
was subjected to Eschenmoser-Claisen rearrangement conditions. The results were
similar, even though rearranged product was obtained the yields were low. More
interestingly after cleavage of the terminal double bond of amide 125 (Scheme 28) to
obtain the aldehyde 126, all attempts at closing the B- ring failed completely. Mulzer
explained these results using the theory that repulsive interactions between the ortho-
methoxy group and the substituents a-to the C13 carbon (morphine numbering) on the
cyclohexyl ring. This steric interaction causes the aromatic ring to twist out of
conjugation with the double bond in the cyclohexyl ring. This assumption had merit
because 'H- NMR of the allylic alcohol clearly showed the two rotomers reminiscent
O
MeOH
NaBH
Et20
2. NH4Cl(aq)
OH
122
O
124
123
OMe
MeO
MeO.
MeC(OMe),NMe:
Xylenes, 24%
1 0s04, NMO
Acetone, H20
2. NaIO EtOfcl Me0
,NMe.
O
O
o
125
126
127
Scheme 28
of the known atropisomerism found in biphenyls. The result is a highly adverse steric
influence at the benzylic sp -hybridized carbon by the aromatic ring. The apparent


none
Pulse Sequence : e2pu1
Solvent: CDC13
Teap- 25 0 C / 288 1 K
Mercury-300 "aercury300"
PULSE SEQUENCE
Pulee 30.1 degree*
Acq. tlae 4.000 tec
Width (313.1 Hz
If repetitions
OSSERVE HI, 2M. 7253(90 MHZ
DATA PROCESSING
Cause apod 1zation 1.429 tec
FT size (553(
Total tas 1 am, 7 tec


106
3-tert-butoxvcarbonvlamino-7a-(2,3-dimethoxyphenyl)-3S,3aS.7aS )-2,3,3a,4,5,7.7a-
hexahvdrofblfuran-2-one (279):
To the crude epimeric mixture of amino acids 278 (0.50 mmol, 0.30 g) was added
a catalytic amount of p-TsOH in CH,C1., (20 ml) and allowed t0 st¡r overnight. The
reaction mixture was diluted with ethyl ether and washed with NaHCOi solution (30 %, 2
X 10 mL). The organic layer was dried with MgS04 and the solvent evaporated under
reduced pressure. The lactone (279) was successively separated by column
chromatography via gradient elution (hexanes: ethyl acetate, 99:1 9:1) to yield white
crystals of A (0.10 g, 65 %); Rf = 0.5 (ethyl acetate: hexanes, 1:4); [Id 96.0 (c 1.0,
CHC13); 'H NMR (CDCI3) 5: 7.1 -6.9 (m, 2H), 6.8 -6.7 (m, 2H), 6.2 (m, 1H), 5.7 (dt, J =
10.0, 1.0 Hz, 1H), 4.9 (d, J = 5.7 Hz, 1H), 4.5 (dd, J = 7.9, 3.0 Hz, 1H), 3.8 (s, 3H), 3.7 (s,
3H), 3.3 (dtd, J = 11.5, 3.5, 1.0 Hz, 1H), 2.3 -2.2 (bm, 2H), 1.7 1.6 (m, 1H), 1.4 (s, 1H),
1.3 (s, 9H); 13C NMR (CDC13) 5: 174.9, 155.3, 153.4, 135.1, 132.5, 126.9, 123.6, 117.2,
112.9, 82.8, 80.3, 59.9, 55.8, 54.1, 42.9, 29.7, 28.2, 22.8, 20.5; IR (KBr/ cm1): 2932,
2253, 1776, 1716, 1506, 1475, 1263; LRMS (Cl/ CH4) m/z (rel. intensity) 389 (m+, 70),
334 (65), 228 (100); HRMS Caled, for C22H36NO6 (m+1) Caled.: 389.2464; Found:
389.5326. Anal Caled, for C23H35N06: C, 64.70; H, 6.90; Found: C, 64.36; H, 6.64.


12
Scheme 11
Schwartz, 4243 in a biosynthetically designed synthesis, used thallium (ID)
trifluoroacetate to effect the ortho-para coupling of N-acylnorreticuline 43, affording the
corresponding salutaridine derivative 44 (Scheme 12). Reduction of this intermediate
with LAIH4 followed by O-ring closure with HC1 resulted in the formation of thebaine
and resulting in a formal total synthesis.
Scheme 12


Solvent i C0C13
A*b1*nt tMpr tur
Marcury-300 "rcury300"
pulse sequence
Puli* 391 d*gr
Acq t1b# 4.000 *c
Width 9313.1 Hz
19 ropotltlonc
OBSERVE HI, 289.75794H MHZ
DATA PROCESSING
Caui apod nation 1 429 iac
FT 1za 95539
Total 11 0 m, 0 aac
. x jJ
L
o
T
3
T
2
-|i i 1 |r
1 PP


15
Scheme 15
A third report in 1983 by White47 described an oxidative coupling approach to (-)-
codeine 2 (Scheme 16). After protection and bromination, (-)-Norreticuline 62,
Scheme 16


99
Reformatsky type reaction to establish Cl3. The morphinan intermediates allow for these
reactions to be attempted either from the nitrogen side chain or from a tether on the
phenol.
Establishment of the C13 center would be followed by a translactamization
reaction to afford the nitrogen bridged intermediate of the type 369. After a Friedel-Kraft
reaction this intermediate begins to look very similar (Scheme 86) to one of the Gates
intermediates 370 from which morphine was synthesized in an additional 7 steps.
Scheme 84
In the course of the project we have also looked at ways to make this approach to
morphine, practical. To this effect, we attempted the direct oxidation of intermediate 364
using a catechol dehyrogenase enzyme, which was recently discovered in the Hudlicky
research group. Success of such a transformation would eliminate 4 synthetic steps


IMP. 29 0 C / 2911 K
Mercury-300 "Brcury300"
PULM SCQUCMCC
Pul* 391 dnr
Acq t1 4.000 *C
width 4313.1 H2
14 repetition*
OOSCRV HI, 299.7449129 MHz
OATA PQOCC&SXMC
Cau* podl2tlon 1-429 *c
FT *12 49934
Total ti 1 am, 7 *c
j i i r
18
T*I~T~T*1 T 1 > f T t T I |-l
16 14
I | I TT
12
1 1 1 1 ^
10
. Li-AlU U
I I l l I ; I I I l"| l I I l ~| I l i I I I '' | 1 1 1 1 1 1 1 1 | 1
42-0 PP
t-Tt-t
6


64
Claisen I-First attempt of Kazmaier Claisen on Morphine Precursor
To perform the Claisen rearrangement, we planned to take advantage of the remaining
allylic alcohol unit in the bicyclic intermediate 270. In order to ensure selective
conversion of the proximal hydroxyl group into the glycinate ester we first had to protect
the distal hydroxyl group as its silyl ether. The thexyldimethylsilyl (TDS) group was well
suited for our substrate because its bulky nature ensures the protection of the least
hindered hydroxyl group, which in this case is the distal hydroxyl. Yields for the step are
typically around 90% for TDS-ether 276. Less bulky silylating groups like TMS-C1 tend
to lead to a large percentage of product resulting from lack of selectivity in the protection
of the distal and the proximal hydroxyl groups. The reaction involves first, generating the
imidazole-TDS complex at -12 C followed by addition of the diol (270) to the reaction
mixture. Our efforts led to isolation of silyl ether 276 (Scheme 54). The next stage in the
synthesis required the functionalization the proximal hydroxyl group as a glycinate ester,
Scheme 54
277


33
/?-bromoethylbenzene 160 was subjected to enzymatic conditions with the expectation
that the larger bromoethyl group would direct the c/s-dihydroxylation. This assumption
proved to be correct because diol 161 was isolated from the fermentation broth using E.
coli JM109 (pDTG601A). Diimide reduction of 161 followed by acetonide protection of
the cd-diol moiety provided the dibromide 162. Introduction of
Scheme 34 Conditions: a) JM109 (pDTG601); b) PAD, HOAc; c) DMP, /?TSA; d) 2-
oxazolidone, NaH; e) B^SnH, AIBN, benzene reflux.
the oxazolidone gave 163, which upon exposure to radical conditions gave a 2:1 mixture
of octahydroisoquinolones 164a and 164b in favor of the isomer with an ep\-C9
configuration (Scheme 34). The lack of stereo control was attributed to the negligible
steric effect of the acetonide. Since the ep/-isomer was in greater availability the decision
was made to pursue the synthesis of erci-morphine. Mitsunobu inversion with
bromoguiacol generated the precursor for the second radical cyclization, ether 166.
Treatment with Bu3SnH/AEBN gave pentacycle 167. To complete the synthesis of the
ent-morphinan, the silyl-protecting group was removed followed by reduction of the


51
235 to give the isomer with correct stereochemistry at C9 and C14 (morphine
numbering).
Inspired by the work of Kazmaier and the subsequent application of this
chemistry by Hudlicky and co-workers78,79 in their approach to the morphine skeleton,
Percy79 and co-workers investigated the possibility of generating y-oxo-P,(3-difluorinated
amino acids by chelated [3.3]-sigmatropic rearrangement of protected glycinate esters of
readily available difluoroallylic alcohols. This type of rearrangement had the potential to
produce amino acids having a CF2 center a to a carbonyl functionality through release of
the masked carbonyl group (Scheme 46).
F2C
OMEM
)
1. 3 eqiuv. LDA
THF, -78C
2. HCHO
237
OMEM
F OH
238
NHX
O
240
1. 3 equiv. LDA
THF, -78C
2. ZnCl2
w
Scheme 46
OMEM
The synthesis started with difluoroallylic alcohol 238, which was converted into the
glycyl ester 240 under DCC coupling conditions. The glycinate was then subjected to
modified Kazmaier Claisen condition which involves the use of 3 equivalents of LDA
added in a reverse addition order to that proposed by Kazmaier (the Lewis acid is added


o*OMc
TDSO
r
^V^'NHBoc
j*l_7\ 1
1.00
0.92
0.01
1.01
0.01 2.06
/V
Aim
LL
i|
pp
9.19
0.19
9.79
19.09


CHAPTER 5
EXPERIMENTAL SECTION
General Procedure
All non-hydrolytic reactions were carried out under a nitrogen or argon
atmosphere, with standard techniques for the exclusion of moisture. Glassware used for
moisture sensitive reactions was flame dried with an internal inert gas sweep. Analytical
TLC was performed on Whatman K6F silica gel 60A plates. Flash chromatography was
performed on chromatographic silica gel, 230-400 mesh (Fisher Chemical). Infrared
spectra were recorded on a Perkin-Elmer FT-IR (KBr). Proton, fluorine and carbon NMR
spectra were obtained on a Varian 300MHz spectrometer using CDCI3/ TMS unless
otherwise indicated in the experimental section or in the case of fluorine NMR spectra, a
CFCI3 standard was utilized. Proton chemical shifts are reported in parts per million
(ppm) relative to chloroform (7.24 ppm) or DMSO-4 (2.49 ppm). Carbon chemical shifts
are reported in parts per million relative to the central line of the CDCI3 triplet (77.0 ppm)
or the central line of the DMSO-/ septet (39.7 ppm). Coupling constants (7) are given in
Hz. Optical rotations were recorded on a Perkin-Elmer 241 digital polarimeter (10'1 deg.
cm g' ). Melting points were obtained on a Thomas-Hoover capillary melting point
apparatus. High resolution mass spectra and elemental analyses were performed at the
University of Florida and Atlantic Microlab Inc.
102


STANOARO hi PARAMETERS
Puls* Sequence: s2pu1
Solventt COC13
Ambient temperature
VXR-JOOS "vKrSOO**
PULSE SEQUENCE
Pulee S7.e degree
Acq. 11 me 3.744 sec
width 4000.0 HZ
14 repetitions
OBSERVE Ml, 219.1468566 Mhz
OATA PROCESSING
Oauss apodlzatlon 2.228 sec
FT Size 32788
Total time 4 min, 0 sec
MeO
BnO
BzO
jL 1AjL-JV L
T
z
-0
T
PP


BIOGRAPHICAL SKETCH
Kofi Oppong was born in Islington, England on July 10, 1969. He attended
elementary school at St. Martin de Porres School and high school at Accra Academy and
Okuapeman Secondary School in Accra Ghana. He obtained admission to the University
of Indianapolis in 1989 to study Organic Chemistry under both an athletic and a
Presidential scholarship. After completing requirements for an Associates Degree in
Chemistry, he obtained employment at DowElanco Pharmaceuticals now Dow
AgroSciences working as a chemistry technician. At DowElanco he worked in the area of
fluorine chemistry under Professor Melvin Druelinger of the University of South
Colorado on sabbatical at DowElanco during that time. Upon completion of his Bachelor
of Science degree in chemistry he decided to pursue graduate studies in Organic
Chemistry specifically in the natural product synthesis area under the direction of
Professor Tomas Hudlicky at the University of Florida. His Ph.D research has focused on
chemoenzymatic approaches to the synthesis of molecules of different complexity. His
major area of focus has been in the synthesis of morphinan intermediates utilizing a
combination of enzymatic and basic synthetic organic chemistry methods. After graduate
school he plans to pursue a career in industry as a medicinal chemist. His life goal is to be
directly involved in the synthesis of one major drug.
188


113
2-(4-dimethvlthexvlsilvloxv-2-Cvclohexenvl)-2R-N-frt-butoxvcarbonvlmethvl
glvcinate (295)
To vinyl bromide 293 (0.70 mmol, 0.34 g) was added to a mixture of catalytic amount of
Adams Catalyst, triethylamine (0.70 mmol, 0.73 mL) and methanol (5.0 mL). The
reaction vessel was evacuated and the solution stirred under hydrogen atmosphere (40
psi) for 3h. After completion of the reaction (as observed by TLC), the suspension was
filtered and the solvent concentrated under reduced pressure. The solid residue was
diluted with ethyl acetate (10 mL) and washed with water (2X2 mL), followed by
NaHC03 (2X2 mL). The organic layer was dried with Na2S04 and concentrated to
afford white crystals of 295 (0.30 g, 89%); Rf = 0.65 (ethyl acetate:hexanes, 1:6); [a]o26
-4.9 (c 1.0, MeOH); 'H NMR (CDC13) 8; 5.05 (d, J = 9.1 Hz, 1H), 4.22 (q, J = 4.5 Hz,
1H), 3.93 (bs, 1H), 3.70 (s, 3H), 1.78-1.44 (m, 8H), 1.41 (s, 9H), 0.88 (d, J = 6.4 Hz, 6H),
0.81 (s, 7H), 0.02 (s, 6H); ,3C NMR (CDC13) 5:172.77, 155.42, 79.51, 65.68, 57.90,
51.95, 40.45, 34.39, 32.90, 28.27, 24.74, 22.86, 21.63, 20.29, 18.62, -3.04; IR (CDC13/
cm'1): 3440, 2929, 1755, 1712, 1503, 1162; HRMS Caled, for C22H44NSO5 (M+l):
430.2922; Found: 430.2988; Anal. Caled, for: C22H43NSi05: C, 61.50; H, 10.09; Found:
C, 61.57; H, 10.12.


I certify that I have read this study and that in my opinion it conforms to
acceptable standards of scholarly presentation and is fully acceptable, in scope and
quality, as a dissertation for the degree of Doctor of Philosophy.
I certify that I have read this study and that in my opinion it conforms to
acceptable standards of scholarly presentation and is fully acceptable, in scope and
This dissertation was submitted to the Graduate Faculty of the Department of
Chemistry in the College of Liberal Arts and Sciences and to the Graduate School and
was accepted as partial fulfillment of the requirements for the degree of Doctor of
Philosophy.
August, 2001
Dean, Graduate School


89
Alternative methods to Setting the C13 quaternary center.
At this point we had to assess the route to establishing the C13 quaternary center.
We still had a couple of options available to achieve this task. The first option was to
take advantage of some of the inherent properties in intermediate 311 to establish the C13
center. If indeed our assumption was correct and alcohol 311 (Scheme 70) was prone to
exhibit atropoisomerism, then a tether at the 2-position of the aromatic ring becomes a
very important group. The effect of the atropoisomerism would essentially position the
tether at the 2-position of the aromatic ring in a desirable position to effect either radical
or nucleophilic attack of the C13 carbon. If the attack at C13 comes from the p-face of
the molecule, this synthesis would eventually lead to morphine. An attack
Claisen
MeO
CO,Me
Figure 10. Strategy for establishment of C13 quaternary center.


IX OISCRVC


76
was the undesired isomer from the Kazmaier Claisen rearrangement (Scheme 63).
Scheme 64
We prepared a series of cyclohexylglycine and cyclohexylalanine derivatives of the type
296 and 303 (Scheme 64) to be utilized as intermediates for the synthesis of MMP
inhibitors. Also as part of the collaborative project, the absolute stereochemistry of ester
289a was determined unambiguously by X-ray crystallography (Figure 7). Esters 296 and
303 were synthesized using similar protocol as has been described earlier in the chapter.
Approaches to compounds of this type through enolate alkylation or aldol type
condensations are quite difficult, hence the Kazmaier Claisen provides a direct route to
these unnatural amino acids with control of stereoselectivity and respectable yields.
Starting from the diol 247, a two step sequence involving protection of the distal
hydroxyl group as the TBS-ether, followed by esterification of the proximal hydroxyl
group by DCC coupling rendered gylcinate ester 292 (Scheme 65). We achieved the
rearrangement to the corresponding acids via Kazmaier Claisen conditions.
Diazomethane was then utilized in the conversion of the acids to the methyl ester
derivatives. The next step involved reduction of the vinyl bromide with Adams catalyst
at 40 psi with triethylamine as the proton scavenger. Finally tetrabutyl ammonium
fluoride mediated deprotection of the TBS group rendered the alcohol 296 which


120
2-(4-dimethlthexvlsilvloxv-2-(2-benzvloxv-3-methoxvphenvl)-(lS,4R)-2-cvclohexenyl-
2S-N-frr-butoxvcarbonvlmethvlglvcinate (312).
To a two neck round bottom flask fitted with a condenser under an argon
atmosphere was added Pd(PPh3)4 (7.00 mmol, 0.010 g). This was followed by addition of
dry benzene (15 mL). A solution of the vinyl bromide 289b (0.350 mmol, 0.176 g)
dissolved in benzene (5 mL) was then added to the reaction flask. This was followed by
the addition of NaiCC^ (2.0 M, 0.60 mL), to the mixture. Boronic acid 313 (0.26 mmol,
0.07g) dissolved in benzene (5 mL) was then added to the reaction mixture, which was
allowed to reflux for 6h. The reaction was quenched with water and the product extracted
with ethyl acetate (3 X 20 mL). The organic layers were combined, washed with brine
and dried over anhydrous MgS04. After filtration the solvent was removed, the crude
product introduced onto a silica gel column, and eluted with ethyl acetate: hexanes (1/3)
to obtain 312 (0.10 g, 70%) as a light yellow oil; Rf = 0.35 (ethyl acetate: hexanes, 1:4);
[ot]D29 +26.7 (c LO, CDCI3); 'H NMR (CDCI3) 8: 7.31 (m, 5H), 6.95 (t, J = 7.8 Hz, 1H),
6.85 (d, J = 7.9 Hz, 1H), 6.58 (d, J = 7.3 Hz, 1H), 5.77 (d, J = 4.6 Hz, 1H) 5.02 (d, J =
11.2 Hz, 1H), 4.91 (d, J = 11.2 Hz, 1H), 4.82 (d, J = 7.3 Hz, 1H), 4.13 (m, 1H), 3.96 (q, J
= 4.0 Hz, 1H), 3.85 (s, 3H), 3.62 (s, 3H), 3.46 (q, J = 7.0 Hz, 1H), 1.78-1.49 (m, 4H),
1.36 (s, 9H), 1.24-1.17 (m, 5H), 0.91 (d, J = 6.7 Hz, 6H), 0.86 (s, 7H), 0.11 (d, J = 8.5
Hz, 6H); 13C NMR (CDC13) 8:172.46, 155.11, 152.24, 144.93, 139.82, 137.82, 135.16,
132.17, 128.16, 128.13, 127.66, 124.24, 122.04, 111.77, 79.19, 74.72, 63.37, 55.69,
54.64, 51.91, 38.48, 34.33, 29.82, 28.28, 27.96, 24.84, 20.38, 18.62, 18.35, 17.91, 15.23,
-2.35, -2.87; IR (CDC13/ cm'1): 3370, 2989, 2959, 1750, 1720, 1698, 1520, 1505, 1454;
HRMS Calcd.for C36H53NO7S (m+): 639.9104 ;Found: 639.9102.


116
6-Bromo-2-dimethylthexvsilvloxv-( 1 S,2R)-5-cyclohexen-1 -vl-N-tert-
alanylcarbonvlglvcinate (301).
A solution of N-Boc-alanine (6.600 mmol, 0.30 g), DCC (9.00mmol, 1.90 g),
DMAP (catalytic) in dichloromethane (10 mL/mmol) was cooled to 0 C and a solution
of the TBS protected diol 298 (6.000 mmol, 2.20 g) in dichloromethane (40 mL) was
added by syringe and the reaction mixture stirred overnight while it was allowed to reach
room temperature. The solution was diluted with ethyl ether and filtered through a bed of
silica gel to remove the precipitate of dicyclohexylurea. Removal of the solvent and
chromatography (silica gel, hexanes:ethyl acetate, 90:10) of the residue, afforded the pure
ester as a light yellow oil (2.40 g, 71%); Rf = 0.5 ethyl acetate :hexanes, 1:6; [oc]d28 -
68.1 (c 1.0, CHC13); H NMR (CDC13) 5: 6.26 (dd, J = 2.6, 5.1 Hz, 1H), 5.53 (d, J = 3.9
Hz, 1H), 5.13 (d, J = 8.1 Hz, 1H), 4.40 (q, J = 7.2 Hz, 1H), 3.94 (dt, J = 3.7 Hz, 1H),
2.32-2.01 (m, 1H), 1.83-1.62 (m, 2H), 1.45 (s, 3H), 1.43 (s, 9H), 0.82 (s, 9H), 0.05 (s,
3H), 0.02 (s, 3H); 13C NMR (CDC13) 8: 172.49, 157.77, 134.67, 1171.71, 79.36, 73.73,
69.37, 67.85, 49.12, 28.24, 25.79, 24.51, 25.64, 25.60, 25.55, 19.15, 18.01, -5.08, -5.17;
IR (KBr/ cm'1): 3435, 2952, 2928, 2855, 1747, 1714, 1649, 1163; HRMS Caled, for
C2oH36BrNSi05 (M+): 478.1636; Found: 478.1624. Anal. Caled, for C2oH36BrNSi054: C,
50.20; H,7.58; Found: C, 50.19; H, 7.64.




71
for a successful Friedel-Craft closure.
Scheme 59. Conditions: a) Oxalyl chloride, DMF, CFLCL; b) PPh3, CCI4, THF; c) Lewis
acid (AICI3, MejAlCl, ZnCU and SnCU).
Claisen II-Ireland Claisen on Phthalovl Ester
Our goal still remained to improve the selectivity of the Kazmaier Claisen
rearrangement. One of the options we had not explored was a sigmatropic rearrangement
zc on nrv
under Ireland conditions, which we hoped might lead to an improvement in the
ratio of rearranged epimeric acids. To attempt the Ireland-Claisen rearrangement, we first
functionalized the silyl ether 276 into the phthaloylester 285 (Scheme 60). Under Ireland
conditions, we observed good conversion of starting ester to products but the product
ratio again favored the undesirable epimer 286a. More importantly, the epimers were also
difficult to separate by column chromatography.


44
constricted due to chelation with the counter ion. While Bartlett64 had always converted
the enolate into the silylketene acetal, Kazmaier discovered that by allowing the chelated
enolates (Figure 1) to simply warm up from -78 C to about -15 C resulted in
OR
M: metal
Y: protecting group
217
Figure 1. Nature of Chelated Enolate in Kazmaier Claisen Rearrangement.
rearranged products in excellent yields and also high diastereoselectivity. The chelated
enolates had several advantages. Since the chelated enolates are significantly more stable
than the corresponding non-chelated lithium enolates, they can be warmed to room
temperature without decomposition and side reactions such as ketene formation via
elimination can be suppressed. Secondly because of the fixed enolate geometry due to
chelation, the reactions proceed with high diastereoselectivity. Due to the inherent
flexibility of this chemistry, many variations of protective groups Y (Figure 1) can be
used. Varying the metal M used can also modify the selectivity and reactivity of the
reaction. Since the coordination sphere of a metal ion is not saturated in a bidentate
enolate system, this allows for additional coordination with external ligands. Lastly
transformation of the high-energy ester enolate into a chelate-bridged stabilized
carboxylate provides a good driving force for the reaction.
When this reaction was applied to acyclic allylic esters the results obtained
confirmed a preferred chair-like transition state. Even though different Lewis acids were
utilized, ZnCh produced the best results (Scheme 42). The formation of the syn product


82
attempts at the Friedel-Craft reaction were unsuccessful we were hopeful that with the
construction of the nitrogen bridge, this precursor would have a more rigid structure with
the aromatic ring in a favorable position to effect cyclization (path y, Scheme 68). The
key step in this synthesis would be the setting of the Cl3 quaternary center by a [3,3]-
sigmatropic rearrangement. The options available were an Ortho-ester Claisen104105
rearrangement or an Eschenmoser106,107 type Claisen rearrangement using the allylic
alcohol moiety in precursor 310 (path x, Scheme 68). Alcohol 310 could in turn be
synthesized through a Mitsunobu108, reaction of alcohol 311. Compound 311 could be
achieved from a two-step sequence involving a Suzuki reaction to couple the methyl ester
and the aromatic boronic acid followed by a fluoride deprotection of the silyl ether.
Boronic acid 313 was synthesized (Scheme 69) using the same protocol that was used for
the synthesis of the dimethoxy boronic acid 273 (pg 61) with similar results in terms of
yield. With boronic acid 313 in hand we were able to achieve coupling with ester
B(OH)2
,OBn
OMe
313
Scheme 69. Conditions: a) Br2, tert-butylamine, toluene, -78 C, 60-62 %; b) BnBr,
K2C03, Acetone, rt 90-94 %; c) Mg, I2 (cat.), B(OEt)3, NH4C1 (satd), 82-86 %; d) t-
BuLi, B(OEt)3, NH4C1 (satd), 75-80 %.


16
underwent successful and selective para-para coupling to afford salutaridine analogue
63, which was further manipulated to bromothebaine 64. Simple hydrolysis followed by
double bond migration afforded the Gates intermediate 65 which on treatment with
LiAlH4 gave (-)-codeine 2.
In 1986, Schafer48 reported another oxidative coupling approach to salutaridine
(Scheme 17). Formamidine 67 was coupled with bromide 66 and the product
MeO OMe
N^tBu 68 16
Scheme 17
reductively cleaved to afford the cyclization precursor 68. Cyclization was achieved
using TiCl4 and subsequent rearomatization of the A-ring using DDQ afforded
salutaridine 16 in 3% overall yield in 15 steps.
In 1987, Fuchs49 reported a total synthesis of morphine using a tandem coupling
reaction to construct the morphinan skeleton. His approach to the morphinan skeleton
used an intramolecular conjugate addition/alkylation sequence in which connections 02-
03 and C9-C14 were formed as a result of one-tandem process. Coupling of aryl 69 to
alcohol 70 under Mistunobu conditions followed by deprotection and an
oxidation/reduction sequence afforded ether 71 with the desired cis stereochemistry
(Scheme 18). The tandem cyclization was achieved by treatment of ether


61
as a result of poisoning of the bacteria by the oxygenated substrate (Table 6). The low
yields that accompanied the biooxidation of 267 to diol 270 the morphine precursor
prompted us to seek other ways of constructing this bicyclic skeleton with the intent of
functionalizing it appropriately into the morphinan skeleton.
This dissertation will focus on the progress made in the second generation of the
chemoenzymatic approach to morphine. The discussion will address how control of the
C9 and C14 centers of morphine was achieved through the use of the Kazmaier-Claisen
rearrangement and epimerization. It will also give an account of the progress made
toward a formal total synthesis of morphine via Overmans intermediate. In addition
some applications in the field of matrix metallo proteinase inhibitors, compounds that are
connected to morphinan intermediates through common structural elements will be
discussed. Finally recent advances in the chemoenzymatic approach to morphine will
also be discussed.
First Generation Synthesis- Control of C9 and C14 Stereocenters of Morphine
The first few steps in the synthesis focused on the Suzuki Coupling protocol in the
synthesis of biphenyl diol derivative 270 (Table 6) which would then be functionalized
into a glycinate ester. Starting from guaiacol (271), a known compound, which is not
commercially available, we employed a procedure used by Hoshino83 and coworkers in
their synthesis of lycoramine. It involves first, the generation of a tert- butylamine
bromine complex by addition of bromine to the amine at -68 C for a 24 48 hour period.
After formation of the complex, which is the actual brominating agent, the reaction
mixture is cooled back to -78 C at which time a solution of guaiacol dissolved in
minimum amount of methylene chloride is added dropwise (Scheme 51). The reaction


17
75 74 73
Scheme 18
71 with n-BuLi, which led to the closure of the Cl2- Cl3, bond and subsequently
underwent alkylative closure of the final ring to yield the tetracycle 72. After oxidative
cleavage of the olefin to the corresponding aldehyde the nitrogen was introduced by
reductive amination and protected as the trimethylsilylethoxycarbonyl ester, and finally
oxidation followed by enol ether formation afforded 73. Base catalyzed elimination of the
sulfonyl group followed by oxidation with DDQ gave dienone 74. Upon removal of the
protecting group, a 1,6-Michael type addition afforded codeinone 21 as well as the
nonconjugated neopinone, which could be readily isomerized to codeinone under
conditions reported by Rapoport and Barber.50 Fuchs completed his total synthesis by
converting codeinone to racemic morphine with reduction and final demethylation.


54
contain the correct stereochemistry at the C9 and C14 (morphine numbering) centers of
morphine.
In the initial model studies, as reviewed in the historical chapter it was discovered
that even though the Claisen rearrangements proceeded with low stereoselectivity, there
was the potential to achieve complete control of the C9, C14 stereocenters through
equilibration of isomers. Efforts in the initial stages of this approach were also directed at
finding efficient ways of obtaining the bicyclic skeleton One of the opportunities for
construction of this bicycle was through direct enzymatic dihydroxylation of substituted
biphenyls. Indeed when selected biphenyls were subjected to biooxidation conditions, the
resultant diene diols were obtained. Unfortunately it became apparent that as the degree
of oxidation in the substrate increased, the yield for the enzymatic process decreased
considerably probably as a result of poisoning of the bacteria by the oxygenated
substrate.
This dissertation will focus on the progress made in the second generation of the
chemoenzymatic approach to morphine. The discussion will address how control of the
C9 and C14 centers of morphine w-as achieved through the use of the Kazmaier-Claisen
rearrangement and epimerization. It will also give an account of the progress made
toward a formal total synthesis ,of morphine via Overmans intermediate. In addition
some applications in the field of matrix metallo proteinase inhibitors, compounds that are
connected to morphinan intermediates through common structural elements will be
discussed. Finally recent advances in the chemoenzymatic approach to morphine will
also be discussed.




58
second Claisen rearrangement. The amino acid 254 is also set up for closure of the C10-
Cll using a Friedel-Craft reaction after conversion of the acid into the aldehyde or the
acid chloride. Before the discussion proceeds into the actual execution of the approach, a
brief history about the development of the chemistry of enzymatic dihydroxylations
would be in order.
In 1968 as a result of studies conducted by David T. Gibson87 on the microbial
oxidation of aromatic hydrocarbons by soil bacteria, the first stable ds-diol 256 was
wild strain of P. putida FI
P. putida FI
CH,

,OH
P. putida Fl
X
o
toluene
dehydrogenase
Cl
256
*OH
cathechol
dehydrogenase
y^0H
Cl
257
acetate
P. putida F39/D
Scheme 50
isolated. The organism responsible for this transformation was a mutant strain of the
bacteria Pseudomonas putida (FI) and was designated Pseudomonas putida (F39/D).
This strain was devoid of the c/s-diol dehydrogenase enzyme hence only produced the
cis-diene diol 256 (Scheme 50). The use of these diols as synthons was initiated in the
late 1980s with work done by Ley88 and coworkers who achieved a racemic synthesis of
pinitol from meso-cis-diols derived from benzene. Since then, one of the leading
researchers in this area of chemistry has been Hudlicky who has been able to utilize the
O
cz's-diene-diols as chiral synthons in the synthesis of a wide variety of compounds
(Figure 5).


98
Procter and Gamble Pharmaceuticals (Scheme 83). Our most challenging endeavor has
Scheme 83
been the attempts at establishing the C13 quaternary center. In our approach to the
Overman intermediate we discovered the hindered nature of the Cl 3 carbon and also the
reasons for our unsuccessful Orthoester Claisen rearrangement. The problem can be
summarized as lability of groups at the C6 (morphine numbering) position and steric
hindrance at the Cl3 position due to what we suspect is atropoisomerism. We realized
that we had an opportunity to achieve functionalization of the C13 center from either a
tether on the 2-position of the aromatic ring or from the nitrogen side chain. Model
studies confirmed the feasibility of a radical closure from a tether on the aromatic ring
and the last part of the project has been dedicated to the synthesis of intermediates that
would allow for the establishment of the C13 center through this reaction.
There are still a few options available to achieve functionalization of the C13
center. We have yet to attempt either a palladium catalyzed SN2 closure or a


115
2-(-2-Cvclohexenvl)-2R-N-fert-butoxvcarbonvlmethylglvcinate (304):
To vinyl bromide 293 (0.10 g, 0.20 mmol) was added to a mixture of catalytic
amount of 10% Pd-C and methanol (1.0 mL). The reaction vessel was evacuated and the
solution stirred under hydrogen atmosphere (15 psi) for lh. After completion of the
reaction (as observed by TLC), the suspension was filtered and the solvent concentrated
under reduced pressure. The solid residue was recrystallized from Ethyl acetate/ Hexanes
to give the ester 304 (0.04 g, 75%) as a white solid; Rf = 0.8 (ethyl acetate:hexanes 1:6);
mp: 110-112 C; [a]D25 -19.7 (c 1.0, CHC13); !H NMR (CDC13) 5: 5.00 (d, J = 8.1 Hz,
1H), 4.18 (dd, J = 8.5, 5.1 Hz, 1H), 3.71 (s, 3H), 1.81-1.56 (m, 10H), 1.41 (s, 9H); 13C
NMR (CDC13) 5: 173.15, 155.81, 79.94, 58.49, 52.18, 41.24, 29.65, 28.54, 28.50, 28.33,
26.17; IR (KBr/ cm'1): 3420, 2950, 1755, 1712, 1503, 1180; HRMS Caled, for
C14H25NO4: 271.2434; Found: 271.2814.


puist ^cvoeHce
Puli* 40.0 decrees
Acq. t11.990 sec
Width 4500.5 HZ
10 repetitions
OOSCRVC HI, 300.0733027 HHZ
OATA PROCCSSINO
Line broadening 1.0 Hz
PT size 32700
Total time 1 minute
Jll
l Av/vr
Vjul
uJL
T
7
E
T
5
T
3
i
ppa


104
6-(2,3-dirnethoxvphenvD-2-dirnethvlthexvsilvoxv-nR,2S)-5-cvclohexen-l-ol (276).
A solution of the diol 270 (0.720 mmol, 0.18 g) and imidazole (0.860 mmol, 0.15
g) dissolved in 0.50 mL of DMF was prepared in a dry round bottom flask under argon
atmosphere. The flask was cooled to -12 C and TDSC1 (0.860 mmol, 0.17 mL) added
with very slow stirring. The flask was stored at -18 C for 12h after which the solution
was diluted with ethyl ether and washed with brine. After separation the aqueous layer
was re-extracted with ethyl ether (2 X 20 mL). The organic layers were combined and
washed with a 10% CuS04 solution (3 X5 mL) to remove the imidazole. The organic
layer was finally washed with brine, dried over anhydrous MgS04 and the solvent
evaporated. The crude product was introduced unto a silica gel column and eluted with
ethyl acetate/ hexane (1: 99) to afford a yellow oil of the silyl ether 276 (0.25 g, 90%); Rf
= 0.7 (ethyl acetate :hexane, 1:4; [a]D32 59.3 (c 1.0, CHC13); *H NMR (CDC13) 5: 7.0 (t,
J = 7.2 Hz, 1H), 6.8 (d, J = 7.7 Hz, 2H), 5.9 (t, J = 3.6 Hz 1H), 4.4 (bs, 1H), 4.0 (dt, J =
10.2, 3.3 Hz, 1H), 3.8 (s, 3H), 3.7 (s, 3H), 2.6 (d, J = 4.1 Hz, 1H), 2.4 2.3 (m, 1H), 2.2 -
2.1 (m, 1H), 2.0 1.9 (m, 1H), 1.7 1.6 (m, 2H), 0.9 0.8 (m, 14H), 0.1 (d, J = 5.5 Hz,
6H); 13C NMR (CDC13) 5: 152.6, 136.3, 136.0, 129.7, 123.9, 122.4, 111.4, 70.8, 69.2,
60.6, 55.8, 34.2, 25.4, 24.9, 24.3, 20.4, 20.2, 20.1, 18.6, 18.5, 2.5, 2.9; IR (KBr/cm1):
3245, 2959, 1470, 1259, 1108, 1011. HRMS; C22H3604Si (M+l) Caled. 393.2383,
Found: 393.2479; Anal. Caled, for: C22H3604Si: C, 67.18; H, 7.25; Found: C, 67.20 ; H,
7.24 .


112
2-(4-dimethlthexvlsilvloxv-(lS,4R)-cyclohexvl)-2S-N-fer?-butoxvcarbonvlmethvl
glvcinate (294).
To vinyl bromide 293 (0.20 mmol, 0.10 g) dissolved in benzene (10 mL) was
added n-Bu3SnH (0.22 mmol, 0.06 g). This mixture was refluxed for approximately 30
min then AIBN (catalytic) was added and the reaction allowed to reflux for another 3 h.
The reaction was quenched with water and the product extracted with ethyl acetate 3 X
10 mL. The organic layers were combined and dried over anhydrous MgS04. After
filtration the solvent was removed under reduced pressure and the solid residue
introduced onto a silica gel column and eluted with ethyl acetate: hexanes (1:6), to obtain
294 (0.07 g, 82%) as a light yellow oil; Rf = 0.75 (ethyl acetate:hexanes, 1:6); [a]D28 -
14.9 (c 1.0, MeOH); 'H NMR (CDC13) 6: 5.85 (m, 1H), 5.46 (d, J = 9.8 Hz, 1H), 4.93 (d,
J = 8.9 Hz, 1H), 4.29 (dd, J = 8.9, 3.8 Hz), 4.06 (d, J = 3.7 Hz, 1H), 3.71 (s, 3H), 2.61 (bs,
1H), 1.76-1.67 (m, 2H), 1.63-1.54 (m, 4H), 1.41 (s, 9H), 0.86 (d, J = 6.7 Hz, 6H), 0.80
(s, 7H), 0.06 (s, 6H); l3C NMR (CDC13) 5:172.87, 156.08, 134.12, 127.27, 112.56, 80.17,
63.73, 57.15, 52.59, 38.15, 34.31, 30.54, 28.24, 27.22, 24.73, 20.63, 20.35, 20.26, 18.57,
-2.07, -2.43. IR (CHCI3/ cm'1): 3448, 2958, 1755, 1710, 1522, 1365; HRMS Caled, for
C22H42NSO5 (M+l): 427.6600; Found: 427.6812; Anal. Caled, for: C22H41NSO5: C,
61.79; H, 9.66; Found: C, 61.77; H, 9.71.


>0)vnl: CUC13
AaDtint t#*iprtuf*
CCMIMI '900D6 "g#*'n13 00"
putse seouewce
Pull# 32.7 o#gr**
AC# tin# 3.111 l#c
Width 4101.1 HZ
14 r#p#t1tlon
O&SfRVC HI, 300 047362 "z
OATA PAOCtSSlNC
tin# 0ro4d#n1ng 0.2 HZ
CAUll #poo1Ztion 1.790 tfC
f T HZ# 655 36
Tot A1 tm# 4 win, 20 lC
7
6
T
5
V
4
3
T
2
T
1
1
ppa


ST AMOAAO 1H OSSKRVC
Pul* S*qu*nc*i tpul
1
W A.
T
7
6
0.94
1-0S
oo
jWv
1 > r i [ t t
i 1
0 ppa
21-M
17
T
1
i.u


28
to NBS and catalytic amount of dibenzoyl peroxide in refluxing cabon tetrachloride
Scheme 29
afforded the morphimethine. Treatment of the styrene 135 under reductive conditions
(L/NH3/THF) yielded the desired heterocyclization product, (-)-dihydrocodeinone 88
after hydrolysis of the ketal 136 using 3N HC1. Unfortunately attempts to convert
dihydrocodeinone to morphine failed probably because of competing oxidation of the
tertiary amine followed by polymerization. In 13 steps and an overall 11.5 % this make
Mulzers synthesis one of the most practical of all attempts at morphine synthesis.


Pul Squnci pt
r*',
vO


126
2-(4-dimethvlthexvlsilvloxv-2-(2-hvdroxv,3-dimethoxvphenvl)-( lS,4R)-2-cyclohexenyl-
2S-N-rert-butoxvcarbonvlmethvlglvcinate (358):
To a two neck round bottom flask fitted with a condenser under an argon
atmosphere was added Pd(PPh3)4 (0.022 g, 0.019 mmol). This was followed by addition
of dry benzene (10 mL). A solution of the vinyl bromide 289b (0.640 mmol, 0.326 g)
dissolved in benzene (5 mL) was then added to the reaction flask. This was followed by
the addition of Na2C03 (2.0 M, 2.5 mL), to the mixture. Boronic acid 357 (0.600 mmol,
0.110 g) dissolved in a mixture of benzene (5 mL) and ethanol (1 mL) was then added to
the reaction mixture, which was allowed to reflux for 6h. The reaction was quenched with
water and the product extracted with ethyl acetate (3 X 20 mL). The organic layers were
combined, washed with brine and dried over anhydrous NaiSCL. After filtration the
solvent was removed, the crude product introduced onto a silica gel column, and eluted
with ethyl acetate: hexanes (1/3) to obtain the coupled product 358 (0.158 g, 45%) as a
light yellow oil; Rf = 0.78 (ethyl acetate: hexanes, 1:1); [cc]d3 (c 1.0, CDC13); H NMR
(CDC13) 5: 6.75 (m, 2H), 6.67 (m, 1H), 5.93 (dd, J = 1.9, 5.0 Hz, 1H), 5.85 (bs, 1H), 4.86
(d, J = 7.8 Hz, 1H), 4.24 (m, 1H),4.04 (dt, J = 4.2, 7.6 Hz, 1H), 3.85 (s, 3H), 3.67 (s, 3H),
3.57 (bs, 1H), 1.74 (m, 2H), 1.65-1.62 (m, 2H), 1.35 (s, 9H), 0.91(dt, J = 1.7, 6.8 Hz,
6H), 0.86 (s, 6H), 0.12 (m, 6H); 13C NMR (CDC13) 8:172.70, 155.21, 146.24, 142.58,
138.68, 132.74, 126.51, 121.86, 119.77, 109.83, 79.28, 63.59, 55.93, 54.78, 52.09, 38.13,
34.39, 29.98, 28.28, 24.88, 20.43, 20.39, 18.67, 18.30, -2.36, -2.83; IR (CDC13/ cm1):
3448, 2955, 2868, 1752, 1721, 1520, 1472, 1279, 1159, 1065; HRMS Calcd.for
C29H47N07S (m+): 549. 7864 ; Found: 549. 3122.


42
stereoselectivity. Also the use of TBDMS chloride instead TMS chloride as the silylating
agent did not increase yield or stereoselectivity. Reaction in a less polar solvent (ether)
proceeded with a slight increase the stereoselectivity but led to a decreased yield.
Table 1. Influence of Conditions on Rearrangement of Amino Esters.
Conditions Yield/ %
*Standard
60-65
Ether
45
20% HMPT/THF solvent
51
KDA
0
1.1 equiv of MgCL,
42
Ratio 212/213
9
10
4
10
*Deprotonation at -75C with 2.1 equiv. of lithium isopropylcyclohexylamide or lithium
diisopropyl amide; silylation with Me3SiCl after 10 min; warming to reflux for lh;
hydrolysis of silyl ester.
Contrastingly the use of HMPA and TMEDA, which are highly dissociating systems as
co-solvents resulted in both lower yield and lower stereoselectivity (Table 1). The use of
a lewis acid (MgCh) also slightly increased stereoselectivity but led to a lower overall
yield. The result of this study is in concurrence with the accepted principle of an E-
enolate geometry and a chair-like transition state for aliphatic substrates. He proposed
that coordination of the counter ion between the carbonyl oxygen and the nitrogen anion
is at least partly responsible for the E-enolate geometry.
Influence of N-Protecting Groups: A variety of N-protecting groups were
explored (Table 2) with varying yields and stereoselectivity. Overall the Boc- protecting


Ginsburg
Mulzer
Scheme 57
Using hydrofluoric acid he was able to achieve the Friedel-Craft annulation, to
obtain the desired diketone 33. Mulzer, in his morphine synthesis, made intermediate
126 which also contained the bicyclic unit comprising the A and C-rings of morphine and
essentially resembles that of Ginsburg, with the exception of the presence of the
dimethylamido group resulting from a prior Eschenmoser-Claisen rearrangement step.
Mulzer was not able to achieve annulation of the B-ring on the aldehyde upon treatment
with various Lewis acids (Scheme 57). With these two contrasting results it was difficult
to make any predictions as to the outcome of our attempts at B-ring closure. Starting from
acid 278, we derivatized it as the acid chloride using three different conditions.
Scheme 58


73
that the source of the problem might be adverse steric interactions between the aromatic
substituent and the metal chelate (Figure 6, pg 67). Our immediate solution to this
problem was to attempt the Kazmaier-Claisen on the cyclohexenyl gylcinate ester 290,
which has a bromine substituent in the a-position to the allylic carbon. Such a substrate
would posses a much minor steric interaction in the boat transition state between the
solvated metal and the ring substituent (as discussed on pg 67) leading to a much
improved product ratio. This also meant that the Suzuki Coupling step, which had
previously preceeded the Claisen rearrangement, would now be performed after the
rearrangement. Our new general retrosynthetic scheme would be as represented by
Scheme 61.
Claisen III-Kazmaier Claisen of Glycinate of Cvclohexadiene Diol
Starting from diol 247 we were able to protect the distal hydroxy group as the
thexyldimethylsilyl ether 291. Using DCC coupling protocol we obtained the glycinate
ester 292. We were now in a position to perform the Kazmaier Claisen on the precursor
THS-C1, Imid.
DMF, -8 C
NHBoc
Scheme 62
292. Using 2.2 equivalents of LDA and 1.4 equivalents of ZnCU we were able to obtain
rearranged product epimeric at C9. We observed the yields for the transformation
increase from 75% to 80-85%; the ratio of the rearranged acids epimeric at C9 also
decreased slightly from a 70: 30 ratio to a 60: 40 ratio in our favor. But the best aspect of



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CHEMOENZYMATIC APPROACH TO THE SYNTHESIS OF THE MORPHINAN SKELETON VIA A CLAISEN REARRANGEMENT APPROACH By KOFI A. OPPONG A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2001

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Dedicated to Nana Akua and Akwasi

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ACKNOWLEDGMENTS I would like to take this opportunity to express gratitude to a number of people who had a positive influence on my life in the last 5 years. First I would like to thank my research advisor Dr. Tomas Hudlicky for his support and guidance over the years. I have come to appreciate the impact and the importance of the training I received from Dr. Hudlicky. Being associated with his group has been one of the landmark experiences in my life something I will not forget. I also wish to show my appreciation to members of my committee ( Dr. Merle Battiste, Dr. William Dolbier, Dr. Dennis Wright, Dr. Vanecia Young and Dr. Howard Johnson) for the help they rendered to me during my time here. I give special thanks to Dr. Battiste and Dr. Dolbier, who as committee members had a direct impact on my development as a student. I also want to acknowledge Dr. Dolbier because he played a huge role in my obtaining admission to this graduate school. I extend thanks to Dr. James Deyrup, Donna Balkom and Lori Clark for their assistance with all the administrative aspects of my stay at the University of Florida. Since joining the faculty of the University of Florida Dr. Dennis Wright has been a tremendous asset to me personally and to all the students in the Hudlicky group in general. I would like to acknowledge Dr. Dennis Wright for all his chemistry suggestions, discussions and contributions all of which added to my growth as a chemist. I extend my gratitude to all the members of the Hudlicky research group who in one way or another helped to nurture me over the years. I would like to iii

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recognize Dr. Yan Fengyan and Dr. Ba Nguyen with whom I collaborated on the fluoro inositol project; and Dr. Larry Brammer, who was instrumental in my training during my first year in graduate school. I thank Dr. David Gonzalez and Dr. Bennett Novak for their advice and chemistry discussions. Dr David Gonzalez was instrumental in my advancement in laboratory techniques and for that I am indebted. The fermentation team also deserves acknowledgment: Dr. Bennett Novak, Dr. Mary Ann Endoma Vu Bui and Natalia Korkina I also acknowledge Dr. Caimin Duan who has been a model of hard work for me I am indebted to Nora Restrepo, Stephan Schilling, Jennifer Lombardi and Jerremy Willis for their friendship and advice in chemistry and other matters. I am grateful to those people with whom I worked together on the morphine project; I thank Dr. David Gonzalez, Charles Stanton and Elizabeth Hobbs for their contribution to the morphine project. Recently it has been my pleasure to work with Dr. Lucillia Santos and Lukaz Koroniak who contributed immensely to the progress of the morphine project. We owe our progress to Vu Bui who kept a constant stream of diol flowing our way. I am also thankful for all the help received from the analytical services department, especially Dr. Ion Ghiriviga, Dr. Khalil Abboud and Lidia Madveeva I would also like to thank Dupont-NOBCChE and the Shell Fellowships for their support of my education. I give special thanks to Dr. Hollinsed for all his assistance I want to acknowledge Dr. Josie Reed for the many chemistry/administrative problems that she solved for me and for the entire Hudlicky group. During my time here she has served as an excellent mother figure for me. All her efforts are appreciated and did not go unnoticed. IV

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I would like to thank some of the friends I have made in Gainesville : Tahra Edwards, Gabriela Feldberg, Jacinth McKenzie and Michael Mosi Jerremey Willis, and Nadia Kunan who made my stay here a great experience and gave me reason to persevere and to finish. V

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TABLE OF CONTENTS ACKNOWLEDGMENT.. .. .. . ........ .. .. ..... .... .. .......... ............... .. .. ..... .... m ABSTRACT......... .. ............ . .. ............. ...... . . ................ ... .. . ........... VII CHAPTERS 1. IN"TRODUCTION ............................................................................. 2. HISTORICAL BACKGROUND. .. .. .. ..... . .. ........... ................ ............. 3 Introduction .. .......... .... .. .. .. .. .. ........... ....... .............. .. . ............... 3 Morphine Biosynthesis.... .. .. . .. .. ....... .. ..... .. ....... ...... .. .. .. ........... ... .. 5 Total and Formal Syntheses of Morphine..... .. .. . .................. ... ............... . 8 Morphine Syntheses via Sigmatropic Rearrangements. . .. ........................ .. .. 21 Recent Related Developments.... ........ ................. ....... .. ....... ................. 29 Chelated Enolate Claisen Rearrangement. ................... .. ..................... ... .. 41 3. RESULTS AND DISCUSSION . .. .. ................. ..... ......... .... .... ......... ....... 55 Introduction ....................... ............................ .. ............ ... .. .. .. ..... 55 Fir st Generation Synthesis : Control of C9 and Cl4 Stereocenters .. ... .. .. .. .. .... 61 Claisen I-First Attempt of Kazmaier Claisen on Morphine Precur s or. ............. 64 Friedel Craft-Attempt at CIO-Cl 1 Closure.. ............. .. ...... ............. .. ... 69 Claisen II Ireland Claisen on Phthaloyl Ester.............. ........ ............. .. .. 71 Claisen 111-Kazmaier Claisen of Glycinate of Cyclohexadiene Diol ...... .. . . 73 Synthesis of Matrix Metalloproteinase Inhibitors (MMP's) ........................... Second Generation Synthesis : Overman' s Intermediate via Claisen Rearrangement.. ........ .. . ........ ..... .. .... .. .. . ................... .. ... .. ........... 81 Alternative Methods to Setting the Cl3 Quaternary Center .. ..... .... ................ 89 4. CONCLUSION........................................ .................. ... .... ... ............ 97 5. EXPERIMENTAL SECTION . ........ .................... .... ................ .......... 102 General Procedure ................ ... . .. ..... ..... .... ... ... ............... ... .... ...... .. 102 Experimental Procedures .. .......... .. .. .... .. .. . .. .... ........ .... . . .... ........... .. 103 LIST OF REFERENCES .......... .. . ........... .... ..... .. ...... .......... .... .......... .... 127 APPENDIX : SELECTED SPECTRA. ........ ........ ............. ....... ...... ......... ... 134 BIOGRAPHICAL SKETCH.. .. .... .. .. .. ...................... ....... ............ .. .. .. .. .... 186 VI

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ABSTRACT Abstract of Di sse rt a tion Pre s ented to the Graduate School of the Uni v er si t y o f Florida in Partial fulfillment of the Requir e m e nt s fo r th e D eg ree of Doctor of Philosophy CHEMOENZYMA TI C APPROACH TO THE SYNTHESIS OF THE MORPHINAN SKELETON VI A A CLAISEN REARRANGEMENT APPROACH Chairman : Dr. Tomas Hudlick y Major Department: Chemi s try R O R O H O By K o fi Oppong Au g u s t 2001 An approach to the morphin a n s kel e t o n with complete control of the C9 and C 14 stereocenters is described The fir s t ge n era tion of the synthesis of the A and C rings of morphine are discussed. Al s o d escr i bed a r e a tt e mpt s at establishing the Cl3 quaternary center with empha s is on con s tru c ti o n of th e D rin g. The use of precursors from the enzymatic biooxidation of a rom at i c co mp o un ds in the construction of the morphinan skeleton through variou s cb e mi ca l mod ifi ca ti o n s i s reported V il

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CHAPTER I INTRODUCTION Morphine (1), one of the world's oldest drugs, is consumed to the tune of one hundred metric tons in the United States alone annually 1 4 Its main legal uses is for pain relief in cases of severe trauma (caused by the agonist binding to thereceptors in the 1 central nervous system) These receptors are responsible for analgesia euphoria, addiction and respiratory depression. In recent years morphine has been used in high doses as an anaesthetic in open-heart surgery due to its ability to slow down respiratory activity without affecting cardiac function Morphine is the major component (20%) of the opium of the poppy Paperver somniferum 4 and its documented use dates back to 1500 BC 5 and its impact on society has been quite remarkable. On average 20 people per day die of drug abuse across Europe In 1999 alone the opium harvest in Afghanistan, a country illegally harvesting morphine was 4581 metric tons. Legally opium is harvested in India ( the only legal producer ) on a multi-ton scale. The alkaloid constituent of the opium poppy is about

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2 25%; of this two of the important alkaloids, morphine (1) and codeine (2) constitute approximately 17%. 6 Although morphine is quite abundant from the isolation of the natural resource, it still remains a viable synthetic target to various research groups around the world The focus is not only to find an efficient synthesis of morphine but more importantly to arrive at a more practical synthesis of the morphinan skeleton, which would allow for a more competent route to some the important derivatives of morphine. Of the twenty-one formal synthesis of morphine only three syntheses have used sigmatropic rearrangements as key steps. Interestingly, the rearrangements were all used to install the quaternary center at C13. None of the above approaches used the rearrangement to transfer stereochemistry inherent in the molecule to another site with the result of correctly setting two important stereocenters in one transformation This thesis describes a Claisen rearrangement approach to the synthesis of the morphinan skeleton Control of the stereo centers C9 and C14 are discussed and recent advances in the synthesis of the morphinan skeleton are also reported.

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CHAPTER 2 HISTORICAL BACKGROUND Introduction According to the available records, the relationship between opium and human beings started in ancient Middle Eastern civilizations about 3500 years ago 6 Since then the potent bioactivity of morphine and its derivatives was an important issue that has crossed the frontiers of medicine and become a socio-political factor. In the sixteenth century, Parcellus popularized the use of opium as an analgesic when he introduced various preparations and named it "laudanum" which is derived from the latin word meaning to praise. Although opium had been used for centuries, morphine was not isolated as a crystalline material until 1803 as reported by Derosne 8 9 Three years later in 1806, Seguin presented a description of the isolation of morphine to the Institute of France, 1 0 and later in the same year, Sertumer was finally credited with the first isolation of crystalline morphine. 11 A century later in 1925 Sir Robert Robinson postulated the correct structure of morphine including relative stereochemistry 1 2 This was later confirmed by X-ray crystallographic analysis in combination with other analytical techniques. 13 1 4 After its isolation morphine 1 was introduced into medical practice and used extensively to treat ailments such as diarrhea asthma, diabetes, ulcers and pain relief. Bayer at the end of the ninteenth century was marketing diacetyl morphine 3

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4 (Diamorphine). 14 It was nicknamed heroin because it was considered a "heroic drug. Heroin 3 has the same physiological effects as morphine (because of rapid hydrolysis to morphine, most of its actions are due to morphine itself) except that it acts faster and is more potent. However there are appropriate differences. Heroin is lipid soluble and rapidly enters the brain Morphine is not as lipophilic and hence its passage to Scheme 2 2 Codeine 3 Heroin Me the brain occurs at a much slower rate. Codeine 2 is approximately one-sixth as effective as morphine as an analgesic. It is best administered orally and acts as a good cough suppressant. In 1952, Gates achieved the first total synthesis of morphine 15 16 and confirmed the structure of morphine as proposed by Robinson. Since Gates historic synthesis, about 20 formal syntheses of morphine have been reported. In spite of these reports and 150 years of effort since its discovery, a truly practical synthesis which would compete economically with the isolation of morphine directly from the opium poppy Papever somniferum has not yet been achieved Astonishingly, of aJI the reported formal synthesis of (-)-morphine to date only three have used some sort of sigmatropic rearrangement. Only the syntheses of Rapoport 11 1 s p 19 20 d M I 2 1 -2s h 1 d h f In J h arsons an u zer ave re 1e on t ese types o reactions. tere s tmg y, t e three syntheses made use of the rearrangement for the same purpose: to install the

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5 quaternary center at C 13 (morphine numbering, while transferring the stereochemistry already present in the starting material to that position. Morphine Biosynthesis It is interesting to note that Robert Robinson, who proposed that morphine consisted of a twisted benzylisoquinoline skeleton, made one of the most important MeO HO HO 11 i viii MeO HO HO HO Scheme 3 MeO .._ vii HO HO MeO HO HO MeO 10 13 HO~ HO 6 ~H 0 HO 8 V HO .._ vi HO HO 9 Enzymes: i)L-tyrosine decarboxylase; ii) phenolase; iii) L-tyrosine transaminase; iv) hydroxyphenylpyruvate decarboxylate; v) (S)-norcoclaurine synthase; vi) norcoclaurine6-0-methyltransferase; vii) tetrahydrobenzylisoquinoline-N-methyltransferase; viii) phenolase; ix) 3 '-hydroxy-N-methyl (S)-coclaurine-4' -0-methyltransferase.

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6 observations that eventually led to the elucidation of the structure of morphine. 12 26 Studies conducted on the biosynthesis of morphine indicate that the morphinan alkaloids are formed by a series of benzylisoquinoline intermediates (Scheme 3) which eventually forms (R)-reticuline 14 (Scheme 4). 27 28 MeO HO HO Meo MeO Scheme 4 13 MeO HO MeO 19 MeO HO MeO R H OH 13 C 17R=H 18 R = Ac Meo 20 MeO ____ HO MeO MeO 0 16 MeO OH 14 MeO HO MeO OH 15 2~1 The benzylisoquinoline skeleton is derived from two molecules of L-tyrosine (4), which is converted into a molecule each of dopamine 6 and 4-hydroxy phenylacetaldehyde 8 through the intermediacy of tyramine 5 and 4-hydroxyphenyacetic acid 7 respectively (Scheme 3). Condensation of these two derivatives of L-tyrosine is catalyzed in a stereospecific manner by (S)-norcoclaurine synthase, which results in the

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7 formation of (S)-norcoclaurine 9, which serves as the skeletal foundation of most of the benzylisoquinoline alkaloids. The next three steps can be summarized a s two enz y me catalyzed methylations and an aromatic hydroxylation to afford ( S ) -reticuline 13 that possesses the opposite configuration to the compound found in the biosynthes i s of morphine ( what would be the C9 center of morphine has the opposite stereocherni s try). Inversion to the correct intermediate is effected in two steps through the intermediate imine dehydroreticuline 14 (Scheme 4) by a highly stereospecific and NADPH/NADPH + dependent reductase to afford (R ) -reticuline 15. 29 3 0 It is likely that the mechanism involves the formation of two phenolate radicals and their subsequent coupling. The next step in the biosynthesis is the conversion of (R)-reticuline into s alutaridine 16 by a membrane-bound cyctochrome P-450 enzyme whose catalytic action is strictly dependent on NADPH and molecular oxygen After the formation of salutaridine 16 the ketone moiety is reduced by an NADPH-dependent oxidoreductase to afford salutaridinol 17 3 1 which then undergoes enzyme-catalyzed acetyl CoA dependent acetylation to yield the acetate 18. 32 The next intermediate formed is thebaine 19 which re s ults from r i ng clo s ure at slightly basic pH. Failure to find a specific enzyme for this step has led to the conclusion that this step is spontaneous. Neopinone 20 is formed by the demethylation of thebaine to form the ketone, which is in chemical equilibrium with codeinone 21. The final steps in the morphine biosynthesis are the conversion of codeinone to codeine ( 2 ) and a final demethylation of codeine to afford morphine (1). An alternate pathway to morphine has also been proposed and it involves arriving at the target first by demethylation of thebaine to obtain the intermediate alcohol 22 then conver s ion to the enone 23 whose reduction by codeinone reductase affords morphine 1 (Scheme 5 ) 33 34

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MeO MeO 19 Scheme 5 8 1 22 23 Total and Formal Synthesis of Morphine Gates landmark synthesis of morphine in 1952 started from naphthalene HO MeO MeO 0 D,. .. OH 0 23 24 25 Scheme 6 diol 23 which was subsequently converted over seven step s to the s ubstituted naphtoquinone 24 ( Scheme 6). 15 1 6 The [ 4+2] cycloaddition of 24 with 1 3 butadiene under thermal conditions afforded the phenanthrene 25. Phenanthrene 25 wa s subjected to hydrogenation in the presence of copper chromite which led to an unexpected cyclization affording tetracyclic amide 26. Although the stereochemistry at C9 ( morphine numbering ) was set correctly during the cyclization it was neces s ary to epimerize the C14 ( morphine numbering) center (Scheme 7) Gates, while attempting to clo s e the furan ring via alpha bromination of the corresponding ketone, achieved this epimerization with dinitroarylhydrazone 27 the most commonly intercepted intermediate in s ubsequent formal morphine syntheses The furan ring was then closed to afford pentacycle 29 and

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9 MeO MeO MeO HO 8 steps ., ArHNN MeO Meo 2 steps., MeO 2 steps 3 steps ., 1 0 28 Scheme 7 completed the construction of the morphine skeleton. Finally, hydrolysis, lithium aluminum hydride reduction, and demethylation completed the first total synthesis of morphine 1. Shortly after Gates' historic synthesis, Ginsburg completed a formal synthesis by synthesizing dihydrothebainone 35 in 1954. 35 In Ginsburg's synthesis, condensation of 0 6 MeOX) + I ,0 MeO 30 MeO 5 steps ..,MeO 0 Scheme 8 31 34 5 steps .., Meo MeO 0 8 steps.., 32 MeO HO 0 MeO 4 steps .., MeO 0 0 33 NMe 35 veratrole 31 via ortho-lithiation to cyclohexanone 30 served as the first step (Scheme 8)

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10 The coupled product was dehydrated and then converted to enone 32. Michael addition with dibenzyl malonate, followed by decarboxylation and a Friedel-Crafts annulation resulted in the formation of the phenanthrenone 33. Finally the D ring was installed using a series of steps culminating in the spontaneous formation of the ethylamine bridge accompanied with cleavage of the C4 methyl ether and formation of the tetracyclic amide 34. An additional 8 steps followed by d-tartaric acid resolution yielded dihydrothebainone 35, and consequently, the first of many formal synthesis of morphine. Nine years later, Barton presented a biomimetic synthesis of a radio labeled thebaine 38 (Scheme 9). 36 Starting from tritium labeled reticuline 36 he performed an MnO 2 promoted oxidative coupling to construct the phenanthrene core. However this step MeO MeO HO HO 2 steps ., NCH 3 NCH 3 NCH 3 MeO MeO OH 0 36 37 38 Scheme 9 proceeded in a poor yield and after two additional steps a radioisotope dilution study of the final thebaine 38 was performed to establish a 0.012% conversion of tritium labeled salutaridine 37. Simultaneous reports presented in 1967 by Grewe 37 38 and Morrison, Waite and Shavel 40 collectively, established a successful path for the coupling of rings A and C (Scheme 10).

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11 I .o + MeO~NH 2 MeO~ Meo V 39 C0 2 H 40 MeO l 4 steps MeO HO HO MeO 0 35 Scheme 10 Substituted benzyltetrahyroisoquinoline 41 was readily obtained after a Birch reduction of the coupled product of compounds 39 and 40. Grewe then used phosphoric acid, while Morrison, Waite and Shave} were successful with 10% aqueous HCI to render the ortho coupled product in 3% yield. The para product was obtained in 37% yield. This process resulted in the formation of dihydrothebainone 35. Other research groups later improved the ortho selectivity of the Grewe cyclization, and this disconnection is found in several of the following formal synthesis. Kametani 41 utilized a Pschorr type cyclization in his approach to thebaine 19 to maximize the orthopara selectivity (Scheme 11). Diazotization of 2-aminobenzyl tetrahydroisoquinoline 42 followed by thermal decomposition yielded racemic salutaridine 16 in a yield of 1.1 %, however no ortho-ortho products were observed.

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MeO BnO MeO Scheme 11 OMe 42 12 I. NaNO 2 H 2 SO4' AcOH 2. 70 C MeO HO MeO 0 22 19 Schwartz, 42 .4 3 in a biosynthetically designed synthesi used thallium (III) trifluoroacetate to effect the ortho-para coupling of N-acylnorreticuline 43 affording the corresponding salutaridine derivative 44 (Scheme 12) Reduction of this intermediate with LiAlH 4 followed by O-ring closure with HCl resulted in the formation of thebaine and resulting in a formal total synthesis. MeO HO MeO OH 43 Scheme 12 MeO TI(TFA) HO NR I eq. MeO OH 44 2 steps., 19 thebaine

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13 Beyerman 44 used a Grewe type cyclization with a symmetric arene to overcome selectivity problems (Scheme 13). The N-methylation of benzyl protected phenol 45 OH MeO MeO BnO 2 steps HO MeO MeO 45 46 Scheme 13 MeO I HCI Grewe reaction HO 2. 5-chloro-1NCH J phenyltetrazole 1CO 3 DMF 0 PhN-f'{, A N O N 47 11, Pd-C 35 followed by hydrogenation and finally a Birch reduction rendered tricycle 46, which readily cyclized in the presence of HCl to 47. Fortunately, the additional hydroxyl group at C2 in 47 was selectively removed by conversion to the corresponding tetrazole ether followed by hydrogenolysis, which afforded dihydrothebainone 35 and formalized Beyerman' s synthesis. Rice 45 is given credit for the most practical synthesis of morphine to date with an overall yield of 29%. Using starting materials similar to those used by Grewe and Morrison, Rice was able to synthesize amine SO by coupling of acid 48 and amine 49. In 3 steps Rice was able to synthesize bromide 51 using a strategy similar to that of Beyerman This was a key intermediate because it possessed a well placed bromine substituent, which blocked para cyclization. Bromonordihydrothebaine 52 was formed in 60% yield, and was eventually converted to dihydrocodienone 53 ( Scheme 14). Overall

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14 the whole synthesis required isolation of only six intermediates, obtained in sufficiently pure form to continue with the synthesis. It still remains the most practical synthesis to date M,OQ M,O~NH, MeO I o COOH + lo 3 steps,. HO HO 48 49 NH MeO 50 i 4 steps MeO MeO Meo 14 % NH 4 .HF .J steps HO ""CF 3 SO 3 H OOC HO NH NCHO NCHO 0 0 0 53 52 51 Scheme 14 In 1983, Evans 46 used the ortho lithiated veratrole 54 in an initial coupling reaction with piperidone 55 in his approach (Scheme 15). After the coupling, dehydration afforded alkene 56, which was further coupled with dibromide 57 Isoquinoline 58 was then converted to the aziridinium salt 59, which was then opened, oxidized to an aldehyde and finally treated with Lewis acid to form the morphinan 60. Removal of the C 10 hydroxyl group followed by oxidation afforded ketone 61, which is one of Gates' intermediates hence resulting in a formal synthesis.

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15 MeO'(l MeoY Meo Li 2 steps ., 54 OD'CH, 55 MeO MeOX) + ~Br 2steps ., Yh 57Br ~N'CH 58 '3 !3 steps MeO MeO ,. 2 steps 0 61 60 Scheme 15 A third report in 1983 by White 47 described an oxidative coupling approach to(-)codeine 2 (Scheme 16). After protection and bromination, (-)-Norreticuline 62, Meo HO Meo OH 62 Scheme 16 MeO HO 3 steps ., MeO MeO 0 63 3 steps .. ,. LiAIH 4 64 !2 steps

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16 underwent successful and selective para-para coupling to afford salutaridine analogue 63 which was further manipulated to bromothebaine 64. Simple hydrolysis followed by double bond migration afforded the Gates intermediate 65 which on treatment with LiAIILi gave ()-codeine 2. In 1986, Schafer 48 reported another oxidative coupling approach to salutaridine (Scheme 17). Formamidine 67 was coupled with bromide 66 and the product Me~?IBS 66Br Meo~ 2 steps ~N BnO II 67 Scheme 17 N 'tBu Meo TBSO MeO OBn 68 2 steps Meo HO MeO 0 16 reductively cleaved to afford the cyclization precursor 68 Cyclization was achieved using TiC1 4 and subsequent rearomatization of the A-ring using DDQ afforded salutaridine 16 in 3% overall yield in 15 steps. In 1987, Fuchs 49 reported a total synthesis of morphine using a tandem coupling reaction to construct the morphinan skeleton. His approach to the morphinan skeleton used an intramolecular conjugate addition/alkylation sequence in which connections C 12C 13 and C9-Cl4 were formed as a result of one-tandem process. Coupling of aryl 69 to alcohol 70 under Mistunobu conditions followed by deprotection and an oxidation/reduction sequence afforded ether 71 with the desired cis stereochemistry (Scheme 18). The tandem cyclization was achieved by treatment of ether

PAGE 24

Meo~ HO~Br Br 69 OH TBSOT SO 2 Ph 70 75 Scheme 18 17 MeO ,. 2 steps nBuLi., yH 3 NTEOC 2 steps 72 73 71 with n-BuLi, which led to the closure of the C12C13 bond and subsequently underwent alkylative closure of the final ring to yield the tetracycle 72. After oxidative cleavage of the olefin to the corresponding aldehyde the nitrogen was introduced by reductive amination and protected as the trimethylsilylethoxycarbonyl ester, and finally oxidation followed by enol ether formation afforded 73. Base catalyzed elimination of the sulfonyl group followed by oxidation with DDQ gave dienone 74. Upon removal of the protecting group, a 1,6-Michael type addition afforded codeinone 21 as well as the nonconjugated neopinone, which could be readily isomerized to codeinone under conditions reported by Rapoport and Barber. 5 Fuchs completed his total synthesis by converting codeinone to racemic morphine with reduction and final demethylation.

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18 In 1992 Tius 51 used an intermolecular Diels-Alder reaction as an early s tep in his formal synthesis. Quinone 75, which was prepared in 7 steps from 3-methoxy-2-hydroxy M e O'QJO I I + EtO r 0 75 s everal s tep s Scheme 19 0 76 77 78 benzaldehyde was heated with diene 76 prepared in 2 steps from 1,4-cyclohexanedione monoethylene ketal to construct phenanthrene 77 (Scheme 19 ). After several subsequent step s Tius completed his synthesis by constructing thebainone 78, thus intercepting Gates approach. Parker and Fokas 5 2 accomplished a well designed formal synthesis of morphine in 1993 Their approach hinged on an efficient radical cascade which in one s tep led to the construction of a morphinan complete with the A, B, C and O-ring of morphine ( Scheme 20 ) To be able to take advantage of this tandem cyclization strategy they had to first construct aryl ether 82 through an eight-step sequence starting from m-methoxy phenethylamine 79 and culminating in a Mitsunobu coupling of the resultant a lcohol 80 with phenol 81. With the aryl ether in hand the ortho allyloxy aryl radical 83 was generated using tributyltin hydride/ AIBN. Tandem closure led to isolation of

PAGE 26

19 NMeTsMeO~ MeO I ,lj HO ll HO I 7 steEs Br SPh )It 81 MeO MeO mitsunobu 79 80 R=TBDMS RO 82 0 I NMeTs ... 86 t MeO MeO I ,lj 0 0 I NMeTs~ SPh SPh NMeTs RO RO 85 84 83 Scheme 20 tetracycle 86 in 35% yield by initial attack of the radical on the proximal but more substituted end of the cyclohexyl ring double bond to establish the furan ring with the correct stereochemistry at CI 3. The radical generated in the formation of the furan NMeTs Li/NH 3 )It Swern NMe 86 87 88 Scheme 21

PAGE 27

20 ring then attacked the P-carbon of the styrene double bond to give rise to the resonance stabilized radical of 85 with the correct stereochemistry at C 14 Final elimination of the phenylthio group from 85 led to formation of styrene 86 Dihydroisocodeine was formed when the tosylamide 86 was treated with Li/NH 3 at 78 C. Swem oxidation of dihydroisocodeinone 87 afforded dihydrocodeinone 88, which then completed her approach The crucial step in Overman's 53 approach was essentially a Grewe type disconnection, but involved an intramolecular Heck reaction to complete the construction of the B-ring. The synthesis started with enantioselective reduction reduction of 2-allyl cyclohexenone 89 which would introduce chirality into the synthesis Condensation of the resultant S-alcohol 90 with phenylisocyanate, oxidation of the side chain olefin with osmium tetraoxide and acetonide protection afforded 91 (Scheme 22). ~---89 MeO BnO 94 Scheme 22 OH QCHNHPh I I V 2 fileS Utr 90 Me0'111 BnO~ + I CHO 93 91 j 92 A copper catalyzed suprafacial SN2' displacement of the allyl carbamate with lithium dimethylphenyl silane, deprotection and diol cleavage yielded an intermediate aldehyde, which then underwent reductive amination with dibenzosuberyl amine to afford 92.

PAGE 28

21 Condensation of allylsilane 92 with iodide 93 (prepared in 7 steps from isovanillin in an overall 62% yield) at 60 C in the presence of Znl 2 followed by iminium ion-allylsilane cyclization yielded the isoquinoline intermediate 94. Palladium mediated coupling led to the formation of the C12-C13 bond and morphinan 95 (Scheme 23) with the correct stereochemistry at C9 C13, and C14. Liberation of the phenolic oxygen and P-face epoxidation of the C6-C7 double bond and subsequent intramolecular ring-opening by the phenolic hydroxyl completed the dihydrofuran ring. Oxidation followed by reductive DBS cleavage in the presence of formaldehyde yielded ()dihydrocodeinone 88 MeO BnO 94 Scheme 23 .. MeO BnO 88 .. 95 Morphine Syntheses via Sigmatropic Rearrangements 96 97 Although a wide variety of synthetic approaches have been applied to the morphine problem sigmatropic rearrangements have rarely been elicited as synthetic tools. Of the more than twenty formal syntheses only three, namely those of Rapoport, 50

PAGE 29

22 P 20 d I M I 21 25 bl . k arsons an recent y u zer were a e to ut1 1ze s1gmatrop1c rearrangements as ey steps in their approaches to morphine. Interestingly, all three approaches used the sigmatropic rearrangement for the same purpose, to install the quaternary center at C 13 (morphine numbering) while transferring the stereochemistry already present in the starting material to that position. Rapoports synthesis began with the conversion of ortho-vanillin 98 to amino acid 99 in twelve steps (Scheme 24). The amino acid then underwent rearrangement in the MeO MeO MeO MeO)Q 12 stees, MeO MeO MeO HO 8 CO 2 H CHO 98 99 100 101 MeO MeO MeO MeO MeO O~OMe MeO OH n 104 103 102 j 6 steps MeO CC OMe OMe ~' Me (Evans, 6 steps) MeO 0 105 106 Scheme 24

PAGE 30

23 presence of acetic anhydride to afford lactam 100 Benzylic oxidation followed by reaction with formic acid yielded, after allylic migration and hydrolysis, alcohol 102. Condensation of the alcohol with trimethyl orthoacetate produced acetal 103, which subsequently underwent rearrangement to afford the methyl ester 104. This compound contained the required quaternary center at C 13 as well as the complete C ring with an adequate pattern of substitution Ring B was emergent in this structure but required more steps to develop. After several attempts, Rapoport decided to intercept the advanced Evans intermediate 105 from which Evans was able to synthesize one of Gates advanced intermediates (1 06 ) in six additional steps. Parsons,2 in 1984 reported the synthesis of the precursor 113, through an interesting sequence. Their synthesis started with the 1,2 addition of the Grignard OMe MgBr A ~0108 Luche .. 107 109 110 DMADA .. PhMe 6 .. 112 Scheme 25 compound 107, to ketone 108. After hydrolysis, the product 109 was reduced using Luche condition to obtain the alcohol 110, which was condensed with dimethylacetamide

PAGE 31

24 dimethyl acetal to form the acetamido acetal 111. Concomitant rearrangement of 111 via an Eschenmoser-Claisen rearrangement gave the amide 112 (Scheme 25). Using this series of transformations, Parsons and Chandler were able to set the stereochemistry at C 13 correctly. Closure of ring B was achieved starting with the ozonolysis of 112 which resulted m the aldehyde 113, which was consequently treated with N-methyl hydroxylamine 0 03 CHNHOH .. PhH D.. + NMe 2 N .... BnO BnO nO O CH 3 112 113 114 0 0 < 0 < 0 0 0 NMe 2 NMe 2 NNHMe BnO Me 115 116 117 Scheme 26 to yield the intermediate 114. The intermediate then accordingly rearranged to produce the isoxazolidine 115 through an intramolecular cycloaddition with an overall 72% yield. The cycloaddition product possessed the correct stereocherrtistry at C 14 but was epimeric at C9. The resultant epimers were separated using chromatography and the N-O bond of the morphine-like isomer was cleaved by hydrogenolysis to produce the amino alcohol 116. The morphinan 117 (Scheme 26) was obtained by heating the resulting hydrochloride salt of 116 under vacuum followed by LAH reduction of the resulting hydroxy amide produced the morphinan 117 with an overall yield of 2.1 %

PAGE 32

25 In Mulzer s 2 1 25 synthesis of morphine, a creative approach towards the morphine skeleton was employed In the first generation of the synthesis he used a model study to explore the possibility of establishing the important benzylic quaternary stereogenic center (C 13) via either conjugate addition of a cu prate to an unsaturated ketone or [3 3] sigmatropic rearrangement. Starting from alcohol 118 Mulzer and co-workers attempted an EschenmoserMeO M e O HO 118 NaBH MeOH MeO MeO 0 120 Scheme 27 MeC(OMe) 2 NMe 2 ., Xylenes A i ttiC=CHMgCI 5 % CuBr-SMe 2 TMSCI., ii ,2 NHCI MeO MeO 0 119 Meo MeO 0 121 Claisen rearrangement to obtain amide 119 in only 21 % yield With this unsatisfactory result they tried both the Ireland and the Johnson variants of the Claisen rearrangement on the alcohol 120 that was obtained after reduction of the enone both failed completely. An explanation for this might be strong conjugation of the double bond (C5-C 13 morphine numbering) to the aromatic ring. Since Claisen rearrangements and 1,4additions of vinyl cuprates are complementary to each other the latter was attempted on the enone 120 with positive results, leading to the formation ketone 121 in 87 % yield over 2 steps.

PAGE 33

26 Another interesting discovery was made during this model study. After preparing a more elaborate substrate 124 from the addition of ortholithiated veratrole to the vinylogous ester 122 followed by hydrolysis and dehydration. Enone 123 after reduction was subjected to Eschenmoser-Claisen rearrangement conditions. The results were similar, even though rearranged product was obtained the yields were low More interestingly after cleavage of the terminal double bond of amide 125 (Scheme 28) to obtain the aldehyde 126, all attempts at closing the Bring failed completely Mulzer explained these results using the theory that repulsive interactions between the orthomethoxy group and the substituents a-to the C 13 carbon (morphine numbering) on the cyclohexyl ring. This steric interaction causes the aromatic ring to twist out of conjugation with the double bond in the cyclohexyl ring. This assumption had merit because 1 HNMR of the allylic alcohol clearly showed the two rotomers reminiscent 122 MeC(OMe) 2 NMe 2 Xylenes. 24 % ., Scheme 28 125 0 Meo l.OsO 4 NMO OMe Acetone, H 2 O MeO 0 2 NaI0 4 EtOt,j; NaBH 1 ., MeOH 126 O 124 Meo HO Meo + 0 127 of the known atropisomerism found in biphenyls. The result is a highly adverse steric influence at the benzylic sp 2 -hybridized carbon by the aromatic ring. The apparent

PAGE 34

27 solution to this setback was to restrict the conformational flexibility of the aromatic ring by means of a tether, which would also provide the two-carbon fragment for the B-ring. This idea led to the synthetic pathway that would eventually result in the synthesis of the morphine skeleton by way of phenanthrone 129. Starting from enantiomerically pure phenanthrone 129 which was synthesized in 3 steps from acid 128, conjugate addition with a variety of funtionalized organocuprates provided good yields of the olefin 130. Mulzer and co-workers discovered that the substitution pattern on the aromatic ring was critical in obtaining clean 1 ,4-adducts. With olefin 130 in hand they were able to effect ring closure using a clever "umpolong" strategy. After trapping the ketone as the silyl enol ether, bromination with NBS in THF at low temperature yielded bromoketone 131 as a 3: I isomeric mixture. The undesirable isomer could however be recycled by way of reductive removal of bromide with zinc and concomitant silylation of the resultant enolate. When a-bromoketone 131 was heated in DMF at l 40C the dihydrofuran was obtained in 20 minutes in quantitative yield. The next stage in the synthesis involved the introduction of the nitrogen functionality at C9 (morphine numbering) Ketone 132 was subjected to a three step sequence that resulted in a) protection as the ethylene ketal b) hydroboration of the vinyl group with BH 3 .SMe 2 followed by oxidation and c) removal of the chloro substituent by catalytic hydrogenation to render alcohol 133. The alcohol was then converted to the benzene sulfonamide derivative 134 using a variation of the Mistunobu protocol which uses N-methylbenzene sulfonamide, 1, l azodicarbonylpiperidine (ADDP) and Bu 3 P. The next step was to introduce a double bond by benzylic radical bromination followed by debromination. Hence exposure of 134

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28 to NBS and catalytic amount of dibenzoyl peroxide in refluxing cabon tetrachloride Meo lo MeO~Cl MeO MeO 128 COOH 131 NSOlh I 134 MeO N 136 Scheme 29 0 129 132 MeO MeO 0 Meo ---11.,_ MeO .. 0 130 steps ., .. OH NSO 2 Ph I 135 MeO II .. CH 3 CH 3 7 1 afforded the morphimethine". Treatment of the styrene 135 under reductive conditions (Li/NH 3 /fHF) yielded the desired heterocyclization product, ()dihydrocodeinone 88 after hydrolysis of the ketal 136 using 3N HCI. Unfortunately attempts to convert dihydrocodeinone to morphine failed probably because of competing oxidation of the tertiary amine followed by polymerization. In 13 steps and an overall 11.5 % this make Mulzers' synthesis one of the most practical of all attempts at morphine synthesis.

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29 Recent Related Developments In addition to the Claisen approach to the morphine skeleton, the Hudlicky group 1s actively pursuing two other approaches toward the morphinan skeleton namely an intramolecular Diels-Alder approach and a Heck coupling cascade approach. Hudlicky, Boros and Boros 54 were able to synthesize the B-, C-, and 0rings using a combination of three important transformations, microbial oxidation, intramolecular Diels-Alder cycloaddition and a Cope rearrangement. Starting from toluene, which was subjected to microbial oxidation to yield diol 138, protection of the distal hydroxyl group afforded the thexyldimethylsilyl ether 139. Alkylation of the proximal hydroxyl group with sorbyl bromide rendered the tetraene 140. The substrate was now ready for an intramolecular Diels-Alder reaction. The Diels-Alder 6 137 _a __ ., Ho,A -V HO 138 :0 139 /"0. _____ h --8~o o):9' o):9' ~o 144 142 143 141 C9 (morphine numbering) Scheme 30 Conditions: a) Toluene dioxygenase; b) THSCl, imidazole, DMF; c) NaH, sorbyl bromide, THF, 0 C to rt., 30h.; d) CC1 4 77 C, 7h.; e) nBu~F-3H 2 0, THF; f) PCC, CH 2 Cl 2 rt.; g) xylenes, sealed tube, 250 C, 22h.; h) NaBH 4 CeC1 3 -7H 2 0, MeOH, rt., 15 min reaction could possibly take two reaction pathways namely, diene k, 1 with dienophile m (Scheme 30) or diene m, n with dienophile k. The latter reaction pathway involving diene

PAGE 37

30 m,n and dienophile k was observed to yield furan 141. Attempts to induce Cope rearrangement to form the desired tricyclic compound 142 were unsuccessful. To supply some driving force for the Cope rearrangement, the THS-ether was converted in two steps into the ketone by first fluoride deprotection of the silyl group followed by PCC oxidation to afford ketone 143. The ketone successfully underwent the rearrangement to afford enone 142. Reduction using Luche conditions produced compound 144 that possesses the carbon skeleton for the lower half of morphine with all the stereocenters correctly set with the exception of what would be C9 (morphine numbering). Hudlicky and Gum 55 published a second generation intramolecular DielsScheme 31 Conditions: a) NaH, sorbyl bromide; b) PPh 3 THF; c) Ac 2 0, pyridine; d)230 C, PhMe. Alder approach towards the morphine skeleton in 1998. Unlike the first generation attempt, provisions were made for eventual closure of the D-ring by appending a nitrogen functionality from the quaternary carbon of the tricycle 149 (Scheme 31 ). During the cyclization of the triene, it was discovered that t~e stereochemistry of the methyl group at what would be C9 (morphine numbering) was indeed P-faced instead of a-faced as had

PAGE 38

31 been reported earlier. This led to the conclusion that the intramolecular Diels-Alder proceeded through an exo transition state. In 1998, Hudlicky5 6 and coworkers published a radical cyclization approach to the morphinan skeleton that represents the most advanced morphinan synthesized in the Hudlicky group. In the first generation of this radical approach, the focus was to 0 HO,~ a,b,c., ,l_J TDSO d e 137 151 BzON ~I O, Br .. TDSO:D 156 155 HOX) Toso' 152 .b ~OH VOMe 150 f ROY') ;y O, Br R=TDS ~'rh TDSO V 153 HON __J ~I 0_ Br TDSO:D 154 Scheme 32 Conditions: a) JM109 (pDTG601); b) PAD, HOAc; c) THSCl, imidazole, DMF; d) BzOH, Bu3P, DEAD, THF; e) NaOMe, MeOH; f) 150, Bu 3 P, DEAD, THF; g) H3O\ h) benzyl bromide, K 2 CO3, acetone; i) Bu3SnH, AIBN, toluene reflux achieve a tandem radical cyclization that would lead to the construction of the A, C D and O-rings of morphine (Scheme 32) with the correct stereochemistry at the chiral centers in a manner analogous to the Parker 52 synthesis but with different connectivity at the C9 C 10 and C 11 carbon atoms. The first step was to validate the tandem process with simple model studies. The initial model examined the feasibility of constructing the Cl2C 13 bond through a radical closure. To this regard bromoguiacol 150 was synthesized in 4 steps starting from an enzymatic transformation with P. putida TG02C and used as a nucleophile in the second Mitsunobu inversion of the alcohol 152 also obtained through

PAGE 39

32 an initial enzymatic step (Scheme 32). With ether 153 in hand the next steps involved protection of the phenol as the benzoate after cleavage of the labile thexyl group Under radical conditions generated by Bu 3 SnH and AIBN ether 155 was transformed to the tricycle 156 with three of the five stereo centers in morphine set correctly. A second model study (Scheme 33) to provide information about the relative O Br HO, HO 157 0 0 0 >=o 0 >=o N N 159b 159a Scheme 33 Conditions : a) PAD, HOAc; b) TBSOTf; c) o-bromophenol, Bu 3 P, DEAD, THF; d) NaH, 2-oxazolidone; e) Bu 3 SnH, AIBN, toluene reflux stereochemistry of the C9-C 14 bond was designed using diene 157, which was functionalized effectively in four steps into the oxazolone 158. Under radical conditions pentacycle 159 was obtained in approximately 10% yield. 1 H NMR analysis confirmed a trans relationship between the protons at C9 and C 14 but it was difficult to ascertain the configuration of these chiral centers relative to CS or C6 and so the product was assigned either as 159a or 159b With these two promising results Hudlicky and coworkers then focused on constructing the entire morphine skeleton. In the second-generation synthesis, o-bromo

PAGE 40

33 ,D-bromoethylbenzene 160 was subjected to enzymatic conditions with the expectation that the larger bromoethyl group would direct the cis-dihydroxylation. This assumption proved to be correct because diol 161 was isolated from the fermentation broth using E. coli JM I 09 (pDTG601 A). Diimide reduction of 161 followed by acetonide protection of the cis-diol moiety provided the dibromide 162. Introduction of OH -J-o cor I 0 't~:c1 HO,(() I b,c Br Br~ Br Br 160 161 162 td -J-o -J-o -J-o o_(Qyo o_(q 0, I (()yo NFO Br\_. 0 0 0 164a 164b 163 Scheme 34 Conditions: a) JM109 (pDTG601); b) PAD, HOAc; c) DMP, pTSA; d) 2oxazolidone, NaH; e) Bu3SnH, AIBN, benzene reflux. the oxazolidone gave 163, which upon exposure to radical conditions gave a 2: I mixture of octahydroisoquinolones 164a and 164b in favor of the isomer with an epi-C9 configuration (Scheme 34). The lack of stereo control was attributed to the negligible steric effect of the acetonide. Since the epi-isomer was in greater availability the decision was made to pursue the synthesis of ent-morphine. Mitsunobu inversion with bromoguiacol generated the precursor for the second radical cyclization, ether 166. Treatment with Bu 3 SnH/AIBN gave pentacycle 167. To complete the synthesis of the ent-morphinan, the silyl-protecting group was removed followed by reduction of the

PAGE 41

34 oxazolidone to yield the alcohol 168. A double Swem oxidation was utilized to convert 168 into the rather unstable ketoaldehyde 169 which upon exposure to trifluoromethanesulfonic acid led to the formation of alcohol 170 which contains the complete morphinan skeleton. Me0)9 M e O 0 1,0 HO:e:O a. b 0 ~ 0 C )I, ~. TBso H H 165 O 166 167 td MeO MeO M e O OH e OH 170 169 168 Scheme 35 Conditions : a) 150, Bu 3 P, DEAD THF; b) TBAF, THF ; c ) Bu 3 SnH AIBN benzene reflux ; d) DIBAL-H CH 2 C}i; e) oxalyl chloride, DMSO Et 3 N CH 2 Cl 2 ; f) TFA. Currently 57 58 a third generation approach using intramolecular Diels-Alder is being developed (Scheme 36) The major improvement in the third generation is the use of a ( E Z ) -diene sy s tem as seen in 171 which will invariably lead to an inver s ion at the C9 ( morphine numbering) stereocenter preceding the formation of compounds of the type 173. Using a nucleophilic displacement by the nitrogen tether onto the leaving group would form B, C, D, and 0rings with correct stereochemistry in 174

PAGE 42

35 r, .. ...... .._ r ..... ...... "'I I I ,~x-Jj -~-Jl o~-~ ~x __ o~x: TDSO' N J TDSO'~NHAc 171 172 ,," ......... I .............. I I I I TDSO:~:HAc 174 173 Scheme 36 Another noteworthy approach to the morphinan skeleton was recently published by Hudlicky and coworkers. 59 It involves a rare Heck cyclization to yield an advanced pentacyclic precursor of morphine. Biooxidation of (2-bromoethyl)-benzene 157, with Escherichia coli JM 109 (pDT601) followed by reduction of the less hindered double bond with diimide yielded diol 175 in 80% yield (Scheme 37). The next step involved protection of the two diol moieties as the benzoate. This was followed by displacement of the bromine by oxazolidine-2,4-dione to afford the dibenzoate 176 After reduction of the more reactive amide carbonyl with NaBH 4 N-acyliminium ion-olefin cyclization and subsequent elimination of the alkyl chloride afforded the tricycle 177. This was followed by deprotection of the benzoate groups and subsequent selective protection of the

PAGE 43

36 homoallylic hydroxyl group as the TBDMS ether. Using Mitsunobu protocol the HO, _lBr_a -HO ,o 157 y RO _~o Br I N ro 179 O ij RO., 180 HO,_()Br b C ---HO .lNJ HO 'OOJ.-.../0 HO' ld e,f 175 176 9H <;>B z RO_M ~'r-0 g, h I N B z O ,CQ' .. ro 0 178 R=TBDMS 0 177 Scheme 37 Conditions: a ) E. coli JM109 (pDTG601); b) PAD AcOH MeOH ; c ) PhCO 2 H, DCC, DMAP, CH 2 Ch; d) Oxazolidine, tetramethylguanidine, THF reflux; e) NABH 4 MeOH ; f) AlCl 3, CH 2 Ch; g) DBU, DMSO, reflux ; h ) LiOH MeOH ; i ) TBDMSOTf imidazole DMF ; j) Bu 3 P, DEAD, bromoguiacol THF; k) Pd(PPh 3 )4, proton s ponge, toluene, reflux unprotected alcohol was converted into the bromoguaiacol derivative to give intermediate 179. Heck cyclization of the tetrasubstituted olefin yielded the tetracycle 180 as the only identifiable product. In a recent publication in Organic Letters, 60 Ogasawara and co-worker undertook a rather elaborate approach to the morphine skeleton that deserves mention because of their clever approach to the construction of the C 14 stereocenter correctly and also their

PAGE 44

37 construction of the C9-C IO bridge. Starting from a mixture of the alcohol 181 they MeO Meo MeO MeO OH a ,,,OAc + 181 ~co 3 [(+)-(R)-182 MeOH (4 7 %: >99 % ee) 82 % (+)-(R)-183 MeO MeO OH ()-(S)-184 ( 48 % : 97 % ee) Scheme 38 Conditions: a) vinyl acetate, lipase PS, Bu 1 Ome, 37 C. are able to obtain the pure S-isomer through an optimized pathway6 1 (Scheme 38 ) using vinyl acetate. Even though this synthesis was undertaken with the racemic mixture the use of isomer 184 is projected for a future synthesis of natural morphine. Starting from the mixture of alcohols 181 they synthesized the bromoacetal 185 as a mixture by utilizing ethyl vinyl ether in the presence of NBS (Scheme 39). Under radical cyclization conditions, they were able to obtain the cyclized product in moderate yields. The authors attributed this to the steric hindrance caused by the methoxy group in the 2-position of the aromatic ring. The cyclized product 186 was converted in 3 steps into the ketone 190 Reduction of the ketone with NaBH 4 yielded the alcohol 191 diastereoselectively. This result might be due to prior coordination of the borohydride reagent to the pivaloyl moiety which results in hydride delivery to the ~-face of the molecule. The xanthate 192 (Scheme 39) obtained from the alcohol 191 was then therrnolyzed to afford the cyclohexene derivative 193 in 81 % yield. Allylic oxidation of 193 using chromium

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38 trioxide and 3,5-dimethylpyrazole complex in CH 2 Cl 2 afforded the enone 194. Using MeO Meo Br MeO O,,(OEt MeO a b ... 161 185 MeO MeO J MeO OPiv MeO 190 189 MeO Meo Meo OPiv~MeO OPiv ~OH 191 192 OEl c 186 OPiv MeO ~MeO MeO MeO )I, 187 id MeO MeO 188 OPiv 193 Meo MeO 0 OH lj 0 194 OPiv Scheme 39 Conditions: a) EVE, NBS, Et 2 O. b) Bu 3 SnH, AIBN (cat.), benzene. c) CPBA, BF 3 .OEt 2 d) LiAI~, THF. e) Piv-Cl, pyridine. f) PDC, CH 2 Ch. g) NaB~, iPrOH. h) Mel, CS2, NaH. i) a-C6~Ch, reflux. j) CrO3 3,5-(Mehpyrazole. Sakurai conditions allyl functionality was introduced at the C 14 center (morphine numbering) by treatment of 194 with allytrimethylsilane (Scheme 40) in the presence of titanium (IV) chloride. Ketone 195 was then transformed into the ketal 196 followed by

PAGE 46

MeO Meo OPiv 0 194 MeO MeO MeO MeO 0 195 0 0 \_J 198 39 MeO Meo OPiv /?' MeO OPi v MeO 0 0 \_J 196 t c 0 0 \_J 197 Scheme 40 Conditions: a) allylTMS, TiC1 4 CH 2 Cli, -78 C b ) ( CH 2 OH h, p-T s OH benzene reflux. c) OsO 4 (cat.), NaIO 4 d) (CH 2 OHh, p-TsOH, benzene, reflux reductive cleavage of the olefin in 196 to afford the aldehyde 197 Upon reflux in benzene in the pre s ence of ethylene glycol and catalytic amount s o f p-toluene s ulfonic acid the hydrophenanthrene 198 was obtained in 85 % yield. Construction of the Dr ing was achi ev ed using Parker conditions, which involved deprotection of the pivaloyl group followed by Mitsunobu ( Scheme 41 ) coupling of the free alcohol 199 with N methyl-p toulenesulfonylamide to give the tosylate 200. Treatment of the tosylate with s odium naphthalenide afforded the morphinan 201 in 89% yield via concomit a nt detosylation followed by regioselective cyclization. Morphinan 201 was then converted in 3 step s to the morphinan 202 which is the O-methylated analogue of dihydrothebainon e 35 ( page 14 )

PAGE 47

MeO MeO 0 0 \_j 199 MeO OH MeO 0 0 \_j 200 40 MeO MeO NMeTs MeO MeO 0 0 0 \_j 202 NMe NMe Scheme 41 Conditions: a) LiAlH 4 MeNHTs, Bu 3 P, DPAP. b) Sodium naphthalenide, THF, -30 C. Chelated Enolate Claisen Rearrangement s In 1977 Wolfgang Steglich 62 63 reported the synthesis of a series of amino acids utilizing a Claisen rearrangement. This was the first time the Claisen rearrangement had been extended to the synthesis of this important class of compounds. Steglich and co workers first synthesized N-benzoyl a-amino acid esters with a general structure such as 205. After transesterification with the allyl alcohol 206, they then observed that under dehydration conditions oxazoles were formed. The oxazoles thus formed concomitantly rearranged without isolation to form oxazolones 209 (Scheme 41). Under conditions of hydrolysis they observed the formation of P-amino acid with the general structure of 210 in yields up to 95%. The oxazole intermediate 208 can be seen as a trapped enolate

PAGE 48

41 whose geometry is fixed by virtue of being in the five membered oxazole ring. This ~~o, 0 203 o I ~N V H 210 Scheme 41 d.:OH O O HO~ [8i0 ] ~I'j~o, NaH ll) H O 4A Mol. Sieves 205 ,. hydrolysis [3 3) Oyf~ N 0 d;;Nb 209 208 important aspect of the reaction meant that the sigmatropic rearrangement could proceed with stereoselectivity. Unfortunately when the substituent a.to the nitrogen is hydrogen there is epimerization at that center leading to a non-stereoselective rearrangement. Paul Bartlett 64 in 1982 decided to investigate the work done earlier by Steglich. His goal was to compare these conditions to the Ireland Claisen 65 rearrangement conditions. Also important was the utilization of this reaction in the synthe s is of y unsaturated amino acids. He also wanted to study the stereochemical influence if any of the a.-substituent in the Claisen rearrangement. Deprotonation Conditions : B a rtlett and coworkers used 2 1 equivalents of LDA to effect enolization The found that shorter ( 2.5 min ) or longer ( 40 min) enolate generation times had no significant influence on yield or

PAGE 49

42 stereoselectivity. Also the use of TBDMS chloride instead TMS chloride as the silylating agent did not increase yield or stereoselectivity. Reaction in a less polar solvent (ether) proceeded with a slight increase the stereoselectivity but led to a decreased yield. Table 1. Influence of Conditions on Rearrangement of Amino Esters 0 0 0 BocNH~o Boc:c BocNHD H I 0 ,,,,,;:::. I # H H 211 212 213 Conditions Yield/% Ratio 212/213 *Standard 60-65 9 Ether 45 10 20% HMPT/THF solvent 51 4 KDA 0 1. 1 equiv of MgC1 2 42 IO *Deprotonation at -75C with 2.1 equiv. of lithium isopropylcyclohexylamide or lithium diisopropyl amide; silylation with Me3SiCI after 10 min; warming to reflux for lh ; hydrolysis of silyl ester. Contrastingly the use of HMPA and TMEDA, which are highly dissociating systems as co-solvents resulted in both lower yield and lower stereoselectivity (Table 1 ). The use of a lewis acid (MgCh) also slightly increased stereoselectivity but led to a lower overall yield. The result of this study is in concurrence with the accepted principle of an enolate geometry and a chair-like transition state for aliphatic substrates. He proposed that coordination of the counter ion between the carbonyl oxygen and the nitrogen anion is at least partly responsible for the E-enolate geometry. Influence of N-Protecting Groups: A variety of N-protecting groups were explored (Table 2) with varying yields and stereoselectivity. Overall the Boeprotecting

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43 Table 2. Effect of N-Protecting Groups on Rearrangement of trans ButenaJGlycinates 0 0 0 R=N~ RB R=Ni;H H I OH 0 ,/? I /? H H 214 215 216 R yield/% Ratio 215/216 1. Boe 60-65 9 2. Cbz 65 4 3 Bz 65 5.4 4. CF 3 CO 58 1.5 5. Phthaloyl 0 6. Et 2 0 group gave the best results. The reduced stereoselectivity with the trifluoroacetyl derivative ( Entry 4 ) was explained by reduced importance of the chelation effect due to the increased acidity of the nitrogen The inability to obtain products in the case of the phthaloyl and N N-diethyl analogues was attributed to the lack of an extended conjugated system for nitrogen-substituted enolate stabilization. Uli Kazmaier 66 7 7 in 1994 published an article about a remarkable variation to the classical enolate Claisen rearrangement that would revolutionalize the synthesis of both natural and unnatural amino acids It had already been established by Steglich 62 63 that enolizable amino acids could undergo rearrangement with moderate to good stereoselectivity if the enolate geometry was fixed either in the form of an oxazole ring or

PAGE 51

44 constricted due to chelation with the counter ion. While Bartlett 6 4 had always converted the enolate into the silylketene acetal, Kazmaier discovered that by allowing the chelated enolates (Figure 1) to simply warm up from -78 C to about -15 C resulted in M : metal Y : protecting group Figure 1. Nature of Chelated Enolate in Kazmaier Claisen Rearrangement. rearranged products in excellent yields and also high diastereoselectivity. The chelated enolates had several advantages. Since the chelated enolates are significantly more stable than the corresponding non-chelated lithium enolates, they can be warmed to room temperature without decomposition and side reactions such as ketene formation via elimination can be suppressed. Secondly because of the fixed enolate geometry due to chelation, the reactions proceed with high diastereoselectivity. Due to the inherent flexibility of this chemistry, many variations of protective groups Y (Figure 1) can be used Varying the metal M used can also modify the selectivity and reactivity of the reaction. Since the coordination sphere of a metal ion is not saturated in a bidentate enolate system, this allows for additional coordination with external ligands. Lastly transformation of the high-energy ester enolate into a chelate-bridged stabilized carboxylate provides a good driving force for the reaction When this reaction was applied to acyclic allylic esters the results obtained confirmed a preferred chair-like transition state. Even though different Lewis acids were utilized Zn Ch produced the best results (Scheme 42). The formation of the syn product

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BocHN~O 0 218 Scheme 42 2.2 eq LDA 1.2 eq ZnCl 2 45 Bocffii~o zn O -r ~ocHN COOH 219 220 is explained by a preferential rearrangement through the chair-like transition state (Figure 2), which avoids the steric interactions between the pseudoaxial hydrogen and fid-H 0 NY \/ Zn / s s Chair !tr \ I H Zn, j____ .... / 'r '-.:){ s s Boat Figure 2. Chair vs boat transition states in the Kazmaier Claisen Rearrangement of acyclic substrates. the chelate complex in the boat transition state. The results obtained in the acyclic series of experiments are summarized in Table 3, which details the influence of substituents at the double bond, the olefin configuration and the different nitrogen-protecting groups as related to the yield and diastereoselectivity of the rearrangement products. All the substituted ally! esters displayed high diastereoselectivity where the formation of syn products from trans substituted esters and anti products from cis substituted esters were favored.

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46 Table 3. Results from Acyclic Kazmaier Claisen Rearrangement R3 R2 R2 R3AR1 R2 R2 rYR1 _:f~R1 RfrR1 R4 2.2 eq LDA XHN~O R~o 1 .2 eq ZnCl 2 XHN "-::::: \ XHN COOH XHN COOH 0 zn O 221 222 223 224 X [a] RI R2 R3 R4 [b] Yield Diastereomer ratio ()-223: ()-224 I z H H H H 88 2 z H CH 3 H H 78 3 z H H C 3 H 1 H 76 95:5 4 z CH 3 H CH 3 H 88 93:7 5 z C 2 H 5 H CH 3 H 98 95 : 5 6 z C 2 H 5 H H Ciig 73 95 : 5 7 Boe CH 3 H CH 3 H 84 96:4 8 Boe H H C 3 H1 H 78 96:4 9 TFA H H C 3 H7 H 79 95:5 10 TFA C 2 H5 H H C4H9 65 94 : 6 11 z H H H D 75 98.5:1.5 [a] Z = benzyloxyearbonyl, Boe= tert-butoxyearbonyl, TFA =trifluoroaeetyl [b] D = tert-butyldiphenylsilyl Due to the excellent results obtained with the acyclic substrates, the chemistry was applied to cycloalkenyl glycinates (Scheme 43). These substrates were of particular interest because their rearrangement would yield y,o-unsaturated amino acids a class of compounds with high activity as enzyme inhibitors. Indeed it had been previously postulated that cyclic allylic esters prefer to rearrange via a boat like transition state. Kazmaier and coworkers investigated the effect of ring size as well as the metal salt used for chelation of the ester enolate (Table 4) As predicted, with the cyclic allylic esters the syn-product is preferred and the best results with respect to yield and stereoselectivity

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y)n BocHN~O 0 225 Scheme 43 I) 2 5 eq LDA 1.2 eq MX 0 47 X BocHN COOMe X BocHN COOMe 226 227 are obtained with cyclohexenyl glycinates (n = 2). All the metal salts used gave good product yields in the cyclohexenyl case (n = 2). The crude amino acids obtained were directly converted into the corresponding methyl esters using diazomethane The best results were obtained with zinc chloride and are summarized in Table 4. Table 4 Results from Rearrangement with Zinc Chloride. n 2 3 4 % Yield 79 83 73 57 Ratio 226:227 80: 20 90 : 10 92 : 8 86 : 14 It was noted during this study that homologous cycloheptenyl substrates (n = 3) showed similar degrees of diastereoselectivity as in the cyclohexenyl case. However increase in ring size to the more flexible cyclooctenyl case (n = 4) resulted in decrease in selectivity. Also noteworthy was the fact that diastereoselectivity in the cyclopentenyl case ( n = I) was lower than that observed for the cyclohexenyl and cycloheptenyl cases respectively. The product formation as well as the diastereoselectivities observed for the six and seven membered esters were explained by rearrangement through a boat-like transition state 6 7

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48 which minimizes the steric interactions between the cycloalkenyl ring and the solvated chelating metal (Figure 3) A~ S, ,,~N ,. 1 \ ,M 0 s 0 chair Boat Y=Boc S = Solvent M=Zn R=TDS Figure 3. Chair vs boat transition states in the Kazmaier Claisen Rearrangement of cyclic substrates. In summary Kazmaier has successfully demonstrated the utility of his variation of the classic enolate Claisen rearrangement. The chelated ester enolate rearrangement is not partial to acyclic substrates but can also be practical for cyclic substrates. High diastereoselectivity and excellent yields are observed for the rearrangements, which proceed via a boat-like transition state for cyclic esters and a chair-like transition state for acyclic esters. In 1997 Hudlicky 78 and coworkers applied the Kazmaier chelated enolate rearrangement to their chemoenzymatic approach to morphine Model studies to obtain optimum reaction conditions were undertaken on compounds of type 232 These glycinates were obtained first by direct oxidation of the aromatic precursor by either the mutant strain Psuedomonas putida F39/D or the more potent recombinant organism Escherichia coli JM109(pDTG601A) to render the diene-diols of type 229 After diimide (potassium azodicarboxylate) reduction of the less hindered double bond the distal

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49 R R R 6 (XOH b _.. (XOH a :,,. OH OH 228 229 230 R = Me, Cl Ph, 2-MeOPh C :,,. OOH OTDS 231 id 232 Scheme 44. Conditions: a) Toluene dioxygenase expressed in Pseudomonas putida F39/D (R = Me; 3.5 g/L) or Escherichia coli JM109 (pDT601A) (R = Cl; 10.0 g/L), (R = Ph; 3.0 g/L), (R= MeOPh; 2.5 g/L). b) PAD, HOAc, MeOH, 0C -rt, 12h., 85 95%. c) TDSCl, imidazole, DMF, 5 C 8h., 80 90%. d) Boc-Gly, DCC, DMAP, CH 2 Ch 24 48h., 75 90%. hydroxyl group was then protected as the THS-ether. DCC coupling protocol was used to convert the proximal hydroxyl group into the Boeprotected glycyl derivative 232 (Scheme 44). The glycinates (R = Me, Cl, Ph, 2-MeOPh) served as the substrates for the first Claisen study. The results obtained were quite promising in term of yield All the glycinates underwent rearrangement under the Kazmaier conditions with yields ranging from 25 90%. Surprisingly the configuration of the major product of the rearrangement was opposite to that expected (Table 5). Due to the fixed enolate geometry, which is a result of the formation of the chelate, the only variable would be the predominance of one transition state over the other. In this case the chair transition state clearly predominates leading to the product ratios observed.

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50 Table 5. Ratio of C9 Epimers for Kazmaier Claisen Rearrangement of glycinates. 0 R NHBocJo :6 TOSO 232 R 233 234 O ve rall yield Ph 75% 25% 80 % CH3 75 % 25% 90% Cl 90 % 10 % 25 % 2-MeOPh 50 % 50 % 75 % Due to the lack of control of stereoselectivity, the authors considered epimerization of the lactones resultant from treatment of the epimeric amino acids with tosic acid (Scheme 45). They reasoned that since the bulky protected amino acid was Toso' lJOOH u 'NHBoc Toso' 233 lXOH u NHBoc 234 Scheme 45 R TsOH, Ci)= CR,Cl 2 )lo o Toso' 235 NHBoc R TsOH, ctr CH 2 Cl 2 0 Toso' NHBoc 236 OBUffHF more accessible in the wrong isomer (situated on the concave face of the bicyclic molecule), it could be effectively epimerized to the more stable isomer. Hence after treatment with DBU in THF for 37h they were able to achieve an 80% epimerization of

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51 235 to g1 ve the isomer with correct stereochemistry at C9 and C 14 ( morphine numbering ). Inspired by the work of Kazmaier and the subsequent application of this chemistry by Hudlicky and co-workers 78 7 9 in their approach to the morphine skeleton Percy 79 and co-workers investigated the possibility of generating y-oxo-~ ~-difluorinated amino acids by chelated [3.3]-sigrnatropic rearrangement of protected glycinate esters of readily available difluoroallylic alcohols This type of rearrangement had the potential to produce amino acid s having a CF 2 center a to a carbonyl functionality through relea s e of the masked carbonyl group ( Scheme 46). OMEM FC) 2 237 Scheme 46 I 3 e qiuv LDA THF 78 C 2 HCHO OMEM FYYH F OH 238 HO~NHX O 239 ?MEM EDC DMAP F YYH C8iCl 2 F o-ir--NHX 0 240 1 1 3 equiv LDA THF 78 C2. ZnCl 2 OMEM FrH B oc HN C0 2 H 241 The synthesis started with difluoroallylic alcohol 238 which wa s converted into the glycyl ester 240 under DCC coupling conditions. The glycinate was then subjected to modified Kazmaier Claisen condition which involves the use of 3 equivalents of LDA added in a reverse addition order to that proposed by Kazmaier ( the Lewis acid is added

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52 after generation of the enolate with LDA). After acidic workup the only isolated product was the rearranged acid 241. In summary the synthesis of morphine has resulted in ingenious strategie s by different research groups over the years to tackle this small yet challenging molecule. While the focus of the various syntheses has been synthesis of the target, the chemistry generated by this pursuit and its application to alkaloid chemi s try is the legacy of morphin e synthesi s. Starting from Gates' 15 1 6 synthesis to the latest synthesi s by Mulzer 2 1 25 it is fascinating to see the many different synthetic p a thways that have been employed in morphine synthesis. Sigmatropic rearrangements have played a s mall yet important role in morphine synthesis The syntheses by Parson s, 20 Rapoport 50 and Mulzer 2 1 25 effectively used sigmatropic rearrangements to establi s h the Cl3 quaternary center of morphine The chelated enolate Claisen Rearrangement had modest beginnings from Steglich 62 63 and coworkers and later Bartlett 64 and coworkers The idea was greatly improved by Kazmaier 66 77 and coworkers who have developed it into one of the more powerful tools in amino acid chemistry. The next chapter of this dissertation will discuss a chemoenzymatic approach to the synthesis of the morphine skeleton. This approach use s a disconnection of the morphine molecule that is unlike any of the preceding s ynthe s e s. More importantly it utilizes a sigmatropic rearrangement the Chelated Enolate Claisen rearrangement ( Kazmaier Claisen ) to establish control of C9 and C 14 stereocenters of morphine in addition to attempting to establish the C 13 quaternary center. Additionally the synthesis uses an enzymatic step which is capable of converting cheap readily available arom a tic

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53 precursors into either catechols (A-ring of morphine) or cyclohexadiene diols ( C-ring of morphine ). With all these factors combined, the chemoenzymatic approach becomes an attractive route to the morphinan skeleton. In 1968 as a result of studies conducted by David T. Gibson 87 on the microbial oxidation of aromatic hydrocarbons by soil bacteria, the first stable cis-diol was isolated. The organism responsible for this transformation was a mutant strain of the bacteria Pseudomonas putida ( Fl ) and was designated Pseudomonas putida ( F39/D ) This strain was devoid of the c is-diol dehydrogenase enzyme hence only produced the cis-diene diol. The use of these dials as synthons was initiated in the late 1980' s with work done b y Ley 88 and coworkers who achieved a racemic synthesis of pinitol from meso-cis-diols derived from benzene. Since then one of the leading researchers in this area of chemistr y has been Hudlicky who has been able to utilize the cis-diene-diols as chiral synthons 86 in the synthesis of a wide variety of compounds In 1988, in the first publication by Hudlicky and co-workers in this area, the idea of Claisen rearrangements of the allylic alcohol unit of the cis-diols was proposed. This idea was actually reduced to practi_ce in 1997 and thus began the initial studies that featured the Claisen rearrangemen! as a key step in the chemoenzymatic approach to the morphine skeleton. 8 6 In the first generation of this approach, conditions for a suitable Claisen rearrangement that would lead to the transfer of stereochemica1 information inherent in the cyclohexadiene-diols were investigated. The Kazmaier-Claisen rearrangement offered the best conditions for this purpose. The goal was to synthesize ~-amino acids of different complexity bearing chiral side chains. Eventually such compounds would

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54 contain the correct stereochemistry at the C9 and C 14 (morphine numbering) centers of morphine. In the initial model studies, as reviewed in the historical chapter it was discovered that even though the Claisen rearrangements proceeded with low stereoselectivity, there was the potential to achieve complete control of the C9, C 14 stereocenters through equilibration of isomers. Efforts in the initial stages of this approach were also directed at finding efficient ways of obtaining the bicyclic skeleton One of the opportunities for construction of this bicycle was through direct enzymatic dihydroxylation of substituted biphenyls. Indeed when selected biphenyls were subjected to biooxidation conditions, the resultant diene diols were obtained. 78 Unfortunately it became apparent that as the degree of oxidation in the substrate increased, the yield for the enzymatic process decreased considerably probably as a result of poisoning of the bacteria by the oxygenated substrate. This dissertation will focus on the progress made in the second generation of the chemoenzymatic approach to morphine. The discussion will address how control of the C9 and C 14 centers of morphine was achieved through the use of the Kazmaier-Claisen rearrangement and epimerization. It will also give an account of the progress made toward a formal total synthesis of morphine via Overman' s intermediate. In addition some applications in the field of matrix metallo proteinase inhibitors, compounds that are connected to morphinan intermediates through common structural elements will be discussed. Finally recent advances in the chemoenzymatic approach to morphine will also be discussed.

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55 CHAPTER 3 RESULTS AND DISCUSSION Introduction The structural complexity of the morphine molecule has prompted many innovative routes to the morphinan skeleton as was detailed in the first chapter. The synthetic design utilized in the chemoenzymatic synthesis of the morphinan skeleton makes it a very attractive route to the morphine molecule. Retrosynthetically, the approach is directed toward the target through the intermediate ~-cyclohexenyl amino acid 242. The amino acid could be obtained through a Claisen rearrangement of the Xxx Scheme 47 RO RO RO OOH RO ===> }loc 0 N1 I -O HO s-HO 1 242 s 243 S = solvent u M=Zn RO:Q RO RO RO B ( OH )i RO RO 246 Br Br <==== ====> H0,6 H0:6 diimide HO h' HO HO 248 247 244 245

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56 glycinate ester 243 which could be synthesized from the biphenyl diol derivative 244. This synthon is available either from direct biooxidation of the biphenyl precursor 245 or through the coupling reaction between the aromatic boronic acid 246 and diol 247 derived from diimide reduction of the cis-diene diol 248 (Scheme 47). The retrosynthetic strategy outlined above uses remarkable design elements that deserve mention. 1) The C-ring of morphine can essentially be described as a cyclohexenyl cis-diol unit. This moiety can be recognized in the structure of the chiral hoH ~OH 248 Scheme 48 Br HO.,~ Ho '~ 248 cis-cyclohexadiene diol 248 with the correct absolute stereochemistry at CS and C6 set as a result of the enzymatic transformation (Scheme 48). 2) The approach capitalizes on the recognition that the main backbone of the morphine skeleton consists of an oxidized biphenyl unit 252 (Figure 4). This structural component, namely 244 (Scheme 47), is also present in various alkaloids like pancratistatin the synthesis of which is being pursued in the Hudlicky group. This unit could be obtained as outlined above either through direct biooxidation of a biphenyl precursor or through the coupling of an aromatic boronic acid with cis-cyclohexadiene diol (Scheme 47). 3) The allylic alcohol unit present in diol 244 (Scheme 47) allows for the introduction of the amino acid side chain into the molecule through a Claisen rearrangement. 4) Finally the C13 quaternary center could be

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morphine codeine OH 250 pancratistatin 57 7-deoxypancratistatin OH 251 narciclasine lycoricidine Figure 4. Synthetic targets with oxidized biphenyl unit. established by utilizing the allylic alcohol moiety present m intermediate 254 via a RO RO ==> I 253 254 t RO RO RO RO }loc <=== ~~0I -O s1 r HO HO s 242 S = solvent Scheme 49 M=Zn

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58 second Claisen rearrangement. The amino acid 254 is also set up for closure of the CI 0C 11 using a Friedel-Craft reaction after conversion of the acid into the aldehyde or the acid chloride. Before the discussion proceeds into the actual execution of the approach, a brief history about the development of the chemistry of enzymatic dihydroxylations would be in order. In 1968 as a result of studies conducted by David T. Gibson 87 on the microbial oxidation of aromatic hydrocarbons by soil bacteria, the first stable cis-diol 256 was I Q Cl 255 Scheme SO P putida Fl,.. toluene dehydrogenase P. putida F39/D wild strain of P. putida Fl ~OH YoH Cl 256 t P. putida Fl cathechol dehydrogenase CH 3 OH OH Cl 257 l acetate isolated. The organism responsible for this transformation was a mutant strain of the bacteria Pseudomonas putida (Fl) and was designated Pseudomonas putida (F39/D). This strain was devoid of the cis-diol dehydrogenase enzyme hence only produced the cis-diene diol 256 (Scheme 50). The use of these diols as synthons was initiated in the late 1980' s with work done by Ley 88 and coworkers who achieved a racemic synthesis of pinitol from meso-cis-diols derived from benzene. Since then, one of the leading researchers in this area of chemistry has been Hudlicky who has been able to utilize the cis-diene-diols as chiral synthons 86 in the synthesis of a wide variety of compounds (Figure 5).

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59 In 1988, in the first publication by Hudlicky and co-workers in this area, the idea of Claisen rearrangements of the allylic alcohol unit of the cis-diols was proposed. This idea was actually reduced to practice in 1997 (pg 49-52, historical section) and thus began the initial studies that featured the Claisen rearrangement as a key step in the < OH HO0 ,,, OH HO~OH 0 0 OH D-chiro-inositol 258 QH R 0 OH OH pancratistatin R = OH 7-deoxypancratistatin R = H 250 MeO 0 ent-morphinan 260 OH QH HO~c J..J j 13-i1 NH2 (-)-trihydroxyheliotridane 259 D-er ythro-s pingosine 262 QH R 0 narciclasine R = OH lycoricidine R = H 251 O~~OH ~OH OH OH kifunensine 261 QH HO:CXOH HOX):O = OH ~ HCI ,, HO OH OH amino-inositol dimer 263 da:;rOEt HO 0 : : 0 HO-' OEt specionin 264 Figure S. (Examples of Targets Synthesized from cis-diols) chemoenzymatic approach to the morphine skeleton. 86 In the first generation of this approach, conditions for a suitable Claisen rearrangement that would lead to the transfer of stereochemical information inherent in the cyclohexadiene-diols were investigated. The Kazmaier-Claisen rearrangement offered the best conditions for this purpose. The goal was to synthesize ~-amino acids of

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60 different complexity bearing chiral side chains. Eventually such compounds would contain the correct stereochemistry at the C9 and C 14 (morphine numbering) centers of morphine. In the initial model studies, as reviewed in the historical chapter (pages 49-51 ), it was discovered that even though the Claisen rearrangements proceeded with low stereoselectivity, there was the potential to achieve complete control of the C9 Cl4 stereocenters through equilibration of isomers. Efforts in the initial stages of this approach were also directed at finding efficient ways of obtaining the bicyclic skeleton 252 (Figure 4) One of the opportunities for construction of this bicycle was through direct enzymatic dihydroxylation of substituted biphenyls. Indeed when selected biphenyls were subjected to biooxidation conditions, the resultant diene diols were obtained. 78 Unfortunately it became apparent that as the degree of oxidation in the substrate increased, the yield for the enzymatic process decreased considerably probably Table 6. Results from Biooxidation of substituted biphenyls. Rl R2 E coli JM109 (pDTG601A) 265 R 1 = H R2 = H 266 RI = H, R2 = OMe 267 RI= OMe R 2 = OMe Subtrate 265 266 267 R2 R2 OH OH 268 RI = H R2 = H 269 Rl = H R2 = OMe 270 RI= OMe R2 = OMe Yield (g/1) 3.0 2.5 0.8

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61 as a result of poisoning of the bacteria by the oxygenated substrate (Table 6). The low yields that accompanied the biooxidation of 267 to diol 270 the morphine precursor prompted us to seek other ways of constructing this bicyclic skeleton with the intent of functionalizing it appropriately into the morphinan skeleton. This dissertation will focus on the progress made in the second generation of the chemoenzymatic approach to morphine. The discussion will address how control of the C9 and Cl4 centers of morphine was achieved through the use of the Kazmaier-Claisen rearrangement and epimerization. It will also give an account of the progress made toward a formal total synthesis of morphine via Overman's intermediate. In addition some applications in the field of matrix metallo proteinase inhibitors, compounds that are connected to morphinan intermediates through common structural elements will be discussed. Finally recent advances in the chemoenzymatic approach to morphine will also be discussed. First Generation SynthesisControl of C9 and Cl4 Stereocenters of Morphine The first few steps in the synthesis focused on the Suzuki Coupling protocol in the synthesis of biphenyl diol derivative 270 (Table 6) which would then be functionalized into a glycinate ester. Starting from guaiacol (271), a known compound, which is not commercially available, we employed a procedure used by Hoshino 83 and coworkers in their synthesis of Iycoramine. It involves first, the generation of a tertbutylamine bromine complex by addition of bromine to the amine at -68 C for a 24 48 hour period. After formation of the complex, which is the actual brominating agent, the reaction mixture is cooled back to -78 C at which time a solution of guaiacol dissolved in minimum amount of methylene chloride is added dropwise (Scheme 51 ). The reaction

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62 typically gives a 50-60 % yield of bromogiuacol (150) m addition to two other CC OH OM e 271 LoH llAOMe 150 ---"--... LoM e llAOMe 272 d~~ c ;::~M e llAOMe 273 Scheme 51. Conditions: a) Br 2 tert-butylamine toluene -78 C 60-62 %; b ) Mel K 2 CO 3 Acetone, rt. 90-94 % ; c) Mg Ii (cat.) B ( OEt h, NH 4 Cl ( sat'd ), 80-85 %; d ) BuLi, B(OEt) 3 N~CI (sat'd), 77-80 % regioisomers. Isolation of bromogiuacol from the reaction mixture is achieved by Kugelroh distillation The next step involved methylation of the phenol with methyl iodide in acetone, employing potassium carbonate as the base. These reactions typically gave a 90-94 % yield of the dimethyl bromocatechol. In the next step the 1 2dimethoxybromobenzene (272) was converted into the corresponding boronic acid ( 273 ) The boronic acid was obtained by using either Grignard condition s or lithium halogen exchange with t-butyllithium. The Grignard conditions gave better overall yields The other coupling partner became available from diimide reduction of the chiral cyclohexadiene diol 248 with potassium azodicarboxylate (PAD ). This procedure which has been optimized in the Hudlicky group, typically gives about 90-95 % of the reduced product 247 ( Scheme 52 ). We also synthesized the boronic a cid derived from v i nyl bromide 247 with the intent of coupling it with 1 2-dimethoxybromobenzene 272 (Scheme 52). Conversion of acetonide 274 to the boronic acid 275 proceeded with low

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63 yields (45-50 %) hence making this route to the coupled product unfavorable. LOH UOH a b > 248 275 Scheme 52. Conditions: a) PAD, HOAc, MeOH, 0 C-rt., 14 h, 90 %; b) DMP, Acetone, TsOH, 95%; t-BuLi, B(OEt)J, -78C, NH 4 Cl (sat'd), 45-50 %. We now turned our attention to the Suzuki Coupling 81 82 step, a technique which has become one of the more efficient methods of bond formation between an aromatic ring and an sp 2 center. In our hands typical conditions involved the use of tetrakis triphenylphosphine palladium (Pd(PPh 3 ) 4 ) as the catalyst and a benzene/ ethanol solvent system with 2M Na 2 CO 3 as the base. The reactions were normally complete after three hours under reflux conditions. Yields were in the 75-80 % range and this was very crucial since the Suzuki coupling was one of the key steps in our synthesis (Scheme 53). MeO MeO:Q B(OH) I a MeO b,c 6::>< ... MeO OH B(OH) 2 273 270 OH 275 Scheme 53. Conditions: a) 0.03 % eq. Pd(PPh 3 ) 4 2M Na 2 CO 3 247, PhH-EtOH, reflux; b) 0.03 % eq. Pd(PPh3) 4 2M Na 2 CO 3 274, PhH-EtOH, reflux; c) H+, THF.

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64 Claisen I-First attempt of Kazmaier Claisen on Morphine Precursor To perform the Claisen rearrangement, we planned to take advantage of the remaining allylic alcohol unit in the bicyclic intermediate 270. In order to ensure selective conversion of the proximal hydroxyl group into the glycinate ester we first had to protect the distal hydroxyl group as its silyl ether. The thexyldimethylsilyl (TDS) group was well suited for our substrate because its bulky nature ensures the protection of the least hindered hydroxyl group, which in this case is the distal hydroxyl. Yields for the step are typically around 90% for TDS-ether 276 Less bulky silylating groups like TMS-Cl tend to lead to a large percentage of product resulting from lack of selectivity in the protection of the distal and the proximal hydroxyl groups The reaction involves first generating the imidazole-TDS complex at -12 C followed by addition of the diol (270) to the reaction mixture. Our efforts led to isolation of silyl ether 276 (Scheme 54). The next stage in the synthesis required the functionalization the proximal hydroxyl group as a glycinate ester MeO MeO OH 270 Scheme 54 THS-Cl Imidazole DMF MeO MeO 276 OH OTHS MeO Meo Gly-Boc DCC, DMAP, CH 2 Cl 2 277 0 0--ll__NHBoc OTHS

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65 the Claisen rearrangement precursor. One of the standard procedures for achieving this type of transformation involves a DCC coupling. 75 In our hands the DCC coupling conditions worked well with Boe-glycine, DCC and catalytic DMAP. Yields ranged from 70-85% Careful workup of the reaction mixture, which requires removal of the reaction solvent (CH 2 Cl 2 ) followed by precipitation of the dicyclohexylurea by-product with diethyl ether a procedure which usually removes about 80 85% of the dicyclohexyl urea (DCU) by-product. Column chromatography is then used to purify the crude mixture. With the glycinate ester 277 in hand we were ready to perform what would be the key step in our approach to morphine. A [3.3] sigmatropic rearrangement to establish the chiral centers at C9 and Cl4 (morphine numbering). As previously discussed, the Kazmaier-Claisen rearrangement provided the best opportunity to perform this transformation. The conditions involve the addition of Lewis acid (usuaJly ZnC)i) to a OMe 0 OMe BocHN_)LO THSO 277 MeO MeO Scheme 55 LDA (2 2 eq ) ZnCl 2 (1.2 eq l 278a 70 OH 278b 30 NHBoc solution of the glycinate ester in THF. After about 15 minutes of stirring the reaction mixture is cooled to -78 C and the base (usually LDA) is added. The reaction mixture

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66 then allowed to warm slowly to room temperature over 36-48h. According to Kazmaier, the rearrangement usually occurs between -10 0 C. In our hands we observed very good conversion of starting material to products with yields of rearranged acids averaging between 75 85% but there were two significant problems. 1) The ratio of the rearranged products 278a and 278b were opposite to that expected We anticipated the product with a syn relationship between the proton at Cl4 and the nitrogen at C9 to be the major product. 2) The two rearranged acids possessed very similar spectroscopic properties so initially it was difficult to ascertain the identity of the isomers. 3 ) These compounds were virtually inseparable using standard chromatographic techniques even after their derivatization into the corresponding methyl esters . The fixed enolate geometry that results from chelate formation in the Kazmaier Claisen rearrangement causes the stereochemical outcome of the rearrangement to be a function of the transition state that the reaction proceeds through For cyclohexyl substrates the unfavorable steric interactions in the chair transition state (Figure 3) S YN I I .... ,,'~, ;M 0 s \ 0 chair R 16 r M-S I t y ,,,,"" I ~ :: N' \ ,_ I Q Boat R = 2 3 dimetho x yphenyl Y=Boc S = Solvent M=Zn R =TDS Figure 6. Chair vs boat transition states in the Kazmaier Claisen Rearrangement of morphinan intermediates. the cyclohexyl ring and the metal chelate causes this transition state to be less preferred to the boat transition state, which is devoid of such interactions. It is very important to

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67 note that Robert Ireland 89 90 who performed rearrangements on silyl ketene acetal analogues of these compounds, observed that both transition states could operate depending on the size and position of the substituents on the cyclohexyl ring. The effect of the large THS group can be neglected, but considerations of the dimethoxy phenyl substituent which is in the a-position to the allylic carbon reveals that in the boat transition state this substituent might have an unfavorable steric interaction with the solvated metal (Figure 6). This leads to two steric arguments; 1) in the chair transition state there is an unfavorable interaction between the solvated metal and the cyclohexyl ring 2) in the boat transition state the steric interactions are between the aromatic ring substituent and the solvated metal. As a result of these opposing steric interactions the energy difference between the two transition states is very small leading to product formation from both pathways In our case the chair transition state is favored resulting in 70 : 30 ratio of products. As previously stated the rearranged acids 278a and 278b had similar spectroscopic properties, and they were virtually inseparable by standard chromatographic techniques One of the options we explored to obtain pure samples of each was to derivatize these acids into the corresponding lactones which would offer a more rigid structure with the anticipation that this might help in the identification of the acids. This transformation was achieved with tosic acid in anhydrous methylene chloride resulting in the formation of the corresponding lactones from the mixture of the epimeric acids (Scheme 56). Even though two possible lactones could have been obtained from this reaction we only observed the lactone derived from the trapping of the benzylic carbocation. Indeed in this way we were able to obtain dimethoxy phenyl lactone 279 in

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68 pure form and were able to obtain spectral data for the compound. Lactone 280 was also Scheme 56 Meo + MeO j TsOH CHiCl 2 anh MeO 0 NHBoc 280 278b H 279 OH NHBoc 0 0 NHBoc 281 isolated and easily converted to lactone 279 through an epimerization reaction with DBU. The data obtained was compared to phenyl lactone 281 which had been synthesized earlier and whose identity had been confirmed by X-ray crystallography. Friedel Craft-Attempt at C 10-C l l Closure Even though we were unable to separate the two epimeric acids 279a and 279b we saw an opportunity to study the feasibility of the Cl 0-C 11 bond ( morphine numbering ) closure through a Friedel-Craft type reaction. We had conflicting literature precedence for this transformation. Ginsburg 3 5 was able to close the Cl 0-C 11 bond under acid conditions from the intermediate acid 282. Although Gin burg s intermediate contains the same bicyclic skeleton as in our example, his compound is much simpler and essentially has only one more functional group, the ketone at CS (morphine numbering ).

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69 MeO MeO 0 MeO COOH MeO 0 l HF 0 , G i n s burg 282 33 M e O MeO OH Mul ze r M e O II :., MeO /I NMe 2 0 0 126 127 Scheme 57 Using hydrofluoric acid he was able to achieve the Friedel-Craft annulation to obtain the desired diketone 33. Mulzer 2 1 25 in his morphine synthe s is made intermediate 126 which also contained the bicyclic unit comprising the A and C-rings of morphine a nd essentially resembles that of Ginsburg, with the exception of the presence of the dimethylamido group resulting from a prior Eschenmoser-Claisen rearrangement step Mulzer was not able to achieve annulation of the B-ring on the aldehyde upon treatment with various Lewis acids (Scheme 57). With these two contrasting results it was difficult to make any predictions as to the outcome of our attempts at B-ring closure. Starting from acid 278 we derivatized it as the acid chloride using thre e different conditions MeO MeO NHB oc 278 Scheme 58 SOCl 2 Lewi s acid Meo BnO PhH "~, THso-' 0 NHBoc 283

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70 Initially we used thionyl chloride as the reagent for this transformation. We realized that these conditions (Scheme 58) were too harsh because we observed cleavage of the thexyl and Boeprotecting groups and or decomposition of the starting material even before addition of the Lewis acid. We saw no evidence of cyclized product (283) in the reaction mixtures and hence decided to resort to milder conditions for synthesizing the intermediate acid chloride. The conditions that we decided to work with involved either making the acid chloride by using oxalyl chloride/DMF or PPh 3 /CC1 4 using conditions analogous to that used by Rapoport 91 in his synthesis of tylophorine. Starting from acid 278, we used a combination of oxalyl chloride and DMF to generate the acid chloride. Typically after four to six hours, we observed disappearance of the OH-stretch of the acid and appearance of a strong signal at 1780 corresponding to the acid chloride. At this point the Lewis acid was added and the reaction refluxed overnight. The various Lewis acids employed were A1Cl 3 Me 2 A1Cl, ZnCii and SnC1 4 The reactions typically after workup led to recovery (Scheme 59) of starting material and a small percentage of by-product due to cleavage of the Boe-protecting group. The results from the triphenyl phosphine/carbon tetrachloride reaction were similar to the oxalyl chloride/ DMF reaction, here too no product from closure of the C 10C 11 bond was isolated. Mulzer 25 in his discussion of his attempt at the Friedel-Craft reaction suggested that there might be a phenomenon similar to that of atropoisomerism of bi phenyl compounds present in these types of substrates. This being the case our A-ring may be twisted out of conjugation with the cyclohexenyl ring making a Friedel-Craft type closure very difficult. The solution to this problem will be to either make the furan ring of morphine or to establish the nitrogen bridge first. This might help to hold the aromatic ring in a more preferable conformation that would allow

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71 for a successful Friedel-Craft closure. MeO MeO MeO a orb MeO )Ir NHBoc NHBoc THso' THso' 278 284 MeO f 0 MeO NHBoc THso 283 Scheme 59 Conditions: a) Oxalyl chloride DMF, CH 2 Cl 2 ; b) PPh 3, CCl 4 THF ; c) Lewis acid (AICh Me 2 AICI, ZnCl 2 and SnCl 4 ). Claisen II-Ireland Claisen on Phthaloyl Ester Our goal still remained to improve the selectivity of the Kazmaier Claisen rearrangement. One of the options we had not explored was a sigm a tropic rearrangement under Ireland 65 89 90 conditions, which we hoped might lead to an improvement in the ratio of rearranged epimeric acids. To attempt the Ireland-Claisen rearrangement we first functionalized the silyl ether 276 into the phthaloylester 285 ( Sch e me 60 ). Under Ireland conditions we observed good conversion of starting ester to products but the product ratio again favored the undesirable epimer 286a More importantly the epimer s were also difficult to separate by column chromatography.

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72 M e O MeO Phthaloyl gly 0 :~ MeO MeO oj(__N OH DCCIDMAP )I, I LOA C1IiC1 2 TMSCI 0 THF 80 % OTHS OTHS 2. CHiN 2 276 285 MeO MeO MeO Meo 0 0 ::re Tttso ::re Tttso 286b 286a 20 80 Scheme 60 At this point we reevaluated our synthetic approach to alleviate the stereoselectivity problem in the Kazmaier-Claisen rearrangement. We rationalized 1 287 Lott UOH Boe Br fyo:A s-~R'o V 248 S 290 Scheme 61 RO~ RO~ 246 THSO THSO B ( OH ) 2 288 OOMe NHB oc H _&,,~~ cc 289b

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73 that the s ource of the problem might be adverse steric interaction between the aromatic substituent and the metal chelate ( Figure 6 pg 67) Our immediate solution to this problem was to attempt the Kazmaier-Claisen on the cyclohexenyl gylcinate ester 290 which has a bromine substituent in the a-position to the allylic carbon Such a substrate would posses a much minor steric interaction in the boat transition state between the solvated metal and the ring substituent (as discussed on pg 67 ) leading to a much improved product ratio This also meant that the Suzuki Coupling s tep which had previously preceeded the Claisen rearrangement would now be performed after the rearrangement. Our new general retrosynthetic scheme would be as represented by Schem e 61. Claisen ill-Kazmaier Claisen of Glycinate of Cyclohexadiene Diol Starting from diol 247 we were able to protect the di s tal hydroxy group as the thexyldimethyl s ilyl ether 291. Using DCC coupling protocol we obtained the glycinate ester 292 We were now in a position to perform the Kazmaier Clai s en on the precursor 247 Scheme 62 THS CI Imid DMF 8 c Br (X OH Gly-Boc DCC DMAP OTHS C1Cl 2 291 B r O 60-"-NHB oc OTHS 292 292 Using 2 2 equivalents of LDA and 1.4 equivalents of ZnC!i we were able to obtain rearranged product epimeric at C9 We observed the yields for the tran s formation increase from 75% to 80-85 %; the ratio of the rearranged acids epimeric at C9 also decreased slightly from a 70 : 30 ratio to a 60: 40 ratio in our favor. But the best aspect of

PAGE 81

74 this reaction was the fact that these epimeric acids, converted to their corresponding methyl esters could be separated by silica gel column chromatography More importantly the faster-eluting major isomer 289a could be equilibrated to the P-isomer (the desired epimer for our morphine synthesis) by an epimerization reaction with DBU Starting from isomer 289a, we are able to obtain a l: l mixture of epimers after 96 hours in refluxing THF. Similar epimerization reactions with TFA and NaOMe gave a 4 : l and 5: 1 ratio of epimers respectively. Even though the reaction is still non-stereoselective we had found a way to obtain the epimer with the correct stereochemistry at C9 and Cl4. This was a huge breakthrough in our synthetic approach because it meant that we now had the opportunity to carry out an enantioselective synthesis of morphine. Br O (:CJl____NHBoc OTHS 292 a, b )lo Br CO Me N9' :amoc vH THSO, 289a 60 C Br CO Me + ~:arnoc -V ~ H THSO 289b 40 Scheme 63. Conditions: a) LDA (2.2 eq.), ZnCh (1.4 eq.), THF, -78 C, 80%; b) CH 2 N 2 Et 2 0, 90%; c) DBU, THF reflux, 65%. We had also achieved control of the C9 and Cl4 (morphine numbering) stereocenters, which is very crucial to a successful morphine synthesis. During this period of time we entered into a collaborative project with scientists at Procter and Gamble Pharmaceuticals who were interested in compounds to be used as scaffolds in their matrix metallo proteinase (MMP) inhibitors studies Dr. Hudlicky recognized structural similarities between their targets (hydroxamic acids with an R

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75 configuration at the a-center of the amino acid) and some of the compounds synthesized from the Kazmaier Claisen rearrangement during the morphine synthesis model study. NHBoc TOSO 293 Figure 7. Structure of morphine precursor used in initial MMP screen. To our surprise, ester 293 as a mixture of R and S-isomers at a-center of the amino acid side chain showed MMP inhibition. This led to the initiation of the collaborative project with Proctor and Gamble Pharmaceuticals where the goal was to synthesize esters of the type 293 to be evaluated for biological activity as MMP inhibitors. This was a great opportunity because it gave us the occasion to apply our chemistry to industrial scale projects. The next section will describe some of the efforts made in the synthesis of matrix metallo proteinase inhibitors in a collaborative effort with researchers at Procter and Gamble Pharmaceuticals. Synthesis of Matrix Metalloproteinase Inhibitors (MMP's) Researchers at Procter and Gamble have been exploring the synthesis of unnatural amino acids to be used as scaffolds in the preparation of potent matrix metalloproteinase inhibitors (MMP's). 92 95 MMP inhibitors have shown activity as antagonists of various diseases where tissue remodeling plays a key role, 96 including osteoarthritis, 97 98 rheumatoid arthritis, 99 tumor metastasis, 100 multiple sclerosis 101 and conjective heart failure. 102 The structural features of their target, resembled ester 289a which interestingly

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76 was the undesired isomer from the Kazmaier Claisen rearrangement (Scheme 63). )voH UOH 248 296 Scheme 64 Ho' 303 ~ 2 Me "NHBoc Me We prepared a series of cyclohexylglycine and cyclohexylalanine derivatives of the type 296 and 303 (Scheme 64) to be utilized as intermediates for the synthesis of MMP inhibitors. Also as part of the collaborative project, the absolute stereochemistry of ester 289a was determined unambiguously by X-ray crystallography (Figure 7). Esters 296 and 303 were synthesized using similar protocol as has been described earlier in the chapter. Approaches to compounds of this type through enolate alkylation or aldol type condensations are quite difficult, hence the Kazmaier Claisen provides a direct route to these unnatural amino acids with control of stereoselectivity and re pectable yields Starting from the diol 247, a two step sequence involving protection of the distal hydroxyl group as the TBS-ether, followed by esterification of the proximal hydroxyl group by DCC coupling rendered gylcinate ester 292 (Scheme 65). We achieved the rearrangement to the corresponding acids via Kazmaier Claisen conditions. Diazomethane was then utilized in the conversion of the acids to the methyl ester derivatives. The next step involved reduction of the vinyl bromide with Adam's catalyst at 40 psi with triethylamine as the proton scavenger. Finally tetrabutyl ammonmm fluoride mediated deprotection of the TBS group rendered the alcohol 296 which

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77 underwent other proprietary transformations before being used in MMP testing. Because Br O 6 0 OMe h J,l_,,NHBoc Br UO c d 1/' 'NHBoc 292 OTBS TBSO 293 / f "NHBoc g "NHBoc --d o OM e do OMe Ho' TBso ~ 0 x:oc TBso 'u 294 296 i s t e p s 0 OM e "NHR R o' 297 295 R = Alkyl 0 R =-~~ 8~Scheme 65. Conditions: a) TBS-Cl, imidazole, DMF -12 C, 85 %; b) DCC DMAP Boc-glycine or N-Boc-alanine CH 2 Cl 2 80%; c) ZnC1 2 LDA THF -78 C 75 %; d ) CH 2 N 2 Et 2 O 90 %; e) Hi/PtO 2 (40 psi), Et 3 N, MeOH, 75%; f) nBu 3 SnH AIBN, PhH.g) TBAF THF, 80%. of the success of the Claisen with the glycine ester we planned to prepare sulfonamide 299 through a DCC coupling reaction with TBS-ether 298 and the alanine moiety already functionalized as the sulfonamide. This reaction proved unsuccessful, hence we prepared ester 301 and following the removal of the Boe protection group were able install the sulfonamide to obtain 299 The Kazmaier Claisen rearrangement o f 299 to 300 worked smoothly as in the case of the glycine ester (Scheme 66) even though yields were lower probably due to the lower chelating potential of the sulfonamide as compared to the carbamate in structure 292. The synthesis of 300 also did not proceed with the s ame

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78 diastereoselectivity as in the earlier cases presumably because of the increased size of the sulfonamide functionality leading to a decrease in preference for the chair transition ~OH u ax)o OTBS 298 Br ~o 6Iro OH NHR CC O NHR Me Me 301 OTBS TBso' 299 300 td !Ch CC B, o~NH, ~o OMe Me NHR e OTBS Ho' 302 0 R=-~-o--o~ f 0 303 Scheme 66. Conditions: a) alanine N-sulfonamide, DCC; b) N-Boc alanine, DCC; c) TFA, CH 2 C'2; d) 4-methoxy-1,1 '-biphenylsulfonyl chloride, Et3N, THF; e) ZnC'2, LDA, THF, -78 C; f) CH 2 N 2 Et 2 O; g) H 2 (40 psi), PtO 2 Et 3 N, MeOH; h) TBAF, THF. state. Even so, acids 300 were converted over three steps to methyl esters 303, the precursors for MMP inhibitors. One of the more difficult steps in this project was the last rO OMe NHR THso' 293 ib cl o OMe NHR THso' 295 a _,,,,....__OXOMe lJ NHR 304 R= Boe Scheme 66. Conditions: a) H 2 (40 psi), 5% or 10% Pd-C, MeOH; b) H 2 (40 psi), PtO 2 Et3N, MeOH.

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79 step involving the removal of the vinyl bromide through hydrogenation. Initial attempts at this transformation utilized 10% and 5% Palladium on Carbon ( Pd/C) at 40 psi in methanol. Even though this resulted in the removal of the vinyl bromide it also resulted in hydrogenolysis of the silyl ether leading to the isolation of ester 304 Even though ester 304 was devoid of the hydroxyl group, the hydroxamic acid derivative this compound surprisingly showed some activity as an MMP inhibitor. After inve tigating several other conditions we discovered that using Adam's catalyst (PtO 2 ) in methanol at 40 psi with Table 7. MMP inhibition activity for glycine and alanine analogs. MMP-2 MMP-3 MMP-13 HO 0 OH oto OH Br O -.OH oto -.: NHR ?" .NHR ?" NHR Me H H .Ho' Ho' HO 305 12 1 ,220 30 306 20 2,490 176 307 38 3,795 13 I 0 R= -~-o-o~ I/ 0 308 251 6,150 338 triethylamine as a proton sponge works nicely leading to isolation of the silyl ether 295 in 89% yield With the completion of the collaborative project, we turned our attention back to morphine synthesis; we now had a stereospecific way of obtaining the methyl ester 289b

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!1 OQ s::: @ 00 00 0

PAGE 88

81 (Scheme 60). The next step involved the coupling of the methyl ester with an aromatic boronic acid to obtain our crucial bicyclic intermediate 242 using the Suzuki conditions that by now had been optimized for the morphine project (Scheme 49, pg 57) Second Generation SynthesisOverman's Intermediate via Claisen Rearrangement In this section the efforts towards synthesizing the Overman 53 intermediate 95 (pg 21-22, Chapter 1) are described. The target was chosen for two main reasons first the synthesis of the Overman intermediate would allow us to achieve a formal total synthesis of morphine since dihydrocodeinone (88) was synthesized in three steps from the Overman intermediate. Also, after coupling ester 289b with an appropriate aromatic piece this bicycle would possess all the functionality needed to achieve the synthesis of the Overman intermediate Retrosynthetically our goal was to arrive at the Overman intermediate through a Friedel-Craft 102 103 reaction on acid 309 Even though our earlier MeO MeO BnO BnO NMe NR NHBoc HO 310 95 309 MeO)Q MeO Meo BnO 0 313 B ( OH ) 2 :=J BnO BnO y Me NHBoc NHBoc THSO HO 312 311 THso' 289b Scheme 68

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82 attempts at the Friedel-Craft reaction were unsuccessful we were hopeful that with the construction of the nitrogen bridge, this precursor would have a more rigid structure with the aromatic ring in a favorable position to effect cyclization (path y, Scheme 68). The key step in this synthesis would be the setting of the C 13 quaternary center by a [3 3] sigmatropic rearrangement. The options available were an Ortho-ester Claisen 104 105 rearrangement or an Eschenmoser 106 107 type Claisen rearrangement using the allylic alcohol moiety in precursor 310 (path x, Scheme 68). Alcohol 310 could in turn be synthesized through a Mitsunobu 108 reaction of alcohol 311 Compound 311 could be achieved from a two-step sequence involving a Suzuki reaction to couple the methyl ester and the aromatic boronic acid followed by a fluoride deprotection of the silyl ether. Boronic acid 313 was synthesized (Scheme 69) using the same protocol that was used for the synthesis of the dimethoxy boronic acid 273 (pg 61) with similar results in terms of yield. With boronic acid 313 in hand we were able to achieve coupling with ester ((YOH ~OMe 271 ~OH llA OMe 150 313 Scheme 69. Conditions: a) Br 2 tert-butylamine, toluene, -78 C, 60-62 %; b) BnBr, K2CO 3 Acetone, rt ., 90-94 %; c) Mg, 1 2 (cat.), B(OEt) 3 NH 4 Cl (sat'd) 82-86 %; d) BuLi, B(OEt) 3 NH 4 Cl (sat'd), 75-80 %.

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83 289b to obtain the bicycle 312 The following reactions were performed on the 2,3dimethoxyphenyl and 2-benzyloxy-3-methoxyphenyl analogs as shown in Scheme 70 but the description of the process will focus on the benzyl-protected analog. To ensure the correct regio-chemistry of the Claisen rearrangement we proceeded to invert the alcohol at C6 (morphine numbering). This process began with a tetrabutyl ammonium fluoride MeO RO MeO RO 0 315 R = Bn 320 R= Me I y 95 R = Bn 321 R= Me MeO!ll ROY B(OH) 2 313 R = Bn 273 R = Me a .. MeO RO XO MeO RO THSO 312 R = Bn 316 R= Me .._ C NHBoc 314 X = Bz R = Bn d 1 318 X = Bz, R =Me ~310X = H. R= Bn 319 X = H, R = Me b 7 MeO BnO HO NHBoc 311 R = Bn 317R=Me Scheme 70 Conditions: a) 0.03 % eq. Pd(PPh3) 4 2M Na 2 CO 3 313 PhH-EtOH, reflux; b) TBAF, THF; c) DEAD, PBu3, BzOH, THF, -10 Crt; d) K 2 CO 3 MeOH. (TBAF) deprotection of the thexyldimethylsilyl group to give alcohol 311. The free a. faced alcohol was then inverted with a Mitsunobu 108 109 reaction (Scheme 70) using

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84 tributylphosphine, benzoic acid and DEAD (diethylazodicarboxylate). The benzoate thus formed was hydrolysed easily with K 2 CO 3 / MeOH to obtain the inverted free alcohol 310. With alcohol 310 in hand the next step was to attempt the Orthoester Claisen rearrangement. Typical conditions involve in-situ formation of the 01thoester followed by subsequent acid catalyzed rearrangement at temperatures ranging from 160 cc to 180 cc. Using a combination of triethyl orthoacetate and catalytic amounts of propionic acid we attempted the Orthoester Claisen using three different solvent systems (Scheme 71 ) The reactions were run either in neat triethyl orthoacetate, xylenes or in toluene. The results obtained were quite consisitent in all three solvents The product of the attempted orthoester-Claisen rearrangement was a compound resulting from cleavage of the ortho ester intermediate and subsequent trapping of the resultant allylic cation by our amine MeO MeO MeO MeO a NHBoc NH HO 319 322 i MeO MeO MeO MeO MeO MeO OEt NHBoc NHBoc 1/" -+o +~ OEt 323 324 325 Scheme 71. Conditions: a) i) triethylorthoacetate, propionic acid (cat.) 160cC-180cC ; ii) triethylorthoacetate, propionic acid (cat.), xylenes, 160cC-180cC; iii) triethylorthoacetate propionic acid (cat.), toluene 160cC-180cc.

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85 functionality. We suspect that thermal and/or acid catalyzed decomposition of the carbamate protecting group leads to the free amine, which then traps the allylic cation. In the first generation synthesis (pg 68) we used the cleavage of the C-0 bond (at C6 morphine numbering) to our advantage in determining the identity of our rearranged acids through a lactonization reaction. Unfortunately in this case it was a significant problem because cleavage of the ortho ester always occurred before any potential rearrangement and so we were unable to proceed further with this route towards Overman' s intermediate. The identity of the orthoester-Claisen product was obtained using NMR experiments namely GHMQC and HETCOR. The sequence 5-6-7-8-14-9 (morphine 0 3. 88/ 56.0 153 1 6.57 130.5 1.51 2 22 25 8 NH Figure 9. Assignment of Orthoester Claisen product. numbering) was seen by the DQCOSY spectrum (HlHl correlation) as CH-CH-CHr CH 2 -CH-CH-. The aryl group was confirmed to be in position 13 by the long range couplings H(l 1 )-C(l 3) and H(5)-C(l 2) as seen in the GHMBC spectrum The methyl ester was confirmed to be in position 9 by the cross-peak H(9)-C(CO). With these correlational experiments the molecule was assembled with the exception of the two open valencies at C6 and C9. The carbon chemical shifts of the atoms suggest that they are

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86 bonded to the nitrogen atom. This molecular formula was further confirmed by HRMS. From these correlation experiments the proton and carbon signals were correctly assigned as shown in Figure 9. From long range coupling experiments, the connectivity of our molecule was confirmed when we observed a long range coupling between the proton at C6 (morphine numbering) whose signal appears at 4.91 ppm and the proton on the a. center of the amino acid (C9 morphine numbering) whose signal appears at 4.06 ppm This was further confirmed by a long-range 1 H13 C coupling between the proton signal at 4 91 ppm and the carbon signal at 59.6 ppm, which belongs to the carbon at the a-center (C9 morphine numbering). Since we now had alcohol 311 in our possession, we reasoned that we could still establish the Cl3 quaternary center by employing a conjugate addition of an MeO MeO MeO BnO BnO BnO a Jt. --11.,.. NHBoc NHBoc NHBoc HO 0 HO 311 326 327 Scheme 72. Conditions: a) PCC, CH 2 Ch; b) (H 2 C=CH)iCuMgCl, THF -78C. organocuprate with the enone obtained from oxidation of the alcohol. Alcohol 311 was subjected to PCC oxidation conditions to obtain enone 326. Upon addition of a vinyl cuprate, no 1,4 addition product was isolated. The major product of the reaction was the

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87 1,2-addition adduct 327. It is our susp1c10n that because this bicyclic compound Figure 10. Possible atropoisomerism of morphinan intermediates exhibits atropoisomerism, the aromatic ring is twisted out of conjugation with the cyclohexenyl ring (Figure 10). This probably causes the aromatic ring to be perpendicular to the cyclohexyl ring so any substituent in the 2-position of the aromatic ring (benzyl in this case) sterically hinders any attack to the C 13 center. In summary our attempt at the Overman intermediate failed because of two main problems The first problem, which was encountered in the orthoester-Claisen is a trend that we had observed earlier in the synthesis (Scheme 56, pg 68) and used to our advantage The C6 (morphine numbering) position easily ionizes if any good leaving groups are present because of the stability of the resultant allylic carbocation which is resonance stabilized by the aromatic ring. Under catalytic or stoichiometric acid conditions, the orthoester intermediates are cleaved either through an SNl or an SN2 mechanism to yield products of the type 322. The second problem is of a steric nature cuprate addition to the C 13 (morphine numbering) center led to recovery of 1 2-addition products exclusively. Mulzer 2 5 in his synthesis of morphine encountered the same problem in hi s attempt at conjugate addition to a similar substrate (Scheme 73 ) Initial model studie s were successful at establishing what would be the C 13 center by cuprate addition. When the same reaction was applied to more advanced intermediates 123 and

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88 329 the conjugate addition yielded only 1,2-adducts. 1 H-NMR spectra of Mulzer 's intermediates demonstrated the presence of atropoisomers and thi s led to his assumption that these intermediates exhibited atropoisomerism. In our case high temperature 1 NMR experiments were inconclusive because even though we observed the presence of two isomers it was impossible to determine whether the isomerism was from the carbamate moiety or due to atropoisomerism The result of the atropoisomerism is that MeO MeO 0 120 MeO MeO 0 123 329 the aromatic Scheme 73 MeO i H 2 C=CHMgCI 5 % CuBr-SMe 2 TMSCI .. MeO ii,2NHCI 0 MeO i H 2 C=CHMgCI MeO 5 % CuBr-SMe 2 TMSCI --~ ii ,2 NHCI >< .. HO i, H 2 C=CHMgCI 5 % CuBr-SMe 2 TMSCI ii ,2 NHCI x .. 121 328 330 --~ residue becomes more or less pependicular to the double bond hindering any attack on the benzylic sp 2 -hybridized carbon.

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89 Alternative methods to Setting the C13 quaternary center. At this point we had to assess the route to establishing the C 13 quaternary center. We still had a couple of options available to achieve this task The first option was to take advantage of some of the inherent properties in intermediate 311 to establish the C 13 center. If indeed our assumption was correct and alcohol 311 (Scheme 70) was prone to exhibit atropoisomerism, then a tether at the 2-position of the aromatic ring becomes a very important group. The effect of the atropoisomerism would e sentially position the tether at the 2-position of the aromatic ring in a desirable position to effect either radical or nucleophilic attack of the C 13 carbon. If the attack at C 13 comes from the P-face of the molecule, this synthesis would eventually lead to morphine. An attack MeO HO > NHR THSO, 331 MeO BnO (a) radical cyclization MeO MeO l ( b ) Pd cat. closure t Claisen MeO HO HO Overman 's intermediate NHR 95 Figure 10. Strategy for establishment of C 13 quaternary center.

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90 from the a-face would lead to ent-morpnine. The second option would be to attempt the C 13 attack from the amino ester side chain either through a palladium catalyzed SNi reaction or a radical type attack. Before applying the alternate routes to the establishment of the C 13 center to the morphinan intermediates we decided that a quick model study to ascertain the feasibility of these reactions would be in order. We prepared enone 340 and silyl ether 343 as shown m Scheme 74 from phenol and 1,3-cyclohexadione (337). Cleavage of the MOM D HO -& D MOMO 335 336 MOMO 0 0 OD EtOD C 0 339 340 337 338 341 MOMO 0 0 h.i MOMO e,f ('o ~o ... g Br ... 0 TDSO TDSO TDSO 339 342 343 344 Scheme 74. Conditions: a) MOM-Cl, NaH, THF; b) EtOH, pTsOH, PhH; c) t-BuLi, THF; e) H+ffHF; f) Bromoacetylbromide, DMAP, CH 2 C!i; g) nBu 3 SnH, AIBN, PhH; h) NaBH4, MeOH; i) TDS-Cl, imidazole, DMF.

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91 protecting group from the bicycle 339 afforded the intermediate alcohol which wa s converted to the bromoacetate 340 the radical cyclization precursor. Silyl ether 343 was obtained from intermediate 342 after cleavage of the MOM protecting group and subsequent appendage of the bromoacetate. The two bromoacetate s were then s ubje c ted to radical conditions using a protocol previously used by Ogasaw a ra 60 and coworker in their synthe s is of 3 4-dimethoxy-7-morphinanone ( pg 39 Ch I ). The radical reaction failed to produce any cyclized product in the case of silyl ether 343. Instead we observed the form a tion of the reduced product exclusively. This was not unexpected due to the fact that for that cyclization to work the reaction had to proceed from a stablilized ester radical to an unstable radical. On the other hand enone 340 subjected to the same conditions yielded the cyclized product 341 in 66% yield with recovery of about 15 % of reduced product. With the success of the model study our attention focu s ed on its application to the morphine synthesis. Our goal was to achieve the synthesis of intermediates of the type 345 or 347 M e O 0 ('o .. ........... ......___, Br NHBoc NHBoc M e o THSO THso 345 346 .1 HO I t y e M e O 0 THSO.('o -.. ./'Y -r 349 Br NHBoc NHBoc 0 347 348 Scheme 75

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92 (Scheme 75) in order to apply our model study to real morphinan intermediates A successful radical closure would lead to the establishment of the C 13 quaternary center ; this would be followed by a translactamization reaction after deprotection of the Boe group to establish the nitrogen bridge as shown in Scheme 75. The first order of business was to redesign our aromatic ring with a protecting group in the 2-position that could be cleaved readily to allow for the appendage of the bromoacetyl group. The first protecting group we worked with was the TBS-group Bromoguaiacol 150 was readily converted to the TBS ether using triethylamine DMAP and TBS-Cl. Unfortunately in the next step that involved the lithium halogen exchange and alkylation using triisopropyl borate, we realized that the TBS-group was too bulky CC Br OH OM e 150 Br ~OTBS VOMe 350 b-,.. CC OTBS OMe 351 Scheme 76 Conditions : a) TBS-Cl, Et 3 N DMAP, CH 2 Cl 2 ; b) B(Oipr h, H+ hence preventing the subsequent alkylation step. The only material isolated from the reaction was starting material and the reduced product 351 (Scheme 76) We were able to confirm the formation of the anion using deuterium exchange experiment s So we realized that the problem lay in the alkylation step The next protecting group considered was the paramethoxybenzyl group (PMB). This was in theory an ideal protecting group for our synthesis because we had prior experience ( in our approach to the Overman intermediate Scheme 69, pg 83 ) on the synthesis of the benzyl protected boronic acid and reasoned that the synthesis of the PMB boronic acid would be analogous Most importantly this group could be cleaved with DDQ which in our estimation would not

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93 affect any of our chiral centers or other protecting groups Using K 2 CO 3 and acetone we protected bromoguaiacol as the PMB ether. In the subsequent s tep we successfully synthesized the boronic acid 353 using n-BuLi and triisopropyl borate Br Br B ( OH ), 6:0H 6:0PMB 6:6PMB b h' OMe OM e OMe 150 352 353 i c M e O M e O HO CO 2 Me ""=f d PMBO 1/. NHB oc NHB oc THso THso-' 355 354 Scheme 77. Conditions : a ) PMB-Br K 2 CO 3 Acetone ; b ) n-Buli B ( oipr )J, H \ c ) 0 03 % eq. Pd(PPh 3)4, 2M Na 2 CO 3 289b, PhH-EtOH, reflux; d) DDQ, H 2 O CH 2 C'2 The Suzuki coupling of the boronic acid with methyl ester 289b ( Scheme 77 ) worked quite well to afford PMB ether 346 At this point we attempted cleavage of the PMB group in order to append the bromoacetyl group on the phenol. Unfortunately this s tep led mostly to decomposition of our starting material. With the failure of the PMB route ~OH ~OM e 150 ('YOH ~OM e 271 Scheme 78 Conditions: a) n-Buli B(oipr) 3 H \

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94 we wondered if we could synthesize the boronic acid directly from bromoguaiacol. This would give us a free phenol going into the coupling step and negate the need for a protecting group. This reaction (Scheme 78) was not successful and resulted in isolation of guaiacol 271 exclusively The MOM-protecting group was considered because of the ease of removal o f the group. Protection of bromoguaiacol as the MOM-phenol proceeded smoothly as did the step to make the boronic acid. Throughout this study of protecting group s we had speculated about the possibility of performing the Suzuki coupling on the free phenol. The Suzuki conditions require the use of 2M Na 2 CO 3 and the concern was whether the alkoxide of the phenol would couple as effectively as the protected phenol. Starting from the MOM-protected boronic acid 356 we were able to obtain the MeO B ( OH \ O?H &OMOM b-. HO OMe NHB oc OM e 356 357 THso 358 MeO MeO i, 0 010 ... d ('o NHBoc Br NHBo c THso THso 359 345 Scheme 79. Conditions: a) TFA, CH2Ch; b) 0 03 % eq. Pd(PPh 3 ) 4, 2M Na 2 CO 3 289a, PhH-EtOH reflux; c ) Bromoacetylbromide, DMAP, CH 2 Ch; d) nBu 3 SnH AIBN PhH free phenol 357 with TF A in methylene chloride. The phenol was then coupled with methyl ester 289b under Suzuki conditions (Scheme 79) leading to isolation of bicycle

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95 358 albeit in a 45% yield With the phenol in hand we were able to synthesize the bromoacetate derivative using DMAP and bromoacetyl bromide in methylene chloride The radical reaction of bromoacetate 345 using the same conditions as was used in the model study resulted in the formation of the reduced product 359. The synthesis of enone 347 proved to be more challenging than expected. Starting from phenol 358 we had two options available. We could first alkylate the phenol as the bromoacetate and then remove the silyl-protecting group followed by subsequent oxidation of the C6 (morphine MeO MeO HO a b NHBoc NHBoc NHBoc Toso 358 345 360 ib MeO MeO MeO HO HO Oto C NHBoc NHBoc Br NHBoc 0 0 361 347 362 Scheme 80. Conditions: a) Bromoacetylbromide, DMAP, CH 2 Ch; b) TBAF THF; c) PCC or MnO 2 or Dess-Martin. numbering) alcohol. Equally we had the option of initial removal of the silyl-protecting group followed by oxidation to the enone and then final alkylation of the phenol to form the bromoacetate Preliminary evidence indicates the formation of a Finkelstein 111 type product in our attempt to cleave the silyl-protecting group in intermediate 345 in the presence of the bromoacetate as shown in scheme 80. Conversely we had problems with

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96 the oxidation of allylic alcohol 361 probably due to reaction of the oxidant with the phenol. The yields for the oxidation step were very low (1015 %) and so this route could not be used to obtain decent quantities of the enone 362. Our final option was to first form the enone from the vinyl bromide and then achieve coupling with boronic acid 357 Indeed this worked quite well with the isolation of the enone 362 In the next step the phenol was converted to the bromoacetate which was then subjected to the radical cyclization conditions. We are currently in the process of optimizing this reaction MeO Br C0 2 M e Br C0 2 Me HO oifmmoc _c(NHBoc NHB oc THso 0 289b 363 362 ic MeO NHBoc ~ .9 ......... Oto Br NHB oc 0 347 348 Scheme 81 Conditions: a) TBAF THF ; b) PCC CH 2 Ch ; c ) 0.03 % eq. Pd ( PPh 3) 4 2M Na 2 C0 3 289a PhH-EtOH, reflux ; d) Bromoacetylbromide DMAP, CH 2 Ch; e) nBu 3 SnH AIBN PhH;

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CHAPTER 4 CONCLUSION Summary and Conclusions In the course of this project we have been able to s uccessfully apply a chemoenzymatic approach towards morphinan alkaloids utilizing the Kazmaier Claisen rearrangement and the Suzuki Coupling reaction to obtain advanced intermediates towards morphine Control of the C9 and C 14 (morphine numbering ) centers was Br &OH OH 247 THS-CI Imid. DMF 8 c CX OH Gly Boc DCC DMAP 291 Br CO M e O~NHBoc ZnCI THF -?" 9 NHBoc CX Br w I. LOA &Br C0 2 Me -2 .....,' 1 4 + ~:amoc ,vH 2 C8iN 2 THSO H OTHS 289a 292 60 THSO 289b 40 t DBU THF Scheme 82 achieved using a combination of Kazmaier Claisen rearrangement and epimerization reactions ( Scheme 82). We were also successful in applying this chemistry to the synthesis of matrix metallo proteinase inhibitors (MMPs) in a collaborative project with 97

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98 Procter and Gamble Pharmaceuticals (Scheme 83). Our most challenging endeavor has &OH OH 247 299 Scheme 83 6 Br LNHBoc 0 OTBS 292 300 0 R= -~-o-o~ f 0 c7 0 OMe 'NHBoc Ho' 296 303 been the attempts at establishing the C 13 quaternary center. In our approach to the Overman intermediate we discovered the hindered nature of the C 13 carbon and also the reasons for our unsuccessful Orthoester Claisen rearrangement. The problem can be summarized as !ability of groups at the C6 (morphine numbering ) position and steric hindrance at the Cl3 position due to what we suspect is atropoisomerism. We realized that we had an opportunity to achieve functionalization of the C 13 center from either a tether on the 2-position of the aromatic ring or from the nitrogen side chain. Model studies confirmed the feasibility of a radical closure from a tether on the aromatic ring and the last part of the project has been dedicated to the synthesi s of intermediate s that would allow for the establishment of the C 13 center through this reaction There are still a few options available to achieve functionalization of the C 13 center. We have yet to attempt either a palladium catalyzed SN 2 closure or a

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99 Reformatsky type reaction to establish C 13. The morphinan intermediates aJlow for these reactions to be attempted either from the nitrogen side chain or from a tether on the phenol. Establishment of the C 13 center would be followed by a translactamization reaction to afford the nitrogen bridged intermediate of the type 369. After a Friedel-Kraft reaction this intermediate begins to look very similar (Scheme 86 ) to one of the Gates' intermediates 370 from which morphine was synthesized in an additional 7 steps. J.X:: oc THso 'v 289b Scheme 84 348 NHBo c 370 Gates' intermedi a te In the course of the project we have also looked at ways to make this approach to morphine, practical. To this effect, we attempted the direct oxidation of intermediate 364 using a catechol dehyrogenase enzyme which was recently discovered in the Hudlicky research group. 112 Success of such a transformation would eliminate 4 synthetic steps

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JOO HO Q HO a b I' B ( OH ) 2 NHBoc Tl NHBoc 331 THso' THso' 364 365 ic / NHBoc HO.366 Scheme 85 Conditions: a) 0.03 % eq. Pd(PPh 3 ) 4 2M Na 2 CO 3 289b, PhH, reflux; b) E coli pDTG 602, c) TBAF, THF; from our synthesis. Unfortunately we ran into feasibility problems because the substrate 364 could not be dissolved in the aqueous media containing the bacteria even after cleavage of the THS-group to give the alcohol 366. Even though this attempt was unsuccessful our goal still remains; to arriving at a truly chemoenzymatic synthesis of morphine (Scheme 85). It is still possible to arrive at compounds like 365 through an initial biooxidation of the aromatic piece followed by Suzuki coupling reaction 0 Br II Jvo NMeBo c I LOA TMSCI, THF, 80% UOTOS 2. CHiN 2 367 Scheme 83 J:X 2 Me u NMeBoc Toso 368 We have also synthesized the sarcosine ester 367 (Scheme 86) and performed the Ireland Claisen rearrangement on this substrate with interesting results. Even though the

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101 rearrangement is not stereospecific we are able to achieve epimerization from a 9: I mixture favoring the wrong isomer to a I: I mixture. Such an intermediate would contain the methyl group on the nitrogen and the intent is to prevent any problems we could encounter later on in the synthesis with the glycine analog in terms of methylating the nitrogen.

PAGE 109

CHAPTER 5 EXPERIMENT AL SECTION General Procedure All non-hydrolytic reactions were carried out under a nitrogen or argon atmosphere, with standard techniques for the exclusion of moisture. Glassware used for moisture sensitive reactions wa flame dried with an internal inert gas sweep. Analytical TLC was performed on Whatman K6F silica gel 60A plates. Flash chromatography was performed on chromatographic silica gel 230-400 mesh (Fisher Chemical). Infrared spectra were recorded on a Perkin-Elmer FT-IR (KBr). Proton, fluorine and carbon NMR spectra were obtained on a Varian 300MHz spectrometer using CDClJI TMS unless otherwise indicated in the experimental section or in the case of fluorine NMR spectra, a CFCI 3 standard was utilized. Proton chemical shifts are reported in parts per million (ppm) relative to chloroform (7.24 ppm) or DMSO-d 6 (2.49 ppm). Carbon chemical shifts are reported in parts per million relative to the central line of the CDC1 3 triplet (77.0 ppm) or the central line of the DMSO-d 6 septet (39.7 ppm). Coupling con tants (J) are given in Hz. Optical rotations were recorded on a Perkin-Elmer 241 digital polarimeter (101 deg cm 2 i 1 ). Melting points were obtained on a Thomas-Hoover capillary melting point apparatus. High resolution ma s spectra and elemental analyses were performed at the University of Florida and Atlantic Micro lab Inc. 102

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103 Experimental Procedures 3-(2,3-dimethoxyphenyl)-( 1 S,2R)-3-cyclohehexenel ,2-diol (270). To a round bottom flask under argon atmosphere was added Pd(PPh3) 4 (0.001 mol, 1.32g). This was followed by addition of 50 mL dry benzene A solution of the bromide 247 (0.040 mol, 7.40 g) dissolved in IOmL of ethanol was then added to the reaction flask. This was followed by the addition of Na 2 CO 3 (36.00 mL, 2.00 M) to the mixture. Dimethoxyphenyl boronic acid 273 (0.046 mol, 8.40g) was dissolved in 50 ml of dry benzene was then added to the reaction mixture, which was allowed to reflux for 6h. The reaction was quenched with water and the product extracted with ethyl acetate (3 X 50 mL) The organic layers were combined, washed with brine and dried over anhydrous MgSO 4 After filtration the solvent was removed, the crude product introduced onto a silica gel column, and eluted with ethyl acetate:hexane (1:3) to obtain (7.10 g, 83%) white crystals of 270; mp: 6667 C; Rf= 0.3 (ethyl acetate: hexane, 1 :1); [a.] 0 20 62.9 (c 1.0, CHCI 3 ); 1 H NMR (CDC1 3 ) o: 7.0 (t, J = 17.7 Hz, lH), 6.9 (d, J = 7 1 Hz, lH), 6.8 (dd, J = 7.4, 0.8 Hz, 1 H), 5.9 (t, J = 3.6 Hz, lH), 4.4 (bs, lH), 3.9-3.8 (m, lH), 3.8 (s, 3H), 3.7 (s, 3H), 2.6 (bs, 2H), 2.3 (m, 2H), 1.9 (m, 2H); 13 C NMR (CDCh) o: 152.5 145.8, 136.6, 135.8 130.5, 124 5, 122 5, 111.6, 69.3, 69.0, 61.0, 55.8, 25.2, 24.2, ; IR (KBr/ cm 1 ) : 1104, 1260, 1470, 1577, 2923, 3362; LRMS (CI/ CH 4 ) m/z (rel. intensity) 250 (m+, 100 ), 232 (35), 206 (93); HRMS Calcd. for C 1 4H 1 s O 4: 250.1205; Found: 250.1208. Anal. Calcd. for: C 1 4H 1 sO4: C, 67.21; H, 7.20; Found: C, 66 62; H, 7.44.

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104 6-(2,3-dimethoxyphenyl)-2-dimethylthexysilyoxy-( 1 R.2S)-5-cyclohexen-1-ol (276). A solution of the diol 270 (0.720 mmol, 0.18 g) and imidazole (0.860 mmol, 0.15 g) dissolved in 0.50 mL of DMF was prepared in a dry round bottom flask under argon atmosphere. The flask was cooled to -12 C and TDSCI (0.860 mmol, 0.17 mL) added with very slow stirring. The flask was stored at -18 C for 12h after which the solution was diluted with ethyl ether and washed with brine. After separation the aqueous layer was re-extracted with ethyl ether (2 X 20 mL). The organic layer were combined and washed with a 10% CuSO 4 solution (3 XS mL) to remove the imidazole. The organic layer was finally washed with brine, dried over anhydrous MgSO 4 and the solvent evaporated. The crude product was introduced unto a silica gel column and eluted with ethyl acetate/ hexane ( l: 99) to afford a yellow oil of the silyl ether 276 (0.25 g, 90%) ; Rf = 0.7 (ethyl acetate :hexa ne I :4; [a]o 32 59.3 (c l.0, CHC1 3 ); 1 H NMR (CDC!J) 6: 7.0 (t, J = 7 2 Hz, IH), 6.8 (d, J = 7.7 Hz, 2H), 5.9 (t, J = 3.6 Hz lH), 4.4 (bs, lH), 4.0 (dt, J = 10.2, 3.3 Hz, IH), 3.8 (s, 3H), 3.7 (s, 3H), 2.6 (d, J = 4.1 Hz, IH), 2.4 2.3 (m, lH), 2.2 2.1 (m, 1 H), 2.0 l.9 (m, 1 H), l.7 1.6 (m, 2H), 0.9 0.8 (m, 14H), 0.1 (d, J = 5.5 Hz, 6H) ; 13 C NMR (CDCl3) 6: 152.6, 136.3, 136.0 129.7 123.9, 122.4, 111.4, 70.8, 69.2, 60.6 55.8, 34.2, 25.4, 24.9, 24.3, 20.4, 20.2, 20.1, 18.6, 18.5, 2.5 2.9; IR (K.Br/cm1 ): 3245, 2959, 1470, 1259, 1108 101 l. HRMS: C22H36O4Si (M+l) Calcd. 393.2383, Found : 393.2479; Anal. Calcd. for: C22H36O 4 Si: C, 67.18; H, 7.25 ; Found: C, 67.20 ; H, 7.24.

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105 6-(2,3-di methoxyphenyl)-2-dimethyl thexysilyloxy-( I R,2S) 5-cyclohexen-1-yl-N-tert butoxycarbonylglycinate (277). A solution of Boe-glycine (6.600 mmol, 0.16 g) and DMAP (catalytic) in CH 2 Cl 2 (60 rnL) was cooled to 0 C. DCC ( 9.000 mmol, 1.90 g) was added to the cooled mixture resulting in a yellow precipitate A solution of the TDS protected diol 276 ( 6.000 mmol 2.20 g) in CH 2 Ch was then added by syringe and the reaction mixture allowed to stir. The solution was diluted with ethyl ether and filtered through a plug of silica gel to remove the precipitate of dicyclohexylurea Removal of the solvent followed by chromatography ( silica gel ethyl acetate:hexanes 1 :9 ) the residue afforded the pure amino ester 277 (4 .00 25 0 g 71 %) a s a thick colorless oil ; Rf= 0.4 ethyl acetate:hexane 80:20 ; [a]o 7 4 ( c 1.0 CHCI 3 ); 1 H NMR ( CDCh) 8: 6.9 ( t J = 7 9 Hz, IH) 6.8 (dd J = 8 2 Hz, IH ), 6 7 (dd J = 7 6 Hz lH) 5 9 ( bs 2H ), 4 9 ( bs 1 H), 4 1 (m, 1 H) 3.8 ( s, 3H ), 3.7 ( s 3H ), 2.2 2.1 (m 2H ), 1.9 ( m, lH ) 1.7 -1.6 (M lH ), 1.6 1.5 ( m lH) 1.4 (s 9H ), 0.9 ( d J = 6.7 Hz 1 3 s: 6H ) 0.8 ( d J = 3.7 Hz, 6H ), 0 1 (d, J = 11.9 Hz, 6H) ; C NMR ( CDCl 3) u : 168.4 155 2 154.1 150.2 134 6 130 8 130 6 129.0, 128.9, 119.8 110.3 79.4 71.7 69 1 54.3 42.3 34.2 28 2 25.0 24.8 24 4 20.2, 20.1 18.4 18 3, -3 2 ; IR (KBr/cm1 ): 3443 2931 2105 1643 1470 1366; HRMS : C 29 H 4s NO1Si (M+) Calcd 550.5983 Found : 550.3197. Anal. Calcd. for : C 2 9 H 4 7 NO 7 Si: C 67.30; H 9.24; Found : C, 67 13; H 9 20.

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106 3-tert-butoxycarbonylamino-7a-(2,3-dimethoxyphenyl)-3S,3aS.7aS)-2.3.3a,4,5,7,7a hexahydro(b]furan-2-one (279) : To the crude epimeric mixture of amino acids 278 (0.50 mmol 0 30 g) was added a catalytic amount of p-TsOH in CH 2 Cl 2 (20 ml ) and allowed to stir overnight. The reaction mixture was diluted with ethyl ether and washed with NaHCO 3 solution ( 30 %, 2 X 10 mL ) The organic layer wa dried with MgSO 4 and the solvent evaporated under reduced pressure. The lactone (279) was successively s eparated by column chromatography v ia gradient elution ( hexane s: ethyl acetate 99 : I 9 : I ) to yield white crystals of A (0 10 g 65 % ); Rf= 0 5 (ethyl acetate: hexanes I : 4 ); [a]o 32 96.0 ( c 1.0 CHCh ); 1 H NMR ( CDCl 3 ) 8: 7.1 -6 9 ( m 2H ), 6.8 -6.7 ( m 2H ) 6 2 ( m IH ), 5 7 ( dt J = 10.0 1.0 Hz IH) 4.9 (d J = 5.7 Hz, IH), 4.5 (dd J = 7.9 3.0 Hz, IH ), 3.8 ( s, 3H ) 3 7 (s 3H) 3 3 ( dtd J=11.5 3.5, 1.0 Hz lH), 2 3 -2 2 ( bm, 2H) 1.7 1.6 ( m lH ), 1.4 (s lH ), 1.3 (s, 9H ); 13 C NMR (CDCl 3 ) 8 : 174.9, 155.3, 153.4 135 1 132.5 126.9 123.6 117.2, 112 9, 82.8 80.3 59 9 55 8 54 1 42.9, 29 7 28.2 22.8, 20 5 ; IR (KBr/ cm 1 ): 2932 2253 1776 1716 1506, 1475 1263 ; LRMS ( CI/ C~ ) m/ z ( rel. intensity ) 389 ( m +, 7 0 ), 334 (65 ), 228 (100); HRMS Calcd for C 22 H 3 6NO 6 (m+l) Calcd .: 389.2464 ; Found : 389.5326 Anal Calcd for C 23 H 3 5 NO 6 : C, 64 70 ; H, 6.90 ; Found : C 64.36 ; H 6 64.

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107 6-(2,3-dimethoxyphenyl)-2-dimethylsilyloxy-( 1 S,2R)-5-cyclohexen-l-yl-N phtholylglycinate (285): A solution of phthaloyl-glycine (1 .40 mmol, 0.30 g), DCC (2.50mmol, 0.50 g), DMAP (catalytic) in dichloromethane (10 mUmmol) was cooled to 0 C and a solution of the TDS protected diol 276 (1.20 mmol 0 50 g) in dichloromethane (2 mL) was added. The cloudy reaction mixture was stirred overnight while it was allowed to reach room temperature. The solution was diluted with ethyl ether and filtered through a bed of silica gel to remove the precipitate of dicyclohexylurea Removal of the solvent and chromatography (silica gel, ethyl acetate:hexanes, 9: 1) of the residue, afforded the pure phthaloyl glycinate 285 as white crystals (0.35 g, 70%) ; Rf= 0.8 (ethyl acetate: hexanes, 1:4); mp : 89 91 C ; [a]o 25 79.7 (c 1.0, CHC1 3 ); 1 H NMR (CDC1 3 ) 8: 7.81 (m, 2H), 7.65 (m, 2H), 6.90 (t, J = 7.9 Hz, 1 H), 6.81 (d, J = 7.9 Hz, lH), 6.49 (d, J = 7 9 Hz, lH), 5 89 (t, J = 3.4 Hz lH) 5.85 (d, J = 2.8 Hz, lH), 4.12 (m, lH), 3.83 (s, 3H), 3 76 (s, 3H), 2.39-2.15 (m, 2H), 1.91-1.50 (m, 2H), 0 88 (dd, J = 6 7 1.2 Hz, 6H), 0.84 (s, 7H), 0.12 (d, J = 5.8 Hz, 6H) ; 13 C NMR (CDCh) 8: 168.80, 167.61 153.32, 147.42, 135.00 134 74 133,93, 132 84, 124.40, 124.10, 122.84, 112.71, 73.43, 69.05, 60.93, 56.18, 39.10, 26 .2 1 25.11, 24.51, 20.41, 20.24, 18.74, 18.62, 9.37, -2.97; IR (KBr/ cm1 ): 2954 1752 1726 1470, 1416, 1205, 1114, HRMS Calcd. for C 32 H 41 NSiO 4 (M+): 579 .2 652; Found : 579 2652. Anal. Calcd. for C32H4 1 NsiO4: C, 63.36; H, 8.62; Found: C, 63.51; H, 8.51.

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108 6-bromo-2-dimethylsilyloxy-( I S,2R)-5-cyclohexenl-yl-N-tert-butoxycarbonyl glycinate (292). A solution of Boe-glycine (0.07 mol, 12.00 g), DCC (0.09 mol, 18.50 g), DMAP (catalytic) in dichloromethane (200 mL) was cooled to 0 C and a solution of the TDS protected diol 291 (0.045 mol, 15.00 g) in dichloromethane (200 mL) was added. The cloudy reaction mixture was stirred overnight while it was allowed to reach room temperature. The solution was diluted with ethyl ether and filtered through a bed of silica gel to remove the precipitate of dicyclohexylurea. Removal of the solvent and chromatography (silica gel, ethyl acetate:hexanes, I :9) of the residue, afforded the pure glycinate (292) as a colorless oil (15,40 g, 70%); Rf= 0.7 (ethyl acetate:hexanes, 1 :4); mp: 89 91 C; [a]o 26 -64.0 (c 1.0, MeOH); 1 H NMR (CDC1 3 ) 6.27 (dd, J = 5 2, 3 1 Hz lH), 5.59 (d, J = 3.9 Hz, lH), 5.00 (bs, 1 H), 3.97 (m, 3H), 2.39-2.19 (m, lH), 2 15-2.09 (m, lH), 1.85-1.62 (m, 2H), 1.43 (s, 9H), 0.84 (s, 3H), 0.82 (s, 3H) 0.77 (d, J = 1.9 Hz, 6H), 0.07 (d, J = 4.6 Hz, 6H); 13 C NMR (CDCl3) 8: 169.59, 155.29, 134.80, 116.96, 79.64 73.88, 69.23 42.33, 34.03, 28.21, 25.49, 24.70, 22.55, 20.01, 18.48, -3.09, -3.15; IR (CHCIJ/ cm1 ): 3445, 2958, 1755, 1715, 1511, 1372; HRMS Calcd. for C 21 H 39 NsiBrO 5 (M+H): 492.1781; Found: 492.1806; Anal. Calcd. for: C2 1 H3sNsiBrO 5 : C, 51.21; H 7.78; Found: C, 51.41; H, 7.75.

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109 2-(4-dimethylthexylsilyloxy-2-bromo-(1S,4R)-2-cyclohexenyl-2R-N-tert butoxycarbonylmethylglycinate (289a): A solution of the glycine ester 292 (12.50 mmol, 6.23 g) in THF (100 mL) and a 1.0 M solution of ZnC'2 (13.70 mmol 13.70 mL,) in ether was cooled to -78C. Then a 1.7 M solution of LDA (31.00 mmol, 19.00 mL) in THF was added dropwise to the reaction mixture and the system allowed to warm to room temperature slowly (overnight). The reaction was quenched with water and the basic solution diluted with ethyl ether. The reaction mixture was then acidified slowly with HCl (IN) until a pH of approximately 2.5 was reached. After extraction with ethyl ether (3 X 100 mL) and drying with Na 2 SO 4 the solvent was removed to afford the crude rearranged amino acids as light yellow cystals. The acids were purified by silica gel chromatography using a gradient elution of ethyl acetate: hexanes (l :6) followed by methanol ( 100%) to afford the mixture of acids. The mixture then treated with diazomethane to obtain the corresponding methyl esters. The epimeric methyl esters were then introduced unto a silica gel column and separated with hexanes ( 100%) to obtain clear oil of 289a (2.33 g 38%); Rf= 0.7 (ethyl acetate: hexanes, 1:4); [a]o 26 -55.7 (c 1.0, CHCl 3 ); 1 H NMR (CDC1 3 ) 8: 6.30 (dd, J = 5.6, 1.3 Hz, lH), 5.21 (d, J = 8.6 Hz, lH), 4.68 (dd, J = 8.7, 2.3 Hz, lH) 4.11 (m, lH), 3.71 (s, 3H), 3.05 (bs, lH), 1.86-1.78 (m, 2H), 1.63-1.50 (m, 2H), 1.43 (s, 9H), 0.84 (d, J = 6.9 Hz, 6H), 0.80 (s, 6H), 0.05 (d, J = 5.3 Hz, 6H); 13 C NMR (CDCl3) 8:171.85, 155.41, 136.30, 125.51, 80.02, 66.68, 55.86, 52.33, 45.13, 34.15, 29.16, 28.3025.76, 24.73, 23.40, 20.18, 18.56, -2.67, -2.88; IR (K.Br/ cm1 ): 3439, 2955, 2867, 1753, 1720, 1498, 1365, 1251, 1164; HRMS Calcd. for C 20 H 36 NsiBrO 5 (M+):

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110 506.1920; Found: 506.1937; Anal. Calcd forC20H3sNSiBrO4: C 52.16; H, 7.96; Found: C, 52.28 ; H, 8.06 Structure was confirmed by X-ray Crystallography (Figure 7, pg 76). 2-( 4-dimethl thexylsilyloxy-2-bromo-( 1 S ,4R)-2-cyclohexenyl-2S-N-tert butoxycarbonylmethyl glycinate (289b): The epimeric methyl esters were then introduced unto a silica gel column and separated with straight hexanes to obtain clear oil of 289b (2.00 g 30%); Rf= 0 65 (ethyl acetate : hexanes, 1 :4); [a]o 32 -27.7 (c 1.0, CHC1 3 ); 1 H NMR (CDC!J) 8: 6.17 (dd, J = 5.6, 1.3 Hz, 1 H), 4.85 (m, 2H ), 4.12 (m, 1 H), 3.74 (s, 3H), 2.96 (bs, 1 H), 1.86-1.76 (m, lH), 1.63-1.50 (m, 3H) 1.42 (s, 9H), 0.87 (d, J = 6.9 Hz, 6H), 0.82 (s, 6H), 0.05 (d, J = 5.3 Hz, 6H); 13 C NMR (CDC1 3 ) 8:171.86 155.46 135.56, 127.99, 79.86 65.49, 55 .3 4, 52 38, 43.84, 34.24, 29.58, 28.29, 24.87, 20.31, 19.99 18.58, -2.47, -2.92; IR (KBr/ cm 1 ): 3443 2956, 2868, 1749 1715 1503, 1367, 1251, 1159 ; HRMS Calcd. for C20H36NsiBrOs (M+): 506.1920 ; Found: 506.1937; Anal. Calcd. for C20H3sNSiBrO4: C, 52.16; H, 7.96; Found : C, 52.34; H, 8.01.

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111 2-(4-dimethyl-tert-butylsilyloxy-2-bromo-(1S,4R)-2-cyclohexenyl-2R-N-tert butoxycarbonylmethylglycinate (293): A solution of the glycine ester 292 (13.40 mmol, 6 23 g) in THF (100 mL) and a 1 0 M solution of ZnC1 2 (21.10 mmol 20.00 mL,) in ether were cooled to 78 C. Then a 2.0 M solution of LDA (37.50 mmol, I 9.00 mL) in THF was added dropwise to the reaction mixture and the system allowed to warm to room temperature slowly (overnight). The reaction was quenched with water and the basic solution diluted with ethyl ether. The reaction mixture was then acidified slowly with HCI (IN) until a pH of approximately 2.5 was reached. After extraction with ethyl ether (3 X 100 mL) and drying with Na2SO 4 the solvent was removed to afford the crude rearranged amino acids as light yellow cystals The acids were purified by silica gel chromatography using a gradient elution of ethyl acetate: hexanes (I :6) followed by methanol ( 100% ). The pure acids were then treated with diazomethane to obtain the corresponding methyl esters. The epimeric methyl esters were then introduced unto a silica gel column and chromatographed with hexanes ( 100%) to obtain white crystal of 293 (2.63 g 40% ); Rf= 0.7 (ethyl acetate:hexanes, 1:4); mp: 115 117 C; [a]o 28 -54.1 (c 1.0, CHCI 3 ) ; 1 H NMR (CDCh) 8: 6.18 (dd, J = 5 6, 1.3 Hz, lH), 5.23 (d, J = 8 6 Hz, lH ), 4.70 (dd, J = 8.7 2.6 Hz, lH) 4 13 (m, lH), 3 72 (s, 3H), 3.09 (bs, lH), 1.92-1.75 (m, 2H), 1.74-1.50 (m, 2H), 1.43 (s, 9H), 0 85 (s, 9H) 0 02 (d, J = 4.4 Hz 6H) ; 13 C NMR (CDCh) 8:171.81 155.37, 136.30, 125.62, 80 00, 66.78, 55.80, 52.29, 45.15, 29.14, 28.34, 28.20, 25.76, 25.67, 23.33, 17.95 -4.77; IR (KBr/ cm1 ): 3394, 2963, 2857 1733, 1710, 1645 1522 1365; HRMS Calcd for C20H36NsiBrOs (M+): 478.1525; Found : 478 .1 525; Anal. Calcd. for C20H3sNSiBrO4 : C 50.20; H, 7.58; Found: C, 50.15; H, 7 50.

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112 2-( 4-dimethlthexylsilylox y-( 1 S ,4R) cyclohex yl)-2S N-tert-butoxyc a rbonylmethyl glycinate (294). To vinyl bromide 293 (0 20 mmol 0.10 g ) dissolved in benzene (10 mL ) was added n-Bu 3 SnH ( 0.22 mmol 0.06 g ) This mixture was refluxed for approximately 30 min then AIBN (catalytic) was added and the reaction allowed to r e flux for another 3 h. The reaction was quenched with water and the product extracted with ethyl acetate 3 X 10 mL The organic layers were combined and dried over anhydrous MgSO 4 After filtration the solvent was removed under reduced pressure a nd the solid residue introduced onto a silica gel column and eluted with ethyl acetate: hexanes ( I : 6 ) to obtain 294 (0.07 g 82 %) as a light yellow oil ; Rf= 0.75 (ethyl acetate : hexanes, 1 : 6 ); [a] 0 28 14 9 ( c 1.0 MeOH ); 1 H NMR ( CDC1 3 ) B : 5 85 ( m lH) 5.46 (d J = 9.8 Hz lH ), 4.93 ( d J = 8.9 Hz lH) 4.29 (dd J = 8 9 3.8 Hz), 4.06 (d J = 3 7 Hz, lH ), 3 71 (s, 3H ), 2.61 ( bs lH), 1.76-1.67 (m 2H) 1.63-1.54 (m 4H), 1.41 (s 9H) 0.86 ( d J = 6.7 Hz, 6H), 0.80 (s 7H), 0.06 (s 6H ); 13 C NMR ( CDCh) B : 172.87 156.08, 134.12 127.27 112.56 80 17 63.73 57.15 52.59 38.15 34 31 30 54, 28 24 27.22, 24 73, 20 63 20 35 20 26 18 57 -2.07, -2.43. IR (CHCl 3 / cm 1 ): 3448 2958, 1755, 1710 1522 1365; HRMS Calcd. for C 22 H 42 NSiO s ( M+ 1 ) : 427.6600 ; Found: 427.6812; Anal. Calcd. for: C 22 H 4 1 NSiO 5 : C 61.79 ; H 9.66; Found: C 61.77 ; H 9 71.

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113 2-( 4-dimethy I thex ylsil ylox y-2-Cycl ohexen y l)-2R-N-te rt-butox ycarbon y I me thy 1 glycinate (295) To vinyl bromide 293 (0.70 mmol, 0.34 g) was added to a mixture of catalytic amount of Adams Catalyst, triethylamine (0.70 mmol, 0.73 mL) and methanol (5.0 mL). The reaction vessel was evacuated and the solution stirred under hydrogen atmosphere ( 40 psi) for 3h. After completion of the reaction (as observed by TLC), the suspension was filtered and the solvent concentrated under reduced pressure. The solid residue was diluted with ethyl acetate (10 mL) and washed with water (2 X 2 mL), followed by NaHCO 3 (2 X 2 mL). The organic layer was dried with Na 2 SO 4 and concentrated to afford white crystals of 295 (0.30 g, 89%); Rf= 0.65 (ethyl acetate:hexanes, 1:6); [a] 0 26 -4.9 (c 1.0, MeOH); 1 H NMR (CDCh) 8: 5.05 (d, J = 9.1 Hz, lH), 4.22 (q, J = 4.5 Hz, 1 H), 3. 93 (bs, 1 H), 3. 70 (s, 3H), 1.78-1.44 (m, 8H), 1.41 (s, 9H), 0.88 ( d, J = 6.4 Hz, 6H), 0.81 (s, 7H), 0.02 (s, 6H); 13 C NMR (CDCl3) 8:172.77, 155.42, 79.51, 65.68, 57 90, 51.95, 40.45, 34.39, 32.90, 28.27, 24.74, 22.86, 21.63, 20.29, 18.62, -3.04; IR (CDCh/ cm1 ): 3440, 2929, 1755, 1712, 1503, 1162; HRMS Calcd. for C 22 H 44 NSiO 5 (M+l): 430 2922; Found: 430.2988; Anal. Calcd. for: C 22 H 43 NSiO 5 : C, 61.50; H, 10.09; Found: C, 61.57; H, 10.12.

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I 14 2-( 4-hydroxy-2-cyclohexenyl)2R)-2R-N-tertbutoxycarbonyl methyl gl ycinate (296) To a solution of the ester 295 (0.800 mmol 0.450 g) in THF ( 10 mL) was added distilled TBAF ( 1.600 mmol 1.60 mL). The mixture was stirred for 3h and monitored by TLC. After consumption of starting material the solvents were removed and the s olid residue introduced onto a s ilica gel column and eluted with ethyl ac e tate : hexanes (1 : 1 ) to afford white flaky crystal s of the alcohol 296 (0 322 g, 90 %). Rf = 0.45 (ethyl acetate:hexane s 1: l ); [a] 0 30 -4.2 (c 1.0 MeOH) ; 1 H NMR (CDCl 3 ) 8 : 5 20 (s lH ), 4.01 ( bs, 1 H ), 3.84 ( s, 3H ), 3.59 (s, 3H ), 1.82 1.42 ( m, 8H ) 1.41 (s, 9H ), 1 39 1 20 ( m 2H) ; 13 C NMR ( CDCh) 8 : 173 73 160 36, 79 94 74.22, 58.49 52 18 41.24 29 65 28.54 28.55, 28.33 21.31, 26.17 ; IR (NaCl/ cm 1 ): 3440 3377 2929 2855 1743 1712 1162; HRMS Calcd. for C 1 4 H 2 5 NO 5 ( m+H H 2 O): 271.3645 ; Found: 271.4012

PAGE 122

115 2-(-2-Cyclohexenyl)-2R-N-tert-butoxycarbonylmethylglycinate (304): To vinyl bromide 293 ( 0 10 g 0.20 mmol) was added to a mixture o f catalytic amount of I 0 % Pd C and methanol ( 1.0 mL). The reaction vessel was evacuated and the solution stirred under hydrogen atmosphere ( 15 psi ) for 1 h After completion of the reaction ( a s observed by TLC) the suspension was filtered and the s olvent concentrated under reduced pres s ure The s olid residue was recrystallized from Ethyl acetate/ Hex a ne s to give the e s ter 304 (0.04 g, 75 %) as a white solid ; Rf= 0.8 ( eth y l a cetate:hexane s 1 : 6 ); mp : 110 -112 C ; [a]o 25 -19 7 ( c 1.0 CHCI 3 ) ; 1 H NMR (CDCh ) 8 : 5.00 (d J = 8.1 Hz lH ), 4.18 ( dd J = 8 5 5 1 Hz IH ), 3.71 ( s, 3H) 1.81 1.56 ( m JOH ) 1.41 ( s 9H ); 13 C NMR ( CDCl 3) 8: 173.15 155.81 79.94 58.49, 52.18 41.24 29.65 28 54 28 50 28 33 26.17; IR (KBr/ cm 1 ): 3420 2950 1755 1712 1503 1180 ; HRMS Calcd. for C 14H 2s NO 4 : 271.2434 ; Found: 271.2814.

PAGE 123

116 6-Bromo-2-dimethylthexysilyloxy-( 1 S,2R)-5-cyclohexenl-yl-N-tert alanylcarbonylglycinate (301). A solution of N-Boc-alanine (6 600 mmol, 0.30 g), DCC (9.00mmol, 1.90 g), DMAP (catalytic) in dichloromethane (IO mL/mmol) was cooled to 0 C and a solution of the TBS protected diol 298 (6.000 mmol, 2.20 g) in dichloromethane (40 mL) was added by syringe and the reaction mixture stirred overnight while it was allowed to reach room temperature. The solution was diluted with ethyl ether and filtered through a bed of silica gel to remove the precipitate of dicyclohexylurea. Removal of the solvent and chromatography (silica gel, hexanes:ethyl acetate, 90: IO) of the residue, afforded the pure ester as a light yellow oil (2.40 g, 71%); Rf= 0.5 ethyl acetate :hexanes, 1 : 6; [a.] 0 28 68.1 (c 1.0, CHC1 3 ); 1 H NMR (CDC1 3 ) o: 6.26 (dd, J = 2.6, 5 1 Hz, lH), 5.53 (d, J = 3.9 Hz, lH), 5.13 (d, J = 8.1 Hz, 1 H), 4.40 (q, J = 7.2 Hz, lH), 3.94 (dt, J = 3.7 Hz, lH), 2.32-2.01 (m, lH), l.83-1.62 (m, 2H), 1.45 (s, 3H), 1.43 (s, 9H) 0.82 (s, 9H), 0.05 (s, 3H), 0.02 (s, 3H); 13 C NMR (CDCh) o: 172.49, 157.77, 134.67, 1171.71, 79.36, 73.73, 69.37, 67.85, 49 12, 28 24, 25.79, 24.51, 25 64, 25.60, 25.55, 19.15, 18.01, -5.08, -5 17; IR (KBr/ cm1 ): 3435, 2952, 2928, 2855, 1747, 1714, 1649, 1163; HRMS Calcd. for C20H36BrNSiOs (M+ ): 478.1636; Found: 478.1624. Anal. Calcd. for C 20 H 3 6BrNSiO 54 : C, 50.20; H,7.58; Found: C, 50 19; H, 7.64.

PAGE 124

117 6-bromo-2-dimethyltert butylsilyloxy-( I S,2R)-5-cyclohexenl-yl al a nine(302). A s olution of the alanine ester 301 (10.00 mmol, 4 80 g ) in CH 2 Cli ( 250 mL ) was cooled to 0 C Freshly distilled TFA (18 IO mmol, 9.60 mL) dis s olved in CH 2 C)i ( 50 mL) was then added dropwise over 30 min. The mixture was stirred for 3h and monitored by TLC. After consumption of starting material the reaction was quenched with NaHCO 3 (saturated ) The phases were separated and the organic layer washed with brine. The combined organic layers were dried over Na 2 SO 4 and concentrated to give white flaky crystals of the free amine 302 (2.84 g 75 % ) Rf= 0 74 (ethyl acetate 100 %); [a] 0 30 59 1 (c 1.0 MeOH ); 1 H NMR (CDC1 3 ) o: 8 50-7 71 (bs 2H) 6 28 ( dd J = 3 6 4.5 Hz, IH) 5 57 ( d J = 3.6 Hz lH ), 4.09 3 97 (m, 2H) 2.34 2.24 ( bm 1 H) 2.12 1.98 ( bm, 2H) 1.84 1.70 ( m, 2H ) 1.66 ( d J = 7 1, 3H) 0.83 (s, 9H ) 0 04 ( s 3H ); 13 C NMR ( CDCh ) o : 169.60 135 53 116 51 75.57 69.28 49.26 26 21 25.84 25 71 18 33 16.27, -4.81 -4 96 ; IR ( NaCl/ cm 1 ) : 3434 3377, 2953 2929 2856, 1752 1677 1203, 1136; HRMS Calcd for C1sH 2 sBrNO 3 Si (m+): 378.3853 ; Found : 378.1100

PAGE 125

118 6-bromo-2-dimethyltert-butylsilyloxy-( l S,2R)-5-cyclohexenl-yl-Nl-phenyl-( 4' methoxy-4-phenyl)-alanyl sulfonamide (299). To a solution of amine 302 (0.530 mo!, 0.200 g), in THF ( l 0 mL) was added Et3N (0.800 mmol, 0.080 g). To this mixture was added the sulfonyl choride (0.080 mmol, 0.218 g) and the reaction mixture stirred for 48h. The reaction mixture filtered through a bed of silica gel followed by removal of the solvent and chromatography (silica gel, ethyl acetate:hexanes, l :8) of the residue, afforded the pure sulfonamide 299 as a white crystalline solid (0.132 g, 40%); Rf= 0.4 (ethyl acetate:hexanes I :4); mp: 114 116; [a] 0 28 44.0 (c 1.0, CHCh): 1 H NMR (CDC1 3 ) 7.87 (m, 2H), 7.62 (m, 2H) 7.50 (m, 2H), 6.97 (m, 2H), 6.20 (m, lH), 5.41 (m, 2H), 4.10 (m, IH) 3.85 (s, 3H), 2.23 2.16 (m, lH), 2.10 -1.90 (m, lH), 1.68 1.61 (m, 2H), 1.56 (s, 3H), 1.51 1.49 (m, 4H), 1.20 (m, lH), 0.77 (m, 9H), 0.82 (s, 3H), -0.02 (m, 6H); 13 C NMR (CDC1 3 ) <5: 170.88, 170.87, 160.01, 145.13, 138.17, 135.06, 131.63, 128.37, 127.69, 127.53, 116.64, 114.44, 74.49, 69.27, 55.37, 51.71, 26.29, 25.76, 25.63, 20.35, 18.06, -5.03, -5 14; IR (CHCIJI cm1 ): 3281, 2951, 2949, 2854, 1743, 1610, 1595, 1519, 1488, 1250; HRMS Calcd. for C2sH39NsiBrO6 (M+): 624.1451; Found: 625.1450.

PAGE 126

119 (1 S.4R)-2-cyclohexenyl-2S-N-l-phenyl-(4' -methoxy-4-phenyl)-alanyl sulfonamide (303). A solution of the alanine ester 300 (0.800 mmol, 0.450 g) in CH 2 Clz (20 mL) was cooled to 0C. Freshly distilled TFA (l.600 mmol, 1.50 mL) dissolved in CH 2 Clz (10 mL) was then added dropwise over 30 min. The mixture was stirred for 3h and monitored by TLC. After consumption of starting material the reaction was quenched with NaHCO 3 (saturated). The phases were separated and the organic layer washed with brine. The combined organic layers were dried over Na 2 SO 4 and concentrated to give white flaky crystals of the alcohol 303 (0.322 g, 90 %). Rf= 0.4, (ethyl acetate:hexanes I: I); [a] 0 30 -5.1 (c 1.0, MeOH); 1 H NMR (CDCh) o: 7.86 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 5.41 (s, IH), 5.20 (bs, IH), 3.84 (s, 3H), 3.61 (s, 3H), 2.05 (bm, 2H), 1.82 1.42 (m, 8H), 1.41 (s, 3H), 1.39 1.20 (m, lH); 13 C NMR (CDCh) o: 173.73, 160.36, 156.65, 145.32, 140.09, 131.75, 128.63, 127.86, 127.15, 114.74, 74.22, 65.37, 55.63, 52.84, 45.83, 29.61, 29.46, 21.31, 21.05, 17.59; IR (NaCl/ cm1 ): 3434, 3377, 2953, 2929, 2856, 1752, 1677, 1203, 1136; HRMS Calcd. for C1sH2sBrNO3Si (m+H H2O): 430.1682; Found: 430.1688.

PAGE 127

120 2-( 4-dimethl thexylsilyloxy-2-(2-benzyloxy-3-methoxyphenyl)-( 1 S ,4R)-2-cyclohexenyl 2S-N-tert-butoxycarbonylmethylglycinate (312). To a two neck round bottom flask fitted with a condenser under an argon atmosphere wa s added Pd ( PPh 3 ) 4 ( 7.00 mmol, 0.010 g ) This was followed by addition of dry benzene ( 15 mL) A solution of the vinyl bromide 289b ( 0 350 mmol 0.176 g ) dissolved in benzene ( 5 mL ) was then added to the reaction flask. This was followed by the addition of Na 2 CO 3 (2.0 M 0.60 mL), to the mixture Boronic acid 313 (0 26 mrnol 0.07g) dissolved in benzene (5 mL ) was then added to the reaction mixture which was allowed to reflux for 6h The reaction was quenched with water and the product extracted with ethyl acetate ( 3 X 20 mL ). The organic layer s were combined washed with brine and dried over anhydrous MgSO 4 After filtration the solvent wa s removed the crude product introduced onto a silica gel column, and eluted with ethyl a cetate: hexanes (1/3) to obtain 312 ( 0.10 g 70 %) as a light yellow oil ; Rf= 0.35 (ethyl a cetate: hex a nes 1 :4 ); [a]o 29 +26 7 ( c 1.0 CDC'3); 1 H NMR (CDC'3) o: 7.31 ( m SH ) 6 95 (t, J = 7 8 Hz 1 H), 6.85 ( d J = 7 9 Hz lH ) 6.58 ( d J = 7.3 Hz 1H) 5 77 (d J = 4 6 Hz 1H ) 5 02 ( d J = 11.2Hz, lH),4 91 ( d J= ll.2Hz, 1H),4.82(d,J=7.3Hz 1H ), 4 13(m 1H) 3.96 ( q,J = 4.0 Hz lH) 3 85 ( s 3H ), 3.62 ( s 3H) 3.46 ( q J = 7.0 Hz lH ), 1.78-1.49 ( m 4 H ), 1.36 (s, 9H ), 1.24-1.17 ( m SH ), 0 91 (d, J = 6 7 Hz 6H) 0.86 (s, 7H ) 0.11 ( d J = 8.5 Hz 6H) ; 13 C NMR ( CDC'3 ) o : 172.46 155 11 152 24 144.93 139.82 137.82 135 16 132.17 128.16 128 13 127 66 124.24, 122.04, 111.77 79 19 74 72, 63 37 55 69, 54.64 51.91 38.48 34 33 29.82 28 28 27 96, 24 84 20 38 18 62 18.35 17.91 15 23 -2.35 -2 87 ; IR (CDCl]i cm 1 ) : 3370 2989, 2959, 1750 1720 1698 1520 1505 1454 ; HRMS Calcd.for C 36 Hs 3 NO1Si (m+) : 639.9104 ; Found: 639.9102

PAGE 128

121 2-( 4-dimethylthexylsilyloxy-2-(2,3-dimethoxyphenyl)-( 1 S ,4R)-2 cyclohexenyl-2S-N tert-butoxycarbonylmethylglyci nate (316). To a two neck round bottom flask fitted with a condenser under an argon atmosphere was added Pd ( PPh 3 ) 4 ( 0 01 mmol 0 0 I 4 g). This was followed by addition of dry benzene (15 mL ). A solution of the vinyl bromide 289b ( 0.400 mmol 0 200 g) dissolved i n benzen e ( 5 mL ) wa s then added to the reaction flask. This was followed by the addition of Na 2 CO 3 ( 2.0 M 1.20 mL) to the mixture. Boronic acid 273 ( 0.600 mmol 0 110 g) dissolved in benzene ( 5 mL) was then added to the reaction mixture which was allowed to reflux for 6h. The reaction was quenched with water and the product extracted with ethyl acetate ( 3 X 20 mL ). The organic layers were combined washed with brine and dried over anhydrous MgSO 4 After filtration the s olvent w a removed the crude product introduced onto a silica gel column and eluted with ethyl acetate : hexanes ( 1/3) to obtain 316 ( 0 10 g, 70 %) a s a light yellow oil ; Rf= 0.40 ( ethyl a cetate : hexanes 1 : 4) ; [a.] 0 30 +26.9 (c 1.0 CDCl 3 ); 1 H NMR (CDCl 3 ) 8: 6.92 ( t J = 7.9 H z, IH ), 6.8l ( d J = 7.9 Hz, lH ), 6.65 ( d J = 7.8 Hz lH ), 5 95 ( d, J = 2.4 Hz lH ), 5 23 ( m lH ), 4 33 ( bs, lH),4.08 (m, lH), 3 83 (s, 3H) 3.79 (s, 3H), 3.65 (s, 3H) 3.45 ( bs lH) 1.94 1.63 (m, 4H ), 1.56 ( bs 1 H) 1.38 ( s 9H ), 0.86 ( m 6H) 0.08 ( m 6H ); 13 C NMR ( CDCh ) 8: 173.21 155.65, 152.57, 146.46 142 15 134 83, 131.37 124.49 122.49 112 31 79 86 63 93, 61.07 56 17 55 35 52.59 39.56 30.45 28.79 19.16 2.45 -2 71 ; IR ( CDC1 3 / cm 1 ): 3348, 2975 2937 1751 1714 1689, 1520, 1474 1259 1225 1159 1062 ; HRMS CaJcd.for C 30 H 49 NO 1 Si ( m+ ) : 563. 0491 ; Found : 563 0451.

PAGE 129

122 2-( 4-hydroxy-2-benzyloxy-3-methoxyphenyl)-( IS ,4R)-2-cyclohexenyl-2S-N-tert butoxycarbonylmethylglycinate (311): To a solution of the silyl ether 312 (0.183 mmol 0 177 g) in THF ( 10 mL) was added TBAF (0.220 mmol, 0.220 mL). This mixture was stirred for 3h while being monitored by TLC The reaction mixture filtered through a bed of silica gel followed by removal of the solvent, trituration with CCL 4 (3 X 20 mL) and chromatography (silica gel, ethyl acetate: hexanes, 1 :8) of the residue, afforded the pure alcohol 311 as a light yellow oil (0.061 g, 75%; Rf= 0.4 (hexanes:ethyl acetate, 1:1); [a] 0 27 + 52 7 (c 1.0, CHCI 3 ): 1 H NMR (CDC1 3 ): 7.32 (m, 4H), 6.95 (t, J = 7.6 Hz, lH), 6.84 (d, J = 7.6 Hz, lH), 6.65 (d, J = 7.6 Hz, lH), 5.79 (d, J = 3.7 Hz, lH), 5.09 (d, J = 8.1 Hz, lH), 5.05 4.90 (m, 2H), 4.19 4 07 (bm, 2H), 3.85 (s, 3H), 3.61 (s, 3H), 3.36 (bs, 1 H), 1.79 (bs, 2H), 1.61 (m, 2H), 1.33 (s, 9H), 1.16 (bm, 1 H); 13 C NMR (CDC'3) o: 172.65, 155.17, 152.36 145.02, 141.36, 137 96, 134.89, 131.01, 128.20, 127.76, 124.17, 121.93, 111.88, 79.38, 74.75 63.53, 55.77, 54.89, 51.89, 39.16, 29.67, 28.28, 18.77 ; IR (CHC'3/ cm1 ): 3350, 2964, 2934, 2359, 1749, 1713, 1517, 1469, 1365, 1258, 1216, 1158; HRMS Calcd. for C2sH36NO1 (M+ 1 ): 498.5900; Found: 498.2491.

PAGE 130

123 2-( 4-hydroxy-2-(2.3-dimethoxyphenyl)-( IS .4R)-2-cyclohexenyl-2S-N-tert butoxycarbonylmethylglycinate (317) To a solution of the silyl ether 316 (0.355 mmol 0 200 g ) in THF ( 10 mL) was added TBAF ( 0 533 mmol 0 533 mL). This mixture was stirred for 3h while being monitored by TLC. The reaction mixture filtered through a bed of s ilica gel followed by removal of the solvent trituration with CCL 4 ( 3 X 20 mL ) and chromatography ( silica gel ethyl acetate: hexane s, I :8 ) of the residue afforded the pure alcohol 317 a s a colorless oil ( 0 120 g 81 %; Rf= 0.4 (hexanes:ethyl acetate l:l ); [a]o 27 + 28 6 ( c 1.0, CHCl 3) : 1 H NMR ( CDC1 3 ) : 8 : 6.92 ( t J = 7 9 Hz lH) 6.8l(d J = 7.9 Hz lH ), 6.65 ( d J = 7.8 Hz lH ), 5 95 ( d J = 2.4 Hz lH), 5.23 ( m l H ), 4.33 ( b s, I H ), 4 08 ( m 1 H ), 3.83 (s 3H) 3 79 ( s 3H ), 3 65 ( s 3H ), 3.45 (b s, lH ), l.94 1.63 ( m 4H ), 1.56 ( b s, lH ), 1.38 ( s, 9H) ; 13 C NMR ( CDCl 3) 8:173.21 155 65 152.57 146.46 14 2 .15 134.83 131.37, 124.49 122.49 112 31 79.86 63 93 61.07 56 17 55.35 52.59, 39.56, 30.45 28 79, 19 16 ; IR ( CDCl 3 / cm 1 ) : 3348 2975, 2937 1751, 1714 1689 1520 1474 1259 1225, 1159, 1062, ; HRMS Calcd.for C30H49NO7Si ( m+): 421. 4910 ; Found : 421. 3720 ;

PAGE 131

124 2-( 4-benzoyl-2-(2-benzyloxy-3-methoxyphenyl)-( 1 S .4R)-2-cyclohexenyl-2S-Nte rt butoxycarbonylmethyl glycinate (314): To a stirred solution of the alcohol 311 (0.183 mmol 0 091 g ) and benzoic acid (0.366 mmol 0.050 rnL ) in dry THF (5 mL) was added a solution of the Mitsunobu reagent previously prepared by addition of diethyl azodicarbox y late ( DEAD ) ( 0 366 mmol 0.058 mL ) to a stirred s olution of PBu 3 (0 366 mmol 0.091 rnL ) in THF ( 5 rnL ) at 0C and stirred at the same temperature for 15 min. The reaction mixture was allowed to warm slowly to room temperature over 3h after which the solvent s were removed under reduced pressure an the crude product purified by chromatography (silica gel, ethyl acetate : hexanes 1 :8 ) of the residue afforded the pure benzoate 314 as a clear oil ( 0.155 g 94 %) ; Rf= 0 6 (ethyl acetate :hexanes 1 :4) ; [a.] 0 27 + 166 8 ( c 1 0 CHCl 3): 1 H NMR (CDCI 3 ): 8 01 ( m IH) 7 92 (d, J = 1.5 Hz IH), 7 567.23 (m JOH ), 6.96 ( t J = 8.1 Hz, lH) 6.84 ( d J = 8 3 Hz IH ), 6 .' 66 ( d J = 8 0 Hz IH) 5.88 (m, IH ) 5.08(d J=11.0 Hz 1 H ), 4 92 ( d J = 11.2 Hz I H ), 4.66 (d, J = 8.3 Hz I H ), 4 15 ( bm 2H ), 3 85 ( s 3H ) 3.59 ( s 3H ), 3.57 ( b s, lH ), 2 21 ( bm IH), 1.71 (bm 2H) 1.35 (s, 9H ), 1.21 ( bm 2H ); 13 C NMR (CDCl3) 6: 172.65 155 17 152.36 145.02 141.36 137.96, 134.89, 131.01 128 20 127.76 124.17 121.93, 111.88 79 38 74 75 63.53 55.77 54.89 51.89 39 16, 29.67 28.28 18.77 ; IR ( CHCI 3 / cm 1 ) : 3370, 2950 1747 1715 1698 1520 1505 1454 ; HRMS Calcd for C 3s H 40 NO s ( m+ ) : 602.2774; Found: 602.2754.

PAGE 132

125 2-[ 4-oxo-2-(2-benzyloxy-3-methoxyphenyl)-( IS ,4R)]-2-cyclohexen yl-2S-N-tert butoxycarbonylmethylglycinate (326): To a solution of the alcohol 311 (0.603 mmol, 0.300 g) in CH 2 Ch (5 mL) was added PCC ( 0 905 mmol, 0.200 g). This mixture was allowed to tir for 12h after which the reaction mixture was filtered through a bed of silica gel followed by removal of solvents. The crude product was chromatographed (silica gel, ethyl ace tate: hexanes 1 :4) to afforded the pure enone 326 as a light brown oil (0.250 g, 84%); Rf = 0 6 (hexanes:ethyl acetate, 1: I); [a.] 0 27 + 18 6 ( c 1.0, CHC'3) : 1 H NMR ( CDC1 3 ): 7.28 ( m 5H) 7 02 ( t J = 7 8 Hz, lH), 6 93 (dd, J = 1.5 Hz, lH), 6.65 (dd, J = 1.5 Hz lH), 5.87 (m, I H) 4 98 ( q J = 11.4 Hz 2H), 4.69 (m, 1 H), 4.40 (bs, 1 H) 3 89 (s, 3H ), 3.63 ( m lH) 3.56 (s, 3H ), 2.52-2.46 ( m, lH ), 2.28-2.18 ( m lH ), 1.84-1.73 (m, 2H), 1.32 (s, 9H); 13 C NMR (CDC'3) o: 198 29 171.92, 160 74, 154.67 152.39 144.43 137.21 133 54 130.98 128.45 128.27, 124 56 121.27 113.17 79.81 75.32, 55.84 54 .7 8 52.22 40.41, 35.24, 28.11, 23.94; IR (CDCl]i cm 1 ) : 3342 2951, 1747, 1706 1676 1471 1454 1366, 1264 1213 1158 ; HRMS Calcd for C 2s H 33 NO 7 [(m+I ) + Na]: 518 .2 154 ; Found: 518.2160.

PAGE 133

126 2-( 4-dimethylthexylsilyloxy-2-(2-hydroxy,3-di methoxyphenyl)-( l S ,4R)-2-cyclohexenyl2S-N-tert-butoxycarbonylmethyl glyci nate (358): To a two neck round bottom flask fitted with a condenser under an argon atmosphere was added Pd(PPh 3 ) 4 (0.022 g 0.019 mmol). This was followed by addition of dry benzene (IO mL). A solution of the vinyl bromide 289b ( 0.640 mmol, 0.326 g) dissolved in benzene (5 mL) was then added to the reaction flask. This was followed by the addition of Na 2 CO 3 (2.0 M, 2.5 mL), to the mixture. Boronic acid 357 (0.600 mmol, 0.110 g) dissolved in a mixture of benzene (5 mL) and ethanol ( 1 mL) was then added to the reaction mixture, which was allowed to reflux for 6h. The reaction was quenched with water and the product extracted with ethyl acetate (3 X 20 mL). The organic layers were combined, washed with brine and dried over anhydrous Na 2 SO 4 After filtration the solvent was removed, the crude product introduced onto a silica gel column and eluted with ethyl acetate: hexanes (1/3) to obtain the coupled product 358 ( 0.158 g, 45%) as a light yellow oil; Rf= 0.78 (ethyl acetate: hexanes, 1: l ); [a.] 0 30 (c 1.0, CDCh); 1 H NMR (CDCl3) b: 6.75 (m, 2H), 6.67 (m, l H), 5.93 (dd, J = l .9, 5.0 Hz l H) 5 85 (bs, l H), 4.86 (d, J = 7.8 Hz, lH), 4.24 (m, lH),4.04 (dt, J = 4.2, 7.6 Hz, IH), 3.85 (s, 3H), 3.67 (s, 3H), 3.57 (bs, I H), 1.74 (m, 2H), 1.65-1.62 (m, 2H), 1.35 (s, 9H), 0.91 ( dt, J = 1.7, 6.8 Hz, 6H), 0.86 (s, 6H), 0.12 (m, 6H); 13 C NMR (CDC)3) (): 172 70, 155 .2 1, 146.24, 142.58, 138.68, 132.74 126.51 121.86 I 19.77, 109.83, 79.28, 63.59 55.93 54.78 52.09 38.13, 34.39, 29.98, 28.28, 24.88, 20.43, 20.39, 18.67, 18.30, -2.36, -2.83; IR (CDCl 3 / cm 1 ): 3448 2955, 2868, 1752, 1721, I 520, 1472 1279, 1159, I 065 ; HRMS Calcd.for C29H47NO7Si ( m+ ): 549 7864; Found: 549. 3122.

PAGE 134

127 LIST OF REFERENCES I. White, P T.; Raymer, S. "The Poppy National Geographic Feb. 1985 167, pp 142-188 2. Rice, K. C. in The Chemistry and Biology of Isoquinoline Alkaloids ; Philipson Eds. ; Springer: Berlin 1985 ; pp 191-203 3 U.S. Drug Enforcement Agency "Controlled Substance Aggregate Production Quota History" Federal Register July 1994. 4. National Narcotics Intelligence Consumers Committee Report 1993, The Supplies of Illicit Drugs to the United States ," DEA-94066 August 1994 5 Santavy F. Alkaloids New York, 1979, 17 385. 6 Terry C E .; Pellens M. The Opium Problem, Bur. Soc H yg., New York 1928 7 Deronse J. F Ann Chim. 1803 45 257 8 For a review on the elucidation of the morphine structure see: Butora G. ; Hudlicky, T in: Organic S y nthesis: Theory and Applications Vol. 4, Hudlicky T. Ed. JAi Pre ss Inc New York 1998 p. 1-54. 9. Seguin M A. Ann. Chim 1806, 92 225. 10. Serturner F. W. A. Trommdorff s J. Pharm. 1806 14 47. 11. Gulland J M .; Robinson R. Proc. Mem Manchest e r Lit. Ph i l. Soc. 1925 69, 79. 12 Mackay M .; Hodgkin D C. J. Chem. Soc 1955, 3261. 13. Bentley K W.; Cardwell H. M E. J. Chem Soc. 1955, 3245.

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128 14. Herbert R. B .; Venter H. ; Pos, S. Natural Products Repor t, 2000 17,317. 15 Gates, M.; Tschudi, G J. Am. Chem. Soc. 1952 74 1109. 16. Gates M. ; Tschudi, G J Am Chem Soc 1954 76, 1380. 17. Moos, W. H .; Gless, R. D. ; Rapoport H.J. Org Chem. 1982 48, 227 18. Weller D. D .; Rapoport, H J Am Chem Soc. 1976, 98 6650 19 Chandler M .; Parson s, P J J. Chem Soc. Chem Commun.1984 322. 20 Par s on s, P J .; Penkett C. S .; Shell, A. J. Chem. Rev 1996 96, 195 21. Mulzer J.; Durner G Ang ew Chem Int. Ed Engl. 1996 35 2830. 22. Mulzer J.; Bat s J W. ; List B ; Opatz, T. ; Trauner D. S y nl e tt 1997 44 1. 23. Mulzer J .; Trauner, D. J. Chirality 1999 11 475. 24. Trauner D. ; Porth S .; Opatz T. ; Bats J W.; Geister G. ; Mulzer J S y nthesis 1998 653. 25. Trauner D. ; Bats J W. ; Werner A.; Mulzer, J. J. Org. Chem. 1998 63 5908. 26. R Robinson The Structural Relations of Natural Products Oxford University Pre ss, Oxford 1955. 27. Zenk M H. ; Reuffer M. ; Kutchan T. M. ; Galneder, E. in Applications of Plant C e ll and Tis s u e Culture Wiley Chichester 1988 p 213 28. Herbert R. B. Natural Products Report 1992 9 511. 29. Loeffler S .; Stadler R. ; Zenk M. H. T e trah e dron Lett. 1990 31 4853 30 De-Ekanamkul W. ; Zenk M H. Ph y t o ch e mist ry, 1992 32 813. 31. Gerardy R. ; Zenk, M H. Ph y to c hemistr y, 1993 34 125 32 Zenk M H .; Lenz R. J. Biol. Chem. 1995 270, 31091. 33 Zenk M H .; Lenz R. Eur. J. Biochem 1995 233 132.

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129 34. Zenk, M. H.; Lenz, R. Tetrahedron Lett. 1995, 36 2449. 35 Ginsburg, D .; Elad D J. Am Chem. Soc. 1954, 76 312. 36. Barton, D. H. R. ; Kirby, G W ; Steglich, W.; Thomas, G. M. Proc. Chem Soc. 1963, 203. 37. Grewe R. ; Freidrichsen W Chem. Ber 1967, 100 1550. 38. Grewe, R.; Fischer, H.; Freidrichsen, W. Chem. Ber 1967, JOO I. 39 Grewe R. ; Fischer H. Chem. Ber. 1963, 96, 1520 40 Morrison G. C. ; Waite R. P. ; Shave) J Tetrahedron Lett 1967, 4055. 41. Kametani T ; !hara, M.; Fukumoto, K.; Yagi H.J Chem. S o c. (C) 1969, 2030. 42. Schwartz, M A.; Marni I. S J Am Chem Soc. 1975 97, 1239 43. Schwartz M A. ; Pham P T K. J. Org. Chem. 1988, 53 2318 44. Lie T. S ; Maat L.; Beyerman, H. C. Reel. Trav Chim. Pa y s-Bas 1979 98 419. 45. Rice K. C. J. Org. Chem. 1980 45, 3135 46. Evans D A. ; Mitch C. H. Tetrahedron Lett. 1982 23, 285. 47. White J. D ; Caravatti G ; Kline, T. B .; Edstrom, E .; Rice K. C. ; Brossi A. Tetrahedron 1983 39 2393 48 Ludwig W. ; Schafer, H.J. Angew. Chem. Int. Ed. Engl. 1986 25, 1025 49. Toth J.E. ; Fuchs, P L. J Org. Chem. 1987, 52,473. 50. Barber R. B .; Rapoport, H.J. Med. Chem. 1976 19 1175. 51. Tius M.A. ; Kerr, M.A. J. Am. Chem. Soc 1992 114, 5959. 52. Parker K. A. ; Fokas D. J Am. Ch e m. Soc. 1992, 114, 9688 53. Hong, C Y ; Kado, N.; Overman L. E J. Am. Chem Soc.1993,115 11028 54. Hudlicky T. ; Boros, C.H. ; Boros, E E. S y nthesis 1992 174.

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130 55. Hudlicky, T. ; Butora, G. ; Gum A.G. ; Abboud, K. A. S y nth e sis 1998, 275 56. Hudlicky T .; Butora G. ; Gum A.G.; Fearnley, S. P.; Stabile, M. R. ; Gonzalez, D. S y nthesis 1998, 665 57 Novak B. ; Hudlicky T.; Reed, J W .; Mulzer J. ; Trauner D. Current Organi c Chemist ry 2000 4 343 58. Novak B Ph D. Dissertation University of Florida, 2000 59. Frey D .; Duan C. ; Hudlicky T. Organic Letters 1999, I, 2085. 60. Yamada O.; Oga awara K. Organic Letters 2000 2 2785 61. Yamada O .; Ogasawara K Tetrahedron Lett. 1998, 39, 7747 (done) 62 Kube!, B. ; Hofle G .; Steglich, W Angew Chem Int Ed Engl. 1975 89 58 63. Engel N.; Kube! B.; Steglich, W. Angew. Chem Int. Ed. En g l. 1977 16 394. 64. Bartlett P A ; Barstow J. F. J. Org. Chem 1982, 47 3933 65. Ireland R. E. ; Mueller, R.H J Am. Chem. Soc. 1972 98 2868 66. Kazmaier U. Ang ew. Ch e m Int. Ed. Engl. 1994 33 998 67. Kazmaier U Liebi g s Ann. R e el 1997 285. 68. Kazmaier, U. ; Maier S. J. Ch e m. Soc Chem Commun. 1995, 56 3572 69 Kazmaier U. ; Maier S. T e trahedron 1996, 52 941. 70 Kazmaier U Tetrahedron 1994, 50 12895. 71. Kazmaier, U .; Schneider, C Synthesis 1998, 1321. 72. Kazmaier U .; Schneider C. Tetrahedron Lett. 1998 39 817 73. Kazmaier U .; Schneider, C. S y nth e sis 1998, 1314 74. Kazmaier, U .; Schneider, C. Eur. J. Org. Chem 1998, 1155. 75 Kazmaier U J. Org. Chem. 1994, 59 6667

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131 76. Kazmaier U .; Maier S. Ch e m. Commun 1998, 2535 77. Kazmaier, U .; Maier S. ; Zumpe F. L. S y nlett 2000 1523 78 Gonzalez D .; Schapiro, V.; Seoane G. ; Hudlicky, T.; Abboud K. J. Or g Ch e m. 1997 62 1194 79. Gonzalez D Ph.D. Dissertat i on, University of Florida 1999 80. Percy J M. ; Prime M E J. Org. Ch e m 1998 63 8049 81. Miyaura N .; Yanagi T. ; Suzuki A. S y nth. Commun. 1981 / / 513 82 M i yaura N .; Suzuki A. Ch e m Re v. 1995 95 2457. 83. Ho s hino O .; Kanematsu A. ; Isoda T .; Ishizaki M .; Ozaki K J. Org. Chem. 1982 47 1807. 84. Ha ss ner A. ; Alexanian V T e trah e dron L e tt 1978 4475. 85. Hudlicky T. ; Gonzalez D.; Gibson D T. Aldrichimica Act a 1999 31 35. 86 Hudlicky T .; Luna H .; Barbieri G. ; Kwart L. D. J. Am. Ch em. So c 1988 / JO 4753 87. Gib s on D. T.; Koch J R .; Schuld C. L. ; Kallio R. E Bi oc h e mistry 1968 7 3795 88 L e y S V .; Sternfield F. ; T a ylor S T e trah e dron Lett 1987 28, 255. 89. Ireland R E .; Wipf P .; Armstrong J. D. J. Or g Ch e m 1991 56 650 90. Ireland R E .; Wipf P .; Xiang J. N. J. Org. Chem. 1991 56 3572. 91. Bu c kley T. F .; Rapoport H J. Org. Ch e m. 1983 4 8 4222 92. Natchu s, M. G .; L a ufersweiler M J .; Bookland R. G .; Pikul S. ; De B .; Janu sz, M. J.; Hsieh L. C. ; Hookfin E. B.; Patel V. S. ; Garver S. M .; Gu S .; Pokros s,

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132 M. ; Peng, S. X. ; Branch T. M.; Hudlicky, T.; Oppong, K. Bioorg. Med Chem Lett., 2001, I 1, 627. 93. Natchus, M. G.; Hudlicky, T.; Mandel, M.; Tiawo, Y. O.; Janusz, M. J.; Hsieh, L. C.; Gu, F .; Dunaway, C. M.; Dietsch, C. R; Dowty, M. E.; Laufersweiler, M. J .; Bookland, R. G .; Pikul, S.; Pikul, S.; De, B.; Cheng, M.; Almstead, M. G. J. Med. Chem. 1999, 42, 5426. 94. O'Brien, P. M.; Ortwine, D. F.; Pavlovski, A.G.; Picard, J. A.; Sliskovic, D.R.; Roth, B. D.; Dyer R. D ; Johnson, L. L; Man, C. F.; Hallak H.J Med Chem. 2000 43 156. 95. Tamura, Y. Watanabe, F.; Makatani, T.; Yasui, K. ; Fuji, M.; Komurasaki, T.; Tsuzuki, H.; Maekawa, R.; Yoshioka, T.; Kawada, K.; Sugita, K.; Ohtani, M. J. Med. Chem. 1998, 41,640. 96. Whittaker, M.; Floyd, C. D. Chem. Rev. 1999, 99, 2735. 97. Leff, R. L. Ann. N Y. Acad Sci. 1999, 878, 201. 98. Shlopov, B. V.; Lie, W.R.; Mainardi, C. L.; Cole, A. A.; Chubinskaya, S.; Hasty, K A. Arthritis, Rheum. 1997, 40, 2065. 99. Ahrens D. ; Koch A E.; Pope, R. M.; Steinpicarella, M.; Niedbala, M. J. Arthritis, Rheum 1996, 39 1576 100.Bramhall, S. R.; Int. J. Pancreat. 1997, 70, 163. 101. Matyszak, M. K.; Perry, V. H.; J. Immunol. 1996, 69, 141. 102. Friedel, C.; Craft, J.M. ; Compt. Rend 1877, 84, 1392. 103.Masuda, S.; Nakajima, T .; Suga, S. Bull Chem. Soc. Jpn. 1983 56, 1083.

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133 104. Johnson W S. ; Wertheman L.; Bartlett, W. R; Brockson, T. J.; Li T. T .; Faulkner, D. J.; Peterson, M R J Am. Chem. Soc. 1970, 92, 741. 105 Stork, G. ; Takahashi T.; Kawamoto, I.; Suzuki, T. J. Am. Chem. Soc. 1978, JOO, 8272. 106. Felix, D. ; Gschwend-Steen K.; Wick, A. E .; Eschenmoser, A. Helv. Chem. Acta 1969 52, 1030. 107. Corey E. J. ; Shibasaki, M.; Knolle, J Tetrahedron Lett 1977 I 625 108. Mitsunobu, 0. S y nthesis 1981, 1 109 Schmidt, U .; Utz R Angew. Chem. Int Ed. Engl. 1984, 23, 723. 110. Auerbach, J.; Weinreb S M J. Chem. Soc. Chem. Commun. 1974 298 111. Finkelstein, H. Ber. 1910 43, 1528. 112. Bui, V. P. ; Hansen, T.; Stentrom, Y.; Hudlicky, T Green Chemistry 2000, 263

PAGE 141

APPENDIX SELECTED SPECTRA The 1 H and 13 C or APT NMR spectra of selected compounds reported in Chapter ill and IV are graphically displayed in this appendix. The spectra along with the proposed structure are shown. 134

PAGE 142

.... 0 0 135 o c Q-b 0 0 :x: :x:

PAGE 143

reduced d iol OBSERVE HI fltE:OUEIICY 300 075 MHz 8PICTltAL WIDTH 4500 5 Hz COUIBITION TIME 1 998 sec RELAXATION DELAY 0 000 1tc PUt.81 WIDTH 5 0 uae c .I.MBUHT TEHPl:RATURE NO REPETITIONS 16 DOUBLE PRiCIBION A CQUISIT I ON DAU PROCEBI INCl LINE BROADEN IN C 1 0 Hz rT 8 I ZE 32 768 TO TAL A CQU ISIT lvN TIHE 1 ntln co td, M eO MeO OH OH JJ UL__l _J ~~-~---~-------~-----...... -~ ---.--~ -r--r~ ..,...---..,..---,-..,..---,-....--.-.-....---.-....--.-,-..,..---~..,..-~-----ll 10 9 8 7 6 5 3 2 0 ppm ,0 .....

PAGE 144

r0UU.TEO DOUBLE PRECIIION ACQUISITION DJ.a PROCEUINC LINE BRO>.OEN INC 3 5 Hz PT IIZE 32768 TOTAL ACQUISITION TIME 17 minute 220 200 180 140 120 MeO MeO OH OH 100 80 60 40 20 0 ppm r

PAGE 145

N ... b I l ( : ~~========--==-----=138

PAGE 146

200 160 160 14 0 120 100 MeO MeO 60 OH OTDS 60 40 20 0 r"l

PAGE 147

IHOVA-500 "gtalnl300" PULS[ S[OU[NC[ =~~~t~!,s,~;y~::, \oltdth 5000.0 HZ 14 re pet tt tons O&S[RV[ HI, 300 0732,44 MHZ OATA PROC[SSlHO lint broadening 1 0 Hz rT ,tu 32768 Total 0 Min, 0 '" 7 MeO MeO 6 5 0 O.Jl_NHBoc OTDS 4 3 2 1 0 '
PAGE 148

PulS( S(OUtNC( =~!~'t~!~'o~:g~::c \/tdth 11711 .7 Hz 1024 repetition, 0&$fRV( C13, 75 4542017 "HZ OfCOUPl( Hl, 300,0750122 "HZ Pc,.,or 30 d& c;onttnuou1ly on \/AlTZll DATA PROC[SSlNO lint broadtnln9 3 5 HZ n 1tzt S27U Total ttH 1 11tn, 4 U C M Ml!O 0 0 .Jl_ NHBoc OTDS '
PAGE 149

MeO MeO THso oc N "
PAGE 150

.. 0 ---1 2 9.787 1 2 4 1 26 -'-=~~II;.=:.:.:.:.:. =-=== ==--=--=-~~1 2 2 06 2 -112 0 1 4 -l ::r: q 77 42! lt~---------------..... ---------------~=-~c:~~ 77 \._7,_575 71 815 '4.752 -----U 5U _ 5, 131 -55 737 -_55_175 52.124 _____ ._731 ----31 113 ----25 7'1 -----11.tU 18.431 u.12, 143

PAGE 151

Solv1n\1 tdt13 Aabttnt uuri oppong ftl11 lCI (NOVA "nar5 PULSf $[0UfNC[ =~:~,1:. 0 ,~;1~:: -.,ldth 4500 5 HZ "f'" t Ion, O&S[RV Hlf 300 0 I JJ02 1 OA l A PROC!SS NO l Int broedtntno 1.0 llz rT 1111 3270 Tot11 ti~, 2 ~tnutcs ~ II l MeO~~I MeO 0 ? 0 H NHBoc __ ll_ __ __ _l_ _ A __ A ____ r-----,---.---r----r 6 s 4 3 2 1 PP """ """

PAGE 152

155 27' 15 3 44 2 l32 454 lU HO 123 636 !17.187 112 ,07 U.HI 145 """'"""'"""'""""tC '-77.000 7'.575 113

PAGE 153

Solvtn\ l CCICl:S Mbltn\ tPrturt m~: o~r~n9 INOVA~OO PULSf S[QUfNCf :~!~t~!;s,~;y~::, \11d\h 5000 0 HZ 14 ropo\ 1 \ton, OISfRVf Hlf 300 0733031 OATA PROCfSS NO l1nt brOadtn1ng l 0 HZ rr ,tu 32768 Tot al t I 0 ial u it s, c ""' M -9 8 7 Mc:Oi OtP I 6 o b MeO .Jl.,_,,N 0 0 OTDS 6 5 4 3 z 1 -.::t'

PAGE 154

~.,, ,.1 1\; '" "'~ ~ Aeb1tnt m~: INOVAtoo 9ea tn1,oo" PUlS[ S[OU[NC[ =~~~it!.'o~:s~::c Wtd\~ lf7fl 7 HZ 10Z4 repnt\tons ONfllV[ CU 75,<542005 ""' O[Cou,l[ HI 300 0750122 ""' '"'" ,o c:on\ t nuou, ly on WAL TZU aoduloUO OATA PllOC[SSINO lint bronlng 3 S Hl ,r IIU 327ft Tot l ,,., 1 atn, 4 ,,c zzo zoo 180 160 MeOi Otp I .& o A MeO )l_,N 0 0 OTDS 140 120 100 80 60 4D zo 0 r"'1'

PAGE 155

To ta l t l mt I Br O (X o ~NHBo< OTD S 12 11 10 9 8 7 6 5 4 3 2 1 -o 00 -.:

PAGE 156

~J:-COTDS 200 180 160 140 120 l O 0 80 60 40 20 0 '<1"

PAGE 157

Standard Hl Pulu Stquonct: 1Zpu l SOlvont : COC13 Allbltnt ttaptraturt O[NINI-300&& vln1300" PUlS[ S[OU[HC[ Pullf 32 7 dtgrttl ACq tlat 3 111 lt C Width 001 1 HZ oll,~:rt 1 ~l~";oo .o,1,,31 OATA PROC[SSINO ~::.b~:=r~!~Yo~ -~ ~=o ,r ,tu 15531 Total 1 t n sec 14 13 NHZ UC 12 11 10 I 0 t~: __ TOSO ,0 Nt1,.001; 9 8 7 6 5 4 3 2 1 -o 0 V)

PAGE 158

N 0 0 ... 0, 0 ... .., 0 ... .... C> -----34.153 ~ 77.421 .................... ~~,77 100 1, s,s -----28 Ut s==========:.....-=--====-:.-:_-:_-::_-::_z_,_._i~~-SSS 151 ~o Z 0 f f ,. "' C r :, .. .. ;: ,. C 0 'D N ... C ::

PAGE 159

1 i Cl --1 I l -l to V, 0 0 <=to .. u, z 0 o, :..1 5 w' 0 g 0 { N ;:;{ 0 { <,) N -1 .. ~.. :-~ ;{ ... .. { .. 152

PAGE 160

N 1 1 C, C, .... 0> C, .... "' .... C, 171.805 155 365 c .~!\~~5 1 25 617 ____ ..,,.~;;:::: 75.571 ~H Ht -----"<'c:_tf.ff7 -----L..~~,~~~1 st.Ill ----~c:~ : ::~ ------4.777 153 -I a, {/) 0 ~o 0 s:: 8

PAGE 161

; { N ;;! .{ 154

PAGE 162

N N C, N C, C, ... 1 ()0 C, ... 0, C, ... C, ... N C> ... c:, c:, ~ OI --0 -0 ,-. ;::=._ 155 172 &7I 1 56 0 80 1 23 1 2 7 722 1 2S 7 0 7 112 560 ,12.517 fl.SH U.7S2 S7 U4 st SIS se u, t 18' ~ 77 Sll _ 77 4,0 77 IU fS4 184 Sl.121 f:2 111 t7 217 25 UI _JU llt .. --CH.74S lt --2.tCI --~.OS !Z :, a. : ;;_ C 0 :, " . . .. :

PAGE 163

I j l ..... 1 J I i J~ 1 l I I I I I I I ... N ,156 -4co ... a ~-cf::~::~~~~ ~rt c:.>"" -Coll -o --- ,. ...... -a:-< .., .. ... <:r --O'JD~ ... "' 4::,::, -.o a-ww...... .. ._, 0 0 ,. NO '-"O,_. -o C or0 VIQ.G.C/11:2"..-...,r-,i (; aw-c,,,1-. w z: N ::, 0 0. 0 -a r ii -z :, ...... .... ,aw .. ::i.. a :,u ::, -c, o .., .. c 0 o "-' ::,o O .... ,c o n :> > -l 0 V) 0 0 0

PAGE 164

Clatt Se..tl lttt ,olvtnt c.de13 fl le IMP ACQUISI T!ON 1frq tn Cl3 at O 14' np 32711 ,w 11,s, o fb 1100 bl 11 tpwr SO PW 5. 0 pl 36 0 d 1 0 d2 0 007 d3 0 001 tOI 34' 2 nt IOH ct 10'6 tlOCk n gain no, uttd fLAOS 11 n In n dp y OISPLAY IP wp 11,s, o S4 0 we 200 hl ... S 30 t 12200 00 rf 1 6511 2 r f p 5f01 I th 20 "' I 000 ""' CdC Ph Of C 6 VT dfrq 300 0 6! Cln H 1 Clpwr 35 dlp 1023 do( 0 CJ yny w df !&00 PROCf SS I NO lb Wlf I 1 I proc fn wer r 'wtMp Wbl \olnt 3 50 ft no t U IICI wft wf t 200 180 160 140 cl o OMe NHBoc TOSO' 120 100 rV')

PAGE 165

= !" .. ... .... N 0 158 1 .. ... I : 0 1 % > n 0 E .. ,,

PAGE 166

l'! 0 .. i: ... IJ .. C ! ----11l 14 S -----lSS all 71 138 _____ ..._c_ 1 _~/-~~, '-._1, a:11 ____ u ... ---'~ 181 159

PAGE 167

... N ... .... .... C> <.D 00 U1 N ... I C> "O "O 160 ir~ -..--c,-. ,,:,__ .,. ,.., .. -w-< H-.< ... ~ .,. &iii o;,, .,. o -"'"' ..... 9 W,"D (") ... 0 -o NO-o C .. C -a.c.1t2.,.o = n ==~o~~a.~ ~:8 ii z -.,. ...CN:r.a.o w--,~ =, 0 : .... ::: =, : : = ~ n C .. .. ... n ,. "" ... :a n :,:

PAGE 168

Pul Squenc apt SOlvan\& CdCIJ Mll1..,\ ,_p.,.uu r e NercuryJOO rcury300 11 AASE SIOUINCI ap\ lot pule 1ao o 2nd pul 23 7 dagraeo acq 1 a1, W1d\h 11,,1 Hz Jl20 rape\1\1on oaslRVI ClJ, ,, ,1 7 4 72 5 "4Hl O(COUPL( Hl, 2H 77251'5 MHZ U di on dur1ng acqu1,ttton WAI.Tll6 -dula\aO OATA PIIOC("ING L 1 ne l>ro.dan1ng l o Hz H o1u 131072 Tot.a 1 t ta 0 t n 0 c t(1y-~ OTBS

PAGE 169

0, 171 1/1 w N ... .,, .,, 162 n ..

PAGE 170

"' "' 0 "' 0 0 .... 0, 0 .... a, 0 .... N 0 .... 0 0 OI C OI C 0 ----1,, ,02 ----lJS 527 ----11 507 2 11.,u 77.238 --====-1 ,,.a14 1s.s10 _____ ,,.21s _____ 4 2,4 2, .211 --------------+-i~--------f-U-a3t n.,,a __ :::::.:.:.:_~-1,-.2::-3n ------(c:::::: 163 ,, C .. .D C :, n ,, ..

PAGE 171

PULS( S(QU(HC( Pulse 57 4 degrees Ac 3 744 sec \/10th 4000 0 11Z 11 repetitions OUfltV[ 111, 2,, ,.,es1 1 "HZ DATA l'ltOCfSSINO a.u,, apod1zat1on 2 22e sec ,r ,1u 3%711 Total I In 0 sec 12 11 10 9 ;_,,,L~R-0-0U O I N-g u u OM, OTBS i 8 7 6 5 4 3 2 1 -o

PAGE 172

N N 0 N 0 0 .... 0, 0 .... a, 0 0 -u -u 170 881 ~~---~ ----, 110 a,s ----145 127 138 170 ____ 13s os, ,--131-'2, / ,-128 3'9 ----~21 ,1, 121 ~ Gt L 121 110 _____ __ 11, ,39 -----114-444 Q~ 0 0 -to z-:z: I O=Vl=O 0 3:: 0 \_, . ... -------. ,1.211 E 77-424 -====-~~-1,., 7' 572 -----55 371 -----51.10, -----c:: : :!! 165 ,, C .. .0 C :, n .. .., ..

PAGE 173

:, .. ... ~-l N ~ t .. ::: o ; : O> en (/1 N ... r I 166 ..... : :, : "' ... = :, n .. :, : C

PAGE 174

N C, C, ,Ot C> ,167 -l C, V, 0 q_8 :c-z M I Q=V>=QO Jill xx ....

PAGE 175

SOlvtn, . J Aablont toaporuuro VX-S v-r300 PULSf SfOUfNCf Pul11 s1 01g r 1,1 ACq 3. 74C II C lfldth 4000 0 HZ O~f~~rtf~!~";tt 9468561 M H Z DATA ~OCfSS?NO O.u11 apodtzatlon 2 22a ,, c rT IIZI 3270 Tota l t i 1 a ln, o ,,c ill1J 8 6 ~ 0 :, 5 9 11 ,, '.::: 0 I,-:::; HO' I OMc 5 4 3 z 1 00

PAGE 176

H .... 1 69

PAGE 177

ID 1/1 w N ... ,, ,, 170

PAGE 178

N C> C> 00 C> .,, C> .,., C> N C> C> "O "O 172 464 ----I SS 110 -----1S2 .23 5 ----144 934 _____ _..r-139 832 ________ 137 823 _____ _,.-135 158 132 uo 127 660 -----1 2 4 2 48 122.038 ----111 768 79 .11 0 H 723 U 372 55 1'3 54.UI 51.H7 38.479 34 32' ;:::/' "' u ,52 '-l7.H7 15.221 ,,-======'--====-,--~-% .,u ---z.,n 171 128 1'7 t77 t:'' 7' 573 28 283 27 IU 11.Ul --l 0 en C> a, ::, 0 ,. C .. "' .. C ::, n .. .. ,, C \ .. C .. C n .. g ::,

PAGE 179

STANDARD HI PARAM[T[RS Pulse Stqutnct: s2pul Solvent : CDC13 AIID1tnt VXR-300S "vn300 PULS[ S[OU[NC[ Pulst $7 4 Otgrttl Acq tlu 3 744 uc lo/10th 4000.0 HZ 11 rtpttlt1ons ~!R~~OC[~ifN~tl 1468S 73 MHZ o.u,, apod1Zat l on 2 228 ,ec H s1u 32768 Total ti"' 1 11tn, o ,,c 12 11 10 MeO BnO 9 8 OMe NHBoc 7 6 s 4 3 2 1 -o ppm N r-

PAGE 180

Puloe Sequence apt SOivent, cdclJ Mb1en\ t -prai u r Mercury-JOO 'llr c ur y3 0D PVI.I( S(QU(NC(1 apt lot puloe 110 0 2"411 ,ul 2J 7 degree, :~:ii,'i;:,! : :1~,c o:!:~rri;:ii;~~J741141 D(~( Hl, 211 7514700 -r 4J Ill on -Ing acqulottlon WAI.TZll -uletell DATA .,_OCHSINO line broadening 1 0 H z fT ,tze 131072 Tot.al O O ,e c 220 200 MHZ MHZ MeO BnO 1 80 160 140 NHBoc 20 100 80 60 <'"I r

PAGE 181

12 STANDARD HI PARAMfTfRS Pulu Suu,nce : s2pu1 s01v,ni, coc13 Aabltnt ttaptr1tur1 VXRJ00S vr)00 PUlSf SfOUfNCf Pulse 57 4 d1ijr11, Acq, ttat 3 744 SIC loltdth 4000 0 HZ 14 reptt It I on, g:~!R~~OCf~ifN~IS 1460566 Hz Oeu,, 1podtz1tton 2 220 ,, c IT stu 32718 Total t 1 int 4 min O ,ec 11 10 9 8 7 MeO BnO BzO 6 5 4 3 z 1' -o PP 'SI' r-

PAGE 182

N N 0 N 0 0 .... O> 0 .... en 0 N 0 0 ,, ,, 175 n ....

PAGE 183

.... (71 .... N .... 0 0, N I 0 176 ,, ..

PAGE 184

H .... 177

PAGE 185

"' N ... "D "D 178

PAGE 186

T"'l'""M'TT"! .....,......... 220 l. I] "I"" 200 180 BnO 0 I 111 I ul 11 I 11 160 ,_,., I I j rn 140 ,..,.,,., 120 [ NHBoc 100 rn l .....,......... 80 ,..,..., I rT"'T"f" 60 m,n .....,......... 40 j ,..,..., lL l ,....,..,,,..,. 20 n-; ii I ii I 0 l"'1"T'T'T"T ppm r

PAGE 187

7 6 MeO MeO HBoc 5 4 :ic5 3 z 1 PPII

PAGE 188

Stndrd Cl3 parameters Pulu Stqu,nce: s2pu\ SOlvont : COC\3 Aabltnt OfNINl-30011 "goln1300 PULSf SfOUfNCf Pu1,, 2s o d,gr,es Acq t I... 0 I H sec Width 173S4 0 HZ 2320 ropotltlon, O&S[RV[ Cl3, 75 4511635 MHZ O[COUPLf Hl, 300 0117366 MHz Powtr 35 d& on during acquisition off during dlr WALTZ-11 odul&ttd DATA PROC[SSINO Lint broadening 3 5 Hz n ,1u 327U Total tlOII O Olin 0 sec 200 180 16 0 140 MeO MeO oc 00 120 100 80 60 40 20 PPII

PAGE 189

12 11 10 9 8 7 M eO H O THSO' 6 NHBoc s 4 3 2 1 -o PP ('I 00

PAGE 190

MeO HO ,.,, ........ , 4#1 ,, ...... p .. 200 180 16 0 140 120 NHBoc 100 80 60 40 20 o ppm (") 00

PAGE 191

ose Pulte Sequence: apt Solvent I cdc 13 T-p 2S 0 C / 298 1 K MercuryJOO ''aercuryJOO PVLS[ S[QU[NC[ I apt lot pul 180 0 2no pul 35 S Acq t1aa 1 815 Width 19S59 S Hz 3120 repat1t1ont OIIS[RV[ Ci3 1 75 3550036 MHZ O[COUPL[ HI, 218 1259150 MHz Power 43 di on during acqu1,1t1on WALTZl5 -oulated DATA PIIOC[SSINC Line broadan1ng l O Hz fT 131012 Totl 11 hr, Sl tn l te 220 200 1 80 160 Br 0 Ct)___,NM,&c OTDS 140 120 100 80 60 ao 2 0 ppll """ 00

PAGE 192

Br O (XO)(_,NMdlo< OTDS 8 6 5 3 z 1 ppm V") X)

PAGE 193

PULSt SlUUt~1.,t Pullt 32 7 dt9rttl AC~ 3 tlt ltt \,lldth 4101.1 HZ U reptt It ton, ~!R~~OCf~iN~00 0673623 ~Int broadening 0 2 Hz 0.UII &podlZatlon 1 7&0 n lllt '5531 Totel O In 0 Ht ~HZ Ht 14 13 12 TOSO' 11 10 9 OMe NHBoc 8 7 6 5 4 3 2 1 -o Xl

PAGE 194

~ult ~qunc: apt Solvnt cdc13 ,~::~~-~::~~ra\ure Nerc:uryD0 wercuryJOO 11 PULS( 5(QU(NC( r apt lat pule 110 0 2nd pult 23 7 acq 1 11, Width lt51t 5 Hz 115 rptltlont OU(RV( CU, 7S J74l949 MH> O(COUPl( HI, 21t 7514700 MH> -r 4J di on during acqu1,1t1on WALT2 OaTa PROC(UXNC L1n broadentng 1 0 Hz fT ,,,. 131072 Tot.1 0 O .. J O I I 220 200 TOSO, ., J L. -I I I 180 160 140 OMe NJ-IBoc ,J, .... I I I I 120 100 80 I . .. I I 60 41 ., I 0 r00

PAGE 195

BIOGRAPHICAL SKETCH Kofi Oppong was born in Islington, England on July 10 1969. He attended elementary school at St. Martin de Porres School and high school at Accra Academy and Okuapeman Secondary School in Accra Ghana. He obtained admission to the University of Indianapolis in 1989 to study Organic Chemistry under both an athletic and a Presidential scholarship. After completing requirements for an Associates Degree in Chemistry, he obtained employment at DowElanco Pharmaceuticals now Dow AgroSciences working as a chemi s try technician. At DowElanco he worked in the area of fluorine chemistry under Professor Melvin Druelinger of the University of South Colorado on sabbatical at DowElanco during that time. Upon completion of his Bachelor of Science degree in chemistry he decided to pursue graduate studies in Organic Chemistry specifically in the natural product synthesis area under the direction of Professor Tomas Hudlicky at the University of Florida. His Ph.D research has focused on chemoenzymatic approaches to the s ynthesis of molecules of different complexity His major area of focus has been in the synthesis of morphinan intermediates utilizing a combination of enzymatic and b as ic s ynthetic organic chemistry methods. After graduate school he plans to pursue a career in industry as a medicinal chemist. His life goal is to be directly involved in the synthesis of one major drug. 1 88

PAGE 196

I certify that I have read this study and that in my opm1on it conforms to acceptable standards of scholarly presentation and is fully acceptable, in scope and quality, as a dissertation for the degree of Doctor of Philosophy. Tomas Hudlicky, Chairman Professor of Chemistry I certify that I have read this study and that in my opm1on it conforms to acceptable standards of scholarly presentation and is fully acceptable, in scope and quality, as a dissertation for the degree of Doctor of Philosophy. Merle Battiste Professor of Chemistry I certify that I have read this study and that in my opinion it conforms to acceptable standards of scholarly presentation and is fully acceptable, in scope and quality, as a dissertation for the degree of Doctor of Philosophy. WlL_~/ William Dolbier Professor of Chemistry I certify that I have read this study and that in my opinion it conforms to acceptable standards of scholarly presentation and is fully acceptable, in scope and quality, as a dissertation for the degree of Doctor of Philosophy. stry

PAGE 197

I certify that I have read this study and that in my opinion it conforms to acceptable standards of scholarly presentation and is fully acceptable, in scope and quality, as a dissertation for the degree of Doctor of Philosophy. I certify that I have read this study and that in my opinion it conforms to acceptable standards of scholarly presentation and is fully acceptable, in scope and quality, as a dissertation for the degree of Doctor of Phil phy. ennis Wright Professor of Chemistry This dissertation was submitted to the Graduate Faculty of the Department of Chemistry in the College of Liberal Arts and Sciences and to the Graduate School and was accepted as partial fulfillment of the requirements for the degree of Doctor of Philosophy. August, 2001 Dean, Graduate School


CHAPTER 2
HISTORICAL BACKGROUND
Introduction
According to the available records, the relationship between opium and human
beings started in ancient Middle Eastern civilizations about 3500 years ago.6 Since then
the potent bioactivity of morphine and its derivatives was an important issue that has
crossed the frontiers of medicine and become a socio-political factor. In the sixteenth
century, Parcellus popularized the use of opium as an analgesic when he introduced
various preparations and named it laudanum which is derived from the latin word
meaning to praise.
Although opium had been used for centuries, morphine was not isolated as a
crystalline material until 1803 as reported by Derosne.89 Three years later in 1806,
Seguin presented a description of the isolation of morphine to the Institute of France,10
and later in the same year, Serturner was finally credited with the first isolation of
crystalline morphine.11 A century later in 1925, Sir Robert Robinson postulated the
correct structure of morphine including relative stereochemistry.12 This was later
confirmed by X-ray crystallographic analysis in combination with other analytical
techniques.13,14 After its isolation morphine 1 was introduced into medical practice and
used extensively to treat ailments such as diarrhea, asthma, diabetes, ulcers and pain
relief. Bayer at the end of the ninteenth century was marketing diacetyl morphine
3


119
(1 S.4R)-2-cvclohexenvl-2S-N-1 -phenvI-(4-methoxv-4-phenvlValanvl sulfonamide
(303).
A solution of the alanine ester 300 (0.800 mmol, 0.450 g) in CH2CI2 (20 mL) was
cooled to 0C. Freshly distilled TFA (1.600 mmol, 1.50 mL) dissolved in CH2CI2 (10
mL) was then added dropwise over 30 min. The mixture was stirred for 3h and monitored
by TLC. After consumption of starting material the reaction was quenched with NaHCC>3
(saturated). The phases were separated and the organic layer washed with brine. The
combined organic layers were dried over Na2SC>4 and concentrated to give white flaky
crystals of the alcohol 303 (0.322 g, 90 %). Rf = 0.4, (ethyl acetate:hexanes 1:1); [(X]d30
-5.1 (c 1.0, MeOH); 'H NMR (CDC13) 8: 7.86 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 8.8 Hz,
2H), 7.52 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 5.41 (s, 1H), 5.20 (bs, 1H), 3.84
(s, 3H), 3.61 (s, 3H), 2.05 (bm, 2H), 1.82 1.42 (m, 8H), 1.41 (s, 3H), 1.39 1.20 (m,
1H); ,3C NMR (CDCI3) 8: 173.73, 160.36, 156.65, 145.32, 140.09, 131.75, 128.63,
127.86, 127.15, 114.74, 74.22, 65.37, 55.63, 52.84, 45.83, 29.61, 29.46, 21.31, 21.05,
17.59; IR (NaCl/ cm'1): 3434, 3377, 2953, 2929, 2856, 1752, 1677, 1203, 1136; HRMS
Caled, for C^H.sBrNOiSi (m+H H20): 430.1682; Found: 430.1688.


121
2-(4-dimethvlthexylsilvloxv-2-(2.3-dimethoxvphenvl)-(lS.4R)-2-cvclohexenyl-2S-N-
rm-butoxycarbonylrnethylglvcinate (316).
To a two neck round bottom flask fitted with a condenser under an argon
atmosphere was added Pd(PPh3)4 (0.01 mmol, 0.014 g). This was followed by addition of
dry benzene (15 mL). A solution of the vinyl bromide 289b (0.400 mmol, 0.200 g)
dissolved in benzene (5 mL) was then added to the reaction flask. This was followed by
the addition of Na2C03 (2.0 M, 1.20 mL), to the mixture. Boronic acid 273 (0.600 mmol,
0.110 g) dissolved in benzene (5 mL) was then added to the reaction mixture, which was
allowed to reflux for 6h. The reaction was quenched with water and the product extracted
with ethyl acetate (3 X 20 mL). The organic layers were combined, washed with brine
and dried over anhydrous MgS04. After filtration the solvent was removed, the crude
product introduced onto a silica gel column, and eluted with ethyl acetate: hexanes (1/3)
to obtain 316 (0.10 g, 70%) as a light yellow oil; Rf = 0.40 (ethyl acetate: hexanes, 1:4);
[a]D30 +26.9 (c 1.0, CDC13); H NMR (CDC13) 8: 6.92 (t, J = 7.9 Hz, 1H), 6.8l(d, J = 7.9
Hz, 1H), 6.65 (d, J = 7.8 Hz, 1H), 5.95 (d, J = 2.4 Hz, 1H), 5.23 (m, 1H), 4.33 (bs,
1H),4.08 (m, 1H), 3.83 (s, 3H), 3.79 (s, 3H), 3.65 (s, 3H), 3.45 (bs, 1H), 1.94-1.63 (m,
4H), 1.56 (bs, 1H), 1.38 (s, 9H), 0.86 (m, 6H), 0.08 (m, 6H); l3C NMR (CDC13) 8:173.21,
155.65, 152.57, 146.46, 142.15, 134.83, 131.37, 124.49, 122.49, 112.31, 79.86, 63.93,
61.07, 56.17, 55.35, 52.59, 39.56, 30.45, 28.79, 19.16, -2.45, -2.71; IR (CDC13/ cm1):
3348, 2975, 2937, 1751, 1714, 1689, 1520, 1474, 1259, 1225, 1159, 1062, ; HRMS
Caled.for C30H49NO7Si (m+): 563. 0491 ; Found: 563. 0451.


118
6-bromo-2-dimethyltert-butvlsilvloxv-(lS,2R)-5-cvclohexen-l-vl-N-l-phenvl-(4-
methoxy-4-phenvl)-alanvl sulfonamide (299).
To a solution of amine 302 (0.530 mol, 0.200 g), in THF (10 mL) was added Et3N
(0.800 mmol, 0.080 g). To this mixture was added the sulfonyl choride (0.080 mmol,
0.218 g) and the reaction mixture stirred for 48h. The reaction mixture filtered through a
bed of silica gel followed by removal of the solvent and chromatography (silica gel, ethyl
acetate:hexanes, 1:8) of the residue, afforded the pure sulfonamide 299 as a white
crystalline solid (0.132 g, 40%); Rf = 0.4 (ethyl acetate:hexanes, 1:4); mp: 114 116;
[a]D28 44.0 (c 1.0, CHCI3): 'H NMR (CDCI3) 7.87 (m, 2H), 7.62 (m, 2H), 7.50 (m,
2H), 6.97 (m, 2H), 6.20 (m, 1H), 5.41 (m, 2H), 4.10 (m, 1H) 3.85 (s, 3H), 2.23 2.16 (m,
1H), 2.10-1.90 (m, 1H), 1.68- 1.61 (m, 2H), 1.56 (s, 3H), 1.51 1.49 (m, 4H), 1.20 (m,
1H), 0.77 (m, 9H), 0.82 (s, 3H), -0.02 (m, 6H); 13C NMR (CDC13) 8: 170.88, 170.87,
160.01, 145.13, 138.17, 135.06, 131.63, 128.37, 127.69, 127.53, 116.64, 114.44, 74.49,
69.27, 55.37, 51.71, 26.29, 25.76, 25.63, 20.35, 18.06, -5.03, -5.14; IR (CHC13/ cm1):
3281, 2951, 2949, 2854, 1743, 1610, 1595, 1519, 1488, 1250; HRMS Caled, for
C28H39NsiBr06 (M+): 624.1451; Found: 625.1450.


4
(Diamorphine).14 It was nicknamed heroin because it was considered a heroic drug.
Heroin 3 has the same physiological effects as morphine (because of rapid hydrolysis to
morphine, most of its actions are due to morphine itself) except that it acts faster and is
more potent. However there are appropriate differences. Heroin is lipid soluble and
rapidly enters the brain. Morphine is not as lipophilic and hence its passage to
Codeine Heroin
Scheme 2
the brain occurs at a much slower rate. Codeine 2 is approximately one-sixth as effective
as morphine as an analgesic. It is best administered orally and acts as a good cough
suppressant.
In 1952, Gates achieved the first total synthesis of morphine1516 and confirmed
the structure of morphine as proposed by Robinson. Since Gates historic synthesis, about
20 formal syntheses of morphine have been reported. In spite of these reports and 150
years of effort since its discovery, a truly practical synthesis, which would compete
economically with the isolation of morphine directly from the opium poppy, Papever
somniferum, has not yet been achieved.
Astonishingly, of all the reported formal synthesis of (-)-morphine to date only
three have used some sort of sigmatropic rearrangement. Only the syntheses of Rapoport,
1718 Parsons,19,20 and Mulzer21'25 have relied on these types of reactions. Interestingly, the
three syntheses made use of the rearrangement for the same purpose: to install the


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TABLE OF CONTENTS
page
ACKNOWLEDGMENT iii
ABSTRACT vii
CHAPTERS
1. INTRODUCTION 1
2. HISTORICAL BACKGROUND 3
Introduction 3
Morphine Biosynthesis 5
Total and Formal Syntheses of Morphine 8
Morphine Syntheses via Sigmatropic Rearrangements 21
Recent Related Developments 29
Chelated Enolate Claisen Rearrangement 41
3. RESULTS AND DISCUSSION 55
Introduction 55
First Generation Synthesis: Control of C9 and C14 Stereocenters 61
Claisen I-First Attempt of Kazmaier Claisen on Morphine Precursor 64
Friedel Craft-Attempt at C10-C11 Closure 69
Claisen II-Ireland Claisen on Phthaloyl Ester 71
Claisen HI-Kazmaier Claisen of Glycinate of Cyclohexadiene Diol 73
Synthesis of Matrix Metalloproteinase Inhibitors (MMPs)
Second Generation Synthesis: Overmans Intermediate via Claisen
Rearrangement 81
Alternative Methods to Setting the C13 Quaternary Center 89
4. CONCLUSION 97
5. EXPERIMENTAL SECTION 102
General Procedure 102
Experimental Procedures 103
LIST OF REFERENCES 127
APPENDIX: SELECTED SPECTRA 134
BIOGRAPHICAL SKETCH 186
VI


CHAPTER 1
INTRODUCTION
Morphine (1), one of the worlds oldest drugs, is consumed to the tune of one
hundred metric tons in the United States alone annually.1'4 Its main legal uses is for pain
relief in cases of severe trauma (caused by the agonist binding to the |i- receptors in the
central nervous system). These receptors are responsible for analgesia, euphoria,
addiction and respiratory depression. In recent years morphine has been used in high
doses as an anaesthetic in open-heart surgery due to its ability to slow down respiratory
activity without affecting cardiac function.
Morphine is the major component (20%) of the opium of the poppy, Paperver
somniferum,4 and its documented use dates back to 1500 BC5 and its impact on society
has been quite remarkable. On average 20 people per day die of drug abuse across
Europe. In 1999 alone the opium harvest in Afghanistan, a country illegally harvesting
morphine, was 4581 metric tons. Legally opium is harvested in India (the only legal
producer) on a multi-ton scale. The alkaloid constituent of the opium poppy is about
1




CHEMOENZYMATIC APPROACH TO THE SYNTHESIS OF THE
MORPHINAN SKELETON VIA A CLAISEN REARRANGEMENT APPROACH
By
KOFI A. OPPONG
A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL
OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT
OF THE REQUIREMENTS FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY
UNIVERSITY OF FLORIDA
2001

Dedicated to
Nana Akua and Akwasi

ACKNOWLEDGMENTS
I would like to take this opportunity to express gratitude to a number of people
who had a positive influence on my life in the last 5 years. First I would like to thank my
research advisor Dr. Tomas Hudlicky for his support and guidance over the years. I have
come to appreciate the impact and the importance of the training I received from Dr.
Hudlicky. Being associated with his group has been one of the landmark experiences in
my life, something I will not forget.
I also wish to show my appreciation to members of my committee (Dr. Merle
Battiste, Dr. William Dolbier, Dr. Dennis Wright, Dr. Vanecia Young and Dr. Howard
Johnson) for the help they rendered to me during my time here. I give special thanks to
Dr. Battiste and Dr. Dolbier, who as committee members had a direct impact on my
development as a student. I also want to acknowledge Dr. Dolbier because he played a
huge role in my obtaining admission to this graduate school. I extend thanks to Dr. James
Deyrup, Donna Balkom and Lori Clark for their assistance with all the administrative
aspects of my stay at the University of Florida. Since joining the faculty of the University
of Florida, Dr. Dennis Wright has been a tremendous asset to me personally and to all the
students in the Hudlicky group in general. I would like to acknowledge Dr. Dennis
Wright for all his chemistry suggestions, discussions and contributions, all of which
added to my growth as a chemist.
I extend my gratitude to all the members of the Hudlicky research group who in
one way or another helped to nurture me over the years. I would like to

recognize Dr. Yan Fengyan and Dr. Ba Nguyen with whom I collaborated on the fluoro-
inositol project; and Dr. Larry Brammer, who was instrumental in my training during my
first year in graduate school. I thank Dr. David Gonzalez and Dr. Bennett Novak for their
advice and chemistry discussions. Dr David Gonzalez was instrumental in my
advancement in laboratory techniques and for that I am indebted. The fermentation team
also deserves acknowledgment: Dr. Bennett Novak, Dr. Mary Ann Endoma, Vu Bui and
Natalia Korkina. I also acknowledge Dr. Caimin Duan who has been a model of hard
work for me. I am indebted to Nora Restrepo, Stephan Schilling, Jennifer Lombardi and
Jerremy Willis for their friendship and advice in chemistry and other matters.
I am grateful to those people with whom I worked together on the morphine
project; I thank Dr. David Gonzalez, Charles Stanton and Elizabeth Hobbs for their
contribution to the morphine project. Recently it has been my pleasure to work with Dr.
Lucillia Santos and Lukaz Koroniak who contributed immensely to the progress of the
morphine project. We owe our progress to Vu Bui who kept a constant stream of diol
flowing our way.
I am also thankful for all the help received from the analytical services
department, especially Dr. Ion Ghiriviga, Dr. Khalil Abboud and Lidia Madveeva.
I would also like to thank Dupont-NOBCChE and the Shell Fellowships for their
support of my education. I give special thanks to Dr. Hollinsed for all his assistance.
I want to acknowledge Dr. Josie Reed for the many chemistry/administrative
problems that she solved for me and for the entire Hudlicky group. During my time here
she has served as an excellent mother figure for me. All her efforts are appreciated and
did not go unnoticed.
IV

I would like to thank some of the friends I have made in Gainesville: Tahra
Edwards, Gabriela Feldberg, Jacinth McKenzie and Michael Mosi, Jerremey Willis, and
Nadia Kunan who made my stay here a great experience and gave me reason to persevere
and to finish.

TABLE OF CONTENTS
page
ACKNOWLEDGMENT iii
ABSTRACT vii
CHAPTERS
1. INTRODUCTION 1
2. HISTORICAL BACKGROUND 3
Introduction 3
Morphine Biosynthesis 5
Total and Formal Syntheses of Morphine 8
Morphine Syntheses via Sigmatropic Rearrangements 21
Recent Related Developments 29
Chelated Enolate Claisen Rearrangement 41
3. RESULTS AND DISCUSSION 55
Introduction 55
First Generation Synthesis: Control of C9 and C14 Stereocenters 61
Claisen I-First Attempt of Kazmaier Claisen on Morphine Precursor 64
Friedel Craft-Attempt at C10-C11 Closure 69
Claisen II-Ireland Claisen on Phthaloyl Ester 71
Claisen HI-Kazmaier Claisen of Glycinate of Cyclohexadiene Diol 73
Synthesis of Matrix Metalloproteinase Inhibitors (MMPs)
Second Generation Synthesis: Overmans Intermediate via Claisen
Rearrangement 81
Alternative Methods to Setting the C13 Quaternary Center 89
4. CONCLUSION 97
5. EXPERIMENTAL SECTION 102
General Procedure 102
Experimental Procedures 103
LIST OF REFERENCES 127
APPENDIX: SELECTED SPECTRA 134
BIOGRAPHICAL SKETCH 186
VI

ABSTRACT
Abstract of Dissertation Presented to the Graduate School
of the University of Florida in Partial fulfillment of the
Requirements for the Degree of Doctor of Philosophy
CHEMOENZYMATIC APPROACH TO THE SYNTHESIS OF THE
MORPHINAN SKELETON VIA A CLAISEN REARRANGEMENT APPROACH
By
Kofi Oppong
August 2001
Chairman: Dr. Tomas Hudlicky
Major Department: Chemistry
An approach to the morphinan skeleton with complete control of the C9 and C14
stereocenters is described. The first generation of the synthesis of the A and C rings of
morphine are discussed. Also described are attempts at establishing the Cl3 quaternary
center with emphasis on construction of the D-ring. The use of precursors from the
enzymatic biooxidation of aromatic compounds in the construction of the morphinan
skeleton through various chemical modifications is reported.
vii

CHAPTER 1
INTRODUCTION
Morphine (1), one of the worlds oldest drugs, is consumed to the tune of one
hundred metric tons in the United States alone annually.1'4 Its main legal uses is for pain
relief in cases of severe trauma (caused by the agonist binding to the |i- receptors in the
central nervous system). These receptors are responsible for analgesia, euphoria,
addiction and respiratory depression. In recent years morphine has been used in high
doses as an anaesthetic in open-heart surgery due to its ability to slow down respiratory
activity without affecting cardiac function.
Morphine is the major component (20%) of the opium of the poppy, Paperver
somniferum,4 and its documented use dates back to 1500 BC5 and its impact on society
has been quite remarkable. On average 20 people per day die of drug abuse across
Europe. In 1999 alone the opium harvest in Afghanistan, a country illegally harvesting
morphine, was 4581 metric tons. Legally opium is harvested in India (the only legal
producer) on a multi-ton scale. The alkaloid constituent of the opium poppy is about
1

2
25%; of this, two of the important alkaloids, morphine (1) and codeine (2), constitute
approximately 17%.6
Although morphine is quite abundant from the isolation of the natural resource, it
still remains a viable synthetic target to various research groups around the world. The
focus is not only to find an efficient synthesis of morphine but more importantly to arrive
at a more practical synthesis of the morphinan skeleton, which would allow for a more
competent route to some the important derivatives of morphine.
Of the twenty-one formal synthesis of morphine only three syntheses have used
sigmatropic rearrangements as key steps. Interestingly, the rearrangements were all used
to install the quaternary center at Cl3. None of the above approaches used the
rearrangement to transfer stereochemistry inherent in the molecule to another site with
the result of correctly setting two important stereocenters in one transformation.
This thesis describes a Claisen rearrangement approach to the synthesis of the
morphinan skeleton. Control of the stereo centers C9 and C14 are discussed and recent
advances in the synthesis of the morphinan skeleton are also reported.

CHAPTER 2
HISTORICAL BACKGROUND
Introduction
According to the available records, the relationship between opium and human
beings started in ancient Middle Eastern civilizations about 3500 years ago.6 Since then
the potent bioactivity of morphine and its derivatives was an important issue that has
crossed the frontiers of medicine and become a socio-political factor. In the sixteenth
century, Parcellus popularized the use of opium as an analgesic when he introduced
various preparations and named it laudanum which is derived from the latin word
meaning to praise.
Although opium had been used for centuries, morphine was not isolated as a
crystalline material until 1803 as reported by Derosne.89 Three years later in 1806,
Seguin presented a description of the isolation of morphine to the Institute of France,10
and later in the same year, Serturner was finally credited with the first isolation of
crystalline morphine.11 A century later in 1925, Sir Robert Robinson postulated the
correct structure of morphine including relative stereochemistry.12 This was later
confirmed by X-ray crystallographic analysis in combination with other analytical
techniques.13,14 After its isolation morphine 1 was introduced into medical practice and
used extensively to treat ailments such as diarrhea, asthma, diabetes, ulcers and pain
relief. Bayer at the end of the ninteenth century was marketing diacetyl morphine
3

4
(Diamorphine).14 It was nicknamed heroin because it was considered a heroic drug.
Heroin 3 has the same physiological effects as morphine (because of rapid hydrolysis to
morphine, most of its actions are due to morphine itself) except that it acts faster and is
more potent. However there are appropriate differences. Heroin is lipid soluble and
rapidly enters the brain. Morphine is not as lipophilic and hence its passage to
Codeine Heroin
Scheme 2
the brain occurs at a much slower rate. Codeine 2 is approximately one-sixth as effective
as morphine as an analgesic. It is best administered orally and acts as a good cough
suppressant.
In 1952, Gates achieved the first total synthesis of morphine1516 and confirmed
the structure of morphine as proposed by Robinson. Since Gates historic synthesis, about
20 formal syntheses of morphine have been reported. In spite of these reports and 150
years of effort since its discovery, a truly practical synthesis, which would compete
economically with the isolation of morphine directly from the opium poppy, Papever
somniferum, has not yet been achieved.
Astonishingly, of all the reported formal synthesis of (-)-morphine to date only
three have used some sort of sigmatropic rearrangement. Only the syntheses of Rapoport,
1718 Parsons,19,20 and Mulzer21'25 have relied on these types of reactions. Interestingly, the
three syntheses made use of the rearrangement for the same purpose: to install the

5
quaternary center at C13 (morphine numbering, while transferring the stereochemistry
already present in the starting material to that position.
Morphine Biosynthesis
It is interesting to note that Robert Robinson, who proposed that morphine
consisted of a twisted benzylisoquinoline skeleton, made one of the most important
Scheme 3
Enzymes: i)L-tyrosine decarboxylase; ii) phenolase; iii) L-tyrosine transaminase; iv) p-
hydroxyphenylpyruvate decarboxylate; v) (S)-norcoclaurine synthase; vi) norcoclaurine-
6-0-methyltransferase; vii) tetrahydrobenzylisoquinoline-A^-methyltransferase; viii)
phenolase; ix) 3-hydroxy-N-methyl (S)-coclaurine-4-(9-methyltransferase.

6
19 9 f\
observations that eventually led to the elucidation of the structure of morphine.
Studies conducted on the biosynthesis of morphine indicate that the morphinan alkaloids
are formed by a series of benzylisoquinoline intermediates (Scheme 3) which eventually
forms (R)-reticuline 14 (Scheme 4).27 28
Scheme 4
The benzylisoquinoline skeleton is derived from two molecules of L-tyrosine (4),
which is converted into a molecule each of dopamine 6 and 4-hydroxy
phenylacetaldehyde 8 through the intermediacy of tyramine 5 and 4-hydroxyphenyacetic
acid 7 respectively (Scheme 3). Condensation of these two derivatives of L-tyrosine is
catalyzed in a stereospecific manner by (S)-norcoclaurine synthase, which results in the

7
formation of (S)-norcoclaurine 9, which serves as the skeletal foundation of most of the
benzylisoquinoline alkaloids. The next three steps can be summarized as two enzyme-
catalyzed methylations and an aromatic hydroxylation to afford (S)-reticuline 13, that
possesses the opposite configuration to the compound found in the biosynthesis of
morphine (what would be the C9 center of morphine has the opposite stereochemistry).
Inversion to the correct intermediate is effected in two steps through the intermediate
imine dehydroreticuline 14 (Scheme 4) by a highly stereospecific and NADPH/NADPH+
dependent reductase to afford (/?)-reticuline 15.29,30 It is likely that the mechanism
involves the formation of two phenolate radicals and their subsequent coupling. The next
step in the biosynthesis is the conversion of (i?)-reticuline into salutaridine 16 by a
membrane-bound cyctochrome P-450 enzyme whose catalytic action is strictly dependent
on NADPH and molecular oxygen. After the formation of salutaridine 16, the ketone
moiety is reduced by an NADPH-dependent oxidoreductase to afford salutaridinol 17,31
which then undergoes enzyme-catalyzed acetyl CoA dependent acetylation to yield the
acetate 18.32 The next intermediate formed is thebaine 19, which results from ring closure
at slightly basic pH. Failure to find a specific enzyme for this step has led to the
conclusion that this step is spontaneous. Neopinone 20 is formed by the demethylation of
thebaine to form the ketone, which is in chemical equilibrium with codeinone 21. The
final steps in the morphine biosynthesis are the conversion of codeinone to codeine (2)
and a final demethylation of codeine to afford morphine (1). An alternate pathway to
morphine has also been proposed and it involves arriving at the target first by
demethylation of thebaine to obtain the intermediate alcohol 22, then conversion to the
enone 23 whose reduction by codeinone reductase affords morphine 1 (Scheme 5).33,34

8
Scheme 5
1
Total and Formal Synthesis of Morphine
Gates landmark synthesis of morphine in 1952 started from naphthalene
HO MeO
Scheme 6
diol 23, which was subsequently converted over seven steps to the substituted
naphtoquinone 24 (Scheme 6).15,16 The [4+2] cycloaddition of 24 with 1,3-butadiene
under thermal conditions afforded the phenanthrene 25. Phenanthrene 25 was subjected
to hydrogenation in the presence of copper chromite which led to an unexpected
cyclization affording tetracyclic amide 26. Although the stereochemistry at C9 (morphine
numbering) was set correctly during the cyclization, it was necessary to epimerize the
C14 (morphine numbering) center (Scheme 7). Gates, while attempting to close the furan
ring via alpha bromination of the corresponding ketone, achieved this epimerization with
dinitroarylhydrazone 27, the most commonly intercepted intermediate in subsequent
formal morphine syntheses. The furan ring was then closed to afford pentacycle 29 and

9
28 29
Scheme 7
completed the construction of the morphine skeleton. Finally, hydrolysis, lithium
aluminum hydride reduction, and demethylation completed the first total synthesis of
morphine 1.
Shortly after Gates historic synthesis, Ginsburg completed a formal synthesis by
synthesizing dihydrothebainone 35 in 1954.35 In Ginsburgs synthesis, condensation of
34 35
Scheme 8
veratrole 31 via ortho-lithiation to cyclohexanone 30 served as the first step (Scheme 8).

10
The coupled product was dehydrated and then converted to enone 32. Michael addition
with dibenzyl malonate, followed by decarboxylation and a Friedel-Crafts annulation
resulted in the formation of the phenanthrenone 33. Finally the D ring was installed using
a series of steps culminating in the spontaneous formation of the ethylamine bridge
accompanied with cleavage of the C4 methyl ether and formation of the tetracyclic amide
34. An additional 8 steps followed by d-tartaric acid resolution yielded (-)-
dihydrothebainone 35, and consequently, the first of many formal synthesis of morphine.
Nine years later, Barton presented a biomimetic synthesis of a radio labeled
thebaine 38 (Scheme 9).36 Starting from tritium labeled reticuline 36 he performed an
MnC>2 promoted oxidative coupling to construct the phenanthrene core. However this step
Scheme 9
proceeded in a poor yield and after two additional steps a radioisotope dilution study of
the final thebaine 38 was performed to establish a 0.012% conversion of tritium labeled
salutaridine 37.
in io
Simultaneous reports presented in 1967 by Grewe and Morrison, Waite and
Shavel40 collectively, established a successful path for the coupling of rings A and C
(Scheme 10).

11
Scheme 10
Substituted benzyltetrahyroisoquinoline 41 was readily obtained after a Birch reduction
of the coupled product of compounds 39 and 40. Grewe then used phosphoric acid, while
Morrison, Waite and Shavel were successful with 10% aqueous HC1, to render the ortho
coupled product in 3% yield. The para product was obtained in 37% yield. This process
resulted in the formation of dihydrothebainone 35.
Other research groups later improved the ortho selectivity of the Grewe
cyclization, and this disconnection is found in several of the following formal synthesis.
Kametani41 utilized a Pschorr type cyclization in his approach to thebaine 19 to maximize
the ortho- para selectivity (Scheme 11). Diazotization of 2-aminobenzyl
tetrahydroisoquinoline 42 followed by thermal decomposition yielded racemic
salutaridine 16 in a yield of 1.1%, however no ortho-ortho products were observed.

12
Scheme 11
Schwartz, 4243 in a biosynthetically designed synthesis, used thallium (ID)
trifluoroacetate to effect the ortho-para coupling of N-acylnorreticuline 43, affording the
corresponding salutaridine derivative 44 (Scheme 12). Reduction of this intermediate
with LAIH4 followed by O-ring closure with HC1 resulted in the formation of thebaine
and resulting in a formal total synthesis.
Scheme 12

13
Beyerman44 used a Grewe type cyclization with a symmetric arene to overcome
selectivity problems (Scheme 13). The N-methylation of benzyl protected phenol 45,
H2, Pd-C
35
Scheme 13
followed by hydrogenation and finally a Birch reduction rendered tricycle 46, which
readily cyclized in the presence of HC1 to 47. Fortunately, the additional hydroxyl group
at C2 in 47 was selectively removed by conversion to the corresponding tetrazole ether
followed by hydrogenolysis, which afforded dihydrothebainone 35 and formalized
Beyermans synthesis.
Rice45 is given credit for the most practical synthesis of morphine to date, with an
overall yield of 29%. Using starting materials similar to those used by Grewe and
Morrison, Rice was able to synthesize amine 50 by coupling of acid 48 and amine 49. In
3 steps Rice was able to synthesize bromide 51 using a strategy similar to that of
Beyerman. This was a key intermediate because it possessed a well placed bromine
substituent, which blocked para cyclization. Bromonordihydrothebaine 52 was formed in
60% yield, and was eventually converted to dihydrocodienone 53 (Scheme 14). Overall

14
the whole synthesis required isolation of only six intermediates, obtained in sufficiently
pure form to continue with the synthesis. It still remains the most practical synthesis to
date.
Scheme 14
In 1983, Evans46 used the ortho lithiated veratrole 54 in an initial coupling
reaction with piperidone 55 in his approach (Scheme 15). After the coupling, dehydration
afforded alkene 56, which was further coupled with dibromide 57. Isoquinoline 58 was
then converted to the aziridinium salt 59, which was then opened, oxidized to an
aldehyde and finally treated with Lewis acid to form the morphinan 60. Removal of the
CIO hydroxyl group followed by oxidation afforded ketone 61, which is one of Gates
intermediates hence resulting in a formal synthesis.

15
Scheme 15
A third report in 1983 by White47 described an oxidative coupling approach to (-)-
codeine 2 (Scheme 16). After protection and bromination, (-)-Norreticuline 62,
Scheme 16

16
underwent successful and selective para-para coupling to afford salutaridine analogue
63, which was further manipulated to bromothebaine 64. Simple hydrolysis followed by
double bond migration afforded the Gates intermediate 65 which on treatment with
LiAlH4 gave (-)-codeine 2.
In 1986, Schafer48 reported another oxidative coupling approach to salutaridine
(Scheme 17). Formamidine 67 was coupled with bromide 66 and the product
MeO OMe
N^tBu 68 16
Scheme 17
reductively cleaved to afford the cyclization precursor 68. Cyclization was achieved
using TiCl4 and subsequent rearomatization of the A-ring using DDQ afforded
salutaridine 16 in 3% overall yield in 15 steps.
In 1987, Fuchs49 reported a total synthesis of morphine using a tandem coupling
reaction to construct the morphinan skeleton. His approach to the morphinan skeleton
used an intramolecular conjugate addition/alkylation sequence in which connections 02-
03 and C9-C14 were formed as a result of one-tandem process. Coupling of aryl 69 to
alcohol 70 under Mistunobu conditions followed by deprotection and an
oxidation/reduction sequence afforded ether 71 with the desired cis stereochemistry
(Scheme 18). The tandem cyclization was achieved by treatment of ether

17
75 74 73
Scheme 18
71 with n-BuLi, which led to the closure of the Cl2- Cl3, bond and subsequently
underwent alkylative closure of the final ring to yield the tetracycle 72. After oxidative
cleavage of the olefin to the corresponding aldehyde the nitrogen was introduced by
reductive amination and protected as the trimethylsilylethoxycarbonyl ester, and finally
oxidation followed by enol ether formation afforded 73. Base catalyzed elimination of the
sulfonyl group followed by oxidation with DDQ gave dienone 74. Upon removal of the
protecting group, a 1,6-Michael type addition afforded codeinone 21 as well as the
nonconjugated neopinone, which could be readily isomerized to codeinone under
conditions reported by Rapoport and Barber.50 Fuchs completed his total synthesis by
converting codeinone to racemic morphine with reduction and final demethylation.

18
In 1992, Tius51 used an intermolecular Diels-Alder reaction as an early step in his
formal synthesis. Quinone 75, which was prepared in 7 steps from 3-methoxy-2-hydroxy
Scheme 19
benzaldehyde, was heated with diene 76, prepared in 2 steps from 1,4-cyclohexanedione
monoethylene ketal, to construct phenanthrene 77 (Scheme 19). After several subsequent
steps Tius completed his synthesis by constructing thebainone 78, thus intercepting
Gates approach.
Parker and Fokas accomplished a well designed formal synthesis of morphine in
1993. Their approach hinged on an efficient radical cascade which in one step led to the
construction of a morphinan complete with the A, B, C and O-rings of morphine (Scheme
20). To be able to take advantage of this tandem cyclization strategy, they had to first
construct aryl ether 82, through an eight-step sequence starting from m-methoxy
phenethylamine 79 and culminating in a Mitsunobu coupling of the resultant alcohol 80
with phenol 81. With the aryl ether in hand the ortho allyloxy aryl radical 83 was
generated using tributyltin hydride/ AIBN. Tandem closure led to isolation of

19
85
84
Scheme 20
tetracycle 86 in 35% yield by initial attack of the radical on the proximal but more
substituted end of the cyclohexyl ring double bond to establish the furan ring with the
correct stereochemistry at Cl3. The radical generated in the formation of the furan
NMeTs
Scheme 21
87

20
ring then attacked the [3-carbon of the styrene double bond to give rise to the resonance
stabilized radical of 85 with the correct stereochemistry at Cl4. Final elimination of the
phenylthio group from 85 led to formation of styrene 86. Dihydroisocodeine was formed
when the tosylamide 86 was treated with L/NH3 at -78 C. Swem oxidation of
dihydroisocodeinone 87 afforded dihydrocodeinone 88, which then completed her
approach.
The crucial step in Overmans53 approach was essentially a Grewe type
disconnection, but involved an intramolecular Heck reaction to complete the construction
of the B-ring. The synthesis started with enantioselective reduction reduction of 2-allyl
cyclohexenone 89 which would introduce chirality into the synthesis. Condensation of
the resultant 5-alcohol 90 with phenylisocyanate, oxidation of the side chain olefin with
osmium tetraoxide and acetonide protection afforded 91 (Scheme 22).
Scheme 22
A copper catalyzed suprafacial Sn2 displacement of the allyl carbamate with lithium
dimethylphenyl silane, deprotection and diol cleavage yielded an intermediate aldehyde,
which then underwent reductive amination with dibenzosuberyl amine to afford 92.

21
Condensation of allylsilane 92 with iodide 93 (prepared in 7 steps from isovanillin in an
overall 62% yield) at 60 C in the presence of Znl2 followed by iminium ion-allylsilane
cyclization yielded the isoquinoline intermediate 94. Palladium mediated coupling led to
the formation of the Cl2-03 bond and morphinan 95 (Scheme 23) with the correct
stereochemistry at C9, 03, and 04. Liberation of the phenolic oxygen and (3-face
epoxidation of the C6-C7 double bond and subsequent intramolecular ring-opening by
the phenolic hydroxyl completed the dihydrofuran ring. Oxidation followed by reductive
DBS cleavage in the presence of formaldehyde yielded (-)- dihydrocodeinone 88.
Scheme 23
Morphine Syntheses via Sigmatropic Rearrangements
Although a wide variety of synthetic approaches have been applied to the
morphine problem, sigmatropic rearrangements have rarely been elicited as synthetic
tools. Of the more than twenty formal syntheses only three, namely those of Rapoport,50

22
20 21 25
Parsons and recently Mulzer' were able to utilize sigmatropic rearrangements as key
steps in their approaches to morphine.
Interestingly, all three approaches used the sigmatropic rearrangement for the
same purpose, to install the quaternary center at Cl3 (morphine numbering) while
transferring the stereochemistry already present in the starting material to that position.
Rapoports synthesis began with the conversion of ortho-vanillin 98 to amino acid
99 in twelve steps (Scheme 24). The amino acid then underwent rearrangement in the
Scheme 24

23
presence of acetic anhydride to afford lactam 100. Benzylic oxidation followed by
reaction with formic acid yielded, after allylic migration and hydrolysis, alcohol 102.
Condensation of the alcohol with trimethyl orthoacetate produced acetal 103, which
subsequently underwent rearrangement to afford the methyl ester 104. This compound
contained the required quaternary center at C13 as well as the complete C ring with an
adequate pattern of substitution. Ring B was emergent in this structure but required more
steps to develop.
After several attempts, Rapoport decided to intercept the advanced Evans
intermediate 105 from which Evans was able to synthesize one of Gates advanced
intermediates (106) in six additional steps.
Parsons,20 in 1984 reported the synthesis of the precursor 113, through an
interesting sequence. Their synthesis started with the 1,2 addition of the Grignard
compound 107, to ketone 108. After hydrolysis, the product 109 was reduced using
Luche condition to obtain the alcohol 110, which was condensed with dimethylacetamide

24
dimethyl acetal to form the acetamido acetal 111. Concomitant rearrangement of 111 via
an Eschenmoser-Claisen rearrangement gave the amide 112 (Scheme 25). Using this
series of transformations, Parsons and Chandler were able to set the stereochemistry at
Cl3 correctly.
Closure of ring B was achieved starting with the ozonolysis of 112 which resulted
in the aldehyde 113, which was consequently treated with N-methyl hydroxylamine
Scheme 26
to yield the intermediate 114. The intermediate then accordingly rearranged to produce
the isoxazolidine 115 through an intramolecular cycloaddition with an overall 72% yield.
The cycloaddition product possessed the correct stereochemistry at C14 but was epimeric
at C9. The resultant epimers were separated using chromatography and the N-0 bond of
the morphine-like isomer was cleaved by hydrogenolysis to produce the amino alcohol
116. The morphinan 117 (Scheme 26) was obtained by heating the resulting
hydrochloride salt of 116 under vacuum followed by LAH reduction of the resulting
hydroxy amide produced the morphinan 117 with an overall yield of 2.1%.

25
21 25
In Mulzers synthesis of morphine, a creative approach towards the morphine
skeleton was employed. In the first generation of the synthesis he used a model study to
explore the possibility of establishing the important benzylic quaternary stereogenic
center (Cl3) via either conjugate addition of a cuprate to an unsaturated ketone or [3,3]-
sigmatropic rearrangement.
Starting from alcohol 118 Mulzer and co-workers attempted an Eschenmoser-
NaBHj
MeOH
Scheme 27
Claisen rearrangement to obtain amide 119 in only 21% yield. With this unsatisfactory
result they tried both the Ireland and the Johnson variants of the Claisen rearrangement
on the alcohol 120 that was obtained after reduction of the enone, both failed completely.
An explanation for this might be strong conjugation of the double bond (C5-C13
morphine numbering) to the aromatic ring. Since Claisen rearrangements and 1,4-
additions of vinyl cuprates are complementary to each other, the latter was attempted on
the enone 120 with positive results, leading to the formation ketone 121 in 87% yield
over 2 steps.

26
Another interesting discovery was made during this model study. After preparing
a more elaborate substrate 124 from the addition of ortholithiated veratrole to the
vinylogous ester 122 followed by hydrolysis and dehydration. Enone 123 after reduction
was subjected to Eschenmoser-Claisen rearrangement conditions. The results were
similar, even though rearranged product was obtained the yields were low. More
interestingly after cleavage of the terminal double bond of amide 125 (Scheme 28) to
obtain the aldehyde 126, all attempts at closing the B- ring failed completely. Mulzer
explained these results using the theory that repulsive interactions between the ortho-
methoxy group and the substituents a-to the C13 carbon (morphine numbering) on the
cyclohexyl ring. This steric interaction causes the aromatic ring to twist out of
conjugation with the double bond in the cyclohexyl ring. This assumption had merit
because 'H- NMR of the allylic alcohol clearly showed the two rotomers reminiscent
O
MeOH
NaBH
Et20
2. NH4Cl(aq)
OH
122
O
124
123
OMe
MeO
MeO.
MeC(OMe),NMe:
Xylenes, 24%
1 0s04, NMO
Acetone, H20
2. NaIO EtOfcl Me0
,NMe.
O
O
o
125
126
127
Scheme 28
of the known atropisomerism found in biphenyls. The result is a highly adverse steric
influence at the benzylic sp -hybridized carbon by the aromatic ring. The apparent

27
solution to this setback was to restrict the conformational flexibility of the aromatic ring
by means of a tether, which would also provide the two-carbon fragment for the B-ring.
This idea led to the synthetic pathway that would eventually result in the synthesis of the
morphine skeleton by way of phenanthrone 129. Starting from enantiomerically pure
phenanthrone 129, which was synthesized in 3 steps from acid 128, conjugate addition
with a variety of funtionalized organocuprates provided good yields of the olefin 130.
Mulzer and co-workers discovered that the substitution pattern on the aromatic ring was
critical in obtaining clean 1,4-adducts. With olefin 130 in hand they were able to effect E-
ring closure using a clever umpolong strategy. After trapping the ketone as the silyl
enol ether, bromination with NBS in THF at low temperature yielded bromoketone 131
as a 3:1 isomeric mixture. The undesirable isomer could however be recycled by way of
reductive removal of bromide with zinc and concomitant silylation of the resultant
enolate. When a-bromoketone 131 was heated in DMF at 140C the dihydrofuran was
obtained in 20 minutes in quantitative yield. The next stage in the synthesis involved the
introduction of the nitrogen functionality at C9 (morphine numbering). Ketone 132 was
subjected to a three step sequence that resulted in a) protection as the ethylene ketal b)
hydroboration of the vinyl group with BHvSMe2 followed by oxidation and c) removal of
the chloro substituent by catalytic hydrogenation to render alcohol 133. The alcohol was
then converted to the benzene sulfonamide derivative 134 using a variation of the
Mistunobu protocol which uses N-methylbenzene sulfonamide, 1,1-
azodicarbonylpiperidine (ADDP) and Bu^P. The next step was to introduce a double
bond by benzylic radical bromination followed by debromination. Hence exposure of 134

28
to NBS and catalytic amount of dibenzoyl peroxide in refluxing cabon tetrachloride
Scheme 29
afforded the morphimethine. Treatment of the styrene 135 under reductive conditions
(L/NH3/THF) yielded the desired heterocyclization product, (-)-dihydrocodeinone 88
after hydrolysis of the ketal 136 using 3N HC1. Unfortunately attempts to convert
dihydrocodeinone to morphine failed probably because of competing oxidation of the
tertiary amine followed by polymerization. In 13 steps and an overall 11.5 % this make
Mulzers synthesis one of the most practical of all attempts at morphine synthesis.

29
Recent Related Developments
In addition to the Claisen approach to the morphine skeleton, the Hudlicky group
is actively pursuing two other approaches toward the morphinan skeleton namely an
intramolecular Diels-Alder approach and a Heck coupling cascade approach.
Hudlicky, Boros and Boros54 were able to synthesize the B-, C-, and O- rings
using a combination of three important transformations, microbial oxidation,
intramolecular Diels-Alder cycloaddition and a Cope rearrangement. Starting from
toluene, which was subjected to microbial oxidation to yield diol 138, protection of the
distal hydroxyl group afforded the thexyldimethylsilyl ether 139. Alkylation of the
proximal hydroxyl group with sorbyl bromide rendered the tetraene 140. The substrate
was now ready for an intramolecular Diels-Alder reaction. The Diels-Alder
* C9 (morphine numbering)
Scheme 30 Conditions: a) Toluene dioxygenase; b) THSC1, imidazole, DMF; c) NaH,
sorbyl bromide, THF, 0 C to rt., 30h.; d) CC14, 77 C, 7h.; e) nBu4NF-3H20, THF; f)
PCC, CH2C12, rt.; g) xylenes, sealed tube, 250 C, 22h.; h) NaBH4, CeCl3-7H20, MeOH,
rt., 15 min.
reaction could possibly take two reaction pathways namely, diene k, 1 with dienophile m
(Scheme 30) or diene m, n with dienophile k. The latter reaction pathway involving diene

30
m,n and dienophile k was observed to yield furan 141. Attempts to induce Cope
rearrangement to form the desired tricyclic compound 142 were unsuccessful. To supply
some driving force for the Cope rearrangement, the THS-ether was converted in two
steps into the ketone by first fluoride deprotection of the silyl group followed by PCC
oxidation to afford ketone 143. The ketone successfully underwent the rearrangement to
afford enone 142. Reduction using Luche conditions produced compound 144 that
possesses the carbon skeleton for the lower half of morphine with all the stereocenters
correctly set with the exception of what would be C9 (morphine numbering).
Hudlicky and Gum55 published a second generation intramolecular Diels-
Scheme 31 Conditions: a) NaH, sorbyl bromide; b) PPh.i, THF; c) AciO, pyridine;
d)230 C, PhMe.
Alder approach towards the morphine skeleton in 1998. Unlike the first generation
attempt, provisions were made for eventual closure of the D-ring by appending a nitrogen
functionality from the quaternary carbon of the tricycle 149 (Scheme 31). During the
cyclization of the triene, it was discovered that the stereochemistry of the methyl group at
what would be C9 (morphine numbering) was indeed p-faced instead of a-faced as had

31
been reported earlier. This led to the conclusion that the intramolecular Diels-Alder
proceeded through an exo transition state.
In 1998, Hudlicky56 and coworkers published a radical cyclization approach to the
morphinan skeleton that represents the most advanced morphinan synthesized in the
Hudlicky group. In the first generation of this radical approach, the focus was to
Br
Scheme 32 Conditions: a) JM109 (pDTG601); b) PAD, HOAc; c) THSC1, imidazole,
DMF; d) BzOH, Bu3P, DEAD, THF; e) NaOMe, MeOH; f) 150, Bu3P, DEAD, THF; g)
FI30+; h) benzyl bromide, K2C03, acetone; i) Bu3SnH, AIBN, toluene reflux.
achieve a tandem radical cyclization that would lead to the construction of the A, C, D,
and O-rings of morphine (Scheme 32) with the correct stereochemistry at the chiral
centers in a manner analogous to the Parker52 synthesis but with different connectivity at
the C9, CIO and Cl 1 carbon atoms. The first step was to validate the tandem process with
simple model studies. The initial model examined the feasibility of constructing the Cl 2-
C13 bond through a radical closure. To this regard bromoguiacol 150 was synthesized in
4 steps starting from an enzymatic transformation with P. putida TG02C and used as a
nucleophile in the second Mitsunobu inversion of the alcohol 152 also obtained through

32
an initial enzymatic step (Scheme 32). With ether 153 in hand the next steps involved
protection of the phenol as the benzoate after cleavage of the labile thexyl group. Under
radical conditions generated by Bu3SnH and AIBN ether 155 was transformed to the
tricycle 156 with three of the five stereo centers in morphine set correctly.
A second model study (Scheme 33) to provide information about the relative
Scheme 33 Conditions: a) PAD, HOAc; b) TBSOTf; c) o-bromophenol, BU3P, DEAD,
THF; d) NaH, 2-oxazolidone; e) Bu3SnH, AIBN, toluene reflux.
stereochemistry of the C9-C14 bond was designed using diene 157, which was
functionalized effectively in four steps into the oxazolone 158. Under radical conditions
pentacycle 159 was obtained in approximately 10% yield. 'H NMR analysis confirmed a
trans relationship between the protons at C9 and C14 but it was difficult to ascertain the
configuration of these chiral centers relative to C5 or C6 and so the product was assigned
either as 159a or 159b.
With these two promising results Hudlicky and coworkers then focused on
constructing the entire morphine skeleton. In the second-generation synthesis, o-bromo-

33
/?-bromoethylbenzene 160 was subjected to enzymatic conditions with the expectation
that the larger bromoethyl group would direct the c/s-dihydroxylation. This assumption
proved to be correct because diol 161 was isolated from the fermentation broth using E.
coli JM109 (pDTG601A). Diimide reduction of 161 followed by acetonide protection of
the cd-diol moiety provided the dibromide 162. Introduction of
Scheme 34 Conditions: a) JM109 (pDTG601); b) PAD, HOAc; c) DMP, /?TSA; d) 2-
oxazolidone, NaH; e) B^SnH, AIBN, benzene reflux.
the oxazolidone gave 163, which upon exposure to radical conditions gave a 2:1 mixture
of octahydroisoquinolones 164a and 164b in favor of the isomer with an ep\-C9
configuration (Scheme 34). The lack of stereo control was attributed to the negligible
steric effect of the acetonide. Since the ep/-isomer was in greater availability the decision
was made to pursue the synthesis of erci-morphine. Mitsunobu inversion with
bromoguiacol generated the precursor for the second radical cyclization, ether 166.
Treatment with Bu3SnH/AEBN gave pentacycle 167. To complete the synthesis of the
ent-morphinan, the silyl-protecting group was removed followed by reduction of the

34
oxazolidone to yield the alcohol 168. A double Swem oxidation was utilized to convert
168 into the rather unstable ketoaldehyde 169, which upon exposure to
trifluoromethanesulfonic acid led to the formation of alcohol 170, which contains the
complete morphinan skeleton.
Scheme 35 Conditions: a) 150, Bu3P, DEAD, THF; b) TBAF, THF; c) Bu3SnH, AIBN,
benzene reflux; d) DIBAL-H, CH2CI2; e) oxalyl chloride, DMSO, Et3N, CIECF; f) TFA.
Currently57, 58 a third generation approach using intramolecular Diels-Alder is
being developed (Scheme 36). The major improvement in the third generation is the use
of a (E, Z)-diene system as seen in 171 which will invariably lead to an inversion at the
C9 (morphine numbering) stereocenter preceding the formation of compounds of the type
173. Using a nucleophilic displacement by the nitrogen tether onto the leaving group
would form B-, C-, D-, and O- rings with correct stereochemistry in 174.

35
I
Scheme 36
Another noteworthy approach to the morphinan skeleton was recently published
by Hudlicky and coworkers.59 It involves a rare Heck cyclization to yield an advanced
pentacyclic precursor of morphine. Biooxidation of (2-bromoethyl)-benzene 157, with
Escherichia coli JM109 (pDT601) followed by reduction of the less hindered double
bond with diimide yielded diol 175 in 80% yield (Scheme 37). The next step involved
protection of the two diol moieties as the benzoate. This was followed by displacement of
the bromine by oxazolidine-2,4-dione to afford the dibenzoate 176. After reduction of the
more reactive amide carbonyl with NaBH4, N-acyliminium ion-olefin cyclization and
subsequent elimination of the alkyl chloride afforded the tricycle 177. This was followed
by deprotection of the benzoate groups and subsequent selective protection of the

36
homoallylic hydroxyl group as the TBDMS ether. Using Mitsunobu protocol the
d, e, f
OH OBz
Scheme 37 Conditions: a) E. coli JM109 (pDTG601); b) PAD, AcOH, MeOH; c)
PhCCbH, DCC, DMAP, CH2CI2; d) Oxazolidine, tetramethylguanidine, THF, reflux; e)
NABH4, MeOH; f) AICI3, CH2C12; g) DBU, DMSO, reflux; h) LiOH, MeOH; i)
TBDMSOTf, imidazole, DMF; j) Bu3P, DEAD, bromoguiacol, THF; k) Pd(PPh3)4,
proton sponge, toluene, reflux.
unprotected alcohol was converted into the bromoguaiacol derivative to give intermediate
179. Heck cyclization of the tetrasubstituted olefin yielded the tetracycle 180 as the only
identifiable product.
In a recent publication in Organic Letters,60 Ogasawara and co-worker undertook
a rather elaborate approach to the morphine skeleton that deserves mention because of
their clever approach to the construction of the C14 stereocenter correctly and also their

37
construction of the C9-C10 bridge. Starting from a mixture of the alcohol 181 they
MeO.
r*i
MeCL
MeO
MeC)
V
MeC)
LJ
MeO
K2CO,
MeOH
82%
^OAc +
(+)-(*)-182
(47% : >99% ee)
(+)-(J?)-183
(-).(5)-184
(48% : 97% ee)
Scheme 38 Conditions: a) vinyl acetate, lipase PS, Bu'Ome, 37 C.
are able to obtain the pure 5-isomer through an optimized pathway61 (Scheme 38) using
vinyl acetate. Even though this synthesis was undertaken with the racemic mixture, the
use of isomer 184 is projected for a future synthesis of natural morphine. Starting from
the mixture of alcohols 181 they synthesized the bromoacetal 185 as a mixture by
utilizing ethyl vinyl ether in the presence of NBS (Scheme 39). Under radical cyclization
conditions, they were able to obtain the cyclized product in moderate yields. The authors
attributed this to the steric hindrance caused by the methoxy group in the 2-position of
the aromatic ring. The cyclized product 186 was converted in 3 steps into the ketone 190.
Reduction of the ketone with NaBPU yielded the alcohol 191 diastereoselectively. This
result might be due to prior coordination of the borohydride reagent to the pivaloyl
moiety, which results in hydride delivery to the (3-face of the molecule. The xanthate 192
(Scheme 39) obtained from the alcohol 191 was then thermolyzed to afford the
cyclohexene derivative 193 in 81% yield. Allylic oxidation of 193 using chromium

38
trioxide and 3,5-dimethylpyrazole complex in CH2CI2 afforded the enone 194. Using
O
194
Scheme 39 Conditions: a) EVE, NBS, Et2. b) Bu3SnH, AIBN (cat.), benzene, c) m-
CPBA, BF3.OEt2. d) LiAlH4, THF. e) Piv-Cl, pyridine. 0 PDC, CH2C12. g) NaBH4,
/PrOH. h) Mel, CS2, NaH. i) 0-C6H4CI2, reflux, j) Cr03 3,5-(Me)2pyrazole.
Sakurai conditions allyl functionality was introduced at the C14 center (morphine
numbering) by treatment of 194 with allytrimethylsilane (Scheme 40) in the presence of
titanium (IV) chloride. Ketone 195 was then transformed into the ketal 196 followed by

39
Scheme 40 Conditions: a) allylTMS, TiCl4, CH2C12, -78 C. b) (CH2OH)2, p-TsOH,
benzene, reflux, c) 0s04 (cat.), NaI04. d) (CH2OH)2, p-TsOH, benzene, reflux.
reductive cleavage of the olefin in 196 to afford the aldehyde 197. Upon reflux in
benzene in the presence of ethylene glycol and catalytic amounts of p-toluenesulfonic
acid, the hydrophenanthrene 198 was obtained in 85% yield. Construction of the D-ring
was achieved using Parker conditions, which involved deprotection of the pivaloyl group
followed by Mitsunobu (Scheme 41) coupling of the free alcohol 199 with N-methyl-p-
toulenesulfonylamide to give the tosylate 200. Treatment of the tosylate with sodium
naphthalenide afforded the morphinan 201 in 89% yield via concomitant detosylation
followed by regioselective cyclization. Morphinan 201 was then converted in 3 steps to
the morphinan 202, which is the 0-methylated analogue of dihydrothebainone 35 (page
14).

40
Scheme 41 Conditions: a) LiAlH4, MeNHTs, B113P, DPAP. b) Sodium naphthalenide,
THF, -30 C.
Chelated Enolate Claisen Rearrangements
In 1977 Wolfgang Steglich62' 63 reported the synthesis of a series of amino acids
utilizing a Claisen rearrangement. This was the first time the Claisen rearrangement had
been extended to the synthesis of this important class of compounds. Steglich and co
workers first synthesized N-benzoyl a-amino acid esters with a general structure such as
205. After transesterification with the allyl alcohol 206, they then observed that under
dehydration conditions oxazoles were formed. The oxazoles thus formed concomitantly
rearranged without isolation to form oxazolones 209 (Scheme 41). Under conditions of
hydrolysis they observed the formation of (3-amino acid with the general structure of 210
in yields up to 95%. The oxazole intermediate 208 can be seen as a trapped enolate

41
whose geometry is fixed by virtue of being in the five membered oxazole ring. This
PPh3/CCl4,
\ r EtjN/CHjCN
Scheme 41
important aspect of the reaction meant that the sigmatropic rearrangement could proceed
with stereoselectivity. Unfortunately when the substituent a- to the nitrogen is hydrogen
there is epimerization at that center leading to a non-stereoselective rearrangement.
Paul Bartlett64 in 1982 decided to investigate the work done earlier by Steglich.
His goal was to compare these conditions to the Ireland Claisen6:i rearrangement
conditions. Also important was the utilization of this reaction in the synthesis of y,8-
unsaturated amino acids. He also wanted to study the stereochemical influence, if any of
the a-substituent in the Claisen rearrangement. Deprotonation Conditions: Bartlett and
coworkers used 2.1 equivalents of LDA to effect enolization. The found that shorter (2.5
min) or longer (40 min) enolate generation times had no significant influence on yield or

42
stereoselectivity. Also the use of TBDMS chloride instead TMS chloride as the silylating
agent did not increase yield or stereoselectivity. Reaction in a less polar solvent (ether)
proceeded with a slight increase the stereoselectivity but led to a decreased yield.
Table 1. Influence of Conditions on Rearrangement of Amino Esters.
Conditions Yield/ %
*Standard
60-65
Ether
45
20% HMPT/THF solvent
51
KDA
0
1.1 equiv of MgCL,
42
Ratio 212/213
9
10
4
10
*Deprotonation at -75C with 2.1 equiv. of lithium isopropylcyclohexylamide or lithium
diisopropyl amide; silylation with Me3SiCl after 10 min; warming to reflux for lh;
hydrolysis of silyl ester.
Contrastingly the use of HMPA and TMEDA, which are highly dissociating systems as
co-solvents resulted in both lower yield and lower stereoselectivity (Table 1). The use of
a lewis acid (MgCh) also slightly increased stereoselectivity but led to a lower overall
yield. The result of this study is in concurrence with the accepted principle of an E-
enolate geometry and a chair-like transition state for aliphatic substrates. He proposed
that coordination of the counter ion between the carbonyl oxygen and the nitrogen anion
is at least partly responsible for the E-enolate geometry.
Influence of N-Protecting Groups: A variety of N-protecting groups were
explored (Table 2) with varying yields and stereoselectivity. Overall the Boc- protecting

43
Table 2. Effect of ^/-Protecting Groups on Rearrangement of trans ButenalGlycinates
0
r=n^A0
0
R=N II
H*fcJpX'OH
H
O
r=n*y^oh
H
214
215
216
R
yield/ %
Ratio 215/216
1. Boc
60-65
9
2. Cbz
65
4
3. Bz
65
5.4
4. CFjCO
58
1.5
5. Phthaloyl
0
6. Et2
0
group gave the
best results. The reduced
stereoselectivity with the
derivative (Entry 4) was explained by reduced importance of the chelation effect due to
the increased acidity of the nitrogen. The inability to obtain products in the case of the N-
phthaloyl and N, /V-diethyl analogues was attributed to the lack of an extended conjugated
system for nitrogen-substituted enolate stabilization.
Uli Kazmaier66 77 in 1994 published an article about a remarkable variation to the
classical enolate Claisen rearrangement that would revolutionalize the synthesis of both
natural and unnatural amino acids. It had already been established by Steglich62 63 that
enolizable amino acids could undergo rearrangement with moderate to good
stereoselectivity if the enolate geometry was fixed either in the form of an oxazole ring or

44
constricted due to chelation with the counter ion. While Bartlett64 had always converted
the enolate into the silylketene acetal, Kazmaier discovered that by allowing the chelated
enolates (Figure 1) to simply warm up from -78 C to about -15 C resulted in
OR
M: metal
Y: protecting group
217
Figure 1. Nature of Chelated Enolate in Kazmaier Claisen Rearrangement.
rearranged products in excellent yields and also high diastereoselectivity. The chelated
enolates had several advantages. Since the chelated enolates are significantly more stable
than the corresponding non-chelated lithium enolates, they can be warmed to room
temperature without decomposition and side reactions such as ketene formation via
elimination can be suppressed. Secondly because of the fixed enolate geometry due to
chelation, the reactions proceed with high diastereoselectivity. Due to the inherent
flexibility of this chemistry, many variations of protective groups Y (Figure 1) can be
used. Varying the metal M used can also modify the selectivity and reactivity of the
reaction. Since the coordination sphere of a metal ion is not saturated in a bidentate
enolate system, this allows for additional coordination with external ligands. Lastly
transformation of the high-energy ester enolate into a chelate-bridged stabilized
carboxylate provides a good driving force for the reaction.
When this reaction was applied to acyclic allylic esters the results obtained
confirmed a preferred chair-like transition state. Even though different Lewis acids were
utilized, ZnCh produced the best results (Scheme 42). The formation of the syn product

45
BocHN^^
O
O
218
2.2 eq LDA
*-
1.2 eq ZnCl2
Scheme 42
is explained by a preferential rearrangement through the chair-like transition state (Figure
2), which avoids the steric interactions between the pseudoaxial hydrogen and
\/
Zn
/
S S
Chair
Figure 2. Chair vs boat transition states in the
acyclic substrates.
Kazmaier Claisen Rearrangement of
the chelate complex in the boat transition state. The results obtained in the acyclic series
of experiments are summarized in Table 3, which details the influence of substituents at
the double bond, the olefin configuration and the different nitrogen-protecting groups as
related to the yield and diastereoselectivity of the rearrangement products. All the
substituted allyl esters displayed high diastereoselectivity where the formation of syn
products from trans substituted esters and anti products from cis substituted esters were
favored.

46
Table 3. Results from Acyclic Kazmaier Claisen Rearrangement
R3 R2
R4
xhn^Y
o
221
R1
R2 R2
R3\J^ .R! R^aJUn R1
XHN COOH XHN COOH
223 224
X [a]
R1
R2
R3
R4[b]
Yield
Diastereomer ratio
()-223: ()-224
1
Z
H
H
H
H
88
_
2
Z
H
ch3
H
H
78
-
3
z
H
H
C3H7
H
76
95:5
4
z
ch3
H
ch3
H
88
93:7
5
z
c2h5
H
ch3
H
98
95:5
6
z
C2H5
H
H
c4h,
73
95:5
7
Boc
ch3
H
CH3
H
84
96:4
8
Boc
H
H
c3h7
H
78
96:4
9
TFA
H
H
c3h7
H
79
95:5
10
TFA
c2h,
H
H
c4h9
65
94:6
11
Z
H
H
H
D
75
98.5:1.5
[a] Z = benzyloxycarbonyl, Boc = tert-butoxycarbonyl, TFA =trifluoroacetyl
[b] D = tert-butyldiphenylsilyl
Due to the excellent results obtained with the acyclic substrates, the chemistry
was applied to cycloalkenyl glycinates (Scheme 43). These substrates were of particular
interest because their rearrangement would yield y,8-unsaturated amino acids, a class of
compounds with high activity as enzyme inhibitors. Indeed it had been previously
postulated that cyclic allylic esters prefer to rearrange via a boat-like transition state.
Kazmaier and coworkers investigated the effect of ring size as well as the metal salt used
for chelation of the ester enolate (Table 4). As predicted, with the cyclic allylic esters the
swi-product is preferred and the best results with respect to yield and stereoselectivity

47
BocHN^^H''-
O
225
Scheme 43
O
)n 1) 2.5 eq LDA
1.2 eq MXn
2) CH2N2
BocHN COOMe BocHN COOMe
226
227
are obtained with cyclohexenyl glycinates (n = 2). All the metal salts used gave good
product yields in the cyclohexenyl case (n = 2). The crude amino acids obtained were
directly converted into the corresponding methyl esters using diazomethane. The best
results were obtained with zinc chloride and are summarized in Table 4.
Table 4. Results from Rearrangement with Zinc Chloride.
n
% Yield
Ratio
226:227
1
79
80: 20
2
83
90: 10
3
73
92 : 8
4
57
86 :14
It was noted during this study that homologous cycloheptenyl substrates (n = 3) showed
similar degrees of diastereoselectivity as in the cyclohexenyl case. However increase in
ring size to the more flexible cyclooctenyl case (n = 4) resulted in decrease in selectivity.
Also noteworthy was the fact that diastereoselectivity in the cyclopentenyl case (n = 1)
was lower than that observed for the cyclohexenyl and cycloheptenyl cases respectively.
The product formation as well as the diastereoselectivities observed for the six and seven
membered esters were explained by rearrangement through a boat-like transition state, 67

48
which minimizes the steric interactions between the cycloalkenyl ring and the solvated
chelating metal (Figure 3).
chair
Boat
Figure 3. Chair vs boat transition states in the Kazmaier Claisen Rearrangement of cyclic
substrates.
In summary Kazmaier has successfully demonstrated the utility of his variation of
the classic enolate Claisen rearrangement. The chelated ester enolate rearrangement is not
partial to acyclic substrates but can also be practical for cyclic substrates. High
diastereoselectivity and excellent yields are observed for the rearrangements, which
proceed via a boat-like transition state for cyclic esters and a chair-like transition state for
acyclic esters.
In 1997 Hudlicky and coworkers applied the Kazmaier chelated enolate
rearrangement to their chemoenzymatic approach to morphine. Model studies to obtain
optimum reaction conditions were undertaken on compounds of type 232. These
glycinates were obtained first by direct oxidation of the aromatic precursor by either the
mutant strain Psuedomonas putida F39/D or the more potent recombinant organism
Escherichia coli JM109(pDTG601 A) to render the diene-diols of type 229. After diimide
(potassium azodicarboxylate) reduction of the less hindered double bond, the distal

49
R = Me, Cl, Ph, 2-MeOPh
NHBoc
Scheme 44. Conditions: a) Toluene dioxygenase expressed in Pseudomonas putida
F39/D (R = Me; 3.5 g/L) or Escherichia coli JM109 (pDT601A) (R = Cl; 10.0 g/L), (R =
Ph; 3.0 g/L), (R= MeOPh; 2.5 g/L). b) PAD, HOAc, MeOH, 0C -rt, 12h 85 95%. c)
TDSC1, imidazole, DMF, 5 C, 8h 80 90%. d) Boc-Gly, DCC, DMAP, CFLC12, 24 -
48h 75 90%.
hydroxyl group was then protected as the THS-ether. DCC coupling protocol was used to
convert the proximal hydroxyl group into the Boc- protected glycyl derivative 232
(Scheme 44).
The glycinates (R = Me, Cl, Ph, 2-MeOPh) served as the substrates for the first
Claisen study. The results obtained were quite promising in term of yield. All the
glycinates underwent rearrangement under the Kazmaier conditions with yields ranging
from 25 90%. Surprisingly the configuration of the major product of the rearrangement
was opposite to that expected (Table 5). Due to the fixed enolate geometry, which is a
result of the formation of the chelate, the only variable would be the predominance of one
transition state over the other. In this case the chair transition state clearly predominates
leading to the product ratios observed.

50
Table 5. Ratio of C9 Epimers for Kazmaier Claisen Rearrangement of glycinates.
R
233
234
Overall yield
Ph
75%
25%
80%
CH3
75%
25%
90%
Cl
90%
10%
25%
2-MeOPh
50%
50%
75%
Due to the lack of control of stereoselectivity, the authors considered
epimerization of the lactones resultant from treatment of the epimeric amino acids with
tosic acid (Scheme 45). They reasoned that since the bulky protected amino acid was
TDSO
233
234
Scheme 45
TsOH,
CH,C1,
TDSO
235 NHBoc
TsOH,
DBU/THF
more accessible in the wrong isomer (situated on the concave face of the bicyclic
molecule), it could be effectively epimerized to the more stable isomer. Hence after
treatment with DBU in THF for 37h they were able to achieve an 80% epimerization of

51
235 to give the isomer with correct stereochemistry at C9 and C14 (morphine
numbering).
Inspired by the work of Kazmaier and the subsequent application of this
chemistry by Hudlicky and co-workers78,79 in their approach to the morphine skeleton,
Percy79 and co-workers investigated the possibility of generating y-oxo-P,(3-difluorinated
amino acids by chelated [3.3]-sigmatropic rearrangement of protected glycinate esters of
readily available difluoroallylic alcohols. This type of rearrangement had the potential to
produce amino acids having a CF2 center a to a carbonyl functionality through release of
the masked carbonyl group (Scheme 46).
F2C
OMEM
)
1. 3 eqiuv. LDA
THF, -78C
2. HCHO
237
OMEM
F OH
238
NHX
O
240
1. 3 equiv. LDA
THF, -78C
2. ZnCl2
w
Scheme 46
OMEM
The synthesis started with difluoroallylic alcohol 238, which was converted into the
glycyl ester 240 under DCC coupling conditions. The glycinate was then subjected to
modified Kazmaier Claisen condition which involves the use of 3 equivalents of LDA
added in a reverse addition order to that proposed by Kazmaier (the Lewis acid is added

52
after generation of the enolate with LDA). After acidic workup the only isolated product
was the rearranged acid 241.
In summary the synthesis of morphine has resulted in ingenious strategies by
different research groups over the years to tackle this small yet challenging molecule.
While the focus of the various syntheses has been synthesis of the target, the chemistry
generated by this pursuit and its application to alkaloid chemistry is the legacy of
morphine synthesis. Starting from Gates l5 16 synthesis to the latest synthesis by
Mulzer it is fascinating to see the many different synthetic pathways that have been
employed in morphine synthesis. Sigmatropic rearrangements have played a small yet
important role in morphine synthesis. The syntheses by Parsons, 20 Rapoport50 and
Mulzer21'25 effectively used sigmatropic rearrangements to establish the C13 quaternary
center of morphine
The chelated enolate Claisen Rearrangement had modest beginnings from
Steglich62 63 and coworkers and later Bartlett64 and coworkers. The idea was greatly
improved by Kazmaier66"77 and coworkers who have developed it into one of the more
powerful tools in amino acid chemistry.
The next chapter of this dissertation will discuss a chemoenzymatic approach to
the synthesis of the morphine skeleton. This approach uses a disconnection of the
morphine molecule that is unlike any of the preceding syntheses. More importantly, it
utilizes a sigmatropic rearrangement, the Chelated Enolate Claisen rearrangement
(Kazmaier Claisen) to establish control of C9 and C14 stereocenters of morphine in
addition to attempting to establish the Cl3 quaternary center. Additionally the synthesis
uses an enzymatic step, which is capable of converting cheap readily available aromatic

53
precursors into either catechols (A-ring of morphine) or cyclohexadiene diols (C-ring of
morphine). With all these factors combined, the chemoenzymatic approach becomes an
attractive route to the morphinan skeleton.
In 1968 as a result of studies conducted by David T. Gibson87 on the microbial
oxidation of aromatic hydrocarbons by soil bacteria, the first stable ds-diol was isolated.
The organism responsible for this transformation was a mutant strain of the bacteria
Pseudomonas putida (FI) and was designated Pseudomonas putida (F39/D). This strain
was devoid of the m-diol dehydrogenase enzyme hence only produced the cis-diene diol.
The use of these diols as synthons was initiated in the late 1980s with work done by
Ley and coworkers who achieved a racemic synthesis of pinitol from meso-cis-diols
derived from benzene. Since then, one of the leading researchers in this area of chemistry
has been Hudlicky who has been able to utilize the ds-diene-diols as chiral synthons86 in
the synthesis of a wide variety of compounds.
In 1988, in the first publication by Hudlicky and co-workers in this area, the idea
of Claisen rearrangements of the allylic alcohol unit of the cA-diols was proposed. This
idea was actually reduced to practice in 1997 and thus began the initial studies that
featured the Claisen rearrangement as a key step in the chemoenzymatic approach to the
morphine skeleton.
In the 'first generation of this approach, conditions for a suitable Claisen
rearrangement that would lead to the transfer of stereochemical information inherent in
the cyclohexadiene-diols were investigated. The Kazmaier-Claisen rearrangement offered
the best conditions for this purpose. The goal was to synthesize (3-amino acids of
different complexity bearing chiral side chains. Eventually such compounds would

54
contain the correct stereochemistry at the C9 and C14 (morphine numbering) centers of
morphine.
In the initial model studies, as reviewed in the historical chapter it was discovered
that even though the Claisen rearrangements proceeded with low stereoselectivity, there
was the potential to achieve complete control of the C9, C14 stereocenters through
equilibration of isomers. Efforts in the initial stages of this approach were also directed at
finding efficient ways of obtaining the bicyclic skeleton One of the opportunities for
construction of this bicycle was through direct enzymatic dihydroxylation of substituted
biphenyls. Indeed when selected biphenyls were subjected to biooxidation conditions, the
resultant diene diols were obtained. Unfortunately it became apparent that as the degree
of oxidation in the substrate increased, the yield for the enzymatic process decreased
considerably probably as a result of poisoning of the bacteria by the oxygenated
substrate.
This dissertation will focus on the progress made in the second generation of the
chemoenzymatic approach to morphine. The discussion will address how control of the
C9 and C14 centers of morphine w-as achieved through the use of the Kazmaier-Claisen
rearrangement and epimerization. It will also give an account of the progress made
toward a formal total synthesis ,of morphine via Overmans intermediate. In addition
some applications in the field of matrix metallo proteinase inhibitors, compounds that are
connected to morphinan intermediates through common structural elements will be
discussed. Finally recent advances in the chemoenzymatic approach to morphine will
also be discussed.

55
CHAPTER 3
RESULTS AND DISCUSSION
Introduction
The structural complexity of the morphine molecule has prompted many
innovative routes to the morphinan skeleton as was detailed in the first chapter. The
synthetic design utilized in the chemoenzymatic synthesis of the morphinan skeleton,
makes it a very attractive route to the morphine molecule. Retrosynthetically, the
approach is directed toward the target through the intermediate (3-cyclohexenyl amino
acid 242. The amino acid could be obtained through a Claisen rearrangement of the Xxx
Scheme 47
248
247
244
245

56
glycinate ester 243 which could be synthesized from the biphenyl diol derivative 244.
This synthon is available either from direct biooxidation of the biphenyl precursor 245 or
through the coupling reaction between the aromatic boronic acid 246 and diol 247
derived from diimide reduction of the cis-diene diol 248 (Scheme 47).
The retrosynthetic strategy outlined above uses remarkable design elements that
deserve mention. 1) The C-ring of morphine can essentially be described as a
cyclohexenyl cfy-diol unit. This moiety can be recognized in the structure of the chiral
Scheme 48
ds-cyclohexadiene diol 248 with the correct absolute stereochemistry at C5 and C6 set as
a result of the enzymatic transformation (Scheme 48). 2) The approach capitalizes on the
recognition that the main backbone of the morphine skeleton consists of an oxidized
biphenyl unit 252 (Figure 4). This structural component, namely 244 (Scheme 47), is also
present in various alkaloids like pancratistatin the synthesis of which is being pursued in
the Hudlicky group. This unit could be obtained as outlined above either through direct
biooxidation of a biphenyl precursor or through the coupling of an aromatic boronic acid
with c/s-cyclohexadiene diol (Scheme 47). 3) The allylic alcohol unit present in diol 244
(Scheme 47) allows for the introduction of the amino acid side chain into the molecule
through a Claisen rearrangement. 4) Finally the Cl3 quaternary center could be

57
Figure 4. Synthetic targets with oxidized biphenyl unit.
established by utilizing the allylic alcohol moiety present in intermediate 254 via a
\ f
V
M = Zn
Scheme 49

58
second Claisen rearrangement. The amino acid 254 is also set up for closure of the C10-
Cll using a Friedel-Craft reaction after conversion of the acid into the aldehyde or the
acid chloride. Before the discussion proceeds into the actual execution of the approach, a
brief history about the development of the chemistry of enzymatic dihydroxylations
would be in order.
In 1968 as a result of studies conducted by David T. Gibson87 on the microbial
oxidation of aromatic hydrocarbons by soil bacteria, the first stable ds-diol 256 was
wild strain of P. putida FI
P. putida FI
CH,

,OH
P. putida Fl
X
o
toluene
dehydrogenase
Cl
256
*OH
cathechol
dehydrogenase
y^0H
Cl
257
acetate
P. putida F39/D
Scheme 50
isolated. The organism responsible for this transformation was a mutant strain of the
bacteria Pseudomonas putida (FI) and was designated Pseudomonas putida (F39/D).
This strain was devoid of the c/s-diol dehydrogenase enzyme hence only produced the
cis-diene diol 256 (Scheme 50). The use of these diols as synthons was initiated in the
late 1980s with work done by Ley88 and coworkers who achieved a racemic synthesis of
pinitol from meso-cis-diols derived from benzene. Since then, one of the leading
researchers in this area of chemistry has been Hudlicky who has been able to utilize the
O
cz's-diene-diols as chiral synthons in the synthesis of a wide variety of compounds
(Figure 5).

59
In 1988, in the first publication by Hudlicky and co-workers in this area, the idea
of Claisen rearrangements of the allylic alcohol unit of the c/s-diols was proposed. This
idea was actually reduced to practice in 1997 (pg 49-52, historical section) and thus
began the initial studies that featured the Claisen rearrangement as a key step in the
OH
D-c/jiVo-inositol
258
OH
pancratistatin r qh
7-deoxypancratistatin R = H
250
260
(-)-trihydroxyheliotridane
259
D-eryf/ira-spingosine
262
OH
narciclasine R = OH
lycoricidine R = H
251
kifunensine
261
OH
amino-inositol dimer
263
O
Figure 5. (Examples of Targets Synthesized from c/s-diols)
or
chemoenzymatic approach to the morphine skeleton.
In the first generation of this approach, conditions for a suitable Claisen
rearrangement that would lead to the transfer of stereochemical information inherent in
the cyclohexadiene-diols were investigated. The Kazmaier-Claisen rearrangement offered
the best conditions for this purpose. The goal was to synthesize p-amino acids of

60
different complexity bearing chiral side chains. Eventually such compounds would
contain the correct stereochemistry at the C9 and C14 (morphine numbering) centers of
morphine.
In the initial model studies, as reviewed in the historical chapter (pages 49-51), it
was discovered that even though the Claisen rearrangements proceeded with low
stereoselectivity, there was the potential to achieve complete control of the C9, C14
stereocenters through equilibration of isomers. Efforts in the initial stages of this
approach were also directed at finding efficient ways of obtaining the bicyclic skeleton
252 (Figure 4). One of the opportunities for construction of this bicycle was through
direct enzymatic dihydroxylation of substituted biphenyls. Indeed when selected
biphenyls were subjected to biooxidation conditions, the resultant diene diols were
obtained. Unfortunately it became apparent that as the degree of oxidation in the
substrate increased, the yield for the enzymatic process decreased considerably probably
Table 6. Results from Biooxidation of substituted biphenyls.
266 Rl = H, R2 = OMe
267 R1 = OMe. R2 = OMe
269 Rl = H, R2 = OMe
270 Rl = OMe, R2 = OMe
Subtrate Yield (g/1)
265
266
267
3.0
2.5
0.8

61
as a result of poisoning of the bacteria by the oxygenated substrate (Table 6). The low
yields that accompanied the biooxidation of 267 to diol 270 the morphine precursor
prompted us to seek other ways of constructing this bicyclic skeleton with the intent of
functionalizing it appropriately into the morphinan skeleton.
This dissertation will focus on the progress made in the second generation of the
chemoenzymatic approach to morphine. The discussion will address how control of the
C9 and C14 centers of morphine was achieved through the use of the Kazmaier-Claisen
rearrangement and epimerization. It will also give an account of the progress made
toward a formal total synthesis of morphine via Overmans intermediate. In addition
some applications in the field of matrix metallo proteinase inhibitors, compounds that are
connected to morphinan intermediates through common structural elements will be
discussed. Finally recent advances in the chemoenzymatic approach to morphine will
also be discussed.
First Generation Synthesis- Control of C9 and C14 Stereocenters of Morphine
The first few steps in the synthesis focused on the Suzuki Coupling protocol in the
synthesis of biphenyl diol derivative 270 (Table 6) which would then be functionalized
into a glycinate ester. Starting from guaiacol (271), a known compound, which is not
commercially available, we employed a procedure used by Hoshino83 and coworkers in
their synthesis of lycoramine. It involves first, the generation of a tert- butylamine
bromine complex by addition of bromine to the amine at -68 C for a 24 48 hour period.
After formation of the complex, which is the actual brominating agent, the reaction
mixture is cooled back to -78 C at which time a solution of guaiacol dissolved in
minimum amount of methylene chloride is added dropwise (Scheme 51). The reaction

62
typically gives a 50-60 % yield of bromogiuacol (150) in addition to two other
271
273
Scheme 51. Conditions: a) Br2, tert-butylamine, toluene, -78 C, 60-62 %; b) Mel,
K2CO3, Acetone, rt., 90-94 %; c) Mg, I2 (cat.), B(OEt)3, NH4C1 (satd), 80-85 %; d) t-
BuLi, B(OEt)3, NH4CI (satd), 77-80 %.
regioisomers. Isolation of bromogiuacol from the reaction mixture is achieved by
Kugelroh distillation. The next step involved methylation of the phenol with methyl
iodide in acetone, employing potassium carbonate as the base. These reactions typically
gave a 90-94 % yield of the dimethyl bromocatechol. In the next step the 1,2-
dimethoxybromobenzene (272) was converted into the corresponding boronic acid (273).
The boronic acid was obtained by using either Grignard conditions or lithium halogen
exchange with r-butyllithium. The Grignard conditions gave better overall yields.
The other coupling partner became available from diimide reduction of the chiral
cyclohexadiene diol 248, with potassium azodicarboxylate (PAD). This procedure, which
has been optimized in the Hudlicky group, typically gives about 90-95 % of the reduced
product 247 (Scheme 52). We also synthesized the boronic acid derived from vinyl
bromide 247 with the intent of coupling it with 1,2-dimethoxybromobenzene 272
(Scheme 52). Conversion of acetonide 274 to the boronic acid 275 proceeded with low

63
yields (45-50 %) hence making this route
to the coupled product unfavorable.
Scheme 52. Conditions: a) PAD, HOAc, MeOH, 0 C-rt 14 h, 90 %; b) DMP, Acetone,
TsOH, 95%; t-BuLi, B(OEt)3, -78C, NH4C1 (satd), 45-50 %.
We now turned our attention to the Suzuki Coupling81'82 step, a technique which has
become one of the more efficient methods of bond formation between an aromatic ring
and an sp2 center. In our hands typical conditions involved the use of tetrakis
triphenylphosphine palladium (Pd(PPh3)4) as the catalyst and a benzene/ ethanol solvent
system with 2M Na2C03 as the base. The reactions were normally complete after three
hours under reflux conditions. Yields were in the 75-80 % range and this was very crucial
since the Suzuki coupling was one of the key steps in our synthesis (Scheme 53).
Scheme 53. Conditions: a) 0.03 % eq. Pd(PPh3)4, 2M Na2C03, 247, PhH-EtOH, reflux;
b) 0.03 % eq. Pd(PPh3)4, 2M Na2C03, 274, PhH-EtOH, reflux; c) H\ THF.

64
Claisen I-First attempt of Kazmaier Claisen on Morphine Precursor
To perform the Claisen rearrangement, we planned to take advantage of the remaining
allylic alcohol unit in the bicyclic intermediate 270. In order to ensure selective
conversion of the proximal hydroxyl group into the glycinate ester we first had to protect
the distal hydroxyl group as its silyl ether. The thexyldimethylsilyl (TDS) group was well
suited for our substrate because its bulky nature ensures the protection of the least
hindered hydroxyl group, which in this case is the distal hydroxyl. Yields for the step are
typically around 90% for TDS-ether 276. Less bulky silylating groups like TMS-C1 tend
to lead to a large percentage of product resulting from lack of selectivity in the protection
of the distal and the proximal hydroxyl groups. The reaction involves first, generating the
imidazole-TDS complex at -12 C followed by addition of the diol (270) to the reaction
mixture. Our efforts led to isolation of silyl ether 276 (Scheme 54). The next stage in the
synthesis required the functionalization the proximal hydroxyl group as a glycinate ester,
Scheme 54
277

65
the Claisen rearrangement precursor. One of the standard procedures for achieving this
type of transformation involves a DCC coupling.75 In our hands the DCC coupling
conditions worked well with Boc-glycine, DCC and catalytic DMAP. Yields ranged from
70-85%. Careful workup of the reaction mixture, which requires removal of the reaction
solvent (CH2CI2) followed by precipitation of the dicyclohexylurea by-product with
diethyl ether a procedure which usually removes about 80 85% of the dicyclohexyl urea
(DCU) by-product. Column chromatography is then used to purify the crude mixture.
With the glycinate ester 277 in hand we were ready to perform what would be the key
step in our approach to morphine. A [3.3] sigmatropic rearrangement to establish the
chiral centers at C9 and C14 (morphine numbering). As previously discussed, the
Kazmaier-Claisen rearrangement provided the best opportunity to perform this
transformation. The conditions involve the addition of Lewis acid (usually ZnCL) to a
OMe
BocHN
OMe
LDA (2.2 eq.)
ZnCl-, (1.2 eq.)
Scheme 55
70
30
solution of the glycinate ester in THF. After about 15 minutes of stirring the reaction
mixture is cooled to -78 C and the base (usually LDA) is added. The reaction mixture

66
then allowed to warm slowly to room temperature over 36-48h. According to Kazmaier,
the rearrangement usually occurs between -10 0 C. In our hands we observed very
good conversion of starting material to products, with yields of rearranged acids
averaging between 75 85% but there were two significant problems. 1) The ratio of the
rearranged products 278a and 278b were opposite to that expected. We anticipated the
product with a syn relationship between the proton at C14 and the nitrogen at C9 to be
the major product. 2) The two rearranged acids possessed very similar spectroscopic
properties so initially it was difficult to ascertain the identity of the isomers. 3) These
compounds were virtually inseparable using standard chromatographic techniques even
after their derivatization into the corresponding methyl esters.
The fixed enolate geometry that results from chelate formation in the Kazmaier-
Claisen rearrangement causes the stereochemical outcome of the rearrangement to be a
function of the transition state that the reaction proceeds through. For cyclohexyl
substrates the unfavorable steric interactions in the chair transition state (Figure 3)
chair
Boat
R = 2,3-dimethoxyphenyl
Figure 6. Chair vs boat transition states in the Kazmaier Claisen Rearrangement of
morphinan intermediates.
the cyclohexyl ring and the metal chelate, causes this transition state to be less preferred
to the boat transition state, which is devoid of such interactions. It is very important to

67
note that Robert Ireland89'90 who performed rearrangements on silyl ketene acetal
analogues of these compounds, observed that both transition states could operate
depending on the size and position of the substituents on the cyclohexyl ring. The effect
of the large THS group can be neglected, but considerations of the dimethoxy phenyl
substituent, which is in the a-position to the allylic carbon, reveals that in the boat
transition state this substituent might have an unfavorable steric interaction with the
solvated metal (Figure 6). This leads to two steric arguments; 1) in the chair transition
state there is an unfavorable interaction between the solvated metal and the cyclohexyl
ring, 2) in the boat transition state the steric interactions are between the aromatic ring
substituent and the solvated metal. As a result of these opposing steric interactions, the
energy difference between the two transition states is very small, leading to product
formation from both pathways. In our case the chair transition state is favored resulting
in 70: 30 ratio of products.
As previously stated the rearranged acids 278a and 278b had similar
spectroscopic properties, and they were virtually inseparable by standard
chromatographic techniques. One of the options we explored to obtain pure samples of
each was to derivatize these acids into the corresponding lactones, which would offer a
more rigid structure with the anticipation that this might help in the identification of the
acids. This transformation was achieved with tosic acid in anhydrous methylene chloride
resulting in the formation of the corresponding lactones from the mixture of the epimeric
acids (Scheme 56). Even though two possible lactones could have been obtained from
this reaction we only observed the lactone derived from the trapping of the benzylic
carbocation. Indeed in this way we were able to obtain dimethoxy phenyl lactone 279 in

68
pure form and were able to obtain spectral data for the compound. Lactone 280 was also
Scheme 56
TsOH,
CH2CI2 anh.
isolated and easily converted to lactone 279 through an epimerization reaction with DBU.
The data obtained was compared to phenyl lactone 281 which had been synthesized
earlier and whose identity had been confirmed by X-ray crystallography.
Friedel Craft-Attempt at C10-C11 Closure
Even though we were unable to separate the two epimeric acids 279a and 279b
we saw an opportunity to study the feasibility of the C10-C11 bond (morphine
numbering) closure, through a Friedel-Craft type reaction. We had conflicting literature
precedence for this transformation. Ginsburg3fi was able to close the C10-C11 bond under
acid conditions from the intermediate acid 282. Although Ginsburgs intermediate
contains the same bicyclic skeleton as in our example, his compound is much simpler and
essentially has only one more functional group, the ketone at C5 (morphine numbering).

Ginsburg
Mulzer
Scheme 57
Using hydrofluoric acid he was able to achieve the Friedel-Craft annulation, to
obtain the desired diketone 33. Mulzer, in his morphine synthesis, made intermediate
126 which also contained the bicyclic unit comprising the A and C-rings of morphine and
essentially resembles that of Ginsburg, with the exception of the presence of the
dimethylamido group resulting from a prior Eschenmoser-Claisen rearrangement step.
Mulzer was not able to achieve annulation of the B-ring on the aldehyde upon treatment
with various Lewis acids (Scheme 57). With these two contrasting results it was difficult
to make any predictions as to the outcome of our attempts at B-ring closure. Starting from
acid 278, we derivatized it as the acid chloride using three different conditions.
Scheme 58

70
Initially we used thionyl chloride as the reagent for this transformation. We realized that
these conditions (Scheme 58) were too harsh because we observed cleavage of the thexyl
and Boc- protecting groups and or decomposition of the starting material even before
addition of the Lewis acid. We saw no evidence of cyclized product (283) in the reaction
mixtures and hence decided to resort to milder conditions for synthesizing the
intermediate acid chloride. The conditions that we decided to work with involved either
making the acid chloride by using oxalyl chloride/DMF or PPlvj/CCL using conditions
analogous to that used by Rapoport91 in his synthesis of tylophorine. Starting from acid
278, we used a combination of oxalyl chloride and DMF to generate the acid chloride.
Typically after four to six hours, we observed disappearance of the OH-stretch of the acid
and appearance of a strong signal at 1780 corresponding to the acid chloride. At this point
the Lewis acid was added and the reaction refluxed overnight. The various Lewis acids
employed were AICI3, Me2AlCl, ZnC^ and SnCU. The reactions typically after workup
led to recovery (Scheme 59) of starting material and a small percentage of by-product due
to cleavage of the Boc-protecting group. The results from the triphenyl phosphine/carbon
tetrachloride reaction were similar to the oxalyl chloride/ DMF reaction, here too no
product from closure of the CIO- Cl 1 bond was isolated. Mulzer25 in his discussion of his
attempt at the Friedel-Craft reaction suggested that there might be a phenomenon similar
to that of atropoisomerism of biphenyl compounds present in these types of substrates.
This being the case our A-ring may be twisted out of conjugation with the cyclohexenyl
ring making a Friedel-Craft type closure very difficult. The solution to this problem will
be to either make the furan ring of morphine or to establish the nitrogen bridge first. This
might help to hold the aromatic ring in a more preferable conformation that would allow

71
for a successful Friedel-Craft closure.
Scheme 59. Conditions: a) Oxalyl chloride, DMF, CFLCL; b) PPh3, CCI4, THF; c) Lewis
acid (AICI3, MejAlCl, ZnCU and SnCU).
Claisen II-Ireland Claisen on Phthalovl Ester
Our goal still remained to improve the selectivity of the Kazmaier Claisen
rearrangement. One of the options we had not explored was a sigmatropic rearrangement
zc on nrv
under Ireland conditions, which we hoped might lead to an improvement in the
ratio of rearranged epimeric acids. To attempt the Ireland-Claisen rearrangement, we first
functionalized the silyl ether 276 into the phthaloylester 285 (Scheme 60). Under Ireland
conditions, we observed good conversion of starting ester to products but the product
ratio again favored the undesirable epimer 286a. More importantly, the epimers were also
difficult to separate by column chromatography.

72
Scheme 60
At this point we reevaluated our synthetic approach to alleviate the
stereoselectivity problem in the Kazmaier-Claisen rearrangement. We rationalized
Scheme 61

73
that the source of the problem might be adverse steric interactions between the aromatic
substituent and the metal chelate (Figure 6, pg 67). Our immediate solution to this
problem was to attempt the Kazmaier-Claisen on the cyclohexenyl gylcinate ester 290,
which has a bromine substituent in the a-position to the allylic carbon. Such a substrate
would posses a much minor steric interaction in the boat transition state between the
solvated metal and the ring substituent (as discussed on pg 67) leading to a much
improved product ratio. This also meant that the Suzuki Coupling step, which had
previously preceeded the Claisen rearrangement, would now be performed after the
rearrangement. Our new general retrosynthetic scheme would be as represented by
Scheme 61.
Claisen III-Kazmaier Claisen of Glycinate of Cvclohexadiene Diol
Starting from diol 247 we were able to protect the distal hydroxy group as the
thexyldimethylsilyl ether 291. Using DCC coupling protocol we obtained the glycinate
ester 292. We were now in a position to perform the Kazmaier Claisen on the precursor
THS-C1, Imid.
DMF, -8 C
NHBoc
Scheme 62
292. Using 2.2 equivalents of LDA and 1.4 equivalents of ZnCU we were able to obtain
rearranged product epimeric at C9. We observed the yields for the transformation
increase from 75% to 80-85%; the ratio of the rearranged acids epimeric at C9 also
decreased slightly from a 70: 30 ratio to a 60: 40 ratio in our favor. But the best aspect of

74
this reaction was the fact that these epimeric acids, converted to their corresponding
methyl esters could be separated by silica gel column chromatography. More importantly
the faster-eluting major isomer 289a could be equilibrated to the (3-isomer (the desired
epimer for our morphine synthesis) by an epimerization reaction with DBU. Starting
from isomer 289a, we are able to obtain a 1: 1 mixture of epimers after 96 hours in
refluxing THF. Similar epimerization reactions with TFA and NaOMe gave a 4: 1 and 5:
1 ratio of epimers respectively. Even though the reaction is still non-stereoselective, we
had found a way to obtain the epimer with the correct stereochemistry at C9 and Cl4.
This was a huge breakthrough in our synthetic approach because it meant that we now
had the opportunity to carry out an enantioselective synthesis of morphine.
c
Scheme 63. Conditions: a) LDA (2.2 eq.), ZnCU (1.4 eq.), THF, -78 C, 80%; b) CH2N2,
Et20, 90%; c) DBU, THF, reflux, 65%.
We had also achieved control of the C9 and C14 (morphine numbering) stereocenters,
which is very crucial to a successful morphine synthesis.
During this period of time we entered into a collaborative project with scientists at
Procter and Gamble Pharmaceuticals who were interested in compounds to be used as
scaffolds in their matrix metallo proteinase (MMP) inhibitors studies. Dr. Hudlicky
recognized structural similarities between their targets (hydroxamic acids with an R-

75
configuration at the a-center of the amino acid) and some of the compounds synthesized
from the Kazmaier Claisen rearrangement during the morphine synthesis model study.
TDSO
293
Figure 7. Structure of morphine precursor used in initial MMP screen.
To our surprise, ester 293 as a mixture of R and S-isomers at a-center of the amino acid
side chain showed MMP inhibition. This led to the initiation of the collaborative project
with Proctor and Gamble Pharmaceuticals where the goal was to synthesize esters of the
type 293 to be evaluated for biological activity as MMP inhibitors. This was a great
opportunity because it gave us the occasion to apply our chemistry to industrial scale
projects. The next section will describe some of the efforts made in the synthesis of
matrix metallo proteinase inhibitors in a collaborative effort with researchers at Procter
and Gamble Pharmaceuticals.
Synthesis of Matrix Metalloproteinase Inhibitors (MMPs)
Researchers at Procter and Gamble have been exploring the synthesis of unnatural
amino acids to be used as scaffolds in the preparation of potent matrix metalloproteinase
inhibitors (MMPs).9295 MMP inhibitors have shown activity as antagonists of various
diseases where tissue remodeling plays a key role,96 including osteoarthritis,97'98
rheumatoid arthritis,99 tumor metastasis,100 multiple sclerosis101 and conjective heart
failure.102 The structural features of their target, resembled ester 289a which interestingly

76
was the undesired isomer from the Kazmaier Claisen rearrangement (Scheme 63).
Scheme 64
We prepared a series of cyclohexylglycine and cyclohexylalanine derivatives of the type
296 and 303 (Scheme 64) to be utilized as intermediates for the synthesis of MMP
inhibitors. Also as part of the collaborative project, the absolute stereochemistry of ester
289a was determined unambiguously by X-ray crystallography (Figure 7). Esters 296 and
303 were synthesized using similar protocol as has been described earlier in the chapter.
Approaches to compounds of this type through enolate alkylation or aldol type
condensations are quite difficult, hence the Kazmaier Claisen provides a direct route to
these unnatural amino acids with control of stereoselectivity and respectable yields.
Starting from the diol 247, a two step sequence involving protection of the distal
hydroxyl group as the TBS-ether, followed by esterification of the proximal hydroxyl
group by DCC coupling rendered gylcinate ester 292 (Scheme 65). We achieved the
rearrangement to the corresponding acids via Kazmaier Claisen conditions.
Diazomethane was then utilized in the conversion of the acids to the methyl ester
derivatives. The next step involved reduction of the vinyl bromide with Adams catalyst
at 40 psi with triethylamine as the proton scavenger. Finally tetrabutyl ammonium
fluoride mediated deprotection of the TBS group rendered the alcohol 296 which

77
underwent other proprietary transformations before being used in MMP testing. Because
297
Scheme 65. Conditions: a) TBS-C1, imidazole, DMF, -12 C, 85%; b) DCC, DMAP, N-
Boc-glycine or A-Boc-alanine, CH2CI2, 80%; c) ZnCb, LDA, THF, -78 C, 75%; d)
CH2N2, Et20, 90%; e) H2/Pt02 (40 psi), Et3N, MeOH, 75%; 0 Bu3SnH, AIBN, PhH.g)
TBAF, THF, 80%.
of the success of the Claisen with the glycine ester, we planned to prepare sulfonamide
299 through a DCC coupling reaction with TBS-ether 298 and the alanine moiety already
functionalized as the sulfonamide. This reaction proved unsuccessful, hence we prepared
ester 301 and following the removal of the Boc protection group, were able install the
sulfonamide to obtain 299. The Kazmaier Claisen rearrangement of 299 to 300 worked
smoothly as in the case of the glycine ester (Scheme 66) even though yields were lower
probably due to the lower chelating potential of the sulfonamide as compared to the
carbamate in structure 292. The synthesis of 300 also did not proceed with the same

78
diastereoselectivity as in the earlier cases presumably because of the increased size of the
sulfonamide functionality leading to a decrease in preference for the chair transition
Scheme 66. Conditions: a) alanine N-sulfonamide, DCC; b) N-Boc alanine, DCC; c)
TFA, CH2CI2; d) 4-methoxy-l,l-biphenylsulfonyl chloride, Et3N, THF; e) ZnCE, LDA,
THF, -78 C; f) CH2N2, Et20; g) H2 (40 psi), Pt02, Et3N, MeOH; h) TBAF, THF.
state. Even so, acids 300 were converted over three steps to methyl esters 303, the
precursors for MMP inhibitors. One of the more difficult steps in this project was the last
Scheme 66. Conditions: a) H2 (40 psi), 5% or 10% Pd-C, MeOH; b) H2 (40 psi), Pt2,
Et3N, MeOH.

79
step involving the removal of the vinyl bromide through hydrogenation. Initial attempts at
this transformation utilized 10% and 5% Palladium on Carbon (Pd/C) at 40 psi in
methanol. Even though this resulted in the removal of the vinyl bromide it also resulted in
hydrogenolysis of the silyl ether leading to the isolation of ester 304. Even though ester
304 was devoid of the hydroxyl group, the hydroxamic acid derivative this compound
surprisingly showed some activity as an MMP inhibitor. After investigating several other
conditions we discovered that using Adams catalyst (Pt2) in methanol at 40 psi with
Table 7. MMP inhibition activity for glycine and alanine analogs.
o,
yOH
YH Br0<
Yh
o
-K
o
X
HO*'
a
"T'nhr ^
ho'
xH, o-U
'4'NHR
ho'
r^V'T'NHR
j Me
IC50 (nM)a
305
306
307
308
MMP-2
12
20
38
251
MMP-3
1,220
2,490
3,795
6,150
MMP-13
30
176
131
338
triethylamine as a proton sponge works nicely leading to isolation of the silyl ether 295 in
89% yield.
With the completion of the collaborative project, we turned our attention back to
morphine synthesis; we now had a stereospecific way of obtaining the methyl ester 289b

Figure 8

81
(Scheme 60). The next step involved the coupling of the methyl ester with an aromatic
boronic acid to obtain our crucial bicyclic intermediate 242 using the Suzuki conditions
that by now had been optimized for the morphine project (Scheme 49, pg 57).
Second Generation Synthesis- Overmans Intermediate via Claisen Rearrangement
In this section the efforts towards synthesizing the Overman53 intermediate 95 (pg
21-22, Chapter 1) are described. The target was chosen for two main reasons, first the
synthesis of the Overman intermediate would allow us to achieve a formal total synthesis
of morphine since dihydrocodeinone (88) was synthesized in three steps from the
Overman intermediate. Also, after coupling ester 289b with an appropriate aromatic
piece this bicycle would possess all the functionality needed to achieve the synthesis of
the Overman intermediate. Retrosynthetically our goal was to arrive at the Overman
intermediate through a Friedel-Craft102'103 reaction on acid 309. Even though our earlier
Scheme 68

82
attempts at the Friedel-Craft reaction were unsuccessful we were hopeful that with the
construction of the nitrogen bridge, this precursor would have a more rigid structure with
the aromatic ring in a favorable position to effect cyclization (path y, Scheme 68). The
key step in this synthesis would be the setting of the Cl3 quaternary center by a [3,3]-
sigmatropic rearrangement. The options available were an Ortho-ester Claisen104105
rearrangement or an Eschenmoser106,107 type Claisen rearrangement using the allylic
alcohol moiety in precursor 310 (path x, Scheme 68). Alcohol 310 could in turn be
synthesized through a Mitsunobu108, reaction of alcohol 311. Compound 311 could be
achieved from a two-step sequence involving a Suzuki reaction to couple the methyl ester
and the aromatic boronic acid followed by a fluoride deprotection of the silyl ether.
Boronic acid 313 was synthesized (Scheme 69) using the same protocol that was used for
the synthesis of the dimethoxy boronic acid 273 (pg 61) with similar results in terms of
yield. With boronic acid 313 in hand we were able to achieve coupling with ester
B(OH)2
,OBn
OMe
313
Scheme 69. Conditions: a) Br2, tert-butylamine, toluene, -78 C, 60-62 %; b) BnBr,
K2C03, Acetone, rt 90-94 %; c) Mg, I2 (cat.), B(OEt)3, NH4C1 (satd), 82-86 %; d) t-
BuLi, B(OEt)3, NH4C1 (satd), 75-80 %.

83
289b to obtain the bicycle 312. The following reactions were performed on the 2,3-
dimethoxyphenyl and 2-benzyloxy-3-methoxyphenyl analogs as shown in Scheme 70 but
the description of the process will focus on the benzyl-protected analog. To ensure the
correct regio-chemistry of the Claisen rearrangement we proceeded to invert the alcohol
at C6 (morphine numbering). This process began with a tetrabutyl ammonium fluoride
THSO
CO,Me
NHBoc
289b
320 R = Me
316 R = Me
C02Me
C02Me
NHBoc
314 X = Bz, R = Bn
318 X = Bz, R =Me
310 X = H, R = Bn
319 X = H, R = Me
317 R = Me
321 R = Me
Scheme 70. Conditions: a) 0.03 % eq. Pd(PPh3)4, 2M NajCCb, 313, PhH-EtOH, reflux; b)
TBAF, THF; c) DEAD, PBu3, BzOH, THF, -10 C rt; d) K2C03, MeOH.
(TBAF) deprotection of the thexyldimethylsilyl group to give alcohol 311. The free de
faced alcohol was then inverted with a Mitsunobu108'109 reaction (Scheme 70) using

84
tributylphosphine, benzoic acid and DEAD (diethyl azodicarboxyl ate). The benzoate thus
formed was hydrolysed easily with K2CO3/ MeOH to obtain the inverted free alcohol
310. With alcohol 310 in hand the next step was to attempt the Orthoester Claisen
rearrangement. Typical conditions involve in-situ formation of the orthoester followed by
subsequent acid catalyzed rearrangement at temperatures ranging from 160 C to 180 C.
Using a combination of triethyl orthoacetate and catalytic amounts of propionic acid we
attempted the Orthoester Claisen using three different solvent systems (Scheme 71). The
reactions were run either in neat triethyl orthoacetate, xylenes or in toluene. The results
obtained were quite consisitent in all three solvents. The product of the attempted
orthoester-Claisen rearrangement was a compound resulting from cleavage of the ortho
ester intermediate and subsequent trapping of the resultant allylic cation by our amine
Scheme 71. Conditions: a) i) triethylorthoacetate, propionic acid (cat.) 160C-180C; ii)
triethylorthoacetate, propionic acid (cat.), xylenes, 160C-180C; iii) triethylorthoacetate,
propionic acid (cat.), toluene, 160C-180C.

85
functionality. We suspect that thermal and/or acid catalyzed decomposition of the
carbamate protecting group leads to the free amine, which then traps the allylic cation. In
the first generation synthesis (pg 68) we used the cleavage of the C-0 bond (at C6
morphine numbering) to our advantage in determining the identity of our rearranged
acids through a lactonization reaction. Unfortunately in this case it was a significant
problem because cleavage of the ortho ester always occurred before any potential
rearrangement and so we were unable to proceed further with this route towards
Overmans intermediate. The identity of the orthoester-Claisen product was obtained
using NMR experiments namely GHMQC and HETCOR. The sequence 5-6-7-8-14-9
6.88
(morphine
Figure 9. Assignment of Orthoester Claisen product.
numbering) was seen by the DQCOSY spectrum (HI- HI correlation) as CH-CH-CH2-
CH2-CH-CH-. The aryl group was confirmed to be in position 13 by the long range
couplings H( 11 )-C( 13) and H(5)-C(12) as seen in the GHMBC spectrum. The methyl
ester was confirmed to be in position 9 by the cross-peak H(9)-C(CO). With these
correlational experiments the molecule was assembled with the exception of the two open
valencies at C6 and C9. The carbon chemical shifts of the atoms suggest that they are

86
bonded to the nitrogen atom. This molecular formula was further confirmed by HRMS.
From these correlation experiments the proton and carbon signals were correctly assigned
as shown in Figure 9. From long range coupling experiments, the connectivity of our
molecule was confirmed when we observed a long range coupling between the proton at
C6 (morphine numbering) whose signal appears at 4.91 ppm and the proton on the a-
center of the amino acid (C9 morphine numbering) whose signal appears at 4.06 ppm.
This was further confirmed by a long-range H- C coupling between the proton signal at
4.91 ppm and the carbon signal at 59.6 ppm, which belongs to the carbon at the a-center
(C9 morphine numbering).
Since we now had alcohol 311 in our possession, we reasoned that we could still
establish the C13 quaternary center by employing a conjugate addition of an
Scheme 72. Conditions: a) PCC, CH2C12; b) (H2C=CH)2CuMgCl, THF, -78C.
organocuprate with the enone obtained from oxidation of the alcohol. Alcohol 311 was
subjected to PCC oxidation conditions to obtain enone 326. Upon addition of a vinyl
cuprate, no 1,4 addition product was isolated. The major product of the reaction was the

87
1,2-addition adduct 327. It is our suspicion that because this bicyclic compound
Figure 10. Possible atropoisomerism of morphinan intermediates
exhibits atropoisomerism, the aromatic ring is twisted out of conjugation with the
cyclohexenyl ring (Figure 10). This probably causes the aromatic ring to be perpendicular
to the cyclohexyl ring so any substituent in the 2-position of the aromatic ring (benzyl in
this case) sterically hinders any attack to the C13 center.
In summary our attempt at the Overman intermediate failed because of two main
problems. The first problem, which was encountered in the orthoester-Claisen, is a trend
that we had observed earlier in the synthesis (Scheme 56, pg 68) and used to our
advantage. The C6 (morphine numbering) position easily ionizes if any good leaving
groups are present because of the stability of the resultant allylic carbocation which is
resonance stabilized by the aromatic ring. Under catalytic or stoichiometric acid
conditions, the orthoester intermediates are cleaved either through an SNl or an Sn2
mechanism to yield products of the type 322. The second problem is of a steric nature,
cuprate addition to the Cl3 (morphine numbering) center led to recovery of 1,2-addition
products exclusively. Mulzer25 in his synthesis of morphine encountered the same
problem in his attempt at conjugate addition to a similar substrate (Scheme 73). Initial
model studies were successful at establishing what would be the Cl3 center by cuprate
addition. When the same reaction was applied to more advanced intermediates 123 and

88
329 the conjugate addition yielded only 1,2-adducts. 'H-NMR spectra of Mulzers
intermediates demonstrated the presence of atropoisomers and this led to his assumption
that these intermediates exhibited atropoisomerism. In our case high temperature 'H-
NMR experiments were inconclusive because even though we observed the presence of
two isomers it was impossible to determine whether the isomerism was from the
carbamate moiety or due to atropoisomerism. The result of the atropoisomerism is that
the aromatic
residue becomes more or less pependicular to the double bond hindering any attack on
the benzylic sp2-hybridized carbon.

89
Alternative methods to Setting the C13 quaternary center.
At this point we had to assess the route to establishing the C13 quaternary center.
We still had a couple of options available to achieve this task. The first option was to
take advantage of some of the inherent properties in intermediate 311 to establish the C13
center. If indeed our assumption was correct and alcohol 311 (Scheme 70) was prone to
exhibit atropoisomerism, then a tether at the 2-position of the aromatic ring becomes a
very important group. The effect of the atropoisomerism would essentially position the
tether at the 2-position of the aromatic ring in a desirable position to effect either radical
or nucleophilic attack of the C13 carbon. If the attack at C13 comes from the p-face of
the molecule, this synthesis would eventually lead to morphine. An attack
Claisen
MeO
CO,Me
Figure 10. Strategy for establishment of C13 quaternary center.

90
from the a-face would lead to enr-morpnine. The second option would be to attempt the
C13 attack from the amino ester side chain either through a palladium catalyzed SN2
reaction or a radical type attack.
Before applying the alternate routes to the establishment of the C13 center to the
morphinan intermediates we decided that a quick model study to ascertain the feasibility
of these reactions would be in order. We prepared enone 340 and silyl ether 343 as shown
in Scheme 74 from phenol and 1,3-cyclohexadione (337). Cleavage of the MOM
Scheme 74. Conditions: a) MOM-C1, NaH, THF; b) EtOH, pTsOH, PhH; c) t-BuLi,
THF; e) H+/THF; f) Bromoacetylbromide, DMAP, CH2C12; g) nBu3SnH, ALBN, PhH; h)
NaBH4, MeOH; i) TDS-C1, imidazole, DMF.

91
protecting group from the bicycle 339 afforded the intermediate alcohol, which was
converted to the bromoacetate 340 the radical cyclization precursor. Silyl ether 343 was
obtained from intermediate 342 after cleavage of the MOM-protecting group and
subsequent appendage of the bromoacetate. The two bromoacetates were then subjected
to radical conditions using a protocol previously used by Ogasawara60 and coworker in
their synthesis of 3,4-dimethoxy-7-morphinanone (pg 39, Ch. 1). The radical reaction
failed to produce any cyclized product in the case of silyl ether 343. Instead we observed
the formation of the reduced product exclusively. This was not unexpected due to the fact
that for that cyclization to work the reaction had to proceed from a stablilized ester
radical to an unstable radical. On the other hand enone 340 subjected to the same
conditions yielded the cyclized product 341 in 66% yield with recovery of about 15% of
reduced product. With the success of the model study our attention focused on its
application to the morphine synthesis.
Our goal was to achieve the synthesis of intermediates of the type 345 or 347
347 348
Scheme 75

92
(Scheme 75) in order to apply our model study to real morphinan intermediates. A
successful radical closure would lead to the establishment of the C13 quaternary center;
this would be followed by a translactamization reaction after deprotection of the Boc-
group to establish the nitrogen bridge as shown in Scheme 75.
The first order of business was to redesign our aromatic ring with a protecting
group in the 2-position that could be cleaved readily to allow for the appendage of the
bromoacetyl group. The first protecting group we worked with was the TBS-group.
Bromoguaiacol 150 was readily converted to the TBS ether using triethylamine, DMAP
and TBS-C1. Unfortunately in the next step that involved the lithium halogen exchange
and alkylation using triisopropyl borate, we realized that the TBS-group was too bulky
Br Br
150 350 351
Scheme 76. Conditions: a) TBS-C1, Et3N, DMAP, CH2CI2; b) B(Oipr)3, H+
hence preventing the subsequent alkylation step. The only material isolated from the
reaction was starting material and the reduced product 351 (Scheme 76). We were able to
confirm the formation of the anion using deuterium exchange experiments. So we
realized that the problem lay in the alkylation step. The next protecting group considered
was the paramethoxybenzyl group (PMB). This was in theory an ideal protecting group
for our synthesis because we had prior experience (in our approach to the Overman
intermediate, Scheme 69, pg 83) on the synthesis of the benzyl protected boronic acid and
reasoned that the synthesis of the PMB boronic acid would be analogous. Most
importantly this group could be cleaved with DDQ, which in our estimation would not

93
affect any of our chiral centers or other protecting groups. Using K2CO3 and acetone we
protected bromoguaiacol as the PMB ether. In the subsequent step we successfully
synthesized the boronic acid 353 using n-BuLi and triisopropyl borate.
c
Scheme 77. Conditions: a) PMB-Br, K7CO3, Acetone; b) n-Buli, B(oipr)3, H+; c) 0.03 %
eq. Pd(PPh3)4, 2M Na2C03, 289b, PhH-EtOH, reflux; d) DDQ, H20, CH2C12.
The Suzuki coupling of the boronic acid with methyl ester 289b (Scheme 77) worked
quite well to afford PMB ether 346. At this point we attempted cleavage of the PMB
group in order to append the bromoacetyl group on the phenol. Unfortunately this step
led mostly to decomposition of our starting material. With the failure of the PMB route
Br
150 271
Scheme 78. Conditions: a) n-Buli, B(oipr)3, H+;

94
we wondered if we could synthesize the boronic acid directly from bromoguaiacol. This
would give us a free phenol going into the coupling step and negate the need for a
protecting group. This reaction (Scheme 78) was not successful and resulted in isolation
of guaiacol 271 exclusively.
The MOM-protecting group was considered because of the ease of removal of the
group. Protection of bromoguaiacol as the MOM-phenoI proceeded smoothly as did the
step to make the boronic acid. Throughout this study of protecting groups we had
speculated about the possibility of performing the Suzuki coupling on the free phenol.
The Suzuki conditions require the use of 2M Na2C03 and the concern was whether the
alkoxide of the phenol would couple as effectively as the protected phenol.
Starting from the MOM-protected boronic acid 356, we were able to obtain the
Scheme 79. Conditions: a) TFA, CH2C12; b) 0.03 % eq. Pd(PPh3)4, 2M Na2C03, 289a,
PhH-EtOH, reflux; c) Bromoacetylbromide, DMAP, CH2C12; d) nBu3SnH, AIBN, PhH.
free phenol 357 with TFA in methylene chloride. The phenol was then coupled with
methyl ester 289b under Suzuki conditions (Scheme 79) leading to isolation of bicycle

95
358 albeit in a 45% yield. With the phenol in hand we were able to synthesize the
bromoacetate derivative using DMAP and bromoacetyl bromide in methylene chloride.
The radical reaction of bromoacetate 345 using the same conditions as was used in the
model study resulted in the formation of the reduced product 359. The synthesis of enone
347 proved to be more challenging than expected. Starting from phenol 358 we had two
options available. We could first alkylate the phenol as the bromoacetate and then remove
the silyl-protecting group followed by subsequent oxidation of the C6 (morphine
Scheme 80. Conditions: a) Bromoacetylbromide, DMAP, CFECF; b) TBAF, THF; c)
PCC or MnC>2 or Dess-Martin.
numbering) alcohol. Equally we had the option of initial removal of the silyl-protecting
group followed by oxidation to the enone and then final alkylation of the phenol to form
the bromoacetate. Preliminary evidence indicates the formation of a Finkelstein111 type
product in our attempt to cleave the silyl-protecting group in intermediate 345 in the
presence of the bromoacetate as shown in scheme 80. Conversely we had problems with

96
the oxidation of allylic alcohol 361 probably due to reaction of the oxidant with the
phenol. The yields for the oxidation step were very low (10- 15%) and so this route could
not be used to obtain decent quantities of the enone 362. Our final option was to first
form the enone from the vinyl bromide and then achieve coupling with boronic acid 357.
Indeed this worked quite well with the isolation of the enone 362. In the next step the
phenol was converted to the bromoacetate, which was then subjected to the radical
cyclization conditions. We are currently in the process of optimizing this reaction.
Scheme 81. Conditions: a) TBAF, THF; b) PCC, CFFCb; c) 0.03 % eq. Pd(PPh3)4, 2M
Na2CC>3, 289a, PhH-EtOH, reflux; d) Bromoacetylbromide, DMAP, CH2CI2; e)
nBu3SnH, AIBN, PhH;.

CHAPTER 4
CONCLUSION
Summary and Conclusions
In the course of this project we have been able to successfully apply a
chemoenzymatic approach towards morphinan alkaloids utilizing the Kazmaier Claisen
rearrangement and the Suzuki Coupling reaction to obtain advanced intermediates
towards morphine. Control of the C9 and C14 (morphine numbering) centers was
Br
C
247
OH
THS-C1, Imid.
Br
OH Gly-Boc. DCC
DMAP
OH
DMF, -8 C ^-^OTHS CH2C12
291
l.LDA,
NHBoc ZnCL.THF
=->-
2. CHjNj THS0'
C02Me
9 NHBoc +
Br
THSO
.s1'
289b
40
a
C02Me
NHBoc
DBU, THF
Scheme 82
achieved using a combination of Kazmaier Claisen rearrangement and epimerization
reactions (Scheme 82). We were also successful in applying this chemistry to the
synthesis of matrix metallo proteinase inhibitors (MMPs) in a collaborative project with
97

98
Procter and Gamble Pharmaceuticals (Scheme 83). Our most challenging endeavor has
Scheme 83
been the attempts at establishing the C13 quaternary center. In our approach to the
Overman intermediate we discovered the hindered nature of the Cl 3 carbon and also the
reasons for our unsuccessful Orthoester Claisen rearrangement. The problem can be
summarized as lability of groups at the C6 (morphine numbering) position and steric
hindrance at the Cl3 position due to what we suspect is atropoisomerism. We realized
that we had an opportunity to achieve functionalization of the C13 center from either a
tether on the 2-position of the aromatic ring or from the nitrogen side chain. Model
studies confirmed the feasibility of a radical closure from a tether on the aromatic ring
and the last part of the project has been dedicated to the synthesis of intermediates that
would allow for the establishment of the C13 center through this reaction.
There are still a few options available to achieve functionalization of the C13
center. We have yet to attempt either a palladium catalyzed SN2 closure or a

99
Reformatsky type reaction to establish Cl3. The morphinan intermediates allow for these
reactions to be attempted either from the nitrogen side chain or from a tether on the
phenol.
Establishment of the C13 center would be followed by a translactamization
reaction to afford the nitrogen bridged intermediate of the type 369. After a Friedel-Kraft
reaction this intermediate begins to look very similar (Scheme 86) to one of the Gates
intermediates 370 from which morphine was synthesized in an additional 7 steps.
Scheme 84
In the course of the project we have also looked at ways to make this approach to
morphine, practical. To this effect, we attempted the direct oxidation of intermediate 364
using a catechol dehyrogenase enzyme, which was recently discovered in the Hudlicky
research group. Success of such a transformation would eliminate 4 synthetic steps

100
Scheme 85. Conditions: a) 0.03 % eq. Pd(PPh3)4, 2M NaaCC^, 289b, PhH, reflux; b) E
coli pDTG 602, c) TBAF, THF;
from our synthesis. Unfortunately we ran into feasibility problems because the substrate
364 could not be dissolved in the aqueous media containing the bacteria even after
cleavage of the THS-group to give the alcohol 366. Even though this attempt was
unsuccessful our goal still remains; to arriving at a truly chemoenzymatic synthesis of
morphine (Scheme 85). It is still possible to arrive at compounds like 365 through an
initial biooxidation of the aromatic piece followed by Suzuki coupling reaction
NMeBoc
1. LDA,
TMSC1,
THF, 80%
2. CH2N2
Scheme 83
We have also synthesized the sarcosine ester 367 (Scheme 86) and performed the Ireland
Claisen rearrangement on this substrate with interesting results. Even though the

101
rearrangement is not stereospecific we are able to achieve epimerization from a 9:1
mixture favoring the wrong isomer to a 1:1 mixture. Such an intermediate would contain
the methyl group on the nitrogen and the intent is to prevent any problems we could
encounter later on in the synthesis with the glycine analog in terms of methylating the
nitrogen.

CHAPTER 5
EXPERIMENTAL SECTION
General Procedure
All non-hydrolytic reactions were carried out under a nitrogen or argon
atmosphere, with standard techniques for the exclusion of moisture. Glassware used for
moisture sensitive reactions was flame dried with an internal inert gas sweep. Analytical
TLC was performed on Whatman K6F silica gel 60A plates. Flash chromatography was
performed on chromatographic silica gel, 230-400 mesh (Fisher Chemical). Infrared
spectra were recorded on a Perkin-Elmer FT-IR (KBr). Proton, fluorine and carbon NMR
spectra were obtained on a Varian 300MHz spectrometer using CDCI3/ TMS unless
otherwise indicated in the experimental section or in the case of fluorine NMR spectra, a
CFCI3 standard was utilized. Proton chemical shifts are reported in parts per million
(ppm) relative to chloroform (7.24 ppm) or DMSO-4 (2.49 ppm). Carbon chemical shifts
are reported in parts per million relative to the central line of the CDCI3 triplet (77.0 ppm)
or the central line of the DMSO-/ septet (39.7 ppm). Coupling constants (7) are given in
Hz. Optical rotations were recorded on a Perkin-Elmer 241 digital polarimeter (10'1 deg.
cm g' ). Melting points were obtained on a Thomas-Hoover capillary melting point
apparatus. High resolution mass spectra and elemental analyses were performed at the
University of Florida and Atlantic Microlab Inc.
102

103
Experimental Procedures
3-(2,3-dimethoxvphenyl)-( 1 S,2R)-3-cvclohehexene-1,2-diol (270).
To a round bottom flask under argon atmosphere was added Pd(PPh3)4 (0.001
mol, 1.32g). This was followed by addition of 50 mL dry benzene. A solution of the
bromide 247 (0.040 mol, 7.40 g) dissolved in lOmL of ethanol was then added to the
reaction flask. This was followed by the addition of NaiC03 (36.00 mL, 2.00 M) to the
mixture. Dimethoxyphenyl boronic acid 273 (0.046 mol, 8.40g) was dissolved in 50 ml
of dry benzene was then added to the reaction mixture, which was allowed to reflux for
6h. The reaction was quenched with water and the product extracted with ethyl acetate (3
X 50 mL). The organic layers were combined, washed with brine and dried over
anhydrous MgS04. After filtration the solvent was removed, the crude product introduced
onto a silica gel column, and eluted with ethyl acetate:hexane (1:3) to obtain (7.10 g,
83%) white crystals of 270; mp: 66 67 C; Rf = 0.3 (ethyl acetate: hexane, 1:1); [oc]d20 -
62.9 (c 1.0, CHC13); 'H NMR (CDC13) 5: 7.0 (t, J = 17.7 Hz, 1H), 6.9 (d, J = 7.1 Hz, 1H),
6.8 (dd, J = 7.4, 0.8 Hz, 1H), 5.9 (t, J = 3.6 Hz, 1H), 4.4 (bs, 1H), 3.9-3.8 (m, 1H), 3.8 (s,
3H), 3.7 (s, 3H), 2.6 (bs, 2H), 2.3 (m, 2H), 1.9 (m, 2H); l3C NMR (CDC13) 5: 152.5,
145.8, 136.6, 135.8, 130.5, 124.5, 122.5, 111.6, 69.3, 69.0, 61.0, 55.8, 25.2, 24.2, ; IR
(KBr/ cm1): 1104, 1260, 1470, 1577, 2923, 3362; LRMS (Cl/ CH4) m/z (rel. intensity)
250 (m+, 100), 232 (35), 206 (93); HRMS Caled, for C,4H,804: 250.1205; Found:
250.1208. Anal. Caled, for: C,4H,804: C, 67.21; H, 7.20; Found: C, 66.62; H, 7.44.

104
6-(2,3-dirnethoxvphenvD-2-dirnethvlthexvsilvoxv-nR,2S)-5-cvclohexen-l-ol (276).
A solution of the diol 270 (0.720 mmol, 0.18 g) and imidazole (0.860 mmol, 0.15
g) dissolved in 0.50 mL of DMF was prepared in a dry round bottom flask under argon
atmosphere. The flask was cooled to -12 C and TDSC1 (0.860 mmol, 0.17 mL) added
with very slow stirring. The flask was stored at -18 C for 12h after which the solution
was diluted with ethyl ether and washed with brine. After separation the aqueous layer
was re-extracted with ethyl ether (2 X 20 mL). The organic layers were combined and
washed with a 10% CuS04 solution (3 X5 mL) to remove the imidazole. The organic
layer was finally washed with brine, dried over anhydrous MgS04 and the solvent
evaporated. The crude product was introduced unto a silica gel column and eluted with
ethyl acetate/ hexane (1: 99) to afford a yellow oil of the silyl ether 276 (0.25 g, 90%); Rf
= 0.7 (ethyl acetate :hexane, 1:4; [a]D32 59.3 (c 1.0, CHC13); *H NMR (CDC13) 5: 7.0 (t,
J = 7.2 Hz, 1H), 6.8 (d, J = 7.7 Hz, 2H), 5.9 (t, J = 3.6 Hz 1H), 4.4 (bs, 1H), 4.0 (dt, J =
10.2, 3.3 Hz, 1H), 3.8 (s, 3H), 3.7 (s, 3H), 2.6 (d, J = 4.1 Hz, 1H), 2.4 2.3 (m, 1H), 2.2 -
2.1 (m, 1H), 2.0 1.9 (m, 1H), 1.7 1.6 (m, 2H), 0.9 0.8 (m, 14H), 0.1 (d, J = 5.5 Hz,
6H); 13C NMR (CDC13) 5: 152.6, 136.3, 136.0, 129.7, 123.9, 122.4, 111.4, 70.8, 69.2,
60.6, 55.8, 34.2, 25.4, 24.9, 24.3, 20.4, 20.2, 20.1, 18.6, 18.5, 2.5, 2.9; IR (KBr/cm1):
3245, 2959, 1470, 1259, 1108, 1011. HRMS; C22H3604Si (M+l) Caled. 393.2383,
Found: 393.2479; Anal. Caled, for: C22H3604Si: C, 67.18; H, 7.25; Found: C, 67.20 ; H,
7.24 .

105
6-(2,3-dimethoxvphenvl)-2-dimethvlthexvsilvloxv-(lR,2S)-5-cvclohexen-l-vl-N-fert-
butoxycarbonvlglvcinate (211).
A solution of Boc-glycine (6.600 mmol, 0.16 g) and DMAP (catalytic) in CH..C1,,
(60 mL) was cooled to 0o C. DCC (9.000 mmol, 1.90 g) was added to the cooled mixture
resulting in a yellow precipitate. A solution of the TDS protected diol 276 (6.000 mmol,
2.20 g) in CHiCh was then added by syringe and the reaction mixture allowed to stir. The
solution was diluted with ethyl ether and filtered through a plug of silica gel to remove
the precipitate of dicyclohexylurea. Removal of the solvent followed by chromatography
(silica gel, ethyl acetate:hexanes, 1:9) the residue afforded the pure amino ester 277 (4.00
g, 71%) as a thick colorless oil; Rf = 0.4 ethyl acetate:hexane 80:20; Md'5 -74.0 (c 1.0,
CHC13); >h NMR (CDC13) 5: 6.9 (t, J = 7.9 Hz, 1H), 6.8 (dd, J = 8.2 Hz, 1H), 6.7 (dd, J
= 7.6 Hz, 1H), 5.9 (bs, 2H), 4.9 (bs, 1H), 4.1 (m, 1H), 3.8 (s, 3H), 3.7 (s, 3H), 2.2 2.1
(m, 2H), 1.9 (m, 1H), 1.7 -1.6 (M, 1H), 1.6 1.5 (m, 1H), 1.4 (s, 9H), 0.9 (d, J = 6.7 Hz,
6H), 0.8 (d, J = 3.7 Hz, 6H), 0.1 (d, J = 11.9 Hz, 6H); 13C NMR (CDC13) 5: 168.4, 155.2,
154.1, 150.2, 134.6, 130.8, 130.6, 129.0, 128.9, 119.8, 110.3,79.4,71.7,69.1,54.3,42.3,
34.2, 28.2, 25.0, 24.8, 24.4, 20.2, 20.1, 18.4, 18.3, -3.2; IR (KBr/cm1): 3443, 2931, 2105,
1643, 1470, 1366; HRMS: C29H48NO7S (M+) Caled. 550.5983, Found: 550.3197. Anal.
Caled, for: C29H47NO7S: C, 67.30; H, 9.24; Found: C, 67.13 ; H, 9.20 .

106
3-tert-butoxvcarbonvlamino-7a-(2,3-dimethoxyphenyl)-3S,3aS.7aS )-2,3,3a,4,5,7.7a-
hexahvdrofblfuran-2-one (279):
To the crude epimeric mixture of amino acids 278 (0.50 mmol, 0.30 g) was added
a catalytic amount of p-TsOH in CH,C1., (20 ml) and allowed t0 st¡r overnight. The
reaction mixture was diluted with ethyl ether and washed with NaHCOi solution (30 %, 2
X 10 mL). The organic layer was dried with MgS04 and the solvent evaporated under
reduced pressure. The lactone (279) was successively separated by column
chromatography via gradient elution (hexanes: ethyl acetate, 99:1 9:1) to yield white
crystals of A (0.10 g, 65 %); Rf = 0.5 (ethyl acetate: hexanes, 1:4); [Id 96.0 (c 1.0,
CHC13); 'H NMR (CDCI3) 5: 7.1 -6.9 (m, 2H), 6.8 -6.7 (m, 2H), 6.2 (m, 1H), 5.7 (dt, J =
10.0, 1.0 Hz, 1H), 4.9 (d, J = 5.7 Hz, 1H), 4.5 (dd, J = 7.9, 3.0 Hz, 1H), 3.8 (s, 3H), 3.7 (s,
3H), 3.3 (dtd, J = 11.5, 3.5, 1.0 Hz, 1H), 2.3 -2.2 (bm, 2H), 1.7 1.6 (m, 1H), 1.4 (s, 1H),
1.3 (s, 9H); 13C NMR (CDC13) 5: 174.9, 155.3, 153.4, 135.1, 132.5, 126.9, 123.6, 117.2,
112.9, 82.8, 80.3, 59.9, 55.8, 54.1, 42.9, 29.7, 28.2, 22.8, 20.5; IR (KBr/ cm1): 2932,
2253, 1776, 1716, 1506, 1475, 1263; LRMS (Cl/ CH4) m/z (rel. intensity) 389 (m+, 70),
334 (65), 228 (100); HRMS Caled, for C22H36NO6 (m+1) Caled.: 389.2464; Found:
389.5326. Anal Caled, for C23H35N06: C, 64.70; H, 6.90; Found: C, 64.36; H, 6.64.

i
107
6-(2,3-dimethoxvphenvl)-2-dimethvlsilvloxv-(lS.2R)-5-cvclohexen-l-yl-N-
phtholylglvcinate (285):
A solution of phthaloyl-glycine (1.40 mmol, 0.30 g), DCC (2.50mmol, 0.50 g),
DMAP (catalytic) in dichloromethane (10 mL/mmol) was cooled to 0 C and a solution
of the TDS protected diol 276 (1.20 mmol, 0.50 g) in dichloromethane (2 mL) was added.
The cloudy reaction mixture was stirred overnight while it was allowed to reach room
temperature. The solution was diluted with ethyl ether and filtered through a bed of silica
gel to remove the precipitate of dicyclohexylurea. Removal of the solvent and
chromatography (silica gel, ethyl acetate:hexanes, 9:1) of the residue, afforded the pure
phthaloyl glycinate 285 as white crystals (0.35 g, 70%); Rf = 0.8 (ethyl acetate: hexanes,
1:4); mp: 89 91 C; [a]D25 -79.7 (c 1.0, CHC13); 'H NMR (CDC13) 5: 7.81 (m, 2H), 7.65
(m, 2H), 6.90 (t, J = 7.9 Hz, 1H), 6.81 (d, J = 7.9 Hz, 1H), 6.49 (d, J = 7.9 Hz, 1H), 5.89
(t, J = 3.4 Hz, 1H), 5.85 (d, J = 2.8 Hz, 1H), 4.12 (m, 1H), 3.83 (s, 3H), 3.76 (s, 3H),
2.39-2.15 (m, 2H), 1.91-1.50 (m, 2H), 0.88 (dd, J = 6.7, 1.2 Hz, 6H), 0.84 (s, 7H), 0.12
(d, J = 5.8 Hz, 6H); ,3C NMR (CDC13) 5:168.80, 167.61, 153.32, 147.42, 135.00, 134.74,
133,93, 132.84, 124.40, 124.10, 122.84, 112.71, 73.43, 69.05, 60.93, 56.18, 39.10, 26.21,
25.11, 24.51, 20.41, 20.24, 18.74, 18.62, 9.37, -2.97; IR (KBr/cm1): 2954, 1752, 1726,
1470, 1416, 1205, 1114, HRMS Caled, for C32H4|NSi04 (M+): 579.2652; Found:
579.2652. Anal. Caled, for C32H41Nsi04: C, 63.36; H, 8.62; Found: C, 63.51; H, 8.51.

108
6-bromo-2-dimethvlsilvloxv-(lS,2R)-5-cyclohexen-l-vl-N-tert-butoxvcarbonyl glycinate
(292).
A solution of Boc-glycine (0.07 mol, 12.00 g), DCC (0.09 mol, 18.50 g), DMAP
(catalytic) in dichloromethane (200 mL) was cooled to 0 C and a solution of the TDS
protected diol 291 (0.045 mol, 15.00 g) in dichloromethane (200 mL) was added. The
cloudy reaction mixture was stirred overnight while it was allowed to reach room
temperature. The solution was diluted with ethyl ether and filtered through a bed of silica
gel to remove the precipitate of dicyclohexylurea. Removal of the solvent and
chromatography (silica gel, ethyl acetate:hexanes, 1:9) of the residue, afforded the pure
glycinate (292) as a colorless oil (15,40 g, 70%); Rf = 0.7 (ethyl acetateihexanes, 1:4);
mp: 89 91 C; [a]D26 -64.0 (c 1.0, MeOH); H NMR (CDC13) 6.27 (dd, J = 5.2, 3.1 Hz,
1H), 5.59 (d, J = 3.9 Hz, 1H), 5.00 (bs, 1H), 3.97 (m, 3H), 2.39-2.19 (m, 1H), 2.15-2.09
(m, 1H), 1.85-1.62 (m, 2H), 1.43 (s, 9H), 0.84 (s, 3H), 0.82 (s, 3H), 0.77 (d, J = 1.9 Hz,
6H), 0.07 (d, J = 4.6 Hz, 6H); l3C NMR (CDC13) 5:169.59, 155.29, 134.80, 116.96,
79.64, 73.88, 69.23, 42.33, 34.03, 28.21, 25.49, 24.70, 22.55, 20.01, 18.48, -3.09, -3.15;
IR (CHC13/ cm'1): 3445, 2958, 1755, 1715, 1511, 1372; HRMS Caled, for C2|H39NsiBr05
(M+H): 492.1781; Found: 492.1806; Anal. Caled, for: C2iH38NsiBr05: C, 51.21; H,
7.78; Found: C, 51.41; H, 7.75.

109
2-(4-dimethvlthexvlsilvloxv-2-bromo-(lS,4R)-2-cvclohexenvl-2R-N-rgr/-
butoxycarbonylmethylglvcinate (289a):
A solution of the glycine ester 292 (12.50 mmol, 6.23 g) in THF (100 mL) and a
1.0 M solution of ZnCh (13.70 mmol 13.70 mL,) in ether was cooled to -78C. Then a
1.7 M solution of LDA (31.00 mmol, 19.00 mL) in THF was added dropwise to the
reaction mixture and the system allowed to warm to room temperature slowly
(overnight). The reaction was quenched with water and the basic solution diluted with
ethyl ether. The reaction mixture was then acidified slowly with HC1 (IN) until a pH of
approximately 2.5 was reached. After extraction with ethyl ether (3 X 100 mL) and
drying with Na2S04, the solvent was removed to afford the crude rearranged amino acids
as light yellow cystals. The acids were purified by silica gel chromatography using a
gradient elution of ethyl acetate: hexanes (1:6) followed by methanol (100%) to afford
the mixture of acids. The mixture then treated with diazomethane to obtain the
corresponding methyl esters. The epimeric methyl esters were then introduced unto a
silica gel column and separated with hexanes (100%) to obtain clear oil of 289a (2.33 g
38%); Rf = 0.7 (ethyl acetate: hexanes, 1:4); [a]D26 -55.7 (c 1.0, CHC13); 'H NMR
(CDCI3) 8: 6.30 (dd, J = 5.6, 1.3 Hz, 1H), 5.21 (d, J = 8.6 Hz, 1H), 4.68 (dd, J = 8.7, 2.3
Hz, 1H ) 4.11 (m, 1H), 3.71 (s, 3H), 3.05 (bs, 1H), 1.86-1.78 (m, 2H), 1.63-1.50 (m, 2H),
1.43 (s, 9H), 0.84 (d, J = 6.9 Hz, 6H), 0.80 (s, 6H), 0.05 (d, J = 5.3 Hz, 6H); l3C NMR
(CDCI3) 8:171.85, 155.41, 136.30, 125.51, 80.02, 66.68, 55.86, 52.33, 45.13, 34.15,
29.16, 28.3025.76, 24.73, 23.40, 20.18, 18.56, -2.67, -2.88; IR (KBr/ cm1): 3439, 2955,
2867, 1753, 1720, 1498, 1365, 1251, 1164; HRMS Caled, for C2oH36NsiBr05 (M+):

110
506.1920; Found: 506.1937; Anal. Caled, for C^oH^NSiBrC^: C, 52.16; H, 7.96; Found:
C, 52.28; H, 8.06. Structure was confirmed by X-ray Crystallography (Figure 7, pg 76).
2-(4-dimethlthexvlsilvloxv-2-bromo-( lS,4R)-2-cvclohexenvl-2S-N-rerr-
butoxycarbonylmethylglycinate (289b):
The epimeric methyl esters were then introduced unto a silica gel column and
separated with straight hexanes to obtain clear oil of 289b (2.00 g 30%); Rf = 0.65 (ethyl
acetate:hexanes, 1:4); [a]D32 -27.7 (c 1.0, CHC13); H NMR (CDC13) 5: 6.17 (dd, J = 5.6,
1.3 Hz, 1H), 4.85 (m, 2H ), 4.12 (m, 1H), 3.74 (s, 3H), 2.96 (bs, 1H), 1.86-1.76 (m, 1H),
1.63-1.50 (m, 3H), 1.42 (s, 9H), 0.87 (d, J = 6.9 Hz, 6H), 0.82 (s, 6H), 0.05 (d, J = 5.3
Hz, 6H); 13C NMR (CDC1-,) 6:171.86, 155.46, 135.56, 127.99, 79.86, 65.49, 55.34, 52.38,
43.84, 34.24, 29.58, 28.29, 24.87, 20.31, 19.99, 18.58, -2.47, -2.92; IR (KBr/ cm'1):
3443, 2956, 2868, 1749, 1715, 1503, 1367, 1251, 1159; HRMS Caled, for
C2oH36NsiBr05 (M+): 506.1920; Found: 506.1937; Anal. Caled, for CioHjsNSiBrdp C,
52.16; H, 7.96; Found: C, 52.34; H, 8.01.

Ill
2-(4-dimethvl-terr-butvlsiIvloxv-2-bromo-(lS,4R)-2-cvclohexenyl-2R-N-fert-
butoxycarbonylmethylglvcinate (293):
A solution of the glycine ester 292 (13.40 mmol, 6.23 g) in THF (100 mL) and a
1.0 M solution of ZnCh (21.10 mmol 20.00 mL,) in ether were cooled to -78C. Then a
2.0 M solution of LDA (37.50 mmol, 19.00 mL) in THF was added dropwise to the
reaction mixture and the system allowed to warm to room temperature slowly
(overnight). The reaction was quenched with water and the basic solution diluted with
ethyl ether. The reaction mixture was then acidified slowly with HC1 (IN) until a pH of
approximately 2.5 was reached. After extraction with ethyl ether (3 X 100 mL) and
drying with Na2SC>4, the solvent was removed to afford the crude rearranged amino acids
as light yellow cystals. The acids were purified by silica gel chromatography using a
gradient elution of ethyl acetate: hexanes (1:6) followed by methanol (100%). The pure
acids were then treated with diazomethane to obtain the corresponding methyl esters. The
epimeric methyl esters were then introduced unto a silica gel column and
chromatographed with hexanes (100%) to obtain white crystal of 293 (2.63 g 40%); Rf =
0.7 (ethyl acetate:hexanes, 1:4); mp: 115-117 C; [a]D28 -54.1 (c 1.0, CHC13); H NMR
(CDCIj) 5: 6.18 (dd, J = 5.6, 1.3 Hz, 1H), 5.23 (d, J = 8.6 Hz, 1H), 4.70 (dd, J = 8.7, 2.6
Hz, 1H ) 4.13 (m, 1H), 3.72 (s, 3H), 3.09 (bs, 1H), 1.92-1.75 (m, 2H), 1.74-1.50 (m, 2H),
1.43 (s, 9H), 0.85 (s, 9H), 0.02 (d, J = 4.4 Hz, 6H); 13C NMR (CDC13) 6:171.81, 155.37,
136.30, 125.62, 80.00, 66.78, 55.80, 52.29, 45.15, 29.14, 28.34, 28.20, 25.76, 25.67,
23.33, 17.95, -4.77; IR (KBr/ cm'1): 3394, 2963, 2857, 1733, 1710, 1645, 1522, 1365;
HRMS Caled, for C2oH36NsiBr05 (M+): 478.1525; Found: 478.1525; Anal. Caled, for
C2oH35NSiBr04: C, 50.20; H, 7.58; Found: C, 50.15; H, 7.50.

112
2-(4-dimethlthexvlsilvloxv-(lS,4R)-cyclohexvl)-2S-N-fer?-butoxvcarbonvlmethvl
glvcinate (294).
To vinyl bromide 293 (0.20 mmol, 0.10 g) dissolved in benzene (10 mL) was
added n-Bu3SnH (0.22 mmol, 0.06 g). This mixture was refluxed for approximately 30
min then AIBN (catalytic) was added and the reaction allowed to reflux for another 3 h.
The reaction was quenched with water and the product extracted with ethyl acetate 3 X
10 mL. The organic layers were combined and dried over anhydrous MgS04. After
filtration the solvent was removed under reduced pressure and the solid residue
introduced onto a silica gel column and eluted with ethyl acetate: hexanes (1:6), to obtain
294 (0.07 g, 82%) as a light yellow oil; Rf = 0.75 (ethyl acetate:hexanes, 1:6); [a]D28 -
14.9 (c 1.0, MeOH); 'H NMR (CDC13) 6: 5.85 (m, 1H), 5.46 (d, J = 9.8 Hz, 1H), 4.93 (d,
J = 8.9 Hz, 1H), 4.29 (dd, J = 8.9, 3.8 Hz), 4.06 (d, J = 3.7 Hz, 1H), 3.71 (s, 3H), 2.61 (bs,
1H), 1.76-1.67 (m, 2H), 1.63-1.54 (m, 4H), 1.41 (s, 9H), 0.86 (d, J = 6.7 Hz, 6H), 0.80
(s, 7H), 0.06 (s, 6H); l3C NMR (CDC13) 5:172.87, 156.08, 134.12, 127.27, 112.56, 80.17,
63.73, 57.15, 52.59, 38.15, 34.31, 30.54, 28.24, 27.22, 24.73, 20.63, 20.35, 20.26, 18.57,
-2.07, -2.43. IR (CHCI3/ cm'1): 3448, 2958, 1755, 1710, 1522, 1365; HRMS Caled, for
C22H42NSO5 (M+l): 427.6600; Found: 427.6812; Anal. Caled, for: C22H41NSO5: C,
61.79; H, 9.66; Found: C, 61.77; H, 9.71.

113
2-(4-dimethvlthexvlsilvloxv-2-Cvclohexenvl)-2R-N-frt-butoxvcarbonvlmethvl
glvcinate (295)
To vinyl bromide 293 (0.70 mmol, 0.34 g) was added to a mixture of catalytic amount of
Adams Catalyst, triethylamine (0.70 mmol, 0.73 mL) and methanol (5.0 mL). The
reaction vessel was evacuated and the solution stirred under hydrogen atmosphere (40
psi) for 3h. After completion of the reaction (as observed by TLC), the suspension was
filtered and the solvent concentrated under reduced pressure. The solid residue was
diluted with ethyl acetate (10 mL) and washed with water (2X2 mL), followed by
NaHC03 (2X2 mL). The organic layer was dried with Na2S04 and concentrated to
afford white crystals of 295 (0.30 g, 89%); Rf = 0.65 (ethyl acetate:hexanes, 1:6); [a]o26
-4.9 (c 1.0, MeOH); 'H NMR (CDC13) 8; 5.05 (d, J = 9.1 Hz, 1H), 4.22 (q, J = 4.5 Hz,
1H), 3.93 (bs, 1H), 3.70 (s, 3H), 1.78-1.44 (m, 8H), 1.41 (s, 9H), 0.88 (d, J = 6.4 Hz, 6H),
0.81 (s, 7H), 0.02 (s, 6H); ,3C NMR (CDC13) 5:172.77, 155.42, 79.51, 65.68, 57.90,
51.95, 40.45, 34.39, 32.90, 28.27, 24.74, 22.86, 21.63, 20.29, 18.62, -3.04; IR (CDC13/
cm'1): 3440, 2929, 1755, 1712, 1503, 1162; HRMS Caled, for C22H44NSO5 (M+l):
430.2922; Found: 430.2988; Anal. Caled, for: C22H43NSi05: C, 61.50; H, 10.09; Found:
C, 61.57; H, 10.12.

114
2-(4-hvdroxv-2-cvclohexenvl)2R)-2R-N-te/-fbutoxvcarbonvlmethvl glvcinate (296)
To a solution of the ester 295 (0.800 mmol, 0.450 g) in THF (10 mL) was added
distilled TBAF (1.600 mmol, 1.60 mL). The mixture was stirred for 3h and monitored by
TLC. After consumption of starting material the solvents were removed and the solid
residue introduced onto a silica gel column and eluted with ethyl acetate: hexanes (1:1) to
afford white flaky crystals of the alcohol 296 (0.322 g, 90 %). Rf = 0.45, (ethyl
acetate:hexanes 1:1); [a]D30 -4.2 (c 1.0, MeOH); H NMR (CDC13) 5: 5.20 (s, 1H), 4.01
(bs, 1H), 3.84 (s, 3H), 3.59 (s, 3H), 1.82 1.42 (m, 8H), 1.41 (s, 9H), 1.39 1.20 (m,
2H); 13C NMR (CDC13) 8: 173.73, 160.36, 79.94, 74.22, 58.49, 52.18, 41.24, 29.65,
28.54, 28.55, 28.33, 21.31, 26.17; IR (NaCl/cm1): 3440, 3377, 2929, 2855, 1743, 1712,
1162; HRMS Caled, for CuFLsNO;, (m+H-H20): 271.3645; Found: 271.4012.

115
2-(-2-Cvclohexenvl)-2R-N-fert-butoxvcarbonvlmethylglvcinate (304):
To vinyl bromide 293 (0.10 g, 0.20 mmol) was added to a mixture of catalytic
amount of 10% Pd-C and methanol (1.0 mL). The reaction vessel was evacuated and the
solution stirred under hydrogen atmosphere (15 psi) for lh. After completion of the
reaction (as observed by TLC), the suspension was filtered and the solvent concentrated
under reduced pressure. The solid residue was recrystallized from Ethyl acetate/ Hexanes
to give the ester 304 (0.04 g, 75%) as a white solid; Rf = 0.8 (ethyl acetate:hexanes 1:6);
mp: 110-112 C; [a]D25 -19.7 (c 1.0, CHC13); !H NMR (CDC13) 5: 5.00 (d, J = 8.1 Hz,
1H), 4.18 (dd, J = 8.5, 5.1 Hz, 1H), 3.71 (s, 3H), 1.81-1.56 (m, 10H), 1.41 (s, 9H); 13C
NMR (CDC13) 5: 173.15, 155.81, 79.94, 58.49, 52.18, 41.24, 29.65, 28.54, 28.50, 28.33,
26.17; IR (KBr/ cm'1): 3420, 2950, 1755, 1712, 1503, 1180; HRMS Caled, for
C14H25NO4: 271.2434; Found: 271.2814.

116
6-Bromo-2-dimethylthexvsilvloxv-( 1 S,2R)-5-cyclohexen-1 -vl-N-tert-
alanylcarbonvlglvcinate (301).
A solution of N-Boc-alanine (6.600 mmol, 0.30 g), DCC (9.00mmol, 1.90 g),
DMAP (catalytic) in dichloromethane (10 mL/mmol) was cooled to 0 C and a solution
of the TBS protected diol 298 (6.000 mmol, 2.20 g) in dichloromethane (40 mL) was
added by syringe and the reaction mixture stirred overnight while it was allowed to reach
room temperature. The solution was diluted with ethyl ether and filtered through a bed of
silica gel to remove the precipitate of dicyclohexylurea. Removal of the solvent and
chromatography (silica gel, hexanes:ethyl acetate, 90:10) of the residue, afforded the pure
ester as a light yellow oil (2.40 g, 71%); Rf = 0.5 ethyl acetate :hexanes, 1:6; [oc]d28 -
68.1 (c 1.0, CHC13); H NMR (CDC13) 5: 6.26 (dd, J = 2.6, 5.1 Hz, 1H), 5.53 (d, J = 3.9
Hz, 1H), 5.13 (d, J = 8.1 Hz, 1H), 4.40 (q, J = 7.2 Hz, 1H), 3.94 (dt, J = 3.7 Hz, 1H),
2.32-2.01 (m, 1H), 1.83-1.62 (m, 2H), 1.45 (s, 3H), 1.43 (s, 9H), 0.82 (s, 9H), 0.05 (s,
3H), 0.02 (s, 3H); 13C NMR (CDC13) 8: 172.49, 157.77, 134.67, 1171.71, 79.36, 73.73,
69.37, 67.85, 49.12, 28.24, 25.79, 24.51, 25.64, 25.60, 25.55, 19.15, 18.01, -5.08, -5.17;
IR (KBr/ cm'1): 3435, 2952, 2928, 2855, 1747, 1714, 1649, 1163; HRMS Caled, for
C2oH36BrNSi05 (M+): 478.1636; Found: 478.1624. Anal. Caled, for C2oH36BrNSi054: C,
50.20; H,7.58; Found: C, 50.19; H, 7.64.

117
6-bromo-2-dimethvltert-butvlsilvloxv-(lS,2R)-5-cvclohexen-l-vl alanine(302).
A solution of the alanine ester 301 (10.00 mmol, 4.80 g) in CH2CI2 (250 mL) was
cooled to 0C. Freshly distilled TFA (18.10 mmol, 9.60 mL) dissolved in CH2CI2 (50
mL) was then added dropwise over 30 min. The mixture was stirred for 3h and monitored
by TLC. After consumption of starting material the reaction was quenched with NaHCCL
(saturated). The phases were separated and the organic layer washed with brine. The
combined organic layers were dried over Na2SC>4 and concentrated to give white flaky
crystals of the free amine 302 (2.84 g, 75%). Rf = 0.74, (ethyl acetate 100%); [ci]d30 -
59.1 (c 1.0, MeOH); 'H NMR (CDC13) 6: 8.50-7.71 (bs, 2H), 6.28 (dd, J = 3.6, 4.5 Hz,
1H), 5.57 (d, J = 3.6 Hz, 1H), 4.09 3.97 (m, 2H), 2.34 2.24 (bm, 1H), 2.12 1.98 (bm,
2H), 1.84 1.70 (m, 2H), 1.66 (d, J = 7.1, 3H), 0.83 (s, 9H), 0.04 (s, 3H); 13C NMR
(CDCI3) 8: 169.60, 135.53, 116.51, 75.57, 69.28, 49.26, 26.21, 25.84, 25.71, 18.33,
16.27, -4.81, -4.96; IR (NaCl/ cm1); 3434, 3377, 2953, 2929, 2856, 1752, 1677, 1203,
1136; HRMS Caled, for Cl5H28BrN03Si (m+): 378.3853; Found: 378.1100.

118
6-bromo-2-dimethyltert-butvlsilvloxv-(lS,2R)-5-cvclohexen-l-vl-N-l-phenvl-(4-
methoxy-4-phenvl)-alanvl sulfonamide (299).
To a solution of amine 302 (0.530 mol, 0.200 g), in THF (10 mL) was added Et3N
(0.800 mmol, 0.080 g). To this mixture was added the sulfonyl choride (0.080 mmol,
0.218 g) and the reaction mixture stirred for 48h. The reaction mixture filtered through a
bed of silica gel followed by removal of the solvent and chromatography (silica gel, ethyl
acetate:hexanes, 1:8) of the residue, afforded the pure sulfonamide 299 as a white
crystalline solid (0.132 g, 40%); Rf = 0.4 (ethyl acetate:hexanes, 1:4); mp: 114 116;
[a]D28 44.0 (c 1.0, CHCI3): 'H NMR (CDCI3) 7.87 (m, 2H), 7.62 (m, 2H), 7.50 (m,
2H), 6.97 (m, 2H), 6.20 (m, 1H), 5.41 (m, 2H), 4.10 (m, 1H) 3.85 (s, 3H), 2.23 2.16 (m,
1H), 2.10-1.90 (m, 1H), 1.68- 1.61 (m, 2H), 1.56 (s, 3H), 1.51 1.49 (m, 4H), 1.20 (m,
1H), 0.77 (m, 9H), 0.82 (s, 3H), -0.02 (m, 6H); 13C NMR (CDC13) 8: 170.88, 170.87,
160.01, 145.13, 138.17, 135.06, 131.63, 128.37, 127.69, 127.53, 116.64, 114.44, 74.49,
69.27, 55.37, 51.71, 26.29, 25.76, 25.63, 20.35, 18.06, -5.03, -5.14; IR (CHC13/ cm1):
3281, 2951, 2949, 2854, 1743, 1610, 1595, 1519, 1488, 1250; HRMS Caled, for
C28H39NsiBr06 (M+): 624.1451; Found: 625.1450.

119
(1 S.4R)-2-cvclohexenvl-2S-N-1 -phenvI-(4-methoxv-4-phenvlValanvl sulfonamide
(303).
A solution of the alanine ester 300 (0.800 mmol, 0.450 g) in CH2CI2 (20 mL) was
cooled to 0C. Freshly distilled TFA (1.600 mmol, 1.50 mL) dissolved in CH2CI2 (10
mL) was then added dropwise over 30 min. The mixture was stirred for 3h and monitored
by TLC. After consumption of starting material the reaction was quenched with NaHCC>3
(saturated). The phases were separated and the organic layer washed with brine. The
combined organic layers were dried over Na2SC>4 and concentrated to give white flaky
crystals of the alcohol 303 (0.322 g, 90 %). Rf = 0.4, (ethyl acetate:hexanes 1:1); [(X]d30
-5.1 (c 1.0, MeOH); 'H NMR (CDC13) 8: 7.86 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 8.8 Hz,
2H), 7.52 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 5.41 (s, 1H), 5.20 (bs, 1H), 3.84
(s, 3H), 3.61 (s, 3H), 2.05 (bm, 2H), 1.82 1.42 (m, 8H), 1.41 (s, 3H), 1.39 1.20 (m,
1H); ,3C NMR (CDCI3) 8: 173.73, 160.36, 156.65, 145.32, 140.09, 131.75, 128.63,
127.86, 127.15, 114.74, 74.22, 65.37, 55.63, 52.84, 45.83, 29.61, 29.46, 21.31, 21.05,
17.59; IR (NaCl/ cm'1): 3434, 3377, 2953, 2929, 2856, 1752, 1677, 1203, 1136; HRMS
Caled, for C^H.sBrNOiSi (m+H H20): 430.1682; Found: 430.1688.

120
2-(4-dimethlthexvlsilvloxv-2-(2-benzvloxv-3-methoxvphenvl)-(lS,4R)-2-cvclohexenyl-
2S-N-frr-butoxvcarbonvlmethvlglvcinate (312).
To a two neck round bottom flask fitted with a condenser under an argon
atmosphere was added Pd(PPh3)4 (7.00 mmol, 0.010 g). This was followed by addition of
dry benzene (15 mL). A solution of the vinyl bromide 289b (0.350 mmol, 0.176 g)
dissolved in benzene (5 mL) was then added to the reaction flask. This was followed by
the addition of NaiCC^ (2.0 M, 0.60 mL), to the mixture. Boronic acid 313 (0.26 mmol,
0.07g) dissolved in benzene (5 mL) was then added to the reaction mixture, which was
allowed to reflux for 6h. The reaction was quenched with water and the product extracted
with ethyl acetate (3 X 20 mL). The organic layers were combined, washed with brine
and dried over anhydrous MgS04. After filtration the solvent was removed, the crude
product introduced onto a silica gel column, and eluted with ethyl acetate: hexanes (1/3)
to obtain 312 (0.10 g, 70%) as a light yellow oil; Rf = 0.35 (ethyl acetate: hexanes, 1:4);
[ot]D29 +26.7 (c LO, CDCI3); 'H NMR (CDCI3) 8: 7.31 (m, 5H), 6.95 (t, J = 7.8 Hz, 1H),
6.85 (d, J = 7.9 Hz, 1H), 6.58 (d, J = 7.3 Hz, 1H), 5.77 (d, J = 4.6 Hz, 1H) 5.02 (d, J =
11.2 Hz, 1H), 4.91 (d, J = 11.2 Hz, 1H), 4.82 (d, J = 7.3 Hz, 1H), 4.13 (m, 1H), 3.96 (q, J
= 4.0 Hz, 1H), 3.85 (s, 3H), 3.62 (s, 3H), 3.46 (q, J = 7.0 Hz, 1H), 1.78-1.49 (m, 4H),
1.36 (s, 9H), 1.24-1.17 (m, 5H), 0.91 (d, J = 6.7 Hz, 6H), 0.86 (s, 7H), 0.11 (d, J = 8.5
Hz, 6H); 13C NMR (CDC13) 8:172.46, 155.11, 152.24, 144.93, 139.82, 137.82, 135.16,
132.17, 128.16, 128.13, 127.66, 124.24, 122.04, 111.77, 79.19, 74.72, 63.37, 55.69,
54.64, 51.91, 38.48, 34.33, 29.82, 28.28, 27.96, 24.84, 20.38, 18.62, 18.35, 17.91, 15.23,
-2.35, -2.87; IR (CDC13/ cm'1): 3370, 2989, 2959, 1750, 1720, 1698, 1520, 1505, 1454;
HRMS Calcd.for C36H53NO7S (m+): 639.9104 ;Found: 639.9102.

121
2-(4-dimethvlthexylsilvloxv-2-(2.3-dimethoxvphenvl)-(lS.4R)-2-cvclohexenyl-2S-N-
rm-butoxycarbonylrnethylglvcinate (316).
To a two neck round bottom flask fitted with a condenser under an argon
atmosphere was added Pd(PPh3)4 (0.01 mmol, 0.014 g). This was followed by addition of
dry benzene (15 mL). A solution of the vinyl bromide 289b (0.400 mmol, 0.200 g)
dissolved in benzene (5 mL) was then added to the reaction flask. This was followed by
the addition of Na2C03 (2.0 M, 1.20 mL), to the mixture. Boronic acid 273 (0.600 mmol,
0.110 g) dissolved in benzene (5 mL) was then added to the reaction mixture, which was
allowed to reflux for 6h. The reaction was quenched with water and the product extracted
with ethyl acetate (3 X 20 mL). The organic layers were combined, washed with brine
and dried over anhydrous MgS04. After filtration the solvent was removed, the crude
product introduced onto a silica gel column, and eluted with ethyl acetate: hexanes (1/3)
to obtain 316 (0.10 g, 70%) as a light yellow oil; Rf = 0.40 (ethyl acetate: hexanes, 1:4);
[a]D30 +26.9 (c 1.0, CDC13); H NMR (CDC13) 8: 6.92 (t, J = 7.9 Hz, 1H), 6.8l(d, J = 7.9
Hz, 1H), 6.65 (d, J = 7.8 Hz, 1H), 5.95 (d, J = 2.4 Hz, 1H), 5.23 (m, 1H), 4.33 (bs,
1H),4.08 (m, 1H), 3.83 (s, 3H), 3.79 (s, 3H), 3.65 (s, 3H), 3.45 (bs, 1H), 1.94-1.63 (m,
4H), 1.56 (bs, 1H), 1.38 (s, 9H), 0.86 (m, 6H), 0.08 (m, 6H); l3C NMR (CDC13) 8:173.21,
155.65, 152.57, 146.46, 142.15, 134.83, 131.37, 124.49, 122.49, 112.31, 79.86, 63.93,
61.07, 56.17, 55.35, 52.59, 39.56, 30.45, 28.79, 19.16, -2.45, -2.71; IR (CDC13/ cm1):
3348, 2975, 2937, 1751, 1714, 1689, 1520, 1474, 1259, 1225, 1159, 1062, ; HRMS
Caled.for C30H49NO7Si (m+): 563. 0491 ; Found: 563. 0451.

122
2-(4-hvdroxv-2-benzvloxv-3-methoxvphenyl)-(lS,4R)-2-cyclohexenvl-2S-N-frt-
butoxvcarbonvlmethylglvcinate (311):
To a solution of the silyl ether 312 (0.183 mmol, 0.177 g) in THF (10 mL) was
added TBAF (0.220 mmol, 0.220 mL). This mixture was stirred for 3h while being
monitored by TLC. The reaction mixture filtered through a bed of silica gel followed by
removal of the solvent, trituration with CCL4 (3 X 20 mL) and chromatography (silica
gel, ethyl acetate: hexanes, 1:8) of the residue, afforded the pure alcohol 311 as a light
yellow oil (0.061 g, 75%; Rf = 0.4 (hexanes:ethyl acetate, 1:1); [oc]d27 + 52.7 (c 1.0,
CHCI3): H NMR (CDCI3): 7.32 (m, 4H), 6.95 (t, J = 7.6 Hz, 1H), 6.84 (d, J = 7.6 Hz,
1H), 6.65 (d, J = 7.6 Hz, 1H), 5.79 (d, J = 3.7 Hz, 1H), 5.09 (d, J = 8.1 Hz, 1H), 5.05 -
4.90 (m, 2H), 4.19 4.07 (bm, 2H), 3.85 (s, 3H), 3.61 (s, 3H), 3.36 (bs, 1H), 1.79 (bs,
2H), 1.61 (m, 2H), 1.33 (s, 9H), 1.16 (bm, 1H); 13C NMR (CDC13) 8: 172.65, 155.17,
152.36, 145.02, 141.36, 137.96, 134.89, 131.01, 128.20, 127.76, 124.17, 121.93, 111.88,
79.38, 74.75, 63.53, 55.77, 54.89, 51.89, 39.16, 29.67, 28.28, 18.77; IR (CHC13/ cm'1):
3350, 2964, 2934, 2359, 1749, 1713, 1517, 1469, 1365, 1258, 1216, 1158; HRMS Caled,
for C28H36N07 (M+ 1): 498.5900; Found: 498.2491.

123
2-(4-hvdroxv-2-(2,3-dimethoxvphenvl)-(lS,4R)-2-cvclohexenvl-2S-N-fert-
butoxycarbonylmethylglycinate (317)
To a solution of the silyl ether 316 (0.355 mmol, 0.200 g) in THF (10 mL) was
added TBAF (0.533 mmol, 0.533 mL). This mixture was stirred for 3h while being
monitored by TLC. The reaction mixture filtered through a bed of silica gel followed by
removal of the solvent, trituration with CCL4 (3 X 20 mL) and chromatography (silica
gel, ethyl acetate: hexanes, 1:8) of the residue, afforded the pure alcohol 317 as a
colorless oil (0.120 g, 81%; Rf = 0.4 (hexanes:ethyl acetate, 1:1); [oc]d27 + 28.6 (c 1.0,
CHCL): 'H NMR (CDCI3): 5: 6.92 (t, J = 7.9 Hz, 1H), 6.81(d, J = 7.9 Hz, 1H), 6.65 (d,
J = 7.8 Hz, 1H), 5.95 (d, J = 2.4 Hz, 1H), 5.23 (m, 1H), 4.33 (bs, 1H),4.08 (m, 1H), 3.83
(s, 3H), 3.79 (s, 3H), 3.65 (s, 3H), 3.45 (bs, 1H), 1.94-1.63 (m, 4H), 1.56 (bs, 1H), 1.38
(s, 9H); 13C NMR (CDC13) 5:173.21, 155.65, 152.57, 146.46, 142.15, 134.83, 131.37,
124.49, 122.49, 112.31, 79.86, 63.93, 61.07, 56.17, 55.35, 52.59, 39.56, 30.45, 28.79,
19.16,; IR (CDCI3/ cm1): 3348, 2975, 2937, 1751, 1714, 1689, 1520, 1474, 1259, 1225,
1159, 1062, ; HRMS Calcd.for C30H49NO7S (m+): 421.4910 ; Found: 421. 3720;

124
2-(4-benzovl-2-(2-benzvloxv-3-methoxvphenvl)-(lS,4R)-2-cvclohexenvl-2S-N-frr-
butoxvcarbonvlmethvlglvcinate (314):
To a stirred solution of the alcohol 311 (0.183 mmol, 0.091 g) and benzoic acid
(0.366 mmol, 0.050 mL) in dry THF (5 mL) was added a solution of the Mitsunobu
reagent previously prepared by addition of diethyl azodicarboxylate (DEAD) (0.366
mmol, 0.058 mL) to a stirred solution of PBU3 (0.366 mmol, 0.091 mL) in THF (5 mL) at
0C and stirred at the same temperature for 15 min. The reaction mixture was allowed to
warm slowly to room temperature over 3h after which the solvents were removed under
reduced pressure an the crude product purified by chromatography (silica gel, ethyl
acetate: hexanes, 1:8) of the residue, afforded the pure benzoate 314 as a clear oil (0.155
g, 94 %); Rf = 0.6 (ethyl acetate :hexanes, 1:4); [oc]d27 + 166.8 (c 1.0, CHCI3): H NMR
(CDCI3): 8.01 (m, 1H), 7.92 (d, J = 1.5 Hz, 1H), 7.56 7.23 (m, 10H), 6.96 (t, J = 8.1 Hz,
1H), 6.84 (d, J = 8.3 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 5.88 (m, 1H), 5.08 (d, J = 11.0 Hz,
1H), 4.92 (d, J = 11.2 Hz, 1H), 4.66 (d, J = 8.3 Hz, 1H), 4.15 (bm, 2H), 3.85 (s, 3H),
3.59 (s, 3H), 3.57 (bs, 1H), 2.21( bm, 1H), 1.71 (bm, 2H), 1.35 (s, 9H), 1.21 (bm, 2H);
13C NMR (CDCI3) 5: 172.65, 155.17, 152.36, 145.02, 141.36, 137.96, 134.89, 131.01,
128.20, 127.76, 124.17, 121.93, 111.88,79.38,74.75, 63.53, 55.77, 54.89,51.89, 39.16,
29.67, 28.28, 18.77; IR (CHC13/cm'1): 3370, 2950, 1747, 1715, 1698, 1520, 1505, 1454;
HRMS Caled, for C35H4oN08 (m+): 602.2774; Found: 602.2754.

125
2-4-oxo-2-(2-benzvloxv-3-methoxvphenvl)-( lS,4R)l-2-cvclohexenyl-2S-N-rerr-
butoxvcarbonvlmethvlglvcinate (326):
To a solution of the alcohol 311 (0.603 mmol, 0.300 g) in CH2CI2 (5 mL) was
added PCC (0.905 mmol, 0.200 g). This mixture was allowed to stir for 12h after which
the reaction mixture was filtered through a bed of silica gel followed by removal of
solvents. The crude product was chromatographed (silica gel, ethyl acetate: hexanes, 1:4)
to afforded the pure enone 326 as a light brown oil (0.250 g, 84%); Rf = 0.6
(hexanes:ethyl acetate, 1:1); [oc]d27 + 18.6 (c 1.0, CHCI3): 'H NMR (CDCI3): 7.28 (m,
5H), 7.02 (t, J = 7.8 Hz, 1H), 6.93 (dd, J = 1.5 Hz, 1H), 6.65 (dd, J = 1.5 Hz, 1H), 5.87
(m, 1H), 4.98 (q, J = 11.4 Hz, 2H), 4.69 (m, 1H), 4.40 (bs, 1H), 3.89 (s, 3H), 3.63 (m,
1H), 3.56 (s, 3H), 2.52-2.46 (m, 1H), 2.28-2.18 (m, 1H), 1.84-1.73 (m, 2H), 1.32 (s, 9H);
l3C NMR (CDCI3) 8: 198.29, 171.92, 160.74, 154.67, 152.39, 144.43, 137.21, 133.54,
130.98, 128.45, 128.27, 124.56, 121.27, 113.17, 79.81,75.32, 55.84, 54.78, 52.22,40.41,
35.24, 28.11, 23.94; IR (CDCI3/ cm'1): 3342, 2951, 1747, 1706, 1676, 1471, 1454, 1366,
1264, 1213, 1158; HRMS Calcd.for C28H33NO7 [(m+l)+ Na]: 518.2154 ; Found:
518.2160.

126
2-(4-dimethvlthexvlsilvloxv-2-(2-hvdroxv,3-dimethoxvphenvl)-( lS,4R)-2-cyclohexenyl-
2S-N-rert-butoxvcarbonvlmethvlglvcinate (358):
To a two neck round bottom flask fitted with a condenser under an argon
atmosphere was added Pd(PPh3)4 (0.022 g, 0.019 mmol). This was followed by addition
of dry benzene (10 mL). A solution of the vinyl bromide 289b (0.640 mmol, 0.326 g)
dissolved in benzene (5 mL) was then added to the reaction flask. This was followed by
the addition of Na2C03 (2.0 M, 2.5 mL), to the mixture. Boronic acid 357 (0.600 mmol,
0.110 g) dissolved in a mixture of benzene (5 mL) and ethanol (1 mL) was then added to
the reaction mixture, which was allowed to reflux for 6h. The reaction was quenched with
water and the product extracted with ethyl acetate (3 X 20 mL). The organic layers were
combined, washed with brine and dried over anhydrous NaiSCL. After filtration the
solvent was removed, the crude product introduced onto a silica gel column, and eluted
with ethyl acetate: hexanes (1/3) to obtain the coupled product 358 (0.158 g, 45%) as a
light yellow oil; Rf = 0.78 (ethyl acetate: hexanes, 1:1); [cc]d3 (c 1.0, CDC13); H NMR
(CDC13) 5: 6.75 (m, 2H), 6.67 (m, 1H), 5.93 (dd, J = 1.9, 5.0 Hz, 1H), 5.85 (bs, 1H), 4.86
(d, J = 7.8 Hz, 1H), 4.24 (m, 1H),4.04 (dt, J = 4.2, 7.6 Hz, 1H), 3.85 (s, 3H), 3.67 (s, 3H),
3.57 (bs, 1H), 1.74 (m, 2H), 1.65-1.62 (m, 2H), 1.35 (s, 9H), 0.91(dt, J = 1.7, 6.8 Hz,
6H), 0.86 (s, 6H), 0.12 (m, 6H); 13C NMR (CDC13) 8:172.70, 155.21, 146.24, 142.58,
138.68, 132.74, 126.51, 121.86, 119.77, 109.83, 79.28, 63.59, 55.93, 54.78, 52.09, 38.13,
34.39, 29.98, 28.28, 24.88, 20.43, 20.39, 18.67, 18.30, -2.36, -2.83; IR (CDC13/ cm1):
3448, 2955, 2868, 1752, 1721, 1520, 1472, 1279, 1159, 1065; HRMS Calcd.for
C29H47N07S (m+): 549. 7864 ; Found: 549. 3122.

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APPENDIX
SELECTED SPECTRA
The H and l3C or APT NMR spectra of selected compounds reported in Chapter
HI and IV are graphically displayed in this appendix. The spectra along with the proposed
structure are shown.
134

r*duc*d dimthoxyphny1 diol
OBSERVE HI
FREQUENCY 300.075 MHz
SPECTRAL WIDTH 4500.5 Hz
ACQUISITION TIME 1.998 **c
RELAXATION DELAY 0.000 f*C
PULSE WIDTH 5.0 u*c
AMBIENT TEMPERATURE
NO. REPETITIONS 16
DOUBLE PRECISION ACQUISITION
DATA PROCESSING
LINE BROADENING 1 0 Hz
FT 8 IZE 32768
TOTAL ACQUISITION TIME 1 nlmil**
MeO
MeO
i
11
T
10
9
t
8
7
4 ' 3 2 0 ppm

r*duc*d dlmthoxyphny1 dio
OBSERVE HI
FREQUENCY 300.075 MHz
SPECTRAL WIDTH 4500.5 Hz
ACQUISITION TIME 1.998 **c
RELAXATION DELAY 0.000 9C
PULBE WIDTH 5.0 u#C
AMBIENT TEMPERATURE
NO. REPETITIONS 16
DOUBLE PRECISION ACQUISITION
DATA PROCESSING
LINE BROADENING 1 0 Hz
FT 81ZE 32768
TOTAL ACQUISITION TIME 1 minutas
ppm
NO
4
I
2
1

r*ducd dimethoxyphsnyl dlol
OBSERVE Cl 3
FREQUENCE 75.62 MHz
SPECTRAL WIDTH 18761.7 Hz
ACQUISITION TIME 0.800 sac
RELAXATION DELAY 0.000 SAC
PULSE WIDTH S.0 us AC
AMBIENT TEMPERATURE
NO. REPETITIONS 13
DECOUPLE HI
LOW POWER 1023
DECOUPLER CONTINUOUSLY ON
WALTZ1 6 MODULATED
DOUBLE PRECISION ACQUISITION
DATA PROCESSING
LINE BROADENING 3.5 Hz
PT SUE 32768
TOTAL ACQUISITION TIME 17 mlnutAS

puist ^cvoeHce
Puli* 40.0 decrees
Acq. t11.990 sec
Width 4500.5 HZ
10 repetitions
OOSCRVC HI, 300.0733027 HHZ
OATA PROCCSSINO
Line broadening 1.0 Hz
PT size 32700
Total time 1 minute
Jll
l Av/vr
Vjul
uJL
T
7
E
T
5
T
3
i
ppa

SOLO

INOVA-500 "ge*1n1300"
pulse sequence
Pulf e 33.5 degree
Acq. t13.277 ec
Width 5000.0 HZ
4 rpit 111on*
OBSERVE HI, 300.0732144 HHZ
OATA PROCESSING
L1nt broadening 1.0 HZ
FT size 32788
Total time 0 *1n, 0 *ec
v_
lL
o
T
3
11r
2
T
1
T '
PP*

MeO
PULSE SCQUtNCE
Pul* 31.1 degrees
Acq. tl* 0.500 *9C
Width 15751.7 HZ
1024 repetition*
053ERVE CIS, 75.4542017 MHZ
OECOUPLE Hi, 300.0750122 MHZ
Power 30 d6
continuously on
WALTZ*15 BOduleted
OATA PROCESSING
Un broadening 3.5 Hz
FT *1Z* 32755
Total t1 1 in, 4 sec
MoO
NHBoc
OTDS

7 6 5 4 3 2 1 ppai
1.00 0.53
1.03
0.51
' p ' 1 i f11* r*
1.22 Pi. 071.98 0.100 .(4
0.512.1? 0.100.17
3.57
*r*T'.*r~P uiP
3.4( l.4(
5.3*
0.65
0.15
11.53
1.41

2 2 0
ZOO
180
160
TT'rT
140
IZO

Solventi cdc13
Aablent temperature
U*eri oppong
File: lecl
I nova-500 -narf
PULSE SEQUENCE
Pulii 40.0 decree*
Acq. tle 1.910 sec
Width 4500.5 HZ
04 repetition*
OBSERVE Ml. 300.0733027 NMZ
DATA PROCESSING
lIne broadening 1.0 Hz
FT size 32700
Total time 2 winut**
u
T
7
6
T
5
T
4
3
T
2
T
1
H
PP*


Solvents c OC13
AaDlent tempereture
Uierj oppong
rill! pnth
INOVA-SOO "gelnl300"
pulse sequence
Pule 335 dear ee*
Acq. t1e 32*7 ec
Width 5000.0 Hz
4 repetition
0SERVE Ml, 300.0733031 **Z
OATA PROCESSING
Une broedenlng 1.0 mz
fT size 32 768
Tote 1 tl 0 In. 4 C
vO
^r
T
3
T
z
T
1
1
PP

*V I I % VUWIJ
AaDimi iaptrtur
Ufrt oppong
illli phthc
I NOVA* S 0 0 "fl1nl300
pulst seouewce
Pulii 31.1 dar #
ACQ. tI0.800 MC
width 18781.7 HZ
1024 rpttttoni
oisctve C13 75.4542005 hhz
OCCOUPlt HI, 300.0750122 "HZ
Pow r 30 d8
Continuoufly on
WALT2*18 oduUttd
OATA PAOCCSSIHO
Lint Drodddnlog 3 *
FT *1Z* 32788
TOtd1 I1f 1 !. 4 *4C
(4
Uhliii ,i,Jk.il y.u.ikl Ji., ikIi.L
mwBmmsimwm
11
220
200
180
160
r~
'T
III II I ll I lili AlM.iibII ,Li | 111 IJ Jill a 4 J, IkllJl
I Wi i'
140
120
100
60
40
20
ppi

add
J L
I
X
2
x
C
x
V
X
X
00
0-
. . I
T^FT
T
S 9
i I . ix
8 6 01
IT
l
i r
2 T
V
30flHN^FT J9
O
( UM \ IP101

Y oA^NHBoc
OTDS
IM* ll^MMJA
i
20 0 180 160 140
I ' I J
120
1[ T T 'H | > I I | I I f * T'H"
100 80 60
-1 I ' 1 T
40
xr
-n r
20
0 ppm

Standard Ml paramattrt
Pull* Stqutnct: 2pul
Solvant: CDC13
AaDltnt ttaptraturt
OEHJNI-30088 "gPInUOO"
PULSE SEQUENCE
Pultt 32.7 dtartat
Acq tlaa 3.111 IH
Width 4801.1 HZ
18 rqpttltlon
OBSERVE HI, 300.0873631 MHZ
DATA PROCESS I MO
Lint proadantna 0.2 Hz
OAUtt apodlzatlon 1.780 ttc
fT tlzt 65536
TotAl tint 1 In, 6 ttc
14
13
l 1
12 11 10
| 1 1 T~r
9 8
T
6
u L
J A^UU.
PP*
o

Stanoar o C13 parata
Pulla Saquanca: 2pul

TBSO
Ov^OMe
Br
NHBoc
A.
0.13 2.13
0.01 1.07
o.eo
. T ^r-' '-T-' W
1.92 1.32 1.11 2.91
1.03 9.94 9.33 2.91
n


o*OMc
TDSO
r
^V^'NHBoc
j*l_7\ 1
1.00
0.92
0.01
1.01
0.01 2.06
/V
Aim
LL
i|
pp
9.19
0.19
9.79
19.09

$tndr Pulll Sequtnct: pt
S Ip
k
eg £
2 *
ia
j
200
180
160
140
H O N
.^5 i
lss
UK
2
a
kk
120
T^rf-n rrr
100
F-r-rr-
80
I M "
\P
41
jl* ^
i
j
*****
PP
\r\
v-)
220

>0)vnl: CUC13
AaDtint t#*iprtuf*
CCMIMI '900D6 "g#*'n13 00"
putse seouewce
Pull# 32.7 o#gr**
AC# tin# 3.111 l#c
Width 4101.1 HZ
14 r#p#t1tlon
O&SfRVC HI, 300 047362 "z
OATA PAOCtSSlNC
tin# 0ro4d#n1ng 0.2 HZ
CAUll #poo1Ztion 1.790 tfC
f T HZ# 655 36
Tot A1 tm# 4 win, 20 lC
7
6
T
5
V
4
3
T
2
T
1
1
ppa

Ote. & VT
diti
Sp 11 mi
df rq
300.065
tolvtnt
ede 13
dn
MI
f 1 li
*P
dpvr
35
ACQUISITION
dip
1023
lri
75 .410
dof
121.0
tn
CU
da
yny
t
0.144
da*
w
np
327M
dmf
5600
IW
I7JS4 .0
PROCESSING
f b
II00
ID
3.50
DI
II
vtf 1 1#
tpvr
so
proc
ft
PW
5.0
tn
not u t 9 0
Pl
31 0
di
0
vtrr
al
0.007
vxp
vft
03
0.001
vbt
wft
tof
344.2
vnt
nt
14331
ct
14331
lock
n
g 1 n
not uttd
flAOS
11
n
1 n
n
dp
y
DISPLAY
*P
711.4
wp
17354.0
V
54
te
0
VC
200
hzm*
5.30
U
12200.00
Ti 1
1511 .2
rp
5101 S
tr
20
1 nt
1.000
n cae ph
" ' ,T'"1 nT)rrrfr *-
200 180
ha*m**yw*J fufyvL1 yyKyta #|>N>
i I t i r T r~ -r-r-r TT I ' IfT ^T TTT i I I ' TWff I
r-rm
80
T
601
160
140
120
100
<0
ppn
iO

ST AMOAAO 1H OSSKRVC
Pul* S*qu*nc*i tpul
1
W A.
T
7
6
0.94
1-0S
oo
jWv
1 > r i [ t t
i 1
0 ppa
21-M
17
T
1
i.u

IX OISCRVC

Pu 1 squnci! 2 pu1
Solvent i C0C13
Aabitnt ttp#r#tur
VXR-300S Hvr300
PUlSC SCQUeNCC
Pull# 57.4 dgrt
Acq t3.744 fc
Width 4000.0 HZ
32 rpt1t lorn
OMCRVt HI, 211.1460571 HM z
OATA PROCESSINO
Oauti Apod 1za 11 on 2.226 SAC
FT s 1 Z A 32766
Total tlA 4 1n, 0 SAC

Pulse Sequence> apt
Solventi cdcl3
Aablent temperature
*#rcury-300 rcuryJOO"
Put SI SiguiMCEi apt
let pulsa 10.0 deyr
2nd puls# 23.7 degrees
Acq. t1ee lll( sec
width HUB S HZ
3120 repetitions
OSSCRVI Cl 31 71.3774725 MHz
OCCOUPIC HI, 200.7725155 Bail
Power 43 dt
on during acquisition
WAtTZ-15 modulated
DATA PQOCCSSING
Line broadening 1.0 Hz
FT size 131072
Total ties 0 sin, 0 sec
220
200
180
1 i i | i i i r r1
160
14 0
I i i i i | i i i i i i i i | i">
120 100

Solvent i C0C13
A*b1*nt tMpr tur
Marcury-300 "rcury300"
pulse sequence
Puli* 391 d*gr
Acq t1b# 4.000 *c
Width 9313.1 Hz
19 ropotltlonc
OBSERVE HI, 289.75794H MHZ
DATA PROCESSING
Caui apod nation 1 429 iac
FT 1za 95539
Total 11 0 m, 0 aac
. x jJ
L
o
T
3
T
2
-|i i 1 |r
1 PP

Pul Squnci pt
r*',
vO

PULSC SEQUENCE
Pul 57.4 dcorces
AC 4 U 3.744 ICC
Width 4000.0 Mz
10 rcpctltlonl
0OSERVE Ml 211.1460517 NHZ
OATA PROCESSINO
OdUlf podlZAtiOn 2.220 lee
7T I1ZC 32760
Tot#1 tloc 1 nln, 0 ice
12
11
10
9
8

PuIf# Saquanc# apt
sD

Standard hi param*t*rs
PulS* StqutnC*: *2pu1
TBSO
JUUUUL
198 1.98
2 02
, i (-
5
0.94
ILL
mJv^L J
3.00
0 86 2.91
ppm
6.34 8.74
6.34
sC
sC

O'
OOT
lXj
3wC3
w£od
osai
in cc *ui sc ti i*\oi
ttilt H id
ZM s c flu J upOJQ tun
ON I 300 W VIVO
MttlOpO* T-21'TV
uoixunls flujjnp vo
8P (C JWOd
ZHM 9ICZ 990 OOC TH 31dft0030
ZMW SO 0 0 Z S9 i 'CIO 3AH3MO
luO|ii;#dj 99CT
ZH 09SCZI M9PIA
3*9 991*0 (! kiV
I99J09P 052 Mind PU2
t j 0 p o 0 9 T Mind lit
Id I3DN3O039 3finw

Solvent. . J
Aaoient teaperature
VXK-300S "vitriOO"
puise seoueNce
Pull* $7.4 dffgros
Acs. tlae 3.744 c
width 4000.0 Hi
If repetitions
0MAVC HI, 211.1468 5 6 5 MHZ
OAT A PROCESS I NO
Oeuss epodlzetlon 2.228 sec
fT size 32788
Tote 1 ties 1 a 1n, 0 sec
OMe
JL
T
5
8
7
6
A
Van^.
x
\0
Z
1
-1
PP

C*
vC
dd o oz
. i.. i... 11... i. i. i
0
09
OS
00T
021
OH
091
>|PT 'y |
081
. i .
002
i i i i i i i I i.
022
.ulii
1 1
f rI n| ''train PF* Mr tT'rP
rnin'Wf rr vu f*r
3WO
.OH
WO
it ut* t I t*ll
tlOttt I* 14
IM 0 t #u l u*D*ojq tv 11
tMinnoiM i*
0*1*1npo* Ifzitvn
uaitiainbo* Suijnp uo
tft 004*114 M2 tM 1XOOO>0
iHM **4i4C-i4 cxo wnno
uO|l|l*d*J JtJ
*h i-mit nom
lift *! *
jfl*o Itl tn4 out
J0p 0'09t *l4 lit
i4 i ion indis nvu

Pult* Saquancai 2pul
Solvent i COCI 3
A*b1nt taaparatura
Marcury-300 %arcury300"
PUCSE SEQUENCE
Pulta 3t1 daaraat
Acq. ttsa 4.000 §ac
Width 43131 Hz
44 r#pt1t1on
OSSERVE HI, 29t7439980 MHZ
DATA PROCESSING
Cau apodlzt1on 1428 c
FT HZ* 44434
Total t1aa 0 am, 0 t#c
UL
T
11Ir
9
T
8
T
iiiii'r
7 6

SUZUKI Cdrbon
Pul*t Stqutnct: iZpul
k
m
<*!<*> I
TIT
'~S
n
ir
k
180
160
T | J | I 1 1 ' ' I l'lr*T
140 120 100 80
¡R S
ss;
J
5 lA
8
i 1
60 40
J.
' I'' '"'r
20
1 I
0 ppa
Tr'
200
10.821

STANDARD Ml PARAMETERS
PulK Stquff net: i2pul
Solvent: CDC13
Aablant t#*prtur
VXR-300S Mvxr300"
PULSE SEQUENCE
Pultt 57.4 dtgraat
Acq. t1* 3.744 sC
Width 4000.0 Hz
If rtptt11Ion*
OBSERVE Ml. 211.1465573 MMz
OATA PROCESSING
Gaui* apod 1zat1 on 2.228 l#c
FT t1Zf 32768
Total 11 mm* 1 *1n, 0 ac
r~
-0
ppm
(N

Pu 1 Sequencei apt
SoIvanti cdc13
Aoblent ttaparatura
Mercury-300 "aercury300"
PULSC SEQUENCE apt
let puWa 100-0 degrttt
2nd pulse 21-7 degrees
acq. t1ae ISIS tac
width 1ISIIS Hz
41024 repetitions
OSSERVE C13I 7S-374104* MHz
DECOUPtE HI, 2007S94700 MHZ
Power 43 dt
on during acquisition
WAlTZ-lt oodulatad
DATA PROCESSING
Una broadening 1.0 H:
FT tiza 131072
Total tlae 0 aln, 0 tac
I I I I I I I I I I I I
220
200
ISO
160
140
20
iWMM
i i I ii i ri
100
WMM
I | I I I I I 'IT
80
TTT
60
4 I
20
ppa

STANOARO hi PARAMETERS
Puls* Sequence: s2pu1
Solventt COC13
Ambient temperature
VXR-JOOS "vKrSOO**
PULSE SEQUENCE
Pulee S7.e degree
Acq. 11 me 3.744 sec
width 4000.0 HZ
14 repetitions
OBSERVE Ml, 219.1468566 Mhz
OATA PROCESSING
Oauss apodlzatlon 2.228 sec
FT Size 32788
Total time 4 min, 0 sec
MeO
BnO
BzO
jL 1AjL-JV L
T
z
-0
T
PP

isc oascRvi
Pula# Sequence apt
Solvent i cdc13
*eblent temperature
it1i NnsoaUclJ
M#r cury-30 0 "ercury300"
PULSE SEQUENCE apt
1st pula# 1*0.0 degrees
2nd pulse 23.7 degrees
Acq. tina 1.010 mc
width HUM Hz
till repettIon*
OOSERVC CIS, 70.3741741 MHz
DECOUPLE HI, 200.7004700 MHz
Powar 43 dft
on during acquisition
WALTZ-14 Modulated
DATA PROCESSING
Una broadening 1.0 Hz
FT iza 131072
Total t1ae 0 a1n, 0 sec
MeO
BnO
BzO
inea
*4
JuJ*
r
60
4
)
20 0 ppa

IMP. 29 0 C / 2911 K
Mercury-300 "Brcury300"
PULM SCQUCMCC
Pul* 391 dnr
Acq t1 4.000 *C
width 4313.1 H2
14 repetition*
OOSCRV HI, 299.7449129 MHz
OATA PQOCC&SXMC
Cau* podl2tlon 1-429 *c
FT *12 49934
Total ti 1 am, 7 *c
j i i r
18
T*I~T~T*1 T 1 > f T t T I |-l
16 14
I | I TT
12
1 1 1 1 ^
10
. Li-AlU U
I I l l I ; I I I l"| l I I l ~| I l i I I I '' | 1 1 1 1 1 1 1 1 | 1
42-0 PP
t-Tt-t
6

*t puU iw.w gr
2nd pule* 3S.S dgr*#
Acq. tin* l.llt §0C
width miM hi
12 rpt1t1on*
S

none
Pulse Sequence : e2pu1
Solvent: CDC13
Teap- 25 0 C / 288 1 K
Mercury-300 "aercury300"
PULSE SEQUENCE
Pulee 30.1 degree*
Acq. tlae 4.000 tec
Width (313.1 Hz
If repetitions
OSSERVE HI, 2M. 7253(90 MHZ
DATA PROCESSING
Cause apod 1zation 1.429 tec
FT size (553(
Total tas 1 am, 7 tec


MeO.
McO
1
jbv
A
j /laJULa
r
T
7
T
5
4
T
3
x
Z
1
-1
ppm

Standard C13 parameters
Pulse Sequence: *2pu1
So Want: C0C13
Ambient temperature
GENlNl-30066 "gen t n 1300"
PULSE SEQUENCE
Pulse 25.0 degrees
Acq. time 0.344 sec
Width 17354.0 Hz
2320 repetitions
OBSERVE C13, 75.4513635 HHz
DECOUPLE HI, 300.0667366 HHz
Power 35 dB
on during acquisition
off during delay
WAlTZ-16 nodulated
DATA PROCESSING
Line broadening 3.5 hz
FT size 32768
Total time 0 min, 0 sec



059
Pulu Sequence: opt
Solvent i ede13
Teap. 250 C / 298 1 K
Morcury-300 aercury300"
PULSE SEQUENCEt apt
1st pulse 180-0 degrees
2nd puli* 35-5 degree*
Acq tlee 1815 eec
Width 19S69-S Hz
3120 repetition*
OBSERVE Cl 3, 75 -3590036 MHz
DECOUPLE HI, 299-7259150 MHz
Power 43 dB
on during acquisition
waltz-16 Modulated
DATA PROCESSING
Line broadening 1-0 Hz
FT size 131072
Total t1a# ll hr, $3 win, 1 *ec
r-T ) 'H 'I'l'l'l FT ~T"T '
160 140
220
' i 1
200
180
1 i 1 1
120
o
0X^NMBoc
OTDS
rv
100
rr11 r-r
80
i ~) T-n
60
40
2 [
t
0
ppm
F-
oo

uidd
j
I
-L
z
e
X

PULSt stUutncL
Pulo* 32.7 dor
Acq. tta# Mil 6c
Width 4801.1 HZ
18 rptttlon
OSSEAVE HI, 300.0673823 NMZ
OATA PROCESSING
tin* OroAdfnlna 0.2 Hz
OAU86 podlZAtIon 1.760 64C
FT IZ4 65536
TotAl tI 0 min, 0 (4C
TDSO
T
14 13 12 11 10 9 8 7
lA__
I1' 1 1 I I ' ' I
6 5 4 3
Ink
u
1I I I I I ' 1 I
2 1-0 pp*
sO
oc

Pula# aquanca: api
So Want i cdcl3
Plant laaparatura
Min Vusuzuk 1
Marcury-300 ,*arcury300"
PUL SC SEQUENCE> apt
1st pulsa ISO 0 dagraas
2nd pulaa 23 7 dagraas
Acq. t1aa 1 SIS sac
width 10S99.S Hz
1CC4 rapatmons
OSSCBVC Cl 3 i 7S.3741040 MHZ
DECOUPLE HI, 2097S947Q0 MHZ
Powar 43 dS
on during acquisition
WALTZ-1* oodulatad
DATA PQOCESSINC
L1na broadanlng 1.0 Hj
FT iza 131072
Total tiaa 0 sin, 0 sac

BIOGRAPHICAL SKETCH
Kofi Oppong was born in Islington, England on July 10, 1969. He attended
elementary school at St. Martin de Porres School and high school at Accra Academy and
Okuapeman Secondary School in Accra Ghana. He obtained admission to the University
of Indianapolis in 1989 to study Organic Chemistry under both an athletic and a
Presidential scholarship. After completing requirements for an Associates Degree in
Chemistry, he obtained employment at DowElanco Pharmaceuticals now Dow
AgroSciences working as a chemistry technician. At DowElanco he worked in the area of
fluorine chemistry under Professor Melvin Druelinger of the University of South
Colorado on sabbatical at DowElanco during that time. Upon completion of his Bachelor
of Science degree in chemistry he decided to pursue graduate studies in Organic
Chemistry specifically in the natural product synthesis area under the direction of
Professor Tomas Hudlicky at the University of Florida. His Ph.D research has focused on
chemoenzymatic approaches to the synthesis of molecules of different complexity. His
major area of focus has been in the synthesis of morphinan intermediates utilizing a
combination of enzymatic and basic synthetic organic chemistry methods. After graduate
school he plans to pursue a career in industry as a medicinal chemist. His life goal is to be
directly involved in the synthesis of one major drug.
188

I certify that I have read this study and that in my opinion it conforms to
acceptable standards of scholarly presentation and is fully acceptable, in scope and
quality, as a dissertation for the degree of Doctor of Philosophy.
Tomas Hudlicky, Chairman
Professor of Chemistry
I certify that I have read this study and that in my opinion it conforms to
acceptable standards of scholarly presentation and is fully acceptable, in scope and
quality, as a dissertation for the degree of Doctor of Philosophy.
Merle Battiste
Professor of Chemistry
I certify that I have read this study and that in my opinion it conforms to
acceptable standards of scholarly presentation and is fully acceptable, in scope and
quality, as a dissertation for the degree of Doctor of Philosophy.
¡M-L
William Dolbier x~J
Professor of Chemistry ^
I certify that I have read this study and that in my opinion it conforms to
acceptable standards of scholarly presentation and is fully acceptable, in scope and
quality, as a dissertation for the degree of Doctor of Philosophy.
u
Vaneica Young
Associate Professor
istry

I certify that I have read this study and that in my opinion it conforms to
acceptable standards of scholarly presentation and is fully acceptable, in scope and
quality, as a dissertation for the degree of Doctor of Philosophy.
I certify that I have read this study and that in my opinion it conforms to
acceptable standards of scholarly presentation and is fully acceptable, in scope and
This dissertation was submitted to the Graduate Faculty of the Department of
Chemistry in the College of Liberal Arts and Sciences and to the Graduate School and
was accepted as partial fulfillment of the requirements for the degree of Doctor of
Philosophy.
August, 2001
Dean, Graduate School



APPENDIX
SELECTED SPECTRA
The H and l3C or APT NMR spectra of selected compounds reported in Chapter
HI and IV are graphically displayed in this appendix. The spectra along with the proposed
structure are shown.
134


Y oA^NHBoc
OTDS
IM* ll^MMJA
i
20 0 180 160 140
I ' I J
120
1[ T T 'H | > I I | I I f * T'H"
100 80 60
-1 I ' 1 T
40
xr
-n r
20
0 ppm


109
2-(4-dimethvlthexvlsilvloxv-2-bromo-(lS,4R)-2-cvclohexenvl-2R-N-rgr/-
butoxycarbonylmethylglvcinate (289a):
A solution of the glycine ester 292 (12.50 mmol, 6.23 g) in THF (100 mL) and a
1.0 M solution of ZnCh (13.70 mmol 13.70 mL,) in ether was cooled to -78C. Then a
1.7 M solution of LDA (31.00 mmol, 19.00 mL) in THF was added dropwise to the
reaction mixture and the system allowed to warm to room temperature slowly
(overnight). The reaction was quenched with water and the basic solution diluted with
ethyl ether. The reaction mixture was then acidified slowly with HC1 (IN) until a pH of
approximately 2.5 was reached. After extraction with ethyl ether (3 X 100 mL) and
drying with Na2S04, the solvent was removed to afford the crude rearranged amino acids
as light yellow cystals. The acids were purified by silica gel chromatography using a
gradient elution of ethyl acetate: hexanes (1:6) followed by methanol (100%) to afford
the mixture of acids. The mixture then treated with diazomethane to obtain the
corresponding methyl esters. The epimeric methyl esters were then introduced unto a
silica gel column and separated with hexanes (100%) to obtain clear oil of 289a (2.33 g
38%); Rf = 0.7 (ethyl acetate: hexanes, 1:4); [a]D26 -55.7 (c 1.0, CHC13); 'H NMR
(CDCI3) 8: 6.30 (dd, J = 5.6, 1.3 Hz, 1H), 5.21 (d, J = 8.6 Hz, 1H), 4.68 (dd, J = 8.7, 2.3
Hz, 1H ) 4.11 (m, 1H), 3.71 (s, 3H), 3.05 (bs, 1H), 1.86-1.78 (m, 2H), 1.63-1.50 (m, 2H),
1.43 (s, 9H), 0.84 (d, J = 6.9 Hz, 6H), 0.80 (s, 6H), 0.05 (d, J = 5.3 Hz, 6H); l3C NMR
(CDCI3) 8:171.85, 155.41, 136.30, 125.51, 80.02, 66.68, 55.86, 52.33, 45.13, 34.15,
29.16, 28.3025.76, 24.73, 23.40, 20.18, 18.56, -2.67, -2.88; IR (KBr/ cm1): 3439, 2955,
2867, 1753, 1720, 1498, 1365, 1251, 1164; HRMS Caled, for C2oH36NsiBr05 (M+):


Figure 8


67
note that Robert Ireland89'90 who performed rearrangements on silyl ketene acetal
analogues of these compounds, observed that both transition states could operate
depending on the size and position of the substituents on the cyclohexyl ring. The effect
of the large THS group can be neglected, but considerations of the dimethoxy phenyl
substituent, which is in the a-position to the allylic carbon, reveals that in the boat
transition state this substituent might have an unfavorable steric interaction with the
solvated metal (Figure 6). This leads to two steric arguments; 1) in the chair transition
state there is an unfavorable interaction between the solvated metal and the cyclohexyl
ring, 2) in the boat transition state the steric interactions are between the aromatic ring
substituent and the solvated metal. As a result of these opposing steric interactions, the
energy difference between the two transition states is very small, leading to product
formation from both pathways. In our case the chair transition state is favored resulting
in 70: 30 ratio of products.
As previously stated the rearranged acids 278a and 278b had similar
spectroscopic properties, and they were virtually inseparable by standard
chromatographic techniques. One of the options we explored to obtain pure samples of
each was to derivatize these acids into the corresponding lactones, which would offer a
more rigid structure with the anticipation that this might help in the identification of the
acids. This transformation was achieved with tosic acid in anhydrous methylene chloride
resulting in the formation of the corresponding lactones from the mixture of the epimeric
acids (Scheme 56). Even though two possible lactones could have been obtained from
this reaction we only observed the lactone derived from the trapping of the benzylic
carbocation. Indeed in this way we were able to obtain dimethoxy phenyl lactone 279 in


18
In 1992, Tius51 used an intermolecular Diels-Alder reaction as an early step in his
formal synthesis. Quinone 75, which was prepared in 7 steps from 3-methoxy-2-hydroxy
Scheme 19
benzaldehyde, was heated with diene 76, prepared in 2 steps from 1,4-cyclohexanedione
monoethylene ketal, to construct phenanthrene 77 (Scheme 19). After several subsequent
steps Tius completed his synthesis by constructing thebainone 78, thus intercepting
Gates approach.
Parker and Fokas accomplished a well designed formal synthesis of morphine in
1993. Their approach hinged on an efficient radical cascade which in one step led to the
construction of a morphinan complete with the A, B, C and O-rings of morphine (Scheme
20). To be able to take advantage of this tandem cyclization strategy, they had to first
construct aryl ether 82, through an eight-step sequence starting from m-methoxy
phenethylamine 79 and culminating in a Mitsunobu coupling of the resultant alcohol 80
with phenol 81. With the aryl ether in hand the ortho allyloxy aryl radical 83 was
generated using tributyltin hydride/ AIBN. Tandem closure led to isolation of


74
this reaction was the fact that these epimeric acids, converted to their corresponding
methyl esters could be separated by silica gel column chromatography. More importantly
the faster-eluting major isomer 289a could be equilibrated to the (3-isomer (the desired
epimer for our morphine synthesis) by an epimerization reaction with DBU. Starting
from isomer 289a, we are able to obtain a 1: 1 mixture of epimers after 96 hours in
refluxing THF. Similar epimerization reactions with TFA and NaOMe gave a 4: 1 and 5:
1 ratio of epimers respectively. Even though the reaction is still non-stereoselective, we
had found a way to obtain the epimer with the correct stereochemistry at C9 and Cl4.
This was a huge breakthrough in our synthetic approach because it meant that we now
had the opportunity to carry out an enantioselective synthesis of morphine.
c
Scheme 63. Conditions: a) LDA (2.2 eq.), ZnCU (1.4 eq.), THF, -78 C, 80%; b) CH2N2,
Et20, 90%; c) DBU, THF, reflux, 65%.
We had also achieved control of the C9 and C14 (morphine numbering) stereocenters,
which is very crucial to a successful morphine synthesis.
During this period of time we entered into a collaborative project with scientists at
Procter and Gamble Pharmaceuticals who were interested in compounds to be used as
scaffolds in their matrix metallo proteinase (MMP) inhibitors studies. Dr. Hudlicky
recognized structural similarities between their targets (hydroxamic acids with an R-


r*ducd dimethoxyphsnyl dlol
OBSERVE Cl 3
FREQUENCE 75.62 MHz
SPECTRAL WIDTH 18761.7 Hz
ACQUISITION TIME 0.800 sac
RELAXATION DELAY 0.000 SAC
PULSE WIDTH S.0 us AC
AMBIENT TEMPERATURE
NO. REPETITIONS 13
DECOUPLE HI
LOW POWER 1023
DECOUPLER CONTINUOUSLY ON
WALTZ1 6 MODULATED
DOUBLE PRECISION ACQUISITION
DATA PROCESSING
LINE BROADENING 3.5 Hz
PT SUE 32768
TOTAL ACQUISITION TIME 17 mlnutAS


CHAPTER 4
CONCLUSION
Summary and Conclusions
In the course of this project we have been able to successfully apply a
chemoenzymatic approach towards morphinan alkaloids utilizing the Kazmaier Claisen
rearrangement and the Suzuki Coupling reaction to obtain advanced intermediates
towards morphine. Control of the C9 and C14 (morphine numbering) centers was
Br
C
247
OH
THS-C1, Imid.
Br
OH Gly-Boc. DCC
DMAP
OH
DMF, -8 C ^-^OTHS CH2C12
291
l.LDA,
NHBoc ZnCL.THF
=->-
2. CHjNj THS0'
C02Me
9 NHBoc +
Br
THSO
.s1'
289b
40
a
C02Me
NHBoc
DBU, THF
Scheme 82
achieved using a combination of Kazmaier Claisen rearrangement and epimerization
reactions (Scheme 82). We were also successful in applying this chemistry to the
synthesis of matrix metallo proteinase inhibitors (MMPs) in a collaborative project with
97


23
presence of acetic anhydride to afford lactam 100. Benzylic oxidation followed by
reaction with formic acid yielded, after allylic migration and hydrolysis, alcohol 102.
Condensation of the alcohol with trimethyl orthoacetate produced acetal 103, which
subsequently underwent rearrangement to afford the methyl ester 104. This compound
contained the required quaternary center at C13 as well as the complete C ring with an
adequate pattern of substitution. Ring B was emergent in this structure but required more
steps to develop.
After several attempts, Rapoport decided to intercept the advanced Evans
intermediate 105 from which Evans was able to synthesize one of Gates advanced
intermediates (106) in six additional steps.
Parsons,20 in 1984 reported the synthesis of the precursor 113, through an
interesting sequence. Their synthesis started with the 1,2 addition of the Grignard
compound 107, to ketone 108. After hydrolysis, the product 109 was reduced using
Luche condition to obtain the alcohol 110, which was condensed with dimethylacetamide


SOLO


Standard hi param*t*rs
PulS* StqutnC*: *2pu1
TBSO
JUUUUL
198 1.98
2 02
, i (-
5
0.94
ILL
mJv^L J
3.00
0 86 2.91
ppm
6.34 8.74
6.34
sC
sC


132
M.; Peng, S. X.; Branch, T. M.; Hudlicky, T.; Oppong, K. Bioorg. Med. Chem.
Lett., 2001, 77,627.
93. Natchus, M. G.; Hudlicky, T.; Mandel, M.; Tiawo, Y. O.; Janusz, M. J.; Hsieh, L.
C.; Gu, F.; Dunaway, C. M.; Dietsch, C. R; Dowty, M. E.; Laufersweiler, M. J.;
Bookland, R. G.; Pikul, S.; Pikul, S.; De, B.; Cheng, M.; Almstead, M. G. J.
Med. Chem. 1999, 42, 5426.
94. OBrien, P. M.; Ortwine, D. F.; Pavlovski, A. G.; Picard, J. A.; Sliskovic, D. R.;
Roth, B. D.; Dyer, R. D.; Johnson, L. L; Man, C. F.; Hallak, H. J. Med. Chem.
2000, 43, 156.
95. Tamura, Y. Watanabe, F.; Makatani, T.; Yasui, K.; Fuji, M.; Komurasaki, T.;
Tsuzuki, H.; Maekawa, R.; Yoshioka, T.; Kawada, K.; Sugita, K.; Ohtani, M. J.
Med. Chem. 1998, 41, 640.
96. Whittaker, M.; Floyd, C. D. Chem. Rev. 1999, 99, 2735.
97. Leff, R. L. Ann. TV. Y. Acad. Sci. 1999, 878, 201.
98. Shlopov, B. V.; Lie, W. R.; Mainardi, C. L.; Cole, A. A.; Chubinskaya, S.; Hasty,
K. A. Arthritis, Rheum. 1997, 40, 2065.
99. Ahrens, D.; Koch, A. E.; Pope, R. M.; Steinpicarella, M.; Niedbala, M. J.
Arthritis, Rheum. 1996, 39, 1576.
100.Bramhall, S. R.; Int. J. Pancreat. 1997, 70, 163.
101. Matyszak, M. K.; Perry, V. H.; J. Immunol. 1996, 69, 141.
102.Friedel, C.; Craft, J. M.; Compt. Rend. 1877, 84, 1392.
103.Masuda, S.; Nakajima, T.; Suga, S. Bull. Chem. Soc. Jpn. 1983, 56, 1083.


49
R = Me, Cl, Ph, 2-MeOPh
NHBoc
Scheme 44. Conditions: a) Toluene dioxygenase expressed in Pseudomonas putida
F39/D (R = Me; 3.5 g/L) or Escherichia coli JM109 (pDT601A) (R = Cl; 10.0 g/L), (R =
Ph; 3.0 g/L), (R= MeOPh; 2.5 g/L). b) PAD, HOAc, MeOH, 0C -rt, 12h 85 95%. c)
TDSC1, imidazole, DMF, 5 C, 8h 80 90%. d) Boc-Gly, DCC, DMAP, CFLC12, 24 -
48h 75 90%.
hydroxyl group was then protected as the THS-ether. DCC coupling protocol was used to
convert the proximal hydroxyl group into the Boc- protected glycyl derivative 232
(Scheme 44).
The glycinates (R = Me, Cl, Ph, 2-MeOPh) served as the substrates for the first
Claisen study. The results obtained were quite promising in term of yield. All the
glycinates underwent rearrangement under the Kazmaier conditions with yields ranging
from 25 90%. Surprisingly the configuration of the major product of the rearrangement
was opposite to that expected (Table 5). Due to the fixed enolate geometry, which is a
result of the formation of the chelate, the only variable would be the predominance of one
transition state over the other. In this case the chair transition state clearly predominates
leading to the product ratios observed.


84
tributylphosphine, benzoic acid and DEAD (diethyl azodicarboxyl ate). The benzoate thus
formed was hydrolysed easily with K2CO3/ MeOH to obtain the inverted free alcohol
310. With alcohol 310 in hand the next step was to attempt the Orthoester Claisen
rearrangement. Typical conditions involve in-situ formation of the orthoester followed by
subsequent acid catalyzed rearrangement at temperatures ranging from 160 C to 180 C.
Using a combination of triethyl orthoacetate and catalytic amounts of propionic acid we
attempted the Orthoester Claisen using three different solvent systems (Scheme 71). The
reactions were run either in neat triethyl orthoacetate, xylenes or in toluene. The results
obtained were quite consisitent in all three solvents. The product of the attempted
orthoester-Claisen rearrangement was a compound resulting from cleavage of the ortho
ester intermediate and subsequent trapping of the resultant allylic cation by our amine
Scheme 71. Conditions: a) i) triethylorthoacetate, propionic acid (cat.) 160C-180C; ii)
triethylorthoacetate, propionic acid (cat.), xylenes, 160C-180C; iii) triethylorthoacetate,
propionic acid (cat.), toluene, 160C-180C.


94
we wondered if we could synthesize the boronic acid directly from bromoguaiacol. This
would give us a free phenol going into the coupling step and negate the need for a
protecting group. This reaction (Scheme 78) was not successful and resulted in isolation
of guaiacol 271 exclusively.
The MOM-protecting group was considered because of the ease of removal of the
group. Protection of bromoguaiacol as the MOM-phenoI proceeded smoothly as did the
step to make the boronic acid. Throughout this study of protecting groups we had
speculated about the possibility of performing the Suzuki coupling on the free phenol.
The Suzuki conditions require the use of 2M Na2C03 and the concern was whether the
alkoxide of the phenol would couple as effectively as the protected phenol.
Starting from the MOM-protected boronic acid 356, we were able to obtain the
Scheme 79. Conditions: a) TFA, CH2C12; b) 0.03 % eq. Pd(PPh3)4, 2M Na2C03, 289a,
PhH-EtOH, reflux; c) Bromoacetylbromide, DMAP, CH2C12; d) nBu3SnH, AIBN, PhH.
free phenol 357 with TFA in methylene chloride. The phenol was then coupled with
methyl ester 289b under Suzuki conditions (Scheme 79) leading to isolation of bicycle


122
2-(4-hvdroxv-2-benzvloxv-3-methoxvphenyl)-(lS,4R)-2-cyclohexenvl-2S-N-frt-
butoxvcarbonvlmethylglvcinate (311):
To a solution of the silyl ether 312 (0.183 mmol, 0.177 g) in THF (10 mL) was
added TBAF (0.220 mmol, 0.220 mL). This mixture was stirred for 3h while being
monitored by TLC. The reaction mixture filtered through a bed of silica gel followed by
removal of the solvent, trituration with CCL4 (3 X 20 mL) and chromatography (silica
gel, ethyl acetate: hexanes, 1:8) of the residue, afforded the pure alcohol 311 as a light
yellow oil (0.061 g, 75%; Rf = 0.4 (hexanes:ethyl acetate, 1:1); [oc]d27 + 52.7 (c 1.0,
CHCI3): H NMR (CDCI3): 7.32 (m, 4H), 6.95 (t, J = 7.6 Hz, 1H), 6.84 (d, J = 7.6 Hz,
1H), 6.65 (d, J = 7.6 Hz, 1H), 5.79 (d, J = 3.7 Hz, 1H), 5.09 (d, J = 8.1 Hz, 1H), 5.05 -
4.90 (m, 2H), 4.19 4.07 (bm, 2H), 3.85 (s, 3H), 3.61 (s, 3H), 3.36 (bs, 1H), 1.79 (bs,
2H), 1.61 (m, 2H), 1.33 (s, 9H), 1.16 (bm, 1H); 13C NMR (CDC13) 8: 172.65, 155.17,
152.36, 145.02, 141.36, 137.96, 134.89, 131.01, 128.20, 127.76, 124.17, 121.93, 111.88,
79.38, 74.75, 63.53, 55.77, 54.89, 51.89, 39.16, 29.67, 28.28, 18.77; IR (CHC13/ cm'1):
3350, 2964, 2934, 2359, 1749, 1713, 1517, 1469, 1365, 1258, 1216, 1158; HRMS Caled,
for C28H36N07 (M+ 1): 498.5900; Found: 498.2491.


90
from the a-face would lead to enr-morpnine. The second option would be to attempt the
C13 attack from the amino ester side chain either through a palladium catalyzed SN2
reaction or a radical type attack.
Before applying the alternate routes to the establishment of the C13 center to the
morphinan intermediates we decided that a quick model study to ascertain the feasibility
of these reactions would be in order. We prepared enone 340 and silyl ether 343 as shown
in Scheme 74 from phenol and 1,3-cyclohexadione (337). Cleavage of the MOM
Scheme 74. Conditions: a) MOM-C1, NaH, THF; b) EtOH, pTsOH, PhH; c) t-BuLi,
THF; e) H+/THF; f) Bromoacetylbromide, DMAP, CH2C12; g) nBu3SnH, ALBN, PhH; h)
NaBH4, MeOH; i) TDS-C1, imidazole, DMF.


24
dimethyl acetal to form the acetamido acetal 111. Concomitant rearrangement of 111 via
an Eschenmoser-Claisen rearrangement gave the amide 112 (Scheme 25). Using this
series of transformations, Parsons and Chandler were able to set the stereochemistry at
Cl3 correctly.
Closure of ring B was achieved starting with the ozonolysis of 112 which resulted
in the aldehyde 113, which was consequently treated with N-methyl hydroxylamine
Scheme 26
to yield the intermediate 114. The intermediate then accordingly rearranged to produce
the isoxazolidine 115 through an intramolecular cycloaddition with an overall 72% yield.
The cycloaddition product possessed the correct stereochemistry at C14 but was epimeric
at C9. The resultant epimers were separated using chromatography and the N-0 bond of
the morphine-like isomer was cleaved by hydrogenolysis to produce the amino alcohol
116. The morphinan 117 (Scheme 26) was obtained by heating the resulting
hydrochloride salt of 116 under vacuum followed by LAH reduction of the resulting
hydroxy amide produced the morphinan 117 with an overall yield of 2.1%.


55
CHAPTER 3
RESULTS AND DISCUSSION
Introduction
The structural complexity of the morphine molecule has prompted many
innovative routes to the morphinan skeleton as was detailed in the first chapter. The
synthetic design utilized in the chemoenzymatic synthesis of the morphinan skeleton,
makes it a very attractive route to the morphine molecule. Retrosynthetically, the
approach is directed toward the target through the intermediate (3-cyclohexenyl amino
acid 242. The amino acid could be obtained through a Claisen rearrangement of the Xxx
Scheme 47
248
247
244
245


25
21 25
In Mulzers synthesis of morphine, a creative approach towards the morphine
skeleton was employed. In the first generation of the synthesis he used a model study to
explore the possibility of establishing the important benzylic quaternary stereogenic
center (Cl3) via either conjugate addition of a cuprate to an unsaturated ketone or [3,3]-
sigmatropic rearrangement.
Starting from alcohol 118 Mulzer and co-workers attempted an Eschenmoser-
NaBHj
MeOH
Scheme 27
Claisen rearrangement to obtain amide 119 in only 21% yield. With this unsatisfactory
result they tried both the Ireland and the Johnson variants of the Claisen rearrangement
on the alcohol 120 that was obtained after reduction of the enone, both failed completely.
An explanation for this might be strong conjugation of the double bond (C5-C13
morphine numbering) to the aromatic ring. Since Claisen rearrangements and 1,4-
additions of vinyl cuprates are complementary to each other, the latter was attempted on
the enone 120 with positive results, leading to the formation ketone 121 in 87% yield
over 2 steps.


11
Scheme 10
Substituted benzyltetrahyroisoquinoline 41 was readily obtained after a Birch reduction
of the coupled product of compounds 39 and 40. Grewe then used phosphoric acid, while
Morrison, Waite and Shavel were successful with 10% aqueous HC1, to render the ortho
coupled product in 3% yield. The para product was obtained in 37% yield. This process
resulted in the formation of dihydrothebainone 35.
Other research groups later improved the ortho selectivity of the Grewe
cyclization, and this disconnection is found in several of the following formal synthesis.
Kametani41 utilized a Pschorr type cyclization in his approach to thebaine 19 to maximize
the ortho- para selectivity (Scheme 11). Diazotization of 2-aminobenzyl
tetrahydroisoquinoline 42 followed by thermal decomposition yielded racemic
salutaridine 16 in a yield of 1.1%, however no ortho-ortho products were observed.


STANDARD Ml PARAMETERS
PulK Stquff net: i2pul
Solvent: CDC13
Aablant t#*prtur
VXR-300S Mvxr300"
PULSE SEQUENCE
Pultt 57.4 dtgraat
Acq. t1* 3.744 sC
Width 4000.0 Hz
If rtptt11Ion*
OBSERVE Ml. 211.1465573 MMz
OATA PROCESSING
Gaui* apod 1zat1 on 2.228 l#c
FT t1Zf 32768
Total 11 mm* 1 *1n, 0 ac
r~
-0
ppm
(N


Solvents c OC13
AaDlent tempereture
Uierj oppong
rill! pnth
INOVA-SOO "gelnl300"
pulse sequence
Pule 335 dear ee*
Acq. t1e 32*7 ec
Width 5000.0 Hz
4 repetition
0SERVE Ml, 300.0733031 **Z
OATA PROCESSING
Une broedenlng 1.0 mz
fT size 32 768
Tote 1 tl 0 In. 4 C
vO
^r
T
3
T
z
T
1
1
PP


66
then allowed to warm slowly to room temperature over 36-48h. According to Kazmaier,
the rearrangement usually occurs between -10 0 C. In our hands we observed very
good conversion of starting material to products, with yields of rearranged acids
averaging between 75 85% but there were two significant problems. 1) The ratio of the
rearranged products 278a and 278b were opposite to that expected. We anticipated the
product with a syn relationship between the proton at C14 and the nitrogen at C9 to be
the major product. 2) The two rearranged acids possessed very similar spectroscopic
properties so initially it was difficult to ascertain the identity of the isomers. 3) These
compounds were virtually inseparable using standard chromatographic techniques even
after their derivatization into the corresponding methyl esters.
The fixed enolate geometry that results from chelate formation in the Kazmaier-
Claisen rearrangement causes the stereochemical outcome of the rearrangement to be a
function of the transition state that the reaction proceeds through. For cyclohexyl
substrates the unfavorable steric interactions in the chair transition state (Figure 3)
chair
Boat
R = 2,3-dimethoxyphenyl
Figure 6. Chair vs boat transition states in the Kazmaier Claisen Rearrangement of
morphinan intermediates.
the cyclohexyl ring and the metal chelate, causes this transition state to be less preferred
to the boat transition state, which is devoid of such interactions. It is very important to


92
(Scheme 75) in order to apply our model study to real morphinan intermediates. A
successful radical closure would lead to the establishment of the C13 quaternary center;
this would be followed by a translactamization reaction after deprotection of the Boc-
group to establish the nitrogen bridge as shown in Scheme 75.
The first order of business was to redesign our aromatic ring with a protecting
group in the 2-position that could be cleaved readily to allow for the appendage of the
bromoacetyl group. The first protecting group we worked with was the TBS-group.
Bromoguaiacol 150 was readily converted to the TBS ether using triethylamine, DMAP
and TBS-C1. Unfortunately in the next step that involved the lithium halogen exchange
and alkylation using triisopropyl borate, we realized that the TBS-group was too bulky
Br Br
150 350 351
Scheme 76. Conditions: a) TBS-C1, Et3N, DMAP, CH2CI2; b) B(Oipr)3, H+
hence preventing the subsequent alkylation step. The only material isolated from the
reaction was starting material and the reduced product 351 (Scheme 76). We were able to
confirm the formation of the anion using deuterium exchange experiments. So we
realized that the problem lay in the alkylation step. The next protecting group considered
was the paramethoxybenzyl group (PMB). This was in theory an ideal protecting group
for our synthesis because we had prior experience (in our approach to the Overman
intermediate, Scheme 69, pg 83) on the synthesis of the benzyl protected boronic acid and
reasoned that the synthesis of the PMB boronic acid would be analogous. Most
importantly this group could be cleaved with DDQ, which in our estimation would not


INOVA-500 "ge*1n1300"
pulse sequence
Pulf e 33.5 degree
Acq. t13.277 ec
Width 5000.0 HZ
4 rpit 111on*
OBSERVE HI, 300.0732144 HHZ
OATA PROCESSING
L1nt broadening 1.0 HZ
FT size 32788
Total time 0 *1n, 0 *ec
v_
lL
o
T
3
11r
2
T
1
T '
PP*


79
step involving the removal of the vinyl bromide through hydrogenation. Initial attempts at
this transformation utilized 10% and 5% Palladium on Carbon (Pd/C) at 40 psi in
methanol. Even though this resulted in the removal of the vinyl bromide it also resulted in
hydrogenolysis of the silyl ether leading to the isolation of ester 304. Even though ester
304 was devoid of the hydroxyl group, the hydroxamic acid derivative this compound
surprisingly showed some activity as an MMP inhibitor. After investigating several other
conditions we discovered that using Adams catalyst (Pt2) in methanol at 40 psi with
Table 7. MMP inhibition activity for glycine and alanine analogs.
o,
yOH
YH Br0<
Yh
o
-K
o
X
HO*'
a
"T'nhr ^
ho'
xH, o-U
'4'NHR
ho'
r^V'T'NHR
j Me
IC50 (nM)a
305
306
307
308
MMP-2
12
20
38
251
MMP-3
1,220
2,490
3,795
6,150
MMP-13
30
176
131
338
triethylamine as a proton sponge works nicely leading to isolation of the silyl ether 295 in
89% yield.
With the completion of the collaborative project, we turned our attention back to
morphine synthesis; we now had a stereospecific way of obtaining the methyl ester 289b


65
the Claisen rearrangement precursor. One of the standard procedures for achieving this
type of transformation involves a DCC coupling.75 In our hands the DCC coupling
conditions worked well with Boc-glycine, DCC and catalytic DMAP. Yields ranged from
70-85%. Careful workup of the reaction mixture, which requires removal of the reaction
solvent (CH2CI2) followed by precipitation of the dicyclohexylurea by-product with
diethyl ether a procedure which usually removes about 80 85% of the dicyclohexyl urea
(DCU) by-product. Column chromatography is then used to purify the crude mixture.
With the glycinate ester 277 in hand we were ready to perform what would be the key
step in our approach to morphine. A [3.3] sigmatropic rearrangement to establish the
chiral centers at C9 and C14 (morphine numbering). As previously discussed, the
Kazmaier-Claisen rearrangement provided the best opportunity to perform this
transformation. The conditions involve the addition of Lewis acid (usually ZnCL) to a
OMe
BocHN
OMe
LDA (2.2 eq.)
ZnCl-, (1.2 eq.)
Scheme 55
70
30
solution of the glycinate ester in THF. After about 15 minutes of stirring the reaction
mixture is cooled to -78 C and the base (usually LDA) is added. The reaction mixture


$tndr Pulll Sequtnct: pt
S Ip
k
eg £
2 *
ia
j
200
180
160
140
H O N
.^5 i
lss
UK
2
a
kk
120
T^rf-n rrr
100
F-r-rr-
80
I M "
\P
41
jl* ^
i
j
*****
PP
\r\
v-)
220


27
solution to this setback was to restrict the conformational flexibility of the aromatic ring
by means of a tether, which would also provide the two-carbon fragment for the B-ring.
This idea led to the synthetic pathway that would eventually result in the synthesis of the
morphine skeleton by way of phenanthrone 129. Starting from enantiomerically pure
phenanthrone 129, which was synthesized in 3 steps from acid 128, conjugate addition
with a variety of funtionalized organocuprates provided good yields of the olefin 130.
Mulzer and co-workers discovered that the substitution pattern on the aromatic ring was
critical in obtaining clean 1,4-adducts. With olefin 130 in hand they were able to effect E-
ring closure using a clever umpolong strategy. After trapping the ketone as the silyl
enol ether, bromination with NBS in THF at low temperature yielded bromoketone 131
as a 3:1 isomeric mixture. The undesirable isomer could however be recycled by way of
reductive removal of bromide with zinc and concomitant silylation of the resultant
enolate. When a-bromoketone 131 was heated in DMF at 140C the dihydrofuran was
obtained in 20 minutes in quantitative yield. The next stage in the synthesis involved the
introduction of the nitrogen functionality at C9 (morphine numbering). Ketone 132 was
subjected to a three step sequence that resulted in a) protection as the ethylene ketal b)
hydroboration of the vinyl group with BHvSMe2 followed by oxidation and c) removal of
the chloro substituent by catalytic hydrogenation to render alcohol 133. The alcohol was
then converted to the benzene sulfonamide derivative 134 using a variation of the
Mistunobu protocol which uses N-methylbenzene sulfonamide, 1,1-
azodicarbonylpiperidine (ADDP) and Bu^P. The next step was to introduce a double
bond by benzylic radical bromination followed by debromination. Hence exposure of 134


35
I
Scheme 36
Another noteworthy approach to the morphinan skeleton was recently published
by Hudlicky and coworkers.59 It involves a rare Heck cyclization to yield an advanced
pentacyclic precursor of morphine. Biooxidation of (2-bromoethyl)-benzene 157, with
Escherichia coli JM109 (pDT601) followed by reduction of the less hindered double
bond with diimide yielded diol 175 in 80% yield (Scheme 37). The next step involved
protection of the two diol moieties as the benzoate. This was followed by displacement of
the bromine by oxazolidine-2,4-dione to afford the dibenzoate 176. After reduction of the
more reactive amide carbonyl with NaBH4, N-acyliminium ion-olefin cyclization and
subsequent elimination of the alkyl chloride afforded the tricycle 177. This was followed
by deprotection of the benzoate groups and subsequent selective protection of the


10
The coupled product was dehydrated and then converted to enone 32. Michael addition
with dibenzyl malonate, followed by decarboxylation and a Friedel-Crafts annulation
resulted in the formation of the phenanthrenone 33. Finally the D ring was installed using
a series of steps culminating in the spontaneous formation of the ethylamine bridge
accompanied with cleavage of the C4 methyl ether and formation of the tetracyclic amide
34. An additional 8 steps followed by d-tartaric acid resolution yielded (-)-
dihydrothebainone 35, and consequently, the first of many formal synthesis of morphine.
Nine years later, Barton presented a biomimetic synthesis of a radio labeled
thebaine 38 (Scheme 9).36 Starting from tritium labeled reticuline 36 he performed an
MnC>2 promoted oxidative coupling to construct the phenanthrene core. However this step
Scheme 9
proceeded in a poor yield and after two additional steps a radioisotope dilution study of
the final thebaine 38 was performed to establish a 0.012% conversion of tritium labeled
salutaridine 37.
in io
Simultaneous reports presented in 1967 by Grewe and Morrison, Waite and
Shavel40 collectively, established a successful path for the coupling of rings A and C
(Scheme 10).


I certify that I have read this study and that in my opinion it conforms to
acceptable standards of scholarly presentation and is fully acceptable, in scope and
quality, as a dissertation for the degree of Doctor of Philosophy.
Tomas Hudlicky, Chairman
Professor of Chemistry
I certify that I have read this study and that in my opinion it conforms to
acceptable standards of scholarly presentation and is fully acceptable, in scope and
quality, as a dissertation for the degree of Doctor of Philosophy.
Merle Battiste
Professor of Chemistry
I certify that I have read this study and that in my opinion it conforms to
acceptable standards of scholarly presentation and is fully acceptable, in scope and
quality, as a dissertation for the degree of Doctor of Philosophy.
¡M-L
William Dolbier x~J
Professor of Chemistry ^
I certify that I have read this study and that in my opinion it conforms to
acceptable standards of scholarly presentation and is fully acceptable, in scope and
quality, as a dissertation for the degree of Doctor of Philosophy.
u
Vaneica Young
Associate Professor
istry


101
rearrangement is not stereospecific we are able to achieve epimerization from a 9:1
mixture favoring the wrong isomer to a 1:1 mixture. Such an intermediate would contain
the methyl group on the nitrogen and the intent is to prevent any problems we could
encounter later on in the synthesis with the glycine analog in terms of methylating the
nitrogen.


2
25%; of this, two of the important alkaloids, morphine (1) and codeine (2), constitute
approximately 17%.6
Although morphine is quite abundant from the isolation of the natural resource, it
still remains a viable synthetic target to various research groups around the world. The
focus is not only to find an efficient synthesis of morphine but more importantly to arrive
at a more practical synthesis of the morphinan skeleton, which would allow for a more
competent route to some the important derivatives of morphine.
Of the twenty-one formal synthesis of morphine only three syntheses have used
sigmatropic rearrangements as key steps. Interestingly, the rearrangements were all used
to install the quaternary center at Cl3. None of the above approaches used the
rearrangement to transfer stereochemistry inherent in the molecule to another site with
the result of correctly setting two important stereocenters in one transformation.
This thesis describes a Claisen rearrangement approach to the synthesis of the
morphinan skeleton. Control of the stereo centers C9 and C14 are discussed and recent
advances in the synthesis of the morphinan skeleton are also reported.


30
m,n and dienophile k was observed to yield furan 141. Attempts to induce Cope
rearrangement to form the desired tricyclic compound 142 were unsuccessful. To supply
some driving force for the Cope rearrangement, the THS-ether was converted in two
steps into the ketone by first fluoride deprotection of the silyl group followed by PCC
oxidation to afford ketone 143. The ketone successfully underwent the rearrangement to
afford enone 142. Reduction using Luche conditions produced compound 144 that
possesses the carbon skeleton for the lower half of morphine with all the stereocenters
correctly set with the exception of what would be C9 (morphine numbering).
Hudlicky and Gum55 published a second generation intramolecular Diels-
Scheme 31 Conditions: a) NaH, sorbyl bromide; b) PPh.i, THF; c) AciO, pyridine;
d)230 C, PhMe.
Alder approach towards the morphine skeleton in 1998. Unlike the first generation
attempt, provisions were made for eventual closure of the D-ring by appending a nitrogen
functionality from the quaternary carbon of the tricycle 149 (Scheme 31). During the
cyclization of the triene, it was discovered that the stereochemistry of the methyl group at
what would be C9 (morphine numbering) was indeed p-faced instead of a-faced as had


*t puU iw.w gr
2nd pule* 3S.S dgr*#
Acq. tin* l.llt §0C
width miM hi
12 rpt1t1on*
S


8
Scheme 5
1
Total and Formal Synthesis of Morphine
Gates landmark synthesis of morphine in 1952 started from naphthalene
HO MeO
Scheme 6
diol 23, which was subsequently converted over seven steps to the substituted
naphtoquinone 24 (Scheme 6).15,16 The [4+2] cycloaddition of 24 with 1,3-butadiene
under thermal conditions afforded the phenanthrene 25. Phenanthrene 25 was subjected
to hydrogenation in the presence of copper chromite which led to an unexpected
cyclization affording tetracyclic amide 26. Although the stereochemistry at C9 (morphine
numbering) was set correctly during the cyclization, it was necessary to epimerize the
C14 (morphine numbering) center (Scheme 7). Gates, while attempting to close the furan
ring via alpha bromination of the corresponding ketone, achieved this epimerization with
dinitroarylhydrazone 27, the most commonly intercepted intermediate in subsequent
formal morphine syntheses. The furan ring was then closed to afford pentacycle 29 and


60
different complexity bearing chiral side chains. Eventually such compounds would
contain the correct stereochemistry at the C9 and C14 (morphine numbering) centers of
morphine.
In the initial model studies, as reviewed in the historical chapter (pages 49-51), it
was discovered that even though the Claisen rearrangements proceeded with low
stereoselectivity, there was the potential to achieve complete control of the C9, C14
stereocenters through equilibration of isomers. Efforts in the initial stages of this
approach were also directed at finding efficient ways of obtaining the bicyclic skeleton
252 (Figure 4). One of the opportunities for construction of this bicycle was through
direct enzymatic dihydroxylation of substituted biphenyls. Indeed when selected
biphenyls were subjected to biooxidation conditions, the resultant diene diols were
obtained. Unfortunately it became apparent that as the degree of oxidation in the
substrate increased, the yield for the enzymatic process decreased considerably probably
Table 6. Results from Biooxidation of substituted biphenyls.
266 Rl = H, R2 = OMe
267 R1 = OMe. R2 = OMe
269 Rl = H, R2 = OMe
270 Rl = OMe, R2 = OMe
Subtrate Yield (g/1)
265
266
267
3.0
2.5
0.8


103
Experimental Procedures
3-(2,3-dimethoxvphenyl)-( 1 S,2R)-3-cvclohehexene-1,2-diol (270).
To a round bottom flask under argon atmosphere was added Pd(PPh3)4 (0.001
mol, 1.32g). This was followed by addition of 50 mL dry benzene. A solution of the
bromide 247 (0.040 mol, 7.40 g) dissolved in lOmL of ethanol was then added to the
reaction flask. This was followed by the addition of NaiC03 (36.00 mL, 2.00 M) to the
mixture. Dimethoxyphenyl boronic acid 273 (0.046 mol, 8.40g) was dissolved in 50 ml
of dry benzene was then added to the reaction mixture, which was allowed to reflux for
6h. The reaction was quenched with water and the product extracted with ethyl acetate (3
X 50 mL). The organic layers were combined, washed with brine and dried over
anhydrous MgS04. After filtration the solvent was removed, the crude product introduced
onto a silica gel column, and eluted with ethyl acetate:hexane (1:3) to obtain (7.10 g,
83%) white crystals of 270; mp: 66 67 C; Rf = 0.3 (ethyl acetate: hexane, 1:1); [oc]d20 -
62.9 (c 1.0, CHC13); 'H NMR (CDC13) 5: 7.0 (t, J = 17.7 Hz, 1H), 6.9 (d, J = 7.1 Hz, 1H),
6.8 (dd, J = 7.4, 0.8 Hz, 1H), 5.9 (t, J = 3.6 Hz, 1H), 4.4 (bs, 1H), 3.9-3.8 (m, 1H), 3.8 (s,
3H), 3.7 (s, 3H), 2.6 (bs, 2H), 2.3 (m, 2H), 1.9 (m, 2H); l3C NMR (CDC13) 5: 152.5,
145.8, 136.6, 135.8, 130.5, 124.5, 122.5, 111.6, 69.3, 69.0, 61.0, 55.8, 25.2, 24.2, ; IR
(KBr/ cm1): 1104, 1260, 1470, 1577, 2923, 3362; LRMS (Cl/ CH4) m/z (rel. intensity)
250 (m+, 100), 232 (35), 206 (93); HRMS Caled, for C,4H,804: 250.1205; Found:
250.1208. Anal. Caled, for: C,4H,804: C, 67.21; H, 7.20; Found: C, 66.62; H, 7.44.


81
(Scheme 60). The next step involved the coupling of the methyl ester with an aromatic
boronic acid to obtain our crucial bicyclic intermediate 242 using the Suzuki conditions
that by now had been optimized for the morphine project (Scheme 49, pg 57).
Second Generation Synthesis- Overmans Intermediate via Claisen Rearrangement
In this section the efforts towards synthesizing the Overman53 intermediate 95 (pg
21-22, Chapter 1) are described. The target was chosen for two main reasons, first the
synthesis of the Overman intermediate would allow us to achieve a formal total synthesis
of morphine since dihydrocodeinone (88) was synthesized in three steps from the
Overman intermediate. Also, after coupling ester 289b with an appropriate aromatic
piece this bicycle would possess all the functionality needed to achieve the synthesis of
the Overman intermediate. Retrosynthetically our goal was to arrive at the Overman
intermediate through a Friedel-Craft102'103 reaction on acid 309. Even though our earlier
Scheme 68


131
76. Kazmaier, U.; Maier, S. Chetn. Commun. 1998, 2535.
77. Kazmaier, U.; Maier, S.; Zumpe, F. L. Synlett 2000, 1523
78. Gonzalez, D.; Schapiro, V.; Seoane, G.; Hudlicky, T.; Abboud, K. J. Org. Chem.
1997,62, 1194.
79. Gonzalez, D. Ph.D. Dissertation, University of Florida, 1999.
80. Percy, J. M.; Prime, M. E. J. Org. Chem. 1998, 63, 8049.
81. Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, //, 513.
82. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
83. Hoshino, O.; Kanematsu, A.; Isoda, T.; Ishizaki, M.; Ozaki, K. J. Org. Chem.
1982, 47, 1807.
84. Hassner, A.; Alexanian, V. Tetrahedron Lett. 1978, 4475.
85. Hudlicky, T.; Gonzalez, D.; Gibson, D. T. Aldrichimica Acta 1999, 31, 35.
86. Hudlicky, T.; Luna, H.; Barbieri, G.; Kwart, L. D. J. Am. Chem. Soc. 1988, 110,
4753.
87. Gibson, D. T.; Koch, J. R.; Schuld, C. L.; Kallio, R. E. Biochemistry 1968, 7,
3795.
88. Ley, S. V.; Sternfield, F.; Taylor, S. Tetrahedron Lett. 1987, 28, 255.
89. Ireland, R. E.; Wipf, P.; Armstrong, J. D. J. Org. Chem. 1991, 56, 650.
90. Ireland, R. E.; Wipf, P.; Xiang, J. N. J. Org. Chem. 1991, 56, 3572.
91. Buckley, T. F.; Rapoport, H. J. Org. Chem. 1983, 48, 4222.
92. Natchus, M. G.; Laufersweiler, M. J.; Bookland, R. G.; Pikul, S.; De, B.; Janusz,
M. J.; Hsieh, L. C.; Hookfin, E. B.; Patel, V. S.; Garver, S. M.; Gu, S.; Pokross,


20
ring then attacked the [3-carbon of the styrene double bond to give rise to the resonance
stabilized radical of 85 with the correct stereochemistry at Cl4. Final elimination of the
phenylthio group from 85 led to formation of styrene 86. Dihydroisocodeine was formed
when the tosylamide 86 was treated with L/NH3 at -78 C. Swem oxidation of
dihydroisocodeinone 87 afforded dihydrocodeinone 88, which then completed her
approach.
The crucial step in Overmans53 approach was essentially a Grewe type
disconnection, but involved an intramolecular Heck reaction to complete the construction
of the B-ring. The synthesis started with enantioselective reduction reduction of 2-allyl
cyclohexenone 89 which would introduce chirality into the synthesis. Condensation of
the resultant 5-alcohol 90 with phenylisocyanate, oxidation of the side chain olefin with
osmium tetraoxide and acetonide protection afforded 91 (Scheme 22).
Scheme 22
A copper catalyzed suprafacial Sn2 displacement of the allyl carbamate with lithium
dimethylphenyl silane, deprotection and diol cleavage yielded an intermediate aldehyde,
which then underwent reductive amination with dibenzosuberyl amine to afford 92.


93
affect any of our chiral centers or other protecting groups. Using K2CO3 and acetone we
protected bromoguaiacol as the PMB ether. In the subsequent step we successfully
synthesized the boronic acid 353 using n-BuLi and triisopropyl borate.
c
Scheme 77. Conditions: a) PMB-Br, K7CO3, Acetone; b) n-Buli, B(oipr)3, H+; c) 0.03 %
eq. Pd(PPh3)4, 2M Na2C03, 289b, PhH-EtOH, reflux; d) DDQ, H20, CH2C12.
The Suzuki coupling of the boronic acid with methyl ester 289b (Scheme 77) worked
quite well to afford PMB ether 346. At this point we attempted cleavage of the PMB
group in order to append the bromoacetyl group on the phenol. Unfortunately this step
led mostly to decomposition of our starting material. With the failure of the PMB route
Br
150 271
Scheme 78. Conditions: a) n-Buli, B(oipr)3, H+;


38
trioxide and 3,5-dimethylpyrazole complex in CH2CI2 afforded the enone 194. Using
O
194
Scheme 39 Conditions: a) EVE, NBS, Et2. b) Bu3SnH, AIBN (cat.), benzene, c) m-
CPBA, BF3.OEt2. d) LiAlH4, THF. e) Piv-Cl, pyridine. 0 PDC, CH2C12. g) NaBH4,
/PrOH. h) Mel, CS2, NaH. i) 0-C6H4CI2, reflux, j) Cr03 3,5-(Me)2pyrazole.
Sakurai conditions allyl functionality was introduced at the C14 center (morphine
numbering) by treatment of 194 with allytrimethylsilane (Scheme 40) in the presence of
titanium (IV) chloride. Ketone 195 was then transformed into the ketal 196 followed by


110
506.1920; Found: 506.1937; Anal. Caled, for C^oH^NSiBrC^: C, 52.16; H, 7.96; Found:
C, 52.28; H, 8.06. Structure was confirmed by X-ray Crystallography (Figure 7, pg 76).
2-(4-dimethlthexvlsilvloxv-2-bromo-( lS,4R)-2-cvclohexenvl-2S-N-rerr-
butoxycarbonylmethylglycinate (289b):
The epimeric methyl esters were then introduced unto a silica gel column and
separated with straight hexanes to obtain clear oil of 289b (2.00 g 30%); Rf = 0.65 (ethyl
acetate:hexanes, 1:4); [a]D32 -27.7 (c 1.0, CHC13); H NMR (CDC13) 5: 6.17 (dd, J = 5.6,
1.3 Hz, 1H), 4.85 (m, 2H ), 4.12 (m, 1H), 3.74 (s, 3H), 2.96 (bs, 1H), 1.86-1.76 (m, 1H),
1.63-1.50 (m, 3H), 1.42 (s, 9H), 0.87 (d, J = 6.9 Hz, 6H), 0.82 (s, 6H), 0.05 (d, J = 5.3
Hz, 6H); 13C NMR (CDC1-,) 6:171.86, 155.46, 135.56, 127.99, 79.86, 65.49, 55.34, 52.38,
43.84, 34.24, 29.58, 28.29, 24.87, 20.31, 19.99, 18.58, -2.47, -2.92; IR (KBr/ cm'1):
3443, 2956, 2868, 1749, 1715, 1503, 1367, 1251, 1159; HRMS Caled, for
C2oH36NsiBr05 (M+): 506.1920; Found: 506.1937; Anal. Caled, for CioHjsNSiBrdp C,
52.16; H, 7.96; Found: C, 52.34; H, 8.01.


45
BocHN^^
O
O
218
2.2 eq LDA
*-
1.2 eq ZnCl2
Scheme 42
is explained by a preferential rearrangement through the chair-like transition state (Figure
2), which avoids the steric interactions between the pseudoaxial hydrogen and
\/
Zn
/
S S
Chair
Figure 2. Chair vs boat transition states in the
acyclic substrates.
Kazmaier Claisen Rearrangement of
the chelate complex in the boat transition state. The results obtained in the acyclic series
of experiments are summarized in Table 3, which details the influence of substituents at
the double bond, the olefin configuration and the different nitrogen-protecting groups as
related to the yield and diastereoselectivity of the rearrangement products. All the
substituted allyl esters displayed high diastereoselectivity where the formation of syn
products from trans substituted esters and anti products from cis substituted esters were
favored.


PuIf# Saquanc# apt
sD


CHEMOENZYMATIC APPROACH TO THE SYNTHESIS OF THE
MORPHINAN SKELETON VIA A CLAISEN REARRANGEMENT APPROACH
By
KOFI A. OPPONG
A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL
OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT
OF THE REQUIREMENTS FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY
UNIVERSITY OF FLORIDA
2001


Pult* Saquancai 2pul
Solvent i COCI 3
A*b1nt taaparatura
Marcury-300 %arcury300"
PUCSE SEQUENCE
Pulta 3t1 daaraat
Acq. ttsa 4.000 §ac
Width 43131 Hz
44 r#pt1t1on
OSSERVE HI, 29t7439980 MHZ
DATA PROCESSING
Cau apodlzt1on 1428 c
FT HZ* 44434
Total t1aa 0 am, 0 t#c
UL
T
11Ir
9
T
8
T
iiiii'r
7 6


43
Table 2. Effect of ^/-Protecting Groups on Rearrangement of trans ButenalGlycinates
0
r=n^A0
0
R=N II
H*fcJpX'OH
H
O
r=n*y^oh
H
214
215
216
R
yield/ %
Ratio 215/216
1. Boc
60-65
9
2. Cbz
65
4
3. Bz
65
5.4
4. CFjCO
58
1.5
5. Phthaloyl
0
6. Et2
0
group gave the
best results. The reduced
stereoselectivity with the
derivative (Entry 4) was explained by reduced importance of the chelation effect due to
the increased acidity of the nitrogen. The inability to obtain products in the case of the N-
phthaloyl and N, /V-diethyl analogues was attributed to the lack of an extended conjugated
system for nitrogen-substituted enolate stabilization.
Uli Kazmaier66 77 in 1994 published an article about a remarkable variation to the
classical enolate Claisen rearrangement that would revolutionalize the synthesis of both
natural and unnatural amino acids. It had already been established by Steglich62 63 that
enolizable amino acids could undergo rearrangement with moderate to good
stereoselectivity if the enolate geometry was fixed either in the form of an oxazole ring or


117
6-bromo-2-dimethvltert-butvlsilvloxv-(lS,2R)-5-cvclohexen-l-vl alanine(302).
A solution of the alanine ester 301 (10.00 mmol, 4.80 g) in CH2CI2 (250 mL) was
cooled to 0C. Freshly distilled TFA (18.10 mmol, 9.60 mL) dissolved in CH2CI2 (50
mL) was then added dropwise over 30 min. The mixture was stirred for 3h and monitored
by TLC. After consumption of starting material the reaction was quenched with NaHCCL
(saturated). The phases were separated and the organic layer washed with brine. The
combined organic layers were dried over Na2SC>4 and concentrated to give white flaky
crystals of the free amine 302 (2.84 g, 75%). Rf = 0.74, (ethyl acetate 100%); [ci]d30 -
59.1 (c 1.0, MeOH); 'H NMR (CDC13) 6: 8.50-7.71 (bs, 2H), 6.28 (dd, J = 3.6, 4.5 Hz,
1H), 5.57 (d, J = 3.6 Hz, 1H), 4.09 3.97 (m, 2H), 2.34 2.24 (bm, 1H), 2.12 1.98 (bm,
2H), 1.84 1.70 (m, 2H), 1.66 (d, J = 7.1, 3H), 0.83 (s, 9H), 0.04 (s, 3H); 13C NMR
(CDCI3) 8: 169.60, 135.53, 116.51, 75.57, 69.28, 49.26, 26.21, 25.84, 25.71, 18.33,
16.27, -4.81, -4.96; IR (NaCl/ cm1); 3434, 3377, 2953, 2929, 2856, 1752, 1677, 1203,
1136; HRMS Caled, for Cl5H28BrN03Si (m+): 378.3853; Found: 378.1100.


r*duc*d dimthoxyphny1 diol
OBSERVE HI
FREQUENCY 300.075 MHz
SPECTRAL WIDTH 4500.5 Hz
ACQUISITION TIME 1.998 **c
RELAXATION DELAY 0.000 f*C
PULSE WIDTH 5.0 u*c
AMBIENT TEMPERATURE
NO. REPETITIONS 16
DOUBLE PRECISION ACQUISITION
DATA PROCESSING
LINE BROADENING 1 0 Hz
FT 8 IZE 32768
TOTAL ACQUISITION TIME 1 nlmil**
MeO
MeO
i
11
T
10
9
t
8
7
4 ' 3 2 0 ppm


Standard Ml paramattrt
Pull* Stqutnct: 2pul
Solvant: CDC13
AaDltnt ttaptraturt
OEHJNI-30088 "gPInUOO"
PULSE SEQUENCE
Pultt 32.7 dtartat
Acq tlaa 3.111 IH
Width 4801.1 HZ
18 rqpttltlon
OBSERVE HI, 300.0873631 MHZ
DATA PROCESS I MO
Lint proadantna 0.2 Hz
OAUtt apodlzatlon 1.780 ttc
fT tlzt 65536
TotAl tint 1 In, 6 ttc
14
13
l 1
12 11 10
| 1 1 T~r
9 8
T
6
u L
J A^UU.
PP*
o


37
construction of the C9-C10 bridge. Starting from a mixture of the alcohol 181 they
MeO.
r*i
MeCL
MeO
MeC)
V
MeC)
LJ
MeO
K2CO,
MeOH
82%
^OAc +
(+)-(*)-182
(47% : >99% ee)
(+)-(J?)-183
(-).(5)-184
(48% : 97% ee)
Scheme 38 Conditions: a) vinyl acetate, lipase PS, Bu'Ome, 37 C.
are able to obtain the pure 5-isomer through an optimized pathway61 (Scheme 38) using
vinyl acetate. Even though this synthesis was undertaken with the racemic mixture, the
use of isomer 184 is projected for a future synthesis of natural morphine. Starting from
the mixture of alcohols 181 they synthesized the bromoacetal 185 as a mixture by
utilizing ethyl vinyl ether in the presence of NBS (Scheme 39). Under radical cyclization
conditions, they were able to obtain the cyclized product in moderate yields. The authors
attributed this to the steric hindrance caused by the methoxy group in the 2-position of
the aromatic ring. The cyclized product 186 was converted in 3 steps into the ketone 190.
Reduction of the ketone with NaBPU yielded the alcohol 191 diastereoselectively. This
result might be due to prior coordination of the borohydride reagent to the pivaloyl
moiety, which results in hydride delivery to the (3-face of the molecule. The xanthate 192
(Scheme 39) obtained from the alcohol 191 was then thermolyzed to afford the
cyclohexene derivative 193 in 81% yield. Allylic oxidation of 193 using chromium


59
In 1988, in the first publication by Hudlicky and co-workers in this area, the idea
of Claisen rearrangements of the allylic alcohol unit of the c/s-diols was proposed. This
idea was actually reduced to practice in 1997 (pg 49-52, historical section) and thus
began the initial studies that featured the Claisen rearrangement as a key step in the
OH
D-c/jiVo-inositol
258
OH
pancratistatin r qh
7-deoxypancratistatin R = H
250
260
(-)-trihydroxyheliotridane
259
D-eryf/ira-spingosine
262
OH
narciclasine R = OH
lycoricidine R = H
251
kifunensine
261
OH
amino-inositol dimer
263
O
Figure 5. (Examples of Targets Synthesized from c/s-diols)
or
chemoenzymatic approach to the morphine skeleton.
In the first generation of this approach, conditions for a suitable Claisen
rearrangement that would lead to the transfer of stereochemical information inherent in
the cyclohexadiene-diols were investigated. The Kazmaier-Claisen rearrangement offered
the best conditions for this purpose. The goal was to synthesize p-amino acids of


123
2-(4-hvdroxv-2-(2,3-dimethoxvphenvl)-(lS,4R)-2-cvclohexenvl-2S-N-fert-
butoxycarbonylmethylglycinate (317)
To a solution of the silyl ether 316 (0.355 mmol, 0.200 g) in THF (10 mL) was
added TBAF (0.533 mmol, 0.533 mL). This mixture was stirred for 3h while being
monitored by TLC. The reaction mixture filtered through a bed of silica gel followed by
removal of the solvent, trituration with CCL4 (3 X 20 mL) and chromatography (silica
gel, ethyl acetate: hexanes, 1:8) of the residue, afforded the pure alcohol 317 as a
colorless oil (0.120 g, 81%; Rf = 0.4 (hexanes:ethyl acetate, 1:1); [oc]d27 + 28.6 (c 1.0,
CHCL): 'H NMR (CDCI3): 5: 6.92 (t, J = 7.9 Hz, 1H), 6.81(d, J = 7.9 Hz, 1H), 6.65 (d,
J = 7.8 Hz, 1H), 5.95 (d, J = 2.4 Hz, 1H), 5.23 (m, 1H), 4.33 (bs, 1H),4.08 (m, 1H), 3.83
(s, 3H), 3.79 (s, 3H), 3.65 (s, 3H), 3.45 (bs, 1H), 1.94-1.63 (m, 4H), 1.56 (bs, 1H), 1.38
(s, 9H); 13C NMR (CDC13) 5:173.21, 155.65, 152.57, 146.46, 142.15, 134.83, 131.37,
124.49, 122.49, 112.31, 79.86, 63.93, 61.07, 56.17, 55.35, 52.59, 39.56, 30.45, 28.79,
19.16,; IR (CDCI3/ cm1): 3348, 2975, 2937, 1751, 1714, 1689, 1520, 1474, 1259, 1225,
1159, 1062, ; HRMS Calcd.for C30H49NO7S (m+): 421.4910 ; Found: 421. 3720;


75
configuration at the a-center of the amino acid) and some of the compounds synthesized
from the Kazmaier Claisen rearrangement during the morphine synthesis model study.
TDSO
293
Figure 7. Structure of morphine precursor used in initial MMP screen.
To our surprise, ester 293 as a mixture of R and S-isomers at a-center of the amino acid
side chain showed MMP inhibition. This led to the initiation of the collaborative project
with Proctor and Gamble Pharmaceuticals where the goal was to synthesize esters of the
type 293 to be evaluated for biological activity as MMP inhibitors. This was a great
opportunity because it gave us the occasion to apply our chemistry to industrial scale
projects. The next section will describe some of the efforts made in the synthesis of
matrix metallo proteinase inhibitors in a collaborative effort with researchers at Procter
and Gamble Pharmaceuticals.
Synthesis of Matrix Metalloproteinase Inhibitors (MMPs)
Researchers at Procter and Gamble have been exploring the synthesis of unnatural
amino acids to be used as scaffolds in the preparation of potent matrix metalloproteinase
inhibitors (MMPs).9295 MMP inhibitors have shown activity as antagonists of various
diseases where tissue remodeling plays a key role,96 including osteoarthritis,97'98
rheumatoid arthritis,99 tumor metastasis,100 multiple sclerosis101 and conjective heart
failure.102 The structural features of their target, resembled ester 289a which interestingly


PULSt stUutncL
Pulo* 32.7 dor
Acq. tta# Mil 6c
Width 4801.1 HZ
18 rptttlon
OSSEAVE HI, 300.0673823 NMZ
OATA PROCESSING
tin* OroAdfnlna 0.2 Hz
OAU86 podlZAtIon 1.760 64C
FT IZ4 65536
TotAl tI 0 min, 0 (4C
TDSO
T
14 13 12 11 10 9 8 7
lA__
I1' 1 1 I I ' ' I
6 5 4 3
Ink
u
1I I I I I ' 1 I
2 1-0 pp*
sO
oc


114
2-(4-hvdroxv-2-cvclohexenvl)2R)-2R-N-te/-fbutoxvcarbonvlmethvl glvcinate (296)
To a solution of the ester 295 (0.800 mmol, 0.450 g) in THF (10 mL) was added
distilled TBAF (1.600 mmol, 1.60 mL). The mixture was stirred for 3h and monitored by
TLC. After consumption of starting material the solvents were removed and the solid
residue introduced onto a silica gel column and eluted with ethyl acetate: hexanes (1:1) to
afford white flaky crystals of the alcohol 296 (0.322 g, 90 %). Rf = 0.45, (ethyl
acetate:hexanes 1:1); [a]D30 -4.2 (c 1.0, MeOH); H NMR (CDC13) 5: 5.20 (s, 1H), 4.01
(bs, 1H), 3.84 (s, 3H), 3.59 (s, 3H), 1.82 1.42 (m, 8H), 1.41 (s, 9H), 1.39 1.20 (m,
2H); 13C NMR (CDC13) 8: 173.73, 160.36, 79.94, 74.22, 58.49, 52.18, 41.24, 29.65,
28.54, 28.55, 28.33, 21.31, 26.17; IR (NaCl/cm1): 3440, 3377, 2929, 2855, 1743, 1712,
1162; HRMS Caled, for CuFLsNO;, (m+H-H20): 271.3645; Found: 271.4012.


Solventi cdc13
Aablent temperature
U*eri oppong
File: lecl
I nova-500 -narf
PULSE SEQUENCE
Pulii 40.0 decree*
Acq. tle 1.910 sec
Width 4500.5 HZ
04 repetition*
OBSERVE Ml. 300.0733027 NMZ
DATA PROCESSING
lIne broadening 1.0 Hz
FT size 32700
Total time 2 winut**
u
T
7
6
T
5
T
4
3
T
2
T
1
H
PP*


77
underwent other proprietary transformations before being used in MMP testing. Because
297
Scheme 65. Conditions: a) TBS-C1, imidazole, DMF, -12 C, 85%; b) DCC, DMAP, N-
Boc-glycine or A-Boc-alanine, CH2CI2, 80%; c) ZnCb, LDA, THF, -78 C, 75%; d)
CH2N2, Et20, 90%; e) H2/Pt02 (40 psi), Et3N, MeOH, 75%; 0 Bu3SnH, AIBN, PhH.g)
TBAF, THF, 80%.
of the success of the Claisen with the glycine ester, we planned to prepare sulfonamide
299 through a DCC coupling reaction with TBS-ether 298 and the alanine moiety already
functionalized as the sulfonamide. This reaction proved unsuccessful, hence we prepared
ester 301 and following the removal of the Boc protection group, were able install the
sulfonamide to obtain 299. The Kazmaier Claisen rearrangement of 299 to 300 worked
smoothly as in the case of the glycine ester (Scheme 66) even though yields were lower
probably due to the lower chelating potential of the sulfonamide as compared to the
carbamate in structure 292. The synthesis of 300 also did not proceed with the same


32
an initial enzymatic step (Scheme 32). With ether 153 in hand the next steps involved
protection of the phenol as the benzoate after cleavage of the labile thexyl group. Under
radical conditions generated by Bu3SnH and AIBN ether 155 was transformed to the
tricycle 156 with three of the five stereo centers in morphine set correctly.
A second model study (Scheme 33) to provide information about the relative
Scheme 33 Conditions: a) PAD, HOAc; b) TBSOTf; c) o-bromophenol, BU3P, DEAD,
THF; d) NaH, 2-oxazolidone; e) Bu3SnH, AIBN, toluene reflux.
stereochemistry of the C9-C14 bond was designed using diene 157, which was
functionalized effectively in four steps into the oxazolone 158. Under radical conditions
pentacycle 159 was obtained in approximately 10% yield. 'H NMR analysis confirmed a
trans relationship between the protons at C9 and C14 but it was difficult to ascertain the
configuration of these chiral centers relative to C5 or C6 and so the product was assigned
either as 159a or 159b.
With these two promising results Hudlicky and coworkers then focused on
constructing the entire morphine skeleton. In the second-generation synthesis, o-bromo-


85
functionality. We suspect that thermal and/or acid catalyzed decomposition of the
carbamate protecting group leads to the free amine, which then traps the allylic cation. In
the first generation synthesis (pg 68) we used the cleavage of the C-0 bond (at C6
morphine numbering) to our advantage in determining the identity of our rearranged
acids through a lactonization reaction. Unfortunately in this case it was a significant
problem because cleavage of the ortho ester always occurred before any potential
rearrangement and so we were unable to proceed further with this route towards
Overmans intermediate. The identity of the orthoester-Claisen product was obtained
using NMR experiments namely GHMQC and HETCOR. The sequence 5-6-7-8-14-9
6.88
(morphine
Figure 9. Assignment of Orthoester Claisen product.
numbering) was seen by the DQCOSY spectrum (HI- HI correlation) as CH-CH-CH2-
CH2-CH-CH-. The aryl group was confirmed to be in position 13 by the long range
couplings H( 11 )-C( 13) and H(5)-C(12) as seen in the GHMBC spectrum. The methyl
ester was confirmed to be in position 9 by the cross-peak H(9)-C(CO). With these
correlational experiments the molecule was assembled with the exception of the two open
valencies at C6 and C9. The carbon chemical shifts of the atoms suggest that they are


53
precursors into either catechols (A-ring of morphine) or cyclohexadiene diols (C-ring of
morphine). With all these factors combined, the chemoenzymatic approach becomes an
attractive route to the morphinan skeleton.
In 1968 as a result of studies conducted by David T. Gibson87 on the microbial
oxidation of aromatic hydrocarbons by soil bacteria, the first stable ds-diol was isolated.
The organism responsible for this transformation was a mutant strain of the bacteria
Pseudomonas putida (FI) and was designated Pseudomonas putida (F39/D). This strain
was devoid of the m-diol dehydrogenase enzyme hence only produced the cis-diene diol.
The use of these diols as synthons was initiated in the late 1980s with work done by
Ley and coworkers who achieved a racemic synthesis of pinitol from meso-cis-diols
derived from benzene. Since then, one of the leading researchers in this area of chemistry
has been Hudlicky who has been able to utilize the ds-diene-diols as chiral synthons86 in
the synthesis of a wide variety of compounds.
In 1988, in the first publication by Hudlicky and co-workers in this area, the idea
of Claisen rearrangements of the allylic alcohol unit of the cA-diols was proposed. This
idea was actually reduced to practice in 1997 and thus began the initial studies that
featured the Claisen rearrangement as a key step in the chemoenzymatic approach to the
morphine skeleton.
In the 'first generation of this approach, conditions for a suitable Claisen
rearrangement that would lead to the transfer of stereochemical information inherent in
the cyclohexadiene-diols were investigated. The Kazmaier-Claisen rearrangement offered
the best conditions for this purpose. The goal was to synthesize (3-amino acids of
different complexity bearing chiral side chains. Eventually such compounds would


Pu 1 Sequencei apt
SoIvanti cdc13
Aoblent ttaparatura
Mercury-300 "aercury300"
PULSC SEQUENCE apt
let puWa 100-0 degrttt
2nd pulse 21-7 degrees
acq. t1ae ISIS tac
width 1ISIIS Hz
41024 repetitions
OSSERVE C13I 7S-374104* MHz
DECOUPtE HI, 2007S94700 MHZ
Power 43 dt
on during acquisition
WAlTZ-lt oodulatad
DATA PROCESSING
Una broadening 1.0 H:
FT tiza 131072
Total tlae 0 aln, 0 tac
I I I I I I I I I I I I
220
200
ISO
160
140
20
iWMM
i i I ii i ri
100
WMM
I | I I I I I 'IT
80
TTT
60
4 I
20
ppa


83
289b to obtain the bicycle 312. The following reactions were performed on the 2,3-
dimethoxyphenyl and 2-benzyloxy-3-methoxyphenyl analogs as shown in Scheme 70 but
the description of the process will focus on the benzyl-protected analog. To ensure the
correct regio-chemistry of the Claisen rearrangement we proceeded to invert the alcohol
at C6 (morphine numbering). This process began with a tetrabutyl ammonium fluoride
THSO
CO,Me
NHBoc
289b
320 R = Me
316 R = Me
C02Me
C02Me
NHBoc
314 X = Bz, R = Bn
318 X = Bz, R =Me
310 X = H, R = Bn
319 X = H, R = Me
317 R = Me
321 R = Me
Scheme 70. Conditions: a) 0.03 % eq. Pd(PPh3)4, 2M NajCCb, 313, PhH-EtOH, reflux; b)
TBAF, THF; c) DEAD, PBu3, BzOH, THF, -10 C rt; d) K2C03, MeOH.
(TBAF) deprotection of the thexyldimethylsilyl group to give alcohol 311. The free de
faced alcohol was then inverted with a Mitsunobu108'109 reaction (Scheme 70) using


128
14. Herbert, R. B.; Venter, H.; Pos, S. Natural Products Report, 2000, 17, 317.
15. Gates, M.; Tschudi, G. J. Am. Chem. Soc. 1952, 74, 1109.
16. Gates, M.; Tschudi, G. J. Am. Chem. Soc. 1954, 76, 1380.
17. Moos, W. H.; Gless, R. D.; Rapoport, H. J. Org. Chem. 1982, 48, 227.
18. Weller, D. D.; Rapoport, H. J. Am. Chem. Soc. 1976, 98, 6650.
19. Chandler, M.; Parsons, P. J. J. Chem. Soc., Chem. Commun. 1984, 322.
20. Parsons, P. J.; Penkett, C. S.; Shell, A. J. Chem. Rev. 1996, 96, 195.
21. Mulzer, J.; Durner, G. Angew. Chem. Int. Ed. Engl. 1996, 35, 2830.
22. Mulzer, J.; Bats J. W.; List, B.; Opatz, T.; Trauner, D. Synlett. 1997, 441.
23. Mulzer, J.; Trauner, D. J. Chirality 1999,11, 475.
24. Trauner, D.; Porth, S.; Opatz, T.; Bats J. W.; Geister, G.; Mulzer, J. Synthesis
1998, 653.
25. Trauner, D.; Bats J. W.; Werner, A.; Mulzer, J. J. Org. Chem. 1998, 63, 5908.
26. R. Robinson The Structural Relations of Natural Products, Oxford University
Press, Oxford, 1955.
27. Zenk, M. H.; Reuffer, M.; Kutchan, T. M.; Galneder, E. in Applications of Plant
Cell and Tissue Culture, Wiley, Chichester, 1988, p. 213.
28. Herbert, R. B. Natural Products Report 1992, 9, 511.
29. Loeffler, S.; Stadler, R.; Zenk, M. H. Tetrahedron Lett. 1990, 31, 4853.
30. De-Ekanamkul, W.; Zenk, M. H. Phytochemistry, 1992, 32, 813.
31. Gerardy, R.; Zenk, M. H. Phytochemistry, 1993 34,125.
32. Zenk, M. H.; Lenz, R. J. Biol. Chem. 1995, 270, 31091.
33. Zenk, M. H.; Lenz, R. Eur. J. Biochem. 1995, 233, 132.


*V I I % VUWIJ
AaDimi iaptrtur
Ufrt oppong
illli phthc
I NOVA* S 0 0 "fl1nl300
pulst seouewce
Pulii 31.1 dar #
ACQ. tI0.800 MC
width 18781.7 HZ
1024 rpttttoni
oisctve C13 75.4542005 hhz
OCCOUPlt HI, 300.0750122 "HZ
Pow r 30 d8
Continuoufly on
WALT2*18 oduUttd
OATA PAOCCSSIHO
Lint Drodddnlog 3 *
FT *1Z* 32788
TOtd1 I1f 1 !. 4 *4C
(4
Uhliii ,i,Jk.il y.u.ikl Ji., ikIi.L
mwBmmsimwm
11
220
200
180
160
r~
'T
III II I ll I lili AlM.iibII ,Li | 111 IJ Jill a 4 J, IkllJl
I Wi i'
140
120
100
60
40
20
ppi


50
Table 5. Ratio of C9 Epimers for Kazmaier Claisen Rearrangement of glycinates.
R
233
234
Overall yield
Ph
75%
25%
80%
CH3
75%
25%
90%
Cl
90%
10%
25%
2-MeOPh
50%
50%
75%
Due to the lack of control of stereoselectivity, the authors considered
epimerization of the lactones resultant from treatment of the epimeric amino acids with
tosic acid (Scheme 45). They reasoned that since the bulky protected amino acid was
TDSO
233
234
Scheme 45
TsOH,
CH,C1,
TDSO
235 NHBoc
TsOH,
DBU/THF
more accessible in the wrong isomer (situated on the concave face of the bicyclic
molecule), it could be effectively epimerized to the more stable isomer. Hence after
treatment with DBU in THF for 37h they were able to achieve an 80% epimerization of


47
BocHN^^H''-
O
225
Scheme 43
O
)n 1) 2.5 eq LDA
1.2 eq MXn
2) CH2N2
BocHN COOMe BocHN COOMe
226
227
are obtained with cyclohexenyl glycinates (n = 2). All the metal salts used gave good
product yields in the cyclohexenyl case (n = 2). The crude amino acids obtained were
directly converted into the corresponding methyl esters using diazomethane. The best
results were obtained with zinc chloride and are summarized in Table 4.
Table 4. Results from Rearrangement with Zinc Chloride.
n
% Yield
Ratio
226:227
1
79
80: 20
2
83
90: 10
3
73
92 : 8
4
57
86 :14
It was noted during this study that homologous cycloheptenyl substrates (n = 3) showed
similar degrees of diastereoselectivity as in the cyclohexenyl case. However increase in
ring size to the more flexible cyclooctenyl case (n = 4) resulted in decrease in selectivity.
Also noteworthy was the fact that diastereoselectivity in the cyclopentenyl case (n = 1)
was lower than that observed for the cyclohexenyl and cycloheptenyl cases respectively.
The product formation as well as the diastereoselectivities observed for the six and seven
membered esters were explained by rearrangement through a boat-like transition state, 67


2 2 0
ZOO
180
160
TT'rT
140
IZO


129
34. Zenk, M. H.; Lenz, R. Tetrahedron Lett. 1995, 36, 2449.
35. Ginsburg, D.;Elad, D. J. Am. Chem. Soc. 1954, 76, 312.
36. Barton, D. H. R.; Kirby, G. W.; Steglich, W.; Thomas, G. M. Proc. Chem. Soc.
1963, 203.
37. Grewe, R.; Freidrichsen, W. Chem. Ber. 1967, 100, 1550.
38. Grewe, R.; Fischer, H.; Freidrichsen, W. Chem. Ber. 1967, 100, 1.
39. Grewe, R.; Fischer, H. Chem. Ber. 1963, 96, 1520.
40. Morrison, G. C.; Waite, R. P.; Shavel, J. Tetrahedron Lett. 1967, 4055.
41. Kametani, T.; Ihara, M.; Fukumoto, K.; Yagi, H. J. Chem. Soc. (C) 1969, 2030.
42. Schwartz, M. A.; Mami, I. S. J. Am. Chem. Soc. 1975, 97, 1239.
43. Schwartz, M. A.; Pham, P. T. K. J. Org. Chem. 1988, 53, 2318.
44. Lie, T. S.; Maat, L.; Beyerman, H. C. Reel. Trav. Chim. Pays-Bas 1979, 98, 419.
45. Rice, K. C. J. Org. Chem. 1980, 45, 3135.
46. Evans, D. A.; Mitch, C. H. Tetrahedron Lett. 1982, 23, 285.
47. White, J. D.; Caravatti, G.; Kline, T. B.; Edstrom, E.; Rice, K. C.; Brossi, A.
Tetrahedron 1983, 39, 2393.
48. Ludwig, W.; Schafer, H. J. Angew. Chem. Int. Ed. Engl. 1986, 25, 1025.
49. Toth, J. E.; Fuchs, P. L. J. Org. Chem. 1987, 52, 473.
50. Barber, R. B.; Rapoport, H. J. Med. Chem. 1976, 19, 1175.
51. Tius, M. A.; Kerr, M. A. J. Am. Chem. Soc. 1992, 114, 5959.
52. Parker, K. A.; Fokas, D. J. Am. Chem. Soc. 1992, 114, 9688.
53. Hong, C. Y.; Kado, N.; Overman, L. E J. Am. Chem. Soc. 1993, 115, 11028.
54. Hudlicky, T.; Boros, C. H.; Boros, E. E. Synthesis 1992, 174.


72
Scheme 60
At this point we reevaluated our synthetic approach to alleviate the
stereoselectivity problem in the Kazmaier-Claisen rearrangement. We rationalized
Scheme 61


86
bonded to the nitrogen atom. This molecular formula was further confirmed by HRMS.
From these correlation experiments the proton and carbon signals were correctly assigned
as shown in Figure 9. From long range coupling experiments, the connectivity of our
molecule was confirmed when we observed a long range coupling between the proton at
C6 (morphine numbering) whose signal appears at 4.91 ppm and the proton on the a-
center of the amino acid (C9 morphine numbering) whose signal appears at 4.06 ppm.
This was further confirmed by a long-range H- C coupling between the proton signal at
4.91 ppm and the carbon signal at 59.6 ppm, which belongs to the carbon at the a-center
(C9 morphine numbering).
Since we now had alcohol 311 in our possession, we reasoned that we could still
establish the C13 quaternary center by employing a conjugate addition of an
Scheme 72. Conditions: a) PCC, CH2C12; b) (H2C=CH)2CuMgCl, THF, -78C.
organocuprate with the enone obtained from oxidation of the alcohol. Alcohol 311 was
subjected to PCC oxidation conditions to obtain enone 326. Upon addition of a vinyl
cuprate, no 1,4 addition product was isolated. The major product of the reaction was the


059
Pulu Sequence: opt
Solvent i ede13
Teap. 250 C / 298 1 K
Morcury-300 aercury300"
PULSE SEQUENCEt apt
1st pulse 180-0 degrees
2nd puli* 35-5 degree*
Acq tlee 1815 eec
Width 19S69-S Hz
3120 repetition*
OBSERVE Cl 3, 75 -3590036 MHz
DECOUPLE HI, 299-7259150 MHz
Power 43 dB
on during acquisition
waltz-16 Modulated
DATA PROCESSING
Line broadening 1-0 Hz
FT size 131072
Total t1a# ll hr, $3 win, 1 *ec
r-T ) 'H 'I'l'l'l FT ~T"T '
160 140
220
' i 1
200
180
1 i 1 1
120
o
0X^NMBoc
OTDS
rv
100
rr11 r-r
80
i ~) T-n
60
40
2 [
t
0
ppm
F-
oo


46
Table 3. Results from Acyclic Kazmaier Claisen Rearrangement
R3 R2
R4
xhn^Y
o
221
R1
R2 R2
R3\J^ .R! R^aJUn R1
XHN COOH XHN COOH
223 224
X [a]
R1
R2
R3
R4[b]
Yield
Diastereomer ratio
()-223: ()-224
1
Z
H
H
H
H
88
_
2
Z
H
ch3
H
H
78
-
3
z
H
H
C3H7
H
76
95:5
4
z
ch3
H
ch3
H
88
93:7
5
z
c2h5
H
ch3
H
98
95:5
6
z
C2H5
H
H
c4h,
73
95:5
7
Boc
ch3
H
CH3
H
84
96:4
8
Boc
H
H
c3h7
H
78
96:4
9
TFA
H
H
c3h7
H
79
95:5
10
TFA
c2h,
H
H
c4h9
65
94:6
11
Z
H
H
H
D
75
98.5:1.5
[a] Z = benzyloxycarbonyl, Boc = tert-butoxycarbonyl, TFA =trifluoroacetyl
[b] D = tert-butyldiphenylsilyl
Due to the excellent results obtained with the acyclic substrates, the chemistry
was applied to cycloalkenyl glycinates (Scheme 43). These substrates were of particular
interest because their rearrangement would yield y,8-unsaturated amino acids, a class of
compounds with high activity as enzyme inhibitors. Indeed it had been previously
postulated that cyclic allylic esters prefer to rearrange via a boat-like transition state.
Kazmaier and coworkers investigated the effect of ring size as well as the metal salt used
for chelation of the ester enolate (Table 4). As predicted, with the cyclic allylic esters the
swi-product is preferred and the best results with respect to yield and stereoselectivity


100
Scheme 85. Conditions: a) 0.03 % eq. Pd(PPh3)4, 2M NaaCC^, 289b, PhH, reflux; b) E
coli pDTG 602, c) TBAF, THF;
from our synthesis. Unfortunately we ran into feasibility problems because the substrate
364 could not be dissolved in the aqueous media containing the bacteria even after
cleavage of the THS-group to give the alcohol 366. Even though this attempt was
unsuccessful our goal still remains; to arriving at a truly chemoenzymatic synthesis of
morphine (Scheme 85). It is still possible to arrive at compounds like 365 through an
initial biooxidation of the aromatic piece followed by Suzuki coupling reaction
NMeBoc
1. LDA,
TMSC1,
THF, 80%
2. CH2N2
Scheme 83
We have also synthesized the sarcosine ester 367 (Scheme 86) and performed the Ireland
Claisen rearrangement on this substrate with interesting results. Even though the


C*
vC
dd o oz
. i.. i... 11... i. i. i
0
09
OS
00T
021
OH
091
>|PT 'y |
081
. i .
002
i i i i i i i I i.
022
.ulii
1 1
f rI n| ''train PF* Mr tT'rP
rnin'Wf rr vu f*r
3WO
.OH
WO
it ut* t I t*ll
tlOttt I* 14
IM 0 t #u l u*D*ojq tv 11
tMinnoiM i*
0*1*1npo* Ifzitvn
uaitiainbo* Suijnp uo
tft 004*114 M2 tM 1XOOO>0
iHM **4i4C-i4 cxo wnno
uO|l|l*d*J JtJ
*h i-mit nom
lift *! *
jfl*o Itl tn4 out
J0p 0'09t *l4 lit
i4 i ion indis nvu


I would like to thank some of the friends I have made in Gainesville: Tahra
Edwards, Gabriela Feldberg, Jacinth McKenzie and Michael Mosi, Jerremey Willis, and
Nadia Kunan who made my stay here a great experience and gave me reason to persevere
and to finish.


95
358 albeit in a 45% yield. With the phenol in hand we were able to synthesize the
bromoacetate derivative using DMAP and bromoacetyl bromide in methylene chloride.
The radical reaction of bromoacetate 345 using the same conditions as was used in the
model study resulted in the formation of the reduced product 359. The synthesis of enone
347 proved to be more challenging than expected. Starting from phenol 358 we had two
options available. We could first alkylate the phenol as the bromoacetate and then remove
the silyl-protecting group followed by subsequent oxidation of the C6 (morphine
Scheme 80. Conditions: a) Bromoacetylbromide, DMAP, CFECF; b) TBAF, THF; c)
PCC or MnC>2 or Dess-Martin.
numbering) alcohol. Equally we had the option of initial removal of the silyl-protecting
group followed by oxidation to the enone and then final alkylation of the phenol to form
the bromoacetate. Preliminary evidence indicates the formation of a Finkelstein111 type
product in our attempt to cleave the silyl-protecting group in intermediate 345 in the
presence of the bromoacetate as shown in scheme 80. Conversely we had problems with


70
Initially we used thionyl chloride as the reagent for this transformation. We realized that
these conditions (Scheme 58) were too harsh because we observed cleavage of the thexyl
and Boc- protecting groups and or decomposition of the starting material even before
addition of the Lewis acid. We saw no evidence of cyclized product (283) in the reaction
mixtures and hence decided to resort to milder conditions for synthesizing the
intermediate acid chloride. The conditions that we decided to work with involved either
making the acid chloride by using oxalyl chloride/DMF or PPlvj/CCL using conditions
analogous to that used by Rapoport91 in his synthesis of tylophorine. Starting from acid
278, we used a combination of oxalyl chloride and DMF to generate the acid chloride.
Typically after four to six hours, we observed disappearance of the OH-stretch of the acid
and appearance of a strong signal at 1780 corresponding to the acid chloride. At this point
the Lewis acid was added and the reaction refluxed overnight. The various Lewis acids
employed were AICI3, Me2AlCl, ZnC^ and SnCU. The reactions typically after workup
led to recovery (Scheme 59) of starting material and a small percentage of by-product due
to cleavage of the Boc-protecting group. The results from the triphenyl phosphine/carbon
tetrachloride reaction were similar to the oxalyl chloride/ DMF reaction, here too no
product from closure of the CIO- Cl 1 bond was isolated. Mulzer25 in his discussion of his
attempt at the Friedel-Craft reaction suggested that there might be a phenomenon similar
to that of atropoisomerism of biphenyl compounds present in these types of substrates.
This being the case our A-ring may be twisted out of conjugation with the cyclohexenyl
ring making a Friedel-Craft type closure very difficult. The solution to this problem will
be to either make the furan ring of morphine or to establish the nitrogen bridge first. This
might help to hold the aromatic ring in a more preferable conformation that would allow


40
Scheme 41 Conditions: a) LiAlH4, MeNHTs, B113P, DPAP. b) Sodium naphthalenide,
THF, -30 C.
Chelated Enolate Claisen Rearrangements
In 1977 Wolfgang Steglich62' 63 reported the synthesis of a series of amino acids
utilizing a Claisen rearrangement. This was the first time the Claisen rearrangement had
been extended to the synthesis of this important class of compounds. Steglich and co
workers first synthesized N-benzoyl a-amino acid esters with a general structure such as
205. After transesterification with the allyl alcohol 206, they then observed that under
dehydration conditions oxazoles were formed. The oxazoles thus formed concomitantly
rearranged without isolation to form oxazolones 209 (Scheme 41). Under conditions of
hydrolysis they observed the formation of (3-amino acid with the general structure of 210
in yields up to 95%. The oxazole intermediate 208 can be seen as a trapped enolate


Solvent. . J
Aaoient teaperature
VXK-300S "vitriOO"
puise seoueNce
Pull* $7.4 dffgros
Acs. tlae 3.744 c
width 4000.0 Hi
If repetitions
0MAVC HI, 211.1468 5 6 5 MHZ
OAT A PROCESS I NO
Oeuss epodlzetlon 2.228 sec
fT size 32788
Tote 1 ties 1 a 1n, 0 sec
OMe
JL
T
5
8
7
6
A
Van^.
x
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9
28 29
Scheme 7
completed the construction of the morphine skeleton. Finally, hydrolysis, lithium
aluminum hydride reduction, and demethylation completed the first total synthesis of
morphine 1.
Shortly after Gates historic synthesis, Ginsburg completed a formal synthesis by
synthesizing dihydrothebainone 35 in 1954.35 In Ginsburgs synthesis, condensation of
34 35
Scheme 8
veratrole 31 via ortho-lithiation to cyclohexanone 30 served as the first step (Scheme 8).


63
yields (45-50 %) hence making this route
to the coupled product unfavorable.
Scheme 52. Conditions: a) PAD, HOAc, MeOH, 0 C-rt 14 h, 90 %; b) DMP, Acetone,
TsOH, 95%; t-BuLi, B(OEt)3, -78C, NH4C1 (satd), 45-50 %.
We now turned our attention to the Suzuki Coupling81'82 step, a technique which has
become one of the more efficient methods of bond formation between an aromatic ring
and an sp2 center. In our hands typical conditions involved the use of tetrakis
triphenylphosphine palladium (Pd(PPh3)4) as the catalyst and a benzene/ ethanol solvent
system with 2M Na2C03 as the base. The reactions were normally complete after three
hours under reflux conditions. Yields were in the 75-80 % range and this was very crucial
since the Suzuki coupling was one of the key steps in our synthesis (Scheme 53).
Scheme 53. Conditions: a) 0.03 % eq. Pd(PPh3)4, 2M Na2C03, 247, PhH-EtOH, reflux;
b) 0.03 % eq. Pd(PPh3)4, 2M Na2C03, 274, PhH-EtOH, reflux; c) H\ THF.


133
104. Johnson, W. S.; Wertheman, L.; Bartlett, W. R; Brockson, T. J.; Li, T. T.;
Faulkner, D. J.; Peterson, M. R. J. Am. Chem. Soc. 1970, 92, 741.
105. Stork, G.; Takahashi, T.; Kawamoto, I.; Suzuki, T. J. Am. Chem. Soc. 1978, 100,
8272.
106. Felix, D.; Gschwend-Steen, K.; Wick, A. E.; Eschenmoser, A. Helv. Chem. Acta
1969, 52, 1030.
107. Corey, E. J.; Shibasaki, M.; Knolle, J. Tetrahedron Lett. 1977, 1625.
108. Mitsunobu, O. Synthesis, 1981, 1.
109. Schmidt, U.; Utz, R. Angew. Chem. Int. Ed. Engl. 1984, 23, 723.
110. Auerbach, J.; Weinreb, S. M. J. Chem. Soc. Chem. Commun. 1974, 298.
111. Finkelstein, H. Ber. 1910, 43, 1528.
112. Bui, V. P.; Hansen, T.; Stentrom, Y.; Hudlicky, T. Green Chemistry 2000, 263


105
6-(2,3-dimethoxvphenvl)-2-dimethvlthexvsilvloxv-(lR,2S)-5-cvclohexen-l-vl-N-fert-
butoxycarbonvlglvcinate (211).
A solution of Boc-glycine (6.600 mmol, 0.16 g) and DMAP (catalytic) in CH..C1,,
(60 mL) was cooled to 0o C. DCC (9.000 mmol, 1.90 g) was added to the cooled mixture
resulting in a yellow precipitate. A solution of the TDS protected diol 276 (6.000 mmol,
2.20 g) in CHiCh was then added by syringe and the reaction mixture allowed to stir. The
solution was diluted with ethyl ether and filtered through a plug of silica gel to remove
the precipitate of dicyclohexylurea. Removal of the solvent followed by chromatography
(silica gel, ethyl acetate:hexanes, 1:9) the residue afforded the pure amino ester 277 (4.00
g, 71%) as a thick colorless oil; Rf = 0.4 ethyl acetate:hexane 80:20; Md'5 -74.0 (c 1.0,
CHC13); >h NMR (CDC13) 5: 6.9 (t, J = 7.9 Hz, 1H), 6.8 (dd, J = 8.2 Hz, 1H), 6.7 (dd, J
= 7.6 Hz, 1H), 5.9 (bs, 2H), 4.9 (bs, 1H), 4.1 (m, 1H), 3.8 (s, 3H), 3.7 (s, 3H), 2.2 2.1
(m, 2H), 1.9 (m, 1H), 1.7 -1.6 (M, 1H), 1.6 1.5 (m, 1H), 1.4 (s, 9H), 0.9 (d, J = 6.7 Hz,
6H), 0.8 (d, J = 3.7 Hz, 6H), 0.1 (d, J = 11.9 Hz, 6H); 13C NMR (CDC13) 5: 168.4, 155.2,
154.1, 150.2, 134.6, 130.8, 130.6, 129.0, 128.9, 119.8, 110.3,79.4,71.7,69.1,54.3,42.3,
34.2, 28.2, 25.0, 24.8, 24.4, 20.2, 20.1, 18.4, 18.3, -3.2; IR (KBr/cm1): 3443, 2931, 2105,
1643, 1470, 1366; HRMS: C29H48NO7S (M+) Caled. 550.5983, Found: 550.3197. Anal.
Caled, for: C29H47NO7S: C, 67.30; H, 9.24; Found: C, 67.13 ; H, 9.20 .


MeO.
McO
1
jbv
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7
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-1
ppm


ACKNOWLEDGMENTS
I would like to take this opportunity to express gratitude to a number of people
who had a positive influence on my life in the last 5 years. First I would like to thank my
research advisor Dr. Tomas Hudlicky for his support and guidance over the years. I have
come to appreciate the impact and the importance of the training I received from Dr.
Hudlicky. Being associated with his group has been one of the landmark experiences in
my life, something I will not forget.
I also wish to show my appreciation to members of my committee (Dr. Merle
Battiste, Dr. William Dolbier, Dr. Dennis Wright, Dr. Vanecia Young and Dr. Howard
Johnson) for the help they rendered to me during my time here. I give special thanks to
Dr. Battiste and Dr. Dolbier, who as committee members had a direct impact on my
development as a student. I also want to acknowledge Dr. Dolbier because he played a
huge role in my obtaining admission to this graduate school. I extend thanks to Dr. James
Deyrup, Donna Balkom and Lori Clark for their assistance with all the administrative
aspects of my stay at the University of Florida. Since joining the faculty of the University
of Florida, Dr. Dennis Wright has been a tremendous asset to me personally and to all the
students in the Hudlicky group in general. I would like to acknowledge Dr. Dennis
Wright for all his chemistry suggestions, discussions and contributions, all of which
added to my growth as a chemist.
I extend my gratitude to all the members of the Hudlicky research group who in
one way or another helped to nurture me over the years. I would like to


36
homoallylic hydroxyl group as the TBDMS ether. Using Mitsunobu protocol the
d, e, f
OH OBz
Scheme 37 Conditions: a) E. coli JM109 (pDTG601); b) PAD, AcOH, MeOH; c)
PhCCbH, DCC, DMAP, CH2CI2; d) Oxazolidine, tetramethylguanidine, THF, reflux; e)
NABH4, MeOH; f) AICI3, CH2C12; g) DBU, DMSO, reflux; h) LiOH, MeOH; i)
TBDMSOTf, imidazole, DMF; j) Bu3P, DEAD, bromoguiacol, THF; k) Pd(PPh3)4,
proton sponge, toluene, reflux.
unprotected alcohol was converted into the bromoguaiacol derivative to give intermediate
179. Heck cyclization of the tetrasubstituted olefin yielded the tetracycle 180 as the only
identifiable product.
In a recent publication in Organic Letters,60 Ogasawara and co-worker undertook
a rather elaborate approach to the morphine skeleton that deserves mention because of
their clever approach to the construction of the C14 stereocenter correctly and also their


Ote. & VT
diti
Sp 11 mi
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300.065
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100
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78
diastereoselectivity as in the earlier cases presumably because of the increased size of the
sulfonamide functionality leading to a decrease in preference for the chair transition
Scheme 66. Conditions: a) alanine N-sulfonamide, DCC; b) N-Boc alanine, DCC; c)
TFA, CH2CI2; d) 4-methoxy-l,l-biphenylsulfonyl chloride, Et3N, THF; e) ZnCE, LDA,
THF, -78 C; f) CH2N2, Et20; g) H2 (40 psi), Pt02, Et3N, MeOH; h) TBAF, THF.
state. Even so, acids 300 were converted over three steps to methyl esters 303, the
precursors for MMP inhibitors. One of the more difficult steps in this project was the last
Scheme 66. Conditions: a) H2 (40 psi), 5% or 10% Pd-C, MeOH; b) H2 (40 psi), Pt2,
Et3N, MeOH.


Pu 1 squnci! 2 pu1
Solvent i C0C13
Aabitnt ttp#r#tur
VXR-300S Hvr300
PUlSC SCQUeNCC
Pull# 57.4 dgrt
Acq t3.744 fc
Width 4000.0 HZ
32 rpt1t lorn
OMCRVt HI, 211.1460571 HM z
OATA PROCESSINO
Oauti Apod 1za 11 on 2.226 SAC
FT s 1 Z A 32766
Total tlA 4 1n, 0 SAC


isc oascRvi
Pula# Sequence apt
Solvent i cdc13
*eblent temperature
it1i NnsoaUclJ
M#r cury-30 0 "ercury300"
PULSE SEQUENCE apt
1st pula# 1*0.0 degrees
2nd pulse 23.7 degrees
Acq. tina 1.010 mc
width HUM Hz
till repettIon*
OOSERVC CIS, 70.3741741 MHz
DECOUPLE HI, 200.7004700 MHz
Powar 43 dft
on during acquisition
WALTZ-14 Modulated
DATA PROCESSING
Una broadening 1.0 Hz
FT iza 131072
Total t1ae 0 a1n, 0 sec
MeO
BnO
BzO
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*4
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4
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14
the whole synthesis required isolation of only six intermediates, obtained in sufficiently
pure form to continue with the synthesis. It still remains the most practical synthesis to
date.
Scheme 14
In 1983, Evans46 used the ortho lithiated veratrole 54 in an initial coupling
reaction with piperidone 55 in his approach (Scheme 15). After the coupling, dehydration
afforded alkene 56, which was further coupled with dibromide 57. Isoquinoline 58 was
then converted to the aziridinium salt 59, which was then opened, oxidized to an
aldehyde and finally treated with Lewis acid to form the morphinan 60. Removal of the
CIO hydroxyl group followed by oxidation afforded ketone 61, which is one of Gates
intermediates hence resulting in a formal synthesis.


96
the oxidation of allylic alcohol 361 probably due to reaction of the oxidant with the
phenol. The yields for the oxidation step were very low (10- 15%) and so this route could
not be used to obtain decent quantities of the enone 362. Our final option was to first
form the enone from the vinyl bromide and then achieve coupling with boronic acid 357.
Indeed this worked quite well with the isolation of the enone 362. In the next step the
phenol was converted to the bromoacetate, which was then subjected to the radical
cyclization conditions. We are currently in the process of optimizing this reaction.
Scheme 81. Conditions: a) TBAF, THF; b) PCC, CFFCb; c) 0.03 % eq. Pd(PPh3)4, 2M
Na2CC>3, 289a, PhH-EtOH, reflux; d) Bromoacetylbromide, DMAP, CH2CI2; e)
nBu3SnH, AIBN, PhH;.


48
which minimizes the steric interactions between the cycloalkenyl ring and the solvated
chelating metal (Figure 3).
chair
Boat
Figure 3. Chair vs boat transition states in the Kazmaier Claisen Rearrangement of cyclic
substrates.
In summary Kazmaier has successfully demonstrated the utility of his variation of
the classic enolate Claisen rearrangement. The chelated ester enolate rearrangement is not
partial to acyclic substrates but can also be practical for cyclic substrates. High
diastereoselectivity and excellent yields are observed for the rearrangements, which
proceed via a boat-like transition state for cyclic esters and a chair-like transition state for
acyclic esters.
In 1997 Hudlicky and coworkers applied the Kazmaier chelated enolate
rearrangement to their chemoenzymatic approach to morphine. Model studies to obtain
optimum reaction conditions were undertaken on compounds of type 232. These
glycinates were obtained first by direct oxidation of the aromatic precursor by either the
mutant strain Psuedomonas putida F39/D or the more potent recombinant organism
Escherichia coli JM109(pDTG601 A) to render the diene-diols of type 229. After diimide
(potassium azodicarboxylate) reduction of the less hindered double bond, the distal


Pulse Sequence> apt
Solventi cdcl3
Aablent temperature
*#rcury-300 rcuryJOO"
Put SI SiguiMCEi apt
let pulsa 10.0 deyr
2nd puls# 23.7 degrees
Acq. t1ee lll( sec
width HUB S HZ
3120 repetitions
OSSCRVI Cl 31 71.3774725 MHz
OCCOUPIC HI, 200.7725155 Bail
Power 43 dt
on during acquisition
WAtTZ-15 modulated
DATA PQOCCSSING
Line broadening 1.0 Hz
FT size 131072
Total ties 0 sin, 0 sec
220
200
180
1 i i | i i i r r1
160
14 0
I i i i i | i i i i i i i i | i">
120 100


39
Scheme 40 Conditions: a) allylTMS, TiCl4, CH2C12, -78 C. b) (CH2OH)2, p-TsOH,
benzene, reflux, c) 0s04 (cat.), NaI04. d) (CH2OH)2, p-TsOH, benzene, reflux.
reductive cleavage of the olefin in 196 to afford the aldehyde 197. Upon reflux in
benzene in the presence of ethylene glycol and catalytic amounts of p-toluenesulfonic
acid, the hydrophenanthrene 198 was obtained in 85% yield. Construction of the D-ring
was achieved using Parker conditions, which involved deprotection of the pivaloyl group
followed by Mitsunobu (Scheme 41) coupling of the free alcohol 199 with N-methyl-p-
toulenesulfonylamide to give the tosylate 200. Treatment of the tosylate with sodium
naphthalenide afforded the morphinan 201 in 89% yield via concomitant detosylation
followed by regioselective cyclization. Morphinan 201 was then converted in 3 steps to
the morphinan 202, which is the 0-methylated analogue of dihydrothebainone 35 (page
14).


124
2-(4-benzovl-2-(2-benzvloxv-3-methoxvphenvl)-(lS,4R)-2-cvclohexenvl-2S-N-frr-
butoxvcarbonvlmethvlglvcinate (314):
To a stirred solution of the alcohol 311 (0.183 mmol, 0.091 g) and benzoic acid
(0.366 mmol, 0.050 mL) in dry THF (5 mL) was added a solution of the Mitsunobu
reagent previously prepared by addition of diethyl azodicarboxylate (DEAD) (0.366
mmol, 0.058 mL) to a stirred solution of PBU3 (0.366 mmol, 0.091 mL) in THF (5 mL) at
0C and stirred at the same temperature for 15 min. The reaction mixture was allowed to
warm slowly to room temperature over 3h after which the solvents were removed under
reduced pressure an the crude product purified by chromatography (silica gel, ethyl
acetate: hexanes, 1:8) of the residue, afforded the pure benzoate 314 as a clear oil (0.155
g, 94 %); Rf = 0.6 (ethyl acetate :hexanes, 1:4); [oc]d27 + 166.8 (c 1.0, CHCI3): H NMR
(CDCI3): 8.01 (m, 1H), 7.92 (d, J = 1.5 Hz, 1H), 7.56 7.23 (m, 10H), 6.96 (t, J = 8.1 Hz,
1H), 6.84 (d, J = 8.3 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 5.88 (m, 1H), 5.08 (d, J = 11.0 Hz,
1H), 4.92 (d, J = 11.2 Hz, 1H), 4.66 (d, J = 8.3 Hz, 1H), 4.15 (bm, 2H), 3.85 (s, 3H),
3.59 (s, 3H), 3.57 (bs, 1H), 2.21( bm, 1H), 1.71 (bm, 2H), 1.35 (s, 9H), 1.21 (bm, 2H);
13C NMR (CDCI3) 5: 172.65, 155.17, 152.36, 145.02, 141.36, 137.96, 134.89, 131.01,
128.20, 127.76, 124.17, 121.93, 111.88,79.38,74.75, 63.53, 55.77, 54.89,51.89, 39.16,
29.67, 28.28, 18.77; IR (CHC13/cm'1): 3370, 2950, 1747, 1715, 1698, 1520, 1505, 1454;
HRMS Caled, for C35H4oN08 (m+): 602.2774; Found: 602.2754.


68
pure form and were able to obtain spectral data for the compound. Lactone 280 was also
Scheme 56
TsOH,
CH2CI2 anh.
isolated and easily converted to lactone 279 through an epimerization reaction with DBU.
The data obtained was compared to phenyl lactone 281 which had been synthesized
earlier and whose identity had been confirmed by X-ray crystallography.
Friedel Craft-Attempt at C10-C11 Closure
Even though we were unable to separate the two epimeric acids 279a and 279b
we saw an opportunity to study the feasibility of the C10-C11 bond (morphine
numbering) closure, through a Friedel-Craft type reaction. We had conflicting literature
precedence for this transformation. Ginsburg3fi was able to close the C10-C11 bond under
acid conditions from the intermediate acid 282. Although Ginsburgs intermediate
contains the same bicyclic skeleton as in our example, his compound is much simpler and
essentially has only one more functional group, the ketone at C5 (morphine numbering).


62
typically gives a 50-60 % yield of bromogiuacol (150) in addition to two other
271
273
Scheme 51. Conditions: a) Br2, tert-butylamine, toluene, -78 C, 60-62 %; b) Mel,
K2CO3, Acetone, rt., 90-94 %; c) Mg, I2 (cat.), B(OEt)3, NH4C1 (satd), 80-85 %; d) t-
BuLi, B(OEt)3, NH4CI (satd), 77-80 %.
regioisomers. Isolation of bromogiuacol from the reaction mixture is achieved by
Kugelroh distillation. The next step involved methylation of the phenol with methyl
iodide in acetone, employing potassium carbonate as the base. These reactions typically
gave a 90-94 % yield of the dimethyl bromocatechol. In the next step the 1,2-
dimethoxybromobenzene (272) was converted into the corresponding boronic acid (273).
The boronic acid was obtained by using either Grignard conditions or lithium halogen
exchange with r-butyllithium. The Grignard conditions gave better overall yields.
The other coupling partner became available from diimide reduction of the chiral
cyclohexadiene diol 248, with potassium azodicarboxylate (PAD). This procedure, which
has been optimized in the Hudlicky group, typically gives about 90-95 % of the reduced
product 247 (Scheme 52). We also synthesized the boronic acid derived from vinyl
bromide 247 with the intent of coupling it with 1,2-dimethoxybromobenzene 272
(Scheme 52). Conversion of acetonide 274 to the boronic acid 275 proceeded with low


uidd
j
I
-L
z
e
X


19
85
84
Scheme 20
tetracycle 86 in 35% yield by initial attack of the radical on the proximal but more
substituted end of the cyclohexyl ring double bond to establish the furan ring with the
correct stereochemistry at Cl3. The radical generated in the formation of the furan
NMeTs
Scheme 21
87


recognize Dr. Yan Fengyan and Dr. Ba Nguyen with whom I collaborated on the fluoro-
inositol project; and Dr. Larry Brammer, who was instrumental in my training during my
first year in graduate school. I thank Dr. David Gonzalez and Dr. Bennett Novak for their
advice and chemistry discussions. Dr David Gonzalez was instrumental in my
advancement in laboratory techniques and for that I am indebted. The fermentation team
also deserves acknowledgment: Dr. Bennett Novak, Dr. Mary Ann Endoma, Vu Bui and
Natalia Korkina. I also acknowledge Dr. Caimin Duan who has been a model of hard
work for me. I am indebted to Nora Restrepo, Stephan Schilling, Jennifer Lombardi and
Jerremy Willis for their friendship and advice in chemistry and other matters.
I am grateful to those people with whom I worked together on the morphine
project; I thank Dr. David Gonzalez, Charles Stanton and Elizabeth Hobbs for their
contribution to the morphine project. Recently it has been my pleasure to work with Dr.
Lucillia Santos and Lukaz Koroniak who contributed immensely to the progress of the
morphine project. We owe our progress to Vu Bui who kept a constant stream of diol
flowing our way.
I am also thankful for all the help received from the analytical services
department, especially Dr. Ion Ghiriviga, Dr. Khalil Abboud and Lidia Madveeva.
I would also like to thank Dupont-NOBCChE and the Shell Fellowships for their
support of my education. I give special thanks to Dr. Hollinsed for all his assistance.
I want to acknowledge Dr. Josie Reed for the many chemistry/administrative
problems that she solved for me and for the entire Hudlicky group. During my time here
she has served as an excellent mother figure for me. All her efforts are appreciated and
did not go unnoticed.
IV


91
protecting group from the bicycle 339 afforded the intermediate alcohol, which was
converted to the bromoacetate 340 the radical cyclization precursor. Silyl ether 343 was
obtained from intermediate 342 after cleavage of the MOM-protecting group and
subsequent appendage of the bromoacetate. The two bromoacetates were then subjected
to radical conditions using a protocol previously used by Ogasawara60 and coworker in
their synthesis of 3,4-dimethoxy-7-morphinanone (pg 39, Ch. 1). The radical reaction
failed to produce any cyclized product in the case of silyl ether 343. Instead we observed
the formation of the reduced product exclusively. This was not unexpected due to the fact
that for that cyclization to work the reaction had to proceed from a stablilized ester
radical to an unstable radical. On the other hand enone 340 subjected to the same
conditions yielded the cyclized product 341 in 66% yield with recovery of about 15% of
reduced product. With the success of the model study our attention focused on its
application to the morphine synthesis.
Our goal was to achieve the synthesis of intermediates of the type 345 or 347
347 348
Scheme 75




125
2-4-oxo-2-(2-benzvloxv-3-methoxvphenvl)-( lS,4R)l-2-cvclohexenyl-2S-N-rerr-
butoxvcarbonvlmethvlglvcinate (326):
To a solution of the alcohol 311 (0.603 mmol, 0.300 g) in CH2CI2 (5 mL) was
added PCC (0.905 mmol, 0.200 g). This mixture was allowed to stir for 12h after which
the reaction mixture was filtered through a bed of silica gel followed by removal of
solvents. The crude product was chromatographed (silica gel, ethyl acetate: hexanes, 1:4)
to afforded the pure enone 326 as a light brown oil (0.250 g, 84%); Rf = 0.6
(hexanes:ethyl acetate, 1:1); [oc]d27 + 18.6 (c 1.0, CHCI3): 'H NMR (CDCI3): 7.28 (m,
5H), 7.02 (t, J = 7.8 Hz, 1H), 6.93 (dd, J = 1.5 Hz, 1H), 6.65 (dd, J = 1.5 Hz, 1H), 5.87
(m, 1H), 4.98 (q, J = 11.4 Hz, 2H), 4.69 (m, 1H), 4.40 (bs, 1H), 3.89 (s, 3H), 3.63 (m,
1H), 3.56 (s, 3H), 2.52-2.46 (m, 1H), 2.28-2.18 (m, 1H), 1.84-1.73 (m, 2H), 1.32 (s, 9H);
l3C NMR (CDCI3) 8: 198.29, 171.92, 160.74, 154.67, 152.39, 144.43, 137.21, 133.54,
130.98, 128.45, 128.27, 124.56, 121.27, 113.17, 79.81,75.32, 55.84, 54.78, 52.22,40.41,
35.24, 28.11, 23.94; IR (CDCI3/ cm'1): 3342, 2951, 1747, 1706, 1676, 1471, 1454, 1366,
1264, 1213, 1158; HRMS Calcd.for C28H33NO7 [(m+l)+ Na]: 518.2154 ; Found:
518.2160.


Standard C13 parameters
Pulse Sequence: *2pu1
So Want: C0C13
Ambient temperature
GENlNl-30066 "gen t n 1300"
PULSE SEQUENCE
Pulse 25.0 degrees
Acq. time 0.344 sec
Width 17354.0 Hz
2320 repetitions
OBSERVE C13, 75.4513635 HHz
DECOUPLE HI, 300.0667366 HHz
Power 35 dB
on during acquisition
off during delay
WAlTZ-16 nodulated
DATA PROCESSING
Line broadening 3.5 hz
FT size 32768
Total time 0 min, 0 sec


34
oxazolidone to yield the alcohol 168. A double Swem oxidation was utilized to convert
168 into the rather unstable ketoaldehyde 169, which upon exposure to
trifluoromethanesulfonic acid led to the formation of alcohol 170, which contains the
complete morphinan skeleton.
Scheme 35 Conditions: a) 150, Bu3P, DEAD, THF; b) TBAF, THF; c) Bu3SnH, AIBN,
benzene reflux; d) DIBAL-H, CH2CI2; e) oxalyl chloride, DMSO, Et3N, CIECF; f) TFA.
Currently57, 58 a third generation approach using intramolecular Diels-Alder is
being developed (Scheme 36). The major improvement in the third generation is the use
of a (E, Z)-diene system as seen in 171 which will invariably lead to an inversion at the
C9 (morphine numbering) stereocenter preceding the formation of compounds of the type
173. Using a nucleophilic displacement by the nitrogen tether onto the leaving group
would form B-, C-, D-, and O- rings with correct stereochemistry in 174.


41
whose geometry is fixed by virtue of being in the five membered oxazole ring. This
PPh3/CCl4,
\ r EtjN/CHjCN
Scheme 41
important aspect of the reaction meant that the sigmatropic rearrangement could proceed
with stereoselectivity. Unfortunately when the substituent a- to the nitrogen is hydrogen
there is epimerization at that center leading to a non-stereoselective rearrangement.
Paul Bartlett64 in 1982 decided to investigate the work done earlier by Steglich.
His goal was to compare these conditions to the Ireland Claisen6:i rearrangement
conditions. Also important was the utilization of this reaction in the synthesis of y,8-
unsaturated amino acids. He also wanted to study the stereochemical influence, if any of
the a-substituent in the Claisen rearrangement. Deprotonation Conditions: Bartlett and
coworkers used 2.1 equivalents of LDA to effect enolization. The found that shorter (2.5
min) or longer (40 min) enolate generation times had no significant influence on yield or


LIST OF REFERENCES
1. White, P. T.; Raymer, S. The Poppy National Geographic Feb. 1985, 167, pp
142-188.
2. Rice, K. C. in The Chemistry and Biology of Isoquinoline Alkaloids; Philipson
Eds.; Springer: Berlin, 1985; pp 191-203.
3. U.S. Drug Enforcement Agency, Controlled Substance Aggregate Production
Quota History, Federal Register, July 1994.
4. National Narcotics Intelligence Consumers Committee Report 1993, The
Supplies of Illicit Drugs to the United States, DEA-94066, August 1994.
5. Santavy, F Alkaloids, New York, 1979, 17, 385.
6. Terry, C. E.; Pellens, M. The Opium Problem, Bur. Soc. Hyg., New York, 1928.
7. Deronse, J. F. Ann. Chim. 1803, 45, 251.
8. For a review on the elucidation of the morphine structure see: Butora, G.;
Hudlicky, T. in: Organic Synthesis: Theory and Applications Vol. 4, Hudlicky, T.,
Ed., JAI Press Inc. New York, 1998, p. 1-54.
9. Seguin, M. A. Ann. Chim. 1806, 92, 225.
10. Serturner, F. W. A. Trommdorffs J. Pharm., 1806, 14, 47.
11. Gulland, J. M.; Robinson, R. Proc. Mem. Manchester. Lit. Phil. Soc. 1925, 69, 79.
12. Mackay, M.; Hodgkin, D. C. J. Chem. Soc. 1955, 3261.
13. Bentley, K. W.; Cardwell, H. M. E. J. Chem. Soc. 1955, 3245.


Stanoar o C13 parata
Pulla Saquanca: 2pul




TBSO
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Br
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A.
0.13 2.13
0.01 1.07
o.eo
. T ^r-' '-T-' W
1.92 1.32 1.11 2.91
1.03 9.94 9.33 2.91
n


52
after generation of the enolate with LDA). After acidic workup the only isolated product
was the rearranged acid 241.
In summary the synthesis of morphine has resulted in ingenious strategies by
different research groups over the years to tackle this small yet challenging molecule.
While the focus of the various syntheses has been synthesis of the target, the chemistry
generated by this pursuit and its application to alkaloid chemistry is the legacy of
morphine synthesis. Starting from Gates l5 16 synthesis to the latest synthesis by
Mulzer it is fascinating to see the many different synthetic pathways that have been
employed in morphine synthesis. Sigmatropic rearrangements have played a small yet
important role in morphine synthesis. The syntheses by Parsons, 20 Rapoport50 and
Mulzer21'25 effectively used sigmatropic rearrangements to establish the C13 quaternary
center of morphine
The chelated enolate Claisen Rearrangement had modest beginnings from
Steglich62 63 and coworkers and later Bartlett64 and coworkers. The idea was greatly
improved by Kazmaier66"77 and coworkers who have developed it into one of the more
powerful tools in amino acid chemistry.
The next chapter of this dissertation will discuss a chemoenzymatic approach to
the synthesis of the morphine skeleton. This approach uses a disconnection of the
morphine molecule that is unlike any of the preceding syntheses. More importantly, it
utilizes a sigmatropic rearrangement, the Chelated Enolate Claisen rearrangement
(Kazmaier Claisen) to establish control of C9 and C14 stereocenters of morphine in
addition to attempting to establish the Cl3 quaternary center. Additionally the synthesis
uses an enzymatic step, which is capable of converting cheap readily available aromatic


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5
quaternary center at C13 (morphine numbering, while transferring the stereochemistry
already present in the starting material to that position.
Morphine Biosynthesis
It is interesting to note that Robert Robinson, who proposed that morphine
consisted of a twisted benzylisoquinoline skeleton, made one of the most important
Scheme 3
Enzymes: i)L-tyrosine decarboxylase; ii) phenolase; iii) L-tyrosine transaminase; iv) p-
hydroxyphenylpyruvate decarboxylate; v) (S)-norcoclaurine synthase; vi) norcoclaurine-
6-0-methyltransferase; vii) tetrahydrobenzylisoquinoline-A^-methyltransferase; viii)
phenolase; ix) 3-hydroxy-N-methyl (S)-coclaurine-4-(9-methyltransferase.


7 6 5 4 3 2 1 ppai
1.00 0.53
1.03
0.51
' p ' 1 i f11* r*
1.22 Pi. 071.98 0.100 .(4
0.512.1? 0.100.17
3.57
*r*T'.*r~P uiP
3.4( l.4(
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0.65
0.15
11.53
1.41


88
329 the conjugate addition yielded only 1,2-adducts. 'H-NMR spectra of Mulzers
intermediates demonstrated the presence of atropoisomers and this led to his assumption
that these intermediates exhibited atropoisomerism. In our case high temperature 'H-
NMR experiments were inconclusive because even though we observed the presence of
two isomers it was impossible to determine whether the isomerism was from the
carbamate moiety or due to atropoisomerism. The result of the atropoisomerism is that
the aromatic
residue becomes more or less pependicular to the double bond hindering any attack on
the benzylic sp2-hybridized carbon.


7
formation of (S)-norcoclaurine 9, which serves as the skeletal foundation of most of the
benzylisoquinoline alkaloids. The next three steps can be summarized as two enzyme-
catalyzed methylations and an aromatic hydroxylation to afford (S)-reticuline 13, that
possesses the opposite configuration to the compound found in the biosynthesis of
morphine (what would be the C9 center of morphine has the opposite stereochemistry).
Inversion to the correct intermediate is effected in two steps through the intermediate
imine dehydroreticuline 14 (Scheme 4) by a highly stereospecific and NADPH/NADPH+
dependent reductase to afford (/?)-reticuline 15.29,30 It is likely that the mechanism
involves the formation of two phenolate radicals and their subsequent coupling. The next
step in the biosynthesis is the conversion of (i?)-reticuline into salutaridine 16 by a
membrane-bound cyctochrome P-450 enzyme whose catalytic action is strictly dependent
on NADPH and molecular oxygen. After the formation of salutaridine 16, the ketone
moiety is reduced by an NADPH-dependent oxidoreductase to afford salutaridinol 17,31
which then undergoes enzyme-catalyzed acetyl CoA dependent acetylation to yield the
acetate 18.32 The next intermediate formed is thebaine 19, which results from ring closure
at slightly basic pH. Failure to find a specific enzyme for this step has led to the
conclusion that this step is spontaneous. Neopinone 20 is formed by the demethylation of
thebaine to form the ketone, which is in chemical equilibrium with codeinone 21. The
final steps in the morphine biosynthesis are the conversion of codeinone to codeine (2)
and a final demethylation of codeine to afford morphine (1). An alternate pathway to
morphine has also been proposed and it involves arriving at the target first by
demethylation of thebaine to obtain the intermediate alcohol 22, then conversion to the
enone 23 whose reduction by codeinone reductase affords morphine 1 (Scheme 5).33,34


22
20 21 25
Parsons and recently Mulzer' were able to utilize sigmatropic rearrangements as key
steps in their approaches to morphine.
Interestingly, all three approaches used the sigmatropic rearrangement for the
same purpose, to install the quaternary center at Cl3 (morphine numbering) while
transferring the stereochemistry already present in the starting material to that position.
Rapoports synthesis began with the conversion of ortho-vanillin 98 to amino acid
99 in twelve steps (Scheme 24). The amino acid then underwent rearrangement in the
Scheme 24


21
Condensation of allylsilane 92 with iodide 93 (prepared in 7 steps from isovanillin in an
overall 62% yield) at 60 C in the presence of Znl2 followed by iminium ion-allylsilane
cyclization yielded the isoquinoline intermediate 94. Palladium mediated coupling led to
the formation of the Cl2-03 bond and morphinan 95 (Scheme 23) with the correct
stereochemistry at C9, 03, and 04. Liberation of the phenolic oxygen and (3-face
epoxidation of the C6-C7 double bond and subsequent intramolecular ring-opening by
the phenolic hydroxyl completed the dihydrofuran ring. Oxidation followed by reductive
DBS cleavage in the presence of formaldehyde yielded (-)- dihydrocodeinone 88.
Scheme 23
Morphine Syntheses via Sigmatropic Rearrangements
Although a wide variety of synthetic approaches have been applied to the
morphine problem, sigmatropic rearrangements have rarely been elicited as synthetic
tools. Of the more than twenty formal syntheses only three, namely those of Rapoport,50


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Dedicated to
Nana Akua and Akwasi


108
6-bromo-2-dimethvlsilvloxv-(lS,2R)-5-cyclohexen-l-vl-N-tert-butoxvcarbonyl glycinate
(292).
A solution of Boc-glycine (0.07 mol, 12.00 g), DCC (0.09 mol, 18.50 g), DMAP
(catalytic) in dichloromethane (200 mL) was cooled to 0 C and a solution of the TDS
protected diol 291 (0.045 mol, 15.00 g) in dichloromethane (200 mL) was added. The
cloudy reaction mixture was stirred overnight while it was allowed to reach room
temperature. The solution was diluted with ethyl ether and filtered through a bed of silica
gel to remove the precipitate of dicyclohexylurea. Removal of the solvent and
chromatography (silica gel, ethyl acetate:hexanes, 1:9) of the residue, afforded the pure
glycinate (292) as a colorless oil (15,40 g, 70%); Rf = 0.7 (ethyl acetateihexanes, 1:4);
mp: 89 91 C; [a]D26 -64.0 (c 1.0, MeOH); H NMR (CDC13) 6.27 (dd, J = 5.2, 3.1 Hz,
1H), 5.59 (d, J = 3.9 Hz, 1H), 5.00 (bs, 1H), 3.97 (m, 3H), 2.39-2.19 (m, 1H), 2.15-2.09
(m, 1H), 1.85-1.62 (m, 2H), 1.43 (s, 9H), 0.84 (s, 3H), 0.82 (s, 3H), 0.77 (d, J = 1.9 Hz,
6H), 0.07 (d, J = 4.6 Hz, 6H); l3C NMR (CDC13) 5:169.59, 155.29, 134.80, 116.96,
79.64, 73.88, 69.23, 42.33, 34.03, 28.21, 25.49, 24.70, 22.55, 20.01, 18.48, -3.09, -3.15;
IR (CHC13/ cm'1): 3445, 2958, 1755, 1715, 1511, 1372; HRMS Caled, for C2|H39NsiBr05
(M+H): 492.1781; Found: 492.1806; Anal. Caled, for: C2iH38NsiBr05: C, 51.21; H,
7.78; Found: C, 51.41; H, 7.75.


31
been reported earlier. This led to the conclusion that the intramolecular Diels-Alder
proceeded through an exo transition state.
In 1998, Hudlicky56 and coworkers published a radical cyclization approach to the
morphinan skeleton that represents the most advanced morphinan synthesized in the
Hudlicky group. In the first generation of this radical approach, the focus was to
Br
Scheme 32 Conditions: a) JM109 (pDTG601); b) PAD, HOAc; c) THSC1, imidazole,
DMF; d) BzOH, Bu3P, DEAD, THF; e) NaOMe, MeOH; f) 150, Bu3P, DEAD, THF; g)
FI30+; h) benzyl bromide, K2C03, acetone; i) Bu3SnH, AIBN, toluene reflux.
achieve a tandem radical cyclization that would lead to the construction of the A, C, D,
and O-rings of morphine (Scheme 32) with the correct stereochemistry at the chiral
centers in a manner analogous to the Parker52 synthesis but with different connectivity at
the C9, CIO and Cl 1 carbon atoms. The first step was to validate the tandem process with
simple model studies. The initial model examined the feasibility of constructing the Cl 2-
C13 bond through a radical closure. To this regard bromoguiacol 150 was synthesized in
4 steps starting from an enzymatic transformation with P. putida TG02C and used as a
nucleophile in the second Mitsunobu inversion of the alcohol 152 also obtained through


i
107
6-(2,3-dimethoxvphenvl)-2-dimethvlsilvloxv-(lS.2R)-5-cvclohexen-l-yl-N-
phtholylglvcinate (285):
A solution of phthaloyl-glycine (1.40 mmol, 0.30 g), DCC (2.50mmol, 0.50 g),
DMAP (catalytic) in dichloromethane (10 mL/mmol) was cooled to 0 C and a solution
of the TDS protected diol 276 (1.20 mmol, 0.50 g) in dichloromethane (2 mL) was added.
The cloudy reaction mixture was stirred overnight while it was allowed to reach room
temperature. The solution was diluted with ethyl ether and filtered through a bed of silica
gel to remove the precipitate of dicyclohexylurea. Removal of the solvent and
chromatography (silica gel, ethyl acetate:hexanes, 9:1) of the residue, afforded the pure
phthaloyl glycinate 285 as white crystals (0.35 g, 70%); Rf = 0.8 (ethyl acetate: hexanes,
1:4); mp: 89 91 C; [a]D25 -79.7 (c 1.0, CHC13); 'H NMR (CDC13) 5: 7.81 (m, 2H), 7.65
(m, 2H), 6.90 (t, J = 7.9 Hz, 1H), 6.81 (d, J = 7.9 Hz, 1H), 6.49 (d, J = 7.9 Hz, 1H), 5.89
(t, J = 3.4 Hz, 1H), 5.85 (d, J = 2.8 Hz, 1H), 4.12 (m, 1H), 3.83 (s, 3H), 3.76 (s, 3H),
2.39-2.15 (m, 2H), 1.91-1.50 (m, 2H), 0.88 (dd, J = 6.7, 1.2 Hz, 6H), 0.84 (s, 7H), 0.12
(d, J = 5.8 Hz, 6H); ,3C NMR (CDC13) 5:168.80, 167.61, 153.32, 147.42, 135.00, 134.74,
133,93, 132.84, 124.40, 124.10, 122.84, 112.71, 73.43, 69.05, 60.93, 56.18, 39.10, 26.21,
25.11, 24.51, 20.41, 20.24, 18.74, 18.62, 9.37, -2.97; IR (KBr/cm1): 2954, 1752, 1726,
1470, 1416, 1205, 1114, HRMS Caled, for C32H4|NSi04 (M+): 579.2652; Found:
579.2652. Anal. Caled, for C32H41Nsi04: C, 63.36; H, 8.62; Found: C, 63.51; H, 8.51.


Ill
2-(4-dimethvl-terr-butvlsiIvloxv-2-bromo-(lS,4R)-2-cvclohexenyl-2R-N-fert-
butoxycarbonylmethylglvcinate (293):
A solution of the glycine ester 292 (13.40 mmol, 6.23 g) in THF (100 mL) and a
1.0 M solution of ZnCh (21.10 mmol 20.00 mL,) in ether were cooled to -78C. Then a
2.0 M solution of LDA (37.50 mmol, 19.00 mL) in THF was added dropwise to the
reaction mixture and the system allowed to warm to room temperature slowly
(overnight). The reaction was quenched with water and the basic solution diluted with
ethyl ether. The reaction mixture was then acidified slowly with HC1 (IN) until a pH of
approximately 2.5 was reached. After extraction with ethyl ether (3 X 100 mL) and
drying with Na2SC>4, the solvent was removed to afford the crude rearranged amino acids
as light yellow cystals. The acids were purified by silica gel chromatography using a
gradient elution of ethyl acetate: hexanes (1:6) followed by methanol (100%). The pure
acids were then treated with diazomethane to obtain the corresponding methyl esters. The
epimeric methyl esters were then introduced unto a silica gel column and
chromatographed with hexanes (100%) to obtain white crystal of 293 (2.63 g 40%); Rf =
0.7 (ethyl acetate:hexanes, 1:4); mp: 115-117 C; [a]D28 -54.1 (c 1.0, CHC13); H NMR
(CDCIj) 5: 6.18 (dd, J = 5.6, 1.3 Hz, 1H), 5.23 (d, J = 8.6 Hz, 1H), 4.70 (dd, J = 8.7, 2.6
Hz, 1H ) 4.13 (m, 1H), 3.72 (s, 3H), 3.09 (bs, 1H), 1.92-1.75 (m, 2H), 1.74-1.50 (m, 2H),
1.43 (s, 9H), 0.85 (s, 9H), 0.02 (d, J = 4.4 Hz, 6H); 13C NMR (CDC13) 6:171.81, 155.37,
136.30, 125.62, 80.00, 66.78, 55.80, 52.29, 45.15, 29.14, 28.34, 28.20, 25.76, 25.67,
23.33, 17.95, -4.77; IR (KBr/ cm'1): 3394, 2963, 2857, 1733, 1710, 1645, 1522, 1365;
HRMS Caled, for C2oH36NsiBr05 (M+): 478.1525; Found: 478.1525; Anal. Caled, for
C2oH35NSiBr04: C, 50.20; H, 7.58; Found: C, 50.15; H, 7.50.


130
55. Hudlicky, T.; Butora, G.; Gum, A. G.; Abboud, K. A. Synthesis 1998, 275.
56. Hudlicky, T.; Butora, G.; Gum, A. G.; Feamley, S. P.; Stabile, M. R.; Gonzalez,
D. Synthesis 1998, 665.
57. Novak, B.; Hudlicky, T.; Reed, J. W.; Mulzer, J.; Trauner, D. Current Organic
Chemistry 2000, 4, 343.
58. Novak, B. Ph.D. Dissertation, University of Florida, 2000.
59. Frey, D.; Duan, C; Hudlicky, T. Organic Letters 1999, /, 2085.
60. Yamada, O.; Ogasawara, K. Organic Letters 2000, 2, 2785.
61. Yamada, O.; Ogasawara, K. Tetrahedron Lett. 1998, 39, 7747.(done)
62. Kubel, B.; Hofle, G.; Steglich, W. Angew. Chem. Int. Ed. Engl. 1975, 89, 58.
63. Engel, N.; Kubel, B.; Steglich, W. Angew. Chem. Int. Ed. Engl. 1977, 16, 394.
64. Bartlett, P. A; Barstow, J. F. J. Org. Chem. 1982, 47, 3933.
65. Ireland R. E.; Mueller, R. H. J. Am. Chem. Soc. 1972, 98, 2868.
66. Kazmaier, U. Angew. Chem. Int. Ed. Engl. 1994, 33, 998.
67. Kazmaier, U. Liebigs Ann., Reel. 1997, 285.
68. Kazmaier, U.; Maier, S. J. Chem. Soc. Chem. Commun. 1995, 56, 3572.
69. Kazmaier, U.; Maier, S. Tetrahedron 1996, 52, 941.
70. Kazmaier, U. Tetrahedron 1994, 50, 12895.
71. Kazmaier, U.; Schneider, C. Synthesis 1998, 1321.
72. Kazmaier, U.; Schneider, C. Tetrahedron Lett. 1998, 39, 817.
73. Kazmaier, U.; Schneider, C. Synthesis 1998, 1314.
74. Kazmaier, U.; Schneider, C. Eur. J. Org. Chem. 1998, 1155.
75. Kazmaier, U. J. Org. Chem. 1994, 59, 6667.


SUZUKI Cdrbon
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19 9 f\
observations that eventually led to the elucidation of the structure of morphine.
Studies conducted on the biosynthesis of morphine indicate that the morphinan alkaloids
are formed by a series of benzylisoquinoline intermediates (Scheme 3) which eventually
forms (R)-reticuline 14 (Scheme 4).27 28
Scheme 4
The benzylisoquinoline skeleton is derived from two molecules of L-tyrosine (4),
which is converted into a molecule each of dopamine 6 and 4-hydroxy
phenylacetaldehyde 8 through the intermediacy of tyramine 5 and 4-hydroxyphenyacetic
acid 7 respectively (Scheme 3). Condensation of these two derivatives of L-tyrosine is
catalyzed in a stereospecific manner by (S)-norcoclaurine synthase, which results in the


ABSTRACT
Abstract of Dissertation Presented to the Graduate School
of the University of Florida in Partial fulfillment of the
Requirements for the Degree of Doctor of Philosophy
CHEMOENZYMATIC APPROACH TO THE SYNTHESIS OF THE
MORPHINAN SKELETON VIA A CLAISEN REARRANGEMENT APPROACH
By
Kofi Oppong
August 2001
Chairman: Dr. Tomas Hudlicky
Major Department: Chemistry
An approach to the morphinan skeleton with complete control of the C9 and C14
stereocenters is described. The first generation of the synthesis of the A and C rings of
morphine are discussed. Also described are attempts at establishing the Cl3 quaternary
center with emphasis on construction of the D-ring. The use of precursors from the
enzymatic biooxidation of aromatic compounds in the construction of the morphinan
skeleton through various chemical modifications is reported.
vii


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r*duc*d dlmthoxyphny1 dio
OBSERVE HI
FREQUENCY 300.075 MHz
SPECTRAL WIDTH 4500.5 Hz
ACQUISITION TIME 1.998 **c
RELAXATION DELAY 0.000 9C
PULBE WIDTH 5.0 u#C
AMBIENT TEMPERATURE
NO. REPETITIONS 16
DOUBLE PRECISION ACQUISITION
DATA PROCESSING
LINE BROADENING 1 0 Hz
FT 81ZE 32768
TOTAL ACQUISITION TIME 1 minutas
ppm
NO
4
I
2
1


56
glycinate ester 243 which could be synthesized from the biphenyl diol derivative 244.
This synthon is available either from direct biooxidation of the biphenyl precursor 245 or
through the coupling reaction between the aromatic boronic acid 246 and diol 247
derived from diimide reduction of the cis-diene diol 248 (Scheme 47).
The retrosynthetic strategy outlined above uses remarkable design elements that
deserve mention. 1) The C-ring of morphine can essentially be described as a
cyclohexenyl cfy-diol unit. This moiety can be recognized in the structure of the chiral
Scheme 48
ds-cyclohexadiene diol 248 with the correct absolute stereochemistry at C5 and C6 set as
a result of the enzymatic transformation (Scheme 48). 2) The approach capitalizes on the
recognition that the main backbone of the morphine skeleton consists of an oxidized
biphenyl unit 252 (Figure 4). This structural component, namely 244 (Scheme 47), is also
present in various alkaloids like pancratistatin the synthesis of which is being pursued in
the Hudlicky group. This unit could be obtained as outlined above either through direct
biooxidation of a biphenyl precursor or through the coupling of an aromatic boronic acid
with c/s-cyclohexadiene diol (Scheme 47). 3) The allylic alcohol unit present in diol 244
(Scheme 47) allows for the introduction of the amino acid side chain into the molecule
through a Claisen rearrangement. 4) Finally the Cl3 quaternary center could be


87
1,2-addition adduct 327. It is our suspicion that because this bicyclic compound
Figure 10. Possible atropoisomerism of morphinan intermediates
exhibits atropoisomerism, the aromatic ring is twisted out of conjugation with the
cyclohexenyl ring (Figure 10). This probably causes the aromatic ring to be perpendicular
to the cyclohexyl ring so any substituent in the 2-position of the aromatic ring (benzyl in
this case) sterically hinders any attack to the C13 center.
In summary our attempt at the Overman intermediate failed because of two main
problems. The first problem, which was encountered in the orthoester-Claisen, is a trend
that we had observed earlier in the synthesis (Scheme 56, pg 68) and used to our
advantage. The C6 (morphine numbering) position easily ionizes if any good leaving
groups are present because of the stability of the resultant allylic carbocation which is
resonance stabilized by the aromatic ring. Under catalytic or stoichiometric acid
conditions, the orthoester intermediates are cleaved either through an SNl or an Sn2
mechanism to yield products of the type 322. The second problem is of a steric nature,
cuprate addition to the Cl3 (morphine numbering) center led to recovery of 1,2-addition
products exclusively. Mulzer25 in his synthesis of morphine encountered the same
problem in his attempt at conjugate addition to a similar substrate (Scheme 73). Initial
model studies were successful at establishing what would be the Cl3 center by cuprate
addition. When the same reaction was applied to more advanced intermediates 123 and


57
Figure 4. Synthetic targets with oxidized biphenyl unit.
established by utilizing the allylic alcohol moiety present in intermediate 254 via a
\ f
V
M = Zn
Scheme 49


13
Beyerman44 used a Grewe type cyclization with a symmetric arene to overcome
selectivity problems (Scheme 13). The N-methylation of benzyl protected phenol 45,
H2, Pd-C
35
Scheme 13
followed by hydrogenation and finally a Birch reduction rendered tricycle 46, which
readily cyclized in the presence of HC1 to 47. Fortunately, the additional hydroxyl group
at C2 in 47 was selectively removed by conversion to the corresponding tetrazole ether
followed by hydrogenolysis, which afforded dihydrothebainone 35 and formalized
Beyermans synthesis.
Rice45 is given credit for the most practical synthesis of morphine to date, with an
overall yield of 29%. Using starting materials similar to those used by Grewe and
Morrison, Rice was able to synthesize amine 50 by coupling of acid 48 and amine 49. In
3 steps Rice was able to synthesize bromide 51 using a strategy similar to that of
Beyerman. This was a key intermediate because it possessed a well placed bromine
substituent, which blocked para cyclization. Bromonordihydrothebaine 52 was formed in
60% yield, and was eventually converted to dihydrocodienone 53 (Scheme 14). Overall