furanoside rhee

Part I. SYNTHESIS OF N-HETEROCYCLIC FURANOSIDES AND PYRANOSIDES

VIA 5- or 6-Exo-TRIG-RADICAL CYCLIZATIONS

Part II. (a) PALLADIUM CATALYZED SILYSTANNYLATIVE CYCLIZATION OF

DIYNES AND ALLENYNES

(b) REGIOSELECTIVE DIELS-ALDER REACTION OF VINYLSILANE AND

ITS APPLICATION TO PAPULACANDIN D CORE STRUCTURE

DISSERTATION

Presented in Partial Fullfilment of the Requirement for

the Degree Doctor of Philosophy in the Graduate School of

The Ohio State University

By

Jong Uk Rhee, M.Sc.

*****


2004

Dissertation Committee:

Professor T. V. RajanBabu Adviser Approved by

Professor Gideon Fraenkel

Professor Jon Parquette _________________________

Adviser

Department of Chemistry

ii

ABSTRACT

Part One: The Barton-McCombie reaction has been widely acknowledged for the efficient deoxygenation

of 2o alcohols through radical process. For the chain process, the radical source initially generated by the

catalytic amount of AIBN attacks the thiocarbnyl sulfur to produce a radical intermediate that is cleaved at

the β-position to give alkyl radicals. Although the sp3 carbon centered radicals have been used commonly

as a precursor of 6-exo-trig ring closure, the radical intermediate in the thiourethane-mediated

deoxygenation of alcohol has never been considered as a precursor of radical cyclization. However, the

radical intermediate can participate in an exo-hex-5-enyl or exo-hept-6-enyl type intramolecular cyclization

when suitable radical acceptors are appropriately placed. Moreover, structurally rare examples of N-

furanosides and N-pyranosides have been synthesized efficiently from carbohydrate-derived imidazoyl and

triazoyl thioates by utilizing the new Barton’s radical-mediated methodology. Depending on the radical

acceptors, glycosides with either C2-carbon or C2-amino substituents are formed. The C2 stereogenic center

of the N-pyranosides formed via exo-hept-6-enyl type radical cyclization can also be controlled by the

stereochemistry of the radical acceptor. While (E)-olefin acceptors make allo/altro mixture, (Z)-olefin

acceptors give stereoselectively altro-isomers.

Part Two: Palladium catalyzed tandem bifunctionalization/cyclization of enynes, diynes, bis(allenes),

alleneynes, allene aldehydes, and allene ketones with R3Sn-SiR’3 is a useful tactic for the synthesis of

synthetically interesting heterocyclic and/or carbocyclic compounds. Although the reaction has a broad

tolerance to functional groups, operationally simple procedure, and high catalytic turnover and

regioselcetivity, the applications of the silylstannylated carbocyclization to further transformation are rare.

The palladium catalyzed silylstannylation/cyclization of 1, 6-diynes gives two atropisomeric isomers with

axial chirality. The silylstannyl dienes themselves do not take part in Diels-Alder reactions, but the

iii

removal of Sn has been achieved efficiently under acidic condition and the resulting silyldienes have

restored this reactivity. In this study a number of fused carbocyclic or heterocyclic compounds were made

by the Diels-Alder reaction and the regioselectivity was controlled by steric effects. This regioselective

Diels-Alder route has been used for the synthesis of an intermediate for a Papulacandin D core synthesis.

Asymmetric version of silylstannylation/carbocyclization of alleneynes has been screened with a various

chiral phosphine ligands.

iv

Dedicated to the late Distinguished Professor Glen A. Russell,

who was past from being an excellent chemist and also a great human being.

He is my eternal mentor.

v

ACKNOWLEDGMENTS

I do not know how I can express my gratitude to my advisor Dr. RajanBabu. He did willingly take

care of me when I was at the most difficult time, and has continually supported me to continue my graduate

studies at the Ohio State University. I understand that if he had not welcomed me as one of his students, I

would not be here right now. He also spent a lot of time to improve not only the quality of my dissertation

but also my poor English. His suggestions were really essential for the current shape of this dissertation.

I also have to thank to Professors Jon Parquette and Gideon Fraenkel, who are my degree program

committee members. The first chapter of this research was initiated by Dr. Brian Bliss, and his Ph. D.

dissertation was the most important source for my research. I am also deeply indebted to the former and

present members of Prof. RajanBabu’s group. Dr. Seunghoon Shin always gave me keen criticisms in

chemistry as well as in my personal life, and Dr. Mei-huey Lin has shown me her endless kindness and help

in the lab. I know I had to have much more difficult time without them. I would also like to thank to

Sandeep Apte, who has exchanged his thoughts with me and listened seriously my opinion. Drs.

Kumareswaran, Zhang, and Saha in the group gave me lots of inspiration in chemistry. I am really lucky to

have known these nice people at OSU. Prof. Woonphil Baik, Dr. Hyun Joo Lee, and the member of Prof.

Baik’s group are the people I have to express my appreciation for their continued support and

encouragement since my undergraduate days at Myong Ji University. I also have to thanks to Dr. Jeong-

Seok Han. For the last five years, I have started my lab work with his hello in the morning, refreshed by

the small coffee break with him, and shared my thoughts as well as the life outside the laboratory. Finally,

I would like to acknowledge to the Myong Ji Univeristy Alumni Association for the Fellowship.

Most of all, I thank to my parents for their love and sacrifice, which made this dissertation

possible.

vi

VITA

May 15, 1968 Born, Iri-Shi, Republic of Korea

February 1994, B.S. Chemistry, Myong Ji University

February 1996, M.S. Chemistry, Myong Ji University

August 1998, M.S. Chemistry, Iowa Sate University

March 1994 - February 1996 Research Assistant


Myong Ji University

April 1996 - August 1997 Visiting Scientist


Iowa State University

August 1997 – May 1998 Research Assistant


Iowa State University

May 1998 – present Teaching and Research Assistant



PUBLICATIONS

1. “Stereochemical control in radical cyclization route to N-glycoside: Role of protecting group and of

the configuration (E versus Z) of the acceptor”, Rhee, J. U.; Bliss, B. I.; RajanBabu, T. V.

Tetrahedron: Asymmetry, 2003, 13, 2939.

vii

2. “A New Reaction Manifold For the Barton Rdical Intermediates. Synthesis of N-Heterocyclic

furanosides and pyranosides via the Formation of the C1-C2 Bond”, Rhee, J. U.; Bliss, B. I.;

RajanBabu, T. V. J. Am. Chem. Soc., 2003, 125, 1492.

3. “A Facile Preparation of Dialkyl Phosphonate Compounds from Steric Hindered p-Nitrocumyl

Halides through the SRN1 Mechanism”, Rhee, J. U.; Russell, G. A.; Baik, W. Tetrahedron Lett. 1998,

39, 8601.

4. “Reaction of p -Nitrobenzyl Halides with Dialkyl Phosphite Anions in Dimethyl Sulfoxide”, Russell,

G. A.; Rhee, J. U.; Baik, W. Heteroatom Chemistry 1998, 9, 201.

5. “Microbial Deoxygenation of N-Oxides with Bakers' Yeast-NaOH”, Baik, W.; Kim, D. I.; Koo, S.;

Rhee, J. U.; Shin, S. H.; Kim, B. H. Tetrahedron Lett. 1998, 38, 845.

6. “DMSO-Ac2O Promoted Nitration of Isoquinolines. One-Step Synthesis of 1-Nitroisoquinolines under

Mild Conditions”, Baik, W.; Yun, S.; Rhee, J. U.; Russell, G. A. J. Chem. Soc., Perkin Trans 1 1996,

1777.

7. “Oxidative Additon of Aryloxide Ions with Electron-Deficient Olefins”, Baik, W.; Min, B.; Choi, H.;

Rhee, J. U. J. of Nat. Sci. 1996, 13, 62.

8. “Selective Reduction of Aromatic Nitroso Compounds with Bakers' Yeast under Neutral Conditions”,

Baik, W.; Rhee, J. U.; Lee, S. H.; Lee, N. H.; Kim, B. H.; Kim, K. S. Tetrahedron Lett. 1995, 36, 2793.

FIELDS OF STUDY

Major Field: Chemistry

viii

TABLE OF CONTENTS

Page

Abstract ii

Dedication iv

Acknowledgments v

Vita vi

List of Tables xi

List of Schemes xiii

List of Figures xvi

List of Abbreviations xviii

Chapters:

1. Synthesis of N-Furanosides and N-Pyranosides from Carbohydrates via 5- or 6-exo Trig Radical

Cyclization 1

1. 1. Introduction 1

1. 1. 1. The Mechanism of Barton-McCombie Deoxygenation 2

1. 1. 2. Applications of the Barton-McCombie Reaction 4

1. 2. 1. 1. The Intramolecular Cyclization by Barton’s Radical 4

1. 2. 1. 2. The 5- and 6-Exo-trig Intramolecular Cyclization of Alkyl Radicals 12

1. 2. 1. 3. The 5- exo-dig Intramolecular Cyclization of Alkyl Radicals 18

1. 2. 1. 4. The Intermolecular Radical Addition of Alkyl Radicals 20

1. 2. 1. 5. The Miscellaneous Reactions 24

1. 2. 1. 6. The Formation of N-Glycoside via 6-exo-trig Cyclization 27

ix

1. 2. Synthesis of Substrates for Radical Cyclization 31

1. 2. 1. Preparation of Precursors for 6-Exo Trig Radical Cyclization 31

1. 2. 2. Preparation of Precursors for 5-Exo Trig Radical Cyclization 52

1. 2. 3. 1,4-Migration of a tert-Butyldimethylsilyl (TBS) group: An Expeditious of

Synthesis of Substrates 61

1. 2. 4. Preparation of Precursor for 5-Exo Trig Radical Cyclization from D-Glucose 67

1. 3. Radical Cyclizations of Thiocarbamates and Thiocarbonate Precursors 75

1. 3. 1. The Early Study of 6-Exo-trig Radical Cyclization 75

1. 3. 2. The Optimum Conditions for 6-exo-trig Radical Cyclization Mediated

by the Barton’s Radical 76

1. 3. 3. The Rationalization of the Stereochemistry for 6-exo-trig Radical Cyclization

by the Barton’s Radical 82

1. 3. 4. 6-Exo-trig Radical Cyclization of Substrates Derived from D-Ribose 94

1. 3. 5. The Role of Protecting Groups in 6-Exo-trig Radical Cyclization 101

1. 3. 6. 6-Exo trig Radical Cyclization of Unactivated Olefins 108

1. 3. 7. Other N-Heterocyclic Glycosides via 6-Exo trig Radical Cyclization 111

1. 3. 8. Synthesis of N-Furanosides via 5-Exo-trig Radical Cyclizations 116

1. 3. 9. Stereochemical Control in 5-Exo trig Radical Cyclizaiton 124

1. 3.10. Radical Reaction with Tris(trimethylsilyl)silane (TTMSH) 134

1. 3.11. Conclusion 139

2. Palladium Catalyzed Silylstannylative Cyclization of Diynes/Allenynes and Regioselecive

Diels-Alder Reaction of Vinylsilanes 141


2. 2. Asymmetric Silylstannylation of Alleneyne 157

2. 3. Bromination of Silylstannanes 162

2. 4. Palladium Catalyzed Carobocyclization of Bis(allenes) 164

2. 5. Palladium Catalyzed carobocyclization of 1, 6-Diynes 165

2. 6. Destannylation of Csp2-Stannanes 167

2. 7. Optimization of Regioselective Diels-Alder Reaction of Vinylsilanes 169

2. 8. Regioselective Diels-Alder Reaction of Vinylsilanes with Various Dienophines 174

2. 9. Conclusion 187

3. Palladium Catalyzed Silylstannylative Cyclization of Diynes and Attempted Synthesis of

Papulacandin D Core Structure 188

x


3. 2. Retrosynthesis of Papulacandin D and Preparation of Diynes 199

3. 3. Palladium Catalyzed Silastannylation of Diynes 202

3. 4. Nickel and Rhodium Catalyzed Silastannylation of Diynes 213

3. 5. Dynamic NMR Studies of Silastanylated 1,3-Dienes, 3-93 and 3-94 216

3. 6. Bromination and Destannylation of Silylstannylated D-gluconosubstituted

(Z,Z)-1,3-Dienes 227

3. 7. Exploratory Studies on Desilylation of the Vinylsilanes 230

3. 8. Diels-Alder Reaction of Vinylsilanes 231

3. 9. Conclusion 240

4. Experimental Section 241

4. 1. General Procedures 241

4. 2. Preparation of Common Reagents 242

4. 3. Preparation of Substrates 251

4. 4. 6-Exo-trig Radical Cyclization 349

4. 5. 5-Exo-trig Radical Cyclization 382

4. 6. 5-Exo-trig radical cyclization by EPHP as a radical source 387

4. 7. Stereochemical Control in 5-Exo trig Radical Cyclizaiton 387

4. 8. Radical Reaction with Tris(trimethylsilyl)silane (TTMSH) 399

4. 9. Palladium Catalyzed Silylstannylation 405

4. 10. Diels-Alder Reaction of Vinyl silanes 413

4. 11. Attempted Synthesis of Papulacandin D Core Structure 431

Bibliography 454

xi

LIST OF TABLES

Table Page

1. 1. The 1,4-TBS Group Migration in a Variety of Conditions 63

1. 2. The Effect of Triphenylphosphineoxide in TBS Migration 65

1. 3. The 1,4-TBS Group Migration with a Variety of Olefins 66

1. 4. 6-Exo trig Ring Closure of 1-196 80

1. 5. 6-Exo trig Radical Ring Closure of 1-208 85

1. 6. Selected Chemical Shifts and Coupling Constants of N-Pyranoside 90

1. 7. 6-Exo trig Radical Ring Closure of Substrate 1-235 92





1. 12. The Chemical Shift and Coupling Constants of the Anomeric Hydrogen of 1-254 101


1. 14. The Chemical Shift and Coupling Constants of the Anomeric Hydrogen of 1-256 103




1. 18. 6-Exo trig Radical Ring Closure of 1-272 and 1-273 111

1. 19. The Chemical Shift and Coupling Constant for β-altro-1-275 114



1. 22. Selected Chemical Shifts and Coupling Constants of N-Furanoside 1-282 121


1. 24. 6-Exo trig Radical Cyclization with 5(R)-Hydroxy-2(R)-phenyl-[1, 3]dioxane-

4(R)-carbaldehyde Derivatives 126

1. 25. A Variety of 5-Exo trig Radical Cyclization with 5(R)-Hydroxy-2(R)-phenyl-

[1, 3]dioxane-4(R)-carbaldehyde Derivatives 132

1. 26. Radical Reaction with TTMSH 136

xii

2. 1. Preliminary Results for the Asymmetric Silystannylation of Alleneynes 160

2. 2. Bromination of Vinyl Stannylsilane 2-42 by NBS in Dichloromethane 164

2. 3. Tandem Carbocyclization/Silastannylation of Bis(allenes) 166

2. 4. Tandem Carbocyclization/Silastannylation of 1,6-Dynes 167

2. 5. Destannylation of Silastannylaed 1,3-Dienes 169

2. 6. Diels-Alder Reaction of Vinylsilane 2-67 173



2. 9. Diels-Alder Reaction of Vinylsilane 2-68 with Various Dienophiles 184

2. 10. Diels-Alder Reaction of Vinylsilane 2-75 with Various Dienophiles 187

3. 1. The summary of Cyclization with a Variety of Pd (0) and Pd (II) 208

3. 2. The Summary of Cyclization with a Variety of Phosphine Ligands 210

3. 3. The Summary of the Reaction with 3-95 and Pd(II) 214

3. 4. The Summary of Cyclization with a Variety of Metal Catalysts 216

3. 5. Bromination of Silastannylated Adducts 3-93, 3-97, and 3-98 229

3. 6. Destannylation of Silastannylated Adducts 3-93, 3-94, 3-97, and 3-98 230

3. 7. Diels-Alder Reaction of 3-113 with Various Dienophiles 235

3. 8. Diels-Alder Reaction of 3-114 with Nitroethene 236

xiii

LIST OF SCHEMES

Scheme Page

1. 1. The Mechanism of Barton-McCombie Deoxygenation 3

1. 2. The Mechanism for Inefficient β-Cleavage of the Barton’s Radical 3

1. 3. The Alternative Mechanism for Deoxygenation, SH2 Mechanism 4

1. 4. The Mechanism for the Formation of Thiolactone and Phenyl Migration 7

1. 5. The Mechanism of Phenyl Migration in the Barton’s Radical in a Tricyclic Ring 9

1. 6. The Mechanism for the Fukuyama Indole Synthesis 10

1. 7. The Mechanism for Thiocarbamate (Y = O), Thioamide (Y = CR2),

and Thiourea (Y = NR2) Cyclization 11

1. 8. The Intramolecular Carboxylation Approach to Podophyllootoxine 12

1. 9. Stereospecific Construction of Spirocyclic Ring by Intramolecular Radical Cyclization 20

1. 10. The Possible Pathways for Radical Addition to Alkenes 23

1. 11. The Mechanism for the Imidoyl Radical Mediated Cyclization 26

1. 12. Mechanism for the Formation of Pyran Ring System via 6-Exo-trig Ring Closing

Mediated by the Barton’s Radical 28

1. 13. Proposed Routes for the Formation of N-Glycosides 30

1. 14 . Synthetic Routes to Prepare Substrates 1-80 31

1. 15. Synthetic Route to Prepare Substrates 1-82 32






1. 21. Failed Attempts to Prepare Thiocarbmate of Hydrazone Derivatives 36

1. 22. Proposed Mechanism for the Formation of 1-95 37

1. 23. The Synthesis of Diphenylhydrazone Derivatives 38

1. 24. Thiocarbamation of 1-79 39

1. 25. Failed Attempts to Prepare Hydrazone Substrates 40

1. 26. Failed Attempts to Prepare Thiocarbamate I 40

xiv

1. 27. Failed Attempts to Prepare Thiocarbamate II 41

1. 28. Failed Attempts to Prepare Thiocarbamate III 42

1. 29. The Mechanism of the Formation of 1-106 43

1. 30. Failed Attempts for Thiocarbonates 43

1. 31. Thiocarbamation of Unactivated Olefin 1-109 44

1. 32. Thiocarbamation of 2-81 with 1,1’-Thiocarbonylditriazole 45

1. 33. Preparation of Benzimidazole Derivative 1-111 46

1. 34. Alternative Preparation of Benzimidazole Derivative 1-111 47

1. 35. Preparation of Indole Derivatives 47

1. 36. Failed Attempts to Prepare Adenines 48

1. 37. Preparation of Triazole Derivative from 1-89 49

1. 38. Preparation of Benzimidazole Derivatives 50

1. 39. Synthetic Route to Prepare Substrates 50


1. 41. Synthesis of 6-Exo trig Radical Precursor 1-133 from Maltose Monohydrate 52

1. 42. Synthesis 1-138 from γ-Lactone 53

1. 43. Synthesis of 5-Exo trig Radical Precursor 1-138 from Maltose Monohydrate 53

1. 44. Failed Attempts to Prepare Radical Reaction Precursor from 1-138 54

1. 45. Reaction of 1-139 with Phenylmagnesium Bromide 55

1. 46. Preparation of Nitrile, Oxime, and Hydrazone Substituted Olefins 55

1. 47. TBS Group Migration in MeOH 56

1. 48. Preparation of Thiocarbamates 57

1. 49. Failed Attepts to Prepare N, N’-Diphenyl hydrazone Derivative 58

1. 50. Deprotection of a TBS Goup of Thiocarbamate Derivatives 58

1. 51. Proposed 5-Exo trig Process for the Formation of Pyrolidines 59

1. 52. Failed pathway to prepare thiocarbamate 1-158 60

1. 53. Mechanism of TBS Group Migration 61

1. 54. The Synthesis of 5(R)-hydroxy-2(R)-phenyl-[1, 3]dioxane-4(R)-carbaldehyde 67

1. 55. Synthesis of α,β-Unsaturated Ester and Its Thiocarbamate Derivatives 69

1. 56. Synthesis of Hydrazone and Oxime and Its Thiocarbamate Derivatives 72

1. 57. Synthesis of Hydrazones and Its Thiocarbamate Derivatives 74

1. 58. The Mechanism of 6-Exo-trig Radical Cyclization of Substrate 1-196 78

1. 59. The Stereoselctivity of allo/altro Conformation by 6-Exo-trig Radical Cyclization 88

1. 60. Rationalization of the Distribution of Products 89

1. 61. Rationalization of Stereoselectivity of 1-235; allo and altro Conformations 93

1. 62. Rationalization of the Distribution of Products from 1-250 106

xv

1. 63. Proposed pathway to β-D-altropyranosyl 1H-benzimidazole 1-277 and

D-ribo-hex-1-enopyranosyl 1H-benzimidazole 1-278 116

1. 64. The Mechanism for the Formation of N-Furanoside via 5-Exo-trig Radical Cyclization 121

1. 65. Rationalization of Diastereomers for 1-282 via 5-Exo trig Radical Cyclization 122

1. 66. The Rationalization of the Stereochemistry for the Radical Cyclization of 3-107 123

1. 67. Origin of Stereoselectivity at C2 of the N-Furanoside 129

1. 68. Propsed Mechansim for Radical Mediated 1,3-Migration of Oxime Derivative 1-196 137

2. 1. Postulated Mechanism for the Pd-Catalyzed Sn-Si Bifunctionalization 142

2. 2. The Mechanism for Tinsilanylation of Allenes 152

2. 3. Formation of a Chiral (Z, Z)-1,3-Diene from a Diyne 153

2. 4. Silylstannylation/Cyclization of Allenyne 155

2. 5. Possible Mechanism of Silylstannylation/Cyclizaiton of Allenynes 156

3. 1. Total Synthesis of Papulacandin D 199

3. 2. Retrosynthesis of Papulacandin D 200

3. 3. Preparation of Diyne 3-82 202

3. 4. Failed Desilanation of Vinylsilanes 3-114 and 3-115 232

3. 5. Application of Silyl-Stannane Adducts for Synthesis of

the Core Structure of Papulacandin D 233

3. 6. Failed Attempts to oxidize 3-126 and 3-127 238

3. 7. Explore of Palladium Catalyzed Tandem Cyclization-[2+4] Reaction 240

xvi

LIST OF FIGURES

Figure Page

1. 1. Chair-like Transition States in 5-Hexenyl Radical Cyclization 15

1. 2. Rationalization of Stereochemistry of D-Glucopyranose Derivatives;

Chair-like/Boat-like Transition States 16

1. 3. Rationalization of Cis Selectivity of 5-Hexyl Radicals 17

1. 4. The Rationalization of the Stereochemistry of Tandem Radical Cyclization

under Barton’s Deoxyzanation Conditions 27

1. 5. Rationalization of the Stereochemistry of 3-5 by Chair Conformation 82

1. 6. nOe Experiment of altro 1-197 83

1. 7. Origin of the altro-Selectivity in the (Z)-Acceptors 86

1. 8. Anomeric Stabilization in Pyranosyl Radicals 87

1. 9. The Representative Results of nOe for 1-203 96

1. 1. Substrates for 6-Exo trig Radical Cyclization 98

1. 11. Products for 6-Exo trig Radical Cyclization. 98



1. 14. The Representative Results of nOe for 1-274-β 112

1. 15. The Representative Results for nOe of 1-274-α 113

1. 16. The Representative Results for nOe of β-altro-1-275 114

1. 17. Representative Results for nOe of 1-286-α 127

1. 18. Representative Results for nOe of 1-286-β 128

1. 19. Representative Substrates for 5-exo-trig Radical Cyclization 131

1. 20. Representative Products for 5-exo-trig Radical Cyclization 131

1. 21. Substrates and Products for the Radical Reaction with TTMSH 135

1. 22. The Representative results for nOe of syn-1-310 138

1. 23. The Representative Results for nOe of anti-1-310 138

2. 1. Phosphine Ligands and Chemical Shift Reagents Used in Silylstannylation Stidies 159

2. 2. Structures of 2-89 and 2-90 172

xvii

2. 3. Representative nOe Results for 2-89 176




2. 7. Representative Products of Diels-Alder Reaction (Eq. 36) 183



3. 1. Structure of Paulacandin A-D and Saricandin 190



3. 4. Tentative Configuration of Dimeric Product 3-95 and 3-99 206



3. 7. Tentative Configuration of Dimeric Product 3-100 and 3-101 215

3. 8. Coalescence Temperature for Enantiomerization of Various Silystanyl Dienes 217

3. 9. Possible Isomers of Glucosides 3-93, 3-94, 3-97, and 3-98 218

3. 10. Various Temperature NMR Spectrum I of 3-93 220

3. 11. Various Temperature NMR Spectrum II of 3-93 221







3. 18. Representative nOe Results for 3-114 and 3-115 231

xviii

LIST OF ABBREVIATIONS

[α] specific rotation

AIBN 2,2’-azobisisobutyronitrile

BINAP 2,2’-bis(diphenylphosphino)-1,1’-binaphthyl

Bn benzyl

Boc tert-butyloxycarbonyl

Bp boiling point

Br broad (spectral)

Bu butyl

t-Bu tert-butyl oC degree celsius

CAN ceric ammonium nitrate

calcd calculated

COSY correlation spectroscopy

CSA 10-camphorsulfonic acid

δ chemical shift in parts per million downfield from tetramethylsilane

d day(s); doublet (spectral)

DABCO 1,4-diazabicyclo[2.2.2]octane

DBU 1,8-diazabicyclo[5.4.0]udec-7-ene

DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone

DEAD diethyl azocarboxylate

Dibal-H diisobutylaluminium hydride

DMAP 4-dimethylaminopyridine

DMDO dimethyl dioxirane

DME 1,2-dimethoxyethane

DMF N,N-dimethylformamide

ee enantiomeric excess

EI electron impact (in mass spectrometry)

EPHP ethylpiperidine hypophosphite

EPR electron paramagnetic resonance

xix

EWG electron withdrawing group

equiv. equivalent(s)

FAB fast atom bombardment (in mass spectrometry)

FID flame ionization detector

FT fourier transfer

g gram(s)

GC gas chromatography

h hour(s)

HRMS high-resolution mass spectrum

Hz hertz

Im imidazole

IR infrared spectroscopy

J coupling constant (in NMR)

L liter(s)

µ micro

m multiplet (spectral)

M moles per liter

mCPBA meta-chloroperoxybenzoic acid

Me methyl

min minute(s)

mM milimoles per liter

mol mole(s)

Mp melting point

MS molecular sieves

Ms methanesulfonyl (mesyl)

m/z mass to charge ratio (in mass spectrometry)

NBS N-bromosuccinimide

NMR nuclear magnetic resonance

NOE nuclear Overhauser effect

NOESY nuclear Overhauser effect spectroscopy

Ph phenyl

PMB 4-methoxybenzyl

Ppm part per million (in NMR)

PPTS pyridinium p-toluenesulfonate

Prep TLC preparative thin layer chromatography

pyr pyridine

xx

q quartet (spectral)

Rf retention factor (in chromatography)

rt room temperature

s singlet (spectral)

TAS tris-dimethylamminosulfonium

TBAF tetra-n-butylammonium fluoride

TBDPS tert-butyldimethylsilyl

TBS tert-butyldimethylsilyl

TLC thin layer chromatography

THF tetrahydrofuran

Ts 4-toluenesulfonyl (tosyl)

TTMSH tris(trimethylsilyl)silane

1

CHAPTER 1

SYNTHESIS OF N-FURANOSIDES AND N-PYRANOSIDES FROM

CARBOHYDRATES VIA 5- OR 6-EXO-TRIG RADICAL CYCLIZATIONS

1. 1. Introduction

Chemoselective deoxygenation of 1o and/or 2 o hydroxyl groups has been extensively studied

during the last few decades, and the importance of the transformation has been increasing in the organic

syntheses, particularly in total synthesis of natural products and carbohydrate chemistry. 1 One of the most

conventional strategies for the deoxygenation is the reduction of suitable alcohol derivatives such as

tosylate, mesylate, and sulphate.2 Another important strategy for the transformation is the nucleophilic

replacement of the hydroxyl group by halogen or thiolate with subsequent reductive dehalogenation3 or

desulfurization. 4 Although those strategies proved to be very efficient methodologies for the

deoxygenation of simple, sterically unhindered alcohols, they have instinctively ionic nature, which causes

difficulties in application to complex, sterically hindered hydroxyl groups and rearrangement and/or

elimination reactions intervene. Fortunately, the drawback of ionic type reaction could be overcome by

radicals as the intermediates in the reaction because radicals are much less susceptible to these

complications. Moreover, the neutral reaction conditions in radical reactions are ideally suited for the total

synthesis of complex natural products with poly functional groups. The radical mediated deoxygenation

involves three distinctive steps: (a) conversion of a suitable alcohol derivative to a radical intermediate, (b)

fragmentation of a C-O bond by β-cleavage into an alkyl radical, (c) reaction with a hydrogen donor to

afford the corresponding hydrocarbons. Especially, the initial step, the conversion of alcohol derivatives to

radical intermediates, can be categorized into three sub-groups based on the way of the formation of a

radical intermediate: (a) addition of radical source to CO or heterocarbonyl group, (b) electron transfer to

2

activated double bond with formation of radical, (c) photolytic excitation of a π system forming the triplet

state.

The deoxygenation of an alcohol via a thiocarbonyl derivatives is the most widely used

methodology in the first category, and it is generally known as the Barton-McCombie reaction.1 The utility

of Barton’s deoxygenation has been increasing since its first report in 19755 because of the mild conditions,

efficiency, convenience, selectivity, and high conversion yield. Moreover, this reaction is one of the best

ways to remove sterically hindered hydroxyl groups,6, 7 which cannot be deoxygenated by traditional SN2

type reactions. Another advantage of the Barton’s radical mediated deoxygenation is that there is no

rearrangement of the products,1b which are commonly found with cationic or anionic deoxygenations. For

the mild and efficient deoxygenation, the desired hydroxyl group has to be first converted to

thiocarbamates,8 thiocarbonates,9 thiobenzoates,10 or xanthates.11 Tributyltin hydride,7 triphenyltin

hydride,12 tirs-(trimethylsilyl)silane,13a,b triphenylsilane,13b triethylsilane,13c tetraphenyldisilane,14

hypophosphorous acid,15a or the corresponding 1-ethylpiperidinium salt15b are used as hydrogen sources.

1. 1. 1. The Mechanism of Barton-McCombie Deoxygenation

Scheme 1.1 shows the general mechanism of Barton-McCombie deoxygenation. 5,16 For the chain

reaction, radical source is initially generated by the catalytic amount of AIBN, attacks the thiocarbonyl

sulfur to produce a radical intermediate 1-2 (the Barton’s radical), which is cleaved at the β position to give

a thiocarbonate 1-3 and an alkyl radical 1-4. The alkyl radical 1-4 abstract a hydrogen from the radical

sources to give an alkane 1-7 and a tributyl stannyl radical, which is used for the radical chain process. The

Barton’s deoxygentation mechanism is supported by observing the key intermediate 1-2 in the EPR

spectrum.13 Absence of a carbonyl group in the IR spectrum of crude reaction mixture may imply the

intermediate 1-3 is unstable and dissociates immediately to 1-5 and 1-6. 16b Although the deoxygenation

mechanism for secondary alcohols is well established by Barton, the β-cleavage of 1-2 dependant on

substituent X (Scheme 1.2).11b

3

X C OR

SX C O

S SnBu3

R

InH

X C S

O

SnBu3

C OS RH

nBu3SnH+ nBu3Sn+

nBu3Sn + +

+

Initiation

Propagation

nBu3SnXX = SMe, SPh, Imidazole, Ph, OPh,

1-1 1-2 1-3 1-4

1-61-5 1-7

nBu3SnH

nBu3Sn+

CN

N N

CN CN

2

CN

R

Scheme 1.1. The Mechanism of Barton-McCombie Deoxygenation.

When the X is H or CH3, inefficient fragmentation of the key intermediate 1-2 (the Barton’s

radical) results in this radical being trapped by excess tributyltin hydride. Unfortunately, the trapped

orthoester 1-10 is not observable under the standard condition because it can decompose easily to 1-9,

which can be isolated or further reduced to 1-12. The tin containing hemithioacetal 1-12 can be converted

to hemithioacetal 1-13, which is subjected to hydrolysis to ROH 1-14 during the workup and/or column

chromatography.

O XR

SSnBu3 Bu3SnH

O X

SSnBu3

HR O H

S

R

Bu3SnHO SSnBu3R

H2O

1-10 1-11 1-121-2X = H and CH3

-Bu3SnX

ROCH2SH and/or ROH

1-141-13

Scheme1.2. The Mechanism for Inefficient β-Cleavage of the Barton’s Radical.

4

An alternate mechanism, (SH2 mechanism), for xanthate decomposition has been proposed by

Baker and Beckwith (Scheme 1.3).17 The alkoxythio radicals 1-9 generated by the SH2 mechanism

undergoes β-cleavage to give a carbonyl sulphide 1-6 and an alkyl radical 1-4. Hydrogen atom transfer

from tributyltin hydride is the last step to complete the chain mechanism via SH2 process. This alternative

mechanism is supported by the observation of key intermediate 1-9 in EPR spectrum at low temperature.17

S

RO SMe

nBu3SnSMe C

S

OR C OS

RH

nBu3Sn+ + +

nBu3SnH

nBu3Sn+

1-8 1-9 1-6 1-4

1-7

R

Scheme 1.3. The Alternate Mechanism for Deoxygenation, SH2 Mechanism.

1. 1. 2. Applications of the Barton-McCombie Reaction

The Barton-McCombie reaction was originally developed for deoxygenation of secondary

alcohols and its effectiveness for new carbon-carbon bond formation has multiplied during the past few

years. 18 The carbon-carbon bond formation can be divided into five sub-groups19: i) intramolecular

cyclization of the Barton’s radical intermediate20; ii) 5- and 6-exo-trig intramolecular cyclization of alkyl

radicals; iii) 5-exo-dig intramolecular cyclization of alkyl radicals; iv) intermolecular addition of the alkyl

radical generated by β-cleavage; v) miscellaneous reactions such as imidoyl radical formation.

1. 1. 2. 1. The Intramolecular Cyclization by Barton’s Radical

Not until the middle of 1980 was an intramolecular cyclization using the Barton’s radical

intermediate (1-2) reported.21 During the study of a tandem intermolecular-intramolecular annulation,

Clive and his associate found12 an unexpected cyclic compound with or without methyl acrylate via 5-exo-

5

dig radical intramolecular cyclization (Eq. 1). However, because their initial goal was not 5-exo-dig

cyclized product but intermolecular-intramolecular cyclization, they did not further study the Barton’s

radical intermediate as a synthetic tool.

O C N

NS

CC

Ph

Ph3SnH

CO2Me

O

HPh

S

H

with or without (1)

Bachi and Bosch were the first chemists to realize that the Barton’s deoxygenation can be

extended as a synthetic tool for new C-C bond formation and/or lactonization through 5-exo-dig and 5-exo-

trig radical processes. In their first communications,12 benzylthionolactone was made from a

dithiocarbonate through 5-exo-dig process (Eq. 2). However, the reaction could not be stopped after the

cyclization but was further reduced by the excess tributyltin hydride. After hydrolysis during the workup,

the final product was isolated as a benzylthionolactone in a yield of 49%.

O

SMe

Ph

S

Bu3SnH

O

Ph

S

O

Ph

SAIBN

Bu3SnH

(2)

In 1988, however, Oshima reported23 that the same ditihiocarbonate could be cyclized through the

Bachi’s mechanism, but stopped at bezylidene-γ-butyrothionolactone without further reduction if triethyl

borane/oxygen was used as a radical initiator (Eq. 3).

O

SMe

R

S

Bu3SnH

BEt3/O2 O

R

SH3O+

O

R

O

R = Ph, 78%, R = SiMe3, 98%

(3)

6

Because of the hydrolysis of bezylidene-γ-butyrothionolactone during the workup, the isolated

product was not thionolactone but bezylidene-γ-butyrolactone, and the yield was much higher than that

observed by Bachi. The same procedure was applied successfully for furnishing a ring-fused lactone with

an excellent yield (Eq. 4).

O

CSMe

S

CR

Bu3SnH

O

Ph

SH3O+

O

Ph

O

R = Ph, 95%, R = SiMe3, 26%

(4)

The same year, Bachi and an associate extended24 their methodology to make thiolactones and

thionolactones through a 5-exo-trig process and suggested a mechanism involving the homolytic attack of

tributyl tin radical on the thioxo sulfur rather than the thio sulfur (Eq. 5).

S S

O Me

MePh

Bu3SnH

Ph

SO

Ph

SO

+ (5)

In another communication,25 Bachi found an interesting phenyl group migration via

spirohydroaromatic system after intramolecular radical addition on a phenyl substituted double bond, and

three years later he summarized10a the tributylstannane mediated intramolecular radical process of

thionocarboxylic acid derivatives involving intramolecular radical process in a full pape. The detailed

mechaism is shown in Sheme 1.4.

The Barton’s radical 1-9 can be cyclized to give intermediate 1-10 via 5-exo-trig mode. The

intermediate can be further reduced to 1-13 by excess tributyl tinhydride or added to the phenyl ring to lead

to a spirohydroaromatic ring 1-11 via 5-exo intramolecular cyclization. Rearomatization of the benzene

ring and elimination of Bu3SnS. give a diphenylmethyl-γ-lactone 1-12. Reduced intermediate 1-13 is

7

subject to the elimination of Bu3SnOPh to lead thionolactone 1-14, which could be converted to

thionolactone 1-15 during the work-up.

Ph

O

O

S

Ph

O

OPh

Ph

Bu3SnH

O

Ph

O

Ph

O

Ph

SSnBu3

O

O

Ph

O

SSnBu3

Bu3SnH

O

Ph

S

S

Ph

O

O

Ph

O

SSnBu3

-[Bu3SnOPh]Bu3Sn.

o

1-8 1-9 1-10

1-11

1-12

1-13

1-14

1-15

Bu3Sn

SSnBu3

Scheme 1.4. The Mechanism for the Formation of Thiolactone and Phenyl Migration.

While Bachi and other research groups have concentrated on developing new C-C bond formation

mediated by the Barton’s radical intermediate and on studying the mechanistic problems, Yamamto and his

research group demonstrated independently26 a stereo-controlled lactone formation. They used homoallylic

xanthates as a precursor for the radical cyclization and trans product was isolated as the major products

(Eq. 6).

MeS O

Me

Et

S

Bu3SnH

AIBNSSnBu3

Et MeSMe

O

S

Et

Et

cis/trans = 4/96

(6)

8

The stereochemistry may be explained by chair like transition state (Eq. 6). However, ring fused

bicyclic thiolactones gave predominantly cis configuration possibly due to the ring strain of trans fused

thiolactone (Eq. 7 and Eq. 8).

SMe

OS

H

HOTBS

OTBS

MeS O

S

Bu3SnH

AIBN

Bu3SnH

AIBN

O

S

H

HOTBS

OTBS

O

S

cis/trans = 99/1

(7)

(8)

H

During the synthesis of (-)-supinidine from (+)-retronecine and (+)-heliotridine, interesting results

were observed by Zalkow. 27 (+)-Retronecine and (+)-heliotridine are epimers at C-7, and they can be

thiocarbonylated easily by phenoxythiocarbonyl chloride after protecting of the hyoxyl group at C-9. The

(+)-heliotridine thiocarbonyl derivative was successfully deoxygenated in good yield under the standard

Barton-McCombie deoxygenation conditions; 1.5 Equiv. of nBu3SnH and 0.2 Equiv. of AIBN in toluene,

stirring at 75 oC for 3 hours. However, the (+)-retronecine thiocarbonyl derivative gave a 5-exo-trig

cyclized product involving a phenyl group migration (Eq. 9).

N

OHH

N

OR3H

HO

N

OR3HH

Bu3SnH/AIBN Bu3SnH/AIBN

N

OR3H

H H

OOR3

Ph

HN

O

2

R1 = H, R2 = OH (+)-RetronecineR1 = OH, R2= H (+)-Heliotridine

R3 = TBS 48%R3 = COPh 60%

R3 = TBS 66%R3 = COPh 64%

1

35

68

9

(9)

7

R2R1

OPh

S

PhO

S

9

The unexpected product can be explained by the mechanism shown in Scheme 1.5. Because the

radical intermediate of (+)-heliotridine thiocarbonyl derivative has an unfavorable geometry to cyclize the

ring due to the steric hindrance, Barton’s deoxygenation process is more favored than 5-exo-trig radical

cyclization. However, (+)-retronecine thiocarbonyl derivative has an excellent geometry for 5-exo-trig

radical cyalization on si face to afford a cyclized product.

N

OR3H

HO

O

S

N

HO OR3

SSnBu3

O

N

OR3H

HO

O

SSnBu3

N

HO

OOR3

Ph

H

N

HO OR3

SSnBu3

O

-Bu3SnS.

1-16 1-17 1-18

1-19 1-20

Bu3Sn

H H

H

Scheme 1.5. The Mechanism of Phenyl Migration in the Barton’s Radical in a Tricyclic ring.

Bachi and his group developed28 a new synthetic strategy involving a free radical process for the

synthesis of (+_ )-α-kainic acid from either racemic isocyanides or isothiocyanate. In another paper,29 they

reported natural (-)-α-kainic acid by using the Barton’s radical intermediate as the key intermediate (Eq.

10). The Barton’s radical was generated from N-alkenyl thioformamide with nBu3SnH/AIBN through the

Barton’s radical mechanism, and cyclized to give (-)-α-kainic acid as 12% overall yield from the starting

material, tert-butyl isocyanoacetate.

H

O

SEt

NC CO2tBu

+

S

NH

SEt

OTMS

CO2tBu

BOC

AIBN

nBu3SnH

N

BOC

OTMS

N

H

CO2H

(-)-α-kainic acid

(10)CO2

tBu CO2tBu

10

Fukuyama reported in 1999 30 the Barton’s radical intermediate could be used for the synthesis of

another natural product (+_ )-catharanthin (Eq. 11). The key step involves 5-exo-trig radical process of

thiocarbamate to furnish an indole ring, and aqueous hypophosphorous acid was used as the radical source

instead of a traditional radical source such as tributyltin hydride.

OAc Cbz

N

H

NS

CO2Me

H3PO2

AIBN/ Et3N

Cbz

N

OAc

N

CO2MeH

N

N

CO2MeH

(11)

In an earlier study,31 Fukuyama and his associates established a formal indole synthesis by using

the Barton’s radical pathways generated by thioamide derivative with AIBN or Et3B. In their

communication, two possible intermediates were proposed; one involves 5-exo-trig radical process to give

a sp3 carbon-centered intermediate containing a C-SSnBu3 bond, the other involves elimination of

HSSnBu3 to give a imidoyl radical species31b followed 5-exo-trig radical cyclization (Scheme 1.6).

NH

R

R'S

N

R

R'

N

R

SSnBu3

R'

H

-Bu3SSnH

N

R

R'

H

N

R

SSnBu3

R'

H

H

1-21 1-22 1-23

1-24 1-25

Bu3Sn

Scheme 1.6. The Mechanism for the Fukuyama Indole Synthesis.

11

More recently, Curran and Du used α-thioaminoalkyl radicals as synthetic equivalents of imidoyl

radicals and developed a formal synthetic route for carbocyclic and heterocyclic fused quinolines (Scheme

1.7).32 The α-thioaminoalkyl radicals are better synthetic intermediates than imidoyl radicals because they

are more stable. Moreover, the α-thioaminoalkyl radicals can be transformed to fused quinoline derivatives

by subsequent 5-exo-trig radical cyclization/oxidative aromatization.

NX Y

R

S

H

TTMS

NX Y

R

S

H

TMST5-exo

NXH

Y

R

STTMS

1,6

X N Y

R

HS

TTMSX N Y

R

H

[O]

-HSTTMS

1-26 1-27 1-28

1-29 1-30

Scheme 1.7. The Mechanism for Thiocarbamate (Y = O), Thioamide (Y = CR2), and Thiourea (Y = NR2)

Cyclization.

A potent tubulin biding antimitoic agent, podophyllotoxin, was synthesized by Sherburn and his

colleagues in 2003 (Scheme 1.8).33 The core structure of podophyllotoxin, aryl tetrahydronaphthalen-

lactone 1-31, would originate from thionocarbonate 1-32 as a result of intramolecular delivery of the

carbonyl carbon to C-2 and an aromatic residue to C-1. The two new carbon-carbon bond formations were

achieved by utilizing the Baton-McCombie reaction via both 5-exo intramolecular cyclization and phenyl

group migration demonstrated by Bachi.

12

O

OO

O

OMe

OMeMeO

H

H

O

O

OO

O

OMe

OMeMeO

H

H

H

P

O

OO

H

OS

MeOOMe

MeO

P

O

OO

H

OS

MeOOMe

MeO

P

MR3

O

OO

H

H

P

SO

MeO

MeO

OMe

MR3

O

OO

H

H

P

SO

MeO

MeO

OMe

MR3H

O

OO

H

H

P

SO

MeO

MeO

OMe

MR3H

eliminationS MR3

H MR3MR3

addition

elimination5-exo

5-exo

1-31 1-32 1-33

1-37 1-34

1-36 1-35

1

2H

Scheme 1.8. The Intramolecular Carboxylation Approach to Podophyllootoxine.

1. 1. 2. 2. The 5- and 6-Exo-trig Intramolecular Cyclization of Alkyl Radicals

Carbon centered radicals 1-4 generated by β-cleavage of thiocarbonate 1-3 are important

intermediates in the Barton-McCombie deoxygenation (see Scheme 1.1). The newly generated radicals

undergo intramolecular trapping by a variety of radical acceptors as well as hydrogen transfer from

tributyltin hydride. To promote the intramolecular ring closing, it is required to make 5-hexenyl or 6-

13

heptenyl radical by the β-cleavage of the desired bond. There are a number of examples for 5-hexenyl

radicals via the Barton’s deoxygenation mechanism.1 Hart reported 34 the first example in this category in

1982. In the paper, his goal was synthesis of indolizidine, which was required to get a tricyclic lactam with

changing of the configuration at C-4 position. Fortunately, the hydroxyl group of the precursor could be

converted to xanthate in good yield, and the subsequent Barton’s deoxygenation performed to give a 5-

hexenyl radical, which was cyclized to give 2:1 mixture of tricyclic lactams in 74% yield (Eq. 12).

N

O

HHOC

S

MeS

HBu3SnH

AIBN NCH3

O

H

H

H

4 (12)

Another important application of 5-hexenyl radical to furnish tetraquinanes was reported by

Paquette in 1985. 35 Their initial goal was the construction of the ophiobolin ring skeleton by oxy-anionic

[3.3]-sigma tropic approach. He could make the core structure of the ophiobolin involving a hydroxyl

group at C-5. The hydroxyl group could be converted to its xanthate and phosphate ester derivatives,

which were subject to deoxygenation. Unfortunately, the deoxygenation did not proceed, but 5-exo-trig

cyclization resulted to afford tetraquinanes (Eq. 13).

Bu3SnH

∆CH3

O

S

SCH3

CH3

CH3

CH3

Li/tBuOH

CH3O

P

O

(OEt)2

CH3

EtNH2 / 0oC

67% 76%5 5

(13)

Miwa reported36 the synthesis of 1-α-O-methyl-loganin from 2,3-hydro-α-D-lyxopyranoside in

1987. 5-Hexenyl radical was generated from the xanthate derivative of the pyranoside, and

tetrahydroncoumalate skeleton was constructed by 5-exo-trig ring closing (Eq. 14).

14

OO

OCH2Ph

OMe

O

OCH2Ph

OMeO

OBz

Bu3SnH

AIBNO

OCH2Ph

OMe

H

HBzO

OMeH

OHO

HCO2Me

(14)

CH3CH3

MeSC

S

The first 6-heptenyl radicals generated from bicyclo [3.1.1] heptanone by Barton’s deoxygenation

was reported by Snider,37 and β-copaene and β-ylangene were synthesized from the radical intermediates

via 6-exo-trig process (Eq. 15). The cyclization was performed with thiocarbamate derivatives under the

standard conditions, but only 15% of desired product was isolated.

SeO2

tBuOOHBu3SnH

H2C O

H2C H

OR

H2CH2C H

O

S Im

Bu3SnH

R = H, CH2SHCH2

OH

(15)

In the same year, Hanessian synthesized38 5- and 6-membered carbocycles from α,β-unsaturated

esters, which are made easily from the corresponding lactol by the Wittig reaction. Subsequent

thiocarbonylation and the Barton’s deoxygenation gave cyclized product in a good yield (Eq. 16 and 17).

O

CO2Et

C SMe

S Bu3SnH

AIBN

CO2Et

(16)

CO2Me

CH3

O CN

N

S

Bu3SnH

AIBN

CO2Me

Me (17)

15

RajanBabu used 5-hexyl radicals generated form highly functionalized carbohydrates to develop

models to explain the stereochemistry of the radical ring closure using transition state models. 39, 40 The

precursor of 5-hexyl radical was readily prepared from 2,3,4,6-tetra-O-benzyl-D-glucopyranose by the

Wittig reaction followed thioacylation with 1,1-thiocarbodiimidazole. The Barton-McCombie

deoxygenation of the precursor could generate the 5-hexyl radical, which was subjected to 5-exo-trig ring

closure. The stereochemistry of isolated product was determined by observing of acyl migrated product as

well as NOE, 1H, 13C spectra of the cyclized product and chemical correlation. The stereochemistry of the

product may be rationalized by “chair-like” transition state, which lead to a 1,5-cis products (Figure 1.1) as

the major componen. 41 A similar stereochemical outcome was observed with another glucopyranose

derivative with a substituted vinyl ether as the radical acceptor.

X

OBnO

OBnBnO OBn

Im S

Bu3SnH

AIBN

OBn

BnO X

BnO OBnOBn

BnO X

BnO OBn

OBn

BnO X

BnO OBn+ +

X = HX = OMe

X = H (74%)X = OMe (75%)

X = H (12%)X = OMe (2%)

X = H (14%)X = OMe (23%)

(18)

CH2OBn

HH

BnOBnO

BnO

1-38

Figure 1.1. Chair-like Transition States in 5-Hexenyl Radical Cyclization.

16

One of the most significant results from RajanBabu’s study is the stereoselective 1,5-trans product

formation from 4,6-benzylidene-2,3-di-O-benzyl-D-glucopyranose derivatives via the Barton-McCombie

deoxygenation (Eq. 19). The exclusive 1,5-trans product cannot be rationalized by chair-like transition

model,39,40, 41 which was commonly adopted for 5-membered radical ring closing. To understand these

unexpected products, he suggested39, 40, 41, 42, 43 a boat-like transition state (Figure 1.2). Because of the small

difference of energy between “chair-like” transition state and “boat-like” transition states (1kcal/mol),45 the

large substituent at C-4 forces the intermediate to orient predominantly in a boat-like conformation to

reduce the A1,3 strain.

(19)

X

O

OBnOBn

Im S

O

OPh

Bu3SnH

AIBN

OBnOBn

O

OPh

X

X = H, OMe

OOPh H

HH

H

H

OOPh

HH

HH

. 12

3

54 4

12

3

5

1,5-cis 1,5-trans

1-39 1-40

Figure 1.2. Rationalization of Stereochemistry of D-Glucopyranose Derivatives; Chair-like/Boat-like

Transition States.

17

The unusual 1,5-trans stereoselectivty of radical ring closing was used for the synthesis of Corey

lactone,42, 46 which is an important intermediate for the synthesis of prostagladin-like molecules48 from

commonly available 3-deoxy-D-glucopyranose as starting material (Eq. 20).

O

OH

HO

HO

OH O

OBn

Im S

O

OPh

OMe

OBn

O

OPh

OMe

OBn

OMeO

OO

Corey Lactone3-deoxy-D-glucose

(20)

He also investigated44 the stereochemistry in 5-hexenyl radical cyclization by 4-substituted cis and

trans-2-(1-but-3-enyl) cyclohexyl radical generated by the Barton’s deoxygenation. When the substituents

are all in the most favorable position, 1,5-cis product was obtained as the major product via “chair-like”

transition state, in which the radical center in cyclohexane ring system interact from its axial face with the

olefin π* orbital. 1,5-Trans outcomes also can be explained by chair-like transition state with axial

preference of the butenyl group. However, stereoselectivity for the trans compounds is lower than those

for the cis compounds, because the population of the axial bulky group is energetically less favored (Figure

1.3).

R HH

HR HR

Ψ-axialΨ-axial

chair boat

R H

Hchair

H

H R

Ψ-axialΨ-eq

H

H

1-41 1-42 1-43

1-44 1-45

H

Figure 1.3. Rationalization of Cis Selectivity of 5-Hexyl Radicals.

18

1. 1. 2. 3. The 5- Exo-dig Intramolecular Cyclization of Alkyl Radicals

Intramolecular cyclization of cyano or acetylenic radical generated by the Barton’s deoxygenation

has not been studied extensively, but was reported as early as in 1984. 48 Clive and his associates found

secondary alcohols can be converted into cyclic ketones by the Baton’s deoxygenation mechanism via 5- or

6-exo-dig intramolecular ring closing followed oxidative cleavage (for X=C) or by hydrolysis (for X=N)

(Eq. 21 and 22). The same protocol was applied for the synthesis of bicyclic ring, and similar results were

obtained (Eq. 23 and 24).

CO

HPh C5H11 Ph Ph

81%

CO

XR

H

R'

Ph3SnH

AIBN

CO

XR

CS

Im

R'

XR

R'n n n

X = H, CN

(21)

(22)

C

OH

N

OH

PhOH

C N

H

Ph

+

79%

67% 11%

(23)

(24)

The 5-exo-dig radical ring closure is an efficient way to construct a double bond to a fused five-

membered ring. Especially, it is interesting that α-silyated radical mediated ring closure allows the double

bond migration by desilylation, which may construct a cyclic alkene frame. 49 Noyori and his associates

generated the α-silyated radical by either the photolysis of m-(trifluoromethyl)benzoate derivative or the

Barton’s deoxygenation of a xanthate derivative followed ring closure of the radical to give a high yield of

19

a bicyclic product (Eq.25). Desilylation of the bicyclic [3.3.0] octane gave the isocarbacyclin , which has

antihypertensive and platelet aggregation inhibiting properties (Eq. 26).

OR3Si

R'

R''

RH

OR3Si

R'

R''

RX

R' R''

R

a, X = C(=S)SCH3, Bu3SnH/AIBN b. X = COC6H4-m-CF3, hυ

a or b(25)

OR

TBSO

COOCH3

OTBS

R3'Si

RO OR

COOCH3

R3'Si

TFA

HO OH

CO2CH3

R = TBS -> OH

a or b

a, X = C(=S)SCH3, Bu3SnH/AIBN, 86% b. X = COC6H4-m-CF3, hυ, 75%

(26)

In 1988, Motherwell reported50 that alkynyl radicals could be used for regio-and stereospecific

construction of spirocyclic quaternary centers via a tandem radical cyclopropylcarbinyl rearrangement

(Scheme 1.9). The ring of cyclopropylcarbinyl radical may be opened by either bond breaking of a or b,

but the product analysis showed the bond breaking of a proceeded predominantly, which might imply the

reaction was kinetically controlled because the cleavage of a produced a primary radical which had higher

energy than a secondary radical generated by cleavage of b. The hex-5-ynyl radical could be closed easily

via 5-exo-dig process.48, 49 The stereoselectivity of the cyclopropylcarbinyl rearrangement as illustrated in

Eq. 27 is also noteworthy.50 An α,β-unsaturated ketone derivative was reduced chemo- and

stereoselectively by L-selectride, and their major epimer was isolated by aqueous workup. The isolated

epimer could be converted to the other epimer by Mitsunobu reaction51 followed solvolysis in the presence

of titanium tetraisopropoxide. After several steps, the desired thiocarbamates were obtained, and they were

subjected to radical cyclization via the Barton’s deoxygenation procedure. These two isomers were

cyclized stereospecifically to give desired products via cyclopropylcarbinyl rearrangement.

20

HXH

H

CH2

Bu3SnH

.(a)

(b)

ab1-46 1-47 1-48

1-50

XBu3SnH

1-491-511-52

Bu3Sn

Scheme 1.9. Stereospecific Construction of Spirocyclic Ring by Intramolecular Radical Cyclization.

O

SiMe3 SiMe3

Me3Si

SiMe3

O Im

S

Me3Si

SiMe3

OH

SiMe3

O Im

S

(27)

1. 1. 2. 4. The Intermolecular Radical Addition of Alkyl Radicals

There are only a few papers covering intermolecular addition by the alkyl radical generated during

the Barton’s deoxygenation. The first paper in this area52 was reported by Giese in 1984. In his paper, α-

D-glucofuranose derivatives reacted with acylonitrile to give two anomers with 73:27 ratio, but α-D-

21

galactofuranose derivatives coupled diastereoselectively with the radical acceptor from exo-side. The

diastereoselectivity may be explained by the steric hindrance of protecting groups. Thiocarbamate

derivatives of deoxygalactopyranoside was also subjected to intramolecular C-C bond coupling, but the

same amount of deoxygenated product was obtained as well as a coupling product.

OOO

OO

X

O

OO

X

OO

OBzO

XOP

OPOCH3

Bu3SnH

H2C=CHCN

Bu3SnH

H2C=CHCN

Bu3SnH

H2C=CHCN

OOO

OO

R

O

OO

R

OO

OBzO

OCH3

OPR

OP

OOO

OOR

OBzO

OCH3

OBz

OP

+

X = OC(=S)Im, R = CH2CH2CN

+ (28)

(29)

(30)

P = Bz

A similar reaction was studied with D-glucopyranosyl derivatives by Araki’s group in 198753, but

only small amount of starting material was converted to alkyl radical via Barton’s mechanism, which led to

poor C-C bond formation. One-year later,54 however, they could generate successfully a ribofuranosyl

radical, which was trapped by dimethyl maleate in a 62% yield and the adduct was used as a precursor for a

formal synthesis of showdomycin (Eq. 31).

O O

O O

BzO C SMe

COOMe

COOMe Bu3SnH

AIBN

O

O O

BzO

COOMe

COOMe

O

O

O

BzO

++ (31)S

During a study of tandem radical annulations to prepare carbocyclic compounds, Clive and his

research group investigated12 β-acetylenic radicals, which might be generated from ether α-halogeno-

22

ketones or thiocarbamate derivatives by Ph3SnH/AIBN (Eq. 32). The radical generated from halogen

derivative was trapped well by Michael-type radical acceptors through 5-exo-dig process, but the acetylenic

radical from thiocarbamate derivatives was not trapped effectively. Fortunately, another radical acceptor,

acrylonitrile, was used for the intermolecular-intramolecular tandem cyclization to give bicyclic

compounds in 26% yield (see also Eq. 1).

O C N

NS

CC

Ph

Ph3SnH

CN

Ph

CN

H

(32)

In 1985, Keck reported55 that thiocarbamate, thiobenzoate, and xanthates derivatives could be

trapped into allytributylstannane. The best result was obtained after photolysis: the yield of reaction was

lower under thermal conditions in the presence of AIBN because 2-cyanopropyl radical from AIBN added

to the carbon rather than initiate the reaction (Eq. 33). However, if crotyltin-n-butylstannane was used for

the reaction instead of allytributylstannane, the carbon-centered radical was not trapped, but a simple

deoxygenation product was obtained along with butadiene (Eq. 34).

XO

OO OBn

O

S Bu3SnH

Bu3SnCH2CH=CH2 O

OO OBn

hυ or ∆

X = SMe, OPh, Imidazole

(33)

RXBu3SnH

H3C SnBu3H2C SnBu3

HRH ++ (34)R Bu3Sn

Another example of a radical addition to tributylstannyl substrates was reported by Baldwin in

1985. 56 A carbon radical trapped by an alkene may give three different products depending on the

23

mechanism. The most common pathway is a with a hydrogen abstraction from radical donor such as

tributyltin hydride. The other pathway is radical addition-elimination process, which may be divided into

two sub-groups; one is pathway b which is commonly known as SH’ mechanism, 57 or the pathway c (the

proximal mechanism). Baldwin and his associate developed new consecutive radical addition-elimination

reactions, which might be applied for new carbon-carbon bond formation, via the proximal pathway c

(Scheme 1.10).

X

Y

X

Y

R

X

Y

R

A

Y

R

XR

B

Y

X

a

b

c

+

+

++

1-53 1-54

1-55

1-56

1-57

R

Scheme 1.10. The Possible Pathways for Radical Addition to Alkenes.

They generated radicals in the presence of excess amount of β-stannyl acrylate (2.0 equiv.). Half

of the radicals were reduced to deoxygenated product via the Barton’s deoxygenation mechanism and the

other half were trapped by the excess β-stannyl acrylate via the proximal pathway c. Although the yields

were low, the results are very useful because the radical addition-elimination gives preparatively useful

product under condition that are mild and neutral (Eq. 35).

24

OOO

OO

XBu3SnCH=CHCO2Et

O

OO

OO

CO2Et

OOO

OO

(35)+

Finally, during the study of diastereoselective vinyl- and carbonyl-initiated intramolecular [3 atom

+ 2 atom] radical cyclization,58 Feldman found an interesting intermolecular version of the [3 atom + 2

atom] radical cyclization (Eq. 36). 59 The ring of a phenyl or gem-dichloro substituted cyclopropyl

thioamide can be opened by addition of Me3Sn. to the thiocarbonyl group, and the resulting product can be

trapped by an electron deficient alkene to form 5-hexenyl radicals. Theses radicals undergo ring closure

through 5-exo-trig process to afford substituted (thiocarbonyl)-cyclopentanes in good yields.

X

Y

R

Z

S

E SSnMe3

Z

RX

Y

E

Z

SRX

Y

E

+

X = Ph, Cl, Y = H, Cl, Z = NMe2, NHtBu, OEtR = H, Me, E = CO2R, CN

.PhH, reflux

(Ph2COSnMe3)2(36)

1. 1. 2. 5. The Miscellaneous Reactions

Most radical acceptors for intra or intermolecular cyclization are olefins; but oxime ether has also

been used as a radical acceptor. 60 In 1988, Bartlett reported that61 oxime derivatives are excellent radical

acceptors for transformation of carbohydrates to carbocycles. 2,3,4,6-Tetra-O-benzyl or tetra-O-methyl-D-

glucopyranose can be converted into benzyl oxime or methyl oxime derivatives with BnONH2•HCl or

MeONH2•HCl under the mild conditions. To generate 5-oxime radicals, the glucopyranose derivatives

were converted to phenylthiocarbonate derivatives, which were subjected to the Barton’s deoxygenation.

Exposure of these substrates to tributyltin hydride and AIBN under refluxing conditions gave

25

diastereomeric mixture of aminocyclo pentitiol, which had predominantly 1,5-cis selectivity like

RajanBabu’s results (Eq. 37). 39

O OH

OR

RO

RO OR

N

O

OR

OR

OROR

OR'

PhO

S NHOR'

RO

RO

OR

OR

NHOR'

RO

RO

OR

OR

+ (37)

Radicals generated from thiocarbamates and their analogues are sp3 carbon centered radicals

containing a C-SSnBu3 bond, but Buchi first reported62 sp2 carbon centered radicals (imidoyl radicals) from

thiocarbamates. The imidoyl radicals are very attractive because they can be used as intermediates in the

synthesis of cyclic ketones. Especially, if the potential radical bearing group (e.g. phenyl group) is

substituted on the nitrogen of imidoyl radicals, a tandem cyclization may take place to afford

polyheterocyclic compounds (Eq. 38).

S

HN

O Ph

SSnBu3

N

O Ph O

N

R

NaH, Bu3SnCl(38)

To make the imidoyl radicals, the bond between carbon-sulfur has to be broken and this is done by

using trialkyltin thioimidates rather than aryl or alkyl thioimidates (Scheme 1.11). 63 The imidoyl radical

can also be generated from N-benzyl(N-alkyl)thioamides because benzyl radical may be eliminated easily

from the substrates to afford trialkyltin thioimidates. The generated imidoyl radical was cyclized via 6-

exo-trig process to give enamines, which are subject to hydrolysis to afford ketone derivatives.

26

S

O Ph

N

Ph

Me

S

O Ph

NMe

SnBu3

CH2Ph

N

O Ph

Me

O

N

Ph

Me

[H2O]

O

O

Ph

SSnBu3

O Ph

N Me-PhCH2

-(Bu3Sn)2S

1-58 1-59 1-60

1-61 1-62 1-63

Bu3Sn Bu3Sn

Scheme 1.11. The Mechanism for the Imidoyl Radical Mediated Cyclization.

Very interesting 1,3-stannyl radical migration following intramolecular cyclization of an α-stannyl

radical was reported by Tsai in 1999. 64 The α-stannyl radicals were generated from α-stannyl xanthate

derivatives with tributyltin hydride and AIBN, and the radicals attacked both a formyl group and an alkenyl

group at the same reaction rate via 5-exo ring closure (Eq. 39). The intramolecular cyclization of the α-

stannyl radical with a formyl group gave γ-stannyl alkoxy radicals, which were subject to 1,3-stannyl

radical migration followed by tandem 5-exo cyclization. The stereochemistry of the tandem cyclized

bicyclic products was trans, which might be rationalized by chair transition state in which the group on C-

1, C-2, and C-3 are all in equatorial positions (Figure 1.4).

H

O

O SnBu3

S SMe

Bu3SnH

AIBN

H

O

Bu3SnCH3

OH

Bu3SnCH3 HO

H

H CH3

H

HHO CH3

+ ++ (39)

27

O

H

SnBu3

H

HO

H

SnBu3

H

H OSnBu3

H

H

..

.23

1

1-64 1-65 1-66

Figure 1.4. The Rationalization of the Stereochemistry of Tandem Radical Cyclization under Barton’s

Deoxyzanation Conditions.

1. 1. 2. 6. The Formation of N-Glycoside via 6-Exo-tirg Cyclization

Although sp3 carbon centered radicals 1-4 (Scheme 1.1) generated by β-cleavage of thiocarbonate

1-3 has been used as a precursors of 6-exo-trig ring closure,37,38 the Barton’s radical 1-2 has not been

considered as the precursor of the 6-exo-trig ring closure until a report by RajanBabu and Bliss (Eq. 40).65

Moreover, if O-phenyl thiocarbonate was used for the cyclization, they observed a phenyl group migration

via spiro aromatic system, which has been reported earlier by Bachi25 and Zalkow27.

TBSO

O OCO2R Ph

O

OO CO2R

OTBS

O O

OO CO2R

OTBS

+(40)

O

OPhS

1-67 1-74 1-70R = Et 30% 0%

R = Et 10% 65%

R = tBu 27% 0%reverse addition

Bliss initially studied the 6-exo-ring closure by using the Barton’s radical generated from O-

phenyl thiocarbonate (Eq. 40). They observed the phenyl group migration during the radical cyclization to

give 1-74, and proposed a mechanism involving spiro aromatic system (Scheme 1.12). The configuration

28

of the isolated 2-deoxy-δ-lactone was altro based on Wilcox’s results,66 conformational analysis, coupling

constant, and NOESY spectrum. However, reverse addition (slow dropping of a mixture of substrates and

AIBN in a solvent into a solution of tributyltin hydride via a syringe pump) might trap the α-methylene

radical generated by 6-exo-trig cyclization before the phenyl group migration to the methylene radical (k3 <

k4). Because excess amount of tributyltin hydride was used, the cyclized intermediate, orthoester, could

eliminate phenyltributyltin moiety, Bu3SnPh, to afford thionolactone, which was subject to further

reduction to furanoside (Scheme 1.12).

Bu3Sn

TBSO

O OCO2Et

O

OO CO2Et

OTBSS

SnBu3

OO

OO CO2Et

SOTBS

Bu3Sn

Bu3SnSOPh

OTBSO

O OCO2Et

O

OO CO2Et

OTBSS

SnBu3

O O

OO

OTBSS

SnBu3

O

CO2Et

TBSO

O OCO2Et

Bu3SnH

Bu3SnH

Bu3SnH

Bu3SnH Bu3SnH

O

Ph

O

OO CO2Et

OTBS

O

OO CO2Et

OTBS

.

k4

.

k2

deoxygenated products

.

.

.

.

k1 k3

k1 >> k2

a b

a

b

1-67

1-71 1-72

1-68 1-69 1-70

1-73 1-74

1-75

if normal addition, k3 >> k4 [Bu3SnH]if reversed addition k3 << k4 [Bu3SnH]

O

OPhS

Scheme 1.12. Mechanism for the Formation of Pyran Ring System via 6-Exo-trig Ring Closing Mediated

by the Barton’s Radical.

29

The cyclized compound 1-74 was obtained as a single isomer, and was chartacterized by 13C

NMR, which had two ester carbonyls at δ 171.5 and δ 170.6 ppm as well as a phenyl group. The

stereochemistry of the lactol 1-70 was assigned as altro configuration based on NOSEY data, and the

measured coupling constant between H-2 and H-3 was in agreement with the theoretical coupling constant

derived from Karplus equation, and the relatively big dipole-dipole correlation between H-2 and H-4 in

NOSEY may rationalize the allo configuration of compound 1-70. Unfortunately, the opposite

configuration of 1-70 and 1-74 at C-2 has not been explained at this point.

More interesting results have been achieved by changing the substrates from thiocarbonates to

thiocarbamates. Slow addition of thiocarbamate and AIBN in benzene to solution of tributyltin hydride

gave cyclized products, which are rare examples of N-heterocyclic-hexopyranosides (Eq. 41). They are

also branched chain N-glycosides. Moreover, this is not only the first example without elimination of

substituent X during the Barton’s radical mediated 5- or 6-exo-trig ring closure, but also a fundamentally

important new glycosylation reaction. Because of the aromatic center carbon at δc = 83.2 ppm in 13C NMR

spectrum, the isolated product was tentatively assigned as α configuration, and small J value (J1,2 = 3.2 Hz)

supported a cis relationship between C-1 and C-2 substituents. A new anomeric hydrogen peak appeared in

the 1H NMR spectrum on standing the sample at room temperature, and the J value was relatively large

(J1,2 = 8.5 Hz), which indicate isomerization to the β-anomer. Based on these results and compared with

the structural analysis of furanoside,60 Bliss concluded the N-glycoside had the allo configuration.

O

O O

Bu3SnH

AIBN

O

OO

OTBS

CO2tBu

N

N

(41)CO2

tBuTBSO

NS

N

The formation of N-glycoside is novel because thus far all radical cyclizations based on the

Barton’s deoxygenation lead the elimination of substituent X (see Scheme 1. 1, 1. 2, and 1. 3). However,

the initial study gave only 37% yield of the desired N-glycoside, and the structural analysis has not been

30

firm because of the lack of NOE or 2D NMR data. Moreover, the new synthetic route for the formation of

2-C branched glycosides is a fundamentally important methodology. Thus, for the general transformation

of carbohydrates to O-and N-glycosides, this work has to be extended to include 5-exo-trig ring closures.

O

YOO

OTBS

X

O

OO CO2

tBu

OTBS N

N

O O

Y

A Glycosylation Reaction?

Rare N-hexopyranoside

New C-C Bond

Rare Branched Chain Sugar*

X = O-sugarX = purine or pyrimidineY = CH2CO2RY = CH2CNY = CH3

Y = radical acceptor

O

HO OH

OHO

D-ribonic-γ-lactone

O

N

TBSO

S

N

Scheme 1.13. Proposed Route for the Formation of N-Glycosides.

31

1. 2. Synthesis of Substrates for Radical Cyclization

1. 2. 1. Preparation of precursor for 6-exo trig radical cyclization

In order to favor, otherwise slow, 6-exo-trig radical cyclization, we attempted to introduce an

electron withdrawing group (EWG) on the acceptor olefin. Synthesis of a substituted enoate from D-

ribonic-γ-lactone is shown in Scheme 1. 14. First, the two hydroxyl groups of 2 and 3 positions of

compound 1-76 were protected by acetone and iodine with small amount of anhydrous magnesium sulfate

to give isopropylidene derivative in high yield (94%). The 2,3-di-O-isopropylidene-D-ribono-γ-lactone (1-

77) was further protected as a tert-butyldimethylsilyl ether to give 1-78.

O OOH

O OOH

O O

O OOTBS

O O

O OHOTBS

a b c d

1-76 1-77 1-78 1-79 1-80

HO OH O O

OH

O O

TBSOCO2R

Scheme 1.14. Synthetic Routes to Prepare Substrates 1-80: (a) acetone, I2, anhydrous MgSO4, rt, 12 h,

94%; (b) TBSCl, imidazole, DMF, 0 oC 1 h and rt 9.5 h, 96%; (c) 1.5 M Dibal-H in toluene, Et2O, -78 oC, 2

h, >99%; (d) R = tBu, Ph3PCHCO2tBu, DME, rt, 4 h and reflux ,4 h, 92%. E/Z = 0.24/1.0; R = Et,

Ph3PCHCO2Et, DME, rt 102 h, 95%. E/Z = 0.32/1.0.

This compound may be used without further purification for the next step, but if it is necessary to

obtain a pure compound, it can be purified by recrystallyzation from pentane or flash column

chromatography to give 96% isolated yield. The fully protected 5-O-tert-butyldimethylsilyl-2,3-O-

isopropylidene-D-ribono-γ-lactone 1-78 was reduced quantitatively with 1. 5 equivalents of Dibal-H at -78

oC in 2 hours. Subsequent olefination was successfully achieved by the Wittig reaction to give E/Z

mixture. In the case of R = tBu, the mixture was isolated by column chromatography to give 92% of

isolated yield with E/Z = 0.24/1.0, while 95% of isolated yield (E/Z = 0.32/1.0) was obtained with R = Et.

32

Alkyl-7-O-(tert-butyldimethylsilyl)-2,3-dideoxy-4,5-O-(isopropylidene)- D-ribo-hept-2-enoate

thiocarbonylimidazole 1-81 and 1-82 (E and Z) was prepared from 1-80 in 89-77% yield with freshly

prepared 1,1-thiocarbonyldiimidazole. THF or dichloroethane can be used as the solvent, and they do not

affect the yield. For convenience, the reaction mixture was not usually worked up, but the solvent was

removed directly before the column chromatography.

OHTBSO

O OCO2R

TBSO

O OCO2R

a

1-80 1-81 R= tBu1-82 R = Et

O

NS

N

Scheme 1.15. Synthetic Route to Prepare Substrates 1-81 and 1-82: (a) R = tBu (Z), 1,1’-thiocarbonyl

diimidazole, DMAP, dichloroethane, reflux, 13.5 h, 89%; R = tBu (E), 1,1’-thiocarbonyldiimidazole,

DMAP, dichloromethane, reflux, 10 h, 86%; R = Et (Z), 1,1’-thiocarbonyldiimidazole, DMAP, THF,

reflux, 17.5 h, 80%; R = Et (E), 1,1’-thiocarbonyldiimidazole, DMAP, THF, reflux, overnight, 77%.

Another EWG substituted olefin was synthesized from the D-ribono-γ-lactol 1-79 with

(cyanomethylene)triphenylphosphorane in toluene. Unfortunately, the reaction mixture gave complex

mixture, which contained TBS group migrated compounds 1-84 and cyclized compounds 1-85 as well as

desired products 2-7. Further purification showed the major product was a mixture of (E)-1-83 and 1-85

(71%, ratio is 1:4), and they could not be isolated by traditional column chromatography. Because of a

serious loss of the product by column chromatography, no more purification was attempted. The combined

yield of the olefin compounds 1-83 and 1-84 and cyclized compound 1-85 were 85% after column

chromatography.

33

O O

O OHOTBS

OHTBSO

O O

CN

OTBSOH

O O

CN

O O

OOTBS

CN

1-79 1-83 1-84 1-85

a+ +

Scheme 1.16. Synthetic Route to Prepare Substrates 1-85: (a) Ph3PCHCN, toluene, rt 9 h, total isolated

yield 85% (E/Z = 0.9/1.0).

The thiocarbamation was applied to the mixture of 1-83 (E) and 1-85. Only compound 1-83 (E)

reacted with 1,1’-thiocarbonyldiimidazole to give compound 2-86 (E) in a yield of 79% based on 1-83 (E).

The cyclic ring of compound 1-85 did not open to make a desired product 1-86 (E), and the starting

material 1-85 was recovered almost quantitatively after column chromatography. The same condition was

used for the compound (Z)- 1-83. The reaction required longer time (24 h), but gave competitive yield

(86%).

OHTBSO

O O

CN

O

OOTBS

CN

OHTBSO

O OCN

TBSO

O O

CN

O O

OOTBS

CNa

+ +

1-83 (E) 1-85 1-86 (E) 1-85

b

1-83 (Z) 1-86 (Z)

O

NS

N

TBSO

O O

O

NS

N

CN

Scheme 1.17. Synthetic Route to Prepare Substrates 1-86: (a) 1,1’-thiocarbonyldiimidazole, THF, DMAP,

reflux 10.5 h, 88% (based on 1-83 (E)) of 1-86 (E) isolated and 35% of 1-85 recovered (cis/trans =

1.0/0.09); (b) 1,1’-thiocarbonyldiimidazole, THF, DMAP, reflux 24 h, 86%.

34

A reaction with an unstabilized Wittig reagent was performed with D-ribono-γ-lactol 1-79 and

methylenetriphenylphosphorane in THF. The required phosphorane was made in situ from the

phosphonium salt and n-butyl lithium at -78 oC to rt. Slow addition of D-ribono-γ-lactol in THF -78 oC gave

immediately yellow solution, which was further stirred at rt for 2 h. A desired product 1-87 was isolated

as a 71% yield, and the isolated compound was reacted with freshly prepared 1,1’-thiocarbonyldiimidazole

and DMAP in THF. After flash column chromatography, a 69% of 1-88 was isolated as yellow oil of the

desired product.

O O

O OHOTBS

OHTBSO

O O

TBSO

O O

a b

1-79 1-87 1-88

O

NS

N

Scheme 1.18. Synthetic Route to Prepare Substrates 1-88: (a) Ph3PCH3Br, nBuLi, THF, -78 oC to rt, 2 h,

71%; (b) 1,1’-thiocarbonyldiimidazole, DMAP, THF, reflux 14 h, 85%.

It has been reported56 that oxime derivatives of 2,3,4,5-tetra-O-benzyl-D-glucopyranose and 4,6-

O-benzylidene-2,3-di-O-benzyl-D-glucopyranose can be cyclized to give cyclopentanes via 5-exo-trig

radical process under the Barton-McCombie conditions (Chapter 1, Eq. 19). To generalize our

methodology for 5- and 6-exo-trig radical cyclization mediated by the Barton’s radical, O-methyoxime

derivatives of D-ribono-γ-lactone were prepared. O-Methylhydroxylamine hydrochloride reacted with D-

ribono-γ-lactol 1-79 in absolute methyl alcohol under refluxing condition for 8 h. After column

chromatography, 66% of colorless oil was obtained as syn/anti mixtures, and they were subjected to the

thiocarbonylation with 1,1’-thiocarbonyldiimidazole. The desired product was obtained as yellow oil in an

excellent yield after flash column chromatography (Scheme 1.19).

35

O O

O OHOTBS

OHTBSO

O O

NOCH3TBSO

O O

NOCH3

1-79

a b

1-89 1-90

O

NS

N

Scheme 1.19. Synthetic Route to Prepare Substrates 1-90: (a) H2NOCH3•HCl, pyridine, MeOH, reflux 5.5

h, 96% (syn/anti = 1.0/0.25). (b) 1,1’-thiocarbonyldiimidazole, THF, reflux 10.5 h, 92% (syn/anti =

1.0/0.32).

Another example for N-substituted substrates is shown in Scheme 1. 20 After stirring of D-ribono-

γ-lactone with N,N’- dimethylhydrazine in absolute methyl alcohol under reflux condition, a mixture of 1-

91 and 1-92 was isolated as yellow oil. The combined yield was 71% and the ratio of 1-91/1-92 was

1.0/0.16. These mixtures were used for the next experiment without further purification due to the

difficulty of isolation by traditional column chromatography. The dimethylhydrazone containing mixture

reacted with 1,1’-thiocarbonyldiimidazole and DMAP in THF under refluxing conditions for 12 h. After

flash column chromatography, 74% (syn/anti = 0.58/1.0) of desired product 1-93 was isolated.

O O

O OHOTBS

OHTBSO

O O

NN(CH3)2

O O

OOTBS

NHN(CH3)2 TBSO

O O

NN(CH3)2

1-79

a b+

1-91 1-92 1-93

O

NS

N

Scheme 1.20. Synthetic Route to Prepare Substrates 1-93: (a) N,N’-dimethylhydrazine, MeOH, reflux,

overnight, 71% (1-91/1-92 = 1.0/0.16). (b) 1,1’-thiocarbonyldiimidazole, DMAP, THF, reflux 12 h, 74%

(syn/anti = 0.58/1.0).

36

The same reaction was performed with p-toluenesulfonylhydrazine under the traditional

conditions. Unfortunately, the isolated product was only a cyclic form like 1-94 as an α/β mixture, and no

acyclic olefin was obtained. After 7 h refluxing, however, all starting material 1-94 was consumed.

Initially, we anticipated opening of the cyclized ring, and thus the hydroxyl group would be converted to a

desired thiocarbamate, because it has been reported that the cyclic forms are in equilibrium with acyclic

forms.67 However, none of the expected product was produced. The only product characterized was 1-95.

O OHOTBS

O O

OOTBS

NHNHTs

O O

XO O

NNHTs

O O

OOTBS

NNHa b

1-79 1-94 1-95

O

NN

S

TBSO

O O

NNHTsOH

NNS

1-94'

TBSO

Scheme 1.21. Failed Attempts to Prepare Thiocarbmate of Hydrazone Derivatives: (a) p-toluenesulfonyl

hydrazine, acetonitrile; (b) 1,1’-thiocarbonyldiimidazole, DMAP, dichloromethane, DMAP, reflux 7 h,

47%.

The formation of 1-95 may be explained by the proposed mechanism shown in Scheme 1. 26.

Because of excellent nucleophilicity of the nitrogen of tosylhydrazone derivatives, the thiocarbonyl group

of 1,1-thiocarbonyldiimidazole can be attacked, which may lead to the unexpected compound 1-95. 1H

NMR spectra shows that one H peak disappears by addition of D2O, which accounts for the hydrogen

connected to a nitrogen. Moreover, 13C NMR shows a singlet peak at 118 ppm, which may imply a C=N

group.

37

O O

OOTBS

NHNHTs

Im C Im

S

O O

OOTBS

HN N

Ts

C

S

Im

O O

OOTBS

NHN S

N

N

OOTBS

N N C

S

ImH

O O

O O

OOTBS

N N

Ts

C

S

Im

H

B

1-94

1-95

+

Scheme 1.22. Proposed Mechanism for the Formation of 1-95.

Therefore, we chose diphenyl hydrazine, which can make an acyclic forms like 1-99 and 1-100,

and performed the thiocarbamation under the traditional refluxing conditions. However, all attempts failed

and no starting material was detected on TLC. Initially, we assumed the acidic environmental of the

reaction condition (the used diphenylhydrazine was a hydrochloride form) might cause the decomposition

of the starting material D-ribono-γ-lactone by the elimination of a TBS group. To resist the acidity of the

applied conditions, the protecting group was changed from a TBS to a TBDPS group as well as quenching

the hydrochloride by either triethyl amine or pyridine. The lactol 1-98 was made from TBDPS substituted

lactone 1-96 by the previously described method; protection of the hydroxyl groups at C-2 and C-3 and

then reduction of the lactone by Dibal-H at –78 oC. The TBSPS protected lactol 1-98 was stirred at rt for 3

days without quenching the HCl of diphenyl hydrazine by base. After column chromatography, a small

amount (less then 10%) of desired product was isolated with inseparable impurities. The diphenyl

hydrazine was quenched by triethyl amine, and the same reaction was performed ar rt for 48 hr.

Unfortunately, more than 90% of starting material 1-98 was recovered. Finally, we found the desired

product 1-99 was made more efficiently after treating the diphenyl hydrazine hydrochloride in prydine at rt

for 30 min. The pyridine treated 1-99 was stirred in methyl alcohol at rt for 24 h. The isolated yield of

hydrazone product 1-99 was approximately 55%, but still some impurities could not be removed from the

38

products. The same condition could be applied successfully for a TBS group substituted D-ribono-γ-lactone

1-79. The neutralized reaction mixture by pyridine was stirred at rt for 24 h, and the mixture was purified

by column chromatography, eluting with hexane:EtOAc = 10:1 solution containing 1% triethyl amine.

Even though about 10 % of stating D-ribono-γ-lactone was recovered, 66% (based on recovered starting

material) of desired product 1-100 was isolated without any significant impurities. The mixture of 1-99

was subject to thiocarbamation under the traditional condition. Even though all of the starting material was

consumed as indicated by TLC, no significant amount of desired product was isolated. Fortunately, the

pure 1-100 was converted to the desired thiocarbamate derivative under the similar condition in a high

yield (98%).

O O

OTBDPSO O

OTBDPS

O O

O O

O OHOTBS

O O

O OHOTBDPS

TBSO

O O

NNPh2

TBDPSO

O O

NHNPh2

TBSO

O O

X

NNPh2

TBDPSO

O O

NNPh2a b c

1-96 1-97 1-98 1-99

c

1-79 1-100

d

d

1-101

OOH

OOH

N

N

S

S

N

N

HO OH

Scheme 1.23. The Synthesis of Diphenyl Hydrazone Derivatives: (a) acetone, I2, MgSO4, rt, 12 h, 98%; (b)

1.5 M Dibal-H in tolune, Et2O, -78oC, 4 h, 82%; (c) Ph2NNH2•HCl, pyridine, MeOH, rt, 24 h, 55% for 1-

99, 66% for 1-100; (d) 1-99, ImC(=S)Im, DMAP, THF, reflux, 12 h, all starting material decomposed; 1-

100, ImC(=S)Im, DMAP, THF, reflux, 24 h, reflux, 20 h, 98%.

39

The cyclic TBS protected -D-ribofuranose 1-79 are equilibrium with acyclic D-ribofuranose 1-79’

in a solution. If the acyclic D-ribofuranose 1-79’ react with 1, 1’-thiocarbonyldiimidazole under our

standard reaction condition for thiocarbamation, we can make an aldehyde substituted precursor for 6-exo

trig radical cyclization via the Barton’s radical intermediate. It is well known aldehyde is a reasonable

radical acceptor due to its strong electron withdrawing ability, which may lead better yield in radical

cyclization. If the reaction is successful, moreover, we may install easily a free hydroxyl group at C-2

position of furanosides and pyranosides.

The reaction was performed with 1, 1’-thiocarbonyldiimidazole and catalytic amount of DMAP in

THF under refluxing condition for 21h. Although small amount of starting material 2-4 was remaining, the

reaction was stoped due to deterioration of the product as shown by TLC, and the product was purified the

new product by column chromatography. Unfortunately, the isolated product was not the desired product

1-102 but 1-103 which is the cyclic D-ribofuranose 1-79.

a

O OHOTBS

1-79

O OXTBSO

O O

O

1-102

O

NS

N

OOTBS

1-103

O O

aTBSO

O O

OOH

1-79'

O N

S

N

Scheme 1.24. Thiocarbamation of 1-79: (a) ImC(=S)Im, DMAP, THF, reflux, 21 h 24% (29% based on

recovered starting material)

To make more hydrazone derivatives of D-ribono-γ-lactone, similar reactions were performed

with methylamine hydrochloride and p-chlorophenyl hydrazine hydrochloride. The applied method was

similar to the above; after quenching the corresponding HCl by pyridine, the mixture of hydrazine and the

sugar were refluxed or stirred at rt as a mixture in absolute alcohol under nitrogen atmosphere until no

40

more starting material was detected on TLC. Even though all starting material was consumed, we failed to

isolate significant amount of any condensation products.

TBSO

O O

NHN Cl

XO O

O OHOTBS

XTBSO

O O

NCH3

1-79

a bOHOH

Scheme 1.25. Failed Attempts to Prepare Hydrazone Substrates: (a) p-Cl-C6H4NHNH2•HCl, MeOH,

reflux, decomposed; (b) CH3NH2•HCl, MeOH, reflux, decomposed.

It is well established that phenyl isocyanate reacts with an alcohol and catalytic amount of triethyl

amine to give a carbamate. With olefin substituent 1-80, the reaction was successful and desired products

were isolated from 91 to 84% yield. The next step was thiocarbonylation of 1-104 by Lawesson’s reagent.

Unfortunately, no significant amount of desired product was isolated after refluxing or warming in toluene

or benzene.

TBSO

O O

CO2RTBSO

O O

CO2R XTBSO

O OCO2R

a b

1-80 1-104 I

OH O O

NHO S

NH

Scheme 1.26. Failed Attempts to Prepare Thiocarbamate I: (a) tBu (E), PhNCO, Et3N, benzene, overnight,

91%; Et (Z), PhNCO, Et3N, benzene, overnight, 84%; (b) Lawesson’s reagent, benzene or toluene, reflux,

overnight, all starting material decomposed.

41

The same reaction was performed with phenyl thioisocyanate and triethyl amine in benzene.

Although prolonged reaction times were used, the reaction was not successful because of the lower

electrophilicity of thiocarbonyl group compared to that of the carbonyl group. After column

chromatography, most starting material was recovered. To overcome the low electrophilicity of phenyl

thioisoycanate, 2.0 equivalents of BF3•OEt2 was added along with 1.2 equivalents of Et3N.

O O

OOTBS CO2R

TBSO

O OCO2R X

TBSO

O O

II

CO2R

1-105

a or b

1-80

c

O

NHS

OH

Scheme 1.27. Failed Attempts to Prepare Thiocarbamate II; (a) R = tBu (E), Et3N, PhNCS, benzene,

reflux, overnight. (b) R= tBu (Z), Et3N, BF3•OEt, PhNCS, benzene, reflux, 2h. (c) R = tBu (Z), NaH, THF, -

78 oC to rt, 5.5 h 87% (α/β = 0.56/1.0); Et (Z), NaH, THF, -78 oC to rt, 1.5 h, 95% (β only).

Unfortunately, all starting material decomposed under 2 h refluxing. Finally, the hydroxyl group

of the substrate was deprotonated first by mineral oil free NaH in dried THF at –78 oC (to rt), and then

phenyl thioisocyanate was added slowly followed stirring at rt. However, the deprotonated substrate of 1-

80 cyclized via a 5-exo-trig mode before it added to phenyl thioisocyanate, and compound 1-105 was the

only isolated product. To reduce the favored 5-exo-trig-cyclization of deprotonated substrate of `1-80 and

enhance the coupling with phenyl thioisocyanate, the addition of reactants was reversed (the solution of 1-

80 was slowly added to the mixture of phenyl thioisocyanate and sodium hydride in THF at –78 oC or 0 oC),

but those attempts failed and gave the same cyclized compound 1-105.

42

To avoid the 5-exo cyclization, the substrate 1-80 was treated with the (Bu3Sn)2O to make a tin

ether (ROSnR3), which could react with PhNCS to give the thiocarbamate due to better nucleophilcity of

the tin ether oxygen compound to the hydroxyl oxygen. However, the desired product was not isolated,

and only product was α,β-unsaturated lactone 1-106, formed in a 55% yield.

TBSO

O O

CO2R XTBSO

O O

CO2R XTBSO

O OCO2R

III

OTBSO

O

O O

1-1061-80

a or b

OHOO

NHBu3SnS

Scheme 1.28. Failed Attempts to Prepare Thiocarbamate III: (a) R = Et (Z), (Bu3Sn)2O, PhNCS, toluene,

reflux 55%; (b) R = tBu (E), (Bu3Sn)2O, toluene, reflux, 3%.

The proposed mechanism for the formation of compound 1-106 is shown in Scheme 1. 29. The

oxygen of tin ether may attack the carbonyl group of an α,β-unsaturated ester to give a cyclized 7-

membered unsaturated intermediate 1-107. There are two possible mechanisms; in the pathway a, the α,β-

unsaturated lactone is formed by 1, 3-tin migration followed by removal of RO-SnBu3. In the other

pathway b, Bu3Sn+ should be removed first and followed the removal of –OR. It has been known that an

ester group can be hydrolyzed by (Bu3Sn)2O to an acid.68 However, this is the first example of an α,β-

unsaturated lactone formation by (Bu3Sn)2O. Although the lactone ring 1-106 can be constructed in a good

yield with R=Et, the yield was lower (~3%) with a bulky substituent R=tBu. It has been known68 that the

removal of a tBu group is of difficult under tin-mediated reactions.

43

O

TBSO

RO O-

Bu3Sn

O

TBSO

RO O SnBu3

O O

TBSO

CO2RO O

O

TBSO

RO O-O O

OTBSO

O

O O

-ORO O

1-1061-80

+ or

-Bu3Sn+

-[RO-SnBu3]

1-107

Sn migration

OH TBSO

O O

OBu3Sn RO

O

Scheme 1. 29. The Mechanism of the Formation of 1-106.

Benzoyl chloride is an excellent protecting reagent for 1o and 2 o alcohols. Especially, if we have

a benzoate derivate, it may be converted to a thiobenzoate, which would be a subject of 5- or 6-exo-trig

radical cyclization mediated by the Barton’s radical. The hydroxyl group of 1-80 was coupled with

benzoyl chloride to give a benzoate in pyridine as a good yield. The isolated benzoate derivative 1-108 was

subject to thiocarbonylation by Lawesson’s reagent in benzene under refluxing condition for more than 30

hr. Unfortunately, almost 100% of starting material was recovered after flash column chromatography.

TBSO

O OCO2

tBu TBSO

O O

CO2tBu

ab

1-80 1-108

TBSO

O O

CO2tBuX

OHO O

O S

Scheme 1. 30. Failed Attempts for Thiocarbonates: (a) PhCOCl, pyridine, 0 oC to rt, overnight, 73%. (b)

Lawesson’s Reagent, benzene, reflux, 30 hr all starting material was recovered.

44

When an EWG is substituted on the olefin of substrates, the deprotonation of hydroxyl group leads

to cyclization via 5-exo-trig even at very low temperature (see Scheme 1.31). To avoid this unwanted

result, we decided to use an unactivated olefin like compound 1-87.

TBSOPhNCS

O O

TBSO

O O

a+

1-87 1-109

OH O

NHS

Scheme 1. 31. Thiocarbamation of Unactivated Olefin 1-109: (a) NaH, THF, rt, 11 h, 96%.

After the substrate was deprotonated by NaH at rt, phenylthioisocyanate was added and the

mixture was stirred at rt for 11 h to give compound 1-109. The proton NMR of isolated compound was

complex, but presence of an olefin (1 H of multiplet at 5.69-6.01 ppm 2 H of multiplet at 5.11-5.32 ppm)

and a thioamide functionality (1H of broad singlelet at 0.53 ppm, which accounts for NH hydrogen of

thioamide) was obvious. The structure can be further confirmed by both 13C NMR (thioamide carbonyl

group at 187.0 ppm, olefin carbon at 117.5 and 122.1 ppm) and IR spectrum (thioamide I peak at 1539 cm-

1, thioamide II peak 1381cm-1, thiocarbonyl group at 1597 cm-1, and NH asymmetric stretching hydrogen

bond 3241 cm-1). We tried to purify the compounds several times by column chromatography and by Prep

TLC, but they always show the same spectra. Because it has been reported30 some thiocarbamate can

undergo slow amide rotation at rt, which account for the complex 1H spectrum, we used this compound for

the 5-exo-trig radical cyclization study without further purification.

Although a series of symmetrical thioureas has been available in the literature, most of them are

less moisture sensitive and thus expected to have lower reactivity comparing to 1,1-thiocarbonyl

45

diimidazole. One thiourea of particular interest is the 1,1-thiocarbonyl di-(1,2,4-triazole) which is more

reactive than imidazole substituted thiourea. For example, 1,1-thiocarbonyl di-(1,2,4-triazole) reacts with

two equivalent of phenol at 25 oC to give dipenylthionocarbonate whereas 1,1-thiocarbonyl diimidazole

requires much higher temperature (90 oC).

The thocarbamation was performed with 1,1’-thiocarbonylditriazole and DMAP under reflux

condition. Unfortunately, the low reactivity of 1,1’-thiocarbonylditriazole led to low yield of the desired

product 1-110. Prolonged the reaction time and addition of more 1,1’-thiocarbonylditriazole did not

improve the reaction and only 28% (70% based on recovered starting material) of 1-110 and starting

material were recovered after column chromatography. The structural assignment was straightforward with

the compound exhibiting the two singlet peaks at down field (at 8.02 and 8.85 ppm) in 1H NMR spectrum.

The thiocarbonyl group was confirmed by observing a singlet peak at 180.69 ppm in 13C NMR spectrum

and a C=S stretching υ = 1239 cm-1 in the IR spectrum.

OHTBSO

O O

TBSO

O O

a

1-80 1-110

O

NS

NN

CO2tBu CO2

tBu

Scheme 1.32. Thiocarbamation of 2-81 with 1,1’-Thiocarbonylditriazole: (a) 1,1’-thiocarbonylditriazole,

DMAP, THF, reflux, 12 h, 28% (70% based on recovered 1-80).

We attempted the thiocarbmation of 1-80 under the standard thiocarbamation condition: refluxing

of the mixture of 1-80, 1,1-thiocarbonyldibenzimidazole, and catalytic amount of DMAP in THF.

Unfortunately, no desired product was obtained and 69% of starting material 1-80 was recovered after

column chromatography. Bliss reported in his Ph. D. dissertation that the thiocarbamation of 1-80 was

46

successfully achieved in 80% at -33 oC. He first deprotoned the hydroxyl group of 1-80 to increase the

nucleophilicity of the oxygen group and added 1,1-thiocarbonyldibenzimidazole. Although we followed

the exactly same procedure, only starting material 1-80 was recovered quantitatively after purification by

column chromatography. In the next we attempt slightly modified Bliss’ procedure: deprotonation by

sodium hydride at rt. Fortunately, we could isolate the desired product 1-111 as 46% yield (based on

recovered starting material) by column chromatography, but there is still more room to improve the yield of

this reaction.

TBSO

O O

a or b

1-111

O

NS

CO2tBu

TBSO

O O

1-80

OH

CO2tBu

N

c TBSO

O O

1-80

OH

CO2tBuX

Scheme 1.33. Preparation of Benzimidazole Derivative 1-111: (a) 1,1-thiocarbonyldibenzimidazole,

DMAP, THF, reflux, 17h, 1-80, 69%; (b) 1,1-thiocarbonyldibenzimidazole, KH, DME, -33 oC to rt, 3h, 1-

80 100%; (c) 1,1-thiocarbonyldibenzimidazole, NaH, DME, rt, 2.5h, 12% (46% based on recovered 1-80).

We expected the imidazole of 1-81 might be replaced by benzimidazole under equilibrium

conditions (the pKa of imidazole is known as 18.6 in DMSO and the pKa of benzimidazole is16.4 in

DMSO).69 Gratifyingly, our expectation was realized by heating the mixture of 1-81, benzimidazole and

catalytic amount of DMAP at 130 oC. After heating for 13 h, the desired product 1-111 was isolated as

85% yield based on recovered starting material, and spectroscopic results of the isolated product was in

agreement with previous results in Bliss’ dissertation.

47

TBSO

O O

a

1-111

O

NS

CO2tBu

N

TBSO

O O

1-81

O

NS

N

CO2tBu

Scheme 1.34. Alternative Preparation of Benzimidazole Derivative 1-111: (a) benzimidazole, DMAP,

heating at 130 oC, 13 h, 62% (85% based on recovered 1-81).

To make more number of thiocarbamate we used indole and 1, 1’-thiocarbonyldiindole under our

optimized reaction condition. However, the reaction of 1-81 with indole and catalytic amount of DMAP at

high temperature failed. We also attempted thiocarbaamtion not only with 1, 1’-thiocarbonyldiindole and

DMAP under refluxing condition, but also with 1, 1’-thiocarbonyldiindole and NaH to increase the

nucleophilicity. However, all attempts were unsuccessful and the stating material either decomposed or

was recovered quantitatively.

TBSO

O O

a

1-112

O

NS

CO2tBu

TBSO

O O

1-81

O

NS

N

CO2tBu

XTBSO

O O

1-80

OH

CO2tBuX

b or c

Scheme 1.35. Preparation of Indole Derivatives: (a) indole, DMAP, heating at 130 oC, 10 h, 1-81 91%; (b)

1, 1’-thiocarbonyldiindole, DMAP. THF, reflux, 12h, decomposed; (c) 1, 1’-thiocarbonyldiindole, NaH,

DME, rt, 12h, 1-80 94%.

48

Our ultimate goal of this research was the synthesis of natural and/or unnatural nucleoside

synthesis via 5- or 6-exo radical cyclization, readily available nucleoside base such as adenine was chosen

for further exploration. The reactions were performed with either thiocarbonyldi(N-benzoyladenine) and 1-

80 or N-benzoyladenine and 1-81. Unfortunately, none of them was successful in our hands and the only

isolated compounds were 1-80 and 1-81 as 58% yield and 27% yield, respectively.

TBSO

O O

aO

NS

N

N

N

TBSO

O O

OH

NHBz

XCO2tBu CO2

tBuTBSO

O O

O

NS

N

CO2tBu

b

X

1-80 1-811-114

Scheme 1.36. Failed Attempts to Prepare Adenines: (a) thiocarnonyldi (N-benzoyladenine), THF,

refluxing, 30h, 1-80 58%; (b) N-benzoyladenine, DMAP, heating at 130 oC, 10 h, 1-81, 37%.

Another triazole derivative was made from the 2,3-O-(1-methylethyldiene)-5-O-[(1,1-

dimethyl)ethyl dimethylsilyl]-D-ribose, O-methylhydroxyl amine 1-89. A similar reaction condition for

imidazole derivatives was applied, but used 1,1’-thiocarbonylditriazole for the thiocarbamation instead of

1,1’-thiocarbonyldiimidazole. As previously shown in the synthesis of another triazole derivative 1-110,

some starting material was recovered in spite of prolonged reaction time (38% recovered) and the desired

product 1-116 was isolated as 74% of yield. The isolated product was a syn/anti mixture in a ratio of

1.69/1.00 based on 1H NMR analysis. The configuration of the product was assigned by 1H NMR spectrum

with the characteristic peak of hydrazone appearing at 7.34 ppm (d, J = 7.6 Hz, 1H) for syn comound and at

6.88 ppm (d, J =5.4 Hz, 1H) for anti compoundnd. Two pairs of hydrogen peaks on the triazole ring at δ

8.05 and 8.92 ppm for the syn isomer, and 8.05 and 8.93 ppm for the anti isomer was also observed. One

49

pair of thiocarbonyl peaks at down filed in 13C NMR spectrum was further support of the structural

assignment (180.54 and 180.80 ppm).

To increase the yield the hydroxyl group of 1-89 was deprotected at -78 oC by sodium hydride and

the reaction was performed at -78 oC to rt. Unfortunately, no product was observed on TLC anaysis and

only starting material was recovered as 62% yield. The hydroxyl group was also deprotonated at rt by

sodium hydride followed by stirring the mixture with 1,1’-thiocarbonylditriazole in DME at rt. However,

intermoecular nucleophilic substitution was not observed at all, and the isolated products were not only

starting material 1-89 but also a cyclic compound 1-116 formed via intramolecular nucleoplic 5-exo

cyclization.

OHTBSO

O O

NOCH3 TBSO

O O

NOCH3a

1-89 1-115

O

NS

NN

TBSO

O O

NHOCH3

1-116

O

b or c

Scheme 1.37. Preparation of Triazole Derivative from 1-89: (a) 1,1’-thiocarbony ditriazole, DMAP, THF,

reflux, 16 h, 45% (74% based on recovered 1-89); (b) NaH, THF, -78 oC to rt, 1-89 62% recovered; (c)

NaH, THF, rt, 1-89 45% recovered, cyclic product 1-116, 16%.

Nucleophilic substitution of imidazole to adenine was performed with 1-89 and adenine in THF

under refluxing condition. Because, in general, purines are alkylated under basic condition almost

exclusively at N9 position with small amount of N7 alkylation occurring under neutral condition, we

expected the adenine may replace the imidazole functionality in thiocarbamate 1-89. Unfortunately, we

could not find any positive evidence for the formation of adenine substituted thiocarbamate 1-117.

50

TBSO

O O

NOCH3a or b O

NS

N

N

N

TBSO

O O

NOCH3

1-89

O

NS

N

NH2

X

1-117

Scheme 1.38. Preparation of Benzimidazole Derivatives: (a) adenine, THF, refluxing, 46 h, 1-89 72%

recovered; (b) adenine, THF, DMAP, 46 h, 1-89 recovered in 61% yield.

Scheme 1.39 shows an attempted procedure for making an N-aziridinoimine, which could act as a

radical acceptor. The ring opening of styrene oxide 1-118 was performed with sulfuric acid in water at rt in

good yield (83% yield). The mesylation of styrene glycol had to be performed at -15 oC otherwise large

amount of dimerized product was formed as the major product, and the desired product 1-120 was isolated

as only 7% yield. In the next step 1-amino-2-phenylaziridine was obtained almost quantitatively after

stirring it with hydrazine hydrate in pentane at rt. Unfortunately, the 1-amino-2-phenylaziridine did not

react with 1-79 (see Scheme 1.14, p. 31), and only 1-122 was isolated as the major product (71%). It is

assumed that the precursor 1-121 reacts with acetone generated from deprotecting of the starting hemiacetal

1-79 (p. 31) in ethyl alcohol to give 1-122.

OH

OHOMs

OMs

X

NPh

NCH3

CH3

TBSO

O O

N N

d

a b c

1-118 1-119 1-120 1-121

1-122

OH Ph

NPh

NH2

O

Scheme1.39. Synthetic Route to Prepare Substrates: (a) H2SO4, H2O, 25oC, 83% (b) MsCl, pyridine, -15 oC, 66%, (c) NH2NH2•H2O, pentane, rt, 100%, (d) 1-79, ethyl alcohol, 0oC, 71%.

51

For 6-exo trig radical cyclization the substrate 1-127 was prepared from easily available TBDPS

protected 2(3H)-furanone 1-123 in three steps. The furanone was reduced to the corresponding lactol by

Dibal-H in Et2O at-78 oC. After routine work-up with saturated disodium tartrate, the cured product was

subjected to olefination with stabilized Wittig reagent, Ph3PCHCO2Et, with catalytic amount of benzoic

acid in DME at rt.

PO O

OEt

OH

TBDPSO O

OEt

O

N

S

N

O

O

OP

O

OH

OP

a b

1-123 1-124 1-125 1-126P = TBDPS

1-125

c

1-127

HO O

OEt

OP

PO O

OEt

OH

+

Scheme 1.40. Synthetic Route to Prepare Substrates 1-127: (a) 1.5 M Dibal-H in toluene, Et2O, -78 oC,

>99%, (b) Ph3PCHCO2Et, cat. DME, rt, 34h, 1-125: 64% (E only), 1-126: 3% (E only). (c) 1, 1’-

thiocarbonyldi-imidazole, DMAP, dichloromethane, reflux, 22h, 83%.

The desired olefin 1-125 was isolated as the major product with E configuration, and small

amount of TBDPS migrated compound 1-126 was isolated by column chromatography (3%). The EWG

substituted olefin further reacted with 1, 1’-thiocarbonyldiimidazole under standard conditions for

thiocarbamation to afford 1-127 in 83% yield.

The stereoselective synthesis of (S)-3-hydroxy-γ-lactone 1-129 was achieved from maltose

monohydrate 1-128, which is very cheap sugar.70 This compound may act as a useful precursor of

compound 1-133, which could be subjected to 6-exo-trig radical ring closure. After protection of the

hydroxyl group of 1-129 as a TBS group, the lactone 1-130 was reduced to the corresponding lactol 1-131

52

by Dibal-H at –78 oC, which was subjected to olefination by a stabilized Wittig reagent. After refluxing of

the olefin 1-132 with 1, 1’-thiocarbonyldiimidazole and DMAP in THF for 12 h, the thiocarbamated

compound 1-133 was isolated as 90% yield, which can be used for a precursor of 6-exo trig radical

cyclization.

1-128

OO

O

HOH2C

HO

OH

HO

OH CH2OH

OH

HO

O

HO

O

O

TBSO

O

O

TBSO

OH

1-129 1-130

1-131 1-132 1-133

a b c

d eO

OEtTBSO

OH

O

OEtTBSO

O

N

S

N

Scheme 1.41. Synthesis of 6-Exo trig Radical Precursor 1-133 from Maltose Monohydrate: (a) NaOH,

H2O2, H2O, 70 oC, 24 h, 80%; (b) TBSCl, imidazole, DMF, 0 oC 15 min then rt 27 h, >99%; (c) 1.5 M

Dibal-H in toluene, Et2O, -78 oC, >99%; (d) Ph3PCHCO2Et, toluene, reflux, 2.5 h, 86% (E/Z =4.4/1.0); (e)

1,1’-thiocarbonyldiimidazole, DMAP, THF, reflux, 12h, 90%.

1. 2. 2. Preparation of Precursor for 5-Exo trig Radical Cyclization from Maltose Monohydrate

(S)-3-Hydroxy-γ-lactone 1-129 can be prepared from maltose monohydrate 1-128 in one step.

This compound may act as a useful precursor of compound 1-138, which could be subjected to 5-exo-trig

radical ring closure. After protection of the hydroxyl group of 1-129 as a p-methoxybenzyl ether, the

lactone was reduced to lactol 1-135 at –78 oC, which was subjected to olefination by a stabilized Wittig

reagent. Protection of the substrate 1-136 by a TBS group and subsequent removal or the PMB group by

DDQ gave a precursor 1-138. This route has been well established in the literature,71 but it requires total 5

steps from the (S)-3-hydroxy-γ-lactone 1-129 and several protection and deprotection procedures.

53

O

HO

O

O

PMBO

O

O

PMBO

OH

1-129 1-134 1-135

1-136

a b c

d

1-138

e

1-137

O

OEtOPMB

HO

O

OEtOH

TBSO

O

OEtOPMB

TBSO

Scheme 1.42. Synthesis 1-138 from γ-Lactone: (a) PMB-trichloroacetimidate, CSA, CH2Cl2, rt, 16 h, 39%;

(b) 1.5 M Dibal-H in toluene, -78 oC, 1.5 h, 86%; (c) Ph3PCHCO2Et, toluene, reflux, 2 h, 61% (E/Z

=1.0/0.1); (d) TBSCl, imidazole, DMF, 0 oC 10 min then rt 12 h, 69%; (e) DDQ, CH2Cl2, H2O, rt, 1.5 h,

40%.

However, if we protect the hydroxyl group of (S)-3-hydroxy-γ-lactone 1-129 by a TBS instead of

a PMB group, and then reduce lactone 1-130 to lactol 1-131 followed by olefination with (carbethoxyl-

methylene)triphenyl-phosphorane, 1-132 may be prepared in a high yield (Scheme 1.43, two steps 86%,

E/Z =4.4/1.0). The compound 1-132 was converted easily to 1-138 in absolute methyl alcohol with triethyl

amine as a catalyst via 1,4-TBS group migration (for more detail, see section 1.23).72 Subsequently,

thiocarbamation was successfully performed under the standard protocol described previously. After

column chromatography the desired product 1-139 was obtained as 90% yield.

1-132

a

1-139

b

1-138

O

OEtOTBS

HO

O

OEtOH

TBSO

O

OEtO

N

S

N

TBSO

Scheme 1. 43. Synthesis of 5-Exo trig Radical Precursor 1-138 from Maltose Monohydrate: (a) Et3N,

MeOH, rt; (E) 87%; (Z) 68%, (b) 1,1’-thiocarbonyldiimidazole, DMAP, THF, reflux, 90%.

54

(E)-Ethyl 6-hydoxy-5(S)-{[(1,1-dimethyl)ethyl dimethylsilyl]oxy}-2-hexenoate 1-138 was reacted

with 1, 1’-thiocarbonylditirazole and DMAP in THF solution under reflux conditions with the hope of

making triazole substituted thiocarbamate. After 6h refluxing most starting material decomposed and the

desired product was not formed at all. Next, we turned our goal to make a thiocarbonate from the olefin 1-

138. The initial plan was to make a benzoate, which may be further converted to thiobenzoate by

Lawesson’s reagent. However, we discarded this plan because the first step, benzoylation of 1-138, was

not successful under two representative conditions for the bezoylation: DMAP, CH2Cl2, and rt, and DMAP,

pyridine, 0 oC to rt.

a

1-138

O

OEtOH

TBSOO

OEtO

N

S

NN

TBSO

X Xb or c

O

OEtO O

TBSO

Scheme 1.44. Failed Attempts to Prepare Radical Reaction Precursor from 1-138: (a) 1, 1’-

thiocarbonylditirazole, DMAP, THF, 6h, reflux, 1-138 16% recovered ; (b) benzoyl chloride, DMAP,

CH2Cl2, rt, 1-138 100% reccovered; (c) benzoyl chloride, DMAP, pyridine, 0 oC to rt, starting material

decomposed.

Although there is a possibility to attack activated carbonyl group of 1-139, we endeavored

thiocarbonation of 1-139 by nucleophilic substitution of the thiocarbonate with phenylmagnesium bromide

in diethyl ether at 0 oC to rt. After 26 h reaction, most starting material was recovered and no desired

product could be isolated by column chromatography.

Several nitrile, oxime, and hydrazone substituted olefins were made from (S)-3-TBS-γ-lactol 1-

131 in DME, CH2Cl2, or absolute methyl alcohol under refluxing (Scheme 1.46). The isolated yield was in

the range of 80% to 26%. Because the applied condition was basic, the TBS group of 1-140 migrated with

55

an EWG group substituted olefin via 1, 4-TBS migration (see Chapter 1, section 1.23 for detailed study of

1, 4-TBS migration) to give 1-145 as a minor product. The TBS group of N,N-dimethylhydrazone

substituted olefin also migrated easily to give 1-148 as the major product and only 26% of the desired

product 2-64 was obtained. The isolated products, 1-143 and 1-148 both were assigned as anti

configuration based on 1H NMR spectra shown the characteristic peaks at 6.61 (t, J = 5.4 Hz) ppm and 6.68

(t, J = 4.7 Hz) ppm, respectively.

a

O

OEtO

N

S

N

TBSO

XO

OEtO S

TBSO

1-139

Scheme 1.45. Reaction of 1-139 with Phenylmagnesium Bromide: (a) PhMgBr, Et2O, 0 oC to rt, 26h, 1-

139 77% recovered.

O

TBSO

OH

1-131

a

TBSO

OH

XX

1-140 X = CN1-141 X = NOCH31-142 X = NOH1-143 X = NN(CH3)21-144 X = NNPh2

b

TBSO

OH

Y

Y = NNHC6H -ClY = NCH3Y = NNHTs

Scheme 1.46. Preparation of Nitrile, Oxime, and Hydrazone Substituted Olefins: (a) X = CN, Ph3PCHCN,

DME, rt, 24 h, 63% (E/Z =1.0/0.45) of 1-140 5% of 1-145, X = NOCH3, CH3ONH2, pyridine, CH2Cl2,

reflux, 43 h, 36%; X = NOH, NH2OH•HCl, pyridine, CH2Cl2 and H2O, rt, 21.5 h, 80%; X = NN(CH3)2,

H2NN(CH3)2, MeOH, rt, 6h, 26%, 1-149 63%; X = NNPh2, Ph2NNH2•HCl, pyridine, MeOH, rt, 2 h, 65%;

(b) Y = NNHC6H4-Cl, Cl-C6H4NHNH2•HCl, pyridine, MeOH, rt, 3h, decomposed; Y = CH3N,

CH3NH2•HCl, CH2Cl2, H2O, reflux, decomposed; Y = NNHTs , H2NNHTs•HCl, MeOH, reflux,

decomposed.

56

The desired compound could be made after stirring the mixture with pyridine at rt, and the

isolation of hydrazone derivatives can be facilated by addition of 1% Et3N during the column

chromatography. Although many of nitrile, oxime, and hydrazone substituted olefin were made from (S)-3-

TBS-γ-lactol 1-131, it was difficult to make some hydrazone substituted compounds under the applied

reaction condition because the TBS group is easily destroyed in spite of using excess amount of pyridine to

quench the acid in situ (similar result was observed in previously, see Scheme 1.23 in p. 38)

The substrates shown in Scheme 1.47 were subjected to the TBS migration with bases in methyl

alcohol. More detailed studies of TBS migration are discussed in section 1.2.3 and the results are

summarized in Table 1.1, 1.2, and 1.3 at end of this chapter. The 1, 4-TBS migration was applied for

preparing the precursors of 5-exo-trig radical cyclization, which will be discussed later in section 1. 2. 3.

The TBS migration works well with either an electron deficient acceptor or imine-containing

substituents. However, if a strong EWG such as CN is substituted, some of starting material would cyclize

via 5-exo-trig mode before the TBS migration. Because the starting material and product are prone to

equilibrium, it is impossible to get the only desired product, but they can be separated by column

chromatography and the major product is a 1,4-TBS-migrated compound. If the reaction is repeated, useful

amount of desired products can be prepared.

OHY

TBSO

OTBS

HO

X

1-132 X = CHCO2Et1-140 X = CHCN1-141 X = NOCH31-142 X = NOH1-143 X = NNMe21-144 X = NNPh2

a

1-138 X = CHCO2Et1-145 X = CHCN1-146 X = NOCH31-147 X = NOH1-148 X = NNMe21-149 X = NNPh2

Scheme 1.47. TBS Group Migration in MeOH: (a) 1-132, Et3N, MeOH, rt; X = CHCO2Et (E), 87%, X =

CHCO2Et (Z), 68%; 1-140, X = CHCN (E and Z) 86%; 1-141, X = NOCH3, 100%; 1-142 X = NOH, 80%;

21-143 X = NN(CH3)2, 33%; 1-144, X = NNPh2, 100%.

57

If the isolated 1-138 (E) was thiocarbamated with 1,1’-thiocarbonyldiimidazole in dichlorometh-

ane or THF to 1-139 in a 90% yield. The same thiocarbamation was performed with compound 1-145 in

the similar conditions of the above procedure, but the isolated yield of desired product 1-150 was moderate

(68%). Diphenyl hydrazone substituted subatrate 1-149 could be converted to thiocarbamate derivatives 1-

151 as 56% yield.

OTBS

HO

X (or Y)

YOTBS

N

S

N

XOTBS

N

S

N

Xb a

1-138 X = CHCO2Et1-145 X = CHCN1-146 X = NOCH31-149 X = NNPh2

1-139 X = CHCO2Et1-150 X = CHCN1-151 X = NNPh2

Y = NOCH3

Scheme 1.48. Preparation of Thiocarbamates: (a) 1,1’-thiocarbonyldiimidazole, DMAP, dichloromethane

or THF, reflux; 1-138 X = CHCO2Et (E), to 1-139 90%; 1-145 X = CHCN (E and Z), to 1-150 68%; 1-149

X = NNPh2, to 1-151 56%. (b) 1-146 Y = NOCH3, decomposed.

Although we failed to effect the benzoylation of (E)-ethyl 5(S)-hydoxy-6-{[(1,1-dimethyl)ethyl

dimethylsilyl]oxy}-2-hexenoate 1-138, we further studied the reaction with hydrazone derivative 1-149

because of the interesting phenyl group migration that has been reported in the intramolecular cyclization

of Barton’s radical intermediate. After 46 h all starting material was consumed, only a single product was

isolated in 50% yield by column chromatography. The hydroxyl group of the substrate 1-149 was

successfully protected by a benzoyl group, but the silyloxy group at C-3 and hydrogen at C-2 eliminated

during the reaction. We did not optimize the reaction further to make the phenyl substituted substrate.

58

1-151 1-149

a aNNPh2

TBSO

OH

NNPh2

TBSO

O ONNPh2

O O X

Scheme 1.49. Failed Attepts to Prepare N, N’-Diphenyl hydrazone Derivative: (a) benzoyl chloride,

DMAP, CH2Cl2, rt, 46h, 50%.

Because the 1, 4-TBS-migration is an equilibrium reaction at rt, it is impossible to get only

migrated product. Moreover, it is very difficult to isolate the desired product only because they decompose

easily during column chromatography: They have very similar Rf values. To overcome these limitations,

the mixture of 1-133 (E and Z) and 1-139 (E and Z) was reacted without column chromatography, and

thiocarbamation was performed with the mixture under the traditional condition. The combined yield of

the mixture of 1-152 (E and Z) and 1-153 (E and Z) was 69% (total 4 compounds and they have almost the

same Rf values). Unfortunately, it was impossible to isolate all 4 products, but only two mixtures were

obtained as a mixture of (E)-1-133 and 1-139 and a mixture of (Z)-1-133 and 1-39.

O

S

N

OEtOTBS

N

O

OEt

N

N

S

OTBS

+O

S

N

OEtOH

N

O

OEt

N

N

S

OH

+a

1-133 1-139 1-152 1-153

Scheme 1.50. Deprotection of a TBS Goup of Thiocarbamate Derivatives: (a) TBAF, THF, 0 oC to rt.

59

After several failed attempts to separate them by column chromatography, the (E)-1-133 and (E)-

1-139 mixture was treated by TBAF at 0 oC to rt to give desilyated products 1-152 and 1-153, with the hope

that may have different Rf values. However, those compounds have the same Rf value, and we failed to

separate them by column chromatography. No further attempt was made to desilyate of a mixture of (Z)-1-

133 and (Z)-1-139 containing mixture.

-0.82 (c 1.84, CHCl3)[α] D20 = +0.62 (c 0.97, CHCl3)[α] D

20 =

HN Ph

CO2EtTBSO

Xaa

1-154 1-155

1-154 1-138 1-156

nBu3SnH

O

OEtHN S

TBSO

O

OEtHN S

TBSO

O

OEtOH

TBSO

O

OEtOH

TBSO

Scheme 1.51. Proposed 5-Exo trig Process for the Formation of Pyrolidines: (a) PPh3, DEAD, PhCSNH2,

THF, 0 oC to rt for 30 min, then reflux for 12 hr, 67%.

Pyrrolidines like 1-155 are widely present in the nature. If we can make thioamide derivatives like

1-154, they can be subjected to 5-exo-trig-radical process to give pyrrolidine derivative 1-155 via the

Barton’s radical intermediate. The 2o hydroxyl group of the compound 1-138 may be a subjected to the

Mitsnobu reaction. We tried the conversion of the 2o hydroxyl group to a thioamide group under the

standard Mitsuniobu condition, but the coupling between hydroxyl group and thioamide was not successful

and we isolated only a single product which has the same spectroscopic characteristrics of 1-138. Based on

60

opposite optical rotation value we assigned the isolated product was 1-156: the optical rotation value for 1-

138, [α] D20

= -0.82 (c 1.84, CHCl3); for 1-156, [α] D20

= +0.62 (c 0.97, CHCl3).

To make phenyl substituted thiocarbamate, phenylisocyanate was reacted with compound 1-138

under reflux condition. The reaction was completewithin several hours with an excellent yield, and the

isolated compound 1-1557 was subject to Lawesson’s reagent in toluene. However, the desired product

was not formed after 16 h refluxing and all starting material completely decomposed. Because of the

difficulty of thiocarbonylation by Lawesson’s reagent, an attempt was made react the substrate 1-138 with

thioisocyanate to make desired product. Unfortunately, however, the attempts were not successful because

of low electrophilicity of thiocarbonyl groups.

O

OTBS

CO2Et

a

1-1571-138

c

1-159

O

OEtOH

TBSO

O

OEtO

TBSO

NHPh

1-138

O

OEtOH

TBSO

1-158

O

OEtO

TBSO

NHPh

SX

X

b

d or e

O

Scheme 1.52. Failed pathway to prepare thiocarbamate 1-158: (a) PhNCO, Et3N, benzene, reflux, 5 h,

96%. (b) Lawesson’s reagent, toluene, reflux, 16 h, decomposed. (c) PhNCS, NaH, THF, rt, 3 h, 56%, (d)

PhNCS, Et3N, benzene, reflux, 24 h, Most srarting material was recovered, (e) (Bu3Sn)2O, PhNCS, tolene,

reflux, decomposed.

Alternatively, the substrate 1-138 was refluxed with (Bu3Sn)2O and PhNCS in toluene because tin

ether RO-SnBu3 may have better nucleophicity than alcohol. Unfortunately, most starting material

decomposed. To overcome the low electrophilicity of the thiocarbonyl group, the hydroxyl group of

61

substrate 1-138 was deprotonated by sodium hydride at low temperature and added thioisocyanate at rt, but

only cyclized compound 1-159 was isolated as a major compound (56% yield).

1. 2. 3. 1, 4-Migration of a tert-Butyldimethylsilyl (TBS) group: An Expeditious of Synthesis of

Substrates

The TBS group is widely used as a protecting group because of easy installation and removal from

1o or 2o hydroxyl groups. It has been reported that the migration of O-silylated group can be promoted in

the presence of bases in a variety of solvents such as DMF, DMSO, CH2Cl2, and MeOH. The intermediate

for the migration possibly involves penta-coordinated silicon, which may be in a 5- or 6-membered cyclic

ring. Even though the 1o silyloxy group is preferred to 2o silyloxy group, it is not possible to get 1o O-

protected product alone because of the equilibrium between 1o and 2o silyloxy groups. While most research

groups have concentrated on studying 2o to 2o migration of TBS group, few references deal with the 2o to 1o

migration of silyl groups. In this section, such a silyl migration is described. This strategy was

successfully applied to shorten a reaction scheme by saving protecting/deprotecting steps (see Scheme 1.46

and 1.47).

1-132 1-1381-132'

O

OEtOH

TBSO

O

OEtTBSO

OH O

OEtOSi O

CH3tBu

H3CH+

Scheme 1.53. Mechanism of TBS Group Migration.

Table 1.1 shows a detailed study of 1, 4-TBS migration with a variety of bases and solvents. To

find the best conditions for the 1, 4-TBS group migration in our substrates, we studied the reaction

62

systematically under the different conditions such as use of different bases, equivalents of bases, and

solvents. Because we realized a TBS group could migrate from C-5 to C-6 during the olefination of

substrate 2-53 (see Scheme 1.47), initially we started the investigation with ethylene triphenylphosphorane

as a base under different conditions. First, the migration was evaluated in absolute methyl alcohol with

(carbethoxy methylene)triphenylphosphorane. After stirring at rt for 17 h, 49% of 1-132 was converted to

1-138 based on GC analysis (Entry 3). However, the prolonged reaction time (36 h) did not increase

significantly the ratio of 1-132 to 1-138 because they are in equilibrium in solution (Entry 4). When

another protic solvent, isopropyl alcohol (Entry 6), was used as the solvent instead of methyl alcohol, the

reaction did not proceed at all even after 48 h stirring at rt; and only starting material 1-138 was detected by

GC analysis. Earlier investigation67shows the TBS migration works well in aprotic solvents as well as

protic solvents, and dichloromethane is one of the commonly used aprotic solvent for TBS migration.

When dichloromethane was used as the solvent in our system, however, the only detectable compound was

starting material after 24 h (Entry 5). At this time, more common organic and inorganic bases were tested.

Use of K2CO3 resulted in deprotonation of the hydroxyl group and cyclization to give 1-159 via 5-exo-trig

within 1 hour (Entry 7). A strong organic base DBU also gave the cyclic compound (Entry 2), but DABCO

gave 10% of desired product 1-138 after 24 h at rt (Entry 1). When 1.0 equivalent of pyridine was used for

the reaction, no compound 1-159 was found even after 4 days at rt (Entry 14), but 2.0 equivalents of

pyridine under the same condition converted 5% of 1-132 to 1-138 after 48 h stirring (Entry 15). The

conversion was promoted without any base in absolute methyl alcohol but it was very slow (Entry 16).

After several attempts, we found triethyl amine is the best catalyst for the 1, 4-TBS migration in methyl

alcohol. The best conditions were found to be using 4.0 equivalents of triethyl amine (Entry 9, 10, and 11);

but there was no big difference if more than 2 equivalents of bases were used; excess amount of triethyl

amine suppressed the TBS migration (or accelerate the equilibrium) to give the almost 1 to 1 ration of 1-

132 and 1-138 (Entry 12). Moreover, the TBS group migration did not proceed at all without added methyl

alcohol (thus, 80% of the starting material could be isolated under these conditions, Entry 13).

63

1-132 1-138 1-159

+base

O

OEtOH

TBSO

O

OEtTBSO

OH O

TBSO

CO2Et

Entry Base Equiv. Solventa Time (h) 1-132 -138 -159

(%)b

1 DABCO 1.0 MeOH 24 90 10 0

2 DBU 1.0 MeOH 24 0 0 100

3 1.0 MeOH 17 51 49 0

4 MeOH 36 55 45 0

5 CH2Cl2 24 100 0 0

6

Ph3P=CHCO2Et

iPrOH 48 100 0 0

7 K2CO3 1.0 MeOH 1 0 0 100

8 1.0 MeOH 72 30 70 0

9 2.0 MeOH 48 24 76 0

10 3.0 MeOH 48 21 79 0

11 4.0 MeOH 48 20 80 0

12 2 mL MeOH 48 42 58 0

13

Et3N

2 mL No Solv. 48 100 0 0

14 1.0 MeOH 4 days 100 0 0

15

Pyridine 2.0 MeOH 48 95 5 0

16 No Base MeOH 8 days 91 9 0

a. The concentration of substrate was 18 mM. b. The ratio is based on GC analysis

Table 1. 1. The 1,4-TBS Group Migration in a Variety of Conditions.

64

Table 1.2 demonstrates the effect of triphenylphophine oxide on the TBS group migration. The

(S)-3-hydroxyl-γ-lactone 1-129 was converted to ethyl-5-O-[(1,1-dimethylethyl)dimethylsilyl]-6-hydroxy-

hex-2-enonate 1-132 in three steps without any purification (see Scheme 1.45 and 1.47). The product

contains some solid phosphine oxide even after several filtrations. The crude product was dissolved in

absolute methyl alcohol, and required base was added as shown in Table 1.2. The table shows that

triphenylphosphine oxide might work as a base in the TBS migration (Entry 5 compare with Entry 16 in

Table 1). When some organic bases or 1 equivalent of ethylene phosphorane was added, the starting

material 1-132 was converted to 1-138. Addition of excess (5.0 Eq.) Et3N promoted the cyclization of 1-

138 in a short time.

Table 1.3 shows the result of TBS migration in different olefinic substrates. The yield is based on

recovered starting material, and the numbers in parenthesis are isolated yields. The TBS migration was not

affected by substituents, but more cyclized product was isolated when a CN group was substituted (Entry 7

and 8). Because a CN is a strong EWG, the cyclized product can be formed more easily. Those silyl group

migrations do work well with a nitrogen substituted olefins. When the substituent is NOCH3, 41% of

product was obtained after 48 h (Entry 9), but the yield increased to 69% after 72 h stirring at rt (Entry 10).

Unfortunately, prolonged reaction does not help to increase the yield significantly (71%, Entry 11), but

decrease the yield of recovered starting material; the yield based on recovered starting material decreased

from 100% to 88%. The similar results were observed with diphenyl hydrazone derivative. After 96 h

reaction, 65% of desired product was obtained by column chromatography (Entry 15). The yield accounts

for 100% based on recovered starting material. However, prolonged reaction time led low recovery of

starting material, and the yield decreased up to 82% based on the recovered starting material (Entry 16).

The TBS group of oxime-substituted derivative could also be migrated from 2o position to 1o position and

the isolated yield was 62% after 7 days stirring at rt (Entry 12). Unfortunately, dimethyl substituted

compound decomposed easily at rt, which caused the low yield of migrated product as well as low recovery

of starting material (Entry 13).

65

1-132 1-138 1-159

+base

O

OEtOH

TBSO

O

OEtTBSO

OH O

TBSO

CO2Et

Entry Base Equiv. Solvent Time(h) 1-132 -138 -159

(%)a

1 DBU 1.0 CH2Cl2 19 3 14 29

2 K2CO3 1.0 MeOH 1 0 0 35

3 1.0 MeOH 10 0 35 0

4 5.0 MeOH 108 0 1 40

5

Ph3P=CHCO2Et

Et3N

No Base MeOH 140 74b 26b 0

a. Yield is isolated yield from lactone 1-129 (total 4 steps). b. The number is the ratio from GC analysis

Table 1. 2. The Effect of Triphenylphosphinoxide in TBS Migration.

66

+base

X

OH

TBSO

X

TBSO

OH O

TBSO

X

1-160 1-161 1-162

Entry X Eq Conc. a Time (hr) Yield (%)b

1-161 1-162

1 (E,Z)-CHCO2Et 1.5 49 mM 96 98 (55)

2 (E)-CHCO2Et 1.5 53 mM 48 87 (57)

3 (E)-CHCO2Et 1.2 9 mM 96 65 (43)

4 (Z)-CHCO2Et 1.2 6 mM 96 68 (34)

5 (E)-CHCO2Et 2.0 18 mM 72 80 (53)

6 (Z)-CHCO2Et 3.0 18 mM 48 56 (42)

7 (E)-CHCN 4.0 18 mM 48 52 (42) 29 (23)

8 (E,Z)-CHCN 2.0 18 mM 72 86 (81) 4 (3)

9 NOCH3 2.0 18 mM 48 51(41)

10 NOCH3 2.0 18 mM 72 100(69)

11 NOCH3 2.0 18 mM 5 days 88(71)

12 NOH 2.0 18 mM 7 days 80(62)

13 NN(CH3)2 2.0 27 mM 48 38 (33)

14 NNPh2 2.0 18 mM 72 95(63)

15 NNPh2 2.0 18 mM 96 100(65)

16 NNPh2 2.0 18 mM 5 days 82(59)

a. Concentration of a substrate in solvents. b. Isolated yield based on recovered starting material. The number in parenthesis is based on starting material.

Table 1. 3. The 1,4-TBS Group Migration with a Variety of Olefins.

67

1. 2. 4. Preparation of Precursors for 5-Exo trig Radical Cyclization from D-Glucose

Conformational control by preexisting ring can often be used to improve the stereoselectivity of

radical annulation processes. To explore this possibility in the present context, we prepared a series of

thiocarbonyl imidazolides starting from readily available D-glucose 1-163 and subjected them to the

cyclization conditions.

The synthetic route is shown in Scheme 1.54 First, two hydroxyl groups at C-5 and C-6 were

protected by benzaldehyde dimethyl acetal in DMF. Because of the reaction is reversible, the unavoidable

byproduct, methyl alcohol, has to be removed successively from the reaction mixture by house vacuum

during the reaction period. After column chromatography eluting with EtOAc (with 1% of Et3N), the

desired product 4,6-O-benzylidene-D-glucopyranose 1-165 was isolated as 56% yield. Two carbons of the

benzylidene glucose were degraded by 2.02 equivalent of sodium periodate and 8 N sodium hydroxide

solution. After removal of the solvent, the product 5(R)-hydroxy-2(R)-phenyl-[1, 3]dioxane-4(R)-

carbaldehyde 1-165 was isolated.

O OO

O

D-glucose

OO O

OO

O

used for the next step without purification

1-163 1-164 1-165 1-165'

OH

OHOH

HO

OH

OH

OH

O

O

H

PhOH OHPh

CHO

Ph

Ph

OH

HO

a b

Scheme 1. 54. The Synthesis of 5(R)-hydroxy-2(R)-phenyl-[1, 3]dioxane-4(R)-carbaldehyde: (a)

benaldehyde dimethylacetal, p-TsOH, DMF, 60 oC; (b) NaIO4, 8N NaOH, H2O, 0 oC.

The 1H and 13C NMR spectra of the crude mixture were complex, but they implied that the crude

mixture contained at least three compounds. We also could not find the characteristic peaks for the

aldehyde functionality of 1-165 at down field in 13C NMR spectrum. Moreover, five carbon peaks between

68

57 and 96 ppm may imply the carbons are associated with oxygen functionality and the compound was

tentatively assigned the structure 1-165’, which is presumably in equilibrium with 1-165.

The crude mixture was isolated from the reaction mixture by column chromatography, but the

isolated yield was much lower than expected, and the purified compound showed the exactly same 1H and

13C NMR spectra and the same Rf values on TLC analysis. Although the crude mixture itself is enough to

use in the next reaction, we pre-dissolved it in ethyl acetate and dried under vacuum to minimize inorganic

salts in the crude mixture. The crude 5(R)-hydroxy-2(R)-phenyl-[1, 3]dioxane-4(R)-carbaldehyde 1-165

was used directly with appropriate Wittig reagent, O-methylhydroxylamine, O-benzylhydroxylamine, or

N,N-dimethylhydrazine for the preparation of the starting material.

The olefination of 5(R)-hydroxy-2(R)-phenyl-[1,3]dioxane-4(R)-carbaldehyde 1-165 was per-

formed with stabilized Wittig reagents such as tert-butyl (triphenylphosphoranylidene)acetate, ethyl

(triphenylphosphoranylidene)acetate, or (cyanomethylene)triphenylphosphine. The α,β-unsaturated ester

1-166 and 1-167 were formed as a E/Z mixture, which could be separated by column chromatography. The

ratio of E/Z was dependent on the solvent used. For example, the E/Z of 2-88 was 1.0/1.9 with toluene as

the solvent, but the ratio decreased to 1.0/2.4 with DME without any significant change of the isolated

yield. Interestingly, if tert-butyl (triphenylphosphoranylidene)acetate was used as the Wittig reagent, the

E/Z ratio of 2-89 increased up to 1.0/5.5 despite the use of toluene as the solvent.

An EWG substituted α,β-unsaturated compounds (E)-1-166, (Z)-1-166, (E)-1-167, (Z)-1-167,

(E)-1-168, and (Z)-1-168 were subject to thiocarbamation with 1,1’-thiocarbonyldiimidazole and catalytic

amount of DMAP in THF under the refluxing condition. Most products were isolated as pure forms by

column chromatography, but 1-172 and 1-174 were slightly contaminated with unknown isomers. The

isolated yield of the products range from excellent (96%) to good (70%), and each of the compounds were

characterized by 1H NMR, 13C NMR, IR, and elemental analysis.

To explore more examples of 5-exo-trig radical cyclizations, oxime and hydrazone derivatives

were made from 5(R)-hydroxy-2(R)-phenyl-[1, 3]dioxane-4(R)-carbaldehyde 1-165, and the results are

summarized in Scheme 1.56. The desired compound could be synthesized excellent to good yield, and they

were isolated by column chromatography. The isolated O-methyl oxime derivative 1-175 and O-benzyl

69

OO

OO O

OO

O

1-165 1-165'

OHPh

CHO

Ph

Ph

OH

HO

OO

OHPh

CNOO

OPh

CN

Im

S

OO

OPh Im

S

NC

OO

OHPh

CO2tBu

OO

OPh Im

StBuO2C

OO

OPh

CO2But

Im

S

OO

OHPh

CO2Et

OO

OPh Im

S

EtO2C

OO

OPh

CO2Et

Im

S

1-168

1-173

1-174

1-167

1-166

1-171 1-172

1-169 1-170

90% (E/Z = 1.0/2.4) with DME90% (E/Z = 1.0/1.9) with toluene

93% (E/Z = 1.0/2.3)

82% (E/Z = 1.0/5.5)

a

b

c

d e

f g

h

i

Scheme 1. 55. Synthesis of α,β-Unsaturated Ester and Its Thiocarbamate Derivatives: (a) Ph3PCHCO2Et,

toluene, 1.5h, 90% (α/β = 1.0/1.9), or Ph3PCHCO2Et, DME, 26h, 90% (α/β = 1.0/1.9); (b) Ph3CHCO2tBu,

toluene, 4h, 82% (α/β = 1.0/5.5); (c) Ph3PCHCN, toluene, 12h, 93% (α/β = 1.0/12.3); (d) Im(C=S)Im,

DMAP, THF, 33h, 96%; (e) Im(C=S)Im, DMAP, THF, 38h, 89%; (f) Im(C=S)Im, DMAP, THF, 6h, 81%;

(g) Im(C=S)Im, DMAP, THF, 28h, 70%; (h) Im(C=S)Im, DMAP, THF, 12h, 70%; (i) Im(C=S)Im, DMAP,

THF, 12h, 80%.

70

oxime derivative 1-176 were syn/anti mixture with a ratio of 1.0/0.18 and 1.0/0.14, respectively, and they

were inseparable by column chromatography. The ratio of syn/anti mixture was determined by the

characteristic peak of oxime in NMR spectroscopy. Generally, the carbon peak of the CH=N for the syn

isomer appears at higher field in 13C NMR but the hydrogen peak of the CH=N for anti is shown at higher

field in 1H NMR.

The hydrazones were found to exist as a single geometric isomer by NMR spectroscopy and they

were assigned as anti (E) isomers. The anti geometries were confirmed by their characteristic peaks on 1H

NMR, which were shown at δ 6.63 (d, J = 3.2 Hz) for 1-177, 7.30 (d, J = 6.0 Hz) for 1-178, 8.37 (app t, J =

2.7 Hz,) for 1-179, and 6.61 (d, J = 3.1 Hz) for 1-180.

The subsequent thiocarbamation of the nitrogen derivatives could be achieved by traditional

procedure: refluxing with 1,1’-thiocarbonyldiimidazole and DMAP in THF. For example, 5(R)-hydroxy-

2(R)-phenyl-[1, 3]dioxane-4(R)-carbaldehyde O-methyl-oxime 1-175 reacted efficiently with 1, 1-

thiocarbonyldiimidazole and catalytic amount of DMAP in THF under refluxing condition for 20h. The

crude mixture was purified by column chromatography to give the corresponding imidazole thioate 2-103

as an inseparable syn/anti mixture. The compound was characterized by spectroscopic methods (1H NMR,

13C NMR, and IR) as well as elemental analysis after column chromatography (91% isolated yield). The

isolated compound was a syn/anti mixture with a ratio of 1.0/0.13 determined by 1H NMR spectroscopy.

The characteristic peak for anti was shown at δ 6.91 (d, J = 5.3 Hz, 1H) but the characteristic peak for syn

isomer overlaped with the aromatic hydrogen peaks in the range of 7.47-7.52 ppm. The assignment was

further proved by comparing the characteristic carbon peaks shown at δ 145.08 and 145.90 for syn and anti,

respectively.

After thiocarbamation of the inseparable syn/anti mixture of O-benzyl oxime 1-176, two

stereoisomers were separated by column chromatography. Although the ratio of starting syn/anti mixture

of 1-176 was 1.0/0.14, we isolated almost pure (syn)-1-176/(anti)-1-176 with a ratio of 1.0/0.04 by column

chromatography. However, the pure (syn)-1-176 was in equilibrium with (anti)-1-176 in CDCl3 at rt., and

the ratio of the syn/anti increased up to 1.0/0.18 in an NMR tube in 3.5 days. A p-toluenesufonyl

71

hydrazone derivative was also made from 5(R)-hydroxy-2(R)-phenyl-[1, 3]dioxane-4(R)-carbaldehyde 1-

165.

In a previous case (see Scheme 1.25) we failed to make a (p-toluene)sufonyl hydrazone derivative

from the D-ribofuranose 1-79 because the (p-toluene)sufonyl hydrazone derivatives are in equilibrium

between cyclic (1-94) and acyclic (trans-1-94’), and the 1,1’-thiocarbonyldiimidazole reacted with only the

cyclic form 1-94’ to produce unwanted 1-95 as the major product. However, the 5(R)-hydroxy-2(R)-

phenyl-[1, 3]dioxane-4(R)-carbaldehyde 1-165 reacted with (p-toluene)sufonyl hydrazone in methyl

alcohol to afford 1-178 as a 75% isolated yield in spite of the equilibrium between 1-165 and 1-165’.

For the tosylhydrazone the next step could proceed relatively easily under our standard

thiocarbamation condition with 1,1’-thiocarbonyldiimidazole and DMAP in THF, but the isolated yield was

moderate (48%) because it is difficult to isolate the product 1-184 by column chromatography. To increase

the yield, the hydrazone derivative 1-178 was used for the next step without separation. After routine

thiocarbamation under standard condition with crude 1-178, the desired product 1-184 was isolated as a

43% yield from the 1-165.

N-Aziridinyl imines were first used in radical reaction by Kim in 1991 and they have received

great attention in the area of radical chemistry since then. We were also attracted to this novel functional

group as a radical acceptor in hex-5-enyl and/or hep-6-enyl radical cyclizations. If the Braton’s radical

mediated intramolecular cyclization proceed with the N-aziridinyl imines substituted precursor, we may

open a new area to make 3-deoxy sugars, 3-deoxy N-pyranosides, and/or 3-deoxy N-furanosides.

Previously, we had failed to make an aziridine derivative from D-ribofuranose 1-79 (see Scheme 1.43),

because the 1-amino-2-phenylaziridine 1-121 reacts with acetone generated from deprotecting of the

starting hemiacetal 1-79 in ethyl alcohol to give 1-122 as the major product. Gratifyingly, the (R)-hydroxy-

2(R)-phenyl-[1, 3]dioxane-4(R)-carbaldehyde 1-165could be used as an excellent precursor in the synthesis

of aziridine derivative 1-179. After column chromatography, the product was isolated as a mixture of two

isomers in 65% yield. The characteristic peak of this compound appears at δ 8.37 (major, app t, J = 2.7 Hz,

1H) in 1H NMR spectrum. Although the 1H NMR spectrum is very clean and it imply only one isomer

exists in the isolated product, the carbon peaks for the aziridine ring and imines split into two in 13C NMR

72

OO

OO O

OO

O

1-165 1-165'

OHPh

CHO

Ph

Ph

OH

HO

OO

OHPh

NNPh2

OO

OPh

NNHTs

Im

S

OO

OPh

NNHPh2

Im

S

OO

OHPh

N

OO

OPh

N

Im

S

OO

OPh

NN(CH3)2

Im

S

OO

OHPh

NOBn

OO

OPh

NOBn

Im

S

OO

OPh

NOCH3

Im

S

1-1771-183

1-184

1-179

1-176

1-185 1-186

1-182 1-181

e f

c

d

b a

OO

OHPh

NOCH3

1-175

OO

OHPh

NNHTs

1-178

OO

OHPh

NN(CH3)2

1-180N

Ph

NPh

gh

i

j

k l

Scheme 1. 56. Synthesis of Hydrazone and Oxime and Its Thiocarbamate Derivatives: (a) CH3ONH2•HCl,

Pyr, MeOH, 5.5h, 91% (syn/anti = 1.0/0.18), (b) BnONH2•HCl, Pyr, MeOH, 3h, 53% (syn/anti = 1.0/0.14);

(c) Ph2NNH2•HCl, Pyr, MeOH, 3h, 86% (anti only); (d) pTsNHNH2, MeOH, 2.5h, 75% (anti only); (e) 1-

amino-2-phenylaziridine, MeOH, 5h, 65% (anti only); (f) (CH3)2NNH2, MeOH, 17.5h, 84% (anti only); (g)

Im(C=S)Im, DMAP, THF, 20h, 90% (syn/anti = 1.0/0.13); (h) Im(C=S)Im, DMAP, THF, 7.5h, 69%

(syn/anti = 1.0/0.04), (i) Im(C=S)Im, DMAP, THF, 27h, 90% (93% based on recovered 1-177, anti only);

(j) Im(C=S)Im, DMAP, THF, 12h, 43% from 1-165 (anti only); (k) Im(C=S)Im, DMAP, THF, 23h, 49%

(major/minor = 1.0/0.67); (h) Im(C=S)Im, DMAP, THF, 3h, 90% (anti only).

73

spectroscopy: δ 161.30 and 161.37 for C=NN, 40.44 and 40.61 for NNCH2CHPh, and 44.00 and 41.13 for

NNCH2CHPh. The thiocarbamation of 1-179 was also performed under our standard condition and the

desired product 1-185 was isolated by column chromatography. The isolated yield of the product was

relatively moderate (49%), and the NMR spectroscopy implies the isolated product is a mixture of two

isomers with a ratio of major/minor = 1.0/0.67. Unfortunately, we could not assign the exact conformation

of the structure at this time.

Next we tured our attention to hydrazone as a radical acceptor in the synthesis of pyranosides

and/or furanosides via 5- or 6-exo radical cyclization mediated by the Barton’s radical intermediate. N-

Acetylhydrazone and N-benzoylhydrazone reacted with the 5(R)-hydroxy-2(R)-phenyl-[1, 3]dioxane-4(R)-

carbaldehyde 1-165 in methyl alcohol at rt to give new hydrazones, 1-187 and 1-188. The crude mixture

was purified by recrystallization with 95% ethyl alcohol to give relatively good yield (72% and 89%) as

white solid forms. The acetohydrazone 1-187 was a mixture of two geometrical isomers with a ratio of

0.52/1.0. NMR spectra implied that the minor portion of 1-187 is syn isomer based on its characteristic

peak at δ 7.25 (d, J = 6.7Hz). The compound 1-188 was isolated as a single isomer after recrystallization.

One doublet (J = 6.3Hz) at very down filed (7.73 ppm) implied the configuration of the product is anti.

The hydrazones, 1-187 and 1-188, were reacted with 1, 1’-thiocarbonyldiimidazole and DMAP in

THF under refluxing condition until all staring material could not be formed on TLC analysis.

Unfortunately, the major portion of the crude mixture was not the desired products, but they still have

hydroxyl functionalities judged by IR spectroscopy. The IR spectra showed a very strong broad peak at

υ 3450 cm-1, which implies that the isolated products have hydroxyl group functionalities. More extensive

spectroscopy work and its interpretation were done with 1H and 13C NMR spectroscopy. For example, the

enamine functionality (C=N) of compound 1-189 can be confirmd by observing a peak at δ 7.01 ppm (d, J

= 5.3 Hz, DMSO-d6) in 1H NMR spectrum as well as a paek at δ 160.04 ppm in 13C NMR spectrum. A

siglet peaks at δ 176.22 ppm in 13C NMR spectrum implies that the compound has a thiocarbonyl group

(C=S). Surplisingly, the carbonyl peaks disappeared but a new hemiacetal peak was observed at δ 66.88

ppm in 13C NMR spectrum, which may be interpreted as the formation of rare heterocyclic seven-

membered ring with a hemiacetal. The molecualar weight measured by electrospray HRMS is 397.0940,

74

which is the exactly the same with the calculated molecular weight for C17H18N4O4SNaNa+ within less than

1.0 ppm difference. Based on those results we proposed the configuration of the products like 1-189 and 1-

192.

OO

OO O

OO

O

1-165'

OHPh

CHO

Ph

Ph

OH

HO

OO

OHPh

NNHCPh

1-187

a

b

OO

OHPh

NNHCCH3

1-165

c

1-189

OO

OPh

NNHCPh

Im

S

1-190

OO

OPh

NNHCCH3

Im

S

1-191

1-192

O

O

d

1-188

O

O

X

X

OO

OPh

NN

ImS

Ph

OH

OO

OPh

NN

ImS

CH3

OH

Scheme 1. 57. Synthesis of Hydrazones and Its Thiocarbamate Derivatives: (a) PhC(=O)NHNH2, EtOH,

rt, 20h, 72% (anti only); (b) CH3C(=O)NHNH2, EtOH, rt, 20h, 89% (syn/anti = 0.52/1.0); (c) ImC(=S)Im,

DMAP, THF, reflux, 8h, 21%; (d) ImC(=S)Im, DMAP, THF, reflux, 10h, 32%.

75

1. 3. Radical Cyclization of Thiocarbamate and Thiocarbonate Precursors

1. 3. 1 The Early Studies of 6-exo-trig Radical Cyclization65

RajanBabu and Bliss initially studied the 6-exo-ring closure by using the Barton’s radical

generated from O-phenyl thiocarbonate (Eq. 42). They observed the phenyl group migration during the

radical cyclization to give 1-194, and proposed a mechanism involving spiro aromatic system (Scheme

1.12, p. 28). However, the radical intermediate generated via 6-exo-trig mode was trapped by the reverse

addition of substrates (k3 < k4)-slow dropping of the mixture of the substrate and AIBN in benzene into a

solution of tributyltin hydride via a syringe pump. The excess tributyltin hydride forced formation of the

cyclized intermediate, orthoester 1-68, which eliminate phenoxytributyltin moiety, Bu3SnOPh, to make 1-

70 (or 1-195) before the phenyl group migration to the radical center (Scheme 1.16).

TBSO

O OCO2Et Ph

O

OO CO2Et

OTBS

O O

OO CO2Et

OTBS

+(42)

O

OPhS

1-193 1-194 1-195R = Et 30% 0%

R = Et 10% 65%

R = tBu 27% 0%reverse addition

The cyclized compound 1-194 was obtained as a single isomer, and was chartacterized by 13C

NMR, which had two ester carbonyls at δ 171.5 and δ 170.6 ppm as well as a phenyl group. The

stereochemistry of the lactone 1-194 was assigned as altro configuration based on NOSEY data, and the

measured coupling constant between H-2 and H-3 is agreement with the theoretical coupling constant

derived from Karplus equation. The stereochemistry of compound 1-195 at C-2 is opposite of comparing

with that of 1-194. Relatively big dipole-dipole correlation between H-2 and H-4 of 1-194 in NOSEY was

interpreted as the allo configuration by Bliss.

76

Bliss also found that the 6-exo-trig ring closure could be used for the synthesis of N-glycoside

after changing the substrate from thiocarbonates to thiocarbamates (Eq. 43). The structure of N-glycoside

was confirmed by finding an anomeric center at δ 83.2 ppm in 13C NMR spectrum as well as a

characteristic anomeric hydrogen peak at δ 5.5 ppm in the 1H NMR. The coupling constant of the anomeric

hydrogen is J1,2 = 3.3 Hz, which may be interpreted as a cis configuration between H-1 and H-2. The

chemical shift of the anomeric center moved downfiled to δ 6.2 ppm in 1H NMR spectrum upon

epimerization and the coupling constant J1,2 shifted from 3.3 Hz to 8.5 Hz.

O

O O

Bu3SnH

AIBN

O

OO

OTBS

CO2tBu

N

N

(43)CO2

tBuTBSO

NS

N

1-196 1-197

The formation of N-glycoside is novel because thus far all radical cyclizations based on the

Barton’s deoxygenation lead the elimination of substituent X (see Scheme 1.1, 1.2, and 1.3 in Chapter 1.1).

Moreover, the new synthetic route for the formation of 2-C branched glycosides is a fundamentally

important methodology. 68 However, the initial study gave only 37% yield of the desired N-glycoside, and

the structural analysis has not been firm because of the lack of nOe or 2D NMR data.

In this chapter, we will discuss the optimum condition for the radical cyclization via 6-exo-trig

radical ring closure mediated by the Barton’s radical, and will document extention of the cyclization to a 5-

exo-trig mode as well as to a variety of unsaturated radical acceptors.

1. 3. 2. The Optimum Condition for 6-Exo-trig Radical Cyclization by the Barton’s Radical

The experimental results are summarized in Table 4. First, the reaction was performed with the same

amount of substrates, radical sources, and initiator as described previously,65but the reaction mixture was refluxed

in either toluene or benzene. Surprisingly, the expected product 1-197 was not detected on TLC, but 1-202 was

77

isolated in a 33% yield after flash column chromatography (see Table 1.4 in p. 80). The thionolactone was

characterized by 13C NMR, which shows the thionolactone carbon at δ 218.4. The thionolactone functionality can

be further proved by IR spectrum, which has characteristic peaks of the thionoester at 1731 cm-1 and 1152 cm-1.64

The stereochemistry of C-2 has been assigned by a large coupling constant (12.3 Hz) between H-2 and H-3, which

may imply trans relationship. The formation of 1-202 can be rationalized by the proposed mechanism shown in

Scheme 1.58 When an EWG is substituted on an olefin of 1-195, the k1 is much faster than k2. Therefore, the

intermediate 1-199 can be formed easily, followed by the second intermediate 1-200. The orthothioamide 1-200

may have two pathways; one is k3, the other is k4. At high temperature the elimination pathway k4 is faster than

k3. To make a desired product 1-197, the reaction requires more than two equivalents of the tin hydride (Scheme

1.58) because one equivalent is used for C-SSnR bond formation and the other equivalent is used for a hydrogen

donation to radical centered carbon. Under the Bliss’ conditions (Entry 16),65 however, only 1.5 equivalents of

radical sources were used, which might lead the lower yield of cyclized product 1-197 due to the insufficient

radical and/or hydrogen sources. Therefore, we used excess amount of tin hydride. Unfortunately, when the

radical and hydrogen source, Bu3SnH, increased to 5 equivalents in toluene, all starting material decomposed

under refluxing condition (Entry 3 and 4) and no significant amount of product was isolated by column

chromatography. However, if the concentration of substrate and Bu3SnH decreased to 0.042M and 0.064M in

toluene, respectively, only dethionated compound 1-203 was isolated as 40% of yield. Because the concentration

of radical sources and substrate is one of the most important factors for the formation of radical cyclization, we

changed the concentration and addition rate. Gratifyingly, we found the following optimized condition for the 6-

exo trig radical cyclization: 0.047M substrate in benzene, 0.063M Ph3SnH in benzene, and 28 µL/min via a

syringe pump. If the concentration of radical source was high (0.2-0.4M, Entry 3 and 4), no desired product was

detected after reflux, but low concentration (0.037-0.080M) gave compound 1-197 or compound 1-202 at 90oC or

under refluxing condition respetvely. The concentration of substrate may also affect the cyclization. High

concentration of substrate (0.103-0.082M, Entry 1 and 2) gave compound 1-202 as a major product under the

refluxing condition, but low concentration (0.042M) led the desired compound 1-197 as a major product under the

same refluxing condition. It is noteworthy to point out the dropping rate of substrate is not critical for this 6-exo-

trig radical cyclization if it is less than 48 µL/min. The formation of 1-203 may be explained by the proposed

78

R3Sn

O

OO CO2

tBu

NN

OTBSS

SnR3

O

OO CO2

tBu

NN

OTBSS

SnR3

TBSO

O OCO2

tBu

O

OO CO2

tBu

SOTBS

R3SnH R3SnH

R3SnH

O

OO CO2

tBu

OTBS N

N

1-197

1-202

k1

k2

deoxygenated products

k3

k4k1 >> k2

k3 >> k4 if 90 oC

k3 << k4 if >110 oC

1-199 1-200

1-201

O

O O

CO2tBu

TBSO

NS

N

1-196

O

O O

CO2tBu

TBSO

NS

N

1-198

R3Sn

k1k2

O

OO CO2

tBu

OTBS

1-203

R3SnH

R3SnH/benzene

R3SnH

Scheme 1. 58. The Mechanism of 6-Exo-trig Radical Cyclization of Substrate 1-196.

79

mechanism in Scheme 1.58. As previously explained for the formation of 1-202, the elimination pathway k4 is

faster than k3 at high temperature (if >110 oC) to afford the thionolactone 1-202 as the major product. Because

excess amount of hydrogen source (5.0 equivalents of Bu3SnH) was used, the thionolactone might be further

reduced to 1-203. Although the high temperature forces the path k4, the hydrogen source Ph3SnH is an excellent

choice to force the pathway k3 (Entry 6): because it has been known65 Ph3SnH is a better hydrogen source than

Bu3SnH. For example, under the refluxing of toluene with Ph3SnH as the hydrogen source in the 6-exo trig

radical cyclization, most substrate 1-196 proceeded to give pyranoside 1-197 as the major product (47%) and only

part of 1-196 gave 1-203 (9%). The better efficiency of Ph3SnH than Bu3SnH in the Barton’s radical

intermediated cyclization was also proved by Entries 7 and 8. Those reactions were performed under the almost

identical reaction condition except for radical/hydrogen sources. When Bu3SnH was used as the hydrogen sources

in radical cyclization, the paranoside 1-197 was made in only 34% yield. Surprisingly, the change of hydrogen

source from Bu3SnH to Ph3SnH facilated the reaction and the isolated yield of 1-197 doubled from 34% to 62%.

Because we recognized the reaction to favor the pathway k4 to afford 1-202 and/or 1-203 at high temperature in

the previous experiment, the reaction temperature was decreased from 80 oC (refluxing condition) to 78 oC (oil-

bath temperature 90 oC). In this case, the pathway k3 is faster than k4 and the pyranoside 1-197 was made much

more efficiently (Entry 7 and Entry 9). To investigate the concentration effect, we fixed the concentration of

substrate and the addition rate, but doubled the concentration of hydrogen source in the reaction. As expected, the

formation of cyclized product 1-197 decreased with the high concentration of hydrogen source (Entry 9 and 10).

If temperature is too low (68 oC), only 3% of desired product was isolated because of insufficient energy for the

C-S bond breaking (Entry 15). We also explored the exo-hept-6-enyl radical cyclization with EPHP

(ethylpiperidine hypophosphite) as the radical/hydrogen source (Entry 16). Unfortunatealy, although all starting

material decomposed, we could not isolate any cyclized compound by column chromatography. Based on the

above results we chose Ph3SnH in benzene as the radical/hydrogen source and performed the reaction at 90oC

under very dilute concentration and slow addition rate (0.047M substrate in benzene and 0.063M Ph3SnH in

benzene. The addition rate of the substrats was 28 µL/min via a syringe pump). We were pleased that the reaction

proceeded very efficiently via 6-exo-trig process mediated by the Barton’s radical intermediate to give the desired

N-glycoside 1-197 in 71% yield, and no unwanted product 1-202 and/or 1-203 were observed in TLC analysis.

80

O

OO CO2

tBu

SOTBS

O

OO CO2

tBu

OTBS N

N

1-197 1-202

O

O O

CO2tBu

TBSO

NS

N

1-196

O

OO CO2

tBu

OTBS

1-203

+ +

Conditions Yield (%)

Entry R3SnH

(Equiv)

AIBN

(Equiv)

Solvents Tempr,

s

Etc. 1-197 1-202 1-203

Comment

1 1.5 0.2 toluene reflux a 33

2 1.5 0.2 benzene reflux b 33

3 5.0 0.5 toluene reflux c Decomposed

4 5.0 0.5 toluene reflux d Decomposed

5 5.0 0.5 toluene reflux e 40

6 5.0 0.5 toluene reflux f 47 9 α/β= 0.34/1.0

7 5.0 0.5 benzene reflux g 34 α/β=13/87

8 5.0 0.5 benzene reflux h 62 α/β= 0.20/1.0

9 5.0 0.5 benzene 90 oC i 57 α/β=14/86

10 10.0 1.0 benzene 90 oC j 54 α/β=15/85

11t 5.0 0.5 benzene 90 oC k 15 37 α/β= 0.16/1.0

12 5.0 0.5 benzene 90 oC l 71 α/β= 0.20/1.0

13 5.0 0.5 benzene 90 oC m 54 α/β=13/87

14 u 5.0 0.5 benzene 90 oC n 61 allo/altro v

15 5.0 0.5 benzene 68 oC o 3

Continued

Table 1. 4. 6-Exo trig Ring Closure of 1-196.

81

Table 1. 4 continued

16 10.0 w 1.0 toluene reflux p Decomposed

17 x 1.5 0.2 toluene 90 oC q 37 α/β=28/72

a. 0.103M Substrate in toluene, 0.077M Bu3SnH in toluene, 25 µL/min via a syringe pump b. 0.082M Substrate in benzene, 0.080M Bu3SnH in benzene, 25 µL/min via a syringe pump c. 0.100M Substrate in toluene, 0.200M Bu3SnH in toluene, 25 µL/min via a syringe pump d. 0.120M Substrate in toluene, 0.400M Bu3SnH in toluene, 25 µL/min via a syringe pump e. 0.042M Substrate in toluene, 0.064M Bu3SnH in toluene, 26 µL/min via a syringe pump f. 0.047M Substrate in toluene, 0.064M Ph3SnH in toluene, 25 µL/min via a syringe pump g. 0.042M Substrate in benzene, 0.064M Bu3SnH in benzene, 26 µL/min via a syringe pump h. 0.047M Substrate in benzene, 0.064M Ph3SnH in benzene, 25 µL/min via a syringe pump i. 0.038M Substrate in benzene, 0.038M Bu3SnH in benzene, 42 µL/min via a syringe pump j. 0.037M Substrate in benzene, 0.069M Bu3SnH in benzene, 48 µL/min via a syringe pump k. 0.047M Substrate in benzene, 0.063M Ph3SnH in benzene, 26 µL/min via a syringe pump l. 0.047M Substrate in benzene, 0.063M Ph3SnH in benzene, 28 µL/min via a syringe pump. m. 0.042M Substrate in benzene, 0.064M Ph3SnH in benzene, 26 µL/min via a syringe pump n. 0.046M Substrate in benzene, 0.064M Ph3SnH in benzene, 27 µL/min via a syringe pump o. 0.037M Substrate in benzene, 0.068M Bu3SnH in benzene, 48 µL/min via a syringe pump p. 0.040M In toluene based on substate and 0.400M in toluene based on EPHP, two times one pot addition of 0.120M AIBN in toluene, q. 0.120M Substrate in benzene, 0.075M Bu3SnH in benzene, 24 µL/min via a syringe pump r. Temperature of an oil bath measured by a thermo-coupled thermometer. s. The temperature of reaction mixture measured by a thermo-coupled thermometer was 78 oC t. E Substrate was used. u. Normal addition: the mixture of Ph3SnH (5.0 Eq) and AIBN (0.5 Eq) in benzene was added to the solution of substrate in benzene via a syringe pump v allo-α:allo-β:altro-α:altro-β = 0.16:0.22:0.23:1.0. w. EPHP (ethylpiperidine hypophosphite) x. From Bliss’ dissertation.

82

1. 3. 3. The Rationalization of the Stereochemistry for 6-Exo-trig Radical Cyclization by the Barton’s

Radical

In the initial study of the reaction, Bliss isolated cyclized compound as a single diastereomer, and

assigned the compound as an α anomer (allo-1-197) based on the peak of C-1 in 13C NMR spectrum. He

also reported the pure anomer was prone to epimerization to give α/β mixture in a ratio of 72/28 on

standing in NMR solvents at rt. However, we failed to isolate the pure anomer; all isolated compounds

were α/β mixtures in a ratio of 87-85/13-15.

O

OTBS

OO CO2

tBu

N

N

O

OTBS

OO CO2

tBu

N

N

OH

O O

HH

X

Y

HCO2But

OTBS

OH

H

O O

HH

X

Y

OTBS

CO2But

O

H Y

X

OTBSH CO2But

O

OH

H

OH

Y

X

OTBSH

O

O

H

CO2But

altro-1-197

allo-1-197

1

2

3

4

5

X = H, Y = Imidazole or X = Imidazole, Y = H

1-204 1-205

1-206 1-207 (Bliss)

H

Figure 1. 5. Rationalization of the Stereochemistry of 1-197 by Chair Conformation.

Because the absolute stereochemistry of 1-197 at C-3, C-4, and C-5 are fixed from the known

stereochemistry of the starting material 1-195, the cyclized compound may have two conformation, allo-

chair forms (1-204 or 1-205) or altro-chair forms (1-206 or 1-207) rotated by a ring flip. Bliss assigned the

isolated compound as an allo-form based on the chemical shift of the anomeric carbon in 13C NMR (δ 83.2

ppm), which compared well with literature.72 He also measured the coupling constant J1,2 is 3.2 Hz, which

might be interpreted as cis relationship between C-1 and C-2. Based on these assignments, an α anomer

83

and cis relationship between C-1 and C-2, he concluded that the diastereomer has allo configuration (1-207,

X = H, Y = imidazole). However, we strongly doubt this assignment for the final product because the

small J value between H-2 and H-3 does not unequivocally support the equatorial substituent (axial H) at

C-2. Moreover, altro configuration may also have a similar coupling constant after calculation by Karplus

equation (1-206 or 1-207, for example) and his conclusion is not the based on NOE or 2D NMR

experiments. For further determination of the relationship between H-1 and H-2, we decided to perform

nOe experiments with the N-cycloside 1-197. Scheme 1.6 shows the result of nOe experiment.

O

OO CO2

tBu

OTBS N

N O

H

N

H

OTBS CO2tBu

O

O

H

HH

altro-1-197

N

5.0%

3.9%1.7%

3.3%

3.5%

12

3

45

altro-1-197

Figure 1. 6. nOe Experiment of altro 1-197.

When we irradiated at the frequency of H-1, strong enhancement of H-5 peak was found (5%),

which may imply the anomeric center should be β, because the stereochemistry of C-5 is fixed as shown in

the Figure 1. 6. Moreover, some interaction (3.3%) between the tBu group of TBS and imidazole has been

observed with irradiation of imidazole, which may further support the β anomeric center. We also found

some interaction (3.9%) between H-1 and H-2, which may imply the stereochemistry between H-1 and H-2

should be cis, and the configuration has to be altro. If the configuration of the cyclized compound is allo,

there has to be no relationship between these two hydrogens, because the dihedral angle is almost 180o in

84

the favorable chair/allo form. An enhancement of the tBu group of C-2 (3.5%) with irradiation of one of

imidazole hydrogen and small interaction (1.7 %) between H-2 and H-5 may also be used for the proving

the altro configuration. The relatively small interaction between H-2 and H-5 may be rationalized by the

equatorial H-2 in altro conformation. Because the stereochemistry of H-5 is fixed and the dihedral angle of

allo form is almost 180o, there should be no enhancement with irradiation of H-5 in the allo/chair

conformation. Finally, the cis relationship between H-1 and H-2 can be further supported by small

coupling constant J1,2 = 3.2 Hz, which measured in 1H NMR spectrum. The major product therefore should

have the altro-configuration with the imidazole in the β-orientation.

Table 1.5 shows the result of hept-6-enyl radical cyclization of 1-208. When the E substrate was

used in the reaction (Entry 1 and 2), an allo/altro mixture was formed like in Table 1.4, Entry 14. The

product 1-210 was isolated as a mixture of cis/trans at C-2 and C-3 with a ratio of 0.2/1.0. The

diastereomer ratio of 1-209 and 1-210 was determined by GC before column chromatography and/or 1H

NMR after column chromatography. The results in the table may also imply that the concentration of

substrate does not affect the radical cyclization too much, but the concentration of radical sources is critical

for the 6-exo-trig radical cyclization. For example, when the substituent had E configuration, the same

compounds 1-209 and 1-210 were isolated by column chromatography, and the 1-209 has 4 diastereomers

detected by 1H NMR. When the substrate was more concentrated (from 0.014M to 0.032M) and Bu3SnH

was more diluted (from 0.172M to 0.063M), the yield of 1-209 increased from 42 to 59% while the yield of

1-210 decreased from 25 to 18% (the total yield increased from 67% to 77%). The Z substrate cyclized to

give two cyclized compounds 1-209 and 1-210 with an almost 1:1 ratio via radical process shown in

Scheme 62. The isolated compound 1-209 had only 2 diastereomers (altro) in a 82/18 ratio, while another

product 1-210 had only trans configuration. Gratifyingly, if the concentration of R3SnH in benzene

decreased from 0.189M to 0.064M and the radical/hydrogen source changed from Bu3SnH to Ph3SnH, the

formation of 1-210 was totally suppressed like in Table 4 and the yield of 1-209 increased up to 68%. It

can been explained that the k3 is much faster than k4 if Ph3SnH is used as radical/hydrogen source in hept-

6-enyl radical cyclization. Because the configuration of 1-209 was dependant on the configuration of 1-

208, the product in Entry 5 had only altro configuration with α/β anomeric mixture.

85

O

OO CO2Et

OTBSO

OO CO2Et

OTBS N

N

1-209 1-210

O

O O

CO2EtTBSO

NS

N

1-208

+


Entry R3SnH AIBN Solvents Temp o Etc. 1-209 1-210

Commentp

1 a 5.0 Eq. 0.5 Eq. benzene 90 oC c 42 25 h 0.12:0.03:1.0:0l

2 a 5.0 Eq. 0.5 Eq. benzene 90 oC d 59 18 i 0.12:0.12:1.0:0.43l

0.13: 0.05:1.0:0.31m

3 a 10.0 Eq. 1.0 Eq. benzene 90 oC e NRk

4 b 5.0 Eq. 0.5 Eq. benzene 90 oC f 36 33 j 0:0:1.0:0.22l

5 b 5.0 Eq. 0.5 Eq. benzene 90 oC g 68 0:0:1.0:0.24m

0:0:1.0:0.26 n

a. E-1-208 was used as the subatrate. b. Z-1-208 was used as the subatrate. c. 0.014M Substrate in benzene, 0.172M Bu3SnH in benzene, 42 µL/min via a syringe pump d. 0.032M Substrate in benzene, 0.063M Bu3SnH in benzene, 42 µL/min via a syringe pump e. 0.033M Substrate in benzene, 0.126M 1-ethylpiperidinium hypophosphorous acid in benzene, 29 µL/min via a syringe pump f. 0.014M Substrate in benzene, 0.189M Bu3SnH in benzene, 42 µL/min via a syringe pump g. 0.047M Substrate in benzene, 0.064M Ph3SnH in benzene, 28 µL/min via a syringe pump h. Cis/trans = 0.2/1.0 i. Cis/trans = 0.4/1.0. j. Trans only k. 34% of starting material was recovered l. Ratio is based on GC before isolation. m. Ratio is based on 1H NMR after column chromatography. n. Ratio is based on 1H NMR before column chromatography. o. Temperature of an oil bath p. The diastereomer distribution; allo-β (3-35):allo-α (3-36):altro-β (3-33):altro-α (3-34)

Table 1. 5. 6-Exo trig Radical Ring Closure of 1-208.

86

The difference in the stereoselectivities of (Z)- and (E)-olefin acceptors (the former giving

exclusively the altro-isomer, i.e. the C2-substituent in the β-configuration) is quite striking. This result

(Table 1.4 and 1.5) can be rationalized on the basis of the conformations of the putative intermediates that

lead to the altro- and allo- products (Figure 1. 7). Inspection of model suggests that there is an added

through-space interaction between the carboethoxy oxygen and the C5 (radical numbering) acetal oxygen in

the transition state 1-211 for the formation of the allo product(s). This is absence in the transition state 1-

212, which might explain why only altro products are obtained from the (Z)-acceptors. There is no such

clear distinction between the respective transition states leading from the (E)-olefin acceptor and a mixture

of allo- and altro-products are obtained in these cases (Scheme 1.59 in p. 85).

H

H

O

OO

R

O

O

S

N

OTBS

O

O HO

TBSON

OSH O

R

1

1

5

5

1-211

1-212

allo-product

altro-product

Figure 1. 7. Origin of the altro-Selectivity in the (Z)-Acceptors (see Table 1.4 and 1.5).

The preponderance of the formation of the β-anomer in the pyranoside formation is highly

suggestive of anomeric stabilization in radical intermediate involved. Unlike in the trans-bicyclic

furanoside system, the α-conformation of glycosyl radical 1-213 would be expected to provise some

anomeric stabilization to the intermediates from which the β-glycoside are formed. It has to be pointed out

87

that in the altro isomers the β-glycoside formation will also be favored by the easy H delivery from α-face

to afford β-pyranoside as the major product in 6-exo trig radical cyclization (Figure 1. 8).

O

H

Im

O

OH

H

TBSOH Y

O

HO

OH

H

TBSOH Y

Im

α-pyranoside

β-pyranoside

1-213-α

1-213-β

Figure 1. 8. Anomeric Stabilization in Pyranosyl Radicals.

Scheme 1.59 and 1.60 may explain the diastereomer distribution for the 6-exo-trig radical

cyclization of 1-208. When the substrate has a Z configuration, the transition states may be drawn as 1-214

or 1-215. If the transition state of the Z compound is 1-215, there is a large van der Waals repulsion

between the ester and γ-oxygen, but if the transition state is 1-214, the 1, 3-interaction is smaller than that

of 1-215; because there is only interaction between ester and γ-hydrogen. Therefore, cyclization of Z

compound would proceed through the transition state 1-218, which lead to altro configuration 1-222 with

two diastereomers (α and β) at an anomeric center. If the substituents have E configurations, the reaction

may proceed through 1-216 and 1-217 because there are no significant differences between these two

transition states. However, the 1-216 could be slightly favored over 1-217 because the product (1-223)

from the later is highly hindered. Therefore, the major cyclic compound of E of 1-208 should be the β-

altro form, 1-222, and some E substrate may also gave 1-223 configuration, which has a β-allo

configuration.

88

OO

OTBSH

H

Im

S SnBu3

ORO

O

HH

OO

OTBSHIm

S SnBu3

O

OR

H

O

H

H

O

OTBS

OO CO2R

Im

S SnBu3

O

OTBS

OO CO2R

Im

S SnBu3

OO

OTBSHIm

S SnBu3

O

HOR

OH

H

OO

OTBSHIm

S SnBu3H

O

H

HO

OR

O

OTBS

OO CO2R

Im

S SnBu3

O

OTBS

OO CO2R

Im

S SnBu3

O

OTBS

OO CO2R

N

N

O

OTBS

OO CO2R

N

N

O

OTBS

OO CO2R

N

N

O

OTBS

OO CO2R

N

N

1-214

1-215

1-216

1-218

1-219

1-217

1-222

1-223

1-220 1-222

vs

1-221 1-223

The Z-enoate acceptor

The E-enoate acceptor

only possible

major

minor

vs

Scheme 1.59. The Stereoselctivity of allo/altro Conformation by 6-Exo-trig Radical Cyclization.

89

O

H OTBS

O

OH Im

OEt

O

O

H

Im

H

OTBS CO2Et

O

OH

HH

O

H

H

Im

OTBS CO2Et

O

OH

HH

O

H

Im

H

OTBSH

O

OH

H

CO2Et

O

H

H

Im

OTBSH

O

OH

H

CO2Et

O

H OTBS

O

OH Im

OEt

O

S SnBu3

O

O O

HIm

HH

CO2Et

OTBS

H

H

O

O O

HH

HH

CO2Et

OTBS

Im

H

1-224 major

1-228

most favorable

1-227 1-231

1-229

1-225 minor

1-226 1-230

O

O O

H

H

Im

HH

OTBS

H

O

O O

H

H

H

HH

OTBS

Im

1-233

CO2Et

CO2Et

Bu3SSn

1-232

Scheme 1.60. Rationalization of the Distribution of Products.

90

Entry Compounds Chemical shift

H1,2 (ppm)

Coupling constant

J1,2 (Hz)

Calculated

angle

1a 1-197 (altro-α) 5.67 8.4 50o

2a 1-197 (altro-β) 5.88 3.2 164o

3a 1-197 (allo-α) 5.93 7.1 21o

4a 1-197 (allo-α) 5.28 10.3 169 o

3b 1-209 (altro-α) 5.68 8.9 51o

4b 1-209 (altro-β) 5,88 3.1 ~180 o

5b 1-209 (allo-α) 5.98 7.0 22 o

6b 1-209 (allo-β) 5.31 10.3 169 o

7c 1-235 (altro-α) 5.35 8.9 54o

8c 1-235 (altro-β) 5.77 2.7 ~180o

9c 1-235 (allo-α) 5.22 10.1 ~180o

10c 1-235 (allo-β) 5.78 6.7 24o

a. 250 MHz 1H NMR b. 400 MHz 1HNMR c. 500 MHz 1HNMR

Table 1. 6. Selected Chemical Shifts and Coupling Constants of N-Pyranoside.

91

Conformation of the major product is assigned as shown in 1-226 by comparison of spectral

properties with those of altro-1-197 (Figure 1.6) and the measured coupling constant (J1,2) of 3.1 Hz.

Another possible conformation, 1-230 was not observed in the NMR. Compound 1-226 could be

epimerized to 1-227. An alternative conformation of 1-227 is 1-231. This might explain the large coupling

constant (8.9 Hz) J1,2 in the isomerized product. The minor allo products arise via 1-217 (Et)-minor. The

large coupling constant (J = 10.3 Hz) and up-field chemical shift (δ 5.31 ppm) is indicative of the

conformation 1-228, for one of allo-products. Epimerization would give the other allo-product, 1-229,

with a J1,2 of 7.0 Hz. Drieding models show dihedral angles of 51o, 169o, 180o, and 22o for the structures 1-

226, 1-227, 1-228, and 1-229, which are consistent with the observed coupling constant 3.1, 8.9, 10.3, and

7.0 Hz respectively (see Table 1.6 for selected chemical shifts and coupling constants).

Table 1.7 shows the result of radical cyclization of unsubstituted olefin substrates 1-234. When

Bu3SnH was used as the radical sources, the cyclized product 1-235 was isolated as 23%, but the yield

increased to 46% with Ph3SnH. The higher yield with Ph3SnH is reasonable because triphenyltin hydride is

a better hydrogen source. After column chromatography, 4 anomeric hydrogen peaks were found in 1H

NMR spectrum. The ratio was 0.32:1.0:0.26:0.55 (as estimated) from these peaks. The stereochemistry

has been determined by comparing the coupling constant of 1H NMR for altro/allo-1-203. The major

product was assigned as having altro configuration with β anomeric glycoside based on early assignment of

1-203. The si face attack may be explained by steric reasons. Because the 1-237 is a geometrically more

favored configuration (less 1,3-allylic interaction) than 1-238, the most favorable N-glycoside should be 1-

239. The small coupling constant J1,2 = 2.7 Hz suggests the cis relationship of the altro conformation of 1-

239. The anomeric hydrogen of the epimer of altro form was shown at δ 5.2 ppm with J1,2 = 16.2 Hz. The

minor product has allo conformation, and the ratio of α/β epimers was 0.46/1.0. The stereochemistry of

those epimers was assigned by the chemical shift and coupling constants, which were measured as 6.8 Hz

and 14.2 Hz respectively. A large coupling constant J = 14.2 Hz may support 1-241 as the β-anomer of the

allo form. After epimerization at C-1, the allo conformation may be drawn as 1-242. The ratio of

altro/allo conformation is 1.6, which is much smaller than that of 1-207 (altro/allo = 6.7). The less

stereoselectivity of 1-235 may be explained by the small steric effect difference between 1-237 and 1-238.

92

O

CH3OO

OTBS N

N

1-235 1-236

O

O O

TBSO

NS

N

1-234

+

O

O

O

NN

OTBS


Entry R3SnH AIBN Solvents Temp.d etc. 1-235 1-236

Comments

1 5.0 Eq. 0.5 Eq. benzene 90 oC a 23

2 5.0 Eq. 0.5 Eq. benzene 90 oC b 46 0.32:1.0:0.26:0.55e

3 5.0 Eq. 0.5 Eq. benzene 90 oC c 30 29 0.42:1.0:0.22/0.35 e

a. 0.052M substrate in benzene, 0.061M Bu3SnH in benzene, 29 µL/min via a syringe pump b. 0.042M substrate in benzene, 0.064M Ph3SnH in benzene, 29 µL/min via a syringe pump c. 0.046M substrate in benzene, 0.063M Ph3SnH in benzene, 29 µL/min via a syringe pump d. Temperature of an oil bath e. The diastereomer distribution; altro-α (1-240):altro-β (1-239):allo-α (1-242):allo-β (1-241) f. The ratio of α/β = 0.37/1.0.

Table 1. 7. 6-Exo trig Radical Ring Closure of Substrate 1-235.

93

O

H

O

H

O

H

OTBS

Im

SSnBu3

O

H

H

O

H

O

H

OTBS

H

Im

CH3

O

H

H

O

H

O

H

OTBS

Im

H

CH3

O

H

O

OTBS

H

H

O

H

Im

SSnBu3

O

H

O

H

O

H

OTBSH

Im

CH3

O

H

O

H

O

H

OTBS

Im

H

H

CH3

OH

O O

HH

OTBSH

ImCH3

H

1-239

1-237

1-240

1-2451-241

1-238

most favorable

1-244

OH

O O

HH

OTBSIm

HCH3

H

1-243

O

H

O

H

O

H

OTBSH

H

O

H

O

H

O

H

OTBS

H

Im

H

CH3

1-2461-242

ImCH3

Scheme 1.61. Rationalization of Stereoselectivity of 1-235; allo and altro Conformations.

94

1. 3. 4. 6-Exo-trig Radical Cyclization of Substrates Derived from D-Ribose

We performed the same reaction with O-phenylthiocarbonate 1-193 under our optimized reaction

conditions and the results are summarized in Table 1.8. First, we explored the reaction with Z substrate as

the reactant and tributyltin hydride (5.0 equivalents) as the radical/hydrogen source. Based on the

mechanism proposed by Bliss and the results from our radical cyclization for thiocarbamate 1-196 and 1-

208, we expected the yield of pyran derivative 1-195 would increase. After column chromatography,

however, phenyl-migrated lactone 1-194 and pyran derivative 1-195 were isolated in 31% and 38%,

respectively (Entry 2). The results may imply that the reaction pathway (k3 or k4, Scheme 1.16 in Chapter

1.1) is not dependant on the reactant addition order, and another mechanism has to be proposed to explain

both Bliss’ and our results. Because the excess amount of tin hydride forced the pathway k3, we might

expect the formation of phenyl migrated product 1-195 would be facilated if Ph3SnH is used as the

radical/hydrogen source. As expected, the product 1-195 was formed as the major product (71%) and only

small amount of 1-194 (3%) was isolated by column chromatography (Entry 3).

It has been reported that O-phenylthiocarbonate can be used for the 5-exo radical cyclization

mediated by the Barton’s radical intermediate. The cyclized radical intermediates can be further reduced to

thionolactone by excess trialkyltin hydride. More interestingly, the phenyl group of the thiocarbonate can

make a spiroaromatic ring in a 5-exo intramolecular cyclizartion to give the phenyl group migration (See

Scheme 1.4 and 1.5 in Chapter 1.1). Bliss reported65 that if O-phenylthiocarbonate 1-193 is used for the

radical cyclization, the phenyl group migration occurs via a spiro aromatic system. However, he found the

reverse addition (slow dropping of a mixture of substrates and AIBN into a solution of trialkyltin hydride)

might trap the α-methylene radical to give thionolactone, which is further reduced to pyran derivative 1-

195 as the major products. The mechanism proposed by Bliss is shown in Scheme 1.12 (p. 28), and he

concluded that the reaction pathway is dependant on the addition order of the substrate/trialkyltin hydride.

The phenyl-migrated compound 1-194 was isolated as a single diastereomer by column

chromatography. The 1H NMR spectrum of the compound implied that the compound had a phenyl group,

but thiono carbonyl function (δ ≈ 190 ppm) could not be observed any more in the 13C NMR spectrum.

Two carbonyl peaks (δ = 171.5 and δ = 170.6) may suggest that the thiocarbonyl group was converted to

95

ester group via the mechanism as shown in the Scheme 1.12 (Chapter 1.1, p. 28). The stereochemistry of

the lactone was assigned as altro by Bliss based on conformational analysis, coupling constants, and

NOSEY data. Bliss also reported that the stereochemistry of 1-195 is allo based on coupling constants and

NOSEY spectra which showed a strong dipole-dipole interaction between H-2 and H-4. However,

comparision of the chemical shifts and coupling constant of 1-195 with 1-203 may imply that the structural

assignment has to be revised as altro because of the enhancement of COtBu, H7a and H7b peaks with

irradiation of H4 peak (Figure 1.9).

TBSO

O O

O

OPhS

1-193

CO2EtPh

O

OO CO2Et

OTBS

O O

OO CO2Et

OTBS

1-194 1-195


Entry Sbstrate R3SnH AIBN Solvents Temp.d Note 1-194 1-195

1 (Z)-193 1.5 Eq. 0.2 Eq. toluene 90 oC a 10 65

2 (Z)-193 5.0 Eq. 0.5 Eq. benzene 90 oC b 31 38

3 (E)-193 5.0 Eq. 0.5 Eq. benzene 90 oC c 3 71

a. Bliss’ Dissertation b. 0.012 M Substrate in benzene, 0.043 M Bu3SnH in benzene, 42 µL/min via a syringe pump c. 0.047 M Substrate in benzene, 0.063 M Ph3SnH in benzene, 26 µL/min via a syringe pump d. Temperature of an oil bath Table 1. 8. 6-Exo trig Radical Ring Closure of Substrate 1-193.

96

O

H

HO

O

H

HH

OTBSCO2

tBu

H

0.7%, 0.6%

12

3

45

1.6, 1.3%

2.5, 1.9%

3.3%

1.4%

0.5%

O

OO CO2

tBu

OTBS

1-203

7

nOe (%) nOe (%) nOe (%)

H3→H7a 2.5 H4→H7a 1.6 H7a→H4 3.3

H3→H7b 1.9 H4→H7b 1.3 H7a→H4b 0.7

H4→COtBu 1.4 H5→H2 0.5 H7a→H4b 0.6

Figure 1.9. The Representative Results of nOe for 1-203.

When a strong EWG is substituted on the olefin acceptor, 6-exo trig radical cyclizations mediated

by the Barton’s radical intermediate proceed very efficiently to give the corresponding altro or the mixture

of altro(major)/allo(minor) N-heterocyclic glycosides depending on the geometry of the olefins. As

described in earlier (see Table 1.4 and 1.5), (Z)- enoate gives better stereoselectivity at C2-position.

Moreover, the major product of the N-heterocyclic glycosides is β-anomer via the exo-hept-6-enyl type

radical cyclization. α,β-Unsaturated nitrile 1-247 (Figure 1.9) also may be used as an excellent radical

acceptor in the 6-exo trig radical cyclizations. When pure Z- isomers of the substrates were used for the

cyclization, we did not observe the formation of any of allo-isomers (Table 1.9, Entry 2). The isolated

product was a mixture of α/β-anomers of altro-1-252 with a ratio of 0.26 to 1.0 determined by 1H NMR

spectroscopy. As explained it in Scheme 1.66, the anomeric stabilization in pyranosyl radicals can be

rationalized in the formation of β-anomers as the major product. In sharp contrast to the results from Z-

isomers, use of E-isomers gave a mixture of altro-1-252 and allo-1-252 even though the major products

97

still have the altro-configuration (Entry 1) as expected from the previous results. It has to be pointed out

that the allo/altro ratio of the N-glycoside decreased to 0.10/1.0 compared to that of tbutyl enoates (1-196,

allo/altro = 0.31/1.0) and ethyl enoates (1-208, allo/altro = 0.14/1.0).

O

O O

TBSO

NS

N

1-247

CN

O

OO CN

OTBSN

N

1-252

Conditions Yield

Entry

1-247 R3SnH AIBN Solvent Temp.e Note 1-252

Comments

1 E 5.0 Eq. 0.5 Eq. benzene 90 oC a 80% 0.27:1.0:0.04:0.09c

2 Z 5.0 Eq. 0.5 Eq. benzene 90 oC b 57% 0.26:1.0d

a. 0,047 M Substrate in benzene, 0.063 M Ph3SnH in benzene, 16 µL/min via a syringe pump b. 0.046 M Substrate in benzene, 0.063 M Ph3SnH in benzene, 21 µL/min via a syringe pump c. altro-α: altro-β: allo-α: allo-β. d. altro-α: altro-β. e. Temperature of an oil bath Table 1. 9. 6-Exo trig Radical Ring Closure of Substrate 1-247.

98

O

O O

TBSO

NS

N

(E)-1-247

TBSO

O O

O

OPhS

(E)-1-193

TBSO

O OCO2Et

O

OPhS

(Z)-1-193

CO2Et O

O O

CNTBSO

NS

N

(Z)-1-247

CN

O

O O

NOCH3TBSO

NS

N

1-248

O

O O

NN(CH3)2TBSO

NS

N

1-249

TBDPSO O

OEt

O

N

S

N

1-250 1-251

O

OEtTBSO

O

N

S

N

Figure 1.10. Substrates for 6-Exo trig Radical Cyclization.

O

OO CN

OTBS N

N

1-252

O

OO

NHOCH3

OTBS N

N

1-253

O

OO

NHN(CH3)2

OTBS N

N

1-254

OO

NHN(CH3)2

OTBS

1-255

Ph

O

OO CO2Et

OTBS

O O

OO CO2Et

OTBS

1-194 1-195

O

CO2Et

N

N

1-257

TBSO

O

CO2Et

OTBS N

N

1-256

Figure 1.11. Products for 6-Exo trig Radical Cyclization.

99

The oxime ether substrate 1-248 which exists as mixtures of syn and anti isomers was investigated

for the 6-exo trig radical cyclization. Bliss performed65 the reaction with 2.5 equivalents of tributyltin

hydride as the radical/hydrogen source with 0.2 equivalents of AIBN in toluene. To initiate the radical

reaction the reaction mixture was irradiated by 500W incandescent lamp at 0 to 50 oC. Although the oxime

ether has been used widely as the radical acceptor in exo-hex-5-enyl cyclization and exo-hept-6-enyl

cyclization, he failed to isolate the corresponding cyclized compound 1-253 from the reaction of 1-248 via

the radical process.

O

O O

NOCH3TBSO

NS

N

1-248

O

OO

NHOCH3

OTBS N

N

1-253


Entry R3SnH AIBN Solvents Temp.d etc. 1-253

Comments

1 2.5 Eq. 0.2 Eq. toluene 0-50 oC a Decomposed

2 5.0 Eq. 0.5 Eq. benzene 90 oC b Decomposed

2 5.0 Eq. 0.5 Eq. benzene 90 oC c 83 0.24:1.0:0.03:0.75e

a. 0.016 M Substrate in toluene, 500W incandescent lamp from Bliss’ dissertation. b. 0,027 M Substrate in benzene, 0.079 M Bu3SnH in benzene, 48 µL/min via a syringe pump c. 0.047 M Substrate in benzene, 0.063 M Ph3SnH in benzene, 24 µL/min via a syringe pump d. Temperature of an oil bath e. altro-α: altro-β: allo-α: allo-β.


100

Because we were aware of the 2.5 equivalents of tin hydride was not enough to cyclize the

glycoside via radical process, 5.0 equivalents of tributyltin hydride were used as the radical/hydrogen donor

along with 0.5 equivalent of AIBN in the reaction. However, no N-heterocyclic glycoside was observed

and all starting material 1-248 was decomposed under our reaction conditions. Interestingly, if 5.0

equivalent of triphenyltin hydride was used as the radical/hydrogen donors in the reaction, we could isolate

the desired N-glycoside in 83% yield as a four isomer mixture (Table 11). Because the substrate 1-248 is a

mixture of syn/anti, we could not avoid the formation of allo isomers in the reaction, but the major product

still had the altro-configuration.

O

O O

NN(CH3)2TBSO

NS

N

1-249

O

OO

NHN(CH3)2

OTBS N

N

1-254

OO

NHN(CH3)2

OTBS

1-255

+


Entry R3SnH AIBN Solvent Temp.d Note 1-254 1-255

Comments

1 5.0 Eq. 0.5 Eq. benzene 90 oC a 41

2 5.0 Eq. 0.5 Eq. benzene 90 oC b 63 0.04:0.09:0:1.0c

a. 0.046 M Substrate in benzene, 0.063 M Bu3SnH in benzene, 21 µL/min via a syringe pump b. 0.026 M Substrate in benzene, 0.080 M Ph3SnH in benzene, 42 µL/min via a syringe pump c. altro-α: altro-β: allo-α: allo-β. d. Temperature of an oil bath


When N,N’-dimethyl hydrazone was used as the radical acceptor in the Barton’s radical

intermediated reaction, deoxygenation (k2) is faster than 6-exo radical cyclization(k1) (p. 78, Scheme 1.62).

The deoxygenated radical intermediate 1-201 might be trapped by excess tin hydrid through the Barton-

101

McCombie deoxygenation mechanism, and gave deoxygenated product 1-255 in a 41% yield. Because the

dimethylsubstituted hydrazone is not as strong EWG as α,β-unsaturated esters, it is reasonable that the

deoxygenation process (k2) is faster than cyclization (k1) (see Scheme 1.58, p. 78). However, if we used

excess amount of triphenyltin hydride as the radical/hydrogen source instead of tributyltin hydride, the tin-

added radical intermediate 1-198 (p. 78) proceeds via the pathway k1 to afford an intermediate like 1-199

(p. 78) followed by C-SSnR bond breaking. The hydrazine substituted pyranoside 1-254 was isolated in

63% yield as a three diastereomer mixture, and the configuration was assigned by comparing the coupling

constant and chemical shift with the similar known products (Table 1.11).

O

OO

NHN(CH3)2

OTBS N

N

1-254

400 MHz 1H NMR altro-α altro-β allo-α allo-β

Chemical shift (ppm) 5.64 5.86 NA 5.18

Coupling constant (Hz) 7.4 3.0 NA 8.5

Ratioa 0.04 0.09 NA 1.0

a. The ratio was determined by 1H NMR after column chromatography.

Table 1.12. The Chemical Shift and Coupling Constants of the Anomeric Hydrogen of 1-254.

1. 3. 5. The Role of Protecting Groups in 6-Exo trig Radical Cyclization

Previously, we have recorded exo-hep-6-enyl radical cyclization with D-ribonolactone-derived

substrates, which have three fixed stereochemistries at C3, C4, and C5. Our results imply that the

streochemisty of C2 can be controlled by the geometry of the substrate. If the substrate has Z configuration,

the products are altro (i.e. trans between C2 and C3). However, if the configuration of the substrate is E, the

products are a mixture of altro and allo (i.e. cis between C2 and C3).

102

To examine more detail the origin of stereoselectivity in exo-hep-6-enyl radical cyclizations, we

prepared two new compounds, 1-250 and 1-251 (p. 108) from carbohydrates. Each of them has only one

fixed stereochemistry at C6 and C5 , respectively. First, we performed the radical cyclization with the

substrate 1-250 under our optimized reaction conditions. Although the formation of cyclohexane

derivatives via exo-hep-6-enyl radical cyclization is 20-30 times slower than the exo-hex-5-enyl radical

cyclization, the reaction proceeded efficiently to give 1-imidazoyl pyranosides in a good yield (80%).

TBDPSO O

OEt

O

N

S

N

1-250

O

CO2Et

OTBSN

N

1-256

1

2

36

Conditions

Entry R3SnH AIBN Solvents Temp.b Cond.

Yield

(%)

comments

1 5.0 Eq. 0.5 Eq. benzene 90 oC a 80 1.0:0.38:0.09c

a. 0.047M Substrate in benzene, 0.064M Ph3SnH in benzene, 24 µL/min via a syringe pump b. Temperature of an oil bath c. The ratio determined after column chromatography by 1H NMR (400 MHz).


Careful 1H NMR investigation of the crude products implied that only three isomers of the four

possible were present in a ratio of 1.0:0.38:0.09 via the exo-hep-6-enyl radical cyclization. Gratifyingly,

we could isolate two of the major product in a pure form, and the structural assignement was determined by

1D nOe experiment as well as coupling constants (J1,2) and chemical shift (ppm). Based on the

spectroscopic data the first and the second major products were assigned as 1-258 and 1-259, respectively.

Table 1.14 summarizes the chemical shift and coupling constants for the anomeric hydrogen of 1-258, 1-

103

259, and 1-260, and Figure 1.12 is the summary of the nOe experiment for the first major compound 1-258.

The large coupling constant (J1,2 = 9.9 Hz) for the anomeric hydrogen of hexapyranoside 1-258 may imply

that trans-diaxial configuration between H1 and H2. nOe Studies further confirm these assignment. For

example, we observed strong enhancement of some peaks during the irradiation of some frequencies: for 1-

258, H1→H3a, H1→H5, H1→H7b, H2→H4b, H2→Imd, and H4b→H2.

The coupling constant for the second major compound is relatively small (J1,2 = 2.4 Hz), and the

calculated dihedral angle of the vicinal hydrogens is 56o from Karplus equation (3J = ACos2φ - 0.28, where

A= 8.5 for 0o ≤ φ ≤ 90 o and A= 9.5 for 90o ≤ φ ≤ 180 o). Because it has been known the coupling constants

(3J value) for equatorial-equatorial and equatorial-axial vicinal hydrogens are between 2-3 Hz, we may

draw three possible configurations for the pyranoside: 1-259 and 1-260. The result of the nOe experiment

for the second major product is summarized in Figure 1.13. Strong enhancement of the peaks at H3a and H5

was observed with the irradiation of H1, while the irradiation of H3a and H5 increased the peak of H1.

Moreover, a strong relationship between H2 and H3a was observed from the nOe experimental data. Based

on these results, we assigned the configuration of the product as a β-anomer (H1: axial, imidazole:

equatorial), and the relation of H1 and H2, cis.

1H NMR (400 MHz)

O

CO2Et

OTBS NN

1-258

O

CO2Et

OTBS NN

1-259

O

CO2Et

OTBS NN

1-260

Chemical Shift (ppm) 5.06 5.86 5.45

Coupling constant J1,2 (Hz) 9.9 5.1 2.4

Ratio 1.0 0.09 0.38

Table 1. 14. The Chemical Shift and Coupling Constants of the Anomeric Hydrogen of 1-256.

104

O

H1

CO2Et

H2

H5

H4bH3b

H3a

H4a

TBDPSO

H6a H6bImH7a

4.4%

2.4%

H7b

2.8%

2.1%

2.7%

0.6%

7.5%

1.8%

15.1%

2.7%

2.9%

6.0%

O

H

ImCO2Et

H

H

TBDPSO

1-258

nOe (%) nOe (%) nOe (%) nOe (%)

H1→H2 0.6 H2→Imd 2.7 H3b→H4a 1.8 H4b→H7a,7b 5.3

H1→H3a 2.4 H3a→H1 1.8 H3b→H4b 7.4 H7a→H1 2.3

H1→H5 4.4 H3a→H3b 14.2 H4a→H3a 6.7 H7a→H2 2.9

H1→H7b 2.8 H3a→H4a 4.9 H4a→H4b 13.5 H7b→H1 2.7

H2→H1 0.6 H3a→H5 1.2 H4b→H2 6.0

H2→H4b 2.1 H3b→H3a 15.1 H4b→H4a 12.2


105

O

H1

H2

H5

H4bH3b

H3a

H4a

TBDPSO

H6a H6bIm

O

H

ImH

H

TBDPSO

CO2Et1-260CO2EtH7a

H7b

1.5%

4.6%

5.2%

4.6%

3.1%

4.2%

6.1%

2.0%

nOe (%) nOe (%) nOe (%) nOe (%)

H1→H2 3.5 H3a→H1 3.1 H4a→H3a 6.1 H5→ H4a 1.0

H1→H3a 1.5 H3a→H2 4.2 H4a→H4b 11.5 H5→H4b 0.9

H1→H5 4.6 H3b→H2 3.7 H4a→H5 5.3 H7a→H7b 11.5

H2→H3a 5.2 H3b→H4a 4.0 H4b→H4a 4.0 H7b→H7a 8.8

H2→H3b 4.6 H3b→H4b 2.1 H5→H1 2.0


106

OO

Im

HCO2Et

H

H

TBDPSO Im

H

HCO2Et

TBDPSO

OO

H

ImCO2Et

H

H

TBDPSO H

Im

HCO2Et

TBDPSO

OO

Im

HH

H

TBDPSOIm

H

H H

TBDPSOCO2Et CO2Et

OO

H

ImH

HTBDPSO H

Im

H H

TBDPSOCO2Et CO2Et

O

S

ImCO2Et

H

H

TBDPSO

SnR3

O

S

Im

H

TBDPSO

SnR3

CO2Et

1-262

1-263

1-258

1-259

1-260

1-261

1-264

1-265

1-267

1-268

K1

K2

TBDPSO O

OEt

O

N

S

N

1-250

Scheme 1. 62. Rationalization of the Distribution of Products from 1-250.

We may rationalize the isomer distribution of 1-256 by Scheme 1.62. The Baron’s radical

intermediate has two possible chair-like conformations 1-262 and 1-263 for the transition state. The first

transition state 1-262 is a more favorable and undergoes the intramolecular exo-hep-6-enyl radical

cyclization. The intramolecular cyclization may lead two isomers, 1-258 and 1-259. Because 1-259 has

van der Wssls repulsion between an imidazole and an axial H5 hydrogen, the most favorable conformation

of pyranoside is 1-258 despite of small interaction between imidazole and ethyl ester. Although other

107

conformers, 1-264 and 1-265 may be drawn by ring flip, those are much less favorable than 1-258 and 1-

259 because axial position of the TBDPS protecting group and the resultant large 1,3 steric repulsions.

If the radical intermediate has the configuration 1-263 and the radical ring closure proceeds via

intramolecular 6-exo cyclization, we may draw two possible isomers, 1-260 and 1-261. As described

above, the isomer 1-261 is less favored because of the 1,3 steric repulsion between the imidazole and

hydrogen. Moreover, although axial ethyl ester substituted methylene is unfavorable, the steric interaction

between an imidazole and an axial H5 hydrogen of 1-259 are much bigger than 1,3 axial interaction of 1-

260. Thus, the 1-260 was formed as the second major product. Note that a long C-S bond reduces the

putative axial intereaction of the S-SnR3 group in the developing transition states, leading to the equatorial

orientation for the imidazole in the major products. The conformation 1-262 for the Barton’s radical

intermediate is probably more stable one (compared 1-263, no axial group) and cyclization should give all

equatorial 1-258, the major product.

Table 1.15 shows the results of the 6-exo-trig radical cyclization of substrate 1-251. The

reaction was performed under three different concentrations of substrate and radical sources in toluene or

benzene; decomposition of the all starting material 1-251 was observed under reflux condition. However,

the cyclized product 1-257 was isolated as 20% yield after slow addition of the mixture of substrate 1-251

and AIBN in benzene at 90oC.

The ratio of diastereomers of was 63:6:31, which was determined by GC before column

chromatography. However, the ratio changed to 1:0.26:0.35:0.08 after column chromatography as

determined by 1H NMR. As we have done previously, using the concentration effect of the hydride and the

power of triphenyltin hydride as the hydrogen source, the isolated yield of the pyranoside could be

increased up to 79% under diluted concentration (0.064M Ph3SnH in benzene). Four possible isomers were

observed in a ratio of 0.21:1.0:0.78:0.22 in 1H NMR spectrum of the crude product. Because we failed to

isolate each of those isomers by column chromatography, the detail of the structures of the diastereomers

were not investigated.

108

1-251

O

OEtTBSO

O

N

S

N

O

CO2Et

N

N

1-257

TBSO1

2

3

5

Conditions

Entry R3SnH AIBN Solvents Temp.f Note

Yield

(%)

comments

1 5.6 Eq. 0.7 Eq. toluene reflux a NRg

2 5.0 Eq. 0.15 Eq. toluene reflux b NRg

3 5.0 Eq. 0.25 Eq. toluene reflux c NRg

4 5.0 Eq. 0.5 Eq. benzene 90 oC d 20 0.1: 1.0:0.49:0.0h

5 5.0 Eq. 0.5 Eq. benzene 90 oC e 79 0.21:1.0:0.78:0.22i

a. 0.047M Substrate in benzene, 0.064M Bu3SnH in benzene, 167 µL/min via a syringe pump b. 0.067M Substrate in toluene, 0.059M Ph3SnH in toluene, 100 µL/min via a syringe pump c. 0.043M Substrate in toluene, 0.085M Ph3SnH in toluene, 50 µL/min via a syringe pump d. 0.070M Substrate in benzene, 0.392M Bu3SnH in benzene, 45 µL/min via a syringe pump e. 0.058M Substrate in benzene, 0.064M Ph3SnH in benzene, 40 µL/min via a syringe pump f. Temperature of an oil bath g. Decomposed starting material. h. The ratio determined by GC before column chromatography. i. The ratio determined by 1H NMR before column chromatography

Table 1.15. 6-Exo trig Radical Ring Closure of 1-251.

1. 3. 6. 6-Exo trig Radical Cyclization of Unactivated Olefins

Table 1.16 shows the reaction of substrate 1-269 with radical source such as tributyltin hydride,

triphenyltin hydride, or EPHP (ethylpiperidinehypophosphoric acid ) salt. Unfortunately, the substrate did

not cyclize under our optimized conditions. When the concentration of the tin hydride was reduced

(0.08M), 19% (49% based on recovered starting material) of olefin 1-270 was formed.

109

TBSO

O OTBSO

O O

1-2701-269

OH

O

NHS

Conditions

Entry R3SnH AIBN Solvents Temp.g Cond.

Yield

(%)

comments

1 5.0 Eq. 0.5 Eq. Benzene 90 oC a 19(49)f

2 5.0 Eq. 0.5 Eq. Benzene 90 oC b 48

3 5.0 Eq. 0.5 Eq. Benzene 90 oC c 50

4 10.0 Eq. 1.0 Eq. Benzene 90 oC d NRi

5 2.0 Eq. 0.1 Eq.h Benzene rt e NRj 4 days

a. 0.026M Substrate in benzene, 0.080M Bu3SnH in benzene, 42 µL/min via a syringe pump b. 0.033M Substrate in benzene, 0.182M Bu3SnH in benzene, 42 µL/min via a syringe pump c. 0.046M Substrate in benzene, 0.063M Ph3SnH in benzene, 25 µL/min via a syringe pump d. 0.033M Substrate in benzene, 0.125M EPHP in benzene, 42 µL/min via a syringe pump e. 0.025M Substrate in benzene, 0.050M Bu3SnH in benzene, 42 µL/min via a syringe pump f. Yield is based on recovered starting material g. Temperature of an oil bath h. 1.0 M Et3B in THF i. All starting material was decomposed j. 85% of starting material was recovered


Although we changed the concentration of the tin hydride (0.182M), the desired product was not

formed via radical process, and only dethiocarbamated product 1-270 was isolated as a 48% yield. Because

we have found previousely that triphenyltin hydride is a better radical/hydrogen source in the radical

110

cyclization, we used it in the reaction of 1-269 under high dilution solution (0.046M substrate in benzene

and 0.063M Ph3SnH in benzene) (Entry 3). However, the reaction did not improve at all, and only the 1-

270 was isolated in a 50% yield. Alternative radical/hydrogen sources such as EPHP and radical raction

initiator (triethyl borane) also failed, andl all starting decomposed (Entry 4) or recovered (Entry 5).

Because we found that O-methyl oxime (Table 1.10) and N,N-dimethyl hydrazone (Table 1.11)

could be used as a radical acceptor in Braton’s radical mediated 6-exo trig cyclization, it was natural for as

to turn to diphenylhydrazone as the radicl acceptor. First, the substrate 1-271 was subjected to 6-exo trig

radical cyclization with tributyltin hydride. However, all starting material decomposed and no amount of

significant products was obtained after column chromatography. Although the hydride was changed from

tributyltin hydride to triphenyltin hydride, and more diluted conditions were employed, we still did not see

any cyclization.

1-271

O

O O

NNPh2TBSO

NS

N

DecomposedX

Conditions

Entry R3SnH AIBN Solvents Temp.c Cond.

Yield

(%)

1 5.0 Eq. 0.5 Eq. benzene 90 oC a NRd

2 5.0 Eq. 0.5 Eq. benzene 90 oC b NRd

a. 0.047M Substrate in benzene, 0.063M Bu3SnH in benzene, 35 µL/min via a syringe pump b. 0.037M Substrate in benzene, 0.058M Ph3SnH in benzene, 25 µL/min via a syringe pump c. Temperature of the oil bath d. All starting material decomposed


1. 3. 7. Other N-Heterocyclic Glycosides via 6-Exo trig Radical Cyclization

111

Initially, Bliss studied the 6-exo radical cyclization with triazole substituted substrates 1-272 and

1-273, but claimed that starting material decomposed under his conditions. Because we found earlier that

use of 5.0 equivalents of triphenyltin hydride and reversed addition were the critical for the success of N-

glycosylation via radical process, the substrate 1-272 and 1-273 were exposed to that conditions, and the

results are summarized in the Table 1.18.

O

YOO

OTBS

N

N

NO

O O

XTBSO

NS

NN

1-272: X = CHCO2tBu

1-273: X = NOCH3

1-274: Y = CH2CO2tBu

1-275: X = NHOCH3

Coonditions Entry Subst

R3SnH AIBN Solvent Tempe Note

Product

Yield

(%)

Commtf

1 1-272 5.0 Eq. 0.5 Eq. Benzene 90 oC a 1-274 87 0.32:1.0

2 1-272 1.6 Eq. 0.2 Eq. Toluene 90 oC b decomposed

3 1-273 5.0 Eq. 0.5 Eq. Benzene 90 oC c 1-275 46 (78)g 0.69:1.0

4 1-273 2.1 Eq. 0.2 Eq. Toluene 90 oC d decomposed

a. 0.048M Substrate in benzene, 0.063M Ph3SnH in benzene, 27 µL/min via a syringe pump b. Bliss’ dissertation: 0.050M substrate in toluene, 0.050M Bu3SnH in toluene. c. 0.046M Substrate in benzene, 0.063M Ph3SnH in benzene, 25 µL/min via a syringe pump d. Bliss’ dissertation: 0.050M substrate in toluene, 0.050M Bu3SnH in toluene. e. Temperature of the oil bath. f. altro-α/altro-β. g. The isolated yielf of altro-β anomer. The number in the paranthesis is estimated yield from the altro-α/altro-β ratio of the crude mixture.

Table 1. 18. 6-Exo trig Radical Ring Closure of 1-272 and 1-273.

112

The Z substrate 1-272 could be cyclized efficiently to give triazole substituted N-pyranoside 1-274

in an 87% yield, and the products have only altro configuration as expected from our previouse

observations. After column chromatography of the crude mixture, the α and β anomers were isolated as a

pure form, which were subjected to nOe experiment to determine the configuration of the products. The

results for the nOe experiment are shown in Figure 1.14 and 1.15. The altro configuration of the 1-274 -α

and 1-274-β is proved by the observation of strong nOe effects between H2 in the both anomers. The α/β

anomeric hydrogens were assigned by double irradiation techniques.

O

H

N

H

OTBS

O

O

H

HH

N

N

CO2tBu

O

OO CO2

tBu

OTBS

N

N

N

1-274-β

2.8%

3.8%

12

3

45

2.5%, 2.5%

0.9%, 1.5%

0.9%, 0.7%

1.2%, 1.4%

3.7%

1.5%, 2.0%

nOe (%) nOe (%) nOe (%) nOe (%)

H1→H2 3.8 H3→H2 1.8 H4→H5 0.8 H7a→ Tra1 0.3

H1→H5 3.2 H3→H4 2.2 H4→H7a 0.6 H7a→ Tra1 0.7

H1→ Tra1 0.2 H3→H7a 2.0 H5→H1 3.7 H7b→H3 2.5

H1→ Tra2 1.4 H3→H7b 1.5 H5→H2 3.8 H7b→H4 0.9

H2→H1 3.7 H4→H3 2.3 H5→H4 1.1 H7b→ Tra1 0.9

H2→H3 1.9 H4→H6a 0.7 H7a→H3 2.5 H7b→ Tra2 1.2

H2→H5 2.8 H4→H6b 1.4 H7a→H4 1.5

Figure 1. 14. The Representative Results of nOe for 1-274-β.

113

O

H

H

N

OTBS

O

O

H

HH

NN

CO2tBu

O

OO CO2

tBu

OTBS

N

N

N

1-274-α

3.6%

1.7%

12

3

45

1.2%

0.7%

4.5%

1.4%

nOe (%) nOe (%) nOe (%) nOe (%)

H1→H3 1.7 H2→H3 1.4 H4→H6b 1.5 H6b→H4 1.1

H1→H7a 0.7 H2→H5 4.5 H5→H2 3.6 H7a→ H3 1.0

H1→H7b 1.2 H4→H6a 1.9 H6a→H4 3.4

Figure 1. 15. The Representative Results of nOe for 1-274-α.

The importance of O-methyl oximes in radical chemistry comes from the fact that they are not

only excellent radical accepors, but also they serve as latent amine functionalities in the products. We have

shown the O-methyl oximes can be used as a radical acceptor for the Barton’s radical mediated ring

closure. Another substrate with oxime functionality 1-273, a triazole derivative, was used in the

investigation of radical cyclization. The expected product 1-275 was efficiently made under our optimized

reaction conditions to give α/β mixture with only altro configuration. Surprisingly, only trace amount allo

isomers were observed in the analysis of the crude 1H NMR spectrum although a mixture of syn/anti

isomers were used as the starting substrate.

Although we failed to isolate the α-anomer of the 1-275 by column chromatography, the β-anomer

was isolated as a pure compound in a 46% yield. The isolated yield was relatively poor, but estimated yield

from the α/β ratio of the crude product in the 1H NMR spectrum was 78%, which is a comparable to other

similar cyclization. The configuration of the 1-275 was determined by not only nOe experiment, but by

chemical shift and coupling constants as well. For example, irradiation of H1 peaks enhanced the peak of

114

H5 proton with an axial position, and relatively small coupling constant (J1,2 = 3.4Hz) may imply that the

configuration of H1 and H2 are in axial-equatoral relationship; i.e. the relation of H1 and H2 is cis. Based on

those results as well as other spectroscopic data we assigned the isolated pure N-pyranoside as β-altro-1-

275.

O

H

N

H

OTBSNHOCH3

O

O

H

HH

N

NO

NHOCH3OO

OTBS

N

N

N

2.3%

3.0%

12

3

45

1.2%0.7%

1-275-β

nOe (%) nOe (%) nOe (%)

H1→H2 3.0 H4→H6b 1.3 OCH3→ H3 0.3

H1→H5 2.3 H4→ OCH3 1.2

H3→H4 1.8 OCH3→ H2 0.3

Figure 1.16. The Representative Results of nOe for β-altro-1-275.


Chemical shift (ppm) 5.95 6.11 5.87

Coupling constant (Hz) 8.8 3.4 2.9

Ratioa 0.69 1.0

a. The ratio was determined by 1H NMR before column chromatography.

Table 1. 19. The Chemical Shift and Coupling Constant for β-altro-1-275

115

Bliss also explored the radical cyclization of 1H-benzimidazole thiocarbamate 1-276 with

tributyltin hydride at 90 oC. Although he isolated the desired N-heterocyclic pyranoside 1-277, the yield

was extremely low (4%) and some sideproduct 1-278 was isolated in 6% yield. He tentatively assigned the

N-pyranoside 1-277 as altro and the anomeric hydrogen with an α-configuration. He also rationalized the

formation of 1-278 by the mechanism proposed in Scheme 1.79. Because we successfully made the 1H-

benzimidazole thiocarbamate 1-276 in the previouse study, the Barton’s radical mediated 6-exo trig radical

cyclization was performed under our optimized condition.

O N

OO CO2

tBu

OTBS

1-277

TBSO

O O

1-276

O

NS

CO2tBu

N

N

O N

OO CO2

tBu

OTBS

1-278

N

+

Conditions Yield

Entry R3SnH AIBN Solvents Tempe Note 1-277 1-278

Comment

1 1.6 Eq. 0.2 Eq. toluene 90 oC a 4 6

2 5.0 Eq. 0.5 Eq. benzene 90 oC b 81e 0.81/1.0 f

3 5.0 Eq. 0.5 Eq. benzene 90 oC c 87 e 0.58/1.0 f

a. Bliss’s dissertation: 0.05M substrate in toluene, 0.05M Bu3SnH in toluene. b. 0.037M Substrate in benzene, 0.063M Ph3SnH in benzene, 23 µL/min via a syringe pump c. 0.047M Substrate in benzene, 0.063M Ph3SnH in benzene, 256 µL/min via a syringe pump d. Temperature of the oil bath e. Product was contaminated with some impurities. f. altro-α: altro-β. The ratio was determined from the crude product by 1H NMR.


116

We found two anomeric hydrogens from the crude reaction mixture at δ 5.43 (J = 7.4Hz) for altro-

α and at δ 5.91 (J = 3.9Hz) for altro-β in a ratio of 0.81/1.0 to 0.58/1.0, but could not find any evidence for

the formation of 1-278. Unfortunately, our best attempt to isolated pure 1-277 (and/or 1-278) failed and the

related yield is based on data on mixture of contaminated product (Table 2, Entry 3).

O

OO CO2

tBu

OTBS

1-279 O N

OO CO2

tBu

OTBS

1-278

N

SSnBu3

BzImH

O N

OO CO2

tBu

OTBS

1-277

N

O

OO CO2

tBu

OTBS

1-280

H

BzImLewis

Base

SiO2

Bu3SnH

Scheme 1.63. Proposed pathway to β-D-altropyranosyl 1H-benzimidazole 1-277 and D-ribo-hex-1-

enopyranosyl 1H-benzimidazole 1-278.

1. 3. 8. Synthesis of N-Furanosides via 5-Exo-trig Radical Cyclizations

In the earlier experiments, we found that imidazole and triazole thioates derived from D-

ribofuranose upon addition to a large excess of an efficient hydrogen donor, underwent cyclization to give

surprisingly good yield of imidazoyl and triazoyl glycosides. As expected from configuration of radical

intermediate, all four possible stereoisomers were formed from E-substrate. However, the stereochemistry

of C2 could be controlled by using Z substrate. We also optimized the reaction conditions of 6-exo-trig

radical cyclizations. The optimized conditions are (i) 5 equivalents of alkyl tin hydride as a radical source,

117

(ii) 0.5 equivalent of AIBN as a radical initiator, and, (iii) 90 oC for the oil bath temperature. In order to get

a higher yield of cyclized compound, it is essential to keep a low concentration of hydrogen/radical sources

in solvents, and the temperature of the oil bath must be controlled carefully.

In this section, we record our attempts to extend the new synthetic method for the synthesis of N-

furanoside from commonly obtained sugar derivatives using these optimum reaction conditions. The 5-

exo-trig cycization was performed under a variety of reaction conditions with the following changes; (i)

hydrogen/radical sources, (ii) concentration of substrate as well as of hydrogen/radical sources, (iii) change

in addition rates via a syringe pump, (iv) the order of addition of reactants for generating the radical

intermediate, and (v) the temperature of the oil bath.

Table 1.21 summarizes 5-exo-trig radical cyclization studies with Barton’s radical intermediate

derived from 1-281. All attempts failed under the refluxing toluene (about 110 oC) conditions. For

example, when 5.0 Eq. of Ph3SnH was used as a radical source along with 0.15 Eq. of radical initiator

AIBN at 110 oC (Entry 1), all the starting material (1-281) was consumed with no formation of significant

identifiable products. In the Entry 2, we changed the concentration of the substrate and the

hydrogen/radical source as well as the equivalents of radical initiator AIBN. There was no improvement in

terms of 5-exo-trig radical cyclization. To find a better radical/hydrogen source than Ph3SnH, we decided

to use excess equivalent of EPHP along with 1.0 Eq. of AIBN (Entry 3). However, the expected product 1-

282 or 1-283 was not isolated any of these conditions. Even though we changed the addition rate as well as

the concentration, the 5-exo-trig radial cyclization could not be successfully carried out (Entry 4 and 5).

Interestingly, cyclized thionolactone 1-283 was isolated in a 58% yield with a diluted concentration of

substrate and Bu3SnH at 110 oC (Entry 6). The isolated compound 1-283 was a mixture of two

diastereomers in a ratio of 2.1/1.0. The stereochemistry at C-4 is fixed and is the known from the

stereochemistry of 1-281. However, the configuration of C-2 is dependent on the stereoselectivity of the

cyclization. The ratio of cis/trans (or trans/cis) between C-2 and C-4 has been determined by the

integration of 1H NMR spectrum, and the thiocarbonyl function was confirmed by the chemical shift in the

13C NMR spectrum, which was shown to have two characteristic peaks at δ 178.5 and 177.4 ppm.

118

+

1-281

O

OEtO

N

S

N

TBSO

O

TBSON

H H

N

CO2Et

O

TBSO

H

CO2Et

S

1-282 1-283

Conditions

Entry R3SnH AIBN Solvents Temp.m Note

Yield

(%)

comments

1 5.0 Eq. 0.15 Eq. toluene reflux a NR

2 5.0 Eq. 0.25 Eq. toluene reflux b NR

3 10.0 Eq. 1.0 Eq. toluene reflux c NR

4 10.0 Eq. 1.0 Eq. toluene reflux d NR

5 10.0 Eq. 1.1 Eq. toluene reflux e NR

6 2.0 Eq. 0.2 Eq. toluene reflux f 58k 2.1/1.0n

7 3.0 Eq. 0.3 Eq. benzene reflux g 7k 1.2/1.0n

8 5.0 Eq. 0.5 Eq. benzene 90 oC h 76l 51:15:29:5o

9 5.0 Eq. 0.5 Eq. benzene 90 oC i 88l p

10 10.0 Eq. 1.0 Eq. benzene 90 oC j 32l 39:19:37:11q

Continued


119

Table 1.21 continued

a. 0.067M Substrate in toluene, 0.059M Ph3SnH in toluene, 100 µL/min via a syringe pump b. 0.043M Substrate in toluene, 0.085M Ph3SnH in toluene, 50 µL/min via a syringe pump c. 0.086M Substrate in toluene, 0.143M EPHP in toluene, 41 µL/min via a syringe pump d. 0.061M Substrate in toluene, 0.087M EPHP in toluene, 83 µL/min via a syringe pump e. A mixture of 0.021M substrate and 0.208M EPHP in toluene, addition of AIBN 333 µL/min via a syringe pump f. 0.021M Substrate in toluene, addition of 0.028M Bu3SnH in toluene, 150 µL/min via a syringe pump g. 0.009M Substrate in benzene, 0.051M Bu3SnH in benzene, 62 µL/min via a syringe pump h. 0.047M Substrate in benzene, 0.064M Ph3SnH in benzene, 45 µL/min via a syringe pump i. 0.047M Substrate in benzene, 0.064M Bu3SnH in benzene, 26 µL/min via a syringe pump j. 0.047M Substrate in benzene, 0.127M EPHP in benzene, 26 µL/min via a syringe pump k. Isolated yield of compound 1-282 l. Isolated yield of compound 1-283 m. Temperature of an oil bath n. The ratio of cis/trans or trans/cis based on 1H NMR o. The ratio was determined after column chromatography (1-292: 1-294: 1-295: 1-297) p. The ratio was not determined (1-292: 1-294: 1-295: 1-297) q. The ratio was determined after work-up

120

However, we could not determine which isomer was the major product. The yield of the thionolactone

decreased from 58% to 7% in refluxing of benzene, but the desired N-furanoside was not found while the

ratio of cis/trans (or trans/cis) mixture changed to 1.2/1.0 based on the 1H NMR spectrum (Entry 7).

Surprisingly, if a mixture of 1-281 and 0.5 Eq. of AIBN in benzene (0.047M substrate in benzene)

was slowly added dropiwse into a mixture of 5.0 Eq. of nBu3SnH in benzene (0.064M Bu3SnH in benzene)

via a syringe pump at a rate of 26 µL/min at 90 oC of oil bath temperature, the desired N-furanoside was

obtained as an 88% of isolated yield (Entry 9). To improve the isolated yield of the cyclized product, we

performed the reaction with Ph3SnH as a radical source. Even though the Ph3SnH is known71 to be a better

hydrogen/radical source than Bu3SnH, the isolated yield of 1-282 decreased to 76% after column

chromatography. Entry 10 shows that EPHP can be used as a radical source and give the same yield of

cyclized compound with alkyl tin hydride. When EPHP was used for 5-exo-trig radical cyclization, the

yield of 1-282 decreased to 32%.

The formation of N-furaoside can be explained by the mechanisms we proposed earlier for the 6-

exo-trig radical cyclization (Scheme 1.64 and 1.65, the structures are tentative; it is difficult to assign

stereochemistry based on nOe in 5-membered rings). Cyclization through the conformation 1-289 (Z =

(E)-CO2Et) would give the presumed major product 1-292. The minor products could be produced through

a chair-like transition state 1-290 (Z = (E)-CO2Et) or through a boat-like transition state 1-291 (Z = (E)-

CO2Et). Epimerization at C-1 would give the trans minor products 1-295 and 1-297. Only the product

presumably 1-292 was isolated as a pure compound and the structures of all the compounds are tentative.

The major product showed a signal (anomeric) at 6.03 ppm in 1H NMR. The chemical shift in relatively

down field region may imply cis relationship between H-1 and H-2 comparing with the chemical shifts of

1-203, 1-209, and 1-235 (see Table 1.6, p. 90). We assigned tentatively this peak as of β hydrogen based

on the chair-like transition state, 1-289, in Scheme 1.65. The second major product peak was shown to

have up field anomeric hydrogen (δ 5.55 ppm) with a smaller coupling constant, J = 5.5 Hz in 1H NMR,

which may be the epimerized product, 1-295, with trans configuration. Two other small peaks at 6.09 and

5.53 ppm could arise from 1-297 (α) and 1-294 (β). All configurations are tentative.

121

Entry Compounds Chemical shift

H1 (ppm)a

Coupling constant

J1,2 (Hz)a

1 1-292, 1-294

1-295, 1-297

6.03, 5.53

5.55, 6.09

6.8, 5.0

5.5, 6.2

2 1-113, 1-114

1-115, 1-116

5.56, 5.97

6.01, 5.62

6.0, 6.6

6.0, 4.8

a. 400 MHz 1H NMR

Table 1. 22. Selected Chemical Shifts and Coupling Constants of N-Furanoside 1-282.

1-281

O

OEtO

N

S

N

TBSO

O

TBSON

H

N

CO2Et

O

TBSO

H

CO2Et

S

1-285

1-283

1-284

O

OEtO

N

S

N

TBSO

SnPh 3

k1

k2 SSnBu3

O

TBSON

H

N

CO2Et

1-286

SSnBu3

O

TBSON

H

N

CO2Et

1-282

H

1-287O

OEt

TBSO

1-288

O

OEt

TBSO

k1

k2

k3

k4

Scheme 1.64. The Mechanism for the Formation of N-Furanoside via 5-Exo-trig Radical Cyclization.

122

OH

Im

SSnPh3

CO2Et

TBSO

O

HTBSO

ZSSnPh3

Im

O

HTBSO

Z

Im

SSnPh3

Ph3SnH

Ph3SnH

Ph3SnH

OH H

Im

H

Z

TBSO

O

HTBSO

Im

HH

Z

O

HTBSO

Im

H

H

Z

OH Im

H

H

Z

TBSO

O

HTBSO

H

H

Im

Z

Z =CO2Et

H

OTBS

Z

H

Im

OH

1-284

ZO

N

S

N

TBSO

SnPh 3

1-290 1-293 1-296

1-291

1-2951-289

1-294

major

minor

minor

1-292

or

1-297

Scheme 1.65. Rationalization of Diastereomers for 1-282 via 5-Exo trig Radical Cyclization.

It is obvious that an EWG can promote the 6-exo or 5-exo radical cyclizations. Table 1.23 shows

the result of 5-exo-trig radical cyclization of thiocarbamate derivatives substituted with a CN group. The

substrate used was E/Z mixture, and the reaction conditions were similar to the ones described above for

CO2Et. After flash column chromatography, two compounds, 1-299 and 1-300, were isolated. The isolated

product 1-299 has four diastereomers based on 1H NMR, and the absolute stereochemistry has been

tentatively assigned as before (Scheme 1.66). The major product presumably was 1-305, which has a cis

configuration between C-1 and C-2, and the second major was 1-307 with trans configuration. The

sturucture of the other diastereomers remain uncertain (see Table 1.12 for the chemical shifts and coupling

constants of the tentative assignment). Interestingly, 8% of 1-300 was isolated as a mixture (cis/trans).

The relative configurations of these isomers were not determined.

123

+

1-298

CNO

N

S

N

TBSO

O

TBSON

H H

N

CN

O

TBSO

H

CN

1-299 1-300

Conditions

Entry R3SnH AIBN Solvents Temp.d Cond.

Yield

(%)

comments

1 5.0 Eq. 0.5 Eq. benzene 90 oC a 39b, 8c 68:25:5:2

a. 0.035M Substrate in benzene, 0.069M Bu3SnH in benzene, 42 µL/min via a syringe pump b. Isolated yield of compound 1-299 c. Isolated yield of compound 1-299, cis/trans or tran/cis = 2:1 of 1-300 d. Temperature of an oil bath e. The ratio of diastereomer determined by 1H NMR after column chromatography (3-69:3-71:3-68:3-70, tentatively assigned)


OIm

SSnBu3

H

TBSO

CN

O

H

TBSOCN

Im

SSnBu3

Si

Re

O

H

TBSO

Im

CN

HH

O

H

TBSO

Im

H

H

CN

O

H

TBSO

H

CN

HIm

O

H

TBSO

H

H

Im

CN

1-302 1-306

1-303 1-3071-305

1-301

CNO

N

S

N

TBSO

SnPh31-304

Scheme 1. 66. The Rationalization of the Stereochemistry for the Radical Cyclization of 3-107.

124

1. 3. 9. Stereochemical Control in 5-Exo trig Radical Cyclizaiton

Previously we found that the stereoselcetivity in the inherently less selective heptenyl radical

cyclization is considerably better when the Z-isomer of the radical acceptor is employed. Although

generally the intramolecular hex-5-enyl radical cyclization is more efficient in terms of isolated yield, the

low stereoselectivity at a C1-C2 bond is the major drawback of this reaction. For examples, earlier we

described that imidazole thioates derived from a 5- or 6-hydroxy-2-3-enoate (Eqs. 44 and 45) upon addition

to a large excess of efficient hydrogen donor, undergo cyclization to give surprisingly good yield of

imidazoyl glycosides. In both cases, not unexpectedly, mixtures of all possible stereoisomers of the

product 1-257and 1-282 are formed in this otherwise efficient transformation. Since major applications of

this chemistry are likely to be in the area of carbohydrates, we wondered whether the structural features

present in the potential class of substrates might offer solutions to this problem.

1-251

O

OEtTBSO

O

N

S

N

O

CO2Et

N

N

1-257

TBSO

1-281

O

OEtO

N

S

N

TBSO

O

TBSON

H H

N

CO2Et1-282

(44)

(45)

Ph3SnH (5.0 Equiv)

benzene, 90 oC79%

Ph3SnH (5.0 Equiv)

benzene, 90 oC88%

The hydroxyl groups on the tether present opportunities for incorporating cyclic acetal-type

protecting groups, which through the resident conformational features, could influence the stereochemistry

of the annulation process. Since both furanosides and pyraosides of N-heterocycles appears to be

125

accessible through the Barton’s radical mediated cyclizations, which inlvolves the formation of C1-C2 bond,

we decide to study in some detail the effect of a various structural parameters of the substrate on the

coursce of this reaction. Thus we examined the effects of protecting groups and Z/E-configuration of

radical acceptors on hex-5-enyl radical cyclization.

The starting material for the hex-5-enyl type cyclization studies was readily prepared from 4-6-O-

phenylmethylglucopyranose upon periodate cleavage followed by olefination and thicarbamation (Chapter

1.2.4, p.67). The radical cyclizations were carried out under conditions optimized for the formation of N-

glycosides. Thus in a typical reaction, 0.16 mmol of (E)-1-283 and 0.08 mmol of AIBN dissolved in 3.4

mL of benzene was added in ~2 h to 0.80 mmol of Ph3SnH in 12.5 mL of benzene in an oil bath at 90 oC.

The reaction was continued for another 30 min at that temperature and the solvent was removed. The

results are summarized in Table 1.24.

OOPh O O

OPh O

H HRO2C

RO2C

N

S

N

N

N

1-283, R = Et1-284, R = tBu

1-285, R = Et1-286, R = tBu

Ph3SnH

benzene/ 90 oC(46)

As we had anticipated, the use of a cyclic acetal protecting group indeed results in an

improvement in the stereoselectivity of the reaction vis-á-vis the acyclic precursor 1-281 in Scheme 1.80

(see also Table 1.21, p. 118). The C2-substitutent in the N-glycoside is formed exclusively with a β-

orientation, irrespective of the geometry of the starting material 1-283 and 1-284. Although the isolated

yield of N-furanoside was moderate, triphenyltin hydride is a more efficient hydrogen donor than tributyltin

hydride. Other radical/hydrogen source like ethylpiperidine hypophosphite (EPHP) could be used in this

reaction, but isolated yield of the product was relatively poor (Entry 7).

126

OOPh O O

OPh O

H HRO2C

RO2C

N

S

N

N

N

1-283, R = Et1-284, R = tBu

1-285, R = Et1-286, R = tBu

Ph3SnH

benzene/ 90 oC

Conditions

Entry

R Radical AIBN Solvent Temp Note

Yield

(%)

Comment

1 (Z)-1-283 Bu3SnH (5.0Eq) 0.5 Eq benzene 90 oC a 32 0.84/1.0k

2 (E)-1-283 Bu3SnH (5.0 Eq) 0.5 Eq benzene 90 oC b 28 0.67/1.0 j

0.66/1.0 k

3 (Z)-1-283 Ph3SnH (5.0 Eq) 0.5 Eq benzene 90 oC c 44 1.13/1.00 k

4 (E)-1-283 Ph3SnH(5.0 Eq) 0.5 Eq benzene 90 oC d 54 0.80/1.0 k

5 (Z)-1-284 Ph3SnH (5.0 Eq) 0.5 Eq benzene 90 oC e 46 0.66/1.0 k

6 (Z)-1-284 Ph3SnH (5.0 Eq) 0.5 Eq benzene 90 oC f 23 0.93/1.0 j

0.97/1.0 k

7 (Z)-1-284 EPHP (10.0 Eq)i 1.0 Eq benzene 90 oC g 14 l

8 (E)-1-284 Ph3SnH (5.0 Eq) 0.5 Eq benzene 90 oC h 40 0.80/1.0 j

0.89/1.0 k

a. 0.046M Substrate in benzene, 0.063M Bu3SnH in benzene, 29 µL/min via a syringe pump b. 0.046M Substrate in benzene, 0.063M Bu3SnH in benzene, 28 µL/min via a syringe pump c. 0.047M Substrate in benzene, 0.063M Ph3SnH in benzene, 29 µL/min via a syringe pump d. 0.046M Substrate in benzene, 0.063M Ph3SnH in benzene, 28 µL/min via a syringe pump e. 0.046M Substrate in benzene, 0.063M Ph3SnH in benzene, 26 µL/min via a syringe pump f. 0.010M Based on substrate and 0.050M based on Ph3SnH in benzene. The reagents was added all together and stirred at 90 oC for 3h. g. 0.046M Substrate in benzene, 0.126M EPHP in benzene, 28 µL/min via a syringe pump h. 0.047M Substrate in benzene, 0.063M Ph3SnH in benzene, 28 µL/min via a syringe pump i. Ethylpiperidine hypophosphite j. The ratio of α/β was determinded before column chromatography by 1H NMR. k. The ratio of α/β was determinded after column chromatograpy. l. The ratio was not determined.

Table 1. 24. 6-Exo trig Radical Cyclization with 5(R)-Hydroxy-2(R)-phenyl-[1, 3]dioxane-4(R)-

carbaldehyde Derivatives.

127

The α- and β-glycoside can be separated by flash column chromatography, and the structures have

been rigorously established by spectroscopic methods. The position of C1-hydrogen gives a reliable

indication of the anomeric configuration. For the α-anomers the C1 hydrogen appears consistently δ 5.80 ±

1.0 ppm and for the β-anomer this proton appears at δ 6.15 ± 1.0 ppm. In addition, nOe studies further

confirm these assignments. For example, the altro-configuration at C2 can be assigned by the observation

of strong nOe effects between H2 and H4 and the β-configuration of the anomeric haydrogen is supported

by nOe’s H1→H3 and H3→H1.

1-286-α

O

OPhO

H2Im

H1ButO2C

H5a

H5e

H7

H4

H3

6

2.6%

2.6%

1.8, 0.8%2.7%

1.4%

1.9, 0.8%

1.5%

1.6, 1.2%

0.5, 0.9%

OOPh O

H NBuO2

tCH

N

nOe (%) nOe (%) nOe (%) nOe (%)

H1→H2 0.9 H2→H4 2.6 H3→H2 0.9 H5a→H5e 15.8

H1→H3 1.4 H2→H6a 1.5 H3→H5a 2.2 H5a→H7 3.8

H1→H6a 1.8 H2→H6b 1.2 H3→H6a 1.6 H5e→H4 6.6

H1→H6e 0.8 H2→ Imd1 1.9 H3→H6b 1.2 H5e→H5a 12.2

H1→ Imd1 0.8 H2→ Imd2 0.8 H3→H7 6.6 H7→H3 5.9

H1→ Imd2 1.5 H3→H1 1.5 H5a→H3 1.1 H7→H5a 2.9

H2→H1 0.8

Figure 1.17. Representative Results for nOe of 1-286-α.

128

The β-anomer 1-286-β was also assigned by nOe experiment. The observation of nOe effect

between H2 and H4, and H3 and H6, can be used as the evidence to support the altro-configuration at C2, and

the β assignement of the anomeric hydrogen may be rationalized by the istrong nteraction between H1 and

H4, and H3 and Imidazole.

OOPh O

H HRO2C

N

NO

OPhO

H2H1

ImButO2C

H5a

H5e

H7

H4

H3

6

1.2%3.4%

2.6%

1.9, 1.1%

1.2%3.1%

1.1, 0.6%

1-286-β

nOe (%) nOe (%) nOe (%) nOe (%)

H1→H2 4.3 H2→H4 3.4 H3→H7 6.1 H4→H5e 2.6

H1→H4 1.2 H2→H6a 0.8 H3→ Imd1 1.9 H7→H3 5.7

H1→ Imd1 1.4 H3→H5a 2.6 H3→ Imd2 1.1 H7→H5a 2.5

H1→ Imd2 2.1 H3→H6a 1.1 H4→H1 1.3 H7→Ph 1.6

H2→H1 4.4 H3→H6b 0.7 H4→H2 3.1

Figure 1.18. Representative Results for nOe of 1-286-β.

It is known that in the Barton-McCombie reaction the slow step is the collapse of the 1-284 (see

Scheme 1.64, p.121). Since the rate of intramolecular addition to an activated acceptor is likely to be faster

than this decomposition, formation of cyclic product, especially in the presence of a sterically demanding,

H-atom donor, is not surprising. Analysis of the transition states that lead to the cyclic products provides a

satisfactory explanation for the exclusive β-orientation formation of the C2-substituent. Of the two possible

129

transition state (Scheme 1.67), one with ‘chair-like’ conformation 1-287 that leads to the C2-β product is

likely to be favored over the ‘boat-like’ transition state 1-291 that results in the C2-α substituent. In

depicting these structures the quasi-axial position at C1 is based on the reasonable assumption that C-S and

S-Sn bonds are significant longer than the C-N bond, and thus the imidazoyl moiety is likely to be sterically

more demanding. Homolytic cleavage of the C-S bond in 1-288 followed by H atom abstraction by the

resulting gkycosyl radical 1-290 will result in the two glycosides. Predictably, there is little difference

between H-abstraction at either α- or β-face of C1.

OOPh O N

SSnPh3

N

X

OOPh O

NN

X

H H

HS SnPh3

OOPh O

NN

X

H H

H

OOPh O

NN

X

H H

HH

R3SnH

OO

OH

Ph

N

S SnR3

N

H X

HH

OOPh O

NN

H

H H

S SnPh3

OOPh O

NN

H

H H

H

X

X

C2-substituent β

1-287 1-288

1-289 1-290

"chair-like"

α- and β- furanosides

1-291"boat-like"

C2-substituent α

1-292

1-293(not formed)

Scheme 1. 67. Origin of Stereoselectivity at C2 of the N-Furanoside.

130

Although stereoelectronic effects are known to play an important role in the capture of the

anomeric radicals by H-atom donor and electron deficient olefins, the conformation of the strained

bicycle[4.3.0]-system (e.g. 1-290) in the present context makes it difficult to achieve any preferential

alignment of the suitable orbitals for one conformation to be favored.

Unstaturated precursors for the synthesis of 1-294 – 1-301 were prepared from the D-glucoside

with (cyanomethylene)triphenylphophorane, O-methylhydroxyl amine, O-benzylhydroxyl amine, N,N-

dimethylhydrazine, N,N-diphenylhydrazine, hydroxylamine hydrochloride, (p-toluene)sulfonyl hydrazine,

and 1-amino-2-pheylaziridine, respectively. The corresponding imidazole thioates were prepared by

thiocarbamtion with 1,1-thiocarbonyl diimidazole in THF or CH2Cl2 under reflux conditions, and the

results of exo-hex-5-enyl cyclization of the substrate 1-294 – 1-301 are shown in Table 1.25. The radical

cyclization was successfully carried out with oxime and hydrazone derivatives 1-294 – 1-301 with

exclusive β-orientation of the C2-substituent. The only exception is in the case of diphenylhydrazone 1-

298, which gave the only the α–anomer 1-307 in low yield (22 %) as well as reduced product 1-308 in 26%

yield (Entry 7). The modest selectivity in the anomeric hydrogen (α-anomers are preferred) of hydrzone 1-

297 and 1-298 can be explained by steric effect. If we doubled the hydrogen source and radical initiator

AIBN (i.e. 10.0 equivalents of Ph3SnH and 1.0 equivalent of AIBN, the concentration of Ph3SnH was

0.126M in benzene), the formation of the reduced product 1-308 increased up to 62% without significant

changing of the yield of 1-307 (Entry8). Oxime-based radical acceptors, O-methyloxime (1-295) and O-

benzyloxime (1-296) are efficient radical acceptors in the 5-exo radical cyclization to make N-furanosides.

Moreover, the E and Z isomers of 1-296 were separated relatively easily by column chromatography, and

we could study more precisely the role of oxime-configuration in stereochemical control via radical

cyclization (Entry 4 and 5). As the results of an EWG substituted olefins (Table 1.24 and Entry 1 and 2 in

Table 1.25), the configuration of oxime did not have any effect in terms of stereochemical control of C2 of

N-furanoside 1-305 in spite of lower yield of cyclized product with the E substrate. Although O-

methyloxime substituted precursor 1-295 gave a slightly better yield than O-benzyloxime substituted

precursor 1-296, the formation of 1-304 as a byproduct is the major drawback of the radical acceptor in the

synthesis of N-furanoside via radical pathway (Entry 3).

131

OOPh O

NN(CH3)2

1-297

OOPh O

N N

1-298

1-295(Z)-1-294

1-3011-300

Im

S

OOPh O

NNPh2

Im

S

OOPh O

NOCH3

Im

SO

OPh O Im

S

OOPh O

NNHTs

Im

S

Ph

Im

S

1-299

OOPh O

N

Im

S

(E)-1-296

OOPh O

N

Im

S

(E)-1-294

OOPh O Im

S

CNNC OBn

(Z)-1-296

OOPh O

N

Im

S

BnO

Figure 1.19. Representative Substrates for 5-exo-trig Radical Cyclization.

OOPh O

H

Im

H

(H3C)2NHNO

OPh O

H

H

Im

Ph2NHNO

OPh O

H

Ph2NHN

OOPh O

H

Im

H

H3COHNO

OPh O

H HNC

OOPh OH

N

OOPh O

H

Im

H

BnOHNO

OPh OH

NOCH3

Im

1-306 1-307 1-308

1-3031-302

1-309

1-304 1-305

Figure 1.20. Representative Products for 5-exo-trig Radical Cyclization.

132

OOPh O

X

Im

SO

OPh O

H H

X Im

Y HY

OOPh O

H H

X ImH

YO

OPh OH

XY

1-294 - 1-301

+ +

1-302 - 1-309

Condition Entry

Reactant R3SnH AIBN Solvent Note

Product Yield

(%)

Ratio of

α/β

1 (E)-1-294 5.0 Eq 0.5 Eq benzene a NR q N/A

2 (Z)-1-294 5.0 Eq 0.5 Eq benzene b 1-302 81 1.0/0.79o

1.0/0.76p

3 1-295 5.0 Eq 0.5 Eq benzene c 1-303 1-304 63 9 1.0/0.83 o

1.0/0.68 p

4 (E)-1-296 5.0 Eq 0.5 Eq benzene d 1-305 38 1.0/0.78 p

5 (Z)-1-296 5.0 Eq 0.5 Eq benzene e 1-305 59 1.0/0.91 o

6 1-297 5.0 Eq 0.5 Eq benzene f 1-306 54 1.0/0.31 o

1.0/0.32 p

7 1-298 5.0 Eq 0.5 Eq benzene g 1-307 1-308 22 26 α only

8 1-298 10.0 Eq 1.0 Eq benzene h 1-307 1-308 20 62 α only

9 1-299 5.0 Eq 0.5 Eq benzene i 1-309 50

10 1-300 5.0 Eq 0.5 Eq benzene j NR q

11 1-301 5.0 Eq 0.5 Eq benzene k NR q

12 1-301 5.0 Eq 0.5 Eq toluene l NR q

13 1-301 5.0 Eq 0.5 Eq benzene m NR q

14 1-301 5.0 Eq. 0.5 Eq benzene n NR q

Continued

Table 1. 25. A Variety of 5-Exo trig Radical Cyclization with 5(R)-Hydroxy-2(R)-phenyl-[1, 3]dioxane-

4(R)-carbaldehyde Derivatives

133

Table 1. 25. continued

a. 0.038M Substrate in benzene, 0.063M Ph3SnH in benzene, 25 µL/min via a syringe pump

b. 0.046M Substrate in benzene, 0.063M Ph3SnH in benzene, 26 µL/min via a syringe pump

c. 0.046M Substrate in benzene, 0.063M Ph3SnH in benzene, 26 µL/min via a syringe pump

d. 0.046M Substrate in benzene, 0.063M Ph3SnH in benzene, 29 µL/min via a syringe pump

e. 0.047M Substrate in benzene, 0.064M Ph3SnH in benzene, 25 µL/min via a syringe pump

f 0.046M Substrate in benzene, 0.063M Ph3SnH in benzene, 21 µL/min via a syringe pump

g. 0.047M Substrate in benzene, 0.063M Ph3SnH in benzene, 28 µL/min via a syringe pump

h. 0.047M Substrate in benzene, 0.126M Ph3SnH in benzene, 22 µL/min via a syringe pump

i. 0.047M Substrate in benzene, 0.063M Ph3SnH in benzene, 26 µL/min via a syringe pump

j. 0.035M Substrate in benzene, 0.063M Ph3SnH in benzene, 24 µL/min via a syringe pump

k. 0.009M Substrate in benzene, 0.063M Ph3SnH in benzene, 112 µL/min via a syringe pump

l. All reagents were added together and heated at 90 oC for 3 h. 0.011M based on substrate and

0.053M Ph3SnH in toluene.

m. All reagents were added together and heated at 90 oC for 2 h. 0.010M based on substrate and

0.050M Ph3SnH in benzene.

n. All reagents were added together and heated at 90 oC for 6 h. 0.020M based on substrate and

0.100M Ph3SnH in benzene.

o The ratio was determined after column chromatography.

p. The ratio was determined by 1H NMR before column chromatography.

q. All starting materials decomposed.

134

Nitrile has been known as an excellent radical acceptor in some radical mediated cyclizations, and

the product will be, after hydrolysis, a ketone. The carbohydrate based nitrile 1-299 was made efficiently

from D-glucose in 5 steps by using the chemoselective transformation of oxime to nitriles, which was

developed in this Lab. Unfortunately, the nitriles in the sysnthesis of N-furanoside via radical cyclizaiton

were not effective radical acceptors. The only product from the reaction mixture was 1-309 in 50% yield.

We also investigated 1-amino-2-phenyl aziridine and (p-toluenesulfonly)hydrazine derived

substrates (1-300 and 1-301, respectively) for the 5-exo radical cyclization. Unfortunately, those

hydrazones could not take part in the reaction. Because of the low solubility of tosylhydrazone deriative 1-

301 in benzene, toluene, or acetonitrile, we could not use the revesed addition procedue, which was

developed for this type of reactions in our laboratory. Thus all reactants (substrate 1-301, triphenyltin

hydride, and AIBN) were mixed in one-pot and heated at 90 oC for 2-6 h. Although all starting materials

were consumed (TLC), we could not isolate any desired product. The azridine derivative 1-300 was also

gave no identifiable products from the reaction mixture.

1. 3. 10. Radical Reaction with Tris(trimethylsilyl)silane (TTMSH)

Tris(trimethylsilyl)silane (TTMSH) has been used as an altenative for tin-based hydrides in radical

reaction with a variety of substrates. Especially, Curran and his associate found that cascade radical

annulations of thiocarbamates, thiocarbamides, and thiourea in the presence of tristrimethyl silane

(TTMSH) gave better resuts than in the presence of tributyltin hydride or hexamethylditin. Because the

reversible addition of the TTMS radical to the thiocarboyl group give stabilized radical intermediates and

they can be cyclized to give fused quinones via 5-exo trig radical pathway, we decided to try TTMSH as

the radical/hydrogen source under our optimized reaction condition for the synthesis of N-furanosides and

pyranosides.

The substrates and products for the radical reactions are shown in Scheme 1.88, and the results for

the reaction are summarized in Table 1.26. Surpisingly, under the thermal conditions, the major poroduct

of the radical reaction with the substrate (Z)-1-296 was neither cyclized product product 1-305 nor

deoxylated product 1-311, but another deoxygenated product, which was isolated as a 28% yield. After

135

carefull investigation of the product by 1D nOe NMR and 1D COSY NMR spectroscopy, we assigned it as

an O-benzyl oxime-migration product 1-310 with a trace amount of the deoxygenated product 1-311.

Although the major portion of product 1-310 could be isolated by column chrmoatgrapy and assigned it to

syn configuration, it was in equilibrium with the anti isomer at rt to give a syn/anti mixture in a ratio of

1.0/0.15. Morover, if we doubled the concentration of the TTMSH (Entry 3), the O-benzyl oxime-

migration product 1-310 was formed almost quatitatively.

The formation of 1-310 can be rationalized by a mechanism, which has a cyclpropanyl radical

intermediate 1-319 shown in Scheme 1.89. Although it has been found the 5-exo radical cyclization (k2)

of Barton’s radical intermediate 1-317 is faster than the deoxygenatiion pathway (k1), the cyclized radical

intermediates 1-321 could be reversible. The deoxygenated radical intermediate 1-318 can be added easily

to the C=N of O-benzyl oxime to give a cyclopropy intermediate 1-319. Ring open again via k4 pathway to

afford the O-benzyl oxime-migrattion product 1-310.

OOPh O

N

N

S

BnO

OOPh O

NNPh2

N

S

OOPh O

EtO2C

N

S

N N N

TBDPSO O

OEt

O

N

S

N

O

CO2Et

OTBSS

OOPh O

OPhO

OPh

NBnO

OOPh O

NH

N

S

BnO

N

OOPh

OOPh O

H

EtO2C S

OOPh OH

NNPh2

N N

OBn

OBn

NNPh2

(Z)-1-296 (E)-1-298(Z)-1-2831-250

1-315

(Z)-1-310 (E)-1-310 (Z)-1-311 1-312

1-316(Z)-1-313 1-314

Figure 1.21. Substrates and Products for the Radical Reaction with TTMSH.

136

Conditions

Entry Reactant TTMSH AIBN Solvent etc

Producct

Yield

(%)

Ratio

1 (Z)-1-296 5.0 Eq 0.5 Eq benzene a 1-310 28% 1.0/0.15h, i

2 (Z)-1-296 5.0 Eq 0.5 Eq benzene b 1-312 6 (51) j

3 (Z)-1-296 10.0 Eq 1.0 Eq benzene c 1-310 >99 1.0/0.15 h

4 (Z)-1-296 5.0 Eq 0.5 Eq benzene d 1-310 47 1.0/0.15 h

5 (E)-1-298 5.0 Eq 0.5 Eq benzene e 1-313 1-314 38 18 anti

6 (E)-1-250 5.0 Eq 0.5 Eq benzene f 1-315 33 0.28/1.0k

7 (Z)-1-283 5.0 Eq 0.5 Eq benzene g 1-316 32

a. 0.047M Substrate in benzene, 0.0634M TTMSH in benzene, 28 µL/min via a syringe pump at 90 oC. b. 0.05M Based on substrate and 0.225M based on TTMSH in benzene, hυ by a sunlamp. c. 0.047M Substrate in benzene, 0.126M TTMSH in benzene, 28 µL/min via a syringe pump at 90 oC. d. 0.05M Based on substrate and 0.225M based on TTMSH in benzene, heated at 90 oC for 6h. e. 0.047M Substrate in benzene, 0.064M TTMSH in benzene, 28 µL/min via a syringe pump at 90 oC. f. 0.046M Substrate in benzene, 0.063M TTMSH in benzene, 22 µL/min via a syringe pump at 90 oC. g. 0.046M Substrate in benzene, 0.063M TTMSH in benzene, 23 µL/min via a syringe pump at 90 oC. h. The ratio of syn/anti i. Trance amount of 1-311 was observed in 1H NMR spectrum after column chrmoatogarphy. j. Recovered (Z)-1-296. k. The ratio of cis/trans.

Table 1. 26. Radical Reaction with TTMSH.

137

(Z)-1-296

OOPh O

N

Im

S

BnO

TTMSH

1-317

OOPh O

N

Im

S

BnOTTMS

1-318

OOPh

NBnO

1-312

OOPh O

NH

Im

S

BnO

OOPh

NBnO

(Z)-1-311

OOPh

NBnO

1-319

1-320

OOPh

1-310

OOPh

k1

k2

k3

k5 k4

OOPh O

H

Im

H

k1

k2

1-321 1-322

BnOHNO

OPh O

H

BnON

STTMS

Im OOPh O

H

BnOHN

STTMS

Im

1-305

TTMSH TTMSH

TTMSH

TTMSH TTMSH

K3

k6

K4

H H

NOBn

NOBn

Scheme1.68. The Propsed Mechansim for Radical Mediated 1,3-Migration of Oxime Derivative 1-196 .

Although we added all reactant in one-pot and heated it at 90 oC, the cyclized product was not

formed and still the O-benzyl oxime-migrated product 1-310 was the major product in 47% yield (Entry 4).

Interestingly, we could not find 1-310 under photolytic conditions under a sunlamp. A small amount of

reduction product 1-312 (6%) was isolated along with recovered starting material (Entry 2).

We also investigated similar reactions of substates with a different radical acceptors such as N,N-

diphenyl hydrazone and α,β-unsaturated ester. We found the hydrazone functionality of substrate (E)-1-

298 migrated in the same fashion to give 3-147 as the major product and small amount of dethiocarbonated

product 1-313 was formed as the monor product (Entry 5). However, if the α,β-unsaturated ester was

138

syn-1-310

OOPh

NOBn O

OPh

NOCH2Ph

H1 H2a

H3

H4

H2b

4.2%

2.0%2.0%

1.8%

0.5%

0.3%

0.3%

0.9%

nOe (%) nOe (%) nOe (%)

H1→H2a 4.2 H2b→H4 0.5 H3→CH2Ph 0.3

H1→ Ph 0.9 H3→H2ab 5.5 H4→H2b 0.9

H2a→H1 2.0 H3→H1 0.3 H4→H3 0.4

H2 a→H3 2.0 H3→H2ab 5.5 CH2Ph→CH2Ph 0.4

H2 b→H3 1.8 H3→H4 0.6 CH2Ph→H4 1.1

Figure 1.23. The Representative Results for nOe of syn-1-310.

anti-1-310

OOPh

N

OBn

O

OPh

N

OCH2Ph

H4

H3

H2aH1

H2b

2.6%

2.1%1.8%

1.3%

nOe (%) nOe (%) nOe (%)

H1→H2a 2.6 H2a→H3 1.8 H3→H2b 1.4

H1→Ph 0.7 H2b→H2a 4.5 CH2Ph→CH2Ph 0.6

H2a→H1 2.1 H2b→H3 1.3

H2a→H2b 3.1 H3→H2a 2.9

Figure 1.24. The Representative results for nOe of anti-1-310.

139

compounds, (E)-1-250 and (Z)-1-283, were used as the substrates, we could not observe the nigration

product but cyclized thinolactones, 1-315 and 1-316 were isolated as the major products.

1. 4. Conclusion

The first radical intermediate in the thiourethane-mediated deoxygenation of alcohol (Barton-

McCombie reaction) can participat in an exo-hex-5-enyl or exo-hept-6-enyl type radical cyclization when a

suitable radical acceptor (e. g. α,β-unsaturated ester, oxime ether, or hydrazone) is appropriately placed.

Carbohydrate derived imidazoyl and triazoyl thiourethanes with such acceptors, upon addition to excess of

a good hydride donor (reversible addition), undego efficient cyclization reactions to give N-heterocyclic

furanosides and pyranosides. Depending on the acceptor, glycosides with either 2-amino or C2-carbon

substitutent are formed. In the exo-hept-6-enyl cyclizations, the (Z)-olefin acceptors give excellent

stereoselectivity in the generation of the C2 stereogenic center. Only altro-isomers are formed. In all cases

both α- and β-glycosides are obtained. A moderate preference for the β-anomer in the pyranoside

formation may have its origin in the anomeric stabilization of the axial radical.

The results of this chapter canbe summarized as follows:

1. Explored a new general synthetic methodology for the synthesis of N-furanoside and N-pyranoside

from commonly available carbohydrates via 5 or 6-exo-trig radical cyclization involving the

Barton’s radical intermediate.

2. The reaction was performed under a variety of conditions, and the reaction conditions were

optimized. The optimized reaction conditions are: (i) 5 equivalents of triphenyltin hydride as a

radical source, (ii) 0.5 equivalent of AIBN as a radical initiator, and, (iii) 90 oC for the oil bath

temperature.

3. Stereochemistry and mechanisms for the 5 and 6-exo-trig radical cyclizations mediated by the

Barton-McCombie intermediates were proposeds.

140

4. Facile synthesis of differentially protected 5,6-dihydroxy hex-2-enoates and other corresponding

unsaturated derivatives were developed.

Further study should focus on the application of this new methodology for the synthesis of other

heterocyclic glycosides, especially for the synthesis of natural/unnatural nucleoside

141

CHAPTER 2

PALLADIUM CATALYZED SILYLSTANNYLATIVE CYCLIZATION OF

DIYNES/ALLENYNES AND REGIOSELECTIVE DIELS-ALDER

REACTION OF VINYLSILANES

2. 1. Introduction

Transition metal catalyzed intramolecular carbocyclizations73 of enynes, 74 diynes, 75 bis(dienes),76

bis(allenes), 77 alleneynes, 78 allene aldehydes, 79 and allene ketones79 have been studied extensively during

the last decade because the resulting compounds may allow further transformations to a variety of

synthetically interesting heterocyclic and/or carbocyclic compounds. Moreover, a broad tolerance to

functional groups, operationally simple procedure, and high catalytic turnover and regioselectivity are

maybe realized in these reactions. The scopes of catalytic tandem addition/cyclization reactions have been

widely expanded by the use of a variety of bisfunctionalization reagents such as R3Sn-SiR’3,74-79 R3Sn-

BX2,80 R3Sn-SnR’3, 77 R3SnH, 81 and numerous transition metals such as palladium, rhodium, nickel,

titanium, and ruthenium. Palladium is the most commonly used catalysts in the transition metal catalyzed

carbocyclization via bis-functionalization reactions.

The catalytic cycle for a typical X-Y (X-Y = R3Si-SnR’3) mediated cyclizations is likely initiated

by the oxidative addition of silylstannane to Pd(0) to give Pd(II) intermediate 2-2. The terminal alkyne is

then coordinated to the palladium center (2-4). Insertion of the coordinated triple bond of alkyne to the Pd-

142

Si bond affords palladium (II) complex 2-5 with the R group anti to the SiMe3 moiety. Subsequent

reductive elimination in 2-5 gives the silylstannylated product 2-6. The Z-configuration of 2-5 is solely

responsible for the exclusive formation of (Z)-vinylsilane derivative 2-6. 73(a)

LnPd(0)

SnBu3PdMe3Si

R SnBu3

SiMe3

Me3Si SnBu3

2-1

2-2

2-3

2-4

2-5

2-6

R

R

Me3Si PdLn SnBu3

Ln = ligand

R

SiMe3PdLnBu3Sn

Scheme 2. 1. Postulated Mechanism for the Pd-Catalyzed Sn-Si Bifunctionalization.

The first Sn-Si bifunctionalization was reported by Chenard and Mitchell independently in 1985.82

Chenard reported that silylstannane was efficiently added to cyclohexenone via exothermic Michael

addition by catalyzed “naked” cyanide catalyst (KCN/18-Crown-6, Bu4NCN, TASCN) in high yield (Eq.

1). He also examined the silylstannylation of acetylene in the presence of catalytic tetrakis(triphenyl-

phophine)palladi-um in THF. At the slightly high temperature (65 oC) the regio- and stereoselective

silylstannylation of acetylene proceeded to yield with Sn in the internal position (Eq 2). The

regioselectivity of the silylstannylation was not affected by the bulkiness of the tin, but the yield decreased

with increasing the bulkyness of the substituent.

143

O

R2 R2R1

OSiMe3

R2 R2R1

SnBu3

+ Bu3SnSiMe3"naked" CN

R1 = R2 = H (75%)R1 = Me; R2 = H (77%)R1 = H; R2 = Me (68%)

(1)

R C C H + Bu3SnSiMe2tBu

H SiMe2

SnMe3R

CMe3

R = Ph (93%)R = CH3(CH2)3 (74%)R = iPr (67%)R = tBu (10%)R = NC(CH2)3 (90%)

(2)(Ph3P)4Pd

Simultaneously, Mitchell reported82(b) the palladium-catalyzed addition of the tin-silane bond to

allens. He used eventually the same substrates and palladium catalyst, which Chenard used in his reaction.

As shown in Eq. 3, a number of alk-1-ynes readily underwent a clean regio- and stereoselective addition to

afford alkenes possessing vicinal sily and stannyl substituents, except for methyl propiolate which gave a

1:1 mixture of two regioisomers. The product with Sn in the internal position increased up to 90% if the

reaction was performed at low temperature (0 oC) despite the required prolonged reaction times (48 h). The

cis configuration of the product was assigned by 1H NMR spectrum, which had a large coupling constant

for the trans-coupled vinyl proton with Sn (JSn-H = 165 – 211 Hz). The corresponding number for cis-JSn-H

= 56 – 60 Hz.

R C C H + Bu3SnSiMe3

H SiMe3

SnMe3R

R = Bu, Ph, PhCH2, Me2NCH2, MeOCH2, HOCH2, HOCHMe, HOCMe2, HOCH2CH3,CO2Me

(3)(Ph3P)4Pd

H SnMe3

SiMe3R

+

Following the above reports, Chenard studied more extensively the palladium-catalyzed

silylstannylation with a variety of acetylenes, solvents, and catalysts, to define the limitation and scope of

144

the reaction.83 He found that the reaction is limited to terminal acetylenes, presumably due to steric

consideration, and bulky terminal acetylenes are reluctant to undergo the silylstannylation. The reaction

has an excellent tolerance to the most functional groups (e.g. Cl, CN, OTHP, OH, and Me3Si), but the

effective catalyst is limited to Pd(Ph3P)4and Pd(OAc)2/triisopropyl phosphites. He also examined the

reactivity of vicinal sily and stannyl substituents in terms of transmetallation, halogenation, and aluminum

chloride catalyzed acylation (Eq. 4).

SmMe3

SiMe2

CMe3

Ph

SiMe2

CMe3

HHO

1. BuLi/TMEDA

2. PhCHO60%

Ph SnBu3

SiMe3

Ph X

SiMe3

X = I (83%)X = F (76%)

I2

N-fluoro-N-norbonyl-p-toluenesulfonamide

or

SnMe3

SiMe2

CMe3

Ph

SiMe2

CMe369%

AlCl3

CH3CCl

(4)

O

O

The silyltin olefins might be further transformed with acid chloride to β-silyl vinyl ketone via

Stille reaction. If the olefins has a large silyl group (e.g. Et3Si or tBuMe2Si), the Stille reaction product

vicinal silane underwent Nazarov cyclization without losing the silane group in the cyclized product (Eq.

5). It is surprising because Denmark reported that β-silyl divinyl ketones may cyclize to give

cyclopentenones without the silane group via Nazarov reactions.

ClSnBu3

SiMe2

CMe3

CCl

+

O

SiMe2

CMe3

Cl

O

Cl

Me3CMe2Si

(5)

80%58%

BF3 Et2O

O

145

Ikenaga and his associate performed84 the bisfunctioanlization of terminal alkynes with (tri-

alkylstannyl)dimethylsilane (HSiMe2SnR3). The major product for the phenylactylenereaction was 1,1-

dimethyl-3,4-diphenylsilacyclopenta-2,4-diene along with silylstannylation product as the minor compound

(Eq. 6).

R C C H + Bu3SnSiMe2H

H SiMe3

SnMe2HR(6)

(Ph3P)4Pd+

R

R

SiMe

Me

R = Ph, p-BrC6H4, naphthyl. Hexyl, CH2OTHP

An excellent example of silylstannylation, which was applied for total synthesis of a natural

product, was reported by Kocieński and his colleagues in 1994. 85 They used the palladium-catalyzed

silylstannylation of terminal alkynes in the synthetic approach to the C26-C32 fragment of Rapamycin, a

metabolite of Streptomyces hygrscopicus with potent cytotoxic and immunosuppressive activities.

Kocieński used a tin-silane reagent bounded on 2-methyl furan, to react with propyne with

tetrakis(triphenylphosphine)palladium in THF solutions (Eq. 7). The expected vicinal tin-silane derivative

possessing the tin at the internal position was obtained in modest yield with excellent stereo- and

regioselectivity.

O

SiMe2

SnBu3

CH3

HH3C

+ O

SiMe2

CH3

SnBu3H3C

(7)Pd(PPh3)4

THF, 60 oC

49%

The scope of silylstannylation of triple bonds was further expended by Mitchell,86 and the results

were reported in 1987. He investigated the addition of the Si-Sn bond to non-terminal alkynes as well as

terminal alkynes with a variety of functional groups. For example, hydroxy-, alkoxy-, amino-, and ester

146

group substituted terminal alkynes were used for the reaction. The product was obtained exclusively with

(Z)-configuration, which might be isomerized to the (E)-isomer by irradiation in the UV region. Non-

terminal alkynes were more limited than terminal alkynes in the reaction. The non-terminal alkynes with

ether functionality did not undergo the Sn-Si bond addition to the triple bonds, or if it proceeded, the yield

was very low. Ester or amide functionalities prompted the reaction to give bisfunctionalized products with

poor regioselectivity. It has to be pointed out that the tin prefers to be on the carbon with a more EWG

substitutent.

(8)R1-C C-R2 Me3SnSiMe3+Pd(PPh3)4 C-R2R1-C

Me3Sn SiMe3

SiMe3R1-C

Me3Sn C-R2+

R1 = Ph, Bu, Me, Me2NCH2C, CO2Et, CO2MeR2 = CO2Et, CO2Me, CONMe2, CH2OMe

Previously, Chenard studied83 extensively the silylstannylation of terminal alkynes with a series of

transition metal catalysts including Pd(OAc)2, Pd(OAc)2-triisopropyl phosphite, (CH3CN)2PdCl2, Pd/C,

Mo(CO)6, (Ph3P)3RhCl, (cyphos)RhCl-dimer, Rh/Al2O3, K2PdCl4, K2PtCl4, as well as Pd(PPh3)4. Except

for Pd(PPh3)4 and Pd(OAc)2-triisopropyl phosphite, all other transition metal catalysts did not catalyze the

reaction. Mitchell also reported the silylstannylation of 1-alkoxyalkynes was not regio- and stereoselective.

The yield was low and the Pd(PPh3)4 catalyzed-reaction required relatively high temperature (60 – 70 oC) to

initiate the catalytic cycle.

(9)+C C OEtR Si SnPd(OAc)2

CN

C COEt

Si

R

Sn

run SiSn

rtR = H, Me

R % Yielda

1

2

3

4

SiMe2ButMe3Sn

SiMe2ButMe3Sn

SiMe3nBu3Sn

SiMe3Me3Sn

H

Me

H

H

92 (>95:5)

99 (>95:5)

75 (>95:5)

99 (55:45)a. The number in the parenthesis is the regio selections

147

Ito and his associates reported that the silylstannylation of terminal alkynes could be carried out

very efficiently at rt by using a new active palladium catalyst Pd(OAc)2 with tert-alkylisocyanide as a

ligand.87 For example, 1-ethoxy-1-propyne underwent silylstannylation using the above palladium catalyst/

and 1,1,3,3,-tetramethylbutyl isocyanide to give syn-adduct, in which the tin was located on the β-carbon

remote from the oxygen substituent as the major product.

A similar silylstannylation of 1-alkoxy 1-propyne was performed with Pd(PPh3)4 and catalytic

amount of galvinoxyl at rt.85(b) The alkoxy alkyne 2-7 reacted very easily with Me3SiSnMe3 in bezene

solution to give syn-adduct 2-8 as a single regioisomer. The regiochemistry of the Sn-Si adduct was

reversed from the above results and the tin was located at the α-carbon from the oxygen (Eq. 10).

+

O

Bu

Pd(PPh3)4Me3Si SnMe3

galvinoxyl (cat)

benzeneSnMe3O

Bu SiMe3

OBn

58%

HO

Bu SiMe3

OBn

BuLi/TMEDA

-78 to -40 oCthen H2O

δH = 6.19 (s)

2-7 2-8 2-9

81%

OBn

(10)

In the same paper, bifunctionalization of 1-phenylthio-1-alkyne was examined with Me3SiSnMe3

in the presence of Pd(PPh3)4. As shown in Eq.11, excellent stereo- and regioselectivity (i.e. tin was located

at the α-carbon from the sulfur) was obtained but the yield was relatively low. The reaction could be

improved by using Pd2(dba)3 and tri-2-furylphosphine in THF, and had a great tolerance to a variety of

functional groups such as tetrahydropyranyl, hydroxyl, ethyl hydroxyl, methoxy, n-propyl, and 4-

phenylaryl ester.

(11)

R

SPh

Pd2(dba)3+ Me3Si SnMe3

tri-2-furylphosphinePhS SnMe3

SiMe3

R

R = OTHP, OH, (CH2)2OH, OMe, nPr, p-PhC6H4CO2

148

The palladium catalyzed reaction of Me3SiSnBu3 with propiolate was initially reported by

Mitchell (see Eq. 8). The addition of Sn-Si bond to the triple bond of the propiolate gave excellent regio-

and stereoselectives in the formation of α-stannyl-β-silylacrylate in 75% yield as expected in other terminal

alkynes.88 However, if triethylbenzylammonium chloride (BnEt3NCl) was used in the reaction as an

additive, 2-12 was obtained as the product. Because the reaction of Me3SiSnBu3 with BnEt3NCl produced

the stannyl anion (or equivalent), it was expected that the reaction would give β-tributylstannyl acrylate 2-

10. The formation of the bis-stannylated product 2-12 has not been explained clearly, but the intermediate

would be 2-13, which is presumed to be in equilibrium with 2-14.

CO2EtMe3SiSnMe3

Pd (0)CO2Me

Bu3Sn Me3SiSnMe3

XBnEt3NCl CO2Me

Bu3Sn

Bu3Sn

OSiMe3

OMe

Bu3Sn SiMe3

CO2Me

Bu3Sn

2-11 2-122-10

2-142-13

Me3SiSnMe3

% Yield of 2-30

based on 2-11 based on Sn-Si

46

91

93

92

1.0 Equiv.

2.0 Equiv.

(12)

Computational calculation of the rate determining step in silylstannylation of terminal acetylene

indicated that the insertion of acetylene into Pd-Sn bond (stannlypalladation; path b, Eq. 13) has lower

activation energy (by 2 kcal/mol) than the insertion of the acetylene into Pd-Si (silapalladation; path a).89

However, the thermodynamic stability of the resulting vinyl palladium species is reversed: the kinetically

favored intermediate 2-17 is less stable than 2-16 (11 kcal/mol). Because the insertion of the Pd into Sn-Si

bond may be reversible, the thermodynamically stable intermediate is formed more favorably in the

reaction.

149

R

SnR3'R3SiPd

SnR3

Si'R3

Pd

R

SnR3

Pd

R

'R3Si

2-15

2-16

2-17

a

b kinetic

insertion into Si-Pd

insertion into Sn-Pd

thermodynamic

(13)

Compared to the dilastannylation of terminal acetylene in the presence of Pd(0), addition of Sn-Si

bond into alkenes has been studied rarely even though the insertion of Si-Si or Ge-Ge into ethylene or C=C

bonds is well-known. Tsuji first explored90 the silylstannylation of C=C double bonds of a variety of

substrates such as ethylene, norbornene, and benzonornonadiene in the presence of Pd(dba)2 and

tributylphosphine or triethylphosphine in toluene at high temperature (130 oC) (Eq.13). Because of steric

congestion, 1-hexene, styrene, cyclohexene, and cyclopentene did not react under the optimized condition.

H2C CH2

2R3Sn SiMe2R1+

2R3Sn SiMe2R1

SnR23

SiMe2R1

SnR23

SiMe2R1

Pd(da)2

PEt3 or PBu3

toluene, 130 oC

up to 97%

up to 95%

upto 59%

(14)

R1 = R2 = MeR1 = Me, R2 = BuR1 = OMe, R2 = BuR1 = tBu, R2 = MeR1 = tBu, R2 = Bu

Although simple alkenes gave the silylstannylation in the presence of palladium(0) catalyst with a

phospine ligand, 1,3-dienes did not undergo silylstannylation under these conditions. With an extensive

survey of transition metal catalysts, Tsuji and his associate found that Pt(CO)2(PPh3)2 can catalyze the

insertion of Sn-Si bond into the 1,3-diene to give 1,4-silylstannation products in moderate to good yields.91

150

The reaction was highly regio- and stereoselective, and the spectral data showed that the product had (E)-

configuration, exclusively (Eq. 15).

R13Sn SiR2

2R3 (15)R4

R5

+R4 CH2SiR2

2R3

R5R13SnCH2Pt(CO)2(PPh3)2

100 oC

R1 = Me, nBuR2 = MeR3 = Me, tBu, PhR4 = H, Me, PhR5 = H, Me

trans

In a study on the addition of Me3SiSnMe3 to allenes, Mitchell found the regioselectivity of the

reaction is dependant on the reaction temperature.92 For example, the palladium catalyzed silylstannylation

of 1,1-dimethylallene with Me3SiMe3 gave a 1:1 mixture of two regioisomers in refluxing THF. The

addition of Sn-Si bond into allenes occurred mainly on the more substituted double bond of the allenes with

the tin atom attached to the end carbon and silane atom attached to the central carbon (kinetic product).

The kinetic product was further isomerized in the presence of palladium(0) at 90 oC to give thermodynamic

product as the major product with a ratio of 4:1 via 1,3-Sn migration. Shortly after the preliminary

investigation, Mitchell and his associates reported full detail of the scope and region- and stereoselectivity

of palladium catalyzed Sn-Si bond addition to allenes. The formation of the kinetic product and its

isomerization to thermodynamic product (E/Z mixture) were consistently observed with a number of

substrates.

(16)R

Me3Sn SiMe3+

Me3Sn SiMe3

R

Me3Sn SiMe3

R

(E/Z)Pd(PPh3)4

85 oC

rt

151

In the course of palladium catalyzed hydrostannation of alkoxyallenes, Koerber found93 that the

regioselectivity of the silylstannylation of methoxyallenes with Me3SiSnBu3 in the presence of Pd(0) is in

contrast with the results reported by Mitchell. 92 The product was exclusively one regioisomer (E/Z

isomers) and the Sn-Si addition preferred less substituted double bond with the silicon attached to the

central carbon (thermodynamic product).

(17)MeO

Bu3Sn SiMe3+Pd(PPh3)4

MeO

SiMe3

SnBu3

SiMe3

SnBu3

MeO+

2 : 1

The most recently, Cheng reported94 highly regio- and stereoselective silylstannylation of allenes

catalyzed by phosphine-free palladium catalysts to give predominantly (E)-alkenylsilane. The catalytic

reaction proceeds via terminal addition of the allenes (not the 1,3-Sn migration) from the opposite face of

the allene’s substituent to minimize steric congestion. The silyl group is added to the central carbon while

the stannyl group is connected to the less substituted terminal carbon of the allenes. To explain the region-

and stereoselctivity, a mechanism involving face-selective coordination of allenes to palladium center was

proposed (Scheme 2.2): Once the palladium(0) is oxidized to Pd(II) by addition of Sn-Si, the less

substituted terminal bond is coordinated favorably to the palladium center from the opposite face of the

substituent R to avoid the steric demanding. The insertion of the double bond into Si-Pd bond gives π-ally

palladium complex, which is prone to reductive elimination to afford the (E)-vinylsilane and Pd(0).

RMe3Si SnR1

3+Pd2(dba)3

SiMe3

SnR13

H

dba R

toluene, rt

E/Z = >99

Yield = 80-99%

2-192-18

(18)

152

Pd(0)

Me3Si SnR13

H H

HR

PdMe3Si SnR13

R

SiMe3

SnR13

PdS

SiMe3

SnR13

H

R

PdMe3Si SnR13

R

2-18

2-20

2-21

2-19

Scheme 2. 2. The Mechanism for Tinsilanylation of Allenes.

Recently, RajanBabu et al reported75 the first tandem bis-functionalization /intramolecular

cyclization of 1,6-diynes assisted by trialkylsilyltrialkyltin reagents and Pd(0) catalyst with phosphine

ligands such as tris-(pentafluorophenyl)phosphine or tris-(o-tolyl)phosphine. The highly stereoselective

reaction proceed in good yield with a great tolerance with a variety of functional group such as ethers,

esters, amides, carbonyl group, and tertiary amines.

CO2MeMeO2CCO2MeMeO2C

Me3Si SnBu3

CO2MeMeO2C

SnBu3MeSi

-40 oCMe3SiSnBu3

Pd2(dba)3 CHCl3PR3

(19)

The cyclized 1,4-disubstituted 1,3-diene with (Z, Z) configuration is a non-planar, helically chiral

structure because of the sterically demanding silicon and tin substitutents. The structure, stereochemistry,

and the fluxional nature of the compounds were unambiguously determined by NMR spectroscopy. VT

(various temperature) NMR studies have shown that the (Z, Z)-1,2-bis-alkylidenecyclopentane is highly

fluxional at 20 oC but is frozen at below -40 oC. The postulated reaction mechanism for the reaction

involves a typical Pd(0)-Pd(II) catalytic cycle (see Scheme 2.1). The reaction is initiated by oxidative

153

addition of Pd(0) into R3SnSiR’3. A successive coordination of the palladium complex to the diyne, cis-

silapalladation, cis-carbametallation, and reductive elimination gives silystanyl carbocycle and regenerate

the Pd(0).

Y

X

YM X

M YX

X Y

M(0)

cis-carbametallation

reductiveelimin. with retention

cis addition

X-Y = R3SnSiR'3

2-22

2-23

2-24

2-25

Scheme 2. 3. Formation of a Chiral (Z, Z)-1,3-Diene from a Diyne.

Kang reported77 palladium(0) catalyzed carbocyclization of bis(allenes) via silanstannylation and

distannylation. The trans stereochemistry of the same silylstannlylated dienes was unambiguously

determined by the large coupling constant (J = 13.3 Hz) at the ring junction, while derivatives of the cis-

distannylated compound were synthesized to determine the cis chemistry. The origin of the reversal of

stereochemistry of the carbocycles has not been fully explained, but one of the possible explanations lies in

the large steric congestion of the trimethylsilyl group due to shorter bond length of Si-C vis-á-vis the longer

Sn-C bond.

TsN

SiMe3

SnBu3

TsN

SnBu3

SnBu3

H H

HH

TsNBu3SnSnBu3

Pd(PPh3)4

Bu3SnSiMe3

Pd(PPh3)4(20)

154

Mori and his associates studied the palladium catalyzed tandem bifunctionalization/cyclization of

enynes with Me3SiSnBu3.74(a) Because the insertion of Sn-Si bond into alkynes is faster than the insertion

into alkenes, the silylstannylation (cis addition) occurs exclusively at the triple bond to give cis-adduct, in

which the silanes are connected at the end carbon of the alkynes. Carbametalation followed by reductive

elimination afford the cyclized product 2-27 with small amount of 2-28. He surveyed a long list of

palladium catalysts to optimize the enyne cyclization and the best results were obtained by using Pd(OH)2

on charcoal (Pearlman’s catalyst). The reaction of enyne, which has an EWG substituted alkenes, gave the

cyclized product in moderate yield while methyl substituted alkynes did not proceed in the catalytic

reaction.

Simultaneously, Lautens reported74(b) the silystannation/cyclization of 1, 6-enynes using

palladium(0) and palladium(II), and he got the eventually same results as Mori.

EtO2C CO2Et

Me3SiSnBu3+Pd(OH)2/C

THF, rt

Bu3SnMe3Si SiMe3

Bu3Sn

EtO2C CO2Et

+

EtO2C CO2Et

entry catalyst temp

yield (%)

2-26 2-27 2-28

2-27 2-28

1

2

3

4

5

6

7

8

Pd(PPh3)4

PdCl2(PPh3)2

Pd(OAc)2dppb

Pd(COD)Cl4

PdCl2

Pd2(dba)3

Pd/C

Pd(OH)2/C

50 oC

reflux

reflux

rt

rt

rt

rt

rt

14

7

20

30

42

63

86

90

80

48

34

(21)

The most important drawback of the cyclization of 1,6-diynes and bis(allenes) aided by

trialkylsilyltrialkylstannanes (R3SiSnR’3) in the presence of Pd(0) is the lack of regioselectivity in

155

unsymmetrical substrates (Eq. 22).78 For example, the proline-derived diyne gave a 1:1 mixture of

regioisomeric products, which are inseparable by column chromatography. To circumvent this problem,

RajanBabu explored the silanstannylation of alleneynes, in which the allene and acetylene have different

reactivities in the palladium catalyzed bifunctionalization/cyclization.

N

HC6D6/60 oC

Pd2(dba)3/(C6F5)3PSnBu3 SiMe3+

N

XY

H

X = Me3Si; Y = Bu3SnX = Bu3Sn; Y = Me3Si

(22)

E

E

E

E

SnBu3

SiMe3

E

E

SnPh

SiMe2tBu

YE

E

X

Pd2(dba)3

Ph3SnSiMe2tBu

(C6F5)3P

Bu3SnSiMe3

Pd(0), rt, 12h

rt, 17h

45 oC, 48h

Pd(0)

(>95%)

(>95%)

(>90%)E = CO2Et

2-29 2-30

2-31 2-32; X = SitBuMe2; Y = Ph3Sn2-33: X = SiMe3; Y = SnBu3

Scheme 2. 4. Silylstannylation/Cyclization of Allenyne

The cyclization of allenynes mediated by Sn-Si reagents gave highly substituted

alkylidenecyclopentanes via the addition of Sn-Si to the allenes. As shown in the silylstannylation of

allenes (see Eq. 18 and Scheme 2.2), the silyl group of the bifunctional reagents is added to the central

156

carbon while the stannyl group is connected to the less substituted terminal carbon of the allenes 2-30. This

intermediates can be isolated in some cases. The bisfuctionalized adducts can further cyclize to

cyclopentane in the presence of a Pd(0) catalyst via cis-carbametallation and reductive elimination (Scheme

2.5). A mechanism that would account for the observed results was proposed, which involves a typical

Pd(0)-Pd(II) catalytic cycle.

Sn

E

E

Si

E

E

E

E PdSnH

Si

H

H

E

EH

PdSnSi

Pd

E

E

Si

Sn

E

E

Si

Sn

Pd(0)

2-29

+ Si Sn

2-34

2-35

2-36

2-38

2-392-39

Scheme 2. 5. Possible Mechanism of Silylstannylation/Cyclizaiton of Allenynes.

The most recent endeavor in the palladium catalyzed regio- and stereoselective tandem

silylstannylation /cyclization in the synthesis of cis-cycopentanols and cyclohexanols by using allene

aldehydes and allene ketones (Eq. 23).79 To find the optimum condition for both silylstannylation and

carbonyl-allyl addition, a variety of palladium and platinum catalysts were investigated. Although the

tandem reaction proceed in the presence of Pd(PPh3)4 in moderate yield, the best catalyst for this reaction is

(π-allyl)2Pd2Cl2.

157

X

O Bu3SnSiMe3

Rn

X

OR

n

SiMe3

SnBu3

OHX

SiMe3H

Rn

(23)(π-allyl)2Pd2Cl2 (π-allyl)2Pd2Cl2

Although several bifunctionalization of alkynes, alkenes, and allenes and tandem silylstannylation/

carbocyclization mediated by trialkylsilytrialkystannanes have been documented in the literatures, the

silylstannylation is currently at an early stage, and there is a still room for further research. In this chapter

we will discuss more details of silylstannylation of symmetric diynes, alleneyne, and bis(allenes) as well as

unsymmetrical diynes, and a possible application to the total synthesis of Papulacandin D.

2. 2. Asymmetric Silylstannylation of Alleneyne

Transition metal catalyzed synthesis of carbocyclic and heterocyclic compounds from olefinic and

acetylenic precursors is one of the most topical areas in organic chemistry. The catalytic method may be

used to cyclize a variety of substrates including dienes, diynes, bis(allenes), eneynes,, eneallenes, and

alleneynes by addition of bisfuctional reagents (X-Y) such as R3Si-SiR’3, R3Sn-Sn-R’3, R3Si-BR’2, R3Sn-

BR’2 as well as more traditional trialkyltin- and trialkylsilane-hydrides. The importances of R3Si-SnR3’ as

the bisfuctional reagents in carbocyclization have been steadily increasing because of the operationally

simple procedures, high catalytic turnover, and exceptionally good functional group tolerance. In addition

two different functional groups at the end of the cyclized products provide other opportunities for further

elaboration. Although these methodologies have a great regio- and stereoselectivities, no studies on

enantioselective silylstannylation have not been explored yet. Therefore, we decided to study the cycliztion

of alleneynes (2-40) with bifunction reagent, R3SnSiR’3 (2-41), in the presence of Pd(0)/Pd(II) and chiral

ligands shown in Figure 2.1

158

EtO2C

EtO2CR3Sn SiR'

SnR3

SiR'3EtO2C

EtO2C+

EtO2C

EtO2C

SnR3

SiR'3+

2-40 2-41 2-42: R = Ph, R' = Me2tBu

2-44: R = Bu, R' = Me3

2-43

Pd(0) or Pd(II)

ligand/C6D6(24)

The preliminary results on the asymmetric silylstannylation of alleneynes are summarized in Table

2.1. Initially we repeated the bisfunctionalization of the allenynes 2-40 with the non-chiral phosphine, tris-

(pentafluorophenyl)phosphine 2-45 in the presence of Pd2(dba)3•CHCl3 following the protocol reported

previously to make a racemic mixture of 2-42 and 2-43 in 84% (>99% based on 1H NMR) and 71% (>95%

based on 1H NMR) yield, respectively. The cyclization of alleneynes was very clean and the isolated yield

of the product was similar or slightly better than previously reported by Shin. Once we have the cyclized

product 2-42 as a 1:1 racemic form, we extensively investigated ways to separate the racemic mixture.

Such endeavors included high performance column chromatography (HPLC) with OJ, OH, and OD

column, gas chromatography with chiral column, and chemical shift reagents such as Eu(hfc)3, Yb(hfc)3,

and Pr(hfc)3 for NMR spectroscopy. Although we failed to separate the racemic mixture by

chromatography (GC and HPLC), we were pleased to find that 1H NMR spectroscopy was useful when

with a chemical shift reagent Europinum tris[3-(heptafluoro-propylhydroxymethylene)-(+)camphorate]

(Eu(hfc)3 2-52) was used.

The initial asymmetric silystannylations of the allenynes 2-40 were performed with a chiral phosphine

ligand 2-46 in the presence of Pd2(dba)3•CHCl3 at rt to give a cyclized product 2-42 in 76% yield (>93% by

1H NMR). The enantiomeric excess (ee) of the mixture was 0-2% based on the 1H NMR spectrum with

chemical shift reagent Eu(hfc)3, which is known to come down-field shift of protons (entry 8) [The limits

of detection by this methods is no better than ∆ (±5%) ee]. To improve the ee and the yield we screened

common solvents for the reaction (Entry 1 and Entry 3 - Entry 7). Among the large number of solvents,

only benzene (or C6D6) gave appreciable reaction. If the reaction was performed at rt to 80 oC with the

same ligand (2-46), the ee increased to approximately to 8%, but isolated yield went down to 53% in spite

of high NMR yield (>95%) (Entry 9). Next, we examined the asymmetric induction with one of the most

159

well-known chiral phosphine ligands (R)-BINAP, 2-47, in the presence of Pd2(dba)3•CHCl3 at rt (Entry 10).

Although the reaction was very sluggish, the isolated yield is reasonably good yield (76%, >95% by NMR)

but the ee was still very low (~2%). To accelerate the rate of the reaction, temperature was increased to 45

oC, but the reaction was still very slow (Entry 11). Even at temperature as high as 80 oC, the reaction was

not complete. Another chiral phophine ligand 2-48 was used for the asymmetric silastannylation of 2-40 in

the presence of Pd(0). Unfortunately, there was no reaction at rt and most starting material was recovered

(Entry 13).

N

Ph2P

PPh2

OtBuO

PPh2

PPh2

OBn

PPh2

OH

PPh2

OAc

PPh2

OiPr

PPh2

(C6F5)3P

2-45 2-46 2-47

2-48 2-49 2-50 2-51

O

CF2CF2CF3

3

EuO

CF2CF2CF3

3

YbO

CF2CF2CF3

3

Pr

2-52 2-53 2-54

Figure 2. 1. Phosphine Ligands and Chemical Shift Reagents Used in Silylstannylation Stidies.

160

Conditions Yield (%)a

Entry Pd Ligand Temp Time 2-61 2-63

eeb

(%)

1 Pd2(dba)3•CHCl3 2-45 rt 24h 71 (>95) N/A

2 c Pd2(dba)3•CHCl3 2-45 rt 24h 84 N/A

3 e Pd2(dba)3•CHCl3 2-46 rt 20h >90 N/A

4 f Pd2(dba)3•CHCl3 2-46 rt 20h >90 N/A

5 g Pd2(dba)3•CHCl3 2-46 rt 20h >90 N/A

6 h Pd2(dba)3•CHCl3 2-46 rt → 80 oC 24h → 18h >90 N/A

7 i Pd2(dba)3•CHCl3 2-46 rt → 80 oC 24h → 18h >90 N/A

8 Pd2(dba)3•CHCl3 2-46 rt 24h 76 (>93) 2

9 Pd2(dba)3•CHCl3 2-46 rt → 80 oC 48h → 14h 53 (>95) 8

10 Pd2(dba)3•CHCl3 2-47 rt 5d 71 (>95) 2

11 Pd2(dba)3•CHCl3 2-47 45 oC 4d d 77 (>92) 4

12 Pd2(dba)3•CHCl3 2-47 rt → 80 oC 28h → 70h 42 26 (58) 6

13 Pd2(dba)3•CHCl3 2-48 rt 24h >90 N/A

14 PdCl2(PhCN)2 2-46 rt → 80 oC 12h → 10h 61 (>95) 2

15 e PdCl2(PhCN)2 2-46 rt → 80 oC 12h → 10h 27 N/A

16 f PdCl2(PhCN)2 2-46 rt → 80 oC 12h → 10h 35 N/A

17 PdCl2(PhCN)2 2-46 45 oC 3d 60 2

18 PdCl2 •2NaCl 2-46 45 oC → 80 oC 48h → 36h 38 (56) N/A

19 PdCl2(NH3)2 2-46 45 oC → 80 oC 48h → 36h 31 (43) N/A

20 PdCl2 2-46 80 oC 36h 39 (55) 2

Continued

Table 2. 1. Preliminary Results for the Asymmetric Silystannylation of Alleneynes.

161


Conditions Yield (%)a

Entry Pd Ligand Temp Time 2-61 2-63

eeb

(%)

21 [Pd(1,3-di-

phenylallyl)Cl]2

2-46 45 oC 48h 52 (65) 3

22 PdCl2(CH3CN)2 2-46 80 oC 48h 55 (63) 2

23 PdCl2(PPh3)2 2-46 80 oC 36h 19

(37)

17 (24) N/A

24 Pd(OAc)2 2-46 45 oC 48h 20 (27) 7

25 [Pd(allyl)Cl]2 2-46 45 oC 48h 55 (63) 3

26 Pd(NH3)2(NO2)2 2-46 45 oC 48h 88 (>99) 4

27 Pd(NH3)2(NO2)2 2-47 80 oC 4d 53 (68) 1

28 Pd(NH3)2(NO2)2 2-49 80 oC 9h 75 (86) 5

29 Pd(NH3)2(NO2)2 2-50 80 oC 48h 55 (66) 5

30 Pd(NH3)2(NO2)2 2-51 80 oC 48h 59 (73) 8

a. Isolated yield. The number in parenthesis is measured by 1H NMR. b. The ee was measured by 1H NMR with chemical shift reagent 2-52, europinum tris[3-(heptafluoro-propylhydroxymethylene)-(+)-camphorate] (Eu(hfc)3 ). c. Large scale reaction in benzene. d. 2-43 was isolated in 7% yield. e. CD3CN was used as the solvent. f. Acetone-d6 was used as the solvent g. DMSO- d6 was used as the solvent h. THF was used as the solvent i. DMF was used as the solvent

162

RajanBabu and Shin had reported that the palladium source was not critical in the silylstannylation

of allenynes but recognized definite trend in the reactivity, when used in conjunction with achiral

poshphine ligands (C6F5)3P, 2-45: PdCl2(PhCN)2 ≈ [Pd(allyl)Cl]2/AgOTf, Pd2(dba)3•CHCl3 >> PdCl2.

Keeping this in mind we extensively investigated a long list of palladium catalysts to maximize the

enatiomeric excess. Because Pd(II) is known as slightly better catalysts than Pd(0) in silastannylation of

allenynes, we chose PdCl2(PhCN)2 with chiral phosphine ligands 2-46 for the next transition metal catalyst.

As shown in Shin’s thesis, the R3Si-SnR’3 mediated cyclization proceeded very cleanly monitored by 1H

NMR spectrum of the reaction mixture. But the ee was not improved (Entry 14). Unfortunately,

alternative solvents (CD3CN or acetone-d6) and lower temperature (45 oC) did not affect the intramolecular

cyclization in terms of enantioselectivity or isolated yield.

A control experiment, achiral phosphine ligand 2-45 was used as a reagent in the tandem

silylstannylation/carbocyclization in the presence of a variety of Pd(0) and Pd(II) catalysts. In contrast to

the previous results, Pd(II) catalysts were less effective than Pd(0) in the cycliztion except for

PdCl2(PhCN)2 (Table 2.1). Gratifyingly, we found that Pd(NH3)2(NO2)2 gave the best catalysts in the

control experiments. The crude reaction mixture of the cyclization was very clean and no other byproducts

were observed by 1H NMR analysis. After column chromatography, the isolated yield was 88% (>99%

based on 1H NMR), which is much higher than results with the best previous Pd-sources, Pd2(dba)3•CHCl3

and PdCl2(PhCN)2. Once we optimized the catalyst, we screened more elaborate BINAP-derived phospine

ligands for the bis-metallative cyclization with Ph3Sn-SiMe2tBu (Entry 26 – 30). Through the entries

prolonged reaction time and high reaction temperature caused decreased the isolated yield of the product 2-

42. The best ee achieved was only 8% by using a chiral posphine ligand 2-51 (Entry 30). No further

attempts were made to increase the selectivity of these reactions.

163

2. 3. Bromination of Silylstannanes

It has been reported that tin-halogen exchange on a vinyl moiety can be easily achieved by

treatment of the proper substrate with iodine or N-bromosuccinimide (NBS) in dichloromethane. While the

vinyl bromines are relatively stable at rt in the light, the vinyl iodines are light sensitive and decompose

easily. To further investigate the asymmetric induction in the bis-functionalization-cyclization of

alleneynes mediated by R3Si-SnR’3, the derivatization of the silylstannane adduct was required. First we

performed the tin-halogen exchange reaction with the racemic mixture of cyclic product 2-42 (or 2-44) and

1.25 equivalents of NBS in dichloromethane at rt over night (20 h).

SnR3

SiR'3EtO2C

EtO2C+ NBS

Br

SiR'3EtO2C

EtO2C

CH2Cl2rt

(25)

2-42: R = Bu, R' = Me2tBu

2-44: R = Bu, R' = Me3

2-55: R' = Me2tBu; 92%

2-56: R' = Me3; 89%

The transformation was quantitative (no other product was observed by TLC analysis except for

succinimide) and 92% and 89% of the halogenated vinyl silanes 2-55 and 2-56 were isolated by column

chromatography as a 1:1 racmic mixture. With the racemic mixture in our hands, we evaluated a number

of techniques to easily separate them. For example, HPLC with chiral columns (OJ, OH, and OD column),

GC with chiral columns, and lanthanide chemical shifting reagent such as Eu(hfc)3, Yb(hfc)3, and Pr(hfc)3

were examined carefully. Gratifyingly, we found a chemical shift reagent tris[3-(heptafluoro-

propylhydroxy-methylene)-(+)-camphorate] (Pr(hfc)3 ) was successful resolving the mixture. As we

describe in the above section, asymmetric tandem bis-functionalization /cyclization of allenynes 2-40 was

performed with chiral phospine lignads in the presence of palladium(0) such as Pd2(dba)3•CHCl3 or

Pd(NH3)2(NO2)2. The isolated cyclic vinyl stannanelysilane 2-42 was brominated by NBS in

dichloromethane at rt to afford the desired product in 86-90% after column chromatography.

Unfortunately, the enantiomeric excesses were less than 3% in all cases.

164

Condition Yield (%)a ee (%)

Entry Pd Ligand Temp Time 2-42 2-55 2-42 b 2-55 c

1 Pd2(dba)3•CHCl3 2-45 rt 24h 84 92 0 0

2 Pd2(dba)3•CHCl3 2-46 rt 48h 86(>99) 90 N/A 0.5

3 Pd2(dba)3•CHCl3 2-46 rt → 80 oC 48h → 14h 53 (>95) 91 8 3

4 Pd2(dba)3•CHCl3 2-47 rt 24 67 (>99) 88 2 1

5 Pd2(dba)3•CHCl3 2-48 80 oC 9h 86 (>99) 90 N/A 1

6 Pd(NH3)2(NO2)2 2-51 80 oC 48h 59 (73) 86 8 1

a. Isolated yield. The number in parenthesis is measured by 1H NMR. b. The ee was measured by 1H NMR with chemical shift reagent 2-52, europinum tris[3-(heptafluoro-propylhydroxymethylene)-(+)-camphorate] (Eu(hfc)3 ). c. The ee was measured by 1H NMR with chemical shift reagent 2-54, praseodymium tris[3-(heptafluoro-propylhydroxymethylene)-(+)-camphorate] (Pr(hfc)3 ).

Table 2. 2. Bromination of Vinyl Stannanelysilane 2-42 by NBS in Dichloromethane.

2. 4. Palladium Catalyzed Carobocyclization of Bis(allenes)

The transition metal-catalyzed cyclizatiion of bis(allenes) assisted by Me3Si-SnBu3 and Bu3Sn-

SnBu3 has been reported by Kang and his associates. The carbocyclization reaction proceeds via

silylstannylation and distannylation of bis(allenes) to form five-membered ring the presence of palladium

catalysts. The best results for the cyclization was achieved by using Pd(PPh3)4 in THF even though some

Pd(II) catalyst like [(π-allyl)2PdCl]2 could be used in the reaction. It has to point out that the

stereochemistry of the fused cyclic ring formed via silastannylation is trans while that formed via

distannylation is cis. Kepping this in mind we decided to perform a similar reaction with another tin-silane

reagent Ph3Sn-SiMe2tBu and a chiral phosphine ligand in the presence of palladium catalyst (Eq. 25).

165

EtO2C

EtO2CPh3Sn SiMe2

tBuSnPh3

SiMe2tBu

EtO2C

EtO2C+ +

2-57 2-41 2-58

Pd(0) or Pd(II)

SnPh3

HEtO2C

EtO2C

2-59

(26)ligand

The summary of the tandem carbocyclization/silastannylation of bis(allenes) is shown in Table

2.3. First, the silylstannylation was investigated by using palladium(II) catalyst without any phosphine

ligand at rt. The reaction proceeded very smoothly to afford trans-fused cyclic ring 2-58 in 63% yield

(>95% yield based on 1H NMR) after column chromatography (Entry 1). The stereochemistry of the

cyclized product was unambiguously determined by the coupling constant between the two-fused

hydrogens (J = 15.6Hz). If phosphine ligand 2-46 (0.1 equivalent) was added to the reaction mixture, the

reaction was sluggish at rt; but was completed by heating at 80 oC to afford the cyclized product. Although

the 1H NMR spectrum of the crude mixture was a little complex, it was obvious that all starting material 2-

57 was consumed and the yield of the cyclizd product 2-58 was more than 90%. After column

chromatography, the crude mixture was isolated in 54% yield (Entry 2). Surprisingly, when (R)-BINAP 2-

47 was used as the phosphine ligand at 80 oC, we obtained not only the cyclic compound 2-58, but also

unexpected cyclized product 2-59 as the minor product (11% yield based on the 1H NMR analysis) (Entry

3). Although the formation of 2-59 has not been explained thoroughly at the present time, we decided to do

further investigation of the cyclization in the presence of another palladium(0) catalyst such as

Pd(NH3)2(NO2)2 or Pd2(dba)3•CHCl3. As observed in the previous experiments, the formation of the cyclic

products was dependent on the chiral phophine ligands added to the reaction mixture. Bis-functonalized

product 2-58 was isolated as the major product with chiral phosipine ligands: the only chiral phosphine

ligands derived from (R)-BINAP leads to the formation of 2-59 (see Table 2.3).

166

Condition Yield (%)a

Entry Pd Ligand Temp Time 2-57 2-58 2-59

1 [Pd(allyl)Cl]2 NO rt 30 63 (>95)

2 [Pd(allyl)Cl]2 2-46 80 oC 9h 54 (>90)

3 [Pd(allyl)Cl]2 2-47 80 oC 48h 35 (>40) (11)

4 Pd(NH3)2(NO2)2 2-46 80 oC 9h 62 (>95)

5 Pd(NH3)2(NO2)2 2-47 80 oC 48h 13 (>20) 17 b (>26)

6 Pd(NH3)2(NO2)2 2-48 80 oC 4d 14 (>20) (>20)

7 Pd2(dba)3•CHCl3 2-48 80 oC 4d (10) 46 (>70) (>20)

a. Isolated yield. The number in parenthesis is measured by 1H NMR. b. A mixture of cis/trans = 0.35/1.0

Table 2. 3. Tandem Carbocyclization/Silastannylation of Bis(allenes)

2. 5. Palladium Catalyzed Silylstannylation of 1, 6-Diynes

RajanBabu et al reported the cycliztion of 1, 6-diynes mediated by trialkylsilyltrialkystannanes

(R3Si-SnR3’) in the presence of Pd(0) to give novel, helically chiral 1, 2-dialkylidenecyclopentanes with

uncommon(Z, Z)-geometry at the double bonds. To investigate detail Diels-Alder reactions of vinyl silanes

with a variety of dienophiles we needed to prepare of the 1, 2-dialkylidenecyclopentanes. Thus we

duplicated the RajanBabu’s protocol for the cyclizattion of 1, 6-diynes with trialkylsilyltrialkystannanes

EtO2C

EtO2CRSn SiR'+

2-60 2-41

SnR

SiR'EtO2C

EtO2C

2-62: R = Bu3, R' = Me32-63: R = Bu3, R' = Me2Ph

(27)

(C6F5)3P

Pd(0)

TsN RSn SiR'+

2-61 2-41

TsNSnR

SiR'

2-69: R = Ph3, R' = Me2tBu

(C6F5)3P

Pd(0)

167

(R3Si-SnR3’) in the presence of Pd(0) (Table 2. 4). As previously reported by RajanBabu and his students,

the cyclized product 2-62 was prepared in 66% yield. We also performed the silastannylation with a

bulkier tin-silane reagent 2-63, which has not been used in bisfunctionalization of diynes catalyzed by

palladium catalysts (Entry 2 and 3). Moreover, nitrogen substituted diene 2-61 gave the carbocyclic

silastannylation to give 2-69 in good yield.

Entry Si-Sn Pd Solvent Temp

( oC)

Time

(h)

Product Yield

(%)

1 Bu3SnSiMe3 Pd2(dba)3•CHCl3 C6H6 50 oC 12 2-62 66

2 Bu3SnSiMe2Ph Pd2(dba)3•CHCl3 C6D6 80 oC 6 2-63 24

3 Bu3SnSiMe2Ph Pd2(dba)3•CHCl3 C6H6 60 oC 12 2-63 44

Table 2. 4. Tandem Carbocyclization/Silastannylation of 1,6-Dynes.

Warren reported in her dissertation that the isolated yield of the 1, 2-dialkylidenecyclopentanes

decreases with increasing the bulkiness of the trialkylsilyltrialkystannanes (R3Si-SnR3’) even at the high

temperatures. Therefore, it is natural we expect the lower yield from the reaction. First, we ran a small

scale reaction in C6D6 at 80 oC. Although all staring materials were consumed within 6 h, we only obtained

24% of the cyclized product 2-63 in keeping with our expectation (Entry 2). We were pleased that the

isolated yield of the cyclized product increased up to 44% in the large scale reaction at 60 oC, but run for

longer periods.

2. 6. Destannylation of Csp2-Stannanes

For the hydrolysis of Csp2-stannanes made by addition of R3Si-SnR’3 to alkynes camphorsulfonic

acid (CSA) or p-toluenesulfonic acid (pTsOH) were previously used. Unfortunately, those acids were not

168

practical reagents for the hydrolysis of 2-62 because the procedure led to very low isolated yields of the

products. Alternatively we may use tin-lithium exchange by methyllithium in THF, followed by quenching

with ammonium chloride at 0 oC, but the yield was not improved in this case either. However, Shin found

that excess amount of carboxylic acid (5.0 equivalents), especially formic acid (HCO2H), could be used for

the selective synthesis of vinly Csp2-stannanes, 2-70. We investigated the scope of the reaction with a broad

spectrum of 1, 2-bis-dialkylidenecyclopentanes and the results are shown in Table 2.5

SnR

SiR'EtO2C

EtO2C

2-62: R = Bu3, R' = Me32-63: R = Bu3, R' = Me2Ph2-64: R = Bu3, R' = Et32-65: R = Bu3, R' = Me2

tBu2-66: R = Ph3, R' = iPr2-67: R = Ph3, R' = Me2

tBu

(28)CH2Cl2/rt

HCO2H SiR'EtO2C

EtO2C

2-70: R' = Me32-71: R' = Me2Ph2-72: R' = Et32-73: R' = Me2

tBu2-74: R' = iPr2-73: R' = Me2

tBu

TsNSnR

SiR'

2-68: R = Bu3, R' = Me32-69: R = Ph3, R' = Me2

tPh

(29)CH2Cl2/rt

HCO2HTsN

SiR'

2-75: R' = Me32-76: R' = Me2Ph

Most substrates we studied could be hydrolyzed easily in dichloromethane at rt within 24 h to

afford the corresponding destannylated products in excellent yields. Because the ethyl esters of the 1, 2-

bis-dialkylidenecyclopentanes could also be hydrolyzed under the acidic conditions, excess formic acid or

longer reaction times were unfavorable for this transformation (Entry 1). The hydrolysis of the vinly Csp2-

stannanes was independent on the size of the stannanes, depended on the size of the vinyl silanes (Table

2.5) even though there are some exception. Because the substrates do not have acid sensitive functional

group, dialkylidenecyclopentanes involving nitrogen were more efficiently hydrolyzed under the acidic

condition (Eq. 28), and two excellent examples for the hydrolysis are in the Table 2.5 (Entry 9 and 10).

169

The destannylated products have to be kept in a refrigerator because they are prone to polymerization

especially when exposed to light.

Entry Substrate HCO2H Time Product Yielda

1 2-62 10.0 Equiv. 24 h 2-70 24%

2 2-62 5.0 Equiv. 6 h 2-70 84%

3 2-62 5.0 Equiv. 14 h 2-70 > 99%

4 2-63 5.0 Equiv. 12 h 2-71 > 99%

5 2-64 5.0 Equiv. 8 h 2-72 65%

6 2-65 5.0 Equiv. 8 h 2-73 73%

7 2-66 5.0 Equiv. 24 h 2-74 44% (70%)

8 2-67 5.0 Equiv. 24 h 2-73 17%

9 2-68 5.0 Equiv. 18 h 2-75 > 99%

10 2-69 5.0 Equiv. 24 h 2-76 > 99%

a. Isolated yield. The number in the parenthesis is yield based on recovered starting material

Table 2. 5. Destannylation of Silastannylaed 1,3-Dienes.

2. 7. Optimization of Regioselective Diels-Alder Reaction of Vinyl Silanes

A preliminary study of Diels-Alder reactions of silylstannyl diene 2-77 with a dienophile, maleic

anhydride 2-78, has been investigated by Warren and Shin. Although the maleic anhydride has been

reported as an excellent dienophiles in Diels-Alder reactions, Warren failed to obtain the corresponding

polycyclic product 2-79, probably due to severe steric hindrance of the diene (Eq. 30). She explained that

the silylstannyl dienes 2-77 behaves as two independent alkenes rather than a conjugated diene because it is

extremely puckered and distorted by the (Z, Z)-geometry of the 1, 3-diene.

170

(30)SiMe3 +

SiMe3

2-77

MeO2CSnBu3

O

O

Ort

CDCl3O

O

OSnBu3

X

2-78 2-79

MeO2C

Even though the silylstannyl dienes themselves do not take part in Diels-Alder reactions, the

removal of the bulky SnBu3 restores this reactivity because the 1, 3-diene is expected to have a near planar

geometry, to which the dienophiles may access more easily. Shin and Warren studied the Diels-Alder

reaction with the destannylated dienes 2-67 or 2-75 and an excellent dienophile, maleic anhydride 2-78.

The reaction proceeded very smoothly at rt or 60 oC to afford the expected polycyclic products 2-80 or 2-81

in an excellent yield. The configuration of the products was unambiguously determined by HMQC and

HMBC and the relative stereochemistry was based on the mechanism of endo transition state upon

formation of the cyclic product (Eq. 31).

(31)

SiMe3EtO2C

EtO2C

+

2-67

SiMe3

EtO2C

EtO2CO

O

O

2-80

O

O

O

2-78

TsNSiMe3 +

2-75

TsN

SiMe3

O

O

O

2-81

O

O

O

2-78

CDCl3

CDCl3

rt

rt

96%

>99%

On the other hand the Diels-Alder reaction of a simple vinylsilane 2-82 with methyl propiolate or

methyl acrylate has been studied independently by two research groups. However, the regioselectivity of

the cyclized product was very poor and yield of the products was relatively low. The preference of ortho- /

171

meta-substituted product is controlled by its intrinsic steric as well as electronic properties of the

trimethylsilyl group.

SiMe3CO2CH3 CO2CH3

or+

SiMe3

CO2CH3

SiMe3

CO2CH3

+∆

Dienophiles 2-83/2-84 Yield (%) Reference

CO2CH3

CO2CH3

CO2CH3

0.8/1.0

1.1/1.0

3.2/1.0

47%

77%

42%

Tetrahedron Lett., 1979, 35, 621

JCS., Chem.Comm, 1976,681

JCS., Chem.Comm, 1976,681

2-82 2-83 2-84

(32)

(33)

SiREtO2C

EtO2C

+X

SiR

HX

EtO2C

EtO2C

TsNSiR

2-75: R = Me3

+X

TsN

SiR

HX

2-67: R = Me32-68: R = Me2Ph

2-86

2-85 Carbocyclic and heterocycliccompounds

Diels-Alder Reaction


Although there is plenty of room for the investigation of regioselectivity controlled by steric

effects in the Diels-Alder reactions of vinylsilane dienes, only limited numbers of reference are available in

172

the literature. Thus, we decided to explore details of the regioselectivity of the Diels-Alder reaction with

vinylsilanes, 2-67, 2-68, and 2-75, which may be used for the synthesis of a variety of carbo- and

heterocyclic rings in total syntheses (Eq. 33).

Me3Si

H

EtO2C

EtO2C

Me3Si

CO2Et

EtO2C

EtO2C

Me3Si

EtO2C

EtO2C

Me3Si

EtO2C

EtO2C

H CO2Et

CO2Et H

CO2Et H

(endo)-2-89

(endo)-2-90

(exo)-2-89

(exo)-2-90

Figure 2. 2. Structures of 2-89 and 2-90.

The representative results are shown in Table 2.6. To optimize the reaction conditions for the

Diels-Alder reaction of vinylsilane 2-67 we chose ethyl acrylate 2-87 as the dienophile, and performed the

reaction under various conditions. First, we carried out the reaction at a variety of temperatures with fixed

equivalents of the dienophile 2-87 (1.5 equivalents) and solvent (benzene). The reaction mixture was

analyzed by gas chromatography and identity of each peak was confirmed by high resolution mass

spectrometry. The reaction was very clear and the GC analysis implied there are no other products, except

for the starting material, and the expected cyclic products 2-89 and 2-90. With increasing of the reaction

temperature, the reaction rate increased, and most starting material was consumed within 24 h under

173

(34)SiMe3

EtO2C

EtO2C+

CO2Et

SiMe3

CO2Et

EtO2C

EtO2C

2-67 2-89

+

SiMe3

EtO2C

EtO2C

2-90

CO2Et

2-87

Condition

Entry 2-89 (Equiv.) Solvent Temp a Time

Yield (%)b

Ratio c

1 1.5 Equiv. benzene 60 oC 4 d 44 1.0/0/0

2 1.5 Equiv. benzene 80 oC 4 d 53 1.0/0.26/0.03

3 1.5 Equiv. benzene benzene ↑↓ 4 d 60 1.0/0.26/trace

4 1.5 Equiv. benzene toluene ↑↓ 27 h 87 1.0/0.32/0.07

5 1.5 Equiv. benzene xylene ↑↓ 24 h 98 1.0/0.36/0.08

6 1.5 Equiv. toluene toluene ↑↓ 48 h 98 1.0/0.32/0.08

7 1.5 Equiv. toluene xylene ↑↓ 12 h 98 1.0/0.35/0.10

8 1.5 Equiv. xylene xylene ↑↓ 12 h > 99 1.0/0.36/0.03

9 3.0 Equiv. benzene benzene ↑↓ 3.5 d 28 1.0/0.10/0

10 3.0 Equiv. benzene toluene ↑↓ 24 h 81 1.0/0.27/0.02

11 3.0 Equiv. benzene xylene ↑↓ 12 h 91 1.0/0.26/0

12 3.0 Equiv. benzene xylene ↑↓ 48 h > 99 1.0/0.26/0

13 3.0 Equiv. toluene toluene ↑↓ 40 h 82 1.0/0.26/0.01

14 3.0 Equiv. toluene xylene ↑↓ 6 h > 99 1.0/0.32/0.05

15 3.0 Equiv. xylene xylene ↑↓ 48 h > 99 1.0/0.23/0

16 5.0 Equiv. toluene xylene ↑↓ 6 h >99 1.0/0.32/0.02

a. The temperature is oil-bath temperature measured by thermo-coupled thermometer. b. The yield was determined by GC analysis. c. The ratio and structures (endo-2-89/endo-2-90/exo-2-89) were tentatively assigned.

Table 2. 6. Diels-Alder Reaction of Vinylsilane 2-67.

174

refluxing condition in xylene (140 oC) (Entry 5). Based on the GC and HRMS analysis of the product(s)

we found three regio- and stereoisomers of cyclic compound (2-89 and 2-90) resulted by in a ratio of

1.0/0.36/0.08, and tentatively assigned as to endo-2-89/endo-2-90/exo-2-89, respectively.

When we used higher boiling solvents such as toluene or xylene, the reaction proceeded faster

than in benzene and the portion of endo-2-90 and exo-2-89 increased. We also examined the reaction with

3.0 equivalents and 5.0 equivalents of ethyl acrylate, and the reaction required shorter reaction time with

increasing concentration of the dienophiles. The reaction was independent on solvents even though

prolonged reaction time was required with lower boiling point solvent. To consume completely the starting

vinylsilane diene 2-67, the reaction mixture had to be heated under xylene refluxing condition.

The vinylsilanes involving tosylamine were also subject to the regioselective Diels-Alder reaction under the

similar reaction condition (Table 2-7). The reaction was much slower than that of 2-67, but could be

completed without any byproduct formation at the prolonged reaction time (Entry 2). Gratifyingly, the GC

analysis implied that the cyclic product was an only mixture of endo-2-91 and endo-2-92.

(35)TsNSiMe3 +

CO2EtTsN

SiMe3

CO2Et

2-75 2-91

+ TsN

SiMe3

2-92

CO2Et

2-87

Condition

Entry 2-96 (Equiv.) Solvent Temp a Time

Yield (%)b

Ratio c

1 3.0 Equiv toluene xylene ↑↓ 3.5 d 94 1.0/0.41

2 3.0 Equiv xylene xylene ↑↓ 3.5 d > 99 1.0/0.44

a. The temperature is oil-bath temperature measured by thermo-coupled thermometer. b. The yield was determined by GC analysis. c. The ratio and structures (endo-2-91/endo-2-92) were tentatively assigned.


175

2. 8. Regioselective Diels-Alder Reaction of Vinyl Silanes with Various Dienophines

After optimization of the reaction condition for the Diels-Alder reaction of vinylsilane dienes with

ethyl acrylate, we performed the reaction with other dienophiles, and the results are shown in Table 2.8.

When a substituted olefin with an electron withdrawing group (EWG) were used in the reaction as the

dienphiles, the vinylsilane dienes 2-67 took part in the Diels-Alder reaction to afford fused carbocyclic

products in excellent yield. However, if the substituent was an electron-donating group (EDG), the

reaction failed even after exposure to prolonged reaction times. Most cases the cyclized products were

isolated by column chromatography as a mixture of 2-93 and 2-94, and the ratio was determined before or

after column chromatography by GC analysis. The stereochemistry of products was unambiguously

determined by nOe experiment while some of them are assigned tentatively. The representative results for

the nOe experiments for 2-89 and 2-90 are shown in Figures 2.3 and 2.4, respectively. For example, strong

enhancement of SiMe3 and H4a peaks was observed by irradiation of H2 and and H3, respectively, which is

greatly agreement with the endo- and cis-configuration at C2-C3. However, an interpretation of 1H NMR

spectrum of an inseparable mixture of 2-89 and 2-90 is difficult. Gratifyingly, the results of nOe

experiment supports that the major product is 2-89 in reaction shown in Eq. 34. The reaction appears to be

controlled by steric effects.

A more sterically demanding vinylsilane diene 2-68 was subjected to the Diels-Alder reaction with

an EWG-substituted olefins (Eq. 37). The reaction was performed under the optimized reaction conditions

to give the corresponding carbocyclic products. The results of reactions are summarized in Table 2.10 and

the corresponding products are shown in Figure 2.6. Based on the analysis of GC and TLC we assume that

the reaction was very clean with consumption of all starting material. The isolated yield of the fused cyclic

product is moderate probably due to instability of the compound upon the column chromatography. While

the Diels-Alder reaction of the vinylsilane 2-68 with ethyl- and tert-butyl acrylate gave a mixture of

regioisomers (Entry 1 and 2), a single diastereomer was obtained from the reaction with dimethyl- and

diethyl fumarate (Entry 5 and 6). The configuration of the products was unambiguously assigned by

extensive nOe studies, which are summarized in Figure 2.5. The trans relationship between C1 and C2 was

176

ascertained by the irradiation of the H1 peak leading to enhancement of the O-methyl peak at C2 while

another trans-relationship between C2-C3 was confirmed by the relatively small nOe effect.

SiMe3

MeO2C

MeO2CH3

H1

H4a H4b

Me3Si

MeO2C

MeO2C

2-89

12

34

OEt

O

OEt

O

H2b

H2a

3.4%

2.6%

1.9%

2.7%

1.5%

nOe(%) nOe(%) nOe(%) nOe(%)

H1 →

SiMe3

1.5 H1 → H6b 1.4 H2b → H3 1.5 SiMe3 →

H1

0.5

H1 → H2a 2.2 H2a →

SiMe3

3.4 H2b → H4b 1.6 SiMe3 →

H2a

0.5

H1 → H2b 1.9 H2a → H1 2.7 H3 → H2a 1.5 SiMe3 →

H3

0.5

H1 → H3 0.4 H2a → H3 2.6 H3 → H4a 1.9 SiMe3 →

H6a

0.5

H1 → H5b 0.5 H2b → H1 2.0 H3 → H4b 0.5

Figure 2.3. Representative nOe Results for 2-89

177

Me3Si

EtO2C

EtO2C

2-90

OEt

O Me3Si

EtO2C

EtO2C

OEt

OH1

H2

H3aH4a H4b

H3b

2.9%

2.0%

H6b

H5b

2.5%

1.8%


H1 → H2 2.9 H1→ H5b 1.8 H2 → H3a 0.4 H4b→ H1 0.5

H1 → H3a 0.4 H1 → H6b 2.5 H2 → H3b 0.8

H1 → H3b 2.0 H2 → H1 1.3 H4a → H4b 3.8

Figure 2.4. Representative nOe Results for 2-90

NPh

O

O

SiMe3

MeO2C

MeO2C

H

H

H

1.9%

H H

2.5%

0.6%1.7% 3.0%

2.2%

NPh

O

O

Me3Si

MeO2C

MeO2C

2-118

12

34


H1 →

SiMe3

1.0 H2 →

SiMe3

1.9 H3 → H4a 0.6 H4a→ H4b 12.5

H1 → H2 1.5 H2 → H1 2.2 H3 → H4b 0.5 H4b→ H3 0.4

H1 → H4b 1.7 H3 →

SiMe3

2.5 H4a → H3 3.0 H4b→ H4a 14.6

Figure 2.5. Representative nOe Results for 2-118.

178

PhMe2Si

MeO2C

MeO2C OMe

OMe

O

O

MeO2C

MeO2C OMe

OMe

O

O

H6a

H5a J5b

H6b

PhMe2Si H1

H4bH4a

H3

H2

1.1%

1.5%

0.9%

0.9%

1.3%

12

34

2-133

Figure 2.6. Representative nOe Results for 2-133.

nOe(%) nOe(%) nOe(%)

H1 → SiMe2Ph 2.4 H1→ H6b 1.5 H2 → SiMe2Ph 2.3

H1 → C2CO2Me 1.1 H2 → H1 0.9 H3 → H4b 0.9

H1 → H2 0.7 H2 → H3 0.9

179

(36)SiMe3

EtO2C

EtO2C+

X

SiMe3

X

EtO2C

EtO2C

2-67 2-93

+

SiMe3

EtO2C

EtO2C

2-94

X

2-93

Condition

Entry

Dienophile Equiv Solvent Temp Time

Yield (%)a

Ratio b

1 OMe

O

3.0 toluene xylene ↑↓ 48 h 69 (> 99) 1.0/0.27

(1.0/0.26/0.02)

2 OEt

O

3.0 toluene xylene ↑↓ 48 h 71 (> 99) 1.0/0.31

(1.0/0.17)

3 OtBu

O

3.0 toluene xylene ↑↓ 24 h 77 (> 99)

(1.0/0.39/0.03)

4 CH3

O

3.0 toluene xylene ↑↓ 48 h 91 (> 99) 1.0/0.05

(1.0/0.09)

5 H

O

3.0 toluene xylene ↑↓ 24 h 79 (> 99) 1.0/0.24/0.07

(1.0/0.24/0.08)

6 CN

O

3.0 toluene xylene ↑↓ 24 h 68 (> 99) 0.80/0.98/0.01/1.0

(0.72/1.0/0.05/1.0)

7 Ph

3.0 toluene xylene ↑↓ 3.5 d 52 (> 85) 1.0/0.21/0.20

8

CO2Me

CO2Me

3.0 toluene xylene ↑↓ 3 d 80 (> 99)

9 CO2Me

MeO2C

3.0 toluene xylene ↑↓ 4 d 65 (> 99)

(1.0/0.08)

Continued


180


Condition

Entry

Dienophile

Equiv

Solvent Temp Time

Yield (%)a

Ratio b

10 CO2Et

EtO2C

3.0 toluene xylene ↑↓ 4 d 59 (> 99) (1.0/0.06/0.03)

11

OMeH3C

O

3.0 toluene xylene ↑↓ 4 d 78 (> 98) 1.0/0.39/0.16

12 Ph

3.0 toluene xylene ↑↓ 6 h (>99) 0.06/1.0

13 OH

O

H3C CH3

3.0 toluene xylene ↑↓ 48 h NR

14

O

O

O

2.0 toluene xylene ↑↓ 20 h (> 99)

15

NTs

O

O

2.0 toluene xylene ↑↓ 2.5 d 50 (> 99)

16 EtO


17 AcO

3.0 toluene xylene ↑↓ 3 d

NR

18 CH2SiMe3

3.0 toluene xylene ↑↓ 3 d NR

19 PhH3C


Continued

181


Condition

Entry


Yield (%)a

Ratio b

20 OCH3H3C


21 Ph

MeO2C


22 OCH3

O

H3C


23 H

O

H3C

3.0 toluene xylene ↑↓ 7 d (43) 1.0/0.21

24 OEt

O

3.0 toluene xylene ↑↓ 24 h 60 (71) 1.0/0.45

(1.0/0.17)

25

OOAc

H3C


26

OOAc

H3CO


3.0 toluene xylene ↑↓ 4d NR

3.0 benzene benzene ↑↓ 4 d NR

27

CHOBr 3.0 CH2Cl2 rt 4 d NR

3.0 toluene toluene ↑↓ 36 h NR

28

OAcNC

3.0 toluene xylene ↑↓ 7 d 18 (82) (1.0/0.78/

0.13/0/05)

Continued

182


Condition

Entry


Yield (%)a

Ratio b

29 CNBr


30 Ph

CO2H

3.0 toluene xylene ↑↓ 6 d (< 6)

31

3.0 toluene xylene ↑↓ 6 d (< 4)

32


a. The yield is isolated yield. The yield in the parenthesis is determined by GC analysis. b. The structures (endo-2-93/endo-2-94/exo-2-93) were tentatively assigned, and the numbers in the parenthesis was determined before column chromatography.

183

O

O

O

Me3Si

MeO2C

MeO2C

Me3Si

EtO2C

EtO2C

2-89

Me3Si

EtO2C

EtO2C

2-90

OEt

O

OEt

O Me3Si

EtO2C

EtO2C

2-95

Me3Si

EtO2C

EtO2C

2-96

OMe

O

OMe

O

Me3Si

EtO2C

EtO2C

2-97

Me3Si

EtO2C

EtO2C

2-98

OtBu

O

OtBu

O Me3Si

EtO2C

EtO2C

2-99

Me3Si

EtO2C

EtO2C

2-100

CH3

O

CH3

O

Me3Si

EtO2C

EtO2C

2-101

Me3Si

EtO2C

EtO2C

2-102

H

O

H

O Me3Si

EtO2C

EtO2C

2-103

Me3Si

EtO2C

EtO2C

2-104

CN

CN

Me3Si

EtO2C

EtO2C

2-105

Me3Si

EtO2C

EtO2C

2-106

Ph

Ph

Me3Si

EtO2C

EtO2C

2-107

OMe

OMe

O

O

Me3Si

EtO2C

EtO2C

2-108

Me3Si

EtO2C

EtO2C

2-109

OEt

OEt

O

O

OMe

OMe

O

O

Me3Si

EtO2C

EtO2C

2-111

Me3Si

EtO2C

EtO2C

2-112

Ph

Ph

2-113

NPh

O

O

Me3Si

MeO2C

MeO2C

2-114

Me3Si

MeO2C

MeO2C

2-115

Me3Si

MeO2C

MeO2C

2-116

H

CH3

CH3

H

O

O

Me3Si

MeO2C

MeO2C

2-117

Me3Si

MeO2C

MeO2C

2-118

Me3Si

MeO2C

MeO2C

2-119

Me3Si

MeO2C

MeO2C

2-120OAc

CN

CN

OAcOEt

OEt

O

O

Me3Si

MeO2C

MeO2CCH3

CO2Et

2-110

Figure 2. 7. Representative Products of Diels-Alder Reaction (Eq. 36).

184

(37)SiMe2PhEtO2C

EtO2C+

X

SiMe2Ph

X

EtO2C

EtO2C

2-68 2-121

+

SiMe2Ph

EtO2C

EtO2C

2-122

X

2-93

Condition

Entry


Yield (%)a

Ratio b

1 OEt

O

3.0 toluene xylene ↑↓ 24 h 60 (> 99) 1.0/0.44

(1.0/0.47)

2 OtBu

O

3.0 toluene xylene ↑↓ 24 h 45 1.0/0.27

3 CH3

O

3.0 toluene xylene ↑↓ 36 h 41

4 H

O

3.0 toluene xylene ↑↓ 36 h 43

5 CO2Me

MeO2C

2.0 toluene xylene ↑↓ 2.5 d 42(> 99)

6 CO2Et

EtO2C

3.0 toluene xylene ↑↓ 2,5 d 51 (> 99) 1.0/0.46

7 CNBr


8

OOAc

H3C

3.0 toluene xylene ↑↓ 6 d 44

Continued

Table 2. 9. Diels-Alder Reaction of Vinylsilane 2-68 with Various Dienophines

185


Condition

Entry


Yield (%)a

Ratio b

9 Ph

MeO2C


10

NTs

O

O

3.0 toluene xylene ↑↓ 2.5 d 66

11 Ph

MeO2C


12

OOAc

H3CO


a. The yield is isolated yield. The yield in the parenthesis is determined by GC analysis. b. The structures (endo-2-121/endo-2-122/exo-2-122) were tentatively assigned, and the numbers in the parenthesis was determined before column chromatography.

186

Me2PhSi

EtO2C

EtO2C

2-123

Me2PhSi

EtO2C

EtO2C

2-124

OEt

O

OEt

O Me2PhSi

EtO2C

EtO2C

2-125

Me2PhSi

EtO2C

EtO2C

2-126

OtBu

O

OtBu

O

Me2PhSi

EtO2C

EtO2C

2-127

Me2PhSi

EtO2C

EtO2C

2-128

CH3

O

CH3

O Me2PhSi

EtO2C

EtO2C

2-129

Me2PhSi

EtO2C

EtO2C

2-130

H

O

H

O

Me2PhSi

EtO2C

EtO2C

2-131

Me2PhSi

EtO2C

EtO2C

2-132

Me2PhSi

EtO2C

EtO2C

2-133

OEt

OEt

OEt

OEt

O

O O

O

OMe

OMe

O

O

Me2PhSi

EtO2C

EtO2C

2-135

Me2PhSi

EtO2C

EtO2C

2-136

COCH3

OAc

OAc

COCH3

NPh

O

O

PhMe2Si

MeO2C

MeO2C

2-134

PhMe2Si

MeO2C

MeO2CCN

OAc

PhMe2Si

MeO2C

MeO2CCN

OAc

2-137 2-138


TsN

Me3Si

2-91

TsN

Me3Si

2-92

OEt

O

OEt

O

TsN

Me3Si

2-139

TsN

Me3Si

2-140

CH3

O

CH3

O

TsN

Me3Si

2-141

TsN

Me3Si

2-142

CN

CN


187

Finally, we choose vinylsilane diene involving nitrogen 2-75 to examine the regioselectivity of the

Diels-Alder reaction (Eq. 39). The diene reacted efficiently with an EWG substituted-α,β-unsaturated

olefins such as ethyl acrylate, methyl vinylketone, and acrylonitrile to afford the corresponding cyclic

products shown in Figure 2.8. As we have demonstrated before, the reactions required high temperature

probably refluxing in xylene, 140 oC for completion the reaction within reasonable reaction time to get

acceptable yield (Entry 1).

(38)TsNSiMe3 +

XTsN

SiMe3

X

2-75 2-143

+ TsN

SiMe3

2-144

X

2-93

Condition

Entry


Yield (%)a

Ratio b

3.0 xylene xylene ↑↓ 3.5 d (> 99) 1.0/0.44

5.0 toluene 80 oC 5 h 18 (1.0/0.16)

1

OEt

O

5.0 toluene toluene ↑↓ 48 h 15

4 CH3

O


5 CN

O


6c EtO

3.0 Toluene

-d8

xylene ↑↓ 24 h NR

a. The yield is isolated yield. The yield in the parenthesis is determined by GC analysis. b. The ratio and structures (endo-2-143/endo-2-144/exo-2-143) were tentatively assigned. c. Run the reaction in a flame-sealed NMR tube.

Table 2. 10. Diels-Alder Reaction of Vinylsilane 2-75 with Various Dienophines

188

2. 9. Conclusion

In this chapter, we have documented our preliminary studies on palladium catalyzed

sylylstannylative cyclization of diynes and allenynes with various chiral phosphine ligands and palladium

catalysts. Although chiral GC and HPLC cannot separate the racemic mixtures of the silylystanylated

cyclic products, they can be separated easily by 1H NMR spectroscopy with chemical shift reagents such as

Eu(hfc)3 or Pr(hfc)3. The best enatiomeric excess (ee) was only 8%. The bifunctionalized 1,3- and 1,4-

dienes can be bromiated with NBS in dichloromethane at rt to give the corresponding vinyl bromide in

quantitative yield. After the bromination of the silylstannylative product, the ee was less than 1%.

We have also studied destannylation of the bifunctionalized 1,3- and 1,4-dienes under acidic

conditions. The optimized reaction conditions are 5.0 equivalent of formic acid (HCO2H) in

dichloromethane at rt to give the corresponding vinyl silanes in excellent to moderate yields. The reaction

is dependant on the size of silane substituents as well as the tin substituents. For example, tributyltin can be

efficiently destannylated in excellent yield, but triphenyltin cannot be easily destannylated under our

optimized conditions.

Finally, we have explored regioselective Diels-Alder reaction of the vinylsilanes with various

dienophines to afford carbocyclic and heterocyclic compounds. The reactions were optimized with 3.0

equivalents of dienophiles, toluene as the solvent, and refluxing in xylene bath (140 oC). The Diels-Alder

reaction proceeds quantitatively with various dienophiles such as ethyl acrylates, methyl vinyl ketone, or

maleic anhydride, and the distiribution of the regioisomers is controlled by the size of the vinyl silanes.

189

CHAPTER 3

PALLADIUM CATALYZED SILYLSTANNYLATIVE CYCLIZATION OF

DIYNES AND ATTEMPTED SYNTHESIS OF

PAPULACANDIN D CORE STRUCTURE

3. 1. Introduction

During the last decade a number of strategies have been reported for the construction of

spiroketals, which are commonly found core structures in many biologically active compounds such as

polyether antibiotics, marine and plant toxins, insect pheromones and antiparistic agents.95 Among those

classes of compounds, a family of Paulacandins isolated from Papularia sphaerospema consists of four

members, Paulacandin A, B, C, and D with in vitro activity against Candida albicans and other fungi.96

Generally, these compounds inhibit the enzymes involved in biosynthesis of the fungal cell wall

component, 1,3-β-glucan (Figure 3. 1).

All the Papulacandins contain both a β-C-glucoside and an α-O-glucoside as a key structural

unit.97 The Papulacandins A, B, and C, which are structurally close to another diglycoside Saricandin

isolated from Fusarium, have a spirocyclic diglycoside linked as esters to two hydroxyl groups at C3 and C6

of a glucopyranose core. Papulacandin D is a relatively simple monosaccharide with a long chain of fatty

acid. Papulacndin D, which has a C-arylglucosyl spiroketal nucleus, has received a great deal of attention

from synthetic chemists due to the synthetic challenge involved in the construction of the novel structure

containing 1,7-dioxaspiro[5.4]decane with a glucose residue. Its effectiveness in treating Pneumocystics

carinii-induced pneumonia is also particularly noteworthy.

190

O

OH

HOO OH

O

OH

HO

O

OH

CH3 CH3

Papulacandin D

O

OH

OO OH

O

OH

HO

O

OH

CH3 CH3

Papulacandin A R =

O

OH

OROH

HO

Biosynthetic pathway

Papulacandin B R =

Papulacandin C R =

O

O OH

OH

3-1

3-2

3-3

3-4O

O

OH

HOO OH

O

OH

HO

O

OH

O

OH

OO OH

O

OH

HO

O

OH

O

OH

OROH

HO

Biosynthetic pathway

O

Saricandin R = 3-5 3-6

Figure 3. 1. Structure of Paulacandin A-D and Saricandin

The first efforts to synthesize Papulacandin D were reported by Danishefsky and his associates in

1987 (Eq. 1).98 They used a Lewis acid-catalyzed, hetero-Diels-Alder reaction of Danishefsky’s diene 3-7

with benzaldehyde derivative 3-8 to prepare 2,3-dihydro-4H-pyran-4-one 3-9, which was further

transformed to a C-arylglucosyl spiroketal nucleus 3-10 by a stereospecific, spiroactalization of C-1

methoxylated aryl glycoside. It has to be pointed out that oxidation of 3-dihydro-4H-pyran-4-one 3-9 with

191

3-chloroperoxy-benzoic acid (mCPBA) in methanol gave the methoxyhydrin 3-11 having the gluco, rather

than manno, configuration at C2. Moreover, the properly placed benzyl alcohol group of methyl glycoside

3-12 is likely to undergo the stereoselective spiroactalization at C1 position.

OMe

OSiMe3 CHOOBz

OBn

OBn

+O

O

H

OBz

OBnBnO

O

BzO

O

H

Ar O

OBzAr

OMe

OH

OAc

AcO

mCPBAMeOH

MeOH

NaOHO

OH

OBz

OBnBnOOH

OHHO

O

OOAc

OAc

AcO

OAc

AcO

AcO

3-7 3-8 3-9 3-10 3-11

3-12 3-13

(1)

OMe

Beau and his associates reported99 palladium(0) catalyzed coupling reaction of stannane-

substituted olefin 3-14 with protected benzyl alcohol 3-15 to give the C-arylated glycal 3-16, which might

be subjected to stereoselective oxidative spiroacetalization mediated by m-CPBA via a epoxidation-

spiroketalization sequence. The stereoselective epoxiation of the olefin in 3-16 may be achieved by

mCPBA at low temperature to afford two isomers 3-17 and 3-18 with the D-gluco configuration, but

hydroboration-oxidation of 1-C-arylated glycal 3-16 did not provide the desired spiroketal 3-17. The

protected spiroketal 3-17 was subjected to a double deprotection- protection sequence to give the core

structure of Papulacandin D, 3-19. They failed to convert undesired spiroketal 3-18 to the desired

spiroketal 3-17 by acid –catalyzed isomerization. During the deprotection of benzyl group in 3-17 and 3-

18, epimerization at the spiro center of 3-18 proceeds spontaneously to give the desired β-configuration. To

isolate efficiently the 1-C-arylated glycal, all hydroxyl groups have to be protected by Ac2O/pyr before

column chromatography.

192

OOPh O

SnBu3TBSO

BrOH

OBn

OBn

+

3-15

OOPh O

TBSO

HO

BnO

OBn

OOPh

O

OHO

BnO

OBn

OOPh O

OHO+

OBn

BnO

AcOAcO

OAcO

OAcO

AcO

OAc

3-14 3-16

3-17 3-18 3-19

(2)

Pd(0)

Na2CO3

mCPBA

(2) H2, Pd/C

(1) TBAF

(3) Ac2O/Pyr

TMSOTMSO

Friesen also used the palladium catalyzed coupling of aryl bromide 3-21 and stannyl glucal 3-20

for the synthesis of spiroketals.100 The coupling followed by stereoselective oxidative spiroketalization of

the derived C-arylglucal 3-22 leads to the synthesis of the spiroketal nucleus of the Papulacandin. Because

the acetyl protected C-arylglucal 3-22 did not take part in oxidative spiroketalizatioon, the protecting

groups had to be removed. The completion of the synthesis of 3-25 required not only stereoselective

installation of a hydroxyl group at C2 but also oxidative ketalization. These two transformations could be

achieved simultaneously by using dimethyl dioxirane (DMDO) via stereoselective α-epoxidation at C1-C2

bond followed by rapid intra molecular cyclization. Even though the spoiroketal 3-24 has unfavorable

configuration, the compound may isomerizes to thermodynamically favorable spoiroketal 3-25 by

pyridinium p-toluenesulfonate (PPTS) as a catalyst.

TBSO OSnBu3TBSO

BrOAc

OBn

OBn

+

3-21

TBSOTBSO

OTBSO

RO

BnO

OBn

TBSOTBSO

O

OHO

BnO

OBn

3-20 3-22: R = Ac 3-23: R = H

3-25

Pd(II)TBSO

DMDO

TBSOO

OHO

OBn

BnO

3-24

TBSOTBSO

TBSOPPTS

(3)

193

Nucleophilic additions of organometallic reagents to lactones have been well-established, but the

application to total synthesis is limited because the basic reagents may abstract the α-hydrogen as well as

undergo nucleophilic addition. Bihovsky and his associate reported101 that the addition of aryllithium 3-27

to the tetra-O-benzylgluconolactone 3-26 gave C-arylglucosyl spiroketal nucleus 3-28 via nucleophilic

addition process, but the yield was very low (14% ) due to the formation of both unfavorable spiroketal 3-

29 and elimination product 3-30. However, if O-silyl protected aryllithium 3-31 was used as the

nucleophiles in the reaction, acyclic hydroxyl ketone 3-32 was formed as the major product. Although the

acyclic product do not cyclize to C-arylglucosyl spiroketals by exposure to hydrogen in the presence of

Pd(0)/C, desilylated acyclic hydroxyl ketones gave the desired spiroketal 3-33 as the only one

diastereomer.

O

OBn

BnOBnO BnO O

BnOBnO

OBnO

OBnO

MOMO

OMOM

BnOBnO

OHBnO

BnO

BnOBnO

OBnO O

BnO+

OMOM

MOMO

O

MOMO

OTBS

OMOM

HOHO

OHO

OHO

MOMO

OMOM

H2, Pd/C

+

LiLiO

OMOM

OMOM3-27

O

OBn

BnOBnO O

LiOTBS

OMOM

OMOM

3-26

3-32 3-33

3-28 3-29

3-30

+

3-31

(4)

Most strategies for the synthesis of the C-arylglucosyl spiroketal of Papulacandins nucleus

involve the sugar moiety as the electrophile and the aglycon as the nucleophile, except for Danishefsky’s

approach, which utilizes a hetero-Diels-Alder reaction to install a D-glucose moiety. However, the

194

nucleophilic addition of lithiated aryl reagents to D-gluconolactone is not a viable route due to the

formation of undesired sideproducts.

Schmidt used fully protected acyclic aldehyde 3-34 as the electrophile in the synthesis of C-aryl-

glucosides.102 He developed two different tactics and arylated 3-38 was used as a common intermediate.

Nucleophilic addition of lithiated aryl to 3-34 and methyl ester derivative 3-36 is better than addition to D-

gluconolactone. Hydrogenolytic debenzylation of 3-38 in the presence of Pd(0)/C and subsequent

acetylation directly led to the desired tricyclic spiroketal 3-39.

3-34

HOBn

O

OBn OBn

OBn OBn

HOOBn

O

OBn OBn

OBn OBn

MeOOBn

O

OBn OBn

OBn OBn

OBn

OH

OBn OBn

OBn OBnOBn

OBnBnO

OBn

OBn OBn

OBn OBnOBn

OBnBnO

AcO O

OAcO

AcO

OAcAcO

OAcO

3-35 3-36

3-37 3-38 3-39

(5)

CrO3

H2SO4

CH2N2

DMSO

Ac2O 1. H2, Pd/C

2. Ac2O, Py

An efficient new approach for the stereoselective construction of the spiroketal moiety of

Papulacandins has been reported by Carretero and his associates (Eq. 6).103 They used fully protected D-

arbino derivative 3-41 as an electrophile and α-lithiated β-phenylsulfonyldihydrofuran 3-40 as nucleophie.

The stereoselective formation of the 1,6-dioxaspiro[4.5]decane 3-42 was achieved by a tandem ring

opening-ring closing sequence, which was initiated by the addition of the lithiated furan to the arabino

derivative. The reduction of 3-42 stereoselectively installed a hydroxyl group at equatorial position by

hydride addition from less hindered face. The final phase of this strategy is reductive elimination of the

sulfonyl group by treatment of 3-43 with Na(Hg) in MeOH to give the desired spiroketal 3-44. Further

transformation to the core structure of the natural Papulacandins has not been performed at this stage.

195

3-40

O

SO2Ph

O

O

Si O

O

OTMStBu

+(1) BuLi

3-41

(2) 3-41(3) LiOH, H2O

OO

SiO

O

OTMS

PhO2S

tBu

tButBuO

NaBH4

OO

SiO

O

OTMS

PhO2S

tBu

tBu

Na(Hg)

Na2HPO4

MeOHOH

OO

SiO

O

OTMS

tBu

tBuOH

Si

OOtBu O

HO

OHO

tBu

3-42

3-43 3-44 3-45

(6)

Brimble reported104 that if O-lithiated benzoamides 3-46 are added to lactones 3-47 by a

nucleophilic addition process, the lactone ring may open to give a keto-alcohol like 3-48, which can be

used as a precursor of aryl spiroketals. The keto-alcohol 3-48 could be cyclized immediately to 3-49 by

exposure to catalytic amount of p-toluenesulfonic acid (p-TsOH). An alternative route for the

spiroketalization has also been developed by the same group. The intermediate phthalide 3-51 was

obtained by a chemoselective reduction-intramolecular ring closing sequence. The spiroketalization could

be achieved by iodosobenzene diacetate and iodine under a sunlamp. The photo-stimulated ring closing

process involves a sequence of single electron transfer (SET), 1,5 H-migration, one electron oxidation by

I2, and intramolecular cyclization.

NiPr2

O

O O+

OH

O

NiPr2

O

OH

OH

NiPr2

O

O

OH

O

O

O

OtBuLi

NaBH4

pTsOH

PhI(OAc)2/I2

3-46 3-47 3-48

3-50 3-51

3-49

pTsOH

(7)

196

Parker synthesized the C-arlyglycoside nucleus of Papulacandins by utilizing aromatization of

quinoles.105 She demonstrated that nucleophilic 1,2-addition of lithiated 3-53 to highly functionalized

quinone 3-54 gave derivative 3-55, which was subjected to reductive aromatization by Na2S2O4 in THF-

H2O solution. Further transformations were very tedious: protection of hydroxyl group by benzylation,

stereoselctive epoxidation from α-face, deprotection of the benzyl ether followed by spiroketalization, and

final protection of free hydroxyl group by triisopropylsilyl chloride.

AcOAcO

OAcO

3-52

Si

OO

OTIPSO

3-53

Si

OO

OTIPSO

3-55

OBnO

OBn

OH

(1) K2CO3

(2) tBu2Si(OTf)2

(3) TIPSCl

(1) nBuLi

O

O

OBn

BnO

(2)

Si

OO

OTIPSO

3-56

OBnBnO

OBn

(1) Na2S2O4

(2) BnBr (2) H2/Pd(C)(3) TIPSCl

Si

OO

O

OHO

TIPSO

OTIPS

3-57

TIPSO

(9)

(1) mCPBA

3-54

BF3 OEt2

Recently, O’Doherty reported106 that Sharpless asymmetric dihydroxylation of 5-vinylfuran-

derived from 3-58 by olefinatioon with unstabilized Wittig reagents gave 3-59, which was further subjected

to Achmatowicz oxidation for ring expansion and acid catalyzed spiroketalization to afford 3-60 (Eq.10).

Subsequently, Luche reduction and dihydroxylation was used to install hydroxyl groups at C4 and C2-C3

double bond, respectively, to give diastereomic mixtures of 3-62 with a ratio of 3:1. These could be

seperated by column chromatography. Because the configuration at C2 is reversed from the desired

equatorial position, a sequence of Dess-Martin oxidation, deprotection of pivaloyl ether, and stereoselective

reduction were required to complete the synthesis of the requisite C-arylglycosides.

197

3-58

OH

O

OTBS

OOH

OTBS

OPiv

Ph3P CH2(1)

(2) ADmix-α

NBS

OMe

MeO

OMe

MeO

TBSO O

O

MeO

OMe

OPiv

(3) PivCl

the 1M HCl

O

O

MeO

OMe

OPivO

(1) NaBH4

(2) TBSCl

TBSO O

O

MeO

OMe

OPiv

HO

HOOsO4 (1) TBSCl

(2) Dess-Martin

TBSO O

O

MeO

OMe

OPiv

TBSOO

TBSO O

O

MeO

OMe

OH

TBSOHO

(1) Dibal-H

(2) LiAlH4

3-59 3-60

3-61 3-62

3-63 3-64

(10)

The first transition metal catalyzed alkyne cyclotrimerization for C-aryglycoside synthesis was

reported by McDonald in 1995 (Eq. 11).107 Fully protected D- gluconolactone 3-65 was subjected to

nucleophilic addition by 2-(trimethylsilyl)ethynyllithium to afford an anomeric mixture of lactols, which

were further transformed to mixture of 3-66 by exposure to acetic anhydride/pyridine. The C-alkynyl-O-

propargyl substrate 3-67 was obtained by Lewis acid-catalyzed glycosylation of the anomeric acetate with

O-propargyl trimethylsilyl ether. After deprotection of the trimethylsilyl group by exposure to basic

aqueous hydroxide, cyclotrimerization of each anomer of diynes with saturated ethanolic solution of

acetylene gave the corresponding spirocyclic C-glycosides in the presence of Wilkinson’s catalyst

(ClRh(PPh3)3).

BnO OBnO

OBnO

BnO O

OBn

3-65

BnOBnO O

BnO O

OBn

BnOBnO

TMS

OAc

BnO O

OBn

BnOBnO

O

Li TMS(1)

(2) Ac2O

OTMS

SnCl4, AgClO4

TMSBnO O

OBn

BnOBnO

O

aq. NaOH

OBn

HC CH

ClRh(PPh3)3

3-66

3-67 3-68 3-69

(11)

198

The first total synthesis of the Papulacandin D was achieved by Barrett in 1995 (Scheme 3. 2).108

He reported that the addition of lithiated aryl precursor 3-71 to fully protected gluconolactone 3-70 gave 3-

72 as an intermediate. The gluconolactone was protected as silyl ethers to circumvent the formation of

elimination products commonly founded in the condensation of an aryllithium with protected

gluconolactone. Direct acidification resulted in partial desilylation and cyclization to afford the desired

spiroketal 3-73 as a single diastereomer. Under the resin mediated acidic condition (Amberlite IR-120), the

TBS and TMS groups could be discriminated from the TIPS groups, which are less acid sensitive. Before

coupling with fatty acid 3-75 by esterification, selective protection of the 4,6-diol unit of the tetrol 3-73 are

required to achieve the O-3-ester selectivly. The last phase to complete the total synthesis was the

esterification of the spiroketal 3-74 with anhydride 3-75 followed by global deprotection by treatment of

tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF).

During the last decade extensive studies on the synthesis of Papulacandin family have been done,

but only one total synthesis has been successfully achieved by Barrett (Scheme 3. 1). The strategies for the

construction of C-arylglycoside nucleus of Papulacandin, which has a spiroketal form as a key component,

can be classified into five sub-groups: a) hetero-Diels-Alder reaction, b) palladium-catalyzed coupling of

stannyl glucal with an aryl halide, c) rhodium-catalyzed alkyne cyclotrimerization, d) condensation of an

aryl lithium with protected gluconolactone, and e) condensation of aryl lithium with fully protected acyclic

precursors. Even though a number of strategies to construct C-arlyglycoside nucleus of the Papulacandins

and total synthesis of the Papulacandin D have been reported, there is still room for further investigations

of this area. The tandem bifunctionalization-cycliztion of diynes mediated by stannane-silane reagents

(R3Sn-SiR’3) developed in our laboratory could be broadly applicable strategy for the synthesis of C-

arlyglycoside.

199

TMSO O

3-70

TMSOTMSO O

iPr3SiO OSiiPr3

OSitBuMe2

Br+TMSO O

TMSOTMSO

OTBS

TMSOTMSO OTIPSTIPSO

Li

HO OHO

OHO

OH

3-73

TIPSO

OTIPS

Si

OOtBu2 O

HO

OHO

TIPSO

OTIPS

tBuLiAmberlite IR-120

MeOH

tBu2

tBu2Si(OTf)2

3-71 3-72

3-74

Me

Me Me

OSiEt3

O

O O Cl

ClCl

Si

OOtBu2 OO

OHO

TIPSO

OTIPS

tBu2

O

MeMeMe

OSiEt3

+

DMAP

Si

OOtBu2 O

HO

OHO

TIPSO

OTIPS

tBu2

O

MeMeMe

OSiEt3

+

TASF

HO OO

OHO

TIPSO

OTIPS

O

MeMeMe

OH

3-75

3-76 3-77

3-78

Papulacandin D

OH

Scheme 3. 1. Total Synthesis of Papulacandin D.

200

3. 2. Retrosynthesis of Papulacandin D and Preparation of Diynes

The retrosynthesis of Papulacndin D is shown in the Scheme 3. 3.109 The molecule can be divided

into two parts: one is a C-arylglycoside nucleus 3-79 with 5-membered spiroketal and a 1,3-dihydroxyl-

benzene ring, and the other is a fatty acid 3-84 with 16 linear carbon chain. The total synthesis of the

Papulacandin D can achieved by chemoselective O-3 esterification of the C-arylglycoside 3-79 using the

fatty acid 3-84. The C-arylglycoside nucleus could be made from the spiroketal, 3-80, by Tamao-Fleming

oxidation followed by oxidative aromatization. The spiroketal 3-80 may be synthesized by regioselective

Diels-Alder reaction with 1,4-bifunctionalized (Z,Z)-1,3-diene 3-81. At this phase we can apply the

palladium catalyzed tandem bis-functionalization-cyclization of diynes to prepare the 1,3-dienes. The

preparation of C-alkynyl-O-propargyl substrate 3-82 could be efficiently achieved by the modification of

known procedure with fully protected tetra-benzyl D-glucose 3-83 in five steps.

O

OH

HOO OH

O

OH

HO

O

OH

CH3 CH3

Papulacandin D -O2C

NH3+

O

OBn

BnOBnO BnO

O

OH

HO

O

OBn

BnOBnO BnO

O

O

OBn

BnOBnO BnO

OX

Y

SiR 3

O

OBn

BnOBnO BnO OH

HO

O

CH3

OH

CH3 CH3

OH

CH3

3-78

3-79 3-80

3-823-83

3-84 3-85

3-87

O

OBn

BnOBnO BnO

O3-81

SnR'3SiR3

D-Glucose

OCH3 CH3

3-86

Isoleucine

Scheme 3. 2. Retrosynthesis of Papulacandin D

201

The synthesis of fatty acid 3-84 from isoleucine 3-87 has been documented by Barrett. The

isoleucine could be converted to the intermediate alkynol 3-85 by a sequence of double Wittig reaction and

propargylation. Separation of C7 epimers of 3-85 can be done successfully by kinetic resolution via

Sharpless epoxidation.

For the synthesis of C-arylglycoside nucleus of Papulacandin D via palladium catalyzed

bifunctionalization-cyclization sequence, we prepared 2-propynyl 1-C-ethynyl-2,3,4,6-tetra-O-benzyl-D-

glucopyranoside 3-82, which was made from commercially available 2,3,4,6-tetra-O-benzyl-D-

gluconopyranose 3-83. The gluconopyranose 3-83 was converted to δ-gluconolactone 3-88 by modified

Swern oxidation in large scale in 72% yield. The lactone can be used as a precursor in two synthetic routes

we explored for the preparation of diyne 3-82. First, the δ-gluconolactone was treated with trimethylsilyl

acetylene and n-butyllithium in THF at -78 oC. The reaction was completed within 2 h and all of the

lactone 3-88 was consumed (by TLC analysis). After work-up with a buffer solution, only two spots were

found on the TLC, but 1H NMR spectrum analysis implied that three acetylenes were present in the crude

mixture. Even though the α/β anomeric mixture (probably with one more acetylene isomer) has a small

difference of Rf value on TLC, we failed to isolate the pure compounds by column chromatograpy. Based

on the 1H NMR peaks, the ratio of three acetylenes was 0.41:1.00:0.89. At this stage we could not assign

configuration of the mixture, but we may assume that the last two acetylenes are the desired diynes with a

major α-anomer.

The mixture of three isomers 3-89 was subjected to further reaction with 3-

trimethylsilyl-2-propyn-1-ol with Montmorillonite K 10 in dichloromethane at rt. The O-

alkylation was very fast and all starting material disappeared as estimated by TLC after 2

h. The TLC analysis of the crude mixture was very clean and only one major spot was

observed with small amount of 3-trimethylsilyl-2-propyn-1-ol. However, the crude

mixture was still contaminated with an unidentified acetylene isomer. Based on 1H NMR

analysis the proportion of acetylenes was 0.24:1.00:0.56. Gratifyingly, we could isolate

202

the α-anomer as a pure form but the isolated β anomer was contaminated with 17% α-

anomer after column chromatography.

O

OBn

BnOBnO

BnO OH

O

OBn

BnOBnO

BnO O

O

OBn

BnOBnO

BnOOH

O

OBn

BnOBnO

BnOOH

TMSO

OBn

BnOBnO

BnOO

TMS

TMS

O

OBn

BnOBnO

BnOO

TMS

O

OBn

BnOBnO BnO

O

3-83 3-88 3-91 3-92

3-823-903-89

a e f

gb

c d

Scheme 3. 3. Preparation of Diyne 3-82: (a) (CF3CO)2O, DMSO, CH2Cl2, -78 oC to -40 oC, 72%; (b) TMS-

C≡CH, nBuLi, THF, -78 oC, 73%; (c) TMS-C≡C-CH2OH, Montmorillonite K 10, CH2Cl2, rt, 98%; (d) 50%

aqueous NaOH, BnNEt3Cl, CH2Cl2/CH3CN, 0 oC to rt, 99%; (e) CH≡C-Li•EDA, THF, -78 oC, 91%; (f)

TMS-C≡C-CH2OH, Montmorillonite K 10, CH2Cl2, rt, 88%; (g) 50% aqueous NaOH, BnNEt3Cl,

CH2Cl2/CH3CN, 0 oC to rt, 87% (85% from 3-90).

Although the major portion of isolated products was still two anomeric mixtures which can be

separated by column chromatography, we did not try further purification due to the difficuty in the

separation, The anomeric mixture of 3-90 could be easily desilylated by exposure to 50% solution of

sodium hydroxide in a mixture of dichloromethane and acetonitrile (1:1) at 0 oC to rt in 30 min. To make a

homogeneous solution small amount of benzyltriethylammonium chloride was added as a phase transfer

reagent. After aqueous work-up of the mixture, the two anomers could be separated on TLC although they

have a small difference in Rf values. Although the isolated β-anomer was contaminated with small amount

(<5%) of unknown compound, the α-anomer was isolated as a pure solid. The optical rotation value of the

α-anomer is [α]D20

= +21.0 (c 0.61 in CHCl3) and the 1H NMR spectrum was exactly in agreement with the

203

results reported by McDonald. Although we may assign tentatively the major portion as an α-anomer

based on the anomeric effect, McDonald did not determined its absolute configuration and our efforts were

not successful either (1H NMR, 13CNMR, COSY, and 1D nOe NMR anlysis) at this stage. However, the

absolute configuration of 3-82 may be deduced from the absolute configuration of silastannylated

compounds, which were unambiguously assigned by COSY and 1D nOe NMR experiments.

To suppress the formation of undesired byproducts, another route has been developed by using

lithiumacetylide diethylamine complex instead of trimethylsilyl acetylene/n-butyllithium. Because a

nucleophilic addition of lithium acetylide diamine complex to D-gluconolactone 3-88 in THF at -78 oC gave

a complex mixture to afford low isolated yield of 3-92, a mixture of D-gluconolactone 3-88 in THF had to

be added to lithiumacetylide complex at -78 oC. Although only one spot was observed on TLC, complex

peaks between 2.53-2.73 ppm in 1H NMR spectrum suggested that the mixture involves at least five

acetylene containing products. If we performed O-alkylation with the crude mixture and 3-trimethylsilyl-2-

propyn-1-ol in the presence of Montmorillite K10, the expected C-alkynyl-O-propagy substrate 3-93 was

not made and the alkyneol 3-92 was recovered in 35% yield after column chromatography. Gratifyingly,

we prepared the O-alkylated product 3-93 in 88% yield after a simple filtration of the reaction mixture

through a short column (91% yield). The isolated C-alkynyl-O-propagyl substrate 3-93 was an

α/β anomeric mixture with a ratio of 0.68/0.32. The purified 3-93 could be easily desilylated under basic

conditions with catalytic amount of phase transfer reagent to afford 2-propynyl 1-C-ethynyl-2,3,4,6-tetra-

O-benzyl-D-glucopyranoside 3-92 in 87% yield. Because the TMS group can decompose easily during the

column chromatography, we performed the propagylation and desilanylation without purification in one

sequence. The α/β anomers of diyne 3-82 were successfully isolated in pure forms and the isolated yield

was 85% (from 3-92) by column chromatography.

204

3. 3. Palladium Catalyzed Silastannylation of Diynes

With a gram quantities of pure α-anomers and slightly contaminated β-anomers (less than 5% of

an unknown compound) of C-alkynyl-O-propargyl substrate 3-82 in our hands, a tandem silastannylation-

cyclization was performed with Bu3Sn-SiMe2Ph under various conditions in an NMR tube in 0.05mmol

scale.

First, we explored the reaction under the optimized condition, which was developed in our

laboratory (5 mol% of Pd2(dba)3•CHCl3, 10 mol% of (C6F5)3P, benzene, and 80 oC). After 10 h, we

observed three new spots on TLC plate, and two of those decreased smoothly with prolonged reaction time

while the other spot increased. The same results were also observed in 1H NMR spectra analysis.

Gratifyingly, the crude mixture could be isolated easily by column chromatography eluting with non-polar

eluent (hexanr:EtOAc = 40:1) to give three cyclized compounds. The most and second non-polar

compounds were assigned structure 3-93 and 3-94, respectively.

O

OBn

BnOBnO BnO

O

Bu3SnSiMe2Ph

Pd(0) or Pd(2+)

O

OBn

BnOBnO BnO

O

SnBu3

SiMe2Ph

+

H

HH

H

O

OBn

BnOBnO BnO

O

SiMe2PhSnBu3

H

HH

H

H

3-82 3-93 3-94

(12)

H

24

6

7

8

24

6

7

8

9 9

The configuration was unambiguously determined by COSY and 1D nOe NMR spectra. The stannane

substituted vinyl hydrogen of the bifunctionalized cyclic compounds can be easily confirmed by observing

a singlet peak with two small sidepeaks originating from 117Sn/119Sn coupling at down filed (5.94 ppm, JSn-

H = 39.5 for 3-93 and 6.38 ppm, JSn-H = 40.1 for 3-94 in C6D6), while silane substituted vinyl hydrogen

peaks of 3-93 and 3-94 were observed as a singlets at δ 6.06 and 5.56 ppm, respectively. The assignment of

the configuration was confirmed by COSY and 1D nOe experiments. For example, if we irradiated the

silane substituted vinyl hydrogen H9 3-93, the frequency for the H2 peak was enhanced, while the

irradiation of stannane substituted vinyl hydrogen H8 enhanced H7a and H7b peaks (H9→ H2, 4.1%; H8→

H7a, 1.1%; H8→ H7b, 1.3%). In sharp contrast to the results, irradiation of the silane substituted vinyl

205

O

OBn

BnOBnO BnO

O

SnBu3

SiMe2PhH

HH

H

HnOe

nOe

nOe

4.1%

1.3%, 1.1%3-93

24

6

7

8

9


H2 → H4 2.2 H5 → H6a 2.1 H8 → H7b 1.3 H9 → SiMe2 1.5

H2 → H9 4.5 H5 → H6b 2.3 H9 → H2 4.1

H4 → H2 1.9 H8 → H7a 1.1 H9 → SiPh 1.4

Figure 3. 2. Representative nOe Results for 3-93.

O

OBn

BnOBnO

BnOO

SiMe2PhSnBu3

H

HH

H

HnOe

nOe

nOe

4.5%

1.2%, 0.9%3-94

2

4 6

8

9


H7a → H7b 13.4 H7b → H8 0.8 H8 → SiMe2 0.7

H7a → H8 1.8 H8 → H7a 1.2 H9 → H2 4.5

H7b → H7a 11.1 H8 → H7b 0.9


206

hydrogen of 3-94 increased H7a and H7b peaks and irradiation of stannane substituted vinyl hydrogen

increased H9 peak. More comprehensive results for the nOe experiment are shown in Figure 3.2 and 3.3.

Unfortunately, we failed to assign unambiguously the configuration for the most polar product in

spite of extensive NMR study. However, the absence of a singlet peak coupled with Sn and two peaks at

high field (s, 5.83 ppm and d, J= 0.7Hz, 5.37ppm) may imply the cyclized compound 3-93 and 3-94 may be

coupled together to afford a dimerized product. The analysis of 13C NMR spectrum showed the chemical

shift pattern of the new compound is very similar to 3-93 or 3-94 except for absence of SnBu3 group. The

1H and 13C NMR spectra showed the dimeric compound is not a single isomer. The molecular weight of

the compound was determined by high resolution mass spectrometer to give M+ = 1476, which is the

exactly same with dimeric compound 3-95. Because the NMR spectrum is complex we did not make any

attempt to assign the absolute configuration of the dimmer (tentative configurations of the dimeric products

are shown in Figure 3.4) .

3-99

O

OBn

BnOBnO BnO

O

PhMe2Si

O

OBn

BnOBnO BnO

O

SiMe2PhH H

H

H

H

H H

H

H

H

3-95

O

OBnBnO

BnO

BnOO

SiMe2Ph

H

H

H

OOBn

BnOBnOBnO

O

SiMe2PhH

HH

H

H

Figure 3. 4. Tentative Configuration of Dimeric Product 3-95 and 3-99.

Once we had pure silylstannylated product 3-93 and 3-94 as well as the NMR spectra, a number of

complex of Pd (0) and Pd (II) were used as catalysts in the silastanylative cyclization of C-alkynyl-O-

propargy substrate 3-92 with Bu3Sn-SiMe2Ph, and the results are shown in Table 3.1. First, We examined

207

the reaction in the presence of Pd2(dba)3•CHCl3 because RajanBabu and Warren reported that this

palladium catalyst is the best for the R3Si-R3Sn’-mediated cyclization of 1,6-diynes. As Warren described

in her dissertation we performed the reaction with (C6F5)3P at 80 oC. Because the reaction is very fast at

that temperature, we could not avoid the formation of dimeric product 3-95 in this case (Entry 1). The

reaction was also performed at 60 oC and 40 oC, respectively. However, all silastannylative cyclic products

3-93 and 3-94 were converted to the dimeric product 3-95 in prolonged reaction time at 60 oC (Entry 2).

Although the formation of the dimeric product was suppressed at 40 oC, the dimeric product 3-95 was still

obtained as a byproduct (Entry 3). Fortunately, the tandem silastannylation-cyclization proceeds smoothly

at rt without the formation of the dimeric products. All C-alkynyl-O-propargyl substrate was consumed

within 3 h and only the cyclic product 3-93 and 3-94 were isolated in 87% yield with a ratio of 1.7/1.0 by

column chromatography (Entry 4). It has to be pointed out that because the Sn-Si mediated

bifunctionalization is extremely fast, the dimeric products can be made even at rt by exposure to prolonged

reaction time (10 h). We also performed the reaction without any phophine ligand (Entry 6). Surprisingly

the silystanylative cyclization proceeded smoothly to afford 3-93 and 3-94 in a reasonably good yield

without changing the ratio of 3-93 and 3-94. Although the reaction may go to completion to afford good

yield of cyclic product in the presence of Pd2(dba)3•CHCl3 , there is still room for further investigation in

terms of isolated yield of 3-93 and 3-94 as well as the ratio of 3-93/3-94.

After extensive search for various catalysts, we found that [Pd(allyl)Cl]2 and [Pd(1,3-di-

phenylallyl)Cl]2 are excellent catalysts for the reaction, but some dimeric product was still formed (Entry

16 and 17). Fortunately, the dimeric product was not formed at all with other Pd (II) catalysts such as

Pd(OAc)2 , PdCl2(NH3)2 , PdCl2 •2NaCl, PdCl2(CH3CN)2, and PdCl2(PhCN)2 . Although most these

catalysts are excellent for silastannylations, the reaction with PdCl2 •2NaCl or Pd(OAc)2 ) is relatively slow

(entry 16 and 17) and the reaction with PdCl2(CH3CN)2) gave slightly decreased the isolated yields of the

cyclic product (Entry 7). We found that the PdCl2(PhCN)2 is a catalyst comparable to Pd2(dba)3•CHCl3 in

terms of reaction time as well as the ratio of monomer/dimmer and isolated yield. Although Pd(PPh3)4 is an

excellent catalyst for the silastannylative cyclic reaction, the catalyst is less efficient than Pd2(dba)3•CHCl3

208

Conditions Ratio

Entry Pd Phosphine Temp Time

Yield (%) 3-93 3-94 3-95 (?)

1 Pd2(dba)3•CHCl3 (C6F5)3P 80 oC 10h 76 0.93 1.0 2.6

2 60 oC 36h 68 1.0

3 40 oC 10h 78 1.8 1.0 2.5

4 rt 3h 87 1.7 1.0

5 rt 10h 98 1.5 1.0 1.0

6 NO

phosphine

rt 2h 65 1.7 1.0

7 PdCl2(CH3CN)2 (C6F5)3P rt 3h 73 1.8 1.0

8 PdCl2(PhCN)2 (C6F5)3P rt 3h 85 1.7 1.0

9 Pd(PPh3)4 (C6F5)3P rt 11h 79 1.6 1.0

10 PdCl2 •2NaCl (C6F5)3P rt 8h 79 1.6 1.0

11 Pd(NH3)2(NO2)2 (C6F5)3P 60 oC 10h 1.8 1.0 0.6

12 18h 1.4 1.0 2.4

13 40h 68 1.0

14 PdCl2(NH3)2 (C6F5)3P 60 oC 16h 86 1.0 14.8

15 Pd(OAc)2 (C6F5)3P rt 8h 87 1.7 1.0

16 [Pd(allyl)Cl]2 (C6F5)3P rt 3h 83 1.8 1.0 0.7

17 [Pd(1,3-di-

phenylallyl)Cl]2

(C6F5)3P rt 3h 84 1.7 1.0 0.3

18 Pd(OH)2/C (C6F5)3P 60 oC 3.5h 99 1.8 1.0 0.7

Table 3.1. The summary of Cyclization with a Variety of Pd (0) and Pd (II).

209

(Entry 9). Finally, we ran the reaction in the presence of palladium amine complex, but found the catalysts

are less efficient than other palladium catalysts in terms of reactivity and regioselectivity (Entry 11 to 14).

Initially, we used tris-(pentafluorophenyl)phosphine as a ligand in the palladium catalyzed

silastanylation of asymmetrical diynes 3-92, and the silystannylated cyclic product was obtained as a

mixture of two regioisomers 3-93 and 3-94 with a ratio of 1.4/1.0 - 1.8/1.0 depending on the palladium

catalysts (Table 3.1). To improve the ratio of the major product, we decided to explore various phosphine

ligands in the presence of Pd2(dba)3•CHCl3, and the results are in Table 3.2. First, we were attracted to

two chiral phosphine ligands, (2S,4S)-tert-butoxycarbonyl-4-diphenylphosphino-2-

(diphenylphophinomethyl)-pyrrolidine and (R)-BINAP. When the chiral ligands and of Pd2(dba)3•CHCl3

were used in the reaction, the bifunctionalized cyclization required high temperature (60 oC ) as well as

prolonged reaction time due to the increased number of phospine per palladium catalysts (Entry 2 and 3).

Moreover, the ratio of 3-93/3-94 decreased to 1.4 and 0.7, respectively. Because increased number of

phospine ligands per metal leads to retardation of the cyclization, we chose simple phosphine ligands such

as tributylphosphine and tri-tert-butylphosphine. For example, when we used tPBu3 as a ligand, the reaction

did not proceed at all at rt and all C-alkynyl-O-propagyl compound 3-92 decomposed at 60 oC (Entry 4).

Although the silastannylative cyclization proceed well with tributylphosphine in the presence of

Pd2(dba)3•CHCl3, we could not observe any improvement of the 3-93/3-94 ratio (>90% yield in NMR, 58%

isolated yield, Entry 5).

In terms of either the reactivity of dialkynes or selectivity, all phosphine ligands we exaimined are

less effective than (C6F5)3P except for (2,4,6-trimethylphenyl)phospine. When we used (2,4,6-

trimethylphenyl)phospine as a ligand in the R3Si-Sn’3-mediated cyclization of asymmetric 1,6-diynes, the

bifunctionalization/cyclization proceeded at rt without any difficulty to afford 3-93/3-94 in 63% yield (95%

based on 1H NMR) with a ratio of 2.2/1.0. It has to be pointed out that the palladium catalyzed

silastannylation/ cyclization proceeds very efficiently even without any phospine ligans at rt, and the yield

and ratio of 3-93/3-94 are acceptable (see Table 3.1).

Once we optimized the reaction conditions, we performed the palladium catalyzed silastanylation/

cyclization with 3-96 with/without phosphine ligands. Although the previous studies on the silastanylation/

210

Conditions Ratio


Yield (%) 3-93 3-94 3-95

1 Pd2(dba)3

•CHCl3

(C6F5)3P rt 3h 87% 1.7 1.0

rt 3h NR 2

N

Ph2P

PPh2

OtBuO

60 oC 2.5h 59% 1.4 1.0 0.6

rt 3h NR

60 oC 2.5 NR

60 oC 24h 35% 0.7 1.0 1.3

3

PPh2

PPh2

60 oC 40h 1.0

rt 2h NR 4 P tBu3

60 oC 3h Decomp.

5 P nBu3 rt 3h 58 (>90%) 1.8 1.0

rt 2h (<7%) 1.2 1.0

rt 6h (<20%) 1.3 1.0

6 P(o-Tol)3

60 oC 2h 73%

rt 2h NR 7 P(p-MeO-C6H4)3

60 oC 10h 7% 1.0

rt 2h NR 8 PCy3

60 oC 3h Decomp.

rt 3h (<4%) 1.3 1.0 1.51 9 PPh3

60 oC 2.5h 67% 1.4 1.0 1.5

Continued

Table 3. 2. The Summary of Cyclization with a Variety of Phosphine Ligands.

211


Conditions Ratio


Yield (%) 3-93 3-94 3-95

rt 3h NR

60 oC 3.5h NR

10 P(OPh)3

60 oC 24h 48% (>85%) 1.2 1.0 7.0

rt 6h NR 11 Pd2(dba)3

•CHCl3 O P

3 60 oC 18h 56% 1.5 1.0

12

3

P

rt 2h 63% (>95%) 2.2 1.0

13 (o-MeO-

C6H5)PPh2

29%

14 DPPP Decomp.

15 DIPHOS Decomp.

16 (S,S)-

CHIRAPHOS

Decomp.

17 NO ligand rt 2h 65 (>95%) 1.7 1.0

212

cyclization with 3-92 implied that Pd2(dba)3•CHCl3 is a slightly more efficient catalyst than PdCl2(PhCN)2,

we used Pd (II) in this exploratory reaction. First, the reaction was examined with the standard phophine

ligand, (C6F5)3P, at 60 oC. As described in earlier (Table 3.1), the asymmetric diynes 3-96 might cyclize in

the presence of palladium catalyst to afford 3-97 and 3-98, which may further be dimerized to 3-99 by

heating (Eq. 13). The reaction could be easily followed by 1H NMR as well as TLC.

O

OBn

BnOBnO BnO

OBu3SnSiMe2Ph

Pd(0) or Pd(2+)

O

OBn

BnOBnO BnO

O +

H

PhMe2SiSnBu3

O

OBn

BnOBnO BnO

O

H

Bu3SnSiMe2Ph

H H

H

H

H

H H

H

H

H

3-96 3-97 3-98

(13)2

3

5

6

7

8

9

23

5

6

7

8

9

If the reaction is performed at rt without phosphine ligand, the formation of the dimeric compound

might be suppressed completely and only desired products 3-97 and 3-98 were observed by TLC analysis.

The isolated yield of the product was 67% and the ratio of 3-97/3-98 was 1.2/1.0 after column

chromatography. If the reaction mixture was stirred for the prolonged reaction time (5 h), the isolated yield

of 3-97/3-98 slightly decreased, while the ratio of 3-97/3-98 increased up to 1.5/1.0. Because we could

prepare the bifunctionalized product 3-97/3-98 in a gram scale, we did not further try to improve the

isolated yield and/or ratio of 3-97/3-98.

The configuration of the cyclized compounds was unambiguously assigned by 2D COSY and 1D

nOe experiments like described in the assignment of 3-93 and 3-94, and the results are shown in Figure 3.5

and 3.6. Two vinyl proton peaks of in 3-96 or 3-97 can be distinguished easily by observing the side bands

due to 117Sn/119Sn coupling, and all other protons are assigned based on coupling constant, coupling pattern,

chemical shift, and COSY NMR data. Once each proton was assigned without any doubt, the assignment

of the structure was refined by 1D nOe spectra. For example, if we irradiated frequency corresponding to

H9 of 3-96, a strong enhancement of H3 peak was observed. Irradiation of stannane substituted vinyl

213

3-96

O

OBn

BnOBnO BnO

O

H

nOe

PhMe2SiSnBu3

H H

H

H

H

6.4%8.3%

2.3%

2

3

5

6

7

8

9


H3 → H9 8.3 H6b → H5 3.6 H8 → H7b 0.2

H5 → H9 1.3 H6b → H6a 13.5 H8 → SiMe2 1.50

H6a → H6b 14.5 H8 → H7a 2.3 H9 → H3 6.4


nOe

O

OBn

BnOBnO BnO

O

H

Bu3SnSiMe2Ph

H H

H

H

H

7.3%

8.9% 1.7%, 1.3%

3-97

2

35

6

7

8

9


H3 → H6 4.8 H5 → H6 8.6 H8 → H7 1.7, 1.3

H3 → H9 8.9 H6 → H9 1.1 H9 → H3 7.3


214

hydrogen (H8) might increase the H7a peak. Similar results were observed in the nOe experiment of 3-97.

We observed a strong enhancement of H3 peak by irradiation of H9 peak (or vice versa) as well as some

interaction between H7 and H8 in 3-97.

Conditions Ratio


Yield

(%) 3-97 3-98 3-99(?)

1 PdCl2(PhCN)2 (C6F5)3P 60 oC 36h 39 1.0 6.4

2 NO rt 5h 53 1.5 1.0

3 NO rt 1.5h 67 1.2 1.0

Table 3. 3. The Summary of the Reaction with 3-95 and Pd(II).

3. 4. Nickel and Rhodium Catalyzed Silastannylation of Diynes

Although Pd (0) and Pd (II) are very efficient catalysts for the silastanylation/cyclization of diynes

3-92 with Bu3Sn-SiMe2Ph, it is still worth investigating the effects of other transition metals such as Ni or

Rh in this novel reaction. Thus, we decided to investigate the reaction with a series of Rh and Ni catalysts

under our optimized condition, and the results are summarized in Table 3.4. First, we chose NiCl2 to

explore the silastannylative cyclization without phosphine ligand. After the reaction mixture was heated at

60 oC for 24 h, no change was observed either on TLC or in NMR spectrum and all starting diyne 3-92 was

recovered quantitatively (Entry 1). Although the reaction was performed with a phospine ligand ((C6F5)3P)

at 60 oC, the ligand did not effect the reaction at all and all starting material was recovered quantitatively.

Next, we examined Ni(acac)2 as the transition metal catalyst with/without phosphine ligand (C6F5)3P in the

Sn-Si mediated bifucntionalization/cyclization, but the same results were obtained as the above. However,

we found that the starting material 3-92 smoothly converted to a new compound upon heating at 60 oC.

215

After 24 hr, we judged >36% of 3-92 was converted to the new product and all remaining was the starting

diynes.

Although the new product was isolated easily by column chromatography, the isolated compound

was a mixture of two isomers based on 1H NMR spectrum. The ratio of two product distribution (0.45/0.55)

may be judged by two different singlet peaks at δ 2.57 ppm and 2.52 ppm. These peaks may imply each

product have an sp3 hydrogen. The acetylene carbon is further proved by observing two peaks at δ 68.68

and δ 68.56 in 13C NMR and weak peak at ~2100 cm-1 in IR spectrum. Two doublet of doublets (δ 6.76

ppm, J = 7.7, 1.1 Hz and δ 6.72 ppm, J = 7.7, 1.4 Hz) with a different ratio (0.45/0.55) prove each product

may have at least one sp2 hydrogen with cis configuration. Because of heavy overlap between δ 3.6 and 5.2

ppm in 1H NMR spectrum, it is difficult to assign the exact configuration of the isomers. High resolution

mass spectrum shows M+ + Na is 1227.5149, which exactly matches the molecular weight of a dimmeric

product of the C-alkynyl-O-propargy substrate 3-92 within 7 ppm (calculated mass for M+ + Na is

1227.5234). Based on these information we postulate that the starting material 3-92 may have dimerized to

3-100 and/or 3-101 in the presence of (Ph3P)2NiCl2 (Entry 3). When we used another phospine bounded Ni

complex, NICl2dppp, at 60 oC, similar results were observed (Entry 4).

3-100

OOBn

BnOBnO BnO

OO

BnOOBnOBn

OBnO

O

OBn

BnOBnO BnO

O

O BnO

OBnOBn

BnOO

3-101

Figure 3. 7. Tentative Configuration of Dimeric Product 3-100 and 3-101.

216

Rh catalysts also were explored for the silastannylative cyclization of 1,6-diynes 3-92 with Bu3Sn-

SiMe2Ph. As shown in the previous Ni catalyzed reaction, only the formation of dimeric products was

observed in TLC and/or 1H NMR analysis. It has to be pointed out that the dimeric reaction in the presence

of Rh catalysts is much milder than in the presence of Ni catalysts. For example, if we used RhCl(PPh3)3 as

the transition metal catalyst in the reaction, all starting 1,6-diynes 3-92 was converted at rt within 24 h to

afford the dimeric mixture in 75% isolated yield.


Entry M Phosphine Temp Time 3-92 3-100/3-101

1 NiCl2 60 oC 24h >99

2 (C6F5)3P 60 oC 24h >99

3 Ni(acac)2 60 oC 24h >99

4 (C6F5)3P 60 oC 24h >99

5 (Ph3P)2NiCl2 60 oC 24h 63 36

6 NICl2dppp 60 oC 24h 64 35

7 [Rh(COD)Cl]2 rt 24h 47

8 RhCl(PPh3)3 rt 24h 75

9 [Rh(PPh3)Cl]2 60 oC 24h 23 36 (>50)

10 Rh(COD)(acac) 60 oC 24h 23

11 RhCl3•H2O 60 oC 24h >99

Table 3. 4. The Summary of Cyclization with a Variety of Metal Catalysts.

217

3. 5. Dynamic NMR Studies of Silastanylated 1,3-Dienes, 3-93 and 3-94

Palladium catalyzed silastanylative cyclization of 1,6-diynes affords 1,4-disubstituted (Z,Z)-1,3-

dienes, which exhibit an axial chirality due to restricted rotation around a single bond. RajanBabu and

Warren observed rapid equilibration between the two helical forms 3-102 and 3-103 at rt without regard to

the size of stannane and silane substitutents (Figure 3.8). However, the fluxional 3-102/3-103 can be

frozen at low temperature, and the rate of enantiomerization depends on the Si and Sn. At the low

temperature, the coalescence temperature and kinetic parameters such as ∆H‡, ∆S‡, and ∆G‡, can be

determined by line shape analysis with variable temperature NMR (VT NMR) techniques. They also

reported that the atropisomerism can be commonly observed in carbocyclic and heterocyclic silistanyl 1,3-

dienes at the corresponding cosalescence temperatures.

3-102

SiR'3R3Sn SiR'3R3Sn

Tc

3-103

CO2MeMeO2C CO2MeMeO2C

R R' Tc

Bu

Bu

Bu

Ph

Ph

Me

Et

t-BuMe2

t-BuMe2

i-Pr

10

20

20

20

-10

3-104

X

SiMe3Bu3Sn

X

SiMe3Bu3Sn

Tc

3-105

X Tc

N-Ts

NCHPhMe

C(CO2Me)2

CH(CO2Me)

-40 oC

-60 oC

+10 oC

-20 oC

Figure 3. 8. Coalescence Temperature for Enantiomerization of Various Silystanyl Dienes.

218

O

OBn

BnOBnO BnO

O

H

H

3-93a (RA)H

O

OBn

BnOBnO BnO

O

H

H

H

H

SnBu3

SiMe2PhO

OBn

BnOBnO BnO

O

H

H

3-93b (SA)H

SnBu3

SiMe2PhTc > ?

O

OBn

BnOBnO BnO

O

H

H

3-94a (RA)H

SiMe2Ph

SnBu3

O

OBn

BnOBnO BnO

O

H

H

3-94b (SA)H

SiMe2Ph

SnBu3Tc > ?

Bu3Sn SiMe2Ph

O

OBn

BnOBnO BnO

O

H

H

H

H

Bu3Sn SiMe2Ph

3-97a (SA) 3-97b (RA)

Tc > ?

O

OBn

BnOBnO BnO

O

H

H

H

H

PhMe2Si SnBu3

O

OBn

BnOBnO BnO

O

H

H

H

H

PhMe2Si SnBu3

3-98a (SA) 3-98b (RA)

Tc > ?

Figure 3. 9. Possible Isomers of Glucosides 3-93, 3-94, 3-97, and 3-98.

All possible atropisomeric isomers of Sn-Si mediated cyclic adducts are shown in Figure 3.9. Pairs

of 3-93a/3-94a and 3-93b/3-94b are regioisomeric so are 3-97a/3-98a and 3-97b/3-98b, while pairs of 3-

93a/3-93b, 3-94a/3-94b, 3-97a/3-97b, and 3-98a/3-98b are diastereomeric as a result of axial chirality.

Each of these regioisomers can be isolated relatively easily by column chromatography, but their

atropisomeric isomers, if it is possible, cannot be isolated at rt because (i) either the conversion between

219

two atropisomers are very fast at rt or (ii) only one isomer is formed, and no separation is needed. Previous

research on 1,4-disubstituted (Z,Z)-1,3-dienes in our laboratory demonstrates that the (Z,Z)-1,3-dienes can

be freely inter-converting above coalescence temperature (Tc) (see Figure 3.8). However, the axially chiral

diastereomers (for example, 3-102 and 3-103) may be frozen below the corresponding coalescence

temperature and these diastereomers can be easily identified by VT NMR experiments.

To determined fluxional nature of 3-93, 3-94, 3-97, and 3-98, we investigated the variable

temperature NMR in the rage of +70 oC to -70 oC and the results are shown in Figure 3.9 - 3.16. First, the

spectra of 3-93 were taken from 20 oC to -60 oC in CD2Cl2, but surprisingly, we could not observe any new

peaks in the VT NMR spectra. The singlet peak of SiMe2Ph (δ 0.42 ppm in 1H NMR at 20 oC) split into

two singlet peaks at 0 oC; but the observation may not support atropisomerism of 3-93 because two methyl

groups in dimethylphenylsilane (DMPS) ether can be separated at rt in 1H NMR because they are

diastereotopic. Moreover, we could not observe any splitting of other hydrogen peaks. Two vinyl proton

peaks became broaden upon lowering the temperature, but splitting was not observed at the temperatures

we examined. To investigate the atropisomerizam at high temperature, we used C6D6 as the NMR solvent.

Interestingly, the chemical shifts of stannane substituted vinyl hydrogen H8 at high field (δ 5.94 ppm) and

silyl substituted vinyl hydrogen H9 at down field (δ 6.06 ppm) are reversed and they appears: δ 6.01 ppm

for H8 and at δ 5.92 ppm for H9. Even though careful VT NMR experiments were performed by heating

upon 70 oC, we could not find any evidence for the atropisomerism of 3-93. We have done the same

experiment with D-gluconosubstituted (Z,Z)-1,3-dienes 3-94, 3-97, and 3-98 in CD2Cl2 and C6D6 in the

range of -70 oC to +70 oC, but no atropisomerism was observed in the dynamic NMR spectra.

Based on the above dynamic NMR study results, we may conclude the silastanylated cyclic

adducts 3-93, 3-94, 3-97, and 3-98, are the first atropisomerically frozen diastereomers. At this point,

unfortunately, we could not determine the absolute configuration of those compounds by nOe experiments.

220

Figure 3. 10. Various Temperature NMR Spectrum I of 3-93.

221

Figure 3. 11. Various Temperature NMR Spectrum II of 3-93.

222


223


224


225


226


227


228

3. 6. Bromination and Destannylation of Silylstannylated D-gluconosubstituted (Z,Z)-1,3-Dienes

Tin-bromine exchange on vinylstanne has been studied before (Chapter 2.3, Eq. 25). The

bromination can be achieved easily by treating the tin substituted vinyl with slightly excess NBS in

dichloromethane at rt. While iodine-substituted at Csp2 is unstable, the bromine-substituted olefins are

stable and can be isolated by column chromatography in excellent yield.

SnR3

SiR'3EtO2C

EtO2C+ NBS

Br

SiR'3EtO2C

EtO2C

CH2Cl2

rt(13)

3-106 3-107

Because we obtained a gram scale of vinyl silastanne 3-93, 3-97, and 3-98, we decided to

investigate the bromine-tin exchange reaction. Pleasantly, the reaction proceeded smoothly at rt to afford

the corresponding brominated substrate 3-108 – 3-110 in excellent to good yield, and the results are

summarized in Table 3.5. Although relatively big functional groups, SiMe2Ph and SnBu3, are substituted

(Z,Z)-1,3-dienes are expected to freze the helical isomerization in the range of -70 to +70 oC, the Br and

SiMe2Ph substituted (Z,Z)-1,3-dienes may be fluxional at these temperature. However, at this time we have

not examined the atropisomerizm in these compounds.

On the other hand, we have also described destannylation of the silastannylative cyclic products 3-

111 to the corresponding vinyl silane 3-112 in the previous chapter (see Chapter 2.6). The destannylation

proceeds slowly but very cleanly in dichloromethane at rt (5.0 equivalent of HCO2H and dichloromethane

at rt), and the destannated vinyl silane can be isolated by flash column chromatography.

XSnR

SiR'(14)

CH2Cl2/rt

HCO2HX

SiR'

3-111 3-112

229

We applied the acidic conditions for destannylation to 1,4-disubstituted (Z,Z)-1,3dienes, 3-93, 3-94, 3-97,

and 3-98. All substrate underwent the reaction very smoothly to afford the corresponding vinyl substrate 3-

113 – 3-116 in excellent yield (>99%), even on a half gram scale reaction. Table 3.6 is a summary of the

destannylation of silastannylated adducts 3-93, 3-94, 3-97, and 3-98. The configurations of the vinylsilanes

are confirmed by nOe experiments and the representative results for 3-114 and 3-115 are shown in Figure

3.14. For example, if we irradiated H9a of 3-114, strong enhancements of H2 and H9b were observed. We

may also deduce of (Z,Z)-confifuration of 1,3-diene 3-94 by observing of SiMe2Ph peak enhancement

when H9b peak was irradiated. The assignment of 3-115 is also very obvious by observing nOe effect

between H9 and H3, H8a and SiMe2Ph, and H8a and H8b.

Conditions Entry

Substrates NBS Temp Time

Product Yield

(%)

1 O

OBn

BnOBnO BnO

O

SnBu3

SiMe2PhH

HH

H

H

nOe

3-93

1.25Eq rt 16 h O

OBn

BnOBnO BnO

O

BrSiMe2PhH

HH

H

H

nOe

3-108

>99

2 O

OBn

BnOBnO BnO

O

H

3-97

PhMe2SiSnBu3

H H

H

H

H

1.25Eq rt 3 d O

OBn

BnOBnO BnO

O

H

3-109

PhMe2SiBr

H H

H

H

H

73

3

3-98

O

OBn

BnOBnO BnO

O

H

Bu3SnSiMe2Ph

H H

H

H

H

1.25Eq rt 3 d

3-110

O

OBn

BnOBnO BnO

O

H

BrSiMe2Ph

H H

H

H

H

69

Table 3. 5. Bromination of Silastannylated Adducts 3-93, 3-97, and 3-98.

230

Conditions Entry

Substrates HCO2

H

Temp Time

Product Yield

(%)

1 O

OBn

BnOBnO BnO

O

SnBu3

SiMe2PhH

HH

H

H

nOe

3-93

5.0

Equiv

rt 24 h O

OBn

BnOBnO BnO

O

HSiMe2PhH

HH

H

H

nOe

3-113

>99

2 O

OBn

BnOBnO

BnOO

SiMe2PhSnBu3

H

HH

H

H

3-94

5.0

Equiv

rt 48 h O

OBn

BnOBnO BnO

O

SiMe2PhHH

HH

H

H

3-114

>99

3 O

OBn

BnOBnO BnO

O

H

3-97

PhMe2SiSnBu3

H H

H

H

H

5.0

Equiv

rt 43 h O

OBn

BnOBnO BnO

O

H

3-115

PhMe2SiH

H H

H

H

H

>99

3

3-98

O

OBn

BnOBnO BnO

O

H

Bu3SnSiMe2Ph

H H

H

H

H

5.0

Equiv

rt 24h

3-116

O

OBn

BnOBnO BnO

O

H

HSiMe2Ph

H H

H

H

H

>99

Table 3. 6. Destannylation of Silastannylated Adducts 3-93, 3-94, 3-97, and 3-98.

231

3-114

O

OBn

BnOBnO

BnOO

SiMe2PhHH

HH

H

H

3.0%

17.6%

3.4%

4.9%18.3%

O

OBn

BnOBnO BnO

O

H

PhMe2Si

H H11.3%

HH

18.6%3.3%

9.3%

3-115

2

4

5

6

7

8

9a2

4

5

6

7

8a

9

9b

8b

Figure 3. 18. Representative nOe Results for 3-114 and 3-115.

3. 7. Exploratory Studies on Desilylation of the Vinylsilanes

Desilanylation of 1,4 –disubstituted (Z,Z)-1,3-diene 3-93 was performed with Bu4NF in DMF at

60 oC. Although the removal of Si at sp3 carbon mediated by tetra-butylammonium fluoride (TBAF) is

well-known, it was difficult to remove the silanes at the sp2 carbon of 3-93. Because of the harsh reaction

condition, all starting decomposed after 20 h.

O

OBn

BnOBnO BnO

O

SnBu3

SiMe2PhH

HH

H

H

O

OBn

BnOBnO BnO

O

SnBu3

HH

HH

H

HBu4NF

DMF60 oC

(15)X

3-93 3-117

Next, we investigated desilylation of destannated vinylsilanes such as 3-114 and 3-115 under

various conditions, and the results are shown in Scheme 3.3. Hydroiodic acid is the most commonly used

in reagent for the desilylation of vinylsilanes to afford olefins, and a small amount of iodine and H2O may

be used for the reaction instead of the hydroiodic acid. The reaction proceeds via protonation to the

vinylsilanes to afford stabilized β-silicon attacked by iodide in the same pot. We explored the desilylation

of both vinylsilane 3-114 and 3-115 under the iodine/H2O system, but the reaction did not proceed at all

and all starting vinylsilane was recovered. We also investigated the desilylation with stochiometric amount

232

of p-TsOH in the mixture of CH3CN-THF-H2O (3:3:1). Unfortunately, the both starting materials

decomposed after 50 h refluxing without formation of the desired olefins like 3-118 or 3-119. Further

efforts were made to do the desilylation of 3-115 under two reported conditions. First, the vinylsilane 3-

119 was heated with excess amount of TBAF (5.0 equivalents) in a mixture of THF-DMSO (= 1:2) at 80

oC. Second, the silane was treated with KOtBu (1.1 equivalent), TBAF (5.0 equivalents), and catalytic

amount of 18-crown-6 in DMSO at rt. Although those reaction conditions are effective for the desilylation

of certain type of vinylsilanes, we failed to obtain the corresponding olefins.

O

OBn

BnOBnO BnO

O

H

PhMe2Si

H H

HH

3-115

O

OBn

BnOBnO BnO

O

SiMe2PhHH

HH

H

H

O

OBn

BnOBnO BnO

O

HHH

HH

H

H

X

3-114 3-118

O

OBn

BnOBnO BnO

O

H

PhMe2Si

H H

HH

3-119

X

a or b

a, b, c, or d

Scheme 3. 4. Failed Desilanation of Vinylsilanes 3-114 and 3-115: (a) I2, H2O, benzene, 45 h, SM

recovered; (b) pTsOH, CH3CN-THF-H2O = 3:3:1, reflux, 50 h, decomposed ; (c) TBAF in 1.0M THF,

THF-DMSO (= 1:2), 80 oC, 23 h, decomposed; KOtBu, TBAF, 18-crown-6, DMSO, rt→0 oC→rt, 24 h, SM

recovered.

233

3. 8. Diels-Alder Reaction of Vinylsilanes

Our initial plan for the synthesis of C-arylglycoside nucleus of Papulacandin D is shown in

Scheme 3.4. The destannylated vinylsilane 3-113 and/or 3-115 may react with dienophiles shown in the

box in the Scheme 3.4 via Diels-Alder reaction. The spiroketal 3-80 and/or 3-120 may further be

transferred to C-arylglycoside 3-79 or 3-121 via Tamao-Fleming oxidation and oxidative aromatization as

key steps. Because C-arylglycoside 3-79 is thermodynamically more stable than 3-121, the C-

arylglycoside 3-121 may be epimerized easily to 3-79 in the presence of PPTS. Two hydroxyl groups in

the aryl moiety of the 3-79 can originate from the vinylsilanes in dienes and ketone equivalents in the

dienophies, which may be generated by Tamao-Fleming oxidation and further transformations,

respectively.

X YO

OBn

BnOBnO BnO

OX

Y


SiMe 2Ph

O

OBn

BnOBnO BnO

O

OH

HO

Br CHO Br CN AcO CNAcO

CH3

OAcO O CH3

O

Possible Dienophiles

NO2

O

OBn

BnOBnO BnO

O

HSiMe2PhH

HH

H

H

nOe

3-113

O

OBn

BnOBnO BnO

O

H

3-115

PhMe2SiH

H H

H

H

H

X Y


O

OBn

BnOBnO BnO

O

H

3-120

H

HPhMe2Si

XY

PPTS

O

OBn

BnOBnO BnO

O

H

H

HHO

OH

3-803-79

3-121

Scheme 3. 5. Application of Silyl-Stannane Adducts for Synthesis of the Core Structure of Papulacandin

D.

234

Diels-Alder reactions of spiro[4.5]decane 3-113 were studied with a variety of dienophiles such as

2-bromo-propanal, 2-bromo-acrylonitrile, acetic acid 1-cyano-vinyl ester, acetic acid 1-methylene-2-oxo-

propyl ester, or acetic acid 1-acetoxy-vinyl ester, and the results are summarized in Table 3.7. We

performed the reaction under various conditions with different solvent and at various temperatures as

limiting factors. Unfortunately, we could not find any evidence for the formation of the Diels-Alder adduct

3-80, and all starting vinylsilane 3-113 decomposed under the conditions we applied.

Becaue our all attempts failed to produce the Diels-Alder adduct like 3-122 or 3-124, we assumed

that the Diels-Alder adducts were formed and further transformations of the crude product ensued (Eq. 16

and 17). However, we also failed to isolate the desired product 3-123 or 3-125, and all starting material

seemed to have decomposed.

Br CNO

OBn

BnOBnO BnO

O

SiMe2PhH

HH

H

H

3-113

O

OBn

BnOBnO BnO

O

H

HH

(16)tolouene

(xyxlene, reflux)

SiMe 2

Ph

Br

CN

O

OBn

BnOBnO BnO

O

H

HH

SiMe 2

Ph

2M KOH

THF/DMSO

O

3-122 3-123

XH

AcO CNO

OBn

BnOBnO BnO

O

SiMe2PhH

HH

H

H

O

OBn

BnOBnO BnO

O

H

HH

(17)tolouene

(xyxlene, reflux)

SiMe 2

Ph

OAc

CN

O

OBn

BnOBnO BnO

O

H

HH

SiMe 2

Ph

2M KOH

THF/DMSO

O

3-113 3-124 3-125

XH

It was known that nitroethylene is one of the strongest electrophiles and its global electrophilicity

power ω, which is unique on relative scale for dienes and dienophiles, is 2.61. The electrophilicity power

ω of nitroethylene is 1.73 times grater than methyl acrylate, which is one of the most widely used

dienophiles in Diels-Alder reaction. Thus, it is reasonable that the Diels-Alder reaction of the sterically

demanding vinylsilane 3-114 would proceed with nitroethylene at high temperature.

235

Entry Conditions

Dienophile Equiv. Solvent Temperature Time (h) Yiled (%)

1 3.0 Toluene rt 30h Decomp

2 3.0 Toluene Benzene ↑↓ 48h Decomp

3 3.0 Toluene Toluene ↑↓ 27h Decomp

4

Br CHO

5.0 Toluene Benzene ↑↓ 22h Decomp


6 3.0 Toluene Xylene ↑↓ 28h Decomp

7

Br CN 3.0 Toluene Xylene ↑↓ 48h Decomp


9 3.0 Toluene 120 oC then Toluene

↑↓

25h → 30h Decomp



12

AcO CN

5.0 Benzene 160 oC 48h Decomp


14 Toluene Xylene ↑↓ 24h Decomp

15

AcOCH3

O 3.0 Toluene Xylene ↑↓ 48h Decomp


17 Toluene Xylene ↑↓ 24h Decomp

18

AcOOCH3

O 3.0 Toluene Xylene ↑↓ 48h Decomp

Table 3. 7. Diels-Alder Reaction of 3-113 with Various Dienophiles.

236

NO2 O

OBn

BnOBnO BnO

O

NO2

O

OBn

BnOBnO BnO

O

SiMe2PhHH

HH

H

H

nOe

3-114 3-126

(18)O

OBn

BnOBnO BnO

O

3-127

NO2

+

SiMe2Ph SiMe2Ph

Conditions

Entry Equiv. Solvent Temp Time Yiled (%)a

1 5.0 Equiv. benzene benzene ↑↓ 3 d 44 (68)

2 5.0 Equiv. benzene benzene ↑↓ 6.5 d 72

3 5.0 Equiv. benzene benzene ↑↓ 7 d 71

4 10.0 Equiv. benzene benzene ↑↓ 7 d 79

5 5.0 Equiv. benzene toluene ↑↓ 4.5 d 17

6 5.0 Equiv. benzene xylene ↑↓ 15 h 27 (32)

7 5.0 Equiv. toluene benzene ↑↓ 7 d 68

8 5.0 Equiv. toluene toluene ↑↓ 4.5 d 41

9 5.0 Equiv. toluene xylene ↑↓ 15 h 41

a. Isolated yield. The number in the parenthesis is yield based on the recovered 3-114.

Table 3. 8. Diels-Alder Reaction of 3-114 with Nitroethene

237

We performed the Diels-Alder reaction of vinylsilane 3-144 with the nitroethylene under various

conditions, and the results are shown in Table 3.8. When the reaction was done with 5 equivalent of

dienophile for 3 d, we isolated the regioisomeric mixture 3-12 and 3-127 in 44% (68% based on recovered

starting material) as well as the starting diene 3-144 (entry 1). After heating the reaction mixture for the

prolonged time (6.5 d), all the starting material was consumed and the isolated yield of the product

increased up to 72%. Gratifyingly, we can optimize the reaction with 10 equivalents of nitroethylene in

benzene and refluxing condition (entry 4). Because the reaction is very slow, the reaction mixture has to be

allowed to stand under refluxing condition for a week. The reaction is independent of the solvent, but

dependant on the reaction temperature. It is probabely that the dienophile, nitroethylene, can decompose at

high temperature. For example, if the reaction temperature in creased to 110 oC (toluene refluxing

condition), the yield of the product was only 17% (Entry 5). When toluene was used as the solvent instead

of benzene, the yield of the Diels-Alder adducts 3-126 and 3-127 decreased as expected from the above

considerations.

Next, the Diels-Alder adducts 3-126 and 3-127 were subjected to oxidation under various

conditions. Because Nef reaction is the most broadly used for the transformation of primary or secondry

nitroalkanes to aldehydes or ketones, we applied this reaction and its modified procedures to our substrates.

Unfortunately, all nitroalkanes 3-126 and 3-127 decomposed under the harsh conditions with basic/acidic

reagents. Even though we applied Oxone® mediated Nef reactions, which is milder than conventional Nef

conditions, we failed to obtain the desired product 3-128 and 3-129. Because silica gel or basic silica gel

may be used for an alternative reagent for the conversion of nitroalkanes to ketones, we performed the

reaction in sealed tubes packed with silicagel/MeOH or basic silicagel at rt or 50 oC, respectively.

However, the desired reaction did not proceed and all starting material 3-126 or 3-127 was either recovered

or decomposed. We also examined the reaction with activated silica gel (KMnO4 /silicagel = 0.5 mmol/g),

the reaction did not proceed. Finally, we explored the transformation with either CAN/Et3N in pyridine or

TiCl3-NH4OAc in THF, but we failed to obtain the desired products 3-128 and 3-129 and all starting

material decomposed under those conditions.

238

O

OBn

BnOBnO BnO

O

NO2

3-126

O

OBn

BnOBnO BnO

O

3-127

NO2

+

O

OBn

BnOBnO BnO

O

O

3-128

O

OBn

BnOBnO BnO

O

3-129

O

+O

OBn

BnOBnO BnO

O

X

Core structure of Papulacandin

a, b, c, d,e, f, g, or h

SiMe2Ph SiMe2Ph

SiMe2ph SiMe2Ph

OH

OH

Scheme 3. 6. Failed Attempts to oxidize 3-126 and 3-127: (a) 1. NaOH (10% in EtOH), 2.6N HCl, 0 oC→rt, decompose; (b) silicagel, MeOH, rt, 20 d, SM recovered; (c) 1. Na2HPO4, NaOH, MeOH, 2.

Oxone®, rt, 2h, decomposed; (d) KMnO4/silicagel (0.5 mmol/g), bezene, reflux, 24 h, decomposed; (e)

basic silicagel (Na/EtOH), 90 oC, 4.5 d, decompose; (f) CAN, Et3N, H2O, Pyr, 50 oC, 5 hdecompose; (g) 1.

NaOH/EtOH, 2. H2SO4, 0 oC, 2 h, decompose; (h) TiCl3-NH4OAc, THF, H2O, rt, 42 h, decomposed.

We studied Diels-Alder reaction with ethyl propiolate in toluene under refluxing conditions. The

reaction was not efficient and only 25% of desired product was isolated as a regioisomeric mixtures (Eq.

19). If we use tert-butyl acrylate as a dienophile, the isolated yield of the Diels-Alder adduct improved, but

it was still low (46%) and the two regioisomers 3-130 and 3-131 could not be isolated by column

chromatography (Eq. 20).

(19)O

OBn

BnOBnO BnO

O

SiMe2PhH

HH

H

H

O

OBn

BnOBnO BnO

O

H

HH

tolouene(xylene, reflux)

OEt

O

OEt

O

25%

H

3-1303-113

O

OBn

BnOBnO BnO

O

H

HH

OEt

O+

3-1313-128/3-129 = 1.0/0.51

239

O

OBn

BnOBnO BnO

O

SiMe2PhH

HH

H

H

O

OBn

BnOBnO BnO

O

H

HH

(20)tolouene

(xylene, reflux)

OtBu

O

OtBu

O

46%

3-113

HO

OBn

BnOBnO BnO

O

H

H H

+

OtBuO

3-132 3-133

However, when we used methylvinyl ketone as a dienophile, the desire product was isolated up to

62% yield with two regioisomeric mixture (3-134/3-135 = 0.2/1.0) (Eq. 21). It is not surprising the latter

reaction gave better isolated yield than that of previous reaction because methyl vinyl ketone is known to

be a better dienophile than ethyl propiolate.

The next step was Bayer-Villiger oxidation of the Diels-Alder products under known conditions.

All starting material 3-134 and/or 3-135 were consumed within 20h and single product was isolated after

work-up and column chromatography. Unfortunately, the isolated product was not desired one, but an

epoxide of the Diels-Alder adduct (Eq. 21). We also run Diels-Alder reaction and Bayer-Villiger oxidation

in situ. Although we found the formation of Diels-Alder products in TLC analysis, we could not

find/isolate any significant product after oxidation with mCPBA under buffered condition (Eq. 22).

O

OBn

BnOBnO BnO

O

SiMe2PhH

HH

H

H

O

OBn

BnOBnO BnO

O

H

HH

(21)


O

OBn

BnOBnO BnO

O

H

HH

mCPBA

CH3

O

CH3

O

NaHCO3

CH2Cl2

62%

3-130/3-131 = 0.2/1.0

48%

OAcO

3-113

HO

OBn

BnOBnO BnO

O

H

H H

+

CH3

O

O

OBn

BnOBnO BnO

O

H

HH

O

OAc

3-134 3-135

3-136 3-137

240

O

OBn

BnOBnO BnO

O

SiMe2PhH

HH

H

H

O

OBn

BnOBnO BnO

O

H

HH


O

OBn

BnOBnO BnO

O

H

HH

mCPBACH3

O

CH3

O

OAc

NaHCO3

CH2Cl2

(22)

2-113 2-134 2-138

X

We explored palladium catalyzed tandem cyclization-[2+4] reaction with bis-functionalization

reagent Bu3Sn-SiMe2Ph. For the reaction ethyl acrylate and methyl vinyl ketone were examined as

electrophiles. Although we followed the reaction very carefully by 1H NMR spectroscopy, we could not

find any evidence for the tandem reaction. After 6h, all diyne 3-92 were consumed and silastannylated

spiroketal 3-139 was isolated in 71 and 63%, respectively. As we described earlier the silatannylated cyclic

compound 3-139 are two diastereomers with a ratio of 1.54/1.0 and 1.67/1.0.

OEt

OO

OBn

BnOBnO BnO

O

Bu3SnSiMe2Ph O

OBn

BnOBnO BnO

O

YXH

HH

H

3-92 3-139

H

PdCl2(PhCN)2

O

OBn

BnOBnO

BnOO

H

HH

Z

O

3-141

Y

+

3-140

X

or

CH3

O

O

OBn

BnOBnO

BnOO

H

HH

Y

ZO

X = Bu3, SiMe2PhY =Bu3, SiMe2PhZ = OEt, CH3

Scheme 3. 7. Explore of Palladium Catalyzed Tandem Cyclization-[2+4] Reaction.

241

3. 9. Conclusion

Palladium catalyzed silylstannylative cyclization of dienes and its application to the synthesis of

the core structure of Papulacandin D have been studied. The silylstannylative cyclizations were performed

with various Pd(0) and Pd(+2) catalysts in the presence of a series of chiral/achiral phosphine ligand. The

axial chiralities of the silylstanylatied 1,3-dienes have been investigated by various temperature NMR

spectroscopy at 70 oC to -70 oC, and atropisomeric isomers have not observed by line shape analysis of 1H

NMR spectra. This is the first example of the atropisomeric frozen silylstanylatied 1,3-dienes.

The silylstanylatied 1,3-dienes can be brominated by NBS and destannylated by formic acid in

CH2Cl2 to give diens, which might react with dienophiles such as nitroethane, methyl vinyl ketone, and

ethyl propiolate via Diels-Alder process.

Further transformation of the Diels-Alder adducts has to be studied to complete the synthesis of

the core structure of Papulacandin D.

242

CHAPTER 4

EXPERIMENTAL SECTION

4. 1. General Procedures

NMR spectra were recorded on Bruker on AM-250 and 400 MHz and CDCl3 was used for the

solvent. For 1H NMR spectra the hydrogen of CDCl3 was used as the standard (δ= 7.260 ppm) unless

otherwise mentioned. The 13C NMR spectrometer was operated at 100 MHz or 62.5MHz and used the

central line of CDCl3 as the standard (δ= 77.00 ppm). Chemical shifts are reported in parts per million on

the δ scale, and Hz is used for the coupling constants. The multiplicity are expressed like following: s =

singlet, d = doublet, t = triplet, q = quartet. Infrared spectra were obtained on Perkin-Elmer 1600 Infrared

Spectrometer and are reported in reciprocal centimeters (cm-1). The relative intensity of IR spectra are

reported as follows: br = broad, s = strong, m = medium, w = weak. High resolution mass spectra were

measured by The Ohio State University’s Shared Analytical Instrumentation Laboratory (SAIL) and

recorded on the Micromass QTOF electrospray mass spectrometer. Optical rotations were measured on

Perkin-Elmer 241 MC polarimeter with a sodium lamp at 589 nm and 1 mm slit, and the concentration is

g/dL. All melting points were determined by Thomas-Hoover capillary melting point apparatus and are

uncorrected.

All solvents were purchased from Fisher Co. and fresh distilled according to the literatures before

the using. Other chemicals were purchased from Aldrich Chemcal Co. or Across Co. and used as received.

Reactions were performed in flame dried glassware under an atmosphere of nitrogen, and monitored by

thin layer chromatography (TLC) using EM Science precoated 60 F254 plates or gas chromatography

(Hewlett Packard 5890). The GC was equipped with HP-1 column and an FID

243

detector connected to an HP 3396 integrator. Products were isolated by column chromatography using 60-

200 mesh silica gel. Preparative TLC was performed on Merck 2 mm preparative TLC plates or common

precoated 60 F254 plates.

4. 2. Preparation of Common Reagents

Preparation of 1-(trimethylsilyl) imidazole108(a)

N

N

SiMe3

Imidazole (6.81 g, 100 mmol) and 1,1,1,3,3,3-hexamethyldisilazane (12.3 g, 76.1 mmol) were

charged into a flame three necked 100 mL flask connected to a condenser. The mixture was refluxed under

positive nitrogen pressure for 10h 30 min. The mixture was cooled to rt, and distilled under reduced

pressure (52-54 oC/ 0.7 mmHg). The product can be distilled under house vacuum, but high vacuum is

more efficient. Previously reported 1-(trimethylsilyl) imidazole (10.1 g, 94%) was collected as a colorless

liquid. Colorless liquid. bp: 115-117 oC/~30 mmHg, 80-82 oC/4 mmHg, or 52-54 oC/ 0.7 mmHg (lit108 97

oC/12 mmHg). The reagent was redistilled before further reaction. 1H NMR (CDCl3, 400 MHz): δ 0.47-

0.49 (m, 9 H), 7.08-7.10 (m, 2 H), 7.60-7.61 (m, 1 H).

Preparation of N,N’-thiocarbonyl-diimidazole109

NN

CN

N

S

1-(Trimethylsilyl) imidazole (7.7 g, 55mmol) of was placed along with 50 mL of dried benzene

(distilled from CaH2) in a flame dried flask fitted with an efficient condenser. The flask was charged with

nitrogen atmosphere, and cooled to a temperature of 0 oC. Thiophosgen (3.2 g, 28 mmol) was slowly added

to the flask by a syringe. After the addition, the mixture was stirred at 0 oC for another 1 h. The solvent

244

was removed under house vacuum to give yellow solid. This solid was dried under high vacuum for

several days. An yellow solid (4.81 g) obtained and the yield was 98%. Yellow Solid. Mp: 98-100 oC

(lit.109 105-106 oC).

Preparation of ethyl (triphenylphosphoranylidene)acetate110

Ph3P CHCO2Et

To a 250 mL of flask was added 26.3g (0.1 mol) of triphenylphophine and 50 mL of dried benzene

was charged. Ethyl bromoacetate (16.7 g, 0.1 mmol) was dropwise a rate that maintains the reaction

mixture at rt or slightly higher. The mixture was stirred at rt for 4 h to give colorless salts. The salts were

filtered, and washed with 60 mL of cold benzene and 40 mL of pentane, and then dissolved in 600mL of

water. To remove some organic impurities, the solution was extracted with diethyl ether. Small amount of

phenolphthalein was added to the aqueous phase, which was cooled down to 0 oC. Sodium hydroxude

solution (2.0 M) was slowly added until the color changed to pink. The solid phophorane was collected by

filtration, and washed with cold water. The wet product was dried under high vacuum for overnight. A

white solid (26.4 g, 76%) was obtained, and the melting point and 1H NMR data are identical to literatures.

Mp: 122-124 oC (lit.110(a) 124-126 oC).

Preparation of 1,1-dimethylethyl (triphenylphosphoranylidene)acetate110

Ph3P CHCO2But

To a 100 mL of flame-dried flask was added 13.11g (0.05 mol) of triphenylphophine and 30 mL

of dried benzene was charged. 1,1-dimethylethyl bromoacetate (9.75 g, 0.05 mmol) was dropwise a rate

that maintains the reaction mixture at rt or slightly higher (around 20 min). The mixture was stirred at rt for

4 h to give white salts. The salts were filtered, and washed with 30 mL of cold benzene and 20 mL of

pentane, and then dissolved in 300mL of water. To remove some organic impurities, the solution was

extracted with diethyl ether. Small amount of phenolphthalein was added to the aqueous phase, which was

245

cooled down to 0 oC. Sodium hydroxude solution (1.0 M) was slowly added until the color changed to pink.

The solid phophorane was collected by filtration, and washed with cold water. The wet product was dried

under high vacuum for overnight. A white solid (16.1g, 86%) was obtained, and the melting point and 1H

NMR data are identical to literatures. Mp: 143-145 oC (lit.110(b) 152-154 oC).

Preparation of (cyanomethylene)triphenylphosphine111

PPh3 CHCN

Chloroacetonitrile (4.77 g, 0.063 mol) and triphenyl phophine (12.46 g, 0.0475 mol) were

dissolved in 70 mL of nitromethane in a flame dried 25 mL flask. The mixture was refluxed for 9 h,

and then the reactor was cooled down to rt. The precipitates were filtered and washed with

dichloromethane to give 6.91 g of white solid. The formed (cyanomethylene)triphenylphosphonium

chloride was suspended in 100 mL of dried dichloromethane. Triethyl amine (7.0 mL) was slowly

added over 15 min., and the mixture was stirred for another 30 min. Cold water (2 X 75 mL) was used

for washing the mixture, and the organic phase was dried over magnesium sulfate. After filtration, the

organic phase was concentrated under vacuum to give yellow solid. The crude ylide was recrystalyzed

by benzene (14 mL/g). Total yield was 23% from chloroacetonitrile. Pale yellow solid. Mp: 188-

189.5 oC (lit.111(b) 152-154 oC). .

Preparation of nbutyltin hydride112

nBuSnH

Bis-tributyltinoixde (30 g, 0.05mol) and and 6 g of (MeSiHO)x were placed in a flame dried three

neck flask connected to a condenser. The mixture was refluxed in an oil bath at 120 oC until no more

bubbles were observed (around 30min. to 1h). A distill head was connected to the flask, and the product

246

was carefully distilled under reduced pressure. The product was collected as a colorless liquid (20.9 g,

72%) at 77 oC/0.7 mmHg (lit.112(b) 114-116 oC/6 mmHg).

Preparation of ethylpiperidine hypophosphite (EPHP) 113

NH3PO2

An aqueous solution of H3PO2 acid (3.93 mL, 5.0 g, 37.9 mmol, 50% in H2O) was charged into a

25 mL of one necked flask. The water was removed completely under high vacuum with heating. To the

water free hypophosphorous acid was added 5.2 mL (37.9 mmol) of N-ethylpiperidine at 0 oC.

Immediately, a white solid was formed, and the mixture was stirred for 30 min. The crude salt was used for

the next experiment without further purification. Mp: 41-43.5 oC.

Preparation of (p-methoxyphenyl)methyl trichloroactimidate114

H3CO

O

NH

CCl3

To a stirring mixture of 2.22 g (16.1mmol) of p-methoxybenzyl alcohol in 20 mL of freshly dried

diethyl ether at rt under nitrogen atmosphere was added 7.7 mg (1.6 mmol) of sodium hydride in 50%

mineral oil. The reaction mixture was stirred until the solid had dissolved and gas evolution had ceased.

The reaction mixture was cooled to 0 oC, and 1.61 mL (16.1 mmol) of tricloroacetonitrile was added

slowly. The mixture was stirred in an ice bath for 10 min., and then at rt for another 30 min. It was

transferred to a separatory funnel, washed with saturated sodium bicarbonate, and brine solution. The

organic phase was dried over magnesium sulfate, the solid was filtered off, and the solvent was removed on

247

the rotary evaporator to get a yellow oil. This crude product was used for the next experimental without

further purification or characterization.

Preparation of (trimethylsilyl)tri-n-butylstannane

Bu3SnSiMe3

A solution of 0.80 mL (5.71 mmol) of di-iso-propylamine in 10 mL of THF was cooled to -78 oC.

After 10 min, 3.4 mL of n-butyl lithium (1.6 M in hexane, 5.5 mmol) was added over 5min. The reaction

mixture was stirred at 0 oC for 5 min and then at rt for another 5 min. To the mixture was added tri-n-

butyltinhydride (1.34 mL, 5.0 mmol) at 0 oC over 5 min and the cooling bath was removed to bring back

the temperature to rt followed stirring for 20 min. Trimethylsilylchloride (0.70 mL, 5.5 mmol) was then

added slowly to the solution at 0 oC. After 10 min, the solution became cloudy (formation of lithium

chloride). The resulting solution was further stirred at rt for 2h. All volatile materials were removed on a

rotary evaporator to give crude product. The crude product was purified by column chromatography

eluting with hexane to give 1.82g of of (trimethylsilyl)tri-n-butylstannane (quantitative yield). 1H NMR

(CDCl3, 400 MHz): δ 0.02 (s, 9 H), 0.81-0.89 (m, 15H), 1.24-1.51 (m, 12H).

Preparation of (tert-butyldimethylsilyl)tri-phenylstannane

Ph3SnSiMe2tBu

A solution of 0.91mL (6.5 mmol) of di-iso-propylamine in 10 mL of THF was cooled to -78 oC.

After 10 min, 3.75 mL of n-butyl lithium (1.6 M in hexane, 6.0 mmol) was added over 5min. The reaction

mixture was stirred at -78 oC for 5 min and then at rt for another 10 min. To the mixture was added tri-

phenyltinhydride (1.28 mL, 5.0 mmol) at 0 oC over 5 min and the cooling bath was removed to bring back

the temperature to rt followed stirring for 30 min. Tert-butyldimethylsilylchloride (0.98 g, 6.5 mmol) was

then added slowly to the solution at 0 oC. After 5 min, the solution became cloudy (formation of lithium

248

chloride). The resulting solution was further stirred at rt for 3h. All volatile materials were removed on a

rotary evaporator to give crude product. The crude product was purified by column chromatography

eluting with hexane to give 2.2g of of (trimethylsilyl)tri-n-butylstannane (92%). White solid (column

chromatography with hexane only). 1H NMR (CDCl3, 500 MHz): δ 0.44 (s, 6H), 1.00 (s, 9H), 7.33-7.37

(m, 9H), 7.51-7.59 (m, 6H). 13C NMR (CDCl3, 125 MHz): δ -2.49, 19.03, 27.47, 128.13, 128.32, 137.50,

140.64.

Preparation of (dimethylphenyl)tri- n-butylstannane

Bu3SnSiMe2Ph

To a solution of 20.5mL (14.6 mmol) of di-iso-propylamine in 250 mL of THF was added slowly

91.3 mL of n-butyl lithium (1.6 M in hexane, 14.6 mmol) was added at -78 oC. The reaction mixture was

stirred at -78 oC for 5 min and then at rt for another 20 min. To the resulting mixture was added slowly

Bu3SnH (35.7 mL, 38.6g, 13.3 mmol) at 0 oC followed by stirring at rt for 30 min.

Dimethylphenylsilylchloride (24.6 mL, 25g, 13.3 mmol) was then added slowly to the solution at 0 oC.

After 10 min, the solution became cloudy (formation of lithium chloride). The solution was further stirred

at rt for 10h. All volatile materials were removed on a rotary evaporator to give crude product. The crude

product was purified by column chromatography eluting with hexane to give the desired

(dimethylphenyl)tri- n-butylstannane as colorless viscous liquid in quantitative yield. Colorless liquid

(column chromatography with hexane only). 1H NMR (CDCl3, 500 MHz): δ 0.51 (s, 6H), 0.85 (t, J = 7.3

Hz, 9H), 0.86 (t, J = 7.0 Hz, 6H), 1.25 (sex, J = 7.3 Hz, 6H), 1.42 (tt, J = 7.2, 7.0 Hz, 6H), 7.32-7.34 (m,

3H), 7.45-7.47 (m, 2H). 13C NMR (CDCl3, 125 MHz): δ -0.39, 8.14, 13.66, 27.51, 30.12, 127.77, 128.36,

133.55, 140.89. IR (NaCl, neat): υ 2956m, 2923m, 1463w, 1244w, 1109w, 834m, 731m, 697m.

249

Preparation of 2-bromoacrolein115

Br CHO

To a solution of dimethyl sulfide (0.40 mmol, 24.9g, 19.4 mL) in acetonitrile (300 mL) was added

bromine (0.22 mmol, 35.2g, 11.3 mL) in carbon tetrachloride (10 mL) at -40 oC under nitrogen atmosphere

to give yellow precipitates. Addition of slightly excess amount of acrolein (0.26 mmol, 14.8g, 17.9 mL) to

the mixture changed the color of the precipitates from yellow to white. The precipitates were collected by

filtration with diethyl ether (200 mL), and the filtrates were washed with additional diethyl ether (100 mL)

and dried under house vacuum. After the solid was dissolved in 5% sodium bicarbonate solution (200 mL)

and stirred at 35 oC for 15 min, the aqueous mixture was extracted by dichloromethane. Combined organic

phase was washed with H2O and brine solution, successively, dried over MgSO4, and concentrated with

small amount of hydroquinone on a rotary evaporator (evaporation of solvent without hydroquinone led

most product polymeric product and yield only 5% of the desired product after vacuum distialltion!). The

crude product was distilled with small amount of hydroquinone under house vacuum to give the desired

product as pale yellow liquid form in 23% yield. Pale yellow liquid. Vacuum distillation. Bp 68-69 oC/38

mmHg (lit.115 45 oC/25 mmHg). 1H NMR (CDCl3, 250 MHz): δ 6.88 (d, J = 2.3 Hz, 1H), 6.90 (d, J = 2.3

Hz, 1H), 9.25 (s, 1H). 13C NMR (CDCl3, 62.5 MHz): δ 132.51, 136.47, 185.65. IR (NaCl, neat): υ 3423Br

s, 1731s, 1698s, 1633w, 1599m, 1416m, 1260m, 1203m, 1062s.

Preparation of 1,2-dibromopropionitrile116

Br

Br CN

A solution of bromine (28.8g, 0.18mol) in dichloromethane (36 mL) was added dropwise to a

solution of acrylontrile (9.6g, 0.18mol) in dichloromethane (20 mL) at 0 oC under indirect light (6 h). The

mixture was exposed to light and the color of the mixture changed from deep red to colorless while the

temperature smoothly increased from 0 oC to rt over 6 h. After the reaction mixture was concentrated on a

250

rotary evaporator, the crude desired 1,2-dibromopropionitrile was obtained as colorless liquid by vacuum

distillation (35.5g, 93%). Colorless liquid. Vacuum distillation; Bp 61-62 oC/0.6 mmHg (lit.116 46-48

oC/0.25 mmHg). 1H NMR (CDCl3, 250 MHz): δ 3.76 (B of ABX, JAB = 10.5 Hz, JBX = 6.5 Hz 1H), 3.79 (A

of ABX, JAB = 10.5 Hz, JAX = 9.0 Hz 1H), 4.54 (X of ABX, JAX = 9.0 Hz, JBX = 6.5 Hz 1H). 13C NMR

(CDCl3, 62.5 MHz): δ 24.86, 29.69, 115.28. IR (NaCl, neat): υ 3040s, 2971s, 2250m, 1614w, 1434s,

1420m, 1298m, 1236s, 1173s, 1126s, 951s, 931s, 910s, 735s, 702m, 616s.

Preparation of 2-bromoacrylonitrile116

Br CN

Freshly dried quinole (over KOH) (21.8 g, 169 mmol) was added dropwise to 2,3-

dibromopropionitrile (35.2 g, 165 mmol) in the presence of hydroquinone at 0 oC under nitrogen

atmosphere and darkness. After stirred at rt for 2h, the reaction mixture was fractionally distilled under

reduced pressure to give 2-bromoacrylonitrile as yellow liquid (19.6 g, 90%). Yellow liquid. Vacuum

distillation. Bp 33 oC/32 mmHg (lit.116 18 oC/20 mmHg). 1H NMR (CDCl3, 250 MHz): δ 6.40 (d, J = 2.5

Hz, 1H), 6.71 (t, J = 2.5 Hz, 1H). 13C NMR (CDCl3, 62.5 MHz): δ 93.35, 115.03, 135.90. IR (NaCl, neat):

υ 3382Br s, 2226m, 1723s, 1600s, 1416m, 1372s, 1266s, 1234m, 1147s, 1107m, 934m, 911m, 878w, 738s,

704s, 617s.

Preparation of methyl α-acetoxyacrylate117

AcO CO2Me

A mixture of methyl pyruvate (0.2 mmol, 20.4 g, 18.1 mL) and acetic anhydride (0.4 mmol, 40.1

g, 37.8 mL) was refluxed for 24 h under nitrogen atmosphere in the presence of pTsOH•H2O (0.5 g). The

reaction mixture was subjected to vacuum distillation under reduced pressure to give the desired methyl α-

251

acetoxyacrylate as colorless liquid (13.3 g, 46%). Colorless liquid. Vacuum distillation; Bp 85 oC/27

mmHg (lit.117 67-69 oC/17 mmHg). 1H NMR (CDCl3, 250 MHz): δ 2.02 (s, 3H), 3.78 (s, 3H), 5.44-5.46

(m, 1H), 6.01-6.02 (m, 1H). 13C NMR (CDCl3, 62.5 MHz): δ 20.30, 52.50, 113.96, 144.49, 161.87, 168.84.

IR (NaCl, neat): υ 3562Br s, 3007w, 2958m, 1770s, 1738s, 1650s, 1440s, 1373s, 1307s, 1218s, 1148s,

1023s, 968m, 931m, 878m, 840m, 795s, 732m.

Preparation of 3-(acyloxy)-3-butene-2-one118

H3COC OAc

To a stirred solution of 2,3-butanedione (0.2 mol, 17.2 g, 17.6 mL) and triethyl amine (0.2 mol,

20.2 g, 27.8 mL) in dried dichloromethane (200 mL) at 0 oC was added dropwise to a solution of acetyl

chloride (0.2 mol, 15.7 g, 14.2 mL) in 50 mL of dichloromethane. The reaction mixture was stirred

overnight. To the stirred solution was added 200 mL of hexane and the precipitates were filtered and the

collected organic phase was concentrated with small amount of hydroquinone on a rotary evaporator. The

crude mixture was purified by vacuum distillation under reduced pressure in the presence of catalytic

amount of hydroquinone. The distillated product was obtained as a yellow liquid form in 41% yield (10.54

g). Yellow liquid. Vacuum distillation; Bp 86 oC/27 mmHg (lit.118(b) 32 oC/5 mmHg). 1H NMR (CDCl3,

400 MHz): δ 5.89 (d, J = 2.4 Hz, 1H), 5.59 (d, J = 2.4 Hz, 1H), 2.32 (s, 3H), 2.20 (s, 3H). 13C NMR

(CDCl3, 100 MHz): δ 20.30, 25.31, 113.95, 151.60, 168.76, 191.54. IR (NaCl, neat): υ 1766s, 1698s,

1643m, 1432m, 1372s, 1300m, 1212s, 1127s, 1024s, 970m, 929m, 874m.

Preparation of 2-chloro-1-cyanoethyl acetate119

C C CN

OAc

Cl

H

H

H

To a aqueous solution of sodium cyanide (100 g, 1.95 mol) in H2O (300 mL) was added dropwise

chloroacetaldehyde (~50% in H2O, 2.0 mol, 254 mL) at -10 oC to 0 oC over 20 min. After stirring for 5

252

min, the mixture was extracted with diethyl ether (4 X 150 mL), and the combined organic phase was dried

over MgSO4, filtered, and concentrated on a rotary evaporator. The crude mixture was purified by vacuum

distillation under reduced pressure, and yellow liquid was obtained as the major fraction in 39% yield (57.5

g). Pale yellow liquid. Vacuum distillation; Bp 67 oC/1.2 mmHg (lit.119 65 oC/1 mmHg). 1H NMR

(CDCl3, 250 MHz): δ 5.54 (t, J = 5.8 Hz, 1H), 3.79 (d, J = 5.9 Hz, 2H), 2.18 (s, 3H). 13C NMR (CDCl3,

62.5 MHz): δ 20.03, 41.72, 60.95, 114.45, 168.57. IR (NaCl, neat): υ 1774s, 1639m, 1431w, 1374s, 1190s,

1069w, 1037m, 972w, 922m, 875w, 735w.

Preparation of 2-(acetyoxy)-2-propenenitrile119

AcO CN

To a 2-chloro-1-cyanoethyl acetate (12.8 g, 86.7 mmol) in diethyl ether (90 mL) was added slowly

dried triethyl amine (8.8 g, 12 mL, 86.7 mmol) at 0 oC. The reaction mixture was stirred at that

temperature for 16 h, and then the resulting mixture was diluted with excess amount of diluted HCl

neutralizing as well as dissolving Et3N•HCl. The combined ether layer was concentrated with small

amount of bezoquinone, and the crude mixture was purified by vacuum distillation to give the desired 2-

(acetyoxy)-2-propenenitrile as colorless liquid in 72% yield (6.9 g). Colorless liquid. Vacuum distillation;

Bp 86-88 oC/27 mmHg (lit119 65 oC/12 mmHg). 1H NMR (CDCl3, 250 MHz): δ 5.74 (d, J = 2.8 Hz, 1H),

5.67 (d, J = 2.8 Hz, 1H), 2.21 (s, 3H). 13C NMR (CDCl3, 62.5 MHz): δ 20.21, 113.06, 119.21, 127.44,

167.19. IR (NaCl, neat): υ 3032w, 2946m, 1757s, 1431s, 1308w, 1222s, 1068s, 1038s, 979w, 938m, 901m,

833w, 768m, 709m.

4. 3. Preparation of Substrates

Preparation of 2,3-O-(1-methyl ethtyldiene)-D-ribonic acid γ-lactone

D-ribonic acid γ-lactone (7.50 g, 50.63 mmol) was dissolved in 180 mL of acetone dried over 4 Å.

Iodine (1.80 g, 7.08 mmol, 14 mol %) and anhydrous MgSO4 were added, and the mixture was stirred at rt

253

(20 oC) under nitrogen atmosphere for 12 h until no more starting material was detected by TLC. After the

reaction mixture was diluted with excess amount of chloroform, the solid was filtered off and washed with

additional chloroform. The organic phase was washed with 0.2 M sodium thiosulfate solution to give pale

yellow solution, and the aqueous phase was back-extracted with additional dichloromethane. The

combined organic phase was washed with brine solution, dried over MgSO4, and filtered under house

vacuum. After removed the solvent in vacuum, pale yellow solid was formed. The solid was recrystallized

from 95% ethyl alcohol to give white solid needles. More product was isolated from the residue by flash

column chromatography eluting with hexane:EtOAc = 1:1solution (total 8.93 g, 94%).

O OOH

O O

1-77

Rf =0.5 (hexane :EtOAc = 1:1). Mp: 134-136 oC [lit.120 134-136 oC]. 1H NMR (CDCl3, 250 MHz): δ 1.39

(s, 3 H), 1.48(s, 3 H), 1.55 (Br s, 1 H), 3.82 (dd, J = 12.1, 1.6 Hz, 1 H), 4.00 (dd, J = 11.1, 2.3 Hz, 1 H),

4.63 (app t, J = 2.1 Hz, 1 H), 4.77 (dd, J = 5.6 Hz, 1 H), 4.84 (dd, J = 5.6 Hz, 1 H).

Preparation of 5-O-[(1,1-dimethyl)ethyl dimethylsilyl]-2,3-O-(1-methylethtyldiene)-D- ribonic acid γ-

lactone.

2,3-O-(1-Methyl ehtyldiene)-D-ribonic acid γ-lactone (6.73 g, 35.8mmol), tert-butyldimethylsilyl

chloride (6. 47 g, 42.9 mmol), and imidazole (6.09 g, 89.4 mmol) were placed in a 100 mL of flame-dried

flask under nitrogen atmosphere. To the flask was 25 mL of DMF dried over 4 Å molecular sieves slowly

added at 0 oC, and the mixture was stirred at 0 oC for 1 h and at rt for 9 h 30 min. After the starting

material disappeared on TLC, the mixture was diluted with dichloromethane, and washed with H2O and

brine solution. The combined organic phase was dried over MgSO4, filtered, and the solvent was removed

in vacuo. The crude mixture may be used for the next experiment without further purification, or purified

254

by flash column chromatography eluting with hexane;EtOAc = 5:1 to 4:1solution. After column

chromatography, 10.9 g (96%) of white solid was obtained as the product.

O OOTBS

O O

1-78

Rf = 0.63 (hexane:EtOAc = 3:1). Mp: 73-75 oC (lit.121 75-76 oC). 1H NMR (CDCl3, 250 MHz): δ 0.06(s, 3

H), 0.08 (s, 3 H), 0.89 (s, 9 H), 1.39 (s, 3 H), 1.48 (s, 3 H), 3.80 (dd, J = 11.3, 1.0 Hz, 1 H), 3.89 (dd, J =

11.3, 1.8 Hz, 1 H), 4.60 (app t, J = 1.5, Hz, 1 H), 4.70 (dd, J = 5.6 Hz, 1 H), 4.73 (dd, J = 5.6 Hz, 1 H).

Preparation of 5-O-[(1,1-dimethyl)ethyl dimethylsilyl]-2,3-O-(1-methylethyldiene)-D-ribofuranose

To a flame dried 250 mL of flask was added 10.3 g (34.05 mmol) of 5-O-[(1,1-dimethylethyl)

dimethylsilyl]-2,3-O-(1-methyl ehtyldiene)-D- ribonic acid γ-lactone under positive nitrogen atmosphere.

Freshly dried diethyl ether (150 mL) was introduced into the flask, and the temperature of the flask was

lowered to -78 oC. Dibal-H (1. 5 equiv., 1.5 M in toluene) was slowly dropwise over 12 min., and the

mixture was stirred at the temperature for 2 h. After starting material disappeared on TLC, the excess

amount of Dibal-H was quenched by 15 mL of absolute methyl alcohol at -78 oC, and the mixture was

diluted with diethyl ether. The organic phase was washed by saturated sodium tartaric acid solution, water,

and brine solution. The combined organic phase was dried over MgSO4, filtered under house vacuum, and

the solvent was removed on a rotary evaporator. The crude mixture maybe used for the next experiment

without further purification, or purified by flash column chromatography eluting with hexane:EtOAc = 4:1.

Without column, 10.34 g (>99%) of colorless oil was obtained as the product, and the oil changed to white

solid on standing at rt for overnight. 1H NMR shows the product is α/β mixture in a ratio of 0.13/1.00.

255

O OHOTBS

1-79

O O

Rf = 0.47 (hexane:EtOAc = 4:1). Mp: 52-53 oC (lit.121 52-54 oC). Major isomer, β; 1H NMR (CDCl3, 250

MHz): δ 0.13 (s, 3 H) 0.14 (s, 3 H), 0.92(s, 9 H), 1.32 (s, 3 H), 1.49 (s, 3 H), 3.72-3.77 (m, 2 H), 4.36 (s, 1

H), 4.50 (d, J = 5.9 Hz, 1 H), 4.70 (d, J = 5.9 Hz, 1 H), 4.77 (d, J = 11.9 Hz, 1 H), 5.28 (d, J = 11.8 Hz, 1

H). Minor isomer, α; 1H NMR (CDCl3, 250 MHz): δ 0.06(s, 6 H), 0.85(s, 9 H), 1.39 (s, 3 H), 1.55 (s, 3 H),

3.73-3.76 (m, 2 H), 4.15 (s, 1 H), and another 4 H overlap over β anomeric peaks.

Preparation of (1’R, 4S, 5R)-(E and Z)-3-{5-O-[2-(tert-butyldimethylsilanyloxy)-1-hydroxyethyl] -2, 2-

dimethyl[1, 3]dioxolan-4-yl}-acrylic acid tert-butyl ester

To a 100 mL of flame-dried three neck round bottom flask connected to a condenser were added

2.09 g (6.86 mmol) of 5-O-[(1,1-dimethylethyl)dimethylsilyl]-2,3-O-(1-methylehtyldiene)-D-

ribonofuranose and 3.09 g (8.23 mmol) of (carbtert-butoxymethylene)triphenylphosphorane.

Dimethoxyethane (35 mL) was added and the mixture was stirred at rt. for 4 h and then refluxed for another

4 h. After the solvent was removed under vacuum, E and Z mixture mixtures were isolated by flash column

chromatography eluting with hexane only to hexane:EtOAc = 95:5. E and Z mixtures were isolated as

colorless oil in a ratio of 0.24/1.0, and the combined isolated yield was 92%.

Major, (Z)-isomer

OHTBSO

O O

(Z)-1-80, R = tBu

CO2tBu

256

Colorless oil (column chromatography, hexane:EtOAc = 95:5). Rf = 0.38 (hexane:EtOAc = 9:1). [α] 20

D

= +69.3 (c 1.0 in CHCl3). 1H NMR (CDCl3, 300 MHz): δ 0.07 (s, 6H), 0.90 (s, 3H), 1.36 (s, 3 H), 1.47 (s,

3 H), 1.47 (s, 9 H), 2.9 (br s, 1H, disappeared with D2O), 3.59 (ddd, J=8.4, 5.4, 3.0 Hz, 1 H), 3.69 (dd,

J=10.2, 5.4 Hz, 1 H), 3.78 (dd, J=10.2, 3.0 Hz, 1 H), 4.26 (dd, J=8.4, 6.3 Hz, 1 H), 5.69 (ddd, J=8.5, 6.3,

1.0 Hz, 1 H), 5.89 (dd, J=11.6, 1.0 Hz, 1 H), 6.18 (dd, J=11.6, 8.6 Hz, 1 H). 13C NMR (CDCl3, 75 MHz):

δ -5.16, -5.12, 18.6, 25.6, 28.2, 28.3, 64.6, 70.3, 74.1, 78.2, 81.4, 109.2, 124.3, 143.5, 165.9. IR (NaCl,

neat): υ 3477m, 2854s, 2933s, 2857s, 1716s, 1652s, 1463m, 1369s, 1254s, 1159s, 1058 s, 836s, 779s.

Anal. Calcd. for C21H37O6Si: C, 59.67; H, 9.52. Found: C, 59.79; H, 9.69.

Minor, (E)-isomer

OHTBSO

O O

(E)-1-80, R = tBu

CO2tBu

Colorless oil (column chromatography, hexane:EtOAc = 95:5). Rf = 0.24 (hexane:EtOAc = 4:1). [α] 20

D

= -4.62 (c 1.19 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ 0.07 (s, 3 H), 0.08 (s, 3 H), 0.90 (s 9 H), 1.36 (s,

3 H), 1.48 (s, 3 H), 1.48 (s, 9 H), 3.56 (ddd, J = 9.0, 5.6, 3.1 Hz, 1 H), 3.65 (dd, J = 10.0, 5.6 Hz, 1 H), 3.79

(dd, J = 10.0, 3.1 Hz, 1 H), 4.10 (dd, J = 9.3, 6.6 Hz, 1 H), 4.80 (app t, J = 5.1 Hz, 1 H), 6.06 (dd, J = 15.6,

1.5 Hz, 1 H), 7.00 (dd, J = 15.6, 5.2 Hz, 1 H). IR (NaCl, neat): υ 3496m, 2979m, 2950m, 2930m, 2885m,

2875m, 1717s, 1658m, 1472m, 1463m, 1368s, 1314m, 1256s, 1217m, 1153s, 1062m, 837s, 779m.

Cyclized byproduct:

OOTBS

O O

CO2tBu

α/β = 1.0/0.56

257

Column; hexane:EtOAc = 95:5 to 9:1. Colorless oil. Rf = 0.32 (hexane:EtOAc = 9:1). Major isomer, α;

1H NMR (CDCl3, 400 MHz): δ 0.05 (s, 6 H), 0.88 (s, 9 H), 1.43 (s, 9 H), 2.53(d, J = 6.8 Hz, 2 H), 3.68 (d, J

= 3.6 Hz, 2 H), 4.04(dd, J = 7.0, 3.5 Hz, 1 H), 4.27 (ddd, J = 11.1, 6.8, 4.3 Hz, 1 H), 4.39-4.46 (m, 1 H),

4.63 (dd, J = 6.5, 3.2 Hz, 1 H). 13C NMR (CDCl3, 100 MHz): δ -5.49, -5.35, 18.32, 25.55, 25.83, 27.40,

28.05, 40.01, 63.85, 78.69, 81.49, 82.03, 83.08, 84.69, 113.60, 169.96. Minor isomer, β; 1H NMR (CDCl3,

400 MHz): δ 0.03 (s, 6 H), 0.88 (s, 9 H), 1.43 (s, 9 H), 2.59(d, J = 6.9 Hz, 1 H), 2.61 (d, J = 6.9 Hz, 1 H),

3.66 (d, J = 3.6 Hz, 2 H), 4.04(dd, J = 7.0, 3.5 Hz, 1 H), 4.39-4.46 (m, 1 H), 4.72 (dd, J = 6.1, 4.4 Hz, 1 H),

4.78 (dd, J = 6.2, 0.6 Hz, 1 H). 13C NMR (CDCl3, 100 MHz): δ -5.56, -5.55, 18.10, 24.97, 25.90, 26.21,

28.05, 36.37, 64.55, 80.41, 80.70, 81.91, 84.00, 84.81, 112.09, 170.41. IR (NaCl, neat): υ 2930s, 2857s,

1733s, 1472m, 1462m, 1381m, 1368s, 1256s, 1212m, 1157s, 1078s, 977m, 949m, 837s, 778s.


dimethyl[1, 3]dioxolan-4-yl}-acrylic acid ethyl ester

A 50 mL of flame-dried three neck round bottom flask was charged with 609 mg (2.0 mmol) of 5-

O-[(1,1-dimethylethyl)dimethylsilyl]-2,3-O-(1-methylehtyldiene)-D-ribonofuranose and 1.39 g (4.0 mmol)

of (carbethoxymethylene)triphenylphosphorane, and 13 mL of dimeoxylethane was introduced into the

flask under nitrogen atmosphere. The mixture was stirred at 20 oC. Even stirring it for 102 h, small

amount of starting material was detected on TLC. The solvent was removed under vacuum, and the (E)

and (Z) products were isolated as well as 9.5% of starting material. Total isolated yield was 95% based on

recovered starting material, and the ratio of (E)/(Z) was 1.0/3.13.

The isomer ratio, the required amount of (carbethoxymethylene)triphenylphosphorane, and

reaction times were dependent on solvents and reaction temperature.

An alternative procedure may be used for the olefination by stabilized Wittig reagent: To a 50 mL

of flame-dried three neck round bottom were charged 609 mg (2.0 mmol) of 5-O-[(1,1-

dimethylethyl)dimethylsilyl] -2,3-O-(1-methylehtyldiene)-D-ribonofuranose and 766 mg (2.2 mmol) of

(carbethoxymethylene)triphenyl-phosphorane, and 15 mL of freshly dried toluene was introduced into the

flask under nitrogen atmosphere. The mixture was stirred under reflux for 8h. After flash column

258

chromatography, 72% of (E)/(Z) mixture (1.27/1.0) and 15% of cyclized byproduct were isolated. The

cyclized byproduct can be avoided by using 0.1 mol% of benzoic acid.

Major, (Z)-isomer

OHTBSO

O O

(Z)-1-80, R = tBu

CO2Et

Rf = 0.45 (hxane:EtOAc = 6:1). [α] 20

D = +78.5 (c 2.33, CHCl3). 1H NMR (CDCl3, 400 MHz): δ 0.04 (s, 3

H), 0.05 (s, 3 H), 0.87 (s, 9 H), 1.25 (t, J = 7.1 Hz, 3 H), 1.31 (s, 3 H), 1.44 (s, 3 H), 2.54 (Br s, 1 H), 3.55-

3.59 (m, 1 H), 3.65 (dd, J = 10.1, 5.7 Hz, 1 H), 3.75 (dd, J = 10.1, 3.0 Hz, 1 H), 4.16 (q, J = 7.1 Hz, 2 H),

4.23 (dd, J = 8.5, 6.3 Hz, 1 H), 5.73 (ddd, J = 8.3, 6.3, 1.0 Hz, 1 H), 5.94 (dd, J = 11.6, 1.1 Hz, 1 H), 6.26

(dd, J = 11.6, 8.6 Hz, 1 H). 13C NMR (CDCl3, 100 MHz): δ -5.49, -5.44, 14.07, 18.27, 25.33, 25.81, 27.89,

60.44, 64.26, 69.92, 73.75, 77.94, 109.01, 122.13, 144.48, 166.01. IR (NaCl, neat): υ 3484m, 2985m,

2931s, 2857s, 2720s, 1649m, 1464m, 1419m, 1381m, 1371m, 1254m, 1221m, 1191s, 1164m, 1057s, 871m,

836s, 779m.

Minor, (E)-isomer

OHTBSO

O O

(Z)-1-80, R = Et

CO2Et

Rf = 0.34 (hxane:EtOAc = 4:1). 1H NMR (CDCl3, 400 MHz): δ 0.07 (s, 6 H), 0.89 (s, 9 H), 1.35(s, 3 H),

1.47(s, 3 H), 2.57 (app d, J = 4.9 Hz, 1 H), 3.47-3.59 (m, 1 H), 3.64 (dd, J = 9.9, 5.4 Hz, 1 H), 3.77 (dd, J =

9.9, 3.1 Hz, 1 H), 4.12 (dd, J = 9.3, 6.7 Hz, 2 H), 4.19 (q, J = 7.1 Hz, 1 H), 4.86 (app td, J = 9.3, 2.1 Hz, 1

H), 6.13 (dd, J = 15.6, 1.5 Hz, 1 H), 7.11 (dd, J = 15.6, 4.9 Hz, 1 H).

259

Cyclized byproducts

This compound was isolated as a pure form.

OOTBS

O O

CO2Et

Rf = 0.49 (hexane:EtOAc = 6:1). [α] 20

D = -12.0 (c 0.89, CHCl3). 1H NMR (CDCl3, 400 MHz) δ 0.04 (s, 3

H), 0.05 (s, 3 H), 0.89 (s, 9 H), 1.23 (t, J = 7.1 Hz, 3 H), 1.32(s, 3 H), 1.52(s, 3 H), 2.61 (d, J = 6.6 Hz, 2

H), 3.68 (d, J = 3.5 Hz, 2 H), 4.06 (dd, J = 6.7, 3.4 Hz, 1 H), 4.13 (qt, J = 7.1, 3.4 Hz, 2 H), 4.31 (ddd, J =

11.1, 6.7, 4.4 Hz, 1 H), 4.41 (dd, J = 6.4, 4.4 Hz, 1 H), 4.65 (dd, J = 6.4, 3.1 Hz, 1 H). 13C NMR (CDCl3,

100 MHz): δ -5.54, -5.38, 14.12, 18.30, 25.51, 25.88, 27.39, 38.82, 60.49, 63.78, 81.25, 82.01, 84.60,

84.85, 113.69, 170.65. IR (NaCl,neat): υ 2930s, 2857m, 1740s, 1472m, 1371m, 1256m, 1213m, 1159m,

1079s, 837m, 778m.

OOTBS

O O

CO2Et

This compound was isolated as an α/β mixtures at C-1 in a ratio of 1.0/0.58.

Rf = 0.49 (hexane:EtOAc = 6:1). 1H NMR (CDCl3, 250 MHz): δ 0.04 (s, 6 H), 0.88 (s, 9 H), 1.24 (t, J = 7.1

Hz, 3 H), 1.32(s, 3 H), 1.46(s, 3 H), 2.67 (dd, J = 6.8, 2.7 Hz, 2 H), 3.62-3.74 (m, 2 H), 4.09-4.18 (m, 1 H),

4.14 (q, J = 7.2 Hz, 2 H), 4.49 (ddd, J = 10.9, 6.8, 4.1 Hz, 1 H), 4.71-4.81 (m, 2 H).

Preparation of (1’R, 4S, 5R)-(Z)-3-{5-O-[2-(tert-butyldimethylsilanyloxy)-1-hydroxyethyl]-2, 2-

dimethyl[1, 3]dioxolan-4-yl}-acrylic acid tert-butyl ester; 1’-O-(1-imidazoyl)thione

A flame-dried three necked round bottom flask was fitted with a double spaced condenser, and

1.00 g (2.45 mmol) of acrylic acid tert-butyl ester (Z)-1-80, R = tBu, 0.97g (4.90 mmol) of 1,1-

260

thiocarbonyldiimidazole, and 0.1g of DMAP were placed under nitrogen atmosphere. Dichloromethane

(dried over 4 Å MS, 20 mL) was added, and the mixture was refluxed for overnight (13 h 30 min.). The

reaction mixture was cooled to rt, and the solvent was removed by rotary evaporation under house vacuum.

The deep brown oil was purified by flash column chromatography eluting with hexane:EtOAc = 97:3 to

95:1mixture. Desired product (1.031 g) and starting material (86 mg) were obtained. The yield was 89%

based on the recovered starting material.

TBSO

O O

(Z)-1-81

O

NS

N

CO2tBu

Pale yellow oil (column chromatography, hexane:EtOAc = 97:3 to 95:5). [α]D20

= +88.5 (c 3.42 in CHCl3).

Rf = 0.23 (hexane:EtOAc = 9:1). 1H NMR (CDCl3, 250 MHz): δ -0.03 (s, 3 H), 0.00 (s, 3 H), 0.84 (s, 9 H),

1.40 (s, 9 H), 1.40 (s, 3 H), 1.51(s, 3 H), 3.92-4.04 (m, 2 H), 4.85 (dd J = 8.1, 6.3 Hz, 1 H), 5.53 (ddd J =

8.1, 4.0, 2.8 Hz, 1 H), 5.68 (dd, J = 11.6, 1.6 Hz, 1 H), 5.75 (ddd, J = 7.8, 6.4, 1.5 Hz, 1 H), 6.13 (dd J =

11.6, 7.8 Hz, 1 H), 6.98 (s, 1 H), 7.53 (s, 1 H), 8.25 (s, 1 H). 13C NMR (CDCl3, 75 MHz): δ -5.3, 18.3,

25.4, 25.9, 27.9, 28.2, 61.2, 74.1, 74.9, 81.3, 109.6, 118.0, 124.6, 130.7, 137.2, 142.3, 164.8, 183.3. IR

(NaCl, neat): υ 3125w, 2980m, 2953m, 2938m, 2884m, 2857m, 1713s, 1658w, 1650m, 1531w, 1463m,

1413m, 1391s, 1371s, 1345m, 1327s, 1282s, 1245s, 1156s, 1109m, 1066s, 1022m, 986m, 957m, 876m,

833s. Anal. Calcd. for C24H40O6N2SSi: C, 56.22; H, 7.87; N, 5.47; S, 6.24. Found: C, 56.42; H, 8.02; N,

5.38; S, 6.07.

Preparation of (1’R, 4S, 5R)-(E)-3-{5-O-[2-(tert-butyldimethylsilanyloxy)-1-hydroxyethyl]-2, 2-


The desired compound has been made by the same procedure with above. Acrylic acid tert-butyl

ester (E)-1-80, R = tBu (471 mg, 1.2mmol), 475 mg (2.4 mol) of 1,1-thiocarbonyldiimidazole, and 50 mg

261

of DMAP were placed into a flame dried 50 mL of three neck flask with a double spaced condenser.

Dichloromethane (dried over 4 Å MS, 15 mL) was added, and the mixture was stirred under refluxing for

10 h. The starting material was completely consumed (TLC), and excess amount of solvent was removed

under vacuum to give deep brown oil. The mixture was purified by flash column chromatography eluting

with hexane:EtOAc = 8:1 to 6:1 solution. 3(E)-{5(R)-[2-(tert-butyl-dimethyl-silanyloxy)-1(R)-(imidazole-

1-carbothioyloxy)-ethyl]-2,2-dimethyl-[1,3]dioxolan-4(S)-yl}-acrylic acid tert-butyl ester (514 mg, 86%)

was isolated as a pale yellow oil.

TBSO

O O

(E)-1-81

O

NS

N

CO2tBu

Pale yellow oil. Column; hexane:EtOAc = 8:1 to 6:1. [α] 20

D = +3.5 (c 1.0, CHCl3). Rf = 0.24

(hexane:EtOAc = 4:1). 1H NMR (CDCl3, 400 MHz): δ -0.04 (s, 3 H), 0.01 (s, 3 H), 0.85 (s, 9 H), 1.35 (s, 9

H), 1.41 (s, 3 H), 1.51(s, 3 H), 3.97 (dd J = 12.0, 2.9 Hz 1 H), 4.06 (dd J = 11.9, 2.3 Hz 1 H), 4.73 (dd J =

8.9, 6.2 Hz, 1 H), 4.86 (ddd J = 7.1, 6.0, 1.3 Hz, 1 H), 5.36 (app dt, J = 9.0, 2.5 Hz m, 1 H), 5.99 (dd J =

15.6, 1.4 Hz, 1 H), 6.64 (dd J = 15.6, 5.7 Hz, 1 H), 7.08 (s, 1 H), 7.58 (s, 1 H), 8.37 (s, 1 H). 13C NMR

(CDCl3, 100 MHz): δ -5.9, 17.9, 25.0, 27.5, 27.6, 60.0, 74.5, 75.8, 80.14 (d), 109.4, 117.4, 124.7, 130.6,

136.6, 138.6, 164.1, 182.0. IR (NaCl, neat): υ 3134m, 2980s, 1932s, 2857s, 1817m, 1713s, 1608m, 1532w,

1742s, 1385s, 837s, 778s.


dimethyl[1, 3]dioxolan-4-yl}-acrylic acid ethyl ester; 1’-O-(1-imidazoyl)thione

This compound was made with pure acrylic acid ethyl ester or (E)/(Z) mixture because it is

difficult to separate the mixture. (Z)-Acrylic acid ethyl ester (Z)-1-80, R = Et (123 mg, 0.337 mmol), 1,1-

thiocarbonyldiimidazole (180 mg 1.012 mmol), and 19 mg of DMAP were used along with freshly dried

262

THF. After refluxing for 12 h, some starting material was detected on TLC. Additional 3.0 equivalents of

thiocarbonyldiimidazole was added to the flask, and refluxed for 5h 30min. The starting material was

completely consumed (TLC), and the mixture was cooled to rt. After removal of the solvent in vacuo,

brown mixture was isolated by flash column chromatography by hexane:EtOAc = 6:1 to 4:1. Desired

compound (121 mg, 80%) was obtained as yellow oil.

TBSO

O O

(Z)-1-82

O

NS

N

CO2Et

Yellow oil. Column; hexane:EtOAc = 6:1 to 4:1. Rf = 0.30 (hexane:EtOAc = 4:1). [α] 20D = +86.3 (c

0.76, CHCl3). 1H NMR (CDCl3, 400 MHz): δ -0.05 (s, 3 H), -0.01 (s, 3 H), 0.83 (s, 9 H), 1.19 (t, J = 7.1

Hz, 3 H), 1.39 (s, 3 H), 1.50 (s, 3 H), 3.93-4.07 (m, 4 H), 4.86(dd, J = 8.4, 6.4 Hz, 1 H), 5.47-5.50 (m, 1 H),

5.72-5.80 (m, 2 H), 6.22 (dd, J = 11.6, 7.7 Hz, 1 H), 6.98 (d, J = 0.7 Hz, 1 H), 7.52 (s, 1 H), 8.22(s, 1 H).

13C NMR (CDCl3, 100 MHz): δ -5.6, 14.0, 18.1, 25.0, 25.7, 27.6, 60.6, 61.0, 74.0, 74.6, 81.1, 109.5, 117.8,

122.5, 130.5, 143.8, 165.2, 182.9. IR (NaCl, neat): υ 3132w, 2985s, 2930s, 2857s, 1716s, 1650m, 1532m,

1464m, 1389m, 1325m, 1283m, 1229m, 1194m, 1109m, 1066m, 1024m, 986m, 957m, 870m, 834s, 778m,

745m, 655m.



Because it is difficult to separate (E)/(Z) mixture of acrylic acid ethyl ester, the starting material

was used without further purification. Acrylic acid ethyl ester 1-80, R = Et (294 mg, 0.806 mmol, E/Z =

1.3/1.0) and 431 mg (2.42 mmol) of 1,1-thiocarbonyldiimidazole were dissolved in 10 mL of freshly dried

THF along with catalytic amount of DMAP. The mixture was refluxed under nitrogen atmosphere for 6 h.

Because some starting material was detected on TLC, another 3.0 equivalents of thiocarbonyldiimidazole

263

were added, and continually refluxed it for overnight (total 19 h). After confirming that all starting material

was consumed (TLC), the solvent was removed under reduced pressure. The brown mixture was purified

by flash chromatography eluting with hexane:EtOAc = 6:1 to 4:1 solution. E product (149 mg) and Z

product (127 mg) were isolated as yellow oil. Total isolated yield was 77% and the (E)/(Z) ratio was 1/1.2.

TBSO

O O

(E)-1-82

O

NS

N

CO2Et

Yellow oil. Column; hexane:EtOAc = 6:1 to 4:1. Rf = 0.10 (hexane:EtOAc = 4:1). 1H NMR (CDCl3, 400

MHz): δ -0.05 (s, 3 H), -0.00 (s, 3 H), 0.83 (s, 9 H), 1.13 (t, J = 7.1 Hz, 3 H), 1.39 (s, 3 H), 1.49 (s, 3 H),

3.93-4.08 (m, 4 H), 4.72 (dd, J = 8.8, 6.2 Hz, 1 H), 4.86 (ddd, J = 7.3, 6.1, 1.5 Hz, 1 H), 5.36 (app dt, J =

8.8, 2.6 Hz, 1 H), 6.05 (dd, J = 15.6, 1.5 Hz, 1 H), 6.73 (dd, J = 15.6, 5.5 Hz, 1 H), 7.26 (s, 1 H), 7.53 (t, J

= 1.1 Hz, 1 H), 8.25 (s, 1 H). 13C NMR (CDCl3, 100 MHz): δ -5.7, 14.0, 18.2, 25.3, 25.7, 27.7, 60.3, 60.5,

74.9, 76.0, 80.4, 109.9, 117.6, 123.1, 130.9, 136.8, 140.1, 165.1, 182.3.


dimethyl[1, 3]dioxolan-4-yl}-acrylonitrile

To a 100 mL of flame-dried three necked round bottom flask was added 378 mg (1.241 mmol) of

D-ribofuranose, 411 mg (1.366 mmol) of (cyanomethylene)triphenylphosphorane, and 52 mg of benzoic

acid under nitrogen atmosphere. Freshly dried toluene (40 mL) was introduced via a syringe, and the

mixture was refluxed. Two more 206 mg samples of (cyanomethylene)triphenyl-phosphorane were added

after 8 h and 12 h, respectively. After the solvent was removed in vacuo, the mixture was purified by flash

column chromatography eluting with hexane:EtOAc = 10:1 to 8:1, to get 146 mg of (E)-1-83 (white solid),

163 mg of (Z)-1-83 (yellow oil), and 6 mg of cyclized product (yellow oil)

264

OHTBSO

O O

(E)-1-83

CN

White solid (column chromatography, hexane:EtOAc = 10:1 to 8:1). Rf = 0.48 (hexane:EtOAc = 4:1). Mp:

68-70 oC. [α]D20

= -6.0 (c 0.55 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ 0.07 (s, 6H), 0.89 (s, 9H), 1.34

(s, 3H), 1.45 (s, 3H), 2.16 (br s, 1H), 3.45 (ddd, J = 9.4, 5.1, 3.1 Hz, 1H), 3.64 (dd, J = 10.1, 5.2 Hz, 1H),

3.78 (dd, J = 10.1, 3.1 Hz, 1H), 4.13 (dd, J = 9.5, 6.9 Hz, 1H), 4.80 (ddd, J = 6.7, 3.8, 2.1 Hz, 1H), 5.72

(dd, J = 16.2, 2.0 Hz, 1H), 7.00 (dd, J = 16.2, 3.8 Hz, 1H). 13C NMR (CDCl3, 100 MHz): δ -5.54, -5.41,

18.27, 24.99, 25.81, 27.38, 64.11, 69.77, 76.62, 77.19, 100.30, 109.87, 117.26, 151.19. IR (NaCl, neat):

υ 3498br s, 2989m, 2956s, 2930s, 2850s, 2227s, 1638m, 1432m, 1463m, 1383s, 1382s, 1257s, 1217s,

1165m, 1067s, 972w, 864m, 837s, 779s. Anal. Calcd. for C16H29O4NSi: C, 58.68; H, 8.93; N, 4.28. Found:

C, 58.66; H, 8.92; N, 4.12.

OHTBSO

O OCN

(Z)-1-83

Yellow oil (column chromatography, hexane:EtOAc = 10:1 to 8:1). Rf = 0.35 (hexane:EtOAc = 4:1).

[α]D20

= -30.4 (c 1.15 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ 0.08 (s, 3H), 0.09 (s, 3H), 0.91 (s, 9H),

1.37 (s, 3H), 1.48 (s, 3H), 2.62 (Br s, 1H), 3.54 (ddd, J = 9.2, 4.5, 3.5 Hz, 1H), 3.70 (dd, J = 10.1, 4.8 Hz,

1H), 4.18 (dd, J = 9.4, 6.4 Hz, 1H), 5.09 (ddd, J = 8.3, 6.4, 0.9 Hz, 1H), 5.52 (dd, J = 11.2, 1.0 Hz, 1H),

6.56 (dd, J = 11.2, 8.5 Hz, 1H). 13C NMR (CDCl3, 100 MHz): δ -5.51, -5.41, 18.29, 25.25, 25.82, 27.68,

63.91, 69.37, 76.10, 77.45, 101.76, 110.21, 115.36, 148.94. IR (NaCl, neat): υ 3498Br s, 3070w, 2989m,

2885s, 2857s, 2224m, 1723w, 1631w, 1472s, 1463m, 1383s, 1372s, 1255s, 1219s, 1164s, 1096s, 1063s,

937w, 869m, 837s, 779s, 736m, 670m. HRMS (Electrospray): Calcd. for C16H29O4NSNa (M++Na),

265

350.1764; Found (M++Na), 350.1760. Anal. Calcd. for C16H29O4NSi: C, 58.68; H, 8.93; N, 4.28. Found:

C, 58.59; H, 9.32; N, 4.24.

OTBSHO

O OCN

(Z)-1-84

Compound (Z)-1-84 was isolated as yellow oil and 3% yield. Rf = 0.24 (hexane:EtOAc = 4:1), [α] 20

D = -

9.8 (c 0.83, CHCl3). 1H NMR (CDCl3, 250 MHz): δ 0.09 (s, 3 H), 0.89 (s, 9 H), 1.49 (s, 3 H), 1.52 (s, 3 H),

1.94 (t, J = 6.1 Hz, OH, disappeared with D2O), 3.68-3.71 (m, 2 H), 3.89-3.96 (m, 1 H), 4.34 (app t, J = 6.1

Hz, 1 H), 5.05 (dd, J = 9.1, 6.2 Hz, 1 H), 5.46 (d, J = 11.1 Hz, 1 H), 6.60 (dd, J = 11.0, 9.3 Hz, 1 H). 13C

NMR (CDCl3, 100 MHz): δ -3.9, -3.7, 18.5, 25.6, 26.3, 28.2, 65.0, 71.4, 75.7, 79.8, 101.7, 109.9, 115.6,

150.2. IR (NaCl, neat): υ 3498s, 2988s, 2931s, 2885s, 2857s, 2224m, 1727w, 1631w, 1472m, 1463m,

1382m, 1372m, 1254s, 1219s, 1164m, 1096m, 1063s, 937m, 869m, 837s, 779s, 670m.

OTBSHO

O O

(E)-1-84

CN

Compound (E)-1-84 was isolated as yellow oil and 1% yield. Rf = 0.24 (hexane:EtOAc = 4:1). 1H NMR

(CDCl3, 250 MHz): δ 0.15 (s, 3 H), 0.89 (s, 9 H), 1.39 (s, 3 H), 1.49 (s, 3 H), 1.93 (app t, J = 6.0 Hz 1 H),

3.64-3.83 (m, 3 H), 4.31 (app t, J = 6.7 Hz, 1 H), 4.75 (ddd, J = 6.3, 4.5, 1.0 Hz, 1 H), 5.70 (dd, J = 16.2,

1.9 Hz, 1 H), 6.60 (dd, J = 16.2, 4.5 Hz, 1 H).

O O

OOTBS

CN

1-85

266

Compound trans-1-85 was isolated as colorless oil and 4% yield. Rf = 0.47 (hexane:EtOAc = 4:1). 1H

NMR (CDCl3, 250 MHz): δ 0.05 (s, 6 H), 0.89 (s, 9 H), 1.35(s, 3 H), 1.50(s, 3 H), 2.65(d, J = 6.7 Hz, 1 H),

3.70 (dd, J = 11.0, 2.8 Hz, 1 H), 3.78 (dd, J = 11.0, 2.9 Hz, 1 H), 4.15 (app t, J = 2.8 Hz, 1 H), 4.42 (app dt,

J = 6.7, 4.3 Hz, 1 H), 4.71 (dd, J = 5.9, 4.3 Hz, 1 H), 4.84 (d, J = 6.1 Hz, 1 H). 13C NMR (CDCl3, 100

MHz): δ -5.7, -5.6, 18.1, 18.9, 24.6, 25.8, 26.0, 65.4, 78.1, 81.3, 83.3, 84.7, 112.8, 117.6.


dimethyl[1, 3]dioxolan-4-yl}-acryllonitrile; 1’-O-(1-imidazoyl)thione

To a flame-dried 100 mL three necked flask fitted with a condenser were added 133 mg (0.406

mmol) of acrylonitrile (E)-1-84, 3.0 equivalents of 1,1-thiocarbonyldiimidazole (217 mg, 1.217 mmol), and

15 mg of DMAP. Freshly dried THF (40 mL) was added to the flask, and the mixture was stirred under

reflux condition. Another 217 mg of 1,1-thiocarbonyldiimidazole was added after 14 h, and refluxing was

continued for 8 h. All solvents were removed under reduced pressure to give crude brown mixtures. The

mixture was isolated by flash column chromatography eluting hexane:EtOAc = 5:1 to 2:1. The desired

product (E)-1-86 was obtained as pale yellow solid (102 mg, 88% based on recovered starting material) as

well as 46 mg of a mixture of (E)-1-86 and two isomers of cyclic byproducts 1-85 and in a ratio of 0.22/1.0

(cis/trans).

TBSO

O O

CN

(E)-1-86

O

NS

N

Pale yellow solid (column chromatography, hexane:EtOAc = 5:1 to 2:1) Rf = 0.25 (hexane:EtOAc = 3:1).

Mp: 51-53 oC. [α]D20

= -9.5 (c 0.61 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ -0.03 (s, 3H), 0.01 (s, 3H),

0.85 (s, 9H), 1.40 (s, 3H), 1.50 (s, 3H), 3.94 (dd, J = 12.0, 3.1 Hz, 1H), 4.03 (dd, J = 12.0, 2.4 Hz, 1H),

4.75 (dd, J = 8.6, 6.5 Hz, 1H), 4.83 (ddd, J = 6.4, 4.7, 1.8 Hz, 1H), 5.39 (app dt, J = 8.5, 2.8 Hz, 1H), 5.68

267

(dd, J = 16.2, 1.8 Hz, 1H), 6.56 (dd, J = 16.1, 4.6 Hz, 1H), 7.05 (d, J = 0.7 Hz, 1H), 7.60 (s, 1H), 8.29 (s,

1H). 13C NMR (CDCl3, 100 MHz): δ -5.69, -5.62, 18.14, 25.09, 25.68, 27.47, 60.43, 74.85, 75.86, 80.46,

101.81, 110.22, 116.16, 117.97, 131.19, 136.40, 147.56, 182.24. IR (NaCl, neat): υ 3412Br s, 3131m,

3332m, 2988s, 2954s, 2931s, 2884s, 2857s, 2227s, 1704m, 1639m, 1533m, 1470s, 1392s, 1324s, 1283s,

1165m, 1108s, 1054m, 1023s, 957s, 837s, 813m, 779s, 744m, 673m, 655s. Anal. Calcd. for

C20H31O4N3SiS: C, 54.89; H, 7.14; N, 9.60. Found: C, 54.93; H, 7.37; N, 9.45.

The Isolated by products were assigned as follows:

O O

OOTBS

CN

cis-1-85 1H NMR (CDCl3, 400 MHz): δ 0.08 (s, 6 H), 0.90 (s, 3 H), 1.35 (s, 3 H), 1.53 (s, 3 H), 3.73 (d, J = 4.2 Hz,

1 H), 4.11-4.21 (m, 1 H), 4.44 (dd, J = 6.4, 4.2 Hz, 1 H), 4.70 (dd, J = 6.4, 2.7 Hz, 1 H). 13C NMR (CDCl3,

100 MHz): δ -5.51, -5.37, 18.37, 22.30, 25.04, 25.93, 27.43, 63.84, 80.47, 82.27, 84.22, 85.65, 114.16,

116.85.

O O

OOTBS

CN

trans-1-85

Rf = 0.47 (hexane:EtOAc = 4:1). 1H NMR (CDCl3, 250 MHz): δ 0.05 (s, 6 H), 0.89 (s, 9 H), 1.35(s, 3 H),

1.50(s, 3 H), 2.65(d, J = 6.7 Hz, 1 H), 3.70 (dd, J = 11.0, 2.8 Hz, 1 H), 3.78 (dd, J = 11.0, 2.9 Hz, 1 H),

4.15 (app t, J = 2.8 Hz, 1 H), 4.42 (app dt, J = 6.7, 4.3 Hz, 1 H), 4.71 (dd, J = 5.9, 4.3 Hz, 1 H), 4.84 (d, J =

6.1 Hz, 1 H). 13C NMR (CDCl3, 100 MHz): δ -5.7, -5.6, 18.1, 18.9, 24.6, 25.8, 26.0, 65.4, 78.1, 81.3, 83.3,

84.7, 112.8, 117.6.

268



The acrylonitrile (Z)-1-83 (143 mg, 0.45 mmol) and 161 mg (0.90 mmol) of 1,1-

thiocarbonyldiimidazole were dissolved in 20 mL of dichloromethane (dried over 4 Å MS). To the flask

was added 30 mg of DMAP, and the mixture was refluxed under nitrogen atmosphere. After 5 h, another

2.0 equivalents of 1,1-thiocarbonyldiimidazole were added, and refluxing was continued. The TLC showed

starting material still remained after 12 h. Finally, 2.0 equivalents more of 1,1-thiocarbonyldiimidazole, 32

mg of DMAP, and 20 mL of dichloromethane were added, and the mixture was refluxed for total 24 h.

After the mixture was cooled to rt, the solvent was removed under reduced pressure to give crude mixture.

The mixture was isolated by flash column chromatography eluting hexane:EtOAc = 4:1, and 62 mg

(26%)of desired product was obtained as yellow oil. TBDMS groups of some starting material migrated to

the nearby hydroxyl groups (1,3 TBS migration), and the resulting product reacted with 1,1-

thiocarbonyldiimidazole. The byproduct was collected as yellow oil (7 mg, 7%).

(Z)-1-86

TBSO

O O

O

NS

N

CN

Brown oil. Column chromatography; hexane:EtOAc = 4:1 to 2:1. Rf = 0.49 (hexane:EtOAc = 2:1). [α]D20

= +22.9 (c 0.55 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ -0.01 (s, 3H), 0.01 (s, 3H), 0.88 (s, 9H), 1.46 (s,

3H), 1.55 (s, 3H), 3.98 (dd, J = 11.9, 3.1 Hz, 1H), 4.10 (dd, J = 11.9, 2.4 Hz, 1H), 4.87 (dd, J = 9.1, 6.3 Hz,

1H), 5.19 (ddd, J = 8.8, 6.3, 0.8 Hz, 1H), 5.40 (dd, J = 11.1, 0.9 Hz, 1H), 5.50 (app dt, J = 9.1, 2.8 Hz, 1H),

6.45 (dd, J = 11.1, 8.9 Hz, 1H), 7.07 (d, J = 0.7 Hz, 1H), 7.59 (s, 1H), 8.34 (s, 1H). 13C NMR (CDCl3, 100

MHz): δ -5.73, -5.69, 18.08, 25.08, 25.62, 27.52, 60.47, 74.55, 75.46, 80.28, 102.78, 110.71, 114.30,

117.52, 131.09, 137.17, 147.90, 182.59. IR (NaCl, neat): υ 3395Br s, 3164m, 3332m, 3120m, 2988m,

2955s, 2931s, 2883s, 2857s, 2224m, 1703m, 1533m, 1464s, 1391s, 1325s, 1284s, 1230s, 1163m, 1102s,

269

1075s, 1025s, 990s, 956s, 911s, 869s, 834s, 813m, 778s, 734s, 656m, 644m. Anal. Calcd. for

C20H31O4N3SiS; C, 54.89; H, 7.14; N, 9.60. Found; C, 54.40; H, 7.06; N, 9.32. HRMS (Electrospray): m/z

Calcd for C20H31N3SiSO4Na (M++Na), 460.1697; Found (M++Na), 460.1671.

Preparation of (1’R, 4S, 5R)-{5-O-[2-(tert-butyldimethylsilanyloxy)-1-hydroxyethyl]-2, 2-dimethyl[1,

3]dioxolan-4-yl}-ethene

Dried methyltriphenylphosphonium bromide (3.55 g, 9.93 mmol) was suspended into a 250 mL of

flame-dried flask, which was charged with 40 mL of fresh THF under nitrogen. The flask was cooled to –

78oC, and 6.2 mL of nBuLi (1.6 M in hexane) was slowly added to give yellow color. The mixture was

stirred at -78 oC for 10 min. and at rt for 2h. The solution was cooled to -78 oC again, and 1.25 g (3.97

mmol) of 5-O-[(1,1-dimethylethyl)dimethylsilyl]-2,3-O-(1-methylehtyldiene)-D-ribonofuranose in 25 mL

of dried THF was dropwised. After the addition, the mixture stirred at -78oC for 10 min. and at rt for 21h.

To quench excess phosphorane, 10 mL of acetone was added, and the mixture stirred for 10min. After

removed the solvent under vacuum, the mixture was purified by flash column chromatography eluting with

hexane:acetone = 10:1. The isolated product was 733.5 mg of 1-87 as colorless oil, and 170.7 mg of

starting material was recovered. The yield was 71% based on the recovered starting material.

OHTBSO

O O

1-87

Column; hexane:Acetone = 10:1. Rf = 0.32 (hexane:EtOAc = 9:1). [α] 20D = -1.55 (c 0.58, CHCl3). 1H

NMR (CDCl3, 400 MHz): δ 0.07 (s, 6 H), 0.89 (s, 9 H), 1.34 (s, 3 H), 1.45 (s, 3 H), 2.44 (Br s, 1 H), 3.60-

3.67 (m, 1 H), 3.66 (dd, J = 15.5, 5.7 Hz, 1 H), 3.79 (dd, J = 9.9, 3.6 Hz, 1 H), 4.04(dd, J = 8.9, 6.3 Hz, 1

H), 4.67 (app tt, J = 12.9, 1.0 Hz, 1 H), 5.26 (ddd, J = 11.7, 1.7, 1.3 Hz, 1 H), 5.40 (app dt, J = 17.1, 3.1 Hz,

1 H), 6.03 (ddd, J = 17.1, 10.4, 6.6 Hz, 1 H). 13C NMR (CDCl3, 100 MHz): δ -5.5, -5.5, 18.3, 25.4, 25.8,

270

27.8, 64.3, 69.5, 77.4, 78.7, 108.7, 117.4, 134.2. IR (NaCl, neat): υ 3561m, 2959s, 2930s, 2856m, 1643w,

1462m, 1370m, 1253m, 1216m, 1167m, 1114m, 1058s, 924m, 873m, 836s, 778m.

Preparation of (1’R, 4S, 5R)-{5-O-[2-(tert-butyldimethylsilanyloxy)-1-hydroxyethyl]-2, 2-dimethyl[1,

3]dioxolan-4-yl}-ethene; 1’-O-(1-imidazoyl)thione

(1’R, 4S, 5R)-{5-[2-(tert-Butyldimethylsilanyloxy)-1-hydroxyethyl]-2, 2-dimethyl[1, 3]dioxolan-

4-yl}-ethene (153 mg, 0.506 mmol), 1,1-thiocarbonyldiimidazole (270 mg, 1.517 mmol), and 40 mg of

DMAP were dissolved in 20 mL of freshly dried THF. The mixture was refluxed under nitrogen

atmosphere for 8 h 30 min., and another 270 mg of 1,1-thiocarbonyldiimidazole was added. The mixture

was refluxed for another 12 h 30 min, and all starting material was consumed (TLC). After the reaction

mixture cooled to rt, the solvent was removed under reduced pressure to give brown oil. The oil was

purified by flash column chromatography with hexane:acetone = 15:1 solution. The product was obtained

as yellow oil (146 mg, 70%).

TBSO

O O

1-88

O

NS

N

Yellow oil. Column; hexane:acetone = 15:1. Rf = 0.22 (hexane:Acetone = 9:1). 1H NMR (CDCl3, 400

MHz): δ -0.04 (s, 3 H), 0.01 (s, 3 H), 0.85 (s, 9 H), 1.39 (s, 3 H), 1.49 (s, 3 H), 3.97 (dd, J = 11.9, 3.4 Hz, 1

H), 4.08 (dd, J = 11.9, 2.5 Hz, 1 H), 4.68 (dd, J = 14.1, 6.3 Hz, 1 H), 4.71 (dd, J = 14.6, 6.3 Hz, 1 H), 5.12

(app dt, J = 10.3, 0.9 Hz, 1 H), 5.32 (app dt, J = 17.0, 1.2 Hz, 1 H), 5.45 (app dt, J = 7.5, 3.2 Hz, 1 H), 5.76

(ddd, J = 17.1, 10.3, 6.8 Hz, 1 H), 7.03 (s, 1 H), 7.58 (s, 1 H), 8.29 (s, 1 H). 13C NMR (CDCl3, 100 MHz):

δ -5.6, 18.2, 25.2, 25.7, 27.6, 60.5, 74.7, 78.3, 81.4, 109.2, 117.8, 118.9, 130.7, 132.2, 136.7, 182.8. IR

271

(NaCl, neat): υ 3179m, 2986s, 2953s, 2930s, 2884m, 2857s, 1646w, 1531w, 1464s, 1388s, 1325s, 1283s,

1247s, 1166m, 1109s, 1054m, 1009m, 958m, 874m, 835s, 778m, 744m, 654m.


dimethyl[1, 3]dioxolan-4-yl}-O-methylhydroxyl amine

A dried 100 mL three necked round bottom flask was equipped with a condenser and a magnetic

stirring bar. To the flask were added 5-O-[(1,1-dimethylethyl)dimethylsilyl]-2,3-O-(1-methylehtyldiene)-

D-ribonofuranose 1-79 (305mg, 1.00 mmol) and 133 mg (1.50 mmol) of O-methylhydroxyl amine

hydrochloride under nitrogen. Methyl alcohol (50 mL) and 1 mL of pyridine were added, and the mixture

was refluxed under nitrogen for 5.5 h. The mixture was taken up water, and extracted with

dichloromethane. The combined organic phase was washed with brine and dried over MgSO4. After the

solid was filtered off, the collected organic phase was concentrated on a rotary evaporator and purified by

flash column chromatography eluting with hexane:EtOAc = 6:1. The isolated product (319 mg of colorless

oil) was obtained as a syn/anti mixture in a ratio of 1.0/0.25, and the yield was 96%.

OHTBSO

O O

NOCH3

1-89

Colorless oil (syn/anti = 1.0/0.25) (column chromatography, hexane:EtOAc = 6:1). Rf = 0.49

(hexane:EtOAc = 4:1). 1H NMR (CDCl3, 250 MHz): major isomer, syn, δ 0.05 (s, 6 H), 0.87 (s, 9 H), 1.32

(s, 3 H), 1.43 (s, 3 H), 2.62 (d, J = 4.8 Hz, 1 H), 3.50-3.70 (m, 3 H), 3.83 (s, 3 H), 4.09 (dd J = 8.5, 6.4 Hz 1

H), 4.72 (app t, J = 7.4 Hz 1 H), 7.16 (d, J = 7.7 Hz 1 H); minor isomer, anti; δ 0.05 (s, 6 H), 0.87 (s, 9 H),

1.11 (s, 3 H), 1.21 (s, 3 H), 2.70 (d, J = 3.8 Hz, 1 H), 3.71-3.83 (m, 3 H), 3.87 (s, 3 H), 4.20 (app t J = 6.7

Hz 1 H), 5.26 (app t, J = 6.3 Hz 1 H), 6.83 (d, J = 6.3 Hz 1 H). 13C NMR (CDCl3, 75 MHz): major isomer,

syn, δ -5.3, -5.1, 18.3, 26.0, 27.0, 28.0, 62.0, 64.3, 69.5, 75.4, 78.6, 109.9, 147.2; minor isomer, anti, δ -5.6,

-5.5, 18.4, 25.3, 25.7, 27.8, 62.4, 63.1, 70.7, 75.9, 82.4, 113.1, 149.1. IR (NaCl, neat): υ 3522Br, 2987s,

272

2956s, 2932s, 2884s, 2875s, 2819w, 1795w, 1741w, 1629w, 1471s, 1468s, 1382s, 1255s, 1219s, 1170s,

1154s, 1117s, 1047s.


dimethyl[1, 3]dioxolan-4-yl}-O-methylhydroxyl amine; 1’-O-(1-imidazoyl)thione

The reaction was performed with 173 mg (0.519 mmol) of O-methylhydroxyl amine 1-89 and 308

mg (1.557 mmol) of 1,1-thiocarbonyldiimidazole in 10 mL of freshly dried THF under nitrogen

atmosphere. The mixture was refluxed in an oil bath for 9 h, and another 1.0 equivalent of 1,1-

thiocarbonyldiimidazole was added. After 1.5 h refluxing, all starting material was consumed (TLC). The

mixture was cooled to rt, and the crude mixture was purified by flash column chromatography eluting with

hexane:EtOAc = 8:1 to 6:1. The isolated product was obtained as yellow oil (212 mg), and yield was 92%

(syn/anti = 1.00/0.32).

TBSO

O O

NOCH3

1-90

O

NS

N

Yellow oil (column chromatography, hexane:EtOAc = 8:1 to 6:1). Rf = 0.29 (hexane:EtOAc = 4:1). 1H

NMR (CDCl3, 400 MHz): major syn, δ 0.00(s, 3 H), 0.04 (s, 3 H), 0.88 (s 9 H), 1.39 (s, 3 H), 1.51 (s, 3 H),

3.57 (s, 3 H), 3.99 (dd, J = 11.7, 2.9 Hz, 1 H), 4.12 (dd, J = 11.9, 2.6 Hz, 1 H), 4.76-4.81 (m, 2 H), 5.49-

5.58(m, 1 H), 7.04 (s, 1 H), 7.27 (d, J = 7.8 Hz, 1 H), 7.61 (s, 1 H), 8.30 (s, 1 H); minor anti, δ 0.01 (s, 3

H), 0.03 (s, 3 H), 0.86 (s 9 H), 1.39 (s, 3 H), 1.52 (s, 3 H), 3.66 (s, 3 H), 3.95-4.03 (m, 2 H), 4.76-4.81 (m, 1

H), 5.31 (app t, J = 6.0 Hz, 1 H), 5.49-5.56 (m, 1 H), 6.80 (d, J = 7.8 Hz, 1 H), 7.04 (s, 1 H), 7.63 (s, 1 H),

8.30 (s, 1 H). 13C NMR (CDCl3, 125 MHz): major syn, δ -5.3, 18.4, 25.3, 25.9, 27.8, 60.7, 61.9, 74.2, 75.1,

80.6, 110.6, 118.1, 131.0, 137.0, 145.9, 182.0. IR (NaCl, neat): υ 3133w, 2989m, 2953m, 2935m, 2897m,

2856m, 1739w, 1626m, 1531w, 1463m, 1391s, 1344m, 1323s, 1283s, 1246s, 1229s, 1109m, 1076m, 1042s.

273

Anal. Calcd. for C19H33O5N2Ssi: C, 51.44; H, 7.50; N, 9.42; S, 7.23. Found: C, 51.57; H, 7.61; N, 9.23; S,

7.11.


dimethyl[1, 3]dioxolan-4-yl}-N,N-dimethylhydrazone

A mixture of 5-O-[(1,1-dimethylethyl)dimethylsilyl]-2,3-O-(1-methylehtyldiene)-D-

ribonofuranose 1-79 (222 mg, 0.73 mmol) and N,N-dimethyl hydrazine (6.6 mg, 1.10 mmol) was dissolved

in 10 mL of absolute methyl alcohol under nitrogen atmosphere. The mixture was refluxed in an oil bath

until no more starting material was detected on TLC (additional N,N-dimethyl hydrazine were added to the

reaction mixture, 2 X 3 equivalents). After the solvent was removed under vacuum, the crude mixture was

purified by flash column chromatography with hexane:EtOAc = 6:1 to 5:1. The product was obtained as

yellow oil (193 mg), which consisted of cyclic and acyclic compounds. The major portion was a syn/anti

mixture (1.0/0.17), and the minor portion was a cyclized α/β product (1.0/0.77). This mixture was used for

the next experiment without further purification.

These two compounds were isolated as mixtures of 1-91/1-92 = 1.0/0.16.

OHTBSO

O O

NN(CH3)2

O O

OOTBS

NHN(CH3)2

+

1-91 1-92

Rf = 0.18 (hexane:EtOAc = 4:1). Major isomer 1-91, Syn,; 1H NMR (CDCl3, 400 MHz): δ 0.06 (s, 6 H),

0.88 (s, 9 H), 1.34 (s, 3 H), 1.45(s, 3 H), 2.81 (s, 6 H), 3.64-3.81(m, 4 H), 4.09 (dd, J = 8.8, 6.2 Hz, 1 H),

4.78 (dd, J = 6.5, 6.4 Hz, 1 H), 6.55 (d, J = 6.8 Hz, 1 H). 13C NMR (CDCl3, 100 MHz): δ -5.49, 19.29,

25.36, 25.83, 27.85, 42.54, 64.18, 69.70, 77.47, 78.37, 108.85, 131.77. anti, 1H NMR (CDCl3, 400 MHz):

δ 0.06(s, 6 H), 0.91 (s, 9 H), 1.39 (s, 3 H), 1.49(s, 3 H), 2.80 (s, 6 H), 3.64-3.81(m, 4 H, overlap over syn

compounds), 4.09 (m, 1 H, overlap over syn compounds), 4.67 (d, J = 6.1 Hz, 1 H), 6.45 (d, J = 5.6 Hz, 1

H). 13C NMR (CDCl3, 100 MHz): δ -5.49, 18.24, 24.45, 25.95, 27.85, 42.42, 64.08, 72.50, 77.19, 78.44,

274

109.07, 131.50. Minor isomer 1-92, α anomer; 1H NMR (CDCl3, 400 MHz): δ 0.04 (s, 3 H), 0.05 (s, 3 H),

0.88 (s, 9 H), 1.31 (s, 3 H), 1.39(s, 3 H), 2.46 (s, 3 H), 2.72-2.79(m, NH, disappeared with D2O), 3.94 (dd, J

= 7.8, 6.5 Hz, 1 H), 4.02 (t, J = 3.7 Hz, 1 H), 4.12-4.18 (m, 1 H), 4.54-4.58 (m, 2 H), 5.10 (d, J = 3.9 Hz, 1

H). 13C NMR (CDCl3, 100 MHz): δ -5.68, 18.24, 26.18, 27.0, 49.86, 64.88, 78.44, 80.48, 81.15, 84.49,

93.22, 111.91. β anomer; 1H NMR (CDCl3, 400 MHz) δ 0.04 (s, 3 H), 0.05 (s, 3 H), 0.87 (s, 9 H), 1.31 (s,

3 H), 1.39(s, 3 H), 2.50 (s, 3 H), 2.50 (s, 3 H), 2.72-2.79(m, NH, disappeared with D2O), 3.94 (m, overlap

over α anomer, 1 H), 4.02 (t, J = 3.7 Hz, overlap over α anomer, 1 H), 4.39 (dd, J = 6.2, 2.7 Hz, 1 H), 4.54-

4.58 (m, overlap over α anomer, 2 H), 4.92 (d, J = 2.6 Hz, 1 H). 13C NMR (CDCl3, 100 MHz) δ -5.43,

18.08, 25.94, 26.80, 49.61, 64.56, 79.31, 81.42, 81.75, 84.74, 98.55, 112.48.


dimethyl[1, 3]dioxolan-4-yl}-N,N-dimethylhydrazone; 1’-O-(1-imidazoyl)thione

A mixture of N,N-dimethylhydrazone 1-91/1-92 (178mg) and thiocarbonyl-diimidazole (407 mg)

was placed in a 25 mL of flame dried three neck flask, which was connected to a double spaced condensor.

Freshly dried THF (10 mL) was added to the flask, and the mixture was refluxed under nitrogen

atmosphere for 10 hr. Another 1.5 equivalent of thiocarbonyl-diimidazole was added and refluxing was

continued for 2 h. All solvents were removed under reduced pressure, and the dark brown mixture was

purified by column chromatography to give 133 mg of 1-93 as yellow oil. The product was a syn/anti

mixture in a ratio of 0.58:1.00 based on 1H NMR spectrum.

TBSO

O O

NN(CH3)2

1-93

O

NS

N

Yellow oil. Column; hexane:EtOAc = 7:1 to 5:1; Rf = 0.28 (hexane:EtOAc = 2:1). Major isomer, anti; 1H

NMR (CDCl3, 400 MHz): δ 0.02 (s, 3 H), 0.04 (s, 3 H), 0.84 (s, 9 H), 1.39(s, 3 H), 1.43(s, 3 H), 2.69 (s, 6

275

H), 3.96 (dd, J = 11.6, 5.1 Hz, 1 H), 4.02 (dd, J = 11.6, 3.6 Hz, 1 H), 4.32 (dd, J = 7.9, 6.7 Hz, 1 H), 4.60

(dd, J = 8.0, 6.4 Hz, 1 H), 5.82-5.84(m, 1 H), 6.29 (d, J = 6.3 Hz, 1 H), 6.99 (s, 1 H), 7.59 (s, 1 H), 8.26 (s,

1 H). Minor isomer, syn; 1H NMR (CDCl3, 400 MHz): δ -0.02 (s, 3 H), 0.02 (s, 3 H), 0.85 (s, 9 H), 1.41(s,

3 H), 1.51(s, 3 H), 2.57 (s, 6 H), 4.10 (dd, J = 11.9, 3.8 Hz, 1 H), 4.13 (dd, J = 11.9, 2.3 Hz, 1 H), 4.72 (dd,

J = 9.3, 6.5 Hz, 1H), 4.86 (app t, J = 6.6 Hz, 1H), 5.50 (app dt, J = 9.2, 2.5 Hz 1H), 6.20 (d, J = 7.3 Hz, 1

H), 7.01 (t, J = 0.8 Hz, 1 H), 7.55(s, 1 H), 8.27 (s, 1 H).

Reaction with 2,3-O-(1-methyl ehthyldiene)-5-O-[(1,1-dimethyl)ethyl dimethylsilyl] -D-ribose, and p-

TsNHNH2

5-O-[(1,1-Dimethylethyl) dimethylsilyl]-2,3-O-(1-methylehtyldiene)-D-ribonofuranose (222 mg,

0.73 mmol) and 143 mg (0.77 mmol) of p-toluenesulfonyl hydrazine were dissolved in 10 mL of dried

acetonitrile (dried over 4 Å MS). The mixture was refluxed for 2 h 30min, and another 1.05 equivalents of

p-toluenesulfonyl hydrazine were added. After refluxing for overnight, all starting material was consumed

(TLC). The mixture was concentrated under vacuum, and purified by flash column chromatography

eluting with hexane: EtOAc = 4:1. Very sticky colorless oil was obtained as the product and the isolated

yield was 80%. NMR spectrum shows the product is α/β mixture in a ratio of 1:2.

OOTBS

NHNHTs

O O

1-94

Rf = 0.25 (hexane:EtOAc = 3:1). Major β anomer; 1H NMR (CDCl3, 400 MHz): δ 0.00 (s, 3 H), 0.01 (s, 3

H), 0.79 (s 9 H), 1.25 (s, 3 H), 1.39 (s, 3 H), 2.38 (s, 3 H), 3.64 (dd, J = 11.5, 2.3 Hz, 1 H), 3.68 (dd, J =

11.3, 2.0 Hz, 1 H), 4.23 (d, J = 1.1 Hz, 1 H) 4.33 (dd, J = 6.0, 0.9 Hz, 1 H), 4.55-4.58 (m, 2 H), 4.74 (d, J =

10.3 Hz, 1 H), 6.53 (s, 1 H), 7.26 (d, J = 8.1 Hz, 2 H), 7.78-7.82 (m, 2 H). 13C NMR (CDCl3, 100 MHz):

δ -5.9, -5.8, 18.1, 21.4, 24.9, 25.7, 26.6, 64.6, 81.6, 83.6, 85.7, 97.3, 112.2, 128.1, 129.3, 135.5, 143.5.

Minor α anomer; 1H NMR (CDCl3, 400 MHz): δ -0.04 (s, 3 H), -0.02 (s, 3 H), 0.79 (s 9 H), 1.27 (s, 3 H),

276

1.40 (s, 3H), 2.38 (s, 3H), 3.57 (dd, J = 11.0, 2.6 Hz, 1H), 3.61 (dd, J = 11.6, 2.3 Hz, 1H), 3.99 (app t, J =

2.4 Hz, 1 H), 4.38 (d J = 11.3 Hz, 1 H), 4.48 (dd, J = 6.0, 4.1 Hz, 1 H), 4.65 (d, J = 6.1 Hz, 1 H), 4.72 (dd, J

= 11.3, 4.0 Hz, 1 H), 6.49 (s, 1 H), 7.26 (d, J = 8.1 Hz, 2 H), 7.78-7.82 (m, 2 H). 13C NMR (CDCl3, 100

MHz): δ -5.8, -5.7, 17.9, 21.4, 24.2, 25.7, 26.0, 65.1, 79.5, 82.1, 82.2, 92.1, 112.3, 128.1, 129.3, 135.5,

143.5. IR (NaCl, neat): υ 3240m, 2955s, 2930s, 2857s, 1599m, 1495w, 1462m, 1382m, 1334m, 1256m,

1211m, 1165s, 1119m, 1091s, 978m, 838s, 813m, 780m, 662m.

The reaction of 1-94 with 1,1’-thiocarbonyldiimidazole

A mixture of 1-94 (233 mg, 0.609 mmol), 1,1-thiocarbonyl-diimidazole (375 mg, 1.892 mmol),

and DMAP (40 mg) was placed in a flame dried flask with a condenser. After 40 mL of dichloromethane

(dried over 4 Å MS) was added via a syringe, the mixture was refluxed under nitrogen for 2 h 30 min.

Another 1.892 mmol of 1,1-thiocarbonyldiimidazole and 40 mg of DMAP were added, and refluxing was

continued for 4 h 30 min. The mixture was cooled to rt and the solvent was removed under vacuum to get

the crude mixture of 1-95. The mixture was isolated by flash column chromatography with

hexane:EtOAc= 2:1 to 1:1 solution. The product (110.5 mg of brown solid) was obtained in an isolated

yield of 47%.

O O

OOTBS

NNH

1-95

NNS

Pale yellow solid. Column: hexane:EtOAc = 2:1 to 1:1. Rf = 0.30 (hexane:EtOAc = 1:2). [α] 20

D = +78.5

(c 2.33, CHCl3). Mp: 100-102 oC. 1H NMR (CDCl3, 400 MHz): δ 0.05 (s, 6 H), 0.87 (s, 9 H), 1.44 (s, 3

H), 1.63 (s, 3 H), 3.46-3.50 (m, 2 H, one H is disappeared with D2O), 3.72 (dd, J = 10.4, 4.4 Hz, 1 H), 3.79

(dd, J = 10.4, 2.5 Hz, 1 H), 4.55 (dd, J = 9.2, 6.5 Hz, 1 H), 5.61 (d, J = 6.5, 1 H), 7.19 (s, 1 H), 7.50 (s, 1

H), 8.13 (s, 1 H). 13C NMR (CDCl3, 100 MHz): δ -5.5 -5.4, 18.3, 24.8, 25.8, 27.2, 64.2, 69.7, 75.3, 77.9,

111.3, 118.4, 131.5, 136.3, 159.6, 169.4. C18H30O4N4SSi 427.1835 (M+ + H), found 427.1825.

277

Preparation of 5-O-[(1,1-dimethyl)ethyl diphenylsilyl]-2, 3-O-(1-methyl ehtyldiene)-D- ribonic acid γ-

lactone.

5-O-[(1,1-Dimethylethyl)diphenylsilyl]-D- ribonic acid γ-lactone (3.87 g, 10.0 mmol) was

dissolved in 36 mL of acetone dried over 4 Å. Iodine (0.36 g, 1.40 mmol, 14 mol %) and 0.75 g of

anhydrous MgSO4 were added, and the mixture was stirred at rt (20 oC) under nitrogen atmosphere for 12h.

All starting material was consumed and starting material was not detected on TLC. After the reaction

mixture was diluted with excess amount of chloroform, the reaction mixture was filtered and the filtrate

was washed with additional chloroform. The collected organic phase was washed with 0.2 M sodium

thiosulfate solution to give pale yellow solution, and the aqueous phase was back extracted with additional

dichloromethane. The combined organic phase was washed with brine solution and dried over MgSO4. the

solid was filtered off under house vacuum. After removal of the solvent in vacuum, pale yellow oil was

obtained. The crude mixture was purified by flash column chromatography eluting with hexane:EtOAc =

7:1 to 5:1 solution. The product was obtained as yellow oil (4.18 g, 98%).

O OOTBDPS

O O

1-97

Pale yellow oil. Column; hexane:EtOAc = 7:1 to 5:1. Rf = 0.42 (hexane:EtOAc = 5:1). [α] 20D = -13.1 (c

0.94, CHCl3). 1H NMR (CDCl3, 400 MHz): δ 1.04(s, 9 H), 1.40 (s, 3 H), 1.49 (s, 3 H), 3.76 (dd, J = 11.5,

1.5 Hz, 1 H), 3.92 (dd, J = 11.5, 2.3 Hz, 1 H), 4.74 (d, J = 5.6 Hz, 1 H), 4.90 (d, J = 5.7Hz, 1 H), 7.37-7.49

(m, 6 H), 7.58-7.65 (m, 4 H). 13C NMR (CDCl3, 100 MHz): δ 19.1, 25.6, 26.7, 26.8, 63.5, 75.8, 78.4, 82.3,

113.1, 127.9, 128.0, 130.2, 131.5, 132.3, 135.4, 135.6, 174.1. IR (NaCl, neat): υ 3071w, 2991m, 2955m,

2933m, 2858m, 1789s, 1589w, 1472m, 1428m, 1384m, 1350m, 1272m, 1239m, 1216m, 1179m, 1152m,

1113s, 1082s, 1017m, 979m, 943m, 890w, 865m, 744m, 727m, 703s, 628m.

278

Preparation of 5-O-[(1,1-dimethyl)ethyl diphenylsilyl]-2, 3-O-(1-methyl ethyldiene)-D-ribonofuranose

To a flame-dried 50mL of flask was added 0.70 g (1.64 mmol) of 5-O-[(1,1-dimethylethyl)

diphemylsilyl] -2,3-O-(1-methyl ethyldiene)-D- ribonic acid γ-lactone and 30 mL of fresh dried diethyl

ether under positive nitrogen atmosphere. The temperature of the flask was lowered to -78 oC. Dibal-H

(1.5 equivalents, 1.5 M in toluene) was slowly dropwise over 10 min., and the mixture was stirred at the

temperature for 4 h. After the starting material was consumed (TLC), the excess amount of Dibal-H was

quenched by 10 mL of absolute methyl alcohol at -78 oC. The mixture was diluted with diethyl ether, and

the organic phase was washed by saturated sodium tartaric acid solution, water, and brine solution. The

combined organic phase was dried over MgSO4, filtered under house vacuum, and the solvent was removed

on a rotary evaporator. The crude mixture was subjected to column chromatography with eluting with

hexane:EtOAc = 9:1. 1H NMR shows the α/β ratio of the product is 0.24/1.00.

O O

O OHOTBDPS

1-98

α/β = 0.24/1.0

Colorless oil. Column: hexane:EtOAc = 9:1. Rf = 0.27 (hexane:EtOAc = 7:1). Major isomer, β; 1H NMR

(CDCl3, 400 MHz): δ 1.00(s, 9 H), 1.31 (s, 3 H), 1.38 (s, 3 H), 3.58 (dd, J = 11.3, 2.8 Hz, 1 H), 3.73 (dd, J

= 11.3, 3.2 Hz, 1 H), 4.20 (app t, J = 2.7 Hz, 1 H), 4.43 (d, J = 10.2 Hz, 1 H), 4.52 (d, J = 5.9 Hz, 1 H), 4.63

(d, J = 5.9 Hz, 1 H), 5.27 (d, J = 9.7 Hz, 1 H), 7.16-7.37 (m, 6 H), 7.54-7.60 (m, 4 H). 13C NMR (CDCl3,

100 MHz): δ 19.0, 24.9, 26.4, 26.8, 65.4, 79,4, 81.6, 87.1, 103.2, 112.0, 127.8, 127.9, 129.8, 130.3, 131.6,

132.3, 135.4. Minor isomer, α; 1H NMR (CDCl3, 400 MHz): δ 0.97(s, 9 H), 1.31 (s, 3 H), 1.47 (s, 3 H),

3.64 (dd, J = 11.1, 2.4 Hz, 1 H), 3.72 (dd, J = 11.1, 2.8 Hz, 1 H), 3.89 (d, J = 11.2 Hz, 1 H), 4.07 (app t, J =

2.2 Hz, 1 H), 4.58 (dd, J = 6.2, 4.1 Hz, 1 H), 4.69 (dd, J = 6.3, 0.7 Hz, 1 H), 5.53 (dd, J = 10.9, 3.9 Hz, 1

H), 7.16-7.37 (m, 6 H), 7.54-7.60 (m, 4 H). 13C NMR (CDCl3, 100 MHz): δ 18.9, 24.6, 26.0, 26.8, 65.9,

81.1, 81.8, 86.9, 97.9, 112.9, 127.8, 129.9, 130.1, 131.7, 132.5, 135.6. IR (NaCl, neat): υ 3428s, 3074s,

279

3050s, 2934s, 2858s, 2358w, 2251w, 1962w, 1894w, 1827w, 1706m, 1589m, 1567w, 1472s, 1428s, 1382s,

1312m, 1267m, 1238m, 1160m, 1112s, 1074s, 999m, 937m, 911m, 871m, 823m, 777m, 738s, 702s, 614s.

Preparation of (1’R, 4S, 5R)-(E and Z)-3-{5-O-[2-(tert-butyldipheylsilanyloxy)-1-hydroxyethyl]-2, 2-

dimethyl[1, 3]dioxolan-4-yl}-N,N-diphethylhydrazone

To a flame dried flask was added 123 mg of 5-O-[(1,1-dimethylethyl)diphenylsilyl]-2,3-O-(1-

methylethyldiene)-D-ribonofuranose in 10 mL of methyl alcohol. To another flask was added 123 mg of

diphenylhydrazine hydrochloride in 10 mL of anhydrous methyl alcohol. To quench the hydrochloride, the

mixture was stirred with 45.4 mg of pyridine under nitrogen atmosphere at rt for 30min. The freshly

prepared diphenyl hydrazine solution was added dropwise into the flask containing D-ribonofuranose

solution. After stirring the mixture at rt for 21 5 h at rt, another 0.75 equiv. of freshly prepared diphenyl

hydrazine solution was added and the mixture was stirred for 3 h. All solvent was removed under reduced

pressure, and the crude mixture was purified by column chromatography eluting with hexane:EtOAc = 10:1

with 1% of Et3N. Reddish oil was obtained as the major portion, which contains the desired product 1-99

with some impurities. Because the impurities could not be removed even by Prep TLC, the mixture was

used for the next step without further purification. The approximate yield was 50%.

TBDPSO

O O

NHNPh2

1-99

OH

Reddish oil. Column; hexane:EtOAc = 10:1 with 1% of Et3N. Rf = 0.33 (hexane:EtOAc = 7:1). 1H NMR

(CDCl3, 250 MHz): δ 0.09 (s, 9 H), 1.19 (s, 3 H), 1.27 (s, 3 H), 2.49(d, J = 5.2 Hz, 1 H), 3.46-3.49 (m, 1

H), 3.71-3.75 (m, 1 H), 4.17 (dd, J = 8.9, 6.3 Hz, 1 H), 4.90 (app t, J = 6.8 Hz, 1 H), 6.44 (d, J = 7.2 Hz, 1

H), Because of some impurities, phenyl signals are not assigned. 13C NMR (CDCl3, 100 MHz) δ 24.99,

26.79, 27.62, 29.22, 64.97, 69.76, 77.52, 78.15, 109.00, 121.02, 122.42, 122.64, 127.70, 128.85, 129.59,

135.52, 143.38, 148.29.

280

Preparation of (1’R, 4S, 5R)-(E and Z)-3-{5-O-[2-(tert-butyldimeylsilanyloxy)-1-hydroxyethyl]-2, 2-

dimethyl[1, 3]dioxolan-4-yl}-N,N-diphethylhydrazone

To a flame dried flask was added 290 mg of diphenylhydrazine hydrochloride dissolved in 10 mL

of anhydrous methyl alcohol, and 139 mg of pyridine. The mixture was stirred under nitrogen atmosphere

at rt for 30 min. To another flame dried flask was taken 267 mg of 5-O-[(1,1-dimethylethyl) dimethylsilyl]

-2,3-O-(1-methylethyldiene)-D-ribonofuranose 1-79 dissolved in 10 mL of methyl alcohol. The freshly

prepared diphenyl hydrazine solution was slowly added into the flask of D-ribonofuranose solution. After

stirring the mixture at rt for 24 h at rt, all starting material was consumed (TLC). The solvent was removed

under reduced pressure and the crude mixture was purified by column chromatography eluting with

hexane:EtOAc = 10:1 with 1% of Et3N.

TBSO

O O

NNPh2

1-100

OH

Yellow oil. Column: hexane:EtOAc = 10:1 with 1% of Et3N. Rf = 0.38 (hexane:EtOAc = 7:1). 1H NMR

(CDCl3, 250 MHz): δ -0.04 (s, 6 H), 0.79 (s, 9 H), 1.25 (s, 6 H), 2.41 (Br s, 1 H), 3.37 (Br s, 1 H), 3.56 (dd,

J = 10.1, 5.1 Hz, 1 H), 3.64 (dd, J = 10.1, 3.4 Hz, 1 H), 4.02 (dd, J = 9.0, 6.1 Hz, 1 H), 4.84 (app t, J = 6.7

Hz, 1 H), 6.42 (d, J = 7.1 Hz, 1 H), 6.98-7.09 (m, 4 H), 7.12-7.19 (m, 2 H), 7.20-7.30 (m, 4 H). 13C NMR

(CDCl3, 100 MHz): δ -5.45, -5.41, 18.28, 25.35, 25.83, 27.72, 64.04, 69.48, 77.51, 78.18, 109.00, 122.43,

124.35, 129.58, 134.39, 143.51. IR (NaCl, neat): 3556m, 3065m, 3037m, 2986s, 2930s, 2856s, 2739w,

2711w, 1932w, 1784w, 1708w, 1591s, 1494s, 1471s, 1381s, 1320m, 901s, 836s.

Preparation of (1’R, 4S, 5R)-(E and Z)-3-{5-O-[2-(tert-butyldimeylsilanyloxy)-1-hydroxyethyl]-2, 2-

dimethyl[1, 3]dioxolan-4-yl}-N,N-diphethylhydrazone; 1’-O-(1-imidazoyl)thione

To a flame dried flask fitted with a double spaced condenser were added 132 mg of N,N-

diphethylhydrazone 1-100, 149.7 mg of thiocarbonyl diimidazole, and 30 mg of DMAP under positive

nitrogen pressure. Freshly distilled THF (20 mL) was added as the solvent, and the mixture was stirred

281

under reflux conditions. The reaction was followed by TLC analysis, and another 149.7 mg of thiocarbonyl

diimidazole was added after 4 h and 20 h respectively. All starting material was consumed after 24 h, and

the mixture was cooled to rt. Solvent was removed on the rotary evaporator, and the crude product was

purified by column chromatography eluting with hexane:EtOAc = 7:1 solution. The desired product 1-101

(159 mg) was obtained as yellow oil.

TBSO

O O

NNPh2

1-101

O

NS

N

Yellow oil. Column; hexane:EtOAc = 7:1. Rf = 0.21 (hexane:EtOAc = 5:1). 1H NMR (CDCl3, 250 MHz):

δ -0.05 (s, 3 H), 0.00 (s, 3 H), 0.85 (s, 9 H), 1.38 (s, 3 H), 1.41 (s, 3 H), 3.90 (dd, J = 11.9, 2.5 Hz, 1 H),

4.76 (dd, J = 8.7, 6.2 Hz, 1 H), 4.99 (dd, J = 7.2, 6.2 Hz, 1 H), 5.36 (app dt, J = 8.6, 2.7 Hz, 1 H), 6.32 (d, J

= 7.4 Hz, 1 H), 6.86-6.89 (m, 4 H), 6.99 (d, J = 0.4 Hz, 1 H), 7.09-7.14 (m, 2 H), 7.26-7.30 (m, 4 H), 7.49

(s, 1 H), 8.25 (s, 1 H). 13C NMR (CDCl3, 100 MHz) δ -5.04, 18.14, 25.31, 25.68, 27.64, 60.25, 74.01,

78.47, 81.05, 109.59, 117.67, 122.02, 124.60, 129.69, 130.63, 130.91, 136.91, 142.88, 182.36. IR (NaCl,

neat): υ 3132m, 3062m, 2953s, 2931s, 1704m, 1592s, 1532w, 1496s, 1463s, 1389s, 1346m, 1323s, 1283s,

1246s, 1218s, 1033s, 834s. C24H40O4N4SSi 581.2618 (M+ + H), found 581.2645.

The Reaction of 1-79 with 1,1-thiocarbonyl diimidazole

To a flame dried flask fitted with a double spaced condenser were added D-ribonofuranose 1-79

(99 mg, 0.325 mmol), 1,1-thiocarbonyl diimidazole (116 mg, 0.650 mmol), and catalytic amount of DMAP

(10 mg) under positive nitrogen pressure. Freshly distilled THF (15 mL) was added as the solvent, and the

mixture was stirred under reflux conditions. The reaction was followed by TLC analysis, and another 116

mg of 1,1-thiocarbonyl diimidazole was added after 13 h. Most D-ribonofuranose 1-79 was consumed after

8 h, and the mixture was cooled to rt. Solvent was removed on the rotary evaporator, and the crude product

282

was purified by column chromatography eluting with hexane:EtOAc = 7:1 solution. The desired product 1-

103 (25 mg) and anomeric mixture (4 mg) were isolated along with the starting D-ribonofuranose 1-79 (18

mg).

OOTBS

1-103

O O

O N

S

N

Yellow oil. Column; hexane:EtOAc = 7:1. [α]D20

= +124.7 (c 1.24 in CHCl3). Rf = 0.31 (hexane:EtOAc =

4:1). 1H NMR (CDCl3, 500 MHz): δ 3.73 (dd, J = 11.1, 3.4 Hz, 1 H), 3.77 (dd, J = 11.1, 3.9 Hz, 1 H), 4.26

(app td, J = 3.1, 0.9 Hz, 1 H), 4.85 (dd, J = 5.9, 0.9 Hz, 1 H), 5.01 (dd, J = 5.9, 1.6 Hz, 1 H), 5.31 (d, J =

1.6 Hz, 1 H), 7.12 (s, 1H), 7.74 s, 1H), 8.45 (s, 1H).


dimethyl[1, 3]dioxolan-4-yl}-acrylic acid tert-butyl ester; 1’-O-phenyl carbamate

To a 10 mL of flame-dried flask was added 73 mg (0.179 mmol) of acrylic acid tert-butyl ester

(E)-1-81, R = tBu in 5 mL of benzene (dried over CaH2 and stored over 4 Å MS) under nitrogen

atmosphere. Triethyl amine (1.2 equiv.) and 2.0 equiv. of PhNCO were added to the above flask. The

mixture was stirred in an oil bath at 120 oC for 3 h 30 min. Another 2. 0 equivalents of PhNCO was added

and the mixture was refluxed for overnight (total refluxing time was 12 h 30 min.) After the solvent was

removed under vacuum, the mixture was purified by flash column chromatography with hexane:EtOAc =

8:1 solution to give 85 mg (91%) of deep brown oil.

283

TBSO

O O

(E)-1-104, R = tBu

O

NHO

CO2tBu

Deep brown oil, Column; hexane:EtOAc = 8:1. Rf = 0.37 (hexane:EtOAc = 6:1). 1H NMR (CDCl3, 400

MHz): δ 0.04 (s, 3 H), 0.05 (s, 3 H), 0.88 (s, 9 H), 1.31 (s, 9 H), 1.35 (s, 3 H), 1.48 (s, 3 H), 3.86 (dd,

J=11.5, 3.6 Hz, 1 H), 3.93 (dd, J=11.5, 2.6 Hz, 1 H), 4.49 (dd, J=8.3, 6.2 Hz, 1 H), 4.75 (ddd, J=8.3, 3.4,

2.8 Hz, 1 H), 4.81 (ddd, J=7.5, 6.0, 1.4 Hz, 1 H), 6.01 (dd, J=15.6, 1.5 Hz, 1 H), 6.78 (Br s, 1 H), 6.86 (dd,

J=15.6, 2.8 Hz, 1 H), 7.03(t, J=7.4 Hz, 1 H), 7.25-7.28 (m, 2 H), 7.37 (d, J=8.1 Hz, 2 H). 13C NMR

(CDCl3, 100 MHz): δ -5.48, -5.44, 18.36, 25.44, 25.85, 27.78, 27.86, 29.24, 62.04, 72.61, 75.58, 76.36,

80.51, 109.26, 118.74, 123.35, 123.79, 128.87, 137.77, 140.88, 151.90, 165.35.


dimethyl[1, 3]dioxolan-4-yl}-acrylic acid ethyl ester; 1’-O-phenyl carbamate

The reaction was performed by the same procedure for the (E)-1-81, R = tBu. 143 mg (0.392

mmol) of (Z)-1-81, R = Et, 187 mg (4.0 equiv.) of PhNCO, and 47.6 mg (1.2 equiv.) of triethylamine were

dissolved in 10 mL of dried benzene. The mixture was refluxed under nitrogen atmospere for 12 h 30 min.

The TLC analysis showed some starting material was remaining in the reaction mixture. To consume all

starting material another 4.0 equivalents of PhNCO and 1.2 equivalents of triethylamine were added, and

the mixture was refluxed until no more starting material was detected on TLC (total refluxing time was 22

h 30min.). The flask was cooled to rt and the excess benzene was removed on a rotary evaporator. The

desired compound was isolated by flash column chromatography eluting with hexane:EtOAc = 9:1 to 7:1 to

gwt 159mg (84%) of a colorless oil.

284

TBSO

O O

(Z)-1-104, R = Et

O

NHO

CO2Et

Colorless oil. Column; hexane:EtOAc = 9:1 to 7:1. Rf = 0.28 (hexane:EtOAc = 7:1). 1H NMR (CDCl3,

400 MHz): δ 0.04 (s, 6 H), 0.88 (s, 9 H), 1.17 (t, J = 7.1 Hz, 3 H), 1.39 (s, 3 H), 1.50 (s, 3 H), 3.84 (dd, J =

11.5, 4.7 Hz, 1 H), 3.92 (dd, J = 11.5, 2.5 Hz, 1 H), 3.95-4.18 (m, 2 H), 4.61 (dd, J = 8.6, 6.4 Hz, 1 H),

4.74-4.83 (m, 1 H), 5.80 (ddd, J = 7.9, 6.7, 1.2 Hz, 1 H), 5.89 (dd, J = 11.6, 1.1 Hz, 1 H), 6.26 (dd, J =

11.5, 8.4 Hz, 1 H), 6.57 (Br s, 1 H), 7.05 (tt, J = 7.0, 1.5 Hz, 1 H), 7.26-7.32 (m, 4 H). 13C NMR (CDCl3,

100 MHz) δ -5.5, -5.4, 6.3, 10.5, 14.0, 18.3, 25.3, 25.8, 25.9, 27.8, 60.4, 62.5, 73.0, 73.7, 75.4, 109.4,

118.6, 122.3, 123.4, 129.0, 137.8, 143.9, 152.

Reaction of 2-5 with (Bu3Sn)2O

Acrylic acid ethyl ester (Z)-1-81, R = Et (107 mg, 0.295 mmol) and (Bu3Sn)2O (185 mg, 0.310

mmol) were dissolved in 20 mL of freshly dried toluene. After the mixture was refluxed under nitrogen

atmosphere for 6 h 30 min., phenylisothiocyanate (2.1 equiv.) was added, and then the mixture was stirred

at 60oC for 23 h. After the solvent was removed under vacuum, the mixture was purified by flash column

chromatography eluting with hexane:EtOAc = 6:1 solution. The product was obtained as a pale brown oil

(53 mg), and the structure was identified as 7-O-[(1,1-dimethylethyl)dimethylsilyl]-6-hydroxy-4,5-O-(1-

methylethyldiene)-hept-2-enoic acid, ε-lactone by 1H NMR, 13C NMR, COSY, and IR spectroscopy.

OTBSO

O

O O

1-106

285

Pale brown oil. Column; hexane:EtOAc = 6:1. Rf = 0.26 (hexane:EtOAc = 6:1). 1H NMR (CDCl3, 400

MHz): δ 0.09 (s, 6 H), 0.90 (s, 9 H), 1.36 (s, 3 H), 1.44 (s, 3 H), 3.92 (dd, J = 11.6, 5.3 Hz, 1 H), 4.01 (dd, J

= 11.6, 2.0 Hz, 1 H), 4.22 (ddd, J = 9.7, 5.3, 2.0 Hz, 1 H), 4.48 (dd, J = 9.7, 7.5 Hz, 1 H), 4.91 (app dt, J =

7.5, 2.0 Hz, 1 H), 5.95 (dd, J = 12.2, 1.9 Hz, 1 H), 6.43(dd, J = 12.2, 2.1 Hz, 1 H).13C NMR (CDCl3, 100

MHz) δ -5.3, 18.4, 24.5, 25.8, 26.9, 62.8, 75.0, 75.3, 78.5, 109.3, 119.7, 141.8, 166.7. IR (NaCl,neat): υ

3406m, 2930s, 2856s, 1731s, 1462w, 1382m, 1257m, 1214m, 1069m, 837m, 779m. C16H30O4Si 351.1604

(M+ + Na), found 351.1602.


dimethyl[1, 3]dioxolan-4-yl}-acrylic acid tert-butyl ester; 1’-O-phenyl carbonate

To a flame dried 25 mL flask was added 189 mg of acrylic acid tert-butyl ester (Z)-1-81, R = tBu

in 10 mL of freshly dried pyridine. The flask was cooled at 0 oC, and 1.0 mL of benzoyl chloride was

slowly added. The mixture was stirred in an ice-bath for 30 min. and then at rt for 24 h. After the excess

pyridine was removed in vacuo over night, the crude product was diluted with dichloromethane. The

organic phase was washed with water (two times) and brine solution. The combined organic phase was

dried over MgSO4, the solid was filtered off, and the solvent was removed under reduced pressure. The

desired product was isolated by preparative TLC as colorless oil.

TBSO

O O

CO2tBu

1-108

OO

Colorless oil. Preparative TLC; hexane:EtOAc = 7:1. Rf = 0.54 (hexane:EtOAc = 7:1). 1H NMR (CDCl3,

400 MHz): δ -0.05 (s, 3 H), -0.03 (s, 3 H), 0.83 (s, 9 H), 1.34 (s, 9 H), 1.39 (s, 3 H), 1.50 (s, 3 H), 3.89 (dd,

J = 11.4, 4.9 Hz, 1 H), 3.94 (dd, J = 12.6, 2.9 Hz, 1 H), 4.73 (dd, J = 8.7, 6.3 Hz, 1 H), 5.13 (ddd, J = 8.5,

4.8, 2.9 Hz, 1 H), 5.59 (dd, J = 11.6, 1.4 Hz, 1 H), 5.80 (ddd, J = 7.9, 6.3, 1.3 Hz, 1 H), 6.14 (dd, J = 11.6,

286

8.2 Hz, 1 H), 7.38 (t, J = 7.5 Hz, 2 H), 7.52 (tt, J = 7.4, 1.3 Hz, 1 H), 7.94-7.96 (m, 2 H). 13C NMR

(CDCl3, 100 MHz): δ -5.53, -5.48, 18.17, 25.37, 25.73, 27.88, 27.93, 62.31, 73.34, 73.64, 75.29, 80.58,

109.12, 124.11, 128.18, 129.72, 130.30, 132.76, 142.26, 164.55, 165.46. IR (NaCl, neat): υ 3064m, 2931s,

2857s, 2358w, 2255m, 1964w, 1911w, 1718s, 1648m, 1602m, 1585m, 1452s, 1414s, 1370s, 1343m, 1314m,

1271s, 1157s, 1069s, 1047s, 991m, 947m.


dimethyl[1, 3]dioxolan-4-yl}-acrylic acid tert-butyl ester; 1’-O-phenylthiocarbonate

To a flame dried 30 mL flask were added 0.76 mmol (230 mg) of 1-87 and 4.56 mmol (617 mg) of

PhNCS dissolved 15 mL of dried THF at rt. Mineral oil free NaH (3.8 mmol, 91 mg) was added slowly,

and the mixture was stirred under nitrogen atmosphere at rt for 11 h. After all starting material was

consumed (TLC), 10 mL of water was added to quench the excess NaH. The reaction mixture was

extracted with dichloromethane, washed with brine, and dried over magnesium sulfate. The organic phase

was filtered through a filter paper and concentrated under reduced pressure to give brown oil. The mixture

was purified by column chromatography eluting with hexane:acetone = 15:1 to give 318 mg of product as a

yellow oil. The isolated yield was 96%.

TBSO

O O

1-109

O

NHS

1H NMR and 13C NMR spectra were complex after column chromatography and Prep TLC.

Yellow oil. Column; hexane:Acetone = 15:1. Rf = 0.26 (hexane:acetone = 9:1). 1H NMR (CDCl3, 250

MHz): δ 0.01 (s, 6 H minor), 0.05 (s, 3 H major), 0.88 (s, 9 H major), 0.89 (s, 9 H minor), 1.37 (s, 3 H),

1.48 (s, 3 H), 3.94 (dd, J = 11.7, 4.3 Hz, 1 H), 4.14(Br d, J = 11.4 Hz, 1 H), 4.43-4.72 (m, 2 H), 4.91-5.52

(m, 1 H), 5.41 (d, J = 8.4 Hz, 1 H), 5.68-6.02(m, 1 H), 7.15 (Br s, NH minor), 7.28-7.39 (m, 5 H), 8.53 (Br

287

s, NH minor). 13C NMR (CDCl3, 100 MHz): δ -5.48, 18.21, 25.29, 25.79, 27.68, 64.31, 77.43, 78.62,

108.93, 117.52, 118.57, 121.47, 125.27, 128.97, 133.06, 187.02. IR (NaCl, neat): υ 3241 Br, 3036m,

2986m, 2930s, 2884m, 2856m, 1949w, 1864w, 1704w, 1597s, 1540s, 1447m, 1381s, 1331m, 1289m, 1254s,

1194s, 1116m, 1061s, 1007m, 938m, 874m, 835s, 778m, 749m, 691m, 607m. C22H35O4NSSi 460.1954 (M+

+ Na), found 460.1958.


dimethyl[1, 3]dioxolan-4-yl}-acrylic acid tert-butyl ester; 1’-O-(1-tridazoyl)thione

A flame dried three neck round bottom flask was fitted with a double spaced condenser, and 192

mg (0.478 mmol) of acrylic acid tert-butyl ester (Z)-1-81 R = tBu, 258 mg (1.434 mmol) of 1,1-

thiocarbonylditriazole, and 10 mg of DMAP were placed under nitrogen atmosphere. Freshly distilled THF

(15 mL) was added, and the mixture was refluxed overnight (12h.). The reaction mixture was cooled to rt,

and the solvent was removed by rotary evaporation under house vacuum. The crude product was purified

by flash column chromatography eluting with hexane:EtOAc = 8:1 solution. Desired product (69 mg) and

starting material (115 mg) were obtained. The isolated yield of 1-110 is 28%, and 70% based on the

recovered starting material.

TBSO

O O

1-110

O

NS

NN

CO2tBu

Colorless oil (column chromatography, hexane:EtOAc = 10:1 to 8:1). Rf = 0.31 (hexane:EtOAc = 6:1).

[α]D20

= +90.6 (c 0.58 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ -0.02 (s, 3H), 0.00 (s, 3H), 0.83 (s, 9H),

1.39 (s, 9H), 1.40 (s, 3H), 1.51 (s, 3H), 4.00 (A of ABX, JAB = 11.8 Hz, JAX = 5.1 Hz, 1H), 4.02 (B of ABX,

JAB = 11.8 Hz, JBX = 2.5 Hz, 1H), 4.88 (dd, J = 7.3, 6.6 Hz, 1H), 5.63 (ddd, J = 7.5, 4.5, 3.1 Hz, 1H), 5.72

(dd, J = 11.6, 1.5 Hz, 1H), 5.78 (ddd, J = 7.9, 6.7, 1.5 Hz, 1H), 6.19 (dd, J = 11.6, 7.8 Hz, 1H), 8.02 (s,

288

1H), 8.85 (s, 1H). 13C NMR (CDCl3, 100 MHz): δ -5.56, 18.15, 25.09, 25.70, 27.56, 27.99, 61.29, 73.97,

75.04, 81.17, 82.38 (two peaks), 109.50, 124.57, 142.38, 153.61, 164.61, 180.69. IR (NaCl, neat): υ 2985s,

2951s, 2929s, 2860s, 1712s, 1643w, 1516w, 1472w, 1462s, 1388s, 1382s, 1321m, 1279s, 1239s, 1201s,

1157s, 1124s, 1066s, 966w, 943m, 835s, 778m, 666m, 651m. Anal. Calcd. for C23H39O6N3SSi: C, 53.77; H,

7.65; N, 8.18; S, 6.24. Found: C, 54.15; H, 7.62; N, 7.33; S, 6.25. HRMS (Electrospray): m/z Calcd for

C23H39O6N3SSiNa (M++Na), 536.2221; Found (M++Na), 536.2231.


dimethyl[1, 3]dioxolan-4-yl}-acrylic acid tert-butyl ester; 1’-O-(1-benzimidazoyl)thione

To a flame dried three neck round bottom flask were placed acrylic acid tert-butyl ester (Z)-1-81

R = tBu (0.540 mmol, 217 mg), 1,1-thiocarbonylbenzimidazole (1.630 mmol, 451 mg), and dried DME (15

mL). Sodium hydride (60% in mineral oil, 0.594 mmol, 24 mg) was slowly added to the flask at rt in a dry

box, the reaction mixture was stirred for 2.5 h. After aqueous work-up (quenched by H2O, extracted with

CH2Cl2, washed with H2O and brine solution, dried over MgSO4, and filtered), the organic phase was

concentrated on a rotary evaporator under reduced pressure. The crude mixture was purified by column

chromatography with eluting hexane:EtOAc = 10:1 to 8:1 to give 35 mg of desired product 1-111 and 162

mg of starting material acrylic acid tert-butyl ester (Z)-1-81 R = tBu was recovered. The isolated yield was

12% and yield based on the recovered starting material was 46%.

Alternatively, we also used nucleophilic substitution at high temperature for the formation of 1’-

O-(1-benzimidazoyl)thione 1-111. To a 10 mL of vial 54 mg of 1’-O-(1-imidazoyl)thione 1-82, 12.5 mg of

benzimidazole, and 1.3 mg of DMAP were placed. The mixture was heated in an oil bath at 130 oC with

stirring for 5 h. Another 25 mg of benzimidazole was added to it and continued the heating for additional

13 h. The deep brown crude mixture was purified by column chromatography eluting with hexane:EtOAc

= 10:1 to 8:1 solution to give 37 mg of pale yellow oil (isolated yield 62%).

289

TBSO

O O

1-111

O

NS

CO2tBu

N

Pale yellow oil. Column chromatography; hexane:EtOAc = 10:1 to 8:1. Rf = 0.38 (hexane:EtOAc = 6:1).

1H NMR (CDCl3, 250 MHz): δ -0.04 (s, 3H), 0.02 (s, 3H), 0.85 (s, 9H), 1.17 (s, 9H), 1.42 (s, 3H), 1.54 (s,

3H), 4.02 (A of ABX, JAB = 12.3 Hz, JAX = 1.1 Hz, 1H), 4.06 (B of ABX, JAB = 12.3 Hz, JBX = 2.9 Hz, 1H),

4.98 (dd, J = 8.1, 6.9 Hz, 1H), 5.62-5.72 (m, 2H), 5.81 (app t, J = 6.5 Hz, 1H), 6.19 (dd, J = 11.5, 7.9 Hz,

1H), 7.30-7.38 (m, 2H), 7.73-7.77 (m, 1H), 8.15-8.19 (m, 1H), 8.83 (s, 1H).


dimethyl[1, 3]dioxolan-4-yl}-O-methylhydroxyl amine; 1’-O-(1-triazoyl)thione

A mixture of O-methylhydroxyl amine 1-89 (131mg), 1,1-thiocarbonyl ditriazole (142 mg), and

10 mg of DMAP was placed in a 50 mL of flame dried three neck flask, which was connected to a double

spaced condenser. Freshly dried THF (20 mL) was added to the flask, and the mixture was refluxed under

nitrogen atmosphere for 6 hr. Another 2.0 equivalent of thiocarbonyl ditriazole was added and refluxing

was continued for 16 h. All solvents were removed under reduced pressure, and the dark brown mixture

was purified by column chromatography to give 79 mg of 1-115 as yellow oil along with 50 mg of starting

material. The product was a syn/anti mixture in a ratio of 1.69/1.00 based on 1H NMR spectrum.

TBSO

O O

NOCH3

1-115

O

NS

NN

290

Yellow oil (syn/anti = 1.69/1.0) (column chromatography, hexane:EtOAc = 10:1 to 8:1). Rf = 0.29

(hexane:EtOAc = 4:1). 1H NMR (CDCl3, 400 MHz): syn (major), δ 0.00 (s, 3H), 0.03 (s, 3H), 0.86 (s, 9H),


4.76-4.83 (m, 2H), 5.61 (ddd, J = 11.0, 8.1, 4.2 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 8.05 (s, 1H), 8.92 (s,

1H); anti (minor), δ 0.00 (s, 3H), 0.01 (s, 3H), 0.84 (s, 9H), 1.38 (s, 3H), 1.50 (s, 3H), 3.70 (s, 3H), 3.98-

4.02 (m, 2H), 4.71-4.78(m, 1H), 5.32 (dd, J = 6.5, 5.5 Hz, 1H), 5.59-5.63 (m, 1H), 6.88 (d, J =5.4 Hz, 1H),

8.05 (s, 1H), 8.93 (s, 1H). 13C NMR (CDCl3, 100 MHz): syn (major), δ -5.60, -5.55, 18.21, 25.19, 25.73,

27.60, 61.05, 62.23, 74.16, 74.87, 81.40, 110.45, 144.43, 146.06, 153.64, 180.54; anti (minor), δ -5.53, -

5.35, 18.16, 24.82, 25.70, 27.21, 61.05, 62.23, 74.16, 74.87, 81.40, 109.76, 144.29, 147.27, 153.61, 180.80.

IR (NaCl, neat): υ 3123w, 2986w, 2952s, 2934s, 2857s, 1797w, 1723w, 1516m, 1466m, 1462m, 1392s,

1378s, 1345m, 1321s, 1279s, 1254s, 1199s, 1124s, 1082s, 1046s, 965s, 942m, 837s, 814m, 779s, 660s.

HRMS (Electrospray): Calcd. for C18H32O5N4SSiNa (M++Na), 467.1755; Found (M++Na), 467.1716.

Preparation of styrene glycol122

After styrene oxide (17.5 g, 0.149 mmol) was dissolved in 150 mL of acetone, 0.5 mL of

concentrate sulfuric acid in 150 mL of H2O was added dropwise while the temperature of the mixture was

kept below 25 oC. The mixture was stirred for another 2 h, and then the acetone was removed under

vacuum at rt. After the solution was saturated by sodium chloride, the mixture was extracted with

diethylether. The organic phase was washed by sodium bicarbonate solution and brine, dried over

magnesium sulfate, and filtered. The excess solvent was removed in vacuo to give 17.5 g of pale yellow

solid. The yellow solid was recrystallized from hexane to give 16.9 g of white solid. The organic residue

was further purified by flash column chromatography eluting with hexane:EtOAc = 3:1 to get 0.12 g of

white solid. The combined yield was 83%.

OH

OH

1-119

291

White solid. Recrystallization by hexane. Mp: 63-65 oC (lit.122 63-64 oC).

Preparation of styrene glycol dimesylate122, 123

To a 100 mL of flask was dissolved 8.726 g (63.15 mmol) of 1-phenyl-1,2-ethanediol in 40 mL of

dried pyridine (over KOH), and the flask was cooled to –15 oC. After mesyl chloride (2.24 Equiv., 16.20 g,

10.9 mL, 141.46 mmol) was added slowly to the flask via a syringe for 30 min, the reaction mixture was

stirred at 0 oC for 4 h. The reaction mixture was mixed with ice at which time the dimesylate precipitated.

After the pH was adjusted to 3 with 6 N HCl, the solid was filtered off, and washed with ice water. The

product was transferred to a separator funnel, and extracted with dichloromethane. The organic phase was

dried over magnesium sulfate, and the solid was filtered off. Small amount of pentane was added to the

solution until crystallization just begun. After the mixture was cooled to -78 oC, the solid was collected by

filtration and washed with cold pentane. The solid was dried under vacuum to get the white solid (11.73 g).

The combined mother liquid was concentrated in a rotary evaporator, and purified by column

chromatography eluting with hexane:EtOAc = 3:1 solution to give addition 0.6 g of the dimesyl compound.

The total isolated yield is 66%.

OMs

OMs

1-120

White solid. Mp: 89-89.5 oC (lit.122(b) 93-95 oC),

Preparation of 1-amino-2-phenylaziridine123

A 100 mL of round bottom flask was charged with 10 mL (0.1 mol) of hydrazine hydrate and 2.0

g (6.79 mmol) of finely powdered styrene glycol dimesylate. After the mixture was gently stirred at rt for

10 min., 60 mL of pentane was slowly added. The mixture was stirred at 25 oC until two clear phases were

292

observed upon stopping of stirring (24 h). The hydrazine hydrate was separated from the pentane, and

extracted with additional pentane. The combined pentane mixture was filtered through glass cotton, and

the solvent was removed on a rotary evaporator at rt. Quantitative amount of yellow oil was obtained, and

the 1H NMR spectrum shows the crude compound has >95% purity. This crude mixture was used for the

next step without further purification.

1-121

NPh

NH2

Yellow oil. 1H NMR (CDCl3, 400 MHz): δ 1.94 (d, J = 7.8 Hz, 1 H), 1.97(d, J = 4.7 Hz, 1 H), 2.54 (dd, J

= 7.8, 4.7 Hz, 1 H), 3.67 (Br s, 2 H), 7.09-7.24 (m, 5 H).

Reaction of 5-O-[(1,1-dimethyl)ethyl dimethylsilyl]-2,3-O-(1-methyl ethyldiene)-D-ribonofuranose

with 1-amino-2-phenyaziridine

D-Ribonofuranose 1-79 (477 mg, 1.57 mmol) and freshly prepared 1-amino-2-phenyaziridine (845

mg, 6.30mmol) in 20 mL of pentane were dissolved in 30 mL of ethyl alcohol at 0 oC. The mixture was

stirred at 0 oC to rt for 6 h. After removal of the solvent in vacuo, the mixture was purified and the product

was isolated by flash column chromatography eluting with hexane:EtOAc = 4:1 to 1:1. Starting material,

ribofuranose, was recovered (71%), and the only other product was 1-122.

NPh

NCH3

CH31-122

Yellow oil. Rf = 0.23 (hexane:EtOAc = 5:1). 1H NMR (CDCl3, 250 MHz): δ 1.82 (s, 3 H), 1.91 (s, 3 H),

2.16 (d, J = 4.6 Hz, 1 H), 2.28 (d, J = 7.6 Hz, 1 H), 2.72 (dd, J = 7.6, 4.6 Hz, 1 H), 7.12-7.20 (m, 5 H).

Preparation of 5(R)-O-{[(1,1-dimethylethyl)diphenylsilyl]oxy}methyltetrahydrofuranol

A flame dried 100 mL of one neck flask was charged with 2.46 g (6.94 mmol) of lactone 1-123

and Et2O (40 mL) under nitrogen atmosphere. Freshly distilled diethyl ether was added via a syringe to the

293

flask at rt and the temperature was decreased to -78 oC. Dibal-H (6.9 mL, 1.5M in toluene) was added

slowly, and the mixture was stirred at the temperature for 1 h. After all starting material was consumed

(TLC), 10 mL of absolute methyl alcohol was added to quench the excess Dibal-H at -78 oC. The mixture

was diluted with diethyl ether and washed with saturated disodium tartarate (0.5 M) and brine. The water

phase was extracted 3 or 4 times by diethyl ether, and combined ether was dried over magnesium sulfate.

After the solid was filtered off, the organic phase was concentrated in vacuo to give colorless oil as α/β

anomeric mixture of the lactols. The crude yield was almost quantities and it was used for the next

experiment without further purification.

Preparation of 6(R)-(E)-ethyl 6-hydoxy-7-{[(1,1-dimethylethyl)diphenylsilyl]oxy}-2-heptenoate

A double spaced condenser was connected to a flame dried 100 mL of three neck flask. Crude

lactol 1-124 (2.08 g, 5.82 mmol), (carbethoymethylene)triphenylphosphorane (3.04 g, 8.73 mmol), and

catalytic amount of benzoic acid (200 mg) were dissolved in 20 mL of freshly distilled DME under

nitrogen atmosphere, and the mixture was stirred at rt for 34 h. After the solvent was removed in vacuo,

the crude mixture was purified by flash column chromatography using hexane:EtOAc = 8:1 to get 1.55 g

(64%) of the desired product as pale yellow oil. Small amount of TBDPS group migrated product (76 mg,

3%) was also isolated as a byproduct.

TBDPSO O

OEt

OH

1-125

Pale yellow oil. Column; hexane:EtOAc = 8:1 to 6:1. Rf = 0.29 (hexane:EtOAc = 5:1). [α]D20

= +1.5 (c

0.89 in CHCl3). 1H NMR (CDCl3, 500 MHz): δ 1.07 (s, 9H), 1.28 (t, J = 7.1 Hz, 3H), 1.48-1.62 (m, 2H),

2.21-2.29 (m, 1H), 2.31-2.39 (m, 1H), 2.47 (d, J = 2.9 Hz, OH), 3.50 (dd, J = 10.1, 7.2 Hz, 1H), 3.66 (dd, J

= 10.1, 3.5 Hz, 1H), 3.69-3.76 (m, 1H), 4.18 (q, J = 7.1 Hz, 2H), 5.81 (dt, J = 15.6, 1.5 Hz, 1H), 6.94 (d, J

= 15.6, 6.9 Hz, 1H), 7.35-7.46 (m, 6H), 7.64-7.68 (m, 4H). 13C NMR (CDCl3, 125 MHz): δ 14.25, 19.22,

26.84, 28.19, 31.08, 60.15, 67.79, 71.04, 121.64, 127.80, 129.87, 133.00, 132.02, 135.52, 148.47, 166.60.

294

IR (NaCl, neat): υ 3084Br s, 3070m, 3050m, 2930s, 1961w, 1894w, 1825w, 1720s, 1652s, 1589m, 1472s,

1428s, 1390s, 1368s, 1302s, 1270s, 1198s, 1112s, 1045s, 985m, 939m, 882w, 823s, 744s, 704s, 614s.

HRMS (Electrospray): m/z Calcd for C25H34O4SiNa (M++Na), 449.2119; Found (M++Na), 449.2125.

Preparation of (6R)-(E)-ethyl 7-{[(1,1-dimethylethyl)diphenylsilyl]oxy}-6-[O-(1-imidazoyl)

thiocarboyloxy]-2-heptenoate

A mixture of 2-heptenoate 1-125 (166mg, 0.389 mmol), 1,1-thiocarbonyl diimidazole (104 mg,

0.584 mg), and 10 mg of DMAP were placed in a 50 mL of flame dried three neck flask, which was

connected to a double spaced condenser. Freshly dried THF (10 mL) was added to the flask, and the

mixture was refluxed under nitrogen atmosphere for 2 hr. Another 1,1-thiocarbonyl diimidazole (120 mg)

was added and refluxing was continued for 22 h. All solvents were removed under reduced pressure, and

the dark brown mixture was purified by column chromatography to give 174 mg of 1-127 as yellow oil

along with 26 mg of starting material. The isolated yield of the thiocarbamated product 1-127 is 83% (99%

based on the recovered starting material).

TBDPSO O

OEt

O

N

S

N

1-127

Pale yellow oil. Column; hexane:EtOAc = 5:1 to 4:1. Rf = 0.46 (hexane:EtOAc = 3:1). [α]D20

= +2.0 (c

0.77 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ 1.04 (s, 9H), 1.27 (t, J = 7.1 Hz, 3H), 2.02-2.06 (m, 1H),

2.07-2.04 (m, 1H), 2.16-2.33 (m, 2H), 3.87 (d, J = 11.6, 4.7 Hz, 1H), 3.94 (dd, J = 11.6, 3.7 Hz, 1H), 4.17

(q, J = 7.1 Hz, 2H), 5.69 (app dq, J = 8.7, 4.8 Hz, 1H), 5.82 (dt, J = 15.6, 1.5 Hz, 1H), 6.92 (d, J = 15.6, 6.8

Hz, 1H), 7.03 (s, 1H), 7.29-7.44 (m, 6H), 7.57-7.66 (m, 5H), 8.28 (s, 1H). 13C NMR (CDCl3, 100 MHz):

δ 14.18, 29.13, 26.69, 27.83, 28.52, 60.26, 63.63, 83.41, 117.80, 122.30, 127.76, 127.80, 129.92, 129.94,

130.73, 132.59, 132.65, 135.40, 135.43, 136.83, 146.72, 166.16, 183.59. IR (NaCl, neat): υ 3134m, 3072s,

295

3050s, 2956s, 2932s, 2859s, 2331m, 1960w, 1825w, 1760m, 1717s, 1655s, 1590w, 1532m, 1465s, 1428s,

1388s, 1326s, 1285s, 1230s, 1170s, 1113s, 1043s, 998s, 965s, 910s, 824s, 800s, 734s, 703s, 655s, 615s.

HRMS (Electrospray): m/z Calcd for C29H36N2O4SSiNa (M++Na), 559.2057; Found (M++Na), 559.2060.

Preparation of 3(S)-hydroxy-γ-butyrolactone124

To a 2 L of three neck flask connected to a condenser was added 8.58 g of sodium hydroxide in

1335 mL (~0.16M). Maltose monohydrate (90% purity, 27.3 g, 75 mmol) was poured into the flask, and

was dissolved at rt with stirring. After 11.25 mL (99 mmol, 30%) of hydrogen peroxide was added to the

mixture, the temperature of the mixture was increased to 80 oC and stirring was continued for 24 h. (Note.

The temperature control and concentration of the mixture is critical to get high yield!). The mixture was

cooled at rt, and small amount of concentrated sulfuric acid was added to adjust the pH to ~1. The mixture

was concentrated to a syrup on a rotary evaporator, then the pH was adjusted to ~7 by addition of some

sodium bicarbonate in an ice bath. Some ethyl acetate was added to the mixture to reduce bubbles. After

the pH of the mixture was adjusted to ~7, 500 mL of ethyl acetate was added and the mixture was stirred

vigorously for 20 min. The mixture was kept standing at rt and ethyl acetate layer was carefully separated.

The same procedure was repeated several times until no more ethyl acetate phase had brown color. The

combined organic phase was dried over magnesium sulfate and was concentrated on a rotary evaporator.

The desired product was isolated by flash column chromatography using hexane:EtOAc = 1:1 to 1:3. The

product can also be isolated by vacuum distillation.

O

HO

O

1-129

Yellow liquid. Column; hexane:EtOAc = 1:1 to 1:3. Rf = 0.42 (hexane:EtOAc = 1:1). Vacuum

distillation; Bp: 122-123 oC/0.6 mm Hg (lit.124 98-100 oC/0.3 mm Hg). 1H NMR (CDCl3, 400 MHz): δ 2.53

(dd, J=17.9, 0.6 Hz, 1 H), 2.76 (dd, J=17.9, 6.1 Hz, 1 H), 2.66-3.10 (Br s, 1 H), 4.30 (d, J=10.3 Hz, 1 H),

4.42 (dd, J=10.3, 4.5 Hz, 1 H), 4.67-4.71 (m, 1 H).

296

Preparation of 3(S)-O-{[(1,1-dimethyl)ethyl dimethylsilyl]oxy}-γ-butyrolactone125

To a flame dried 25 mL of one necked flask were added 2.30 g (22.5 mmol) of 2-39, 4.07 g (27

mmol) of TBSCl, and 3.63 g (56.3 mmol) of imidazole under nitrogen atmosphere. DMF (dried over 4 Å

MS, 5.0 mL) was slowly added to the flask with stirring in an ice bath. The mixture was stirred at the

temperature for 15 min. and at rt for 27 h. After all starting material was consumed (TLC), the mixture was

diluted with dichloromethane. The organic phase was washed with water and brine, dried over magnesium

sulfate, and filtered. The solvent was removed in vacuo. Almost 100% yield of crude product was

obtained as a white solid, and this was used for the next experiment without further purification. If pure

compounds are needed, they can be purified by recrystallization from petroleum ether or column

chromatography with hexane:EtOAc = 6:1 to 3:1 as eluent.

O

TBSO

O

1-130

White Solid. Recrystallization; Pet Ether. Column; hexane:EtOAc = 6:1 to 3:1. Mp: 61-62 oC. Rf = 0.3

(hexane:EtOAc = 4:1). 1H NMR (CDCl3, 400 MHz): δ 0.07 (s, 6 H), 0.87 (s, 9 H), 2.42 (dd, J=17.5, 2.7

Hz, 1 H), 2.68 (dd, J=17.5, 6.1 Hz, 1 H), 4.16 (dd, J=9.7, 2.3 Hz, 1 H), 4.36 (dd, J=9.7, 4.8 Hz, 1 H), 4.57-

4.61 (m, 1 H). 13C NMR (CDCl3, 100 MHz) δ -4.93, -4.87, 17.86, 25.57, 38.11, 68.05, 76.06, 175.65.

HRMS (electrospray) m/z calcd for C10H20O3Si 239.1079 (M+ + Na), found 239.1086.

Preparation of 3(S)-O-{[(1,1-dimethyl)ethyl dimethylsilyl]oxy}-γ-butyrolactol

A flame dried 100 mL of one neck flask was charged with 2.35 g (10.9 mmol) of 3(S)-O-{[(1,1-

dimethylethyl) dimethylsilyl]oxyl}-γ-butyrolactone under nitrogen atmosphere. Freshly distilled diethyl

ether was added via a syringe to the flask at rt and the temperature was decreased to -78 oC. Dibal-H (1.5

equiv., 1.5M in toluene) was added slowly, and the mixture was stirred at the temperature for 2 h. After all

297

starting material was consumed (TLC), 20 mL of absolute methyl alcohol was added to quench the excess

Dibal-H at -78 oC. The mixture was diluted with diethyl ether and washed with saturated disodium

tartarate (0.5 M) and brine. The water phase was extracted 3 or 4 times by diethyl ether, and combined

ether was dried over magnesium sulfate. After the solid was filtered off, the organic phase was

concentrated in vacuo to give colorless oil as α/β anomeric mixture of the lactols. The crude yield was

almost quantities and it was used for the next experiment without further purification. The mixture could

be purified by flash column chromatography with hexane:EtOAc = 6:1.

O

TBSO

OH

1-131

α/β anomer mixture = 0.22/1.00

Colorless liquid. Column; hexane:EtOAc = 6:1. Rf = 0.36 (hexane:EtOAc = 3:1). Major epimer, β; 1H

NMR (CDCl3, 400 MHz): δ 0.10 (s, 3 H), 0.11 (s, 3 H), 0.89 (s, 9 H), 1.96 (td, J=17.5, 4.5 Hz, 1 H), 2.05

(d, J=13.3 Hz, 1 H), 3.88 (dd, J=9.5, 3.8 Hz, 1 H), 3.94 (d, J=11.3 Hz, 1 H), 4.06 (d, J=9.5 Hz, 1 H), 4.46-

4.49 (m, 1 H), 5.41 (dd, J=10.6, 4.6 Hz, 1 H). Minor epimer, α; 1H NMR (CDCl3, 400 MHz) :δ 0.06 (Br s,

6 H), 0.88 (s, 9 H), 1.93-1.97 (m, 1 H), 2.03-2.19 (m, 1 H), 3.70 (dd, J=9.1, 2.5 Hz, 1 H), 3.86-3.95 (m, 1

H), 4.10 (dd, J=9.0, 5.0. Hz, 1 H), 4.54-4.62 (m, 1 H), 5.66 (dd, J=4.7, 2.7 Hz, 1 H).

After column chromatography, (S)-2-O-[(1,1 dimethylethyl)dimethylsilyl]-butane-1,2-4-triol was

isolated as a byproduct.

OH

OH

TBSO

298

White solid. Column; hexane:EtOAc = 3:1. Rf = 0.35 (hexane:EtOAc = 1:1). 1H NMR (CDCl3, 400

MHz): δ 0.04 (s, 3 H), 0.05 (s, 3 H), 0.85 (s, 9 H), 1.76 (app qd, J = 5.5, 1.5 Hz, 2 H), 3.43 (Br s, 2 H), 3.52

(dd, J = 5.1, 3.4 Hz, 2 H), 3.59-3.68 (m, 1 H), 3.68-3.79 (m, 1 H), 3.89 (app tt, J = 5.0 Hz, 1 H).

Preparation of (E) and (Z)-ethyl 6-hydoxy-5(S)-{[(1,1-dimethyl)ethyl dimethylsilyl]oxy}-2-hexenoate

To a flame dried 250 mL one necked flask were added 4.216 g (19.3 mmol) of lactol and 7.396 g

(21.2 mmol) of (carbethoymethylene) triphenylphosphorane under nitrogen. Freshly distilled toluene (100

mL) was added, and the mixture was stirred under refluxing for 2 h 30 min. After the oslvent was removed

in vacuo, the mixture was purified by flash column chromatography eluting with hexane:EtOAc = 5:1 to

give colorless E/Z mixture. The isolated yield was 86% and E/Z ratio was 4.4/1.0.

(E)-1-132

O

OEtTBSO

OH


MHz) δ 0.08 (s, 3 H), 0.09 (s, 3 H), 0.90 (s, 9 H), 1.28 (t, J=7.1 Hz, 3 H), 2.17 (s, 1 H), 2.32-2.44 (m, 2 H),

3.48 (dd, J=11.2, 5.0 Hz, 1 H), 3.57 (dd, J=11.2, 3.9 Hz, 1 H), 3.78-3.89 (m, 1 H), 4.19 (q, J=7.1 Hz, 2 H),

5.86 (ddd, J=15.6, 2.6, 1.3 Hz, 1 H), 6.92 (dt, J=15.6, 7.6 Hz, 1 H). 1H NMR (DMSO-d6, 400 MHz) δ 0.01

(s, 3 H), 0.03 (s, 3 H), 0.83 (s, 9 H), 1.18 (t, J=7.1 Hz, 3 H), 2.21-2.24 (m, 1 H), 2.38-2.48 (m, 1 H), 3.10-

3.39 (m, 2 H), 3.71-3.74 (m, 1 H), 4.10 (q, J=7.1 Hz, 2 H), 4.62-4.76 (m, 1 H), 5.86 (d, J=15.6 Hz, 1 H),

6.89 (dt, J=15.6, 7.5 Hz, 1 H). 13C NMR (CDCl3, 100 MHz): δ -4.61, 14.25, 18.05, 25.82, 36.88, 53.82,

60.22, 66.10, 123.84, 144.72, 166.65. IR (NaCl, neat): υ 3460s, 3056w, 2927s, 1724s, 1657s, 1471m.

HRMS (electrospray) m/z calcd for C14H28O4Si 311.1655 (M+ + Na), found 311.1664.

(Z)-1-132TBSO

OHOEtO

299

Pale yellow oil. Column; hexane:EtOAc = 9:1 to 7:1. Rf = 0.52 (hexane:EtOAc = 3:1). [α] 20

D = +58.7 (c

1.16, CHCl3). 1H NMR (CDCl3, 400 MHz): δ 0.07 (s, 3 H), 0.08 (s, 3 H), 0.88 (s, 9 H), 1.27 (t, J = 7.2 Hz,

3 H), 2.57 (Br s, 1 H), 2.72 (dddd, J = 14.5, 7.2, 7.2, 1.4 Hz, 1 H), 3.02 (dddd, J = 14.6, 8.7, 4.8, 1.2 Hz, 1

H), 3.38-3.52 (m, 2 H), 3.92 (app dt, J = 10.7, 5.4 Hz, 1 H), 4.16 (q, J = 7.1 Hz, 2 H), 5.88 (d, J = 11.6 Hz,

1 H), 6.30 (ddd, J = 11.6, 8.7, 7.3 Hz, 1 H). 13C NMR (CDCl3, 100 MHz), δ -4.7, 14.2, 18.0, 25.7, 33.1,

60.1, 65.5, 71.9, 121.7, 145.4, 166.8. IR (NaCl, neat): υ 3476s, 2954s, 2929s, 2886s, 2857s, 1721s, 1646m,

1474m, 1464m, 1415m, 1388m, 1362m, 1254s, 1178s, 1111s, 1040s, 837s, 777s.

When the reaction was performed for prolonged time (14 hrs) and with excess amount (3.0

equivalents) of and (carb ethoxymethylene)triphenylphosphorane, significant amount of TBS group

migrated products and cyclized compounds were formed.

1-138

O

OEtOH

TBSO

Yellow oil. Column; hexane:EtOAc = 9:1 to 5:1, Rf = 0.33 (hexane:EtOAc = 6:1). 1H NMR (CDCl3, 400

MHz): δ 0.07 (s, 3 H), 0.08 (s, 3 H), 0.90 (s, 9 H), 1.28 (t, J=7.1 Hz, 3 H), 2.37 (td, J=7.5, 1.2 Hz, 2 H),

3.46 (dd, J=9.9, 6.7 Hz, 1 H), 3.63 (dd, J=10.0, 3.7 Hz, 1 H), 3.78-3.80 (m, 1 H), 4.19 (q, J=7.1 Hz, 2 H),

5.90 (dd, J=15.7, 1.3 Hz, 1 H), 6.98 (dt, J=15.6, 7.9 Hz, 1 H).

O CO2Et

TBSO


MHz): δ 0.47(s, 3 H), 0.56 (s, 3 H), 0.88 (s, 9 H), 4.26 (t, J=7.1 Hz, 3 H), 1.68 (ddd, J=12.7, 7.7, 5.8 Hz, 1

H), 2.00 (ddd, 2.42 J=12.7, 5.5, 1.6 Hz, 1 H), 2.48(A of ABX, J=15.2, 5.9 Hz, 1 H), 2.59 (B of ABX,

J=15.2, 7.2 Hz, 1 H), 3.61 (dd, J=9.2, 4.6 Hz, 1 H), 4.16(qd, J=7.2, 1.1 Hz, 1 H), 4.43-4.47 (m, 2 H). 13C

300

NMR (CDCl3, 100 MHz) δ -4.83, -4.77, 14.19, 18.03, 25.78, 40.40, 41.80, 60.50, 72.59, 74.43, 76.05,

171.11.

Preparation of (E) and (Z)-ethyl 5(S)-{[(1,1-dimethyl)ethyl dimethylsilyl]oxy}-6-[(N-imidazoyl

thiocarbonyl) oxy]-2-hexenoate

To a flame dried flask were added 1.289g (4.47 mmol) of 1-132, 4.0 equivalents of 1,1’-

thiocarbonyl diimidazole, and 180 mg of DMAP along with 80 mL of dichlroethane (dried over 4 Å MS).

The mixture was refluxed for 3 h, and all starting material was consumed (TLC). After the solvent was

removed on a rotary evaporator, the product was isolated by flash column chromatography with

hexane:EtOAc = 6:1 to 5:1 to give 157 mg of Z product and 789 mg of E product. Total isolate yield was

54% from lactone (total 4 steps).

(Z)1-133TBSO

O

N

S

N

OEtO


MHz): δ 0.00 (s, 3 H), 0.01 (s, 3 H), 0.89 (s, 9 H), 1.28 (t, J = 7.1 Hz, 3 H), 2.90-3.08 (m, 2 H), 4.16 (q, J =

7.2 Hz, 2 H), 4.28 (m, 1 H), 4.55 (dd, J = 11.1, 5.0 Hz, 1 H), 4.64 (dd, J = 11.1, 5.9 Hz, 1 H), 5.93 (dd, J =

11.5 Hz, 1 H), 6.36 (app dt, J = 11.5, 7.5 Hz, 1 H), 7.05 (s, 1 H), 7.67 (s, 1 H), 8.40 (s, 1 H). 13C NMR

(CDCl3, 100 MHz), δ -4.7, 14.2, 17.9, 25.6, 33.8, 60.1, 68.8, 75.9, 118.0, 122.3, 130.7, 137.0, 144.0, 166.1,

184.3.

301

(E)-1-133

O

OEtTBSO

O

N

S

N


MHz): δ 0.07 (s, 3 H), 0.09 (s, 3 H), 0.89 (s, 9 H), 1.29 (t, J = 7.1 Hz, 3 H), 2.46 (dddd, J = 14.3, 7.5, 6.2,

1.2 Hz, 1 H), 2.53 (dddd, J = 14.5, 7.3, 5.9, 1.3 Hz, 1 H), 4.20 (q, J = 7.1 Hz, 2 H), 4.25 (quin, J = 5.8 Hz, 1

H), 4.57 (dd, J = 11.2, 4.7 Hz, 1 H), 4.64 (dd, J = 11.2, 5.7 Hz, 1 H), 5.91 (app dt, J = 15.7, 1.2 Hz, 1 H),

6.96 (app dt, J = 15.6, 7.9 Hz, 1 H), 7.06 (d, J = 0.7 Hz, 1 H), 7.62 (s, 1H), 8.35 (s, 1 H).

Preparation of 3(S)-O-{[(p-methoxyphenyl)methyl]oxy}-γ-butyrolactone126

To a 809 mg (7.92 mmol) of the γ-lactone in 10 mL of freshly distilled dichloromethane at rt under

nitrogen atmosphere was added crude (p-methoxyphenyl)methyl trichloroactimidate followed by

camphorsulfonic acid (93 mg, 0.40 mmol). After the mixture was stirred at rt. for 16 h, it was diluted with

petroleum ether. The precipitate formed was removed by filtration, and the filtrate was washed by

saturated sodium bicarbonate. Combined organic phase was dried over magnesium sulfate, the solid was

filtered off, and then the solvent was removed in vacuo. The crude mixture was purified by flash column

chromatography eluting with hexane:EtOAc = 3:1 to 2:1 to get 683 mg (39%) of a brown oil, identified as

shown below.

O

PMBO

O

1-134


MHz): δ 2.53 (dd, J = 17.7, 1.6 Hz, 1 H), 2.62 (dd, J = 17.7, 5.3 Hz, 1 H), 3.75 (s, 3 H), 4.21-4.33 (m, 3 H),

302

4.41 (d, J = 1.6 Hz, 2 H), 6.86 (d, J = 8.6 Hz, 2 H), 7.21 (d, J = 8.5 Hz, 2 H). 13C NMR (CDCl3, 100 MHz):

δ 34.6, 54.9, 70.4, 72.8, 73.4, 113.6, 128.8, 129.1, 159.1, 175.3.

Preparation of 3(S)-O-{[(p-methoxyphenyl)methyl)methyl]oxy}-γ-butyrolactol126

To 1-134 (642 mg, 2.89 mmol) in freshly distilled diethyl ether (15 mL) at -78 oC under nitrogen

atmosphere was added 4.34 mmol of 1.5 M Dibal-H in toluene. The mixture was stirred at -78 oC for 1.5 h,

at which time all starting material was consumed (TLC). Absolute methyl alcohol (10 mL) was added at -

78 oC to quench the excess Dibal-H. The mixture was diluted with diethyl ether, and washed with saturated

sodium tartaric acid solution and brine. The aqueous phase was back extracted 2 times with diethyl ether,

and then combined ether phase was dried over magnesium sulfate. The solid was filtered off, and the

solvent was removed under vacuum. The crude mixture (559 mg, 86%) was obtained, and the mixture used

for the next experiment without further purification.

O

PMBO

OH

1-135

Preparation of (E) and (Z)-ethyl 5(S)-{[(p-methoxyphenyl)methyl]oxy}-6-hydroxyl-2-hexenoate

A double spaced condenser was connected to a flame dried 100 mL of three neck flask. Crude 1-

135 (559 mg, 2.49mmol) and (carbethoymethylene)triphenylphosphorane (955 mg, 2.74 mmol) was

dissolved in 15 mL of freshly distilled toluene under nitrogen atmosphere, and the mixture was refluxed for

2 h. After the solvent was removed in vacuo, the crude mixture was purified by flash column

chromatography using hexane:EtOAc = 4:1 to 1:1 to get 446.4 mg of yellow oil, which was E/Z mixture

with 1.0/0.1 ratio. Because the Z compound decomposed being rapidly, only E compound was

characterized.

303

(E)-1-136

O

OEtOPMB

HO


MHz): δ 1.71 (t, J = 7.1 Hz, 3 H), 2.33 (app t, J = 6.3 Hz, 2 H), 2.76 (Br s, 1 H), 3.38-3.53 (m, 3 H), 3.66

(s, 3 H), 4.07 (q, J = 7.1 Hz, 2 H), 4.31-4.43 (m, 2 H), 5.77 (d, J = 15.7 Hz, 1 H), 6.75 (d, J = 8.3 Hz, 2 H),

6.84 (app dt, J = 15.1, 7.4 Hz, 1 H), 7.14 (d, J = 8.4 Hz, 2 H). 13C NMR (CDCl3, 100 MHz): δ 13.9, 33.7,

54.9, 59.9, 63.4, 71.1, 77.7, 113.6, 123.3, 129.1, 129.9, 144.5, 159.0, 166.0.

(Z)-1-136PMBO

OHOEtO

Z compounds were isolated a mixture with the E-isomer. 1H NMR (CDCl3, 250 MHz): δ 1.69 (t, J = 7.1

Hz, 3 H), 2.36 (Br s, 1 H), 2.74-2.91 (m, 2 H), 3.38-3.59 (m, 3 H), 3.68 (s, 3 H), 4.06 (q, J = 7.1 Hz, 2 H),

4.38 (dd, J = 13.1 Hz, 1 H), 4.48 (dd, J = 11.3 Hz, 1 H), 5.77 (d, J = 11.6 Hz, 1 H), 6.18 (app dt, J = 11.5,

7.9 Hz, 1 H), 6.73-6.78 (m, 2 H), 7.10-7.14 (m, 2 H).

Preparation of (E)-ethyl 6-{[(1, 1-dimethyl)ethyl dimethylsilyl]oxy}-5(S)-{[(p-methoxyphenyl) methyl]

oxy}-2-hexenoate

A mixture of (E)-1-136 (309.5 mg, 1.05 mmol) and immidazole (179 mg, 2.63 mol) was dissolved

in 1 mL of DMF (dried over 4 Å MS). To the flask was added 189.9 mg (1.26 mmol) of TBSCl at 0 oC,

and the mixture was stirred at the temperature for 10 min, and at rt for 12 h under nitrogen. The mixture

was diluted with dichloromethane, washed with water and brine, and dried over magnesium sulfate.

Filtered organic phase was concentrated on a rotary evaporator, and purified by flash column

chromatography eluting with hexane:EtOAc = 9:1. The desired compound (295.3 mg) was isolated as

yellow oil in a yield of 69%.

304

1-137

O

OEtOPMB

TBSO

Yellow oil. Column; hexane only to hexane:EtOAc = 9:1. Rf = 0.34 (hexane:EtOAc = 9:1). 1H NMR

(CDCl3, 400 MHz): δ 0.00 (s, 6 H), 0.85 (s, 9 H), 1.27 (t, J = 7.2 Hz, 3 H), 2.33 (app dt, J = 13.5, 6.4 Hz, 1

H), 2.45 (app dt, J = 11.6, 5.6 Hz, 1 H), 3.45-3.55 (m, 1 H), 3.58-3.67 (m, 1 H), 3.72 (s, 3 H), 4.13 (q, J =

7.1 Hz, 2 H), 4.45 (d, J = 11.4 Hz, 1 H), 4.52 (d, J = 11.4 Hz, 1 H), 5.81 (d, J = 15.7 Hz, 1 H), 6.80 (d, J =

8.5 Hz, 2 H), 6.93 (app dt, J = 15.1, 7.4 Hz, 1 H), 7.24 (d, J = 8.5 Hz, 2 H). 13C NMR (CDCl3, 100 MHz):

δ -5.6, -5.5, 14.1, 18.1, 25.8, 34.5, 55.1, 59.9, 64.7, 78.0, 113.7, 123.3, 129.2, 144.3, 159.5, 166.5.

Preparation of (E)-ethyl 5(S)-hydoxy-6-{[(1,1-dimethyl)ethyl dimethylsilyl]oxy}-2-hexenoate

To 1-137 (284.7 mg, 0.70 mmol) in a mixture of dichloromethane/water (5 mL/0.5 mL), was

added DDQ (190.7 mg, 0.84 mmol) at rt. After the mixture was stirred for 1.5 h, the solvent was removed

in vacuo to get the crude mixture. The mixture was purified by flash column chromatography eluting with

hexane:EtOAc = 4:1 solution. The desired product (81.3 mg, 43%) was obtained as pale yellow oil.

1-138

O

OEtOH

TBSO

Preparation of (E)-ethyl 5(S)-hydoxy-6-{[(1,1-dimethyl)ethyl dimethylsilyl]oxy}-2-hexenoate

via TBS migration

To a 250 mL of one neck flask was added 2.30 g (7.98 mmol) of (E)-1-132 dissolved in 150 mL

of absolute methyl alcohol with 1.67 mL (1.5 equivalents) of triethylamine. After stirring for 48 h, the

mixture was washed with H2O and extracted with dichloromethane. The combined organic phase was

dried over magnesium sulfate, filtered, and concentrated under reduced pressure. After flash column

305

chromatography with hexane:EtOAc = 7:1 to 4:1, 1.32 g (86.6% based on recovered starting material) of

desired product (E)-1-138 was obtained. Cyclized compound (181 mg, 11.9% based on recovered starting

material) was isolated as a byproduct. Starting material (775.8 mg, 33.7%) was also recovered.

1-138

O

OEtOH

TBSO

Yellow oil. Column; hexane:EtOAc = 7:1 to 4:1. Rf = 0.33 (hexane:EtOAc = 6:1). [α] 20D = -0.48 (c 1.45,

CHCl3). 1H NMR (CDCl3, 400 MHz): δ 0.07 (s, 3 H), 0.08 (s, 3 H), 0.90 (s, 9 H), 1.28 (t, J=7.1 Hz, 3 H),

2.37 (td, J=7.5, 1.2 Hz, 2 H), 3.46 (dd, J=9.9, 6.7 Hz, 1 H), 3.63 (dd, J=10.0, 3.7 Hz, 1 H), 3.78-3.80 (m, 1

H), 4.19 (q, J=7.1 Hz, 2 H), 5.90 (dd, J=15.7, 1.3 Hz, 1 H), 6.98 (dt, J=15.6, 7.9 Hz, 1 H). 1H NMR (C6D6,

400 MHz): δ 0.05 (s, 6 H), 0.90 (s, 9 H), 0.98 (t, J=7.1 Hz, 3 H), 1.91 (d, J=4.6 Hz, 1 H), 2.03-2.10 (m, 2

H), 3.17-3.31(m, 3 H), 3.46-3.56 (m, 1 H), 4.09 (q, J=7.1 Hz, 2 H), 5.96 (ddd, J=15.6, 2.9, 1.4 Hz, 1 H).

1H NMR (DMSO-d6, 400 MHz): δ -0.05 (s, 6 H), 0.85 (s, 9 H), 1.21 (t, J=7.0 Hz, 3 H), 2.19-2.23 (m, 1 H),

2.37-2.42 (m, 1 H), 3.0-3.39 (m, 1 H), 3.49-3.56 (m, 1 H), 3.56-3.75 (m, 1 H), 4.10 (q, J=7.1 Hz, 2 H), 4.80

(d, J= 5.1 Hz, 1 H), 5.85 (d, J=15.3 Hz, 1 H), 6.91 (dt, J=15.6, 7.2 Hz, 1 H). 13C NMR (CDCl3, 100 MHz):

δ -5.42, -5.39, 14.25, 18.25, 25.84, 35.98, 60.24, 66.47, 70.52, 123.69, 144.65, 166.28. IR (NaCl, neat): υ

3478m, 2932s, 2859m, 1720s, 1654m, 1467m, 1367m, 1318m, 1258m, 1207m, 1167m, 1118m, 1045m,

982w, 839s, 770m. HRMS (electrospray) m/z calcd for C14H28O4Si 311.1655 (M+ + Na), found 311.1652.

Preparation of (Z)-ethyl 5(S)-hydoxy-6-{[(1,1-dimethyl)ethyl dimethylsilyl]oxy}-2-hexenoate

via TBS migration

The same reaction was performed with isolated Z substrates. To a 250 mL of one neck flask was

179mg (0.621 mmol) of Z substrate dissolved in 100 mL of absolute methyl alcohol with 104 µL (0.745

mmol) of triethyl amine. After the mixture was stirred at rt for 72 h, and the solvent was removed under

reduced pressure. The mixture purified by flash column chromatography to give 111.6 mg (67.9% based

306

on recovered starting material) of TBS migrated compound (Z)-2-44 along with 14.9 mg (8.3%) of starting

material.

(Z)-1-138HO

OTBSOEtO

Pale yellow oil. Column; hexane:EtOAc = 6:1, Rf = 0.49 (hexane:EtOAc = 3:1). [α] 20D = +6.1 (c 1.31,

CHCl3). 1H NMR (CDCl3, 400 MHz): δ 0.07 (s, 6 H), 0.90 (s, 9 H), 1.28 (t, J = 7.1 Hz, 3 H), 2.76 (dddd, J

= 15.4, 7.9, 7.9, 1.6 Hz, 1 H), 2.86 (dddd, J = 15.1, 7.6, 4.3, 1.6 Hz, 1 H), 3.49(dd, J = 10.0, 6.8 Hz, 1 H),

3.63 (dd, J = 10.0, 4.1 Hz, 1 H), 3.77 (ddd, J = 10.9, 7.1, 3.0 Hz, 1 H), 4.16 (q, J = 7.1 Hz, 2 H), 5.90 (app

dt, J = 11.5, 1.6 Hz, 1 H), 6.40 (app dt, J = 11.5, 7.5 Hz, 1 H). 13C NMR (CDCl3, 100 MHz): δ -5.43, -5.40,

14.21, 18.25, 25.84, 32.59, 52.99, 66.86, 71.31, 121.53, 145.80, 166.62. IR (NaCl, neat): υ 3471s, 2955s,

2929s, 2857s, 1720s, 1644m, 1472m, 1464m, 1445w, 1415m, 1388m, 1362w, 1255m, 1176s, 1120s, 1036m,

1006w, 939w, 837s, 778m. HRMS (electrospray) m/z calcd for C14H28O4Si 311.1655 (M+ + Na), found

311.1647.

Preparation of (E)-ethyl 6-{[(1,1-dimethyl)ethyl dimethylsilyl]oxy}-5(S)-[(N-imidazoyl

thiocarbonyl)oxy]-2-hexenoate

To a flame dried three neck flask were added 1.386 g (4.81 mmol) of 1-138, 1.43 g (7.22 mmol) of

1,1’-thiocarbonyldiimidazole, and 0.2g of DMAP along with 80 mL of dichloromethane (dried over 4 Å

MS). The mixture was refluxed under nitrogen atmosphere for 5 h, and another 0.5 equivalent of 1,1’-

thiocarbonyldiimidazole was added. Additional refluxing for 1 h consumed all starting material 1-138

(TLC), and the mixture was concentrated in vacuo to give brown oil. The crude product was purified by

flash column chromatography to give 1.72g (90%) of desired product 1-139 as a yellow oil.

307

1-139

O

OEtO

N

S

N

TBSO


CHCl3). 1H NMR (CDCl3, 400 MHz) δ 0.05 (s, 3 H), 0.04 (s, 3 H), 0.88 (s, 9 H), 1.28 (t, J=7.1 Hz, 3 H),

2.80 (t, J= 6.4 Hz, 2 H), 3.88 (ddd, J=12.7, 12.0, 2.8 Hz, 1 H), 4.19 (q, J=7.1 Hz, 2 H), 5.68 (ddd, J=14.4,

8.0, 1.8 Hz, 1 H), 5.95 (ddd, J=15.6, 2.6, 1.3 Hz, 1 H), 6.92 (dt, J=15.6, 7.8 Hz, 1 H), 7.05 (s, 1H), 7.61 (s,

1 H), 8.33 (s, 1 H). 13C NMR (CDCl3, 100 MHz): δ -5.51, 14.21, 18.13, 25.70, 32.69, 60.49, 62.43, 77.21,

82.14, 117.88, 125.05, 130.75, 141.82, 165.83, 183.40 IR (NaCl, neat): υ 3129w, 2932s, 2859m, 2361w,

1721s, 1657m, 1531w, 1467s, 1389s, 1322s, 1283s, 1234s, 1173m, 1103s, 1045m, 971s, 839s, 779m.

C18H30O4N2SSi 399.1774 (M+ + H), found 399.1805.

Preparation of (E and Z)-5-cyano-2(S)-{[(1,1-dimethyl)ethyl dimethylsilyl]oxy}-4-hexen-1-ol

The reaction procedure was the same as with other Wittig reaction conditions. To a flame dried

100 mL of three neck flask were added 1.08 g (4.95 mol) of lactol 1-131, 2.98 g (9.89 mmol) of the Wittig

reagent, and 10 mol% of benzoic acid in 30 mL of flash dried toluene. The mixture was stirred under

refluxing for 6 h 30 min, and cooled at rt. The solvent was removed on a rotary evaporator, and the crude

mixture was purified by flash column chromatography to give yellow oil. Small amount of pure Z-

compound was isolated during the column, but most fractions were E/Z mixtures while some isolated E-

compound contained 5% of TBS migrated compound. These mixtures were used for the next experiment

without further purification to reduce product decomposition. Total isolated yield was 63%.

(Z)-1-140TBSO

OH CN

308


MHz): δ 0.08 (s, 6 H), 0.87 (s, 9 H), 2.58-2.70 (m, 2 H), 3.49 (dd, J = 11.2, 5.0 Hz, 1 H), 3.52 (dd, J = 11.2,

4.5 Hz, 1 H), 3.91 (app tt, J = 5.4 Hz, 1 H), 5.40 (app dt, J = 11.0, 1.3 Hz, 1 H), 6.56 (app dt, J = 11.0, 7.7

Hz, 1 H). 13C NMR (CDCl3, 100 MHz): δ -4.8, -4.7, 17.9, 25.7, 36.4, 65.9, 71.2, 101.4, 115.8, 151.0. IR

(NaCl, neat): 3456s, 3072w, 2954s, 2930s, 2885m, 2857s, 2222m, 1722w, 1624m, 1472m, 1464m, 1389w,

1362m, 1255s, 1113s, 1048s, 1006m, 982w, 939w, 838s, 810m, 778s, 742m, 669m.

Preparation of (E)-5-cyano-1-{[(1,1-dimethyl)ethyl dimethylsilyl]oxy}-4-hexen-2(S)-ol

via TBS migration

To a 100 mL of one neck flask was added 319 mg (1.32 mmol) of 1-140 (E/Z = 1.00/0.50 based on

1H NMR) dissolved in 75 mL of absolute ethyl alcohol containing of 368 µL of triethyl amine. After

stirring at rt for 3 days, the product was isolated by flash column chromatography eluting with

hexane:EtOAc = 4:1 to give 213 mg (93% based on recovered starting material) of TBS group migrated

mixture (E/Z = 1.00/0.36 based on 1H NMR) as well as 90 mg of recovered starting material. The

recovered mixture was subjected to the same reaction again, which gave another 62 mg (68.9%, E/Z =

2.97/1.00 based on isolated compounds) of desired product and 15.6 mg (17%) of starting material. The

total 2 step-yield was 89% based on recovered starting material.

1-145

CNOH

TBSO

Pale yellow oil. Column; hexane:EtOAc = 4:1, Rf = 0.56 (hexane:EtOAc = 2:1). 1H NMR (CDCl3, 400

MHz): δ 0.08 (s, 6 H), 0.89 (s, 9 H), 2.36 (app dt, J = 7.0, 1.1 Hz, 1 H), 2.37 (app dt, J = 7.2, 1.6 Hz, 1 H),

2.50 (Br s, 1H), 3.44 (dd, J = 10.1, 6.4 Hz, 1H), 3.61 (dd, J = 10.0, 3.9 Hz, 1H), 3.77 (Br s, 1H), 5.43 (app

dt, J = 16.4, 1.6 Hz, 1 H), 6.78 (app dt, J = 16.2, 7.2 Hz, 1 H). 13C NMR (CDCl3, 100 MHz), δ -5.49, -5.45,

18.2, 25.8, 36.9, 66.3, 70.0, 101.8, 117.2, 151.9. IR (NaCl, neat): υ 3456s, 2955s, 2929s, 2858s, 2360w,

309

2225m, 1634m, 1472m, 1390w, 1362w, 1255m, 1124m, 970w, 939w, 838s, 778s. HRMS (electrospray) m/z

calcd for C12H23O2N 264.1396 (M+ + Na), found 264.1400.

Preparation of 4-hydroxy-3(S)-{[(1,1-dimethyl)ethyl dimethylsilyl]oxy}butyl-O-methyloxime

The γ-lactol 1-131 (185 mg, 2.22 mmol) and O-methylhydroxyl amine hydrochloride (216 mg,

2.44 mmol) were taken in a 50 mL flask. Dichloromethane (20 mL), 386 mg (4.89 mmol) of pyridine, and

0.5 mL of water were added to the flask. After refluxing the mixture for 25 h, another 1.0 equivalent of

pyridine and 0.5 equivalent of O-methylhydroxyl amine hydrochloride were added. The mixture was

refluxed until no more starting material was detected on TLC (total refluxing time was 43 h). After diluting

with dichloromethane, the mixture was washed with 10% hydrochloric acid solution, 5% of sodium

bicarbonate solution, and brine. The combined organic phase was dried over magnesium sulfate, filtered,

and concentrated in vacuum. The crude mixture was purified by flash column chromatography eluting with

hexane:EtOAc = 6:1 to 5:1 solution. Desired product (195.8 mg, 35.7%, syn/anti = 1.16/1.0) was isolated

as colorless oil as well as 114.8 mg (20.9%) of a mixture of TBS migrated compound (syn/anti = 1.17/1.0)

and a cyclized compound (α/β = 0.46/1.0).

1-141

NOCH3

OTBS

HO

syn/anti = 1.16/1.0

Colorless oil. Column; hexane:EtOAc = 6:1 to 5:1. Rf = 0.30 (hexane:EtOAc = 4:1). Syn; 1H NMR

(CDCl3, 400 MHz): δ 0.05 (s, 6 H), 0.85 (s, 9 H), 2.27 (Br s, 1 H), 2.37 (t, J = 6.2 Hz, 1 H), 3.39-3.56 (m, 2

H), 3.77 (s, 3 H), 3.85-4.0 (m, 1 H), 7.34(d, J = 6.4 Hz, 1 H). 13C NMR (CDCl3, 100 MHz): δ -4.7, 17.9,

25.7, 33.3, 61.2, 65.9, 70.8, 147.8. Anti; 1H NMR (CDCl3, 400 MHz): δ 0.06 (s, 6 H), 0.85 (s, 9 H), 2.27

(Br s, 1 H), 2.37 (t, J = 6.2 Hz, 1 H), 3.39-3.56 (m, 2 H), 3.83 (s, 3 H), 3.85-4.0 (m, 1 H), 6.72 (t, J = 5.7

Hz, 1 H). 13C NMR (CDCl3, 100 MHz): δ -4.9, 17.9, 25.6, 30.2, 61.5, 66.0, 70.1, 147.8. IR (NaCl, neat): υ

310

3439s, 2954s, 2930s, 2898s, 2858s, 2359w, 1632w, 1472m, 1362m, 1256m, 1103s, 1052s, 1006m, 976m,

939w, 837s, 807m, 777s.

1-146

NOCH3

OH

TBSO

O

TBSO

NHOCH3+

1-146'

1-146/1-146’ = 2.9/1.0

The isolated compounds were the mixture of 1-146 and 1-146’ in a ratio of 2.9 to 1.0. Major product, 2-55

exists as syn/anti mixtures with 2/1ratio. Yellow oil. Column; hexane:EtOAc = 4:1 to 3:1. Rf = 0.49

(hexane:EtOAc = 3:1). 1H NMR (CDCl3, 400 MHz): δ 0.05 (s, 6 H, anti), 0.07 (s, 6 H, syn), 0.86(s, 9 H,

anti), 0.88 (s, 9 H, syn), 2.37-2.40 (m, 1 H), 2.43-2.62(m, 1 H), 3.39-3.59 (m, 2 H), 3.80 (s, 3 H, syn), 3.86

(s, 3 H, anti), 3.88-3.99 (m, 1 H), 6.74 (t, J = 5.7 Hz, 1 H, anti), 7.37 (t, J = 6.3 Hz, 1 H, syn).

Minor product, 1-141’, the cyclic products are α/β mixture in a ratio of 2.6 to 1. 1H NMR (CDCl3,

400 MHz): δ 0.03 (s, 6 H, β), 0.04 (s, 6 H, α), 0.88 (s, 9 H, β), 0.89 (s, 9 H, α), 1.92-2.13 (m, 2 H), 3.59-

3.77 (m, 3 H), 3.80 (s, 3 H, α), 3.85 (s, 3 H, β), 4.30-4.37 (m, 1 H, β), 4.50-4.57 (m, 1 H, α), 5.05 (dd, J =

5.8, 2.9 Hz,1 H, β), 5.22 (dd, J = 5.4, 2.5 Hz,1 H, α).

Preparation of 3(S)-hydroxy-4-{[(1,1-dimethyl)ethyl dimethylsilyl]oxy}butyl-methyloxime

via TBS migration

To a flask was added 177 mg (0.716 mmol) of 1-141 in 40 mL of absolute alcohol and 200 µL of

triethyl amine. After the mixture was stirred at rt for 40 h, it was concentrated in vacuo and the crude

product was purified by flash column chromatography eluting with hexane: EtOAc = 4:1 to get 73.2 mg

(51.2% based on recovered starting material) of 1-146 as colorless oil. The starting material was also

recovered as colorless oil (34 mg, 19%).

311

1-146

NOCH3

OH

TBSO

Colorless oil. Column; hexane:EtOAc = 4:1. Rf = 0,52 (Hexane:EtOAc = 4:1). 1H NMR (CDCl3, 400

MHz): δ 0.08 (s, 6 H), 0.90 (s, 9 H), 2.30-2.42 (m, 2 H), 2.61 (d, J = 4.3 Hz, 1 H), 3.51 (dd, J = 10.0, 6.4

Hz, 1 H), 3.65(dd, J = 10.0, 4.1 Hz, 1 H), 3.83 (s, 3 H), 3.84-3.90 (m, 1 H), 7.46(d, J = 5.9 Hz, 1 H). 13C

NMR (CDCl3, 100 MHz): δ -5.43, -5.40, 18.3, 25.8, 33.3, 61.4, 66.4, 69.7, 148.0. IR (NaCl, neat):

υ 3415s, 2954s, 2929s, 2857s, 1472m, 1361w, 1255m, 1112m, 1055m, 940w, 837m, 778m. HRMS

(electrospray) m/z calcd for C11H25O2NSi 270.1501 (M+ + Na), found 270.1496.

Preparation of 4-hydroxy-3(s)-{[(1,1-dimethyl)ethyl dimethylsilyl]oxy}butyl-hydroyloxime

To a 50 mL of three neck flask were added 450 mg (2.06 mmol) of lactol 1-131, 156 mg (2.27

mmol) of hydroxylamine hydrochloride, and 358 mg (4.53 mmol) of pyridine. To dissolve hydroxylamine

hydrochloride, 20 mL of dichloromethane and 0.5 mL of H2O were used as the solvent. After refluxing for

21 h 30 min, the mixture was diluted with dichloromethane, and washed by 5% sodium bicarbonate

solution and brine. The combined organic phase was dried over magnesium sulfate, the solid was filtered

off, and the product was concentrated in vacuo. The crude mixture was purified by flash column

chromatography eluting hexane:EtOAc = 3:1 to 2:1 to give 403 mg (84%) of colorless oil as syn/anti

mixture (0.86/1.00).

1-142

NOH

OTBS

HO

syn/anti = 0.86/1.0

Colorless oil. Column; hexane:EtOAc = 3:1 to 2:1. Rf = 0.21 (hexane:EtOAc = 2:1). Major isomer, anti;

1H NMR (CDCl3, 400 MHz): δ 0.06 (s, 3 H), 0.07 (s, 3 H), 0.87 (s, 9 H), 2.51 (app dt, J = 15.2, 5.7 Hz, 1

312

H), 2.70 (app dt, J = 15.2, 5.8 Hz, 1 H), 2.88 (Br s, 1 H), 3.48 (dd, J = 11.2, 5.0 Hz, 1 H), 3.53 (dd, J =

11.3, 5.1 Hz, 1 H), 4.00 (app tt, J = 5.4 Hz, 1 H), 6.83 (t, J = 5.8 Hz, 1 H), 9.27 (Br s, 1 H). 13C NMR

(CDCl3, 100 MHz): δ -4.8, 18.0, 25.7, 29.7, 65.9, 70.8, 149.2. Minor isomer, syn; 1H NMR (CDCl3, 400

MHz): δ 0.06 (s, 3 H), 0.08 (s, 3 H), 0.87 (s, 9 H), 2.41 (app t, J = 6.1 Hz, 2 H), 2.88 (Br s, 1 H), 3.48 (dd, J

= 11.2, 5.0 Hz, 1 H), 3.53 (dd, J = 11.3, 5.1 Hz, 1 H), 3.92 (app tt, J = 5.4 Hz, 1 H), 7.43 (t, J = 6.4 Hz, 1

H), 9.71 (Br s, 1 H). 13C NMR (CDCl3, 100 MHz): δ -4.7, 18.0, 25.7, 38.8, 65.6, 70.1, 148.8. IR (NaCl,

neat): υ 3314s, 2954s, 2849s, 1658m, 1472s, 1389m, 1362s, 1311m, 1257s, 1098s, 1005m, 978m, 938m,

888m, 837s, 808s, 778s, 671m.

Preparation of 3(S)-hydroxy-4-{[(1,1-dimethyl)ethyl dimethylsilyl]oxy}butyl-hydroyloxime via TBS

migration

A solution of 1-142 (113 mg, 0.484 mmol) in 27 mL of absolute methyl alcohol was stirred with

2.0 equivalents of triethyl amine at rt for 7 days. TLC showed the ratio of product/starting material was

6/4. After removed the solvent in vacuo, the mixture was purified by flash column chromatography to give

69.6 mg (80.3% based on recovered starting material) of colorless oil as well as 26.3 mg (23.3%) of

starting material.

1-147

NOH

OH

TBSO

syn/anti = 1.1/1.0

Colorless oil. Column; hexane:EtOAc = 2:1. Rf = 0.38 (hexane:EtOAc = 2:1). 1H NMR (CDCl3, 400

MHz): δ 0.07 (s, 6 H, syn), 0.08 (s, 6 H, anti), 0.89 (s, 9 H, syn), 0.89 (s, 9 H, anti), 2.43-2.32(m, 1 H),

2.46-2.62 (m, 1 H), 3.46-3.54 (m, 1 H), 3.61-3.66 (m, 1 H), 3.84-3.92 (m, 1 H), 6.93 (Br s, 1 H, anti), 7.52

(t, J = 6.0 Hz, 1 H, syn). 13C NMR (CDCl3, 100 MHz): δ -5.4, -5.4, 18.3, 25.8, 33.3, 66.5 (syn), 66.8

(anti), 69.3 (anti), 69.6 (syn), 149.4. IR (NaCl, neat): υ 2224s, 2954s, 2929s, 2857s, 1658w, 1472m,

313

1390w, 1362w, 1256m, 1115s, 1006w, 938w, 838s, 778s, 668w. HRMS (electrospray) m/z calcd for

C10H23O2NSi 256.1345 (M+ + Na), found 256.1346.

Preparation of 4-hydroxy-3(S)-{[(1,1-dimethyl)ethyl dimethylsilyl]oxy}butyl-N,N’-dimethyl

hydrazone and 3(S)-hydroxy-4-{[(1,1-dimethyl)ethyl dimethylsilyl]oxy}butyl-N,N’-dimethyl

hydrazone by TBS migration

A mixture of lactol 1-131 (0.530g, 2.43 mmol) and N,N’-dimethyl hydrazine (1.021g, 17.0 mmol)

was dissolved in 15 mL of absolute methyl alcohol, and the mixture was refluxed under nitrogen

atmosphere for 6 h. After removal of the solvent in vacuo, the mixture was purified by flash column

chromatography eluting with hexane:EtOAc = 6:1 to 3:1. The desired product 1-143 (51.9 mg), migrated

product 1-148 (295. 9mg), and the mixture (1-143/1-148 = 0.88/1.00, 215.3mg) were isolated. After

dissolving in 10 mL of absolute methyl alcohol with 87 µL of triethyl amine, the mixture of 1-143 and 1-

148 was stirred at rt for 63 h. After all 1-143 was consumed (TLC), the mixture was purified by flash

column chromatography eluting with hexane:EtOAc = 6:1 to 3:1. The isolated alcohol 1-148 was 98.6 mg

as yellow oil. The stereochemistry was assigned as anti based on the chemical shift (δ 6.61 ppm) and the

relatively small coupling constant (J = 5.4 Hz) of H-1 comparing of 1-141.

1-143

NN(CH3)2

OTBS

HO

anti

Yellow oil. Column; hexane:EtOAc = 6:1 to 3:1. Rf = 0.32 (hexane:EtOAc = 1:1). [α] 20D = +10.8 (c 0.93,

CHCl3). 1H NMR (CDCl3, 400 MHz): δ 0.07 (s, 6 H), 0.89 (s, 9 H), 2.32 (Br s, 1 H), 2.45 (app t J = 5.6

Hz, 2 H), 2.72 (s, 6 H), 3.50 (dd, J = 11.1, 4.9 Hz, 1 H), 3.56 (dd, J = 11.1, 4.4 Hz, 1 H), 3.93 (app t, J = 4.9

Hz, 1 H), 6.61 (t, J = 5.4 Hz, 1 H). 13C NMR (CDCl3, 100 MHz): δ -4.63, -4.59, 18.0, 25.8, 37.5, 43.1,

66.2, 71.7, 134.5. IR (NaCl, neat): υ 3382s, 2954s, 2928s, 2884m, 2856s, 2785w, 1607w, 1472m, 1444m,

314

1361m, 1255s, 1103s, 1052s, 1006m, 938w, 832s, 776s. C12H28O2N2Si 283.1818 (M+ + Na), found

283.1792.

1-148

NN(CH3)2

OH

TBSO

anti


CHCl3). 1H NMR (CDCl3, 400 MHz), δ 0.02 (s, 6 H), 0.85 (s, 9 H), 2.26-2.45 (m, 2 H), 2.69 (s, 6 H), 3.15

(Br s, 1 H), 3.50 (dd, J = 9.9, 6.3 Hz, 1 H), 3.57 (dd, J = 10.0, 4.9 Hz, 1 H), 3.79-3.85 (m, 1 H), 6.68 (t, J =

4.7 Hz, 1 H). 13C NMR (CDCl3, 100 MHz): δ -5.5, 18.2, 25.8, 36.0, 43.0, 66.5, 70.5, 135.2. IR (NaCl,

neat): υ 3418s, 2954s, 2928s, 2856s, 2783w, 1611w, 1471m, 1444m, 1361w, 1253s, 1111s, 1006m, 939w,

837s, 777m. C12H28O2N2Si 283.1818 (M+ + Na), found 283.1821.

Preparation of 4-hydroxy-3(S)-{[(1,1-dimethyl)ethyl dimethylsilyl]oxy}butyl-N,N’-diphenyl

hydrazone

To a flame dried flask were added 245 mg (1.12 mmol) of lactol 1-131 and small amount of 4 Å

molecular sieves under nitrogen atmosphere. Absolute methyl alcohol (10 mL) was used as the solvent.

To another flame dried flask was dissolved 372 mg (1.68 mmol) of N,N’-diphenyl hydrazine hydrochloride

in 10 mL of absolute methyl alcohol and 181 µL of pyridine under nitrogen stream. The mixture was

stirred at rt for 30min, and then slowly added to the mixture of lactol 1-131 via a syringe. After the mixture

was stirred at rt for 2 h, the solvent was removed under reduced pressure. The crude product was purified

by flash column chromatography eluting with hexane:EtOAc = 8:1 with 1% of Et3N. The desired product

1-144 was isolated as a yellow oil (218 mg), and TBS group migrated compound 1-149 was also obtained

as a yellow oil (62mg). The stereochemistry was assigned as anti based on the chemical shift (δ 6.53 ppm)

and the relatively small coupling constant (J = 5.6 Hz) of H-1 comparing of 1-141.

315

1-144

NNPh2

OTBS

HO

anti only

Yellow oil. Column; hexane:EtOAc = 8:1 with 1% of Et3N. Rf = 0.25 (hexane:EtOAc = 7:1). 1H NMR

(CDCl3, 400 MHz): δ 0.01 (s, 3 H), 0.06 (s, 3 H), 0.84 (s, 9 H), 2.52 (app t, J = 5.8 Hz, 2 H), 3.49 (dd, J =

11.2, 5.2 Hz, 1 H), 3.58 (dd, J = 11.2, 4.1 Hz, 1 H), 3.96 (ddd, J = 11.3, 10.3, 6.0 Hz, 1 H), 6.53 (t, J = 5.6

Hz, 1 H), 7.07-7.17 (m, 6 H), 7.34-7.39 (m, 4 H). 13C NMR (CDCl3, 100 MHz): δ -4.6, 17.9, 25.7, 37.2,

66.2, 71.5, 122.3, 124.0, 129.7, 135.9, 143.9. IR (NaCl, neat): υ 3406m, 3061w, 2953m, 2927m, 2856m,

1591s, 1496s, 1472m, 1377w, 1299m, 1253m, 1211m, 1092m, 1066m, 836m, 777m, 748m, 700m.

Preparation of 4-hydroxy-3(S)-{[(1,1-dimethyl)ethyl dimethylsilyl]oxy}butyl-N,N’-diphenyl

hydrazone

To a flame dried 25 mL flask were added 113.5 mg of 1-144 and 59.7 mg of triethyl amine in 16.8

mL of absolute methyl alcohol. The mixture was stirred at rt under nitrogen atmosphere for 36 h. After

removed the solvent in vaccuo, the crude mixture was purified by column chromatography (hexane:EtOAc

= 7:1 to 5:1) to give 74 mg of desired product along with 39 mg of the starting material. The isolated yield

was 65% (>99% based on recovered starting material).

1-149

NNPh2

OH

TBSO

Yellow oil. Column; hexane:EtOAc = 12:1. Rf = 0.41 (hexane:EtOAc = 7:1). 1H NMR (CDCl3, 250

MHz): δ 0.04 (s, 6 H), 0.89 (s, 9 H), 2.37-2.55 (m, 2 H), 3.55 (dd, J = 10.0, 6.3 Hz, 1 H), 3.66 (dd, J = 10.0,

4.5 Hz, 1 H), 3.93 (app tt, J = 11.5, 5.3 Hz, 1 H), 6.52 (t, J = 5.0 Hz, 1 H), 7.06-7.17 (m, 6 H), 7.33-7.41

316

(m, 4 H). 13C NMR (CDCl3, 100 MHz), δ -5.40, 18.29, 25.88, 36.01, 66.53, 70.23, 122.31, 124.09, 129.71,

136.56, 143.94. C22H32O2N2Si 407.2131 (M+ + Na), found 407.2124.

Preparation of (E) and (Z)-1-cyano-5-{[(1,1-dimethyl)ethyl dimethylsilyl]oxy}-4(S)-[(N-imidazoyl-

thiocarbonyl) oxy]-hex-1-ene

To a flame dried three neck flask were added 257 mg (1.06 mmol, E/Z = 2.8/1.0) of 1-145, 569 mg

(3.20 mmol) of 1,1’-thiocarbonyldiimidazole, and 30 mg of DMAP along with 20 mL of freshly distilled

THF. The mixture was refluxed under nitrogen atmosphere for 13 h, and another 3.0 equivalents of 1,1’-

thiocarbonyldiimidazole were added. Continued refluxing for 8 h consumed all starting material (TLC).

The solvent was removed under reduced pressure to give deep brown oil. The mixture was purified by

flash column chromatography to give 252 mg (68%, E/Z = 3.5/1.0) of desired products as an E/Z mixture.

OTBS

N

S

N

CN

(Z)-1-150

Pale yellow oil. Column; hexane:EtOAc = 4:1. Rf = 0.21 (hexane:EtOAc = 3:1). 1H NMR (CDCl3, 400

MHz): δ 0.09 (s, 3 H), 0.11 (s, 3 H), 0.89 (s, 9 H), 2.72-2.76 (m, 2 H), 4.30 (app tt, J = 5.5 Hz, 1 H), 4.53

(dd, J = 11.1, 5.3 Hz, 1 H), 4.67 (dd, J = 11.2, 5.6 Hz, 1 H), 5.50 (d, J = 11.0 Hz, 1 H), 6.61 (app dt, J =

10.9, 7.5 Hz, 1 H), 7.06 (s, 1 H), 7.65 (s, 1 H), 8.38 (s, 1 H). 13C NMR (CDCl3, 100 MHz): δ -4.7, -4.8,

17.9, 25.6, 36.8, 67.9, 75.1, 102.7, 115.5, 117.8, 130.9, 137.3, 149.3, 183.8. IR (NaCl, neat): υ 2953m,

2929m, 2856m, 2220s, 1621s, 1531s, 1464m, 1389s, 1322m, 1286s, 1231s, 970w, 1114s, 998s, 838s, 778s.

317

OTBS

N

S

N

(E)-1-150

CN

1H NMR (CDCl3, 400 MHz): δ 0.09 (s, 3 H), 0.08 (s, 3 H), 0.90 (s, 9 H), 2.84 (dd, J = 7.5, 1.2 Hz, 1 H),

2.86 (dd, J = 7.5, 1.4 Hz, 1 H), 3.87 (dd, J = 11.4, 4.4 Hz, 1 H), 3.91 (dd, J = 11.5, 4.4 Hz, 1 H), 5.51 (app

dt, J = 16.3, 1.5 Hz, 1 H), 5.70 (app dt, J = 6.2, 4.4 Hz, 1 H), 5.74 (app dt, J = 16.3, 7.3 Hz, 1 H), 7.06 (s, 1

H), 7.65 (s, 1 H), 8.38 (s, 1 H).

Preparation of (Z)-4-{[(1,1-dimethyl)ethyl dimethylsilyl]oxy}-3(S)-[(N-imidazoyl-thiocarbonyl)

oxy]butyl N,N’-diphenyl hydarzaone

In a flame dried 50 mL flask fitted with a double spaced condensor were charged 103 mg of 4-

hydroxy-3(s)-{[(1,1-dimethyl)ethyl dimethylsilyl]oxy}butyl-N,N’-diphenyl hydrazone, 143 mg of

thiocarbonyl diimidazole, and 23 mg of DMAP in 20 mL of freshly distilled THF. The mixture was stirred

under nitrogen stream. Another 143 mg and 95 mg of thiocarbonyl diimidazole were added after 22 h and

44 h, and refluxing was conyinued. After total 55 h refluxing, the solvent was removed under reduced

pressure and the mixture was purified by column chromatography eluting with hexan:EtOAc solution.

NNPh2OTBS

N

S

N

1-151

Yellow oil. Column; hexane:EtOAc = 7:1. Rf = 0.29 (hexane:EtOAc = 4:1). 1H NMR (CDCl3, 400 MHz):

δ 0.02 (s, 6 H), 0.03 (s, 3 H), 0.86 (s, 9 H), 2.81-2.85 (m, 2 H), 2.89 (dd, J = 11.4, 4.8 Hz, 1 H), 3.95 (dd, J

= 11.3, 4.0 Hz, 1 H), 5.86 (app tt, J = 10.8, 6.1 Hz, 1 H), 6.47 (t, J = 5.2 Hz, 1 H), 7.02 (s, 1 H), 7.03 (d, J =

7.9 Hz, 4 H), 7.11 (t, J = 7.4 Hz, 2 H), 7.35 (t, J = 7.8 Hz, 4 H), 7.54 (s, 1 H), 8.31 (s, 1 H). 13C NMR

318

(CDCl3, 100 MHz): δ -5.52, 18.13, 25.69, 33.19, 62.95, 83.30, 117.86, 122.21, 124.27, 129.71, 130.56,

132.83, 136.71,143.63, 183.59. IR (NaCl, neat): υ 3129w, 3060m, 3037m, 2952s, 2927s, 2856s, 1928w,

1704m, 1593s, 1531s, 1495s, 1463s, 1387s, 1323s, 1284s, 1231s, 1174m, 1095s, 1022m, 963s, 837s.

Preparation of (E)-ethyl 6-{[(1,1-dimethyl)ethyl dimethylsilyl]oxy}-5-[(phenylcarbamy) oxy]-2-

hexenoate

To a 25 mL of flame dried three neck flask was taken 215 mg (.0746 mmol) of (E)-ethyl 5(S)-

hydoxy-6-{[(1,1-dimethyl)ethyl dimethylsilyl]oxy}-2-hexenoate, 1-138, dissolved in 7.5 mL of dried

benzene. After addition of triethyl amine (1.2 equiv.) and PhNCO (1.1 equiv.) to the solution, the mixture

was refluxed under nitrogen atmosphere. After 5h, another 1.1 equivalents of PhNCO were added and

reflux was continued for 1h. The mixture was concentrated under reduced pressure, and the product was

purified by flash column chromatography eluting with hexane:EtOAc = 6:1 to 5:1 to get 292 mg of yellow

oil. The isolated yield was 96%.

1-157

O

OEtO

TBSO

NHPh

O


MHz), δ 0.06 (s, 6 H), 0.89 (s, 9 H), 1.28 (t, J = 7.1 Hz, 3 H), 2.53-2.67 (m, 2 H), 3.67 (dd, J = 10.8, 5.4

Hz, 1 H), 3.73 (dd, J = 10.7, 4.9 Hz, 1 H), 4.17 (q, J = 7.1 Hz, 2 H), 4.95 (app tt, J = 5.3 Hz, 1 H), 5.91 (d, J

= 15.6 Hz, 1 H), 6.64 (Br s, 1 H, the peak was disappeared with D2O), 6.95 (app dt, J = 15.6, 7.4 Hz, 1 H),

7.07 (t, J = 7.3 Hz, 1 H), 7.30 (t, J = 7.5 Hz, 2 H), 7.36-7.38 (m, 2 H). 13C NMR (CDCl3, 100 MHz): δ -

5.6, 14.1, 18.1, 25.6, 30.7, 33.4, 60.2, 63.4, 118.6, 123.3, 124.0, 128.8, 137.7, 143.6, 152.8, 166.1. IR

(NaCl, neat): 3330s, 3138w, 3059w, 2954s, 2929s, 2898m, 2857s, 2358w, 1938w, 1720s, 1656m, 1601s,

1540s, 1502m, 1472m, 1444s, 1390m, 1369m, 1313s, 1254s, 1219s, 1178s, 1108m, 1048m, 1028m, 979m,

838s, 778s, 754m, 693m.

319

The reaction of 2-44 with PhNCS and NaH inTHF

In a flame dried flask was taken 0.187 mmol (54 mg) of 1-138 dissolved in 10 mL of a flame-

dried flask. After mineral oil free NaH (0.225 mmol, 5.4 mg was added at rt, 0.281 mmol (38 mg) of

PhNCS were added slowly. The mixture was stirred under nitrogen atmosphere at rt for 3 h. It was

quenched with water and the product was extracted with dichloromethane. The organic phase was washed

with brine, dried over magnesium sulfate, and filtered through sintered funnel. The solvent was removed

under reduced pressure and purified it by flash column chromatography eluting hexane:EtOAc = 6:1 to get

30 mg of brown oil (56%), identified as 1-159.

O

OTBS

CO2Et

1-159

cis/trans = 0.75/1.0

Brown oil. Column; hexane:EtOAc = 6:1. Rf = 0.53 (hexane:EtOAc = 4:1). Major isomer, trans; 1H NMR

(CDCl3, 400 MHz): δ 0.04(s, 3 H), 0.05 (s, 3 H), 0.88 (s, 9 H), 1.25 (t, J = 7.1 Hz, 3 H), 1.67 (ddd, J = 15.3,

9.5, 5.8 Hz, 1 H), 2.00 (ddd, J = 12.8, 5.6, 1.4 Hz, 1 H), 2.48 (dd, J = 15.2, 5.9 Hz, 1 H), 2.59 (dd, J = 15.2,

7.2 Hz, 1 H), 3.61 (ddd, J = 9.2, 2.5, 0.5 Hz, 1 H), 3.99 (dd, J = 9.2, 4.8 Hz, 1 H), 4.11-4.22 (m, 2 H), 4.40-

4.49 (m, 2 H). 13C NMR (CDCl3, 100 MHz): δ -4.9, 14.2, 18.0, 25.8, 40.4, 41.8, 60.5, 72.5, 74.4, 76.0,

171.1; minor isomer, cis, δ -4.8, -4.9, 14.2, 18.0, 25.8, 40.9, 41.1, 60.4, 72.6, 75.0, 75.6, 171.4. IR (NaCl,

neat): υ 2970s, 2930s, 2857m, 1737s, 1538w, 1472m, 1384m, 1302w, 1256m, 1157m, 1111m, 1078m,

1030m, 910m, 837m, 776m. Minor isomer, cis; δ 0.05(s, 6 H), 0.87 (s, 9 H), 1.25 (t, J = 7.1 Hz, 3 H), 1.61-

1.65 (m 1 H), 2.26 (ddd, J = 13.3, 7.5, 6.3 Hz, 1 H), 2.58 (dd, J = 15.5, 6.5 Hz, 1 H), 2.76 (dd, J = 15.5, 7.2

Hz, 1 H), 3.73 (ddd, J = 9.2, 2.9, 0.8 Hz, 1 H), 3.78 (dd, J = 9.2, 4.8 Hz, 1 H), 4.11-4.22 (m, 2H), 4.35

(dddd, J = 1 3.8, 7.3, 5.8, 1.4 Hz, 1 H), 4.40-4.49 (m, 1 H).

320

Preparation of 4,6-O-benzylidene-D-glucopyranose127

OOPh O

OHOHHO

1-164

A mixture of D-glucose (10.0 g, 55.5 mmol), benzaldehyde dimethyl acetal (9.3 g, 61 mmol), and

catalytic amount of p-toluensulfonic acid (12 mg) in 40 mL of DMF (dried over 4 Å MS) was heated at 60

oC under house vacuum with nitrogen bubbling to remove methyl alcohol formed during the reaction as a

byproduct. The heating was stopped after 3h and 0.3 mL of triethyl amine was added to the reaction

mixture at 0 oC, and the excess solvent was removed under high vacuum. The crude mixture was purified

by column chromatography eluting with EtOAc (with 1% of Et3N). The desired product was obtained as a

white solid (8.38 g), and the isolated yield was 56%.

Preparation of (2R, 4R, 5R)-5-hydroxy-2-phenyl-[1, 3]dioxane-4-carbaldehyde and its dimmer

(165/165’)

Sodium periodate (6.63g) in 65 mL of water and 8N sodium hydroxide solution (1.82 mL) were

added slowly to the solution of 4,6-O- benzylidene-D-glucopyranose2 (4.12 g) in 50 mL of water in an ice-

bath (the temperature of reactants should be lower than 10 oC). The mixture was stirred at rt for additional

3 h, and to it was added about 1.8 mL of 8N sodium hydroxide solution to adjust the pH to 7 or little lower

than 7. After water was removed in a rotary evaporator, white solid was obtained. The crude product was

dissolved in excess amount of EtOAc, and filtered it under reduced pressure, and the filtrated was washed

several times with EtOAc. The combined organic phase was subjected to rotary evaporation to give

quantitative amount of 165’, which is equilibrium with its dimmer 165. This product was used for the next

experiment without further purification. The 1H NMR spectrum shows that the isolated compound is a

mixture of at least three compounds, but the 13C NMR spectrum and subsequent reactions imply that the

major compound is the dimmer (165).

321

OO

OO O

OO

O

1-165 1-165'

OHPh

CHO

Ph

Ph

OH

HO

White solid (column chromatography, hexane:EtOAc = 1:3). Rf = 0.43 (hexane:EtOAc = 1:1). Mp: 147-

149 oC. 1H NMR (DMSO-d6, 250 MHz) is complex. Three isomers were observed in 13C NMR spectrum,

and the major isomer shows δ 57.3, 66.4, 78.9, 84.6, 96.2, 122.5, 124.2, 124.8, 134.1 (Note: there is no

carbonyl carbon).

Preparation of (2R, 4S, 5R)-(E and Z)-3-(5-Hydroxy-2-phenyl-[1, 3]dioxin-4-yl)-acrylic acid ethyl

ester

To a 25 mL of flame-dried three-necked round bottom flask connected to a condenser were added

78 mg (estimated as 0.310 mmol) of crude (2R, 4R, 5R)-5-hydroxy-2-phenyl-[1, 3]dioxane-4-carbaldehyde

(1-165) and 133 mg (0.384 mmol) of (carbtert-butoxymethylene)triphenylphosphorane. Freshly dried

toluene (10 mL) was added and the mixture was stirred under refluxing condition for 1 h 40 min. After the

solvent was removed under vacuum, the product as an E and Z mixture was isolated by flash column

chromatography eluting with hexane:EtOAc = 2:1. The E and Z compounds were isolated as a white solid

and a colorless oil respectively in a ratio of 1.0/1.89, and the combined isolated yield was 90%.

The same reaction was also performed in dimethoxyethane at rt. The mixture of 78 mg (estimated

as 0.310 mmol) of crude (2R, 4R, 5R)-5-hydroxy-2-phenyl-[1, 3]dioxane-4-carbaldehyde (1-165) and 221

mg (0.634 mmol) of (carbtert-butoxymethylene) triphenylphosphorane in 10 mL of DME was stirred under

nitrogen atmosphere for 26h, and all starting material was disappeared on TLC. After the solvent was

removed in a rotary evaporator, the crude mixture was purified by column chromatography eluting with

hexane:EtOAc = 2:1. The isolated yield was the same (90%), but the proportion of Z compound increased

to 2.4 to 1.

322

(E)-1-166

OOPh OH

CO2Et

White solid (column chromatography, hexane:EtOAc = 3:1). Rf = 0.33 (hexane:EtOAc = 2:1). Mp: 93-95

oC. [α]D20

= -31.7 (c 0.71 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ 1.30 ( t, J = 7.1 Hz, 3H), 2.71 (Br s,

1H), 3.67 (d, J = 7.5 Hz, 2H), 4.22 (q, J = 7.1 Hz, 2H), 4.21-4.25 (m, 1H), 4.32 (d, J = 5.6 Hz, 1H), 5.56 (s,

1H), 6.22 (dd, J = 15.8, 1.7 Hz, 1H), 7.18 (dd, J = 15.8, 4.5 Hz, 1H), 7.34-7.41 (m, 3H), 7.49-7.51 (m, 2H).

13C NMR (CDCl3, 100 MHz): δ 14.2, 60.7, 65.3, 71.1, 80.4, 100.8, 122.4, 126.1, 128.3, 129.1, 137.2,

143.4, 166.5. IR (NaCl, neat): υ 3476Br s, 2984m, 2924m, 2862m, 1702s, 1656m, 1453m, 1394m, 1370m,

1301s, 1274m, 1224m, 1189m, 1144m, 1082s, 1026s, 979m, 918w, 850w, 757m. Anal. Calcd. for

C15H18O5: C, 64.74; H, 6.52. Found: C, 64.22; H, 6.75.

(Z)-1-166

OOPh OH

EtO2C

Colorless oil (column chromatography, hexane:EtOAc = 3:1). Rf = 0.42 (hexane:EtOAc = 2:1). [α]D20

= -

66.1 (c 0.61 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ 1.33 ( t, J = 7.1 Hz, 3H), 3.62-3.73 (m, 1H), 3.83

(d, J = 6.7 Hz, 2H), 4.24 (qd, J = 7.1, 2.9 Hz, 2H), 4.41 (dd, J = 10.3, 4.5 Hz, 1H), 5.19 (app td, J = 9.1, 1.4

Hz, 1H), 5.55 (s, 1H), 6.09 (dd, J = 11.8, 1.2 Hz, 1H), 6.34 (dd, J = 11.7, 7.8 Hz, 1H), 7.35-7.37 (m, 3H),

7.47-7.50 (m, 2H). 13C NMR (CDCl3, 100 MHz): δ 14.1, 61.5, 65.6, 72.1, 78.5, 100.7, 122.4, 126.1, 128.3,

129.0, 137.3, 145.2, 168.1. IR (NaCl, neat): υ 3431Br s, 3037w, 2982m, 2930m, 2854m, 1722s, 1694s,

1658m, 1455m, 1422m, 1386s, 1302w, 1209s, 1090s, 1207s, 871w, 827m, 755m, 699s. Anal. Calcd. for

C15H18O5: C, 64.74; H, 6.52. Found: C, 63.90; H, 6.70.

323

Preparation of (2R, 4S, 5R)-(E and Z)-3-(5-Hydroxy-2-phenyl-[1, 3]dioxin-4-yl)-acrylic acid tert-buty

ester

A 100 mL of flame-dried three neck round bottom flask was charged with 708 mg (estimated as

3.10 mmol) of crude (2R, 4R, 5R)-5-hydroxy-2-phenyl-[1, 3]dioxane-4-carbaldehyde (1-165) and 1.40 g

(3.72mmol) of of (carb tert-butoxymethylene)triphenylphosphorane and 50 mL of flash dried toluene was

introduced into the flask under nitrogen atmosphere. After the mixture was stirred under refluxing

condition for 4 h, the solvent was removed in a rotary evaporator to give crude mixture. The crude mixture

was purified by column chromatography eluting with hexane:EtOAc = 5:1 to 4:1. E and Z compounds

were isolated as white solid and combined yield was 82%. The ratio of E/Z was 1.0/5.5.

OOPh OH

CO2tBu(E)-1-167

White solid. Column chromatography; hexane:EtOAc = 1 to 4:1. Rf = 0.42 (hexane:EtOAc = 2:1). Mp:

69-71 oC. 1H NMR (CDCl3, 400 MHz): δ 1.49 (s, 9H), 2.86 (Br s, 1H), 3.61-3.69 (m, 2H), 4.27-4.34 (m,

1H), 5.55 (s, 1H), 6.13 (dd, J = 15.8, 1.6 Hz, 1H), 7.05 (dd, J = 15.8, 4.7 Hz, 1H), 7.34-7.41 (m, 3H), 7.48-

7.52 (m, 2H). 13C NMR (CDCl3, 100 MHz): δ 28.04, 65.14, 71.12, 70.53, 80.95, 100.81, 124.20, 126.12,

128.24, 129.05, 137.27, 142.22, 165.92. IR (NaCl, neat): υ 3444 Br s, 3037w, 2978s, 2930s, 2855s, 1714s,

1694s, 1660s, 1455s, 1393s, 1369s, 1316s, 1257s, 1219s, 1155s, 1084s, 1029s, 980s, 917m, 858m, 759m,

698s. Anal. Calcd. for C17H22O5; C, 66.65; H, 7.24. Found; C, 65.45; H, 7.42.

OOPh OH

ButO2C

(Z)-1-167

White solid. Column chromatography; hexane:EtOAc = 5:1 to 4:1. Rf = 0.58 (hexane:EtOAc = 2:1). Mp:

93-94 oC. [α]D20

= -41.2 (c 1.16 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ 1.51 (s, 9H), 3.64 (app td, J =

9.2, 4.4 Hz, 1H), 3.71 (app t, J = 10.3 Hz, 1H), 4.40 (dd, J = 10.5, 4.6 Hz, 1H), 5.16 (app td, J = 9.1, 1.2

324

Hz, 1H), 5.57 (s, 1H), 6.02 (dd, J = 11.8, 1.2 Hz, 1H), 6.25 (dd, J = 11.8, 7.8 Hz, 1H), 7.34-7.39 (m, 3H),

7.48-7.52 (m, 2H). 13C NMR (CDCl3, 100 MHz): δ 27.97, 65.51, 72.05, 78.30, 82.44, 100.62, 124.13,

126.08, 128.23, 128.98, 137.34, 143.96, 167.58. IR (NaCl, neat): υ 3420 Br s, 3036w, 2977s, 2930m,

1787w, 1766m, 1714s, 1683s, 1456s, 1393s, 1369s, 1316m, 1251s, 1158s, 1127s, 1090s, 1028s, 979s,

917m, 852m, 827m, 750m, 698s, 654m. Anal. Calcd. for C17H22O5; C, 66.65; H, 7.24. Found; C, 65.87; H,

7.47.

Preparation of (2R, 4S, 5R)-(E and Z)-3-(5-Hydroxy-2-phenyl-[1, 3]dioxin-4-yl)-acrylonitrile


259 mg (estimated as 1.244 mmol) of crude (2R, 4R, 5R)-5-hydroxy-2-phenyl-[1, 3]dioxane-4-

carbaldehyde (1-165) and 412 mg (1.368 mmol) of (cyanomethylene)triphenylphosphorane. Fresh dried

toluene (40 mL) was added and the mixture was stirred under refluxing condition for 12 h. Additional 206

mg of carb tert-butoxymethylene)triphenylphosphorane was added and continued the refluxing under

nitrogen atmosphere for 2h. After the solvent was removed under vacuum, the crude mixture was purified

by column chromatography eluting with hexane:EtOAc = 3:1. The isolated E and Z compound were

yellowsh brown solid in both, and the ratio of E/Z was 1.0/2.3 (isolated yield 93%).

OOPh OH

CN(E)-1-168

Yellowish brown solid. Column chromatography; hexane:EtOAc = 3:1. Rf = 0.52 (hexane:EtOAc = 1:1).

Mp: 113-115 oC. [α]D20

= -35.2 (c 0.50 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ 2.64 (Br s, 1H), 3.60-

3.63 (m, 1H), 3.65 (app t, J = 10.1 Hz, 1H), 4.22 (ddd, J = 8.9, 3.6, 2.2 Hz, 1H), 4.30 (dd, J = 9.9, 4.1 Hz,


7.49 (m, 2H). 13C NMR (CDCl3, 100 MHz): δ 65.56, 71.61, 80.24, 100.85, 101.34, 115.41, 126.52, 128.81,

129.75, 137.30, 150.82. IR (NaCl, neat): υ 3603m, 3442s, 3055s, 2982m, 2920w, 2866m, 2306m, 2240s,

1639s, 1494w, 1452m, 1422m, 1391s, 1370m, 1323m, 1310m, 1265s, 1219m, 1142s, 1083s, 1027s, 967s,

325

921m, 896m, 739s, 706s, 667w, 632m. Anal. Calcd. for C13H13O3N; C, 67.52; H, 5.67; N, 6.06. Found; C,

66.76; H, 5.86; N, 5.93.

OOPh OH

NC(Z)-1-168

Yellowish brown solid. Column chromatography; hexane:EtOAc = 3:1. Rf = 0.39 (hexane:EtOAc = 1:1).

Mp: 98-99 oC. [α]D20

= -156.1 (c 0.71 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ 2.68 (Br s, 1H), 3.60-

3.65 (m, 1H), 3.69 (app t, J = 10.2 Hz, 1H), 4.31 (dd, J = 9.9, 4.2 Hz, 1H), 4.53 (app td, J = 7.9, 0.8 Hz,


7.53 (m, 2H). 13C NMR (CDCl3, 100 MHz): δ 64.99, 70.81, 80.53, 100.80, 102.62, 115.50, 126.08, 129.18,

136.74, 148.88. IR (NaCl, neat): υ 3458Br s, 3068m, 2977m, 2926m, 2860s, 2225s, 1714w, 1634w, 1494w,

1455s, 1402s, 1385s, 1316w, 1295m, 1267m, 1216m, 1134s, 1086s, 1028s, 919m, 872w, 737s, 701s, 675m,

645m. Anal. Calcd. for C13H13O3N; C, 67.52; H, 5.67; N, 6.06. Found; C, 66.77; H, 5.87; N, 5.85.

Preparation of (2R, 4S, 5R)-(Z)-3-[(Imidazole-1-carbothioyloxy]-2-phenyl-[1, 3]dioxin-4-yl)-acrylic

acid ethyl ester

To a 50 mL of flame dried flask were added 50 mg (0.180 mmol) of (2R, 4S, 5R)-(Z)-3-(5-

Hydroxy-2-phenyl-[1, 3]dioxin-4-yl)-acrylic acid ethyl ester (Z)-1-166, 3.0 equivalents of 1,1’-

thiocarbony-ldiimidazole, and 7 mg of DMAP along with 20 mL of THF. After refluxing the mixture for 5

h, some starting material was detected on TLC. Another 180 mg of 1,1’-thiocarbony-ldiimidazoleand was

added and continued the refluxing for 28h. Additional 100 mg of of 1,1’-thiocarbony-ldiimidazole was

required to consume all starting material with refluxing 10h. After the solvent was removed on a rotary

evaporator, the product was isolated by flash column chromatography with hexane:EtOAc = 3:1 to give

66.9 mg of desired product as yellow solid. The isolated yield was 96%.

326

OOPh O Im

S

1-169EtO2C

Yellow solid. Column chromatography; hexane:EtOAc = 3:1. Rf = 0.33 (hexane:EtOAc = 2:1). Mp: 101-

103 oC. [α]D20

= -51.0 (c 2.06 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ 1.26 ( t, J = 7.2 Hz, 3H), 3.92

(app t, J = 10.3 Hz, 1H), 4.18 (app tt, J = 7.1, 3.8 Hz, 2H), 4.67 (dd, J = 10.6, 5.2 Hz, 1H), 5.58 (app td, J =

9.8, 5.2 Hz, 1H), 5.70 (s, 1H), 5.99 (dd, J = 11.7, 0.8 Hz, 1H), 6.02 (app t, J = 9.4 Hz, 1H), 6.20 (dd, J =

11.7, 8.8 Hz, 1H), 7.03 (d, J = 0.8 Hz, 1H), 7.36-7.40 (m, 3H), 7.49-7.52 (m, 2H), 7.65 (s, 1H), 8.39 (s,

1H). 13C NMR (CDCl3, 100 MHz): δ 14.1, 60.8, 66.6, 73.0, 74.0, 101.2, 118.4, 124.4, 126.1, 128.3, 129.3,

130.2, 136.5, 136.9, 142.9, 165.4, 182.5. IR (NaCl, neat): υ 3133m, 3037w, 2982m, 2926m, 1715s, 1659m,

1532m, 1469s, 1392s, 1333s, 1295s, 1279s, 1231s, 1199s, 1126s, 1094s, 1005s, 947w, 919m, 872w, 828m,

752m, 698m. Anal. Calcd. for C19H20O5N2S; C, 58.75; H, 5.19; N, 7.21. Found; C, 58.05; H, 5.37; N, 7.13.

Preparation of (2R, 4S, 5R)-(E)-3-[(Imidazole-1-carbothioyloxy]-2-phenyl-[1, 3]dioxin-4-yl)-acrylic

acid ethyl ester

To a flame dried 50 mL flask were added 51 mg (0.183 mmol) of (2R, 4S, 5R)-(E)-3-(5-Hydroxy-

2-phenyl-[1, 3]dioxin-4-yl)-acrylic acid ethyl ester (E)-1-166, 98 mg (0.550 mmol) of 1,1’-

thiocarbonyldiimidazole, and 7 mg of DMAP along with 20 mL of fresh distilled THF. The mixture was

refluxed under nitrogen atmosphere for 14 h, and another 200 mg of 1,1’-thiocarbonyldiimidazole were

added. Continued refluxing for 5.5 h, but some starting material was detected on TLC. Finally, 150 mg of

1,1’-thiocarbonyldiimidazole and 18 h refluxing were required to consume all starting material. The

solvent was removed under reduced pressure to give deep brown oil as crude product. The mixture was

purified by flash column chromatography with hexane:EtOAc = 2:1, and 62.1 mg (89%) of desired product

was obtained as pale yellow solid.

327

OOPh O

CO2Et

Im

S

1-170

Pale yellow solid. Column chromatography; hexane:EtOAc = 2:1. Rf = 0.17 (hexane:EtOAc = 2:1). Mp:

100-102 oC [α]D20

= -106.7 (c 0.45 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ 1.26 ( t, J = 7.1 Hz, 3H),

3.84 (app t, J = 10.4 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 4.71 (dd, J = 10.8, 5.3 Hz, 1H), 4.74-4.69 (m, 1H),

5.54 (app td, J = 9.8, 5.2 Hz, 1H), 5.68 (s, 1H), 6.23 (dd, J = 15.7, 1.5 Hz, 1H), 6.96 (dd, J = 15.7, 4.9 Hz,

1H), 7.09 (s, 1H), 7.38-7.42 (m, 3H), 7.50-7.54 (m, 2H), 7.61 (s, 1H), 8.41 (s, 1H). 13C NMR (CDCl3, 100

MHz): δ 14.1, 60.8, 66.7, 73.4, 76.9, 101.2, 118.0, 124.0, 126.1, 128.4, 129.4, 130.8, 136.3, 136.7, 140.4,

165.6, 181.9. IR (NaCl, neat): υ 3416Br s, 3128m, 3038w, 2979m, 1728s, 1713s, 1666m, 1532m, 1470s,

1392s, 1334s, 1184s, 1139s, 1097s, 1004s, 920m, 852w, 748m, 699m, 653m. Anal. Calcd. for

C19H20O5N2S; C, 58.75; H, 5.19; N, 7.21. Found; C, 58.61; H, 5.33; N, 7.20.

Preparation of (2R, 4S, 5R)-(Z)-3-[(Imidazole-1-carbothioyloxy]-2-phenyl-[1, 3]dioxin-4-yl)-acrylic

acid tert-butyl ester

To a flame dried 100 mL flask were added 472 mg (1.56 mmol) of (2R, 4S, 5R)-(E)-3-(5-

Hydroxy-2-phenyl-[1, 3]dioxin-4-yl)-acrylic acid tert-butyl ester (Z)-1-167 and 832 mg (4.67 mmol) of

1,1’-thiocarbony-ldiimidazole and 7 mg of DMAP along with 50 mL of THF. The mixture was refluxed

under nitrogen atmosphere for 6 h. After removed all solvent in vaccuo, the crude mixture was purified by

column chromatography with hexane:EtOAc = 5:1 to give 278 mg of desired product along with 221 mg of

the starting material. The isolated yield was 81% based on recovered starting material.

OOPh O Im

S

1-171BuO2

tC

Yellow oil. Column chromatography; hexane:EtOAc 5:1. Rf = 0.37 (hexane:EtOAc 3:1). [α]D20

= -30.0 (c

1.17 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ 1.47 (s, 9Η), 3.91 (app t, J = 10.3 Hz, 1H), 4.66 (dd, J =

328

10.6, 5.2 Hz, 1H), 5.53 (app td, J = 9.9, 5.2 Hz, 1H), 5.69 (s, 1H), 5.90 (d, J = 11.2 Hz, 1H), 6.03 (app t, J =

9.2 Hz, 1H), 6.11 (dd, J = 11.3, 8.9 Hz, 1H), 6.97 (dd, J = 1.6, 0.7 Hz, 1H), 7.34-7.39 (m, 3H), 7.48-7.52

(m, 2H), 7.64 (app t, J = 1.4 Hz, 1H), 8.34 (s, 1H). 13C NMR (CDCl3, 100 MHz): δ 27.94, 66.51, 72.82,

73.59, 82.27, 101.03, 118.15, 126.05, 128.20, 129.18, 130.63, 136.54, 137.06, 141.07, 164.61, 182.75. IR

(NaCl, neat): υ 3131s, 3037s, 2977s, 2931s, 2872s, 1954s, 1655m, 1602m, 1455s, 1392s, 1363s, 1314s,

1426s, 1157s, 1126s, 1092s, 1009s, 949m, 918m, 853m, 827m, 738s, 699s, 662m.

Preparation of (2R, 4S, 5R)-(E)-3-[(Imidazole-1-carbothioyloxy]-2-phenyl-[1, 3]dioxin-4-yl)-acrylic


To a flame dried 50 mL flask were added 64 mg (0.211 mmol) (2R, 4S, 5R)-(E)-3-(5-Hydroxy-2-

phenyl-[1, 3]dioxin-4-yl)-acrylic acid tert-butyl ester (E)-1-167 and 113 mg (0.633 mmol) of 1,1’-

thiocarbony-ldiimidazole and 7 mg of DMAP along with 30 mL of THF. The mixture was refluxed under

nitrogen atmosphere for 13 h, and another 180 mg of 1,1’-thiocarbony-ldiimidazole was added. The

mixture was refluxed continually until no more starting material was detected on TLC (15 h). All solvent

was removed in vaccuo to give crude mixture, which was subject to column chromatography with

hexane:EtOAc = 2:1. The desired product was isolated as yellow oil (53 mg) and 1H NMR spectrum

implied the isolated compound is the mixture of two diastereomers with a ratio of 0.16/1.0.

OOPh O

CO2tBu

Im

S

1-172

Yellow oil. Column chromatography; hexane:EtOAc = 2:1. Rf = 0.18 (hexane:EtOAc = 2:1). [α]D20

= -

81.0 (c 0.62 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ 1.45 (s, 9H), 3.1 (app t, J = 10.3 Hz, 1H), 4.67

(ddd, J = 9.7, 4.9, 1.4 Hz, 1H), 4.72 (dd, J = 10.7, 5.2 Hz, 1H), 5.53 (app td, J = 9.8, 5.2 Hz, 1H), 5.67 (s,

1H), 6.14 (dd, J = 15.6, 1.5 Hz, 1H), 7.07 (s, 1H), 7.37-7.41 (m, 3H), 7.50-7.57 (m, 2H), 7.59 (s, 1H), 8.33

(s, 1H). 13C NMR (CDCl3, 100 MHz): δ 27.94, 66.74, 73.46, 77.11, 81.10, 101.46, 117.92, 125.89, 126.15,

329

128.37 (two peaks), 129.43, 131.07, 136.40, 139.23, 164.25, 182.06. IR (NaCl, neat): υ 3127w, 2977m,

2926w, 2871w, 1713s, 1661w, 1532w, 1469m, 1393s, 1368m, 1333s, 1296s, 1231s, 1155s, 1099s, 1004s,

920m, 846m, 759m, 699s.

Preparation of (2R, 4S, 5R)-(Z)-3-[(Imidazole-1-carbothioyloxy]-2-phenyl-[1, 3]dioxin-4-yl)-

acrylonitrile

To a flame-dried 25 mL flask were added 94 mg (0.407 mmol) of (2R, 4S, 5R)-(Z)-3-(5-Hydroxy-

2-phenyl-[1, 3]dioxin-4-yl)-acrylonitrile (Z)-1-168, 217 mg (1.220 mmol) of 1,1’-thiocarbonyldiimidazole,

and 17 mg of DMAP along with 20 mL of freshly distilled THF. The mixture was refluxed under nitrogen

atmosphere for 7 h, and another 217 mg of 1,1’-thiocarbonyldiimidazole was added. Refluxing was

continued for 5h at which time all starting material was consumed (TLC). The solvent was removed under

reduced pressure to give the crude mixture, which was purified by flash column chromatography eluting

with hexane:EtOAc = 4:1 to 1:1. The desired product was obtained as pale yellow solid (97 mg) in an

isolated yield of 70%.

OOPh O Im

S

1-173NC

Pale yellow solid (column chromatography, hexane:EtOAc = 4:1 to 1:1). Rf = 0.55 (hexane:EtOAc = 1:1).

Mp: 136-137 oC. [α]D20

= -90.0 (c 0.41 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ 3.91 (app t, J = 10.4 Hz,

1H), 4.70 (dd, J = 10.8, 5.3 Hz, 1H), 5.10 (app t, J = 9.1 Hz, 1H), 5.58 (dd, J = 11.0, 0.6 Hz, 1H), 5.66 (app

td, J = 9.8, 5.3 Hz, 1H), 5.72 (s, 1H), 6.52 (dd, J = 11.1, 8.7 Hz, 1H), 7.07 (d, J = 0.9 Hz, 1H), 7.38-7.42

(m, 3H), 7.50-7.54 (m, 2H), 7.68 (app t, J = 1.3 Hz, 1H), 8.41 (s, 1H). 13C NMR (CDCl3, 100 MHz):

δ 66.52, 71.92, 77.38, 101.42, 104.42, 114.85, 117.77, 126.07, 128.37, 129.53, 131.31, 135.94, 137.55,

147.03, 182.43. IR (NaCl, neat): υ 3143Br s, 3110m, 3082m, 3039m, 2948m, 2872s, 2253m, 2223s,

1767w, 1713w, 1644w, 1534s, 1480s, 1467s, 1392s, 1330s, 1297s, 1276s, 1216s, 1131s, 1097s, 1069m,

330

1053m, 1006s, 971s, 910s, 871m, 834s, 759s, 735s, 702s, 653s. Anal. Calcd. for C17H15O3N3S: C, 59.81;

H, 4.43; N, 12.31. Found: C, 59.86; H, 4.76; N, 11.70.

Preparation of (2R, 4S, 5R)-(E)-3-[(Imidazole-1-carbothioyloxy]-2-phenyl-[1, 3]dioxin-4-yl)-

acrylonitrile

To a flame dried 25 mL flask were added 40 mg (0.172 mmol) of (2R, 4S, 5R)-(E)-3-(5-Hydroxy-

2-phenyl-[1, 3]dioxin-4-yl)-acrylonitrile (E)-1-168, 92 mg (0.515 mmol) of 1,1’-thiocarbonyldiimidazole,


atmosphere for 7 h, and another 92 mg of 1,1’-thiocarbonyldiimidazole was added. Continued refluxing

for 5 h consumed all starting material (TLC). The solvent was removed under reduced pressure to give

crude mixture, which was purified by flash column chromatography eluting with hexane:EtOAc = 4:1 to

1:1. The desired product was obtained as yellow oil (44 mg) and the isolated yield is 80%. The isolated

compound wasthe mixture of one major isomer and two minor diastereomers, and the ratio of major/two

minor was ratio 0.42/1.0 based on 1H NMR analysis. Further purification was not performed and only the

major diastereomer was assigned.

OOPh O

CN

Im

S

1-174

Yellow oil. Column chromatography; hexane:EtOAc = 4:1 to 1:1. Rf = 0.26 (hexane:EtOAc = 1:1). [α]D20

= -86.0 (c 0.25 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ 3.84 (app t, J = 10.5 Hz, 1H), 4.23-4.27 (m,

1H), 5.56 (app td, J = 9.9, 5.2 Hz, 1H), 5.68 (s, 1H), 5.82 (dd, J = 16.2, 1.9 Hz, 1H), 6.79 (dd, J = 16.2, 4.0

Hz, 1H), 7.07-7.09 (m, 1H), 7.36-7.42 (m, 3H), 7.44-7.51 (m, 2H), 7.60 (app t, J = 1.5 Hz, 1H), 8.32 (s,

1H). IR (NaCl, neat): υ 3129Br s, 3068s, 2965m, 2863s, 2228s, 1770m, 1641w, 1534m, 1469s, 1393s,

1334s, 1291s, 1231s, 1175m, 1141s, 1094s, 1008s, 916s, 874w, 832m, 754s, 732s, 699s, 651s. HRMS

(Electrospray): m/z Calcd for C17H15O3N3SNa (M++Na), 364.0726; Found (M++Na), 364.0722.

331

Preparation of (2R, 4S, 5R)-5-Hydroxy-2-phenyl-[1, 3]dioxane-4-carbaldehyde; O-methyloxime

To a 100 mL of flame-dried three-necked round bottom flask connected to a condenser were

added 222 mg (estimated as 1.07 mmol) of crude (2R, 4R, 5R)-5-hydroxy-2-phenyl-[1, 3]dioxane-4-

carbaldehyde (1-165) and 142 mg (1.60 mmol) of O-methylhydroxyl amine hydrochloride in 50 mL of

methyl alcohol and 1 mL of pyridine. After the mixture was refluxed under nitrogen atmosphere for 5.5h,

and all solvent was removed in a rotary evaporator to get the crude product. The crude mixture was

purified by column chromatography eluting with hexane:EtOAc = 4:1, and 216 mg of the desired product

was obtained as a white solid (isolated yield 91%). The isolated compound is a syn/ anti mixture with a

ratio of 1.0/0.18 based on 1H NMR analysis.

OOPh OH

NOCH3

1-175

syn/ anti = 1.0/0.18

White solid (syn/ anti = 1.0/0.18) (column chromatography, hexane:EtOAc = 4:1). Rf = 0.60

(hexane:EtOAc = 1:1). Mp: 105-108 oC. 1H NMR (CDCl3, 400 MHz): syn δ 3.70 (app t, J = 10.5 Hz, 1H),

3.90 (s, 3H), 3.99 (ddd, J = 10.2, 9.1, 5.2 Hz, 1H), 4.25 (dd, J = 8.9, 3.9 Hz, 1H), 4.38 (dd, J = 10.9, 5.2 Hz,

1H), 5.54 (s, 1H), 7.23-7.42 (m, 3H), 7.47-7.52 (m, 3H); anti δ 3.67 (app t, J = 9.6 Hz, 1H), 3.80 (app td, J

= 9.9, 5.1 Hz, 1H), 3.96 (s, 3H), 4.38 (dd, J = 10.8, 5.0 Hz, 1H), 4.90 (dd, J = 9.5, 5.3 Hz, 1H), 5.51 (s,

1H), 6.91 (d, J = 5.3 Hz, 1H), 7.33-7.42 (m, 3H), 7.47-7.52 (m, 2H). 13C NMR (CDCl3, 100 MHz):

syn δ 62.19, 63.99, 70.15, 78.69, 101.35, 126.13, 128.33, 129.21, 137.04, 148.70, anti δ 62.51, 71.11,

75.62, 77.92, 100.71, 126.10, 128.33, 129.21, 136.94, 149.95. IR (NaCl, neat): υ 3489br s, 2978w, 3939w,

2252s, 1462m, 1390m, 1221w, 1086m, 1041m, 908s, 733s, 650m. Anal. Calcd. for C12H15O4N: C, 60.75;

H, 6.37; N, 5.90. Found: C, 60.87; H, 6.62; N, 5.94.

332

Preparation of (2R, 4S, 5R)-5-Hydroxy-2-phenyl-[1, 3]dioxane-4-carbaldehyde; O-benzyloxime

To a 50 mL of flame-dried three-necked round bottom flask connected to a condenser were added

1.49 g (estimated as 7.16 mmol) of crude (2R, 4R, 5R)-5-hydroxy-2-phenyl-[1, 3]dioxane-4-carbaldehyde

(1-165) and 1.37 g (8.59 mmol) of O-benzylhydroxyl amine hydrochloride in 20 mL of methyl alcohol and

2 mL of pyridine. After the mixture was refluxed under nitrogen atmosphere for 5.5h, and all solvent was

removed in a rotary evaporator to get the crude product. The crude mixture was purified by column

chromatography eluting with hexane:EtOAc = 3:1, and 1.19 mg of the desired product was obtained as a

white solid (isolated yield 53%). The isolated compound is a syn/ anti mixture with a ratio of 1.0/0.14

based on 1H NMR analysis.

OOPh OH

NOBn1-176

syn/ anti = 1.0/0.14

Pale yellow solid. Recrystalization by hexane:EtOAc = 3:1 or Column; hexane:EtOAc = 3:1. Rf = 0.39

(hexane:EtOAc = 3:1). Mp: 139-140 oC. 1H NMR (CDCl3, 400 MHz): syn (major), δ 2.07 (Br s, OH), 3.67

(app t, J = 10.6 Hz, 1H), 3.96 (ddd, J = 10.2, 9.1, 5.2 Hz, 1H), 4.24 (dd, J = 8.9, 3.9 Hz, 1H), 4.36 (dd, J =

10.9, 5.2 Hz, 1H), 5.12 (s, 2H), 5.52 (s, 1H), 7.30-7.40 (m, 8H), 7.46-7.50 (m, 2H); anti (minor), δ 2.07 (Br

s, OH), 3.65 (dd, J = 10.8, 10.1 Hz, 1H), 3.80 (app td, J = 9.8, 5.1 Hz, 1H), 4.33-4.38 (overlap with syn

isomer, 1H), 4.92 (dd, J = 9.5, 5.3 Hz, 1H), 5.16 (d, J = 11.9 Hz, 1H), 5.20 (d, J = 120.0 Hz, 1H), 5.50 (s,

1H), 6.95 (d, J = 5.3 Hz, 1H), 7.30-7.40 (m, 8H), 7.46-7.50 (m, 2H). 13C NMR (CDCl3, 100 MHz): syn

(major) δ 63.95, 70.10, 76.52, 78.76, 101.34, 126.12, 128.21, 128.32, 128.38, 128.70, 129.20, 136.85,

137.02, 149.21. IR (NaCl, neat): υ 3053w, 3031w, 2968m, 2924w, 2881m, 1635m, 1451s, 1396s, 1374s,

1336s, 1274w, 1226s, 1160w, 1110s, 1077s, 1019s, 998s, 950s, 923s, 897s, 870w, 748s, 695s, 654m, 618m.

HRMS (Electrospray): m/z Calcd for C18H19NO4Na (M++Na), 336.1206; Found (M++Na), 336.1296.

333

Preparation of (2R, 4S, 5R)-4-(Diphenylhydrazonomethyl)-2-phenyl-[1, 3]dioxane-5-ol

To a 100 mL of flame-dried one neck round bottom flask were added 780 mg (estimated as 3.10

mmol) of crude (2R, 4R, 5R)-5-hydroxy-2-phenyl-[1, 3]dioxane-4-carbaldehyde (1-165) and 1.37 g (6.20

mmol) of N,N’-dimethyl hydrazine hydrochloride with 50 mL of methyl alcohol, 552 µL of pyridine (6.82

mmol), and small amount of 4 Å MS. The mixture was stirred at rt under nitrogen atmosphere for 17.5h.

After the solvent was removed in a rotary evaporator, the crude product was purified by column

chromatography eluting with hexane:EtOAc = 7:1 to give 993 mg of the desired product as white solid

(isolated yield 86%). The isolated compound is assigned as anti based on the chemical shift and coupling

constant of its characteristic hydrogen (6.63 ppm, d, J = 3.2 Hz) on 1H NMR spectrum.

1-177

OOPh OH

NNPh2

anti

White solid. Column chromatography; hexane:EtOAc = 7:1. Rf = 0.27 (hexane:EtOAc = 5:1). Mp: 119-

120 oC. [α]D20

= +58.8 (c 0.40 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ 3.42 (Br s, 1H), 3.75 (app t, J =

10.5 Hz, 1H), 4.14 (app td, J = 10.0, 5.3 Hz, 1H), 4.35 (dd, J = 8.9, 3.2 Hz, 1H), 4.43 (dd, J = 10.9, 5.2 Hz,

1H), 5.56(s, 1H), 6.63 (d, J = 3.2 Hz, 1H), 7.11 (d, J = 7.4 Hz, 2H), 7.35-7.43 (m, 7H), 7.47-7.50 (m, 2H).

13C NMR (CDCl3, 100 MHz): δ 64.66, 70.20, 80.64, 101.43, 122.35, 124.86, 128.26, 129.91, 135.90,

137.26, 142.95. IR (NaCl, neat): υ 3453Br s, 3062m, 3036m, 2973m, 2927m, 2856m, 2358w, 2248m,

1955w, 1809w, 1703w, 1591s, 1495s, 1455s, 1395s, 1298s, 1215s, 1157s, 1074s, 1027s, 910s, 750s, 733s,

699s, 648s. Anal. Calcd. for C23H22O3N2; C, 73.78; H, 5.92; N, 7.48. Found; C, 72.89; H, 6.14; N, 7.42.

Preparion of (2R, 4S, 5R)-4-[(p-Toluenesulfonyl)hydrazonmethyl]-2-phenyl-[1, 3]dioxane}-5-ol


314 mg (estimated as 1.248 mmol) of crude (2R, 4R, 5R)-5-hydroxy-2-phenyl-[1, 3]dioxane-4-

carbaldehyde (1-165) and 279 mg (1.498 mmol) of (p-toluene)sulfonyl hydrazine with 50 mL of methyl

334

alcohol and small amount of 4 Å MS. The mixture was stirred under reflux condition for 2.5 h, and all

solvent was removed in a rotary evaporator. The crude product was purified by column chromatography

eluting with hexane:EtOAc = 3:1 to 2:1 to give 354 mg of the desired product as white solid (isolated yield

75%). The isolated compound is assigned as anti based on the chemical shift and coupling constant of its

characteristic hydrogen (7.30 ppm, d, J = 6.0 Hz) on 1H NMR spectrum.

1-178

OOPh OH

NNHTs


143-144 oC. 1H NMR (acetone-d6, 400 MHz): δ 2.39 (s, 3H), 3.63(app t, J = 10.4 Hz, 1H), 3.73 (app dt, J

= 9.2, 5.1 Hz, 1H), 3.76 (s, 0.84 NH, disappeared with D2O), 3.77 (s, 0.16 NH, disappeared with D2O), 4.12

(dd, J = 9.2, 6.0 Hz, 1H), 4.21 (dd, J = 10.5, 5.1 Hz, 1H), 4.31 (d, J = 5.6 Hz, OH), 5.57 (s, 1H), 7.30 (d, J

= 6.0 Hz, 1H), 7.31-7.36 (m, 3H), 7.37 (d, J = 8.0 Hz, 2H), 7.39-7.43 (m, 2H), 7.76 (dd, J = 6.6, 1.7 Hz,

2H). 13C NMR (acetone-d6, 100 MHz): δ 21.39, 63.91(d), 71.49, 81.91 (d), 101.28, 127.07, 128.44, 128.72,

129.48, 130.34, 137.32, 138.98, 144.61, 147.74 (d). IR (NaCl, neat): υ 3456Br s, 2924m, 2871m, 1698m,

1597m, 1455m, 1397m, 1328m, 1218w, 1164s, 1089s, 1028m, 915w, 814w. Anal. Calcd. for C18H20O5N2S;

C, 57.43; H, 5.36; N, 7.44. Found; C, 59.90; H, 6.66; N, 6.30. HRMS (Electrospray): m/z Calcd for

C18H20O5N2SNa (M++Na), 399.0985; Found (M++Na), 399.1004.

Preparation of (2R, 4S, 5R)-4-[(2-Phenylaziridin-1-yl-imino)-methyl]-[1, 3]dioxane]-5-ol


mmol) of crude (2R, 4R, 5R)-5-hydroxy-2-phenyl-[1, 3]dioxane-4-carbaldehyde (1-165) and fresh prepared

1-amino-2-phenylaziridine (323 mg, 2.4 mmol) with 40 mL of ethyl alcohol and small amount of 4 Å MS.

The mixture was stirred at rt under nitrogen atmosphere for 5 h. The solid of the mixture was filtered off

and the organic phase was concentrated in a rotary evaporator. The crude product was purified by column

335

chromatography eluting with hexane:EtOAc = 6:1 to 4:1 to give 212 mg of the desired product as yellow

solid (isolated yield 65%).

1-179

OOPh OH

N NPh

Yellow solid. Column chromatography; hexane:EtOAc = 6:1 to 4:1. Rf = 0.14 (hexane:EtOAc = 3:1).

Mp: 78-80 oC. 1H NMR (CDCl3, 400 MHz): δ 2.41 (app dt, J = 4.9, 1.1 Hz, 1H), 2.48 (ddd, J = 7.8, 5.2,

0.8 Hz, 1H), 3.08 (app dt, J = 7.8, 4.9 Hz, 1H), 3.43 (d, J = 1.7Hz, 1H), 3.71 (t, J = 10.6 Hz, 1H), 3.95-4.02

(m, 1H), 4.25 (dd, J = 8.9, 2.4 Hz, 1H), 4.37 (dd, J = 10.9, 5.2 Hz, 1H), 5.55 (s, 1H), 7.24-7.29 (m, 3H),

7.31-7.39 9m, 5H), 7.48-7.50 (m, 2H), 8.37 (app t, J = 2.7 Hz, 1H). 13C NMR (CDCl3, 100 MHz): δ 40.44

(major), 40.51 (minor), 44.00 (major), 41.13 (minor), 64.26, 70.08, 79.36, 101.32, 126.08, 126.08, 127.46,

128.25, 18.39, 129.12, 137.05, 137.72, 161.30 (major), 161.37 (minor). IR (NaCl, neat): υ 3394Br s,

3065s, 3035s, 2976s, 2856s, 2248m, 1956w, 1884w, 1813w, 1703m, 1644w, 1606m, 1497m, 1455s, 1393s,

1315m, 1221m, 1086s, 1011s, 912m, 735m, 698s. Anal. Calcd. for C19H20O3N; C, 70.35; H, 6.21; N, 8.64.

Found; C, 67.60; H, 6.13; N, 8.32.

Prepartion of (2R, 4S, 5R)-(dimethylhydrazonomethyl)-2-phenyl-[1, 3]dioxane-5-ol


780 mg (estimated as 3.10 mmol) of crude (2R, 4R, 5R)-5-hydroxy-2-phenyl-[1, 3]dioxane-4-carbaldehyde

(1-165) and 932 mg (15.5mmol, 1.18 mL) of N,N’-dimethyl hydrazine with 50 mL of methyl alcohol and

small amount of 4 Å MS. After the mixture was refluxed under nitrogen atmosphere for 17.5h, and all

solvent was removed in a rotary evaporator to give crude product. The crude mixture was purified by

column chromatography eluting with hexane:EtOAc = 6:1 to 4:1 to give 652 mg of the desired product as

pale yellow solid (isolated yield 84%). The isolated compound is assigned as anti based on the chemical

shift and coupling constant of its characteristic hydrogen (6.61ppm, d, J = 3.1 Hz) on 1H NMR spectrum.

336

1-180

OOPh OH

NN(CH3)2

anti

Pale yellow solid. Column chromatography; hexane:EtOAc = 6:1 to 4:1. Rf = 0.35 (hexane:EtOAc = 1:1).

Mp: 66-68 oC. [α]D20

= +8.3 (c 0.55 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ 2.83 (s, 6H), 3.64 (Br s,

1H), 3.70 (app t, J = 10.6 Hz, 1H), 3.98 (ddd, J = 10.2, 9.1, 5.2 Hz, 1H), 4.24 (dd, J = 8.9, 3.2 Hz, 1H),

4.36 (dd, J = 10.8, 5.2 Hz, 1H), 5.57 (s, 1H), 6.61 (d, J = 3.1 Hz, 1H), 7.31-7.42 (m, 3H), 7.48-7.57 (m,

2H). 13C NMR (CDCl3, 100 MHz): δ 42.41, 65.09, 70.02, 80.54, 101.24, 126.12, 128.21, 128.95, 133.64,

137.46. IR (NaCl, neat): υ 3392Br s, 2966m, 2862s, 2778m, 2358w, 1597m, 1457s, 1396s, 1316w, 1264m,

1220m, 1085s, 1027s, 918m, 823m, 762s, 699s. Anal. Calcd. for C13H18O3N2; C, 62.38; H, 7.25; N, 11.19.

Found; C, 62.17; H, 7.21; N, 11.03.

Prepartion of (2R, 4S, 5R)-Imidazole-1-carbothionic acid {O-[4-(methoxyimino)methyl]-2-phenyl-[1,

3]dioxin-5-yl} ester

To a flame dried 100 mL flask were added 163 mg (0.687 mmol) of (2R, 4S, 5R)-5-hydroxy-2-

phenyl-[1, 3]dioxane-4-carbaldehyde; O-methyloxime 1-175, 367 mg (2.061 mmol) of 1,1’-

thiocarbonyldiimidazole, and 20 mg of DMAP along with 50 mL of freshly distilled THF. The mixture

was refluxed under nitrogen atmosphere for 8.5 h, and another 200 mg of 1,1’-thiocarbonyldiimidazole was

added. Continued refluxing for 11 h consumed all starting material (TLC). The solvent was removed

under reduced pressure to give crude mixture, which was purified by flash column chromatography eluting

with hexane:EtOAc = 6:1. The desired product 1-181 was obtained as yellow solid (215 mg) and the

isolated yield is 90%. The isolated compound is syn/anti mixture with a ratio of 1.0/0.13 based on 1H

NMR spectrum.

337

OOPh O

NOCH3

Im

S

1-181

syn/anti = 1.0/0.13

Yellow solid (syn/ anti = 1.0/0.13). Column chromatography; hexane:EtOAc = 6:1. Rf = 0.41

(hexane:EtOAc = 1:1). Mp: 85-88 oC. 1H NMR (CDCl3, 400 MHz): syn δ 3.78 (s, 3H), 3.87 (app t, J =

10.5 Hz, 1H), 4.68 (dd, J = 9.7, 6.7 Hz, 1H), 4.75 (dd, J = 10.7, 5.3 Hz, 1H), 5.66 (s, 1H), 5.69 (app td, J =

9.9, 5.3 Hz, 1H), 7.05 (d, J = 1.2 Hz, 1H), 7.37-7.41 (m, 4H), 7.49-7.52 (m, 2H), 7.61 (app t, J = 1.2 Hz,

1H), 8.31 (s, 1H), anti δ 3.82 (s, 3H), 3.90 (app t, J = 10.2 Hz, 1H), 4.69 (dd, J = 9.5, 5.0 Hz, 1H), 5.39 (dd,

J = 11.2, 4.4 Hz, 1H), 5.65 (s, 1H), 5.66 (app td, J = 9.9, 5.3 Hz, 1H), 6.82 (d, J = 5.3 Hz, 1H), 7.05 (d, J =

1.2 Hz, 1H ), 7.37-7.41 (m, 3H), 7.49-7.52 (m, 2H), 7.63 (app t, J = 1.2 Hz, 1H), 8.31 (s, 1H). 13C NMR

(CDCl3, 100 MHz): syn δ 62.14, 66.80, 71.49, 76.59, 101.58, 118.14, 126.12, 129.49, 131.07, 136.23,

145.08, 182.60, anti δ 62.31, 66.80, 71.01, 76.59, 101.31, 118.14, 126.12, 129.49, 130.97, 136.79, 145.90,

182.44. IR (NaCl, neat): υ 3412Br s, 3129m, 3037m, 2966m, 2938m, 2870m, 1631w, 1532m, 1469s,

1393s, 1355s, 1294s, 1233s, 1103s, 1039s, 1006s, 920m, 887m, 752m, 699m, 651m. Anal. Calcd. for

C16H17O4N3S; C, 55.32; H, 4.93; N, 12.10. Found; C, 56.03; H, 5.38; N, 11.65.

Prepartion of (2R, 4S, 5R)-Imidazole-1-carbothionic acid {O-[4-(benzyloxyimino)methyl]-2-phenyl-[1,

3]dioxin-5-yl} ester

To a flame dried 50 mL flask were added 1.32 g (4.21 mmol) of (2R, 4S, 5R)-5-hydroxy-2-phenyl-

[1, 3]dioxane-4-carbaldehyde; O-benzylloxime 1-176, 1.50 g (8.43 mmol) of 1,1’-thiocarbonyldiimidazole,


atmosphere for 4.5 h, and another 300 mg of 1,1’-thiocarbonyldiimidazole was added. Continued refluxing

for 3 h consumed all starting material (TLC). The solvent was removed under reduced pressure to give

crude syn/anti mixture, which was isolated by flash column chromatography eluting with hexane:EtOAc =

3:1 and then recrylstalization over hexane. The pure syn isomer of 1-182 was obtained as white solid (1.17

338

g) and the pure anti isomer of 1-182 was obtained as brown oil (56 mg). The combined isolated yield is

69%.

OOPh O

NOBn

Im

S

1-182

syn

White solid. Column; hexane:EtOAc = 3:1, then recrystalization over hexane. Rf = 0.16 (hexane:EtOAc =

3:1). [α]D20

= -85.2 (c 0.27 in CHCl3). Mp: 108-109 oC. 1H NMR (CDCl3, 500 MHz): δ 3.84 (app t, J =

10.4 Hz, 1H), 3.69 (dd, J = 9.6, 6.3 Hz, 1H), 4.72 (dd, J = 10.8, 5.4 Hz, 1H), 5.00 (s, 2H), 5.65 (s, 1H),

5.72 (app td, J = 9.9, 5.4 Hz, 1H), 7.04 (s, 1H), 7.19-7.25 (m, 5H), 7.38-7.41 (m, 3H), 7.48-7.52 (m, 4H),

8.29 (s, 1H). 13C NMR (CDCl3, 125 MHz): δ 66.71, 71.48, 76.38, 76.44, 101.61, 118.09, 127.97, 128.01,

128.30, 128.40, 130.43, 136.22, 136.75, 136.86, 145.72, 182.21. IR (KBr): υ 3118w, 3033w, 2952m,

2884m, 1651w, 1628m, 1531m, 1498m, 1463s, 1297s, 1373s, 1329s, 1308s, 1292s, 1277s, 1236s, 1213s,

1128s, 1098s, 1017s, 952m, 932s, 829m, 750s, 696s, 680m, 649s, 618m, 579w. HRMS (Electrospray): m/z

Calcd for C22H21N3O4SNa (M++Na), 446.1145; Found (M++Na), 446.1151; Calcd for C22H21N3O4SH

(M++H), 424.1326; Found (M++H), 424.1303.

OOPh O

NOBn

Im

S

1-182

anti

Brwon oil. Column; hexane:EtOAc = 4:1 to 3:1. Rf = 0.26 (hexane:EtOAc = 3:1). 1H NMR (CDCl3, 400

MHz): δ 3.88 (app t, J = 10.3 Hz, 1H), 4.65 (dd, J = 10.8, 5.1 Hz, 1H), 5.02 (d, J = 12.3 Hz, 1H), 5.07 (d, J

= 12.3 Hz, 1H), 5.43 (dd, J = 9.5, 6.7 Hz, 1H), 5.64 (s, 1H), 5.67 (app td, J = 9.7, 5.2 Hz, 1H), 6.88 (d, J =

6.7 Hz, 1H), 7.00 (s, 1H), 7.29-7.40 (m, 8H), 7.47-7.55 (m, 3H), 8.28 (s, 1H). 13C NMR (CDCl3, 100

MHz): δ 66.66, 70.90, 71.52, 16.97, 101.21, 118.12, 126.10, 127.95, 128.27, 128.36, 128.46, 128.50,

339

129.46, 130.81, 136.21, 136.46, 136.93, 146.16. IR (NaCl, neat): υ 2953s, 2857m, 1736s, 1498w, 1473w,

1428m, 1377w, 1243w, 1243w, 1185w, 1143w, 1112s, 1031m, 923w. HRMS (Electrospray): m/z Calcd for

C22H21N3O4SNa (M++Na), 446.1145; Found (M++Na), 446.1164; Calcd for C22H21N3O4SH (M++H),

424.1326; Found (M++H), 424.1289.

Preparation of (2R, 4S, 5R)-Imidazole-1-carbothioic acid O-[4-(diphenylhydrazonomethyl)-2-phenyl-

[1,3]dioxan-5-yl] ester

To a flame dried 100 mL flask were added 716 mg (2.06 mmol) of (2R, 4S, 5R)-4-(diphenyl

hydrazonomethyl)-2-phenyl-[1, 3]dioxane-5-ol 1-177, 1.10 g (6.18 mmol) of 1,1’-thiocarbonyl diimidazole,

and 80 mg of DMAP along with 60 mL of freshly distilled THF. After the mixture was refluxed under

nitrogen atmosphere for 17.5 h, another 1.10 g of 1,1’-thiocarbonyl diimidazole was added. After 9 h

refluxing, all starting material was disappeared on TLC. The solvent was removed under reduced pressure

to give crude mixture, which was purified by flash column chromatography eluting with hexane:EtOAc =

6:1 to 4:1. The desired product 1-183 was obtained as yellow solid (833 mg) and 26 mg of the starting

material was recovered. The isolated yield is 90% (93% based on the recovered starting material). The

isolated compound is assigned as anti based on the chemical shift and coupling constant of its characteristic

hydrogen (6.46 ppm, d, J = 5.7 Hz) on 1H NMR spectrum.

OOPh O

NNPh2

Im

S

1-183

anti

Yellow solid. Column chromatography; hexane:EtOAc = 6:1 to 4:1. Rf = 0.29 (hexane:EtOAc = 2:1).

Mp: 65-67 oC. [α]D20

= +26.0 (c 0.45 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ 3.93 (app t, J = 10.5 Hz,

1H), 4.68 (dd, J = 10.7, 5.4 Hz, 1H), 4.79 (dd, J = 9.5, 5.7 Hz, 1H), 5.68 (s, 1H), 5.83 (app td, J = 9.9, 5.4

Hz, 1H), 6.46 (d, J = 5.7 Hz, 1H), 6.98 (dd, J = 8.6, 1.2 Hz, 4H), 7.03 (d, J = 0.7 Hz, 1H), 7.15 (td, J = 7.4,

1.0 Hz, 2H), 7.30-7.33 (m, 4H), 7.36-7.40 (m, 3H), 7.49-7.52 (m, 2H), 7.64 (s, 1H), 8.37 (s, 1H). 13C NMR

340

(CDCl3, 100 MHz): δ 66.89, 72.14, 79.33, 101.64, 117.98, 122.21, 124.82, 126.19, 128.35, 129.38, 129.74,

130.92, 131.29, 136.55, 136.80, 142.84, 182.77. IR (NaCl, neat): υ 3129m, 3064m, 3038m, 2967m, 2246w,

1955w, 1767w, 1702w, 1592s, 1532w, 1495s, 1464m, 1392s, 1335s, 1300s, 1279s, 1232s, 1157m, 1098s,

1004s, 911s, 831s, 750s, 733s, 699s, 644m. Anal. Calcd. for C27H24O3N4S; C, 66.48; H, 4.99; N, 11.56.

Found; C, 66.48; H, 5.30; N, 10.79.

Preparation of (2R, 4S, 5R)-Imidazole-1-carbothioic acid O-{4-[(p-toluenesulfonyl) hydrazono

methyl)-2-phenyl-[1,3]dioxan-5-yl} ester

To a flame dried 100 mL flask were added 174 mg (0.462 mmol) of (2R, 4S, 5R)-4-(p-

toluenesulfonyl-hydrazonmethyl)-2-phenyl-[1, 3]dioxane}-5-ol 1-178, 247 mg (1.387 mmol) of 1,1’-

thiocarbonyldiimidazole, and 14 mg of DMAP along with 50 mL of freshly distilled THF. After the

mixture was refluxed under nitrogen atmosphere for 12 h, all starting material was disappeared on TLC.

The solvent was removed under reduced pressure to give crude mixture, which was purified by flash

column chromatography eluting with hexane:EtOAc = 1:1. The desired product 1-84 was obtained as

white solid (108 mg) and the isolated yield is 48%. This reaction was also performed with crude (2R, 4S,

5R)-4-(p-toluenesulfonyl-hydrazonmethyl)-2-phenyl-[1, 3]dioxane}-5-ol 1-178, which was not purified by

column chromatography. In this case, the yield was 43% from 1-164 (total 3 steps). The isolated

compound is assigned as anti based on the chemical shift and coupling constant of its characteristic

hydrogen (7.40 ppm, d, J = 5.3 Hz) on 1H NMR spectrum.

OOPh O

NNHTs

Im

S

1-184

anti

White solid. Column chromatography; hexane:EtOAc = 1:1. Rf = 0.39 (hexane:EtOAc = 1:2). Mp: 166-

167 oC. 1H NMR (acetone-d6, 400 MHz): δ 2.33 (s, 3H), 3.74 (s, NH), 4.02(app t, J = 10.8 Hz, 1H), 4.85

(dd, J = 9.6, 5.3 Hz, 1H), 5.67 (app td, J = 10.0, 5.4 Hz, 1H), 5.81 (s, 1H), 7.02 (dd, J = 1.6, 0.8 Hz, 1H),

341

7.18 (dd, J = 7.9, 0.4 Hz, 2H), 7.35-7.39 (m, 3H), 7.40 (d, J = 5.3 Hz, 1H), 7.47-7.50 (m, 2H), 7.60 (app t, J

= 1.5 Hz, 1H), 7.62 (d, J = 8.3 Hz, 2H), 8.20 (s, 1H). 13C NMR (acetone-d6, 100 MHz): δ 21.49, 66.83,

69.16, 72.26, 78.13, 101.99, 119.16, 127.17, 128.13, 128.92, 129.91, 130.23, 131.69, 136.99, 137.67,

138.14, 144.69, 145.09, 180.38. IR (NaCl, neat): υ 3053m, 2982m, 2362w, 2306w, 2229m, 2130w, 2066w,

1696s, 1598m, 1482w, 1459m, 1417m, 1388m, 1266s, 1153m, 1094m, 1052m, 894w, 815w, 738s, 699m.

HRMS (Electrospray) m/z calcd. For (M++Na); 209.0924. Found (M++Na); 209.0901. Anal. Calcd. for

C22H22O4N2S2; C, 54.31; H, 4.56; N, 11.52. Found; C, 54.33; H, 4.79; N, 11.43.

Preparation of (2R, 4S, 5R)-Imidazole-1-carbothionic acid O-{-2-phenyl-4-[(2-phenylaziridin-1-

ylimino)-methyl]-[1, 3]dioxane-5-yl} ester

To a flame dried 50 mL flask were added 104 mg (0.321 mmol) (2R, 4S, 5R)-4-[(2-Phenylaziridin-

1-yl-imino)-methyl]-[1, 3]dioxane]-5-ol 1-179, 171 mg (0.962 mmol) of 1,1’-thiocarbonyldiimidazole, and

12 mg of DMAP along with 30 mL of freshly distilled THF. After the mixture was refluxed under nitrogen

atmosphere for 5 h, another 171 mg of 1,1’-thiocarbonyldiimidazole was added and stirred it under reflux

condition for 17.5 h. The solvent was removed under reduced pressure to give crude mixture, which was

purified by flash column chromatography eluting with hexane:EtOAc = 4:1 to 1:1. The desired product 1-

185 was obtained as brown oil (64 mg) and the isolated yield is 49%.

1-185

OOPh O

N NPh

Im

S

Brown oil. Column chromatography; hexane:EtOAc = 4:1 to 2:1. Rf = 0.26 (hexane:EtOAc = 1:1). 1H

NMR (CDCl3, 400 MHz): δ 3.74 (d, J = 9.8 Hz, minor 1H), 3.76 (d, J = 10.0 Hz, major 1H), 3.92 (app t, J

= 10.4 Hz, major 1H), 3.93 (app t, J = 10.6 Hz, minor 1H), 4.69 (dd, J = 10.7, 5.3 Hz, 1H), 4.81-4.90 (m,

2H), 5.66 (s, major 1H), 5.67 (s, minor 1H), 5.79 (app tt, J = 10.0, 3.3 Hz, 1H), 7.05 (dd, J = 1.6, 0.9 Hz,

major 1H), 7.06 (dd, J = 1.5, 0.7 Hz, minor 1H), 7.35-7.41 (m, 8H), 7.47-7.51 (m, 3H), 7.58-7.60 (m, 1H),

8.31 (s, minor 1H), 8.33 (s, major 1H). 13C NMR (CDCl3, 100 MHz): δ 42.85, 53.66 (major), 53.77

342

(minor), 66.81, 71.61, 79.10, 101.52, 117.90, 126.09, 127.25 (minor), 127.44 (major), 128.39, 128.80

(minor), 128.84 (major), 129.19, 129.50, 131.23, 136.13 (major), 136.16 (minor), 137.26, 137.77 (major),

138.15 (minor). IR (NaCl, neat): υ 3401Br s, 3127m, 3060m, 3033m, 2966m, 2931m, 2872m, 2245w,

1760w, 1694s, 1652w, 1533w, 1495m, 1467s, 1393s, 1335s, 1283s, 1278s, 1231s, 1179s, 1154s, 1099s,

1005s, 917m, 832w, 765s, 733s, 699s, 652m.

Preparation of (2R, 4S, 5R)-Imidazole-1-carbothioic acid O-[4-(dimethylhydrazonomethyl)-2-phenyl-

[1,3]dioxan-5-yl] ester

To a flame dried 100 mL flask were added 363 mg (1.45 mmol) of (2R, 4S, 5R)-(dimethyl

hydrazonomethyl)-2-phenyl-[1, 3]dioxane-5-ol 1-180, 775 mg (4.35 mmol) of 1,1’-thiocarbonyl

diimidazole, and 50 mg of DMAP along with 50 mL of freshly distilled THF. After the mixture was

refluxed under nitrogen atmosphere for 3 h, all starting material was consumed (TLC). The solvent was

removed under reduced pressure to give crude mixture, which was purified by flash column

chromatography eluting with hexane:EtOAc = 3:1. The desired product 1-186 was obtained as yellow solid

(215 mg) and the isolated yield is 90%. The isolated compound is assigned as anti based on the chemical

shift and coupling constant of its characteristic hydrogen (6.41ppm, d, J = 5.9 Hz) on 1H NMR spectrum.

OOPh O

NN(CH3)2

Im

S

1-186

anti

Pale yellow solid. Column chromatography; hexane:EtOAc = 3:1. Rf = 0.28 (hexane:EtOAc = 1:1). Mp:

89-90 oC. [α]D20

= -92.7 (c 0.94 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ 2.76 (s, 6H), 3.88 (app t, J =

10.4 Hz, 1H), 4.64 (dd, J = 9.7, 6.0 Hz, 1H), 4.69 (dd, J = 10.6, 5.3 Hz, 1H), 5.67 (s, 1H), 4.77 (app td, J =

9.9, 5.3 Hz, 1H), 6.41 (d, J = 5.9 Hz, 1H), 7.03 (d, J = 0.7 Hz, 1H), 7.26 (s, 1H), 7.33-7.41 (m, 3H), 7.51-

7.54 (m, 2H), 7.60 (s, 1H), 8.30 (s, 1H). 13C NMR (CDCl3, 100 MHz): δ 42.17, 66.97, 72.85, 79.85,

101.60, 126.19, 127.46, 128.28, 128.34, 129.28, 130.80, 136.77, 183.09. IR (NaCl, neat): υ 3431Br s,

343

3135w, 2958w, 2859m, 2790w, 1594m, 1531w, 1466s, 1392s, 1333s, 1292s, 1279s, 1232s, 1162w, 1101s,

1004s, 919m, 827w, 752m. Anal. Calcd. for C17H20O3N4S; C, 56.65; H, 5.59; N, 15.54. Found; C, 56.59;

H, 5.79; N, 15.19.

Prepartion of (2R, 4S, 5R)-(Benzoylhydrazonomethyl)-2-phenyl-[1, 3]dioxane-5-ol


mmol) of crude (2R, 4R, 5R)-5-hydroxy-2-phenyl-[1, 3]dioxane-4-carbaldehyde (1-165) and 314 mg (2.31

mmol) of benzoylhydrazine with 10 mL of ethyl alcohol. White precipitates were formed by stirring the

mixture at rt, and the resulting mixture stand inder nitrogen atmosphere at rt for 20 h. The crude mixture

was purified by recrylstalization over 95% EtOH to give white solid. The product was further obtained

from the mother liquid by column chromatography eluting hexane:EtOAc = 1:3. The combined yield of the

product was 490 mg (72% yield). The isolated compound is assigned as anti based on the chemical shift

and coupling constant of its characteristic hydrogen (7.73 ppm, d, J = 6.3 Hz) on 1H NMR spectrum.

OO

OHPh

NNHCPh

1-187 O

anti

White solid. Column; hexane:EtOAc = 1:3,then recrystalization with 95% EtOH. Rf = 0.40 (hexane:EtOAc

= 1:3). Mp: 207-209 oC. 1H NMR (DMSO-d6, 500 MHz): δ 3.61 (app t, J = 10.3 Hz, 1H), 3.68 (app td, J

= 9.3, 4.7 Hz, 1H), 4.18 (dd, J = 10.3, 4.8 Hz, 1H), 4.21 (app t, J = 8.3 Hz, 1H), 5.47 (d, J = 5.9 Hz, OH,

smaller up to 0.1H with D2O), 5.69 (s, 1H), 7.34-7.38 (m, 3H), 7.41-7.42 (m, 1H), 7.50 (t, J = 7.5 Hz, 2H),

7.58 (t, J = 7.3 Hz, 1H), 7.73 (d, J = 6.3 Hz, 1H), 7.84 (d, J = 7.5 Hz, 2H), 11.5 (s, NH, disappeared with

D2O). 13C NMR (DMSO-d6, 125 MHz): δ 62.74, 70.70, 81.20, 100.01, 126.30, 127.66, 128.18, 128.65,

128.95, 132.02, 133.16, 137.82, 147.72, 163.46. IR (KBr): υ 3446Br s, 3194s, 3072s, 2917m, 2854m,

1659s, 1629m, 1601m, 1579m, 1559s, 1492w, 1451m, 1393m, 1366s, 1351s, 1306s, 1289s, 1280s, 1261m,

1227w, 1210w, 1176w, 1145s, 1107m, 1089s, 1074s, 1047s, 1033s, 1011s, 978m, 961m, 933w, 916w,

344

898w, 750s, 705s, 696s, 652m, 572m. HRMS (Electrospray): m/z Calcd for C18H18N2O4SNa (M++Na),

349.1159; Found (M++Na), 349.1141.

Prepartion of (2R, 4S, 5R)-(Acetylhydrazonomethyl)-2-phenyl-[1, 3]dioxane-5-ol


mmol) of crude (2R, 4R, 5R)-5-hydroxy-2-phenyl-[1, 3]dioxane-4-carbaldehyde (1-165) and 198 mg (2.40

mmol) of acetylhydrazine with 10 mL of ethyl alcohol. White precipitates were formed by stirring the

mixture at rt, and the resulting mixture stand inder nitrogen atmosphere at rt for 20 h. The crude mixture

was purified by recrylstalization over 95% EtOH to give white solid. The product was further obtained

from the mother liquid by column chromatography eluting hexane:EtOAc = 1:3. The combined yield of the

product was 514 mg (89% yield). The isolated compound is syn/anti mixture with a ratio of 0.52/1.0.

OO

OHPh

NNHCCH3

1-188 O

syn/anti = 0.52/1.0

White solid. Column; hexane:EtOAc = 1:1 to 1:3,then recrystalization with 95% EtOH. Rf = 0.14

(hexane:EtOAc = 1:3). Mp: 194-196 oC. 1H NMR (DMSO-d6, 400 MHz): syn (minor), δ 2.09 (s, 3H),

3.54-3.65 (m, 2H), 4.08-4.18 (m, 2H), 5.37 (d, J = 5.5 Hz, OH, disappeared with D2O), 5.60 (s, 1H), 7.25

(d, J = 6.7 Hz, 1H), 7.34-7.36 (m, 3H), 7.39-7.41 (m, 2H), 11.13 (s, NH, disappeared with D2O); anti

(major), δ 1.89 (s, 3H), 3.54-3.65 (m, 2H), 4.08-4.18 (m, 2H), 5.35 (d, J = 6.2 Hz, OH, disappeared with

D2O), 5.60 (s, 1H), 7.34-7.35 (m, 2H), 7.39-7.41 (m, 3H), 11.24 (s, NH, disappeared with D2O). 13C NMR

(DMSO-d6, 100 MHz): syn (minor), δ 20.10, 62.60, 70.56, 80.97, 99.79, 126.16, 128.00, 128.79, 137.73,

142.46, 171.87; anti (major), δ 21.46, 62.68, 70.64, 81.12, 97.79, 126.16, 128.00, 128.76, 137.73, 145.21,

165.66, 1.07, 62.15, 66.88, 70.10, 79.00, 99.73, 119.59, 125.82, 128.09, 128.50, 128.78, 137.36, 137.87,

160.04, 176.12. IR (KBr): υ 3450Br s, 3192s, 3064s, 2909m, 2850m, 1678s, 1570s, 1456s, 1401s, 1372s,

1315m, 1282s, 1257s, 1226m, 1216s, 1168s, 1092s, 1071s, 1020s, 991s, 970s, 949s, 929s, 873m, 755s,

345

698s, 682m, 640s, 600s, 571m, 499m. HRMS (Electrospray): m/z Calcd for C13H16N2O4Na (M++Na),

287.1002; Found (M++Na), 287.1014.

Reaction of (2R, 4S, 5R)-(Benzyoyllhydrazonomethyl)-2-phenyl-[1, 3]dioxane-5-ol with 1,1’-

thiocarbonyl diimidazole

To a flame dried 50 mL flask were added 487 mg (1.49 mmol) of (2R, 4S, 5R)-

(acetylhydrazonomethyl)-2-phenyl-[1, 3]dioxane-5-ol 1-187, 532 mg (2.99 mmol) of 1,1’-thiocarbonyl


refluxed under nitrogen atmosphere for 4h, another 320 mg of 1,1’-thiocarbonyl diimidazole. All starting

material was consumed (TLC) after 8 h refluxing. The solvent was removed under reduced pressure to

give crude mixture, which was purified by flash column chromatography eluting with hexane:EtOAc = 3:1.

The desired product 1-189 was obtained as pale yellow solid (134 mg) and the isolated yield is 21%.

1-189

OO

OPh

NN

ImS

Ph

OH

White solid. Column; hexane:EtOAc = 1:1, then recrystalization with hexane. Rf = 0.20 (hexane:EtOAc =

1:1). [α]D20

= -40.0 (c 0.17 in MeOH). Mp: 206-208 oC. 1H NMR (DMSO-d6, 500 MHz): δ 3.58-3.63 (m,

1H), 3.61 (app t, J = 10.5 Hz, 1H), 4.11 (dd, J = 10.8, 5.4 Hz, 1H), 4.56 (dd, J = 9.3, 5.5 Hz, 1H), 5.65 (d,

J = 5.3 Hz, 1H), 5.68 (s, 1H), 6.98 (s, 1H), 7.11 (d, J = 5.5 Hz, 1H), 7.35-7.38 (m, 5H), 7.55 (s, 1H), 7.60-

7.63 (m, 2H), 7.65-7.69 (m, 1H), 7.89-7.91 (m, 2H), 8.04 (s, 1H); 1H NMR (Acetone-d6, 500 MHz): δ 3.61

(app td, J = 9.3, 5.2 Hz, 1H), 3.70-3.75 (1H, overlap with Acetone-d6), 4.24 (dd, J = 10.4, 5.8 Hz, 1H),

4.65 (dd, J = 9.3, 5.2 Hz, 1H), 6.97 (s, 1H), 7.27 (d, J = 5.2 Hz, 1H), 7.32-7.38 (m, 3H), 7.46-7.49 (m, 2H),

7.56 (s, 1H), 7.60-7.68 (m, 3H), 7.96-7.99 (m, 2H), 8.01 (s, 1H). 13C NMR (DMSO-d6, 125 MHz): δ 62.15,

67.27, 70.08, 79.14, 119.66, 121.79, 125.69, 126.29, 128.04, 128.58, 128.71, 129.53, 132.82, 137.38,

138.00, 158.56, 175.81; 13C NMR (Acetone-d6, 125 MHz): δ 60.49, 63.48, 68.43, 71.47, 80.82, 101.24,

346

120.46, 123.38, 126.79, 127.26, 128.84, 129.50, 129.73, 130.26, 133.52, 138.70, 138.85, 159.80, 177.50.

IR (KBr): υ 3446Br s, 3146s, 3064m, 2974s, 2928s, 2854s, 1638s, 1522m, 1500m, 1454s, 1413s, 1324s,

1312s, 1293s, 1257s, 1229s, 1147s, 1095s, 1072s, 1031m, 1014s, 998s, 920m, 902m, 832s, 816s, 748s,

723s, 710m, 696s, 671m, 654m, 632m, 602m, 602m, 516m. HRMS (Electrospray): m/z Calcd for

C17H18N4O4SNa (M++Na), 397.0941; Found (M++Na), 397.0940.

Reaction of (2R, 4S, 5R)-(Acetylhydrazonomethyl)-2-phenyl-[1, 3]dioxane-5-ol with 1,1’-thiocarbonyl

diimidazole

To a flame dried 50 mL flask were added 390 mg (1.48 mmol) of (2R, 4S, 5R)-

(acetylchydrazonomethyl)-2-phenyl-[1, 3]dioxane-5-ol 1-188, 526 mg (2.95 mmol) of 1,1’-thiocarbonyl


refluxed under nitrogen atmosphere for 10h, another 320 mg of 1,1’-thiocarbonyl diimidazole. All starting

material was consumed (TLC) after 3 h refluxing. The solvent was removed under reduced pressure to

give crude mixture, which was purified by flash column chromatography eluting with hexane:EtOAc = 3:1.

The desired product 1-192 was obtained as pale yellow solid (175 mg) and the isolated yield is 32%.

1-192

OO

OPh

NN

ImS

CH3

OH

White solid. Column; hexane:EtOAc = 1:1 to 1:3,then recrystalization with hexane. Rf = 0.40

(hexane:EtOAc = 1:3). [α]D20

= +70.4 (c 0.27 in MeOH). Mp: 205-206 oC. 1H NMR (DMSO-d6, 500

MHz): δ 2.39 (s, 3H), 3.39 (app td, J = 9.5, 5.4 Hz, 1H), 3.59 (app t, J = 10.4 Hz, 1H), 4.09 (dd, J = 10.8,

5.4 Hz, 1H), 4.47 (dd, J = 9.3, 5.3 Hz, 1H), 5.64 (s, 2H), 6.95 (s, 1H), 7.01 (d, J = 5.3 Hz, 1H), 7.31-7.37

(m, 5H), 7.45 (s, 1H), 7.94 (s, 1H); 1H NMR (Acetone-d6, 400 MHz): δ 2.42 (s, 3H), 3.56 (app td, J = 9.7,

5.3 Hz, 1H), 3.70 (app t, J = 10.5 Hz, 1H), 3.74 (Br s, NH), 4.21 (dd, J = 10.7, 5.3 Hz, 1H), 4.52 (dd, J =

9.2, 5.1 Hz, 1H), 5.67 (s, 2H), 6.95 (s, 1H), 7.15 (d, J = 5.1 Hz, 1H), 7.33-7.38 (m, 3H), 7.41-7.48 (m, 3H),

347

7.91 (s, 1H). 13C NMR (DMSO-d6, 100 MHz): δ 11.07, 62.15, 66.88, 70.10, 79.00, 99.73, 119.59, 125.82,

128.09, 128.50, 128.78, 137.36, 137.87, 160.04, 176.12; 13C NMR (Acetone-d6, 100 MHz): δ 11.37,

63.44,68.08, 72.33, 80.67, 101.35, 120.37, 126.85, 128.85, 129.52, 129.57, 131.44, 138.66, 138.75, 160.70,

177.95. IR (KBr): υ 3451Br s, 3147m, 3064m, 2975m, 2929m, 2854m, 2360w, 1949w, 1814w, 1742w,

1997w, 1676w, 1639s, 1582w, 1522m, 1500m, 1483m, 1454s, 1411s, 1390s, 1363m, 1394m, 1324s, 1312s,

1294s, 1258s, 1244m, 1229s, 1147s, 1096s, 1072s, 1032m, 1014s, 998s, 988s, 978s, 940w, 920m, 902m,

833s, 816s, 748s, 724s, 710m, 696s, 671m, 646m, 634m, 602m. HRMS (Electrospray): m/z Calcd for


4. 4. 6-Exo-trig Radical Cyclization

The Reaction of (1’R, 4S, 5R)-(Z)-3-{5-O-[2-(tert-butyldimethylsilanyloxy)-1-hydroxyethyl]-2, 2-


A flame-dried three neck 25 mL flask was connected to a condenser, and the flask was charged

with 302 mg of Ph3SnH (0.860 mmol) and 13.6 mL of benzene (dried over CaH2 and stored over 4 Å MS in

nitrogen atmosphere) under nitrogen atmosphere. The flask was immersed into an oil bath and the oil bath

temperature was adjusted to be 90 oC. To the flask was added a solution of 88 mg (0.172 mmol) of (1’R,

4S, 5R)-(Z)-3-{5-O-[2-(tert-butyldimethylsilanyloxy)-1-hydroxyethyl]-2, 2-dimethyl[1, 3]dioxolan-4-yl}-

acrylic acid tert-butyl ester; 1’-O-(1-imidazoyl)thione (Z)-1-196 and 14 mg (0.086 mmol) of AIBN in 3.7

mL of benzene via a syringe pump during 2 h 15 min, and the mixture was stirred for another 0.5 h at 90 oC

(oil bath temperature). The mixture was cooled to rt, and the solvent was removed in vacuo to give crude

product. The concentrated mixture was purified by flash column chromatography eluting with

hexane:EtOAc = 3:1. The cyclized N-pyranoside was obtained as pale yellow oil (59.0 mg, 71%) with a

ratio of α/β = 0.20/1.0.

348

O

OO CO2

tBu

OTBS N

N

1-197-α

O

OO CO2

tBu

OTBS N

N

1-197-β

1-197-α/1-197-β = 0.1/1.0

Colorless oil. Column; hexane:EtOAc = 24:1, Rf = 0.63 (Hexane:EtOAc = 8:1). Major 1-197-β; 1H NMR

(CDCl3, 500 MHz): δ 0.03 (s, 3 H), 0.04 (s, 3 H), 0.87 (s, 9 H), 1.23 (s, 3 H), 1.36 (s, 9 H), 1.48 (s, 3 H),

1.98 (dd, J = 16.8, 5.8 Hz, 1 H), 2.21(dd, J = 16.8, 8.6 Hz 1 H), 2.84 (dddd, J = 8.9, 5.6, 3.6, 3.2 Hz, 1 H),

3.66-3.74 (m, 1 H), 3.76 (dd, J = 11.5, 4.4 Hz, 1 H), 3.87 (dd, J = 11.5, 2.0 Hz, 1 H), 4.21-4.26 (m, 2 H),

5.89 (d, J = 3.2 Hz, 1 H), 6.92 (s, 1 H), 7.04 (s, 1 H), 7.58 (s, 1 H). IR (NaCl, neat): υ 3118 Brm, 3002s,

2991s, 2980s, 2930s, 2851s, 1728s, 1461m, 1369s, 1254s, 1219s, 1154s, 1064s, 1000m, 941m, 906m, 838s,

779m, 739m, 662m. Minor 1-197-α was assigned by the characteristic peak is shown at δ 5.64 (d, J = 8.5

Hz, 1H).

An NOE experimental was performed on 1-197 by a 500MHz NMR, and the results are

summarized in the below.

O

OO CO2

tBu

OTBS N

N

1-197-β

O

H

N

H

OTBS CO2tBu

O

O

H

HH

N

5.0%

3.9%1.7%

3.3%

3.5%

12

3

45

349

The Reaction of (1’R, 4S, 5R)-(E)-3-{5-O-[2-(tert-butyldimethylsilanyloxy)-1-hydroxyethyl]-2, 2-





temperature was adjusted to be 90 oC. To the flask was added a solution of 92 mg (0.180 mmol) (1’R, 4S,

5R)-(E)-3-{5-O-[2-(tert-butyldimethylsilanyloxy)-1-hydroxyethyl]-2, 2-dimethyl[1, 3]dioxolan-4-yl}-

acrylic acid tert-butyl ester; 1’-O-(1-imidazoyl)thione (E)-1-196 and 15 mg (0.093 mmol) of AIBN in 3.9

mL of benzene via a syringe pump during 2 h 25 min, and the mixture was stirred for another 0.5 h at 90 oC



hexane:EtOAc = 3:1. The cyclized N-pyranoside was obtained as pale yellow oil (53.0 mg, 61%) with a

ratio of altro-α/ altro-β/ allo-α/ allo-β = 0.23/1.0/0.16/0.22 after column chromatography.

The alllo compounds were not characterized, but their characteristic peak (anomeric hydrogen

peak) was used for the assignment of their configuration.

O

OO CO2

tBu

OTBS N

N

altro-1-197-β

O

OO CO2

tBu

OTBS N

N O

OO CO2

tBu

OTBS N

N O

OO CO2

tBu

OTBS N

N

altro-1-197-α allo-1-197-β allo-1-197-α


Chemical shift (ppm) 5.67 5.88 5.93 5.28

Coupling constant (Hz) 8.4 3.2 7.1 10.3

Ratioa 0.20 1.00 0.08 0.10


350


dimethyl[1, 3]dioxolan-4-yl}-acrylic acid tert-butyl ester; 1’-O-(1-imidazoyl)thione at high

temperature


with 157 mg of Bu3SnH (0.54 mmol) and 7 mL of toluene (freshly dried over Na) under nitrogen

atmosphere. To the flask was added a solution of 185 mg (0.36 mmol) of (1’R, 4S, 5R)-(Z)-3-{5-O-[2-

(tert-butyldimethylsilanyloxy)-1-hydroxyethyl]-2, 2-dimethyl[1, 3]dioxolan-4-yl}-acrylic acid tert-butyl

ester; 1’-O-(1-imidazoyl)thione (Z)-1-196 and 12 mg (0.072 mmol) of AIBN in 3.5 mL of toluene under

reflux condition via a syringe pump during 2 h 20 min, and the mixture was refluxed for another 3 h. The

mixture was cooled to rt, and the solvent was removed in vacuo to give crude product. The concentrated

mixture was purified by flash column chromatography eluting with hexane:EtOAc = 5:1. The isolated

product was 4-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-6-thioxo-tetrahydro-[1,3]dioxolo[4,5-

c]pyran-7-carboxylic acid tert-butyl ester obtained as pale yellow oil (53.7 mg, 33%).

O

OO CO2

tBu

SOTBS

1-202

Yellow oil. Preparative TLC; hexane:EtOAc = 5:1. Rf = 0.17 (hexane:EtOAc = 4:1). 1H NMR (CDCl3,

400 MHz): δ 0.11(s, 3 H), 1.12(s, 3 H), 0.90 (s, 9 H), 1.34 (s, 3 H), 1.46 (s, 9 H), 1.49 (s, 3 H), 2.74(dd, J =

16.4, 3.6 Hz, 1 H), 2.97 (dd, J = 16.4, 8.7 Hz, 1 H), 3.08 (ddd, J = 12.3, 8.7, 3.7 Hz, 1 H), 3.95 (dd, J =

12.1, 4.2 Hz, 1 H), 4.04 (dd, J = 8.9, 6.9 Hz, 1 H), 4.11 (dd, J = 11.9, 1.6 Hz, 1 H), 4.25-4.36 (m, 2 H). 13C

NMR (CDCl3, 100 MHz): δ -5.2, -5.3, 18.4, 24.7, 25.9, 26.9, 28.0, 37.1, 50.9, 62.0, 71.0, 74.9, 78.8, 82.6,

111.3, 170.7, 218.4. IR (NaCl, neat): υ 2957m, 2930s, 2857m, 1731s, 1472m, 1368m, 1338m, 1268s,

1212m, 1152s, 1076m, 836m. HRMS (electrospray) m/z calcd for C21H38O6SSi 469.2056 (M+ + Na), found

469.2057.

351


dimethyl[1, 3]dioxolan-4-yl}-acrylic acid tert-butyl ester; 1’-O-(1-imidazoyl)thione by Reversed

addition


with 81 mg (0.158 mmol) of (1’R, 4S, 5R)-(Z)-3-{5-O-[2-(tert-butyldimethylsilanyloxy)-1-hydroxyethyl]-2,

2-dimethyl[1, 3]dioxolan-4-yl}-acrylic acid tert-butyl ester; 1’-O-(1-imidazoyl)thione 1-196 and 12.6 mL

of benzene (dried over CaH2 and stored over 4 Å MS in nitrogen atmosphere) under nitrogen atmosphere.

The flask was immersed into an oil bath and the oil bath temperature was adjusted to be 90 oC. To the flask

was added a solution of 278 mg (0.791 mmol) of Ph3SnH and 13 mg (0.079 mmol) of AIBN in 3.4 mL of

benzene via a syringe pump during 2 h 15 min, and the mixture was stirred for another 0.5 h at 90 oC (oil

bath temperature). The mixture was cooled to rt, and the solvent was removed in vacuo to give crude


hexane:EtOAc = 3:1. The isolate products were [4-(tert-butyl-dimethyl-silanoyloxymethyl)-2,2-dimethyl-

tetrahydro-[1,3]dioxolo[4,5,c]pyran-7-y]-acetic acid tert-butyl ester 1-197 (24.1 mg, 37%) as well as [4-

(tert-butyl-dimethyl-silanoyloxymethyl)-6-imidazol-1-yl-2,2-dimethyl-tetrahydro-[1,3]dioxolo[4,5,c]pyran-

7-y]-acetic acid tert-butyl ester 1-203 (11.1 mg, 15%).

O

OO CO2

tBu

OTBS

1-203

Colorless oil. Column chromatography; hexane:EtOAc 20:1 to 15:1. Rf = 0.40 (hexane:EtOAc 8:1). [α]D20

= +24.4 (c 1.23 in CHCl3). 1H NMR (CDCl3, 500 MHz): δ 0.06 (s, 3H), 0.07 (s, 3H), 0.90 (s, 9H), 1.35 (s,

3H), 1.44 (s, 9H), 1.49 (s, 3H), 2.29-2.35 (m, 1H), 2.44-2.50 (m, 2H), 3.32 (ddd, J = 8.4, 5.6, 2.1 Hz, 1H),

3.65 (dd, J = 11.5, 5.6 Hz, 2H), 3.76 (dd, J = 11.6, 2.3 Hz, 1H), 3.82 (dd, J = 11.5, 2.1 Hz, 1H), 3.90 (dd, J

= 8.9, 5.1 Hz, 1H), 4.09 (dd, J = 4.9, 1.3 Hz, 1H). 13C NMR (CDCl3, 125 MHz): δ -5.23, -5.26, 18.45,

26.00, 26.40, 28.07, 28.25, 33.90, 36.23, 63.81, 65.93, 69.79, 75.38, 79.18, 80.72, 108.84, 171.24. IR

352

(NaCl, neat): υ 2982m, 2948m, 2929s, 2858m, 1731s, 1462w, 1368m, 1278m, 1255m, 1219m, 1152s,

1087m, 1060s, 1004w, 938w, 861m, 836s, 778m. Anal. Calcd. for C21H40O6Si; C, 60.54; H, 9.68. Found;

C, 60.27; H, 10.12. HRMS (Electrospray) Calcd. (M++Na); 439.2486. Found (M++Na); 439.2505.

The configuration has been determined by nOe experiment and the result is shown in below.

O

OO CO2

tBu

OTBS

1-203

O

H

HO

O

H

HH

OTBSCO2

tBu

H

0.7%, 0.6%

1

23

45

1.6, 1.3%

2.5, 1.9%

3.3%

1.4%

0.5%

nOe (%) nOe (%) nOe (%)

H3→H7a 2.5 H4→H7a 1.6 H7a→H4 3.3

H3→H7b 1.9 H4→H7b 1.3 H7a→H4b 0.7

H4→COtBu 1.4 H5→H2 0.5 H7a→H4b 0.6








acrylic acid ethly ester; 1’-O-(1-imidazoyl)thione (Z)-1-208 and 15 mg (0.090 mmol) of AIBN in 3.8 mL

353

of benzene via a syringe pump during 2 h 16 min, and the mixture was stirred for another 0.5 h at 90 oC (oil


product. The ratio of α/β anomeric mixture of the crude mixture was 0.26/1.0 measured by 1H NMR

spectroscopy. The concentrated mixture was purified by flash column chromatography eluting with

hexane:EtOAc = 3:1. The cyclized N-pyranoside was obtained as colorless oil (55.4 mg, 68%) with a ratio

of α/β = 0.24/1.0.

O

OO CO2Et

OTBS N

N

altro-1-209-β

O

OO CO2Et

OTBS N

N

altro-1-209-α

altro-β/ altro-α = 1.0/0.24

Colorless oil. Column; hexane:EtOAc = 1:2. Rf = 0.33 (hexane:EtOAc = 1:3). Major altro-1-209-β; 1H

NMR (CDCl3, 400 MHz): δ 0.07 (s, 3 H), 0.08 (s, 3 H), 0.90 (s, 9 H), 1.20 (t, J = 7.1 Hz, 3 H), 1.37 (s, 3

H), 1.52 (s, 3 H), 2.12-2.27 (m, 1 H), 2.24-2.41 (m, 1 H), 2.94 (app dtd, J = 6.3, 3.4 Hz, 1 H), 3.66-3.72 (m,

1 H), 3.79 (dd, J = 11.4, 4.4 Hz, 1 H), 3.91 (dd, J = 11.4, 2.1 Hz, 1 H), 4.06 (q, J = 7.1 Hz, 2 H), 4.19-4.26

(m, 1 H), 4.26-4.33 (m, 1 H), 5.89 (d, J = 3.1 Hz, 1 H), 6.97 (s, 1 H), 7.11 (s, 1 H), 7.66 (s, 1 H). 13C NMR

(CDCl3, 100 MHz): δ -5.34, -5.29, 14.04, 18.34, 25.81, 25.91, 27.99, 30.31, 38.33, 61.03, 62.71, 68.60,

75.30, 79.45, 83.01, 109.87, 116.21, 129.13, 134.89, 171.23. IR (NaCl, neat): υ 3391Br, 2931s, 2857m,

2361w, 1733s, 1494m, 1471m, 1373m, 1255s, 1220s, 1153m, 1086s, 1064s, 838s, 779m, 663m. HRMS

(electrospray) m/z calcd for C22H38O6N2Si 455.2577 (M+ + H), found 455.2572. 2nd major altro-1-209-α;

1H NMR (CDCl3, 400 MHz): δ 0.05 (s, 3 H), 0.06 (s, 3 H), 0.87 (s, 9 H), 1.20 (t, J = 7.1 Hz, 3 H), 1.36 (s, 3

H), 1.47 (s, 3 H), 2.12-2.27 (m, 1 H), 2.24-2.41 (m, 1 H), 2.66-2.80 (m, 1 H), 3.66-3.72 (m, 1 H), 3.71-3.84

(m, 1 H), 3.84-3.96 (m, 1 H), 4.06 (q, J = 7.1 Hz, 2 H), 4.19-4.26 (m, 1 H), 4.26-4.33 (m, 1 H), 5.70 (d, J =

8.9 Hz, 1 H), 7.11 (s, 1 H), 7.16 (s, 1 H), 7.72 (s, 1 H). 13C NMR (CDCl3, 100 MHz): δ -5.44, 14.04, 18.27,

354

25.57, 25.81, 27.63, 29.16, 39.51, 60.94, 64.45, 71.86, 75.19, 77.45, 82.79, 109.90, 117.01, 129.33, 136.45,

170.88.




with 241 mg of Bu3SnH (0.828 mmol) and 13.0 mL of benzene (dried over CaH2 and stored over 4 Å MS

in nitrogen atmosphere) under nitrogen atmosphere. The flask was immersed into an oil bath and the oil

bath temperature was adjusted to be 90 oC. To the flask was added a solution of 74 mg (0.153 mmol) of

(1’R, 4S, 5R)-(E)-3-{5-O-[2-(tert-butyldimethylsilanyloxy)-1-hydroxyethyl]-2, 2-dimethyl[1, 3]dioxolan-4-

yl}-acrylic acid ethly ester; 1’-O-(1-imidazoyl)thione (E)-1-208 and 14 mg (0.090 mmol) of AIBN in 5.0

mL of benzene via a syringe pump during 2 h min, and the mixture was stirred for another 0.5 h at 90 oC



hexane:EtOAc = 3:1. The major product was N-Pyranoside 1-209 (59%, altro-β/ altro-α/ allo-β/ allo-α =

0.13: 0.05:1.0:0.31) and the minor product was 1-210 (altro/allo = 1.0/0.11)

O

OO CO2Et

OTBS N

N

altro-1-209-β

O

OO CO2Et

OTBS N

N O

OO CO2Et

OTBS N

N O

OO CO2Et

OTBS N

N

altro-1-209-α allo-1-209-β allo-1-209-α

altro-β/ altro-α/ allo-β/ allo-α = 67/21/9/3

The allo-1-209-β and allo-1-209-α could not be characterized fully, but the characteristic peaks

were shown at δ 5.31 (d, J = 10.3 Hz) and 5.98 (d, J = 7.0 Hz) respectively.

355

O

OO CO2Et

OTBS

altro-1-210


MHz): δ 0.07 (s, 6 H), 0.89 (s, 9 H), 1.26 (t, J = 7.1 Hz, 3 H), 1.35 (s, 3 H), 1.50 (s, 3 H), 2.40 (d, J = 14.3,

5.1 Hz, 1 H), 2.55 (dd, J = 14.2 Hz, 1 H), 3.34 (ddd, J = 8.6, 5.6, 2.2 Hz, 1 H), 3.65 (dd, J = 11.4, 5.6 Hz, 1

H), 3.65-3.71 (m, 1 H), 3.78 (dd, J = 11.8, 2.8 Hz, 2 H), 3.82 (dd, J = 11.8, 2.8 Hz, 1 H), 3.92 (dd, J = 8.7,

5.1 Hz, 1 H), 4.10 (dd, J = 5.1, 2.1 Hz, 1 H), 4.16 (q, J = 7.1 Hz, 1 H). IR (NaCl,neat): υ 3418Brs, 2982s,

2952s, 2929s, 2882s, 2842m, 1731s, 1463m, 1377m, 1258m, 1179m, 1114m, 1071m, 1029m, 976w, 869m,

837s.

The Reaction of (1’R, 4S, 5R)-{5-O-[2-(tert-butyldimethylsilanyloxy)-1-hydroxyethyl]-2, 2-dimethyl[1,






5R)-{5-O-[2-(tert-butyldimethylsilanyloxy)-1-hydroxyethyl]-2, 2-dimethyl[1, 3]dioxolan-4-yl}-ethene; 1’-

O-(1-imidazoyl)thione 1-234 and 19 mg (0.115 mmol) of AIBN in 5.0 mL of benzene via a syringe pump

during 3 h, and the mixture was stirred for another 0.5 h at 90 oC (oil bath temperature). The mixture was

cooled to rt, and the solvent was removed in vacuo to give crude product. The concentrated mixture was

purified by flash column chromatography eluting with hexane:EtOAc = 2:1 to 1:2. The isolated products

were 7-endo-cyclized compound 1-236 (25.5 mg, 29%, α/β = 0.39/1.0) as well 6-exo-cyclized compound

1-235 (26.4 mg, 30%, 4 diastereomers with a ratio of altro-α/ altro-β/allo-α/ allo-β= 0.42/1.0/0.22/0.35).

356

O

CH3OO

OTBS N

N

1-235

This compound was isolated as four diastreomer mixture and only two of them were fully characterized.

Pale yellow oil. Column chromatography; hexane:EtOAc 2:1 to 1:2. Rf = 0.23 (hexane:EtOAc 1:3). IR

(NaCl, neat): υ 3118Br s, 2979s, 2932s, 2843s, 1727w, 1681w, 1592w, 1499m, 1473m, 1462m, 1382s,

1250s, 1220s, 1150s, 1105s, 1070s, 1004m, 938i, 879m, 837s, 778m, 735m, 661m. HRMS (Electrospray);

Calc. (M++Na) 405.2180, found (M++Na) 405.2186.

O

CH3OO

OTBS N

N

altro-1-235-β

1H NMR (CDCl3, 500 MHz): δ 0.07 (s, 3H), 0.08 (s, 3H), 0.85 (d, J = 7.3 Hz, 1H), 0.90 (s, 9H), 1.38 (s,

3H), 1.53 (s, 3H), 2.48 (dqd, J = 11.6, 7.2, 2.6 Hz, 1H), 3.66 (ddd, J = 8.1, 3.8, 1.6 Hz, 1H), 3.80 (dd, J =

11.6, 4.3 Hz, 1H), 3.89 (dd, J = 11.7, 2.0 Hz, 1H), 4.23-4.27 (m, 1H), 5.77 (d, J = 2.7 Hz, 1H), 6.99 (s, 1H),

7.09 (s, 1H), 7.70 (s, 1H). 13C NMR (CDCl3, 125 MHz): δ -5.29, -5.32, 10.32, 18.35, 25.81, 16.11, 28.20,

36.56, 62.62, 68.65, 77.85, 79.91, 83.85, 109.51, 116.28, 128.73, 134.88.

The structure has been confirmed by nOe experiment and the key result is shown below.

O

CH3OO

OTBS N

N

altro-1-235-β

O

H

N

H

CH3

O

O

H

HH

N

12

3

45

3.5%6.0%

OTBS

2.8%1.8%

4.0%

357

O

CH3OO

OTBS N

N

altro-1-235-α 1H NMR (CDCl3, 500 MHz): δ 0.03 (s, 3H), 0.05 (s, 3H), 0.88 (s, 9H), 1.02 (d, J = 6.7 Hz, 1H), 1.37 (s,

3H), 1.47 (s, 3H), 2.30-2.40 (m, 1H), 3.76 (app td, J = 11.5, 6.3 Hz, 1H), 3.84-3.91 (m, 2H), 4.03 (dd, J =

8.3, 6.7 Hz, 1H), 4.20 (app t, J = 6.8 Hz, 1H), 5.35 (d, J = 8.9 Hz, 1H), 7.09 (s, 2H), 7.46 (s, 1H). 13C

NMR (CDCl3, 125 MHz): δ -5.43, 14.73, 18.26, 25.37, 25.83, 27.67, 37.39, 64.52, 71.79, 74.42, 79.98,

85.15, 109.61, 116.81, 129.50, 136.28.

O

CH3OO

OTBS N

N

allo-1-235-β

1H NMR (CDCl3, 400 MHz): δ -0.02 (s, 3H), 0.00 (s, 3H), 0.85 (s, 9H), 0.89 (d, J = 7.5 Hz, 3H), 1.38 (s,

3H), 1.53 (s, 3H), 2.26-2.35 (m, 1H), 3.60 (ddd, J = 9.1, 5.1, 2.0 Hz, 1H), 3.72 (dd, J = 11.9, 5.0 Hz, 1H),

3.86 (dd, J = 11.7, 2.0 Hz, 1H), 4.08 (dd, J = 9.1, 4.9 Hz, 1H), 4.35-4.38 (m, 1H), 5.22 (d, J = 10.1 Hz, 1H),

7.03 (s, 1H), 7.10 (s, 1H), 7.67 (s, 1H). 13C NMR (CDCl3, 125 MHz): δ -5.24, 12.14, 18.39, 25.83, 26.20,

28.40, 37.74, 62.90, 70.51, 79.22, 85.31, 109.66, 116.60, 128.94, 136.17.

O

CH3OO

OTBS N

N

allo-1-235-α

1H NMR (CDCl3, 400 MHz): δ -0.02 (s, 3H), 0.00 (s, 3H), 0.84 (s, 9H), 1.14 (d, J = 7.5 Hz, 3H), 1.40 (s,

3H), 1.53 (s, 3H), 2.71-2.78 (m, 1H), 3.14 (ddd, J = 9.7, 4.7, 2.2 Hz, 1H), 3.72-3.75(m, 1H), 3.86 (dd, J =

358

11.7, 2.0 Hz, 1H), 4.08 (dd, J = 9.7, 5.1 Hz, 1H), 4.35-4.38 (m, 1H), 5.78 (d, J = 6.7 Hz, 1H), 7.11 (s, 1H),

7.54 (s, 1H), 8.17 (s, 1H). 13C NMR (CDCl3, 125 MHz): δ -5.42, 12.73, 18.35, 26.24, 28.05, 34.14, 62.40,

70.28, 70.33, 74.44, 77.81, 83.42, 109.95, 117.01, 129.22, 139.22.

1-236

O

O

O

NN

OTBS


The isolated product was α/β mixture as a ratio of 0.37/1.0. IR (NaCl, neat): υ 3118 Br s, 2985w, 2954s,

2931s, 2882s, 2872s, 1749w, 1723w, 1495m, 1472m, 1462m, 1381s, 1252s, 1219s, 1150s, 1108s, 1075s,

1005m, 939m, 882m, 837s, 779m, 733m, 662m. HRMS (Electrospray); Calc. (M++Na) 405.2180, found

(M++Na) 405.2152.

β-1-236

O

O

O

NN

OTBS

O N

O

O

NTBSO

H H

H

H

5.9%

5.6%

2.5%

2.2%H

HH

2.2%1.7%

1H NMR (CDCl3, 500 MHz): δ -0.03 (s, 3H), -0.01 (s, 1H), 0.86 (s, 9H), 1.34 (s, 3H), 1.45 (s, 3H), 1.91-

2.02 (m, 2H), 2.04-2.15 (m, 1H), 2.22-2.27 (m, 1H), 3.60 (dd, J = 11.1, 7.6 Hz, 3H), 3.74 (ddd, J = 9.7, 7.6,

2.1 Hz, 1H), 3.87 (dd, J = 11.0, 2.1 Hz, 1H), 4.14 (dd, J = 9.8, 6.8 Hz, 1H), 4.36-4.41 9m, 1H), 5.35 (dd, J

= 9.2, 2.2 Hz, 1H), 7.05 (s, 1H), 7.06 (s, 1H), 7.69 (s, 1H). 13C NMR (CDCl3, 100 MHz): δ -5.52, -5.35,

18.29, 24.67, 25.82, 26.17, 27.55, 31.98, 63.83, 64.90, 76.12, 77.79, 80.09, 88.91, 108.86, 116.97, 128.85,

135.31. Anal. Calcd. for C19H34O4N2Si; C, 59.65; H, 8.96; N, 7.32. Found; C, 57.56; H, 8.34; N, 6.99.

The configuration has been determined by nOe experiment. And the result is shown in below.

359

α-1-236

O

O

O

NN

OTBS

1H NMR (CDCl3, 500 MHz): δ 0.01 (s, 3H), 0.00 (s, 1H), 0.85 (s, 9H), 1.36 (s, 3H), 1.43 (s, 3H), 1.91-2.02

(m, 1H), 2.04-2.15 (m, 1H), 2.22-2.27 (m, 1H), 2.63 (app dt, J = 14.7, 11.0 Hz, 3H), 3.45 (ddd, J = 9.8, 5.0,

1.8 Hz, 1H), 3.68 (dd, J = 11.1, 1.6 Hz, 1H), 3.96 (dd, J = 10.1, 5.0 Hz, 1H), 4.36-4.41 (m, 1H), 5.61 (dd, J

= 10.7, 5.0 Hz, 1H), 7.08 (s, 1H), 7.18 (s, 1H), 7.85 (s, 1H). 13C NMR (CDCl3, 100 MHz): δ -5.41, -5.32,

18.54, 23.31, 24.13, 25.82, 27.16, 28.42, 63.83, 72.83, 74.55, 76.13, 84.30, 107.76, 117.84, 128.74, 135.48.

Reaction of (1’R, 4S, 5R)-(E)-3-{5-O-[2-(tert-butyldimethylsilanyloxy)-1-hydroxyethyl]-2, 2-

dimethyl[1, 3]dioxolan-4-yl}-acrylic acid ethyl ester; 1’-O-(O-phenyl)thione





5R)-(E)-3-{5-O-[2-(tert-butyldimethylsilanyloxy)-1-hydroxyethyl]-2, 2-dimethyl[1, 3]dioxolan-4-yl}-

acrylic acid ethyl ester; 1’-O-(O-phenyl)thione (E)-1-193 and 15 mg (0.092 mmol) of AIBN in 3.9 mL of

benzene via a syringe pump during 2.5 h, and the mixture was stirred for another 0.5 h at 90 oC (oil bath

temperature). The mixture was cooled to rt, and the solvent was removed in vacuo to give crude product.

The concentrated mixture was purified by flash column chromatography eluting with hexane:EtOAc = 2:1

to 1:2. The isolated products were 1-195 (51 mg, 71%) and penyl group migrated compound 1-194 (3 mg,

3%).

360

O

OO CO2Et

OTBS

altro-1-195


MHz): δ 0.07 (s, 6 H), 0.89 (s, 9 H), 1.26 (t, J = 7.1 Hz, 3 H), 1.35 (s, 3 H), 1.50 (s, 3 H), 2.40 (d, J = 14.3,

5.1 Hz, 1 H), 2.55 (dd, J = 14.2 Hz, 1 H), 3.34 (ddd, J = 8.6, 5.6, 2.2 Hz, 1 H), 3.65 (dd, J = 11.4, 5.6 Hz, 1

H), 3.65-3.71 (m, 1 H), 3.78 (dd, J = 11.8, 2.8 Hz, 2 H), 3.82 (dd, J = 11.8, 2.8 Hz, 1 H), 3.92 (dd, J = 8.7,

5.1 Hz, 1 H), 4.10 (dd, J = 5.1, 2.1 Hz, 1 H), 4.16 (q, J = 7.1 Hz, 1 H). IR (NaCl,neat): υ 3418Brs, 2982s,

2952s, 2929s, 2882s, 2842m, 1731s, 1463m, 1377m, 1258m, 1179m, 1114m, 1071m, 1029m, 976w, 869m,

837s.








acryllonitrile; 1’-O-(1-imidazoyl)thione (Z)-1-247 and 12 mg (0.073 mmol) of AIBN in 3.2 mL of benzene

via a syringe pump during 2 h 30 min, and the mixture was stirred for another 0.5 h at 90 oC (oil bath



to 1:1. The cyclized N-pyranoside was obtained as pale yellow oil (31.9 mg, 57%) with a ratio of altro-α/

altro-β= 0.26/1.0 after column chromatography.

361

O

OO CN

OTBS N

N

1-252

The compound was isolated as a mixture of two (from Z substrates) or four (E substrates) diastereomers at

C-1 and C-2, and only two major compounds (altro-α and altro-β) have been assigned. Yellow oil.

Column chromatography; hexane:EtOAc = 3:1 to 1:1. Rf = 0.24 (hexane:EtOAc = 1:6). IR (NaCl, neat):

υ 3115 w, 2987m, 2955s, 2991s, 2892s, 2857m, 2253w, 1700w, 1494m, 1472m, 1424w, 1384m, 1370m,

1312w, 1285w, 1253s, 1221s, 1159s, 1077s, 939w, 906w, 838s, 780i, 661m. HRMS (Electrospray); Calcd.

(M++Na); 430.2133. Found (M++Na); 430.2116. Anal. Calcd. for C20H33O4N3Si; C, 58.94; H, 8.16; N,

10.31. Found; C, 58.35; H, 8.27; N, 9.94.

O

OO CN

OTBS N

N

altro-1-252-β

1H NMR (CDCl3, 400 MHz): δ 0.07 (s, 3H), 0.08 (s, 3H), 0.90 (s, 9H), 1.41 (s, 3H), 1.54 (s, 3H), 2.06 (dd,

J = 17.3, 5.4 Hz, 1H), 2.38 (dd, J = 17.3, 9.7 Hz, 1H), 2.69-2.79 (m, 1H), 3.73 (ddd, J = 8.9, 4.3, 2.1 Hz,

1H), 3.82 (dd, J = 11.6, 4.4 Hz, 1H), 3.93 (dd, J = 11.6, 2.0 Hz, 1H), 4.33 (dd, J = 8.9, 5.4 Hz, 1H), 4.52

(dd, J = 5.4, 3.4 Hz, 1H), 5.90 (d, J = 2.9 Hz, 1H), 6.98 (s, 1H), 7.15 (s, 1H), 7.69 (s, 1H). 13C NMR

(CDCl3, 100 MHz): δ -5.35, -5.33, 14.06, 18.35, 25.80, 25.93, 29.23, 39.24, 65.58, 68.19, 74.43, 80.08,

82.29, 110.31, 115.66, 117.23, 130.18, 136.10.

O

OO CN

OTBS N

N

altro-1-252-α

362

1H NMR (CDCl3, 400 MHz): δ 0.00 (s, 6H), 0.89 (s, 9H), 1.39 (s, 3H), 1.50 (s, 3H), 2.10 (dd, J = 17.3, 4.5

Hz, 1H), 2.31 (dd, J = 17.2, 9.5 Hz, 1H), 2.69-2.76 (m, 1H), 3.82 (dd, J = 11.6, 4.4 Hz, 1H), 3.98 (dd, J =

11.5, 2.3 Hz, 1H), 4.10 (app td, J = 4.6, 2.3 Hz, 1H), 4.28-4.35 (m, 2H), 5.74 (d, J = 10.0 Hz, 1H), 7.09 (s,

1H), 7.15 (s, 1H), 7.78 (s, 1H). 13C NMR (CDCl3, 100 MHz): δ -5.41, -5.36, 16.36, 18.38, 25.33, 25.83,

27.71, 40.53, 68.20, 72.23, 73.90, 75.51, 80.15, 82.01, 110.18, 116.09, 116.44, 129.06, 136.13.







5R)-(E)-3-{5-O-[2-(tert-butyldimethylsilanyloxy)-1-hydroxyethyl]-2-2-dimethyl[1, 3]dioxolan-4-yl}-

acryllonitrile; 1’-O-(1-imidazoyl)thione (E)-1-247 and 14 mg (0.084 mmol) of AIBN in 3.6 mL of benzene

via a syringe pump during 2 h 40 min, and the mixture was stirred for another 0.5 h at 90 oC (oil bath



to 1:1. The cyclized N-pyranoside was obtained as pale yellow oil (51.0 mg, 80%) with a ratio of altro-α/

altro-β/allo-α/ allo-β= 0.27/1.0/0.04/0.09 after column chromatography.

O

OO CN

OTBS N

N

1-252

363




Ratioa 0.27 1.00 0.04 0.09


The Reaction of (1’R, 4S, 5R)-3-{5-O-[2-(tert-butyldimethylsilanyloxy)-1-hydroxy ethyl]-2, 2-

dimethyl[1, 3]dioxolan-4-yl}-O-methylhydroxyl amine; 1’-O-(1-imidazoyl)thione





4S, 5R)-3-{5-O-[2-(tert-butyldimethylsilanyloxy)-1-hydroxy ethyl]-2, 2-dimethyl[1, 3]dioxolan-4-yl}-O-

methylhydroxyl amine; 1’-O-(1-imidazoyl)thione 1-90 and 10 mg (0.061 mmol) of AIBN in 2.6 mL of

benzene via a syringe pump during 2 h 10 min, and the mixture was stirred for another 0.5 h at 90 oC (oil



hexane:EtOAc = 2:1 to 1:1. After column chromatography, 39.0 mg (83%) of 4-diastereomermixture was

isolated as yellow oil with a ratio of altro-α/ altro-β/ allo-α/ allo-α/ = 0.24/1.0/0.03/0.75, only the major

compound (altro-β) has been assigned. The configuration has been assigned by the comparing the

chemical shift and coupling constant with known configuration (vide infra 1-197).

O

OO

NHOCH3

OTBS N

N

1-253

364

Colorless oil. Column chromatography; hexane:EtOAc = 2:1 to 1:1. Rf = 0.16 (hexane:EtOAc = 1:3). IR

(NaCl, neat): υ 3168 Br s, 2981m, 2952s, 2932s, 2893s, 2856s, 2250w, 2211w, 1698w, 1494m, 1472s,

1458s, 1383s, 1251s, 1219s, 1146s, 1064s, 1033s, 1004m, 938w, 911w, 837s, 779s, 733s. HRMS

(Electrospray); Calcd. (M++Na): 436.2238, found (M++Na): 436.2259. Anal. Calcd. for C19H35O5N3Si; C,

55.18; H, 8.53; N, 10.16. Found; C, 54.04; H, 8.48; N, 9.28.

O

OO

NHOCH3

OTBS N

N

altro-1-253-β

1H NMR (CDCl3, 400 MHz): δ 0.05 (s, 3H), 0.06 (s, 3H), 0.89 (s, 9H), 1.24 (Br s, 1H), 1.37 (s, 3H), 1.52

(s, 3H), 3.46 (s, 3 H), 3.51-3.61 (m, 1H), 3.72 (ddd, J = 8.5, 4.3, 1.9 Hz, 1H), 3.78 (dd, J = 11.4, 4.4 Hz,

1H), 3.90 (dd, J = 11.5, 2.0 Hz, 1H), 4.31 (dd, J = 8.5, 6.2 Hz, 1H), 4.46 (dd, J = 6.0, 4.4 Hz, 1H), 5.80 (d,

J = 2.9 Hz, 1H), 7.09 (s, 1H), 7.17 (s, 1H), 7.88 (s, 1H). 13C NMR (CDCl3, 100 MHz): δ -5.37, -5.33,

18.39, 25.45, 25.83, 29.24, 59.89, 62.17, 63.06, 69.43, 73.05, 78.87, 81.83, 109.78, 117.69, 128.81, 136.19.




Ratioa 0.24 1.0 0.03 0.75


The Reaction of (1’R, 4S, 5R)-3-{5-O-[2-(tert-butyldimethylsilanyloxy)-1-hydroxye thyl]-2, 2-

dimethyl[1, 3]dioxolan-4-yl}-N,N-dimethylhydrazone



365



4S, 5R)-3-{5-O-[2-(tert-butyldimethylsilanyloxy)-1-hydroxyethyl] -2, 2-dimethyl[1, 3]dioxolan-4-yl}-N,N-

dimethylhydrazone 1-249 and 12 mg (0.077 mmol) of AIBN in 3.3 mL of benzene via a syringe pump

during 2 h 10 min, and the mixture was stirred for another 0.5 h at 90 oC (oil bath temperature). The

mixture was cooled to rt, and the solvent was removed in vacuo to give crude product. The concentrated

mixture was purified by flash column chromatography eluting with hexane:EtOAc = 2:1 to 1:1. After

column chromatography, 41.2 mg (63%) of 3-diastereomermixture was isolated as yellow oil with a ratio of

altro-α/ altro-β/ allo-α/ allo-α/ = 0.04/0.09/0/1.0.

O

OO

NHN(CH3)2

OTBS N

N

1-254


IR (NaCl, neat): υ 2985w, 2956s, 2931s, 2856s, 2817m, 2772m, 1716w, 1679w, 4198m, 1472m, 1382m,

1472m, 1382m, 1372m, 1285m, 1248s, 1230s, 1152s, 1080s, 1056s, 963w, 906w, 838s, 780s, 732w, 661m.

HRMS (Electrospray); Calcd. (M++Na): 449.2555, found: (M++Na) 449.2558. Anal. Calcd. for

C20H38O4N3Si; C, 56.31; H, 8.98; N, 13.13. Found; C, 55.66; H, 9.15; N, 11.86.

The product was isolated as three diastereomer mixture, and only allo-β was fully characterized. The

configuration of the structure was assigned based on comparing the chemical shift and coupling constant

with known configuration (vide infra 1-197).

366

O

OO

NHN(CH3)2

OTBS N

N

allo-1-254-β

1H NMR (CDCl3, 500 MHz): δ -0.02 (s, 3H), -0.01 (s, 3H), 0.85 (s, 9H), 1.46 (s, 3H), 1.47 9s, 3H), 2.23 (s,

6H), 3.20 (dd, J = 10.4, 8.5 Hz, 1H), 3.55 (app t, J = 9.1 Hz, 1H), 3.69 (dd, J = 10.5, 9.1 Hz, 1H), 3.72-3.78

(m, 2H), 3.86-3.91 (m, 1H), 5.18 (d, J = 8.5 Hz, 1H), 7.06 (s, 1H), 7.07 (s, 1H), 7.69 (s, 1H). 13C NMR

(CDCl3, 100 MHz): δ -5.35, 18.33, 25.80, 26.50, 26.79, 49.01, 62.89, 63.26, 74.38, 78.11, 78.28, 86.35,

111.86, 117.75, 128.82, 137.03.

Two other diastereomers have been assigned partially due to the lack of information.

O

OO

NHN(CH3)2

OTBS N

N

altro-1-254-β

13C NMR (CDCl3, 100 MHz): δ -5.32, -5.27, 18.42, 25.46, 25.88, 27.76, 47.63, 57.89, 62.92, 73.59, 78.21,

82.46, 109.87, 117.02, 128.22, 135.52.




Ratioa 0.04 0.09 1.0


367

The Reaction of (1’R, 4S, 5R)-3-{5-O-[2-(tert-butyldimethylsilanyl oxy)-1hydroxy ethyl]-2, 2-

dimethyl[1, 3]dioxolan-4-yl}-N,N-dimethylhydrazone with Bu3SnH


with 384 mg of Bu3SnH (1.32 mmol) and 16.4 mL of benzene (dried over CaH2 and stored over 4 Å MS in


temperature was adjusted to be 90 oC. To the flask was added a solution of 120.7 mg (0.264 mmol) (1’R,

4S, 5R)-3-{5-O-[2-(tert-butyldimethylsilanyloxy)-1-hydroxyethyl]-2, 2-dimethyl[1, 3]dioxolan-4-yl}-N,N-

dimethylhydrazone 1-249 and 21.7 mg (0.132 mmol) of AIBN in 10 mL of benzene via a syringe pump

during 4 h, and the mixture was stirred for another 0.5 h at 90 oC (oil bath temperature). The mixture was

cooled to rt, and the solvent was removed in vacuo to give crude product. The concentrated mixture was

purified by flash column chromatography eluting with hexane:EtOAc = 7:1 to 2:1. After column

chromatography, 41.4 mg (41%) deoxygenated product was obtained.

OO

NHN(CH3)2

OTBS

1-255

Yellow oil. Column; hexane:EtOAc = 7:1 to 2:1. Rf = 0.56 (hexane:EtOAc = 4:1). [α] 20D = +20.5 (c 0.64,

CHCl3). 1H NMR (CDCl3, 400 MHz): δ 0.03(s, 3 H), 0.04 (s, 3 H), 0.88 (s, 9 H), 1.40 (s, 3 H), 1.41 (s, 3

H), 1.76-1.84 (m, 2 H), 2.81 (s, 6 H), 3.69-3.78 (m, 2 H), 3.98 (ddd, J=12.3, 8.3, 3.9 Hz, 1 H), 4.18 (dd,

J=8.5, 6.7 Hz, 1 H), 6.33 (d, J=6.5 Hz, 1 H). 13C NMR (CDCl3, 100 MHz): δ -5.38, -5.35, 18.3, 25.9, 27.0,

27.2, 35.2, 42.5, 59.8, 76.0, 81.9, 108.6, 130.5. IR (NaCl, neat): υ 2984m, 2953s, 2856m, 2363w, 1802w,

1694w, 1598w, 1472m, 1378m, 1252m, 1167m, 1090s, 1022m, 940s, 883m, 836s, 776m. HRMS

(electrospray) m/z calcd for C16H34O3N2Si 353.2236 (M+ + Na), found 353.2234.

368

Reaction of (6R)-(E)-ethyl 7-{[(1,1-dimethylethyl)diphenylsilyl]oxy}-6-[O-(1-imidazoyl)

thiocarboyloxy]-2-heptenoate


with Ph3SnH (253 mg, 0.720 mmol) and 11.3 mL of benzene (dried over CaH2 and stored over 4 Å MS in


temperature was adjusted to be 90 oC. To the flask was added a solution of 6R)-(E)-ethyl 7-{[(1,1-

dimethylethyl)diphenylsilyl]oxy}-6-[O-(1-imidazoyl) thiocarboyloxy]-2-heptenoate 1-250 (77.3 mg, 0.144

mmol) and AIBN (12 mg, 0.072 mmol)in 3.1 mL of benzene via a syringe pump during 2 h 10 min, and the

mixture was stirred for another 0.5 h at 90 oC (oil bath temperature). The mixture was cooled to rt, and the

solvent was removed in vacuo to give crude product. The concentrated mixture was purified by flash

column chromatography eluting with hexane:EtOAc = 1:1. After column chromatography, 40 mg of 1-258,

15 mg of 1-260, and 3.7 mg of three diastereomer mixtures were obtained, respectively (combined isolated

yield is 80%).

1H NMR (400 MHz)

O

CO2Et

OTBS NN

1-258

O

CO2Et

OTBS NN

1-259

O

CO2Et

OTBS NN

1-260

Chemical Shift (ppm) 5.06 5.86 5.45

Coupling constant J1,2 (Hz) 9.9 5.1 2.4

Ratio 1.0 0.09 0.38

O

CO2Et

OTBS N

N

1-258

Colorless oil. Column; hexane:EtOAc = 1:1. Rf = 0.26 (hexane:EtOAc = 1:2). [α]D20

= +2.7 (c 0.78 in

CHCl3). 1H NMR (CDCl3, 500 MHz): δ 1.02 (s, 9H), 1.21(t, J = 7.2 Hz, 3H), 1.49 (app qd, J = 12.7, 3.5

369

Hz, 1H), 1.58 (app ddt, J = 12.8, 6.9, 6.2 Hz, 1H), 1.79 (Br d, J = 12.2 Hz, 1H), 1.99 (dd, J = 15.7, 8.1 Hz,

1H), 2.07 (dd, J = 15.7, 4.4 Hz, 1H), 2.13 (app dtd, J = 12.7, 6.9, 3.8 Hz, 1H), 2.14-2.29 (m, 1H), 3.67 (app

t, J = 6.9 Hz, 1H), 3.71-3.73 (m, 2H), 4.05 (qd, J = 7.2, 1.9 Hz, 2H), 5.07 (d, J = 8.9 Hz, 1H), 7.01 (s, 1H),

7.08 (s, 1H), 7.30 (m, 4H), 7.38-7.42 (m, 2H), 7.57 (s, 1H), 7.60-7.63 (m, 4H). 13C NMR (CDCl3, 125

MHz): δ 14.12, 19.27, 26.77, 27.09, 28.61, 35.70, 38.62, 60.70, 66.46, 79.03, 87.52, 116.86, 127.59 (two

C), 127.65, 129.62 (two C), 133.38, 133.45, 133.58, 135.62, 132.43, 171.16. IR (NaCl, neat): υ 2976w,

2926w, 2286w, 1734w, 1379m, 1294m, 1261m, 1210w, 1194w, 1154m, 1083s, 1017s, 910w, 754w, 699m.

HRMS (Electrospray): m/z Calcd for C29H38N2O4SiNa (M++Na), 529.2493; Found (M++Na), 529.2417.

O

CO2Et

OTBSN

N

1-260

Colorless oil. Column; hexane:EtOAc = 1:1. Rf = 0.21 (hexane:EtOAc = 1:2). [α]D20

= -6.9 (c 0.26 in

CHCl3). 1H NMR (CDCl3, 500 MHz): δ 1.07 (s, 9H), 1.20 (t, J = 7.2 Hz, 3H), 1.55 (app dt, J = 3.9, 1.9

Hz, 1H), 1.68-1.76 (m, 1H), 1.92 (app tt, J = 13.8, 4.3 Hz, 1H), 2.00 (app dtd, J = 14.2, 4.4, 2.1 Hz, 1H),

2.08 (dd, J = 16.1, 4.5 Hz, 1H), 2.41 (dd, J = 16.1, 9.7 Hz, 1H), 2.56-2.58 (m, 1H), 3.72-3.80 (m, 1H), 4.03

(q, J = 7.1 Hz, 2H), 5.45 (d, J = 2.5 Hz, 1H), 6.96 (s, 1H), 7.08 (s, 1H), 7.37-7.45 (m, 6H), 7.63 (s, 1H),

7.68 (dd, J = 8.4, 1.5 Hz, 2H), 7.69 (dd, J = 8.1, 1.3 Hz, 2H). 13C NMR (CDCl3, 125 MHz): δ 14.11, 19.28,

21.58, 25.94, 26.78, 30.02, 35.58, 60.61, 66.38, 79.72, 87.17, 115.84, 127.73, 127.74, 129.07, 129.77,

129.78, 133,36, 133.39, 134.51, 135.54, 135.56, 172.07. IR (NaCl, neat): υ 3070w, 2953s, 2931s, 2856s,

1733s, 1589w, 1492m, 1473m, 1428m, 1390w, 1308w, 1281m, 1228w, 1113s, 1073m, 1032m. HRMS

(Electrospray): m/z Calcd for C29H38N2O4SiNa (M++Na), 529.2493; Found (M++Na), 529.2445.

370

O

H1

CO2Et

H2

H5

H4bH3b

H3a

H4a

TBDPSO

H6a H6bImH7a

H7bO

H

ImCO2Et

H

H

TBDPSO

1-258

4.4%

2.4%

2.8%

2.1%

2.7%

0.6%

7.5%

1.8%

15.1%

2.7%

2.9%

6.0%

nOe (%) nOe (%) nOe (%) nOe (%)

H1→H2 0.6 H2→Imd 2.7 H3b→H4a 1.8 H4b→H7a,7b 5.3

H1→H3a 2.4 H3a→H1 1.8 H3b→H4b 7.4 H7a→H1 2.3

H1→H5 4.4 H3a→H3b 14.2 H4a→H3a 6.7 H7a→H2 2.9

H1→H7b 2.8 H3a→H4a 4.9 H4a→H4b 13.5 H7b→H1 2.7

H2→H1 0.6 H3a→H5 1.2 H4b→H2 6.0

H2→H4b 2.1 H3b→H3a 15.1 H4b→H4a 12.2

O

H1

H2

H5

H4bH3b

H3a

H4a

TBDPSO

H6a H6bImO

H

ImH

H

TBDPSO

CO2Et1-260CO2EtH7a

H7b

1.5%

4.6%

5.2%

4.6%

3.1%

4.2%

6.1%

2.0%

nOe (%) nOe (%) nOe (%) nOe (%)

H1→H2 3.5 H3a→H1 3.1 H4a→H3a 6.1 H5→ H4a 1.0

H1→H3a 1.5 H3a→H2 4.2 H4a→H4b 11.5 H5→H4b 0.9

H1→H5 4.6 H3b→H2 3.7 H4a→H5 5.3 H7a→H7b 11.5

H2→H3a 5.2 H3b→H4a 4.0 H4b→H4a 4.0 H7b→H7a 8.8

H2→H3b 4.6 H3b→H4b 2.1 H5→H1 2.0

371

The Reaction of (E)-ethyl 5(S)-{[(1,1-dimethyl)ethyl dimethylsilyl]oxy}-6-[(N-imidazolythio

carbonyl)oxy]-2-hexenoate




temperature was adjusted to be 90 oC. To the flask was added a solution of 55 mg (0.138 mmol) (E)-ethyl

5(S)-{[(1,1-dimethyl)ethyl dimethylsilyl]oxy}-6-[(N-imidazoyl thiocarbonyl) oxy]-2-hexenoate 1-251 and

9.4 mg (0.057 mmol) of AIBN in 2.4 mL of benzene via a syringe pump during 1 h, and the mixture was

stirred for another 0.5 h at 90 oC (oil bath temperature). The mixture was cooled to rt, and the solvent was

removed in vacuo to give crude product. The α/β ratio of the crude product was altro-α/ altro-β/ allo-α/

allo-α/ = 0.21/1.0/0.78/0.22. The concentrated mixture was purified by flash column chromatography

eluting with hexane:EtOAc = 2:1 to 1:1. After column chromatography, 40.1 mg (79%) of 4-

diastereomermixture was isolated as yellow oil with a ratio of altro-α/ altro-β/ allo-α/ allo-β/ =

0.19/1.0/0.23/0.93. The configuration was assigned tentatively.

O

CO2Et

N

N

TBSO

allo-1-257-β


1H NMR (CDCl3, 500 MHz): δ 0.09 (s, 3H), 0.08 (s, 3H), 0.90 (s, 9H), 1.19 (t, J = 7.2 Hz, 3H), 1.96 (app

dt, J = 13.7, 6.1 Hz, 1H), 2.04 (app dt, J = 14.1, 4.5 Hz, 1H), 2.10 (dd, J = 16.5, 5.2 Hz, 1H), 2.62-2.68 (m,

1H), 2.70 (dd, J = 16.5, 8.5 Hz, 1H), 3.72-3.79 (m, 2H), 3.87 (app tt, J = 8.6, 4.2 Hz, 1H), 4.03 (qd, J = 7.1,

1.7 Hz, 2H), 5.57 (d, J = 3.6 Hz, 1H), 7.08 (s, 1H), 7.10 (s, 1H), 7.72 (s, 1H). 13C NMR (CDCl3, 100

MHz): δ -4.90, 14.07, 17.99, 25.72, 33.19, 33.83, 34.54, 60.55, 65.12, 70.97, 85.01, 117.33, 128.98,

135.96, 172.15. IR (NaCl, neat): υ 3113w, 2954s, 2938s, 2896s, 2857s, 1732s, 1494m, 1472m, 1390m,

1362m, 1284m, 1255s, 1227s, 1176s, 1096s, 1035s, 918m, 879m, 838s, 777s, 739m, 662m. HRMS

372

(Electrospray); Calc. (M++Na) 369.2209, found (M++Na) 369.2205. The structure has been confirmed by

nOe experiment and the result is shown below.

O

H

N

H

HH

HH

N

H

TBSO

EtO2C

12

3

45

1.0%

7.1%

1.5%

12.3%

4.8%

O

CO2Et

N

N

TBSO

allo-1-257-β

O

CO2Et

N

N

TBSO

altro-1-257-β


1H NMR (CDCl3, 500 MHz): δ 0.06 (s, 6H), 0.88 (s, 9H), 1.21 (t, J = 7.1 Hz, 3H), 1.83 (ddd, J = 14.1,

10.1, 4.4 Hz, 1H), 2.08-2.25 (m, 1H), 2.11 (dd, J = 15.7, 5.2 Hz, 1H), 2.38 (dd, J = 15.8, 9.5 Hz, 1H), 2.80

(ddd, J = 9.4, 7.6, 4.3 Hz, 1H), 3.43 (dd, J = 11.2, 9.3 Hz, 1H), 4.02 (app tt, J = 9.8, 4.8 Hz, 1H), 4.07-4.13

(m, 1H), 4.09 (q, J = 7.1 Hz, 2H), 5.48 (d, J = 3.0 Hz, 1H), 6.94 (s, 1H), 7.07 (s, 1H), 7.64 (s, 1H). 13C

NMR (CDCl3, 100 MHz): δ -4.88, -4.84, 14.10, 18.01, 25.68, 31.63, 35.53, 36.15, 60.78, 62.14, 72.47,

86.27, 116.27, 129.19, 134.90, 171.62.

O

H

N

H

H

HHH

N

CO2Et

H

TBSO

12

3

45

3.4%

2.1%

4.6%1.5%

1.5%

2.9%

4.3%

3.4%

O

CO2Et

N

N

TBSO

altro-1-257-β

373

O

CO2Et

N

N

TBSO

O

CO2Et

N

N

TBSO

O

CO2Et

N

N

TBSO

O

CO2Et

N

N

altro-1-257-α

TBSO

altro-1-257-β allo-1-257-α allo-1-257-β




Ratioa 0.19 1.00 0.23 0.93


The Reaction of (1’R, 4S, 5R)-{5-O-[2-(tert-butyldimethylsilanyloxy)-1-hydroxyethyl]-2, 2-dimethyl[1,





temperature was adjusted to be 90 oC. To the flask was added a solution of (1’R, 4S, 5R)-{5-O-[2-(tert-

butyldimethylsilanyloxy)-1-hydroxyethyl]-2, 2-dimethyl[1, 3]dioxolan-4-yl}-ethene; 1’-O-(1-

imidazoyl)thione 1-269 (142 mg, 0.324 mmol) and AIBN (27 mg, 0.162 mmol) in 7.1 mL of benzene via a

syringe pump over 4 h 40 min, and the mixture was stirred for another 0.5 h at 90 oC (oil bath temperature).

The mixture was further stirred under refluxing condition for 8 h to consume all starting material 1-269.

After removed all solvent on a rotary eveaporator under reduced predure, the crude mixture was purified by

column chromatographyl eluting hexane:EtOAc = 12:1 to give colorless oil (49 mg, 50%). The isolated

product was assigned as dethiocarbamated product 1-270.

374

TBSO

O O

1-270

OH


dimethyl[1, 3]dioxolan-4-yl}-acrylic acid tert-butyl ester; 1’-O-(1-tridazoyl)thione


with Ph3SnH (233 mg, 0.663 mmol) and benzene (10.5 mL, dried over CaH2 and stored over 4 Å MS in


temperature was adjusted to be 90 oC. To the flask was added a solution of (1’R, 4S, 5R)-(Z)-3-{5-O-[2-

(tert-butyldimethylsilanyloxy)-1-hydroxyethyl]-2, 2-dimethyl[1, 3]dioxolan-4-yl}-acrylic acid tert-butyl

ester; 1’-O-(1-tridazoyl)thione 1-272 (68 mg, 0.113 mmol) and AIBN (11 mg, 0.066 mmol) in 2.8 mL of

benzene via a syringe pump during 3 h, and the mixture was stirred for another 0.5 h at 90 oC (oil bath


The α/β ratio of the crude product was 0.32/1.0. The concentrated mixture was purified by flash column

chromatography eluting with hexane:EtOAc = 8:1 to 7:1. The α-altro and β-altro of as [4-(tert-butyl-

dimethyl-silanoyloxymethyl)-6-imidazol-1-yl-2,2-dimethyl-tetrahydro-[1,3]dioxolo[4,5,c]pyran-7-yl]-

acetic acid tert-butyl ester 1-274 were isolated as 55.5 mg (87%).

O

OO

OTBS

N

N

N

CO2tBu

altro-1-274-α


[α]D20

= +20.7 (c 0.58 in CHCl3). 1H NMR (CDCl3, 500 MHz): δ 0.02 (s, 3H), 0.04 (s, 3H), 0.86 (s, 9H),


375

2.30 (app dq, J = 9.6, 5.1 Hz, 1H), 3.75 (dd, J = 11.6, 5.4 Hz, 1H), 3.88 (dd, J = 11.6, 2.3 Hz, 1H), 4.10

(ddd, J = 7.7, 5.3, 2.3 Hz, 1H), 4.28 (app t, J = 7.3 Hz, 1H), 4.31 (dd, J = 9.3, 7.0 Hz, 1H), 5.90 (d, J = 9.4

Hz, 1H), 7.97 (s, 1H), 8.33 (s, 1H). 13C NMR (CDCl3, 125 MHz): δ -5.41, -5.36, 18.31, 25.29, 25.81,

27.46, 28.02, 35.56, 38.50, 72.05, 74.62, 74.92, 81.25, 84.41, 110.37, 136.13, 152.01, 170.33. IR (NaCl,

neat): υ 3122w, 2985s, 2954s, 2930s, 2857s, 1725s, 1507m, 1472m, 1401m, 1431m, 1369s, 1272s, 1256s,

1214s, 1152s, 1078s, 999m, 955w, 919w, 837s, 778s, 733m.


O

OO

OTBS

N

N

N

CO2tBu

altro-1-274-α

O

H

H

N

OTBS

O

O

H

HH

NN

CO2tBu

3.6%

1.7%

1

23

45

1.2%

0.7%

4.5%

1.4%

O

OO

OTBS

N

N

N

CO2tBu

altro-1-274-β


[α]D20

= -4.3 (c 1.25 in CHCl3). 1H NMR (CDCl3, 500 MHz): δ 0.04 (s, 3H), 0.05 (s, 3H), 0.88 (s, 9H),


3.01 (ddd, J = 13.7, 7.1, 4.1 Hz, 1H), 3.72 (dd, J = 9.1, 4.9, 1.7 Hz, 1H), 3.76 (dd, J = 11.4, 5.0 Hz, 1H),

3.91 (dd, J = 11.4, 1.7 Hz, 1H), 4.30 (dd, J = 9.2, 6.3 Hz, 1H), 4.42 (app t, J = 6.2 Hz, 1H), 6.41 (d, J = 4.0

Hz, 1H), 7.98 (s, 1H), 8.24 (s, 1H). 13C NMR (CDCl3, 125 MHz): δ -5.30, 18.37, 25.43, 25.84, 27.66,

376

27.98, 32.73, 37.56, 63.06, 69.71, 74.40, 77.83, 81.24, 84.39, 109.47, 143.11, 152.14, 170.55. IR (NaCl,

neat): υ 3122w, 2985s, 2954s, 2931s, 2857s, 1739w, 2236w, 1727s, 1506m, 1472m, 1461m, 1369s, 1272s,

1255s, 1214s, 1157s, 1066s, 1022m, 956m, 939m, 910m, 875m, 837s, 814m, 779s, 734s, 678m. HRMS

(Electrospray); Calc. (M++Na) 506.2657, found (M++Na) 506.2665.


O

OO

OTBS

N

N

N

CO2tBu

altro-1-274-β

O

H

N

H

OTBS

O

O

H

HH

N

N

CO2tBu

2.8%

3.8%

12

3

45

2.5%, 2.5%

0.9%, 1.5%

0.9%, 0.7%

1.2%, 1.4%

3.7%

1.5%, 2.0%

The Reaction of (1’R, 4S, 5R)-(E and Z)-3-{5-O-[2-(tert-butyldimethylsilanyloxy)-1-hydroxy ethyl]-2,

2-dimethyl[1, 3]dioxolan-4-yl}-O-methylhydroxyl amine; 1’-O-(1-triazoyl)thione




temperature was adjusted to be 90 oC. To the flask was added a solution of (1’R, 4S, 5R)-(E and Z)-3-{5-

O-[2-(tert-butyldimethylsilanyloxy)-1-hydroxy ethyl]-2, 2-dimethyl[1, 3]dioxolan-4-yl}-O-methylhydroxyl

amine; 1’-O-(1-triazoyl)thione 1-273 (41 mg, 0.092 mmol) and of AIBN (7.6 mg, 0.046 mmol) in 2.0 mL

of benzene via a syringe pump during 1 h 20 min, and the mixture was stirred for another 0.5 h at 90 oC (oil


product. The ratio of altro-α/ altro-β of the crude mixture is 0.69/1.0. The concentrated mixture was

purified by flash column chromatography eluting with hexane:EtOAc = 6:1. After column

377

chromatography, 17.6 mg (46%) of 3-diastereomermixture was isolated as yellow oil The structure has

been confirmed by nOe experiment.

O

NHOCH3OO

OTBS

N

N

N

altro-1-275-β

Pale yellow oil. Column chromatography; hexane:EtOAc = 6:1. Rf = 0.23 (hexane:EtOAc = 2:1). [α]D20

=

-7.4 (c. 0.42 in CHCl3). 1H NMR (CDCl3, 500 MHz): δ 0.06 (s, 3H), 0.08 (s, 3H), 0.88 (s, 9H), 1.37 (s,

3H), 1.51 (s, 3H), 3.46 (s, 3 H), 3.74 (ddd, J = 8.9, 4.5, 2.0 Hz, 1H), 3.77 (dd, J = 11.4, 4.4 Hz, 1H), 3.81

(dd, J = 5.6, 3.4 Hz, 1H), 3.91 (dd, J = 11.7, 2.0 Hz, 1H), 4.33 (dd, J = 8.7, 6.7 Hz, 1H), 4.44 (app t, J = 6.3

Hz, 1H), 6.11 (d, J = 3.4 Hz, 1H), 8.01 (s, 1H), 8.51 (s, 1H). 13C NMR (CDCl3, 100 MHz): δ -5.33, 18.43,

25.23, 25.87, 27.58, 59.76, 62.12, 63.03, 69.82, 72.50, 77.85, 82.81, 109.83, 144.08, 151.83. IR (NaCl,

neat): υ 3263 Br s, 3118w, 2985m, 2954s, 2931s, 2862s, 1752w, 1508m, 1472m, 1463m, 1382s, 1276s,

1252s, 1218s, 1134s, 1068s, 954m, 914w, 836s, 813m, 780s, 734m, 698w, 677m. HRMS (Electrospray);

Calc. (M++Na) 437.2191, found (M++Na) 437.2183.




Ratioa 0.69 1.0


378

O

NHOCH3OO

OTBS

N

N

N

altro-1-275-β

O

H

N

H

OTBSNHOCH3

O

O

H

HH

N

N

2.3%

3.0%

1

23

45

1.2%0.7%

nOe (%) nOe (%) nOe (%) nOe (%)

H1→H2 3.8 H3→H2 1.8 H4→H5 0.8 H7a→ Tra1 0.3

H1→H5 3.2 H3→H4 2.2 H4→H7a 0.6 H7a→ Tra1 0.7

H1→ Tra1 0.2 H3→H7a 2.0 H5→H1 3.7 H7b→H3 2.5

H1→ Tra2 1.4 H3→H7b 1.5 H5→H2 3.8 H7b→H4 0.9

H2→H1 3.7 H4→H3 2.3 H5→H4 1.1 H7b→ Tra1 0.9

H2→H3 1.9 H4→H6a 0.7 H7a→H3 2.5 H7b→ Tra2 1.2

H2→H5 2.8 H4→H6b 1.4 H7a→H4 1.5


dimethyl[1, 3]dioxolan-4-yl}-acrylic acid tert-butyl ester; 1’-O-(1-benzylimidazoyl)thione


with Ph3SnH (109 mg, 0.311 mmol) and benzene (4.9 mL, dried over CaH2 and stored over 4 Å MS in


temperature was adjusted to be 90 oC. To the flask was added a solution of 1’-O-(1-

benzylimidazoyl)thione 1-276 (35 mg, 0.062 mmol) and AIBN (5 mg, 0.031 mmol) in 1.3 mL of benzene

via a syringe pump during 50 min, and the mixture was stirred for another 0.5 h at 90 oC (oil bath

temperature). The crude 1H NMR spectrum implies that a a/b mixture of N-pyranosides 1-277 were formed

along with 1-278. After all solvent was removed on a rotary eveaporator, the crude mixture was subjected

to column chromatography to give contaminated N-pyranosides 1-277 (estimated yield is 87%).

379

O N

OO CO2

tBu

OTBS

1-277

N

250 MHz 1H NMR altro-α altro-β

Chemical shift (ppm) 5.43 5.91

Coupling constant (Hz) 7.4 3.9

Ratioa 0.58 1.0


4. 5. 5-Exo-trig Radical Cyclization

The reaction of (E)-Ethyl 6-{[(1,1-dimethyl)ethyl dimethylsilyl]oxy}-5(S)-[(N-imidazoyl

thiocarbonyl)oxy]-2-hexenoate


with 37 mL of benzene (dried over CaH2 and stored over 4 Å MS in nitrogen atmosphere) under nitrogen

atmosphere. The flask was immersed into an oil bath, and the bath temperature was adjusted to be 90 oC,

and Ph3SnH (2.35 mmol, 825 mg) was added to it. A solution of 0.47mmol (187 mg) of 1-281 and 0.235

mmol (38 mg) of AIBN in 10 mL of benzene was added dropwise with stirring via a syringe pump during 3

h 40 min, and the mixture was stirred for another one hour. The mixture was cooled to rt, and the solvent

was removed the solvent in vacuo. The concentrated mixture was purified by flash column

chromatography eluting hexane:EtOAc = 1:1 to 1:3. The isolated yield of N-furanoside was 88%.

380

O

TBSON

H H

N

CO2Et1-282

O

TBSON

H H

N

CO2Et

1-282-a

O

TBSON

H H

N

CO2Et

1-282-b

O

TBSON

H H

N

CO2Et

1-282-c

O

TBSON

H H

N

CO2Et

1-282-d

Colorless oil. Column; hexane:EtOAc = 1:1 to 1:3. Rf = 0.23 (hexane:EtOAc = 1:3). The stereochemistry

was assigned tentatively. Major 1-282-a; about 2 mg was isolated as a pure form. 1H NMR (CDCl3, 400

MHz): δ 0.08 (s, 6 H), 0.94 (s, 9 H), 1.21 (t, J = 7.1 Hz, 3 H), 1.85 (dd, J = 17.4, 8.7 Hz, 1 H), 1.95 (ddd, J

= 12.8, 11.2, 11.2 Hz, 1 H), 2.03 (ddd, J = 12.8, 6.8, 5.4 Hz, 1 H), 2.17 (dd, J = 17.4, 7.5 Hz, 1 H), 3.02

(ddddd, J = 13.2, 13.2, 8.6, 6.6, 2.1 Hz, 1 H), 3.79 (dd, J = 11.5, 3.1 Hz, 1 H), 4.02 (dd, J = 11.4, 3.0 Hz, 1

H), 4.09 (qd, J = 7.2, 1.0 Hz, 2 H), 4.17 (app tt, J = 6.9, 3.5 Hz, 1 H), 6.05 (d, J = 6.8 Hz, 1 H), 7.04 (s, 1

H), 7.20 (s, 1 H), 7.68 (s, 1 H). 13C NMR (CDCl3, 100 MHz): δ -5.5, -5.3, 14.1, 18.6, 26.0, 30.2, 33.2,

41.2, 60.8, 63.5, 81.0, 88.2, 117.5, 128.5, 136.0, 171.9. IR (NaCl,neat): υ 3116 Br s, 2956s, 2930s, 2859s,

1731s, 1493m, 1469m, 1419m, 1386m, 1343m, 1255s, 1183m, 1077s, 1026m, 920m, 838s, 779s, 663m.

HRMS (electrospray) m/z calcd for C18H32O4N2Si 369.2209 (M+ + H), found 369.2210. 2nd major 1-282-

b; 1H NMR (CDCl3, 400 MHz): δ 0.07 (s, 3 H), 0.08 (s, 3 H), 0.91 (s, 9 H), 1.21 (t, J = 7.1 Hz, 3 H), 1.77

(dd, J = 12.8, 8.3 Hz, 1 H), 2.20-2.63 (m, 3 H), 2.85-2.97 (m, 1 H), 3.65 (dd, J = 11.0, 3.6 Hz, 1 H), 3.78

(dd, J = 11.1, 3.7 Hz, 1 H), 4.08 (q, J = 7.2 Hz, 2 H), 4.33 (app tt, J = 7.3, 3.6 Hz, 1 H), 5.55 (d, J = 5.5Hz,

1 H), 7.07 (s, 1 H), 7.09 (s, 1 H), 7.66 (s, 1 H). 13C NMR (CDCl3, 100 MHz), δ -5.40, -5.38, 14.11, 18.37,

25.91, 32.31, 36.71, 42.85, 60.91, 64.69, 79.89, 91.04, 116.49, 129.82, 136.00, 171.32. Minor 3-59; 1H

NMR (CDCl3, 400 MHz): δ 0.07 (s, 3 H), 0.08 (s, 3 H), 0.91 (s, 9 H), 1.22 (t, J = 7.1 Hz, 3 H), 1.74-1.89

(m, 1 H), 2.20-2.63 (m, 3 H), 2.85-2.97 (m, 1 H), 3.68 (dd, J = 11.0, 3.7 Hz, 1 H), 3.81 (dd, J = 11.1, 3.7

Hz, 1 H), 4.09 (q, J = 7.2 Hz, 2 H), 4.27 (app tt, J = 6.9, 3.5 Hz, 1 H), 5.53 (d, J = 5.0 Hz, 1 H), 7.07 (s, 1

381

H), 7.17 (s, 1 H), 7.85 (s, 1 H). 13C NMR (CDCl3, 100 MHz): δ -5.38, -5.35, 14.11, 18.37, 26.00, 32.00,

36.13, 42.67, 60.86, 65.20, 79.93, 91.24, 116.49, 129.82, 136.00, 171.15.

The 1-282-c and 1-282-d could not be fully characterized because only small amount of the

product was made; but the characteristic peak was found at δ 6.10 (d, J = 6.2 Hz) and at δ 5.60 (d, J = 5.7

Hz) were found, respectively.

Compound 1-283 was isolated as a major product under refluxing condition (see Table 12 for

detail)

O

TBSO

H

CO2Et

S

1-283

cis/trans = 2.1/1.0

Yellow oil. Column; hexane:EtOAc = 6:1 to 3:1. Rf = 0.13 (hexane:EtOAc = 4:1). Major, cis; 1H NMR

(CDCl3, 400 MHz): δ 0.08 (s, 3 H), 0.09 (s, 3 H), 0.89 (s, 9 H), 1.28 (t, J = 7.1 Hz, 3 H), 1.93 (ddd, J =

12.6, 11.3, 9.6 Hz, 1 H), 2.43-2.62 (m, 2 H), 3.24 (dd, J = 17.0, 3.8 Hz, 1 H), 3.29-3.34 (m, 1 H), 3.79 (dd,

J = 11.5, 2.6 Hz, 1 H), 3.98 (dd, J = 11.5, 2.7 Hz, 1 H), 4.10-4.23 (m, 2 H), 4.83 (app dq, J = 6.7, 3.5 Hz, 1

H). 13C NMR (CDCl3, 100MHz): δ -.5.42, -5.36, 14.16, 18.32, 25.82, 30.19, 35.13, 37.20, 60.91, 64.02,

78.68, 171.31, 177.41. Minor, trans; 1H NMR (CDCl3, 400 MHz), δ 0.07 (s, 3 H), 0.09 (s, 3 H), 0.89 (s, 9

H), 1.27 (t J = 7.1 Hz, 3 H), 2.07 (app dt, J = 8.4, 5.1 Hz, 1 H), 2.43-2.62 (m, 2 H), 3.15 (dd, J = 16.8, 4.0

Hz, 1 H), 3.47 (app dq, J = 9.4, 4.0 Hz, 1 H), 3.72 (dd, J = 11.8, 3.7 Hz, 1 H), 3.97 (dd, J = 11.7, 3.4 Hz, 1

H), 4.10-4.23 (m, 2 H), 4.92 (app dq, J = 8.8, 2.7 Hz, 1 H). 13C NMR (CDCl3, 100MHz): δ -.5.62, -5.31,

14.15, 18.32, 25.80, 30.14, 35.56, 36.18, 60.86, 65.08, 78.01, 171.31, 178.45. IR (NaCl, neat): υ 2956s,

2928s, 2853m, 2360m, 1776w, 1736s, 1463m, 1352m, 1254s, 1183m, 1125m, 1028m, 839s, 780m. HRMS

(electrospray) m/z calcd for C15H28O4SSi 355.1375 (M+ + Na), found 355.1372.

382

The Reaction of (E) and (Z)-1-cyano-5-{[(1,1-dimethyl)ethyl dimethylsilyl]oxy}-4(S)-[(N-imidazoly-

thiocarbonyl) oxy]-hex-1-ene


with 35 mL of benzene (dried over CaH2 and stored over 4 Å MS in nitrogen atmosphere) under nitrogen

atmosphere. The flask was immersed into an oil bath, and the bath temperature was adjusted to be 90 oC,

and Bu3SnH (1.73 mmol, 503 mg) was added to it. A solution of 0.345 mmol (121 mg) of 1-298 (E/Z =

1.0/0.25) and 0.173 mmol (28 mg) of AIBN in 10 mL of benzene was added dropwise with stirring via a

syringe pump during 3 h 40 min, and the mixture was stirred for another one hour. The mixture was cooled

to rt, and the solvent was removed the solvent in vacuo. The concentrated mixture was purified by flash

column chromatography eluting hexane:EtOAc = 1:3. The isolated yield of the product 1-299 and 1-300

were 39% and 8%, respectively.

O

TBSON

H H

N

CN

1-299

O

TBSON

H H

N

CN

1-299-a

O

TBSON

H H

N

CN

1-299-b

O

TBSON

H H

N

CN

1-299-c

O

TBSON

H H

N

CN

1-299-d

Yellow oil. Column; hexane:EtOAc = 1:3. Rf = 0.15 (hexane:EtOAc = 1:3). Major 1-299-a; 1H NMR

(CDCl3, 400 MHz): δ 0.13 (s, 6 H), 0.94 (s, 9 H), 1.98 (dd, J = 7.8, 2.2 Hz, 2 H), 2.55 (dd, J = 16.8, 7.6 Hz,

1 H), 2.67 (dd, J = 16.9, 6.2 Hz, 1 H), 2.92-3.02 (m, 1 H), 3.79 (dd, J = 11.8, 2.7 Hz, 1 H), 4.06 (dd, J =

11.7, 2.7 Hz, 1 H), 4.22 (dddd, J = 8.0, 5.4, 5.4, 2.7 Hz, 1 H), 5.97 (d, J = 6.6 Hz, 1 H), 7.10 (s, 1 H), 7.30

(s, 1 H), 7.88 (s, 1 H). 13C NMR (CDCl3, 100 MHz): δ -5.40, 14.11, 18.36, 25.91, 32.31, 36.71, 42.85,

383

60.91, 66.69, 79.89, 91.04, 116.49, 129.82, 135.20, 171.32. IR (NaCl, neat): υ 3123 Brs, 2956s, 2930s,

2859s, 2254m, 1693s, 1493m, 1469m, 1422m, 1391m, 1362m, 1256s, 1226m, 1181m, 1088s, 1011m, 982m,

838s, 664m. HRMS (electrospray) m/z calcd for C16H27O2N3Si 344.1770 (M+ + Na), found 344.1769. 2nd

major 1-299-b; 1H NMR (CDCl3, 400 MHz): δ 0.09 (s, 6 H), 0.92 (s, 9 H), 2.10-2.20 (m, 1 H), 2.59-2.67

(m, 1 H), 2.81-2.90 (m, 1 H), 3.65 (dd, J = 11.3, 3.1 Hz, 1 H), 3.85 (dd, J = 11.3, 3.2 Hz, 1 H), 4.37 (app tt,

J = 7.5, 3.1 Hz, 1 H), 5.62 (d, J = 4.8 Hz, 1 H), 7.03 (s, 1 H), 7.71 (s, 1 H), 7.78 (s, 1 H). 13C NMR

(CDCl3, 100 MHz): δ -5.48, 14.11, 18.36, 26.00, 32.00, 36.13, 42.68, 60.87, 65.20, 79.94, 91.04, 116.52,

121.70, 135.20, 171.16

The 1-299-c and 1-299-d could not be isolated in pure forms but the anomeric hydrogen observed

at 5.56 ppm ( J = 6.0 Hz) and 6.01 ppm ( J = 6.0 Hz) suggest diastereomeric structres.

O

TBSO

H

CN

1-300

Yellow oil. Column; hexane:EtOAc = 10:1. Rf = 0.27 (hexane:EtOAc = 5:1).

3 diasteromers were isolated as a mixture in a ratio of 0.43/0.27/0.26 based on 13C NMR, and the

stereochemistry was not assigned. Only 1H NMR spctrum of two diasteromer have been assigned.

Major; 1H NMR (CDCl3, 400 MHz): δ 0.07 (s, 3 H), 0.08 (s, 3 H), 0.89 (s, 9 H), 1.49-1.62 (m, 2 H), 1.67-

1.85 (m, 1H), 2.44 (dd, J = 13.8, 7.8 Hz, 1 H), 2.45 (dd, J = 14.5, 6.8 Hz, 1 H), 2.56-2.66 (m, 1 H), 3.50-

3.66 (m, 2 H), 3.82-3.87 (m, 1 H), 3.99-4.04 (m, 1 H), 13C NMR (CDCl3, 100 MHz): δ -5.35, 18.32, 20.92,

25.96, 33.07, 36.01, 64.98, 72.36, 79.93, 118.43. HRMS (electrospray) m/z calcd for C24H42O6N2Si

483.2890 (M+ + H), found 483.2903. Minor; 1H NMR (CDCl3, 400 MHz): δ 0.05 (s, 3 H), 0.06 (s, 3 H),

0.91 (s, 9 H), 1.49-1.62 (m, 2 H), 2.08 (ddd, J = 13.0, 8.0, 6.3 Hz, 1 H), 2.21 (app dt, J = 12.7, 5.3 Hz, 1 H),

2.31-2.39 (m, 2 H), 3.47-3.52 (m, 1 H), 3.63-3.66 (m, 1 H), 3.74 (dd, J = 8.0, 3.7 Hz, 1 H), 4.09-4.15 (m, 1

H), 13C NMR (CDCl3, 100 MHz): δ -5.40, 18.43, 20.68, 25.89, 33.14, 36.33, 65.46, 72.25, 78.87, 118.65.

384

2nd minor; 13C NMR (CDCl3, 100 MHz): δ -4.78, 16.30, 20.68, 25.77, 29.68, 36.59, 64.25, 70.52, 72.89,

118.00.

4. 6. 5 -Exo-trig radical cyclization by EPHP as a radical source

To a flame-dried 50 mL of three neck flask connected to a condenser was added 4.69 mmol (840

mg) of EPHP dissolved in 37 mL of dried benzene under positive pressure of nitrogen. The temperature of

the flask was adjusted to be 90 oC, and added a mixture of 0.469 mmol (187 mg) of 1-281 and 0.469 mmol

(77 mg) of AIBN in 10 mL of benzene via a syringe pump at 26 µL/min. After addition, the mixture was

stirred at 90 oC for another one hour. The mixture was washed with water, and crude product was extracted

with dichloromethane. The combined organic phase was dried over magnesium sulfate, filtered, and the

solvent was removed under reduced pressure. The concentrated mixture was purified by flash column

chromatography eluting with hexane:EtOAc = 1:1 to 3:1 to give the desired products. The isolated yield of

1-281 was 32% (1-281-a:1-282-b:1-282-c:1-283-d = 39:19:37:11).

4. 7. Stereochemical Control in 5-Exo trig Radical Cyclizaiton

The Reaction of (2R, 4S, 5R)-(E)-3-[(Imidazole-1-carbothioyloxy]-2-phenyl-[1, 3]dioxin-4-yl)-acrylic

acid ethyl ester




temperature was adjusted to be 90 oC. To the flask was added a solution of 60.9 mg (0.157 mmol) of (2R,

4S, 5R)-(E)-3-[(imidazole-1-carbothioyloxy]-2-phenyl-[1, 3]dioxin-4-yl)-acrylic acid ethyl ester (E)-1-283,

and 13 mg (0.079 mmol) of AIBN in 3.4 mL of benzene via a syringe pump over 2 h , and the mixture was

stirred for another 0.5 h at 90 oC (oil bath temperature). The mixture was cooled to rt, and the solvent was

removed in vacuo to give crude product. The concentrated mixture was purified by flash column

385

chromatography eluting with hexane only to hexane:EtOAc = 1:2. The cyclized N-pyranoside was

obtained as white solid (30.5 mg, 54%) with the ratio of α/β = 0.8/1.0).

OOPh O

H Im

HEtO2C

1-285-α

White solid. Column chromatography; hexane only to hexane:EtOAc = 1:2. Rf = 0.12 (hexane:EtOAc =

1:4). [α]D20

= +25.0 (c 0.62 in CHCl3). Mp: 126-129 oC. 1H NMR (CDCl3, 400 MHz): δ 1.11 (t, J = 7.2

Hz, 3H), 2.60 (dd, J = 15.5, 8.5 Hz, 1H), 2.84 (dd, J = 15.4, 4.9 Hz, 1H), 3.15 (dddd, J = 8.8, 8.3, 7.0, 4.9

Hz, 1H), 3.65 (dd, J = 10.6, 8.8 Hz, 1H), 3.88-4.05 (m, 4H), 4.54 (dd, J = 9.3, 3.9 Hz, 1H), 5.58 (s, 1H),

5.78 (d, J = 7.0 Hz, 1H), 7.14 (s, 1H), 7.35-7.41 (m, 4H), 7.49-7.52 (m, 2H), 7.71 (s, 1H). 13C NMR

(CDCl3, 100 MHz): δ 13.90, 34.21, 45.28, 61.17, 70.75, 73.10, 82.78, 88.93, 102.61, 117.08, 126.22,

128.40, 129.01, 129.43, 136.16, 136.42, 170.20. IR (NaCl, neat): υ 3394 Br m, 3119m, 2982m, 1731s,

1495w, 1455w, 1428w, 1370m, 1282m, 1228m, 1165m, 1094m, 1047s, 1028s, 970s, 913m, 756s, 699s,

661m. HRMS (Electrospray) Calcd. for (M++Na); 381.1421. Found (M++Na); 381.1447. Anal. Calcd. for

C19H22O5N2; C, 63.67; H, 6.19; N, 7.82. Found; C, 64.45; H, 6.93; N, 6.39.

1-285-β

OOPh O

H H

ImEtO2C


1:4). [α]D20

= -84.0 (c 0.77 in CHCl3). Mp: 57-60 oC. 1H NMR (CDCl3, 400 MHz): δ 1.77 (t, J = 7.1 Hz,

3H), 1.80 (dd, J = 17.8, 11.4 Hz, 1H), 2.69 (dd, J = 17.8, 3.5 Hz, 1H), 3.11 (app tdd, J = 11.4, 7.6, 3.5 Hz,

1H), 3.62 (dd, J = 11.6, 9.0 Hz, 1H), 3.75 (ddd, J = 9.9, 9.0, 4.0 Hz, 1H), 4.03 (app t, J = 11.0 Hz, 1H),

4.05 (q, J = 7.1 Hz, 2H), 4.63 (dd, J = 9.8, 4.3 Hz, 1H), 5.62 (s, 1H), 6.29 (d, J = 7.5 Hz, 1H), 6.94 (s, 1H),

7.11 (s, 1H), 7.35-7.41 (m, 3H), 7.48-7.59 (m, 2H), 7.60 (s, 1H). 13C NMR (CDCl3, 100 MHz): δ 14.04,

386

31.03, 43.25, 61.11, 70.97, 73.05, 81.42, 86.95, 102.84, 117.42, 126.25, 128.42, 128.99, 129.62, 136.15,

136.42, 171.60. IR (NaCl, neat): υ 3388 Br m, 3119m, 3061m, 2983m, 2928m, 1729s, 1494m, 1478m,

1428s, 1376s, 1324m, 1228s, 1212s, 1080s, 1027s, 996s, 972s, 914m, 699s, 662m. HRMS (Electrospray)

Calcd. for (M++Na); 381.1421. Found (M++Na); 381.1433.

The Reaction of (2R, 4S, 5R)-(Z)-3-[(Imidazole-1-carbothioyloxy]-2-phenyl-[1, 3]dioxin-4-yl)-acrylic



with 309 mg of Ph3SnH (0.880 mmol) and 14 mL of benzene (dried over CaH2 and stored over 4 Å MS in



4S, 5R)-(Z)-3-[(imidazole-1-carbothioyloxy]-2-phenyl-[1, 3]dioxin-4-yl)-acrylic acid tert-butyl ester (Z)-1-

11, and 14.5 mg (0.088 mmol) of AIBN in 3.8 mL of benzene via a syringe pump during 2 h 25 min, and

the mixture was stirred for another 0.5 h at 90 oC (oil bath temperature). The mixture was cooled to rt, and

the solvent was removed in vacuo to give crude product. The concentrated mixture was purified by flash

column chromatography eluting with hexane only to hexane:EtOAc = 1:2. The cyclized N-pyranoside was

obtained as white solid (31 mg, 46%) with the ratio of α/β = 0.66/1.0).

1-286-α

OOPh O

H Im

HButO2C


1:2). [α]D20

= +34.9 (c 0.59 in CHCl3). Mp: 125-128 oC. 1H NMR (CDCl3, 500 MHz): δ 1.33 (s, 9H), 2.54

(dd, J = 15.1, 8.5 Hz, 1H), 2.82 (dd, J = 15.1, 4.7 Hz, 1H), 3.18 (dddd, J = 8.8, 8.5, 6.9, 4.8 Hz, 1H), 3.65

(dd, J = 10.4, 8.9 Hz, 1H), 3.94 (app t, J = 10.1 Hz, 1H), 4.00 (app td, J = 9.8, 4.1 Hz, 1H), 4.58 (dd, J =

9.5, 4.1 Hz, 1H), 5.62 (s, 1H), 5.82 (d, J = 6.9 Hz, 1H), 7.20 (s, 1H), 7.21 (s, 1H), 7.41-7.46 (m, 3H), 7.53-

7.58 (m, 2H), 7.81 (s, 1H). 13C NMR (CDCl3, 100 MHz): δ 27.72, 35.87, 45.26, 70.76, 72.92, 81.84, 83.04,

387

89.05, 102.67, 117.08, 126.25, 128.39, 129.43, 130.29, 136.43, 136.70, 169.43. IR (NaCl, neat): υ 3393 Br

m, 3119m, 2983m, 2931m, 2872m, 1716m, 1396w, 1369m, 1281m, 1225w, 1150s, 1089s, 1045s, 963s,

934m, 913m, 831w, 760m, 700m. HRMS (Electrospray) Calcd. for (M++Na); 387.1915. Found; (M++Na)

387.1944.

1-286-α

O

OPhO

H2Im

H1ButO2C

H5a

H5e

H7

H4

H3

6

2.6%

2.6%

1.8, 0.8%2.7%

1.4%

1.9, 0.8%

1.5%

1.6, 1.2%

0.5, 0.9%

OOPh O

H NBuO2

tCH

N

nOe (%) nOe (%) nOe (%) nOe (%)

H1→H2 0.9 H2→H4 2.6 H3→H2 0.9 H5a→H5e 15.8

H1→H3 1.4 H2→H6a 1.5 H3→H5a 2.2 H5a→H7 3.8

H1→H6a 1.8 H2→H6b 1.2 H3→H6a 1.6 H5e→H4 6.6

H1→H6e 0.8 H2→ Imd1 1.9 H3→H6b 1.2 H5e→H5a 12.2

H1→ Imd1 0.8 H2→ Imd2 0.8 H3→H7 6.6 H7→H3 5.9

H1→ Imd2 1.5 H3→H1 1.5 H5a→H3 1.1 H7→H5a 2.9

H2→H1 0.8

1-286-β

OOPh O

H H

ImButO2C


1:2). [α]D20

= -129.6 (c 0.46 in CHCl3). Mp: 59-61 oC. 1H NMR (CDCl3, 500 MHz): δ 1.37 (s, 9H), 1.71

(dd, J = 17.9, 11.5 Hz, 1H), 2.64 (dd, J = 17.8, 3.3 Hz, 1H), 3.07 (app tdd, J = 11.3, 7.5, 3.3 Hz, 1H), 3.59

(dd, J = 11.7, 9.0 Hz, 1H), 3.74 (app td, J = 9.1, 4.4 Hz, 1H), 4.03 (app t, J = 10.0 Hz, 1H), 4.62 (dd, J =

9.8, 4.4 Hz, 1H), 5.61 (s, 1H), 6.30 (d, J = 7.5 Hz, 1H), 6.94 (s, 1H), 7.11 (s, 1H), 7.37-7.40 (m, 3H), 7.47-

388


87.14, 102.82, 117.63, 126.25, 128.40, 129.20, 130.14, 136.16, 136.46, 170.92. IR (NaCl, neat): υ 3388 Br

m, 3119m, 2978m, 2931m, 2872m, 1723s, 1494m, 1455m, 1369s, 1247m, 1227m, 1157s, 1080s, 1046s,

971s, 913m, 755s, 699s. HRMS (Electrospray) Calcd. for (M++Na); 387.1915. Found; (M++Na) 387.1902.

Anal. Calcd. for C21H26O5N2; C, 65.27; H, 6.78; N, 7.25. Found; C, 62.68; H, 6.93; N, 5.64.

OOPh O

H HRO2C

N

NO

OPhO

H2H1

ImButO2C

H5a

H5e

H7

H4

H3

6

1.2%3.4%

2.6%

1.9, 1.1%

1.2%3.1%

1.1, 0.6%

1-286-β

nOe (%) nOe (%) nOe (%) nOe (%)

H1→H2 4.3 H2→H4 3.4 H3→H7 6.1 H4→H5e 2.6

H1→H4 1.2 H2→H6a 0.8 H3→ Imd1 1.9 H7→H3 5.7

H1→ Imd1 1.4 H3→H5a 2.6 H3→ Imd2 1.1 H7→H5a 2.5

H1→ Imd2 2.1 H3→H6a 1.1 H4→H1 1.3 H7→Ph 1.6

H2→H1 4.4 H3→H6b 0.7 H4→H2 3.1

The Reaction of (2R, 4S, 5R)-(Z)-3-[(Imidazole-1-carbothioyloxy]-2-phenyl-[1, 3]dioxin-4-yl)-

acrylonitrile





4S, 5R)-(Z)-3-[(Imidazole-1-carbothioyloxy]-2-phenyl-[1, 3]dioxin-4-yl)- acrylonitrile (Z)-1-294 and 14.5

mg (0.088 mmol) of AIBN in 3.6 mL of benzene via a syringe pump during 2 h 20 min, and the mixture

was stirred for another 0.5 h at 90 oC (oil bath temperature). The mixture was cooled to rt, and the solvent

389

was removed in vacuo to give crude product. The concentrated mixture was purified by flash column

chromatography eluting with hexane:EtOAc = 1:1 to 1:2. The cyclized N-pyranoside was obtained as pale

yellow solid (38.5 mg, 81%) with the ratio of α/β = 0.79/1.0).

1-302

OOPh O

H H

ImNC

Pale yellow solid (α/β = 1.0/0.79). Column chromatography; hexane:EtOAc 1:1 to 1:2. Rf = 0.12 (EtOAc

only). Mp: 126-130 oC. 1H NMR (CDCl3, 400 MHz): α-anomer, δ 2.73 (dd, J = 17.5, 4.6 Hz, 1H), 2.88

(dd, J = 17.5, 5.2Hz, 1H), 2.96-3.06 (m, 1H), 3.75-3.81 (m, 1H), 3.95 (app t, J = 9.7 Hz, 1H), 4.01-4.07 (m,

1H), 4.57 (dd, J = 9.6, 4.2 Hz, 1H), 5.63 (s, 1H), 5.82 (d, J = 7.2 Hz, 1H), 7.13 (s, 1H), 7.19 (s, 1H), 7.37-

7.42 (m, 3H), 7.49-7.52 (m, 2H), 7.79 (s, 1H); β-anomer, δ 1.91 (dd, J = 17.2, 9.9 Hz, 1H), 2.51 (dd, J =

17.2, 4.9Hz, 1H), 2.96-3.06 (m, 1H), 3.68 (d, J = 11.2, 9.2 Hz, 1H), 3.75-3.81 (m, 1H), 4.01-4.07 (m, 1H),

4.64 (dd, J = 9.9, 4.3 Hz, 1H), 5.64 (s, 1H), 6.17 (d, J = 7.5 Hz, 1H), 7.06 (s, 1H), 7.20 (s, 1H), 7.37-7.42

(m, 3H), 7.49-7.52 (m, 2H), 7.76 (s, 1H). 13C NMR (CDCl3, 100 MHz): α-anomer, δ 16.15, 44.85, 70.56,

73.43, 81.15, 87.60, 102.75, 116.53, 116.60, 126.22, 128.46, 129.59, 131.13, 136.06, 136.48; β-anomer,

δ 14.57, 69.42, 70.07, 73.08, 81.34, 85.90, 102.84, 115.73, 117.38, 126.18, 128.44, 129.55, 130.49, 136.00,

136.21. IR (NaCl, neat): υ 3115 m, 2971s, 2879s, 2251m, 1698s, 1493s, 1455m, 1421m, 1380s, 1314m,

1285m, 1229s, 1168s, 1142m, 1080s, 1048s, 969s, 912s, 823w, 755s, 732s, 701s, 660s. HRMS

(Electrospray) Calcd. for (M++Na); 334.1162. Found (M++Na); 334.1180. Anal. Calcd. for C17H17O3N3;

C, 65.58; H, 5.50; N, 13.50. Found; C, 64.48; H, 5.99; N, 12.04.

The Reaction of (2R, 4S, 5R)-Imidazole-1-carbothionic acid {O-[4-(methoxyimino)methyl]-2-phenyl-

[1, 3]dioxin-5-yl} ester




390

temperature was adjusted to be 90 oC. To the flask was added a solution of 74 mg (0.232 mmol) of (2R, 4S,

5R)-imidazole-1-carbothionic acid {O-[4-(methoxyimino)methyl]-2-phenyl-[1, 3]dioxin-5-yl} ester 1-295

and 19 mg (0.16 mmol) of AIBN in 5.0 mL of benzene via a syringe pump during 3 h 15 min, and the



column chromatography eluting with hexane:EtOAc = 1:1 to 1:2. The cyclized N-pyranoside 1-303 was

obtained as pale yellow solid (42.2 mg, 63%) with the ratio of α/β = 1.0/0.83) and dethiocarbamated

product (2R, 4S, 5R)-5-H=hydroxy-2-phenyl-[1, 3]dioxane-4-carbaldehyde; O-methyloxime 1-304 (5 mg,

9%).

OOPh O

H

H3COHN Im

H

1-303

α/β = 1.0/0.83

Pale yellow oil (α/β = 1.0/0.83). Column chromatography; hexane:EtOAc = 1:1 to 1:2. Rf = 0.22

(hexane:EtOAc = 1:6). Mp: 96-99 oC. 1H NMR (CDCl3, 400 MHz): α- anomer, δ 3.58 (s, 3H), 3.72-3.81

(m, 1H), 3.91-3.97 (m, 2H), 4.00-4.11 (m, 2H), 4.55 (dd, J = 9.5, 4.2 Hz, 1H), 5.57 (s, 1H), 5.86 (d, J = 5.3

Hz, 1H), 7.14 (s, 2H), 7.36-7.41 (m, 3H), 7.47-7.50 (m, 2H), 7.75 (s, 1H); β- anomer, δ 3.07 (s, 3H), 3.72-

3.81 (m, 1H), 3.91-3.97 (m, 2H), 4.00-4.11 (m, 2H), 4.58 (dd, J = 9.8, 4.0 Hz, 1H), 5.59 (s, 1H), 6.06 (d, J

= 6.8 Hz, 1H), 7.06 (s, 1H), 7.12 (s, 1H), 7.36-7.41 (m, 3H), 7.47-7.50 (m, 2H), 7.68 (s, 1H). 13C NMR

(CDCl3, 100 MHz): α-anomer, δ 61.36, 62.89, 69.00, 70.65, 72.38, 78.92, 87.65, 116.53, 126.24, 129.08,

129.44, 130.41, 136.05, 136.30; β-anomer, δ 53.82, 64.61, 69.41, 70.80, 71.06, 79.44, 85.94, 118.29,

126.25, 129.08, 128.37, 129.45, 136.23, 137.02; IR (NaCl, neat): υ 3112 Br m, 2940s, 2893s, 2802w,

2238w, 1701m, 1495s, 1458m, 1425w, 1379s, 1313m, 1283m, 1226s 1058s, 1078s, 1049s, 1229s, 975s,

911s, 822w, 792w, 733s, 700s, 660s. HRMS (Electrospray) Calcd. for (M++Na); 340.1268. Found

(M++Na); 340.1290. Anal. Calcd. for C16H19O4N3; C, 60.56; H, 6.04; N, 13.24. Found; C, 60.17; H, 6.45;

N, 11.19.

391

The Reaction of (2R, 4S, 5R)-(Z)-Imidazole-1-carbothionic acid {O-[4-(benzyloxyimino)methyl]-2-

phenyl-[1, 3]dioxin-5-yl} ester




temperature was adjusted to be 90 oC. To the flask was added a solution of 131 mg (0.309 mmol) of (2R,

4S, 5R)-(Z)-imidazole-1-carbothionic acid {O-[4-(benzyloxyimino)methyl]-2-phenyl-[1, 3]dioxin-5-yl}

ester (Z)-1-296 and 25 mg (0.155 mmol) of AIBN in 6.6 mL of benzene via a syringe pump during 4 h 30

min, and the mixture was stirred for another 0.5 h at 90 oC (oil bath temperature). The mixture was cooled

to rt, and the solvent was removed in vacuo to give crude product. The concentrated mixture was purified

by flash column chromatography eluting with hexane:EtOAc = 1:1 to 1:2. The cyclized N-pyranoside 1-

305 was obtained as pale yellow solid (19.2 mg, 38%) with the ratio of α/β = 1.1/1.0).

1-305

OOPh O

H H

ImBnOHN

α/β = 1.1/1.0

White solid. Column; hexane:EtOAc = 1:1 to 1:2. Rf = 0.34 (hexane:EtOAc = 1:4). Mp: 96-99 oC. 1H

NMR (CDCl3, 500 MHz): α anomer, δ 3.90 (app t, J = 9.0 Hz, 2H), 3.95-4.00 (m, 3H), 4.52 (dd, J = 9.5,

4.2 Hz, 1H), 4.69 (d, J = 11.9 Hz, 1H), 5.51 (s, 1H), 5.68 (d, J = 5.4 Hz, 1H), 6.00 (Br s, NH, disappeared

with D2O), 7.06 (s, 1H), 7.12 (s, 1H), 7.27-7.40 (m, 7H), 7.48-7.51 (m, 3H), 7.56 (s, 1H); β anomer, δ 3.72

(app t, J = 9.7 Hz, 2H), 3.77 (app td, J = 9.3, 4.3 Hz, 1H), 4.03 (d, J = 11.7 Hz, 1H), 4.10-4.15 (m, 1H0,

4.19 (d, J = 11.3 Hz, 1H), 4.57 (dd, J = 9.7, 4.0 Hz, 1H), 4.73 (dd, J = 12.0 Hz, 1H), 5.56 (s, 1H), 5.59 (Br

s, NH, disappeared with D2O), 6.06 (d, J = 6.9 Hz, 1H), 7.10 (s, 1H), 7.18 (s, 1H), 7.27-7.40 (m, 7H), 7.48-


76.90, 78.80, 79.48, 79.68, 85.95, 87.40, 102.49, 102,72, 116.51, 118.56, 126.20, 127.96, 128.33, 128.47,

392

128.51, 128.59, 128.70, 128.97, 129.06, 129.38, 129.43, 130.28, 136.18, 136.20, 136.32, 136.67, 136.80,

137.19, 137.38, 139.00; Because of the overlap of some aromatic carbons, the number of peaks found is

smaller than expected. IR (KBr): υ 2922w, 2859w, 1640s, 1515m, 1496m, 1478m, 1453m, 1428m, 1384s,

1217m, 1273m, 1225s, 1168m, 1097s, 1082s, 1054s, 1028s, 1009m, 961s, 916m, 824m, 792m, 754s, 726s,

699s, 658s, 632m, 597m. HRMS (Electrospray): m/z Calcd for C22H23N3O4Na (M++Na), 416.1581; Found

(M++Na), 416.1580.

The Reaction of (2R, 4S, 5R)-Imidazole-1-carbothioic acid O-[4-(dimethylhydrazonomethyl)-2-

phenyl-[1,3]dioxan-5-yl] ester

A flame-dried three neck 50 mL flask was connected to a condenser, and the flask was charged with 618

mg of Ph3SnH (1.760 mmol) and 28.0 mL of benzene (dried over CaH2 and stored over 4 Å MS in nitrogen

atmosphere) under nitrogen atmosphere. The flask was immersed into an oil bath and the oil bath

temperature was adjusted to be 90 oC. To the flask was added a solution of 117 mg (0.352 mmol) of

imidazole-1-carbothioic acid (2R, 4S, 5R)-Imidazole-1-carbothioic acid O-[4-(dimethylhydrazonomethyl)-

2-phenyl-[1,3]dioxan-5-yl] ester 1-297 and 29 mg (0.176 mmol) of AIBN in 7.6 mL of benzene via a

syringe pump during 4 h 35 min, and the mixture was stirred for another 0.5 h at 90 oC (oil bath



to only EtOAC. The cyclized N-pyranoside was obtained as pale yellow solid (57.6 mg, 54%) with the

ratio of α/β = 1.0/0.32).

1-306-α

OOPh O

H

(H3C)2NHN

Im

H

Pale yellow solid. Column chromatography; hexane:EtOAc = 1:1 to EtOAc only with 1% of Et3N. Rf =

0.10 (EtOAc only) or 0.67 (EtOAc:MeOH = 9:1). Mp: 120-123 oC 1H NMR (CDCl3, 400 MHz): δ 2.40 (s,

393

6H), 3.80-3.91 (m, 2H) 3.96 (app t, J = 10.1 Hz, 1H), 4.06 (app td, J = 9.7, 4.3 Hz, 1H), 4.56 (dd, J = 9.6,

4.3 Hz, 1H), 5.55 (s, 1H), 5.75 (d, J = 4.9 Hz, 1H), 7.11 (s, 1H), 7.18 (s, 1H), 7.35-7.42 (m, 3H), 7.47-7.50

(m, 2H), 7.75 (s 1H); NH peak is overlapped with 3 Hs between 3.80-4.09. The integration of this region

becomes smaller as much as 0.4 H with D2O. 13C NMR (CDCl3, 100 MHz): δ 48.26, 66.19, 70.80, 72.26,

81.71, 90.66, 102.58, 116.44, 126.22, 128.40, 129.44, 130.00, 136.04, 136.42. IR (NaCl, neat): υ 3209Br s,

3116s, 3039m, 2982s, 2948s, 2880s, 2857s, 2778s, 1698w, 1666w, 1494s, 1454s, 1428m, 1379s, 1313s,

1282s, 1224s, 1165s, 1078s, 1049s, 1027s, 991s, 966s, 912s, 813m, 792m, 761s, 735s, 700s, 660s. HRMS

(Electrospray); Calcd. (M++Na); 353.1584. Found (M++Na); 353.1581. Anal. Calcd. for C17H22O3N4; C,

61.80; H, 6.71; N, 16.96. Found; C, 61.49; H, 6.77; N, 15.99.

The Reaction of (2R, 4S, 5R)-Imidazole-1-carbothioic acid O-[4-(diphenylhydrazonomethyl)-2-

phenyl-[1,3]dioxan-5-yl] ester


with 1.06 g of Ph3SnH (3.02 mmol) and 24.0 mL of benzene (dried over CaH2 and stored over 4 Å MS in


temperature was adjusted to be 90 oC. To the flask was added a solution of 138 mg (0.302 mmol) (2R, 4S,

5R)-imidazole-1-carbothioic acid O-[4-(diphenylhydrazonomethyl)-2-phenyl-[1,3]dioxan-5-yl] ester 1-298




column chromatography eluting with hexane to hexane:EtOAc = 1:2. The cyclized N-pyranoside was

obtained as pale yellow solid (25.7 mg, 20%) 1-307 with 72.4 mg (62%) of 1-308. The isolated N-

pyranoside 1-307 was only α-anomer.

1-307-α

OOPh O

H

Ph2NHN

Im

H

394

Pale yellow oil. Column chromatography; hexane only to hexane:EtOAc = 2:1. Rf = 0.34 (hexane:EtOAc

= 1:2). [α]D20

= -1.9 (c 0.43 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ 3.95 (app t, J = 9.8 Hz, 1H), 3.98

(app t, J = 9.3 Hz, 1H), 4.08 (dd, J = 9.6, 4.2 Hz, 1H), 4.16 (ddd, J = 9.0, 5.4, 1.7 Hz, 1H), 4.53 (s, NH,

disappeared with D2O), 4.55 (dd, J = 9.7, .4.4 Hz, 1H), 5.53 (s, 1H), 5.89 (d, J = 5.4 Hz, 1H), 6.93 (dd, J =

8.5, 0.9 Hz, 4H), 7.00 (s, 1H), 7.05 (app td, J = 7.4, 0.8 Hz, 2H), 7.12 (s, 1H), 7.24-7.28 (m, 4H), 7.38-7.41

(m, 3H), 7.46-7.49 (m, 2H), 7.51 (s, 1H). 13C NMR (CDCl3, 100 MHz): δ 66.35, 69.49, 70.81, 72.35,

82.85, 89.84, 102.65, 116.78, 120.49, 123.57, 126.23 (two peaks), 128.45, 129.48, 129.99, 136.29, 148.05.

IR (NaCl, neat): υ 3059m, 2966m, 2926m, 2359w, 2320w, 1702m, 1666w, 1589s, 1494s, 1461m, 1379m,

1313m, 1266s, 1224m, 1175m, 1078s, 1049s, 1028s, 969m, 910m, 736s, 698s. HRMS (Electrospray);

Calcd. (M++Na): 477.1897, found (M++Na): 477.1877.

1-308

OOPh O

H

Ph2NHN

Pale yellow solid. Column chromatography; hexane only to hexane:EtOAc = 7:1. Rf = 0.53

(hexane:EtOAc = 4:1). Mp: 74-77 oC. [α]D20

= -54.6 (c 0.70 in CHCl3). 1H NMR (CDCl3, 400 MHz):

δ 3.60 (app td, J = 9.6, 4.5 Hz, 1H), 3.78 (app t, J = 9.1 Hz, 1H), 3.92 (app t, J = 9.8 Hz, 1H), 3.95 (app t, J

= 8.0 Hz, 1H), 4.01 (dd, J = 9.0, 6.0 Hz, 1H), 4.16 (dd, J = 8.9, 8.1 Hz, 1H), 4.42 (Br s, NH), 4.51 (dd, J =

9.7, 4.5 Hz, 1H), 5.48 (s, 1H), 7.05 (app td, J = 7.3, 1.1 Hz, 2H), 7.14-7.18 (m, 4H), 7.29-7.34 (m, 4H),

7.36-7.40 (m, 3H), 7.46-7.49 (m, 2H). 13C NMR (CDCl3, 100 MHz): δ 59.09, 71.35, 71.75, 72.42, 84.35,

102.23, 102.57, 122.90, 126.25, 128.30, 129.17, 129.24, 136.96, 148.03. IR (NaCl, neat): υ 3271m, 3061s,

3035s, 2982s, 2880s, 2240w, 1952w, 1703w, 1588s, 1495s, 1455s, 1379s, 1311s, 1271s, 1214m, 1169s,

1079s, 1049s, 1028s, 964s, 911m, 885w, 826w, 751s, 697s. HRMS (Electrospray); Calcd. (M++Na):

411.1679, found (M++Na): 411.1689. Anal. Calcd. for C24H24O3N2; C, 74.21; H, 6.23; N, 7.21. Found; C,

73.38; H, 6.53; N, 8.14.

395

The Reaction of (2R, 4S, 5R)-Imidazole-1-carbothioic acid O-[4-cyanomethyl-2-phenyl-[1,3] dioxan-5-

yl] ester




temperature was adjusted to be 90 oC. To the flask was added a solution of 67 mg (0.233 mmol) (2R, 4S,

5R)-Imidazole-1-carbothioic acid O-[4-(diphenylhydrazonomethyl)-2-phenyl-[1,3]dioxan-5-yl] ester 1-299




column chromatography eluting with hexane:EtOAc = 1:1 to 1:2. The isolated product was only

dethiocarbamated compound 1-309 (24 mg, 50%).

OOPh OH

N1-309


143-144 oC. [α]D20

= +6.8 (c 0.38 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ 2.64 (Br s, 1H), 3.66 (dd, J =

11.4, 10.2 Hz, 1H), 4.12 (app td, J = 9.9, 5.3 Hz, 1H), 4.38 (dd, J = 11.4, 5.3 Hz, 1H), 4.45 (d, J = 9.5 Hz,

1H), 5.46 (s, 1H), 7.37-7.41 (m, 3H), 7.44-7.48 (m, 2H). 13C NMR (CDCl3, 100 MHz): δ 63.47, 70.53,

70.91, 101.54, 116.17, 126.12, 128.42, 129.64, 135.66. Anal. Calcd. for C11H11O3N; C, 64.38; H, 5.40; N,

6.83. Found; C, 63.54; H, 5.60; N, 6.69.

4. 8. Radical Reaction with Tris-trimethyl silane (TTMSH)


phenyl-[1, 3]dioxin-5-yl} ester with Tris-trimethyl silane (TTMSH)

396


with TTMSH (610 mg, 2.456 mmol) and 19.3 mL of benzene (dried over CaH2 and stored over 4 Å MS in


temperature was adjusted to be 90 oC. To the flask was added a solution of (2R, 4S, 5R)-(Z)-imidazole-1-

carbothionic acid {O-[4-(benzyloxyimino)methyl]-2-phenyl-[1, 3]dioxin-5-yl} ester (Z)-1-296 (104 mg,

0.246 mmol) and AIBN (202 mg, 1.446 mmol) in 5.2 mL of benzene via a syringe pump during 3 h 5 min,

and the mixture was stirred for another 0.5 h at 90 oC (oil bath temperature). The mixture was cooled to rt,

and the solvent was removed in vacuo to give crude product. The concentrated mixture was purified by

flash column chromatography eluting with hexane:EtOAc = 40:1 to 20:1. 1,3-Migrated product 1-305 was

obtained as pale yellow quantatively with the ratio of E/Z = 1.1/1.0.

(Z)-1-310

OOPh

NOBn

Pale yellow oil. Column; hexane:EtOAc = 40:1 to 20:1. Rf = 0.24 (hexane:EtOAc = 15:1). 1H NMR

(CDCl3, 400 MHz): δ 2.42-2.44 (m, 1H), 4.21 (dd, J = 11.5, 2.5 Hz, 2H), 4.25 (app t, J = 11.5 Hz, 2H),

5.11 (s, 2H), 5.56 (s, 1H), 7.30-7.40 (m, 8H), 7.46-7.48 (m, 2H), 8.03 (d, J = 7.4 Hz, 1H). 13C NMR

(CDCl3, 100 MHz): δ 35. 46, 69.85, 75.75, 102.03, 126.07, 127.81, 128.14, 128.29, 128.38, 129.06,

137.59, 138.07, 151.26. IR (NaCl, neat): υ 350m, 3034s, 2956s, 2924s, 2857s, 1497m, 1455s, 1379s,

1314w, 1234s, 1213m, 1165s, 1112s, 1082s, 1045s, 1027s, 1010s, 961m, 920m, 839m, 748s, 698s. HRMS

(Electrospray); Calcd. C18H19NO3 (M++Na): 320.1257. Found (M++Na): 320.1248.

syn-1-310

OOPh

NOBn O

OPh

NOCH2Ph

H1 H2a

H3

H4

H2b

4.2%

2.0%2.0%

1.8%

0.5%

0.3%

0.3%

0.9%

397

nOe (%) nOe (%) nOe (%)

H1→H2a 4.2 H2b→H4 0.5 H3→CH2Ph 0.3

H1→ Ph 0.9 H3→H2ab 5.5 H4→H2b 0.9

H2a→H1 2.0 H3→H1 0.3 H4→H3 0.4

H2 a→H3 2.0 H3→H2ab 5.5 CH2Ph→CH2Ph 0.4

H2 b→H3 1.8 H3→H4 0.6 CH2Ph→H4 1.1

anti-1-310

OOPh

NOBn

O

OPh

N

OCH2Ph

H4

H3

H2aH1

H2b

2.6%

2.1%1.8%

1.3%

nOe (%) nOe (%) nOe (%)

H1→H2a 2.6 H2a→H3 1.8 H3→H2b 1.4

H1→Ph 0.7 H2b→H2a 4.5 CH2Ph→CH2Ph 0.6

H2a→H1 2.1 H2b→H3 1.3

H2a→H2b 3.1 H3→H2a 2.9


phenyl-[1, 3]dioxin-5-yl} ester with Tris-trimethyl silane (TTMSH) under a sunlamp

A Pyrex tube was charged with a mixture of (Z)-1-296 (85 mg, 0.20 mmol) and AIBN (66 mg,

0.40 mmol) in benzene (4 mL). The reaction mixture was degassed by nitrogen bubbling for 5 min. To the

tube was added TTMSH ( 225 mg, 0.90 mmol) and the mixture was irradiated with stirring under a

sunlamp for 48 h. After removed the solvent under reduced pressure, the mixture was purified by column

chromatography eluting hexane to hexane:EtOAc = 20:1. The major portion of the isolated product was the

starting material (43.1 mg, syn/anti = 1.0/0.09) and the the minor portion was 1-312 (5.2 mg, 6%).

398

1-312

OOPh O

NH

Im

S

BnO

Pale yellow oil. Column; hexane to hexane:EtOAc = 20:1. Rf = 0.21 (hexane:EtOAc = 20:1). 1H NMR

(CDCl3, 400 MHz): δ 3.78 (app t, J = 10.5 Hz, 1H), 1.45-1.52 (m, 1H), 4.54 (dd, J = 9.6, 6.6 Hz, 1H), 4.59

(dd, J = 10.8, 5.4 Hz, 1H), 5.06 (s, 2H), 5.39 (d, J = 12.1 Hz, 1H), 5.44 (d, J = 12.1 Hz, 1H), 5.57 (s, 1H),

5.58 (app td, J = 9.7, 5.4 Hz, 1H), 7.25-7.32 (m, 3H), 7.35-7.39 (m, 8H), 7.47-7.50 (m, 3H). 13C NMR

(CDCl3, 100 MHz): δ 67.10, 71.20, 75.29, 76.46, 100.40, 126.19, 127.93, 128.19, 128.35, 128.39, 128.54,

128.66, 128.82, 129.35, 134.12, 136.57, 137.13, 145.93.

The Reaction of (2R, 4S, 5R)-Imidazole-1-carbothioic acid O-[4-(diphenylhydrazonomethyl)-2-

phenyl-[1,3]dioxan-5-yl] ester with Tris-trimethyl silane (TTMSH)




temperature was adjusted to be 90 oC. To the flask was added a solution of (2R, 4S, 5R)-imidazole-1-

carbothioic acid O-[4-(diphenylhydrazonomethyl)-2-phenyl-[1,3]dioxan-5-yl] ester 1-298 ( 96 mg, 0.198

mmol) and AIBN (16 mg, 0.099 mmol) in 4.2 mL of benzene via a syringe pump during 2 h 30 min, and

the mixture was stirred for another 0.5 h at 90 oC (oil bath temperature). The mixture was cooled to rt, and

the solvent was removed in vacuo to give crude product. The concentrated mixture was purified by flash

column chromatography eluting with hexane to hexane:EtOAc = 20:1. The 1,3-migrated product 1-313

and dethiocarbamated product 1-314 were isolated as 38% and 18% yield, respectively.

anti-1-313

OOPh

NNPh2

399

Pale yellow oil. Column; hexane to hexane:EtOAc = 20:1. Rf = 0.34 (hexane:EtOAc = 8:1). 1H NMR

(CDCl3, 500 MHz): δ 2.52 (app t, J = 2.6 Hz, 1H), 4.21 (dd, J = 11.6, 1.6 Hz, 2H), 4.31 (d, J = 11.0 Hz,

2H), 7.00 (d, J = 5.9 Hz, 1H), 7.13-7.15 (m, 6H), 7.31-7.39 (m, 9H). 13C NMR (CDCl3, 125 MHz):

δ 37.79, 70.10, 101.88, 122.39, 124.11, 126.13, 128.29, 128.98, 129.72, 138.36, 138.69, 144.07.

Reaction of (6R)-(E)-ethyl 7-{[(1,1-dimethylethyl)diphenylsilyl]oxy}-6-[O-(1-imidazoyl)

thiocarboyloxy]-2-heptenoate with Tris-trimethyl silane (TTMSH)




temperature was adjusted to be 90 oC. To the flask was added a solution of 6R)-(E)-ethyl 7-{[(1,1-

dimethylethyl)diphenylsilyl]oxy}-6-[O-(1-imidazoyl) thiocarboyloxy]-2-heptenoate 1-250 (74.7 mg, 0.139

mmol) and AIBN (12 mg, 0.07 mmol) in 3.0 mL of benzene via a syringe pump during 2 h 15 min, and the



column chromatography eluting with hexane:EtOAc = 40:1 to 12:1. After column chromatography, brown

oil was obtained as 21.4 mg (33%) with a ratio of cis/trans = 0.28/1.0.

O

CO2Et

OTBS

1-315

S


Brown oil. Column; hexane:EtOAc = 40:1 to 12:1. Rf = 0.20 (hexane:EtOAc = 10:1). 1H NMR (CDCl3,

500 MHz): cis (minor), δ 1.07 (s, 9H), 1.27 (t, J = 7.1 Hz, 3H), 1.45-1.52 (m, 1H), 1.81-1.85 (m, 1H), 2.04-

2.09 (m, 2H), 2.84 (dd, J = 16.8, 7.3 Hz, 1H), 2.96-3.01 (m, 1H), 3.22 (dd, J = 16.8, 4.3 Hz, 1H), 3.86 (dd,

J = 11.0, 3.9 Hz, 1H), 3.69-3.76 (m, 1H), 3.90 (dd, J = 11.0, 5.0 Hz, 1H), 4.13-4.23 (m, 2H), 4.52 (app qd,

J = 10.7, 4.6 Hz, 1H), 7.38-7.48 (m, 3H), 7.66-7.70 (m, 2H); trans (major), δ 1.11 (s, 9H), 1.28 (t, J = 7.2

400

Hz, 3H), 1.45-1.52 (m, 1H), 1.81-1.85 (m, 1H), 2.04-2.09 (m, 2H), 2.46 (dd, J = 16.5, 6.7 Hz, 1H), 3.12

(app qd, J = 9.1, 4.7 Hz, 1H), 3.19 (dd, J = 16.4, 6.0 Hz, 1H), 3.82 (dd, J = 11.0, 5.3 Hz, 1H), 3.94 (dd, J =

11.0, 4.8 Hz, 1H), 4.13-4.23 (m, 2H), 4.60 (app qd, J = 9.1, 4.7 Hz, 1H), 7.38-7.48 (m, 3H), 7.66-7.70 (m,

2H). 13C NMR (CDCl3, 125 MHz): cis (minor), δ 14.19, 19.24, 23.39, 26.80, 31.91, 40.86, 45.90, 65.55,

68.19, 84.29, 127.79, 129.86, 132.76, 133.06, 135.67, 171.60, 223.78; trans (major), δ 114.19, 19.24,

23.91, 25.16, 26.80, 40.86, 44.02, 60.70, 65.15, 80.86, 127.79, 129.86, 132.93, 132.97, 135.60, 135.64,

171.68, 223.99. IR (NaCl, neat): υ 2929s, 2858s, 1734s, 1472w, 1428m, 1365w, 1279m, 1254m, 1185m,

1160m, 1133m, 1113s, 1030w, 824w, 742w, 703s. HRMS (Electrospray): m/z Calcd for C26H34O4SSiNa

(M++Na), 493.1839; Found (M++Na), 493.1837.

The Reaction of (2R, 4S, 5R)-(Z)-3-[(Imidazole-1-carbothioyloxy]-2-phenyl-[1, 3]dioxin-4-yl)-acrylic

acid ethyl ester with Tris-trimethyl silane (TTMSH)




temperature was adjusted to be 90 oC. To the flask was added a solution of (2R, 4S, 5R)-(Z)-3-[(imidazole-

1-carbothioyloxy]-2-phenyl-[1, 3]dioxin-4-yl)-acrylic acid ethyl ester (Z)-1-283 (90 mg, 0.232 mmol) and

AIBN (19 mg, 0.116 mmol) in 5.0 mL of benzene via a syringe pump over 3 h 10 min , and the mixture

was stirred for another 0.5 h at 90 oC (oil bath temperature). The mixture was cooled to rt, and the solvent

was removed in vacuo to give crude product. The concentrated mixture was purified by flash column

chromatography eluting with hexane only to hexane:EtOAc = 20:1. The isolated product was obtained as

brown oil (13.9 mg, 32%).

OOPh O

HEtO2C

1-316

S

401

Brown oil. Column; hexane:EtOAc = 20:1. Rf = 0.34 (hexane:EtOAc = 9:1). 1H NMR (CDCl3, 400 MHz):

δ 1.25 (t, J = 7.1 Hz, 3H), 2.83 (dd, J = 16.7, 5.7 Hz, 1H), 3.00 (dd, J = 16.7, 5.8 Hz, 1H), 3.40 (app dt, J =

11.6, 5.7 Hz, 1H), 4.01 (dd, J = 11.7, 9.3 Hz, 1H), 4.10 (app t, J = 10.0 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H),

4.36 (app td, J = 9.9, 4.4 Hz, 1H), 4.67 (dd, J = 9.7, 4.3 Hz, 1H), 5.64 (s, 1H), 7.38-7.40 (m, 3H), 7.47-7.50

(m, 2H). 13C NMR (CDCl3, 100 MHz): δ 14.12, 34.22, 53.97, 610.., 69.51, 77.43, 82.60, 102.96, 126.33,

128.40, 129.50, 136.07, 170.43, 218.50. IR (NaCl, neat): υ 2976w, 2926w, 2286w, 1734w, 1379m, 1294m,

1261m, 1210w, 1194w, 1154m, 1083s, 1017s, 910w, 754w, 699m. HRMS (Electrospray): m/z Calcd for


4. 9. Palladium Catalyzed Silylstannylation

Preparation of Diethyl-2,3-butandienyl malonate

H

EtO2C

EtO2C

To a solution of diethylpropargyl malonate (6.87 mmol) in CH3CN (15 mL) was added

paraformaldehyde (628 mg, 20.91 mmol), CuBr (938 mg, 6.54 mmol), and iPr2NH (1.59 g, 15.68 mL) and

the mixture was heated to reflux for 16 h. The solvent was evaporated on a rotary evaporator and the

residue was directly loaded on a silica gel eluting hexane:EtOAc = 15:1. The desired diethyl-2,3-

butandienyl malonate was isolated as colorless oil. The isolated yield was 28%.

Preparation of Diethyl-2,3-butandienyl malonate

EtO2C

EtO2C

2-40

402

To a solution of diethyl-2,3-butandienyl malonate (404 mg, 1.90 mmol) in THF (5.4 mL) was

added KH (99 mg, 2.47 mmol) portionwise. The mixture was stirred for 30 min at rt and propargyl

bromide (565 mg, 3.80 mmol) was added. The resulting mixture was stirred at rt for 11 h, and the

quenched with saturated NH4Cl solution (3 mL). Normal extractive work-up (extracted with Et2O, washed

with H2O and brine solution, dried over MgSO4, filtered, and concentrated on a rotary evaporator), the

crude mixture was purified by column chromatography eluting hexane:EtOAc = 15:1 to give colorless oil

quantatitatively.

Palladium catalyzed silylstannylation of alleneyne

Phosphine ligand (0.1 equiv) and Pd2(dba)3•CHCl3 (0.05 equiv, 2.6 mg, 0.005 mmol) were

dissolved in C6D6 (1.0 mL) in an NMR tube, and the mixture was standed at rt for 30 min. To the mixture

were added Bu3Sn-SiMe3 (1.1 equiv, 40 mg, 0.11 mmol) and diethyl (2,3-butandienyl-2-

propynyl)propanate (1.0 equiv, 0.10 mmol, 25 mg). The mixture was standed at rt or proper temperature

(60 oC or 80 oC), and the reaction was monitored by 1H NMR spectroscopy. After all starting material

disappeared in 1H NMR spectrua the mixture was concentrated on a rotary evaporator. The residue was

purified by column chromatography eluting hexane with 1% of Et3N.

2-44

SnPh3

SiMe3EtO2C

EtO2C

Colorless oil. Column; hexane with 1% of Et3N. Rf = 0.63 (hexane:EtOAc = 8:1). 1H NMR (CDCl3, 500

MHz): δ 0.13 (s, 9H), 0.79 (t, J = 8.3 Hz, 6H), 0.87 (t, J = 7.3 Hz, 9H), 1.22 (app td, J = 7.2, 3.2 Hz, 6H),

1.27 (sex, J = 7.4 Hz, 6H), 1.39-1.45 (m, 6H), 1.99 (dd, J = 13.2, 6.0 Hz, 1H), 2.80 (dd, J = 13.1, 8.7 Hz,

1H), 2.83 (d, J = 15.7 Hz, 1H), 3.23 (app dt, J = 1.7, 2.0 Hz, 1H), 3.29 (t, J = 7.3, 1.4 Hz, 1H), 4.05-4.11

(m, 1H), 4.14-4.21 (m, 3H), 5.35 (dd, J = 2.1, 1.4 Hz, 1H), 5.67 (t, J = 2.1 Hz, 1H), 5.96 (s, J Sn-H = 61.7

Hz, 1H). 13C NMR (CDCl3, 125 MHz): δ -0.44, 9.85, 13.67, 13.94, 14.02, 27.35, 29.12, 40.88, 45.74,

49.61, 59.29, 61.34, 123.37, 124.68, 153.46, 158.70, 171.44, 171.60. IR (NaCl, neat): υ 2956s, 2926s,

403

2872m, 2854m, 2359w, 1735s, 1616w, 1464m, 1366m, 1267s, 1248s, 1190s, 1152s, 1066s, 1020m, 931m,

856s, 838s, 758m, 690m. HRMS (Electrospray): m/z Calcd for C17H27O4BrSiNa (M++Na), 425.0754;

Found (M++Na), 425.0746.

Bromination of Silylstannanes

To a solution of silylstannylated product 2-42 (52 mg, 0.0727 mmol) in 1.5 mL of CH2Cl2 was

added 1. 24 equiv of NBS (16.2 mg, 0.0901 mmol) at rt, and the mixture was stirred ar rt over night. After

all solvent removed on a rotary evaporator, the residue was purified by column chromatography eluting

hexane with 1% of Et3N.

2-55

Br

SiMe2PhEtO2C

EtO2C


MHz): δ 0.12 (s, 3H), 0.14 (s, 3H), 0.94 (s, 9H), 1.24 (t, J = 7.1 Hz, 6H), 1.91 (dd, J = 13.1, 7.6 Hz, 1H),

2.88 (dd, J = 13.0, 9.4 Hz, 1H), 2.96 (d, J = 15.6 Hz, 1H), 3.02 (dt, J = 15.6, 2.2 Hz, 1H), 3.54 (app t, J =

8.0 Hz, 1H), 4.10-4.21 (m, 4H), 5.39 (d, J = 2.0 Hz, 1H), 5.61 (s, 1H), 6.20 (s, 1H). 13C NMR (CDCl3, 125

MHz): δ -5.09, -4.73, 14.01, 26.94, 42.18, 42.77, 48.49, 59.66, 61.65, 100.57, 125.54, 147.27, 148.63,

170.70, 170.89. IR (NaCl, neat): υ 2985s, 2931s, 2856s, 1756s, 1643w, 1464m, 1390w, 1267s, 1248s,

1195s, 1097m, 1069s, 1017w, 932w, 862w, 825s, 769s. HRMS (Electrospray): m/z Calcd for

C20H33O4BrSiNa (M++Na), 467.1224; Found (M++Na), 467.1248.

2-56

Br

SiMe3EtO2C

EtO2C


MHz): δ 0.15 (s, 9H), 1.23 (t, J = 7.1 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H), 1.90 (dd, J = 13.2, 7.9 Hz, 1H), 2.85

404

(ddd, J = 13.1, 8.6, 1.1 Hz, 1H), 2.98 (d, J = 15.6 Hz, 1H), 3.03 (app dt, J = 15.6, 2.2 Hz, 1H), 3.53 (app t, J

= 8.1 Hz, 1H), 4.11-4.22 (m, 4H), 5.37 (d, J = 2.1 Hz, 1H), 5.52 (app t, J = 1.4 Hz, 1H), 6.17 (s, 1H). 13C

NMR (CDCl3, 125 MHz): δ -0.10, 14.01, 41.87, 42.71, 61.64, 61.65, 100.60, 123.59, 147.21, 151.32,

170.68, 170.87. IR (NaCl, neat): υ 29858s, 2957s, 2894m, 1733s, 1644w, 1447m, 1367m, 1270s, 1248s,

1194s, 1096m, 1069s, 1019m, 929m, 856s, 839s, 758m, 692w. HRMS (Electrospray): m/z Calcd for

C17H27O4BrSiNa (M++Na), 425.0754; Found (M++Na), 425.0746.

Palladium catalyzed carobocyclization of bis(allenes)

Phosphine ligand (C6F3) 3P (0.1 equiv) and Pd2(dba)3•CHCl3 (0.05 equiv, 2.6 mg, 0.005 mmol)

were dissolved in C6D6 (1.0 mL) in an NMR tube, and the mixture was standed at rt for 30 min. To the

mixture were added Ph3Sn-SiMe3 (1.1 equiv, 51 mg, 0.11 mmol) and diethyl (di-2,3-butandienyl) propanate

(1.0 equiv, 0.10 mmol, 26 mg). The mixture was standed at rt or proper temperature (60 oC or 80 oC), and

the reaction was monitored by 1H NMR spectroscopy. After all starting material disappeared in 1H NMR

spectra the mixture was concentrated on a rotary evaporator. The residue was purified by column

chromatography eluting hexane with 1% of Et3N. The major portion and the minor portion were assigned

as 2-58 and 2-59, respectively.

SnPh3

SiMe2tBu

EtO2C

EtO2C

2-58

White solid. Column; hexane with 1% of Et3N. Rf = 0.47 (hexane:EtOAc = 9:1). Mp: 82-84 oC. 1H NMR

(CDCl3, 500 MHz): δ -0.05 (s, 3H), -0.01 (s, 3H), 0.79 (s, 9H), 1.18 (t, J = 7.1 Hz, 3H), 1.20 (t, J = 7.1 Hz,

3H), 2.32 (dd, J = 13.3, 7.9 Hz, 1H), 2.38 (dd, J = 13.1, 2.7 Hz, 1H), 2.40 (dd, J = 13.8, 7.4 Hz, 1H), 2.66

(dd, J = 13.8, 8.0 Hz, 1H), 3.02 (app dt, J = 7.7, 2.3 Hz, 1H), 3.34 (app q, J = 7.8 Hz, JSn-H = 66.8 Hz, 1H),

4.07-4.17 (m, 4H), 5.41 (d, J = 1.5 Hz, 1H), 5.45 (s, JSn-H = 81.0 Hz, 1H), 5.65 (s, 1H), 6.03 (s, JSn-H =

179.0 Hz, 1H), 7.33-7.37 (m, 9H), 7.49-7.59 (m, 6H). 13C NMR (CDCl3, 125 MHz): δ -6.03, -5.77, 13.97,

17.19, 26.71, 39.10, 41.14, 47.24, 49.78, 58.81, 61.29, 61.47, 128.17, 128.21, 128.86, 130.69, 137.23,

405

139.15, 148.17, 154.04, 171.39, 172.46. IR (NaCl, neat): υ 3064w , 2954s, 2929s, 2864s, 1731s, 1480m,

1463m, 1444m, 1429s, 1388w, 1366w, 1298m, 1253s, 1184s, 1095m, 1074m, 1053w, 1022w, 930w, 824s,

770m, 729s, 699s. HRMS (Electrospray): m/z Calcd for C29H50O4SiSnNa (M++Na), 753.2396; Found

(M++Na), 753.2356.

SnPh3

HEtO2C

EtO2C

2-59



MHz): major δ 1.22 (t, J = 7.1 Hz, 6H), 2.11 (dd, J = 14.1, 3.5 Hz, 1H), 2.38-2.47 (m, 3H), 2.66-2.69 (m,

1H), 3.14-3.16 (m, 1H), 4.15 (qd, J = 7.1, 1.9 Hz, 4H), 4.63 (app dt, J = 17.0, 1.2 Hz, 1H), 4.80 (dd, J =

10.4, 1.0 Hz, 1H), 5.51 (s, 1H), 5.58 (ddd, J = 17.0, 10.3, 8.8 Hz, 1H), 6.01(s, JSn-H = 175.8 Hz, 1H), 7.34-

7.38 (m, 8H), 7.46-7.56 (m, 7H); minor δ 1.19 (t, J = 7.2 Hz, 3H), 1.90 (dd, J = 13.2, 9.8 Hz, 1H), 1.92 (t, J

= 7.2 Hz, 3H), 2.01 (dd, J = 13.4, 12.2 Hz, 1H), 2.38-2.47 (m, 2H), 2.55 (dd, J = 13.4, 7.0 Hz, 1H), 2.66-

2.69 (m, 1H), 4.11-4.28 (m, 8H), 4.77-4.81 (m, 1H), 4.92 (dd, J = 10.4, 1.5 Hz, 1H), 5.43 (d, J = 1.7 Hz,

1H), 5.54-5.62 (m, 1H), 6.05 (s, 1H), 7.34-7.38 (m, 8H), 7.46-7.56 (m, 7H). 13C NMR (CDCl3, 125 MHz):

major δ 14.00, 36.88, 39.15, 45.94, 51.44, 58.36, 61.43, 61.50, 115.76, 128.47, 128.67, 128.96, 137.17,

138.54, 138.80, 151.14, 172.19, 172.61; minor δ 13.91, 39.52, 41.84, 49.06, 56.89, 57.99, 61.25, 115.62

[some peaks are overlap with the major compound], 137.16, 138.62, 139.34, 152.09, 171.67, 172.50. IR

(NaCl, neat): υ 3064w , 2979m, 1730s, 1480w, 1429m, 1366w, 1256s, 1180w, 1097m, 1074m, 997w, 920w,

860w, 729s, 699s. HRMS (Electrospray): m/z Calcd for C33H36O4SiSnNa (M++Na), 639.1528; Found

(M++Na), 639.1570.

The trans configuration of the 2-58 was further transferred to 2-58’by brominzation with NBS.

406

+ NBSCH2Cl2

rtSnPh3

SiMe2tBu

EtO2C

EtO2C

2-58

Br

SiMe2tBu

EtO2C

EtO2C

2-58'

1H NMR (CDCl3, 500 MHz): δ 0.08 (s, 3H), -0.01 (s, 3H), 0.13 (s, 3H), 0.85 (s, 9H), 1.24 (t, J = 7.2 Hz,

3H), 1.25 (t, J = 7.2 Hz, 3H), 2.30 (dd, J = 13.2, 5.9 Hz, 1H), 2.56 (dd, J = 14.7, 5.4 Hz, 1H), 2.58 (app t,

J = 12.8 Hz, 1H), 2.69 (dd, J = 14.6, 8.4 Hz, 1H), 3.01 (app dt, J = 12.6, 6.1 Hz, 1H), 3.21 (app dt, J = 8.4,

5.7 Hz, 1H), 3.21 (app dt, J = 8.4, 5.7 Hz, 1H), 4.13-4.25 (m, 4H), 5.47 (d, J = 2.1 Hz, 1H), 5.52 (s, J = 1.7

Hz, 1H), 5.60 (d, J = 1.9 Hz, 1H), 5.87 (s, 1H).

Palladium catalyzed silylstannylation of 1, 6-diynes

Phosphine ligand (0.1 equiv) and Pd2(dba)3•CHCl3 (0.05 equiv, 2.6 mg, 0.005 mmol) were

dissolved in C6D6 (1.0 mL) in an NMR tube, and the mixture was standed at rt for 30 min. To the mixture

were added Ph3Sn-SiMe3 (1.1 equiv, 51 mg, 0.11 mmol) and dimethyl dipropargylmalonate (1.0 equiv, 0.10

mmol, 21 mg). The mixture was standed at rt or proper temperature (60 oC or 80 oC), and the reaction was

monitored by 1H NMR spectroscopy. After all starting material disappeared in 1H NMR spectra the

mixture was concentrated on a rotary evaporator. The residue was purified by column chromatography

eluting hexane:EtOAc = 20:1

MeO2C

MeO2C

SiMe2Ph

SnBu3

2-62


MHz): δ 0.35 (s, 6H), 0.82-0.86 (m, 6H), 0.88 (t, J = 7.3 Hz, 9H), 1.27 (sex, J = 7.3 Hz, 6H), 1.37-1.42 (m,

6H), 2.97 (Br s, 4H), 3.70 (s, 6H), 5.45 (s, 1H), 5.70 (t, J = 1.5 Hz, JSn-H = 50.0 Hz, 1H), 7.31-7.33 (m, 3H),

7.47-7.50 (m, 2H). 13C NMR (CDCl3, 100 MHz): δ -0.66, 10.68, 13.66, 27.31, 28.96, 43.89, 44.26, 52.78,

54.98, 123.23, 127.08, 128.69, 133.66, 140.05, 155.13, 157.76, 172.07. IR (NaCl, neat): υ 254s, 2923s,

407

2849m, 1738s, 1600w, 1458w, 1434m, 1376w, 1248s, 1196m, 1167m, 1111w, 1061w, 850m, 825m. HRMS

(Electrospray): m/z Calcd for C31H50O4SiSnNa (M++Na), 657.2393; Found (M++Na), 657.2390.

TsNSiMe2

tBu

SnPh3

2-69

1H NMR (CDCl3, 500 MHz): δ 0.62 (s, 9H), 2.48 (s, 3H), 3.91 (s, 2H), 4.10 (s, 2H), 5.26 (s, 2H), 6.30 (s,

JSn-H = 59.1 Hz, 1H), 7.34-7.36 (m, 2H), 7.39-7.43 (m, 3H), 7.79 (d, J = 8.2 Hz, 2H).

Destannylation of Csp2-stannanes

To the solution of silylstannylated 1,4-diene (1.0 equiv, 0.126 mmol) in CH2Cl2 (1 mL) was added

formic acid (5.0 equiv, 0.623 mmol). The mixture was stirred at rt until all 1,4-diene were consumed based

on judging TLC analysis. After removed solvent on a rotary evaporator under reduced pressure, the residue

was purified by column chromatography eluting hexane:EtOAc = 15:1.

SiMe3EtO2C

EtO2C

2-67

1H NMR (CDCl3, 500 MHz): δ 0.14 (s, 9H), 3.05 (s, 2H), 3.08 (d, J = 1.8 Hz, 2H), 3.73 (s, 6H), 5.30 (app t,

J = 2.1 Hz, 1H), 5.52 (s, 1H), 5.71 (s, 1H).

SiMe2PhEtO2C

EtO2C

2-68


MHz): δ 0.37 (s, 6H), 3.02 (s, 2H), 3.15 (d, J = 1.8 Hz, 2H), 4.92 (app t, J = 1.8 Hz, 1H), 5.11 (app t, J =

2.2 Hz, 1H), 5.69 (app t, J = 1.8 Hz, 1H), 7.31-7.33 (m, 3H), 7.49-7.53 (m, 2H). 13C NMR (CDCl3, 125

MHz): δ -1.51, 42.00, 45.47, 52.80, 57.00, 112.04, 121.41, 127.77, 128.81, 133.69, 139.04, 144.43, 154.81,

171.75. IR (NaCl, neat): υ 2953m, 1737s, 1591w, 1428m, 1288m, 1251s, 1201m, 1158m, 1067m, 893w,

408

846m, 732m, 701m. HRMS (Electrospray): m/z Calcd for C19H24O4SiNa (M++Na), 367.1336; Found

(M++Na), 367.1346.

SiEt3EtO2C

EtO2C

2-69


MHz): δ 0.65 (q, J = 7.8 Hz, 6H), 0.91(t, J = 7.9 Hz, 9H), 3.05 (s, 2H), 3.09 (s, 2H), 3.72 (s, 6H), 5.01 (s,

1H), 5.33 (s, 1H), 5.43 (s, 1H). 13C NMR (CDCl3, 125 MHz): δ 4.20, 7.55, 41.92, 45.54, 52.69, 52.76,

57.00, 109.90, 120.61, 145.37, 154.14, 171.80. IR (NaCl, neat): υ 2953m, 2875m, 1739s, 1434w, 1288w,

1254m, 1201w, 1158w, 1067w, 1016w, 890w, 831w, 735m. HRMS (Electrospray): m/z Calcd for

C17H28O4SiNa (M++Na), 347.1649; Found (M++Na), 347.1673.

SiMe2tBu

EtO2C

EtO2C

2-70


MHz): δ 0.10 (s, 6H), 0.89 (s, 9H), 3.03 (s, 2H), 3.09 (d, J = 1.9 Hz, 2H), 3.72 (s, 6H), 5.03 (s, 1H), 5.33

(app t, J = 1.9 Hz, 1H), 5.53 (s, 1H). 13C NMR (CDCl3, 125 MHz): δ -5.14, 17.13, 26.32, 42.07, 45.48,

52.75, 56.85, 110.78, 121.14, 144.92, 154.06, 171.79. IR (NaCl, neat): υ 2953s, 2928m, 2884m, 2856s,

1734s, 1598s, 1463m, 1435m, 1362w, 1287s, 1252s, 1201s, 1159s, 1066m, 892m, 829s. HRMS

(Electrospray): m/z Calcd for C17H28O4SiNa (M++Na), 347.1649; Found (M++Na), 347.1649.

SiiPrEtO2C

EtO2C

2-71


MHz): δ 1.07 (d, J = 7.2 Hz, 18H),.1.17 (hept, J = 7.3 Hz, 3H), 3.06 (d, J = 2.1 Hz, 2H), 3.12 (d, J = 1.5

409

Hz, 2H), 3.72 (s, 6H), 4.96 (s, 1H), 5.38 (s, 1H), 5.44 (s, 1H). 13C NMR (CDCl3, 125 MHz): δ 12.59,

19.00, 41.98, 46.26, 52.75, 56.85, 109.35, 119.17, 145.38, 154.49, 171.82. IR (NaCl, neat): υ 2949m,

2865m, 1740s, 1462w, 1286w, 1255m, 1201w, 1158w, 1071w, 883w. HRMS (Electrospray): m/z Calcd for


TsNSiMe3

2-75

1H NMR (CDCl3, 500 MHz): δ 0.11 (s, 9H), 2.42 (s, 3H), 3.93 (d, J = 1.9 Hz, 2H), 3.97 (app t, J = 2.1 Hz,

2H), 5.07 (s, 1H), 5.32 (app t, J = 2.2 Hz, 1H), 5.50 (s, 1H), 7.32 (d, J = 8.3 Hz, 2H), 7.70 (d, J = 8.2 Hz,

2H). 13C NMR (CDCl3, 125 MHz): δ -0.84, 21.52, 54.04, 56.44, 110.64, 124.61, 127.96, 129.68, 132.75,

141.55, 143.72, 148.70.

4. 10. Diels-Alder Reaction of Vinyl silanes

To a 3 mL ample were added vinyl silane 2-67 (59.5 mg, 0.211 mmol), ethyl acrylate (63.2 mg,

0.632 mmol) and catalytic amount of benzoquinone in toluene (2 mL). The ample was sealed tightly by

flame and immersed into an 150 mL one-necked flask filled with xylene (or toluene or xylene). After

assembled with a condenser, the flask was heated in an oil-bath for 48 h. The reaction mixture was

concentrated on a rotary evaporator under reduced pressure to give crude mixture, which was subjected to

column chromatography hexane:EtOAc = 12:1.

Me3Si

EtO2C

EtO2C

2-89

Me3Si

EtO2C

EtO2C

2-90

OEt

O

OEt

O

Colorless oil. Column chromatography; hexane:EtOAc = 12:1. Rf = 0.31 (hexane:EtOAc = 8:1). The

isolated compound was 2-89/2-90 mixture with a ratio of 0.75/0.25. 1H NMR (CDCl3, 500 MHz): δ 0.18

(s, 0.25 X 9H), 0.33 (s, 075 X 9H), 1.21 (t, J = 7.1 Hz, 3H), 1.77-1.82 (m, 0.25H), 1.86 (dd, J = 13.1, 6.6

410

Hz, 0.25H), 1.88 (dd, J = 13.1, 6.6 Hz, 0.75H), 1.95 (dd, J = 13.2, 3.4 Hz, 0.25H), 1.96 (dd, J = 13.2, 3.4

Hz, 0.75H), 2.06 (Br s, 0.25H), 2.14-2.24 (m, 1.75H), 2.52-2.58 (m, 0.75H), 2.63 (dt, J = 6.6, 4.4 Hz,

0.25H), 2.78-3.04 (m, 4H), 3.70 (s, 0.25 X 3H), 3.70 (s, 0.25 X 3H), 3.71 (s, 0.75 X 3H), 3.71 (s, 0.25 X

3H), 4.11 (q, J = 7.2 Hz, 2H). 13C NMR (CDCl3, 100 MHz): major δ -1.31, 14.17, 25.84, 27.51, 27.53,

38.45, 43.50, 44.12, 52.64, 52.69, 57.96, 60.25, 127.56, 132.90, 172.65, 172.85, 175.47; minor δ -1.50,

23.07, 24.71, 28.26, 40.75, 43.63, 44.28, 52.68, 52.73, 57.89, 60.35, 128.32, 131.51, 172.58, 172.94,

175.77. IR (NaCl, neat): υ 2954s, 2903s, 2848m, 1736s, 1435s, 1272m, 1252s, 1198s, 1167s, 1116m,

1074s, 1049s, 1031s, 998m, 962m, 838s, 756m, 690m. HRMS (Electrospray): Calcd. for C19H30O6SiNa

(M++Na), 405.1704; Found (M++Na), 405.1684.

SiMe3

MeO2C

MeO2CH

H

H H

Me3Si

MeO2C

MeO2C

2-89

12

34

OEt

O

OEt

O

H

H

3.4%

2.6%

1.9%

2.7%

1.5%


H1 → SiMe3 1.5 H1 → H6b 1.4 H2b → H3 1.5 SiMe3 → H1 0.5

H1 → H2a 2.2 H2a → SiMe3 3.4 H2b → H4b 1.6 SiMe3 → H2a 0.5

H1 → H2b 1.9 H2a → H1 2.7 H3 → H2a 1.5 SiMe3 → H3 0.5

H1 → H3 0.4 H2a → H3 2.6 H3 → H4a 1.9 SiMe3 → H6a 0.5

H1 → H5b 0.5 H2b → H1 2.0 H3 → H4b 0.5

411

Me3Si

EtO2C

EtO2C

2-90

OEt

O Me3Si

EtO2C

EtO2C

OEt

OH1

H2

H3aH4a H4b

H3b

2.9%

2.0%

H6b

H5b

2.5%

1.8%


H1 → H2 2.9 H1→ H5b 1.8 H2 → H3a 0.4 H4b→ H1 0.5

H1 → H3a 0.4 H1 → H6b 2.5 H2 → H3b 0.8

H1 → H3b 2.0 H2 → H1 1.3 H4a → H4b 3.8

Me3Si

EtO2C

EtO2C

2-95

Me3Si

EtO2C

EtO2C

2-96

OMe

O

OMe

O



(s, 0.21 X 9H), 0.04 (s, 0.79 X 9H), 1.60 (Br s, 0.79H), 1.65 (Br s, 0.21H), 1.86 (dd, J = 10.7, 6.1 Hz,

0.21H), 1.89 (dd, J = 10.7, 6.5 Hz, 0.79H), 1.97 (app dt, J = 13.2, 4.0 Hz, 1H), 2.03-2.09 (m, 0.21H), 2.11-

2.26 (m, 1.79H), 2.54-2.62 (m, 0.79H), 2.67(app dt, J = 6.4, 4.1 Hz, 0.21H), 2.79-2.90 (m, 1.21H), 2.95-

3.02 (m, 1.79H), 3.64 (s, 0.21 X 3H), 3.68 (s, 0.21 X 6H), 3.71 (s, 0.79 X 3H), 3.72 (s, 0.79 X 6H). 13C

NMR (CDCl3, 100 MHz): major δ -1.28, 25.88, 27.50, 27.55, 38.34, 43.47, 44.12, 52.72, 52.74, 57.95,

127.48, 132.92, 172.67, 172.87, 175.98; minor δ -1.50, 23.05, 24.61, 28.11, 40.59, 43.62, 44.23, 52.68,

52.70, 57.83, 128.38, 131.38, 170.60, 172.96, 176.27. IR (NaCl, neat): υ 2953s, 2844m, 1736s, 1435s,

1252s, 1199s, 1167s, 1073m, 1019w, 837s. HRMS (Electrospray): Calcd. for C18H28O6SiNa (M++Na),

391.1547; Found (M++Na), 391.1543.

412

Me3Si

EtO2C

EtO2C

2-97

Me3Si

EtO2C

EtO2C

2-98

OtBu

O

OtBu

O


isolated compound was 2-97/2-98 mixture with a ratio of 0.60/0.28/0.12. 1H NMR (CDCl3, 400 MHz):

δ 0.01 (s, 040 X 9H), 0.03 (s, 060 X 9H), 1.41 (s, 0.12 X 9H), 1.42 (s, 0.60 X 9H), 1.44 (s, 0.12 X 9H),

1.53-1.52 (m, 1H), 1.74-1.98 (m, 2H), 1.98-2.21 (m, 2H), 2.28 (app dtd, J = 11.8, 5.3, 2.7 Hz, 0.12H), 2.47

(app dtd, J = 9.9, 6.3, 3.4 Hz, 0.6H), 2.56 (app dt, J = 6.6, 4.2 Hz, 0.28H), 2.79-3.06 (m, 4H), 3.70 (s, 0.28

X 6H), 3.71 (s, 0.12 X 6H), 3.72 (s, 0.60 X 6H). 13C NMR (CDCl3, 100 MHz): 1st major δ -1.32, 25.85,

27.56, 27.70, 28.04, 41.62, 43.70, 44.41, 52.67, 57.90, 128.17, 131.79, 172.66, 173.01, 175.10; 2nd major

δ -1.41, 23.14, 24.95, 27.99, 28.04, 41.62, 43.70, 44.41, 52.67, 57.90, 128.17, 13.79, 172.66, 173.01,

175.10. IR (NaCl, neat): υ 2953s, 2846m, 1736s, 1435s, 1392m, 1367s, 1251s, 1198s, 1152s, 1074m,

999w, 968m, 838s, 756w, 690w. HRMS (Electrospray): Calcd. for C21H34O6SiNa (M++Na), 433.2071;

Found (M++Na), 433.1987.

Me3Si

EtO2C

EtO2C

2-99

Me3Si

EtO2C

EtO2C

2-100

CH3

O

CH3

O


isolated compound was 2-99/2-100 mixture with a ratio of 0.80/0.20. 1H NMR (CDCl3, 500 MHz): δ -0.01

(s, 0.2 X 9H), 0.05 (s, 0.8 X 9H), 1.60 (Br s, 0.8H), 1.73-1.83 (m, 1.2H), 1.95 (d, J = 12.9 Hz, 1H), 2.07-

2.19 (m, 2H), 2.14 (s, 0.2 X 3H), 2.15 (s, 0.8 X 3H), 2.56-2.62 (m, 0.8H), 2.65 (dd, J = 9.6, 4.9 Hz, 0.2H),

2.80 (dd, J = 16.1 Hz, 0.8H), 2.89 (d, J = 15.4 Hz, 1.4H), 2.99 (app t, J = 17.0 Hz, 1.8H), 3.71 (s, 0.2 X

6H), 3.72 (s, 0.8 X 6H). 13C NMR (CDCl3, 125 MHz): major δ -1.96, 26.10, 27.07, 27.80, 43.49, 44.08,

46.30, 52.73, 52.75, 57.96, 127.56, 133.07, 172.63, 172.85, 201.94; minor δ -1.37, 23.16, 24.27, 26.96,

413

28.00, 43.54, 44.34, 48.58, 52.68, 52.73, 57.87, 128.30, 131.66, 172.57, 172.92, 210.71. IR (NaCl, neat):

υ 2958s, 2849m, 1736s, 1713s, 1434m, 1358m, 1252s, 1199m, 1073m, 839s. HRMS (Electrospray): Calcd.

for C18H28O5SiNa (M++Na), 375.1598; Found (M++Na), 375.1568.

Me3Si

EtO2C

EtO2C

2-101

Me3Si

EtO2C

EtO2C

2-102

H

O

H

O

Pale yellow oil. Column chromatography; hexane:EtOAc = 10:1. Rf = 0.29 (hexane:EtOAc = 6:1). The


δ 0.38 (s, 9H), 1.58 (Br s, 1H), 1.68-1.97 (m, 2H), 2.00-2.23 (m, 1H), 2.49-2.52 (m, 1H), 2.77-3.06 (m,

4H), 3.71 (s, 6H), 9.51 (s, 0.20H), 9.60 (s, 0.75H), 9.74 (s, 0.05H). 13C NMR (CDCl3, 125 MHz): 1st major

δ -1.61, 24.67 (3 carbon peaks), 43.55, 44.09, 45.15, 52.73, 52.76, 57.89, 127.37, 133.75, 172.58, 204.12;

2nd major δ -1.22, 21.14, 22.00, 26.26, 43.55, 44.35, 46.93, 52.71, 52.73, 57.82, 129.38, 131.29, 172.47,

172.82, 205.82. IR (NaCl, neat): υ 3474Br s, 2953s, 2847m, 2723w, 1736s, 1435s, 1252s, 1120s, 1168s,

1074s, 964w, 839s, 757w, 734m, 691m. HRMS (Electrospray): Calcd. for C17H26O5SiNa (M++Na),

361.1442; Found (M++Na), 361.1448.

Me3Si

EtO2C

EtO2C

2-103

Me3Si

EtO2C

EtO2C

2-104

CN

CN



δ 0.02 (s, 0.37 X 9H), 0.05 (s, 0.32 X 9H), 0.08 (s, 0.31 X 9H), 1.51-1.63 (m, 1H), 1.76-1.81 (m,1H), 1.95-

2.06 (m, 1H), 2.16-2.36 (m, 2H), 2.64-2.85 (m, 1H), 2.88-3.15 (m, 4H), 3.67-3.73 (m, 6H). 13C NMR

(CDCl3, 125 MHz): (three isomers) δ -2.30, -1.85, -1.32, 22.01, 23.88, 23.91, 24.51, 25.50, 25.76, 26.56,

27.86, 28.49, 28.96, 29.01, 30.79, 43.31, 43.41, 43.45, 43.79, 43.92, 44.07, 52.81 (three carbon peaks),

414

52.87 (three carbon peaks), 57.59, 57.72, 57.77, 122.07, 122.71, 122.72, 126.08, 127.32, 128.82, 129.82,

132.99, 133.50, 172.24, 172.46, 172.49, 172.75, 172.78. IR (NaCl, neat): υ 2952s, 2844m, 2237w, 1733s,

1731s, 1434s, 153s, 1200s, 1163s, 1074s, 962w, 840s, 755w, 691w. HRMS (Electrospray): Calcd. for

C17H25O4NSiNa (M++Na), 358.1445; Found (M++Na), 358.1443.

Me3Si

EtO2C

EtO2C

2-105

Me3Si

EtO2C

EtO2C

2-106

Ph

Ph


isolated compound was 2-105/2-106 mixture with a ratio of 0.20/0.63/0.10/0.07. 1H NMR (CDCl3, 400

MHz): δ -0.31 (s, 0.07 X 9H), -0.04 (s, 0.10 X 9H), 0.00 (s, 0.63 X 9H), 0.03 (s, 0.20 X 9H), 1.18-1.19 (m,

0.5H), 1.43-1.58 (m, 1.5H), 1.59-1.71 (m, 1H), 1.77-1.93 (m, 1H), 1.93-2.23 (m, 1H), 2.78-2.96 (m, 2H),

2.99-3.13 (m, 2H), 3.68 (s, 0.10 X 6H), 3.70 (s, 0.63 X 6H), 3.71 (s, 0.07 X 6H), 3.72 (s, 0.20 X 6H), 7.07-

7.26 (m, 5H). 13C NMR (CDCl3, 100 MHz): δ -0.96, 21.96, 29.29, 32.50, 39.78, 43.70, 44.53, 52.69,

52.72, 58.06, 125.69, 127.20, 128.14, 128.31, 129.71, 132.09, 172.94, 172.95. IR (NaCl, neat): υ 2952m,

2896w, 2837w, 1737s, 1493w, 1449w, 1434m, 1251s, 1198m, 1163m, 1073m, 838s, 758m, 700s. HRMS

(Electrospray): Calcd. for C22H30O4SiNa (M++Na), 409.1806; Found (M++Na), 409.1800.

Me3Si

EtO2C

EtO2C

2-107

OMe

OMe

O

O

Colorless oil. Column chromatography; hexane:EtOAc = 10:1. Rf = 0.32 (hexane:EtOAc = 3:1). 1H NMR

(CDCl3, 500 MHz): δ 0.79 (s, 9H), 2.15 (Br s, 1H), 2.26 (dd, J = 17.7, 4.0 Hz, 1H), 2.41-2.48 (m, 1H), 2.66

(ddd, J = 10.4, 6.4, 3.6 Hz, 1H), 2.80 (dd, J = 15.4, 1.8 Hz, 1H), 2.86 (d, J = 15.4 Hz, 1H), 2.96 (d, J = 15.7

Hz, 1H), 2.99 (d, J = 15.2 Hz, 1H), 3.32 (dd, J = 3.4, 1.2 Hz, 1H), 3.60 (s, 3H0, 3.70 (s, 6H), 3.71 (s, 3H).

13C NMR (CDCl3, 125 MHz): δ -1.28, 24.60, 29.69, 39.56, 41.87, 43.17, 43.90, 51.87, 51.83, 52.73, 52.75,

415

58.21, 127.73, 131.40, 172.30, 172.76, 173.95, 173.97. IR (NaCl, neat): υ 3002m, 2953m, 1738s, 1835s,

1435s, 1255s, 1201s, 1182s, 1111m, 1073m, 1020m, 880m, 839s. HRMS (Electrospray): Calcd. for


Me3Si

MeO2C

MeO2C OMe

OMe

O

O

H

H

0.8%

0.9%

H H

H

5.5%1.9%

Me3Si

EtO2C

EtO2C

2-107

OMe

OMe

O

O


SiMe3 → H2 0.8 H2 → H1 2.6 H4a → H6a 11.7

SiMe3 → H3 0.9 H2 → H3 3.4 H4b→ C3CO2Me 1.9

SiMe3 → H5a 0.6 H3 → SiMe3 3.8 H4b→ H4a 11.7

SiMe3 → H5b 0.9 H3 → H2 3.5 H5b→ H1 2.7

H1 → H2 3.4 H3 → H4a 3.4 H5b→ H6b 2.9

H1 → H5b 3.0 H4a → H3 5.5 H6a → SiMe3 2.2

H1 → H6b 3.5 H4a → H4b 14.7 H6b→ H1 0.5

H2 → SiMe3 3.8 H4a →H5a 1.8 H6b→ H5b 11.4

Me3Si

EtO2C

EtO2C

2-108

OMe

OMe

O

O

416

Pale yellow oil. Column chromatography; hexane:EtOAc = 15:1. Rf = 0.16 (hexane:EtOAc = 5:1). 1H

NMR (CDCl3, 500 MHz): δ 0.02 (s, 9H), 2.13 (m 1H), 2.17 (s, 1H), 2.24-2.31 (m, 1H), 2.54 (app td, J =

11.0, 4.7 Hz, 1H), 2.75 (dd, J = 11.0, 9.5 Hz, 3H), 2.85 (d, J = 17.3 Hz, 1H), 2.91 (d, J = 16.5 Hz, 1H), 2.99

(d, J = 16.5 Hz, 1H), 3.08 (d, J = 17.3 Hz, 1H), 3.64 (s, 3H), 3.66 (s, 3H), 3.73 (s, 3H). 13C NMR (CDCl3,

125 MHz): δ -1.98, 27.50, 28.47, 43.55, 43.92, 44.14, 45.11, 51.89, 51.95, 52.78, 52.84, 57.98, 127.39,

131.52, 172.54, 172.63, 175.02, 175.27. IR (NaCl, neat): υ 2952m, 2860w, 1737s, 1435m, 1348m, 1255s,

1199s, 1170m, 1117w, 1073m, 841s. HRMS (Electrospray): Calcd. for C20H30O8SiNa (M++Na), 449.1602;

Found (M++Na), 449.1635.

Me3Si

EtO2C

EtO2C

2-109

OEt

OEt

O

O


(CDCl3, 400 MHz): δ 0.02 (s, 9H), 1.23 (t, J = 7.1 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H), 2.11-2.28 (m, 3H),

2.51 (app td, J = 10.8, 5.1 Hz, 1H), 2.75 (dd, J = 11.0, 9.3 Hz, 1H), 2.87 (d, J = 16.9 Hz, 1H), 2.91 (d, J =

15.0 Hz, 1H), 2.99 (d, J = 16.5 Hz, 1H), 3.07 (d, J = 16.4 Hz, 1H), 3.72 (s, 3H), 3.73 (s, 3H), 4.00-4.23 (m,

4H). 13C NMR (CDCl3, 100 MHz): δ -1.88, 13.98, 14.10, 27.74, 28.41, 43.56, 43.94, 44.31, 44.91, 52.76,

52.82, 58.01, 60.67, 60.86, 127.37, 131.66, 172.49, 172.65, 174.62, 174.85. IR (NaCl, neat): υ 2954s,

2908m, 2849m, 1738s, 1735s, 1436m, 1370m, 1340m, 1254s, 1178s, 1114m, 1073m, 1035m, 841s. HRMS


Me3Si

MeO2C

MeO2CCH3

CO2Et

2-110


(CDCl3, 500 MHz): δ 0.02 (s, 9H), 1.21 (s, 3H), 1.55-1.64 (m, 2H), 1.22 (app t, J = 13.6 Hz, 1H), 1.55-1.64

417

(m, 1H), 1.77 (app dt, J = 16.5, 1.6 Hz, 1H), 2.14 (ddd, J = 13.4, 6.1, 2.4 Hz, 3H), 2.49 (d, J = 16.6 Hz,

1H), 2.77-2.85 (m, 2H), 2.91-2.96 (m, 2H), 3.60 (s, 3H), 3.70 (s, 3H), 3.72 (s, 3H). 13C NMR (CDCl3, 125

MHz): δ -2.35, 24.43, 26.94, 34.92, 35.31, 42.51, 42.63, 51.70, 52.66, 52.67, 58.30, 129.65, 132.28,

172.57, 172.94, 177.15. IR (NaCl, neat): υ 2952m, 2896w, 1736s, 1456m, 1434m, 1252s, 1201m, 1168m,

1093m, 1073m, 862m, 837s. HRMS (Electrospray): Calcd. for C19H30O6SiNa (M++Na), 405.1704; Found

(M++Na), 405.1716 .

Me3Si

MeO2C

MeO2CCH3

CO2Et

2-110

MeO2C

MeO2C

SiMe3

CH3H3a

H5a

H6a H2a

H2b

CO2Me

H3b

H6b

H5b

H1

1.2%14.7%

16.1% 4.5%

1.5%

2.6%

17.7%


SiMe3 → H1 0.5 H2a→ H1 1.5 H3a → CH3 4.5

SiMe3 → H2a 0.3 H2 → H2b 17.7 H3b → H3a 14.7

SiMe3 → H6a 0.4 H2 → SiMe3 2.6 H3b → CH3 1.2

SiMe3 → CH3 0.4 H3a → H2b 16.1

NPh

O

O

Me3Si

MeO2C

MeO2C

2-114


(CDCl3, 500 MHz): δ 0.13 (s, 9H), 2.34 (Br s, 1H), 2.37-2.41 (m, 1H), 2.61 (d, J = 16.6 Hz, 1H), 2.88-2.96

(m, 2H), 3.01-3.08 (m, 2H), 3.22 (dd J = 9.0, 1.2 Hz, 1H), 3.32 (app td J = 8.8, 1.8 Hz, 1H), 3.66 (s, 3H),

3.73 (s, 3H), 7.22-7.24 (m, 2H), 7.34-7.38 (m, 1H), 7.42-7.46 (m, 2H). 13C NMR (CDCl3, 125 MHz): δ -

418

1.69, 24.63, 27.89, 39.67, 40.74, 43.60, 44.52, 52.78, 57.89, 126.43, 127.22, 128.49, 129.04, 132.01,

133.85, 172.47, 179.22, 179.73. IR (NaCl, neat): υ 2953s, 2895w, 2849w, 1732s, 1712s, 1598w, 1499s,

1435s, 1386s, 1337w, 1262s, 1197s, 1157s, 1109w, 1072m, 957w, 915w, 876m, 840s, 760m, 731m, 692m.

HRMS (Electrospray): Calcd. for C24H29O6NSiNa (M++Na), 478.1656; Found (M++Na), 478.1664.

NPh

O

O

SiMe3

MeO2C

MeO2C

H

H

H

1.9%

H H

2.5%

0.6%1.7% 3.0%

2.2%

NPh

O

O

Me3Si

MeO2C

MeO2C

2-114

12

34


H1 → SiMe3 1.0 H2 → H1 2.2 H4a → H3 3.0

H1 → H2 1.5 H3 → SiMe3 2.5 H4a→ H4b 12.5

H1 → H4b 1.7 H3 → H4a 0.6 H4b→ H3 0.4

H2 → SiMe3 1.9 H3 → H4b 0.5 H4b→ H4a 14.6

Me3Si

MeO2C

MeO2C

2-115

Me3Si

MeO2C

MeO2C

2-116

H

CH3

CH3

H

O

O



δ 0.07 (s, 0.25 X 9H), -0.01 (s, 0.41 X 9H), 0.06 (s, 0.34 X 9H), 0.99 (d, J = 6.6 Hz, 0.34 X 3H), 1.02 (d, J

= 6.6 Hz, 0.25 X 3H), 1.09 (d, J = 6.8 Hz, 0.41 X 3H), 1.62-1.75 (m, 1H), 1.93-1.97 (m, 0.25H), 2.07-2.11

(m, 0.75H), 2.16-2.26 (m, 1.25H), 2.33 (d, J = 5.1, 3.2 Hz, 0.34H), 2.41 (app td, J = 5.2, 3.0 Hz, 0.41H),

2.82-2.91 (m, 3H), 3.00 (d, J = 14.0 Hz, 0.34H), 3.07 (d, J = 16.3 Hz, 0.41H), 3.11 (d, J = 14.7 Hz, 0.25H),

419

3.71-3.74 (m, 3H), 9.54 (d, J = 2.6 Hz, 0.41H), 9.55 (d, J = 1.5 Hz, 0.25H), 9.70 (d, J = 3.1 Hz, 0.34H. 13C

NMR (CDCl3, 100 MHz): 1st major δ 0.18, 19.09, 27.82, 29.23, 31.17, 43.35, 44.04, 52.79, 55.01, 57.82,

129.49, 131.09, 172.50, 172.71, 204.76; 1.64, 14.15, 21.47, 24.17, 25.23, 27.03, 37.89, 57.00, 57.19, 60.47,

125.83, 127.41, 129.70, 131.23, 134.18, 143.35, 174.77; 2nd major δ -1.08, 19.61, 27.90, 30.88, 43.70,

43.77, 52.78, 55.27, 58.25, 129.36, 130.73, 172.66, 172.75, 205.81; 3rd major δ -1.43, 19.66, 25.19, 29.95,

32.82, 44.00, 44.04, 52.51, 52.74, 57.90, 129.49, 130.68, 172.68, 172.80, 204.45. IR (NaCl, neat): υ 2954s,

2856s, 2362w, 1737s, 1435s, 1252s, 1200m, 1163m, 1073m, 840s. HRMS (Electrospray): Calcd. for


Me3Si

MeO2C

MeO2C

2-117

Me3Si

MeO2C

MeO2C

2-118OAc

CN

CN

OAc



(s, 0.83 X 3H), 0.41 (s, 0.17 X 6H), 0.43 (s, 0.83 X 3H), 1.61-1.67 (m, 1H), 2.02-2.06 (m, 1H), 2.17 (s,

3H), 2.11-2.21 (m, 1H), 2.27-2.30 (m, 1H), 2.72-2.76 (m, 0.17H), 2.79-2.84 (m, 1.17H), 2.89-2.90 (m,

0.83H), 2.93-2.99 (m, 2H), 3.71 (s, 3H), 3.72 (s, 3H), 7.30-7.40 (m, 3H), 7.46-7.49 (m, 2H). 13C NMR

(CDCl3, 125 MHz): 1st major δ -1.68, -1.16, 20.91, 22.71, 30.91, 42.94, 44.02, 52.80, 52.88, 58.31, 74.76,

118.63, 128.05, 129.52, 130.64, 133.91, 137.37, 168.92, 171.85, 172.54.

Me2PhSi

EtO2C

EtO2C

2-123

Me2PhSi

EtO2C

EtO2C

2-124

OEt

O

OEt

O


isolated compound was a 2-123/2-124 mixture with a ratio of 0.70/0.30. 1H NMR (CDCl3, 400 MHz):

δ 0.28 (s, 0.3 X 3H), 0.03 (s, 0.7 X 3H), 0.35 (s, 0.3 X 3H), 0.36 (s, 0.7 X 3H), 1.15-1.20 (m, 3H), 1.78-

420

1.90 (m, 2H), 1.91-2.03 (m, 1H), 2.08-2.23 (m, 2H), 2.37 (Br s,0.3H), 2.48-2.53 9m, 0.7H), 2.58-2.66 (m,

0.3H), 2.63-2.76 (m, 1H), 2.87-2.97 (m, 3.7H), 3.69 (s, 0.3 X 3H), 3.70 (s, 0.7 X 3H), 3.72 (s, 0.7 X 3H),

3.73 (s, 0.3 X 3H), 3.90-4.03 (m, 0.3 X 2H), 4.09-4.19 (m, 0.7 X 2H), 7.33-7.35 (m, 3H), 7.48-7.50 (m,

2H). 13C NMR (CDCl3, 100 MHz): major δ -2.91, -2.85, 14.18, 25.71, 27.47, 27.57, 38.26, 43.74, 44.10,

52.71, 52.89, 60.23, 127.84, 128.36, 129.11, 132.41, 133.74, 183.17, 172.69, 172.86, 175.43; minor δ -

3.21, -2.88, 14.12, 22.96, 24.37, 27.82, 39.83, 40.68, 43.78, 44.27, 52.70, 57.75, 60.36, 127.81, 129.00,

129.15, 131.12, 133.87, 137.90, 172.61, 172.97, 175.53. IR (NaCl, neat): υ 2954m, 2849w, 1732s, 1435m,

1259s, 1199m, 1173m, 1114w, 1074w, 911s, 817w, 733s. HRMS (Electrospray): Calcd. for C24H32O6SiNa

(M++Na), 467.1860; Found (M++Na), 467.1886.

Me2PhSi

EtO2C

EtO2C

2-125

Me2PhSi

EtO2C

EtO2C

2-126

OtBu

O

OtBu

O



δ 0.27 (s, 0.22 X 3H), 0.28 (s, 0.29 X 3H), 0.31 (s, 0.49 X 3H), 0.32 (s, 0.22 X 3H), 0.33 (s, 0.29 X 3H),

0.57 (s, 0.49 X 3H), 1.37 (s, 0.29 X 9H), 1.40 (s, 0.49 X 9H), 1.44 (s, 0.22 X 9H), 1.62-1.68 (m, 0.5H),

1.72-1.92 (m, 2H), 2.06 (d, J = 16.7 Hz, 0.5H), 2.11-2.18 (m, 1H), 2.28 (Br s, 0.25H), 2.38 (m, 0.75H),

2.57 (app dt, J = 9.5, 3.9 Hz, 0.25H), 2.72 (d, J = 16.6 Hz, 0.75H), 2.79-3.00 (m, 4H), 3.68 (s, 0.29 X 3H),

3.70 (s, 0.49 X 3H), 3.71 (s, 0.22 X 3H), 3.72 (s, 0.49 X 6H), 3.73 (s, 0.29 X 3H), 7.32-7.35 (m, 3H), 7.48-

7.51 (m, 2H). 13C NMR (CDCl3, 125 MHz): 1st major δ -3.01, -2.81, 25.67, 27.44, 27.75, 28.03, 43.68,

44.10, 52.69, 52.77, 57.90, 127.83, 128.59, 129.06, 132.29, 133.75, 138.29, 172.72, 172.91, 174.74; 2nd

major δ -3.16, -2.70, 25.43, 27.86, 27.96, 28.06, 41.59, 43.76, 44.38, 52.64, 52.70, 57.77, 128.80, 129.10,

130.24, 133.81, 138.16, 172.65, 172.99, 174.81. IR (NaCl, neat): υ 2978m, 2952m, 2849m, 1736s, 1434m,

1392w, 1367m, 1255s, 1198m, 1152s, 1115m, 1073m, 833m, 817m. HRMS (Electrospray): Calcd. for


421

Me2PhSi

EtO2C

EtO2C

2-127

Me2PhSi

EtO2C

EtO2C

2-128

CH3

O

CH3

O



(s, 0.29 X 3H), 0.34 (s, 0.71 X 3H), 0.37 (s, 0.29 X 3H), 0.38 (s, 0.71 X 3H), 1.64-1.73 (m, 1H), 1.84-2.01

(m,3H), 2.09-2.14 (m, 1H), 2.42 (app dtd, J = 14.6, 5.9, 2.4 Hz, 0.71H), 2.60(app dt, J = 6.4, 4.4 Hz,

0.21H), 2.74-2.97 (m, 4H), 3.70 (s, 0.29 X 3H), 3.71 (s, 0.71 X 3H), 3.72 (s, 0.29 X 3H), 3.74 (s, 0.71 X

3H), 7.31-7.37 (m, 3H), 7.45-7.51 (m, 2H). 13C NMR (CDCl3, 125 MHz): major δ -2.82, -2.51, 26.15,

26.57, 27.17, 27.98, 43.59, 45.12, 15.85, 52.74, 52.76, 97.93, 127.95, 128.46, 129.26, 132.46, 133.75,

138.01, 172.66, 172.89, 210.90; minor δ -3.63, -2.51, 22.64, 23.22, 26.76, 27.53, 43.67, 44.21, 48.53,

52.69, 52.74, 57.82, 127.89, 128.98, 129.26, 131.31, 133.98, 137.83, 172.58, 172.95, 201.53. IR (NaCl,

neat): υ 2952s, 2919m, 2849m, 1736s, 1711s, 1434m, 1358m, 1254s, 1199m, 1167m, 1114m, 1073m, 833m,

816m, 775m, 737m, 703m. HRMS (Electrospray): Calcd. for C23H30O5SiNa (M++Na), 437.1755; Found

(M++Na), 437.1757.

Me2PhSi

EtO2C

EtO2C

2-129

Me2PhSi

EtO2C

EtO2C

2-130

H

O

H

O


isolated compound was 2-129/2-130 mixture with a ratio of 0.63/0.37. 1H NMR (CDCl3, 500 MHz):

δ 0.32 (s, 3H), 0.36 (s, 0.63 X 3H), 0.40 (s, 0.37 X 3H), 1.61-1.68 (m, 0.63H), 1.77-1.89 (m, 2.37H), 1.98-

2.02 (m, 0.37H), 2.07-2.11 (m, 0.63H), 2.10-2.21 (m, 0.73H), 2.28 (Br s, 0.37H), 2.37-2.44 (m, 1H), 2.72

(d, J = 15.2 Hz, 0.73H), 2.80 (d J = 16.3 Hz, 0.37H), 2.86-2.91 (m, 3H), 3.70 (s, 0.37 X 3H), 3.71 (s, 0.63

X 3H), 3.73 (s, 0.63 X 3H), 3.72 (s, 0.37 X 3H), 7.33-7.38 (m, 2H), 7.47-7.49 (m, 2H), 9.43 (s, 0.37H),

422

9.52 (s, 0.63H). 13C NMR (CDCl3, 125 MHz): major δ -3.11, 24.56, 24.65, 24.73, 43.67, 44.10, 45.02,

52.74, 52.77, 57.82, 127.94, 128.01, 129.25, 129.39, 133.70, 137.85, 172.59, 172.77, 203.89; minor δ -

2.52, 20.86, 21.96, 26.05, 43.64, 44.31, 46.92, 52.74, 52.77, 57.72, 128.01, 128.09, 130.05, 130.82, 133.23,

137.53, 172.47, 172.85, 204.77. IR (NaCl, neat): υ 2953s, 2861m, 2719m, 1735s, 1434m, 1256s, 1199m,

1163m, 1114m, 1073m, 832m, 818m, 736m, 702m. HRMS (Electrospray): Calcd. for C22H28O5SiNa

(M++Na), 423.1598; Found (M++Na), 423.1613.

Me2PhSi

EtO2C

EtO2C

2-131

OMe

OMe

O

O


(CDCl3, 500 MHz): δ 0.24 (s, 3H), 0.32 (s, 3H), 2.18-2.25 (m, 1H), 2.43 (d, J = 10.0 Hz, 1H), 2.50 (dd, J =

11.1, 4.9 Hz, 1H), 2.71 (d, J = 16.7 Hz, 1H), 2.80 (dd, J = 11.1, 9.5 Hz, 1H), 2.86 (d, J = 15.1 Hz, 1H), 2.91

(d, J = 15.8 Hz, 1H), 2.99 (d, J = 15.8 Hz, 1H), 3.38 (s, 3H), 3.62 (s, 3H), 3.69 (s, 3H), 3.70 (s, 3H), 7.31-

7.35 (m, 3H), 2.47-2.49 (m, 2H). 13C NMR (CDCl3, 125 MHz): δ -3.84, -3.77, 27.54, 28.06, 43.63, 43.86,

44.18, 45.21, 51.80, 52.86, 52.70, 52.82, 57.87, 127.74, 127.82, 129.28, 131.35, 134.09, 137.18, 172.49,

172.59, 174.93, 174.00. IR (NaCl, neat): υ 2952m, 2849w, 1736s, 1434m, 1349m, 1257s, 1200s, 1171m,

1115m, 1073w. HRMS (Electrospray): Calcd. for C25H32O8SiNa (M++Na), 511.1759; Found (M++Na),

511.1748.

PhMe2Si

MeO2C

MeO2C OMe

OMe

O

O

MeO2C

MeO2C OMe

OMe

O

O

H6a

H5a J5b

H6b

PhMe2Si H1

H4bH4a

H3

H2

1.1%

1.5%

0.9%

0.9%

1.3%

1 2

34

2-131

423

Me2PhSi

EtO2C

EtO2C

2-132

Me2PhSi

EtO2C

EtO2C

2-133

OEt

OEt

OEt

OEt

O

O O

O


isolated compound was 2-132/2-133 mixture with a ratio of 0.68/0.32. 1H NMR (CDCl3, 500 MHz): major

δ 0.26 (s, 3H), 0.33 (s, 3H), 1.12 (t, J = 7.1 Hz, 3H), 1.22 (t, J = 7.2 Hz, 3H), 2.11-2.20 (m, 1H), 2.17 (s,

1H), 2.43-2.48 (m, 1H), 2.48 (app td, J = 13.8, 3.9 Hz, 1H), 2.69 (d, J = 16.1 Hz, 1H), 2.83 (dd, J = 11.2,

9.3 Hz, 1H), 2.80-2.93 (m, 2H), 2.99 (d, J = 17.5 Hz, 1H), 3.69 (s, 3H), 3.70 (s, 3H), 3.75-3.83 (m, 2H),

7.18-7.41 (m, 2H), 7.30-7.34 (m, 3H), 7.46-7.50 (m, 2H); minor δ 0.26 (s, 3H), 0.33 (s, 3H), 1.25 (t, J = 6.5

Hz, 6H), 2.11-2.20 (m, 2H), 2.36 (d, J = 17.7 Hz, 1H), 2.62-2.63 (m,1H), 2.72 (d, J = 16.1 Hz, 1H), 2.99-

2.81 (m, 2H), 2.99 (d, J = 17.5 Hz, 1H), 3.70 (s, 3H), 3.73 (s, 3H), 3.85-3.92 (m, 2H), 3.99-4.04 (m, 2H),

7.30-7.34 (m, 3H), 7.46-7.50 (m, 2H). 13C NMR (CDCl3, 125 MHz): major δ -3.99, -3.44, 13.86, 14.09,

27.78, 27.94, 43.64, 43.88, 44.40, 44.91, 52.72, 52.80, 57.88, 60.66, 127.73, 127.79, 130.24, 131.49,

134.02, 137.40, 172.52, 172.62, 174.57, 174.60. IR (NaCl, neat): υ 2955m, 1732s, 1434m, 1371m, 1256s,

1196s, 1114m, 1072m, 1035m, 823w, 737w. HRMS (Electrospray): Calcd. for C27H36O8SiNa (M++Na),

539.2072; Found (M++Na), 539.2066.


H1 → SiMe2Ph 2.4 H1→ H6b 1.5 H2 → SiMe2Ph 2.3

H1 → C2CO2Me 1.1 H2 → H1 0.9 H3 → H4b 0.9

H1 → H2 0.7 H2 → H3 0.9

424

NPh

O

O

PhMe2Si

MeO2C

MeO2C

2-134


(CDCl3, 500 MHz): δ 0.42 (s, 3H), 0.51 (s, 3H), 1.72-1.77 (m, 1H), 2.33 (d, J = 17.0 Hz, 1H), 2.61 (s, 1H),

2.85-2.99 (m, 4H), 3.04 (app td, J = 9.0, 1.5 Hz, 1H), 3.20 (dd, J = 9.1,1.1 Hz, 1H), 3.66 (s, 3H), 3.75 (s,

3H), 7.20 (dd, J = 8.6, 2.3 Hz, 2H), 7.33-7.38 (m, 3H), 7.40-7.44 (m, 3H), 7.53 (dd, J = 7.9, 1.4 Hz, 2H).

13C NMR (CDCl3, 125 MHz): δ -3.58, -3.35, 24.51, 27.65, 39.42, 40.86, 43.67, 44.56, 52.78, 52.80, 57.75,

128.42, 128.13, 128.16, 128.49, 129.03, 129.84, 132.10, 133.98, 133.74, 133.85, 136.45, 172.05, 172.55,

179.33, 179.59. IR (NaCl, neat): υ 2952w, 2872w, 1732s, 1712s, 1598w, 1499m, 1434w, 1385m, 1262m,

1197m, 1157m, 1115w, 1072w, 833w, 736w, 702w. HRMS (Electrospray): Calcd. for C29H31O6SiNa

(M++Na), 540.1812; Found (M++Na), 540.1803.

Me2PhSi

EtO2C

EtO2C

2-135

Me2PhSi

EtO2C

EtO2C

2-136

COCH3

OAc

OAc

COCH3



(s, 0.24 X 3H), 0.31 (s, 0.76 X 3H), 0.34 (s, 0.24 X 3H), 0.35 (s, 0.24 X 3H), 0.76 (Br s, 1H), 1.84 (dd, J =

13.0, 10.2 Hz, 1H), 1.96 (dd, J = 14.1, 5.7 Hz, 1H), 2.04 (s, 0.76 X 3H), 2.06 (s, 0.76 X 3H), 2.07 (s, 0.24 X

3H), 2.09 (s, 0.24 X 3H), 2.13-2.18 (m, 1H), 2.51-2.57 (m, 0.76H), 2.69 (app t, J = 15.3 Hz, 1H), 2.78-2.90

(m, 2H), 2.98 (d, J = 16.8 Hz, 1H), 3.13 (d, J = 14.5 Hz, 0.24H), 3.69 (s, 0.24 X 3H), 3.70 (s, 0.76 X 3H),

3.71 (s, 0.76 X 3H), 3.76 (s, 0.24 X 3H), 7.34-7.37 (m, 3H), 7.46-7.49 (m, 2H). 13C NMR (CDCl3, 125

MHz): 1st major δ -4.02, -3.71, 21.02, 23.16, 24.36, 32.10, 32.81, 43.16, 43.37, 52.77, 52.81, 58.26, 84.07,

127.99, 128.25, 129.28, 138.68, 133.64, 170.39, 172.37, 172.58, 205.62.

425

PhMe2Si

MeO2C

MeO2CCN

OAc

PhMe2Si

MeO2C

MeO2CCN

OAc

2-137 2-138



(s, 0.83 X 3H), 0.41 (s, 0.17 X 6H), 0.43 (s, 0.83 X 3H), 1.61-1.67 (m, 1H), 2.02-2.06 (m, 1H), 2.17 (s,

3H), 2.11-2.21 (m, 1H), 2.27-2.30 (m, 1H), 2.72-2.76 (m, 0.17H), 2.79-2.84 (m, 1.17H), 2.89-2.90 (m,

0.83H), 2.93-2.99 (m, 2H), 3.71 (s, 3H), 3.72 (s, 3H), 7.30-7.40 (m, 3H), 7.46-7.49 (m, 2H). 13C NMR

(CDCl3, 125 MHz): 1st major δ -1.68, -1.16, 20.91, 22.71, 30.91, 42.94, 44.02, 52.80, 52.88, 58.31, 74.76,

118.63, 128.05, 129.52, 130.64, 133.91, 137.37, 168.92, 171.85, 172.54.

TsN

Me3Si

2-91

TsN

Me3Si

2-92

OEt

O

OEt

O


isolated compound was 2-91/2-92 mixture with a ratio of 0.66/0.34. 1H NMR (CDCl3, 500 MHz): δ -0.06

(s, 0.34 X 9H), -0.03 (s, 066 X 9H), 1.17 (t, J = 7.1 Hz, 0.34 X 3H), 1.20 (t, J = 7.1 Hz, 0.66 X 3H), 1.53

(Br s, 1H), 2.01 (Br s, 0.34H), 2.10 (Br d, J = 12.9 Hz, 0.66H), 2.16-2.22 (m, 1H), 2.42 (s, 3H), 2.53-2.57

(m, 0.66H), 2.61-2.63 (0.34H), 3.87-3.99 (m, 2H), 4.01-4.07 (m, 2H), 4.05 (q, J = 7.1 Hz, 0.34 X 2H), 4.09

(q, J = 7.1 Hz, 0.66 X 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.70 (dd, J = 8.2, 3.2 Hz, 1H). 13C NMR (CDCl3, 100

MHz): major δ -1.64, 14.15, 21.47, 24.17, 25.23, 27.03, 37.89, 57.00, 57.19, 60.47, 125.83, 127.41, 129.70,

131.23, 134.18, 143.35, 174.77; minor δ -1.74, 14.09, 20.84, 22.63, 24.17, 26.34, 40.25, 57.14, 57.39,

60.56, 126.33, 127.41, 129.69, 130.03, 134.22, 143.30, 175.23. IR (NaCl, neat): υ 2954s, 2856m, 1731s,

1598w, 1455m, 1251s, 1165s, 1099s, 1033m, 838s, 664s, 597s. HRMS (Electrospray): Calcd. for

C21H31O4SNSiNa (M++Na), 444.1635; Found (M++Na), 444.1599.

426

TsN

Me3Si

TsN

Me3Si

CH3

CH3

O

O

2-139 2-140

Colorless oil. Column chromatography; hexane:EtOAc = 5:1 to 4:1. Rf = 0.29 (hexane:EtOAc = 3:1). The

isolated compound was 2-139/2-140 mixture with a ratio of 0.10/0.09/0.69/0.12. 1H NMR (CDCl3, 500

MHz): δ -0.06 (s, 0.22 X 9H), -0.02 (s, 0.78 X 9H), 1.54 (Br s, 1H), 1.57-1.67 (m, 1H), 1.72-1.82 (m, 1H),

1.87-1.95 (m, 1H), 1.98-2.06 (m, 1H), 2.12 (s, 0.12 X 3H), 2.13 (s, 0.69 X 3H), 2.13 (s, 0.09 X 3H), 2.22

(s, 0.10 X 3H), 2.42 (s, 3H), 2.63-2.49 (m, 1H), 3.83-3.90 (m, 1H), 4.01-4.07 (m, 3H), 7.29-7.32 (m, 2H),

7.68-7.71 (m, 2H). 13C NMR (CDCl3, 125 MHz): major δ -1.50, 21.48, 24.21, 24.34, 26.66, 27.97, 45.64,

57.04, 57.15, 116.13, 125.87, 127.40, 129.73, 134.15, 143.41, 209.96. IR (NaCl, neat): υ 2951s, 2861s,

1711s, 1598w, 1513w, 1455w, 1344s, 1250m, 1164s, 1099m, 839s, 667s. HRMS (Electrospray): Calcd. for

C20H29O3NSiSNa (M++Na), 414.1530; Found (M++Na), 414.1508.

TsN

Me3Si

2-141

TsN

Me3Si

2-142

CN

CN

Brown oil. Column chromatography; hexane:EtOAc = 5:1. Rf = 0.27 (hexane:EtOAc = 3:1). The isolated

compound was a/b/c/d mixture with a ratio of 0.23/0.16/0.04. 1H NMR (CDCl3, 400 MHz): δ -0.02 (s, 0.04

X 9H), -0.01 (s, 0.16 X 9H), 0.02 (s, 0.57 X 9H), 0.13 (s, 0.23 X 9H), 1.62-1.72 (m, 1.27H), 1.81 (Br s,

0.73H), 1.96-2.03 (m, 2H), 2.18-2.29 (m, 1H), 2.43 (s, 3H), 2.92-2.94 (m, 0.16H), 2.97-3.02 (m, 0.57H),

3.01-3.04 (m, 0.23H), 3.11-3.13 (m, 0.04H), 3.89-4.82 (m, 4H), 7.33 (d, J = 8.0 Hz, 3H), 7.71 (d, J = 8.2

Hz, 3H). 13C NMR (CDCl3, 125 MHz): 1st major δ -1.50, 19.89, 21.50, 23.52, 26.17, 29.15, 56.92, 57.12,

116.16, 172.33, 128.35, 129.86, 134.08, 136.54, 143.63; 2nd major δ -1.42 (SiMe3); 3rd major δ -2.18

(SiMe3); 4th major δ -2.66 (SiMe3). IR (NaCl, neat): υ 2953s, 2919s, 2861m, 2238w, 1731w, 1598w,

427

1454m, 1345s, 1253s, 1164s, 1099m, 1069m, 842s, 666s. HRMS (Electrospray): Calcd. for

C19H26O3N2SSiNa (M++Na), 397.1376; Found (M++Na), 397.1360.

4. 11. Attempted Synthesis of Papulacandin D Core Structure

Preparation of 3,4,5-Tri-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-one128

n-Butyllithium (1.6M in hexane, 226 mL, 141mL) was added dropwise to a stirred solution of

propagyl alcohol (102 mmol, 5.74g, 5.96 mL) in 300 mL of THF at -78 oC under nitrogen atmosphere.

After 30 min, chlorotrimethylsilane (307 mmol, 39 mL), was added dropwise to the solution at -78 oC and

followed increasing the temperature to rt. Aqueous solution of hydrochloric acid (2M, 200mL) wad added

slowly and stirred it over night (about 8h). After separation of organic phases from the mixture, the

aqueous phase was extracted with diethyl ether (2 X 200 mL). Combined organic phase was dried over

MgSO4, filtered, concentrated in a rotary evaporator to give a crude mixture. The crude mixture was flash

column chromatography eluting with hexane. After evaporation of the hexane, the residue was distillated

under reduced pressure.

TMSOH

Yellow liquid. Column chromatography; hexane and then hexane:Et2O = 1:1. Rf = 0.17 (hexane:Et2O =

1:1). Vacuum distillation; Bp 102-104 oC/30 mmHg (lit128 95-96 oC/22 mmHg). 1H NMR (CDCl3, 500

MHz): δ 0.15 (s, 9H), 2.52 (Br s, 1H), 4.22 (s, 2H). 13C NMR (CDCl3, 125 MHz): δ -0.24, 51.66, 90.71,

103.79. IR (NaCl, neat): υ 3340Br s, 2961s, 2896w, 2177m, 1674w, 1652w, 1410w, 1251s, 1043s, 984m,

843s, 760m.

3,4,5-Tri-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-one

To a flame dried three neck 500 mL flask connected with a 100 mL dropping funnel were added

10 mL of dichloromethane and 4.26 mL of dimethyl sulfoxide. 20 mL of acetic anhydride in 20 mL of

dichloromethane was slowly added at -78 oC (the inner temperature of the flask was between -75 oC and -

428

73 oC ) under nitrogen atmosphere. The dropping funnel was washed by 10 mL of dichloromethane and

added to the reaction mixture followed by stirring at -78 oC for 20min. 2,3,4,6-tetra-O-benzyl-D-

gluconopyranose 3-83 (40 mmol, 21.6g) dissolved in 40 mL of DMSO and 40 mL of dichloromethane was

added to the 500 mL flask at -78 oC (the inner temperature of the flask was <-70 oC ) through a dropping

funnel and the dropping funnel was washed by additional 420 mL of dichloromethane, which was added to

the flask. Then, the temperature increased to -40 oC and the mixture was stirred for 1h. After addition of

diisopropylethyl amine (102 mmol, 18.1 mL) at -40 oC, the temperature increased to rt and stirred the

mixture for 2h. The mixture was washed with saturated Na2HPO4 (100 mL), saturated NaHCO3 (100 mL),

and brine solution (100 mL). Combined organic phase was dried over MgSO4, filtered through a filter

paper, and concentrated in a rotary evaporator to give a crude mixture. The crude mixture was purified by

column chromatography eluting with hexane:EtOAc = 8:1 to 7:1.

O

OBn

BnOBnO

BnO O

3-88

Colorless oil. Column chromatography; hexane:EtOAc = 8:1 to 7:1. Rf = 0.29 (hexane:EtOAc = 5:1). 1H

NMR (CDCl3, 500 MHz): δ 3.69 (dd, J = 11.0, 3.3 Hz, 1H), 3.76 (dd, J = 11.0, 2.3 Hz, 1H), 3.93 (app t, J =

6.7 Hz, 1H), 3.98 (dd, J = 8.3, 6.9 Hz, 1H), 4.15 (d, J = 6.6 Hz, 1H), 4.48 (app dt, J = 8.5, 2.7 Hz, 1H), 4.50

(d, J = 12.1 Hz, 1H), 4.54 (d, J = 11.2 Hz, 1H), 4.59 (d, J = 12.0 Hz, 1H), 4.62 (d, J = 11.3 Hz, 1H), 4.67

(d, J = 11.4 Hz, 1H), 4.73 (d, J = 11.4 Hz, 1H), 4.76 (d, J = 11.4 Hz, 1H), 5.02 (d, J = 11.4 Hz, 1H), 7.18-

7.23 (m, 2H), 7.27-7.43 (m, 16H), 7.39-7.43 (m, 2H). 13C NMR (CDCl3, 125 MHz): δ 68.18, 73.50, 73.68,

73.89, 75.99, 77.34, 78.10, 80.89, 127.78, 127.90, 127.96, 128.07, 128.35, 128.40, 128.43, 136.88, 137.44,

137.47, 137.53, 169.30. IR (NaCl, neat): υ 3063m, 3030s, 2919s, 2868s, 1954w, 1878w, 1755s, 1496m,

1454s, 1363m, 1210m, 1164m, 1097s, 1073s, 1028m, 912w, 737s, 697s.

429

3,4,5-Tris-benzyloxy-6-benzyloxymethyl-2-trimethylsilanylethynyl-tetrahydro-pyran-2-ol

A flame-dried 25 mL of flask was charged with trimethylsilyl acetylene (2.03 mmol, 199 mg) in

10 mL of THF. To the solution was added slowly n-butyllithium (1.6M in hexane, 1.27 mL) at -78 oC for

30 min. After a mixture of 3,4,5-tri-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-one 3-88 (1.35

mmol, 729 mg) in 5 mL of THF was added slowly, the reaction mixture was stirred at -78 oC for 2h and

allowed to warm to rt for 1h. After all starting material was consumed (TLC), the mixture was diluted with

diethyl ether (50 mL). The diluted mixture was washed with saturated ammonium chloride (2 × 20 mL),

dried over MgSO4, filtered, and concentrated in vacuo. The crude mixture was used for the next step

without further purification. If it was necessary, the crude mixture was purified by column chromatography

eluting with hexane:EtOAc = 20:1 to 12:1.

O

OBn

BnOBnO

BnOOH

TMS

3-89

Colorless oil (The compounds was isolated as a mixture of three diastereomers). Column chromatography;

hexane:EtOAc = 20:1 to 12:1. Rf = 0.31 (hexane:EtOAc = 4:1). 1H NMR (CDCl3, 500 MHz): major

isomer, δ 0.23 (s, 9H), 3.76-3.77 (m, 1H), 3.79-3.84 (m, 1H), 3.94-3.97 (m, 1H), 4.01-4.04 (m, 1H), 4.09-

4.15 (m, 2H), 4.57 (d, J = 12.2 Hz, 1H), 4.64 (d, J = 10.2 Hz, 6H), 4.73 (d, J = 11.4 Hz, 1H), 4.74 (d, J =

12.1 Hz, 1H), 4.79 (d, J = 11.8 Hz, 1H), 4.84 (d, J = 11.8 Hz, 1H), 4.92 (d, J = 10.7 Hz, 1H), 5.16 (d, J =

11.4 Hz, 1H), 7.17-7.52 (m, 20H). 13C NMR (CDCl3, 125 MHz): major (Because of overlap of peaks in

aromatic region, the peaks are not assigned), δ -0.38, 68.74, 72.96, 73.46, 74.26, 74.49, 75.18, 75.35, 75.18,

75.35, 80.30, 81.53, 91.85, 93.61, 99.46; minor (Because of overlap of peaks in aromatic region, the peaks

are not assigned), δ -0.45, 69.36, 71.77, 73.22, 73.24, 74.49, 74.98, 75.07, 78.21, 80.14, 88.72, 92.54,

103.43. IR (NaCl, neat): υ 3420 Br s, 3063s, 3031s, 2949s, 2927s, 2873s, 1951w, 1870w, 1805w, 1644m,

1496m, 1454s, 1395w, 1361m, 1251s, 1210m, 1070s, 1028s, 845s, 735s, 697s.

430

3,4,5-Tris-benzyloxy-6-benzyloxymethyl-2-trimethylsilanylethynyl-2-[trimethylsilanylprop-2-

ynyloxy]-tetrahydro-pyran

Montmorillonite A (300 mg) and 4 Å MS (450 mg) were placed into a 50 mL of flask. After dried

by flame under reduced pressure, the flask was cooled at rt under a stream of nitrogen. Dichloromethane (7

mL) was added to the flask and stirred it for 1min. To the suspension was added a mixture of 3,4,5-tris-

benzyloxy-6-benzyloxymethyl-2-trimethylsilanylethynyl-tetrahydro-pyran-2-ol 3-89 (0.367 mmol, 234

mg) and 3-Trimethylsilyl-2-propyn-1-ol (1.102 mmol, 141 mg) in 5 mL of dichloromethane. After stirring

at rt for 1.5h under nitrogen atmosphere, all starting material was consumed. The resulting mixture was

filtered through Celite® pad followed by addition of 10 mL of dichloromethane to the pad. All solvent was

removed under reduced pressure to give crude product. This crude product was used for the next step

without further purification. If it was necessary, the crude product was purified by column chromatography

eluting with hexane:EtOAc = 50:1 to 20:1.

O

OBn

BnOBnO

BnOO

TMS

TMS

3-90

Colorless oil. Column chromatography; hexane:EtOAc = 50:1 to 20:1. Rf = 0.42 (hexane:EtOAc = 9:1).

Only α anomer was isolated as pure compounds. 1H NMR (CDCl3, 500 MHz): δ 0.16 (s, 9H), 0.20 (s,

9H), 3.72-3.80 (m, 3H), 3.97 (app t, J = 9.3 Hz, 1H), 4.02 (d, J = 3.0 Hz, 1H), 4.07 (dd, J = 9.5, 2.9 Hz,

1H), 4.28 (d, J = 15.3 Hz, 1H), 4.47 (d, J = 15.3 Hz, 1H), 4.53 (d, J = 10.7 Hz, 1H), 4.57 (d, J = 12.1 Hz,

1H), 4.46 (s, 2H), 4.67 (d, J = 12.0 Hz, 1H), 4.84 (d, J = 10.7 Hz, 1H), 4.91 (d, J = 11.4 Hz, 1H), 4.97 (d, J

= 11.4 Hz, 1H), 7.15-7.18 (m, 2H), 7.25-7.31 (m, 11H), 7.32-7.36 (m, 5H), 7.44 –7.46 (m, 2H). 13C NMR

(CDCl3, 125 MHz): δ -0.43, -0.19, 52.02, 68.93, 72.32, 73.22, 73.57, 74.32, 75.19, 74.32, 75.19, 75.27,

78.38, 80.41, 91.07, 91.09, 96.88, 99.84, 101.05, 127.32, 127.38, 127.44, 127.47, 127.64, 127.86, 128.02,

128.16, 128.24, 128.31, 138.23, 138.50, 138.52, 138.54. β (major) was isolated as a mixture of α/β with a

ratio of 0.17/1.0. 1H NMR (CDCl3, 400 MHz): δ 0.00 (s, 9H), 0.02 (s, 9H), 3.51-3.65 (m, 3H), 3.74 (ddd, J

= 10.1, 3.6, 1.8 Hz, 1H), 3.85 (app t, J = 9.3 Hz, 1H), 4.28 (d, J = 13.5 Hz, 2H), 4.35 (d, J = 111.8 Hz, 1H),

431

4.37 (d, J = 10.6 Hz, 1H), 4.49 (d, J = 12.1 Hz, 1H), 4.64 (d, J = 11.2 Hz, 1H), 4.66 (d, J = 10.7 Hz, 1H),

4.67 (d, J = 11.9 Hz, 1H), 4.74 (d, J = 11.1 Hz, 1H), 4.86 (d, J = 10.8 Hz, 1H), 6.97-.7.01 (m, 2H), 7.27-

7.28 (m, 23H). 13C NMR (CDCl3, 125 MHz): δ -0.45, -0.19, 52.84, 68.20, 71.96, 73.37, 75.50, 75.60,

75.92, 77.75, 82.07, 84.25, 90.78, 91.95, 96.06, 100.29, 101.45, 127.52, 127.62, 127.67, 127.69, 127.93,

128.18, 128.20, 128.30, 128.33, 128.35, 138.09, 138.14, 138.82. IR (NaCl, neat): υ 3288s, 3062s, 3030s,

2958s, 2905s, 2182m, 1951m, 1872w, 1809w, 1606m, 1586w, 1496s, 1454s, 1402s, 1360s, 1308s, 1250s,

1250s, 1109s, 910m, 858s, 734s, 697s.

2,3,5-Tris-benzyloxy-6-benzylmethyl-2-ethynyl-tetrahydro-pyran-2-ol

To a flame-dried flask was added lithium acetylide ethylene diamine complex (19.8 mmol, 2.02g)

and 60 mL of THF at -78 oC under nitrogen atmosphere. After a mixture of 2,3,4,6-tetra-O-benzyl-D-

gluconolactone 3-88 (9.9 mmol, 5.33g) in 60 mL of THF was added slowly to the mixture at -78 oC, the

mixture was sirred at -78 oC for 3h. (a small amount of 2,3,4,6-tetra-O-benzyl-D-gluconolactone was

detected on TLC). To consume all starting material additional lithium acetylide ethylene diamine complex

(118mg) was added and continued stirring for another 1h at -78 oC. To the reaction mixture was added

saturated ammonium chloride solution (70 mL) -78 oC with stirring. The mixture was diluted by diethyl

ether and separated the organic phase by a separation funnel. All combined organic phase was washed with

water abd brine solution, dried over MgSO4, filtered, and concentrated in a rotary evaporator. The crude

mixture was purified by column chromatogramphy eluting with hexane:EtOAc = 20:1 to 7:1. Colorless oil

was obtained (5.1g, 91%) as a mixture of 2 isomers.

O

OBn

BnOBnO

BnOOH

3-91

Colorless oil. Column chromatography; hexane:EtOAc = 20:1 to 7:1. Rf = 0.27 (hexane:EtOAc = 5:1). 1H

NMR (CDCl3, 500 MHz): major: δ 2.73 (s, 1H), 3.62-3.76 (m, 4H), 3.90 (app t, J = 9.3 Hz, 1H), 3.96 (app

dt, J = 10.0, 3.2 Hz, 1H), 4.50-4.58 (m, 2H), 4.63 (d, J = 12.2 Hz, 1H), 4.78-4.86 (m, 2H), 4.90 (d, J = 12.1

432

Hz, 1H), 4.96 (d, J = 10.9 Hz, 1H), 5.04 (d, J = 11.3 Hz, 1H), 7.12-7.21 (m, 2H), 7.25-7.36 (m, 18H);

minor: δ 2.59 (s, 1H) 3.53 (d, J = 9.6 Hz, 1H), 3.62-3.76 (m, 3H), 3.83 (app t, J = 9.3 Hz, 1H), 4.04 (ddd, J

= 11.1, 4.2, 2.1 Hz, 1H), 4.50-4.58 (m, 2H), 4.65 (d, J = 12.2 Hz, 1H), 4.78-4.86 (m, 3H), 4.90 (d, J = 12.1

Hz, 1H), 5.03 (d, J = 10.3 Hz, 1H), 7.12-7.21 (m, 2H), 7.25-7.36 (m, 18H). 13C NMR (CDCl3, 125 MHz):

major: δ (aromatic peaks are omitted) 68.43, 71.96, 73.40, 74.80, 74.96, 75.74, 75.84, 77.57, 82.40, 83.56,

82.40, 83.56, 83.72, 91.82; minor: δ (aromatic peaks are omitted) 68.46, 72.19, 73.40, 74.54, 75.29, 75.74,

76.42, 80.17, 82.86, 83.97, 95.27. IR (NaCl, neat): υ 3380Br s, 3292s, 3088m, 3062s, 3030s, 2919s, 2869s,

2116w, 1953w, 1877w, 1809w, 1746w, 1605w, 1496s, 1454s, 1398m, 1361s, 1266m, 1210s, 1070Br s,

911m, 736m, 698s.

Trimethyl-[3-(3,4,5-tri-benzyloxy-6-benzyloxymethyl-2-ethynyl-tetrahydro-pyran-2-yloxyl)-prop-1-

ynyl]-silane

After Montmorillonite K 10 (5g) and 4 Å MS were placed into a 250 mL flask, the flask was dried

by flame under reduced pressure. Once the flask cooled completely at rt dichloromethane (80 mL) was

added. To the suspension was added a mixture of 3-trimethylsilyl-2-propyn-1-ol (13.4 mmol, 1.72g) and

2,3,5-tris-benzyloxy-6-benzylmethyl-2-ethynyl-tetrahydro-pyran-2-ol 3-91 (8.96 mmol, 5.06g) in

dichloromethane (80 mL) at rt. After stirred at rt under nitrogen atmosphere for 2h, the resulting mixture

was filtered through a Celite® pad. The pad was washed with additional dichloromethane (50 mL).

Combined organic mixture was concentrated under reduced pressure to give crude product, which used for

the next step without further purification. If it was necessary to purify it, the crude mixture was subjected

to column chromatography eluting hexane:EtOAc = 20:1 to 7:1.

O

OBn

BnOBnO

BnOO

TMS

3-92

433


The compound was isolated as α/β mixture with a ratio of 0.68/0.32. 1H NMR (CDCl3, 500 MHz): δ 2.63

(s, 0.68H), 2.83 (s, 0.32H), 3.64 (d, J = 9.5 Hz, 0.32H), 3.71 (t, J = 9.3 Hz, 0.32H), 3.75-3.87 (m, 2.68H),

3.90 (t, J = 9.2 Hz, 1H), 3.94 (ddd, J = 8.0, 4.0, 2.0 Hz, 0.32H), 4.04-4.09 (m, 2H), 4.15 (dd, J = 9.5, 2.8

Hz, 0.68H), 4.36 (d, J = 15.3 Hz, 0.68H), 4.52 (d, J = 17.9 Hz, 0.68H), 4.54 (d, J = 15.4 Hz, 0.32H), 4.52-

4.57 (m, 2H), 4.66 (d, J = 15.1 Hz, 0.32H), 4.68 (d, J = 12.2 Hz, 0.32H), 4.73 (s, 0.32H), 4.76 (s, 2H), 4.84

(dd, J = 11.3, 7.9 Hz, 0.68H), 4.89 (d, J = 9.0 Hz, 0.32H), 4.91 (d, J = 10.6 Hz, 0.68H), 4.98 (s, 0.68 X 2H),

5.02 (d, J = 10.9 Hz, 0.32H), 5.12 (d, J = 11.3 Hz, 0.32H), 7.20-7.25 (m, 2H), 7.23-7.41 (m, 16H), 7.45-

7.53 (m, 2H). 13C NMR (CDCl3, 125 MHz): major: δ (aromatic peaks are omitted) 100.76, 96.93, 91.31,

83.44, 80.42, 77.25, 75.21, 74.29, 74.24, 73.72, 73.32, 72.48, 68.93, 52.19, -0.23; minor: δ (aromatic peaks

are omitted) 101.34, 99.15, 91.04, 83.40, 79.18, 78.87, 76.47, 75.74, 75.07, 74.57, 73.35, 72.48, 68.46,

53.66, -0.23.

3,4,5-Tris-benzyloxy-6-benzyloxymethyl-2(S)-ethynyl-2-prop-2-ynyloxy-tetrahydro-pyran

Crude trimethyl-[3-(3,4,5-tri-benzyloxy-6-benzyloxymethyl-2-ethynyl-tetrahydro-pyran-2-

yloxyl)-prop-1-ynyl]-silane 3-92 (8.96 mmol estimated from 3-91) and 408 mg of benzyltriethyl

ammonium chloride were dissolved in a mixture of acetonitril/dichloro methane (100 mL, 1:1 mixture).

After treated by 50% sodium hydroxide solution (1.2 mL) at 0 oC, the mixture was stirred at at 0 oC for

5min and at rt for 30min. The mixture was diluted with diethyl ether, washed with water and brine

solution, dried over MgSO4, filtered, and concentrated in a rotary evaporator. The crude mixture was

purified column chromatography eluting with hexane:EtOAc = 20:1 to 15:1. The major product, α anomer,

was isolated as pure compound, but the minor product, β anomer, was contaminated <5% with unknown

compounds.

A similar procedure (except for using double volume of 50% sodium hydroxide solution) was

used for the transformation of 3,4,5-tris-benzyloxy-6-benzyloxymethyl-2-trimethylsilanylethynyl-2-[tri-

methylsilanylprop-2-ynyloxy]-tetrahydro-pyran to 3,4,5-tris-benzyloxy-6-benzyloxymethylethynyl-2-prop-

2-ynyloxy-tetrahydro-pyran 3-89.

434

3-82-α

O

OBn

BnOBnO BnO

O

White solid. Column chromatography; hexane:EtOAc = 20:1 to 15:1. Rf = 0.25 (hexane:EtOAc = 6:1).

[α]D20

= +21.0 (c 0.61 in CHCl3). 1H NMR (CDCl3, 500 MHz): δ 2.43 (app t, J = 2.5 Hz, 9H), 2.64 (s, 1H),

3.73 (dd, J = 11.0, 1.8 Hz, 6H), 3.77 (app t, J = 10.3 Hz, 1H), 3.78 (d, J = 9.6 Hz, 1H), 3.81 (dd, J = 11.0,

3.9 Hz, 1H), 3.95 (ddd, J = 10.1, 3.7, 1.8 Hz, 1H), 4.07 (app t, J = 10.3 Hz, 1H), 4.48 (B of ABX, JAB= 15.5

Hz, JBX= 2.5 Hz, 1H), 4.51 (A of ABX, JAB= 15.5 Hz, JAX= 2.6 Hz, 1H), 4.55 (d, J = 12.2 Hz, 1H), 4.58 (d,

J = 10.7 Hz, 1H), 4.69 (d, J = 12.1 Hz, 1H), 4.86 (d, J = 11.0 Hz, 1H), 4.87 (d, J = 10.7 Hz, 1H), 4.91 (d, J

= 10.9 Hz, 1H), 4.95 (d, J = 11.0 Hz, 1H), 5.02 (d, J = 10.9 Hz, 1H), 7.18-7.20 (m, 2H), 7.28-7.43 (m,

18H). 13C NMR (CDCl3, 125 MHz): δ 52.22, 68.13, 72.25, 73.36, 74.39, 74.98, 75.07, 75.68, 75.84, 77.67,

79.04, 79.35, 83.72, 96.14, 127.51, 127.57, 127.68, 127.71, 127.80, 127.90, 128.18, 128.30, 128.32,

128.37, 137.90, 138.03, 138.07, 138.59. IR (NaCl, neat): υ 3286s, 3060m, 3030s, 2923s, 2246m, 2121m,

1954w, 1878w, 1807w, 1606w, 1496m, 1450s, 1361s, 1212m, 1149s, 1087s, 910m, 734s, 698s. HRMS

(Electrospray): Calcd. for C39H38O6Na (M++Na), 625.2561; Found (M++Na), 625.2525.

O

OBn

BnOBnO BnO

O

3-82-β


1H NMR (CDCl3, 500 MHz): δ 2.49 (app t, J = 2.3 Hz, 9H), 2.82 (s, 1H), 3.63 (d, J = 9.5 Hz, 6H), 3.69-

3.80 (m, 3H), 3.88 (app t, J = 9.3 Hz, 1H), 3.90-3.92 (m, 1H), 4.56-4.51(m, 4H), 4.66 (d, J = 12.3 Hz, 1H),


7.18-7.21 (m, 2H), 7.26-7.45 (m, 23H). 13C NMR (CDCl3, 125 MHz): δ 52.93, 68.40, 73.32, 74.03, 74.14,

74.70, 75.04, 75.61, 75.71, 75.78, 76.38, 77.17, 79.19, 79.59, 83.36, 83.67, 99.29, 127.48, 127.51, 127.55,

435

127.63, 127.70, 127.78, 127.90, 127.94, 128.08, 128.17, 128.21, 128.26, 128.30, 128.33, 128.34, 128.38,

138.06, 138.13, 138.31, 138.61. IR (NaCl, neat): υ 3285s, 3088m, 3063s, 3031s, 2866s, 2359m, 2109m,

1952w, 1875w, 1810w, 1605w, 1586w, 1496s, 1454s, 1397m, 1361s, 1295s, 1210s, 1074 Br s, 911m, 735s,

697s.

(S)-8, 9, 10-tris-benzyloxy-7-benzyloxymethyl-4-[(dimethylphenylsilanyl)-methylene]-1,6-dioxa-3-

[(tri-butylstannanyl)-methylene]- spiro[4.5]decane

2(S)-3, 4 ,5-Tris-benzyloxy-6-benzyloxymethyl-2-ethynyl-2-prop-2-ynyloxy-tetrahydro-pyran 3-

82-α (50 µmol, 30.1mg), (C6F5)3P (5 µmol, 2.7 mg), Bu3SnSiMe2Ph (55 µmol, 23.4 mg), and

Pd2(dba)3•CHCl3 (2.5 µmol, 1.3 mg) were placed into an NMR tube. After 1 mL of C6D6 was added to the

tube, it was shaken vigorous and stand at rt. The reaction was followed by 1H NMR and TLC. After all

starting material was disappeared in 1H NMR spectrum and/or TLCanalysis, the solvent was removed

under reduced pressure. The crude mixture was purified by column chromatography eluting with

hexane:EtOAc = 40:1.

The same reaction was successful in a large scale (3.75 mmol) using PdCl2(PhCN)2 and benzene,

and a similar procedure was used for thepalladium catalyzed silylstannylative cyclization of 3-82-β.

O

OBn

BnOBnO BnO

O

SnBu3

SiMe2PhH

HH

H

3-93

H

24

6

7

8

9

Colorless oil. Column chromatography; hexane:EtOAc = 40:1. Rf = 0.50 (hexane:EtOAc = 10:1). 1H

NMR (CDCl3, 500 MHz): δ 0.40 (s, 3H), 0.42 (s, 3H), 0.83 (t, J = 7.3 Hz, 9H), 0.81-0.87 (m, 6H), 1.22

(sex, J = 7.3 Hz, 6H), 1.26-1.39 (m, 6H), 3.61 (d, J = 11.2 Hz, 1H), 3.72 (d, J = 9.3 Hz, 1H), 3.75 (dd, J =

9.6 Hz, 1H), 3.82 (dd, J = 11.2, 3.6 Hz, 1H), 3.93 (ddd, J = 10.0, 3.4, 1.4 Hz, 1H), 4.03 (app t, J = 9.3 Hz,

1H), 4.39-4.43 (m, 3H), 4.51 (dd, J = 10.8, 1.0 Hz, 1H), 4.57 (d, J = 11.9 Hz, 1H), 4.64 (d, J = 10.8 Hz,


436

1H), 5.92 (s, 1H), 6.01 (s, JSn-H = 37.5 Hz, 1H), 7.17-7.30 (m, 23H), 7.47 (d, J = 6.7 Hz, 2H) . 1H NMR

(C6D6, 500 MHz): δ 0.49 (s, 3H), 0.51 (s, 3H), 0.94 (t, J = 7.3 Hz, 9H), 0.98-1.09 (m, 6H), 1.36 (sex, J =

7.3 Hz, 6H), 1.48-1.61 (m, 6H), 3.67 (dd, J = 11.1, 1.3 Hz, 1H), 3.79 (d, J = 9.3 Hz, 1H), 3.88 (dd, J = 11.0,

3.4 Hz, 1H), 4.02 (app t, J = 9.6 Hz, 1H), 4.23-4.25 (m, 1H), 4.38 (d, J = 12.3 Hz, 1H), 4.39 (app t, J = 9.3

Hz, 1H), 4.42 (d, J = 10.2 Hz, 1H), 4.48 (d, J = 11.8 Hz, 1H), 4.56 (d, J = 9.6 Hz, 1H), 4.58 (d, J = 11.8 Hz,


1H), 4.97 (d, J = 11.3 Hz, 1H), 5.94 (s, JSn-H = 39.5 Hz, 1H), 6.06 (s, 1H), 6.99-7.08 (m, 6H), 7.12-7.19 (m,

11H), 7.18-7.26 (m, 4H), 7.34 (d, J = 7.5 Hz, 2H), 7.53-7.56 (m, 2H). 1H NMR (CD2Cl2, 500 MHz): δ 0.42

(s, 6H), 0.78-0.92 (m, 6H), 0.85 (t, J = 7.3 Hz, 9H), 1.24 (sex, J = 7.3 Hz, 6H), 1.34-1.48 (m, 6H), 3.61 (dd,

J = 11.1, 1.6 Hz, 1H), 3.71 (app t, J = 9.6 Hz, 1H), 3.72 (d, J = 11.9 Hz, 1H), 3.81 (dd, J = 11.1, 3.6 Hz,

1H), 3.88 (ddd, J = 11.6, 3.4, 1.6 Hz, 1H), 3.96 (app t, J = 9.3 Hz, 1H), 4.37-4.42 (m, 2H), 4.4- (d, J = 11.8

Hz, 1H), 4.56 (d, J = 11.7 Hz, 1H), 4.63 (d, J = 11.4, Hz, 1H), 4.65 (d, J = 12.6 Hz, 1H), 4.71 (d, J = 10.9

Hz, 1H), 4.80 (d, J = 11.1 Hz, 1H), 4.82 (d, J = 11.1 Hz, 1H), 5.95 (s. 1H), 6.04 (s, JSn-H = 39.5 Hz, 1H),

7.04-7.09 (m, 2H), 7.17-7.38 (m, 21H), 7.50 (d, J = 6.7 Hz, 2H). 13C NMR (C6D6, 100 MHz): δ -0.84, -

0.27, 11.31, 13.92, 27.74, 29.38, 69.80, 73.02, 73.95, 74.24, 74.88, 75.55, 78/71, 81.40, 84.71, 106.37,

126.75, (the peaks of benzene rings are omitted because of overlap), 134.10 139.18, 139.28, 139.41,

139.55, 139.71, 154.39, 156.84. 13C NMR (CDCl3, 100 MHz): δ -1.34, -0.23, 10.98, 13.64, 27.27, 28.89,

69.41, 72.36, 73.73, 73.94, 74.07, 74.77, 74.59, 75.59, 78.28, 80.93, 84.24, 124.07, 126.86, 127.03, 127.38,

127.40, 127.53, 127.60, 127.72, 127.76, 127.81, 127.99, 128.23, 128.24, 128.30, 128.86, 129.26, 133.62,

138.54, 138.63, 138.65, 138.74, 138.99, 153.22, 155.99. IR (NaCl, neat): υ 3064m, 3029m, 2954s, 1606w,

1454m, 1427w, 1362m, 1248m, 1208m, 1146m, 1095s, 1028s, 820m, 732s, 697s. HRMS (Electrospray):

Calcd. for C59H76O6SiSnNa (M++Na), 1051.4326; Found (M++Na), 1051.4264.

O

OBn

BnOBnO BnO

O

SnBu3

SiMe2PhH

HH

H

HnOe

nOe

nOe

4.1%

1.3%, 1.1%3-93

24

6

7

8

9

437


H2 → H4 2.2 H5 → H6a 2.1 H8 → H7b 1.3 H9 → SiMe2 1.5

H2 → H9 4.5 H5 → H6b 2.3 H9 → H2 4.1

H4 → H2 1.9 H8 → H7a 1.1 H9 → SiPh 1.4

O

OBn

BnOBnO

BnOO

SiMe2PhSnBu3

H

HH

H

H

3-94

24

6

7

8

9


NMR (C6D6, 500 MHz): δ 0.48 (s, 3H), 0.54 (s, 3H), 0.89 (t, J = 7.3 Hz, 9H), 0.96-1.0 (m, 6H), 1.27-1.35

(m, 6H), 1.48-1.54 (m, 6H), 3.69 (dd, J = 11.1, 1.7 Hz, 1H), 3.86 (dd, J = 11.1, 3.5 Hz, 1H), 3.88 (d, J = 9.5

Hz, 1H), 4.02 (app t, J = 9.6 Hz, 1H), 4.25 (ddd, J = 10.0, 3.4, 1.7 Hz, 1H), 4.36 (d, J = 10.6 Hz, 1H), 4.43

(app t, J = 9.3 Hz, 1H), 4.46 (d, J = 12.1 Hz, 1H), 4.52 (d, J = 10.2 Hz, 1H), 4.58 (d, J = 12.1 Hz, 1H), 4.70


(d, J = 11.3 Hz, 1H), 5.05 (d, J = 11.8 Hz, 1H), 5.56 (s, 1H), 6.38 (s, JSn-H = 40.1 Hz, 1H), 6.99-7.35 (m,

23H), 7.55-7.57 (m, 2H). NMR (CD2Cl2, 500 MHz): δ 0.38 (s, 3H), 0.40 (s, 3H), 0.82 (t, J = 7.3 Hz, 9H),

0.79-0.88 (m, 6H), 1.17-1.27 (m, 6H), 1.35-1.48 (m, 6H), 3.63 (d, J = 11.0 Hz, 1H), 3.74 (app t, J = 9.6 Hz,

1H), 3.79-3.83 (m, 2H), 3.89 (d, J = 10.0 Hz, 1H), 4.02 (app t, J = 9.3 Hz, 1H), 4.38 (d J = 10.2 Hz, 1H),



5.71 (s, 1H), 6.30 (s, JSn-H = 38.4 Hz, 1H), 7.17-7.36 (m, 23H), 7.48-7.51 (m, 2H). 13C NMR (C6D6, 125

MHz): δ -0.75, -0.20, 11.16, 13.88, 27.71, 29.32, 69.65, 73.09, 73.89, 74.14, 74.91, 75.57, 78.86, 81.05,

84.81, 106.05, 123.76, 126.69, 139.23, 139.39, 139.55, 139.64, 139.88, 154.68, 156.30. IR (NaCl, neat):

υ 3088m, 3053m, 3031m, 2955s, 2922s, 2852s, 1731w, 1607w, 1496m, 1454m, 1427w, 1361m, 1248m,

438

1143m, 1094s, 1028s, 821m, 731s. HRMS (Electrospray): Calcd. for C59H76O6SiSnNa (M++Na),

1051.4326; Found (M++Na), 1051.4360.

O

OBn

BnOBnO

BnOO

SiMe2PhSnBu3

H

HH

H

HnOe

nOe

nOe

4.5%

1.2%, 0.9%3-94

2

4 6

8

9


H7a → H7b 13.4 H7b → H8 0.8 H8 → SiMe2 0.7

H7a → H8 1.8 H8 → H7a 1.2 H9 → H2 4.5

H7b → H7a 11.1 H8 → H7b 0.9

O

OBn

BnOBnO BnO

O

H

PhMe2SiSnBu3

H H

H

H

H

3-97

25

6

7

8

9

3


NMR (CDCl3, 500 MHz): δ 0.42 (s, 3H), 0.53 (s, 3H), 0.84-1.10 (m, 6H), 0.97 (t, J = 7.3 Hz, 9H), 1.37

(sex, J = 7.4 Hz, 6H), 1.45-1.61 (m, 6H), 3.56 (d, J = 9.7 Hz, 1H), 3.64 (d, J = 10.0 Hz, 1H), 3.85 (dd, J =

10.5, 3.0 Hz, 1H), 3.92 (app t, J = 9.7 Hz, 1H), 3.96 (d, J = 9.9 Hz, 1H), 4.18 (app t, J = 9.3 Hz, 1H), 4.47



(d, J = 11.3 Hz, 1H), 5.01 (d, J = 11.0 Hz, 1H), 6.03 (s, JSn-H = 38.5 Hz, 1H), 6.23 (s, 1H), 7.21-7.24 (m,

2H), 7.30-7.41 (m, 21H), 7.56 (d, J = 7.0 Hz, 2H) . ). 1H NMR (C6D6, 500 MHz): δ 0.45 (s, 3H), 0.53 (s,

3H), 1.37 (t, J = 7.5 Hz, 9H), 0.99-1.14 (m, 6H), 1.36 (sex, J = 7.4 Hz, 6H), 1.48-1.63 (m, 6H), 3.78 (d, J =

9.2 Hz, 2H), 3.94 (dd, J = 11.0, 4.0 Hz, 1H), 4.04 (app t, J = 9.2 Hz, 1H), 4.13 (d, J = 9.8 Hz, 1H), 4.32

439

(app t, J = 9.4 Hz, 1H), 4.37-4.43 (m, 3H), 4.57 (d, J = 12.2 Hz, 1H), 4.69 (d, J = 11.4 Hz, 1H), 4.76 (d, J =

10.8 Hz, 1H), 4.78 (d, J = 10.5 Hz, 1H), 4.89 (d, J = 11.4 Hz, 1H), 4.94 (d, J = 11.4 Hz, 1H), 4.99 (d, J =

11.4 Hz, 1H), 5.85 (s, JSn-H = 41.2 Hz, 1H), 6.49 (s, 1H), 7.03-7.14 (m, 15H), 7.16-7.18 (m, 2H), 7.27-7.29

(m, 6H), 7.59 (dd, J = 7.3, 1.3 Hz, 2H) . 13C NMR (CDCl3, 125 MHz): δ -0.60, -0.54, 10.91, 13.68, 27.28,

28.94, 68.83, 71.68, 71.91, 72.58, 73.50, 74.89, 75.04, 75.32, 78.18, 83.44, 83.50, 106.19, 127.22, 127.41,

127.49, 127.57, 127.73, 127.86, 127.89, 127.96, 128.06, 128.18, 128.27, 128.76, 129.57, 132.99, 133.74,

138.12, 138.34, 138.61, 138.74, 138.89, 152.97. IR (NaCl, neat): υ 3088m, 3065s, 3029s, 2955s, 2923s,

2861s, 2247w, 1948w, 1877w, 1807w, 1743w, 1606m, 1496s, 1454s, 1427s, 1399m, 1359s, 1247s, 1208s,

1108s, 1067s, 1028s, 909s, 824s, 776m, 732s, 697s, 596m. HRMS (Electrospray): Calcd. for

C59H76O6SiSnNa (M++Na), 1051.4326; Found (M++Na), 1051.4271.

3-96

O

OBn

BnOBnO BnO

O

H

nOe

PhMe2SiSnBu3

H H

H

H

H

6.4%8.3%

2.3%

2

3

5

6

7

8

9


H3 → H9 8.3 H6b → H5 3.6 H8 → H7b 0.2

H5 → H9 1.3 H6b → H6a 13.5 H8 → SiMe2 1.50

H6a → H6b 14.5 H8 → H7a 2.3 H9 → H3 6.4

O

OBn

BnOBnO BnO

O

H

Bu3SnSiMe2Ph

H H

H

H

H

3-98

3

25

6

7

8

9

440


NMR (CDCl3, 500 MHz): δ 0.36 (s, 3H), 0.52 (s, 3H), 0.84-0.95 (m, 6H), 0.89 (t, J = 7.3 Hz, 9H), 1.23-

1.33 (m, 6H), 1.38-1.52 (m, 6H), 3.62 (d, J = 9.8 Hz, 2H), 3.76 (dd, J = 10.9, 4.2 Hz, 1H), 3.79 (app t, J =

9.5 Hz, 1H), 3.94 (d, J = 10.0 Hz, 1H), 4.17 (app t, J = 9.6 Hz, 1H), 4.50 (d, J = 12.5 Hz, 1H), 4.51 (d, J =

11.1 Hz, 1H), 4.57 (dd, J = 11.0, 1.6 Hz, 1H), 4.61 (d, J = 10.4 Hz, 1H), 4.65 (d, J = 12.5 Hz, 1H), 4.77 (d,

J = 11.2 Hz, 1H), 4.87 (d, J = 10.8 Hz, 1H), 4.89 (d, J = 10.8 Hz, 1H), 4.90 (d, J = 11.7 Hz, 1H), 5.06 (d, J

= 10.9 Hz, 1H), 5.72 (s, 1H), 6.54 (s, JSn-H = 40.5 Hz, 1H), 7.17-7.19 (m, 2H), 7.30-7.40 (m, 21H), 7.59

(dd, J = 7.7, 1,7 Hz, 2H) . 1H NMR (CD2Cl2, 500 MHz): δ 0.31 (s, 3H), 0.46 (s, 3H), 0.82 (t, J = 7.3 Hz,

9H), 0.85-0.79 (m, 6H), 1.19-1.27 (m, 6H), 1.37-1.43 (m, 6H), 3.49 (ddd, J = 10.1, 3.5, 1.7 Hz, 1H), 3.53

(dd, J = 10.4, 1.9 Hz, 1H), 3.67 (app t, J = 9.5 Hz, 1H), 3.68 (dd, J = 10.2, 3.6 Hz, 1H), 3.79 (d, J = 9.9 Hz,

1H), 4.07 (app t, J = 9.7 Hz, 1H), 4.40 (dd, J = 11.1, 1.2 Hz, 1H), 4.43 (d J = 12.1 Hz, 1H), 4.51 (dd, J =

11.1, 1.9 Hz, 1H), 4.53 (d, J = 12.1 Hz, 1H), 4.55 (d, J = 10.6 Hz, 1H), 4.69 (d, J = 11.4 Hz, 1H), 4.80 (d, J

= 10.6 Hz, 1H), 4.81 (d, J = 11.1 Hz, 2H), 4.98 (d, J = 11.1 Hz, 1H), 5.67 (s, 1H), 6.50 (s, JSn-H = 40.4 Hz,

1H), 7.13-7.16 (m, 2H), 7.21-7.35 (m, 21H), 7.52-7.55 (m, 2H) . 13C NMR (CDCl3, 125 MHz): δ -0.16,

0.09, 10.69, 13.65, 27.28, 28.85, 68.79, 71.67, 72.61, 73.30, 74.95, 75.31, 75.60, 78.42, 83.28, 83.90,

106.35, 123.44, 127.25, 127.43, 127.56, 127.79, 127.83, 127.85, 127.90, 128.03, 128.09, 128.25, 128.28,

128.36, 128.42, 128.87, 133.66, 134.47, 138.01, 138.24, 138.73, 138.83, 139.70, 149.50, 155.41. IR (NaCl,

neat): υ 3065m, 3030m, 2943s, 2924s, 2861s, 1048w, 1878w, 1813w, 1737w, 1623m, 1496m, 1454s,

1428m, 1359m, 1248m, 1209m, 1068s, 907m, 842s, 792m, 731s, 697s. HRMS (Electrospray): Calcd. for

C59H76O6SiSnNa (M++Na), 1051.4326; Found (M++Na), 1051.4376.

nOe

O

OBn

BnOBnO BnO

O

H

Bu3SnSiMe2Ph

H H

H

H

H

7.3%

8.9% 1.7%, 1.3%

3-97

2

35

6

7

8

9


441

H3 → H6 4.8 H5 → H6 8.6 H8 → H7 1.7, 1.3

H3 → H9 8.9 H6 → H9 1.1 H9 → H3 7.3

Bromination of Silylstannylated D-gluconosubstituted (Z,Z)-1,3-Dienes

To a mixture of (S)-8, 9, 10-tris-benzyloxy-7-benzyloxymethyl-4-[(dimethylphenylsilanyl)-

methylene]-1,6-dioxa-3-[(tri-butylstannanyl)-methylene]- spiro[4.5]decane 3-93 (16 µmol, 16.5 mg)in 0.5

mL of NBS (20 µmol, 3.6mg) at rt. The mixture was stirred at rt until no more starting material was

detected on TLC (16h). After all solvent was removed in a rotary evaporator, the crude mixture was

purified by column chromatography eluting with hexane:EtOAc = 20:1.

O

OBn

BnOBnO BnO

O

BrSiMe2PhH

HH

H

H

nOe

3-108

Yellow oil. Column chromatography; hexane:EtOAc = 20:1. Rf = 0.11 (hexane:EtOAc = 10:1). 1H NMR

(CDCl3, 500 MHz): δ 0.51 (s, 3H), 0.56 (s, 3H), 3.74 (d, J = 9.6 Hz, 2H), 3.80 (app t, J = 9.6 Hz, 1H), 3.85

(dd, J = 11.5, 3.8 Hz, 1H), 3.99 (ddd, J = 10.0, 3.6, 1.7 Hz, 1H), 4.02 (app t, J = 9.3 Hz, 1H), 4.53-4.56 (m,

2H), 4.56 (d, J = 10.2 Hz, 1H), 4.66 (d, J = 12.4 Hz, 1H), 4.67 (s, 2H), 4.69 (d, J = 11.0 Hz, 1H), 4.88 (d, J

= 10.7 Hz, 1H), 4.90 (d, J = 10.3 Hz, 1H), 4.92 (d, J = 11.3 Hz, 1H), 6.26 (s, 1H), 6.36 (s, 1H), 7.27-7.35

(m, 23H), 7.58 (d, J = 6.8 Hz, 2H). 13C NMR (CDCl3, 125 MHz): δ -2.24, -1.04, 68.87, 71.71, 73.45,

73.51, 74.95, 74.98, 75.58, 78.09, 82.40, 83.32, 101.94, 106.55, 127.40, 127.49, 127.54, 127.58, 127.62,

127.90, 128.07, 128.12, 128.29, 128.34, 128.83, 129.70, 133.83, 138.04, 138.41, 138.64, 138.86, 140.91,

151.09. IR (NaCl, neat): υ 3062m, 3030m, 2922s, 2854s, 1730w, 1623w, 1496w, 1454m, 1427w, 1362m,

1428m, 1209w, 1144m, 1092s, 1028s, 839m, 733s, 697s. HRMS (Electrospray): Calcd. for

C47H49O6SiBrNa (M++Na), 839.2374; Found (M++Na), 839.2374.

442

O

OBn

BnOBnO BnO

O

H

3-109

PhMe2SiBr

H H

H

H

H

Pale yellow oil. Column chromatography; hexane:EtOAc = 10:1. Rf = 0.17 (hexane:EtOAc = 10:1). 1H

NMR (CDCl3, 400 MHz): δ 0.38 (s, 6H), 3.51 (app dt, J = 10.1, 1.8 Hz, 1H), 3.56 (dd, J = 10.9, 1.7 Hz,

1H), 3.64 (d, J = 11.0 Hz, 1H), 3.69-3.64 (m, 1H), 3.79 (d, J = 9.3 Hz, 1H), 4.02 (app t, J = 8.9 Hz, 1H),

4.23 (dd, J = 10.6, 1.7 Hz, 1H), 4.38 (d, J = 9.7 Hz, 1H), 4.39 (d, J = 12.5 Hz, 1H), 4.47 (d, J = 10.7 Hz,


1H), 4.74 (d, J = 11.0 Hz, 1H), 4.76 (d, J = 11.4 Hz, 1H), 4.83 (d, J = 11.0 Hz, 1H), 5.99 (s, 1H), 6.27 (s,

1H), 7.07-7.11 (m, 3H), 7.14-7.25 (m, 20H), 7.41 (d, J = 6.8 Hz, 2H). 13C NMR (CDCl3, 100 MHz): δ -

2.32, -1.95, 68.78, 69.16, 72.81, 73.25, 74.89, 75.05, 75.17, 78.28, 82.83, 83.56, 127.34, 127.40, 127.42,

127.60, 127.71, 127.76, 128.05, 128.17, 128.21, 128.33, 128.38, 128.81, 132.12, 133.98, 138.12, 138.33,

138.40, 138.46, 138.69, 140.30, 145.83.

3-110

O

OBn

BnOBnO BnO

O

H

BrSiMe2Ph

H H

H

H

H


NMR (CDCl3, 400 MHz): δ 0.38 (s, 3H), 0.52 (s, 3H), 3.48 (ddd, J = 10.0, 4.2, 1.9 Hz, 1H), 3.66 (dd, J =

10.6, 1.8 Hz, 1H), 3-68-3.72 (m, 2H), 3.81(app t, J = 9.5 Hz, 1H), 3.93 (d, J = 9.7 Hz, 1H), 4.52 (d, J =

12.4 Hz, 1H), 4.56 (d, J = 10.6 Hz, 1H), 4.58 (s, 2H), 4.62 (d, J = 12.4 Hz, 1H), 4.68 (d, J = 11.4 Hz, 1H),


5.93 (s, 1H), 6.84 (s, 1H), 7.14-7.16 (m, 2H), 7.26-7.36 (m, 21H), 7.55 (dd, J = 7.2, 1.7 Hz, 2H). 13C NMR

(CDCl3, 100 MHz): δ -3.24, -0.76, 68.64, 71.63, 72.93, 73.38, 74.50, 75.20, 75.67, 77.96, 82.26, 84.14,

443

107.63, 108.57, 126.64, 127.49, 127.53, 127.63, 127.76, 127.82, 127.86, 127.92, 128.12, 128.24, 128.30,

128.35, 128.43, 128.81, 137.89, 138.12, 138.38, 138.44, 138.53, 139.20, 148.35.

Destannylation of Silylstannylated D-gluconosubstituted (Z,Z)-1,3-Dienes

To a mixture of (S)-8,9,10-tris-benzyloxy-7-benzyloxymethyl-4-[(dimethylphenylsilanyl)-

methylene]-1,6-dioxa-3-[(tri-butylstannanyl)-methylene]- spiro[4.5]decane 3-93 (0.168 mmol, 172 mg)in 5

mL of dichloromethane was added formic acid (0.839 mmol, 32 µL) at rt. The mixture was stirred at rt

until no more starting material was detected on TLC (24h). After all solvent was removed in a rotary

evaporator, the crude mixture was purified by column chromatography eluting with hexane:EtOAc = 20:1.

O

OBn

BnOBnO BnO

O

HSiMe2PhH

HH

H

H

nOe

3-113


NMR (CDCl3, 400 MHz): δ 0.26 (s, 3H), 0.27 (s, 3H), 3.51 (dd, J = 11.3, 1.8 Hz, 1H), 3.56-3.63 (m, 3H),

3.78 (ddd, J = 10.1, 3.8, 1.8 Hz, 1H), 3.86 (app t, J = 9.3 Hz, 1H), 4.36-4.41 (m, 4H), 4.45-4.48 (m, 2H),

4.56 (d, J = 10.7 Hz, 1H), 4.68 (d, J = 9.3 Hz, 1H), 4.70 (s, 2H), 4.82 (s, 1H), 5.11 (app t, J = 2.2 Hz, 1H),

5.90 (s, 1H), 7.03-7.05 (m, 2H), 7.07-7.14 (m, 21H), 7.31-7.32 (m, 2H). 13C NMR (CDCl3, 100 MHz): δ -

2.34, -1.54, 68.68, 71.54, 72.99, 73.21, 74.87, 75.52, 75.56, 78.30, 82.88, 83.79, 123.46, 127.43, 127.46,

127.48, 127.59, 127.65, 127.76, 127.85, 127.97, 128.16, 128.29, 128.34, 129.14, 133.65, 137.87, 138.21,

138.43, 138.57, 138.88, 143.35, 154.53. IR (NaCl, neat): υ 3062m, 3031m, 2921s, 2855s, 1731w, 1605w,

1497m, 1454m, 1428w, 1362m, 1250w, 1208w, 1149m, 1092s, 1028m, 837m, 732s, 697s. HRMS


444

O

OBn

BnOBnO BnO

O

SiMe2PhHH

HH

H

H

3-114


1H NMR (CDCl3, 500 MHz): δ 0.45 (s, 3H), 0.46 (s, 3H), 3.67 (d J = 9.5 Hz, 1H), 3.73 (dd, J = 11.1, 1.7

Hz, 1H), 3.78 (app t J = 9.7 Hz, 1H),, 3.82 (dd, J = 11.2, 4.0 Hz, 1H), 4.02 (ddd, J = 10.0, 3.8, 1.7 Hz, 1H),

4.09 (app t, J = 9.3 Hz, 1H), 4.56 (d, J = 12.2 Hz, 1H), 4.60 (d, J = 10.9 Hz, 1H), 4.65 (d, J = 12.7 Hz, 1H),

4.66 (d, J = 10.7 Hz, 1H), 4.75 (d, J = 12.6 Hz, 1H), 4.73 (s, 2H), 4.88-4.93 (m, 3H), 7.24-7.27 (m, 4H),

7.29-7.38 (m, 19H), 7.58 (dd, J = 7.7, 1.2 Hz, 2H),. 13C NMR (CDCl3, 125 MHz): δ -1.96, -1.81, 68.80,

72.72, 73.26, 74.29, 74.84, 75.09, 75.64, 78.23, 82.49, 83.72, 127.44, 127.49, 127.58, 127.64, 127.74,

127.78, 127.84, 127.94, 128.15, 128.27, 128.33, 129.12, 133.68, 138.15, 138.21, 138.41, 138.27, 138.77,

145.63, 152.67. IR (NaCl, neat): υ 3064m, 3030m, 2922s, 2861s, 1951w, 1881w, 1807w, 1731w, 1604w,

1496m, 1453s, 1428m, 1361m, 1249m, 1208m, 1154s, 1093s, 1048s, 909m, 860w, 835m, 733s, 698s.

HRMS (Electrospray): Calcd. for C47H50O6SiNa (M++Na), 761.3269; Found (M++Na), 761.3291.

3-114

O

OBn

BnOBnO

BnOO

SiMe2PhHH

HH

H

H

3.0%

17.6%

3.4%

4.9%18.3%

2

4

5

6

7

8

9a

9b

O

OBn

BnOBnO BnO

O

H

3-115

PhMe2SiH

H H

H

H

H

445


1H NMR (CDCl3, 500 MHz): δ 0.50 (s, 3H), 0.53 (s, 3H), 3.76-3.84 (m, 4H), 4.00 (d J = 9.1 Hz, 1H), 4.20

(app t J = 8.8 Hz, 1H), 4.51 (d, J = 12.3 Hz, 1H), 4.61 (d, J = 12.0 Hz, 1H), 4.68 (d, J = 10.7 Hz, 1H), 4.69


(d, J = 11.6 Hz, 1H), 4.92 (d, J = 10.6 Hz, 1H), 5.01 (d, J = 12.9 Hz, 1H), 5.02 (s, 1H), 5.32 (s, 1H), 6.16

(s, 1H), 7.27-7.28 (m, 2H), 7.30-7.40 (m, 21H), 7.58 (dd, J = 7.8, 1.1 Hz, 2H),. 13C NMR (CDCl3, 125

MHz): δ -2.11, -0.97, 69.08, 69.52, 72.50, 73.20, 73.90, 75.09, 75.11, 78.23, 82.69, 83.65, 108.13, 110.29,

126.01, 127.22, 127.41, 127.57, 127.70, 127.77, 127.88, 128.06, 128.10, 128.45, 128.21, 128.31, 128.39,

128.99, 133.68, 138.20, 138.17, 138.43, 138.54, 138.94, 143.50, 150.01. IR (NaCl, neat): υ 3087m, 3064s,

3029s, 2912s, 2872s, 2246w, 1952w, 1879w, 1810w, 1650w, 1604w, 1586s, 1496s, 1453s, 1427m, 1396w,

1360m, 1249m, 1209m, 1072s, 1028s, 908m, 833s, 732s, 697s. HRMS (Electrospray): Calcd. for


O

OBn

BnOBnO BnO

O

H

PhMe2Si

H H11.3%

HH

18.6%3.3%

9.3%

3-115

2

4

5

6

7

8a

9

8b

Diels-Alder Reaction of Vinylsilane 3-113 with Ethyl propiolate

Vinylsilane 3-113 (90 mg, 0.122 mmol) and ethyl propiolate (36 mg, 0.365 mmol) in toluene (122

µL) were placed into an 1 mL ample. To the mixture catalytic amount of benzoquinone was added, and the

ample was sealed tightly by flame. The reaction mixture was immersed into an 100 mL one necked-flask

filled with xylene. The flask was heated in an oil-bath under refluxing condition for 2 d. After removed

the solvent on a rotary evaporator under reduce pressure, the resulting mixture was purified by column

chromatography eluting hexane:EtOAc = 10:1 to 8:1. The Diels-Alder product was obtained as a mixture

of 3-130 and 3-131 (pale yellow oil) with a ratio of 1.0/0.2. The isolated yield is 14% (14 mg).

446

O

OBn

BnOBnO BnO

O

H

HH

SiMe 2

Ph

OEt

O

3-130

O

OBn

BnOBnO BnO

O

H

HH

SiMe 2

Ph

OEt

O

3-131


1H NMR (CDCl3, 400 MHz): major δ 0.65 (s, 3H), 0.69 (s, 3H), 1.39 (t J = 7.1 Hz, 3H), 3.30 (d, J = 9.0

Hz, 1H), 3.50 (d, J = 10.7 Hz, 1H), 3.70 (dd, J = 10.5, 1.4 Hz, 1H), 3.83 (app t, J = 9.6 Hz, 1H), 3.87 (dd, J

= 10.6, 3.5 Hz, 1H), 3.97 (app t, J = 9.2 Hz, 1H), 4.02 (d, J = 10.7 Hz, 1H), 4.13 (dd, J = 10.2, 1.9 Hz, 1H),

4.38 (q, J = 7.1 Hz, 2H), 4.43 (d, J = 11.5 Hz, 1H), 4.52 (d, J = 11.5 Hz, 1H), 4.64 (d, J = 10.9 Hz, 1H),

4.77 (s, 2H), 4.82 (d, J = 10.9 Hz, 1H), 5.12 (d, J = 12.3 Hz, 1H), 5.21 (d, J = 12.3 Hz, 1H), 6.60 (d, J = 6.9

Hz, 2H), 6.99-7.42 (m, 23H), 7.56-7.58 (m, 2H), 7.90 (s, 1H), 9.26 (d, J = 1.0 Hz, 1H). 13C NMR (CDCl3,

100 MHz): mixture δ -0.65, 0.26, 14.26, 61.77, 73.72, 73.93, 74.06, 75.10, 75.44 , 75.45, 84.27, 84.55,

111.66, 120.30, 123.72, 127.75, 127.78, 127.99, 128.22, 128.30, 128.32, 128.42, 128.58, 128.67, 128.76,

128.79, 128.95, 128.97, 130.11, 131.13, 134.92, 135.56, 137.77, 138.65, 139.05, 139.23, 139.97, 142.20,

142.58, 167.07. IR (NaCl, neat): υ 3060m, 3030m, 2924m, 2860m, 1717s, 1647w, 1602w, 1497m, 1454m,

1428w, 1365w, 1289m, 1236w, 1217w, 1181w, 1108s, 1089s, 1028m, 838m, 817m, 780w, 736m, 698s.

HRMS (Electrospray): Calcd. for C52H56O8SiNa (M++Na), 859.3637; Found (M++Na), 859.3640.

Diels-Alder Reaction of Vinylsilane 3-113 with Methyl Vinylketone

Vinylsilane 3-113 (101 mg, 0.137 mmol) and methyl vinylketone (29 mg, 0.410 mmol) in toluene

(137 µL) were placed into an 1 mL ample. To the mixture catalytic amount of benzoquinone was added,

and the ample was sealed tightly by flame. The reaction mixture was immersed into an 100 mL one

necked-flask filled with xylene. The flask was heated in an oil-bath under refluxing condition for 2 d.

After removed the solvent on a rotary evaporator under reduce pressure, the resulting mixture was purified

by column chromatography eluting hexane:EtOAc = 10:1 to 8:1. The Diels-Alder product was obtained as

a mixture of 3-134 and 3-135 (pale yellow oil) with a ratio of 1.0/0.2. The isolated yield is 62% (68 mg).

447

O

OBn

BnOBnO BnO

O

H

HH

SiMe 2

Ph

CH3

O

O

OBn

BnOBnO BnO

O

H

H H

Si CH3

O

3-134 3-135


1H NMR (CDCl3, 400 MHz): major δ 0.19 (s, 3H), 0.27 (s, 3H), 1.26 (Br s, 1H), 1.40 (app td J = 12.8, 5.1

Hz, 1H), 1.81 (s, 3H), 1.80-1.90 (m, 1H), 2.46 (dd J = 4.9, 1.9 Hz, 1H), 2.54-2.62 (m, 2H), 2.64-2.74 (m,

1H), 3.30 (dd, J = 5.9, 3.0 Hz, 1H), 3.58 (dd, J = 9.7, 6.1 Hz, 1H), 3.62 (dd, J = 9.8, 4.4 Hz, 1H), 4.12 (d, J

= 10.4, 5.7 Hz, 1H), 4.17 (dd, J = 7.0, 3.1 Hz, 1H), 4.20 (d, J = 11.1 Hz, 1H), 4.26 (d, J = 11.8 Hz, 1H),

4.41 (d, J = 11.1 Hz, 1H), 4.49 (d, J = 4.2 Hz, 1H), 4.50-4.56 (m, 1H), 4.61-4.71 (m, 3H), 4.84 (d, J = 7.2

Hz, 1H), 4.86 (d, J = 11.3 Hz, 1H), 7.19-7.39 (m, 25H). 13C NMR (CDCl3, 100 MHz): mixture δ -2.80, -

2.51, -2.28, -1.96, 19.61, 20.19, 20.41, 20.53, 27.87, 28,05, 28.40, 28.87, 29.69, 30.90, 45.45, 45.55, 70.21,

70.41, 70.67, 71.l44, 71.91, 72.01, 72.08, 72.39, 73.36, 73.39, 74.22, 75.13, 75.32,l 76.05, 78.33, 80.63,

80.72, 84.42, 85.73, 119.88, 120.56, 122.60, 122.81, [over lap in aromatic region], 210.28, 210.39. IR

(NaCl, neat): υ 3065m, 3028m, 2918m, 2854m, 1710s, 1496w, 1453m, 1426w, 1364w, 1303w, 1250w,

1208w, 1111s, 1028m, 815m, 736s, 698s. HRMS (Electrospray): Calcd. for C51H56O7SiNa (M++Na),

831.3688; Found (M++Na), 831.3649.

Oxidation of 3-132 and 3-133 with mCPBA

To the mixture of 3-134 and 3-135 (72 mg, 89 µmol) in CH2Cl2 (10 mL) were added mCPBA (70-

75%, 31 mg, 0.173 mmol) and NaHCO3 (60 mg, 0.714 mmol) at rt, and the resulting mixture was stirred at

rt for 2 h. All starting material 3-134 and 3-135 was consumed (judged by TLC analysis). The mixture

was diluted with CH2Cl2, washed with H2O and brine solution, dried over MgSO4, filtered, and

concentrated on a evaporator under reduced pressure. The residue was purified by column chromatography

eluting hexane:EtOAc = 10:1 to 8:1. The major portion was obtained as colorless oil (27 mg, 48%), which

is assigned as a mixture of 3-136 and 3-137 with a ratio of 1.0/0.2.

448

O

OBn

BnOBnO BnO

O

H

HH

SiMe 2

Ph

OAcO

O

OBn

BnOBnO BnO

O

H

HH

Si

O

OAc

3-136 3-137


13C NMR (CDCl3, 100 MHz): δ -3.52, -1.26, 16.74, 22.29, 25.46, 27.71, 43.75, 60.74, 68.43, 68.97, 71.28,

71.50, 73.54, 73.59, 74.37, 77.20, 77.47, 82.13, 97.78, 104.19, 127.10, 127.53, 127.64, 127.76, 127.99,

128.06, 128.20, 128.28, 128.39, 129.61, 134.09, 138.39, 138.49, 139.02, 139.08, 211.48. HRMS


449

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