Preparation of novel ligands for rhodium (II) and palladium (II) catalysts and application in the synthesis of palmerolide A and conversion of biomass into formic acid

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Content PREPARATION OF NOVEL LIGANDS FOR RHODIUM (II) AND PALLADIUM

(II) CATALYSTS AND APPLICATION IN THE SYNTHESIS OF PALMEROLIDE A

AND CONVERSION OF BIOMASS INTO FORMIC ACID

by

Prasanna Pullanikat

A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(CHEMISTRY)

December 2010

Copyright 2010 Prasanna Pullanikat
ii

Dedicated to
Michael J. Jackson
Who made this world a better place with his extraordinary
artistry, compassion, and humanitarian efforts for
children everywhere.
He truly changed the world.

iii

ACKNOWLEDGMENTS

I thank this universe for all the positive responses. I heartily thank Prof. K.W.
Jung, my mentor, for giving me a great opportunity to work in his lab. I am grateful to
him for letting me work on different projects. I would also like to thank Prof. K. W. Jung
for the continuous motivation and support.
My special thanks to Dr. Cheol Hwan Yoon for all his support when I started
working in this group at the University of South Florida. I also thank Dr. Kyung Soo Yoo
for all his help and support in my research program especially with the project focusing
on the coversion of biomass into formic acid. I am thankful to Dr. Joo Ho Lee for his
input for the biomass conversion project and for helping me in collecting spectral data of
13
C labeled glycolic acid. I would also like to extend my gratitude to all my labmates for
constant support throughout the program. I would like to thank Dr. Young Jung with
whom I started working in the beginning when I joined Prof. K. W. Jung’s group at the
University of South Florida. It was a very good experience working with him on the
kainic acid project. My thanks are also due to other members including Richard, Victor,
Justin, Dr. Park, Kisoo Park and Goo. I am thankful to Richard for all inspiring
discussions of topics of science to world peace and problems.
I would like to thank all the undergraduates and high school students, Kristy
Chun, Parth Shah, Thomas and Johny who have worked with me on the rhodium (II)
catalyzed desymmetrisation and oxidative degradation of biomass.
I thank my thesis committee members Professor K. Surya Prakash and Professor
Nouri Neamati. Also, I would like to extend my thanks to other members of my
qualifying exam committee Professor Thieo E. Hogen-Esch, Professor Nicolaou Petasis
iv

for their guidance and helpful discussions. I would like to express my gratitude to Prof.
Surya Prakash for his constant inspiration and motivation, and for his wise suggestions. I
am thankful to Professor Thiego E. Hogen-Esch for his time and suggestions as well.
In addition, I am thankful to Dr. Thomas Mathew for his help, knowledge and
support. There are many other individuals in Olah-Prakash group who provided support
and friendship during my graduate studies especially, my very caring and loving friend
Inessa, Arjun and Clement. I would like to thank Dr. Farzaneh Paknia for her help.
I would like to thank Prof. Travis Williams for his chemistry discussions. I am
thankful to his former students as well, especially to Kim Hamilton for her continuous
friendship and support.
Also, I would like to thank other staff members of the USC Chemistry
Department and Loker Hydrocarbon Institute, especially Michele Dea, Heather Connor,
Carole Philips, Katie McKissic and David Hunter for their support. I thank Mr. Allan
Kershaw for technical help with NMR spectrometers. I thank Mr. Jim Merit for helping
me with glass blowing and Darrel in the stock room for all the help.
In addition I would like to thank the USF chemistry department. I would like to
thank Professor Turos and Professor Baker as well for the chemistry discussions during
JACS meetings. I learned a lot during those discussions. I extend my thanks for my
friends at USF, Lisa, Olivia, Julio and Marcia for their love and support as well.
I would also like to thank professor Jared Butcher and professor Marcia
Kieliszewski for their kindness and help. I would not have been able to continue my
studies without their help.
v

I would like to thank all the teachers of my undergrad and graduate studies
especially Dr. Ramana, for initiating interest in chemistry and teaching strong basics in
organic chemistry, and Professor Subha for her continuous support.
Thanks are also due to my ex-colleagues in Dr. Reddy’s Research Foundation,
India especially to Dr. Reeba Vikramadityan and Dr. Narayan Reddy. Also, I would like
to thank all my wonderful friends, especially, Sreelatha, Ravi Jonna, Punam Tiwary,
Rajendar Tiwary, Pragathy Hegde, Sailaja Mudda, Chetana Williamson, Vindya Kumari,
Harish Vasudevan, Michael Harvey, Karan Jani and Anu for their continuous support and
love. They did not hesitate to help whenever their help was needed. Also, I am gratful to
Dr. Spring and Dr. Greco for their time and support. Without their help it would have
been very difficult to finish writing my dissertation. I would also like to thank my friends
Cat, Catherine Coy and Elizabeth Olney for their love and support during the hardest
time in my life.
Finally, I would like to thank my loving and caring mother, sister Sreelatha and
brother Sathyan and his wife Sindu, as well as wonderful nephew Sunil and nieces
Swathy, Sivani and Shreyafor their unconditional love and support. I am so much
indebted and thankful to my father for his love and inspiration when he was in this world.

vi

TABLE OF CONTENTS

DEDICATION ii

ACKNOWLEDGMENTS iii

LIST OF TABLES ix

LIST OF FIGURES x

LIST OF SCHEMES xxxv

ABSTRACT xxxviii

Chapter 1: Studies towards the total synthesis of palmerolide A 1
1.1 Introduction
1.1.1 Isolation and Biological Activity 1
1.1.2 Brabander’s approach 2
1.1.3 Chandrasekhar’s approach 2
1.1.4 Nicolaou’s approach 4
1.1.5 Maier’s approach 5
1.1.6 Hall’s approach 6
1.1.7 Dudley’s approach 6
1.1.8 Baker’s approach. 7
1.1.9 Kalippan's approach 8
1.2 Aim and Scope of the Present Work 8
1.3 Conclusion 31
1.4 Experimental 31
1.4.1 General 31
1.4.2 General Procedures 32
1.5 Spectral Data 82
1.6 Representative Spectra 98
1.7 References 178

Chapter 2: Rhodium-II catalysed disymmetrization reactions 183
2.1 Introduction 183
2.2 Results and Discussion 188
2.2.1 Preparation of methyl oxazolidin-3-yl)-2-diazo-2-
(phenylsulfonyl) ethanone 188
2.2.2 C-H insertion reaction of (S)-1-(4-(2-((tert-butyldimethyl silyl)
oxy)ethyl)-2,2-dimethyl oxazolidin-3-yl)-2-diazo-2-(phenyl
sulfonyl)ethanone 189

vii

2.2.3 Rh-II catalyzed desymmetrization reactions of diazoamide
compounds 190
2.2.4 Preparation of 1-[4,4-bis-(tert-butyl-dimethyl
silanyloxymethyl)-2,2-dimethyloxazolidin-3-yl]
2-diazo-ethanone 192
2.2.5 C-H activation of 1-(4,4-bis(((tert-butyldimethyl
silyl)oxy)methyl)- 2,2-dimethyloxazo- lidin-3-yl)
2-diazoethanone 193
2.2.6 Preparation of 1-trifluoromethanesulfonyl-imidazolidin
2-one ligands 195
2.2.7 CH activation of 1-[4,4-bis-(tert-butyl-dimethyl
silanyloxy- methyl)2,2-dimethyl-oxazolidin-3-yl]
2-diazo-butane-1,3-dione 196
2.2.8 Preparation of 1-[3,3-bis-(tert-butyl-dimethyl
silanyloxymethyl)-1-oxa-4- aza-spiro[4.5]dec-4-yl]-
2-diazo-ethanone (48) 197
2.2.9 C-H activation of 1[3,3-bis-(tert-butyl-dimethyl-sianyloxy
methyl)-1-oxa-4-aza-spiro[4.5]dec-4-yl]-2-diazo-ethanone 199
2.2.10 C-H activation of 1-[3,3-bis-(tert-butyl-dimethyl-silanyl
oxymethyl)-1-oxa-4-aza-spiro[4.5]dec-4-yl]-2-diazo-butane
1,3-dione (57) 200
2.2.11 C-H activation of trans-1-benzylhexahydro-1H-indol
(3H)-one 201
2.2.12 C-H activation of N-cyclohexyl-2-diazo-N-phenyl
2-(phenylsulfonyl)acetamide 202
2.3 Conclusion 203
2.4 Scope for the future work 204
2.5 Experimental 205
2.5.1 General 205
2.5.2 General Procedures 207
2.6 Spectral Data 226
2.7 Representative Spectra 233
2.8 References 304

Chapter 3 : Preparation of NHC-Pd-II complex. Application in the oxidative
degradation of biomass into formic acid 309
3.1 Introduction 309
3.2 Results and Discussion 311
3.2.1 Preparation of NHC-Pd complex 311
3.2.2 Direct Conversion of biomass such as Glycerol
into Formic Acid via Water Stable Pd(II) Catalyzed
Oxidative Carbon-Carbon Bond Cleavage 312

viii

3.2.3 Catalytic oxidative Carbon-Carbon bond cleavage of
glycerol with Oxygen and additives agents in the
presence of 1 at RT 313
3.2.4 Optimization of reaction condition for the oxidative
degradation of glycerine to formic acid 314
3.2.5 Oxidative degradation of
13
C labeled glycerol 322
3.2.6 Proposed mechanism 326
3.2.7 Studies to support the proposed mechanism 331
3.2.8 Oxidative degradation reactions with Cationic Palladium complex 338
3.2.9 Oxidative degradation of glycerol with
Cationic Palladium complex and Oxygen in
presence of additives 340
3.2.10 Oxidative degradation of starch, cellulose and grass 340
3.2.11 NHC-Pd catalyzed oxidative degradation of glycerine, ethylene
glycol and glycolic acid with NaBO
3
342
3.3 Conclusion 342
3.4 Experimental 343
3.5 Sprectral Data 346
3.6 Representative Spectra 348
3.7 References 450

Chapter 4: Oxidative Degradation of Reducing Carbohydrates to
Ammonium Formate with H
2
O
2
and NH
4
OH 455
4.1 Introduction 455
4.2 Results and Discussion 457
4.2.1 Optimization of oxidative degradation of glucose 457
4.2.2 Oxidative degradation of carbohydrates to
ammonium formate 458
4.3 Conclusion 462
4.4 Experimental 463
4.5 Representative Spectra 465
4.6 References 491

Comprehensive bibliography 494

ix

LIST OF TABLES

Table 2.1 Commercially available Rh-II catalysts used for C-H activation 194

Table 3.1 Catalytic oxidative Carbon-Carbon bond cleavage of glycerol
with various oxidizing agents in the presence of 1 at RT. 313

Table 3.2 Oxidative degradation reactions of glycerol with oxygen in
presence of metallic and nonmetallic additives 314

Table 3.3 Typical results of catalytic oxidative C-C cleavage of glycerol
into formic acid 318

Table 3.4 Oxidative degradation studies of carbohydrates and
dihydroxyacetone in presence of the NHC-Pd complex 1 323

Table 3.5 Oxidative degradation of other hydroxy substrates 332

Table 3.6 Oxidative degradation studies of carbohydrates and dihydroxyacetone
in presence of the NHC-Pd complex 1 337

Table 3.7 Oxidative degradation of ethylene glycol with cationic
NHC-Pd complex 1 339

Table 3.8 Reactions with cationic palladium in the presence of metallic
additives and oxygen in a closed system: 340

Table 3.9 Oxidative degradation of starch

, cellulose and grass 341

Table 3.10 NHC-Pd catalyzed oxidative degradation of glycerine, ethylene glycol
and glycolic acid with NaBO
3
342

Table 4.1 Optimization of oxidative degradation of glucose 457

Table 4.2 Oxidative degradation of carbohydrates to ammonium formate 459

Table 4.3 Oxidative degradation of ketoses to ammonium formate and
ammonium glycolate 460

x

LIST OF FIGURES
Figure 1.1 Original and Revised Structures of palmerolide 2
Figure 1.2 Brabander’s approach 3
Figure 1.3 Chandrasekhar’s approach 3
Figure 1.4 Retrosythetic analysis of originally proposed palemerolide A 4
Figure 1.5 Maier’s approach 5
Figure 1.6 Hall’s approach 6
Figure 1.7 Dudley’s approach 6
Figure 1.8 Baker’s approach 7
Figure 1.9 Kalippan’s approach 8
Figure 1.10 A diastereomer of originally proposed structure 9

Figure 1.11 Preparation of (E)-ethyl octa-2,7-dienoate 32

Figure 1.12 Preparation of (R,E)-ethyl 7,8-dihydroxyoct-2-enoate 33

Figure 1.13 Preparation of (R,E)-ethyl 8-((tert-butyldiphenylsilyl)
oxy)-7-hydroxyoct-2-enoate 34

Figure 1.14 (R,E)-ethyl 8-((tert-butyldiphenylsilyl)oxy)-7-(methoxymethoxy)
oct-2-enoate 35

Figure 1.15 (R,E)-ethyl 8-hydroxy-7-(methoxymethoxy)oct-2-enoate 36

Figure1.16 (R,E)-ethyl 7-(methoxymethoxy)-8-((methylsulfonyl)oxy)
oct-2-enoate 36

Figure 1.17 Preparation of (R,E)-ethyl 8-iodo-7-(methoxymethoxy)
oct-2-enoate 37

Figure 1.18 Preparation of (4S,5S)-dimethyl 2,2-dimethyl-1,3-dioxolane
4,5-dicarboxylate 38

xi

Figure 1.19 Preparation of ((4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5
diyl)dimethanol 38

Figure 1.20 Preparation of ((4R,5R)-5-(((4-methoxybenzyl)oxy)methyl)-2,2-
dimethyl-1,3-dioxolan-4-yl)methanol 40

Figure 1.21 ((4R,5R)-5-(((4-methoxybenzyl)oxy)methyl)-2,2-dimethyl-1,3
dioxolan-4-yl)methyl4-methylbenzene sulfonate 41

Figure 1.22 (2R,3R)-2,3-dihydroxy-4-((4-methoxybenzyl)oxy)butyl
4-methylbenzenesulfonate 41

Figure 1.23 (R)-2-((4-methoxybenzyl)oxy)-1-((R)-oxiran-2
yl)ethanol 42

Figure 1.24 (R)-2-((R)-2-((4-methoxybenzyl)oxy)-1-(methoxymethoxy)
ethyl) oxirane 42

Figure 1.25 (2R,3R)-1-((4-methoxybenzyl)oxy)-2-(methoxy
methoxy)hex-5-yn-3-ol 44

Figure 1.26 (4R,5S)-4-(iodomethyl)-5-(((4-methoxybenzyl)oxy)
methyl)-2,2-dimethyl-1,3-dioxolane 44

Figure 1.27 (R)-1-((4-methoxybenzyl)oxy)but-3-en-2-ol 45

Figure 1.28 (R,E)-(8-ethoxy-2-hydroxy-8-oxooct-6-en-1-
yl)triphenylphosphonium iodide 46

Figure 1.29 Preparation of hex-5-en-1-yl benzoate 46

Figure 1.30 Preparation of (R)-5,6-dihydroxyhexyl benzoate 47

Figure 1.31 Preparation of (R)-5-((tert-butyldimethylsilyl)
oxy)-6-hydroxyhexyl benzoate 48

Figure 1.32 Preparation of (R)-5-((tert-butyldimethylsilyl)oxy)-6-
hydroxyhexylbenzoate 49

Figure 1.33 Preparation of (R)-5-((tert-butyldimethylsilyl)oxy)
6-oxohexylbenzoate 50

Figure 1.34 Preparation of (R, E)-5-((tert-butyldimethylsilyloxy)-7-iodo
hept-6-en-1-yl benzoate 50

xii

Figure 1.35 Preparation of methyl 2-(2-methyl-1,3-dioxolan-2-yl)acetate 51

Figure 1.36 Preparation of 2-(2-methyl-1,3-dioxolan-2-yl)ethanol 52

Figure 1.37 Preparation of 2-(2-methyl-1,3-dioxolan-2-yl)acetaldehyde 52

Figure 1.38 (E)-ethyl 4-(2-methyl-1,3-dioxolan-2-yl)but-2-enoate 53

Figure 1.39 Preparation of (E)-4-(2-methyl-1,3-dioxolan-2-yl)
but-2-en-1-ol 54

Figure 1.40 Preparation of ((2R,3R)-3-((2-methyl-1,3-dioxolan-2-yl)
methyl)oxiran-2-yl)methanol 54

Figure 1.41 Preparation of (2S,3R)-2-methyl-4-(2-methyl-1,3
dioxolan-2-yl)butane-1,3-diol 55

Figure 1.42 Preparation of (4R,5S)-2-(4-methoxyphenyl)-5-methyl-4-((2-methyl-
1,3-dioxolan-2-yl)methyl)-1,3-dioxane 56

Figure 1.43 Preparation of (4R,5S)-2-(4-methoxyphenyl)-5
methyl-4-(2-methylallyl)-1,3-dioxane 57

Figure 1.44 Preparation of (2R,3S)-3-methyl-1-(2-methyl-1,3-dioxolan
2-yl)pent-4-yn-2-ol and (4R,5S)-4-hydroxy-5-methylhept-6-
yn-2-one 58

Figure 1.45 Preparation of tert-butyldimethyl(((2R,3S)-3-methyl-1
(2-methyl-1,3-dioxolan-2-yl)hex-4-yn-2-yl) oxy) silane 59

Figure 1.46 Preparation of (E)-methyl 5-methylhexa-2,5-dienoate 60

Figure 1.47 Preparation of (E)-5-methylhexa-2,5-dien-1-ol 60

Figure 1.48 Preparation of ((2R,3R)-3-(2-methylallyl)oxiran-2-yl)methanol 61

Figure 1.49 Preparation of (2S,3R)-2,5-dimethylhex-5-ene-1,3-diol 62

Figure 1.50 Preparation of (4R,5S)-2-(4-methoxyphenyl)-5-methyl
4-(2-methylallyl)-1,3-dioxane 63

Figure 1.51 Preparation of (4S,5R,E)-5-((4-methoxybenzyl)oxy)
2,4,7-trimethylocta-2,7-dienal 64

xiii

Figure 1.52 Preparation of (2R,3R)-hept-6-yne-1,2,3-triol 65

Figure 1.53 Preparation of methyl 2-((4S,4'R,5R)-2,2,2',2'-tetramethyl
[4,4'-bi(1,3- dioxolan)]-5-yl)acetate 65

Figure 1.54 Preparation of 4-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-4
hydroxy-but-2-enoic acid methyl ester 66

Figure 1.55 Preparation of 4-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-4
hydroxy-but-2-enoic acid methylester 67

Figure 1.56 Preparation of (4S,E)-methyl 4-((tert-butyldiphenylsilyl)
oxy)-4-(2,2-dimethyl-1,3-dioxolan-4-yl)but-2-enoate 68

Figure 1.57 Preparation of (S,E)-4-((tert-butyldiphenylsilyl)oxy)-4-((R)-2,2-
dimethyl-1,3-dioxo lan-4-yl)but-2-en-1-ol 69

Figure 1.58 Preparation of (S,E)-4-((tert-butyldiphenylsilyl)oxy)
4-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)but-2-enal 70

Figure 1.59 Preparation of 4-((4-methoxybenzyl)oxy)butan-1-ol 70

Figure 1.60 Preparation of 1-((4-iodobutoxy)methyl)-4-methoxybenzene 71

Figure 1.61 Preparation of 1-((4-iodobutoxy)methyl)-4-methoxybenzene 72

Figure 1.62 Preparation of (5S,E)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)
8-(4-((4- methoxy benzyl)oxy)butyl)-2,2,10,10,11,11-hexa
methyl-3,3-diphenyl-4,9-dioxa-3,10-disiladodec-6-ene 73

Figure 1.63 Preparation of (2R,3S,E)-3-((tert-butyldiphenylsilyl)oxy)
10-((4-methoxybenzyl) oxy)dec-4-ene-1,2,6-triol 74

Figure 1.64 Preparation of (2R,3S,E)-3,6-bis((tert-butyldiphenylsilyl)oxy)
10-((4-methoxybenzyl) oxy)dec-4-ene-1,2-diol 75

Figure 1.65 Preparation of (2R,3S,E)-3,6-bis((tert-butyldiphenylsilyl)
oxy)-2-hydroxy-10-((4-methoxybenzyl)oxy)dec-4-en-1
yl benzoate 75

Figure 1.66 Preparation of (2R,3S,E)-3,6-bis((tert-butyldiphenylsilyl)oxy) -10
((4-methoxybenzyl)oxy)-2-((methylsulfonyl)oxy)dec-4-en-1-yl
benzoate 76

xiv

Figure 1.67 Preparation of (8S,E)-5-(4-((4-methoxybenzyl)oxy)butyl)-
2,2,11,11-tetramethyl-8-((S)-oxiran-2-yl)-3,3,10,10-tetra-
phenyl-4,9-dioxa-3,10-disiladodec-6-ene 77
Figure 1.68 Preparation of (4S,5R)-4-(((4-methoxybenzyl)oxy)
methyl)-2,2-dimethyl-5-((phenyl sulfonyl)methyl)-
1,3-dioxolane 78

Figure 1.69 Preparation of (3R)-7-((tert-butyldimethylsilyl)oxy)-3-
((4-methoxybenzyl)oxy)-1-((4R,5S)-5-(((4-methoxy
benzyl)oxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-1
(phenylsulfonyl) heptan-2-yl acetate 79

Figure 1.70 Preparation of tert-butyl(((S,E)-4-((4-methoxybenzyl)oxy)-1-((S)-
oxiran-2-yl)but-2-en-1-yl)oxy)diphenylsilane 80

Figure 1.71 Preparation of (5R,6S,E)-6-((tert-butyldiphenylsilyl)oxy)-9-((4-
methoxybenzyl) oxy) non-7-en-1-yn-5-ol 80

Figure 1.72 Preparation of (4S,5R,E)-4-((tert-butyldiphenylsilyl)oxy)
5-hydroxynon-2-en-8-ynal 81

Figure 1.73
1
H NMR of (E)-ethyl octa-2,7-dienoate
(Scheme 1.2, compound 24) 98

Figure 1.74
1
H NMR of (R,E)-ethyl 7,8-dihydroxyoct-2-enoate
(Scheme 1.2, compound 25) 99

Figure 1.75
13
C NMR of (R,E)-ethyl 7,8-dihydroxyoct-2-enoate
(Scheme 1.2, compound 25) 100

Figure 1.76
1
H NMR of (R,E)-ethyl 8-((tert-butyldiphenylsilyl)oxy)
7-hydroxyoct-2-enoate
(Scheme 1.2, compound 26) 101

Figure 1.77
13
C NMR of (R,E)-ethyl 8-((tert-butyldiphenylsilyl)oxy)
7-hydroxyoct-2-enoate
(Scheme 1.2, compound 26) 102

Figure 1.78 Cosy NMR of (R,E)-ethyl 8-((tert-butyldiphenylsilyl)oxy)
7-hydroxyoct-2-enoate
(Scheme 1.2, compound 26) 103

Figure 1.79
1
H NMR of (R,E)-ethyl 8-((tert-butyldiphenylsilyl)
oxy)-7-(methoxy methoxy)oct-2-enoate
(Scheme 1.2, compound 27) 104
xv

Figure 1.80
13
C NMR of (R,E)-ethyl 8-((tert-butyldiphenylsilyl)
oxy)-7-(methoxy methoxy)oct-2-enoate
(Scheme 1.2, compound 27) 105

Figure 1.81
1
H NMR of (R,E)-ethyl 8-hydroxy-7-(methoxy
methoxy)oct-2-enoate
(Scheme 1.2, compound 28) 106

Figure 1.82
1
H NMR of (R,E)-ethyl 7-(methoxymethoxy)-8-((methyl
sulfonyl)oxy)oct-2-enoate
(Scheme 1.2, compound 29) 107

Figure 1.83
13
C NMR of (R,E)-ethyl 7-(methoxymethoxy)-8-((methyl
sulfonyl)oxy)oct-2-enoate
(Scheme 1.2, compound 29) 108

Figure 1.84
1
H NMR of (R,E)-ethyl 8-iodo-7-(methoxymethoxy)oct-2-enoate
(Scheme 1.2, compound 30) 109

Figure 1.85
1
H NMR of (4S,5S)-dimethyl 2,2-dimethyl-1,3
dioxolane-4,5-dicarboxylate
(Scheme 1.3, compound 33) 110

Figure 1.86
1
H NMR of Hex-5-en-1-yl benzoate
(Scheme 1.13, compound 78) 111

Figure 1.87
13
C NMR of (4S,5S)-dimethyl 2,2-dimethyl-1,3
dioxolane-4,5-dicarboxylate
(Scheme 1.3, compound 33) 112

Figure 1.88
1
H NMR of ((4S,5S)-5-(((4-methoxybenzyl)oxy)methyl)
2,2-dimethyl-1,3-dioxolan-4-yl)methanol
(Scheme 1.3, compound 36) 113

Figure 1.89
13
C NMR of ((4R,5R)-5-(((4-methoxybenzyl)oxy) methyl)
2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzene
sulfonate (Scheme 1.3, compound 37) 114

Figure 1.90
1
H NMR of (R)-2-((R)-2-((4-methoxybenzyl)
oxy)-1-(methoxymethoxy)ethyl)oxirane
(Scheme 1.3, compound 39) 115

Figure 1.91
1
H NMR of (R)-1-((4-methoxybenzyl)oxy)but-3-en-2-ol
(Scheme 1.4, compound 46) 116

xvi

Figure 1.92
1
H NMR of (R,E)-ethyl-7-hydroxy-8-iodooct-2-enoate
(Scheme 1.5, compound 46) 117

Figure 1.93
1
H NMR of (R,E)-(8-ethoxy-2-hydroxy-8-oxooct-6-en-1-yl)
triphenyl phosphonium iodide
(Scheme 1.5, compound 48) 118

Figure 1.94
1
H NMR of (R)-5,6-dihydroxyhexyl benzoate
(Scheme 1.13, compound 79) 119

Figure 1.95
1
H NMR of (R)-5-((tert-butyldimethylsilyl)oxy)
6-hydroxyhexyl benzoate
(Scheme 1.13, compound 81) 120

Figure 1.96
1
H NMR of (R)-5,6-bis((tert-butyldimethylsilyl)oxy)
hexyl benzoate
(Scheme 1.13, compound 80) 121

Figure 1.97
1
H NMR of (R)-5-((tert-butyldimethylsilyl)oxy)
6-oxohexyl benzoate
(Scheme 1.16, compound 82) 122

Figure 1.98
1
H NMR of (R,E)-5-((tert-butyldimethylsilyl)oxy)
7-iodohept-6-en-1-yl benzoate
(Scheme 1.13, compound 83) 123

Figure 1.99
1
H NMR of (4S,5R)-4-(((4-methoxybenzyl)oxy)methyl)
2,2-dimethyl-5-((phenyl sulfonyl)methyl)-1,3-dioxolane
(Scheme 1.15, compound 84) 124

Figure 1.100
1
H NMR of (3R)-7-((tert-butyldimethylsilyl)oxy-
3-((4-methoxybenzyl)oxy)-1-(phenylsulfonyl)
heptan-2-yl acetate
(Scheme 1.15, compound 86) 125

Figure 1.101 Ethyl-2-(2-methyl-1,3-dioxolan-2-yl)acetate
(Scheme 1.11, compound 59") 126

Figure 1.102
1
H NMR of methyl 2-(2-methyl-1,3-dioxolan-2-yl)acetate
(Scheme 1.11, compound 59’) 127

Figure 1.103
13
C NMR of 2-(2-methyl-1,3-dioxolan-2-yl)ethanol
(Scheme 1.11, compound 60) 128

xvii

Figure 1.104
1
H NMR of 2-(2-methyl-1,3-dioxolan-2-yl)ethanol
(Scheme 1.11, compound 59’’) 129

Figure 1.105
1
H NMR of 2-(2-methyl-1,3-dioxolan-2-yl)acetaldehyde
(Scheme 1.12, compound 70) 130

Figure 1.106
1
H NMR of ((2R,3R)-3-((2-methyl-1,3-dioxolan-2-yl)
methyl)oxiran-2-yl)methanol
(Scheme 1.11, compound 63) 131

Figure 1.107
1
H NMR of (2S,3R)-2-methyl-4-(2-methyl-1,3-dioxolan-2-yl)
butane-1,3-diol (Scheme 1.11, compound 64) 132

Figure 1.108
1
H NMR of (2S,3R)-2-methyl-4-(2-methyl-1,3-dioxolan-2-yl)
butane-1,3-diol
(Scheme 1.11, compound 64) 133

Figure 1.109 COSY NMR of (2S,3R)-2-methyl-4-(2-methyl-1,3-dioxolan-2-yl)
butane-1,3-diol
(Scheme 1.11, compound 64) 134

Figure 1.110
1
H NMR of (4R,5S)-2-(4-Methoxyphenyl)-5-methyl-4
((2-methyl-1,3-dioxolan-2-yl)methyl)-1,3-dioxane
(Scheme 1.11, compound 65) 135

Figure 1.111
1
H NMR of (4R,5S)-2-(4-methoxyphenyl)-5-methyl-4-(2-methyl
allyl)-1,3-dioxane
(Scheme 1.11, compound 66) 136

Figure 1.112
1
H NMR of (R)-but-3-yn-2-yl methanesulfonate
(Scheme 1.12, compound 69) 137

Figure 1.113
1
H NMR of (4R,5S)-4-hydroxy-5-methylhept-6-yn-2-one
(Scheme 1.12, compound 71) 138

Figure 1.114
1
H NMR of (2R,3S)-3-methyl-1-(2-methyl-1,3-dioxolan-2-yl)
pent-4-yn-2-ol
(Scheme 1.12, compound 72) 139

Figure 1.115
1
H NMR of tert-butyldimethyl(((2R,3S)-3-methyl-1-
(2-methyl-1,3-dioxolan-2-yl)hex-4-yn-2-yl)oxy)silane
(Scheme 1.12, compound 72) 140

Figure 1.116
1
H NMR of (E)-methyl 5-methylhexa-2,5-dienoate
(Scheme 1.13, compound 77)1 141
xviii

Figure 1.117
1
H NMR of (E)-5-methylhexa-2,5-dien-1-ol
(Scheme 1.13, compound 80) 142

Figure 1.118
1
H NMR ((2R,3R)-3-(2-methylallyl)oxiran-2-yl)methanol
(Scheme 1.13, compound 79) 143

Figure 1.119
1
H NMR of (2S,3R)-2,5-dimethylhex-5-ene-1,3-diol
(Scheme 1.13, compound 80) 144

Figure 1.120
1
H NMR of (2S,3R)-2,5-dimethylhex-5-ene-1,3-diol
(Scheme 1.13, compound 80) 145

Figure 1.121
1
H NMR of (2R,3R)-hept-6-yne-1,2,3-triol
(Scheme 1.8, compound 54) 146

Figure 1.122
1
H NMR of 4-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-4-hydroxy
but-2-enoic acid methyl ester
(Scheme 1.18, compound 88) 147

Figure 1.123 COSY NMR of 4-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-4-hydroxy
but-2-enoic acid methyl ester
(Shceme 1.18, compound 88) 148

Figure 1.124
1
H NMR of methyl 2-((4S,4'R,5R)-2,2,2',2'-tetramethyl
[4,4'-bi(1,3-dioxolan)]-5-yl)acetate
(Scheme 1.18, compound 89) 149

Figure 1.125 (4S,E)-methyl-4-((tert-butyldiphenylsilyl)oxy)
4-(2,2-dimethyl-1,3-dioxolan-4-yl)but-2-enoate
(Scheme 1.18, compound 90) 150

Figure 1.126
1
H NMR of (S,E)-4-((tert-butyldiphenylsilyl)oxy)
4-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)but-2-en-1-ol
(Scheme 1.18, compound 91) 151

Figure 1.127 COSY NMR of (S,E)-4-((tert-butyldiphenylsilyl)oxy)
4-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)but-2-en-1-ol
(Scheme 1.18, compound 91) 152

Figure 1.128
13
C NMR of (S,E)-4-((tert-butyldiphenylsilyl)oxy)
1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)but-2-en-1-ol
(Scheme 1.18, compound 92) 153

xix

Figure 1.129
1
H NMR of (S,E)-4-((tert-butyldiphenylsilyl)oxy)
1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)but-2-en-1-ol
(Scheme 1.18, compound 92) 154

Figure 1.130 Cosy NMR of (S,E)-4-((tert-butyldiphenylsilyl)oxy)
1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)but-2-en-1-ol
(Scheme 1.18, compound 92) 155

Figure 1.131
1
H NMR of (S,E)-4-((tert-butyldiphenylsilyl)oxy)-4
((R)-2,2-dimethyl-1,3-dioxolan-4-yl)but-2 al
(Scheme 1.18, compound 93) 156

Figure 1.132 Cosy NMR of (S,E)-4-((tert-butyldiphenylsilyl)oxy)-4
((R)-2,2-dimethyl-1,3-dioxolan-4-yl)but-2-enal
(Scheme 1.18, compound 93) 157

Figure 1.133
13
C NMR of (S,E)-4-((tert-butyldiphenylsilyl)oxy)-4
((R)-2,2-dimethyl-1,3-dioxolan-4-yl)but-2-enal
(Scheme 1.18, compound 93) 158

Figure 1.134
1
H NMR of 4-((4-methoxybenzyl)oxy)butan-1-ol
(Scheme 1.19, compound 96) 159

Figure 1.135
1
H NMR of 1-((4-iodobutoxy)methyl)-4-methoxybenzene
(Scheme 1.19, compound 97) 160

Figure 1.136
1
H NMR of (1S,E)-1-((tert-butyldiphenylsilyl)oxy)
1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-8-((4-methoxy
benzyl)oxy)oct-2-en-4-ol
(Scheme 1.20, compound 95) 161

Figure 1.137
1
H NMR of (5S,8S,E)-5-((R)-2,2-dimethyl-1,3-dioxolan
4-yl)-8-(4-((4-methoxy benzyl)oxy)butyl)-2,2,10,10,11,11
hexamethyl-3,3-diphenyl-4,9-dioxa-3,10-disila dodec-6-ene
(Scheme 1.20, compound 95) 162

Figure 1.138
13
C NMR of (5S,8S,E)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)
8-(4-((4-methoxy benzyl)oxy)butyl)-2,2,10,10,11,11-hexamethyl
3,3-diphenyl-4,9-dioxa-3,10-disila dodec-6-ene
(Scheme 1.20, compound 95) 163

Figure 1.139 Cosy NMR of (5S,E)-5-((R)-2,2-dimethyl-1,3-dioxolan
4-yl)-8-(4-((4-methoxybenzyl)oxy)butyl)-2,2,10,10,11,11-hexa
methyl-3,3-diphenyl-4,9-dioxa-3,10-disiladodec-6-ene
(Scheme 1.20, compound 98) 164
xx

Figure 1.140
1
H NMR of (2R,3S,E)-3-((tert-butyldiphenylsilyl)oxy)
10-((4-methoxybenzyl) oxy) dec-4-ene-1,2,6-triol
(Scheme 1.20, Compound 96) 165

Figure 1.141 Cosy NMR of (2R,3S,E)-3-((tert-butyldiphenylsilyl)
oxy)-10-((4-methoxybenzyl) oxy)dec-4-ene-1,2,6-triol
(Scheme 1.20, Compound 96) 166

Figure 1.142
1
H NMR of (2R,3S,E)-3,6-bis((tert-butyldiphenylsilyl)
oxy)-10-((4-methoxybenzyl) oxy)dec-4-ene-1,2-diol
(Scheme 1.20, Compound 98) 167

Figure 1.143
13
C NMR of (2R,3S,E)-3,6-bis((tert-butyldiphenyl
silyl)oxy)-10-((4-methoxybenzyl) oxy)dec-4-ene-1,2-diol
(Scheme 1.20, Compound 98) 168

Figure 1.144
1
H NMR of (2R,3S,E)-3,6-bis((tert-butyldiphenyl
silyl)oxy)-10-((4-methoxybenzyl) oxy)-2-((methylsulfonyl)
oxy)dec-4-en-1-yl benzoate
(Scheme 1.20, compound 99) 169

Figure 1.145
1
H NMR of (8S,E)-5-(4-((4-methoxybenzyl)oxy)butyl)
2,2,11,11-tetramethyl-8-((S)-oxiran-2-yl)-3,3,10,10-tetra
phenyl-4,9-dioxa-3,10-disiladodec-6-ene
(Scheme 1.20, compound 100) 170

Figure 1.146 Cosy NMR of (8S,E)-5-(4-((4-methoxybenzyl)oxy)butyl)
2,2,11,11-tetramethyl-8-((S)-oxiran-2-yl)-3,3,10,10-tetraphenyl
4,9-dioxa-3,10-disiladodec-6-ene
(diastereomer-lower spot on TLC)
(Scheme 1.20, compound 100) 171

Figure 1.147
13
C NMR NMR of (8S,E)-5-(4-((4-methoxybenzyl)oxy)
butyl)-2,2,11,11-tetramethyl-8-((S)-oxiran-2-yl)-3,3,10,10-
tetraphenyl-4,9-dioxa-3,10-disiladodec-6-ene
(diastereomer-lower spot on TLC)
(Scheme 1.20, compound 100) 172

Figure 1.148
1
H NMR of tert-butyl(((S,E)-4-((4-methoxybenzyl)oxy)-1-((S)
oxiran-2-yl) but-2-en-1-yl)oxy)diphenylsilane
(Scheme 1.21, compound 109) 173

xxi

Figure 1.149
13
C NMR of tert-butyl(((S,E)-4-((4-methoxybenzyl)oxy)-1
((S)-oxiran-2-yl) but-2-en-1-yl)oxy)diphenylsilane
(Scheme 1.21, compound 109) 174

Figure 1.150
1
H NMR of (5R,6S,E)-6-((tert-butyldiphenylsilyl)oxy)
9-((4-methoxy benzyl)oxy)non-7-en-1-yn-5-ol
(Scheme 1.21, compound 111) 175

Figure 1.151
1
H NMR of (4S,5R,E)-4-((tert-butyldiphenylsilyl)oxy)
5-hydroxynon-2-en-8-ynal
(Scheme 1.21, compound 112) 176

Figure 1.152
13
C NMR (4S,5R,E)-4-((tert-butyldiphenylsilyl)oxy)
5-hydroxynon-2-en-8-ynal
(Scheme 21, compound 112) 177

Figure 2.3 Preparation of (S)-4-(3-(tert-butyldimethylsilyloxy)propyl)
2,2-dimethyloxazoli-dine or (L)-glutamic acid dimethylester 207

Figure 2.4 Preparation of (S)-2-aminopentane-1,5-diol 208

Figure 2.5 Preparation of (S)-3-(2,2-dimethyloxazolidin-4-yl)propan-1-ol 209

Figure 2.6 Preparation of (S)-4-(3-((tert-butyldimethylsilyl)oxy)propyl)-2,2-
dimethyl oxazo- lidine 209

Figure 2.7 Preparation of (S)-1-(4-(3-((tert-butyldimethylsilyl)oxy)
propyl)-2,2-dimethyloxazoli din-3-yl)-2-chloroethanone 210

Figure 2.8 Preparation of (S)-1-(4-(3-((tert-butyldimethylsilyl)oxy)propyl)
2,2- dimethyloxazo-lidin-3-yl)-2-(phenylsulfonyl)ethanone 211

Figure 2.9 Preparation of (S)-1-(4-(3-((tert-butyldimethylsilyl)oxy)
propyl)-2,2-methyloxazol- idin-3-yl)-2-diazo-2-(phenyl
sulfonyl)ethanone 212

Figure 2.10 Preparation of (6S,7S,7aS)-7-(((tert-butyldimethylsilyl)
oxy)methyl)-3,3-dimethyl-6-(phenylsulfonyl)tetrahydro
pyrrolo[1,2-c]oxazol-5(3H)-one 213

Figure 2.11 Preparation of 2,2-dimethyl oxazoli dine-4,4-diyl)dimethanol 213

Figure 2.12 Preparation of 4,4-bis((tert-butyldimethylsilyloxy)methyl)-2,2-
dimethyloxazolidine 214

xxii

Figure 2.13 Preparation of 1-(4,4-bis((tert-butyldimethylsilyloxy)
methyl)-2,2-dimethyloxazoli din-3-yl)butane-1,3-dione 215

Figure 2.14 1-(4,4-bis((tert-butyldimethylsilyloxy)methyl)-2,2-
dimethyloxazolidin-3-yl)-2-diazobutane-1,3-dione 216

Figure 2.15 Preparation of 1-(4,4-bis((tert-butyldimethylsilyloxy)methyl)-2,2-
dimethyloxazoli- din-3-yl)-2-diazoethanone 217

Figure 2.16 Preparation of 7-(tert-butyldimethylsilyloxy)-7a-((tert-butyl
dimethyl silyloxy)methyl)-3,3-dimethyl-dihydro-pyrrolo[1,2-
c]oxazol-5 (1H,3H,6H)-one 218

Figure 2.17 Preparation of 6-acetyl-7a-(((tert-butyldimethylsilyl)oxy)
methyl)-3,3-dimethyl-1,7a-dihydropyrrolo[1,2-c]oxazol-5(3H)-one 218

Figure 2.18 (S)-2-amino-3,3-dimethylbutan-1-ol 219

Figure 2.19 Preparation of (3aR,7aR)-1-((trifluoromethyl)sulfonyl)
hexahydro-1H-benzo[d]imi-dazol-2(3H)-one 220

Figure 2.20 Preparation of (4R, 5R)-Diphenyl-imidazolidin-2-one 220

Figure 2.21 (4R,5R)-Diphenyl-1-trifluoromethanesulfonyl-imidazolidin-2-one 221

Figure 2.22 (R)- 3,5-dihydro-4H-Dinaphtho[2,1-d:1',2'-f][1,3]diazepin-4-one 222

Figure 2.23 3-((trifluoromethyl)sulfonyl)-3H-dinaphtho[2,1-d:1',2'-f][1,3]
diazepin-4(5H)-one 222

Figure 2.24 Preparation of complex with (3aR,7aR)-1-((trifluoromethyl)
sulfonyl)hexahydro-1H-benzo[d]imidazol-2(3H)-one and 1/3
equivalent of Rh
2
(OAc)
4
223

Figure 2.25 2-Benzenesulfonyl-N-benzyl-N-cyclohexyl-acetamide 224

Figure 2.26 Preparation of 1-[3,3-bis-(tert-butyldimethylsilanyloxymethyl)
1-oxa-4-aza-spiro[4,5]dec-4-yl-2-diazoethanone 224

Figure 2.27 Preparation of N-cyclohexyl-2-diazo-N-phenyl-2-(phenylsulfonyl)
Acetamide 225

Figure 2.28
1
H NMR of (S)-4-(3-(tert-butyldimethylsilyoxy)propyl)
2,2-dimethylsilyoxy)propyl)-2,2-dimethyloxazolidine
(Scheme 2.3, compound 12) 233
xxiii

Figure 2.29
1
H NMR of (S)-3-(2,2-dimethyloxazolidin-4-yl)propan-1-ol
(Scheme 2.3, compound 14) 234

Figure 2.30
1
H NMR of (S)-4-(3-((tert-butyldimethylsilyl)oxy)propyl)
2,2-dimethyl oxazolidine
(Scheme 2.3, compound 16) 235

Figure 2.31
1
H NMR of (S)-4-(3-(tert-butyldimethylsilyloxy)propyl)
2,2-dimethyloxa zolidine
(Scheme 2.3, compound 16) 236

Figure 2.32 (S)-1-(4-(3-((tert-butyldimethylsilyl)oxy)propyl)-2,2-dimethyl
oxazolidin-3-yl)-2-chloroethanone
(Scheme 2.3, compound 17) 237

Figure 2.33
1
H NMR of (6S,7S,7aS)-7-(((tert-butyldimethylsilyl)oxy)
methyl)-3,3-dimethyl-6-(phenylsulfonyl)tetrahydropyrrolo
[1,2-c]oxazol-5(3H)-one
(Scheme 2.3, compound 7) 238

Figure 2.34
1
H NMR of (2,2-dimethyloxazolidine-4,4-diyl)dimethanol
(Scheme 2.6, compound 25) 239

Figure 2.35
13
C NMR of (2,2-dimethyloxazolidine-4,4-diyl)dimethanol
(Scheme 2.6, compound 25) 240

Figure 2.36 COSY NMR of (2,2-dimethyloxazolidine-4,4-diyl)dimethanol
(Scheme 2.6, compound 25) 241

Figure 2.37
1
HNMR of 4,4-bis((tert-butyldimethylsilyloxy)methyl)-2,2
dimethyloxa zolidine
(Scheme 2.6, compound 26) 242

Figure 2.38
13
C NMR of 4,4-bis((tert-butyldimethylsilyloxy)methyl)-2,2-
dimethyloxazo lidine
(Scheme 2.6, compound 26) 243

Figure 2.39 COSY NMR of 4,4-bis((tert-butyldimethylsilyloxy)
methyl)-2,2-demithyl-Oxazolidine
(Scheme 2.6, compound 26) 244

Figure 2.40
1
HNMR of 1-(4,4-bis((tert-butyldimethylsilyloxy)
methyl)-2,2-dimethyloxa zolidin-3-yl)-2-diazobutane-1,3-dione
(Scheme 2.6, compound 29) 245
xxiv

Figure 2.41
13
C NMR of 1-(4,4-bis((tert-butyldimethylsilyloxy)
methyl)-2,2-dimethyl oxa zolidin-3-yl)-2-diazoethanone
(Scheme 2.6, compound 29) 246

Figure 2.42 COSY NMR of 1-(4,4-bis((tert-butyldimethylsilyloxy)
methyl)-2,2-dimethyl oxa- zolidin-3-yl)-2-diazoethanone
(Scheme 2.6, compound 29) 247

Figure 2.43
1
H NMR of 1-[3,3-bis-(tert-butyl-dimethyl-silanyloxy
methyl)-1-oxa-4-aza-spiro [4.5] dec-4-yl]-2-diazo-etha none
(Scheme 2.6, compound 30) 248

Figure 2.44
13
C NMR of 1-[3,3-bis-(tert-butyl-dimethyl-silanyloxy
methyl)-1-oxa-4-aza-spiro [4.5] dec-4-yl]-2-diazo-etha none
(Scheme 2.6, compound 30) 249

Figure 2.45 COSY NMR of 1-[3,3-bis-(tert-butyl-dimethyl-silanyloxy
methyl)-1-oxa-4-aza-spiro [4.5] dec-4-yl]-2-diazo-etha none
(Scheme 2.6, compound 30) 250

Figure 2.46
1
H NMR of 7-(tert-butyldimethylsilyloxy)-7a-((tert-butyldimethyl
silyloxy) methyl-3,3-dimethyl-dihydro-pyrrolo[1,2-c]oxazol-
5(1H,3H,6H)one (Scheme 2.6, compound 35) Cyclized product
with Rh
2
(OAc)
4
251

Figure 2.47 COSY NMR of 7-(tert-butyldimethylsilyloxy)
7a-((tert-butyldimethyl silyloxy)methyl)-3,3-dimethyl-dihydro-
pyrrolo[1,2-c]oxazol-5(1H,3H,6H)-one
(Scheme 2.6, compound 35) 252

Figure 2.48
1
H NMR of crude compound 7-(tert-butyldimethylsilyloxy)
7a-((tert-butyl dimethyl silyloxy) methyl-3,3-dimethyl-dihydro-
pyrrolo[1,2-c]oxazol-5(1H,3H,6H)-one
(Scheme 2.6, compound 25) Cyclized product with Rh
2
(OAc)
4
253

Figure 2.49 CH activation product 25 with catalyst-Doyle
dirhodium (Rh
2
(5R-MEPY)
4
254

Figure 2.50
1
H NMR of crude CH activation product with premixed
Rh
2
(OAc)
4
and ligand (3aR,7aR)-1-((trifluoromethyl)
sulfonyl)hexahydro-1H-benzo[d]imidazol-2(3H)-one 255

Figure 2.51
1
H NMR of CH activation product with premixed catalyst
from (R)-4-(tert-butyl)oxazolidin-2-one (40) and Rh
2
(OAc)
4
256

xxv

Figure 2.52
1
H NMR of CH activation product with premixed catalyst
from (R)-4-(tert-butyl)oxazolidin-2-one (40) and Rh
2
(OAc)
4
257

Figure 2.53
1
H NMR of 7-(tert-butyldimethylsilyloxy)-7a
((tert-butyldimethyl silyloxy) methyl) -3,3-dimethyl
dihydro- pyrrolo[1,2-c]oxazol-5(1H,3H,6H)-one
Doyle dirhodium catalyst Rh(4S-MEOX)
4
258

Figure 2.54
1
H NMR of 3,3-bis-(tert-butyl-dimethyl-silanyloxymethyl)
1-oxa-4-aza-spiro[4.5]dec-4-yl]-2-diazo-butane-1,3-dione 259

Figure 2.55 COSY NMR of 3,3-bis-(tert-butyl-dimethylsilanyoxymethyl)
1-oxa-4aza-spiro[4,5]dec-4yl]-2-diazo-butane-1,3-dione 260

Figure 2.56
1
H NMR of 1-[3,3-bis-(tert-butyl-dimethyl-silanyloxymethyl)
1-oxa-4-aza-spiro[4.5]dec-4-yl]-butane-1,3-dione
(Scheme 2.10, compound 45) 261

Figure 2.57
1
H NMR of 1-[3,3-bis-(tert-butyl-dimethyl-silanyloxy
methyl)-1-oxa-4-aza-spiro[4.5]dec-4-yl]-2-diazo-butane
1,3-dione (Scheme 2.10, compound 47) 262

Figure 2.58
1
H NMR of 1-[3,3-bis-(tert-butyl-dimethyl-silanyloxymethyl)
1-oxa-4-aza-spiro[4.5]dec-4-yl]-2-diazo-ethanone 263

Figure 2.59
13
C NMR of 1-[3,3-bis-(tert-butyl-dimethyl-silanyloxymethyl)
1-oxa-4-aza-spiro[4.5]dec-4-yl]-2-diazo-ethanone 264
Figure 2.60 COSY NMR of 1-[3,3-bis-tert-butyldimethylsilanyloxy
methyl)-1-oxa-aza-spiro[4,5]dec-4-yl)-2-diazoethanone 265

Figure 2.61
1
H NMR of CH activation of 1-(3,3-bis(((tert-butyldimethyl
silyl)oxy) methyl)-1-oxa-4-azaspiro [4.5]decan-4-yl)-2-diazo
ethanone 266

Figure 2.62
1
H NMR of CH activation of 1-(3,3-bis(((tert-butyldimethyl
silyl) oxy) methyl)-1-oxa-4-azaspiro [4.5]decan-4-yl)-2-diazo
ethanone (Scheme 2.11, compound 51’) 267

Figure 2.63 CH activation with Tetrakis[N-phthaloyl (S)-phenylalaninato]
dirhodium ethylacetate 268

Figure 2.64
13
C NMR of CH activation with Tetrakis[N-phthaloyl (S)-phenyl
alaninato] dirhodium ethylacetate 269

xxvi

Figure 2.65 (Tetrakis[1{4-alkyl(C11-C13)phenylsulfonyl}
(2S)-pyrrolidinecarboxyl-ate]dirhodium (II) 270

Figure 2.66
1
H NMR of N-benzylidenecyclohexanamine 271

Figure 2.67
13
C NMR of N-benzylidenecyclohexanamine 272

Figure 2.68
1
H NMR of Benzyl-cyclohexyl-amine 273

Figure 2.69
1
H NMR of 2-Benzenesulfonyl-2-diazo-1-(2,2,5-trimethyl
oxazolidin-3-yl)-ethanone 274

Figure 2.70 COSY NMR of 2-Benzenesulfonyl-2-diazo-1-(2,2,5-trimethyl
oxazolidin-3-yl-ethanone 275

Figure 2.71
13
C NMR of 2-Benzenesulfonyl-2-diazo-1-(2,2,5-trimethyl
oxazolidin-3-yl)-ethanone 276

Figure 2.72
1
H NMR of Benzyl-cyclohexyl-amine 277

Figure 2.73 Cosy NMR of Benzyl-cyclohexyl-amine 278

Figure 2.74
1
H NMR of N-phenyl-N-cyclohexyl-2-diazo-3-oxo-butyramide

279

Figure 2.75
1
H NMR of N-benzyl-N-cyclohexyl-2-diazo-2-(phenylsulfonyl)
acetamide 280

Figure 2.76
13
C NMR of N-benzyl-N-cyclohexyl-2-diazo-2-(phenylsulfonyl)
acetamide 281

Figure 2.77 COSY NMR of N-benzyl-N-cyclohexyl-2-diazo-2-(phenyl
sulfonyl)acetamide 282

Figure 2.78 1-Benzyl-3-(phenylsulfonyl)hexahydro-1H-indol-2(3H)-one 283

Figure 2.79
1
H NMR of [1-Diazo-2-oxo-2-(2,2,5-trimethyl-oxazolidin-3-yl)
ethyl]phosphonic acid diethyl ester 284

Figure 2.80 COSY NMR of [1-Diazo-2-oxo-2-(2,2,5-trimethyl-oxazolidin
3-yl)-ethyl]-phosphonic acid diethyl ester 285

Figure 2.81
1
H NMR of 2-diazo-2-(phenylsulfonyl)-1-(2,2,5-trimethyl
oxazolidin-3-yl)ethanone 286

xxvii

Figure 2.82 COSY NMR 2-diazo-2-(phenylsulfonyl)-1-(2,2,5-trimethyl
oxazolidin-3-yl)ethanone 287

Figure 2.83
1
H NMR of 4,5-Diphenyl-imidazolidin-2-one 288

Figure 2.84
1
H NMR of (4R,5R)-4,5-diphenylimidazolidin-2-one 289

Figure 2.85
1
H NMR of (R)-1,11-dimethyl-5-((trifluoromethyl)sulfonyl)-5H-
dibenzo[d,f] [1,3] diazepin-6(7H)-one 290

Figure 2.86 Cosy NMR of (R)-1,11-dimethyl-5-((trifluoromethyl)sulfonyl)-5H-
dibenzo[d,f][1,3] diazepin-6(7H)-one 291

Figure 2.87
1
H NMR of 3H-dinaphtho[2,1-d:1',2'-f][1,3]diazepin-4(5H)-one 292

Figure 2.88
1
H NMR of (R)-3-((trifluoromethyl)sulfonyl)-3H-dinaphtho
[2,1-d:1',2'-f][1,3] diazepin-4(5H)-one 293

Figure 2.89
1
H NMR of (R)-3-((trifluoromethyl)sulfonyl)-3H-dinaphtho[2,1-
d:1',2'-f][1,3] diazepin-4(5H)-one 294

Figure 2.90 Cosy NMR of (R)-3-((trifluoromethyl)sulfonyl)-3H-dinaphtho[2,1-
d:1',2'-f][1,3] diazepin-4(5H)-one 295

Figure 2.91
1
H NMR of (S)-2-amino-3,3-dimethylbutan-1-ol 296

Figure 2.92
1
H NMR of 4-tert-Butyl-oxazolidin-2-one
(Scheme 8, compound 40) 297

Figure 2.93
1
H NMR of 4S-tert-Butyl-oxazolidin-2-one
(Scheme 8, compound 40) 298

Figure 2.94 COSY NMR of 4S-tert-Butyl-oxazolidin-2-one
(Scheme 8, compound 40) 299

Figure 2.95
13
C NMR of 4S-tert-Butyl-oxazolidin-2-one
(Scheme 8, compound 40) 300

Figure 2.96
1
H NMR of 1-Trifluoromethanesulfonyl-octahydro-benzoimidazol
2-one (Scheme 2.8, compound 50) 301

Figure 2.97
13
C NMR of 1-Trifluoromethanesulfonyl-octahydro-benzoimidazol
2-one (Scheme 2.8, compound 50) 302

xxviii

Figure 2.98 COSY NMR of
1
H NMR of 1-Trifluoromethanesulfonyl
octahydrobenzoimidazol-2-one (Scheme 2.8, compound 50) 303

Figure 3.1 NHC-Pd 1 310

Figure 3.2 Glycerol to formic acid-optimization of reaction conditions 315

Figure 3.3
1
H NMR study for the degradation pathway of glycolic acid 317

Figure 3.4
1
H-NMR spectra for the oxidative degradation reaction of
1,3-
13
C-glycerol (A) and 2-
13
C-glycerol (B) 324

Figure 3.5 A plausible carbon-carbon bond cleavage process of glycerol via
retro-aldol reaction 326

Figure 3.6 Proposed mechanism if the primary alcohol group of glycerol
is oxidized first 328

Figure 3.7 Proposed mechanism if secondary alcohol group of glycerol is
is oxidized first 329

Figure 3.8 Proposed mechanism for the oxidation of glycolic acid to
formic acid 330

Figure 3.9 Proposed mechanism for the oxidation of glycolic acid to
formic acid 331

Figure 3.10
1
H NMR of 2-bromo-N-(2-methoxyethyl)acetamide
(Scheme 3.1, compound 348

Figure 3.11
13
C NMR of 2-bromo-N-(2-methoxyethyl)acetamide
(Scheme 3.1, compound 3) 349

Figure 3.12
1
H NMR of 2-Benzimidazol-1-yl-N-(2-methoxy-ethyl)acetamide
(Scheme 3.1, compound 4) 350

Figure 3.13
13
C NMR of 2-Benzimidazol-1-yl-N-(2-methoxy-ethyl)acetamide
(Scheme 3.1, compound 4) 351

Figure 3.14
1
H NMR of 3-[(2-Methoxy-ethylcarbamoyl)-methyl]-1-methyl-3H-
benzoimidazol-1-ium; iodide 352

Figure 3.15
13
C NMR of 3-[(2-Methoxy-ethylcarbamoyl)-methyl]
1-methyl-3H-benzoimidazol-1-ium; iodide
(Scheme 1, compound 5) 353
xxix

Figure 3.16
1
H NMR NHC-Pd 1 Complex 354

Figure 3.17
13
C NMR NHC-Pd 1 Complex 355

Figure 3.18
1
H wet 1D NMR of entry 2, Table 3.1 356

Figure 3.19
1
H wet 1D NMR of entry 3, Table 3.1 357

Figure 3.20
1
H wet 1D NMR of entry 4, Table 3.1 358

Figure 3.21
1
H wet 1D NMR of entry 6, Table 3.1 359

Figure 3.22
1
H wet 1D NMR of entry 7, Table 3.1 360

Figure 3.23
1
H wet 1D NMR of entry 1, Table 3.3 361

Figure 3.24
1
H wet 1D NMR of entry 2, Table 3.3 362

Figure 3.25
1
H wet 1D NMR of entry 3, Table 3.3 363

Figure 3.26
1
H wet 1D NMR of entry 4, Table 3.3 364

Figure 3.27
1
H wet 1D NMR of entry 5, Table 3.3 365

Figure 3.28
1
H wet 1D NMR of entry 6, Table 3.3 366

Figure 3.29
1
H wet 1D NMR of entry 7, Table 3.3 367

Figure 3.30
1
H wet 1D NMR of entry 8, Table 3.3 368

Figure 3.31
1
H wet 1D NMR of entry 9, Table 3.3 369

Figure 3.32
1
H wet 1D NMR of entry 10, Table 3.3 370

Figure 3.33
1
H wet 1D NMR of entry 11, Table 3.3 371

Figure 3.34
1
H wet 1D NMR of entry 12, Table 3.3 372

Figure 3.35
1
H wet 1D NMR of entry 13, Table 3.3 373

Figure 3.36
1
H wet 1D NMR of entry 14, Table 3.3 374

Figure 3.37
1
H wet 1D NMR of entry 15, Table 3.3 375

xxx

Figure 3.38
1
H wet 1D NMR of entry 16, Table 3.3 376

Figure 3.39
1
H wet 1D NMR of entry 17, Table 3.3 377

Figure 3.40
1
H wet 1D NMR of entry 18, Table 3.3 378

Figure 3.41
1
H wet 1D NMR of entry 19, Table 3.3 379

Figure 3.42
1
H wet 1D NMR of entry 20, Table 3.3 380

Figure 3.43
1
H wet 1D NMR of entry 21), Table 3.3 381

Figure 3.44
1
H wet 1D NMR of entry 22, Table 3.3 382

Figure 3.45
1
H wet 1D NMR of entry 23, Table 3.3 383

Figure 3.46
1
H wet 1D NMR of entry 24, Table 3.3 384

Figure 3.47
1
H wet 1D NMR of entry 25, Table 3.3 385

Figure 3.48
1
H wet 1D NMR of entry 27, Table 3.3 386

Figure 3.49
1
H wet 1D NMR of entry 28, Table 3.3 387

Figure 3.50
1
H wet 1D NMR of entry 29, Table 3.3 388

Figure 3.51
1
H wet 1D NMR of entry 30, Table 3.3 389

Figure 3.52
1
H wet 1D NMR of entry 1, Table 3.4 390

Figure 3.53
13
C NMR of entry 1, Table 3.4 391

Figure 3.54
1
H wet 1D NMR of entry 2, Table 3.4 392

Figure 3.55
1
H wet 1D NMR of entry 3, Table 3.4 393

Figure 3.56
1
H wet 1D NMR of entry 4, Table 3.4 394

Figure 3.57
1
H wet 1D NMR of entry 5, Table 3.4 395

Figure 3.58
1
H wet 1D NMR of entry 6, Table 3.4 396

Figure 3.59
1
H wet 1D NMR of entry 1, Table 3.5 397

Figure 3.60
1
H wet 1D NMR of entry 2, Table 3.5 398
xxxi

Figure 3.61
1
H wet 1D NMR of entry 3, Table 3.5 399

Figure 3.62
1
H wet 1D NMR of entry 4, Table 3.5 400

Figure 3.63
1
H wet 1D NMR of entry 5, Table 3.5 401

Figure 3.64
1
H wet 1D NMR of entry 6, Table 3.5 402

Figure 3.65
1
H wet 1D NMR of entry 7, Table 3.5 403

Figure 3.66
1
H wet 1D NMR of entry 8, Table 3.5 404

Figure 3.67
1
H wet 1D NMR of entry 9, , Table 3.5 405

Figure 3.68
13
C NMR of entry 9, Table 3.5 406

Figure 3.69
1
H wet 1D NMR of entry 10, Table 3.5 407

Figure 3.70
1
H wet 1D NMR of entry 11, Table 3.5 408

Figure 3.71
1
H wet 1D NMR of entry 12 , Table 3.5 409

Figure 3.72
1
H wet 1D NMR of entry 13, , Table 3.5 410

Figure 3.73
1
H wet 1D NMR of entry 14, Table 3.5 411

Figure 3.74
1
H wet 1D NMR of entry 15, Table 3.5 412

Figure 3.75
1
H wet 1D NMR of entry 16, Table 3.5 413

Figure 3.76
1
H wet 1D NMR of entry 17, Table 3.5 414

Figure 3.77
1
H wet 1D NMR of entry 18, Table 3.5 415

Figure 3.78
1
H wet 1D NMR of entry 19, Table 3.5 416

Figure 3.79
1
H wet 1D NMR of entry 20, Table 3.5 417

Figure 3.80
1
H wet 1D NMR of entry 21, Table 3.5 418

Figure 3.81
13
C NMR of entry 23, Table 3.5 419

Figure 3.82
1
H wet 1D NMR of entry 24, Table 3.5 420

xxxii

Figure 3.83
1
H wet 1D NMR of entry 25, Table 3.5 421

Figure 3.84
1
H wet 1D NMR of entry 26, Table 3.5 422

Figure 3.85
1
H wet 1D NMR of entry 27, Table 3.5 423

Figure 3.86
1
H wet 1D NMR of entry 28, Table 3.5 424

Figure 3.87
1
H wet 1D NMR of entry 29, Table 3.5 425

Figure 3.88
1
H wet 1D NMR of entry 30, Table 3.5 426

Figure 3.89
1
H wet 1D NMR of entry 31, Table 3.5 427

Figure 3.90
1
H wet 1D NMR of entry 32, Table 3.5 428

Figure 3.91
1
H wet 1D NMR of entry 33, Table 3.5 429

Figure 3.92
1
H wet 1D NMR of entry 34, Table 3.5 430

Figure 3.93
1
H wet 1D NMR of entry 35, Table 3.5 431

Figure 3.94
1
H wet 1D NMR of entry 1, Table 3.6 432

Figure 3.95
1
H wet 1D NMR of entry 1, Table 3.8 433

Figure 3.96
1
H wet 1D NMR of entry 2, Table 3.8 434

Figure 3.97
1
H wet 1D NMR of entry 3, Table 3.8 435

Figure 3.98
1
H wet 1D NMR of entry 4, Table 3.8 436

Figure 3.99
1
H wet 1D NMR of entry 5, Table 3.8 437

Figure 3.100
1
H wet 1D NMR of entry 6, Table 3.8 438

Figure 3.101
1
H wet 1D NMR of entry 7, Table 3.8 439

Figure 3.102
1
H wet 1D NMR of entry 8, Table 3.8 440

Figure 3.103
1
H wet 1D NMR of entry 9, Table 3.8 441

Figure 3.104
1
H wet 1D NMR of entry 10, Table 3.8 442

Figure 3.105
1
H wet 1D NMR of entry 1, Table 3.9 443
xxxiii

Figure 3.106
1
H wet 1D NMR of entry 2, Table 3.9 444

Figure 3.107
1
H wet 1D NMR of entry 3, Table 3.9 445

Figure 3.108
1
H NMR of
13
C1 labeled glycolic acid 446

Figure 3.109
13
C NMR of
13
C1 labeled glycolic acid 447

Figure 3.110
1
H NMR of oxidative degradation of
13
C1 labeled glycolic acid 448

Figure 3.111
1
H NMR ofTable 3.4,
1
H wet 1D NMR of entry 5 449

Figure 4.1
1
H wet 1D NMR of entry 1, Table 1 465

Figure 4.2
1
H wet 1D NMR of entry 2, Table 1 466

Figure 4.3
1
H wet 1D NMR of entry 3, Table 1 467

Figure 4.4
1
H NMR of entry 4, Table 1 468

Figure 4.5
1
H NMR of entry 5, Table 1 and entry 4, Table 2 469

Figure 4.6
1
H NMR of entry 6, Table 1 470

Figure 4.7
1
H wet 1D NMR of entry 7, Table 1 471

Figure 4.8
13
C NMR of entry 7, Table 1 472

Figure 4.9
1
H wet 1D NMR of entry 8, Table 1 473

Figure 4.10
1
H wet 1D NMR of entry 1, Table 2 474

Figure 4.11
1
H wet 1D NMR of entry 2, Table 2 475

Figure 4.12
1
H wet 1D NMR of entry 3, Table 2 476

Figure 4.13
1
H wet 1D NMR of entry 4, Table 2 is same as entry 5, Table 1 477

Figure 4.14
1
H wet NMR of entry 6, Table 2 478

Figure 4.15
1
H wet1D NMR of entry 7, Table 2 479

Figure 4.16
13
C NMR of entry 7, Table 2 480

xxxiv

Figure 4.17
1
H wet 1D NMR of entry 8, Table 2 481

Figure 4.18
13
C NMR of entry 8, Table 2 482

Figure 4.19
1
H wet 1D NMR of entry 9, Table 2 483

Figure 4.20
1
H wet 1D NMR of entry 10, Table 2 484

Figure 4.21
1
H wet 1D NMR of entry 11, Table 2 485

Figure 4.22
1
H wet 1D NMR of entry 12, Table 2 486

Figure 4.23
1
H 1D NMR of NMR of entry 13, Table 2 487

Figure 4.24
1
HNMR of entry 14, Table 2 488

Figure 4.25
1
H wet 1D NMR of ammonium formate 489

Figure 4.26
1
H wet 1D NMR of mixture of formic acid and
ammonium formate 490

xxxv

LIST OF SCHEMES

Scheme 1.1 The retrosynthetic analysis of a diastereomer of palmerolide A
(C19 (S) and C20 (R)) 9

Scheme 1.2 Synthesis of C1-C8 subunit 10
Scheme 1.3 Synthesis of C9-C15 subunit 12
Scheme 1.4 Elimination leading to olefine 14
Scheme 1.5 (R,E)-(8-ethoxy-2-hydroxy-8-oxooct-6-en-1-yl)triphenyl
phosphonium iodide 15

Scheme 1.6 ((1E,6E)-8-ethoxy-8-oxoocta-1,6-dien-1-yl)triphenyl
phosphonium iodide 15

Scheme 1.7 (3R)-ethyl 3-hydroxy-2-(iodotriphenylphosphoranyl)
Cyclohexanecarboxylate 16

Scheme 1.8 (R)-4-((R)-1-((4-methoxybenzyl)oxy)pent-4-yn-1-yl)
2,2-dimethyl-1,3-dioxolane 17

Scheme 1.9 (2R,3R)-1-((4-Methoxybenzyl)oxy)-2-(methoxymethoxy)
hept-6-yn-3-ol 17

Scheme 1.10 Retrosynthetic analysis of N-((4S,5R,E)-5-hydroxy-4,7
dimethylocta-2,7-dien 2-yl)-3-methylbut-2-enamide 18

Scheme 1.11 Synthesis of (2S,3R)-3-((4-methoxybenzyl)oxy)-2,5
dimethylhex-5-en-1-ol 19

Scheme 1.12 Synthesis of tert-butyldimethyl(((2R,3S)-3-methyl-1
(2-methyl-1,3- dioxo lan-2-yl)hex-4-yn-2-yl)oxy)silane 20

Scheme 1.13 Synthesis of (2S,3R)-2,5-dimethylhex-5-ene-1,3-diol 21

Scheme 1.14 Retrosynthetic analysis of Palmerolide A 22

Scheme 1.15 Preparation of ((R,E)-5-((tert-butyldimethylsilyl)oxy)
7-iodohept-6-en-1-yl benzoate 23

Scheme 1.16 Modified scheme for the synthesis of Palmerolide A 24

xxxvi

Scheme 1.17 (3S)-7-((tert-butyldimethylsilyl)oxy)-3-((4-methoxybenzyl)
oxy)-1-((4R,5S)-5-(((4-methoxybenzyl)oxy)methyl)-2,2
dimethyl-1,3-dioxolan-4-yl)-1-(phenylsulfonyl) heptan-2
yl acetate 24

Scheme 1.18 (1S,E)-1-((tert-butyldiphenylsilyl)oxy)-1-((R)-2,2-dimethyl
1,3-dioxolan-4-yl)-8-((4-methoxybenzyl)oxy)oct-2-en-4-ol 26

Scheme 1.19 1-((4-iodobutoxy)methyl)-4-methoxybenzene 27

Scheme 1.20 Preparation of (8S,E)-5-(4-((4-methoxybenzyl)oxy)butyl)
2,2,11,11-tetramethyl-8-((S)-oxiran-2-yl)-3,3,10,10-tetra
phenyl-4,9-dioxa-3,10-disiladodec-6-ene (104) 29

Scheme 1.21 (8S,9S,E)-9-((tert-butyldimethylsilyl)oxy)-8-((tert-butyl
diphenylsilyl)oxy)-1-((4-methoxybenzyl)oxy)tridec-6-en
12-yn-5-ol (113) 30
Scheme 2.1 C-H insertion of (S)-1-(4-(tert-butoxymethyl)-2,2-dimthyl
oxazolidin-3yl)-2-diazo-2-(phenylsulfonyl)ethanone 185
Scheme 2.2 Retrosynthetic route through Rh-II CH insertion reaction 187

Scheme 2.3 Preparation of (S)-1-(4-(2-((tert-butyldimethylsilyl)oxy)
ethyl)- 2,2-dime thyloxazolidin-3-yl)-2-diazo-2-(phenyl
sulfonyl)ethanone 189

Scheme 2.4 CH activation of (S)-1-(4-(2-((tert-butyl dimethyl silyl)
oxy) ethyl)-2,2-dimethyl oxazolidin-3-yl)-2-diazo-2-
(phenylsulfonyl)ethanone 190
Scheme 2.5 Salinsporamide A (NPI-0052), cinnabaramide A and G 191
Scheme 2.6 Preparation of 1-(4,4-bis(((tert-butyldimethylsilyl)oxy)
methyl)-2,2-dimethyloxazo- lidin-3-yl)-2-diazoethanone 193
Scheme 2.7 CH activation of 1-(4,4-bis(((tert-butyldimethylsilyl)oxy)
methyl)-2,2- dimethyloxazo- lidin-3-yl)-2-diazoethanone 194
Scheme 2.8 Preparation of 1-trifluoromethanesulfonyl-imidazolidin-2-one
ligands 196
xxxvii

Scheme 2.9 CH activation of 1-[4,4-bis-(tert-butyl-dimethyl-silanyloxy
methyl)-2,2-dimethyl-oxazolidin-3-yl]-2-diazo-butane
1,3-dione 197
Scheme 2.10 Preparation of 1-[3,3-bis-(tert-butyl-dimethyl-silanyloxy
methyl)-1-oxa-4-aza-spiro[4.5]dec-4-yl]-2-diazo-ethanone 198
Scheme 2.11 CH activation of 1-[3,3-bis-(tert-butyl-dimethyl-silanyloxy
methyl)-1-oxa- 4-aza-spiro[4.5]dec-4-yl]-2-diazo-ethanone 200
Scheme 2.12 C-H activation of 1-[3,3-bis-(tert-butyl-dimethyl-silanyloxy
methyl)-1-oxa-4-aza-spiro[4.5]dec-4-yl]-2-diazo-butane
1,3-dione 201
Scheme 2.13 Preparation of N-benzyl-N-cyclohexyl-2-diazo-2
(phenylsulfonyl)acetamide 202

Scheme 2.14 C-H activation of N-benzyl-N-cyclohexyl-2-diazo-2
(phenyl sulfonyl)acetamide 202

Scheme 2.15 C-H activation of N-cyclohexyl-2-diazo-N-phenyl-2-(phenyl
sulfonyl)acetamide 203
Scheme 3.1 Preparation of NHC-Pd complex 1 312
Scheme 3.2 Oxidative degradation of different substrates with NHC-Pd 1
and H
2
O
2
331
Scheme 4.1 Possible mechanism for the oxidative degradation of aldose
and ketose to ammonium formate 461
Scheme 4.2 Nonreducing trisaccharides 462

xxxviii

ABSTRACT
This dissertation focuses on the studies toward total synthesis of palmerolide A,
preparation of ligands for rhodium catalyzed C-H activation reaction. Preparation of
NHC-Pd (II) catalyst and the application in the conversion of biomass into formic acid.
In chapter 1, different schemes were discussed in the synthesis of subunits of
palmerolide A.
In chapter 2, ligands were prepared and used in Rhodium (II) catalyzed C-H
desymmetrization reactions. Preparation of intermediates were discussed in the synthesis
of kainic acid and allokainic acid.
In chapter 3, Preparation of NHC-Pd catalyst and its application in the conversion
of biomass into formic acid was discussed. Oxidative degradation of biomass in presence
of cationic palladium was also discussed.
In chapter 4, oxidative degradation of carbohydrates under mild conditions in
presence of hydrogen peroxide and ammonium hydroxide was discussed.

1

Chapter 1: Studies towards the total synthesis of
palmerolide A

1.1 Introduction

1.1.1 Isolation and Biological Activity
Palmerolide A, a potent enamide polyketide macrolide was isolated from
Antarctic marine tunicate synoicum adareanum by Baker et al.
1
This unique natural
compound possessed an unusual selectivity against a number of cell lines in the 60 cell
panel of the National Cancer Institue (NCI) which correlated to several vacular ATPase
inhibitors.
1-5
The interesting characteristic of the molecule is its selective activity against
the melanoma cell line UACC-62 at LC50=18 nm in NCI’s 60 cell line panel.
1
The
biological studies further supports that the molecule is also a potent inhibitor of bovine
brain V-ATPase at IC50 ~2 nM.
1-3
Originally, the structure of the palmerolide A was
proposed by Baker’s group (1a, Figure 1) and later it was revised as 1b (Figure 1) by
Brabander’s group
4,5

The structure and absolute stereochemistry of palmerolide A, shown as 1b (Figure
1), was solved by NMR studies and conformed as a 20-membered macrolide with an
interesting unique polyunsaturated N-acyl dienamine side chain.
1-5
According Baker et al. the nOe interactions and coupling constants of the
palmerolide A indicated the possibility of both syn structures.
1-7
Later, the Mosher ester
studies explained the absolute stereochemistry at the C7, C10, and C11 positions. The
synthesis of the molecule was inevitable to explain the absolute stereochemistry of the
molecule.
1-6
De Brabander’s report on the studies of total synthesis of the unnatural
2

enantiomer explains the absolute stereocenters of this polyketide. The studies of total
synthesis of the original proposed molecule and the diastereomer of the original proposed
structure revealed the relative stereochemistry between the C7-C11 and C19-C20
positions as well as the absolute configuration of the molecule.
1, 5, 6
These studies
confirmed that the diastereomer of the original proposed structure is the actual
palmerolide A (1b, Figure 1). Later Nicolaou and coworkers proposed the total synthesis
of both original and revised structures of palmerolide A.
6,7
Also, different other groups
have worked on the total synthesis of palmerolide A.
2,8,9,10

.
Figure 1.1 : Original and Revised Structures of Palmerolide A

1.1.2 Brabander’s approach

Brabander’s group envisioned a retrosynthetic analysis via fragments 2-4. The
fragments 3 and 4 were cross coupled via Horner-Wadsworth-Emmons olefination
(Figure 2). The interesting N-acyl dienamine functionality of the molecule was
introduced by a Curtius rearrangement followed by reacting the isocyanate with 2-
methylpropenyl magnesium bromide at the final step of the total synthesis.

3

Figure 1.2: Brabander’s approach

1.1.3 Chandrasekhar’s approach

Figure 1.3: Chandrasekhar et al. approach
4

Chandrasekhar et al. has described the synthesis of C1–C14 fragment of palmerolide A.
2

The key steps involved in this synthesis are deoxygenative rearrangement of an alkynol
followed by an asymmetric dihydroxylation of a diene ester and CBS reduction.

I.1.4 Nicolaou’s approach

Nicolaou’s group has proposed the total synthesis of the originally
proposed and revised structures of palemrolide A.
7
Nicoloau’s approach envisioned a
retrosynthetic analysis via three subunits 2-4. The key steps in the coupling of these
subunits include a Stille coupling reaction, a Yamaguchi esterification, a ring-closing
metathesis, and an enamide coupling reaction.
Nicolaou’s group also developed synthetic methods to make several new
palmerolide A analogues and the biological evaluation of all the synthesized palmerolides
against an array of tumor cells.
5,6,7

Figure 1.4: Retrosynthetic analysis of originally proposed Palmerolide A

5

1.1.5 Maier’s approach
The key steps in Maier’s total synthesis of Palmerolide A

includes the Evan’s
aldol reaction to generate the stereocenters at C19

and C20, Noyori transfer
hydrogenation of an alkynone to generate the stereocenter at C7, chain extension via a
Claisen rearrangement, and an ADH reaction on an enyne, to generate stereocenters at
C10-C11. The cross coupling by the Heck cyclization resulted only with the desired C14-
C16 E-diene.
8

xx
.x.2009
Formal Tota
Figure 1.5: Maier’s Approach

1.1.6 Hall’s approach
12

Hall’s synthesis includes a novel Claisen-Ireland rearrangement with an
alkenylboronate as a masked hydroxyl, which generates two stereogenic
6

secondary carbinols (C10 and C11) starting from pyran. Macrolactonization
via an sp
2
-Sp
3
β-alkyl Suzuki coupling leads to the molecule.
Tota
Figure 1.6: Hall’s Approach

1.1.6
1.1.7 Dudley’s approach
Dudley and coworkers approach described the synthesis of the C1–C15 sub unit of
palmerolide A. The key steps in the synthesis involved a Claisen-type condensation
of vinylogous acyl triflates providing the C1–C8 part of the subunit, which on Horner–
Wittig olefination delivers the C1–C15 portion of palmerolide A.
13
7

Figure 1.7: Dudley’s approach
1.1.7 Baker’s approach
Baker and co-workers synthesized the C3-C14 fragment of palmerolide A using a
chiral pool based strategy from commercially available fragments.
14

Figure 1.8: Baker’s approach

8

1.1.8 Kalippan’s approach
15

The key steps inKalippan’s approach includes the formation of a syn aldol by
Shimizu reaction, Julia–Kocienski reaction to introduce C14-15 double bond,Yamaguchi
esterification, and a cyclization by RCM to introduce the double between C8-C9 carbons.

Figure 1.9: Kalippan’s approach

1.2 Aim and Scope of the Present Work
The interesting biological properties and intriguing structure of the molecule led
us to work on studies toward the synthesis of the marine natural product palmerolide A.
When we started the studies on the synthesis of palmerolide A, all the stereocenters were
not assigned to the molecule. A retrosynthetic analysis of the molecule was proposed
9

based on the assumption that the stereocenters at carbons C19

(S) and C20

(R) were anti
and the rest of the molecule is as shown in the original proposed structure (Figure 1.10).

Figure 1.10: A diastereomer of originally proposed structure

Scheme 1.1: Retrosynthetic analysis of a diastereomer of palmerolide A (C19 (S) and
C20 (R))

10

The retrosynthetic analysis was envisioned via Boron-Heck macrocyclization, a method
developed by our group as key step (scheme 1.1).
16
The units 3 and 4 could be coupled by
an esterification reaction. However, the C8 and C9 olefin was envisioned via Horner-
Wordsworth-Emmons (HWE) reaction
17
and C15-C16 connection was through a Boron-
Heck reaction.

1.21 Synthesis of C1-C8 subunit ((R,E)-(8-ethoxy-2-(methoxymethoxy)-8-oxo oct-
6-en-1-yl)triphenylphosphonium iodide) (Scheme 1.2)

The C1-C8 subunit was prepared starting from 5-hexene-1-ol. 5-Hexene-1-ol, (23) on
Swern oxidation
18
followed by treatment with ethyl 2-(triphenyl phosphoranyli-
dene)acetate
19
lead to (E)-ethyl octa-2,7-dienoate (24). The terminal double bond in 24

Scheme 1.2: Synthesis of C1-C8 subunit
11

was dihydroxylated under Sharpless dihydroxylation conditions led to (R,E)-ethyl 7,8-
dihydroxy- oct-2-enoate (25).
20-22
The terminal alcohol in diol (25) was selectively
protected by tert-butyldiphenylsilyl (TBDPS) group to give (R,E)-ethyl 8-((tert-
butyldiphenyl silyl)oxy)-7-hydroxyoct-2-enoate (26).
23
The secondary alcohol in
compound 26 was protected with methoxymethyl (MOM) group to yield (R,E)-ethyl-8-
((tert-butyldiphenylsilyl)oxy)-7-(methoxymethoxy)oct-2-enoate (27).
24, 25
The TBDPS
group in compound 27 was deprotected in presence of tetrabutyl ammonium fluoride
(TBAF) to give (R,E)-ethyl 8-hydroxy-7-(methoxymethoxy)oct-2-enoate (28).
25
The
primary alcohol in compound 28 was mesylated to make (R,E)-ethyl-7-
(methoxymethoxy)-8-((methylsulfonyl)oxy)oct-2-enoate (29) which on Finkelstein
iodination reaction lead to (R,E)-ethyl 8-iodo-7-(methoxymethoxy)oct-2-enoate (30).
26

The compound 30 did not react with triethoxyphosphine to make the substrate to perform
HWE reaction to introduce olefin by coupling with the subunit C9-C15. The compound
30 was refluxed in anhydrous tetrahydrofuran with triphenyl phosphine to give (R,E)-(8-
ethoxy-2-(methoxymethoxy)-8-oxooct-6-en-1-yl)triphenylphosphonium iodide (31).
26

1.22 Synthesis of C9-C15 (2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(methoxy
methoxy) hept-6-ynal (Scheme 1.3)

The subunit with C9 to C15 carbons was introduced starting from (2S,3S)-2,3-
dihydroxysuccinic acid (32). (2S,3S)-2,3-Dihydroxysuccinic acid (32) was converted into
(4S,5S)-dimethyl 2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate (33) which on reduction
lead to ((4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-diyl)dimethanol (34).
28, 29
The diol (34)
was mono substituted with tert-butyldimethylsilyl or p-methoxybenzyl group to give
12

compound (36)
30- 32
and the second free alcohol was substituted with tosyl group to give
((4R,5R)-5-(((4-methoxybenzyl)oxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl-4-
methylbenzene sulfonate (37)
33
The acetonide group in compound 37 was deprotected in
presence of DOWEX
®
in methanol to give the (2R,3R)-2,3-dihydroxy-4-((4-methoxy

Scheme 1.3: Synthesis of C9-C15 subunit

benzyl)oxy)butyl 4-methylbenzenesulfonate (38).
34
The diol 38 was treated K
2
CO
3
in
presence of 1:1 mixture of CH
2
Cl
2
and CH
3
OH to give compound (R)-2-((4-
methoxybenzyl)oxy)-1-((R)-oxiran-2-yl)ethanol (39).
33, 35
The secondary alcohol group in
39 was protected with methoxymethyl (MOM) group to give compound (R)-2-((R)-2-
13

((4-methoxybenzyl)oxy)-1-(methoxymethoxy)ethyl) oxirane (40).
36
The epoxide in 40
was opened with propagylmagnesium bromide to give compound (2R,3R)-1-((4-methoxy
benzyl)oxy)-2-(methoxymethoxy)hept-6-yn-3-ol (41).
37, 38
To improve the yields the
secondary alcohol was protected with tertiarybutyldimethylsilyl (TBS) group instead of
MOM group to avoid the chelation with copper in epoxide ring opening with propargyl
magnesium bromide. The free secondary alcohol group in compound 41 was protected
with TBS group to give (5R,6R)-6-(but-3-yn-1-yl)-5-(((4-methoxybenzyl)oxy)methyl)-
8,8,9,9-tetramethyl-2,4,7-trioxa-8-siladecane (42).
39
Deprotection of p-methoxybenzyl
(PMB) group on primary alcohol in 42 with MgBr
2
.OEt
2
Me
2
S in dichloromethane at
room temperature and its oxidation lead to (2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-
(methoxymethoxy)hept-6-ynal (44).
40- 42
((4R,5R)-5-(((4-Methoxybenzyl)oxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)
methanol (36) was converted into (4R,5S)-4-(iodomethyl)-5-(((4-methoxy benzyl)
oxy)methyl)-2,2-dimethyl-1,3-dioxolane (45).
43
When the compound 45 was reacted with
TMS protected propargylmagnesium bromide, elimination occurred and lead to (R)-1-
((4-methoxybenzyl)oxy)but-3-en-2-ol (Scheme 4, 46) instead of (4R,5R)-4-(but-3-yn-1-
yl)-5-(((4-methoxybenzyl)oxy)methyl)-2,2-dimethyl-1,3-dioxolane (46’). Compound 45
on treatment with lithium in THF at -78
o
C lead to protduct 46 which was also thought of
as a substrate to generate stereocenter at C7 position and genterate C8 carbon of double
bond C8-C9 double bond in palmerolide A by metathesis reaction.
44,6,7
Compound 46 was used to extend the chain to make C3 to C8 with the desired
C7 (S) configuration. The coupling between (R,E)-(8-ethoxy-2-(methoxymethoxy)-8-
oxooct-6-en-1-yl)triphenylphosphonium iodide (31) and (2S,3R)-3-((tert-butyldimethyl
14

silyl)oxy)-2-(methoxymethoxy)hept-6-ynal (44) did not proceed. (R,E)-(8-Ethoxy-2-
(methoxy methoxy)-8-oxooct-6-en-1-yl)triphenylphosphonium iodide (31) in n-BuLi lead
to the double bond by eliminating acetonide protection (Scheme 1.4).

Scheme 1.4: Elimination leading to olefin
1.2.3 Synthesis of C1-C8 subunit ((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-
(methoxy methoxy) hept-6-ynal)

To avoid the elimination of –OMOM in compound 30 in presence of n-BuLi,
MOM group was deprotected to make a free iodo alcohol, (R,E)-ethyl 7-hydroxy-8-
iodooct-2-enoate (47). The compound 47 was converted into (R,E)-(8-ethoxy-2-hydroxy-
8-oxooct-6-en-1-yl)triphenylphosphonium iodide (48) (Scheme 1.5).
15

Scheme 1.5: (R,E)-(8-ethoxy-2-hydroxy-8-oxooct-6-en-1-yl)triphenylphosphonium
Iodide

Expected coupling product was not formed when compound 47 and compound
43 were reacted. (R,E)-(8-Ethoxy-2-hydroxy-8-oxooct-6-en-1-yl)triphenylphosphonium
iodide underwent elimination in presence of n-BuLi to give ((1E,6E)-8-ethoxy-8-
oxoocta-1,6-dien-1-yl)triphenylphosphonium iodide (49).

Scheme 1.6: ((1E,6E)-8-ethoxy-8-oxoocta-1,6-dien-1-yl)triphenylphosphonium iodide

The coupling product was not formed from aldehyde 44 and triphenylphospho-
nium iodide 31 as well as 48. Compound 31 in presence of base lead to elimination to
give compound 49 (Scheme 1.6).
However, the compound 48 underwent cyclization in presence of a base to give
the compound 50.
13
α,β-Unsaturated bond was not observed in the cyclic compound
16

(3R)-ethyl 3-hydroxy-2-(iodotriphenylphosphoranyl)cyclohexanecarboxylate (50) formed
from the compound 46 (Scheme 1.7).

Scheme 1.7: (3R)-ethyl-3-hydroxy-2-(iodotriphenylphosphoranyl)cyclohexanecarbo-
xylate

To avoid this side reaction, the Scheme 1.7 was modified and the C3-C8 subunit
was constructed starting from primary alcohol protected (benzoyl, PMB or TBS) 5-
hexene-1-ol.
30, 31

Very low yields were observed in epoxide opening with propargyl magnesium
bromide (Scheme 3). To reduce the number of steps and improve the yields, attempts
were made to introduce the propargyl group. An alternative scheme was proposed to
construct C9-C15 subunit starting from propargyl alcohol (Scheme 1.8).
45
Pent-4-yn-1-ol was oxidized and the resulting aldehyde on Wittig reaction gave
(E)-ethyl hept-2-en-6-ynoate (52).
45, 46
Compound 52 was reduced to (E)-hept-2-en-6-yn-
1-ol (53). The two stereocenters on C
10
and C
11
positions of the palmerolide A
diastereomer were introduced by Sharpless dihyroxylation on 53 to yield 54.
46, 47
The

17

Scheme 1.8: (R)-4-((R)-1-((4-methoxybenzyl)oxy)pent-4-yn-1-yl)-2,2-dimethyl-1,3-
dioxolane

terminal diols in the resulting triol 53 were selectively protected as acetonide to give
compound 55. The free secondary alcohol in compound 55 was protected with PMB
group to give (R)-4-((R)-1-((4-methoxybenzyl)oxy)pent-4-yn-1-yl)-2,2-dimethyl-1,3-
dioxolane (56).
(2R,3R)-1-((4-Methoxybenzyl)oxy)-2-(methoxymethoxy)hept-6-yn-3-ol (58) was
also prepared from (2R,3R)-hept-6-yne-1,2,3-triol (54) (Scheme 1.9).
48

Scheme 1.9: (2R,3R)-1-((4-Methoxybenzyl)oxy)-2-(methoxymethoxy)hept-6-yn-3-ol

18

1.2.4 Retrosynthetic analysis of subunit C
16
-C
29
N-((4S,5R,E)-5-hydroxy-4,7-
dimethylocta-2,7-dien-2-yl)-3-methylbut-2-enamide (22)

Scheme 1.10: Retrosynthetic analysis of N-((4S,5R,E)-5-hydroxy-4,7-dimethylocta-2,7-
dien 2-yl)-3-methylbut-2-enamide

Retrosynthesis of subunit C16-C29, N-((4S,5R,E)-5-hydroxy-4,7-dimethylocta-
2,7-dien-2-yl)-3-methylbut-2-enamide (22) was envisioned in three different ways as
shown in scheme 1.10.
1.2.5 Preparation of (4S,5R,E)-5-((4-methoxybenzyl)oxy)-2,4,7-trimethylocta-2,7
dienal

Protection of keto group in methyl 3-oxobutanoate with ethylene glycol followed
by the reduction of ester led to 2-(2-methyl-1,3-dioxolan-2-yl)ethanol (60). Oxidation of
compound 60

followed by treatment with ethyl-2-(triphenyl phosphor anylidene)acetate
lead to (E)-ethyl 4-(2-methyl-1,3-dioxolan-2-yl)but-2-enoate (61). Reduction of the
compound 61 with DIBAL-H followed by Sharpless expoxidation lead to ((2R,3R)-3-((2-
methyl-1,3-dioxolan-2-yl)methyl)oxiran-2-yl)methanol (63).
48-52

Selective ring opening of epoxide (63) with methyl lithium/CuI condition lead to
(4R,5S)-4,6-dihydroxy-5-methyl hexan-2-one (64).
56
The protection of 1,3-diol in
19

compound 64 as PMP (p-methoxyphenyl) acetal lead to 1-((4R,5S)-2-(4-methoxyphenyl)-
5-methyl-1,3-dioxan-4-yl)propan-2-one (65).
57, 58
The compound 65 on treatment with
Tebbe reagent lead to (4R,5S)-2-(4-methoxyphenyl)-5-methyl-4-(2-methylallyl)-1,3-
dioxane.
59
(4R,5S)-2-(4-Meth oxyphenyl)-5-methyl-4-(2-methylallyl)-1,3-dioxane on
treatment with DIBAL-H in dichloromethane (anhydrous condition) opened the PMP
acetal to give (2S,3R)-3-((4-methoxybenzyl)oxy)-2,5-dimethylhex-5-en-1-ol (68).
60

Oxidation of the primary alcohol group in the compound 68 lead to (2R,3R)-3-((4-
methoxy benzyl)oxy)-2,5-dimethylhex-5-enal (118).
47
The compound 118 on refluxing
with 2-(triphenylphosphoranylidene)propanal in dichloromethane lead to (4S,5R,E)-5-((4-
methoxybenzyl)oxy)-2,4,7-trimethylocta-2,7-dienal (119).
61, 62

Scheme 1.11: Synthesis of (2S,3R)-3-((4-methoxybenzyl)oxy)-2,5-dimethylhex-5-en-1-ol

20

1.2.6 Synthesis of tert-butyldimethyl(((2R,3S)-3-methyl-1-(2-methyl-1,3-dioxolan-2-
yl)hex-4-yn-2-yl)oxy)silane

Scheme 1.12: Synthesis of tert-butyldimethyl(((2R,3S)-3-methyl-1-(2-methyl-1,3-
dioxolan-2-yl)hex-4-yn-2-yl)oxy)silane

tert-Butyldimethyl(((2R,3S)-3-methyl-1-(2-methyl-1,3-dioxolan-2-yl)hex-4-yn-2-
yl) oxy)silane (72) was prepared starting from (R)-but-3-yn-2-yl methanesulfonate (69).
(R)-but-3-yn-2-yl methanesulfonate
63-66
in a solution of Ph
3
P and Pd(OAc)
2
was added
to 2-(2-methyl-1,3-dioxolan-2-yl)acetaldehyde (70)
67
followed by the addition of
diethylzinc to yield (2R,3S)-3-methyl-1-(2-methyl-1,3-dioxolan-2-yl)pent-4-yn-2-ol
(72).
68-71
During work-up, some of the compound 72 was converted into the deprotected
compound (4R,5S)-4-hydroxy-5-methylhept-6-yn-2-one (71) with a free keto group. The
free secondary alcohol group in compound 72 was protected with TBS group (73) and the
terminal alkyne was methylated to yield tert-butyldimethyl(((2R,3S)-3-methyl-1-(2-
methyl-1,3-dioxolan-2-yl)hex-4-yn-2-yl) oxy)silane (74).
68

21

1.2.7 Synthesis of (2S,3R)-2,5-dimethylhex-5-ene-1,3-diol
The anti C19 and C20

positions were also constructed by a more concise
method starting from methyl acrylate and isobutylene in presence of anhydrous
AlCl
3
.
72-73
This method introduces the double bond between C16 and C17 required for

Scheme 1.13: Synthesis of (2S,3R)-2,5-dimethylhex-5-ene-1,3-diol
the coupling reaction in the subunit C16-C29. The anti stereocenters at C19 and C20
positions of the molecule were introduced by Sharpless epoxidation to give the ((3R)-3-
(2-methylallyl)oxiran-2-yl)methanol (79)
48-52
followed by epoxy ring opening with
methyl lithium to yield (2S,3R)-2,5-dimethylhex-5-ene-1,3-diol (80).
53
When we found that the generation of ylides from 31 and 48 was not successful,
the scheme was modified to introduce the C8-C9 double bond. We did not continue the
scheme to generate the C8

-C9

double bond by metathesis as it was later reported.
6,7

22

Scheme 1.14: Retrosynthetic analysis of Palmerolide A

1.2.7 Preparation of C
3
-C
8
subunit (R,E)-5-((tert-butyldimethylsilyl)oxy)-7-
iodohept-6-en-1-yl benzoate

C3-C8 subunit was constructed starting from hex-5-en-1-ol . The primary alcohol group
in hex-5-en-1-ol was protected with benzoyl group
74-75
and the olefin in hex-5-en-1-yl
benzoate (78) was dihydroxylated by Sharpless dihydroxylation method (to introduce
the chirality on C7.
20-22
Both hydroxyl groups in (R)-5,6-dihydroxyhexyl benzoate (79)
were protected with TBS groups to make (R)-5,6-bis((tert-butyldimethylsilyl)oxy)hexyl
benzoate (80). The TBS group from the primary alcohol in (R)-5,6-bis((tert-
butyldimethylsilyl)oxy)hexyl benzoate (80) was selectively deprotected in the presence
of acatalytic amount of camphorsulfonic acid (CSA) in a 1:1 mixture of CH
2
Cl
2
and
CH
3
OH at 0
o
C.

The free alcohol in (R)-5-((tert-butyl dimethylsilyl)oxy)-6-hydroxyhexyl
23

benzoate (81) was oxidized with trichlorocyanuric acid in the presence of a catalytic
amount of TEMPO to aldehyde (82).
76-77
The terminal double bond was introduced in

Scheme 1.15: Preparation of ((R,E)-5-((tert-butyldimethylsilyl)oxy)-7-iodohept-6-en-1-
yl)benzoate

aldehyde (82) in the presence of Cr(II)Cl
2
and iodoform to yield (R,E)-5-((tert-
butyldimethylsilyl)oxy)-7-iodohept-6-en-1-yl benzoate.
78
1.2.8 Retrosynthetic analysis of revised palmerolide A
The retrosynthesis of revised palmerolide A was envisioned through a Julia
olefination to introduce C8-C9 double bond, Boron-Heck macrocyclization to introduce
the C15 and C16 bond. The syn C19 hydroxy group and C20 methyl were introduced by
using Evan’s chiral oxazolidinones.

24

Scheme 1.16: Modified scheme for the synthesis of Palmerolide A
1.2.9 Preparation of tert-butyl(((S,E)-5-((4-methoxybenzyl)oxy)-7-((4S,5S)-5-(((4-
methoxy benzyl) oxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)hept-6-en-1-
yl)oxy) dimethyl silane

Scheme 1.17: (3S)-7-((tert-butyldimethylsilyl)oxy)-3-((4-methoxybenzyl)oxy)
1-((4R,5S)-5-(((4-methoxybenzyl)oxy)methyl)-2,2-dimethyl-1,3-
dioxolan-4-yl)-1-(phenylsulfonyl) heptan-2-yl acetate

25

(4R,5S)-4-(Iodomethyl)-5-(((4-methoxybenzyl)oxy)methyl)-2,2-dimethyl-1,3-
dioxolane (45) was converted into (4S,5R)-4-(((4-methoxybenzyl)oxy)methyl)-2,2-
dimethyl-5-((phenylsulfonyl)methyl)-1,3-dioxolane (84) in the presence of sodium
benzenesulfinate in DMF. The carbanion generated from the compound (84) in the
presence of n-BuLi was added to (S)-6-((tert-butyldimethylsilyl)oxy)-2-((4-methoxy
benzyl)oxy)hexanal (85) to yield (3S)-7-((tert-butyldimethylsilyl)oxy)-3-((4-methoxy
benzyl)oxy)-1-((4R,5S)-5-(((4-meth oxybenzyl)oxy)methyl)-2,2-dimethyl-1,3-dioxolan-
4-yl)-1-(phenyl sulfonyl) heptan-2-yl acetate (87).
79
The double bond in compound tert-
butyl(((S,E)-5-((4-methoxybenzyl)oxy)-7-((4S,5S)-5-(((4-methoxybenzyl)oxy)methyl)-
2,2-dimethyl-1,3-dioxolan-4-yl)hept-6-en-1-yl)oxy) dimethylsilane (87) was envisioned
under Julia olefination conditions.
An alternative retrosynthetic analysis was followed to introduce C8-C9 double
bond starting from D(+)-Gluconic acid. D(+)-Gluconic acid was converted into (R)-
methyl 2-hydroxy-2-((4R,4'R,5R)-2,2,2',2'-tetramethyl-[4,4'-bi(1,3-dioxolan)]-5-yl) ace
tate (88).
80
(R)-methyl 2-hydroxy-2-((4R,4'R,5R)-2,2,2',2'-tetramethyl-[4,4'-bi(1,3-dioxol
an)]-5-yl)acetate on reflux with triphenylphosphine and iodine in pyridine gave methyl
2-((4S,4'R,5R)-2,2,2',2'-tetramethyl-[4,4'-bi(1,3-dioxolan)]-5-yl)acetate (89).
80-82
In
presence of LiHMDS or tert-BuOK , compound 89 underwent elimination to provide
the double bond (C8-C9 double bond in the target molecule) of the product. (S,E)-
methyl 4-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-hydroxybut-2-enoate (90).
80-82
The
free secondary alcohol in the compound 90 was protected with TBDPS group to yield
(S,E)-methyl 4-((tert-butyldiphenylsilyl)oxy)-4-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)but-
2-enoate (91).
82
The compound 91was reduced to(S,E)-4-((tert-butyldiphenylsilyl)oxy)-
26

4-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)but-2-en-1-ol (92) with DIBAL-H.
82
During the
reduction silyl migration occured from secondary alcohol to primary alcohol and made
(S,E)-4-((tert-butyldiphenylsilyl)oxy)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)but-2-en-1-
ol (93). Both products were separated by column chromatography. Compound 92 on
allylic oxidation with MnO
2
gave (S,E)-4-((tert-butyldiphenylsilyl)oxy)-4-((R)-2,2-
dimethyl-1,3-dioxolan-4-yl)but-2-enal (94).
83, 84, 85

.

Scheme 1.18: (1S,E)-1-((tert-butyldiphenylsilyl)oxy)-1-((R)-2,2-dimethyl-1,3-dioxolan-
4-yl)-8-((4-methoxybenzyl)oxy)oct-2-en-4-ol

1-((4-Iodobutoxy)methyl)-4-methoxybenzene (97) was prepared starting from
butane-1,4-diol as starting material. The monoalkoxide generated from butane-1,4-diol
with one equivalent of sodium hydride was treated with freshly prepared p-methoxy
27

benzyl bromide to get 4-((4-methoxybenzyl)oxy)butan--ol. The free primary alcohol
group in 4-((4-methoxybenz yl) oxy)butan-1-ol was iodinated using triphenylphosphine,
I
2
/ pyridine system to obtain 1-((4-iodobutoxy)methyl)-4-methoxybenzene (Scheme
1.19).

Scheme 1.19: 1-((4-Iodobutoxy)methyl)-4-methoxybenzene

The anion generated from 1-((4-iodobutoxy)methyl)-4-methoxybenzene (97)

With tert-BuLi was added to (S,E)-4-((tert-butyldiphenylsilyl)oxy)-4-((R)-2,2-dimethyl-

1,3-dioxolan-4-yl)but-2-enal (94) at -78
o
C to yield (1S,E)-1-((tert-butyldiphenylsilyl)

oxy)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-8-((4-methoxybenzyl)oxy)oct-2-en-4-ol.

The diastereomers were separated on column chromatography.

The pure diastereomers were used for the next step. The free secondary alcohol in

the diastereomer (corresponding to the polar product on TLC) was protected with aTBS
group to give (5S,E)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-8-(4-((4-methoxybenzyl)
oxy) butyl)-2,2,10,10,11,11-hexamethyl-3,3-diphenyl-4,9-dioxa-3,10-disiladodec-6-ene
(98). The acetonide deprotection in CuCl
2
/methanol reflux condition deprotected the TBS
on secondary alcohol and made (2R,3S,E)-3-((tert-butyldiphenylsilyl)oxy)-10-((4-
methoxybenzyl)oxy)dec-4-ene-1,2,6-triol (99). To avoid the deprotection on this
secondary alcohol, the secondary alcohol in the diastereomer (95) was protected with
28

TBDPS group to afford (5S,E)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-8-(4-((4-methoxy
benzyl)oxy)butyl)-2,2,11,11-tetramethyl-3,3,10,10-tetraphenyl-4,9-dioxa-3,10-disila
dodec-6-ene (100). The TBDPS protected compound was refluxed in methanol in
presence of CuCl
2
to give free terminal diol, (2R,3S,E)-3,6-bis((tert-butyldiphenyl
silyl)oxy)-10-((4-methoxy benzyl)oxy)dec-4-ene-1,2-diol (101). The primary alcohol in
the diol 101 was protected with benzoyl group to give monobenzoyl derivative
(2R,3S,E)-3,6-bis((tert-butyldiphenylsilyl)oxy)-2-hydroxy-10-((4-methoxy benzyl)oxy)
dec-4-en-1-yl benzoate (102). Mesetylation of the free secondary alcohol in the
compound 102 lead to (2R,3S,E)-3,6-bis((tert-butyldiphenylsilyl)oxy)-10-((4-
methoxybenzyl)oxy)-2-((methylsulfonyl) oxy)dec-4-en-1-yl benzoate (103). Compound
102 in sodium methoxide in methanol condition lead to epoxide, (8S,E)-5-(4-((4-
methoxybenzyl)oxy)butyl)-2,2,11,11-tetramethyl-8-((S)-oxiran-2-yl)-3,3,10,10-tetra
phenyl-4,9-dioxa-3,10-disiladodec-6-ene (104) with the generation of the desired
stereocenter at C11 (Scheme 1.20).
The C1-C15 fragment was also prepared starting from (S,E)-4-((tert-butyl
diphenylsilyl)oxy)-4-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)but-2-en-1-ol by introducing
propargyl group first (Scheme 21). The free allylic alcohol group in tert-butyl(((S,E)-1-
((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-((4-methoxybenzyl)oxy)but-2-en-1-yl)oxy)
diphenylsilane (92) was protected with PMB group to make tert-butyl(((S,E)-1-((R)-2,2-
dimethyl-1,3-dioxolan-4-yl)-4-((4-methoxybenzyl)oxy)but-2-en-1-yl)oxy)diphenyl
silane (105). The acetonide group in compound 105 was deprotected with CuCl
2
.2H
2
O in
methanol under reflux condition led to (2R,3S,E)-3-((tert- butyldiphenylsilyl)oxy)-6-((4-
methoxybenzyl)oxy)hex-4-ene-1,2-diol (106).
29

Scheme 1.20: Preparation of (8S,E)-5-(4-((4-methoxybenzyl)oxy)butyl)-2,2,11,11-
tetramethyl-8-((S)-oxiran-2-yl)-3,3,10,10-tetra phenyl-4,9-dioxa-3,10-
disiladodec-6-ene (104)

The terminal alcohol group in the diol 106 was protected with benzoyl to give (2R,3S,E)-
3-((tert-butyldiphenylsilyl) oxy)-2-hydroxy-6-((4-methoxybenzyl)oxy)hex-4-en-1-yl
benzoate (107). The free secondary alcohol group in the compound 107, on mesetylation
led to (2R,3S,E)-3-((tert-butyldiphenylsilyl)oxy)-6-((4-methoxybenzyl)oxy)-2-
((methylsulfonyl)oxy)hex-4-en-1-yl benzoate (108). The crude reaction mixture 108 was
treated with K
2
CO
3
in methanol to give (5S,6S,E)-6-((tert-butyldiphenylsilyl)oxy)-9-((4-
methoxy benzyl)oxy)non-7-en-1-yn-5-ol (109). The epoxide ring opening of the
compound 109 with propargyl magnesium bromide led to 110.The PMB protection in the
30

compound 110 was deprotected in the presence of MgBr
2
.OEt
2
Me
2
S in dichloromethane
at room temperature to give (4S,5S,E)-4-((tert-butyldiphenyl silyl)oxy)non-2-en-8-yne-
1,5-diol (111).
39
The free allylic alcohol in the compound diol 111 was oxidized with

Scheme 1.21: (8S,9S,E)-9-((tert-butyldimethylsilyl)oxy)-8-((tert-butyldiphenylsilyl)
oxy)-1-((4-methoxybenzyl)oxy) tridec-6-en-12-yn-5-ol (113).
31

Manganese dioxide to give (4S,5S,E)-4-((tert-butyldiphenylsilyl)oxy)-5-hydroxynon-2-
en-8-ynal (112). The free secondary alcohol group in the compound 112 was protected
with TBS group to lead to (4S,5S,E)-5-((tert-butyldimethylsilyl)oxy)-4-((tert-
butyldiphenylsilyl) oxy)non-2-en-8-ynal (113). The aldehyde 112 was treated with the
anion generated from 1-((4-iodobutoxy)methyl)-4-methoxybenzene and tert-BuLi to give
two diastereomers of (8S,9S,E)-9-((tert-butyldimethylsilyl)oxy)-8-((tert-butyldipheny
lsilyl)oxy)-1-((4-methoxy benzyl)oxy) tridec-6-en-12-yn-5-ol (113).
1.3 Conclusion
C3-C15 subunit of palmerolide A was prepared. The C10 and C11 stereo centers were
introduced starting from L-tartaric acid. The C8-C9 E-olefin was introduced by known
elimination reaction of an ester acetonide in presence of base. Work is in progress with a
modified scheme.
1.4 Experimental
1.4.1 General
Unless otherwise mentioned, all the chemicals were purchased from commercial
sources. Ethyl 2-(triphenyl phosphoranylidene)acetate was prepared by following a
reported procedure. The products were identified by
1
H,
13
C NMR spectral analysis.
1
H
and
13
C NMR spectra were recorded on 400 MHz Varian and 250 Bruker NMR
spectrometers using CD
3
OD or CDCl
3
as solvents.
1
H and
13
C NMR chemical shifts were
determined relative to residual solvent peak at δ 7.26 ppm for CDCl
3
.
13
C NMR shifts
were determined relative to the residual solvent peak (at δ 77.16 ppm for CDCl
3
).

32

1.4.2 General procedures
1.4.2.1 Preparation of (E)-ethyl octa-2,7-dienoate (Scheme 1.2, compound 24)

Figure 1.11: Preparation of (E)-ethyl octa-2,7-dienoate
To DMSO (14.78 mL, 208 mmol) in CH
2
Cl
2
(40 mL), oxalyl chloride (9.47 mL, 108
mmol) was added drop wise at -78
o
C was added. After 5 minutes stirring at -78
o
C, 5-
hexene-1-ol (8.4 g, 83.3 mmol) in CH
2
Cl
2
(10 mL) was added drop wise and the reaction
mixture continued stirring at -78
o
C for 90 minutes. Triethyl amine (69.35 mL, 499
mmol) was added and the reaction mixture was brought to 0
o
C. The reaction mixture was
stirred at 0
o
C for 1 hour. Ethyl 2-(triphenylphosphoranylidene)acetate (29.06 g, 83.4
mmol) was added to the reaction mixture. The reaction mixture was stirred at 0
o
C for
one hour and passed through a silicagel pad to remove the solid. The solvent was
removed under reduced pressure and the residue was purified by column chromatography
(230-400 mesh size silicagel) using hexane and CH
2
Cl
2
(10:1) as eluent to yield (E)-
ethyl octa-2,7-dienoate (11.3 g, 81 %).

33

1.4.2.2 Preparation of (R,E)-ethyl 7,8-dihydroxyoct-2-enoate
(Scheme 1.2, compound 25)

Figure 1.12: Preparation of (R,E)-ethyl 7,8-dihydroxyoct-2-enoate
K
3
FeCN
6
(45.43 g, 220 mmol), K
2
CO
3
(30.42 g, 220 mmol) and CH
3
SO
2
NH
2
(6.966, 73
mmol) were ground together and mixed with a premixed mixture of (DHQD)
2
PHAL
(0.57 g, 0.73 mmol) and K
2
OsO
2
(OH)
2
(0.27, 0.73 mmol). The mixture was taken in a 1:1
mixture of
t
BuOH (136 mL) and H
2
O (136 mL). The above mixture was brought to 0
o
C
and (E)-ethyl octa-2,7-dienoate (11.3 g, 73.3 mmol) was added dropwise. The reaction
mixture was stirred at 0
o
C for 10 hours and extracted with ethyl acetate. The ethyl
acetate extracts were combined, washed with potassium hydroxide, dried over sodium
sulfate and concentrated. The crude product was purified by column chromatography
(230-400 mesh size silicagel) using CH
2
Cl
2
and CH
3
OH (20:1) as eluent to yield the
product (4.1 g, 30%).

34

1.4.2.3 Preparation of (R,E)-ethyl 8-((tert-butyldiphenylsilyl)oxy)-7-
hydroxyoct-2-enoate (Scheme 1.2, compound 26)

Figure 1.13: Preparation of (R,E)-ethyl-8-((tert-butyldiphenyl silyl)oxy)-7
hydroxyoct-2-enoate

To (R,E)-ethyl 7,8-dihydroxyoct-2-enoate (0.07 g, 0.35 mmol), imidazole (0.024 g, 0.35
mmol) and tert-butyldiphenylsilyl chloride (0.095 g, 0.35 mmol) were added at 0
o
C. The
reaction mixture was stirred at 0
o
C for 1 hour. The reaction mixture was treated with
water and extracted with hexane. The hexane extracts were combined and concentrated.
The crude compound was purified by column chromatography (230-400 mesh size
silicagel) eluent with hexane and ethyl acetate (10:1) as eluent to yield the product (0.076
g, 52 %).

35

1.4.2.4 Preparation of (R,E)-ethyl 8-((tert-butyldiphenylsilyl)oxy)-7-
(methoxymethoxy) oct-2-enoate (Scheme 1.2, compound 27)

Figure 1.14: (R,E)-ethyl 8-((tert-butyldiphenylsilyl)oxy)-7-(methoxymeth oxy)
oct-2-enoate

To (R,E)-ethyl 8-((tert-butyldiphenylsilyl)oxy)-7-hydroxyoct-2-enoate (0.060 g, 0.124
mmol) in CH
2
Cl
2
(5 mL), diisopropylethyl amine (0.024 g, 0.18 mmol), DMAP (0.002
g), and KI (0.002 g) were added. To the reaction mixture, chloromethylmethyl ether
(0.011 mL, 0.148 mmol) was added and stirred at room temperature for 2 hours. The
reaction mixture was taken in water and extracted with dichloromethane. The
dichloromethane extract was concentrated and the residue was purified on column
chromatography (230-400 mesh size silicagel) using hexane and ethyl acetate (12:1 and
10:1) as eluent to yield the product 27 (0.06 g, 91 %).

36

1.4.2.5 Preparation of (R,E)-ethyl 8-hydroxy-7-(methoxymethoxy)oct-2-
enoate (Scheme 1.2, compound 28)

Figure 1.15 (R,E)-ethyl 8-hydroxy-7-(methoxymethoxy)oct-2-enoate
To (R,E)-ethyl 8-((tert-butyldiphenylsilyl)oxy)-7-(methoxymethoxy)oct-2-enoate (2.7 g,
5.54 mmol), tetrabutylammonium fluoride (5.54 mL, 5.54 mmol) was added dropwise at
0
o
C. The reaction mixture was stirred at 0
o
C for 1 hour. Saturated ammonium chloride
was added and extracted with ethyl acetate. The ethyl acetate extracts were combined,
dried over sodium sulfate, filtered and concentrated. The residue was purified by column
chromatography (230-400 mesh size silicagel) using hexane and ethyl acetate (5:1) as
eluent to yield the product 28 (1.05 g, 76.6 %).
1.4.2.6 Preparation of (R,E)-ethyl-7-(methoxymethoxy)-8-((methylsulfonyl)
oxy)oct-2-enoate (Scheme 1.2, compound 29)

Figure 1.16: (R,E)-ethyl 7-(methoxymethoxy)-8-((methylsulfonyl)
oxy)oct-2-enoate
37

To (R,E)-ethyl 8-hydroxy-7-(methoxymethoxy)oct-2-enoate (0.1 g, 0.4 mmol) in CH
2
Cl
2

(10 mL), triethylamine (0.067 mL, 0.48 mmol) and methanesulfonyl chloride were added
at 0
o
C. The reaction mixture was stirred at 0
o
C for 1 hour and saturated ammonium
chloride was added. The organic layer was separated, dried over sodium sulfate and
concentrated. The crude product was purified by column chromatography (230-400 mesh
size silicagel) using hexane and ethyl acetate (10:1) as eluent to yield the product 29
(0.12 g, 92 %).
1.4.2.7 Preparation of (R,E)-ethyl 8-iodo-7-(methoxymethoxy)oct-2-enoate
(Scheme 1.2, compound 30)

Figure 1.17: Preparation of (R,E)-ethyl 8-iodo-7-(methoxymethoxy)
oct-2-enoate

To (R,E)-ethyl 7-(methoxymethoxy)-8-((methylsulfonyl)oxy)oct-2-enoate (0.12 g, 0.37
mmol) in acetone, sodium iodide (0.115g, 0.74 mmol) was added and refluxed for 5
hours. The reaction mixture was filtered to remove the solid and the filtrate was
concentrated to yield the crude product 30 (0.131 g, 99.9%). The crude product was used
directly for the next step without further purification.

38

1.4.2.8 Preparation of (4S,5S)-dimethyl 2,2-dimethyl-1,3-dioxolane-4,5-dicar-
boxylate (Scheme 1.3, compound 33)

Figure 1.18: Preparation of (4S,5S)-dimethyl 2,2-dimethyl-1,3-dioxolane
4,5-dicarboxylate

To (2S,3S)-2,3-dihydroxysuccinic acid (5.29 g, 30.05 mmol) in 250 mL acetone, p-
toluenesulfonic acid (0.315 g, 1.65 mmol), and 2,2-dimethoxy propane, methanol were
added and refluxed for six hours. Sodium bicarbonate (0.139 g, 1.65 mmol) is added to
the reaction mixture to neautralize the p-toluenesulfonic acid and concentrated. The
crude reaction mixture was purified on column chromatography (230-400 mesh size
silicagel) using hexane and ethyl acetate (6:1) as eluent to yield (4S,5S)-dimethyl 2,2-
dimethyl-1,3-dioxolane-4,5-dicarboxylate 33 (5.43 g, 83.6 %).
Note: p-Toluenesulfonic acid monohydrate was taken in benzene and the water was
removed by azeotropic distillation. The azeotropic distillation was repeated until all the
water was removed.
1.4.2.9 Preparation of ((4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-iyl)dimethanol
(Scheme 1.3, compound 34)

Figure 1.19: Preparation of ((4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-
diyl)dimethanol
39

(4S,5S)-dimethyl 2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate (95 g, 0.439 mmol) was
taken in anhydrous THF (880 mL) and cooled to 0
o
C. To this LAH (Lithium Aluminium
Hydride) (28 g, 737 mmol) was added in small portions for 1 hour. After complete
addition of LAH, the reaction mixture was brought to room temperature and continued
stirring for 12 hours. After 12 hours stirring at room temperature, the reaction mixture
was brought to 0
o
C and water (28 mL) was added drop wise in order to avoid vigorous
quenching of unreacted LAH. 20 % NaOH (28 mL) was added drop wise followed by
drop wise addition of water (56 mL). The white slurry obtained was stirred for 0.5 hour
and filtered. The solid was stirred in ethyl acetate and filtered. The ethyl acetate washings
were repeated until all the product was completely transferred into organic layer. The
organic layers were combined, dried over sodium sulfate and concentrated to yield the
product 34 (55.5 g, 78 %). The crude compound was used for the next step without
further purification.
1.4.2.10 1-Bromomethyl-4-methoxy-benzene (Scheme 1.3, compound 32)

To 4-Methoxybenzyl alcohol (4.56gm, 30 mmol) in diethylether (20 mL), triethylamine
(4.59 mL, 33 mmol) was added. The reaction mixture was brought to 0
o
C and 1.04 mL
(11.01 mmol) of phosphorous tribromide was added dropwise. During the addition fumes
were observed. After complete addition of phosphorous tribromide, the reaction mixture
was stirred at 0
o
C for one hour. The reaction mixture was treated with ice water and
extracted with diethylether. The ether layers were combined, dried over anhydrous
sodium sulfate, filtered and concentrated. The crude product was taken in CH
2
Cl
2
and
treated with anhydrous sodium sulfate to remove traces of water. The solution was
40

filtered and concentrated. The crude product 32 obtained was directly used for the
protection of the primary alcohol group in the next step.
1.4.2.11 Preparation of ((4R,5R)-5-(((4-methoxybenzyl)oxy)methyl)-2,2-
dimethyl-1,3-dioxolan-4-yl)methanol (Scheme 1.3, compound 36)

Figure 1.20: Preparation of ((4R,5R)-5-(((4-methoxybenzyl)oxy)methyl)-2,2-
dimethyl-1,3-dioxolan-4-yl)methanol

To a 0.2 M solution of ((4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-diyl)dimethanol (4.86 g,
30 mmol) in THF (1500 ml), 60% sodium hydride (1.32 g, 33 mmol) prewashed with
pentanes is added in small portions for 0.5 hour. The white slurry obtained was stirred at
room temperature and stirred for 12 hours. The white slurry was cooled to 0
o
C and p-
methoxybenzyl bromide in THF was added drop wise. After complete addition, the
reaction mixture was brought to room temperature and continued stirring for 12 h. The
reaction mixture was treated with ice water and extracted with ethyl acetate. The ethyl
acetate layers were combined, dried over sodium sulfate, filtered and concentrated. The
crude compound was purified by column chromatography (230-400 mesh size silicagel)
using 3:1 hexane and ethyl acetate system to yield the product ( 3.5 g, 41 %).

41

1.4.2.12 Preparation of ((4R,5R)-5-(((4-methoxybenzyl)oxy)methyl)-2,2-
dimethyl-1,3-dioxolan-4-yl)methyl4-methylbenzene sulfonate
(Scheme 1.3, compound 37)

Figure 1.21: Preparation of ((4R,5R)-5-(((4-methoxybenzyl)oxy)methyl)-2,2-
dimethyl-1,3-dioxolan-4-yl)methyl4-methylbenzene sulfonate

To ((4R,5R)-5-(((4-methoxybenzyl)oxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methan-
ol (3.5g, 12.39 mmol) in dichloromethane triethylamine was added. At 0
o
C tosyl
chloride (crystallized from hexane) was added and stirred at room temperature for three
hours. The reaction mixture was washed with water, dried over sodium sulfate and
concentrated. The residue was purified on column chromatography (230-400 mesh size
silicagel) using a mixture of hexane and ethyl acetate (15:1) as eluent to yield the product
(4.74g, 86.87%).
1.4.2.13 Preparation of (2R,3R)-2,3-dihydroxy-4-((4-methoxybenzyl)oxy)butyl
4-methylbenzenesulfonate (Scheme 1.3, compound 38)

Figure 1.22: Preparation of (2R,3R)-2,3-dihydroxy-4-((4-methoxybenzyl)
oxy)butyl-4-methylbenzenesulfonate

42

((4R,5R)-5-(((4-methoxybenzyl)oxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl4-
methylbenzene sulfonate (4.70 g, 10.85 mmol) in methanol (50 mL), DOWEX
®
(2.70 g)
was added and stirred at room temperature for 10 h. The reaction mixture was filtered and
concentrated. The residue (4.05 g, 95.07 %) was used directly for the next step without
further purification.
1.4.2.14 Preparation of (R)-2-((4-methoxybenzyl)oxy)-1-((R)-oxiran-2-yl)
ethanol (Scheme 1.3, compound 39)

Figure 1.23: Preparation of (R)-2-((4-methoxybenzyl)oxy)-1-
((R)-oxiran-2-yl)ethanol

To (2R,3R)-2,3-dihydroxy-4-((4-methoxybenzyl)oxy)butyl 4-methylbenzenesulfonate
(2.23 g, 5.61 mmol) in 1:1 mixture of CH
2
Cl
2
and CH
3
OH (20 mL), K
2
CO
3
(0.927 g,
5.61 mmol) was added and stirred at room temperature for 12 hours. The solid potassium
carbonate was separated by filtration and the filtrate was concentrated. The crude
product was purified by column chromatography (230-400 mesh size silicagel) using
hexane and ethyl acetate (2:1) as eluent to yield the product 39 (0.45 g, 35.7%).
1.4.2.15 Preparation of (R)-2-((R)-2-((4-methoxybenzyl)oxy)-1-(methoxy
methoxy)ethyl) oxirane (Scheme 1.3, compound 40)

Figure 1.24: Preparation of (R)-2-((R)-2-((4-methoxybenzyl)oxy)-1
(methoxymethoxy)ethyl) oxirane
43

To (R)-2-((4-methoxybenzyl)oxy)-1-((R)-oxiran-2-yl)ethanol (0.42 g, 1.87 mmol) in
CH
2
Cl
2
, N,N-diisoproylethylamine (1.36 mL, 2.06 mmol) and DMAP (0.011 g, 0.93
mmol) were added. The reaction mixture was brought to 0
o
C and methoxymethyl
chloride (MOMCl) (0.15 g, 1.87 mmol) was added. After the addition, the reaction
mixture was brought to room temperature and stirred at room temperature for 12 hours.
The reaction mixture was diluted with CH
2
Cl
2
and washed with water, dried over sodium
sulfate and concentrated. The crude product was purified by column chromatography
(230-400 mesh size silicagel) using a mixture of hexane and ethyl acetate (2:1) as eluent
to yield the product 40 (0.22 g, 44 %).
1.4.2.16 Preparation of propargylmagnesium bromide
(Scheme 1.3, compound 41)

Magnesium metal (0.025 g) was taken in a flash dried flask. Iodine (~2 mg) was added
and heated to activate the metal. Anhydrous ether (10 mL) was added to the metal and
treated with ethyl bromide (0.005 mL). The reaction mixture was heated to initiate the
Grignard reaction. Bubbles on the metal surface indicated the formation of Grignard
reagent. Propargyl bromide (0.45 mL, 5.15 mmol) was added dropwise and the reaction
mixture was occasionally heated activate the metal. The reaction mixture was stirred for 1
hour and the grey solution formed was directly used for the next step.

44

1.4.2.17 Preparation of (2R,3R)-1-((4-methoxybenzyl)oxy)-2-(methoxy
methoxy)hex-5-yn-3-ol (Scheme 1.3, compound 42)

Figure 1.25: Preparation of (2R,3R)-1-((4-methoxybenzyl)oxy)-2
(methoxymethoxy)hex-5-yn-3-ol

To CuI (0.02 g, 0.1 mmol) in anhydrous THF (2 mL) in a flash dried flask, propagyl
magnesium bromide was added at -78
o
C and stirred for 5 minutes. (R)-2-((R)-2-((4-
methoxybenzyl)oxy)-1-(methoxy-methoxy)ethyl)oxirane (0.147 g, 1.03 mmol) in THF (5
mL) was added dropwise to the mixture under nitrogen atmosphere. The reaction mixture
was stirred for 1 hour and brought to 0
o
C. Saturated ammonium chloride was added to
the above mixture and extracted with ethylacetate. The ethyl acetate layers were
combined, dried over sodium sulfate and concentrated. The crude was purified by column
chromatography (230-400 mesh size silicagel) using hexane and ethyl acetate system
(10:1) to yield the product 42 (0.032 g, 19.8 %).
1.4.2.18 Preparation of (4R,5S)-4-(iodomethyl)-5-(((4-methoxybenzyl)oxy)
methyl)-2,2-dimethyl-1,3-dioxolane (Scheme 1.4, compound 45)

Figure 1.26: Preparation of (4R,5S)-4-(iodomethyl)-5-(((4-methoxybenzyl)
oxy)methyl)-2,2-dimethyl-1,3-dioxolane
45

To ((4S,5S)-5-(((4-methoxybenzyl)oxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol
36 (2.0 g, 7.08 mmol) in dioxane (7 mL), triphenylphosphine (3.72 g, 14.2 mmol), iodine
(3.59 g, 14.2 mmol) and pyridine (1.68 mL, 20.8 mmol) were added. The flask is covered
with aluminium foil and the reaction mixture is stirred in dark at room temperature for 12
hours. The reaction mixture was treated with solid sodiumsulfite and the reaction mixture
was extracted with dichloromethane. The dichloromethane extracts were combined and
concentrated. The crude product was purified by column chromatography (230 mesh size
silicagel) using hexane and ethyl acetate (40:1 and 35:1) as eluents. The fractions were
concentrated and the white solid was filtered. The filtrate was concentrated to yield the
product 45 (2.30 g, 82 %).
1.4.2.19 Preparation of (R)-1-((4-methoxybenzyl)oxy)but-3-en-2-ol (Scheme
1.4, compound 46)

Figure 1.27: Preparation of (R)-1-((4-methoxybenzyl)oxy)but-3-en-2-ol

To (4R,5S)-4-(iodomethyl)-5-(((4-methoxybenzyl)oxy)methyl)-2,2-dimethyl-1,3-
dioxolane 45 (0.39 g, 1.0 mmol) in anhydrous THF, lithium (0.012 g, 2 mmol) was added
and stirred at room temperature for 3 h. The reaction mixture was brought to 0
o
C and
methanol (0.3 mL) was added dropwise. The temperature of the reaction mixture was
brought to RT and the solvent was removed under reduced pressure. The residue was
46

dissolved in ethyl acetate. The ethyl acetate layer was washed with water, dried over
sodium sulfate and concentrated to yield the product 46 (0.16 g, 78 %).
1.4.2.20 Preparation of (R,E)-(8-ethoxy-2-hydroxy-8-oxooct-6-en-1-
yl)triphenylphosphonium iodide (Scheme 1.5, compound 48)

Figure 1.28: Preparation of (R,E)-(8-ethoxy-2-hydroxy-8-oxooct
6-en-1-yl)triphenylphosphonium iodide

To (R,E)-ethyl 7-hydroxy-8-iodooct-2-enoate (0.075 g, 24 mmol) in anhydrous THF (5
mL), triphenyl phosphine (0.126 g, 48 mmol) was added and refluxed for 5 hours. The
solvent was removed under reduced pressure and the residue was given hexane washings
to remove unreacted triphenyl phosphine. The crude was dried and under vaccum to yield
the product (0.105 g, 76.64 %).
1.4.2.21 Preparation of hex-5-en-1-yl benzoate (Scheme 1.15, compound 78)

Figure 1.29: Preparation of hex-5-en-1-yl benzoate
47

To hex-5-en-1-ol (4.17, 41.6 mmol) in CH
2
Cl
2
(83 mL), triethylamine (8.66 mL, 62.4
mmol), DMAP (0.051 g, 0.42 mmol) were added. The reaction mixture was cooled to
room 0
o
C and benzoyl chloride (4.83 mL, 41.6 mmol) was added drop wise. The
reaction mixture was stirred for 1 hour and ice pieces were added. The dichloromethane
was separated and the aqueous layer was extracted with dichloromethane. All the extracts
were combined and given water washings. The organic layer was dried over sodium
sulfate, filtered and concentrated. The crude product was purified on column
chromatography (230-400 mesh silicagel) using hexane and ethyl acetate (30:1) as eluent
to yield the product (7.3 g, 85.8 %).
1.4.2.22 Preparation of (R)-5,6-dihydroxyhexyl benzoate
(Scheme 1.15, compound 79)

Figure 1.30: Preparation of (R)-5,6-dihydroxyhexyl benzoate
K
3
FeCN
6
(50.07 g, 152 mmol), K
2
CO
3
(21.0 g, 152 mmol) were ground together and
mixed with a premixed mixture of (DHQD)
2
PHAL (0.395 g, 0.50 mmol) and
K
2
OsO
2
(OH)
2
(0.187, 0.50 mmol). The mixture was taken in a 1:1 mixture of tert-BuOH
(136 mL) and H
2
O (136 mL). The above mixture was brought to 0
o
C and hex-5-en-1-yl
benzoate (10.35 g, 50.7 mmol) was added dropwise. The reaction mixture was stirred at 0
o
C for 5 hours and extracted with ethyl acetate. The ethyl acetate extracts were combined
48

and concentrated. The crude product was purified on column chromatography (230-400
mesh size silicagel) using a mixture of CH
2
Cl
2
and CH
3
OH (20:1) as eluent to yield the
product 79 (2.67 g, 85.8 %).
1.4.2.23 (R)-5-((tert-butyldimethylsilyl)oxy)-6-hydroxyhexyl benzoate
Scheme 1.15, compound 81)

Figure 1.31: Preparation of (R)-5-((tert-butyldimethylsilyl)
oxy)-6-hydroxyhexyl benzoate

To (R)-5,6-dihydroxyhexyl benzoate (2.7 g, 11 mmol) in CH
2
Cl
2
(55 mL), N,N-
dimethylaminopyridine (0.138 g, 1.1 mmol) and triethyl amine (3.93 mL, 28.3 mmol)
added. To the above mixture tert-butyldimethylsilyl chloride (3.42 g, 22.6 mmol) was
added at 0
o
C. After the addition, the reaction mixture was stirred at room temperature for
6 hours. The reaction mixture was quenched with water and extracted with
dichloromethane (25 mLx3). The dichloromethane extracts were combined, dried over
sodium sulfate and concentrated. TLC of the crude reaction mixture showed two spots.
The crude mixture containing mono protected as well as diprotected products was
purified on column chromatography (230-400 mesh silica gel) using a mixture of 30:1
hexane and ethyl acetate as eluent. The nonpolar product on TLC corresponded to
diprotected compound, (R)-5,6-bis((tert-butyldimethylsilyl)oxy)hexyl benzoate (1.21 g,
49

22.8%) and the polar spot corresponded to monoprotected compound, (R)-6-((tert-
butyldimethylsilyl)oxy)-5-hydroxyhexyl benzoate (2.58, 64.6 %). The primary alcohol
group in (R)-5,6-bis((tert-butyldimethylsilyl)oxy)hexyl benzoate was protected with tert-
butyldimethylsily chloride to make (R)-6-((tert-butyldimethylsilyl)oxy)-5-hydroxyhexyl
benzoate to use in the next step.
1.4.2.24 Preparation of (R)-5-((tert-butyldimethylsilyl)oxy)-6-hydroxyhexyl
benzoate (Scheme 1.15, compound 81)

Figure 1.32: Preparation of (R)-5-((tert-butyldimethylsilyl)oxy)-6-
hydroxyhexylbenzoate

To (R)-5,6-bis((tert-butyldimethylsilyl)oxy)hexyl benzoate (1.21 g, 2.59 mmol) in a
mixture of CH
3
OH (21.5 mL) and CH
2
Cl
2
(21.5 mL) at 0
o
C, camphorsulfonic acid
(CSA) (0.3 g, 1.29 mmol). The reaction mixture was stirred for 1 hour at 0
o
C. TLC of
the reaction mixture showed mono and di TBS deprotected compound. The reaction
mixture was treated with solid sodium bicarbonate to neutralize the CSA and the solvents
were removed under reduced pressure. The residue was purified on column
chromatography (230-400 mesh silicagel) eluted with a mixture of hexane and ethyl
acetate (3:1) system to give the product (0.755g, 82.6%).

50

1.4.2.25 Preparation of (R)-5-((tert-butyldimethylsilyl)oxy)-6-oxohexyl
benzoate (Scheme 1.15, compound 82)
76-77

Figure 1.33: Preparation of (R)-5-((tert-butyldimethylsilyl)oxy)
6-oxohexylbenzoate

To (R)-5-((tert-butyldimethylsilyl)oxy)-6-hydroxyhexyl benzoate (0.4 g, 1.13 mmol) in
anhydrous CH
2
Cl
2
(30 mL), trichlorocyanuric acid (0.277 g) and TEMPO (0.002 g) were
added at 0
o
C. The reaction mixture was stirred at 0
o
C for 30 min and the reaction
mixture was extracted with CH
2
Cl
2
(10 mlx3) and washed with water. The CH
2
Cl
2
layer
was dried over sodium sulfate and concentrated. The crude product was used for the next
step without further purification.
1.4.2.26 Preparation of (R, E)-5-((tert-butyldimethylsilyloxy)-7-iodohept-6-en-
1-yl benzoate (Scheme 1.15, compound 83)

Figure 1.34: Preparation of (R, E)-5-((tert-butyldimethylsilyloxy)-7-iodo
hept-6-en-1-yl benzoate
51

To (R)-5-((tert-butyldimethylsilyl)oxy)-6-oxohexyl benzoate (0.350 g, 1 mmol) in
anhydrous THF, Cr(II)Cl
2
(0.38 g, 3.1 mmol) and iodoform (0.78 g, 2 mmol) were added
at room temperature. The reaction mixture was stirred at room temperature for 3 h in
dark. The reaction mixture was diluted with THF and filtered through celite. The filtrate
was concentrated and the crude reaction mixture was purified by column chromatography
(230-400 mesh silica gel) using a mixture of hexane and ethyl acetate (20:1) as eluent to
yield the product (0.43 g, 90.9 %) .
1.4.2.27 Preparation of methyl 2-(2-methyl-1,3-dioxolan-2-yl)acetate
(Scheme 1.11, compound 59)

Figure 1.35: Preparation of methyl 2-(2-methyl-1,3-dioxolan-2-yl)acetate

To methyl acetoacetate (26.9 g, 232 mmol) in benzene (460 mL), PTSA (0.498 g, 2.6
mmol) and ethylene glycol (19.4 mL, 347 mmol) were added. The reaction mixture was
refluxed and water formed was removed by azeotropic distillation. The reaction was
monitored by
1
H NMR. Solid sodium bicarbonate was added to neutralize the PTSA. The
solvent was removed under reduced pressure and the crude compound was taken in
CH
2
Cl
2
and filtered to remove the undissolved solids. The filtrate was concentrated and
the crude compound (27 g, 73 %) was used without further purification.

52

1.4.2.28 Preparation of 2-(2-methyl-1,3-dioxolan-2-yl)ethanol (Scheme 1.11,
compound 60)

Figure 1.36: Preparation of 2-(2-methyl-1,3-dioxolan-2-yl)ethanol

To THF (50 mL) in 100 mL three neck flask, LiAlH
4
(2.7 g, 133 mmol) was added in
small portions. The slurry was brought to 0
o
C and methyl 2-(2-methyl-1,3-dioxolan-2-
yl)acetate (9.9 g, 53 mmol) was added drop wise. The reaction mixture was brought to
room temperature and stirred for 6 h. The reaction mixture was cooled to 0
o
C and water
(2.7 mL) was added drop wise. After 10 minutes stirring, aqueous NaOH (20 %, 2.7 mL)
was added drop wise. The reaction mixture was stirred for 10 minutes and water (5.4 mL)
was added. The reaction mixture was stirred for 30 min and extracted with ethyl acetate.
The ethyl acetate extracts were combined, dried over sodium sulfate and concentrated.
The crude product was used directly for the next step without further purification.
1.4.2.29 Preparation of 2-(2-methyl-1,3-dioxolan-2-yl)acetaldehyde (Scheme
1.12, compound 70)
76-77

Figure 1.37: Preparation of 2-(2-methyl-1,3-dioxolan-2-yl)acetaldehyde

53

To (2-methyl-1,3-dioxolan-2-yl)methanol in CH
2
Cl
2
(116 mL), Trichlorocyanuric acid
(13.97 g) and TEMPO (0.112 g) were added at 0
o
C. The reaction mixture was stirred at 0
o
C for 20 minutes and solid sodium bicarbonate was added. The dichloromethane layer
was separated, water washed, dried over sodium sulfate and concentrated. The crude
product was used for the next step without further purification.
1.4.2.30 Preparation of (E)-ethyl 4-(2-methyl-1,3-dioxolan-2-yl)but-2-enoate
(Scheme 1.11, compound 61)

Figure 1.38: (E)-ethyl 4-(2-methyl-1,3-dioxolan-2-yl)but-2-enoate
The crude product 2-(2-methyl-1,3-dioxolan-2-yl)acetaldehyde (68) was taken in
dichloromethane and treated with 2-(triphenylphosphoranylidene)acetate (22.74 g). The
reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was
filtered to separate the solid and the filtrate was concentrated. The crude compound was
purified by column chromatography using a mixture of hexane and ethyl acetate (20:1) as
eluent to yield the product 61.

54

1.4.2.31 Preparation of (E)-4-(2-methyl-1,3-dioxolan-2-yl)but-2-en-1-ol
(Scheme 1.11, compound 62)

Figure 1.39: Preparation of (E)-4-(2-methyl-1,3-dioxolan-2-yl)
but-2-en-1-ol

To (E)-ethyl 4-(2-methyl-1,3-dioxolan-2-yl)but-2-enoate (15 g, 75 mmol) in CH
2
Cl
2
(188
mL), DIBAL-H in hexane (38 mL) was added drop wise at -78
o
C. The reaction mixture
was brought to 0
o
C and stirred for 2 h. The reaction mixture was treated with saturated
sodium sulfate solution and passed through a pad of celite. The filtrate was dried over
sodium sulfate, filtered and concentrated to yield 8.3 g (72 %) of the product.
1.4.2.32 Preparation of ((2R,3R)-3-((2-methyl-1,3-dioxolan-2-yl)methyl)oxiran-
2-yl)methanol (Scheme 1.11, compound 63)

Figure 1.40: Preparation of ((2R,3R)-3-((2-methyl-1,3-dioxolan-2-yl)
methyl)oxiran-2-yl)methanol

To a suspension of crushed 4A
o
molecular sieves in CH
2
Cl
2
(10 mL) cooled to -25
o
C
were added D(-)-DIPT (0.05 mL, 0.237 mmol) and Ti(O
i
Pr)
4
(0.048 mL, 0.161 mmol). A
solution of (E)-4-(2-methyl-1,3-dioxolan-2-yl)but-2-en-1-ol (0.34 g, 2.15 mmol) in
55

CH
2
Cl
2
(1.70 mL) was added via canula. The reaction mixture was placed in a deep
refrigerator for 12 hours. The reaction was brought to -25
o
C and stirred for 30 min. The
reaction mixture was brought to -35
o
C and tert-BuOOH (0.78 mL) was added drop
wise. The reaction mixture was stirred at -30
o
C for 8 hours and placed the flask in the
refrigerator for 12 hours. 30 % NaOH (0.213 mL) saturated with sodium chloride was
added at -30
o
C and the temperature was brought to -10
o
C. MgSO
4
(0.21 g) and the
celite (0.026 g) were added. The reaction mixture was stirred for 0.5 hour and the product
was extracted with dichloromethane. The dichloromethane extracts were combined, dried
over sodium sulfate and concentrated. The crude compound was purified on column
chromatography (230-400 mesh silicagel) eluted with a mixture of hexane and ethyl
acetate (1:1) to yield 63 (0.23 g, 63.78%).
1.4.2.33 Preparation of (2S,3R)-2-methyl-4-(2-methyl-1,3-dioxolan-2-yl)butane
1,3-diol (Scheme 1.11, compound 64)

Figure 1.41: Preparation of (2S,3R)-2-methyl-4-(2-methyl-1,3
dioxolan-2-yl)butane-1,3-diol

CuCN (1.62 g, 18.1 mmol) was taken in a flash dried flask and anhydrous THF (8 mL)
was added. Methyl lithium was added drop wise at -78
o
C. After 0.5 hour at -78
o
C,
((2R,3R)-3-((2-methyl-1,3-dioxolan-2-yl)methyl)oxiran-2-yl)methanol (0.35 g, 2.01
mmol) in THF (10 mL) was added. The reaction mixture was brought to -20
o
C and
stirred for 2 h. A mixture of saturated ammonium chloride (4mL) and ammonium
56

hydroxide (2 mL) solutions were added to the reaction mixture at -20
o
C. The reaction
mixture was brought to room temperature and stirred further for 1.5 h room temperature.
Organic layer was separated. The aqueous layer was extracted with dichloromethane. The
extracts were combined, dried over sodium sulfate and concentrated. The residue was
purified on column chromatography (230-400 mesh silicagel) eluted with a mixture of
hexane and ethyl acetate (1:1) system to yield the product 64 (0.1 g, 26 %).
1.4.2.34 Preparation of (4R,5S)-2-(4-methoxyphenyl)-5-methyl-4-((2-methyl-
1,3-dioxolan-2-yl)methyl)-1,3-dioxane (Scheme 1.11, compound 65)

Figure 1.42: Preparation of (4R,5S)-2-(4-methoxyphenyl)-5-methyl-4-((2-methyl-
1,3-dioxolan-2-yl)methyl)-1,3-dioxane
To ZnCl
2
(0.161 g, 1.18 mmol) and 1-(dimethoxymethyl)-4-methoxybenzene (0.045 mL,
0.263 mmol) in 10:1 mixture of THF and CH
2
Cl
2
, (2S,3R)-2-methyl-4-(2-methyl-1,3-
dioxolan-2-yl)butane-1,3-diol (0.05 g, 0.263 mmol) was added. The reaction mixture was
stirred at room temperature for 1 hour. The reaction mixture was passed through celite
pad. The filtrate was concentrated and the crude was purified on column chromatography
(230-400 mesh size silicagel) using hexane and ethyl acetate (15:1) as eluent to yield the
product 65 (0.045, 55.5 %) and product 65’ (0.03 g, 43.3 %).

57

1.4.2.35 Preparation of (4R,5S)-2-(4-methoxyphenyl)-5-methyl-4-(2-methyl
allyl)-1,3-dioxane (Scheme 1.11, compound 66)

Figure 1.43: Preparation of (4R,5S)-2-(4-methoxyphenyl)-5
methyl-4-(2-methylallyl)-1,3-dioxane

To 1-((4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl)propan-2-one (0.04 g,
0.015 mmol) in a flash dried flask and flushed with nitrogen. Anhydrous THF (0.01 mL)
was added to the compound and the solution was brought to -40
o
C. Tebbe reagent (1.3
equivalents) was added at -40
o
C for 10 minutes and stirred for 30 min at -40
o
C. The
reaction mixture was slowly brought to 0
o
C and stirred for 1 h. The reaction mixture was
brought to room temperature and stirred for 1 h. The resulting dark solution was diluted
with 10 mL of anhydrous THF with vigorous stirring. The reaction mixture was brought
to -10
o
C and 2 mL of aqueous NaOH (10 %) was added dropwise. The evolution of gas
was observed. The reaction mixture was passed through a pad of celite and the celite pad
was given ether washings. The filtrate and ether wahsings are mixed, the solvents were
removed under reduced pressure. The residue was purified on column chromatography
(230-400 mesh size silicagel) using a mixture of hexand and ethyl acetate (20:1) as eluent
to yield the product 66 (0.025 g, 63 %).

58

1.4.2.36 Preparation of (R)-but-3-yn-2-yl methanesulfonate (Scheme 1.12,
compound 69)

To (R)-but-3-yn-2-ol (1.54 g, 11 mmol) in CH
2
Cl
2
(110 mL), triethylamine (3.97 mL,
14.3 mmol) was added. The reaction mixture was brought to -20
o
C and methane-
sulfonyl chloride (1.70 mL, 11 mmol) was added. The reaction mixture was stirred for
one hour and quenched with ice.The reaction mixture was extracted with
dichloromethane (25 mLx3). Dichloromethane extracts were combined, washed with
water, dried over sodium sulfate and concentrated. The crude compound was used
directly for the next step without further purification.
1.4.2.37 Preparation of (2R,3S)-3-methyl-1-(2-methyl-1,3-dioxolan-2-yl)pent-4-
yn-2-ol and (4R,5S)-4-hydroxy-5-methylhept-6-yn-2-one (Scheme 1.12,
compounds 71 and 72)

Figure 1.44: Preparation of (2R,3S)-3-methyl-1-(2-methyl-1,3-dioxolan
2-yl)pent-4-yn-2-ol and (4R,5S)-4-hydroxy-5-methylhept-6-
yn-2-one

Ph
3
P (0.037 g, 0.052 mmol) was added to a solution of Pd(OAc)
2
(0.033 g, 0.052 mmol)
on THF (30 mL) at -78
o
C. The mixture was stirred until a clear solution was formed.
(R)-but-3-yn-2-yl methanesulfonate 67 (0.62, 4.93 mmol) was added and then, 2-(2-
methyl-1,3-dioxolan-2-yl)acetaldehyde (0.642 g, 4.93 mmol). A solution of Et
2
Zn in
hexane (8.648 mL) was added drop wise at -78
o
C. The reaction mixture was stirred at -
59

78
o
C for 10 minutes. The reaction temperature was brought to -20
o
C and stirred for 16
hours. Ammonium chloride was added to the reaction mixture and extracted with ethyl
acetate. The ethyl acetate layer were combined, dried over sodium sulfate and
concentrated. The crude reaction mixture was purified on column chromatography (230-
400 mesh silicagel) using a mixture of hexane and ethyl acetate (3:1) as eluent to yield
the products 71(0.53, 71.4%) and 72 (0.10, 17% ).
1.4.2.38 Preparation of tert-butyldimethyl(((2R,3S)-3-methyl-1-(2-methyl-1,3-
dioxolan-2-yl)hex-4-yn-2-yl) oxy) silane (Scheme 1.12, compound 74)

Figure 1.45: Preparation of tert-butyldimethyl(((2R,3S)-3-methyl-1
(2-methyl-1,3-dioxolan-2-yl)hex-4-yn-2-yl) oxy) silane

To tert-butyldimethyl(((2R,3S)-3-methyl-1-(2-methyl-1,3-dioxolan-2-yl)pent-4-yn-2-
yl)oxy)silane (0.45 g, 1.49 mmol) in anhydrous THF (9 mL), n-butyl lithium (1.79 mL,
4.47 mmol) was added drop wise at -78
o
C. The reaction mixture was stirred at -78
o
C for
0.5 hour and methyl iodide was added drop wise. The reaction mixture was brought to 0
o
C for 3 hours and saturated ammonium chloride (10 mL) was added drop wise. The
reaction mixture was extracted with CH
2
Cl
2
. All the CH
2
Cl
2
were combined, dried over
sodium sulfate, filtered and concentrated. The crude reaction mixture was purified by
column chromatography using a mixture of hexane and ethyl acetate (15:1) as eluant
yield the product 64 (0.32 g, 71 %).

60

1.4.2.39 Preparation of (E)-methyl 5-methylhexa-2,5-dienoate
(Scheme 1.13, compound 77)
72-73

Figure 1.46: Preparation of (E)-methyl 5-methylhexa-2,5-dienoate

To methyl propiolate and anhydrous AlCl
3
in a round bottomed flask at -78
o
C, isobutene
gas is passed and sealed the flask. The contents were stirred at room temperature for 12 h.
The reaction mixture was cooled to 0
o
C and the contents were added to ice. The aqueous
mixture was extracted with dichloromethane (30 mLx 3). The dichloromethane extracts
were combined, washed with water, dried over sodium sulfate and concentrated. The
crude product was used for the next step without further purification.
1.4.2.40 Preparation of (E)-5-methylhexa-2,5-dien-1-ol
(Scheme 1.13, compound 78)

Figure 1.47: Preparation of (E)-5-methylhexa-2,5-dien-1-ol
To (E)-methyl 5-methylhexa-2,5-dienoate (3.0 g, 21.4 mmol) in CH
2
Cl
2
(50 mL), 1M
DIBAL-H solution in CH
2
Cl
2
(54 mL, 53.5 mmol) was added at -78
o
C. The reaction
mixture was brought to 0
o
C and stirred for 1 h. Ammonium chloride solution was added
to the reaction mixture and stirred for 0.5 h. The reaction mixture was extracted CH
2
Cl
2
with . The CH
2
Cl
2
extracts were combined, dried over sodium sulfate, filtered and
61

concentrated. The residue was purified on column chromatography (230-400 mesh
silicagel) using a mixture of hexane and ethyl acetate (4:1) as eluant to yield the product
78 (0.55 g, 23 %).
1.4.2.41 Preparation of ((2R,3R)-3-(2-methylallyl)oxiran-2-yl)methanol
(Scheme 1.13, compound 79)

Figure 1.48: Preparation of ((2R,3R)-3-(2-methylallyl)
oxiran-2-yl)methanol

Molecular sieves (powdered) were taken in a flask and flash dried. After cooling
anhydrous CH
2
Cl
2
was added to the flask and stirred at -25
o
C. D-(-)-DIPT (0.176 mL)
was added to the flask. To the above reaction mixture, Ti(O
i
Pr)
4
(0.168 mL) and (E)-5-
methylhexa-2,5-dien-1-ol (0.42 g, 3.79 mmol) in CH
2
Cl
2
(5 mL) were added and stirred
at -25
o
C for 8 hours. The reaction mixture was brought to -30
o
C and
t
After 12 hours,
the reaction mixture was treated with sodium hydroxide (0.392 mL), saturated with
sodium chloride. The reaction mixture was diluted with ether and brought to 10
o
C. After
10 minutes, magnesium sulfate (375 mg) and celite (46 mg) were added. The reaction
mixture was stirred for 30 minutes and extracted with diethyl ether. The diethyl ether
extracts were combined, dried over sodium sulfate and concentrated. The residue was
purified on column chromatography (230-400 mesh silicagel neutralized by washing with
2 % triethylamine in hexane) using a mixture of hexane and ethyl acetate (10:1) as eluent
to yield the product 79 (0.32 g, 66 %).
62

1.4.2.42 Preparation of (2S,3R)-2,5-dimethylhex-5-ene-1,3-diol
Scheme 1.13, compound 80)

Figure 1.49: Preparation of (2S,3R)-2,5-dimethylhex-5-ene-1,3-diol

To CuCN (0.81 g, 9 mmol) in anhydrous ether, 1.6 M solution of MeLi in ether (10.68
mL was added at -20
o
C. The reaction mixture was stirred for 15 minutes and ((2R,3R)-
3-(2-methylallyl)oxiran-2-yl)methanol (0.13 g, 1 mmol) in anhydrous ether was added
drop wise at -20
o
C. The reaction mixture was stirred for 1 h and a 2:1 mixture of
saturated ammonium chloride (3.2 mL) and ammonium hydroxide (1.61 mL) was added
at -20
o
C. The reaction mixture was stirred for 0.5 hour and extracted with CH
2
Cl
2
. All
the extracts were combined, dried over sodium sulfate and concentrated. The residue was
purified on column chromatography (230-400 mesh silicagel) using a mixture of hexane
and ethyl acetate (4:1) as eluent to yield the product 80 (0.1 g, 66.66 %) .

63

1.4.2.43 Preparation of (4R,5S)-2-(4-methoxyphenyl)-5-methyl-4-(2-methyl
allyl)-1,3-dioxane (Scheme 1.11, compound 66)

Figure 1.50: Preparation of (4R,5S)-2-(4-methoxyphenyl)-5-methyl
4-(2-methylallyl)-1,3-dioxane

To (2S,3R)-2,5-dimethylhex-5-ene-1,3-diol (0.1 g, 0.69 mmol) in CH
2
Cl
2
(5 mL), CSA
(0.001 g, 0.069 mmol) and p-methoxy benzaldehyde acetal (0.126 g, 0.69 mmol) were
added. The reaction mixture was stirred at room temperature for 5 hours. Reaction
mixture was treated with saturated sodium bicarbonate solution and extracted with
dichloromethane. The dichloromethane extracts were combined, dried over sodium
sulfate and concentrated. The residue was purified on column chromatography (230-400
mesh size silicagel) using hexane and ethyl acetate (15:1) as eluent to yield the product
80 (0.15 g, 82 %).
1
H NMR showed 6.5:1 diastereomers from acetal proton.

64

1.4.2.44 Preparation of (4S,5R,E)-5-((4-methoxybenzyl)oxy)-2,4,7-trimethyl
octa-2,7-dienal (Scheme 1.11, compound 119)

Figure 1.51: Preparation of (4S,5R,E)-5-((4-methoxybenzyl)oxy)
2,4,7-trimethylocta-2,7-dienal

To DMSO (1.478 mL, 20.8 mmol) in CH
2
Cl
2
(10 mL), oxalyl chloride (0.95 mL, 10.8
mmol) was added drop wise at -78
o
C. After 5 minutes stirring at -78
o
C, (2S,3R)-3-((4-
methoxybenzyl)oxy)-2,5-dimethylhex-5-en-1-ol (0.95 g, 3.59 mmol) in CH
2
Cl
2
(5 mL)
was added drop wise and the reaction mixture continued stirring at -78
o
C for 90 minutes.
Triethyl amine (6.93 mL, 49.9 mmol) was added and the reaction mixture was brought to
0
o
C. The reaction mixture was stirred at 0
o
C for 1 hour. (1.48 g, 4.67 mmol) was added
to the reaction mixture. The reaction mixture was stirred at 0
o
C for one hour and passed
through the silica gel pad to remove the solid. The solvent was removed under reduced
pressure and the residue was purified on column chromatography (230-400 mesh size
silicagel) using hexane and CH
2
Cl
2
(10:1) as eluent to yield the product 119 (0.85 g, 78
%).

65

1.4.2.45 Preparation of (2R,3R)-hept-6-yne-1,2,3-triol
(Scheme 1.8, compound 54)

Figure 1.52: Preparation of (2R,3R)-hept-6-yne-1,2,3-triol

To AD-mix-beta-benzenesulfonamide in a mixture of tert-BuOH and water (1:1), a
premixed mixture of (DHQD)
2
PHAL (0.187, 0.24 mmol) and K
2
OsO
2
was added, and
stirred for 10 minutes. (E)-Hept-2-en-6-yn-1-ol (2.64 g, 24 mmol) was added to the
reaction mixture dropwise and stirred. The reaction mixture was treated with sodium
thiosulfate solution and extracted with ethyl acetate. The ethyl acetate extracts were
combined, dried over sodium sulfate and concentrated. The crude reaction mixture was
purified on column chromatography (230-400 mesh silicagel) using a mixture of hexane
and ethyl acetate (5:1) as eluent to yield the product 54 (0.89 g , 35 %) with a recovery
of the starting material (1.4 g, 53 %).
1.4.2.46 Preparation of methyl 2-((4S,4'R,5R)-2,2,2',2'-tetramethyl-[4,4'-bi(1,3-
dioxolan)]-5-yl)acetate (Scheme 1.18, compound 89)

Figure 1.53: Preparation of methyl 2-((4S,4'R,5R)-2,2,2',2'-tetramethyl
[4,4'-bi(1,3- dioxolan)]-5-yl)acetate

66

Iodine (87.2 g, 343 mmol), triphenyl phosphine (120 g, 458 mmol) and pyridine (37 mL,
458 mmol) were taken in toluene (1.5 L) and stirred at RT for 15 minutes. To this 33.21
gm (114.5 mmol) of hydroxy-(2,2,2',2'-tetramethyl-[4,4']bi[[1,3]dioxolanyl]-5-yl)-acetic
acid methyl ester in toluene was added drop wise between 60
o
C and 70
o
C (At 60
o
C
only iodo derivative was observed) for 3.5 hour. The reaction mixture was refluxed for 12
hours for complete deiodination. Then, the reaction mixture was cooled, filtered. The
filtrate was concentrated and purified by column chromatography (250-400 mesh size
silicagel) using hexane as eluent to remove nonpolar impurity followed by eluting with a
mixture of hexane and ethyl acetate (10:1) as eluent to collect (2,2,2',2'-Tetramethyl-
[4,4']bi[[1,3]dioxolanyl]-5-yl)-acetic acid methyl ester 89 (21.93 g, 69.9 %).
1.4.2.47 4-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-4-hydroxy-but-2-enoic acid methyl
ester (Scheme 1.18, compound 90)

Figure 1.54: Preparation of 4-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-4
hydroxy-but-2-enoic acid methyl ester

A solution of 0.84 g (5mmol) of LiHMDS in 5 mL of THF was added drop wise to 0.2M
solution of 1.37 g (5mmol) of (2,2,2',2'-tetramethyl-[4,4']bi[[1,3]dioxolanyl]-5-yl)-acetic
acid methyl ester in 25 mL anhydrous THF at –78
o
C. The stirring was continued at –78
o
C for 1.5 hour. Reaction mixture was quenched with aqueous ammonium chloride and
extracted with ethyl acetate. Ethyl acetate layer was dried over sodium sulfate, filtered
and concentrated. The crude compound was purified on column chromatography eluted
67

with 10:1 hexane and ethyl acetate system to give 0.74 g (70%) of 4-(2,2-dimethyl-
[1,3]dioxolan-4-yl)-4-hydroxy-but-2-enoic acid methyl ester .

1.4.2.48 4-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-4-hydroxy-but-2-enoic acid methyl
ester (Scheme 1.18, compound 90)

Figure 1.55 Preparation of 4-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-4
hydroxy-but-2-enoic acid methylester

Potassium tertiary butoxide (2.74 g, 10 mmol) was added in small portions to 0.2 M
solution of (2,2,2',2'-tetramethyl-[4,4']bi[[1,3]dioxolanyl]-5-yl)-acetic acid methyl ester (
2.74 g, 10 mmol) in anhydrous THF (50 ml) at –78
o
C. The stirring was continued at –78
o
C for 1.5 hour. The reaction mixture was treated with aqueous ammonium chloride and
extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate,
filtered and concentrated. The crude compound was purified on column chromatography
(230-400 mesh size silicagel) using a mixture of hexane and ethylacetate (7:1, 4:1 and
3:1 ) as eluent to yield 4-(2,2-dimethyl-[1,3]dioxolan-4-yl)-4-hydroxy-but-2-enoic acid
methyl ester 90 (1.9 g, 87.9 %).

68

1.4.2.49 Preparation of (4S,E)-methyl 4-((tert-butyldiphenylsilyl)oxy)-4-(2,2-
dimethyl-1,3-dioxolan-4-yl)but-2-enoate (Scheme 1.18, compound 91)

Figure 1.56: Preparation of (4S,E)-methyl 4-((tert-butyldiphenylsilyl)
oxy)-4-(2,2-dimethyl-1,3-dioxolan-4-yl)but-2-enoate

To (4S,E)-methyl 4-(2,2-dimethyl-1,3-dioxolan-4-yl)-4-hydroxybut-2-enoate (16.7 g,
77.3 mmol) in DMF, imidazole (7.89 g, 115.9 mmol) was added. The reaction mixture
was brought to 0
o
C and TBDPSCl (23.37 g, 85 mmol) was added. The reaction mixture
was stirred at room temperature for 6 hours. The contents were taken in water and
extracted with hexane. The hexane layers were combined, dried over sodium sulfate and
concentrated to yield 30 g (85.7 %) of the product. The crude compound was used for the
next step without further purification.

69

1.4.2.50 Preparation of (S,E)-4-((tert-butyldiphenylsilyl)oxy)-4-((R)-2,2-
dimethyl-1,3-dioxo lan-4-yl)but-2-en-1-ol
(Scheme 1.18, compound 92)

Figure 1.57: Preparation of (S,E)-4-((tert-butyldiphenylsilyl)oxy)-4-((R)-2,2-
dimethyl-1,3-dioxo lan-4-yl)but-2-en-1-ol

To (S,E)-methyl 4-((tert-butyldiphenylsilyl)oxy)-4-((R)-2,2-dimethyl-1,3-dioxolan-4-
yl)but-2-enoate (4.2 g, 9.4 mmol) in CH
2
Cl
2
, 1M solution of DIBAL-H in CH
2
Cl
2
(18.8
mL, 18.8 mmol) was added at -78
o
C and stirred at 0
o
C for 1 hour. The reaction mixture
was treated with saturated sodium sulfate solution and stirred for 0.5 hour at room
temperature. The reaction mixture was extracted with CH
2
Cl
2
and all the extracts were
combined, dried over sodium sulfate, and concentrated. The residue was purified on
column chromatography (230-400 mesh size silicagel) using hexane and ethyl acetate
(2:1) as eluent to yield (S,E)-4-((tert-butyldiphenylsilyl)oxy)-4-((R)-2,2-dimethyl-1,3-
dioxolan-4-yl)but-2-en-1-ol 92 (3.1 g, 77.5 %) and (S,E)-4-((tert-butyldiphenylsilyl)oxy)-
1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)but-2-en-1-ol 93(0.5 g, 12.5 %).

70

1.4.2.51 Preparation of (S,E)-4-((tert-butyldiphenylsilyl)oxy)-4-((R)-2,2-
dimethyl-1,3-dioxolan-4-yl)but-2-enal (Scheme 1.18, compound 94)

Figure 1.58: Preparation of (S,E)-4-((tert-butyldiphenylsilyl)oxy)
4-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)but-2-enal

To (S,E)-4-((tert-butyldiphenylsilyl)oxy)-4-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)but-2-
en-1-ol (3 g, 7 mmol) in CH2Cl2 (50 mL), MnO2 (1 gm) was added and stirred at room
temperature for 6 hours. The reaction was monitored by TLC, filtered the MnO2 and the
filtrate concentrated to yield the product (2.9 g, 97.3 %). The crude product was used
directly for the next step without further purification.
1.4.2.52 Preparation of 4-((4-methoxybenzyl)oxy)butan-1-ol
(Scheme 1.19, compound 96)

Figure 1.59: Preparation of 4-((4-methoxybenzyl)oxy)butan-1-ol
71

60 % NaH (4.99 g, 0.125 mmol) was given pentane washings to remove the oil and THF
(600 mL) was added. The slurry was brought to 0
o
C and butane-1,4-diol (11.26 g, 125
mmol) in THF (25 mL) was added dropwise at 0
o
C. The white slurry formed was stirred
at room temperature for 12 hours to make a selective mono alkoxide ion. p-Methoxy
benzyl bromide was prepared in situ was taken in anhydrous THF (25 mL) and was
added to the monoalkoxide drop wise at 0
o
C. The reaction mixture was stirred at 0
o
C
for 3 hours and treated with ice water. The acqueous mixture was extracted with ethyl
acetate. Ethyl acetate extracts were combined, dried over sodium sulfate and
concentrated. The residue was purified on column chromatography eluted with 10:1
hexane and ethyl acetate system to yield 17.86 g (67.3 %) of the product.
1.4.2.53 Preparation of 1-((4-iodobutoxy)methyl)-4-methoxybenzene
(Scheme 19, compound 97)

Figure 1.60: Preparation of 1-((4-iodobutoxy)methyl)-4-methoxybenzene

To 4-((4-methoxybenzyl)oxy)butan-1-ol (12 g, 57 mmol) in dioxane (60 mL), triphenyl
phosphine (29.92, 114 mmol), iodine (28.96 g, 114 mmol), and pyridine (9.23 mL, 114
mmol) were added. The reaction mixture was stirred in dark at room temperature for 6
hours. The reaction mixture was treated with sodium thiosulfate solution and extracted
with dichloromethane. The dichloromethane extracts were combined, dried over sodium
72

sulfate and concentrated. The residue was purified on column chromatography eluted
with 20:1 hexane and ethyl acetate system to yield 15 g (82.2 %) of the product.
1.4.2.54 Preparation of (1S,E)-1-((tert-butyldiphenylsilyl)oxy)-1-((R)-2,2-
dimethyl-1,3-dioxolan-4-yl)-8-((4-methoxybenzyl)oxy)oct-2-en-4-ol
(Scheme 18, compound 95)

Figure 1.61: Preparation of 1-((4-iodobutoxy)methyl)
4-methoxybenzene
To 1-((4-iodobutoxy)methyl)-4-methoxybenzene (2.59 g, 8.29 mmol) in ether (25 mL),
t
BuLi (4.88 mL, 8.29 mmol) was added at -78
o
C. The reaction mixture was stirred for
0.5 hour and (S,E)-4-((tert-butyldiphenylsilyl)oxy)-4-((R)-2,2-dimethyl-1,3-dioxolan-4-
yl)but-2-enal (2.7 g, 6.38 mmol) in anhydrous diethyl ether (10 mL) was added drop wise
at -78
o
C. The reaction mixture was stirred for 2 hours and treated with aqueous
ammonium chloride solution. The reaction mixture was extracted with ethyl acetate. The
ethyl acetate extracts were combined, dried over sodium sulfate and concentrated to yield
the crude product (1.25 g, 32 %). The crude product was purified on column
chromatography eluted with 7:1 hexane and ethyl acetate to separate two distereomers.
One of the diastereomers (0.54 g) obtained was a non polar spot on TLC and the other
73

diastereomer (0.43 g) separated was polar spot on TLC in 3:1 hexane and ethyl acetate
system.
1.4.2.55 (5S,E)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-8-(4-((4-methoxy benzyl)
oxy)butyl)-2,2,10,10,11,11-hexamethyl-3,3-diphenyl-4,9-dioxa-3,10-
disiladodec-6-ene (Scheme 1.20, compound 98)

Figure 1.62: Preparation of (5S,E)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-8-(4-((4-
methoxy benzyl)oxy)butyl)-2,2,10,10,11,11-hexamethyl-3,3-diphenyl-
4,9-dioxa-3,10-disiladodec-6-ene

To (1S,E)-1-((tert-butyldiphenylsilyl)oxy)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-8-((4-
methoxy benzyl) oxy)oct-2-en-4-ol (0.5 g, 0.81 mmol) in CH
2
Cl
2
(5 mL), 2,6-lutidine
(0.19 mL, 1.62 mmol) and tert-butyldimethylsilyl trifluorosulfonate (0.32 g, 1.21 mmol)
were added at 0
o
C. Saturated ammonium chloride was added at 0
o
C and the reaction
mixture was extracted with CH
2
Cl
2
. The CH
2
Cl
2
extracts were combined, dried over
sodium sulfate and concentrated. The residue was purified on column chromatography
eluted with 15:1 hexane and ethyl acetate system separate the two diasteromers to yield
one of the diasteromers (non polar spot) (0.37 g, 62.5 %) and the diastereomer (polar
spot) (0.42 g, 49.75 %).

74

1.4.2.56 Preparation of (2R,3S,E)-3-((tert-butyldiphenylsilyl)oxy)-10-((4-
methoxybenzyl) oxy)dec-4-ene-1,2,6-triol
(Scheme 1.20, compound 99)

Figure 1.63: Preparation of (2R,3S,E)-3-((tert-butyldiphenylsilyl)oxy)
10-((4-methoxybenzyl) oxy)dec-4-ene-1,2,6-triol

To (5S,E)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-8-(4-((4-methoxybenzyl)oxy)butyl)-
2,2,10,10,11,11-hexamethyl-3,3-diphenyl-4,9-dioxa-3,10-disiladodec-6-ene (2.0 g, 2.7
mmol) in methanol (25 mL), CuCl
2
.2H
2
O (0.02 g, 0.13 mmol) was added and refluxed
for 2 hours. The solvent was removed under reduced pressure and the crude compound
was purified on column chromatography eluted with 3:1 hexane and ethyl acetate system
to yield the product (0.95 g, 60 %).

1.4.2.57 Preparation of (2R,3S,E)-3,6-bis((tert-butyldiphenylsilyl)oxy)-10-((4-
methoxybenzyl) oxy)dec-4-ene-1,2-diol (Scheme 1.20, compound 101)

To (5S,E)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-8-(4-((4-methoxybenzyl) oxy) butyl)-
2,2,11,11-tetramethyl-3,3,10,10-tetraphenyl-4,9-dioxa-3,10-disiladodec-6-ene (diastereo-
mer corresponding to lower spot on TLC) (1.5 g, 1.75 mmol) in methanol (25 mL),
CuCl
2
.H
2
O (0.015 g, 0.877 mmol). The reaction mixture was refluxed for
75

Figure 1.64: Preparation of (2R,3S,E)-3,6-bis((tert-butyldiphenylsilyl)oxy)
10-((4-methoxybenzyl) oxy)dec-4-ene-1,2-diol

2 hours. The solvent was removed under reduced pressure. The crude compound was
purified on column chromatography eluted with 5:1 hexane and ethyl acetate system to
yield 0.83 g (58 %) of the product.

1.4.2.58 Preparation of (2R,3S,E)-3,6-bis((tert-butyldiphenylsilyl)oxy)-2- hydroxy
10-((4-methoxybenzyl)oxy) dec-4-en-1-yl benzoate
(Scheme 1.20, compound 102)

Figure 1.65: Preparation of (2R,3S,E)-3,6-bis((tert-butyldiphenylsilyl)
oxy)-2-hydroxy-10-((4-methoxybenzyl)oxy)dec-4-en-1
yl benzoate

76

To (2R,3S,E)-3,6-bis((tert-butyldiphenylsilyl)oxy)-10-((4-methoxybenzyl)oxy)dec-4-ene-
1,2-diol (0.37 g, 0.54 mmol) in pyridine (0.85 mL), DMAP (0.015 g) was added. The
reaction mixture was brought to -30
o
C and benzoyl chloride (0.064 g, 0.45 mmol) was
added drop wise with continuous stirring. The reaction mixture was stirred for 2 hours
and ice pieces were added. The aqueous solution was extracted with CH
2
Cl
2
. The extracts
were combined, dried over sodium sulfate and concentrated. The crude compound was
sed for the next step without further purification.
1.4.2.59 Preparation of (2R,3S,E)-3,6-bis((tert-butyldiphenylsilyl)oxy)-10-((4-
methoxybenzyl)oxy)-2-((methylsulfonyl) oxy)dec-4-en-1-yl benzoate
(Scheme 1.20, compound 103)

Figure 1.66: Preparation of (2R,3S,E)-3,6-bis((tert-butyldiphenylsilyl)oxy) -10
((4-methoxybenzyl)oxy)-2-((methylsulfonyl)oxy)dec-4-en-1-yl
benzoate

To (2R,3S,E)-3,6-bis((tert-butyldiphenylsilyl)oxy)-2-hydroxy-10-((4-methoxybenzyl)
oxy)dec-4-en-1-yl benzoate (0.18 g, 0.197 mmol) in pyridine at 0
o
C, DMAP (0.005 g)
was added. The reaction mixture was brought to 0
o
C and methanesulfonyl chloride
(0.045 g, 0.197 mmolo) was added drop wise. The reaction mixture was stirred for 1 hour
at 0
o
C. Ice pieces were added to the reaction mixture and extracted with
77

dichloromethane. The dichloromethane extracts were given water washings, dried over
sodium sulfate, filtered and concentrated. The crude compound was used for the next step
without further purification.

1.4.2.60 Preparation of (8S,E)-5-(4-((4-methoxybenzyl)oxy)butyl)-2,2,11,11-
tetramethyl-8-((S)-oxiran-2-yl)-3,3,10,10-tetraphenyl-4,9-dioxa-3,10-
disiladodec-6-ene (Scheme 1.20, compound 104)

Figure 1.67: Preparation of (8S,E)-5-(4-((4-methoxybenzyl)oxy)butyl)-
2,2,11,11-tetramethyl-8-((S)-oxiran-2-yl)-3,3,10,10-tetra-
phenyl-4,9-dioxa-3,10-disiladodec-6-ene

To (2R,3S,E)-3,6-bis((tert-butyldiphenylsilyl)oxy)-10-((4-methoxybenzyl)oxy)-2-
((methylsulfonyl)oxy) dec-4-en-1-yl benzoate (0.2 g, 0.20 mmol) in methanol, sodium
methoxide (0.054 g, 1 mmol) was added and stirred at room temperature. The reaction
mixture was passed through celite and concentrated. The residue was purified on column
chromatography eluted with 10:1 hexane and ethyl acetate system to yield the product
(0.072 g, 43 %).

78

1.4.2.61 Preparation of (4S,5R)-4-(((4-methoxybenzyl)oxy)methyl)-2,2-
dmethyl-5-((phenyl sulfonyl)methyl)-1,3-dioxolane
(Scheme 1.15, compound 84)

Figure 1.68: Preparation of (4S,5R)-4-(((4-methoxybenzyl)oxy)
methyl)-2,2-dimethyl-5-((phenyl sulfonyl)methyl)-
1,3-dioxolane

To (4R,5S)-4-(iodomethyl)-5-(((4-methoxybenzyl)oxy)methyl)-2,2-dimethyl-1,3-
dioxolane (0.476 g, 1.2 mmol) in DMF (5 mL), benzene sulfinic acid sodium salt (0.664
g, 4 mmol) was added and heated at 50
o
C for 12 hours. The reaction mixture was
extracted with hexane and concentrated. The residue was purified on column
chromatography eluted with 10:1 hexane and ethyl acetate system to yield 0.43 g (85.8
%) of the product.

79

1.4.2.62 Preparation of (3R)-7-((tert-butyldimethylsilyl)oxy)-3-((4-methoxy
benzyl)oxy)-1-((4R,5S)-5-(((4-methoxy benzyl) oxy)methyl)-2,2-
dimethyl-1,3-dioxolan-4-yl)-1-(phenylsulfonyl)heptan-2-yl acetate
(Scheme 1.15, compound 86)

Figure 1.69: Preparation of (3R)-7-((tert-butyldimethylsilyl)oxy)-3-
((4-methoxybenzyl)oxy)-1-((4R,5S)-5-(((4-methoxy
benzyl)oxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-1
(phenylsulfonyl) heptan-2-yl acetate

To (4S,5R)-4-(((4-methoxybenzyl)oxy)methyl)-2,2-dimethyl-5-((phenylsulfonyl)methyl)-
1,3-dioxolane (0.25 g, 0.6 mmol) in anhydrous THF (5.5 mL) at -78
o
C,
n
BuLi was
added drop wise. The contents were stirred for 30 minutes at -78
o
C. A light yellow color
was observed. (4S,5R)-4-(((4-methoxybenzyl)oxy)methyl)-2,2-dimethyl-5-((phenyl
sulfonyl)methyl)-1,3-dioxolane in THF (1 mL) was added drop wise and stirred at -78
o
C
for 3 hours. The reaction mixture was treated with ammonium chloride and extracted
with ethyl acetate. The ethyl acetate extracts were combined, dried over sodium sulfate
and concentrated. The residue was purified on column chromatography eluted with 4:1
hexane and ethyl acetate system to yield the product.

80

1.4.2.63 Preparation of tert-butyl(((S,E)-4-((4-methoxybenzyl)oxy)-1-((S)-
oxiran-2-yl)but-2-en-1-yl)oxy)diphenylsilane
(Scheme 1.21, compound 109)

Figure 1.70: Preparation of tert-butyl(((S,E)-4-((4-methoxybenzyl)oxy)-1-((S)-
oxiran-2-yl)but-2-en-1-yl)oxy)diphenylsilane

(2R,3S,E)-3-((tert-butyldiphenylsilyl)oxy)-6-((4-methoxybenzyl)oxy)-2-((methyl
sulfonyl)oxy)hex-4-en-1-yl benzoate (1.05 g, 1.52 mmol) in CH
3
OH (15 mL), sodium
methoxide (0.41 g, 7.59 mmol) was added at 0
o
C and stirred for 2 hours. The reaction
mixture was passed through celite to remove the solid and the solvent was removed under
reduced pressure. The crude compound was purified on column chromatography eluted
with 5:1 hexane and ethyl acetate system to yield 0.45 g (68.18 %) of the product.
1.4.2.64 Preparation of (5R,6S,E)-6-((tert-butyldiphenylsilyl)oxy)-9-((4-methoxy
benzyl) oxy) non-7-en-1-yn-5-ol (Scheme 1.21, compound 111)

Figure 1.71: Preparation of (5R,6S,E)-6-((tert-butyldiphenylsilyl)oxy)-9-((4-
methoxybenzyl) oxy) non-7-en-1-yn-5-ol
81

To tert-butyl(((S,E)-4-((4-methoxybenzyl)oxy)-1-((R)-oxiran-2-yl)but-2-en-1-yl)oxy)
diphenylsilane (0.12 g, 0.245 mmol) in anhydrous ether (10 mL), propargyl magnesium
bromide (0.22 mL, 1.47 mmol) was added at -78
o
C drop wise. The reaction mixture was
brought to 0
o
C and stirred for 1 hour. The reaction mixture was treated with saturated
ammonium chloride and extracted with ether. The ether layers were combined, dried over
sodium sulfate, filtered and concentrated. The residue was purified on column
chromatography eluted with 3:1 hexane and ethyl acetate system to yield the product
(0.062 g, 48 %).
1.4.2.65 Preparation of (4S,5R,E)-4-((tert-butyldiphenylsilyl)oxy)-5-hydroxy
non-2-en-8-ynal (Scheme 1.21, compound 111)

Figure 1.72 : Preparation of (4S,5R,E)-4-((tert-butyldiphenylsilyl)oxy)
5-hydroxynon-2-en-8-ynal

To (4S,5R,E)-4-((tert-butyldiphenylsilyl)oxy)non-2-en-8-yne-1,5-diol (0.25 g, 0.575
mmol) in CH
2
Cl
2
(5 mL), MnO
2
(0.05 g) was added and stirred at room temperature for 5
hours. The solid was filtered and the filtrate was concentrated to give the crude product
44 (0.235 g, 94.7 %).

82

1.5 Spectral Data
1.5.1 (E)-Ethyl octa-2,7-dienoate (Scheme 1.2, compound 24)
1
H NMR (CDCl
3
, 250 MHz) δ6.97-6.88 (dt, 1H, J=5.5 Hz, 13.5 Hz), 5.84-5.78 (dm, 1H,
J=14.25 Hz), 5.77-5.72 (m, 1H), 5.04-4.98 (d, 1H, J=15.75 Hz), 4.97-4.94 (m, 1H), 4.21-
4.13 (q, 2H, J=7.25 Hz, 21.5 Hz), 2.24-2.15 (q, 2H, J=6.75 Hz, 21.75 Hz), 2.11-2.03 (q,
2H, J=7.25 Hz, 21.25 Hz), 1.61-1 .51 (q, 2H, J=9Hz, 16.5 Hz), 1.30-1.24 (t, 3H, J=14.5
Hz).
1.5.2 (R,E)-Ethyl 7,8-dihydroxyoct-2-enoate (Scheme 1.2, compound 25)
1
H NMR (CDCl
3
, 400 MHz) δ7.01-6.89 (dt, 1H, J=7 Hz, 11.2Hz), 5.86-5.79 (dt, 1H,
J=14.4 Hz), 4.22-4.14 (q, 2H, J=11.6 Hz), 3.75-3.69 (m, 1H), 3.64-3.63 (d, 1H, J= 5.2
Hz), 3.47-3.40 (dd, 1 H, J=12 Hz), 2.28-2.20 (q, 2H, J=6.25 Hz), 1.69-1.41 (m, 4 H),
1.31-1.26 (t, 3H, J=7Hz).
13
C NMR (CDCl
3
, 250 MHz) δ166.9, 149.02, 121.47, 71.87, 66.53, 60.26, 32.36, 31.99,
24.01, 14.18
1.5.3 (R,E)-Ethyl 8-((tert-butyldiphenylsilyl)oxy)-7-hydroxyoct-2-enoate (Scheme
1.2, compound 26)

1
H NMR (CDCl
3
, 400 MHz) δ8.02-8.00 (m, 4H), 7.81-7.61 (m, 6H), 7.29-7.25 (dt, 1H,
J=15.6 Hz), 6.16-6.12 (d, 1H, J=16.4 Hz), 4.55-4.49 (q, 2H, J=7.2 Hz), 4.01 (bs, 1H),
4.0-3.98 (dd, 1H, J=8 Hz), 3.85-3.80 (t, 1H, J=17.6 Hz), 2.88 (s, 1H), 2.61-2.51 (m, 2H),
1.98 (m, 1H), 1.98-1.79 (m, 3H), 1.62 (t, 3H), 1.40 (s, 9H);
13
C NMR (CDCl
3
, 250 MHz) δ148.78, 135.56, 133.17, 129.90, 127.85, 121.65, 71.65,
67.97, 60.17, 32.17, 32.09, 26.89, 24.02, 19.28, 14.30

83

1.5.4 (R,E)-Ethyl-8-((tert-butyldiphenylsilyl)oxy)-7-(methoxymethoxy)oct-2-enoate
(Scheme 1.2, compound 27)

1
H NMR (CDCl
3
, 400 MHz) δ7.68-7.64 (m. 4H), 7.46-7.33 (m, 6H), 6.98-6.90 (dt, 1H,
J=4Hz, 7.2 Hz), 5.829-5.789 (d, 1H, J=1.6 Hz), 4.77-4.75 (d, 1H, J=6.8 Hz), 4.62-4.60
(d, 1H, J=6.8 Hz), 4.21-4.15(q, 2H, J=24), 3.67-3.66 (m, 2H), 3.59-3.58 (d, 1H, J=5.2
MHz), 3.34 (s, 3H), 2.2 (s, 2H), 1.58-1.49 (m, 4H), 1.30-1.27 (t, 3H, J=10.8 MHz),1.03
(s, 9H).
13
C NMR (CDCl
3
, 250) δ148.87, 135.65, 133.47, 129.75, 127.82, 121.59, 96.21, 66.25,
55.57, 32.17, 31.30, 26.85, 23.80, 19.21, 14.30
1.5.5 (R,E)-Ethyl 8-hydroxy-7-(methoxymethoxy)oct-2-enoate (Scheme 1.2,
compound 28)

1
H NMR (CDCl
3
, 400 MHz) δ6.97-6.85 (m, 1H), 5.86-5.79 (d, 1H, J=28), 4.41-4.21 (m,
1H), 4.19-4.17 (d, 2H, J=8 Hz), 4.16-4.07 (m, 1H), 3.10-3.08 (t, 3H), 2.27-2.24 (m, 2H),
1.73-1.64 (m, 2H), 1.61-1.47 (m, 4H), 1.30-1.26 (t, 3H, J=15.2 Hz);
1.5.6 (R,E)-Ethyl-7-(methoxymethoxy)-8-((methylsulfonyl)oxy)oct-2-enoate
(Scheme 1.2, compound 29)

1
H NMR (CDCl
3
, 400 MHz) δ 6.94-6.89 (dt, 1H, J=8 Hz), 5.84-5.80 (d, 1H, J-15.2 Hz),
4.72-4.70 (q, 2H, J=17.2 Hz), 4.67 (m, 1H), 4.28-4.24 (m, 1H), 4.20-4.11 (m, 1H), 4.18-
4.17 (d, 1H, J=4.8), 3.81-3.79 (s, 1H), 3.40 (s, 3H), 3.13 (s, 3 H), 2.22 (m, 2H), 1.67-1.58
(m, 4H), 1.29-1.23 (t, 3H).
13
C NMR (CDCl
3
, 250) δ148.35, 122.16, 96.48, 75.08, 70.96, 60.48, 56.07, 46.11, 37.78,

32.12, 31.17, 23.82, 14.49, 8.83

84

1.5.7 (R,E)-ethyl 8-iodo-7-(methoxymethoxy)oct-2-enoate (Scheme 1.2, compound
30)

1
H NMR (CDCl
3
, 250 MHz) δ6.93-6.89 (dt, 1H, J=10 Hz), 5.84-5.80 (dt, 1H, J=10 Hz),
4.191-4.13 (q, 1H, J=4. 5Hz), 3.4 (s, 3H), 3.30-3.27 (t, 2H, J=5Hz), 3.18-3.11 (m, 2H),
2.25-2.13 (m, 1H), 1.67-1.59 (m, 2H), 1.47-1.44 (t, 3H, J=4.75Hz), 1.28-1.26 (t, 3H,
J=4.25Hz).

1.5.8 (4S,5S)-dimethyl 2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate (Scheme 1.3,
compound 33)

1
H NMR (CDCl
3
, 400 MHz) δ4.80 (s, 2H), 3.81 (s, 4H), 1.48 (s, 6H)

1.5.9 ((4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-diyl)dimethanol (Scheme 1.3,
compound 35)

1
H NMR (CDCl
3
, 250 MHz) δ3.97 (s, 4H), 3.76-3.72 (t, 2H, J=5.5 Hz), 1.95-1.90 (t, 2H,
J=5.75 Hz), 1.34 (s, 3H).
1.5.10 ((4S,5S)-5-(((4-methoxybenzyl)oxy)methyl)-2,2-dimethyl-1,3-dioxolan-
4-yl)methanol (Scheme 1.3, compound 36)

1
H NMR (CDCl
3
, 250 MHz) δ7.24-7.21 (d, 2H, J=8.5 Hz), 6.87-6.84 (d, 2H, J=9 Hz),
4.49 (s, 2H), 4.01-3.96(m, 1H, 10.75 Hz), 3.92-3.86 (m, 1H, J=4.25), 3.78 (s, 3H), 3.71-
3.70 (d, 1H, J=4.25), 3.68-3.65 (dd, 1H, J=6.75 Hz), 3.63-3.61 (d, 1 H, J=5.25 Hz), 3.52-
3.46 (dd, 1H, J=6 Hz), 2 (bs, 1H), 1.37 (s, 3H).

1.5.11 ((4R,5R)-5-(((4-methoxybenzyl)oxy)methyl)-2,2-dimethyl-1,3-dioxo
lan-4-yl)methyl 4-methylbenzenesulfonate (Scheme 1.3, compound 37)

13
C NMR (CDCl
3
, 250 MHz) δ138.67, 128.25, 127.39, 114.42, 127.75, 170.16, 33.47,

29.13, 25.42.

85

1.5.12 (R)-2-((R)-2-((4-methoxybenzyl)oxy)-1-(methoxymethoxy)ethyl)
oxirane (Scheme 1.3, compound 40)

1
H NMR (CDCl
3
, 400 MHz) δ7.27-7.25 (d, 2H, J=8.8 Hz), 6.89-6.87 (d, J=8.4 Hz), 4.51

(s, 2H), 3.81 (S, 3H), 3.77-3.75 (m, 1H), 3.60-3.54 (m, 2H), 3.11-3.08 (dd, 1H, J=4.4

Hz), 2.79-2.74 (m, 2H), 2.25-2.23 (d, 1H, J=6 Hz).

1.5.13 (4R,5S)-4-(iodomethyl)-5-(((4-methoxybenzyl)oxy)methyl)-2,2-dimethyl-1,3-
dioxolane (Scheme 1.4, compound 45)

1
H NMR (CDCl
3
, 250 MHz) δ7.64-7.61 (d, 2H, J=8.5 Hz), 7.27-7.23 (d, 2H, J=8.25 Hz),
4.88 (s, 2H), 4.32-4.27 (m, 1H), 4.23-4.19 (m, 1H), 4.17 (s, 3H), 3.99-3.96 (dt, 2H, J=2
Hz, 5Hz), 3.74-3.68 (dd, 1H, J=5.25 Hz, 10 Hz), 3.65-3.59 (dd, 1H, J=0.5 Hz, 6Hz), 1.83
(s, 3H), 1.77 (s, 3H).
1.5.14 (R)-1-((4-methoxybenzyl)oxy)but-3-en-2-ol (Scheme 4, compound 46)

1
H NMR (CDCl
3
, 250 MHz) δ7.63-7.69 (dd, 2H, J=3.25Hz, 5.75 Hz), 7.26-7.22 (dt, 2H,
J=2 Hz, 5.75 Hz), 6.24-6.11 (m, 1H), 5.74-5.66 (dq, J=3.75H, 17 Hz), 5.56-5.51 (dm, 1H,
J=12Hz), 4.87 (s, 2H), 4.68 (bs, 1H), 4.16 (s, 3H), 3.89-3.84 (dd, J=1 Hz, 9.75 Hz), 3.73-
3.65 (dd, 1H, J=8 Hz), 2.78 (bs, 1H).
1.5.15 (R,E)-ethyl 7-hydroxy-8-iodooct-2-enoate (Scheme 5, compound 46)
1
H NMR (CDCl
3
, 250 MHz) 7.29-6.90 (dt, 1H, J=7.25 Hz), 5.89-5.82 (d, 1H, J=18.75
Hz), 4.25-4.16 (q, 2H, J=21.5), 3.57-3.54 (bs, 1H), 3.43-3.37 (dd, 1H, J=3.5 MHz, 10
MHz), 3.28-3.21 (dd, 1H, J=7 MHz, 10.25 MHz), 2.84-2.22 (m, 2H), 2.01-1.98 (d, 1H,
J=5.5 MHz), 1.34-1.28 (t, 3H, J=5.25 MHz).

86

1.5.15 (R)-4-((R)-1-((4-methoxybenzyl)oxy)pent-4-yn-1-yl)-2,2- dimethyl-1,3-
dioxolane (Scheme 1.8, compound 56)

CDCl
3
, 400 MHz), 7.29-7.26 (d, 2H, J=8.8 Hz), 6.89-6.86 (dt, 2H, J=8.8 Hz), 5.29 (s,
2H), 4.75-4.71 (d, 1H, J=10.8 Hz), 4.56-4.53 (d, 1H, J=10.8 Hz), 4.23-4.18 (q, 1H, J=6.4
Hz), 4.00-3.96 (dd, 1H, J=6.4 Hz), 3.80 (s, 3H), 3.72-3.68 (dd, 1H, J=7.6 Hz), 3.62-3.58
(m, 1H).
1.5.16 (R,E)-(8-ethoxy-2-hydroxy-8-oxooct-6-en-1-yl)triphenylphosphonium iodide
(Scheme 1.5, compound 48)

1
H NMR (CDCl
3
, 250 MHz) δ7.72-7.7.43 (m, 15H), 6.85-6.76 (dt, 1H, J=6.75, 14Hz),

5.72-5.66 (d, 1H, J=15.75 Hz), 4.17-4.01 (q, 2H), 3.99-3.92 (m, 1H), 3.89-3.85 (m, 1H),

3.36-3.09 (m, 1H), 2.17-2.12 (m, 2H), 2.09-2.04 (m, 2H), 1.8-1.72 (m, 2H), 1.25-1.19 (t,

3H, J=7);

1.5.17 Hex-5-en-1-yl benzoate (Scheme 13, Compound 78)

1
H NMR (CDCl
3
, 250 MHz) δ8.06-8.02 (d, 2H, J=2.75 Hz), 7.59-7.52 (m, 1H), 7.47-7.40
(m, 2H), 5.87-5.77 (m, 1H), 5.08-4.35 (m, 2H), 4.35-4.30 (t, 3H, 2.17-2.08 (m, 2H), 1.85-
1.73 (m, 2H), 1.61-1.49 (m, 2H).
1.5.18 (R)-5,6-dihydroxyhexyl benzoate (Scheme 13, compound 79)

1
H NMR (CDCl
3
, 250 MHz) δ 8.05-8.01 (dd, 2H, J=6.25 Hz), 7.55-7.39 (m, 3H), 4.34-
4.29 (t, 2H, J=6.5 Hz), 3.71-3.81 (m, 2H), 3.46-3.39 (, 2H), 1.81-1.76 (m, 2H), 1.62-1.48
(m, 4H).
1.5.19 (R)-5-((tert-butyldimethylsilyl)oxy)-6-hydroxyhexyl benzoate (Scheme 13,
Compound 81)

1
H NMR (CDCl
3
, 250 MHz) δ8.077-8.069 (d, J=2 Hz, 2H), δ8.043-8.035 (d, J=2
Hz,1H), δ7.573-7.542 (t, J=7.5 Hz, 2H), δ4.38-4.316 (t, J=13 Hz, 2H), δ 3.85 (m, 1H),
87

δ3.77-3.48 (m, J=5Hz, 2H), δ1.929-1.824 (t, J=26.25 Hz, 1H), δ1.79-1.76 (m, J=6.75 Hz,
2H), δ 1.61-1.53 (m, J=6.75 Hz, 3H), δ0.92 (s, 9H), δ0.090 (s, 6H);
1.5.20 (R)-5,6-bis((tert-butyldimethylsilyl)oxy)hexyl benzoate (Scheme 13,
compound 80)

1
H NMR (CDCl
3
, 250 MHz) δ8.048-8.010, (d, J=8.25Hz, 2H), δ7.541-7.394 (m, 3H),
δ4.336-4.31 (t, 2H), δ4.28 (bs, 1H), δ3.567-35 (m,1H), δ3.39-3.37 (m, 2H), δ1.789-1.741
(m, 2H), δ1.48-1.45 (m, 2H), δ1.45-1.43 (m, 2H), 0.85 (s, 9H), 0.06 (s, 6H).
1.5.21 (R)-5-((tert-butyldimethylsilyl)oxy)-6-oxohexyl benzoate (Scheme 13,
compound 82)

1
H NMR (CDCl
3
, 250 MHz) δ9.6 (s, 1H), 8.048-8.00 (d, 2H, J=10Hz), 7.55-7.46 (m,
1H), 7.43-7.42 (m, 2H), 4.34-4.33 (t, 2H, J=2.25 Hz), 4.44-4.31 (m, 1H), 3.73-3.70 (m,
1H), 1.84-1.59 (m, 6H), 0.96 (s, 9H), 0.09 (s, 6H).
1.5.22 (R,E)-5-((tert-butyldimethylsilyl)oxy)-7-iodohept-6-en-1-yl benzoate
1
H NMR (CDCl
3
, 250 MHz) δ8.056-8.017 (d, 2H, J=8.5 Hz), 7.559-7.529 (m, 1H), 7.47-
7.43 (m, 2H), 6.56-6.50 (dd, 1H, J=6 Hz, J=6Hz), 6.24-6.18 (d, 14.5Hz), 4.34-4.31 (t,
2H, J=6.5 Hz), 4.28 (m, 1H), 1.79-1.73 (m, 2H), 1.55-1.50 (m, 4H), 0.88 (s, 9H), 0.026
(s, 6H).
1.5.23 (4S,5R)-4-(((4-methoxybenzyl)oxy)methyl)-2,2-dimethyl-5-
((phenylsulfonyl)methyl)-1,3-dioxolane

1
H NMR (CDCl3, 250 MHz) δ7.92-7.88 (d, 2H, J=9.5 Hz), 7.64-7.60 (t, 1H, J=8.5),
7.55-7.49 (t, 2H, J=7 Hz), 7.26 (s, 1H), 7.25-7.21 (d, 2H, J=8.5 Hz), 6.91-6.87 (d, 2H,
J=4.75 Hz), 4.46 (s, 2H), 4.33-4.26 (1H, dt, 7.75 Hz), 3.92-3.06 (m, 1H), 3.86 (s, 3H),
3.69-3.63 (dd, 1H, J=5.25 Hz, 10 Hz), 3.53-3.50 (d, 1H, 5.75 Hz), 3.49-3.31(m, 2H).

88

1.5.24 (3R)-7-((tert-butyldimethylsilyl)oxy)-3-((4-methoxybenzyl)oxy)-1-((4R,5S)-5-
(((4-methoxy benzyl) oxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-1-(phenyl
sulfonyl) heptan-2-yl acetate

1
H NMR (CDCl
3
, 250 MHz) 7.90-7.84 (d, 2H, J=14.25 Hz), 7.66-7.54 (m, 1H), 7.58-7.48
(m, 2H), 7.30-7.23 (m, 1H), 7.21-7.16 (d, 2H, J=11.5 Hz), 7.01-6.94 (dd, 1H, 3.75, 14.5
Hz), 6.89-6.83 (dd, 3H), 6.55-6.48 (1H, dd, J=15.75 Hz), 5.63-5.61 (mq, 1H), 4.50-4.48
(d, 1H, J=4.75 Hz), 4.46-4.43 (d, 2H, J=17.5 Hz), 3.8 (s, 3H), 3.58-3.52 (dd, 2H, J=3.5
Hz), 3.53-3.34 (m, 1H), 3.52 (s, 3H).
1.5.25 2-(2-methyl-1,3-dioxolan-2-yl)ethanol
1
H NMR (CDCl3, 250) δ3.99 (s, 4H), 3.80 (dd, 2H, J=10.5 Hz), 2.80-2.76 (t, 1H,
J=5.5Hz), 1.97-1.93 (t, 2H, J=5.25 Hz), 1.36 (s, 3H).
1.5.26 2-(2-Methyl-1,3-dioxolan-2-yl)acetaldehyde (Scheme 12, Compound 70)

1
H NMR (CDCl
3
, 250 MHz) δ 9.71 (t, 1H), δ9.72 (t, 1H), 4.00-3.95 (m, 4H), 2.68-2.67
(d, 2H), 1.39 (s, 3H).
1.5.27 ((2R,3R)-3-((2-methyl-1,3-dioxolan-2-yl)methyl)oxiran-2-yl)methanol
(Scheme 11, compound 63)

1
H NMR (CDCl
3
, 250 MHz) δ3.99 (m, 4H), 3.87-3.61 (dd, 1H, J=13.25 MHz), 3.10-294
(dt, 1H), 1.91-1.88 (d, 2H, J=5.25 Hz), 1.38 (s, 3H).
1.5.28 (2S,3R)-2-methyl-4-(2-methyl-1,3-dioxolan-2-yl)butane-1,3-diol (Scheme 11,
compound 64)

1
H NMR (CDCl
3
, 250MHz) δ4.04 (s, 4H), 3.87 (t, 1H), 3.68-3.65 (m, 2H), 1.99-1.83 (q,
2H, J=14.25 MHz), 1.71-1.66 (m, 1H), 1.40 (s, 3H), 0.91-0.89 (d, 3H).

89

1.5.29 (2S,3R)-2-methyl-4-(2-methyl-1,3-dioxolan-2-yl)butane-1,3-diol (Scheme 11,
compound 64)

1
H NMR (CDCl
3
, 250 MHz) δ4.32-4.28 (s, 4H), 4.01-3.96 (m, 1H), 3.90-3.69 (m, 2H),
3.82-3.80 (m, 1H), 2.34-2.26 (dd, 1H, J=14.75 Hz), 2.16-2.13 (m, 1H), 1.97-1.89 (dd,
1H, J=14.75 Hz), 1.68 (s, 3H), 1.30-1.26 (d, 3H, J=9.75 Hz,)
13
C NMR (CDCl
3
, 250 MHz) 170.91, 166.12, 143.24, 124.37, 121.62, 108.79, 64.71,
60.46, 60.11, 42.05, 37.55, 23.94, 20.89, 14.16.
1.5.30 (4R,5S)-2-(4-Methoxyphenyl)-5-methyl-4-((2-methyl-1,3-dioxolan-2-
yl)methyl)-1,3-dioxane (Scheme 11, compound 65)
1
H NMR (CDCl3, 250 MHz) δ7.39-7.36 (d, 1H, J=8.5 Hz), 6.90-6.85 (d, J=12 Hz), 5.47
(s, 1H), 4.15-4.02 (dd, 1H, 12.5 Hz), 4.02-3.93 (m, 1H, J=10.25 Hz), 3.80 (s, 3H), 3.57-
3.48 (t, 1H, J=11.25), 2.71-2.68 (t, 1H, J=8.5 Hz), 2.22 (s, 3H), 1.60 (m, 1H), 0.80-0.78
(d, 3H).
1.5.31 (4R,5S)-2-(4-methoxyphenyl)-5-methyl-4-(2-methylallyl)-1,3-dioxane
(Scheme 11, compound 66)

1
H NMR (CDCl
3
, 250) δ7.41-7.37 (d, 2H, J=9 Hz), 6.88-6.84 (d, 2 H, J=8.75 Hz), 5.42
(s, 1H), 4.81-4.79 (d, 2H, J=4.75 Hz), 4.11-4.05 (dd, 1H, J=5 Hz), 3.78 (s, 3H), 3.61-3.57
(m, 1H, J=10.5 Hz), 3.49-3.44 (d, 1H, J= 11.25 Hz), 2.45-2.40 (d, 1H, J=12), 2.32-2.23
(dd, 1H, J=8.5 Hz), 1.90-1.84 (m, 1H), 1.81 (s, 3H), 1.53 (s, 3H), 0.95 (m, 1H), 0.81-0.78
(d, 3H, J=6.75 Hz).
1.5.32 (R)-but-3-yn-2-yl methanesulfonate (Scheme 12, compound 69)

1
H NMR (CDCl
3
, 250 MHz) 5.32-5.25 (m, 1H), 3.12 (s, 3H), 2.70-2.69 (t, 1H, J=2 Hz)¸

1.66-1.59 (d, 3H).

90

1.5.33 (2R,3S)-3-methyl-1-(2-methyl-1,3-dioxolan-2-yl)pent-4-yn-2-ol
(Scheme 12, compound 70)

1
H NMR (CDCl
3
, 250 MHz) δ 4.00 (s, 4H), 3.92-3.84 (m, 1H), 3.56 (s, 1H), 2.58-2.54
(m, 1H), 2.11-2.10 (d, 2.5 Hz), 1.96-1.94 (d, 2H), 1.64 (s, 1H), 1.38 (s, 3H), 1.24-1.23 (d,
3H, J=4.5 Hz).
1.5.35 (4R,5S)-4-hydroxy-5-methylhept-6-yn-2-one (Scheme 12, compound 69)
1
H NMR (CDCl
3
, 400 MHz) δ4.08-4.05 (m, 1H), 2.91-2.90 (d, 1H, J=2.75 Hz), 2.78-2.76
(d, 1H, J=6.75 Hz), 2.65-2.61 (m, 1H), 2.24 (s, 3H), 2.18-2.17 (d, 1H), 1.67 (s, 1H),
1.29-1.27 (d, 3H, J=3.75 Hz).
1.5.36 tert-Butyldimethyl(((2R,3S)-3-methyl-1-(2-methyl-1,3-dioxolan-2-yl)hex-4-
yn-2-yl)oxy)silane (Scheme 12, compound 72)

1
H NMR (CDCl
3
, 250 MHz) δ3.92-3.91 (m, 4H), 3.86 (m, 1H), 3.34 (m, 2H), 1.77-1.76
(t, 3H, J=2.75), 1.38-1.37 (d, 3H, J=7Hz), 1.08 (d, 3H), 1.059 (m, 1H), 0.88 (s, 9H), 0.07
(s, 3H), 0.04 (s, 3H).
1
H NMR (CDCl
3
, 400 MHz)16.96-6.92 (dt, 1H, J=15.6Hz), 5.85-5.81(d, 1H, J=17.2Hz),
4.8-4.71 (d, 2H, J=32.4Hz), 3.7 (s, 3H), 2.86-2.84 (d, 2H, J=7.6 Hz), 1.75 (s, 3H).
1.5.37 (E)-5-methylhexa-2,5-dien-1-ol (Scheme 13, compound 80)
1
H NMR (CDCl
3
, 400 MHz) δ5.67-5.63 (m, 2H), 4.71-4.67 (d, 2H, I=16 Hz), 4.07-4.06
(d, 2H, J=4.4 Hz), 2.71-2.70 (d, 2H, J=5.2 Hz), 2.31 (bs, 1H), 1.69 (s, 3H).
1.5.38 ((2R,3R)-3-(2-methylallyl)oxiran-2-yl)methanol (Scheme 13, compound 79)

1
H NMR (CDCl
3
, 250 MHz) δ4.74-4.72 (d, 2H, J=4.75 MHz), 3.85-3.78 (dm, 1H, J=12.5
MHz), 3.58-3.51 (m, 1H), 3.01-2.86 (dtd, 2H, J=5.75 MHz), 2.93-2.88 (t, 1H, J=4.5
MHz), 2.20-2.16 (t, 2H, J=11.25 MHz), 1.21 (s, 3H), 1.23-1.20 (dd, 1H, J=6 MHz).

91

1.5.39 (2S,3R)-2,5-dimethylhex-5-ene-1,3-diol (Scheme 13, compound 80)
1
H NMR (CDCl
3
, 250MHz) 4.93-4.82 (d, 2H, J=23.5 MHz), 3.71-3.62 (m, 3H), 2.31 (d,
1H), 2.16-2.12 (d, 1H, J=10.25 MHz), 1.76 (s, 3H), 0.92-0.89 (d, 3H, J=10.75 MHz)
1.5.40 1-((4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl)propan-2-one
(Scheme 11, compound 65)

1
H NMR (CDCl
3
, 250 MHz) 7.84-7.81 (d, 2H, J=7.25 Hz), 7.31-7.28 (d, 2H, J=8.75 Hz),
5.86 (s, 1H), 5.25-5.23 (d, 2 H, J=3.25 Hz), 4.55-4.44 (dd, 1H, J=11.25 Hz), 4.22 (s, 3H),
4.05-4.01 (m, 1H), 3.97-3.88 (t, 1H, J=11.5 Hz), 2.89-2.83 (d, J=14.5 Hz), 2.76-2.67 (dd,
1H, J=8.25 Hz), 2.30 (s, 3H), 2.14 (s, 2H), 1.98 (s, 3H), 1.25-1.22 (d, 3H, J=7Hz).
1.5.41 (2R,3R)-hept-6-yne-1,2,3-triol (Scheme 8, compound 54)
1
H NMR (CDCl3, 250MHz) δ4.34-4.32 (d, 1H, J=5.25 Hz), 4.11-4.05 (m, 1H), 3.94-3.92
(d, 1H), 3.76-3.64 (m, 3H), 3.56-3.54 (m, 1H), 3.36-2.31 (tm, 2H, J=6.25 Hz), 2.02-2.00
(t, 1H, J=2.75 Hz), 1.73-1.68 (m, 2H).
1.5.42 Methyl 2-((4S,4'R,5R)-2,2,2',2'-tetramethyl-[4,4'-bi(1,3-dioxolan)]-5-
yl)acetate (Scheme 18, compound 89)

(CDCl
3
, 250 MHz) 4.36-4.28 (ddd, 1H, J=3.25 Hz), 4.15-4.10 (dd, 1H, J=14 Hz), 4.06-
3.99 (m, 1H), 3.96-3.91 (dd, 1H, J=12.5 Hz), 3.71 (s, 3H), 3.6-3.54 (t, 1H, J=7.75 Hz).
1.5.43 methyl 2-(2-methyl-1,3-dioxolan-2-yl)acetate (Scheme 11, compound 59)
1
H NMR (CDCl
3
, 250) 3.86 (s, 4H), 3.58 (s, 3H), 2.57 (s, 2H), 1.38 (s, 3H).
13
C NMR (CDCl
3
, 250) 64.45, 64.35, 63.47, 58.69, 57.43, 45.27, 40.12, 30.26, 23.67

92

1.5.44 4-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-4-hydroxy-but-2-enoic acid methyl ester
(Scheme 11, compound 61)

1
H NMR (CDCl
3
, 250 MHz) δ6.94-6.89 (dd, 1H, J=4 Hz, 15.5 Hz), 6.21-6.14 (dt. 1H,
J=15.75Hz), 4.49-4.83 (m, 1H), 4.17-4.12 (m, 1H), 3.96-3.83 (m, 2H), 3.75 (s, 3H), 2.38
(bs, 1H), 1.44 (s, 3H), 1.35 (s, 3H).
1.5.45 Ethyl 2-(2-methyl-1,3-dioxolan-2-yl)acetate (Scheme 11, compound 59’’)

1
H NMR (CDCl
3
, 250) δ4.08-4.05 (q, 2H, J=7 Hz), 3.9 (s, 4H), 2.57 (s, 2H), 1.42-1.41 (s,
3H), 1.20-1.14 (t, 3H, J=14.5 Hz)
1.5.46 (4S,E)-methyl 4-((tert-butyldiphenylsilyl)oxy)-4-(2,2-dimethyl-1,3-dioxolan-
4-yl)but-2-enoate (Scheme 18, compound 90)

1
H NMR (CDCl
3
, 400MHz) δ7.73-7.59 (m, 4H), 7.44-7.34 (m, 6H), 6.81-6.72 (dd, 1H,
J=6Hz), 5.77-5.70 (dd, 1H, J=15.75Hz), 4.32-4.27 (1H, t, J=6.25Hz), 4.06-3.99 (q, 1H,
J=5.75), 3.92-3.87 (dd, 1H, J=6.5Hz), 3.76-3.70 (dd, 1H, J=6Hz), 1.28 (s, 6H), 1.08 (s,
9H).
1.5.47 (S,E)-4-((tert-butyldiphenylsilyl)oxy)-4-((R)-2,2-dimethyl-1,3-dioxolan-4-
yl)but-2-en-1-ol (Scheme 18, compound 91)

1
H NMR (CDCl3, 400 MHz) δ7.69-7.67 (dt, 2H, J=7.6 Hz), 7.64-7.63 (dt, 2H, J=7.2 Hz),
7.42-7.32 (m, 6H), 5.46-5.40 (ddt, 1H, J=7.6Hz), 5.36-5.29 (dt, 1H, J=15.6 Hz), 4.22-
4.19 (td, 1H, J=5.6 Hz), 4.04-3.99 (q, 2H, J=6Hz), 3.95-3.90 (m, 1H), 3.79-3.75 (m, 2H),
1.33 (s, 3H), 1.30 (s, 3H), 1.04 (s, 9H).
13
C NMR (CDCl3, 400 MHz) δ136.16, 136.01, 134.80, 134.40, 133.57, 132.51, 130.70,
129.77, 129.68, 129.65, 127.72, 127.59, 127.40, 109.42, 78.96, 74.81, 66.33, 62.78,
53.43, 31.59, 27.00, 26.55, 26.52, 25.39, 22.66, 19.35, 14.12.

93

1.5.48 (S,E)-4-((tert-butyldiphenylsilyl)oxy)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-
yl)but-2-en-1-ol (Scheme 18, compound 92)

1
H NMR (CDCl
3
, 400 MHz) δ7.69-7.66 (dt, 2H, J=6.4 Hz), 7.64-7.61(dt, 2H, J=8.4 Hz),
7.42-7.26 (m, 6H), 5.62-5.56 (ddt, 1H, J=7.6Hz), 5.38-5.31 (dt, 1H, J=4.8Hz), 4.31-4.28
(dd, 2H, J=4.8Hz), 4.19-4.15 (t, 1H, J=13.6 Hz), 4.06-4.03 (q, 1H, J=5.6 Hz), 3.99-3.95
(dd, 1H, J=6.4Hz), 3.84-3.80 (dd, 1H, J=6.4Hz), 1.31 (s, 6H), 1.05 (s, 9H).
1.5.49 (S,E)-4-((tert-butyldiphenylsilyl)oxy)-4-(®-2,2-dimethyl-1,3-dioxolan-4-
yl)but-2-enal (Scheme 18, compound 93)

1
H NMR (CDCl
3
, 400 MHz) 9.34-9.32 (d, 1H, J=8Hz) 7.68-7.66 (d, 2H, J=8 Hz), 7.63-
7.60 (dt, 2H, J=8Hz), 7.45-7.33 (m, 6H), 6.63-6.58 (dd, 1H, J=16Hz), 6.03-5.97 (ddt,
8H), 4.39-4.36 (td, 1H, J=5.6 Hz), 4.09-4.04 (q, 1H, J=6Hz), 3.97-3.93 (dd, 1H,
J=6.4Hz), 3.77-3.74 (dd, 1H, J=6Hz), 1.307 (s, 3H), 1.301 (s, 3H), 1.1 (s, 9H).
13
C NMR (CDCl
3
, 400 MHz) δ193.17, 155.05, 135.91, 135.87, 132.71, 127.77, 109.77,
78.37, 73.91, 66.59, 26.80, 26.96, 26.43, 25.18, 19.37.
1.5.50 4-((4-methoxybenzyl)oxy)butan-1-ol (Scheme 19, compound 96)
1
H NMR (CDCl
3
, 250 MHz) δ7.63-7.59 (d, 2H, J=9 Hz), 7.25-7.21 (2H, J=10 Hz), 4.80
(s, 2H), 4.16 (s, 3H), 4.01-3.95 (q, 2H, J=5.75 Hz), 3.87-3.82 (t, 2H, J=5.75 Hz), 2.77
(bs, 1H), 2.10-1.99 (m, 6H).
1.5.51 1-((4-iodobutoxy)methyl)-4-methoxybenzene (Scheme 19, compound 97)

1
H NMR (CDCl
3
, 400 MHz) δ7.63-7.61 (d, 2H, J=11.2 Hz), 7.26-7.23 (d, J=8.4 Hz),

4.79 (s, 2H), 4.18 (s, 3H), 3.84-3.81 (t, 2H, J=12.4Hz), 3.58-3.54 (t, 2H, J=14 Hz), 2.33-

2.25 q, 2H, J=7.6Hz), 2.10-2.01 (m, 2H).

94

1.5.52 (1S,E)-1-((tert-butyldiphenylsilyl)oxy)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-
8-((4-methoxybenzyl)oxy)oct-2-en-4-ol (Scheme 18, compound 95)
1
H NMR (CDCl
3
, 400 MHz) δ7.69-7.67 (dd, 2H, J=1.6 Hz, 8.4 Hz), 7.64-7.62 (dd, 2H,
J=1.6 Hz, 8Hz), 7.43-7.30 (m, 6H), 7.25 (d, 2H, J=8.4 Hz), 6.88-6.85 (d, 2H, J=9.2 Hz),
5.46-5.40 (dd, 1H, J=7.6 Hz), 5.29-5.23 (dd, 1H, J=8.8 Hz), 4.44-4.40 (d, 1H, J=10Hz),
4.09 (s, 2H), 4.24-4.21 (dd, 5.2 Hz), 4.06-4.01 (dd, 1H, J=6.4 Hz), 3.99-3.96 (dd, 1H,
J=6.4 Hz), 3.91-3.88 (dd, 1H, J=6.4 Hz), 3.50-3.42 (dt, 1H, J=6 Hz), 3.38-3.34 (t, 2H,
J=8Hz), 1.71-1.61 (m, 1H), 1.53-1.47 (m, 1H), 1.44-1.37 (m, 2H), 1.34 (s, 3H), 1.31 (s,
3H), 1.27-1.22 (m, 1H), 1.19-1.14 (m, 2H), 1.04 (s, 9H).
1.5.53 (5S,8S,E)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-8-(4-((4-methoxy
benzyl)oxy)butyl)-2,2,10,10,11,11-hexamethyl-3,3-diphenyl-4,9-dioxa-3,10-
disila dodec-6-ene (Scheme 20, compound 95)

1
H NMR (CDCl
3
, 400 MHz) δ7.69-7.67 (dt, 2H, J=10 Hz), 7.63-7.61 (dt, J=2H, J=8Hz),
7.40-7.30 (m, 6H), 7.27-7.25 (d, 2H, J=8Hz), 6.88-6.86 (d, 2H, J=8 Hz), 5.46-5.44 (dd,
1H, J=7.6Hz), 5.26-5.20 (dd, 1H, J=6.4 Hz), 4.24 (s, 2H), 4.20-4.17 (dd, 1H, J=5.2 Hz),
4.02-3.99 (dd, 1H, J=5.6 Hz), 3.95-3.91 (dd, 1H, J=14Hz), 3.88-3.87 (m, 1H), 3.8 (s,
3H), 3.80-3.76 (dd, 1H, J=6.8Hz), 3.37-3.33 (t, 2H, J=13.6 Hz), 1.51-1.47 (m, 2H), 1.29
(s, 6H), 1.25-1.23 (m, 2H), 1.09-1.03 (m, 1H), 1.03 (s, 9H), 1.09-0.85 (m, 1H), 0.83 (s,
9H), -0.02 (s, 3H), -0.07 (s, 3H).
13
C NMR (CDCl
3
, 400 MHz) δ159.06-135.97, 130.73, 129.65, 129.55, 129.19, 127.48,
113.73, 109.12, 74.61, 70.0, 66.17, 55.24, 29.69, 26.95, 26.44, 25.82, 25.36, 19.35, 18.14,
-4.42, -4.91.

95

1.5.54 (2R,3S,E)-3-((tert-Butyldiphenylsilyl)oxy)-10-((4-methoxybenzyl) oxy) dec-4-
ene-1,2,6-triol (Scheme 20, compound 96)

1
H NMR (CDCl
3
, 400 MHz) δ7.68-7.67 (t, 1H, J=1.2 Hz), 7.66-7.56 (m, 2H), 7.64-7.63
(t, 1H, J=3.6Hz), 7.24-7.22 (d, 2H, J=6.4 Hz), 6.88-6.85 (d, 2H, J=8.4 Hz), 5.51-5.49
(dd, 1H, J=8.8Hz), 5.19-5.13 (dd, 1H, J=6.8Hz), 4.39 (s, 2H), 4.23-4.20 (dd, 1H, J=12.8
Hz), 3.79 (s, 3H), 3.76-3.74 (d, 1H, J=8Hz), 3.65-3.61 (m, 3H), 3.38-3.35 (t, 2H,
J=6.4Hz), 3.35 (bs, 1H), 2.04 (bs, 1H), 1.52-1.49 (t, 2H, J=6.8Hz), 1.35-1.30 (m, 2H),
1.23-1.21 (m, 2H), 1.06 (s, 9H).
1.5.55 (2R,3S,E)-3,6-bis((tert-butyldiphenylsilyl)oxy)-10-((4-methoxybenzyl)
oxy)dec-4-ene-1,2-diol (Scheme 20, Compound 98)

1
H NMR (CDCl
3
, 250 MHz) δ7.65-7.53 (m, 8H), 7.46-7.29 (m, 12H), 7.25-7.22 (d, 2H,
J=7.5 Hz), 6.88-6.85 (dt, 2H, J=6.5 Hz), 5.28-5.26 (d, 2H, J=5.75 Hz), 4.38 (s, 2H), 4.10
(bs, 1H), 4.01 (bs, 1H), 3.8 (s, 3H), 3.41 (m, 2H), 3.35 (m, 1H), 3.29-3.23 (t, 2H, J=6.75
Hz), 2.01 (s, 1H), 1.87 (bas, 1H), 1.58 (s, 1H), 1.39-1.34 (m, 2H), 1.13-1.09 (m, 4H),
1.02 (s, 18 H).
13
C NMR (CDCl
3
, 250 MHz) δ136.71, 135.86, 135.84, 134.07, 133.32, 133.07, 130.72,

129.97, 129.76, 129.66, 129.56, 127.52, 127.47, 74.47, 73.51, 72.50, 69.97, 63.04, 55.28,

37.29, 29.58, 26.93, 21.00, 19.30, 19.26.

1.5.56 (2R,3S,E)-3,6-bis((tert-butyldiphenylsilyl)oxy)-2-hydroxy-10-((4-
methoxybenzyl) oxy)dec-4-en-1-yl benzoate (Scheme 20, Compound 98)

1
H NMR (CDCl
3
, 250 MHz) δ7.99-7.96 (d, 2H), 7.70-7.56 (m, 12H), 7.477.29 (m, 13H),
7.26-7.24 (d, 2H, J=7.5 Hz), 6.94-6.90 (d, 2H, J=7.5 Hz), 5.62-5.53 (dd, 1H, J=6.75 Hz),
5.41-5.38 (m, 1H), 4.70-4.62 (dd, 1H, J=8.25 Hz), 4.56-4.52 (dd, 1H, J=3Hz), 4.47-4.45
96

(d, 1H, J=3.75 Hz), 4.42 (bs, 3H), 4.14-4.12 (dd, 1H, J=5Hz), 3.85 (s, 3H), 3.30-3.25 (t,
2H, J=7 Hz), 1.42-1.28 (m, 4H), 1.17-1.11 (m, 2H), 1.07 (s, 9H), 1.06 (s, 9H).
1.5.57 (2R,3S,E)-3,6-bis((tert-butyldiphenylsilyl)oxy)-10-((4-methoxybenzyl) oxy)-2-
((methylsulfonyl)oxy)dec-4-en-1-yl benzoate (Scheme 20, compound 99)

1
H NMR (CDCl
3
, 250 MHz) δ8.04-8.01 (d, 1H, J=7.75 Hz), 5.25-5.05 (m, 9H), 7.48-7.21
(m, 17 H), 6.88-6.85 (dt, 2H, J=8.75 Hz), 5.35-5.32 (m, 2H), 4.75-4.72 (m, 1H), 4.37 (s,
2H), 4.36-4.33 (m, 2H), 4.29 (d, 1H, J=7.5 Hz), 4.23-4.17 (dd, 1H, J=5 Hz), 4.04-4.02
(m, 1H), 3.8 (s, 3H), 1.44-1.13 (m, 6H), 1.03 (s, 9H), 0.99 (s, H)
1.5.58 (8S,E)-5-(4-((4-methoxybenzyl)oxy)butyl)-2,2,11,11-tetramethyl-8-((S)-
oxiran-2-yl)-3,3,10,10-tetraphenyl-4,9-dioxa-3,10-disiladodec-6-ene (Scheme
1.20, compound 102)

1
H NMR (CDCl
3
, 400 MHz) 7.67-7.53 (m, 10H), 7.39-7.7.19 (m, 10H), 6.84-6.82 (d, 1H,
J=8.8 Hz), 5.42-5.36 (dd, 1H, J=6Hz), 5.30-5.24 (dd, 1H, J=6.4Hz), 4.35 (s, 2H), 4.04-
4.00 (q, 1H, J=6 Hz), 3.77 (s, 3H), 3.75-3.70 (t, 2H, J=8Hz), 3.27-3.24 (t, J=7.2 Hz),
2.84-2.80 (m, 1H), 2.48-2.46 (t, 1H, J=9.2 Hz), 2.18-2.16 (dd, 1H, J=2.8 Hz), 1.42-
1.36(m, 2H), 1.26-1.13 (m, 4H), 1.01 (s, 9H). 0.98 (s, 9H).
1.5.59 (8S,E)-5-(4-((4-methoxybenzyl)oxy)butyl)-2,2,11,11-tetramethyl-8-((S)-
oxiran-2-yl)-3,3,10,10-tetraphenyl-4,9-dioxa-3,10-disiladodec-6-ene(dia
stereomer-lower spot on TLC) (Scheme 1.20, compound 100)

13
C NMR (CDCl
3
, 400 MHz) 159.06, 135.87, 135.49, 135.87, 133.62, 129.55, 129.45,
129.16, 128.24, 127.42, 127.35, 113.70, 75.72. 73.54, 72.46, 55.24, 44.26, 37.34, 29.59,
26.87, 19.32, 19.27.
1.5.60 tert-Butyl(((S,E)-4-((4-methoxybenzyl)oxy)-1-((S)-oxiran-2-yl)but-2-en-1-
yl)oxy)di phenylsilane

1
H NMR (CDCl
3
, 250 MHz) δ7.72-7.64 (m, 4H), 7.42-7.32 (m, 6H), 7.22-7.18 (dt, 2H,
J=8.5 Hz), 6.88-6.85 (dt, 2H, J=8.5 Hz), 5.65-5.62 (m, 2H), 4.32 (s, 2H), 4.00-3.98 (t,
97

1H), 3.87-3.86 (d, 2H), 3.82 (s, 3H), 3.05-3.04 (m, 1H), 2.71-2.70 (t, 1H, J=4.25 Hz), dd,
1H, J=2.25 Hz), 1.08 (s, 9H).
13
C NMR (CDCl
3
, 250 MHz) δ159.16, 135.93, 135.91, 133.72, 133.53, 130.34, 130.26,
129.68, 129.62, 129.27, 129.08, 127.48, 127.45, 113.73, 75.05, 71.58, 69.47, 55.30,
55.25, 44.37, 27.00, 26.94, 19.38.
1.5.61 (5R,6S,E)-6-((tert-Butyldiphenylsilyl)oxy)-9-((4-methoxybenzyl)
oxy)non-7-en-1-yn-5-ol

1
H NMR (CDCl3, 250 MHz) δ3.62-3.37 (m, 4H), 7.46-7.28 (m, 6H), 7.16-7.09 (dd, 2H,
J=6.75 Hz), 6.85-6.82 (dt, 2H, J=5.25 Hz), 5.65-5.56 (ddt, 1H, J=8 Hz), 5.33-5.22 (m,
1H, J=5.25 Hz), 4.19 (s, 2H), 4.03-4.97 (t, 1H, J=7.5 Hz), 3.79 (s, 3H), 3.72-3.70 (d, 2H,
J=5.25 Hz), 3.67-3.57 (m, 1H), 2.42-2.40 (d, 1H, J=5 Hz), tm, 2H, J=7.75 Hz), 1.92-1.89
(q, 1H, J=1 Hz), 1.75-1.60 (m, 1H), 1.53-1.40 (m, 1H), 1.05 (s, 9H).
1.5.62 (4S,5R,E)-4-((tert-Butyldiphenylsilyl)oxy)-5-hydroxynon-2-en-8-ynal
(Scheme 21, compound 111)

1
H NMR (CDCl
3
, 250 MHz) δ9.36-9.33 (dd, 1H, J=1Hz, 7.75Hz), 7.67-7.58 (m, 4H),
7.44-7.33 (m, 6H), 6.66-6.57 (dd, 1H, J=6.75Hz), 6.01-5.91 (dd, 1H, J=7.75Hz), 4.56-
4.51 (tm, 1H, J=4.75 Hz), 3.88-3.84 (p, 1H, J=5.25 Hz), 3.41-3.37 (m, 2H), 3.45-3.2 (m,
1H), 2.52-2.49 (dd, 1H, J=4.5Hz), 1.62 (d, 1H, J=1Hz), 1.1 (s, 9H).
13
C NMR (CDCl
3
, 400 MHz) δ192.80, 152.81, 135.82, 135.78, 133.65, 132.53, 132.30,

130.34, 130.31, 127.94, 127.82, 74.41, 73.97, 33.96, 26.97, 19.31.

98

1.6 Representative Spectra

Figure 1.73
1
H NMR of (E)-ethyl octa-2,7-dienoate (Scheme 1.2, compound 24)

99

Figure 1.74
1
H NMR of (R,E)-ethyl 7,8-dihydroxyoct-2-enoate
(Scheme 1.2, compound 25)

100

Figure 1.75
13
C NMR of (R,E)-ethyl 7,8-dihydroxyoct-2-enoate (Scheme 1.2,
compound 25)

101

Figure 1.76
1
H NMR of (R,E)-ethyl 8-((tert-butyldiphenylsilyl)oxy)-7-hydroxyoct-
2-enoate (Scheme 1.2, compound 26)

102

Figure 1.77
13
C NMR of (R,E)-ethyl 8-((tert-butyldiphenylsilyl)oxy)-7-hydroxyoct-
2-enoate (Scheme 1.2, compound 26)

103

Figure 1.78 Cosy NMR of (R,E)-ethyl 8-((tert-butyldiphenylsilyl)oxy)-7-
hydroxyoct-2-enoate (Scheme 1.2, compound 26)

104

Figure 1.79
1
H NMR of (R,E)-ethyl 8-((tert-butyldiphenylsilyl)oxy)-7-
(methoxymethoxy)oct-2-enoate (Scheme 1.2, compound 27)

105

Figure 1.80
13
C NMR of (R,E)-ethyl 8-((tert-butyldiphenylsilyl)oxy)-7-
(methoxymethoxy)oct-2-enoate (Scheme 1.2, compound 27)

106

Figure 1.81
1
H NMR of (R,E)-ethyl 8-hydroxy-7-(methoxymethoxy)oct-2-enoate
(Scheme 1.2, compound 28)

107

Figure 1.82
1
H NMR of (R,E)-ethyl 7-(methoxymethoxy)-8-((methylsulfonyl)
oxy)oct-2-enoate (Scheme 1.2, compound 29)

108

Figure 1.83
13
C NMR of (R,E)-ethyl 7-(methoxymethoxy)-8-((methylsulfonyl)oxy)
oct-2-enoate (Scheme 1.2, compound 29)

109

Figure 1.84
1
H NMR of (R,E)-ethyl 8-iodo-7-(methoxymethoxy)oct-2-enoate
(Scheme 1.2, compound 30)

110

Figure 1.85
1
H NMR of (4S,5S)-dimethyl 2,2-dimethyl-1,3-dioxolane-4,5-
dicarboxylate (Scheme 1.3, compound 33)

111

Figure 1.86
1
H NMR of Hex-5-en-1-yl benzoate (Scheme 1.13, compound 78)

112

Figure 1.87
13
C NMR of ((4S,5S)-dimethyl-2,2-dimethyl-1,3-dioxolan-4,5
dicarboxylate (Scheme 1.3, compound 33)

113

Figure 1.88
1
H NMR of ((4S,5S)-5-(((4-methoxybenzyl)oxy)methyl)-2,2-dimethyl-
1,3-dioxolan-4-yl)methanol (Scheme 1.3, compound 36)

114

Figure 1.89
13
C NMR of ((4R,5R)-5-(((4-methoxybenzyl)oxy)methyl)-2,2-dimethyl-
1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (Scheme 1.3,
compound 37)

115

Figure 1.90
1
H NMR of (R)-2-((R)-2-((4-methoxybenzyl)oxy)-1-(methoxymethoxy)
ethyl)oxirane (Scheme 1.3, compound 39)

116

Figure 1. 91
1
H NMR of (R)-1-((4-methoxybenzyl)oxy)but-3-en-2-ol (Scheme 1.4,
compound 46)

117

Figure 1.92
1
H NMR of (R,E)-ethyl 7-hydroxy-8-iodooct-2-enoate (Scheme 1.5,
compound 46)

118

Figure 1.93
1
H NMR of (R,E)-(8-ethoxy-2-hydroxy-8-oxooct-6-en-1-yl)triphenyl
phosphonium iodide (Scheme 1.5, compound 48)

\

119

Figure 1.94
1
H NMR of (R)-5,6-dihydroxyhexyl benzoate
(Scheme 1.13, compound 79)

120

Figure 1.95
1
H NMR of (R)-5-((tert-butyldimethylsilyl)oxy)-6-hydroxyhexyl
benzoate (Scheme 1.13, compound 81)

121

Figure 1.96
1
H NMR of (R)-5,6-bis((tert-butyldimethylsilyl)oxy)hexyl benzoate
(Scheme 1.13, compound 80)

122

Figure 1.97
1
H NMR of (R)-5-((tert-butyldimethylsilyl)oxy)-6-oxohexyl benzoate
(Scheme 1.16, compound 82)

123

Figure 1.98
1
H NMR of (R,E)-5-((tert-butyldimethylsilyl)oxy)-7-iodohept-6-en-1-yl
benzoate (Scheme 1.13, compound 83)

124

Figure 1.99
1
H NMR of (4S,5R)-4-(((4-methoxybenzyl)oxy)methyl)-2,2-dimethyl-5-
((phenyl sulfonyl)methyl)-1,3-dioxolane (Scheme 1.15, compound 84)

125

1.100
1
H NMR of (3R)-7-((tert-butyldimethylsilyl)oxy)-3-((4-methoxy benzyl)
((oxy)-1-((4R,5S)-5-(((4-methoxy benzyl)oxy)methyl)-2,2-dimethyl-1,3-
dioxolan-4-yl)-) )-1-(phenylsulfonyl)heptan-2-yl acetate
(Scheme 1.15, compound 86)

126

Figure 1.101 Ethyl 2-(2-methyl-1,3-dioxolan-2-yl)acetate
(Scheme 1.11, compound 59’’)

127

Figure 1.102
1
H NMR of methyl 2-(2-methyl-1,3-dioxolan-2-yl)acetate
(Scheme 1.11, compound 59’)

128

Figure 1.103
13
C NMR of 2-(2-methyl-1,3-dioxolan-2-yl)ethanol (Scheme 11.1,
compound 60)

129

Figure 1.104
1
H NMR of 2-(2-methyl-1,3-dioxolan-2-yl)ethanol
(Scheme 1.11, compound 59’’)

130

Figure 1.105
1
H NMR of 2-(2-methyl-1,3-dioxolan-2-yl)acetaldehyde
(Scheme 1.12, compound 70)

131

Figure 1.106
1
H NMR of ((2R,3R)-3-((2-methyl-1,3-dioxolan-2-yl)methyl)oxiran-2-
yl)methanol (Scheme 1.11, compound 63)

132

Figure 1.107
1
H NMR of (2S,3R)-2-methyl-4-(2-methyl-1,3-dioxolan-2-yl)butane-
1,3-diol (Scheme 1.11, compound 64)

133

Figure 1.108
1
H NMR of (2S,3R)-2-methyl-4-(2-methyl-1,3-dioxolan-2-yl)butane-
1,3-diol (Scheme 1.11, compound 64)

134

Figure 1.109 COSY NMR of (2S,3R)-2-methyl-4-(2-methyl-1,3-dioxolan-2-
yl)butane-1,3-diol (Scheme 1.11, compound 64)

135

Figure 1.110
1
H NMR of (4R,5S)-2-(4-Methoxyphenyl)-5-methyl-4-((2-methyl-1,3-
dioxolan-2-yl)methyl)-1,3-dioxane (Scheme 1.11, compound 65)

136

Figure 1.111
1
H NMR of (4R,5S)-2-(4-methoxyphenyl)-5-methyl-4-(2-methylallyl)-
1,3-dioxane (Scheme 1.11, compound 66)

137

Figure 1.112
1
H NMR of (R)-but-3-yn-2-yl methanesulfonate (Scheme 1.12,
compound 69)

138

Figure 1.113
1
H NMR of (4R,5S)-4-hydroxy-5-methylhept-6-yn-2-one (Scheme 1.12,
compound 71)

139

Figure 1.114
1
H NMR of (2R,3S)-3-methyl-1-(2-methyl-1,3-dioxolan-2-yl)pent-4-
yn-2-ol (Scheme 1.12, compound 72)

140

Figure 1.115
1
H NMR of tert-butyldimethyl(((2R,3S)-3-methyl-1-(2-methyl-1,3-
dioxolan-2-yl)hex-4-yn-2-yl)oxy)silane (Scheme 1.12, compound 72)

141

Figure 1.116
1
H NMR of (E)-methyl 5-methylhexa-2,5-dienoate (Scheme 1.13,
compound 77)

142

Figure 1.117
1
H NMR of (E)-5-methylhexa-2,5-dien-1-ol
(Scheme 1.13, compound 80)

143

Figure 1.118
1
H NMR ((2R,3R)-3-(2-methylallyl)oxiran-2-yl)methanol
(Scheme 1.13, compound 79)

144

Figure 1.119
1
H NMR of (2S,3R)-2,5-dimethylhex-5-ene-1,3-diol
(Scheme 1.13, compound 80)

145

Figure 1.120
1
H NMR of (2S,3R)-2,5-dimethylhex-5-ene-1,3-diol
(Scheme 1.13, compound 80)

146

Figure 1.121
1
H NMR of (2R,3R)-hept-6-yne-1,2,3-triol (Scheme 1.8, compound 54)

147

Figure 1.122
1
H NMR of 4-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-4-hydroxy-but-2-enoic
acid methyl ester (Scheme 1.18, compound 88)

148

Figure 1.123 COSY NMR of 4-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-4-hydroxy-but-2-
enoic acid methyl ester (Shceme 1.18, compound 88)

149

Figure 1.124
1
H NMR of methyl 2-((4S,4'R,5R)-2,2,2',2'-tetramethyl-[4,4'-bi(1,3-
dioxolan)]-5-yl)acetate (Scheme 1.18, compound 89)

150

Figure 1.125 (4S,E)-methyl 4-((tert-butyldiphenylsilyl)oxy)-4-(2,2-dimethyl-1,3-
dioxolan-4-yl)but-2-enoate (Scheme 1.18, compound 90)

151

Figure 1.126
1
H NMR of (S,E)-4-((tert-butyldiphenylsilyl)oxy)-4-((R)-2,2-dimethyl-
1,3-dioxolan-4-yl)but-2-en-1-ol (Scheme 1.18, compound 91)

152

Figure 1.127 COSY NMR of (S,E)-4-((tert-butyldiphenylsilyl)oxy)-4-((R)-2,2-
dimethyl-1,3-dioxolan-4-yl)but-2-en-1-ol (Scheme 1.18, compound 91)

153

Figure 1.128
13
C NMR of (S,E)-4-((tert-butyldiphenylsilyl)oxy)-1-((R)-2,2-dimethyl-
1,3-dioxolan-4-yl)but-2-en-1-ol (Scheme 1.18, compound 92)

154

Figure 1.129
1
H NMR of (S,E)-4-((tert-butyldiphenylsilyl)oxy)-1-((R)-2,2-dimethyl-
1,3-dioxolan-4-yl)but-2-en-1-ol (Scheme 1.18, compound 92)

155

Figure 1.130 Cosy NMR of (S,E)-4-((tert-butyldiphenylsilyl)oxy)-1-((R)-2,2-
dimethyl-1,3-dioxolan-4-yl)but-2-en-1-ol
(Scheme 1.18, compound 92)

156

Figure 1.131
1
H NMR of (S,E)-4-((tert-butyldiphenylsilyl)oxy)-4-((R)-2,2-dimethyl-
1,3-dioxolan-4-yl)but-2 al (Scheme 1.18, compound 93)

157

Figure 1.132 Cosy NMR of (S,E)-4-((tert-butyldiphenylsilyl)oxy)-4-((R)-2,2-
dimethyl-1,3-dioxolan-4-yl)but-2-enal (Scheme 1.18, compound 93)

158

Figure 1.133
13
C NMR of (S,E)-4-((tert-butyldiphenylsilyl)oxy)-4-((R)-2,2-dimethyl-
1,3-dioxolan-4-yl)but-2-enal (Scheme 1.18, compound 93)

159

Figure 1.134
1
H NMR of 4-((4-methoxybenzyl)oxy)butan-1-ol
(Scheme 1.19, compound 96)

160

Figure 1.135
1
H NMR of 1-((4-iodobutoxy)methyl)-4-methoxybenzene
(Scheme 1.19, compound 97)

161

Figure 1.136
1
H NMR of (1S,E)-1-((tert-butyldiphenylsilyl)oxy)-1-((R)-2,2-dimethyl-
1,3-dioxolan-4-yl)-8-((4-methoxybenzyl)oxy)oct-2-en-4-ol
(Scheme 1.20, compound 95)

162

Figure 1.137
1
H NMR of (5S,8S,E)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-8-(4-((4-
methoxy benzyl)oxy)butyl)-2,2,10,10,11,11-hexamethyl-3,3-diphenyl-
4,9-dioxa-3,10-disila dodec-6-ene (Scheme 1.20, compound 95)

163

Figure 1.138
13
C NMR of (5S,8S,E)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-8-(4-((4-
methoxy benzyl)oxy)butyl)-2,2,10,10,11,11-hexamethyl-3,3-diphenyl-
4,9-dioxa-3,10-disila dodec-6-ene (Scheme 1.20, compound 95)

164

Figure 1.139 Cosy NMR of (5S,E)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-8-(4-((4-
methoxybenzyl)oxy)butyl)-2,2,10,10,11,11-hexamethyl-3,3-diphenyl-
4,9-dioxa-3,10-disiladodec-6-ene (Scheme 1.20, compound 98)

165

Figure 1.140
1
H NMR of (2R,3S,E)-3-((tert-butyldiphenylsilyl)oxy)-10-((4-
methoxybenzyl) oxy) dec-4-ene-1,2,6-triol
(Scheme 1.20, Compound 96)

166

Figure 1.141 Cosy NMR of (2R,3S,E)-3-((tert-butyldiphenylsilyl)oxy)-10-((4-
methoxybenzyl) oxy)dec-4-ene-1,2,6-triol
(Scheme 1.20, Compound 96)

167

Figure 1.142
1
H NMR of (2R,3S,E)-3,6-bis((tert-butyldiphenylsilyl)oxy)-10-((4-
methoxybenzyl) oxy)dec-4-ene-1,2-diol (Scheme 1.20, Compound 98)

168

Figure 1.143
13
C NMR of (2R,3S,E)-3,6-bis((tert-butyldiphenylsilyl)oxy)-10-((4-
methoxybenzyl) oxy)dec-4-ene-1,2-diol (Scheme 1.20, Compound 98)

169

Figure 1.144
1
H NMR of (2R,3S,E)-3,6-bis((tert-butyldiphenylsilyl)oxy)-10-((4-
methoxybenzyl) oxy)-2-((methylsulfonyl) oxy)dec-4-en-1-yl benzoate
(Scheme 1.20, compound 99)

170

Figure 1.145
1
H NMR of (8S,E)-5-(4-((4-methoxybenzyl)oxy)butyl)-2,2,11,11-
tetramethyl-8-((S)-oxiran-2-yl)-3,3,10,10-tetraphenyl-4,9-dioxa-3,10-
disiladodec-6-ene (Scheme 1.20, compound 100)

171

Figure 1.146 Cosy NMR of (8S,E)-5-(4-((4-methoxybenzyl)oxy)butyl)-2,2,11,11-
tetramethyl-8-((S)-oxiran-2-yl)-3,3,10,10-tetraphenyl-4,9-dioxa-3,10-
disiladodec-6-ene (diastereomer-lower spot on TLC)
(Scheme 1.20, compound 100)

172

Figure 1.147
13
C NMR NMR of (8S,E)-5-(4-((4-methoxybenzyl)oxy)butyl)-
2,2,11,11-tetramethyl-8-((S)-oxiran-2-yl)-3,3,10,10-tetraphenyl-4,9-
dioxa-3,10-disiladodec-6-ene (diastereomer-lower spot on TLC)
(Scheme 1.20, compound 100)

173

Figure 1.148
1
H NMR of tert-butyl(((S,E)-4-((4-methoxybenzyl)oxy)-1-((S)-oxiran-
2-yl)but-2-en-1-yl)oxy)diphenylsilane (Scheme 1.21, compound 109)

174

Figure 1.149
13
C NMR of tert-butyl(((S,E)-4-((4-methoxybenzyl)oxy)-1-((S)-oxiran-
2-yl)but-2-en-1-yl)oxy)diphenylsilane (Scheme 1.21, compound 109)

175

Figure 1.150
1
H NMR of (5R,6S,E)-6-((tert-butyldiphenylsilyl)oxy)-9-((4-methoxy
benzyl)oxy)non-7-en-1-yn-5-ol (Scheme 1.21, compound 111)

176

Figure 1.151
1
H NMR of (4S,5R,E)-4-((tert-butyldiphenylsilyl)oxy)-5-hydroxynon-
2-en-8-ynal (Scheme 1.21, compound 112)

177

Figure 1.152
13
C NMR (4S,5R,E)-4-((tert-butyldiphenylsilyl)oxy)-5-hydroxynon-2-
en-8-ynal (Scheme 21, compound 112)

178

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183

Chapter 2: Rhodium-II catalysed desymmetrization
reactions

2.1 Introduction
The roles of transition metal complexes on C-H activation reactions and their
mechanistic studiesn were well documented.
1-26
Though C-H activation of
unfunctionalized C-H bonds has been extensively studied for more than last two decades,
there is always a need of demand for the development of practical catalytic C-H
activation reactions and their mechanistic pathways.
27-28
Reports show that the intra- and
intermolecular C-H bond insertion reactions of diazoacetate esters in the presence of
chiral catalysts give products with high entantioselectivities.
29-36
There is a continuous
demand for more efficient ways to construct complex chemical structures from simple,
readily available molecules. A fascinating approach to reach this demand would be
through selective functionalization of unactivated C-H bonds.
29-36

The C-H bond insertion reactions can facilitate and reduce the number of steps in
the synthesis of natural products, pharmaceuticals and industrially relevant targets. It is
challenging because it requires reagents sufficiently reactive to cleave the strong C-H
bond but in a selective and controllable fashion. One of the promising approaches is the
C-H activation by means of rhodium metal induced C-H insertions.
37-39
Highly functionalized γ-lactams are key intermediates for the synthesis of
numerous biologically significant natural products. Rhodium catalyzed intramolecular C-
H insertion reaction of various diazo compounds are utilized in the construction of cyclic
compounds
38,40-43.
and systems including  and  lactams.
44-46

184

Our group has also demonstrated the rhodium catalyzed intramolecular C-H
insertion of diazo- -(phenylsulfonyl)- acetamides to afford -,–lactams with high regio-
and stereoselectivity.
47-48
High regio- and stereoselective γ-lactams are obtained by
intramolecular C-H insertion of α-diazo-α- (phenylsulfonyl) acetamides derived from α-
amino acids, which possess various functional groups.
47
The chemo and regioselctivity of C-H insertion reactions are affected based on the
type of α-substituent of the carbenoid carbon .
37, 47
The phenylsulfonyl moiety could alter
the electron density at the carbenoid center which would exert a steric effect to enhance
the regio- and stereoselectivities. It was reported that during the C-H insertion reaction,
the conformationally restricted metallocarbenoid would adopt a s-cis conformer as a
result of the severe non-bonding interaction between the tert-butyl group and the
carbonyl substituents present in the s-trans conformer (conformational effect).
47
Based
on Padwa and Doyle reports, the C-H activation of the α-diazo-α- (phenylsulfonyl)
acetamide derivatives afforded a mixture of the β- and γ-lactams.The two regioisomeric
β- and γ-lactams are obtained via two different transition states with the s-cis conformer
as the suitable one for the cyclization. γ-lactam was the major product when a rhodium
catalyst with an electron-donating ligand was used.
37, 47, 57

It was assumed that the selective C-H activation occurred through a late transition
state which was influenced by an electron-donating ligand stabilization of an electrophilic
carbenoid carbon. Hence, the cyclization would occur through the stereoelectronically
favorable transition state.
47, 50
“The formation of trans-stereochemistry at C-3/C-4 in
kainic acid was also explained by a chairlike transition state, wherein the C-Rh bond
185

would be aligned with the target C-H bond and the phenyl group would occupy a
pseudoequatorial position (Figure 1)”.
47, 50, 57

Figure 2.1

A substituent effect was also presumed in addition to the effect of electron-
donating ligand, which can affect the variation of electron density at the C-H insertion
center. For example, the deactivating influence of electron with drawing groups such as a
carboethoxy group on C-H insertion on the adjacent methylene group would give rise to
the β-lactam instead of the γ-lactam. However, an electron donating group like TBS
(tertiary butyl silyl) ether yielded the γ-lactam exclusively in high yield.
47

Based on the above results a novel synthesis of clasto-Lactocystin β-Lactone was

Scheme 2.1: C-H insertion of (S)-1-(4-(tert-butoxymethyl)-2,2-dimthyloxazolidin-3yl)-2-
diazo-2-(phenylsulfonyl)ethanone.
47

reported via a C-H activation route. The intermediate 2 (Scheme 2.1) was the key
intermediate efficiently derived by stereoselective C-H insertion of diazoamide 4.

186

“An outstanding aspect of the synthesis is that the formation of two stereocenters
in compound 2 was effected without employing either chiral auxiliaries or chirality
inducing reagents”.
47 “
The high stereo- and regioselectivity was driven by the -
phenylsulfonly group, which could stabilize the electrophilic carbenoid carbon in a
favored transition state in the cylization reaction to give exclusively the γ-lactam”.
47-49
Our group expanded this methodology to various α-diazo-α-(phenyl- sulfonyl)-
acetamides derived from α-aminoacids to form highly functionalized chiral γ-lactam
motifs in high yields.
47-50
The gem-dimethyl moiety of -diazo- -(phenylsulfonyl)-
acetamides favors s-cis conformation, which is the predominant form in the transition
state to force the C-H insertion reaction.
51-53
This precedence directed our group to study
the effect of α-substituents on the regio- and stereoselectivities of Rh-II catalyzed C-H
insertion reactions of α-diazomides. These studies further supported that the
conformation rather than α-substituents play a key role in the transition state of Rh-II
catalyzed C-H insertion reactions of α-diazomides.
54-57

Later, a Rh-II catalyzed C-H activation of diazomide protocol was used in the
large scale preparation of an intermediate -lactam 4 (Scheme 2.2) in the synthesis of
(+)- -allokainic acid and also to introduce cis-3,4-stereocenters. “These are among the
most challenging steps in the synthesis of (-)- -kainic acid and the stereocenters at these
positions are important factors in the biological activity of this natural product.
57, 58
The
key step in the synthesis of γ-lactam 7 is our Rh-II catalyzed C-H insertion reaction
187

which could be easily converted to the pyrrolidine core of kainic acid and allokainic
acid”.
57

Scheme 2.2: Retrosynthetic route through Rh-II CH insertion reaction.
57

The present work focuses on the preparation of (6S,7S,7aS)-7-(((tert-butyldi-
methylsilyl)oxy)methyl)-3,3-dimethyl-6-(phenylsulfonyl)tetrahydropyrrolo[1,2-c]oxazol-
5(3H)-one (7)
57
and desymmetrization of -diazoamide by a regio- and stereoselective
intramolecular Rh(II) catalyzed C-H insertion reaction to make highly substituted chiral
-lactams. This methodology could be applied in the construction of the -lactam core of
Salinosporamide A (Figure 2), Clasto-Lactacystin- -lactone, Ecteinascidin 743 and their
analogues.
59

Firstly, desymmetrization reactions of -diazomides were studied using
commercially available catalysts. All these catalysts showed a single diastereomer upon
188

C-H activation of diazoamide derivatives into cyclic lactams but, C-H activation by these
catalysts gave only reasonably good enantioselectivity. New ligands were also prepared
and used in the desymmetrization reactions to construct stereoselective quarternary
centers of -lactams.
59

Figure 2.2
2.2 Results and Discussion
2.2.1 Preparation of methyl oxazolidin-3-yl)-2-diazo-2-(phenylsulfonyl)ethanone

Rh-II catalyzed C-H insertion reaction of (S)-1-(4-(2-((tert-butyldimethylsilyl)
oxy)ethyl)-2,2-dimethyl oxazolidin-3-yl)-2-diazo-2-(phenylsulfonyl) ethanone gave
highly regio- and stereoselective (6S,7S,7aS)-7-(((tert-butyldimethylsilyl)oxy)methyl)-
3,3-dimethyl-6-phenylsulfonyl)tetrahydropyrrolo[1,2-c]oxazol-5(3H)-one. Commercially
available L-glutamic acid was converted into five membered N,O-acetonide 6 from the
amino diol 13 in three steps: esterification (12), reduction, and a regeoselective protection
as acetonide (14) (Scheme 2.3).
60

The free alcohol group in the acetonide 14 was protected by TBDMS followed by
chloroacetylation reaction to give compound 17.
61
The substitution of the chloro group in
17 with the phenylsulfonyl group followed by treatment with ABSA and DBU in
189

acetonitrile made diazoamide derivative 6. The Rh-II catalyzed C-H insertion reaction of
(S)-1-(4-(2-((tert-butyl dimethyl silyl) oxy) ethyl)-2,2-dimethyl oxazolidin-3-yl)-2-diazo-
2-(phenylsulfonyl)ethanone (6) gave a stereoselective derivative γ-lactam 7. The
stereochemistry at C-6 and C-7 was explained based on our previously reported work.
47,
48, 50

Scheme 2.3 Preparation of (S)-1-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2,2-di
methyl oxazolidin-3-yl)-2-diazo-2-(phenylsulfonyl)ethanone

2.2.2 C-H insertion reaction of (S)-1-(4-(2-((tert-butyldimethyl silyl) oxy) ethyl)-
2,2-dimethyl oxazolidin-3-yl)-2-diazo-2-(phenyl sulfonyl)ethanone

The unfavorable s-trans conformer is predominant in the absence of the gem
dimethyl moiety in diazoamide derivative 6 and C-H insertion does not occur under the
given conditions.
62,63 “
A cis-conformation, which is the only suitable conformation for C-
H activation due to influence from both the gem dimethyl group explains the
stereochemistry achieved in the product. The synthetic route used in the generation of the
challenging cis-C3, C4 conformation in the γ-lactam 7 is by a more favored transition
190

state directed by a stereogenic induction from L-glutamic acid without using any chiral
auxiliaries (Scheme 2.4)”.
57

Scheme 2.4 C-H activation of (S)-1-(4-(2-((tert-butyl dimethyl silyl) oxy) ethyl)-
2,2-dimethyl oxazolidin-3-yl)-2-diazo-2-(phenylsulfonyl)ethanone

The transition state 20 shows 1,3-diaxial interactions with the bulky R group in a
pseudo axial position which makes it less favorable for C-H activation. In contrast, the
bulky group R takes a pseudoequatorial position in the transition state 21 leading to the
expected stereocenters at the C-3, C-4 and C-5 positions in γ-lactam 7. The C-H
insertion reaction generates stereocenters at C3 and C-4 positions which were induced by
the existing chirality of the R-group in the amino acid.
2.2.3 Rh-II catalyzed desymmetrization reactions of diazoamide compounds

Diastereoselective and enantioselective Rh-II catalyzed desymmetrization
reactions were studied to develop a new methodology to facilitate the construction of the
γ-lactam core structures. These reactions can generate two or greater chiral centers,
including a chiral quarternary stereocenter by Rh-II catalyzed C-H insertion reactions of
191

diazoamide compounds derived from achiral starting materials. This methodology can be
applied in the total synthesis of an anticancer compound Salinsporamide A (NPI-0052)
(10) and compounds cinnabaramide A (22) as well as G (23) (Scheme 2.5).
64-67

Scheme 2.5: Salinsporamide A (NPI-0052), cinnabaramide A and G

Salinosporamide A (10) a potent inhibitor of the 20S proteasome, is currently in
phase I human clinical trials for the treatment of multiple myeloma.
68
Structurally,
Salinosporamide A comprises a β-lactone- -lactam bicyclic ring system substituted with
methyl, cyclohex-2-enylcarbinol, and chloroethyl substituents that give rise to specific
and mechanistically important interactions within the proteasome active site.
68

Salinosporamide A (10) bears a methyl group and a cyclohex-2-enyl moiety at C-3 and
C-5, respectively, This dense functionality, which includes five contiguous stereocenters,
makes 10 an extremely attractive and challenging synthetic target. The biological and
chemical properties of compounds cinnabaramide A and G, isolated from the terrestrial
Streptomyces strain JS360, were found to imitate those of salinosporamide A.
64-67
Due to
their biological activities and interesting structural features, the development of a new
methodology was initiated for C-H insertion reactions in a highly stereo- and
regeoselective construction of the -lactam.
192

2.2.4 Preparation of 1-[4,4-bis-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-
dimethyloxazolidin-3-yl]-2-diazo-ethanone

Diazoamides 1-[4,4-bis-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-
oxazolidin-3-yl]-2-diazo-ethanone (30) and 1-[4,4-bis-(tert-butyl-dimethyl-silanyloxy
methyl)-2,2-dimethyl-oxazolidin-3-yl]-2-diazo-butane-1,3-dione (29) were prepared
starting from 2-amino-2-(hydroxymethyl) propane-1,3-diol hydrochloride (Scheme 2.6).
Commercially available 2-amino-2-(hydroxymethyl)propane-1,3-diol hydro-
chloride (24) was neutralized with aqueous sodium bicarbonate and water was removed
by azeotropic distillation. The crude compound was taken in MeOH and filtered to
remove to remove undissolved salt. Attempts to make the acetonide 4,4-
bis(dihydroxymethyl)-2,2-dimethyloxazolidine (25) by known methods failed due to the
insolubility of the starting material in acetone. Hence the reaction was carried out in a
sealed tube at 100
o
C for 6 hours in acetone in presence of molecular sieves.
1
H NMR of
the crude reaction product showed complete conversion of the starting material.
Approximately 98% yield was obtained in this reaction after filtration followed by
concentration of the filtrate. Then, the alcoholic functionalities in acetonide 25 were
protected with TBS groups to make 4,4-bis(((tert-butyldimethylsilyl)oxy)methyl)-2,2-
dimethyloxazolidine (26). Refluxing the compound 26 with 2,2,6-trimethyl-4H-1,3-
dioxin-4-one in xylene for an hour lead to 1-(4,4-bis(((tert-
butyldimethylsilyl)oxy)methyl)-2,2-dimethyloxazolidin-3-yl)butane-1,3-dione (28).
Compound 28 on diazotization lead to 1-(4,4-bis(((tert-butyl dimethylsilyl)oxy)methyl)-
2,2-dimethyloxazolidin-3-yl)-2-diazobutane-1,3-dione (29).
59
Diazoamide 29 on
deacetylation with LiOH in the presence of a 5:1 acetonitrile water mixture gave 1-(4,4-
193

bis(((tert-butyldimethylsilyl)oxy)methyl)-2,2-dimethyloxazolidin-3-yl)-2-diazoethanone
(30) (Scheme 2.6).

Scheme 2.6: Preparation of 1-(4,4-bis(((tert-butyldimethylsilyl)oxy)methyl)-2,2-
dimethyloxazolidin-3-yl)-2-diazoethanone

The diazoamide 26 upon C-H activation with Rh
2
(OAc)
4
gave exclusively one
diastereomer. It was presumed that the diasteromer 31 which was formed through a more
favorable transition state 29 as the transition state 27 experiences extremely repulsive 1,3
steric interactions (Scheme 2.7).
57
2.2.5 C-H activation of 1-(4,4-bis(((tert-butyldimethylsilyl)oxy)methyl)- 2,2-
dimethyloxazo- lidin-3-yl)-2-diazoethanone

The transition state 34 is unfavorable due to a trans bicyclic system which could explain

why the diasteromer 36 was not formed. The diastereoselectivity in the C-H activation

reaction encouraged us to explore the enantioselective C-H activation with commercially

available Rh-II catalysts (Table 1). For a preliminary screening, the
194

Scheme 2.7: C-H activation of 1-(4,4-bis(((tert-butyldimethyl silyl)oxy)methyl)-2,2-
dimethyloxazolidin-3-yl)-2-diazoethanone

.reactions were done in one hour at room temperature and the reactions were carefully
monitored using HPLC. However, good enantioselectivity was not achieved by C-H
activation.
Table 2.1 Commercially available Rh-II catalysts used for C-H activation

Entry Chiral Rh-II catalyst

1
Tetrakis-N-phthaloyl-(S)-Phenylalaninato dirhodium,
ethylacetate complex

2
Tetrakis[1{4- alkyl(C11-C13) phenylsulfonyl}-(2S)-
pyrrolidine carboxylate]-dirhodium(II)
3 Doyle dirhodium Rh
2
(5S-MEPY)
4

4 Rh
2
(4SMEOX)
4

In order to improve the selectivity reactions were performed from –78
o
C to 0
o
C.
More than 99 % starting material remained intact when reactions were run at low
temperatures.

195

2.2.6 Preparation of 1-trifluoromethanesulfonyl-imidazolidin-2-one ligands

To increase the selectivity further, previously reported as well as new ligands were
prepared starting from chiral diamines (Scheme 8). A known procedure was used in the
preparation of ligands 37-41 starting from commercially available diamines.
59
The
diamines were converted into their corresponding imidazolidin-2-ones 32-36. The
imidazoldin-2-ones were treated with triflic anhydride at -78
o
C to get 1-
trifluoromethanesulfonyl-imidazolidin-2-ones 37-41(Scheme 8). Triflamides 37 and 38
showed an inseparable impurity in
1
H NMR though the compounds did not show any
impurity on TLC. These ligands 37-41 were used without further purification for making
premixed Rh-II catalysts.

These ligands were used to make premixed Rh-II catalysts and to improve the
enantioselective C-H activation in desymmetrization reactions. Rh
2
(OAc)
4
and ligand
(1:1.2 mole ratio) were taken in dichloromethane and the mixture was stirred at room
temperature for 1-5 hours to make a premixed catalyst for further CH activation studies.
From HPLC data, none of the premixed Rh-II catalysts prepared from ligands 47-51
showed improved enantioselectivity on C-H activation of 1-(4,4-bis(((tert-butyl dimethyl
silyl)oxy)methyl)-2,2-dimethyloxazolidin-3-yl)-2-diazoethanone (30) at room
temperature.

196

Scheme 2.8: Preparation of 1-trifluoromethanesulfonyl-imidazolidin-2-one ligands
59

2.2.7 CH activation of 1-[4,4-bis-(tert-butyl-dimethyl-silanyloxy- methyl)-2,2-
dimethyl-oxazolidin-3-yl]-2-diazo-butane-1,3-dione

Diazoamide 1-[4,4-bis-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyloxa-
zolidin-3-yl]-2-diazo-butane-1,3-dione (29) did not undergo C-H activation even under
reflux conditions with dichloromethane, benzene and chlorobenzene as solvents. Though
the starting material was completely consumed in a sealed tube reaction at 100
o
C in
197

dichloromethane with Rh
2
(OAc)
4
, the C-H activation product 49 was not obtained.
Instead, a major elimination product 50 was observed in
1
H NMR (Scheme 9). The
elimination occurred through the formation of an enolate generated due to the elimination
of the acidic proton adjacent to the acetyl group in compound 49.

Scheme 2.9: CH activation of 1-[4,4-bis-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-
dimethyl-oxazolidin-3-yl]-2-diazo-butane-1,3-dione

2.2.8 Preparation of 1-[3,3-bis-(tert-butyl-dimethyl-silanyloxymethyl)- 1-oxa-4-
aza-spiro[4.5]dec-4-yl]-2-diazo-ethanone (48)

Having known that the gem dimethyl moiety in diazoamide 6 directed formation
of the s-cis conformation, we decided to study the effect of the cyclohexyl ring in the
conformation during C-H activation reaction. Cyclohexyl protected compound 1-[3,3-
bis-(tert-butyl-dimethyl-silanyloxymethyl)-1-oxa-4-aza-spiro[4.5]dec-4-yl]-2-diazoethan-
one (48) was prepared starting from 2-amino-2-(hydroxymethyl)propane-1,3-diol
hydrochloride (24) in good yields (Scheme 2.10).
198

Scheme 2.10 : Preparation of 1-[3,3-bis-(tert-butyl-dimethyl-silanyloxymethyl)-1-oxa-4-
azaspiro[4.5]dec-4-yl]-2-diazoethanone

Commercially available 2-amino-2-(hydroxymethyl)propane-1,3-diol hydro-
chloride was neutralized with aqueous sodium bicarbonate solution and water was
removed by azeotropic distillation. The crude compound was dissolved in MeOH and
filtered to remove undissolved salt. Concentration of the filtrate gave the free amine. The
crude product was protected and treated with cyclohexanone to make 1-oxa-4-azaspiro
[4.5]decane-3,3-diyldimethanol and refluxed in the presence of benzene as solvent using
a Dean-Stark apparatus to remove water by azeotropic distillation. The free diols of 1-
oxa-4-azaspiro [4.5]decane-3,3-diyl-dimethanol were protected with TBS groups to make
3,3-bis(((tert-butyl dimethylsilyl)oxy)methyl)-1-oxa-4-azaspiro[4.5]decane (55).
Refluxing the compound 55 with 2,2,6-trimethyl-4H-1,3-dioxin-4-one in xylene for an
hour gave 1-(3,3-bis(((tert-butyldimethylsilyl)oxy)methyl)-1-oxa-4-azaspiro[4.5]decan-4-
199

yl)butane-1,3-dione (56). Compound 56 on diazotization lead to 1-(3,3-bis(((tert-butyldi-
methylsilyl)oxy)methyl)-1-oxa-4-azaspiro[4.5]decan-4-yl)-2-diazobutane-1,3-dione (57).
Deacetylation of diazoamide (57) with LiOH in a mixture of 5:1 acetonitrile and water
gave 1-(3,3-bis(((tert-butyldimethylsilyl)oxy)methyl)-1-oxa-4-azaspiro[4.5]decan-4-yl)-
2-diazoethanone (58)(Scheme 2.10).
2.2.9 C-H activation of 1[3,3-bis-(tert-butyl-dimethyl-sianyloxymethyl)-1-oxa-4-
aza-spiro[4.5]dec-4-yl]-2-diazo-ethanone

The C-H activation of 1-[3,3-bis-(tert-butyl-dimethyl-silanyloxymethyl)-1-oxa-4-
aza-spiro[4.5]dec-4-yl]-2-diazo-butane-1,3-dione (58) with Rh
2
(OAc)
4
in dichlorometh-
ane at room temperature gave one of the major diastereomers. It was assumed that the
major diastereomer was compound 61 as it was obtained via a less sterically hindered
stable transition state 49 (Scheme 2.11). In order to make the other diastereomer 62, the
rhodium complex has to go through a less stable transition state 60 since it has a trans
ring fused system.
A minor isomer was observed on
1
H NMR, presumably formed via a transition
state 63 where C-H activation occurred on a six membered cyclic ring to give compound
64 (Scheme 2.11). Attempts to control the formation of exclusively one product failed by
lowering the reaction temperature. C-H activation did not occur below room temperature
(23
o
C). The ratio of compounds 61 and 64 observed from
1
H NMR is 2:1 The C-H
activation of the compound 58 was done using commercially available chiral tetrakis-N-
phthaloyl-(S)-phenylalaninato dirhodium, ethylacetate complex, tetrakis[1{4-alkyl

200

Scheme 2.11: C-H activation of 1-[3,3-bis-(tert-butyl-dimethyl-silanyloxymethyl)-1-
oxa-4-aza-spiro[4.5]dec-4-yl]-2-diazo-ethanone

(C11-C13) phenylsulfonyl}-(2S)-pyrrolidine carboxylate]-dirhodium (II) catalyst, Doyle
dirhodium Rh
2
(5S-MEPY)
4
, Rh
2
(4SMEOX)
4
as well as with premixed catalysts prepared
from Rh
2
(OAc)
4
and the ligands 47-51. The
1
H NMR of the crude product obtained from
CH activation reaction of all these catalysts showed 61 as a major diasteromer and 64 as
minor compound.
2.2.10 C-H activation of 1-[3,3-bis-(tert-butyl-dimethyl-silanyloxymethyl)-1-oxa-4-
aza-spiro[4.5]dec-4-yl]-2-diazo-butane-1,3-dione (57)

C-H activation of 1-[3,3-bis-(tert-butyl-dimethyl-silanyloxymethyl)-1-oxa-4-aza-
spiro[4.5]dec-4-yl]-2-diazo-butane-1,3-dione (57) was not observed with Rh-II catalyst in
dichloromethane, benzene and chlorobenzene as solvents at room temperature as well as
201

at reflux conditions. The
1
H NMR of the crude reaction mixture obtained from heating at
130
o
C in a closed tube for 5 hours showed compound 54 where C-H activation occurred

Scheme 2.12: C-H activation of 1-[3,3-bis-(tert-butyl-dimethyl-silanyloxymethyl)-1-
oxa-4-aza-spiro[4.5]dec-4-yl]-2-diazo-butane-1,3-dione

on the six membered cyclic structure instead of activation on methyloxy TBS protected

carbon (Scheme 2.12).

2.2.11 C-H activation of trans-1-benzylhexahydro-1H-indol-2(3H)-one

Trans-1-benzylhexahydro-1H-indol-2(3H)-one was prepared starting from
cychlohexylamine. Cyclohexylamine was protected with benzyl group by treating with
benzaldehyde followed by the reduction of the imine formed to give N-benzylcyclo
hexanamine (72). The compound 72 chloroacetylated to yield N-benzyl-2-chloro-N-
cyclohexylacetamide (73) and the compound 73 was converted into N-benzyl-N-
cyclohexyl-2-(phenylsulfonyl)acetamide (74). Diazotisation of phenylsulfonylacetamide
202

74, in the presence of ABSA and DBU lead to N-benzyl-N-cyclohexyl-2-diazo-2-
(phenylsulfonyl)acetamide (75).

Scheme 2.13: Preparation of N-benzyl-N-cyclohexyl-2-diazo-2-(phenylsulfonyl)
acetamide

Trans-1-benzylhexahydro-1H-indol-2(3H)-one (76) did not undergo C-H activation
with Rh
2
(OAc)
4
in CH
2
Cl
2
, benzene, chlorobenzene at room temperature as well as at
reflux conditions. Whereas in chlorobenzene heated at 130
o
C in a sealed tube showed the
product spots on thin layer chromatography (TLC) plate. One of the major spots was
isolated and
1
H NMR of the compound showed the formation of product (Scheme 2.14).

Scheme 2.14: C-H activation of N-benzyl-N-cyclohexyl-2-diazo-2-(phenyl sulfonyl)
acetamide

2.2.12 C-H activation of N-cyclohexyl-2-diazo-N-phenyl-2-(phenylsulfonyl)
acetamide

Similarly, N-cyclohexyl-2-diazo-N-phenyl-2-(phenylsulfonyl)acetamide (78) was
prepared starting from aniline and cyclohexanone. Rhodium catalyzed CH activation of
203

the compound lead to racemic mixture of favorable trans fused 1-phenylhexahydro-1H-
indol-2(3H) –one (79).

Scheme 2.15: C-H activation of N-cyclohexyl-2-diazo-N-phenyl-2-(phenylsulfonyl)
acetamide

2.3 Conclusion
The Rh-II catalyzed intramolecular C-H insertion reaction of (S)-1-(4-(2-((tert-
butyl dimethyl silyl)oxy)ethyl)-2,2-dimethyloxazolidin-3-yl)-2-diazo-2-phenyl sulfonyl)
ethanone (6) was used in the large scale preparation of γ-lactam (6S,7S,7aS)-7-(((tert-
butyl dimethyl silyl)oxy) methyl)-3,3-dimethyl-6-(phenylsulfonyl) tetrahydropyrrolo[1,2-
c] oxazol-5(3H)-one (7). This highly regio- and stereoselective γ-lactam is a useful
precursor in the synthesis of α-kainic acid and allokainic acid.
43,49,57
The
desymmetrization reaction of achiral diazoamides was studied with commercially
available Rh-II catalysts as well as with premixed catalysts obtained from various
ligands. Diazoamides 1-[4,4-bis-(tert-butyl-dimethylsilanyloxymethyl)-2,2-dimethyl-
oxazolidin-3-yl]-2-diazo-ethanone (19) and 1-[4,4-bis-(tert-butyl-dimethyl-silanyloxy
methyl)-2,2-dimethyl-oxazolidin-3-yl]-2-diazo-butane-1,3-dione (20) were prepared
starting from commercially available inexpensive 2-amino-2-(hydroxymethyl)propane-
1,3-diol hydrochloride. (Scheme 6). The Rh-II catalyzed C-H insertion reaction of 1-[4,4-
bis-(tert-butyl-imethylsilanyloxymethyl)-2,2-dimethyloxa-zolidin-3-yl]-2-diazo-ethanone
(19) gave exclusively a single diastereomer.
204

Preparation of new chiral 3-((trifluoromethyl)sulfonyl)-3H-dinaphtho[2,1-d:1',2'-
f] [1,3]diazepin-4(5H)-one, 1,11-dimethyl-5-((trifluoromethyl)sulfonyl)-5H-dibenzo[d,f]
[1,3] diazepin-6(7H)-one were discussed and these ligands were used for making
premixed Rh-II catalysts in Rh-II CH insertion reaction. These premixed Rh-II catalysts
did not give the enantioselective CH activation product. This is assumed due to bulkiness
or nonreactivity of these ligands, or due to racemization during the process of making
urea from chiral compounds. Reported ligands (4R,5S)-4,5-diphenyl-1-((tri fluoromethyl)
sulfonyl)imidazolidin-2-one, (R)-4-(tert-butyl)oxazolidin-2-one, (3aR,7aR) 1-((trifluoro
methyl)sulfonyl)hexahydro-1H-benzo[d]imidazol-2(3H)-one were also prepared and used
for making premixed catalysts in Rh-II C-H insertion reactions. The present work is to
modify the ligands to improve the enantioselective Rh-II catalyzed CH activation.

2.4 Scope for the future work

Substrates to generate quaternary chiral center with other substrates

Scheme 2.16: CH activation of 2-diazo-1-(2,2-dimethyl-3-oxa-1-azaspiro[4.5]decan-1-yl)
ethanone
205

Scheme 2.17: 2-diazo-1-(2,2-dimethyl-3-oxa-1-azaspiro[4.4]nonan-1-yl)ethanone

Scheme 2.18: 2-diazo-1-(6,6-dimethyl-7-oxa-5-azaspiro[3.4]octan-5-yl)ethanone

2.5 Experimental
2.5.1 General
Unless otherwise noted, all reagents were purchased from commercial sources and used
without further purification. All experiments were carried out under nitrogen atmosphere
206

using extremely dry (dried in oven followed by flame drying) glassware. Tetrahydrofuran
(THF) and diethyl ether were distilled over sodium metal and benzophenone, under
nitrogen, prior to use. Dichloromethane (CH
2
Cl
2
) was distilled over CaH
2
, under nitrogen
prior to use.
Column chromatography was done using 230-400 mesh silica gel. TLC was
performed on Aluminium backed silica plates (60F
254
, 0.2 mm) which were visualized
using UV fluorescence and iodine. The plate was also charred to identify non UV active
compounds using PMA and/or ninhydrin solutions in ethanol.
The
1
H and
13
C spectra were recorded on a Bruker 250 NMR spectrometer at 250
MHz, Mercury 400 NMR spectrometer at 400 MHz and Varian AS400 NMR
spectrometer at 400 MHz.
19
F NMR was run on a Mercury 400 NMR spectrometer at
400 MHz and Varian AS400 NMR spectrometer at 400 MHz. Chemical shifts (δ
H
) are
given in parts per million (ppm). The
1
H NMR chemical shifts were determined relative
to internal tetramethylmethylsilane (TMS) at (  0.0) or to the signal of a residual
protonated solvent: CDCl
3
. (  7.24), The
13
C NMR chemical shifts were determined
relative to the
13
C signal of solvent: CDCl
3
at (  77.0) or CD
3
OD at (  49.0). The
19
F
NMR chemical shifts were determined relative to internal CFCl
3
at (  0.0). J values are
given in Hz.

207

2.5.2 General Procedures

2.5.2.1 Preparation of (S)-4-(3-(tert-butyldimethylsilyloxy)propyl)-2,2-dimethyl
oxazoli-dine or (L)-glutamic acid dimethylester
(Scheme 2.3, compound 12)
57

Figure 2.3: Preparation of (S)-4-(3-(tert-butyldimethylsilyloxy)propyl)
2,2-dimethyloxazoli-dine or (L)-glutamic acid dimethylester

To a solution of L-glutamic acid (100g, 680 mmol) in methanol (700 mL) at 0
o
C was
added 2 equavalents of thionyl chloride (162g, 1360 mmol). Cooling was maintained
until all the thionyl chloride was added drop wise from a dropping funnel. After complete
addition the reaction mixture was brought to room temperature and continued stirring for
12 hours. The resulting solution was concentrated under vacuum and dissolved in MeOH
(500ml). The solution was neutralized to pH=7.0 by adding solid NaHCO
3
. The white
solid obtained was an insoluble salt in MeOH which was filtered to separate from the
product. The filtrate was concentrated to evaporate the solvent. The colorless oily
compound obtained was (L)-glutamic acid dimethylester. The oily compound was taken
500 ml of DCM to precipitate the salt sodium chloride and unreacted sodium bicarbonate.
The solution was filtered to give the free (S)-4-(3-(tert-butyldimethylsilyloxy)propyl)-
2,2-dimethyl oxazolidine as a colorless oil (115g, ~96%). The crude product was used for
the next step without further purification.
208

Note: Reaction was repeated starting with different amounts of L-glutamic acid and the
yields of the reactions were consistent most of the time. Sometimes more than expected
yields were observed probably due to the formation of insoluble sulfides from thionyl
chloride. Drop wise addition of thionyl chloride was maintained at 0
o
C to avoid the
formation of insoluble sulfides as side products.
2.5.2.2 Preparation of (S)-2-aminopentane-1,5-diol (Scheme 2.3, compound 14)
57

Figure 2.4 : Preparation of (S)-2-aminopentane-1,5-diol

Lithium aluminum hydride (62g, 1628 mmol) was added to 500 mL of anhyrous THF at
0 °C in small portions in a three necked 2 L flask with continuous stirring. To this slurry
a solution of (L)-glutamic acid dimethylester (138g, 775 mmol) in 200 ml of anhydrous
THF was added drop wise from a dropping funnel. After complete addition of the ester,
the reaction mixture was stirred for 0.5 hour at 0
o
C. Then, the reaction mixture was
brought to room temperature and continued stirring at room temperature for 12 hours.
The unreacted lithium aluminium hydride was quenched by slow addition of water (62
mL) followed by 20% NaOH (62mL) and water (124 mL). The precipitate was filtered
and washed with THF. The filtrate was dried over Na2SO4 and concentrated to give the
amino alcohol as an oily compound (67%), which was used for the next step without
further purification. The reaction was repeated with different amounts of starting material
to make large quantities of product.
209

2.5.2.3 Preparation of (S)-3-(2,2-dimethyloxazolidin-4-yl)propan-1-ol (Scheme 2.3,
compound 15)
57

Figure 2.5: Preparation of (S)-3-(2,2-dimethyloxazolidin-4-yl)propan-1-ol

To (S)-2-aminopentane-1,5-diol (40 g, 0.34 mol) in 400 mL DCM, acetone (600 mL) was
added. The mixture was heated to 40
o
C and anhydrous MgSO4 (42 g, 0.34 mol) was
added in small portions. Then, the reaction mixture was refluxed for 2 hours, filtered and
concentrated to give the acetonide intermediate (87%).

2.5.2.4 Preparation of (S)-4-(3-((tert-butyldimethylsilyl)oxy)propyl)-2,2-dimethyl
oxazo- lidine (Scheme 2.3, compound 16)
57

Figure 2.6 : Preparation of (S)-4-(3-((tert-butyldimethylsilyl)oxy)propyl)-2,2-
dimethyl oxazo- lidine

A solution of (S)-3-(2,2-dimethyloxazolidin-4-yl)propan-1-ol (20g, 125 mmol) in
anhydrous THF (70 ml) was added to a suspension of 60% NaH (6.0 g, 150 mmol,
washed with hexane twice) in freshly distilled THF (785 ml) at 0°C. The mixture was
stirred at room temperature for 30 minutes., then a solution of TBDMSCl (18.93 g, 126
210

mmol) and triethyl amine (2.6 mL) in anhydrous THF (75 ml) was added at 0°C. The
reaction mixture was vigorously stirred for 45 minutes at room temperature. Ice pieces
were added slowly to quench the remaining NaH. The reaction mixture was poured into
ethyl acetate (400 mL), and the EtOAc layer was separated. The water layer was
extracted with ethyl acetate. All the ethyl acetate layers were combined and washed with
brine twice (500 mL each time), dried over Na
2
SO
4
, and concentrated in vacuo to give
the protected (S)-4-(3-((tert-butyldimethylsilyl)oxy)propyl)-2,2-dimethyloxazolidine
(30g, 83%). The resulting crude compound was used for the next step without further
purification.
2.5.2.5 Preparation of (S)-1-(4-(3-((tert-butyldimethylsilyl)oxy)propyl)-2,2-
dimethyloxazoli din-3-yl)-2-chloroethanone (Scheme 2.3, compound 17)
57

Figure 2.7: Preparation of (S)-1-(4-(3-((tert-butyldimethylsilyl)oxy)propyl)-2,2-
dimethyloxazoli din-3-yl)-2-chloroethanone

Chloroacetyl chloride (16.9 g, 150 mmol) was added dropwise to a mixture of (S)-4-(3-
((tert-butyldimethylsilyl)oxy)propyl)-2,2-dimethyloxazo-lidine (36.24 g, 125 mmol) and
triethylamine (25.3 g, 250 mmol) in CH
2
Cl
2
(300 mL) at 0 °C. After stirring for 3 hours at
0 °C, the reaction mixture was washed with brine, and the aqueous layer was extracted
twice with CH
2
Cl
2
(100 mL each time). The combined CH
2
Cl
2
layers were washed with
brine, dried over Na2SO4 and concentrated. The compound was purified by column
211

chromatography with hexane and EtOAc system to give (S)-1-(4-(3-((tert-
butyldimethylsilyl)oxy)propyl)-2,2-dimethyloxazolidin-3-yl)-2-chloroethanone (20.8 g
47%) as a colorless oily compound.
2.5.2.6 Preparation of (S)-1-(4-(3-((tert-butyldimethylsilyl)oxy)propyl)-2,2-
dimethyloxazo-lidin-3-yl)-2-(phenylsulfonyl)ethanone
(Scheme 2.3, compound 18)
57

Figure 2.8: Preparation of (S)-1-(4-(3-((tert-butyldimethylsilyl)oxy)propyl)
2,2- dimethyloxazo-lidin-3-yl)-2-(phenylsulfonyl)ethanone

To a solution of (S)-1-(4-(3-((tert-butyldimethylsilyl)oxy)propyl)-2,2-dimethyloxazoli
din-3-yl)-2-chloroethanone (0.79 g, 59.4 mmol) in DMF (300 mL) at room temperature,
PhSO
2
Na (14.63 g, 89.10 mmol) was added. The reaction mixture was stirred for six
hours and ethyl acetate was added. Then, the ethyl acetate layer was washed with water
and dried over sodium sulfate and concentrated. The crude reaction mixture was purified
by column chromatography to give (S)-1-(4-(3-((tert-butyldimethylsilyl)oxy)propyl)-2,2-
dimethyloxazolidin-3-propyl)-2-(phenylsulfonyl) ethanone (35 g, 89%). The reaction was
repeated in different large scales and the results observed were consistent.

212

2.5.2.7 Preparation of (S)-1-(4-(3-((tert-butyldimethylsilyl)oxy)propyl)-2,2-dimethyl
oxazol- idin-3-yl)-2-diazo-2-(phenylsulfonyl)ethanone
(Scheme 2.3, compound 6)
57

Figure 2.9: Preparation of (S)-1-(4-(3-((tert-butyldimethylsilyl)oxy)propyl)-2,2-
dimethyl oxazol- idin-3-yl)-2-diazo-2-(phenylsulfonyl)ethanone

To a solution of (S)-1-(4-(3-((tert-butyldimethylsilyl)oxy)propyl)-2,2-dimethyloxazo-
lidin-3-yl)-2-(phenylsulfonyl)ethanone (15 g, 31.7 mmol) in CH
3
CN (160 mL), 1,8-diaza
bicyclo[5.4.0] undeca-7-ene (DBU) (15mL, 79.5 mmol) was added at 0
o
C with stirring.
To the resulting solution 4-acetamidobenzene sulfonyl azide (ABSA) (9.17 g, 38.2 mmol)
was added at 0
o
C and the reaction mixture was slowly brought to RT and continued
stirring for 3 hours. Then, the reaction mixture was taken in EtOAc, washed with water,
dried with sodium sulfate and concentrated. The crude reaction mixture was purified by
column chromatography using a 2:1 hexane: EtOAc system to give (S)-1-(4-(3-((tert-
butyldimethylsilyl)oxy)propyl)-2,2-dimethyloxazolidin-3-yl)-2-diazo-2-(phenylsulfonyl)
ethanone (12.7 g, 80.0%). The reaction was repeated in different large scales and the
results were consistent.

213

2.5.2.8 Preparation of (6S,7S,7aS)-7-(((tert-butyldimethylsilyl)oxy)methyl)-3,3-
dimethyl-6-(phenylsulfonyl)tetrahydropyrrolo[1,2-c]oxazol-5(3H)-one
(Scheme 2.3, compound 7)
57

Figure 2.10: Preparation of (6S,7S,7aS)-7-(((tert-butyldimethylsilyl)oxy)
methyl)-3,3-dimethyl-6-(phenylsulfonyl)tetrahydropyrrolo
[1,2-c]oxazol-5(3H)-one

To a solution of (S)-1-(4-(3-((tert-butyldimethylsilyl)oxy)propyl)-2,2-dimethyloxazoli-
din-3-yl)-2-diazo-2-(phenylsulfonyl)ethanone (12.72 g, 25.5 mmol) in CH
2
Cl
2
(511 mL)
Rh
2
(OAc)
4
(0.113 g, 0.25 mmol) was added and refluxed for six hours. Reaction mixture
turned to greenish solution. Completion of starting material was monitored by TLC. The
reaction mixture was filtered to separate the catalyst and purified by column
chromatography to give (6S,7S,7aS)-7-(((tert-butyldimethylsilyl)oxy)methyl)-3,3-
dimethyl-6-(phenylsulfonyl)tetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (8.06 g, 67%).
2.5.2.9 Preparation of 2,2-dimethyl oxazoli dine-4,4-diyl)dimethanol
(Scheme 2.6, compound 25)
57

Figure 2.11: Preparation of 2,2-dimethyl oxazoli dine-4,4-diyl)dimethanol

214

2-Amino-2-(hydroxymethyl)propane-1,3-diol hydrochloride (1 g, 6.4 mmol) was
neutralized with aqueous sodium bicarbonate (0.54 g, 6.4 mmol) and water was removed
under reduced pressure. The residue was dissolved in methanol (10 mL each, repeated
thrice), filtered and concentrated. Traces of water from the residue were removed by
azeotropic distillation with benzene. The crude 2-amino-2-(hydroxymethyl)propane-1,3-
diol obtained was taken in acetone and heated in a sealed tube at 100
o
C for 6 hours in
presence of molecular sieves. Then, the reaction mixture was brought to room
temperature and heated in acetone. The dissolved compound was filtered and
concentrated to give (2,2-dimethyloxazolidine-4,4-diyl)dimethanol (1.37g, 98%). The
process was repeated until all the compound was separated.
2.5.2.10 Preparation of 4,4-bis((tert-butyldimethylsilyloxy)methyl)-2,2-
dimethyloxazolidine (Scheme 6.26, compound 26)
57

Figure 2.12: Preparation of 4,4-bis((tert-butyldimethylsilyloxy)methyl)-2,2-
dimethyloxazolidine

To the crude (2,2-dimethyloxazolidine-4,4-diyl)dimethanol (0.55 g, 3.42 mmol) in
anhydrous DMF was added imidazole (0.488g, 7.17 mmol) and tertiarybutyldimethylsilyl
chloride (1.03 g, 6.83 mmol). The reaction mixture was stirred at room temperature for 6
hours. The crude reaction mixture was dissolved in water and extracted with 30 mL of
hexane for three times (10 mL each time). All the hexane extracts were combined, dried
over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced
215

pressure to give of 4,4-bis((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyloxazolidine
(1.1 g, 83%).

2.5.2.11 Preparation of 1-(4,4-bis((tert-butyldimethylsilyloxy)methyl)-2,2-
dimethyloxazoli din-3-yl)butane-1,3-dione (Scheme 2.6, compound 28)

Figure 2.13: Preparation of 1-(4,4-bis((tert-butyldimethylsilyloxy)methyl)-2,2-
dimethyloxazoli din-3-yl)butane-1,3-dione
To the crude 4,4-bis((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyloxazolidine (1.1 g,

2.82) in xylene (5 mL), 2,2,6-trimethyl-4H-1,3-dioxin-4-one (0.375 mL, 2.82 mmol) was

added and the reaction mixture was refluxed for 1 hour. The solvent was removed under

reduced pressure to afford crude 1-(4,4-bis((tert-butyldimethylsilyloxy)methyl)-2,2-

dimethyl oxazolidin-3-yl) butane- 1,3-dione (1.34g). The crude product was used for the

next step without further purification.

216

2.5.2.12 1-(4,4-bis((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyloxazolidin-
3-yl)-2-diazobutane-1,3-dione (Scheme 2.6, compound 29 )

Figure 2.14: Preparation of 1-(4,4-bis((tert-butyldimethylsilyloxy)
methyl)-2,2-dimethyloxazolidin-3-yl)-2-diazobutane
1,3-dione

To the crude 1-(4,4-bis((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyl oxazolidin-3-l)-
2-diazobutane-1,3-dione (1.34 g) in acetonitrile (10 mL) ABSA (1.94 g, 8.05 mmol), and
DBU (2.00 g, 13.4 mmol) were added. The reaction mixture was stirred at room
temperature for 6 hours. The crude reaction mixture was then taken in water and
extracted with EtOAc (30 mL) thrice. The extracts were combined, dried over anhydrous
sodium sulfate, filtered and concentrated. The crude reaction mixture underwent column
chromatography and eluted with 20:1 → 15:1 hexane/EtOAc. The fractions were
combined to yield 0.40 g (29%) of 1-(4,4-bis((tert-butyldimethylsilyloxy) methyl)-2,2-
dimethyloxazolidin-3-yl)-2-diazobutane-1,3-dione.

217

2.5.2.13 Preparation of 1-(4,4-bis((tert-butyldimethylsilyloxy)methyl)-2,2-
dimethyloxazoli- din-3-yl)-2-diazoethanone
(Scheme 2.6, compound 30)

Figure 2.15: Preparation of 1-(4,4-bis((tert-butyldimethylsilyloxy)methyl)-2,2-
dimethyloxazoli- din-3-yl)-2-diazoethanone

To 1-(4,4-bis((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyloxazolidin-3-yl)-2-diazo
butane-1,3-dione (0.30 g, 0.42 mmol) in 5:1 mixture of CH
3
CN (3 mL) and water (0.60
mL), LiOH (0.05 g, 1.26 mmol) was added and the mixture was stirred at room
temperature. The reaction was complete after 24 hours. 10 mL of water were added to
the reaction mixture and extracted with EtOAc. The EtOAc extracts were combined,
dried over sodium sulfate and concentrated. The residue underwent column
chromatography with 20:1 hexane and EtOAc to yield (0.19 g, 70 %) of 1-(4,4-bis((tert-
butyldimethylsilyloxy)methyl)-2,2-dimethyloxazolidin-3-yl)-2-diazoethanone.

218

2.5.2.14 Preparation of 7-(tert-butyldimethylsilyloxy)-7a-((tert-butyldimethyl
silyloxy)methyl)-3,3-dimethyl-dihydro-pyrrolo[1,2-c]oxazol-5 (1H,3H,6H)-
one (Scheme 2.6, compound 35)

Figure 2.16: Preparation of 7-(tert-butyldimethylsilyloxy)-7a-((tert-butyl
dimethyl silyloxy)methyl)-3,3-dimethyl-dihydro-pyrrolo[1,2-
c]oxazol-5 (1H,3H,6H)-one

To 1-(4,4-bis((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyloxazolidin-3-yl)-2-
diazoethanone (0.0055 g, 0.01 mmol) in dichloromethane Rh
2
(OAc)
4
(0.001, 0.002
mmol) was added and stirred for 0.5 hour. The reaction mixture was passed through silica
get to remove the catalyst and the fractions were concentrated and dried to yield 7-(tert-
butyldimethylsilyloxy)-7a-((tert-butyldimethylsilyloxy) methyl)-3,3-dimethyl-dihydro-
pyrrolo[1,2-c]oxazol-5(1H,3H,6H)-one (0.0049 g, 96%).

2.5.2.15 Preparation of 6-acetyl-7a-(((tert-butyldimethylsilyl)oxy)methyl)-3,3-
dimethyl-1,7a-dihydropyrrolo[1,2-c]oxazol-5(3H)-one
(Scheme 2.9, compound 54)

Figure 2.17: Preparation of 6-acetyl-7a-(((tert-butyldimethylsilyl)oxy)methyl)-3,3-
dimethyl-1,7a-dihydropyrrolo[1,2-c]oxazol-5(3H)-one
219

To a solution of 1-(4,4-bis(((tert-butyldimethylsilyl)oxy)methyl)-2,2-dimethyloxazolidin-
3-yl)-2-diazobutane-1,3-dione (0.05 g, 1 mmol) in CH
2
Cl
2
(2 mL), Rh
2
(OAc)
4
(0.001g,
0.0006 mmol) was added and heated in a sealed tuble at 100
o
C for 6 hours. The reaction
mixture underwent column chromatography and eluted with 10:1 hexane/EtOAc. The
major compound isolated was 6-acetyl-7a-(((tert-butyldimethylsilyl)oxy)methyl)-3,3-
dimethyl-1,7a-dihydropyrrolo[1,2-c]oxazol-5(3H)-one (0.003 g, 88%).
2.5.2.16 (S)-2-amino-3,3-dimethylbutan-1-ol (Scheme 2.8, compound 46)
69

Figure 2.18: (S)-2-amino-3,3-dimethylbutan-1-ol
3.935 g (30 mmol) of L-ter-leucine was taken in a flame dried 250 ml flask equipped
with cooling condenser, magnetic stir bar and dropping funnel. At 0
o
C NaBH
4
(2.5 gm,
66 mmol) was added in small portions. Then, iodine was dissolved in 17 ml of THF and
taken in a dropping funnel and added slowly to the above mixture at 0
o
C. (dropwise
addition was maintained). After hydrogen gas evolution ceased, the reaction mixture was
refluxed for 16 hours. The reaction mixture was brought to room temperature and
methanol was added. The mixture was treated with 20 % aqueous potassium hydroxide
and stirred at room temperature for 12 hours. The solvents were removed under reduced
pressure. The crude compound was passed through a small pad of silica gel eluting with
CH
2
Cl
2
and 20 % methanol in CH
2
Cl
2
. The fractions were concentrated under vaccum.
220

2.5.2.17 Preparation of (3aR,7aR)-1-((trifluoromethyl)sulfonyl)hexahydro-1H-
benzo[d]imi-dazol-2(3H)-one (Scheme 2.8, compound 51)
59

Figure 2.19 : Preparation of (3aR,7aR)-1-((trifluoromethyl)sulfonyl)
hexahydro-1H-benzo[d]imi-dazol-2(3H)-one

A solution of (1R, 2R)-cyclohexyldiamine urea (0.25 gm, 1.78 mmol) and triethylamine
(1ml, 0.71 mmol) in 1mL dichloromethane was cooled to -78
o
C. Trifluoroacetic
anhydride (1.15 gm, 4.1 mmol) was added dropwise via syringe. The resulting solution
was stirred at -78
o
C for 45 minutes and a solution of 1:1 H
2
O and CH
3
OH was added.
The reaction mixture was warmed to room temperature and maintained for 30 minutes,
diluted with 1N HCl (50 ml) brine, dried over Na
2
SO
4
, filtered and concentrated. The
crude product was purified by column chromatography eluting with CH
2
Cl
2
to yield 65 %
(0.31 g, 63.92%) of α- diazo-α-(phenylsulfonyl)acetamides.
2.5.2.18 Preparation of (4R, 5R)-Diphenyl-imidazolidin-2-one
(Scheme 2.8, compound 50)
59

Figure 2.20: Preparation of (4R, 5R)-Diphenyl-imidazolidin-2-one

221

(1R,2R)-Diphenylethanediamine ( 1.23 g, 4.84 mmol) and N,N-dimethylaminopyridine
(0.64 g, 5.28 mmol) were dissolved in CH
3
CN (30 ml). To the above mixture Boc
2
O
(1.152 g, 5.28 mmol) was added in one portion and the reaction mixture was stirred at
room temperature overnight. The solvent was removed under reduced pressure and the
resulting residue was purified by column chromatography. (1:1 CH
2
Cl
2
:EtOAc) to yield
0.84 g (72.7 %) of the cyclic urea as a white solid.
2.5.2.19 (4R,5R)-Diphenyl-1-trifluoromethanesulfonyl-imidazolidin-2-one
(Scheme 2.8, compound 48)
59

Figure 2.21: (4R,5R)-Diphenyl-1-trifluoromethanesulfonyl-imidazolidin-2-one

A solution of (4R,5R)-diphenyl-imidazolidin-2-one (0.445 g, 1.87 mmol) and Et
3
N (1.04
mL, 7.47 mmol) in CH
2
Cl
2
(10 mL) was cooled to –78 ºC. Triflic anhydride (0.72 mL,
4.26 mmol) was added dropwise via syringe. The resulting solution was stirred at –78 ºC
for 45 min and a 1:1 solution of H
2
O-MeOH (5 mL) was added. The reaction mixture
was warmed to room temperature, maintained for 30 minutes, and then diluted with Et
2
O
(300 mL). The organic layer was washed with 1N HCl (50 mL), brine (50 mL), dried,
filtered and then concentrated under reduced pressure. Purification of this residue by
flash chromatography (SiO
2
, 100% CH
2
Cl
2
) gave the mono triflamide (0.62 g, 89.4%) as
a white solid.
222

2.5.2.20 (R)- 3,5-dihydro-4H-Dinaphtho[2,1-d:1',2'-f][1,3]diazepin-4-one
(Scheme 2.8, compound 42)

Figure 2.22: (R)- 3,5-dihydro-4H-Dinaphtho[2,1-d:1',2'-f][1,3]
diazepin-4-one

To a solution of (R)-[1,1'-Binaphthalene]-2,2'-diamine (0.56g, 1.97 mmol) and DMAP
(0.48 g, 3.9 mmol) in acetonitrile (25 mL), (Boc)
2
O (0.34 g, 1.97 mmol) was added and
stirred at room temperature overnight. A white solid precipitated was filtered and dried
under vaccum. The solid obtained (0.59 g, 96.7 %) was insoluble in CH
2
Cl
2
, CH
3
CN and
methanol.

2.5.2.21 3-((trifluoromethyl)sulfonyl)-3H-dinaphtho[2,1-d:1',2'-f][1,3]diazepin-
4(5H)-one (Scheme 2.8, compound 47)

Figure 2.23: 3-((trifluoromethyl)sulfonyl)-3H-dinaphtho[2,1-d:1',2'-f][1,3]
diazepin-4(5H)-one

Triflic anhydride was added dropwise to a solution of starting material (0.64 g, 2.06
mmol) and pyrrolidine (1.72 mL, 2.06 mmol)in DMF (2ml). An exothermic reaction and
fumes were observed inside the flask. After complete addition, the reaction mixture was
223

brought to 80
o
C and stirred. TLC 1:1 showed a spot more nonpolar than the starting
material spot.
1
H NMR showed peaks corresponding to a pyrrolidine impurity.
Note: Reaction was also run in presence of triethylamine as base. Though compound was

purified on column with 100% CH
2
Cl
2
and a single spot was observed on TLC, NMR

spectrum showed peaks corresponding to triethyl amine.

2.5.2.22 Preparation of complex with (3aR,7aR)-1-((trifluoromethyl)sulfonyl)

hexahydro-1H-benzo[d]imidazol-2(3H)-one and 1/3 equivalent of
Rh
2
(OAc)
4
59

Figure 2.24: Preparation of complex with (3aR,7aR)-1-((trifluoromethyl)
sulfonyl)hexahydro-1H-benzo[d]imidazol-2(3H)-one and 1/3
equivalent of Rh
2
(OAc)
4

Molecular sieves (5 mg, 4 A
o
) were taken in a 10 mL flask and flame dried under
nitrogen atmosphere. To the above contents, chlorobenzene was added followed by the
addition of (3aR,7aR)-1-((trifluoromethyl)sulfonyl)hexahydro-1H-benzo[d]imidazol-
2(3H)-one (0.206 mmol) and Rh
2
(OAc)
4
(0.029g, 0.066 mmol). Sodium carbonate
(0.010g, 0.094 mmol) was placed in a pressure equivalizing funnel connected to the
flask. The contents in the flask were refluxed for 20 hours. The solvent was removed
under reduced pressure. The solid obtained was slightly soluble in methanol and becomes
pink in color.
1
H NMR in CH
3
OD did not show the amide peak corresponding to the
complex between amide nitrogen and rhodium.

224

2.5.2.23 2-Benzenesulfonyl-N-benzyl-N-cyclohexyl-acetamide

Figure 2.25: 2-Benzenesulfonyl-N-benzyl-N-cyclohexyl-acetamide

To 2-benzenesulfonyl-N-benzyl-N-cyclohexyl-acetamide (0.3 g, 0.79 mmol) in CH
3
CN
(0.2 M solution), ABSA (0.29 g, 1.19 mmol) and DBU (0.3 ml, 1.9 mmol) were added
and stirred at room temperature for 12 hours. The reaction mixture treated with water and
extracted with ethyl aceate. The ethyl acetate extracts were combined, dried over sodium
sulfate, filtered and the solvent was removed under reduced pressure. The crude product
underwent column chromatography using 230-400 mesh silica gel eluted by 7:1 → 2:1
hexane and EtOAc.
2.5.2.24 Preparation of 1-[3,3-bis-(tert-butyldimethylsilanyloxymethyl)-1-oxa-
4-aza-spiro[4,5]dec-4-yl-2-diazoethanone
(Scheme 2.12, compound 67)

Figure 2.26: Preparation of 1-[3,3-bis-(tert-butyldimethylsilanyloxymethyl)-1-oxa-4-
aza-spiro[4,5]dec-4-yl-2-diazoethanone
225

To 1-[3,3-bis-(tert-butyl-dimethyl-silanyloxymethyl)-1-oxa-4-aza-spiro[4.5]dec-4-yl]-2-

diazo-butane-1,3-dione in chlorbenzene in a sealed tube was added tetrakis-N-pthaloyl-

(S)-phenylalaninato dirhodium, ethylacetate compex. The reaction mixture was heated to
reflux at 130
o
C for 12 hours. The solvent was removed under reduced pressure and the
proton NMR (CDCl
3
) of the crude compound indicated a 3:1 diastereomeric ratio of the
product. The product was purified by column chromatography using 230-400 mesh silica
gel. The column was eluted by 4:1 hexane and CH
2
Cl
2
followed by 2:1 systems.
3.5.2.25 Preparation of N-cyclohexyl-2-diazo-N-phenyl-2-(phenylsulfonyl)
acetamide (Scheme 2.13, Compound 70)

Figure 2.27: Preparation of N-cyclohexyl-2-diazo-N-phenyl-2-(phenyl
sulfonyl)acetamide

To N-cyclohexyl-N-phenyl-2-(phenylsulfonyl)acetamide (0.488 g, 1.77 mmol) and
ABSA (0.4 g, 2.66 mmol) in 3ml of CH
3
CN, DBU (0.66 mL, 4.68 mmol) was added.
After six hours stirring the reaction mixture was diluted with 10 mL of ethylacetate.
Then, the reaction mixture was given water washings twice, dried over sodium sulfate
and concentrated. The crude compound was purified on column chromatography with
30:1 hexane and ethyl acetate system to give N-benzyl-N-cyclohexyl-2-diazo-2-
(phenylsulfonyl)acetamide (0.08g, 15% ).
226

2.6 Spectral Data
Spectral data of (S)-4-(3-(tert-butyldimethylsilyloxy)propyl)-2,2-dimethyl oxazoli-
dine or (L)-glutamic acid dimethylester (Scheme 2.3)

1
H NMR (400 MHz, CDCl3): 7.67 (s, 1H), 4.23 (t, 1H, J = 6.4 Hz), 3.74 (s, 3H), 3.62 (s,
3H), 2.68-2.48 (m, 2H), 2.43-2.21 (m, 2H);
Spectral data of (S)-2-aminopentane-1,5-diol
1
H NMR (400 MHz, CD
3
OD): 3.62-3.43 (m, 3H), 3.4-3.2 (m, 1H), 2.80-2.71 (m, 1H),
1.70-1.41 (m, 3H), 1.39-1.25 (m, 1H);
Spectral data of (S)-3-(2,2-dimethyloxazolidin-4-yl)propan-1-ol
1
H NMR (400 MHz, CDCl3) : 3.90 (t, 1H, J=7.18), 3.63-3.42 (m, 2H), 3.39-3.24 (m, 1H),
3.19 (t, 1H, J= 7.8 Hz), 1.67-1.53 (m, 3H), 1.52~1.43 (m, 1H), 1.36 (s, 3H), 1.24 (s, 3H);

Spectral data of (S)-4-(3-((tert-butyldimethylsilyl)oxy)propyl)-2,2-dimethyloxazo-
lidine (Scheme 2.3, compound 16)

1
H NMR (400 MHz, CDCl
3
) : 3.92 (t, 1H, J= 7.2 Hz), 3.61 (t, 2H, J= 5.65 Hz), 3.40-3.32

(m, 1H), 3.22 (t, 1H, J= 8.2 Hz), 1.61-1.40 (m, 4H), 1.39 (s, 3H), 1.26 (s, 3H), 0.85 (s,

9H), 0.00 (s,6H);

Spectral data of (S)-1-(4-(3-((tert-butyldimethylsilyl)oxy)propyl)-2,2-dimethyloxazoli
din-3-yl)-2-chloroethanone (Scheme 2.3, compound 17)

1
H NMR (400 MHz, CDCl3) : 4.10 (ABq, 1H, JAB= 12.4 Hz), 3.94 (ABq, 1H, JAB= 12.4
Hz), 3.92-3.88 (m, 2H), 3.82-3.81 (m, 1H), 3.66-3.54 (m, 2H), 1.83-1.70 (m, 1H), 1.61 (s,
3H), 1.58~1.40 (m, 3H), 1.46 (s, 3H), 1.83 (s, 9H), 0.00 (s, 6H)
Spectral data for (S)-1-(4-(3-((tert-butyldimethylsilyl)oxy)propyl)-2,2-dimethyloxa-
zolidin-3-yl)-2-diazo-2-(phenylsulfonyl) ethanone (Scheme 2.3, compound 6)

1
H NMR (400 MHz, CDCl3) : 7.90-7.53 (m, 5H), 4.31 (ABq, 1H, JAB= 13.6 Hz), 4.20-
227

4.16 (m, 1H), 3.98 (ABX, 1H, JAB= 9.2 Hz, JAX= 5.2 Hz), 3.97 (ABq, 1H, JAB= 13.6 Hz),
3.83 (ABX, 1H, JAB= 9.2 Hz, JAX= 0 Hz), 3.70-3.61 (m, 2H), 1.82-1.70 (m, 1H), 1.70-
1.50 (m, 3H), 1.56 (s, 3H), 1.47 (s, 3H), 0.87 (s, 9H), 0.05 (s, 6H);
Spectral data of (6S,7S,7aS)-7-(((tert-butyldimethylsilyl)oxy)methyl)-3,3-dimethyl-6-
(phenylsulfonyl)tetrahydropyrrolo[1,2-c]oxazol-5(3H)-one
(Scheme 2.3, compound 7)

1
H NMR (400 MHz, CDCl3) : 7.99 (d, 2H, J= 7.2 Hz), 7.65 (m, 1H), 7.54 (m, 2H), 4.12
(d, 1H, J= 10.0 Hz), 4.08 (ABX, 1H, JAB= 8.6 Hz, JAX= 5.4 Hz), 3.92-3.80 (m, 1H), 3.78-
3.50 (m, 2H), 3.44 (ABX, 1H, JAB= 8.6 Hz, JBX= 9.0 Hz), 2.90-2.81 (m, 1H), 2.38-2.29
(m, 1H), 1.80-1.68 (m, 1H), 1.46 (s, 3H), 1.37 (s, 3H), 0.89 (s, 9H), 0.07 (s, 3H), 0.05 (s,
3H);
Spectral data of 2,2-dimethyl oxazoli dine-4,4-diyl)dimethanol

1
H NMR (400 MHz, CD
3
OD) 4.93 (s, 2H, -OH), 3.79 (s, 2H, ring-OCH
2
); 1.57 (s,
4H, -OCH
2
); 1.39(s, 6H, gem dimethyl).
13
C NMR (250 MHz, CD
3
OD) 70.81; 69.15; 65.56; 65.29; 29.18.

Spectral data of 4,4-bis((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyloxazolidine
(Scheme 2.6, compound 26)

1
HNMR (400 MHz, CDCl
3
) 3.69 (s, 2H, ring-OCH
2
); 3.48-3.56 (q, 4H, -OCH
2
); 1.32
(s, 6H, Acetonide dimethyl); 0.85 (s, 9H, -
t
BuSi); 0.00 (s, 12H, Di-Me
2
Si).
13
C NMR (250 MHz, CDCl
3
) 94.62; 77.50; 76.99; 76.48; 69.28; 64.93; 28.60; 25.81;
18.18; -5.56; -5.59.

228

Spectral data of 1-(3,3-bis(((tert-butyldimethylsilyl)oxy)methyl)-1-oxa-4-azaspiro-
[4.5]decan-4-yl)butane-1,3-dione (Scheme 2.10, compound 56)

1
H NMR (400MHz, CDCl
3
) 3.76 (s, 2H); 3.66-3.62 (d, 2H, J=16.4 Hz); 3.54-3.50

d, 2H, J=16.4 Hz); 2.47-2.46 (d, 2H, J= 4 Hz); 1.99 (s, 3H); 1.97-1.38 (m, 10H);

0.61 (s, 18H); 0.21 (s, 12H).

Spectral data of (4,4-bis((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyloxazolidin-
3-yl)-2-diazobutane-1,3-dione.

1
H NMR(400 MHz, CDCl
3
) 4.00 (s, 2H, -CH
2
); 3.87-3.84 (d, 2H, J=12Hz, -OCH
2
);

3.71-3.74 (d, 2H, J=12Hz, -OCH
2
); 2.19 (s, 3H, Acetyl); 1.57 (s, 6H, -Acetonide di-

methyl); 0.80 (s, 9H, -
t
BuSi); 0.00 (s, 12H, Di-Me
2
Si);

Spectral data of 1-[3,3-bis-(tert-butyl-dimethyl-silanyloxymethyl)-1-oxa-4-aza-
spiro[4.5] dec-4-yl]-2-diazo-butane-1,3-dione (Scheme 2.10, compound 57)

1
H NMR(400 MHz, CDCl
3
) 3.88 (s, 2H); 3.74-3.72 (d, 2H, J=10 Hz); 3.63-3.60 (d, 2H,
J=10 Hz); 2.07 (s, 3H);1.85-1.82(tm, 2H, J
AX
=4.8 Hz, J
BX
=7.6 Hz; 1.67-1.64( d, J=12.4
Hz); 1.49-1.46 (bm, 5H); 1.43-1.41 (m, 1H); 0.70(s, 18H); 0.12 (s, 12H).
1-(4,4-bis((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyloxazoli- din-3-yl)-2-
diazoethanone

1
HNMR (250 MHz, CDCl
3
) 3.89 (s, 2H, ring-OCH
2
); 3.82-3.72 (m, 4H, -OCH
2
); 1.54

(s, 6H, Acetonide dimethyl); 0.83 (s, 9H, -
t
BuSi); 0.00 (s, 12H, Di-Me
2
Si).

13
C NMR (250 MHz, CDCl
3
) 62.59; 48.56; 26.03; 25.78; 18.21; -5.59;

1-[3,3-bis-(tert-butyl-dimethyl-silanyloxymethyl)-1-oxa-4-aza-spiro[4.5]dec-4-yl]-2-
diazo-ethanone (Scheme 2.10, compound 58)

1
H NMR (200 MHz, CDCl
3
) 5.3 (s,1H), 3.86(s, 2H), 3.79-3.74 (m, 4H), 1.59-1.48(m,

8H), 1.2-1.02(m, 2H), 0.82 (s, 18H), 0.00 (s, 12H).
229

7-(tert-butyldimethylsilyloxy)-7a-((tert-butyldimethylsilyloxy) methyl)-3,3-dimethyl-
dihydro-pyrrolo[1,2-c]oxazol-5(1H,3H,6H)-one (Scheme 2.6, compound 35)

1
HNMR (400 MHz, CDCl
3
) 4.29-4.279 (d, 1H, J=4.4Hz, -OCH
2
); 4.051-4.072(d, 1H,
J=8.4Hz, OCH
2
); 3.742-3.72(d, 1H, J=8.8Hz, -OCH
2
); 3.65-3.625 (d, 1H, J=9.6Hz, -
OCH
2
); 3.391-3.367(d, 1H, J=9.6Hz, -OCH
2
); 3.02-3.03 (dd, 1H, 4.4Hz, -OCH
2
); 2.24-
2.28(d, 1H, J=16Hz, -OCH
2
); 1.55 (s, 3H, Acetonide dimethyl) ; 1.45(s, 3H, Acetonide)
Cis-7'-((tert-butyldimethylsilyl)oxy)-7a'-(((tert-butyldimethylsilyl)oxy)methyl)dihy
dro-1'H-spiro[cyclohexane-1,3'-pyrrolo[1,2-c]oxazol]-5'(6'H)
(Scheme 2.10, compound 61)

Note: Spectral data collected with crude reaction mixture

1
H NMR (400 MHz, CDCl
3
)  4.28-4.27 (d, 1H, J=4.8 Hz); 4.00-3.98 (d, 1H, J=9.6 Hz);
3.72-3.70 (d, 1H, J=8.4 Hz); 3.63-3.61 (d, 1H, J=9.6 Hz); 3.37-3.34 (d, 1H, J=10.4 Hz);
3.08-3.04 (d, 1H, J=16.4); 2.30-2.26 (d, 1H, J=16.4); 0.86 (s, 9H); 0.849 (s, 9H (merged
with
t
Bu protons of the other CH activation product 51’); 0.05 (s, 3H); 0.04 (s, 3H); 0.008
(s, 3H); 0.001 (s, 3H).
3,3-bis(((tert-butyldimethylsilyl)oxy)methyl)hexahydro-2H-oxazolo[2,3-i]indol-
5(3H)-one (Scheme 2.11, compound 64)

1
H NMR (400 MHz, CDCl
3
) (for product from CH activation on cyclohexyl ring ) 4.26
(s, 2H); 3.99-3.96 (1H, d, J=10 Hz); 3.92-3.90 (d, 1H, J=9.6 Hz); 3.74-3.72 (d, 1H, J=10
Hz); 3.68-3.65 (d, 1H, J=10 Hz);
6-acetyl-7a-(((tert-butyldimethylsilyl)oxy)methyl)-3,3-dimethyl-1,7a-dihydropyrrolo
[1,2-c]oxazol-5(3H)-one (Scheme 2.13, compound 54)

1
H NMR (250 MHz, CDCl
3
) δ7.86-7.85 (d, 1H, J=2 Hz); 4.11-4.07 (d, 1H, J=8.5 Hz);
4.05-4.01 (d, 1H, J=10 Hz); 3.48-3.45 (d, 1H, J=8.5 Hz); 3.36-3.32 (d, 1H, J=10 Hz);
230

2.51 (s, 3H); 1.58 (s, 3H); 1.51(s, 3H); 0.85 (s, 9H); 0.05-0.04 (d, 3H, J=1.5 Hz); 0.03-
0.02 (d, 3H, J=1.75 Hz) ppm.
13
C NMR (250 MHz, CDCl
3
) δ154.67; 93.82; 74.16; 66.92; 64.97; 29.05; 28.96; 25.73;
22.82; -5.57; -5.60;
6-acetyl-3,3-bis(((tert-butyldimethylsilyl)oxy)methyl)hexahydro-2H-oxazolo[2,3-
i]indol-5(3H)-one (Scheme 2.11, compound 70)

1
H NMR (400 MHz, CDCl
3
) 3.97-3.95 (d, 1H, J=9.6 Hz); 3.87-3.84 (d, 1H, J=9.6 Hz);
3.75-3.72 (d, 1H, J=10.4); 3.69-3.66 (d, 1H, J=12.8); 3.68-3.66 (1H, d, J=10 Hz); 3.58-
3.50 (q, 1H, J=10 Hz); 2.84-2.79 (dd, 1H, J=12.8 Hz); 2.35 (s, 3H); 2.18-2.15 (d, 1H,
J=11.2 Hz); 1.72-1.58 (m, 5H ); 1.62 (s, 3H); 1.38-1.19 (m, 5H); 0.86 (s, 9H); 0.85 (s,
9H); 0.03 (s, 6H); 0.01 (s, 3H); 0.00 (s, 3H).
Spectral data of (S)-2-amino-3,3-dimethylbutan-1-ol
1
HNMR (400 MHz, CD
3
OD) δ3.82-3.79 (dd, J=14 Hz, 1H), 3.38(2H).
(3aR,7aR)-1-((trifluoromethyl)sulfonyl)hexahydro-1H-benzo[d]imi-dazol-2(3H)one
(Scheme 2.11, compound 51)

1H NMR (CDCl
3
) 5.6 (bs,1H), 3.75-3.68 (td,1H, J=12Hz), 3.37.3.30 (tt,1H, J=12Hz),
2.51-2.46 (dm, 1H, J=12Hz), 2.09-2.06 (1H, m, J=12Hz), 1.94-1.86 (dm, 1H, J=28Hz),
1.74-1.69 (qd,1H, J= 12.4Hz), 1.55-1.43 (m, 3H).
(3aR,7aR)-1-((trifluoromethyl)sulfonyl)hexahydro-1H-benzo[d]imi-dazol-2(3H)-one
(Scheme 2.11, compound 51)

1
H NMR (CDCl
3
,
400 MHz,): δ 7.49-7.36 (m, 8H), 7.25 (dd, 2H, J = 2.0 Hz, 8.0 Hz),
5.89 (br s, 1H), 5.01 (d, 1H, J = 3.5 Hz), 4.77 (d, 1H, J = 3.5 Hz) ppm;
231

13
C NMR (CDCl
3
, 400 MHz): δ 153.5, 139.3, 138.8, 129.7, 129.6, 129.6, 129.4, 126.4,
125.5, 119.0 (q, J = 321 Hz), 69.9, 62.4 ppm;
(R)- 3,5-dihydro-4H-Dinaphtho[2,1-d:1',2'-f][1,3]diazepin-4-one
1
H NMR (CDCl
3
,
400 MHz,): 9.64(s, 2H); 8.605(s), 7.207(t, 7.6Hz, 8Hz), 7.047(d,
7.6Hz), 6.971(d, 8Hz), δ8.605(s), 7.207(t, 7.6Hz, 8Hz), 7.047(d, 7.6Hz), 6.971(d, 8Hz),
13
C NMR (CD
3
OD) 68.69; 63.60; 49.52; 37.58
Complex with (3aR,7aR)-1-((trifluoromethyl)sulfonyl)hexahydro-1H-benzo[d]
imidazol -2(3H)-one and 1/3 equivalent of Rh
2
(OAc)
4

1
H NMR (400 MHz, DMSO-D6) 3.90-3.82 (t, 1H, J=2.4 Hz); 3.3-3.25 (m, 1H, J=10
Hz); 3.2-3.12 (m, 1H, J=2.8 Hz); 3.12-3.05 (1H, m, J=11.6); 3.08-2.98 (m, 1H, J=2.4
Hz); 2.90-2.75 (m, 1H, J=10.8 Hz); 2.52-2.26 (m, 2H, J=8.4 Hz); 2.10-1.74 (m, 8 H)
1.67-1.52 (m, 2H); 1.28 (m, 7H); 1.27-1.16 (tm, 3H, J=3.2 Hz); 1.13-0.97 (dm, 2H, J=8
Hz).
Spectral data of N-cyclohexylidene-1-phenylmethanamine

1
H NMR(200 MHz, CDCl
3
) 8.32 (s, 1H); 7.76-7.71 (dd, 2H, J=2.2 Hz, 9.8 Hz) 7.44-
7.39 (m, 3H, J=3.8 Hz, 10 Hz); 3.24-3.16 (m, 1H); 1.88-1.58 (m, 9H); 1.54-1.29 (m, 3H);
(Extra protons from starting material cyclohexyl amine).
13
C NMR (CDCl
3
) 131.43; 109.49; 103.15; 102.3; 101.36; 100.89; 100.65; 42.85; 23.05;
7.21; -1.50; -2.32; -2.54.

232

Spectral data of N-Benzylcyclohexanamine

1
H NMR(CDCl
3
) 7.36-7.34(m, 4H, J=9.2 Hz); 7.28-7.26 (m, 1H); 3.85 (s, 2H); 2.54-
2.49(m, 1H, J=6.4Hz); 1.97-1.94 (d, 1H; J=20 Hz); 1.79-1.35 (dt, J=4 Hz); 1.66-1.64
(J=10.8 Hz) 1.31-1.26 (m, 3H); 1.21-1.14 (m, 3H).
N-cyclohexyl-2-diazo-N-phenyl-2-(phenylsulfonyl)acetamide
(Scheme 2.13, Compound 70 )

1
H NMR(400MHz, CDCl
3
) δ4.91-4.81 (m, 1H, J=4.8 Hz); 2.41(s, 3H); 1.86-1.78 (m, 2H,
J=4 Hz); 1.70-1.60 (m, 2H, J=2.4 Hz); 1.48-1.44 (m, 2H); 1.43-1.41 (t, 1H, J=8.8 Hz);
1.41-1.37 (m, 1H, J=2.8); 1.36-1.31 (m, 1H); 1.31-1.18 (m, 2H); 1.21-1.14 (m, 3H).

233

2.7 Representative Spectra
Figure 2.28
1
H NMR of (S)-4-(3-(tert-butyldimethylsilyloxy)propyl)-2,2-dimethyl
oxazolidine (Scheme 2.3, compound 12)

234

Figure 2.29
1
H NMR of (S)-3-(2,2-dimethyloxazolidin-4-yl)propan-1-ol
(Scheme 2.3, compound 14)

235

Figure 2.30
1
H NMR of (S)-4-(3-((tert-butyldimethylsilyl)oxy)propyl)-2,2-
dimethyl oxazolidine (Scheme 2.3, compound 16)

236

Figure 2.31

1
H NMR of (S)-4-(3-(tert-butyldimethylsilyloxy)propyl)-2,2-dimethyl
oxazolidine (Scheme 2.3, compound 16)

237

Figure 2.32
1
H NMR of (S)-1-(4-(3-((tert-butyldimethylsilyl)oxy)propyl)-2,2-
dimethyloxazolidin-3-yl)-2-chloroethanone (Scheme 2.3, compound 17)

238

Figure 2.33
1
H NMR of (6S,7S,7aS)-7-(((tert-butyldimethylsilyl)oxy)methyl)-3,3-
dimethyl-6-(phenylsulfonyl)tetrahydropyrrolo[1,2-c]oxazol-5(3H)-one
(Scheme 2.3, compound 7)

239

Figure 2.34
1
H NMR of (2,2-dimethyloxazolidine-4,4-diyl)dimethanol
(Scheme 2.6, compound 25)

240

Figure 2.35
13
C NMR of (2,2-dimethyloxazolidine-4,4-diyl)dimethanol
(Scheme 2.6, compound 25)

241

Figure 2.36 COSY NMR of (2,2-dimethyloxazolidine-4,4-diyl)dimethanol
(Scheme 2.6, compound 25)

242

Figure 2.37
1
HNMR of 4,4-bis((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyl
oxa zolidine (Scheme 2.6, compound 26)

243

Figure 2.38
13
C NMR of 4,4-bis((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyl
oxazolidine (Scheme 2.6, compound 26)

244

Figure 2.39 COSY NMR of 4,4-bis((tert-butyldimethylsilyloxy)methyl)-2,2-
demithyloxazolidine (Scheme 2.6, compound 26)

245

Figure 2.40
1
HNMR of 1-(4,4-bis((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyl
oxazolidin-3-yl)-2-diazobutane-1,3-dione (Scheme 2.6, compound 29)

246

Figure 2.41
13
C NMR of 1-(4,4-bis((tert-butyldimethylsilyloxy)methyl)-2,2-
dimethyloxazolidin-3-yl)-2-diazoethanone (Scheme 2.6, compound 29)

247

Figure 2.42 COSY NMR of 1-(4,4-bis((tert-butyldimethylsilyloxy)methyl)-2,2-
dimethyloxa- zolidin-3-yl)-2-diazoethanone
(Scheme 2.6, compound 29)

248

Figure 2.43
1
H NMR of 1-[3,3-bis-(tert-butyl-dimethyl-silanyloxymethyl)-1-oxa-4-
aza-spiro [4.5] dec-4-yl]-2-diazo-etha none (Scheme 2.6, compound 30)

249

Figure 2.44
13
C NMR of 1-[3,3-bis-(tert-butyl-dimethyl-silanyloxymethyl)-1-oxa-4-
aza-spiro [4.5] dec-4-yl]-2-diazo-etha none (Scheme 2.6, compound 30)

250

Figure 2.45 COSY NMR of 1-[3,3-bis-(tert-butyl-dimethyl-silanyloxymethyl)-1-
oxa-4-aza-spiro [4.5] dec-4-yl]-2-diazo-etha none
(Scheme 2.6, compound 30)

251

Figure 2.46
1
H NMR of 7-(tert-butyldimethylsilyloxy)-7a-((tert-butyldimethyl
silyloxy)methyl-3,3-dimethyl-dihydro-pyrrolo[1,2-c]oxazol-
5(1H,3H,6H)-one (Scheme 2.6, compound 35) Cyclized product with
Rh
2
(OAc)
4

252

Figure 2.47 COSY NMR of 7-(tert-butyldimethylsilyloxy)-7a-((tert-butyldimethyl
silyloxy)methyl)-3,3-dimethyl-dihydro-pyrrolo[1,2-c]oxazol-
5(1H,3H,6H)-one (Scheme 2.6, compound 35)

253

Figure 2.48
1
H NMR of crude compound 7-(tert-butyldimethylsilyloxy)-7a-((tert-
butyldimethyl silyloxy)methyl-3,3-dimethyl-dihydro-pyrrolo[1,2-
c]oxazol-5(1H,3H, 6H)-one (Scheme 2.6, compound 25) Cyclized
product with Rh
2
(OAc)
4

254

Figure 2.49 CH activation product 25 with catalyst-Doyle dirhodium (Rh
2
(5R-
MEPY)
4

255

Figure 2.50
1
H NMR of crude CH activation product with premixed Rh
2
(OAc)
4

and ligand (3aR,7aR)-1-((trifluoromethyl)sulfonyl)hexahydro-1H-
benzo[d]imidazol-2(3H)-one

256

Figure 2.51
1
H NMR of CH activation product with premixed catalyst from (R)-4-
(tert-butyl)oxazolidin-2-one (40) and Rh
2
(OAc)
4

257

Figure 2.52
1
H NMR of CH activation product with premixed catalyst from (R)-4-
(tert-butyl)oxazolidin-2-one (40) and Rh
2
(OAc)
4

258

Figure 2.53
1
H NMR of 7-(tert-butyldimethylsilyloxy)-7a-((tert-butyldimethyl
silyloxy)methyl) -3,3-dimethyl-dihydro- pyrrolo[1,2-c]oxazol-
5(1H,3H,6H)-one Doyle dirhodium catalyst Rh(4S-MEOX)
4

259

Figure 2.54
1
H NMR of 3,3-bis-(tert-butyl-dimethyl-silanyloxymethyl)-1-oxa-4-
aza-spiro[4.5]dec-4-yl]-2-diazo-butane-1,3-dione

260

Figure 2.55 COSY NMR of 3,3-bis-(tert-butyl-dimethyl-silanyloxymethyl)-1-oxa-
4-aza-spiro[4.5]dec-4-yl]-2-diazo-butane-1,3-dione

261

Figure 2.56
1
H NMR of 1-[3,3-bis-(tert-butyl-dimethyl-silanyloxymethyl)-1-oxa-4-
aza-spiro[4.5]dec-4-yl]-butane-1,3-dione (Scheme 2.10, compound 45)

262

Figure 2.57
1
H NMR of 1-[3,3-bis-(tert-butyl-dimethyl-silanyloxymethyl)-1-oxa-
4-aza-spiro[4.5]dec-4-yl]-2-diazo-butane-1,3-dione
(Scheme 2.10, compound 47)

263

Figure 2.58
1
H NMR of 1-[3,3-bis-(tert-butyl-dimethyl-silanyloxymethyl)-1-oxa-
4-aza-spiro[4.5]dec-4-yl]-2-diazo-ethanone

264

Figure 2.59
13
C NMR of 1-[3,3-bis-(tert-butyl-dimethyl-silanyloxymethyl)-1-oxa-4-
aza-spiro[4.5]dec-4-yl]-2-diazo-ethanone

265

Figure 2.60 COSY NMR of 1-[3,3-bis-(tert-butyl-dimethyl-silanyloxymethyl)-1-
oxa-4-aza-spiro[4.5]dec-4-yl]-2-diazo-ethanone

266

Figure 2.61
1
H NMR of CH activation of 1-(3,3-bis(((tert-butyldimethylsilyl)oxy)
methyl)-1-oxa-4-azaspiro [4.5]decan-4-yl)-2-diazoethanone

267

Figure 2.62
1
H NMR of CH activation of 1-(3,3-bis(((tert-butyldimethylsilyl) oxy)
methyl)-1-oxa-4-azaspiro [4.5]decan-4-yl)-2-diazoethanone (Scheme
2.11, compound 51’)

268

Figure 2.63 CH activation with Tetrakis[N-phthaloyl (S)-phenylalaninato]
dirhodium ethylacetate

269

Figure 2.64
13
C NMR of CH activation with Tetrakis[N-phthaloyl (S)-phenyl
alaninato] dirhodium ethylacetate

270

Figure 2.65 (tetrakis[1{4-alkyl(C11-C13)phenylsulfonyl}-(2S)-pyrrolidine
carboxyl-ate]dirhodium (II)

271

Figure 2.66
1
H NMR of N-benzylidenecyclohexanamine

272

Figure 2.67
13
C NMR of N-benzylidenecyclohexanamine

273

Figure 2.68
1
H NMR of Benzyl-cyclohexyl-amine

274

Figure 2.69
1
H NMR of 2-Benzenesulfonyl-2-diazo-1-(2,2,5-trimethyl-oxazolidin-
3-yl)-ethanone

275

Figure 2.70 COSY NMR of 2-Benzenesulfonyl-2-diazo-1-(2,2,5-trimethyl-
oxazolidin-3-yl)-ethanone

276

Figure 2.71
13
C NMR of 2-Benzenesulfonyl-2-diazo-1-(2,2,5-trimethyl-oxazolidin-
3-yl)-ethanone

277

Figure 2.72
1
H NMR of Benzyl-cyclohexyl-amine

278

Figure 2.73 COSY NMR of Benzyl-cyclohexyl-amine

279

Figure 2.74
1
H NMR of N-phenyl-N-cyclohexyl-2-diazo-3-oxo-butyramide

280

Figure 2.75
1
H NMR of N-benzyl-N-cyclohexyl-2-diazo-2-(phenylsulfonyl)acet-
amide

281

Figure 2.76
13
C NMR of N-benzyl-N-cyclohexyl-2-diazo-2-(phenylsulfonyl)acet-
amide

282

Figure 2.77 COSY NMR of N-benzyl-N-cyclohexyl-2-diazo-2-(phenylsulfonyl)acet
amide

283

Figure 2.78 1-Benzyl-3-(phenylsulfonyl)hexahydro-1H-indol-2(3H)-one

284

Figure 2.79
1
H NMR of [1-Diazo-2-oxo-2-(2,2,5-trimethyl-oxazolidin-3-yl)-ethyl]-
phosphonic acid diethyl ester

285

Figure 2.80 COSY NMR of [1-Diazo-2-oxo-2-(2,2,5-trimethyl-oxazolidin-3-yl)-
ethyl]-phosphonic acid diethyl ester

286

Figure 2.81
1
H NMR of 2-diazo-2-(phenylsulfonyl)-1-(2,2,5-trimethyloxazolidin-3-
yl)ethanone

287

Figure 2.82 COSY NMR 2-diazo-2-(phenylsulfonyl)-1-(2,2,5-trimethyloxazolidin-
3-yl)ethanone

288

Figure 2.83
1
H NMR of 4,5-Diphenyl-imidazolidin-2-one

289

Figure 2.84
1
H NMR of (4R,5R)-4,5-diphenylimidazolidin-2-one

290

Figure 2.85
1
H NMR of (R)-1,11-dimethyl-5-((trifluoromethyl)sulfonyl)-5H-
dibenzo[d,f] [1,3] diazepin-6(7H)-one

291

Figure 2.86 Cosy NMR of (R)-1,11-dimethyl-5-((trifluoromethyl)sulfonyl)-5H-
dibenzo[d,f][1,3] diazepin-6(7H)-one

292

Figure 2.87
1
H NMR of 3H-dinaphtho[2,1-d:1',2'-f][1,3]diazepin-4(5H)-one

293

Figure 2.88
1
H NMR of (R)-3-((trifluoromethyl)sulfonyl)-3H-dinaphtho[2,1-
d:1',2'-f][1,3] diazepin-4(5H)-one

294

Figure 2.89
1
H NMR of (R)-3-((trifluoromethyl)sulfonyl)-3H-dinaphtho[2,1-
d:1',2'-f][1,3] diazepin-4(5H)-one

295

Figure 2.90 Cosy NMR of (R)-3-((trifluoromethyl)sulfonyl)-3H-dinaphtho[2,1-
d:1',2'-f][1,3] diazepin-4(5H)-one

296

Figure 2.91
1
H NMR of (S)-2-amino-3,3-dimethylbutan-1-ol

297

Figure 2.92
1
H NMR of 4-tert-Butyl-oxazolidin-2-one (Scheme 8, compound 40)

298

Figure 2.93
1
H NMR of 4S-tert-Butyl-oxazolidin-2-one (Scheme 8, compound 40)

299

Figure 2.94 COSY NMR of 4S-tert-Butyl-oxazolidin-2-one
(Scheme 8, compound 40)

300

Figure 2.95
13
C NMR of 4S-tert-Butyl-oxazolidin-2-one (Scheme 8, compound 40)

301

Figure 2.96
1
H NMR of 1-Trifluoromethanesulfonyl-octahydro-benzoimidazol-2-
one (Scheme 2.8, compound 50)

302

Figure 2.97
13
C NMR of 1-Trifluoromethanesulfonyl-octahydro-benzoimidazol-2-
one (Scheme 2.8, compound 50)

303

Figure 2.98 COSY NMR of
1
H NMR of 1-Trifluoromethanesulfonyl-octahydro-
benzoimidazol-2-one (Scheme 2.8, compound 50)

304

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309

Chapter 3: Preparation of NHC-Pd-II complex.
Application in the oxidative degradation of biomass into
formic acid

3.1 Introduction

The CH bond activation reactions of transition metals are well documented in
organometallic chemistry.
1-26
Many recent studies report that a large number of metal
complexes show selective C-H bond activation under mild conditions.
17,

27-30
Though an
extensive research work is been reported in this field, there is still an increasing demand
to develop methods and study mechanisms for a milder reaction conditions as the C-
metal bonds and catalysts are sensitive to harsh reaction conditions which are required to
break the C-H bonds.
1-31
Also, “the presence or formation of water during the reaction
often results in the deactivation of the catalyst”.
31
These challenges demand a water
compatible catalyst.

Reports show that N-heterocyclic carbene (NHC) ligands show better C-H
activation due to improved -donor coordination
32-40
It is also reported that NHC ligands
enhance the stability of many metals at different oxidation states and improve the ability
of C-H activation mostly in intramolecular reactions.
41-47
Not many examples of
intramolecular and catalytic reactions were reported. To overcome these draw backs, our
group has reported NHC-Pd-II complex 1 (Figure 3.1) which was prepared starting from
commercially available aminoethanol.
48,49

310

Figure 3.1: NHC-Pd 1

It was reported that NHC-palladium complex 1 is a thermally stable and reactive
catalyst that facilitates C-H activation of less reactive hydrocarbons.
48-49
Also, the high
stability of this complex in nucleophilic solvents such as water and alcohol allows for
conditions amenable to green chemistry and hydrothermal processes.
48-49
We found that
facile oxidative carbon-carbon bond cleavage of glycerol was demonstrated by the use of
hydrogen peroxide to afford formic acid as a safe (equation 1) and easily transportable
source of hydrogen for fuel cells.

Recently, the DFAFC (direct formic acid fuel cells) have been of increasing
interest compared with hydrogen and methanol based fuel cells because of their ease of
refuelling, efficiency. As an emerging technology, DFAFC are currently being tested by
major producers of portable electronics in phones, laptops, and computers.
50-58
With
continuing development, there is a great potential for DFAFC to challenge traditional
batteries as power sources for mobile electronic devices and large-scale applications of
DFAFC technology are expected to follow.

311

Glycerol, which is widely available and rich in functionality, can be found
naturally in the form of fatty acid esters. It is also a large by-product of biodiesel
production and traditional soap manufacturing processes. Therefore use of glycerol for
the synthesis of value-added chemicals has great industrial importance. In particular, the
oxidation of glycerol could produce potentially valuable C2 ~ C3 chemical products such
as glyceraldehydes, glyceric acid, hydroxypyruvic acid, tartronic acid, glycolic acid, and
oxalic acid. Although a number of studies dealing with the metal supported catalytic
partial oxidation of glycerol to acquire C2 ~ C3 products has been reported, the formation
of C1 products such as formic acid is still being explored.
59-67

The present work describes the preparation of NHC-Pd-II complex (1) and its
application in the oxidative degradation of biomass such as glycerine, carbohydrates and
grass. Possible reaction mechanisms in the oxidative degradation of glycerine to formic
acid involved are discussed.
3.2 Results and Discussion
3.2.1 Preparation of NHC-Pd complex

In the present work, NHC-Pd-II complex (1) was prepared starting from
commercially available methoxyethylamine (Scheme 1). Bromoacetylation of
methoxyethylamine gave the bromoamid derivative 3 which on treatment with
benzimidazole lead to the amide 4. The amide on reflux with methyl iodide in
tetrahydrofuran lead to the methyl iodide salt 5 following by complexation with silver
and then, transmetallation with palladium-II gave the NHC-Pd-II complex 1 (Scheme 1).
312

Scheme 3.1: Preparation of NHC-Pd complex 1

3.2.2 Direct Conversion of biomass such as Glycerol into Formic Acid via Water
Stable Pd(II) Catalyzed Oxidative carbon-carbon Bond Cleavage

Initially, to evaluate the feasibility of an oxidative palladium-catalyzed carbon-
carbon bond cleavage of glycerol to obtain formic acid, we investigated the role of the Pd
source and oxidant. The reaction in the presence of NHC-Pd complex 1 and hydrogen
peroxide at room temperature for 6 hours consumed 41% of glycerol and provided formic
acid (8.05 x 10
-5
mol) and glycolic acid (3.50 x 10
-5
mol) against the initial glycerol
content (10.8 x 10
-5
mol) (entry 1, Table 1). Using tert-butyl peroxide and oxone, the
conversion to cleavage reaction products was very low (entries 2 and 3). We found that
the reaction did not proceed at all by use of K
2
S
2
O
8
and molecular oxygen as oxidizing
reagents (entries 4 and 5). In addition, in the presence of PdCl
2
or Pd(OAc)
2
with
hydrogen peroxide, the conversions were lower than those using NHC-Pd complex 1
313

(entries 6 and 7). From these results, we determined that NHC-palladium complex 1-
hydrogen peroxide system is a valuable catalyst-oxidant system, for generating formic
acid from glycerol (Table 1).

Table 3.1 Catalytic oxidative Carbon-Carbon bond cleavage of glycerol with various
oxidizing agents in the presence of 1 at r.t.
a

EEntry Entry

Oxidant

Catalyst
Glycerol
Conv.
(%)
[Product]x10
-5
mole
d

Glycolic acid Formic acid
1
2
b

3
b
4
b

5
c

6
7
8
H
2
O
2

t-BuO
2
H
b
Oxone
K
2
S
2
O
8

O
2

H
2
O
2

H
2
O
2
PhI(OAc)
2
b
1
1
1
1
1
PdCl
2

Pd(OAc)
2
1
41
-
35
26
n.r.
trace
6
n.r.
3.50
-
0.61
-
-
trace
0.16
-
8.05
-
1.14
-
-
trace
0.20
-

a
All reactions were performed with glycerol (10 mg, 10.8 x10
-5
mol), Pd catalyst (5
mol%), and 30% H
2
O
2
(400 mL) in H
2
O (100 mL) at room temperature for 6 hrs. [b] in
H
2
O (400 mL). [c] Continuous flow with O
2
[d] The conversion was determined by
1
H
NMR spectra with internal standard (MeOH).
b
Reaction was also performed at 60
o
C for
3 hr. Note: n.r. = no reaction.
3.2.3 Catalytic oxidative carbon-carbon bond cleavage of glycerol with Oxygen
and additives agents in the presence of 1 at RT

Oxidative degradative reactions of glycerol were also performed with NHC-Pd
complex 1 and different metallic as well as non metallic additives in the presence of
oxygen. But none of these reaction conditions showed any oxidative degradation product.
The reactions performed in the presence of oxygen in a closed bomb system at room
temperature as well as at 60
o
C did not undergo oxidative degration (Table 2).

314

Table 3.2 Oxidative degradation reactions of glycerol with oxygen in presence of
metallic and nonmetallic additives.
a

Entry Metallic additive
(mole %)
Temperature
(
o
C)
Time
(h)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
CuI (1.5)
CuCO
3
(1.2)
CuCO
3
(1.2)
Mn(C
2
H
3
O
2
)
2
(5.3)
Mn(C
2
H
3
O
2
)
2
(5.3)
Mn(C
2
H
3
O
2
)
2
(9)
Al
2
O
3
(10)
Al
2
O
3
(10)
SiO
2
(10)
SiO
2
(10)
CuCl
2
(12)
CuO (10)
FeSO
4
.7H
2
O (12.1)
FeSO
4
.7H
2
O (12.1)
Cu
2
O (5.72)
Cu
2
O (5.72)
CrCl
2
(5.72)
CrCl
2
(5.72)
Co(acac)
3
(1.76)
Co(acac)
3
(1.76 )
CeCl
3
(5.9)
CeCl
3
(5.9)
FeSO
4
(5.9)
FeSO
4
(5.9)
FeCl
3
(5.9)
FeCl
3
(5.9)
AgOTs (10)
RT
RT
60
0
RT
60
RT
60

RT
60
60
RT
RT
60
RT
60
RT
60
RT
60
RT
60
RT
60
RT
60
RT
8
5
5
5
10
10
5
5
5
5
5
5
10
10
10
10
10
10
10
10
10
10
3
3
3
3
5
a
All the reactions were performed with glycerol (10 mg, 1.086X10
-4
moles), NHC-Pd (1)
(2.36 mol %) in 0.4 ml D
2
O in presence of O
2
(150 psi); Reactions were also performed
in DMSO. Product was not observed in none of the above reaction conditions.

3.2.4 Optimization of reaction condition for the oxidative degradation of glycerine
to formic acid:

To obtain optimal reaction conditions, we investigated the oxidative C-C cleavage
reactions of glycerol (10.8 x 10
-5
mol) with 30 % hydrogen peroxide and NHC-Pd
complex 1 (5 mol%) by screening reactions with various hydrogen peroxide
315

concentrations, reaction temperatures, and reaction times. As depicted in Figure 3.2 (A),
by increasing the hydrogen peroxide concentration at 40
o
C, the cleavage reaction of
glycerol also produced formic acid and glycolic acid in increased amounts. However, by
using an elevated reaction temperature (50 to 60
o
C), the yield of formic acid was not
improved although glycerol was significantly consumed (Figure 3.2B). Additionally, a
longer reaction time was not sufficient to enhance the formation of formic acid (Figure
3.2 C). From these results, we determined that: i) the generation of formic acid was
achieved through the formation of glycolic acid as an oxidized intermediate, ii) over-
oxidation of formic acid or glycolic acid could occur at an elevated temperature and
longer reaction time.

Figure 3.2: Glycerol to formic acid-optimization of reaction conditions . Glycerol (red
square), Formic acid (blue diamond), and Glycolic acid (green triangle).
[Glycerol] = 10.8 ×10
-5
moles, NHC-Pd (II): 5 mol%.

Based on the above results, we considered that the controlled oxidation of
glycerol is important in order to improve the yields of formic acid. In an experiment
designed to study the time and temperature dependence of slow addition with hydrogen
peroxide, a solution of glycerol in the presence of NHC-Pd complex 1 (5 mol%) in H
2
O
316

(100 mL) was reacted by slow addition of hydrogen peroxide and
1
H-NMR spectra of the
reactions at different conditions are exhibited in Figure 3 to compare relative reactivity.
As shown in Figure 3.3 (B and C), the conversion of formic acid and glycolic acid by
slow addition of hydrogen peroxide was increased to 20% and 72%, respectively, versus
the one pot addition at 60
o
C for 6 hours, respectively. However, glycolic acid still
remained, although glycerol was completely consumed under this set of conditions.
Although the conversion to formic acid and glycolic acid was also improved using slow
addition of hydrogen peroxide at 0
o
C for 3 hrs and then remaining at room temperature
for 8 hrs, glycerol was not completely consumed as shown in Figure 3.3 (D). However,
when the sequential slow addition at 0
o
C for 3 hrs and 60
o
C for 3 hrs was utilized, we
found that the substrate was entirely converted to formic acid without any glycerol and
glycolic acid present (Figure 3.3E). The slow addition of hydrogen peroxide could
therefore avoid formation of carbon dioxide via over oxidation of formic acid and
glycolic acid. Though we did not observe the formation of oxalic acid, it is possible that
oxalic acid formed could easily be oxidized to carbon dioxide under the given conditions
(equation 2).

OH
OH
HO
(1)
2HCO
2
H + CO
2
(2)
H
2
O
2
RT-60
o
C
OH
O
HO
OH
O
HO
O
+
+
317

Figure 3.3:
1
H NMR study for the degradation pathway of glycolic acid (A) [glycerol] =
10.8 x 10
-5
mol. (B) 400 L H
2
O
2
for 6 hr at 60
o
C, (C) 400 L H
2
O
2
for 6
hr at 60
o
C for 6 hr slow addition. (D) 400 L H
2
O
2
for 6 hr at 0
o
C for 3 hr
slow addition and stirred for 8 hr at r.t. (E) 300 L H
2
O
2
at 0
o
C for 3 hr
slow addition and 200 L H
2
O
2
for 3 hr slow addition.

As shown in equations 2 and 3, we identified that glycolic acid and formic acid
were easily converted to carbon dioxide in the presence of NHC-Pd complex 1 and
hydrogen peroxide at 60
o
C for 3 hrs. However, an initial reaction at a low temperature
was necessary to reduce formation of carbon dioxide.

318

Subsequently, we found that glycerol was entirely converted to formic acid by
sequential slow addition of hydrogen peroxide after changing the reaction temperature
from 0
o
C to 60
o
C as predicted in Table 3.3 (entry 10). With this optimal condition, we
then reevaluated the effect of the palladium catalyst. Without NHC-Pd catalyst 1, the
reaction did not proceed (Table 3.3, entry 26). In the case of PdCl
2
and Pd(OAc)
2
, the
conversions were unsatisfactorily low (Table 3.3, entries 27-30). These results imply that
our NHC-Pd catalyst system is efficient for this oxidative carbon-carbon bond cleavage
reaction due to its stability in aqueous conditions. Therefore, the catalytic reaction was
not inhibited by coordination of water to palladium.
Table 3.3 Typical results of catalytic oxidative C-C cleavage of glycerol.
a

Entry

Catalyst

Reaction
conditions

Glycerol
Conversion
c
(%)
Product x 10
-5

(mole)
c
Formic
acid
Glycolic
acid
1 1 30 % H
2
O
2
(100 l)
40
o
C, 1 hour
63.4 2.97 0.71

2 1 30 % H
2
O
2
(100 l)
40
o
C, 2 hour
86.4 0.88 0.28
3 1 30 % H
2
O
2
(100 l)
40
o
C, 2 hour
91.89 1.7 0.44

4 1 30 % H
2
O
2
(400 l)
40
o
C, 3 h
97.2 3.98 1.57

319

Table 3.3, continued
5 1 30 % H
2
O
2
(400 l) 40
o
C, 6 h
96.8 7.97 1.75
6 1 30 % H
2
O
2
(400 l)
slow addition, 0
o
C, 3
h
87.9 17.12 2.68
7 1 30 % H
2
O
2
(400 l) 0
o
C, then at 60 for 3 h
67.2 3.74 0.81
8 1 30 % H
2
O
2
(400 l)
slow addition at 0
o
C 6
h
75 1.27 4.25
9

1 30 % H
2
O
2
(400 l)
slow addition, 0
o
C, 3
hours. Then, stirred at
RT for 6 hours and
then,
30 % H
2
O
2
(200 l)
slow addition, 60
o
C, 3
hours.
80.8 6.54 3.44
10 1 30 % H
2
O
2
(300 l)
slow addition, 0
o
C, 3
h
+ 30 % H
2
O
2
(200 l)
slow addition, 60
o
C, 3
h
100 14.76 -
11 1 30 % H
2
O
2
(300 l)
slow addition, 0
o
C, 3
h + 30 % H
2
O
2
(100
l) slow addition, 60
o
C, 3 h
81.2 7.47 2.04
12 1 30 % H
2
O
2
(300 l)
slow addition, 0
o
C, 3
h
+ 30 % H
2
O
2
(100 l)
slow addition, 60
o
C, 6
h
93.94 6.37 1.24
13 1 30 % H
2
O
2
(600 l)
slow addition, 40
o
C, 1
h
89.0 4.28 1.13

320

Table 3.3, continued
14 1 30 % H
2
O
2
(400 l) slow
addition, 0
o
C, 3 hours. Then, 3
hours at 40
o
C.
77.0 5.06 2.51
15 1 30 % H
2
O
2
(400 l) slow
addition, 0
o
C, 3 hours. Then,
stirred for 3 hours at 60
o
C.
82.97 3.82 3.19
16 1 30 % H
2
O
2
(400 l) slow
addition, 0
o
C, 3 h. Then,
stirred for 8 h at RT, then,
heated at 60
o
C for 3 h.
94.45 5.19 0.98

17 1 30 % H
2
O
2
(400 l) slow
addition at RT, 3 hours and
then, continued stirring at RT
for 1 hour.
86.69 4.0 1.62
18 1 30 % H
2
O
2
(400 l) slow
addition, RT, 3 h then, stirred
at RT for 1 h
84.8

4.45 2.24
19 1 30 % H
2
O
2
(400 l) slow
addition, 40
o
C, 3 hours, then,
stirred at 40
o
C for 1 hour

87.62
4.97

0.89
20 1 30 % H
2
O
2
(400 l) slow
addition, 0
o
C, 3 hours, then,
stirred at 40
o
C for 1 hour
96.6

3.84 0.76
21 1 30 % H
2
O
2
(400 l) slow
addition, 0
o
C, 3 hours, then,
stirred at RT for 8 hours
83.7

5.82 1.25
22 1 30 % H
2
O
2
(400 l) slow
addition, 40
o
C, 6 hours. Then,
stirred for 1 hour at 40
o
C

90.33

3.98 0.42

321

Table 3.3, continued
23

1 30 % H
2
O
2
(600 l) slow
addition, 40
o
C, 1 hour.
Then, stirred for 1 hour
at 40
o
C

95.30

4.6

0.60
24

1 30 % H
2
O
2
(500 l) slow
addition, 60
o
C, 3 hours.
100 6.66

2.07

25 1 30 % H
2
O
2
(400 l) slow
addition, 60
o
C, 1 h
94.5 6.69 2.24
26 - 30 % H
2
O
2
(300 l) slow
addition, 0
o
C, 3 h
+ 30 % H
2
O
2
(200 l)
slow addition, 60
o
C, 3 h
- - -
27 PdCl
2
30 % H
2
O
2
(300 l) slow
addition, 0
o
C, 3 h
+ 30 % H
2
O
2
(200 l)
slow addition, 60
o
C, 3 h
7.0 0.17 0.29

28

Pd(OAc)
2

30 % H
2
O
2
(300 l) slow
addition, 0
o
C, 3 h
+ 30 % H
2
O
2
(200 l)
slow addition, 60
o
C, 3 h
11.0 0.32 0.41
29 PdCl
2
30 % H
2
O
2
(300 l) slow
addition, 0
o
C, 3 hours
40.2 4.8 1.0

322

Table 3.3, continued
30 Pd(OAc)
2
30 % H
2
O
2
(300 l) slow
addition, 0
o
C, 3 hours
- - -
31 1 D
2
O (400 l) - - -
[a] All reactions were performed with glycerol (10 mg, 10.8 x10
-5
mol), Pd
catalyst (5 mol %), and 30% H
2
O
2
(400 mL) in H
2
O (100 mL).
[b] Continuous flow with O
2
[c] The conversions were determined by
1
H NMR
spectra with internal standard (MeOH).
3.2.5 Oxidative degradation of
13
C labeled glycerol:

Furthermore, to understand the oxidative carbon-carbon bond cleavage pathway
of glycerol, we demonstrated the degradation reaction using 1,3-
13
C-labeled glycerol and
2-
13
C-labelled glycerol. The reactions of
13
C-labeled glycerols 4 and 5 were followed by
slow addition of hydrogen peroxide at 60
o
C for 6 hrs in the presence of NHC-Pd
complex 1. As shown in Figure 3, the reaction of 1,3-
13
C-labeled glycerol (6) afforded
both
13
C-labelled formic acid and unlabelled formic acid in a 2:1 ratio, as well as trace
amount of
13
C-labeled glycolic acid on the second carbon position. In the case of 2-
13
C-
glycerol (4), a 1:3 ratio of
13
C-formic acid to unlabeled normal formic acid, as well as
13
C-glycolic acid (5) on the carbonyl carbon were provided. In addition,
13
C-NMR
analysis further confirmed the assignment by
13
C-
12
C coupled for
13
C-glycolic acid (5) [d
= 176.3 and 175.6] and (7) [d = 63.0 and 62.3]. These result indicate that the formic acid
is formed from all the carbons from glycerol. One equivalent of glycerol is converted into
one equivalent of glycolic acid and one equivalent of formic acid. When glycolic acid is
involved in the oxidative degradation pathway, one equivalent of glycolic acid gives once
323

equivalent of formic acid. The carboxylic group of glycolic acid is converted into carbon
dioxide.
1
H NMR of oxidative degradation of
13
C labeled glycolic acid showed that the
carboxylic part of glycolic acid does not make formic acid.
Table 3.4 Oxidative degradation of
13
C labeled glycerol
a
Entry Reaction Conditions
1

13
C
2
-Glycerol 10mg, NHC-Pd 4 mg, 0.3 mL H
2
O
2
slow addition at 0
o
C
for 3 hours, then, 0.2 mL at 60
o
C for 3 hours

2

13
C
2
-Glycerol (2.4 mg, 2.5x10
-5
moles), NHC-Pd Cat (10 mg, 2.57x10
-5

moles). sealed J. Young NMR tube, sonicator 0.5 hour. Peak observed
at 9.2 ppm
3

13
C
1,3
-Glycerol 2.4 mg, NHC-Pd 10mg, D
2
O sealed J. Young NMR
tube, sonicator 0.5 hour. Peak observed at 9.2 ppm
4

13
C
2
-Glycerol 10mg, 0.3 mL H
2
O
2
for 3 hours at 0
o
C and 0.2 mL all at
once. Continued heating at 60
o
C for 3 hours.
5
13
C
2
-Glycerol 10mg, NHC-Pd 4 mg, 0.3 mL H
2
O
2
for 3 hours at 0
o
C
then,0.2 mL H
2
O
2
for 3 hours at 60
o
C.
6
13
C
1,3
-Glycerol, NHC-Pd , 0.3mL H
2
O
2
at 0
o
C for 3 hours; then, 0.2
mL H
2
O
2
at 60
o
C for 3 hours
[a] All reactions were performed with glycerol (10 mg, 10.8 x10
-5
mol), NHC-Pd catalyst
1 (5 mol %), and 30% H
2
O
2
in H
2
O (100 mL).

Consequently, this result indicates that the formation of formic acid could involve
oxidation of the secondary carbon as well as the primary carbons of glycerol. Also, we
found that carbon dioxide was generated via thermal over-oxidation of formic acid. On
the basis of these results, we would like to suggest a plausible reaction pathway as shown
in Figure 4. Many oxidative carbon-carbon cleavage reaction mechanisms of diols with
different metals have been previously proposed.
61-67
We believe that the results obtained
from the present work can be rationalized by the involvement of a palladium
hydroperoxo species (Pd-OOH). Metal-hydroperoxo species (M-OOH) have been
324

Figure 3.4:
1
H-NMR spectra for the oxidative degradation reaction of 1,3-
13
C-glycerol (A)
and 2-
13
C-glycerol (B)

325

proposed as key intermediates of metal catalyzed alcohol oxidation reactions.
68-78
In the proposed plausible reaction pathway, an NHC-Pd-alkoxide:HCl complex is
formed from NHC-Pd-OOH and an alcohol followed by -hydrogen elimination to
liberate a carbonyl compound and form a NHC-Pd-hydride (HCl) species.
79-81
This NHC-
Pd-hydride species can reductively eliminate to reduce hydrogen peroxide to water and
simultaneously oxidize and cleave the C-C bond to afford glycolaldehyde and formic acid
from glyceraldehyde or glycolic acid and formaldehyde from dihydroxyacetone.
Both glycolaldehyde and formaldehyde were further oxidized to glycolic acid and
formic acid, respectively. Glycolic acid was then converted to formic acid by further
oxidative cleavage with palladium and hydrogen peroxide. Finally, the generated formic
acid was transformed to carbon dioxide via thermal oxidation in the presence of NHC-Pd
compound and hydrogen peroxide. Dihydroxy acetone formed from glycerol can be
equilibrated to glyceraldehyde through a Lewis acid coordination of NHC-Pd. Then, an
alternative C-C bond cleavage could also be thought to originate from retro-aldol reaction
(Figure 3.5) of 2,3-dihydroxy propionaldehyde, 2,3-dihydroxy propionic acid to give
glycolaldehyde and glycolic acid, respectively along with formaldehyde. Oxidation of
glyceric acid leads to tartronic acid, and in some cases C-C cleavage to form glycolic
acid, oxalic acid and carbon dioxide is observed.
82-87

326

[O]
HCHO +
retro-
aldol
HO
O
H
[O]
2 HCO
2
H CO
2
HO OH
OH
Pd H
2
O
2
HO O
OH
HO O
OH
OH
HCHO + HO
O
OH
retro-
aldol
HCO
2
H CO
2
+
[O]
[O]

Figure 3.5: A plausible carbon-carbon bond cleavage process of glycerol via retro-aldol
reaction

3.2.6 Proposed mechanism:

A plausible mechanism is proposed based on the results of NHC-Pd 1 catalyzed
oxidative degradation of glycerol with hydrogen peroxide. The number of equivalents of
formic acid formed is greater than two equivalents and less then three equivalents from
one equivalent of glycerol. This shows that both primary and secondary alcohol groups of
glycerol are oxidized first during oxidative degradation. Here, we report a new oxidative
carbon-carbon bond cleavage reaction protocol for the production of formic acid from
glycerol and propose a reaction pathway.
3.2.6.1 Proposed mechanism when the primary alcohol group of glycerol is
oxidized first:
A mechanism is proposed when the primary alcohol of glycerol is oxidized first
(Figure 3.6). Two possible pathways or either of the pathways can be possible in the
oxidation of glycerol to glyceraldehyde (Figure 3.6). In one of the pathways, glycerol
reacts with NHC-Pd 1 complex to form alkoxy NHC-Pd complex (12). Hydride
327

migration in complex 12 leads to NHC-Pd hydride complex 13 giving glyceraldehyde 14.
However, in the other pathway NHC-Pd complex 1 can react with hydrogen peroxide to
give NHC-Pd hydroperoxide complex 11. The hydroperoxide complex 11 can oxidize the
primary alcohol group in glycerol to glyceraldehyde. A hydride migration can occur
during the oxidation to give NHC-Pd hydride complex 13 and glyceraldehyde 14.
Complex 13 oxidatively degrdades glyceraldehyde through an alkoxy complex 15 giving
NHC-Pd hydride 13, formic acid (first equivalent of formic acid) and glycolaldehyde 16.
Complex 13 forms complex 17 with glycolaldehyde 16 in presence of hydrogen peroxide.
Complex 17 oxidatively degrades to formic acid (second equivalent of formic acid),
formaldehyde giving either complex 13 or complex 18. Formaldehyde is oxidized to
formic acid through an alkoxy complex 19. Complex 20 can also be made either from
complex 11 or complex 13 which on oxidatively cleaved to give glyceraldehyde. This
mechanism explains the formation of three equivalents of formic acid from one
equivalent of glycerol through the formation of glyceraldehyde as the initial oxidized
product (Figure 5). When an experiment was run with NHC-Pd complex 1 and glycerol
in a 1:1 ratio, formation of glyceraldehyde was not observed. This indicates that
glyceraldehyde is formed through the formation of hydroperoxide complex.

328

Figure 3.6: Proposed mechanism when primary alcohol group of glycerol is oxidized
first
N
N
Pd
N
O
Cl
O
Me
N
N
Pd
N
O
Cl
Me
N
N
Pd
N
O
Me
OH
H
H
OH
O
H
HCl
N
N
Pd
N
O
Me
HCl
O
OH
H
O
O
H
O
H
H
H O
H
N
N
N
O
Me
O
Pd
N
N
N
O
Me
O
O
O
Pd
H
HCl
H
H
O
O
H
H
N
N
Pd
N
O
Me
O
O
O
H
OH
15
17
N
N
N
O
Me
Pd
H
HCl
O
H
O
O
H
O
H H
O
H
HCl
HCl
N
N
N
O
Me
Pd
HO
HCl
O
O
H H
H
2
O
2
N
N
N
O
Me
Pd
HCl
O
O
H
HO H
19
O
CH
3
OH
O
H
OH
H
N
N
Pd
N
O
Cl
Me
O
CH
3
OH
O
H
N
N
Pd
N
O
Me
HCl
O
O
H
O
H
O
CH
3
H
OH
OH
1
11
O
CH
3
13
HCl
H
3
C
12
HCO
2
H H
O H
HCl
O
HO
O H
H
OH
13
18
HCO
2
H
13
14
16
H
N
N
Pd
N
O
O
O
HCl
H
OH
OH
H
20
H
2
O
2
Glycerol
HCO
2
H
H
3
C
329

3.2.6.2 Proposed mechanism when the secondary alcohol group of glycerol is
oxidized first :
A mechanism is proposed when the secondary alcohol of glycerol is oxidized first
(Figure 6). Two possible pathways or either of the pathways can be involved in the
oxidation of glycerol to dihydroxyketone (Figure 3.7). In one of the pathways, glycerol
reacts with NHC-Pd complex 1 to make alkoxy NHC-Pd complex (20). Hydride
migration in complex 20 leads to dihydroxyacetone 21 and hydride complex 13 or
Formaldehyde oxidizes to give the first equivalent of formic acid and glycolic acid from
dihydroxyacetone 21 (Figure 3.7).
Figure 3.7: Proposed mechanism if the secondary alcohol group of glycerol is oxidized
first
330

3.2.6.3 Proposed mechanism glycolic acid to formic acid:
Glycolic acid is oxidized to formic acid and carbon dioxide either through the
formation of the complex 23 or the complex 24 (Figure 3.8). Glycolic acid can also be
oxidized by an alternative mechanism via the formation of a complex 25 (Figure 3.9).

Figure 3.8: Proposed mechanism for the oxidation of glycolic acid to formic acid

331

Figure 3.9: Proposed mechanism for the oxidation of glycolic acid to formic acid
3.2.7 Studies to support the proposed mechanism
3.2.7.1 Studies on the oxidative degradation of different substrates with NHC-Pd 1
and H
2
O
2
to propose the mechanism for the conversion of glycerol into
formic acid:

Scheme 3.2: Oxidative degradation of different substrates with NHC-Pd 1 and H
2
O
2

332

Monitoring oxidative degradation of tartaric acid, malic acid and mandelic acid
did not show the formation of formic acid (Table 3.5, entries 1-5) and
1
H and
13
C NMR
show that the carboxylic group is converted into carbon dioxide without the formation of
formic acid. These reactions explain that there is no hydride transfer from α-carbon to
carboxylic group inorder to make formic acid. Glyoxal and glyoxylic acid monohydrate
on oxidation lead to formic acid Table 3.5, entries 6,7).
Table 3.5 Oxidative degradation of different hydroxyl substrates

Entry

30% H
2
O
2
(mL), Time (hr)
Temperature (
o
C)

Reaction
Condition

Product
(%)

Unreacted
Substrate
(%)

1 Tartaric acid (6.66x10
-5
)
a
RT, 1 hr - 15.4
2 L-Malic acid
a
219 RT, 1 hr - -
3 Mandelic acid
b
RT, 12 h
c
- 70.15
4 Mandelic acid(1.085x10
-5
)

d

d
Benzoic acid -
5 Glyoxal (1.72x10
-5
)
e
RT, 1 hr Formic acid
(15)
-
6 Glyoxal (1.72x10
-5
)
e
0
o
C,3h then,
RT, 6h
Formic acid
(22.5)
-
7 Glyoxal (1.72x10
-5
)
d
Formic acid
(98.8)
-
8 Glyoxylic acid
monohydrate
(1.08x10
-5
)
RT, 1 hr Formic acid
(11.9)
-
9 Glyoxylic acid
monohydrate
(1.08x10
-5
)
f
0
o
C, 3 h Formic acid
(42)
-

333

Table 3.5, continued
10 Glyoxylic acid
monohydrate
(1.08x10
-5
)
g

RT, 12 h - 100
11 Glycolic acid (1.315x10
-
4
)
h

h
Formic acid
(33)
19.80
12 Glycolic acid (6.58x10
-
5
)
i

60
o
C, 3 h Formic acid
(50)
34.00
13 Ethylene glycol
(1.611x10
-4
)
j

60
o
C, 3 h Formic acid
(6.87)
2.43
14 Ethylene glycol
(1.611x10
-4
)
k

0
o
C, 1 h Formic acid
(1.8)
4.96
15 Ethylene
glycol(1.611x10
-4
)

d
Formicacid
(17.17)
Glycolic acid
(1.7)
Glycolaldehyde
(3.4)
2.24

16 Formic acid (2.17x10
-4
)
l
RT, 3 h - >99
17 Formic acid (3.56x10
-4
)
n
60
o
C, 5 h - 9.7
18 Sodium formate
(1.47x10
-4
)
i
RT, 12 h - 38
19 Benzoic acid
m
60
o
C, 12 h - ~100
20 Formaldehyde solution
(1.29x10
-4
)
n
0
o
C, 2 h Formic acid
(80.5)
-
21 Oxalic acid
d
- -
22 Methanol (2.45x10
-5
)
n
RT, 12 h
1
H NMR
showed
formic acid
50

334

Table 3.5, continued
23 Acetone (20 µL)
o
RT, 24 h Formic acid,
acetic acid
*
24 Pinacol (8.46x10
-5
) RT, 6 h - *
25 Pinacol (8.46x10
-5
)
p
60
o
C, 1 h Formic acid
(9.3) Acetic
acid
*
26 3-Hydroxy-butan-2-one RT, 36 h
q
Butane-2,3-
dione,
acetic acid
*
27 3-Hydroxy-butan-2-one 60
o
C, 12 h
q
Butane-2,3-
dione,
acetic acid
*
28 1-Phenyl-ethane-1,2-
diol (7.24x10
-5
)

d
Formic acid
(28%)

-
29 1,3-Propanediol
(1.32x10
-4
)
r
RT, 6 h *
30 1,3-Propanediol
(1.32x10
-4
)

d
*
31 4-phenylbutanol
(6.67x10
-5
)
60
o
C, 3 h
r
Formic acid
(13)
May oxidized
compounds
15.3
32 4-phenyl-2-butanol
(6.67x10
-5
)
60
o
C, 3 h
r
Formic acid
(19.2)
May oxidized
compounds
-

335

Table 3.5, continued
33 (2,2-dimethyl-1,3-
dioxolan-4-yl)
(8.33x10
-5
)
r
RT, 1 h Formic acid (5),
glycolic acid
(10)
~59.3
a
NHC-Pd 1 (1.03x10
-5
moles), H
2
O
2
(0.1 mL); NP =
1
H NMR did not show formation of
formic acid after 1 hr at RT;
b
Mandelic acid (0.010 g), NHC-Pd 1 (0.002 g), H
2
O
2
(0.4
mL);
c
0.3 mL H
2
O
2
;
d
0.3 mL H
2
O
2
at 0
o
C. Then, 0.2 ml for 3 hr at 60
o
C. NHC-Pd (4
mg);
e
0.1 mL H
2
O
2
in a closed system.
f
0.3 mL 30 % H
2
O
2
, slow addition.
g
NHC-Pd 1
(0.001 g), D
2
O (0.4 mL);.
h
NHC-Pd 1mg, 0.4 mL H
2
O
2
at 60
o
C. For 3 hours and then
stirred at 60
o
C for 1 hour.
h
0.4 mL H
2
O
2
at 60
o
C for 3 hours and then stirred at 60
o
C for
1 hour.
i
NHC-Pd 1mg, 0.2 mL H
2
O
2

j
NHC-Pd (4 mg); 0.4 mL H
2
O
2
, slow addition.
Then, stirred for 1 hour at 60
o
C, 3 h.
k
NHC-Pd 1 (1.03x10
-5
moles), 0.1 mL H
2
O
2
slow
addition, NHC Pd 4mg, 6.4 mole%, 1.03x10
-5
moles.
l
0.2 mL 30 % H
2
O
2.
m
NHC-Pd (1
mg).
o
NHC-Pd (1 mg), 0.4 mL 30 % H
2
O
2
;
p
NHC-Pd 1 (2 mg), H
2
O
2
(0.2 mL);
q
NHC-Pd
1 (2 mg), H
2
O
2
(0.6 mL);
r
NHC-Pd (4 mg), 0.1 mL H
2
O
2
; *Most of the substrate
remained unreacted.

Benzoic acid in presence of NHC-Pd 1 catalyst in D
2
O remained unreactive at 60
o
C after 12 hours (Table 3.5, entry 19) remained intact. Formaldehyde is converted into
formic acid (80.5%) on treatment with 0.2 mL of 30% H
2
O
2
(Table 3.5, entry 20). Formic
acid on treatment with 0.2 mL of 30% H
2
O
2
in presence of NHC-Pd 1 at 60
o
C for five
hours is decomposed to carbondioxide (Table 3.5, entry 17). Oxalic acid was not
observed on
13
C NMR on teatement 0.3 mL H
2
O
2
at 0
o
C followed by 0.2 ml for 3 hr at
60
o
C in presence of NHC-Pd (4 mg). These reactions explain the conversion of
carboxylic group into carbondioxide under these oxidative reaction conditions.
Formic acid and sodium formate slowly decomposed to carbon dioxide in
presence of NHC-Pd 1 and hydrogen peroxide. Acetone on oxidation in presence of
NHC-Pd lead to acetic acid and formic acid. Oxidation of pinacol under heating
conditions showed acetic acid and formic acid peaks on
1
H NMR.
336

Oxidation of 2-hydroxy-2-methyl-propionic acid gave 2,3-butanedione, acetic
acid and formic acid. However, 2-hydroxy-2-methyl-propionic acid gave acetone, acetic
acid and formic acid.
Oxidation of 1,3-propanediol gave formic acid. Sequential addition of hydrogen
peroxide increased the amount of formic acid formed. Besides the formic acid, other
oxidized products were also observed.
4-phenylbutan-1-ol and 4-phenylbutan-2-ol on oxidation with NHC-Pd 1 and
H
2
O
2
at 60
o
C for 3 hours showed the formation formic acid on
1
H NMR. Many peaks
were seen in the aliphatic region which explains further oxidation of the rest of the
carbons in the compounds.
2,2-dimethyl-1,3-dioxolan-4-yl was treated with H
2
O
2
in presence of NHC-Pd 1
and stirred at room temperature for 1 hour.
1
H NMR of the crude reaction mixture
showed acetone peak at 2 ppm as starting material is deacetylated. Acetic acid peak is
observed which showed that acetone is converted into acetic acid and formic acid. The
deprotected starting material is converted into formic acid and glycolic acid.
3.2.7.2 Oxidative degradation studies of carbohydrates and dihydroxy acetone in
presence of NHC-Pd complex 1

Oxidative degradation of glucose was studied with hydrogen peroxide in the
presence of the NHC-Pd complex (1). Entries 1 and 3 (Table 3. 6) show that all the
glucose is oxidatively degraded. Formation of formic acid and glycolic acid (Entries 2-4,
Table 4) shows that glucose is oxidatively degraded into formic acid and corresponding
lower polyhydroxy aldehydes until glycolic acid is formed. Glycolic acid is further
337

Table 3.6 Oxidative degradation studies of carbohydrates and dihydroxyacetone in
presence of the NHC-Pd complex 1
a

Entry

30% H
2
O
2
(mL), Time (h)
Temperature (
o
C)

%
Conversion
of glucose
b
% formic acid
(moles)
b
% Glycolic
acid
(moles)
c
1

0.1 mL, 1h, 0
o
C

66 3.4
(0.66x10
-5
)

-
2 0.8 mL, 7 h, 60
o
C 88.3

4.23
(1.978X10
-5
)
9.80
(0.54X10
-5
)

3 0.6 mL
d
6 h, RT

~90

14.18
(3.14X10
-5
)
16.17
(0.89X10
-5
)
4 0.6 mL
f
, 3 h, 60
o
C Most of the
glucose
decomposed
14.99
(2.96X10
-5
)
5.2
(0.67X10
-5
)
5 0.3mL (0
o
C 3 h addition),
Then, 0.2 mL, 6 h, 60
o
C
65.56 19.8
(4.4X10
-5
)
22
(1.23X10
-5
)
6 0.3 ml H
2
O
2
at 0
o
C for 3
hours addition then, stirred
at RT for 6 hours then, at 60
o
C, 0.2 ml addition for 3 h.
76.26 28.8
(9.59x10
-5
)
40.8
(2.26x10
-5
)
7 0.5 mL, 6 h, 60
o
C and then,
3 h heating.

Traces
4.2
(3.18x10
-5
)
23.74
(1.862x10
-5
)

8
h
0.6 mL, 3 h, 40
o
C 0 - -
9
i

RT, 18 h, closed system Traces 34
(3.78x10
-5
)

29.63
(0.82x10
-5
)
11 0.3 ml H
2
O
2
at RT complete 92.8
23.22x10
-5

25.57
(3.19x10
-5
)
a
Glucose (5.53x10
-5
moles); NHC-Pd 1 (5.15X10
-6
moles, 9.3 mole%);
b
% Yields/moles
were calculated based on the assumption that oxidative degradation of one mole of
glucose gives four moles of formic acid and one mole of glycolic acid.
c
% Yields/moles
were calculated based on the assumption that oxidative degradation of one mole of
glucose gives six moles of formic acid.
d
H
2
O
2
was added all at once.
f
Slow addition of
H
2
O
2
for three hours at 60
o
C
h
Sucrose (5.53X10
-5
moles), NHC-Pd 1 (5.53X10
-5
moles);
I
D-Glucose, 2.77x10
-5
moles; NHC-Pd, 1 mg, 0.4 mL H
2
O
2
;
g
Dihydroxyacetone
(12.5X10
-5
moles); NHC-Pd 1 (1.03X10
-6
moles).
338

oxidatively degraded into formic acid. The low yield of formic acid explains the
conversion of the formic acid into carbon dioxide at higher temperatures. Oxidative
degradation of the 1,3-dihydroxyketone (Entry 11, Table 3.6) by slow addition of 0.3 mL
of hydrogen peroxide in the presence of the NHC-Pd complex 1 shows the formation of
91 % of the formic acid and 25 % of the glycolic acid. The percentage yields were
calculated based on the assumption that one mole of 1,3-dihydroxyketone gives one mole
of formic acid and one mole of glycolic acid. Glycolic acid is further oxidized to one
mole of the formic acid and carbon dioxide. From the percentage of glycolic acid in the
reaction mixture and the percentage of formic acid obtained, it is evident that one mole of
1,3-dihydroxyketone gives two moles of formic acid. This supports the hypothesis that
carbon dioxide is generated from the carboxylic group in the glycolic acid.
3.2.8 Oxidative degradation reactions with cationic palladium complex

The cationic NHC-Pd complex catalyzed oxidative degradation of glycerol,
ethylene glycol and glycolic acid was studied in the presence of hydrogen peroxide as an
oxidizing agent. The cationic NHC-Pd complex was prepared by stirring a mixture of the
NHC-Pd complex 1 and AgBF
4
in CH
3
CN for 0.5 hr. The white precipitate AgCl formed
was filtered off and the filtrate was concentrated to furnish the crude NHC-Pd
+
BF
4
-

(cationic NHC-Pd complex). The crude was directly used for the oxidative degradation
reactions. Glycerol, ethylene glycol and glycolic acid were oxidatively degraded in the
presence of the cationic NHC-Pd complex with hydrogen peroxide (Table 3.7). The

339

Table 3.7 Oxidative degradation of ethylene glycol with cationic NHC-Pd complex 1

Entry

Reaction condition

Formic
acid
% yield
(moles)

Glycolic
acid
%Yield
(moles)

Unreacted
substrate
(%)
1
a
0.3 mL H
2
O
2
, RT, 2 h 36
(11.6x10
-5
)
15
(1.65x10
-5
)
20.0

2
a

0.3 mL H
2
O
2
, RT, 24 h 42.8
(13.9x10
-5
)
18
(1.96x10
-5
)
24.0

3
a

0.3 mL H
2
O
2
, 3 hr slow
addition at 0
o
C. Then, 0.2
mL H
2
O
2
slow additon at
60
o
C for 3 h
16.78
(1.8x10
-5
)

24.4
(2.63x10
-5
)

24.0
(2.63X10
-5
)

4
b
0.3 mL H
2
O
2
, RT, 2 h 34.5
(11.1x10
-5
)
6
(0.98x10
-5
)
25.0

5
b
0.3 mL H
2
O
2
, RT, 24 h 49.7
(11.1x10
-5
)

4.86
(9.8x10
-6
)
30.6
6
b
0.3 mL H
2
O
2
slow addition
at 0
o
C for 3 h, then, 0.2mL
60
o
C slow addition for 3 h
26.7
(4.3x10
-5
)
7.6
(1.2x10
-5
)
7.97
(1.28X10
-5
)
7
c
0.3 mL, RT, 2h 28
(4.5x10
-5
)
34.5 34.5
8
c
0.3 mL, RT, 2 h 37
(4.9x10
-5
)
37.0 26.5

9
c

0.3 mL (addition at 0
o
C for
3 hr). Then, 0.2 ml addition
at 60
o
C for 3 h
45
(5.9x10
-5
)
24.9
(3.28x10
-5
)
30.6

a
Glycerol (10.8x10
-5
moles), NHC-Pd (9.5 mol%,1.03x10
-5
moles), AgBF
4
(11.8 mol%,
1.28x10
-5
moles).
b
Ethylene glycol (16.1x10-5 moles), NHC-Pd 1 (6.4 mol%, 1.03x10
-5
moles), AgBF
4
(7.95 mole%, 1.28x10
-5
moles).
c
Glycolic acid (13.1x10
-5
moles), NHC-
Pd 1 (3.93 mole%, 5.15x10
-6
moles), AgBF
4
(3.93 mole%, 5.15x10
-6
moles)

340

yields (%) and amounts (in moles) were calculated based on the assumption of formation
of two moles of formic acid from one mole of glycerol, two moles of formic acid from
one mole of ethylene glycol and one mole of formic acid from one mole of glycolic acid.
3.2.9 Oxidative degradation of glycerol with cationic palladium complex and
oxygen in presence of additives:

Reactions were performed with the cationic palladium complex in the presence of
metallic additives in a closed system with continuous supply of oxygen as an oxidant to
find a suitable condition for better and inexpensive oxidation. However, cationic NHC-Pd
1 catalyzed reactions with oxygen both in the presence and absence of additives such as
CuCl
2
, CuSO
4
and CuCO
3
did not give any oxidative degradation products (Table 3.8).
Table 3.8 Reactions with cationic palladium in the presence of metallic additives and
oxygen in a closed system:
a

Entry
Metallic additive
1
2
3
4
-
CuCl
2
(12 mole%)
CuSO
4
(12 mole%)
CuCO
3
(12 mole%)

a
All reactions were performed with glycerol (2.72X10
-5
moles), NHC-Pd (1) (2.94
mol%) and AgBF
4
(2.94 mol%) in 0.4 ml D
2
O in presence of O
2
(150 psi) at 50
o
C for
16hr.

3.2.10 Oxidative degradation of starch, cellulose and grass

Oxidative degradation of starch with hydrogen peroxide in presence of NHC-Pd 1
was studied with varying catalyst amounts and temperatures in open as well closed
systems. A maximum yield of 37 % was obtained with hydrogen peroxide in presence of
NHC-Pd 1 at 60
o
C for in a closed system (Table 3.9 , entry 2). Increasing the number of
341

hours affected the yields due to over oxidation of formic acid into carbondioxide.
Lowering the temperature did not improve the yield. Glycolic acid formed in the reaction
remained from undergoing further reaction at lower temperatures.
Formic acid was obtained in the NHC-Pd catalyzed oxidative degradation of
cellulose 60
o
C with hydrogen peroxide. However most of the starting material remained
unreacted. NHC-Pd 1 catalysed Oxidative degradation of starch showed very small
quantities of formic acid in
1
H NMR with varying temperatures and hydrogen peroxide
concentrations.
Table 3.9 Oxidative degradation of starch
a
, cellulose and grass
Entry Reaction condition
b
Formic acid formed
Moles (%)
1 H
2
O
2
(0.4 mL); 60
o
C, 16 4.89x10
-5
(29)
2 H
2
O
2
(0.4 mL); 60
o
C, 6 h, closed
system
5.16x10
-5
(37)
3 H
2
O
2
(0.4 mL); 60
o
C, 1 h, closed
system
4.99x10
-5
(30)
4 H
2
O
2
(0.4 mL); 60
o
C, 1 h 3.51x10
-5
(21.16)
5 H
2
O
2
(0.2 mL); 60
o
C, 5 h 3.54x10
-5
(21.31)
6 H
2
O
2
(0.2 mL); 60
o
C, 3 h 3.54x10
-5
(21.46)
7 H
2
O
2
(0.3 mL); 50
o
C, 5 h 2.70x10
-5
(16.3)
8 H
2
O
2
(0.3 mL); 40
o
C, 2 h 4.99x10
-5
(30.0)
9 H
2
O
2
(0.4 mL); 30
o
C, 4 h 3.98x10
-5
(23.8)
10

H
2
O
2
(0.2 mL); 60
o
C, 5 h Formic acid formed
11
d
Varying H
2
O
2
and temperature with
time
Very small quantities

a
Starch (5 mg, 2.77x10
-5
moles), NHC-Pd (2 mg);; % Calculations based on the
assumption that one equivalent of starch gives six equivalents of formic acid.
b
All
reactions were performed in vials closed with septa or lid except entries 2 and 3.
Reactions in entries 2 and 3 were run in a bomb shell.
c
Cellulose (M) 10 mg.
d
Grass (fresh
and dry)
342

3.2.11 NHC-Pd catalyzed oxidative degradation of glycerine, ethylene glycol and
glycolic acid with NaBO
3
:

NHC-Pd catalyzed oxidative degradation of glycerine, ethylene glycol and glycolic acid
with sodium borate gave formic acid but the reactions were incomplete and yields were
relatively lower than those with hydrogen peroxide (Table 3.10).
Table 3.10 NHC-Pd catalyzed oxidative degradation of glycerine, ethylene glycol and
glycolic acid with NaBO
3

Entry Reaction condition
b

Formic acid
(%)
1
a
NaBO
3
(6 eq); D
2
O (200 uL); RT for 6
hours
21
2
a
NaBO
3
(6 eq); D
2
O (200 uL); 60
o
C for
6 hours
~6
3
b
NaBO
3
(4 eq); D
2
O (200 uL); RT for 6
hours;
~5
4
c
NaBO
3
(4 eq); D
2
O (200 uL); RT for 6
hours;

10
5
c
NaBO
3
(4 eq); D
2
O (200 uL); 60
o
C for
6 hours;

~5

a
Glycerol (10mg, 10.86x10
-5
moels); NHC-Pd (1 mg);
b
Ethylene glycol (10mg, 16.11x10
-
5
moles); NHC-Pd (1 mg);
c
Glycolic acid (10 mg, 13.15x10
-5
moles); ); NHC-Pd (1 mg);

3.3 Conclusion
In conclusion, we have successfully demonstrated a method to produce formic
acid as the sole product via the oxidative NHC-Pd catalyzed carbon-carbon bond
cleavage of glycerol with hydrogen peroxide as an oxidizing agent. The direct conversion
of glycerol into formic acid was gently facilitated under mild reaction conditions. As we
proposed in the credible glycerol cleavage pathway, if over-oxidation of formic acid is
controlled, our designed NHC-Pd complex could be useful for the degradation of
343

carbohydrate compounds, such as biomass, to afford value-added organic chemicals. A
mechanism was proposed for the oxidative degradation of glycerol and glycolic acid to
formic acid and supporting reactions were performed to explain the reaction pathways.
Mechanistic studies are ongoing to confirm the formation of NHC-Pd hydride and NHC-
Pd hydroperoxide complex formation.
NHC-Pd catalyzed oxidative degradation of starch, cellulose and grass were also
studied. Due to less solubility of cellulose, low yields of formic acid were observed.
Oxidative degradation of glycerine, ethylene glycol and glycolic acid were studied using
cationic NHC-Pd complex. Though formic acid was obtained in all these reactions, the
yields were not improved.
NHC-Pd catalyzed oxidative degradation of glycerine, ethylene glycol and
glycolic acid were also studied using sodium borate as source of oxygen. The reactions
were incomplete and yields of formic acid observed in these reactions were very low.
Solid waste is another concern of the reactions with sodium borate as an oxidant.
3.4 Experimental

All reagents and solvents were purchased from either Aldrich or Acros Chemical
and used without further purification unless otherwise mentioned. Prior to use,
dichloromethane (CH
2
Cl
2
) was distilled over calcium hydride. Tetrahydrofuran (THF)
was refluxed in presence of sodium metal and benzophenone and distilled prior to use.
Thin-layer chromatography (TLC) was performed using commercially available 60 mesh
silica gel plates visualized with short-wavelength UV light (254 nm). Silica gel 60 (9385,
230-400 mesh) was used for column chromatography. The reported yields are isolated
344

yields.
1
H and
13
C NMR spectra were recorded on a 400MHz Varian instrument.
Chemical shifts were reported in ppm relative to solvents used for NMR (CDCl
3
and
CD
3
OD).
All the experiments were run in a vial and stirred using magnetic stirrer. Aqueous H
2
O
2

(30%) solution was purchased from Mallinckrodt Chemicals and aqueous NH
4
OH (25%)
solution used was from EMD. MeOH was used as standard to calculate the percentage
yields. Wet NMR spectra were recorded on Varian Mercury 400 NMR spectroscopy
using water and D
2
O mixture as solvent. Known mixture of methanol in water was
prepared and the volume corresponding to 1 or 2 µL methanol was used for formic acid
percentage calculations. Finnpipette or Hamilton chromatography syringe was used to
measure the solvents.
Preparation of 2-bromo-N-(2-methoxyethyl)acetamide (Scheme 1, compound 3)

To a stirred solution of bromoacetyl bromide (15.14 g, 6.55 mL, 75 mmol) in DCM (30
mL) was added dropwise over 15 minutes a solution of methoxylethyl amine and
triethylamine in dry CH
2
Cl
2
(90 mL). The mixture was allowed to warm to R.T and
stirred for 15 minutes at which time, the reaction was quenched by the addition of water.
The layers were separated. The organic layer was washed with aqueous HCl (1%, 100
mL), H
2
O (100 mL), aqueous NaHCO
3
(10%) and brine. Then, dried over sodium sulfate,
filtered and concentrated in rotatory evaporator under reduced pressure. The crude
product was purified on column chromatography, eluted with 20:1 hexane and EtOAc to
give 6 g (~41 %) of the product.

345

Preparation of 2-Benzimidazol-1-yl-N-(2-methoxy-ethyl)acetamide (Scheme 3.1,
compound 4)

A mixture of benzimidazole (,3.62 g, 30 mmol), N-bromoacetyl methoxy ethylamine (6g,
30 mmol), KOH (1.71 g, 30 mmol) in DMF (61 mL) was stirred at RT for 12 hours.
EtOAc was added to the reaction mixture and the solid (KBr) separated was removed by
filtration. The filtrate was washed with brine twice, dried over Na
2
SO
4
and concentrated.
The oily compound obtained was purified on column chromatography eluted with EtOAc
and then, MeOH as eluent to give 4.98 g (70%) of 2-benzimidazol-1-yl-N-(2-methoxy-
ethyl)acetamide
3-[(2-Methoxy-ethylcarbamoyl)-methyl]-1-methyl-3H-benzoimidazol-1-ium; iodide
(Scheme 3.1, compound 5)

To 1.5 gm (6.44 mmol) of 2-benzoimidazol-1-yl-N-(2-methoxy-ethyl)-acetamide in
anhydrous THF (150 mL), methyl iodide (2.75 g, 19.3 mmol) was added and refluxed
for 6 hours. The solid separated was filtered and dried to yield 2.3 g (90 %) of 3-[(2-
Methoxy-ethylcarbamoyl)-methyl]-1-methyl-3H-benzoimidazol-1-ium; iodide.
Note: Sometimes the solvent was removed to get the solid.
Preparation of Ag-NHC-Ligand Complex (Scheme 3.1, compound 6)
To 3-[(2-Methoxy-ethylcarbamoyl)-methyl]-1-methyl-3H-benzoimidazol-1-ium; iodide
(1.1 g, 2.98 mmol) in CH
2
Cl
2
(50mL), Ag
2
O (0.31 g, 1.34 mmol) was added and stirred
at room temperature for 6 hours. White precipitate was separated. The solvent was
removed under reduced pressure. Slowly the white solid was turned to brown color.

346

Preparation of Pd(II)-NHC-Ligand Complex 1 (Scheme 3.1, compound 1)

To the crude silver complex in CH
3
CN (100 mL) was added PdCl
2
(CH3CN)2 (0.76 g,
2.99 mmol) in dark at room temperature. Then, the resulting suspension was stirred for 2
hours and filtered through a plug of glass fiber filter paper. The filtrate was evaporated to
dryness under reduced pressure in rotatory evaporator to afford an orange colored Pd(II)-
NHC-ligand complex 1 (0.85 g, 75 % yield).
Glycerol to formic acid: A mixture of glycerol (10 mg, 10.86 mmol) and catalyst 1 (5
mole %) in 0.2 mL of water was taken in a rubber stoppered vial. To the above mixture,
0.3 mL of 30% H
2
O
2
was added for 3 hours at 0
o
C by using syringe pump. After
complete addition, the reaction mixture was brought to 60
o
C and then, 0.2 mL of 30%
H
2
O
2
was added for 3 hours.
1
Hwet1D NMR of the crude reaction mixture showed the
complete conversion of glycerol to give 14.76 mmol (45.43 %, percentage yield was
calculated assuming that three equivalents of formic acid from one equivalent of
glycerol) of formic acid.
1
H wet 1D : δ8.1 (s, 1H).
Note: Known volumes of MeOH and D
2
O mixture were prepared and volumes
corresponding to 1 or 2 µL MeOH were used to dilute the reaction mixture to run the
1
H
NMR.
3.5 Spectral data
2-bromo-N-(2-methoxyethyl)acetamide (Scheme 3.1, compound 3)
1
H NMR (400 MHz, CDCl
3
) 6.93 (bs, NH, 1H); 3.79(s, 2H), 3.41-3.36 (m, 4H, J=3.2

Hz); 3.27 (s, 3H);

13
C NMR (400 MHz, CDCl
3
) 165.64; 70.47; 58.62; 39.67; 28.84.

347

2-Benzimidazol-1-yl-N-(2-methoxy-ethyl)acetamide (Scheme 3.1, compound 4)

1
H NMR (400 MHz, CCl3) 8.2 (s, 1H); 7.72-7.70 (d, 2H, J=7.2 Hz); 7.51-7.49 (d, 1H,

J=8 Hz); 7.35-7.33 (m, 2H); 5.02 (s, 2H); 3.51-3.49 (t, 2H, J=1.6Hz); 3.48-3.44 (t, 2H,

J=4.2 Hz); 3.37 (s, 3H). p10-39

13
C NMR (400MHz, CD
3
OD) 168.98; 145.66; 143.78; 135.23; 124.40; 123.64; 120.09;

111.22; 71.69; 58.86; 48.09; 48.06; 40.36.

3-[(2-Methoxy-ethylcarbamoyl)-methyl]-1-methyl-3H-benzoimidazol-1-ium; iodide
(Scheme 3.1, compound 5)

1
H-NMR (400 MHz, CD3OD): δ 9.56 (s, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 8.8

Hz, 1H), 7.74-7.71 (m, 2H), 5.35 (s, 2H), 4.19 (s, 3H), 3.53-3.50 (m, 2H), 3.46-3.44 (m,

2H), 3.37 (s, 3H);

13
C-NMR (400 MHz, CD3
114.23; 114.09; 71.38; 58.77; 40.36; 34.14.

Pd(II)-NHC-Ligand Complex 1
1
HNMR (CD3 J = 7.2 Hz, 1H), 7.51 (d, J = 7.2 Hz, 1H) 7.40-7.36 (m,

2H), 5.62 (s, 2H), 4.35 (s, 3H), 3.45 (m, 2H), 3.39 (m, 2H), 3.32 (s, 3H);

13
CNMR (CD3 .5, 134.7, 134.4, 123.6, 117.8, 110.6, 110.2, 70.2,

57.6, 50.6, 39.1, 34.2;

348

3.6 Representative spectra
Figure 3.10
1
H NMR of 2-bromo-N-(2-methoxyethyl)acetamide (Scheme 3.1,
compound 3)

349

Figure 3.11
13
C NMR of 2-bromo-N-(2-methoxyethyl)acetamide (Scheme 3.1,
compound 3)

350

Figure 3.12
1
H NMR of 2-Benzimidazol-1-yl-N-(2-methoxy-ethyl)acetamide
(Scheme 3.1, compound 4)

351

Figure 3.13
13
C NMR of 2-Benzimidazol-1-yl-N-(2-methoxy-ethyl)acetamide
(Scheme 3.1, compound 4)

352

Figure 3.14
1
H NMR of 3-[(2-Methoxy-ethylcarbamoyl)-methyl]-1-methyl-3H-
benzoimidazol-1-ium; iodide

353

Figure 3.15
13
C NMR of 3-[(2-Methoxy-ethylcarbamoyl)-methyl]-1-methyl-3H-
benzoimidazol-1-ium; iodide (Scheme 1, compound 5)

354

Figure 3.16
1
H NMR NHC-Pd 1 Complex

355

Figure 3.17
13
C NMR NHC-Pd 1 Complex

356

Figure 3.18
1
H wet 1D NMR of entry 2, Table 3.1

357

Figure 3.19
1
H wet 1D NMR of entry 3, Table 3.1

358

Figure 3.20
1
H wet 1D NMR of entry 4, Table 3.1

359

Figure 3.21
1
H wet 1D NMR of entry 6, Table 3.1

360

Figure 3.22
1
H wet 1D NMR of entry 7, Table 3.1

361

Figure 3.23
1
H wet 1D NMR of entry 1, Table 3.3

362

Figure 3.24
1
H wet 1D NMR of entry 2, Table 3.3

363

Figure 3.25
1
H wet 1D NMR of entry 3, Table 3.3

364

Figure 3.26
1
H wet 1D NMR of entry 4, Table 3.3

365

Figure 3.27
1
H wet 1D NMR of entry 5, Table 3.3

366

Figure 3.28
1
H wet 1D NMR of entry 6, Table 3.3

367

Figure 3.29
1
H wet 1D NMR of entry 7, Table 3.3

368

Figure 3.30
1
H wet 1D NMR of entry 8, Table 3.3

369

Figure 3.31
1
H wet 1D NMR of entry 9, Table 3.3

370

Figure 3.32
1
H wet 1D NMR of entry 10, Table 3.3
.

371

Figure 3.33
1
H wet 1D NMR of entry 11, Table 3.3

372

Figure 3.34
1
H wet 1D NMR of entry 12, Table 3.3

373

Figure 3.35
1
H wet 1D NMR of entry 13, Table 3.3

374

Figure 3.36
1
H wet 1D NMR of entry 14, Table 3.3

375

Figure 3.37
1
H wet 1D NMR of entry 15, Table 3.3

376

Figure 3.38
1
H wet 1D NMR of entry 16, Table 3.3

377

Figure 3.39
1
H wet 1D NMR of entry 17, Table 3.3

378

Figure 3.40
1
H wet 1D NMR of entry 18, Table 3.3

379

Figure 3.41
1
H wet 1D NMR of entry 19, Table 3.3

380

Figure 3.42
1
H wet 1D NMR of entry 20, Table 3.3

381

Figure 3.43
1
H wet 1D NMR of entry 21, Table 3.3

382

Figure 3.44
1
H wet 1D NMR of entry 22, Table 3.3

383

Figure 3.45
1
H wet 1D NMR of entry 23, Table 3.3

384

Figure 3.46
1
H wet 1D NMR of entry 24, Table 3.3

385

Figure 3.47
1
H wet 1D NMR of entry 25, Table 3.3

386

Figure 3.48
1
H wet 1D NMR of entry 27, Table 3.3

387

Figure 3.49
1
H wet 1D NMR of entry 28, Table 3.3

388

Figure 3.50
1
H wet 1D NMR of entry 29, Table 3.3

389

Figure 3.51
1
H wet 1D NMR of entry 30, Table 3.3

390

Figure 3.52
1
H wet 1D NMR of entry 1, Table 3.4

391

Figure 3.53
13
C NMR of entry 1, Table 3.4

392

Figure 3.54
1
H wet 1D NMR of entry 2, Table 3.4

393

Figure 3.55
1
H wet 1D NMR of entry 3, Table 3.4

394

Figure 3.56
1
H wet 1D NMR of entry 4, Table 3.4

395

Figure 3.57
1
H wet 1D NMR of entry 5, Table 3.4

.

396

Figure 3.58
1
H wet 1D NMR of entry 6, Table 3.4

397

Figure 3.59
1
H wet 1D NMR of entry 1, Table 3.5

398

Figure 3.60
1
H wet 1D NMR of entry 2, Table 3.5
.

399

Figure 3.61
1
H wet 1D NMR of entry 3, Table 3.5

400

Figure 3.62
1
H wet 1D NMR of entry 4, Table 3.5

401

Figure 3.63
1
H wet 1D NMR of entry 5, Table 3.5

402

Figure 3.64
1
H wet 1D NMR of entry 6) , Table 3.5

403

Figure 3.65
1
H wet 1D NMR of entry 7, Table 3.5

404

Figure 3.66
1
H wet 1D NMR of entry 8, Table 3.5

405

Figure 3.67
1
H wet 1D NMR of entry 9, Table 3.5

406

Figure 3.68
13
C NMR of entry 9, Table 3.5

407

Figure 3.69
1
H wet 1D NMR of entry 10, Table 3.5

408

Figure 3.70
1
H wet 1D NMR of entry 11, Table 3.5

409

Figure 3.71
1
H wet 1D NMR of entry 12, Table 3.5

410

Figure 3.72
1
H wet 1D NMR of entry 13, Table 3.5

411

Figure 3.73
1
H wet 1D NMR of entry 14, Table 3.5

412

Figure 3.74
1
H wet 1D NMR of entry 15, Table 3.5

413

Figure 3.75
1
H wet 1D NMR of entry 16, Table 3.5

414

Figure 3.76
1
H wet 1D NMR of entry 17, Table 3.5

415

Figure 3.77
1
H wet 1D NMR of entry 18, Table 3.5

416

Figure 3.78
1
H wet 1D NMR of entry 19, Table 3.5

417

Figure 3.79
1
H wet 1D NMR of entry 20, Table 3.5

418

Figure 3.80
1
H wet 1D NMR of entry 23, Table 3.5

.

419

Figure 3.81
13
C NMR of entry 23, , Table 3.5

420

Figure 3.82
1
H wet 1D NMR of entry 24, Table 3.5

421

Figure 3.83
1
H wet 1D NMR of entry 25, Table 3.5

.

422

Figure 3.84
1
H wet 1D NMR of entry 26, Table 3.5

423

Figure 3.85
1
H wet 1D NMR of entry 27, Table 3.5

424

Figure 3.86
1
H wet 1D NMR of entry 28, Table 3.5

425

Figure 3.87
1
H wet 1D NMR of entry 29, Table 3.5

426

Figure 3.88
1
H wet 1D NMR of entry 30, Table 3.5

427

Figure 3.89
1
H wet 1D NMR of entry 31, Table 3.5

428

Figure 3.90
1
H wet 1D NMR of entry 32, Table 3.5

429

Figure 3.91
1
H wet 1D NMR of entry 33, Table 3.5

430

Figure 3.92
1
H wet 1D NMR of entry 34, Table 3.5

431

Figure 3.93
1
H wet 1D NMR of entry 35, Table 3.5

432

Figure 3.94
1
H wet 1D NMR of entry 1, Table 3.6

433

Figure 3.95
1
H wet 1D NMR of entry 1, Table 3.9

434

Figure 3.96
1
H wet 1D NMR of entry 2, Table 3.9

435

Figure 3.97
1
H wet 1D NMR of entry 3, Table 3.9

436

Figure 3.98
1
H wet 1D NMR of entry 4, Table 3.9

437

Figure 3.99
1
H wet 1D NMR of entry 5, Table 3.9

438

Figure 3.100
1
H wet 1D NMR of entry 6, Table 3.9

439

Figure 3.101
1
H wet 1D NMR of entry 7, Table 3.9

440

Figure 3.102
1
H wet 1D NMR of entry 8, Table 3.9

441

Figure 3.103
1
H wet 1D NMR of entry 9, Table 3.9

442

Figure 3.104
1
H wet 1D NMR of entry 10, Table 3.9
.

443

Figure 3.105
1
H wet 1D NMR of entry 1, Table 3.9

444

Figure 3.106
1
H wet 1D NMR of entry 2, Table 3.9

445

Figure 3.107
1
H wet 1D NMR of entry 3, Table 3.9

446

Figure 3.108
1
H NMR of
13
C1 labeled glycolic acid

447

Figure 3.109
13
C NMR of
13
C1 labeled glycolic acid

448

Figure 3.11
1
H NMR of oxidative degradation of
13
C1 labeled glycolic acid

449

Figure 3.111
1
H wet 1D NMR of entry 5, Table 3.4

450

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454

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455

Chapter 4: Oxidative degradation of reducing
carbohydrates to ammonium formate with H
2
O
2
and
NH
4
OH.

4.1 Introduction

The conversion processes of biomass waste to value-added products are receiving
great attention, especially those using environmentally benign methods to avoid
environmental pollution and its consequences.
1-3
For instance, carbohydrate biomass can
be converted into formic acid, which is an important source of hydrogen used in fuel
cells. In fact, direct formic acid fuel cells (DFAFC) can become an alternative to
methanol based fuel cells.
4-12
Major producers of portable electronics in phones and
computers are currently testing the efficiency of DFAFC in their devices.
7-9,13-21
With
continuing development, there is potential for DFAFC to challenge traditional batteries as
power sources for mobile electronic devices.
8
Ammonium formate is also used in
Leuckart reaction, the reductive amination of aldehydes and ketones to amines
22-24
and in
the preparation of formamide an industrial application
25
As a result, there may be
continuing demand for the large-scale preparation of formic acid from inexpensive and
abundant materials such as biomass waste. Recent work in this area facilitates the
efficient generation of formic acid from carbohydrate biomass under mild conditions

Isbell et al. published this work on a series of reports on oxidative degradations of
aldoses, ketoses and keto acids in the presence of alkaline hydrogen peroxide. The formic
acid yields depended on the ratios of alkali bases and hydrogen peroxide. The reaction
rate was low in the presence of bases with the gradual addition of peroxide, and the
456

conversion was accelerated to some degree in the presence of hydrogen peroxide with
the gradual addition of bases.
26-34
Most reducing sugars were converted to formic acid
chemoselectively and efficiently, however there were a few practical shortcomings.
In order to keep the chemoselectivity high, the reactions were run over a long period
of time at lower temperatures such as 0
o
C. For example, glucose and galactose were
converted to formic acid chemoselectively, but 4 weeks of reaction time were necessary
to achieve an 84% yield from glucose, and similarly 5 days were required for a 94% yield
from galactose. Shorter reaction times of two days or less resulted in yields of
approximately 20 – 40%.
27-34
Later studies using Fe(II) salts
35
showed that these reactions
could be accelerated slightly although many carbohydrates including glucose still
required long reaction times at low temperatures. Therefore, these methods proved to be
far from practical. Another recent report showed significant improvements in
hydrothermal oxidation of carbohydrates in the presence of alkali, however
chemoselectivy was not as good as in the previous methods. Besides, this hydrothermal
protocol required harsh conditions including high temperatures (i.e., 250
o
C), and the
maximum reported yield was 75%.
36-38
Though the aforementioned studies are remarkable initiatives in the conversion of
carbohydrates into formic acid, further research is required to mitigate the common
concerns such as high or low temperatures, long reaction hours, and the use of strong
bases. Thus, we embarked on the study to explore potential solutions by varying reagents
and conditions, and ultimately learned that the use of ammonium hydroxide instead of
alkali metal bases provided significantly improved methods with pragmatic conditions
457

such as room temperature, short reaction time (i.e., 1 h), and the use of water as the
solvent of choice. Chapter 4 explains the oxidative degradation of reducing carbohydrates
to ammonium formate.
4.2 Results and Discussion
4.2.1 Optimization of oxidative degradation of glucose

As shown in the Table 1, we sought optimal ratios of hydrogen peroxide and
ammonium hydroxide, and learned that the increase in ammonium hydroxide enhanced
the formation of ammonium formate (entries 1-2). While this trend was reiterated in
entries 3-5, no conversion was observed without ammonium hydroxide (entry 6),
underscoring the important role of ammonium hydroxide in comparison with alkali metal
bases used in the previously known methods. The amounts of hydrogen peroxide also
affected the results significantly (entries 1 vs. 4, and entries 2 vs. 5), with the optimal
conditions as shown in entry 5. Thus we successfully converted glucose to formate under
mild conditions in a chemoselective manner with an excellent conversion (99%, entry 5).
Table 4.1 Optimization of oxidative degradation of glucose
a

Entry 30% H
2
O
2
( L) 25% NH
4
OH
(mL)
Conversion to formate
(%)
b

1
2
3
4
5
6
7
130
130
150
150
150
300
300
10
30
5
10
30
0
30
17
41
23
44
99
0
c

99
d

a
Reaction conditions: Glucose (0.028 mmol), 30% H
2
O
2
(150 μL), 25% NH
4
OH (30 μL),
RT for 1h.
b
The remaining % was accounted for by unreacted starting material.
c
No
reaction.
d
Glucose (0.028 mmol), 30% H
2
O
2
(300 μL), 25% NH
4
OH (30μL), RT for 24
h.
458

The conversion yields were calculated based on the assumption that the
theoretical yield would be six equivalents of formic acid from each glucose. In all the
cases, formic acid was an exclusive product, and the remaining mass balance was starting
material or the lower aldoses.
26-34
We could find little or no over oxidation or
decomposition of ammonium formate, even under extreme conditions such as higher
concentration of hydrogen peroxide and longer hours (entry 7). The product was
compared with commercially available ammonium formate and formic acid. The reports
show that the reactions run in presence of base form corresponding formate salts.
26-34

Under present reaction conditions, ammonium hydroxide converts formic acid to
ammonium formate. Oxidative degradation of glucose was done in one gram scale and
the yields of the product was reproducible. The reaction was smooth and efficient at
room temperature in aqueous medium, making the reactions practical and environment
friendly.
1
H NMR of the reaction mixture showed that the percentage conversion to
formic acid increased with time, and often the reaction went to completion or stopped in
1 h. Having determined the optimal conditions, various aldoses, ketoses, disaccharides,
and trisaccharides were examined by our oxidative degradation protocol in the presence
of ammonium hydroxide as a base.
4.2.2 Oxidative degradation of carbohydrates to ammonium formate

Under the developed conditions, monomeric aldoses including D-erythrose, D-

xylose, D-ribose, D-glucose, and D-galactose were smoothly converted into formic acid in

32, 92, 96, 99, and 93% yields, respectively (Table 2, entries 1–5). However, oxidative

degradation of ketoses such as 1,3-dihydroxyacetone dimer, D-tagatose, and D-fructose

459

were degraded into glycolic acid and formic acid.
15
The conversion yields were 99, 83, and

46%, respectively (entries 6–8). When the reaction was performed with glycolic acid under

similar conditions, no degradation or oxidation products were observed. Hence, it would be

natural to assume that two carbons in the ketose were converted into one equivalent of

glycolic acid and the remaining carbons were transformed into formic acid. In fact, the

ratios of these two degradation products were well aligned with our expected range,

showing a 1:1 ratio from dihydroxyacetone and 4:1 ratio from hexoses as illustrated in

Table 3.

Table 4.2 Oxidative degradation of carbohydrates to ammonium formate

Entry Carbohydrate Conversion to
Formate (%)
a,d

1
2
3
4
5
6
7
8
9
10
11
12
13
14
D-erythrose
D-xylose

D-(-)-ribose
D-glucose

D-galactose

Dihydroxyacetone
e
D-tagatose
e
D-fructose
e
Sucrose

α-D-lactose

Maltose

D-(+)-cellobiose

Raffinose
Melezitose
32

92
96
99
93
99
83
46
0
b,c

99
b

99
b

70
b

00
26

a
Reaction conditions: Aldose/Ketose/Disacchride/Trisaccharide (5 mg), 30% H
2
O
2
(150
μL), 25% NH
4
OH(30 μl), RT for 1 h;
b
After 24 h at RT;
c
After 48 h at 60
o
C.
d
The
remaining percentage was unreacted starting material except in D-erythrose.
e
Yields here
calculated based on the lower aldose formed during oxidative degradation.

460

Table 4.3 Oxidative degradation of ketoses to ammonium formate and ammonium
glycolate

Entry Reactant Formate, Glycolate
a

ratio
1
2
3
Dihydroxyacetone
D-Tagatose
D-Fructose
1/1
4/1

4/1
a
Reaction conditions: Ketose (5mg), 30% H
2
O
2
(150 ul),
25% NH
4
OH (30 ul), RT for 1h.

As shown in the Table 2, several disaccharides were examined under similar
conditions. Reducing disaccharides such as -D-lactose monohydrate, maltose, and D-
(+)-cellobiose underwent oxidative degradation completely in 24 h to generate formate in
99, 99, and 70% yields, respectively, while non-reducing sucrose remained intact (entries
9–12). The reaction did not proceed with sucrose even at 60
o
C, implying that the
conversion of non-reducing carbohydrates would not be feasible due to mechanistic
mismatch. Nonetheless, these conditions furnished an improved method to oxidatively
degrade reducing carbohydrates rapidly at ambient temperatures with reliable
chemoselectivities.
Earlier reports show that the degradation of carbohydrates follow five different
paths such as -hydroxy hydroperoxide-cleavage mechanism, the Baeyer Villiger
mechanism, the ester mechanism, the dihydroxy-epoxide mechanism, and a radical
mechanism.
31-32
Based on these reported mechanisms,
31-32
the alkaline hydrogen peroxide
degrades reducing sugars by nucleophilic addition of hydrogen peroxide to the carbonyl
group. Likewise, under our conditions, the adduct, -hydroxy hydroperoxide would
decompose rapidly into formic acid and the next lower aldoses by -hydroxy
461

hydroperoxide cleavage (Scheme 1). These lower aldoses would further follow similar
degradation steps until completely oxidized to formic acid.
26-44
In a separate experiment
where glucose was treated with triethylamine N-oxide with or without ammonium
hydroxide, we observed no oxidation or degradaton products. This rules out the
involvement of N-oxide in the oxidative degradation, and further supports nucleophilic
addition of hydroperoxide.

Scheme 4.1: Possible mechanism for the oxidative degradation of aldose and ketose to
ammonium formate

On the other hand, ketoses would give rise to the formation of glycolic acid and
lower aldoses, which further react to give one equivalent of glycolic acid and the
remaining carbon number of formic acid. Our results corroborate this potential pathway
H)
n
(HO
CH
2
OH
Ketose
H O
O O
CH
2
OH
Hydroperoxide
adduct
Lower Aldose
nHCOO NH
4
Through
Hydroper-
oxide adduct
O
CH
2
OH
CH
2
OH
COOH
NH
4
OH
rt
H
2
O
2
No oxidation or
degradation
product
O H
H)
n
(HO
CH
2
OH
Aldose
H O
H O
O NH
4
Hydroperoxide
adduct
HCOO NH
4
Lower Aldose
nHCOO NH
4
NH
4
OH
rt
Through
Hydroper-
oxide adduct
H
2
O
2
Glycolic
acid
OH
(H OH)
n-1
CH
2
OH
OH
H
OH
NH
4
H)
n-1
(HO
CH
2
OH
H
OH
COO NH
4
CH
2
OH
Ammonium
glycolate
NH
4
OH
rt
H
2
O
2
462

(Table 3). In addition, the oxidation results of disaccharides (Table2, entries10-12) can
also be explained by the proposed mechanism, which allow only the hemiacetal part of
the disaccharide to afford the acyclic reducing form, ultimately generating formic acid.
34

Sucrose being a non-reducing sugar with an acetal linkage between glucose and fructose
does not undergo ring opening to give an acyclic aldose. Therefore, sucrose does not
undergo oxidation under the given conditions to give ammonium formate.
Based on these concepts, two different trisaccharides
45
were investigated (Table 2,
entries 13 - 14). Non-reducing trisaccharide, raffinose was not hydrolysed under the
present conditions to the corresponding acyclic form, therefore showing no reactivity
towards oxidative degradation. In contrast, reducing trisacharide melizitose
45
was
partially hydrolysed to undergo oxidative degradation, which accounted for the marginal
yield of ammonium formate.

Scheme 4.2: Nonreducing trisaccharides.
45

4.3 Conclusion

In conclusion, oxidative degradation of reducing sugars to ammonium formate
was established under mild conditions in the presence of 30% aqueous hydrogen peroxide
and 25% ammonium hydroxide at room temperature. The number of equivalents of
463

ammonium formate produced was equivalent to the number of carbons present in the
corresponding aldoses. For instance, glucose and ribose upon oxidative degradation gave
six and five equivalents of ammonium formate, respectively. In the case of ketoses,
oxidative degradation led to ammonium formate and glycolic acid in predictable ratios.
However, the oxidative degradation of disaccharides and trisaccharides to ammonium
formate depended on the presence of acetal or hemiacetal linkages between the
monosaccharide units. The presence of a hemiacetal facilitated hydrolysis of reducing
sugars to acyclic forms, which underwent oxidation to give ammonium formate whereas
non-reducing sugars were resistant to oxidative degradation. We believe that the
conditions developed herein are more practical and useful compared to the previously
known methods due to the high efficiency, mild conditions at ambient temperature, short
reaction time, use of environment friendly solvent, and high chemoselectivities. The
contents of the chapter 4 are published recently.
46

4.4 Experimental

All the experiments were run in a vial and stirred using magnetic stirrer. Aqueous H
2
O
2

(30%) solution was purchased from Mallinckrodt Chemicals and aqueous NH
4
OH (25%)
solution used was from EMD. MeOH was used as standard to calculate the percentage
yields. 1,3-Dihydroxyacetone dimmer, D-(+)galactose, D-(+)-cellobiose, D-(+)-xylose, α-
D-lactose, D-(+)-maltose monohydrate, D-erythrose, D-(+)-melezitose, D-(+)-raffinose
were purchased from Alfa Aesar, D-glucose was from Mallinckrodt chemicals and
sucrose was purchased from JT Baker. Wet NMR spectra were recorded on Varian
Mercury 400 NMR spectroscopy using water and D
2
O mixture as solvent. Known
464

mixture of methanol in water was prepared and the volume corresponding to 1 or 2 µL
methanol was used for formic acid percentage calculations. Finnpipette or Hamilton
chromatography syringe was used to measure the solvents.

465

4.5 Representative Spectra

Figure 4.1
1
H wet 1D NMR of entry 1, Table 1

Glucose (5 mg, 0.028 mmol), 130 μL H
2
O
2
and 10 μL NH
4
OH at rt for 1 hr; 1 μL of
MeOH as standard was used for NMR. Formic acid observed was 17 %.

466

Figure 4.2
1
H wet 1D NMR of entry 2, Table 1

Glucose (5mg, 0.028 mmol), 130 μL H
2
O
2
and 30 μL NH
4
OH at rt for 1 hr; 1 μL of
MeOH as standard was used for NMR. Formic acid observed was 41 %.

467

Figure 4.3
1
H wet 1D NMR of entry 3, Table 1
Glucose (5mg, 0.028 mmol), 150 μL H
2
O
2
and 5 μL NH
4
OH at rt for 1 hr; 2 μL of MeOH
as standard was used for NMR. Formic acid observed was 23 %.

468

Figure 4.4
1
H NMR of entry 4, Table 1.
Glucose (5mg, 0.028 mmol), 150 μL H
2
O
2
and 10μL NH
4
OH at rt for 1 hr; 2 μL of
MeOH as standard was used for NMR. Formic acid observed was 44 %.

469

Figure 4.5
1
H NMR of entry 5, Table 1 and entry 4, Table 2
Glucose (5mg, 0.028 mmol), 150 μL H
2
O
2
and 30 μL NH
4
OH at rt for 1 hr; 1 μL of
MeOH as standard was used for NMR. Formic acid observed was 99 %.

470

Figure 4.6
1
H NMR of entry 6, Table 1
Glucose (5mg, 0.028 mmol), 100 μL H
2
O
2
and 30 μL NH
4
OH at rt for 24 hr; 2 μL of
MeOH as standard was used for NMR. Formic acid observed was 67%.

471

Figure 4.7
1
H wet 1D NMR of entry 7, Table 1
Glucose (5mg, 0.028 mmol), 300 μL H
2
O
2
and 30 μL NH
4
OH at rt for 24 hr; 2 μL of
MeOH as standard was used for NMR. Formic acid observed was 99.8%.

472

Figure 4.8
13
C NMR of entry 7, Table 1

473

Figure 4.9
1
H wet 1D NMR of entry 8, Table 1

Glucose (5mg, 0.028 mmol), 300 μL H
2
O
2
and without NH
4
OH at rt for 1 hr; 1 μL of
MeOH as standard was used for NMR. Formic acid observed was 0%.

474

Figure 4.10
1
H wet 1D NMR of entry 1, Table 2
Erythrose (0.042 mmol), 150 μL H
2
O
2
and 30 μL NH
4
OH at rt for 1 hr; 2 μL of MeOH as
standard was used for NMR. Formic acid observed was 32%.

475

Figure 4.11
1
H wet 1D NMR of entry 2, Table 2
Xylose (0.013 mmol (1hr) 150 μL H
2
O
2
and 30 μL NH
4
OH at RT for 1 hr; 2 μL of
MeOH as standard was used for NMR. Formic acid observed was 92%.

476

Figure 4.12
1
H wet 1D NMR of entry 3, Table 2
Ribose (0.033 mmol)150 μL H
2
O
2
and 30 μL NH
4
OH at RT for 1 hr; 2 μL of MeOH as
standard was used for NMR. Formic acid observed was ~99%.

477

Figure 4.13
1
H wet 1D NMR of entry 5, Table 2

Galactose (0.005gm, 0.028 mmol), 150 μL H
2
O
2
and 30 μL NH
4
OH at RT for 1 hr; 2 μL

of MeOH as standard was used for NMR. Formic acid observed was 93%.

478

Figure 4.14
1
H wet NMR of entry 6, Table 2
Dihydroxyacetone (0.005gm, 0.056 mmol), 150 μL H
2
O
2
and 30 μL NH
4
OH at RT for 1
hr; 2 μL of MeOH as standard was used for NMR. Formic acid observed was 99%.

479

Figure 4.15
1
H wet1D NMR of entry 7, Table 2
Tagatose (0.005 gm, 0.028 mmol) 150 μL H
2
O
2
and 30 μL NH
4
OH at RT for 1 hr; 2 μL
of MeOH as standard was used for NMR. Formic acid observed was 83%.

480

Figure 4.16
13
C NMR of entry 7, Table 2

481

Figure 4.17
1
H wet 1D NMR of entry 8, Table 2
Fructose (0.005 gm, 0.28 mmol) 150 μL H
2
O
2
and 30 μL NH
4
OH at RT for 1 hr; 2 μL of
MeOH as standard was used for NMR. Formic acid observed was 46%.

482

Figure 4.18
13
C NMR of entry 8, Table 2

483

Figure 4.19
1
H wet 1D NMR of entry 9, Table 2

Sucrose (0.005gm, mmol), 150 μL H
2
O
2
and 30 μL NH
4
OH at RT for 1 hr; 2 μL of
MeOH as standard was used for NMR. Formic acid observed was 0%.

484

Figure 4.20
1
H wet 1D NMR of entry 10, Table 2
α-D-Lactose (0.005 gm, 0.015 mmol), 150 μL H
2
O
2
and 30 μL NH
4
OH at RT for 24 hr; 2
μL of MeOH as standard was used for NMR. Formic acid observed was 99%

485

Figure 4.21
1
H wet 1D NMR of entry 11, Table 2
Maltose (0.005 gm, 0.015 mmol), 150 μL H
2
O
2
and 30 μL NH
4
OH at RT for 24 hr; 2 μL
of MeOH as standard was used for NMR. Formic acid observed was 99%.

486

Figure 4.22
1
H wet 1D NMR of entry 12, Table 2
Cellobiose (0.005 gm, 0.015 mmol), 150 μL H
2
O
2
and 30 μL NH
4
OH at RT for 24 hr; 2
μL of MeOH as standard was used for NMR. Formic acid observed was 70%.

487

Figure 4.23
1
H 1D NMR of NMR of entry 13, Table 2
Raffinose (0.005 gm, 0.01 mmol) 150 μL H
2
O
2
and 30 μL NH
4
OH at RT for 24 hr; 2 μL
of MeOH as standard was used for NMR. Formic acid observed was 0%.

488

Figure 4.24
1
HNMR of entry 14, Table 2

Melezitose (0.005 gm, 0.01 mmol) 150 μL H
2
O
2
and 30 μL NH
4
OH at RT for 24 hr; 2 μL
of MeOH as standard was used for NMR. Formic acid observed was 26%.

489

Figure 4.25
1
H wet 1D NMR of ammonium formate

(10 mg, 1.59x10
-4
moles) (20 µL of solution was used for NMR as a methanol standard

corresponding to 2µL MeOH from a solution of 20 µL methanol in 180 µL D
2
O mixture)

490

Figure 4.26
1
H wet 1D NMR of mixture of formic acid and ammonium formate

formic acid (10 µL) and ammonium formate (6.9 mg, 1.09x10
-3
moles)

491

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Abstract (if available)

Abstract This dissertation focuses on the studies toward total synthesis of palmerolide A, preparation of ligands for rhodium catalyzed C-H activation reaction. Preparation of NHC-Pd (II) catalyst and the application in the conversion of biomass into formic acid.

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University of Southern California Dissertations and Theses

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New bifunctional catalysts for ammonia-borane dehydrogenation, nitrile reduction, formic acid dehydrogenation, lactic acid synthesis, and carbon dioxide reduction

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Novel methods for functional group interconversions in organic synthesis and structural characterization of new transition metal heterogeneous catalysts for potential carbon neutral hydrogen storage

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Creator Pullanikat, Prasanna (author)

Core Title Preparation of novel ligands for rhodium (II) and palladium (II) catalysts and application in the synthesis of palmerolide A and conversion of biomass into formic acid

School College of Letters, Arts and Sciences

Degree Doctor of Philosophy

Degree Program Chemistry

Publication Date 12/16/2012

Defense Date 10/25/2010

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag ((2R,3R)-3-((2-methyl-1,3-dioxolan-2-yl)methyl)oxiran-2-yl)methanol,((2R,3R)-3-(2-methylallyl)oxiran-2-yl)methanol,((4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-diyl)dimethanol,((4R,5R)-5-(((4-methoxybenzyl)oxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol,((4R,5R)-5-(((4-methoxybenzyl)oxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl4-methylbenzene sulfonate,(2R,3R)-1-((4-methoxy benzyl)oxy)-2-(methoxymethoxy)hex-5-yn-3-ol,(2R,3R)-2,3-dihydroxy-4-((4-methoxybenzyl)oxy)butyl-4-methylbenzenesulfonate,(2R,3R)-hept-6-yne-1,2,3-triol,(2R,3S)-3-methyl-1-(2-methyl-1,3-dioxolan-2-yl)pent-4-yn-2-ol and (4R,5S)-4-hydroxy-5-methylhept-6-yn-2-one,(2R,3S,E)-3-((tert-butyldiphenylsilyl)oxy) 10-((4-methoxybenzyl) oxy)dec-4-ene-1,2,6-triol,(2R,3S,E)-3,6-bis((tert-butyldiphenylsilyl) oxy)-2-hydroxy-10-((4-methoxybenzyl)oxy)dec-4-en-1 yl benzoate,(2R,3S,E)-3,6-bis((tert-butyldiphenylsilyl)oxy) 10-((4-methoxybenzyl) oxy)dec-4-ene-1,2-diol,(2R,3S,E)-3,6-bis((tert-butyldiphenylsilyl)oxy)-10 ((4-methoxybenzyl)oxy)-2-((methylsulfonyl)oxy)dec-4-en-1-ylbenzoate,(2S,3R)-2,5-dimethylhex-5-ene-1,3-diol,(2S,3R)-2-methyl-4-(2-methyl-1,3-dioxolan-2-yl)butane-1,3-diol,(4R,5S)-2-(4-methoxyphenyl)-5-methyl-4-((2-methyl-1,3-dioxolan-2-yl)methyl)-1,3-dioxane,(4R,5S)-2-(4-methoxyphenyl)-5-methyl-4-(2-methylallyl)-1,3-dioxane,(4R,5S)-4-(iodomethyl)-5-(((4-methoxybenzyl)oxy)methyl)-2,2-dimethyl-1,3-dioxolane,(4S,5R)-4-(((4-methoxybenzyl)oxy)methyl)-2,2-dimethyl-5-((phenyl sulfonyl)methyl)-1,3-dioxolane,(4S,5R,E)-5-((4-methoxybenzyl)oxy)-2,4,7-trimethylocta-2,7-dienal,(4S,5S)-dimethyl 2,2-dimethyl-1,3-dioxolane -4,5-dicarboxylate,(4S,E)-methyl 4-((tert-butyldiphenylsilyl)oxy)-4-(2,2-dimethyl-1,3-dioxolan-4-yl)but-2-enoate,(5S,E)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)8-(4-((4-methoxybenzyl)oxy)butyl)-2,2,10,10,11,11-hexamethyl-3,3-diphenyl-4,9-dioxa-3,10-disiladodec-6-ene,(8S,E)-5-(4-((4-methoxybenzyl)oxy)butyl)-2,2,11,11-tetramethyl-8-((S)-oxiran-2-yl)-3,3,10,10-tetra-phenyl-4,9-dioxa-3,10-disiladodec-6-ene,(E)-4-(2-methyl-1,3-dioxolan-2-yl)but-2-en-1-ol,(E)-5-methylhexa-2,5-dien-1-ol,(E)-ethyl 4-(2-methyl-1,3-dioxolan-2-yl)but-2-enoate,(E)-ethyl octa-2,7-dienoate,(E)-methyl 5-methylhexa-2,5-dienoate,(R)-1-((4-methoxybenzyl)oxy)but-3-en-2-ol,(R)-2-((4-methoxybenzyl)oxy)-1-((R)-oxiran-2-yl)ethanol,(R)-2-((R)-2-((4-methoxybenzyl)oxy)-1-(methoxy methoxy)ethyl) oxirane,(R)-5-((tert-butyldimethylsilyl)oxy)-6-hydroxyhexyl benzoate,(R)-5-((tert-butyldimethylsilyl)oxy)6-oxohexylbenzoate,(R)-5,6-dihydroxyhexyl benzoate,(R,E)-(8-ethoxy-2-hydroxy-8-oxooct-6-en-1- yl)triphenylphosphonium iodide,(R,E)-ethyl 7-(methoxymethoxy)-8-((methylsulfonyl)oxy)oct-2-enoate,(R,E)-ethyl 7,8-dihydroxyoct-2-enoate,(R,E)-ethyl 8-((tert-butyldiphenylsilyl)oxy)-7-(methoxymethoxy) oct-2-enoate,(R,E)-ethyl 8-((tert-butyldiphenylsilyl)oxy)-7-hydroxyoct-2-enoate,(R,E)-ethyl 8-hydroxy-7-(methoxymethoxy)oct-2-enoate,(R,E)-ethyl 8-iodo-7-(methoxymethoxy)oct-2-enoate,(S,E)-4-((tert-butyldiphenylsilyl)oxy)-4-((R)-2,2-dimethyl-1,3-dioxo lan-4-yl)but-2-en-1-ol,(S,E)-4-((tert-butyldiphenylsilyl)oxy)-4-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)but-2-enal,1-((4-iodobutoxy)methyl)-4-methoxybenzene,1-(4,4-bis(((tert-butyldimethylsilyl)oxy)methyl)- 2,2-dimethyloxazo- lidin-3-yl)-2-diazoethanone,1-[3,3-bis-(tert-butyl-dimethylsilanyloxymethyl)-1-oxa-4- aza-spiro[4.5]dec-4-yl]-2-diazo-ethanone,1-[3,3-bis-(tert-butyl-dimethyl-silanyloxymethyl)-1-oxa-4-aza-spiro[4.5]dec-4-yl]-2-diazobutane-1,3-dione,1-[4,4-bis-(tert-butyl-dimethyl silanyloxymethyl)-2,2-dimethyloxazolidin-3-yl]2-diazo-ethanone,1-[4,4-bis-(tertbutyldimethylsilanyloxy- methyl)2,2-dimethyl-oxazolidin-3-yl]2-diazo-butane-1,3-dione,1-[4,4-bis-(tert-butyl-dimethylsilanyloxymethyl)-2,2-dimethyloxazolidin-3-yl]-2-diazo-ethanone,1-trifluoromethanesulfonylimidazolidin-2-one ligands,2-(2-methyl-1,3-dioxolan-2-yl)acetaldehyde,2-(2-methyl-1,3-dioxolan-2-yl)ethanol,4-((4-methoxybenzyl)oxy)butan-1-ol,4-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-4 hydroxy-but-2-enoic acid methylester,4-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-4-hydroxy-but-2-enoic acid methylester,biomass,carbohydrates,diazoamide compounds,ethylene glycol,glycerol,glycolic acid,hex-5-en-1-yl benzoate,methyl 2-((4S,4'R,5R)-2,2,2',2'-tetramethyl [4,4'-bi(1,3- dioxolan)]-5-yl)acetate,methyl 2-(2-methyl-1,3-dioxolan-2-yl)acetate,N-cyclohexyl-2-diazo-N-phenyl 2-(phenylsulfonyl)acetamide NHC-Pd complex,OAI-PMH Harvest,oxidative degradation,Palmerolide A,R, E)-5-((tert-butyldimethylsilyloxy)-7-iodohept-6-en-1-yl benzoate,tert-butyldimethyl(((2R,3S)-3-methyl-1(2-methyl-1,3-dioxolan-2-yl)hex-4-yn-2-yl) oxy) silane,trans-1-benzylhexahydro-1H-indol-(3H)-one

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Jung, Kyung Woon (committee chair), Neamati, Nouri (committee member), Prakash, G.K. Surya (committee member)

Creator Email ppullani@gmail.com,pullanik@usc.edu

Permanent Link (DOI) https://doi.org/10.25549/usctheses-m3603

Unique identifier UC1481730

Identifier etd-Pullanikat-4182 (filename),usctheses-m40 (legacy collection record id),usctheses-c127-440514 (legacy record id),usctheses-m3603 (legacy record id)

Legacy Identifier etd-Pullanikat-4182.pdf

Dmrecord 440514

Document Type Dissertation

Rights Pullanikat, Prasanna

Type texts

Source University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

Repository Name Libraries, University of Southern California

Repository Location Los Angeles, California

Repository Email cisadmin@lib.usc.edu