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

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Title:
Chemoenzymatic approach to the synthesis of the morphinan skeleton via a Claisen rearrangement approach
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vii, 188 leaves : ill. ; 29 cm.
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Oppong, Kofi A., 1969-
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Subjects / Keywords:
Organic compounds -- Synthesis   ( lcsh )
Morphine   ( lcsh )
Claisen condensation   ( lcsh )
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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.
Statement of Responsibility:
by Kofi A. Oppong.
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Printout.
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Vita.

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Full Text












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





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(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+;