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INTRAMOLECULAR CYCLIZATION REACTIONS OF AZIRIDINES WITH ALLYLSDLANES. APPLICATION TO TOTAL SYNTHESIS OF (-)- YOHIMBANE AND ENT-ALLOYOHIMBANE.

DISSERTATION

Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate

School of The Ohio State University

By

Punit P. Seth, B.S (Pharmacy).

*****

The Ohio State University

1999

Dissertation Committee: Approved by Professor Stephen C. Bergmeier, Advisor Professor Robert W. Curley Professor Nigel D. Priestley Advisor Professor Larry W. Robertson College of Pharmacy UMX Nimber: 9919911

UMI Microform 9919911 Copyright 1999, by UMI Company. All rights reserved.

This microform edition is protected against unauthorized copying under Title 17, United States Code.

UMI 300 North Zeeb Road Ann Arbor, MI 48103 ABSTRACT

Two novel reactions for asymmetric synthesis of nitrogen containing heterocycles were studied. More specifically, two modes of intramolecular cyclization between aziridine and allylsilanes were developed. In one mode, treatment of aziridine-allylsilanes with greater than a stoichiometric amount of BF 3*OEt 2 provided aminomethyl substituted carbocycles as the exclusive products (Sakurai reaction). The stereoselectivity of the reaction was found to be dependent on the length of the tether between the aziridine and the allylsilane. The synthetic utility of the intramolecular cyclization reaction was demonstrated by utilizing this reaction as a key step in the synthesis of (-)-yohimbane. In the second mode, treatment of aziridine-allylsilanes with a catalytic amount of

BF3*OEt 2 provided bicyclic pyrrolidines as the major products (3+2 annulation reaction). Once again the stereoselectivity was dependent on the length of the tether between the aziridine and the allylsilane. The nature of the silyl group was found to have a profound effect in improving the rate of 3+2 aimulation over that of the Sakurai reaction. The synthetic utility of the 3+2 aimulation was explored by using this reaction for the synthesis of potential ligands for nACh receptors. During the course of this work novel methods for the synthesis and deprotection of enantiopure iV-tosylaziridines were also developed.

u Dedicated to my family

ui ACKNOWLEDGMENTS

I wish to first thank my advisor. Dr. Stephen Bergmeier for his help and guidance. His constant support and encouragement are truly appreciated. I would like to thank Dr.

Priestley for all his help over the past five years. I would also like to thank my colleagues and firiends Abhi, Dionne, Susan, Kristjan, Dave, Manesh and Jignesh for their fiiendship.

A big thanks to Jim Mobley for his help with the HPLC, to Dr. Brueggemeier for letting me use their machine, to Dr. Doskoteh for his help with nOe experiments and to Kathy Brooks for all her help. I also wish to thank my mom, dad, my sisters Charu and ShaUee and other members of my family for their support and encouragement Finally, a big thanks to Aarti for being such a great and special fiiend.

IV VITA

May 30, 1972 ...... Bom - Bombay, India

1993...... B.S. Pharmacy, Bombay University 1993 - present ...... Graduate Teaching Assistant, The Ohio State University

PUBLICATIONS

Research Publications

1. Bergmeier, S.C.; Seth, P.P. Tetrahedron Lett., 1995, 36, 3793.

2. Bergmeier, S.C.; Seth, P.P. J. Org. Chem., 1997, 52, 2671.

FIELDS OF STUDY Major Field: Pharmacy TABLE OF CONTENTS

Page

Abstract ...... ii Dedication ...... iii Acknowledgments ...... iv

Vita...... V Table of contents ...... vi List of Tables ...... x List of Figures ...... xii List of Schemes ...... xiii Chapters:

I. REACTIONS OF AZIRIDINES WITH ALLYLSILANES...... 1 LI Introduction ...... I 1.2 Reactions of Allylsilanes ...... 3 1.2.1 Sakurai Reaction of AUylsUanes ...... 3 1.2.1.1 Stereochemical control in allylsilane reactions ...... 5 1.2.1.2 Reactions of allylsilanes with imines ...... 8 1.2.1.3 Reaction of allylsilanes with a,P-unsaturated systems ...... 9 1.2 .1.4 Reactions of allylsilanes with epoxides and aziridines 10 1.2.2 3+2 and 2+2 Aimulation Reactions of Allylsilanes...... 13 1.2.2.1 Mechanistic Rationale ...... 15 1.2.2.2 3+2 Annulation of allylsilanes with aldehydes ...... 16 1.2.2.3 Intramolecular 3+2 annulation of allylsilanes ...... 17 1.2.2.4 Effect of Silicon in Annulation Reaction ...... 18 vi 1.3 Reactions of Aziridines ...... 20 1.3.1 Nucleophiiic Ring Opening Reactions of Activated Aziridines ..... 2 1 1.3.1.1 Ring opening reactions of Af-sulfonyl aziridines with carbon nucleophiles ...... 21 1.3.1.2 Reactions of iV-acyl aziridines with carbon nucleophiles... 22 1.3.1.3 Reactions of ^-phosphinyl substituted aziridines ...... 23 1.3.1.4 Reactions of activated aziridines with heteroatom nucleophiles ...... 24 1.3.2 Ring Opening Reactions of Activated and Unactivated Aziridines in the presence of Lewis acids ...... 25 1.3.2.1 Reactions with carbon nucleophiles ...... 25 1.3.2.2 Reactions with heteroatom nucleophiles ...... 26 1.3.2.3 Reactions of N-acyl aziridines in the presence of azaphilic and oxophilic Lewis acids ...... 27 1.4 Intramolecular Aziridine-Allylsilane Cyclization Reactions ...... 28 1.4.1 Application of the Sakurai reaction of aziridine-allylsilanes for Rauwolfia alkaloid synthesis ...... 28 1.4.2 Synthetic applications of 3+2 annulation reactions of aziridine- allylsilanes ...... 30 1.5 Summary...... 32

2. SYNTHESIS AND REACTIVITY OF AZIRIDINE-ALLYLSILANES...... 33 2.1 Introduction ...... 33 2.2 Initial synthesis of aziridine-allylsilanes ...... 34 2.3 First generation synthesis of aziridine-allylsilanes via metal nitrenoids . 35 2.4 Regiochemistry in aziridine-allylsilane cyclizations ...... 38 2.5 Aziridine-allylsilane cyclizations ...... 39 2.6 Stereochemical determination ...... 40 2.6.1 n = 1 ...... 40 2.6.2 n = 2 ...... 41 2.7 Aziridine-allylsilane cyclization: Rationale for stereochemistry ...... 43 2.7.1 n = 1 ...... 43 2.7.2 n = 2 ...... 45 2.8 Second generation synthesis of aziridine allylsilanes via epoxides ...... 46 2.9 Third generation synthesis of aziridine-allylsilane via V-tosyl- O-tosyl-aziridinemethanols ...... 50 2.9.1 Synthesis of iV-tosyl-O-tosyl-aziridinemethanol ...... 52 2.9.2 Reactions of V-tosyl-O-tosyl-aziridinemethanol with Grignard and Organolithium reagents ...... 53 2.9.3 Reactions of Reactions of V-tosyl-O-tosyl-aziridinemethanol with Organocuprate reagents ...... 53 2.10 Determination of absolute configuration of aziridines synthesized via ring opening/closing reaction of V-tosyl-O-tosyl-aziridine- methanol ...... 55 2.1 1 Determination of ee of aziridines synthesized via ring opening/ closing reaction of V-tosyl-O-tosyl-aziridinemethanol...... 56 2.12 Reactions of V-tosyl-O-tosyl-aziridinemethanol with other organocuprate reagents ...... 59 2.13 Synthesis of aziridine-allylsilanes from V-tosyl-O-tosyl-aziridine methanol ...... 6 1 2.14 Reactions of differentially protected aziridinemethanols with organocuprate reagents ...... 63

vii 2.14.1 Reactions of /V-Cbz-O-TBS-aziridinemethanol with organocuprate reagents ...... 64 2.14.2 Reaction of Af-Boc-O-Ts-aziridinemethanol with organocuprate reagents ...... 65 2.14.3 Reaction of Af-Ns-O-TBS-aziridinemethanol with organocuprate reagents ...... 66 2.15 Deprotection of A/-sulfonylaziridines ...... 67 2.15.1 Deprotection of ^-tosylaziridine-allyIsilane using sodium/ naphthalenide ...... 68 2.15.2 Deprotection of A/-tosylaziridines containing an ether linkage 70 2.15.3 Deprotection of Af-tosylaziridine containing an ester or amide linkage ...... 71 2.15.4 Deprotection of Af-tosylaziridines containing an aromatic ring.... 73 2.15.5 Deprotection of Bicyclic AAtosylaziridines ...... 74 2.16 Summary...... 75 3. TOTAL SYNTHESIS OF (-)-YOHIMBANE AND ENT-ALLO YOHIMBANE...... 76 3.1 Introduction ...... 76 3.2 Retrosynthesis ...... 77 3.3 Synthesis of N-tosylaziridine-allylsilane ...... 79 3.3.1 Single step synthesis of aziridine-allylsilane ...... 80 3.3.2 Stepwise synthesis of aziridine-allylsilane ...... 80 3.4 Cyclization of aziridine-allylsilane ...... 81 3.5 Total synthesis of (-)-yohimbane and enr-alloyohimbane ...... 82 3.5.1 Alkylation of amino-olefin 287 ...... 82 3.51.1 Attepmted alkylation of amino-olefin 287 using bromide 288 ...... 83 3.5.1.2 Attempted alkylation of amino-olefin 287 by Mitsunobu reaction ...... 83 3.5.1.3 Attempted alkylation of amino-olefin 287 using acyl chloride ...... 84 3.5.1.4 Attempted alkylation of amino-olefin 287 by deprotection of tosyl group ...... 85 3.5.1.5 Attempted cyclization ofN-benzylaziridine-allylsilane to avoid alkylation of 287 ...... 86 3.5.1.6 Alkylation of 287 using mesylate 303 ...... 87 3.5.2 Hydroboration and oxidation of alkylated product 289 ...... 89 3.5.3 Deprotection of ester 307 ...... 92 3.5.4 Bischler-Napieralski reaction of lactam 309 ...... 93 3.6 Summary...... 94 4. 3+2 ANNULATION REACTION OF AZIRIDINES WITH ALLYLSILANES...... 95 4.1 3+2 Annulation: Exploratory studies ...... 95 4.2 3+2 Annulation using aziridine-trimethylallylsilanes ...... 98 4.3 3+2 Annulation using aziridine-phenyldimethylallylsilanes ...... 101 4.3.1 Retrosynthesis ...... 102 4.3.2 Preparation of PhMe 2SiCH2MgCl...... 102 4.3.3 Wenkert Coupling using PhMe 2SiCH2MgCl...... 103 4.3.4 Synthesis of aziridine-phenyldimethylallylsilanes ...... 104 4.3.4.1 Alternative synthesis of aziridine-phenyl

viii dimethylallyisilanes ...... 105 4.3.5 3+2 Annulations of aziridine-phenyldimethylallylsiianes ...... 106 4.4 3+2 Annulation: Stereochemical determination ...... 108 4.5 Stereochemical Rationale ...... 111 4.5.1 n = I ...... I l l 4.5.2 n = 2 ...... 113 4.6 Nicotinic receptor modulators ...... 114 4.7 Functionalization of bicyclic pyrrolidines ...... 116 4.7.1 Oxidation of phenyldimethylsilyl group ...... 116 4.7.2 Mitsunobu reaction ...... 117 4.7.3 Mesylation/displacement approach ...... 118 4.7.4 Deprotection of tosyl group ...... 119 4.8 Model studies using prolinol ...... 120 4.9 Alternate synthetic approach using N-Eoc protecting group ...... 121

5. CONCLUSIONS...... 123

6 . EXPERIMENTAL...... 127

UST OF REFERENCES...... 189 APPENDIX: NOE SPECTRA...... 198 1 Structure determination of 152a and 152b by nOe spectroscopy 199-201 2 Original NMR of 155 ...... 202 3 Structure determination of 155 by nOe spectroscopy ...... 203-204 4 Original NMR spectrum of 156 ...... 205 5 Structure determination of 156 by nOe spectroscopy ...... 206 6 Original NMR spectrum of 336a ...... 207 7 Structure determination of 336a by nOe spectroscopy ...... 208-210 8 Original NMR spectrum of 335a ...... 211 9 Structure determination of 335a by nOe spectroscopy ...... 212-213 10 Original NMR spectrum of 335b ...... 214 11 Structure determination of 335b by nOe spectroscopy ...... 215-216 12 NMR spectra of (-)-yohimbane ...... 217 13 0 (2 NMR spectra of (-)-yohimbane ...... 218 14 1H NMR spectra of enr-alloyohimbane ...... 219 15 0 (2 NMR spectra of enr-alloyohimbane ...... 220

IX LIST OF TABLES

Table Page

1.1 Silyl groups in annulation reactions ...... 19

2.1 Synthesis of epoxide 172 from aldehyde 171 ...... 49

2.2 Reactions of .V-Cbz-O-TBS aziridinemethanol with organocuprate reagents ...... 65

3.1 Attempted alkylation of 287 using bromide 288 and alcohol 294 under Mitsunobu conditions ...... 84

3.2 Attempted alkylation of 287 using acid chlorides ...... 85

3.3 Attempted conversion of alcohol 304 to carboxylic acid 306 ...... 90

3.4 Oxidation of aldehyde 305 to acid 306 ...... 91

4.1 3+2 annulation of aziridine-allylsilane 211 using different reaction conditions ...... 99

4.2 Results obtained from 3+2 annulation using aziridine-trimethyi allylsilanes ...... 100

4.3 Wenkert reaction of dihydropyran with PhMe 2 SiCH2MgCl using different Ni catalysts ...... 103

X 4.4 3+2 annulation of aziridine-allylsilane 334 using different reaction conditions ...... 106

4.5 3+2 aimulation of aziridine-allylsilane 334 using different Lewis acids...... 107

4.6 Results obtained from 3+2 annulation using aziridine-phenyldimethyl allylsilanes ...... 108

XI LIST OF FIGURES

Figure Page

1.1 Structures of some representative Rauwolfîa alkaloids ...... 29

2.1 Stereochemical determination of five membered carbocycles 152a and 152b ...... 40

2.2 Stereochemical determination of six membered carbocycles 153a and 153b ...... 41

2.3 NMR spectrum of 191 containing 5% (bottom) and 20% (top) of 206 ...... 58

3.1 Structures of (-)-yohimbane and enr-alloyohimbane ...... 76

4.1 Stereochemical determination of 336a using nOe spectroscopy ...... 108

4.2 Stereochemical determination of 335a using nOe spectroscopy ...... 109

4.3 Stereochemical determination of 335b using nOe spectroscopy ...... 110

4.4 Structures of some nicotinic receptor modulators ...... 114

4.5 SAR of nicotinic receptor modulators ...... 115

xii LIST OF SCHEMES

Scheme Page

1.1 Intramolecular cyclization reactions between aziridines and allylsilanes.... 2

1.2 All reaction pathways involving allylsilanes ...... 3

1.3 Sakurai reaction of allylsilanes ...... 4

1.4 Mechanism of Sakurai reaction ...... 5

1.5 Conformations of an allylsilane during reaction with an electrophile ...... 5

1.6 Reactions of E and Z allylsilanes with MCPBA ...... 6

1.7 Reaction of substituted Z allylsilane with MCPBA ...... 7

1.8 Antiperiplanar vs. synclinal transition states in reactions of allylsilanes ...... 8

1.9 Reactions of allylsilanes with iminium ions ...... 9

1.10 Intramolecular reaction of an allylsilane with an enone ...... 10

1.11 Intermolecular reactions of allylsilanes with epoxides and aziridines 11

1.12 Intramolecular Reactions of allylsilanes with epoxides ...... 12

xiii 1.13 Sakurai and 2+2 reactions of allylsilanes ...... 13

1.14 3+2 annulation reaction of allylsilanes ...... 14

1.15 3+2 vs 2+2 annulation of allylsilanes with enones ...... 14

1.16 Siliranium ions in annulation reactions of allylsilanes ...... 15

1.17 1,2-silyl shift in annulation reactions of allylsilanes ...... 16

1.18 3+2 annulation of a chiral crotylsilane with an aldehyde ...... 17

1.19 Intramolecular 3+2 annulation of allylsilanes with electrophiles...... 18

1.20 Effect of silicon in annulation reactions of allylsilanes ...... 19

1.21 Ring opening reactions of activated aziridines ...... 21

1.22 Ring opening reactions of N-tosy 1 aziridines ...... 22

1.23 Reactions of iV-acyl aziridines with carbon nucleophiles ...... 23

1.24 Reactions of iV^phosphinyl aziridines with organometallic reagents ...... 24

1.25 Reactions of activated aziridines with heteroatom nucleophiles ...... 24

1.26 Ring opening reaction of an aziridine promoted by a Lewis acid ...... 25

1.27 Reaction of aziridines requiring prior activation with a Lewis acid ...... 26

1.28 Reactions of activated aziridines with heteroatoms requiring Lewis acid activation ...... 26

1.29 Reactions of iV-acyl aziridines with azaphilic and oxophilic Lewis acids.. 27 xiv 1.30 Intramolecular cyclization between aziridines and allylsilanes ...... 28

1.31 Synthesis of rauwolfia alkaloids mediated by aziridine-allylsilanes ...... 30

1.32 Applications of 3+2 annulation reaction of aziridines with allylsilanes 31

2.1 Synthetic routes to aziridine-allylsilanes via aldehydes ...... 33

2.2 Initial synthesis of aziridine-allylsilanes via epoxides ...... 34

2.3 Synthesis of iV-tosyl aziridine-aldehyde via metal nitrenoids ...... 35

2.4 Synthesis of aziridine-allylsilanes using Flem ing’s procedure ...... 37

2.5 Synthesis of aziridine-allylsilanes starting firom pentanediol ...... 38

2.6 Regiochemical possibilities in reactions of aziridines with allylsilanes 39

2.7 Results from intramolecular Sakurai reaction of aziridines with allylsilane ...... 40

2.8 Stereochemical determination of lactams 155 and 156 ...... 42

2.9 Stereochemical rationale for formation of five membered carbocycles 152a and 152b ...... 44

2.10 Stereochemical rationale for formation of six membered carbocycles 153a and 153b ...... 45

2.11 Retrosynthesis of aziridine-allylsilanes via epoxides ...... 47

2.12 Synthesis of aziridine-allylsilanes via epoxides ...... 48

2.13 Possible pathways in reactions of aziridine 176 with organometallic reagents ...... 51

XV 2.14 Reactions of giycidyi tosylate with nucleophiles ...... 5 1

2.15 Synthesis of iV-tosyl-O-tosyl-azindinemethanol ...... 52

2.16 Reaction of iV-tosyl-O-tosyl-aziridinemethanol with 2 eq of R 2CuLi...... 53

2.17 Reaction of A/-tosyl-0-tosyl-aziridinemethanol with I eq of R 2CuLi...... 54

2.18 Stepwise synthesis of 60 from iV-tosyl-O-TBS-aziridinemethanol ...... 55

2.19 Attempted synthesis of opposite enantiomer of 189 from (5)-serine ...... 56

2.20 Synthesis of aziridine 206 (opposite enantiomer of 191) from (5)-serine.. 57

2.21 Reactions of N-tosyl-O-tosyl-aziridinemethanol with other organocuprate reagents ...... 60

2.22 Retrosynthetic analysis for synthesis of aziridine-allylsilanes from 189 ... 61

2.23 Synthesis of aziridine-allylsilanes from ditosyl aziridine 189 ...... 62

2.24 Retrosynthesis of differentially substituted aziridine-allylsilanes ...... 63

2.25 Synthesis of iV-Cbz-O-TBS-aziridinemethanol 223 from (S)-serine ...... 64

2.26 Reaction of 7V-Boc-0-Ts-aziridinemethanol with organocuprate reagents ...... 66

2.27 Reaction of iV-Ns-O-TBS-aziridinemethanol with organocuprate reagents ...... 66

2.28 Deprotection of iV-tosylaziridine-allylsilanes ...... 67

2.29 Deprotection of some iV-protected aziridines ...... 67 xvi 2.30 Deprotection of iV-tosyl aziridines by single electron transfer ...... 68

2.31 Synthesis of differentially substituted aziridine-allylsilanes from an iV-tosylaziridine ...... 69

2.32 Deprotection of iV-tosylaziridines containing an ether linkage ...... 70

2.33 Deprotection of iV-tosylaziridine containing an ester or amide linkage 71

2.34 Deprotection of iV-tosylaziridine with adjacent benzoyl group ...... 72

2.35 Deprotection of iV-tosylaziridine containing a pivaloyl ester ...... 73

2.36 Deprotection of A/^tosylaziridines containing an aromatic ring ...... 74

2.37 Deprotection of bicyclic iV-tosylaziridine derived from (-)-nopol ...... 74

3.1 Intramolecular Sakurai cyclization between an aziridine and an allylsilane ...... 77

3.2 Retrosynthesis synthesis of rauwolfia alkaloids ...... 78

3.3 Preparation of yohimbane analogs ...... 79

3.4 Single step synthesis of aziridine-allylsilane ...... 79

3.5 Step wise synthesis of aziridine-allylsilanes ...... 80

3.6 Cyclization of aziridine-allylsilane 211 ...... 81

3.7 Attempted alkylation of amino-olefin 287 using bromide 288 ...... 82

3.8 Synthesis of bromide 288 starting from indole ...... 83

xvii 3.9 Deprotection of amino-olefin 287 ...... 86

3.10 Projected synthesis of yohimbane by cyclization of A/-aikylaziridine-ailylsUane ...... 86

3.11 Attempted cyclization of iV-benzylaziridine-allylsilane ...... 87

3.12 Alkylation of 287 using mesylate 3 0 3 ...... 88

3.13 Hydroboration of alkylated product 289...... 89

3.14 Stepwise conversion of alcohol 304 to ester 3 0 7 ...... 91

3.15 Amide formatioa during deprotection of 3 0 7 ...... 92

3.16 Total synthesis of (-)-yohimbane and enf-alloyohimbane ...... 93

3.17 Bischler-Napieralski rearrangement of lactam 309 ...... 93

4.1 Formation of desilyated bicycle during Sakurai reaction of aziridine-allylsilanes ...... 95

4.2 Mechanistic rationale for formation of desilyated bicycle ...... 96

4.3 All possible reaction pathways for aziridine-allylsilane 211 ...... 97

4.4 Retrosynthesis of aziridine-allylsilanes with different groups on silicon ...... 101

4.5 Single step synthesis of aziridine-phenyldimethylallylsilanes ...... 104

4.6 Stepwise synthesis of aziridine-phenyldimethylallylsilanes ...... 105

4.7 Stereochemical rationale for formation of five membered carbocycles during 3+2 annulation ...... 112

xvm 4.8 Stereochemical rationale for formation of six membered carbocycles during 3+2 annulations ...... 113

4.9 Oxidation of phenyldimethylsilyl group in bicyclic pyrrolidines ...... 116

4.10 Mitsunobu reaction between alcohol 351 and 3-hydroxypyridine ...... 117

4.11 Synthesis of pyridyl ether 356 via mesylation/displacement approach.... 118

4.12 Attempted deprotection of tosyl group in pyridyl ether 356 ...... 119

4.13 Synthesis of differentially protected prolinols ...... 119

4.14 Reactions of differentially substituted prolinols ...... 120

4.15 Attempted synthesis of nicotinic modulators using N-Boc protecting group ...... 121

XIX CHAPTER 1

REACTIONS OF AZIRIDINES WITH ALLYLSILANES

1.1 Introduction. The field of drug design and discovery continues to be a leading area in pharmaceutical research today. An important aspect of drug discovery relies on the availability of new lead drug molecules. Historically, natural products such as alkaloids, terpenes, steroids etc. have been some of the major sources for the discovery of these lead molecules. These lead molecules are then modified synthetically, to reduce structural complexity while retaining biological activity and a useful pharmacokinetic profile. Alkaloids are a group of stmcturally diverse natural products possessing a wide range of biological activities. Although alkaloids can be obtained fiom a variety of sources, they may be present in very minute amounts or may be difficult to isolate. Consequently this may require elaborate procedures for their extraction. Sometimes these sources may be certain rare plant or animal species. Relying on them for supply may constitute a danger to their survival. Due to these difficulties in obtaining natural products, organic synthesis has been an attractive option for providing an alternate source of these compounds. Though alkaloids are complex molecules, in a large number of cases the pharmacophore is usually a simpler nitrogen containing heterocycle. Organic synthesis allows for preparation of simpler structural analogs which help to reduce structural complexity while retaining useful biological activity. General methods for the synthesis of

1 alkaloids and other nitrogen containing heterocycles are thus of immense importance to the pharmaceutical sciences.

We have been interested in developing methodology for the synthesis of alkaloids and other nitrogen containing heterocycles which could serve as potential drug candidates. We have discovered a method which could be a general and useful procedure for the synthesis of these molecules. Specifically, we can convert an aziridine-allylsilane 1 to either the olefin 2, or the bicycle 3 (scheme 1.1).

S1R3

( ( ) n l NR ^Lewisacid Lewis acjd, ......

3, n = 1,2 " 2,n=1,2 1, n = 1,2

Scheme 1 .1 : Intramolecular cyclization reactions between aziridines and allylsilanes

Molecules such as 2 and 3 could be extremely useful precursors to other more complex nitrogen containing heterocycles. To better understand the formation of these products and to address some of the more complex issues of stereochemistry, one needs to look at the reactivity profile of the two functional groups involved in this reaction. In the first section of this chapter the reactions of allylsilanes with some important electrophiles and some of the factors influencing the stereochemical outcome of reactions involving allylsilanes will be discussed in depth. In the second section of this chapter, ring opening reactions of differentially substituted aziridines with a variety of nucleophiles will be discussed. Finally in the third section of this chapter, the types of products formed by intramolecular reactions of aziridines with allylsilanes and the significance of these products for the synthesis of biologically important molecules will be discussed. 1.2 Reactions of Allylsilanes. Allylsilanes are well known nucleophiles and react with a variety of electrophiles. ^ As compared to other allylic metals, allylsilanes are allylically stable and can be carried through a number of steps in a synthesis. At the appropriate step in the synthesis they can react with the desired electrophile to provide allylated or aimulated products. Another very useful aspect of silicon chemistry which has emerged recently, is that certain silyl groups can be oxidized to hydroxyl groups.^

Lewis Acid (LA) Ri^Ra RgSi 4 5

X = O, NR, CHCOR elimination -SiRg 1,2 Silyl shift XH Ra Ri LA SiRs >r Ra Ri Oxid. 8

3+2 HO

Oxid. RaSi Ra Ri 10

Scheme 1.2: All reaction pathways involving allylsilanes

1.2.1 Sakurai Reaction of Allylsilanes. In scheme 1.2 are shown all the possible reaction pathways involving allylsilanes with an electrophilic partner. The reaction

3 we will first look at is exemplified by the conversion of 6 to 7. The reactions of allylsilanes with ot,P-unsaturated carbonyl compounds, aldehydes and acetals were first independently investigated by Sakurai and Dunogues (scheme 1.3).^ The reaction involved addition of allyltrimethylsilane to a carbonyl compound 13, in CH 2CI2 using TiCU as the Lewis acid, to provide the corresponding homoallylic alcohol 14. A. similar reaction of allyltrimethylsilane with cyclohexenone results in addition of the allyl group in a Michael fashion to provide the allylated ketone 16.^ Since the first report of this reaction, allylsilanes have been used extensively in organic synthesis. The reactions of allylsilanes have been exhaustively reviewed on numerous occasions.^

OH

TÎCI4 , CH2 CI2 13 14,87% O

TÎCI4, CH2CI2

15 16,85%

Scheme 13: Sakurai reaction of allylsilanes

The mechanism of reaction of allylsilanes can be best rationalized through an anti -Se' (substitution - elimination) mode of addition (scheme 1.4).5 It involves an electrophilic attack on the K bond of the allylsilane to provide a cationic intermediate 17.

This intermediate is stabilized by hyperconjugative overlap of the C-Si bonding orbital with the empty p orbital. The cationic intermediate can now undergo an elimination reaction to provide the olefin 14. N u '-^ " 3 S \u R3S1 ...H S h LA 14 H H H"' C3 H7 17

Scheme 1.4: Mechanism of Sakurai reaction

1.2.1.1 Stereochemical control in allylsilane reactions. In most cases allylsilanes react with electrophiles with anti stereoselectivity (scheme 1.5). The preferred conformation for attack has the hydrogen eclipsing the double bond. The approach of the electrophile is usually anti to the bulky silyl group.® This conformation is usually influenced to some extent, by the size of the substituent A. If A is relatively small (such as hydrogen), a second Conformation B is possible^ (scheme 1.5). Due to the steric demands imposed by the substituent A, in allylsilanes with 1,2 substituted double bonds, the Z isomer reacts with cleaner stereochemistry than the E isomer. This is seen in the reaction of the allylsilanes 21 and 24 with MCPBA.*

Conformation A

RaSi ?A

R H H 18 20 19

Conformation B

. 8 R "A RaSi 18

Scheme 1.5: Conformations of an allylsilane during reaction with an electrophile In allylsilanes 21 and 24 (scheme 1.6), conformation A is favored over conformation B. However in 24, the unfavorable interaction between the two eclipsed methyl groups is greater than the A^'^ interaction between the eclipsed methyl and hydrogen in 21. This difference is borne out in the final ratio of the epoxides which are formed Grom these allylsilanes. Thus with allylsilane 24, a smaller amount of the epoxide

26, arising from conformation B, is seen (22:23 = 61:39 as compared to 25:26 = 95:5).

RaSi. H Me

Conf.A Me'H ( "

21 ^ M C P B A 22,61% I MCPBA H, R Me Me H Conf. B Me H R3S 1 RaSi 23,39%

R3S 1. H H Me Conf. A M e - ^ ( Me Me^ 24» ^ MCPBA 25,95%

MCPBA H. Pv ,H -Me Me Me Me RaSr 26,5% R3 S 1

Scheme 1.6: Reactions of E and Z allylsilanes with MCPBA

Another factor which influences this stereoselectivity is the size of the R group adjacent to the silyl group. In allylsilane 27, preference for conformation A increases as the size of the R group increases (scheme 1.7).^

6 RgSi H H Conf.A Me

MCPBA 28

MCPBA H. A .H H. Conf. B Me -R Me R3 S 1 29 28:29 R = CH3 6139 R = CgHg 89:11 R = iPr 953

Scheme 1.7: Reaction of substituted Z allylsilane with MCPBA

In an elegant study to test whether synclinal or antiperiplanar transition states are preferred in reactions of allylsilanes, the allylsilane aldehyde 30 was cyclized using different Lewis acids (scheme 1.8).^0 It was found that the synclinal transition state is usually preferred over the antiperiplanar transition state and, that the nature of the Lewis acid substantially affected the stereochemical outcome of these types of reactions . Unfortunately no conclusions could be drawn from these results. Syndinal Antiperiplanar

% = A . .

3Ci ^SIR a

LA 31:32 SnCU 49:51 EtaAICI 6634 FeClg 7030 BFg^OEtg 8030

Scheme 1.8: Antiperiplanar vs synclinal transition states in reactions of allylsilanes

Thus, some of the important factors which influence the stereochemical outcome of reactions involving allylsilanes include substitution pattern on the allylsilane, synclinal vs antiperiplanar transition states and the types of Lewis acid employed for the reaction. We shall later see how some of these factors influence stereochemistry in the reaction of aziridines with allylsilanes. 1.2.1.2 Reactions of allylsilanes with imines. Reactions of allylsilanes with a number of electrophiles have been reported.^ A few examples of reactions of allylsilanes (scheme 1.9) with some important electrophiles such as imines and a,P- unsaturated compounds will be discussed. Iminium ions generated from aldehydes react rapidly with allylsilanes to provide allylated products. ^ ^ However, iminium ions derived from ketones are less reactive. In one case, an iminium ion generated from a ketone was reacted photochemically with an allylsilane to provide the allyated product^- Iminium ions generated in situ by reaction of aldehyde 33 with p-toluenesulfbnamide in the presence of

BF3«OEt2 provided the aminocyclopentane 34. Use of Lewis acids other than BF 3»OEt2 resulted in decomposition of the starting aldehyde. Interestingly, the stereochemical 8 integrity of the chiral center adjacent to the aldehyde group in 33 was maintained during the

reaction. Typically these reactions work best when aldehydes are used for generating the iminium ion. If formation of the iminium ion is not rapid, the major product of the reaction is that resulting from attack of the allylsilane onto the carbonyl compound.

TsNHa BF^OEtg MeaSiPhO fpr NHTs NW 34

CF3CO2H

o 36

Scheme 1.9: Reactions of allylsilanes with iminium ions

Iminium ions generated from primary and secondary amines have been used in both inter- and intramolecular reactions with allylsilanes. Some of the most useful examples of these type of reactions have been carried out using acyliminium ions which serve as good electrophilic partners in the Sakurai reaction of allylsilanes. These reactions have proved useful in the synthesis of nitrogen containing heterocycles. Cyclization of the acyliminium

ion generated by treatment of a-hydroxyamide 35 with CF 3CO2H provided the bicyclic pyrrolidine 36.1'^^ 1.2.1.3 Reaction of allylsilanes with a,^-unsaturated systems.

Another electrophilic partner which has been investigated frequently in the Sakurai reaction of allylsilanes are a,P-unsaturated carbonyl compounds. ^ Allylsilanes react with o,p-

unsaturated aldehydes by direct attack on the carbonyl carbon. However, allylsilanes react with ot,P-unsaturated ketones by conjugate addition. ot,P-unsaturated esters are poor

9 electrophilic partners in this reaction.*^ Typically this problem can be overcome using acyl halides or acyl cyanides. The intramolecular cyclization reaction between a,P-unsaturated enones and an allylsilane is a powerful strategy for the synthesis of carbocyclic ring systems. This reaction has been used for the synthesis of different ring size carbocycles, fused and spirocyclic ring systems. ^ An example of an intramolecular reaction between an allylsilane and an enone is shown in scheme 1.10. Treatment of the enone 37 with TiCU, efficiently joined the quaternary centers to provide 38.20

37 38

Scheme 1.10: Intramolecular reaction of an allylsilane with an enone

1.2.1.4 Reactions of allylsilanes with epoxides and aziridines. As compared to other electrophilic species, there are fewer reports of reactions between allylsilanes and three membered ring electrophiles such as epoxides and aziridines.

Ethylene oxide reacts with the allylsilane 39 to provide ring opened product 4 0 .2 1 However, higher epoxides such as propylene oxide do not give a clean reaction with allylsüanes.22 Similarly, mono substituted iV-tosyl aziridines do not react with aUylsUanes.22 After we reported the first intramolecular reaction between aziridine and allylsilanes, 24 Taddei et a l , reported an intermolecular reaction of the phenyl aziridine 41 with allyltrimethylsilane to provide a mixture of the 3+2 adduct 42 and the corresponding olefin 43 (scheme 1 . 1 1 ) .2 5

1 0 o

TiCk 3B 40

Ar,

NTs + NHTs C,A^ BFaOBj Ar

41

Scheme 1.11: Inteimolecular reactions of allylsilanes with epoxides and aziridines

The intramolecular reaction of epoxides with allylsilanes has been exploited for the synthesis of 5 , 6 and 7 membered carbocycles (scheme 1.12). Treatment of the allylsilane epoxide 44 with TiCL* provided the cis fused carbocycle 45 as the major product in 55% yield.26 Similarly, treatment of the epoxide 46 with BF 3«OEt2 provided the 6 membered carbocycle 47 as the exclusive product.^7 This product was then transformed to provide racemic karahana ether. Another reaction reported by Jung involved treatment of the epoxy alcohol 48 with Et 2AIF to provide the cyclized product 49.28 In an extension of this methodology for synthesis of 7 membered carbocycles, epoxide 50 was cyclized to provide the alcohol 51.29 jjj ^ reaction similar to a biomimetic polyene cyclization, the polyene 52 was cyclized to provide the substituted decalin ring system 53, which was then transformed to labadienoic acid .20

II TiCU V A ^ o h

44 45, (trans:ds=1;4)

MesSi

COgR COgR 46 47

MegSi EtaAlF

M e a S i ^ ^ BFaOEtg

OH so 51

SIMea BFaOEta HO

52 S3

Scheme 1.12: Intramolecular reactions of allylsilanes with epoxides

Thus the Sakurai reaction of allylsilanes has proved useful for the stereocontroUed synthesis of a variety of structurally and biologically interesting molecules. The corresponding intramolecular reaction of allylsilanes and aziridines is the subject of this dissertation and chapter 2 details that work. 1.2.2 3+2 and 2+2 Annulation Reactions of Allylsilanes. Santelli and some other workers had reported formation of cyclobutane rings as side products in the 12 Sakurai reaction (scheme 1.13).^* In one specific case treatment of the enone 54 with allyltrimethylsilane provided a mixture of the desired Sakurai products 56,57 and the cyclobutane 58. It was rationalized that the cyclobutanes were formed by attack of the intermediate enolate 55, formed by addition of a nucleophile to the enone system, on the transient carbocation via a formal 2+2 cycloaddition process.^ 1^

.LA

TiCU

56,75% 57,8% 58,17%

Scheme 1.13: Sakurai and 2+2 reactions of allylsilanes

It was not until much later that Knolker showed that the product structures were incorrectly assigned and that these products were more likely to be the corresponding cyclopentanes 60.^2 They rationalized the formation of the cyclopentanes as occurring via the intermediacy of a pentavalent silicon species. Le. the siliranium ion 59 (scheme 1.14).

.LA

SIMea

Mea H 59 eo

Scheme 1.14: 3+2 Annulation reaction of allylsilanes

13 In an interesting study, Meyer et a l , showed that addition of triisopropyisilane to the bicyclic lactam 61 produced either the cyclobutane 62 ( 2+2 cycloadduct) or the cyclopentane 63 (3+2 cycloadduct) as the major product (scheme 1.15).^^ They found that when the reaction was quenched at lower temperatures (-78 “C to -20 "C), ± e cyclobutane was found to be the major product. On the other hand when the reaction was quenched at 0

“C, the cyclopentane was the major product Another interesting observation was that when 62 was treated with TiCLt and the reaction warmed to room temperature, the cyclobutane rearranged completely to the cyclopentane 63. It was concluded that the formation of the 3+2 annulated products was under thermodynamic control while that of the 2+ 2 annulated products was under kinetic control.

o'^COaR COaR 61 62

TiCU, -78 *0 to 0 "C TiCU, -78 *0 to 0 *0

63

Scheme 1.15: 3+2 vs. 2+2 Annulation of allylsilanes with enones

1.2.2.1 Mechanistic rationale. The first step of the mechanism of the 3+2 and the 2+2 annulation is similar to that discussed earlier for the Sakurai reaction (scheme 1.4). Thus treatment of an electrophilic partner with an allylsilane in the presence of a Lewis acid provides the cationic intermediate 6, which is stabilized by hyperconjugation (also called 14 nonvertical stabilization). The intermediate 6 could now equilibrate to form the siliranium ion 64 (also called vertical stabilization - scheme 1.16). Depending upon the reaction conditions employed, 64 is susceptible to nucleophilic attack either at C 2- to provide the 2+2 cycloadduct 11, or at C( - to provide the 3+2 cycloadduct 12. Although this appears to be a reasonable explanation, theoretical calculations do not support the formation of siliranium ions in solution.^^

Siliranium ion RaSi formation

[2+2]

X X RgSi

Scheme 1.16: Siliranium ions in annulation reactions of allylsilanes

Lambert et al, have investigated the two pathways (vertical vs. nonvertical stabilization) and concluded that the nonvertical stabilization model is a more accurate mechanistic explanation for these annulations (scheme 1.17).36 In the nonvertical stabilization model, the formation of the 3+2 cycloadducts is explained as occurring via a

1,2-silyl shift of the cationic intermediate 6 to provide 65, which can undergo nucleophilic capture to provide 12. While the exact mechanism of the silyl transfer is still debatable, a uitique feature of intermediates 6 and 65 is that they do not rotate around the C 1-C2 single bond.^^ It has been suggested that the nonvertical stabilization is a function of the cosine of the angle between the C-Si bonding orbital and the empty p orbital, with a maximum at 0°

15 and 180* and a minimum at 90*.3<5b Thus nucleophilic capture of these transient cations takes place anti to the silicon and is stereospecific or highly stereoselective resulting in the formation of a single stereocenter during the ring closure.^^

,LA [2+2] R3 S 1 Ra Ri 6 11

1 ,2 -silyl shift

SIRa'X ' [3+2] R3S1 Ra Ri 12

Scheme 1.17: 1,2-Silyl shift in annulation reactions of allylsilanes

1.2.2.2 3+2 Annulation of allylsilanes with aldehydes. The inability of the silyl stabilized carbocations to rotate about the single bond carrying the positive charge is illustrated in the reaction of the crotylsilane 66 with a-benzyloxyacetaldehyde in the presence of BF 3*OEt 2 to provide the tetrahydrofuran 67 as the major product.^? The first bond formation takes place via an antiperiplanar transition state resulting in the formation of

68 which is stabilized by hyperconjugation. Cation 68 now undergoes a 1,2-silyl shift (69) followed by a stereospecific attack of the intramolecular nucleophile anti to the silicon to provide 67 as the final product No rotation about the C 4-C5 single bond is seen during the ring closure (scheme 1.18).

1 6 SiMsaPh BFa'Eta SiMeaPh O HC OBn

66 67

MeaPhSi MeaPhSi LA s J ' a nSSs'

f ^ s H V OBn COaMe OBn COaMe OBn COaMe 68 69

Scheme 1.18: 3+2 Annulation of a chiral crotylsilane with an aldehyde

1.2.2.3 Intramolecular 3+2 annulation of allylsilanes. Prior to this work, there were only two reports of intramolecular 3+2 annulation reactions of allylsilanes (scheme 1.19). Schinzer has reported an intramolecular version of the 3+2 cycloaddition reaction of allylsilanes with ketones in their synthesis of triterpenoids.^® The first step in this reaction involves attack of the allylsilane on the activated ketone to provide 71, which then undergoes a 1,2-silyl transfer followed by a second ring closure to provide 72. Some of the corresponding olefin formed by elimination of the silicon group is also seen in the reaction. In another version of the intramolecular 3+2 annulation, the amine 73 was reacted with CHO-CHO and TFA to provide the intermediate imine, which is attacked by the allylsilane to form the positively charged intermediate 74. The cationic intermediate 74 is then trapped by an adjacent nucleophile to provide the final product 75.^^

17 SiRa EtoAICI 1 .2 -silylshift . A D- ^ '^ 3 and ring LA Ml closure 70 72,62%

,0 H 0 ^ 0 H

Ph-“I' 'NH " ' S V iSiMea ^ ^ h TH SiMea

73 7474 75,45%

Scheme 1.19: Intramolecular 3+2 annulation of allylsilanes with electrophiles

1.2.2.4 Effect of Silicon in Annulation Reaction. In all of the reactions described above, a key factor is the nature of the silyl group used in the cyclization.^^ Use of silyl groups with smaller R groups on the silicon, such as trimethylsilyl, typically result in elimination (scheme 1.20). This is because the smaller groups on the silicon do not impede the approach of the incoming nucleophile which causes the elimination reaction. When the methyl groups have been replaced by bulkier groups such as phenyl, f-butyl, or isopropyl, the steric bulk on the silicon impedes the incoming nucleophile thereby reducing the rate of the elimination reaction.

X = O. NR, CHCOR

Scheme 1.20: Effect of silicon in annulation reactions of allylsilanes

18 Typically the trimethylsilyl group is not retained very well in the annulation reactions. Another disadvantage of the trimethylsilyl group is that it can only be removed from the product by a protodesilyation reaction.'*® In contrast, some of the other silyl groups which have at least one phenyl group on the silicon can be oxidized to a hydroxyl group.2 This allows incorporation of a wide variety of functionality into these annulated products. Some of the useful silyl groups which have been employed in these annulation reactions include phenyldime±yl,^ trityldimethyl,'** triisopropyl,^^ tripheny 1,^*2 diisopropyl-phenyl'*^ and r-butyldiphenylsilyl.'*'*

Silyl group Ease of oxidation Retention in annulation

MegSi not possible poor

PhMeiSi excellent good

TrMe2Si good excellent

i-PrsSi not possible excellent

(r-Pr)2PhSi good excellent

PhsSi moderate excellent

f-BuPh 2Si fair excellent

Table 1.1: Silyl groups in annulation reactions

All these groups have certain advantages and disadvantages associated with them. The advantage of the phenyldimethylsilyl group is that the starting materials for it’s synthesis are commercially available and that it can be readily oxidized to a hydroxyl group. However, the phenyldimethylsilyl group does not have quite enough steric bulk and there have been reports where this group has not been satisfactorily retained in the annulation reactions.^3*^ In contrast the trityldimethyl, triisopropyl, triphenyl, diisopropyIphenyl and

19 r-butyldiphenylsilyl groups are extremely bulky and are usually retained very well in the annulation reactions. While the triisopropyl group is retained very well in the annulation reactions, it suffers from a disadvantage that it cannot be oxidized to a hydroxyl group. The r-butyldiphenylsilyl and the triphenylsilyl group can also be resistant to oxidation and may require forcing conditions which are not desirable at times. The trityldimethylsilyl and the diisopropylphenylsilyl groups are sufBciently bulky that they are well retained in the armulation reactions and they can be oxidized quite easily to the hydroxyl group. The disadvantages of these groups is the oxidation may have to be carried out in a two step sequence and starting materials for their synthesis are not commercially available. From our discussion of reactions of allylsilanes, we can see that allylsilanes have proven to be extremely useful reagents in organic synthesis. The intramolecular reaction of allylsilanes with different electrophiles has been used for the synthesis of a variety of different ring systems. In reactions of allylsilanes with optically pure three membered rings, it is possible to transfer chirality from the electrophile into the final product Thus an intramolecular reaction between a chiral aziridine and an allylsilane could be an effective route for the asymmetric introduction of nitrogen into molecules. Another very useful aspect of silicon chemistry, which has emerged recently is that certain silyl groups can be oxidized to a hydroxyl group. When the oxidation reaction is used in conjunction with the annulation reactions where silicon is retained in the molecule, the allylsilane can serve as a hydroxy 1,3-dipole. This could allow for incorporation of a wide variety of functionality into the annulated products.

1.3 Reactions of Aziridines. In this section, we shall discuss the ring opening reactions of differentially N-substituted aziridines with a variety of different nucleophiles. Aziridines, like epoxides are strained 3 membered nitrogen containing heterocycles and their chemistry is dominated by ring opening reactions.'^^ The manner in which an aziridine ring wiU open depends on the type of substituents on the nitrogen and also on the reaction

20 conditions employed. The different nitrogen substituents which have been studied most extensively include sulfonyl, acyl, alkyl, carbamate and phosphinyl .^ 5

EWG I © N Nu' EWG~N EWGHN )—V )—\ r R Nu R Nu 7B 77 78

EWG = SO 2 R. COR, COOR, PORg

Scheme 1.21: Ring opening reactions of activated aziridines

1.3.1 Nucleophilic Ring Opening Reactions of Activated Aziridines. Aziridines which have electron withdrawing groups on the nitrogen can react directly with nucleophiles to provide ring opened products. In these reactions the negative charge on the intermediate formed on ring opening is stabilized by delocalization on the electron withdrawing substituent (scheme 1.21).

1.3.1.1 Ring opening reactions of N-sulfonyl aziridines with carbon nucleophiles. The most popular N protecting groups in aziridine chemistry are the N- arenesulfonamides. These aziridines undergo a clean ring opening with a variety of different nucleophiles (scheme 1.22).

21 TsHN Me

UAIH4 H NHTs HOkV-\^OTBS

KHMDS y^^COgtBu t K " C r BuOgC SOgPh )—' " 84 83 SOaPh

Scheme 1.22: Ring opening reactions of /V-tosyl aziridines

Best results for ring opening of A/-sulfonyl aziridines with an organometallic reagent are obtained using organocuprate reagents. These reactions proceed with excellent tegio control to provide products which arise horn attack of the nucleophile at the less hindered carbon of the aziridine ring. Thus ring opening of the benzyl aziridine 79 with an organocuprate reagent provides 80 exclusively.^ In disubstituted aziridines the direction of ring opening is usually controlled by the nature of the nucleophilic species and the substituents adjacent to the aziridine ring. For example when ± e aziridine ring has an adjacent hydroxymethyl group 81, approach of the nucleophile is directed by the hydroxyl group to provide the ring opened product 82.^^7 The only intramolecular reaction between an aziridine and an enolate was reported by Rapoport et al.^^ This reaction results in the formation of the amino substituted carbocycle 84. 1.3.1.2 Reactions of iV-acyl aziridines with carbon nucleophiles. Reactions of iV-acyl and iV-carbamoyl aziridines are complicated by the competing attack of the nucleophile at the carbonyl group of the activating group, instead of attack at the aziridine ring.'^^ Reaction of Af-benzoyl aziridine 85 with /i-BuLi, provides the phenyl

22 ketone 87 in good yieid.'^^*’ This problem could be avoided by the right choice of ^-acyl or iV-carbamoyl protecting group and nature of the nucleophilic species. Thus the N-Boc aziridine 88 undergoes a clean ring opening reaction with PhMgBr in the presence of

CuBr.SMe2-^® Another useful ring formation/opening reaction of N-acyl aziridines for the synthesis of vicinal amino alcohols was reported by our group recently.51 Thermolysis of

an azidoformate 90 provides the bicyclic aziridine 91, which can be opened with a variety of nucleophiles to provide oxazolidinone 92 (scheme 1.23).

h N - f ------J^NH , X _ / Ph / Fh^nBu "aC 85 æ 87,80% Boc^ NHBoc PhMgBr __ CuBfSMeg OBn OBn 8 8 89 o o g Nu- «A.

go 91 92

Scheme 1.23: Reactions of ^-acyl aziridines with carbon nucleophiles

1.3.1.3 Reactions of iV-phosphlnyl substituted aziridines.

The iV-phosphinyl protecting groups are another useful class of aziridine activating groups (scheme 1.24). These aziridines undergo clean ring opening with organocuprate reagents and they have an additional advantage in that the phosphonyl group may be cleaved without destroying the aziridine ring.52 Another advantage of this class of protecting groups is that, deprotection of the ring opened products can be carried out under fairly mild conditions such as TFA or dilute HC1.52

23 MegCuLi , Ph" N POPhg NHPOPhg 93 94 EtMgBr CuBr»SEt2

NHPOPha 96

Scheme 1.24: Reactions of Af-phosphinyl aziridines with organometallic reagents

1.3.1.4 Reactions of activated aziridines with heteroatom nucleophiles. In addition to carbon nucleophiles, aziridines also undergo ring opening reactions with a variety of heteroatom nucleophiles. Aziridine carboxylate 96 undergoes ring opening with the a-amino group of histidine to provide the corresponding ring opened product.53 Aziridines (98) also undergo ring opening reactions with other heteroatom nucleophiles such as PhgP to provide ylides which can then react with carbonyl compounds (scheme 1.25).^^

CO2M8 ! H NaOH T s H N ^ ^ Me02C 96 0 ^ 0 H 97

B oc.^0 Boo. Boo. Boo NH NH RCHO ©PPt^ PPty 98 99 99 100 1 0 1

Scheme 1.25: Reactions of activated aziridines with heteroatom nucleophiles

24 1.3.2 Ring Opening Reactions of Activated and Unactivated

Aziridines in the Presence of Lewis acids. A second mode of ring opening of aziridines which operates for all aziridines involves initial complexation of the aziridine with a Lewis or protic acid. This activated aziridine can then undergo ring opening with a desired nucleophile (scheme 1.26).

H Ê- %'l NU- /A ZA ^ ) V R R Nu 102 103 104 Ri = EWG or alkyl Nu‘

Nu NHRi

R 106

Scheme 1.26: Ring opening reaction of an aziridine promoted by a Lewis acid.

1.3.2.1 Reactions with carbon nucleophiles. Some aziridines are not activated enough to undergo ring opening with nucleophiles. In the case of iV-benzyl aziridine 106, ring opening with Me 2CuLi proceeds in the presence of BF 3«OEt2 to provide ring opened products.^^ Sometimes Lewis acid activation is required even for activated aziridines when a weak nucleophile is used for the ring opening reaction. The aziridine carboxylate 110 was treated with indole to provide protected tryptophan derivatives. It was found that Zn(OTf )2 was the only Lewis acid which could catalyze this reaction (scheme l.27).56

25 ••‘'I Bn O'l.. N -B n MepCuLi _ N—Bn XO'" X^N-Bn BF3«OEt2 N -B n >4:0 NHBn 106 107 108

COaBn

NHCbz Cbz

109 110 111

Scheme IJlli Reaction of aziridines requiring prior activation with a Lewis acid

1.3.2.2 Reactions with heteroatom nucleophiles. In addition to carbon nucleophiles, a variety of other heteroatom nucleophiles have also been used in the Lewis acid catalyzed ring opening of aziridines. Some selected examples of these types of ring opening reaction with alcohols,^^ thiols,^® and amines^^ are shown in scheme 1.28.

COpBn ,0H N c r 'COaBn 'COgBn BFsOEtg 113 112 I^Ha 5 PhSH ^ 'Y ^ C 0 2 M e Ph*" ''COgMe BFsOEtg SPh 114 115

BnNH2 ^Y ^N H B n Yb(OTf)2 NHTs 116 117

Scheme 1.28: Reactions of activated aziridines with heteroatoms requiring Lewis acid activation

26 1.3.2.3 Reactions of A/^-acyl azirtdines in the presence of azaphilic and oxophilic Lewis acids.In an interesting reaction, Lectka showed that the aziridine 118 could undergo differential ring opening depending on the type of Lewis acid employed (scheme 1.29).^ Use of an oxophilic Lewis acid (Ti(0iPr)4, Yb(biphenol)OTf} resulted in ring opening by the nucleophile employed while use of an azaphilic Lewis acid

{Sn(OTf) 2, Cu(OTf)2, Zn(OTf) 2 } resulted in ring opening by the oxygen of the acyl group on the aziridine nitrogen.

V I ROCN Nu N O ^ Oxophilic LA Azaphilic LA ^ ^

119 120 118

HgN Nu H2 N Nu

121 122

Scheme 1.29: Reactions of A^-acyl aziridines with azaphilic and oxophilic Lewis acids.

From the above reactions it is evident that ring opening of aziridines is dependent to a large extent on the substituent which is present on the aziridine nitrogen. A(-sulfonyl arenesulfonamides are the most useful nitrogen protecting group as these aziridines give clean ring opening reactions with a variety nucleophiles. Reactions of ALacyl aziridines with nucleophiles are sometimes complicated by competing attack at other sites. In both these cases the regiochemistry of the ring opening could be controlled by the right choice of reaction conditions. Lewis acids also play an important role in the reactions of aziridines.

27 Sometimes choice of a particular Lewis acid could be a key factor in the success of a particular aziridine opening reaction. Since aziridines can be synthesized in their enantiomerically pure form, they are extremely versatile molecules for the synthesis of chiral nitrogen containing compounds.

1.4 Intramolecular Aziridine*A liylsilane Cyclization Reactions. The product of an intramolecular reaction between an aziridine and an allylsiiane could be eitherthe amino olefin 2 (Sakurai reaction) or the bicyclic pyrrolidine 3 (3+2 annulation). In either case both of these products would be formed by initial attack of the allylsiiane at the more substituted carbon of the aziridine ring. We have discovered that when 1 is treated with greater than stoichiometric amounts of BFgOEt], the amino olefin is the major product On the other hand treatment of 1 with catalytic amounts of BF 3*OEt 2 provides the bicyclic pyrrolidine as the major product (scheme 1.30).

^SiR a . L e ^

3 ,n = 1,2 " 2.n=1.2 1, n = 1,2

Scheme UO: Intramolecular cyclization between aziridines and allylsilanes

1.4.1 Application of the Sakurai reaction of aziridine-allylsilanes for Rauwolfla alkaloid synthesis. We envisioned that amino olefins such as 2 could be useful for the synthesis of members of the Rauwolfla alkaloid family Some representative members of this alkaloid family include reserpine, yohimbine, ajmalicine, yohimbane and alloyohimbane (figure 1.1). These alkaloids have a number of interesting

28 biological activities including antihypertensive and antipsychotic actions.^2 Yohimbine and related alkaloids have also been used for the differentiation of a-adrenergic receptors.^^

H H

H'‘1 H''| (-)-yohimbane (-)-alloyohimbane MeOaC"* (+)-yohimbine OH

H3 CO

MeOgC Y ^ O C H 3 {-)ajmalidne (+)-reserpine OCH3

Figure 1.1: Structures of some representative Rauwolfia alkaloids

Members of the Rauwolfia family have a characteristic pentacyclic ring firamework. Previous synthetic work in this area has shown that ring C can be constructed by a Bischler-Napieralski rearrangement reaction.^ The intramolecular cyclization between aziridines and allylsilanes should provide a quick access to lactam 5 via the amino olefins 7. When there is no substitution along the tether between the aziridine and the allylsiiane, this reaction could be useful for the synthesis of simpler alkaloids such as yohimbane and alloyohimbane. By incorporating additional functionality along the tether, this reaction should be useful for the synthesis of more complex members of this alkaloid family (scheme 1.31). Thus, developing a general method for the synthesis of amino olefin 7 should allow us to develop a general synthetic route to the Rauwolfia family.

29 JOçO

H

125 R i^ Y " 'R 3 Ra

Scheme U l : Synthesis of Rauwolfîa alkaloids mediated by aziridine-allylsilanes

1.4.2 Synthetic applications of 3+2 annulation reactions of aziridine- allylsilanes. A useful application of the 3+2 annulation reaction of aziridines with allylsilanes could be synthesis of bicyclic proline analogs such as 128. Bicyclic proline analogs such as those shown in scheme 1.32 have been tested as analgesics,^^ Angiotensin Converting Enzyme (ACE) inhibitors ^ and peptidomimetics.^^ Most of these compounds were prepared as racemates and the route employed for their syntheses did not allow for much stereocontrol at the centers bearing stereochemistry. As we will discuss in chapter 4, the 3+2 annulation reaction of aziridines with allylsilanes is enantioselective and allows for control of stereochemistry at the ring junctions formed.

Another interesting application of this chemistry would be the synthesis of molecules such as 129 as potential ligands for nicotinic cholinergic receptors. Nicotinic receptor modulators (scheme 1.32) have received a lot of attention lately due to their utility as analgesic agents and for their usefulness in the treatment of Alzheimer’s disease.^^

30 Bicyclic pyrrolidines such as 129 could serve as ring constrained, more lipophilic analogs or even antagonists of the known nicotinic receptor modulators.

Proline Analogs Nicotinic Receptor Moduiators H H ÇO2H

COgH NH N CD- Me H H H

Me "COgH d ; - d 5 - H COgH H H Cl

Epibatidine

OH

NR NR 127

OH

NR NH

12B 129

Scheme 132: Applications of 3+2 annulation reaction of aziridines with allylsilanes

Either one of these classes of molecules (proline analogs or nicotinic modulators) could be synthesized from the alcohol 127 which in turn could be synthesized by oxidation of the silyl group in 3. The silyl containing bicyclic pyrrolidines would in turn arise by a 3+2 annulation reaction between an aziridine and an allylsiiane.

31 Summary* From the above discussion one can see that the products from aziridine-allyisilane cyclizations could be very useful for the synthesis of structurally and biologically interesting nitrogen containing molecules. If aziridine-allyisilane 1 could be synthesized in its enantiomerically pure form, this reaction could be a useful tool for the asymmetric incorporation of nitrogen into molecules. In the subsequent chapters of this dissertation, the synthetic approach for synthesis of racemic and enantiopure N- tosylaziridine-allylsilanes and synthesis of aziridine-allylsilanes with nitrogen protecting groups other than the tosyl group will be discussed. Results from the Sakurai and 3+2 aimulation reactions of difrerentially substituted aziridines and allylsilanes will also be discussed in detail. The issues influencing the regio and stereo selectivity observed in the cyclization experiment will also be discussed. The utility of the Sakurai reaction of aziridines with allylsilanes will be illustrated by the use of this reaction as a key step in the total synthesis of (-)-yohimbane. Finally, results from the exploratory work on the synthesis of nicotinic modulators will be presented.

32 CHAPTER 2 SYNTHESIS AND REACTIVITY OF AZIRIDINE-ALLYLSILANES

2.1 Introduction. At the time this project was started, there had been no reported reaction between an aziridine and an allylsiiane. The first challenge was to develop a workable, high yielding route to the aziridine-allyisilane 1. The allylsiiane 1 could be synthesized from an aziridine-aldehyde 130 by a Wittig reaction.2l Aziridine 130 could be synthesized from the epoxide 131 by ring opening with azide followed by ring closure to the corresponding aziridine.69 Aziridine 130 could also be synthesized from the olefin 134 by reaction with a metal nitrenoid.^0 In both routes, commercially available hexanediol could be used as the starting material (scheme 2 .1).

< N' 1 130

.OR

131 O 132

Scheme 2.1: Synthetic routes to aziridine-allylsilanes via aldehydes

33 2.2 Initial synthesis of aziridine allylsilanes. Monoprotection^ ^ of hexanediol provided 133, which was oxidized to the aldehyde 134 by a Swem oxidation The aldehyde 134 was converted to the epoxide by treatment with trimethylsulfonium ylide Ring opening of the epoxide with sodium azide provided the azido alcohol, which was treated with tosyl chloride to provide 136. Next, synthesis of the

N-tosyl aziridine 137, by reducing the azide group by catalytic hydrogenation followed by treatment of the intermediate aziridine with tosyl chloride was attempted. Unfortunately the product of this reaction was not the aziridine 137, but the tosylated amine 140. The formation of 140 could be explained as taking place by hydrogenolysis of the tosylate followed by reduction of the azide group to the amine which was subsequently tosylated

(scheme 2 .2 ).

^^^OTBS .OTBS ^^.OTBS ^ PCC, 78% f ^ (CH3)2SCH2, 50% ^

o O' 133 134 135

1)NaN3 2)TsCI (65% from 135)

OTBS ^^^OTBS 1) H9. Pd/C CC NHTs 2) TsCI ' ^ / r ^ N 3 (59% from 8 ) qT s 138 136

OTBS

Ts 137

Scheme 2.2: Initial synthesis of aziridine-allylsilanes via epoxides 34 2.3 First generation synthesis of aziridine-allylsilanes via metal- nitrenoids. Due to failure of the above route, the oiefin/nitrenoid^O route for the synthesis of the aziridine allylsiiane 1 (scheme 2.3) was examined. The synthesis started by monoprotection of hexanediol to provide 133 which was oxidized to the aldehyde 134 using PCC.^'^ These conditions provided the aldehyde 134 in good yield when the reaction was carried out on a smaller scale ( 6 gm of 134,78% ), but the yield dropped drastically ( 25 - 30 % on a 13 gm scale) on scale up. This could be attributed to the decomposition of the aldehyde during purification (vacuum distillation) and also due to the difficulty in extracting the aldehyde from the black mass left after the PCC oxidation. This problem was avoided by using the Swem procedure which gave reproducible results on a larger scale (> 10 gm of 133). The aldehyde 134 was then converted to the olefin 139 ( 85 % ) by a

Wittig reaction.^5

OTBS ^ \ .O T B S ^% ^,OTBS Ph3PCH2,85% r PhlNTs. _ r a ------CuCI04.49% 134 139 % 140

nBu^NF, 76%

f ^ TRAP. NMO [

142 Ts 141 Ts

Scheme 23: Synthesis of Af-tosyl aziridine-aldehyde via metal nitrenoids

The olefin 139 was then converted to the aziridine 140 using PhlNTs in the presence of a copper catalyst.^® The advantage of this method is that an olefin can be

35 converted to the tosylated aziridine in a single step. The drawback of this reaction is that a 5

fold excess of the olefin is needed for optimum results and that this procedure is only useful for the synthesis of IV-tosyl aziridines. These drawbacks made this route a little impractical, but it could provide a quick access to the desired aziridines. We therefore

attempted the reaction using 5 eq of the olefin 139, 1 eq. of PhE

36 Wittig reaction.2* This reaction is a one pot synthesis for the conversion of an aldehyde to an allylsiiane (scheme 2.4).

PhsPCHgl • , PhgPCHa PhsPCHgCHgSilVlesI

n-BuLI

PhaPCHCHaSiMes

143 s 142

Scheme 2.4: Synthesis of aziridine-allylsilanes using Fleming's procedure^ ^

The procedure involves treatment of PhsPCHgl with I eq. of n-BuLi to generate

Ph 3PCH2. Alkylation of the y lid with Me 3SiCH2p^ generates a second phosphonium salt

Ph 3PΠ2CH2SiMe3, which is deprotonated with a second eq. of n-BuLi to provide

Ph 3PCHCH2SiMe3. The second ylid is then reacted with an aldehyde to provide the corresponding allylsiiane. This procedure provides predominantly the cis olefin. This was confirmed when decoupling of the allylic methylene protons gave a coupling constant of 10.8 Hz between the vinyl protons. This reaction provided the allylsiiane in 35% yield. While the yield was not good, it did provide us wi± the key allylsiiane 143. Since none of the starting aldehydes were recovered (TLC of the reaction mixture indicated no starting material after the reaction was stirred at room temperature for 16 hours after addition of the aldehyde) it is possible that the Wittig reagent may have opened the aziridine under the reaction conditions.

37 .OTBS OTBS ^ ^ O T B S Swem Oxi. Ph^PCHo 85% C. OH 82% c 144 145

PhlNTs, CUCIO4 , 61%

OTBS TPAP. NMO n-BUdNF C 86% 75% % % T 148 147 146

PhaPCHCHaSiMea, 36% ,SiMea

Scheme 2.5: Synthesis of aziridine-allyisilane starting from pentanediol

Using the same procedure described above pentanediol was converted to the aziridine-allyisilane 149 as shown in scheme 2.5.

2.4 Regiochemistry in aziridine-allyisilane cyclizations. During reactions of epoxides with allylsilanes, only products which could arise from ring opening at the more substituted carbon are isolated.26-30 This could be attributed to greater polarization of the more substituted carbon heteroatom bond on the coordination of a three membered ring electrophile, with a Lewis acid. One would expect that the reaction of aziridines with allylsilanes should show a similar regiochemical profile to that of reactions of epoxides with allylsilanes. In ± e cyclization of 143 and 149 two regioisomers could be formed, depending on the site of attack on the aziridine ring (scheme 2.6). Attack at the

38 more substituted carbon would lead to the formation of products such as 150 via a 5-exo­ trig ring closure (or 6-exo-trig when n = 2). On the other hand, attack at the less substituted carbon could lead to the formation of product such as 151 via a 6-exo-trig ring closure (or 1-exo-trig when n = 2). A third possibility could be that a mixture of 150 and 151 could be obtained. All these ring closures would be favorable according to Baldwin's rules of ring closure.^8

C2 attack^ ( < C Y ^

150 1 Ci attack

' ç r * NHR 151

Scheme 2.6: Regiochemical possibilities in reactions of aziridines with allylsilanes

2.5 Aziridine

(400 mol%) in CH 2CI2 (O.IM) provided a mixture of cis and trans fused carbocycles, 152a and 152b in 84% yield (scheme 2.7).24 The ratio of 152a to 152b was found to be

2.6:1. The ratio was determined by integrating signals corresponding to the methylamino group. The major isomer was shown to be the cis isomer 152a by nOe studies. The yield for the cyclization of 143 was equally good (90%). Again the ratio of the diastereomeric sulfonamides 153a to 153b was 2.7:1. However, in this case the trans isomer 153b was found to be the major product. The reaction was found to be highly regioselective with

39 attack taking place at the mote substituted carbon atom of the aziridine ring. None of the

products which could arise from ring opening at the less substituted carbon atom of the aziridine ring were isolated.

BF^OEto. 400 mol% O ^ H T s 84% 152a 152b 149 152a:152b = 2.7:1

BFq«OEto. 400 mol% 90% CC-. • CC-. 153a 153b 143 153a:153b =1:2.8

Scheme 2.7: Results &om intramolecular Sakurai reaction of aziridines with allylsilanes

2.6 Stereochemical determination.

5.4%

HcT/TNHTs .N H T s Me 2.6 % 152a 152b

Figure 2.1: Stereochemical determination of five membered carbocycles 152a and 152b

2.6.1 n = 1: In both the cis, five and six membered rings, protons He and He’ show up as a single multiplet. In both the trans five and six membered rings, protons He and He’ show up as separate multiplets.^^ The assignments for these protons was made by

40 COSY spectroscopy and homonuclear decoupling NMR experiments. For the cyclization leading to the formation of the five membered carbocycle, stereochemistry was readily determined by both NOES Y and nOe spectra (figure 2.1). The major isomer 152a showed crosspeaks between Ha and Hy, while the minor isomer 152b showed no crosspeaks between and Hy. The major cis isomer 152a also showed a 5.4 % enhancement of Ha upon irradiation of Hb. In the case of the minor trans isomer 152b a 2.6 % enhancement of He and He’ was seen on irradiation of Ha.

NHTs T^NHTs H^c He'

153a nOe 153b

Figure 2.2: Stereochemical determination of six membered carbocycles 153a and 153b

2.6.2 n = 2: The stereochemistry of the minor isomer 153a (figure 2.2) of the six membered ring cyclization was determined by an examination of the coupling constant of the allylic methine Ha. If the minor isomer was trans then the coupling constant Ja,b would be 7-10 Hz. If the minor isomer was the cis isomer then the coupling constant Ja,b would be 2-3 Hz. The COSY spectra of these compounds showed that this methine was coupled to the olefinic proton (7 = 8.8 Hz), methine Hb and a methylene at 6 1.4 ppm.

Irradiation of the methylene (1.4 ppm) collapsed the multiplet for the methine to a broad doublet (7 = 8.8 Hz). This indicated that the other coupling constant to the methine Hb was small (2 -3 Hz) indicating that this was the cis isomer 153a. These results were further confirmed by looking at the NOESY spectra of these compounds. In the minor isomer a crosspeak was seen between Ha and Hb, but unfortunately no crosspeaks could be unambiguously assigned for the major isomer 153b.

41 H H OH r t " 9-BBN, 90% \ ^ î ^ - N H T s c t r ^NHTs H H 153 154

RuCla, Nal04, 74%

H H

k^i^NTs " k^s^NTs H H 155 156 6.8 % Ha Hfl 2 1 % Hc

155 42% 156

Scheme 28: Stereochemical determination of lactams 155 and 156

In order to unambiguously assign the stereochemistry of 153a b it was decided to convert them to the lactams 155 and 156 respectively (scheme 2.8). To this end the olefin of 153 was hydroborated using 9-BBN to provide the primary alcohol 154 as the exclusive product. The alcohol 26 was then oxidized^^^ to the N-tosyl lactams 155 and

156, which were separable by flash chromatography. The stereochemistry of these lactams was then confirmed by examination of coupling constants and by nOe spectroscopy

In lactam 155, hydrogens Ha to Hf, all showed up as distinct signals in the NMR spectrum. These assignments were made by homonuclear decoupling and by looking at the coupling constants between the hydrogen atoms. Due to the trans ring fusion, the coupling constants between Ha-Hd (11.46 Hz) and Hy-Hg (11.75 Hz) were large (diaxial coupling constants). In comparison, the coupling constant between Ha-Hc

42 (4.52 Hz) and Hb*Hf (4.9 Hz) were small (axial-equatorial coupling constants). Hj also

showed an nOe to Hb (4.2%) but not to Ha, while He (6.1%) showed an nOe to Ha but not to Hb, indicating a trans ring fusion. In lactam 156, hydrogens Ha to Hy showed up as distinct signals in the *H NMR spectrum. Due to a cis ring fusion, the dihedral angle between both, Ha-Hc and Ha-Hd should be small. As a results the coupling constants between Ha-Hc (6.26 Hz) and Ha-Hd (5 Hz) were smaller. Irradiation of He in the nOe experiment showed enhancements in the signals for both Ha (6.6%) and Hb (2.1%), indicating a cis relationship between these protons and consequently confirming the cis ring fusion in 156. 2.7 Aziridine-allyisilane cyclization: Rationale for stereochemistry. 2.7.1 n = 1. The formation of the major cis isomer (scheme 2.9) could be explained as occurring via a chair like conformation (A). Here the aziridine and the allylsiiane orient themselves in an equatorial orientation. This arrangement reduces the unfavorable steric interactions which are seen in conformation C and conformation D.*® An alternate arrangement of the aziridine and the allylsiiane (B), in which both these moieties are in an axial arrangement would seem to be precluded due to unfavorable steric interactions. Coordination of the Lewis acid with the aziridine causes polarization of the more substituted C-N bond of the aziridine ring. This induces an attack by the allylsiiane which results in opening of the aziridine ring in a Sn2 fashion to form the positively charged intermediate 157, which can now undergo an elimination reaction to provide 152a. Note that in conf A, Ha and Hb are on the same side. On ring closure this orientation results in the formation of the cis substituted cyclopentane 152a. The formation of the minor trans isomer 152b could be explained as occurring via conformation C or conformation D. In these conformations either the aziridine or the allylsiiane adopts an axial conformation. The unfavorable steric interactions in both of these conformations makes them less favorable as compared to conformation A. In both

43 conformation C and conformation D, hydrogens Ha and Hb are on opposite sides and this results in the formation of the minor trans diastereomer 152b.

confonnation A H.. Ha ^ antkSp

Ts-N A"'SiMe3 NHTs LJ^ H 152a 149 157

conformation B Ha Hb Ha anthSe •SiM ea, ►n - la H ^ "-NTs R 3 sT h 5 ® t= RaSi H LA ^ ^NHTs 158 152a

conformation C RaSi. H RaSi. H

anthSp -SIMe.T ^ Ha \ 3 ^ H b Strain Hb TS-N + NHTs LA 152b 159

conformation D SIMea SIMea H%^H anthSp -SIMSrt

LA" ; NHTs Ts 152b 160

Scheme 2.9; Stereochemical rationale for formation of five membered carbocycles 152a and 152b

44 conformation A

H, » n £ h ®=' antf-S^ -SiR^ ,- N ,H Ts + LA rN Ts NHTs Hb LA 15 153b conformation B H

anti-Sp ,3 Strain5 V -SiR:^

t sn : TsHN LA 162 J 153b conformation C Ha anti-SEL Ha ^ H+N II -SiR;ï ^ H -y /@ LA 2 H - , / H H - y NHTs Strain SiMea " SiMea 153a 163

conformation D

anti-Sp -SiRq SiMea ^LAH H TsN. TsHN LA 153a 164

Scheme 2.10: Stereochemical rationale for formation of six membered carbocycles 153a and 153b

2.7.2 n = 2. The formation of the major trans isomer (scheme2.10) could be explained as occurring via a chair like conformation (A). Here the aziridine and the allylsiiane orient themselves in an equatorial orientation.*® This arrangement reduces the

45 unfavorable steric interactions which are seen in conformation C and conformation D. An alternate arrangement of the aziridine and the allylsiiane (B), in which both these moieties are in an axial arrangement would seem to be precluded due to unfavorable steric interactions. Due to the longer length of the tether between the aziridine and the allylsiiane, Ha and Hy are now on opposite sides. Thus, the trans fused carbocycle 153b is the major product formed in this cyclization reaction. The formation of the minor cis isomer 153b could be explained as occurring via conformation C or conformation D. In these conformations either the aziridine or the allylsiiane adopts an axial conformation. This results in unfavorable steric interactions in both of these conformations. In both of these orientations, Ha and Hy are on the same side of the forming six membered ring, resulting in the formation of the minor cis fused carbocycle.

2.8 Second generation synthesis of aziridine allylsilanes via epoxides. Now that we had determined that the intramolecular cyclization reaction of aziridine-allylsilanes could be accomplished successfully, we decided to look into the synthetic use of this cyclization reaction. But before we could do this, we still had to develop a workable route to the aziridine-allylsilanes. From our previous results we had seen that our earlier synthetic route was not ideal for the synthesis of aziridine-allylsilanes. This procedure included two low yielding steps for the introduction of both, the aziridine and the allylsiiane moieties. One of the reasons for low yield during the allylsiiane formation step was decomposition of the aziridine ring. This could be avoided by introduction of the allylsiiane prior to introduction of the aziridine ring. In our earlier route (section 2.3), the aziridine was synthesized by the addition of a metal-nitrenoid to an olefin. This precluded the inclusion of the allylsiiane moiety before the synthesis of the aziridine.

46 167 165

SiRg

«C OTBS OTBS 169 168

Scheme 2.11: Retrosyntbesis of aziridine-allylsilanes via epoxides

Keeping in mind the above considerations, we decided to introduce the allylsiiane prior to introduction of the aziridine ring in our new synthetic plan (scheme 2 .11). Aziridine-allyisilane 165 could be synthesized from the epoxide 166 by ring opening with azide followed by ring closure of the intermediate azido alcohol.69 The epoxide 166 could be synthesized from the aldehyde 167, which would arise from 168 by desilyation followed by oxidation. Finally, the protected allylsiiane alcohol 168 could be synthesized from the corresponding aldehyde by a Wittig reaction.^ ^ Another advantage of this route is that it allows for synthesis of an N-H aziridine, which could then allow introduction of different groups on the aziridine nitrogen. This route could potentially allow us to investigate the role of ±e nitrogen protecting group in the cyclization reaction.

47 SIMea

1) Swem Oxid. 82% 2) PhaPCHCHaSiMes ^ ^ ^ O T B S OTBS 133 1) m-Bu^NF 2) Swem Oxi.' (70% from 170) SIMea SIMea SIMea

N a N r, MeoSOCHo c £ - . 80% 55% OH 173

174

Scheme 2.12: Synthesis of aziridine-allylsilanes via epoxides

The synthesis of the N-H aziridine-allyisilane 174 is outlined in scheme 2.12. The first step in the synthesis involved monoprotection of hexanediol using NaH and TBSCl.^^ On a larger scale (100 mmol), this reaction resulted in the formation of a significant amount of the corresponding diprotected alcohol. This problem was overcome by using 5 eq. of the starting diol and 1 eq. of TBSCl. This modification provided the monoprotected alcohol 133 in 73% yield. This procedure was amenable for the synthesis of large quantity of 133 (500 mmol of hexanediol and 100 mmol of TBSCl). The protected alcohol 133 was oxidized to the aldehyde 134 by a Swem oxidation ^7 in excellent yield. The aldehyde was

48 now converted to the allylsiiane 170 by using a modification of Reming's original procedure.*^ The next step involved deprotection of the silyl protecting group in 170. Best results for this reaction were obtained using 1.1 eq. of / 1-BU4NF at 0 “C. Use of a larger excess of this reagent resulted in some protodesilyation of the allylsiiane. This deprotection could also be accomplished using PPTS in quantitative yield.* l The alcohol thus formed was oxidized to the aldehyde 171 by a Swem oxidation.

Entry Me2SCH2 ylid formn. Temp. 172 (yield)

1 1 eq. 30 min - 5 'C 58%

2 1 eq. 60 min -5 "C 53%

3 1 eq. 25 min -10 "C 52%

4 1 eq. 5 min 0 “C <50%

5 2 eq. 8 min - 5 “C 60%

6 10 eq. 8 min - 5 'C 65%

7 10 eq. 8 min -5'C 70%

Table 2.1: Synthesis of epoxide 172 from aldehyde 171

The next step in the synthesis involved conversion of aldehyde 171 to epoxide 172.^3 This was accomplished by the addition of trimethylsulfonium ylid to 171 (table 2.1). A drawback of this procedure is that trimethylsulfonium ylid is unstable and has to be used within minutes of its formation. Best results in this reaction are also typically obtained by using non-enolizable aldehydes.^^ Unfortunately this was not the case in our system, resulting in a lower yield (< 50%) of 172. A number of different conditions were attempted, but none of these resulted in improved yields of epoxide 172. Best yield for this reaction was obtained using a five fold excess of the sulfur ylid to aldehyde 171.

49 However, when these conditions were attempted on a larger scale very poor results were

obtained. TLC analysis of the reaction indicated substantial decomposition of the aldehyde had taken place during the reaction. Due to the poor results obtained with the trimethylsulfonium ylid, we decided to investigate the reaction using the more stable trimethylsulfoxonium ylicL^^a This

modification did provide us with the desired epoxide in a reasonable yield (50 - 55%) when the reaction was carried out on a relatively large scale (34 mmol). Epoxide 172 was opened by treatment with NaNg in MeOH to provide the corresponding azido alcohol 173. Conversion of 173 to the aziridine 174 was attempted by treatment with PhgP. Although, this procedure provided us with the desired aziridine, the yield was low and the reaction was not reproducible. Thus our second generation synthesis of the aziridine-allylsilanes did not prove to be an effective route for the synthesis of aziridine-allylsilanes. The difficulty in conversion of the aldehyde to the allylsiiane at times, the less than satisfactory yield during conversion of 171 to the epoxide, the capricious reaction for synthesis of the aziridine 174 and the long linear route made this method unsuitable for our work. In the rest of this chapter the third generation synthesis of aziridine allylsilanes via a novel rearrangement reaction of aziridines will be discussed. 2.9 Third generation synthesis of aziridine-allyisilane via iV-tosyl-O- tosyl-aziridinemethanols. At this stage, we had already investigated the two most common methods available in the literature for the synthesis of aziridines. It became apparent that we had to develop an alternative procedure which would be more suitable for our work. We needed a method which would be convergent, high yielding and allow for synthesis of optically pure aziridine-allylsilanes.

50 R® b

m - - n , - {Si-^75 175

(fl)-178

Scheme 2.13: Possible pathways in reactions of aziridine 176 with organometaiUc reagents

Our plan (scheme 2.13) was to prepare the aziridine 176 and to examine the reactivity of this molecule with a variety of organometallic reagents.^^ The reaction of the aziridine ring with cuprates, organolithium reagents and Grignard reagents is well known.®^ We were not certain where nucleophilic attack would take place with an aziridine such as 176, and a variety of products were possible. If nucleophilic attack takes place at the tosyl ester, (S)-175 would be the result We had hoped that attack would take place on the aziridine ring and lead to intermediate 177, which would then recyclize to form aziridine (/?)-178.

_52ÇuU_ T sO ^^R

1» 1 ®

182

Scheme 2.14: Reactions of giycidyl tosylate with nucleophiles

51 A similar strategy has been used in reactions of giycidyl tosyiate (scheme 2.14).*3 When glycidyl tosyiate was reacted with heteroatom nucleophiles, displacement of the tosyiate was observed to be the major reaction pathway. Reaction of glycidal tosyiate with organometailic reagents, however, gave products resulting horn exclusive epoxide ring opening. Such a strategy would allow the preparation of a number of monosubstituted aziridines from a single aziridine precursor. 2.9.1 Synthesis of iV-tosyl-O-tosyl-azirldinemethanoi. The preparation of aziridine 189 was carried out as shown in scheme 2.15. The readily available (S)- serine, was esterified, tosylated and the free hydroxyl group was protected as a /- butyldimethylsilyl ether. Reduction of the methyl ester was most efBciently carried out with lithium borohydride to produce 186.^ Reduction of 185 using LiAlH 4, provided the desired alcohol in low yield (<50%). The aziridine ring was then formed via a Mitsunobu reaction.*^ Desilylation of 187 provided aziridine 188 in 44% overall yield from (S)- serine. Tosylation of 188 produced the desired W-tosyl, 0-tosyl-aziridine 189.

1)TsCI,75% NHa NHTs 183 ^184, R = H TBSCI, 100%(^ 185, R = TBS

UBHa, 77%

. Phf^P. DEAD T B S 0 ^ " * Y ^ Q ^ 88% NHTs " 1»

n-BU4 NF, 187, R = TBS > 188, R = H TsCI, 77% f ^ 189,R = Ts

Scheme 2.15: Synthesis of A/-tosyl-0-tosyI-aziridinetnethanoI

52 2.9.2 Reactions of AT-tosyl-O-tosyl-aziridinemethanol with Grignard and Organolithium reagents. We initially looked at the reaction of 189 with Grignard reagents, cuprates derived from Grignard reagents and organolithioum reagents. Treatment with Grignard reagents such as MeMgBr, resulted in decomposition of 189. Reaction of 189 with organocuprate reagents prepared from the corresponding Grignard reagents and catalytic amounts of Cul resulted in ring opening of the aziridine ring in 189 with halide along with a complex mixture of other products as well. Reaction of 189 with n-BuLi surprisingly resulted in no reaction at all.

n-BugCuLi (2 eq) TsO ^ N ^ B u ©NTs 189 190

B u '^ ^ j^ B u NHTs 192 191

Scheme 2.16: Reaction of iV-tosyl-O-tosyl-aziridinemethanoI with 2 eq of R 2 CuLi

2.9.3 Reactions of Reactions of iV-tosyl-G-tosyl-aziridinemethanol with Organocuprate reagents. A survey of the literature at this stage indicated that best results during aziridine ring opening are usually obtained using organocuprate reagents derived from organolithium reagents and Cul or CuCN.^^’"*^ To this end, the aziridine 189 was treated with 2 eq. of n-Bu 2CuLi (scheme 2.16). This reaction did not provide an aziridine but instead, provided the tosylamide 192. This result indicated that the cuprate reagent could had opened the aziridine ring in 189 to provide the ring opened intermediate.

53 which then cyclised to provide the aziridine 191. Since an excess of the organometailic reagent was used, the second eq. of the cuprate reagent must have reacted with the new aziridine (191) to provide 192 as the final product. A second explanation could be that the organocuprate reagent had indiscriminately attacked both the aziridine ring and the tosyl ester to provide 192 as the final product.

T s O ^ ^ , _q-Bu2Cuü^ J > ^ B u ^ B u ^ ^ B u ^ H % Ts H NHTs 189 191 192

® 198

Scheme 2-17: Reaction of AA-tosyl-O-tosyl-aziridinemethanoI with 1 eq of RgCuLi

The reaction was then attempted using exactly one equivalent of n-Bu 2CuLi (scheme 2.17). This reaction provided the desired aziridine 191 in moderate yield (60%). Two other products were also isolated from this reaction. One of the products was the tosylamide 192 while the other product was identified as the iodide 193. After extensive experimentation it was found that, it was important to use a slight excess of organolithium reagent ( 1.15 - 1.25 eq titrated against diphenylacetic acid prior to use) to Cul (1 eq) during generation of the organocuprate reagent. This modification usually minimized formation of the iodide 193 It was also found that quenching the reaction at -78 °C, 15 - 20 min after the addition of the ditosylaziridine 189 to the organocuprate reagent reduced the amount of 192 which was formed in the reaction. However, it was not possible to completely eliminate the formation of 192 during the reaction.

54 ^BugCuU, 8 6 % W NHTs 194, R = TBS n-Bu^NF. 98%( ^ 195, R = H

PhaP, DEAD, 8 8 %

(fl)-191

Scheme 2.18: Stepwise synthesis of 191 from ^-tosyl-O-TBS-aziridinemethanol

2.10 Determination of absolute configuration of aziridine 191 synthesized via ring opening/closing reaction of ^-tosyi-O -tosyI- aziridinemethanol. Now that the yield of the aziridine 191 had been optimized, it was still to be determined if the absolute configuration of 191 was R or 5, or a mixture of the two. The absolute configuration of 191 would be /? if the reaction had proceeded by opening of the aziridine ring in 189, followed by ring closure onto the tosyl ester. The absolute configuration of 191 would be S, if the reaction had proceeded by displacement of the tosyl ester. In order to unambiguously assign the absolute stereochemistry, the aziridine 191 with the R configuration was prepared by an alternate route (Scheme 2.18).

Starting from aziridine 187, reaction with «-Bu 2CuLi gave a single ring opened product 194. Desilylation and aziridine formation via a Mitsunobu reaction gave 195 with the R configuration. This compound was identical with respect to optical rotation with 191 prepared via the single step aziridine opening/aziridine reformation reaction. This study conducted above confirmed our original belief that the reaction of aziridine 189 with organometailic reagents proceeds by a ring opening/closing sequence.

55 COaMe PhaP. DEAD

NHTs 98% % H 197 183 UBH4 . 80% ^ UAIH 4 HsCy -' o h i g g NHTs decomposition

TBS0^>^0 H nTrCI.Et^.67% I>?^OTr NHTs 2 )n-Bu 4 NF.7 5 % N 3) PhaP, DEAD. 80% rs 188 199

P d /C H a gas

H3 C. ^Y^OTir + other products NHTs 200

Scheme 2.19: Attempted synthesis of opposite enantiomer of 189 from (5)-serine

2.11 Determination of ee of aziridine 191 synthesized via ring opening/ closing reaction of A/>tosy 1*0 -tosyl-aziridinemethanol. We now wished to determine the enantiomeric purity of the aziridines formed by the ring opening/closing sequence. The enantiomeric excess (ee) of 191 could be determined by chiral HPLC or by NMR, utilizing a chiral shift or a chiral solvating agent. To determine the ee of 191 using a chiral shift or solvating agent, the other enantiomer of 191 was needed. For this purpose aziridine 206 (enantiomer of 191) was prepared from the aziridine tosyiate 205 (enantiomer of 189). A number of routes which could lead to 205 from (5)-serine were examined (scheme 2.19). The aziridine ester 197 was prepared from 183 via a Mitsunobu reaction.^^ Reduction of the ester using LiAlHa resulted in

decomposition products. Reduction using LiBH 4 gave only the completely reduced product 198. Another route which was attempted involved protection of the free hydroxyl of 186

56 with a trityl group. DesUyation followed by a Mitsunobu reaction gave the trityl protected aziridine 199. Hydrogenation of 199 using Pd on charcoal gave a mixture of products. The major product 200 was found to be the one arising from hydrogenolysis of the aziridine ring.^*^

COgMe COgMe H O ^ Y 11 TsCI NHg 2)TrCI NHTs 91% (over 2 steps) 201 183 1) U B H 4 , 2) TBSCI. 87% (over 2 steps)

Pd(OH)2 /G. Hg H O ^ " Y ^ °T B S TiO ^ Y ^ O T B S NHTs 60% NHTs 203 202

PhgP, DEAD, 6 6 %

1) n-BuaNF "jX ^O T B S 2) TsCI, EtaN, % H 72% (over 2 steps) 2 0 4 205

n-BugCuU, 65"^

Scheme 2.20: Synthesis of aziridine 206 (opposite enantiomer of 191) from (5)-serine

The method which ultimately worked is depicted in scheme 2.20. The methyl ester of (5)-serine was Af-tosylated, followed by tritylation of the free hydroxyl group to provide 201. Reduction of the methyl ester and protection of the resulting alcohol with r-butyl- dimethylsilyl chloride gave 202. Removal of the trityl group proved to be difficult. Use of

57 palladium on activated charcoal resulted in long reaction times and low yields o f203.

Hydrogenation using 100 w t % of Pearlman’s catalyst provided 203 in a 33% yield ( 60% considering recovered starting material). Use of more vigorous conditions resulted in

complete removal of the trityl as well as the silyl protecting group. Detritylation using

formic acid in ether provided the desired product in only 39% yield.8? As before, the

aziridine 204 was formed via a Mitsunobu reaction of the vicinal amido alcohol.

Deprotection of the silyl group, followed by tosylation of the alcohol, produced 205.

Aziridine 205 was then treated with n-Bu 2CuLi to provide 206.

y

UH6 pp»*»

kLf ppr**^e/V»-n'tl‘onneV^ JU

' * I * t .m I m I

Figure 2.3: NMR spectrum of 191 containing 5% (bottom) and 20% (top) of 206

With the enantiomeric aziridines 191 and 206 in hand, we attempted to determine the optical purity of the aziridine 191 using a chiral shift agent (+)-Eu(hfc) 3. This reagent did not allow for differentiation of the aziridine 191 from its enantiomer 206. Differentiation of peaks corresponding to the two enantiomers 191 and 206 using (+)-

58 Eu(hfc) 3, was only seen when a 4:1 mixture of 191 and 2 0 6 was present in the sample.

Peaks from 2 0 6 were not seen when it was present in a lower concentration (< 10%) in the sample.

We then decided to investigate the chiral solvating agents (5)- or (/f)-(-)-2,2,2- trifluoro-l-(9-anthryl) ethanol, for the ee determination (figure 2.3). We had to first

establish if we could differentiate by NMR, the signals for aziridines 191 and 2 0 6 (using chiral solvating agents) when they were present in a mixture. To this end, ca. 3 mg

of the aziridine 191 (containing approx. 5% of 2 0 6 ) and 25 mg of the solvating agent (R)- (-)-2,2,2-trifluoro-l-(9-anthryl) ethanol were dissolved in benzene-d^ (0.5 - 0.6 mL). For

aziridines 191 and 2 0 6 , the doublet at 1.46 ppm corresponding to one of the methylene

protons on the aziridine ring, was shifted to 1.44 ppm for 2 0 6 (5 enantiomer) and 1.46

ppm for 2 0 6 (R enantiomer). Integration of the above signals allowed us to assign an

optical purity of 91% to aziridine 191. To confirm that the signal (barely visible above the

baseline noise) at 1.44 ppm arose from the m inor aziridine 2 0 6 , the NMR experiment was repeated using additional 206 (20%). This led to enhancement of the signal at 1.44 ppm confirming that this signal arose from the minor aziridine 2 0 6 . None of the peaks arising from 2 0 6 were seen when pure 191 was used for the NMR experiment, indicating that optical purity of 191 was > 97% (inherent limitation of the procedure).

2 .1 2 Reactions of iV*tosyl-0*tosyl*aziridinemethanol with other organocuprate reagents Satisfied that the reaction of 1 89 with a cuprate would provide

191 via a ring opening - ring closing sequence, we turned our attention to the use of other organometailic reagents. The cuprates derived from commercially available methyllithium, hexyllithium and trimethylsilylmethyllithium gave acceptable yields of the corresponding aziridines 2 0 7 - 2 0 9 (scheme 2.21). When methyllithium was used, the diopened product was obtained in a greater amount as compared to reactions using other organolithium

59 reagents. The increased amount of diopened product could be attributed to the smaller size of Me 2CuLi which makes the ring opening reaction more favorable.

T s X s 189 (fl)-191, R = n-Bu, 74% (fl)-207, R = Me. 60% (R)-208, R = CH2Si(CH3)3, 69% (fl)-209, R = rhHexyl, 68% (fl)-210, R , 70%

(R)-211,R = '^

Scheme 2.21: Reactions of Af-tosyl-O-tosyl-aziridlnemethanol with other organocuprate reagents

We also attempted to prepare and use a cuprate prepared from j-BuLi. Although this reagent did provide us with some of the desired aziridine, this reaction was not as clean as the reactions using the cuprates derived from primary organolithiums. Similarly cuprates derived from phenyl lithium, vinyl lithium and vinyl magnesium bromide only resulted in the decomposition of 189. In reactions using vinyl and phenyl cuprates, it was very difGcult to stop the reaction after addition of a single equivalent of the organocuprate reagent to 18 9 . It was observed that these cuprates, being more stable are also less reactive. Thus it is not possible to accomplish the ring opening reaction of 189 at -78 "C using 1 eq of the organocuprate reagent in question. The ring opening can be accomplished when ca 3 - 5 eq. of the organocuprate reagent is used and when the reaction is carried out at a higher temperature (-10-0 “Q . Unfortunately, under these conditions, addition of 2 eq of the organocuprate to 189 and opening of 189 with halide becomes a major problem, thus limiting the use of more stable cuprates in this reaction.

60 2.13 Synthesis of aziridine-allylsilanes from ^ tosy 1-0-tosyi- aziridinemethanoi. We now turned our attention to using this procedure for the synthesis of our target aziridine-ailyisitanes (scheme 2.22). The aziridine ailylsilane 210 could be synthesized by reaction of cuprate 212 with ditosyl aziridine 189. The cuprate 212 could in turn be synthesized form the iodide 214 by a halogen-metal exchange reaction.*^ The iodide 214 could then be synthesized from alcohol 216» which could be prepared by a Wenkert coupling reaction between a cyclic enol ether and a Grignard reagent in the presence of a Ni catalysL*^

-IzCuU H n = 1.212 189

n = 1 , 2 1 0

I ^ n = 1,216 n = 1,214

)n + SiMeaCHaMgCI

Scheme 2.22: Retrosynthetic analysis for synthesis of aziridine-allylsilanes from 189

Ring opening of dihydrofuran with Me 3SiCH2MgCI provided the alcohol 216 in good yield. Ring opening of dihydropyran with Me 3SiCH2MgCl provided ± e product allylsilane-alcohol 217 in low yield (20%). The reason for the low yield is that dihydrofuran reacts faster than dihydropyran due to greater relief of ring strain during the

6 1 coupling reaction. The yield of 217 improved slightly (35 %) when dihydropyran was stirred over sodium or CaH 2 overnight and distilled just before use.

An experimental difficulty encountered in this reaction is that, the coupling reaction is carried out in benzene, while the commercially available Grignard reagents are available as ethereal solutions. This necessitates removal of ether from the reaction by distillation.*^ It is conceivable that any residual ether in the reaction could coordinate the nickel catalyst and lower the effective concentration of the catalyst available for the reaction thereby reducing the yield of the final product 217. To eliminate this possibility, ether was distilled out of ±e reaction untill pure benzene distilled over. This modification resulted in slight improvement of yield of the ailylsilane alcohol 217 (45%). Although this was not a high yielding reaction, it did provide us with 217 in a single step. The reaction was also amenable for larger scale preparation of 217, thus making it practical for our work.

MeaSi SiMeaCHaMgCI 0"O > " (PhgPlaNiCIa 216, n = 1. 60- 70% n = 1,2 217,0 = 2,35 - 45%

1)TsCI 2) Nal, acetone, 90% SiMea

^ t-BuLi, n-BuaP. Cul 214, n = 1 N n ' H 215, n = 2 Ts Ts 21 0 , n = 1 189 2 1 1 , n = 2

Scheme 2.23: Synthesis of aziridine-allylsilanes from ditosyl aziridine 189

62 The synthesis of aziridine-allylsilanes 210 and 211 starting from dihydrofuran and dihydropyran is shown in scheme 2.23. The alcohols 216 and 217 were converted to the iodides 214 and 215 respectively, by tosylation followed by displacement with iodide.® ^ The iodide 215 was cleanly converted to the corresponding organolithium reagent by treating it with f-BuLi at -78 “C in Et20.®® Treatment of the intermediate organolithium with Cul resulted in the formation of an insoluble cuprate which did not provide very good yields of 211 (30 - 34%). This problem was overcome by the addition of n-BugP^ to the reaction, producing 211 in 75% yield. Using a sim ilar protocol, the iodide 214, was converted to the aziridine 210. 2.14 Reactions of differentially protected aziridinemethanois with organocuprate reagents.

MeaSi ^ r^<^OTBS _ N H IgCuU R " RHN OTBS 218 n = 1 , 2 1 2 219 R = Ns, Cbz, Boc

220

Scheme 2.24: Retrosynthesis of differentially substituted aziridine-allylsilanes

Now that we had developed a suitable synthetic route for A/-tosyIaziridine- allylsilanes, we wished to expand the scope of this chemistry for the synthesis of aziridine- allylsilanes with N-protecting groups other that tosyl. We thought that if we could open 63 aziridines such as 218 with organocuprate reagents, we could eventually transform the ring opened intermediates to the corresponding dirierentially substituted aziridine-allylsilanes

220 (scheme 2.24). If the nitrogen protecting group was either Cbz, Boc or Ns, we could potentially deprotect the iV-protecting group in 220, to provide the corresponding N-H aziridine-allylsilane, which could then be protected with the substituent of choice. To this end, we synthesized the N-Cbz-O-TBS-aziridinemethanol 223 starting firom (S)-serine as shown in scheme 2.25.

NHs+Cr 2 ) TBSCI NHZ 58% (over 2 steps) 221

1 ) U B H 4 . 7 3 %

l^ % ^ O T B S PhaP. dead . 84% T B S O ^ ^ |^ O H Z H NHZ 223 222

Scheme 2.25: Synthesis of ^-Cbz-O-TBS-aziridinemethanol 223 horn (S)-serine

2.14.1 Reactions of iV-Cbz-0>TBS-aziridinemethanol with organocuprate reagents. Treatment of 223 with a variety of organcuprate reagents (table 2.2) did not provide any of the desired ring opening product Instead, only products arising from attack of the cuprate reagent on the Cbz carbonyl were isolated. This was not very surprising, as organometailic reagents are known to attack the carbonyl carbon of the acyl protecting group in preference to attack on the aziridine ring."^9

64 nng opening

iJV ^ O T B S T B S O ^ ^ j^ B u 0= < " NHZ 223 p 224 Bn attack on Cbz group

No. Cuprate Solvent Temp Time Result

1. n-Bu 2CuLi/n-Bu 3P (leq) ether -78° C - rt Ih Cbz attack

2. n-Bu 2CuLi/n-Bu 3P (2eq) ether -78° C - rt 1 h Cbz attack

3. n-Bu 2CuLi (1.2 eq) THF 0 °C -rt Ih Cbz attack

4. n-Bu 2CuLi/Bp 3"OEt2 (1.2 eq) THF -78° C - 0° C 1 h Cbz attack

5. n-Bu 2CuLi (2 eq) THF -78° C Ih Cbz attack

6. n-Bu 2CuLi/BF3»OEt2 (5 eq) THF -78° C - 0° C 1 h Cbz attack

7. n-Bu 2CuLi (1.2 eq) THF -40° C Ih Cbz attack

8. n-Bu 2CuCN2Li (2 eq) THF -78° C 1 h Cbz attack

9. n-Bu 2CuCN2Li (1 eq) THF -78° C - rt 18h Cbz attack

Table 2J2: Reactions of A^-Cbz-O-TBS aziridinemethanoi with organocuprate reagents.

Some 223 was recovered in all the cases. In entry S BF 3 .0 Et2 was mixed with the aziridine and the mixture was added to the cuprate solution.

2.14.2 Reaction of iV*Boc>0>Ts-aziridinemethanoI with organocuprate reagents. Since the N-Cbz aziridine 223 did not show satisfactory reaction with n-Bu 2CuLi, we decided to investigate aziridine 225, where the Cbz protecting group was replaced with the bulkier r-Boc protecting group and the silyl ether replaced with a tosyl ester. It was thought that the iV-Boc aziridine 225, would not be activated enough to undergo nucleophilic ring opening with R 2CuLi and the bulky r-Butyl

65 substituent would hinder attack of RzCuLi on the acyl carbon. These modifications could potentially allow one to displace the tosyl ester in 225 with R 2CuLi and at the same time preserve the unreactive A^carfaamoyl aziridine to provide 226 as the product

Unfortunately, aziridine 225 was completely unreactive when treated with n-Bu 2CuLi and ra-Bu2CuCNLi and none of the desired aziridine 226 was obtained from this reaction (scheme 2.26).

^ displacement of tosyl ester

X -- Boc H n-BuaCuU Boc H 225 226

Scheme 2.26: Reaction of iy-Boc-O-Ts-aziridinemethanol with organocuprate reagents

2.14.3 Reaction of iV-Ns-O-TBS-aziridinemethanol with organocuprate reagents. Lastly, the p-nitrophenylsulfonyl protecting group for the synthesis of differentially substituted aziridine-allylsilanes was also investigated. The aziridine 227 was synthesized from 223 by catalytic hydrogenation followed by treatment with p-nitrobenzenesulfonyl chloride (scheme 2.27). Unfortunately, treatment of 227 with n-Bu 2CuLi resulted in complete decomposition and none of the desired ring opened product was obtained.

1) Hg. Pd/C (10%w/w) Z " 2) p-NOaPhSOaCI. __ 223 EtaN. 75% 227 (over 2 steps) n-BugCuLi/nBuaP

decomposition

Scheme 2.27: Reaction of A^-Ns-O-TBS-aziridinemethanoI with organocuprate reagents. 66 RX ( On

228 229 230

Scheme 2JH: Deprotection of A^-tosylaziridine-allylsilanes

2.15 Deprotection of iV-sulfonylaziridines. We still needed a procedure which would allow us to synthesize aziridine-allylsilanes with different nitrogen protecting groups. An attractive method to access aziridines such as 230, would be by deprotection of N-tosylaziridine-aUylsilane 228 to provide the corresponding deprotected aziridine 220, followed by reaction of 230 with the protecting group of choice (scheme 2.28).

^ BuaCuLi B n - . ^ + PhgPOBu N POPha H 61% 231 232

BugCuLi . P h - ^ 96% N SOPhCHa H 233 234

Na/NHa N 50% 236

OTES TFA. EtSH OMtr 64% H OTes 238

Scheme 2.29: Deprotection of some A^-protecied aziridines

67 A difficulty typically encountered in deprotection reactions of aziridines, is the competing ring opening reaction.^* This ring opening reaction can potentially be avoided, if the nitrogen protecting group is one which does not strongly activate the aziridine towards ring opening such as trity l,^ phosphinyU^h sulfinyl,^ or alkoxy.^** (scheme 2.29) Removal of iV-tosyl groups is substrate dependent and typically requires harsh conditions such as HBr/AcOH, Na/NHg and Na/Hg.^3 one would not expect an iV-tosylaziridine ring to be stable under these conditions. It was not surprising that there were very few reports in the literature of deprotection of ^-tosylaziridines.^ One of these reports had indicated that certain aziridines undergo SET (single electron transfer) to the sulfonyl group faster than reductive cleavage of the C-N bond of the aziridine ring.^^^ Unfortunately, these authors could only obtain the deprotected aziridines in low yield (scheme 2.30). It was felt that there was a chance of improving the yield of the deprotected aziridines by investigating alternative reaction conditions for the SET reaction.

OTRQ ^ 1) Na/naph. 16% NTs 2) n-Bu^NF

Na/anthracene

241 242

Scheme 2.30: Deprotecdon of yV-tosyl aziridines by single electron transfer

2.15.1 Deprotection of iV-tosylaziridine-allylsilane using sodium/ naphthalenide. We first attempted to deprotect aziridine 211 using sodium

6 8 naphthalenide^^ (3 eq in THF) as the reducing agent at 0 "C. This reaction provided the desired aziridine 243 in 52% yield. The yield improved to 69% when sodium- naphthalenide was added dropwise (see experimental) to a cold (-78 “Q solution of aziridine 211. With aziridine 243 in hand, the aziridines 244-246 were synthesized by reaction with benzylbromide,^^ /7-nitrobenzenesulfonyI chloride and phenacetylchloride respectively (scheme 2.31).

Na/naphthalenide

211 243(69%)

RX

244. R = Bn. 12% 245. R = Ns. 78% 246. R = Phenacetyl. 56%

Scheme 231z Synthesis of differentially substituted aziridine-allylsilanes from an iV-tosylaziridine

It was perceived that this methodology could be a useful general procedure for synthesis of a variety of differentially iV-protected aziridines from a single iV-tosylaziridine precursor. This combined with the fact that chiral and racemic iV-tosylaziridines can be easily synthesized from the corresponding olefin by using methodology developed by

Evans and other groups.^0.97 ^gre compelling reasons to explore the compatibility of the

69 deprotection conditions with different functional groups (other that those which were already known to be incompatible with sodium naphthalenide).^^

2.15.2 Deprotection of iV

(scheme 2 .3 2 ) Deprotection of the tosyl group in 187 provided the aziridine 247 in excellent yield (90%). A similar yield ( 100%) was obtained when the deprotection was carried out at 0 "C. It was also observed that best results were obtained when the deprotection was carried out in DME as opposed to THF.

T B S O ^ '^ , Na/naphthalenide 183 Ts 247,89%

BnBr. Ki HO- -OH K2CO 3, 78% H O - -OBn 248

TsCINa, PTAB, 15%

TBSO^^^^/A^OBn . TgSa.^°/°- HO^ ,O B n

250 249

Na/naphthalenide

N TBSO^^^//-\^OBn 251 (76%)

Scheme 232: Deprotection of iV-tosylaziridines containing an ether linkage

70 We also wanted to examine the stability of other ether groups in this reaction. For this purpose, the O-TBS-O-Bn aziridine 250 was synthesized starting from butenediol (scheme 2.32). Monoprotection of butendiol^ with BnBr provided 248 which was converted to the aziridine 249 using conditions described by Sharpless.^^ The firee hydroxyl group was then protected as the TBS ether to provide 250. Deprotection of 250 using sodium naphthalenide provided the aziridine 251 ( 76 %).* 02b \ small amount of the benzyl cleaved aziridine was also detected by tic of the crude reaction mixture. The successful deprotection of 250 indicates that the conditions are mild enough that even the reductively labile benzyl ethers are stable under the reaction conditions.

2.15.3 Deprotection of iV-tosylaziridlne containing an ester or amide linkage. Next, the deprotection reaction when a carbonyl group is present in the molecule

(scheme 2.33) was explored. The aziridine ester 253 was synthesized from the known acid

252 by estérification with f-BuOH using DCC as the coupling reagent Unfortunately, deprotection of the ester 253 resulted in decomposition and none of the desired product was seen either by tic or in NMR of the crade reaction mixture. Decomposition in this case could have resulted from attack of the intermediate nitrogen anion onto the carbonyl carbon of the ester group. Decomposition could have also resulted from cleavage of the C- N bond of the aziridine ring, adjacent to the carbonyl group,

f-BuOH, BuO' ^ Na/naph. decomp. DCC, 46%. N 253 Ts H O - ^ 252 Ts O f-BuNH2, Na/naph. _ TBTU, 50%) BuHN N N H 254 Ts 255 (93%)

Scheme 233: Deprotection of A/-tosyIaziridine containing an ester or amide linkage.

71 To test for this possibility, the aziridiner-butylamide 254 was synthesized by a coupling reaction between the known acid 252 and t-butylamine using TBTU as the coupling reagent (scheme 2.33). Deprotection of the amide 254 at -78 "C provided the desired aziridine 255 in excellent yield (93%). This result indicated that presence of an adjacent carbonyl group does not necessarily lead to decomposition.

BzCI, 75%.

249 256

Na/naph.

decomp.

Scheme 2,34: Deprotection of iV-tosylaziridine with adjacent benzoyl group

We next wished to examine the compatibility of an ester linkage at other positions within the molecule. The benzoate ester 256 was prepared by benzoylation of alcohol

249.102 Unfortunately, deprotection of 256 using sodium/naphthalenide resulted in decomposition (scheme 2.34). It was not readily apparent if the decomposition resulted due to SET to the benzoyl carbonyl groups or due to a fragmentation reaction facilitated by a relatively good leaving group adjacent to the aziridine ring. It was then decide to move the ester functionality further away from the aziridine ring. For this purpose the aziridine 258 was synthesized from the alcohol 257 by treatment with pivaloyl chloride (scheme 2.35). Interestingly, deprotection of the tosyl group in 258, provided the desired aziridine 259 (63%) which was contaminated with a small amount of the 262 ( 15%). The formation of 262 could be rationalized by acyl transfer resulting from attack of the negatively charged intermediate aziridine anion onto the pivalate ester. The distance of the pivalate ester from the aziridine ring and the fact that

72 0J4- dipivalate product was formed indicated that the acyl transfer was intermoiecuiar and not intramolecular. This problem was avoided simply by carrying out the reaction in more dilute solution (0.07 M in DME), which eliminated the intermoiecuiar acyl transfer reaction to provide the deprotected aziridine 259 (88%).

^ v ^ O P iv PivCI, 70% Na/naph. a " % Vs 141 258 259(88%) Na/naph.

H ^ ^ / O P i v [ + [ +299 (62 %) Rv 250 261 (15%) 262,15%

Scheme U S : Deprotection of iV-tosylaziridine containing a pivaloyl ester

2.15.4 Deprotection of A/^-tosylaziridines containing an aromatic ring. The compatibility of aromatic rings under the deprotection conditions was examined next(scheme 2.36). The known aziridines 263 and 265 were deprotected using sodium/ naphthalenide at -78 °C. In case of 263, the deprotected aziridine 264 was obtained in excellent yield (89%) when the reaction was carried out at -78 “C. None of ±e desired product 264 was obtained when the reaction was carried out at 0 °C. In case of 265, the deprotected aziridine 266 (64%) was obtained along with a small amount of N- tosylphenethylamine (19%), which arises from reduction of the benzylic C-N bond of the aziridine ring. This result was not entirely unexpected, as deprotection of 265 using Sml 2 provided only the reduced product.^

73 Na/naphthaiide c r ^ 263 264(89%)

NTs Na/naphthalide

265 2661

Scheme 2J6: Deprotection of Af-tosylaziridines containing an aromatic ring

2.15.5 Deprotection of Bicycllc iV-tosylaziridines. Lastly, deprotection of bicycllc N^tosylaziridines which are more strained as compared to acyclic aziridines was addressed. For this purpose iV-tosylcyclohexylaziridine^o was deprotected using sodium/naphthalenide at -78 °C. Although this reaction provided us with the desired product (as indicated by tic), it was very difficult to isolate the volatile product Attempts to isolate the cyclohexylaziridine as its N-Boc or IV-benzoyl derivative, by in situ acylation provided the corresponding aziridines only in low yield (< 30%).

OTBS

OTBS PhlNTs

267

OH OH Na/naph.

270 (84%) 269

Scheme 2.37: Deprotection of bicyclic iV-tosylaziridine derived from (-)-nopol

74 We then looked at another W-tosyl bicyclic aziridine 269, derived from (-)-nopol (scheme 2.37). The synthesis of 269 is outlined in scheme 2.38. Protection of the hydroxyl group in nopol with TBSCI, followed by aziridination using PhlNTs provided 268, which was then desilyated using n-Bu^NF to provide aziridine 269. Deprotection of 269 using Na/naphthalenide at -78°C provided the desired deprotected aziridine 270 (84%). The successful deprotection of 269 also indicates that a hydroxyl group adjacent to the aziridine ring is tolerated in the deprotection reaction. 2.16 Summary: The challenge faced when this project was started, was to develop an efBcient workable synthetic route to aziridine-allylsilanes and to elucidate the products formed during the intramolecular cyclizations aziridines with allylsilanes. Ideally the synthetic route had to be convergent, highly yielding, enantioselective and also allow us to synthesize aziridine-allylsilanes with different substituents on the aziridine nitrogen. After some exploratory work a synthesis of the aziridine-allylsilanes starting from (5)-serine was developed. This route was convergent, high yielding and enantioselective.

This synthesis of aziridine-allylsilanes in conjunction with the deprotection reaction of N- tosylaziridines, allowed access differentially substituted aziridine-allylsilanes. During the course of this work the ring/opening closing reaction of ditosyl-aziridinemethanols was published as a general procedure for the synthesis of scalemic aziridines. A second manuscript dealing with deprotection of iV-tosylaziiidines has also been submitted. Another important aspect which was addressed in this chapter was the structural elucidation of products obtained from reactions of aziridines with allylsilanes and the stereochemical rationale for their formation. A third manuscript resulting from this work was also published. In the succeeding chapter of this dissertation, the application of this methodology toward the synthesis of the rauwolfia alkaloids (-)-yohimbane and (+)- alloyohimbane will be discussed.

75 CHAPTER 3

TOTAL SYNTHESIS OF (-)-YOHIMBANE AND EiVr-ALLOYOHIMBANE

3.1 Introduction. (-)-Yohimbane 271 and (-)-alloyohimbane 272 (figure 3.1) are members of the rauwolfia alkaloid family.^ ^ Representative members of this family include reserpine, ajmalicine and yohimbine (figure 1.1). These alkaloids have a

characteristic pentacyclic ring firamework. These alkaloids also possess a wide range of interesting biological activities including antihypertensive and antipsychotic actions.*^^

H"

271, (-)-yohimbane 272, (-)-alloyohimbane

Figure 3.1: Structures of (-)-yohimbane and (-)-alIoychiinbane

Yohimbine is a potent antagonist of the a-adrenergic receptors. Analogs of yohimbine have been used as important pharmacological tools for the differentiation of a

adrenergic receptors.^3 However, most of the SAR studies have been carried out using

related alkaloids and semisynthetic compounds. We believe that developing a suitable synthetic route to this alkaloid family will allow us to carry out more comprehensive SAR of these alkaloids. The first step in this direction was to develop a synthesis of the relatively simpler alkaloid yohimbane, with the intention of using the chemistry developed, for the 76 synthesis of more complex analogs later on. We will discuss how our synthesis can be applied to the preparation of yohimbine analogs in section 3.2 of this chapter. Since the first synthesis of reserpine*^ and yohimbine, (08 a number of other synthetic approaches to this alkaloid family have been reported. (09 While the synthesis of racemic 271 and 272 has been addressed on numerous occasions, to our knowledge only two asymmetric syntheses of (-)-yohimbane have been reported. The first asymmetric synthesis of (-)-yohimbane was reported in 1991.( (0 These authors synthesized (-)- yohimbane utilizing an in situ 1,4-addition/ring closure reaction of a chiral a-sulfinyl ketimine anion with an ene ester. Recently, Aube et al published an elegant oxaziridine rearrangement approach to this alkaloid family.*^

Lewis Acid (LA) NHTs NTs

143 153b (major product)

Scheme 3.1: Intramolecular Sakurai cyclization between an aziridine and an allylsilane

In chapter 2, the intramolecular cyclization reaction of aziridines with allylsilanes was described. The product of this reaction is an aminomethyl substituted carbocycle 153. It was envisioned that amino olefins such as 153 could be extremely useful for the asymmetric synthesis of alkaloids, especially the rauwolfia family. In order to demonstrate the synthetic utility of these amino olefins, it was decided to use this cyclization reaction as a key step in the synthesis of (-)-yohimbane, emoute to developing a general synthetic route to this alkaloid family. 3.2 Retrosynthesis: A well known method to construct the C ring of rauwolfia alkaloids is the Bischler-Napieralski reaction of lactam 274.^ The lactam 274 could be

77 synthesized from the corresponding ring opened ester 275 by deprotection of the tosyl

group followed by intramolecular amide formation. The ester 275 could be synthesized from the indole-olefin 276 by hydroboration-oxidation of the olefin moiety. The indole- olefin 276 could then be synthesized by a simple alkylation of the amino olefin 277, which in turn would arise from the aziridine-allylsilane 278, via a cyclization reaction.

When there is no functionality along the tether between the aziridine and the allylsilane, this reaction could be useful for synthesis of simpler members of this alkaloid family such as yohimbane and alloyohimbane.

TsN.

273 274 R3 275 ^2

TsHN NTs

Ra 278

Scheme 3.2: Retrosynthetic analysis of Rauwolfia alkaloids

Analogs of yohimbane such as those shown in scheme 3.3 showed some selectivity

for the tt 2 receptor. It is conceivable that by further altering the aromatic ring and the

position of the hydroxyl group along the E ring might provide compounds which have a better pharmacological profile. These types of analogs could be easily synthesized starting

78 from aziridine-allylsilane 283 as shown in scheme 3.3. The aromatic ring of choice could then be easily appended on to the amino olefin formed by cyclization of 283 by using conditions described in section 3.5.1.6.

279 H 280 H" 2S1 H" 1659 Og:ai 126 OH OH OH

O 282 n = 0 ,1,2,3

R = OH

Scheme 3J: Preparation of yohimbane analogs

3.3 Synthesis of iV-tosylaziridine>aliyisilane.

MeaSi

72-78% )2Cuü Æ >t^OTs Is H 189 (fl)-211

Scheme 3.4: Single step synthesis of aziridine-allylsilane

79 3.3.1 Single step synthesis of aziridine-allylsilane. The initial synthetic efforts were directed towards developing a convenient synthesis of the aziridine-allylsilane 211. The first generation synthesis of these type of molecules was racemic and involved two low yielding steps to introduce both the aziridine and the allylsilane moieties. After exploring a few other routes as discussed in chapter 2, it was realized that 211 could be synthesized by the reaction of an aziridine 189 with an appropriate organocuprate reagent (scheme 3.4).

SiMes MeaSi

^ . nBuaP/ether, 97% “ ^ O T B S - 213 Is H NHTs 187 ^ 285, R = TBS nBu4NF, 91 %( V 286, R = H

PhaP, DEAD 89%

(fl)-211

Scheme 3.5: Stepwise synthesis of aziridine-allylsilanes.

3.3.2: Stepwise synthesis of aziridine-allylsilanes. While this was a useful method to provide a quick access to chiral 211 (>97% ee), it was not possible to get reproducible yields when the reaction was carried out on a scale > 2mmol. Hence, it was decided to synthesize 211 via a stepwise process starting from the aziridine 187 (scheme 3.5). Reaction with the cuprate 213 provided the ring opened product 285 in almost quantitative yield. Deprotection of the silyl ether using n-BuaNF provided the alcohol 286, which was then converted without any purification, to the aziridine 211 via a Mitsunobu 80 reaction. This sequence provided a slightly higher yield (83% from 187) as compared to the single step procedure. This sequence could be conveniently carried out on a 5 mmol or greater scale.

3.4 Cyclization of aziridine-allylsilane 211. The aziridine 211 was then cyclized by treatment with BF 3*OEt 2 (300 - 400 mol%) to provide the amino olefins trans- 287b and cw-287a (scheme 3.6) as an inseparable mixture (diastereoselectivity 2.8:1 - 2:1). The stereoselectivity of the reaction was dependent on the temperature at which the

Lewis acid was added to the reaction. Typically when BF 3«OEt2 was added to the reaction at -78 °C and the reaction was allowed to warm to room temperature gradually and then stirred for 24 hours, the ratio of 287a:287b was observed to be 1:2.8. However when the

BF3*OEt 2 was added to the reaction at 0 'C and the reaction then allowed to warm to room temperature and stirred for 24 hours, the ratio of 287a:287b was observed to be ca. 1:2.

90-94% d b - • c t - . H H 287a 287b 287a:287b =1:2.8-1:2

Scheme 3.6: Cyclization of aziridine-allylsilane 211

A number of different Lewis acids were used in an attempt to improve the stereoselectivity of the reaction. Unfortunately, use of stronger Lewis acids such as TiCU and SnCU or Lewis acids with strongly nucleophilic counter ions such as MgBr 2 resulted in opening of the aziridine ring with the Lewis acid counterion even at -78 "C. Use of TMSOTf did provide some of the desired product but this was usually accompanied by protodesilyation as well as formation of some other unidentified products. Use of weaker

81 Lewis acids such as Ti(OiPr)a, Yb( 0 Tf)3 and Zn( 0 Tf)2 did not result in any reaction even

at elevated temperatures. Use of protic acids such as CF 3CO2H resulted in decomposition.

Use of solvents other than CH 2CI2 was also unsuccessful.

3.5 Total synthesis of (-)-yohimbane and en/-aIloyohimbane. The initial plan was to separate the diastereomeric sulfonamide by preparative HPLC and use diastereomerically pure sulfonamide 287b for the synthesis. After some experimentation, it was found that separation of 287a and 287b was only seen when the retention time was relatively long (over 60 min. on a reverse phase column). Any attempt to reduce the retention time did not provide satisfactory baseline separation. Next, separation of the two diastereomers by using preparative HPLC was attempted. Unfortunately, the separation proved to be difBcult and extremely time consuming. At this point of time it became obvious that separating 287a-b by HPLC, was not feasible without investing a lot of time in investigating different solvent systems and solid supports. Hence it was decided to go ahead with our synthesis of (-)-yohimbane, with the intention of separating the final products at the end of the synthesis.

NHTs Br

2B7 288

Scheme 3.7: Attempted alkylation of amino-olefin 287 using bromide 288

3.5.1 Alkylation of amino-olefin 287. The first step in the synthesis involved alkylation of the tosylamide 287. The initial plan was to react 287 with the bromide 288, to provide the alkylated product 289 (scheme 3.6). For this purpose the bromide 288 was synthesized starting from indole ^ ^ * (scheme 3.8). 82 Reaction of indole with oxalyl chloride provided the chloride 290 as a yellow solid.

Reduction with LAH provided the alcohol 291, which was protected with TBSCI to provide 292. The indole nitrogen in 292 was then protected using tosylchloride, followed by deprotection of the silyl group using n-Bu^NF to provide 294. The alcohol 157 was then converted to the bromide 288 using CBr^ and PPh]. ^ ^2

CICOCOCI C o «

TsCI C o Ra o-Bu^Npr^' ^2 - Ts. Ri - OTBS tr s c I C = O " ORr r ^ 292, Ri = OTBS 288. R 2 = Ts. Ri = B r

Scheme 3.8: Synthesis of bromide 288 starting from indole

3.5.1.1 Attempted alkylation of amino-olefîn 287 using bromide 288. The alkylation of 287 using the bromide 288 was attempted (table 3.1). Although this transformation appeared fairly straight forward, it proved to be rather difficult. Reaction of the bromide with 287 did not provide any of the desired alkylated product. Instead only the vinyl indole 296 was obtained along with unreacted 287. Similar results were obtained even when a large excess of the bromide 288 was used. A number of different bases and solvents were also tried without any success. 3.5.1.2 Attempted alkylation of amino-olefin 287 by Mitsunobu reaction. The coupling was next attempted by means of a Mitsunobu r e a c t i o n ^ between

83 the alcohol 294 and the tosylamide 287. Once again the only product obtained was the unreacted tosylamide. Use of a large excess of reagents and different reaction conditions also failed completely (table 3.1).

y 2B7 + sRa CX Ts H Ts 288, Ri = Br 289, Rg — In 296 294, Ri = OH not formed 295, Ri = O

No. Rl (eq.) Solvent Base Temp Tune Product

1 B r(l.l) DMF KH (1.1) rt 18h 296

2 B r(l.l) DMF KH(l.l) 65“ C 18h 296

3 B r(l.l) DMF NaH (1.1) rt 18h 296

4 B r(l.l) DMF B uL i(l.l) rt 24h 296

5 Br(5) DMF K2CO3 (6) rt to 65" C 18h 296

6 Br(5) DMF NaH (1.1) rt to 65“ C 18h 296

7 OH (1.1) THF Mit. (1.1) rt 18h 296

8 OH (5) THF Mit. (5) rt 18h 296

9 0H (1) THF Mit. (1) rt 18h 296

9 0(1) THF NaBH(OAc)3 rt. 18h 296

Table 3.1: Attempted alkylation of 287 using bromide 288 and alcohol 294 under Mitsunobu

conditions.

3.5.1.3 Attempted alkylation of amino-olefin 287 using acyl chlorides. The coupling was also attempted by utilizing the chlorides 290 and 297^ 84 again with no success. Once again a number of different reaction conditions were employed with little success (table 3.2).

Cl 287 b ase Co Ra no reaction

290, R-) = Ra = O 297, Rt = O, Ra = Ha

No. In-Cl Solvent Base Temp Time Product

1 33 (1.1) DMF NaH (1.1) rt 7h nr

2 33 (5) DMF NaH (1.1) 50 “C 48h nr

3 33 (5) DMF K2CO3 (10) rt 48h nr

4 34(1.1) DMF KH(l.l) rt 18h nr

5 34 (5) DMF K2 CO3 (6) 65“ C 18h nr

Table 3.2: Attempted alkylation of 287 using acid chlorides.

3.5.1.4 Attempted alkylation of 287 by deprotection of tosyl group. We then turned our attention toward deprotection of the tosylamide 287 with the intention of alkylating the amine 298, which was thought to be relatively facile. A number of standard protocols for the deprotection of the tosyl group including Na/NH],^^'^ Sml 2,^'^ HBr/phenoN were attempted (scheme 3.9). The desired amine was only obtained in trace amounts from the above reactions. It was not sure if the low yield was due to decomposition of 287 during the reaction or due to difficulty in isolating the low molecular amine 298. In order to increase the molecular weight of the product amine the olefin in 287 was hydroborated and the hydroxyl group protected with TBSCI to provide 299.

85 Once again, deprotection of 299 with Na/NHs gave very poor results. Hence this approach of deprotection of the tosylamide was abandoned.

H H

.NHTs .NHa H H 287 298 1)B2He 2 ) TBSCI

OTBS OTBS Na/NHg NHTs c b NHg H H 299 300

Scheme 3.9: Deprotection of amino-olefin 287

3.5.1.5 Attempted cyclization of iV-benzylaziridine-allylsilane to avoid alkylation of 287.

HN 302 hydroborate' H'1 oxidize, 301 cydize

(-)-yohimbane

Scheme 3.10: Projected synthesis of yohimbane by cyclization of iV-alkylaziridine-allylsiiane

One way to avoid alkylation of 287 would be to use aziridine-allylsilane such as 301 for the cyclization reaction (scheme 3.10). To test this possibility, the iV-benzyl aziridine-allylsilane 244 was synthesized from 211 as described in section 2.15.1.

8 6 Lewis acid decomp.

Bn 211

Scheme 3.11: Attempted cyclization of iV-benzylaziridine-allylsilane

Unfortunately aziridine 244 was completely unreactive in the cyclization experiment (scheme 3.11). A number of different Lewis acids and other activators were employed to effect the cyclization between the aziridine and the allylsilane in 244. As in the case of the iV-tosylaziridine-allylsilanes, use of Lewis acids such as TiCLj and SnCU, resulted in protodesilyation aziridine and ring opening with the Lewis counter ion. Use of

BF3»OEt2, CF3CO2H and TMSOTf, predominantly resulted in protodesilyation. Use of other activators like Boc-anhydride and aceQfl chloride resulted in decomposition or no reaction at all. From ±ese results, it became obvious that a strong activating group was required to effect the cyclization reaction. As a result it was decided to continue with the original plan of completing the synthesis using the tosylamide 287. 3.5.1.6 Alkylation of 287 using mesylate 303. We decided to examine leaving groups other than the bromide 288 in the alkylation reaction. For this purpose mesylate 303 was synthesized from alcohol 294 (99%) by treatment with mesyl chloride and Et 3N. Initially alkylation of 287 was attemptedusing the mesylate 303 in DMF and KH as the base. This reaction provided the desired alkylated product in low yield (ca.

25%). Encouraged by this result, some other bases such as NaH and K 2CO3 were examined in this reaction.

87 H K2CO3, DMF. 92% CDNHTs ^OM s TsN H ' 287 O a Ts 289 303

Scheme 3.12: Alkylation of 287 using mesylate 303

The reaction using K 2CO3 as the base, worked extremely well to provide the alkylated product 289 in excellent yield (scheme 3.12). Although some amount of the vinyl indole 296 was obtained from the reaction, this was of no consequence, as 296 could be easily separated form the final product 289. It was found that the alkylation reaction works best when the tosylamide 287 is treated with a slight excess (2 eq) of the mesylate 303 and

K2CO3, in DMF, followed by warming the reaction to 70 “C for 12 h. It was also found that best results were obtained when DMF is used straight firom the bottle. Use of DMF which had been distilled over BaO prior to use gave poor results. It was also important to maintain the reaction temperature at or slightly over 70 °C to ensure that the reaction went to completion. It was a little surprising that very little of the alkylated product 289, was obtained using bromide 288, acyl chlorides 290, 297 and the alcohol 294 (Mitsunobu reaction) but 289 was obtained exclusively when the mesylate 303 was used. A possible explanation is as follows: bromide and PhgPO are bulkier leaving groups as compare to a mesyl group. Hence it is possible that 287 which is relatively hindered at the reacting site prefers either to eliminate or not react at all when the bromide (288) or the alcohol (294) were used. However, use of a smaller leaving group such as mesylate allows the tosylamide in 287 to access the carbon bearing the leaving group to effect the displacement reaction.

8 8 3.5.2 Hydroboration and oxidation of alkylated product 289. The next step in the synthesis involved functicnalizaticn of the olefin unit in 289 (scheme 3.13). Use of BH] as the hydroborating agent provided mixtures of the primary and the secondary alcohol (ca. 3:1). This was rectified by using the bulkier hydroborating agent, 9-BBN. This reaction proceeded with excellent regio control to provide the primary alcohol 304 in high yield. Oxidation of the alcohol 304 to the carboxylic acid 306 was attempted nexL

9-BBN. 89% TsN.

HO

289 304

Scheme 3.13: Hydroboration of alkylated product 289

A number of different oxidants were available for this purpose. ^ It was decided to use Ru0 2 as the oxidizing agent. Although this system is known to oxidatively cleave double bonds and aromatic rings, this problem can be avoided by the right choice of reaction conditions. U 8 The advantage of using this system is that only catalytic amounts of

Ruthenium are needed to effect the oxidation. Another attractive feature was that the alcohol 304 could be oxidized to the carboxylic acid in a single step. This oxidizing system however, gave very poor results. The products of this reaction appeared to be the corresponding aldehyde which showed considerable decomposition in the aromatic region of the iH NMR spectra of the crude product. A number of different oxidizing agents were then attempted in order to oxidize 304 to 306 (table 3.3).

89 TsN Oxid, O cO % H HO H O 304 306

Entry Oxidant Conditions Time Result

1 RUCI3, 3H2 0 /N aI0 4 CH3CN, CH2CI2, H2O 18h decomp.

2 C1O 3, Pyr, AC2O fBuOH I8 h decomp.

3 RUCI3, 3 H2O/ K2S2O8 H2O 5hr nr

4 RUCI3. 3H2O/ NaI0 4 CH2CI2, H2O 18h decomp.

5 Tempo, NaOCI CH2CI2, H2O I8 h nr

6 Cr0 3 , H2SO4 Acetone Ih decomp.

7 H5IO6, Cr0 3 CH3CNI8 h decomp.

8 Tempo, NaOCl, NaCI 0 2 CH3CN 4h nr

Table 33: Attempted conversion of alcohol 304 to carboxylic acid 306

In entry 4, CH 2CI2, H2O was used as the solvent system for the reaction. It has been reported in literature that CH 3CN increases the activity of RU 2O as an oxidizing agent.

It was thought that omitting CH 3CN from the reaction would attenuate the activity of the catalyst and thus prevent it from oxidizing the aromatic rings in 304. However, this variation resulted in no improvement. Similarly, very poor results were obtained using a number of other oxidizing systems (entries 5 - 8 ).*

90 Swem. 88% TsN TsN HO

304 305

KMn04

Tsjsj SiMe3CHN2 Ts 80% from 305

Scheme 3.13: Stepwise conversion of alcohol 304 to ester 307

Due to the poor results obtained above, this transformation was attempted in a stepwise fashion. The alcohol 304 was oxidized to the aldehyde 305 using the Swem conditions in excellent yield. The oxidation was also successful when DMP^^O qj - pcc^4 was used as the oxidant. However the Swem conditions were found to give the best results. A number of conditions were then attempted to oxidize the aldehyde to the corresponding carboxylic acid 306. (table 3.4).

1 Entry Oxidant Solvent 1 Time Result

1 RuCb, 3 H2O/ NaI0 4 CH^CN, CH2CI2, H2O ! 3 hr decomp.

2 NaOCl 120 CH3CO2H, MeOH I I hr decomp.

3 KMn04i22 f-BuOH, NaHP0 4 (5%) | I hr 306

Table 3.4: Oxidation of aldehyde 305 to acid 306

91 Use of KMn 0 4 in buffered phosphate solution provided good yield of the crude acid ( 100%). The crude acid 306 was then readily converted to the methyl ester using methyl chloroformate and triethylamine.*^ This procedure provided the methyl ester 307 in satisfactory yield (62% over two steps). The crude acid could also be converted to the ester 307 using SiMc 3CHN2 in good yield (80% from 3 0 5 ). ^24

TsN Na-naphthalenide. 77%

MeO- MeO-

308 307

309

Scheme 3.15: Amide formation during deprotection of 307

3.5.3 Deprotection of ester 307. The next crucial step in the synthesis was deprotection of the two tosylamide protecting groups in 307. The deprotection was first attempted using Sml 2.^^ This reaction did not provide the desired product. The reaction was then attempted using sodium naphthalide.^5 Ttiis procedure worked well but provided the lactam 309 (77%) instead of the free amine. The explanation of this transformation is outlined in scheme 3.15. The nitrogen anion, formed on deprotection of the tosyl group, attacks the methyl ester to provide the six membered lactam.

92 POCk 309 NaBH4

H'I I H'

(-)-yohimbane, 59% enr-alloyohimbane, 2 2 %

Scheme 3.16: Total synthesis of (-)-yohimbane and ent-alloyohimbane

3.5.4 Bischler-Napieralski reaction of lactam 309. The lactam 309, was then subjected to the Bischler-Napieralski^ conditions. This reaction provided (-)- yohimbane and enr-alloyohimbane as a mixture which could be easily separated by chromatography on silica gel, ±us completing our total synthesis. The optical rotation of the synthesized product, [a]o -82.1“ was in complete agreement with that reported in literature!^ [a]o -81°.

In O ^ N POCIa Cl Cl

309

yohimbane

312b H 313b

enf-ailoyohimbane

H"

313a

Scheme 3.17: Bischler-Napieralski rearrangement of lactam 309

93 The Bischler-Napieralski reaction involves an interesting transformation, where the amide first reacts with POCI 3 to provide a chloroiminium species 310. The next step involves attack by the indole ring on to the chloroiminium ion provide the indoleimine 313. The imine 313 is finally reduced stereoselectively by NaBHa to provide the final product (scheme 3.17). Use of reducing agents other than NaBtU for the final reduction step, provides different r e s u lts .^26

3.6 Summary. In conclusion (-)-yohimbane was synthesized in 8 steps and 24% overall yield (from 211), utilizing a novel aziridine-allylsilane cyclization reaction as the key step in the synthesis. Although, the diastereomeric sulfonamides 287a and 287b could not be seperated at the start of the synthesis or the diastereomeric ratio of 287a to 287b could not be improved, it was shown that the aziridine-allylsilane cyclization reaction can be a useful reaction for the synthesis of complex natural products. This synthesis has allowed us to explore some of the transformations which can be carried out on the amino- olefin 287. This synthesis has also made us aware of some of the difficulties which could be encountered during functionalization of the amino olefins. This synthetic route to yohimbane and alloyohimbane can now serve as a guide for the synthesis of more complex systems if desired.

94 CHAPTER 4

3+2 ANNULATION REACTION OF AZIRIDINES WITH ALLYLSILANES

4.1 3+2 Annulation: Exploratory studies. In the last two chapters the synthesis and reactivity of aziridine-allylsilanes and the application of this chemistry towards developing a total synthesis of (-)-yohimbane was discussed. During some of the cyclization experiments, it was observed that there was another product being formed during the cyclization reaction of 211. On closer examination, this product appeared to be the bicycle 314 (scheme 4.1).

C ^ H T S ^ H H 211 287 314

Scheme 4.1: Formation of desilyated bicycle during Sakurai reaction of aziridine-allylsilanes

The reasons for formation of 314 were not readily apparent (scheme 4.2). It was possible that 314 could have been formed from the bicycle 315 by a protodesilyation reaction."^ Bicycle 314 could have also been formed from the amino olefin 287 by an acid catalyzed ring closure of the tosylamide on to the olefin. To test for this possibility,

95 2 8 7 was reacted with BF 3«OEt2. It was observed that 2 8 7 could be converted to 3 1 4 only when the reaction was carried out practically using BF 3«OEt2 as the solvent. Hence, formation of 3 1 4 from 2 8 7 appeared to be less likely under the conditions normally used for the cyclization reaction (ca 4(X) moi% BF 3«OEt2). The other possibility was that 314 was being formed by protodesilyation of 3 15.

H / H

NHTs BFsOEtg O p H H 314 315 BFa^OEtg V. large excess

c k " . H 287

Scheme 4.2: Mechanistic rationales for formation of desilyated bicycle

To better understand the formation of 315 we decided to look at the mechanism of the reaction (scheme 4.3). Co-ordination of the Lewis acid with the aziridine induces attack by the allylsilane to provide the cationic intermediate 316. At this point this intermediate could undergo an elimination to provide 287 (Sakurai reaction). Alternatively, the positive charge could be trapped intramolecularly, by the tosylamide to provide 3 1 5 (3+2 annulation).35 A second possibility was that 3 1 6 could undergo a 1,2-silyl shift to provide a second cationic intermediate 317, which could also react with the tosylamide to provide

3 1 8 (3+3 annulation).34 Quite obviously, the product of protodesilyation of 3 1 8 is not

96 314. Hence, the bicycle 314 must have been formed from 315 by a protodesilyation reaction.

H y-SiM eg

Path a _ NTs [3+2] H H 316 315

1,2 -silyl shift

C D ™ H 287 LA 318 317

Scheme 43: All possible reaction pathways for aziridine-allylsilane 316

While this was an interesting transformation, we had little use for 314. On the other hand if one could retain the silicon in the bicyclic products and oxidize the silyl group to a hydroxyl group, one could think of a number of uses for bicyclic pyrrolidines such as 315. It was therefore decided to look into conditions which would allow retention of the silyl group during the annulation reaction. Typically, protodesilyation of silyl groups is carried out using protic acids. It was possible that the BFg'OEt? could have built up protic acid by reaction with atmospheric moisture on standing. To eliminate this possibility, freshly distilled BF 3»OEt2 was used for the cyclization reaction. This modification provided the annulated product 315 (ca. 40 - 45%) along with the olefin 287 (ca. 45 - 40%). For the annulation reaction to be of any synthetic use, it was important to improve the yield of the bicycle formation and reduce the amount of olefin 287 which was formed during the

97 reaction. This could be accomplished by (a) varying reaction conditions such as

temperature, Lewis acid concentration, type of Lewis acid and solvents etc. (b) Using a bulkier silyl group.

4.2 3+2 Annulation using aziridine-trimethylallylsilanes. We first

attempted to improve the yield of bicycle formation by varying the amount of BF 3*OEt 2, temperature and time of reaction. The results fiom those cyclization experiments are summarized in table 4.1. It was found that the reaction proceeds very slowly when the reaction is carried out at temperatures below -20 °C, even when a high concentration of the Lewis acid was used. At temperatures above -20 °C, the reaction proceeds fairly rapidly using less than stoichiometric amounts of BF 3»OEt2, to provide the bicycle 315 as the major product. However, at temperatures between -10 "C and -20"C, complete conversion of 211 to 315 was never seen. When the temperature of the reaction was increased to 0

“C, the reaction proceeded rapidly using as little as 15 mol% of BF 3«OEt2, to provide the bicycle 315 as the major product Use of other Lewis acids provided results similar to those obtained earlier.

98 NTs NHTs

211 315 287

Entry Reactant BF3.0Et2 Time Temp. Products 1 2 1 1 10 moI% 15 min 0°C 2 1 1 2 2 1 1 10 moI% 30 min O'C 211 >315 >287 3 2 1 1 10 moI% 60 min 0°C 211 >315 =287 4 2 1 1 15 moI% 15 min O'C 315 >287 >211 5 2 1 1 15 moI% 30 min O'C 315 >287 >211 6 2 1 1 20 moI% 15 min O'C 315 >287 7 2 1 1 20 moI% 15 min -20'C 315 >287 >211 8 2 1 1 25 moI% 5 min O'C 315 >287 >211 9 2 1 1 25 moI% 15 min O'C 315 >287 >211 10 2 1 1 25 moI% 30 min O'C 315 >287 >211 II 2 1 1 25 moI% 60 min - 10' C 287 > 3 1 5 12 2 1 1 25 moI% 60 min -20'C 211 >315 >287 13 2 1 1 50 moI% 15 min O'C 315 >287 >211 14 2 1 1 50 moI% 60 min - 10'C 315 >287 >211 15 2 1 1 50 moI% 60 min -20'C 315 >287 >211 16 2 1 1 50 moI% 60 min -30'C 315 >287 >211 17 2 1 1 100 moI% 60 min -3 0 'C 315 >287 >211 18 2 1 1 150 mol% 8 hr 2 5 'C 287 19 2 1 1 150 mol% 15 min O'C 287 > 315 > 87 20 2 1 1 150 mol% 30 min O'C 287 » 315 21 2 1 1 150 moI% 60 min O'C 287 » 315 22 2 1 1 150 mol% 8 hr - 10' C 287 > 3 1 5 23 2 1 1 150 mol% 8 hr -4 0 'C 211 >287 >315 24 2 1 1 150 mol% 8 hr -7 8 'C 2 1 1

Table 4.1: 3+2 annulation of aziridine-allylsilane 211 using different reaction conditions

99 From this study, it was realized that best results from the annulation were obtained using 50 mol% Bp 3«OEt2 at -20 *C or 15 mol% of Bp 3*OEt 2 at 0 “C. Results from cyclization of 210 and 211 using the conditions mentioned above are shown in table 4.2

--SiMes SiMea

NTs + ( + (<)n NHTs H

2 1 0 , n = 1 319a, n = 1 n = 1 , not formed 320, n = 1 2 1 1 , n = 2 315a, n = 2 315b, n = 2 287, n = 2

Entry Reactant Condition bicycle olefin (cis:trans) 1 2 1 0 A 319a, 49% 320 (1.5:1), 33% 2 2 1 0 B 319a, 46% 320 (1.1:1), 36% 3 2 1 1 A 315a:315b (1:3.5), 54% 287 (1:1.6), 27% 4 2 1 1 B 315a:315b (1:2.8), 59% 287 (1:1.9), 34%

Table 4.2: Results obtained &om 3+2 annulation using aziridine-trimethylallyisilanes. Condition A:

BF3 «OEt2 (I5mol%), 0* C, 30 min. Condition B: BF 3 »OEt2 (50mol%), -20' C, 30 min.

Annulation of 210 provided the cis fiised pyrrolidine 319a (single enantiomer) was obtained as the only annulated product along with olefin 320 (mixture of cis and trans isomers). The formation of a trans fused bicyclic system is precluded in this case, due to ring strain. None of the product which could arise from a 3+3 annulation (1,2-silyl shift) was seen during the cyclization. The annulation of 211 provided a mixture (ca. 3:1) of the trans fused bicycle 315b (single enantiomer) and the cis fused bicycle 315a (single enantiomer). A significant amount of the olefin 287 (mixture of cis and trans isomers) was also obtained from the

ICX) reaction. Once again, none of the product which could arise from a 3+3 annulation ( 1,2- silyl shift) was seen during the annulation reaction. 4.3 3+2 Annulation using aziridine-phenyldimethylailylsilanes. From the results obtained above, it appeared that the optimum conditions for the 3+2 annulation reaction using trimethylsilyl group had been determined. The yield of the bicyclic products obtained from 210 and 211 was still only moderate. As was discussed in chapter I, the

Sakurai reaction (olefin formation) and the annulation reaction (bicycle formation) are competing pathways in reactions of allylsilanes. Usually, the rate of the Sakurai reaction can be reduced by using silyl groups which have bulky substituents on the silicon. A number of different silyl groups were available for this purpose. We wanted to use a silyl group which could be oxidized to a hydroxyl group. This would allow introduction of a wide variety of functionality into the bicyclic products. Another consideration which influenced the choice of the silyl group, was the ease with which it could be introduced using our previously developed synthesis of aziridine-allylsilanes. The retrosynthetic approach adopted is outlined in scheme 4.4.

R3S1

Ts 322 189

321

RaSi + OH RaSiCHaMgCI 323 324

R = phenyldimethyl, trityldimethyl, triphenyl, triisopropyl, f-butyldiphenyl, phenyldiisopropyl etc. RaSiCHaCI 325

Scheme 4.4: Retrosynthesis of aziridine-allylsilanes with different groups on silicon 101 4.3.1 Retrosynthesis. To synthesize aziridine-aliylsiianes such as 321 one would need access to the iodide 322. The iodide 322 could be synthesized from the corresponding alcohol 323 by tosylation followed by displacement with iodide. The alcohol 323 could in turn be synthesized from dihydrofuran or dihydropyran by reaction with the Grignard reagent 324, in the presence of a Ni catalyst. It was realized that

PhMe 2SiCH2MgCI could be synthesized from commercially available PhMe 2SiCH2Cl. Unfortunately, none of the other chloromethylsilanes were commercially available. Hence for the sake of convenience, it was decided to first investigate the phenyldimethylsilyl group in the 3+2 armulation reaction of aziridines with allylsilanes. 43.2 Preparation of PhMegSiCHzMgCl. The preparation of

PhMe 2SiCH2MgCl by reaction of PhMe 2SiCH2Cl with Mg and ethylene bromide in THF had been reported previously by Comins.^^^ The use of THF however, was not suitable for the Wenkert reaction which is carried out in benzene and requires the ethereal solvent to be distilled out of the reaction (bp of THF is 78 ’C while that of benzene is 80*Q. Thus, the distillation step precluded the use of THF as the solvent for formation of the Grignard reagent. This problem could be avoided simply by generating PhMe 2SiCH2MgCl in ether as opposed to THF. Unfortunately, it was very difficult to generate PhMe 2SiCH2MgCl in ether. Attempts to generate PhMe 2SiCH2MgCl in benzene, toluene and benzene/ether as the solvents also failed completely. The reaction was then attempted again using a different grade of Mg with smaller particle size (-12+50 mesh) which provided us with slightly better results. After some experimentation it was found that complete conversion of Mg to the Grignard reagent was seen only when PhMe 2SiCH2Cl was added to the reaction approximately 20 min after addition of ethylene bromide, while maintaining the reaction at reflux during the entire time.

102 MeaPhSi Ni c a t ^ ~ ^ ) n + MeaPhSiCHaMgCI OH n n = 1 326, n = 1 n = 2 327, n = 2

Entry Catalyst mol % 327 (yield)

1 (Ph 2PCH2CH2PPh 2)NiCl2 (328) 10 59%

2 (Ph 2PCH2CH2PPh 2)NiCl2 (328) 10 42%

3 (Ph 2PCH2CH2PPh 2)NiCl2 (328) 10 13%

4 (Ph 2PCH2CH2CH2PPh 2)NiCl2 (329) 10 16%

5 (PPh3)2NiCl2(330) 10 33%

6 (PPh3)2NiCl2 (330) 5 57%

Table 4J: Wenkert reaction of dihydropyran with PbMe2 SiCH2 MgCl using different Ni catalysts

4.3.3 Wenkert Coupling using PhMezSiCHzMgCl. The Grignard reagent formed on reaction of PhMe 2SiCH2Cl and Mg, was reacted with dihydropyran in the presence of a Ni catalyst. At least three different catalysts were explored in the coupling reaction (table 4.3). It was initially found that best results (59%) were obtained using 10 mol% of 328 as the catalyst (entry 1). However, good results with 328 were only obtained using a new bottle of the catalyst. Over time the yield of the alcohol 327 dropped considerably (entries 2 and 3) using catalyst 328. It is conceivable that reaction with atmospheric moisture and oxygen may have changed the nature of the catalyst over time. We then attempted the reaction using 329 (entry 4) and 330 (entry 5) as the catalysts. These catalysts provided us with lower yield of alcohol 327. It was also noticed that all of these reactions also provided other unidentified products which appeared to be arising from the organic ligands on the catalyst. This made purification of 327 difficult, especially when 103 the reaction was carried out on a relatively larger scale (30 -45 mmol). To avoid difficult purifications, the reaction was attempted using only 5 moI% of 330. This modification surprisingly, worked better to provide alcohol 327 in 57% yield. The synthesis of the alcohol 326 from dihydrofuran was accomplished in a similar manner using either 328 (71%) or 330 (69%) as the catalyst.

MegPhSi MegPhSiCHaMgCI Ç k ) „ OH (Ph3P)2Nia2 n 326, n = 1,70% n = 1 , 2 327, n = 2,59%%

1)TsCI 2) Nal, acetone

SiPhMea MeaPhSi (\)n f-BuU, n-BuaP. Cul r x ^ o T s 331, n = 1,90% % " 332, n = 2, 90% 333, n = 1,72% 189 334,0 = 2,69%

Scheme 4.5: Single step synthesis of aziridine-phenyldimethylallylsilanes

4.3.4 Synthesis of aziridine-phenyldimethylaiiylsilanes. The synthesis of aziridine-phenyldimethylallylsilanes 333 and 334 is outlined in scheme 4.5. The alcohols 326 and 327 were converted to the corresponding iodides 331 and 332 respectively, by treatment with TsCl and Nal. The iodides 331 and 332 were then converted to the corresponding cuprates which were treated with 189 to provide ±e aziridine-aliylsiianes 333 (>97% ee) and 334 (> 97% ee) respectively.^^

104 ,SiPhMe2 MeaPhSi^

: n-BugP/ether. 97% ^ O T B S ' NHTs ^ % "187 ooo,336, n R = = TBS11 n-Bu4 NF, 91% ^ 337, R = H

PhaP, DEAD 89%

334

Scheme 4.6: Stepwise synthesis of aziridine-phenyldimethylallylsilanes

4.3.4.1 Alternative synthesis of aziridine-phenyldimethylallylsilanes. The one step procedure for the synthesis of aziridine-aliylsiianes worked well when the reaction was carried out on a smaller scale (< 2 mmol). The synthesis of 334 was accomplished in a step wise manner from 187 when larger quantities (> 5 mmol) of 334 were required (scheme 4.6). The use of other cuprates for the synthesis of 334 was also investigated, to see if one could reduce the amoimt of iodide 332 which was required for the reaction. To this end ring opening of 187 was attempted using cuprates derived from CuCN and higher order cyano cuprates with a dummy ligand (thiophene). Unfortunately, the cuprate derived from CuCN (RCuCNLi) was found to be unreactive in the ring opening reaction of 187. The cuprates RCu(thiophene)CNLi and RCu(thiophene)(Bu 3P)CNLi were found to be insoluble required in ether (solvent used for the generation of the organolithium reagent from the iodide 332),** thereby precluding their use.

105 ^SiPhMea d f » - c f c - . H H 334 335 287

Entry Solvent Reactant BF3.0Et2 Time Temp. 334:335:287 I CH2CI2 334 (O.IM) 3(X) mol% 8 h -40° C 0 :7 4 : 26 2 Œ 2CI2 334 (0.1 M) 50 mol% 60 min -20° C 0 :7 0 : 22 3 CH2CI2 334 (0.1 M) 25 mol% 5 min 0° C 8 : 77 : 15 4 Œ 2Q 2 334 (0.1 M) 25 mol% 15 min 0° C 14:75: 11 5 CH2CI2 334 (0.1 M) 15 mol% 30 min 0°C 0.5 : 86 ; 13.5 6 CH2CI2 334 (0.1 M) 15 mol% 60 min 0°C 2 : 81: 17 7 CH2CI2 334 (0.1 M) 10 mol% 30 min 0° C no reaction 8 CH2CI2 334 (0.1 M) 10 mol% 60 min 0°C no reaction 9 CH2CI2 334 (0.2 M) 10 mol% 30 min 0°C no reaction 10 CH2CI2 334 (0.2 M) 5 mol% 30 min 0° C no reaction 11 CH2CI2 334 (0.25 M) 5 mol% 30 min 0° C no reaction 12 CF3C6H5 334 (0.1 M) 50 mol% 60 min 0° C 0 : 55 : 22

Table 4.4: 3+2 annulation of aziridine-allylsilane 334 using different reaction conditions

4.3.5 3+2 Annulations of aziridine*phenyldimethyIaUylsilanes. With the phenyldimethylsilyl-aziridines 323 and 334 in hand, different reaction conditions to identify the optimum conditions for the annulation reaction were investigated. The results from these experiments are summarized in table 4.4. The reactivity of 333 and 334 was found to be very similar to the reactivity of 210 and 211. No appreciable reaction between the aziridine and the allylsilane was seen when the temperature of the reaction was below -40 °C. Optimum conditions for bicycle formation were seen when the temperature of the reaction was between -20 °C and 0 °C and when 50 - 15 mol% of BF 3*OEt 2 was used. No

106 reaction between the aziridine and the allylsilane was seen using less than 15 mol% of

BF3«OEt2 even when the reaction was carried out in more concentrated solution in CH 2CI2

(to increase effective concentration of BF 3»OEt2 in CH 2CI2). Altering the Lewis acid in the annulation reaction was also investigated. Unfortunately, this resulted in decomposition of 334 or no reaction at all. Results &om these experiments are summarized in table 4.5.

Lewis Acid Reactant L. A. (conc.) Tune Temp. Result EtAlCl2 334 100 mol% 60 min -78" C no reaction EtAlQ2 334 100 mol% 60 min -40" C no reaction EtAlQ2 334 100 mol% 60 min -20" C no reaction TMSOTf 334 100 mol% 60 min -78" C no reaction TMSOTf 334 100 mol% 60 min -40" C no reaction TMSOTf 334 100 mol% 60 min -20" C no reaction TiCU 334 100 mol% 60 min -78" C decomp.

Table 4.5: 3+2 annulation of aziridine-allylsilane 334 using different Lewis acids

Best results firom the cyclization were once again, obtained either by using 50 mol%

of BF 3»OEt2 at -20 °C or by using 15 mol% of BF 3»OEt2 at 0 °C (table 4.6). As in the case of the trimethylallylsilanes, 333 provided the cis fused pyrrolidine 336a as the major product along with the olefin 320. Similarly, cyclization of 334 provided a easily separable mixture (ca. 3:1) of the trans fused pyrrolidine 335b and the cis fused

pyrrolidine 335b. Some amount of the olefin 287 was also obtained from this reaction. Thus the use of the phenyldimethylsilyl group resulted in a moderate decrease in the amount of olefin which was formed during the annulation reaction. The phenyldimethylallylsilane provided us with the bicyclic pyrrolidines 336 and 335 in reasonable yield (65 - 72%). It was felt that these yields were high enough that one could now start further investigations into the synthetic uses of the 3+2 annulated products.

107 NHTs

333, n = 1 336a, n = 1 n = 1, not formed 320, n = 1 334,n = 2 335a, n = 2 335b, n = 2 287,n = 2

Entry Reactant Condition bicycle olefin I 333 A. 336a, 65% 320 (1.5:1), 28% 2 333 B 336a, 60% 320 (1:1), 32% 3 334 A 335a:335b (1:3), 72% 287 (1:1.6), 20% 4 334 B 335a:335b (1:4), 70% 287 (1:1.9), 22%

Table 4.6: Results obtained from 3+2 annulation using aziridine-phenyldimethylallyisilanes. Condition

A: BF3 «OEt2 (15moI%), 0* C, 30 min. Condition B: BF 3 »OEt2 (50mol%), -20* C, 30 min.

4.4 3+2 Annulation: Stereochemical determination. The stereochemistry of the bicyclic pyrrolidines obtained &om cyclization of 333 and 334 was determined by nOe spectroscopy (figure 4.1 - 4.3). In bicycles 336a, 335a and 335b the assignment of protons Ha - He in the NMR spectrum was done by homonuclear ^H decoupling experiments and by examination of chemical shifts of these protons.

SiPhMea 6.5%

4.9 ^ Ha= Hf HR

CH3

8.5% 5% 336a

Figure 4.1: Stereochemical determination of 336a using nOe spectroscopy

108 In 336a (figure 4 .1 ), hydrogens Hy, He, Hy and Hf appeared as distinct signals in the ‘H NMR spectrum. The absolute stereochemistry of the carbon bearing Hy was predetermined as it arises from the starting aziridine 333 (> 97% ee). Irradiation of Hy showed enhancements in the signal for Ha and Hj, thereby defining a cis relationship between these protons and consequently a cis ring fusion. Irradaition of Hy lead to enhancement in the signals for Hy. Interestingly, Hj also showed nOe to the ortho hydrogen He of the tosyl group. Similarly, irradiation of Hf showed enhancements in the signals for Ha and Hg. On the other hand, irradiation of He did not show enhancements in the signals for Hy or He- These results indicated that Hg and the silyl group were on opposite side of Ha, Hy, Hj and Hf in the bicyclic pyrrolidine 336a. The nOe between H j - He and Hf- Hg and the absence of an nOe between Hg - Hg made sense because one would expect the tosyl group to orient itself away from the bulky silyl group.

SiPhMea 8 .9% Ha= __

H c\ H

5.8 % 7 .7 % 335a

Figure 4.2: Stereochemical determination of 335a using nOe spectroscopy

The absolute stereochemistry of the carbon bearing Hy in 335a (figure 4.2) was predetermined as it arises from the starting aziridine 334 (> 97% ee). Irradiation of Hf resulted in enhancements in the signals for Ha, Hy and the aromatic proton Hg, thereby indicating a cis relationship between these protons. Irradiation of Hj resulted in enhancements of Hg and Hy, thus confirming a cis relationship between H j. Hy, Ha and

109 Hr- Once again, here the tosyl group orients itself away from the bulky silyl group. Unfortunately, the ring junction protons were buried due to which it was not possible to irradiate any one of them to confirm some of the stereochemical assignments.

SiPhMea 9.6%^ Ha: / - s r f r ' H bHc Hd He

10.5%

Figure 43: Stereochemical determination of 335b using nOe spectroscopy

In 335b (figure 4.3) the hydrogens He, Hd, Hf all showed up as distinct multiplets. Once again, the absolute stereochemistry of the carbon bearing Hy was predetermined as it arises from the starting aziridine 334 (> 97% ee). Irradiation of Hd resulted in enhancement of Hy but not of He- Irradiation of He resulted in enhancement of He but not of Hy. Irradiation of Hf resulted in enhancements of both He and Ha. Thus these results indicated that Ha, He and Hf were on the same side of the bicyclic system as both He and Hf showed NOE's to He- On the other hand, Hy and Hd were on the opposite side of the bicyclic system as compared to Ha, He and Hf. Thus there was no direct or indirect evidence that Ha and Hy were cis to each other, so they had to be trans. In all these compounds an important aspect of the stereochemical determination was nOe to a proton (He) on the aromatic ring of the tosyl group. An explanation for this is as follows. To avoid steric interactions with the bulky silyl group, the aromatic ring of the tosyl group orients itself on the opposite side of the bicyclic ring system. This type of orientation probably positions the ortho hydrogen of the tosyl group in close proximity to

110 Hu and Hf in 336a and 335a and to He and Hf in 335b. Thus irradiation of any of these protons results in an enhancement of the signal for Hg. It was not sure if these enhancements are of one or both the ortho hydrogens as both of them have the same chemical shift. In any case this should not matter as both these hydrogens should be on the same side of the bicyclic system. The results obtained from the stereochemical determinations of 336a, 335a and 335b were in agreement with the earlier studies where it was unambiguously shown that cyclization leading to formation of the five membered carbocycle provided predominantly, a cis ring junction while cyclization leading to the formation of the six membered carbocycle provided predominantly a trans ring junction.

4.5 Stereochemical Rationale 4.5.1 n = 1. The formation of the major cis isomer 336a could be explained as taking place via a chair-like conformation A (scheme 4.7). In this conformation, both the aziridine and the allylsilane are in an equatorial orientation (A). This minimizes the unfavorable steric interactions (A which would otherwise exist if either the aziridine or the allylsilane were to be in an axial orientation (C or D).*® A fourth orientation (B) where both the aziridine and the allylsilane are in an axial conformation would seem to be precluded. The first ring formation takes place via an anti-Sg' mode of addition, to provide the cis disubstituted cyclopentane 337 where the positive charge is stabilized by hyper conjugation with the p-silicon. The formation of the second ring takes place via a stereospecific or a highly stereoselective 5-exo-trig ring closure of the intramolecular tosylamide onto the positive charge. The highly stereoselective nature of the second ring closure could be explained by the fact that these ^-silicon stabilized carbocations do not rotate around the C 1-C2 single bond^>^"^ and that approach of the nucleophile has to take place anti to the silicon. Interestingly, hydrogens Hy and He which are cis in the allylsilane 333 are also cis in the bicycle 336a. Thus, the cis olefin geometry of the allylsilane is

111 retained in 336a. The cationic intermediates formed in conformation C and conformation D cannot undergo a second ring closure and instead eliminate to provide the olefin 320.

Conformation A

Ha ÿ anthSp - bond rotation and % Ts-N A'"SiMe3 cyclization Is^SiRs H 336a 333 337 Conformation B Hb, Hb antf-Sg bond 336a rotation and ''NTs cyclization RaSf H g RgSi H la 333 338

Conformation C

R3SL RsSi.. H

anfASp -SiR^ Hb A’-^Strain ... StrednV^ NHTs 320b

Conformation D

antf-Sp -SiRq 320b

LA' 333 340

Scheme 4.7: Stereochemical rationale for formation of five membered carbocycles during 3+2 annulation

112 Conformation A

H SiRs jnthSg;^ bond rotation and cyclization Ts^^LA 334 335a Confonnation B

anti-Sc A'-^ Strain -SiR^

^ L A 334 TsHN TsN- l a 3 « 287b

Confonnation C Ha antl-Sp bond rotation and lA cyclization B:H A^’^ Strain SiRg " SiRg 334 343 335a

Confonnation 0 Hh anti-Sq bond rotation and 335a cyclization TsN. LA 334 344

Scheme 4.8: Stereochemical rationale for formation of six membered carbocycles during 3+2 annulation

4.5.2 n = 2. The stereochemical rationale for the formation of the major trans isomer is outlined in figure 4.8. Once again, the reaction takes place via a chair-like conformation where both the aziridine and the allylsilane are in an equatorial orientation.

113 However, due to the longer tether between the aziridine and the allylsilane, Ha and Hb are on opposite sides (A). This results in the formation of the trans disubstituted cyclohexane 341, where the positive charge is stabilized by hyper conjugation with the 3-silicon. As before, this intermediate now undergoes a stereospecific or highly stereoselective 5-exo-trig ring closure to provide the final product 335b. Once again, the cis olefin geometry of the starting allylsilane is retained in the final product. An alternate arrangement where both the aziridine and the allylsilane would be in an axial orientation (B) would seem to be precluded.^0 The formation of the minor cis fused bicycle could be explained as taking place via conformation C or conformation D. Over here, either the aziridine or the allylsilane are in an axial orientation, which results in unfavorable steric interactions in conformation C and conformation D, making them less favorable as compare to conformation A . Either conformation C or conformation D eventually leads to formation of the cis fused bicycle 287a. 4.6 Nicotinic receptor modulators. In 1992 it was shown that epibatidine^^S

(figure 4.4) possessed extraordinary analgesic properties and that epibatidine was a extremely potent nAChR modulator. However, epibatidine is a potent toxin (isolated from the skin of a poisonous frog) and has an extremely narrow therapeutic index.

N Me Me 345 N 346 347

Me Me - IN Epibatidine 348 349

Figure 4.4: Structures of some nicotinic receptor modulators

114 This discovery sparked synthetic activity towards developing epibatidine analogs which retained useful biological activity and at the same time did not possess the toxicity of epibatidine. As a result novel nAChR modulators were synthesized,^*-‘29 some of which are shown in figure 4.4. Based on the clinical observations of uses of nicotine, coupled with a growing understanding of the pharmacology of nAChR agonists, these epibatidine analogs could find application in treatment of cognitive and attention disorders, Alzheimer’s disease, Parkinson’s disease, schizophrenia, analgesia, depression, smoking cessation and anxiety.‘29

substitution H ^^aiter stereochemistry

N Me 345 alter ring size \ U isosteric modify alkyl group replacement aromatic ring replacement OH

NR NRNR

350

Figure 4.5: SAR of nicotinic receptor modulators

The nAChR modulators, have been subjected to extensive SAR studies (figure 4.5).®* Most of the synthetic work has involved modification of the aromatic ring, altering stereochemistry adjacent to the aliphatic nitrogen, replacement of the pyrrolidine ring with different size heterocyclic ring systems and isosteric replacement of the oxygen in the ether

115 linkage. However, there are very few reports where these molecules have been synthesized with different substituents on the pyrrolidine ring. There are no reports of replacing the pyrrolidine ring by bicyclic ring systems. It was thought that molecules such as 350 where the pyrrolidine ring was replaced with a bicyclic ring system, could serve as ring constrained or more lipophilic analogs or even antagonists o f345. Hence it was decided to undertake the synthesis of molecules such as 350, which would not only add to our existing knowledge of SAR of the nAChR modulators, but also serve as an interesting and useful application of the 3+2 annulation reaction of aziridines with allylsilanes. 4.7 Functionalization of bicyclic pyrrolidines.

-.-SiPhMea ^O H

SiPhMea OH

NTs Hfl(OAc)2 , NTs CH 3 CO 3 H 91%

Scheme 4,9: Oxidation of phenyldimethylsilyl group in bicyclic pyrrolidines

4.7.1 Oxidation of phenyldimethylsilyl group. The first step towards synthesis of molecules such as 350 was to oxidize the silyl group to a hydroxyl group.- This would then allow us to introduce a wide variety of functionality into these bicyclic

116 pyrrolidines. A number of procedure were available in the literature for the oxidation of the phenyldimethylsilyl group. The oxidation (scheme 4.9) was accomplished successfully by using Fleming's procedure (mercuric acetate-peracetic acid), which is a one pot protocol for conversion of certain silyl groups to a hydroxyl group. This procedure provided us with the desired alcohols in good yield 351,352 and 353 (60 - 91%).

—SiPhMea -OH -OPyr H H NTs

H H 336a 354

H H \ H ph

Ts Ph 355

approach of nucleophile

Scheme 4.10: Mitsunobu reaction between alcohol 351 and 3-hydroxypyridine

4.7.2 Mitsunobu reaction. We now attempted to synthesize 354 where the hydroxyl group was replaced with an ether linkage. We first attempted to synthesize the pyridyl ether by means of a Mitsunobu reaction (PPhg and DEAD) between 3- hydroxypyridine and the alcohol 351 (scheme 4.10). Unfortunately, this reaction did not provide any of the desired product. The only products formed, appeared to be those resulting from alkylation of 351 with DEAD. Similar results were obtained using n-BugP and DEAD. An explanation for this abnormal reactivity could be that 3-hydroxypyridine is too bulky to get underneath the concave surface of the activated intermediate 355, which is eventually alkylated by the other smaller nucleophile in the system (DEAD in this case).

117 H MTsNTs NaH, DMF— w " T " X )

MsCI, EtaN

OMs

NTs

3S8 357 Y)N' 363, (4 eq)

Scheme 4.11: Synthesis of pyridyl ether 356 via mesylation/displacement approach

4.7.3 Mesylation/ displacement approach. An alternative method to synthesize the pyridyl ether linkage involved reacting alcohol 353 with 3-bromopyridine (scheme 4. II). Unfortunately this reaction did not provide any of the desired. Only unchanged 353 was recovered from the reaction. Once again the lack of reactivity of the anion of 353 towards 3-bromopyridine could be attributed to the steric congestion around the reacting centers in the bicyclic pyrrolidines. A third approach to synthesize the pyridyl ether linkage was then investigated (scheme 4.11). The alcohol 353 was converted to the mesylate 357, which was reacted with an excess of 3-hydroxy pyridine (4 eq). This procedure provided he desired alkylated product 356 in good yield. A small amount of the olefin 358 (10 - 15%) which is formed by elimination of the mesyl group was also isolated from the reaction.

118 L T ° - 0

Scheme 4.12: Attempted deprotection of tosyl group in pyridyl ether 356

4.7.4 Deprotection of tosyl group. The last step in the synthesis involved deprotection of the tosyl protecting group (scheme 4.12). The deprotection was first attempted using sodium-naphthalenide which had provided excellent results previously. Unfortunately, these conditions only resulted in decomposition in 356 and the desired product 359 which was contaminated with another unidentified product was obtained in trace amounts (< 10%). A number of other procedures including HBr/phenol/acetic acid,

HC104,I31 Na/Hg (3 - 6%),132 Red-Al,l33 PhMe2SiUl34 and Mg/MeOH were investigated for removal of the tosyl group. All of these procedures did not provide the desired product but only resulted in decomposition of 356. At this point, it became obvious that the tosyl group was not the best choice of protecting group over here.

O ^ O H C y ^ O H — SdiSL. Q _ 0 M s M H N 357, R = Ns 360. R = Ns 358, R = Mtr 361,R = Mtr 359, R = Boc 362, R = Boo

Scheme 4.13: Synthesis of differentially protected prolinols

4.8 Model studies using Prolinol. We have since explored some other easily cleaved nitrogen protecting groups using prolinol as a model system. To this end, commercially available prolinol was protected with BociO, NsCl, MtrCl*^^ to provide the

119 corresponding N-protected prolinols 357,358 and 359 (scheme 4.13). The /V-protected prolinols were then mesylated and reacted with 3-hydroxypyridine (4 eq) in DMF. The results obtained form these reactions are shown in scheme 4.14.

d m f . 120 C decomp. Ns 363 (4 eq) 360

Ç ^ O M s D?fF°i20-C c R c o ÿ r Mtr 363 (4eq) Mtr ^ Thioanisole, 361 3 6 4 ^ MegS

362 / 366 365 only product KgCOg, DMF, 120 *C 363(20eq)

367 368 Hcr

Scheme 4.14: Reactions of differentially substituted prolinols

The nosyl protected prolinol 360 was found to be unstable under the conditions of the alkyation reaction and very little of the desired alkylated product was isolated. Alkylation of 361 (Mtr protecting group) provided the desired alkylated product 364. Unfortunately, deprotection of the Mtr protecting group in 364 resulted in decomposition thus making the Mtr group unsuitable for this work. The Boc protected prolinol 362 did not provide any of the desired product 367 when the alkylation was carried out using 4 eq of 3-hydroxypyridine, but provided the oxazolidinone 366 instead. This fragmentation

120 reaction of A/-Boc protecting groups is well documented in the literature This problem was eventually overcome by using 20 eq of 3-hydroxypyridine in the alkylation reaction. Deprotection of the Boc protecting group in 367 had been reported previously, hence it was decided to use Boc as the protecting group in the bicyclic pyrrolidines.

OH OH

NTs 1) Na-naohthatenide NBoc 2) BocgO (62% from 353) 353 369 MsCI

OMs

NBoc DMF. 120 *0 363 (4eq) H 370 371

Scheme 4.15: Attempted synthesis of nicotinic modulators using iV-Boc protecting group

4.9 Alternate synthetic approach using iV-Boc protecting group. To examine the feasibility of using a N-Boc protecting group deprotection of the alcohol 353 was attempted using HBr/phenol. Unfortunately this reaction only resulted in decomposition. The deprotection of 353 was next attempted using sodium naphthalenide. This reaction provided the desired amino alcohol which was difficult to isolate. This problem was avoided by treating the crude reaction mixture obtained on deprotection of 353 with BocoO, to provide 369 in reasonable yield. The Boc protected amino alcohol 369 was then mesylated to provide 370 which was then reacted with 3-hydroxypyridine (20 eq). Unfortunately, this reaction did not provide the desired alkylated product. Only the oxazolidinone 371 was obtained from this reaction (scheme 4.15). Once again the low

121 reactivity of 370 in the alkylation reaction could be attributed to the greater steric crowding in the bicyclic system 370 as opposed to the test system 362 4.10 Summary In this chapter we discussed the intramolecular 3+2 annulation reaction of aziridines with allylsilanes. This is the first and one of only three reported examples^*-^^ of an intramolecular 3+2 armulation reaction of allylsilanes. This reaction results in the formation of 2 rings and three stereocenters in a single step to provide a single enantiomer of the final bicyclic pyrrolidines. The stereoselectivity at the ring junction of the bicyclic products was similar to that observed in the Sakurai reaction of aziridines with allylsilanes described in chapter 2. Interestingly, the reaction showed retention of the cis olefin geometry of the starting allylsilane. In previous examples where this reaction has been used for the synthesis of optically pure products, the chirality was transferred from the nucleophile (allylsilane) into the final products.^ This is the first time it has been demonstrated that it is also possible to transfer chirality from the electrophile into the final product in these types of reactions. The synthetic utility of the bicyclic pyrrolidines was demonstrated by using this reaction for the synthesis of novel nACHr modulators.

Although the tosyl group could not be removed successfully, we have shown how one could accomplish the synthesis of these types of molecules. We have since, also examined the use of other protecting groups in this synthesis. This chemistry should prove helpful to anyone who wishes to finally complete the synthesis of these types of molecules.

122 Chapter 5 Conclusions

Two modes of reactivity between aziridines and allylsilanes have been developed.

In the first mode, treatment of an aziridine-allylsilane with greater than a stoichiometric amount of BF 3*OEt 2 provided the amino olefin 2 in high chemical yield and modest diastereoselectivity. The reaction was found to be highly regioselective with attack of the allylsilane taking place exclusively at the more substituted carbon atom of the aziridine ring. The ratio of cis to trans isomers formed during the cyclization reaction was found to be dependent on the length of the tether between the aziridine and the allylsilane. The cis isomer was found to be the major product during formation of the five membered carbocycle . The trans isomer was found to be the major product during formation of the six membered carbocycle. All attempts to increase the stereoselectivity by altering reaction conditions such as temperature, solvent and Lewis acid were unsuccessful. Cyclization of aziridine-aliylsiianes with different protecting groups revealed that it was important to have an electron withdrawing substituent on the nitrogen atom such as tosyl, nosyl or phenacetyl to effect the cyclization reaction. No reaction between the aziridine and the allylsilane was seen when the substituent was either benzyl or phenethyl. Our first generation synthesis of aziridine-aliylsiianes involved two low yielding reactions for the synthesis of the aziridine and the allylsilane moieties. After exploring a

123 few other routes it was realized that one could synthesize aziridine-aliylsiianes from ditosyl aziridinemethanol (derived from 5-serine), by reaction with an appropriate organometallic reagent. The reaction was found to proceed via opening of the aziridine ring in ditosyl- aziridinemethanol, followed by ring closure of the intermediate tosylamide onto the adjacent tosyl ester. This reaction was found to be highly selective, with attack of the organometallic reagent taking place exclusively on the aziridine ring with no attack on the tosyl ester. This protocol provided the desired aziridine-aliylsiianes in high optical purity (>97%). We also attempted to extend this methodology to synthesize aziridine-aliylsiianes with AAprotecting groups other than tosyl. Unfortunately, aziridinemethanol with an N-Boc group was found to be unreactive while aziridinemethanols with W-Cbz and A/-Ns groups decomposed during the reaction. The synthesis of aziridine-aliylsiianes with different N substituents was eventually accomplished by deprotection of an iV-tosylaziridine-allylsilane with sodium naphthalenide to provide the corresponding N-H aziridine, which could then be protected using the substituent of choice. It was perceived that this deprotection protocol for removal of a tosyl group from an aziridine ring, could be a useful procedure for the synthesis of a variety of N substituted aziridines from a single iV-tosyl aziridine precursor. Very little was however, known about the compatibility of sodium/naphthalenide with different types of N- tosylaziridines. For this purpose, a variety of different V-tosylaziridines were synthesized and deprotected successfully, using sodium/naphthalenide. A number of different functional groups including silyl and benzyl ethers, olefins, aromatic rings, amides, certain esters and bicyclic aziridines were tolerated under the deprotection conditions employed. It was envisioned that amino olefins such as 2 could be extremely useful for the synthesis of natural products. To demonstrate the synthetic utility of the aziridine-allylsilane cyclization reaction, this reaction was used as a key step in the enantioselective synthesis of rauwolfia alkaloid (-)-yohimbane. The total synthesis of (-)-yohimbane was accomplished

124 in 8 steps and 24% overall yield from the starting aziridine-allylsilane. A key step in the synthesis was alkylation of the tosylamide in 2. After extensive experimentation it was found that the alkylation reaction could be carried out successfully when the leaving group in the electrophile was a mesylate. Functional group manipulation of alkylated product followed by a Bischler-Napieralski reaction provided a mixture of (-)-yohimbane and ent- alloyohimbane, which could be separated easily on silica gel. This synthesis of (-)- yohimbane can now serve as a guide for the synthesis of more complex rauwolfia alkaloids via aziridine-allylsilane cyclizations.

On treatment of aziridine-allylsilane with catalytic amount of BF 3»OEt2, a second mode of reactivity (3+2 annulation) was seen. The product of this reaction was found to be the bicyclic pyrrolidine 3. As before, cyclization leading to the formation of a 5-5 bicyclic system provided the cis fused isomer as the major product. Cyclization leading to the formation of a 6-5 bicyclic system provided the trans fused isomer as the major product. The second ring closure to form the pyrrolidine ring was found to be highly stereoselective to provide a single stereocenter during the second ring closure. As a result, retention of the olefin geometry of the starting allylsilane was seen during the cyclization reaction. A substantial amount of olefin 2 was also formed when the reaction was carried out using trimethylallylsilanes. To reduce the amount of olefin 2 formed during the 3+2 armulation reaction, the aziridine-phenyldimethylallylsilanes were synthesized. Cyclization of the aziridine-phenyldimethylallylsilanes reduced the amount of olefin formed during the annulation reaction and provided synthetically useful yields of 3. The phenyldimethylsilyl group in the bicyclic pyrrolidines was then oxidized to the corresponding hydroxyl group. We have since investigated the use of the bicyclic pyrrolidines for the synthesis of novel nAChR modulators by replacing the hydroxyl group with a pyridyl ether linkage. Unfortunately, synthesis of these compounds could not be completed due to unexpected difficulty in removing the tosyl group from the pyridyl ethers. Some other easily cleaved N

125 protecting groups were also attempted, to complete the synthesis of nAChR modulators. Unfortunately, we have yet to find a suitable protecting group which is compatible with both, the reaction conditions used for synthesis of the pyridyl ether, as well as the final deprotection reaction.

126 Chapter 6 Experimental

General Methods Thin layer chromatography (tic) was performed on Whatman

precoated silica gel F 254 aluminum foils. Visualization was accomplished with UV light and/or phosphomolybdic acid solution followed by heating. Purification of ±e reaction products was carried out by flash column chromatography using a glass column dry packed with silica gel (230-400 mesh ASTM) according to the method of Still. NMR and NMR (proton decoupled) spectra referenced to TMS were recorded using a IBM AC 250, IBM AC 270, or Bruker DRX 400 model spectrometer. nOe experiments were carried out using a IBM AC 270 or Bruker DRX 400 spectrometer. COSY and NOES Y experiments were carried out using a Bruker AM 500 spectrometer at The Ohio State University

Campus Chemical Instrument Center. Unless noted, all spectra were recorder in CDCI 3. Data are reported as follows; chemical shift in ppm Grom internal standard tetramethylsilane on the Ô scale, multiplicity (b = broad, s = singlet, d = doublet, t = triplet, q = quartet and m = multiplet), integration, coupling constant (Hz). All reactions were carried out under an atmosphere of nitrogen unless specified otherwise. Glassware was flame dried under a flow of nitrogen. Tetrahydrofuran and diethylether was distilled over Sodium/benzophenone ketyl immediately prior to use. Dichloromethane and benzene were distilled over CaH? prior to use. Exact mass measurements recorded in the electron impact

127 (El) or fast atom bombardment (FAB) modes were detremined at The Ohio State University

Campus Chemical Instrument Center with a Kratos MS-30 mass spectrometer. Combustion analysis were performed at Quantitative Technologies Inc., Whitehouse, New Jersey or at Oneida Research Services, Whitesboro, New York. Optical rotations were recorded using a Perkin-Elmer 241 model polarimeter.

OTBS

C OH 133 5>[(/

TBSCl. The reaction was quenched by addition of water ( 10 mL) and diluted with Et 2 0 (90 mL). The organic layer was washed with water, sat. NaHCOg solution, brine, dried (MgSO^) and concentrated. Chromatography of the residue (25% EtOAc in hexanes) afforded 6.02 gms of 133 (52%) as a clear o il. Ry^O.36 (25 % EtOAc in hexanes). ^H

NMR (CDCI3, 250 MHz) S 3.6 (m, 4H), 1.65-1.3 ( m, 8 H), 0.88 (s, 9H) , 0.04 (s , 6 H).

128 OTBS

CO 134

5-[(r-butyldimethylsilyl)oxy]-l-hexanal (134). The alcohol 133 (6 g, 26 mmol) in CH 2CI2 (50 mL), was added to PCC (8.37 g, 38.85 mmol) in CH 2CI2 (215 mL) over 30 min and the reaction then stirred at rt for 90 min. The reaction was diluted with petroleum ether (150 mL) and filtered through a bed of silica gel and celite (each 1 inch thick). The filtrate was dried (MgS 0 4 ), concentrated and chromatographed immediately (3% EtOAc in hexanes) to afford the aldehyde 134 (78 %) a colorless oil. Ry^O.23 (3%

EtOAc in hexanes). NMR (CDCI 3, 250 MHz), 5 9.75 (s, IH), 3.6 (t, 2H, J = 7), 2.5-

2.25 (m, 2H), 1.7-1.2 (m, 6H), 0.88 (s, 9H), 0.04 (s, 6H).

Alternate preparation of 134 by Swern oxidation. A solution of DMSO (6 mL, 79 mmol) in CH 2CI2 (35 mL) and added to a cold (-78 °C) solution of freshly distilled oxalyl chloride (3.86 mL, 43.2 mmol) in CH 2CI2 (70 mL) over 20 min and the reaction was stirred at - 78 “C for I h. The alcohol 133 dissolved in CH 2CI2 (35 mL) was added to the reaction and the whole stirred for an additional 1 h at -78 “C. Triethylamine ( 14.6 mL, 180 mmol) dissolved in CH 2CI2 (35 mL) was then added to the reaction and the resulting solution was allowed to warm to rt over a period of 45 min. The reaction was then diluted with CH 2CI2 (150 ml) and washed with water, IM HCl, sat. NaHCOg, brine, dried

(MgS0 4 ) and concentrated. The resulting oil was chromatographed (4 % EtOAc in hexanes) immediately to afford the aldehyde 134 (58 %)

129 OTBS

O' 136

5-[(r>butyldimethylsiIyI)oxy]-heptane-l,2 epoxide (135). NaH (0.97 g, 24.21 mmol) was washed with hexanes. DMSO (36 mL) was added to NaH above and the mixture was stirred at 75 °C for 30 min. THF (60 mL) was added to the above solution and the reaction was cooled to -10 °C. Trimethy(sulfonium iodide (4.94 g, 24.21 mmol) in DMSO (22 mL) was added dropwise to the reaction over 10 min and the temperature of the reaction was maintained at -5 “C during the addition. The aldehyde 134 (4.68 g, 20.18 mmol) in THF (15 mL) was then added to the y lid solution over 5 min. The reaction was wanned to room temperature and stirred for 2 h. The reaction was stopped by addition of water (200 mL) and the aqueous layer was extracted with Et 2 0 /pet.ether (1:1,3 x 100 mL).

The combined organic fractions were washed with brine, dried (MgS 0 4 ) and concentrated. Chromatography (3 % EtOAc in hexanes) provided 2.12 g of 135 (43 %). R/0.26 (3 %

EtOAc in hexanes). ^H NMR (CDCI 3, 250 MHz), 3.6 (t, 2H, J = 7), 2.9 (m, IH), 2.74

(m, IH), 2.45 (m, IH), 1.6-1.2- (m, 6H), 0.88 (s, 9H), 0.04 (s, 6H) .

O T B S

N3 OH

5>[(/>butyIdimethylsilyI)oxy]-l-azido-2-heptanol. Sodium azide (8.13 g, 125.13 mmol) was added to a mixture of epoxide 135 (2.12 g, 8.67 mmol) and EtgN (0.28 mL,

2mmol) in methanol (120 mL) and the reaction refluxed for 17 h. The reaction was quenched by addition of water (300 mL) and the aq.layer was extracted with EtOAc (4 x 50 mL). The organic layers were combined, dried (MgS 0 4 ) and concentrated. Chromatography (15% EtOAc in hexanes) provided azido alcohol in 65 % yield. R/0.25

( 15 % EtOAc in hexanes).

130 7). 3.4-3.27 (del, 2H. 7 = 7, 15), 3.27-3.15 (dd, 2H, 7 = 7. 15) . 1.6-1.1 (m, 6 H), 0.88

(s, 9H), 0.04 (s, 6 H).

^ v ^ O T B S

OTs 136

5 -[(r-butyldimethylsilyl)oxy]- 2 -(/7 -toluenesulfonyioxy)-l-azido-heptane

(136). DMAP (68 mg, 0.56 mmol) and Et]N (1.55 mL, 11.26 mmol) were added to azido alcohol above (1.62 g, 5.63 mmol) in CH 2CI2 (5.6 mL) at 0 °C. Tosyl chloride (1.61 g, 8.45 mmol) was added in one portion and the reaction was stirred at 0 °C for another 10 min. The reaction was then allowed to stir at rt for 9 h after which it was diluted with

CH2CI2 (20 mL). The organic phase was washed with IM HCl, sat. NaHCOs, brine, dried (MgSO^) and concentrated. Chromatography (5 % EtOAc in hexanes) provided the tosylated azido alcohol 136 (59 %). R/0.20 (5% EtOAc in hexanes). NMR (CDCI 3, 250 MHz) 5 7.8 (d, 2H, 7 = 10.5), 7.4 (d, 2H, 7 = 10.5), 4.6-4.5 (m, IH), 3.5 (t, 2H, 7

= 7), 3.5-3.4 (dd, 2H, 7=7, 15), 1.6-1.1 (m, 6H), 0.88 (s, 9H), 0.04 (s, 6 H).

Preparation of PhI=NTs.70 p-toluenesulfbnamide (3.42 g, 20 mmol) and KOH (2.8 g, 50 mmol) were dissolved in methanol (80 mL) and the mixture was cooled in an ice bath. PhI(OAc )2 (6.44 g ) was added to the reaction which was then stirred at rt for 18 h. The reaction was then diluted with water (300 mL) while rapidly stirring to provide a fine white suspension. The precipitate was allowed to stand for 10 h after which it was filtered and dried under high vaccum (2 mm Hg) for 18 h to provide PhlNTs (5.71 g, 77%). Melting point 102-103 °C.

Synthesis of Copper perchlorate.^^ CU 2O (4.14 g) was treated with 70% HCIO 4

( 11.62 g) in CH 3CN (80 mL). The mixture was re fluxed for I h after which the reaction 131 was filtered. The precipitate obtained during filtration was recrystallized from MeCN to provide a crystalline white precipitate which was then dried under vaccum (2 mm Hg) for 18h and immediately stored in a tightly sealed container.

139 7-[(/-butyldimethylsiIyl)oxy]-l-heptene (139) n-BuLi (29.56 mL of a 1.75 M solution, 51.73 mmol) was added to a suspension of dry PhgBCHgl (18.48 g, 51.74 mmol ) in THF (180 mL) at 0 “C . The red solution thus formed was stirred at 0 °C for 30 min and then cooled to -78 “C. Aldehyde 134 (10 g, 43.12 mmol) in THF (50 mL) was added to the ylid solution and the reaction was stirred at -78 "C for 1 h and then at rt for 14 h. The reaction was stopped by diluting with petroleum ether (250 mL) and washed with sat. NH4CI, brine, dried (MgS 0 4 ) and concentrated. Vacuum distillation (0.02 - 0.03 mm of Hg, 4 r-4 2 “ C ) provided the olefin 139 (3.69 g) as a colorless oil. ^H NMR (CDCI 3,

250 MHz), 5 5.80-5.73 (m, 1 H ), 5.01-4.88 (m, 2 H), 3.57 (t, 2 H, 7 = 6 .6), 2.07-1.99

(m, 2 H), 1.62-1.2 (m, 6 H), 0.87 (s, 9H), 0.02 (s, 6 H). NMR (CDCL3, 62.5 MHz)

6 139.04, 114.22, 63.23, 33.77, 32.76, 28.77, 25.99, 25.37, 18.37, -5.2.

OTBS

% 140 rV-(p-Toluenesulfonyl)-2{5[(f-butyldimethylsilyr)oxy]-rt-pentyU-aziridine (140) PhlNTs (3.82 g, 10.23 mmol) was added over 2 h, to a mixture of copper perchlorate (10 mol. %, 224 mg) and olefin 139 (1.57 g, 6.82 mmol) in CH 3CN (7 mL) at 0 °C. The reaction was allowed to stir at rt for another 45 min after which the green solution was filtered through a plug of silica gel. The filtrate was concentrated and purified

132 by flash chromatography (10 % EtOAc in hexanes) to give the aziridine 140 (1.19 g) in

43% yield. NMR (CDCI3, 250 MHz). 5 7.82-7.78 (d, H, 7 = 8 .3 1 ), 7.33-7.29 (d,

2H, J = 8.05), 3.54-3.49 (t, 2H, J = 6.26), 2.75- 2.62 (m, IH), 2.62-2.59 (d, IH, J =

6.94), 2.42 (s, 3H), 2.04-2.02 (d, IH, 7 = 4.48), 1.6-1.15 (m, 8 H) , 0.85 (s, 9H) , 0.01

(s, 6H). I3c NMR ( CDCI3, 62.5 MHz) Ô 144.3, 135.5, 129.59, 128.01, 62.94, 40.33,

33.74, 32.61, 31.31, 26.53, 25.96, 25.33, 21.55, 18.4, -5.3. HRMS caic.for

C2oH 35NS0 3 Si 397.2123, found 397.2091

OH

Ts 141

A^-(/7 -ToluenesuIfonyl)- 6 ,7 -aziridino-l-n-heptanol (141) n-Bu^NF (8.26 mL of a 1 M solution in THF) was added to aziridine 140 (2.2 g, 5.51 mmol) in THF (11 mL). at 0 "C and the reaction was stirred for 2 h. The reaction was diluted with water (10 mL) and the aqueous layer extracted with EtOAc (3 x 10 mL), dried (MgS 0 4 ) and concentrated.

Chromatography (4 % MeOH in CHCI 3) gave the alcohol 141 (1.18 g 76 %). ^H NMR

(CDCI3, 250 MHz), Ô 7.72-7.68 (d, 2H, 7 = 8.24), 7.25-7.22 (d, 2H, 7 = 8.07), 3.46-

3.41 (t, 2H, 7 = 6.31), 2.62- 2.5 (m, IH), 2.50-2.48 (d, IH, 7 = 7.04), 2.32 (s, 3H),

1.97-1.95 (d, IH, 7 = 4.5), 1.57-1.10 (m, 8 H). »3c NMR (CDCI3, 62.5 MHz) S 144.2,

134.9, 129.4, 127.7, 62, 40, 33.5, 32.1, 30.9, 28.2, 24.8, 21.3. HRMS calc for

C 14H21NSO3 283.1258, found 283.1241.

133 T s 142 iV-(^-Toluenesulfonyl)-6,7-aziridino-l-n*HeptanaI (142). TPAP (31 mg, 5 mol% ) was added to a suspension of alcohol 141 (0.5 g, 1.75 mmol), NMO (0.37 g,

2.63 mmol) and powdered molecular sieves (500 mg per mmol of 141, 875 mg ) in

CH2 CI2 (3.5 mL) at 0 °C. The reaction was allowed to stir at 0 “C for 20 min and then at rt for 75 min during which the initially greenish solution turned black. The reaction was then filtered through celite (0.5 inch) and the filter medium washed with EtOAc (25 mL). The solution thus obtained was concentrated and the resulting oil was purified by flash chromatography (35 % EtOAc in hexanes) to yield aldehyde 142 (0.45g, 8 6 %). NMR

(CDCI3 , 250 MHz), S 9.62-9.60 (t, IH, J = 1.5), 7.73-7.70 (d, 2H, / = 8.31), 7.27-

7.20 (d, 2H, 7 = 8 .3 1 H z), 2.66- 2.55 ( m, IH), 2.54-2.51 (d, IH, J = 6.96), 2.35 (s,

3H), 2.28-2.22 (m, 2H), 1.99-1.97 (d, IH, 7 = 4.43), 1.65-1.10 (m, 6 H) . NMR

(CDCI3 , 62.5 MHz) 5 201.75, 144.32, 135.07, 129.47, 127.78, 43.33, 39.69, 33.51,

30.76, 26.12, 21.34, 21.24. HRMS calc, for C 14H 19NSO3 281.1102, found 281.1085

143 iV-(p-ToIuenesuifonyI)-2-[7-(trimethy!)silyl-n-hept-5-en]aziridine (142). n- BuLi (0.44 mL of a 2 M solution, 0.9 mmol) was added to a suspension of PhgPCH^Br

(0.32 g, 0.9 mmol) in THF (1.4 mL) at 0 °C and the resulting red solution was stirred for

Ih at rt. lodomethyltrimethylsilane (0.193 g, 0.9 mmol) was added to the above ylid solution at 0 °C after which the reaction was warmed to rt and stirred 60 min. The reaction

134 was then cooled to 0 C and a second equivalent of n-BuLi ( 0.44 mL of a 2 M solution,

0.90 mmol) was added, after which the reaction was warmed to rt and stirred for another

90 min. The reaction was then cooled to -78 °C and aldehyde 142 (0.78 mmol) in THF (2 mL) was added to the reaction. The reaction was stirred at -78 °C for I h and then at rt for

16 h. The reaction was quenched by addition of sat. NH 4 CI and the aq layer was extracted with hexanes, dried (MgSO^) and concentrated.Chromatography (10 % EtOAc in hexanes) of the oil provided 143 (33 %, 95.2 mg). NMR (CDCI3 , 250 MHz), S 7.82-7.79 (d,

2H, J = 8.28) , 7.33-7.29 (d, 2H, J = 8.49), 5.41-5.24 (m, IH). 5.21-5.06 (m, IH),

2.76-2.62 (m, IH), 2.62-2.59 (d, IH, J = 6.96), 2.4 (s, IH), 2.04-1.02 (d, IH, / =

4.52), 1.95-1.8 (m, 2H), 1.62-1.12 (m, 2H), 1.45-1.2 (m, 6 H), -0.03 (s, 9H). ‘3 c NMR

(CDCI3 , 62.5 MHz) S 144.29, 135.54, 129.58, 128.01, 127.03, 125.68, 40.36, 33.71,

31.26, 29.17, 26.77, 26.47, 21.55, 18.46, -1.78. HRMS calc, for Ci 9 H3 iN S 0 2 Si

351.1705, found 351.1684.

OTBS

145

6 -[(r-butyldimethylsilyl)oxy]-l-hexene (145). /i-BuLi (65 mL of a 1.75 M solution, 114 mmol) was added to a suspension of dry PhgPCHgl (46 g, 114 mmol ) in

THF (300 mL) at 0 “C . The red solution thus formed was stirred at 0 °C for 30 min and then cooled to -78 °C. Aldehyde 144 (22 g, 95 mmol) in THF (50 mL) was added to the ylid solution and the reaction was stirred at -78 °C for 1 h and then at rt for 14 h. The reaction was stopped by diluting with petroleum ether (250 mL) and washed with sat.

NH4 CI, brine, dried (MgSO^) and concentrated. Vacuum distillation (0.02 - 0.03 mm of

Hg, 41°-42° C) provided the olefin 145 (7.42 g) as a colorless oil. ^H NMR (CDCI3 , 250 MHz), Ô 5.86-5.7 (m, IH), 5.02-4.89 (m, 2H), 3.59 (t, 2H, 7= 6.12), 2.1-2 (q, 2H, 7 =

135 6 .8 8 ), 1.7-1.2 (m, 4H). 0.88 (s, 9H), 0.02 (s, 6 H). '^C MMR (CDCI3 . 62.5 MHz) Ô

138.88, 114.33, 66.04, 33.54, 32.35, 25.99, 25.24, 18.35, -5.28.

OTBS

T 146

A/^-0-Toluenesulfonyl)*2{4[(r-butyldimethylsilyl)oxy]-/i-butyl }aziridine

(146). PhlNTs (12.8 g, 34.36 mmol) was added over 2 h, to a mixture of copper perchlorate (10 mol. %, 1.12 g) and olefin 145 (7.4 g, 34.4 mmol) in CH3 CN (34 mL) at

0 *C. The reaction was allowed to stir at rt for another 45 min after which the green solution was filtered through a plug of silica gel. The filtrate was concentrated and purified by flash chromatography (10 % EtOAc in hexanes) to give the aziridine 146 (4.2 g) in

34% yield. NMR (CDCI 3 , 250 M Hz), S 7.82-7.78 (d, 2H, J = 8.31). 7.32-7.3 (d,

2H, J = 8.05), 3.5 (t, 2H, J = 6.26), 2.76- 2.65 (m, IH), 2.65-2.58 (d, IH, J = 6.94),

2.4 (s, 3H), 2.04-2 (d, IH, J = 4.48), 1.62-1.13 (m, 6 H), 0.88 (s, 9H ) , 0.02 (s, 6 H).

OC NMR (CDCI3 , 62.5 MHz) 5 144.3, 135.52, 129.6. 128.00, 62.72, 40.31, 33.72,

32.17, 31.09, 29.69, 25.94, 23.10, 21.56, 16.30.

OH

% 147

A-(p-Toluenesulfonyl)-5,6-aziridino-l-hexanoI (147). n-BuN 4 F (8.26 mL of a

1 M solution in THF) was added to aziridine 146 (2 g, 5.2 mmol) in THF ( 11 mL) at 0 °C and the reaction was stirred for 2 h. The reaction was diluted with water ( 10 mL) and the aqueous layer extracted with EtOAc (3 x 10 mL), dried (MgS0 4 ) and concentrated.

Chromatography (4 % MeOH in CHCI3 ) gave the alcohol 147 (1.04 g, 75 %). ^H NMR

(CDCI3 , 250 MHz) Ô 7.67-7.64 (d, 2H, J = 8.31), 7.22-7.18 (d. 2H, J = 8.32), 3.39- 136 3.32 (t, 2H, J = 6.26). 2.90-2.87 (l, IH, J = 5.03), 2.57- 2.5 (m, IH). 2.45-2.43 (d, IH,

J = 6.98), 2.28 (s, 3H), 1.94-1.92 (d, IH, 7 = 4.5), 1.53-1.12 (m, 6 H) . NMR

(CDCI3 , 62.5 MHz) 6 144.19, 134.5, 129.30, 127.52, 61.67, 39.82, 33.43, 31.48,

30.50, 22.61, 21.13. HRMS calc. for C 13H 19NSO3 269.1102, found 269.1094.

, 0

Ts 148 iV-(p-ToIuenesulfonyl)-6,7-aziridino-l-Hexanal (148). TPAP (40 mg, 5 mol% ) was added to a suspension of alcohol 147 (0.65 g, 2.41 mmol), NMO (0.42 g, 3.63 mmol) and powdered molecular sieves (5(X) mg per mmol of 147 1.2 mg) in CH2 CI2 (5 mL) at 0 °C. The reaction was allowed to stir at 0 °C for 20 min and then at rt for 75 min during which the initially greenish solution turned black. The reaction was then filtered through celite (0.5 inch) and the filter medium washed with EtOAc (25 mL). The solution thus obtained was concentrated and the resulting oil was purified by flash chromatography

(35 % EtOAc in hexanes) to yield aldehyde 148 (0.45g, 8 6 %). ^H NMR (CDCI3 , 250

MHz), 6 9.59-9.58 (t, 3H, / = 1.3), 7.74-7.71 (d, 2H, J = 8.27), 7.27-7.24 (d, 2H, J =

8.01), 2.68- 2.60 (m, IH), 2.54-2.51 (d, IH, 7= 6.96), 2.35 (s, 3H), 2.30 (m, 2H),

1.99-1.97 (d, IH, 7 = 4.48), 1.7-1.15 (m, 4H ). NMR (CDCI 3 , 62.5 MHz) Ô 201.33,

144.47, 134.96, 129.54, 127.60, 42.62, 39.43, 33.45, 30.27, 21.38, 19.13. HRMS calc, for C13H 17 NSO3 267.0945, found 267.0917.

149 iV-(p-ToluenesuifonyI)-2-[6-(trimethyl)siIyl-n-hex-4-en]aziridine (149). 137 n-BuLi (0.46 mL of a 2 M solution, 0.94 mmol) was added to a suspension of PhgPCHgBr (0.34 g, 0.94 mmol) in THF (1.4 mL) at 0 ’C and the resulting red solution was stirred for Ih at rt. lodomethyltrimethylsilane (0.2 g, 0.94 mmol) was added to the above ylid solution at 0 °C after which the reaction was warmed to rt and stirred 60 min. The reaction was then cooled to 0 °C and a second equivalent of n-BuLi ( 0.46 mL of a 2 M solution, 0.94 mmol) was added, after which the reaction was warmed to rt and stirred for another 90 min. The reaction was then cooled to -78 "C and aldehyde 148 (0.78 mmol) in THF (2 mL) was added to the reaction. The reaction was stirred at -78 °C for I h and then at rt for 16 h. The reaction was quenched by addition of sat. NH 4CI and the aq layer was extracted with hexanes, dried (MgSOa) and concentrated.Chromatography (10 % EtOAc in hexanes) of the oil provided 149 (33 %, 107 mg). ^H NMR (CDCI 3, 250 MHz), 5 7.82- 7.79 (d, 2H, y = 8.28) , 7.33-7.29 (d, 2H, / = 8.49), 5.41-5.24 (m ,1H), 5.21-5.06 (m,

3H), 2.76-2.62 (m, IH), 2.62-2.56 (d, IH, / = 6.96), 2.4 (s, IH), 2.04-1.02 (d, IH, / =

4.52), 1.95-1.8 (m, 2H), 1.62-1.12 (m, 2H), 1.45-1.2 (m, 6 H), -0.03 (s, 9H). NMR

(CDCI3, 62.5 MHz) 6 145.09, 135.30, 130.38, 128.77, 127.34, 126.93, 41.05, 34.54,

31.72, 27.54, 27.16, 22.34, 19.27, -1.01. HRMS caic.for CigHzgNSOiSi: 351.1705, found 351.1684.

V A ^ N H T s 152a 152b CIS-2-vinyI-l-[(4-methylphenyi)suIfonyl]aminomethyl-cyclopentane (152a) and fra/is-2-vinyl-l-[(4-methylphenyl)sulfonyllaminomethyl-cyclopentane

(152b). Freshly distilled BF 3»OEt2 (0.4 mL, 1.12 mmol) in CHiCL (1 mL), was added

138 to a solution of the aziridine 149 (0.1 g, 0.28 mmol) in CH 2CI2 (2 mL) at 0 ’C over 5 min. The reaction was stirred at 0 ”C for 60 min after which it was warmed to rt and stirred for

18 h. The reaction was quenched by the addition of sat. K 2CO3 solution. The organic layer was then washed with sat. K 2CO3, brine, dried (MgS 0 4 ) and concentrated. Chromatography (12% EtOAc in hexanes) provided an inseparable mixture of 152a: 152b (1:2, 65 mg, 90%) as a colorless oil. NMR (CdDg, 500 MHz), 5 7.91 (d, 2H, J =

8.15) , 6.83 (d, 2H, J = 7.9), 5.51-5.39 (m, IH), 5.36* (m, 0.28H, NH), 5.3 (m, 0.72H, NH), 4.9-4.79 (m, 2H), 3.0-2.97* (m, 0.28H), 2.89-2.79 (m, 1.44H), 2.76- 2.71* (m, 0.28H), 2.35 (m, 0.72H), 1.95-1.85 (m, 0.72H) ovelapping 1.90 (s, 3H),

1.81-1.77* (m, 0.28H), 1.67-1.62* (m, 0.28H), 1.59-1.1 (m, 6H).‘3c NMR (CDCL 3, 62.5 MHz) 5 143.1, 142.0* 138.6, 137.1*, 129.5, 127.0, 115.2, 114.3*, 48.8*, 46.9*,

45.6, 45.1*, 44.7, 43.2, 33.0*, 31.3, 29.9*, 28.8, 23.6*. 23.1, 21.4 (* indicates signal arising due to minor- trans isomer). HRMS calcd for C 15H21 NO2 S 279.1309, found

279.1287.

C C . . . 0 0 - 153a 153b ci5 -2 -vinyl-l-[( 4 -methylphenyl)sulfonyl]aminomethyl-eyciohexane (153a) and ^raizs-2-vinyl-I-[(4-methylphenyl)sulfonyl]aminomethyl-cyclohexane

(153b). Freshly distilled BF 3*OEt 2 (1.5 mL, 12.3 mmol) in CH 2CI2 (3 mL), was added to a solution of the aziridine 143 (1.5 g, 4.1 mmol) in CH 2CI2 (38 mL) at 0 "C over 5 min. The reaction was stirred at 0 °C for 60 min after which it was warmed to rt and stirred for

18 h. The reaction was quenched by the addition of sat. K 2CO3 solution. The organic layer was then washed with sat. K 2CO3, brine, dried (MgS 0 4 ) and concentrated. Chromatography (12% EtOAc in hexanes) provided an inseparable mixture of 153a: 153b (2:1, 1.13 g, 94%) as a colorless oil. ^H NMR (CôDô, 250 MHz), 5 7.89 (d. 2H. 7 =

139 8.23), 6.82 (d, 2H. J = 8.27), 5.69-5.65* (m, 0.27H), 5.43-5.46 ( m, 0.73H), 5.25(t, 0.73H, J = 6.39), 5.18* (t, 0.27H, J = 6.3), 4.94-4.8 (m, 2H), 3.06-3.01 (m, 0.73H), 2.77-2.74* (m, 0.54H ), 2.65-2.6 (m, 0.73H), 2.18* (m, 0.27H), 1.9 (s, 3H), 1.74-1.71

(m, 0.73H), 1.54-0.92 (m, 7H). NMR ( CDCL 3, 62.5 MHz ) 5 143.1*, 142.6,

138.1*, 137.3, 129.5, 127.0, 115.8*, 114.7, 47.4, 46.2, 45.8*, 41.5, 41.3*, 39.8*, 33.3,30.6*, 29.8, 26.1*, 25.6, 25.5, 24.6*, 22.1*, 21.4 (* indicates signal due to minor- cis isomer). HRMS calcd for C 16H23NO2 S 293.1466, found 293.1480.

H

H 154 (IS, 2i{)-l-(2-hydroxyethyl)-2-[(4-methylphenyl)sulfonyllaminoinethyl- cyclohexane (154b) and (IR, 2R)-l-(2-hydroxyethyl)-2-[(4-methyI phenyl)sulfonyi]aminomethyl-cycIohexane (154a). 9-BBN (5.5 mL, 2.7 mmol, 0.5 M solution in THF) was added to a solution of the olefin 287 (0.2 g, 0.68 mmol) in THF (1.4 mL). The reaction was then stirred at rt for 3.5 h. The reaction was cooled in an ice bath and the excess 9-BBN was quenched with EtOH (1.6 mL) and stirred for 5 min followed by addition of 6N NaOH (0.54 mL) and H 2O2 (I mL, 30 % solution). The reaction was refluxed for 60 min and cooled to rt. The reaction was then diluted with water and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried (MgSO^) and concentrated. Chromatography (35% EtOAc in hexanes) provided 154 (0.19 g, 90%, 2:1 naixture of trans and cis isomers). R/0.24 (35% EtOAc in hexanes), ‘H NMR Ô 7.69 (d, 2H, J = 8.26), 7.22 (d, 2H, J = 8.15), 5.88* (t, IH, J =

6.41), 5.67 (t, IH, J = 6.43), 3.7-3.5 (m, 2H), 2.9-2.4 (m, 3H), 2.36 (s, 3H), 1.85-1.09 (m, lOH), 1.08-0.8 (m, IH). NMR (* indicates signal arising from minor cis isomer) 5 143, 142.9*, 137.1*, 137, 129.5, 126.9. 61*, 60.2, 46.1, 44.2*. 41.4. 39.4*, 35.5,

140 35.4. 32.2*. 31.6. 30.1. 28.8*. 26.2*. 25.6. 25.5. 24.1*. 22.1*. 21.3. Anal. Calcd for

C 16H25NO3S : C. 61.7; H. 8.09; N, 4.49. Found C. 61.9; H, 8.37; N. 4.1.

H H 155 156 (4aS, 8ai?)-Af-[(4-inethylphenyl)sulfonyl]-decahydroisoquinolin-3-one (155). (4aÆ, 8a/?)

1.9 mmol). The reaction was then stirred for 18 hrs after which it was diluted with water (5 mL) and the aqueous layer was extracted with CHCI 3 (2 x 5 mL) and the combined organic layers dried (MgS0 4 ) and concentrated. Chromatography (20% EtOAc in hexanes) provided 155 (78 mg, 47%) and 156 (36 mg, 22%). Analytical data for 155: R/0.6 (35% EtOAc in hexanes), [a]o = +31.4“ (c 1.52, EtOAc), iH NMR Ô 7.9 (d, 2H, J = 8.36), 7.3

(d, 2H, J = 8.31), 4.16 (dd, IH, J = 4.52, 11.73), 3.16 (t, IH, / = 11.46), 2.45 (partially overlapped dd, IH, J = 4.9, 17.97), 2.42 (s, 3H), 2.05 (dd, IH, J = 11.75, 17.83), 1.9-

1.65 (m, 4H), 1.6-0.8 (m, 6H). ‘3c NMR 169.7, 144.5, 136.1, 129.1, 128.5, 52.1, 40.9, 38.5, 36.5, 32.1, 29.3,25.1, 25, 21.5. Analytical data for 156:R/0.51 (35%

EtOAc in hexanes), [alo = +27.3“ (c 1.35, EtOAc), ‘H NMR 6 7.86 (d, 2H, 7 = 8.41),

7.28 (d, 2H, J = 8.58), 3.95 (dd, IH, 7 = 6.26, 12.3), 3.79 (dd, IH, 7 = 5 , 12.3), 2.42 (s, 3H), 2.35 (partially overlapped dd, 2H, 7 = 2.95, 6.93), 1.9 (m, 2H), 1.7-1.2 (m,

8 H). ‘3c NMR 6 170, 144.6, 136.2, 129.2, 128.6, 49.3, 36.7, 33.4, 32.1, 28.2, 25.9,

23.1, 21.9, 21.6. Anal. Calcd for C 16H21NO3S: C, 62.51; H, 6.89; N, 4.56. Found C, 62.57; H, 7.05; N, 4.36.

141 SiMea

{8-[(r-butyl-dimethyIslIyl)oxy]-l[(trimethyl)silyl]}-2-octene(170) n-BuLi

(9.55 mL of a 2 M solution, 19.7 mmol) was added to a suspension of Ph 3PCH2 Br (7.97 g, 19.74 mmol) in THF (35 mL) at 0 “C and the resulting red solution was stirred for Ih at rt. lodomethyltrimethylsilane (4.2 g, 19.74 mmol) was added to the above ylid solution at 0 °C after which the reaction was warmed to rt and stirred 60 min. The reaction was then cooled to 0 "C and a second equivalent of n-BuLi (9.55 mL of a 2 M solution, 19.7 mmol) was added, after which the reaction was warmed to rt and stirred for another 90 min. The reaction was then cooled to -78 "C and aldehyde 134 (3.88 g, 17.9 mmol) in THF (2 mL) was added to the reaction. The reaction was stirred at -78 “C for 1 h and then at rt for 16 h.

The reaction was quenched by addition of sat. NH 4CI and the aq layer was extracted with hexanes, dried (MgSOa) and concentrated-Chromatography (10 % EtOAc in hexanes) of the oU provided 170 (3.78g, 70%). iH NMR (CDCI 3, 250 MHz), 5 5.4-5.21 (m, 2H),

3.58 (t, 2H, J = 6.27), 1.95 (m, 2H) ,1.97-1.31 (m, 8 H), 0.87 (s, 9H), 0.03 (s, 6H),

-0.02 (s, 9H). 13c NMR (CDCI3, 62.5 MHz), 127.66, 125.35, 63.28, 32.89, 29.64, 27.11, 26.02, 25.67, 18.45, 18.37, -1.75, -5.23.

SiMea

OH l[(trimethyl)silyl]-2-octene-8-ol. nBuNaF (12.33 mL of a 1 M solution in THF. 12.33 mmol) was added to 170 (3.89 g, 12.33 mmol) in THF (24 mL) at 0 °C and the reaction was stirred for 2 h. The reaction was diluted with water (30 mL) and the aqueous layer extracted with EtOAc (3 x 20 mL), dried (MgSOa) and concentrated. The alcohol

142 ( L04 g, 75 %) thus obtained was used without any further purification. ' H NMR (CDCI 3, 250 MHz). 5 5.4 - 5.16 (m, 2H), 3.59 (t, 2H / = 6.5), 1.97 (m, 2H), 1.74 (s. IH). 1.56 -

1.22 (m. 8 H). -0.03 (s. 9H). NMR (CDCI3. 62.5 MHz). 127.38. 125.46. 62.90. 32.71. 29.53. 26.95. 25.49. 18.39. -1.83.

SiMea

l[(trimethyl)silyll-2>octene-8-al (171) A solution of DMSO (2 mL. 27.5 mmol) in

CH2CI2 (20 mL) and added to a cold (-78 “Q solution of fineshly distilled Oxalyl chloride

(0.42 mL, 13.8 mmol) in CH 2CI2 (20 mL) over 20 min and the reaction was stirred at - 78

°C for 1 h. The alcohol obtained above in CH 2CI2 (20mL) was added to the reaction and the whole stirred for an additional 1 h at -78 °C. Triethy lamine (5.2 mL, 38 mmol) dissolved in CH 2CI2 (20 mL) was then added to the reaction and the resulting solution was allowed to warm to rt over a period of 45 min. The reaction was then diluted with CH 2CI2 (150 ml) and washed with water. IM HCl. sat. NaHCO], brine, dried (MgS04) and concentrated. The resulting oil was chromatographed (4 % EtOAc in hexanes) immediately to afford the aldehyde 171 (84 %). ^H NMR (CDCI 3. 270 MHz), 5 9.7 (s. IH). 5.6-5.12

(m. 2H). 2.38 (t. 2H / = 7.1), 1.98 (m. 2H). 1.6 (m. 2H). 1.4-1.28 (m. 4H). -0.3 (s,

9H). 13c NMR (CDCI3. 67.5 MHz). 201.93, 127.88. 125.73, 43.82. 29.53, 26.69, 22.42. 18.26, -1.99.

172

143 8,9-epoxy-l-[(trimethyl)silyIl-2-nonene (172) NaH (0.82 g, 20.6 mmol) was washed with hexanes. DMSO (60 mL) was added to NaH above and the mixture was stirred at 75 *C for 30 min. THF (80 mL) was added to the above solution and the reaction was cooled to -10 °C. Trimethylsulfonium iodide (4.4 g, 21 mmol) in DMSO (25 mL) was added dropwise to the reaction over 10 min and the temperature of the reaction was maintained at -5 “C during the addition. The aldehyde 171 (3.4 g, 20.6 mmol) in THF (15 mL) was then added to the ylid solution over 5 min. The reaction was warmed to room temperature and stirred for 2 h. The reaction was stopped by addition of water (200 mL) and the aqueous layer was extracted with EtiO (3 x I(X) mL). The epoxide was used without any further purification. Alternate preparation of 172. TrimethyIsulfoxonium iodide (4.54 g, 20.6 mmol) was added to a suspension of NaH (0.82 g, 20.6 mmol, previously washed with 25 mL hexanes) in DMSO (60 mL). The mixture was stirred at rt for 2 h during which the suspension turned into a clear solution. THF (50 mL) was added to the above solution and the mixmre was stirred well for 10 min. The aldehyde 171 (3.4 g, 17.17 mmol) dissolved in THF/DMSO (60 mL DMSO/ 50 mLTHF) was added to the above ylid solution over 15 min. The resulting solution was then stirred at room temperature for another 2 h. The reaction was stopped by adding water (300 mL) and the aqueous layer was extracted with

Et2 0 (2 X 100 mL). The organic fractions were combined .washed with brine, dried

(MgS0 4 ) and concentrated. The epoxide was used without any further purification. ,SiMe3

l[(trimethyi)silyl]-9-azido-2-nonen-8-ol (173). Sodium azide (8.49 g, 131 mmol) was added to a mixture of epoxide 172 (2 g, 9.34 mmol) and Et]N (0.3 mL, 2.14 mmol) in methanol ( 120 mL) and the reaction re fluxed for 17 h. The reaction was quenched

144 by addition of water (200 mL) and the aq.layer was extracted with EtiO (4 x 50 mL). The organic layers were combined, dried (MgSOa) and concentrated. Chromatography (15% EtOAc in hexanes) provided azido alcohol 173 in a 65 % yield. R/0.25, 15 % EtOAc in

hexanes). NMR (CDCI 3, 250 MHz). 5 5.45 - 5.12 (m, 2H), 3.73 (m, IH), 3.4 - 3.18

(m, 2H), 1.94 (m, 2H), 1.55-1.26 (m, 8 H), -0.03 (s, 9H).

174 2-[7-(trimethyl)silyl-it-hept-5-en]aziridine (174) TriphenyIphosphine (0.86 g,3.26 mmol ) was added to a solution of azido alcohol 173 (0.84 g, 3.26 mmol) in

CH3CN (3.3 mL) resulting in evolution of N 2. The reaction was warmed slowly over a period of 3 - 4 h and then refluxed overnight. The reaction was stopped by the addition of

petroleum ether which resulted in precipitation of Ph 3P0 . The supernatant solution was concentrated and the resulting oil was purified by flash chromatography (5 % MeOH in

CHCI3). IH NMR (CDCI3, 250 MHz) Ô 5.4 - 5.12 (m, 2H), 2.4 - 1.86 (m. 3H), 1.7 (d,

IH / = 5.7), 1.5 - 1.33 (m, 9H), -0.03 (s, 9H).

NHTs 186 Methyl-0-r-ButyIdimethyIsilyi-iV-(4-methylphenyI)suIfonyl-(S)serinate (185) Triethy lamine (7.58 g, 75 mmol) was added to a solution of alcohol 184 ( 13.62 g,

50 mmol) and DMAP (0.61 g, 5 mmol) in CH 2CI2 (40 mL) at 0 “C. rerr-butyldimethylsilyl chloride (8.29 g, 55 mmol) in CH 2CI2 ( 10 mL) was added dropwise to the above solution

145 over a period of 10 min. After the addition was complete, the reaction was warmed to rt and allowed to stir overnight. The reaction was diluted with CH 2CI2 (25 mL) and quenched by the addition of I M HCl (25 mL). The two layers were separated and the aqueous layer was extracted with CH 2CI2 (25 mL). The organic layers were combined and washed with sat. NaHCO] solution (25 mL), brine, dried (MgS04) and concentrated. Chromatography

(15% EtOAc in hexanes) provided 185 (18.5 g, 100 %). 'H NMR (CDCI 3, 250 MHz), 6

7.71 (d, 2H, J = 8.51), 7.25 (d, 2H, J = 8.10), 5.60 (d, IH, 7 = 9.08), 4.05-3.99 (m, IH), 3.90 (dd, IH, J = 3.15, 9.97), 3.72, (dd, IH, J = 3.79, 9.98), 3.50 (s, 3H), 2.37

(s, 3H), 0.79 (s, 9H), -0.03 (s, 3H), -0.042 (s, 3H). l^C NMR (CDCI3, 62.5 MHz) S,

169.80, 143.18, 137.32, 129.31, 128.87, 64.13, 57.41, 51.97, 25.37, 21.11, 17.82, -5.87, -5.99.

TBSO NHTs

0-r-Butyldimethylsilyl-iV-(4-inethylphenyi)sulfonyl-(S)serinol (186) Ester 185 (8.33 g, 21.46 mmol) in THF/ EtOH (1:2,90 mL) was treated with anhydrous LiCl (2.72 g, 64.38 mmol) and NaBHa (2.43 g, 64.4 mmol) at 0° C. After the addition of all the sodium borohydride, the reaction was warmed to rt and stirred for another 6 h. The reaction was quenched by careful addition of acetone (19 mL) followed by addition of 5 % HCl till the reaction became clear. The solution was extracted with ether (2 x 100 mL), dried (MgSOa) and concentrated. Purification of the oil by flash chromatography (20 %

EtOAc in hexanes) afforded the alcohol 186 (74%). ^H NMR (CDCI 3, 250 MHz), 5 7.71

(d, 2H, J = 8.51). 7.25 (d, 2H, J = 8.10), 5.40 (d, IH, J = 9.08), 3.70-3.40 (m, 4H), 3.40-3.2 (m, IH), 2.75-2.63, (m, IH), 2.39 (s, 3H), 0.79 (s, 9H), -0.03 (s, 3H), -0.04

(s, 3H). NMR (CDCI3, 62.5 MHz) 5, 143.38, 137.57, 129.62, 128.98, 62.86,

62.51, 55.59, 25.65, 21.33, 18.02, -5.75.

146 TBSO^SC^, H % 1 8 7 (2/f)-2-(r-ButyldîmethylsiIoxy)inethyI-/V-[(4-methylphenyl)sulfonyi] aziridine (187) Diethyl azodicarboxylate ( 3.89 g, 22.36 mmol) was slowly added to a stirred solution of the alcohol 186 (6.9 g, 20.33 mmol) and triphenylphosphine (5.87 gm,

22.36 mmol) in THF (88 mL) at 0“ C. The reaction was allowed to stir for four hours after which all the solvent was removed by concentration under reduced pressure to give a thick brown oil. The oilwas triturated with hexanes which resulted in precipitation of PhgPO which was removed by filtration. Chromatography (8%-12% EtOAc in hexanes) provided aziridine 187 (6.06 g, 88 %) as a colorless oil which solidifies on cooling. NMR

(CDCI3, 250 MHz), 5 7.76 (d, 2H, J = 8.20), 7.26 ( d, 2H, J = 8.37), 3.63 ( dd, IH, J =

3.92, 11.54), 3.52, (dd, IH, J = 3.79, 11.58), 2.85 (m, IH), 2.57 (d, IH, J = 7.08), 2.37 (s, 3H), 2.15 (d, IH, J = 4.5), 0.76 (s, 9H), -0.08 (s, 3H), -0.05 (s, 3H).

NMR (CDCI3, 62.5 MHz) 5 144.25, 135.14, 129.49, 127.87, 62.23, 40.68, 30.37,

25.62, 21.42, 18.09, -5.60, -5.63.

1 8 8 (2R)-2-Hydroxymethyl-iV-[(4-methyIphenyl)sulfonyl]aziridine (188) n-

BU4NF ( 16 mL of I M solution in THF, 16 mmol) was added dropwise to an ice cold solution of aziridine 187 (5 g, 14.61 mmol) in THF (28 mL). The solution was stirred for an hour after which it was diluted with water and extracted with EtOAc (2 x 25 mL). The layers were separated and the organic layer was dried (MgSO^) and concentrated by removal of solvent under reduced pressure. The yellow oil obtained was used without any further purification.

147 ' “O i 189 2/{)-2-[(4-inethylphenyl)suIfonyIoxy]inethyI-l-[(4-inethylphenyI)sulfonyl] aziridine (189). Triethy lamine (2.9 g, 29.2 mmol) was added to a solution of 188 ( 13.6 g, 14.6 mmol) and DMAP (ISO mg, 1.5 mmol) in CH 2CI2 (15 mL) at 0 °C. p- Toluenesulfonyl chloride (2.9 g, 15.3 mmol) was added to the reaction over a period of 5 minutes. After the addition was complete, the solution was warmed to room temperature and allowed to stir for another 90 minutes. The reaction was diluted with CH 2CI2 (20 mL) and quenched by the addition of I M HCl (15 mL). The two layers were separated and the aqueous layer was extracted with CH 2CI2 (20 mL). The organic layers were combined and washed with sat. NaHCOg solution (15 mL), brine, dried (MgS 0 4 ) and concentrated. Chromatography (35% ethyl acetate in hexanes) gave 4.28 g (75%) of 189 as a white solid. [a]D +18.7° (c 8.4, EtOAc), NMR (CDCI 3. 250 MHz), S 7.71 (d, 2H, 7 =

8.35), 7.61 (d, 2H, J = 8.37), 7.30 (m, 4H), 4.01 (dd, IH, J = 4.79, 11.24), 3.84 (dd,

IH, J = 6.32, 11.18), 2.98-2.90 (m, IH), 2.61 (d, IH, J = 7.07), 2.39 (s, 6 H), 2.13 (d,

IH, / = 4.28). 13c NMR (CDCI 3, 62.5 MHz) Ô 145.0, 144.8, 134.4, 132.6, 129.8,

129.6, 127.9, 127.7, 68.4, 36.6, 30.8, 21.4. Anal. Calcd for C 17 H 19NO5S2: C, 53.52; H, 5.02; N, 3.67. Found: C, 53.20; H, 4.76; N, 3.69.

191 (R)-2-PentyI-A^-[(4-methylphenyl)suIfonyI]-aziridine (191). A solution of n- BuLi ( 1 mmol, 0.43 ml of a 2.3 M solution in hexanes) was added to a cold (-78 °C) suspension of Cul (95 mg, 0.5 mmol) in THF (1.5 mL). The resulting solution was warmed to -40 °C and stirred for 10 min after which it was recooled to -78 °C. A solution

148 of 189 ( 195 mg, 0.5 mmol), dissolved in THF ( I mL) was added to the reaction via cannula under a positive pressure of nitrogen. The reaction was allowed to stir at -78 "C for

60 min after which it was quenched by the addition of saturated NH 4CI solution at -78 °C, and the aqueous solution was extracted with EtOAc (2x5 mL), dried (MgSO^) and concentrated. Chromatography gave 99 mg (74%) of 191. Rf 0.23 ( 6 % EtOAc in hexanes), [a ]365 +18.5“ (c 3.0, EtOAc), »H NMR (CDCI3, 250 MHz), 5 7.79 (d, 2H, J =

8.21), 7.29 (d, 2H, J = 8.31), 2.63 (m, IH), 2.59 (d, IH, / = 6.95), 2.40 (s, 3H), 2.02

(d, IH, 7 = 4.33), I.6-I.1 (m, 8 H), 0.78 (m, 3H). NMR (CDCI 3, 62.5 MHz) Ô

144.3, 135.5, 129.5, 128.0, 40.4, 33.6, 31.2, 31.1, 26.3, 22.3, 21.5, 13.7. Anal. Calcd for C 14H21NO2S: C, 62.88; H, 7.91; N, 5.20. Found: C, 62.86; H, 7.81; N, 5.20.

Alternate preparation of (/?)-2-Pentyl-iV-[(4-methyIphenyl)suIfonyl]- aziridine (191).

NHTs 194 n-BuLi (1.21 mL of a 2.3 M solution in hexanes, 2.8 mmol) was added to a suspension of Cul (270 mg, 1.4 mmol) in THF (2.8 mL) at -40 “C. The bluish black solution that was formed was allowed to stir at -40 “C for another 40 minutes. A solution of 189 in THF ( 1 mL) was added to the cuprate solution and the reaction was allowed to stir at -78 “C for 60 minutes after which it was warmed to room temperature and stirred for another 60 minutes.

The reaction was quenched by the addition of saturated NH 4CI solution (10 mL) and the aqueous layer was extracted with ethyl acetate (2x10 mL). The organic layers were combined, dried (MgSOa) and concentrated. Chromatography ( 8 % ethyl acetate in hexanes) gave 249 mg ( 8 6 %) of 194. ^H NMR (CDCI3, 250 MHz). 5 7.72 (d, 2H, J =

8.31), 7.25 (d, 2H, J = 8.15), 4.73 (d, IH, 7 = 8.29), 3.40 (dd, IH, 7 = 3.27, 9.96),

149 3.30 (dd. IH, J = 4.28. 9.95). 3.15 (m. I H) 1.63-1.08 (tn. 8 H). 0.81 (s. I2H). -0.06

(s. 3H). -0.08 (s. 3H). NMR (CDCI 3, 62.5 MHz) 5 143.1, 138.6, 129.5. 127.1,

64.3. 55.1, 32.1. 31.5. 25.8, 25.2, 22.4, 21.4, 18.2. 13.8. -5.6.

NHTs 195 Tetrabutylammonium flouride (0.8 mL of 1 M solution in THF, 0.8 mmol) was added dropwise to an ice cold solution of 194 (240 mg, 0.63 mmol) in THF (1.5 mL). The solution was stirred for an hour after which it was diluted with water and extracted with ethyl acetate (2x5 mL). The layers were separated and the combined organic layers were dried (MgSOa) and concentrated. Chromatography (3% methanol in chloroform) gave 180 mg (98%) of 195. ^H NMR (CDCI 3, 250 MHz), 5 7.75 (d, 2H, J = 8.18), 7.25 (d, 2H, J

= 8.36), 5.36 (m, IH), 3.5 (m, 2H), 3.28 (m, 2H), 2.76 (m, 1 H), 2.37 (s, 3H), 1.36-

LOO (m, 8 H), 0.73 (t, 3H, / = 6.47). NMR (CDCI 3. 62.5 MHz) S 143.3, 137.9,

129.6, 127.1, 64.8, 55.7, 31.6, 31.3, 25.1 22.3, 21.3, 13.7.

191 Diethyl azodicarboxylate (120 mg, 0.70 mmol) was slowly added to a stirred solution of 195 (180 mg, 0.63 mmol) and triphenylphosphine (180 mg, 0.70 mmol) in THF (3.5 ml) at 0 °C. The reaction was allowed to stir for four hours after which all the solvent was removed by concentration under reduced pressure to give a thick brown oil.

Chromatography ( 10% ethyl acetate in hexanes) gave 143 mg ( 88 %) of 191 as a colorless oil. Analytical data was identical to that reported for 191 prepared by reaction of n- BuzCuLi with 189.

150 TrQXv^COzM e

NHTs 201

MethyI-0-triphenylinethyl-A/^-(4-[nethylphenyl)sulfonyl-(5)-serinate (201). Triethy lamine (6.2 ml, 45.0 mmol) was added dropwise to a cold stirring suspension of

methyl (5) serinate hydrochloride (3.1 g, 20.0 mmol) in CH 2CI2 (20 mL). The suspension was stirred for 30 min. at 0 °C. Tosyl chloride (3.8 g, 20.0 mmol) was added to the reaction in small portions over 10 minutes. After the addition was completed, the reaction was warmed to room temperature and allowed to stir for 8 hrs. The reaction was then cooled to 0 "C followed by a further addition of triethylamine (4 mL, 28.0 mmol). Trityl chloride (11.1 g, 40.0 mmol) was then added to the reaction in small portions over 10 minutes and the whole was stirred at room temperature for 10 hrs. The reaction was then diluted with CH 2CI2 (40 mL), and washed successively with IM HCl, sat. NaHCOs, brine, dried (MgS 0 4 ) and concentrated. Chromatography ( 8 % EtOAc in Hexanes) provided 9.41 g (91%) of 201 as a white solid. [a]o +5.8° (c 7.9, EtOAc), ^H NMR

(CDCI3, 250 MHz), Ô 7.67 (d, 2H, J = 8.30), 7.35 (m, 17H), 5.51 (d, IH, J = 9.18),

4.05 (m, IH), 3.54 (s, 3H), 3.43 (dd, IH, J = 3.4 Hz, 9.06), 3.34 (dd, IH, J = 3.58,

9.07), 2.39 (s, 3H). l^C NMR (CDCI 3, 62.5 MHz) 6 170.2, 143.4, 143.2, 137.2, 129.6,

128.5, 127.8, 127.2, 127.1, 8 6 .8 , 77.5, 77.0, 76.5, 64.6, 56.1, 52.4, 21.4. HRMS calculated for C 30H29NO5S 515.1767, Found 515.1757

NHTs 202 0-triphenylmethyl-0-tert-ButyId!methylsiIyI-iV-(4-methylphenyl)suifonyl- (S)-serinoI (202). A solution of 201 (1.4 g, 2.7 mmol) in THF/ EtOH (1:2, 12 mL)

was treated with anhydrous LiCl (340 mg, 8 .1 mmol) followed by NaBBL (300 mg, 8 .1 mmol) at 0 °C. After the addition of all the sodium borohydride, the reaction was warmed 151 to room temperature and stirred for another six hours. The reaction was quenched by addition of acetone (2 triL) followed by addition of 5 % HCI till the reaction became clear.

The solution was extracted with ether (2x 10 mL), dried (MgS 0 4 ) and concentrated. The oil obtained was sUyated without any further purification. The crude oil thus obtained was

dissolved in CH 2CI2 (3 mL). DMAP (30 mg, 0.27 mmol) and triethylamine (0.64 mL, 4.6 mmol) were added to the above solution and the whole was cooled in an ice bath, tert- Butyldimethylsilyl chloride (810 mg, 5.4 mmol) was added to the cold solution and the reaction was allowed to stir overnight at room temperature. The mixture was then diluted

with CH 2CI2 (5 mL), and washed successively with IM HCI, sat. NaHCO], brine, dried (MgSO^) and concentrated. Chromatography (10% EtOAc in hexanes) provided 1.42 g

(87%) of 202. [a]D +6.2“ (c 3.4, EtOAc), ‘H NMR (CDCI3, 250 MHz), 5 7.65 (d, 2H, /

= 8.27), 7.35 (m, 17H), 4.90 (d, IH, J = 7.61), 3.81 (dd, IH, J = 3.60, 9.88), 3.63 (dd, IH, J = 6.07, 9.86), 3.37 (m, IH), 3.28 (dd, IH, / = 4.52, 8.95), 3.0 (dd, IH, J = 6.18,

8.97), 2.41 (s, 3H), 0.83 (s, 9H), 0.0 (d, 6H). I^C NMR (CDCI3, 62.5 MHz) 5 143.6,

143.0, 138.0, 129.5, 128.5, 127.7, 127.0, 126.9, 8 6 .8 , 62.1, 61.9, 54.6, 25.8, 21.4, 18.1, -5.6.

NHTs 203 0-tert-ButyldimethyIsiIyl-iV-(4-methylphenyl)suIfonyl-(S)-serinol (203). A mixture of the protected diol 202 (250 mg, 0.41 mmol) and 250 mg of 20% Pd(OH) 2/C in EtOAc (2 mL) was hydrogenated at atmospheric pressure for 24 hours. The reaction mixture was then filtered through a bed of celite and evaporated. Chromatography (20%

152 EtOAc in hexanes) gave 50 mg (34%) of the detritylated product 203 as well as 106 mg of the starting material 202 (43%). Analytical data was identical to that reported in literature.^

206 (25)*2-[(4-methyIphenyl)sulfonyloxy]methyl-l-[(4-methylphenyl)sulfonyI] aziridine (205) Prepared on a 1.1 mmol using the same procedure for the conversion of 188 to 189. Analytical data was identical to that reported for 189 except for [a]o -20.4° (c 3.0, EtOAc).

(S)-2-PentyI-A(-[(4-methyiphenyl)sulfonyl]-aziridine (206) Prepared using the same procedure for the conversion of 189 to 191. Analytical data was identical to that reported for 191 except for [a ]365 -18.6° (c 1.5, EtOAc).

General procedure for the preparation of Aziridines 207, 208, 209. A solution of the desired organolithium (1-1.35 mmol) was added to a cold (-78 °C) suspension of Cul (95 mg, 0.5 mmol) in THF (1.5 mL). The resulting solution was warmed to -40 °C and allowed to stir for 10 minutes after which it was cooled to -78 °C. A solution of 189 ( 195 mg, 0.5 mmol), dissolved in THF ( I mL) was added to the reaction via cannula under a positive pressure of nitrogen. The reaction was allowed to stir at -78 °C for 60 minutes after which it was quenched by the addition of saturated NH 4CI solution at

-78 °C, and the aqueous solution was extracted with EtOAc (2x5 mL), dried (MgSÜ 4) and concentrated. Chromatography gave the aziridines 207, 208, 209.

153 e c 207 (/2)-2>Ethyl-iV-[(4-methylphenyl)sulfonyl]-aziridine (207). Prepared by the general procedure using MeLi (1.2 mmol, 1.05 ml of a 1.14 M solution in ether) to give 67 mg (60%) of 207. Rf 0.21 (6% EtOAc in hexanes), [a ]365 -7.9° (c 3.2, EtOAc), NMR

(CDCI3, 250 MHz), 5 7.82 (d, 2H, J = 8.35), 7.33 (d, 2H, J = 7.96), 2.69 (m, IH), 2.61

(d, IH, 7 = 6.97), 2.44 (s, 3H), 2.07 (d, IH, 7 = 4.48), 1.6 (m, IH), 1.35 (m, IH), 0.83

(t, 3H, 7 = 7.42). I3c NMR (CDCI 3, 62.5 MHz) S 144.3, 135.4, 129.5, 127.9, 41.6,

33.4, 24.4, 21.5, 10.6. Anal. Calcd for C 11H 15NO2S: C, 58.63; H, 6.71; N, 6.21. Found: C, 58.56; H, 6.52; N, 6.21.

SiMes

206

(/?)-2-[2-(trimethyIsiIyl)>ethyl]-A^-[(4-methylphenyI)sulfonyl]-azirldine (208). Prepared by the general procedure using trimethylsilylmethyl lithium (1.2 mmol,

1.53 ml of a 0.78 M solution in pentane) to give 102 mg (69%) of 208. Rf 0.27 ( 6 %

EtOAc in hexanes), [a]365 -32.7° (c 3.0, EtOAc), iH NMR (CDCI3, 250 MHz), 5 7.78

(d, 2H, 7 = 8.29), 7.28 (d, 2H, 7 = 8.58). 2.69 (m, IH), 2.55 (d, IH, 7 = 6.91), 2.39 (s, 3H), 2.01 (d, IH, 7 = 4.58), 1.39 (m, 2H), 0.36 (t, 2H, 7 = 8.67), -0.11 (s, 9H).

NMR (CDCI3, 62.5 MHz) Ô 144.1, 135.3, 129.4, 127.9, 42.6, 33.7, 25.8, 21.4, 13.1,

-2.1. Anal. Calcd for Ci4H23N02SiS: C, 56.52; H, 7.79; N, 4.71. Found: C, 56.34; H,

7.98; N, 4.68.

209

154 (/?)-2-HeptyI>iV-[(4-methylphenyl)sulfonyl]-aziridine (209). Prepared by the general procedure using n-Hexy I lithium ( 1.35 mmol, 0.75 mi of a 1.8 M solution in hexanes) to give 100 mg ( 68 %) of 209. [aJses +23.8° (c 3.9, EtOAc), *H NMR (CDCI 3, 270 MHz), Ô 7.79 (d, 2H, J = 8.29), 7.29 (d, 2H, J = 8.07), 2.55 (m, IH), 2.59 (d, IH,

J = 6.97), 2.40 (s, 3H), 2.02 (d, IH, 7 = 4.48), 1.6-1.1 (m, 12H), 0.83 (t, 3H, J =

6 .6 8 ). ‘3c NMR (CDCI3, 67.5 MHz) S 144.3, 135.3, 129.5, 128.0, 40.4, 33.7, 31.6,

31.3, 29.0, 28.9, 26.7, 22.5, 21.5, 14.0. Anal. Calcd for C 16H25NO2S: C, 65.04; H, 8.52; N, 4.74. Found: C, 64.87; H, 8.24; N, 4.74.

211 (R)-2-[7-(trimethylsilyl)-hept-S-en]-iV-[(4>methylphenyl)sulfonyI]-aziridine (211). r-BuLi ( 3.7 mmol, 4.16 ml of a 0.89 M solution in pentane) was added to a solution of 6-iodo-1 -trimethylsily 1-2-hexene^ ‘ (500 mg, 1.8 mmol) in Et 2 0 (5 ml) at -78 °C. The reaction was stirred at -78 °C for 10 minutes after which it was warmed to room temperature and allowed to stir for another hour. The reaction was recooled to -78 °C and a solution of Cul (119 mg, 0.63 mmol) and n-Bu 3? (0.75 ml, 3.0 mmol) in Et 2 0 (5 ml) was added to the reaction via carmula. The reaction was warmed to -40 °C for 10 min after which it was cooled to -78 °C and allowed to stir for another 40 minutes. A solution of

189 (240 mg, 0.63 mmol) in THF:Et 2 0 (1:1,2 ml) was added to the cuprate solution and the reaction was stirred for another 60 minutes after which it was quenched by the addition of saturated NH 4CI solution at -78 °C. The aqueous solution was extracted with EtOAc

(2x5 mL), dried (MgS 0 4 ) and concentrated. Chromatography (7% EtOAc in Hexanes) gave 173 mg (75%) of 211. Rf 0.26 ( 6 % EtOAc in hexanes), [a ]365 +34.0° (c 3.0.

EtOAc), ‘H NMR (CDCI3, 270 MHz). 5 7.79 (d. 2H. J = 8.28). 7.30 (d. 2H. J = 8.51). 155 5.35 (tn, I H), 5.15 (m, I H), 2.69 (m, I H), 2.59 (d, IH, 7 = 6.98), 2.41 (s, 3H). 2.02

(d, I H, 7 = 4.49), 1.85 (tn, 2H), 1.39 (d, 2H, 7 = 8.18), 1.6-1.1 (m, 6 H), -0.03 (s, 9H).

»3C NMR (CDCI3. 67.5 MHz) 5 144.3, 135.4, 129.5, 127.9, 127.0, 125.6, 40.3, 33.6,

31.2, 29.1, 26.7, 26.4, 21.5, 18.4, -1.8. Anal. Calcd for CigHsiNOiSiS: C, 62.42; H, 8.55; N, 3.83. Found: C, 62.45; H, 8.51; N, 3.84.

210 (R)-2-[6-(trimethylsilyI)-hex-4-en]-iV-[(4-niethylphenyI)sulfonyl]-aziridine

(210). This aziridine was prepared according to the general procedure described above to provide 210. Chromatography ( 8 % EtOAc in Hexanes) gave 650 mg (70%) of 210. Rf

0.25 (6 % EtOAc in hexanes), [a]]65 +7.9' (c 3.15, EtOAc), ‘H NMR (CDCI 3, 250 MHz), 5 7.77 (d, 2H, 7 = 8.33), 7.28 (d, 2H, 7 = 8.31), 5.30 (m, IH), 5.10 (m, IH),

2.66 (m, IH), 2.57 (d, IH, 7 = 6.98), 2.38 (s, 3H), 2.0 (d, IH, 7 = 4.54), 1.85 (m, 2H),

1.50 (m, IH), 1.37 (d, 2H, 7 = 8.55), 1.37-1.2 (m, 3H), -0.06 (s, 9H). NMR

(CDCI3, 62.5 MHz) 5 144.3, 135.6, 129.6, 128.0, 126.5, 126.1, 40.2, 33.7, 30.9, 26.8,

26.4, 21.5, 18.5, -1.8. Anal. Calcd for CigHigNOiSiS: C, 61.49; H, 8.31; N, 3.98. Found; C, 61.38; H, 8.14; N, 3.88.

243 (R)-2-[7-(trimethylsiIyl)-hept-5-en]-aziridine (243). A sodium naphthalide solution was prepared by stirring together finely chopped sodium metal (0.23 g, 10 mmol) 156 and naphthalene ( 1.4 g, II mmol) in THF ( 10 mL) for 2 h to give a greenish black solution. The Sodium naphthalide solution was then added dropwise via a syringe to a cold solution (-78 °C) of the aziridine 211 in THF (21 mL) via a syringe, till a dark green color persisted for 5 min. The reaction was then quenched by the addition of a few drops of water and the reaction was partitioned between ether and water. The organic layer was isolated and dried (MgS 0 4 ) and concentrated. Chromatography (3% MeOH in CHCI 3) provided the aziridine 243 (0.3 g, 69%) as a yellow oil. Rf 0.25 (3% MeOH in CHCI 3),

[a]D = +6.97° (c = 2.18, EtOAc), ^H NMR (250 MHz, CDCI 3), 5 5.4-5.15 (m, 2H), 2-

1.85 (m, 3H). 1.7 (d, IH, J = 5.7), 1.42 (d,overIapped, 2H, J = 8.29), 1.42-1.3 (m,

8 H), -0.04 (s, 9H). NMR (62.5 MHz, CDCI3), 5 127.4, 125.4, 34.4, 30.3, 29.6,

27.3, 27, 25.1, 18.4, -1.8. HRMS CtzHzfNSi: Calcd. 211.1756, found 211.1768.

Bn 244 (/?)-2-[7-(trimethylsilyI)-hept-5-en]-iV-(benzyI)-aziridine (244). Benzylbromide (0.06 mL, 0.5 mmol) was added to a mixture of the aziridine 243 (70 mg,

0.33 mmol), K2CO3 (0.15 g, 1.1 mmol) and 18-crown-6 (0.7 mg, 2.5 jimol) in THF (1 mL) and the reaction was then allowed to stir for 6 h at rt. The reaction was then diluted with water and the aqueous layer was extracted with EtOAc (2x5 mL). Chromatography (20% EtOAc in hexanes) provided 244 ( 14 mg, 13%) as a yellowish oil. Ry^O.32 (15%

EtOAc in hexanes), [a ]365 = +7.76° (c = 0.43, EtOAc), ^H NMR (250 MHz, CDCI 3), 5

7.36-7.2(m, 5H), 5.4-5.14 (m, 2H), 3.5 (d, IH, J = 13.25), 3.35 (d, IH, J = 13.26), 2.05 (m, IH), 1.95 (m, 2H), 1.63 (d, IH, J = 2.93), 1.45 (d. overlapped, 2H, J = 8.4),

1.45-1.23 (m, lOH), 0.01 (s, 9H). NMR (62.5 MHz, CDCI3), 5 139.4, 128.3,

157 128.2, 127.5. 127, 125.4, 65, 39.8, 34.1, 32.9, 29.5, 27.2, 27, 18.4, -1.8. HRMS CigHjiNSi: Calcd. 301.2227, found 301.2232.

Ns 245 (R)>2-[7-(trimethyIsilyl)-hept>5-en]-A^-[(4*nitrophenyl)sulfonyl]-aziridine

(245). p-nitrosulfonyichloride (88 mg, 0.4 mmol) was added to a cold solution (-78 °Q of 243 (70 mg, 0.33 mmol) and triethylamine (0.09 mL, 0.66 mmol) in CH 2CI2 (1 mL). After 5 min at -78 “C, the reaction was warmed to 0 *C over 20 min. The reaction was then diluted with CHCI 3 and the organic phase was washed with IM HCI, sat. NaHCOg, dried

(MgSO^) and concentrated. Chromatography ( 8 % EtOAc in hexanes) provided the aziridine 245 (0.11 g, 85%) as a yellow oil which crystallized upon standing. RyO.35 (15% EtOAc in hexanes), [aJo = +8.01° (c 2.1, EtOAc), iR NMR (250 MHz, CDCI 3), 6 8.36 (d, 2H,

/ = 8.74), 8.12 (d, 2H, J = 8.82), 5.5-5.2 (m, 2H), 2.85 (m, IH), 2.70 (d, IH, J = 7), 2.13 (d, IH, J = 4.7), 1.95-1.88 (m, 2H), 1.6 (m, IH), 1.38 (d, 2H, J = 8.71), 1.4-1.25

(m, 7H), -0.05 (s, 9H). 13c NMR (62.5 MHz, CDCI 3), Ô 150.6, 144.2, 129.2, 126.7,

125.9, 124.2, 41.3, 34.5, 31.1, 29, 26.6, 26.4, 18.4, -1.9. HRMS CigH28N204SiS: Calcd. 396.1740, found 396.1527.

COCHaPh 246

158 (/{)-2>[7>(trimethylsilyI)-hept-5

(70 mg, 0.33 mmol) and triethylamine (0.09 mL, 0.66 mmol) in CH 2CI2 ( I mL). After 5 min at -78 °C, the reaction was warmed to 0 °C over 20 min. The reaction was then diluted with CHCI 3 and the organic phase was washed with IM HCI, sat. NaHCOg, dried

(MgS0 4 ) and concentrated. Chromatography ( 8 % EtOAc in hexanes) provided the aziridine 246 (56 mg, 52%) as a colorless oil. R/0.35 (15% EtOAc in hexanes), [a]o = -30.63° (c

1.6, EtOAc), ‘H NMR (250 MHz, CDCI3), 5 7.4-7.2 (m, 5H), 5.5-5.2 (m, 2H), 3.7 (s,

2H), 2.4 (m, IH), 2.29 (d, IH, / = 5.86), 2.1 (m, 2H), 1.89 (d, IH, 7 = 3.37), 1.43 (d,

2H, partially overlapped, J = 8.26), 1.5-1.3 (m, 6H), -0.03 (s, 9H), NMR (62.5

MHz, CDCI3). 5 183.3, 134.6, 129.3, 128.5, 127.1, 126.9, 125.7, 44, 37.6, 32.1, 30.7,

29.4, 26.8, 26.5, 18.4, -1.8. HRMS C 2oH 3 iNOSi; Calcd. 329.2176 found 329.2177.

General procedure for deprotection of other iV-tosyl aziridines: Finely chopped sodium metal (0.12 g, 5 mmol) and naphthalene (0.72 g, 5.5 mmol) were dissolved in DME (5 mL). The reaction was allowed to stir for 2 h, to provide a dark green solution.^ The desired iV-tosylaziridine (0.25 mmol) in DME ( 1 mL) was cooled to -78 °C.

The Na-naphthalenide solution was added dropwise to ±e reaction via a syringe, until a dark green color persisted for 5 min. The reaction was quenched at -78 °C with 1-2 drops of water (to discharge the green color) and the reaction was diluted with Et 2 0 to provide a cloudy solution which was dried (MgSO^), filtered and concentrated. Purification (2 - 5%

MeOH in CHCI 3, silica gel) provided the A/-7f-aziridines. NOTE: Care should be exercised while isolating the final aziridines, most o f which are slightly volatile.

T B S O ^ '^ , : 247

159 Analytical data for 247: Prepared from 187 (0.1 g, 0.29 mmol) using general procdedure to provide 247 (0.5 g, 90%). (R/0.33 (5% MeOH in CHCI 3), [a|o +11.85 (c 0.54,

EtOAc), >H NMR (250 MHz, CDCI3) 5 3.68 (d, 2H, J = 3.89), 2.08 (m, IH), 1.62 (d,

IH, 7 = 5.51), 1.51 (d, 1H,7 = 3.47), 0.85 (s, 9H), 0.03 (s, 6 H). NMR (62.5 MHz,

CDCI3) Ô 63.3, 31.1, 25.8, 21.9, 18.3, -5.4, -5.41. HRMS calcd. for CgHiiNOSi:

187.1393. found 187.1362.

N

251 Analytical data for 251: Prepared from 250 (50 mg, 0.11 mmol) using the general procedure to provide 251102b (33 mg, 76%). R/0.36 (5% MeOH in CHCL3), iH NMR

(250 MHz, CDCI3) S 7.35-7.18 (m, 5H), 4.5 (d, IH, J = 11.93), 4.42 (d, IH, 7 = 11.87

Hz), 3.T-3.4 (m, 4H), 2.4-2.2 (m, 2H), 1.62 (br, IH), 0.8 (s, 9H), -0.03 (s, 3H), -0.04

(s, 3H). 13c NMR (62.5 MHz, CDCI3) 6 138.2, 128.4, 127.7, 127.6, 73.1, 69.6, 62.7,

35.2, 33.4, 25.9, 18.3, -5.2, -5.4.

O

: 254

Preparation of 254. r-BuNH 2 (0.36 mL, 3.5 mmol) was added to a cold (0 °C) solution of the acid 252 (0.32 g, 1.33 mmol) and TBTU (0.56 g, 1.74 mmol) in CH 3CN (13 mL). The resulting milky solution was stirred for 5 h after which the reaction was diluted with H?0 ( 10 mL) and extracted with EtOAc (2 x 10 mL). The organic layers were combined and washed with brine, dried (MgSO^) and concentrated. Chromatography (25-33%

160 EtOAc in hexanes) provided 254 as a colorless oil (0.22g, 58%). R/0.25 (25% EtOAc in hexanes), ‘H NMR (250 MHz, CDCI3 ) 6 7.83 (d, 2H, / = 8.19), 7.38 (d, 2H, J = 7.98),

6 (br, IH), 3.15 (m, IH), 2.71 (d, IH, 7 = 7.64), 2.47 (s, 3H), 2.36 (d, IH, J = 4.22),

1.27 (s, 9H). '3c NMR (62.5 MHz, CDCI 3 ) 5 164.6, 145.3, 133.5, 129.8, 128.1, 51.2,

38.4, 33.2, 28.3, 21.5. HRMS calcd. for C14H2 0 N 2 O3 S: 296.1196, found 296.1203.

O

©uHN

255

Analytical data for 255: Prepared from 254 (72 mg, 0.24 mmol) using general procedure

B to provide 255 (34 mg, 935). R/0.3 (5% MeOH in CHCI3 ), 'H NMR (250 MHz,

CDCI3 ) 5 6.22 (br, IH), 2.36 (br, IH), 1.83 (br, IH), 1.75 (br, IH), 1.35 (s, 9H). '3c

NMR (62.5 MHz, CDCI 3 ) 8 169.8, 51.1, 30.9, 28.7, 26. HRMS calcd. for C 7 H 14N 2 O:

142.1107, found 142.1127.

N BnO,.^^%^-\,^OBn 256

Preparation of 256: Benzoyl chloride (0.08 mL, 0.7 mmol) was added to a cold (0 °C) solution of alcohol 249'^2 (0.12 g, 0.35 mmol), triethylamine (0.14 mL, 1 mmol) and

DMAP (4.3 mg, 0.035 mmol) in CH2 CI2 (1 mL). The resulting solution was stirred for 2 h and then diluted with CHCI3 followed by extraction of the organic layer with IM HCI, sat.

NaHC0 3 , brine, dried (MgSO^) and concentrated. Chromatography (10% EtOAc in hexanes) provided 256 as a colorless oil (0.12 g, 75%). R/0.23 ( 10% EtOAc in hexanes)

'H NMR (250 MHz, CDCI3 ) 8 7.85-7.7 (m, 4H), 7.5 (m, IH), 7.4-7.1 (m, lOH), 4.44

(d, 2H, J = 5.07), 4.4 (dd, partially overlapped, IH, J = 1.64), 4.28 (dd, IH, J = 12.03,

7.75), 3.6 (m, 2H), 3.2 (m, 2H), 2.24 (s, 3H). '3C NMR (62.5 MHz, CDCI 3 ) 8 165.7,

161 144.5. 137.4. 133, 129.6. 129.5, 129.3, 128.3, 128.2, 128. 127.7, 127.6, 73, 66.4.

61.3, 41.5. 40.9, 21.5. HRMS calcd. for C2 5 H2 6 NO5 S; 451.1455, found 451.1432.

^ ^ O P i v

258

Preparation of 258: Pivaloyl chloride (0.41 mL, 3.3 mmol) was added to a cold (0 °C) solution of alcohol 141(03 (0 . 8 6 g, 3 mmol), triethylamine (0.7 mL, 5 mmol) and DMAP

(37 mg, 0.3 mmol) in CH 2 CI2 ( 6 mL). The resulting solution was stirred for 12 h and then diluted with CHCI3 followed by extraction of the organic layer with IM HCI, sat.

NaHCO], brine, dried (MgSO^) and concentrated. Chromatography (15% EtOAc in hexanes) provided 258 as a colorless oil (0.83 g, 75%). R/0.28 (15% EtOAc in hexanes)

(H NMR (250 MHz, CDCI3 ) S 7.79 (d, IH, / = 7.56), 7.31 (d, 2H, J = 7.92), 3.95 (t,

2H, J = 6.53), 2.7 (m, IH), 2.59 (d, IH, J = 7), 2.42 (s, 3H), 2.03 (d, IH, J = 4.47),

1.65-1.2 (m, 9H), 1.15 (s, 9H). NMR (62.5 MHz, CDCI 3 ) ô 178.5, 144.4, 135.3,

129.6, 128, 64, 40.1, 38.7, 33.7, 31.1, 28.4, 27.2, 26.4, 25.4, 21.5. HRMS calcd. for

C 19H2 9 NO4 S: 367.1819, found 367.1816.

OPiv

: 2S9

Analytical data for 259: Prepared from 258 (75 mg, 0.2 mmol) using the general procedure B to provide 259 (37 mg, 8 8 %). RyO.34 (5% MeOH in CHCI 3 ), 'H NMR

(CDCI3 ) S 4.0 (t, 2H, J = 6.53), 1.88 (m, IH). 1.69 (d, IH, J = 5.8), 1.6 (m, 2H), 1.5-

1.3 (m, 6 H), 1.25 (d, IH, 7 = 3.56), 1.13 (s, 9H).(3C NMR (62.5 MHz, CDCI 3 ) ô

162 178.5, 64.2, 38.7, 34.2, 30.1, 28.6, 27.2, 25.8, 25. HRMS calcd. for C 1 2 H2 3 NO2 :

213.1730, found 213.1732.

268

Preparation of 268; PhlNTs (5.2 g, 14 mmol) was added (over 45 min via a solid addition funnel) to a cold (0 °C) solution of 267 (5 g, 18 mmol) and CUCIO4 (0.6 g, 1.8 mmol) in

CH3 CN (40 mL). The reaction was stirred for 2 h after which it filtered through a plug of silica gel (7 cm) and concentrated. The solution thus obtained was concentrated and the residual oil purified by chromatography (5-10% EtOAc in hexanes). R/0.2 (6 % EtOAc in hexanes) [a]o -75.3 (c 0.46, EtOAc), iR NMR (CDCI3 ) 5 7.79 (d, 2H, / = 7.31), 7.25

(d, 2H, J = 7.3), 4.2-3.95 (m, 2H), 2.97 (d, IH, J = 5.36), 2.5-2.35 (m, 2H), 2.37 (s,

3H), 2.3-2.15 (m, IH), 2.1-1.8 (m, 2H), 1.7-1.5 (m, 3H), 1.22 (s, 3H), 0.9 (s, 3H),

0.86 (s, 9H), 0.05 (s, 6 H). NMR (62.5 MHz, CDCI 3 ) 5 143.3, 138.6, 129.3, 127,

60.5, 58.9, 43.7, 43.5, 39.8, 39.6, 36.4, 26.7, 25.9, 25.7, 21.4, 20.6, 18.1, -5.2, -5.4.

HRMS calcd. for C2 4 H3 gN0 3 SSi: 449.2422, found 449.2439.

OH

269

Preparation of 269: «BU4 NF (1.3 mL of a 1 M solution in THF, 1.33 mmol) was added to a cold (0 °C) solution of 268 (0.5 g, 1.12 mmol) in THF (2 mL) and the reaction was stirred for 4 h after which it was diluted with H?0 ( 10 mL). The resulting solution was extracted with EtOAc (2x10 mL) and the combined organic layers were extracted with brine, dried (MgSO^) and concentrated. Chromatography (40% EtOAc in hexanes)

163 provided 269 as a colorless oil (0.35 g, 95%). R/0.3 (50% EtOAc in hexanes) [aJo

-100.3 (c 0.35, EtOAc), 'H NMR (CDCI3 ) 5 7.8 (d, 2H, 7 = 7.31), 7.27 (d, 2H, J = 7.3),

4.1-3.9 (m, 2H), 2.95 (d, IH, 7 = 5.46), 2.65 (br, IH), 2.5-2.25 (m, 4H), 2.39 (s, 3H),

2.1-1.85 (m, 2H), 1.7-1.5 (m, 3H), 1.24 (s, 3H), 0.9 (s, 3H). NMR (62.5 MHz,

CDCI3 ) 5 143.6, 139.5, 129.5, 127, 59.1, 58.5, 43.5, 43.3, 39.8, 39.6, 35.5, 26.7,

25.9, 25.8, 21.5, 20.6,

»

270

Analytical data for 270: Prepared from 269 (75 mg, 0.2 mmol) using general procedure B to provide 270 (31 mg, 84%). R/0.55 (10% MeOH in CHCI 3 ), [a]o -78.7 (c 0.15,

EtOAc), IH NMR (CDCI3 ) S 3.65 (m, 2H), 2.56 (br, 2H), 2.17 (d, IH, 7 = 5.75), 2.1

(m, IH), 2.03 (t, overlapped, 2H, 7 = 5.9), 2.0 (m, IH), 1.81 (dd, IH, 7 = 14.78, 2.7),

1.58 (m, IH), 1.55 (m, IH), 1,26 (s, 3H), 1.17 (t, 2H, 7 = 10.68), 0.93 (s, 3H).

NMR 8 59.3, 44.6, 41.2, 41, 40.9, 37.1, 32.3, 27.1, 26.8, 26.1, 20.4. HRMS calcd. for

C 11 H 19NO: 181.1468, found 181.1462.

Alternate preparation of (R)-2-[7-(trimethyIsilyI)-hept-5-en]-A^-[(4- methyIphenyl)suIfonyl]-azir!dine (211)

SiM03

NHTs

164 (8/?)-l>(trimethylsiIyl)-8-[(4-inethyiphenyI)sulfonyl]ainino-9-[(r- butyldimethyl)siiyl]oxo-non>2-ene (285). fBuLi (19.5 mLof a 1.58 M solution in pentane, 30.8 mmol) was added dropwise to a solution of l(trimethylsilyl)-6-iodohex-2- ene*^ ( 3.95 g, 14 mmol) in Et 2 0 (28 mL) at -78 “C. The reaction was then allowed to stir at -78 °C for 10 min after which it was allowed to warm to rt and stirred for an additional 60 min. The reaction was then recooled to -78 "C. In a separate flask Cul (0.95 g, 5 mmol) was dissolved in / 1-BU3P (5.8 mL, 23.5 mmol) and Et 2 0 (2 mL). The slightly turbid solution of CuI/n-BugP in Et 2Û was then transferred to the organolithium prepared above using additional Et 2 0 (26 mL). The yellowish cuprate solution thus formed, was wanned to -40 "C and stirred for 10 min after which it was recooled to -78 °C. The aziridine 187 ^ (

(1.71 g, 5 mmol) was dissolved in Et 2 0 (2 mL) and added to the reaction via cannula. The reaction was stirred at -78 "C for 30 min after which it was warmed to rt and stirred for another 30 min. The reaction was quenched by adding sat. NH 4CI solution and the organic layer washed with sat NH 4CI, brine, dried (MgS 0 4 ) and concentrated. Chromatography (4% EtOAc in hexanes - 15% EtOAc in hexanes) provided 285 (2.42 g, 97%) as a colorless oil. R/0.3 (15% EtOAc in hexanes), [a]o +20.9° (c 2.07, EtOAc), NMR 5

7.69 (d, 2H, J = 8.26), 7.22 (d, 2H, / = 8.05), 5.33-5.13 (m, 2H), 4.76 (d, IH, J = 8.32), 3.37 (dd, IH, J = 3.25, 9.97), 3.26 (dd, IH, 7 = 4.39, 9.97), 3.15 (m, IH), 2.36

(s, 3H), 1.85 (m, 2H), 1.37 (d, overlapped, 2H, 7 = 7.76), 1.46-1.1 (m, 6 H), 0.78 (s, 9H), -0.06 (s, 9H), -0.09 (s, 3H), -0.1 (s, 3H). NMR 5 143.1, 138.4, 129.5, 127.2,

127, 125.4, 64.1, 54.9, 32, 29.4, 26.8, 25.8, 25.3, 21.4, 18.4, 18.2, -1.8, -5.7. Anal.

Calcd for C 25H4?N0 3 Si2S 0.25 HoO: C, 59.78; H, 9.53; N, 2.78. Found C, 59.69; H, 9.52; N, 2.67.

165 211 n-Bu 4NF (5.5 mL of a 1 M solution in THF, 5.5 mmol) was added dropwise over 5 min to a solution of the alcohol 285 (2.42 g, 5 mmol) in THF ( 5 mL) at 0 'C. The reaction was stirred for 30 min after which it was diluted with water. The aqueous layer was then extracted with EtOAc (3x10 mL) and the combined organic layers washed with brine, dried (MgSO^) and concentrated. The crude product thus obtained was dried under vaccum (2 mm Hg) overnight and used without any further purification. The crude alcohol 286 obtained from above was transferred to a flame dried flask containing triphenylphosphine (1.34 g, 5.11 mmol), using THF (19 mL) and the resulting solution was cooled in an ice bath. Diethylazodicarboxylate (0.81 mL, 5.11 mmol) was added to the reaction over 5 min via a syringe and the reaction was then allowed to stir for 3 h after which the solvent was removed under vaccum. The resulting thick oil was triturated with hexanes resulting in precipitation of a white solid (PhgPO), which was filtered to provide a solution which was then concentrated. Chromatography ( 8 % EtOAc in hexanes) provided the aziridine 211 (1.51 g, 83% from 285) as a colorless oil. The analytical data for 211 was identical to that reported earlier.

H H

NHTs H H 287a 287b (1/J, 2/{)-2-vinyl-2-[(4-methyIphenyi)sulfonyl]aminomethyl-cyclohexane (287a) and (IS, 2/?)-2-vinyl-2-[(4-methylphenyi)sulfonyl]aininomethyi-

166 cyclohexane (287b). Freshly distilled Bp 3*OEt 2 (1.5 mL, 12.3 mmol) in CH 2CI2 (3 mL), was added to a solution of the aziridine 211 (1.5 g, 4.1 mmol) in CH 2CI2 (38 mL) at 0 C over 5 min. The reaction was stirred at 0 °C for 60 min after which it was warmed to rt and stirred for 18 h. The reaction was quenched by the addition of sat. K 2CO3 solution.

The organic layer was then washed with sat. K 2CO3, brine, dried (MgS 0 4 ) and concentrated. Chromatography ( 12% EtOAc in hexanes) provided an inseparable mixture of 287a;287b (1:2, 1.13 g, 94%) as a colorless oil. Analytical data was identical to that reported for 153a-b. Cc OH H 291

3[2-(hydroxy)ethyl]indole (291) A solution of Oxalyl chloride (7.5 mL, 86 mmol) in

Et2 0 (10 mL) was aded to a solution of indole (5 g, 43 mmol) in Et 2 0 ( 140 mL) at 0 °C. The reaction was stirred for 30 min after which it was filtered to provide a yellow-orange solid 290. The solid was dried under high vaccum for Ih after which it was dissolved in

THF (60 mL) and the resulting solution was added to a suspension of LiAlHa (15.75 g, 450 mmol) in THF (250 mL) at 0 “C. The reaction was then stirred ovemite during which the reaction gradually warmed to rt. The reaction was then recooled to 0 °C after which it was carefully quenched with water (16 mL) followed by 15% NaOH (16 mL) and water (48 mL). The resulting suspension was stirred for Ih after which it was filtered through celite. The filtrate was then dried (MgSOa) and concentrated to provide the crude alcohol 291 which was used withoput any further purification.

OTBS C c H 292

167 3-{2[(tert-butyI-dimethyIsilyi)oxy]ethyl}indole (292) TBSCI (2.52 g, 16.77 mmol) was added to a solution of crude alcohol 291 (2.45 g, 15.25 mmol), triethylamine (3.08 g, 30.5 mmol) and DMAP (0.18 g, 1.52 mmol) in dry DMF ( 15 mL) at 0°C. The reaction was allowed to stir ovemite after which it was diluted with ether (30 mL) and the organic layer was washed successively with IM HCI, sat. NaHCOg. The aqueous layer was extracted with EtOAc (3 x 15mL) and the organic layers were combined and washed with brine, dried (MgSO^) and concentrated. Purification of the reddish yellow oil with 5% EtOAc in Hexanes provided the protected alcohol 292 (50% from indole). ^H NMR (CDCb, 250 M Hz), 5 7.9 (br, IH), 7.56 (d, IH, J = 8.75), 7.25 (d, IH, / = 8.75),

7.19-7.05 (m, 2H), 6.95 (s,lH), 3.85 (t, 2H, J = 7.5), 2.94 (t, 2H, J = 7.5) 0.92 (s,

9H), 0.00 (s, 6 H).

OTBS

CoTs 293 A^-p-toIuensulfonyl-3-{2[(^-butyl-dîmethylsilyI)oxy]ethyl}indole (293) 10% NaOH solution (200 mL) was added to a solution of alcohol 292 (4.7 g, 17 mmol),

M-BU4NHSO4 (0.12 g, 0.34 mmol) and tosylchloride (3.24 g, 17 mmol) in toluene (110 mL) at 0 °C. The resulting biphasic solution was stirred vigorously for 14 h, after which the reaction was diluted with water (lOOmL) and extracted with EtOAc. The combined organic layers were washed with brine, dried (MgS 0 4 ) and concentrated. The resulting solid was used without any further purification.

OH C u Ts 2 9 4

168 A/^-/7 -toluensulfonyl- 3 -(2 -hydroxyethyI]indole (294) n-BuN^F (7 ml of a IM solution in THF ) was added to a solution of alcohol 293 in THF (7 mL). The reaction was allowed to stir for 5 h at rt. The reaction was diluted with water and extracted with EtOAc (3x15 mL). The organic layers were combined and washed with brine, dried (MgSO^) and concentrated. Purification of the oil gave the alcohol 284 (680 mg, 90% overall yield from 293). ^H NMR (CDCI3, 250 MHz) , 5 8 (d, IH, J = 8.75), 7.74 (d, 2H, J = 8.31),

7.48 (d, IH, J = 8.75), 7.42 (s, IH), 7.35 - 7.16 (m, 2H), 7.14 (d, 2H / = 8.31), 3.85 (t, 2H, J = 7.5), 2.94 (t, 2H, J = 7.5), 2.28 (s, 3 H), 2.12 (br, IH).

Br O: r ' Ts

A(-/7 -toluensulfonyl- 3 -[2 -bromoethyl]indole (288) A solution of CBra (0.78 g, 2.36 mmol) in MeCN (2.5 mL) was added to a solution of alcohol 294 (680 mg, 2.15 mmol) and triphenylphosphine (621 mg, 2.36 mmol) in MeCN (4.5 mL) at 0 “C. The reaction was warmed to rt and stirred for 14h. The solvent was then removed under vaccum to provide a thich brownish oil. Chromatography (35% chloroform in hexanes) provided bromide 288 (760 mg, 93 %). ^H NMR (CDCI 3 ,250 M H z), Ô 8 (d, IH, / =

8.75), 7.74 (d, 2H, J = 8.31), 7.48 (d, IH, J = 8.75), 7.42 (s, 1 H), 7.35 - 7.16 (m, 2 H), 7.14 (d, 2H / = 8.31), 3.55 (t, 2H, J = 7.5), 3.15 (t, 2H, J = 7.5), 2.2 (s, 3H).

,O M s

Ts 303 A^-(4-methylphenyl)sulfonyl-3-[(2-methylsulfonyloxo)ethyl]-indoIe (303).

Freshly distilled Methanesulfonylchloride (2.48 g, 21.7 mmol) in CH 2CI2 (5 mL) was slowly added to an ice cold solution of the 294 (6.22 g, 19.7 mmol), triethylamine (4.12

169 mL, 29.55 mmol) and DMAP (0.25 g, 2 mmol) in CH 2CI2 (20 mL). The reaction was stirred for 3 h after which it was diluted with CHCI 3 and the organic phase was extracted with IM HCI, sat. NaHCO], brine, dried (MgS 0 4 ) and concentrated. Chromatography (35% EtOAc in hexanes) provided the mesylate 303 (7.73 g, 100%) as viscous, sticky oil. R/0.3 (35% EtOAc in hexanes). >H NMR 5 7.98 (d, IH, / = 8.32), 7.74 (d, 2H, 7 = 8.41

Hz), 7.45 s (2H), 7.4-7.2 (m, 4H), 4.43 (t, 2H, J = 6.84), 3.12 (t, 2H, J = 7), 2.83 (s, 3H), 2.32 (s, 3H). NMR 5 144.9, 135.4, 135.2, 130.3, 129.9, 126.8, 125, 124.2,

123.3, II9.I, 117.3, 113.8, 68.4, 37.4, 25.2, 21.4. HRMS for C 18 H 19NO5S2: Calcd. 393.0706, found 393.0712

289

Indole olefin (289). K 2CO3 (1.4 1 g, 10.2 mmol) was added to a solution of the tosylamide 287 (0.75 g, 2.5 mmol) and the mesylate 303 (2 g, 5.11 mmol) in DMF (7 mL) and the reaction was then warmed to 70 °C and stirred for 24 h. The reaction was then diluted with water and extracted with EtOAc (3 x 10 mL) and the combined organic layers were washed with water, brine, dried (MgS 0 4 ) and concentrated. Chromatography (25% hexanes in CHCI 3) provided 289 (1.32 g, 92%, 3:1 mixture of trans and cis isomers) as a foamy solid. Rf = 0.33 (20% hexanes in CHCI 3), ^H NMR (400 MHz, CDCI3), 5 7.89 (d,

IH, 7 = 8.25), 7.69 (d, 2H, 7 = 8.21), 7.41 (m, IH), 7.27, 7.14 (m, 7H), 5.8* (m, IH),

5.43 (m, IH), 4.97-4.83 (m, 2H), 3.3-2.68 (m, 6H), 2.35 (s, 3H), 2.27 (s, 3H), 1.9 (m, IH), 1.59-0.5 (m, I IH). NMR (* indicates signal arising form minor cis isomer) Ô

144.7, 143. I*, 143, 142.4, 138.6*, 136.6, 136.5*, 135.2, 135.1, 130.4, 129.7, 129.5, I27.I, 127*. 126.9*. 126.7, 124.6, 123.4, 123.3*, 123, 119.2, 119.1. 115.6*, 114.6,

170 113.6. 53.4, 51.4*, 48.5, 46.3, 41.8*, 40.1, 38.3*, 33.4, 30.4*, 29.8, 25.8*, 25.5,

25.4, 25*. 24.8, 24. L*, 22.3*. 21.4, 21.3. Anal. Calcd for C 33H38 N2O4S2 0.5 H2O: C, 66.08; H, 6.65; N, 4.67. Found C, 66.14; H, 6.4; N, 4.39.

304

Indole alcohol (304). 9-BBN (17.6 mL of a 0.5 M solution in THF, 8.8 mmol) was added to a solution of the olefin 289 (1.3 g, 2.2 mmol) in THF (4 mL). The reaction was

stirred at rt for 3.5 h. The reaction was cooled in an ice bath and the excess 9-BBN was

quenched with EtOH (5.2 mL) and stirred for 5 min followed by addition of 6N NaOH

(1.8 mL) and H 2O2 (3.5 mL, 30 % solution). The reaction was refluxed for 60 min and cooled to rt. The reaction was then diluted with water and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine, dried (MgSOa) and concentrated. Chromatography (35% EtOAc in hexanes) provided 304 (1.17 mg, 90%, 3:1 mixture of trans and cis isomers). R/= 0.32 (40% EtOAc in hexanes), ^H NMR Ô 7.94

(d, IH, J = 7.72), 7.73 (d, 2H, J = 8.37), 7.66 (d, 2H, J = 8.3), 7.44 (m, IH), 7.29-

7.17 (m, 8 H), 3.7-3.5 (m, 2H), 3.4-3.15 (m, 2H), 3.05-2.79 (m, 3H), 2.4 (s, 3H), 2.3

(s, 3H), 1.9-0.9 (m, 14H). NMR (* indicates signal arising form minor cis isomer) 6

144.9, 143.3, 143.2*, 136.6, 136.4*, 135.4, 135.2, 130.5, 129.8, 129.7, 127.2, 126.8, 124.7, 123.5, 123.4*, 123.2, 119.3, 113.7, 61.2*, 60.6, 53.1, 50.2*, 48.7, 48.5*, 40.1, 38.2*, 36.7, 36.1, 33.2*, 31.3*, 31.2, 29.7, 28.5*, 26*, 25.4*, 25.1, 25, 23.8*,

22.7*, 21.5, 21.4. Anal. Calcd for C 33H40N2O5S2: C, 65.1; H, 6.62; N, 4.6. Found C, 64.8; H, 6.75; N, 4.2.

171 3 0 5

Indole aldehyde (305). Dimethylsulfoxide (0.16 mL, 2.2 mmol) in CH 2CI2 (I mL) was slowly added to a cold (-78 °C) solution of freshly distilled oxalylchloride (0.1 mL,

1.2 mmol) in CH 2CI2 (1 mL). The resulting solution was then stirred for 45 min at -78 °C.

The alcohol 304 (0.54 g, 0.88 mmol) in CH 2CI2 (ImL) was then added to the reaction via a cannula and the whole stirred at -78 “C for 60 min. EtgN (0.4 mL, 3 mmol) in CH 2CI2 ( ImL) was then added to the reaction, which was then slowly allowed to warm to rt over 30 min. The reaction was quenched by the addition of a few drops of IM HCI and diluted with CHCI 3. The organic phase was then washed with IM HCI, sat. NaHCOg, brine, dried (MgS0 4 ) and concentrated. Chromatography (30% EtOAc in hexanes) provided the aldehyde 305 (0.47 g, 8 8 %, 3:1 mixture of transrcis isomers). R/0.35 (30% EtOAc in hexanes), ‘H NMR 6 9.65 (m, IH), 7.96 (d, IH, J = 7.09). 7.75 (d, 2H, J = 8.28), 7.56

(d, 2H, y = 8.28), 7.5 (m, IH), 7.45-7.2 (m, 8 H), 3.4-3.25 (m 2H), 3.1-2.9 (m, 4H), 2.5-2.4 (m, overlapped, IH), 2.4 (s, 3H), 2.33 (s, 3H), 2.33-2.11 (m, overlapped, IH), 1.9-1.6 (m, 4H), 1.5-0.9 (m, 5H). NMR (* indicates signal arising form minor cis isomer) Ô 202.3*, 202.1, 144.9, 143.5*, 143.4, 136.4, 136.2*, 135.4, 135.2, 130.5,

129.9, 129.8*, 129.7, 127.2, 126.8, 124.8, 123.6, 123.5*, 123.2, 119.3, 119.2, 113.7, 53, 48.8, 48.4*, 48.1, 42.9*, 40, 37.7*, 34.9, 32.4, 30.9*, 29.6, 29.3*, 26*, 25.2, 25,

24.8, 23.7*, 22.2*, 21.5, 21.4. Anal. Calcd for C 33H38 N2O5S2 0.5 H2O: C, 64.36: H, 6.38; N, 4.54. Found C, 64.12; H, 6.27; N, 4.42.

172 TsN

M eO

307

Indole ester (307). A IM KMn 0 4 solution (3 mL) was added to a solution of the aldehyde 305 (0.3 g, 0.45 mmol) in rBuOH (3 mL) containing a 5 - 10 drops of CHCI 3 and 5% NaH 2P0 4 solution (2 mL) at 0 °C. The reaction was then stirred for 10 min and quenched by the addition of solid Na 2S0 3 till the solution turned a dark brown from the initial dark purple color. IM HCI was added to the reaction till the pH of the solution was <1. The reaction was then extracted with EtOAc (2 x lOmL) and the combined layers were washed with brine, dried (MgS 0 4 ), concentrated. The crude material was then dissolved in

MeOH (1 mL) and benzene (3.5 mL). Me 3SiCHN2 (1 M solution in hexanes, 0.32 mL, 0.64 mmol) was then added to the reaction via a syringe and the whole stirred for 30 min after which the reaction was diluted with water and extracted with EtOAc (2 x 5 mL). The combined organic layers were then washed with brine, dried (MgS 0 4 ) and concentrated. Flash chromatography (25% EtOAc in hexanes) provided the ester 307 (0.25 g, 80% from 305) as a white foam. R/0.32 (25% EtOAc in hexanes), ^H NMR S 7.94 (d, IH, J =

7.15), 7.72 (d, 2H, J = 8.38), 7.65 (d, 2H, / = 8.25), 7.48 (d, IH, J = 6.91), 7.3-7.15

(m, 8 H), 3.61* (s, 3H), 3.6 (s, 3H), 3.4-2.8 (m, 5H), 2.38 (s, 3H), 2.34-2.1 (m, overlapped, 2H), 2.29 (s, 3H), 1.9-0.9 (m, 9H). NMR (* indicates signal arising form minor cis isomer) 5 173.3*, 173.1, 144.7, 143.3, 143.2, 136.3, 136.2*, 135.2*

135.1, 130.4, 129.7, 129.6*, 129.5, 127.1*, 127.1, 126.7, 124.7, 123.5*, 123.4, 123.1, 119.2, 119.1, 113.6, 52.6, 51.4*, 51.3, 48.6, 48.3*, 39.7, 38.4, 37.1, 37*, 34.3*, 31.9, 29.4, 29.1*, 25.8*, 25.2, 25.1*, 24.9, 24.8, 23*, 22.9*, 21.4, 21.3. Anal.

Calcd for C 34H40N2O6S2 0.5 H2O: C, 63.23; H, 6.4; N, 4.33. Found C, 63.47; H. 6.45; N, 4.17.

173 309

Indole lactam (309). Finely chopped sodium metal (66 mg, 2.9 mmol) and naphthalene (0.37 g, 2.9 mmol) were stirred in DME (3.8 mL) for 90 min during which a greenish black solution formed. The reaction was then cooled in an ice bath. The ester 307 (0.19g, 0.29 mmol) in DME (2.3 mL) was then added to the reaction via cannula and the solution stirred for 60 min. The reaction was then quenched with water and the aqueous layer was extracted with EtOAc. The organic layer was then washed with brine, dried (MgSO^) and concentrated. Chromatography (2% MeOH in CHCI 3) provided the lactam 309 (66 mg,

77%) as a light brown soUd. R/0.25 (2% MeOH in CHCI 3), ‘H NMR 5 8.27 (s, br, IH),

7.67 (d, IH, J = 7.45), 7.35 (d, IH, J = 7.64), 7.21-7 (m, 4H), 3.75-3.6 (m, 2H), 3.2-

2.8 (m, 4H), 2.6-2.4 (m, IH), 2.1-1.9 (m, IH), 1.85-1.6 (m, 5H), 1.6-1.1 (m, 6 H), 1- 0.8 (m, IH). NMR (* indicates signal arising form minor cis isomer) 5 169.6,

169.3*, 138.3, 128.3*, 127.6, 122*, 121.9, 121.9, 119.3, 118.8, 113.3, 111.1, 54.4, 51.1*, 48.1*, 48, 39.5, 38.4, 37.1, 35.2*, 33*, 32.6, 32.5*, 29.7, 28.3*, 26.5*, 25.4,

23.1*, 23, 22.6*. Anal. Calcd for C 19H24N2O 0.75 H 2O: C, 73.82; H, 8.07; N, 9.06.

Found C, 74.04; H, 8.03; N, 8 .66 .

(-)-yohimbane enf-alloyohimbane

(-)-Yohimbane and erar-alloyohlmbane. The lactam 309 was re fluxed in freshly distilled POCI3 (0.2 mL, 0.2 mmol) for 60 min. Benzene {1.3 mL) was then added to the 174 reaction which was then refluxed for another 2.5 h. The solvent was then removed by evaporation under vaccum until dryness. The residue thus obtained was taken up in MeOH (2.4 mL) and the reaction was cooled in an ice bath followed by addition of NaBHa (20 mg, 0.53 mmol), after which the reaction was stirred for 60 min. The reaction was then quenched by the addition of a few drops of AcOH. The solvent was removed in vaccuo and the resudue was partitioned between EtOAc and sat. NaHCO] solution. The organic phase was dried (MgSOa) and concentrated. Chromatography (17% EtOAc, 1% EtsN, 82%

Toluene) provided (-)-yohimbane (22 mg, 59%) and enr-alloyohimbane (8 mg, 22%). Analytical data for (-)-yohimbane: R/0.19 (17% EtOAc, 1% EtgN, 82% Toluene), [a]o

-82.9" (c 0.38, EtOH) [Ut.l26 [a]^ _gr (c 0.5, EtOH)]. ‘H NMR (400 MHz, CDCI3), ô

7.71 (s, IH), 7.45 (d, IH. / = 7.5), 7.27 (d, IH, J = 7.78), 7.12-7.04 (m, 2H), 3.26 (d,

IH, / = 11.13), 3.1-2.95 (m, 2H), 2.88 (dd, IH, 7 = 3.6, 11.06), 2.69 (m, IH), 2.59 (m, IH), 2.11 (t, IH, 7 = 10.94), 1.95 (m, 2H), 1.8-1.58 (m, 4H), 1.5-0.9 (m, 8H).13c NMR 5 136.1, 135.2, 127.6, 121.2, 119.3, 118.1, 110.7, 108.1, 62.1, 60.2, 53.2, 42,

37, 32.9, 30.4,26.5, 26.1, 21.8. Analytical data for enf-alloyohimbane; R/0.24 (17% EtOAc, 1% Et]N, 82% Toluene), [a]o +146° (c O.l, Pyridine) [lit.64 [(x]Q of (-)- alloyohimbane -164° (c 0.5, Pyridine)]. ^H NMR (400 MHz, CDCI 3), d 7.7 (s, IH), 7.44 (d, IH, 7 = 7.5), 7.27 (d, IH, J = 7.69), 7.1-7 (m, 2H), 3.2 (m, IH), 3.17-2.92 (m, 2H), 2.75 (d, IH, 7 = II.I), 2.68 (m, IH), 2.53-2.49 (m, 2H), 1.95-0.7 (m, 12H). NMR Ô 136.1, 135.6, 127.6, 121.2, 119.4, 119.1, 110.7, 108.3, 62, 60.5, 53.5, 36.8,

34.9, 31.7, 30.6, 26.6, 26.5, 21.8, 20.9.

Condition A for aziridine-allylsilane cyclization:

175 y SiMe3

H 319a (l/{y3a/{,6a5)-iV-[(4-methylphenyl)sulfonyl]-l-[(trimethylsilyI)methyl] hexahydrocyclopenta[c]pyrrole (319a). The aziridine 210 (35 mg, O.l nunol) was dissolved in CH 2CI2 (0.8 mL) and the reaction was cooled in an ice bath (0 “C). A solution

(0.2 mL) of freshly distilled BF 3*OEt 2 ( l.SpL, 0.015 mmol) in CH 2CI2, was added to the reaction which was then allowed to stir for 30 min at 0 "C. The reaction was then diluted with CHCI 3 (5 mL) and quenched by the addition of sat. NaHC 0 3 solution (3 mL). The aqueous layer was then extracted with CHCI 3 (5 mL) and the combined organic layers were dried (MgS0 4 ) and concentrated. Chromatography ( 8 % EtOAc in hexanes) provided 17 mg (49%) of 319a as a colorless oil. Further elution of the column (15% EtOAc in hexanes) provided 9 mg (33%) of the olefin 320 (inseperable mixture of cis and trans isomers). Data for 319a; R/0.26 (8 % EtOAc in hexanes). [a]o +103.4° (c 0.79, EtOAc), NMR

(CôDô, 250 MHz), 5 7.75 (d, 2H, J = 8.20), 6.88 (d, 2H, / = 8.04), 3.22 (m, IH), 3.15

(dd, IH, J = 8.96, J = 11.10), 3.03 (dd, IH, J = 6.26, J = 11.04), 2.01 (dd, IH, J =

6.09, y = 9.19), 1.94 (s, 3H), 1.7 (m, IH), 1.60-1.10 (m, 6H), 1.01 (dd, IH, J = 11.99, J = 14.78), 0.02 (s, 9H). NMR (CeDe, 62.5 MHz) 5 142.8, 135.6, 129.5, 128.3,

61.7, 55.2, 49.4, 40.6, 31.4, 27.5, 26.2, 21.1, 19.9, -0.7. Anal. Calcd for CigH29N02SiS: C, 61.49; H, 8.31; N, 3.98. Found: C, 61.46; H, 8.39; N, 3.80.

NTs NTs H H 315a 315b

176 (l/î, 3skR, 7aS)-iV-[(4-methylphenyl)suIfonyIl-l-[(triniethylsiIyI) methyl] octahydro-lH-isoindoIe (315a) and (15, 3aRy 7alS)-iV-[(4-methylphenyI) suIfonyI]-l-[(trimethylsilyI) methyl] octahydro-lH-isoindole (315b). These were prepared from the aziridine 211 (40 mg, 0.11 mmol), according to Condition A described above. Chromatography ( 8 % EtOAc in hexanes) provided 14 mg (35%, 54% considering recovered 211) of 315a and 315b as a separable mixture (ca 3: i transxis, colorless oil). Further elution of the column ( 15% EtOAc in hexanes) provided 5 mg ( 18%, 27% considering recovered 211) of the olefin 287 (inseparable mixture of cis and trans isomers). Data for 315a: R/0.25 (8 % EtOAc in hexanes), [ajo +76.3“ (c 0.14, EtOAc),

•H NMR (CDCI3, 250 MHz), 5 7.67 (d, 2H, J = 8.19), 7.30 (d, 2H, J = 8.15), 3.5-3.3

(m, 3H), 2.41 (s, 3H), 1.8-0.7 (m, 12H), 0.02 (s, 9H). ^^C NMR (CDCI 3, 62.5 MHz) 143.0, 135.2, 129.5, 127.7, 64.0, 50.1, 42.2, 36.3, 24.9, 24.5, 22.7, 21.5, 20.6, 18.5,

-0.8. Data for 315b: R/0.27 ( 8 % EtOAc in hexanes). [aJo -27.4° (c 0.52, EtOAc), ^H NMR (CôDô, 250 MHz), 5 7.78 (d, 2H, J = 8.18), 6.83 (d, 2H, J = 8.05), 4.0 (m, IH),

3.46 (dd, IH, J = 7.0, J = 9.25), 2.58 (dd, IH, J = 9.53, J = 10.45), 1.88 (s, 3H), 1.5- l.l (m, 5H), 0.97 (dd, 2H, 7 = 6.82, 14.9), 0.73 (dd, IH, J = 6.74, 14.89), 0.9-0.4 (m, 4H), 0.29 (s, 9H). 13c NMR (CôDô, 62.5 MHz) S 142.6, 136.6, 129.5, 128.3, 60.9,

53.6, 48.8, 40.3, 29.6, 26.8, 25.5, 25.4, 21.5, 21.1, -0.2. Anal. Calcd for 315a and

315b Ci9H3 iN0 2 SiS: C, 62.42; H, 8.55; N, 3.83. Found: C, 62.43; H, 8.50; N, 3.60.

MeaPhSi-v.^^^^ 1 ^ 0 H 326 5-(dimethylphenylsilyl)-pent-3-en-l-ol (326). Magnesium (530 mg, 22 mmol) was flame dried and suspended in ether (23 mL). Ethylene bromide (0.61 mL, 7 mmol)

177 was added and the reaction was allowed to stir for 10 min followed by a slow addition (over 5 min) of chloro-methyldimethylphenylsilane (2.7 mL, 15 mmol). After the addition was complete, the reaction was then allowed to reflux for 60 min during which all the magnesium dissolved resulting in the formation of a greyish suspension. Benzene (45 mL) was then added to the reaction and the ether was distilled out of the reaction flask (till the distillate coming over had a temperature of 78 °C). l,2-bis(Ph2P)ethaneNiCl2 (887 mg, 1.25 mmol) was then added to the reaction as solid and the above mixture was refluxed for 90 min. 2,3-dihydrofuran (0.96 mL, 13 mmol) was then added to the reaction and the whole refluxed for 10 hrs. The reaction was then cooled to rt and quenched by the addition of sat. NH 4C3 solution. The organic layer was seperated and the aqueous layer was extracted with EtOAc (25 mL). The combined organic layers were then washed with brine (50 mL), dried (MgSO^) and concentrated. Chromatography (15% EtOAc in hexanes) gave

1.9 g (69%) of 326 as a colorless oil. R/0.2 (15% EtOAc in hexanes). NMR (CDCI 3,

250 MHz), 6 7.50 (m, 2H), 7.35 (m, 3H), 5.55 (m, IH), 5.25 (m, IH), 3.52 (m, 2H),

2.19 (m, 2H), 1.74 (d, 2H, J = 8.70), 1.28 (s, IH), 0.28 (s, 6H). NMR (CDCI3, 62.5 MHz) Ô 138.7, 133.6, 129.0, 128.2, 127.8, 123.5, 62.4, 30.7, 18.0, -3.3. Anal.

Calcd for Ci 3H2oOSi: C, 70.84; H, 9.15. Found: C, 70.42; H, 8.90.

MegPhSi,

6-(dimethylphenylsilyl)-hex-4-en-l-ol (327). This alcohol was prepared according to the general procedure described above except 2,3-dihydropyran (0.38 mL, 4.16 mmol) was used for the reaction. Chromatography (15% EtOAc in hexanes) gave 570 mg (59%) of 327 as a colorless oil. Ry^0.21 (15% EtOAc in hexanes). •H NMR (CDCI 3, 250 MHz), 5 7.50 (m, 2H), 7.35 (m, 3H), 5.50-5.20 (m, 2H), 3.56 (t, 2H, J = 6.46),

1.99 (m, 2H), 1.70 (d, 2H, J = 8.39), 1.53 (m. 2H), 1.23 (s. IH), 0.27 (s, 6 H).

178 NMR (CDCI3. 62.5 MHz) 5 138.9, 133.6, 129.0, 127.7, 127.4, 125.3, 62.7, 32.7, 23.4,

17.7, -3.3. Anal. Calcd for CuH iiO Si: C. 71.73; H, 9.46. Found: C, 71.72; H, 9.25.

MeaPhSi

331 l-Iodo-5-(dimethylphenyIsilyi)-pent-3-ene (331). The alcohol 326 ( 2.7 g, 12.2 mmol), triethylamine (3.4 mL, 24.4 mmol) and DMAP ( 150 mg, 1.2 mmol) were dissolved in CH 2CI2 (13 ml) and the reaction was cooled in an ice bath (0 °C). p- Toluenesulfonyl chloride (2.4 g, 12.8 mmol) was added to the reaction over 5 min and the reaction was allowed to stir for another 4 hrs. The reaction was then diluted with CHCI 3 (25 mL) and the organic phase was washed with IM HCl (10 mL), saL NaHCOg solution

(10 mL) and brine (10 mL), dried (MgS 0 4 ) and concentrated to provide the crude tosylate which was used without any further purification. The tosylate obtained above was dissolved in acetone (63 mL) and treated with Nal (7.6 g, 50.4 mmol). The reaction was then refluxed for 4 hrs. after which it was cooled to room temperature and poured into water (100 mL). The aqueous phase was then extracted with hexanes (50 mL) and the organic phase was then washed with sat. Na 2S2 0 3 solution, brine, dried (MgS 0 4 ) and concentrated. Chromatography (hexanes) provided 2.83 g (75% from 326) of the iodide 331 as a colorless oU. R/0.8 (hexanes). NMR (CDCI 3, 250 MHz), 5 7.50 (m, 2H), 7.35 (m, 3H), 5.52 (m, IH), 5.19 (m, IH), 2.94 (t, 2H, J =

7.46), 2.46 (m, 2H), 1-69 (d, 2H, / = 8.67), 0.28 (s, 6 H). 13c NMR (CDCI3, 62.5 MHz) Ô 138.4, 133.6, 129.2, 127.8, 127.6, 126.4, 31.5, 18.3, 5.1, -3.3. Anal. Calcd for

C i3H i9SiI: C, 47.27; H, 5.79. Found; C, 47.41; H, 5.56.

MegPhSi

332

179 l-Iodo-6-(dimethyIphenylsilyl)-hex-4-ene (332). This iodide was prepared from the alcohol 327 (2.3 g, 9.6 mmol) by the procedure described above. Chromatography (hexanes) provided 2.91 g (90% from 327) of the iodide 332 as a colorless oil. NMR

(CDCI3, 250 MHz), 6 7.50 (m, 2H), 7.35 (m, 3H), 5.50-5.20 (m, 2H), 3.13 (t, 2H, J =

6.46), 1.99 (m, 2H), 1.70 (m, 4H), 0.29 (s, 6 H). NMR (CDCI3, 62.5 MHz) 5

138.7, 133.6, 129.0, 127.7, 126.5, 125.8, 33.5, 27.9, 17.9, 6.4, -3.3. Anal. Calcd for

C i4H2 iSiI: C, 48.84; H, 6.15. Found: C, 48.94; H, 6.19.

333 (R)-2-[6-(dimethylphenylsilyl)-hex-4-en]-iV-[(4-methyIphenyl)sulfonyi]- aziridine (333). This aziridine was prepared according to the procedure described for preparation of 211. Chromatography ( 8 % EtOAc in Hexanes) gave 440 mg (67%) of 192.

R/0.25 (8 % EtOAc in hexanes), [a]365 +8.5' (c 0.96, EtOAc), iH NMR (CDCI 3, 250 MHz), 5 7.81 (d, 2H, J = 8.23), 7.50 (m, 2H), 7.35 (m, 5H), 5.35 (m, IH), 5.10 (m,

IH), 2.65 (m, IH), 2.60 (d, IH, J = 6.98), 2.44 (s, 3H), 2.02 (d, IH, 7 = 4 .4 9 ), 1.85

(m, 2H), 1.66 (d, 2H, J = 8.48), 1.65-1.1 (m, 4H), 0.26 (s, 6H). NMR (CDCI3,

62.5 MHz) 6 144.3, 138.8, 135.5, 133.6, 129.6, 129.0, 128.0, 127.7, 127.3, 125.3,

40.2, 33.7, 30.9, 26.6, 26.4, 21.5, 17.7, -3.3. Anal. Calcd for CzsHgiNOiSiS: C, 66.78; H, 7.55; N, 3.39. Found: C, 66.49; H, 7.51; N, 3.34.

334

1 8 0 (/?)-2«[7-(dimethylphenylsilyl)-hept-5

R/0.24 (8 % EtOAc in hexanes), [aJses +31.0° (c 2.36, EtOAc), ‘H NMR (CDCI 3, 250

MHz), Ô 7.81 (d, 2H, / = 8.30), 7.52 (m, 2H), 7.35 (m, 5H), 5.31 (m, IH), 5.15 (m,

IH), 2.68 (m, IH), 2.62 (d, IH, J = 6.95), 2.42 (s, 3H), 2.03 (d, IH, / = 4.47), 1.82

(m, 2H), 1.66 (d, 2H, / = 8.41), 1.65-1.1 (m, 6 H), 0.27 (s, 6 H). NMR (CDCI3, 62.5 MHz) 5 144.2, 138.8, 135.5, 133.5, 129.5, 129.0, 128.0, 127.7, 127.6, 125.0,

40.3, 33.6, 31.1, 29.0, 26.8, 26.4, 21.5, 17.6, -3.3. Anal. Calcd for C24H33N02S1S: C, 67.40; H, 7.77; N, 3.28. Found: C, 67.78; H, 7.38; N, 3.17.

Alternate preparation of (/?)-2-[6-(dimethylphenyI)-hept-5-en]-iV-[(4- methylphenyl)sulfonyl]-aziridine (334).

SiPhMea

NHTs

(SR)-l-(dimethylphenylsilyl) 8-[(4-methyiphenyl)suIfonyl]amlno-9- [(tbutyldlmethyl)silyl]oxo-non-2-ene (336). rBuLi (32.4 mL of a 1.49 M solution in pentane, 48.28 mmol) was added dropwise to a solution of 332 (7.55 g, 21.3 mmol) in

Et2 0 (44 mL) at -78 °C. The reaction was then allowed to stir at -78 °C for 10 min after which it was warmed to rt and stirred for an additional 60 min. The reaction was then recooled to -78 °C. In a separate flask Cul ( 1.4 g, 7.8 mmol) was dissolved in « 8 0 3 ?

(9.35 mL, 37.5 mmol) and Et 2 0 (10 mL). The slightly turbid solution of CuI/nBu 3P in

Et2 0 was then transferred to the organolithium prepared above using additional Et 2 0 (34 mL). The yellowish cuprate solution thus formed, was warmed to -40 “C and stirred for 10

181 min after which it was recooled to -78 °C. The aziridine 187*^ (2.67 g, 7.82 mmol) was dissolved in EtzO (4 mL) and added to the reaction via cannula. The reaction was stirred at -78 ’C for 15 min after which it was warmed to rt and stirred for another 30 min. The reaction was quenched by adding sat. NH 4CI solution and the organic layer washed with sat. NH4CI, brine, dried (MgSOa) and concentrated. Chromatography (3% - 8 % EtOAc in hexanes) provided 3.93 g ( 90%) of 336 as a colorless oil. R/0.3 ( 15% EtOAc in hexanes), [a]o +17.2° (c 1.29, EtOAc), ‘H NMR (CDCI 3. 250 MHz), 5 7.74 (d, 2H, 7 =

7.98), 7.48 (m, 2H), 7.34 (m, 3H), 7.25 (d, 2H, 7 = 8.12), 5.36-5.25 (m, IH), 5.22- 5.13 (m, IH), 4.82 (d, IH, 7= 8.26), 3.41(dd, IH, 7= 2.85, 9.99), 3.31 (dd, IH, 7 = 4.10, 9.74), 3.21-3.13 (m, IH), 2.38 (s, 3H), 1.84-1.79 (m, 2H), 1.66 (d, 2H, 7 =

8.48), 1.46-1.36 ( m, 2H), 1.20-1.11 (m, 4H), 0.83 (s, 9H), 0.26 (s, 6H), -0.04 (s, 3H),

-0.06 (s, 3H). I3c NMR (CDCI3, 62.5 MHz ), S 143.0, 138.8, 138.4, 133.5, 129.5,

128.9, 127.9, 127.6, 127.0, 124.7, 64.1, 54.9, 32.0, 29.3, 26.6, 25.8, 25.2, 21.4,

18.1, 17.5, -3.3, -5.7. Anal. Calcd for C 3oH49N0 3 Si2S : C, 64.34; H, 8.64; N, 2.50. Found C, 64.66; H, 8.93; N, 2.59.

SiPhMea

334 nBuaNF (7.75 mL of a 1 M solution in THF, 7.75) was added dropwise over 5 min to a solution of silyl ether 336 (3.94 g, 7.04 mmol) in THF (8 mL) at 0 °C. The reaction was stirred for 30 min after which it was diluted with water. The aqueous layer was then extracted with EtOAc (3x10 mL) and the combined organic layers washed with brine, dried (MgSO^) and concentrated. The crude 337 thus obtained was dried under vacuum (2 mm Hg) overnight and used without any further purification. The crude alcohol obtained was transferred to a flame dried flask containing triphenylphosphine (2 g, 7.74 mmol), 182 using THF (35 ntiL) and the resulting solution was cooled in an ice bath.

Diethylazodicarboxylate (1.23 mL, 7.74 mmol) was added to the reaction over 5 min via a syringe and the reaction was then allowed to stir for 3 h after which the solvent was removed in vacuo. The resulting thick oil was triturated with hexanes resulting in precipitation of a white solid (PhgPO), which was filtered to provide a solution which was then concentrated. Chromatography ( 10% EtOAc in hexanes) provided 2.25 g (76% from 187) of aziridine 334 as a colorless oil.

Condition B for Aziridine-allylsilane cyclization

u --SiPhMea

H 336a (l/{,3ai?,6aS)-iV-[(4-methyIphenyl)sulfonyl]-l-[(diniethylphenylsilyl) methyl] hexahydrocyclopenta[c]pyrrole (336a). The aziridine 333 (34 mg, 0.08 mmol) was dissolved in (ZH 2CI2 (0.16 mL) and the reaction was cooled to -20 °C. A solution (0.67 mL) of freshly distilled BF 3»OEt2 (5.2 |iL, 0.042 mmol) in Œ 2CI2, was added to the reaction which was then allowed to stir for 60 min at -20 °C. The reaction was then diluted with CHCI 3 (5 mL) and quenched by the addition of sat. NaHC 0 3 solution (3 mL). The aqueous layer was then extracted with CHCI 3 (5 mL) and the combined organic layers were dried (MgS0 4 ) and concentrated. Chromatography ( 8 % EtOAc in hexanes) provided 20 mg (60%) of 336a as a colorless oil. Further elution of the column (15% EtOAc in hexanes) provided 7 mg (32%). of the olefin 320 (inseperable mixture of cis and trans isomers). Data for 336a; R/0.25 (8 % EtOAc in hexanes). [aJo +l 15.0° (c 0.78, EtOAc), >H NMR (CeDe, 270 MHz), 5 7.63 (d, 2H, J = 8.15), 7.53 (m, 2H), 7.22 (m,

3H), 6.81 (d, 2H, y = 8.22), 3.25 (m, IH), 3.14 (dd, IH, 7 = 9.04,7= 11.06), 3.0 (dd,

183 IH, y = 6.77, y = 11.08), 2.36 (dd, IH, J = 2.89, J = 14.78), 1.92 (s, 3H), 1.87 (m,

IH), 1.62 (m, IH), 1.62-0.9 (m, 9H), 0.26 (s, 6 H). '^c NMR (CDCI3, 62.5 MHz) S

143.0, 138.6, 135.7, 129.4, 129.3, 129.1, 127.9, 127.8, 61.5, 55.0, 49.3, 40.3, 30.9, 27.1, 25.7, 21.4, 19.3, -2.1, -2.4. Anal. Calcd for CzsHsiNOaSiS: C, 66.78; H, 7.55; N, 3.39. Found: C, 67.16; H, 7.65; N, 3.30.

—SiPhMea ^SiPhMeg

H H 335a 335b (1/J, 3a/J, 7a5)-iV-[(4-methylphenyl)sulfonyl]-l-[(dimethyIphenylsilyI) methyl] octahydro-lH-isoindole (335a) and (15, 3a/J, 7aR)-A(-[(4- methyiphenyi)suIfonyl]-l<[(dimethylphenylsiiyI) methyl] octahydro-IH- isoindole (336a) These were prepared from the aziridine 334 (40 mg, 0.09 mmol), according to Condition B described above. Chromatography ( 8 % EtOAc in hexanes) provided 27 mg (70%) of 335a and 336b as a separable mixture (ca 3:1 trans:cis, colorless oil). Further elution of the column (15% EtOAc in hexanes) provided 6 mg (22%) of the olefin 287 (inseparable mixture of cis and trans isomers). Data for 335a: R/0.25

(8 % EtOAc in hexanes). [a]o +122.1“ (c 1.04, EtOAc), ^H NMR (CôDô, 270 MHz), Ô

7.65 (d, 2H, y = 8.10), 7.57 (m, 2H), 7.22 (m, 3H). 6.78 (d, 2H, J = 8.12), 3.30 (m, 2H), 2.52 (m, IH), 1.89 (s, 3H), 1.5-0.5 (m, lOH), 0.0243 (s, 3H), 0.24 (s, 3H).

NMR (CDCI3, 62.5 MHz) 5 142.8, 138.5, 134.5, 133.7, 129.4, 129.0, 127.8, 127.6,

63.7, 49.9, 41.9, 36.1, 24.8, 24.3, 22.7, 21.4, 20.5, 18.1, -2.1, -2.6. Data for 335b: R/

0.27 ( 8 % EtOAc in hexanes), [ajo -24.1 (c 0.29, EtOAc), ^H NMR (C^D^, 250 MHz), 5

7.72 (d, 2H, y = 8.25), 7.66 (m, 2H), 7.26, (m, 3H), 6.79 (d, 2H, J = 7.87), 4.0 (m,

IH), 3.46 (dd, IH, y = 6.88, J = 9.13), 2.53 (dd, IH, J = 9.29, J = 9.13), 1.86 (s, 3H),

1.5-1.1 (m, 7H), 1.30 (dd, 2H, y=5.8,y= 15.03), 1.0 (dd, IH, J = 7.44, J = 15.07).

184 0.9-0.4 (m, 4H), 0.59 (s, 3H), 0.57 (s, 3H). NMR (CDCI 3, 62.5 MHz) 5 142.8,

139.1, 135.0, 133.7, 129.4, 129.7, 127.7, 127.4, 60.3, 53.3, 49.4, 40.1, 29.3, 26.6, 25.3, 25.1, 21.4, 20.7, -1.9, -2.1. Anal. Calcd for 335a and 335b C24H33N02SiS: C, 67.40; H, 7.77; N, 3.27. Found: C, 67.61; H, 7.78; N, 3.14.

General procedure for oxidation of phenyldimethylsiiyl group

H r ° ”

H 351 (liî,3ai?,6aS)-lV-[(4-methylphenyi)suIfonyl]-l-hydroxymethyl hexahydro- cyclopenta[c]pyrrole (351). Mercuric acetate (60 mg, 0.19 mmol) was added to a solution of bicycle 336a (45 mg, 0.11 mmol) in peracetic acid (0.54 mL, of a 32% solution in acetic acid, 3.25 mmol), glacial acetic acid (0.54 mL) in EtOAc (0.5 mL). The reaction was then stirred at rt for 3 hours. The reaction was diluted with water (5 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were then washed with sat. Na2S2 0 3 solution (5 mL), H 2O (2x5 mL), sat. NaHCO], brine, dried (MgSOa) and evaporated in vacuo. Chromatography (35% EtOAc in hexanes) provided 351 (19 mg, 60%) as a colorless oil. R/0.36 (35% EtOAc in hexanes) [aJo +60“ (c 0.98, EtOAc),

NMR (CDCI3, 250 MHz), Ô 7.78 (d, 2H, / = 8.33), 7.29 (d, 2H, J = 8.09), 3.86 (dd,

IH, y = 7.14,7= 12.12), 3.75 (m (hr), IH), 3.45 (m, 2H), 3.29 (dd, IH, 7 = 9.03, 7 = II.42), 3.05 (dd, IH, 7= 7.12, 11.19), 2.40 (s, 3H), 2.18-2.09 (m, IH), 1.70-1.30 (m, 7H)

185 H c e » H 3S2

(1/î, 3aRf 7aS)-iV-[(4-methylphenyl)sulfonyI]-l-hydroxymethyl octahydro-IH-isoindole (352). This bicycle was prepared using the same general procedure as described for 351 except bicycle 335a (0.13 g, 0.3 mmol) was used. Chromatography (30% EtOAc in hexanes) provided of 352 (80 mg, 89%) as a colorless oil. R f 0.36 (15% EtOAc in hexanes), [ a b +29.6* (c 1.69, EtOAc), NMR (CDCI 3, 250 MHz), 5 7.71 (d, 2H, / = 8.25), 7.31 (d, 2H, / = 8.25), 3.9-3.5 (m, 3H), 3.48-3.2

(m, 3H), 2.41 (s, 3H), 2 (m, IH). 1.7-0.7 (m, IIH). (CDCI 3, 62.5 MHz) 143.1, 133.9, 129.8, 127.8, 67.7, 63.6, 51.5, 41.9, 36, 24.6, 24.3, 22, 21.5, 20.7.

OH

(IS, 3aR, 7a/J)-A^-[(4-methyIphenyl)suIfonyl]-l-hydroxymethyi octahydro-lH-isoindole (353). This alcohol was prepared using the general procedure, except 335b (0.23 g, 0.53 mmol) was used to provide 353 (0.16 g, 91%), R/

0.39 (15% EtOAc in hexanes), [a]o -2.52° (c 0.56, EtOAc), ^H NMR (CDCI 3, 250 MHz), Ô 7.69 ( d, 2H, 7=8.24), 7.29 (d, 2H, 7 = 8.05), 3.71 (m ,br, IH), 3.62-3.55 (m,

3H), 2.94-2.88 (m, IH), 2.53 (dd, IH, 7 = 8.81, 10.95), 2.40 (s, 3H), 1.82-1.58 (m,

5H), 1.20-0.71 (m, 5H). 13c (CDCI 3, 62.5 MHz) 143.5, 133.8, 129.6, 127.6, 63.9,

63.2, 54.2, 46.9, 41.4, 29.1, 25.9, 25.5, 25.1, 21.4. Anal. Calcd for C 16H23NO3S: C, 62.11; H, 7.49; N, 4.53. Found: C, 62.22; H, 7.45; N, 4.42.

186 General procedure for preparation of pyrldyl ethers.

Mesyl chloride (0.2 tnL, 0.25 mmol) was added to a solution of alcohol 352 (61 mg, 0.2 mmol), triethylamine (0.07 mL, 0.5 mmol) and DMAP (3 mg, 0.025 mmol) in CH 2CI2

(0.4 mL) at 0 ”C. The reaction was stirred for 2 h after which it was diluted with CHCI 3 and the organic phase was washed with IM HCl, sat. NaHCOg, brine, dried (MgS 0 4 ) aand concentrated. The mesylate was used without any further purification. NMR

(CDCI3, 250 MHz), 5 7.69 ( d, 2H, / =8.24), 7.31 (d, 2H, J = 8.05), 4.84 (dd, IH, J =

5,58, 10.23), 4.23 (t, IH, J = 10.23), 3.6 (m, IH), 3.4-3.2 (m, 2H), 3.03 (s, 3H), 2.39

(s, 3H), 2.1 (s, IH), 1.8-0.8 (m, lOH). NMR (CDCI 3, 62.5 MHz) 143.9, 133.3, 129.8, 127.8, 68.5, 50.7, 40, 37.1, 35.8, 24.4, 24, 21.8, 21.4, 20.4. The crude mesylate (80 mg, 0.2 mmol) and 3-hydroxy pyridine (73 mg, 0.8 mmol) were dissolved in DMF (1 mL). K2CO3 (0.22 g, 1.56 mmol) was added to the solution and the reaction was immersed in an oil bath preheated to 120 °C and the stirred for 90 min after which it was cooled to rt and water (5 mL) was added to the reaction. The aq. layer was extracted with EtOAc (3x5 mL) and the combined organic layers were washed with water, brine,dried

(MgS0 4 ) and concentrated. Chromatography (5% MeOH in CHCI 3) provided the pyridyl ether (70%). ^H NMR (CDCI 3, 250 MHz), 5 3.32 (d, IH, J = 2.54), 8.23 (m, IH), 7.74

(d, 2H, J = 8.29), 7.34 (d, 2H, J = 8.05), 4.72 (dd, IH, J = 4.58, 9.35), 4.1 (t, IH, J = 9.48), 3.7 (m, IH), 3.5-3.2 (m, 2H), 2.45 (s, 3H), 2.25 (m, IH), 1.7-0.8 (m, lOH).

(CDCI3, 62.5 MHz) 154.8, 143.7, 142.3, 138.7, 134.1, 129.8, 127.8, 123.8, 120.6, 67.2, 62.5, 50.8, 40.3, 36.1, 24.6, 24.3, 22, 21.5, 20.8.

187 356 The trans pyridyl ether 356 was prepared using a similar procedure from 353 (0.12 g, 0.4 mmol) to provide 356 (92 mg, 67%). Analytical data for mesylate 357 7.64 (d, 2H, J — 8.26), 7.25 (d, 2H, J = 8.04), 4.3 (dd, IH, J = 6.39, 10.47), 4.22 (dd, IH, J = 2.72, 10.47), 3.6 (m, IH), 3.5 (dd, IH, J = 6.43, 8.53), 3.03 (s, 3H), 2.43 (dd, IH, J = 8.64,

10.87), 2.37 (s, 3H), 1.85-1.6 (m, 5H), 1.3-0.7 (m, 4H). (CDCI 3, 62.5 MHz) 143.7, 133.5, 129.7, 127.4, 69.4, 59.9, 53.5, 46.9, 40.1, 36.9, 28.7, 25.6, 25.3, 24.8,

21.3. Analytical data for 356. ‘H NMR (CDCI 3, 250 MHz), 5 8.3-8.2 (m, 2H), 7.72 (d,

2H, J = 8.26), 7.3-7.1 (m, 4H), 4.3-4.1 (m, 2H), 3.9 (m, IH), 3.57 (dd, IH, J = 6.39,

8.43), 2.6 (m, IH), 2.43 (s, 3H), 2-1.7 (m, 5H), 1.3-0.8 (m, 5H). I3c (CDCI 3, 62.5 MHz) 154.5, 143.4, 142.2, 138.5, 134.2, 129.6, 127.4, 123.7, 120.6, 68.3, 60.2, 53.5, 47.3, 40.1, 28.8, 26, 25.5, 25.1, 21.3.

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88. (a) Bailey, W.F.; Punzalan, E.R. J. Org. Chem. 1990, 55, 5404. (b) Negishi, E.; Swanson, D R.; Rousset, C.J. J. Org. Chem. 1990,55, 5406. 89. (a) Wenkert, E.; Ferreira, V.F.; Michelotti, E.L.; Tingoli, M. J. Org. Chem. 1985, 50, 719. (b) Kocien’ski, P.; Dixon, N.J.; Wadman, S. Tetrahedron Lett. 1988, 29, 2353. 90. O’Reilly, J.M.; Lin, J.M.; Duax, W.L.; Brueggemeier. R.W. J. Med. Chem. 1995, 38, 2842. 91. Fleming, I.: Frackenpohl, J.; Ila, H. J. Chem. Soc., Perkin Trans. 1, 1998, 1229. 194 92. (a) Baldwin, J.E.; Farthing, C.N.; Russell, A.T.; Schofield, C.J.; Spivey, A.C. Tetrahedron Lett. 1996, 37, 3761. (b) Cantrill, A.A.: Osborn, Sweeney, J. Tetrahedron 1998,54, 2181. (c) Davis, F.A.; Zhou, P. Liang, C.-H.; Reddy, R.E. Tetrahedron Asymmetry 1995,6, 1511. (d) Vedejs, E.; Sano, H. Tetrahedron Lett. 1992, 33, 3261. 93. For deprotection of N-tosyl amine protecting group see: Greene, T.W.; Wuts, P.G.M. in Protective Groups in Organic Synthesis. J. Wiley and Sons, 1991, 380. 94. (a) Bellos, K.; Stamm, H.; Speth, D. J. Org. Chem. 1991, 56, 6846. (b) Falkenstein, R.; Mall, T.; Speth, D.; Stamm, H. J. Org. Chem. 1993, 58, 7377. (c) Vedejs, E.; Lin, S. J. Org. Chem. 1994,59, 1602. (d) Nakajima, S.; Yoshida, K.; Mori, M.; Ban, Y.; Shibasaki, M. J. Chem. Soc., Chem. Commun. 1990, 468.- These authors reported deprotection of a V-sulfonyl aziridine using Na/naphthalenide in low yield ( 16%).

95. Ji, S.; Gortler, L.B.; Waring, A.; Battisti, A.; Bank, S.; Closson, W.D.; Wriede, P. J. Am. Chem. Soc. 1967, 89, 5311. 96. Ahman, J.; Somfai, P. Syn. Comm. 1994, 1121. 97. Jeong, J.U.; Tao, B.; Sagasser, I.; Henniges, H.; Sharpless, K.B. J. Am. Chem. Soc. 1998,120, 6844. (e) Ando, T.; Kano, D.; Minakata, S.; Ryu, I.; Komatsu, M. Tetrahedron 1998, 54, 13485. 98. Bergmeier, S.C.; Seth, P.P. J. Org. Chem. 1997, 62, 2671. 99. Hiremath, S.V.; Reddy, D R.; Kumar, M. Indian J. Chem., Sect. B, 1988, 27B(6), 558. 100. Baldwin, I.E.; Adlington, R.M.; O'Neil, I.A.; Schofield, C.; Spivey, A C.; Sweeney, J.B. J. Chem. Soc., Chem. Commun. 1989, 1852. 101. Molander, G.A.; Stengel, P.J. Tetrahedron 1997,53, 8887. 102. The benzoate ester 126 was prepared by benzoylation of the known alcohol. Tanner, D.; He, H.M.; Somfai, P. Tetrahedron 1992,48, 6069. (b) Aahman, J.; Jarevaang, T.; Somfai, P. J. Org. Chem. 1996, 61, 8148. 103. Bergmeier, S.C.; Seth, P.P. Tetrahedron Lett. 1995, 36, 3793. 104. Bates, G.S.; Ramaswamy, S. Can. J. Chem. 1980, 58, 716. 105. Effenberger, F.; Stelzer, U. Tetrahedron Asymmetry 1995, 6, 283. 106. Bates, G.S.; Varelas, M.A. Can. J. Chem. 1980, 58, 2562. 107. Woodward, R. B.; Bader, F. E.; Bickel, H.; Frey, A. J.; Kierstead, R, W. Tetrahedron 1958,2, 1.

195 108. Van Tamelen, E. E.; Shamma, M.; Burgstahier, A. W.; WoIin.sky, J.; Tamm, R.; Aldrich. P. E. J. Am. Chem. Soc. 1958, 80, 5006. 109. (a) Hua, D. H.; Bharathi, S. N.; Takusagawa, F.; Tsujimoto. A.; Panangadan, J. A. K.; Hung, M.-H.; Bravo, A. A.; Erpelding, A. M. J. Org. Chem. 1989, 54, 659. (b) Hua, D. H.; Bharathi, S. N.; Panangadan, J. A. K.; Tsujimoto, A. J. Org. Chem. 1991, 56, 6998. 110. (a) For a recent review of syntheses of yohimbine alkaloids see: Baxter, E. W.; Mariano, P. S. In Alkaloids: Chemical and Biological Perspectives', Pelletier, S. W., Ed.; Springer-Verlag: New York, Vol. 8,1992, 197-319. (b) For a recent racemic approach to these alkaloids see Wender, P. A.; Smith, T. E.; J. Org. Chem. 1996,61, 824. For asymmetric syntheses of yohimbine, yohimbone, alloyohimbane and related alkaloids see (c) Hirai, Y.; Terada, T.; Yamazaki, T.; Momose, T. J. Chem. Soc. Perkin Trans I 1992, 517. (d) Hirai, Y.; Terada, T.; Okaji, Y.; Yamazaki, T.; Momose, T. Tetrahedron Lett. 1990,3 1 , 4755. (e) Kuehne, M. E.; Randy, R. S. J. Org. Chem. 1991, 56, 2701. (f) Meyers, A. I.; Highsmith, T. K.; Buonora, P. T. J. Org. Chem. 1991,56, 2960. (g) Hua, D. H.; Bharathi, S. N.; Takusagawa, F.; Tsujimoto, A.; Panangadan, J. A. K.; Hung, M.-H.; Bravo, A. A.; Erpelding, A. M. J. Org. Chem. 1989, 54, 659. (h) Meyers, A. I.; Miller, D. B.; V ^ te , F. H. J. Am. Chem. Soc. 1988, 110, 4778. (i) Riva, R.; Banfi, L.; Danieli, B.; Guanti, G.; Lesma, G.; Palmisano, G. J. Chem. Soc. Chem. Commun. 1987, 299. (j) Kametani, T.; Takagi, N.; Kanaya, N.; Honda, T. J. Het. Chem. 1982, 19, 1217. (k) Okamura, K.; Yamada, S.-I. Chem. Pharm. Bull. 1978, 26, 2305. 111. (a) Lin, Y.; Oh, T. Tetrahedron Lett. 1997, 38, 727. (b) Elderfield, R. C.; Fischer, B.A. J. Org. Chem. 1958, 23, 949. (c) Hochstein, F.A.; Paradies, A. M. J. Am. Chem. Soc. 1957, 79, 5735. 112. Trost, B. M.; Quale, P. J. Am. Chem. Soc. 1984, 106, 2469. 113. Tsunoda, T.; Yamamoto, H.; Goda, K.; Ito, S. Tetrahedron Lett. 1996, 37, 2457. Tsunoda, T.; Ozaki, F.; Ito, S. Tetrahedron Lett. 1994, 35, 5081. 114. Bergman, J.; Backvall, J. E.; Lindstrom, J. O. Tetrahedron, 1973,29, 971. 115. Yamazaki, N.; Kibayashi, C. J. Am. Chem. Soc. 1989, 111, 1396. 116. Roemmele, R.C.; Rapoport, J. J. Org. Chem. 1988, 53, 2367.

117. Larock, R. C. in Comprehensive Organic Transformations. A guide to functional group preparations; VCH Publishers, Inc. 1989, 834-841. 118. Behrens, C. H.; Sharpless, K. B. J. Org. Chem. 1985, 50, 5696. (c) Paquette, L.A.; Dressel, J.; Panesgrau, P.O. Tetrahedron Lett. 1987, 28, 4965. 119. (a) Millar, J. G.; Oehlschlager, A. C.; Wong, J. W. J. Org. Chem. 1983, 48, 4404. (b) Anelli, P. L.; Biffi, C.; Montanan, F.; Quici, S. J. Org. Chem. 1987, 52, 2559. (c) Corey, E.J.; Samuelsson, B. J. Org. Chem. 1984, 49, 4735.

196 [20. Stevens, R.V.; Chapman, K.T.; Stubbs, C.A.; Tam, W.W.; Albizati, K. F. Tetrahedron Lett. 1982, 23, 4647. 121. (a) Dess, D.B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (b) Meyer, S.D.; Schreiber, S.L. J. Org. Chem. 1994,59, 7550. (c) Ireland, R.E.; Liu, L. J. Org. Chem. 1993, 58, 2899. 122. Abiko, A.; Roberts, J. C.; Takemasa, T.; Masamune, S. Tetrahedron Lett. 1986, 27, 4537. 123. Kim. S.; Kim, Y .; Lee, J. Tetrahedron Lett. 1983, 24, 3365. 124. Hashimoto, N.; Aoyama, T.; Shioiri, T. Chem. Pharm. Bull. 1981,29, 1475. 125. Martin, S.F.; Rueger, H.; Williamson, S.A.; Grzejszczak, S. J. Am. Chem. Soc. 198 7, 109, 6124. 126. Morrison, G. C.; Cetenko, W.A.; Shavel, J., Jr. J. Org. Chem. 1966, 31, 2695. 127. Commins, D.L; Al-awar, R.S. J. Org. Chem. 1995,60, 4249. 128. Spande, T.F.; Garraffo, H.M.; Edwards, M.W.; Yeh, H.J.C.; Panned, L.; Daly, J.W. J. Am. Chem. Soc. 1992,114, 3475. 129. McDonald, LA.; Cosford, N.; Vernier, J.-M. Annual Reports in Medicinal Chemistry, 1995, 41. 130. Fleming, I.; Sanderson, P.E.J. 1987, 36, 4229. 131. Kudav, D.P.; Samant, S.P.; Hosangadi, B.D.; Syn. Commun. 1987,17, 1185. 132. Trost, B.M.; Arndt, H.C.; Strege, P.E.; Verhoeven, T.R. Tetrahedron Lett. 1976, 3477. 133. Gold, E.H.; Babad, E. J. Org. Chem. 1972, 37, 2208. 134. Fleming, L; Roberts, R.S.; Smith, S.C. J. Chem. Soc., Perkin Trans. 11998, 1209. 135. Saito, K.; Higashijima, T.; Miyazawa, T.; Wakimasu, M.; Fujino, M. Chem. Pharm. Bull. 1984,52, 2187. 136. Ho. M.; Chung, J.K.K.; Tang, N. Tetrahedron Lett. 1993, 34, 6513.

197 APPENDIX nOe SPECTRA

198 -UiL L ... I I I n #4,

t4»(mev)

5;'4% k ; u u u

r % NHTs Ihc-ZT-nhts (I'.O 2.6»> 152b

(IHQ

—1— — I— ^ 3.5 9.0 4.9 4.0 3.9 1.0 2.9 2.0 1.9 1.0 %

c-i

- ^ 5.4%

Hr-7^NHTs VHc-^V'NHTs 2.6»/^ 152b

1 —"- T—'—«- HbTsO Hd 155

He

~t f r T I ? I T f ^ T r 'T ? I I i ~ r I i i i i i t i r r r i i t t i t i t i | t r r » f ri'i'TT r r f m r r i | i t fT'r rrf rr r r t t i i i i i | t t i rr i t t r r r fr-ri t % rt » f-r t ppm 8 6 4 2 0 I n t e g r a i

m-

2.21

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100.0

26.05

3.73

5 . 0 0

202 :.negral

§ i

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at X

25.60

100.0 'X

4.17

203 156

S

i Hj

r t - T - m t * r DDm 10 6 .6 % 2 .1%

156

§

RI o iS o ni I ru

nmmmu|WHminiiiMnnnnHiiiimnmi|in imnmnmimmiiiiii|iiimiiiiiiiii»iim iiiimiiii|itiiniiiiiiniiiJiiiiimii»jiiiiiiii|iiiiiiiiiaiiinnniiiiinn[uiiinT|iiiiiiiini»iiiiniiiiiiiiiim niiiir[iiniiiiiiniiiiiiiiiiiiiiiiiiimiiiii|iniiiiiiiiiiimiiiiiiiiniiiiiiniiii|iiinm nriiiiiiiitii^iiliiiliiiiiiijiimiiiiiniiiiim ppm 9 8 7 6 5 4 3 2 ‘ 1 w (Q

0(0 X

w

3T r <-

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206 LOI

O

t n

eo

c s i X * n û. COO • ü s

in CH;

H b 6.4%, 336a

PPM SiPhMe.

W § 5% 336a

v v

r •j 7 0 56 0 5.5 5.0 4.5 4.0 3.53.02.5 2.0 1.5fi 1 0 5 OIZ

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CM

CM X COO To

X a a

i n i n

: o SiPhMe; 5^2^ 8 .9%

CH;

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-T" r ' T ’ 1-'- T •- 5 go 8 5 8 0 75 70 5.5 6 0 5 5 5.0 15 1 0 3.5 3 0 2.5 2.0 1.5 1.0 .5 0.0 PPM r

I 1 Hb W.

SiPhMeg

Ha =.Hf He n n

5.8% 7 .7%

/ VU

-^T—- —r ■ ■■ •■ I... I "-T MO 05 F)0 ; 5 70 6.5 6 0 5 5 5.0 4 5 4 0 3.5 3 0 2 5 2.0 . 1.5 1.0 .5 0 0 PPM Ha He

HbHc Hd He 335b

m (N

JHJ

T T T 5 9 0 0 5 0 0 7 5 7 0 6 5 6 0 5.5 5 0 4 5 4 0 3 5 3.0 2 5 2.0 1.5 1.0 .5 0.0 PPM i

SIPhMeg 9.6%-n 12.2% TtefVHe

HbHc Hd He 335b (N

' l~ '~ I ' ' ' '- r• ' I — r—- ' r — 2.0 1.5 1.0 .5 00 0 5 GO 5.5 5.0 a 5 1 0 3.5 3.0 2.5 5 go 05 00 7 5 7 0 PPM Ha

PPM /

JV I 1-

SiPhMeg

HbHc "Hd He II,

VO N 335b

ii

T~ -t—--- — ~i~— ' ' " I ’ 5 q 0 85 80 75 70 6 5 6.0 5.5 5 0 4 3 4 0 3 5 3.0 2.5 2.0 15 1.0 0.0 PPM o ' Intcgral 1.0000

0 . 9 7 9 7

1 . 2 5 4 0 T iT iT

Oï-

1 . 0 3 9 2

2 . 3 0 4 8

1 . 0 7 0 3

2 . 2 0 6 7 '

1 . 1 7 1 6

1 . 9 3 0 0 '

4 . 6 8 8 7 y- a . 4 7 0 5

217 (-)-yohimbane

OG Cl I«.ceqr4l

"O 3

1 .000 0 9 9 5^ ~ - 2 .157 ------1 ..871

m- 3 P % z I

I(D #

0 . 9 9 2

2 . 0 7 3

2 . 1 3 8

1 . 9 6 2

I n j —

2 5 . 8 4 6

3.948

219 enf-alloyohimbane

o nri IMAGE EVALUATION TEST TARGET (QA-3) /

w r % r/ ■ &

%

1.0 12.2 |06

l.l 1.8

1.25 1.4 1.6

150mm

V /IPPL IE D ^ IIVMBE . Inc 1653 East Main street Rocfiester, NY 14609 USA Ptione: 716/482-0300 ------Fax; 716/288-5989

/> e 1993. A pplied Im age. Inc.. Ail Rlghts R eserved

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