development of oxidative methodologies and application toward

DEVELOPMENT OF OXIDATIVE METHODOLOGIES AND APPLICATION TOWARD

TETRODOTOXIN CORE

by

Brian Alan Mendelsohn

B.Sc., University of Washington, 2000

A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE

DEGREE OF

DOCTOR OF PHILOSOPHY

in

THE FACULTY OF GRADUATE STUDIES

(Chemistry)

THE UNIVERSITY OF BRITISH COLUMBIA

(Vancouver)

December 2010

© BRIAN ALAN MENDELSOHN, 2010

ii

Abstract

This thesis covers a novel approach to tetrodotoxin that relies on the oxidative amidation of a

phenol and intramolecular nitrile oxide cycloaddition to install a -hydroxynitrile unit among the key

steps. These transformations, and others contained herein, effectively set the tetrasubstituted C-8a

stereocenter, as well C-4a formyl equivalent and C-5, C-7 and C-8 hydroxyl groups. Novel reaction types

were developed in the course of this work, including a new method for the oxidation of oximes to nitrile

oxides using hypervalent iodine reagents. Additionally, I identified a tandem reaction sequence,

involving the dearomatization of a phenol, followed by [3+2]-dipolarcycloaddition, the first of its kind.

This tandem sequence proved a powerful tool for the rapid construction of multicyclic compounds from

structurally simpler starting materials. These studies resulted in advanced intermediates which contained

much of the structure of the tetrodotoxin core.

iii

Preface

The work presented in this thesis was in part a collaborative effort. However, primarily I, in

conjunction with my supervisor Professor Marco A. Ciufolini, developed the ideas and design of the

research projects presented herein.

The introductory section (Chapter 1) of this thesis covers a review of previous work by other

scientists. Chapter 2 of this thesis covers the work I performed during the course of my Ph.D. studies. I

performed the vast majority of the work presented in this thesis, and exceptions are noted in this Preface

section. The data described in Tables 2.10, 2.11, 2.12 and 2.13 was generated in conjunction with Mr.

Tim Jen, a talented undergraduate student who worked under my direction over two summers.

Compounds 2.113 and 2.115 were synthesized by another Ciufolini group member Mr. Florian Tessier.

Dr. Brian Patrick of the Department of Chemistry at UBC performed all crystal structure data

collection and analysis. Mr. David Wong and Mr. Marshall Lapawa of the Department of Chemistry at

UBC performed all high-resolution mass spectrometry experiments and all elemental analyses.

iv

Table of contents

Abstract ........................................................................................................................................................ ii

Preface ......................................................................................................................................................... iii

Table of contents ......................................................................................................................................... iv

List of tables ................................................................................................................................................ xi

List of figures ............................................................................................................................................. xii

List of schemes .......................................................................................................................................... xiv

List of abbreviations .................................................................................................................................. xvi

Acknowledgements ................................................................................................................................... xxi

1 Introduction ..................................................................................................................................1

1.1 Tetrodotoxin ..................................................................................................................................1

1.1.1 Isolation, characterization and natural occurrence ...................................................................2

1.1.2 Tetrodotoxin biosynthesis ........................................................................................................4

1.1.3 Voltage-gated sodium channels................................................................................................5

1.1.4 TTX and naturally occurring voltage-gated sodium channel inhibitors ...................................6

1.2 Synthetic studies ............................................................................................................................7

1.2.1 Kishi’s total synthesis ...............................................................................................................7

1.2.2 Isobe’s total synthesis and related studies ..............................................................................11

1.2.3 Du Bois’ total synthesis ..........................................................................................................23

1.2.4 Sato’s total syntheses .............................................................................................................27

1.2.5 Funabashi ...............................................................................................................................34

1.2.6 Keana ......................................................................................................................................36

1.2.7 Fraser-Reid .............................................................................................................................37

1.2.8 Alonso ....................................................................................................................................40

1.2.9 Taber ......................................................................................................................................41

1.2.10 Fukuyama ...............................................................................................................................43

1.2.11 Ohfune ....................................................................................................................................46

1.2.12 Summary ................................................................................................................................48

2 The oxidative amidation strategy ...............................................................................................50

2.1 General strategy ...........................................................................................................................50

2.2 Oxidative amidation ....................................................................................................................53

2.2.1 Oxidative amidation in total synthesis ...................................................................................54

2.3 Bimolecular oxidative amidation.................................................................................................57

v

2.3.1 Optimization of scalable bimolecular oxidative amidation conditions ..................................57

2.4 Nitrile oxide [3+2] cycloaddition ................................................................................................61

2.5 Kemp-type keto-isooxazoline fragmentation ..............................................................................73

2.5.1 Access to a suitable dihydroxylation substrate .......................................................................76

2.6 Osmylation of substituted cyclohexene derivative ......................................................................79

2.7 Iodine(III)-mediated oxime oxidation to nitrile oxides ...............................................................82

2.7.1 Oximes as nitrile oxide precusors ..........................................................................................82

2.7.2 Optimization of DIB as a reagent for oxime to nitrile oxide oxidations ................................83

2.7.3 Oxidation of -oxo-ketoximes and ’-dioxo-ketoximes ....................................................89

2.7.4 Intramolecular nitrile oxide cycloaddition .............................................................................93

2.8 Tandem oxidative dearomatization/nitrile oxide [3+2] cycloaddition ........................................95

2.8.1 Sorensen’s use of tandem dearomitization/nitrile oxide [3+2] cycloaddition in Cortistatin

core synthesis .........................................................................................................................97

2.9 Diastereoselective tandem oxidative amidation—INOC.............................................................99

2.10 Summary ...................................................................................................................................103

References .................................................................................................................................................104

Appendices ................................................................................................................................................115

A. Experimental protocols .............................................................................................................116

A.1 Preparation of methyl 2-(1-acetamido-4-oxocyclohexa-2,5-dienyl)acetate (2.32) ...................116

A.2 Preparation of methyl 2-((1r,4r)-1-acetamido-4-(tert-butyldiphenylsilyloxy)cyclohexa-2,5-

dienyl)acetate (2.37) .................................................................................................................118

A.3 Preparation of 2-((1r,4r)-1-acetamido-4-(tert-butyldiphenylsilyloxy)cyclohexa-2,5-dienyl)acetic

acid (2.38) .................................................................................................................................119

A.4 Preparation of N-((1r,4r)-4-(tert-butyldiphenylsilyloxy)-1-(3-nitro-2-oxopropyl)cyclohexa-2,5-

dienyl)acetamide (2.39) ............................................................................................................120

A.5 Preparation of N-((3aS,7aS)-2-oxo-2,3,3a,7a-tetrahydrobenzofuran-3a-yl)acetamide (2.41) ...121

A.6 Preparation of N-((2aR,2a1S,3S,5aS)-3-(tert-butyldiphenylsilyloxy)-7-oxo-2a,2a1,3,5a,6,7-

hexahydroindeno[1,7-cd]isoxazol-5a-yl)acetamide (2.43) .......................................................122

A.7 Preparation of N-((3aS,7aS,E)-2-(nitromethylene)-2,3,3a,7a-tetrahydrobenzofuran-3a-

yl)acetamide (2.44) ...................................................................................................................123

A.8 Preparation of N-((1r,4r)-1-(2-(tert-butyldimethylsilyloxy)-3-nitropropyl)-4-(tert-

butyldiphenylsilyloxy)cyclohexa-2,5-dienyl)acetamide (2.46) diastereomers .........................124

A.9 Preparation of compounds 2.49, 2.50, 2.51 and 2.52 ................................................................125

A.9.1 Compound 2.49 ....................................................................................................................126

A.9.2 Compound 2.50 ....................................................................................................................127

A.9.3 Compound 2.51/2.52 ............................................................................................................128

vi

A.10 Preparation of trans-9-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-2-methyl-3-nitro-1-

azaspiro[5.5]undeca-2,7,10-trien-4-one (2.55) .........................................................................129

A.11 Preparation of methyl 2-((1S,4S,5R,6S)-1-acetamido-4-(tert-butyldiphenylsilyloxy)-6-cyano-5-

hydroxycyclohex-2-enyl)acetate (2.59) ....................................................................................130

A.12 Preparation of N-((2aR,2a1S,3S,5aS)-3-hydroxy-7-oxo-2a,2a1,3,5a,6,7-hexahydroindeno[1,7-

cd]isoxazol-5a-yl)acetamide (2.60) ..........................................................................................131

A.13 Preparation of methyl 2-((1S,5R,6S)-1-acetamido-6-cyano-5-hydroxy-4-oxocyclohex-2-

enyl)acetate (2.62) ....................................................................................................................132

A.14 Preparation of N-((2aR,2a1S,3R,5aS)-3-(tert-butyldiphenylsilyloxy)-7-oxo-2a,2a1,3,5a,6,7-

hexahydroindeno[1,7-cd]isoxazol-5a-yl)acetamide (2.66) .......................................................133

A.15 Preparation of methyl 2-((1S,4R,5R,6S)-1-acetamido-4-(tert-butyldiphenylsilyloxy)-6-cyano-5-


A.16 Preparation of compounds 2.76-2.88 ............................................................................................136

A.16.1 Preparation of 3-(4-methoxyphenyl)-5-phenyl-4,5-dihydroisoxazole (2.76) .......................136

A.16.2 Preparation of 3,5-diphenyl-4,5-dihydroisoxazole (2.77) ....................................................137

A.16.3 Preparation of 3-(3-nitrophenyl)-5-phenyl-4,5-dihydroisoxazole (2.78) .............................138

A.16.4 Preparation of 3-pentyl-5-phenyl-4,5-dihydroisoxazole (2.79) ............................................139

A.16.5 Preparation of 3-phenethyl-5-phenyl-4,5-dihydroisoxazole (2.80) ......................................140

A.16.6 Preparation of 3a,4,5,6,7,7a-hexahydro-3-phenyl-4,7-methano-1,2-benzisoxazole (2.81) ..141

A.16.7 Preparation of 3a,4,5,6,7,7a-hexahydro-3-(3-nitrophenyl)-4,7-methano-1,2-benzisoxazole

(2.82) ....................................................................................................................................142

A.16.8 Preparation of 3a,4,5,6,7,7a-hexahydro-3-pentyl-4,7-methano-1,2-benzisoxazole (2.83) ...143

A.16.9 Preparation of 3a,4,5,6,7,7a-hexahydro-3-(2-phenylethyl)-4,7-methano-1,2-benzisoxazole

(2.84) ....................................................................................................................................144

A.16.10 Preparation of 3-(1,1-dimethylethyl)-3a,4,5,6,7,7a-hexahydro4,7-methano-1,2-

benzisoxazole (2.85) .............................................................................................................145

A.16.11 Preparation of 3a,4,5,6,7,7a-hexahydro-3-(4-methoxyphenyl)-4,7-methano-1,2-

benzisoxazole (2.86) .............................................................................................................146

A.16.12 Preparation of 5-(3-bromopropyl)-4,5-dihydro-3-phenyl-isoxazole (2.87) .......................147

A.16.13 Preparation of 3,5-diphenylisoxazole (2.88) ......................................................................148

A.17 Preparation of 1-(3a,4,5,6,7,7a-hexahydro-4,7-methano-1,2-benzisoxazol-3-yl)-ethanone (2.90)

..................................................................................................................................................149

A.18 Preparation of 1-(4,5-dihydro-5-phenyl-3-isoxazolyl)-ethanone (2.91) ....................................150

A.19 Preparation of 3a,4,5,6,7,7a-hexahydro-4,7-methano-1,2-benzisoxazole-3-carboxylic acid ethyl

ester (2.93) ................................................................................................................................151

A.20 Preparation of 4,5-dihydro-5-phenyl-3-isoxazolecarboxylic acid ethyl ester (2.94) .................153

A.21 Preparation of 2-isonitrosocyclopentanone (2.100) ...................................................................155

A.22 Preparation of compound 2.101 ................................................................................................156

vii

A.23 Preparation of methyl 4-(5-phenyl-4,5-dihydroisoxazol-3-yl)butanoate (2.102) ......................157

A.24 Preparation of 2-isonitrosocyclohexanone (2.103) ....................................................................158

A.25 Preparation of compound 2.104 ................................................................................................159

A.26 Preparation of methyl 5-(5-phenyl-4,5-dihydroisoxazol-3-yl)pentanoate (2.105) ....................160

A.27 Preparation of 3-(hydroxyimino)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one (2.106) .............161

A.28 Preparation of compounds 2.107/2.108 .....................................................................................162

A.29 Preparation of (1S,3R)-methyl 1,2,2-trimethyl-3-(5-phenyl-4,5-dihydroisoxazol-3-yl)

cyclopentanecarboxylate (2.109/2.110) ....................................................................................163

A.30 Preparation of 3,7-dimethyl-6-octenoxime (2.111) ...................................................................164

A.31 Preparation of (6S)-3,3a,4,5,6,7-hexahydro-3,3,6-trimethyl-2,1-benzisoxazole (2.112) ..........165

A.32 Preparation of 4-hydroxy-benzenepropanal oxime (2.123) .......................................................166

A.33 Preparation of N-[(4aR,7aS,7bR)-3,4,7a,7b-tetrahydro-7-oxoindeno[1,7-cd]isoxazol-4a(7H)-yl]-

acetamide (2.124) .....................................................................................................................167

A.34 Preparation of 4,4a,7a,7b-tetrahydro-4a-methoxy-indeno[1,7-cd]isoxazol-7(3H)-one (2.125) 168

A.35 Preparation of N-benzyl, N-tosyl tyrosine (2.130) ....................................................................169

A.36 Preparation of N-[2-(hydroxyimino)-1-[(4-hydroxyphenyl)methyl]ethyl]-4-methyl-N-

(phenylmethyl)-benzenesulfonamide (2.132) ...........................................................................171

A.37 Preparation of N-[(3R,4aR,7aS,7bR)-3,4,7a,7b-tetrahydro-3-[[(4-methylphenyl)sulfonyl]

(phenylmethyl)amino]-7-oxoindeno[1,7-cd]isoxazol-4a(7H)-yl]-acetamide (2.134) ..............173

B. Experimental section ................................................................................................................174

B.1 1H-NMR spectrum and

13C-NMR spectrum for: methyl 2-(1-acetamido-4-oxocyclohexa-2,5-

dienyl)acetate (2.32) .................................................................................................................174


13C-NMR spectrum for: methyl 2-((1r,4r)-1-acetamido-4-(tert-

butyldiphenylsilyloxy)cyclohexa-2,5-dienyl)acetate (2.37) .....................................................175


13C-NMR spectrum for: 2-((1r,4r)-1-acetamido-4-(tert-

butyldiphenylsilyloxy)cyclohexa-2,5-dienyl)acetic acid (2.38) ...............................................176


13C-NMR spectrum for: N-((1r,4r)-4-(tert-butyldiphenylsilyloxy)-1-(3-

nitro-2-oxopropyl)cyclohexa-2,5-dienyl)acetamide (2.39) ......................................................177


13C-NMR spectrum for: N-((3aS,7aS)-2-oxo-2,3,3a,7a-

tetrahydrobenzofuran-3a-yl)acetamide (2.41) ..........................................................................178


13C-NMR spectrum for: N-((2aR,2a1S,3S,5aS)-3-(tert-

butyldiphenylsilyloxy)-7-oxo-2a,2a1,3,5a,6,7-hexahydroindeno[1,7-cd]isoxazol-5a-

yl)acetamide (2.43) ...................................................................................................................179


13C-NMR spectrum for: N-((3aS,7aS,E)-2-(nitromethylene)-2,3,3a,7a-

tetrahydrobenzofuran-3a-yl)acetamide (2.44) ..........................................................................180


13C-NMR spectrum for: N-((1r,4r)-1-(2-(tert-butyldimethylsilyloxy)-3-

nitropropyl)-4-(tert-butyldiphenylsilyloxy)cyclohexa-2,5-dienyl)acetamide (2.46) ................181

B.9 1H-NMR spectrum for: compound 2.49 ....................................................................................182

viii


13C-NMR spectrum for: compound 2.50 .............................................183

B.11 1H-NMR spectrum for: compound 2.51/2.52 ............................................................................184


13C-NMR spectrum for: trans-9-[[(1,1-

dimethylethyl)diphenylsilyl]oxy]-2-methyl-3-nitro-1-azaspiro[5.5]undeca-2,7,10-trien-4-one

(2.55) ........................................................................................................................................185


13C-NMR spectrum for: methyl 2-((1S,4S,5R,6S)-1-acetamido-4-(tert-

butyldiphenylsilyloxy)-6-cyano-5-hydroxycyclohex-2-enyl)acetate (2.59) .............................186


13C-NMR spectrum for: N-((2aR,2a1S,3S,5aS)-3-hydroxy-7-oxo-

2a,2a1,3,5a,6,7-hexahydroindeno[1,7-cd]isoxazol-5a-yl)acetamide (2.60) .............................187


13C-NMR spectrum for: methyl 2-((1S,5R,6S)-1-acetamido-6-cyano-5-

hydroxy-4-oxocyclohex-2-enyl)acetate (2.62) .........................................................................188

B.16 1H-NMR spectrum for: N-((2aR,2a1S,3R,5aS)-3-(tert-butyldiphenylsilyloxy)-7-oxo-

2a,2a1,3,5a,6,7-hexahydroindeno[1,7-cd]isoxazol-5a-yl)acetamide (2.66) .............................189


13C-NMR spectrum for: methyl 2-((1S,4R,5R,6S)-1-acetamido-4-(tert-

butyldiphenylsilyloxy)-6-cyano-5-hydroxycyclohex-2-enyl)acetate (2.67) .............................190


13C-NMR spectrum for: 3-(4-methoxyphenyl)-5-phenyl-4,5-

dihydroisoxazole (2.76) ............................................................................................................191


13C-NMR spectrum for: 3,5-diphenyl-4,5-dihydroisoxazole (2.77) ....192


13C-NMR spectrum for: 3-(3-nitrophenyl)-5-phenyl-4,5-

dihydroisoxazole (2.78) ............................................................................................................193


13C-NMR spectrum for: 3-pentyl-5-phenyl-4,5-dihydroisoxazole (2.79)

..................................................................................................................................................194


13C-NMR spectrum for: 3-phenethyl-5-phenyl-4,5-dihydroisoxazole

(2.80) ........................................................................................................................................195


13C-NMR spectrum for: 3a,4,5,6,7,7a-hexahydro-3-phenyl-4,7-

methano-1,2-benzisoxazole (2.81) ...........................................................................................196


13C-NMR spectrum for: 3a,4,5,6,7,7a-hexahydro-3-(3-nitrophenyl)-4,7-



13C-NMR spectrum for: 3a,4,5,6,7,7a-hexahydro-3-pentyl-4,7-methano-

1,2-benzisoxazole (2.83) ..........................................................................................................198

B.26 1H-NMR spe ctrum and

13C-NMR spectrum for: 3a,4,5,6,7,7a-hexahydro-3-(2-phenylethyl)-4,7-



13C-NMR spectrum for: 3-(1,1-dimethylethyl)-3a,4,5,6,7,7a-

hexahydro4,7-methano-1,2-benzisoxazole (2.85) ....................................................................200


13C-NMR spectrum for: 3a,4,5,6,7,7a-hexahydro-3-(4-methoxyphenyl)-

4,7-methano-1,2-benzisoxazole (2.86) .....................................................................................201


13C-NMR spectrum for: 5-(3-bromopropyl)-4,5-dihydro-3-phenyl-

isoxazole (2.87) ........................................................................................................................202


13C-NMR spectrum for: 3,5-diphenylisoxazole (2.88) ........................203

ix


13C-NMR spectrum for: 1-(3a,4,5,6,7,7a-hexahydro-4,7-methano-1,2-

benzisoxazol-3-yl)-ethanone (2.90) ..........................................................................................204


13C-NMR spectrum for: 1-(4,5-dihydro-5-phenyl-3-isoxazolyl)-

ethanone (2.91) .........................................................................................................................205


13C-NMR spectrum for: 3a,4,5,6,7,7a-hexahydro-4,7-methano-1,2-

benzisoxazole-3-carboxylic acid ethyl ester (2.93) ..................................................................206


13C-NMR spectrum for: 4,5-dihydro-5-phenyl-3-isoxazolecarboxylic

acid ethyl ester (2.94) ...............................................................................................................207


13C-NMR spectrum for: 2-isonitrosocyclopentanone (2.100) .............208


13C-NMR spectrum for: compound 2.101 ...........................................209


13C-NMR spectrum for: methyl 4-(5-phenyl-4,5-dihydroisoxazol-3-

yl)butanoate (2.102) .................................................................................................................210


13C-NMR spectrum for: 2-isonitrosocyclohexanone (2.103)...............211


13C-NMR spectrum for: compound 2.104 ...........................................212



yl)pentanoate (2.105) ................................................................................................................213


13C-NMR spectrum for: compounds 2.107/2.108 ................................214


13C-NMR spectrum for: (1S,3R)-methyl 1,2,2-trimethyl-3-(5-phenyl-

4,5-dihydroisoxazol-3-yl) cyclopentanecarboxylate (2.109/2.110) ..........................................215


13C-NMR spectrum for: diastereomers (6S)-3,3a,4,5,6,7-hexahydro-

3,3,6-trimethyl-2,1-benzisoxazole (2.112) ...............................................................................216


13C-NMR spectrum for: major diastereomer (6S)-3,3a,4,5,6,7-

hexahydro-3,3,6-trimethyl-2,1-benzisoxazole (2.112) .............................................................217


13C-NMR spectrum for: N-[(4aR,7aS,7bR)-3,4,7a,7b-tetrahydro-7-

oxoindeno[1,7-cd]isoxazol-4a(7H)-yl]-acetamide (2.124) .......................................................218


13C-NMR spectrum for: 4,4a,7a,7b-tetrahydro-4a-methoxy-indeno[1,7-

cd]isoxazol-7(3H)-one (2.125) .................................................................................................219


13C-NMR spectrum for: N-benzyl, N-tosyl tyrosine (2.130) ...............220


13C-NMR spectrum for: N-[2-(hydroxyimino)-1-[(4-

hydroxyphenyl)methyl]ethyl]-4-methyl-N-(phenylmethyl)-benzenesulfonamide (2.132) ......221


13C-NMR spectrum for: N-[(3R,4aR,7aS,7bR)-3,4,7a,7b-tetrahydro-3-

[[(4-methylphenyl)sulfonyl](phenylmethyl)amino]-7-oxoindeno[1,7-cd]isoxazol-4a(7H)-yl]-

acetamide (2.134) .....................................................................................................................222

C. X-ray crystallography data .......................................................................................................223

C.1 X-ray data of methyl 2-(1-acetamido-4-oxocyclohexa-2,5-dienyl)acetate (2.32) .....................223

C.2 X-ray data of N-((3aS,7aS,E)-2-(nitromethylene)-2,3,3a,7a-tetrahydrobenzofuran-3a-

yl)acetamide (2.44) ...................................................................................................................229

C.3 X-ray data of N-((2aR,2a1S,3S,5aS,7R)-3,7-dihydroxy-2a,2a1,3,5a,6,7-hexahydroindeno[1,7-

cd]isoxazol-5a-yl)acetamide (2.53) ..........................................................................................235

x

C.4 X-ray data of trans-9-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-2-methyl-3-nitro-1-

azaspiro[5.5]undeca-2,7,10-trien-4-one (2.55) .........................................................................243

C.5 X-ray data of methyl 2-((1S,4R,5R,6S)-1-acetamido-4-(tert-butyldiphenylsilyloxy)-6-cyano-5-


C.6 X-ray data of N-[(4aR,7aS,7bR)-3,4,7a,7b-tetrahydro-7-oxoindeno[1,7-cd]isoxazol-4a(7H)-yl]-

acetamide (2.124) .....................................................................................................................265

xi

List of tables

Table 2.1. Optimization of scalable conditions for bimolecular oxidative amidation. ..............................59

Table 2.2. Larger-scale reproducible conditions for oxidative amidation of phenol 2.31 with acetonitrile.

.....................................................................................................................................................................60

Table 2.3. Reduction of dienone 2.32. .......................................................................................................62

Table 2.4. Initial attempts to dehydrate nitroketone 2.39. .........................................................................65

Table 2.5. Nitroketone 2.39 dehydration optimization. .............................................................................69

Table 2.6. Refinements to [3+2] cycloaddition conditions. .......................................................................70

Table 2.7. Optimization of tricycle 2.43 fragmentation. ............................................................................74

Table 2.8. DIB-mediated bimolecular [3+2] dipolar cycloaddition: optimization studies. .......................84

Table 2.9. DIB-mediated bimolecular [3+2] dipolar cycloaddition: substrate scope. ...............................86

Table 2.10. DIB-mediated bimolecular [3+2] dipolar cycloaddition: optimization studies. .....................87

Table 2.11. DIB-mediated oxidation of -oxo-aldoximes 2.89 and 2.92. .................................................88

Table 2.13. DIB-mediated oxidation of -oxo-ketoximes. .......................................................................92

xii

List of figures

Figure 1.1. The structure of (−)-tetrodotoxin (TTX). ..................................................................................1

Figure 1.2. Orthoester-lactone equilibrium. ................................................................................................3

Figure 1.3. Method of extracting tetrodotoxin.21

.........................................................................................3

Figure 1.4. Some tetrodotoxin derivatives found in nature36

. ......................................................................4

Figure 1.5. Possible TTX biosynthetic pathway. .........................................................................................5

Figure 1.6. Sodium channel inhibitors: tetrodotoxin, saxitoxin and gonyautoxin 3. ...................................6

Figure 1.7. Kishi’s retrosynthetic analysis. .................................................................................................7

Figure 1.7. Isobe’s deoxy tetrodotoxin analogs. ........................................................................................11

Figure 1.8. Isobe’s (−)-tetrodotoxin retrosynthetic rationale from 2-acetoxy-tri-O-acetyl-D-glucal. .......12

Figure 1.9. Isobe’s (−)-tetrodotoxin retrosynthetic rationale from levoglucosenone and isoprene. ..........17

Figure 1.10. Isobe’s updated C-11 hydroxylation and comparison to 1.43. ..............................................22

Figure 1.11. Du Bois’ tetrodotoxin retrosynthetic analysis. ......................................................................23

Figure 1.12. Sato’s retrosynthetic analysis for (±)-tetrodotoxin from myo-inositol. .................................27

Figure 1.13. Sato’s (−)-tetrodotoxin retrosynthetic analysis. ....................................................................30

Figure 1.14. Sato’s updated retrosynthetic analysis for (−)-tetrodotoxin intermediate 1.84. ....................32

Figure 1.15. Funabashi’s retrosynthetic approach to (−)-tetrodotoxin. .....................................................34

Figure 1.16. Fraser-Reid’s retrosynthetic considerations. .........................................................................37

Figure 1.17. Fukuyama’s TTX-core synthon 1.147. .................................................................................43

Figure 1.18. Ohfune’s approach to (−)-tetrodotoxin. ................................................................................46

Figure 1.19. Comparison of retrosynthetic intermediates between completed total syntheses to date......49

Figure 2.1. Retrosynthetic hypothesis for tetrodotoxin. ............................................................................50

Figure 2.2. Generalized strategy for the elaboration of the tetrodotoxin core. ..........................................51

Figure 2.3. Our elaborated tetrodotoxin retrosynthetic analysis. ...............................................................52

Figure 2.4. Oxidative amidation of para-phenols. ....................................................................................53

Figure 2.5. Oxidative amidation of para-phenols. ....................................................................................53

Figure 2.6. Kikugawa-Glover-type reactions. ...........................................................................................54

Figure 2.7. Structures of FR901483 and TAN1251C and Ciufolini’s retrosynthetic logic for the

construction of their ring systems. ...............................................................................................................55

Figure 2.8. Sorensen’s144,145

and Honda’s146-148

oxidative cyclization of phenolic secondary amines. .....55

Figure 2.9. Ciufolini modes of oxidative amidation of phenols. ...............................................................56

Figure 2.10. Possible DIB-mediated bimolecular oxidative amidation mechanism. .................................57

Figure 2.11. Effect of phenol concentration on reaction outcome. ............................................................58

Figure 2.12. Desymmetrization of dienone 2.8. ........................................................................................61

xiii

Figure 2.13. Theoretical dehydration of nitroketone 2.39. ........................................................................64

Figure 2.14. Nitrile oxide [3+2] dipolar cycloaddition..............................................................................64

Figure 2.15. Torssell cyclization: silyl nitronates as 1,3-dipoles...............................................................67

Figure 2.16. Probable enolization of nitroketone 2.39 can inhibit [3+2] cyclization. ...............................72

Figure 2.17. All cis-relationship of compound 2.43. .................................................................................72

Figure 2.18. Comparison of prepared enone 2.62 to proposed tetrodotoxin retron 2.5. ............................75

Figure 2.19. Rationale for expected (but not observed) rate difference between nitroketones 2.39/2.65. 77

Figure 2.20. X-ray image of crystalline 2.67 and rationalization of expected facial selectivity. ..............78

Figure 2.21. Comparison of 1H-NMR: olefin osmylation. ........................................................................80

Figure 2.22. 1H-NMR couplings for 2.68. .................................................................................................81

Figure 2.23. Comparison of advanced intermediate 2.68 with TTX retron 1.170. ....................................81

Figure 2.24. Dimerization of nitrile oxides. ..............................................................................................82

Figure 2.25. Conversion of oximes to nitrile oxides and subsequent trapping. .........................................83

Figure 2.26. Predicted course of the DIB oxidation of -oxo-ketoximes. ................................................89

Figure 2.27. Hypothetical tandem oxidative amidation-intramolecular nitrile oxide cycloaddition. ........95

Figure 2.28. Predicted course of the INOC reaction. ................................................................................99

Figure 2.28. NOe NMR spectral expansion of 2.134. .............................................................................102

xiv

List of schemes

Scheme 1.1. Kishi’s Diels-Alder and Beckmann transformations. ..............................................................8

Scheme 1.2. Kishi’s installation of C-11 and C-6 oxygen atoms. ...............................................................8

Scheme 1.3. Installation of C-9 -acetoxy moiety. .....................................................................................9

Scheme 1.4. Baeyer-Villiger oxidation and intramolecular epoxide-opening cyclization. ..........................9

Scheme 1.5. Kishi’s (±)-tetrodotoxin end game strategy. ............................................................................9

Scheme 1.6. Isobe’s cyclohexane skeleton synthesis: Sonogashira coupling and Claisen rearrangement.

.....................................................................................................................................................................13

Scheme 1.7. Isobe’s cyclohexane skeleton synthesis: C-5 and C-11 hydroxyl installation. ......................14

Scheme 1.8. Isobe’s cyclohexane skeleton synthesis: cyclohexanone and exo-olefin installation. ...........14

Scheme 1.9. Isobe’s introduction of nitrogen through intramolecular conjugate addition. .......................15

Scheme 1.10. Isobe’s stereoselective lactone formation. ...........................................................................16

Scheme 1.11. Isobe’s introduction of the guanidine moiety and completion of the total synthesis. .........17

Scheme 1.12. Isobe’s carbocyclic core formation. ....................................................................................18

Scheme 1.13. Isobe’s use of the Overman rearrangement. ........................................................................18

Scheme 1.14. Isobe’s C-8 oxygenation sequence. .....................................................................................18

Scheme 1.15. Isobe’s inversion of C-8 and oxygenation at C-7. ...............................................................19

Scheme 1.16. Isobe’s C-11/C-6 oxygenation sequence and addition of the C-10 acetylide group. ..........19

Scheme 1.17. Isobe’s epoxide-opening cyclization. ..................................................................................20

Scheme 1.18. Isobe’s ortho lactonization and end-game strategy. ............................................................21

Scheme 1.19. Du Bois’ Rh-carbenoid C-H insertion. ................................................................................24

Scheme 1.20. Du Bois’ methylenation. ......................................................................................................24

Scheme 1.21. Du Bois’ allylic oxidation and establishment of C-4a and C-5 configurations. ..................25

Scheme 1.22. Du Bois’ Rh-catalyzed nitrene C-H insertion and guanidine formation. ............................26

Scheme 1.23. Sato’s setup for spiro -chloroepoxide formation. ..............................................................28

Scheme 1.24. Sato’s -chloroepoxide formation and azide ion-mediated ring-opening. ..........................28

Scheme 1.25. Sato’s end game strategy: lactone/orthoester formation, guanidine formation. ..................29

Scheme 1.26. Sato’s synthesis of nitro cyclitol 1.93 employing an intramolecular Henry reaction. .........31

Scheme 1.27. Sato’s McMurry-Nef transformation to common intermediate 1.90. ..................................31

Scheme 1.28. Sato’s Ferrier(II) sequence to common intermediate 1.90. .................................................33

Scheme 1.29. Funabashi’s approach to (−)-tetrodotoxin. ..........................................................................34

Scheme 1.30. Sato’s early independent work on (−)-tetrodotoxin. ............................................................35

Scheme 1.31. Keana’s most advanced tetrodotoxin intermediate. .............................................................36

xv

Scheme 1.32. Fraser-Reid’s synthesis of dioxadamantane core 1.129 via D-mannosan. ..........................38

Scheme 1.33. Fraser-Reid’s synthesis of advanced intermediate 1.134. ...................................................39

Scheme 1.34. Alonso’s radical-cyclization approach. ...............................................................................40

Scheme 1.35. Taber’s C-H insertion strategy. ...........................................................................................42

Scheme 1.36. Fukuyama’s route to diiodo 1.152 enroute to 1.147. ...........................................................43

Scheme 1.37. Fukuyama’s racemic route to TTX core synthon 1.147. .....................................................45

Scheme 1.38. Ohfune’s approach to C-5, 6, 7, 11 tetraol system in (−)-tetrodotoxin. ..............................47

Scheme 2.1. Initial conditions for bimolecular oxidative amidation.153

.....................................................57

Scheme 2.2. Synthesis of nitroketone 2.39. ...............................................................................................63

Scheme 2.3. Undesired cyclization reaction of intermediate 2.40/2.38. ....................................................63

Scheme 2.4. An undesired reaction of nitroketone intermediate 2.39. ......................................................65

Scheme 2.5. Reduction/protection sequence of nitroketone 2.39. .............................................................66

Scheme 2.6. [3+2]-dipolar cycloaddition of 2.46. .....................................................................................67

Scheme 2.7. Confirmation of structural geometry: X-ray crystallographic analysis of 2.53. ....................68

Scheme 2.8. Unusual Knoevenagel-type condensation of nitroketone 2.39. .............................................69

Scheme 2.9. Optimized conditions for dehydration of nitroketone 2.39. ..................................................71

Scheme 2.10. Ring-fragmentation and comparison to Kemp-elimination188-190

products. .........................73

Scheme 2.11. Kemp-type fragmentation: methanolysis of tricycle 2.43. ..................................................74

Scheme 2.12. Fragmentation sequence: conversion of 2.43 to desymmetrized enone 2.62. .....................75

Scheme 2.13. Synthesis of nitroketones 2.39 and 2.65. .............................................................................76

Scheme 2.14. Synthesis of tricycles 2.43 and 2.66. ...................................................................................77

Scheme 2.15. Methanolysis of tricycle 2.66. .............................................................................................78

Scheme 2.16. Osmylation sequence. ..........................................................................................................79

Scheme 2.17. Dimerization of oxime 2.73. ................................................................................................83

Scheme 2.18. The first intramolecular variant. ..........................................................................................93

Scheme 2.19. Other intramolecular variants from Ciufolini group. ...........................................................94

Scheme 2.20. The synthesis of oxime 2.123. .............................................................................................96

Scheme 2.21. Tandem oxidative amidation—INOC. ................................................................................96

Scheme 2.22. Tandem oxidative methoxylation—INOC. .........................................................................97

Scheme 2.23. Sorensen’s use of tandem oxidative dearomatization—INOC towards the cortistatin

pentacyclic core. ..........................................................................................................................................98

Scheme 2.24. Synthesis of oxime 2.132. ..................................................................................................100

Scheme 2.25. Diastereoselective tandem oxidative amidation—INOC. .................................................101

xvi

List of abbreviations

1D one-dimensional

2D two-dimensional

[]20

D specific rotation at 20 °C and wavelength of sodium D line

[O] oxidation

(S)-CBS (S)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2c][1,3,2]oxazaborole

°C degrees centigrade

AB AB system

ABq AB quartet

Ac acetyl

acac acetylacetonate

AcOH acetic acid

AIBN azobisisobutyronitrile

Alloc allyloxycarbonyl

aq aqueous

B.C.E. before the common era

Bn benzyl

BRSM/brsm based on recovered starting material

Boc tert-butyloxycarbonyl

Boc2O di-tert-butyl-pyrocarbonate

BOM benzyloxymethyl

Bz benzoyl

c concentration

calcd calculated

cat. catalytic

cf. confer

CDI carbonyldiimidazole

cm-1

inverse centimeter/wavenumber

d deuterio

xvii

d / dd / ddd doublet / doublet of doublets / doublet of doublet of doublets

chemical shift

DBU 1,8-diazabicycloundec-7-ene

dd doublet of doublets

DIB diacetoxy iodobenzene (iodobenzene diacetate)

DIBAL diisobutyl aluminum

DMAP 4-(N,N-dimethylamino)-pyridine

DMF dimethylformamide

DMSO dimethyl sulfoxide

CAN cerium ammonium nitrate

CSA camphor sulfonic acid

EDC 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide

Et ethyl

etc. et cetera

eq equivalents

g gram

G a generic group (see associated text)

GTX gonyautoxin

h hour(s)

HFIP 1,1,1,3,3,3-hexafluoroisopropanol

HRMS high-resolution mass spectrometry

Hz hertz

IBX 2-iodoxybenzoic acid

IC50 half maximal inhibitory concentration

IDCP iodonium dicollidine perchlorate

INOC intramolecular nitrile oxide-olefin cycloaddition

ISOC intramolecular siloxynitronate-olefin cycloaddition

iPr isopropyl

J coupling constant

Jaa axial-axial coupling constant

xviii

Jae axial-equatorial coupling constant

kg kilogram

L liter

L generic sterically demanding group (see text)

LD50 oral median lethal dose

LDA lithium diisopropylamine

LRMS low-resolution mass spectrometry

M molar

m multiplet

mCPBA meta-chloroperoxybenzoic acid

Me methyl

mg milligram

MHz megahertz

min minute

mL milliliter

MMTr 4-monomethoxytrityl

mol mole

mmol millimole

MOM methoxymethyl

MP melting point

Ms mesyl (methane sulfonyl)

n an integer (0, 1, 2, etc.)

nBu normal butyl (linear butyl)

NBS N-bromosuccinimide

NCS N-chlorosuccinimide

NIS N-iodosuccinimide

NMO N-methyl morpholine oxide

NMR nuclear magnetic resonance

NOe/nOe nuclear Overhauser effect

NOESY nuclear Overhauser effect spectroscopy

xix

Nu generic nucleophile (see text)

o ortho

ON overnight (12-16 h)

P generic protecting group (see text)

p para

PCC pyridinium chlorochromate

Ph phenyl

Pht phthalate

PIFA phenyliodine bis(trifluoroacetate)

Piv pivaloyl

PMB para-methoxy benzyl

ppm parts per million

PPTS pyridinium toluene-4-sulphonate

psi pounds per square inch

PTSA/p-TsOH para-toluene sulfonic acid

PyBOP benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate

q quartet

R generic functional group (defined in text)

rt room temperature

s singlet

s seconds

S-H generic solvent

SM reaction starting material

SN2’ bimolecular nucleophilic substitution

STX saxitoxin

t triplet

TBAF tetrabutylammonium fluoride

TBHT di-tert-butyl hyponitrite

TBS tert-butyldimethylsilyl

TBDPS tert-butyldiphenylsilyl

xx

tBu tert-butyl

TEA triethylamine

TEMPO 2,2,6,6-tetramethylpiperidine-1-oxyl

TES triethylsilyl

Tf triflyl/triflate

TFA trifluoroacetic acid

TFAA trifluoroacetic acid anhydride

TFE trifluoroethanol

THF tetrahydrofuran

TLC thin-layer chromatography

TMS trimethylsilyl

TPAP tetrapropylammonium perruthenate

Ts tosyl

TTX tetrodotoxin

g microgram

mol micromole

L microliter

v/v volume per volume

w/ with

w/o without

xxi

Acknowledgements

There is no doubt that this dissertation could not have been possible without the guidance of my

advisor, Professor Marco A. Ciufolini. I owe him many thanks for allowing me to join his laboratory and

giving me a great deal of intellectual freedom on my research endeavors. While many days were

difficult, these times taught me patience and I am grateful for his guidance.

I would also like to thank the members of my advisory committee: Professor Jennifer A. Love,

Professor Michael D. Fryzuk and most especially my second reader Professor Gregory R. Dake. Thank

you for your sagacious advice and discussions over the past five years. I would also like to acknowledge

Graduate Advisor Professor Chris Orvig for his support. The UBC Chemistry Department NMR staff

also was indispensable due to their help and advice in setting up NMR experiments, and thanks go out to

Dr. Nick Burlinson, Dr. Maria B. Ezhova, and Zorana Danilovic. Many thanks also go to Brian

Ditchburn for the many last-minute glassware repairs and many hours spent introducing me to (the art of)

glassblowing.

I have had the pleasure to work in Ciufolini group with some exceptional undergraduate students,

graduate students and post-doctoral researchers. I would like to thank especially Tim Jen, Simon J. Kim,

Srini Masuna, Bhaskar Reddy, Virender S. Aulakh, Bryan Chan, Dylan Turner, Jaclyn Chau, Kam Ho

and Catherine Diering for their friendship and camaraderie. I would also like to acknowledge Dr. Josh

Zaifman and Dr. Mathew Smith for their careful proof-reading of my thesis manuscript.

My Ph.D. work was not possible without the love and support of my Mom and Dad. Thank you

for always listening to me, even when you had no idea what I was talking about.

Finally, I would like to thank my wife Lynne. You are my best friend and my staunchest

supporter. With you, life and all things are much more meaningful.

1

1 Introduction

1.1 Tetrodotoxin

Tetrodotoxin (TTX, Figure 1.1) is recognized as one of the most poisonous non-protein

molecules known.1,2

With a long history traced back to ancient times, tetrodotoxin has left its mark on

Egyptian, Chinese and Haitian civilizations among others. Ancient Egyptian hieroglyphics of several

Fifth Dynasty (ca. 2700 B.C.E.) tombs clearly depict the poisonous tetrodotoxin-containing puffer

Tetraodon stallatus.3,4

An early Chinese record from the second century B.C.E., the Pen-T’so Chin (The

Herbal), lists the eggs of tetraodon (four tooth) fish among its drugs.5

Figure 1.1. The structure of (−)-tetrodotoxin (TTX).

Interestingly, and perhaps horrifyingly, tetrodotoxin poisoning renders the body in a low

metabolic state, yet the brain remains unaffected. Near lethal doses can leave a victim of tetrodotoxin

poisoning in a near-death state for days, while remaining conscious for the duration. Victims of

tetrodotoxin poisoning typically undergo feelings of numbness and weakness, followed by paralysis of

the limbs and chest muscles which typically leads to death by asphyxiation. Currently, there is no known

antidote; however, in vivo studies in mice have indicated possible treatment of tetrodotoxin poisoning

with a monoclonal antibody.6 Patients suffering tetrodotoxin poisoning are typically kept alive on

ventilators until they either recover, or do not. The oral median lethal dose (LD50) of tetrodotoxin in mice

is 334 g per kg.7 The lethal dose by injection is 8 g per kg, or about 0.5 mg for a 75 kg human

assuming the lethal dose is similar for humans and mice.8

2

Ethnobotanist Wade Davis alleged in the 1980s that tetrodotoxin-containing tissue from puffer

fish were an ingredient of Haitian voodooism.9 Davis claimed that the partial limb paralysis and other

symptoms of lethal and non-lethal doses of tetrodotoxin matched depictions of Haitian voodoo zombies,

especially recounts involving the burying of apparently dead victims followed later by exhumation and

revivification. Other scientific studies of modern-day Haitian zombie powders have indicated the

presence of tetrodotoxin.10

More recent analyses generally claim that folklore and stories of zombies

created in this manner differ from victims of tetrodotoxin poisoning11

and question the amount of

tetrodotoxin that can be administered transdermally in the form of a zombie powder. In modern-day

Japan, high-end sushi restaurants still offer carefully prepared puffer fish for adventurous patrons. When

prepared properly, consumption of puffer fish sushi results in tingling sensations of the lips and inner

mouth surfaces. When prepared incorrectly puffer fish consumption can result in death.

A century after its discovery, tetrodotoxin remains an ambitious and worthwhile target that

necessarily expands the envelope of current synthetic chemical technology, as evidenced by the large

amount of synthetic studies (Chapter 1.2). Efficient syntheses could lead to TTX analogues with varying

activities to further the understanding of voltage-gated sodium channels. The unique architecture of

tetrodotoxin has provided synthetic chemists with many opportunities to explore new reaction types and

procedures to piece together tetrodotoxin and analogues. The work described in this thesis details one

such path, as our approach to the tetrodotoxin core yielded new reaction types hitherto unexplored.

1.1.1 Isolation, characterization and natural occurrence

Tetrodotoxin remains a daring target for synthetic chemistry, not only due to its unprecedented

highly hydroxylated dioxa-adamantane structure (Figure 1.1), but also due to its extreme toxicity. It is

this toxicity that initially drove researchers to attempt isolation studies. In 1910, Japanese scientist

Yoshizumi Tahara published and patented complete isolation procedures and characterization

analyses.12,13

Though Tahara’s original extracts are now known to contain only trace quantities of

tetrodotoxin,4 it is remarkable that he was able to contribute as much knowledge as he did given the crude

equipment available during that era. It was not until 1950, well after the isolation of many plant alkaloids

(atropine, morphine and strychnine, etc.) and most vitamins (pantothenic acid and biotin, etc.) when

tetrodotoxin was isolated in pure form from the ovaries of the puffer fish.14

The abundantly available

pool of tetrodotoxin-containing fish spurred wide interest in its isolation and structure elucidation.

Complicating the structure determination of tetrodotoxin is the fact that the compound is zwitterionic,

highly polar (only soluble in aqueous acid) and exists in equilibrium between orthoester form 1.1 and

lactone form 1.2 (Figure 1.2).15

3

Figure 1.2. Orthoester-lactone equilibrium.

The structure of tetrodotoxin was determined through chemical degradations as well as x-ray

crystallographic studies of tetrodotoxin derivatives.1,15-17

In 1964, groups led by R. B. Woodward, H. S.

Mosher, K. Tsuda and T. Goto all reported the correct structure of tetrodotoxin in Kyoto at the Natural

Products Symposium of the International Union of Pure and Applied Chemistry. The absolute

configuration was elucidated via crystallographic studies a few years later.18

With pure crystalline

tetrodotoxin in hand, researchers began to isolate other tetrodotoxin-derivatives from various species of

Tetraodon fish.5,19,20

Recently, a United States patent was issued describing a new process for extracting

tetrodotoxin from the ovaries of the puffer fish.21

This invention doubles the yield of pure crystalline

tetrodotoxin (Figure 1.3).

Figure 1.3. Method of extracting tetrodotoxin.21

4

Tetrodotoxin is found in the tissues of several different animals throughout the world, including

species of puffer fish, trigger fish, gobies,22,23

parrotfish, blue-ringed octopodes (Hapalochlaena), moon

snails,24

sea stars,25

polyclad flatworms,26

nemerteans, xanthid crabs, frogs,27

western newts (Taricha)1

and other species.28

1.1.2 Tetrodotoxin biosynthesis

Puffer fish species grown in captivity do not contain detectable amounts of tetrodotoxin until they

are fed tissues from tetrodotoxin-containing fish.29-31

When tetrodotoxin-containing fish were fed

radiolabeled metabolic precursors (14

C-labeled acetate, arginine, citrulline and glucose), the fish failed to

produce any labeled tetrodotoxin, yet did produce common metabolites (cholesterol, amines, amino acids,

etc.) with 14

C incorporation.32

The elucidation of the biosynthesis of tetrodotoxin is an actively

researched area; current understanding is based upon analogy to other tetrodotoxin derivatives isolated

from various organisms (Figure 1.4).33-35

O

OH

O

OH

HO

NHHN

NH

HO

CH3

OH

11-deoxyTTX

O

OH

O

HO

NHHN

NH

HO

CH3

5,6,11-trideoxyTTX

O

OH

O

OH

HO

NHHN

NH

HO

OH

6-epi TTX

OH

O

OH

O

OH

HO

NHHN

NH

HO

CH3

6,11-dideoxyTTX

5-deoxyTTX

O

OH

O

HO

NHHN

NH

HOOH

OH

O

OH

O

OH

HO

NHHN

NH

HOOH

OH

TTX

11

654 4a 8

8a

7

10

9

Figure 1.4. Some tetrodotoxin derivatives found in nature36

.

Since tetrodotoxin is found in such a variety of different organisms, most of which are unrelated

phylogenically, and since studies of puffer fish and Taricha newts showed a lack of endogenous

tetrodotoxin production in these animals, it has been considered that tetrodotoxin found in these animals

comes from an exogenous source, perhaps through the food chain or the environment.37

Various studies38

have determined that tetrodotoxin is actually biosynthesized by various types of bacteria species

(Pseudoalteromonas tetraodonis28

certain species of Pseudomonas and Vibrio28

Serratia marcescens39

).

5

Little is known about the actual biosynthesis of TTX, but studies have indicated that TTX

precursors may come from the amino acid arginine,40

a known precursor for guanidinium functional

groups in natural products and a C5 isoprene unit (most probably isopentenyl diphosphate33

).41

The

currently accepted biosynthetic pathway is shown in Figure 1.5, yet this proposal has not been confirmed

conclusively.

arginine isopentenyl diphosphate

CH3

OP

OO

OH

P

O

OHOHHN

NH2

HN

H2NCO2H

HNNH2

HN

H2N CO2HCH3

OP

OO

OH

P

O

OHOH

+

TTX

Figure 1.5. Possible TTX biosynthetic pathway.

1.1.3 Voltage-gated sodium channels

The ability for rapid cell-to-cell communication is an important feature of living organisms.

Excitable cells communicate rapidly with one another through short-lived electrical potentials, known as

action potentials, across their membranes. Every neuron has a separation of charges across its membrane,

and at rest this potential is called the resting membrane potential. Electrical signals and transmissions all

involve a temporary disruption of this resting potential.42

The resting membrane potential is determined

by resting ion channels.

Neuronal cells generate action potentials via voltage gated ion channels embedded in the cell’s

plasma membrane.43

These ion channel proteins are closed when the voltage potential across the

membrane is near the resting potential of the cell, but they quickly open when the voltage potential is

raised above a threshold value. When the ion channels open, a rapid flux of ions across the membrane

occurs, resulting in a decrease in the charge separation (voltage) across the membrane (depolarization),

and the electrical signal propagates the length of the membrane. During depolarization, a rapid influx of

sodium ions causes the polarity of the membrane to reverse relative to the resting state, and this closes the

voltage-gated sodium channels. The lipid bilayer of a cell membrane is nearly impervious to the

movement of sodium ions, and thus the cell actively pumps these ions back across the lipid bilayer to

reset the cell for a future action potential. As sodium ions are pumped out of the cell, potassium channels

open to allow the influx of potassium ions into the cell, thus returning the cell to its resting potential.

6

1.1.4 TTX and naturally occurring voltage-gated sodium channel inhibitors

Tetrodotoxin, along with saxitoxin (STX), members of the gonyautoxin (GTX) family of

compounds (Figure 1.6) and the neurotoxic conotoxin peptides, binds tightly to the extracellular pore

opening of the voltage-gated sodium channels.2 Studies suggest that the guanidinium group acts as a

bioisostere for sodium ions, and binds like a plug partway into the sodium channel.44

Studies of TTX

derivatives (Figure 1.4) have indicated that important H-bonding interactions between the hydroxyl

groups and residues on the outside of the pore opening of the sodium channel exist, and are substantially

responsible for the binding to the sodium channel.45

Blockage of the sodium channel effectively

suppresses action potentials by stopping the influx of sodium ions. Sodium channels are transmembrane

proteins, and as such are difficult to isolate and characterize. Tetrodotoxin is an important

pharmacological tool for probing the structure and function of sodium channels.46

By isolating sodium

channel proteins, or protein fragments, structural information can be gleaned by checking for TTX

binding.47

tetrodotoxin

NH

N

OH

OH NH2

HO

OH

OO

O

OHH

H

saxitoxin gonyautoxin 3

N NH

NH2

HNNH

H2N

HO

HO

O3SOO

O NH2

N NH

NH2

HNNH

H2N

HO

HO O

O NH2

Figure 1.6. Sodium channel inhibitors: tetrodotoxin, saxitoxin and gonyautoxin 3.

In recent years, it has become apparent that small molecules capable of selective, partial blocking

of ion channel function may be useful therapeutic resources to combat a number of human diseases,48

such as Parkinson’s disease, and perhaps chronic pain management in terminally ill patients.49

7

1.2 Synthetic studies

1.2.1 Kishi’s total synthesis

The first total synthesis of racemic tetrodotoxin by Kishi in 1972 remains to this day a historic

conquest in synthetic chemistry, especially when considering the technologies available to his group at

the time.50-53

Kishi’s retrosynthetic analysis (Figure 1.7) features a number of well designed

transformations, including Baeyer-Villiger oxidation, intramolecular epoxide-opening cyclization, Lewis

acid mediated Diels-Alder chemistry and a Beckmann rearrangement. Central to this synthesis is Kishi’s

utilization of the bowl-like shape of the cis-decalin system to direct the stereochemistry of the subsequent

oxidation/reduction steps to complete the racemic synthesis.

H

AcHN

CH3

O

OCH3

O

ON

H3C

HO

(±)-tetrodotoxin

Baeyer-Villigeroxidation

intramolecularepoxide-opening

cyclization

Diels-Alder

Beckmann rearrangement

guanidineformation

orthoacidformation

4

4

4 4a4a

4a

4aNO

H

OO

OHOH

N

HOO

HH2N

HO

H

O

HO

HO

H

H

OAcN

OAc

OAcO

O

AcHN

AcHN OAc

4

4a

O

O NH

H

AcO OAc

O

OAc

Ac

ONH

H

AcO OAc

O

OAc

Ac

O

NH

H

AcO OAc

O

OAc

Ac

OO

O

4

4a

4

4a 6

7

6

76

7

8a

8a

8a

1.8 1.7 1.5

1.4

1.3

1.6

Figure 1.7. Kishi’s retrosynthetic analysis.

Kishi’s retrosynthetic disconnections, and those of nearly all of the other synthetic work in the

area, begin with the release of the guanidine functionality and formation of the orthoester. Woodward’s

pioneering elucidation work15

demonstrated the spontaneous ortholactonization of bridging lactones such

as 1.3. Kishi establishes both the trans-relationship between the C-6 and C-7 centers and the cis-

relationship between C-8a and C-7 via a trans-lactonization/intramolecular epoxide-opening cyclization

operation from 1.4. Seven-membered lactone 1.4 was generated through a Baeyer-Villiger oxidation

from the corresponding ketone 1.5 which derives from 1.6. The synthesis begins from cis-decalin 1.7,

which was produced from oxime 1.8 by Diels-Alder cycloaddition and Beckmann rearrangement.

8

O

OH3C

NHAc

H

NHAc

H3C

O

OH3C

O

O N

CH3

OH

SnCl4H

H3C

O

O

H3C N

OH

1) MsCl, Et3N 2) H2O, heat

4a

8a4a

8a

1.8 1.9 1.7

Scheme 1.1. Kishi’s Diels-Alder and Beckmann transformations.

Kishi began his synthesis (Scheme 1.1) from benzoquinone oxime 1.8 as a dienophile for a tin-

mediated Diels-Alder reaction with butadiene to give the cis-fused decalone 1.9 as the sole isomer. This

Diels-Alder reaction appeared to be the first example of a dienophile containing an oxime. Despite the

addition of Lewis acid SnCl4 to accelerate the reaction, the regioselectivity of the reaction was controlled

by the electron deficient oxime. Cycloadduct 1.9 was transformed into 1.7 through Beckmann

rearrangement, setting the C-8a carbinol center with the necessary geometry relative to C-4a by nature of

the cis-ring fusion.

O

OH3C

NHAc

1) NaBH4

2) mCPBA, CSA

NHAc

H3C

OOH

O

1) CrO3, pyridine

2) ethylene glycol, BF3•OEt2

NHAc

H3C

O

O

O

O

1) Al(OiPr)3

2) Ac2O, pyridine

NHAc

H3C

OO

O

OAc

H

1) mCPBA2) Ac2O3) TFA; Ac2O

NHAc

OO

O

OAc

H

1) SeO2 2) NaBH4

O

OAcNHAc

AcO

O

O

8a4a

58

8

8a5 4a

11

6

OH

8

8

6

1.7

1.10

11

Scheme 1.2. Kishi’s installation of C-11 and C-6 oxygen atoms.

Bicycle 1.7 was treated with a series of reduction/oxidation and epoxidation operations, utilizing

the facial bias of the cis-shaped ring fusion to stereoselectively generate the other stereogenic centers

around the cyclohexane skeleton (Scheme 1.2). The C-5 carbinol center, by virtue of the differing steric

environments between C-5 and C-8 ketones, was set through NaBH4 reduction and intramolecular

epoxide opening. The C-8 stereocenter was generated from a stereoselective Meerwein-Ponndorf-Verley

reduction, SeO2-mediated allylic oxidation set the C-11 hydroxyl, and mCPBA epoxidation from the -

face (convex side) installed the necessary oxygen functionality at C-6.

9

O

OAcNHAc

AcO

O

O1) (EtO)3CH, CSA; Ac2O

2) o-Cl2C6H4, heat O

OAcNHAc

AcO

O

OEt

1) mCPBA, K2CO3

2) AcOH, H2OO

OAcNHAc

AcO

O

O

OAc

1.10 1.11 1.5

9 9

Scheme 1.3. Installation of C-9 -acetoxy moiety.

Kishi then turned his attention to the installation of the -acetoxy moiety at C-9 (Scheme 1.3).

Treatment of 1.10 with CSA and triethyl orthoformate gave the corresponding diethyl ketal, which

eliminated after heating in dichlorobenzene to give enol ether 1.11. Another -directed stereoselective

mCPBA-mediated epoxidation generated the C-9 -acetoxy unit after opening the epoxide with aqueous

acetic acid. With 1.5 in hand, Baeyer-Villiger oxidation with mCPBA gave ring-expanded lactone 1.4

(Scheme 1.4). Lactone-ring opening of 1.4 with potassium acetate caused the resulting free-carboxylate

at C-10 to undergo an intramolecular epoxide-ring opening at C-7 giving 1.12. Acetylation of the C-6

hydroxyl moiety and thermal elimination gave 1.13 with the dihydrofuran serving as precursor to a C-4

aldehyde.

Scheme 1.4. Baeyer-Villiger oxidation and intramolecular epoxide-opening cyclization.

4

NO

H

OO

OHOH

N

HOO

HH2N

HO

HO

O

O AcO

NHAcOAc

OAcAcO

Et3OBF4, Na2CO3 O

O

O AcO

NH2OAc

OAcAcO

EtS SEt

NAc1)

2) AcNH2

3) NH3

OO

O AcO

NOAc

OAcAcO

NH2

NAc

1) OsO4 2) NaIO4 3) NH4OH

(±)-tetrodotoxin1.13 1.14 1.15

4 H

Scheme 1.5. Kishi’s (±)-tetrodotoxin end game strategy.

Scheme 1.5 outlines Kishi’s end game strategy. Treatment of 1.13 with Et3OBF4/Na2CO3

effected removal of the acetamide group afforded 1.14, and the monoacetylguanidine moiety was

installed in a three-step operation. Kishi completed the racemic tetrodotoxin synthesis in three additional

steps from 1.15. Dihydroxylation of the dihydrofuran with OsO4 followed by sodium periodate cleavage

10

of the resulting 1,2-diol unmasked the C-4 aldehyde. A final aminolysis of the acetyl groups with

NH4OH caused the formation of the orthoacid and guanidine and yielded racemic tetrodotoxin.

Kishi’s effective work in the construction of the tetrodotoxin core, and full elaboration to the

racemic natural product set a standard for three decades. Kishi’s racemic total synthesis was

accomplished in 32 linear steps and in 0.52% overall yield. Several elegant transformations were

employed, including an unusual Diels-Alder reaction with a dienophile containing an oxime. The

synthesis possesses a high degree of substrate control in the creation of the required stereocenters, all

stemming originally from cis-decalin 1.7. Kishi expertly used substrate-controlled hydride reductions,

stereospecific substrate-controlled epoxidations, carboxylate attack onto an epoxide and stereospecific

substrate-controlled epoxidation of enol ether. Kishi also developed a then-novel procedure for the

creation of the guanidine functionality that was used in several later syntheses of tetrodotoxin.

11

1.2.2 Isobe’s total synthesis and related studies

Before Isobe published his two asymmetric tetrodotoxin syntheses,54,55

his group worked on and

published the synthesis of several deoxy-analogues of tetrodotoxin (Figure 1.7).56-62

In 2003, Isobe

published the first asymmetric total synthesis of (−)-tetrodotoxin. His retrosynthetic analysis is described

in Figure 1.8 and differs significantly from not only his previous work on the deoxy-series of TTX

analogues, but also from his second asymmetric total synthesis of TTX,55

which was based upon his work

in the deoxy-series.

O

OH

O

OH

HO

NHHN

NH

HO

CH3

OH

11-deoxyTTX

O

OH

HO

NHHN

NH

HO

CH3

8,11-trideoxyTTX

O

OH

O

HO

NHHN

NH

HO

CH3

5,11-dideoxyTTX

OH

O

OH

Figure 1.7. Isobe’s deoxy tetrodotoxin analogs.

Isobe’s late stage guanidine formation and closing of the ortho acid closely mirror Kishi’s

approach (Chapter 1.2.1). Installation of the C-8 nitrogen functionality was planned to come from a

diastereoselective Overman rearrangement and the creation of the carbocycle through aldol chemistry.

12

(-)-tetrodotoxin

conjugateaddition

aldolcondensation

guanidineformation

Claisenrearrangement

Sonogashira

NO

H

OO

OHOH

N

HOO

HH2N

HO

H

O

O

O

CH3

CH3

H HN

OBOM

COCCl3AcO

BzO

O

O

CH3

CH3

H

OBOM

BzO

OH

TBDPSO

O

O

TBDPSO

BzO

OCH3

OTBS

H

H3C

O

O

OH

HO

OiPr

OTBS

H

O

O OiPr

OTBS

O

I

O OiPr

OTBS

O

O

OAc

OAc

AcO

OAc

CH3

orthoesterformation

AcO

OHHN

Boc

OOBz

O

OH3C

H3C

OBOM

AcO

OHHN

Boc

OOBz

O

OH3C

H3C

OBOM

O

HO H

1.171.16

1.181.191.20

1.21 1.22 1.23

TMS

Figure 1.8. Isobe’s (−)-tetrodotoxin retrosynthetic rationale from 2-acetoxy-tri-O-acetyl-D-glucal.

Isobe began from 2-acetoxy-tri-O-acetyl-D-glucal derivative 1.23, which was converted to

(trimethylsilyl)acetylene 1.22 in six-steps, including Sonogashira coupling with (trimethylsilyl)acetylene

(Scheme 1.6). With 1.22 in hand, a Claisen rearrangement effectively transferred the stereochemistry of

the allylic isopropenyl ether to the C-4a position in 1.24.

13

O O

OH

HO iPr

1) TBSCl2) SO3•pyridine, Et3N, DMSO

3) I24) NaBH4, CeCl3

O O

OH

TBSO iPr

I

1) Pd(OAc)2

2) PPTS

H3C OCH3

Si(CH3)3O O

O

TBSO iPr

Si(CH3)3

CH3

K2CO3

o-Cl2C6H4

150 °C

O OTBSO iPr

Si(CH3)3

OH3C

1.22

1.24

4

4

4a

4a

1.23

Scheme 1.6. Isobe’s cyclohexane skeleton synthesis: Sonogashira coupling and Claisen rearrangement.

Isobe next installed the C-5 and C-11 hydroxyl groups through a series of regioselective

enolizations (Scheme 1.7). Compound 1.24 was trapped as the terminal silyl enol ether, and then treated

with lead tetraacetate before deprotections of the C-11 acetate and the trimethylsilyl group gave 1.25.

Enolization of the ketone toward C-5 proved difficult; thus, oxidation of the C-11 hydroxyl allowed for

MOM-trapping of the corresponding (and readily enolizable) -keto aldehyde, which was then reduced

with NaBH4/CeCl3 to 1.26. Epoxidation of 1.26 and treatment of the resulting products with acidic

Amberlyst 15 ion-exchange resin gave dihydroxylacetone 1.21 in a 7:1 ratio of diastereomers at C-5.

Oxymercuration and protecting group adjustments gave compound 1.27 as a precursor to intramolecular

aldol ring closing.

14

O OiPrTBSO

Si(CH3)3

OH3C

1) TBSOTf2) Pb(OAc)4

O OiPrTBSO

Si(CH3)3

O

TBS

AcO

AcO

3) TBAF4) Et3N, CH3OH, H2O

O OiPrTBSO

O

OH

O OiPrTBSO

O

OH

1) SO3•pyridine, Et3N, DMSO2) MOM-Cl3) NaBH4, CeCl3

MOM

1) mCPBA2) Amberlyst 15

O OiPrTBSO

O

OH

1) TBDPS-Cl2) BzCl, DMAP

3) H2SO4, CH3OH; then HgO4) TBS-OTf5) TBS-Cl

HO

4

4a

1.24 1.25

5

4a

5

1.261.211.27

O OTBSO

CH3

O

OTBDPS

BzO

OTBS

5

11

Scheme 1.7. Isobe’s cyclohexane skeleton synthesis: C-5 and C-11 hydroxyl installation.

Isobe next completed the cyclohexane core (Scheme 1.8). A TBAF-mediated annulation reaction

followed by dehydration with trichloroacetyl chloride gave carbocycle 1.20. With the carbocycle core in

hand, nine-steps modifying the eastern portion of 1.20 gave 1.19.

O OTBSO CH3

O

OTBDPS

BzO

OTBS

1) TBAF2) Cl3CCOCl, DMAP

O

HOBz

OCH3

O

O

TBDPSOTBS

1) NaBH4, CeCl32) BOM-Cl, DMAP3) CSA, CH3OH4) Ac2O, pyridine

OH

HBzO

OBOM

O

TBDPS

O

O CH3

CH3

O

HOBz

OCH3

OBOM

O

TBDPSOAc

O

HOBz

OH

OBOM

O

TBDPSOH

1) HgO, PPTS2) Mg(OEt)2

1) NaBH4

2) (CH3)2C(OCH3)2, CSA, acetone

3) PPTS, CH3OH

5

1.27 1.20 1.28

1.291.19

54a

8

54a

8

Scheme 1.8. Isobe’s cyclohexane skeleton synthesis: cyclohexanone and exo-olefin installation.

In previous work on the deoxy-tetrodotoxin series, and later in his 2004 total synthesis, Isobe

employed an Overman rearrangement to set the C-8 nitrogen functionality. Attempts to do so with

15

compound 1.19 failed repeatedly. To overcome this, Isobe introduced the nitrogen functionality through

an intramolecular conjugate addition reaction (Scheme 1.9). Primary alcohol 1.19 was converted to -

unsaturated methyl ester 1.30 in four steps. The C-5 hydroxyl group was then converted to the

corresponding carbamate in two steps with trichloroacetyl isocyanate, and treatment with KOtBu gave

bicycle 1.31. The C-5 stereocenter effectively controls the geometry at C-8a when nitrogen is installed.

The cyclic carbamate of 1.32 was hydrolyzed to give cyclohexene 1.33.

1) DIBAL-H2) TEMPO, NCS

3) NaClO2, NaH2PO4, (CH3)2C=CHCH3

4) (CH3)3Si-CHN2

1) Cl3CCONCO

2) Et3N, CH3OH

3) KOtBuOBOM

NH

CO2CH3

O O

H3C CH3

TBDPSO

O

H

O

H

1) LiBH4

2) MMTr-Cl

OBOM

NH

O O

H3C CH3

TBDPSO

O

H

O

H

OMMTr

1) Boc2O, Et3N, DMAP2) LiOH, CH3OHHO

HOH

NHBoc

BOMO

OMMTr

O

OCH3

CH3

1.19

1.33 1.32

1.30 1.31

5

8a

5

8a

5

8a

8a

5

OH

HBzO

OBOM

O

TBDPS

O

O CH3

CH35

4a

8CO2CH3

HHO

OBOM

O

TBDPS

O

O CH3

CH3

Scheme 1.9. Isobe’s introduction of nitrogen through intramolecular conjugate addition.

Stereoselective lactone formation and inversion at C-5 were then addressed (Scheme 1.10).

Seven steps were taken to convert 1.33 to 1.34 in anticipation of the 6-exo-tet epoxide ring-opening.

When compound 1.34 was treated with DBU in dichlorobenzene at 130 °C, the cyclic vinyl ether 1.17

was generated under stereoelectronic control, presumably though intermediate Z-enolate 1.35. Successive

oxidations with OsO4 and IBX gave -ketolactone 1.37. Reduction of 1.37 with NaBH4 provided 1.16 as

the sole diastereomer; the axial C-5 acetoxy group provided severe steric hindrance, forcing hydride

reduction from the front face. Bicyclic cyclohexane 1.33 contained the necessary functional features and

proper configurations for (−)-tetrodotoxin, and Isobe at this point focused on the introduction of the

guanidine and the completion of the total synthesis.

16

1) mCPBA2) BzCl, Et3N3) Ac2O4) NaBH4

5) Ac2O

OH

HHO NHBoc

OBOM

OMMTr

O

O

H3CCH3

BzO

HAcO NHBoc

OBOM

OMMTr

O

O

H3CCH3

O

1) TFA, CH3OH2) IBX, DMSO

BzO

HAcO NHBoc

OBOM

CHO

O

O

H3CCH3

O

DBUo-Cl2C6H4

130 °C

AcO

OHN

Boc

OOBz

O

OH3C

H3C

OBOM

AcO

OHHN

Boc

OOBz

O

OH3C

H3C

OBOM

OsO4, NMO

AcO

OHHN

Boc

OOBz

O

OH3C

H3C

OBOM

OH

HO

IBX, DMSO

AcO

OHHN

Boc

OOBz

O

OH3C

H3C

OBOM

O

O NaBH4

AcO

OHHN

Boc

OOBz

O

OH3C

H3C

OBOM

O

HO H

1.33 1.18 1.34

1.17

1.161.37

1.36 1.35

5 8a

Scheme 1.10. Isobe’s stereoselective lactone formation.

The final stage of the 2003 synthesis (Scheme 1.11) focused on the late-stage introduction of the

cyclic guanidine group. A 13-step sequence, mostly involving protection/deprotection transformations,

saw the unmasking of the C-7 hydroxyl group, subsequent ortho acid formation and conversion of the C-4

cyclic acetal to the requisite aldehyde for cyclic guanidinylation. The first asymmetric total synthesis of

(−)-tetrodotoxin was accomplished in 69 total steps, of which 25 steps involved protecting group

manipulations and less than 0.4% overall yield. Isobe’s 2003 TTX synthesis featured Claisen

rearrangement, epoxidation of an enol ether and configurational inversion, stereospecific, substrate-

controlled epoxidation, intramolecular enolate attack on epoxide, stereospecific, substrate-controlled

hydride reduction, intramolecular conjugate addition of a carbamate, and stereospecific, substrate-

controlled hydride reduction.

17

1) Et3N, CH3OH 2) BzCl, Et3N; Ac2O, DMAP 3) H2, Pd(OH)2/C 4) Ac2O, DMAP 5) TFA, CH3OH 6) CAN, CH3CN/H2O

AcO

OHHN

Boc

OOBz

O

OH3C

H3C

OBOM

O

HO HO

OAcH2N

OOBzHO

HO OAc

OAc

AcO H

BocHN

NBoc

SCH3

HgCl2, Et3N

O

OAcHN

OOBzHO

HO OAc

OAc

AcO H

NBocBocHN

1) NaIO4

2) TFA, CH3OHO

OAcNH

OOBz

OAc

OAc

AcO H

BocN

BocNHO

1) 4 M HCl, THF; 4 M HCl, CH3OH

2) Ac2O3) Et3N, CH3OH4) 2% d-TFA/D2O

O

OHNH

OOH

OH

O

HO H

H2N

HNHO

()-tetrodotoxin

1.16 1.38

1.40

1.39

Scheme 1.11. Isobe’s introduction of the guanidine moiety and completion of the total synthesis.

In 2004, Isobe published another synthesis of optically active tetrodotoxin55

as the culmination of

much work in the deoxy-TTX series.56-62

As an alternative route to TTX, Isobe employed several key

transformations, including a Diels-Alder [4+2] between isoprene and levoglucosenone, a readily available

carbohydrate-derived chiral building block, for the creation of the carbocycle core (Figure 1.9).

Additionally, a highly diastereoselective Overman rearrangement was successfully used to introduce the

nitrogen functionality at C-8a.

Overmanrearrangement

H3C

O

O

CH3

CH3

H

H

OHO

O

O

H H

Diels-Alder

H3C

H3C

O

O

CH3

CH3

H HN

O

CCl3

H3C

O

O

CH3

CH3

H HN

O

CCl3

OHH3C

O

O

CH3

CH3

H HN

O

CCl3

OH

OH(-)-tetrodotoxin

NO

H

OO

OHOH

N

HOO

HH2N

HO

H

guanidineformation

orthoacidformation

1.411.42 1.43

1.441.45

NHO

TES

Cl3C

O O

O

O TES

OHOTES

O

O

AcO

Figure 1.9. Isobe’s (−)-tetrodotoxin retrosynthetic rationale from levoglucosenone and isoprene.

18

O

O

O

H HO

O

O

H H

Br

H3C

BF3•OEt2

O

CH3

O

O

Br

H

CH3

O

O

H3C

CH3

H

H

HO

1) NaBH4

2) TFA, Ac2O3) Zn-Cu

4) LiAlH4

5) CSA,

Br2,Et3N

levoglucosenone -bromo levoglucosenone 1.47 1.45

4a

(CH3)2C(OCH3)2

Scheme 1.12. Isobe’s carbocyclic core formation.

Isobe’s Diels-Alder sequence (Scheme 1.12) began from an -bromo levoglucosenone

derivative62

with a bromine atom in place as a handle to allow for later-stage oxygenation at C-8.

Compound 1.47 was converted to 1.45 in five steps as a prelude to the installation of the C-8a nitrogen

functionality via Overman rearrangement (Scheme 1.13). Treatment of 1.45 with trichloroacetonitrile

afforded 1.46, which upon heating with K2CO3 in xylenes gave 1.44 as the sole diastereomer with the

required C-4a/C-8a configuration. Oxygenation at C-8 was accomplished via an intramolecular SN2’

reaction on dibromo 1.48 with the trichloroacetamide appendage on C-8a, effectively transferring the

necessary oxygen atom to C-8 in 1.49, albeit with the incorrect stereochemical configuration for (−)-

tetrodotoxin (Scheme 1.14).

Scheme 1.13. Isobe’s use of the Overman rearrangement.

H3C

O

O

CH3

CH3

H HN

O

CCl3

PyHBr3

K2CO3

H3C

O

O

CH3

CH3

H HN

O

CCl3

BrBr

DBU

SN2'

H3C

O

O

CH3

CH3

H

O

N

CCl3

H

p-TsOH

H3C

O

O

CH3

CH3

H HN

O

CCl3

OH8 8

8

1.44 1.48 1.49 1.43

8a

8a

Scheme 1.14. Isobe’s C-8 oxygenation sequence.

19

H3C

O

O

CH3

CH3

H HN

O

CCl3

OH

mCPBA

H3C

O

O

CH3

CH3

H HN

O

CCl3

OHO

H3C

O

O

CH3

CH3

H HN

O

CCl3

OH

OH

Ti(OiPr)4

H3C

O

O

CH3

CH3

H HN

O

CCl3

OH

OH

1) IBX

2) LiAlH(tBuO)3,

LiBr

3) NaBH4, CeCl3

78

1.43 1.50 1.51 1.42

8a8

8a

7

Scheme 1.15. Isobe’s inversion of C-8 and oxygenation at C-7.

Regio- and stereoselective epoxidation of 1.43, followed by a Ti(OiPr)4-mediated elimination

installed the C-7 oxygen moiety to give 1.51 (Scheme 1.15). Configurational inversion of both C-7 and

C-8 carbinol centers was accomplished with a sequence of IBX-oxidation to the corresponding -keto

cyclohexenone and hydride reductions of the dicarbonyl compound to give 1.42. Isobe’s next sequence

(Scheme 1.16) installed the C-11 and C-6 oxygen centers, as well as set the C-9 stereocenter by the

addition of the C-10-containing acetylide fragment. TES-protection and allylic oxidation of 1.42 installed

the C-11 hydroxyl group, and mCPBA epoxidation installed the C-6 oxygen in the correct configuration

and primed the C-5 position for later-stage lactonization sequence (Scheme 1.17). The stereoselective

addition of an acetylide as a C-10 carboxylic equivalent gave 1.54 in a 4:1 ratio of diastereomers at C-9

(Scheme 1.16).

H3C

O

O

CH3

CH3

H HN

O

CCl3

OH

OH

1) TESOTf

2) SeO2

3) NaBH4, CeCl3

O

O

CH3

CH3

H HN

O

CCl3

OTES

OTESOH

1) TESOTf

2) mCPBA3) O3

O

O

O

CH3

CH3

H HN

O

CCl3

OTES

OTESTESO

O

O

O

CH3

CH3

H HN

TESO

OTESTESO

O

(H3C)3Si MgBr

Si(CH3)3

OH

COCCl31) Ac2O

2) TBAF, -10 °C

O

O

CH3

CH3

H HN

TESO

OTESTESO

O

OAc

COCCl3

8

8a

7

11

5

6 11

5

6

9

9

10

9

10

1.42 1.52 1.53

1.541.55

Scheme 1.16. Isobe’s C-11/C-6 oxygenation sequence and addition of the C-10 acetylide group.

20

The cleavage of the acetylenic unit was accomplished in a two-step procedure starting with

treatment of 1.55 with KMnO4 and sodium periodate (Scheme 1.17). To affect an epoxide-opening

cyclization, -keto acid 1.56 was cleaved with alkaline hydrogen peroxide to furnish 1.57, with the

required C-5 oxygen moiety in place as part of the lactone bridge. Re-protection of 1.57 lead to 1.41.

This epoxide opening sequence was quite reminiscent of Isobe’s 2003 total synthesis54

(Scheme 1.10) in

that the C-10 unit attack at C-5 closed the lactone while setting C-5 or C-7.

O

O

CH3

CH3

H HN

TESO

OTESTESO

O

OAc

COCCl3KMnO4, NaIO4

O

O

CH3

CH3

H HN

TESO

OTESTESO

O

OAc

COCCl3

COOHO

O

O

CH3

CH3

H HN

TESO

OTESTESO

O

OAc

COCCl3

OO

H2O2, NaHCO3

1) TESOTf -40 °C2) Ac2O

NHO

TES

Cl3C

O O

O

O TES

OHOH

O

O

HO

NHO

TES

Cl3C

O O

O

O TES

OHOTES

O

O

AcO

5

1.55 1.56

1.41 1.57

10

5

10

10

5

Scheme 1.17. Isobe’s epoxide-opening cyclization.

Isobe constructed the ortholactone (Scheme 1.18) by TBAF removal of the silyl groups of 1.41

followed by spontaneous ortho acid formation with the newly released C-7 oxygen. Global protection of

the hydroxyl groups with acetic anhydride lead to 1.59, and HIO4-mediated cleavage of the acetonide

yielded the C-4a aldehyde which was protected as the dimethylacetal 1.60. Mixed acetal 1.61 was

generated in a 6:1 ratio of diastereomers at C-8a following selective deprotection of C-9 and C-10 acetate

groups and silyl protection of the ortho acid. Reduction of the trichloroacetamide unit allowed for facile

introduction of the guanidine moiety in a similar manner to both Kishi’s 1972 racemic synthesis (Scheme

1.5) and Isobe’s 2003 synthesis (Scheme 1.11).

21

NHO

TES

Cl3C

O O

O

O TES

OHOTES

O

O

AcO

TBAF

NHO

H

Cl3C

O O

OH

O

OHOH

O

O

AcO

Ac2O

NHO

Ac

Cl3C

O O

OAc

O

OAcOAc

O

O

AcO

1) H5IO6

2) (CH3O)3CH, CSA

NHO

Ac

Cl3COC

OO

OAcOAc

OOAcO

OAc1) NH4OH2) TBSOTf

NHO

Ac

Cl3COC

OO

OAcOAc

H3CO

OOTBS

10

H3C

7

5

8a

8a

1) DIBAL-H -40 °C2)

BocN

SCH3

NHBoc

TFA, H2O

NHO

H

OO

OHOH

H3CO

OOTBS

BocHN

BocN

NO

H

OO

OHOH

N

OO

H

H2N

H

4,9-anhydrotetrodotoxin

+

NO

H

OO

OHOH

N

HOO

HH2N

H

tetrodotoxin

O

H

HgCl2

1.41 1.58 1.59

1.601.61

1.62

H3C

Scheme 1.18. Isobe’s ortho lactonization and end-game strategy.

Isobe and co-workers have generated several tetrodotoxin intermediates and derivatives through a

number of routes and still appear to be working on synthetic improvements. Recently, Isobe published an

update to the 2004 synthesis in which the C-11 oxygen atom is installed early on the isoprene-unit (1.66)

during Diels-Alder construction of the carbocyclic core (Figure 1.10).63

22

H3C

O

O

CH3

CH3

H HN

O

CCl3

OH7

8

1.43

8a

O

O

CH3

CH3

H HN

O

CCl3

OH7

8

1.63

8a

HO

1111

O

O

CH3

CH3

H HN

O

CCl3

78

1.64

8a

HO

11

O

O

CH3

CH3

H

78

1.65

8a

HO

11

OH

OR

OO

Br

O

+

Diels-Alder

Overman rearrangement

C-8hydroxylation

-bromo levoglucosenone1.66

Figure 1.10. Isobe’s updated C-11 hydroxylation and comparison to 1.43.

23

1.2.3 Du Bois’ total synthesis

Justin Du Bois published an impressive stereoselective synthesis of (−)-tetrodotoxin64

shortly

after Isobe. This route to (−)-TTX (Figure 1.11) followed a similar late-stage guanidine and orthoacid

formation as did Kishi (Figure 1.7) and Isobe (Figures 1.8, 1.9), but ingeniously utilized two C-H

activation steps to install the two tetrasubstituted centers C-6 and C-8a. The installation of the nitrogen

functionality at C-8a through a nitrene insertion reaction into the C-8a C-H bond is unique. An

intramolecular rhodium carbenoid C-H insertion reaction at C-6 was used in the construction of the

carbocycle, a general strategy also employed by Taber in his work (Chapter 1.2.9) on the tetrodotoxin

core.

O

OHNH

OOH

OH

O

HO H

H2N

HNHO

()-tetrodotoxin

O

OH

OO

O

O

O H

CH3

CH3

CH3

CH3

stereospecificC-H amination

H2N

O

Cl

O

OO

O

CH2

H

CH3

H3C

O(H3C)2N

PivO

H3CCH3

stereospecificRh-catalyzedC-H insertion

methylenation

O

OPivO

TBSO

O

N2

O

O

H3C

CH3

HBnO

O

O O

OBn

TBSOO

O

CH3

CH3

HOHC+

orthoacid formation

guanidine formation

6

5

8a

4a

9

8a

6

58a

9

9

4a8

8a49

10

10

6

8

10

9

4

4a

6

aldol

1.72

1.71 1.70 1.69

1.67 1.68

OO

O

H3C CH3O

O

CH3H3C

O

HO

H2N

Figure 1.11. Du Bois’ tetrodotoxin retrosynthetic analysis.

Du Bois began his synthesis from chiral aldehyde 1.71, which is a readily available derivative of

D-isoascorbic acid (Scheme 1.19). A sodium acetate-mediated aldol reaction with dibenzyloxalacetate

1.72 and chiral aldehyde 1.71 provided 1.73, forming the new C-8 to C-8a carbon-carbon bond.

Compound 1.73 was converted into diazoketone 1.70 to test the rhodium-catalyzed C-6 carbene C-H

insertion. Reaction conditions were screened, and reaction with 1.70 and 1.5 mol % Rh2(NHCOCPh3)4

resulted in the production of cyclic ketone 1.75 as the only detected product. The configuration of the C-

9 and C-4a stereocenters were set by exploiting the shape of bicyclic 1.75. Reduction of the C-4a

carbonyl occurred from the less sterically crowded convex face, as did hydrogenation of the C-8a/C-9

olefin. Acetonide-protection gave compound 1.76, which was oxidatively opened at the lactone, and then

methylenated in anticipation of C-5 oxygenation (Scheme 1.20).

24

Scheme 1.19. Du Bois’ Rh-carbenoid C-H insertion.

1) (CH3)2NH2) TPAP, NMO

Zn, CH2I2, TiCl4cat. PbCl2

OO

O

O

O

PivO

CH3H3C

CH3

H3C

H

CH2

NH3C

CH3

O

OO

O

O

O

PivO

CH3H3C

CH3

H3C

H

1.76

8a 54a

1.77 1.69

8a4a

OO

O

O

O

PivO

CH3H3C

CH3

H3C

H

O

NH3C

CH3

8a4a

55

Scheme 1.20. Du Bois’ methylenation.

An uncommon allylic oxidation of 1.69 with Ph2Se2 and PhIO2 gave enone 1.78, which was well

suited for the establishment of the C-5 and C-4a configurations (Scheme 1.21). Treatment of 1.78 with

vinyl cuprate afforded 1,4-addition product which was selectively protonated from the convex face,

setting the C-4a configuration. Borane reduction of the resulting ketone gave compound 1.79 as the sole

diastereomer, again taking advantage of the convex shape of the molecule, and set the C-5 hydroxyl in the

necessary configuration. The C-5 hydroxyl group in 1.79 was made to cleave the stable C-10 amide

functionality and pivaloate ester-deprotection afforded -lactone 1.80. The C-8a tetrasubstituted

carbinolamine was to be set through a rhodium nitrene C-H insertion reaction. A four-step transformation

converted 1.80 into intermediate 1.68, the precursor to the planned nitrene insertion.

25

Scheme 1.21. Du Bois’ allylic oxidation and establishment of C-4a and C-5 configurations.

Compound 1.68, with the requisite C-9-appended primary carbamate, indeed underwent the

desired oxidation at C-8a to give oxazolidinone 1.82 with retention of configuration when reacted with 10

mol % Rh2(NHCOCF3)4 (Scheme 1.22). With the C-8a carbinol in place, Du Bois needed to introduce

the cyclic guanidine ring and close the ortho acid. A five-step transformation lead from 1.82 to amino

alcohol 1.67. The Boc-protected guanidine was introduced in a manner similar to Isobe (Schemes 1.11,

1.18), and ozonolysis unmasked the C-4 aldehyde. Wholesale acetonide- and Boc-deprotections with wet

TFA gave (−)-tetrodotoxin.

26

Rh2(NHCOCF3)4

(10 mol%),PhI(OAc)2, MgO O

O

O

H3C CH3O

O

CH3H3C

O

OCl

N

O

H

1) NaSePh2) mCPBA3) Boc2O, DMAP4) K2CO3, CH3OH5) H2O, 110 °C

OO

O

H3C CH3O

O

CH3H3C

O

HO

H2N

BocHN

NBoc

SCH3

HgCl2, Et3N

OO

O

H3C CH3O

O

CH3H3C

O

HO

NBocN

NHBoc

H

O3; (CH3)2Sthen aq. TFAO

O

HO

OHOH

OHO

ON

H2NHN

H

H

()-tetrodotoxin

OO

O

H3C CH3O

O

CH3H3C

O

O

OH2N

Cl

8a

9

1.68 1.82 1.67

1.83

Scheme 1.22. Du Bois’ Rh-catalyzed nitrene C-H insertion and guanidine formation.

Du Bois completed his synthesis of (−)-tetrodotoxin in 28 linear steps from known aldehyde 1.71

with 0.96% overall yield. This work demonstrated an alternative approach to the Diels-Alder chemistry

used to build the six-member carbon framework. Du Bois utilized C-H functionalization as a central

feature of his approach, leading to a short and concise synthesis relative to other tetrodotoxin syntheses.

The mild conditions for the C-H functionalization reactions, along with other transformations including

diastereoselective aldol addition, substrate-controlled hydrogenation, and substrate-controlled hydride

reduction, as well as the relative lack of protection/deprotection transformations clearly mark this

synthesis as an impressive achievement.

27

1.2.4 Sato’s total syntheses

In 2005, Ken-Ichi Sato published a racemic synthesis of tetrodotoxin starting from myo-inositol.65

His novel and stereocontrolled synthesis involved the typical orthoesterification/guanidine formation as

the end-game strategy and the central feature of his route was the formation of a spiro -chloroepoxide

and subsequent azide ion-mediated ring-opening (Figure 1.12).

NH

N

OH

OH NH2

HO

OH

OO

O

OHH

H

(±)-tetrodotoxin

NH2

OO O

OO

O

OH

H3CCH3

C

N

orthoacidformation

OH

OH

HO

HOHO

OH

HOOH

OH

OH

OH OH

OO O

CHO

OO

H3CCH3

CH3H3C

N3

OTBDPS

guanidine formation

azide ring opening

spiro -chloroepoxide

formation

OO

CH3H3C

OO

O

H3C CH3

OTBDPS

O

Cl

myo-inositol

NH

OO OH

OO

O

OMOM

H3CCH3

H3CH3C O

NBoc

NHBoc

1.84 1.85

MOM

TBDPS

1.861.87

MOMMOM

Figure 1.12. Sato’s retrosynthetic analysis for (±)-tetrodotoxin from myo-inositol.

To begin, Sato orthogonally protected the secondary hydroxyl groups of myo-inositol in a seven-

step transformation to give compound 1.88 (Scheme 1.23). Another 10-step sequence converted 1.88 to

compound 1.89, with the C-4a ketone in place to introduce the C-4 carbon fragment. A Peterson

olefination/hydroboration operation and subsequent TBDPS-protection/C-8a oxidation afforded 1.90 with

the requisite C-8a ketone in place to introduce the C-9 carbon unit and set up for the key spiro -

chloroepoxide formation. An approach to advanced tetrodotoxin intermediates using the spiro -

chloroepoxide as a means of installing the C-8a nitrogen and the C-9 carbon center was worked on by

Sato in the early 1990’s66

(Scheme 1.30).

28

OH

OH

HO

HOHO

OH

OO O

O

OH OBn

MOMOH

1) CH(OEt)3, TsOH

2) NaH, BnBr

3) MOM-Cl, iPr2NEt

4) (COCl)2, DMSO

5) LDA, CH2Cl26) nBu4NOH, DMSO

7) NaBH4

1) NaH, BnBr2) HCl3) Ac2O4) TBS-Cl5) AcOH

6) (CH3)2C(OCH3)2, PPTS7) CH2(OCH3)2, P2O5

8) Pd(OH)2/C, H2

9) (CH3)2C(OCH3)2, PPTS10) (COCl)2, DMSO

OOO

H3CCH3

O O

H3C CH3

OMOM

O

TBS

1) (CH3)3SiCH2MgCl2) NaH3) BH3, NaOH; then H2O2 aq4) TBAF

5) TBDPS-Cl6) Dess-Martin periodinane

OO

CH3H3C

OO

O

H3CCH3

OTBDPS

OH

Cl

OO

CH3H3C

OO

O

H3CCH3

OTBDPS

OMOMLDA, CH2Cl2

MOM Cl

myo-inositol

11

11

68a

8a

4a6

6

8a

4a6

4a

1.88 1.89

1.901.91

Scheme 1.23. Sato’s setup for spiro -chloroepoxide formation.

When treated with sodium azide and 15-crown-5 in DMSO, 1.91 closed to give spiro -

chloroepoxide 1.87, which was subsequently ring-opened with azide ion to give 1.86 containing the C-8a

nitrogen functionality and an aldehyde group at C-9 (Scheme 1.24).

OO

CH3H3C

OO

O

H3CCH3

OTBDPS

O

ClMOM

NaN3,15-crown-5,DMSO

OO O

CHO

OO

CH3H3C

CH3

H3C

N3

OTBDPS

MOM

OO

CH3H3C

OO

O

H3CCH3

OTBDPS

OH

ClMOM Cl

1.91

8a

4a6

1.87 1.86

8a8a

9

9

9

Scheme 1.24. Sato’s -chloroepoxide formation and azide ion-mediated ring-opening.

The C-9 aldehyde unit of 1.86 was treated with trimethylsilyl cyanide and protected, giving 1.85

as a 3:2 mixture of C-9 diastereomers; the undesired/minor diastereomer was separated out and recycled

back to the desired 1.85 by retreatment with trimethylsilyl cyanide (Scheme 1.25). Sato’s remaining

synthetic manipulations, chiefly reduction/oxidation of the C-10 nitrile to the carboxylic acid and lactone-

ring closure, lead to 1.92 which was converted to racemic tetrodotoxin following a sequence with

similarity to Kishi (Scheme 1.5), Isobe (Schemes 1.11, 1.18) and Du Bois (Scheme 1.22).

29

1) (CH3)3SiCN, Et3N2) CH2(OCH3)2, P2O5

N3

OO OTBDPS

OO

O

OMOM

H3CCH3

H3C C

N

MOM

NH2

OO OH

OO

O

OMOM

H3CCH3

H3C

H3CO

1) DIBAL-H2) CrO3, H2SO4 aq3) H2, Pd/C4) TBAF

(BocNH)2C=S, HgCl2

NH

OO OH

OO

O

OMOM

H3CCH3

H3CH3C O

NBoc

NHBoc

1) PCC2) i) 4 M HCl ii) TFA aq iii) AcOH aq

NH

N

OH

OH NH2

HO

OH

OO

O

OHH

H

(±)-tetrodotoxin

OO O

CHO

OO

H3CCH3

CH3

H3C

N3

OTBDPS

MOM

1.86

8a

9

1.85 1.92

1.84

H3C

8a

9

10

10

9

8a

10

9

8a

Scheme 1.25. Sato’s end game strategy: lactone/orthoester formation, guanidine formation.

With compound 1.86 in hand, Sato rapidly installed key functionalities on the tetrodotoxin

backbone, setting the C-4a nitrogen unit and C-9/C-10 unit, closing the bridging lactone and finally

orthoacid and guanidine ring closure. Sato’s synthesis of racemic tetrodotoxin was completed in 36 steps

with an overall yield of 0.12% from myo-inisitol.

The Sato group achieved a stereoselective synthesis of (−)-tetrodotoxin in 2008, beginning from

D-glucose.67

Novel features of this synthesis include an intramolecular Henry reaction followed later by a

McMurry-Nef reaction to access 1.90 (Figure 1.13), a common intermediate with Sato’s racemic

synthesis of tetrodotoxin from 2005 (Scheme 1.23). This approach by Sato is based significantly on not

only the Funabashi approach68

(Chapter 1.2.5), of which Sato participated, but also early independent

work by Sato66

himself (Scheme 1.30) from two decades prior.

30

NH

N

OH

OH NH2

HO

OH

OO

O

OHH

H

()-tetrodotoxin

orthoacidformation

O

OH

HOHO

OH

OHOHOH

OBnBnO

NO2

SPh

guanidine formation

D-Glucose

HO

OHO

OBnO

H3C

CH3BnO

NO2

OH

HOH

OBnO

BnO

PhS

PhS

NO2

PhS

Henryreaction

O

OO OTBDPS

OO

O

H3CCH3

H3CCH3

MOMspiro -

chloroepoxidation

ring-opening

Nefreaction

N3

OO OTBDPS

OO

O

OMOM

H3CCH3

H3C C

N

MOMNH

OO OH

OO

O

OMOM

H3CCH3

H3CH3C O

NBoc

NHBoc

OO O

CHO

OO

H3CCH3

CH3H3C

N3

OTBDPS

MOM

H3C

1.86

1.851.84

1.90

1.951.94

1.93

Figure 1.13. Sato’s (−)-tetrodotoxin retrosynthetic analysis.

Sato accessed aldehyde 1.97 in five-steps from known glucose-derivative 1.9669-73

(Scheme 1.26).

Henry reaction with the sodium nitronate of nitromethane afforded nitro alcohol 1.98 as an

inconsequential 10:1 mixture of diastereomers. Treatment of the 1.98 mixture of diastereomers with

methanesulfonyl chloride and triethyl amine afforded nitro-olefin 1.99. Reaction of 1.99 with lithium

dithioacetal anion gave 1.100. Acetonide deprotection of 1.100 with refluxing glacial acetic acid gave

nitro-hemiacetal 1.94. Nitro cyclitol 1.93 was formed through an intramolecular Henry reaction by

treatment of 1.94 with methanolic sodium bicarbonate.

31

3 steps67-71

1) mCPBA2) NaOH aq3) NaH, BnBr

4) AcOH aq5) NaIO4

O

OH

HOHO

OH

D-Glucose

HO

OHO

O

CH3

CH3

O

O

CH3

H3C

OHO

O

CH3

CH3

O

BnO

OBn

CH3-NO2,CH3ONa, CH3OH

OHO

OBnO

CH3

CH3BnO

NO2

OHO

OBnO

CH3

CH3BnO

NO2OH

MsCl,Et3N

CH2(SPh)2,nBuLi

OHO

OBnO

BnO

PhS

PhS

NO2

CH3

CH3

85% AcOH aqreflux

OH

HOH

OBnO

BnO

PhS

PhS

NO2 NaHCO3,CH3OH, H2O

OHOHOH

OBnBnO

NO2

SPhPhS

1.96 1.97

1.98

1.93

1.991.100

1.94

Scheme 1.26. Sato’s synthesis of nitro cyclitol 1.93 employing an intramolecular Henry reaction.

Sato protected the vicinal diol of 1.93 as an acetonide and the C-5 axial hydroxyl group, then

converted the dithiane to the TBDPS-protected primary alcohol to give 1.101 (Scheme 1.27). Conditions

were screened for the conversion of the C-8a-nitro group to the required C-8a-ketone and found that

potassium tert-butoxide and ozone, McMurry’s conditions,74

were effective. Deprotection and

reprotection of the C-6/C-11 diol gave known tetrodotoxin intermediate 1.90.

Scheme 1.27. Sato’s McMurry-Nef transformation to common intermediate 1.90.

With common intermediate 1.90, Sato’s synthesis proceeded to (−)-tetrodotoxin by their

established route for racemic tetrodotoxin,65

including the successive spiro -chloroepoxide formation

and azide ion-mediated ring-opening sequence (Schemes 1.23, 1.24, 1.25).

32

Sato further optimized the synthesis for the common intermediate 1.90 in 2010, again starting

from D-glucose as starting material (Figure 1.14).75

His updated synthesis accessed common tetrodotoxin

intermediate 1.90 through an olefination at C-4a to install the C-4 carbon unit, and a Ferrier(II) reaction of

enol acetate 1.104 to build the cyclohexane framework.

O

OCH3

MOMOO

O

OAc

BnO

H3C

H3C

MOMO

O

OAc

OH

OBn

O

O

H3C

H3C

O

O

OO

OMOM

CH2

OTBS

H3CCH3

H3CCH3

Ferrier(II)reaction

olefination

NH

N

OH

OH NH2

HO

OH

OO

O

OHH

H

()-tetrodotoxin

orthoacidformation

O

OH

HOHO

OH

guanidine formation

D-Glucose

HO

O

OO OTBDPS

OO

O

H3CCH3

H3C CH3

MOMspiro -

chloroepoxidation

ring-opening

N3

OO OTBDPS

OO

OOMOM

H3CCH3

H3C C

N

MOMNH

OO OH

OO

O

OMOM

H3CCH3

H3CH3C O

NBoc

NHBoc

OO O

CHO

OO

H3CCH3

CH3H3C

N3

OTBDPS

MOM

CH3

4a6

4a

4

6

8a

8a4a

6

1.86

1.851.84

1.90

1.1041.103

1.102

Figure 1.14. Sato’s updated retrosynthetic analysis for (−)-tetrodotoxin intermediate 1.84.

Sato began this route from commercially available 1.10576

(Scheme 1.28). Peterson olefination

of 1.105 installed the C-11 carbon and subsequent epoxidation and base-hydroylsis of the epoxide set the

C-11 and C-6 hydroxyl groups. Oxidation of deprotected C-8a hydroxyl to the unstable aldehyde and

immediate trapping as the enol acetate afforded 1.104 as the sole isomer. Conditions for the key

Ferrier(II) reaction were screened, and it was found that mercury diacetate optimally converted 1.104 into

cyclohexanone 1.103 as the major diastereomer, the ratio of the major diastereomer to the sum of the

other three diastereomers was found to be 2:1. Sato finished his route to (−)-tetrodotoxin precursor 1.90

in a six-step sequence, borrowing from his 2005 synthesis (Scheme 1.23) the Peterson

olefination/hydroboration installation of C-4 and the C-4 oxygen moiety.

33

4 steps74O

OH

HOHO

OH

D-Glucose

HO O OCH3

OBn

O

O

OPh

1) (CH3)3SiCH2MgCl

2) AcOH aq

3) PivCl

4) CH2(OCH3)2, P2O5

5) mCPBA

6) nBu4NOH

7) (CH3)2C(OCH3)2, pTsOH

8) TFAA, Et3N

9) K2CO3, Ac2O Hg(OAc)2, AcOH,then NaCl aq

1) Pd(OH)2/C, H2

2) (CH3)2C(OCH3)2, pTsOH

3) i) (CH3)3SiCH2MgCl ii) TBS-Cl

1) i) BH3; H2O2, NaOH ii) TBAF

2) TBDPS-Cl3) Dess-Martin periodinane

O

OCH3

MOMOO

O

OAc

BnO

H3C

H3C

MOMO

O

OAc

OH

OBn

O

O

H3C

H3C

O

O

OO

OMOM

O

H3CCH3

H3CCH3

O

OO O

OO

O

H3CCH3

H3CCH3

MOM

4a6

4a

4

6

8a

8a

4a

6

TBDPS

TBS

6

11

1.90

1.104

1.1031.102

1.105

Scheme 1.28. Sato’s Ferrier(II) sequence to common intermediate 1.90.

34

1.2.5 Funabashi

In 1980, the Funabashi laboratory, including Kenichi Sato (Chapter 1.2.4), published a synthetic

approach to optically active tetrodotoxin68

based upon then-current work in their group on hexose

functionalization. Their strategy employed an intramolecular Henry reaction to create the 6-membered

carbocycle 1.106 (Figure 1.15) as a proposed tetrodotoxin precursor.

NH

N

OH

OH NH2

HO

OH

OO

O

OHH

H

(-)-tetrodotoxin

O

OH

HOHO

OH

D-Glucose

HOOHOH OH

OH

CHOHO

NO2

H

CHO

OHH

CH2OHHO

OHH

CHOH

CH2NO2

intramolecularHenry cyclization

1.106

Figure 1.15. Funabashi’s retrosynthetic approach to (−)-tetrodotoxin.

Funabashi began from D-glucose derivative 1.107.77,78

Aldehyde 1.108 was generated after

protection/deprotection steps and sodium periodate cleavage of the resulting 1,2-diol. A Henry reaction

with the nitronate of nitromethane on 1.108 and subsequent elimination set the stage for the Michael

reaction of 2-lithio-1,3-dithiane to give 1.110. Base-mediated deprotection and intramolecular Henry

reaction gave completed carbocycle 1.111.

O

H

H

HOH2C O

OH HO

H

OO

H3C

CH3

CH3

H3C

1.107

O

H

O

O H

O

H3C

CH3

1.109

NO2

O

1) CH2Br2, NaH2) AcOH aq3) NaIO4

S

SLi

O

H

O

O H

O

H3C

CH31.110

O2N

O

S

S

NaHCO3

OHOH OH

OO

NO2

S

S

1.111

1) CH3NO2, NaOCH3

2) MsCl, Et3N

O

H

O

O H

OO

H3C

CH3

O

1.108

Scheme 1.29. Funabashi’s approach to (−)-tetrodotoxin.

35

Intermediate 1.111 appeared to be the most advanced TTX-intermediate assembled by Funabashi,

but his former student Sato pursued this route independently,66

using the intramolecular Henry cyclization

as the key step in assembling the carbocyclic framework as Funabashi. Sato further elaborated the

approach by employing an azide-mediated opening of a spiro -chloro-epoxide derivative (Scheme 1.30)

to create a more advanced (−)-tetrodotoxin precursor 1.115. This early work set the stage for his eventual

conquest of optically active tetrodotoxin65,67

(Chapter 1.2.4) roughly a decade and a half later.

OO

O

OROR

OCH3

O

ClR

OO

O

OROR

OCH3

O

ClR

Cl

NaN3,15-crown-5,DMSO

ORO

OR CHO

OO

N3

OCH3

R

OHOH OH

OO

NO2

S

Ph

Ph

S

1) CH2(OCH3)2, P2O5

2) HgO, HgCl2, BF3•OEt2, (CH3O)3CH

OROR OR

OO

O

OCH3

OCH3

R = MOM

OCH3

OCH3

LDA, CH2Cl2

Li

OCH3

1) NaBH4

2) PMB-Cl, NaH3) H2, Pd/C; then BrCN4) NH4OH

ORO

O

OO

N

H3CO

R

OCH3

OPMB

NH

NH2

H

1.112 1.113

1.1141.115

R

Scheme 1.30. Sato’s early independent work on (−)-tetrodotoxin.

36

1.2.6 Keana

Over nearly two decades, Keana worked on the synthesis of tetrodotoxin and published several

papers in the 1970’s and 1980’s reporting their progress.79-81

Generally, Keana approached the synthesis

of tetrodotoxin by the construction of the carbocyclic framework via Diels-Alder chemistry (Scheme

1.31) while simultaneously, and uniquely forming the cyclic guanidine at an early stage. Diels-Alder

reaction between dienophile pyrimidone 1.116 and 1-acetoxy-3-methyl-butadiene afforded racemic

hydroquinazoline 1.117. Stoichiometric osmium tetraoxide-mediated dihydroxylation of 1.117 gave

compound 1.118 as the major diastereomer. Advanced intermediate 1.118 appeared to be the most

advanced proposed tetrodotoxin precursor reported by Keana, containing several key structural

components.

THF165 °C

OAc

H3C

N

HN

H3C

O

NHAc

O

NH

HN NAc

O

H3C O

H3C

AcO

+OsO4 then H2S

NH

HN NAc

O

H3C O

H3C

AcO

HO

HO

H H

1.117 1.1181.116

Scheme 1.31. Keana’s most advanced tetrodotoxin intermediate.

37

1.2.7 Fraser-Reid

In the 1990s, Fraser-Reid’s laboratory, including Ricardo Alonso (Chapter 1.2.8), published

several reports on progress toward the formal synthesis of tetrodotoxin.82-84

Fraser-Reid reasoned that

then-recent free-radical methods had been shown to be tolerant of a variety of functional groups85,86

whereas previous methods proved incompatible with sugar-derived substrates. Fraser-Reid proposed a

possible avenue to a formal synthesis of tetrodotoxin (Figure 1.16) beginning from a carbohydrate-

derived source.

NH

N

OH

OH NH2

HO

OH

OO

O

OHH

H

tetrodotoxin

NR'

HO O

OR

OOH

OR

ORH

H

OOR

OR

NHR'OR

CHOOHHO

O

O

OH

NHR'OH

O

O

O

O

OH

OH

OH

D-Mannosan(1,6-anhydro--D-mannopyranose)

OO

OAc

NHAcOAc

OHO OAc

AcO

Kishi-Gotointermediate

1.121 1.120

1.119

1.12

R and R' were suitable protection moieties

Figure 1.16. Fraser-Reid’s retrosynthetic considerations.

Initially, Fraser-Reid began his sugar-based approach to tetrodotoxin from 1,6-anhydro--D-

mannopyranose, exploiting the different reactivity of the sugar’s various hydroxyl groups to achieve

suitably functionalized advanced intermediate 1.123 (Scheme 1.32). Olefination-product 1.124 was

deprotected with HF and reacted with trichloroacetonitrile to give oxazoline 1.125 which was opened

with HCl and protected as the triacetate 1.126. Fraser-Reid was able to directly convert 1.126 to 1.127 by

reaction with tert-butylhyponitrite (TBHT) in refluxing tert-butyl alcohol. After protecting group

manipulation, dioxadamantane 1.129 was afforded from reaction of 1.128 with TES-OTf/Ac2O.

38

O

O

OH

OH

OH

D-Mannosan

O

O

O

OTBDPS

O SnBu2steps841) Br2

2) Ac2OO

O

OAc

TBDPSO O

O

O

OAc

TBDPSO CHCN

CN(EtO)2P

O

O

O

OAc

O CHCN

HF;then Cl3CCN, DBU

N

Cl3C

O

O

OAc

ON

CCl3

NC1) HCl2) Ac2O

O

O

OAc

OAcNHAc

NCO

O

OAc

NHAcOAc

O

1.127 1.126

1.1231.122 1.124

1.125

O

O

OBn

NHAcOBn

O

Ac2O, TES-OTf

O

OAc

OBn

NHAcOBn

O

1.128

O

AcO

OBn

NHAcOBn

O

OAc

1.129

TBHT

TBHT = O N N O

steps84

Scheme 1.32. Fraser-Reid’s synthesis of dioxadamantane core 1.129 via D-mannosan.

Several years later, Fraser-Reid reported the synthesis of an advanced intermediate of similarity

to the Kishi-Goto intermediate 1.12 (Scheme 1.33). Compound 1.128 was allylated under radical

conditions to afford compound 1.130 as the major diastereomer. A reduction/iodination sequence,

followed by ozonolysis under Schreiber conditions87

gave the desired methyl ester 1.131. Reductive

elimination with Zn in refluxing ethanol, PMB-protection of the hemi-acetal and basic hydrolysis gave

compound 1.132 which was ready for an iodolactonization procedure. Iodolactonization of 1.132,

promoted by iodonium dicollidine perchlorate (I(collidine)2ClO4, IDCP), lead to 1.133. Oxygenation was

affected under radical conditions with tributyltin hydride and molecular oxygen to give 1.134, which

correlates to the structurally similar Kishi-Goto intermediate 1.12. Conceivably, this approach could be

exploited to facilitate a synthesis of tetrodotoxin, but further studies by Fraser-Reid have not appeared in

the chemical literature.

39

OO

OAc

NHAcOAc

OAcO OAc

AcO

Kishi-Gotointermediate

O

O

OBn

NHAcOBn

O

1.128

1) pyridinium bromide perbromide, AcOH2) allyltributyltin, AIBN

O

O

OBn

NHAcOBn

O

1.130

1) NaBH4

2) I2, PPh3, imidazole3) O3, CH3OH; Ac2O, Et3N

O

O

OBn

NHAcOBn

I

1.131

O

HOCH3

1) Zn2) PMB-Cl3) LiOH

IDCP

O2, Bu3SnH, Et3B

OOBn

NHAcOBn

OHOO

OPMB OOBn

NHAcOBn

OIO

OPMB OOBn

NHAcOBn

HOO

OPMB

1.1321.1331.134

HH

Scheme 1.33. Fraser-Reid’s synthesis of advanced intermediate 1.134.

40

1.2.8 Alonso

Following his experience with Fraser-Reid, Ricardo Alonso also independently pursued a

mannose-based radical cyclization approach to the synthesis of tetrodotoxin. His approach (Scheme 1.34)

used a combination of iodoacetal 1.136 as a radical cyclization precursor containing an aldoxime ether as

a radical trap.88,89

The cis ring fusion, and thus the C-8a carbinolamine configuration, were set in a

radical annulation reaction. Upon treatment with AIBN and Ph3SnH, iodoacetal 1.136 underwent an

efficient intramolecular 5-exo-trig cyclization, forcing the approach of the tethered radical chain to the

concave face of the bicyclic structure and setting the C-8a tertiary center’s configuration in compound

1.137. After protection as an oxazolidinone, Jones oxidation and installation of the exomethylene,

compound 1.140 was created in a stereocontrolled manner.

NH

N

OH

OH NH2

HO

OH

OO

O

OHH

H

tetrodotoxin

O

O

O

OH

O

1,6-anhydro-2,3-isopropylidene--D-

mannopyranose

CH3

CH3

1) TBDPS-Cl

2) HOAc aq

3) nBu2SnO; Br2

4) H2NOCH3

O

O

OH

TBDPSO NOCH3

1) NIS,

2) TBAF

O O

O

O

OHNOCH3

I

OCH2CH3

AIBN, Ph3SnH

O

O

O

OHN CH2

OCH2CH3

O

O

OH

ONHOCH3

OCH2CH3

triphosgeneO

OO

ONOCH3

OCH2CH3

O

CrO3,H2SO4

O

OO

ONOCH3

O

ONaH,

(H2CO)n

O

OO

ONOCH3

O

O

8a

8a

8a

1.135 1.136

1.1371.138

1.139 1.140

OCH3

Scheme 1.34. Alonso’s radical-cyclization approach.

41

1.2.9 Taber

In the early 2000s, Taber proposed an approach to optically active tetrodotoxin based on the

functionalization of a cyclohexenone created by an intramolecular alkylidene carbene cyclization

(Scheme 1.35).90

Taber synthesized an advanced intermediate towards (−)-tetrodotoxin using

established91

carbene-based C-H insertion technology to set the C-6 tertiary alcohol stereocenter. Readily

available 1,2;5,6-di-O-isopropylidene-D-mannitol was used to test the feasibility of Taber’s proposed C-

H insertion strategy. A Sharpless asymmetric epoxidation92

of the corresponding allylic alcohol gave

compound 1.141, which was ring-opened with CuBr/isopropenylmagnesium bromide93,94

and the resulting

diol protected as the cyclic ketal 1.142. Ozonolysis of the terminal olefin gave 1.143 as a precursor to

attempt the intramolecular alkylidene C-H insertion reaction on the C-6 methine. Treatment of 1.143

with trimethylsilyl diazomethane and nbutyl lithium gave compound 1.144 after warming. Taber used the

same approach to set the C-6 tertiary stereocenter was employed by Du Bois (Chapter 1.2.3) in his

synthesis of optically active tetrodotoxin.64

Ozonolysis, annulation and redox adjustment of 1.144,

followed by epimerization of the C-4a center, gave cyclohexenone 1.146, containing stereochemical

features substantially contained in the core of (−)-tetrodotoxin.

42

NH

N

OH

OH NH2

HO

OH

OO

O

OHH

H

(-)-tetrodotoxin

OO

OHHO

O

O

H3CCH3

CH3

CH3

1,2;5,6-di-O-isopropylidene-D-mannitol

1) NaIO4; then

2) DIBAL-H

3) D-(-)-diethyl tartrate,

Ti(OiPr)4, tBuOOH

OO

O

OH

H3CCH3

(EtO)2P

O O

OEt

H2C

MgBr

CH3

1) CuBr,O

O

O

O

H3CCH3

H3C

H2C

2) PTSA,O

O3; then Ac2O

OO

O

O

H3CCH3

H3C

O

(CH3)3SiCHN2,O

O

O

O

H3CCH3

H3C

C H

H3CO

O

O

OCH3

CH3

O

O

O

O

O

1) O3; DBU; Ac2O2) DBU3) NaBH4, CeCl3

6

6

Dess-Martin periodinane

OH

O

O

O

O

6

4a

CH3

CH3

CH3

CH3

4a

1.1411.142

1.143

nBuLi

1.144

1.1461.145

Scheme 1.35. Taber’s C-H insertion strategy.

43

1.2.10 Fukuyama

Fukuyama’s approach to the core structure of racemic tetrodotoxin was centered on an

intramolecular [3+2]-dipolar cycloaddition of a nitrile oxide to set the all cis C-8a, C-4a, C-5

configurations.95

Tricycle 1.147 was envisioned as a possible TTX synthon, containing several of the

functional moieties in tetrodotoxin with the correct relative configurations (Figure 1.17).

Figure 1.17. Fukuyama’s TTX-core synthon 1.147.

Fukuyama began his synthetic inquiry with imidodicarbonate 1.150, prepared in six-steps from p-

anisaldehyde (Scheme 1.36). With precursor 1.150 in hand, Fukuyama approached the

iodoaminocyclization reaction according to Taguchi’s protocol96

with LiAl(tBuO)4 and excess I2 to access

1.151 which was converted to diiodo-1.152 straightforwardly. Compound-1.152 served well as a

precursor to the forthcoming intramolecular nitrile oxide 1,3-dipolar cycloaddition.

CHO

OCH3

1) allyl-MgBr2) O3; NaBH4

OCH3

HO OH1) Li, NH3

2) PPTS, HOCH3

OCH3

HO OH

H3CO

OCH3

O OTBS

H3CO

1) TBSCl2) triphosgene, benzyl carbamate

CbzHN

O

OCH3H3CO

I

O

N

OTBSO

Cbz

1.148 1.149

1.1501.151

LiAl(tBuO)4;

I2

OCH3H3CO

I

O

N

IO

Cbz

1.152

1) TBAF

2) I2, PPh3, imidazole

Scheme 1.36. Fukuyama’s route to diiodo 1.152 enroute to 1.147.

44

Deprotection of the dimethyl ketal and concomitant dehydroiodination of the secondary iodide

with hot aqueous acetic acid afforded enone 1.153, which was converted to the silyl enol ether and then

the primary iodide was substituted with sodium nitrite to 1.154 (Scheme 1.37). Fukuyama treated 1.154

with di-tert-butyl dicarbonate and DMAP97

to dehydrate the primary nitro group to the corresponding

nitrile oxide and induce the subsequent intramolecular 1,3-dipolar cycloaddition with the C-5/C-4a olefin

to give tetracycle 1.155 as a single diastereomer. The C-7/C-8 olefin was installed by treatment of silyl

enol ether 1.155 with phenylselenium chloride in methanol and mCPBA oxidation to give unsaturated

mixed acetal 1.156. A DBU-mediated oxazolidinone-opening gave tricycle 1.157 that was primed for

attempts to oxidize the cyclopentene unit. Fukuyama found that dihydroxylation of 1.157 proceeded from

the convex face of the bowl-shaped tricycle, and reductive workup with Na2SO3 gave the corresponding

oxazolidinone. Oxazolidinone formation suitably protected the C-9 hydroxyl group, allowing

manipulation of the C-10 hydroxyl group to proceed specifically after reduction of the isooxazoline C=N

bond and Alloc protection. Oxidation at C-10 with Dess-Martin periodinane and Baeyer-Villiger

oxidation afforded ring-expanded lactone 1.159. Methanolysis of lactone 1.160 and palladium-mediated

deprotection of the Alloc group afforded isooxazoline 1.147 containing the oxidation level at C-4 found in

TTX.

45

H3CO

OH

OCH3H3CO

I

O

N

IO

Cbz

1.152

O

O

N

IO

Cbz

1.153

OTBS

O

N

NO2

O

Cbz

1.154

O

N

O

N

OTBS

O

1.155

OTBS

O

N

N

O

Cbz

O

[3+2]

HOAc aq

1) TBSOTf2) NaNO2

Boc2O, DMAP

O

N

O

N

OTBS

O

Cbz

1.156

H3COO

N

CbzHN

OTBS

1.157

H3COO

N

O

HN

OTBS

O

1.158

Alloc

H

H3COO

N

OTBS

1.159

Alloc

O

O

O

HN

O

H

H3COO

N

OTBS

1.160

Alloc

CO2CH3O

HN

OHO

H

H3COO

N

OTBS

1.147

CO2CH3O

HN

O

11

57

HO

HO

OH

CHO

HO

H2N

CO2HHO

OH

6

core skeleton

57 6

1) PhSeCl, CH3OH2) mCPBA; NaHCO3

DBU

1) OsO4

2) NaBH4

3) Alloc-Cl

1) Dess-Martin periodinane

2) mCPBA

K2CO3, CH3OH

Pd(PPh3)4

4a

58

7

8 8

Cbz

109

9 9

10 10

44

100 °C

4

4

4

4a

5

Scheme 1.37. Fukuyama’s racemic route to TTX core synthon 1.147.

46

1.2.11 Ohfune

In early 2003, the Ohfune group communicated work in their laboratory on the stereoselective

construction of a tetraol system corresponding to the C-5, 6, 7, 11 hydroxyl groups in (−)-tetrodotoxin.98

The consecutive hydroxyl groups in (−)-tetrodotoxin have proved to be one of the challenges in the

construction of the unique core structure. Ohfune approached the tetraol part of tetrodotoxin (Figure

1.18) through a series of repetitive stereoselective epoxidation/base-induced ring-fragmentation reactions

beginning from (−)-quinic acid derivative 1.161 which already contained the correct C-6 geometry.

Figure 1.18. Ohfune’s approach to (−)-tetrodotoxin.

Ohfune generated allyl sulfone 1.162 as the sole regioisomer via the dehydration of diol 1.161

with (PhS)2/Bu3P, as developed in their laboratory (Scheme 1.38).99

Epoxidation occurring from the less-

sterically demanding -face of the allyl sulfone and subsequent base-mediated ring-opening/olefin

isomerization gave 1.164 with the correct configuration of the C-5 hydroxy group. The same mCPBA

epoxidation/base-mediated ring-opening sequence was repeated on 1.164 to generate 1,3-diaxial diol

1.166. Having set the diaxial C-5, C-7 stereochemistry, Ohfune tackled the installation of the C-6, 11

diol. Protection of 1.166 as the cyclic acetal, removal of the phenyl sulfone group and deprotection of the

-OTBS group afforded 1.168. Inversion of the C-4 stereocenter was accomplished through an

oxidation/reduction sequence, and osmium tetraoxide-based dihydroxylation of the exo olefin lead to

1.169 containing the C-5, 6, 7, 11 tetraol system in (−)-tetrodotoxin. Ohfune’s stereoselective route to the

tetraol system by successive epoxidation and allyl sulfone ring-opening operations effectively addressed a

method of accessing the 1,2,3-triaxial hydroxyl groups of (−)-tetrodotoxin on a simpler (−)-quinic acid

derivative.

47

1.161

OO

OCH3

H3C

OCH3

H3C

TBSO OHOH

(PhS)2/Bu3P

1.162

OO

OCH3

H3C

OCH3

H3C

OTBSSPh

mCPBA

1.163

OO

OCH3

H3C

OCH3

H3C

OTBSSO2Ph

O

KOtBu

1.164

OO

OCH3

H3C

OCH3

H3C

OTBSSO2Ph

OHmCPBA

1.165

OO

OCH3

H3C

OCH3

H3C

OTBSSO2Ph

OH

OKOtBu

1.166

OO

OCH3

H3C

OCH3

H3C

OTBSSO2Ph

OH

HO

1.167

OO

OCH3

H3C

OCH3

H3C

OTBSSO2Ph

O

O

NaH, CH2Br2

1) nBuMgCl,

Pd(acac)2

2) TBAF

1.168

OO

OCH3

H3C

OCH3

H3COH CH2

O

O 1) Dess-Martin periodinane

2) NaBH(OCH3)33) TBSOTf4) OsO4 1.169

OO

OCH3

H3C

OCH3

H3C

TBSOO

O

OH

OH

5

7

5

6

11

Scheme 1.38. Ohfune’s approach to C-5, 6, 7, 11 tetraol system in (−)-tetrodotoxin.

48

1.2.12 Summary

Several groups have pursued tetrodotoxin as a synthetic target. The history of the synthesis of

tetrodotoxin and of the tetrodotoxin core is marked with various themes which have evolved over time.

In comparing the completed tetrodotoxin syntheses to date, it is easy to recognize similar finishing

strategies due to tetrodotoxin’s polar guanidine and ortho acid functionalities. Other similarities between

synthetic approaches are abundant. Funabashi created synthetic tetrodotoxin intermediates via

intramolecular Henry addition, a theme used later by Sato in his initial synthesis of optically active (−)-

tetrodotoxin from D-glucose. The Taber group achieved a synthesis of an advanced intermediate for

tetrodotoxin by using an intramolecular carbene insertion to install the C-6 center, a similar method which

was used by Du Bois in his remarkable conquest of (−)-tetrodotoxin where he utilized two impressive C-

H-activation transformations to build (−)-tetrodotoxin, using synthetic methodology published only a

couple of years before. Keana approached the carbocyclic framework synthesis via Diels-Alder

chemistry, as did Kishi and Isobe, but with a twist to simultaneously, and thus far uniquely, install the

cyclic guanidine functionality early-stage. Fraser-Reid completed advanced tetrodotoxin intermediates

via radical cyclization chemistry, an approach further explored by Alonso. Ohfune used repetitive

epoxidation/ring-opening sequences in construction of the tetraol core, similar to work by Isobe. Both

Kishi and Isobe approached the hexasubstituted cyclohexane ring through intramolecular epoxide ring-

opening events, which also set the requisite stereocenters. Fukuyama’s use of a nitrile oxide in an

intramolecular 1,3-dipolar cycloaddition to set the all-cis C-8a/C-4a/C-7 configurations lead to work

described in Chapter 2 of this thesis as an approach to the core of tetrodotoxin.

Despite the major advances in the synthesis of tetrodotoxin and its core, the structural complexity

of tetrodotoxin ensures that it will continue to be a synthetic target for years to come. All current total

syntheses (summarized in Figure 1.19) to date are long (28-40 linear steps), and the densely

functionalized carbocyclic core makes convergent approaches to shorten the synthesis difficult, as evident

by the lack of shorter syntheses almost 40 years after the structural elucidation of tetrodotoxin.

Tetrodotoxin serves as not only a template upon which to test new reactions and transformations, but also

as a source for the very creation and discovery of new reaction types.

49

6

8a

NH

N

OH

OH NH2

HO

OH

OO

O

OHH

H

CHO

OHHO

HO

OH

HO

NH2

CO2HHO

O

O

CH3

H

AcHNR

HO

O

O

H3C

CH3

R"

R'

O

PivO

OO OTBS

O

O

CH3

CH3

HOOH

OHOH

HOHO

tetrodotoxin

O

O

CH3

H3C

NHO

O

OAc

OAc

OAcAcO

OHO

HO

O

OHHO

Sato 2005racemic

Kishi 1972racemic

Isobe 2003asymmetric

Du Bois 2003asymmetric

O

OH

HOHO

OH

HO

O

OO OTBDPS

OO

O

H3CCH3

H3C CH3

MOM

Sato 2008/2010asymmetric

O

Br

O

O

Isobe 2004/2010asymmetric

1.170

1.7 1.751.90

8a

6 8a

6 8a 68a

6

generalized TTX-core synthon

1.19 R = OBOM, R' = OTBDPS, R" = OBz1.45 R = R' = R" = H

Figure 1.19. Comparison of retrosynthetic intermediates between completed total syntheses to date.

50

2 The oxidative amidation strategy

2.1 General strategy

It is in the greater context of the afore-mentioned works that we examined tetrodotoxin as a target

for total synthesis. The dense and intricate structure of tetrodotoxin provided an opportunity for the

exploration of new and unique synthetic strategies. Bearing this in mind, we recognized the possibility

described in Figure 2.1. Compound 2.2, which is a generalized product of oxidative amidation of a

phenol of type 2.1 where G = an oxygen functionality, or appropriate precursor thereof, may be mapped

nicely onto compound 1.170. Compound 1.170 emerges upon release of the guanidine and orthoacid

functionalities of tetrodotoxin and is a common retrosynthetic intermediate as per Kishi, Du Bois and

Isobe.

tetrodotoxin

NH

N

OH

OH NH2

HO

OHO

O

O

OHH

H

OH

OH

COOH

HO

NH2

HO

HO

CHO

OH

COOR

O

NHAcG

COOR

HO

G

1.170

2.1 2.2

4a

6

8a

8a

6

4a

4

5

5

Figure 2.1. Retrosynthetic hypothesis for tetrodotoxin.

The conversion of compound 2.2 into 1.170 requires, among other things, the stereocontrolled

introduction of the C-5 hydroxyl group and C-4 aldehyde (or equivalent moiety). Fukuyama’s work95

(Chapter 1.2.10) indicated that the stereocontrolled introduction of these elements across the C-4a/C-5

olefin could be accomplished via an intramolecular nitrile oxide-olefin cycloaddition (INOC)

reaction.100,101

We further envisioned that fragmentation of isooxazoline 2.4 could lead to the revealing of

both the C-5 hydroxyl group and also the C-4 formyl unit masked as a cyano group (Figure 2.2).

51

O

AcHN

COOR

G

O

AcNG

O

N

O

OO

O NH

H

AcN G

Nu

[?]

O

CO

AcHNG

Nu

OH

CNH

H

[?]

[?]

H2C

CO

NG

Nu

O

CNH

H

P

P

[?]

OH

HO

NH2HO

HO

OH

CHO

COOH

OH

2.2

1.170 2.6 2.5

2.3 2.4

H H

H

4

5

Figure 2.2. Generalized strategy for the elaboration of the tetrodotoxin core.

Our elaborated retrosynthetic analysis is depicted in Figure 2.3 and features a common end-game

strategy involving ortholactone and guanidine formation. A sequence involving methylenation to install

the C-11 carbon unit, common to the work of Sato (Schemes 1.26, 1.28), as well as osmium tetraoxide

dihydroxylations to install the four hydroxyl units across C-6, C-11, C-7 and C-8, elaborates the

carbocycle 1.170. Functionalized enone 2.5 is a product of an intramolecular 1,3-dipolar cycloaddition

reaction and subsequent isooxazoline fragmentation, with the pendant C-9 arm delivering the dipole to the

C-4a/C-5 olefin in a stereocontrolled manner. Dienone 2.2 is rapidly and uniquely assembled from an

oxidative amidation reaction of a phenol of type 2.1.

52

orthoacidformation

guanidineformation

methylenation

OsO4 dihydroxylations

COOR

O

H

H

NHAc

HO

OHCG

dienonefunctionalization

oxidativeamidation

OH

OH

COOH

HO

NH2

HO

HO

OHC

OH

1.170

4a

6

8a

4

5

tetrodotoxin

NH

N

OH

OH NH2

HO

OH

OO

O

OHH

H

COOR

O

NHAcG

2.2

8a

6

4a

5

COOR

HO

G

2.1

2.5

4

8a4a

5

6

8a

6

9

9

10

10

7

7

8

8

11

6

8a

Figure 2.3. Our elaborated tetrodotoxin retrosynthetic analysis.

53

2.2 Oxidative amidation

The oxidative amidation of phenols102,103

entails the creation of aza-substituted dienones of type

2.8 from phenolic substrates of type 2.7 (or ortho-substituted derivatives of 2.7). Group N is a suitable

nucleophilic nitrogen moiety in 2.7 and is an amide functionality in 2.8 (Figure 2.4). The dashed-curve

indicates that the N-group may be either covalently tethered to the phenolic ring (intramolecular) or may

be an independent molecule (bimolecular). Hypervalent iodine (III) reagents,104-110

especially PhI(OAc)2

(diacetoxy iodobenzene, DIB) and PhI(OCOCF3)2 (phenyliodine bis(trifluoroacetate), PIFA), are uniquely

competent in effecting oxidative amidation reactions of phenols, a special case of oxidative

dearomatization of phenols.111

HO

oxidation

O

NN

2.82.7

Figure 2.4. Oxidative amidation of para-phenols.

Oxidative amidation reactions of phenols proceed through an electrophilic intermediate such as

2.9 which is trapped with the nucleophilic N-group (Figure 2.5). The chemical literature is rife with

examples of the oxidation of a phenol112

to a transient electrophilic species followed by interception with

suitable nucleophiles. Barton113-115

published initial discoveries in this area in the 1950’s as well as

others.116,117

As synthetic organic technologies evolved, newer and more effective oxidants were used in

phenol oxidation reactions,118

however the development and widespread use of hypervalent iodine

reagents permitted easy access to reactions of this type. Contributions to the chemical literature over the

past 25 years by Kita,119-121

Pelter,122

Barret,123

and Wipf124,125

testify to the transcendence of oxidative

dearomatization of phenols reactions from a novelty-class of reaction to a widely useful paradigm for the

creation of synthetically useful products.

Figure 2.5. Oxidative amidation of para-phenols.

54

Oxidative dearomatization reactions, as described in Figures 2.4 and 2.5, are mechanistically

distinct from related transformations (Figure 2.6) such as Kikugawa-Glover-type reactions.126-140

These

involve the oxidation of an amide unit of type 2.10 to an electrophilic nitrogen-containing intermediate of

type 2.11. The nucleophilic electron-rich aromatic ring attacks the electrophilic nitrogen, resulting in

products of type 2.12 which formally resemble products of oxidative amidation (2.8) as in Figure 2.5.

Kikugawa-Glover-type reactions

RO

2.10

NH

OZ

Z = CH3O, PhtN

RO

2.11

N

OZ

O

2.12

N

OZ

[O]

Figure 2.6. Kikugawa-Glover-type reactions.

2.2.1 Oxidative amidation in total synthesis

The recognition that oxidative amidation technology could allow the rapid assembly of various

nitrogen-containing substances led the development and subsequent refinements of this methodology.

Oxidative amidation reactions of the type described in Figure 2.4 were developed in the Ciufolini

laboratory to approach synthetic challenges in natural product synthesis programs such as FR901483141

and TAN1251C142

(Figure 2.7). The investigation of different modes of oxidative amidation of phenols

can be categorized into three distinct generations (Figure 2.9), all of which evolved to solve specific

synthetic challenges in natural product synthesis. All three generations of oxidative amidation reaction

are promoted by DIB.143

The first generation of oxidative amidation reaction involved the cyclization of

phenolic oxazolines, and was applied to the synthesis of FR901483 and TAN1251C (Figure 2.7).

Independently, Sorensen144,145

and Honda146-148

developed oxidative dearomatization-cyclization reactions

of phenolic secondary amines 2.13 and 2.15 in their syntheses of FR901483 and TAN1251C (Figure 2.8).

The second generation of oxidative amidation involved the intramolecular oxidative cyclization of ortho-

and para-phenolic sulfonamides and was applied to the synthesis of (−)-cylindricine C149

and towards the

himandrine core.150

The third generation oxidative amidation reaction type is the bimolecular reaction of

2- and 4-substituted phenols with nitriles and has been applied towards histrionicotoxins151

and

tetrodotoxin.152

The development of the third generation of oxidative amidation as a reliable large-scale

(50-100g) reaction was significantly advanced as a result of the synthetic ventures described in Chapter

2.3.1 of this thesis.

55

Figure 2.7. Structures of FR901483 and TAN1251C and Ciufolini’s retrosynthetic logic for the

construction of their ring systems.

Figure 2.8. Sorensen’s144,145

and Honda’s146-148

oxidative cyclization of phenolic secondary amines.

56

Figure 2.9. Ciufolini modes of oxidative amidation of phenols.

57

2.3 Bimolecular oxidative amidation

The initial conditions (Scheme 2.1) for the bimolecular mode of oxidative amidation in the

presence of nitriles153,154

suffered from two main drawbacks: variable yields and costly solvent

(1,1,1,3,3,3-hexafluoroisopropanol, HFIP or 2,2,2-trifluoroethanol, TFE). These fluorinated alcohols

were initially selected as solvents based on work by Kita,119-121

which indicated that phenol oxidations

promoted by DIB proceed best in these solvents, presumably due to their acidic and non-nucleophilic

nature. The development of a procedure which reliably allows for efficient large-scale synthesis of

compounds of type 2.30 and also avoids costly solvents emerged as an important goal.

HO

RPhI(OAc)2,CH3CN, HFIP

O

RN

H

O

CH3

2.302.29

50-85%

Scheme 2.1. Initial conditions for bimolecular oxidative amidation.153

2.3.1 Optimization of scalable bimolecular oxidative amidation conditions

Figure 2.10. Possible DIB-mediated bimolecular oxidative amidation mechanism.

58

Bimolecular oxidative amidation reactions in which the nitrile nucleophile serves as co-solvent

suffer when run at higher concentrations of phenol (Figure 2.11). Phenols are better nucleophiles than

nitriles such as acetonitrile, and thus tar-like oligomers are obtained from oxidative amidation reactions,

which ceteris paribus, are run at higher concentration of phenol starting material. Reactions run at large

scale under the initial conditions for oxidative amidation153

yield products contaminated with oligomeric

matter which complicates the isolation of the desired dienone products (2.30) by requiring lengthy

chromatographic purifications. Fluorinated alcohol solvents such as HFIP and TFE are highly costly, and

their avoidance in these oxidative amidation reactions is merited.

Figure 2.11. Effect of phenol concentration on reaction outcome.

Phenol 2.31 was selected as the starting material to begin optimization studies, since the product

of its oxidative amidation, compound 2.32, was required for work in assembling the tetrodotoxin core.

Our initial optimization studies focused on small-scale optimization (1g of phenol 2.31) based upon the

initial 2005 conditions153

(Table 2.1). This reaction worked best when the phenol was added to a solution

of DIB in acetonitrile/co-solvent in order to keep the concentration of phenol minimized (see Figure 2.11)

and avoid undesired side reaction. A reaction (Table 2.1, entry d) was observed in which PIFA was used

without the presence of any fluoro-solvents in the bimolecular oxidative amidation reaction. This

observation is in accord with work by Wood,155

and suggested that perhaps small amounts of TFA were

sufficient replacement for HFIP or TFE in these types of reactions. Entry e in Table 2.1 further indicated

that DIB could be used in oxidative amidation reactions of this type, and a more thorough optimization of

the bimolecular oxidative amidation reaction was carried out based upon this.154

59

Table 2.1. Optimization of scalable conditions for bimolecular oxidative amidation.

Work to scale this reaction to >10 g indicated that the addition of phenol 2.31 to a solution of

acetonitrile/TFA containing DIB was best done with solid, crystalline 2.31. Experiments involving the

dissolution of the solid phenol in acetonitrile followed by a slow syringe pump addition gave less efficient

yields compared to reactions in which the phenol 2.31 was added as a solid (Table 2.2). Each of the

entries in Table 2.2 were carried out at least in triplicate. The sensitivity of this oxidative amidation

reaction to the presence of water was also examined. The yield of a reaction solution containing 1% v/v

H2O was compared to the corresponding anhydrous solution and found to be nearly equivalent. The color

of the reaction mixture for the solution containing 1% H2O was dark brown, compared to the dark

blue/purple color of the anhydrous reaction mixture, but no significant difference was observed in the

yield or isolation of the product (2.32). Entry f in Table 2.2 showed 70% yield for the reaction when very

small amounts of phenol 2.31 were added to the DIB solution over the course of three hours (addition was

done manually). These conditions were repeated six times with the same results. In all cases examined in

Table 2.2, the workup and isolation remained the same. The crude reaction mixture was concentrated in

vacuo by rotorary evaporation (12.7 Torr, 40 °C) and the residue passed through a small plug of silica gel

(75 g). Non-polar impurities were eluted with 50:50 ethyl acetate:hexanes, and product eluted with 100%

60

ethyl acetate. The enriched product 2.32 crystallized upon standing, and was recrystallized from a hot

solution of acetone:diethyl ether (1:1). Very large crystals of compound 2.32 were obtained from

recrystallization (2cm X 2cm X 1cm) which allowed for X-ray crystallographic analysis.156

40-50

HO

CO2CH3

O

HN CH3

O

a after flash column chromatographyb additional product present in supernatant following recrystallization

CO2CH3

DIBCH3CN/TFA

additive

entry yielda (%)

a N/A 25-30

b N/A 20-30

c N/A 40-50

d

70b+

2.31 2.32

additive

H2O1 % v/v

f N/A

DIB = iodobenzene diacetate

addition

syringe pump(3 h)

solid addition(all at once)

solid addition(500 mg/30 min)

solid addition(500 mg/30 min)

solid addition(constant manualaddition over 3 h)

10 g

45-55e N/Asolid addition(250 mg/15 min)

Table 2.2. Larger-scale reproducible conditions for oxidative amidation of phenol 2.31 with acetonitrile.

61

2.4 Nitrile oxide [3+2] cycloaddition

The next objective, once the bimolecular oxidative amidation reaction to create dienone 2.32 was

optimized, was to convert 2.32 into a functionalized enone of type 2.5 as Figure 2.3. The

desymmetrization of dienones of type 2.8 enables stereoselective access to the tetrasubstituted nitrogen-

bearing carbon in enantiomers 2.33 and 2.34 (Figure 2.12). Structures of type 2.33/2.34 would arise from

the selective addition of a generic reagent X-Y across either the pro-(R) or pro-(S) -bond of 2.8. 1,3-

Dipolar cycloaddition reactions offered a rapid route for the construction of a wide variety of five-

membered heterocycles,157,158

and are well-documented methods for the synthesis of isooxazolines.159-162

Isooxazolines are established precursors to amino ketones, oxo alcohols and other functional groups as

well as a variety of natural products from reduction of the N-O bond or other ring-fragmentations.157-162

It

was in this mode that we approached the desymmetrization as described generally in Figure 2.2: a nitrile

oxide 1,3-dipolar cycloaddition reaction with the C-9 arm delivering the dipole to the dienone to install

the functional units at C-4a/C-5.

Figure 2.12. Desymmetrization of dienone 2.8.

In anticipation for the advancement of the ester functionality of 2.32 to an -nitroketone163

as a

precursor to reactive nitrile oxide intermediate 2.3 (Figure 2.2), the reduction and protection of dienone

2.32 was desired. Dienone 2.32 proved to be an excellent Michael-acceptor, and the reduction/protection

sequence suppressed the possibility of unwanted later-stage intramolecular Michael additions. Various

reduction conditions were screened (Table 2.3). Initial conditions involved NaBH4 and

NaBH4/CeCl3164,165

and resulted in roughly a 1:1 ratio of diastereomers 2.35 and 2.36. A DIBAL-H

reduction of 2.32 at –78 °C gave, in good yield, the -diastereomer 2.35. The diastereoselectivity of this

62

reduction can be reversed with a (S)-CBS/BH3 reduction166,167

using 1 mol % of CBS reagent at room

temperature.168

Both diastereomers 2.35 and 2.36 have further downstream utility in this approach to the

tetrodotoxin core. The relative configurations of the doubly allylic alcohols 2.35 and 2.36 was

determined on the basis of X-ray crystallographic studies of later intermediates (vide infra).

Table 2.3. Reduction of dienone 2.32.

63

Compound 2.35, the -diastereomer from the DIBAL-H-mediated reduction of dienone 2.32, was

protected as the TBDPS-ether using standard conditions, and the methyl ester cleaved with aqueous

sodium hydroxide to afford carboxylic acid 2.38 (Scheme 2.2). Acidification of the reaction mixture after

saponification of the methyl ester with aqueous sodium hydroxide needed to be done carefully, ensuring

that the apparent pH of the solution stayed >2 to avoid lactonization to 2.41 as per Scheme 2.3.169

Activation of acid 2.38 with carbonyldiimidazole (CDI)170,171

and condensation of the resultant acid

imidazolide with the nitronate of nitromethane (generated in situ from nitromethane and potassium tert-

butoxide) generated nitroketone 2.39 in high yield after flash column chromatography.172

Scheme 2.2. Synthesis of nitroketone 2.39.

ONHAc

CO2HTBDPS

-OTBDPS = 2.40-OTBDPS = 2.38

pH < 2

O

O

H

NHAc

2.41

quantitative

Scheme 2.3. Undesired cyclization reaction of intermediate 2.40/2.38.

The conversion of nitroketone 2.39 to the reactive intermediate nitrile oxide 2.42 formally

entailed a dehydration reaction. A generic reagent X-Y could be reacted across the nitro group as

indicated in Figure 2.13, affecting the dehydration of nitroketone 2.39 to -keto-nitrile oxide173-175

2.42.

64

O NHAc

H

TBDPS

ON

OO

X-Y

HH

O NHAc

H

TBDPS

ON

OO

H

XY

O NHAc

H

TBDPS

ONO

2.422.39

Figure 2.13. Theoretical dehydration of nitroketone 2.39.

The dehydration of nitroketone 2.39 proved quite troublesome (Table 2.4). Initially this was

examined using various reagents known for their use in nitro-dehydration reactions. A technique for

converting nitroalkanes to their corresponding nitrile oxides was Mukaiyama’s aromatic isocyanate

method176

which used such reagents as 4-chlorophenyl isocyanate.177,178

Reactions with nitroketone 2.39

and 4-chlorophenyl isocyanate gave complex mixtures of products. Other known methods for converting

alkyl nitro compounds into their nitrile oxide derivatives were attempted as well. Shimizu’s method179

using ethyl chloroformate resulted in the slow conversion of nitroketone 2.39 to adduct 2.43. Hassner’s

method,97

used by Fukuyama in his work on the TTX core (Chapter 1.2.10), using 4-(N,N-

dimethylamino)-pyridine (DMAP) and di-tert-butyl-pyrocarbonate (Boc2O) was ineffective as well.

These methods and reagents, and several others, failed to efficiently produce the desired intramolecular

nitrile oxide cycloaddition product 2.43 (Figure 2.14). Common side product 2.44, whose structure was

ascertained by X-ray crystallography, arose formally from the intramolecular O-alkylation of the

nitroketone enolate via allylic displacement of the OTBDPS unit, and could be generated in high yield by

treating the nitroketone 2.39 with triethylamine (Scheme 2.4). The initial data from the studies described

in Table 2.4 were tantalizing: trace amount of the desired tricycle 2.43 appeared to be present according

to 1H-NMR studies on crude reaction materials. This indicated that the transformation indeed must be

possible, but that efficient reaction conditions remained elusive.

O NHAc

H

TBDPS

OO2N

O

O

NHAc

H

TBDPS

NO

O NHAc

H

TBDPS

ONO

[3+2] dipolar cycloaddition

2.432.422.39

Figure 2.14. Nitrile oxide [3+2] dipolar cycloaddition.

65

Table 2.4. Initial attempts to dehydrate nitroketone 2.39.

ONHAc

TBDPS

O

NO2

Et3N

CH2Cl2 OH

NHAc

2.44

NO2

63%2.39

Scheme 2.4. An undesired reaction of nitroketone intermediate 2.39.

66

Sensing that the -keto-group of nitroketone 2.39 could be responsible for the undesired

reactivity seen thus far, we sought to alleviate this potential issue through a reduction/protection sequence

(Scheme 2.5). Thus, NaBH4 treatment of nitroketone 2.39 provided unstable nitro alcohol 2.45, a

sensitive material that was prone to undergo a retro-Henry fragmentation event, especially upon

manipulations or attempted purification. Accordingly, crude nitro alcohol 2.45 was immediately O-

silylated with TBSCl/imidazole.

O

NO2

TBDPSO

NHAc

2.39

NaBH4 (5 eq)CH3OH

OH

NO2

TBDPSO

NHAc

2.45

TBSCl (1.5 eq)imidazole

OTBS

NO2

TBDPSO

NHAc

2.46

Scheme 2.5. Reduction/protection sequence of nitroketone 2.39.

A careful analysis of 1H-NMR data from the crude reaction mixture to synthesize compound 2.46

indicated the presence of small quantities of tricyclic materials of the type 2.49/2.50/2.51/2.52. The O-

silylation event indicated in Scheme 2.6 proceeded with concomitant Torssell-type cyclization162

(Figure

2.15). Thus purified TBS-ether 2.46 was treated with TBSCl (4 eq) and imidazole (4 eq) and resulted in a

1:1 mixture of tricyclic isooxazolines 2.49/2.50 (Scheme 2.6). The lack of diastereoselectivity signaled

that the steric demand of the OTBS group was insufficient to exert stereocontrol during the cycloaddition

step (see Figure 2.12). Notably, minor amounts of a mixture of diastereomeric nitroso acetals180

2.51 and

2.52 were isolated following flash column chromatography of the desired isooxazolines 2.49/2.50. Upon

prolonged standing, both 2.51 and 2.52 spontaneously converted to the desired 2.49 and 2.50. A sample

of enriched diastereomer 2.51/2.52 (6% yield) was isolated by flash column chromatography and

characterized. These materials (2.51/2.52) converted to compound 2.49/2.50 upon standing. The

presence of nitroso acetals 2.51 and 2.52 implicated the intermediacy of siloxy nitronate162,180-184

2.48 en

route to desired isooxazolines 2.49 and 2.50. The desired product formed from an intramolecular

siloxynitronate-olefin cycloaddition (ISOC) process. It was unclear if the ISOC pathway occurs

simultaneously with the expected INOC pathway or exclusively.

67

Scheme 2.6. [3+2]-dipolar cycloaddition of 2.46.

Figure 2.15. Torssell cyclization: silyl nitronates as 1,3-dipoles.

Treatment of diastereomers 2.49 and 2.50 with TBAF to release the alcohols afforded a 1:1

mixture of diols 2.53 and 2.54 (Scheme 2.7). Slowly, tiny crystals of 2.53 formed from the reaction

mixture and allowed for X-ray structural study185

which elucidated the relative configuration between the

C-4a and C-6 (tetrodotoxin numbering) that had been set during a low temperature DIBAL-H reduction of

dienone 2.32 (Table 2.3 and Scheme 2.2).

68

8a

6

TBDPSO

O N

OTBS

NHAc

TBAF

HO

O N

OH

NHAc

2.53

HO

O N

OH

NHAc

2.54

+

= 2.49 = 2.50

Scheme 2.7. Confirmation of structural geometry: X-ray crystallographic analysis of 2.53.

The success with the TBSCl-mediated conversion of 2.46 to cyclized products 2.49/2.50

prompted attempts to try similar conditions for the originally-planned nitroketone dehydration. Treatment

of nitroketone 2.39 under various conditions based around TBSCl (Table 2.5) were attempted. This

reaction appeared to be quite slow, with conversions to product taking place over approximately a week.

Attempts to accelerate the reaction by the addition of 10 equivalents of TBSCl and imidazole each

resulted in the unexpected formation of the noteworthy dihydropyridone 2.55 as the major product (65%,

Scheme 2.8) with concomitant decrease in the yield of the desired isooxazoline 2.43 (5% yield after flash

column chromatography). The architecturally unique structure of 2.55 was elucidated by X-ray

crystallographic analysis and there appeared to be no other reports of similar molecules in the literature.

The compound formally evolved from an unusual Knoevenagel-type186,187

intramolecular condensation of

the nitroketone arm of 2.39 with the attached acetamide; it was presumed to proceed through the O-silyl

imino ether derivative of the C-8a acetamide unit. Other reactive silylating reagents such as TMS-OTf

and TBS-OTf resulted in the rapid and complete degradation of starting nitroketone 2.39.

69

2.39 2.43

conditions

O

NHAc

H

TBDPS

O

NO2

O

O

NHAc

H

TBDPS

NO

entry reagent base solvent temp time result

a

b

c

d

e

f

g

h

i

j

k

TBSCl (2 eq) - DMF 65 °C 24 h 2.44

TBSCl (2 eq) - DMF RT 24 h 2.44

TBSCl (1.2 eq) DMAP (cat.) CH2Cl2 RT 3 days SM + 2.44

TBSCl (1.2 eq) TEA (1.3 eq) CH2Cl2 RT 3 days SM + 2.44

TBSCl (2.5 eq) imidazole (3 eq) 65 °CDMF 24 h complex mixture

TBSCl (2 eq) imidazole (2 eq) DMF 65 °C 24 h trace 2.43a

TBSCl (2 eq) imidazole (2 eq) DMF RT 6 days trace 2.43a

TBSCl (10 eq) imidazole (10 eq) DMF RT 3 days 2.55

TBSCl (6 eq) imidazole (8 eq) CH2Cl2 RT 5 days trace 2.43a, 2.55

TBSCl (2 eq) imidazole (4 eq) DMF RT 4 days trace 2.43a

TBSCl (4 eq) imidazole (2 eq) DMF RT 6 days 16% 2.43b

l TBSCl (2 eq) imidazole (2 eq) DMF, H2O RT 6 days SM, trace 2.43a

m TBSCl (1.1 eq) imidazole (3 eq) DMF RT 6 days trace 2.43a

n TBSCl (1 eq) imidazole (1.1 eq) CH2Cl2 RT 4 days mostly SM

a based on crude 1H-NMRb after flash column chromatography

Table 2.5. Nitroketone 2.39 dehydration optimization.

ONHAc

TBDPS

O

NO2 2.55

TBSCl (10 eq),imidazole (10 eq),

DMF

65%

HN

CH3

NO2

O

TBDPSO

2.39

Scheme 2.8. Unusual Knoevenagel-type condensation of nitroketone 2.39.

70

Further attempts to refine conditions for the desired conversion of 2.39 to tricycle 2.43 (Table

2.6) narrowed the search to two-equivalents each of TBSCl and imidazole in dichloromethane at room

temperature. These reactions were run at small scale (25-50 mg each). At this time, it was still not

possible to resolve the question of whether 2.43 is formed via an INOC or an ISOC mechanism or

possibly both. Entry k in Table 2.6 showed that a moderate amount of desired product 2.43 could be

obtained after treatment of nitroketone 2.39 with TBSCl/imidazole (2 equivalents each), after a week-long

reaction time at room temperature.

Table 2.6. Refinements to [3+2] cycloaddition conditions.

The small scale conditions (Table 2.6, entry k) were transferred to a larger scale (1-5 g) and the

same yield was observed (Scheme 2.9). It was noted that the product began to decompose slowly over

time in the reaction mixture, so the reaction was typically stopped after a week and the crude material

purified by silica gel chromatography. The starting material (2.39) was recovered (35%) in addition to

71

the desired product, thus bringing the yield of 2.43 to a moderate 58% based on recovered starting

material (BRSM).

Scheme 2.9. Optimized conditions for dehydration of nitroketone 2.39.

We speculated that the relatively poor reactivity of the -nitro ketone 2.39 could have been due to

the facile enolization of 2.39 (Figure 2.16). When enolate 2.57 was exposed to TBSCl/imidazole, we

speculated that the formation of both 2.56 and 2.58 were possible. Reaction on the oxygen atom which

was formerly the -ketone would lead to synthetic dead-end 2.58 which was unable to undergo either of

the desired INOC or ISOC pathways. Conversely, reaction of the silyl halide on an oxygen atom of the

nitro group could lead to intermediate 2.56 which we postulate undergoes the desired [3+2] cycloaddition

in an ISOC and/or INOC mode. The slow conversion of nitroketone 2.39 to tricycle 2.43 could also have

been due to a possible interconversion of silyl intermediates 2.58 and 2.56.

72

OTBDPSO

NHAc

2.39

O

N

TBDPSO

NHAc

2.57

OTBDPSO

NHAc

N

O

O

TBS

2.58

[3+2] not possible

TBSClimidazole

TBSClimidazole

OTBDPSO

NHAc

N

O

OTBS

2.56

[3+2] possible

TBDPSO

O N

O

NHAc

2.43

ISOC/INOC

O

ON

O

O

[?]

Figure 2.16. Probable enolization of nitroketone 2.39 can inhibit [3+2] cyclization.

[3+2] Cycloaddition product 2.43 contains important structural features of the tetrodotoxin core.

Chiefly, the all cis-relationship of the C-5, C-4a and C-8a units in the six-membered carbocycle (Figure

2.17) provided a template for which to test our synthetic plans.

4a6

8a

45

10

O

O

NHAc

H

TBDPS

NO

all cis-relationship2.43

Figure 2.17. All cis-relationship of compound 2.43.

73

2.5 Kemp-type keto-isooxazoline fragmentation

At this juncture, attention turned to focus on the development of a procedure for the

fragmentation of keto-isooxazoline 2.43. The base-mediated ring-opening of benzisooxazoles to give -

cyano phenols is known as the Kemp elimination188-190

(Scheme 2.10). The resulting Kemp-elimination

fragment contained the requisite hydroxyl group (for C-5) and a formyl-equivalent nitrile (for C-4a) if this

concept were applied towards keto-isooxazolines such as 2.43. The tricyclic ring geometry of compounds

like 2.43 suffered from strain, and if a nuclophile such as methoxide were to add to the carbonyl, we

hypothesized that a ring fragmentation event would follow, yielding an -cyano alcohol formally

resembling Kemp-elimination products. As with the previous section, the implementation of an efficient

method to achieve the desired outcome required a good deal of experimentation.

Scheme 2.10. Ring-fragmentation and comparison to Kemp-elimination188-190

products.

Initial attempts to fragment tricyclic isooxazoline structures as per Figure 2.2 were centered on

intermediate 2.43 (Table 2.7). Treatment of 2.43 with sodium methoxide in methanol or potassium

carbonate in alcohols (methanol, ethanol, benzyl alcohol) failed to induce the desired conversion.

Catalytic amounts of lithium carbonate in methanol resulted in some conversion to the desired 2.59,

however reaction times were long and complex mixtures of cyclohexene 2.59 were obtained. Imidazole

in methanol as well as DMAP did not have any effect on isooxazoline 2.59. Finally, it transpired that

efficient recovery (68% isolated yield) of the desired 2.59 was achieved by ring opening with catalytic

amounts of lithium carbonate and imidazole in methanol (Table 2.7, entry g).

74

conditions

conditions yield

K2CO3, CH3OH trace 2.59a

imidazole, CH3OH 0%

2.43 2.59

NaOCH3, CH3OH 0%

LiOCH3, CH3OH 0%

O

O

NHAc

H

TBDPS

NO

O CO2CH3

H

TBDPS

HO N

NHAc

RT, ON

Li2CO3, imidazole, CH3OH 68%b

DMAP, CH3OH 0%

Li2CO3, CH3OH 10%b

a based on crude 1H-NMR of reaction mixtureb after flash column chromatography

entry

a

b

c

d

e

f

g

Table 2.7. Optimization of tricycle 2.43 fragmentation.

O CO2CH3

H

TBDPS

HO N

NHAc

68%O

O

NHAc

H

TBDPS

NO

CH3OH, imidazole,Li2CO3

2.43 2.59

Scheme 2.11. Kemp-type fragmentation: methanolysis of tricycle 2.43.

Enone 2.62 was ultimately prepared from isooxazoline 2.43 in a short sequence (Scheme 2.12).

Desilylation of 2.43 with TBAF or anhydrous HF•pyridine complex resulted in a complex mixture of

degradation products. Aqueous 35% HF in acetonitrile effectively liberated the hydroxyl moiety resulting

75

in a 70% recovered yield of compound 2.60. A Dess-Martin191,192

oxidation of enol 2.60 provided

diketone 2.61 which degraded upon prolonged chemical manipulations. For this reason, crude diketone

2.61 was treated with catalytic lithium carbonate and imidazole in methanol to afford the target (2.62) in

38% isolated yield over the two chemical transformations.

a) aq HF, THF; b) Dess-Martin periodinane, CH2Cl2; c) CH3OH, imidazole, Li2CO3.

O

CO2CH3

HO N

NHAc

O

O

NHAc

H

TBDPS

NO

c38%over2-steps

a

70%HO

O

NHAc

H NO

b

O

O

NHAc

NO

2.43 2.60 2.61

2.62

Scheme 2.12. Fragmentation sequence: conversion of 2.43 to desymmetrized enone 2.62.

My work in this thesis described thus far had demonstrated the feasibility of the planned approach

to the tetrodotoxin core (Figure 2.3) with the C-8 nitrogen installed through the oxidative amidation of a

phenol and the successful introduction of the C-5 hydroxyl and the C-4a formate-equivalent nitrile.

Planned TTX retron 2.5 (cf. Figure 2.3) possessed similarity to isolated product 2.62; formally a C-9

oxidation and a partial reduction of the C-4a cyano group were necessary to elaborate our TTX-core

intermediate. Other key features of the tetrodotoxin core molecule not yet addressed at this point

included the installation of the C-11 hydroxymethyl unit and the cis-dihydroxylation across the C-7/C-8

olefin.

O

CO2CH3

OHN

NHAc

2.62

H

HO

OHO

NHAc

2.5

H

H CO3CH3

OP8a

6 4a5

7

8

oxidation

reduction

Figure 2.18. Comparison of prepared enone 2.62 to proposed tetrodotoxin retron 2.5.

76

2.5.1 Access to a suitable dihydroxylation substrate

With the synthesis of enone 2.62 accomplished, attention turned to the selective C-7/C-8

dihydroxylation. Advanced intermediates of the type 2.5/2.62 (Figure 2.18) were not suitable substrates

for the exploration of the required selective dihydroxylation due to the lack of steric encumbrance on the

-face of the carbocycle. Cyclohexene-derivative 2.59 was likewise not a suitable substrate as the bulky

-OTBDPS group would likely have directed an osmium tetraoxide-mediated dihydroxylation from the

incorrect face of the molecule. However, if the C-6 epimer of compound 2.59 were obtained (see

compound 2.67), we envisioned that a large -OTBDPS group could provide enough steric demand as to

block the bottom face and appropriately direct the dihydroxylation. With this in mind, we revisited the

reduction of dienone 2.32 (cf. Table 2.3). A CBS-reduction of dienone 2.32 provided an inseparable

mixture of doubly-allylic alcohols 2.35 and 2.36 in approximately 1:2 ratio. This mixture of

diastereomers was treated with the same reaction sequence as in Scheme 2.2 to provide a mixture of

nitroketones 2.39 and 2.65 (Scheme 2.13). In this sequence, none of the diastereomeric product mixtures

were rigorously purified and all compounds were carried forward without purification.

HONHAc

CO2CH3HO

NHAc

CO2CH3+

1 : 2

TBDPS-ClimidazoleCH2Cl2

ONHAc

CO2CH3O

NHAc

CO2CH3+

1 : 2

TBDPS TBDPS

NaOHH2O/THF

ONHAc

CO2HO

NHAc

CO2H+

1 : 2

TBDPS TBDPS

1) CDI, THF2) KOtBu, CH3NO2

ONHAc

ONHAc

+

1 : 2

TBDPS TBDPS

O O

NO2NO2

2.35 2.36 2.37 2.63

2.642.382.652.39

Scheme 2.13. Synthesis of nitroketones 2.39 and 2.65.

Additionally, it warranted mention that we expected the conversion of nitroketone 2.65 to tricycle

2.66 (Scheme 2.14) to proceed at a faster rate relative to the conversion of nitroketone 2.39 to tricycle

2.43. This expectation was based on the hypothesis that the nitrile oxide-containing arm, as it approached

the olefin, could encounter the bulky -OTBDPS unit (Figure 2.19). We expected that this steric clash,

which was not possible for nitroketone 2.65 with its -OTBDPS unit orientated away from the emerging

1,3-dipole, would result in a difference in reaction rate and could enhance the efficiency of the dipolar

cycloaddition of nitroketone 2.65 relative to nitroketone 2.39.

77

Figure 2.19. Rationale for expected (but not observed) rate difference between nitroketones 2.39/2.65.

It was not possible to efficiently separate nitroketone intermediates 2.39 and 2.65, thus the

mixture was treated with the conditions optimized for [3+2] cycloaddition (Chapter 2.4). Similar yields

were obtained using the mixture of diasteromers 2.39 and 2.65 as were obtained from the single

diasteromer 2.39. Recovered nitroketones 2.39 and 2.65 were recycled following flash column

chromatography, rendering tricyclic products 2.43 and 2.66 in 20% and 47% yield respectively based on

the recovered starting materials. The results indicated in Scheme 2.14 showed that our expectation that

nitroketone 2.65 would react faster than nitroketone 2.39 was incorrect.

TBS-Cl,imidazole,

CH2Cl2

+

1 : 2

O N

NHAc

OO

TBDPS

+

O N

NHAc

OO

TBDPS

12%20% BRSM

28%47% BRSM

ONHAc

ONHAc

+TBDPS TBDPS

O O

NO2NO2

40% recovery of starting material

2.39 2.65

2.39 2.652.43 2.66

+

Scheme 2.14. Synthesis of tricycles 2.43 and 2.66.

78

Tricycle 2.66 was ring-fragmented under the same conditions as tricycle 2.43 (cf. Scheme 2.11)

using lithium carbonate in methanol with a catalytic amount of imidazole to give substituted cyclohexene

2.67 (Scheme 2.15). Large crystals of intermediate 2.67 were grown for an X-ray diffraction study to

examine the ring geometry of this system in anticipation of the planned osmium tetraoxide

dihydroxylation. The X-ray crystal structure generated indicated that the OTBDPS unit was blocking the

-face in a suitable manner to direct a proposed dihydroxylation event to occur from the less-sterically-

encumbered -face (Figure 2.20).

O N

NHAc

OO

TBDPS

Li2CO3

CH3OH imidazole

OH

O CN

CO2CH3

NHAc

90%

2.66 2.67

TBDPS

Scheme 2.15. Methanolysis of tricycle 2.66.

OH

O CN

CO2CH3

NHAc

2.67

TBDPS

C

N

NH

H3CO2C

Ac O

H

TBDPS

bottom face blocked

top face accessible

Figure 2.20. X-ray image of crystalline 2.67 and rationalization of expected facial selectivity.

79

2.6 Osmylation of substituted cyclohexene derivative

Compound 2.67 was treated with N-methyl morpholine oxide and catalytic osmium tetraoxide193

but no reaction was observed after more than a week reaction time (this reaction was monitored

periodically for 60 days). Not dissuaded by the failure of the commonly used Upjohn-procedure, we

attempted to use stoichiometric osmium tetraoxide to cause the osmylation of the C-7/C-8 olefin. In an

NMR-scale experiment (Scheme 2.16), compound 2.67 was dissolved in d5-pyridine and to this solution

was added solid crystals of osmium tetraoxide. The reaction was monitored by 1H-NMR and the addition

of solid OsO4 continued until the starting material 2.67 was fully consumed.

Scheme 2.16. Osmylation sequence.

Osmate ester 2.68 proved to be too fragile for rigorous purification/isolation sequence. Attempts

to isolate pure 2.68 resulted in the decomposition of the product. Additionally, the purported osmate 2.68

appeared to be resistant to (unoptimized) attempts at removing the osmium moiety. The structure of

compound 2.68 was proposed to be that indicated in Scheme 2.16 based on enriched samples of 2.68 and

careful analysis of 1D and 2D NMR data (cf. Figures 2.21 and 2.22).

80

Figure 2.21. Comparison of 1H-NMR: olefin osmylation.

The structural assignment of compound 2.68 rested upon an analysis of the vicinal coupling

constants gleaned from the 1H-NMR and COSY spectral data. Specifically the C-6 proton showed an 8.2

Hz coupling to the C-7 proton indicative of a trans-diaxial coupling (Figure 2.22). We expected the C-

6/C-7 axial-axial coupling constant (Jaa) to be about 9.5 Hz as calculated for dihedral angles close to

180°, and the 8.2 Hz coupling indicated a less-than-perfect cyclohexane framework which we understood

to be a result of the osmium pinching the backbone. This coupling constant was key to the structural

assignment of 2.68, and indicates the osmylation event took place from the top face as anticipated. If the

OsO4 had approached the olefin from the bottom face, then we expected the C-6/C-7 coupling constant

(Jae) to be closer to 4 Hz.

OH

O CN

CO2CH3

NHAc

2.67

TBDPS

OH

O CN

CO2CH3

NHAcO

Os

O

O

O

2.68

TBDPS

81

Figure 2.22. 1H-NMR couplings for 2.68.

Compound 2.68 contains key structural features compared to TTX retron 1.170. The lack of C-9

hydroxyl group and the C-11 hydroxymethyl group in compound 2.68 were the major differences

between these structures.

HO

O

NC CO2CH3

NHAc

O

O

2.68

TBDPS OH

OH

COOH

HO

NH2

HO

HO

OHC

OH

1.170

4a

6

8a

4

5

78

10

6

4a8a5

78

4

10

OsO2

Figure 2.23. Comparison of advanced intermediate 2.68 with TTX retron 1.170.

82

2.7 Iodine(III)-mediated oxime oxidation to nitrile oxides

The apparent sluggish reaction times for the conversion of nitroketones 2.39 and 2.65 to their

respective tricyclic isooxazoline products (Scheme 2.14) led us to investigate alternative nitrile oxide

precursors.

2.7.1 Oximes as nitrile oxide precusors

Oximes are established nitrile oxide precursors.100,101

Oxidation of oximes with various reagents

have generated nitrile oxide intermediates which can be trapped in a [3+2]-mode with a variety of

dipolarophiles (Figures 2.24 and 2.25). Nitrile oxides (generated from oximes or otherwise) were also

known to dimerize194

to give furoxans195,196

of the type 2.71 (Figure 2.24); these products were often used

as evidence for the formation of highly reactive nitrile oxide intermediates. Reagents known to oxidize

oximes to nitrile oxide species included lead tetraacetate,197

chloramine-T,198

mercuric acetate,199

1-

chlorobenzotriazole,200

manganese dioxide,201

halogens,202,203

dimethyldioxirane,194

and alkali

hypohalite204

such as tert-butyl hypochlorite205

and NaClO.206,207

Ceric ammonium nitrate has been used

to oxidize aromatic aldoximes to nitrile oxides with modest efficiency.208

Potassium ferricyanide-

mediated oxime oxidations were known to proceed only in aqueous solvents.209

Treatment of oximes

with N-chlorosuccinimide (NCS) generated the corresponding oximoyl chlorides, and subsequent addition

of base can cause the generation of a nitrile oxide as used by Ray and co-workers in their synthesis of

pyrimidoazepine-based derivatives.210,211

H

NOH

2.702.69

NN

O

RR C N OR

2.71

O O

CH3H3C

R

O

Figure 2.24. Dimerization of nitrile oxides.

Oximes can also be converted to nitrile oxides using iodine(III) reagents such as iodosylbenzene

(PhIO)194

and PhICl2212

(Figure 2.25). These iodine(III) reagents were known to require an alkaline

workup after the oxidation event, limiting the use of these reagents to base-insensitive substrates.212,213

Hypervalent iodine reagents have also been known to induce oxidative deoximation214-221

in lieu of nitrile

83

oxide formation. Despite the variety of methods that were available for the oxidation of oximes to nitrile

oxides, finding a new oxidizing agent would contribute to the chemistry of nitrile oxides.

H

NOH

2.702.69

N O

R3

R1R1Ph I

O

CHCl3

C N OR1

R2 R3

R2

2.72

Figure 2.25. Conversion of oximes to nitrile oxides and subsequent trapping.

2.7.2 Optimization of DIB as a reagent for oxime to nitrile oxide oxidations

There was no precedent in the chemical literature for the use of hypervalent iodine reagents

commonly employed for oxidative amidation reactions (DIB or PIFA) to oxidize oximes to nitrile oxides.

Our initial attempts (not optimized) to use DIB as a reagent to oxidize oximes centered on commercially

available oxime 2.73. When treated with DIB in methanol, oxime 2.73 readily formed known furoxan

2.74 which crystallized from the reaction mixture. Furoxan 2.74 was compared to literature data194

and

found to be identical, in addition to an unambiguous X-ray crystallographic derived structure (Scheme

2.17).

H

NOH

2.73

NN

O

OPhI(OAc)2

CH3OH

35-40%unoptimized

2.74

Scheme 2.17. Dimerization of oxime 2.73.

A test of the feasibility of a DIB-mediated oxime oxidation and subsequent capture of the newly

formed nitrile oxide with a dipolarophile began with commercially available oxime 2.75. The test

oxidation of 2.75 with DIB in a variety of solvents with varying equivalents of styrene as the

dipolarophile trap was summarized in Table 2.8. The typical procedure was dissolving oxime 2.75 in the

appropriate solvent followed by the slow addition of the oxime solution to a room temperature solution of

DIB and styrene in the same solvent. After the given time, the reaction mixture was concentrated in

vacuo and the crude reaction residue was purified by flash column chromatography. Excess of styrene

trap had a minor effect on recovered yields. Additionally, methanol was found to be an adequate

84

replacement for the much more costly fluorinated alcohol solvents such as HFIP and TFE. The addition

of a small amount of trifluoroacetic acid (TFA) enhanced both the solubility of DIB in methanol and the

recovered yield in the test reaction (Table 2.8, entry k). The best results obtained for this reaction

involved the room temperature addition of the oxime to a solution of 1.1 equivalents of both DIB and

styrene.

H

NOH

2.762.75

PhI(OAc)2,styrene,

solvent

entry styrene (eq) solvent yielda

a 31%

b 28%

c 23%

d 68%

e 54%

f 54%

g 51%

h 64%

i 59%

j 32%

k 91%

l 51%

H3CO

DIB (eq)time(min)

N O

Ph

H3CO

1.1 4.0 CHCl3 35

1.1 1.1 THF 90

1.1 1.1 THF 240

1.2 1.4 TFE 15

1.3 1.3 HFIP 35

1.3 1.1 HFIP 150

1.2 4.0 HFIP 45

1.2 2.0 HFIP 17

1.2 1.3 CH3OH 20

1.1 1.1 CH3CN 60

1.1 1.1 CH3OH + TFA (1.5 % v/v)

60

1.1 1.1 CH3CN + TFA (1.2 eq)

30

a after flash column chromatography

Table 2.8. DIB-mediated bimolecular [3+2] dipolar cycloaddition: optimization studies.

85

The optimized conditions from Table 2.8, entry k were applied to a variety of different oximes

and dipolarophiles (Table 2.9). Aromatic oximes with activating and deactivating groups were reacted in

good to excellent recovered yields. The aliphatic oximes tested worked with similar efficiency.

Replacement of the olefin trap with a terminal alkyne resulted in the fully aromatic isoxazole 2.88, but

with diminished efficiency (Table 2.9, entry l). Variable amounts of 3,5-diphenyl-1,2,4-oxadiazole 4-

oxide, the dimer of benzonitrile oxide, were also recovered from the reaction of oxime 2.73 with

phenylacetylide (Table 2.9, entry l). The reaction mixtures for these reactions became unusually dark

colored, perhaps resulting from a competing in situ formation of alkynyliodonium species.107,221-224

The

subsequent reaction of any alkynyliodonium species with methanol (or other nucleophile) could have

reduced the amount of dipolarophile available for reaction with a nitrile oxide. Other terminal alkyne

traps such as 1-hexyne provided isoxazole products in even lower recovered yields.

Similar to aromatic and aliphatic aldoximes, -oxo-aldoximes were oxidized to -oxo-nitrile

oxides in the presence of DIB. The nitrile oxides formed in such a manner were trapped in good to

excellent recovered yields (Table 2.10). A screen of reaction conditions using -oximinoacetone 2.89

and norbornylene as the dipolarophile trap was embarked on and summarized in Table 2.10. Similar to

before225

(Table 2.8), the best conditions involved room temperature reaction of -oximinoacetone 2.89

and 1.2 equivalents of both DIB and norbornylene in methanol with TFA (0.1 – 1% v/v) (Table 2.10,

entries d and e). In this case, we observed a good recovered yield from the oxidation of -

oximinoacetone 2.89 in methanol with no added trifluoroacetic acid (Table 2.10, entry c), though this

appeared to be an exceptional case.

86

Table 2.9. DIB-mediated bimolecular [3+2] dipolar cycloaddition: substrate scope.

87

Table 2.10. DIB-mediated bimolecular [3+2] dipolar cycloaddition: optimization studies.

88

The DIB-mediated oxidation, and subsequent trapping with norbornylene or styrene, of

commercially available -oxo-aldoximes 2.89 and 2.92, using conditions from Table 2.10, entry k,

proceeded to produce isooxazoline products 2.90/2.91 and 2.93/2.94 with high efficiency (Table 2.11).

Good to excellent recovered yields were obtained. Note that entries d and e in Table 2.10 and entry a in

Table 2.11 were equivalent. This method permitted access to carbethoxy-formonitrile oxide

(CEFNO)174,226-228

and related CEFNO cycloadducts 2.93 and 2.94.

Table 2.11. DIB-mediated oxidation of -oxo-aldoximes 2.89 and 2.92.

89

2.7.3 Oxidation of -oxo-ketoximes and ’-dioxo-ketoximes

The DIB-mediated oxidation of oximes to their corresponding nitrile oxides was not only applied

to aromatic, aliphatic and -oxo-aldoximes (Chapter 2.7.2), but also to -oxo-ketoximes and ’dioxo-

ketoximes. We predicted that -oxo-ketoximes such as compound 2.95 would react with DIB to give

reactive intermediates of the type 2.96, which in turn could react with appropriate nucleophilic solvents

leading to the formation of nitrile oxides of the type 2.97 which could be trapped with various

dipolarophiles (Figure 2.26). Our hope in this endeavor was to broaden the synthetic utility of the DIB-

mediated oxime oxidation reactions to allow for wider range of applications and synthetically useful

products of the type 2.98 and others.

Figure 2.26. Predicted course of the DIB oxidation of -oxo-ketoximes.

We predicted that nitrile oxides would form from -oxo-ketoximes via the oxidative cleavage of

the carbonyl-imino bond (Figure 2.26). As a test of this hypothesis, we reacted ’dioxo-ketoxime

2.99 with DIB and norbornylene under the conditions which worked well for aromatic, aliphatic, and -

oxo-aldoximes (Table 2.12, entry a). The isolated yield from the reaction was a moderate 52%, with

nearly a third of the unreacted oxime recovered from the reaction mixture. Despite the moderate isolated

yields, attempts were made to screen for better conditions by modifying DIB and norbornylene

stoichiometry and solvent conditions (Table 2.12). Unfortunately, all other conditions employed only

served to decrease the recovered yield for this system, and therefore rigorous optimization studies were

left for a future time.

The typical procedure for the reactions listed in Table 2.12 was as follows: a solution of ketoxime

2.99 (1.5 mmol) in an appropriate solvent (3 mL) was added very slowly at room temperature to a stirred

solution of DIB and norbornylene in the same solvent (2 mL). Appropriate amounts of TFA (or HFIP)

were added only to the solution with DIB and norbornylene. Another portion of solvent (0.5 mL) was

used to wash any remaining ketoxime 2.99 into the reaction mixture. After the stated time, the mixture

was evaporated in vacuo and the residue was purified by flash chromatography.

90

Table 2.12. DIB-mediated oxidation of ’-dioxo-ketoximes: optimization attempts.

Several -oxo-ketoximes were synthesized and tested as substrates in the DIB-mediated

oxidation/dipolarophile-trap paradigm. Reactions were run under the same conditions as those in Table

2.11 and the results of the DIB-oxidation of -oxo-ketoximes 2.100, 2.103 and 2.106 are summarized in

Table 2.13. Nitrile oxide formation occurred with concomitant solvolytic oxidative C-C bond fission,

presumably by the mechanism illustrated in Figure 2.26 where Nu = methanol. The expected adducts of

norbornylene were all isolated in good yields. Compounds of the type 2.100 (Table 2.13, entry a) were

especially noteworthy as they have been used as building blocks for the synthesis of some prostaglandin

91

analogs.229

The conversion of (D)-camphor-derived -oxo-ketoxime 2.106 into a 1:1 mixture of exo-

cyclic adducts 2.107/2.108 proceeded in high conversion and recovery. For unknown reasons, the

conversion of this chiral-ketoxime 2.106 with styrene as the dipolarophile trap consistently proceeded

with diminished efficiency relative to the norbornylene adducts (Table 2.13, entry f).

92

Table 2.13. DIB-mediated oxidation of -oxo-ketoximes.

93

2.7.4 Intramolecular nitrile oxide cycloaddition

Several intramolecular versions of the DIB-mediated oxime-oxidation reaction were examined

(Schemes 2.18 and 2.19). The first intramolecular variant of this reaction involved the oxime 2.111, a

derivative of citronellal, which cyclized in 85% conversion upon exposure to conditions optimized from

the bimolecular studies. The citronellal-derived isooxazoline 2.112 was obtained as a mixture of

diastereomers in a ratio of 3.8:1 as determined from 1H-NMR peak integration. Terpene 2.112 was quite

volatile and pleasant smelling, and material was repeatedly lost upon vacuum concentration and during

purification. Thus, the reaction yield was calculated by the addition of a 1H-NMR standard to the crude

reaction mixture. A known amount of 1,3,5-trimethoxybenzene was added to the crude reaction mixture

of 2.112, 1H-NMR data was obtained (the D1 NMR parameter was increased to 20 seconds for

quantitative integration) and the reaction conversion was calculated to be 85% based on the comparison

of the 2.112 methyl 1H-NMR signals with those of the methoxy

1H-NMR signals from the 1,3,5-

trimethoxybenzene. A portion of the crude material was purified fully for characterization purposes, and

had an []20

D = –87.0 (CH2Cl2, c = 0.01). The configuration of this material was not determined due to

the nature of the molecule not lending itself to accurate determination of coupling constants: the

resonances of the axial hydrogen on the methylene adjacent to the oximino group of 2.112 (about 1.8

ppm) and of the methyl-bearing methine of 2.112 (about 1.50 ppm) overlap with those of other ring

hydrogen atoms, precluding the accurate determination of the coupling constants, and thus preventing the

determination of the configuration.

Scheme 2.18. The first intramolecular variant.

Two other intramolecular examples were completed in conjunction with another student in the

Ciufolini group (Scheme 2.19). Florian Tessier synthesized225

oximes 2.113 and 2.115 and we observed

60-69% recovered yields of the tricyclic isooxazolines 2.114 and 2.116 using the optimized conditions.

94

Scheme 2.19. Other intramolecular variants from Ciufolini group.

Shortly after our initial publication on the DIB-mediated INOC reaction,225

another research

group used DIB (and also Koser’s reagent: [hydroxyl(tosyloxy)iodo]benzene) to convert aldoximes to N-

acetoxy or N-hydroxy amides through a nitrile oxide intermediate.230

95

2.8 Tandem oxidative dearomatization/nitrile oxide [3+2] cycloaddition

The use of DIB in both phenol dearomatizations and also in oxime oxidations, under similar

reaction conditions (polar/acidic solvents, room temperature) seemed a convenient twist of fate; I had

wondered if there was some way to tie these two reactions together into one-pot. Extensive

experimentation with the DIB-mediated INOC reaction, both intermolecularly and intramolecularly,

indicated a rate of oxidation of aldoximes to nitrile oxides to be on the order of an hour for complete

conversion for the reactions under typical concentrations of 0.5-1.0 M. Comparatively, the rate of

reaction for DIB-mediated oxidative dearomatizations at similar reaction concentrations was, practically

speaking, instantaneous. This apparent difference in reaction rates boded well for the feasibility of a

tandem oxidative dearomatization of phenols/intramolecular nitrile oxide cycloaddition sequence, with

both oxidations mediated by DIB sequentially (Figure 2.27). Dienones arising from oxidative amidation,

or other oxidative dearomatization type, would be captured by an in situ generated nitrile oxide (2.118) to

afford structures of the type 2.119. Dienone products of oxidative dearomatization were already known

to be able to participate in tandem reactions, especially 1,4-addition processes, and products of these

tandem sequences were densely functionalized, synthetically valuable intermediates. In fact, an oxidative

amidation/conjugate addition procedure was a central step in the synthesis of (–)-cylindricine C.149

Other

examples include a tandem sequence involving an oxidative hydroxylation/Michael cyclization118,124

of

tyrosine derivatives which was used as a key transformation in the synthesis of Stemona alkaloids125

and

of hydroxylated amino acids related to parkacine, aeruginosine and castanospermine.231

However, no

examples existed in the literature involving a tandem oxidative dearomatization followed by a second

oxidation event.

Figure 2.27. Hypothetical tandem oxidative amidation-intramolecular nitrile oxide cycloaddition.

Oxime 2.123 served to explore the feasibility of the hypothesized tandem oxidative amidation-

INOC sequence. Aldoxime 2.123 was synthesized in a straightforward manner from phenol 2.120

(Scheme 2.20). Conversion of compound 2.120 to the corresponding Weinreb-amide232

2.121 occurred

96

with good efficiency, and lithium aluminum hydride reduction233

on the crude residue gave crude

aldehyde 2.122 upon workup. Aldehyde 2.122 was converted to known oxime 2.123234

over three-steps

using standard conditions.225

Oxime 2.123 was subjected to the optimized conditions for oxidative

amidations, but with an additional equivalent of DIB to account for the second oxidation step, and to our

delight tricycle 2.124 was isolated in 71% yield after chromatographic purification (Scheme 2.21). The

structural geometry of 2.124 was confirmed by X-ray crystallography: the all-cis C-8a/C-4a/C-5 units are

clearly shown in the goblet-shaped image. Remarkable to this tandem transformation was the rapid,

stereoselective creation of three new stereogenic carbons from an achiral phenol 2.123 in a single

chemical operation.

HO N

OH2.123

HO N

O

2.121

OCH3

CH3

HO OH

2.120

O

HO H

2.122

O

EDCI, TEAHCl•HN(OCH3)CH3

LiAlH4

Na2CO3

HCl•H2NOH

Scheme 2.20. The synthesis of oxime 2.123.

Scheme 2.21. Tandem oxidative amidation—INOC.

97

2.8.1 Sorensen’s use of tandem dearomitization/nitrile oxide [3+2] cycloaddition in Cortistatin

core synthesis

We also subjected oxime 2.123 to similar reaction conditions optimized for the DIB-mediated

oxidation of oximes (cf. Table 2.9): chiefly acetonitrile was replaced with methanol which changed the

reaction type to a tandem oxidative methoxylation/INOC sequence. Compound 2.125 was isolated in

51% purified yield following reaction of oxime 2.123 with DIB in methanol/TFA. Isooxazoline 2.125

was highly polar and seemed to irreversibly adsorb onto silica gel during purification. Thus, a crude

reaction conversion was determined to be 65% using the same technique and 1H-NMR standard as for

terpene 2.112. This reaction was the first tandem oxidative alkoxylation/INOC sequence to appear in the

chemical literature.

Scheme 2.22. Tandem oxidative methoxylation—INOC.

A few months after this tandem oxidative methoxylation-intramolecular nitrile oxide

cycloaddition was published,225

it was adopted by Erik Sorensen and co-workers as the solution to the

construction of the pentacyclic core structure of the cortistatins235

(Scheme 2.23). Their approach utilized

a phenol as a latent A-ring featuring a tandem intramolecular oxidative cyclodearomatization/dipolar

cycloaddition event. The use of our tandem dearomatization/dipolar cycloaddition sequence in this work

rendered the rapid construction of the corresponding rings.

98

Scheme 2.23. Sorensen’s use of tandem oxidative dearomatization—INOC towards the cortistatin

pentacyclic core.

According to Professor Erik Sorensen, the use of our tandem sequence allowed for his completion

of the pentacyclic Cortistatin core; without this sequence, alternative routes toward the construction of the

pentacytclic core structure would have been less-efficient and contrived.236

The use of this technology by

another group shortly after its initial publication stands as a testament of its potential utility for the

generation of synthetically useful molecules.

99

2.9 Diastereoselective tandem oxidative amidation—INOC

The second oxidation in the tandem sequence (the INOC step) caused desymmetrization of the

dienone intermediate. Specifically, the intramolecular nitrile oxide cycloaddition caused the acetamide-

bearing carbon (C-8a) to become stereogenic (see Figure 2.12). Selectivity for the pro-(S) double bond

could be controlled through utilization of the principle illustrated in Figure 2.28. If the group L were a

sterically demanding group, preferably something suitable for later-stage isooxazoline-ring fragmentation,

then the INOC step of reactive intermediate 2.127 could proceed through either transition states 2.128 or

2.129. For transition state 2.129, the bulky L group is forced into the developing concavity of the

tricyclic framework and would thus suffer from significant steric congestion. In the case of transition

state 2.128, the bulky L group would point to the convexity of the emerging bowl-shaped cycloadduct,

and since the external orientation of the group L would suffer from less unfavorable steric interactions the

reaction is predicted to proceed in this manner.

Figure 2.28. Predicted course of the INOC reaction.

We already had attempted an INOC sequence with compound 2.46, and observed a 1:1 ratio of

the possible diastereomeric products (cf. Scheme 2.6). This result indicated that with regard to compound

2.126/2.127, an OTBS group was not of sufficient bulk to have a diastereoselective effect on the INOC

step as predicted in Figure 2.28. We then considered other entities which could satisfy the requirements

for compounds of the type 2.127. Compound 2.127 could be derived from tyrosine if the L group were a

100

protected nitrogen atom. Oxime 2.132 was synthesized from racemic tyrosine in an eight-step sequence

(Scheme 2.24). We hoped that the N-benzyl tosylamido group (–N(Ts)Bn) would be large enough to

exert the desired diastereoselectivity. Earlier compounds (derivatives of compound 2.132) which we

synthesized that contained a monoprotected nitrogen unit, an N-tosylamido group (–NH-Ts) underwent

oxidative amidation followed by conjugate addition instead of the desired INOC; conjugate addition

products of this type were published in the chemical literature shortly after our finding by Wipf in related

systems.231

Our plan was for the N-benzyl tosylamido group of compound 2.132 to allow for the

alleviation of nonbonding interactions (steric avoidance), avoiding transition state 2.129 and favoring

2.128, while also disfavoring any possible Michael addition pathways.

()-2.132

HO

CO2H

NH2

()-tyrosine

1) SOCl2, CH3OH2) PhCHO3) NaBH4, CH3OH

4) TsCl5) NaOH, H2O/THF

HO

CO2H

NTs

Ph

HN(OCH3)CH3,PyBOP, Et3N

HON

Ts

PhHO

NTs

Ph

N OHO

NO

CH3

CH3

()-2.131

()-2.130

1) LiAlH4

2) H2NOH, Na2CO3

Et2O, H2O

64% over five-steps

11% over three-steps(unoptimized)

Scheme 2.24. Synthesis of oxime 2.132.

The exposure of oxime 2.132 to the action of DIB in acetonitrile/TFA resulted in the formation of

2.134 as a single diastereomer (Scheme 2.25). The observed stereochemical outcome was explained by

considering that the presumed nitrile oxide (2.133) arising from the DIB-mediated oxidation of oxime

2.132, following the dearomatization of the phenol moiety, indeed observed the principle outlined in

Figure 2.28. The transition 2.129 was disfavored due to unfavorable steric compression from the bulky

N-benzyl tosylamido group, represented by group L in Figure 2.28, orientated in the concavity of the

molecule. Transition state 2.128 conveniently avoided these higher-energy interactions with the bulky N-

benzyl tosylamido group residing on the convex face of the incipient product. Thus tricyclic isooxazoline

2.134 was synthesized diastereoselectively in 44% isolated yield. The majority of the remaining mass

101

from this reaction appeared to be side products related to unintentional oxidations of the N-benzyl

tosylamido group.237

HO

N

N

OH

Bn

Ts

()-2.132

PhI(OAc)2 2.2 eq,TFA 1% v/v,

CH3CN

O

O N

NHAc

N

Bn

Ts

()-2.134

44%

O

O N

NHAc

N

Bn

Ts

()-2.135

not detected

HO

N

N

O

Bn

Ts

()-2.133

Scheme 2.25. Diastereoselective tandem oxidative amidation—INOC.

The configuration of isooxazoline 2.134 was ascertained on the basis of nuclear Overhauser

enhancements (nOe; NOESY spectroscopy) as indicated in Figure 2.28. Specifically, the C-8 olefinic

hydrogen atom showed crosspeaks with both the C-4a hydrogen atom and the C-9 hydrogen atom in the

NOESY spectra. These crosspeaks indicated a nOe enhancement and therefore spacial proximity. The

other diastereomer possible from the reaction in Scheme 2.25 was compound 2.135, and there was no

trace of this compound in the crude reaction mixture or in any chromatographic fractions.

102

Figure 2.28. NOe NMR spectral expansion of 2.134.

103

2.10 Summary

The advances accompanying this route towards the tetrodotoxin core fell into two major

categories. First, we have further optimized a scalable, less-costly and more-reproducible method for the

IIII

-mediated oxidative amidation of 4-hydroxyphenyl acetate (2.31). The challenges associated with this

primarily included developing a method for the slow addition of the phenol to the reaction mixture,

without causing the formation of oligiomeric side products, and also an efficient method for purification

of the dienone products. Second, we have explored new methods for the creation of nitrile oxides from

oximes. Oximes are established precursors to nitrile oxides, but until now there was not a mild and

reliable method for this conversion mediated by hypervalent iodine reagents. Aldoximes and ketoximes

of different types have now been shown to undergo DIB-mediated oxidative transformations to nitrile

oxides, and these have been used to generate a number of synthetically useful isooxazoline and isooxazole

products.

The combination of the two main elements contained in this thesis allowed us to create a tandem

sequence where the oxidative dearomatization step is immediately, and in the same pot, followed by an

oxidative event converting an oxime into the corresponding nitrile oxide and the subsequent

intramolecular [3+2] cycloaddition. This was the first example of a tandem hypervalent iodine—induced

oxidative dearomatization—nitrile oxide cycloaddition, the development of which relied heavily on the

extensive advancement of the individual steps: chiefly the optimization of bimolecular oxidative

amidation of 4-substituted phenols and the oxidation of oximes to nitrile oxides under similar conditions.

This technology was immediately adopted by other synthetic chemists working on related systems.

We have created and detailed new reactivity and have showcased the ability of our tandem

sequence to stereoselectively generate complex tetrodotoxin core intermediates. With access to

functionalizable core structures for TTX, we hope that analogues could be produced with altered and

potentially useful biological activities. The creation of our advanced tetrodotoxin core intermediates

should serve as a solid foundation for future studies to our approach to tetrodotoxin.

104

References

(1) Mosher, H. S.; Fuhrman, F. A.; Buchwald, H. D.; Fischer, H. G. Science 1964, 144, 1100.

(2) Fuhrman, F. A. Tetrodotoxin, Saxitoxin, and the Molecular Biology of the Sodium Channel; New

York Academy of Sciences: New York, 1986; Vol. 479.

(3) Gaillard, C. Mem. Inst. Francais Arch. Orient. 1923, 51, 97.

(4) Halstead, B. W. In Poisonous and Venomous Marine Animals of the World 1988.

(5) Kao, C. Y. Pharmacol. Rev. 1966, 18, 997.

(6) Rivera, V. R.; Poli, M. A.; Bignami, G. S. Toxicon 1995, 33, 1231.

(7) Material Safety Data Sheet Tetrodotoxin ACC# 01139.

https://fscimage.fishersci.com/msds/01139.htm

(8) Material Safety Data Sheet Tetrodotoxin. Sigma-Aldrich Version 1.6 updated 10 March 2007.

(9) Davis, W. The Serpent and the Rainbow; Simon and Schuster: New York, 1985.

(10) Benedek, C., Rivier, L. Toxicon 1989, 27, 473.

(11) Hines, T. Skeptical Inquirer 2008, 32, 60.

(12) Tahara, Y. Biochem. Z. 1911, 10, 255.

(13) Tahara, Y. U.S.A., 1913.

(14) Yokoo, A. J. Chem. Soc. Jpn. 1950, 71, 590.

(15) Woodward, R. B. Pure Appl. Chem. 1964, 9, 49.

(16) Goto, T.; Kishi, Y.; Takahashi, S.; Hirata, Y. Tetrahedron 1965, 21, 2059.

(17) Tsuda, K.; Ikuma, S.; Kawamura, M.; Tachikawa, R.; Sakai, K.; Tamura, C.; Amakasu, O. Chem.

Pharm. Bull. 1964, 12, 1357.

(18) Furusaki, A.; Tomie, Y.; Nitta, I. Bull. Chem. Soc. Jpn. 1970, 43, 3325.

(19) Nakamura, M.; Yasumoto, T. Toxicon 1985, 23, 331.

(20) Shiomi, K.; Inaoka, H.; Yamanaka, H.; Kikuchi, T. Toxicon 1985, 22, 381.

(21) Zhou, M.; Shum, F. H. K.; States, U., Ed.; Wex Medical Instrumentation Co., Ltd., Hong Kong:

United States, 2003; Vol. US 6,552,191 B1.

(22) Hashimoto, Y.; Noguchi, T. Toxicon 1971, 9, 79.

(23) Noguchi, T.; Hashimoto, Y. Toxicon 1973, 11, 305.

(24) Hwang, D. F.; Tai, K. P.; Chueh, C. H.; Lin, L. C.; Jeng, S. S. Toxicon 1991, 8, 1019.

105

(25) Noguchi, T.; Narita, H.; Maruyama, J.; Hashimoto, K. Nippon Suisan Gakkaishi 1982, 48, 1173.

(26) Ritson-Williams, R.; Yotsu-Yamashita, M.; Paul, V. J. Proc. Natl. Acad. Sci. 2006, 103, 3176.

(27) Kim, Y. H.; Brown, G. B.; Mosher, H. S.; Fuhrman, F. A. Science 1975, 189, 151.

(28) Miyazawa, K.; Noguchi, T. J. of Toxicology: Toxin Reviews 2001, 11.

(29) Anderson, P. A. V. J. Exp. Biol. 1987, 231.

(30) Anderson, P. A. V. Evolution of the First Nervous Systems; Plenum Press: New York, 1990.

(31) Anderson, P. A. V.; Holman, M. A. Proc. Natl. Acad. Sci. 1993, 7419.

(32) Shimizu, S.; Kobayashi, M. Chem. Pharm. Bull. 1983, 31, 3625.

(33) Kotaki, Y.; Shimizu, Y. J. Am. Chem. Soc. 1993, 115, 827.

(34) Yotsu-Yamashita, M.; Yamagashi, Y.; Yasumoto, T. Tetrahedron Lett. 1995, 36, 9329.

(35) Jang, J.-H.; Yotsu-Yamashita, M. Toxicon 2007, 50, 947.

(36) Note: the numbering schemes for all chemical structures in this thesis are based on the

corresponding tetrodotoxin (TTX) numbering.

(37) Hwang, D. F.; Lu, Y. H. Recent Advances in Marine Biotechnology 2002, 7, 53.

(38) Matsumura, K. Nippon Juishikai Zasshi 1998, 51, 231.

(39) Yan, Q.; Yu, P. H.-F.; Li, H.-Z. World J. Microbiol. Biotechnol. 2005, 21, 1255.

(40) Dewich, P. Med. Nat. Prod. 2001, 2, 396.

(41) Shimizu, Y.; Norte, M.; Hori, A.; Genenah, A.; Kobayshi, M. J. Am. Chem. Soc. 1984, 106, 6433.

(42) Kandel, E. R.; Schwartz, J. H.; Jessell, T. M. Principles of Neural Science; 4th ed.; New York,

McGraw-Hill, 2000.

(43) Hille, B. Ion Channels of Excitable Membranes; 3rd ed.; Sunderland, MA: Sinauer Associates,

Inc., 2001.

(44) Satin, J.; Limberis, J. T.; Kyle, J. W.; Rogart, R. B.; Fozzard, H. A. Biophys. J. 1994, 67, 1007.

(45) Yotsu-Yamashita, M.; Sugimoto, A.; Takai, A.; Yasumoto, T. J. Pharm. Exp. Therap. 1999, 289,

1688.

(46) Hucho, F. Angew. Chem., Int. Ed. 1995, 34, 39.

(47) Denac, H.; Mevissen, M.; Scholtysik, G. Naunyn-Schmiedeberg's Arch. Pharmacol. 2000, 362,

453.

(48) Slaughter, R. S.; Garcia, M. L.; Kaczorowski, G. J. Current Pharmaceutical Design 1996, 2, 610.

106

(49) Gilman, V. Chem. Eng. News 2004.

(50) Kishi, Y.; Fukuyama, T.; Aratani, M.; Nakatsubo, F.; Goto, T.; Inoue, S.; Tanino, H.; Sugiura, S.;

Kakoi, H. J. Am. Chem. Soc. 1972, 94, 9219.

(51) Kishi, Y.; Aratani, M.; Fukuyama, T.; Nakatsubo, F.; Goto, T.; Inoue, S.; Tanino, H.; Sugiura, S.;

Kakoi, H. J. Am. Chem. Soc. 1972, 94, 9217.

(52) Kishi, Y.; Nakatsubo, F.; Aratani, M.; Goto, T.; Inoue, S.; Kakoi, H. Tetrahedron Lett. 1970, 59,

5129.

(53) Kishi, Y.; Nakatsubo, F.; Aratani, M.; Goto, T.; Inoue, S.; Kakoi, H.; Sagiura, S. Tetrahedron

Lett. 1970, 59, 5127.

(54) Ohyabu, N.; Nishikawa, T.; Isobe, M. J. Am. Chem. Soc. 2003, 125, 8798.

(55) Nishikawa, T.; Urabe, D.; Isobe, M. Angew. Chem., Int. Ed. 2004, 43, 4782.

(56) Nishikawa, T.; Urabe, D.; Yoshida, K.; Iwabuchi, T.; Asai, M.; Isobe, M. Chem. Eur. J. 2004, 10,

452.

(57) Nishikawa, T.; Urabe, D.; Yoshida, K.; Iwabuchi, T.; Asai, M.; Isobe, M. Pure Appl. Chem. 2003,

75, 251.

(58) Nishikawa, T.; Urabe, D.; Yoshida, K.; Iwabuchi, T.; Asai, M.; Isobe, M. Org. Lett. 2002, 4,

2679.

(59) Nishikawa, T.; Asai, M.; Isobe, M. J. Am. Chem. Soc. 2002, 124, 7847.

(60) Asai, M.; Nishikawa, T.; Ohyabu, N.; Yamamoto, N.; Isobe, M. Tetrahedron 2001, 57, 4543.

(61) Nishikawa, T.; Asai, M.; Ohyabu, N.; Yamamoto, N.; Isobe, M. Angew. Chem. Int. Ed. 1999, 38,

3081.

(62) Nishikawa, T.; Asai, M.; Ohyabu, N.; Yamamoto, N.; Fukuda, Y.; Isobe, M. Tetrahedron 2001,

57, 3875.

(63) Satake, Y.; Nishikawa, T.; Hiramatsu, T.; Araki, H.; Isobe, M. Synthesis 2010, 12, 1992.

(64) Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510.

(65) Sato, K.; Akai, S.; Sugita, N.; Ohsawa, T.; Kogure, T.; Shoji, H.; Yoshimura, J. J. Org. Chem.

2005, 70, 7496.

(66) Sato, K.; Kajihara, Y.; Nakamura, Y.; Yoshimura, J. Chem. Lett. 1991, 1559.

(67) Sato, K. I.; Akai, S.; Shoji, H.; Sugita, N.; Yoshida, S.; Nagai, Y.; Suzuki, K.; Nakamura, Y.;

Kajihara, Y.; Funabashi, M.; Yoshimura, J. J. Org. Chem. 2008, 73, 1234.

(68) Funabashi, M.; Wakai, H.; Sato, K.; Yoshimura, J. J. Chem. Soc., Perkin Trans 1 1980, 14.

107

(69) Kinoshita, M.; Taniguchi, M.; Morioka, M.; Takami, H.; Mizusawa, Y. Bull. Chem. Soc. Jpn.

1988, 61, 2147.

(70) Kartha, K. P. R. Tetrahedron Lett. 1986, 27, 3415.

(71) Yoshimura, J.; Sato, K.; Hashimoto, K. Chem. Lett. 1977, 1327.

(72) Szarek, W. A.; Jewell, J. S.; Szczerek, I.; Jones, J. K. N. Can. J. Chem. 1969, 47, 4473.

(73) Rosenthal, A.; Sprinzl, M. Can. J. Chem. 1969, 47, 4477.

(74) McMurry, J. E.; Melton, J.; Padgett, H. J. Org. Chem. 1974, 39, 259.

(75) Akai, S.; Seki, H.; Sugita, N.; Kogure, T.; Nishizawa, N.; Suzuki, K.; Nakamura, Y.; Kajihara,

Y.; Yoshimura, J.; Sato, K. Bull. Chem. Soc. Jpn. 2010, 83, 279.

(76) Fairweather, J. K.; McDonough, M. J.; Stick, R. V.; Tilbrook, D. M. G. Aust. J. Chem. 2004, 57,

197.

(77) Yoshimura, J.; Kobayashi, K.; Sato, K.; Funabashi, M. Bull. Chem. Soc. Jpn. 1972, 45, 1806.

(78) Funabashi, M.; Sato, K.; Yoshimura, J. Bull. Chem. Soc. Jpn. 1976, 49, 788.

(79) Keana, J. F. W.; Bland, J. S.; Boyle, P. J.; Erion, M.; Hartling, R.; Husman, J. R.; Roman, R. B.;

Ferguson, G.; Parvez, M. J. Org. Chem. 1983, 48, 3627.

(80) Keana, J. F. W.; Boyle, P. J.; Erion, M.; Hartling, R.; Husman, J. R.; Richman, J. E.; Roman, R.

B.; Wah, R. M. J. Org. Chem. 1983, 48, 3621.

(81) Keana, J. F. W.; Kim, C. U. J. Org. Chem. 1971, 36, 118.

(82) Fraser-Reid, B.; Burgey, C. S.; Vollerthun, R. Pure Appl. Chem. 1998, 70, 285.

(83) Burgey, C. S.; Vollerthun, R.; Fraser-Reid, B. J. Org. Chem. 1996, 61, 1609.

(84) Alonso, R. A.; Burgey, C. S.; Venkateswara R. B.; Vite, G. D.; Vollerthun, R.; Zottola, M. A.;

Fraser-Reid, B. J. Am. Chem. Soc. 1993, 115, 6666.

(85) Motherwell, W. B.; Crich, D. Free Radical Chain Reactions in Organic Synthesis; Academic

Press, 1992.

(86) Giese, B. Radicals in Organic Synthesis: Formation of Carbon-Carbon Bonds; Pergamon Press,

Oxford, 1986.

(87) Schreiber, S. L.; Claus, R. E.; Reagan, J. Tetrahedron Lett. 1982, 23, 3867.

(88) Noya, B.; Paredes, M. D.; Ozores, L.; Alonso, R. J. Org. Chem. 2000, 65, 5960.

(89) Noya, B.; Alonso, R. Tetrahedron Lett. 1997, 38, 2745.

(90) Taber, D. F.; Storck, P. H. J. Org. Chem. 2003, 68, 7768.

(91) Lee, E.; Choi, I.; Song, S. Y. J. Chem. Soc., Chem. Commun. 1995, 3, 321.

108

(92) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974.

(93) Tius, M. A.; Fauq, A. H. J. Org. Chem. 1983, 48, 4131.

(94) Roush, W. R.; Adam, M. A.; Walts, A. E.; Harris, D. J. J. Am. Chem. Soc. 1986, 108, 3422.

(95) Itoh, T.; Watanabe, M.; Fukuyama, T. Synlett 2002, 1323.

(96) Fujita, M.; Kitagawa, O.; Suzuki, T.; Taguchi, T. J. Org. Chem. 1997, 62, 7330.

(97) Basel, Y.; Hassner, A. Synthesis 1997, 309.

(98) Ohtani, Y.; Shinada, T.; Ohfune, Y. Synlett 2003, 619.

(99) Shinada, T., Yoshida, S., Yamamura, S. Tetrahedron Lett. 1998, 39, 6027.

(100) Mulzer, J.; Altenbach, H. J.; Braun, M.; Krohn, K.; Reissig, H. U. Organic Synthesis Highlights;

VCH: Weinheim, 1990; Vol. 1.

(101) Nair, V.; Suja, T. D. Tetrahedron 2007, 63, 12247.

(102) Liang, H.; Ciufolini, M. A. Tetrahedron 2010, 66, 5884.

(103) Ciufolini, M. A.; Braun, N. A.; Canesi, S.; Ousmer, M.; Chang, J.; Chai, D. Synthesis 2007, 3759.

(104) Moriarty, R. M. J. Org. Chem. 2005, 70, 2893.

(105) Wirth, T. Angew. Chem., Int. Ed. 2005, 44, 3656.

(106) Hamamoto, H.; Anilkumar, G.; Tohma, H.; Kita, Y. Chem. Eur. J. 2002, 8, 5377.

(107) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2002, 102, 2523.

(108) Moriarty, R. M. Org. React. 2001, 57, 327.

(109) Varvoglis, A. Hypervalent Iodine in Organic Synthesis; Academic Press: London, 1997.

(110) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 1996, 96, 1123.

(111) Pouysegu, L.; Deffieux, D.; Quideau, S. Tetrahedron 2010, 66, 2235.

(112) Yamamura, S. In The Chemistry of Phenols; Rappoport, Z., Ed.; John Wiley & Sons: Chichester,

UK, 2003; Vol. 2, p 1153.

(113) Barton, D. H. R. Pure Appl. Chem. 1964, 9, 35.

(114) Barton, D. H. R.; Deflorin, A. M.; Edwards, O. E. J. Chem. Soc. 1956, 530.

(115) Barton, D. H. R.; Kirby, G. W. J. Chem. Soc. 1962, 806.

(116) Kametani, T.; Fukumoto, K. Yakugaku Kenkyu 1963, 35, 426.

109

(117) Scott, A. I.; McCapra, F.; Buchanan, R. L.; Day, A. C.; Young, D. W. Tetrahedron 1965, 21,

3605.

(118) Rodriguez, S.; Wipf, P. Synthesis 2004, 2767.

(119) Kita, Y.; Fujioka, H. Pure Appl. Chem. 2007, 79, 701.

(120) Kita, Y.; Tohma, H.; Kikuchi, K.; Inagaki, M.; Yakura, T. J. Org. Chem. 1991, 56, 435.

(121) Tamura, Y.; Yakura, T.; Haruta, J. I.; Kita, Y. J. Org. Chem. 1987, 52, 3927.

(122) Pelter, A.; Elgendy, S. Tetrahedron Lett. 1988, 29, 677.

(123) Barret, R.; Daudon, M. Tetrahedron Lett. 1991, 32, 2133.

(124) Wipf, P.; Jung, J. K. Chem. Rev. 1999, 99, 1469.

(125) Wipf, P.; Spencer, S. R. J. Am. Chem. Soc. 2005, 127, 225.

(126) Kawase, M.; Kitamura, T.; Kikugawa, Y. J. Org. Chem. 1989, 54, 3394.

(127) Kikugawa, Y.; Kawase, M. J. Am. Chem. Soc. 1984, 106, 5728.

(128) Kikugawa, Y.; Nagashima, A.; Sakamoto, T.; Miyazawa, E.; Shiiya, M. J. Org. Chem. 2003, 68,

6739.

(129) Kikugawa, Y.; Shimada, M.; Matsumoto, K. Heterocycles 1994, 37, 293.

(130) Kikugawa, Y. K., M. Chem. Lett. 1990, 581.

(131) Glover, S. A.; Goosen, A.; McCleland, C. W.; Schoonraad, J. L. J. Chem. Soc., Perkin Trans. 1

1984, 2255.

(132) Glover, S. A.; Scott, A. P. Tetrahedron 1989, 45, 1763.

(133) Clemente, D. T. V.; Lobo, A. M.; Prabhakar, S.; Marcelo-Curto, M. J. Tetrahedron Lett. 1994,

35, 2043.

(134) Prata, J. V.; Clemente, D. T. S.; Prabhakar, S.; Lobo, A. M.; Mourato, I.; Branco, P. S. J. Chem.

Soc., Perkin Trans. 1 2002, 513.

(135) Wardrop, D. J.; Basak, A. Org. Lett. 2001, 3, 1053.

(136) Wardrop, D. J.; Burge, M. S. Chem. Commun. 2004, 10, 1230.

(137) Wardrop, D. J.; Burge, M. S. J. Org. Chem. 2005, 70, 10271.

(138) Wardrop, D. J.; Burge, M. S.; Zhang, W.; Ortiz, J. A. Tetrahedron Lett. 2003, 44, 2587.

(139) Wardrop, D. J.; Landrie, C. L.; Ortiz, J. A. Synlett 2003, 1352.

(140) Wardrop, D. J.; Zhang, W.; Landrie, C. L. Tetrahedron Lett. 2004, 45, 4229.

110

(141) Ousmer, M.; Braun, N. A.; Ciufolini, M. A. Org. Lett. 2001, 3, 765.

(142) Ousmer, M.; Braun, N. A.; Bavoux, C.; Perrin, M.; Ciufolini, M. A. J. Am. Chem. Soc. 2001, 123,

7534.

(143) Note: whereas PIFA has been used as a reagent for these oxidations, it was not as efficient and we

generally preferred to use DIB.

(144) Scheffler, G.; Seike, H.; Sorensen, E. J. Angew. Chem., Int. Ed. 2000, 39, 4593.

(145) Seike, H.; Sorensen, E. J. Synlett 2008, 695.

(146) Mizutani, H.; Takayama, J.; Soeda, Y.; Honda, T. Tetrahedron Lett. 2002, 43, 2411.

(147) Mizutani, H.; Takayama, J.; Soeda, Y.; Honda, T. Heterocycles 2004, 62, 343.

(148) Mizutani, H.; Takayama, J.; Honda, T. Synlett 2005, 328.

(149) Canesi, S.; Bouchu, D.; Ciufolini, M. A. Angew. Chem., Int. Ed. 2004, 43, 4336.

(150) Liang, H.; Ciufolini, M. A. Org. Lett. 2010, 12, 1760.

(151) Braun, N. A.; Ousmer, M.; Bray, J. D.; Bouchu, D.; Peters, K.; Peters, E. M.; Ciufolini, M. A. J.

Org. Chem. 2000, 65, 4397.

(152) Mendelsohn, B. A.; Ciufolini, M. A. Org. Lett. 2009, 11, 4736.

(153) Canesi, S.; Bouchu, D.; Ciufolini, M. A. Org. Lett. 2005, 7, 175.

(154) Liang, H.; Ciufolini, M. A. J. Org. Chem. 2008, 73, 4299.

(155) Drutu, I.; Njardarson, J. T.; Wood, J. L. Org. Lett. 2002, 4, 493.

(156) Patrick, B. O.; Mendelsohn, B. A.; Ciufolini, M. A. Z. Kristallogr.-New Cryst. Struct. 2008, 223,

205.

(157) Gothelf, K. V.; Jorgensen, K. A. Chem. Rev. 1998, 98, 863.

(158) In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; John Wiley & Sons: New York, 1984;

Vol. 1 and 2.

(159) Kanemasa, S.; Tsuge, O. Heterocycles 1990, 30, 719.

(160) Kozikowski, A. P. Acc. Chem. Res. 1984, 17, 410.

(161) Curran, D. P. In Advances in Cycloaddition; Curran, D. P., Ed.; JAI Press: Greenwich, 1988; Vol.

1, p 129.

(162) In Nitrile Oxides, Nitrones, and Nitronates in Organic Synthesis; Torssell, K. B. G., Ed.; VCH:

New York, 1988.

(163) Ballini, R.; Bosica, G.; Fiorini, D.; Palmieri, A. Tetrahedron 2005, 61, 8971.

111

(164) Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226.

(165) Gemal, A. L.; Luche, J. L. J. Am. Chem. Soc. 1981, 103, 5454.

(166) Itsuno, S.; Ito, K.; Hirao, A.; Nakahama, S. J. Chem. Soc., Chem. Commun. 1983, 8, 469.

(167) Corey, E. J.; Shibata, S.; Bakshi, R. K. J. Org. Chem. 1988, 53, 2861.

(168) Huan Liang performed initial/unoptimized CBS-reduction studies on dienone systems such as

2.32.

(169) Cyril Benhaim first observed this type of reaction with a related system.

(170) Staab, H. A. Angew. Chem., Int. Ed. Engl. 1962, 1, 351.

(171) Armstrong, A.; Li, W. N,N'-Carbonyldiimidazole. In e-EROS Encyclopedia of Reagents for

Organic Synthesis; Wiley, 2006.

(172) Cyril Benhaim worked out conditions to prepare a TBS-version of nitroketone 2.39.

(173) Paul, R.; Tchelitcheff, S. Bull. Soc. Chim. Fr. 1962, 2215.

(174) Kozikowski, A. P.; Adamcz, M. J. Org. Chem. 1983, 48, 366.

(175) Martin, S. F.; Dappen, M. S.; Dupre, B.; Murphy, C. J.; Colapret, J. A. J. Org. Chem. 1989, 54,

2209.

(176) Mukaiyama, T.; Hoshino, T. J. Am. Chem. Soc. 1960, 82, 5339.

(177) Mukaiyama, T.; Hoshino, T. J. Am. Chem. Soc. 1960, 82, 5339.

(178) Baranski, A.; Kelarev, V. I. Chem. Nat. Compd. 1992, 28, 253.

(179) Shimizu, T.; Hayashi, T.; Shibafuchi, H.; Teramura, K. Bull. Chem. Soc. Jpn. 1986, 59, 2827.

(180) Denmark, S. E.; Baiazitov, R. Y. J. Org. Chem. 2006, 71, 593.

(181) Andersen, S. H.; Das, N. B.; Joergensen, R. D.; Kjeldsen, G.; Knudsen, J. S.; Sharma, S. C.;

Torssell, K. B. G. Acta. Chem. Scand. B 1982, 36, 1.

(182) Klebe, J. F. J. Am. Chem. Soc. 1964, 86, 3399.

(183) Namboothiri, I. N. N.; Hassner, A.; Gottlieb, H. E. J. Org. Chem. 1997, 62, 485.

(184) Shitkin, V. M.; Ioffe, S. L.; Kashutina, M. V.; Tartakovskii, V. A. Izv. Akad. Nauk SSSR, Ser.

Khim. 1977, 2266.

(185) Patrick, B. O.; Mendelsohn, B. A.; Ciufolini, M. A. Z. Kristallogr.-New Cryst. Struct. 2008, 223,

203.

(186) Knoevenagel, E. Berichte der deutschen chemischen Gesellschaft 1898, 31, 2596.

112

(187) March, J. Advanved Organic Chemistry: Reactions, Mechanisms, and Structure; 3rd ed.; Wiley:

New York, 1985.

(188) Kemp, D. S.; Paul, K. J. Am. Chem. Soc. 1970, 92, 2553.

(189) Casey, M. L.; Kemp, D. S.; Paul, K. G.; Cox, D. D. J. Org. Chem. 1973, 38, 2294.

(190) Kemp, D. S.; Cox, D. D.; Paul, K. G. J. Am. Chem. Soc. 1975, 97, 7312.

(191) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.

(192) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.

(193) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976, 17, 1973.

(194) Tanaka, S.; Ito, M.; Kishikawa, K.; Kohmoto, S.; Yamamoto, M. Nippon Kagaku Kaishi 2002, 3,

471.

(195) Vigalok, I.; Moisak, I. E.; Svetakov, N. V. Chem. Heterocycl. Compd. 1969, 5, 133.

(196) Duranleau, R. G.; Larkin, J. M.; Newman, S. R. US Patent, 1978, 4089867.

(197) Just, G.; Dahl, L. Tetrahedron 1968, 24, 5251.

(198) Hassner, A.; Rai, K. M. L. Synthesis 1989, 57.

(199) Rai, K. M. L.; Linganna, N.; Hassner, A.; Murthy, C. A. Org. Prep. Proc. Int. 1992, 24, 91.

(200) Kim, J. N.; Rui, E. K. Synth. Commun. 1990, 20, 1373.

(201) Kiegiel, J.; Poplawska, M.; Jozwik, J.; Kosior, M.; Jurczak, J. Tetrahedron Lett. 1999, 40, 5605.

(202) Eibler, E.; Kasbauer, J.; Pohl, H.; Sauer, J. Tetrahedron Lett. 1987, 28, 1097.

(203) Corbett, D. F. J. Chem. Soc., Perkin Trans. 1 1986, 421.

(204) Grundaman, C.; Dean, J. M. J. Org. Chem. 1965, 30, 2809.

(205) Tsuji, M.; Ukaji, Y.; Inomata, K. Chem. Lett. 2002, 1112.

(206) Larsen, K. E.; Torssell, K. B. G. Tetrahedron 1984, 40, 2985.

(207) de la Cruz, P.; Espildora, E.; Garcia, J. J.; de la Hoz, A.; Langa, F.; Martin, N.; Sanchez, L.

Tetrahedron Lett. 1999, 40, 4889.

(208) Giurg, M.; Mlochowski, M. Pol. J. Chem. 1997, 71, 1093.

(209) Gagneux, A. R.; Meier, R. Helv. Chim. Acta. 1970, 53, 1883.

(210) Miller, M. L.; Ray, P. S. Tetrahedron 1996, 52, 5739.

(211) Miller, M. L.; Ray, P. S. Heterocycles 1997, 45, 501.

113

(212) Radhakrishna, A. S.; Sivaprakash, K.; Singh, B. B. Synth. Commun. 1991, 21, 1625.

(213) Varvoglis, A. Synthesis 1984, 709.

(214) De, S. K.; Mallik, A. K. Tetrahedron Lett. 1998, 39, 2389.

(215) Corsaro, A.; Chiacchio, U.; Librando, V.; Pistara, V.; Rescifina, A. Synthesis 2000, 1469.

(216) Chaudhari, S. S.; Akamanchi, K. G. Synthesis 1999, 760.

(217) Bose, D. S.; Narsaiah, A. V. Synth. Commun. 1999, 29, 937.

(218) Chaudhari, S. S.; Akamanchi, K. G. Tetrahedron Lett. 1998, 39, 3209.

(219) Bose, D. S.; Srinivas, P. Synlett 1998, 977.

(220) Stang, P. J. Chem. Rev. 2002, 102, 2523.

(221) Stang, P. J.; Zhdankin, V. V. Chem. Rev. 1996, 96, 1123.

(222) Lodaya, J. S.; Koser, G. F. J. Org. Chem. 1990, 55, 1513.

(223) Rebrovic, L.; Koser, G. F. J. Org. Chem. 1984, 49, 4700.

(224) Margida, A. J.; Koser, G. F. J. Org. Chem. 1984, 49, 4703.

(225) Mendelsohn, B. A.; Lee, S.; Kim, S.; Teyssier, F.; Aulakh, V. S.; Ciufolini, M. A. Org. Lett.

2009, 11, 1539.

(226) Skinner, G. S. J. Am. Chem. Soc. 1924, 46, 731.

(227) Panizzi, L. Gazz. Chim. Ital. 1939, 69, 332.

(228) Vaughan, W. R.; Spencer, J. L. J. Org. Chem. 1960, 25, 1160.

(229) Bondar, N. F.; Isaenya, L. P.; Skupskaya, R. V.; Lakhvich, F. A. Russ. J. Org. Chem. 2003, 39,

1089.

(230) Ghosh, H.; Patel, B. K. Org. Biomol. Chem. 2010, 8, 384.

(231) Pierce, J. G.; Kasi, D.; Fushimi, M.; Cuzzuppe, A.; Wipf, P. J. Org. Chem. 2008, 73, 7807.

(232) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.

(233) Goel, O. P.; Krolls, U.; Stier, M.; Kesten, S. Organic Syntheses 1989, 67, 69.

(234) Kusama, H.; Yamashita, Y.; Uchiyama, K.; Narasaka, K. Bull. Chem. Soc. Jpn. 1997, 70, 965.

(235) Frie, J. L.; Jeffrey, C. S.; Sorensen, E. J. Org. Lett. 2009, 11, 5394.

(236) Sorensen, E. J., Personal communication.

114

(237) Simon Kim performed some preliminary unpublished work in the area of tandem oxidative

amidation-INOC sequences.

115

Appendices

Unless otherwise indicated, 1H (300 MHz) and

13C (75 MHz) NMR spectra were recorded at

room temperature from either CDCl3 or d6-acetone solutions as indicated. Chemical shifts are reported as

ppm on the d scale and coupling constants, J, are in Hz. Multiplicities are described as s (singlet), d / dd /

ddd (doublet / doublet of doublets / doublet of doublet of doublets), t, (triplet), q (quartet), p (pentet), sept

(septuplet), m (multiplet), ABq (AB quartet), and further qualified as app (apparent), b (broad), c

(complex). All 2D NMR spectra were recorded at 300 MHz (1H) or 75 MHz (

13C) unless otherwise

stated.

Infared (IR) spectra (cm-1

) were recorded on a Perkin-Elmer model 1710 Fourier transform

spectrometer from films deposited on NaCl plates or on a Perkin-Elmer Spectrum 100 Fourier transform

spectrometer from samples deposited on a Universal ATR Sampling Accessory. Optical rotations were

measured on a Jasco P-1010 polarimeter at the sodium D line (589 nm). Unless otherwise stated, low

resolution mass spectra (m/z) were obtained in the electrospray (ESI) mode or the atmospheric pressure

chemical ionization (APCI) mode on a Waters Micromass ZQ mass spectrometer. High-resolution mass

spectra (m/z) were recorded in the ESI or APCI mode on a Micromass LCT mass spectrometer by the

David Wong and Marshall Lapawa of the UBC Mass Spectrometry laboratory. Melting points

(uncorrected) were measured on a Mel-Temp apparatus. All X-ray single crystal measurements were

made by Dr. Brian Patrick on a Bruker X8 APEX II diffractometer or a Bruker APEX DUO

diffractometer (as indicated) and the refinements were performed using the SHELXTL crystallographic

software package of Bruker-AXS.

All reagents and solvents were commercial products and used without further purification except

for tetrahydrofuran (THF) which was freshly distilled from Na/benzophenone under argon atmosphere

and methylene chloride (CH2Cl2) which was freshly distilled from CaH2 under argon atmosphere. Flash

column chromatography was performed with Silicycle 230–400 mesh silica gel. All reactions were

performed in flame-dried or oven-dried glassware equipped with TeflonTM

magnetic stirbars. All flasks

were fitted with rubber septa for the introduction of substrates, reagents and solvents via syrings.

116

A. Experimental protocols

A.1 Preparation of methyl 2-(1-acetamido-4-oxocyclohexa-2,5-dienyl)acetate (2.32)

O

NHAc

CO2CH3

2.32

Chemical Formula: C11H13NO4

Exact Mass: 223.08

Molecular Weight: 223.23

Procedure A

To a 1000-mL round-bottomed flask equipped with magnetic stirring bar was added 21.3 g (67.30 mmol)

of iodosobenzene diacetate. The flask was fitted with rubber septa through which a large-gauge needle

was passed to flush the system with dry argon. After the vessel had been thoroughly purged, 500 mL

acetonitrile and 5 mL TFA was added by syringe and stirred at room temperature for 30 min. To this

suspension was added portions of crystalline methyl 4-hydroxy-phenylacetate 2.31 (250 mg every 15

minutes) until a total of 10.0 g (60.18 mmol) methyl 4-hydroxy-phenylacetate had been added. The

reaction mixture was allowed to stir at room temperature for 16 h. The clear reddish-colored solution was

concentrated to a dark-red colored oil in vacuo on a rotary evaporator (12.7 torr, 40 °C) and passed

through a short plug of silica gel (75 g), eluting non-polar impurities with 50% ethyl acetate in hexanes

and enriched product with 100% ethyl acetate. The enriched product fractions were combined and

concentrated to an orange-colored solid (9.5 g – 11.2 g). The enriched product is dissolved in hot acetone

(50 mL) and diethyl ether (50 mL) and crystallized at –20 °C overnight. Product crystals were collected

by vacuum filtration and washed with minimal amounts of diethyl ether to give 6.95 g – 7.35 g (50 –

55%) of the desired dienone 2.32 as off-white crystals.

117

Procedure B

To a 1000-mL round-bottomed flask equipped with magnetic stirring bar was added 21.3 g (67.30 mmol)

of iodosobenzene diacetate. The flask was fitted with rubber septa through which a large-gauge needle

was passed to flush the system with dry argon. After the vessel had been thoroughly purged, 500 mL

acetonitrile and 5 mL TFA was added by syringe and stirred at room temperature for 30 min. To this

suspension was added manually portions of crystalline methyl 4-hydroxy-phenylacetate 2.31 (continuous

addition of the solid phenol 2.31 over 3 h) until a total of 10.0 g (60.18 mmol) methyl 4-hydroxy-

phenylacetate had been added. The reaction mixture was allowed to stir at room temperature for 16 h.

The clear reddish-colored solution was concentrated to a dark-red colored oil in vacuo on a rotary

evaporator (12.7 torr, 40 °C) and passed through a column of silica gel (~200 g), eluting non-polar

impurities with 50% ethyl acetate in hexanes and enriched product with 100% ethyl acetate. The enriched

product fractions were combined and concentrated to an orange-colored solid which was recrystallized

from hot acetone (~100 mL). Product crystals were collected by vacuum filtration and washed with

minimal amounts of diethyl ether to give 9.4 g (42.13 mmol, 70%) of the desired dienone 2.32 as off-

white crystals. Note: repurification/recrystallization of the supernatant could provide additional 2.32.

1H (d6-acetone): 7.56 (s, 1H), 7.18 (d, 2H, J = 10.23), 6.15 (d, 2H, J = 10.20), 3.61 (s, 3H), 3.02 (s, 2H),

1.88 (s, 3H).

13C (d6-acetone): 184.14, 169.34, 168.81, 148.56, 127.90, 53.09, 50.93, 41.40, 22.24.

MP: 104–105 °C.

IR: 1735, 1675, 1662.

ESI-MS: 246.2 [M + Na]+.

HRMS: calcd for C11H13NO4 [M + Na]+ = 246.0742, found 246.0736.

EA: calcd C 59.19%, H 5.87%, N 6.28%; found C 59.27%, H 5.84%, N 6.24%.

118

A.2 Preparation of methyl 2-((1r,4r)-1-acetamido-4-(tert-butyldiphenylsilyloxy)cyclohexa-2,5-

dienyl)acetate (2.37)

TBDPSO

NHAc

CO2CH3H

2.37

Chemical Formula: C27H33NO4Si

Exact Mass: 463.22


Commercial DIBAL-H solution (1M in hexanes, 36.8 mL, 36.8 mmol) was added to a cold (–78 °C), well

stirred solution of 2.32 (5.5 g, 24.5 mmol) in THF (250 mL), under argon atmosphere. The mixture was

stirred at –78 C for 4 h, and then it was quenched by the sequential addition of water (4 mL), 10% aq

NaOH (4 mL), and again water (12 mL). The volatile organics were removed in vacuo, and the crude

product was suspended in acetone (200 mL) and filtered through methanol-washed celite. The filtrate was

evaporated in vacuo and the residue (5.1 g, 22.6 mmol, 92% yield) was advanced to the next step without

further purification. Thus, a portion of this material (3.0 g, 13.3 mmol) in CH2Cl2 (30 mL) was treated

with TBDPS-Cl (5.1 mL, 20 mmol) and imidazole (1.4 g, 20 mmol), and the mixture was stirred at rt

under an argon atmosphere for 18 h. The mixture was then treated with 0.05M HCl (30 mL) and

extracted with ethyl acetate. The combined extracts were dried over anhydrous MgSO4, filtered and

concentrated in vacuo. The crude product was purified by flash column chromatography (step gradient of

20-40-100% ethyl acetate/hexanes). Pure fractions were concentrated to give 2.37 (5.3 g, 11.4 mol, 87%)

as a clear viscous oil.

1H (d6-acetone): 7.73 (m, 4H), 7.45 (m, 6H), 6.99 (brs, 1H), 6.14 (d, 2H, J = 10.1), 5.80 (dd, 2H, J2 =

10.3; J1 = 2.8), 4.60 (m, 1H), 3.62 (s, 3H), 2.96 (s, 2H) 1.75 (s, 3H), 1.07 (s, 9H).

13C (d6-acetone): 170.7, 169.7, 136.5, 134.6, 131.0, 130.7, 130.0, 128.6, 64.5, 52.2, 51.6, 43.3, 27.3,

23.5, 19.7.

IR: 1739, 1653.

ESI-MS: 486.2 [M + Na]+.

HRMS: calcd for C27H33NO4Si•Na+ [M + Na]

+ = 486.2077, found 486.2059.


119

A.3 Preparation of 2-((1r,4r)-1-acetamido-4-(tert-butyldiphenylsilyloxy)cyclohexa-2,5-

dienyl)acetic acid (2.38)

TBDPSO

NHAc

CO2HH

2.38

Chemical Formula: C26H31NO4Si

Exact Mass: 449.2


A solution of 2.37 (2.2 g, 4.7 mmol) in THF (70 mL) was treated with aqueous 1M NaOH (15 mL) and

the mixture was stirred for 18 h at rt. The volatile organics were removed in vacuo, and the residue was

partitioned between 50% AcOH/H2O (60 mL) and ethyl acetate (100 mL). The organic layer was dried

over MgSO4, filtered and concentrated to give pure 2.38 (2.1 g, 4.7 mmol, 99% yield) as a glassy-solid.

1H (600 MHz, d6-acetone): 7.73 (m, 4H), 7.46 (m, 6H), 6.96 (brs, 1H), 6.14 (d, 2H, J = 8.7), 5.80 (dd,

2H, J2 = 10.3; J1 = 3.0), 4.62 (m, 1H), 2.88 (s, 2H), 1.74 (s, 3H), 1.06 (s, 9H).

13C (150 MHz, d6-acetone): 172.0, 170.1, 137.1, 135.2, 131.8, 131.3, 130.6, 130.2, 129.2, 65.3, 52.5,

43.6, 27.8, 24.1, 20.3.

ESI-MS: 472.2 [M + Na]+.

HRMS: calcd for C26H31NO4Si•Na+ [M + Na]

+ = 472.1920, found 472.1912.

120

A.4 Preparation of N-((1r,4r)-4-(tert-butyldiphenylsilyloxy)-1-(3-nitro-2-oxopropyl)cyclohexa-

2,5-dienyl)acetamide (2.39)

TBDPSO

NHAc

H

2.39

ONO2

Chemical Formula: C27H32N2O5Si

Exact Mass: 492.21


Carbonyldiimidazole (874 mg, 5.4 mmol) was added to a solution of acid 2.38 (2.0 g, 4.5 mmol) in THF

(10 mL) and the mixture was stirred at rt for 1 h. Nitromethane (1.5 mL, 26.9 mmol) followed by KOtBu

(2.0 g, 18.0 mmol) were then added and after stirring for an additional 2 h, the volatiles were removed in

vacuo. The residue was partitioned between 50% AcOH/H2O (100 mL) and CH2Cl2 (150 mL). The

organic layer was dried (MgSO4) filtered and concentrated to give crude nitroketone 2.39, which was

purified by flash column chromatography using a step gradient from 30% ethyl acetate/hexanes to 100%

ethyl acetate. This afforded 1.8 g (3.7 mmol, 82% yield) of pure 2.39 as a light-yellow colored amorphous

solid.

1H (d6-acetone): 7.74 (m, 4H), 7.47 (m, 6H), 6.18 (dd, 2H, J2 = 10.2; J1 = 1.7), 5.86 (dd, 2H, J2 = 10.3; J1

= 3.2), 5.67 (s, 2H), 4.59 (m, 1H), 3.30 (s, 2H), 1.78 (s, 3H), 1.07 (s, 9H).

13C (d6-acetone): 195.5, 170.4, 136.6, 134.5, 130.9, 130.8, 130.2, 128.7, 85.2, 64.2, 52.2, 48.7, 27.3,

23.5, 19.7.

IR: 1736, 1700, 1656, 1558.

ESI-MS: 515.2 [M + Na]+.

HRMS: calcd for C27H32N2O5Si•Na+ [M + Na]

+ = 515.1978, found 515.1962.

121

A.5 Preparation of N-((3aS,7aS)-2-oxo-2,3,3a,7a-tetrahydrobenzofuran-3a-yl)acetamide (2.41)

O

O

NHAc

H

2.41


Exact Mass: 193.07


Carboxylic acid 2.38 (also 2.40 and mixtures of the two) readily converts to 2.41 upon treatment with

acidic media such as 1M aq HCl. Lactone 2.41 was commonly seen as a side product during the workup

and extraction of carboxylic acid 2.38. Lactone 2.41 was intentionally prepared by exposing compound

2.38 to any amount of HCl for a prolonged period of time.

1H (d6-acetone): 6.12 (m, 1H), 6.00 (m, 2H, 1 olefinic H + NH signals), 5.88 (m, 2H), 5.45 (br d, 1H, J =

3.8), 3.28 (d, 1H, B part of AB, J = 17.5), 2.81 (d, 1H, A part of AB, J = 17.5), 2.01 (s, 3H).

13C (d6-acetone): 174.2, 170.6, 129.4, 125.9, 123.3, 123.0, 80.8, 57.6, 39.7, 23.9.

ESI-MS: 216.3 [M + Na]+.

HRMS: calcd for C10H11NO3 •Na+ [M + Na]

+ = 216.0637, found 216.0634.

122

A.6 Preparation of N-((2aR,2a1S,3S,5aS)-3-(tert-butyldiphenylsilyloxy)-7-oxo-2a,2a1,3,5a,6,7-

hexahydroindeno[1,7-cd]isoxazol-5a-yl)acetamide (2.43)

O

O

NHAc

H

TBDPS

NO

2.43


Exact Mass: 474.2


A solution of 2.39 (27 mg, 55 mol), TBSCl (17 mg, 110 mol) and imidazole (8 mg, 110 mol) in dry

CH2Cl2 (0.5 mL) was stirred at rt for 120 h, then it was concentrated in vacuo. Purification of the crude

2.43 residue by flash column chromatography (50% ethyl acetate/hexanes to 100% ethyl acetate) gave

pure 2.43 (10 mg, 38% yield) as a foamy colorless solid.

1H (d6-acetone): 7.79 (d, 2H, J = 6.8), 7.73 (d, 2H, J = 7.7), 7.64 (brs, 1H), 7.47 (m, 6H), 6.09 (ddd, 1H,

J3 = 10.3; J1 = J2 = 1.6), 5.70 (ddd, 1H, J3 = 10.3; J2 = 3.0; J1 = 1.2), 5.01 (dd, 1H, J3 = 11.1; J2 = 5.0; J1 =

1.4), 4.81 (ddd, 1H, J3 = 4.9; J2 = 2.9; J1 = 1.8), 4.70 (dd, 1H, J2 = 11.1; J1 = 1.0), 3.36 (d, 1H, B part of

AB, J = 18.0), 3.04 (d, 1H, A part of AB, J = 18.0), 1.71 (s, 3H), 1.11 (s, 9H).

13C (d6-acetone): 192.0, 170.3, 163.1, 137.9, 136.6, 136.5, 134.5, 134.3, 130.9, 130.8, 130.4, 128.7,

128.7, 85.4, 67.3, 57.3, 56.0, 52.3, 27.3, 23.0, 19.8.

MP: 92–96 °C.

IR: 1747, 1660, 1599, 1538.

ESI-MS: 497.2 [M + Na]+.


+ = 497.1873, found 497.1866.

123

A.7 Preparation of N-((3aS,7aS,E)-2-(nitromethylene)-2,3,3a,7a-tetrahydrobenzofuran-3a-

yl)acetamide (2.44)

OH

NHAc

2.44

NO2

Chemical Formula: C11H12N2O4

Exact Mass: 236.08


A solution of nitroketone 2.39 (33 mg, 67 mol) and triethylamine (50 L) in anhydrous THF (300 L)

was stirred for 24 h at rt, then it was concentrated in vacuo. Flash column chromatography of the residue

(50% ethyl acetate/hexanes to 75% ethyl acetate) afforded 2.44 (10 mg, 42 mol, 63%) as a crystalline

solid (crystallized from ethyl acetate).

1H (d6-acetone): 7.72 (br s, 1H), 7.19 (s, 1H), 6.17 (dd, 1H, J2 = 9.7; J1 = 5.3), 6.10 (d, 1H, J = 9.5), 5.99

(dd, 1H, J2 = 9.7; J1 = 5.4), 5.88 (dd, 1H, J2 = 9.7; J1 = 3.6), 5.67 (d, 1H, J = 3.6), 4.17 (d, 1H, B part of

AB, J = 19.0), 3.40 (d, 1H, A part of AB, J = 19.0), 1.90 (s, 3H).

13C (d6-acetone): 172.9, 169.7, 131.5, 125.8, 122.6, 121.0, 118.1, 87.0, 58.3, 45.5, 22.3.

MP: 154–156 °C.

ESI-MS: 237.2 [M + H]+; 259.1 [M + Na]

+.

HRMS: calcd for C11H12N2O4•Na+ [M + Na]

+ = 259.0695, found 259.0688.

124

A.8 Preparation of N-((1r,4r)-1-(2-(tert-butyldimethylsilyloxy)-3-nitropropyl)-4-(tert-

butyldiphenylsilyloxy)cyclohexa-2,5-dienyl)acetamide (2.46) diastereomers

OTBS

NO2

TBDPSO

NHAc

2.46

Chemical Formula: C33H48N2O5Si2Exact Mass: 608.31


Nitro alcohol intermediate:

ESI-MS: 517.1 [M + Na]+.

HRMS: calcd for C27H34N2O5 [M + Na]+ = 517.2135, found 517.2152.

Product 2.46 diastereomers:

Note: NMR data shows overlapping signals which appeared difficult to deconvolute.

1H (d6-acetone, 400 MHz): 7.74 (m, 4H), 7.46 (m, 6H), 6.91 (br s, 1H), 6.15 (c br m, 1H), 5.94 (c m,

2H), 5.85 (br c m, 1H), 4.81 (c m, 1H), 4.56 (br s, 1H), 4.47 (c m, 1H) 4.40 (c m, 1H), 2.47 (c br m, 1H),

2.29 (c br m, 1H), 1.75 (br s, 3H), 1.07 (br s, 9H), 0.86 (br s, 9H), 0.17 (br s, 3H), 0.08 (br s, 3H).

13C (d6-acetone, 100 MHz): 169.59, 136.77, 136.75, 136.42, 134.65, 132.11, 131.34, 130.94, 130.79,

130.65, 128.81, 128.80, 136.77, 136.75, 136.42, 134.65, 132.11, 131.34, 130.94, 130.79, 130.65, 128.81,

128.80, 82.37, 68.63, 64.49, 52.94, 43.88, 27.43, 26.43, 26.18, 23.83, 19.78, 18.57, -3.81, -4.79.

ESI-MS: 631.3 [M + Na]+.

HRMS: calcd for C33H48N2O5 [M + Na]+ = 631.2999, found 631.2994.


125

A.9 Preparation of compounds 2.49, 2.50, 2.51 and 2.52

TBDPSO

O N

OTBS

NHAc

= 2.49 = 2.50



TBDPSO

O N

OTBS

OTBS

NHAc

H

= 2.51 = 2.52



Solid NaBH4 (1.4 g, 36.7 mmol) was added to a cold (0 °C), well stirred solution of nitroketone 2.39

(3.61 g, 7.33 mmol) in methanol (50 mL), and stirring was continued for 2 h. The mixture was carefully

poured into 50% AcOH/H2O (100 mL; CAUTION: release of flammable H2 gas) and the acetic acid

solution was extracted with ethyl acetate (3 x 150 mL). The combined extracts were dried over MgSO4,

filtered and concentrated in vacuo. The alcohol intermediate was found to be extremely sensitive and

readily decomposed in a retro-Henry mode. Thus, the crude reaction residue was immediately dissolved

in CH2Cl2, and to this solution was added imidazole (2.0 g, 29.4 mmol) and TBSCl (4.4 g, 29.3 mmol).

The reaction mixture was stirred for 168 h and then it was concentrated in vacuo. Purification of the

residue by flash column chromatography (step gradient 5, 10, 15, 20, 25, 30, 40, 50 and then 100% ethyl

acetate/hexanes) yielded the following compounds: ester 2.37 (200 mg, 432 mol, 6% yield), 2.49 (725

mg, 1.2 mmol, 17% yield), 2.50 (775 mg, 1.3 mmol, 18% yield), and a mixture of compounds 2.51 and

2.52 (300 mg, 420 mol, 6% yield, note: the spontaneous conversion of 2.51 and 2.52 to the

isooxazolines 2.49 and 2.50 occurred slowly over time).

126

A.9.1 Compound 2.49

TBDPSO

O N

OTBS

NHAc

2.49



Colorless oil.

1H (d6-acetone): 7.76 (m, 4H), 7.44 (m, 6H), 5.85 (B-part of AB-type system, app br dt, 1H, J = 10.2),

5.59 (A-part of AB-type system, br d, 1H, J = 10.2), 4.78 (m, 1H), 4.75 (m, 1H), 4.61 (m, 1H), 4.28 (br d,

1H, J = 10.2), 2.90 (B-part of AB-type system, dd, 1H, J2 = 14.0; J1 = 6.9), 2.38 (A-part of AB-type

system, dd, 1H, J2 = 14.0; J1 = 4.0), 1.68 (s, 3H), 1.10 (s, 9H), 0.89 (s, 9H), 0.12 (s, 3H), 0.10 (s, 3H).

ESI-MS: 589.6 [M – H]-; 613.4 [M + Na]

+.

HRMS: calcd for C33H46N2O4Si2•Na+ [M + Na]

+ = 613.2894, found 613.2891.

127

A.9.2 Compound 2.50

TBDPSO

O N

OTBS

NHAc

2.50



Colorless oil.

1H (d6-acetone): 7.76 (m, 4H), 7.44 (m, 6H), 7.31 (br s, 1H), 5.88 (B-part of AB-type system, app dt,

1H, J2 = 10.2; J2 = 1.6), 5.69 (A-part of AB-type system, br d, 1H, J = 10.2), 5.11 (dd, 1H, J2 = 9.6; J1 =

4.5 ), 4.66 (m, 1H), 4.63 (m, 1H), 4.28 (br d, 1H, J = 10.2), 2.90 (B-part of AB-type system, dd, 1H, J2 =

13.8; J1 = 9.7), 2.19 (A-part of AB-type system, dd, 1H, J2 = 13.8; J1 = 4.6), 1.67 (s, 3H), 1.08 (s, 9H),

0.90 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H).

13C (d6-acetone): 169.0, 166.0, 135.8, 135.7, 133.8, 133.6, 132.2, 129.8, 127.7, 127.6, 80.2, 66.8, 65.7,

57.8, 51.9, 51.6, 26.4, 25.2, 22.2, 18.9, 17.9, -5.6, -5.9.

ESI-MS: 589.5 [M – H]-; 613.4 [M + Na]

+.


+ = 613.2894, found 613.2883.

128

A.9.3 Compound 2.51/2.52

TBDPSO

O N

OTBS

OTBS

NHAc

H

= 2.51 = 2.52



Colorless oil.

1H (d6-acetone): 7.71 (m, 4H), 7.44 (m, 6H), 7.02 (brs, 1H), 6.01 (d, 1H, J = 10.1), 5.61 (ddd, 1H, J3 =

10.1; J1 = J2 = 4.3), 4.76 (dd, 1H, J2 = 8.4; J1 = 2.2 ), 4.24 (m, 1H), 4.01 (dd, 1H, J2 = 8.4; J1 = 4.8), 3.80

(app q, 1H, J = 6.3), 3.63 (app t, 1H, J = 8.4), 2.91 (dd, 1H, B part of AB-type system, J = 13.9, 6.3), 2.38

(dd, 1H, A part of AB-type system, J = 13.9, 4.2), 1.88 (s, 3H), 1.08 (s, 9H), 0.91 (s, 9H), 0.89 (s, 9H),

0.13 (s, 6H), 0.07 (s, 3H), 0.05 (s, 3H).

ESI-MS: 729.6 [M + Na]+.


+ = 729.3908, found 729.3915.

129

A.10 Preparation of trans-9-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-2-methyl-3-nitro-1-

azaspiro[5.5]undeca-2,7,10-trien-4-one (2.55)

2.55

HN

CH3

NO2

O

TBDPSO


Exact Mass: 474.2


A solution of nitroketone 2.39 (1.7 g, 3.4 mmol) TBSCl (5.1 g, 34.0 mmol) and imidazole (2.3 g, 34.0

mmol) in anhydrous CH2Cl2 (20 mL) was stirred for 48 h at rt, then the reaction was concentrated in

vacuo. Silica gel flash column chromatography (50% ethyl acetate/hexanes to 100% ethyl acetate) of the

reaction residue afforded 1.1 g (2.2 mmol, 65%) of 2.55 as a crystalline solid, (recrystallized from ethyl

acetate), and 83 mg (180 mol) of isoxazoline 2.43.

1H (d6-acetone): 7.72 (m, 4H), 7.45 (m, 6H), 5.99 (s, 4H), 4.58 (m, 1H), 2.59 (s, 2H), 2.28 (s, 3H), 1.06

(s, 9H).

13C (d6-DMSO): 178.9, 161.9, 135.3, 133.0, 131.2, 130.1, 128.0, 127.5, 125.2, 63.0, 52.5, 45.6, 26.7,

19.7, 18.7.

MP: 212–213 °C

ESI-MS: 475.2 [M +H]+; 497.2 [M + Na]

+.

HRMS: calcd for C27H29N2O4Si [M – H]– = 473.1897, found 473.1913.


130

A.11 Preparation of methyl 2-((1S,4S,5R,6S)-1-acetamido-4-(tert-butyldiphenylsilyloxy)-6-cyano-

5-hydroxycyclohex-2-enyl)acetate (2.59)

OH

O CN

CO2CH3

NHAc

2.59

TBDPS


Exact Mass: 506.22


Isooxazoline 2.43 (15 mg, 0.0317 mmol) was dissolved in methanol (0.5 mL) at ambient temperature. To

this solution was added imidazole (1 mg, 0.0147 mmol) and lithium carbonate (1 mg, 0.0135 mmol). The

solution was allowed to stir for 1 h, before the reaction mixture was concentrated in vacuo. The crude

residue was passed through a small plug of silica gel (150 mg) using ethyl acetate/hexanes (30-75% ethyl

acetate/hexanes). Compound 2.59 was obtained in 68% yield (11 mg, 0.0217 mmol) as a glassy solid.

1H (d6-acetone): 7.78 (m, 4H), 7.45 (m, 6H), 7.31 (br s, 1H), 5.86 (ddd, 1H, J3 = 10.4; J1 = J2 = 1.8),

5.52 (ddd, 1H, J3 = 10.5; J1 = J2 = 2.9), 4.41 (m, 1H), 4.33 (3, 1H), 4.26 (m, 1H), 3.67 (s, 3H), 3.33 (d,

1H, B part of AB, J = 15.8), 3.17 (d, 1H, A part of AB, J = 15.8), 1.82 (s, 3H), 1.12 (s, 9H).

13C (d6-acetone): 170.9, 170.3, 136.8, 136.7, 134.4, 133.9, 130.9, 130.9, 130.0, 128.7, 128.6, 119.2, 69.0,

68.9, 68.8, 54.8, 51.9, 41.5, 38.3, 27.3, 23.5, 19.9.

IR: 2243, 1737, 1661.

ESI-MS: 529.2 [M + Na]+.


+ = 529.2135, found 529.2123.

131

A.12 Preparation of N-((2aR,2a1S,3S,5aS)-3-hydroxy-7-oxo-2a,2a1,3,5a,6,7-


HO

O

NHAc

H NO

2.60


Exact Mass: 236.08


To a solution of isooxazoline 2.43 (40 mg, 0.084 mmol) in dry CD3CN (1 mL) was added drop-wise

HF/H2O (35% HF v/v, 3 drops). This reaction was allowed to stir for 96 h, after which volatile organics

were removed in vacuo. The crude product was purified via flash column chromatography (50%

acetone/hexanes, then 75% acetone/hexanes, then 100% acetone) to give pure 2.60 (14 mg, 0.059 mmol,

70% yield) as a glassy solid. Unreacted compound 2.43 was also recovered (3 mg, 0.006 mmol, 7%).

1H (d6-acetone): 7.73 (brs, 1H), 6.05 (ddd, 1H, J3 = 10.3; J1 = J2 = 1.6 ), 5.70 (ddd, 1H, J = 10.3, 3.0,

1.2), 5.22 (ddd, 1H, J3 = 11.1, 5.2, 1.4), 4.85 (dd, 1H, J = 11.1, 0.9), 4.54 (br m, 1H), 4.22 (br d, 1H, J =

8.2), 3.45 (d, 1H, B part of AB, J = 18.0), 3.04 (d, 1H, A part of AB, J = 18.0), 1.85 (s, 3H).

13C (d6-acetone): 192.1, 170.5, 163.5, 138.8, 129.9, 85.5, 65.1, 57.7, 56.0, 52.3, 23.2.

ESI-MS: 259.2 [M + Na]+.


+ = 259.0695, found 259.0695.

132

A.13 Preparation of methyl 2-((1S,5R,6S)-1-acetamido-6-cyano-5-hydroxy-4-oxocyclohex-2-

enyl)acetate (2.62)

O

CO2CH3

HO N

NHAc

2.62


Exact Mass: 266.09


To a solution of 2.60 (14 mg, 0.0593 mmol) in CD3CN (1.5 mL) was added Dess-Martin periodinane (30

mg, 71 mol). This solution was monitored by 1H-NMR until the reaction had completed (12 h). The

crude reaction was filtered through celite and concentrated in vacuo. Crude N-[(4aR,7aS,7bR)-3,4,7a,7b-

tetrahydro-3,7-dioxoindeno[1,7-cd]isoxazol-4a(7H)-yl]-acetamide (2.61) was thus obtained.

1H (d6-acetone): 8.16 (br s, 1H), 6.55 (dd, 1H, J = 10.4, 2.0), 6.29

(dd, 1H, J = 10.4, 0.6), 5.19 (dd, 1H, J = 10.7, 0.7), 4.78 (dd, 1H, J =

10.7, 1.8), 3.45 (d, 1H, B part of AB, J = 18.0), 3.23 (d, 1H, A part of

AB, J = 18.0), 1.89 (s, 3H).

ESI-MS: 257.1 [M + Na]+.


+ = 257.0538, found

257.0541.

Diketone 2.61 was not purified nor thoroughly characterized due to significant reactivity. Instead, it was

dissolved in dry methanol (700 L) and to this was added Li2CO3 (1 mg, 14 mol), and the mixture was

stirred at rt for 8 h. The suspension was filtered through celite and concentrated in vacuo. The reaction

residue was purified by flash column chromatography (30% ethyl acetate/hexanes, then 75% ethyl

acetate/hexanes, then 100% ethyl acetate) to give pure 2.62 (6 mg, 23 mol, 38% yield) as a glassy solid.

1H (CD3CN): 7.25 (dd, 1H, J = 10.3, 1.5), 6.10 (d, 1H, J = 10.3), 4.74 (d, 1H, J = 5.0), 4.42 (dd, 1H, J2 =

5.0; J1 = 1.4), 3.68 (s, 3H), 3.18 (app. d, 2H, actually compressed AB system, J = 15.7), 1.87 (s, 3H).

13C (CD3CN, 100 MHz): 196.46, 171.67, 170.34, 149.24, 127.54, 117.79, 70.16, 56.20, 52.61, 43.74,

41.19, 23.31.

IR: 2251, 1732, 1699, 1655.

ESI-MS: 289.1 [M + Na]+.


+ = 289.0800, found 289.0794.

O

O

NHAc

NO

2.61


Exact Mass: 234.06Molecular Weight: 234.21

133

A.14 Preparation of N-((2aR,2a1S,3R,5aS)-3-(tert-butyldiphenylsilyloxy)-7-oxo-2a,2a1,3,5a,6,7-


O

O

NHAc

H

TBDPS

NO

2.66


Exact Mass: 474.2


Dienone 2.32 (15.0 g, 67.3 mmol) was dissolved in THF (200 mL) at room temperature under argon

atmosphere. To this solution was added (S)-(–)2-methyl-CBS-oxazaborolidine (1.83 g, 6.73 mmol)

followed by the addition of BH3-DMS complex (6.38 mL, 67.3 mmol). This reaction was allowed to stir

overnight. The crude reaction residue (mostly 2.35 and 2.36) was thoroughly concentrated in vacuo. The

crude reaction residue was dissolved in CH2Cl2 (500 mL) and to this was added imidazole (5.04 g, 74.0

mmol) and TBDPS-Cl (20.3 g, 74.0 mmol). The reaction was allowed to stir overnight at ambient

temperature under an argon atmosphere. The crude reaction mixture was poured into a solution of 0.05M

aqueous HCl (400 mL) and the aqueous phase was extracted with CH2Cl2 (2 x 400 mL). The combined

organic phase was dried over anhydrous MgSO4, filtered through a short plug of silica gel and

concentrated in vacuo. The crude mixture of TBDPS-alcohols 2.37/2.63 was dissolved in THF (500 mL)

and to this was added a solution of 1M aqueous NaOH (270 mL). The biphasic mixture was vigorously

stirred overnight. The volatile organics were removed in vacuo, and the residue was partitioned between

50% AcOH/H2O (500 mL) and ethyl acetate (400 mL). The aqueous layer was extracted a second time

with ethyl acetate (250 mL), and the combined organic layer was dried over anhydrous MgSO4, filtered

and concentrated in vacuo. The crude mixture of carboxylic acids 2.38/2.64 was dissolved in THF (250

mL) and to this was added carbonyldiimidazole (13.1 g, 80.8 mmol) with stirring at room temperature.

The reaction mixture was stirred for 1 h at room temperature, and then nitromethane (100 mL) was added,

followed by the addition of solid potassium tert-butoxide (30.2 g, 269.2 mmol). The reaction mixture

was stirred at room temperature for 2 h and then the volatiles were removed in vacuo. The residue was

partitioned between 50% AcOH/H2O (500 mL) and CH2Cl2 (400 mL). The organic phase was separated

and the aqueous phase was washed with additional CH2Cl2 (2 x 400 mL). The combined organic phase

was dried over anhydrous MgSO4, filtered through a short silica gel plug and concentrated to give

134

enriched nitroketones 2.39/2.65. The mixture of crude nitroketones was dissolved in CH2Cl2 (300 mL)

and to this was added imidazole (9.12 g, 134 mmol) and TBS-Cl (20.20 g, 134 mmol). The reaction

mixture was allowed to stir at room temperature under an argon atmosphere for 5 days. The reaction

mixture was concentrated in vacuo and purified by flash column chromatography using (50% ethyl

acetate/hexanes to 100% ethyl acetate) to give 2.43 (2.7 g, 8% yield over 5 steps) and 2.66 (6.3 g, 20%

yield over 5 steps). Significant amount of nitroketones 2.39 and 2.65 were recovered (~28%) and

recycled.

1H (d6-acetone): 7.73 (m, 4H),7.47 (m, 6H), 6.15 (ddd, 1H, J3 = 10.3; J1 = J2 = 1.1 ), 6.01 (ddd, 1H, J =

10.0, 5.3, 0.8), 5.17 (ddd, 1H, J3 = 10.9, 2.0, 0.8), 5.05 (app d, 1H, J = 5.4), 4.16 (dd, 1H, J = 5.4, 2.0),

3.55 (d, 1H, B part of AB, J = 18.3), 3.12 (d, 1H, A part of AB, J = 18.3), 1.93 (s, 3H), 1.09 (s, 9H).

ESI-MS: 473.5 [M – H]–, 497.4 [M + H]

+, 497.4 [M + Na]

+.


+ = 475.2053, found 475.2059.

135

A.15 Preparation of methyl 2-((1S,4R,5R,6S)-1-acetamido-4-(tert-butyldiphenylsilyloxy)-6-cyano-


OH

O CN

CO2CH3

NHAc

2.67

TBDPS


Exact Mass: 506.22


Isooxazoline 2.66 (900 mg, 1.90 mmol) was dissolved in methanol (10 mL) at ambient temperature. To

this solution was added imidazole (10 mg) and lithium carbonate (50 mg). The solution was allowed to

stir for 1 h, before the reaction mixture was concentrated in vacuo. The crude residue was passed through

a small plug of silica gel (1 g) using ethyl acetate/hexanes (30-75% ethyl acetate/hexanes). Compound

2.67 was obtained in 90% yield (864 mg, 1.71 mmol) as a glassy solid.

1H (d6-acetone): 7.78 (m, 4H), 7.45 (m, 6H), 7.33 (brs, 1H), 5.92 (ddd, 1H, J3 = 10.3; J2 = 1.3 J1 = 0.4),

5.52 (ddd, 1H, J3 = 10.3, J2 = J1 =2.6), 5.00 (d, 1H, J = 4.7), 4.50 (c m, 1H), 4.34 (dd, 1H, J2 = 4.0 J1 =

1.0), 4.26 (m, 1H), 3.62 (s, 3H), 3.35 (d, 1H, A part of ABq, J = 15.5), 2.88 (d, 1H, B part of ABq, J =

15.5), 1.89 (s, 3H), 1.09 (s, 9H).

13C (d6-acetone): 169.70, 169.69, 135.91, 135.84, 133.97, 133.30, 131.26, 129.84, 129.83, 128.10,

127.69, 127.64, 117.91, 71.61, 69.50, 55.04, 50.94, 39.98, 39.52, 26.46, 22.67, 19.04.

IR: 2247 cm-1

, 1719 cm-1

, 1639 cm-1

.

ESI-MS: 529.5 [M + Na]+.


+ = 529.2135, found 529.2122.

136

A.16 Preparation of compounds 2.76-2.88

Representative procedure for the results listed in Tables 2.8 and 2.9:

A solution of oxime (1 mmol) in methanol (1 mL) was added slowly (syringe pump, 1 h) at room

temperature to a stirred solution of DIB (1.1 eq) and olefin (1.1 eq) in methanol (2 mL) containing TFA

(15 L). A white precipitate formed immediately and then slowly redissolved as the reaction progressed.

Upon consumption of starting oxime (TLC, about 1 h), the mixture was concentrated in vacuo and the

residue was purified by flash column chromatography using a step gradient: 5%-10%-20% ethyl

acetate/hexanes.

A.16.1 Preparation of 3-(4-methoxyphenyl)-5-phenyl-4,5-dihydroisoxazole (2.76)

H3CO

ON


Exact Mass: 253.11


2.76

Representative procedure is located in Appendix section A.16.

colorless crystals.

91% yield.

1H (CDCl3): 7.63 (d, 2H, J = 8.9), 7.39 (m, 5H), 6.93 (d, 2H, J = 8.9), 5.71 (dd, 1H, J = 10.9, 8.2), 3.84

(s, 3H), 3.76 (dd, 1H, J = 16.5, 10.9), 3.32 (dd, 1H, J = 16.5, 8.2).

13C (CDCl3): 161.24, 155.81, 141.24, 128.88, 128.43, 128.30, 126.03, 122.19, 114.30, 82.44, 55.51,

43.60.

MP: 100-101 °C.

ESI-MS: 276.3 [M + Na]+.

HRMS: calcd for C16H15NO2Na [M + Na]+ = 276.1000, found 276.1001.

137

A.16.2 Preparation of 3,5-diphenyl-4,5-dihydroisoxazole (2.77)

ON


Exact Mass: 253.11


2.77


colorless crystals.

71% yield.

1H (CDCl3): 7.70 (m, 2H), 7.40 (m, 8H), 5.75 (dd, 1H, J = 11.2, 8.4), 3.79 (dd, 1H, J = 16.4, 11.2), 3.35

(dd, 1H, J = 16.4, 8.2).

13C (CDCl3): 156.23, 141.06, 130.27, 129.61, 128.89, 128.87, 128.35, 126.88, 126.00, 82.70, 43.30.

MP: 72-73 °C.

ESI-MS: 224.3 [M + H]+; 246.3 [M + Na]

+.

HRMS: calcd for C15H13NONa [M + Na]+ = 246.0895, found 246.0894.

138

A.16.3 Preparation of 3-(3-nitrophenyl)-5-phenyl-4,5-dihydroisoxazole (2.78)

ON


Exact Mass: 253.11


2.78

O2N


yellow oil.

91% yield.

1H (CDCl3): 8.44 (t, 1H, J = 1.9), 8.27 (ddd, 1H, J = 8.2, 2.4, 1.0), 8.12 (dt, H, J = 7.9, 1.2), 7.61 (t, 1H,

J = 8.0), 7.39 (m, 5H), 5.84 (dd, 1H, J = 8.3, 11.4), 3.84 (dd, 1H, J = 11.4, 16.5), 3.39 (dd, 1H, J = 16.5,

8.3).

13C (CDCl3): 154.62, 148.62, 140.37, 132.37, 131.49, 130.00, 129.05, 128.67, 125.93, 124.74, 121.72,

83.51.

ESI-MS: 269.2 [M + H]+; 291.2 [M + Na]

+.

HRMS: calcd for C15H12N2O3Na [M + Na]+ = 291.0746, found 291.0736.

139

A.16.4 Preparation of 3-pentyl-5-phenyl-4,5-dihydroisoxazole (2.79)

ON

Chemical Formula: C14H19NO

Exact Mass: 217.15


2.79


colorless oil.

74% yield.

1H (CDCl3): 7.34 (m, 5H), 5.54 (dd, 1H, J = 10.8, 8.0), 3.36 (dd, 1H, J = 16.7, 10.8), 2.89 (dd, 1H, J =

16.7, 8.0), 2.38, (t, 2H, J = 7.7), 1.59 (m, 2H), 1.32 (m, 4H), 0.89 (m, 3H).

13C (CDCl3): 158.69, 141.51, 128.75, 128.05, 125.80, 81.28, 45.45, 31.46, 27.73, 26.16, 22.40, 14.03.

ESI-MS: 218.4 [M + H]+.


140

A.16.5 Preparation of 3-phenethyl-5-phenyl-4,5-dihydroisoxazole (2.80)

ON


Exact Mass: 251.13


2.80


colorless oil.

63% yield.

1H (CDCl3): 7.38-7.19 (m, 10H), 5.53 (dd, 1H, J = 1.0, 8.0), 3.31 (dd, 1H, J = 16.8, 11.0), 2.94 (m, 2H),

2.90 (dd, 1H, J = 16.8, 8.0), 2.71 (m, 2H).

13C (CDCl3): 157.90, 141.37, 140.55, 128.80, 128.73, 128.44, 128.15, 126.52, 125.87, 81.49, 45.72,

32.82, 29.54.

ESI-MS: 274.3 [M + Na]+.


141

A.16.6 Preparation of 3a,4,5,6,7,7a-hexahydro-3-phenyl-4,7-methano-1,2-benzisoxazole (2.81)

ON


Exact Mass: 213.12


2.81


colorless crystals.

95% yield.

1H (CDCl3): 7.71 (m, 2H), 7.39 (m, 3H), 4.64 (d, 1H, J = 8.4), 3.50 (d, 1H, J = 8.4), 2.57 (d, 2H, J =

30.4), 1.56 (m, 3H), 1.35 (m, 1H), 1.18 (m, 2H).

13C (CDCl3): 156.98, 129.78, 129.50, 128.77, 126.92, 87.97, 57.15, 43.09, 39.36, 32.41, 27.52, 22.81.

MP: 98-99 °C.

ESI-MS: 214.3 [M + H]+.


142

A.16.7 Preparation of 3a,4,5,6,7,7a-hexahydro-3-(3-nitrophenyl)-4,7-methano-1,2-benzisoxazole

(2.82)

ON


Exact Mass: 258.1


2.82

O2N


colorless crystals.

77% yield.

1H (CDCl3): 8.47 (t, 1H, J = 1.8), 8.23 (ddd, 1H, J = 8.4, 2.4, 0.9), 8.09 (dt, 1H, J = 7.9, 0.9), 7.58 (t, 1H,

J = 8.0), 4.73 (d, 1H, J = 8.6), 3.52 (d, 1H, J = 8.6), 2.67 (app br s, 1H), 2.52 (app br s, 1H), 1.72-1.32 (m,

4H), 1.23 (m, 2H).

13C (CDCl3): 155.55, 148.67, 132.55, 131.52, 129.90, 124.32, 121.57, 89.00, 56.61, 43.12, 39.26, 32.52,

27.55, 22.76.

MP: 76-77 °C.

ESI-MS: 259.3 [M + H]+.


143

A.16.8 Preparation of 3a,4,5,6,7,7a-hexahydro-3-pentyl-4,7-methano-1,2-benzisoxazole (2.83)


colorless oil.

91% yield.

1H (CDCl3): 4.39 (d, 1H, J = 8.2), 2.99 (d, 1H, J = 8.2), 2.51 (brd, 1H, J = 3.2), 2.32 (m, 2H), 2.16 (ddd,

1H, J = 15.3, 8.7, 6.0), 1.57 (m, 4H), 1.43 (m, 1H), 1.33, (m, 4H), 1.14 (m, 3H), 0.89 (m, 3H).

13C (CDCl3): 158.97, 86.04, 59.47, 42.96, 38.29, 32.24, 31.64, 27.38, 26.72, 26.08, 22.82, 22.45, 14.04.

ESI-MS: 208.4 [M + H]+; 230.4 [M + Na]

+.


144

A.16.9 Preparation of 3a,4,5,6,7,7a-hexahydro-3-(2-phenylethyl)-4,7-methano-1,2-benzisoxazole

(2.84)


colorless oil.

79% yield.

1H (CDCl3): 7.33-7.18 (m, 5H), 4.41 (d, 1H, J = 8.2), 2.93 (m, 3H), 2.65 (ddd, 1H, J = 15.8, 8.7, 6.5),

2.48 (m, 2H), 2.30 (brs, 1H), 1.51 (m, 2H), 1.40 (m, 1H), 1.12 (m, 3H).

13C (CDCl3): 158.34, 141.07, 128.63, 128.40, 126.36, 86.26, 59.68, 42.96, 38.32, 32.61, 32.27, 28.70,

27.36, 22.82.

ESI-MS: 264.3 [M + Na]+.


145

A.16.10 Preparation of 3-(1,1-dimethylethyl)-3a,4,5,6,7,7a-hexahydro4,7-methano-1,2-

benzisoxazole (2.85)


colorless oil.

75% yield.

1H (CDCl3): 4.40 (d, 1H, J = 8.3), 3.05 (dd, 1H, J = 8.3, 1.3), 2.53 (brs, 2H), 1.50 (m, 3H), 1.23 (s, 9H),

1.15 (m, 3H).

13C (CDCl3): 165.27, 87.07, 58.35, 42.79, 39.81, 33.30, 32.18, 29.41, 27.67, 22.85.

ESI-MS: 194.3 [M + H]+; 216.3 [M + Na]

+.


146

A.16.11 Preparation of 3a,4,5,6,7,7a-hexahydro-3-(4-methoxyphenyl)-4,7-methano-1,2-

benzisoxazole (2.86)

ON


Exact Mass: 243.13


2.86

H3CO


colorless crystals.

90% yield.

1H (CDCl3): 7.65 (d, 2H, J = 8.9), 6.91 (d, 2H, J = 8.9), 4.60 (d, 1H, J = 8.3), 3.83 (s, 3H), 3.46 (d, 1H, J

= 8.3), 2.55 (dd, 2H, J = 30.2, 2.9), 1.57 (m, 3H), 1.35 (m, 1H), 1.17 (m, 2H).

13C (CDCl3): 160.86, 156.56, 128.46, 122.07, 114.22, 87.68, 57.49, 55.47, 43.11, 39.41, 32.43, 27.56,

22.83.

MP: 95-96 °C.

ESI-MS: 244.3 [M + H]+; 266.3 [M + Na]

+.

HRMS: calcd for C15H17NO2Na [M + Na]+ = 266.1157, found 266.1152.

147

A.16.12 Preparation of 5-(3-bromopropyl)-4,5-dihydro-3-phenyl-isoxazole (2.87)


colorless crystals.

83% yield.

1H (CDCl3): 7.65 (m, 2H), 7.40 (m, 3H), 4.76 (m, 1H), 3.50 (m, 2H), 3.43 (dd, 1H, J = 16.4, 10.4), 3.00

(dd, 1H, J = 16.4, 7.7), 2.06 (m, 2H), 1.84 (m, 2H).

13C (CDCl3): 156.50, 130.11, 129.64, 128.76, 126.66, 80.39, 40.16, 33.98, 33.52, 28.80.

MP: 53-54 °C.

ESI-MS: 268.2 and 270.2 [M + H]+.

HRMS: calcd for C12H14NO79

BrNa [M + Na]+ = 290.0156, found 290.0163.

148

A.16.13 Preparation of 3,5-diphenylisoxazole (2.88)


colorless crystals.

50% yield.

1H (CDCl3): 7.87 (m, 2H), 7.47 (m, 8H), 6.84, (s, 1H).

13C (CDCl3): 170.41, 162.98, 130.22, 130.01, 129.14, 129.01, 128.93, 127.47, 126.82, 125.84, 97.47.

MP: 138-140 °C.

ESI-MS: 222.3 [M + H]+; 244.3 [M + Na]

+.


149

A.17 Preparation of 1-(3a,4,5,6,7,7a-hexahydro-4,7-methano-1,2-benzisoxazol-3-yl)-ethanone

(2.90)

A solution of oxime 2.89 (120 mg, 1.4 mmol) in methanol (3 mL) was added dropwise at room

temperature to a solution of norbornylene (158 mg, 1.68 mmol, 1.2 eq), PhI(OAc)2 (541 mg, 1.68 mmol,

1.2 eq), TFA (0.1% v/v, 5 L) and methanol (2 mL) with rapid stirring. The reaction mixture was stirred

overnight. The crude product 2.90 was purified by flash column chromatography using a step-gradient:

5%, 10%, 15%, and 20% ethyl acetate/hexanes. Pure fractions of 2.90 were combined and concentrated

in vacuo, yielding compound 2.90 as clear viscous oil (0.188 g, 76%).

1H (CDCl3): 4.65 (d, 1H, J = 8.4), 3.25 (d, 1H, J = 8.4), 2.61 (br s, 1H), 2.51 (br s, 1H), 2.45 (s, 3H),

1.62-1.46 (m, 2H), 1.38-1.02 (m, 4H).

13C (CDCl3): 193.49, 158.98, 91.01, 54.47, 43.16, 39.20, 32.41, 27.38, 27.16, 22.73.

IR: 1685 cm-1

, 1567 cm-1

.

ESI-MS: 202.3 [M + Na]+.

HRMS: calcd for C10H13NO2Na = 202.0844, found 202.0841.

Literature characterization is also available in Cecchi, L.; De Sarlo, F.; Machetti, F. Eur. J. Org. Chem.

2006, 21, 4852-4860.

Alternative method of synthesis is available in Cecchi, L.; De Sarlo, F.; Machetti, F. Tetrahedron Lett.

2005, 46, 7877-7879.

150

A.18 Preparation of 1-(4,5-dihydro-5-phenyl-3-isoxazolyl)-ethanone (2.91)

A solution of oxime 2.89 (138 mg, 1.6 mmol) in methanol (3 mL) was added dropwise at room

temperature to a solution of styrene (200 mg, 1.92 mmol, 1.2 eq), PhI(OAc)2 (618 mg, 1.92 mmol, 1.2

eq), TFA (0.1% v/v, 5 L) and methanol (2 mL) with rapid stirring. The reaction mixture was stirred

overnight and then concentrated in vacuo. The pale-yellow crude product 2.91 was purified by flash

column chromatography using a step-gradient: 5%, 10%, 15%, and 20% ethyl acetate/hexane. Pure

fractions of 2.91 were combined and concentrated in vacuo, yielding 2.91 as clear viscous oil (0.224 g,

75%).

1H (CDCl3): 7.43-7.27 (m, 5H), 5.77 (dd, 1H, J2 = 11.6, J1 = 8.9), 3.55 (dd, 1H, J2 = 17.9, J1 = 11.6),

3.14 (dd, 1H, J2 = 17.9, J1 = 8.9), 2.55 (s, 3H).

13C (CDCl3): 193.18, 158.02, 139.68, 129.04, 128.83, 126.01, 85.69, 39.89, 26.90.

IR: 1686 cm-1

, 1577 cm-1

.

ESI-MS: 190.5 [M + H]+; 212.3 [M + Na]

+.



2006, 21, 4852-4860.


2005, 46, 7877-7879.

151

A.19 Preparation of 3a,4,5,6,7,7a-hexahydro-4,7-methano-1,2-benzisoxazole-3-carboxylic acid

ethyl ester (2.93)

Procedure A

A solution of 2.99 (263 mg, 1.65 mmol) in methanol (3 mL) was added dropwise at room temperature to

a solution of norbornylene (186 mg, 1.98 mmol, 1.2 eq), PhI(OAc)2 (638 mg, 1.98 mmol, 1.2 eq), TFA

(1% v/v, 55 L) and methanol (2 mL) with rapid stirring. The reaction mixture was stirred overnight and

then concentrated in vacuo. The crude product was purified by flash column chromatography using a

step-gradient: 5%, 10%, 15%, and 20% ethyl acetate/hexane. Pure fractions of product 2.93 were

combined and concentrated in vacuo, yielding 2.93 as clear viscous oil (0.178 g, 52%). Oxime 2.99 (76

mg, 29%, 52% brsm) was also recovered from the purification of the crude 2.93 indicating that the

reaction required longer reaction time.

152

Procedure B


a solution of norbornylene (117 mg, 1.25 mmol, 1.2 eq), PhI(OAc)2 (402 mg, 1.25 mmol, 1.2 eq), TFA

(1% v/v, 70 L) and methanol (5 mL) with rapid stirring. The reaction appeared complete in 30 min by

TLC. The crude product 2.93 was purified by flash column chromatography using a step-gradient: 5%,

10%, 15%, and 20% ethyl acetate/hexane. Pure fractions of 2.93 were collected and concentrated in

vacuo, yielding 2.93 as clear viscous oil (0.194 g, 90%).

1H (CDCl3): 4.65 (d, 1H, J = 8.5), 4.39-4.22 (m, 2H, J = 3.6), 3.27 (d, 1H, J = 8.5), 2.57 (br d, 2H, J =

10.0), 1.62-1.46 (m, 2H), 1.44-1.37 (m, 1H), 1.34 (t, 3H, J = 7.1), 1.29-1.16 (m, 2H), 1.16-1.06 (m, 1H).

13C (CDCl3): 160.91, 152.35, 90.31, 61.86, 55.74, 42.98, 39.43, 32.34, 27.23, 22.70, 14.18.

IR: 1715 cm-1

, 1580 cm-1

.

ESI-MS: 232.3 [M + Na]+.



2006, 21, 4852-4860.


2005, 46, 7877-7879.

153

A.20 Preparation of 4,5-dihydro-5-phenyl-3-isoxazolecarboxylic acid ethyl ester (2.94)

Procedure A


a solution of styrene (197 mg, 1.90 mmol, 1.2 eq), PhI(OAc)2 (611 mg, 1.90 mmol, 1.2 eq), TFA (1% v/v,

55 L) and methanol (2 mL) with rapid stirring. The reaction mixture was stirred overnight and then

concentrated in vacuo. The crude product was purified by flash column chromatography using a step-

gradient: 5%, 10%, 15%, and 20% ethyl acetate/hexane. Pure fractions of product 2.94 were combined

and concentrated in vacuo, yielding 2.94 as clear viscous oil (0.205 g, 59%). Oxime 2.99 (98 mg, 39 %)

was also recovered from the purification of the crude 2.94 indicating that the reaction required longer

reaction time.

154

Procedure B


a solution of styrene (115 mg, 1.22 mmol, 1.2 eq), PhI(OAc)2 (402 mg, 1.22 mmol, 1.2 eq), TFA (1% v/v,

70 L) and methanol (5 mL) with rapid stirring. The reaction appeared complete in 30 min by TLC. The

crude product 2.94 was purified by flash column chromatography using a step-gradient: 5%, 10%, 15%,

and 20% ethyl acetate/hexane. Pure fractions of 2.94 were collected and concentrated in vacuo, yielding

2.94 as clear viscous oil (0.183 g, 82%).

1H (CDCl3): 7.43-7.28 (m, 5H), 5.77 (dd, 1H, J2 = 11.7, J1 = 8.9), 4.36 (q, 2H, J = 7.1), 3.63 (dd, 1H, J2

= 17.9, J1 = 11.7), 3.21 (dd, 1H, J2 = 17.9, J1 = 8.9), 1.37 (t, 3H, J = 7.1).

13C (CDCl3): 160.67, 151.23, 139.63, 128.97, 128.74, 125.96, 85.04, 62.23, 41.55, 14.21.

IR: 1716 cm-1

, 1589 cm-1

.

ESI-MS: 220.3 [M + H]+; 242.3 [M + Na]

+.



2006, 21, 4852-4860.


2005, 46, 7877-7879.

155

A.21 Preparation of 2-isonitrosocyclopentanone (2.100)

Oxime 2.100 was synthesized from 3.12 g of α-carbethoxycyclopentanone as detailed by:

Cope, A. C.; Estes, L. L. Jr.; Emery, J. R.; Haven, A. C. Jr. J. Amer. Chem. Soc. 1951, 73, 1199.

1H (CDCl3): 9.92 (br s, 1H), 2.83 (t, 2H, J = 7.6), 2.49 (t, 2H, J = 7.8), 2.07 (quin, 2H, J = 7.7).

13C (CDCl3): 203.91, 156.32, 38.47, 25.33, 17.57.

IR: 1713 cm-1

, 1634 cm-1

.

ESI-MS: 136.2 [M + Na]+.


156

A.22 Preparation of compound 2.101

A solution of 2.100 (50 mg, 0.44 mmol) in methanol (3.5 mL) was added dropwise at room temperature

to a solution of norbornylene (50 mg, 0.53 mmol, 1.2 eq), PhI(OAc)2 (170 mg, 0.53 mmol, 1.2 eq), TFA

(1% v/v, 55 L) and methanol (2 mL) with rapid stirring. The reaction appeared complete in 30 min by

TLC. The crude product 2.101 was purified by flash column chromatography using a step-gradient: 5%,

10%, 15%, and 20% ethyl acetate/hexane. Pure fractions of 2.101 were combined and concentrated in

vacuo, yielding compound 2.101 as clear viscous oil (0.074 g, 70%).

1H (CDCl3): 4.34 (d, 1H, J = 8.2), 3.61 (s, 3H), 2.95 (d, 1H, J = 8.2), 2.44 (br s, 1H), 2.40-2.12 (m, 5H),

2.00-1.76 (m, 2H), 1.56-1.29 (m, 3H), 1.22-0.96 (m, 3H).

13C (CDCl3): 173.50, 157.88, 86.09, 59.33, 51.54, 42.84, 38.18, 33.25, 32.12, 27.21, 26.01, 22.67, 21.40.

IR: 2953 cm-1

, 1732 cm-1

.

ESI-MS: 260.4 [M + Na]+.


157

A.23 Preparation of methyl 4-(5-phenyl-4,5-dihydroisoxazol-3-yl)butanoate (2.102)


to a solution of styrene (43 mg, 0.41 mmol, 1.2 eq), PhI(OAc)2 (131 mg, 0.41 mmol, 1.2 eq), TFA (1%

v/v, 55 L) and methanol (2 mL) with rapid stirring. The reaction was stirred overnight. The crude

product 2.102 was purified by flash column chromatography using a step-gradient: 5%, 10%, 15%, and

20% ethyl acetate/hexane. Pure fractions were combined and concentrated in vacuo, yielding 2.102 as

clear viscous oil (0.034 g, 40%).

1H (CDCl3): 7.47-7.28 (m, 5H), 5.55 (dd, 1H, J2 = 11.4, J1 = 8.2), 3.68 (s, 3H), 3.37 (dd, 1H, J2 = 17.0,

J1 = 10.9), 2.91 (dd, 1H, J2 = 17.0, J1 = 8.2), 2.50-2.36 (m, 4H), 1.94 (quin, 2H, J = 7.3).

13C (CDCl3): 173.50, 157.65, 141.24, 128.77, 128.12, 125.79, 81.46, 51.72, 45.42, 33.26, 27.22, 21.56.

IR: 2951 cm-1

, 1731 cm-1

.

ESI-MS: 270.4 [M + Na]+.


Compound 2.102 was known previously in the literature: Ignatovich, Zh. V.; Chernikhova, T. V.;

Skupskaya, R. V.; Bondar', N. F.; Koroleva, E. V.; Lakhvich, F. A. Chem. Heterocycl. Compd. 1999,

35(2), 248-249.

158

A.24 Preparation of 2-isonitrosocyclohexanone (2.103)

A solution of 1,2-cyclohexanedione (0.500 g, 4.459 mmol) in diethyl ether (5 mL) was combined with a

solution of NaOH (0.178 g, 1.0 eq, 4.459 mmol) and HCl.H2NOH (0.310 g, 1.0 eq, 4.459 mmol) in 5 mL

of water and was stirred vigorously overnight. The biphasic reaction mixture was -extracted with diethyl

ether (5 times) and dried over anhydrous MgSO4. The crude product 2.103 was filtered and conventrated

and purified by flash column chromatography using a step-gradient: 5%, 10%, 15%, 20%, and 30% ethyl

acetate/hexane. Pure fractions of 2.103 were combined and concentrated in vacuo, yielding oxime 2.103

(0.139 g, 25%) as viscous oil.

1H (CDCl3): 9.56 (s, 1H), 2.79 (t, 2H, J = 6.5), 2.58 (t, 2H, J = 6.5), 1.97-1.74 (m, 4H).

13C (CDCl3): 196.61, 154.19, 41.03, 25.19, 22.66, 21.78.

IR: 1701 cm-1

.

ESI-MS: 150.2 [M + Na]+.


A similar preparation is known:

Wu, S.; Fluxe, A.; Janusz, J. M.; Sheffer, J. B.; Browning, G.; Blass, B.; Cobum, K.; Hedges, R.;

Murawsky, M.; Fang, B.; Fadayel, G. M.; Hare, M.; Djandjighian, L. Bioorg. Med. Chem. Lett. 2006, 16,

5859-5863.

159

A.25 Preparation of compound 2.104

A solution of oxime 2.103 (69 mg, 0.54 mmol) in methanol (1.5 mL) was added dropwise at room


1.2 eq), TFA (1% v/v, 25 L) and methanol (1 mL) with stirring. The reaction mixture was stirred

overnight. The crude product 2.104 was purified by flash column chromatography using a step-gradient:

5%, 10%, 15%, and 20% ethyl acetate/hexane. Pure fractions of 2.104 were combined and concentrated

in vacuo, yielding 2.104 as clear viscous oil (0.076 g, 56%).

1H (CDCl3): 4.35 (d, 1H, J = 8.2), 3.61 (s, 3H), 2.94 (d, 1H, J = 8.2), 2.46 (s, 1H), 2.37-2.07 (c m, 5H),

1.73-1.30 (c m, 7H), 1.22-0.97 (c m, 3H).

13C (CDCl3): 173.78, 158.31, 86.06, 59.33, 51.50, 42.86, 38.21, 33.63, 32.15, 27.26, 26.38, 25.67, 24.56,

22.70.

IR: 2952 cm-1

, 1733 cm-1

.

ESI-MS: 252.4 [M + H]+; 274.4 [M + Na]

+.

HRMS: calcd for C14H22NO3 = 252.1600, found 252.1595.

Compound 2.104 was previously known in the literature:

Bondar, N. F.; Isaenya, L. P.; Skupskaya, R. V.; Lakhvich, F. A. Russ. J. Org. Chem. 2003, 39(8), 1089-

1094.

160

A.26 Preparation of methyl 5-(5-phenyl-4,5-dihydroisoxazol-3-yl)pentanoate (2.105)


to a solution of styrene (74 mg, 0.71 mmol, 1.2 eq), PhI(OAc)2 (228 mg, 0.71 mmol, 1.2 eq), TFA (0.1%

v/v, 3 L) and methanol (1 mL) with rapid stirring. The reaction mixture was stirred overnight. The

crude product 2.105 was purified by flash column chromatography using a step-gradient: 5%, 10%, 15%,

and 20% ethyl acetate/hexane. Pure fractions of 2.105 were collected and concentrated in vacuo, yielding

2.105 as clear viscous oil (0.036 g, 23%).

1H (CDCl3): 7.41-7.27 (m, 5H), 5.55 (dd, 1H, J2 = 10.7, J1 = 8.2), 3.67 (s, 3H), 3.36 (dd, 1H, J2 = 16.8,

J1 = 10.7), 2.90 (dd, 1H, J2 = 16.8, J1 = 8.2), 2.46-2.30 (m, 4H), 1.80-1.59 (m, 4H).

13C (CDCl3): 173.88, 158.11, 141.41, 128.83, 128.16, 125.86, 81.46, 51.69, 45.47, 33.70, 27.59, 25.89,

24.56.

IR: 2950 cm-1

, 1732 cm-1

.

ESI-MS: 262.5 [M + H]+; 284.4 [M + Na]

+.


161

A.27 Preparation of 3-(hydroxyimino)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one (2.106)

Compound 2.106 was synthesized as detailed by:

Chen, Y. K.; Jeon, S.-J.; Walsh, P. J.; Nugent, W. A. Org. Synth. 2005, 82, 87.

162

A.28 Preparation of compounds 2.107/2.108

A solution of 2.106 (500 mg, 2.76 mmol) in methanol (12.5 mL) was added dropwise at room


1.2 eq), TFA (1% v/v, 225 L) and methanol (10 mL) with rapid stirring. The reaction apeared complete

in 30 min by TLC. The crude products 2.107/2.108 were purified by flash column chromatography using

a step-gradient: 5%, 10%, and 15% ethyl acetate/hexane. Pure fractions were combined and concentrated

in vacuo, yielding an inseparatable mixture of 2.107/2.108 (0.609 g, 72%) as clear viscous oil. The

diastereoselectivity of the product mixture was determined from 1H-NMR integration to be 1 : 1.

Diastereomer 1:

1H (CDCl3): 4.42 (d, 1H, J = 8.3), 3.67 (s, 3H), 3.05 (d, 1H, J = 8.3), 2.86-2.17 (m, 5H), 1.92-1.74 (m,

1H), 1.61-1.36 (m, 4H), 1.29-1.03 (m, 9H), 0.77 (s, 3H).

13C (CDCl3): 176.50, 158.91, 86.28, 60.27, 56.46, 51.66, 46.45, 46.16, 43.16, 38.44, 32.28, 27.46, 24.39,

23.48, 22.88, 22.38, 21.15.

Diastereomer 2:

1H (CDCl3): 4.36 (d, 1H, J = 8.3), 3.69 (s, 3H), 2.94 (d, 1H, J = 8.3), 2.86-2.17 (m, 5H), 2.07-1.92 (m,

1H), 1.61-1.36 (m, 4H), 1.29-1.03 (m, 9H), 0.86 (s, 3H).

13C (CDCl3): 176.68, 158.82, 85.64, 77.36, 60.78, 55.95, 47.20, 45.67, 42.75, 39.43, 32.44, 27.66, 25.81,

22.88, 22.14, 20.48.

IR: 2960 cm-1

, 1723 cm-1

.

ESI-MS: 306.4 [M + H]+; 328.4 [M + Na]

+.


163

A.29 Preparation of (1S,3R)-methyl 1,2,2-trimethyl-3-(5-phenyl-4,5-dihydroisoxazol-3-yl)

cyclopentanecarboxylate (2.109/2.110)

A solution of oxime 2.106 (500 mg, 2.76 mmol) in methanol (12.5 mL) was added dropwise at room

temperature to a solution of styrene (345 mg, 3.31 mmol, 1.2 eq), PhI(OAc)2 (1067 mg, 3.31 mmol, 1.2

eq), TFA (1% v/v, 225 L) and methanol (10 mL) with rapid stirring. The reaction appeared complete in

30 min by TLC. The crude products 2.109/2.110 were purified by flash column chromatography using a

step-gradient: 5%, 10%, and 15% ethyl acetate/hexane. Pure fractions were collected and concentrated in

vacuo, yielding a mixture of 2.109/2.110 (0.206 g, 24%) as clear viscous oil. The diastereoselectivity of

the product mixture was determined from 1H-NMR integration to be 1 : 0.8.

Diastereomer 1:

1H (CDCl3): 7.41-7.27 (m, 5H), 5.62-5.47 (m, 1H), 3.66 (s, 3H), 3.44 (dd, 1H, J2 = 16.5, J1 = 10.6), 3.04-

2.80 (m, 2H), 2.73-2.54 (m, 1H), 2.16-1.82 (m, 2H), 1.62-1.46 (m, 1H), 1.28-1.13 (m, 6H), 0.68 (s, 3H).

Diastereomer 2:

1H (CDCl3): 7.41-7.27 (m, 5H), 5.62-5.47 (m, 1H), 3.68 (s, 3H), 3.29 (dd, 1H, J2 = 16.5, J1 = 10.6), 3.04-

2.80 (m, 2H), 2.73-2.54 (m, 1H), 2.16-1.82 (m, 2H), 1.62-1.46 (m, 1H), 1.28-1.13 (m, 6H), 0.79 (s, 3H).

Diastereomers 1 and 2:

13C (CDCl3): 176.45, 176.43, 159.08, 158.75, 141.46, 141.08, 128.83, 128.80, 128.20, 128.08, 125.91,

125.60, 81.58, 81.16, 77.37, 56.15, 56.11, 51.72, 47.17, 47.04, 46.94, 46.76, 46.46, 46.26, 32.58, 24.16,

24.09, 22.85, 22.81, 22.32, 21.21, 21.14.

IR: 2964 cm-1

, 1722 cm-1

.

ESI-MS: 316.4 [M + H]+; 338.4 [M + Na]

+.


164

A.30 Preparation of 3,7-dimethyl-6-octenoxime (2.111)

The first report of the preparation of 2.111 appeared to be:

Semmler, Ber., 1893, 26, 2255.

Oxime 2.111 was synthesized according to the procedure outlined in:

Caldwell, A. G.; Jones, E. R. H. J. Chem. Soc. 1946, 599-601.

165

A.31 Preparation of (6S)-3,3a,4,5,6,7-hexahydro-3,3,6-trimethyl-2,1-benzisoxazole (2.112)

A solution of the oxime 2.111 (99 mg, 0.44 mmol) in CH3OH (2 mL) was slowly added to a solution of

DIB (461 mg, 1.43 mmol) and TFA (15 L) in CH3OH (3 mL) over 15 min. The mixture was stirred at

room temperature for 45 min, and then it was concentrated in vacuo. A 1H-NMR spectrum of the crude

product thus obtained revealed the presence of two products in a ratio of 3.8:1. These products proved to

be quite volatile, especially under reduced pressure. This complicated the calculation of a reaction yield.

Accordingly, a crude reaction mixture obtained as detailed above was treated with a known amount (1

mmol) of 1,3,5-trimethoxy benzene as an internal standard, and a 1H-NMR spectrum of the mixture was

recorded using a delay of 20 seconds between pulses. Integration of the signals of the internal standard

and of the products indicated a chemical yield of 85% for the 3.8:1 mixture of products. Flash column

chromatography (33% diethyl ether/pentane) afforded a pure sample of the major diastereomer (30 mg,

18 mmol, 41%) for characterization.

1H (CDCl3): major: 2.72 (ddd, 1H, J = 13.8, 4.1, 1.4), 2.60 (dd, 1H, J = 12.0, 5.4), 1.87-1.68 (m, 2H),

1.55 (m, 1H), 1.4-1.3 (m, 2H), 1.38 (s, 3H), 1.22 (s, 3H), 1.11 (m, 1H), 1.02 (d, 3H, J = 6.5).

13C (CDCl3): major: 160.63, 84.24, 56.22, 33.91, 33.35, 33.31, 28.47, 26.61, 22.25, 22.07.

ESI-MS: 168.3 [M + H]+.

HRMS: calcd for C10H19NO [M + H]+ = 168.1388, found 168.1384.

[]D20

= –87.0° (0.01 g/mL, CH2Cl2).

166

A.32 Preparation of 4-hydroxy-benzenepropanal oxime (2.123)

Known compound 2.123 (Kusama, H.; Yamashita, Y.; Uchiyama, K.; Narasaka, K.; Bull. Chem. Soc.

Jpn., 70, 1997, 965-975) was synthesized from commercially available 3-(4-hydroxyphenyl)propanal

(2.122) according to Oresmaa, L.; Kotikoski, H.; Haukka, M.; Salminen, J.; Oksala, O.; Pohjala, E.;

Moilanen, E.; Vapaatalo, H.; Vainiotalo, P.; Aulaskari, P., J. Med. Chem. 2005, 48, 4231-4236.

ESI-MS: 166.1 [M + H]+; 188.4 [M + Na]

+.

HRMS: calcd for C9H10NO2 [M – H]– = 164.0712, found 164.0708.

167

A.33 Preparation of N-[(4aR,7aS,7bR)-3,4,7a,7b-tetrahydro-7-oxoindeno[1,7-cd]isoxazol-4a(7H)-

yl]-acetamide (2.124)

A solution of 2.123 (62 mg, 0.375 mmol) in acetonitrile (5 mL) was slowly added to a solution of DIB

(226 mg, 0.825 mmol) and TFA (15 L) in acetonitrile (20 mL). This reaction mixture was stirred at

room temperature for 1 h, and then the volatile organics were removed in vacuo. The crude product 2.124

was purified by flash column chromatography using a step gradient: 25%-50%-100% ethyl

acetate/hexanes, to afford 58 mg of compound 2.124 as colorless crystals (0.266 mmol, 71%).

1H (d6-acetone): 7.84 (brs, 1H), 6.41 (dd, 1H, J = 10.3, 2.0), 6.15 (dd, 1H, J = 10.3, 0.5), 4.72 (dd, 1H, J

= 9.7, 0.5), 4.28 (ddd, 1H, J = 9.7, 2.0, 1.6), 2.69 (m, 1H), 2.64 (m, 2H), 2.37 (m, 1H), 1.84 (s, 1H).

13C (d6-acetone): 191.12, 170.45, 169.26, 146.53, 132.66, 79.80, 63.57, 53.49, 42.18, 42.12, 23.07,

19.34.

MP: 162.163 °C.

ESI-MS: 243.3 [M + Na]+.


168

A.34 Preparation of 4,4a,7a,7b-tetrahydro-4a-methoxy-indeno[1,7-cd]isoxazol-7(3H)-one (2.125)

A solution of 2.123 (38 mg, 0.23 mmol) in methanol (1.3 mL) was slowly added to a solution of DIB

(162 mg, 0.50 mmol) and TFA (15 L) in methanol (2 mL). This reaction mixture was stirred at room

temperature for 1 h, and then the volatile organics were removed in vacuo. The crude product was

purified by flash column chromatography (step gradient 50%-100% ethyl acetate/hexanes) to afford 29

mg of compound 2.125 (0.15 mmol, 51%).

1H (d6-acetone): 6.66 (dd, 1H, J = 10.5, 1.9), 6.36 (dd, 1H, J = 10.5, 0.4), 4.84 (d, 1H, J = 10.1), 4.33

(dd, 1H, J = 10.1, 1.8), 3.20 (s, 3H), 2.69 (m, 2H), 2.49 (m, 2H).

13C (d6-acetone): 192.28, 169.20, 148.93, 134.26, 77.77, 77.23, 60.57, 53.17, 43.32, 20.46.

ESI-MS: 216.3 [M + Na]+.

HRMS: calcd for C10H12NO3 [M + H]+ = 216.0637, found 216.0635.

169

A.35 Preparation of N-benzyl, N-tosyl tyrosine (2.130)

To a solution of SOCl2 (10 mL) in methanol (100 mL) was added tyrosine (10.0 g, 45.9 mmol). This

solution was allowed to stir at room temperature over night. Volatile organics were removed in vacuo by

rotary evaporation. This crude residue was suspended in methanol (10 mL), and added dropwise to a

stirring solution of diethyl ether (300 mL). The white precipitate was collected by filtration and the

supernatant discarded. The methyl ester intermediate was dissolved in acetonitrile (100 mL) and

triethylamine (6.40 mL, 45.9 mmol). Benzaldehyde (5.13 mL, 50.5 mmol) was added via syringe, and

the reaction was allowed to stir at room temperature. The reaction finished (by TLC) after 2 h, and was

concentrated in vacuo. This crude residue was taken up in methanol (200 mL) and cooled in a 0 °C ice

bath for 15 min. To this was added solid NaBH4 (2.08 g, 55.1 mmol), and the reaction mixture was

allowed to warm to room temperature overnight. Methanol and volatile organics were removed in vacuo,

and the crude residue was suspended in ethyl acetate (250 mL) and extracted successively with saturated

aqueous NaHCO3, and saturated aqueous NaCl, dried over anhydrous MgSO4, filtered and concentrated in

vacuo. Without further purification, the residue was suspended in pyridine (25 mL) followed by the

addition of solid tosyl chloride (21.9 g, 115 mmol), and this reaction mixture was stirred over night at

room temperature. Pyridine was removed in vacuo, and the crude residue suspended in ethyl acetate (200

mL) and washed with 0.1 M aqueous HCl (200 mL) and H2O (200 mL). The organic phase was dried

(MgSO4), filtered through a short silica gel plug (10 g) and concentrated in vacuo. This viscous bis-tosyl-

tyrosine ester residue was dissolved in THF (100 mL), and to this was added a solution of NaOH (7.34 g,

183.6 mmol) in H2O (100 mL). (Upon addition of aqueous NaOH, a white cloudy precipitate formed

which slowly disappeared over the course of the reaction.) The reaction was heated to 75 °C and allowed

to stir overnight. The reaction was concentrated in vacuo, and re-suspended in ethyl acetate (250 mL).

The organic solution was washed successively with 1.0 M aqueous HCl (100 mL) and H2O (100 mL),

dried over anhydrous MgSO4, filtered and concentrated in vacuo. Pure 2.130 (12.5 g, 29.4 mmol, 64%)

was obtained as colorless crystals from crystallization in refluxing CH2Cl2.

170

1H (d6-acetone): 8.20 (brs, 1H), 7.73 (d, 2H, J = 8.3), 7.35 (d, 2H, J = 8.3), 7.35-7.23 (m, 5H), 6.90 (d,

2H, J = 8.5), 6.69 (d, 2H, J = 8.5), 4.65 (d, 1H, J = 16.1), 4.64 (m, 1H), 4.43 (d, 1H, J = 16.1), 3.07 (dd,

1H, J = 13.9, 8.3), 2.72 (dd, 1H, J = 13.9, 6.5), 2.41 (s, 3H).

13C (d6-acetone): 171.43, 156.93, 144.23, 138.66, 138.46, 131.03, 130.29, 129.21, 128.92, 128.85,

128.46, 128.09, 115.92, 62.36, 50.20, 36.99, 21.40.

MP: 154-156 °C.

ESI-MS: 426.4 [M + H]+; 448.1 [M + Na]

+; 424.3 [M – H]

-.

HRMS: calcd for C23H23NO5SNa [M + Na]+ = 448.1195, found 448.1209.

171

A.36 Preparation of N-[2-(hydroxyimino)-1-[(4-hydroxyphenyl)methyl]ethyl]-4-methyl-N-

(phenylmethyl)-benzenesulfonamide (2.132)

Carboxylic acid 2.130 (5.00 g, 11.8 mmol) was dissolved in THF (20 mL) at room temperature. To this

solution was added HN(CH3)OCH3•HCl (1.73 g, 17.7 mmol), triethylamine (4.9 mL, 35.4 mmol) and

PyBOP (9.21 g, 17.7 mmol). The reaction was stirred for 12 hours, and then the solvent was removed in

vacuo. The crude residue was diluted with ethyl acetate (200 mL) and washed successively with 100 mL

portions of 0.1 M aqueous HCl and H2O. The organic solution was dried over anhydrous MgSO4, filtered

through a silica gel plug (10 g) and concentrated in vacuo. The crude Weinreb amide product was

dissolved in THF (100 mL), and this solution was cooled in a 0 °C ice-bath. A suspension of LiAlH4

(0.67 g, 17.7 mmol) in THF (50 mL) was added with vigorous stirring. This heterogeneous reaction

mixture was stirred at 0 °C for 4 h. The reaction was quenched at 0 °C by the addition of saturated

aqueous NaHSO4 (3 mL) and stirred for 0.5 h, followed by the addition of aqueous 1 M aqueous HCl (5

mL) and then diluted with H2O (100 mL) and extracted with ethyl acetate (100 mL). The organic phase

was dried over anhydrous MgSO4, filtered through a silica gel plug (10 g) and concentrated in vacuo. The

crude aldehyde was immediately dissolved in diethyl ether (50 mL), and to this was added sequentially a

solution of H2NOH•HCl (3.44 g, 35.4 mmol) in H2O (50 mL) and a solution of Na2CO3 (6.25 g, 59 mmol)

in H2O (50 mL). This reaction was stirred at room temperature over night and then diluted with diethyl

ether (50 mL) and the organic phase was separated, dried over anhydrous MgSO4, filtered and

concentrated in vacuo. Pure 2.132 (0.55 g, 1.30 mmol, 11%) was obtained following flash column

chromatography with 30% ethyl acetate/hexanes. Note: this reaction sequence was not optimized for

higher recovered yield.

172

1H (d6-acetone): 9.97 (s, 1H), 8.14 (s, 1H), 7.72 (d, 2H, J = 8.3), 7.36 (m, 5H), 7.28 (d, 2H, J = 8.3), 7.15

(d, 2H, J = 6.0), 6.82 (d, 2H, J = 8.7), 6.69 (d, 2H, J = 8.3), 4.61 (ddd, 1H, J1 = 9.1, J2 = J3 = 6.0), 4.46

(ABq, 2H, J = 29.4, 16.0), 3.0 (dd, 1H, J = 13.6, 9.1), 2.87 (s, 3H), 2.71 (dd, 1H, J = 13.6, 6.0), 2.43 (s,

3H).

13C (d6-acetone): 156.82, 148.49, 144.24, 138.98, 138.93, 131.09, 130.51, 129.28, 129.16, 129.12,

128.26 (two overlapping signals), 115.90, 60.41, 49.67, 37.74, 21.42.

ESI-MS: 425.2 [M + H]+, 447.2 [M + Na]

+.

HRMS: calcd for C23H24N2O5SNa [M + Na]+ = 447.1354, found 447.1362.

173

A.37 Preparation of N-[(3R,4aR,7aS,7bR)-3,4,7a,7b-tetrahydro-3-[[(4-methylphenyl)sulfonyl]

(phenylmethyl)amino]-7-oxoindeno[1,7-cd]isoxazol-4a(7H)-yl]-acetamide (2.134)

A solution of oxime 2.132 (20 mg, 0.047 mmol) in acetonitrile (3 mL) was slowly added to a solution of

DIB (36 mg, 0.113 mmol) and TFA (15 L) in acetonitrile (3 mL) over 10 min. The mixture was stirred

at room temperature for 1 h, and then it was diluted with heptanes (0.4 mL) and concentrated in vacuo by

rotary evaporation. The reaction residue was immediately purified by flash column chromatography

using a step gradient: 50%-100% ethyl acetate/hexanes, to afford 10 mg of compound 2.134 (0.021 mmol,

44%) as a glassy solid.

1H (d6-acetone): 7.82 (d, 2H, J = 8.5), 7.76 (brs, 1H), 7.43 (d, 2H, J = 8.5), 7.36 (m, 5H), 6.32 (dd, 1H, J

= 10.2, 2.0), 6.08 (dd, 1H, J = 10.2, 0.4), 4.68 (dd, 1H, J = 9.8, 0.4), 4.64 (m, 1H), 4.58 (d, 1H, J = 15.9),

4.32 (d, 1H, J = 15.9), 3.93 (dt, 1H, J = 9.8, 2.0), 2.87 (dd, 1H, J = 13.6, 8.1), 2.63 (dd, 1H, J = 13.6, 9.2),

2.44 (s, 3H), 1.77 (s, 3H).

13C (d6-acetone): 189.86, 170.41, 170.33, 166.65, 145.55, 144.85, 137.80, 137.55, 132.59, 130.71,

129.43, 129.31, 128.69, 128.39, 80.95, 62.09, 51.74, 51.66, 51.53, 49.98, 49.92, 22.95, 22.91, 21.44.

ESI-MS: 502.2 [M + Na]+; 478.3 [M – H]

–.

HRMS: calcd for C25H24N3O5S [M - H]- = 478.1437, found 478.1446.

174

B. Experimental section


13C-NMR spectrum for: methyl 2-(1-acetamido-4-oxocyclohexa-2,5-

dienyl)acetate (2.32)

O

HN CH3

O

CO2CH3

2.32

O

HN CH3

O

CO2CH3

2.32

175


13C-NMR spectrum for: methyl 2-((1r,4r)-1-acetamido-4-(tert-

butyldiphenylsilyloxy)cyclohexa-2,5-dienyl)acetate (2.37)

TBDPSO

NHAc

CO2CH3H

2.37

TBDPSO

NHAc

CO2CH3H

2.37

176


13C-NMR spectrum for: 2-((1r,4r)-1-acetamido-4-(tert-

butyldiphenylsilyloxy)cyclohexa-2,5-dienyl)acetic acid (2.38)

TBDPSO

NHAc

CO2HH

2.38

TBDPSO

NHAc

CO2HH

2.38

177


13C-NMR spectrum for: N-((1r,4r)-4-(tert-butyldiphenylsilyloxy)-1-

(3-nitro-2-oxopropyl)cyclohexa-2,5-dienyl)acetamide (2.39)

TBDPSO

NHAc

H

2.39

ONO2

TBDPSO

NHAc

H

2.39

ONO2

178


13C-NMR spectrum for: N-((3aS,7aS)-2-oxo-2,3,3a,7a-

tetrahydrobenzofuran-3a-yl)acetamide (2.41)

OO

NHAc

H

2.41

OO

NHAc

H

2.41

179


13C-NMR spectrum for: N-((2aR,2a1S,3S,5aS)-3-(tert-

butyldiphenylsilyloxy)-7-oxo-2a,2a1,3,5a,6,7-hexahydroindeno[1,7-cd]isoxazol-5a-yl)acetamide

(2.43)

O

O

NHAc

H

TBDPS

NO

2.43

O

O

NHAc

H

TBDPS

NO

2.43

30

O

O N

TBDPSO

NHAc

H

H

180


13C-NMR spectrum for: N-((3aS,7aS,E)-2-(nitromethylene)-

2,3,3a,7a-tetrahydrobenzofuran-3a-yl)acetamide (2.44)

OH

NHAc

2.44

NO2

OH

NHAc

2.44

NO2

181


13C-NMR spectrum for: N-((1r,4r)-1-(2-(tert-butyldimethylsilyloxy)-

3-nitropropyl)-4-(tert-butyldiphenylsilyloxy)cyclohexa-2,5-dienyl)acetamide (2.46)

OTBS

NO2

TBDPSO

NHAc

2.46

OTBS

NO2

TBDPSO

NHAc

2.46

182

B.9 1H-NMR spectrum for: compound 2.49

183


13C-NMR spectrum for: compound 2.50

184

B.11 1H-NMR spectrum for: compound 2.51/2.52

185


13C-NMR spectrum for: trans-9-[[(1,1-

dimethylethyl)diphenylsilyl]oxy]-2-methyl-3-nitro-1-azaspiro[5.5]undeca-2,7,10-trien-4-one (2.55)

186


13C-NMR spectrum for: methyl 2-((1S,4S,5R,6S)-1-acetamido-4-

(tert-butyldiphenylsilyloxy)-6-cyano-5-hydroxycyclohex-2-enyl)acetate (2.59)

187


13C-NMR spectrum for: N-((2aR,2a1S,3S,5aS)-3-hydroxy-7-oxo-

2a,2a1,3,5a,6,7-hexahydroindeno[1,7-cd]isoxazol-5a-yl)acetamide (2.60)

188


13C-NMR spectrum for: methyl 2-((1S,5R,6S)-1-acetamido-6-cyano-

5-hydroxy-4-oxocyclohex-2-enyl)acetate (2.62)

189

B.16 1H-NMR spectrum for: N-((2aR,2a1S,3R,5aS)-3-(tert-butyldiphenylsilyloxy)-7-oxo-

2a,2a1,3,5a,6,7-hexahydroindeno[1,7-cd]isoxazol-5a-yl)acetamide (2.66)

O N

NHAc

OO

TBDPS

2.66

190


13C-NMR spectrum for: methyl 2-((1S,4R,5R,6S)-1-acetamido-4-

(tert-butyldiphenylsilyloxy)-6-cyano-5-hydroxycyclohex-2-enyl)acetate (2.67)

OH

O CN

CO2CH3

NHAc

2.67

TBDPS

OH

O CN

CO2CH3

NHAc

2.67

TBDPS

191


13C-NMR spectrum for: 3-(4-methoxyphenyl)-5-phenyl-4,5-

dihydroisoxazole (2.76)

192


13C-NMR spectrum for: 3,5-diphenyl-4,5-dihydroisoxazole (2.77)

193


13C-NMR spectrum for: 3-(3-nitrophenyl)-5-phenyl-4,5-

dihydroisoxazole (2.78)

194


13C-NMR spectrum for: 3-pentyl-5-phenyl-4,5-dihydroisoxazole

(2.79)

N O

2.79

N O

2.79

195


13C-NMR spectrum for: 3-phenethyl-5-phenyl-4,5-dihydroisoxazole

(2.80)

196


13C-NMR spectrum for: 3a,4,5,6,7,7a-hexahydro-3-phenyl-4,7-

methano-1,2-benzisoxazole (2.81)

N O H

H

2.81

N O H

H

2.81

197


13C-NMR spectrum for: 3a,4,5,6,7,7a-hexahydro-3-(3-nitrophenyl)-

4,7-methano-1,2-benzisoxazole (2.82)

ON

2.82

O2N

ON

2.82

O2N

198


13C-NMR spectrum for: 3a,4,5,6,7,7a-hexahydro-3-pentyl-4,7-

methano-1,2-benzisoxazole (2.83)

199

B.26 1H-NMR spe ctrum and

13C-NMR spectrum for: 3a,4,5,6,7,7a-hexahydro-3-(2-phenylethyl)-

4,7-methano-1,2-benzisoxazole (2.84)

N O H

H

2.84

N O H

H

2.84

200


13C-NMR spectrum for: 3-(1,1-dimethylethyl)-3a,4,5,6,7,7a-

hexahydro4,7-methano-1,2-benzisoxazole (2.85)

ON

2.85

ON

2.85

201


13C-NMR spectrum for: 3a,4,5,6,7,7a-hexahydro-3-(4-

methoxyphenyl)-4,7-methano-1,2-benzisoxazole (2.86)

ON

2.86H3CO

ON

2.86H3CO

202


13C-NMR spectrum for: 5-(3-bromopropyl)-4,5-dihydro-3-phenyl-

isoxazole (2.87)

N O

Br

2.87

N O

Br

2.87

203


13C-NMR spectrum for: 3,5-diphenylisoxazole (2.88)

N O

2.88

N O

2.88

204


13C-NMR spectrum for: 1-(3a,4,5,6,7,7a-hexahydro-4,7-methano-

1,2-benzisoxazol-3-yl)-ethanone (2.90)

205


13C-NMR spectrum for: 1-(4,5-dihydro-5-phenyl-3-isoxazolyl)-

ethanone (2.91)

206


13C-NMR spectrum for: 3a,4,5,6,7,7a-hexahydro-4,7-methano-1,2-

benzisoxazole-3-carboxylic acid ethyl ester (2.93)

207


13C-NMR spectrum for: 4,5-dihydro-5-phenyl-3-isoxazolecarboxylic

acid ethyl ester (2.94)

208


13C-NMR spectrum for: 2-isonitrosocyclopentanone (2.100)

209



210



yl)butanoate (2.102)

211


13C-NMR spectrum for: 2-isonitrosocyclohexanone (2.103)

212



213



yl)pentanoate (2.105)

214


13C-NMR spectrum for: compounds 2.107/2.108

215


13C-NMR spectrum for: (1S,3R)-methyl 1,2,2-trimethyl-3-(5-phenyl-

4,5-dihydroisoxazol-3-yl) cyclopentanecarboxylate (2.109/2.110)

216


13C-NMR spectrum for: diastereomers (6S)-3,3a,4,5,6,7-hexahydro-

3,3,6-trimethyl-2,1-benzisoxazole (2.112)

NO

H

2.112

crude mixture of diastereomers (3.8:1)

NO

H

2.112

crude mixture of diastereomers (3.8:1)

217


13C-NMR spectrum for: major diastereomer (6S)-3,3a,4,5,6,7-

hexahydro-3,3,6-trimethyl-2,1-benzisoxazole (2.112)

NO

H

2.112

major diastereomer

NO

H

2.112

major diastereomer

218


13C-NMR spectrum for: N-[(4aR,7aS,7bR)-3,4,7a,7b-tetrahydro-7-

oxoindeno[1,7-cd]isoxazol-4a(7H)-yl]-acetamide (2.124)

O

O

NHAc

N

2.124

O

O

NHAc

N

2.124

219


13C-NMR spectrum for: 4,4a,7a,7b-tetrahydro-4a-methoxy-

indeno[1,7-cd]isoxazol-7(3H)-one (2.125)

O

O

OCH3

N

2.125

O

O

OCH3

N

2.125

220


13C-NMR spectrum for: N-benzyl, N-tosyl tyrosine (2.130)

HOCOOH

N

Ts

Ph

2.130

HOCOOH

N

Ts

Ph

2.130

221


13C-NMR spectrum for: N-[2-(hydroxyimino)-1-[(4-

hydroxyphenyl)methyl]ethyl]-4-methyl-N-(phenylmethyl)-benzenesulfonamide (2.132)

HO N

N Ph

OH

Ts

2.132

HO N

N Ph

OH

Ts

2.132

222


13C-NMR spectrum for: N-[(3R,4aR,7aS,7bR)-3,4,7a,7b-tetrahydro-

3-[[(4-methylphenyl)sulfonyl](phenylmethyl)amino]-7-oxoindeno[1,7-cd]isoxazol-4a(7H)-yl]-

acetamide (2.134)

O

NH

O N

O

NTs

2.134

O

NH

O N

O

NTs

2.134

223

C. X-ray crystallography data

C.1 X-ray data of methyl 2-(1-acetamido-4-oxocyclohexa-2,5-dienyl)acetate (2.32)

O

HN CH3

O

CO2CH3

2.32

Crystal Data

Empirical Formula C11H13NO4

Formula Weight 223.22

Crystal Color, Habit colorless, prism

Crystal Dimensions 0.20 X 0.20 X 0.40 mm

Crystal System orthorhombic

Lattice Type primitive

Lattice Parameters a = 9.1171(15) Å

b = 14.639(2) Å

c = 16.626(3) Å

= 90°

= 90°

= 90°

V = 2219.0(6) Å3

Space Group P bca (#61)

Z value 8

Dcalc 1.366 g/cm3

F000 944.00

(MoK) 1.02 cm-1

224

Intensity Measurements

Diffractometer Bruker X8 APEX II

Radiation MoK ( = 0.71073 Å)

graphite monochromated

Data Images 1235 exposures @ 20.0 seconds

Detector Position 36.00 mm

2max 56.0°

No. of Reflections Measured Total: 24567

Unique: 2658 (Rint = 0.024)

Corrections Absorption (Tmin = 0.843, Tmax = 0.980)

Lorentz-polarization

Structure Solution and Refinement

Structure Solution Direct Methods (SIR97)

Refinement Full-matrix least-squares on F2

Function Minimized w (Fo2 – Fc

2)

2

Least Squares Weights w = 1/(2(Fo

2) + (0.0545P)

2 + 0.7113P)

Anomalous Dispersion All non-hydrogen atoms

No. Observations (I>0.00(I)) 2658

No. Variables 151

Reflection/Parameter Ratio 17.60

Residuals (refined on F2, all data): R1; wR2 0.059; 0.124

Goodness of Fit Indicator 1.05


Residuals (refined on F): R1; wR2 0.042; 0.109

Max Shift/Error in Final Cycle 0.00

Maximum peak in Final Diff. Map 0.26 e-/Å

3

Minimum peak in Final Diff. Map -0.23 e-/Å

3

225

Atomic coordinates (x104) and equivalent isotropic displacement parameters

(A2 x 103) for mc010.

U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.

________________________________________________________________

x y z U(eq)

________________________________________________________________

C(1) 8932(2) 4498(1) 8594(1) 43(1)

C(2) 9535(2) 3680(1) 8566(1) 45(1)

C(3) 8715(2) 2875(1) 8315(1) 43(1)

C(4) 7157(2) 3002(1) 8149(1) 44(1)

C(5) 6543(2) 3819(1) 8178(1) 40(1)

C(6) 7334(2) 4672(1) 8428(1) 37(1)

C(7) 6540(2) 5006(1) 9192(1) 44(1)

C(8) 7074(2) 5890(1) 9551(1) 48(1)

C(9) 6339(3) 7110(1) 10383(1) 69(1)

C(10) 7579(2) 5285(1) 7050(1) 43(1)

C(11) 7281(2) 6091(1) 6516(1) 58(1)

N(1) 7151(1) 5385(1) 7820(1) 41(1)

O(1) 9316(1) 2131(1) 8228(1) 60(1)

O(2) 8274(2) 6205(1) 9501(1) 78(1)

O(3) 5988(1) 6284(1) 9952(1) 57(1)

O(4) 8171(1) 4594(1) 6804(1) 59(1)

________________________________________________________________

Bond lengths [A] and angles [deg] for mc010.

_____________________________________________________________

C(1)-C(2) 1.319(2)

C(1)-C(6) 1.5047(19)

C(1)-H(1) 0.9300

C(2)-C(3) 1.456(2)

C(2)-H(2) 0.9300

C(3)-O(1) 1.2275(17)

C(3)-C(4) 1.459(2)

C(4)-C(5) 1.3213(19)

C(4)-H(4) 0.9300

C(5)-C(6) 1.5011(18)

C(5)-H(5) 0.9300

C(6)-N(1) 1.4634(18)

C(6)-C(7) 1.541(2)

C(7)-C(8) 1.506(2)

C(7)-H(7A) 0.9700

C(7)-H(7B) 0.9700

C(8)-O(2) 1.190(2)

C(8)-O(3) 1.326(2)

C(9)-O(3) 1.441(2)

C(9)-H(9A) 0.9600

C(9)-H(9B) 0.9600

C(9)-H(9C) 0.9600

C(10)-O(4) 1.2168(18)

C(10)-N(1) 1.3457(19)

C(10)-C(11) 1.502(2)

C(11)-H(11A) 0.9600

C(11)-H(11B) 0.9600

C(11)-H(11C) 0.9600

N(1)-H(1N) 0.870(18)

226

C(2)-C(1)-C(6) 123.44(13)

C(2)-C(1)-H(1) 118.3

C(6)-C(1)-H(1) 118.3

C(1)-C(2)-C(3) 122.05(13)

C(1)-C(2)-H(2) 119.0

C(3)-C(2)-H(2) 119.0

O(1)-C(3)-C(2) 121.47(14)

O(1)-C(3)-C(4) 121.68(14)

C(2)-C(3)-C(4) 116.83(12)

C(5)-C(4)-C(3) 121.37(13)

C(5)-C(4)-H(4) 119.3

C(3)-C(4)-H(4) 119.3

C(4)-C(5)-C(6) 124.05(13)

C(4)-C(5)-H(5) 118.0

C(6)-C(5)-H(5) 118.0

N(1)-C(6)-C(5) 110.29(12)

N(1)-C(6)-C(1) 110.95(11)

C(5)-C(6)-C(1) 112.01(11)

N(1)-C(6)-C(7) 106.87(11)

C(5)-C(6)-C(7) 105.52(11)

C(1)-C(6)-C(7) 110.94(12)

C(8)-C(7)-C(6) 116.59(12)

C(8)-C(7)-H(7A) 108.1

C(6)-C(7)-H(7A) 108.1

C(8)-C(7)-H(7B) 108.1

C(6)-C(7)-H(7B) 108.1

H(7A)-C(7)-H(7B) 107.3

O(2)-C(8)-O(3) 123.58(15)

O(2)-C(8)-C(7) 127.05(15)

O(3)-C(8)-C(7) 109.36(13)

O(3)-C(9)-H(9A) 109.5

O(3)-C(9)-H(9B) 109.5

H(9A)-C(9)-H(9B) 109.5

O(3)-C(9)-H(9C) 109.5

H(9A)-C(9)-H(9C) 109.5

H(9B)-C(9)-H(9C) 109.5

O(4)-C(10)-N(1) 122.54(14)

O(4)-C(10)-C(11) 122.37(15)

N(1)-C(10)-C(11) 115.08(14)

C(10)-C(11)-H(11A) 109.5

C(10)-C(11)-H(11B) 109.5

H(11A)-C(11)-H(11B) 109.5

C(10)-C(11)-H(11C) 109.5

H(11A)-C(11)-H(11C) 109.5

H(11B)-C(11)-H(11C) 109.5

C(10)-N(1)-C(6) 123.18(12)

C(10)-N(1)-H(1N) 117.2(11)

C(6)-N(1)-H(1N) 119.6(11)

C(8)-O(3)-C(9) 116.70(15)

_____________________________________________________________

Symmetry transformations used to generate equivalent atoms:

227

Anisotropic displacement parameters (A2 x 103) for mc010.

The anisotropic displacement factor exponent takes the form:

-2 2 [ h2 a*2 U11 + ... + 2 h k a* b* U12 ]

_______________________________________________________________________

U11 U22 U33 U23 U13 U12

_______________________________________________________________________

C(1) 36(1) 36(1) 55(1) 0(1) -4(1) -7(1)

C(2) 34(1) 43(1) 57(1) 4(1) -8(1) -1(1)

C(3) 45(1) 31(1) 51(1) 7(1) -1(1) 2(1)

C(4) 42(1) 32(1) 57(1) 0(1) -5(1) -7(1)

C(5) 36(1) 35(1) 50(1) 1(1) -7(1) -4(1)

C(6) 37(1) 28(1) 44(1) 2(1) -2(1) -2(1)

C(7) 43(1) 43(1) 45(1) 0(1) 2(1) -8(1)

C(8) 51(1) 48(1) 45(1) -4(1) 0(1) -6(1)

C(9) 89(1) 56(1) 62(1) -17(1) 9(1) -3(1)

C(10) 38(1) 43(1) 47(1) 3(1) 1(1) -5(1)

C(11) 62(1) 57(1) 55(1) 15(1) -2(1) -8(1)

N(1) 47(1) 29(1) 47(1) 2(1) 3(1) 4(1)

O(1) 54(1) 34(1) 92(1) 1(1) -3(1) 7(1)

O(2) 56(1) 72(1) 107(1) -38(1) 9(1) -20(1)

O(3) 64(1) 51(1) 56(1) -11(1) 12(1) -5(1)

O(4) 61(1) 57(1) 57(1) -5(1) 12(1) 10(1)

_______________________________________________________________________

228

Hydrogen coordinates (x104) and isotropic displacement parameters (A2 x 103)

for mc010.

________________________________________________________________

x y z U(eq)

________________________________________________________________

H(1) 9525 4993 8723 51

H(2) 10515 3614 8711 53

H(4) 6584 2497 8021 52

H(5) 5561 3868 8034 48

H(7A) 5507 5074 9067 52

H(7B) 6622 4534 9599 52

H(9A) 6773 6956 10891 103

H(9B) 5459 7456 10471 103

H(9C) 7018 7467 10073 103

H(11A) 8174 6425 6431 87

H(11B) 6570 6482 6767 87

H(11C) 6908 5883 6008 87

H(1N) 6730(20) 5898(13) 7949(10) 50(5)

________________________________________________________________

Torsion angles [deg] for mc010.

________________________________________________________________

C(6)-C(1)-C(2)-C(3) 4.4(2)

C(1)-C(2)-C(3)-O(1) 174.00(16)

C(1)-C(2)-C(3)-C(4) -4.3(2)

O(1)-C(3)-C(4)-C(5) -174.20(16)

C(2)-C(3)-C(4)-C(5) 4.1(2)

C(3)-C(4)-C(5)-C(6) -4.1(2)

C(4)-C(5)-C(6)-N(1) 127.64(16)

C(4)-C(5)-C(6)-C(1) 3.5(2)

C(4)-C(5)-C(6)-C(7) -117.28(16)

C(2)-C(1)-C(6)-N(1) -127.42(16)

C(2)-C(1)-C(6)-C(5) -3.7(2)

C(2)-C(1)-C(6)-C(7) 113.94(17)

N(1)-C(6)-C(7)-C(8) -59.72(16)

C(5)-C(6)-C(7)-C(8) -177.13(13)

C(1)-C(6)-C(7)-C(8) 61.35(16)

C(6)-C(7)-C(8)-O(2) -27.0(3)

C(6)-C(7)-C(8)-O(3) 153.43(13)

O(4)-C(10)-N(1)-C(6) -1.1(2)

C(11)-C(10)-N(1)-C(6) 179.36(13)

C(5)-C(6)-N(1)-C(10) -58.91(18)

C(1)-C(6)-N(1)-C(10) 65.79(17)

C(7)-C(6)-N(1)-C(10) -173.14(13)

O(2)-C(8)-O(3)-C(9) -3.8(3)

C(7)-C(8)-O(3)-C(9) 175.79(14)

________________________________________________________________

229

C.2 X-ray data of N-((3aS,7aS,E)-2-(nitromethylene)-2,3,3a,7a-tetrahydrobenzofuran-3a-

yl)acetamide (2.44)

OH

NHAc

2.44

NO2

Crystal Data

Empirical Formula C11H12N2O4


Crystal Color, Habit colorless, needle


Crystal System monoclinic



b = 9.6959(4) Å

c = 13.3029(5) Å

= 90.0°

= 96.914(2)°

= 90.0°

V = 1101.35(7) Å3

Space Group P 21/c (#14)

Z value 4

Dcalc 1.425 g/cm3

F000 496.00

(MoK) 1.10 cm-1

230







2max 50.0°


Unique: 1936 (Rint = 0.033)







2)

2


2) + (0.0486P)

2 + 0.3430P)



No. Variables 159








3


3

231


(A2 x 103) for mc013.


________________________________________________________________

x y z U(eq)

________________________________________________________________

C(1) 8669(2) 1754(2) 9456(1) 35(1)

C(2) 7705(3) 649(2) 9859(2) 47(1)

C(3) 6566(3) 21(2) 9273(2) 54(1)

C(4) 6156(2) 394(2) 8226(2) 51(1)

C(5) 6837(2) 1449(2) 7816(2) 40(1)

C(6) 7981(2) 2369(2) 8440(1) 29(1)

C(7) 7095(2) 3656(2) 8768(1) 31(1)

C(8) 7871(2) 3970(2) 9800(1) 30(1)

C(9) 7764(2) 5075(2) 10401(1) 34(1)

C(10) 10253(2) 1914(2) 7539(1) 29(1)

C(11) 11505(2) 2509(2) 6980(2) 39(1)

N(1) 9248(2) 2811(2) 7876(1) 30(1)

N(2) 6732(2) 6166(2) 10131(1) 35(1)

O(1) 6758(2) 7153(2) 10727(1) 57(1)

O(2) 5814(2) 6126(1) 9346(1) 40(1)

O(3) 8813(2) 2941(1) 10157(1) 42(1)

O(4) 10154(2) 661(1) 7692(1) 36(1)

________________________________________________________________


_____________________________________________________________

C(1)-O(3) 1.478(2)

C(1)-C(2) 1.493(3)

C(1)-C(6) 1.530(3)

C(1)-H(1) 1.0000

C(2)-C(3) 1.324(3)

C(2)-H(2) 0.9500

C(3)-C(4) 1.441(4)

C(3)-H(3) 0.9500

C(4)-C(5) 1.328(3)

C(4)-H(4) 0.9500

C(5)-C(6) 1.502(3)

C(5)-H(5) 0.9500

C(6)-N(1) 1.460(2)

C(6)-C(7) 1.551(2)

C(7)-C(8) 1.484(3)

C(7)-H(7A) 0.9900

C(7)-H(7B) 0.9900

C(8)-O(3) 1.336(2)

C(8)-C(9) 1.347(3)

C(9)-N(2) 1.401(2)

C(9)-H(9) 0.9500

C(10)-O(4) 1.237(2)

C(10)-N(1) 1.341(2)

C(10)-C(11) 1.496(3)

C(11)-H(11A) 0.9800

C(11)-H(11B) 0.9800

C(11)-H(11C) 0.9800

232

N(1)-H(1N) 0.80(2)

N(2)-O(2) 1.232(2)

N(2)-O(1) 1.241(2)

O(3)-C(1)-C(2) 109.90(16)

O(3)-C(1)-C(6) 104.35(14)

C(2)-C(1)-C(6) 115.07(17)

O(3)-C(1)-H(1) 109.1

C(2)-C(1)-H(1) 109.1

C(6)-C(1)-H(1) 109.1

C(3)-C(2)-C(1) 121.5(2)

C(3)-C(2)-H(2) 119.2

C(1)-C(2)-H(2) 119.2

C(2)-C(3)-C(4) 122.1(2)

C(2)-C(3)-H(3) 119.0

C(4)-C(3)-H(3) 119.0

C(5)-C(4)-C(3) 121.4(2)

C(5)-C(4)-H(4) 119.3

C(3)-C(4)-H(4) 119.3

C(4)-C(5)-C(6) 121.5(2)

C(4)-C(5)-H(5) 119.3

C(6)-C(5)-H(5) 119.3

N(1)-C(6)-C(5) 111.75(15)

N(1)-C(6)-C(1) 109.55(15)

C(5)-C(6)-C(1) 114.50(16)

N(1)-C(6)-C(7) 109.28(14)

C(5)-C(6)-C(7) 108.78(14)

C(1)-C(6)-C(7) 102.51(14)

C(8)-C(7)-C(6) 104.11(14)

C(8)-C(7)-H(7A) 110.9

C(6)-C(7)-H(7A) 110.9

C(8)-C(7)-H(7B) 110.9

C(6)-C(7)-H(7B) 110.9

H(7A)-C(7)-H(7B) 109.0

O(3)-C(8)-C(9) 117.63(17)

O(3)-C(8)-C(7) 111.22(15)

C(9)-C(8)-C(7) 131.15(17)

C(8)-C(9)-N(2) 122.34(18)

C(8)-C(9)-H(9) 118.8

N(2)-C(9)-H(9) 118.8

O(4)-C(10)-N(1) 121.50(17)

O(4)-C(10)-C(11) 121.89(16)

N(1)-C(10)-C(11) 116.61(16)

C(10)-C(11)-H(11A) 109.5

C(10)-C(11)-H(11B) 109.5

H(11A)-C(11)-H(11B) 109.5

C(10)-C(11)-H(11C) 109.5

H(11A)-C(11)-H(11C) 109.5

H(11B)-C(11)-H(11C) 109.5

C(10)-N(1)-C(6) 122.18(16)

C(10)-N(1)-H(1N) 119.9(15)

C(6)-N(1)-H(1) 117.8(15)

O(2)-N(2)-O(1) 121.80(17)

O(2)-N(2)-C(9) 121.03(16)

O(1)-N(2)-C(9) 117.15(17)

C(8)-O(3)-C(1) 110.85(14)

_____________________________________________________________


233



-2 2 [ h2 a*2 U11 + ... + 2 h k a* b* U12 ]

_______________________________________________________________________

U11 U22 U33 U23 U13 U12

_______________________________________________________________________

C(1) 40(1) 33(1) 34(1) 1(1) 11(1) 8(1)

C(2) 63(2) 34(1) 49(1) 12(1) 31(1) 15(1)

C(3) 55(2) 30(1) 85(2) 0(1) 42(1) -2(1)

C(4) 34(1) 40(1) 80(2) -17(1) 13(1) -8(1)

C(5) 32(1) 41(1) 46(1) -10(1) 4(1) 1(1)

C(6) 30(1) 26(1) 32(1) -1(1) 9(1) 1(1)

C(7) 32(1) 30(1) 32(1) 0(1) 6(1) 1(1)

C(8) 30(1) 32(1) 30(1) 5(1) 7(1) 1(1)

C(9) 35(1) 38(1) 29(1) 1(1) 4(1) 0(1)

C(10) 34(1) 26(1) 28(1) -3(1) 5(1) 0(1)

C(11) 44(1) 34(1) 41(1) -2(1) 18(1) -1(1)

N(1) 37(1) 21(1) 33(1) 0(1) 12(1) -1(1)

N(2) 41(1) 33(1) 35(1) -2(1) 15(1) -2(1)

O(1) 79(1) 40(1) 51(1) -15(1) 12(1) 9(1)

O(2) 38(1) 42(1) 40(1) 1(1) 7(1) 6(1)

O(3) 53(1) 38(1) 33(1) -1(1) -3(1) 12(1)

O(4) 45(1) 22(1) 45(1) -2(1) 12(1) 0(1)

_______________________________________________________________________


for mc013.

________________________________________________________________

x y z U(eq)

________________________________________________________________

H(1) 9737 1381 9392 42

H(2) 7913 391 10551 56

H(3) 6002 -697 9552 65

H(4) 5382 -127 7821 61

H(5) 6595 1625 7112 48

H(7A) 7198 4439 8302 38

H(7B) 5970 3451 8780 38

H(9) 8413 5115 11031 40

H(11A) 12534 2290 7344 58

H(11B) 11378 3512 6933 58

H(11C) 11422 2114 6298 58

H(1N) 9300(20) 3610(20) 7741(15) 37(6)

________________________________________________________________

234


________________________________________________________________

O(3)-C(1)-C(2)-C(3) 133.5(2)

C(6)-C(1)-C(2)-C(3) 16.1(3)

C(1)-C(2)-C(3)-C(4) -2.1(3)

C(2)-C(3)-C(4)-C(5) -4.4(3)

C(3)-C(4)-C(5)-C(6) -4.5(3)

C(4)-C(5)-C(6)-N(1) 143.55(19)

C(4)-C(5)-C(6)-C(1) 18.3(3)

C(4)-C(5)-C(6)-C(7) -95.7(2)

O(3)-C(1)-C(6)-N(1) 90.11(17)

C(2)-C(1)-C(6)-N(1) -149.40(16)

O(3)-C(1)-C(6)-C(5) -143.46(15)

C(2)-C(1)-C(6)-C(5) -23.0(2)

O(3)-C(1)-C(6)-C(7) -25.84(17)

C(2)-C(1)-C(6)-C(7) 94.66(17)

N(1)-C(6)-C(7)-C(8) -93.40(17)

C(5)-C(6)-C(7)-C(8) 144.36(16)

C(1)-C(6)-C(7)-C(8) 22.75(17)

C(6)-C(7)-C(8)-O(3) -11.50(19)

C(6)-C(7)-C(8)-C(9) 169.02(19)

O(3)-C(8)-C(9)-N(2) -175.46(16)

C(7)-C(8)-C(9)-N(2) 4.0(3)

O(4)-C(10)-N(1)-C(6) -0.1(3)

C(11)-C(10)-N(1)-C(6) -179.44(16)

C(5)-C(6)-N(1)-C(10) -62.6(2)

C(1)-C(6)-N(1)-C(10) 65.4(2)

C(7)-C(6)-N(1)-C(10) 176.99(16)

C(8)-C(9)-N(2)-O(2) 3.7(3)

C(8)-C(9)-N(2)-O(1) -178.00(18)

C(9)-C(8)-O(3)-C(1) 173.94(16)

C(7)-C(8)-O(3)-C(1) -5.6(2)

C(2)-C(1)-O(3)-C(8) -103.34(18)

C(6)-C(1)-O(3)-C(8) 20.56(19)

________________________________________________________________


Hydrogen Bonds

Donor --- H....Acceptor [ ARU ] D - H H...A D...A D -

H...A

-----------------------------------------------------------------------------

N1 --H1N ..O4 [ 2756.01] 0.807(19) 2.130(19) 2.926(2)

169.5(18)

Translation of ARU-code to Equivalent Position Code

===================================================

[ 2756. ] = 2-x,1/2+y,3/2-z

235

C.3 X-ray data of N-((2aR,2a1S,3S,5aS,7R)-3,7-dihydroxy-2a,2a1,3,5a,6,7-hexahydroindeno[1,7-

cd]isoxazol-5a-yl)acetamide (2.53)

HO

O N

OH

NHAc

2.53

Crystal Data





Crystal System orthorhombic



b = 9.5690(14) Å

c = 14.822(2) Å

= 90.0°

= 90.0°

= 90.0°

V = 1020.0(3) Å3

Space Group P 212121 (#19)

Z value 4

Dcalc 1.551 g/cm3

F000 504.00

(MoK) 1.19 cm-1

236







2max 56.2°


Unique: 2485 (Rint = 0.036)







2)

2


2) + (0.0367P)

2 + 0.2803P)



No. Variables 167








3


3

237


(A2 x 103) for mc009.


________________________________________________________________

x y z U(eq)

________________________________________________________________

C(1) 4914(3) 637(2) 6160(1) 20(1)

C(2) 4089(3) 298(2) 6920(1) 21(1)

C(3) 4957(3) -590(2) 7627(1) 19(1)

C(4) 7042(2) -397(2) 7680(1) 18(1)

C(5) 8007(2) -70(2) 6791(1) 16(1)

C(6) 6865(2) 230(2) 5923(1) 17(1)

C(7) 7885(3) 1478(2) 5473(1) 24(1)

C(8) 9314(3) 2080(2) 6140(1) 20(1)

C(9) 8748(2) 1342(2) 6981(1) 18(1)

C(15) 6673(2) -2263(2) 5523(1) 18(1)

C(16) 6826(3) -3320(2) 4785(1) 25(1)

N(10) 8404(2) 1848(2) 7746(1) 21(1)

N(13) 6891(2) -939(2) 5286(1) 19(1)

O(11) 7435(2) 821(1) 8249(1) 22(1)

O(12) 4112(2) -378(1) 8485(1) 23(1)

O(14) 9386(2) 3530(2) 6173(1) 25(1)

O(17) 6397(2) -2624(1) 6303(1) 25(1)

________________________________________________________________

238


_____________________________________________________________

C(1)-C(2) 1.314(3)

C(1)-C(6) 1.497(3)

C(1)-H(1) 0.9500

C(2)-C(3) 1.486(2)

C(2)-H(2) 0.9500

C(3)-O(12) 1.425(2)

C(3)-C(4) 1.513(3)

C(3)-H(3) 1.0000

C(4)-O(11) 1.465(2)

C(4)-C(5) 1.522(2)

C(4)-H(4) 1.0000

C(5)-C(9) 1.479(2)

C(5)-C(6) 1.553(2)

C(5)-H(5) 1.0000

C(6)-N(13) 1.464(2)

C(6)-C(7) 1.553(2)

C(7)-C(8) 1.538(2)

C(7)-H(7A) 0.9900

C(7)-H(7B) 0.9900

C(8)-O(14) 1.389(2)

C(8)-C(9) 1.489(2)

C(8)-H(8) 1.0000

C(9)-N(10) 1.259(2)

C(15)-O(17) 1.223(2)

C(15)-N(13) 1.324(2)

C(15)-C(16) 1.494(2)

C(16)-H(16A) 0.9800

C(16)-H(16B) 0.9800

C(16)-H(16C) 0.9800

N(10)-O(11) 1.416(2)

N(13)-H(13N) 0.84(2)

O(12)-H(12O) 0.87(3)

O(14)-H(14O) 0.80(3)

C(2)-C(1)-C(6) 124.04(16)

C(2)-C(1)-H(1) 118.0

C(6)-C(1)-H(1) 118.0

C(1)-C(2)-C(3) 123.73(17)

C(1)-C(2)-H(2) 118.1

C(3)-C(2)-H(2) 118.1

O(12)-C(3)-C(2) 111.63(15)

O(12)-C(3)-C(4) 111.03(14)

C(2)-C(3)-C(4) 112.61(15)

O(12)-C(3)-H(3) 107.1

C(2)-C(3)-H(3) 107.1

C(4)-C(3)-H(3) 107.1

O(11)-C(4)-C(3) 108.54(14)

O(11)-C(4)-C(5) 104.28(14)

C(3)-C(4)-C(5) 115.53(14)

O(11)-C(4)-H(4) 109.4

C(3)-C(4)-H(4) 109.4

C(5)-C(4)-H(4) 109.4

C(9)-C(5)-C(4) 100.79(14)

C(9)-C(5)-C(6) 100.33(13)

C(4)-C(5)-C(6) 120.94(14)

C(9)-C(5)-H(5) 111.1

239

C(4)-C(5)-H(5) 111.1

C(6)-C(5)-H(5) 111.1

N(13)-C(6)-C(1) 111.24(14)

N(13)-C(6)-C(5) 112.68(14)

C(1)-C(6)-C(5) 110.46(13)

N(13)-C(6)-C(7) 107.73(14)

C(1)-C(6)-C(7) 110.08(15)

C(5)-C(6)-C(7) 104.38(14)

C(8)-C(7)-C(6) 109.11(14)

C(8)-C(7)-H(7A) 109.9

C(6)-C(7)-H(7A) 109.9

C(8)-C(7)-H(7B) 109.9

C(6)-C(7)-H(7B) 109.9

H(7A)-C(7)-H(7B) 108.3

O(14)-C(8)-C(9) 117.01(15)

O(14)-C(8)-C(7) 114.94(16)

C(9)-C(8)-C(7) 100.26(14)

O(14)-C(8)-H(8) 108.0

C(9)-C(8)-H(8) 108.0

C(7)-C(8)-H(8) 108.0

N(10)-C(9)-C(5) 116.89(16)

N(10)-C(9)-C(8) 128.73(17)

C(5)-C(9)-C(8) 111.87(14)

O(17)-C(15)-N(13) 122.65(16)

O(17)-C(15)-C(16) 120.88(17)

N(13)-C(15)-C(16) 116.46(16)

C(15)-C(16)-H(16A) 109.5

C(15)-C(16)-H(16B) 109.5

H(16A)-C(16)-H(16B) 109.5

C(15)-C(16)-H(16C) 109.5

H(16A)-C(16)-H(16C) 109.5

H(16B)-C(16)-H(16C) 109.5

C(9)-N(10)-O(11) 107.66(14)

C(15)-N(13)-C(6) 124.01(15)

C(15)-N(13)-H(13N) 121.6(15)

C(6)-N(13)-H(13N) 114.4(15)

N(10)-O(11)-C(4) 110.17(12)

C(3)-O(12)-H(12O) 106.5(16)

C(8)-O(14)-H(14O) 106.0(19)

_____________________________________________________________


240



-2 2 [ h2 a*2 U11 + ... + 2 h k a* b* U12 ]

_______________________________________________________________________

U11 U22 U33 U23 U13 U12

_______________________________________________________________________

C(1) 24(1) 19(1) 17(1) -1(1) -5(1) 3(1)

C(2) 20(1) 24(1) 20(1) -5(1) -1(1) 3(1)

C(3) 26(1) 17(1) 14(1) -3(1) 4(1) -1(1)

C(4) 25(1) 17(1) 12(1) -1(1) -1(1) 3(1)

C(5) 18(1) 17(1) 12(1) 0(1) -1(1) 2(1)

C(6) 25(1) 16(1) 10(1) 0(1) -2(1) -1(1)

C(7) 34(1) 22(1) 16(1) 3(1) -2(1) -7(1)

C(8) 19(1) 21(1) 20(1) 0(1) 2(1) -1(1)

C(9) 15(1) 21(1) 18(1) 0(1) -3(1) 1(1)

C(15) 19(1) 20(1) 15(1) -2(1) 3(1) -1(1)

C(16) 36(1) 22(1) 18(1) -5(1) 7(1) -4(1)

N(10) 23(1) 24(1) 17(1) -1(1) -2(1) -1(1)

N(13) 28(1) 19(1) 9(1) -2(1) 2(1) -2(1)

O(11) 30(1) 24(1) 11(1) -2(1) 0(1) -5(1)

O(12) 33(1) 19(1) 16(1) -1(1) 9(1) -1(1)

O(14) 26(1) 20(1) 30(1) 0(1) 0(1) -6(1)

O(17) 42(1) 17(1) 15(1) 0(1) 6(1) -2(1)

_______________________________________________________________________


for mc009.

________________________________________________________________

x y z U(eq)

________________________________________________________________

H(1) 4232 1174 5734 24

H(2) 2867 640 7024 25

H(3) 4727 -1584 7453 23

H(4) 7617 -1247 7956 22

H(5) 9034 -748 6668 19

H(7A) 8523 1160 4918 29

H(7B) 6975 2209 5304 29

H(8) 10572 1730 5962 24

H(16A) 7897 -3928 4899 38

H(16B) 6993 -2841 4206 38

H(16C) 5690 -3884 4765 38

H(13N) 7090(30) -710(20) 4747(15) 27(6)

H(14O) 8370(40) 3780(30) 6309(17) 41(8)

H(12O) 4080(40) 520(30) 8572(16) 44(7)

________________________________________________________________

241


________________________________________________________________

C(6)-C(1)-C(2)-C(3) -2.9(3)

C(1)-C(2)-C(3)-O(12) 158.39(17)

C(1)-C(2)-C(3)-C(4) 32.7(2)

O(12)-C(3)-C(4)-O(11) -41.97(19)

C(2)-C(3)-C(4)-O(11) 84.04(17)

O(12)-C(3)-C(4)-C(5) -158.61(14)

C(2)-C(3)-C(4)-C(5) -32.6(2)

O(11)-C(4)-C(5)-C(9) -2.36(16)

C(3)-C(4)-C(5)-C(9) 116.66(16)

O(11)-C(4)-C(5)-C(6) -111.44(16)

C(3)-C(4)-C(5)-C(6) 7.6(2)

C(2)-C(1)-C(6)-N(13) 102.5(2)

C(2)-C(1)-C(6)-C(5) -23.4(2)

C(2)-C(1)-C(6)-C(7) -138.15(18)

C(9)-C(5)-C(6)-N(13) 145.34(14)

C(4)-C(5)-C(6)-N(13) -105.33(18)

C(9)-C(5)-C(6)-C(1) -89.55(16)

C(4)-C(5)-C(6)-C(1) 19.8(2)

C(9)-C(5)-C(6)-C(7) 28.73(16)

C(4)-C(5)-C(6)-C(7) 138.06(16)

N(13)-C(6)-C(7)-C(8) -131.14(16)

C(1)-C(6)-C(7)-C(8) 107.41(17)

C(5)-C(6)-C(7)-C(8) -11.14(19)

C(6)-C(7)-C(8)-O(14) -137.60(16)

C(6)-C(7)-C(8)-C(9) -11.22(19)

C(4)-C(5)-C(9)-N(10) -0.6(2)

C(6)-C(5)-C(9)-N(10) 123.96(17)

C(4)-C(5)-C(9)-C(8) -164.16(14)

C(6)-C(5)-C(9)-C(8) -39.64(17)

O(14)-C(8)-C(9)-N(10) -3.8(3)

C(7)-C(8)-C(9)-N(10) -128.8(2)

O(14)-C(8)-C(9)-C(5) 157.36(16)

C(7)-C(8)-C(9)-C(5) 32.38(18)

C(5)-C(9)-N(10)-O(11) 3.4(2)

C(8)-C(9)-N(10)-O(11) 163.74(17)

O(17)-C(15)-N(13)-C(6) 1.2(3)

C(16)-C(15)-N(13)-C(6) -177.35(16)

C(1)-C(6)-N(13)-C(15) -80.6(2)

C(5)-C(6)-N(13)-C(15) 44.1(2)

C(7)-C(6)-N(13)-C(15) 158.70(18)

C(9)-N(10)-O(11)-C(4) -4.89(18)

C(3)-C(4)-O(11)-N(10) -119.25(14)

C(5)-C(4)-O(11)-N(10) 4.42(17)

________________________________________________________________

242

Hydrogen Bonds


H...A

-----------------------------------------------------------------------------

O(12) --H(12O) ..O(17) [ 4656.01] 0.87(3) 1.82(3) 2.6792(19)

170(3)

N(13) --H(13N) ..O(11) [ 2654.01] 0.84(2) 2.25(2) 3.061(2)

162.2(18)

O(14) --H(14O) ..O(12) [ 4656.01] 0.80(3) 1.98(3) 2.771(2)

172(3)


===================================================

[ 4656. ] = 1-x,1/2+y,3/2-z

[ 2654. ] = 3/2-x,-y,-1/2+z

243

C.4 X-ray data of trans-9-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-2-methyl-3-nitro-1-

azaspiro[5.5]undeca-2,7,10-trien-4-one (2.55)

2.55

HN

CH3

NO2

O

TBDPSO

Crystal Data

Empirical Formula C27H30N2O4Si







b = 13.8571(13) Å

c = 12.6366(14) Å

= 90°

= 106.644(5)°

= 90°

V = 2500.0(4) Å3


Z value 4

Dcalc 1.261 g/cm3

F000 1008.00

(MoK) 1.29 cm-1

244







2max 56.6°


Unique: 6127 (Rint = 0.032)







2)

2


2) + (0.0528P)

2 + 0.6852P)



No. Variables 316








3


3

245


(A2 x 103) for mc014.


________________________________________________________________

x y z U(eq)

________________________________________________________________

C(1) 9155(1) 3055(1) 5472(1) 24(1)

C(2) 9175(1) 2614(1) 4482(1) 25(1)

C(3) 8477(1) 1928(1) 3932(1) 26(1)

C(4) 7711(1) 1769(1) 4479(1) 28(1)

C(5) 8061(1) 1810(1) 5739(1) 22(1)

C(6) 7246(1) 1849(1) 6212(1) 29(1)

C(7) 7101(1) 1213(1) 6917(1) 32(1)

C(8) 7722(1) 375(1) 7338(1) 28(1)

C(9) 8535(1) 334(1) 6876(1) 29(1)

C(10) 8693(1) 973(1) 6179(1) 24(1)

C(11) 9738(1) 3893(1) 5999(1) 34(1)

C(12) 5536(1) -1512(1) 6909(1) 35(1)

C(13) 5710(2) -2049(2) 5926(2) 59(1)

C(14) 4910(1) -645(2) 6449(2) 52(1)

C(15) 5032(1) -2178(2) 7519(2) 53(1)

C(16) 6697(1) -455(1) 9099(1) 26(1)

C(17) 5992(1) 188(1) 9129(1) 38(1)

C(18) 5993(1) 683(1) 10081(2) 48(1)

C(19) 6711(1) 558(1) 11026(1) 42(1)

C(20) 7432(2) -45(1) 11015(1) 50(1)

C(21) 7425(1) -549(1) 10070(1) 42(1)

C(22) 7467(1) -2234(1) 8291(1) 29(1)

C(23) 7356(1) -2810(1) 9152(2) 44(1)

C(24) 7891(2) -3627(1) 9492(2) 50(1)

C(25) 8553(1) -3890(1) 8981(2) 45(1)

C(26) 8682(1) -3337(1) 8131(1) 39(1)

C(27) 8144(1) -2521(1) 7789(1) 30(1)

N(1) 8600(1) 2710(1) 6027(1) 25(1)

N(2) 9876(1) 2888(1) 3966(1) 32(1)

O(1) 10181(1) 3717(1) 4066(1) 48(1)

O(2) 10140(1) 2277(1) 3420(1) 51(1)

O(3) 8411(1) 1534(1) 3044(1) 38(1)

O(4) 7188(1) -493(1) 7043(1) 29(1)

Si(1) 6723(1) -1148(1) 7838(1) 24(1)

________________________________________________________________

246


_____________________________________________________________

C(1)-N(1) 1.3182(17)

C(1)-C(2) 1.4001(19)

C(1)-C(11) 1.4886(19)

C(2)-N(2) 1.4309(18)

C(2)-C(3) 1.434(2)

C(3)-O(3) 1.2263(16)

C(3)-C(4) 1.510(2)

C(4)-C(5) 1.5268(18)

C(4)-H(4A) 0.9900

C(4)-H(4B) 0.9900

C(5)-N(1) 1.4722(17)

C(5)-C(10) 1.4980(19)

C(5)-C(6) 1.5000(19)

C(6)-C(7) 1.315(2)

C(6)-H(6) 0.9500

C(7)-C(8) 1.485(2)

C(7)-H(7) 0.9500

C(8)-O(4) 1.4312(17)

C(8)-C(9) 1.489(2)

C(8)-H(8) 1.0000

C(9)-C(10) 1.316(2)

C(9)-H(9) 0.9500

C(10)-H(10) 0.9500

C(11)-H(11A) 0.9800

C(11)-H(11B) 0.9800

C(11)-H(11C) 0.9800

C(12)-C(14) 1.529(3)

C(12)-C(15) 1.530(2)

C(12)-C(13) 1.532(2)

C(12)-Si(1) 1.8894(16)

C(13)-H(13A) 0.9800

C(13)-H(13B) 0.9800

C(13)-H(13C) 0.9800

C(14)-H(14A) 0.9800

C(14)-H(14B) 0.9800

C(14)-H(14C) 0.9800

C(15)-H(15A) 0.9800

C(15)-H(15B) 0.9800

C(15)-H(15C) 0.9800

C(16)-C(17) 1.387(2)

C(16)-C(21) 1.391(2)

C(16)-Si(1) 1.8699(14)

C(17)-C(18) 1.384(2)

C(17)-H(17) 0.9500

C(18)-C(19) 1.367(3)

C(18)-H(18) 0.9500

C(19)-C(20) 1.364(3)

C(19)-H(19) 0.9500

C(20)-C(21) 1.381(2)

C(20)-H(20) 0.9500

C(21)-H(21) 0.9500

C(22)-C(27) 1.394(2)

C(22)-C(23) 1.397(2)

C(22)-Si(1) 1.8606(16)

C(23)-C(24) 1.380(3)

C(23)-H(23) 0.9500

247

C(24)-C(25) 1.375(3)

C(24)-H(24) 0.9500

C(25)-C(26) 1.376(2)

C(25)-H(25) 0.9500

C(26)-C(27) 1.382(2)

C(26)-H(26) 0.9500

C(27)-H(27) 0.9500

N(1)-H(1N) 0.87(2)

N(2)-O(2) 1.2263(17)

N(2)-O(1) 1.2294(17)

O(4)-Si(1) 1.6466(10)

N(1)-C(1)-C(2) 119.64(13)

N(1)-C(1)-C(11) 114.83(12)

C(2)-C(1)-C(11) 125.51(13)

C(1)-C(2)-N(2) 119.75(12)

C(1)-C(2)-C(3) 121.63(12)

N(2)-C(2)-C(3) 118.53(12)

O(3)-C(3)-C(2) 126.56(13)

O(3)-C(3)-C(4) 118.76(13)

C(2)-C(3)-C(4) 114.42(12)

C(3)-C(4)-C(5) 113.26(11)

C(3)-C(4)-H(4A) 108.9

C(5)-C(4)-H(4A) 108.9

C(3)-C(4)-H(4B) 108.9

C(5)-C(4)-H(4B) 108.9

H(4A)-C(4)-H(4B) 107.7

N(1)-C(5)-C(10) 108.85(11)

N(1)-C(5)-C(6) 108.48(11)

C(10)-C(5)-C(6) 112.02(11)

N(1)-C(5)-C(4) 106.81(11)

C(10)-C(5)-C(4) 110.43(12)

C(6)-C(5)-C(4) 110.08(12)

C(7)-C(6)-C(5) 123.71(14)

C(7)-C(6)-H(6) 118.1

C(5)-C(6)-H(6) 118.1

C(6)-C(7)-C(8) 124.08(14)

C(6)-C(7)-H(7) 118.0

C(8)-C(7)-H(7) 118.0

O(4)-C(8)-C(7) 108.79(12)

O(4)-C(8)-C(9) 108.65(12)

C(7)-C(8)-C(9) 112.51(12)

O(4)-C(8)-H(8) 108.9

C(7)-C(8)-H(8) 108.9

C(9)-C(8)-H(8) 108.9

C(10)-C(9)-C(8) 123.93(14)

C(10)-C(9)-H(9) 118.0

C(8)-C(9)-H(9) 118.0

C(9)-C(10)-C(5) 123.72(13)

C(9)-C(10)-H(10) 118.1

C(5)-C(10)-H(10) 118.1

C(1)-C(11)-H(11A) 109.5

C(1)-C(11)-H(11B) 109.5

H(11A)-C(11)-H(11B) 109.5

C(1)-C(11)-H(11C) 109.5

H(11A)-C(11)-H(11C) 109.5

H(11B)-C(11)-H(11C) 109.5

C(14)-C(12)-C(15) 109.31(15)

C(14)-C(12)-C(13) 107.44(16)

248

C(15)-C(12)-C(13) 109.70(16)

C(14)-C(12)-Si(1) 112.75(12)

C(15)-C(12)-Si(1) 110.76(12)

C(13)-C(12)-Si(1) 106.76(12)

C(12)-C(13)-H(13A) 109.5

C(12)-C(13)-H(13B) 109.5

H(13A)-C(13)-H(13B) 109.5

C(12)-C(13)-H(13C) 109.5

H(13A)-C(13)-H(13C) 109.5

H(13B)-C(13)-H(13C) 109.5

C(12)-C(14)-H(14A) 109.5

C(12)-C(14)-H(14B) 109.5

H(14A)-C(14)-H(14B) 109.5

C(12)-C(14)-H(14C) 109.5

H(14A)-C(14)-H(14C) 109.5

H(14B)-C(14)-H(14C) 109.5

C(12)-C(15)-H(15A) 109.5

C(12)-C(15)-H(15B) 109.5

H(15A)-C(15)-H(15B) 109.5

C(12)-C(15)-H(15C) 109.5

H(15A)-C(15)-H(15C) 109.5

H(15B)-C(15)-H(15C) 109.5

C(17)-C(16)-C(21) 116.19(14)

C(17)-C(16)-Si(1) 123.60(11)

C(21)-C(16)-Si(1) 120.19(12)

C(18)-C(17)-C(16) 121.97(16)

C(18)-C(17)-H(17) 119.0

C(16)-C(17)-H(17) 119.0

C(19)-C(18)-C(17) 120.21(17)

C(19)-C(18)-H(18) 119.9

C(17)-C(18)-H(18) 119.9

C(20)-C(19)-C(18) 119.32(16)

C(20)-C(19)-H(19) 120.3

C(18)-C(19)-H(19) 120.3

C(19)-C(20)-C(21) 120.52(17)

C(19)-C(20)-H(20) 119.7

C(21)-C(20)-H(20) 119.7

C(20)-C(21)-C(16) 121.75(16)

C(20)-C(21)-H(21) 119.1

C(16)-C(21)-H(21) 119.1

C(27)-C(22)-C(23) 117.02(14)

C(27)-C(22)-Si(1) 122.43(11)

C(23)-C(22)-Si(1) 120.55(12)

C(24)-C(23)-C(22) 121.62(16)

C(24)-C(23)-H(23) 119.2

C(22)-C(23)-H(23) 119.2

C(25)-C(24)-C(23) 119.96(16)

C(25)-C(24)-H(24) 120.0

C(23)-C(24)-H(24) 120.0

C(24)-C(25)-C(26) 119.86(16)

C(24)-C(25)-H(25) 120.1

C(26)-C(25)-H(25) 120.1

C(25)-C(26)-C(27) 120.14(16)

C(25)-C(26)-H(26) 119.9

C(27)-C(26)-H(26) 119.9

C(26)-C(27)-C(22) 121.39(14)

C(26)-C(27)-H(27) 119.3

C(22)-C(27)-H(27) 119.3

C(1)-N(1)-C(5) 123.81(12)

249

C(1)-N(1)-H(1N) 118.4(12)

C(5)-N(1)-H(1N) 117.1(12)

O(2)-N(2)-O(1) 122.22(13)

O(2)-N(2)-C(2) 117.89(13)

O(1)-N(2)-C(2) 119.88(13)

C(8)-O(4)-Si(1) 127.16(9)

O(4)-Si(1)-C(22) 108.34(6)

O(4)-Si(1)-C(16) 110.63(6)

C(22)-Si(1)-C(16) 108.00(7)

O(4)-Si(1)-C(12) 104.53(6)

C(22)-Si(1)-C(12) 110.14(7)

C(16)-Si(1)-C(12) 115.02(7)

_____________________________________________________________


250



-2 2 [ h2 a*2 U11 + ... + 2 h k a* b* U12 ]

_______________________________________________________________________

U11 U22 U33 U23 U13 U12

_______________________________________________________________________

C(1) 28(1) 22(1) 20(1) 3(1) 6(1) -3(1)

C(2) 29(1) 27(1) 19(1) 2(1) 9(1) -5(1)

C(3) 35(1) 25(1) 17(1) 3(1) 6(1) -5(1)

C(4) 28(1) 30(1) 22(1) 2(1) 4(1) -8(1)

C(5) 26(1) 22(1) 21(1) 1(1) 10(1) -4(1)

C(6) 31(1) 24(1) 39(1) 2(1) 18(1) 3(1)

C(7) 37(1) 29(1) 39(1) -3(1) 25(1) -4(1)

C(8) 38(1) 27(1) 22(1) 2(1) 11(1) -11(1)

C(9) 25(1) 27(1) 32(1) 6(1) 4(1) -1(1)

C(10) 22(1) 26(1) 26(1) 0(1) 8(1) -3(1)

C(11) 46(1) 30(1) 27(1) -4(1) 11(1) -14(1)

C(12) 33(1) 43(1) 33(1) -9(1) 14(1) -11(1)

C(13) 52(1) 79(2) 50(1) -35(1) 21(1) -19(1)

C(14) 40(1) 67(1) 43(1) -2(1) -2(1) -4(1)

C(15) 39(1) 62(1) 61(1) 1(1) 19(1) -20(1)

C(16) 31(1) 23(1) 26(1) 2(1) 13(1) -4(1)

C(17) 35(1) 40(1) 37(1) -9(1) 6(1) 6(1)

C(18) 47(1) 44(1) 54(1) -18(1) 18(1) 6(1)

C(19) 64(1) 33(1) 33(1) -10(1) 20(1) -9(1)

C(20) 66(1) 47(1) 29(1) -4(1) -1(1) 4(1)

C(21) 44(1) 42(1) 34(1) -3(1) 3(1) 11(1)

C(22) 36(1) 24(1) 32(1) 1(1) 18(1) -3(1)

C(23) 62(1) 33(1) 50(1) 11(1) 38(1) 7(1)

C(24) 74(1) 36(1) 50(1) 17(1) 33(1) 9(1)

C(25) 56(1) 31(1) 49(1) 6(1) 17(1) 11(1)

C(26) 40(1) 36(1) 44(1) -3(1) 19(1) 4(1)

C(27) 36(1) 29(1) 30(1) 0(1) 16(1) -4(1)

N(1) 36(1) 21(1) 20(1) -2(1) 11(1) -7(1)

N(2) 35(1) 40(1) 23(1) 1(1) 12(1) -9(1)

O(1) 60(1) 46(1) 46(1) -3(1) 29(1) -26(1)

O(2) 56(1) 61(1) 49(1) -13(1) 35(1) -10(1)

O(3) 57(1) 37(1) 20(1) -6(1) 13(1) -16(1)

O(4) 40(1) 26(1) 26(1) 1(1) 14(1) -10(1)

Si(1) 28(1) 23(1) 25(1) 0(1) 13(1) -4(1)

_______________________________________________________________________

251


for mc014.

________________________________________________________________

x y z U(eq)

________________________________________________________________

H(4A) 7420 1131 4254 33

H(4B) 7221 2266 4215 33

H(6) 6810 2363 5989 35

H(7) 6566 1295 7174 38

H(8) 7959 417 8161 34

H(9) 8965 -184 7097 35

H(10) 9240 899 5943 29

H(11A) 9528 4473 5552 51

H(11B) 10396 3766 6049 51

H(11C) 9674 3993 6741 51

H(13A) 6087 -2626 6190 89

H(13B) 6045 -1625 5547 89

H(13C) 5108 -2238 5411 89

H(14A) 4368 -860 5853 79

H(14B) 5266 -169 6162 79

H(14C) 4695 -353 7039 79

H(15A) 4427 -2371 7018 79

H(15B) 4932 -1835 8154 79

H(15C) 5416 -2752 7777 79

H(17) 5493 293 8476 46

H(18) 5494 1110 10077 57

H(19) 6707 888 11684 51

H(20) 7942 -119 11663 60

H(21) 7931 -970 10083 50

H(23) 6902 -2635 9513 53

H(24) 7802 -4007 10080 60

H(25) 8921 -4453 9213 54

H(26) 9141 -3517 7780 46

H(27) 8237 -2148 7199 36

H(1N) 8618(12) 2974(13) 6656(16) 35(5)

________________________________________________________________

252


________________________________________________________________

N(1)-C(1)-C(2)-N(2) -170.33(13)

C(11)-C(1)-C(2)-N(2) 8.0(2)

N(1)-C(1)-C(2)-C(3) 13.1(2)

C(11)-C(1)-C(2)-C(3) -168.52(14)

C(1)-C(2)-C(3)-O(3) 176.88(14)

N(2)-C(2)-C(3)-O(3) 0.3(2)

C(1)-C(2)-C(3)-C(4) 2.9(2)

N(2)-C(2)-C(3)-C(4) -173.73(12)

O(3)-C(3)-C(4)-C(5) 149.48(13)

C(2)-C(3)-C(4)-C(5) -36.00(18)

C(3)-C(4)-C(5)-N(1) 50.88(16)

C(3)-C(4)-C(5)-C(10) -67.32(15)

C(3)-C(4)-C(5)-C(6) 168.47(12)

N(1)-C(5)-C(6)-C(7) -121.14(16)

C(10)-C(5)-C(6)-C(7) -1.0(2)

C(4)-C(5)-C(6)-C(7) 122.32(16)

C(5)-C(6)-C(7)-C(8) 0.0(2)

C(6)-C(7)-C(8)-O(4) -120.14(16)

C(6)-C(7)-C(8)-C(9) 0.3(2)

O(4)-C(8)-C(9)-C(10) 121.07(15)

C(7)-C(8)-C(9)-C(10) 0.5(2)

C(8)-C(9)-C(10)-C(5) -1.7(2)

N(1)-C(5)-C(10)-C(9) 121.77(15)

C(6)-C(5)-C(10)-C(9) 1.81(19)

C(4)-C(5)-C(10)-C(9) -121.28(15)

C(21)-C(16)-C(17)-C(18) -2.3(3)

Si(1)-C(16)-C(17)-C(18) 179.49(14)

C(16)-C(17)-C(18)-C(19) 1.1(3)

C(17)-C(18)-C(19)-C(20) 1.1(3)

C(18)-C(19)-C(20)-C(21) -2.0(3)

C(19)-C(20)-C(21)-C(16) 0.7(3)

C(17)-C(16)-C(21)-C(20) 1.5(3)

Si(1)-C(16)-C(21)-C(20) 179.69(15)

C(27)-C(22)-C(23)-C(24) -0.1(3)

Si(1)-C(22)-C(23)-C(24) 179.08(16)

C(22)-C(23)-C(24)-C(25) 0.1(3)

C(23)-C(24)-C(25)-C(26) 0.1(3)

C(24)-C(25)-C(26)-C(27) -0.3(3)

C(25)-C(26)-C(27)-C(22) 0.3(3)

C(23)-C(22)-C(27)-C(26) -0.2(2)

Si(1)-C(22)-C(27)-C(26) -179.27(12)

C(2)-C(1)-N(1)-C(5) 7.0(2)

C(11)-C(1)-N(1)-C(5) -171.48(13)

C(10)-C(5)-N(1)-C(1) 80.84(16)

C(6)-C(5)-N(1)-C(1) -157.03(13)

C(4)-C(5)-N(1)-C(1) -38.40(18)

C(1)-C(2)-N(2)-O(2) 149.99(14)

C(3)-C(2)-N(2)-O(2) -33.4(2)

C(1)-C(2)-N(2)-O(1) -31.1(2)

C(3)-C(2)-N(2)-O(1) 145.53(14)

C(7)-C(8)-O(4)-Si(1) -99.62(13)

C(9)-C(8)-O(4)-Si(1) 137.58(11)

C(8)-O(4)-Si(1)-C(22) -103.19(12)

C(8)-O(4)-Si(1)-C(16) 15.02(14)

C(8)-O(4)-Si(1)-C(12) 139.38(12)

C(27)-C(22)-Si(1)-O(4) -14.59(15)

253

C(23)-C(22)-Si(1)-O(4) 166.32(13)

C(27)-C(22)-Si(1)-C(16) -134.45(13)

C(23)-C(22)-Si(1)-C(16) 46.46(16)

C(27)-C(22)-Si(1)-C(12) 99.18(14)

C(23)-C(22)-Si(1)-C(12) -79.91(15)

C(17)-C(16)-Si(1)-O(4) 84.30(14)

C(21)-C(16)-Si(1)-O(4) -93.80(14)

C(17)-C(16)-Si(1)-C(22) -157.30(13)

C(21)-C(16)-Si(1)-C(22) 24.61(15)

C(17)-C(16)-Si(1)-C(12) -33.84(16)

C(21)-C(16)-Si(1)-C(12) 148.06(13)

C(14)-C(12)-Si(1)-O(4) -60.25(13)

C(15)-C(12)-Si(1)-O(4) 176.89(12)

C(13)-C(12)-Si(1)-O(4) 57.50(14)

C(14)-C(12)-Si(1)-C(22) -176.44(12)

C(15)-C(12)-Si(1)-C(22) 60.71(14)

C(13)-C(12)-Si(1)-C(22) -58.68(15)

C(14)-C(12)-Si(1)-C(16) 61.25(14)

C(15)-C(12)-Si(1)-C(16) -61.60(15)

C(13)-C(12)-Si(1)-C(16) 179.01(13)

________________________________________________________________


Hydrogen Bonds


H...A

-----------------------------------------------------------------------------

N(1) --H(1N) ..O(3) [ 4555.01] 0.868(19) 1.987(19) 2.8434(16)

168.8(18)


===================================================

[ 4555. ] = x,1/2-y,1/2+z

254

C.5 X-ray data of methyl 2-((1S,4R,5R,6S)-1-acetamido-4-(tert-butyldiphenylsilyloxy)-6-cyano-


OH

O CN

CO2CH3

NHAc

2.67

TBDPS

Crystal Data

Empirical Formula C29H36N2O5SiCl2 (C28H34N2O5Si + CH2Cl2)


Crystal Color, Habit colorless, plate


Crystal System triclinic



b = 10.1186(11) Å

c = 17.608(2) Å

= 78.541(2)°

= 77.525(2)°

= 69.229(2)°

V = 1539.6(3) Å3

Space Group P -1 (#2)

Z value 2

Dcalc 1.276 g/cm3

F000 624.00

(MoK) 2.89 cm-1

255


Diffractometer Bruker APEX DUO





2max 61.0°


Unique: 9366 (Rint = 0.028)







2)

2


2) + (0.0524P)

2 + 0.5909P)



No. Variables 393








3


3

256


(A2 x 103) for mc044.


________________________________________________________________

x y z U(eq) occ

________________________________________________________________

C(1) 7750(1) 5449(1) 9308(1) 13(1)

C(2) 8310(1) 5712(1) 8555(1) 13(1)

C(3) 8193(1) 7172(1) 8105(1) 12(1)

C(4) 7168(1) 8344(1) 8591(1) 12(1)

C(5) 7421(1) 7950(1) 9456(1) 11(1)

C(6) 6989(1) 6595(1) 9843(1) 11(1)

C(7) 7512(1) 6041(1) 10650(1) 13(1)

C(8) 7042(1) 4790(1) 11099(1) 13(1)

C(9) 9003(1) 7760(1) 9497(1) 14(1)

C(15) 4331(1) 7951(1) 10366(1) 13(1)

C(16) 2682(1) 8197(1) 10369(1) 22(1)

C(19) 7449(2) 3016(1) 12197(1) 22(1)

C(21) 7092(1) 8049(1) 5858(1) 16(1)

C(22) 7436(2) 7522(2) 5059(1) 31(1)

C(23) 7394(2) 9472(2) 5759(1) 31(1)

C(24) 5398(2) 8319(2) 6185(1) 27(1)

C(25) 7652(1) 4997(1) 6732(1) 14(1)

C(26) 8214(1) 4036(1) 6175(1) 17(1)

C(27) 7773(2) 2831(1) 6274(1) 21(1)

C(28) 6755(2) 2558(1) 6931(1) 20(1)

C(29) 6175(1) 3501(1) 7485(1) 19(1)

C(30) 6616(1) 4703(1) 7388(1) 16(1)

C(31) 10320(1) 6123(1) 6346(1) 15(1)

C(32) 11101(2) 7029(2) 5902(1) 26(1)

C(33) 12685(2) 6578(2) 5743(1) 32(1)

C(34) 13525(2) 5230(2) 6036(1) 27(1)

C(35) 12786(2) 4310(2) 6486(1) 27(1)

C(36) 11207(2) 4749(1) 6632(1) 22(1)

N(10) 10240(1) 7620(1) 9521(1) 20(1)

N(13) 5327(1) 6998(1) 9911(1) 12(1)

O(11) 7457(1) 9632(1) 8254(1) 15(1)

O(12) 7553(1) 7384(1) 7412(1) 15(1)

O(14) 6170(1) 4308(1) 10930(1) 16(1)

O(17) 4738(1) 8584(1) 10769(1) 15(1)

O(18) 7721(1) 4279(1) 11734(1) 16(1)

Si(20) 8194(1) 6654(1) 6593(1) 12(1)

C(37) 9750(14) 9010(30) 2305(7) 53(5) 0.70(2)

Cl(1) 8649(10) 8810(11) 1685(5) 88(2) 0.70(2)

Cl(2) 8626(9) 9554(8) 3186(5) 102(3) 0.70(2)

Cl(2B) 8504(2) 9465(2) 3126(1) 38(1) 0.30(2)

Cl(1B) 8885(3) 8491(3) 1609(1) 44(1) 0.30(2)

C(37B) 9765(4) 8882(9) 2278(2) 25(1) 0.30(2)

________________________________________________________________

257


_____________________________________________________________

C(1)-C(2) 1.3300(16)

C(1)-C(6) 1.5171(15)

C(1)-H(1) 0.9500

C(2)-C(3) 1.5094(16)

C(2)-H(2) 0.9500

C(3)-O(12) 1.4267(13)

C(3)-C(4) 1.5214(15)

C(3)-H(3) 1.0000

C(4)-O(11) 1.4153(14)

C(4)-C(5) 1.5444(15)

C(4)-H(4) 1.0000

C(5)-C(9) 1.4708(15)

C(5)-C(6) 1.5564(15)

C(5)-H(5) 1.0000

C(6)-N(13) 1.4761(14)

C(6)-C(7) 1.5415(15)

C(7)-C(8) 1.5099(16)

C(7)-H(7A) 0.9900

C(7)-H(7B) 0.9900

C(8)-O(14) 1.2132(14)

C(8)-O(18) 1.3354(14)

C(9)-N(10) 1.1477(16)

C(15)-O(17) 1.2421(14)

C(15)-N(13) 1.3433(15)

C(15)-C(16) 1.5036(16)

C(16)-H(16A) 0.9800

C(16)-H(16B) 0.9800

C(16)-H(16C) 0.9800

C(19)-O(18) 1.4477(15)

C(19)-H(19A) 0.9800

C(19)-H(19B) 0.9800

C(19)-H(19C) 0.9800

C(21)-C(22) 1.5306(18)

C(21)-C(23) 1.5363(19)

C(21)-C(24) 1.5393(18)

C(21)-Si(20) 1.8941(12)

C(22)-H(22A) 0.9800

C(22)-H(22B) 0.9800

C(22)-H(22C) 0.9800

C(23)-H(23A) 0.9800

C(23)-H(23B) 0.9800

C(23)-H(23C) 0.9800

C(24)-H(24A) 0.9800

C(24)-H(24B) 0.9800

C(24)-H(24C) 0.9800

C(25)-C(26) 1.4050(16)

C(25)-C(30) 1.4072(17)

C(25)-Si(20) 1.8814(12)

C(26)-C(27) 1.3936(17)

C(26)-H(26) 0.9500

C(27)-C(28) 1.3925(19)

C(27)-H(27) 0.9500

C(28)-C(29) 1.3895(18)

C(28)-H(28) 0.9500

C(29)-C(30) 1.3917(17)

C(29)-H(29) 0.9500

258

C(30)-H(30) 0.9500

C(31)-C(32) 1.3994(18)

C(31)-C(36) 1.4048(18)

C(31)-Si(20) 1.8812(12)

C(32)-C(33) 1.397(2)

C(32)-H(32) 0.9500

C(33)-C(34) 1.376(2)

C(33)-H(33) 0.9500

C(34)-C(35) 1.387(2)

C(34)-H(34) 0.9500

C(35)-C(36) 1.3935(18)

C(35)-H(35) 0.9500

C(36)-H(36) 0.9500

N(13)-H(13N) 0.842(17)

O(11)-H(11O) 0.85(2)

O(12)-Si(20) 1.6485(9)

C(37)-Cl(2) 1.750(7)

C(37)-Cl(1) 1.753(7)

C(37)-H(37A) 0.9900

C(37)-H(37B) 0.9900

Cl(2B)-C(37B) 1.760(3)

Cl(1B)-C(37B) 1.761(3)

C(37B)-H(37C) 0.9900

C(37B)-H(37D) 0.9900

C(2)-C(1)-C(6) 123.59(10)

C(2)-C(1)-H(1) 118.2

C(6)-C(1)-H(1) 118.2

C(1)-C(2)-C(3) 125.38(10)

C(1)-C(2)-H(2) 117.3

C(3)-C(2)-H(2) 117.3

O(12)-C(3)-C(2) 110.77(9)

O(12)-C(3)-C(4) 106.85(9)

C(2)-C(3)-C(4) 111.34(9)

O(12)-C(3)-H(3) 109.3

C(2)-C(3)-H(3) 109.3

C(4)-C(3)-H(3) 109.3

O(11)-C(4)-C(3) 108.65(9)

O(11)-C(4)-C(5) 111.01(9)

C(3)-C(4)-C(5) 111.12(9)

O(11)-C(4)-H(4) 108.7

C(3)-C(4)-H(4) 108.7

C(5)-C(4)-H(4) 108.7

C(9)-C(5)-C(4) 109.53(9)

C(9)-C(5)-C(6) 111.72(9)

C(4)-C(5)-C(6) 110.88(9)

C(9)-C(5)-H(5) 108.2

C(4)-C(5)-H(5) 108.2

C(6)-C(5)-H(5) 108.2

N(13)-C(6)-C(1) 109.40(9)

N(13)-C(6)-C(7) 111.56(9)

C(1)-C(6)-C(7) 109.42(9)

N(13)-C(6)-C(5) 106.89(8)

C(1)-C(6)-C(5) 108.65(9)

C(7)-C(6)-C(5) 110.84(9)

C(8)-C(7)-C(6) 114.78(9)

C(8)-C(7)-H(7A) 108.6

C(6)-C(7)-H(7A) 108.6

C(8)-C(7)-H(7B) 108.6

259

C(6)-C(7)-H(7B) 108.6

H(7A)-C(7)-H(7B) 107.5

O(14)-C(8)-O(18) 123.73(11)

O(14)-C(8)-C(7) 126.60(10)

O(18)-C(8)-C(7) 109.66(9)

N(10)-C(9)-C(5) 179.20(14)

O(17)-C(15)-N(13) 122.36(10)

O(17)-C(15)-C(16) 121.59(10)

N(13)-C(15)-C(16) 116.04(10)

C(15)-C(16)-H(16A) 109.5

C(15)-C(16)-H(16B) 109.5

H(16A)-C(16)-H(16B) 109.5

C(15)-C(16)-H(16C) 109.5

H(16A)-C(16)-H(16C) 109.5

H(16B)-C(16)-H(16C) 109.5

O(18)-C(19)-H(19A) 109.5

O(18)-C(19)-H(19B) 109.5

H(19A)-C(19)-H(19B) 109.5

O(18)-C(19)-H(19C) 109.5

H(19A)-C(19)-H(19C) 109.5

H(19B)-C(19)-H(19C) 109.5

C(22)-C(21)-C(23) 109.83(12)

C(22)-C(21)-C(24) 108.71(11)

C(23)-C(21)-C(24) 107.74(11)

C(22)-C(21)-Si(20) 111.37(9)

C(23)-C(21)-Si(20) 112.24(9)

C(24)-C(21)-Si(20) 106.79(8)

C(21)-C(22)-H(22A) 109.5

C(21)-C(22)-H(22B) 109.5

H(22A)-C(22)-H(22B) 109.5

C(21)-C(22)-H(22C) 109.5

H(22A)-C(22)-H(22C) 109.5

H(22B)-C(22)-H(22C) 109.5

C(21)-C(23)-H(23A) 109.5

C(21)-C(23)-H(23B) 109.5

H(23A)-C(23)-H(23B) 109.5

C(21)-C(23)-H(23C) 109.5

H(23A)-C(23)-H(23C) 109.5

H(23B)-C(23)-H(23C) 109.5

C(21)-C(24)-H(24A) 109.5

C(21)-C(24)-H(24B) 109.5

H(24A)-C(24)-H(24B) 109.5

C(21)-C(24)-H(24C) 109.5

H(24A)-C(24)-H(24C) 109.5

H(24B)-C(24)-H(24C) 109.5

C(26)-C(25)-C(30) 117.43(11)

C(26)-C(25)-Si(20) 121.76(9)

C(30)-C(25)-Si(20) 120.77(9)

C(27)-C(26)-C(25) 121.27(12)

C(27)-C(26)-H(26) 119.4

C(25)-C(26)-H(26) 119.4

C(28)-C(27)-C(26) 120.20(12)

C(28)-C(27)-H(27) 119.9

C(26)-C(27)-H(27) 119.9

C(29)-C(28)-C(27) 119.51(12)

C(29)-C(28)-H(28) 120.2

C(27)-C(28)-H(28) 120.2

C(28)-C(29)-C(30) 120.29(12)

C(28)-C(29)-H(29) 119.9

260

C(30)-C(29)-H(29) 119.9

C(29)-C(30)-C(25) 121.29(11)

C(29)-C(30)-H(30) 119.4

C(25)-C(30)-H(30) 119.4

C(32)-C(31)-C(36) 116.70(12)

C(32)-C(31)-Si(20) 123.98(10)

C(36)-C(31)-Si(20) 119.30(9)

C(33)-C(32)-C(31) 121.43(13)

C(33)-C(32)-H(32) 119.3

C(31)-C(32)-H(32) 119.3

C(34)-C(33)-C(32) 120.62(14)

C(34)-C(33)-H(33) 119.7

C(32)-C(33)-H(33) 119.7

C(33)-C(34)-C(35) 119.40(13)

C(33)-C(34)-H(34) 120.3

C(35)-C(34)-H(34) 120.3

C(34)-C(35)-C(36) 120.00(14)

C(34)-C(35)-H(35) 120.0

C(36)-C(35)-H(35) 120.0

C(35)-C(36)-C(31) 121.83(13)

C(35)-C(36)-H(36) 119.1

C(31)-C(36)-H(36) 119.1

C(15)-N(13)-C(6) 123.96(9)

C(15)-N(13)-H(13N) 118.8(11)

C(6)-N(13)-H(13N) 117.0(11)

C(4)-O(11)-H(11O) 107.2(13)

C(3)-O(12)-Si(20) 132.22(7)

C(8)-O(18)-C(19) 115.81(10)

O(12)-Si(20)-C(31) 111.71(5)

O(12)-Si(20)-C(25) 108.42(5)

C(31)-Si(20)-C(25) 107.94(5)

O(12)-Si(20)-C(21) 103.04(5)

C(31)-Si(20)-C(21) 116.13(6)

C(25)-Si(20)-C(21) 109.34(5)

Cl(2)-C(37)-Cl(1) 110.7(7)

Cl(2)-C(37)-H(37A) 109.5

Cl(1)-C(37)-H(37A) 109.5

Cl(2)-C(37)-H(37B) 109.5

Cl(1)-C(37)-H(37B) 109.5

H(37A)-C(37)-H(37B) 108.1

Cl(2B)-C(37B)-Cl(1B) 112.94(19)

Cl(2B)-C(37B)-H(37C) 109.0

Cl(1B)-C(37B)-H(37C) 109.0

Cl(2B)-C(37B)-H(37D) 109.0

Cl(1B)-C(37B)-H(37D) 109.0

H(37C)-C(37B)-H(37D) 107.8

_____________________________________________________________


261



-2 2 [ h2 a*2 U11 + ... + 2 h k a* b* U12 ]

_______________________________________________________________________

U11 U22 U33 U23 U13 U12

_______________________________________________________________________

C(1) 12(1) 10(1) 16(1) -3(1) -4(1) -2(1)

C(2) 12(1) 12(1) 16(1) -5(1) -3(1) -1(1)

C(3) 11(1) 13(1) 12(1) -3(1) -2(1) -3(1)

C(4) 11(1) 11(1) 12(1) -2(1) -2(1) -3(1)

C(5) 10(1) 11(1) 13(1) -2(1) -2(1) -4(1)

C(6) 9(1) 11(1) 13(1) -2(1) -3(1) -3(1)

C(7) 12(1) 13(1) 14(1) -2(1) -4(1) -4(1)

C(8) 11(1) 13(1) 12(1) -3(1) -1(1) -2(1)

C(9) 14(1) 13(1) 14(1) -3(1) -2(1) -4(1)

C(15) 11(1) 11(1) 16(1) -1(1) -2(1) -4(1)

C(16) 11(1) 21(1) 38(1) -13(1) -3(1) -4(1)

C(19) 21(1) 22(1) 19(1) 7(1) -4(1) -8(1)

C(21) 16(1) 15(1) 15(1) -1(1) -3(1) -4(1)

C(22) 38(1) 31(1) 15(1) -4(1) -9(1) 2(1)

C(23) 33(1) 17(1) 45(1) 6(1) -17(1) -9(1)

C(24) 16(1) 31(1) 26(1) 5(1) -6(1) -3(1)

C(25) 12(1) 14(1) 16(1) -2(1) -4(1) -3(1)

C(26) 17(1) 16(1) 18(1) -4(1) 0(1) -5(1)

C(27) 23(1) 16(1) 24(1) -6(1) -4(1) -6(1)

C(28) 22(1) 16(1) 26(1) -1(1) -8(1) -9(1)

C(29) 16(1) 20(1) 19(1) 1(1) -3(1) -8(1)

C(30) 13(1) 17(1) 16(1) -3(1) -3(1) -3(1)

C(31) 14(1) 20(1) 14(1) -4(1) -2(1) -6(1)

C(32) 19(1) 32(1) 26(1) 8(1) -8(1) -12(1)

C(33) 20(1) 50(1) 26(1) 8(1) -5(1) -19(1)

C(34) 14(1) 46(1) 24(1) -12(1) -2(1) -10(1)

C(35) 15(1) 26(1) 40(1) -11(1) -7(1) -1(1)

C(36) 16(1) 18(1) 32(1) -5(1) -4(1) -5(1)

N(10) 15(1) 24(1) 23(1) -5(1) -4(1) -7(1)

N(13) 10(1) 12(1) 15(1) -4(1) -3(1) -4(1)

O(11) 17(1) 11(1) 16(1) -2(1) 1(1) -4(1)

O(12) 15(1) 16(1) 12(1) -4(1) -4(1) -2(1)

O(14) 14(1) 16(1) 18(1) -2(1) -4(1) -6(1)

O(17) 13(1) 15(1) 18(1) -6(1) -1(1) -5(1)

O(18) 18(1) 19(1) 14(1) 2(1) -6(1) -7(1)

Si(20) 12(1) 12(1) 11(1) -2(1) -2(1) -4(1)

C(37) 46(9) 37(7) 70(10) -6(6) -15(7) -5(6)

Cl(1) 64(2) 66(3) 143(5) -23(3) -42(2) -13(2)

Cl(2) 63(3) 81(4) 96(4) 20(2) 10(2) 27(2)

Cl(2B) 38(1) 27(1) 28(1) 3(1) 14(1) 0(1)

Cl(1B) 34(1) 63(1) 42(1) -3(1) -13(1) -23(1)

C(37B) 15(2) 28(2) 29(2) -4(2) 5(2) -9(2)

_______________________________________________________________________

262


for mc044.

________________________________________________________________

x y z U(eq)

________________________________________________________________

H(1) 7831 4491 9522 15

H(2) 8826 4915 8277 16

H(3) 9228 7267 7957 15

H(4) 6088 8473 8572 14

H(5) 6747 8760 9747 13

H(7A) 8631 5760 10573 15

H(7B) 7097 6832 10973 15

H(16A) 2266 7721 10860 33

H(16B) 2579 7807 9925 33

H(16C) 2126 9223 10323 33

H(19A) 6364 3232 12400 32

H(19B) 8020 2710 12636 32

H(19C) 7779 2251 11868 32

H(22A) 6796 8236 4704 46

H(22B) 7228 6622 5125 46

H(22C) 8506 7372 4838 46

H(23A) 8404 9381 5454 47

H(23B) 7342 9722 6276 47

H(23C) 6627 10222 5483 47

H(24A) 4784 9026 5817 40

H(24B) 5159 8677 6692 40

H(24C) 5174 7425 6256 40

H(26) 8908 4210 5724 21

H(27) 8169 2193 5891 25

H(28) 6458 1734 7000 24

H(29) 5473 3324 7933 22

H(30) 6210 5338 7772 19

H(32) 10543 7972 5704 31

H(33) 13186 7208 5429 38

H(34) 14602 4933 5931 33

H(35) 13357 3381 6696 32

H(36) 10716 4102 6933 26

H(13N) 4997(18) 6547(17) 9677(10) 17(4)

H(11O) 6840(20) 10280(20) 8517(12) 36(5)

H(37A) 10555 8090 2418 63

H(37B) 10245 9725 2039 63

H(37C) 10599 8018 2434 30

H(37D) 10215 9631 2014 30

________________________________________________________________

263


________________________________________________________________

C(6)-C(1)-C(2)-C(3) -4.13(18)

C(1)-C(2)-C(3)-O(12) -126.21(12)

C(1)-C(2)-C(3)-C(4) -7.46(16)

O(12)-C(3)-C(4)-O(11) -76.58(11)

C(2)-C(3)-C(4)-O(11) 162.34(9)

O(12)-C(3)-C(4)-C(5) 161.01(9)

C(2)-C(3)-C(4)-C(5) 39.93(12)

O(11)-C(4)-C(5)-C(9) -60.39(12)

C(3)-C(4)-C(5)-C(9) 60.64(12)

O(11)-C(4)-C(5)-C(6) 175.86(9)

C(3)-C(4)-C(5)-C(6) -63.11(11)

C(2)-C(1)-C(6)-N(13) 99.09(13)

C(2)-C(1)-C(6)-C(7) -138.41(11)

C(2)-C(1)-C(6)-C(5) -17.27(14)

C(9)-C(5)-C(6)-N(13) 168.87(9)

C(4)-C(5)-C(6)-N(13) -68.64(11)

C(9)-C(5)-C(6)-C(1) -73.16(11)

C(4)-C(5)-C(6)-C(1) 49.32(11)

C(9)-C(5)-C(6)-C(7) 47.10(12)

C(4)-C(5)-C(6)-C(7) 169.58(9)

N(13)-C(6)-C(7)-C(8) 56.74(12)

C(1)-C(6)-C(7)-C(8) -64.46(12)

C(5)-C(6)-C(7)-C(8) 175.74(9)

C(6)-C(7)-C(8)-O(14) -9.25(16)

C(6)-C(7)-C(8)-O(18) 171.70(9)

C(4)-C(5)-C(9)-N(10) 19(10)

C(6)-C(5)-C(9)-N(10) 142(10)

C(30)-C(25)-C(26)-C(27) -0.57(18)

Si(20)-C(25)-C(26)-C(27) -178.30(10)

C(25)-C(26)-C(27)-C(28) 0.15(19)

C(26)-C(27)-C(28)-C(29) 0.4(2)

C(27)-C(28)-C(29)-C(30) -0.46(19)

C(28)-C(29)-C(30)-C(25) 0.03(18)

C(26)-C(25)-C(30)-C(29) 0.48(17)

Si(20)-C(25)-C(30)-C(29) 178.23(9)

C(36)-C(31)-C(32)-C(33) 0.9(2)

Si(20)-C(31)-C(32)-C(33) 179.44(12)

C(31)-C(32)-C(33)-C(34) -1.5(2)

C(32)-C(33)-C(34)-C(35) 0.7(2)

C(33)-C(34)-C(35)-C(36) 0.6(2)

C(34)-C(35)-C(36)-C(31) -1.2(2)

C(32)-C(31)-C(36)-C(35) 0.4(2)

Si(20)-C(31)-C(36)-C(35) -178.18(11)

O(17)-C(15)-N(13)-C(6) 0.46(18)

C(16)-C(15)-N(13)-C(6) -178.84(11)

C(1)-C(6)-N(13)-C(15) 177.47(10)

C(7)-C(6)-N(13)-C(15) 56.26(14)

C(5)-C(6)-N(13)-C(15) -65.06(13)

C(2)-C(3)-O(12)-Si(20) -68.26(13)

C(4)-C(3)-O(12)-Si(20) 170.30(8)

O(14)-C(8)-O(18)-C(19) 4.61(16)

C(7)-C(8)-O(18)-C(19) -176.31(10)

C(3)-O(12)-Si(20)-C(31) -30.74(12)

C(3)-O(12)-Si(20)-C(25) 88.08(11)

C(3)-O(12)-Si(20)-C(21) -156.10(10)

C(32)-C(31)-Si(20)-O(12) -88.41(12)

264

C(36)-C(31)-Si(20)-O(12) 90.09(11)

C(32)-C(31)-Si(20)-C(25) 152.49(11)

C(36)-C(31)-Si(20)-C(25) -29.01(11)

C(32)-C(31)-Si(20)-C(21) 29.35(13)

C(36)-C(31)-Si(20)-C(21) -152.15(10)

C(26)-C(25)-Si(20)-O(12) -171.17(9)

C(30)-C(25)-Si(20)-O(12) 11.17(11)

C(26)-C(25)-Si(20)-C(31) -50.00(11)

C(30)-C(25)-Si(20)-C(31) 132.34(9)

C(26)-C(25)-Si(20)-C(21) 77.18(11)

C(30)-C(25)-Si(20)-C(21) -100.48(10)

C(22)-C(21)-Si(20)-O(12) -175.57(10)

C(23)-C(21)-Si(20)-O(12) 60.82(11)

C(24)-C(21)-Si(20)-O(12) -57.03(10)

C(22)-C(21)-Si(20)-C(31) 61.98(11)

C(23)-C(21)-Si(20)-C(31) -61.63(11)

C(24)-C(21)-Si(20)-C(31) -179.47(9)

C(22)-C(21)-Si(20)-C(25) -60.42(11)

C(23)-C(21)-Si(20)-C(25) 175.97(10)

C(24)-C(21)-Si(20)-C(25) 58.12(10)

________________________________________________________________

Hydrogen Bonds


H...A

-----------------------------------------------------------------------------

O(11) --H(11O) ..O(17) [ 2677.01] 0.85(2) 1.92(2) 2.7578(13)

167(2)

N(13) --H(13N) ..O(14) [ 2667.01] 0.842(17) 2.168(18) 3.0024(15)

170.8(16)


===================================================

[ 2677. ] = 1-x,2-y,2-z

[ 2667. ] = 1-x,1-y,2-z

265

C.6 X-ray data of N-[(4aR,7aS,7bR)-3,4,7a,7b-tetrahydro-7-oxoindeno[1,7-cd]isoxazol-4a(7H)-

yl]-acetamide (2.124)

O

O N

NHAc

2.124

Crystal Data



Crystal Color, Habit colorless, irregular





b = 7.6194(3) Å

c = 18.2141(9) Å

= 90.0°

= 92.696(2)°

= 90.0°

V = 1539.6(3) Å3


Z value 4

Dcalc 1.419 g/cm3

F000 464.00

(MoK) 1.05 cm-1

266







2max 56.0°


Unique: 2466 (Rint = 0.030)







2)

2


2) + (0.0455P)

2 + 0.3215P)



No. Variables 150








3


3

267


(A2 x 103) for mc017.


________________________________________________________________

x y z U(eq)

________________________________________________________________

C(1) 4782(2) 8132(2) 1234(1) 25(1)

C(2) 4993(2) 9785(2) 1015(1) 27(1)

C(3) 3495(2) 11032(2) 942(1) 28(1)

C(4) 1663(2) 10528(2) 1217(1) 28(1)

C(5) 1555(1) 8679(1) 1519(1) 24(1)

C(6) 2985(1) 7286(1) 1359(1) 22(1)

C(7) 3042(2) 6165(2) 2071(1) 29(1)

C(8) 2813(2) 7472(2) 2711(1) 31(1)

C(9) 2006(2) 9041(2) 2321(1) 27(1)

C(15) 2077(2) 6802(2) 51(1) 24(1)

C(16) 1947(2) 5468(2) -560(1) 33(1)

N(10) 1966(1) 10644(2) 2514(1) 34(1)

N(13) 2538(1) 6159(1) 727(1) 25(1)

O(11) 1393(1) 11644(1) 1867(1) 37(1)

O(12) 3726(2) 12512(1) 703(1) 44(1)

O(14) 1793(1) 8374(1) -58(1) 30(1)

________________________________________________________________

268


_____________________________________________________________

C(1)-C(2) 1.3324(16)

C(1)-C(6) 1.5105(15)

C(1)-H(1) 0.9500

C(2)-C(3) 1.4656(16)

C(2)-H(2) 0.9500

C(3)-O(12) 1.2245(14)

C(3)-C(4) 1.5228(17)

C(4)-O(11) 1.4787(14)

C(4)-C(5) 1.5160(16)

C(4)-H(4) 1.0000

C(5)-C(9) 1.5079(16)

C(5)-C(6) 1.5406(15)

C(5)-H(5) 1.0000

C(6)-N(13) 1.4629(14)

C(6)-C(7) 1.5521(15)

C(7)-C(8) 1.5479(17)

C(7)-H(7A) 0.9900

C(7)-H(7B) 0.9900

C(8)-C(9) 1.5011(17)

C(8)-H(8A) 0.9900

C(8)-H(8B) 0.9900

C(9)-N(10) 1.2715(16)

C(15)-O(14) 1.2308(14)

C(15)-N(13) 1.3532(15)

C(15)-C(16) 1.5063(16)

C(16)-H(16A) 0.9800

C(16)-H(16B) 0.9800

C(16)-H(16C) 0.9800

N(10)-O(11) 1.4509(14)

N(13)-H(13N) 0.854(17)

C(2)-C(1)-C(6) 124.47(10)

C(2)-C(1)-H(1) 117.8

C(6)-C(1)-H(1) 117.8

C(1)-C(2)-C(3) 122.69(11)

C(1)-C(2)-H(2) 118.7

C(3)-C(2)-H(2) 118.7

O(12)-C(3)-C(2) 120.69(12)

O(12)-C(3)-C(4) 119.49(11)

C(2)-C(3)-C(4) 119.67(10)

O(11)-C(4)-C(5) 103.44(9)

O(11)-C(4)-C(3) 106.01(9)

C(5)-C(4)-C(3) 114.64(9)

O(11)-C(4)-H(4) 110.8

C(5)-C(4)-H(4) 110.8

C(3)-C(4)-H(4) 110.8

C(9)-C(5)-C(4) 99.69(9)

C(9)-C(5)-C(6) 100.66(9)

C(4)-C(5)-C(6) 121.52(9)

C(9)-C(5)-H(5) 111.2

C(4)-C(5)-H(5) 111.2

C(6)-C(5)-H(5) 111.2

N(13)-C(6)-C(1) 107.54(9)

N(13)-C(6)-C(5) 114.86(9)

C(1)-C(6)-C(5) 111.01(9)

N(13)-C(6)-C(7) 109.35(9)

269

C(1)-C(6)-C(7) 111.82(9)

C(5)-C(6)-C(7) 102.28(9)

C(8)-C(7)-C(6) 105.98(9)

C(8)-C(7)-H(7A) 110.5

C(6)-C(7)-H(7A) 110.5

C(8)-C(7)-H(7B) 110.5

C(6)-C(7)-H(7B) 110.5

H(7A)-C(7)-H(7B) 108.7

C(9)-C(8)-C(7) 102.23(9)

C(9)-C(8)-H(8A) 111.3

C(7)-C(8)-H(8A) 111.3

C(9)-C(8)-H(8B) 111.3

C(7)-C(8)-H(8B) 111.3

H(8A)-C(8)-H(8B) 109.2

N(10)-C(9)-C(8) 130.38(11)

N(10)-C(9)-C(5) 115.88(11)

C(8)-C(9)-C(5) 112.23(10)

O(14)-C(15)-N(13) 122.25(10)

O(14)-C(15)-C(16) 122.18(11)

N(13)-C(15)-C(16) 115.57(10)

C(15)-C(16)-H(16A) 109.5

C(15)-C(16)-H(16B) 109.5

H(16A)-C(16)-H(16B) 109.5

C(15)-C(16)-H(16C) 109.5

H(16A)-C(16)-H(16C) 109.5

H(16B)-C(16)-H(16C) 109.5

C(9)-N(10)-O(11) 106.84(10)

C(15)-N(13)-C(6) 122.79(9)

C(15)-N(13)-H(13N) 118.0(11)

C(6)-N(13)-H(13N) 118.0(11)

N(10)-O(11)-C(4) 107.58(8)

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270



-2 2 [ h2 a*2 U11 + ... + 2 h k a* b* U12 ]

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U11 U22 U33 U23 U13 U12

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C(1) 22(1) 23(1) 28(1) -2(1) -1(1) 4(1)

C(2) 26(1) 24(1) 29(1) -1(1) 2(1) -2(1)

C(3) 38(1) 18(1) 27(1) -1(1) -2(1) 1(1)

C(4) 30(1) 22(1) 31(1) -4(1) -5(1) 7(1)

C(5) 20(1) 24(1) 28(1) -2(1) -1(1) 2(1)

C(6) 24(1) 18(1) 24(1) 0(1) -1(1) 2(1)

C(7) 35(1) 24(1) 27(1) 4(1) -1(1) 0(1)

C(8) 35(1) 33(1) 25(1) 2(1) 1(1) -3(1)

C(9) 23(1) 32(1) 27(1) -4(1) 4(1) 0(1)

C(15) 22(1) 25(1) 26(1) 0(1) 1(1) -2(1)

C(16) 39(1) 32(1) 27(1) -4(1) 2(1) -4(1)

N(10) 35(1) 35(1) 32(1) -6(1) 4(1) 4(1)

N(13) 32(1) 16(1) 26(1) -1(1) -1(1) 1(1)

O(11) 44(1) 28(1) 39(1) -8(1) 2(1) 12(1)

O(12) 59(1) 21(1) 52(1) 7(1) 7(1) 3(1)

O(14) 34(1) 25(1) 31(1) 4(1) -3(1) 3(1)

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271


for mc017.

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x y z U(eq)

________________________________________________________________

H(1) 5833 7437 1316 30

H(2) 6163 10172 903 32

H(4) 691 10736 829 33

H(5) 311 8191 1445 29

H(7A) 2056 5291 2053 34

H(7B) 4204 5538 2134 34

H(8A) 1995 6998 3076 37

H(8B) 3986 7762 2961 37

H(16A) 900 5734 -888 49

H(16B) 1812 4293 -350 49

H(16C) 3042 5511 -838 49

H(13N) 2780(20) 5070(20) 764(9) 40(4)

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272


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C(6)-C(1)-C(2)-C(3) 6.23(18)

C(1)-C(2)-C(3)-O(12) -176.07(12)

C(1)-C(2)-C(3)-C(4) 8.35(17)

O(12)-C(3)-C(4)-O(11) -64.99(14)

C(2)-C(3)-C(4)-O(11) 110.64(11)

O(12)-C(3)-C(4)-C(5) -178.42(11)

C(2)-C(3)-C(4)-C(5) -2.79(15)

O(11)-C(4)-C(5)-C(9) -22.36(10)

C(3)-C(4)-C(5)-C(9) 92.58(11)

O(11)-C(4)-C(5)-C(6) -131.31(10)

C(3)-C(4)-C(5)-C(6) -16.37(15)

C(2)-C(1)-C(6)-N(13) 102.91(12)

C(2)-C(1)-C(6)-C(5) -23.50(15)

C(2)-C(1)-C(6)-C(7) -137.03(11)

C(9)-C(5)-C(6)-N(13) 157.55(9)

C(4)-C(5)-C(6)-N(13) -94.01(12)

C(9)-C(5)-C(6)-C(1) -80.20(10)

C(4)-C(5)-C(6)-C(1) 28.24(14)

C(9)-C(5)-C(6)-C(7) 39.22(10)

C(4)-C(5)-C(6)-C(7) 147.65(10)

N(13)-C(6)-C(7)-C(8) -159.61(9)

C(1)-C(6)-C(7)-C(8) 81.40(11)

C(5)-C(6)-C(7)-C(8) -37.44(11)

C(6)-C(7)-C(8)-C(9) 19.32(12)

C(7)-C(8)-C(9)-N(10) -158.72(13)

C(7)-C(8)-C(9)-C(5) 6.46(13)

C(4)-C(5)-C(9)-N(10) 13.30(13)

C(6)-C(5)-C(9)-N(10) 138.18(11)

C(4)-C(5)-C(9)-C(8) -154.18(10)

C(6)-C(5)-C(9)-C(8) -29.31(12)

C(8)-C(9)-N(10)-O(11) 167.17(12)

C(5)-C(9)-N(10)-O(11) 2.43(14)

O(14)-C(15)-N(13)-C(6) -8.92(17)

C(16)-C(15)-N(13)-C(6) 170.69(10)

C(1)-C(6)-N(13)-C(15) -70.52(13)

C(5)-C(6)-N(13)-C(15) 53.59(14)

C(7)-C(6)-N(13)-C(15) 167.86(10)

C(9)-N(10)-O(11)-C(4) -18.10(12)

C(5)-C(4)-O(11)-N(10) 25.77(11)

C(3)-C(4)-O(11)-N(10) -95.20(10)

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273

Hydrogen Bonds


H...A --------------------------------------------------------------------

------------

N(13) --H(13N) ..O(12) [ 1545.01] 0.851(15) 2.077(15) 2.9166(13)

169.0(15)


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[ 1545. ] = x,-1+y,z

development of oxidative methodologies and application toward

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