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Chemoenzymatic synthesis and utility of vinyl aziridines

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Title:
Chemoenzymatic synthesis and utility of vinyl aziridines an approach to the synthesis of (+)-7-deoxypancratistatin and the preparation of several truncated analogs
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Schilling, Stefan, 1974-
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English
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xi, 228 leaves : ill. ; 29 cm.

Subjects

Subjects / Keywords:
Acetates ( jstor )
Alcohols ( jstor )
Alkaloids ( jstor )
Alkenes ( jstor )
Aziridines ( jstor )
Epoxy compounds ( jstor )
Ethers ( jstor )
Lactones ( jstor )
Oxidation ( jstor )
Tetrahedrons ( jstor )
Aziridines ( lcsh )
Chemistry thesis, Ph. D ( lcsh )
Dissertations, Academic -- Chemistry -- UF ( lcsh )
Heterocyclic compounds -- Synthesis ( lcsh )
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bibliography ( marcgt )
theses ( marcgt )
non-fiction ( marcgt )

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Thesis:
Thesis (Ph. D.)--University of Florida, 2001.
Bibliography:
Includes bibliographical references (leaves 221-227).
General Note:
Printout.
General Note:
Vita.
Statement of Responsibility:
by Stefan Schilling.

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CHEMOENZYMATIC SYNTHESIS AND UTILITY OF VINYL AZIRIDINES: AN APPROACH TO THE SYNTHESIS OF (+)-7-DEOXYPANCRATISTATIN AND THE
PREPARATION OF SEVERAL TRUNCATED ANALOGS














By

STEFAN SCHILLING


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



































In memory of my mother.














ACKNOWLEDGEMENTS


I would like to express my deepest thanks and appreciation to my research advisor, Dr. Tomas Hudlicky, for his continual advice, supervision, and encouragement during my graduate career at the University of Florida. His zest and enthusiasm for chemistry are constant, and for this spirit, I will always be indebted. Additional thanks are extended to Drs. Merle Battiste, William Dolbier, Dennis Wright, Vanecia Young, and Kenneth Sloan for their support during my tenure at the University of Florida and for serving as members of my committee.

I also would like to thank all faculty members in the organic division of the chemistry department for their thoughts, opinions, and discussion of chemistry. In particular, I would like to offer my gratitude to Drs. Tomas Hudlicky, Merle Battiste, William Dolbier, Dennis Wright, and Eric Enholm for instilling the principles of organic chemistry in me.

My heartfelt appreciation goes out to all of the present and former members of the Hudlicky research group for their friendship, suggestions, and knowledge. I especially thank Uwe Rinner and Collin Chan for their assistance with my Ph.D. project as well as Dr. Mary Ann Endoma and Vu Bui for their devoted time in preparing starting materials. I am also grateful to all members of the research group for providing a pleasant working environment and for offering their help in crucial times of my academic career.

I am also grateful to the members of the analytical services for their assistance in the characterization of compounds. I would particularly like to extend my sincere thanks to Ion Ghiviriga for his aid with NMR spectroscopic experiments and interpretation. In








addition, I am appreciative of the help provided by those responsible for mass spectrometry as well as elemental analysis.

I also extend my thanks to Donna Balkcom and Lori Clark for tending to my registration in graduate classes as well as reminding me of the Graduate School's requirements.

Finally, I am most grateful to my family for their endless encouragement, love, and advice. First, I would like to express my thanks to my parents for their belief in me and for their continuous support of my decisions both now and in the future. I would also like to acknowledge my two brothers, Michael and Andreas, for their friendship and support. Without the guidance provided by my family, I would not be where I am today.














TABLE OF CONTENTS



ACKNOWLEDGEMENTS ............................................................... iii

L IST O F T A B LE S .......................................................................... vii

L IST O F FIG U R E S ........................................................................ viii

A B ST R A C T ................................................................................. x

I IN T R O D U C TIO N ....................................................................... 1

2 H IST O R IC A L ........................................................................... 4

Amaryllidaceae Alkaloids ..................................................... 4
Isolation and Structure Determination ................................ 4
B iological A ctivity ...................................................... 5
Total Syntheses ............................................................ 7
Pancratistatin ........ ....... ..................... 8
7-Deoxypancratistatin .............................................. 22
Synthetic Approaches .................................................... 35
Vinyl Aziridine Synthesis ..................................................... 40
Preparation from Dienes by Nitrene Insertion ........................ 41
Preparation from Amino Alcohol Derivatives ........................ 44
Preparation via Transition Metal Catalysis ........................... 47
Preparation from Functionalized Azides ............................. 49
Preparation from azido alcohols ................................... 49
Preparation from azidodienes ...................................... 49
Preparation from Imines ................................................ 51
Preparation by Miscellaneous Methods ............................... 52
Preparation from unsaturated oximes ............................. 52
Preparation from aziridinyl aldehydes/ketones .................. 54
Preparation from aziridinyl diols .................................. 55
Epoxyaziridine Synthesis ..................................................... 56
Preparation from Functionalized Olefins ............................. 56
Preparation via Internal Substitution ................................... 57
Preparation from Oxazines .............................................. 59
Nucleophilic Ring Openings of Aziridines .................................. 61








Intermolecular Ring Openings ......................................... 62
Openings by organometallic reagents ............................ 62
Openings by aromatic systems ................................... 70
Openings by allylsilanes ........................................... 73
Intramolecular Ring Openings .......................................... 74
Anionic cyclizations ................................................ 74
Lewis acid mediated cyclizations ............................... 75

3 D ISC U SSIO N ........................................................................... 78

Introduction ...................................................................... 78
Retrosynthetic Analysis for Truncated Analogs ...................... 79
Retrosynthetic Analysis for (+)-7-deoxypancratistatin .............. 80
Synthesis of Vinylaziridines ................................................... 82
Preparation from Dienes ................................................ 82
Preparation from Amino Alcohols .................................... 83
Synthesis of Truncated Analogs of (+)-7-deoxypancratistatin ............ 84
Intramolecular Aziridine Cyclization Approach ............................ 89
Vinylaziridine Oxidation ................................................ 90
Projected Versus Actual Synthetic Sequence ........................ 92
Intramolecular Anionic Cyclization Approach ........................ 93
Intramolecular Lewis Acid Cyclization Approach .................. 95
Further Functionalizations of Arylconduramines ..................... 101
B enzylic oxidation ................................................. 101
D etosylation studies ................................................ 103
Final Transformations .................................................... 106
Structure A ssignm ent ........................................................... 111
Structure Correlation by Independent Synthesis ........................... 122
Correction of the Design of Aryl Ether Precursor of Type 325 ........... 124

4 CONCLUSIONS AND FUTURE WORK ........................................... 126
C onclusions ...................................................................... 126
Future W ork ...................................................................... 127

5 EXPERIMENTAL ...................................................................... 128
General Procedures and Instrumentation ..................................... 128
Experimental Procedures and Data ............................................ 129

APPENDIX SELECTED SPECTRA ................................................ 157

R E FE R E N C E S .............................................................................. 22 1

BIOGRAPHICAL SKETCH .............................................................. 228














LIST OF TABLES


Table pAge

1. Regioselective Opening of Trans 2,3-Aziridinyl Alcohols (252a-b) ............. 66

2. Regioselective Opening of Cis 2,3-Aziridinyl Alcohols (254a-b) ............... 66

3. Ring Opening of N-Diphenyphosphinyl Aziridines (256) by Nucleophiles .... 67 4. Ring Opening Reactions of Vinylaziridine 266 by Organometallics ............ 69

5. Ring Opening Reactions of Vinylaziridine 269 by Organometallics ............ 70

6. Ring Opening Reactions of Optically Pure Aziridines (280) by Indoles ........ 72 7. Friedel-Crafts Alkylation of Azulenes with Activated Aziridines ............... 73














LIST OF FIGURES


Figure pae

1. Alkaloids Derived from Halocyclohexadiene-cis-diols ............................ 2

2. Amaryllidaceae Alkaloids Derived from Bromocyclohexadiene-cis-diol ....... 3 3. Representative Amaryllidaceae Alkaloids ........................................... 5

4. Isolation of Pancratistatin .............................................................. 6

5. Phenanthridone System ................................................................. 8

6. Activated and Nonactivated Aziridines .............................................. 62

7. Synthetic T argets ........................................................................ 79

8. TLC Comparison with (+)-7-deoxypancratistatin ................................... 108

9. TLC Comparison with the Tetraacetate of (+)-7-deoxypancratistatin ............ 110

10. Assignments of the Piperonyl, Tosyl, and Benzyl Moities in Amide 332a...... 112 11. Assignments of the Acetonide Unit of Tosylamide 332a .......................... 113

12. Partial NOESY Spectrum of Amide 332a ............................................ 113

13. Partial DQCOSY Spectrum of Amide 332a ......................................... 114

14. Carbon Hydrogen Framework of the Cyclohexyl Unit of Amide 332a .......... 115

15. HETCOR Spectrum of Amide 332a .................................................. 115

16. Connectivity of the Piperonyl Unit of Tosylamide 332a ........................... 116

17. Location of the Benzyl Group of Amide 332a ...................................... 117

18. Significant nOe's of the Tosyl Group in Amide 332a .............................. 117

19. Complete Structural Assignment of Amide 332a ................................... 118








20. Proton Assignment of Amide 332a .................................................... 119

21. 5N GHMQC Spectrum of Tosylamide 332a ......................................... 120














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 SYNTHESIS AND UTILITY OF VINYL AZIRIDINES: AN APPROACH TO THE SYNTHESIS OF (+)-7-DEOXYPANCRATISTATIN
AND THE PREPARATION OF SEVERAL TRUNCATED ANALOGS By

Stefan Schilling

August 2001

Chairman: Tomas Hudlicky
Major Department: Chemistry

Approaches to the syntheses of (+)-7-deoxypancratistatin (6) as well as several structurally related truncated analogs (296) are described by chemical manipulation of the enantiomerically pure bromocyclohexadiene-cis-diol (lb). Among the key steps in the synthesis of the truncated analogs are the SN2 opening of a vinylaziridine (298) which gives a functionalized cyclohexene (297) and oxidative degradation of the cyclohexene (297) to give the desired derivatives (296). The approach to the synthesis of (+)-7deoxypancratistatin (6) is based on the selective opening of the oxirane in an epoxyaziridine (301) by piperonylic species. Unfortunately, selective opening of the aziridine ring was found to occur resulting in formation of the functionalized epoxide (329), only ascertained through the identification of the tetraacetate (353) at the end of the synthesis which was aided by "5N spectroscopy. Lewis acid mediated intramolecular cyclization of the epoxide (329) gave the corresponding alcohol (332a) which was








ultimately transformed into the final tetracetate (353). A corrected approach to the synthesis of (+)-7-deoxypancratistatin (6) will be described in which the selective opening of a cyclic sulfate (360) by nucleophilic species serves as the key step.














CHAPTER 1
INTRODUCTION


Aziridines are useful synthetic intermediates as evidenced by the extensive reviews1 on the chemistry of aziridines and their utility in the synthesis of biologically important compounds.' Over the last decade, chiral aziridines have emerged as an attractive class of compounds for asymmetric synthesis since a number of procedures are available for the preparation of these heterocycles in enantiomerically pure (or highly enriched) form. As a result of the intrinsic ring strain and polarization, aziridines are rendered susceptible to ring-opening reactions which dominate their chemistry. Moreover, such reactions often proceed in a highly stereospecific and regioselective manner, chemoselectivity dictated by the nature of substituents on the carbon and nitrogen atoms, which makes aziridines useful substrates for synthetic endeavors.

Among the variously functionalized aziridines, vinylaziridines have proven to be the most interesting and useful compounds as a consequence of the unique transformations3 and rearrangements4 which vinylaziridines undergo. Nevertheless, methodologies for the preparation of these molecules are few in number and are usually plagued by low overall yields. The utility of vinyl aziridines stems from the presence of two reactive sites, the three-membered ring and the olefin, each of which possesses distinct chemical reactivity and thus can be independently functionalized.

Halocyclohexadiene-cis-diols la-b have served not only as precursors to optically pure vinylaziridines5 but also as chiral synthons in the enantioselective








syntheses of several natural products, including manojirimycin (2),6 (+)-kifunensine (3),7 specionin (4),8 and (+)-lycoricidine (5)9 among others. The diols la-b contain elements useful for both diastereoselective and regioselective chemical operations; that is, diastereoselectivity is controlled through steric effects associated with the diol moiety, while regioselectivity is governed by the polarization of the diene system. These chemical features must be considered during the course of designing the enantioselective synthesis of target molecules.


0
HN, rOH HO _:! :OH
OH
2 mannojirimycin


OH OH
3 kifunensine


~X


OH

la X= C1 lb X= Br


OH
0"1 0 OH t 0 OH


f OEt
10 0
4 specionin 5 lycoricidine

Figure 1. Alkaloids Derived from Halocyclohexadiene-cis-diols.


In order to demonstrate the utility of the diols la-b in organic chemistry, approaches to the total syntheses of (+)-7-deoxypancratistatin (6) in addition to several








structurally related truncated analogs will be described. The regioselective and stereospecific chemical operations used in attempting to correctly set the six contiguous chiral centers of the C ring in the alkaloid will be discussed. This methodology will ultimately serve as a model for the synthesis of the more potent alkaloid, (+)pancratistatin (7), and thus sustains the creditability of halocyclohexadiene-cis-diols la-b in rational synthetic design.



OH OH
HOH X HOOH

(~~~HOH KZZJ OH E Z

OH 0 0
7 (+)-pancratistatin lb X = Br 6 (+)-7-deoxypancratistatin

Figure 2. Amaryllidaceae Alkaloids Derived from Bromocyclohexadiene-cis-diol














CHAPTER 2
HISTORICAL


Amaryllidaceae Alkaloids


Isolation and Structure Determination

The use of plant extracts derived from the Amaryllidaceae family for medicinal purposes dates back to at least the fourth century;'0 moreover, several alkaloids possessing a diverse array of biological activities have been isolated from this species in more recent times. The Amaryllidaceae alkaloids constitute a class of natural products consisting of over 1000 species in 85 distinct genera." Over thirty different plants of the Amaryllidaceae family are in use today as agents in the primitive treatment of cancer. In 1877, the first member of the Amaryllidaceae species, lycorine (8), was isolated from Narcissus pseudonarcissus."2 During the late 1960s, the Okamoto research group discovered the presence of narciclasine (9) as well as lycoricidine (5) in Lycoris radiata."3 In the past two decades, Pettit and co-workers extracted a more highly oxygenated phenanthridone alkaloid, pancratistatin (7), from Pancratium littorale,"4 while the laboratories of Ghosa15 reported the isolation of 7-deoxpancratistatin (6) from the bulbs of Haemanthas kalbreyeri. In addition to these natural products, more than 100 unique tyramine based structures have been found in the Amaryllidaceae family since the initial disclosure of the alkaloidal constituents present within this species of plant.









Biological Activity

Many of the natural products derived from the Amaryllidaceae family display a wide spectrum of pharmacological properties, most notably the confirmed levels of



OH OH
OH OH OH < Z OH < OH R R 0 8, lycorine 5, R = H, lycoricidine 6, R = H, 7-deoxypancratistatin 9, R = OH, narciclasine 7, R = OH, pancratistatin Figure 3. Representative Amaryllidaceae Alkaloids


anticancer activity exhibited by certain alkaloids within this class. The work of the Fitzgerald group16 in 1958 has demonstrated that the antitumor activity of lycorine stems from its ability to inhibit murine P-388 lymphocytic leukemia. Both narciclasine and lycoricidine inhibit the growth of murine Ehrlich carcinoma and also exhibit carcinostatic activity.13, " Narciclasine displays anticancer activity against human HeLa and HEP,, carcinomas,3, while pancratistatin has shown antitumor activity in vivo against murine P-5076 ovarian sarcoma in addition to murine P-388 lymphocytic leukemia.'9 Furthermore, clinical studies have suggested that pancratistatin exhibits notably higher therapeutic indices relative to its congeners narciclasine and lycoricidine. The antineoplastic activity of pancratistatin has also been detected within 7deoxypancratistatin in vitro; moreover, a better therapeutic index has been observed for 7-deoxypancratistatin relative to pancratistatin as a result of decreased toxicity.2'












Bulbs (68 kg)

1. MeOH-CH2C2 (1:1 ; 120 L)
2. H20 (exuded by bulbs)


Aqeous Fraction


CH2CI2 Fraction


Aqeous Fraction

n-BuOH-H20 F_ 7


Aqeous Fraction
Inactive







Insoluble Fraction In vivo inactive


MeOH, CH2C12 added Re-extract bulbs 20 % H20 added


CH2Cl2 Fraction


n-BuOH Fraction


(1.5 L)


MeOH (1.5 L)


Insoluble Fraction
Inactive

Soluble Fraction


Sephadex LH-20 (2.5 kg);
MeOH-CH2C12


Hexane Fraction T/C Inactive


Soluble Fraction


MeOH/H20
Hexane
--I
Aqeous Fraction
T/C Inactive


Pancratistatin (1.3 g)
T/C Active


Figure 4. Isolation of Pancratistatin









Of these alkaloids, only the mode of action by which narciclasine exhibits its antineoplastic activity is well documented.2' Studies have established that the mechanism of action for narciclasine involves inhibition of the growth of eukaryotic cells via obstruction of protein biosynthesis. Specifically, results suggest that narciclasine prevents binding of tRNA to the peptidal transferase center of the 60s ribosomal subunit.Ia As a result of the structural similarities among narciclasine, pancratistatin, and 7-deoxypancratistatin, it has been speculated that similar modes of activity exist for all of these alkaloids; nevertheless, a more detailed explanation for pancratistatin's and 7deoxypancratistatin's mechanism of action has not presently been elucidated. Total Syntheses

The portfolio of biological activity displayed by certain members of the Amaryllidaceae family as well as the challenging structural motifs found in these alkaloids, which are exemplified by narciclasine (9), lycoricidine (5), pancratistatin (7) and 7-deoxypancratistatin (6), has prompted the synthetic community to prepare several of these natural products." The synthesis of lycoricidine9' 23 has been reported by several groups; in addition, the unnatural enantiomer (-)-lycoricidine has also been successfully prepared.24 More recently, the asymmetric synthesis of the natural enantioner (+)narciclasine2527e has been reported by two research groups. Since the initial racemic synthesis of (+/-)-pancratistatin by Danishefsky and Lee26 in 1989, there have been four total asymmetric syntheses of (+)-pancratistatin27 as well as one formal synthesis of the alkaloid.28 The natural product (+)-7-deoxypancratistatin has also been synthesized several times,29 including two syntheses23ab in route to lycoricidine which were performed prior to the isolation of (+)-7-deoxypancratistatin from natural resources. The following









section will discuss the methodology employed in the total syntheses of (+)-pancratistatin

(7) and (+)-7-deoxypancratistatin (6) and will describe various synthetic approaches to the preparation of these natural products.

The most notable structural features which complicate synthetic endeavors aimed at preparing these alkaloids include the trans B-C amide ring junction, the high degree of substitution of the aromatic A-ring, and the stereochemistry pertaining to the various functionalities embedded along the C-ring. In general, the majority of the syntheses initially construct the A- and C-rings and then establish the B-C ring junction which results in formation of the phenanthridone core present in these alkaloids.22



@3






1 3



R 0


Figure 5. Phenanthridone System



Pancratistatin

As shown in Scheme 1, the first total synthesis of (+/-)-pancratistatin disclosed by Danishefsky and Lee26 began with pyrogallol 10a which was converted to orthoester 10b using triethyl orthoformate. Carbamoylation of phenol 10b with diethylcarbamoyl chloride, cleavage of the orthoester, and construction of the methylenedioxy unit afforded








llb which was transformed into amide 12a in modest yield via an anionic Fries rearrangement. Protection of the hydroxyl group as the silyl ether followed by ortholithiation and subsequent treatment with N,N-dimethylformamide generated aldehyde 13. Formation of the arylbutadiene 14 was achieved by treatment of aldehyde 13 with allylmagnesium bromide, activation of the resulting alcohol with mesyl chloride, and elimination of the homoallylic mesylate with DBU. A Diels-Alder reaction of diene 14 with P-nitrovinylsulfone gave cyclohexene 15 which was reduced with tri-n-butyltin hydride to furnish cyclohexadiene 16a. Deprotection of silyl ether 16a with tetra-nbutylammonium flouride followed by treatment of the resulting alcohol with bis(tributyltin)oxide furnished the corresponding stannyl ether which upon exposure to iodine afforded lactone 17a. Benzylation of the phenol followed by catalytic osmylation produced the corresponding diol lactone which, upon treatment with DBU, underwent an elimination to form diol 18. In a Moffatt-like transformation, diol 18 was treated with 2acetoxyisobutyl bromide to provide the acetoxy derivatives 19a and 19b. Dihydroxylation of the olefin in 19b furnished diol 20, an intermediate containing a fully functionalized C-ring present in pancratistatin. Following an intricate protection and reductive elimination sequence, imidate 23 was prepared from alcohol 22 by reaction with sodium hydride and trichloroacetonitrile. Pyrolysis of imidate 23 invoked an Overman rearrangement to generate trichloroacetamide 24 which was converted into diol 25 by catalytic osmylation. Treatment of diol 25 with potassium carbonate in refluxing methanol resulted in successful hydrolysis of the lactone to produce lactam 26 after DCC coupling of the intermediate amino acid. Removal of the benzyl group provided the target molecule (+/-)-pancratistatin in 26 steps and in an overall 0.13 % yield.








The first asymmetric synthesis of (+)-pancratistatin was published by Hudlicky and co-workers27ab in 1995 as illustrated in Scheme 2 which started from the enatiomerically pure synthon lb obtained by whole cell bio-oxidation of bromobenzene.3 Protection of the diol as the acetonide under standard conditions followed by reaction with (N-tosylimino)phenyliodinane" according to Evans' protocol32 furnished vinylaziridine 27 which was subsequently reduced to aziridine 28 under radical conditions. In the pivotal step of the synthesis, stereospecific opening of aziridine 28 with a higher order cyanocuprate (Ar2Cu(CN)2Li) in a SN2 fashion gave rise to tosylamide 29 which contains the carbocyclic skeleton of the natural product. Conversion of primary tosylamide 29 into the N-acyl derivative 30 and subsequent reductive detosylation afforded carbamate 31 following desilylation. Reduction of the aryl amide moiety and protection of the phenol as the benzyl ether produced aldehyde 32 which was oxidized to acid 33 and immediately converted into methyl ester 34. Following deprotection of the acetonide, hydroxyl directed epoxidation generated epoxide 35 stereospecifically as the cyclization precursor. Treatment of epoxide 35 with a catalytic amount of sodium benzoate resulted in deprotection of the carbamate, ensuing cyclization to the lactam, solvolysis of the epoxide and debenzylation to ultimately furnish (+)-pancratistatin in an overall yield of 2 % and in 13 steps.

An additional enantioselective synthesis of (+)-pancratistatin depicted in Scheme 3 was achieved by Trost and Pulley7c which took advantage of the availablity of diol 36 and its palladium-catalyzed desymmetrization.33 After protection of the diol as the dicarbonate, desymmetrization in the presence of a chiral ligand afforded azide 37 in greater than 95 % enantiomeric excess. Treatment azide 37 with cuprous cyanide and








OCONEt 2

ii ~RR


OTBS

vi < 0 CONEt2
O CHO


iv


10a R, R', R=OH
S 10b R', R"=CHOEt, R=H

OR0

H

xiii__ 17a R=H 17b R=Bn


xiv, xv
01


r---- 11 R', R"=H ,
iit- lb R', R"=-CH2-


xii


r-16a R=TBS Xi _.16b R=H


'0
kH X-


12a R=H
VL-- 12b R=TBS

OTBS
o,6 CON Et2
me x < / '" ix


NON
15 OSO2Ph


13

1 vii, viii
OTBS


0 1

14


OBn O


OBn O


19b


i. HC(OEt)3, Amberlyst-15, benzene; ii. NaH, THF, Et2NCOCI, DMAP; iii. K2CO3, CH2Br2, CuO, DMF; iv. a) s-BuLi, TMEDA, THF; b) NH4CI; v. TBSCI, imidazole, CH2C12; vi. a) s-BuLi, TMEDA, THF; b) DMF; vii. Allylmagnesium bromide, Et2O; viii. a) CH3SO2CI; Et3N, CH2CI; b) DBU; ix. 1-(benzenesulfonyl)-2-nitroethene, CHC13; x. Bu3SnH, AIBN, toluene; xi. TBAF, THF; xii. a) (Bu3Sn)20, toluene; b) 12; THF; xiii. BnBr, Ag2O, DMF; xiv. OsO, NMO, CH2C2, THF, H.0; xv. DBU, benzene; xvi. 2acetoxyisobutyryl bromide, CH3CN.


Scheme 1. First Total Synthesis of (+/-)-Pancratistatin (Part I)


OR"


R0?












OBn 0


S 0 H
0 H
AcO
Br


OR
HO OH O 0 OH OD NH
OR O
.r-- 26 R=Bn XXlVL7 R=H


OBn


-xvii :


H
AcO


-9xxiii


OBn 0
0 -, L3

-x - < OR xix
H'
AcO OR'
Br
21a R=H, R'=-CH2C6H4(4-OCH3) 21b R=Bn, R'=-CH2C6H4(4-OCH3
21c R=Bn, R'=H


OBn 0

O 0 0H O Bn xxii
H
CI3COHN ' OH
OH


OBn 0

< 0 HOBn4 x
( I Hxxi

H
CI3C0HN
24


OBn 0


O H OBn
H
SOH

22

xx


OBn 0


< 0 OBn
H
0
23 HN 1CC13


xvii. OsO4, NMO, CHC12, THF, H20; xviii. a) Bu2SnO, toluene; then 4-methoxybenzyl bromide, n-Bu4NI; b) BnBr, Ag20, DMF; c) DDQ, CH2C12, H20; xix. Zn(dust), AcOH, H20, CH2CI2; xx. NaH, CC13CN, THF; xxi. 100-105 'C, 0.05-0.1 mmHg; xxii. OsO4, NMO, THF, H20; xxiii. K2C03, MeOH, CH2C2; then DCC, CH2C12; xxiv. H2, Pd(OH)2, EtOAc.


Scheme 1. First Total Synthesis of (+/-)-Pancratistatin (Part II)








aryl Grignard reagent resulted in a SN2' addition to form azide 38 which contains a cyclohexene unit resembling the C-ring of the alkaloid. Dihydroxylation of the olefin, protection of the resulting hydroxyl groups, and bromination of aromatic ring generated aryl bromide 39 as the precursor to cyclization. Conversion of azide 39 to the corresponding isocyanate was followed by metal halogen exchange to give an aryllithium species which underwent cyclization producing lactam 40, an intermediate which contains the core of the natural product. Desilylation of lactam 40 gave the the resulting diol which was converted into cyclic sulfate 41. Stereospecific and regioselective nucleophilic attack of sulfate 41 with cesium benzoate gave rise to ester 42 following simultaneous clevage of the acetonide and the alkyl sulfate under acidic conditions. Removal of the benzoyl and methyl ether groups completed the synthesis of (+)pancratistatin in 15 steps from diol 36 and in an II % overall yield.

A formal synthesis of (+)-pancratistatin was disclosed by the Haseltine group28 in 1997 as displayed in Scheme 4 which intercepted a late stage intermediate of Danishefsky and Lee's26 synthesis. The synthesis began with diol 36 which was subjected to the sequence for desymmetrization of Johnson et a].:3 enzymatic acetylation to furnish acetate 43a, protection to give silyl ether 43b and deacetylation to afford alcohol 43c. Benzylation of the alkoxide derived from alcohol 43c with piperonyl bromide generated allylic alcohol 44 after removing the silyl group. The carbon skeleton was obtained via an intramolecular cyclization of piperonylated conduritol 44 to produce pentacycle 45 which was oxidized to acetal 46a as a single diastereomer. The installed acetal tether in 46a was used to direct lithiation of the arene ring which gave phenol 46b upon oxidation. Deprotection of the acetal group in phenol 46b gave the corresponding








lactol 47 which upon oxidation and ketal hydrolysis furnished lactone 48. Selective protection of the allylic hydroxyl group in lactone 48, benzylation of the remaining alcohol, and hydrolysis of the methoxyethoxymethyl ether afforded alcohol 49c whose spectral data were consistent with those reported by Danishefsky and Lee,26 thus establishing a formal synthesis of (+)-pancratistatin.

As shown in Scheme 5, Magnus and Sebhat2d are credited with a total synthesis of (+)-pancratistatin which starts with addition of the aryllithium species derived from 3,4-methylenedioxy-5-methoxybromobenzene to ketone 50 producing the styrene derivative 51 after dehydration. Catalytic hydrogenation of the olefin followed by ketal hydrolysis afforded cyclohexanone 52 which was converted to triisopropylsilyl enol ether 53 in greater than 85 % enantiomeric excess. Treatment of silyl enol ether 53 with iodosylbenzene resulted in a P3-azidonation reaction furnishing azide 54 as a mixture (3.5:1) of trans- and cis- diastereomers. Reduction of the azide functionality and subsequent protection of the corresponding amine generated carbamate 55. Treatment of carbamate 55 with m-chloroperoxybenzoic acid followed by acid catalyzed hydrolysis of the resulting silyl enol ether gave ester 56a stereoselectively. Epimerization of carbamate 56a under basic conditions (t-BuOK, HMPA) gave the more stable equatorial isomer 56b which was subsequently converted into silyl enol ether 57. Transformation of enol ether 57 to enone 58 was accomplished through a two sequence involving selenylation followed by oxidative elimination. Stereoselective epoxidation of enone 58 followed by reduction of the ketone functionality gave rise to carbamate 59. Treatment of epoxide 59 with sodium benzoate in water under solvolytic conditions followed by acetylation of the resulting tetraol afforded polyacetate 60 which upon Bischler-Napieralski cyclization












i, ii


Ts
__27 X=Br ii 28 X= H


0
i 0 vi, vii < 'ONMe2 M 4T
Ne2 O-- " CONMe2
OR'
29 R=H, R'=TBS
vEi30 R=BOC, R'=TBS


)H xii


OBn


NHBOC
CO2Me


NHBOC C02R


x_ 33 R=H
34 R=Me


i. DMP, p-TsOH, acetone; ii. PhI=NTs, Cu(acac)2, CH3CN; iii. Bu3SnH, AIBN, THF; iv. a) s-BuLi, TMEDA, THF; b) aziridine 28; c) BF3Et20; v. s-BuLi, (BOC)20, THF; vi. Na/anthracene, DME; vii. Morpholine-SMEAH, THF; viii. BnBr, K2CO3, DMF; ix. NaC102, KH2PO4, 2-methyl-2-butene, t-BuOH, H20; x. CH2N2; xi. a) HOAc, THF, H20; b) t-BuOOH, VO(acac)2, benzene; xii. C6HCOONa, H20, 100 �C.


Scheme 2. First Asymmetric Synthesis of (+)-Pancratistatin.


NHBOC
CHO


R'=H R'=Bn


OH O
7


viiiE, 32









TESO,


OH OH 36




OH


"0


Io I


OCO2CH3


i

N3
37



0

HPh ',0, )H


iv, v, vi.._


vii

OTES
TESO II 0 K viii 0 0
0 NH

OCH30


i. n-BuLi, THF; then methyl chloroformate; ii. 0.5 mol % (7T-C3H7PdCI)2. 0.75 mol % chiral ligand, TMSN3, CH2C2; iii. 1,2(methylenedioxy)-3-methoxybenzenemagnesium bromide, CuCN, THF, ether; iv. cat. OsO4, NMOH20, CH2C12; V. TESOSO2CF3, 2,6-lutidine, CH2CI2; vi. NBS, DMF; vii. a) (CH3)3P, THF, H20; b) COCI2, THF, (C2H5)3N; c) t-BuLi, ether, 78 'C; viii. a) TBAF, THF, -78 'C to 0 'C; b) SOC12; (C2H5)N; c) cat. RuC13 H20, NaIO4, CC14, CH3CN, H20; ix. PhCO2C, DMF; then workup with THF, H20, cat. H2SO4; x. K2CO3, CH3OH; xi. LiC, DMF.


Scheme 3. Total Asymmetric Synthesis of (+)-Pancratistatin


.0 ix


OH O
7









OH

0C>K


OH
OR

i, ii rK", 0\0 iii, ivK


OR'
43a R=H, R'=Ac 44
43b R=TBS, R'=Ac 43b R=TBS, R'=H


~OH

-OH
- 0 OBn O
48


x, xi


I 0
OBn OH


viii, ix




OH


X O OCH3
46a X=H vii 46b X=OH


5 steps


OBn 0
49a R=MEM, R'=H 49b R=MEM, R'=Bn 49c R=H, R'=Bn


i. Amano P-30 lipase, isoprenyl acetate, ii. a) TBSCI, imidazole, DMF; b) K2C03, MeOH; iii. iv. TBAF, THF; v. Tf2O, 2,6-lutidine, CH2C12; vi. DDQ, 2-methoxyethanol, CH2C12; vii. HOAc/H202; viii. NaH, BnBr, Bu4NI, THF; ix. CSA, THF, H20; x. TPAP, NMO, CH2C12; iPr2NEt, CH2C12; b) Ag20, BnBr; c) p-TsOH, MeOH.


NaH, piperonyl bromide, Bu4NI, THF; t-BuLi, DME; then B(OCH3)3; then xi. HCI, H20, THF; xii. a) MEMC1,


Scheme 4. Formal Synthesis of (+)-Pancratistatin


-V-a


OH O
7








followed by deprotection of the acetate groups furnished (+)-pancratistatin in 22 steps and in 1.2 % overall yield.

Most recently, Rigby and co-workers"e have synthesized (+)-pancratistatin in which a stereo- and regiocontrolled aryl enamide photocyclization serves to construct the trans-fused phenanthridone system present in the alkaloid as illustrated in Scheme 6. The enantiomerically pure syn-epoxy alcohol 61, obtained through McGowen and Berchtold's procedure,35 was protected as its silyl ether and subsequently hydrolyzed to provide acid 62. After conversion of acid 62 to the isocyanate 63 via a Curtius rearrangement, addition of the lithiated species derived from aryl bromide 64 resulted in formation of enamide 65 as the cyclization precursor. Irradiation of enamide 65 under standard conditions gave rise to the phenanthridone 66 which contains the correct stereochemistry present in the core structure of (+)-pancratistatin. Alkylation of the phenol, removal of the silyl protecting group, oxidation of the ensuing alcohol, and stereoselective reduction of the resulting ketone furnished epoxide 68 after benzylation. Selective axial opening of epoxide 68 with a phenylselenide species followed by selenoxide elimination afforded allylic alcohol 69 which was subsequently dihydroxylated to provide the triol 70 in good yield. Simultaneous removal of both the benzyl and p-methoxybenzyl protecting groups via hydrogenolysis followed by removal of the methyl group furnished (+)-pancratistatin in 17 steps and in 2.8 % overall yield from epoxy alcohol 61.

The structural intricacy of (+)-pancratistatin has posed a challenge to the synthetic community thus resulting in only six syntheses of the alkaloid. Both the control of stereochemistry of the functionalities along the C-ring and the establishment of the trans B-C ring junction become a formidable task for any synthetic endeavor aimed at










0-)
0
i, iil iii

0
OMe
51


NHCO2C H3


OMe
56a


-.c viii


.OTIPS


OMe
52


vi, vii


NHCO2CH3


OMe
55


i. 3,4-methylenedioxy-5-methoxybromobenzene, n-BuLi, THF, -78 'C; ii. DBU, POC13 pyridine; iii. a) H2, Pd/C, MeOH; b) H2S04, H20, dioxane; iv. (+)-bis((a-methylbenzyl)amine, n-BuLi, THF, -78 'C, then LiCI, TIPSOTf, THF; v. PhIO, TMSN3, CH2C2,; vi. LiAH4, Et2O; vii. CH3OCOCI, pyridine, CH2C2; viii. a) niCPBA, imidazole, CH2C12; b) EtOH, HCI, H20.


Scheme 5. Total Synthesis of (+)-Pancratistatin (Part I)


5 50












-x 3.


,,? NHCo2CH3 OMe
56a


NHCO2CH3


'Y:'OCOAr N(TMS)CO2CH3


56b


0

O OCOAr o0-:T NHCO2CH3

OMe


xiii, xiv


OAc


-U0 xvii, xviii


xv, xvi


OMe


OH


( 0 OH . OD( NHCO2CH3
OMe


ix. t-BuOK, HMPA; x. Et3N, TMSOTf, CH2C12; xi. AgCO2CF3, PhSeC1, CH2C12; then H202, pyridine, CH2C12; xiii. NaHCO3, H202, THF, MeOH, H20; xiv. L-selectride, THF; xv. C6H.CO2Na, H20, 100 'C; xvi. Ac2O, pyridine; xvii. Tf2O, DMAP, CH2C12; xviii. a) BBr3, CH2C12, -78 'C; b) NaOME, THF.


Scheme 5. Total Synthesis of (+)-Pancratistatin (Part II)


OH O
7










TBSO O


CO2H


,'O
TBSO,,


NCO


0~

OEE
64


TBSO.,


iii
N NH
OEE O
65


viii


68

OH
BnO ,IOH



< OH ON NPMB
OMe O


TBSO,, -*

.vi, vii <0 1 - V
SNPMB

H
67


x, xi


OH
HO OH

< 0 OH 0o NH
OH O
7


i. a) TBSC1, imidazole; b) LiOH; ii. a) DPPA; b) toluene, 110 'C; iii. n-BuLi, THF; iv. a) NaH, pmethoxybenzylbromide; b) PPTS; v. hv, benzene; vi. a) NaH, Mel; b) TBAF; vii. a) Dess-Martin, CH2C12; d) NaBH4; b) NaH, BnBr; viii. (PhSe), NaBH4, H202; ix. Os04; t-BuOH; x. H2, Pd(OH)2; xi. LiCI, DMF.


Scheme 6. Total Synthesis of (+)-Pancratistatin


HO,..Q ..a..



CO2CH3
61


H
66









preparing the natural product in enantiopure form. The development of more efficient methodology towards constructing the six contiguous asymmetric centers will lead to a .more practical synthesis of the alkaloid, and research in this area remains to be performed in the future.


7-Deoxypancratistatin

The earliest synthesis of 7-deoxypancratistatin dates back to 1976 when Ohta and Kimoto23" prepared the alkaloid in racemic form, prior to its isolation from natural resources, in route to the prepration of (+/-)-lycoricidine. Reaction of ethyl acrylate with 3,4-methylenedioxyphenyl allyl carbinol 71 furnished a mixture of Diels-Alder adducts 72 which were used to prepare acid 73 as displayed in Scheme 7. Acid 73 was converted into the corresponding acyl azide via a modified Curtius reaction which was used to generate isocyanate 74 as the cyclization precursor. Lewis acid catalysis led to successful formation of lactam 75a which was protected as its acetate. Hydrolysis of lactam 75b, bromination of the resulting olefinic acid, and subsequent lactonization generated the acetamide 76. Base induced elimination of acetamide 76 provided olefin 77 which underwent transamidation upon exposure to aqeous sodium hydroxide producing alcohol 78a. Protection of alcohol 78a as its tetrahydropyranyl ether followed by oxidation of the olefinic bond gave epoxide 79 which was transformed into allylic alcohol 80a using Sharpless and Lauer's procedure.36 Acetylation of the hydroxyl functionality, removal of the tetrahydropyranyl protecting group, stereocontrolled dihydroxylation of the olefin, and hydrolysis of the acetate afforded the alkaloid in racemic form, which was used to prepare (+/-)-lycoricidine via a dehydration protocol.









The first asymmetric preparation of (+)-7-deoxypancratistatin was performed by Paulsen and Stubbe23b in route to (+)-lycoricidine in which the chirality is derived from D-glucose as illustrated in Scheme 8. Reaction of the aryl anion derived from isopropyl 6-bromo-(3,4-methylenedioxy)benzoate with olefin 81 gave rise to acetonide 82 as a mixture of idofuranose and glucofuranose derivatives. Cleavage of the acetonide in the mixture of furanose derivatives with acetic acid followed by cyclization of the resulting diol under basic conditions (K-C03, MeOH) afforded lactone 83 which contains the functionalized C-ring of the alkaloid. Reduction of the nitro functionality was carried out concurrently with debenzylation producing amino lactone 84 which after hydrolysis and subsequent transamidation furnished (+)-7-deoxypancratistatin.

The total synthesis of (+)-7-deoxypancratistatin has also been achieved by Keck et al.9 in 1995 which utilized a radical cyclization strategy as shown in Scheme 9. The synthesis began with diol 85, prepared from D-gulonolactone, which after protection of the hydroxyl functionalities, reduction, and oxime formation gave hydroxy oxime 86. Protection of the hydroxyl moiety as a methoxymethyl ether, selective removal of the silyl ether, and ensuing oxidation produced acid 87b which was then converted into ester 88 under Mitsunobu conditions. Lithium halogen exchange of aryl bromide 88 gave the rearranged alcohol upon warming which was immediately oxidized to aldehyde 89. Desilylation of aldehyde 89 followed by cyclization afforded ketone 90 after protection of the resulting lactol functionality. Ketone reduction followed by acylation furnished oxime 91 as the radical cyclization precursor. Formation of the radical derived from the thinocarbamate 91 and subsequent trapping by the oxime functionality generated the protected lactol 92 as a single stereoisomer which after acylation, desilylation, and










O -OH

71

RO


0

0
x[' 78a RH
78b R=THP


xi


0 C
0, CO2Et


i.J X


770


THPO ,9


O N 00


xii


< 0 *- Y iii, iv
O07 COOH
73


AcHN .,l

viii 0 vii <

00
0:0;


xiv, xv


0

xiii --- 80a R=THP, R'=H
80b R=H, R'=Ac


vc_ 75a R=H v- 75b R=Ac
OH
HO OH

O0 OH

O TNH
0
6


i. Ethyl acrylate, p-TSA; ii. NaOEt, EtOH, then H20; iii. C1COEt, Et3N, acetone; H20; iv. NaN3, H20, then toluene, reflux; v. BF3Et2O; vi. Ac2O, pyridine; vii. a) I N KOH, MeOH; b) NBS, THF; viii. DBU, pyridine; ix. 20 % aqueous NaOH, EtOH; x. 2,3-dihydropyran, p-TSA; xi. JnCPBA, CHC13; xii. Diphenyldiselenide, EtOH, NaBH4, then H202, xiii. a) AcO, pyridine; b)p-TSA, AcOH, MeOH,; xiv. Os04, pyridine; xv. I N KOH, MeOH.


Scheme 7. First Synthesis of (+/-)-7-Deoxypancratistatin


N ,R









OBn


;- Bno ONO2 BnO 0O 00 R='Pr
81 82 83






OH OH HO OH 0 0 OH


0- NH 0 NH2

6 84

i. a) Isopropyl (6-bromo-3,4-(methylenedioxy))benzoate, n-BuLi, THF, -110 'C; b) nitroolefin 81; ii. a) 50 % aqeous HOAc; reflux; b) K2CO3, MeOH; iii. H2, Pd/C, MeOH; iv. K2CO3, MeOH, reflux.


Scheme 8. First Synthesis of (+)-7-Deoxypancratistatin








H 0 0 HO
H0 05


85

OMOM
TBSO 0 0



0 NOBn \---O 91 X=


i, ii, iii


iv, v, vi-


TBSO"


0 OMOM

viiiN
TBSO 01<
N-OBn


vii i_ 87a X=H
87bX=OH


xi, xii


S
,\,'' N


xiii OMOM


OMOM


xiv, xv, xvia


xvii, xviii.


O TFA OBn \-O 93


<0 0 * 0
N, OBn

88


O OMOM

0
CHO I K
N.OBn
89 P=TBS

OH
HO OH


<( K OH
O0 NH
0
6


i. TBSC1, imidazole; ii. DIBAL, -78 �C; iii. BnONH2,HCI; iv. MOMCI, DIEA; v. HFPyridine; vi. TPAP, NMO, vii. NaCIO, KH2PO4; viii. Ph3P, DEAD, 4-bromo-5-(hydroxymethyl)-1,2-(methylenedioxy)benzene; ix. a) n-BuLi; b) TPAP, NMO; x. a) HFPyridine; b) TBSCI, imidazole; xi. NaBH4, MeOH; xii. TCDI, DMAP, 1,2-dichloroethane; xiii. nBu3SnH, AIBN, toluene; xiv. TFAA, pyridine, DMAP; xv. TBAF, THF; xvi. TPAP, NMO; xvii. SmI,; xviii. a) Dowex H resin;b) K2CO3, MeOH.


Scheme 9. Synthesis of (+)-7-Deoxypancratistatin









oxidation produced lactone 93. Completion of the synthesis of (+)-7-deoxypancratistatin involved cleavage of the nitrogen oxygen bond, deprotection of the acetonide and methoxymethyl ether groups, and removal of the trifluoroacetamide group which occurred with concomitant lactone to lactam reorganization.

In a second generation synthesis, Keck and co-workers29e prepared (+)-7deoxypancratistatin by way of an aryl radical cyclization of a tethered N-aziridinylimine as shown in Scheme 10. Alkylation of alcohol 94 with the trichloroacetimidate of 6iodopiperonol genertaed aryl iodide 95 which was transformed into alcohol 96 following reduction of the lactone and oxime formation. A four step sequence converted alcohol 96 into N-aziridinylimine 97 as the cyclization precursor. Radical cyclization of aryl iodide 97 generated benzopyran 98 as a single diastereomer which upon clevage of the nitrogen oxygen bond and subsequent acylation gave trifluoroacetamide 99. Oxidation of the benzylic position followed by simulataneous removal of the silyl ether and acetonide groups produced triol 100 which was converted to the alkaloid following deprotection of the trifluoroacetamide and ensuing lactone to lactam rearrangement.

Hudlicky and coworkers29,.b have also synthesized (+)-7-deoxypancratistatin in an asymmetric fashion beginning with diol lb which is obtained in enantiomerically pure form by whole cell biooxidation of bromobenzene.3� Protection of the diol as the acetonide followed by reaction with methyl p-(nitrophenylsulfonyl)oxycarbamate generated aziridine 101. Debromination under radical conditions afforded vinylaziridine 102 which was subsequently coupled with the higher order cyanocuprate derived from 4.bromo-l,2-(methylenedioxy)benzene to generate carbamate 103 which contains the carbocyclic skeleton of the alkaloid. Removal of the acetonide under standard conditions









and subsequent hydroxyl-directed epoxidation of the olefin afforded epoxide 104 which was opened in a stereoselective fashion to provide tetracetate 105 following peracetylation. Bischler-Napieralski cyclization of carbamate 105 gave lactam 106 which upon deprotection furnished the alkaloid in 2.6 % overall yield and in 12 steps.

The laboratories of Chidag29 have also completed a synthesis of (+)-7deoxypancratistatin starting from D-glucose in which an intramolecular Heck reaction is used to construct the nucleus of the alkaloid as shown in Scheme 12. Protection of the known diol 10738 as the bis-(methoxymethyl) ether occurred concurrently with partial halide exchange to furnish the azides 108a and 108b as an inseparable mixture of compounds. Dehalogenation of the mixture of azides (108a-b) followed by Ferrier rearrangement of the resulting pyranoside afforded cyclohexanone 109 which was immediately converted into enone 110 via elimination. Luche reduction of enone 110 occurred in a stereoselective fashion to provide alcohol Ilia which was subsequently protected as its p-methoxybenzyl ether. Reduction of the azide in cyclohexene l1b followed by condensation of the resulting amine with 6-bromopiperonylic acid under the protocol of Yamada et al.'9 gave aryl bromide 112 as the cyclization precursor. Following alkylation of the amide, intramolecular palladium catalyzed cyclization according to the conditions of Grigg et al.4� furnished phenanthridone 113 which contains the core of the alkaloid. Stereoselective hydrogenation of olefin 113 followed by protection of the alcohol generated triflate 114. Substitution of the triflate with acetate provided phenanthridone l15a which was converted into alcohol 115b following deprotection. Conversion of alcohol 115b into its triflate and subsequent base induced elimination furnished the cyclohexene 116 following removal of the alcohol










TBSO>-AjjOH"Q


94


NHCOCF3


OTBS ,
95 OO

OTBS 0 0 ." __- ix, x [ ' ]/ ' )


NHOBn
0
\o


ii, iii1


OH

< 0i1 T fo 0

TBSO O
N9
96 OBn


iv, v, vi, vii


OH

0
N N.
OBn
Ph


HO OH xiii 0 " J[- : OH
Oam- NH



6


i. a) 6-iodopiperonol, NaH, CI3CN; b) TfOH, THF; ii. L-Selectride, CH2C12, -78 �C; iii. Pyridine, HCIH2NOBn; iv. TBSOTf, 2,6-lutidine, CH2C1,; v. HFpyridine, THF; vi. TPAP, NMO; vii. l-amino-2-phenylaziridine, EtOH, 0 'C; viii. Ph3SnH, AIBN, benzene; ix. Sml,; x. trifluoroacetic anhydride, pyridine, DMAP; xi. PCC, CI-lCl,, 55 'C; xii. BF3Et2O, CHCI3 xiii. K2CO3, MeOH.


Scheme 10. Total Synthesis of (+)-7-Deoxypancratistin








Br


OH


I, ii


lb

OAc
AcO OAc

<0 QAc
NH
0
0
106


N
CO2CH3 101


N
CO2CH3
102


OAc
AcO OAc
ix < 0O1OAc
"0'': NHCO2CH3


,, vii, viii


0 K
0 0

O: -.. H 0

103
0 vi


OH

O0 - NHCO2CH3


OH
HO OH < 0 OH
0 NH

6


i. DMP, p-TsOH, acetone; ii. NaHCO, H20, methyl (p-nitrophenylsulfonyl)oxycarbamate, Bn(Et)3NCI, CH.Cl; iii. nBu3SnH, AIBN, THF; iv. a) 4-bromo-1,2-(methylenedioxy) benzene, n-BuLi, THF; b) CuCN; c) aziridine 102; d) BF3Et2O; v. AcOH, THF, H20; vi. t-BuOOH, VO(acac)2, benzene; vii. C6H CONa, H20; viii. Ac20, DMAP, pyridine; ix. Tf2O, DMAP, CHC12; x. NaOCH3, MeOH.


Scheme 11. Synthesis of (+)-7-Deoxypancratistatin


x











Br

HO. 0 HO ',OCH,
N3 107



OMPM
OMOM


O< OMOM
0 - NMPM

0


MOMO" MOMO 0
N3
108a X= Br 108b X= Cl




viii

C


0
J&OMOM
ii iiiOMOM
"- HO " -Y OMOM


OMPM

&OMOM
Br OMOM

-NH

00


vii


iv'


110

4v

OR &OMOM

OMOM
N3


llla R= H
vi - I Ib R= MPM


i. MOMCI, i-Pr,Net, CH2C12; ii. DBU, toluene; iii. Hg(OCOCF3)2, acetone/H20; iv. MsCl, Et3N, CH2C12; v. NaBH4, CeC13 7H20, MeOH; vi. MPMCI, NaH, DMF; vii. a) LAH, ether; b) 6-bromopiperonylic acid, (EtO)2P(O)CN, Et3N, DMF; viii. a) MPMC1, NaH, DMF; b) Pd(OAc)2, 1,2-bis(diphenylphosphino)ethane; TIOAc, DMF.


Scheme 12. Total Synthesis of (+)-7-Deoxypancratistatin (Part I)









OMPM
OMOM

0


OTf
OMOM


o 0Z OMOM
o -~ MPM
0 N Ma


l5a R= Ac 115b R= H


OAc


xvii


-.4 xv, xvi


0,OOH O0 OH O- NMPM

0


116


ix. H2, Pd/C, EtOH/EtOAc; x. Tf2O, pyridine; xi. KOAc, 18-crown-6, benzene; xii. THF-1 N aq. HCI; xiii. a) Tf 0, pyridine; b) KOAc, 18-crown-6, benzene; c) THF-1 N aq. HCI, 50 'C; xiv. mnCPBA, (CICH2)2, pH = 8; xv. NaOAc, DMF/H20, 60 'C; xvi. Ac20, ZnCI2; xvii. a)H2, 5 % Pd/C, I N aq. HCI, EtOH b) NaOMe, MeOH.


Scheme 12. Total Synthesis of (+)-7-Deoxypancratistatin (Part 11)








protecting groups. Hydroxyl-directed epoxidation of olefin 116 generated epoxide 117 stereoselectively which underwent trans-diaxial opening with acetate to afford polyacetate 118 following acetylation of the remaining hydroxyl groups. Removal of the p-methoxyl benzyl group followed by hydrolysis of the resulting polyacetate under basic conditions provided (+)-7-deoxypancratistin.

The most recent synthesis of (+)-7-deoxypancratistatin has been disclosed by Acena et al.T in which addition of the lithium species derived from the functionalized aryl bromide 120 to vinyl sulfone 119'� afforded cyclohexenol 121 as illustrated in Scheme 13. Stereoselective epoxidation of the olefin followed by reduction of the sulfone with sodium amalgam produced epoxide 122 which was subsequently converted into epoxy azide 123 through a two step sequence. Oxidation of the styrene unit under ruthenium tetroxide catalysis generated the corresponding acid which underwent intramolecular cyclization via opening of the epoxide resulting in formation of lactone 124. Simultaneous removal of the benzyl group and reduction of the azide via hydrogenolysis followed by ketal hydrolysis gave the corresponding amino triol which underwent a lactone to lactam rearrangement to furnish (+)-7-deoxypancratistatin in 19 steps and in 8 % overall yield.

The syntheses of (+)-7-deoxypancratistatin demonstrate the various stratagies which have been employed to construct the alkaloid. The construction of the C ring in the natural product and the stereochemical control of its substituents are issues which have been addressed via different methodologies in each of the syntheses of (+)-7deoxypancratistatin. Additional stratagies aimed at preparing (+)-7-deoxypancratistatin in a more efficient manner continue to be explored in the future.














Ph2S11(:D Br
00


119 120


OH
HO OH

O OH zvii, viii, ix OD6 NH
0
6


PhO2S S 0

O N ii, iii
i< OH


121


iv, V
0

vij 0 OK0
0* N3


123


0


i. n-BuLi, THF/toluene, -78 'C; ii. t-BuOOH, n-BuLi, THF, -78 'C; iii. Na/Hg, MeOH/THF; iv. Tf2O, pyridine, CH2C12; v. Bu4NN3, benzene; vi. NaIO4, RuCI3, CH3CN/CCI4/HO; vii. H2, Pd/C 10 %, MeOH; viii. CF3COOH; ix. K2C03, MeOH.


Scheme 13. Total Synthesis of (+)-7-Deoxypancratistatin







Synthetic Approaches

The high degree of functionality and stereochemical features present in (+)pancratistatin and (+)-7-deoxypancratistatin has resulted in a plethora of approaches towards efficiently synthesizing the phenanthridone system present in these natural products.22 A number of these stratagies are outlined below and demonstrate the various synthetic methodologies which can be applied towards the synthesis of both of these alkaloids.

Clark and researchers4 utilized a Lewis acid mediated condensation between anhydride 125 and imine 126 to produce lactam 127 as the major adduct. It was ratioinalized that the addition of triethylaluminum enriched the diastereoselectivity of the reaction through coordination of the Lewis acid to the imine during the course of the condensation. The resulting product, as shown in Scheme 14, contains four contiguous chiral centers representative of the stereochemistry in (+)-7-deoxypancratistatin.



OBn
OBn CH302C
OO + i0 2I A1Me3 0 B'


00 CH2C12 N, PMB
0 PMB N 0

125 126 127

Scheme 14. Clark's Strategy



Kallmerten and Thompson42 successfully prepared a highly funtionalized phenanthridone system related to (+)-7-deoxypancratistatin in which an intramolecular aldol condensation served as the key step shown in Scheme 15. Formation of the C ring







was accomplished by a base induced aldol cyclization of the keto aldehyde derived from olefin 128 which ultimately gave phenanthridone 129 upon further chemical manipulation, an intermediate possessing four of the six stereogenic centers present in the C-ring of the alkaloid.



OBn
OBn T0O .OBn HO Q OBn l i"OBn i. iiIn iv iv. NaCNBH3, MeOH-HC1

Scheme 15. Kallmerten's Approach



Bender and Gauthier43 have reported the preparation of a functionalized system related to (+)-7-deoxypancratistatin starting from myo-inositol as illustrated in Scheme 16. Selective deprotection of inositol derivative 130 followed by treatment of the ensuing diol with base provided alcohol 131 via internal displacement of the tosylate. Alkylation of alcohol 131 with 6-bromopiperonyl bromide gave aryl bomide 132. Exposure of bromide 132 to n-butyllithium gave an intermediate aryllithiated species which cyclized onto the epoxide furnishing pentacycle 133. The benzopyran 133 contains the correct absolute stereochemical configuration of the C-ring present within (+)-7deoxypancratistatin. Both the introduction of nitrogen and oxidation of the benzylic








position are required in order to arrive at a more advanced intermediate which can undergo the transamidation process leading to construction of the phenaanthridone core.


OPMB



OTs 130


i, ii


OFMB
HI~O

0*


��11
0 OPMB
0 00iv ]C r0


OH
0
\-O 133 132

i. p-TsOH, EtOH, CH2C12; ii. NaOMe, MeOH; iii. NaH, 6-bromopiperonyl bromide, DMF; iv. n-BuLi, Et20, -78 'C

Scheme 16. Bender's Strategy


Mehta and Mohal have recently described a stereoselective approach to densely functionalized cyclohexanoids related to the phenanthridone nucleus of (+)-7deoxypancratistatin. The Diels-Alder reaction between 3,4-dimethoxystyrene (135) and 5,5-dimethoxy- 1,2,3,4-tetrachlorocyclopentadiene (134) produced endo-adduct 136 which was converted to aryl-7-norborneone 137 by way of reductive dechlorination and deketalization. A sequence involving Baeyer-Villiger oxidation of 137, hydrolysis of the resulting mixture of lactones, and esterification gave rise to the allylic alcohol 138. Acyl azide 139 was obtained from olefin 138 following dihydroxylation of the olefin, protection of the resulting diol, and functionalization of the ester group. Curtius


>








rearrangement of acyl azide 139 generated the intermediate carbamate which underwent cyclization to give the lactam 140 as shown in Scheme 17.




Me" O e 0
MeO OMe C[ C CI CI 4.


13 0 4 i OM e P 1OCH 3
I OMe H

OCH3 OCH3

134 135 136 137


Iiii, iv
OBn OBn OH BnO , , v BnO" 4], BnO .,,o 3 -Bno
HN y ocH3 N OCH3 H3CO OCH3
O OCH3 OCH 3

140 139 138

i. A; a) Na, NH3; b) Amberlyst-15 resin, acetone iii. 30 % H202, AcOH; iv. NaOH, aq. THF then CH2N2; v. a) Os04; NMO, aq. acetone; b) NaH, BnBr; c) 20 % KOHIMeOH; d) (COC)2, pyridine, CH2C12 then NaN3, acetone; vi. a) xylene, A; b) MeOH, A vii. POC13, 80 C.

Scheme 17. Mehta's Approach



The labs of Branchaud45 have published an approach to the synthesis of (+)-7deoxypancratistatin in which a palladium-mediated aryl-enone reductive cyclization gives rise to a highly fuctionalized benzopyran system as shown in Scheme 18. Alkylation of iodide 141 with the piperonol derivative 142 occurred with concomitant elimination of hydrogen iodide to ultimately furnish alkene 143. A Ferrier rearrangement of alkene 143








generated ketone 144 which was then converted into enone 145 in a five step sequence. Palladium catalyzed cyclization of aryl enone 145 afforded benzopyran 146 which is an advanced intermediate related to (+)-7-deoxypancratistatin.


H3CO "
9> O 0l


0. . OCH3

141 142


H3CO,,,

0
on oOCH

143


'OCH3


iii, iv, v, vi, vii


145


144


\.-O 146

i. Nail, DMF; ii. Hg(OCOCF3)2, acetone/H20; iii. TBDMSOTf, 2,6-lutidine; iv. LiA1H(OtBu)3; v. MsCl, Et3N, CH2Cl2; vi. TBAF; vii. (COCI)2, DMSO, Et3N, CH2Cl2; viii. Pd(OAc)2, PPh3, Et3N, THF

Scheme 18. Branchaud Strategy



In summary, both (+)-pancratistatin and (+)-7-deoxypancratistatin have been synthesized via unique synthetic sequences. In addition, many approaches aimed at efficiently preparing these natural products have been explored by various research








groups. Numerous less densely functionalized model systems have been synthesized which attests to the difficulty in synthesizing these alakaloids. The chemical features of these alkaloids, most notably the functionality and stereochemistry present in the C-ring, the trans- B-C amide ring junction, and the high degree of substitution in the aromatic Aring, make efficient syntheses of these natural products a formidable challenge to the synthetic community.


Vinyl Aziridine Synthesis

Aziridines compromise an important class of compounds displaying unique reactvity which can be applied in organic synthesis.' Like other three-membered rings, aziridines are highly strained; consequently, nucleophiles participate in ring opening reactions of aziridines. Such reactions of aziridines have attracted the attention of the synthetic community, and the applicabilty of these reactions in synthetic chemistry during the past three decades have been reviewed.IaA

Introduction of additional functionality into aziridines enables for more unique chemistry to occur which can result in the construction of more complex systems. Vinylaziridines can be considered as a useful class of functionalized aziridines as a result of their ability to undergo various transformations3 and rearrangements.4 Unfortunately, methods for the generation of vinylaziridines are few; nevertheless, the synthetic community has obtained a renewed interest in developing methodologies for the efficient preparation of vinylaziridines because of the unique reactivity associated with these heterocycles.








Preparation from Dienes by Nitrene Insertion

One of the more general methods employed for the synthesis of aziridines involves the reaction of an olefin with a nitrene which affords the corresponding aziridine. Since the disclosure of the addition of nitrene47 and carboethoxynitrene8a to 1,3-butadiene to give vinylaziridines 148 and 150 as illustrated in Scheme 19, the addition of nitrenes to dienes has seen increased use in synthetic chemistry as a method for the preparation of vinylaziridines.




H2NOSO3- CH3ONa, MeOH
2 1,3-butadiene N
H

147 148 N3-CO2Et hv
1.3-butadiene N
I
CO2Et
149 150

Scheme 19



Rees and Atkinson49 have generated nitrenes by oxidation of 3-aminobenzoxazoline-2-one (151) mediated by lead tetraacetate and has trapped the resulting nitrenes with a variety of conjugated dienes to give vinylaziridines 152 and 153 as depicted in Scheme 20.












'Pb(OAc)4

N 0 NH2
151


R
N


152

R
N


Scheme 20



The labs of Lwowski48b have studied the reaction of carboethoxynitrenes with 1,3dienes and have also observed the formation of vinylaziridines. Generation of carboethoxynitrene via photolytic degradation of ethyl azidoformate in the presence of isoprene (154), cyclopentadiene (156), and 1,3-cyclohexadiene (158) produced the vinyl aziridines 155, 157, and 159 as shown below.


J EtO2CN3,hv


155


CN-,co2Et 157 O1N5CO9 t 159


Scheme 21


154



0
156



0
158


R
N
1 1








The formation of vinylaziridines through insertion of a nitrene species into a diene can generate chiral synthons which are useful in the asymmetric synthesis of important alkaloids. For example, the Hudlicky research group5' 2 has generated vinylaziridines 27 and 101, key intermediates in the synthesis of members in the Amaryllidaceae family of alkaloids, via insertion of a nitrene species into the polarized 1,3-diene 160 as demonstrated in Scheme 22. The polarization of the diene via the electron withdrawing halogen controls the regioselectivity of the aziridination process; whereas, the stereoselectivity of the cycloaddition is dictated by steric factors attributed to the acetonide functionality.


PhI=NTs, Cu(acac)2
CH3CN


Br 160


Br


N*'
I
Ts
27


p-NO2C6H4SO3NHCO2CH3 NaHCO3, Bn(Et)3NCI, CH2Cl2


Br

0
N
C02CH3 101


Scheme 22



Knight and Muldowney12' have also studied the aziridination of several 1,3-dienes under copper catalysis32a'b using (N-tosylimino)phenyliodinane as the nitrene source as illustrated in Scheme 23. In the case of unsymmetrical dienes 161 and 163, formation of








aziridines 162 and 164 occurred at the more electron rich olefin; whereas, the regioselectivity of the aziridination of the electronically similar dienes 154 and 166 was governed by steric factors producing vinylaziridines 165 and 167 as the major products.




OAc N OAc

161 F162


r "-\2CO2Et 163 _1CO6


PhIN=Ts, Cu(acac)2 N154 165

T\,


166
Ts
N


03
158 168 Scheme 23



Preparation from Amino Alcohol Derivatives

Another effective method by which vinylaziridines can be prepared involves intramolecular cyclization of amino alcohols following activation of the hydroxyl functionality. Moreover, the availability of enantiomerically pure amino alcohol







derivatives enables this methodology to be utilized in the preparation of chiral vinylaziridines which can be used in asymmetric synthesis.

As shown in Scheme 24, treatment of the anti amino alcohols 169a-b under Mitsunobu conditions afforded the corresponding vinylaziridines 170a-b in reasonable yields and in optically pure form."



OH

R R Ph3P, DEAD, toluene R NH2 reflux H 169a R = Ph(CH2)2, R' = H 170a 169b R = BnOCH2, R'= H 170b


Scheme 24



In addition, the amino alcohols 172 and 173, obtained as a diastereomeric mixture from the addition of vinyl organometallic reagents to amino aldehyde 171, have been



OH R , H' N 'H
NHR' I R ,.CHO 172 174 NHR' OH R 171
NHR' N 173 175
R = alkyl, aryl; R' = BOC, Ts i. vinyl-M (M = Li, Mg, etc.); ii. PPh3-(NCO2Et)2 Scheme 25








converted to the vinylaziridines 174 and 175 upon activation of the hydroxyl groups of the amino alcohols.51

The Olivo laboratory52 has recently disclosed an efficient method for the synthesis of activated vinylaziridines upon exposing N-substituted 1,4-aminoalcohols to Mitsunobu conditions. The cis-1,4-aminoalcohols 176a-e underwent an SN2' type displacement following activation of the hydroxyl functionality to generate the vinylaziridines 177a-e as shown in Scheme 26. An attractive feature of this methodology is the limited amount of oxazoline formation,'�4 a common side reaction which occurs via nucleophilic attack of the carbonyl oxygen present in the carbamate functionality, as in 176d.



OH
PPh3, DEAD, THF_)n n
NHR R 176a R = Bn, n = 1 177a R = Bn, n = 1 176b R = Bn, n = 2 177b R = Bn, n = 2 176c R = Bn, n = 3 177c R = Bn, n = 3
176d R = CBz, n = 2 177d R = CBz, n = 2
176e R = Ts, n = 2 177e R = Ts, n = 2 Scheme 26



In addition, this methodology has been utilized in the synthesis of optically pure vinylaziridnes. The chiral amino alcohol derivatives 178a-c, when treated under Mitsunobu conditions, generated vinylaziridines 179a-c in enantiomerically pure form as illustrated in Scheme 27.








OH
(NrO PPh3, DEAD, THF


NHR

178a R = Bn 178b R = CBz 178c R = BOC


N
R

179a R = Bn 179b R = CBz 179c R = BOC


Scheme 27



Preparation via Transition Metal Catalysis

Another less utilized process which has been employed in the synthesis of vinylaziridines involves cyclization of amino functionalities onto unsaturated systems, such as alkenes, via transition-metal catalysis. For example, the N-protected methyl carbonates 180 and 181 were converted to the corresponding vinylaziridines 182 and 183 under palladium(O)-catalysis through a decarboxylative ring closure as depicted in Scheme 28."'


[ 0002OH3
2 Pd(PPh3)4, THF

NH Mts 180


02CH3


NH Mts 181


Mts 182


Pd(PPh3)4, THF


+ HN H
Mts 183


95 : 5


Scheme 28








The stereoselectivity associated with the intramolecular cyclization is an attractive feature of this synthetic methodology. An additional advantage of this methodology is that both isomeric carbonates 180 and 181 lead to the formation of vinylaziridines 182 and 183 in the same ratio.

Similarly, the allylic carbonates 184a-c underwent cyclization upon exposure to catalytic amounts of palladium to provide the corresponding vinylaziridines 185a-c and 186a-c as shown in the following scheme.



OCO2CH3 RR ,
R< ) Pd(Ph3)4, THF .+
H H + H H
NHRI
NHR'R R' 184a R = iPr; R'= Mts 185a 186a 184b R = iBu, R'= Ts 185b 186b 184c R = Bn, R'= Mts 185c 186c


Scheme 29



Amino allenes have also been shown to undergo intramolecular cyclization via transition metal catalysis to furnish vinylaziridines in a stereospecific manner. For instance, the Ibuka group53 has demonstrated that the amino allenes 187a-b are readily converted into vinylaziridines 188a-b and 189a-b with good stereoselectivity upon exposure to palladium and an arylating agent as illustrated in Scheme 30.









Pd(PPh3)4, K2CO3, Phi
1,4-dioxane, reflux


187aR' = Pr', R = Mts 187bR' = Bn, R = Mts


188a 188b


189a (84:16)
189b (85 15)


Scheme 30



Preparation from Functionalized Azides Preparation from azido alcohols

Another method employed for aziridine synthesis involves a reductive cyclization sequence of functionalized azido alcohols; moreover, this concept has also been applied to the preparation of vinylaziridines. Wipf and Fritch54 have reported a procedure for the syntheses of vinylaziridines 191a-b from the azido alcohols 190a-b via a Staudinger reaction as shown in Scheme 31.


HO R' 0 R> 'A Oakyt PPh3, CH3CN


190a R = CH3, R' = H, R" = H
190b R = H, R' = CH3, R" = CH3 Scheme 31


R' 0 R I Oalkyl

H
191a 191b


Preparation from azidodienes

The [4 + 1] addition of azidodienes serves as a powerful means of constructing vinylaziridines which occurs via initial cycloaddition to form the intermediate triazoline


H

R!, NHR H







which upon extrusion of nitrogen gives the vinylaziridine. Scheiner5 pioneered the dipolar 1,3-cycloaddition of azides with dienes; for instance, dienes such as isoprene (154) and 1,3-cyclohexadiene (158) were converted into triazolines 192 and 193 which upon photolysis gave vinylaziridines 194 and 195 as shown in Scheme 32.



Ar
N__ N N-NAr hV N 154 p-BrC6H4N3 192 194


Qm-N -h-V c N -Ar 158 193 Ar 195
Ar =p-Br-C6H4


Scheme 32



The azide diene cycloaddition has also been shown to occur in an intramolecular fashion; for instance, cycloaddition of azidodiene 196 afforded vinylaziridine 197 which


-~OEt Toluene, A



196 197 C02Et H 00?E 450 0C



199 198 C02Et

Scheme 33
upon pyrolysis gave a mixture of pyrrolines 198 and 199 with high regioselectivity as illustrated in Scheme 33.56 Moreover, this methodology has been extensively used in the







construction of both the pyrrolizidine and indolizidine skeletons, both of which are useful in alkaloid synthesis.5657


Preparation from Imines

Vinylaziridines have also been prepared by the addition of ylides to activated imines. The Dai group58 has reported the formation of vinylaziridines 202 through the reaction of N-sulfonylimines 200 with sulfonium salt 201 under phase-transfer conditions as illustrated in Scheme 34. In addition to sulfonium salts, both telluronium and phosphorus allylic ylides have been utilized in the aziridination procedure.


++ M2S KOH, CH3CN R

R-CH'N-Ts + H NH Br' N
Ts
200 201 202

R = C6H5,p-C-C6H4, o-CH30-C6H4, c-napthyl Scheme 34



In a preliminary communication, the Dai laboratory59 has shown that treatment of Nsulfonylimines, such as 203, with cinnamyl bromide (204) under dimethyl sulfide catalysis generates the corresponding vinylaziridines 205 as a mixture of cis and trans isomers as shown in Scheme 35.








Ph
R-CH N -Ts + Ph '"" Br Me2S, K2C03 - RNHCH3CN H I

Ts
203 204 205

R = p-C1-C6H4, p-N02-C6H4, o-CH30-C6H4 Scheme 35




The Davis labs6� have generated chiral vinylaziridines through a Darzens-type reaction between an enolate and enantiopure xj3-unsaturated sulfinimines. Condensation of the lithium enolate of methyl bromoacetate with sulfinimine 206 resulted in the formation of vinyl aziridine 207 in high optical purity as depicted in Scheme 36.




OCH3 p-TolylI ,, so H H pToyle %N-" R R0C THF, -78 0 C
206 R = n-C 12H25 207 Scheme 36



Preparation by Miscellaneous Methods Preparation from unsaturated oximes

Laurent and Chaabouni6' have shown that vinylaziridines can be synthesized by the addition of Grignard reagents to oxp-unsaturated oximes; for example, the unsaturated oximes 208a-b upon treatment with various Grignard reagents gave vinylaziridines 210a-








b. It has been postulated that this transformation proceeds via formation of azirine 209 which undergoes nucleophilic attack by a Grignard species to produce the vinylaziridine.


R
C6H5MgBr, toluene C6H5


R R"
208a R = H, R'= C6H5, R" = H 208b R = CH3, R'= CH3, R" = CH3



C6H5MgBr N



209


NOH

208b


R R"
210a 210b


C6H5MgBrN
then H20


Scheme 37



Another method employed for the preparation of vinylaziridines involves a reductive cyclization of oxjp-unsaturated oximes. Treatment of the unsaturated oxime 211


LiAIH4, THF


[(CH30(CH2)20)2AIH2]Na, THF


H
N


212
H H H



213 214 215


Scheme 38


NH

C6H5 210b


OH
N



211








with lithium aluminum hydride produced vinylaziridine 212; whereas, the use of sodium bis(2-methoxyethoxy)aluminum hydride as the reducing agent gave rise to the isomeric vinylaziridines 213-215 as shown in Scheme 38.62


Preparation from aziridinyl aldehydes/ketones

A few reports pertaining to the preparation of vinylaziridines by Wittig olefination of the appropriately functionalized aldehydes have been disclosed. For instance, the labs of Vessi~re63 have converted a number of 2-formylaziridines (216a-c) into the corresponding vinylaziridines 217a-c via a Wittig reaction as shown in Scheme 39.




R Ph3P=CHR'" RHR N N
A A R R 216a R = C(CH3)3, R'= H, R" = CH3, R1' = CH2 217a 216b R = CH2Ph, R' = H, R" = Ph, R.' = CH2 217b 216c R = C(CH3)3, R' = H, R" = H, R.' = CH=CO2C2H5 217c Scheme 39



In addition, the Oshima research group64 has generated the N-tosyl vinylaziridines 219a-c from the requisite aldehydes 218a-c by way of a Wittig olefination as illustrated in Scheme 40.








OHC tR' Ph P=CHR R Ph N H N I . I
Ts Ts 218a R = CH=CH2,.R =CH3 219a 218b R= CH=CHC3H7,R= CH3 219b 218c R = C(CH3)=CH2, R CH3 219c Scheme 40



Preparation from aziridinyl diols

An additional strategy which has been used for the synthesis of vinylaziridines involves installation of the olefin through elimination of an appropriately functionalized diol moiety present within the molecule. Rihnisch65 has reported the preparation of vinylaziridines by way of this strategy as depicted in Scheme 41; that is, the thiocarbonate derivatives 220a-b, obtained from the requisite diols, were transformed into vinylaziridines 221a-b via the Corey procedure.66



Ph
S N"P" NC0Et L.-J 220a R = BOC 221a 220b R = Bn 221b Scheme 41



In summary, the utility of vinylaziridines in organic chemistry has increased during the past few decades; consequently, the synthetic community has experienced a







renewed interest in the efficient preparation of vinylaziridines. A variety of substrates can be utilized to efficiently prepare vinylaziridines, such as dienes, amino alcohols, imines and azides. In addition, many of the precursors used for the synthesis of vinylaziridines are available in enantiopure form thus providing a means of generating optically pure vinylaziridines which are useful in asymmetric synthesis.


Epoxyaziridine Synthesis

Epoxyaziridines serve as valuable intermediates in synthetic organic chemistry, yet limited methodology presently exists for the preparation of such compounds. The presence of two strained ring systems, each of which possess the capability of being opened independently under appropriate conditions, allows for the controlled introduction of nucleophilic components in both a stereospecific and regioselective manner. The unique reactivity associated with epoxyaziridines can be used for the construction of rather complex systems in an expeditious manner which validates the importance of these compounds to the synthetic community.


Preparation from Functionalized Olefins

One method by which epoxyaziridines are prepared involves oxidation of olefinic aziridines in order to generate the oxirane ring. The Prinzbach labs67b have prepared epoxyaziridine 223 from aziridinyl olefin 222 via peroxytrifluoroacetic acid mediated epoxidation as depicted in Scheme 42.

In a similar tansformation, the oxidation of diphenylphosphinoyl aziridine 224 was successfully accomplished using either m-CPBA or methyl(trifluoromethyl)dioxirane as the oxidizing agent to yield epoxyaziridines 225 and 226 as a mixture of stereoisomers








Ts, OMes
t5 --OCOCH3 CF3CO3H



222


Ts, OMes

S- OCCH3


223


Scheme 42


as depicted in Scheme 43.68


0
Ph-P-49

224


m-CPBA, NaHCO3 0 OP< CH2CI - Phy-P-NCO,-O+ PhF--P- D o

225 226 9:81

Oxzone, CF3COCH3 Na2EDTA, NaHCO. OP < . OCH3CN/H20 2 PhF-'-P- 0 + Ph--P-9 0 225 226
56:31


Scheme 43



Preparation via Internal Substitution

Another method by which epoxyaziridines have been prepared involves internal displacement of a suitably placed leaving group, a process which can be used to form either the aziridine or the oxirane ring. The Prinzbach group67 has performed a cishydroxyamination of epoxyalkene 227 by Sharpless and Herranz's protocol69 generating amino alcohol 228 stereoselectively as shown in Scheme 44. Treatment of amino alcohol 228 with base afforded epoxyaziridine 229 via an internal displacement of bromide.








0

Br Sharpless Brcis-hydroxyamination
HO NHR
227 IIR


DBN BF-- Br--'
THF
HC


R = S02C6H5 R = S02C6H4-p-CH3


Scheme 44



Similarly, dihydroxylation of aziridinyl olefin 230 gave rise to diol 231 which upon exposure to sodium glycolate underwent internal displacement of bromide to furnish epoxyaziridine 232 as shown in the following scheme.


Ts
I
B- Br Sharpless
cis-hydroxylation


230


Sodium glycolate
THF OH


Scheme 45



The synthesis of epoxyaziridines via internal displacement has also been reported by O'Brien and Pilgram68 in which epoxyaziridine 234 is generated upon reduction of



H O._-T 1. PPh3, THF, reflux 0

N " 2. Ph2POCI, Et3N, DMAP
233 234


Scheme 46








epoxy azide 233,70 alcohol activation, and ensuing cyclization as shown in Scheme 46.


Preparation from Oxazines

The Viehe group " has reported an efficient methodology for the prepartion of epoxyaziridines in a stereospecific manner by way of the epoxyepimination of N-vinyl oxazines. For example, the oxazines 236a-d, generated by the [4+2] cycloaddition of cyclopentadiene with the corresponding nitrosoalkenes, isomerize at room temperature to give the epoxyaziridines 237a-d as depicted in Scheme 47.71bc


R_ N-OH

R.R

235a R=H, R'=R"=CI 235b R=R'=R"= C1 235c R=CH3, R'=R"=C1 235d R=H, R'=R"=Br


0


236a R=H, R'=R"=Cl 236b R=R'=R"= Cl 236c R=CH3, R'=R"=C1 236d R=H, R'=R"=Br


237a R=H, R'=R"=C1 237b R=R'=R"= Cl 237c R=CH3, R'=R"=CI 237d R=H, R'=R"=Br

Scheme 47


In addition, the Viehe labs71acd have utilized this synthetic methodology for the preparation of optically pure epoxyaziridines through the use of a carbohydrate based nitroso derivative. For instance, cycloaddition of the cx-chloronitroso mannose derivative







239 with the optically pure cyclohexadiene 238 results in formation of the chiral oxazine 240 which was subsequently alkylated with J-chloro-cc-tert-butylthioacrylonitrile to generate the N-functionalized oxazine 241. Upon thermolysis, oxazine 241 rearranges in a stereospecific fashion to provide epoxyaziridine 242 which contains four asymmetric centers. The transfer of chirality to all four dienic carbon atoms of cyclohexadiene 238 through this epoxyepimination process validates the utility of this methodology in asymmetric synthesis; moreover, the preparation of chiral aminocyclitols from epoxyaziridines generated in this manner demonstrates the applicability of the epoxyepimination procedure to organic synthesis.




NH'HCI



+ QAc OAc "L (CI
238 239 240 OAc



CN
Et3N, CH2Cl2




S 0 AN
NC ..OAc ddToluene, 1 10 0C QAcOc


242


241


Scheme 48








The importance of epoxyaziridines in organic synthesis stems from the presence of two strained rings, each of which can be selectively opened under appropriate conditions. The renewed interest in efficiently preparing epoxyaziridines in addition to the unique reactivity associated with these molecules has provided the synthetic community with a valuable intermediate which can be used for the synthesis of a variety of compounds.


Nucleophilic Ring Openings of Aziridines

Aziridines are an attractive class of compounds which contain enormous potential in organic synthesis as a result of the unique reactivity associated with these heterocycles; moreover, the chemistry of aziridines is dominated by ring opening recactions which occur as a result of the inherent ring strain present in these molecules. More recently, ring opening reactions of chiral aziridines have been used for the preparation of enantiomerically pure compounds as intermediates in the asymmetic synthesis of biologically active molecules.2

In a general sense, aziridines can be categorized into two groups based on the nature of the substituent on nitrogen.72 Activated aziridines possess an electronwithdrawing functionality which allows for conjugative stabilization of the developing negative charge on nitrogen occurring during the transition state of nucleophilic ring opening reactions; consequently, such reactions can take place in the absence of catalysis. Nonactivated aziridines, on the other hand, lack the ability to stabilize the developing negative charge on nitrogen which results from nucleophilic ring opening and therefore usually require acid catalysis in order to faciltate ring opening reactions.








V7 1V7
N N

"Activated" "Nonactivated"
R = COR, CO2R, SO2R, etc. R = H, alkyl, aryl, etc.


Figure 6. Activated and Nonactivated Aziridines



Both activated and nonactivated aziridines are susceptible to ring opening reactions; moreover, the vast amount of research has demonstrated that both the appropriate choice of functionality on nitrogen and the substitution pattern on the carbon framework of the aziridine dictate the regio- and stereoselectivity of ring opening reactions. Aziridines have undergone ring opening reactions with a host of noncarbon nucleophiles, such as oxygen based nucleophiles73, halide ions74 and nitrogen based nucleophiles"5 among others. This section will focus on perhaps the most useful reaction of these strained heterocyles which is the ring opening reactions of aziridines by carbon centered nucleophiles resulting in carbon-carbon bond formation under relatively mild conditions.


Intermolecular Ring Openings

Openings by organometallic reagents

The reaction of organometallic reagents with aziridines which affords ring opened products has seen increased use by the synthetic community since the initial work of Hassner and Kascheres16 in which aziridinecarbamate 243 was allowed to react with a variety of alkyllithium species. As illustrated in Scheme 49, both benzyllithium and t-








butyllithium resulted in the formation of ketones 244 via carbonyl attack; whereas, trityllithium only furnished carbamate 245 arising from nucleophilic ring opening.



0
R
R -kR
R = Ph, t-Bu
N-CO2Et R-Li 244 243
R NHCO2Et

R = (Ph)3C
245

Scheme 49



These results suggest that the course of the reaction is controlled by nucleophilicity rather than basicity; that is, the stronger nucleophiles tend to react at the carbonyl functionality while weaker nucleophiles are inclined to attack the ring carbon of the aziridine.

The Kozikowski labs77 have studied the regiochemical preference in the attack of organometallic reagents on unsymmetrical aziridines. For example, an array of organometallic nucleophiles, including organolithium species, Grignard reagents, and cuprates, were allowed to react with aziridine 246 resulting in formation of the ring opened products 247-249 as depicted in the Scheme 50. The regioselectivity of the ring opening reactions is dictated by electronic factors; that is, transfer of the alkyl substituent occurs at the carbon atom which best accomodates partial carbonium ion character. In the case of reactions involving excess Grignard reagent, the ring opening becomes completely regiospecific as a consequence of the ability of the excess Grignard species to act as a Lewis acid which activates the aziridine even further to nucleophilic attack at the







Ts
I
N




246


CH3MgBr (1 equiv.),
Et20/THF


NHTs CH3

ph ,) ,, + p h , , NHts
247 248
(1 :3.5), 1 equiv. CH3MgBr (0 : 100), 4 equiv. CH3MgBr


)Y Li (4 equiv.)

OTHP
MgBr2, Et20/THF


Ph NHTs
249


NHTs
P h,- ,, +
247


(1:2)


(CH3)2CuLi,
Et20


OH3
PhALNHTs

248


Scheme 50



more electrophilic benzylic center.

The ability of Lewis acids to promote ring opening reactions of aziridines by organometallic species has been displayed by Eis and Ganem.8 As illustrated below, a


It N- R


250a R = Bn, R'= H 250b R = CH3, R'= H 250c R = Bn, R'= CH3


(R")2CuLi, BF3"Et2O
THF


R., ,,NHR
R '

251a R = Bn, R'= H, R''= CH3 251b R = CH3, R' = H, R" = C4H9 251c R = Bn, R'= CH3, R" = Ph


Scheme 51








variety of primary and secondary amines 251a-c were successfully prepared via borontriflouride diethyletherate mediated nucleophilic ring opening of the unactivated aziridines 250a-c by several diorganocopperlithium reagents.

The laboratories of Tanner la,79 have reported the regioselective opening of 2,3ariridinyl alcohols by various cuprates and other alkyl-transfer reagents (Scheme 52). Nucleophilic addition of either Gilman reagents or Lipshutz cyanocuprates to transaziridinyl alcohols 252a-b generated tosylamides 253a-b; whereas, addition to the cisaziridinyl alcohols 254a-b gave tosylamides 255a-b with satisfactory C-2 regioselectivity (Tables 1 and 2). The use of trimethylaluminum as the nucleophilic reagent, on the other hand, resulted in excellent C-3 regioselectivity furnishing the primary tosylamides 253b and 255b as the major products. The C-2 regioselectivity of the cuprate additions in the ring opening reactions results from initial complexation of the reagent to the C-1 hydroxyl group followed by intramolecular attack at C-2 of the aziridine ring. The use of trimethylaluminum as the nucleophilic species results in C-3 regioselectivity as a result of intramolecular delivery of the methyl group to the more proximal (C-3) carbon following formation of the complex between trimethylaluminum and the alkoxy group (C-4) of the aziridine. The control of the regiochemistry resulting from the attack of organometallic reagents on such aziridinyl alcohols is dictated by the substituent on the oxygen atom at C-I; that is, the substituent on the oxygen atom can be used to direct attack of the organometallic agent to C-2 via complexation with the attacking species or to C-3 by exerting steric effects.

The Sweeney group8� has described the ring opening reactions of enantiopure Ndiphenylphosphinyl aziridines with various of carbon nucleophiles. As shown in Scheme








I
H,, .2 3 ,,HO ,- O
N 4
1
Ts
252a R = Bn
252b R = SitBuMe2


HONOOR
IN 4
Ts


,,, V OR HO H NHTs


253a


HOJ "NHOR HO Ns


HO,,

TH d
Ts~ N OR


253b


+ HO
OR


254a R = Bn 255a 255b 254b R = SitBuMe2


Scheme 52



Table 1. Regioselective Opening of Trans-2,3-Aziridinyl Alcohols (252a-b)


Substrate
252a 252b 252a 252b 252a 252b


Reaction Conditions LiMe2Cu, Et20, -20 'C LiMe2Cu, EtO, -20 OC Li2Me2CuCN, THF, -20 'C Li2Me2CuCN, THF, -20 'C A1Me3, toluene, 75 0 C A1Me3, toluene, 75 0 C


253a:253b
>99:1 >99:1 92:8 >99:1 <1:99 15:85


Yield (%)
80
98 81 92 71 82


Table 2. Regioselective Opening of Cis-2,3-Aziridinyl Alcohols (254a-b)


Substrate
254a 254b 254b 254a 254b


Reaction Conditions
Li2Me2CuCN, THF, -20 'C Li2Me2CuCN, THF, -20 �C LiMe2Cu, Et20, -20 �C A1Me3, toluene, 75 0 C A1Me3, toluene, 75 0 C


255a:255b
79:21 88:12 78:22 <1:99 33:66


Yield (%)
73 68 87 92 60








53, nucleophilic attack occurs at the least hindered carbon of aziridines 256 to provide diphenylphosphinylamides 257 in a selective manner.



R-X
N7 Nuc- R Nuc
N
D NHDpp 256 257

Scheme 53



Table 3. Ring Opening of N-Diphenylphosphinyl Aziridines (256) by Nucleophiles

R Nucleophile Reaction Conditions Yield (%)
PhCH2 Me2CuLi THF, -78 0C to 0 �C 87
M2CHCH2 Me2CuLi THF, -78 �C to 0 �C 53
PhCH2 CH3CH2MgBr CuBr SEt2, THF, reflux 73
M2CHCH2 CI-IgMgBr CuBr SEt, THF, reflux 84
PhCH2 Me2CHMgBr CuBr SEt2, THF, reflux 88



Baldwin and researchers8 have studied the ring opening reactions of aziridine-2carboxylate esters by organometallic reagents as illustrated in Scheme 54. Treatment of N-tosylaziridinylcarboxylate 258 with various organometallic reagents gave rise to a mixture of tosylamides 259 and 260 which are useful for amino acid synthesis.



770C02c(CH 3)3 RMgC1, CuBrSMe2 N~ CONHTs R
Ng u RIJ.,,CO C(CH) + TsHNSAcoC cCH3)

Is
Ts
258 259 260
R = Me, i-Pr, n-Bu, Et

Scheme 54








A study of the modes of reactivity in the ring opening reactions of a series of vinylaziridines by different organometallic species has been reported by the Hudlicky group.' Reaction of vinylaziridines 28 and 261 with Grignard species gave rise to tosylamides 262 and 263 via SN2 opening; whereas, reaction of vinylaziridine 28 with lithium diphenylcuprate afforded tosylamides 264 and 265 resulting from both SN2 and SN2' opening as depicted in Scheme 55.


x
0

N I
Ts
28X=H 261 X=C


. K

Is
Ts
28


MeMgBr, Cul
THF/Et20, -45


Ph2CuLi, THF
-78 �C to RT


X

IC

NHTs

262 X = H 263 X = CI
Ph

c>< + P

NHTs

264


Scheme 55



The laboratories of Ibuka b have also investigated the regiochemical outcome from the addition of various organometallic species to vinylaziridines. Reaction of the diastereomerically pure 03-aziridinyl-x,o-enoate 266 with several organometallic reagents afforded tosylamides 267 and 268 as illustrated in Scheme 56. Moreover, these ring opening reactions proceed with high regio- and stereoselectivity in which tosylamide 268


NHTs

265








is the major product resulting from an anti SN2' addition of the organometallic species relative to the C -N bond.



H- rH CO2Me

I
Ts
266


y l _ C O2Me NHTs
267


NHTs
268


Scheme 56


Table 4. Ring Opening Reactions of Vinylaziridine 266 by Organometallics

Compound Organometallic Reagent 267:268 Yield (%)
266 Me3ZnLi, 30 mol % CuCN 4:90 94 266 MeZnLi, 30 mol % CuCN 3:81 84 266 Me3ZnLi, 30 mol % CuCN 4:94 98 266 MeCu(CN)Li 6:93 99


Wipf and Fritch54 have examined the reaction of vinylaziridines with a variety of organocuprate reagents. Treatment of vinylaziridine 269 with several organocuprates under boron-triflouride diethyletherate catalysis provided benzamides 270 as the major product formed via SN2' attack of the nucleophile along with minor amounts of benzamides 271 as shown in Scheme 57. In addition, the reaction between the








organocuprate species and the vinylaziridines occurred with a high degree of diastereoselectivity (98 to 95 % de) which is a consequence of an anti SN2' attack of the nucleophile.


0
0 0 0 PhA NH 0 R'-Cu h,,NAOR + H OR Ph ,, 0 R' R' 269 270 271

Scheme 57



Table 5. Ring Opening Reactions of Vinylaziridine 269 by Organometallics

Cuprate (Additive) R' 270:271 Yield (%)
MeCu (BF3) Me 62:6 68
MeCu(CN)Li (BFI) Me 60:3 63
BuCu (BF3) Bu 69:14 83 PhCu (BF3) Ph 32:0 32



Openings by aromatic systems

Aromatic systems also can act as nucleophiles in ring opening reactions of aziridines resulting in an aminoethylation of the aromatic group, but such types of Friedel-Crafts reactions are somewhat rare. These reactions usually only occur under conditions involving double activation82 of the aziridine; that is, the reaction proceeds under acid catalysis only with aziridines containing electron withdrawing groups.

Various N-sulfonated aziridines have undergone ring opening reactions with aromatic molecules as reported by the Stamm research group.83 As shown in Scheme 58, aziridines 272a-c were opened to produce sulfonamides 273a-c in the presence of








benzene under Lewis acid activation. In the case of the unsymmetrical aziridines 274a-c, ring opening reactions proceeded in a regioselective manner generating sulfonamides 275a-c in which nucleophilic attack took place at the benzylic site.


DN-R

272a R = S02C6H4-P-C 272b R = S02C6H5 272c R = SO2CH3

Ph
N-R


274a R = S02C6H4-P-C 274b R = S02C6H5 274c R = SO2CH3


A1C13, Benzene MH3





A1C13, Benzene


273a R = S02C6H4-p-CH3 273b R = S02C6H5 273c R = SO2CH3


Ph
P h, NHR

275a R = S02C6H4-p-CH3 275b R = S02C6H5 275c R = SO2CH3


Scheme 58



Indoles have also been shown to act as nucleophiles in ring opening reactions of activated aziridines under Lewis acid catalysis. Pfeil and Harder4 have alkylated both indole and 2-methylindole with the readily accessible85 aziridinium tetrafluoroborate 277


~V7
R + .NH3
H BF4

276a R= H 277 276b R = CH3


70 �C


278a R = H 278b R = CH3


Scheme 59







furnishing the aminoalkylated indoles 278a-b as depicted in Scheme 59.

Optically pure tryptophan derivatives have been prepared by Sato and Kozikowski86 via methodology involving the ring opening of chiral aziridines by various substituted indoles. Treatment of the aziridinylcarboxylates 280 with zinc triflate in the presence of indoles 279 gave rise to the trytophan derivatives 281 in which alkylation occurred at the 3 position of the indole.



R'


x



2H
279


NR
R,


Zn(OTf)2, CHC13


280


Scheme 60


Table 6. Ring Opening Reactions of

Entry X R
1 H H 2 5-OCH3 H 3 4-NO2 H 4 5-CH3 H 5 H H


Optically Pure Aziridines (280) By Indoles

R1 R" Yield (%) CO2Bu Cbz 64 CO2Me Cbz 35 CO2Bn Cbz 4 CO2Bn Cbz 57 CO,Me BOC 41


Kurokawa and Anderson87 have also performed Friedel-Crafts alkylation reactions of several activated aziridines using azulene derivatives as the nucleophilic component. Aluminum chloride mediated opening of butanoylaziridines 283 by the substituted azulenes 282 afforded the azulenylethanamine derivatives 284 as illustrated in Scheme 61.





73


,COC3H7
HN
,,, R"~ R + AICI3, CH2Cl2
N

R -R1COC3H7 R
282 283 284

Scheme 61



Table 7. Friedel-Crafts Alkylation of Azulenes with Activated Aziridines

Entry R R' R" R"' Yield (%)
1 H H H H 21 2 CH3 CH3 CH(CH)0, CH, 57 3 H H H CH3 20 4 CH3 CH3 CH(CH3)2 H 8



Openings by allylsilanes

Allylsilanes serve as ambient nucleophiles in the ring opening reactions of aziridines; however, few examples of intermolecular allylsilane additions to aziridines have been reported. The use of allylsilanes as nucleophiles is advantageous to organometallic reagents since the conditions for the ring opening reactions usually allow for a broader range of functionality present on the substrates.

The intermolecular addition of a variety of allylsilanes to activated aziridines has been examined by Schneider et al.88 The reaction of several allylsilanes with Ntosylaziridine 285 under boron triflouride diethyletherate catalysis produced the corresponding y-amino olefins 286a-c in a regioselective manner as illustrated in Scheme 62.











N
I
Ts
285




Si Me3 O-SiMe3 ~Iie BF3Et20, CH2C12 BF3Et20, CH2C%2 7 BF3Et2O, CH2Cl2 C1

NHTs NN HTs 1N~

CI"C
CI
286a 286b 286c

Scheme 62



Intramolecular Ring Openings

More recently, intramolecular cyclizations have seen increased use in synthetic methodology in which a tethered nucleophilic species undergoes a ring opening reaction with an aziridine. In many cases, such intramolecular processes proceed stereoselectively which allows for the synthesis of functionalized carbocyclic products.


Anionic cyclizations

The first example of an intramolecular ring opening reaction of an aziridine was disclosed by Rapoport et al." in course to the synthesis of carbocyclic nucleotides. Treatment of esters 287a-b with base generated the corresponding enolates which








underwent an intramolecular cyclization onto the activated aziridine to produce cyclopentanes 288a-b as shown in Scheme 63.



CO2R

NHSO2Ph
--N KHMDS, THF, -78 �C,,.
N RO2C
SO2Ph

287a R = Me 288a R = Me 287b R = tBu 288b R =tBu Scheme 63



Lewis acid mediated cyclizations

The intramolecular cyclization of aziridines with allylsilanes mediated by Lewis acids provides a means of generating functionalized cyclopentanes and cyclohexanes. Bergmeier and Seth9� have successfully synthesized cyclopentanes 290a-b and cyclohexanes 292a-b as mixtures of stereoisomers from aziridines 289 and 291 following Lewis acid activation of the aziridine as depicted in Scheme 64.

In addition, the Bergmeier labs9' have found that treatment of the aziridines 293ab with smaller amounts of Lewis acid gave tosylamides 294a-b and 295a-b as the major products formed via a [3+2] cycloaddition as illustrated in Scheme 65.

Clearly the ring opening reactions of aziridines by carbon centered nucleophiles are an important class of reactions in synthetic organic chemistry; moreover, this methodology has been used in the preparation of a variety of biologically active compounds including alkaloids, amino acid analogs, and 1-lactam antibiotics. These








SiM e3

/BF3"OEt2 (300 mole %)

CH2Cl2
N
I
Ts 289


C!- NHTs


+ ' NHTs


2.6: 1


290a


290b


BF3"OEt2 (300 mole %) N + K r,
CH2C12 CCHTs HTs

2.7: 1
292a 292b


Scheme 64



heterocycles can be generated in enantiomerically pure form and thus can be regarded as key intermediates for the asymmetric synthesis of organic molecules. The suitable choice


BF3"OEt2 (15 mole %)C CH2CI2
N
I
Ts
293a R = CH3 293b R = Ph(CH3)2


'51H
H 3 H:j -R
(j, N-Ts + (I N-Ts

H H


294a R = CH3 295a R = CH3 294b R = Ph(CH3)2 295b R = Ph(CH3)2


Scheme 65





77


of substituents on the carbon and nitrogen atoms of the aziridine allows for excellent stereospecific and regioselective additions of nucleophiles making aziridines an invaluable class of compounds in the field of organic synthesis.














CHAPTER 3
DISCUSSION


Introduction

Both (+)-pancratistatin (7) and (+)-7-deoxypancratristatin (6) are Amaryllidaceae alkaloids which exhibit anticancer activity19'20 and have shown promise as therapeutic agents. Unfortunately, these natural products are present in low abundance from their natural resources; for example, (+)-pancratistatin was isolated from Pancratium littorale (-0.000091 %, dry weight) by Pettit and researchers. 4a The limited supply of these alkaloids has impeded further biological evaluation which would provide insight with respect to structure-activity relationships. The scarce availability of these natural products and their inherent structural complexity have resulted in extensive synthetic work in this area as demonstrated by several syntheses of (+)-pancratistatin27'2' and (+)-7deoxypancratistatin.29

The challenge posed by all synthetic endeavors aimed at preparing these alkaloids resides in the construction of the six contiguous asymmetric centers of the highly funtionalized C-ring. The structural motifs present within these natural products which complicate synthetic approaches include the high degree of substitution of the aromatic A-ring, the stereochemistry of the functionalities embedded along the C-ring, and the trans B-C amide ring junction. These combined structural features must be thoroughly addressed when designing a synthetic approach to the synthesis of (+)-pancratistatin (7),








(+)-7-deoxypancratistatin (6), or their related analogs.

The availability of the cis-dihydrocyclohexadiene (1b) as a chiral synthon has given the synthetic community a means of incorporating asymmetric methodology in the preparation of important intermediates. Issues of diastereoselectivity are dictated by either directing or steric factors associated with the diol functionality; whereas, aspects of regioselectivity of initial functionalizations are determined by the polarization of the diene system. The remarkable ability of this system to control the stereo- and regiochemical outcome of synthetic transformations serves as the basis for an approach to the preparation of (+)-7-deoxypancratistatin (6) in addition to several truncated analogs (296) as shown below.



OH
H OH BrR

<%O~ 0 OR
(. N H 0~HO N2
0
6 lb 296 Figure 7. Synthetic Targets



Retrosynthetic Analysis for Truncated Analogs

The synthesis of the truncated analogs (296) was viewed retrosynthetically as shown in Scheme 66. The functionalized cyclohexene 297 serves as the precursor to the truncated analogs (296) via complete oxidative degradation of the cyclohexenyl ring. Stereo- and regioselective addition of aryl nucleophile 299 to vinylaziridine 298 should afford cyclohexene 297 in which the trans relationship between the aromatic system and








the amino functionality is established. Vinylaziridine 298 in turn can be obtained by selective chemical manipulation of the diene system present within cisdihydrocyclohexadiene lb.



RO O R2


o NR2 (

296 297



Br
~OH 0 r22< + )0 M e , � + < :

OH N

lb 298 299


Scheme 66. Retrosynthetic Analysis (Truncated Analogs)



Retrosynthetic Analysis for (+)-7-deoxypancratistatin

As illustrated in Scheme 67, it was envisioned that (+)-7-deoxypancratistatin (6) could be obtained via a transamidation protocol involving hydrolysis of lactone 303 and concomitant formation of the amide bond. The lactone 303 in principle could be generated from either ether 302a or ester 302b via two different synthetic routes. In the ether approach, the highly functionalized aziridine 302a could be transformed into lactone 303 through a sequence comprising of intramolecular cyclization of the aromatic system onto the aziridine ring followed by benzylic oxidation of the activated benzopyran unit. For the ester approach, it was envisioned that intramolecular cyclization of the








aziridine 302b could give rise to lactone 303 directly in which the oxidation sequence is avoided. The ester approach utilizes a more deactivated aromatic system as the nucleophilic component which may encumber the cyclization process; whereas, in the ether approach, such deactivation of the piperonyl moiety is not an issue. Coupling of the


OR'


303


300a, R = H2 300b, R = 0


R OR + I

N N'
R""
301 302a, R =H2 302b, R =0 Br


OH


Scheme 67. Retrosynthetic Analysis ((+)-7-Deoxypancratistatin)



suitable piperonyl species (300a or 300b) with epoxyaziridine 301 under conditions in which the oxirane is selectively opened should furnish the functionalized aziridines (302a








or 302b) as the cyclization precursors. The epoxyaziridine 301 can be aquired from cisdihydrocyclohexadiene lb through selective funtionalization of the diene system.


Synthesis of Vinylaziridines

As illustrated by the retrosynthetic analyses which describe the approaches to both the synthesis of (+)-7-deoxypancratistatin (6) (Scheme 67) and several related truncated analogs (296) (Scheme 66), the manipulation of functionalized chiral aziridines serves as the basis for the preparation of these molecules. Two different methodologies which both begin with bromocyclohexadiene-cis-diol lb have been used for the preparation of chiral vinylaziridines, and these synthetic routes will be discussed in the following sections.


Preparation from Dienes

As depicted in Scheme 68, vinylaziridine 28 has been synthesized by functionalization of the diene system present within diol l b according to recently reported procedures.5 Protection of the halodiene lb with 2,2-dimethoxypropane under p-toluenesulfonic acid catalysis furnished acetonide 160 in essentially quantitative yield. Treatment of diene 160 with Yamada's iodonium ylide 304"' following the protocol of Evans et al.32a afforded N-tosyl aziridine 27 albeit in rather poor yield; nonetheless, recovery of acetonide 160 and resubjection to the aziridination conditions increased the overall productivity of the process to approximately 50 % overall yield. Dehalogenation of vinylaziridine 27 was readily achieved under typical conditions (nBu3SnH, AIBN, THF, reflux) to provide vinylaziridine 28 in 78 % yield.








Br Br Br

OH N
OH I Ts Ts
lb 160 27 28

i. 2,2-dimethoxypropane, p-TsOH, acetone; ii. PhI=NTs (304), Cu(acac)2,
CH3CN, 22 % (over two steps); iii. nBu3SnH, AIBN, THF, 78 % Scheme 68



Preparation from Amino Alcohols

In addition, several vinylaziridines have been successfully prepared from amino alcohol derivatives as disclosed by the Olivo group52 through a SN2' type displacement under Mitsunobu conditions. As shown in Scheme 69, oxazines 305a-c can be prepared via a regio- and stereospecific hetero Diels-Alder cycloaddition between acetonide 160 and nitroso dienophiles which are generated as transient intermediates through the oxidation of hydroxamic acids (NaIO4, MeOH/H20). Reductive cleavage of the nitrogenoxygen bond present within oxazines 305a-c using Keck's aluminum amalgam procedure92 gives rise to the cis-l,4-aminoalcohols 306 and 178b-c in good yields. Treatment of the cis- 1,4-aminoalcohols under Mitsunobu3 conditions (PPh3, DEAD, THF) furnished the corresponding 2-vinylaziridines 102 and 179b-c. The preparation of vinylaziridines from 1,4-aminoalcohols under Mitsunobu conditions (Scheme 69) is much improved to the copper-catalyzed aziridination of dienes (Scheme 68) in terms of the yield of the reaction, the ease of purification of the product, and the versatiltiy in choice of N-activating groups. Moreover, N-carbamoyl aziridines are advantageous to








N-tosyl aziridines with regard to deprotection of the amino functionality since removal of the tosyl group is difficult and frequently requires harsh conditions.94


102, R = CO2CH3 179b, R = CO2CH2C6H5 179c, R = CO2C(CH3)3


R.
N


ii


305a, R = CO2CH3 305b, R = CO2CH2C6H5 305c, R = CO2C(CH3)3


Br
OH

OH lb









N


i. 2,2,-dimethoxypropane, p-TsOH, acetone; ii. RNHOH, NaIO4, MeOH/H20; 65-74 % iii. AI(Hg), THF/H20; 66-70 % iv. PPh3, DEAD,
THF; 64-84 %

Scheme 69



Synthesis of Truncated Analogs of (+)-7-deoxypancratistatin

With an efficient preparation of various N-substituted 2-vinylaziridines (298) in hand, the synthesis of several truncated analogs of (+)-7-deoxypancratistatin was investigated. Following the methodology reported by the Hudlicky labs27b,29a in the synthesis of (+)-7-deoxypancratistatin (6), regio- and stereocontrolled ring opening of N-


Br


OH



NHR

306, R = CO2CH3 178b, R = CO2CH2C6H5 178c, R = CO2C(CH3)3


iv








tosyl aziridine 28 with the higher order cyanocuprate 307 afforded primary sulfonamide 308 as illustrated in Scheme 70.

Initially, the direct oxidative cleavage of the olefin bond in sulfonamide 308 by ozonolysis was attempted; however, this reaction failed to effectively cleave the olefin and produced a complex mixture of products. With no success in effecting oxidative degradation of the cyclohexenyl ring through ozonolysis, the dihydroxylation of the olefin in sulfonamide 308 was examined with the hope of cleaving the resulting diol by conventional methods. Unfortunately, dihydroxylation of the olefin using osmium tetraoxide as the oxidizing agent met with failure even after prolonged reaction times; nevertheless, oxidation of cyclohexene 308 under ruthenium catalysis95 occurred stereospecifically and furnished diol 309 in 75 % yield.

With sufficient amounts of diol 309 in hand, the stage was set for investigation of the oxidative degradation of the functionalized cyclohexyl ring. Accordingly, ketal hydrolysis of diol 309 under acidic conditions (TFA, THF/H20), complete oxidative cleavage of the resultant tetrol (NaIO4, acetone/H20), and reduction of the ensuing dialdehyde (NaBH4, MeOH) gave rise to tosylamide 310 which possesses the skeletal framework of the desired truncated analogs.

In order to obtain the fully deprotected truncated analog, tosylamide 310 had to be reduced to the corresponding amine. Although the tosyl group is an effective protecting group for amines as a result of its tolerance to various acidic and basic conditions, cleavage of sulfonamides by reported methods in the literature has proven to be troublesome .9










O+0,. )2Cu(CN)Li2 iO/ +o : 1 o0 NHTs
N"
I
Ts
28 307 308 OH
HO HO,. ,L i ( H OH iii, iv, v 0

. NHTs -' NHTs
310 309

i. BF3 Et2O, THF, -78 'C; 21 %; ii. RuCI33H20, NaIO4, EtOAc/CH3CN, 75 %; iii. TFA/THF/H20; iv. NaIO4, acetone/H20; v. NaBH4; MeOH; 60 % (over 3 steps) Scheme 70



To this end, the deprotection of tosylamide 310 was first examined under reductive conditions including sodium/naphthalene96 and samarium (II) iodide.94 Disappointingly, both sets of detosylation conditions failed to produce the amine of interest; therefore, tosylamide 310 was subjected to acylation conditions (NaH, (BOC)20, THF) based on a report in the literature on the decreased reduction potential of N-acyl sulfonamides97 and their conversion to carbamates.98 Interestingly, treatment of tosylamide 310 with greater than three equivalents of both sodium hydride and di-tertbutyl dicarbonate provided alcohol 314 as shown in Scheme 71. The sole production of alcohol 314 is postulated to form via the intermediate dicarbonate 311 in which transfer of the acyl group from the carbonate to the deprotonated tosylamide occurs.








HO BOCO

OH NaH, (BOC)20, THF NH s 85% o < BOC Ts
310 314

1. Nai
2. (BOC)20( H20


BOCO 0 C-Na BOCO

A" O,a . OP BOCO-'"2f" N OX0 -Y ONa

Ts Na Ar Ts\ BOC Ts

31 312 313


Ar ="t



Scheme 71



Unfortunately, treatment of tosylamide 314 with excess sodiumlanthracene99 in an attempt to remove the tosyl group failed to deliver the corresponding carbamate which warranted consideration of a more easily removed amino protecting group.

Difficulties encountered with the removal of the tosyl group shifted the focus of the synthesis to the coupling of the higher order cyanocuprate 307 with vinylaziridine 102 under the notion that deprotection of the methyl carbamate would be more facile. To this end, coupling of cyanocuprate 307 with vinylaziridine 102 mediated by boron triflouride diethyletherate proceeded as reported by the Hudlicky group29a resulting in formation of carbamate 315 as depicted in Scheme 72. Similar to the methodology carried out with sulfonamide 308, oxidation of the olefin under ruthenium tetroxide








catalysis9" provided diol 316 which was converted to carbamate 317 via a three step sequence consisting of deprotection of the acetonide, complete oxidative degradation of the resulting tetrol, and reduction of the ensuing dialdehyde. Base induced hydolysis of carbamate 317 and subsequent decarboxylation occured smoothly resulting in formation of the free amine which was isolated as the hydrochloride salt 318 under standard conditions.






, c +i 1 NHCO2CH3
I0
N "
CO2CH3
102 307 315 OH ii
HO HO,,

< . OH - ii,iv,V / < 0K
\ - NHCO2CH3 - NHCO2CH3
317 316



vi0 HO

< 0 OH NH HCI

318

i. BF3Et20, THF, -78 'C; 18 %; ii. RuCI33H2O, NalO4, EtOAc/CH3CN, 69 %; iii. TFA/THF/H20; iv. NalO4, acetone/H20; v. NaBH4; MeOH; 45 % (over 3 steps); vi. 20 % aq. KOH, MeOH then HCI, MeOH; 82 % Scheme 72








In summary, several truncated analogs structurally related to the alkaloid (+)-7deoxypancratistatin were successfully prepared in which a stereoselective and regioselective opening of different vinylaziridines serves as the key step. Besides the simplified "seco analogs," there has been no detailed structure-activity investigation with respect to (+)-pancratistatin or (+)-7-deoxypancratistatin.'�� The analogs discussed in the previous section were synthesized with the purpose of gaining an understanding of possible structure-activity relationships; unfortunately, screening of all truncated derivatives showed no indication of biological activity similar in magnitude to that displayed by (+)-pancratistatin or (+)-7-deoxypancratistatin. Interestingly, derivative 314 displayed some activity and gave indication of cancer cell line inhibition with G150 values of 5.3 gg/ml against pancreas-a BXPG-3 and 8.5 jig/ml with lung NCI-H460.'O�


Intramolecular Aziridine Cyclization Approach

With the availabilty of various N-substituted vinylaziridines, an effort toward completing a second generation synthesis of the alkaloid (+)-7-deoxypancratistatin was undertaken. As described earlier and illustrated in Scheme 73, a highly functionalized aziridine (302a-b) in which a tethered piperonyl substituent capable of undergoing intramolecular cyclization was required for the projected synthesis of the alkaloid. Successful intramolecular cyclization would ultimately lead to the generation of lactone 303 which upon hydrolysis and recyclization would give the phenanthridone core of the alkaloid. Therefore, the construction of the key intermediates, aziridines 302a-b, became the initial focus of the synthetic endeavor.




Full Text

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CHEMOENZYMATIC SYNTHESIS AND UTILITY OF VINYL AZIRIDINES: AN APPROACH TO THE SYNTHESIS OF (+)-7-DEOXYPANCRATISTATIN AND THE PREPARATION OF SEVERAL TRUNCATED ANALOGS By STEFAN SCHILLING 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

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In memory of my mother.

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ACKNOWLEDGEMENTS I would like to express my deepest thanks and appreciation to my research advisor, Dr. Tomas Hudlicky, for his continual advice, supervision, and encouragement during my graduate career at the University of Florida. His zest and enthusiasm for chemistry are constant, and for this spirit, I will always be indebted. Additional thanks are extended to Drs. Merle Battiste, William Dolbier, Dennis Wright, Vanecia Young, and Kenneth Sloan for their support during my tenure at the University of Florida and for serving as members of my committee. I also would like to thank all faculty members in the organic division of the chemistry department for their thoughts, opinions, and discussion of chemistry. In particular, I would like to offer my gratitude to Drs. Tomas Hudlicky, Merle Battiste, William Dolbier, Dennis Wright, and Eric Enholm for instilling the principles of organic chemistry in me. My heartfelt appreciation goes out to all of the present and former members of the Hudlicky research group for their friendship, suggestions, and knowledge. I especially thank Uwe Rinner and Collin Chan for their assistance with my Ph.D. project as well as Dr. Mary Ann Endoma and Vu Bui for their devoted time in preparing starting materials. I am also grateful to all members of the research group for providing a pleasant working environment and for offering their help in crucial times of my academic career. I am also grateful to the members of the analytical services for their assistance in the characterization of compounds. I would particularly like to extend my sincere thanks to Ion Ghiviriga for his aid with NMR spectroscopic experiments and interpretation. In

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addition, I am appreciative of the help provided by those responsible for mass spectrometry as well as elemental analysis. I also extend my thanks to Donna Balkcom and Lori Clark for tending to my registration in graduate classes as well as reminding me of the Graduate SchoolÂ’s requirements. Finally, I am most grateful to my family for their endless encouragement, love, and advice. First, I would like to express my thanks to my parents for their belief in me and for their continuous support of my decisions both now and in the future. I would also like to acknowledge my two brothers, Michael and Andreas, for their friendship and support. Without the guidance provided by my family, I would not be where I am today. IV

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TABLE OF CONTENTS page ACKNOWLEDGEMENTS iii LIST OF TABLES vii LIST OF FIGURES viii ABSTRACT x 1 INTRODUCTION 1 2 HISTORICAL 4 Amaryllidaceae Alkaloids 4 Isolation and Structure Determination 4 Biological Activity 5 Total Syntheses 7 Pancratistatin 8 7-Deoxypancratistatin 22 Synthetic Approaches 35 Vinyl Aziridine Synthesis 40 Preparation from Dienes by Nitrene Insertion 41 Preparation from Amino Alcohol Derivatives 44 Preparation via Transition Metal Catalysis 47 Preparation from Functionalized Azides 49 Preparation from azido alcohols 49 Preparation from azidodienes 49 Preparation from Imines 51 Preparation by Miscellaneous Methods 52 Preparation from unsaturated oximes 52 Preparation from aziridinyl aldehydes/ketones 54 Preparation from aziridinyl diols 55 Epoxyaziridine Synthesis 56 Preparation from Functionalized Olefins 56 Preparation via Internal Substitution 57 Preparation from Oxazines 59 Nucleophilic Ring Openings of Aziridines 61 v

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Intermolecular Ring Openings 62 Openings by organometallic reagents 62 Openings by aromatic systems 70 Openings by allylsilanes 73 Intramolecular Ring Openings 74 Anionic cyclizations 74 Lewis acid mediated cyclizations 75 3 DISCUSSION 78 Introduction 78 Retrosynthetic Analysis for Truncated Analogs 79 Retrosynthetic Analysis for (+)-7-deoxypancratistatin 80 Synthesis of Vinylaziridines 82 Preparation from Dienes 82 Preparation from Amino Alcohols 83 Synthesis of Truncated Analogs of (+)-7-deoxypancratistatin 84 Intramolecular Aziridine Cyclization Approach 89 Vinylaziridine Oxidation 90 Projected Versus Actual Synthetic Sequence 92 Intramolecular Anionic Cyclization Approach 93 Intramolecular Lewis Acid Cyclization Approach 95 Further Functionalizations of Arylconduramines 101 Benzylic oxidation 101 Detosylation studies 103 Final Transformations 106 Structure Assignment Ill Structure Correlation by Independent Synthesis 122 Correction of the Design of Aryl Ether Precursor of Type 325 124 4 CONCLUSIONS AND FUTURE WORK 126 Conclusions 126 Future Work 127 5 EXPERIMENTAL 128 General Procedures and Instrumentation 128 Experimental Procedures and Data 129 APPENDIX SELECTED SPECTRA 157 REFERENCES 221 BIOGRAPHICAL SKETCH 228 vi

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LIST OF TABLES Table page 1 . Regioselective Opening of Trans 2,3-Aziridinyl Alcohols (252a-b) 66 2 . Regioselective Opening of Cis 2,3-Aziridinyl Alcohols (254a-b) 66 3. Ring Opening of N-Diphenyphosphinyl Aziridines (256) by Nucleophiles.... 67 4 . Ring Opening Reactions of Vinylaziridine 266 by Organometallics 69 5. Ring Opening Reactions of Vinylaziridine 269 by Organometallics 70 6. Ring Opening Reactions of Optically Pure Aziridines (280) by Indoles 72 7. Friedel-Crafts Alkylation of Azulenes with Activated Aziridines 73 vii

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LIST OF FIGURES Figure page 1 . Alkaloids Derived from Halocyclohexadiene-cB-diols 2 2. Amaryllidaceae Alkaloids Derived from Bromocyclohexadiene-cA-diol 3 3. Representative Amaryllidaceae Alkaloids 5 4. Isolation of Pancratistatin 6 5. Phenanthridone System 8 6. Activated and Nonactivated Aziridines 62 7. Synthetic Targets 79 8. TLC Comparison with (+)-7-deoxypancratistatin 108 9. TLC Comparison with the Tetraacetate of (+)-7-deoxypancratistatin 1 10 10. Assignments of the Piperonyl, Tosyl, and Benzyl Moities in Amide 332a 1 12 1 1 . Assignments of the Acetonide Unit of Tosylamide 332a 113 12. Partial NOESY Spectrum of Amide 332a 1 13 13. Partial DQCOSY Spectrum of Amide 332a 1 14 14. Carbon Hydrogen Framework of the Cyclohexyl Unit of Amide 332a 1 15 15. HETCOR Spectrum of Amide 332a 115 16. Connectivity of the Piperonyl Unit of Tosylamide 332a 116 17. Location of the Benzyl Group of Amide 332a 117 18. Significant nOeÂ’s of the Tosyl Group in Amide 332a 117 19. Complete Structural Assignment of Amide 332a 118 viii

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20. Proton Assignment of Amide 332a 1 19 21. 15 N GHMQC Spectrum of Tosylamide 332a 120 IX

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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 SYNTHESIS AND UTILITY OF VINYL AZIRIDINES: AN APPROACH TO THE SYNTHESIS OF (+)-7-DEOXYPANCRATISTATIN AND THE PREPARATION OF SEVERAL TRUNCATED ANALOGS By Stefan Schilling August 2001 Chairman: Tomas Hudlicky Major Department: Chemistry Approaches to the syntheses of (+)-7-deoxypancratistatin (6) as well as several structurally related truncated analogs (296) are described by chemical manipulation of the enantiomerically pure bromocyclohexadiene-c/s-diol (lb). Among the key steps in the synthesis of the truncated analogs are the S N 2 opening of a vinylaziridine (298) which gives a functionalized cyclohexene (297) and oxidative degradation of the cyclohexene (297) to give the desired derivatives (296). The approach to the synthesis of (+)-7deoxypancratistatin (6) is based on the selective opening of the oxirane in an epoxyaziridine (301) by piperonylic species. Unfortunately, selective opening of the aziridine ring was found to occur resulting in formation of the functionalized epoxide (329), only ascertained through the identification of the tetraacetate (353) at the end of the synthesis which was aided by l5 N spectroscopy. Lewis acid mediated intramolecular cyclization of the epoxide (329) gave the corresponding alcohol (332a) which was x

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ultimately transformed into the final tetracetate (353). A corrected approach to the synthesis of (+)-7-deoxypancratistatin (6) will be described in which the selective opening of a cyclic sulfate (360) by nucleophilic species serves as the key step. xi

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CHAPTER 1 INTRODUCTION Aziridines are useful synthetic intermediates as evidenced by the extensive reviews' on the chemistry of aziridines and their utility in the synthesis of biologically important compounds. 2 Over the last decade, chiral aziridines have emerged as an attractive class of compounds for asymmetric synthesis since a number of procedures are available for the preparation of these heterocycles in enantiomerically pure (or highly enriched) form. As a result of the intrinsic ring strain and polarization, aziridines are rendered susceptible to ring-opening reactions which dominate their chemistry. Moreover, such reactions often proceed in a highly stereospecific and regioselective manner, chemoselectivity dictated by the nature of substituents on the carbon and nitrogen atoms, which makes aziridines useful substrates for synthetic endeavors. Among the variously functionalized aziridines, vinylaziridines have proven to be the most interesting and useful compounds as a consequence of the unique transformations 3 and rearrangements 4 which vinylaziridines undergo. Nevertheless, methodologies for the preparation of these molecules are few in number and are usually plagued by low overall yields. The utility of vinyl aziridines stems from the presence of two reactive sites, the three-membered ring and the olefin, each of which possesses distinct chemical reactivity and thus can be independently functionalized. Halocyclohexadiene-cA-diols la-b have served not only as precursors to optically pure vinylaziridines 5 but also as chiral synthons in the enantioselective 1

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2 syntheses of several natural products, including manojirimycin (2), 6 (+)-kifunensine (3), 7 specionin (4), 8 and (+)-lycoricidine (5) 9 among others. The diols la-b contain elements useful for both diastereoselective and regioselective chemical operations; that is, diastereoselectivity is controlled through steric effects associated with the diol moiety, while regioselectivity is governed by the polarization of the diene system. These chemical features must be considered during the course of designing the enantioselective synthesis of target molecules. 4 specionin 5 lycoricidine Figure 1. Alkaloids Derived from Halocyclohexadiene-c/s-diols. In order to demonstrate the utility of the diols la-b in organic chemistry, approaches to the total syntheses of (+)-7-deoxypancratistatin (6) in addition to several

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3 structurally related truncated analogs will be described. The regioselective and stereospecific chemical operations used in attempting to correctly set the six contiguous chiral centers of the C ring in the alkaloid will be discussed. This methodology will ultimately serve as a model for the synthesis of the more potent alkaloid, (+)pancratistatin (7), and thus sustains the creditability of halocyclohexadiene-ds-diols la-b in rational synthetic design. 7 (H-)-pancratistatin lb X = Br 6 (+)-7-deoxypancratistatin Figure 2. Amaryllidaceae Alkaloids Derived from Bromocyclohexadiene-ds-diol

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CHAPTER 2 HISTORICAL Amarvllidaceae Alkaloids Isolation and Structure Determination The use of plant extracts derived from the Amaryllidaceae family for medicinal purposes dates back to at least the fourth century; 10 moreover, several alkaloids possessing a diverse array of biological activities have been isolated from this species in more recent times. The Amaryllidaceae alkaloids constitute a class of natural products consisting of over 1000 species in 85 distinct genera. 11 Over thirty different plants of the Amaryllidaceae family are in use today as agents in the primitive treatment of cancer. In 1877, the first member of the Amaryllidaceae species, lycorine (8), was isolated from Narcissus pseudonarcissus , 12 During the late 1960s, the Okamoto research group discovered the presence of narciclasine (9) as well as lycoricidine (5) in Lycoris radiata.' 3 In the past two decades, Pettit and co-workers extracted a more highly oxygenated phenanthridone alkaloid, pancratistatin (7), from Pancratium littorale , 14 while the laboratories of Ghosal 15 reported the isolation of 7-deoxpancratistatin (6) from the bulbs of Haemanthas kalbreyeri. In addition to these natural products, more than 100 unique tyramine based structures have been found in the Amaryllidaceae family since the initial disclosure of the alkaloidal constituents present within this species of plant. 4

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5 Biological Activity Many of the natural products derived from the Amaryllidaceae family display a wide spectrum of pharmacological properties, most notably the confirmed levels of OH < R O 8, lycorine 5, R = H, lycoricidine 6, R = H, 7-deoxypancratistatin 9, R = OH, narciclasine 7, R = OH, pancratistatin Figure 3. Representative Amaryllidaceae Alkaloids anticancer activity exhibited by certain alkaloids within this class. The work of the Fitzgerald group 16 in 1958 has demonstrated that the antitumor activity of lycorine stems from its ability to inhibit murine P-388 lymphocytic leukemia. Both narciclasine and lycoricidine inhibit the growth of murine Ehrlich carcinoma and also exhibit carcinostatic activity. 13, 17 Narciclasine displays anticancer activity against human HeLa and HEP n carcinomas, 13, 18 while pancratistatin has shown antitumor activity in vivo against murine P-5076 ovarian sarcoma in addition to murine P-388 lymphocytic leukemia. 19 Furthermore, clinical studies have suggested that pancratistatin exhibits notably higher therapeutic indices relative to its congeners narciclasine and lycoricidine. The antineoplastic activity of pancratistatin has also been detected within 7deoxypancratistatin in vitro\ moreover, a better therapeutic index has been observed for 7-deoxypancratistatin relative to pancratistatin as a result of decreased toxicity. 20

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6 Bulbs (68 kg) 1. MeOH-CH 2 Cl 2 (1:1; 120 L) 2. H 2 0 (exuded by bulbs) Aqeous Fraction CH 2 C1 2 Fraction MeOH, CH 2 C1 2 added Re-extract bulbs 20 % H 2 0 added Aqeous Fraction CH 2 C1 2 Fraction n-BuOH-FUO Aqeous Fraction n-BuOH Fraction Inactive MeOH (1.5 L) MeOH (1.5 L) Insoluble Fraction Inactive Soluble Fraction Insoluble Fraction In vivo inactive Soluble Fraction Sephadex LH-20 (2.5 kg); MeOH-CH 2 Cl 2 MeOH/H 2 0 Hexane Hexane Fraction T/C Inactive \ Aqeous Fraction T/C Inactive Pancratistatin (1.3 g) T/C Active Figure 4. Isolation of Pancratistatin

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7 Of these alkaloids, only the mode of action by which narciclasine exhibits its antineoplastic activity is well documented. 21 Studies have established that the mechanism of action for narciclasine involves inhibition of the growth of eukaryotic cells via obstruction of protein biosynthesis. Specifically, results suggest that narciclasine prevents binding of tRNA to the peptidal transferase center of the 60s ribosomal subunit. 213 As a result of the structural similarities among narciclasine, pancratistatin, and 7-deoxypancratistatin, it has been speculated that similar modes of activity exist for all of these alkaloids; nevertheless, a more detailed explanation for pancratistatinÂ’ s and 7deoxypancratistatinÂ’s mechanism of action has not presently been elucidated. Total Syntheses The portfolio of biological activity displayed by certain members of the Amaryllidaceae family as well as the challenging structural motifs found in these alkaloids, which are exemplified by narciclasine ( 9 ), lycoricidine ( 5 ), pancratistatin ( 7 ) and 7-deoxypancratistatin (6), has prompted the synthetic community to prepare several of these natural products. 22 The synthesis of lycoricidine 9 23 has been reported by several groups; in addition, the unnatural enantiomer (-)-lycoricidine has also been successfully prepared. 24 More recently, the asymmetric synthesis of the natural enantioner (+)narciclasine 25,276 has been reported by two research groups. Since the initial racemic synthesis of (+/-)-pancratistatin by Danishefsky and Lee 26 in 1989, there have been four total asymmetric syntheses of (+)-pancratistatin 27 as well as one formal synthesis of the alkaloid. 28 The natural product (+)-7-deoxypancratistatin has also been synthesized several times, 29 including two syntheses 233 ' 15 in route to lycoricidine which were performed prior to the isolation of (+)-7-deoxypancratistatin from natural resources. The following

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8 section will discuss the methodology employed in the total syntheses of (+)-pancrati statin (7) and (+)-7-deoxypancratistatin (6) and will describe various synthetic approaches to the preparation of these natural products. The most notable structural features which complicate synthetic endeavors aimed at preparing these alkaloids include the trans B-C amide ring junction, the high degree of substitution of the aromatic A-ring, and the stereochemistry pertaining to the various functionalities embedded along the C-ring. In general, the majority of the syntheses initially construct the Aand C-rings and then establish the B-C ring junction which results in formation of the phenanthridone core present in these alkaloids. 22 Figure 5. Phenanthridone System Pancratistatin As shown in Scheme 1 , the first total synthesis of (+/-)-pancratistatin disclosed by Danishefsky and Lee 26 began with pyrogallol 10a which was converted to orthoester 10b using triethyl orthoformate. Carbamoylation of phenol 10b with diethylcarbamoyl chloride, cleavage of the orthoester, and construction of the methylenedioxy unit afforded

PAGE 20

9 lib which was transformed into amide 12a in modest yield via an anionic Fries rearrangement. Protection of the hydroxyl group as the silyl ether followed by ortho lithiation and subsequent treatment with N,N-dimethylformamide generated aldehyde 13. Formation of the arylbutadiene 14 was achieved by treatment of aldehyde 13 with allylmagnesium bromide, activation of the resulting alcohol with mesyl chloride, and elimination of the homoallylic mesylate with DBU. A Diels-Alder reaction of diene 14 with (3-nitrovinylsulfone gave cyclohexene 15 which was reduced with tri-n-butyltin hydride to furnish cyclohexadiene 16a. Deprotection of silyl ether 16a with tetra-nbutylammonium flouride followed by treatment of the resulting alcohol with bis(tributyltin)oxide furnished the corresponding stannyl ether which upon exposure to iodine afforded lactone 17a. Benzylation of the phenol followed by catalytic osmylation produced the corresponding diol lactone which, upon treatment with DBU, underwent an elimination to form diol 18. In a Moffatt-like transformation, diol 18 was treated with 2acetoxyisobutyl bromide to provide the acetoxy derivatives 19a and 19b. Dihydroxylation of the olefin in 19b furnished diol 20, an intermediate containing a fully functionalized C-ring present in pancratistatin. Following an intricate protection and reductive elimination sequence, imidate 23 was prepared from alcohol 22 by reaction with sodium hydride and trichloroacetonitrile. Pyrolysis of imidate 23 invoked an Overman rearrangement to generate trichloroacetamide 24 which was converted into diol 25 by catalytic osmylation. Treatment of diol 25 with potassium carbonate in refluxing methanol resulted in successful hydrolysis of the lactone to produce lactam 26 after DCC coupling of the intermediate amino acid. Removal of the benzyl group provided the target molecule (+/-)-pancratistatin in 26 steps and in an overall 0.13 % yield.

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10 The first asymmetric synthesis of (+)-pancratistatin was published by Hudlicky and co-workers 27ab in 1995 as illustrated in Scheme 2 which started from the enatiomerically pure synthon lb obtained by whole cell bio-oxidation of bromobenzene. 30 Protection of the diol as the acetonide under standard conditions followed by reaction with (N-tosylimino)phenyliodinane 31 according to EvansÂ’ protocol 32 furnished vinylaziridine 27 which was subsequently reduced to aziridine 28 under radical conditions. In the pivotal step of the synthesis, stereospecific opening of aziridine 28 with a higher order cyanocuprate (Ar 2 Cu(CN) 2 Li) in a S N 2 fashion gave rise to tosylamide 29 which contains the carbocyclic skeleton of the natural product. Conversion of primary tosylamide 29 into the N-acyl derivative 30 and subsequent reductive detosylation afforded carbamate 31 following desilylation. Reduction of the aryl amide moiety and protection of the phenol as the benzyl ether produced aldehyde 32 which was oxidized to acid 33 and immediately converted into methyl ester 34 . Following deprotection of the acetonide, hydroxyl directed epoxidation generated epoxide 35 stereospecifically as the cyclization precursor. Treatment of epoxide 35 with a catalytic amount of sodium benzoate resulted in deprotection of the carbamate, ensuing cyclization to the lactam, solvolysis of the epoxide and debenzylation to ultimately furnish (-t-)-pancratistatin in an overall yield of 2 % and in 13 steps. An additional enantioselective synthesis of (-t-)-pancratistatin depicted in Scheme 3 was achieved by Trost and Pulley 27c which took advantage of the availablity of diol 36 and its palladium-catalyzed desymmetrization. 33 After protection of the diol as the dicarbonate, desymmetrization in the presence of a chiral ligand afforded azide 37 in greater than 95 % enantiomeric excess. Treatment azide 37 with cuprous cyanide and

PAGE 22

OR" OCONEt„ OR O OTBS 1 X Ov m > x > X := x X C3 X H := < > Q o X £ w « x ~ 3 E CQ O I * X) '3 g > .2 C /5 < u < (N ' wX CQ > £ x U S O Q x 03 (N > X X ... X u ^ s X c 3-S X CL, < . X X g i> Q 5 > _3 X 2 6 . * fS z IX x „ x x < x X H c 00 X 1 pU X (N m a x U X o" u z < _ Q Q w U H o ,_r Z 3 X X X I X X H X u O tt w X y z X ^ .3 x 3 1/5 u c — 1 x u ggffi" “Ru X /f 1 «J X" 13 ^x £ S O •? uU g X X £> >, Z 3 u, w 2| q.sU O 3 ^ w w 3 33 1 3 u u 6 ^ Scheme 1. First Total Synthesis of (+/-)-Pancratistatin (Part I)

PAGE 23

12 CD X o o o c CO o O O h x x o o o ly J
PAGE 24

13 aryl Grignard reagent resulted in a S N 2 addition to form azide 38 which contains a cyclohexene unit resembling the C-ring of the alkaloid. Dihydroxylation of the olefin, protection of the resulting hydroxyl groups, and bromination of aromatic ring generated aryl bromide 39 as the precursor to cyclization. Conversion of azide 39 to the corresponding isocyanate was followed by metal halogen exchange to give an aryllithium species which underwent cyclization producing lactam 40, an intermediate which contains the core of the natural product. Desilylation of lactam 40 gave the the resulting diol which was converted into cyclic sulfate 41. Stereospecific and regioselective nucleophilic attack of sulfate 41 with cesium benzoate gave rise to ester 42 following simultaneous clevage of the acetonide and the alkyl sulfate under acidic conditions. Removal of the benzoyl and methyl ether groups completed the synthesis of (+)pancratistatin in 15 steps from diol 36 and in an 1 1 % overall yield. A formal synthesis of (+)-pancratistatin was disclosed by the Haseltine group 28 in 1997 as displayed in Scheme 4 which intercepted a late stage intermediate of Danishefsky and LeeÂ’s 26 synthesis. The synthesis began with diol 36 which was subjected to the sequence for desymmetrization of Johnson et al.: 34 enzymatic acetylation to furnish acetate 43a, protection to give silyl ether 43b and deacetylation to afford alcohol 43c. Benzylation of the alkoxide derived from alcohol 43c with piperonyl bromide generated allylic alcohol 44 after removing the silyl group. The carbon skeleton was obtained via an intramolecular cyclization of piperonylated conduritol 44 to produce pentacycle 45 which was oxidized to acetal 46a as a single diastereomer. The installed acetal tether in 46a was used to direct lithiation of the arene ring which gave phenol 46b upon oxidation. Deprotection of the acetal group in phenol 46b gave the corresponding

PAGE 25

14 lactol 47 which upon oxidation and ketal hydrolysis furnished lactone 48. Selective protection of the allylic hydroxyl group in lactone 48, benzylation of the remaining alcohol, and hydrolysis of the methoxyethoxymethyl ether afforded alcohol 49c whose spectral data were consistent with those reported by Danishefsky and Lee, 26 thus establishing a formal synthesis of (+)-pancratistatin. As shown in Scheme 5, Magnus and Sebhat 27d are credited with a total synthesis of (+)-pancratistatin which starts with addition of the aryllithium species derived from 3,4-methylenedioxy-5-methoxybromobenzene to ketone 50 producing the styrene derivative 51 after dehydration. Catalytic hydrogenation of the olefin followed by ketal hydrolysis afforded cyclohexanone 52 which was converted to triisopropylsilyl enol ether 53 in greater than 85 % enantiomeric excess. Treatment of silyl enol ether 53 with iodosylbenzene resulted in a (3-azidonation reaction furnishing azide 54 as a mixture (3.5:1) of transand cisdiastereomers. Reduction of the azide functionality and subsequent protection of the corresponding amine generated carbamate 55. Treatment of carbamate 55 with m-chloroperoxybenzoic acid followed by acid catalyzed hydrolysis of the resulting silyl enol ether gave ester 56a stereoselectively. Epimerization of carbamate 56a under basic conditions (t-BuOK, HMPA) gave the more stable equatorial isomer 56b which was subsequently converted into silyl enol ether 57. Transformation of enol ether 57 to enone 58 was accomplished through a two sequence involving selenylation followed by oxidative elimination. Stereoselective epoxidation of enone 58 followed by reduction of the ketone functionality gave rise to carbamate 59. Treatment of epoxide 59 with sodium benzoate in water under solvolytic conditions followed by acetylation of the resulting tetraol afforded polyacetate 60 which upon Bischler-Napieralski cyclization

PAGE 26

15 cr V o o ~ck ' PQ •>-j X < s xQ 3 ai 00 c Pp (0 m ^ i— • ~ JS . _ -w c . r, c 3 X ^ u z X u > £ X ?H o ^5 O 3 -X u u to O H X Z 9 j, x J3 3 X CQ :3 ^ O O -*— * a X X" X CQ 9 'o *7 od i. o-i X X so o u Z g J Scheme 2. First Asymmetric Synthesis of (+)-Pancratistatin.

PAGE 27

16 A X X 'f I X O O :3 U (N 3 X u u CN X U o z; o 00 d E— Z T3 4 s o .2? O o .c C/3 u o 03 3 E £ c u ,o c 2 N O g JP P2 U >N — X >, o -3 jc t> t> E E X O 1? d? „ SC z . O O U U ao °° uX « 5 PL 1 •o U oo o PJ 00 , f— i r— o & 3
PAGE 28

17 c CQ II GC II DeS v ON T T Z XT' Tt ^Lh D u « o ^ •3 m* 6 g m 2 x E x ~ H >N W c 5; 0 S tQ X -A O U > X o X -*— » Vi . _ CQ _C H U u Ss u 5 *r o pq < Z 0 Jr E fc Scheme 4. Formal Synthesis of (+)-Pancratistatin

PAGE 29

18 followed by deprotection of the acetate groups furnished (+)-pancratistatin in 22 steps and in 1.2 % overall yield. Most recently, Rigby and co-workers 27e have synthesized (+)-pancratistatin in which a stereoand regiocontrolled aryl enamide photocyclization serves to construct the trans fused phenanthridone system present in the alkaloid as illustrated in Scheme 6. The enantiomerically pure syn-epoxy alcohol 61, obtained through McGowen and BerchtoldÂ’s procedure, 35 was protected as its silyl ether and subsequently hydrolyzed to provide acid 62. After conversion of acid 62 to the isocyanate 63 via a Curtius rearrangement, addition of the lithiated species derived from aryl bromide 64 resulted in formation of enamide 65 as the cyclization precursor. Irradiation of enamide 65 under standard conditions gave rise to the phenanthridone 66 which contains the correct stereochemistry present in the core structure of (+)-pancratistatin. Alkylation of the phenol, removal of the silyl protecting group, oxidation of the ensuing alcohol, and stereoselective reduction of the resulting ketone furnished epoxide 68 after benzylation. Selective axial opening of epoxide 68 with a phenylselenide species followed by selenoxide elimination afforded allylic alcohol 69 which was subsequently dihydroxylated to provide the triol 70 in good yield. Simultaneous removal of both the benzyl and p-methoxybenzyl protecting groups via hydrogenolysis followed by removal of the methyl group furnished (+)-pancratistatin in 17 steps and in 2.8 % overall yield from epoxy alcohol 61. The structural intricacy of (+)-pancratistatin has posed a challenge to the synthetic community thus resulting in only six syntheses of the alkaloid. Both the control of stereochemistry of the functionalities along the C-ring and the establishment of the trans B-C ring junction become a formidable task for any synthetic endeavor aimed at

PAGE 30

OTIPS 19 O oo U fN X u z oo X O N C > X 11 I B, *J3 y u > X .o 'S > CL u o u <0 X u > :3 + > o fN m S O. X x X J X < Scheme 5. Total Synthesis of (+)-Pancratistatin (Part I)

PAGE 31

20 O u X S3 z CL < S Q O • — . r 'i . 4— X H U X u > x , X CL >3 . CLQ r. rM O < c o sz > X u n-i o U s o I °.d n ™ 2Cl z CN AO & U . O 1 . u U 00 < PL X Ex ul U r,X u H cj • a: U -r H O GO S H O 03 z X oo r-U “ ° £ x X i o 3 03 li. X E— A U O rsl >-U a: u Scheme 5. Total Synthesis of (+)-Pancratistatin (Part II)

PAGE 32

21 ~ ffl aa a 7 z ^ T3 Oj ’ r-i . U — I u £ •£ H I . 3 c /2 O m “ o r se U a -3 U o 03 c/3 CJ a o3 a, +“ o C/3 55
PAGE 33

22 preparing the natural product in enantiopure form. The development of more efficient methodology towards constructing the six contiguous asymmetric centers will lead to a more practical synthesis of the alkaloid, and research in this area remains to be performed in the future. 7-Deoxvpancratistatin The earliest synthesis of 7-deoxypancratistatin dates back to 1976 when Ohta and Kimoto' 3,1 prepared the alkaloid in racemic form, prior to its isolation from natural resources, in route to the prepration of (+/-)-lycoricidine. Reaction of ethyl acrylate with 3,4-methylenedioxyphenyl allyl carbinol 71 furnished a mixture of Diels-Alder adducts 72 which were used to prepare acid 73 as displayed in Scheme 7. Acid 73 was converted into the corresponding acyl azide via a modified Curtius reaction which was used to generate isocyanate 74 as the cyclization precursor. Lewis acid catalysis led to successful formation of lactam 75a which was protected as its acetate. Hydrolysis of lactam 75b, bromination of the resulting olefinic acid, and subsequent lactonization generated the acetamide 76. Base induced elimination of acetamide 76 provided olefin 77 which underwent transamidation upon exposure to aqeous sodium hydroxide producing alcohol 78a. Protection of alcohol 78a as its tetrahydropyranyl ether followed by oxidation of the olefinic bond gave epoxide 79 which was transformed into allylic alcohol 80a using Sharpless and LauerÂ’s procedure. 36 Acetylation of the hydroxyl functionality, removal of the tetrahydropyranyl protecting group, stereocontrolled dihydroxylation of the olefin, and hydrolysis of the acetate afforded the alkaloid in racemic form, which was used to prepare (+/-)-lycoricidine via a dehydration protocol.

PAGE 34

23 The first asymmetric preparation of (+)-7-deoxypancratistatin was performed by Paulsen and Stubbe~ 1h in route to (+)-lycoricidine in which the chirality is derived from D-glucose as illustrated in Scheme 8. Reaction of the aryl anion derived from isopropyl 6-bromo-(3,4-methylenedioxy)benzoate with olefin 81 gave rise to acetonide 82 as a mixture of idofuranose and glucofuranose derivatives. Cleavage of the acetonide in the mixture of furanose derivatives with acetic acid followed by cyclization of the resulting diol under basic conditions (K 2 CO„ MeOH) afforded lactone 83 which contains the functionalized C-ring ot the alkaloid. Reduction of the nitro functionality was carried out concurrently with debenzylation producing amino lactone 84 which after hydrolysis and subsequent transamidation furnished (+)-7-deoxypancratistatin. The total synthesis of (+)-7-deoxypancratistatin has also been achieved by Keck et al.‘ 9d in 1995 which utilized a radical cyclization strategy as shown in Scheme 9. The synthesis began with diol 85, prepared from D-gulonolactone, 37 which after protection of the hydroxyl functionalities, reduction, and oxime formation gave hydroxy oxime 86. Protection of the hydroxyl moiety as a methoxymethyl ether, selective removal of the silyl ether, and ensuing oxidation produced acid 87b which was then converted into ester 88 under Mitsunobu conditions. Lithium halogen exchange of aryl bromide 88 gave the rearranged alcohol upon warming which was immediately oxidized to aldehyde 89. Desilylation of aldehyde 89 followed by cyclization afforded ketone 90 after protection ot the resulting lactol functionality. Ketone reduction followed by acylation furnished oxime 91 as the radical cyclization precursor. Formation of the radical derived from the thinocarbamate 91 and subsequent trapping by the oxime functionality generated the protected lactol 92 as a single stereoisomer which after acylation, desilylation, and

PAGE 35

24 n r p o < II II QC Qi « JO irj W3 ru > rr" x cu „ p p t— 11 ii Cd D C C3 „C OC OC tt" « I O X O X Jl £ a || cu bi 2 ^ g ^ •5 o (N 0 * rj ^ s 1 T. . '“ P ° £ X w y _c W jg 3 Z °°r, ~ o < < 00 ^7 ^ *• r-i ,U, g CQ >’ X CQ S3 z sc o w ci tj "E P ii O <0 ) c < £ o y 6 a CL x > 'x < • s 00 p H O I ,0 CL CJ 2 < a • >>< rE c/3 o f— CO (N ^ . JO X . . , OJ P .s 0 s ffl >> „ CL 1 n O Q, 3 o Z < Scheme 7. First Synthesis of (+/-)-7-Deoxypancratistatin

PAGE 36

25 Scheme 8. First Synthesis of (+)-7-Deoxypancratistatin

PAGE 37

OMOM P OMOM 26 QC QC on CO H II Q. ON QC © ON o o v g w =< X o X o U c3 2 6 CL. < 0_ H
PAGE 38

27 oxidation produced lactone 93. Completion of the synthesis of (+)-7-deoxypancratistatin involved cleavage of the nitrogen oxygen bond, deprotection of the acetonide and methoxymethyl ether groups, and removal of the trifluoroacetamide group which occurred with concomitant lactone to lactam reorganization. In a second generation synthesis, Keck and co-workers 29e prepared (+)-7deoxypancratistatin by way of an aryl radical cyclization of a tethered N-aziridinylimine as shown in Scheme 10. Alkylation of alcohol 94 with the trichloroacetimidate of 6iodopiperonol genertaed aryl iodide 95 which was transformed into alcohol 96 following reduction of the lactone and oxime formation. A four step sequence converted alcohol 96 into N-aziridinylimine 97 as the cyclization precursor. Radical cyclization of aryl iodide 97 generated benzopyran 98 as a single diastereomer which upon clevage of the nitrogen oxygen bond and subsequent acylation gave trifluoroacetamide 99. Oxidation of the benzylic position followed by simulataneous removal of the silyl ether and acetonide groups produced triol 100 which was converted to the alkaloid following deprotection of the trifluoroacetamide and ensuing lactone to lactam rearrangement. Hudlicky and coworkers 29ab have also synthesized (+)-7-deoxypancratistatin in an asymmetric fashion beginning with diol lb which is obtained in enantiomerically pure form by whole cell biooxidation of bromobenzene. 30 Protection of the diol as the acetonide followed by reaction with methyl p-(nitrophenylsulfonyl)oxycarbamate generated aziridine 101 . Debromination under radical conditions afforded vinylaziridine 102 which was subsequently coupled with the higher order cyanocuprate derived from 4bromo-l,2-(methylenedioxy)benzene to generate carbamate 103 which contains the carbocyclic skeleton of the alkaloid. Removal of the acetonide under standard conditions

PAGE 39

28 and subsequent hydroxyl-directed epoxidation of the olefin afforded epoxide 104 which was opened in a stereoselective fashion to provide tetracetate 105 following peracetylation. Bischler-Napieralski cyclization of carbamate 105 gave lactam 106 which upon deprotection furnished the alkaloid in 2.6 % overall yield and in 12 steps. The laboratories of Chida 29 " have also completed a synthesis of (+)-7deoxypancratistatin starting from D-glucose in which an intramolecular Heck reaction is used to construct the nucleus of the alkaloid as shown in Scheme 12. Protection of the known diol 107 8 as the bis-(methoxymethyl) ether occurred concurrently with partial halide exchange to furnish the azides 108a and 108b as an inseparable mixture of compounds. Dehalogenation of the mixture of azides (108a-b) followed by Ferrier rearrangement of the resulting pyranoside afforded cyclohexanone 109 which was immediately converted into enone 110 via elimination. Luche reduction of enone 110 occurred in a stereoselective fashion to provide alcohol 111a which was subsequently protected as its p-methoxybenzyl ether. Reduction of the azide in cyclohexene 111b followed by condensation of the resulting amine with 6-bromopiperonylic acid under the protocol of Yamada et al. 39 gave aryl bromide 112 as the cyclization precursor. Following alkylation of the amide, intramolecular palladium catalyzed cyclization according to the conditions of Grigg et al. 40 furnished phenanthridone 113 which contains the core of the alkaloid. Stereoselective hydrogenation of olefin 113 followed by protection of the alcohol generated triflate 114. Substitution of the triflate with acetate provided phenanthridone 115a which was converted into alcohol 115b following deprotection. Conversion of alcohol 115b into its triflate and subsequent base induced elimination furnished the cyclohexene 116 following removal of the alcohol

PAGE 40

29 > U o c o QQ ' 0 K z 9 £w u g 1 is , c (X « X ;= j Cu U g 0 .2 00 5 ra U o m «n U u u u Cl Cl < • UUL I a: h H V af .2 2 1 M CL u f: r . ., • r-i L u •» 3 CL T 'a. ^ O (N Ig VD O — « 00 « PQ E— CL rs -a >» x: c C 3 _o •*— < O • CJ s u c
PAGE 41

30 -o Cl, 'A 02 x u u z ; < Q o r-j o < w M > c Z A' cou°„ » D T a u * § 'T' « E X5 2; « . . r< •e t o s I U O L— W~. x ._• "X O JU -d 3 >-» CQ •—’ c i *r S3 . E O V _r j X f I O' | y I X) g « Z ^t:3 "c? o > C S x »-rM CJ hU C3 = z 9 £ H < dx CL c s ^ Qffl .-• c X u c c3 z 0 W s — ^ c-i rX 1 U u. X H X O o < CL < H O
PAGE 42

11, 111 31 2 s o o m z u o ex j >x o c c3 O c U X ^ u z I o <0 £s5 C3 u I : = t" r* U
PAGE 43

OMPM OTf 32 O O Scheme 12. Total Synthesis of (+)-7-Deoxypancratistatin (Part IT)

PAGE 44

33 protecting groups. Hydroxyl-directed epoxidation of olefin 116 generated epoxide 117 stereoselectively which underwent trans-d\ax\a\ opening with acetate to afford polyacetate 118 following acetylation of the remaining hydroxyl groups. Removal of the /;-methoxyl benzyl group followed by hydrolysis of the resulting polyacetate under basic conditions provided (+)-7-deoxypancratistin. The most recent synthesis of (+)-7-deoxypancratistatin has been disclosed by Acena et al. :c ' f in which addition of the lithium species derived from the functionalized aryl bromide 120 to vinyl sulfone 119 Â’ 05 afforded cyclohexenol 121 as illustrated in Scheme 13. Stereoselective epoxidation of the olefin followed by reduction of the sulfone with sodium amalgam produced epoxide 122 which was subsequently converted into epoxy azide 123 through a two step sequence. Oxidation of the styrene unit under ruthenium tetroxide catalysis generated the corresponding acid which underwent intramolecular cyclization via opening of the epoxide resulting in formation of lactone 124 . Simultaneous removal of the benzyl group and reduction of the azide via hydrogenolysis followed by ketal hydrolysis gave the corresponding amino triol which underwent a lactone to lactam rearrangement to furnish (+)-7-deoxypancratistatin in 19 steps and in 8 % overall yield. The syntheses of (+)-7-deoxypancratistatin demonstrate the various stratagies which have been employed to construct the alkaloid. The construction of the C ring in the natural product and the stereochemical control of its substituents are issues which have been addressed via different methodologies in each of the syntheses of (+)-7deoxypancratistatin. Additional stratagies aimed at preparing (+)-7-deoxypancratistatin in a more efficient manner continue to be explored in the future.

PAGE 45

PhCLS 34 q, '-t— I H X c := 6 r-i o r-7 oo U tU z U, U X H X u J — £' 3 U m 3 i cz I o O 3 0 z 3 • m > 1 ^ • ** O • c ~
PAGE 46

35 Synthetic Approaches The high degree of functionality and stereochemical features present in (+)pancratistatin and (+)-7-deoxypancratistatin has resulted in a plethora of approaches towards efficiently synthesizing the phenanthridone system present in these natural products. 2 ' A number of these stratagies are outlined below and demonstrate the various synthetic methodologies which can be applied towards the synthesis of both of these alkaloids. Clark and researchers 41 utilized a Lewis acid mediated condensation between anhydride 125 and imine 126 to produce lactam 127 as the major adduct. It was ratioinalized that the addition of triethylaluminum enriched the diastereoselectivity of the reaction through coordination of the Lewis acid to the imine during the course of the condensation. The resulting product, as shown in Scheme 14, contains four contiguous chiral centers representative of the stereochemistry in (+)-7-deoxypancratistatin. OBn OBn 125 126 127 Scheme 14. ClarkÂ’s Strategy Kallmerten and Thompson 42 successfully prepared a highly funtionalized phenanthridone system related to (+)-7-deoxypancratistatin in which an intramolecular aldol condensation served as the key step shown in Scheme 15. Formation of the C ring

PAGE 47

36 was accomplished by a base induced aldol cyclization of the keto aldehyde derived from olefin 128 which ultimately gave phenanthridone 129 upon further chemical manipulation, an intermediate possessing four of the six stereogenic centers present in the C-ring of the alkaloid. i. 0 3 , MeOH, -78 °C; Me 2 S; ii. DBU, THF; iii. PhCH 2 NH 2 , PPTS; iv. NaCNBHj, MeOH-HCl Scheme 15. Kallmerten’s Approach Bender and Gauthier 43 have reported the preparation of a functionalized system related to (+)-7-deoxypancratistatin starting from myoinositol as illustrated in Scheme 16. Selective deprotection of inositol derivative 130 followed by treatment of the ensuing diol with base provided alcohol 131 via internal displacement of the tosylate. Alkylation of alcohol 131 with 6-bromopiperonyl bromide gave aryl bomide 132. Exposure of bromide 132 to n-butyllithium gave an intermediate ary llithiated species which cyclized onto the epoxide furnishing pentacycle 133. The benzopyran 133 contains the correct absolute stereochemical configuration of the C-ring present within (+)-7deoxypancratistatin. Both the introduction of nitrogen and oxidation of the benzylic

PAGE 48

37 position are required in order to arrive at a more advanced intermediate which can undergo the transamidation process leading to construction of the phenaanthridone core. OPMB OFMB i. p-TsOH, EtOH, CH 2 C1 2 ; ii. NaOMe, MeOH; iii. NaH, 6-bromopiperonyl bromide, DMF; iv. n-BuLi, Et 2 0, -78 °C Scheme 16. Bender’s Strategy Mehta and Mohal 44 have recently described a stereoselective approach to densely functionalized cyclohexanoids related to the phenanthridone nucleus of (+)-7deoxypancratistatin. The Diels-Alder reaction between 3,4-dimethoxystyrene (135) and 5,5-dimethoxy-l,2,3,4-tetrachlorocyclopentadiene (134) produced endo adduct 136 which was converted to aryl-7-norborneone 137 by way of reductive dechlorination and deketalization. A sequence involving Baeyer-Villiger oxidation of 137, hydrolysis of the resulting mixture of lactones, and esterification gave rise to the allylic alcohol 138. Acyl azide 139 was obtained from olefin 138 following dihydroxylation of the olefin, protection of the resulting diol, and functionalization of the ester group. Curtius

PAGE 49

38 rearrangement of acyl azide 139 generated the intermediate carbamate which underwent cyclization to give the lactam 140 as shown in Scheme 17. i. A; a) Na, NH 3 ; b) Amberlyst-15 resin, acetone iii. 30 % H 2 0 2 , AcOH; iv. NaOH, aq. THF then CH 2 N 2 ; v. a) 0s0 4 ; NMO, aq. acetone; b) NaH, BnBr; c) 20 % KOH/MeOH; d) (COCl) 2 , pyridine, CH 2 C1 2 then NaN 3 , acetone; vi. a) xylene, A; b) MeOH, A vii. POCl 3 , 80 °C. Scheme 17. Mehta’s Approach The labs of Branchaud 45 have published an approach to the synthesis of (+)-7deoxypancratistatin in which a palladium-mediated aryl-enone reductive cyclization gives rise to a highly fuctionalized benzopyran system as shown in Scheme 18. Alkylation of iodide 141 with the piperonol derivative 142 occurred with concomitant elimination of hydrogen iodide to ultimately furnish alkene 143. A Ferrier rearrangement of alkene 143

PAGE 50

39 generated ketone 144 which was then converted into enone 145 in a five step sequence. Palladium catalyzed cyclization of aryl enone 145 afforded benzopyran 146 which is an advanced intermediate related to (+)-7-deoxypancratistatin. i. NaH, DMF; ii. Hg(OCOCF 3 ) 2 , acetone/H 2 0; iii. TBDMSOTf, 2,6-lutidine; iv. LiAlH(0‘Bu) 3 ; v. MsCl, Et 3 N, CH 2 C1 2 ; vi. TBAF; vii. (COCl) 2 , DMSO, Et 3 N, CH,C1 2 ; viii. Pd(OAc) 2 , PPh 3 , Et 3 N, THF Scheme 18. Branchaud Strategy In summary, both (+)-pancratistatin and (+)-7-deoxypancratistatin have been synthesized via unique synthetic sequences. In addition, many approaches aimed at efficiently preparing these natural products have been explored by various research

PAGE 51

40 groups. Numerous less densely functionalized model systems have been synthesized which attests to the difficulty in synthesizing these alakaloids. The chemical features of these alkaloids, most notably the functionality and stereochemistry present in the C-ring, the transB-C amide ring junction, and the high degree of substitution in the aromatic Aring, make efficient syntheses of these natural products a formidable challenge to the synthetic community. Vinyl Aziridine Synthesis Aziridines compromise an important class of compounds displaying unique reactvity which can be applied in organic synthesis . 1 Like other three-membered rings, aziridines are highly strained; consequently, nucleophiles participate in ring opening reactions of aziridines. Such reactions of aziridines have attracted the attention of the synthetic community, and the applicabilty of these reactions in synthetic chemistry during the past three decades have been reviewed . 13,46 Introduction of additional functionality into aziridines enables for more unique chemistry to occur which can result in the construction of more complex systems. Vinylaziridines can be considered as a useful class of functionalized aziridines as a result of their ability to undergo various transformations 3 and rearrangements . 4 Unfortunately, methods for the generation of vinylaziridines are few; nevertheless, the synthetic community has obtained a renewed interest in developing methodologies for the efficient preparation of vinylaziridines because of the unique reactivity associated with these heterocycles.

PAGE 52

41 Preparation from Dienes bv Nitrene Insertion One of the more general methods employed for the synthesis of aziridines involves the reaction of an olefin with a nitrene which affords the corresponding aziridine. Since the disclosure of the addition of nitrene 47 and carboethoxynitrene 483 to 1,3-butadiene to give vinylaziridines 148 and 150 as illustrated in Scheme 19, the addition of nitrenes to dienes has seen increased use in synthetic chemistry as a method for the preparation of vinylaziridines. h 2 n-o-so 3 ‘ CH^ONa, MeOH 1,3-butadiene 147 N I H 148 N 3 — C0 2 Et 149 1 .3-butadiene N C0 2 Et 150 Scheme 19 Rees and Atkinson 49 have generated nitrenes by oxidation of 3-aminobenzoxazoline-2-one (151) mediated by lead tetraacetate and has trapped the resulting nitrenes with a variety of conjugated dienes to give vinylaziridines 152 and 153 as depicted in Scheme 20.

PAGE 53

42 Scheme 20 The labs of Lwowski 48b have studied the reaction of carboethoxynitrenes with 1 ,3dienes and have also observed the formation of vinylaziridines. Generation of carboethoxynitrene via photolytic degradation of ethyl azidoformate in the presence of isoprene (154), cyclopentadiene (156), and 1,3-cyclohexadiene (158) produced the vinyl aziridines 155, 157, and 159 as shown below. 158 159 Scheme 21

PAGE 54

43 The formation of vinylaziridines through insertion of a nitrene species into a diene can generate chiral synthons which are useful in the asymmetric synthesis of important alkaloids. For example, the Hudlicky research group 5 29a has generated vinylaziridines 27 and 101, key intermediates in the synthesis of members in the Amaryllidaceae family of alkaloids, via insertion of a nitrene species into the polarized 1,3-diene 160 as demonstrated in Scheme 22. The polarization of the diene via the electron withdrawing halogen controls the regioselectivity of the aziridination process; whereas, the stereoselectivity of the cycloaddition is dictated by steric factors attributed to the acetonide functionality. Br PhI=NTs, Cu(acac )2 ch 3 cn Scheme 22 /?-no 2 c 6 h 4 so 3 nhco 2 ch 3 NaHC0 3 , Bn(Et) 3 NCl, CH 9 C1 2 Br 101 Knight and Muldowney 32c have also studied the aziridination of several 1,3-dienes under copper catalysis 32ab using (N-tosylimino)phenyliodinane 31 as the nitrene source as illustrated in Scheme 23. In the case of unsymmetrical dienes 161 and 163, formation of

PAGE 55

44 aziridines 162 and 164 occurred at the more electron rich olefin; whereas, the regioselectivity of the aziridination of the electronically similar dienes 154 and 166 was governed by steric factors producing vinylaziridines 165 and 167 as the major products. Scheme 23 Preparation from Amino Alcohol Derivatives Another effective method by which vinylaziridines can be prepared involves intramolecular cyclization of amino alcohols following activation of the hydroxyl functionality. Moreover, the availability of enantiomerically pure amino alcohol

PAGE 56

45 derivatives enables this methodology to be utilized in the preparation of chiral vinylaziridines which can be used in asymmetric synthesis. As shown in Scheme 24, treatment of the anti amino alcohols 169a-b under Mitsunobu conditions afforded the corresponding vinylaziridines 170a-b in reasonable yields and in optically pure form. 50 In addition, the amino alcohols 172 and 173, obtained as a diastereomeric mixture from the addition of vinyl organometallic reagents to amino aldehyde 171, have been OH '2 H 169aR = Ph(CH 2 ) 2 , R' = H 169bR = BnOCH 2 , R' = H 170a 170b Scheme 24 OH NHR' RÂ’ 172 OH 174 NHR' 171 173 R' 175 R = alkyl, aryl; R' = BOC, Ts i. vinyl-M (M = Li, Mg, etc.)-, ii. PPh 3 -(NC0 2 Et) 2 Scheme 25

PAGE 57

46 converted to the vinylaziridines 174 and 175 upon activation of the hydroxyl groups of the amino alcohols. 51 The Olivo laboratory 52 has recently disclosed an efficient method for the synthesis of activated vinylaziridines upon exposing N-substituted 1,4-aminoalcohols to Mitsunobu conditions. The cis-\ ,4-aminoalcohols 176a-e underwent an S N 2Â’ type displacement following activation of the hydroxyl functionality to generate the vinylaziridines 177a-e as shown in Scheme 26. An attractive feature of this methodology is the limited amount of oxazoline formation, 104 a common side reaction which occurs via nucleophilic attack of the carbonyl oxygen present in the carbamate functionality, as in 176d. O'r I NHR PPh 3 , DEAD, THF n R 176a R = Bn, n = 1 176b R = Bn, n = 2 176c R = Bn, n = 3 176d R = CBz, n = 2 176e R = Ts, n = 2 177a R = Bn, n = 1 177b R = Bn, n = 2 177c R = Bn, n = 3 177d R = CBz, n = 2 177e R = Ts, n = 2 Scheme 26 In addition, this methodology has been utilized in the synthesis of optically pure vinylaziridnes. The chiral amino alcohol derivatives 178a-c, when treated under Mitsunobu conditions, generated vinylaziridines 179a-c in enantiomerically pure form as illustrated in Scheme 27.

PAGE 58

47 OH PPh v DEAD, THF NHR I R 178a R = Bn 179a R = Bn 179b R = CBz 179c R = BOC 178b R = CBz 178c R = BOC Scheme 27 Preparation via Transition Metal Catalysis Another less utilized process which has been employed in the synthesis of vinylaziridines involves cyclization of amino functionalities onto unsaturated systems, such as alkenes, via transition-metal catalysis. For example, the N-protected methyl carbonates 180 and 181 were converted to the corresponding vinylaziridines 182 and 183 under palladium(0)-catalysis through a decarboxylative ring closure as depicted in Scheme 28. 51 OCO„CH NH i Mts Mts 181 Scheme 28

PAGE 59

48 The stereoselectivity associated with the intramolecular cyclization is an attractive feature of this synthetic methodology. An additional advantage of this methodology is that both isomeric carbonates 180 and 181 lead to the formation of vinylaziridines 182 and 183 in the same ratio. Similarly, the allylic carbonates 184a-c underwent cyclization upon exposure to catalytic amounts of palladium to provide the corresponding vinylaziridines 185a-c and 186a-c as shown in the following scheme. oco 2 ch 3 Pd(Ph 3 ) 4 ,THF > NHR' v y= H-y-H + R' H N H 1 R' 184a R = L Pr; R' = Mts 185a 186a 184bR = 1 Bu,R'-Ts 185b 186b 184c R = Bn, R ' = Mts 185c 186c Scheme 29 Amino allenes have also been shown to undergo intramolecular cyclization via transition metal catalysis to furnish vinylaziridines in a stereospecific manner. For instance, the Ibuka group 53 has demonstrated that the amino allenes 187a-b are readily converted into vinylaziridines 188a-b and 189a-b with good stereoselectivity upon exposure to palladium and an arylating agent as illustrated in Scheme 30.

PAGE 60

49 R Pd(PPh 3 ) 4 , K 2 C0 3 , Phi 1 ,4-dioxane, reflux I R 187aR' = Pr 1 , R = Mts 187bR' = Bn, R = Mts 188a 189a (84 : 16) 188b 189b (85:15) Scheme 30 Preparation from Functionalized Azides Preparation from azido alcohols Another method employed for aziridine synthesis involves a reductive cyclization sequence of functionalized azido alcohols; moreover, this concept has also been applied to the preparation of vinylaziridines. Wipf and Fritch 54 have reported a procedure for the syntheses of vinylaziridines 191a-b from the azido alcohols 190a-b via a Staudinger reaction as shown in Scheme 31. R' O Oakyl PPh 3 -CH 3 C Nr H 190a R = CH 3 , R' = H, R" = H 191a 190b R = H, R' = CH 3 , R" = CH 3 191b Scheme 31 Preparation from azidodienes The [4+1] addition of azidodienes serves as a powerful means of constructing vinylaziridines which occurs via initial cycloaddition to form the intermediate triazoline

PAGE 61

50 which upon extrusion of nitrogen gives the vinylaziridine. Scheiner 55 pioneered the dipolar 1,3-cycloaddition of azides with dienes; for instance, dienes such as isoprene (154) and 1,3-cyclohexadiene (158) were converted into triazolines 192 and 193 which upon photolysis gave vinylaziridines 194 and 195 as shown in Scheme 32. 158 h\' Ar I N 194 hV' N-Ar 193 Ar 195 Ar -pBr-C^H^ Scheme 32 The azide diene cycloaddition has also been shown to occur in an intramolecular fashion; for instance, cycloaddition of azidodiene 196 afforded vinylaziridine 197 which Scheme 33 upon pyrolysis gave a mixture of pyrrolines 198 and 199 with high regioselectivity as illustrated in Scheme 33. 56 Moreover, this methodology has been extensively used in the

PAGE 62

51 construction of both the pyrrolizidine and indolizidine skeletons, both of which are useful in alkaloid synthesis. 56 ' 57 Preparation from Imines Vinylaziridines have also been prepared by the addition of ylides to activated imines. The Dai group 58 has reported the formation of vinylaziridines 202 through the reaction of N-sulfonylimines 200 with sulfonium salt 201 under phase-transfer conditions as illustrated in Scheme 34. In addition to sulfonium salts, both telluronium and phosphorus allylic ylides have been utilized in the aziridination procedure. In a preliminary communication, the Dai laboratory 59 has shown that treatment of Nsulfonylimines, such as 203, with cinnamyl bromide (204) under dimethyl sulfide catalysis generates the corresponding vinylaziridines 205 as a mixture of cis and trans 200 201 Ts 202 R CgH^p-Cl-CgH^, o-CH^O-C^H^, a-napthyl Scheme 34 isomers as shown in Scheme 35.

PAGE 63

52 R — CH==N — Ts + Me 2 S, K 2 C0 3 ch 3 cn Ph Ts 203 204 205 R =/>Cl-C 6 H 4 ,p-N0 2 -C 6 H 4 , o-CH 3 0-C 6 H 4 Scheme 35 The Davis labs 60 have generated chiral vinylaziridines through a Darzens-type reaction between an enolate and enantiopure a,(3-unsaturated sulfinimines. Condensation of the lithium enolate of methyl bromoacetate with sulfinimine 206 resulted in the formation of vinyl aziridine 207 in high optical purity as depicted in Scheme 36. p-Tolyl' 206 OCH, Br ^ou THF, -78 0 C R = n-C 12 H 25 P-Tolyl 0 Scheme 36 Preparation by Miscellaneous Methods Preparation from unsaturated oximes Laurent and Chaabouni 61 have shown that vinylaziridines can be synthesized by the addition of Grignard reagents to a,(3-unsaturated oximes; for example, the unsaturated oximes 208a-b upon treatment with various Grignard reagents gave vinylaziridines 210a-

PAGE 64

53 b. It has been postulated that this transformation proceeds via formation of azirine 209 which undergoes nucleophilic attack by a Grignard species to produce the vinylaziridine. R 208a R = H, R' R 208bR = CH 3 , RÂ’ = CH 3 ,R" = CH3 210b Scheme 37 Another method employed for the preparation of vinylaziridines involves a reductive cyclization of a,(3-unsaturated oximes. Treatment of the unsaturated oxime 211 OH N 211 214 215 Scheme 38

PAGE 65

54 with lithium aluminum hydride produced vinylaziridine 212; whereas, the use of sodium bis(2-methoxyethoxy)aluminum hydride as the reducing agent gave rise to the isomeric vinylaziridines 213-215 as shown in Scheme 38. 62 Preparation from aziridinvl aldehvdes/ketones A few reports pertaining to the preparation of vinylaziridines by Wittig olefination of the appropriately functionalized aldehydes have been disclosed. For instance, the labs of Vessiere 63 have converted a number of 2-formylaziridines (216a-c) into the corresponding vinylaziridines 217a-c via a Wittig reaction as shown in Scheme 39. 216a R = C(CH 3 ) 3 , R' = H, R" = CH 3 , R"Â’ = CH 2 217a 216b R = CH 2 Ph, RÂ’ H, R" Ph, RÂ’" = CH 2 217b 216c R = C(CH 3 ) 3 , RÂ’ = H, R" = H, R'" = CH=C0 2 C 2 H 5 217c Scheme 39 In addition, the Oshima research group 64 has generated the N-tosyl vinylaziridines 219a-c from the requisite aldehydes 218a-c by way of a Wittig olefination as illustrated in Scheme 40.

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55 'W R Ph 3 P=CHR Y\/ ] N “ H N Ts Ts 218aR = CH=CH 2 ,R = CH 3 219a 218bR = CH=CHC 3 H 7 , R= CH 3 219b 218c R = C(CH 3 )=CH 2 , R = CH 3 219c Scheme 40 Preparation from aziridinvl diols An additional strategy which has been used for the synthesis of vinylaziridines involves installation of the olefin through elimination of an appropriately functionalized diol moiety present within the molecule. Jahnisch 65 has reported the preparation of vinylaziridines by way of this strategy as depicted in Scheme 41; that is, the thiocarbonate derivatives 220a-b, obtained from the requisite diols, were transformed into vinylaziridines 221a-b via the Corey procedure. 66 N C0 =P I R 220a R = BOC 220b R = Bn Scheme 41 *^<^C0 2 Et I R 221a 221b In summary, the utility of vinylaziridines in organic chemistry has increased during the past few decades; consequently, the synthetic community has experienced a

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56 renewed interest in the efficient preparation of vinylaziridines. A variety of substrates can be utilized to efficiently prepare vinylaziridines, such as dienes, amino alcohols, imines and azides. In addition, many of the precursors used for the synthesis of vinylaziridines are available in enantiopure form thus providing a means of generating optically pure vinylaziridines which are useful in asymmetric synthesis. Epoxvaziridine Synthesis Epoxyaziridines serve as valuable intermediates in synthetic organic chemistry, yet limited methodology presently exists for the preparation of such compounds. The presence of two strained ring systems, each of which possess the capability of being opened independently under appropriate conditions, allows for the controlled introduction of nucleophilic components in both a stereospecific and regioselective manner. The unique reactivity associated with epoxyaziridines can be used for the construction of rather complex systems in an expeditious manner which validates the importance of these compounds to the synthetic community. Preparation from Functionalized Olefins One method by which epoxyaziridines are prepared involves oxidation of olefinic aziridines in order to generate the oxirane ring. The Prinzbach labs 67b have prepared epoxyaziridine 223 from aziridinyl olefin 222 via peroxytrifluoroacetic acid mediated epoxidation as depicted in Scheme 42. In a similar tansformation, the oxidation of diphenylphosphinoyl aziridine 224 was successfully accomplished using either m-CPBA or methyl(trifluoromethyl)dioxirane as the oxidizing agent to yield epoxyaziridines 225 and 226 as a mixture of stereoisomers

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57 Ts. OMes -OCOCH, CF^CChH TsxS OMes -OCOCHc 222 O 223 Scheme 42 as depicted in Scheme 43 . 68 m-CPBA, NaHC0 3 ch 2 ci 2 Ph— P-M^J| — 224 Oxzone, CF 3 COCH 3 Na 2 EDTA, NaHCO^ ch 3 cn/h 2 o Ph— P-<^J;,0 + Ph— P-N^^O 225 9 : 81 226 Ph— P-N^^;.0 + Ph— 225 56 : 31 226 Scheme 43 Preparation via Internal Substitution Another method by which epoxyaziridines have been prepared involves internal displacement of a suitably placed leaving group, a process which can be used to form either the aziridine or the oxirane ring. The Prinzbach group 67 has performed a cishydroxyamination of epoxyalkene 227 by Sharpless and Herranz’s protocol 69 generating amino alcohol 228 stereoselectively as shown in Scheme 44. Treatment of amino alcohol 228 with base afforded epoxyaziridine 229 via an internal displacement of bromide.

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58 Sharpless c/s-hydroxyamination 227 228 229 R = S0 2 C 6 H 5 R = SO ? C 6 H 4 -p-CH 3 Scheme 44 Similarly, dihydroxylation of aziridinyl olefin 230 gave rise to diol 231 which upon exposure to sodium glycolate underwent internal displacement of bromide to furnish epoxyaziridine 232 as shown in the following scheme. Ts Ts I I N N B ,./\_ Br 5!2rE!H5 \ — / cw-hydroxylation \ / HO OH 230 231 Scheme 45 The synthesis of epoxyaziridines via internal displacement has also been reported by O’Brien and Pilgram 68 in which epoxyaziridine 234 is generated upon reduction of 1. PPh 3 , THF, reflux 2. Ph 9 POCl, Et 3 N, DMAP 233 Ph rS-O 234 Ts I Sodium glycolate^ THF •A HO 232 Scheme 46

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59 epoxy azide 233, 70 alcohol activation, and ensuing cyclization as shown in Scheme 46. Preparation from Qxazines The Viehe group 71 has reported an efficient methodology for the prepartion of epoxyaziridines in a stereospecific manner by way of the epoxyepimination of N-vinyl oxazines. For example, the oxazines 236a-d, generated by the [4+2] cycloaddition of cyclopentadiene with the corresponding nitrosoalkenes, isomerize at room temperature to give the epoxyaziridines 237a-d as depicted in Scheme 47. 71b,c N-OH O R" R 235a R=H, R'=R"=C1 235b R=R'=R"= Cl 236a R=H, R'=R"=C1 236b R=R'=R"= Cl 236c R=CH 3 , R'=R"=C1 235c R=CH 3 , R'=R"=C1 235d R=H, R'=R"=Br r 237a R=H, RÂ’=R"=C1 237b R=R'=R"= Cl 237c R=CH 3 , RÂ’=R"=C1 237d R=H. R'=R"=Br Scheme 47 In addition, the Viehe labs 71a,c,d have utilized this synthetic methodology for the preparation of optically pure epoxyaziridines through the use of a carbohydrate based nitroso derivative. For instance, cycloaddition of the a-chloronitroso mannose derivative

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60 239 with the optically pure cyclohexadiene 238 results in formation of the chiral oxazine 240 which was subsequently alkylated with (3-chloro-a-rerr-butylthioacrylonitrile to generate the N-functionalized oxazine 241. Upon thermolysis, oxazine 241 rearranges in a stereospecific fashion to provide epoxyaziridine 242 which contains four asymmetric centers. The transfer of chirality to all four dienic carbon atoms of cyclohexadiene 238 through this epoxyepimination process validates the utility of this methodology in asymmetric synthesis; moreover, the preparation of chiral aminocyclitols from epoxyaziridines generated in this manner demonstrates the applicability of the epoxyepimination procedure to organic synthesis. NH-HCI 238 / 239 240 OAc N S CN O NC 242 Toluene, 1 10 °C Scheme 48

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61 The importance of epoxyaziridines in organic synthesis stems from the presence of two strained rings, each of which can be selectively opened under appropriate conditions. The renewed interest in efficiently preparing epoxyaziridines in addition to the unique reactivity associated with these molecules has provided the synthetic community with a valuable intermediate which can be used for the synthesis of a variety of compounds. Nucleophilic Ring Openings of Aziridines Aziridines are an attractive class of compounds which contain enormous potential in organic synthesis as a result of the unique reactivity associated with these heterocycles; moreover, the chemistry of aziridines is dominated by ring opening recactions which occur as a result of the inherent ring strain present in these molecules. More recently, ring opening reactions of chiral aziridines have been used for the preparation of enantiomerically pure compounds as intermediates in the asymmetic synthesis of biologically active molecules . 2 In a general sense, aziridines can be categorized into two groups based on the nature of the substituent on nitrogen . 72 Activated aziridines possess an electronwithdrawing functionality which allows for conjugative stabilization of the developing negative charge on nitrogen occurring during the transition state of nucleophilic ring opening reactions; consequently, such reactions can take place in the absence of catalysis. Nonactivated aziridines, on the other hand, lack the ability to stabilize the developing negative charge on nitrogen which results from nucleophilic ring opening and therefore usually require acid catalysis in order to faciltate ring opening reactions.

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62 rr N R "Activated" "Nonactivated" V7 N R R = COR, C0 2 R, SO ? R, etc. R = H, alkyl, aryl, etc. Figure 6. Activated and Nonactivated Aziridines Both activated and nonactivated aziridines are susceptible to ring opening reactions; moreover, the vast amount of research has demonstrated that both the appropriate choice of functionality on nitrogen and the substitution pattern on the carbon framework of the aziridine dictate the regioand stereoselectivity of ring opening reactions. Aziridines have undergone ring opening reactions with a host of noncarbon nucleophiles, such as oxygen based nucleophiles 73 , halide ions 74 and nitrogen based nucleophiles 75 among others. This section will focus on perhaps the most useful reaction of these strained heterocyles which is the ring opening reactions of aziridines by carbon centered nucleophiles resulting in carbon-carbon bond formation under relatively mild conditions. Intermolecular Ring Openings Openings by organometallic reagents The reaction of organometallic reagents with aziridines which affords ring opened products has seen increased use by the synthetic community since the initial work of Hassner and Kascheres 76 in which aziridinecarbamate 243 was allowed to react with a variety of alkyllithium species. As illustrated in Scheme 49, both benzyllithium and t-

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63 butyllithium resulted in the formation of ketones 244 via carbonyl attack; whereas, trityllithium only furnished carbamate 245 arising from nucleophilic ring opening. [>-C0 2 Et 243 Scheme 49 These results suggest that the course of the reaction is controlled by nucleophilicity rather than basicity; that is, the stronger nucleophiles tend to react at the carbonyl functionality while weaker nucleophiles are inclined to attack the ring carbon of the aziridine. The Kozikowski labs 77 have studied the regiochemical preference in the attack of organometallic reagents on unsymmetrical aziridines. For example, an array of organometallic nucleophiles, including organolithium species, Grignard reagents, and cuprates, were allowed to react with aziridine 246 resulting in formation of the ring opened products 247-249 as depicted in the Scheme 50. The regioselectivity of the ring opening reactions is dictated by electronic factors; that is, transfer of the alkyl substituent occurs at the carbon atom which best accomodates partial carbonium ion character. In the case of reactions involving excess Grignard reagent, the ring opening becomes completely regiospecific as a consequence of the ability of the excess Grignard species to act as a Lewis acid which activates the aziridine even further to nucleophilic attack at the O R ^ R R = Ph, /-Bu 244 ,NHC0 2 Et R = (Ph) 3 C 245

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64 246 CH 3 MgBr(l equiv.), Et ? 0/THF • * (4 equiv.) OTHP MgBr 2 , Et 2 0/THF f w NKTs CH 3 JL ^ + JL -NHTs PYT^' 247 248 (1 : 3.5), 1 equiv. CH^MgBr (0 : 100), 4 equiv. CH 3 MgBr PIT 249 (CH^CuLi, Et 2 0 NHTs CH NHTs Ph" ^ Ph JL ^ + JC .NHTs 247 248 ( 1 : 2 ) Scheme 50 more electrophilic benzylic center. The ability of Lewis acids to promote ring opening reactions of aziridines by organometallic species has been displayed by Eis and Ganem. 78 As illustrated below, a 250a R = Bn, R' = H 250b R = CH 3 , R' = H 250c R = Bn, R' = CH 3 (R”) 2 CuLi, BF 3 'Et 2 0 THF R'^Y NHR R‘ 251a R = Bn, R' = H, R" = CH 3 251b R = CH 3 , R' = H, R" = C 4 H 9 251c R = Bn, R' = CFG R" = Ph ^ 5 Scheme 51

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65 variety of primary and secondary amines 251a-c were successfully prepared via borontriflouride diethyletherate mediated nucleophilic ring opening of the unactivated aziridines 250a-c by several diorganocopperlithium reagents. The laboratories of Tanner 13,79 have reported the regioselective opening of 2,3ariridinyl alcohols by various cuprates and other alkyl-transfer reagents (Scheme 52). Nucleophilic addition of either Gilman reagents or Lipshutz cyanocuprates to transaziridinyl alcohols 252a-b generated tosylamides 253a-b; whereas, addition to the cisaziridinyl alcohols 254a-b gave tosylamides 255a-b with satisfactory C-2 regioselectivity (Tables 1 and 2). The use of trimethylaluminum as the nucleophilic reagent, on the other hand, resulted in excellent C-3 regioselectivity furnishing the primary tosylamides 253b and 255b as the major products. The C-2 regioselectivity of the cuprate additions in the ring opening reactions results from initial complexation of the reagent to the C-l hydroxyl group followed by intramolecular attack at C-2 of the aziridine ring. The use of trimethylaluminum as the nucleophilic species results in C-3 regioselectivity as a result of intramolecular delivery of the methyl group to the more proximal (C-3) carbon following formation of the complex between trimethylaluminum and the alkoxy group (C-4) of the aziridine. The control of the regiochemistry resulting from the attack of organometallic reagents on such aziridinyl alcohols is dictated by the substituent on the oxygen atom at C-l; that is, the substituent on the oxygen atom can be used to direct attack of the organometallic agent to C-2 via complexation with the attacking species or to C-3 by exerting steric effects. The Sweeney group 80 has described the ring opening reactions of enantiopure Ndiphenylphosphinyl aziridines with various of carbon nucleophiles. As shown in Scheme

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66 N 4 Ts 252a R = Bn 252b R = Si'BuMe 2 Ts 254a R = Bn 254b R = Si r BuMe 0 Scheme 52 Table 1. Regioselective Opening of Trans2,3-Aziridinyl Alcohols (252a-b) Substrate Reaction Conditions 253a:253b Yield (%) 252a LiMe 2 Cu, Et 2 0, -20 °C >99:1 80 252b LiMe 2 Cu, E^O, -20 °C >99:1 98 252a Li 2 Me 2 CuCN, THF, -20 °C 92:8 81 252b Li 2 Me 2 CuCN, THF, -20 °C >99:1 92 252a AlMe 3 , toluene, 75 ° C <1:99 71 252b AlMe 3 , toluene, 75 ° C 15:85 82 Table 2. Regioselective Opening of CA-2,3-Aziridinyl Alcohols (254a-b) Substrate Reaction Conditions 255a:255b Yield (%) 254a Li 2 Me 2 CuCN, THF, -20 °C 79:21 73 254b Li 2 Me 2 CuCN, THF, -20 °C 88:12 68 254b LiMe 2 Cu, Et 2 0, -20 °C 78:22 87 254a AlMe 3 , toluene, 75 0 C <1:99 92 254b AlMe 3 , toluene, 75 0 C 33:66 60

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67 53, nucleophilic attack occurs at the least hindered carbon of aziridines 256 to provide diphenylphosphinylamides 257 in a selective manner. 'V Nuc ~ Dpp 256 R Y^Nuc NHDpp 257 Scheme 53 Table 3. Ring Opening of N-Diphenylphosphinyl Aziridines (256) by Nucleophiles R Nucleophile Reaction Conditions Yield (%) PhCH : Me 2 CuLi THF, -78 °C to 0 °C 87 Me 2 CHCH 2 Me 2 CuLi THF, -78 °C to 0 °C 53 PhCH 2 CH 3 CH 2 MgBr CuBr SEt 2 , THF, reflux 73 Me 2 CHCH 2 C 5 H 9 MgBr CuBr SEt 2 , THF, reflux 84 PhCH 7 Me 2 CHMgBr CuBr SEtj, THF, reflux 88 Baldwin and researchers 81 have studied the ring opening reactions of aziridine-2carboxylate esters by organometallic reagents as illustrated in Scheme 54. Treatment of N-tosylaziridinylcarboxylate 258 with various organometallic reagents gave rise to a mixture of tosylamides 259 and 260 which are useful for amino acid synthesis. v7* N CO ? C(CH ) 3'3 RMgCl, CuBr'SMe 9 Ts 258 NHTs R R J "'C0 2 C(CH 3 ) 3 + TsHN \^co 2 c(ch 3 ) 259 260 R = Me, /-Pr, r?-Bu, Et Scheme 54

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68 A study of the modes of reactivity in the ring opening reactions of a series of vinylaziridines by different organometallic species has been reported by the Hudlicky group. 5 Reaction of vinylaziridines 28 and 261 with Grignard species gave rise to tosylamides 262 and 263 via S N 2 opening; whereas, reaction of vinylaziridine 28 with lithium diphenylcuprate afforded tosylamides 264 and 265 resulting from both S N 2 and S n 2’ opening as depicted in Scheme 55. X Ts 28 X = H 261 X = Cl X MeMgBr, Cul THF/Et 2 0, -45 °C NHTs 262 X = H 263 X = Cl Ph ? CuLi, THF — -78 °C to RT Ph CCx * jCO< NHTs NHTs 28 264 265 Scheme 55 The laboratories of Ibuka' b have also investigated the regiochemical outcome from the addition of various organometallic species to vinylaziridines. Reaction of the diastereomerically pure P-aziridinyl-a,(3-enoate 266 with several organometallic reagents afforded tosylamides 267 and 268 as illustrated in Scheme 56. Moreover, these ring opening reactions proceed with high regioand stereoselectivity in which tosylamide 268

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69 is the major product resulting from an anti S N 2Â’ addition of the organometallic species relative to the C y -N bond. NHTs NKTs 267 268 Scheme 56 Table 4. Ring Opening Reactions of Vinylaziridine 266 by Organometallics Compound Organometallic Reagent 267:268 Yield (%) 266 Me.ZnLi, 30 mol % CuCN 4:90 94 266 Me,ZnLi, 30 mol % CuCN 3:81 84 266 Me 3 ZnLi, 30 mol % CuCN 4:94 98 266 MeCu(CN)Li 6:93 99 Wipf and Fritch 54 have examined the reaction of vinylaziridines with a variety of organocuprate reagents. Treatment of vinylaziridine 269 with several organocuprates under boron-triflouride diethyletherate catalysis provided benzamides 270 as the major product formed via S N 2 attack of the nucleophile along with minor amounts of benzamides 271 as shown in Scheme 57. In addition, the reaction between the

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70 organocuprate species and the vinylaziridines occurred with a high degree of diastereoselectivity (98 to 95 % de) which is a consequence of an anti S N 2Â’ attack of the nucleophile. 269 270 271 Scheme 57 Table 5. Ring Opening Reactions of Vinylaziridine 269 by Organometallics Cuprate (Additive) RÂ’ 270:271 Yield (%) MeCu (BF,) Me 62:6 68 MeCu(CN)Li (BF,) Me 60:3 63 BuCu (BF 3 ) Bu 69:14 83 PhCu (BFO Ph 32:0 32 Openings by aromatic systems Aromatic systems also can act as nucleophiles in ring opening reactions of aziridines resulting in an aminoethylation of the aromatic group, but such types of Friedel-Crafts reactions are somewhat rare. These reactions usually only occur under conditions involving double activation 82 of the aziridine; that is, the reaction proceeds under acid catalysis only with aziridines containing electron withdrawing groups. Various N-sulfonated aziridines have undergone ring opening reactions with aromatic molecules as reported by the Stamm research group. 83 As shown in Scheme 58, aziridines 272a-c were opened to produce sulfonamides 273a-c in the presence of

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71 benzene under Lewis acid activation. In the case of the unsymmetrical aziridines 274a-c, ring opening reactions proceeded in a regioselective manner generating sulfonamides 275a-c in which nucleophilic attack took place at the benzylic site. £n-R AlCl^, Benzene NHR 272a R = S0 2 C 6 H 4 -p-CH 3 272bR = S0 2 C 6 H 5 272 cR = SO 0 CH 3 273a R = S0 2 C 6 H 4 -p-CH 3 273bR=S0 2 C 6 H 5 273 cR = S0 2 CH 3 A1C1 3 , Benzene Ph NHR 274a R = S0 9 C 6 H 4 -/>CH 3 274b R = S0 2 C 6 H 5 274c R = S0 2 CH 3 275a R = S0 2 C 6 H 4 -/>CH 3 275b R = S0 2 C 6 H 5 275c R = S0 2 CH 3 Scheme 58 Indoles have also been shown to act as nucleophiles in ring opening reactions of activated aziridines under Lewis acid catalysis. Pfeil and Harder 84 have alkylated both indole and 2-methylindole with the readily accessible 85 aziridinium tetrafluoroborate 277 H 276a R= H 276b R = CH 3 277 278a R = H 278b R = CH 3 Scheme 59

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72 furnishing the aminoalkylated indoles 278a-b as depicted in Scheme 59. Optically pure tryptophan derivatives have been prepared by Sato and Kozikowski 86 via methodology involving the ring opening of chiral aziridines by various substituted indoles. Treatment of the aziridinylcarboxylates 280 with zinc triflate in the presence of indoles 279 gave rise to the trytophan derivatives 281 in which alkylation occurred at the 3 position of the indole. Scheme 60 Table 6. Ring Opening Reactions of Optically Pure Aziridines (280) By Indoles Entry X R R’ R” Yield (%) 1 H H CO^Bu Cbz 64 2 5-OCH 3 H C0 2 Me Cbz 35 3 4-N0 2 H C0 2 Bn Cbz 4 4 5-CHj H CO^Bn Cbz 57 5 H H C0 2 Me BOC 41 Kurokawa and Anderson 87 have also performed Friedel-Crafts alkylation reactions of several activated aziridines using azulene derivatives as the nucleophilic component. Aluminum chloride mediated opening of butanoylaziridines 283 by the substituted azulenes 282 afforded the azulenylethanamine derivatives 284 as illustrated in Scheme 61 .

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73 Scheme 61 Table 7. Friedel-Crafts Alkylation of Azulenes with Activated Aziridines Entry R R’ R” R’” Yield (%) 1 H H H H 21 2 CH, CH, CH(CH,), CH, 57 3 H H H ch 3 20 4 CH, CH, CH(CH,) ? H 8 Openings by allvlsilanes Allylsilanes serve as ambient nucleophiles in the ring opening reactions of aziridines; however, few examples of intermolecular allylsilane additions to aziridines have been reported. The use of allylsilanes as nucleophiles is advantageous to organometallic reagents since the conditions for the ring opening reactions usually allow for a broader range of functionality present on the substrates. The intermolecular addition of a variety of allylsilanes to activated aziridines has been examined by Schneider et al. 88 The reaction of several allylsilanes with Ntosylaziridine 285 under boron triflouride diethyletherate catalysis produced the corresponding y-amino olefins 286a-c in a regioselective manner as illustrated in Scheme 62 .

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74 Scheme 62 Intramolecular Ring Openings More recently, intramolecular cyclizations have seen increased use in synthetic methodology in which a tethered nucleophilic species undergoes a ring opening reaction with an aziridine. In many cases, such intramolecular processes proceed stereoselectively which allows for the synthesis of functionalized carbocyclic products. Anionic cvclizations The first example of an intramolecular ring opening reaction of an aziridine was disclosed by Rapoport et al . 89 in course to the synthesis of carbocyclic nucleotides. Treatment of esters 287a-b with base generated the corresponding enolates which

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75 underwent an intramolecular cyclization onto the activated aziridine to produce cyclopentanes 288a-b as shown in Scheme 63. S0 2 Ph 287a R = Me 287bR = t Bu KHMDS, THF, -78 °C : NHSOpPh £ ro 2 c 288a R = Me 288b R = l Bu Scheme 63 Lewis acid mediated cvclizations The intramolecular cyclization of aziridines with allylsilanes mediated by Lewis acids provides a means of generating functionalized cyclopentanes and cyclohexanes. Bergmeier and Seth 90 have successfully synthesized cyclopentanes 290a-b and cyclohexanes 292a-b as mixtures of stereoisomers from aziridines 289 and 291 following Lewis acid activation of the aziridine as depicted in Scheme 64. In addition, the Bergmeier labs 91 have found that treatment of the aziridines 293ab with smaller amounts of Lewis acid gave tosylamides 294a-b and 295a-b as the major products formed via a [3+2] cycloaddition as illustrated in Scheme 65. Clearly the ring opening reactions of aziridines by carbon centered nucleophiles are an important class of reactions in synthetic organic chemistry; moreover, this methodology has been used in the preparation of a variety of biologically active compounds including alkaloids, amino acid analogs, and (3-lactam antibiotics. These

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76 SiMe, ' o BF 3 ‘OEt 2 (300 mole %) ch 2 ci 2 cC + C^^NHTs i 2.6 : 1 Ts 289 290a 290b i ^SiMe 3 d N BF 2 'OEt 2 (300 mole %) ch 2 ci ? CC * \^v_NHTs cr X^'.-^NHTs 1 Ts 2.7 : 1 291 292a 292b Scheme 64 heterocycles can be generated in enantiomerically pure form and thus can be regarded as key intermediates for the asymmetric synthesis of organic molecules. The suitable choice r ^SiRo H f 3 ^SiRo H ' 3 BF 2 'OEt 2 (15 mole %) CfJ N ~ Ts + ct>ch 2 ci 2 f\T 1 H H 1 Ts 293a R = CH 3 294a R = CH 3 295aR = CH 3 293b R = Ph(CH 3 ) 2 294b R = Ph(CH 3 ) 2 295bR = Ph(CH 3 ) 2 Scheme 65

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77 of substituents on the carbon and nitrogen atoms of the aziridine allows for excellent stereospecific and regioselective additions of nucleophiles making aziridines an invaluable class of compounds in the field of organic synthesis.

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CHAPTER 3 DISCUSSION Introduction Both (+)-pancratistatin (7) and (+)-7-deoxypancratristatin (6) are Amaryllidaceae alkaloids which exhibit anticancer activity 19 ' 20 and have shown promise as therapeutic agents. Unfortunately, these natural products are present in low abundance from their natural resources; for example, (+)-pancratistatin was isolated from Pancratium littorale (-0.000091 %, dry weight) by Pettit and researchers. 143 The limited supply of these alkaloids has impeded further biological evaluation which would provide insight with respect to structure-activity relationships. The scarce availability of these natural products and their inherent structural complexity have resulted in extensive synthetic work in this area as demonstrated by several syntheses of (+)-pancratistatin 27,28 and (+)-7deoxypancratistatin. 29 The challenge posed by all synthetic endeavors aimed at preparing these alkaloids resides in the construction of the six contiguous asymmetric centers of the highly funtionalized C-ring. The structural motifs present within these natural products which complicate synthetic approaches include the high degree of substitution of the aromatic A-ring, the stereochemistry of the functionalities embedded along the C-ring, and the trans B-C amide ring junction. These combined structural features must be thoroughly addressed when designing a synthetic approach to the synthesis of (+)-pancratistatin (7), 78

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79 (+)-7-deoxypancratistatin ( 6 ), or their related analogs. The availability of the c/s-dihydrocyclohexadiene (lb) as a chiral synthon has given the synthetic community a means of incorporating asymmetric methodology in the preparation of important intermediates. Issues of diastereoselectivity are dictated by either directing or steric factors associated with the diol functionality; whereas, aspects of regioselectivity of initial functionalizations are determined by the polarization of the diene system. The remarkable ability of this system to control the stereoand regiochemical outcome of synthetic transformations serves as the basis for an approach to the preparation of (+)-7-deoxypancratistatin (6) in addition to several truncated analogs (296) as shown below. Figure 7. Synthetic Targets Retrosynthetic Analysis for Truncated Analogs The synthesis of the truncated analogs (296) was viewed retrosynthetically as shown in Scheme 66. The functionalized cyclohexene 297 serves as the precursor to the truncated analogs (296) via complete oxidative degradation of the cyclohexenyl ring. Stereoand regioselective addition of aryl nucleophile 299 to vinylaziridine 298 should afford cyclohexene 297 in which the trans relationship between the aromatic system and

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80 the amino functionality is established. Vinylaziridine 298 in turn can be obtained by selective chemical manipulation of the diene system present within cisdihydrocyclohexadiene lb. Scheme 66. Retrosynthetic Analysis (Truncated Analogs) R etrosynthetic Analysis for (+)-7-deoxvpancratistatin As illustrated in Scheme 67, it was envisioned that (+)-7-deoxypancratistatin (6) could be obtained via a transamidation protocol involving hydrolysis of lactone 303 and concomitant formation of the amide bond. The lactone 303 in principle could be generated from either ether 302a or ester 302b via two different synthetic routes. In the ether approach, the highly functionalized aziridine 302a could be transformed into lactone 303 through a sequence comprising of intramolecular cyclization of the aromatic system onto the aziridine ring followed by benzylic oxidation of the activated benzopyran unit. For the ester approach, it was envisioned that intramolecular cyclization of the

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81 aziridine 302b could give rise to lactone 303 directly in which the oxidation sequence is avoided. The ester approach utilizes a more deactivated aromatic system as the nucleophilic component which may encumber the cyclization process; whereas, in the ether approach, such deactivation of the piperonyl moiety is not an issue. Coupling of the OH OH OH 6 OR' R 300a, R = H 2 300b, R = O Scheme 67. Retrosynthetic Analysis ((+)-7-Deoxypancratistatin) suitable piperonyl species (300a or 300b) with epoxyaziridine 301 under conditions in which the oxirane is selectively opened should furnish the functionalized aziridines (302a

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82 or 302b) as the cyclization precursors. The epoxyaziridine 301 can be aquired from cisdihydrocyclohexadiene lb through selective funtionalization of the diene system. Synthesis of Vinvlaziridines As illustrated by the retrosynthetic analyses which describe the approaches to both the synthesis of (+)-7-deoxypancratistatin (6) (Scheme 67) and several related truncated analogs (296) (Scheme 66), the manipulation of functionalized chiral aziridines serves as the basis for the preparation of these molecules. Two different methodologies which both begin with bromocyclohexadiene-m-diol lb have been used for the preparation of chiral vinylaziridines, and these synthetic routes will be discussed in the following sections. Preparation from Dienes As depicted in Scheme 68, vinylaziridine 28 has been synthesized by functionalization of the diene system present within diol lb according to recently leported procedures. Protection of the halodiene lb with 2,2-dimethoxypropane under /?-toluenesulfonic acid catalysis furnished acetonide 160 in essentially quantitative yield. Treatment of diene 160 with YamadaÂ’s iodonium ylide 304 31 following the protocol of Evans et al. afforded N-tosyl aziridine 27 albeit in rather poor yield; nonetheless, recovery of acetonide 160 and resubjection to the aziridination conditions increased the overall productivity of the process to approximately 50 % overall yield. Dehalogenation of vinylaziridine 27 was readily achieved under typical conditions (nBu 3 SnH, AIBN, THF, reflux) to provide vinylaziridine 28 in 78 % yield.

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83 i. 2,2-dimethoxypropane, p-TsOH, acetone; ii. PhI=NTs (304), Cu(acac) 2 , CH,CN, 22 % (over two steps); iii. nBu 3 SnH, AffiN, THF, 78 % Scheme 68 Preparation from Amino Alcohols In addition, several vinylazindines have been successfully prepared from amino alcohol derivatives as disclosed by the Olivo group 52 through a S N 2Â’ type displacement under Mitsunobu conditions. As shown in Scheme 69, oxazines 305a-c can be prepared via a regioand stereospecific hetero Diels-Alder cycloaddition between acetonide 160 and nitroso dienophiles which are generated as transient intermediates through the oxidation of hydroxamic acids (NaI0 4 , MeOH/H 2 0). Reductive cleavage of the nitrogenoxygen bond present within oxazines 305a-c using KeckÂ’s aluminum amalgam procedure 92 gives rise to the c/s-M-aminoalcohols 306 and 178b-c in good yields. Treatment of the cA-l,4-aminoalcohols under Mitsunobu 93 conditions (PPh 3 , DEAD, THF) furnished the corresponding 2-vinylaziridines 102 and 179b-c. The preparation of vinylaziridines from 1 ,4-aminoalcohols under Mitsunobu conditions (Scheme 69) is much improved to the copper-catalyzed aziridination of dienes (Scheme 68) in terms of the yield of the reaction, the ease of purification of the product, and the versatiltiy in choice of N-activating groups. Moreover, N-carbamoyl aziridines are advantageous to

PAGE 95

84 N-tosyl aziridines with regard to deprotection of the amino functionality since removal of the tosyl group is difficult and frequently requires harsh conditions. 94 lb 160 N I R 305a, R = C0 2 CH 3 305b, R = C0 2 CH 2 C 6 H 5 305c, R = C0 2 C(CH 3 ) 3 NHR 1 02, R = C0 2 CH 3 306, R = C0 2 CH 3 179b, R = C0 2 CH 2 C 6 H 5 178b, R = C0 2 CH 2 C 6 H 5 179c, R = C0 2 C(CH 3 ) 3 178c, R = C0 2 C(CH 3 ) 3 i. 2,2,-dimethoxypropane, pTsOH, acetone; ii. RNHOH, NaI0 4 , MeOH/H 2 0; 65-74 % iii. Al(Hg), THF/H 2 0; 66-70 % iv. PPh, DEAD THF; 64-84 % Scheme 69 Synthesis of Trun cated Analogs of (+V7-deoxvpancratistatin With an efficient preparation of various N-substituted 2-vinylaziridines (298) in hand, the synthesis of several truncated analogs of (+)-7-deoxypancratistatin was investigated. Following the methodology reported by the Hudlicky labs 27b ' 29a in the synthesis of (+)-7-deoxypancratistatin (6), regioand stereocontrolled ring opening of N-

PAGE 96

85 tosyl aziridine 28 with the higher order cyanocuprate 307 afforded primary sulfonamide 308 as illustrated in Scheme 70. Initially, the direct oxidative cleavage of the olefin bond in sulfonamide 308 by ozonolysis was attempted; however, this reaction failed to effectively cleave the olefin and produced a complex mixture of products. With no success in effecting oxidative degradation of the cyclohexenyl ring through ozonolysis, the dihydroxylation of the olefin in sulfonamide 308 was examined with the hope of cleaving the resulting diol by conventional methods. Unfortunately, dihydroxylation of the olefin using osmium tetraoxide as the oxidizing agent met with failure even after prolonged reaction times; nevertheless, oxidation of cyclohexene 308 under ruthenium catalysis 95 occurred stereospecifically and furnished diol 309 in 75 % yield. With sufficient amounts of diol 309 in hand, the stage was set for investigation of the oxidative degradation of the functionalized cyclohexyl ring. Accordingly, ketal hydrolysis of diol 309 under acidic conditions (TFA, THF/fUO), complete oxidative cleavage of the resultant tetrol (NaI0 4 , acetone/H 2 0), and reduction of the ensuing dialdehyde (NaBH 4 , MeOFI) gave rise to tosylamide 310 which possesses the skeletal framework of the desired truncated analogs. In order to obtain the fully deprotected truncated analog, tosylamide 310 had to be reduced to the corresponding amine. Although the tosyl group is an effective protecting group for amines as a result of its tolerance to various acidic and basic conditions, cleavage of sulfonamides by reported methods in the literature has proven to be troublesome. 94

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86 OH i. BFj'EtA THF, -78 °C; 21 %; ii. RuC 1 3 3H 2 0, NaI0 4 , EtOAc/CH 3 CN, 75 %; iii. TFA/THF/HjO; iv. NaI0 4 , acetone/H 2 0; v. NaBH 4 ; MeOH; 60 % (over 3 steps) Scheme 70 To this end, the deprotection of tosylamide 310 was first examined under reductive conditions including sodium/naphthalene 96 and samarium (II) iodide. 94 Disappointingly, both sets of detosylation conditions failed to produce the amine of interest; therefore, tosylamide 310 was subjected to acylation conditions (NaH, (B0C) 2 0, THF) based on a report in the literature on the decreased reduction potential of N-acyl sulfonamides 97 and their conversion to carbamates. 98 Interestingly, treatment of tosylamide 310 with greater than three equivalents of both sodium hydride and di -tertbutyl dicarbonate provided alcohol 314 as shown in Scheme 71. The sole production of alcohol 314 is postulated to form via the intermediate dicarbonate 311 in which transfer of the acyl group from the carbonate to the deprotonated tosylamide occurs.

PAGE 98

87 1. NaH 2. (BOC) 2 0 Scheme 71 Unfortunately, treatment of tosylamide 314 with excess sodium/anthracene 99 in an attempt to remove the tosyl group failed to deliver the corresponding carbamate which warranted consideration of a more easily removed amino protecting group. Difficulties encountered with the removal of the tosyl group shifted the focus of the synthesis to the coupling of the higher order cyanocuprate 307 with vinylaziridine 102 under the notion that deprotection of the methyl carbamate would be more facile. To this end, coupling of cyanocuprate 307 with vinylaziridine 102 mediated by boron triflouride diethyletherate proceeded as reported by the Hudlicky group 293 resulting in formation of carbamate 315 as depicted in Scheme 72. Similar to the methodology carried out with sulfonamide 308, oxidation of the olefin under ruthenium tetroxide

PAGE 99

88 catalysis 95 provided diol 316 which was converted to carbamate 317 via a three step sequence consisting of deprotection of the acetonide, complete oxidative degradation of the resulting tetrol, and reduction of the ensuing dialdehyde. Base induced hydolysis of carbamate 317 and subsequent decarboxylation occured smoothly resulting in formation of the free amine which was isolated as the hydrochloride salt 318 under standard conditions. i. BFj'EtA THF, -78 °C; 18 %; ii. RuC 1 3 3H 2 0, NaI0 4 , EtOAc/CH 3 CN, 69 %; iii. TFA/THF/H 2 0; iv. NaI0 4 , acetone/H 2 0; v. NaBH 4 ; MeOH; 45 % (over 3 steps); vi 20 % aq. KOH, MeOH then HC1, MeOH; 82 % Scheme 72

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89 In summary, several truncated analogs structurally related to the alkaloid (+)-7deoxypancratistatin were successfully prepared in which a stereoselective and regioselective opening of different vinylaziridines serves as the key step. Besides the simplified “seco analogs,” there has been no detailed structure-activity investigation with respect to (+)-pancratistatin or (+)-7-deoxypancratistatin. 100 The analogs discussed in the previous section were synthesized with the purpose of gaining an understanding of possible structure-activity relationships; unfortunately, screening of all truncated derivatives showed no indication of biological activity similar in magnitude to that displayed by (+)-pancratistatin or (+)-7-deoxypancratistatin. Interestingly, derivative 314 displayed some activity and gave indication of cancer cell line inhibition with GI 50 values of 5.3 (ig/ml against pancreas-a BXPG-3 and 8.5 pg/ml with lung NCI-H460. 101 Intramolecular Aziridine Cvclization Approach With the availabilty of various N-substituted vinylaziridines, an effort toward completing a second generation synthesis of the alkaloid (+)-7-deoxypancratistatin was undertaken. As described earlier and illustrated in Scheme 73, a highly functionalized aziridine (302a-b) in which a tethered piperonyl substituent capable of undergoing intramolecular cyclization was required for the projected synthesis of the alkaloid. Successful intramolecular cyclization would ultimately lead to the generation of lactone 303 which upon hydrolysis and recyclization would give the phenanthridone core of the alkaloid. Therefore, the construction of the key intermediates, aziridines 302a-b, became the initial focus of the synthetic endeavor.

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90 Scheme 73. Projected Synthesis of (+)-7-deoxypancratistatin Vinvlaziridine Oxidation At the onset of the study, intramolecular cyclization of the piperonyl group following formation of an intermediate aryl organometallic species was proposed based on Bender and GauthierÂ’s related intramolecular cyclization of an o-tethered lithiated piperonyl moiety onto an epoxide. 43 The epoxidation of the olefin in vinylaziridine 28 was examined since it was anticipated that opening of the epoxide by a nucleophilic piperonyl derivative could be selectively achieved leaving the aziridine functionality intact. The attempted oxidation of tosyl aziridine 28 with mCPBA at room temperature gave only trace amounts of the desired epoxide even after prolonged reaction times; however, treatment of tosyl aziridine 28 with raCPBA in 1,2-dichloroethane at reflux produced an inseparable mixture of a and (3 epoxaziridines 319a-b (2.6:1) as illustrated in Scheme 74.

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91 wCPBA, C1CH 2 CH 2 C1 80% 1 28 319a 319b 2.6 : 1 Scheme 74 Although the oxidation of vinylaziridine 28 gives an inseperable mixture of a and (3 epoxyaziridines 319a-b, both isomers can be used for subsequent reactions. As illustrated in Scheme 75, trans diaxial opening of the oxirane in either isomer 319a or 319b with an appropriately substituted alcohol would generate the alcohols 320a and 320b respectively. Alkylation of the hydroxyl functionality in both 320a and 320b with the same group rendered into an electrophile would provide aziridine 320c, an intermediate in which both oxygens contain identical functionality. Ts Ts 319b 320b Scheme 75

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92 Such “redundant operations” greatly improve the practicality of such a synthetic sequence because no attention need be paid to either the control of stereochemistry at the intermediate stage or to the separation of the isomeric epoxyaziridines. 106 Projected Versus Actual Synthetic Sequence With the mixture of epoxyaziridines 319a-b in hand, the construction of the key cyclization precursors as described in Scheme 73 was begun following previous reports internal to the research group regarding the selective opening of the oxirane ring within epoxyaziridines 319a-b by carboxylate salts under basic conditions. 107 The selective opening of the epoxide moiety present in the mixture of epoxyaziridines 319a-b did not occur as anticipated; rather, as shown in Scheme 76, a nucleophilic attack on the aziridine ring by the piperonylic species occurred exclusively, only ascertained at the end of the synthesis when tetraacetate 353 was isolated and identified. OAc Projected^ ^ O ,OAc 'OAc Ts 325 106 O Ts 319a-b Actual 'OAc ,OAc 327 353 NHAc Scheme 76

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93 In the following sections, the projected transformations believed to have been performed in the presumed path to the synthesis of (+)-7-deoxypancratistatin (6) will be compared with a description of the actual results, although these were NOT known until the very end of the synthesis following an unsuccessful match between tetracatates 353 and 106 (Scheme 88). Intramolecular Anionic Cvclization Approach With a sufficient amount of the mixture of N-tosyl epoxyaziridines 319a-b available, the anticipated selective opening of the epoxide moiety with various piperonyl derivatives was examined. Based on an assumed precedent obtained within the research group, 107 it was envisioned that opening of the epoxide by piperonylic species would be more facile than attack on the aziridine ring and thus lead to the preferential formation of the corresponding alcohols. Initially, the potassium salt of 2-bromopiperonol was reacted with epoxyaziridines 319a-b which was expected to result in a regioand stereoselective opening of the oxirane thus producing alcohol 321 as depicted in the projected path, Scheme 77. Ensuing benzylation of the hydroxyl group believed to arise from opening of the epoxide appeared to afford ether 322. The potassium salt of 2-bromopiperonol was first used as the nucleophilic species based on the prospect that transmetalation of the aryl unit in 322 would be followed by cyclization of the intermediate organometallic species onto the activated aziridine ring. Unfortunately, it was subsequently discovered that nucleophilic attack of the aziridine ring by the potassium salt of 2-bromopiperonol occurred exclusively generating tosylamide 323 which was converted into N-benzyl tosylamide 324 as illustrated in the actual sequence, Scheme 77.

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94 Projected : Ts 319a-b Actual: Ts 319a-b 18-crown-6, DME 56 % NRTs 323, R = H 324, R = Bn Scheme 77 NaH, BnBr, n-Bu^NI, THF 90% Standard nuclear magnetic resonance spectrosopic techniques failed to unambiguously discriminate between aziridine 321 of the projected path and epoxide 323 of the actual synthetic sequence (Scheme 77). For example, the remarkable similarity in the chemical shifts and splitting patterns for the aziridine and oxirane methine protons in epoxyaziridines 319a-b complicated the analysis of the 'H NMR spectrum. The inability to adequately distinguish between aziridine 321 and epoxide 323 in combination with the assumed precedent obtained within the research group 107 regarding the selective opening of the oxirane within epoxyaziridines 319a-b by piperonyl nucleophiles led to the initial structure misassignment.

PAGE 106

95 Several transmetalation conditions were examined in an effort to bring about the intramolecular cyclization of postulated aziridine 322 which, if successful, would furnish tosylamide 326 as shown in the projected path, Scheme 78. The tosylamide 326 represents an advanced intermediate in which the six contiguous chiral centers of the Cring in the alkaloid are established. The conditions employed to effect transmetalation of the piperonyl functionality with either r-butyllithium or «-butyllithium in diethyl ether failed to afford tosylamide 326 and only resulted in extensive decomposition. However, treatment of the presumed tosylamide 322 with either f-butyllithium or /r-butyllithium in THF or DME did not result in decomposition but appeared to only furnish the dehalogenated derivative 325 as illustrated in the projected path, Scheme 78. The sole observation of reduction of the aryl bromide under these conditions confirmed the formation of the intermediate organometallic species, and it was anticipated that intramolecular cyclization may proceed under prolonged reaction times or at elevated temperatures. Unfortunately, attempts to invoke cyclization under these conditions all met with failure and only resulted in debromination of the aryl ring. In actuality, the transmetalation conditions were implemented on epoxide 324 which failed to bring about the intramolecular cyclization; moreover, treatment of epoxide 324 with n-butyllithium or /-butyllithium in THF or DME generated the debrominated derivative 327 as depicted in the actual sequence. Scheme 78. Intramolecular Lewis Acid Cyclization Approach As a result of the encountered difficulties with successfully acheiving intramolecular cyclization under transmetalation conditions, an attempt to bring about the cyclization via Lewis acid catalysis was investigated based on reports of intramolecular

PAGE 107

96 Conditions: a) /-BuLi, ether, -78 °C b) /-BuLi, CuCN, ether, -78 °C c) n-BuLi, ether, -78 °C d) Mg, I 2 , THF Actual: 1. »-BuLi, THF, -78 °C 2. H 3 0 + , 81 % Scheme 78 cyclialkylations of tethered epoxides 102 in addition to reports of Friedel-Crafts reactions between aromatic systems and activated aziridines. 83 ' 8486 ' 87 As illustrated in Scheme 79, it was envisioned that closure of the piperonyl moiety through its electron rich pi system onto the postulated aziridine ring could be invoked under acidic conditions. The results

PAGE 108

97 of several investigations of the proposed acid mediated intramolecular cyclization will be discussed in the following section. 325a OBn OBn Scheme 79 The synthetic route used to prepare the postulated aziridine 325 was also based on earlier reports internal to the research group 107 indicating that nucleophilic attack of the oxirane would be more facile than opening of the aziridine under basic conditions. Presumed selective opening of the epoxide ring upon treatment of the epoxyaziridines 319a-b with either the potassium salt of piperonol or the potassium salt of piperonylic acid furnished the postulated aziridines 325 and 328 following benzylation as depicted in the projected path, Scheme 80. Initially, examination of the acid mediated closure was studied on the presumed aziridine 325 in which the piperonyl unit is tetherd as an ether since the postulated aziridine 328 contains a more deactivated piperonyl unit tethered as

PAGE 109

98 an ester. In actuality, treatment of epoxyaziridines 319a-b with the potassium salts of piperonol or piperonylic acid resulted in selective attack of the aziridine ring leading to the formation of the tosylamides 327 and 331 following benzylation as shown in the actual sequence, Scheme 80. Projected : >vCT 0K 1 8-crown-6, DME t KActual: O O K N I Ts 319a-b 2. NaH, BnBr, Bu 4 NI, THF SO* 0 " 1 8-crown-6, DME, reflux 2. NaH, BnBr, Bu 4 NI, THF vC^ 0 * 18-crown-6, DME OBn O o >< 329X-H 2 , R-H —] NaH, BnBr, Bu 4 NI 327 X = H 2 , R = Bn-«-J THF ’ 71 % ( 2 ste P s ) 330 X = O, R = H, 28 % | Na H, BnBr, Bu 4 NI 331 X = O, R = Bn ^JTHF, 80 % Scheme 80

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99 Unfortunately, it was discovered that both piperonyl nucleophiles actually open the aziridine ring within epoxyaziridines 319a-b under basic conditions only following identification of lactone 353 (Scheme 76) at the end of the synthesis. With the presumption that a means of generating aziridine 325 had been established, the acid mediated intramolecular cyclization was attempted using trifluoroacetic acid, boron trifluoride diethyletherate, and alumina, all of which failed to invoke cyclization. However, treatment of the postulated aziridine 325 with dimethylaluminum chloride at -25 °C in methylene chloride successfully invoked intramolecular cyclization giving rise to tosylamide 326 as illustrated in the projected path, Scheme 81. Actual: Q„ Scheme 81

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100 It was subsequently determined that Lewis acid mediated intramolecular cyclization of epoxide 327 proceeded to form alcohol 332a via closure of the electron rich piperonyl moiety onto the oxirane as ahown in the actual sequence, Scheme 81. The attempted cyclization of the presumed ester 328 using dimethylaluminum chloride as the acid left ester 328 unchanged and failed to generate the corresponding lactone 333 as shown in the projected path, Scheme 82. At this time, it was assumed that the failed cyclization was possibly attributed to the enhanced deactivation of the aryl ring in the postulated aziridine 328 towards electrophilic aromatic substitution. In retrospect, the Lewis acid mediated cyclization of ester 331 was actually attempted and failed to produce lactone 334 as depicted in the actual path, Scheme 82. Nevertheless, the Lewis acid mediated cyclization of ether 327 proceeded well to furnish pentacycle 332a as mentioned previously and illustrated in Scheme 81. Scheme 82

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101 Further Functionalizations of Arvlconduramines While it appeared that the postulated tosylamide 326 was reached, the stage was set to perform additional functionalization which would presumably allow for formation of the lactam functionality present in the alkaloid. Included among such auxiliary functionalizations are the oxidation of the benzylic position present in the benzopyran unit, the removal of the tosyl group, and finally hydrolysis and rearrangement which would provide the skeleton of the natural product. Benzvlic oxidation Oxidation of the benzylic position of the benzopyran system present within the postulated tosylamide 326 would allow for the construction of the corresponding lactone which could undergo hydrolysis and concomitant transamidation. Successful oxidation of the benzylic position was found to proceed upon treatment of the presumed tosylamide 326 with DDQ 103 followed by trapping of the intermediate oxonium ion with 2methoxyethanol furnishing the postulated acetal 335 as shown in the projected path, Scheme 83. Cleavage of the acetal unit with camphorsulfonic acid afforded the lactol which was immediately oxidized with pyridinium chlorochromate to give the presumed lactone 336. In actuality, benzylic oxidation of the activated benzopyran unit in alcohol 332a provided acetal 337 which was subsequently converted into lactone 338 via hydrolysis of the acetal group followed by oxidation of the ensuing lactol as illustrated in the actual sequence, Scheme 83. However, it was not until the isolation and identification of tetracetate 353 (Scheme 76) at the end of the synthesis that the actual benzylic oxidation sequence was resolved.

PAGE 113

102 OBn 1. CSA, THF/H 2 0 2. PCC, CH 9 C1 ? Actual: 1. CSA, THF/H 2 0 2. PCC, CH 9 C1 9 68 % Scheme 83

PAGE 114

103 Detosylation studies In order to establish the best stage at which to remove the tosyl group in the presumed path to the alkaloid, the deprotection of several sulfonamides generated throughout the proposed synthesis was examined. Acylation of the postulated sulfonamide 326 resulted in generation of the assumed benzopyran 339 as shown in the projected path, Scheme 84. Reductive detosylation occurred smoothly to seemingly produce the terf-butyl carbamate 340; nevertheless, the attempted oxidation of the benzylic position with DDQ and 2-methoxyethanol as descibed previously (Scheme 83) failed to afford the acetal 341. At this time, the reductive detosylation process appeared to provide a means of preparing tert butyl carbamates which can be easily converted to the corresponding free amines necessary for the transamidation process. In retrospect, acylation of the hydroxyl functionality present in benzopyran 332a occurred to generate carbonate 332b which was subsequently transformed into N-benzylamine 332c under reductive detosylation conditions as illustrated in the actual sequence, Scheme 84. The attempted oxidation of the benzylic position within the activated benzopyran system using DDQ and 2-methoxyethanol was actually performed on N-benzylamine 332c which failed to produce acetal 342. As a result of failure in oxidizing the benzylic position within benzopyran 340, the detosylation sequence was applied to the presumed sulfonamide 335 (Scheme 83) in which the acetal unit has already been incorporated into the molecule. Following acylation of the postulated acetal 335, which was presumed to generate the corresponding N-acyl sulfonamide, reductive detosylation was performed supposedly furnishing the acetal 343 as shown in the projected path, Scheme 85.

PAGE 115

104 Projected : Actual: NaH, (B0C) 2 0, THF 86 % Scheme 84

PAGE 116

105 Projected : 1. NaH, (B0C) 2 0,THF 2. Na/Naphthalene, DME Actual: 1 . NaH, (B0C) 2 0, THF 2. Na/Naphthalene, DME 85 % Scheme 85 In actuality, hydroxy acetal 337 was subjected to the acylation conditions to give the corresponding carbonate which upon reductive detosylation furnished N-benzylamine 344 as illustrated in the actual sequence, Scheme 85. Unfortunately, standard spectroscopic techniques failed to adequately distinguish between compounds in the projected and actual paths in the detosylation sequences. It was not until the preparation and identification of tetracetate 353 (Scheme 76) at the conclusion of the synthesis that the actual synthetic transformations performed throughout the detosylation studies were determined.

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106 Final Transformations With the methodology developed for generating the postulated acetal 343, the final transformations, including further oxidation of the acetal functionality, removal of protecting groups, and the transamidation protocol, were performed in the presumed path to the alkaloid. Cleavage of the acetal functionality in the postulated carbamate 343 under acidic conditions furnished the lactol which was immediately converted into the assumed lactone 345 via pyridiniumn chlorochromate mediated oxidation as shown in the projected path, Scheme 86. Unfortunately, it was subsequently discovered that cleavage of acetal 344 followed by oxidation of the crude lactol afforded lactone 346 as illustrated in the actual sequence, Scheme 86. Projected : 1. CSA, THF/H 2 0 2. PCC, CH 2 C1 2 OBn Scheme 86

PAGE 118

107 The removal of the protecting groups present in the functionalized cyclohexyl ring of the postulated lactone 345 was examined. First, deprotection of the tertbutoxycarbonyl group by thermolysis followed by removal of the acetonide generated the presumed diol 347 as illustrated in the projected path, Scheme 87. Further treatment of the postulated amino diol 347 with potassium carbonate in methanol should have furnished lactam 348 in which the skeleton of the alkaloid would have been constructed. Projected : OBn OBn Actual: Scheme 87

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108 In retrospect, deprotection of the carbonate in lactone 346 followed by removal of the acetonide group produced triol 349 which was subsequently transformed into triol 350 via hydrolysis as depicted in the actual sequence, Scheme 87. In addition to the production of trans-lactone 350 , the hydrolysis also gave the c/s-lactone 349 . Removal of the benzyl group in the postulated lactam 348 (Scheme 87) should have furnished the natural product; however, the conditions utilized for the final debenzylation (H 2 , Pd(OH) 2 , MeOH) did not produce (+)-7-deoxypancratistatin (6) based on thin layer chromatography as represented in Figure 8. Figure 8. TLC Comparison with (+)-7-deoxypancratistatin The failure in generating a physical match by thin layer chromatography in combination

PAGE 120

109 with difficulties in purifying the product obtained from the hydrogenation gave the appearance that the debenzylation conditions were ineffective for conversion of the presumed lactam 348 (Scheme 87) to the natural product. Therefore, an effort to convert the presumed lactam 348 into the tetraacetate of (+)-7-deoxypancratistatin was examined. Acylation of the hydroxyl groups in the postulated lactam 348 appeared to give the triacetate 351 as shown in the projected path, Scheme 88. Removal of the benzyl group by hydrogenation followed by acylation of the resulting alcohol would give the known tetraceate of (+)-7-deoxypancratistatin. 29a,c Debenzylation of the presumed lactam 351 occurred smoothly to produce what appeared to be the corresponding alcohol which was then subjected to acylation with the hope that the tetracetate of (+)-7-deoxypancratistatin (106) would be obtained. Projected : OBn OH OH OR' 1 . H 2 , Pd(OH) 2 , MeOH I 351, R’ = Bn, R = Ac 2. Ac 2 0, DMAP, Pyridine ‘-^106, R’ = R = Ac Scheme 88

PAGE 121

110 The sequence involving debenzylation and subsequent acylation ultimately led to the isolation of a compound whose 'H NMR spectrum was remarkably similar to that of the tetracetate of (+)-7-deoxypancratistatin (106) yet not identical. In addition, the R f values in thin layer chromatography did not coincide as represented in Figure 9. Figure 9. TLC Comparison with the Tetraacetate of (+)-7-deoxypancratistatin Only at this stage of the synthesis was it discovered that the actual synthetic sequence and the projected path to the alkaloid were not in agreement. In retrospect, triol 350 was converted into triacetate 352 which upon debenzylation and acylation of the resulting free amine gave tetracetate 353 as illustrated in the actual path, Scheme 88.

PAGE 122

Ill In this synthesis, the functionalized lactone 353 was prepared in 14 steps from the epoxyaziridines 319a-b in which a Lewis acid mediated intramolecular cyclization served as the key step. Interestingly, the c/s-lactone 349 did isomerize to the rrans-lactone 350 (actual sequence. Scheme 87) both of which manifest distinctly different chromatographic and spectral properties. Unfortunately, standard nuclear magnetic resonance spectroscopic experiments failed to adequately distinguish between aziridine 321 and epoxide 323 in the projected and actual paths respectively (Scheme 77). The ambiguity in the NMR spectra continued to be problematic in discriminating between the projected and actual transformations which were performed throughout the synthesis. Only after discrepancies arose in the comparison of the ‘H NMR spectra and R f values in thin layer chromatography for tetraacetates 353 and 106 (Scheme 88) was it determined that the projected path to the alkaloid did not coincide with the actual synthetic sequence. Structure Assignment As it was clear at this point that the tetraacetate of (+)-7-deoxypancratistatin had not been prepared, several correlational NMR spectroscopic experiments were performed in order to evaluate the structural integrity of the intermediates prepared in the projected path to the alkaloid. The results of a variety of two dimensional NMR experiments discussed below failed to adequately distinguish between the tosylamide 326 of the projected path and alcohol 332a of the actual sequence as shown in Scheme 89. Ultimately, the unambiguous assignment of alcohol 332a was made by means of l5 N GHMQC spectroscopy described at the end of the following section.

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112 Actual: Ts 319a-b Scheme 89 In the aromatic region of the proton spectrum of tosylamide 332a, the two doublets of the tosyl moiety, the overlapping signal from the benzyl group, and the signals of the piperonyl functionality were identified by long range 'Hi3 C couplings within these fragments as shown in Figure 10. 6.43 104.1 4.50 4.58 67.2 7.19 128.1 128.8 r \5i27., 19 6 Figure 10. Assignments of the Piperonyl, Tosyl, and Benzyl Moieties in Amide 332a

PAGE 124

113 From long range 'HI3 C coupling experiments, the protons of the methyl groups of the acetonide (1.29 and 1.31 ppm) couple with the carbon at 109.8 ppm which, in turn, exhibits long range coupling with the proton at 4.75 ppm (Figure 11). 1.29 24.9 Figure 11. Assignments of the Acetonide Unit of Tosylamide 332a As shown in Figure 12, the signal at 1.31 ppm of the methyl group from the acetonide displays an nOe with the protons (4.75 and 4.28 ppm) located at the bridgehead of the cyclohexyl and acetonide rings. Figure 12. Partial NOESY Spectrum of Amide 332a

PAGE 125

114 This nOe indicates that the methyl group of the acetonide at 1.31 ppm and the protons of the cyclohexyl ring at 4.28 and 4.75 ppm are in a cis relationship relative to one another as illustrated in Figure 1 1 . The proton signals of the inositol moiety were identified from the DQCOSY spectrum (Figure 13) giving the coupling sequence 4.21-2.47-3.89-4.28-4.75-3.69-4.21 along the functionalized cyclohexyl ring. Figure 13. Partial DQCOSY Spectrum of Amide 332a The assignment of the carbon atoms was obtained from the GHMQC spectrum and is shown in the complete assignment of the inositol moiety of tosylamide 332a, Figure 14.

PAGE 126

115 1.29 24.9 Figure 14. Carbon Hydrogen Framework of the Cyclohexyl Unit of Amide 332a Long range 'H-' 3 C coupling in the HETCOR spectrum (Figure 15) between the proton at 6.75 ppm and the carbon atom at 39.9 ppm confirmed the connectivity between the piperonyl species and the inositol unit as illustrated in Figure 16. Additional evidence Oh N OB ^ <*> «« OBL ,-\i ops ^ cn «r o *o o c ON O .% X O’~ 0* 57 CV <\ CVi 1.31 t.92 3:88 5.60 6.43 6.76 6M /,83 Figure 15. HETCOR Spectrum of Amide 332a

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116 for the connectivity between the piperonyl moiety and the inositol fragment as shown in Figure 16 arises from long range ‘H13 C coupling (HETCOR spectrum, Figure 15) of the protons at 4.50 and 4.58 ppm with carbon atom at 76.0 ppm. 1.29 24.9 4.58 Figure 16. Connectivity of the Piperonyl Unit of Tosylamide 332a The location of the benzyl group was also determined from significant long range 'H13 C couplings in the HETCOR spectrum, Figure 15. Long range coupling of the carbon atom at 64.6 ppm with the methylene protons (4.50 and 4.44 ppm) associated with the benzyl functionality confirmed the connectivity between the inositol unit and the benzyl group as illustrated in Figure 17. Indirect evidence for the location of the tosyl moiety in amide 332a was obtained through examination of significant nOe’s of the tosyl group which are revealed in NOESY spectrum as shown in Figure 18. The proton at 1.92 ppm (Figure 19) is coupled with the proton at 3.89 ppm (DQCOSY) and exchanges with water (NOESY), thus

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117 1.29 24.9 Figure 17. Location of the Benzyl Group of Amide 332a confirming that the proton at 1 .92 ppm is attached to a heteroatom. While the proton at 1.92 ppm displays expected nOeÂ’s with the protons at 6.75, 2.47, 3.89 and 4.28 ppm, no nOe is observed between the proton at 1.92 ppm and the proton at 7.83 ppm of the tosyl functionality (Figure 10). Figure 18. Significant nOEÂ’s of the Tosyl Group in Amide 332a

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118 On the other hand, the proton at 7.83 ppm of the tosyl group displays nOeÂ’s with the protons at 3.69, 4.75, 4.21, 4.44 and 4.50 ppm (Figure 18) which suggests that the tosyl functionality is vicinal to the oxygen atom of the benzopyranyl system and adjacent to the benzyl group as shown in the in Figure 19. 1.29 24.9 Figure 19. Complete Structural Assignment of Amide 332a The nOeÂ’s exhibited between the protons of the methyl group of the acetonide at 1.29 ppm and the protons of the inositol unit at 3.69 and 3.89 ppm indicate that all these protons are on the same face of the ring. In addition, all other protons on the inositol ring (2.47, 4.21, 4.28, and 4.75 ppm) display mutual nOeÂ’s indicating that these protons are in a cis relationship relative to one another as shown in Figure 19. Unfortunately, the 'H-H

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119 couplings, nOe’s, and long range 'Hli C couplings failed to adequately discriminate between between tosylamide 326 and alcohol 332a of the projected and actual synthetic sequences as shown previously in Scheme 89. Absolute proof of the structural integrity of alcohol 332a as shown below was obtained by l5 N nuclear magnetic resonance spectroscopy. Acquisition of the proton spectrum in deuterated toluene at 70 °C gave first order spectra, the proton assignment shown in Figure 20. 5.68 Figure 20. Proton Assignment of Amide 332a Long range ‘HI5 N coupling (Figure 21) between the nitrogen nucleus (277.9 ppm) with the protons of the benzyl group (4.44 and 4.51 ppm) and with the proton of the inositol unit at 4.16 ppm confirmed the connectivity of the tosylamide to the functionalized cyclohexyl ring as illustrated in Figure 20.

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120 Figure 21. I5 N GHMQC Spectrum of Tosylamide 332a Only after acquisition of the 15 N GHMQC spectra was the actual synthetic sequence, as depicted in Scheme 90, ascertained and the identification of tetracetate 353 made. Ts 319a-b Scheme 90

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121 In summary, tetraacetate 353 was prepared in 14 steps and in 3.3 % overall yield starting from the mixture of a and (3 epoxyaziridines 319a-b as depicetd in Scheme 91. Ts 319a-b ix, x i. Potassium Piperonoxide, DME, 18-crown-6; ii. NaH, BnBr, «-Bu 4 NI, THF 71 % (over 2 steps); iii. Me 2 AlCl, CH,C1 2 , -25 °C, 77 %; iv. DDQ, 2-methoxyethanol, CH 2 C1 2 , 78 %; v. NaH, (B0C) 2 0, THF; vi. Na/Naphthalene, DME, -50 °C, 85 % (over 2 steps); vii. CSA, THF/H 2 0; viii. PCC, CH 2 C1 2 , 72 % (over 2 steps); ix. C 6 H 5 C0 2 Na, MeOH/H 2 0, reflux; x. p-TsOH, MeOH, 84 % (over 2 steps); xi. K 2 C0 3 , MeOH, reflux, 44 %; xii. Ac 2 0, pyridine, DMAP, 61 %; xiii. H 2 , Pd(OH) 2 , MeOH; xiv. Ac 2 0, pyridine, DMAP, 55 % (over 2 steps) Scheme 91

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122 Structure Correlation by Independent Synthesis In addition to the spectroscopic evidence for the structure of alcohol 332a, the synthetic sequence as depicted in Scheme 90 was proved through a structure correlation. As shown in Scheme 92, treatment of vinylaziridine 28 with the potassium salt of piperonol in 1 ,2-dimethoxyethane furnished tosylamide 354 which was converted into sulfonamide 355 upon benzylation. Scheme 92 With tosylamide 355 in hand, a stereoselective epoxidation of the olefin, if successful, would give epoxide 327 (Scheme 90) and provide the structure correlation. Unfortunately, several attempts to oxidize the olefin with an array of epoxidizing agents, including mCPBA, dimethyldioxirane, and many hydrogen peroxide derived oxidants, failed to generate epoxide 327 as depicted in Scheme 93. Scheme 93

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123 Successful oxidation of N-benzyl tosylamide 355 with ruthenium tetroxide 95 gave cis diol 356; moreover, stereoselective opening of the epoxide ring in tosylamide 327 with hydroxide furnished trans diol 357 as shown in Scheme 94. It was envisioned that the two stereisomeric diols 356 and 357 could be converted into a common intermediate via oxidative degradation of the diol moiety followed by reduction of the crude dialdehyde. Treatment of both diol 356 and 357 with sodium periodate resulted in cleavage of the diol unit generating the corresponding dialdehydes. Interestingly, cleavage of cis diol 356 proceeded at a rate five times faster than that for trans diol 357. Reduction of the crude dialdehydes generated from oxidative degradation of diols 356 and 357 gave diol 358 (Scheme 94). 355 RuC 1 3 H 2 0, NaI0 4 CH 3 CN/EtOAc 66% OH KOH, H 2 0, 1,4-dioxane, reflux 56% OH 1. NaI0 4 , aq. acetone 2. NaBH 4 , MeOH 49 % Scheme 94

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124 The spectral and physical properties (‘H NMR, [a] D , TLC, IR) of diol 358, prepared indepedently from both vinylaziridine 28 and epoxyaziridines 319a-b, were identical in all respects thus proving the synthetic sequence shown in Scheme 90 via correlation. Correction of the Design of Aryl Ether Precursor of Type 325 Since it was discovered that piperonyl nucleophiles selectively attack the aziridine ring in epoxyaziridines 319a-b under basic conditions, a modified approach to the synthesis of (+)-7-deoxpancratistatin (6) was examined. Stereoselective dihydroxylation of vivnylaziridine 28 with ruthenium tetroxide 95 generated diol 359 which was subsequently converted into cyclic sulfate 360 by established procedures 108 as shown in Scheme 95. It was envisioned that nucleophilic attack on the sulfate could proceed without detriment to the aziridine based on reported openings of cyclic sulfates by the ammonium salts of carboxylic acids. 109 Treatment of sulfate 360 with ammonium benzoate resulted in a regioselective and stereoselective attack of the cyclic sulfate furnishing alcohol 361 following sulfate hydrolysis. Protection of the hydroxyl functionality as the silyl ether afforded benzoate 362 which was transformed into alcohol 363 via hydrolysis of the ester.

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125 Ts Ts 363 362 i. RuCl, 3H 2 0, NaI0 4 , EtOAc/CH 3 CN, 45 %; ii. S0 2 C1 2 , Et 3 N, CH 2 C1 2 ; iii. (a) Ammonium benzoate, DMF, 70 °C; (b) H 2 S0 4 , H 2 0, THF; 51 % (over 3 steps); iv. TBSC1, imidazole, CH 2 C1 2 , 81 %; v. NaOMe, THF/MeOH, 48 %. Scheme 95

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CHAPTER 4 CONCLUSIONS AND FUTURE WORK Conclusions Clearly, the synthetic route to the synthesis of (+)-7-deoxypancratistatin (6) via epoxyaziridines 319a-b is plagued by the unexpected opening of the aziridine ring rather than the oxirane by piperonyl nucleophiles under basic conditions. Unfortunately, the selective opening of the aziridine ring by piperonyl reagents was only determined with the identification of tetraacetate 353 at the conclusion of the synthesis as shown in Scheme 96. Scheme 96 However, in the corrected approach, nucleophilic opening of cyclic sulfate 360 with ammonium benzoate occurs with retention of the aziridine ring affording alcohol 361 which can be converted into aziridine 363 in a two step sequence shown in Scheme 97. 126

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127 Ts Ts Ts 360 361 363 Scheme 97 Future Work The key steps which remain in the approach to the synthesis of (+)-7deoxypancratistatin (6) include alkylation of alcohol 363 with piperonyl bromide which would furnish ether 364. Lewis acid mediated intramolecular cyclization would give benzopyran 365 which could be converted to lactone 366 via the methodology employed in the synthesis of tetraaceate 353. Hydrolysis of lactone 366 followed by transamidation would ultimately lead to the preparation of the alkaloid as illustrated in Scheme 98. OTBS Ts 363 OTBS OTBS Scheme 98

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CHAPTER 5 EXPERIMENTAL General Procedures and Instrumentation All reactions were carried out in an argon atmosphere with standard techniques for the exclusion of air and moisture. Glassware used for moisture-sensitive reactions was flame-dried under vacuum. Tetrahydrofuran and 1,2-dimethoxyethane were distilled from sodium benzophenone ketyl. Dichloromethane and 1 ,2-dichloroethane were distilled from calcium hydride. Reactions were monitored by thin layer chromatography using K6F silica gel (Whatman) plates. Flash column chromatography was performed on Merck silica gel (grade 60, 230-400 mesh). Melting points were determined on a Thomas Hoover Uni-melt apparatus and are uncorrected. Infrared spectra were obtained on a Perkin Elmer 1600 Series FT-IR spectrometer. High resolution mass spectra were measured on a Sinnigan Mat 95Q mass spectrometer. Nuclear magnetic resonance spectra were recorded on either a Varian Unity-300, Gemini 300, or Inova 500 FT-NMR spectrometer in CDC1 3 unless otherwise noted. Coupling constants are measured in hertz and chemical shifts are reported in ppm downfield from trimethyl silane. Optical rotations were measured on a Perkin Elmer model 341 polarimeter. 128

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129 Experimental Procedures and Data N-rn/?.2/?.35.45.55.651-2-n.3-Benzodioxol-5-yn-3.4-dihydroxy-5.6(isopropvlidenedioxy)cyclohex-l-yll-4’-methylbenzenesulfonamide (3091 A solution of sulfonamide 308 (2.30 g, 5.19 mmol) in a 1:1 mixture of CH 3 CN/EtOAc (65 mL) at 0 °C was treated with a solution of RuCl 3 H 2 0 (81 mg, 0.39 mmol) and NaI0 4 (1.66 g, 7.76 mmol) in H 2 0 (1 1 mL) and stirred at 0 °C for 3 minutes. The reaction was subsequently quenched with a 50 % aqueous solution of Na 2 S 2 0 3 (100 mL) and then warmed to room temperature. The organic and aqueous phases were separated, and the aqueous phase was extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were dried over Na2S0 4 and concentrated in vacuo. The residue was purified by chromatography (silica gel, 2:1 ethyl acetate/hexanes) to afford diol 309 (1.87 g, 75 %) as a white solid: R^O.14 (2:1 hexanes/ethyl acetate); m.p.: 103-105 ° C; [a] 29 D -27.1 (c 1.0, CH 3 OH); IR (KBr) v 3482, 1599, 1490, 1246, 1159, 1036 cm 1 ; 'H NMR (500 MHz, acetone) 5 7.49 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 8.2 Hz, 2H), 6.59 (d, J = 1.7 Hz, 1H), 6.58 (d, J = 8.0 Hz, 1H), 6.52 (dd, J = 8.0, 1.6 Hz, 1H), 6.34 (d, J =9.6 Hz, 1H), 5.94 (m, 2H), 4.51 (m, 1H), 4.32 (dd, J = 5.9, 2.9 Hz, 1H), 4.21 (t, J = 6.1 Hz, 1H), 4.02 (m, 1H), 3.94 (ddd, J = 8.5, 6.0 Hz, 1H), 3.77 (td, J = 8.8, 6.3 Hz, 1H), 3.67 (d, J = 5.8 Hz, 1H), 2.83 (t, J = 8.8 Hz, 1H), 2.40 (s, 3H), 1.49 (s, 3H), 1.28 (s, 3H); 13 C NMR (75 MHz, CDC1 3 ) 5 147.0, 145.8, 142.1, 137.4, 132.6, 128.5, 126.1, 121.4, 108.4, 107.5, 100.2, 76.5, 75.9, 71.0, 69.7, 56.7, 49.4, 26.4, 24.3, 20.7; HRMS (FAB) calcd for C 23 H 28 N0 8 S 478.1536, found 478.1516; Anal. Calcd for C 23 H 27 NQ 8 S: C, 57.85; H, 5.70; N, 2.93. Found: C, 57.76; H, 5.79; N, 2.83.

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130 N-l((l/L2R)-2-(L3-Benzodioxol-5-yl)-3-hydroxy-l-(hydroxymethyl))propvl]-4’methvlbenzenesulfonamide ( 310 ) A solution of diol 309 (1.72 g, 3.60 mmol) in a 4:1:1 mixture of THF/H 2 0/TFA (30 mL) was stirred at room temperature for 17 hours. After removal of the solvents by Kiigelrohr distillation, the residue was dissolved in a 3:2 mixture of acetone/H,0 (30 mL) and subsequently treated with a solution of NaI0 4 (2.13 g, 9.97 mmol) in H 2 0 (13 mL). The resulting solution was stirred at room temperature for 4 hours and then diluted with water (5 mL). Excess acetone was removed under reduced pressure, and the remaining solution was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were dried over Na 2 S0 4 and then concentrated in vacuo. A solution of the remaining residue in CHjOH (120 mL) at 0 °C was treated with NaBH 4 (1.60 g, 42.3 mmol) and then slowly warmed to room temperature. After stirring for a period of 14 hours, the solution was diluted with H 2 0 (20 mL) and excess methanol removed under reduced pressure. The resulting solution was extracted with ethyl acetate (2 x 60 mL), and the combined organic extracts were dried over Na 2 S0 4 . Removal of the solvent under reduced pressure and purification of the residue by chromatography (silica gel, 3:2 CH 2 Cl 2 /acetone) gave tosylamide 310 (820 mg, 60 %) as a white solid: R / 0.61 (1:1 CH 2 Cl 2 /acetone); m.p.: 137139 °C; [a] 25 D +50.7 (c 1.0, CHC1 3 ); IR (KBr) v 3464, 3303, 1501, 1440, 1334, 1156, 1025 cm’ 1 ; ’H NMR (300 MHz, CDC1 3 ) 5 7.68 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 9.0 Hz, 2H), 6.71 (d, J = 7.8 Hz, 1H), 6.61-6.58 (m, 2H), 5.94 (s, 2H), 4.90 (d, J = 8.4 Hz, 1H), 3.95 (t, J = 9.9 Hz, 1H), 3.71-3.59 (m, 2H), 3.53-3.40 (m, 2H), 3.16 (bs, 1H), 2.92 (dt, J = 8.6, 5, Hz, 1H), 2.63 (bs, 1H), 2.41 (s, 3H); 13 C NMR (75 MHz, CDC1 3 ) 6 147.8, 146.8, 143.5, 137.0, 131.6, 129.6, 126.9, 121.6, 108.5, 108.4, 101.0, 62.9, 62.8, 55.9, 48.8, 21.5;

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131 HRMS (Cl) calcd for C ]8 H 22 N0 6 S 380.1168, found 380.1166; Anal. Calcd for C 18 H 21 N0 6 S: C, 56.98; H, 5.58; N, 3.69. Found: C, 56.83; H, 5.52; N, 3.66. N-(ferf-butoxycarbonyI)-N-r((H?.2i?)-2-(L3-Benzodioxol-5-yl)-3-(fertbutoxvcarbonyloxy)-l-(hydroxymethyl))propyll-4’-methy]benzenesulfonamide ( 314 ) To a suspesion of NaH (87.0 mg, 3.63 mmol) in THF (7 mL) at 0 °C was added a solution of diol 310 (425 mg, 1.12 mmol) in THF (7 mL), and the resulting solution was stirred at 0 °C for 20 minutes. A solution of di-tert-butyl dicarbonate (783 mg, 3.58 mmol) in THF (5 mL) was added dropwise and the solution was allowed to slowly warm to room temperature. After stirring for 20 hours, the reaction was quenched with H 2 0, and the reaction mixture was then extracted with ethyl acetate (3 x 35 mL). The combined organic extracts were dried over MgS0 4 and the solvent removed under reduced pressure. The remaining residue was purified via chromatography (silica gel, 2: 1 hexanes/ethyl acetate) to afford alcohol 314 (552 mg, 85 %) as a white solid: R., 0.62 (1:1 hexanes/ethyl acetate); m.p. 67-69 °C; [a] 25 D +18.1 (c 1.0, CHC1 3 ); IR (KBr) v 3284, 1744, 1492, 1252, 1160, 1091 cm' 1 ; ] H NMR (500 MHz, CDC1 3 ) 8 7.67 (d, J = 8.2 HZ, 2H), 7.25 (d, J = 8.5 Hz, 2H), 6.68 (d, J =7.7 Hz, 1H); 6.55-6.56 (m, 2H), 5.90 (s, 2H), 4.52 (bs, 1H), 4.21 (dd, J = 1 1.0, 7.6 Hz, 1H), 4.15 (dd, J = 1 1.0, 6.0 Hz, 1H), 3.93-3.81 (m, 3H); 3.13 (dd, J = 10.7, 7.1 Hz, 1H); 2.40 (s, 3H); 1.42 (s, 18 H); 13 C NMR (76 MHz, CDC1 3 ) 5 168.6, 168.5, 153.0, 152.8, 147.8, 147.1, 143.3, 137.3, 129.5, 129.4, 127.0, 121.9, 108.7, 108.4, 101.0, 82.5, 82.1, 66.3, 66.1, 52.6, 44.8, 27.6, 27.5, 21.5; HRMS (El) calc for C 28 H 37 NO, 0 S 579.2138, found 579.2128; Anal. Calcd for C 28 H 37 NO l0 S: C, 58.02; H, 6.43; N, 2.42. Found: C, 57.75; H, 6.43; N, 2.33.

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132 Methyl N-r(l/?.2R.3S,4S.55'.6S)-2-(L3-Benzodioxol-5-yl)-3.4-dihydroxy-5,6(isopropylidenedioxylcyclohex-l-vllcarbamate ( 316 ) A solution of RuC 1 3 H 2 0 (81 mg, 0.39 mmol) and NaI0 4 (1.65 g, 7.71 mmol) in H 2 0 (10 mL) was added to a solution of carbamate 315 (1.79 g, 5.14 mmol) in a 1:1 mixture of CHjCN/EtOAc (50 mL) at 0 °C. The resulting solution was stirred at 0 °C for 3 minutes and then quenched with 50 % aqueous Na 2 S 2 0 3 solution (50 ml). After separation of the organic and aqueous layers, the aqueous phase was extracted with ethyl acetate (3 x 75 mL). The combined organic extracts were dried over Na 2 S0 4 , and the solvent was removed under reduced pressure. The resulting residue was purified by chromatography (silica gel, 4:1 ethyl acetate/hexanes) to furnish diol 316 (1.35 g, 69 %) as a white solid: R f 0.27 (4:1 ethyl acetate/hexanes); m.p.: 115-117 °C; [a] 29 D -47.7 (c 1.0, CHC1 3 ); IR (KBr) v 3398, 1702, 1508, 1491, 1248, 1058 cm 1 ; ‘H NMR (500 MHz, CDC1 3 ) 8 6.78 (m, 2H), 6.70 (dd, J = 8.2, 1.4 Hz, 1H), 5.96 (s, 2H), 4.64 (bs, 1H), 4.37 (dd, J = 5.3, 2.7 Hz, 1H), 4.34 (q, J = 2.3 Hz, 1H), 4.19 (m, 1H), 4.02 (dt, J =10.2, 2.9 Hz, 1H), 3.90 (q, J = 9.7 Hz, 1H), 3.53 (s, 3H), 2.95 (t, J = 9.5 Hz, 1H), 2.76 (m, 1H), 1.87 (m, 1H), 1.60 (s, 3H), 1.39 (s, 3H); 13 C NMR (75 MHz, CDC1 3 ) 6 156.5, 148.0, 146.9, 131.8, 122.2, 109.2, 108.6, 108.4, 101.0, 77.3, 76.7, 72.3, 69.5, 55.5, 52.0, 47.9, 27.8, 25.8; HRMS (FAB) calcd for C 18 H 24 N0 8 383.1502, found 383.1500; Anal. Calcd for C 18 H 23 N0 8 : C, 56.69; H, 6.08; N, 3.67. Found: C, 56.42; H, 6.18; N, 3.53. Methyl N-rn/?.2R)-2-(l,3-Benzodioxol-5-yD-3-hydroxy-l-(hydroxymethyl')propyll carbamate ( 317 ) A solution of diol 316 (1.97 g, 5.17 mmol) in a 4:1:1 mixture of THF/H 2 0/TFA (45 mL) was stirred at room temperature for 16 hours. Removal of the solvents via Kiigelrohr distillation afforded a residue which was dissolved in a 3:2 mixture of acetone/H 2 0 (40

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133 mL) and subsequently treated with a solution of NaI0 4 (3.73 g, 17.4 mmol) in H 2 0 (20 mL). After stirring at room temperature for 4 hours, the solution was diluted with H 2 0 (5 mL) and excess acetone removed under reduced pressure. The remaining solution was extracted with ethyl acetate (3 x 60 mL), dried over Na 2 S0 4 , and concentrated in vacuo. A solution of the residue in CH 3 OH (175 mL) at 0 °C was treated with NaBH 4 (2.43 g, 64.2 mmol) and then slowly warmed to room temperature over a period of 20 hours. The solution was diluted with H 2 0 (25 mL) and excess methanol was removed under reduced pressure. The remaining solution was extracted with ethyl acetate (2 x 70 mL) and then dried over Na 2 S0 4 . Removal of the solvent under reduced pressure and purification of the residue by chromatography (silica gel, 3:2 CH 2 Cl 2 /acetone) provided carbamate 317 (654 mg, 45 %) as a film: R r 0.36 (3:2 CH 2 Cl 2 /acetone); [a] 26 D -55.2 (c 1.0, CHC1 3 ); IR (neat) v 3392, 1694, 1505, 1488, 1249, 1038 cm '; 'H NMR (500 MHz, CDC1 3 ) 6 6.77 (d, J = 8.0 Hz, 1H), 6.69 (d, J = 1.1 Hz, 1H), 6.64 (dd, J = 8.0, 1.5 Hz, 1H), 5.95 (s, 2H), 5.02 (d, J = 9.1 Hz, 1H), 4.16 (sx, J = 4.7 Hz, 1H), 3.82 (t, J = 4.8 Hz, 1H), 3.75 (m, 1H), 3.71 (s, 3H), 3.68-3.61 (m, 2H), 3.55 (dd, J = 1 1.6, 5.4 Hz, 1H), 3.03 (dt, J = 9.6, 2.5 Hz, 1H), 2.19 (bs, 1H); 13 C NMR (75 MHz, CDC1 3 ) § 158.2, 147.8, 146.7, 131.8, 121.6, 108.7, 108.4, 101.0, 63.4, 63.0, 52.9, 52.5, 48.8; HRMS (FAB) calcd for C 13 H 18 N0 6 284.1 134, found 284.1 138; Anal. Calcd for C 13 H 17 N0 6 : C, 55.12; H, 6.05. Found: C, 54.96; H, 5.99. (2R,3i?)-2-amino-3-(L3-Benzodioxol-5-vlVL4-dihvdroxvbutane hydrochloride (3181 To a solution of diol 317 (198 mg, 0.700 mmol) in CH 3 OH (6 mL) was added a solution of 10 % aqueous KOH (4.5 mL), and the resulting solution was heated at reflux for 14 hours. The reaction was allowed to cool to room temperature, and the reaction mixture was extracted with diethyl ether (3 x 20 mL). The combined organic extracts were dried

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134 over Na 2 S0 4 and concentrated in vacuo. A solution of the remaining residue in CH 3 OH (5 mL) was added to a saturated HC1 solution in CH 3 OH at 0 °C. After allowing the resulting solution to stir for 5 minutes, the solvent was removed under reduced pressure. The residue was dissolved in isopropanol and filtered into chilled diethyl ether. The resulting precipitate was collected by filtration to give amine hydrochloride 318 (149 mg, 82 %) as a pale beige solid: [a] 25 D +59.0 (c 1 .0, CH 3 OH); IR (neat) v 3416, 1504, 1490, 1250, 1040 cm 1 ; 'H NMR (300 MHz, CD 3 OD) 8 6.79 (s, 1H), 6.73 (m, 2H), 5.86 (s, 2H), 4.24 (t, J = 8.6 Hz, 1H), 4.13 (dd, J = 10.4, 6.3 Hz, 1H), 3.85-3.78 (m, 2H), 3.66 (dd, J = 9.1, 7.4 Hz, 1H), 3.31 (td, J = 7.4, 4.6 Hz, 1H); 13 C NMR (75 MHz, CD 3 OD) 8149.8, 148.6, 133.7, 122.1, 109.5, 108.7, 102.6, 75.8, 72.2, 59.8, 51.5; HRMS (Cl) calcd for C,,H 16 N0 4 (M+H-Cl) 226.1079, found 226.1082. ( 15.25.4/?, 55.65.751-5, 6-(isopropylidenedioxv)-3-(4’ -methylphenylsulfonyl)-8-oxa-3aza-tricyclor5.1.0.01octane (319a) (lR.25.4R.55 , .65.7Rl-5.6-(isopropylidenedioxyV3-(4’-methylphenylsulfonyl)-8-oxa-3aza-tricvclor5. 1 .0.OIoctane (319bl To a degassed solution of aziridine 28 (2. 1 8g, 6.79 mmol) in 1 ,2-dichloroethane (70 mL) was added mCPBA (8.37g, 70 % reagent, 34.0 mmol) along with 3-fm-butyl-4-hydroxy5-methylphenyl sulfide ( 1 .2 1 g, 3.40 mmol) as a radical inhibitor. The resulting solution was heated at reflux for 12 hours. After allowing the solution to cool to room temperature, the reaction mixture was diluted with CH 2 C1 2 and washed with saturated NaHS0 3 followed by saturated NaHC0 3 solution. The organic phase was dried over Na 2 S0 4 and the solvent removed under reduced pressure. The remainder was purified by chromatography (10 % deactivated silica gel, 4:1 hexanes/ethyl acetate) to give a mixture of epoxyaziridines 319a-b (1.83g, 80%) as a white solid: R f 0.43 (2:1 hexanes/ethyl

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135 acetate); m.p.: 107-108 °C; [a] 28 D -56.5 (c 0.8, CHC1 3 ); IR (neat) v 3000, 1595, 1330, 1255, 1158, 1082 cm 1 ; 'H NMR (300 MHz, CDC1 3 ) 6 7.84 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 4.36 (d, J = 5.7 Hz, 1H), 4.24 (d, J = 6.3 Hz, 1H), 3.53 (t, J = 3.6 Hz, 1H), 3.37 (dd, J = 6.8, 3.8 Hz, 1H), 3.12 (dd, J = 3.3, 1.2 Hz, 1H), 3.03 (dd, J = 6.9, 1.2 Hz, 1H), 2.45 (s, 3H), 1.44 (s, 3H), 1.35 (s, 3H); ,3 C NMR (75 MHz, CDC1 3 ) 5 144.8, 134.1, 129.6, 127.7, 109.9, 70.6, 69.5, 49.9, 46.5, 37.1, 35.4, 27.2, 25.0, 21.5; HRMS (FAB) calcd for C 16 H 20 NO 5 S 338.1062, found 338. 1061 ; Anal. Calcd for C 16 H 19 N0 5 S: C, 56.97; H, 5.68; N, 4.56. Found: C, 57.37; H, 5.96; N, 3.72. N-K lR.2R.3S.4S.5S.6SV2-(6’-bromobenzof 1.31dioxolo-5-ylmethoxy)-4.5(isopropylidenedioxyV7-oxa-bicyclor4.1.01hept-3-yH-4’-methvlbenzenesulfonamide (323) To a suspension of KH (21 mg, 0.52 mmol) in DME (3 mL) was added a solution of 6bromopiperonol (121 mg, 0.524 mmol) in DME (1 mL), and the resulting mixture was stirred for 20 minutes. A solution of epoxyaziridines 319a-b (35 mg, 0.15 mmol) in DME (0.5 mL) was added dropwise followed by the addition of a catalytic amount of 18crown-6. The resulting solution was stirred for 15 hours. The reaction was quenched with saturated NH 4 C1 solution, and the reaction mixture was extracted with CH 2 C1 2 (4 x 20 mL). The combined organic extracts were dried over MgS0 4 and concentrated in vacuo. The remaining residue was purified by chromatography (silica gel, 5:1 hexanes/ethyl acetate) to give tosylamide 323 (118 mg, 56%) as a colorless oil: R f 0.35 (2:1 hexanes/ethyl acetate); [a] D 27 +30.9 (c 1.0, CHC1 3 ); IR (neat) v 3500, 3332, 1504, 1480, 1334, 1248, 1090, 1039 cm '; 'H NMR (500 MHz, CDC1 3 ) 8 7.78 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 6.95 (s, 1H), 6.87 (s, 1H), 5.95 (m, 2H), 5.11 (d, J = 10.5 Hz, 1H), 4.52 (dd, J = 6.3, 1.1 Hz, 1H), 4.35 (dd, J = 12.5, 0.5 Hz, 1H), 4.24 (ddt, J = 6.3,

PAGE 147

136 3.4, 1.0 Hz, 1H), 4.16 (dd, J = 12.4, 0.5 Hz, 1H), 3.86 (ddd, J = 10.5, 2.9, 0.9 Hz, 1H), 3.55 (t, J = 2.4 Hz, 1H), 3.29 (ddt, J = 3.6, 2.5, 1.1 Hz, 1H), 3.22 (dt, J = 3.5, 1.2 Hz, 1H), 2.42 (s, 3H), 1.41 (s, 3H), 1.30 (s, 3H); 13 C NMR (126 MHz, CDC1 3 ) 8 147.8, 147.5, 143.8, 137.6, 130.0, 127.1, 112.6, 112.4, 109.9, 109.0, 101.7,73.7,73.3,71.3,69.3,52.8, 52.6, 47.6, 27.0, 24.9, 21.5; HRMS (Cl) calcd for C 24 H 27 N0 8 SBr 568.0641. found 568.0636. N-Benzyl-N-in/?,2R.35'.45.55.65'V2-(6’-bromobenzo[1.31dioxolo-5-yImethoxy)-4.5(isopropylidenedioxy)-7-oxa-bicyclol4. 1 .01hept-3-yll-4’-methylbenzenesulfonamide 024 } A suspension of NaH (68.4 mg, 60 % reagent, 1.71 mmol) in THF (10 mL) was treated with a solution of tosylamide 323 (971 mg, 1.71 mmol) in THF (10 mL) and stirred for 20 minutes after which benzyl bromide (251 |lL, 2.07 mmol) was added dropwise followed by the addition of a catalytic amount of tetrabutylammonium iodide. The resulting solution was stirred for 40 hours and then quenched with water. The organic and aqueous layers were separated and the aqueous phase was extracted with ethyl acetate (4 x 45 mL). The combined organic extracts were dried over MgS0 4 and the solvent removed in vacuo. The remainder was purified by chromatography (silica gel, 5:1 hexanes/ethyl acetate) to give tosylamide 324 (1.02 g, 90 %) as a pale beige solid: R f 0.49 (3:1 hexanes/ethyl acetate); m.p. 67-70 °C; [a] D 27 -9.4 (c 1.0, CHC1 3 ); IR (KBr) v 1500, 1481, 1331, 1250, 1158, 1036 cm 1 ; 'H NMR (300 MHz, CDC1 3 ) 8 7.83 (d, J = 8.2 Hz, 2H), 7.19-7.13 (m, 8 H), 7.02 (s, 1H), 6.02 (m, 2H), 4.63-4.56 (m, 2H), 4.30-4.18 (m, 4H), 3.38 (m, 2H), 2.39 (s, 3H), 1.45-1.36 (m , 6H); 13 C NMR (75 MHz, CDC1 3 ) 8 147.8, 147.5, 142.9, 138.1, 136.3, 130.0, 129.1, 128.8, 128.4, 128.2, 127.8, 112.8, 112.2, 110.1,

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137 109.9, 101.7, 72.7, 70.6, 57.1, 52.1, 27.3, 25.5, 21.5; HRMS (FAB) calcd for C 31 H 33 N0 8 SBr 658.1 1 10, found 658.1 126. N-Benzyl-N-rn/?.2R.35.45.55.65V2-('Benzon.31dioxolo-5-ylmethoxy')-4.5(isopropylidenedioxy)-7-oxa-bicycIor4.1.01hept-3-yll-4’-methylbenzenesulfonamide 027) To a suspension of KH (757 mg, 0.0189 mmol) in DME (12 mL) was added a solution of piperonol (2.51 g, 16.5 mmol) in DME (7 mL), and the resulting solution was stirred for 20 minutes. A solution of epoxyaziridines 319a-b (1.59 g, 4.72 mmol) in DME (8 mL) was added dropwise followed by the addition of 18-crown-6 (436 mg, 1.65 mmol). The resulting solution was stirred for 20 hours. The reaction was quenched with saturated NH 4 C1 solution and the reaction mixture was extracted with CH 2 C1 2 (4 x 75 mL). The combined organic extracts were dried over MgS0 4 and concentrated in vacuo. A solution of the remaining residue in THF (35 mL) was added dropwise to a suspension of NaH (841 mg, 60 % reagent, 35.0 mmol) in THF (35 mL). The resulting solution was stirred for 20 minutes, and then benzyl bromide (4.30 mL, 36.2 mmol) was added followed by a catalytic amount of tetrabutylammonium iodide. The solution was stirred for 44 hours and then quenched with water. The reaction mixture was extracted with ethyl acetate (4 x 60 mL), and the combined organic extracts were dried over MgS0 4 . The solvent was removed under reduced pressure and the residue purified by chromatography (silica gel, 5:1 hexanes/ethyl acetate) to provide epoxide 327 (1.40 g, 71 %) as a white solid: R^O.27 (3:1 hexanes/ethyl acetate); m.p. 63-65 °C; [a] 26 D -6.9 (c 1.0, CHC1 3 ); IR (KBr) v 2987, 1492, 1445, 1251, 1036 cm 1 ; 'H NMR (300 MHz, CDC1 3 ) 5 7.82 (d, J = 8.0 Hz, 2H), 7.18-7.10 (m, 7H), 6.81-6.79 (m, 3H), 5.99 (s, 2H), 4.54-4.48 (m, 2H), 4.31-4.26 (m, 2H), 4.16-4.04 (m, 3H), 3.38 (d, J = 3.3 Hz, 1H), 3.30 (d, J = 3.0 Hz, 1H), 2.40 (s, 3H),

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138 1.46-1.33 (m, 6H); 13 C NMR (75 MHz, CDC1 3 ) 6 147.7, 147.4, 142.8, 138.0, 136.4, 130.9, 129.0, 128.7, 128.3, 128.2, 127.6, 122.1, 110.1, 109.2, 108.0, 101.0, 72.7, 71.3, 57.2, 52.1, 27.3, 25.6, 21.5; HRMS (FAB) calcd for C 31 H 34 N0 8 S 580.2005, found 580.2050; Anal. Calcd for C 31 H 33 N0 8 S: C, 64.23; H, 5.74; N, 2.42. Found: C, 64.51; H, 5.93, N, 2.28. N-l(lR,2R.35 l .4S.5S.6A)-2-lBenzori.31dioxolo-5-carbonyloxy')-4.5(isopropylidenedioxv)-7-oxa-bicvclor4.1.01hept-3-yn-4’-methylbenzenesulfonamide 13301 To a refluxing suspension of potassium piperonylate (2.0 g, 9.8 mmol) and 18-crown-6 in DME (25 mL) was added a solution of epoxyaziridines 319a-b (801 mg, 2.49 mmol) in DME (10 mL) over a period of 12 hours. The reaction was stirred at reflux for an additional 6 hours. The reaction was quenched with water, and the reaction mixture was extracted with ethyl acetate (4 x 75 mL). The combined organic extracts were dried over Na 2 S0 4 and the solvent removed under reduced pressure. The remaining residue was purified by chromatography (silica gel, 3:1 hexanes/ethyl acetate) to provide tosylamide 330 (343 mg, 28 %) as an oil: R f 0.34 (2:1 hexanes/ethyl acetate); [a] D 26 +41.6 (c 1.0, CHC1 3 ); IR (neat) v 3300, 1718, 1508, 1490, 1260, 1161, 1074 cm 1 ; 'H NMR (300 MHz, CDC1 3 ) § 7.80 (d, J = 7.9 Hz, 2H), 7.64 (dd, J = 8.2, 1.5 Hz, 1H), 7.44 (m, 1H), 7.31 (d, J = 8.2 Hz, 2H), 7.27 (s, 1H), 6.83 (d, J = 8.2 Hz, 1H), 6.05 (s, 2H), 5.17 (d, J = 10.4 Hz, 1H), 5.07 (s, 1H), 4.58 (d, J = 6.1 Hz, 1H), 4.31 (m, 1H), 4.03 (dd, J = 10.7, 2.8 Hz, 1H), 3.42 (m, 1H), 3.27 (m, 1H), 2.43 (s, 3H), 1.47 (s, 3H), 1.35 (s, 3H); 13 C NMR (75 MHz, CDC1 3 ) § 164.3, 152.1, 147.7, 143.7, 137.7, 129.8, 126.9, 125.9, 123.1, 109.9, 109.7, 108.0, 101.9, 73.5, 69.2, 66.5, 52.6, 52.1, 49.1, 27.4, 25.0, 21.5; HRMS (FAB) calcd for C 24 H 26 N0 9 S 504.1328, found 504.1326.

PAGE 150

139 N-Benzyl-N-KlR.2/L35'.45'.55'.6S)-2-(BenzorL31dioxolo-5-carbonyloxy)-4.5(isopropvlidenedioxy)-7-oxa-bicyclo[4.1.01hept-3-yn-4’-methylbenzenesulfonamide (331) To a suspension of NaH (7.2 mg, 60 % reagent, 0.18 mmol) in THF (1 mL) was added a solution of tosylamide 330 (91 mg, 0.81 mmol) in THF (1 mL). The resulting solution was stirred for 20 minutes after which benzyl bromide (33 pL, 0.27 mmol) was added dropwise followed by a catalytic amount of tetrabutylammonium iodide. The reaction was stirred for 48 hours and then quenched with water. The organic and aqueous phases were separated and, the aqueous phase was extracted with ethyl acetate (4 x 20 mL). The combined organic extracts were dried over MgS0 4 and concentrated in vacuo. The residue was purified by chromatography (silica gel, 5:1 hexanes/ethyl acetate) to give tosylamide 331 (86 mg, 80 %) as an oil: R f 0.44 (3: 1 hexanes/ethyl acetate); [a] D 25 + 19.7 (c 1.0, CHC1 3 ); IR (neat) v 1718, 1491, 1260, 1160, 1037 cm 1 ; 'H NMR (300 MHz, CDCI3) 5 7.85 (d, J = 7.8 Hz, 1H), 7.78 (d, J = 7.8 Hz, 2H), 7.65 (s, 1H), 7.17-7.07 (m, 7H), 6.91 (d, J = 8.4 Hz, 1H), 6.07 (s, 2H), 4.64-4.47 (m, 3H), 4.32 (ABq, J = 15. 9 Hz, 2H), 4.10 (m, 1H), 3.42 (d, J =3.0 Hz, 1H), 3.29 (d, J = 3.0 Hz, 1H), 2.35 (s, 3H), 1.57 (s, 3H), 1.40 (s, 3H); 13 C NMR (75 MHz, CDC1 3 ) 5 164.9, 152.0, 147.8, 143.0, 137.8, 135.6, 129.1, 128.5, 128.4, 128.0, 127.9, 126.4, 123.2, 110.4, 110.1, 108.1, 101.8, 72.7, 72.1, 68.0, 58.8, 57.7, 52.1, 48.4, 27.6, 25.6, 21.4; HRMS (Cl) calcd for C 31 H 32 N0 9 S 594.1798, found 594.1795. (15.2i?.35.4/?.55'.6i?yi-hvdroxy-2.3-(isopropylidenedioxy)-4-[N-benzyl-(4’methylphenylsulfonvnaminol-2.3.4.4a.6.1 lb-hexahydro-lH-5.8.10-trioxacvclopentarblphenanthrene (332a) A solution of epoxide 327 (210 mg, 0.36 mmol) in CH 2 C1 2 (25 mL) at -25 °C was treated with a 1 .0 M solution of Me 2 AlCl in hexanes (400 pL, 0.4 mmol) and stirred at -25 °C

PAGE 151

140 for 2 hours. The reaction was quenched with saturated NH 4 C1 solution, and the reaction mixture was extracted with CH 2 C1 2 (4 x 20 mL). The combined organic extracts were dried over MgS0 4 and the solvent removed under reduced pressure. The remaining residue was purified by chromatography (silica gel, 4:1 hexanes/ethyl acetate) to furnish tosylamide 332a (161 mg, 77 %) as a white solid: R f 0.44 (1:1 hexanes/ethyl acetate); m.p. 114-116 °C; [ot] 27 D -49.0 (c 1.0, CHC1 3 ); IR (KBr) v 3504, 1484, 1329, 1238, 1156, 1038 cm 1 ; 'H NMR (500 MHz, CDC1 3 ) 5 7.83 (d, J = 7.8 Hz, 2H), 7.26 (d, J = 9.0 Hz, 2H), 7.19 (m, 5H), 6.75 (s, 1H), 6.43 (S, 1H), 5.89 (s, 2H), 4.75 (dd, J = 9.7, 7.4 Hz, 1H), 4.58 (d, J = 15.1 Hz, 1H), 4.55-4.43 (m, 3H), 4.28 (t, J = 7.4 Hz, 1H), 4.21 (dd, J = 5.9, 4.5 Hz, 1H), 3.89 (dd, J = 11.2, 7.1 Hz, 1H), 3.69 (dd, J =9.4, 6.6 Hz, 1H), 2.47 (dd, J = 11.6, 4.2 Hz, 1H), 2.42 (s, 3H), 1.92 (s, 1H), 1.30 (m, 6H); 13 C NMR (75 MHz, CDC1 3 ) 8 146.8, 145.9, 143.2, 137.9, 136.1, 129.3, 128.7, 128.2, 128.1, 127.8, 127.6, 123.4, 111.1, 109.8, 104.1, 100.9, 81.0, 75.9, 73.3, 70.9, 67.4, 64.3, 52.4, 39.8, 27.1, 25.0, 21.5; HRMS (Cl) calcd for C 31 H 34 N0 8 S 580.2005, found 580.2001; Anal. Calcd for C 31 H 33 N0 8 S: C, 64.23; H, 5.74; N, 2.42. Found: C, 63.97; H, 5.87; N, 2.36. (15.2R.35.4R.55.6/?Vl-f?err-butoxycarbonyloxy)-2.3-(isopropylidenedioxy)-4-lN-benzyl(4’ -methylphenylsulfonvl N )aminol-2.3.4.4a.6. 1 1 b-hexahvdro1 H-5.8. 10-trioxacvclopentalblphenanthrene 1332b) To a suspension of NaH (35 mg, 60 % reagent, 0.88 mmol) in THF (5 mL) was added a solution of tosylamide 332a (354 mg, 0.611 mmol) in THF (8 mL). The resulting solution was allowed to stir for 20 minutes after which a solution of di-rm-butyl dicarbonate (202 mg, 0.926 mmol) in THF (3 mL) was added dropwise. The resulting solution was heated at reflux for 1.5 hours. After allowing the solution to cool to room temperature, the reaction was quenched with water and then diluted with ethyl acetate.

PAGE 152

141 Following separation of the organic and aqueous phases, the aqueous phase was extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were dried over MgS0 4 and then concentrated in vacuo. The resulting residue was purified by chromatography (silica gel, 1:1 hexanes/ethyl acetate) to provide carbonate 332b (355 mg, 86 %) as a white solid: R f 0.44 (2:1 hexanes/ethyl acetate); m.p. 197-198 °C; [a] 25 D -43.3 (c 1.0, CHC1 3 ); IR (KBr) v 1740, 1506, 1488, 1277, 1148, 1039 cm' 1 ; 'H NMR (300 MHz, CDCI 3 ) 5 7.85 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 7.22-7.13 (m, 5H), 6.61 (s, 1H), 6.42 (s, 1H), 5.89 (m, 1H), 5.81 (m, 1H), 5.00 (dd, J = 11.9, 7.4 Hz, 1H), 4.81 (m, 1H), 4.61 (ABq, J = 14.7 Hz, 2H), 4.47-4.44 (m, 3H), 4.28 (t, J = 4.7 Hz, 1H), 3.65 (m, 1H), 2.59 (dd, J = 12.2, 3.8 Hz, 1H), 2.43 (s, 3H), 1.29 (m, 12H), 1.22 (s, 3H); 13 C NMR (75 MHz, CDC1 3 ) 5 151.9, 146.7, 145.8, 143.3, 137.9, 135.9, 129.3, 128.9, 128.2, 127.8, 127.7, 123.1, 110.4, 109.9, 104.2, 100.7, 82.3, 78.3, 76.0, 75.4, 73.7, 67.4, 64.3, 52.5, 38.9, 27.4, 27.1, 25.1, 21.5; HRMS (FAB) calcd for C 36 H 42 NO 10 S 680.2529, found 680.2528; Anal. Calcd for C 36 H 41 NO 10 S: C, 63.61; H, 6.08; N, 2.06. Found: C, 63.78; H, 6.18; N, 2.04. ( 1 5.2R.35.4R.55.6RF4-benzvlamino1 -( fgrr-butoxycarbonyloxv)-2.3(isopropylidenedioxv V2.3,4.4a.6, 1 1 b-hexahvdro1 H-5.8. 1 0-trioxacvclopentalblphenanthrene (332c) A solution of tosylamide 332b (235 mg, 0.346 mmol) in DME (1.5 mL) cooled to -50 °C was treated with a 0.6 M solution of Na/naphthalene in DME until the color of the solution remained dark. The reaction was stirred at -50 °C for 15 minutes and then quenched with saturated NH 4 C1 solution. After separation of the organic and aqueous phases, the aqueous phase was extracted with ethyl acetate (3 x 35 mL). The combined organic extracts were dried over MgS0 4 and the solvent removed under reduced pressure.

PAGE 153

142 The remaining residue was purified by chromatography (silica gel, 3:1 hexanes/ethyl acetate) to give carbonate 332c (140 mg, 77 %) as a white solid: R f 0.21 (2:1 hexanes/ethyl acetate); m.p. 196-197 °C; [a] 26 D -53, 4 (c 1.0, CHC1 3 ); IR (KBr) v 3340, 1736, 1488, 1370, 1239, 1036 cm 1 ; 1 H NMR (300 MHz, CDC1 3 ) 5 7.26-7.17 (m, 5H), 6.60 (s, 1H), 6.39 (s, 1H), 5.83 (m, 1H), 5.74 (m, 1H), 5.07 (dd, J = 11.7, 7.8 Hz, 1H), 4.69 (Abq J = 14.7 Hz, 2H); 4.36 (t, J = 6.6 Hz, 1H), 4.12 (t, J = 6.6 Hz, 1H), 3.86 (m, 2H), 3.79 (t, J = 3.8 Hz, 1H), 3.12 (dd, J = 6.9, 4.2 Hz, 1H), 2.60 (dd, J = 1 1.4, 3.0 Hz, 1H), 1.69 (s, 1H); 1.36 (s, 3H), 1.27-1.26 (m, 12H); 13 C NMR (75 MHz, acetone) 5 153.1, 147.5, 146.6, 129.0, 128.9, 127.4, 125.6, 111.0, 109.9, 104.9, 101.6, 81.8, 78.6, 78.2, 77.8, 77.3, 68.4, 60.5, 52.6, 39.0, 28.1, 27.6, 26.0; HRMS (FAB) calcd for C 29 H 36 N0 8 526.2441, found 526.2477. (\S.2R.3SAR.5S.6R)-\ -hvdroxy-2. 3-(isopropvlidenedioxy)-6-(2’-methoxyethoxy)-4-[NbenzyI-(4’-methylphenylsulfonyl)aminol-2.3.4.4a,6.1 lb-hexahydro-lH-5.8.10-trioxacvclopentarblphenanthrene (337) A degassed solution of tosylamide 332a (320 mg, 0.55 mmol) and 2-methoxyethanol (0.33 mL, 4.2 mmol) in CH 2 C1 2 (25 mL) was treated with DDQ (188 mg, 0.828 mmol). The resulting solution was stirred at room temperature for 23 hours. The solvent was removed under reduced pressure and the remaining residue was purified by chromatography (silica gel, 2.5:2: 1 hexanes/ethyl acetate/triethylamine) to afford acetal 337 (282 mg, 78 %) as a white solid: RyO.31 (1:1 hexanes/ethyl acetate); m.p. 87-90 °C; [a] 27 D + 2.7 (c 1.0, CHC1 3 ); IR (KBr) v 3448, 1485, 1328, 1242, 1039 cm 1 ; 'H NMR (500 MHz, CDC1 3 ) 6 7.83 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.5 Hz, 2H), 7.19-7.13 (m, 5H), 6.72 (s, 1H), 6.69 (s, 1H), 5.91 (m, 2H), 5.46 (s, 1H), 4.73-4.62 (m, 2H), 4.44 (ABq, J = 15.3 Hz, 2H), 4.30 (t, J = 7.3 Hz, 1H), 3.93-3.86 (m, 3H), 3.71-3.59 (m, 3H), 3.43 (s,

PAGE 154

143 3H), 2.42 (s, 3H), 2.38 (d, J = 12.0 Hz, 1H), 2.07 (s, 1H), 1.35-1.33 (m, 6H); 13 C NMR (75 MHz, CDC1 3 ) 5 147.2, 146.9, 143.1, 137.8, 135.7, 129.2, 129.0, 128.2, 128.0, 127.7, 127.3, 124.5, 110.5, 109.8, 107.1, 101.0, 96.8, 81.1, 73.7, 72.0, 69.7, 68.3, 67.2, 63.6, 59.0, 52.5, 39.6, 27.1, 24.9, 21.5; HRMS (FAB) calcd for C 34 H 40 NO 10 S 654.2373, found 654.2409. (lS.2/L3S.4.R.5S.6./?)-l -hydroxv-2. 3-(isopropylidenedioxv)-4-rN-benzyl-(4’methylphenylsulfonyl)aminol2.3.4.4a.6.1 lb-hexahydro-lH-5.8.10-trioxacyclopentarblphenanthren-6-one ( 338 ) A solution of acetal 337 (158 mg, 0.242 mmol) in 30 % aqueous THF (3.4 mL) was treated with CSA (56 mg, 0.24 mmol) and stirred at room temperature for 17 hours. The solution was then diluted with ethyl acetate and washed successively with saturated NaHC0 3 solution, water, and brine. The organic layer was dried over NajSCb and then concentrated in vacuo. To a solution of the remaining residue in CH 2 C1 2 (8 mL) along with several 3 A molecular sieves was added PCC (85 mg, 0.39 mmol). The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was then filtered over Celite which was subsequently washed with several portions of CH 2 C1 2 . Removal of the solvent under reduced pressure and purification of the residue by chromatography (silica gel, 1 : 1 hexanes/ethyl acetate) provided lactone 338 (98 mg, 68 %) as a white solid: R f 0.29 (1:1 hexanes/ethyl acetate); m.p. 145-148 °C; [a] 28 D -45.1 (c 1.0, CHClj); IR (KBr) v 3483, 1719, 1483, 1326, 1259, 1156, 1039 cm' 1 ; 'H NMR (300 MHz, CDCl,) 5 7.86 (d, J = 8.4 Hz, 2H), 7.48 (s, 1H), 7.32 (d, J = 8.1 Hz, 2H), 7.24-7.14 (m, 5H), 6.72 (s, 1H), 6.05 (m, 2H), 5.24 (t, J = 4.5 Hz, 1H), 4.88 (t, J = 8.0 Hz, 1H), 4.45 (ABq J = 15.3 Hz, 2H), 4.33 (t, J = 7.2 Hz, 1H), 3.92 (m, 1H), 3.78 (dd, J = 8.3, 5.0 Hz, 1H), 2.86 (dd, J = 11.6, 4.1 Hz, 1H), 2.44 (s, 3H), 2.04 (bs, 1H), 1.31 (s, 3H), 1.21 (s,

PAGE 155

144 3H); 13 C NMR (75 MHz, CDC1 3 ) 5 162.9, 152.1, 148.1, 143.9, 137.0, 135.1, 133.3, 129.6, 128.9, 128.5, 128.0, 127.9, 117.7, 109.8, 109.7, 109.2, 102.1,80.8,79.7, 74.4, 69.2, 63.4, 52.6, 40.3, 27.1, 25.1, 21.5; HRMS (Cl) calcd for C 31 H 32 N0 9 S 594.1798, found 594.1858. ( 15.2R.35.4R.55'.6/?V4-benzylamino-l-(rerr-butoxycarbonyloxyV2.3(isopropyIidenedioxy)-6-(2’ -methoxyethoxy)-2.3.4.4a.6. 1 lb-hexahvdro1 H-5,8. 10trioxa-cvclopentarblphenanthrene ( 344 ) To a suspension of NaH (12 mg, 0.50 mmol) in THF (5 mL) was added a solution of acetal 337 (208 mg, 0.319 mmol) in THF (8 mL). The resulting solution was stirred at room temperature for 20 minutes after which a solution of di-rert-butyl dicarbonate (105 mg, 0.481 mmol) in THF (2 mL) was added dropwise. The solution was heated at reflux for 5 hours. After allowing the solution to cool to room temperature, the reaction was quenched with water and then extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were dried over MgS0 4 and concentrated in vacuo. A solution of the remaining residue in DME (5 mL) cooled to -50 °C was treated with a 0.6 M solution of Na/naphthalene in DME until a dark color persisted. The resulting solution was stirred at -50 °C for 30 minutes and then quenched with water. After warming the solution to room temperature, the reaction mixture was extracted with ethyl acetate (3 x 25 mL), and the combined organic extracts were dried over MgS0 4 . Removal of the solvent under reduced pressure and purification of the residue by chromatography (silica gel, 3:1:1 hexanes/ethyl acetate/triethylamine) gave carbonate 344 (163 mg, 85 %) as a white foam: RyO.24 (1:1 hexanes/ethyl acetate); [a] 25 D +21.5 (c 1.0, CHC1 3 ) IR (KBr) v 3448, 1751, 1508, 1490, 1243, 1039 cm 1 ; ’H NMR (300 MHz, CDC1 3 ) 8 7.34-7.32 (m, 5H), 6.74 (s, 1H), 6.63 (s, 1H), 5.86 (d, J = 18.0 Hz, 2H), 5.64 (s, 1H), 5.09 (dd, J = 11.7, 7.8 Hz, 1H), 4.43-4.38 (m, 2H), 4.20 (t, J = 5.9 Hz, 1H), 4.01-3.82 (m, 4H), 3.58 (m, 2H), 3.34 (s, 3H),

PAGE 156

145 3.23 (dd, J = 6.7, 3.3 Hz, 1H), 2.64 (dd, J = 1 1 .6, 2.9 Hz, 1H), 1.69 (bs, 1H), 1.45 (s, 3H), 1.35 (s, 3H), 1.32 (s, 9H); ,3 C NMR (75 MHz, CDC1 3 ) 5 152.8, 147.7, 147.3, 140.3, 128.9, 128.7, 127.6, 126.6, 112.6, 110.2, 109.9, 108.1, 101.3,98.0, 82.6,78.0, 77.9,76.4, 72.4, 69.9, 68.0, 59.4, 59.2, 52.7, 38.8, 28.3, 27.9, 26.4; HRMS (FAB) calcd for C 32 H 42 NO 10 600.2809, found 600.2813. ( 1 S.2R.3S.4R.5S.6R)-4-benzylamino1 -( rgrr-butoxycarbonyloxyV2.3(isopropylidenedioxvV2.3.4.4a.6.1 lb-hexahydro-lH-5.8.10-trioxacyclopentalblphenanthrene-6-one ( 346 ) A solution of acetal 344 (204 mg, 0.340 mmol) in 30 % aqueous THF (13 mL) was treated with CSA (395 mg, 1.70 mmol) and stirred at room temperature for 21 hours. The solution was then diluted with ethyl acetate and washed successively with saturated NaHC0 3 solution, water, and brine. The organic layer was dried over Na 2 S0 4 and then concentrated in vacuo. To a solution of the remaining residue in CH 2 C1 2 (9 mL) along with several 3 A molecular sieves was added PCC (1 12 mg, 0.520 mmol). The resulting solution was stirred at room temperature for 3 hours. The reaction mixture was then filtered over Celite which was subsequently washed with several portions of CH 3 OH. Removal of the solvent under reduced pressure and purification of the residue by chromatography (silica gel, 1:1 hexanes/ethyl acetate) provided lactone 346 (131 mg, 72 %) as a white solid: Rj.0.23 (1:1 hexanes/ethyl acetate); m.p. 201-203 °C; [a] 27 D -28.1 (c 1.0, CHC1 3 ); IR (KBr) v 3318, 1733, 1702, 1501, 1485, 1260, 1038 cm 1 ; 'H NMR (500 MHz, CDC1 3 ) 6 7.55 (s, 1H), 7.33-7.26 (m, 5H), 6.72 (s, 1H), 6.05 (m, 1H), 5.96 (m, 1H), 5.07 (dd, J = 11.5, 7.5 Hz, 1H), 4.72 (t, J = 3.5 Hz, 1H), 4.40 (dd, J = 7.5, 5.8 Hz, 1H), 4.22 (t, J = 5.4 Hz, 1H), 3.94 (ABq, J = 12.9 Hz, 2H), 3.48 (dd, J = 5.0, 3.4 Hz, 1H), 2.99 (dd, J = 11.5, 3.4 Hz, 1H), 1.63 (bs, 1H), 1.43 (s, 3H), 1.36 (s, 3H), 1.30 (s, 9H); 13 C

PAGE 157

146 NMR (75 MHz, CDC1 3 ) 6 163.5, 152.2, 152.1, 148.1, 139.6, 134.6, 128.8, 128.4, 127.6, 1 18.9, 1 10.3, 1 10.2, 108.7, 102.2, 82.9, 79.3, 77.4, 76.9, 75.2, 58.3, 52.7, 38.8, 28.1, 27.6, 26.2; HRMS (FAB) calcd for C 29 H 34 N0 9 540.2234, found 540.2238. ( 1 5 l .2/?.3S.4R.5S.6R')-4-benzylamino1 .2.3-trihydroxy-2.3 ,4,4a.6. 1 1 b-hexahvdro1 H5.8.10-trioxa-cyclopentafblphenanthrene-6-one (3491 A solution of carbonate 346 (17.5 mg, 0.0295 mmol) in 3:2 MeOH/H 2 0 (3.5 mL) was treated with a catalytic amount of sodium benzoate and heated at reflux for 17 hours. After allowing the solution to cool to ambient temperature, the reaction mixture was extracted with ethyl acetate (4x15 mL). The combined organic extracts were dried over Na 2 S0 4 and the solvent removed under reduced pressure. The resulting residue was dissolved in MeOH (1.2 mL) to which excess p-toluenesulfonic acid (95 mg, 0.50 mmol) was added. The resulting solution was stirred at room temperature for 38 hours. The reaction mixture was concentrated in vacuo and then diluted with ethyl acetate. The organic phase was washed with saturated NaHC0 3 solution. Following separation of the aqueous and organic phases, the aqueous phase was extracted with ethyl acetate (4 x 25 mL). The combined organic extracts were dried over Na 2 S0 4 and the solvent removed under reduced pressure. The remainder was purified by chromatography (silica gel, 9:1 CHCl 3 /MeOH) to give diol 349 (9.9 mg, 84 % over two steps) as a white solid: R f 0.28 (9:1 CHCl 3 /MeOH); m.p. 173-176 °C (dec.); [a] 26 D -81.0 (c 1.0, CHC1 3 ); IR (KBr) v 3417, 1703, 1503, 1482, 1260, 1034 cm '; 'H NMR (500 MHz, acetone) 5 7.38 (d, J = 7.4 Hz, 2H), 7.32 (s, 1H), 7.29 (t, J = 7.4 Hz, 2H), 7.21 (t, J = 7.4 Hz, 1H), 6.89 (s, 1H), 6.10 (m, 2H), 4.75 (td, J = 2.9, 1.3 Hz, 1H), 4.14 (m, 1H), 3.91 (ABq, J = 14.0 Hz, 2H), 3.85 (m, 2H), 3.68-3.38 (m, 4H); 3.32 (t, J = 2.6 Hz, 1H), 3.1 1 (m, 1H); 13 C NMR (75 MHz,

PAGE 158

147 CDC1 3 ) 8 164.8, 152.0, 147.5, 137.8, 129.8, 128.5, 128.3, 128.1, 117.2, 109.7, 108.9, 101.9, 78.7, 72.8, 69.8, 59.4, 52.3, 41.1; HRMS (FAB) calcd for C 21 H 22 N0 7 400.1396, found 400.1312. ( 1 S.2R.3SARAeiS. 1 1 bi?)-2-benzylamino1 .3.4-trihvdroxy1 ,2.3.4.4a. 1 1 b-hexahvdro1 H5.8.10-trioxa-cyclopentarblphenanthrene-6-one ( 350 ) A solution of triol 349 (43 mg, 0.1 1 mmol) in MeOH (4 mL) was treated with K,C0 3 (31 mg, 0.22 mmol) and then heated at reflux for 13 hours. The reaction was quenched with saturated NH 4 C1 solution and then diluted with ethyl acetate. The organic and aqueous phases were separated, and the aqueous phase was extracted with ethyl acetate (4 x 30 mL). The combined organic extracts were dried over Na 2 S0 4 and the solvent removed under reduced pressure. The remaining residue was purified by chromatography (silica gel, 9:1 CHCl 3 /MeOH) to give triol 350 (19 mg, 44 %) as a thin film: R f 0.42 (9:1 CHCl 3 MeOH); [oc] 25 D -60.4 (c 1.0, CHC1 3 ); IR (neat) v 3410, 1690, 1484, 1261, 1026 cm' 'H NMR (500 MHz, acetone) 6 7.40 (d, J = 7.2 Hz, 2H), 7.36 (s, 1H), 7.30 (t, J = 7.7 Hz, 2H), 7.22 (t, J = 7.2 Hz, 1H), 6.94 (d, J = 0.8 Hz, 1H), 6.10 (m, 2H), 4.68 (s, 1H), 4.58 (dd, J = 12.2, 9.4 Hz, 1H), 4.37 (s, 1H), 4.27 (td, J = 3.2, 1.3 Hz, 1H), 4.22 (dd, J = 9.4, 3.2 Hz, 1H), 3.91 (s, 2H), 3.45 (ddd, J = 12.3, 2.6, 0.7 Hz, 1H), 3.38 (t, J = 2.8 Hz, 1H), 3.0-2.62 (m, 3H); i3 C NMR (126 MHz, acetone) 5 163.8, 152.5, 147.0, 140.8, 138.0, 128.3, 126.9, 120.1, 108.7, 105.6, 102.3, 78.5, 74.2, 70.3, 69.1, 60.3, 52.0, 39.7; HRMS (FAB) calcd for C 21 H 22 N0 7 400.1396, found 400.1379.

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148 (IS, 2R, 3S, 4R, 4aS, 1 lbR)-2-benzylamino-1.3.4-triacetoxy-1.2,3.4.4a.llb-hexahydrolH-5,8,10-trioxa-cvclopentarblphenanthrene-6-one ( 352 ) A solution of triol 350 (8.2 mg, 0.016 mmol) in pyridine (0.25 ml) was treated with neat acetic anhydride (58 |lL, 0.61 mmol) followed by a catalytic amount of DMAP. The reaction was stirred for 32 hours. The solvent was removed and the remainder purified by chromatography (silica gel, 1:1 hexanes/ethyl acetate) to give triacetate 352 (6.6 mg, 61 %) as an oil: R f 0.44 (1:1 hexanes/ethyl acetate); [a] 26 D -16.2 (c 1.0, CHC1 3 ); IR (neat) v 3441, 1742, 1505, 1485, 1372, 1230, 1040 cm 1 ; 'H NMR (300 MHz, CDC1 3 ) 5 7.54 (s, 1H), 7.38-7.28 (m, 5H), 6.40 (s, 1H), 6.06 (m, 2H), 5.61-5.56 (m, 2H), 5.52 (m, 1H), 4.91 (dd, J = 12.2, 20.7 Hz, 1H), 3.96 (ABq, J = 13.2 Hz, 2H); 3.77 (dd, J = 12.3, 3.0 Hz, 1H), 3.30 (t, J = 2.6 Hz, 1H), 2.10 (s, 3H), 2.05 (s, 3H), 1.98 (s, 3H), 1.7 Hz (bs, 1H); HRMS (FAB) calcd for C 27 H 28 NO 10 526.1713, found 526.1718. (IS, 2R, 3S, 4R, 4aS, 1 lbR)-2-acetyIamino-l,3,4-triacetoxy-1.2.3.4,4a.l lb-hexahvdrolH-5,8,10-trioxa-cvclopentarblphenanthrene-6-one (3531 A solution of triacetate 352 (5.7 mg, 0.01 1 mmol) and Pd(OH) 2 (25 mg) in MeOH (1.5 ml) was subjected to an atmosphere of hydrogen for 40 minutes. The reaction was filtered over Celite and the filtrate concentrated in vacuo. The remaining residue was dissolved in pyridine (0.15 mL) to which acetic anhydride (15 |iL, 0.16 mmol) was added followed by a cataytic amount of DMAP. The reaction was allowed to stir for 19 hours. The solvent was removed and the residue purified by chromatography (silica gel, 1:1 hexanes/ethyl acetate) to provide tetraacetate 353 (2.8 mg, 55 %) as a film: 'H NMR (300 MHz, CDC1 3 ) 6 7.44 (s, 1H), 6.99 (d, J = 8.1 Hz, 1H), 6.62 (s, 1H), 6.06 (m, 2H), 5.71 (s, 1H), 5.53-5.46 (m, 2H), 4.89 (dd, J = 12.2, 10.1 Hz, 1H), 4.54 (m, 1H), 3.53 (dd, J = 10.5, 1.8 Hz, 1H); 2.08 (m, 9H), 1.98 (s, 3H).

PAGE 160

149 N-i(l/?.2S.5/L66Â’)-2-(Benzoll.31dioxol-5-ylmethoxy)-5.6(isopropvlidenedioxy)cyclohex-3-en-l-yll-4Â’-methylbenzenesulfonamide (354) To a suspension of KH (108 mg, 2.69 mmol) in DME (3 mL) was added a solution of piperonol (378 mg, 2.49 mmol) in DME (5 mL). The resulting solution was allowed to stir for 20 minutes after which a solution of vinylaziridine 28 (228 mg, 0.710 mmol) in DME (3 mL) was added dropwise followed by 18-crown 6 (66 mg, 0.25 mmol). The reaction was stirred for 24 hours and then quenched with saturated NH 4 C1 solution. The reaction mixture was extracted with CH 2 C1 2 (4 x 50 mL) and the combined organic extracts dried over Na 2 S0 4 . The solvent was removed under reduced pressure and the remainder purified by chromatography (silica gel, 2: 1 hexanes/ethyl acetate) to furnish tosylamide 354 (223 mg, 56 %) as a white foam: R, 0.38 (1:1 hexanes/ethyl acetate); [a] D 29 -10.5 (c 1.0, CHC1 3 ); IR (neat) v 3269, 1503, 1599, 1492, 1445, 1326, 1251, 1156, 1094, 1039 cm 1 ; 'H NMR (500 MHz, CDC1 3 ) 6 7.80 (d, J = 8.3 Hz, 2H), 7.19 (d, J = 8.3 Hz, 2H), 6.73 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 1.6 Hz, 1H), 6.68 (dd, J = 7.9, 1.8 Hz, 1H), 5.94 (s, 2H), 5.88 (dd, J = 10.3, 1.0 Hz, 1H), 5.84 (ddd, J = 10.1, 3.2, 1.8 Hz, 1H), 5.10 (d, J = 7.4 Hz, 1H), 4.53 (dd, J = 6.3 Hz, 1H), 4.36 (d, J = 11.6 Hz, 1H),4.27 (d, J = 1 1.5 Hz, 1H), 4.05 (dd, J = 9.4, 6.1 Hz, 1H), 3.80 (dq, J = 9.2, 1.6 Hz, 1H), 3.55 (td, J = 9.2, 7.4 Hz, 1H), 2.37 (s, 3H), 1.36 (s, 3H), 1.29 (s, 3H); 13 C NMR (126 MHz, CDC1 3 ) 5 147.9, 147.2, 142.9, 139.0, 132.6, 131.9, 129.3, 127.6, 124.5, 121.6, 110.8, 109.0, 108.2, 101.0, 76.4, 75.7, 72.2, 70.8, 57.3, 27.8, 26.0, 21.7; HRMS (FAB) calcd for C 24 H 28 N0 7 S 474.1586, found 474.1587.

PAGE 161

150 N-Benzvl-N-K lR.2S.5R.6S)-2-(Benzo[ 1 .31dioxol-5-ylmethoxy)-5,6nsopropylidenedioxy)cyclohex-3-en-l-vn-4’-methvIbenzenesu]fonamide (355) To a suspension of NaH (10.8 mg of 60 % reagent, 0.270 mmol) in THF (2 mL) was added a solution of tosylamide 354 (117 mg, 0.208 mmol) in THF (5 mL). The resulting solution was stirred for 20 minutes after which benzyl bromide (36 |lL, 0.28 mmol) was added followed by a catalytic amount of tetrabutylammonium iodide. The solution was stirred for 18 hours and then quenched with water. The reaction was diluted with ethyl acetate and the aqueous and organic layers separated. The aqueous phase was extracted with ethyl acetate (4 x 40 mL) and the combined organic extracts dried over Na 2 S0 4 . Removal of the solvent in vacuo provided a residue which was purified by chromatography (silica gel, 3:1 hexanes/ethyl acetate) generating tosylamide 355 (114 mg, 84 %) as a solid: R f 0.21 (5:1 hexanes/ethyl acetate); m.p. 157-160 °C; [a] D 25 +3.2 (c 1.0, CHClj); IR (neat) v 1599, 1503, 1492, 1445, 1330, 1251, 1156, 1040 cm '; 'H NMR (300 MHz, CDC1 3 ) 6 7.86 (d, J = 8.1 Hz, 2H), 7.22-7.15 (m, 7H), 6.81-6.78 (m, 3H), 5.97-5.94 (m, 3H), 5.80 (d, J = 9.9 Hz, 1H), 4.57-4.31 (m, 6H), 2.40 (s, 3H), 1.32-1.25 (m, 6H); ,3 C NMR (75 MHz, CDC1 3 ) 8 147.6, 142.9, 138.1, 136.4, 133.0, 131.7, 129.1, 128.9, 128.2, 127.5, 123.0, 121.6, 112.0, 110.3, 108.9, 107.9, 100.9, 73.6, 72.7, 70.6, 27.5, 25.7, 21.5; HRMS (FAB) calcd for C 31 H 34 N0 7 S 564.2056, found 564.2099. N-BenzvI-N-l(lR.2R,35,45,55.65)-3.4-dihydroxy-5.6-(isopropylidenedioxy)-2-(3’.4’methylenedioxyphenvlmethvBcyclohex-l-yll^’-methylbenzenesulfonamide (3561 A solution of tosylamide 355 (16.2 mg, 0.0288 mmol) in 1:1 CH 3 CN/EtOAc (0.80 mL) at 0 °C was treated with a solution of NaI0 4 (10.1 mg, 0.0432 mmol) and RuC 1 3 H 2 0 in water (0.5 mL). The resulting solution was stirred at 0 °C for 3 minutes and then quenched with saturated Na 2 S 2 0 3 solution. The reaction mixture was extracted with

PAGE 162

151 CH 2 C1 2 (4 x 10 mL) and the combined organic extracts dried over Na 2 S0 4 . The solvent was removed under reduced pressure and the residue purified by chromatography (silica gel, 2:1 ethyl acetate/hexanes) to provide diol 356 (1 1.3 mg, 66 %) as a film: R f 0.34 (2:1 ethyl acetate/hexanes); [a] D 26 -27.9 (c 1.0, CHC1 3 ); IR (neat) v 3460, 1504, 1492, 1445, 1328, 1251, 1156, 1040 cm' 1 ; 'H NMR (300 MHz, acetone) 8 7.75 (d, J = 7.8 Hz, 2H), 7.24-7.15 (m, 7H), 6.88 (s, 1H); 6.80-6.78 (m, 2H), 6.00 (s, 2H), 4.60 (d, J = 11.1 Hz, 1H), 4.45-4.38 (m, 3H), 4.28-4.14 (m, 4H), 4.03-3.79 (m, 3H), 3.93 (bs, 1H), 2.38 (s, 3H), 1.28-1.24 (m, 6H); 13 C NMR (75 MHz, CDC1 3 ) 8 147.7, 147.3, 142.8, 138.3, 136.2, 131.8, 129.1, 128.8, 128.2, 128.0, 127.5, 122.1, 109.3, 109.2, 108.1, 101.0, 76.5, 73.0, 69.7, 27.4, 25.4, 21.4; HRMS (FAB) calcd for C 31 H 36 N0 9 S 598.21 11, found 598.2108. N-Benzyl-N-r(lR.2R.3R.45.55.65V3.4-dihydroxy-5.6-(isopropylidenedioxy)-2-(3Â’.4Â’methylenedioxyphenvImethyDcvclohex1 -vll-4Â’ -methvlbenzenesulfonamide (3571 A solution of epoxide 327 (17.2 mg, 0.0297 mmol) in a 1:1 mixture of 1 ,4-dioxane/H 2 0 (1 mL) was treated with KOH (16.7 mg, 0.297 mmol) and then heated at reflux for 48 hours. The reaction mixture was diluted with ethyl acetate and the organic and aqueous layers separated. The aqueous layer was extracted with ethyl acetate (4 x 20 mL) and the combined organic extracts dried over Na 2 S0 4 . Removal of the solvent under reduced pressure afforded a residue which was purified by chromatography (silica gel, 4: 1 ethyl acetate/hexanes) to give diol 357 (9.9 mg, 56 %) as a film: R f 0.36 (4:1 ethyl acetate/hexanes); [a] D 27 -35.4 (c 1.0, CHC1 3 ); IR (neat) v 3478, 1493, 1445, 1326, 1246, 1156, 1038 cm' 1 ; 'H NMR (300 MHz, CDC1 3 ) 8 7.82 (d, J = 8.1 Hz, 2H), 7.24-7.20 (m, 7H), 6.76-6.75 (m, 3H), 5.97 (s, 2H), 4.48 (m, 2H), 4.38-4.24 (m, 3H), 4.10-4.06 (m, 2H), 3.98-3.90 (m, 2H), 3.73 (t, J = 6.0 Hz, 1H), 2.42 (s, 3H), 1.35 (s, 3H), 1.25 (s, 3H); 13 C

PAGE 163

152 NMR (75 MHz, CDC1 3 ) 8 147.7, 147.4, 143.1, 137.8, 136.3, 131.2, 129.2, 128.8, 128.4, 128.0, 127.7, 122.0, 109.5, 109.1, 108.1, 101.0, 77.8, 75.3, 74.1, 72.5, 70.5, 69.4, 61.0, 50.9, 27.4, 25.2, 21.5; HRMS (FAB) calcd for C 31 H 35 N0 9 S + Na 620.1930, found 620.1910. (2R.3R.4S.5R)-2-(Benzori.31-dioxol-5-ylmethoxy)-3-(N-benzyl-(4’methylphenylsulfonyPaminoV 1 .6-dihydroxy-4.5-(isopropylidenedioxy)hexane OSS') A solution of diol 356 (21.1 mg, 0.0353 mmol) in 40 % aqueous acetone (2 mL) was treated with a solution of NaI0 4 (10.2 mg, 0.0477 mmol) in water (0.2 mL) and stirred at room temperature for three hours. The reaction mixture was concentrated in vacuo and the resulting solution was extracted with ethyl acetate (4 x 25 mL). The combined organic extracts were dried over Na 2 S0 4 and the solvent removed under reduced pressure. The remaining residue was dissolved in MeOH (1 mL) and cooled to 0 °C after which neat NaBH 4 was added. The solution was slowly warmed to room temperature and was stirred for 18 hours. The reaction mixture was treated with water and then concentrated in vacuo. The remaining solution was extracted with ethyl acetate (4 x 20 mL) and the combined organic extracts dried over Na 2 S0 4 . Removal of the solvent under reduced pressure gave a residue which was purified by chromatography (silica gel, 2:1 ethyl acetate/hexanes) furnishing diol 358 (11.1 mg, 52 %) as a film: R f 0.30 (2:1 ethyl acetate/hexanes); [a] D 25 + 66.8 (c 1.0, CHC1 3 ); IR (neat) v 3501, 1503, 1491, 1445, 1332, 1251, 1157, 1039 cm 1 ; ’H NMR (300 MHz, CDC1 3 ) 8 7.56 (d, J = 8. 1 Hz, 2H); 7.36-7.34 (m, 2H), 7.21-1.15 (m, 5H), 6.73 (d, J = 8.7 Hz, 1H), 6.62-6.60 (m, 2H), 5.93 (m, 2H), 4.60 (d, J = 15.9 Hz, 1H), 4.39-4.27 (m, 4H), 4.13 (d, J = 11.7 Hz, 1H), 3.93 (m, 1H), 3.69-3.58 (m, 2H), 3.44-3.40 (m, 4H), 2.37 (s, 3H), 2.03 (bs, 1H), 1.13 (s, 3H), 1.0 (s,

PAGE 164

153 3H); 13 C NMR (75 MHz, CDC1 3 ) 5 147.8, 147.5, 143.0, 138.1, 137.0, 131.2, 128.8, 128.0, 127.7, 126.8, 121.9, 108.8, 108.0, 107.9, 101.1, 78.5, 73.2, 72.3, 61.2, 58.9, 55.2, 49.6, 27.7, 25.0, 21.4; HRMS (FAB) calcd for C 31 H 38 N0 9 S 600.2267, found 600.2264. (Note: An analagous procedure can be applied to diol 357 which also affords diol 358 ). t liS'.25.35.45.55.6R')-2.3-dihydroxy-4.5-(isopropylidenedioxy)-7-(4’methylphenylsulfonvl)-7-azabicyclo|~4. 1 .0~)heptane ( 359 ) A solution of vinylaziridine 28 (595 mg, 1.85 mmol) in a 1:1 mixture of CH 3 CN/EtOAc (50 mL) at 0 °C was treated with a solution of NaI0 4 (595 mg, 2.78 mmol) and RuCl 3 3H 2 0 (32 mg, 0.15 mmol) in H 2 0 (4 mL). The solution was stirred at 0 °C for 3 minutes and then quenched with 20 % aqueous Na 2 S 2 0 3 solution (20 mL). The organic and aqueous layers were separated and the aqueous phase extracted with ethyl acetate (4 x 40 mL). The combined organic extracts were dried over Na 2 S0 4 and the solvent removed under reduced pressure. The remaining residue was purified by chromatography (silica gel, 1 : 1 hexanes/ethyl acetate) to afford diol 359 (296 mg, 45 %) as a white solid: R f 0.28 (1:1 hexanes/ethyl acetate); m.p.: 166-168 °C; [a] D 26 +6.6 (c 1.0, CHC1 3 ); IR (neat) v 3367, 1329, 1 173, 1056 cm' 1 ; ‘H NMR (300 MHz, acetone) 5 7.87 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 4.41-4.34 (m, 2H), 4.16 (m, 1H), 3.92 (m, 1H), 3.31 (d, J = 6.6 Hz, 1H), 3.24 (d, J = 9.9 Hz, 1H), 3.05 (d, J = 6.9 Hz, 1H), 2.46 (m, 3H), 1.39 (s, 3H), 1.28 (s, 3H); 13 C NMR (75 MHz, CDC1 3 ) 5 145.6, 133.5, 130.1, 128.0, 110.0, 76.9, 69.2, 68.2, 61.8, 45.2, 43.1, 27.2, 24.8, 21.7; HRMS (FAB) calcd for C ]6 H 22 N0 6 S 356.1168, found 356.1166; Anal. Calcd for C, 6 H 2l N0 6 S: C, 54.07; H, 5.96. Found: C, 54.04; H, 5.97.

PAGE 165

154 (lS,2/L3S,4S.5S,6R)-2-(benzovloxyV3-hydroxy-4,5-(isopropylidenedioxvV7-(4’methylphenysulfonyl)-7-azabicycoir4. 1 .Olheptane ( 361 ) A solution of diol 359 (323 mg, 0.909 mmol) in CH 2 C1 2 (15 mL) at 0 °C was treated with Et 3 N (1.1 mL, 7.9 mmol) followed by sulfuryl chloride (2.73 mL, 1.0 M solution in CH 2 C1 2 , 2.73 mmol) and slowly warmed to room temperature. The reaction was stirred for 5 hours and subsequently quenched with water. After separation of the organic and aqueous phases, the aqueous phase was extracted with CH 2 C1 2 (4 x 40 mL). The combined organic extracts were dried over Na 2 S0 4 and concentrated in vacuo. The remaining residue was purified by chromatography (5:1 hexanes/ethyl acetate) to provide cyclic sulfate 360 as a solid: R f 0.44 (3:1 hexanes/ethyl acetate); m.p.: 208-211 °C; [a] D 24 -51.8 (c 1.0, CHClj); IR (neat) v 1394, 1330, 1212, 1164, 1066 cm 1 ; *H NMR (300 MHz, CDC1 3 ) 8 7.83 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.2 Hz, 2H), 5.26 (m, 1H), 5.01 (d, J = 6.1 Hz, 1H), 4.62 (d, J = 5.6 Hz, 1H), 4.54 (d, J = 4.1 Hz, 1H), 3.54 (d, J = 6.4 Hz, 1H), 3.38 (dd, J = 6.1, 3.8 Hz, 1H), 2.46 (s, 3H), 1.43 (s, 3H), 1.37 (s, 3H); 13 C NMR (75 MHz, acetone) 8 146.2, 135.1, 130.7, 129.3, 1 1 1.3, 78.7, 78.0, 73.7, 69.9, 42.9, 38.6, 27.4, 25.3, 21.7; HRMS (Cl) calcd for C, 6 H 20 NO 8 S 2 418.0630, found 418.0639; Anal. Calcd for C 16 H 19 NO g S 2 : C, 46.04; H, 4.59. Found: C, 46.18; H, 4.49. A solution of crude sulfate 360 and ammonium benzoate (297 mg, 2.14 mmol) in DMF (7 mL) was heated at 70 °C for two hours. The solvent was removed under vacuum and the residue dissolved in THF (20 mL) to which H 2 0 (30 p.L) and concentrated H 2 S0 4 (30 pL) were added. The resulting solution was stirred at room temperature for one hour and then quenched with saturated NaHC0 3 solution (5 mL). The reaction mixture was diluted with ethyl acetate, and the organic and aqueous layers were separated. The aqueous phase was extracted with ethyl acetate (4 x 50 mL) and the combined organic

PAGE 166

155 extracts dried over Na 2 S0 4 . The remainder was purified by chromatography (silica gel, 3:1 hexanes/ethyl acetate) to provide alcohol 361 (213 mg, 51 %) as an oil: R f 0.26 (3:1 hexanes/ethyl acetate); [a] D 25 +41.6 (c 1.0, CHC1 3 ); IR (neat) v 3494, 1723, 1332, 1270, 1163, 1070 cm' 1 ; ‘H NMR (500 MHz, CDC1 3 ) 6 8.06 (d J = 8.0 Hz, 2H), 7.85 (d, J = 8.3 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1 H), 7.45 (t, J = 7.7 Hz, 2H), 7.40 (t, J = 7.9 Hz, 2H), 5.12 (d, J = 5.4 Hz, 1H), 4.56 (d, J = 6.1 Hz, 1H), 4.19 (t, J = 5.7 Hz, 1H), 3.96 (dt, J = 8.1, 5.4 Hz, 1H), 3.33 (m, 2H), 2.73 (d, J = 8.4 Hz, 1H), 2.48 (s, 3H), 1.52 (s, 3H), 1.36 (s, 3H); 13 C NMR (126 MHz, CDC1 3 ) 6 165.6, 145.7, 134.0, 133.7, 130.4, 130.1, 129.4, 128.7, 128.3, 110.2, 75.2, 70.5, 68.4, 68.1, 41.5, 39.7, 27.7, 25.3, 21.9; HRMS (FAB) calcd for C 23 H 26 N0 7 S 460.1430, found 460.1441. ( \S.2R. 35.45.55.6R)-2-(benzoyloxy)-3-r('fgrf-butyldimethylsilvl s )oxvl-4.5(isopropylidenedioxy)-7-(4’-methylphenysulfonylV7-azabicycoir4.1.01heptane ( 362 ) A solution of alcohol 361 (156 mg, 0.341 mmol) in CH 2 C1 2 (8 mL) was treated with imidazole (231 mg, 3.40 mmol) followed by tert-butyldimethylsilyl chloride (512 mg, 3.40 mmol). The reaction was stirred at room temperature for 17 hours. The reaction mixture was filtered over Celite and the filtrate concentrated in vacuo. The remaining residue was purified by chromatography (silica gel, 6:1 hexanes/ethyl acetate) to give benzoate 362 (158 mg, 81 %) as an oil: R f 0.47 (5:1 hexanes/ethyl acetate); [a] D 26 +20.9 (c 1.0, CHC1 3 ); IR (neat) v 1725, 1599, 1335, 1268, 1164 cm 1 ; ‘H NMR (300 MHz, CDC1 3 ) 8 8.04 (d, J = 8.4 Hz, 2H), 7.85 (d, J = 8.1 Hz, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.5 Hz, 2H), 7.37 (d, J = 8.7 Hz, 2H), 4.92 (m, 1H), 4.52 (m, 1H), 3.94-3.90 (m, 2H), 3.34 (d, J = 6.3 Hz, 1H), 3.10 (d, J = 6.0 Hz, 1H), 2.47 (s, 3H), 1.55 (s, 3H), 1.37 (s, 3H), 0.74 (s, 9H), 0.08 (s, 3H), -0.02 (s, 3H); 13 C NMR (76 MHz, CDC1 3 ) 5 165.2, 144.8,

PAGE 167

156 134.4, 133.3, 129.9 129.7, 129.3, 128.3, 128.0, 109.6, 76.5, 71.4, 70.9, 70.2, 42.8, 38.8, 28.0, 25.7, 25.5, 21.6, 17.8, -4.7, -4.9; HRMS (FAB) calcd for C 29 H 40 NO v SSi 574.2295, found 574.2293. (15'.2R.35'.45.55'.6R)-3-f(fgrr-butyldimethylsilyl)oxyl-2-hydroxy-4.5(isopropylidenedioxy)-7-(4’-methylphenysulfonyl)-7-azabicycoir4.1.01heptane (363) A solution of benzoate 362 (136 mg, 0.238 mmol) in THF (7 mL) was treated with a 0.5 M sodium methoxide solution (0.57 mL) in methanol. The reaction was stirred for 15 minutes and then quenched with saturated NH 4 C1 solution. The organic and aqueous layers were separated and the aqueous phase extracted with ethyl acetate (4 x 35 mL). The combined organic extracts were dried over Na 2 S0 4 and the solvent removed under reduced pressure. The remaining residue was purified by chromatography (silica gel, 5:1 hexanes/ethyl acetate) to afford alcohol 363 (54 mg, 48 %) as an oil: R f 0.23 (5:1 hexanes/ethyl acetate); [a] D 26 -5.8 (c 1.0, CHC1 3 ); IR (neat) v 3515, 1332, 1251, 1163 cm' ’; ‘H NMR (300 MHz, CDC1 3 ) 7.80 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 4.34 (d, J = 5.4 Hz, 1H), 3.97 (t, J = 5.3 Hz, 1H), 3.88 (t, J = 4.8 Hz, 1H), 3.69 (ddd, J = 9.1, 4.1, 1.4 Hz, 1H), 3.19 (d, J = 6.6 Hz, 1H), 3.04 (d, J = 6.6 Hz, 1H), 2.76 (d, J = 9.0 Hz, 1H), 2.44 (s, 3H), 1.49 (s, 3H), 1.32 (s, 3H), 0.82 (s, 9H), 0.05 (s, 3H), 0.02 (s, 3H); 13 C NMR (76 MHz, CDC1 3 ) 5 144.9, 134.9, 129.9, 128.2, 109.7, 76.1, 71.2, 70.3, 68.0, 42.2, 39.2, 28.1, 25.9, 25.8, 21.9, 18.1, -4.7, -4.8; HRMS (FAB) calcd for C 22 H 36 N0 6 SSi 470.2032, found 470.2020.

PAGE 168

APPENDIX SELECTED SPECTRA The 'H and 13 C or APT NMR spectra of selected compounds reported in Chapter 5 are shown in this appendix along with the proposed structures. 157

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ppm 158

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159

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220 ZOO ISO 160 140 1Z0 100 80 60 40 ZO ppm 187

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220 200 180 160 140 120 *1 0 O' 80 60 40 20 0 ppm 191

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REFERENCES 1. (a) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994 , 33, 599. (b) Tanner, D. Angew. Chem. 1994 , 1 06, 625. (c) Tanner, D. Pure Appl. Chem. 1993 , 65, 1319. (d) Hudlicky, T.; Seoane, G.; Price, J. D.; Gadamasetti, K. G. Synlett 1990 , 433. 2. (a) Dureault, A.; Greek, C.; Depezay, J. C. Tetrahedron Lett. 1986 , 27, 4157. (b) Legters, J.; Thijs, L.; Zwanenburg, B. Tetrahedron Lett. 1989 , 30, 4881. (c) Haddach, M.; Pastor, R.; Riess, J.G. Tetrahedron Lett. 1990 , 31, 1989. (d) Hashimoto, M.; Yamada, K.; Terashima, S. Chem. Lett. 1992 , 975. 3. (a) Satake, A.; Shimizu, I.; Yamamoto, A. Synlett 1995 , 64. (b) Ibuka, T.; Nakai, K.; Habashita, H.; Hotta, Y.; Fujii, N.; Mimura, N.; Miwa, Y.; Taga, T.; Yamamoto, Y. Angew. Chem., Int. Ed. Engl. 1994 , 33, 652. (c) Fujii, N.; Nakai, K.; Tamamura, H.; Otaka, A.; Mimura, N.; Miwa, Y.; Taga, T.; Yamamoto, Y.; Ibuka, T. J. Chem. Soc., Perkin Trans. 1 1995 , 1359. (d) Spears, G. W.; Nakanishi, K.; Ohfune, Y. Synlett 1991 , 91. (e) Tanner, D.; Somfai, P. Bioorg. Med. Chem. Lett. 1993 , 3, 2415. 4. (a) Hudlicky, T.; Reed, J. W. In Comprehensive Organic Synthesis', Trost, B. M.; Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 5, pp 899-970. (b) Ahman, J.; Somfai, P. J. Am. Chem. Soc. 1994 , 116, 9781. (c) Somfai, P.; Ahman, J. Tetrahedron Lett. 1995 , 36, 1953. (d) Ahman, J.; Somfai, P. Tetrahedron Lett. 1995 , 36, 303. 5. Hudlicky, T.; Tian, X.; Konigsberger, K.; Rouden, J. J. Org. Chem. 1994 , 59, 4037. 6. Hudlicky, T.; Rouden, J.; Luna, H. J. Org. Chem. 1993 , 58, 985. 7. (a) Rouden, J.; Hudlicky, T. J. Chem. Soc., Perkin Trans. 1 1993 , 1095. (b) Hudlicky, T.; Rouden, J.; Luna, H.; Allen, S. J. Am. Chem. Soc. 1994 , 116, 5099. 8. Hudlicky, T.; Natchus, M. J. Org. Chem. 1992, 57, 4740. 9. (a) Hudlicky, T.; Olivo, H. F.; McKibben, B. J. Am. Chem. Soc. 1994 , 116, 5108. (b) Hudlicky, T; Olivo, H. F. J. Am. Chem. Soc. 1992 , 114, 9694. 10. Hartwell, J. L. Lloydia 1967 , 30, 379. 11. Martin, S. F. In The Alkaoids, Brosii, A. R., Ed.; Academic Press: New York, 1987; Vol. XXX, pp 252-376. 221

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BIOGRAPHICAL SKETCH Stefan Schilling is the second of three brothers born to Peter and the late Inge Schilling in April of 1974 in Wurzburg, Germany. After moving to the United States with his family, Stefan was raised in Charleston, South Carolina, where he lived for over 20 years. Always wishing for the best, StefanÂ’s parents emphasized the importance of a good education from an early age. Accordingly, StefanÂ’s parents demanded academic excellence yet instilled a sense of humility with any accomplishments. After successfully completing grade school, Stefan attended Bishop England High School in Charleston, South Carolina, where he became interested in mathematics and in the sciences. Following completion of the high school curriculum, Stefan attended the College of Charleston that he majored in chemistry and graduated with honors. It was in the sophomore organic chemistry classes and in undergraduate research at the College of Charleston where Stefan began to take a keen interest in synthetic organic chemistry. In August of 1996, Stefan committed to attend the graduate program in chemistry at the University of Florida and worked under the direction of Dr. Tomas Hudlicky. Research in addition to course work at the graduate level was very fascinating but often difficult. Stefan successfully passed his qualifying examination in August of 1999 and was admitted as a candidate in the doctoral program in chemistry. Currently, Stefan is working towards his Ph.D. in organic chemistry under the direction of his research advisor, Dr. Tomas Hudlicky. His research centers around strategies for the synthesis of (+)-7-deoxypancratistatin as well as structurally related analogs. Upon receiving his 228

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229 Ph.D., Stefan plans to move to Raleigh, NC, where he plans to perform post-doctoral research at North Carolina State University under the supervision of Dr. Daniel Comins.

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I certify that I have read this study and that in my opinion it conforms to acceptable standards of scholarly presentation and is fully acceptable, in scope and quality, as a dissertation for the degree of Doctor of Philosophy. Tomas Hudlicky, Chairman Professor of Chemistry I certify that I have read this study and that in my opinion it conforms to acceptable standards of scholarly presentation and is fully acceptable, in scope and quality, as a dissertation for the degree of Doctor of Philosophy. Merle Battiste Professor of Chemistry I certify that I have read this study and that in my opinion it conforms to acceptable standards of scholarly presentation and is fully acceptable, in scope and quality, as a dissertation for the degree of Doctor of Philosophy. /c^‘ f William Dolbier Professor of Chemistry I certify that I have read this study and that in my opinion it conforms to acceptable standards of scholarly presentation and is fully acceptable, in scope and quality, as a dissertation for the degree of Doctor of Philosophy. V, Vaneica Young Associate Professor of Chemistry

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