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20m LIBRARY
Michigan State
University
This is to certify that the

dissertation entitled

SYNTHETIC 8: MECHANISTIC INVESTIGATIONS OF
THE NITTIG REARRANGEMENTS AND
SYNTHETIC STUDIES TOWARD AMPHIDINOLIDE A

presented by

FENG GENG

has been accepted towards fulfillment
of the requirements for

PH 1] degreein (ZHEMISIR!

 

rig/«5%) L [106”:

 

Major professor

Date MARCH 231 2001

 

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6/01 cJCIFIC/DateDue.p65—p.15

SYNTHETIC & MECHANISTIC INVESTIGATIONS OF
THE WITTIG REARRANGEMENTS AND
SYNTHETIC STUDIES TOWARD AMPHIDINOLIDE A
By

Feng Geng

A DISSERTATION
Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree of
DOCTOR OF PHILOSOPHY
Department of Chemistry

2001

 

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4' 't"

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ABSTRACT

SYNTHETIC & MECHANISTIC INVESTIGATIONS OF
THE WI'ITIG REARRANGEMENT S AND
SYNTHETIC STUDIES TOWARD AMPHIDINOLIDE A

By

Feng Geng

Synthetic & Mechanistic Investigations of The Wittig Rearrangements

Stereospecificity of [1,2]- Wittig rearrangement reactions

The [l,2]-Wittig rearrangement is an unique radical pair dissociation-
recombination process which can be highly stereoselective. Recent studies suggest that
there could be two distinct mechanisms by which the stereochemical outcome is decided.
Schreiber reported a case in which chelation control sets up the stereochemistry, while
Nakai showed that the [l,2]-Wittig rearrangements of enantiodefined 0t metallated ether
proceeds with inversion of the metal bearing terminus.

We thought it intriguing to consider substrates with an ether oxygen capable of
coordinating with the lithium of the stereodefined lithium terminus, such that Schreiber’s
and Nakai’s mechanism would be in stereochemical conflict. Thus we prepared a set of
stereodefined stannanes and studied their Wittig rearrangements. Our results show that
the "normal" tendency for the worry lithium species to undergo an inversion of
configuration can be suppressed, and even overturned, by controling chelation.

Wittig rearrangements of a—alkoxysilanes
Lewis aCid catalized reaction of ally] and benzyl trichloroacetimidates with oz-silyl

alcohols was found to be a general method for the synthesis of a—alkoxysilanes. Upon

CXposure to CsF, these a—alkoxysilanes could undergo [2,3]-Wittig rearrangement with an

 

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efficiency similar to that realized by the analogous but more toxic a-alkoxylstannanes.
The Wittig rearrangements of these a-alkoxysilanes promoted by alkyllithiums were also
studied. Depending on both the substrates and reaction conditions employed, the [2,3]-,
[1,2]- or [l,4]-Wittig products can be realized. These rearrangements were shown to be
initiated by either Si/Li exchange or deprotonation on to the silane, giving synthetically
valuable silicon containing compounds.

Synthetic Studies Toward Amphidinolide A

Amphidinolide A, isolated by Kobayashi in 1986 from the marine dinoflagellate
Amphidinum sp, is the first member of the amphidinolide family of ca. 20 natural
products. It has marked biological properties, especially activity against L1210 marine
leukemia cells and human epidermoid carcinoma KB cells in vitro. In addition, this 20-
membered lactone has several striking structural features, including the exocyclic olefins
and both conjugated and non-conjugated dienes. Giving these intriguing structural and
biological features, we chose amphidinolide A as a target for total synthesis.

The purpose of this synthetic project is two fold. As this biologically active
compound exists in only extremely limited quantities, part of our goal is to prepare more
material and analogs so as to fully evaluate the biology of these compounds. On the other
hand, the structural features of this molecule provide the challenge and opportunity for us
to invent and develop synthetic methods. Of particular interest are organometallic
methods such as Stille reactions, indium-induced allylations of alkynes, and ring closing
metathesis (RCM) reactions. As a result of out synthetic studies, a molecule with the
proposed amphidinolide A structure was synthesized. During this synthesis, the
aforementioned organometallic reactions were studied and utilized in the key steps, and

valuable insight into these reactions was obtained.

To Bun-Young

iv

 

 

mick .TIC'

ACKNOWLEDGMENTS

I would like to express my deep appreciation to Professor Robert E. Maleczka, Jr.
for his guidance and encouragement throughout the course of my Ph.D. studies. I also
want to thank Professors William Reusch, Gary Blanchard, and John McCracken for
serving in my guidance committee.

I wish to thank Professors Peter Wagner and Babak Borhan for their help. I also
acknowledge Professor Harold Hart for a fellowship founded in his name. I am very
grateful to NMR staff Le Long Dinh and Kermit Johnson, Bev Chamberlin and Rui
Huang at the Mass Spec Facility, and Dr. Donald Ward who conducted the single crystal
X-ray diffraction analysis. Without their support my work would be impossible. I must
also thank our excellent and very supportive secretarial staff Lisa Dillingharn, Nancy
Lavrik, Diane Frost, and DeAnn Pierce. Thanks to all my colleagues in Professor
Maleczka’s group for their friendship and help, especially Lamont Terrell and Joseph
Ward, who have worked so hard to finish our cooperative project. To my friends Ina,
Volker, Edwin, Eric, Gang, and lie, thanks for making my life in the past five years so

much more enjoyable.

TABLE OF CONTENTS

LIST OF TABLES ........................................................................................................... viii
LIST OF SCHEMES .......................................................................................................... ix
LIST OF SYMBOLS AND ABBREVIATIONS .............................................................. xii
CHAPTER 1
INTRODUCTION
1.1. Mechanism studies on the Wittig rearrangement reactions .............................. 1
1.2. Synthetic studies toward amphidinolide A ....................................................... 2
CHAPTER 2
STEREOSPECIFICITY OF [l,2]-WITTIG REARRANGEMENT REACTION
2. 1. Introduction ...................................................................................................... 5
2.2. Preparation of the model compounds ............................................................... 7
2.3. [l,2]-Wittig rearrangements of the model compounds .................................... 8
2.4. Conclusions .................................................................................................... 14
CHAPTER 3
PREPARATION AND WITI'IG REARRANGEMENTS OF a-ALKOXYSILANES
3. 1. Introduction .................................................................................................... 15
3.2. Preparation of a-alkoxysilanes ............................................................. ‘ .......... 1 9
3.3. Wittig rearrangements of a-alkoxysilanes induced by CsF ........................... 20
3.4. Wittig rearrangements of or-alkoxysilanes induced by MeLi ......................... 24
CHAPTER 4
PALLADIUM CATALYZED SYNTHESIS OF ACYLSILANES
4. 1 . Introduction .................................................................................................... 29
4.2. Results and discusson ..................................................................................... 31
CHAPTER 5
SYNTHETIC STUDIES TOWARD AMPHIDINOLIDE A
5. 1. Introduction ....................................... , ............................................................. 33
5.2. Retrosynthetic analysis ................................................................................... 36
5.3. The synthesis of the BCD piece ..................................................................... 37
5.4. The synthesis of fragment A ........................................................................... 47
5.5. Coupling of fragment AB with BCD and subsequent ring closing efforts 51
EXPERIMENTAL PROCEDURES ................................................................................. 55
REFERENCES ................................................................................................................ 111

vi

APPENDICES ................................................................................................................. l 19

APPENDIX 1
NMR SPECTRA OF NEW COMPOUNDS ................................................................... 120
APPENDIX 2
ORTEP REPRESENTATION OF COMPOUND II-22 ................................................ 195

vii

LIST OF TABLES

Table 1. CsF promoted Wittig rearrangements of or-alkoxysilanes ................................... 21

Table 2. Methyllithium induced Wittig rearrangements of a—alkoxysilanes ..................... 26

viii

LIST OF SCHEMES

Scheme 1.1. Wittig rearrangements ..................................................................................... 1

Scheme 1.2. Amphidinolides .............................................................................................. 3

Scheme 2.1. [l,2]-Wittig rearrangement where chelation sets the stereochemistry of the
newly formed alcohol ..................................................................................... 5

Scheme 2.2. [l,2]-Wittig rearrangement with "normal" inversion of configuration at the

metal terminus ................................................................................................ 6
Scheme 2.3. Experimental setup ......................................................................................... 6
Scheme 2.4. Preparation of the model compounds ............................................................. 7
Scheme 2.5. Preparation of the predicted Wittig products of II-12 and II-l3 .................... 8
Scheme 2.6. [l,2]-Wittig rearrangement of model compounds II-12 and II-13 ................. 8
Scheme 2.7. Nakai’s observations on the [l ,2]-Wittig rearrangement ................................ 9
Scheme 2.8. The design of new model compounds ............................................................ 9
Scheme 2.9. [l,2]-Wittig rearrangement of model compound II-06 ................................ 10
Scheme 2.10. [l,2]-Wittig rearrangement of model compound II-l7 .............................. 11
Scheme 2.11. [1,2]-Wittig rearrangement of model compounds II-18 and II-l9 ............. 12
Scheme 2.12. lH-NMR coupling patterns of Wittig rearrangement products ................... 13
Scheme 2.13. The determination of the stereochemical structure of II-08 ....................... 13
Scheme 3.1. Wittig rearrangements of 0, S—acetals initiated by lithium naphthalide ....... 15
Scheme 3.2. Wittig rearrangements initiated by 1,5-hydrogen transfer ............................ 16
Scheme 3.3. Fluoride induced Wittig rearrangements ? .................................................... 16
Scheme 3.4. Relevant previous studies by Reetz .............................................................. 17
Scheme 3.5. Relevant previous studies by N akai .............................................................. 17
Scheme 3.6. Relevant previous studies by Adam .............................................................. 17
Scheme 3.7. Wittig rearrangements of a-alkoxysilanes ? ................................................. 18

Scheme 3.8. Wittig rearrangements of or-alkoxysilanes triggered by Si/Li substitution... 18

Scheme 3.9. Preparation of various or-hydroxysilanes ...................................................... 19

ix

Eden: 3
km): 3

he: 3

 

Scheme 4,
|

Sedan: 4..
313:: 4.
35:2. .3 3,

l5
3 .
“it-31C *.
T I
S‘RIUC '9,

S‘L-S'h" <
S

I;§.‘J\

Scheme 3.10. Failed attempts to prepare various a-alkoxysilanes .................................... l9
scheme 3.11. Preparation of various a-alkoxysilanes ...................................................... 20

Scheme 3.12. exo-Transition state of Wittig rearrangemnets ........................................... 22

Scheme 3.13. Possible intermediate species of flouride promoted Wittigs of

a—alkoxysilanes ............................................................................................ 22
Scheme 3.14. Wittig rearrangements of Ot-alkoxysilane III-02a induced by MeLi .......... 23
Scheme 3.15. Brook rearrangement of III-12a initiated by catalytic amounts of base ..... 24
Scheme 3.16. Origin of III-13a/b ..................................................................................... 24
Scheme 3.17. Isotopic studies of the Wittig rearrangements of or-alkoxylsilanes ............. 25
Scheme 3.18. Formation of B-silyl ketones ....................................................................... 27
Scheme 3.19. Formation of acylsilanes ............................................................................. 27
Scheme 4.1. Formation of acylsilanes ............................................................................... 28
Scheme 4.2. Reactions of acylsilanes ......... . ...................................................................... 28
Scheme 4.3. Preparation of acylsilanes ............................................................................. 29
Scheme 4.4. Preparation of acylsilanes ..................... 29
Scheme 4.5. Pd catalyzed coupling of TMSTBS with carbonyl compounds .................... 30
Scheme 4.6 The formation of tributyltinbenzoate ............................................................. 31
Scheme 5.1 Amphidinolides ............................................................................................. 32
Scheme 5.2. The first synthetic work by Williard ............................................................. 33
Scheme 5.3. Pattenden’s model study on amphidinolide A ............................................. 34
Scheme 5.4. Pattenden’s study towards amphidinolide A ................................................ 34
Scheme 5.5. Retrosynthetic analysis ................................................................................. 35
Scheme 5.6. Retrosynthetic analysis of Suzuki coupling route ......................................... 36
Scheme 5.7. Preparation of V-22 ...................................................................................... 36
Scheme 5.8. Preparation of V-16 ...................................................................................... 37
Scheme 5.9. The stereochernistry of V-16 ........................................................................ 38
Scheme 5.10. DCC coupling of V-16 and (Z)-V-04 ......................................................... 38

Scheme 5.11. Retrosynthetic analysis of nucleophilic replacement route ......................... 39

Scheme 5.12. The synthesis of V-28 ................................................................................. 40
Scheme 5.13. Model study of possible 8N2 coupling route ............................................... 40
Scheme 5.14. Retrosynthetic analysis of RCM route ........................................................ 41
Scheme 5.15. Preparation of V-34 .................................................................................... 41
Scheme 5.16. Indium mediated allylation: Formation of the 1,4-diene ............................ 42
Scheme 5.17. Epoxidation of V-37 ................................................................................... 43
Scheme 5.18. Inversion of the secondary alcohol via Mitsunobu esterification ............... 43
Scheme 5.19. Inversion of the secondary alcohol via oxidation-reduction ....................... 44
Scheme 5.20. The preparation of compound V40 via anti-aldol reaction ....................... 44
Scheme 5.21. The prepartion of BCD fragment ................................................................ 45
Scheme 5.22. The synthesis of V-50 ................................................................................. 46
Scheme 5.23. The synthesis of V-58 ......................................................................... . ....... 47
Scheme 5.24. Synthetic investigations towards fragment AB from D-Glucose ............... 48
Scheme 5.25. Synthetic investigations towards fragment AB from D-Glucose ............... 49
Scheme 5.26. Preparation of V-73 ............................ y ........................................................ 50
Scheme 5.27. Attempted RCM of V-73 and V-75 ............................................................ 50
Scheme 5.28. Trost’s alder-ene reaction ........................................................................... 51
Scheme 5.29. Preparation of V-79 .................................................................................... 51
Scheme 5.30. Preparation of V-82 .................................................................................... 51
Scheme 5.31. Preparation of V-83 and V-84 .................................................................... 51
Scheme 5.32. Ring closing attempts using Trost’s alder-ene reaction ............................. 52
Scheme 5.33. Ring closing metathesis of V-73 ................................................................. 52
Scheme 5.34. Preparation of V-01 .................................................................................... 52
Scheme 5.35. Synthesis of iso-V-01 .................................................................................. 53

xi

Ac
acac
AIBN
aq

CI

Cy

DBU
de
DIAD
DIBAL
DMAP
DME
DMF
DMSO
El

3‘1
FAB

HMPA
HRMS

KHMDS
LHMDS
mCPBA

LIST OF SYMBOLS AND ABBREVIATIONS

acetyl

acetylacetonate
2,2’-azobisisobutyronitrile
aqueous

chemical ionization

cyclohexyl
dicycloheylcarbodiirnide
l,8-diazabicyclo[5,4,0]undcc-7-ene
diastereomeric excess

diisopropyl azodicarboxylate
disiobutylalurninum hydride
4-(dimethylamino)pyridine
dimethoxylethane
N,N-dimethylformarnide

dimethyl sulfoxide

electric ionization

equivalent

fast atom bombardment

hour

hexamethyl phosphorarnide

high resolution mass spectrometry
Homer-Wadsworth-Emmons reaction
potassium bis(trimethylsilyl)amide
lithium bis(trimethylsilyl)amide

m-chloroperbenzoic acid

xii

11:3

3th

Fl

moi
MOM
MS

NIHMC‘
. BS

DIP

 

 

NOE
P318

RCM

Mes
Mesyl

mmol
MOM
MS
NaHMDS

NMP
NOE
PMB

RCM

TBAF
TBS
Tf

Tosyl
Tr
TSA

2,4,6-trimethyl phenyl
methanesulfonyl

minute

milliliter

millimole
methoxymethyl
molecular sieves

sodium bis(trimethylsilyl)amide
N—bromosuccinimide
N-methyl prolidinone
nuclear Overhauser effect
p-methoxybenzyl
pyridine

ring closing metathesis
room temperature
tetrabutylarnmonium fluoride
t—butyldimethylsilyl
trifluoromethanesulfonyl
tetrahydrofuran
trimethylsilyl
toluenesulfonyl
triphenylmethyl

p-toluenesulfonic acid

xiii

CHAPTER 1
INTRODUCTION

1.1. Mechanism studies on the Wittig rearrangement reactions

In 1942 Wittig and LDhmann first described the rearrangement reaction of
a-lithiated ethers to lithio alkoxides.l Since then such reactions of (It-metallated ethers
have been termed “Wittig rearrangements”, and involve the breaking of a C—O bond and
formation of a C—C bond (Scheme 1.1).2 Among them, the [2,3]-rearrangement is a

2 The [l,2]-rearrangement is

concerted process, allowed by Woodward-Hoffman rules.
now generally accepted as a diradical dissociation-recombination process.3 Less is
known about [l,4]-rearrangement. However, it is likely to proceed via a mechanism

similar to that of the [l,2]-rearrangement.2

Scheme 1.1. Wittig rearrangements

 

— 1, I9 Me
[2,3]-shift ‘ 0’ § 2. /
. \ , R"
R 3 R" R' \ 2 OH
3, _ -
2' ,,
/ R .. ' ‘ ® / R"
1, Wittig . 9 1' M '
10 rearrangement [1.ZI-Shlfl 1 o - H ‘
.3 4 A». / —» .. \ .0“
R' \ 2 M R' \
‘ 3 L R
M = Li’, K‘, Cs‘, etc. R"
TNR" MED I
[1,4]-shift ' 09 1' H

 

.__—__.> .1 —>
7 /2 R" O
1“”

In the years following its discovery, the [2,3]—rearrangement has been well studied

 

 

2 Early studies on the [1,2]-

and has found wide applications in organic synthesis.
rearrangement have been mainly mechanistic in origin due to limitations in substrate
scope and the frequently observed low yields of this process. Over the past two decades,

however, the [l,2]-rearrangement has attracted more attention.“ It was found that this

unique reaction, although of radical nature, can be highly stereoselective.4 This intriguing
feature opened the door for useful applications in asymmetric organic synthesis.

In our studies, we aimed to gain a deeper understanding of the [1,2]-
rearrangement, namely how chelation affects the stereochemical outcome of the
rearrangement of stereodefined oc-lithiated ethers.

We also looked at modifying these old reactions by using a-silyl ethers as the
starting substrates. By comparing the chemistry of a-silyl ethers with their stannane
analogs, we obtained new and valuable insight into these rearrangements. Our studies of

the Wittig rearrangement of a-silyl ethers also expanded the scope of this reaction.

1.2. Synthetic studies toward amphidinolide A

The construction of natural and unnatural compounds is the ultimate goal of
synthetic organic chemistry. Total synthesis of natural products serves medical science
by providing bioactive substances and new chemotherapeutic regiments. Organic
synthesis is also a means to measure the aptitude of contemporary organic chemistry, a
theater for the debut of new reactions and reagents, and a driving force for the exploration
and discovery of new chemistry.

Amphidinolide A was isolated by Kobayashi in 1986 from the marine
dinoflagellate Amphidinum sp.sal It was the first of the amphidinolides (Scheme 1.2), a
novel class of approximately 20 natural products, to be isolated.5c The amphidinolides
have marked biological properties, especially activity against L1210 marine leukemia
cells and human epidermoid carcinoma KB cells in vitro. Following their discovery,
these compounds have been the subject of much synthetic effort.6 Williams’ group first
achieved the total synthesis of amphidinolide .I in 1998.6a One year later, the total
synthesis of amphidinolide K was also reported by the same group.6b’° In 2000, they also
accomplished the total synthesis of amphidinolide P.6d However, despite two reported

efforts from Williard and Pattenden,7 amphidinolide A has not been synthesized.

Scheme 1.2. Representative amphidinolides

 

Amphidinolide J Amphidinolide P

In addition to its impressive anti-cancer activity, the ZO-membered lactone has
several striking structural features, including the presence of lipophilic and hydrophilic
moieties as well as the presence of exocyclic olefins and both 1,3 and 1,4 dienes. It is for
these structural and biological features that amphidinolide A was chosen as a target for
our total synthesis.

The relative stereochemistry of amphidinolide A was proposed in 1991 by
Kobayashi based on “suggested information” provided by nOe NMR data.5b However, as
the author pointed out, the “interpretation of the relative stereochemistry of chiral centers
of macrocyclic compounds by spectral means is still not easy”.5b In this particular case,
the correlation between the relative stereochemistry of the hydrophilic moiety and the
lipOphilic moiety is especially weak, thus the assigned relative stereochemical

relationship between the right and left “halves” of amphidinolide A may be in error.

Scheme 1.3. Questions about the relative stereochemistry of amphidinolide A

 

proposed stereostructure possible structure (or its enantiomer)

The purpose of this project is many-fold. Considering the fact that this
biologically active compound exists in only extremely limited quantities, part of our goal
is to prepare more material and analogs so as to more fully evaluate the biologic influence
of these compounds. It is possible that via total synthesis, bioactive unnatural isomers or
derivatives may prove chemotherapeutically superior to the natural product or prove
valuable as tools in evaluating the mechanism by which the amphidinolides act.
Furthermore, we expect our total synthesis to provide unambiguous confirmation of the
proposed structure of this compound. The structural features of this molecule also
provide us with the challenge and opportunity to explore new synthetic methodologies.
Of particular interest are organometallic methods such as Stille reactions,8 indium-

induced allylations of alkynes,9 and ring closing metathesis (RCM) reactions.IO

CHAPTER 2
STEREOSPECIFICITY OF 1,2-WITTIG REARRANGEMENT REACTION

2.1. Introduction
Since its discovery the rearrangement of a-metallated ethers, particularly the
[2,3]-Wittig rearrangement, has been the subject of intensive mechanistic and synthetic

1 Relative to the [2,3]-shift, the [1,2]-Wittig rearrangement has received

investigations.
relatively little publicity. Most studies of the [1,2]-Wittig have been mechanistic in
origin, resulting in the widely accepted theory that the reaction proceeds via a radical pair
dissociation-recombination mechanism.2

In 1987, Schreiber3 reported an important observation on the stereospecific nature
of this rearrangement (Scheme 2.1). Deprotonation of “-01 resulted in “synthetically
useful levels” of the [l,2]-rearrangement product that was heavily biased towards the syn
isomer (II-03). Schreiber postulated that the product arose from bond reorganization via
a diradical transition state in which a lithium tether (ll-02) sets up the syn

stereochemistry. Another surprising stereochemical feature of this rearrangement was the

high level of retention (94%) at the migrating center.

Scheme 2.1. [1 ,2]-Wittig rearrangement where chelation sets the stereochemistry of the
newly formed alcohol

10:1 syn

fl
9 n-BuLi 9H 9

 

/\/0\/\/0 -78 °C to rt,6min \ . O
/ _ 3 VW
: (ca,30°/o yield) ; ‘\
Me Me 94%
"-01 "-03 retention
H
O\Ll‘ ’O+
H , . ‘ H
3 Me 0
"-02

. . . . 4 .. s
Thls observation became more Interesting upon Cohen's and Bruckner’s recent

evidence that [1,2]-Wittig rearrangements proceeded with inversion of the lithium

bearing terminus. Nakai" addressed this question and showed clearly that the [l,2]—Wittig
rearrangements of enantiodefined a-alkoxy lithium’s proceed with retention of the
migrating center and with inversion of the lithium bearing terminus (Scheme 2.2). In
these examples the stereochemistry of the product alcohols is not the result of chelation

control, but rather decided by the configuration of the stannane precursor.

Scheme 2.2. [ l ,2]-Wittig rearrangement with "normal" inversion of configuration at the
metal terminus

90% inversuon

 

Bu3Srj, H /L . \HQ H
¢_ n-BuLI 1
\/1<o 3 ph T th
(IS 38) THF, -78 °C 3
. (87%) ".05 :
"-104 1 98% retention
H; LIQ; H
LL, H \/Q — \/§
Vt A —~ ow QL = 9L
0 Ph (R) P“ (R) P"

While there is little argument with either mechanistic explanation for the observed
stereochemistries, it is important to note that the examples reported by Nakai (as well as
those reported by Cohen and Bruckner) did not have the possibility of chelation control.7
We found it intriguing to consider substrates with an ether oxygen capable of
coordinating with the lithium of the stereo defined lithium terminus. In such substrates
the appropriate stereochemical combination could put Schreiber's mechanism in

stereochemical conflict with the results of Nakai, Cohen, and Bruckner (Scheme 2.3).

Scheme 2.3. Experimental setup

chelation controlled I 1.Z]-Wittig with “normal"
[1.2]-Wittig Bu3Sn Ph Inversron of lithium
rearrangement bearing terminus

I 1 0&0 I
(1R,38) 0+
9H 9 "-06 OH 9
E ? O M0
\/\/\/
a II-07Ill-08=? s
)- C3 )5.

Ph
retention "-07 inverSIon "-08
We therefore sought to prepare and study such substrates so as to provide a deeper
understanding of the [l,2]-Wittig rearrangement. We believed that knowledge of the

stereochemical influences imparted by these two mechanistic pathways, would allow the

discovery of new reaction conditions which should enable the practitioner to predict and
control the stereochemical course of the [1,2]-Wittig rearrangement. Such reaction
control would be of considerable value as it would represent a means for the selective

construction of either syn and anti-1,3 polyols, via a common reaction mannifold.

2.2. Preparation of the model compounds

Our experiments began with the preparation of the stereodefined stannanes “-12
and "-13. We initially chose these compounds as our model compounds because it
would be convenient to analyze and determine the stereochemistry of the Wittig
rearrangement products (vide infra). The syntheses of these compounds paralleled
established procedures8 and involved the displacement of the known enantiodefined
stannyl mesylates9 (R)- and (S)-II-ll by alkoxides of the erythro and threo forms of l-C-
phenyl-2,3-0-isopropylidene-D—glycerols "-09 and "-1010 (Scheme 2.4). This method
provided the desired stannanes in 80-90% yield and in greater than 95% de as judged by

the ‘H—NMR.

Scheme 2.4. Preparation of the model compounds

E 811380 E
- 1 NaH, BUaN', f

Ho/Y\O 2. THF, 0°C IO 11. 3h \/1LO/3\(\O
o ' o
+ Bugs“ H 1R, 3R ‘fi
"-10 \X (S)-ll-11 ".12
OMs

(80%)

JY\ 1. NaH. Bu4Nl. Bu389
HO O 2. THF. 0°C to rt, 3h 3

0+
0
"4’9 BU3$n P‘H (R)-ll-11 18. 38 T“
\)\OM3 "-13

(78%)

 

 

2.3. [1,2]-Wittig rearrangements of the model compounds
2.3.1. Investigation of the [1,2]-Wittig rearrangement of compounds “-12 and [LB
The predicted products of model compounds II-12 and “-13 can be easily
obtained by hydrogenation of the products formed during Schreiber’s study (Scheme 2.5).
Thus it would be useful to repeat Schreiber’s experiments, establish the stereochemistry
of the predicted products, and then study the Wittig rearrangement of our model
compounds. Unfortunately, many attempts to repeat the Schreiber chemistry under the
conditions reported in their Tetrahedron Letters publication33 failed. Attempts to carry
out the Wittig rearrangement of these compounds at —20 0C in THF gave only very
complex mixtures, from which no desired compounds were isolated. After checking the
doctoral dissertation of Goulet,3b we found there was a slight but crucial difference
between the reported conditions and those in the dissertation. Instead of a reaction
temperature of —20 °C as indicated in the paper, the detailed experimental procedure in
the dissertation involved adding n-BuLi at —76 °C and warming the reaction to rt in 6 min
prior to workup. After we adopted the conditions in the thesis, the Wittig rearrangements
were successful albeit low yielding. Thus following this protocol with saturation of the

alkene the enantiodefined products expected from our own rearrangements were

prepared.

Scheme 2.5. Preparation of the predicted Wittig products of II-12 and lI-13

5:1 syn: anti

n-BuLi 9H Ask 10%H Pd/C OH ’9‘?
v ’ I.

With our enantiodefined Wittig products in hand, we attempted the Wittig
rearrangements of model compounds II-12 and “-13. However, under Wittig conditions,

the reactions gave complex mixtures, from which no Wittig rearrangement product was

isolated (Scheme 2.6).

Scheme 2.6. [l,2]-Wittig rearrangement of model compounds II-12 and “-13

81.138“ 5
\X ’ n-BuLi 0H 9
o/Y\O r 0
0+ 0%
"-12 or "-13

This observation echoed Nakai’s conclusions from a study‘r’b‘ll

reported at about
the same time, that for the Wittig rearrangement reaction to proceed, at least one of the

fragments must have some radical stabilizing features (Scheme 2.7).

Scheme 2.7. Nakai’s observations on the [l,2]-Wittig rearrangement

 

 

 

SnBu3 "’B_“7LgégHF en
P" O (90%) HO
SnBu3 "‘Bj‘g'aiggHF Ph
PhAo) A? L
(0%) HO
/L SnBu3 "8";lgbgHF
° C’H‘5 (0%) Ho cIHIs

2.3.2. [1,2]-Wittig rearrangements of compound “-06, II-17, II-18 and II-l9

Scheme 2.8. The design of new model compounds

"-06, "-17. "-18 or "-19

 

Bu3Sn Bu3Sn Bu3Sn Ph Bu3Sn Eh

IR 33 0‘1/\1R3:h°‘f\ 13.33 0+ IS. 3R 0%
"-13 ".19

ll- 17

 

 

Given the experimental results with compounds II-12 and II-13, we reasoned that
a phenyl group instead of the methyl group at C3 should provide the needed radical
stabilization (Scheme 2.8). Thus we prepared compound II-06 and three of its
diastereomers II-l7, II-l8, and II-19 via a parallal route to that used before (Scheme 2.4),
‘ and then studied their Wittig rearrangements.

When a racemic mixture of compounds II-06, II-17, II-l8, and “-19 was
subjected to the Wittig conditions in THF, we were pleased to see the Wittig
rearrangement products were formed in a combined 95% yield. The dramatic difference
between the behavior of II-06, Il-17, ll-18, II-19 and their methyl substituted
counterparts II—12 and [LB convincingly demonstrated the importance of the radical
stabilizing effect.

The [1,2]-Wittig rearrangement of compound “-06 was first investigated by
exposing it to n-BuLi in 30% THF/hexanes, the same solvent system employed by
Schreiber. The reaction product was a mixture of both the syn and anti alcohols (vide
infra),‘2 with the syn alcohol (II-07) in slight excess. While the selectivity was not great,
it did represent evidence that the chelation controlled reaction pathway was operative

(Scheme 2.9).

Scheme 2.9. [l,2]-Wittig rearrangement of model compound “-06

anti

syn

A A
HES“ 9" 9H 9% 0H 9%
\A n-BuLi 7 -‘ 0 Mo

IR, 33 0 retention ) 5h inversjon ) 5h
"-06 "-07 "-08

 

Solvent II-O7III-08

 

10% THE! Hexanes 68 / 32

30% THF/ Hexanes 63 I 37
T 43 l 57

HF
LiCI saturated THF 37 I63

 

 

 

We reasoned that a less polar solvent would further favor the chelation controlled
PrOduct. This proved to be the case as an experiment using 10%THF/hexanes as the

solvent increased the ratio of II-07:II-08 to 68:32 (Scheme 2.9). The same line of

thinking would suggest that a more polar solvent would disfavor the production of the
chelation controlled product. Indeed, running the reaction in pure THF reversed the
stereochemical outcome. Compound II-08, which results from an inversion of the
configuration at the C1 center, became the major product albeit in only slight excess
(II-07:11-08; 43:57). Finally, THF saturated with LiCl was examined in the expectation
that the excess lithium counter ion would break up the intramolecular chelation even
further. In fact, this experiment resulted in a stereochemical turnaround from the
10%THF/hexanes solvent system. The inversion product “-08 was now favored by a
ratio of 2: 1.

Consistent with previous studies, it was found that there was a high level of
retention of configuration at the migrating carbon center. In this case the observed level
of retention was always higher than 90%.

We observed the same pattern upon [1,2]-Wittig rearrangement of compound II-
17 (Scheme 2.10). With this substrate however, changing the solvent polarity had an
even more dramatic effect. Here, we were able to reverse the ratio of II-20:II-21 from
2:1 under conditions for retention of configuration or chelation control
(10%THF/hexanes) to 1:4 in favor of the inversion of configuration or non-chelation
controlled anti product.12

Scheme 2.10. [1,2]-Wittig rearrangement of model compound “-17

syn anti

f'\ r‘\
33L H, 9% .0 9k
. .‘ O

 

n-BuLi 7 " O
1 0/3\(\O —. \/)\‘/\/ + \/)k‘/\/
1R,3R 0+ retention Ph inversion Ph
"-17 "-20 "-21
Solvent ll-20/ll-21

 

10% THFI Hexanes 70 l 30
30% THFI Hexanes 47 I 53
THF 28 I 72
LiCl saturated THF 19 / 5"

 

 

 

For “-18 and “-19, the chelation controlled reaction pathway leads to the
inversion of C1 configuration. So even if a change in the solvent system were to
influence the extent of chelation during the reaction, it should not greatly affect the
stereochemistry of the products. Indeed, the [1,2]-Wittig rearrangement of II-18 and II-
19 always gave the syn alcohol as the main product, regardless of variations in the solvent
system (Scheme 2.11).12

Scheme 2.1 l. [l,2]-Wittig rearrangement of model compounds "-18 and II-19

88-92% syn
A

BU3SQ Ph HQ 9
t E F 0
18,38 0 P“ ~100% retention
64-79% syn
A
81.1339 Eh HQ 9
\/'\o ' slower : : O
1 3 o ___, \/\‘/\/
133/? 0 Ph ‘ ,
89-96% retention
"-19 "'20

It should be noted that regardless of solvent the rearrangment of II-l8 was always
more stereoselective than for that of “-19. This suggests that there is a mutual
recognition on the enantiomers during the recombination of the two radical species.6
Apparently, the RS radical pair is the matched pair and recombines faster than the R,R or
mis-matched pair (Scheme 2.11).

These results clearly Show that the "normal" tendency for the or-oxy lithium
species to undergo an inversion of configuration can be suppressed, and even overturned,
by the solvent effect on chelation. In systems like II-06 and “—17, the stereochemical
course can be controlled to give either syn or anti 1,3-diol compounds as the main
products.

2.3.3. Assignment of the stereochemistry
To determine the influence of chelation effect on the stereochemical outcome of

the reaction, we measured the ratio of the products formed under different conditions by

12

HPLC. Due to the low UV absorbance of the Wittig products, we decided to first esterify
the reaction mixture with 3,5-dinitrobenzoyl chloride, and then measure the product
mixture.

The stereostructure of the alcohols “-07, "-08, “-20 and II-21 were assigned
using both 1H-NMR and single crystal X-ray analysis. The benzyl protons of these
alcohols showed very different coupling patterns (Scheme 2.12). The relative
stereochemistries of diastereomers II-07 and "-20 were easily determined by the 1H-
NMR method emplOyed by Bruckner et al. on similar molecules, due to their distinctive
axial-equatorial-axial and axial-axial-axial couplings respectively.12

Scheme 2.12. lH-NMR coupling patterns of Wittig rearrangement products

4.5Hz

.d
o--H-.o
H
Ph 0
H

"-07 "-08
(axial-equatorial-axial coupling) (equatorial-axiaI-axial coupling)

9.6Hz

 

9.9Hz

3.0Hz

   

"-20 "-21
(axial-axiaI-axial coupling) (axial-axiaI-equatorial coupling)

The sterochemistry of “-08 was secured by a combination of 1H-NMR and single
crystal X-Ray analysis of the tris-3,5-dinitrobenzoate derivative of II-08, compound II-22
(Scheme 2.13). The stereochemistry of the last diastereomer, compound “-21, was thus

assigned by default.

Scheme 2.13. The determination of the stereochemical structure of II-08

 

OH 9% l 0 TN HCI ODNB ODNB
Mo 2 3,5-dinitrbenzoyl chloride (4 eq ), Py 3' ODNB
: o t i
"~08 "-22

2.4. Conclusions

Our results showed that the "normal" tendency for the a-oxy lithium species to
undergo an inversion of configuration could be suppressed, and even overturned, by the
solvent effect on chelation. It was also demonstrated, by the sharp contrast between the
efficiency by which the methyl and phenyl substituted compounds undergo Wittig
rearrangement, that the presence of a radical-stabilizing functionality is crucial for [1,2]-

Wittig rearrangement.

l4

v '7'
lb-

lub—

ITA- ' r

--|\ I

‘-‘-le;._ ‘
l

 

 

 

 

 

 

CHAPTER 3
THE PREPARATION AND WITTIG REARRANGEMENTS OF a-ALKOXYSILANES

3.1 . Introduction

As seen in the previous chapter, Wittig rearrangements are typically initiated by
the formation of an a-metallated ether which undergoes a subsequent rearrangement,
usually in the form of a [2,3], [1,2], or [1,4] shift. While direct deprotonation of an ether
at the a-carbon, usually facilitated by the presence of anion stabilizing groups such as
carbonyls, nitriles, as well as vinyl, phenyl, or alkynyl moieties,l can be used to initiate
the Sigmatropic event, this approach is limited to those compounds possessing sufficiently
acidic or hydrogens. In 1978, Still and Mitra showed that this restriction could be
overcome by generating the a-alkoxy carbanion via tin-lithium exchange.2 In the years
following their pioneering work, the Wittig-Still rearrangement has earned its place as a
powerful synthetic tool. Despite its demonstrated potential, broad application of this
protocol has been governed by its reliance on the relatively toxic3 organnostannes as well

as the need for strong air and moisture-sensitive bases such as n-BuLi.

In order to circumvent these two limitations, several groups have sought "tin free"
alternatives to the regioselective generation of a-ethereal carbanions. Some successful
approaches to this problem have been based on the reductive cleavage of 0,S-acetals with
lithium naphthalenide4 (Scheme 3.1), while others involve Smlz mediated reduction of

diallyl acetals5 or vinyl halides capable of 1,5-hydrogen transfer6 (Scheme 3.2).

Scheme 3.1. Wittig rearrangements of 0,S-acetals initiated by lithium naphthalenide

, //
o/\/\suw Li® Napmria

A

R 81311

// _ _
OMsubst [2,3l-Wltilg 09 L16)
subst
R ‘ Q

 

 

R Li

15

Is" At“

5..

 

 

 

Scheme 3.2. Wittig rearrangements initiated by 1,5-hydrogen transfer

I I 2 5 S"“2 QE/ (Pb \E/ (Pb 1,5 H transfer
0V9" rt, 10 min 0 0
OH

1;!” Sml2 \[L/GDE P“ 56% /\‘/I\Ph
o

In our research group, there were several ongoing projects focusing on the

 

 

development of “tin free” alternatives for reactions such as the Stille coupling.7 Thus we
were drawn to the idea of combining our interest in the synthetic utility of the Wittig
rearrangement with our goal of minimizing the tin requirements in reactions involving
organostannane reactants. In considering tin free alternations for the Wittig-Still reaction,
we envisaged the possibility of a-alkoxysilanes being made to undergo Wittig

rearrangements by the action of fluoride (Scheme 3.3).

Scheme 3.3. Fluoride induced Wittig rearrangements ?

3. 3'

2 M‘F' 2' .
TMS Fifi?" _____________ , M Hf‘R'
. M=K’.Cs’, .
M 1 HMO I

R' ‘\ 2 O Bu3N’.etc.

 

/ / R
1. Wittig . .
rearrangement H 3 R“ H 1
""""" :"m‘ R‘ \ 2 OH R' \ 2 OH R.
2' H [2,3]-shift [1.21-shm [1,4]-shift

Not surprisingly such an approach has been the subject of prior, though very
limited, investigations.8'lo In fact, prior to the original disclosure of Still,2 Reetz and
Greif had shown8 (Scheme 3.4) that the thermal rearrangement of fluorene derivatives

could be facilitated by catalytic quantities of tetrabutylammonium fluoride (TBAF).

‘II an,
1
unit I.
9....” '
I.~yu“
\' v-
‘ I
.Il“‘

 

Scheme 3.4. Relevant previous studies by Reetz

O SlMe3 01 eq TBAF OSIM83

o .. e
O O O 0

Several years later, Nakai reported the fluoride ion-promoted [2,3]-Wittig

 

rearrangement of two C—silylated or-allyloxy esters9 (Scheme 3.5). Interestingly, he noted

that the attempted Wittig rerrangement of the TMS vinyl ether failed.

Scheme 3.5. Relevant previous studies by Nakai

 

 

\ 1. TBAF, -85 °C /
2 H o’
O COzMe ' 3 ‘
31/19., (100%) Ho 002w.-
N 1. TBAF, 435 °C
OYcone 2' ”30 A /
SIMe, (100%) Ho COzMe

W 1. TBAF. as °c
0M8 + /
2. H30

0
%OTMS

(00/0) HO 002Me

To our knowledge the only other report of a fluoride triggered Wittig
rearrangement was by Adam, who converted a-phenoxybenzylsilane into an alcohol
which would appear to be the product of a [1,2]-Wittig (Scheme 3.6).10 However, the
author makes the point that this reaction proceeds via an intramolecular ipso-substitution

Scheme 3.6. Relevant previous studies by Adam
SiMe;

0 \

I / TBAF, MeCN
\ N ft
/ _
N CF; (70%)

 

CF3

. . . . . . . . 11
as Opposed to the radical pair d1ssocratIon-recombmation mechanism of an actual

[1 ,2]-Wittig rearrangement.

 

...~ ‘

 

At the same time, we noted that there are two Wittig rearrangement manifolds
available to a-alkoxysilanes under traditional conditions, such as deprotonation by MeLi
or n-BuLi. In addition to serving as a carbanion mask, the silyl moiety in or-alkoxysilanes
can also be viewed as an anion stabilizing group,“ 13b“: thus both Si/Li exchange and
deprotonation are plausible ways to initiate the Wittig rearrangements of a-alkoxysilanes

(Scheme 3.7).

Scheme 3.7. Wittig rearrangements of a-alkoxytrimethylsilanes ?

3.
2. 3' M R 7 / R" Wittig
TMS\ /H / R" RLi M rearrangement?
. .................. -
. R‘ \ o ‘
R=HorTMS

Interestingly, the Si/Li exchange of a-alkoxytrimethylsilanes, a seemingly
straightforward alternatives to the Wittig-Still rearrangement, has received little attention,
even though such exchange reactions are well precedented.l3 To the best of our

l3a

knowledge, only two examples (Scheme 3.8), both reported by Muzler and List, stand

alone as the only [2,3]-Wittig rearrangements triggered by Si/Li substitution.

Scheme 3.8. Wittig rearrangemnets of a-alkoxysilanes triggered by Si/Li substitution

) ’é’iéL‘Iiié
OH

 

M8354 (68%)
n-BuLi. THF
M -5 ac to 5 cc / \
(0 (78%) 7
OH

SiMe;

Surprisingly, in spite of the fact that the deprotonation path would afford an
unique access to the synthetically malleable silanes,l4 we are unaware of any examples
where the direct deprotonation of a-alkoxysilanes has been used to initiate a Wittig

rearrangement. I 5’ l 6

18

Given the mechanistic uncertainties and narrow substrate scope of these previous
Studies, coupled with little advancement of this chemistry for over a decade, we decided
to explore the possibilities of Wittig rearrangements of a-alkoxysilanes. Key to our study
would be an examination of substrates which would allow the direct comparison of

a-alkoxysilanes with the more established ot-alkoxystannanes.

3.2. Preparation of a-alkoxysilanes

Upon beginning our study, we were quick to realize that few general methods
exist for the synthesis of a-alkoxysilanes with more complexity than that of the (TMS)

17,18

methyl ethers. (Perhaps the main reason for lack of progress in this area.) Although

substituted a-hydroxysilanes are easily obtained via retro-Brook rearrangement'9
(Scheme 3.9), the alkylation of these alcohols in situ20 or under basic conditions proved
difficult21 (Scheme 3.10). Furthermore, while we could efficiently tosylate
a-hydroxybenzylsilane, nucleophilc displacement of the product also failed to provide
any of the desired ethers (Scheme 3.10).

Scheme 3.9. Preparation of various or-hydroxysilanes

 

 

 

 

n-BuLi; OH Ill-01a. R1 = Ph (89%)
TMSCI
THF. 0 “C; R, We, Ill-01b. R1 = —CH=CH2 (90%) 1 Pd/C
RICHon T—B—L—> ‘
l 83er ' 111-o1 Ill-01c. R1 = Et (62%) ._:i 2' ”33*“
Scheme 3.10. Failed attempts to prepare various a-alkoxysilanes
n-BuLi;
then TMSCI
then I-BULI 0U Ban 0A Ph
————>
THF. 0 °c
TosyICl
TEA MOE /
0” THF, 0 ‘c OTosyl ' o/V
PD TMS (80%) Ph TMS (0%) pr. TMS

Several literature reports had demonstrated the compatibility of oc-hydroxysilanes

to acid catalyzed methylation and acetalizations.20’22 Following this lead, we found that

TMSOTf catalyzed etherification of a-hydroxybenzyl and a-hydroxyallylsilane via the
trichloroacetimidates of benzyl, propargyl, and various allylic alcohols23 afforded the
desired a-alkoxysilanes in 50-95% yields24 after silica gel chromatography (Scheme
3.11).

Scheme 3.11. Preparation of various a-alkoxysilanes

 

 

 

 

 

 

 

 

 

 

 

 

 

 

NH
RZOgCCIa

5% TMSOTf.

cyclohexane

rt. overnight

R1 R2 Yield(%)

Iii-02a Ph (B-CHZCH=CHCH3 67
Ill-02b Ph -CH(CH3)CH=CH2 25
Ill-02c Ph -CH2(CH3)C=CH2 55
"1.0“ -CH=CH2 -CH(Ph)CH=CH2 67
Ill-020 Ph -CH2Ph 52
111.021 Ph -CH2CECH 54
Ill-029 -c:H=CH2 -CH2Ph 53
III-02h Et -CH2Ph 63
"1.021 -CH=CH2 (Z)-CHZCH=CHEt 31

 

 

 

 

 

 

3.3. Wittig rearrangements of a-alkoxysilanes induced by CSF

With our general route to a-alkoxysilanes in place, we set out to explore the
action of fluoride on these substrates. Surveying several fluoride sources, we found that
contrary to previous reports, TBAF was not especially effective at promoting Wittig
rearrangement. For example, reaction of III-02b with TBAF in the presence of 4A
molecular sieves gave the [2,3]-rearrangement product III-04 in only 20% yield.
Similarly, neither KF or tetrabutylammonium difluorotriphenylstannate25 provided any
Wittig products. On the other hand, CsF in DMF proved to be relatively efficient at the

Promotion of [2,3]-Wittig rearrangements (Table 3.1). With CSF all of our substrates

20

 

capable of undergoing a [2,3]-shift (III-02a-d) gave [2,3]-products in yields that were

comparable to the analogous lithium anion initiated rearrangements.1

Table 3.1. CSF promoted Wittig rearrangements of a-alkoxysilanes

 

 

 

 

 

 

 

 

 

 

starting .
entry material products (yield)
/ OH
OM [2 3] thig (80V)
1 Ph \ j ' ' °
ph/k TMS 55.45 erythro/three
ill-028 m_03
H
O/iV /?\/\/
2 A ph \ [2.3]-Wittig (60%)
Ph TMS [(1.04
III-02b
3 , 0
MIA ms Ph [2.31-wIttIg (79 lo)
III-02c Ill-05
Ph OH 1:1
/ H \ J
4 0 \ \ Pl'l \
v Ph
ms III-06 III-07
Ill-02d [2.3I-Vthi9 (54%) [1.2I-Wltti9 (13%)
A Ph /\ Ph
5 i j (61%)
Ph ms
III-020 9" Ill-08
/\
5 i \ j/\\\ (54%)
Ph ms
Ill-02f P" III-09
/\
\i P“ o/\ Ph 0A Ph
7 \ TMS ‘12 "1°10 (63%) V
Ill-029 88:12 E/Z Ill-11 (14%)
0A Ph
8 \A No Reaction
TMS (80% recovery of Ill-02h)
Ill-02h

 

 

 

 

While the scope of this preliminary investigation limits us in making any
extensive stereochemical comparisons to the rearrangement of analogous a-lithio
compounds, the rearrangement of III-02a did exhibit the same (albeit poor) inherent
stereochemical bias towards the erythro product, as its lithio counterpart."26 Likewise,

the exclusive E-olefin formation observed in entries 2 and 4 (Table 3.1) would suggest

21

that the fluoride induced Wittigs proceed via an exo transition state as proposed by Nakai

for traditional Wittig rearrangements of this type (Scheme 12). “27

Scheme 3.12. exo-Transition state of Wittig rearrangements

i H- . , Ph
9

Ph M H

 

 

Our initial results indicate that efficient fluoride promotion may be primarily
limited to [2,3]-sigmatropic events. Only entry 4 (Table 3.1) showed any propensity for
another Wittig manifold, providing the [1,2]-species as a minor product. Only loss of the
silyl group was observed for other substrates set up to undergo [1,2]-Wittig
rearrangement (Table 3.1; entries 5-7). This observation that the fluoride promoted
rearrangements mimic their lithio counterparts during the concerted [2,3]-shift, but not
during the radical pair dissociation-recombination driven [1,2]-Wittig rearrangement,
suggests the involvement of a metal associated carbanionic intermediate. This would
contrast with the traditional Wittig-Still, for which Briickner28 has put forth experimental
evidence of a metal free carbanion. What is less clear is whether these fluoride promoted
Wittigs involve a pentavalent silicon intermediate (Scheme 3.13, I)'7b‘29 and/or the type

of cation coordinated species suggested by ab initio calculations (Scheme 3.13, 11).30

Scheme 3.13. Possible intermediate species of fluoride promoted Wittigs of
ot-alkoxysilane

Om [/ 0:74. Ph H O
A ——’ P" PKG and/or /Si\— —2—> Ph \
Ph M F i F

22

Finally, it would appear that some activation of the starting material (benzylic or
allylic) is required. Aliphatic a-alkoxysilanes (Table 3.1; entry 8), for example, failed to

react under our conditions.

23

3.4. Wittig rearrangements of a-alkoxysilanes induced by MeLi

Next, we evaluated these a-alkoxysilanes under "standard" Wittig rearrangement
conditions. Thus a solution of a-alkoxysilane III-02a in THF was subjected to 1.5 eq. of
a 1.4M ethereal solution of MeLi at room temperature (Scheme 3.14). We were
immediately struck by the formation of C-silyl containing reaction products (III-lZa/b),
providing clear evidence of III-02a undergoing deprotonation followed by subsequent
Wittig rearrangement. This is in contrast to exclusive silicon-lithium exchange reported

a

for the two Wittig precursors studied by Muzler.l3 The C-silyl alcohols were
accompanied by a diasteromeric mixture of desilylated alcohols (III-03a/b), along with a

small amount of the corresponding silyl ethers (III-13a/b).

Scheme 3.14. Wittig rearrangements of a-alkoxysilane III-02a induced by MeLi

 

/ HO J’MS 0“ QTMS
CM 1.5 eq. 1.4M MeLi/E120 :‘ '
/]\ 2 Ph \ + ph \ + Ph/Y\
Pn TMS THF, rt, 16h; then H20
Ill-023 Ill-12!!!) (1.4;1) Ill-0381b (1.2;1) III-1381b (2 1)
(41%) (20%) (9%)

The formation of such a reaction mixture posed several challenges. First,
although the level of stereocontrol displayed by the reaction was poor,” we wished to
specifically identify the stereochemistry of III-12a and III-12b. Fortunately, both
diastereomers proved readily separable by flash silica gel chromatography. Therefore, we
could subject pure III-12a (the major isomer) to base catalyzed Brook rearrangement
(Scheme 3.15).32 Since such rearrangements proceed with an inversion of configuration at
carbon,” the reaction afforded a single silyl ether. Desilylation then afforded the known
alcohol III-03b31’34, which was the minor alcohol produced by the reaction. Thus the
Brook product could be assigned as III-l3a, furthermore given the stereospecificity of the
Brook rearrangement, we could also confidently assign the relative stereochemistries of

III-12a and III-12b.

24

 

 

 

 

' a. ‘v-
1

k‘_.‘
5

Scheme 3.15. Brook rearrangement of III-12a initiated by a catalytic amount of base

HO JMS (cat) MeLi, QTMS QH
3 THF, 1‘1; E HCI ?
Ph \ -———> Ph \ —-‘ Ph \
then H20 THF
Ill-128 III-13a III-03b

Additionally, the contrasting (albeit small) stereoselective preferences observed in
the formation of the C-silyl alcohols (syn with respect to the oxygen and Me group
preferred) vs. the silyl ethers (anti with respect to the oxygen and Me group preferred) is
evidence that III-l3a/b are the result of III-12a and III-12b undergoing in situ Brook

rearrangement prior to quenching (Scheme 3.16).

Scheme 3.16. Origin of III-13a/b

,—

Li SQTMS 7

Pn)\‘/\

/\%\ /\%\ H Fms H sows
MeLi i H20 ‘ + I \
P" TMS Ph TMS
111-0211 L' lll-12alb (1.4:1) 111-1 3a/b (2: 1)

LiO \JMS (41%) (9%)

 

 

What was less clear was the origin of the desilylated alcohols (III-03a/b).
Obviously, Si/Li exchange initiated [2,3]-rearrangement would account for their
formation, but an alternative path involving in situ loss of the silyl group from either III-

lZa/b or III-l3a/b was also envisaged.

While the stereochemical course of the reaction could again be used to argue
against the in situ conversion of 111-13 to III-03, the very low levels of selectivity made it
difficult to rule out this option with any significant degree of certainty. So to bring more
Clarity to this issue, we decided to prepare and react (Scheme 3.17) the deuterated analog
0f III-02a (III-02a-d1). The starting material was prepared by LAD reduction of methyl
benzoate,35 followed by a retro-Brook sequence36 and then etherifcation. Wittig

rearrangement of III-02a-d, gave the C-silyl, dessilyl, and O-Silyl materials, although in

25

this case the dessilyl alcohols (III-03a/b-d1) were the major products, reflecting a
relatively large deuterium isotope effect.37 Significantly this material appeared to be fully
deuterated as judged by lH-NMR, providing strong evidence that it is produced solely via

the Si/Li exchange pathway.

Scheme 3.17. Isotopic studies of the Wittig rearrangements of a-alkoxylsilanes

NH

 

 

(99%) Mo CCls
PhCOzMe > ph OH > /i\
2. n-BULI. TMSCI D 5% TMSOTf, P" D "“5
THF, 0 °C; Ill-01a-d1 cyclohexane. rt. 12h |||.023_d1
then i-BuLl, (56%)
-78 °C (21%)
MeLi THF H oms
rt,16h
then H20
I|l12alb(1 4 1) lll13a/b (2 1) Ill-03a-d1/lll-03b-d1(1 1 1)
(12%) (1. 5%) (73%)

Having gained a reasonable understanding of the behavior of III-02a towards
Wittig-Still conditions, we next subjected several other oc-alkoxylsilanes to methyllithium
(Table 3.2). With substrates set up for [2,3]-Wittig reaction (entries 1 and 2), the overall
efficiency of the rearrangements were good. However, once again, the rearrangements
proceeded via both the Si/Li exchange and a-Silyl anion manifolds. With substrates set
up to only undergo [l,2]-Wittig rearrangement (entries 3 and 4), the anticipated reaction
did occur. However, as is often the observation with [1,2]-Wittigs, the yields were low
and again both Si/Li exchange and a-silyl anion formation appeared operative.
Unfortunately, our attempts to drive these rearrangements down a single reaction path via
standard methods were less than fruitful.

Intriguingly, when we moved from the a-alkoxylbenzylsilanes to
OL-alkoxylallylsilanes (entries 5-7), the extent of Si/Li exchange was significantly
curtailed. However, these substrates did displayed a propensity for silyl migration to
afford B-silyl ketones. For example, a-alkoxylallylsilane III-02i gave the [3-silyl ketone

III-21 in a remarkable 92% yield. We propose that this product comes about via [2,3]-

26

Wittig rearrangement of the a-silyl anion followed by a net 1,3-silyl migration (Scheme

3.18)”.

Table 3.2. Methyllithium induced Wittig rearrangements of or-alkoxylsilanes

 

 

 

 

 

 

 

 

 

 

 

entry figs; products (yield)
/|\¢ 0H Ill-04 R = H (75%)
o Ill-14 R = TMS (21%)
1 A P“ \ [a 21w1r
. - llQ
Ph TMS R
Ill-02b
0H Ill-15 R =TMS (50%)
2 i M Ill-05 R = H (32%)
Ph
P" we R (3.21-wmig
Ill-02c
/\
3 i p" 0” Ill-16 (9%)
p 1. -w '
Ph TMS ph ” i 2] ““9
Ill-020
0/\\\ H / 111-17 R = H (33%)
4 A / Ill-18 R = TMS (15%)
96 ms Ph 1 2w .
Ill-021 R l . 1 “"9
P“ m 0 111.19 (60%) via
0*? \ Ph [2.3j-Wittlg
5 \A OH
\ ms \/‘\/\/ Ill-20 (20%)
Ill-02d \ \ 9" [2.3l-VVittig
Et
ms 0
CA) W 111-21 (92%)
6 \
\ . .
TMS Et Via [2,3}-V\flttig
Ill-021
p
OAPh h 0 ms 0
7 v |\)i\/Ph
TMS TMS
"(.029 111-22 (60%) 111-23 (21%)
[1 .4]-\N1ttig via [1 .2]-Wittig

 

 

In a further departure from the a-alkoxylbenzylsilanes, allysilane III-02g
rearranged in high yields albeit via a mixture of both [1,4]- and [1,2]-Wittigs (111-22 and

l3c,39 l3c,40

III-23). Given the synthetic utility reported for acylsilanes and B-silyl ketones,
this route enhanced the synthetic value of both the a-alkoxysilanes and the Wittig
rearrangement reactions. Additionally, since this compound is formed via an enolate
intermediate, it is also perceiveable that combining these rearrangements with the capture

of Various electrophiles will lead to an even more diversified group of acylsilanes.

27

M y"-
Unis

~\i.

Indeed, our preliminary results showed that, when the Wittig rearrangement reaction was
quenched with allyl bromide, the a-allylated product III-27 could be formed in 16% yield
(Scheme 3.19).

Scheme 3.18. Formation of B-silyl ketones

51 TM 0

1.
1 /\/l 3‘ 1 5 eq. 1.4 M MeLi/EtZO Et
d 2' THF, rt. 16h
2 TMS = /

 

 

 

(92%)
Ill-02l III-21
MeLi ’
[2,31-Wm19 H30
TMS Cu 1 I 7 1 TM 0L1
\ Et 51 y mngra Ion ‘ / a
2 3,
/ /
Ill-24 Ill-25

Scheme 3.19. Formation of acylsilanes

1.

 

/\ 1.59q. 1.4MMeLi/Et20
1
d p" THF. rt, 16h Wi
. _ Ph
3 2 TMS (60%) TMS
Ill-029 Ill-22
MeLi H30.
[1 ,4]-Wittig

O

OL' allyl Br, TEA Pn
PhM - ms
TMS (16%) \
Ill-26 Ill-27

 

28

 

1.
Mpu .

LG,

 

{V ‘3',

u ”"H

CHAPTER 4
PALLADIUM CATALYZED SYNTHESIS OF ACYLSILANES

4.1 . Introduction

During our study on the Wittig rearrangement reactions of a-alkoxylsilanes,
acylsilane (III-22) was isolated in very high yields from one of the reactions. This is the
first time an acylsilane has been prepared via a Wittig rearrangement reaction. Because
this reaction proceeds through an enolate intermediate, a variety of acylsilanes are
accessable through the same path. This discovery opened the door for a new route to

these useful compounds.

Scheme 4.1. Formation of acylsilanes

‘1

1 OAPh 1.5 eq. 1.4 M MeLi/EtZO O

 

THF. rt. 16h
4 v TMS - Ph \/\/u\
a 2 (92%) ”‘5
Ill-029 “1.22

Indeed, acylsilanes have attracted much attention as a versatile tool in organic
synthesis since many unique and valuable reactions can take place with these

compounds.1 Scheme 4.2 illustrated two such possible transformations. Via simple

1a

reactions, both 2-silylthiacycloalk-Z-enes of various ring sizes and variety of enol

etherslb can be obtained.

Scheme 4.2. Reactions of acylsilanes

TMS

o
5 SH
RM st R NaHCOa R r: NaOH \ 1
n TMS __. n TMS—a n ms ————-—~ 3 ) l)
x C n
x x

R

G) OTMS
0 L10 TMS OTMS E

R TM R \ R \ R E (2)
S \ R' Ll \ R' Y

R'

 

 

 

29

Along with these studies, many methods have been developed to synthesize this
family of compounds. One of the most common methods mirrors the synthesis of normal

ketones, namely hydrolysis of silylated 1,3-dithianes.2

However, this method suffers
from mediocre yields and requires the often difficult hydrolysis of the dithianes (Scheme
4.3, entry 1).2 Another general method is the acylation of silyl-metal compounds, but this

method often suffers from rather poor yields (Scheme 4.3, entry 2).3

Scheme 4.3. Preparation of acylsilanes

HgClz, HgO
m MeOH, H20 0

S><S

R TMS

 

(1)
25-60% R ms

9 (9]
o [TMS M

JL - JL (2)

R Cl M = Li. Cu. AI R TMS

 

Recently, a very convenient and safe method was reported by Yamamoto.4 When
substituted benzoyl chlorides reacted with hexamethyldisilane under palladium catalyst,
acylsilanes were produced in 37-81% yields. However, the authors reported that this

method failed to provide aliphatic acylsilanes.4’ 5

Scheme 4.4. Preparation of acylsilanes

o 5% [(n3-03H5)PdCI]2 o
10% P(Et0)3
x + Me3SiSiMe3 ; S'M‘” + TMSX
_ 0
R (37 71/0) R

Due to the absence of a general and convenient method to prepare these

 

synthetically useful acysilanes, we decided to investigate the possibility of modifying
Yamamoto’s method to allow the preparation of both aromatic and aliphatic acylsilanes.
Based on the fact that the transmetallation of tin is much more facile than that of silicon,6
we speculated that trimethylsilyltributylstannane (TMSTBS), a commercially available

and easily prepared compound,7 should be a good silicon source for this reaction.

30

4.2. Results and discussion

Scheme 4.5. Pd catalyzed coupling of TMSTBS with carbonyl compounds

5% [(na-C3H5)PdCI]2

 

 

 

 

 

 

 

 

 

 

 

 

o 0
/U\ + n-Bu3SnSiMe3 = + n-Bu3SnX
R X 10% P(Et0)3 R SiMes
Entry R x Temp. (°C) Time Yield (%)
1 n-C4H9 Cl 100-110 20 min 63
2 n-C7H15 Cl rt 15 days 43
3 n-C7H15 Cl 100-110 16 h 74
4 C.HiEt)CH Cl 75 10 h 45‘
5 cyclo—CQHH CI 75 12 h 56
6 Ph Cl 100-110 20 min 66
7 Ph PhCOO 100-110 20 min 18
8 Ph CI 75 100 min 57’
9 o-ClPh Cl 100-110 20 min 30
10 p-MeOPh Ci 100-110 20 min 35

 

 

 

 

 

 

 

 

a. reactions were carried out under CO atmosphere

Thus TMSTBS and benzoyl chloride were mixed together with di-m-chloro-
bis(n3-allyl)dipalladium and triethylphosphide4 at 110 °C, the same catalyst and
temperature used by Yamamoto. We were pleased to see the pale yellow solution turned
black after 10 min due to the formation of metallic Pd, suggesting sucessful coupling.
Indeed, GC analysis showed that at this point the acyl chloride was completely consumed.
With hexamethyldisilane, the reaction needed more than 1.8 h according to Yamamoto’s
report. Later it was found that even at room temperature the reaction also took place. A
reaction of n-octonyl chloride at rt over 15 days gave the acylsilane in 43% yield. In light
Of this observation, the reaction temperature was later set at 75 °C. Although the reaction

of aliphatic compounds took ca. 10 h to complete, those of aromatic compounds were

31

1 ‘- N1

..
.3

”3‘.

 

'0-

complete in 2-3 h. The possibility of carrying out the reaction at lower temperature is
important since some of the acylsilane compounds are not very stable. In the original
method, the reaction did not occur at 70 °C.

This method appears to be general. Both aliphatic and aromatic acysilanes can be
obtained with fair yields (Table 4.1). The major drawback of this method is the
competing formation of the corresponding acylstannane species. For example, although
the reaction of benzoyl chloride proceeded clean and fast, significant amount of
benzoylstannane was formed (29%), diminishing the yield of the acylsilane. However,
the unstable acylstannane compounds8 can be easily separated from the acylsilane and
ultimately converted back to the starting acid chloride.

Scheme 4.6. The formation of tributyltinbenzoate

O 02 (air) 0 O

)L

Ph SnBu3 ph OSUBU3 Ph Cl

 

32

CHAPTER 5

SYNTHETIC STUDIES TOWARD AMPHIDINOLIDE A

5. 1. Introduction

Scheme 5.1 Amphidinolides

 

Amphidinolide A man Amphidinolide J (v-oz)

   

33H

 

Am phidinolide K (V413) Amphidinolide P (V-04)

Marine microalgae are of considerable interest as new promising sources of
bioactive substances. The amphidinolides (A-V) (Scheme 5.1), a novel and significant
class of natural products, were isolated by Kobayashi from such algae.l Amphidinolide
A (V -01) was isolated and identified in 1986 from the marine dinoflagellate Amphidimim
Sp.” Since 1986, approximately twenty members of this unique series of polyolefinic
macrolide compounds have been isolated. However only a few amphidinolides have had
their stereochemistries fully elucidated. The relative stereochemistry of amphidinolide A
was proposed in 1991 by Kobayashi based on information provided by nOe NMR data.lb
However, as the author pointed out, the “interpretation of the relative stereochemistry of
chiral centers of macrocyclic compounds by spectral means is still not easy”.5b In this

particular case, the correlation between the relative stereochemistry of the C8-C 12 moiety

33

and the C18-C22 moiety is especially weak; thus the assigned relative stereochemical
relationship between the right and left “halves” of amphidinolide A may be in error

(Scheme 1.3).

In addition, this 20-membered lactone has several striking structural features,
including the presence of lipophilic and hydrophilic moieties, as well as the presence of
exocyclic olefins and both conjugated and non-conjugated dienes. Amphidinolide A also
has marked biological properties, especially activities against L1210 marine leukemia
cells and human epidermoid carcinoma KB cells in vitro. It is for these biological and

structural features that amphidinolide A is a current target for total synthesis.2

To date, only two other groups in addition to ours3a have reported synthetic efforts
toward this target. The first reported synthetic work was from Williard in 1989.3b

Scheme 5.2. The first synthetic work by Williard

OMOM

V-OS

 

V~07

Williard’s work was done prior to Kobayashi’s stereochemistry elucidation.
Therefore in his approach, methodology was developed to prepare all possible
stereoisomers of the Clo-C19 fragment V-05, in order to make an unambiguous
assignment of the stereochemistry. From his reaction sequences, the other stereoisomers
were readily available through the simple change of chirality in the starting material.
Either enantiomer of ester V-06 was readily available from (+) or (-)-tartaric acid; and

sulfone V-07 was prepared from commercially available (S)-(+)-methy1-3-hydroxy-2-

34

111""
3.

1"1'
“Ln

1“.“
“is g
A

methylpropinate, whose enantiomer is also commercially available. Since this early and

limited publication in 1989, no other effort has been reported by the Williard group.

The second group to embark on the challenging task of synthesizing
amphidinolide A was Pattenden’s.3°‘d In 1994, Pattenden published his first of two
studies on amphidinolide A, in which a model study was undertaken to investigate the
feasibility of a cross-coupling macrocyclization (Scheme 5.3).3c The chemical
transformation investigated was a palladium mediated intramoleculer coupling of an
alkenyl stannane and an allylic halide. The methodology proved moderately successful
when applied to the model system V-08. The desired macrocycle V-09 was obtained in a
38% yield along with the Z-isomer (6%) and the allylic isomer V-10 (2%).

Scheme 5.3. Pattenden’s model study on amphidinolide A

 

E/Z 6.3/1
/
+ /
Mo I / / O
v-oe ° v-10 °
(44%) (2%)

In his second publication, Pattenden outlined his synthetic approach towards the
natural product (Scheme 5.4).3d The underlying theme of this retro-analysis was the
application of the above mentioned spz-sp3 coupling methodology. In studies aimed at
providing the properly functionalized coupling partners, he prepared the C7-C13

Scheme 5.4. Pattenden’s study towards amphidinolide A

 

Amphidinolide A

 

35

ii:

{31

II

ene-tetrol unit V-ll, from a readily available derivative of D-glucose in 13 linear steps

with an overall yield of 2%.

Although to date no total synthesis of amphidinolide A has been reported, the
total synthesis of three members of this unique series of natural products, amphidinolide

J, K, and P, have been accomplished by Williams?

Besides the desire to obtain amphidinolide A, its isomers, and derivatives for
biological testing, a goal of this research venture was to apply and evaluate new synthetic

methodologies, especially those involving organometallic chemistry.

5.2. Retrosynthetic analysis

Scheme 5.5. Retrosynthetic analysis

 

V-14

An early retrosynthetic analysis, shown in Scheme 5.5, gave four unique building
blocks, with V-13 being utilized twice. This convergent plan allowed us the freedom of
Choosing the sequence and order in which the fragments would be joined. Formation of
the C7-C8 and C12-C13 bonds can be envisaged via a chelation controlled nucleophilic
addition of a vinyl metallic species to the precursor aldehydes. The conjugated diene can
be constructed via Stille type6 cross-coupling to form the C3-C4 0 bond, while the
laetone linkage can be formed with traditional methods such as DCC or Mitsunobu
coupling. To form the C16—Cl7 bond, we decided to first explore a Suzuki type8

Coupling of V-15 and V-13 or their derivatives.

36

11‘
l”
’I)

1‘).
SJ)

‘JI
1‘)

£01;

'I.
i-)
’J‘

 

 

 

 

 

i» r‘ "
I 21‘”); ..

~ 1'." "4,
:Iicru‘

5.3. Synthesis of the BCD piece
5.3.1. Suzuki coupling route
5.3.1.a Synthetic plan

Scheme 5 .6. Retrosynthetic analysis of Suzuki coupling route

 

 

 

 

 

 

 

 

 

{IL ("(3)2B
Br
v.13 . '3 . =9 5 5‘ \‘
s. a‘ - 6‘
1 OH
W we V46
0
V-14

To explore the planned construction of the C 16—C l7 bond through a Suzuki
coupling,8 we would need to prepare boronic acid V-lS. Thus alkene V-l6, which could

be readily hydroborated, became our initial target.
5.3.1.b Preparation of compound V-16

Scheme 5.7. Preparation of V-22

 

 

 

 

o o 0
H01 Um Me JL H 1) n-euu Mk JL
Me—NH OH — ‘N N’ ~ N N
\_/ 160-21 590. 3 hr \_1 2) proponyl chloride \_./
~13“ ’Pn 50% Me‘ 9911 °°°’“ Ma‘ ’1»:
quant.
v-17 we
0 O
1)NaHMDS M, )L W 1)H2Pd/C /\/\/ 1)Swem
4, ‘N N , —. H0 3 :
2) attyi bromide \_l é 2) 1.18114 5 2) Ph3P=CHCOOEt
46°C overnight ~“ ‘2 62 % 96%
quant. W P“ V-20
me
o
DIBAL W
.=. 80% 5
v-21 V'22

The preparation of V-16 followed the procedure shown in Schemes 5.7 and 5.8.
Following Well established procedures, the acylation of V-l7 and subsequent allylation

Proceeded with nearly quantitative yields. No column chromatography was needed until

37

cl

iii

the isolation of V-20. One-pot Swem oxidation and Wittig olefination provided V-21 in
very high yield. The Sharpless epoxidation of V-22 also proceeded smoothly (Scheme
5.8) as did oxidation to the aldehyde. However, the addition of isopropenyl magnesium
bromide to V-24 gave a mixture of two diastereomers. A simple model study suggested
that a chelated addition should lead to the desired R configuration at the alcohol center.
However, the reactions carried out in THF with magnesium bromide etherate added as a

chelating reagent gave a separable 1.2: lmixture of V-l6 and its diastereomer iso-V-16.

Scheme 5 .8. Preparation of V-16

W SharPIGSS HO\/\J\/\ 803' P’ OW
0‘
V 24

§ 66%

 

 

v-22 V- 23
isopropenyl MgBr
THF -CBO-1OO _ i
‘ ‘ - V + ‘5‘
f 5 60 6‘
53%) 6H CH
V-16 1.221 Ito-V4 6

In pure benzene, the addition of isopropenyl magnesium bromide to aldehyde
V-24 gave a complex mixture. Crude 1H NMR of the major products suggested that the

epoxide ring was not tolerated under these reaction conditions.

Given the difficulty of controlling the stereoselectivity of this addition, we
decided to solve this problem by correcting the “wrong” chiral center later during the
esterification step. This of course would be possible by joining V-16 and V-l4 by way of

a Mitsunobu type reaction (vide infra).9

To determine the stereostructure of the two diastereomers V-16 and iso-V-16, the
(S)-(+)- and (R)-(-)-methoxyphenylacetates of V-l6 were prepared. By comparing the
chemical shifts in the 1H-NMR of these compounds, the stereostructure of the secondary
a1C0hol center in compounds V-25 and V-26 was determined using methods developed

by Mislow, Mosher, and Trost.lo The 1H NMR signals of the C1 protons of V-26 (4.72

38

and 4.60 ppm) appear at higher fields than those of V-25 (4.99 and 4.93 ppm) as a result
of the shielding effect of the phenyl group. Similarly, the C4 proton of V-25 (2.30 ppm)
appears at higher field than that of V-26 (2.64 ppm). Applying the empirical rules
described by Trost,10 it was clear that V-l6 has an R configuration at C3, the same

configuration as the C19 center of amphidinolide A.

Scheme 5 .9. The stereochemistry of V-16

(R)-(-)-a-methoxyphenylacetic acid

 

 

 

DCC. DMAP(eat.) O 6
T
1 ‘ PM" aw V45
2 3 ; 5 _
1 5st"
6H 1 ‘
V45 2 3 5 5
(S)-(+)-a-methoxyphenylaoetic acid 5 5w
= o 6
DCC. DMAP(caL) .
61% j: V 26
Ph 0M6

5.3.1.c Connection of fragment C to B and D

Knowing the stereochemistry of this carbon center, we then subjected V-l6 to a
DCC coupling with (E)-V-l4. This reaction successfully provided compound V-27 in
54% yield. Unfortunately, the stereoselective hydroboration of compound V-27 to form

V-lS was problematic.ls Thus despite all efforts this route was abandoned.

Scheme 5.10. DCC coupling of V-l6 and (Z)-V-l4

  

 

 

(H0123
1 COOH -
. ’ (AV-04 ; - t' : - \"
= \' O a O
i a“ = ---------- r»
M X
occ.oMAP(cat) I / ' /
V4 6 54% V-27 V-1 5

39

5.3.2. Nucleophilic replacement route
5.3.2.a Synthetic plan

After abandoning the Suzuki approach, we investigated the possibility of forming
the C16-C17 bond by 8N2 displacement of an activated oxy group or halide at C17 by a
vinyl metal species. The original plan was to metallate V-l3, and react it with a primary
halide or tosylate (V-28). However, the vinyl cuprate of V-l3 could not effect the SN2
displacement of tosylate V-28. Attempts at generating and reacting the corresponding
vinyl lithium also failed to provide any desired coupling. However, the failure of this
reaction may have been due to difficulties in generating the active lithium species (i.e.
allene formation). Thus it was decided that this approach should be further investigated,

but with a different building block, compound V-29.

Scheme 5.11. Retrosynthetic analysis of nucleophilic replacement route

 

 

1'03le v.23

\

 

 

 

CTBS

 

 

 

 

 

Br I OH
\ /
“TMS W
5.3.2.b Synthesis of compound V-28

The synthesis of compound V-28 paralleled that of compound V-16 (Scheme
5.12). Compound V-22 was oxidized to aldehyde V-30, which was then subjected to an
Evans aldol reaction,ll providing compound V-31 as the sole product in fair yield. After
prechelating the hydroxyl group with tri—n-butylborane,ll it was then reduced with LiBH4
to give the diol V-32 in good yield. Monotosylation was also successful, and after
protection of the secondary alcohol, this modified C fragment (compound V-28) was

ready to be coupled.

4O

Scheme 5.12. The synthesis of V-28

1. SOaPy, DMSO
2. BUZBOTf. TEA O£N Acetic acid "'BUgB
acyiAx then LiBH.
/
. Pig—j ,,

 

 

74%

“5340 TosyiO
TWMAP 0' TEA TBDMSOTi. TEA
quant
ores”

5.3.2.a 8N2 coupling: model study

 

 

 

 

 

 

Dithiane V-29 was subjected to the lithium-halogen exchange by t-BuLi (Scheme
5.13). The resultant vinyl lithium species was treated with mesylate and alkyl halides.
Alternatively, it was pre-treated with MgBrz to form the corresponding vinyl Grignard
prior to addition of the halide. Judging from the experimental observation of color
change and deuterium quenching results, it is clear that the vinyl metallic species I and II
were formed successfully (Scheme 5.13). However, no displacement of the bromide or
mesylate occurred. After overnight stirring at rt or 50-60°C, the vinyl metallic species

were protonated before workup.

Scheme 5.13. Model study of possible 8N2 coupling route

(Us $3.,” WU MgBr2 or CuCN (:L/IL
s 46% s M

-78°C
M = W. CU
I

 

M,

X = mesyl or Br /\
I or II > K
46% - rt - 55°C. overnight 5

(0%)

l or II
(69%) 0

 

 

ll

41

5.3.3. Ring-closing metathesis (RCM) route
5.3.3.a Synthetic plan

Given the unsuccessful attempts to form the C16-C17 bond by coupling fragment
B and C, we sought alternative means to construct the Cl4-C17 skipped diene. Literature
reports indicated that In(O) mediated allylation of alkynes proceeded in a Markovinikov
fashion to give 1,4-dienes.4 Thus if tosylate V-28 could be displaced by lithium
acetylide, reaction of the product (V-34) with allyl bromide and indium should provide a
1,4-diene. That diene, V-35 (Scheme 5.14), could then partake in a ring closing

metathesis (RCM) to form the macrocycle.7

Scheme 5.14. Retrosynthetic analysis of RCM route

 

 

 

 

 

 

 

 

 

5.3.3.b Preparation of compound V-35

Thus we investigated the displacement of the tosylate on V-28 by lithium
acetylide. Although it is necessary to carry out the reaction in a glove bag, and crucial to
keep the concentration of the lithium acetylide at 2 M,12 displacement of tosylate V-28

under these conditions consistently gave V-34 in high yields (Scheme 5.15).

Scheme 5.15. Preparation of V-34

1'03le \
W "CCUEDA. ( 2 eq) M
\ t
; DMSO \
.. 86% .

ores '
V.” V.“

 

42

 

ORE

110‘:

‘St

Next, we tested the indium-mediated allylation of alkynes (Scheme 5.16). The
original paper showed regiochemical differences (anti-Markovinikov) for reaction of
propargylic alcohols.4 We needed to know if this was due to the hydroxyl group being
proximal to the alkyne or if it was a problem for all free alcohols. A model study using
4-pentyn-1-ol consistently and cleanly provided the 1,4-diene in high yields. However,
several trials failed when allyl alcohol V-36 was subjected to these reaction conditions
(Scheme 5.16). Each time a complex mixture formed, and the NMR and IR spectrum of
the major product suggested loss of the hydroxyl group. Literature stated that a free
hydroxyl group in the alkyne could speed up the reaction and slightly improve yields.4
However, no previous studies involved allyl alcohols. These results suggest that allylic
alcohols are not tolerated in this reaction. Indeed, when TBS ether V-34 was employed,
the reaction proceeded smoothly and provided the desired 1,4-diene V-35 as the sole

product in consistently high yields (Scheme 5.16).

Scheme 5.16. Indium mediated allylation: Formation of the 1,4-diene

 

 

\\ Allyl Br In
OH
\/\/ sonication A/lL/VOH
m:
AIM Br, In
: \ sonicaflon
6TBS v.34 6138
l TBAF
100%
\\
Allyl Br, In
\ —>
5 soniwtion
6H v.35

With compound V-35 in hand, we turned to the problem of forming the epoxide.
Since V-37 is stereochemically mismatched for Sharpless epoxidation conditions,13 we
deCided to first try the epoxidation with m-CPBA. The epoxidation of compound V-37 in

CH2C1; gave a mixture of two products (Scheme 5.17). Unfortunately, compound V-38

was found to possess the undesired epoxide stereochemistry. This assignment was made
by comparing the m-CPBA product with the matched Sharpless epoxidation product.

They were found to be identical.
Scheme 5.17. Epoxidation of V-37

m-CPBA
———-.

CH2012

 

(41%)

   

TKO-Pm, (-)odiethy1 D-tartrate.
TBHP. 01-12012. MS. -20°C

 

(80%)

At this point we decided to invert the stereostructure of the allyl alcohol so the
correct epoxide can be installed by a matched Sharpless epoxidation. The inverted
carbon center would later be “corrected” via the Mitsunobu coupling of the resulted
compound with V-14.9 The inversion of the secondary alcohol was realized by
Mitsunobu esterification9 followed by hydrolysis. However, Mitsunobu esterification of
allyl alcohols has potential complications of regeoselectivity. It has been observed that

acid attack of the activated allyl alchol in SN2’ fashion, can lead to the other regioisomer.9

Scheme 5.18. Inversion of the secondary alcohol via Mitsunobu esterification

 

 

 

8602010 801d, K2C03,0360H
60
DIAD. P113? \ \
81°/ 81%
i 0) OBz ( 1 OH

(contaminated with regioisomer ?)

To prove that V-40 was indeed the desired regioisomer, V-37 was oxidized and
the resultant ketone V-41 was reduced to give a mixture of two diastereomers (Scheme
5.19). The new diastereomer was separated from V-37 by careful silica gel

chromatography and proved to be identical with V40.

44

Sharpless epoxidation of compound V40 proceeded smoothly (Scheme 5.19).
Only one isomer was observed by NMR spectra and TLC.

Scheme 5.19. Inversion of the secondary alcohol via oxidation-reduction

 

 

\ Doss-Martin [0) \ NaBHa. MeOH
é (61%) 2) chromatography
OH 0
v-37 v-41
/ TKO—Pm, (+)-diethyl L-tartrate.
\ TBHP. 0142012. MS. -20°c
OH (69%) ,

 

V40
(34%, with 51% V-37 and V40 mixture)

V42

The preparation of V42, although successful, was further improved by carrying
out an anti-aldol reaction of aldehyde V-30 with the Abiko—Masainune auxiliary (V43)
(Scheme 5.20).14 Thus by directly making the anti-aldol product,15 the initial Mitsunobu

reaction could be bypassed.

Scheme 5.20. The preparation of compound V-42 via anti-aldol reaction

 

L TEA. 01/2310") on o on resort
Ph -78 °C. 2h ; 2,6 Lut.
5 Yk / ——-
3" the" § CH2012'0°C
iii’ 4:) 6’N\s0Me = 20min,94%
n 8
$0ng 0/ / . 2 v44
V‘“ 50% -
ores
DIBAL
; CHZCIa-‘gz/ 078°C
BON/ \302M03

Compound V-42 was subjected to Mitsunobu esterification with (Z)-V-14. This
reaction proved somewhat inefficient. Many modified procedures were examined, but
the reaction was never able to proceed to completion. This problem was believed to be
due to the low nucleophilicity of the acid, which not only is conjugated, but also contains

the electron withdrawing iodine. Under traditional conditions, the desired compound

45

V47 was prepared in modest yields and less than 70% conversion. It was later found
that adding molecular sieves to the reaction improved the yield and conversion
significantly. Though the reasons remain unclear, carrying out the reaction with freshly

activated 4A molecular sieves provided V47 in 79% yield.

Scheme 5.21. The preparation of BCD fragment

Ph3P. DIAD

(E)-V-14. 4A sieves

Ph3P. DIAD

‘

 

(Z)-V-14, 4A sieves

(93%) (79%)
V42

   

(68% on 69% without sieves) V47

Under the same reaction conditions, the other isomer (E)-V-l4 coupled with V42

smoothly, routinely gave V48, the BCD fragment of amphidinolide A, in high yields.

To further solidify the regiochemical structure assignment of V48, 6 sample was
subjected to hydrolysis, and the resultant alcohol was then oxidized to the ketone. This

ketone was found to be identical to that formed via oxidation of V42.

46

5.4. Synthesis of fragment A
5.4. 1. Introduction

With the BCD fragment in hand, we started to investigate an alternative route
toward A, which had been previously synthesized from D-mannitol.2a Specifically, we
sought to take advantage of D-arabitol, which possess the desired stereochemistry for the
C9 and C11 alcohols along with the two primary hydroxyl groups which could be used

for further manipulation.
5.4.2. Arabitol route

Transformation of D-arabitol to the diol V-50 proceeded smoothly (Scheme 5.22).
For the dipentylidenation of arabitol, DMF was found to be a better solvent than 1,2-
dimethoxyl ethane. Although at rt the reaction was very slow, elevated temperature led
to poor regeoselectivity, thus the optimum reaction temperature was determined to be 35-
40 °C. For the subsequent Wittig olefination, the sequence in which reagents were added
proved crucial. For example, when the freshly generated Wittig reagent was added to the
crude ketone, heavy epimerization at the allylic carbon center occurred. Whereas when
the reaction was carried out by adding the ketone into the Wittig reagent, no such
epimerization was observed, and the alkene was formed as a single diastereomer. After
deprotection of the dipentylidene the two primary hydroxyl groups were protected as
TIPS ethers.

Scheme 5.22. The synthesis of V-50 from D-arabitol

E!
Et

Et
Et 5, X8
. E
D-a b'toi d'methoxy' mm 6740 9X t 5°an TE" W0 PhaPCHSBf
ra 1 ¢ = O .

 

 

Tosy|OH. DMF W DMSO. CHzCiz

 

 

NaHMDS
5H 0
V'51 v.52
E! E!
5:74 X8 OH QH 0” 9H
oval/if 161011.107- 1101 H0\/'\”/‘\/on 2 eq. TIPSCi. T'PS°\/'m/\/°T'PS
THF reflux TEA. DMAP
. V-50
V-54
V-53 (52% from D—arabitol)

47

Next, the two secondary hydroxyl groups were to be protected as PMB ethers.
This protective group was chosen because PMB groups are amenable to chelation
controlled addition reactions (necessary to selectively form the C12-C13 and C7-C8
bonds of amphidinolide A). Furthermore, they can be removed with DDQ oxidation, a
method mild enough to be tolerated by the variety of functional groups present in the

final stages of our synthetic plan.

Surprisingly, I encountered great difficulties with traditional etherification
methods. With both KH and NaHMDS as the base, the reactions were very sluggish and
slow decomposition of the alcohol was observed. The desired compound was isolated in
only low yields. Giving these difficulties, I examined the protection reaction under acidic
conditions. The protection of hydroxyl groups with the PMB trichloroacetimidate (PMB
TCA) reagent under acid catalyst has been widely used,'68 with the acid usually being
HOTf, HCl, TsOH, or TMSOTf. However, only moderate success was achieved with
TMSOTf or toluene sulfonic acid as the catalyst. Eventually, I found that yields could be

much-improved with trityl perchloride as the catalyst (Scheme 5.23).16b

Scheme 5.23. The synthesis of V-58

 

1. PMB TCA
OH 8H TrCIO4 PMBO QPMB P'VC‘ PMBO gPMB
“PSOWVOTIPS 2. TBAF HO\/'\n/:\/OH ' P10\/Sr\/OP2
——'——.
83% Py
V-50 V-SG V-56 P1, P2 = H 12%
V-57 P1. P2 = Piv 10%

V-58 P1 = H. P2 = Piv 56%

Compound V-55 was deprotected to give compound V-56. The subsequent
monoprotection with PivCl was also troublesome. With 1.1 eq. of PivCl, a mixture of the
desired monoprotected V-58, the diprotected V-57, as well as the starting material V-56
was formed each time. However, compounds V-57 and V-56 could be easily separated
from V-58 and recycled, giving a good overall yield of V-58. Thus despite this

selectivity problem, the synthesis of compound V-58 was more efficient compared to our

48

previous synthesis of a similar interrnidiate.3a Thus this synthesis was adopted for our

final route to amphidinolide A.l7
5.4.3. Synthetic investigations towards fragment AB from D-Glucose

Having established a better route toward subtarget A, we set out to look into a
third route starting from D-glucose. The stereostructure of the C2, C3, and C5 carbon
centers in D-glucose coincide with those of C9, C11, and C12 in amphidinolide A. The
C4 hydroxyl group should well serve the purpose of installing the alkene, while the C6
hydroxyl group would be a handle for joining other fragments. Indeed, in Pattenden’s
synthetic approach, he started with D-glucose and prepared the properly functionalized

C7-Cl3 ene-tetraol unit V-ll (Scheme 5.4) in 13 linear steps with an overall yield of 2%.

A major difference in our synthetic plan from Pattenden’s was that we would
utilize the aldehyde functionality in glucose to install the C13-C14 alkene, via a Wittig
olefination. This step would simultaneously install the ester group at C15, which could
be transformed into an activated allylic alcohol and coupled with a vinyl species to form

the crucial 1,4-diene moiety.

Scheme 5.24. Synthetic investigations towards fragment AB from D-Glucose

 

  
 

 

 

 

acetone XDHO my
anlz. H3P04 0“" KH, Ban 0“"
D-Gluoose ..,,
a a

b}
v- 59 v-oo
PlvO

1. AcOH. H20 PM)
2. PivCl, TEA. DMAP ,, 1_ M90”. so w.
3. KH. BnBr and“ 2. KH, $323. ‘ and
t '0', : M8
80% BnO .zoj/ 83% Soc 368"
v-ea v-es
OBn Bn 0
1.AeOH.l-120 can gan o , , 9
2. Ph3P=ChCOOEt ”VOW Bess-Mam“ P~° \ OE,
é CE! 3
i 5. 76°/o =
91% 6H 68" 0 Can
v-a7 V'“

49

Thus starting from D-glucose, V-68 was easily obtained via a series of highly
reliable and routine transformations, with no chromatographic separation needed except
for compounds V-63, V-67, and V-68. The only challenging step was the Wittig reaction
at C10. With Ph3P=CH2, no product was isolated, presumably due to the basicity of this
reagent. Even with the milder Lombardo’s reagent,'8‘3d decomposition was still a serious
problem. However, this reagent did provide the desired product in a modest 30-50%
yield. Compound V-7l was then prepared and coupled with the vinyl stannane under

stande conditions.19

Scheme 5.25. Synthetic investigations towards fragment AB from D-Glucose

8n 98H b 03" 9°" 2 11:62:53”)
: Lom ardo's reagent . : ' ‘
Pwo : \ OEt _ PNO ; \ OEt Py, DMAP _
= 8 V
0 Dan ca. 30%
V-GO

 

 

 

den 82%
v-es
8 Sn OH
A00 ; \ OAC ; HO ’ \ H
53" Pd(dba)2, LiCI. DMF 5
Bo
v-71 50% W]:

In the end, though, this route was not as successful when we tried to use PMB
protective groups instead of benzyl groups. Thus it was not adopted to our synthesis of

amphidinolide A.

50

VI.

5.5. Coupling of fragment AB with fragment BCD and subsequent ring closing efforts

With the synthesis of all the subunits in place, we were ready to explore their
union and final elaboration of amphidinolide A. Compounds V-48 and V-49 were joined
via Cu catalyzed cross-coupling reaction (Scheme 5.26).20 The resultant compound V-73
was then subjected to Grubbs’ RCM conditions (Scheme 5.27).7 Unfortunately, the ring
closing reaction was complicated by the truncation of the allylic olefin.” Although this
process can be prevented by protecting the hydroxyl group, reaction of the TMS ether led
to another side reaction, the homo-metathesis of compound V-75 at the C16 double bond

(Scheme 5.27).

Scheme 5.26. Preparation of V-73

 

v-75 V-7B

Due to the difficulties encountered with compound V-73, we briefly investigated

the Ru mediated alder-ene reaction, developed by Trost,S to close the ring (Scheme 5.28).

51

Thus two new building blocks V-79 and V-82 were prepared (Scheme 5.29 and 5.30).
From these compounds, the corresponding compounds V-83 and V-84 were prepared

(Scheme 5.31) and subjected to Trost conditions (Scheme 5.32). However, this effort

 

     
  

  

 

 

 

 

was not fruitful.
Scheme 5.28. Trost’s alder-ene reaction
R
F‘ \ [CpRu(CH3CN)3]PF6 l
\ 1’ MW ; R2 /
8‘ RI
R=HorTMS R=HorTMS
Scheme 5 .29. Preparation of V-79
\ §
\ (+)-diethyl L-tartrate \\
Two-Pr). TBHP ”‘39- D"?
\ CHZCIZ. MS. 20% (E)-V-04. 4A Slaves a w
r 3 |
OH (84%) (78%) W
v-77 o
v-7e v-7e
Scheme 5.30. Preparation of V-82
\ TMS \ (+)-diethyl L-tartrate
\ . \ mom», TBHP
\ n-BuLt. TMSCI ‘ \ CH2CI2. Ms. -2o°c _
86% (68%)
0“ 0H
V-77 v.50

PhaP. DIAD
(E)-V-04, 4A sieves

 

v

(75%)

   

Pd2(dba)3
AsPh3

g

30%

 

V438=H
VMRaTMS

 

52

Scheme 5.32. Ring closing attempts using Trost’s alder-ene reaction

  
 

[CpRu(CH3CN)3]PF5 PMBO

0% 7830“"

 

33331118

Given the failure of the alder-ene reaction, we decided to re-examine the RCM
approach. Literature reports suggested that the second generation Grubbs’ catalyst was
not prone to the truncation reaction.7c Indeed, when we used the second generation
catalyst developed by Grubbs (Scheme 5.33),7 the desired ring-closing product was
obtained in 88% yield. After a three-step deprotection, the material with the proposed

structure of amphidinolide A (V-Ol) was obtained (Scheme 5.34).

Scheme 5.33. Ring‘closing metathesis of V-73

 

 

V-87 V-01

However, the 'H and UC NMR spectra of V-01 did not match those of the natural
compound. Guided by our early concerns about the potential error in the stereochemical
relationship between the hydrophilic and lipophilic halves, we are currently undertaking
the synthesis of the hydrophilic half from L—arabitol following the same route.17 This

would provide us iso-V-49, the enantiomer of compound V-49, which will be coupled

53

with compound V-48 to eventually form iso-V-Ol. Hopefully we will then have prepared
the natural material or its enantiomer. Thus the total synthesis and structure of

amphidinolide A will be secured.

Scheme 5.35. Synthesis of iso-V—01

I=D L-arabitol

 

54

‘A ;

(it;

P'-

EXPERIMENTAL PROCEDURES

Materials and Methods

All air or moisture sensitive reactions were carried out in oven- or flame-dried
glassware under nitrogen atmosphere, unless otherwise noted. All solvents were reagent
grade. Anhydrous diethyl ether and tetrahydrofuran (THF) were freshly distilled under
nitrogen from sodium benzophenoneketyl. Dichloromethane was freshly distilled from
calcium hydride under nitrogen. Triethylamine and diisopropylethylamine (Hunnig base)
were distilled under nitrogen from calcium hydride and stored over freshly activated 4 A
molecular sieves. N,N’-Dimethylformamide (DMF), dimethylsulfoxide (DMSO), and
acetonitrile were distilled under nitrogen from anhydrous calcium sulfate. Anhydrous
pyridine was purchased from Aldrich and stored over freshly activated 4 A molecular
sieves. n-Butyllithium was purchased from Aldrich as a hexane solution. Except as
otherwise indicated, all reactions were magnetically stirred and monitored by thin layer
chromatography with Whatman 0.25-mm precoated silica gel plates. Flash
chromatography was performed with silica gel 60 A (particle size 230-400 Mesh ASTM)
supplied by Whatman Inc. High performance liquid chromatography (HPLC) was
performed with Ranin component analytical/semiprep system. Yields refer to
chromatographically and spectroscopically pure compounds, unless otherwise stated.
Melting points were determined on a Thomas-Hoover apparatus, uncorrected. Infrared
spectra were recorded on a Nicolet IR/42 spectrometer. Proton and carbon NMR spectra
were recorded on Varian Gemini-300 or VXR 500 spectrometer. Chemical shifts for lH
NMR and 13 C NMR are reported in parts per million (ppm) relative to CDC13 (6 = 7.24
ppm for 1H NMR or 5 = 77.0 ppm for 13 C NMR ). Optical rotations were measured with

a Perkin-Elmer Model 341 polarimeter. High resolution mass spectra (HRMS) data were

55

obtained: (a) at the Michigan State University Mass Spectrometry Facility; (b) at the
Mass Spectrometry Laboratory in Department of Chemistry & Biochemistry at the
University of South Carolina. Combustion analysis was performed by Robertson
Microlit Laboratories, Inc., Madison, NJ 07940. Single-crystal X-ray structure
determinations were performed at the Michigan State University with a Siemens CCD

diffractometer.

Preparation of model compounds “-06, “-17, II-l8 and Il-19. General procedure: A
solution of alcohol II-l4 (210 mg, 1.0 mmol) and Ble (ca. 50 mg) in THF (5 mL) was
cooled to 0°C. NaH (60%, suspended in mineral oil, 48 mg, 1.2 mmol) was added in
portions while the flask was purged with nitrogen from a side arm. The suspension was
stirred under nitrogen at 0 °C for 15 min. To the resulting cloudy solution was added
dropwise a solution of (R)-II-11 (430 mg, 1.0 mmol) in 1 mL THF. After an additional 2
h during which the reaction temperature was allowed to warm to room temperature, the
reaction was quenched with saturated aqueous NH4C1 (2 mL), diluted with ether (5 mL),
washed with water and brine. The organic phase was dried over MgSO4 and
concentrated. Flash chromatography (light petroleum ether/ether, 95:5) furnished II-06
(440 mg, 84% yield) as a colorless oil: {a}? +17.l° (c 1.08, THF); IR (neat) 2959 (m),
1595 (s), 1456 (s), 1379 (s), 1215 (s), 1070 (s) cm"; lH NMR (300 MHz, CDC13) 5 7.40-
7.22 (m, 5 H), 4.30 (dd, J= 14.0, 6.9 Hz, 1 H), 4.15 (d, J = 6.9 Hz, 1 H), 3.71 (dd, J=
8.5, 5.2 Hz, 1 H), 3.64-3.50 (m, 2 H), 1.92-1.74 (m, 1 H), 1.76-1.60 (m, l H), 1.60-1.40
(m, 6 H), 1.40-1.20 (m, 12 H), 1.35 (s, 3 H), 1.31 (s, 3 H), 1.00-0.80 (m, 12 H); 13C NMR
(75 MHz, CDCl3) 5 138.9, 128.2, 128.1, 127.8, 109.8, 83.6, 78.9, 77.2, 66.0, 29.3, 28.6,
27.6, 26.4, 25.5, 13.7, 12.7, 9.4; HRMS (EI) m/z 525.2383 [(M-CH3)+; calcd for
C26H4503Sn, 525.2390]. Anal. Calcd for C27H4303Sn: C, 59.97, H, 8.95. Found: C,
60.28, H, 8.92.

56

Applying the procedure above to 60 mg (0.28 mol) of II-15 and 60 mg (0.14 mol)
(R)-II-11 furnished 45 mg "-17 as colorless oil in 60% yield: [0180 -80,7°. (c 3.30, THF);
IR (neat) 2957 (m), 1454 (s), 1379 (s), 1215 (s), 1076 (s) cm"; 1H NMR (300 MHz,
CDC13) 8 7.21-7.41 (m, 5 H), 4.37 (d, J = 6.6 Hz, 1 H), 4.04-4.20 (m, 3 H), 3.72 (dd, J =
7.2, 3.6 Hz, 1 H), 1.94-2.10 (m, 1 H), 1.78-1.64 (m, 1 H), 1.44 (s, 3 H), 1.31 (s, 3 H),
1.54-1.38 (m, 6 H), 1.36-1.20 (m, 12 H), 1.00-0.80 (m, 12 H); l3C NMR (75 MHz,
CDCl3) 8 139.7, 128.2, 127.9, 127.9, 109.2, 79.9, 79.3, 74.1, 67.1, 29.1, 27.5, 26.7, 25.4,

25.1, 137,117, 9.2; HRMS (131) m/z 525.1942 [(M-CH3)+; calcd for C26H4503Sn,
525.2390].

Applying the procedure above to 350 mg (1.7 mol) of II-l4 and 600 mg (1.4 mol)
(S)-II-11 fumished 600 mg “-18 as colorless oil in 79% yield: [0118o +75.2° (c 1.22,
THF); IR (neat) 2957 (m), 1599 (s), 1458 (s), 1377 (s), 1257 (s), 1174 (s), 1037 (s) cm“;
1H NMR (300 MHz, CDC13) 5 7.40-7.20 (m, 5 H), 4.39 (d, J= 6.6 Hz, 1 H), 4.30 (dd, J=
13.2, 6.6 Hz, 1 H), 3.76-3.65 (m, 2 H), 3.60 (dd, J= 8.5, 6.8 Hz, 1 H), 2.06-1.88 (m, 1
H), 1.84-1.66 (m, 1 H), 1.34 (s, 3 H), 1.27 (s, 3 H), 1.52-1.16 (m, 15 H), 0.95 (t, J= 7.2
HZ, 3 H), 0.85-0.65 (In, 12 H); 13C NMR (75 MHZ, CDC13) 5 138.7, 128.2, 128.0, 127.9,
109.5, 81.3, 78.7, 75.4, 65.7, 29.1, 27.5, 26.4, 26.1, 25.6, 13.7, 11.8, 9.2; HRMS (E1) m/z
541.2712 [(M+H)+; calcd for C27H4903Sn, 541.2703].

Applying the procedure above to 160 mg (0.77 mol) of II-lS and 300 mg (0.70
mol) (.S')-II-ll furnished 287 mg II-l9 as colorless oil in 76% yield: [05112)0 -22.4° (c 3.70,
THF); IR (neat) 2932 (m), 1454 (s), 1368 (s), 1253 (s), 1215 (s), 1064 (s) cm"; 1H NMR
(300 MHz, CDC13) 8 7.42-7.22 (m, 5 H), 4.20 (m, 4 H), 3.78 (t, J = 6.0 Hz, 1 H), 1.76-
1.62 (m, 2 H), 1.60-1.15 (m, 24 H), 0.96-0.76 (m, 12 H); 13C NMR (75 MHz, CDC13) 8
140.2, 128.1, 127.8, 127.7, 109.3, 82.8, 79.5, 77.3, 66.7, 29.1, 27.5, 26.4, 26.1, 25.6, 13.7,
11.8, 9.2; HRMS (El) m/z 525.2394 [(M-CH3)+; calcd for C26H4503Sn, 525.2390].

57

Applying the procedure above to 120 mg (0.8 mmol) of "-09 and 300 mg (0.70
mmol) (R)-Il-11 furnished 265 mg II-l3 as colorless oil in 80% yield: [018° +30.4° (c
2.30, toluene); IR (neat) 2959 (s), 1456 (s), 1377 (s), 1070 (s) cm"; 1H NMR (300 MHz,
CDC13) 8 3.94-4.06 (m, 1 H), 3.74-3.95 (m, 3 H), 3.41 (p, J= 6.3 Hz, 1 H), 1.60-1.90 (m,
2 H), 1.15-1.56 (m, 18 H), 1.11 (d, J= 6.0 Hz, 3 H), 0.79-0.95 (m, 18 H); 13C NMR (75
MHz, CDC13) 8 108.9, 79.2, 74.5, 74.1, 67.3, 29.2, 27.5, 26.7, 26.4, 25.5, 16.5, 13.7,
11.8, 9.2; HRMS (EI) m/z 421.1767 [(M-C4H9)+; calcd. for C13H37O3Sn, 421.1765].

Applying the procedure above to 330 mg (2.26 mmol) of II-10 and 750 mg (1.76
mmol) (S)-II-11 furnished 650 mg “-12 as colorless oil in 78% yield: [0180 -13.0° (c 2.2,
toluene); IR (neat) 2957 (s), 1458 (s), 1377 (s), 1072 (s) cm’l‘lH NMR (300 MHz,
CDC13) 8 4.05 (dd, J= 6.6, 12.9 Hz, 1 1H), 3.84-3.95 (m, 2 H), 3.67 (dd, J= 7.8, 8.4 Hz, 1
H), 3.41 (p, J= 6.0 Hz, 1 H), 1.7-1.9 (m, 2 H), 1.2-1.6 (m, 18 H), 1.05 (d, J: 6.0 Hz, 3
H), 0.79-1.00 (m, 18 H); 13C NMR (75 MHz, CDC13) 8 109.1, 78.3, 77.7, 76.0, 65.4,
29.3, 28.3, 27.5, 26.5, 25.2, 15.4, 13.7, 12.3, 9.1; HRMS (El) m/z 421.1770 [(M-C4H9)+;
calcd. for C13H37O3Sn, 421.1765].

[l,2]-Wittig rearrangement reaction of the model compounds “-06, II-l7, II-
18 and “-19. General procedure: Compound “-06 (60 mg, 0.11 mmol) was dissolved in
4 mL solvent (10 mL when using LiCl saturated THF) and the solution was cooled to -76
0C. n-BuLi (1.6 M in hexanes, 0.36 mL, 0.57 mmol) was added dropwise via a syringe.
After an additional 45 min the reaction was quenched with saturated aqueous NH4C1 (2
mL), diluted with ether (5 mL), washed with water and brine. The organic phase was
dried over MgSO4 and concentrated. The crude product was dissolved in 1 mL dry
pyridine and the solution was cooled to 0 0C. 3,5-Dinitrobenzoyl chloride (75 mg, 0.3
mmol) was then added and the solution was stirred overnight at ambient temperature.
The dark red solution was then diluted with 5 mL ether and washed with 0.1 N HCl,

water and brine. The organic phase was then dried over MgSO4 and concentrated. This

58

crude product mixture was then analyzed by HPLC to measure the ratio of the four

diastereomers (hexanes/ether, 90:10, 1 mL/min).

Preparation of alcohols II-07, lI-08, “-20, and II-21. A diastereomeric mixture
of II-06, II-l7, II-18, and II-19 (0.9 g, 1.7 mmol) was dissolved in 50 mL THF and the
solution was cooled to -76°C. n-BuLi (2.5 M in hexanes, 1.4 mL, 3.4 mmol) was added
dropwise via a syringe. After an additional 45 min the reaction was quenched with
saturated aqueous NH4C1 (3 mL), diluted with ether (20 mL), washed with water and
brine. The organic phase was dried over MgSO4, concentrated. Column chromatography
(hexanes/ether, 85:15) furnished II-07, II-08, II-20, and II-21 (in equal amounts, 95%

total yield) as colorless oils.

11-07: R, 0.24 (petroleum ether/ether, 5:1); [0:160 .297" (c 2.6, CHC13); IR (neat)
3460 (br), 2984 (m), 2934(s), 1454(5), 1369(5), 1221(5), 1062(s) cm"; 1H NMR (300
MHz, CDC13) 5 7.40-7.19 (m, 5 H), 4.59 (ddd, J ——~ 11.5, 8.0, 5.5 Hz, 1 H), 4.04 (dd, J =
8.0, 6.0 Hz, 1 H), 3.90 (ddd, J= 12.1, 8.0, 4.4 Hz, 1 H), 3.51 (m, 1 H), 2.75 (dd, J: 5.5,
4.1 Hz, 1 H), 2.09 (s br, 1 H), 1.60-1.20 (m, 2 H), 1.34 (s, 3 H), 1.30 (s, 3 H), 0.94 (t, J=
7.2 Hz, 3 H); 13C NMR (75 MHz, CDC13) 8 136.9, 130.4, 128.1, 127.1, 109.1, 77.5, 75.0,
67.6, 52.3, 28.0, 26.5, 25.6, 10.2; LRMS (131) m/z 235.2 [(M-CH3)+; calcd for C14H1903,
235.1334].

II-08: Rf 0.14 (petroleum ether/ether, 5:1); [416° +15.1° (c 0.63, CHC13); IR (neat)
3478 (br), 2988 (m), 2937 (s), 1455 (s), 1381 (s), 1203 (s), 1066 (s) cm‘“ ‘H NMR (300
MHz, CDC13) 8 7.39-7.18 (m, 5 H), 4.66 (ddd, J = 8.5, 6.1, 4.4 Hz, 1 H), 4.03 (ddd, J =
9.1, 9.1, 2.8 Hz, 1 H), 3.98 (dd, J= 8.0, 6.0 Hz, 1 H), 3.54 (dd, J= 8.5, 8.0 Hz, 1 H), 2.78
(dd, J= 9.6, 4.5 Hz, 1 H), 2.30 (s br, 1 H), 1.35 (s, 3 H), 1.30 (s, 3 H), 1.32-1.12 (m, 2 H),
0.89 (t, J= 7.4 Hz, 3 H); 13C NMR (75 MHz, CDC];) 5 138.5, 129.5, 128.2, 126.9, 108.6,
76.2, 73.8, 67.1, 53.0, 28.3, 26.3, 25.5, 9.6.

59

11-20: R, 0.37 (petroleum ether/ether, 5:1); [418° -5.3° (c 0.49, CHC13); IR (neat)
3524 (br), 2986 (m), 2936 (s), 1454 (s), 1371 (s), 1217 (s), 1061 (s) cm“ 1H NMR (300
MHz, CDC13) 8 7.39-7.01 (m, 5 H), 4.50 (ddd, J= 9.9, 7.4, 5.8 Hz, 1 H), 4.21 (s br, 1 H),
4.03 (ddd, J: 9.1, 8.3, 3.3 Hz, 1 H), 3.67 (dd, J: 8.5, 5.8 Hz, 1 H), 3.49 (dd, J: 8.5, 7.4
Hz, 1 H), 2.64 (t, J= 9.9 Hz, 1 H), 1.48 (s, 3 H), 1.40 (s, 3 H), 1.32-1.02 (m, 2 H), 0.87 (t,
J= 7.2 Hz, 3 H); ”C NMR (75 MHz, CDCl;) 8 138.6, 128.8, 128.2, 127.2, 110.4, 80.6,
76.6, 69.3, 55.4, 27.5, 26.7, 25.8, 9.3.

II-21: Rf 0.30 (petroleum ether/ether, 5:1); [018° +48.7o (c 0.29, CHC13); IR (neat)
3486 (br), 2986 (m), 2936 (s), 1496 (s), 1369 (s), 1217 (s), 1064 (s) cm"" 1H NMR (300
MHz, CDC13) 8 7.35-7.20 (m, 5 H), 4.69 (ddd, J = 9.6, 6.3, 6.3 Hz, 1 H), 4.02 (ddd, J =
8.2, 4.7, 3.0 Hz, 1 H), 3.81 (dd, J= 8.5, 6.0 Hz, 1 H), 3.47 (dd, J: 8.2, 6.9 Hz, 1 H), 2.73
(dd, J= 9.6, 3.0 Hz, 1 H), 1.95 (s br, 1 H), 1.46 (s, 3 H), 1.40 (s, 3 H), 1.46-1.14 (m, 2 H),
0.93 (t, J: 7.2 Hz, 3 H); 13C NMR (75 MHz, CDC13) 8 137.8, 129.4, 128.4, 127.1, 129.5,
76.3, 73.2, 68.8, 54.4, 27.7, 27.0, 25.7, 10.5; LRMS (EI) m/z 235.2 [(M-CH3)*; calcd for
C14H1903, 235.1334]; Anal. Calcd. for C15H2203: C, 71.95; H, 8.86. Found: C, 71.86; H,
8.85.

3,5-Dinitrobenzoyl esters of alcohol II-07, II-08, “-20 and "-21. General
procedure: Alcohol II-07 (78 mg, 0.3 mmol) was dissolved in 2 mL dry pyridine and the
solution was cooled to 0°C. 3,5-Dinitrobenzoyl chloride (92 mg, 0.4 mmol) was then
added and the solution was stirred overnight before being diluted with 5 mL ether and
washed with 0.1 N HCl, water and brine. The organic phase was then dried over MgSO4
and concentrated. Column chromatography (petroleum ether/ether, 90: 10) furnished 115
mg (83%) the 3,5-dinitrobenzoic ester of alcohol “-07 (II-07-DNB) as pale yellow
crystals: mp 126-127 °C; [4180 —l4.2° (c 0.35, CHC13); IR (CHC13) 2980 (m), 1732 (s),
1547 (s), 1344 (s), 1275 (s) cm'“ ‘H NMR (300 MHz, CDCl3) 8 9.17 (m, 1 H), 8.97 (m, 2
H), 7.46-7.16 (m, 5 H), 5.61 (ddd, J= 12.3, 7.8, 6.3 Hz, 1 H), 4.48 (ddd, J= 7.8, 6.0, 5.4

60

Hz, 1 H), 4.05 (dd, J= 7.8, 6.0 Hz, 1 H), 3.48 (r, J: 7.8 Hz, 1 H), 3.10 (r, J: 5.4 Hz, 1
H), 1.96-1.80 (m, 1 H), 1.80-1.66 (m, 1 H), 1.28 (s, 3 H), 1.22 (s, 3 H), 0.98 (t, J = 7.2
Hz, 3 H); ”C NMR (75 MHz, CDCl;) 8 162.2, 148.5, 136.4, 134.1, 130.0, 129.2, 128.3,
127.5, 122.2, 109.2, 79.1, 75.5, 67.5, 51.0, 26.3, 25.5 (2 C), 9.7; HRMS (131) m/z
445.1603 [(M+H)*; calcd. for szstNzOg, 445.1610].

Applying the procedure above to 48 mg (0.19 mmol) of II-08 furnished 76 mg 11-
08-DNB in 88% yield as pale yellow crystals. mp 128-129 °C; IR (CHC13) 2980 (m),
1730 (s), 1547 (s), 1344 (s), 1275 (s) cm“; 1H NMR (300 MHz, CDC13) 8 9.25 (t, J =
2.1 Hz, 1 H), 9.19 (t, J= 2.1 Hz, 2 H), 7.31 (s, 5 H), 5.68 (ddd, J= 9.6, 5.4, 3.6 Hz, 1 H),
4.44 (ddd, J: 8.4, 6.3, 4.2 Hz, 1 H), 3.90 (dd, J= 7.8, 6.0 Hz, 1 H), 3.36 (t, J = 7.8 Hz, 1
H), 3.13 (dd, J: 9.6, 4.5 Hz, 1 H), 1.78-1.60 (m, 1 H), 1.60-1.46 (m, 1 H), 1.19 (s, 3 H),
1.18 (s, 3 H), 0.84 (t, J= 7.2 Hz, 3 H); 13C NMR (75 MHz, CDC13) 8 161.9, 148.8, 136.5,
134.1, 130.0, 129.3, 128.4, 127.6, 122.5, 109.0, 78.9, 74.7, 67.2, 50.6, 26.2. 25.5 (2 C),
9.1; HRMS (El) m/z 444.1501 [(M)+; calcd. for C22H24N208, 444.1532].

Applying the procedure above to 94 mg (0.37 mmol) of “-20 furnished 137 mg
II-20-DNB in 82% yield as pale yellow crystals; mp 126-129 °C; IR (CHC13) 3103 (m),
1732 (s), 1549 (s), 1346 (s), 1275 (s) cm’“ 1H NMR (300 MHz, CDC13) 8 9.24-9.18 (m, 3
H), 7.37—7.19 (m, 5 H), 5.64 (ddd, J: 12.4, 8.8, 3.6 Hz, 1 H), 4.49 (ddd, J: 9.3, 8.2, 5.8
Hz, 1 H), 3.57 (dd, J: 8.5, 5.8 Hz, 1 H), 3.34 (t, J= 8.2 Hz, 1 H), 3.11 (t, J= 8.8 Hz, 1
H), 1.72-1.49 (m, 2 H), 1.26 (s, 3 H), 1.09 (s, 3 H), 0.88 (t, J= 7.2 Hz, 3 H); ”C NMR
(300 MHz, CDCl;) 8 162.9, 148.5, 137.3, 135.1, 129.5, 129.1, 128.5, 127.9, 122.0, 109.8,
80.0, 77.7, 69.1, 53.8, 26.8, 25.6, 24.8, 9.7; HRMS (E1) m/z 445.1615 [(M+H)*; calcd. for
C22H25N203, 445.1610].

Applying the procedure above to 56 mg (0.23 mmol) of II-21 furnished 75 mg II-
Zl-DNB in 74% yield as pale yellow crystals; mp 127-129 °C; IR (in CHC13) 2982 (m),

61

1’3

011‘

 

 

1728 (s), 1547 (s), 1344 (s), 1275 (s) cm-“ 'H NMR (300 MHz, CDC13) 8 9.21 (s, 1 H),
9.09 (d, J: 2.1 Hz, 2 H), 7.45-7.21 (m, 5 H), 5.68 (m, 1 H), 4.48 (ddd, J: 12.4, 10.2, 6.3
Hz, 1 H), 3.77 (dd, J = 8.2, 5.7 Hz, 1 H), 3.46 (dd, J = 8.2, 6.6 Hz, 1 H), 3.02 (dd, J =
10.2, 3.8 Hz, 1 H), 1.72 (q, J= 7.14 Hz, 2 H), 1.45 (s, 3 H), 1.34 (s, 3 H), 0.96 (t, J: 7.4
Hz, 3 H); ”C NMR (75 MHz, CDC13) 8 161.9, 148.6, 136.7, 134.2, 129.4, 129.2, 128.8,
127.8, 122.2, 109.9, 78.3, 75.7, 68.6, 52.6, 27.1, 25.6 (2 C), 10.0; HRMS (131) m/z
445.1615 [(M+H)*; calcd. for szstNzog, 445.1610].

Preparation of II-22. To a solution of II-08 (73 mg, 0.29 mmol) in THF (3 mL)
was added 1 N HCl (2 mL) and the solution was refluxed for 10 min at which time TLC
indicated the reaction complete. The solution was cooled and sodium bicarbonate
powder was added in small portions with vigorous stirring until the pH of the mixture
was 7. The mixture was then extracted with n-BuOH (3 mL X 4). The combined organic
phase was dried over MgSO4 and concentrated to dryness. The crude triol (white
powder) was dissolved in 5 mL pyridine and the solution was cooled to 0 0C. 3,5-
dinitrobenzoyl chloride (200 mg, 0.86 mmol) was then added and the solution was stirred
overnight before it was diluted with 10 mL CHzClz and washed with 0.1 N HCl, water
and brine. The organic phase was then dried over MgSO4. Column chromatography
(hexanes/ether, 80:20) furnished 159 mg (70%) tris-3,5-dinitrobenzoyl ester II-22 as
yellow crystals: mp 195-196°C; 10:180 +2.3° (c 0.42, CHC13); IR (CHC13) 2924 (m), 1734
(s), 1545 (s), 1344 (s), 1271 (s) cm’“ ‘H NMR (300 MHz, CDC13) 8 9.29 (t, J= 2.1 Hz, 1
H), 9.26 (t, J: 2.1 Hz, 1 H), 9.16-9.08 (m, 5 H), 8.82 (d, J= 2.1 Hz, 2 H), 7.60-7.40 (m,
5 H), 6.06 (m, 1 H), 5.78 (m, 1 H), 4.80 (dd, J= 12.3, 2.7 Hz, 1 H), 4.05 (dd, J = 12.3,
8.7 Hz, 1 H), 3.55 (dd, J== 10.8, 3.0 Hz, 1 H), 1.64-1.52 (m, 2 H), 0.86 (t, J = 7.5 Hz, 3
H); 13C NMR (75 MHz, CDCl3) 8 162.7, 162.6, 162.0, 148.9, 148.8, 148.6, 134.5, 133.3,
132.8, 132.6, 129.7, 129.5, 129.4, 129.3, 129.1, 129.0, 123.0, 122.9, 122.7, 76.0, 71.3,

62

67111, 5

581.11

 

67.0, 50.6, 25.6, 9.1; HRMS (E1) m/z 581.1140 [(M-C7H3Nzo,)*; calcd. for C26H21N4012,
581.1155].

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Preparation of a-(trimethylsilyl)benzy1 alcohol (III-01a). A solution of benzyl
alcohol (12 g, 0.11 mol) in 200 mL THF was cooled to 0 °C under nitrogen atmosphere.
n-BuLi (1.6 M in hexanes, 75 mL, 0.12 mol) was added dropwise. After an additional 15
min 15 mL (0.12 mol) TMSCI was added dropwise while the solution was well stirred.
The solution was stirred under nitrogen at 0 °C for 15 min before it was cooled to -76 °C.
t-BuLi (1.7 M in hexanes, 82 mL, 0.14 mol) was than added dropwise. After an
additional 1 hr during which time the reaction temperature was allowed to warm to room
temperature, the reaction was diluted with diethyl ether, quenched with saturated aqueous
NH4C1 and washed with water and brine. The organic phase was dried over MgSO4 and
concentrated. Distillation (0.3 mm Hg, 65-68 °C) gave 17.6 g (89%) of la as a light
yellow liquid. The spectroscopic data for 111-01a were consistent with those previously
reported in the literature (Chuang, T.-H.; Fang, J.-M.; Jiaang, W.-T.; Tsai, Y.-M. J. Org.
Chem. 1996, 61, 1794-1805).

Preparation of a-(trimethylsilyl) or-d-benzyl alcohol (III-01411). A solution of
01,01-d2-benzyl alcohol (1.1 g, 10 mmol) in THF was cooled to 0 °C under a nitrogen
atmosphere. MeLi (7.9 mL, 1.4 M in diethyl ether, 11 mmol) was added dropwise via
syringe. Upon complete addition the reaction was stirred for another 15 min before 1.52
mL (12 mmol) TMSCI was added dropwise. The solution was then stirred under nitrogen
at 0 °C for an additional 15 min before being cooled to -76 °C. t-BuLi (10 mL, 1.7 M in
hexanes, 14 mmol) was then added dropwise. After 5 min the dry ice-acetone bath was
removed. The solution was stirred for an additional 1 hr before it was diluted with
diethyl ether and quenched with saturated aqueous NH4C1. The organic phase was
washed with water and brine. It was then dried over MgSO4 and concentrated. Silica gel
chromatography (3 to 10% diethyl ether in pentane gradient) afforded 0.38 g (21%) of
III-01-d1 (along with 1.22 g (67%) of a,a-d2-benzyltrimethylsilyl ether) as a colorless

liquid. The spectroscopic data for III-Ol-dl were consistent with those previously

64

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reported in the literature (Chuang, T.-H.; Fang, J.-M.; Jiaang, W.-T.; Tsai, Y.-M. J. Org.
Chem. 1996, 6], 1794-1805).

Preparation of or-(trimethylsilyl)allyl alcohol (III-01b). Applying the
procedure above to 10 g (0.17 mol) of allyl alcohol furnished 20 g crude product (111-
01b) as a greenish yellow liquid in 89% yield which was used without further
purification. The spectroscopic data for III-01b were consistent with those previously
reported in the literature (Danheiser, R. L.; Fink, D. M.; Okano, K.; Tsai, Y.-M.;
Szczepanski, S. W. Org. Syn. 1987, 66, 14-21).

Preparation of or-(trimethylsilyl) n-propyl alcohol (III-01c). To a solution of
0.8 g (6.2 mmol) or-(trimethylsilyl)allyl alcohol III-01b in 10 mL EtOAc was added 0.1 g
10% Pd/C(10%). The mixture was stirred overnight at room temperature. The catalyst
was then removed via filtration and the solvent was carefully distilled off. The crude
material was disolved in 20 mL 95% MeOH and the solution was cooled to 0°C before
0.15 g (3.0 mmol) NaBH4 was added carefully. After refluxing for 30 min, the reaction
was carefully concentrated. The mixture was diluted with water and extracted with ether.
The organic phase was washed with water and brine. It was then dried over MgSO4 and
concentrated to give the crude III-01c, which was used without further purification.
However, an analytical sample was obtained by distillation using a distillation head with
a vacuum jacket. The spectroscopic data for III-01c were consistent with those
previously reported in the literature (Soderquist, J. A.; Lee, S.-J. H. Tetrahedron 1988,
44, 4033-4042).

Preparation of trichloroacetimidates.

Benzyl trichloroacetimidate: To a suspension of 60 mg (1.5 mmol) NaH in 25 mL
EtZO was added 1.6 g benzyl alcohol (15 mol) at rt. The mixture was stirred at rt for 15

min before it was cooled to 0°C, and 1.5 mL (15 mmol) tn'chloroacetonitrile was added.

65

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The pale yellow solution was stirred for 10 min at 0 °C and 60 min at rt, before
concentrated under reduced pressure. The residue was then diluted with 50 mL
cyclohexane containing 0.07 mL (1.5 mmol) MeOH. After vigorous shaking, the mixture
was filtered through a celite pad. The crude benzyl trichloroacetimidate was stored as a

cyclohexane solution under N2 in a freezer and used without further purification.

Applying the procedure above to 7.5 g (104 mmol) crotyl alcohol and 10 mL (100
mmol) trichloroacetonitrile furnished a cyclohexane solution of crotyl

trichloroacetimidate which was used without further purification.

Applying the procedure above to 7.2 g (100 mmol) 2-methy-2-propen-l-ol and 10
mL (100 mmol) trichloroacetonitrile furnished. a cyclohexane solution of the
trichloroacetimidate of 2-methy-2-propen-1-ol which was used without further

purification.

Applying the procedure above to 8 g (60 mmol) cinnamyl alcohol and 6 mL (60
mmol) trichloroacetonitrile . furnished a cyclohexane solution of cinnamyl

trichloroacetimidate which was used without further purification.

Applying the procedure above to 1.7 g (30 mmol) propargyl alcohol and 3 mL (30
mmol) trichloroacetonitrile furnished a cyclohexane solution of propargyl

trichloroacetimidate which was used without further purification.

Applying the procedure above to 5.2 g cis-2-penten-1-ol (60 mmol) and 6 mL (60
mmol) trichloroacetonitrile furnished a cyclohexane solution of the trichloroacetimidate

of cis-2-penten-l-ol which was used without further purification.

Preparation of III-02a and III-02b. To a solution of a-(trimethylsilyl)benzyl
alcohol III-01a (0.85 g, 4.7 mmol) in 50 mL cyclohexane was added the

trichloroacetimidate of crotyl alcohol (2.0 g, 9.2 mmol). To the well stirred solution was

66

—.,..’,

 

 

added 0.1 mL TMSOTf in 1 mL cyclohexane via syringe. A white precipitation formed
in several minutes. The reaction mixture was stirred at room temperature overnight
before being filtered. The filtrate was diluted with petroleum ether, washed with
saturated aqueous NaHCO3, 1 N HCl, and brine. The organic phase was dried over
MgSO4 and concentrated. Silica gel chromatography (1% diethyl ether in pentane)

furnished 740 mg (67%) of III-02a and 277 mg (25%) of III-02b as colorless oils.

For III-02a: IR (neat) 3024, 2959, 1600, 1450, 1248, 1051 cm“; 1H NMR (300
MHz, CDCl3) 8 7.33-7.12 (m, 5 H), 5.60 (m, 2 H), 4.14 (s, 1 H), 4.09401 (m, 1 H),
3.72-3.63 (m, 1 H), 1.73 (dd, J = 4.8, 1.0 Hz, 3 H), 0.0 (s, 9 H); ”C NMR (75 MHz,
CDC13) 8 141.7, 128.6, 128.3, 128.0, 125.9, 125.5, 76.9, 71.1, 17.8, -39; HRMS (E1) m/z
233.1361 [(M-H)*; calcd for C14H21081, 233.1362].

For III-02b: A 1:1 mixture of two diastereomers; IR (neat) 3024, 2928, 1450,
1248, 1020 cm“; 'H NMR (300 MHz, CDCl;) 8 7.18-7.13 and 7.33-7.26 (m, 5 H), 5.83
and 5.65 (ddd, J = 5.5, 10.4, 17.3 Hz and 7.7, 10.2, 17.3 Hz, 1 H), 5.23-4.98 (m, 2 H),
4.26 and 4.23 (s, 1 H), 3.88 and 3.74 (q, J= 6.32 and 6.32 Hz, 1 H), 1.20 and 1.23 (d, J=
6.30 and 6.30 Hz, 3 H), 0.00 and -0.02 (s, 9 H); ”C NMR (75 MHz, CDC13) 8 142.3 and
142.2, 141.4 and 140.5, 127.9 and 127.8, 125.9 and 125.7, 125.4 and 125.4, 116.2 and
113.6, 75.5 and 75.0, 74.7 and 74.0, 22.4 and 22.2, -3.96 and -3.96; HRMS (E1) m/z
233.1356 [(M-HY; calcd for C14H210Si 233.1362].

Preparation of III-02a-d1. Applying the representative procedure above to 0.53
g (2.9 mmol) of III-01-d1 and 1.6 g (7.3 mmol) of the trichloroacetimidate of crotyl
alcohol afforded after silica gel chromatography (3% diethyl ether/pentane) 0.71 g (56%)
of 111-02a-d. as a colorless oil. IR (neat) 2963, 2070, 1601, 1493, 1440, 1248 cm"; 'H
NMR (300 MHz, CDC13) 8 7.33-7.12 (m, 5 H), 5.60 (m, 2 H), 4.09-4.01 (m, 1 H), 3.72-

67

 

111
('41..

 

3.63 (m, 1 H), 1.73 (dd, J = 4.8, 1.0 Hz, 3 H), 0.0 (s, 9 H); ”C NMR (75 MHz, CDCl;) 8
141.6, 128.5, 128.3, 128.0, 125.8, 125.5, 76.3 (t, Jog = 19.8 Hz), 71.0, 17.8, -3.9.

Preparation of III-02c: Applying the representative procedure above to 1.0 g
(5.5 mmol) of III-01a and 2.4 g (11 mmol) of the trichloroacetimidate of 2-methyl-2-
propen-l-ol afforded after silica gel chromatography (1% diethyl ether in pentane) 0.71 g
(55%) of III-02c as a colorless liquid. IR (neat) 2959, 1769, 1451, 1248, 841 cm"; lH
NMR (300 MHz, CDCl3) 8 7.40-7.10 (m, 5 H), 4.89 (m, 2 H), 4.13 (s, 1 H), 3.81, (AB, A
= 105.5 Hz, J= 12.4 Hz, 2 H), 1.74, (s, 3 H), 0.00 (s, 9 H); 13C NMR (75 MHz, CDC13) 8
142.7, 141.4, 128.0, 125.9, 125.6, 111.8, 76.9, 74.1, 19.6, -3.9; GC/MS (E1) m/z 179.2,
77.0, 73.1; Anal. Calcd. for C14H220Si: C, 71.75; H, 9.47; Found: C, 71.62; H, 9.39.

Preparation of III-02d: Applying the representative procedure above to 1.0 g
(7.7 mmol) of III-01b and 3.9 g (14 mmol) of the trichloroacetimidate of cinnamyl
alcohol afforded after silica gel chromatography (1% diethyl ether in pentane) 1.25 g
(67%) of III-02d as a colorless liquid. IR (neat) 2959, 1628, 1451, 1248, 1030, 841
cm"'; 1H NMR (300 MHz, CDC13) 8 7.45-7.20 (m, 5 H), 5.89-5.65 (m, 2 H), 5.35-5.15
(m, 2 H), 5.15-4.95 (m, 2 H), 4.85 (d, J = 8.2 Hz, 1 H), 3.94 (dt, J = 6.9, 1.4 Hz, 1 H),
0.09 (s, 9 H); ”C NMR (75 MHz, CDC13) 8 142.4, 139.0, 137.2, 128.1, 127.0, 126.3,
117.4, 112.4, 80.8, 72.8, -3.9; HRMS (E1) m/z 246.1440 [(M)+; calcd. for C15szOSi,
246.1433].

Preparation of III-02c: Applying the representative procedure above to 0.9 g (5
mmol) of III-01a and 2.5 g (10 mmol) benzyl trichloroacetimidate afforded after silica
gel chromatography (1% diethyl ether in pentane) 0.7 g (52%) of lIl-02e as a colorless
liquid. IR (neat) 3027, 2959, 1496, 1451, 1248, 1059, 841 cm"; 1H NMR (300 MHz,
CDC13) 8 7.40-7.12 (m, 10 H), 4.46 (ABq, A = 124.5 Hz, J= 12.0 Hz, 2 H), 4.15 (s, 1 H),
0.00 (s, 9 H); 13C NMR (75 MHz, CDC13) 8 141.3, 139.1, 128.2, 128.1, 127.7, 127.3,

68

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126.0, 125.7, 77.2, 72.0, -3.93; GC/MS (El) m/z 179.1, 163.2, 73.1; Anal. Calcd. for
CnHZZOSi: C, 75.52; H, 8.21; Found: C, 75.17; H, 7.98.

Preparation of III-02f: Applying the representative procedure above to 1.0 g
(5.5 mmol) of III-01a and 2.6 g (13 mmol) of the trichloroacetimidate of propargyl
alcohol afforded after silica gel chromatography 0.78 g (64%) of III-02f as a colorless
liquid. IR (neat) 3308, 2959, 1767, 1450, 1248, 1059 cm“; 1H NMR (300 MHz, CDC13)
8 7.40-7.10 (m, 5 H), 4.39 (s, 1 H), 4.08 (ABq, A = 87.0 Hz, J= 15.6, 2.1 Hz, 2 H), 2.38
(t, J = 2.4 Hz, 1 H), 0.00 (s, 9 H); 13C NMR (75 MHz, CDC13) 8 140.3, 128.2, 126.1,
126.1, 80.5, 76.6, 73.7, 57.3, -4.0; HRMS [CI (NH3)] m/z 236.1468 [(M+NH4)+; calcd for
C13H22N0Si, 236.1471].

Preparation of III-02g: Applying the representative procedure above to 0.9 g
(6.8 mmol) of III-01b and 3.5 g (14 mmol) benzyl trichloroacetimidate afforded after
silica gel chromatography 0.8 g (53%) of III-02g as a colorless liquid. IR (neat) 3032,
2959, 1248, 1055 cm“; 1H NMR (300 MHz, CDC13) 8 7.43-7.25 (m, 5 H), 5.91-5.79 (m,
1 H), 5.15-5.07 (m, 2 H), 4.72 (d, J= 12.1 Hz, 1 H), 4.34 (d, J= 12.1 Hz, 1 H), 3.64 (dt, J
= 7.14, 1.37 Hz, 1 H), 0.04 (s, 9 H); ”C NMR (75 MHz, CDC13) 8 139.2, 137.3, 128.2,
127.6, 127.2, 112.6, 75.9, 71.8, -3.98; HRMS (El) m/z 220.1287 [(M)+; calcd for
C13H200Si, 220.1283].

Preparation of III-02h: Applying the representative procedure to 0.5 g (3.8
mmol) of III-01c and 2.5 g (10 mmol) benzyl trichloroacetimidate afforded after silica
gel chromatography 0.52 g (63%) of III-02h as a colorless liquid. IR (neat) 2959, 1454,
1248 cm'l; 1H NMR (300 MHz, CDC13) 8 7.41-7.20 (m, 5 H), 4.52 (ABq, A = 48 Hz, J =
11.4 Hz, 2 H), 3.04 (dd, J= 7.5, 5.7 Hz, 1 1H), 1.80-1.58 (m, 2 H), 1.01 (t, J= 7.2 Hz, 3
H), 0.07 (s, 9 H); 13C NMR (75 MHz, CDCl;) 8 139.3, 128.2, 127.7, 127.3, 75.4, 73.4,

69

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23.8, 11.7, -2.80; HRMS [CI (NH3)] m/z 223.1514 [(M+H)*; calcd for C13H230Si,
223.1518].

Preparation of 111-021. Applying the representative procedure above to 1.32 g
(10 mmol) a-(trimethylsilyl)allyl alcohol and 4.3 g (18.6 mmol) of the
trichloroacetimidate of cis-2-penten-l-ol afforded after silica gel chromatography (3%
diethyl ether in pentane) 0.61 g (31%) of III-021 as a colorless liquid. IR (neat) 2967,
1767, 1746, 1458, 1248, 841 cm’1;'H NMR (300 MHz, CDCl;) 8 5.77 (ddd, J = 18.0,
10.8, 7.2 Hz, 1 H), 5.59-5.39 (m, 2 H), 5.10-4.90 (m, 2 H), 4.13-4.06 (m, l H), 3.93-3.89
(m, 1 H), 3.57 (dt, J = 7.2, 3.0, 1.5 Hz, 1 H), 2.03 (quent, J = 7.2 Hz, 2 H), 0.94 (t, J =
7.2, 14.4 Hz, 3 H), 0.00 (s, 9 H); ”C NMR (75 MHz, CDC13) 8 137.6, 135.0, 126.2,
112.1, 75.7, 65.7, 20.9, 14.3, -3.98; HRMS (E1) m/z 198.1438 [(M)+; calcd for
CHHZZOSi, 198.1440].

Wittig rearrangement reaction of III-02a with CsF. In a glove bag purged
with nitrogen, CsF powder (ca. 100 mg, 6.4 mmol) was suspended in DMF (4 mL). The
resulting mixture was stirred for 5 min before III-02a (50 mg, 0.21 mmol) was added
dropwise via syringe. The solution was stirred overnight at room temperature, before
being diluted with diethyl ether, quenched with saturated aqueous NH4C1, washed with
0.1 N HCl, water, and then brine. The organic phase was dried over MgSO4 and
concentrated. Silica gel chromatography (5 to 10% diethyl ether in pentane gradient)
afforded 28 mg (80%) of III-03 as an inseparable mixture (1.2:1) of syn and anti
diastereomers. The spectroscopic data were consistent with those previously reported
(Kobayashi, S.; Nishio, K. J. Org. Chem. 1994, 59, 6620-6628; also see: Kang, S-K.;
Kim, D-Y.; Hong, R-K.; Ho, P-S. Synth. Commun. 1996, 26, 1493-1498).

Wittig rearrangement reaction of III-02b with CsF. Applying the Wittig

rearrangement conditions above to 48 mg (0.20 mmol) of III-02b afforded after silica gel

70

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chromatography (10% diethyl ether in pentane) 20 mg (60%) of 111-04 as a colorless oil.
The spectroscopic data were consistent with those reported in the literature (Kang, S-K.;

Kim, D-Y.; Hong, R-K.; Ho, P-S. Synth. Commun. 1996, 26, 1493-1498).

Wittig rearrangement reaction of III-02c with CsF. Applying the Wittig
rearrangement conditions above to 35 mg (0.15 mmol) of III-02c afforded after silica gel
chromatography (10% diethyl ether in pentane) 19 mg (79%) of III-05 as a colorless oil.
The spectroscopic data were consistent with those previously reported in the literature

(Kobayashi, S.; Nishio, K. J. Org. Chem. 1994, 59, 6620-6628).

Wittig rearrangement reaction of III-02d with CsF. Applying the Wittig
rearrangement conditions above to 45 mg (0.18 mmol) of III-02d afforded after silica gel
chromatography (10% diethyl ether in pentane) 17 mg (54%) of III-06 and 4 mg (13%)
of 111-07 as an inseparable mixture (1:1) of syn and anti diastereomers. The
spectroscopic data for these products were consistent with those reported in the literature
(For III-06 see: Enholm, E. 1.; Satici, 11.; Prasad, G. J. Org. Chem. 1990, 55, 324-329.
For III-07 see: Newman-Evans, R. H.; Simon, R.; Carpenter, B. K. J Org. Chem. 1990,
55, 695-711).

Attempted Wittig rearrangement reaction of III-02c with CsF. Applying the
Wittig rearrangement conditions above to 71 mg (0.26 mmol) of III-02c afforded no
Wittig rearrangement reaction product. After silica gel chromatography (1 :5 diethyl ether
in pentane) 43 mg of dibenzyl ether III-08 was isolated in 82% yield. The spectroscopic
data were consistent with those previously reported in the literature (Herzog, H.; Scharf,
H.-D. Synthesis 1986, 788-790).

Attempted Wittig rearrangement reaction of III-02f with CsF. The Wittig
rearrangement conditions above were applied to 110 mg (0.50 mmol) of 21' but no

rearrangement product was observed. Silica gel chromatography (1:20 diethyl ether in

71

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pentane) afforded 40 mg (54%) of desilylated compound III-09. The spectroscopic data
of this product were consistent with those previously reported in the literature (Boger, D.

L.; Palanki, M. S. S. J. Am. Chem. Soc. 1992, 114, 9318-9327).

Attempted Wittig rearrangement reaction of III-02g with CsF. The Wittig
rearrangement conditions above were applied to 88 mg (0.40 mmol) of III-02g but no
Wittig was observed. Silica gel chromatography (1 :50 diethyl ether in pentane) afforded
37 mg (63%) of III-10 as an inseparable mixture of geometric isomers (E:Z 88:12) and 8
mg (14%) of 111-11. The spectroscopic data were consistent with those previously
reported in the literature (For III-10 see: Dickinson, J. M.; Murphy, J. A.; Patterson, C.
W.; Wooster, N. F. J. Chem. Soc., Perkin Trans. 1 1990, 1179-1184. For III-11 see:
Zimmerman, S. C.; Crarner, K. D.; Galan, A. A. J. Org. Chem. 1989, 54, 1256-1264).

Attempted Wittig rearrangement reaction of III-02h with CsF. The Wittig
rearrangement conditions above were applied to 50 mg of III-02h but no reaction was

observed. The starting material was recovered in 81% yield.

Wittig rearrangement reaction of III-02a with MeLi. A solution of 176 mg
(0.73 mmol) of silane III-02a in 10 mL THF was cooled to 0 °C under nitrogen. MeLi
(1.4 M in diethyl ether, 0.9 mL, 1.26 mmol) was added dropwise via syringe. The
solution was stirred overnight at room temperature. 1t was then quenched with saturated
aqueous NH4C1, diluted with diethyl ether, washed with 1 N HCl, water, and brine. The
organic phase was dried over MgSO4 and concentrated. Silica gel chromatography (1 to
5% diethyl ether in hexane gradient) afforded 35 mg (20%) of III-12a, 38 mg (22%) of
III-12b, 24 mg (20%) of III-03a/b as an inseparable mixture (1.221) of diastereomers,
and 16 mg (9%) of III-13a/b as an inseparable mixture (2:1) of diastereomers, all as

colorless oils.

72

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For III-12a: IR (neat) 3567, 3065, 2961, 1444, 1248 cm“; 1H NMR (300 MHz,
CDC13) 8 7.39-7.03 (m, 5 H), 5.51 (ddd, J= 17.1, 10.8, 5.4 Hz, 1 H), 5.12-4.98 (m, 2 H),
3.15 (m, 1 H), 1.59 (bs, 1 H), 1.25 (d, J: 6.9 Hz, 3 H), -002 (s, 9 H); ”C NMR (75
MHz, CDCl;) 8 147.2, 138.8, 128.0, 125.1, 124.1, 116.7, 72.8, 43.4, 14.5, -23; HRMS
(E1) m/z 233.1359 [(M-HY; calcd for C.4H2.os1, 233.1362].

For III-12b: IR (neat) 3567, 3065, 2961, 1444, 1248 cm"; 1H NMR (300 MHz,
CDC13) 8 7.40-7.10 (m, 5 H), 6.06 (m, 1 H), 5.30-5.10 (m, 2 H), 2.98 (m, l H), 1.60 (bs,
1 H), 0.77 (d, J = 6.9 Hz, 3 H), -0.05 (s, 9 H); l3C NMR (75 MHz, CDC13) 8 145.9, 141.4,
128.0, 125.0, 124.3, 115.6, 74.1, 45.3, 13.4, -2.44; HRMS (El) m/z 233.1359 [(M-H)+;
calcd for C14H210Si, 233.1362].

For III-03a/b: The spectroscopic data were consistent with those previously
reported in the literature (For III-03a see: Kobayashi, S.; Nishio, K. J. Org. Chem. 1994,
59, 6620-6628. For III-03b see: Kang, S-K.; Kim, D-Y.; Hong, R-K.; Ho, P-S. Synth.
Commun. 1996, 26, 1493-1498).

For III-l3a/b: 1H NMR (300 MHz, CDC13) 8 7.40-7.10 (m, 5 H), 5.85 and 5.70
(m, 1 H), 5.05-4.86 (m, 2 H), 4.46 and 4.44 (d, J= 6.6 Hz, 1 H), 2.52-2.38 (m, 1 H), 1.00
and 0.88 (d, J = 6.9 Hz, 3 H), 0.00 (s, 9 H); 13C NMR (75 MHz, CDC13) 8 143.8 and
143.7, 141.3 and 140.9, 127.7 and 127.6, 126.9 and 126.8, 127.7 and 126.6, 114.3 and
114.2, 79.0 and 78.7, 46.0 and 45.8, 16.2 and 14.6, 0.1 and 0.1. For a prior preparation
see: Hollis, T. K.; Robinson, N. P.; Whelan, J.; Bosnich, B. Tetrahedron Lett. 1993, 34,
4309-4312.

Wittig rearrangement reaction of III-02a-d1 with MeLi. Applying the
representative procedure above to 90 mg (0.38 mmol) of III-02a-d1 afforded after silica
gel chromatography (3 to 10% diethyl ether in pentane gradient) 11 mg (12%) of III-
12a/b as a mixture (1.4:1) of diastereomers, 66 mg (73 %) of III-03a/b-d1 as a mixture

73

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(1.1:1) of diastereomers, all as colorless oils. (Though not isolated, 1H NMR spectrum of
the crude reaction mixture revealed that a 1.2:] mixture of III-13a/b was also formed in

approximately 1.5% yield.)

For 111-0321mm: IR (neat) 3412, 2961, 1640, 1449 cm"; ‘H NMR (300 MHz,
CDCl;) 8 7.40-7.20 (m, 5 H), 5.87-5.70 (m, 1 H), 5.25-5.00 (m, 2 H), 2.59 and 2.48 (m, 1
H), 1.82 (bs, 1 H), 1.10 and 0.87 (d, J = 6.6 Hz, 3 H); ”C NMR (75 MHz, CDC13) 8
142.5 and 142.4, 140.6 and 140.2, 128.2 and 128.1, 127.6 and 127.3, 126.8 and 126.5,
116.9 and 115.6, 77.8 and 77.2, 46.2 and 44.5, 16.5 and 13.9; GC/MS (131) m/z 162.0,
107.1, 77.0.

Wittig rearrangement reaction of III-02b with MeLi. Applying the
representative procedure above to 117 mg (0.50 mmol) of silane III-02b afforded after
silica gel chromatography (3 to 10% diethyl ether in pentane gradient) 61 mg (75%) of
111-04 and 24 mg (21%) of 111-14 as colorless oils.

For III-04: The spectroscopic data were consistent with those previously reported
in the literature (Kang, S-K.; Kim, D-Y.; Hong, R-K.; Ho, P-S. Synth. Commun. 1996,
26, 1493-1498).

For 111-14: IR (neat) 3341, 2961, 1696, 1450, 1248 cm“; 1H NMR (300 MHz,
CDC13) 8 7.39-7.03 (m, 5 H), 5.54-5.50 (m, 1 H), 5.20-5.00 (m, 1 H), 2.80-3.00 (m, l H),
2.54 (dd, J= 14.1, 9.9 Hz, 1 H), 1.89 (br s, 1 H), 1.60 (dt, J: 6.3, 1.5, 1.5 Hz, 3 H), 0.03
(s, 9 H); ”C NMR (75 MHz, CDC13) 8 145.9, 131.3, 127.9, 125.0, 124.9, 124.6, 70.5,
39.9, 18.0, -4.18; HRMS (E1) m/z 233.1359 [(M-H)+; calcd for CMHuosr 233.1362].

Wittig rearrangement reaction of III-02c with MeLi. Applying the

representative procedure above to 118 mg (0.51 mmol) of silane III-02c afforded after

74

silica gel chromatography (3 to 10% diethyl ether in pentane gradient) 59 mg (50%) of
III-15 and 26 mg (32%) of III-05 as colorless oils.

For 111-15: IR (neat) 3503, 2967, 1634, 1487, 1223, 1032 om“;‘H NMR (300
MHz, CDC13) 8 7.40-7.20 (m, 5 H), 4.88 (m, 1 H), 4.68 (m, 1 H), 2.76 (AB, A = 74.7 Hz,
J = 13.8 Hz, 2 H), 1.58 (bs, 1 H), 1.26 (s, 3 H), -0.01 (s, 9 H); ”C NMR (75 MHz,
CDCl;) 8 146.1, 141.3, 127.7, 125.0, 124.7, 115.8, 69.0, 44.3, 24.7, -4.1; GC/MS (131) m/z
234.2, 233.2, 219.2, 179.2, 73.0, 55.0; HRMS (131) m/z 233.1355 [(M-HY; calcd for
C(4H2108i, 233.1362].

Wittig rearrangement reaction of III-02e with MeLi. Applying the
representative procedure above to 74 mg (0.27 mmol) of silane lII-02e afforded afier
silica gel chromatography (10% diethyl ether in pentane) 5 mg (9%) of 111-16 as the sole
rearrangement product. The spectroscopic data for III-16 were consistent with those
previously reported in the literature (Sidduri, A.; Rozema, M. J.; Knochel, P. J. Org.
Chem. 1993, 58, 2694-2713).

Wittig rearrangement reaction of III-02f with MeLi. Applying the
representative procedure above to 400 mg (1.83 mmol) of silane III-02f and 3.3 mL (4.6
mmol) MeLi afforded after silica gel chromatography (5 to 10% diethyl ether in pentane
gradient) 89 mg (33%) of III-l7 and 60 mg (15%) of III-18 as colorless oils.

For III-17: The spectroscopic data were consistent with those previously reported
in the literature (Shinokubo, H.; Miki, 1-1.; Yokoo, T.; Oshima, K.; Utimoto, K.
Tetrahedron 1995, 51, 1 1681-11692).

For III-18: IR (neat) 3509, 3305, 2959, 1248, 841 cm"; lH NMR (300 MHz,
CDC13) 8 7.40-7.16 (m, 5 H), 2.92 (ABd, A = 39.3 Hz, J= 16.8, 2.7 Hz, 2 H), 2.22 (br s,
1 H), 1.89 (t, J: 2.4 Hz, 1 H), 0.00 (s, 9 H); ”C NMR (75 MHz, CDC13) 8 144.9, 128.0,

75

125.7, 124.8, 79.8, 72.0, 70.3, 28.2, -4.1; HRMS (El) m/z 217.1041 [(M-H)+; calcd for
C13H170Si, 217.1049].

Wittig rearrangement reaction of III-02d with MeLi. Applying the
representative procedure above to 73 mg (0.30 mmol) of silane III-02d afforded after
silica gel chromatography (5 to 10% diethyl ether in pentane gradient) 43 mg (59%) of
III-l7 and 10 mg (19%) of 111-18 as colorless oils.

For III-l7: IR (neat) 2953, 1716, 1240, om“;'H NMR (300 MHz, CDC13)
8 7.40-7.10 (m, 5 H), 6.47 (d, J: 16.2 Hz, 1 H), 6.31 (dt, J= 6.6, 16.2 Hz, 1 H), 3.34 (d,
J = 6.6 Hz, 2 H), 2.41-2.48 (m, 2 H), 0.74-0.81 (m, 2 H), 0.00 (s, 9 H); 13C NMR (75
MHz, CDC13) 8 209.7, 136.9, 133.4, 128.5, 127.5, 126.2, 122.3, 46.2, 37.1, 10.2, -1.8;
HRMS (El) m/z 246.1432 [calcd for C15H220Si, 246.1440].

For 111-18: The spectroscopic data were consistent with those previously reported

in the literature (Enholm, E. J .; Satici, H.; Prasad, G. J. Org. Chem. 1990, 55, 324-329).

Wittig rearrangement reaction of III-02i with MeLi. Applying the
representative procedure above to 130 mg (0.66 mmol) of silane III-021 afforded after
silica gel chromatography (10% diethyl ether in pentane) 119 mg (92%) of 111-19 as a
clear oil. IR (neat) 2959, 1717, 1636, 1250, 839 cm"; lH NMR (300 MHz, CDC13) 8
5.76-5.64 (m, 1 H), 5.17-5.11 (m, 2 H), 3.03 (q, J = 7.8 Hz, 1 H), 2.50-2.24 (m, 2 H),
1.75 (sep, J = 7.5 Hz, 1 H), 1.48 (sep, J: 7.5 Hz, 1 H), 0.85 (t, J = 7.5 Hz, 3 H), 0.75-
0.69 (m, 2 H), -0.02 (s, 9 H); 13C NMR (75 MHz, CDCl;;) 8 211.7, 136.5, 117.5, 58.9,
36.1, 24.3, 11.7, 9.9, -1.8; HRMS (131) m/z 198.1424 [calcd forC; (szOSi 198.1440].

Wittig rearrangement reaction of III-02g with MeLi. Applying the

representative procedure above to 82 mg (0.37 mmol) of silane III-02g afforded after

76

silica gel chromatography (3% diethyl ether in pentane) 49 mg (60%) of III-22 and 16
mg (20%) of III-23 as colorless oils.

For 111-22: IR (neat) 2942, 1716, 1640, 1497, 1252, 847 om“;‘H NMR (300
MHz, CDC13) 8 7.40-7.10 (m, 5 H), 2.62 (t, J = 7.4 Hz, 2 H), 2.58 (t, J = 7.5 Hz, 2 H),
1.85 (q, J = 7.5 Hz, 2 H), 0.18 (s, 9 H); ”C NMR (75 MHz, CDC13) 8 247.9, 141.8,
128.4, 128.3, 125.9, 47.6, 35.2, 23.7, -3.2; HRMS (131) m/z 219.1210 [(M-HY; calcd for
C13H19os1 219.1210].

For 111-23: IR (neat) 2953, 1718, 1250, 841 cm", 1H NMR (300 MHz, CDC13) 8
7.40-7.10 (m, 5 H), 2.70 (s, 2 H), 2.39-2.45 (m, 2 H), 0.71-0.77 (m, 2 H), -0.05 (s, 9 H);
”C NMR (75 MHz, CDC13) 8 209.2, 134.4, 129.3, 128.6, 126.9, 49.3, 36.6, 10.2, -1.9;
HRMS (131) m/z 233.1279 [calcd for C13H200Si 220.1283].

Preparation of III-27. A solution of 74 mg (0.73 mmol) of silane III-02g in 3
mL THF was cooled to 0°C under nitrogen. MeLi (1.4 M in diethyl ether, 0.48 mL, 0.67
mmol) was added dropwise via syringe. The solution was stirred for 2 hr at rt. To the
reaction mixture was added a mixture of 0.07 mL (0.5 mmol) TEA and 0.05 mL (0.5
mmol) freshly distilled allyl bromide. The reaction mixture was stirred for 4.5 hr at rt
before quenched with saturated aqueous NH4Cl, diluted with diethyl ether, washed with 1
N HCl, water, and brine. The organic phase was dried over MgSO4 and concentrated.
Silica gel chromatography (1 to 5% diethyl ether in hexane gradient) afforded 14 mg
(16%) of 111-27 as colorless oil: IR (neat) 2955, 1713, 1639, 1454, 1250 cm‘l; 1H NMR
(300 MHz, CDC13) 8 7.3-7.1 (m, 5 H), 5.59-5.75 (m, 1 H), 4.95-5.10 (m, 2 H), 3.02 (pent,
J = 6.6 Hz, 1 H), 2.25-2.42 (m, 1 H), 2.42-2.55 (m, 2 H), 2.01-2.15 (m, 1 H), 1.89-2.01
(m, 1 H), 1.50-1.65 (m, 1 H), 0.18 (s, 9 H); 13C NMR (75 MHz, CDC13) 8 250.2, 141.8,
135.7, 128.3, 128.2, 125.8, 116.6, 54.7, 33.6, 33.5, 30.7, -2.63; HRMS (El) m/z 260.1589
[(M)*; calcd. for C16H24OS1, 260.1596].

77

 

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Preparation 0f the acylsilanes. Representative procedure: Under an argon
atmosphere, di-m-chloro-bis(n3-allyl)dipalladium (38 mg, 0.2 mmol) was placed into a 5
mL round bottle flask and the flask was sealed with a septum. Triethylphosphite (96 mg,
0.4 mmol) and Me3SiSnBu3 (1.6 g, 4.4 mmol) were added via a syringe and the mixture
was stirred at ambient temperature for 3 min. Octonyl chloride (0.69 mL, 4.0 mmol) was
then added via a syringe and the solution was heated to 110 0C for 16 h. It was then
allowed to cool to room temperature. The mixture was transferred onto a short silica gel
column (3% ether in pentane) and a crude product was separated, the main impurity being
tn'butyltin chloride. This semicrude material was purified by flush chromatography with
pure pentane to fumish octonyl silane (Scheme 4.5; entry 3) in 74% yield as a pale yellow
liquid. The spectroscopic data were consistent with those previously reported in the

literature (Yamamoto, K.; Suzuki, 8.; Tsuji, J. Tetrahedron Lett. 1980, 21, 1653-1656).

The synthesis of other acyl silanes were carried out using the same procedure,
with variations of temperature and reaction time (see Scheme 4.5). The spectroscopic

data of these acyl silanes were consistent with those previously reported in the literature:

For pentanoyl silane (Scheme 4.5; entry 1) and cyclohexanecarbonyl silane
(Scheme 4.5; entry 5), see: Kuwajima, 1.; Mori, A.; Kato, M. Bull. Chem. Soc. Jpn. 1980,
53, 2634-2638.

For benzoyl silane (Scheme 4.5; entries 6-8), see: Tongco, E. C.; Wang, Q.‘

9

Prakash, G. K. S. Synth. Commun. 1997, 27, 2117-2124.

For o-chlorobenzoyl silane (Scheme 4.5; entry 9), see: Picard, J-P.; Calas, R.;

Dunogues, J .; Duffaut, N.; Gerval, J .; Lapouyade, P. J. Org. Chem. 1979, 44, 420-423.

For p-methoylbenzoyl silane (Scheme 4.5; entry 10), see: Cambie, R. C.; Mui, L.
C. M.; Putledge, P. S.; Woodgate, P. D. J. Organomet. Chem. 1994, 464, 171-182.

78

Preparation of (V-17). A mixture of 50 g (-)-ephedrine hydrochloride (247.8
mmol) and 45 g urea (750 mmol) was heated for 100 min at 170-175 °C. The clear liquid
was then heated to 200-210 °C for 1 hour before it was cooled to 80 °C and quenched
with water. The solid was filtered and washed thoroughly with 5% HCl and water.
Recrystalization from 95% ethanol afforded 28 g V-l7 (50%) as a white solid. mp 174-
177 °C (lit. 177°C); lat";o -45.0° (c 0.97, MeOH); 1H NMR (300 MHz, CDC13) 5 7.3 (m, 5
H), 4.7 (d, J = 8.4 Hz, 1 H), 4.6 (br s, 1 H), 3.8 (dq, J= 9.0, 6.3 Hz, 1 H), 2.7 (s, 3 H),
0.73 (d, J = 6.6 Hz, 3 H); 13‘C NMR (75 MHz, CDC13) 5 162.4, 138.1, 128.5, 128.0,
127.2, 58.2, 57.5, 28.2, 14.3. For a previous synthesis, see: Clark, W. M.; Bender, C. J.
Org. Chem. 1998, 63, 6732-6734.

Preparation of V-l8. Compound V-17 (27.5 g, 147 mmol) was disolved in 560
mL THF with the help of gentle heating. The solution was cooled to 0 °C and 100 mL n-
BuLi (1.6 M in hexanes, 160 mmol) was added dropwise. The dark purple solution was
stirred at 0 °C for 30 minutes. Then propionyl chloride (15.6 mL, 180 mmol) was added
and the clear solution was allowed to stir for 1 h and warm to room temperature. The
reaction was quenched with saturated NaHCO3 (aq.) and the organic layer was washed
with brine and dried over MgSO4. Concentration of the organic layer afforded 36 g
(quantitative yield) of V-18 as a white solid. mp 105-106 °C (lit. 106°C); ‘H NMR (300
MHz, CDC13) 5 7.3 (m, 5 H), 5.2 (d, J= 6.3 Hz, 1 H), 3.8 (dq, J= 9.0, 7.0 Hz, 1 H), 2.9
(q, .1: 7.0 Hz, 2 H) 2.7 (s, 3H), 1.0 (t, J= 7.0, 3 H), 0.75 (d, J= 6.6 Hz, 3 H); l3C NMR
(75 MHZ, CDC13) 6 173.5, 155.9, 136.7, 128.4, 127.9, 126.8, 59.2, 53.9, 29.3, 28.1, 14.8,
8.5. For a previous synthesis, see: Drewes, S. E.; Malissar, D. G. S.; Roos, G. H. P.
Chem. Ber. 1993, 2663-2673.

Preparation of V-19. NaHMDS (100 mL, 1 M in THF, 100 mmol) was cooled to
—78 °C. A solution of V-18 (22.0 g, 90 mmol) in 200 mL THF was added dropwise via a

cannula. The cannula was passed though a dry ice/acetone bath to precool the solution,

79

and the addition process took about 3 h. After an additional 2 h at ~75°C, allyl bromide
(9.0 mL, 100 mmol) was added dropwise over 90 min. The resulting solution was stirred
at -78 °C for 12 h before it was quenched with 50 mL 1 N HCl and diluted with 200 mL
EtZO. The organic phase was washed with brine, dried over MgSO4, filtered, and
concentrated to gave 25.5 g colorless oil (quantitative yield) which solidified upon sitting.
This waxy material was shown by NMR to be pure V-19. [016° -50.3° (c 0.55, CHC13);
IR (neat) 2976, 1730, 1684, 1387, 1234 cm'l; 1H NMR (300 MHz, CDCl3) 6 7.3 (m, 5 H),
5.6 (m, 1 H), 5.2 (d, J: 8.7 Hz, 1 H), 4.9 (m, 2 H), 3.9 (m, l H), 3.8 (m, 1 H), 2.7 (s, 3
H), 2.3 (m, 1 H), 2.0 (m, 1 H), 1.0 (d, J = 6.9 Hz, 3 H) 0.75 (d, J = 6.6 Hz, 3 H); 13C
NMR (75 MHz, CDC13) 6 175.8, 155.5, 136.6, 128.4, 128.3, 127.8, 126.9, 116.5, 59.2,
53.6, 37.9, 37.1, 28.1, 16.1, 14.9; HRMS (El) m/z 287.1758 [(M+H)+, calcd. for
C17H23N202, 287.1760].

Preparation of V-20. To a solution of 25.5 g V-19 in 250 mL ethyl acetate was
added 1.4 g Pd/C (10%). The flask was evacuated via aspirator and then charged with H2
via balloon. The process was repeated 3 times to sufficiently degas the sample. Then
reaction was allowed to stir under a hydrogen atmosphere for 6 h, at which time NMR
showed the reaction complete. The suspension was then filtered and concentrated to
furnish 26 g of a colorless oil (quant. yield). No impurity was observed by NMR. [€116o -
37.00 (c 0.30, CHC13); IR (neat) 2961, 1734, 1686, 1337, 1224 cm"; 1H NMR (300 MHz,
CDC13) 6 7.40-7.00 (m, 5 H), 5.28 (d, J= 9.0 Hz, 1 H), 4.00-3.80 (m, 2 H), 2.81 (s, 3 H),
1.75-1.55 (m, 1 H), 1.40-1.10 (m, 3 H), 1.08 (d, J= 6.9 Hz, 3 H), 0.81 (t, J= 7.2 Hz, 3
H), 0.79 (d, J = 6.6 Hz, 3 H); l3C NMR (75 MHz, CDCl;) 6 176.7, 155.6, 136.8, 128.3,
127.8, 126.8, 59.2, 53.5, 37.2, 35.9, 28.1, 19.9, 16.6, 14.9, 13.9; HRMS (BI) m/z
289.1923 [(M+H)+, calcd. for C17H25N202, 289.1916].

To the solution of 25.5 g this crude product (ca. 88.5 mmol) in diethyl ether (250

mL) was added 1.8 mL water (100 mmol) and the solution cooled to —10 °C (internal

80

Ii.

 

 

temperature). Then 52 mL LiBH4 (100 mmol, 2M in THF) was added dropwise.
Clouding and gas evolsion was observed. The reaction was warmed to room temperature
after 3 h. After an additional 2 h the reaction was cooled to —10 °C and quenched by the
addition of l M aq. NaOH. Large amounts of white solid formed at this point. It was
filtered and air dried. 1H NMR indicated it was a mixture of V-20 and an unidentified
inorganic salt. The filtrate was concentrated and the resulting residue was
chromatographed (30% EtOAc/hexanes) on silica gel to afford 7 .4 g V-20 as a colorless
liquid (82%). The spectroscopic data were consistent with those previously reported in
the literature. [c213o -12.0° (c 1.80, CHC13); 1H NMR (300 MHz, CDC13)6 3.42 (qd, J =
8.0, 5.7 Hz, 2 H), 1.60 (m, 1 H), 1.28 (m, 4 H), 1.08 (m, 1 H), 0.89 (d, J= 6.8 Hz, 3 H),
0.88 (t, J: 6.8 Hz, 3 H); 13C NMR (75 MHz, CDC13)6 68.4, 34.5, 35.4, 20.0, 16.5, 14.3.

Preparation of V-21. Oxalyl chloride 5.3 mL (60 mmol) was added to CHzClz at
—50°C and the temperature was further lowered to —70 °C. DMSO 8.5 mL (120 mmol)
was added dropwise (gas evolsion). After 10 min, a solution of 5.7 g V-20 (56 mmol) in
CH2C12 (70 mL) was added dropwise via a cannula. After 5 min, i-PerEt 43.5 mL (250
mmol) was added. The dry ice bath was replaced by an ice bath after 15 min before the
Wittig reagent Ph3P=CHC02Et was added in portions under-nitrogen. The mixture was
further stirred for 2.5 h before it was quenched by the addition of 1 M aq. HCl, and was
extracted with EtzO. The organic phase was washed with brine, dried over magnesium
sulfate, and concentrated. The resulting residue was chromatographed (10% EtzO in
pentane) on silica gel to afford 9.5 g (quant. yield) of V-21 as colorless liquid. IR (neat)
2963, 1722, 1653, 1224 cm"; [011230 +14.6° (c 4.38, CHCI3); 1H NMR (300 MHz, CDC13)
6 6.84 (dd, J= 8.0, 15.5 Hz, 1 H), 5.75 (d, J= 14.1 Hz, 1 H), 4.16 (dd, J: 14.3, 7.2 Hz, 2
H), 2.29 (m, 1 H), 1.27 (t, J= 7.2 Hz, 3 H), 1.2-1.4 (m, 4 H), 1.02 (d, J = 6.8 Hz, 3 H),
0.81-0.91 (m, 3 H); 13C NMR (75 MHz, CDCl3) 6 166.9, 154.7, 119.5, 60.1, 38.2, 36.2,
20.3, 19.4, 14.2, 14.0; HRMS (E1) m/z 170.1307 [(M)+, calcd. for Clongoz, 170.1306].

81

1111
add

901'

 

 

Preparation of V-22. To a -70°C solution of 162 g DIBAL (1 M in hexanes, d
0.7, 206 mmol) in 250 mL CHzClz was added a solution of 14 g (82.3 mmol) V-21 in 100
mL CHzClz via a cannula. After 50 min the temperature was warmed to 0 °C. After an
additional 30 min the reaction mixture was poured into 420 mL 0.5 M solution of sodium
potassium tartrate and stirred overnight at rt. The mixture was extracted with CH2C12 and
EtZO. The organic phase was combined, washed with brine, dried over magnesium
sulfate, and concentrated. The resulting residue was chromatographed (10% 320 in
hexanes) on silica gel to afford 9.1 g V-22 as a colorless liquid (82%). IR (neat) 3327,
2961, 1456, 1379, 972 cm]; [0160 +23.6° (c 2.06, CHCl3); 1H NMR (300 MHz, CDC13) 6
5.55-5.65 (m, 2 H), 4.06-4.12 (m, 2 H), 2.04-2.22 (m, 1 H), 1.43, (s, 1 H), 1.20-1.34 (m, 4
H), 0.97 (d, J = 6.8 Hz, 3 H), 0.87 (t, J = 6.5 Hz, 3 H); 13C NMR (75 MHz, CDCl3) 6
139.3, 126.9, 63.8, 39.0, 36.0, 20.3, 20.3, 14.0; HRMS (E1) m/z 127.1123 [(M-H)+, calcd.
for C3H150, 127.1123].

Preparation of V-23. Freshly activated 4 A molecular sieves were added to a
250 mL round bottom flask and was flame dried under vaccum for 5 min. After cooling
under N2, 50 mL CH2C12 was added followed by 2.98 mL (10 mmol) Ti(O-iPr)4. The
temperature was further lowered to —20 °C before 2.06 g (10 mmol) (+)-diethyl L-tartrate
in 8 mL CHzClz was added dropwise (1 mL / min). The solution was stirred for 50 min
during which time the temperature slowly warmed to —5 °C. The temperature was then
lowered to —40 °C and a solution of 1.28 g V-22 (10 mmol) in 10 mL CHzClz was added
dropwise. Upon complete addition the solution was stirred for 10 min at -25 °C. tert-
Butyl hydroperoxide 4.9 mL (4.1 M in toluene, 20 mmol) was added, and the mixture was
stirred overnight at -20°C before it was quenched with 10 mL saturated Na2S03 aqueous
solution and 10 mL saturated Na2S04 aqueous solution. The reaction mixture was diluted
with 40 mL diethyl ether and stirred overnight. The mixture was extracted with CHzClz

and 320. The organic phase was combined, washed with brine, dried over magnesium

82

sulfate, and concentrated. Silica gel chromatography (10% EtOAc in hexanes) furnished
1.24 g V-23 (86%) as a colorless oil. [011230 -24.0° (c 3.24, CHCl3); IR (neat) 3422, 2961,
1458, 1379, 1070, 893 cm"; 1H NMR (300 MHz, CDC13) 6 3.91 (d, J = 12.2 Hz, 1 H),
3.61 (dd, J= 12.6, 3.7 Hz, 1 H), 2.93 (p, J= 2.2 Hz, 1 H), 2.76 (dd, J= 7.1, 2.2 Hz, 1 H),
1.70 (br s, 1 H), 1.15—1.55 (m, 5 H), 0.84-0.96 (m, 6 H); 13C NMR (75 MHz, CDC13) 6
61.9, 60.6, 57.3, 36.5, 34.9, 19.8, 15.5, 14.0; HRMS (E1) m/z 145.1229 [(M+H)+, calcd.
for CanOz, 145.1228].

Preparation of V-24. To a solution of 251 mg (1.7 mmol) V-23 in 4 mL DMSO
and 10 mL was added SO3-Py 560 mg (3.5 mol) at 0 °C. The reaction was stirred at this
temperature for 120 min before it was quenched by the addition of water. It was diluted
with pentane and was extracted with EtZO. The organic phase was washed with brine,
dried over magnesium sulfate, and concentrated to give 198 mg (80%) crude product.

This material was immediately used in the next reaction without further purification.

Preparation of V-l6 and iso-V-16. A solution of V-24 (195 mg, 1.37 mmol) in
THF (30 mL) was cooled to 0 0C. Magnesium bromide etherate (336 mg, 1.3 mmol) was
desolved in 3 mL Et20/3 mL benzene, and this solution was added dropwise to the
aldehyde solution at 0 0C. After stirring at rt for 3-5 min the clear solution was cooled to
—95 °C and the Grignard reagent isopropenyl MgBr (0.5 M in THF, 2.5 mmol) was added
dropwise. The mixture was kept in a sealed dry ice bath overnight. The reaction was
quenched by the addition of 1 M aq. HCl and was diluted with 320. The organic phase
was washed with brine, dried over magnesium sulfate, and concentrated in vaccum. 1H
NMR spectrum of the resulting residue showed that V-16 and iso-V-16 was formed in a
1.2 to 1 ratio. Flash chromatography (15% 320 in pentane) on silica gel furnished 30 mg
(9%) iso-V-06, 62 mg (19%) V-16, and 78 mg (24%) mixture of the two diastereomers

all as oils.

83

For V-16: IR (neat) 3449, 2961, 1716, 1653, 1456, 1379, 1242 cm"; [0111230 -22° (c
0.15, CHCI3); 1H NMR (300 MHz, CDC13) 5 5.08 (m, 1 H), 4.94 (m, 1 H), 3.86 (d, J =
5.1 Hz, 1 H), 2.83 (dd, J= 5.1, 2.4 Hz, 1 H), 2.75 (dd, J= 7.2, 2.4 Hz, 1 H), 2.1 (br s, I
H), 1.80 (s, 3 H), 1.6-1.2 (m, 5 H), 1.0-0.8 (m, 6 H); l3C NMR (75 MHz, CDCl3) 6 144.1,
112.1, 74.9, 61.5, 59.5, 36.7, 35.1, 20.0, 18.9, 15.7, 14.2, HRMS (E1) m/z 185.1542
[(M+H)+, calcd. for C. 1H2IOZ, 185.1541].

For iso-V-l6: [011230 +5.1° (c 0.1, CHC13); 1H NMR (300 MHz, CDC13) 5 5.07 (m,
1 H), 4.96 (m, 1 H), 4.27 (d, J: 2.7 Hz, 1 H), 2.9-2.8 (m, 2 H), 1.79 (s, 3 H), 1.6-1.2 (m,
5 H), 1.0-0.8 (m, 6 H); I3C NMR (75 MHz, CDCl3) 6 143.5, 112.9, 72.3, 59.6, 58.6, 36.7,
35.1, 20.0, 18.2, 15.8, 14.2.

Preparation of V-26. To a solution of V-16 (22 mg, 0.12 mmol) in CHzClz (5
mL) was added DCC (31 mg, 0.15 mmol), DMAP (2.5 mg, 0.02 mmol) and (S)-(+)-01-
methoxyphenylacetic acid (25 mg, 0.15 mmol). After stirring at rt overnight the mixture
was diluted with 320 and was washed with 1 N aq. lHCl, brine, dried over magnesium
sulfate, and concentrated in vacuum. The resulting residue was chromatographed (10%
320 in pentane) on silica gel to afford V-26 (24 mg, 61%) as a colorless oil. [011125o +76°
(c 0.24, CHC13); IR (neat) 2930, 1755, 1456, 1172, 1116 cm"; 1H NMR (300 MHz,
CDCl3) 8 7.5-7.2 (m, 5 H), 4.87 (d, J = 6.9 Hz, 1 H), 4.81 (s, 1 1H), 4.72 (m, l H), 4.60
(m, 1 H), 3.41 (s, 3 H), 2.84 (dd, J = 6.9, 2.4 Hz, 1 H), 2.64 (dd, J = 7.2, 2.4 Hz, 1 H),
1.56 (s, 3 H), 1.6-1.1 (m, 5 H), 1.0-0.8 (m, 6 H); l3C NMR (75 MHz, CDC13) 8 169.4,
139.7, 136.1, 128.8, 128.6, 127.4, 113.4, 82.3, 78.2, 61.6, 57.4, 56.9, 36.6, 35.1, 20.0,
19.1, 15.7, 14.2, HRMS (E1) m/z 333.2066 [(M+H)+, calcd. for C20H2904, 333.2067].

Preparation of V-25. This compound was prepared by the same method as V-26,
using 34 mg (0.19 mmol) V-06 and 40 mg (0.24 mmol) (R)-(—)-01-methoxyphenylacetic
acid. Silica gel chromatography (10% EtzO in pentane) afforded V-25 (49 mg, 80%) as a

84

 

 

 

$1

31

colorless oil. laléo -56° (c 0.29, CHCl3); IR (neat) 2959, 1757, 1456, 1172, 1116 cm"; 1H
NMR (300 MHz, CDClg) o 7.5-7.2 (m, 5 H), 5.06 (d, J = 5.4 Hz, 1 H), 4.99 (m, 1 H),
4.93 (m, 1 H), 4.82 (s, 1 H), 3.44 (s, 3 H), 2.85 (dd, J: 5.4, 2.1 Hz, 1 H), 2.30 (dd, J =
7.2, 2.1 Hz, 1 H), 1.76 (s, 3 H), 1.5-1.1 (series of m, 5 H), 0.86 (t, J= 6.9 Hz, 3 H), 0.77
(d, J = 6.6 Hz, 3 H); 13C NMR (75 MHz, CDC13) 6 169.7, 140.2, 136.1, 128.8, 128.6,
127.1, 113.8, 82.6, 76.8, 60.7, 57.4, 57.0, 36.5, 35.0, 19.8, 19.4, 15.6, 14.2, HRMS (E1)
m/z 333.2064 [(M+H)+, calcd. for C20H2904, 333.2067].

Preparation of V-27. To a solution of V-26 (11 mg, 0.06 mmol) in CHzClz (5
mL) was added DCC (21 mg, 0.10 mmol), DMAP (2.5 mg, 0.02 mmol) and (Z)-V-04 (22
mg, 0.10 mmol). Afier stirring at rt overnight the mixture was diluted with 320 and was
washed with 1 N aq. HCl, brine, dried over magnesium sulfate, and concentrated in
vacuum. The resulting residue was chromatographed (10% EtzO in pentane) on silica gel
to afford v27 (12 mg, 54%) as a colorless oil. lalé° -6° (c 0.2, CHC13); IR (neat) 2959,
1704, 1628, 1169 cm"; 'H NMR (300 MHz, CDC13) o 6.39 (d, J = 1.8 Hz, 1 H), 5.07(s, 1
H), 5.00 (s, 1 H), 4.95 (s, 1 H), 2.93 (dd, J= 6.6, 1.8 Hz, 1 H), 2.75 (d, J= 1.5 Hz, 3 H),
2.71 (dd, J= 7.2, 1.8 Hz, 1 H), 1.82 (s, 3 H), 1.6-1.2 (series of m, 6 H), 1.0-0.8 (m, 6 H);
13C NMR (74.5 MHz, CDCl3) 5 163.1, 140.3, 125.1, 114.7, 113.8, 77.6, 61.5, 57.2, 36.7,
36.6, 35.2, 20.0, 19.5, 15.8, 14.2, HRMS (E1) m/z 379.0770 [(M+H)+, calcd. for
C15H2503I, 379.0769].

Preparation of V-30. A solution of V-22 (2.29 g, 17.9 mmol) in CHzClz (10 mL)
was cooled to 0 °C and 40 mL DMSO was added followed by 5.6 mL TBA (40 mmol).
S03 pyridine complex (6 g, 37 mmol) was then added in small portions. After 3 h stirring
at 0 °C the reaction was quenched by the addition of 10% HCl. The layers were separated
and the aq. phase extracted with ether (20 mL X 2). The organic phases were combined,
and washed with 10% HCl, brine, dried over MgSO4, and concentrated. Chromatography
(silica gel, 20% ether in hexanes, 1% TBA buffered) afforded the desired product V-30

85

(1.98 g, 88%) as a oil. [406° +27.7° (c 0.82, CHC13); IR (neat) 2932 (s), 1738 (s), 1687 (s),
1458 (s), 1373 (s), 1240 (s) cm"; 1H NMR (300 MHz, CDC13) 6 9.4 (d, J = 7.7 Hz, 1H),
6.7 (ABq, J = 15.6, 7.4 Hz, 1 H), 6.0 (ABq, J = 15.6, 7.9 Hz, 1 H), 2.4 (9, J = 6.6 Hz, 1
H), 1.0 (m, 6 H), 0.8 (m, 4 H); 13c NMR (75 MHz, CDC13) 6 194.3, 164.3, 131.2, 38.0,
36.7, 20.2, 19.1, 14.0, HRMS (EI) m/z 126.1041 [(M+H)*, calcd. for C8H150, 126.1045].

Preparation of V-31. To a —15 °C solution of N-acyl oxazolidinone (7.8 g, 33.5
mmol) in CH2Cl2 (50 mL) was added di-n-butylboryl triflate (36.8 mL of a l M in THF
soln., 36.8 mmol) dropwise via syringe pump. After 5 min freshly distilled TEA (5.6 mL,
40 mmol) was added dropwise via syringe pump. The reaction temperature was
maintained at 0 °C for 45 min. The solution was cooled to —78 °C and V-30 (3.9 g, 31
mmol) in CH2Cl2 (50 mL) was added dropwise. The reaction was then stirred at —75 °C
overnight. The reaction was quenched by the addition of pH 7 phosphate buffer (30 mL)
followed by 150 mL MeOH. After 15 min 30 mL of 30% H202 in 30 mL MeOH was
added and the resulting mixture was stirred at 0 °C for l 11. The mixture was extracted
with CH2C12 (50 mL X 3) and the combined extracts were washed with 5% NaHCO; and
brine, dried over MgSO4, filtered, and concentrated to yield a yellow oil. Silica gel
chromatography (1:3 EtOAczhexanes) furnished the desired product V-31 (8.2 g, 74%
yield) as a colorless oil. tall")O +18.5° (c 0.465, CHC13); IR (CDC13) 3537 (m), 3155 (s),
3020 (m), 2961 (s), 1782 (s), 1697 (s), 1458 (s) cm'l; 1H NMR (300 MHz, CDC13) 6 7.45-
7.20 (m, 5 H), 5.66 (d, J= 7.8 Hz, 1 H), 5.65 (ddd, J= 15.9, 7.8, 1.2 Hz, 1 H), 5.40 (ddd,
J: 15.3, 6.9, 0.9 Hz, 1 H), 4.78 (p, J= 6.7 Hz, 1 H), 4.41 (m, 1 H), 3.82 (m, 1 H), 2.80
(br s, 1 H), 2.76 (d, J= 3.0 Hz, 1 H), 2.15 (m, 1 H), 1.25 (m, 4 H), 1.19 (d, J= 6.9 Hz, 3
H), 0.9 (d, J = 6.3 Hz, 3 H), 0.8 (d, J = 6.6 Hz, 6 H); l3C NMR (75 MHz, cock.) 8
176.5, 152.7, 139.1, 133.0, 128.8, 128.7, 127.0, 125.6, 78.9, 72.7, 54.8, 42.8, 39.0, 36.1,
20.5, 20.4, 14.3, 14.1, 10.9; HRMS (EI) m/z 359.2088 [(M)+; calcd. for C21H29NO4:
359.2097].

86

Preparation of V-32. To a solution of V-3l (114 mg, 0.32 mmol) in THF (10
mL) was added dropwise 0.03 mL acetic acid (0.48 mmol) followed by 0.35 mL of 31.133
(1 M in THF, 0.35 mmol). This mixture was stirred at rt for 1.5 h. The reaction was
cooled to 0 °C and LiBH4 (0.4 mL, 2 M in THF, 0.8 mmol) was added dropwise. The
reaction was stirred at 0 °C for 6 h. Then 1.2 mL MeOH, 0.6 mL pH 7 buffer was added,
followed by 0.6 mL of 30% H202. The reaction was stirred for 12 h at rt and extracted
with CH2C12 (5 x 15 mL). The combined organic phase was washed with brine, dried
over MgS04, and concentrated. Chromatography (50% EtOAc in hexanes) afforded V-32
(52 mg, 88%) as a oil. [011210 +15.6° (c 1.9, CHCl3); IR (neat) 3360 (br s), 2959 (s), 2874
(s), 1728 (m, 1458 (m), 1379 (m), 1288 (m), 1032 (m) 972 (m) cm"; 1H NMR (300 MHz,
CDC13)6 5.5 (m, 2 H), 4.2 (m, 1 H), 3.6 (m, 2 H), 2.4 (br s, 2 H), 2.1 (m, 1 1H), 1.9 (m, 1
H), 1.2 (m, 4 H), 0.96 (d, J= 6.9 Hz, 3 H), 0.86 (t, J= 6.9 Hz, 3 H), 0.84 (d, J= 7.2 Hz, 3
H); 13C NMR (75 MHz, CDC13) 6 138.9, 127.8, 76.1, 66.2, 39.8, 39.0, 36.2, 20.5, 20.3,
14.1, 11.5; HRMS (E1) m/z 185.1540 [(M-H)+, calcd. for C(1H2102,185.1541].

Preparation of V-33. To a solution of V-32 (52 mg, 0.28 mmol) in 15 mL
CH2Cl2 was added 65 mg tosyl chloride (0.34 mmol) followed by 0.05 mL TEA (0.35
mmol), and a catalytic amount of DMAP. The solution was stirred at rt overnight. It was
then diluted with 50 mL CH2Cl2 and washed with 10% HCl, water and brine. The
organic phase was dried over MgS04 and concentrated. Chromatography (25%
EtOAc/hexane) afforded 49 mg V-33 (67%) as an oil. 12 mg of compound V-32 (23%)
was recovered. 1a16° +3.4° (c 1.5, CHC13); IR (neat) 3547 (br s), 2959 (s), 1599 (s), 1458
(s), 1359 (s), 1176 (s), 968 (s), 814 (s), 667 (s) cm"; 1H NMR (300 MHz, CDC13) 8 7.7
(d, J= 8.1 Hz, 2 H), 7.3 (d, J= 8.1 Hz, 2 H), 5.47 (dd, J= 15.6, 7.8 Hz, 1 H), 5.34 (dd, J
= 15.6, 6.6 Hz, 1 H), 4.0 (m, 2 H), 3.89 (m, 1 H), 2.44 (s, 3 H), 2.0 (m, 1 H), 1.91 (m, 1
H), 1.46 (d, J= 4.2 Hz, 1 H), 1.23 (m, 4 H), 0.92 (d, J= 6.6 Hz, 3 H), 0.87 (d, J= 6.6 Hz,
3 H), 0.86 (t, J= 5.1 Hz, 3 H); 13C NMR (75 MHz, CDC13) 6 144.7, 139.1, 132.9, 129.8,

87

128.0, 127.8, 72.3, 72.28, 38.9, 38.5, 36.1, 21.6, 20.4, 20.36, 14.1, 10.8, HRMS (E1) m/z
341.1782 [(M+H)+, calcd. for (3131129048, 341.1787].

Preparation of V-28. To a solution of V-33 (4.02 g, 11.8 mmol) in CH2C12 (50
mL) was added TEA (2.8 mL, 20 mol) at 0 °C followed by 4.8 g TBSOTf (18 mmol)
and the solution was stirred at rt for 4 h. The reaction was quenched with 10% HCl and
diluted with 100 mL CH2Cl2. The organic phase was washed with 10% HCl, water and
brine, dried over MgSO4 and concentrated. Silica gel chromatography (10%
EtOAc/hexanes) furnished 5.45 g v-2s (quant. yield) as colorless oil. lalé° +104 (c 1.42,
CHC13); IR (neat) 2959 (s), 2930 (s), 2858 (s), 1599 (m), 1464 (s), 1367 (s), 1251 (2),
1178 (s), 1097 (s), 972 (s), 837 (s) cm“; 1H NMR (300 MHz, CDCl;) 8 7.80 (d, J = 9.0
Hz, 2 H), 7.30 (d, J= 9.0 Hz, 2 H), 5.35 (dd, J= 16.2, 8.7 Hz, 1 H), 5.22 (dd, J= 16.2,
6.9 Hz, 1 H), 4.01 (m, 2 H), 3.80 (dd, J= 9.3, 6.9 Hz, 1 H), 2.42 (s, 3 H), 2.01 (m, 1 H),
1.82 (m, 1 H), 1.22 (m, 4 H), 0.90 (d, J= 6.9 Hz, 3 H), 0.84 (d, J= 6.9 Hz, 3 H), 0.83 (t, J
= 6.9 Hz, 3 H), 0.79 (s, 9 H), 0.06 (s, 6 H); 13c NMR (75 MHz, CDC13) 8 144.5, 138.2,
133.0, 129.7, 128.5, 127.9, 73.3, 72.6, 39.8, 38.9, 36.0, 25.7, 21.6, 20.5, 20.4, 18.0, 14.1,
11.4, -4.0, -5.1, HRMS (E1) m/z 453.2488 [(M-H)+, calcd. for C24H4104SSi, 453.2495].

Preparation of V-34. In a glove bag purged with nitrogen, 1.54 g lithium
acetylide ethylene diamine complex (16.7 mmol) was placed in a round bottom flask and
8 mL DMSO was added. The suspension was well stirred while 2.95 g neat V-28 (6.5
mmol) was added dropwise. TLC indicated product forming after 30 min, and the
reaction was complete after 6 h. The reaction mixture was diluted with 50 mL diethyl
ether and washed with 10% HCl, water, and brine. The organic layer was dried over
Mg304 and concentrated. Chromatography (100% hexanes) furnished 1.74 g V-34
(86%) as a colorless oil. [4180 +137 (c 0.903, CHCl3); IR (neat) 3316 (s), 2959 (s), 2858
(s), 1471 (s), 1251 (s), 1030 (s), 837 (s), 775 (s), 630 (s); 1H NMR (300 MHz, CDCI3) 6
5.36 (ABd, A = 39.6 Hz, J= 15.6, 6.8 Hz, 2 H), 4.03 (dd, J= 4.7, 6.6 Hz, 1 H), 2.32 (dd,

88

 

h‘\
‘6‘»

J: 6.3, 3.3 Hz, 1 H), 2.27 (dd, J= 5.7, 3.3 Hz, 1 H), 2.11 (p, J: 6.6 Hz, 1 H), 1.92-2.04
(m, 1 H), 1.7 (p, J: 6.9 Hz, 1 H), 1.20-1.21 (m, 4 H), 0.96 (d, J: 6.6 Hz, 3 H), 0.94 (d, J
= 6.6 Hz, 3 H), 0.84-0.90 (m, 3 H), 0.88 (s, 9 H), 0.03 (s, 3 H), 0.00 (s, 3 H); ”C NMR
(75 MHz, CDC13) 8 137.7, 129.3, 75.7, 68.8, 39.6, 39.1, 36.0, 25.8, 22.0, 20.6, 20.3, 18.2,
14.4, 14.1, -4.1, -49, HRMS (E1) m/z 309.2619 [(M+H)*, calcd. for CroH37OSi,
309.2614].

Preparation of V-35. To a mixture of 191 mg V-34 (0.62 mmol) and 0.43 mL
freshly distilled allyl bromide (5 mmol) was added 143 mg indium metal (1.24 mmol).
0.7 mL THF was added and the flask was purged with nitrogen and sonicated for 5.5 h.
The metal dissolved within 5 min. The reaction mixture was diluted with 50 mL diethyl
ether and washed with l M HCl, water, and brine. The organic phase was dried over
MgSO4, and concentrated. Silica gel chromatography (hexanes) furnished 184 mg V-35
(85%) as a colorless oil. [61112)o +19.4 (c 0.45, CHCl3); IR (neat) 2959 (s), 1643 (s), 1402
(s), 1251 (s); 'H NMR (300 MHz, CDCl3) 6 5.72-5.90 (m, 1 H), 5.24-5.44 (m, 2 H), 4.97-
5.10 (m, 2 H), 4.77 (s, 1 H), 4.73, (s, l H), 3.86 (dd, J= 4.4, 5.8 Hz, 1 H), 2.62-2.80 (m, 2
H), 2.27 (dd, J = 9.3, 19.1 Hz, 1 H), 2.05-2.17 (m, 1 H), 1.58-1.74 (m, 2 H), 1.17-1.37
(m, 4 H), 0.95 (d, J = 6.8 Hz, 3 H), 0.83-0.91 (m, 12 H), 0.77-0.83 (m, 3 H), 0.02 (s, 3 H),
0.00 (s, 3 H); ”C NMR (75 MHz, CDC13) 8 147.1, 137.5, 136.5, 129.8, 116.0, 111.3,
77.5, 40.4, 39.3, 39.2, 37.8, 36.1, 25.9, 20.7, 20.4, 18.2, 14.6, 14.2, -4.0, -4.8, HRMS (E1)
m/z 351.3059 [(M+H)+, calcd. for C22H430Si, 351.3083].

Through a parallel route, starting from V-46 (Scheme 5.20), compounds iso-V-28,
iso-V-34, and iso-V-35 were prepared. These compounds differ from V-28, V-34, and V-

35 in the configuration of the allylic alcohol center.

Preparation of iso-V-28. To a solution of V-46 (920 mg, 2.7 mmol) in 20 mL
CH2C12 was added i-Pr2NEt (0.7 mL, 4.0 mol) at 0 °C followed by 0.8 g TBSOTf (3

89

mmol) and the solution was stirred at rt for 20 min. The reaction was quenched with 10%
HCl and diluted with 100 mL CH2Cl2. The organic phase was washed with 10% HCl,
water and brine, dried over MgS04 and concentrated. Silica gel chromatography (10%
EtOAc/hexanes) furnished 0.72 g iso-V-28 (59%) as colorless oil. [61115o +0.9o (c 0.94,
CHC13); IR (neat) 2959 (s), 2858(8), 1599 (s), 1464 (s), 1367 (s), 1251 (s), 1176 (s), 939
(s), 837 (s) cm"; 1H NMR (300 MHz, CDC13) 8 7.79 (d, J= 8.4 Hz, 2 H), 7.34 (d, J= 8.4
Hz, 2 H), 5.26 (ABd, A = 42.9 Hz, J= 15.6, 7.4 Hz, 2 H), 4.06 (ab, J= 9.6, 6.0 Hz, 1 H),
3.82-3.98 (m, 2 H), 2.45 (s, 3 H), 2.01-2.15 (m, 1 H), 1.76-1.91 (m, 1 H), 1.16-1.30 (m, 4
H), 0.95 (d, J = 6.6 Hz, 3 H), 0.78-0.91 (m, 6 H), 0.81 (s, 9 H), -0.01 (s, 3 H), -0.02 (s, 3
H); ”C NMR (75 MHz, CDCl;) 8 144.5, 139.0, 133.0, 129.7, 129.0, 127.9, 75.0, 72.6,
39.6, 39.0, 36.2, 25.7, 20.4, 20.3, 20.0, 14.0, 13.1,-3.8, -5.0; HRMS (CI, NH4) m/z
472.2910 [(M+NH4)+, calcd. for C24H46N04SSi, 472.2917].

Preparation of iso-V-34. In a glove bag purged with nitrogen, 266 mg lithium
acetylide ethylene diamine complex (2.8 mmol) was placed in a round bottom flask and
1.2 mL DMSO was added. The suspension was well stirred while 430 mg iso-V-28 (0.94
mmol) was added neat. The reaction was stirred overnight at rt before it was diluted with
10 mL diethyl ether and washed with 10% MC], water, and brine. The organic layer was
dried over Mg804 and concentrated. Chromatography (100% hexanes) filrnished 230 mg
iso-V-34 (80%) as a colorless oil. [alts0 +103 (0 1.56, CHC13); IR (neat) 2959 (s), 2858
(s), 2174 (s), 1471 (s), 1250 (s); 1H NMR (300 MHz, CDC13) 6 5.34 (ABd, A = 36.9 Hz, J
= 15.6, 7.5 Hz, 2 H), 3.91 (t, J= 6.9 Hz, 1 H), 2.33 (ddd, J= 16.8, 4.8, 2.7 Hz, 1 H), 2.07-
2.22 (m, 2 H), 1.96 (t, J= 2.7 Hz, 1 H), 1.66-1.78 (m, 1 H), 1.22-1.34 (m, 4 H), 0.99 (d, J
= 6.9 Hz, 3 H), 0.95 (d, J= 6.9 Hz, 3 H), 0.93-0.99 (m, 3 H), 0.89 (s, 9 H), 0.06 (s, 3 H),
0.03 (s, 3 H); 13C NMR (75 MHz, CDC13) 6 138.4, 129.6, 83.6, 76.9, 69.0, 39.2, 39.0,
36.3, 25.9, 22.6, 20.5, 18.1, 15.4, 14.1, -3.9, -4.9; HRMS (E1) m/z 309.2619 [(M+H)+,
calcd. for C19H370Si, 309.2614].

90

1111 116

“is“ 8110‘
501111100
.111011161
reaction
1111116. (1:
C111 0111111
11111 55
1645, 1-
111.7.
13.6.1

11391111,?

 

Preparation of iso-V-35. To a mixture of 458 mg iso-V-34 (1.48 mmol) and 1.0
mL freshly distilled allyl bromide (12 mmol) was added 345 mg indium metal (3 mmol).
1.5 mL THF was added and the flask was purged with nitrogen and sonicated for 5 h at
18 °C. The metal dissolved within 7 min. The reaction mixture was diluted with 20 mL
diethyl ether and washed with 1 M HCI, water, and brine. The organic phase was dried
over MgSOa, and concentrated. Silica gel chromatography (hexanes) furnished 420 mg
iso-V-35 (81%) as a colorless oil. [403° +17.86 (c 3.74, CHC13); IR (neat) 3078 (m), 2959
(s), 2858 (s), 1645 (s), 1462 (s), 1253 (s); 1H NMR (300 MHz, CDCl3) 6 5.75-5.85 (m, 1
H), 5.25-5.42 (m, 2 H), 4.99-5.12 (m, 2 H), 4.80 (s, l H), 4.76, (s, 1 H), 3.84 (d, J = 6.0
Hz, 1 H), 2.65-2.82 (m, 2 H), 2.25-2.40 (m, 1 H), 2.05-2.20 (m, 1 H), 1.62-1.78 (m, 2 H),
1.22-1.32 (m, 4 H), 0.98 (d, J= 6.6 Hz, 3 H), 0.90 (m, 9 H), 0.84-0.94 (m, 3 H), 0.79 (d, J
= 6.6 Hz, 3 H), 0.04 (s, 3 H), 0.02 (s, 3 H); 13C NMR (75 MHz, CDC13) 6 147.1, 137.8,
136.5, 129.6, 116.0, 111.5, 77.8, 40.3, 39.4, 39.2, 37.6, 36.4, 25.9, 20.8, 20.7, 18.2, 15.0,
14.1, -3.9, -4.8; HRMS (EI) m/z 351.3083 [(M+H)+, calcd. for C22H430Si, 351.3083].

Preparation of V-37. To a solution of 184 mg V-35 (0.52 mmol) in 5 mL THF
was added 1.0 mL TBAF (1.0 M in THF, 1.0 mmol) and 60 mg HOAc (1.0 mmol). The
solution was stirred at rt overnight. TLC indicates the reaction was not complete.
Another 1.0 mL TBAF was added and the temperature was warmed to 40 °C. The
reaction was stirred for 4 h before it was diluted with 320, washed with 1 N HCl and
brine, dried over magnesium sulfate, and concentrated under reduced pressure. Silica gel
chromatography (1-10% B20 in pentane) afforded 77 mg V-37 (62%) as a yellow oil,
with 55 mg V85 (30%) recovered. [a16° +13.0° (c 0.20, CHC13); IR (neat) 3400, 2961,
1645, 1456 cm"; 1H NMR (300 MHz, CDC13) 8 5.75-5.91 (m, 1 H), 5.48 (ABd, A = 30.7
Hz, J= 15.8, 6.9 Hz, 2 H), 5.02-5.12 (m, 2 H), 4.83 (s, 1 H), 4.80, (s, 1 H), 3.95 (dd, J =
4.3, 6.1 Hz, 1 H), 2.76 (d, J= 7.3 Hz, 2 H), 2.07-2.37 (m, 2 H), 1.72-1.87 (m, 2 H), 1.17-
1.39 (m, 4 H), 0.99 (d, J= 6.8 Hz, 3 H), 0.83-0.94 (m, 6 H); 13C NMR (75 MHz, CDC13)

91

 

6 146.6, 138.5, 136.4, 129.3, 116.1, 111.8, 76.3, 40.3, 39.4, 39.1, 36.5, 36.2, 20.6, 20.4,
14.4, 14.1; HRMS (EI) m/z 235.2064 [(M-H)+, calcd. for C16H270, 235.2062].

m-CPBA Epoxidation of V-37 (Preparation of V-38). A solution of 104 mg V-
37 (0.44 mmol) in 10 mL CH2Cl2 was cooled to 0 °C. m-CPBA (103 mg, 0.6 mmol) was
added as a fine powder. The mixture was stirred for 12 h at 0 °C before it was quenched
with water. The reaction was not completed (another trail showed the reaction did not go
to completion after 24 h). The reaction mixture was diluted with 50 mL diethyl ether and
washed with 1M HCl, water, and brine. The organic phase was dried over MgSO4, and
concentrated. Silica gel chromatography (5%-15% EtOAc in hexanes) furnished 45 mg
V-38 (41%) and 14 mg iso-V-38 ( 13%) as colorless oils. 12 mg V-37 (12%) was

recovered.

For V-38: la16° .040 (c 0.60, CHC13); IR (neat) 3470, 2961, 2926, 1734, 1645,
1458, 1261 cm"; 1H NMR (300 MHz, CDC13) 8 5.92-5.70 (m, 1 H), 5.15-5.00 (m, 2 H),
4.82 (d, J= 9.89 Hz, 2 H), 3.64-3.72 (m, 2 H), 2.74 (d, J: 6.59 Hz, 2 H), 2.35-2.20 (m, 1
H), 2.03-1.83 (m, 2 H), 1.77 (d, J= 2.93 Hz, 1 H), 1.62 (br s, 1 H), 1.48-1.10 (m, 5 H),
1.00 (d, J = 6.59 Hz, 3 H), 0.97-0.81 (m, 6 H); ”C NMR (75 MHz, CDC13) 8 145.9,
136.2, 116.3, 112.3, 71.4, 60.2, 59.2, 40.3, 39.8, 35.5, 35.1, 33.8, 20.1, 16.7, 14.2, 14.0;
HRMS (EI) m/z 253.2162 [(M+H)+, calcd. for C16H2902, 253.2168].

For iso-V-38: 141130 .470" (c 0.24, CHC13); IR (neat) 3441, 2961, 1718, 1643,
1458, 1182 cm"; 1H NMR (300 MHz, CDC13) 8 5.71-5.90 (m, 1 H), 5.53 (dd, J= 15.38,
7.14 Hz, 1 H), 5.36 (dd, J: 15.38, 7.69 Hz, 1 H), 5.07-5.13 (m, 2 H), 4.37 (t, J: 7.41
Hz, 1 H), 3.31-3.51 (m, 2 H), 2.29-2.57 (m, 2 H), 2.08-2.23 (m, 1 H), 1.84 (dd, J= 12.63,
7.69 Hz, 1 H), 1.62 (br s, 1 H), 1.53 (dd, J: 12.63, 8.24 Hz, 1 H), 1.16-1.37 (m, 5 H),
0.97 (d, J = 6.59 Hz, 3 H), 0.79-0.94 (m, 6 H); ”C NMR (75 MHz, CDC13) 8 139.6,
134.4, 126.1, 118.0, 84.1, 83.4, 67.0, 42.3, 39.9, 39.1, 37.1, 36.1, 20.4, 20.3, 15.5, 14.1;

92

 

 

HRMS (CI, NH4) m/z 253.2165 [(M+H)+, calcd. for C16H2902, 253.2168].

Sharpless epoxidation of V-37 (Preparation of V-38). 4 A Molecular sieves
were added to a 25 mL round bottom flask that was then flame dried under vacuum for 5
min. After cooling under N2, 7 mL CH2C12 was added followed by 60 111 (0.2 mmol)
Ti(0-iPr)4. The temperature was further lowered to —20 °C before 34 111 (0.2 mmol) (-)-
diethyl D-tartrate in 1 mL CH2Cl2 was added dropwise. The solution was stirred for 50
min during which the temperature slowly warmed to —5 °C. The temperature was then
lowered to —40 °C and a solution of 47 mg V-37 (0.2 mmol) in 1 mL CH2Cl2 was added
dropwise. Upon complete addition the solution was stirred for 10 min at —25 °C. tert-
Butyl hydroperoxide 0.1 mL (4.2 M in toluene) was added, and the mixture was stirred
overnight at —20 °C before it was quenched with 1 mL saturated Na2S03 aqueous solution
and 1 mL saturated Na2804 aqueous solution. The reaction mixture was diluted with 10
mL diethyl ether and meso-tartraric acid was added. The mixture was then stirred for 2 h
and washed with 1 M HCl, water and brine. The organic phase was dried over MgSOa,
and concentrated. Silica gel chromatography (10% EtOAc in hexanes) furnished 31 mg
V-38 (66%) as a colorless oil, which was spectroscopically identical to the previously

prepared material.

Preparation of V-39. To a solution of 72 mg V-37 (0.31 mmol) in 5 mL THF ,
was added 83 mg (0.68 mmol) benzoic acid. The solution was cooled to 0 °C before 178
mg (0.68 mmol) Ph3P was added, followed by 137 mg (0.68 mL) DIAD in 1 mL THF. 1
The reactio'n was stirred at rt for 6 h, at which time TLC showed no starting material.
The reaction mixture was diluted with diethyl ether and washed with 1 M HCl, water, and
brine. The organic phase was dried over MgS04, and concentrated. The resulting
material was passed through a short column and the crude material (V-39) (84 mg, 81%)

was subjected to hydrolysis without further purification.

93

 

 

Preparation of V-40 (Hydrolysis of V-39). The crude V-39 from above (84 mg,
0.25 mmol) was disolved in 10 mL MeOH and 1 mL sat. K2C03 was added. The mixture
was stirred at 60°C for 4 h. TLC showed no starting material and the formation of one
major product with slightly more polarity that V-37. The mixture was concentrated,
diluted with 10 mL diethyl ether and washed with 1M HCl, water, and brine. The organic
phase was dried over MgS04 and concentrated. Silica gel chromatography (5%-15%
EtOAc in hexanes) furnished 33 mg V-40 (57%) as a colorless oil. [0160 +12.8° (c 0.5,
CHCl3); IR (neat) 3441, 2961, 1724, 1643, 1456, 1377 cm"; ‘H NMR (300 MHz, CDC13)
6 5.93-5.72 (m, 1 H), 5.35-5.60 (m, 2 H), 5.01-5.17 (m, 2 H), 4.81 (d, J= 11.54 Hz, 2 H),
3.82-3.99 (m, 1 H), 2.67-2.83 (m, 2 H), 2.08-2.35 (m, 2 H), 1.71-1.94 (m, 2 H), 1.62 (br
s, 1H), 1.14-1.40 (m, 4 H), 0.99 (d, J= 7.14 Hz, 3 H), 0.70-0.95 (m, 6 H); I3C NMR (75
MHz, CDC13) 6 146.6, 139.5, 136.3, 128.5, 116.1, 111.7, 77.2, 40.4, 39.6, 39.1, 36.5,
36.4, 20.7, 20.5, 14.9, 14.1; HRMS (E1) m/z 236.2140 [(M)+, calcd. for C16H230,
236.2139].

Preparation of V-4l. To a 0 °C solution of 29 mg V-27 (0.12 mmol) in CH2C12
was added 64 mg (0.15 mmol) of Dess-Martin periodinane (Dess, D. B.; Martin, J. C. J.
Org. Chem. 1983, 48, 4155-4156.). TLC indicated the reaction was complete after 15
min. The mixture was diluted with 10 mL CH2Cl2 and washed with 1M HCl, sat.
NaHC03, water, and brine. The organic phase was dried over MgS04, and concentrated
to fumish 23 mg V-41 (80%) as colorless oil. IR (neat) 2963, 1695, 1672, 1628, 1458,
983 cm"; 1H NMR (300 MHz, CDC13) 6 6.78 (dd, J = 15.93, 7.69 Hz, 1 H), 6.12 (d, J=
15.93 Hz, 1 H), 5.70-5.91 (m, 1 H), 5.01-5.15 (m, 2 H), 4.79 (d, J= 18.68 Hz, 2 H), 2.90-
3.07 (m, 1 H), 2.77 (d, J = 7.14 Hz, 2 H), 2.46 (dd, J = 14.83, 6.59 Hz, 1 H), 2.24-2.40
(m, 1 H), 2.02 (dd, J= 14.28, 7.69 Hz, 1 H), 1.17-1.43 (m, 4 H), 0.97-1.13 (m, 6 H), 0.90
(t, J = 7.14 Hz, 3 H); 13C NMR (75 MHz, CDCl3) 6 203.6 152.9, 145.3, 136.1, 127.0,
116.4, 112.3, 41.6, 40.7, 39.3, 38.3, 36.6, 20.4, 19.5, 16.5, 14.0.

94

 

 

Preparation of V-40 (Reduction of V-4l). To a solution of 33 mg V-31 (0.14
mmol) in 10 mL MeOH was added 52 mg (0.14 mmol) CeCl3-7H20 and the solution was
cooled to —78 °C. NaBHa 17 mg (0.4 mmol) was carefully added to the solution and the
mixture was stirred for 2 h during which the temperature warmed to rt. TLC indicated the
reaction was complete and two products were formed. The reaction was carefully
quenched with water and the mixture was concentrated and diluted with 20 mL diethyl
ether, washed with 1 M HCl, water, and brine. The organic phase was dried over MgS04,
and concentrated. Silica gel chromatography (12% EtOAc in hexanes) furnished 11 mg
V-40 (34%) and 17 mg mixture (51%) of V-40 and V-37 (1:4.5) as colorless oils.

For v.40: [408° +12.8° (c 0.50, CHC13); IR (neat) 3441, 2961, 1724, 1456, 1377,
972 cm"; 1H NMR (300 MHz, CDC13) 8 5.93-5.72 (m, 1 H), 5.35-5.60 (m, 2 H), 5.01-
5.17 (m, 2 H), 4.81 (d, J= 11.54 Hz, 2 H), 3.82-3.99 (m, l H), 2.67-2.83 (m, 2 H), 2.08-
2.35 (m, 2 H), 1.71-1.94 (m, 2 H), 1.62 (br s, 1 H), 1.14-1.40 (m, 4 H), 0.99 (d, J= 7.14
Hz, 3 H), 0.70-0.95 (m, 6 H); ”C NMR (75 MHz, CDC13) 8 146.6, 139.5, 136.3, 128.5,
116.1, 111.7, 77.2, 40.4, 39.6, 39.1, 36.5, 36.4, 20.7, 20.5, 14.9, 14.1; HRMS (E1) m/z
236.2140 [(M)*, calcd. for C16H230, 236.2139].

Preparation of V-42. Molecular sieves (4 A) were added to a 25 mL round
bottom flask that was then flame dried under vaccum for 5 min. After cooling under N2,
8 mL CH2C12 was added followed by 42 mg (0.148 mmol) Ti(0-iPr)4. The temperature
was further lowered to —20 °C before 46 mg (0.197 mmol) (+)-diethyl L-tartrate in 1 mL
CH2C12 was added dropwise. The solution was stirred for 50 min during which time the
temperature slowly warmed to —5 °C. The temperature was lowered to —40 °C and a
solution of 52 mg V-40 (0.220 mmol) in 1 mL CH2Cl2 was added dropwise. Upon
complete addition the solution was stirred for 10 min at —25 °C. tert-Butyl hydroperoxide
55 111 (4.2 M in toluene, 0.231 mmol) was added, and the mixture was stirred overnight at

—20 °C before it was quenched with 0.5 mL saturated Na2S03 aqueous solution and 0.5

95

 

 

 

mL saturated Na2S04 aqueous solution. The reaction mixture was diluted with 10 mL
diethyl ether and one drop of glycerol was added via pipette. The mixture was then
stirred for 3 h, then washed with 1M HCl, water, and brine. The organic phase was dried
over MgS04, and concentrated. Silica gel chromatography (10% EtOAc in hexanes)
furnished 48 mg V42 (89%) as a colorless oil. [416° +16.7° (c 0.90, CHC13); IR (neat)
3445, 2928, 1728, 1641, 1458, 1379, 1288, 1070 cm"; IH NMR (300 MHz, CDCl3) 6
5.73-5.93 (m, 1 H), 5.01-5.16 (m, 2 H), 4.84 (d, J= 9.89 Hz, 2 H), 3.69 (br s, 1 H), 2.82-
2.92 (m, 2 H), 2.77 (d, J= 6.59 Hz, 2 H), 2.33-2.47 (m, 1 H), 1.83-1.99 (m, 3 H), 1.61 (br
s, 1 H), 1.20-1.59 (m, 4 H), 0.83-1.00 (m, 9 H); 13C NMR (75 MHz, CDC13) 6 146.0,
136.3, 116.3, 112.2, 72.0, 59.5, 57.9, 40.3, 39.1, 36.7, 35.2, 34.6, 20.0, 15.9, 15.0, 14.2;
HRMS (E1) m/z 253.2165 [(M+H)+, calcd. for C(6H2902, 253.2168].

Preparation of V-47. To a solution of 262 mg (0.97 mmol) Ph3P in 5 mL THF
was added 4 A MS followed by 202 mg (0.97 mL) DIAD at 0 °C. After about 2 min,
large amounts of white precipitation formed. To this milky suspension was quickly
added a premixed solution of 122 mg (0.48 mmol) V-42 and 212 mg (Z)-V-l4 (0.97
mmol) in 3 mL THF. Shortly after the addition the solution turned clear. The reaction
was stirred at 0 °C for 30 min before a white precipitate formed again. The reaction was
stirred overnight at rt and was diluted with diethyl ether and washed with 1M HCl, water,
and brine. The organic phase was dried over MgS04, and concentrated. Silica gel
chromatography (1% EtOAc in hexanes) furnished 155 mg V-47 (71%) along with 20 mg
(16%) V-42 recovered, both as colorless oils. 1011210 -4.5° (c 1.6, CHC13); IR (neat) 2963,
1734, 1628, 1458, 1170 cm“; 1H NMR (300 MHz, CDC13) 8 6.36 (s, 1 H), 5.68-5.88 (m,
1 H), 4.98-5.12 (m, 2 H), 4.86 (s, 1 H), 4.79 (s, 1 H), 4.72 (dd, J = 6.04, 4.94 Hz, 1 H),
2.91 (dd, J = 6.59, 2.20 Hz, 1 H), 2.69-2.77 (m, 5 H), 2.64 (dd, J = 7.14, 2.20 Hz, 1 H),
2.34 (dd, J= 13.73, 4.40 Hz, 1 H), 2.01-2.16 (m, 1 H), 1.85 (dd, J= 13.73, 9.89 Hz, 1 H),
1.17-1.55 (m, 5 H), 0.82-1.01 (m, 9 H); 13C NMR (75 MHz, CDC13) 6 163.5, 145.0,

96

 

136.1, 125.3, 116.4, 114.2, 112.8, 77.0, 61.6, 56.5, 40.3, 39.0, 36.6, 36.6, 35.3, 33.5, 19.9,
15.8, 15.0, 14.2; HRMS (CI, CH4) m/z 447.1406 [(M+H)+, calcd for C20H32IO3,
447.1396].

Preparation of V-48. To a solution of 613 mg (2.34 mmol) Ph3P in 10 mL THF
was added 473 mg (2.34 mL) DIAD at 0°C. After about 2 min, large amounts of white
precipitate formed. To this milky suspension was quickly added a premixed solution of
295 mg (1.17 mmol) V-42 and 496 mg (E)-V-l4 (2.34 mmol) in 5 mL THF. Shortly after
the addition the solution turned clear. The reaction was stirred overnight at rt and was
diluted with diethyl ether and washed with 1 M HCl, water, and brine. The organic phase
was dried over MgSOa, and concentrated. Silica gel chromatography (1% EtOAc in
hexanes) furnished 484 mg V-48 (93%) as a colorless oil. 1611123o -19.5° (c 1.46, CHC13);
IR (neat) 2963, 1718, 1616, 1332, 1178, 1074 cm'l; lH NMR (300 MHz, CDC13) 6 6.66-
6.74 (m, 1 H), 5.71-5.91 (m, 1 H), 4.98-5.14 (m, 2 H), 4.87 (s, 1 H), 4.78 (s, l H), 4.62
(dd, J= 5.1, 6.9 Hz, 1 H), 3.01 (s, 3 H), 2.89 (dd, J: 6.9, 2.1 Hz, 1 H), 2.68-2.78 (m, 2
H), 2.65 (dd, J= 5.1, 7.2 Hz, 1 H), 2.30 (dd, J= 8.7, 13.8 Hz, 1 H), 1.98-2.14 (m, 1 H),
1.85 (dd, J: 6.9, 13.8 Hz, 1 H), 1.22-1.57 (m, 5 H), 0.86-1.03 (m, 9 H); 13C NMR (75
MHz, CDCl3) 6 163.3, 144.9, 136.0, 131.0, 121.3, 116.4, 112.9, 61.6, 56.7, 54.1, 40.2,
39.1, 36.6, 35.2, 33.5, 31.1, 19.9, 15.8, 14.9, 14.2; HRMS (CI, CH4) m/z 447.1395
[(M+H)+, calcd. for C20H32103, 447.1396].

Preparation of V-Sl. A mixture of 9.6 g D-arabitol (63 mmol), 18 g 3,3-
dimethoxyl propane (136 mmol), and 0.45 g TosleH in 65 mL DMF was slowly heated
to 35 °C and stirred at that temperature for 3.5 h. TLC indicated the reaction was
complete. Approximately 3 mL TEA were added and the mixture was concentrated under
reduced pressure. The resulting thick oil was disolved in 200 mL diethyl ether and
washed with 1 M HCl, sat. NaHC03, water, and brine. The organic phase was dried over

MgSOa, and concentrated to give ca. 18 g of a clear liquid (quant. yield). This material

97

 

was used in the next reaction without further purification.

Preparation of V-52. To a solution of crude V-Sl (18 g; 63 mmol) in 100 mL
CH2C12 and 100 mL DMSO (both solvent were anhydrous) was added 20 mL TEA (138
mol) at 0 °C. 20 g (123 mmol) SO3-Py was then added in portions. TLC indicated the
reaction was complete in 1 h. The mixture was diluted with 200 mL CH2Cl2 and washed
with 1M HCl, sat. NaHC03, water and brine. The organic phase was dried over MgSOa,
and concentrated to give ca. 17 g of a clear liquid (quant. yield). 1H NMR of this material
showed that it was mainly V-52, with almost no aldehyde by-product. This material was
used in the next reaction without further purification. lH NMR (300 MHz, CDC13) 6 4.79
(t, J: 7.5 Hz, 2 H), 4.28 (t, J= 8.1 Hz, 2 H), 3.94 (dd, J= 8.1, 6.9 Hz, 2 H), 1.50-1.79
(m. 8 H), 0.81-1.01 (m, 12 H).

Preparation of V-53. To a well stirred suspension of 32.5 g Ph3PCH3BI‘ (91
mmol) in 200 mL THF was added 70 mL NaHMDS (1 M in THF, 70 mol) at 0°C. The
mixture turned bright yellow. The ice bath was removed and the mixture was stirred at rt
for 30 min before it was cooled down to 0 °C. A solution of 17 g V-52 (60 mmol) in 150
mL THF was added dropwise. The reaction was stirred at 0 °C for 3 h, TLC showed no
starting material remaining. The reaction mixture was filtered though a celite pad,
concentrated and diluted with 100 mL diethyl ether/hexanes (1 :1). More solid
precipitated. The mixture was then passed though a short silica gel column and
concentrated. NMR of the resulting light yellow oil showed that it was mainly V-53, and
no terminal alkene or racemized diastereomer was observed. It was subjected to
hydrolysis without further purification. 1H NMR (300 MHz, CDCl3) 6 5.33 (s, 1 H), 5.32
(s, 1 H), 4.54 (dd, J= 7.8, 6.6 Hz, 2 H), 4.21 (t, J: 7.5 Hz, 2 H), 3.58 (t, J= 6.0 Hz, 2 H),
1.50-1.79 (m, 8 H), 0.75-1.01 (m, 12 H).

Preparation of V-54. Crude V-53 from above (18 g, 63 mmol) was disolved in

98

 

30 mL THF and 30 mL MeOH was added followed by 30 mL 10% HCl. The mixture
was refluxed for 2 h, during which time the mixture turned homogeneous. The solution
was concentrated under reduced pressure and then put under high vacuum to remove the
volatiles. A thick brown oil was obtained (10 g). TLC indicated this material to be

mainly one compound (V-54). This material was used in the next reaction without

further purification.

Preparation of V-50. Crude V-54 from above (10 g, ca. 63 mmol) was disolved
in 100 mL CH2C12 and DMF (1:1) mixture. TBA (21 mL, 150 mmol) and DMAP (1.8 g,
15 mmol) were added and the solution was cooled to 0 °C. 24.3 g TIPSCl (126 mmol)
was added dropwise. The reaction was stirred for 3 h, during which the temperature
warmed to rt. The reaction mixture was diluted with CH2C12 and washed with 1 M HCl,
water and brine. The organic phase was dried over MgS04, and concentrated. Silica gel
chromatography (5-10% EtOAc in hexanes) fumished 15.1 g V-50 (52% based on D-

arabitol) and 2.7 g mono protected V-54 (14%) both as colorless oils.

For v-50: [a]??? +18.6° (c 1.0, CHCl3); IR (neat) 3443, 2866, 1464, 1385, 1248,
1107 cm", 1H NMR (300 MHz, CDCl,) 8 5.31 (s, 2 H), 4.27 (dd, J= 8.1, 3.9 Hz, 2 H),
3.87 (dd, J= 9.6, 3.9 Hz, 2 H), 3.64 (dd, J= 9.6, 8.1 Hz, 2 H), 3.15 (br, 2 0H), 1.00-1.19
(m, 18 H); ”C NMR (75 MHz, CDC13) 8 146.1, 113.4, 73.4, 67.3, 17.9, 11.8; HRMS (Cl)
m/z 461.3470 [(M-H)+, calcd. for C24H53048i2, 461.3482].

Preparation of V-55. Procedure A.“ To a well stirred solution of 5.4 g V-50 (11.7
mmol) in 80 mL 3:1 mixture of THF and DMSO was added 26 mL NaHMDS (l M in
THF, 26 mmol) at 0°C, followed by 4.0 g PMBCl (26 mmol). The solution was stirred
overnight during which time the temperature warmed to rt. TLC showed no starting
material. The reaction mixture was quenched with water, concentrated and diluted with

100 mL diethyl ether and washed with 1 M HCl, water and brine. The organic phase was

99

 

dried over MgS04, and concentrated. Silica gel chromatography (5-10% EtOAc in
hexanes) fumished 2.4 g V-55 (29%) as a colorless oil. 1H NMR (300 MHz, CDCl3) 6
7.24-7.30 (m, 4 H), 6.82-6.88 (m, 4 H), 5.43 (s, 2 H), 4.60 (d, J = 11.7 Hz, 2 H), 4.42 (d,
J= 12.0 Hz, 2 H), 3.90-4.00 (m, 2 H), 3.81 (s, 6 H), 3.61-3.81 (m, 4H), 1.00 (s, 42 H);
13C NMR (75 MHz, CDC13) 6 158.9, 144.7, 130.8, 129.2, 129.0, 113.6, 80.5, 70.4, 67.0,
55.2, 18.0, 11.9; HRMS (CI, NH4) m/z 701.4627 [(M+H)+, calcd. for C40H6306Si2,

701.4633].
Preparation of V-SS. Procedure B: In a glove bag, 5 mg (15 umol) TrC104 was
added to a tared bottle. 25 mL 320 was added and to this well stirred suspension was
added 565 mg (2 mmol) PMB trichloroacetimidate and 180 mg (0.39 mmol) V-50. The
solution was stirred overnight before it was quenched with water, diluted with CH2C12
and washed with 1 M HCl, water and brine. The organic phase was dried over MgSOa,
and concentrated. Silica gel chromatography furnished 365 mg of a colorless oil. This

material was mainly V-55, but contained inseparable inpurities. V-55 was used in the
next reaction without further purification.

Preparation of V-56. TBAF 1 mL (1 M in THF, 1 mmol) was added to a

solution of crude V-55 (see above) (365 mg, 3.4 mmol) in 8 mL THF and the solution

was stirred at rt overnight. It was quenched with water and concentrated. Silica gel

chromatography of the resultant material fumished 125 mg (83%) V-56 as a viscous oil.
IR (neat) 3381, 2936, 1710, 1612, 1514, 1250 cm", 1H NMR (300 MHz, CDCl3) 6

7.26(d, J: 8.7 Hz, 4 H), 6.90 (d, J= 9.0 Hz, 4 H), 5.52 (s, 2 H), 4.59 (d, J= 11.4 Hz, 2
H), 4.31 (d, J: 11.1 Hz, 2 H), 3.91-4.01 (m, 2 H), 3.82 (s, 6 H), 3.61-3.63 (m, 4 H), 1.60

(br, CH); ”C NMR (75 MHz, CDC13)6 159.3, 142.7, 129.7, 129.4, 117.2, 113.9, 80.1,
77.4, 77.0, 76.6, 70.5, 65.1, 55.2; HRMS (CI, NH4) m/z 406.2224 [(M+NH,)*, calcd. for

C22H32N06, 406.2230].

100

Preparation of V-58. To a solution of 1.3 g V-56 (3.4 mmol) in 20 mL CH2Cl2
was added 10 mL pyridine and the solution was cooled to —78 °C. 0.42 mL PivCl (3.4
mmol) was added dropwise. The reaction was stirred for 4 h, during which time the
temperature warmed to rt. The reaction mixture was diluted with CH2C12 and washed
with 1 M HCl, water and brine. The organic phase was dried over MgS04, and
concentrated. Silica gel chromatography (5-30% EtOAc in hexanes) furnished 900 mg
V-58 (56%), 190 mg diacylated V-57 (10%) and 120 mg starting material V-56 (12%) as

colorless oils.

For v-57: IR (neat) 2968, 1728, 1612, 1514, 1464, 1251 cm", 'H NMR (300
MHz, CDC13) 8 7.25 (d, J= 8.4 Hz, 4 H); 6.84-6.89 (m, 4 H), 5.54 (s, 2 H), 4.56 (d, J=
11.7 Hz, 2 H), 4.35 (d, J: 11.1 Hz, 2 H), 4.05-4.28 (m, 6 H), 3.80 (s, 6 H), 1.21 (s, 18
H); 13C NMR (75 MHz, CDC13) 8 178.3, 159.2, 142.5, 129.9, 129.3, 117.7, 113.8, 76.9,
70.6, 65.8, 55.2, 38.7, 27.2; HRMS (C1, NH4) m/z 574.3378 [(M+NH,)*, calcd. for
C32H4303N, 574.3380].

For V-58: 14:16o +73.8° (c 0.89, CHCl3); 1H NMR (300 MHz, CDC13) 8 7.26 (d, J
= 8.4 Hz, 4 H); 6.84-6.94 (m, 4 H), 5.53 (s, 2 H), 4.58 (dd, J= 11.1, 2.1 Hz, 2 H), 3.97-
4.40 ( series of m, 8 H), 3.81 (s, 3 H), 3.82 (s, 3 H), 2.22 (br s, 1 H), 1.21 (s, 9 H); 13C
NMR (75 MHz, CDC13) 8 178.3, 159.2, 159.1, 142.5, 129.8, 129.7, 129.4, 129.2, 117.1,
113.8, 113.7, 80.0, 76.9, 70.4, 65.7, 65.1, 55.1, 38.6, 27.1.

Preparation of V-61. To a solution of 14 g (40 mmol) V-60 in 100 mL MeOH
was added a 0 °C solution of 70 mL acetic acid and 28 mL formic acid in 21 mL water.
The reaction was stirred for 6 h at rt. TLC indicated that the reaction was complete. The
reaction mixture was concentrated under reduced pressure. The resulting syrup was
diluted with water, and Na2C03 powder was added until gas evolsion ceased. The

mixture was extracted with CH2Cl2. The organic phase was dried over MgSO4, and

101

 

concentrated. Silica gel chromatography (30% EtOAc in hexanes) furnished 13.5 g V-61
(quant.) as a thick syrup. This material was used in the next reaction without further

purification.

Preparation of V-62. To a solution of crude V-61 (13.5 g, 43.4 mmol) in 100
mL CH2C12 was added 6 mL pyridine and the solution was cooled to 0 °C. 5.25 g PivCl
(43.5 mmol) was added dropwise. The reaction was stirred for 14 h, during which time
the temperature warmed to rt. TLC indicated that the reaction complete. The reaction
mixture was diluted with CH2C12 and washed with 1 M HCl, water and brine. The
organic phase was dried over MgSO4, and concentrated under reduced pressure to give a
syrup. This material was used in the next reaction without further purification. IR (neat)
3485, 2936, 1728, 1456, 1373, 1089 cm'l; HRMS (E1) m/z 395.2074 [(M+H)+, calcd. for
C21H3107, 395.2070].

Preparation of V-63. To a suspension of 1.76 g KH (44 mmol) in 100 mL THF
was added a solution of 15 g crude V-62 (38 mmol) in 100 mL THF at rt in 30 min.
Upon complete addition, 5.44 mL BnBr (46 mmol) was added followed by catalytic
amount of Ble. The reaction was stirred for 3 h at rt. The reaction mixture was
quenched with 1 N HCl and extacted with CH2Cl2. The organic phase was dried over
MgS04, and concentrated under reduced pressure. Silica gel chromatography (20% B20
in hexanes) furnished 17 g V-63 (80% from V-60) as a thick syrup. IR (neat) 2934, 1734,
1701, 1456, 1078 cm"; 1H NMR (300 MHz, CDC13) 8 7.2-7.4 (m, 10 H), 5.93 (d, J= 3.6
Hz, 1 H), 4.3-4.8 (m, 7 H), 4.0-4.3 (m, 3 H), 1.49 (s, 3 H), 1.33 (s, 3 H), 1.24 (m, 9 H);
l3C NMR (75 MHz, CDCl3) 6 178.2, 138.2, 137.4, 127.4-128.5 (6 C), 111.8, 105.0, 81.8,
81.5, 78.6, 74.2, 71.9, 72.0, 63.3, 38.8, 27.2, 26.7, 26.3; HRMS (131) m/z 485.2521
[(M+H)+, calcd. for C23H3707, 485.2539].

Preparation of V-64. To a solution of 10 g V-63 (20 mmol) in 200 mL Me0H

102

 

was added 3 mL concentrated H2S04. The mixture was stirred for 30 h at rt. TLC
indicated the reaction was complete, and two new spots appeared coresponding to the two
anomers. Na2C03 powder was added to the reaction mixture until no gas evolsion and
the mixture was concentrated under reduced pressure. The resulted syrup was diluted
with water, and was extracted with CH2Cl2. The organic phase was dried over MgS04,
and concentrated to give a thick syrup. This material was used for the next reaction

without further purification.

Preparation of V-65. A solution of 1.14 g (2.5 mmol) of crude V-64 in 20 mL
THF was added dropwise to a suspension of 0.1 g KH (2.5 mmol) in 30 mL THF at rt in
30 min. Upon complete addition, catalytic amount of Ble was added followed by a
solution of 0.3 mL BnBr (2.5 mmol) in 10 mL THF, which was added dropwise via
cannula. The reaction was stirred overnight at rt before it was quenched with 1 N HCl
and extracted with CH2Cl2. The organic phase was dried over MgSOa, and concentrated
under reduced pressure to give 1.7 g V-65 as a thick syrup. This material was used for

the next reaction without further purification.

Preparation of V-66. A 60% aqueous TFA solution was cooled to 0 °C and
poured in a solution of 1.7 g crude V-65 in 10 mL dioxane. The mixture was stirred for
20 h at rt. TLC indicated the reaction was complete. The reaction mixture was
concentrated under reduced pressure. The resulted syrup was diluted with water, and
Na2C03 powder was added until gas evolsion ceased. The mixture was extracted with
CH2Cl2. The organic phase was dried over MgSO4, and concentrated to give 0.85 g V-66
(87%) as a thick syrup. This material was used for the next reaction without further

purification.

Preparation of V-67. To a solution of 545 mg V-66 (1 mmol) in 10 mL CH2C12
was added 1 g Ph3P=CHC00Et (3 mmol) and the reaction was refluxed overnight. The

103

 

reaction mixture was quenched with 1 N HCl and extacted with CH2Cl2. The organic
phase was dried over MgSO4, and concentrated under reduced pressure. This mixture
was passed though a short silica gel pad before it was purified by silica gel
chromatography to give 561 mg V-67 (91%) as an oil. [“160 -0.5° (C 0.72, CHC13); IR
(neat) 3503, 2974, 1728, 1454, 1284, 1165 cm'l; 1H NMR (300 MHz, CDC13) 6 7.2-7.4
(m, 15 H), 7.00 (dd, J= 6.8, 15.8 Hz, 1 H), 6.15 (dd, J= 15.8, 1.2 Hz, 1 H), 3.5-4.9 (m,
14 H), 3.3 (br s, 1 H), 1.34 (t, J= 7.1 Hz, 3 H), 1.23 (s, 9 H); 13C NMR (75 MHz, CDC13)
6 178.5, 165.8, 144.2, 138.0, 137.8, 137.5, 127.6-128.3 (15 C), 123.9, 80.1, 78.2, 77.0,
74.5, 71.6, 71.3, 69.4, 61.8, 60.4, 38.8, 27.1, 14.1; HRMS (E1) m/z 605.3114 [(M+H)+,

calcd for C36H4503, 605.3114].

Preparation of V-68. To a solution of 0.89 g V-67 (1.47 mmol) in 25 mL
CH2C12 was added 0.75 g of the Dess-Martin periodinane (Dess, D. B.; Martin, J. C. J.
Org. Chem. 1983, 48, 4155-4156.) (1.77 mol) at 0°C. The reaction was stirred for 14 h,
during which the temperature rised to rt. TLC indicated the reaction was complete. The
reaction mixture was quenched with aqueous NaHC03 and extracted with CH2Cl2. The
organic phase was dried over MgS04, and concentrated under reduced pressure to give a
syrup. Silica gel chromatography (20% EtOAc in hexanes) furnished 0.67 g V-68 (76%)
as a thick syrup. 1011230 +45.l° (c 1.50, CHC13); IR (neat) 2976, 1728, 1456, 1175 cm'l; 'H
NMR (300 MHz, CDC13) 6 7.2-7.5 (m, 15 H), 6.94 (dd, J= 6.2, 15.8 Hz, 1 H), 6.06 (dd, J
= 15.8, 1.3 Hz, 1 H), 4.0-4.8 (m, 13 H), 1.34 (t, J= 7.1 Hz, 3 H), 1.20 (s, 9 H); 13C NMR
(75 MHz, CDC13) 6 205.2, 177.9, 165.5, 143.3, 137.2, 136.8, 136.7, 127.7-128.4 (15 C),
124.2, 82.8, 80.8, 78.3, 73.9, 72.6, 71.8, 63.2, 60.5, 38.6, 27.0, 14.1; HRMS (E1) m/z
603.2965 [(M+H)+, calcd for C36H4303, 603.2958].

Preparation of V-69. To a solution of 55 mg V-68 (0.09 mmol) in 5 mL CH2Cl2
was added at rt 0.7 mL (ca. 0.3 mmol) Lombardo’s reagent (Lombardo, L. Tetrahedron

Lett. 1982, 41, 4293-4296.). The reaction was stirred for 3 h at rt. The reaction mixture

104

 

was quenched with 1 N HCl and extracted with CH2Cl2. The organic phase was dried
over MgSOa, and concentrated under reduced pressure to give a syrup. Silica gel
chromatography (20% EtOAc in hexanes) furnished 16 mg V-69 (30%) as a thick syrup.
14:16o +49.5° (c 0.60, CHC13); IR (neat) 2976, 1724, 1454, 1280, 1159 cm'1;_‘H NMR
(300 MHz, CDC13) 6 7.2-7.5 (m, 15 H), 7.00 (dd, J = 5.3, 15.8 Hz, 1 H), 6.11 (dd, J =
15.8, 1.5 Hz, 1 H), 5.63 (s, 1 H), 5.47 (s, 1 H), 3.8—4.8 (series of m, 13 H), 1.32 (t, J= 7.2
Hz, 3 H), 1.21 (s, 9 H); l3C NMR (75 MHz, CDC13) 6 166.0, 144.6, 142.0, 138.3, 137.8,
137.5, 1274-1284 (16 C), 123.4, 116.5, 80.3, 79.4, 78.2, 72.0, 71.2, 71.1, 66.1, 60.5,
38.7, 27.1, 14.2; HRMS (E1) m/z 601.3144 [(M+H)+, calcd for C37H4507, 601.3165].

Preparation of V-70. To a —70 °C solution 30 mg (0.05 mmol) V-69 in 3 mL
CH2C12 was added 3 mL DIBAL (1 M in hexanes, 3 mmol). After 3 h the reaction
mixture was quenched with pH 7 buffer and tartrate acid. The mix was stirred for 30
min. The mixture was extracted with CH2C12 and 320. The organic phase was
combined, washed with brine, dried over magnesium sulfate, and concentrated. The
resulting residue was chromatographed on silica gel to afford 25 mg V-70 as a colorless
oil (quant.). [01130 +579" (c 2.0, CHC13); IR (neat) 3420, 2924, 2864, 1454, 1068 cm"; 1H
NMR (300 MHz, CDCl3) 6 7.2-7.5 (m, 15 H), 5.90 (dt, J= 5.1, 15.7 Hz, 1 H), 5.75 (dd, J
= 15.7, 6.9 Hz, 1 H), 5.57 (s, 1 H), 5.49 (s, 1 111), 3.9-4.8 (m, 11 H), 3.64 (dd, J= 3.7, 11.7
Hz, 1 H), 3.49 (dd, J= 7.2, 11.7 Hz, 1 H), 1.28 (br s, 2 H); l3C NMR (75 MHz, CDCl3) 6
142.7, 138.2, 138.0, 133.6, 127.6-128.4 (16 C), 116.8, 80.9, 80.7, 80.4, 71.0, 70.9, 70.8,
64.8, 62.8; HRMS (E1) m/z 475.2485 [(M+H)+, calcd. for C30H3505, 475.2484].

Preparation of V-7l. To a solution of 0.35 g V-70 (0.75 mmol) in 30 mL
CH2C12 was added 0.16 mL pyridine (2 mmol) and the solution was cooled to 0 °C.
Acetic anhydride (153 mg, 1.5 mmol) was added dropwise, followed by a catalytic
amount of DMAP. The reaction was stirred for 14 h, during which time the temperature

warmed to rt. The reaction mixture was diluted with CH2CI2 and washed with l M HCl,

105

 

water, and brine. The organic phase was dried over MgSOa, and concentrated under

reduced pressure to give 0.51 g syrup. This material was used in the next reaction

without further purification.

Preparation of V-72. To a solution of 40 mg V-71 (0.07 mmol) in 0.1 mL DMF
was added 3-6 mg 3-tributyltin-l-butenol (0.1 mmol) and 8.8 mg LiCl (0.21 mmol). The
mixture was well stirred and Pd(dba)2 45 mg (8 mol) was added. The reaction was
stirred for 24 h at rt before it was diluted with CH2C12 and washed with 1 M HCl, water
and brine. The organic phase was dried over MgSOa, and concentrated under reduced
pressure. The resulting residue was chromatographed on silica gel to afford 19 mg (50%)
V-72 as a thick syrup. IR (neat) 3439, 2959, 2926, 1726, 1454, 1377, 1271, 1072 cm";
1H NMR (300 MHz, CDCl3) 6 7.4-7.2 (m, 15 H), 5.45-5.85 (m, 2 H), 5.57 (s, 1 H), 5.47
(s, 1 H), 4.93 (s, 1 H), 4.89 (s, 1 H), 4.7-4.5 (m, 3 H), 4.5-3.8 (m, 6 H), 3.8-3.6 (m, 2 H),
3.62 (dd, J= 11.7, 3.9 Hz, 1 H), 3.47 (dd, J= 11.7, 7.5 Hz, 1 H), 2.7-2.9 (m, 2 H), 2.31 (t,
J= 6.3 Hz, 2 H), 2.0 (s, 0H, 2 H); 13C NMR (75 MHz, CDC13) 6 144.2, 142.8, 138.1,
133.0, 1285-1275 (18 C), 116.4, 113.0, 81.4, 80.9, 80.1, 71.0, 70.9, 70.5, 65.0, 60.2,

39.1, 38.9.

Preparation of V-78. Molecular sieves (4 A) was added to a 10 mL round
bottom flask that was then flame dried under vaccum for 5 min. After cooling under N2,
167 mg (0.59 mmol) Ti(0-iPr)4 was added followed by 3 mL CH2Cl2. The temperature
was lowered to —40 °C before 171 mg (0.73 mmol) (+)-diethyl L-tartrate in 1 mL CH2C12
was added dropwise. The solution was stirred for 40 min during which time the
temperature slowly warmed to —5 °C. The temperature was lowered to —25 °C and a
solution of 0.18 mL tert-butyl hydroperoxide (4.2 M in toluene, 0.75 mmol) was added
dropwise. Upon complete addition the solution was stirred for 15 min at —25 °C. Then
110 mg V-77 (0.56 mmol) in 2 mL CH2Cl2 was added, and the mixture was stirred

overnight at ——20 °C before it was quenched with 0.5 mL saturated Na2S03 aqueous

106

 

solution and 0.5 mL saturated Na2804 aqueous solution. The reaction mixture was

diluted with 10 mL diethyl ether and one drop of glycerol was added via a pipette. The
mixture was then stirred for 3 h and washed with 1 M HCl, water, and brine. The organic
phase was dried over MgSO4, and concentrated. Silica gel chromatography (10% EtOAc
in hexanes) fumished 100 mg V-78 (84%) as a colorless oil. [04123o -6° (c 0.28, CHCI3); IR
(neat) 3456, 3312, 2963, 1458, 1381, 1250, 904 cm", 1H NMR (300 MHz, CDC13) 6 3.71
(dd, J= 3.3, 7.3 Hz, 1 H), 2.91 (dd, J: 3.3, 2.5 Hz, 1 H), 2.82 (dd, J= 2.3, 7.3 Hz, 1 H),
2.39 (Ade, A = 30.9 Hz, J = 16.8 Hz, J= 2.7, 7.3 Hz, 2 H), 2.01 (t, J = 2.7 Hz, 1 H),
1.78-1.92 (m, 1 H), 1.64 (br s, 1 H), 1.23-1.59 (m, 5 H), 1.15 (d, J= 6.9 Hz, 3 H), 0.89-
1.00 (m, 6 H); 13C NMR (75 MHz, CDC13) 6 199.9, 128.7, 83.0, 76.1, 69.4, 39.0, 37.9,

36.3, 25.6, 21.8, 20.4, 15.4, 14.1; HRMS (Fab) m/z 193.1597 [(M-H0)+, calcd for
C13H210,193.1592].

Preparation of V-79. To a solution of 249 mg (0.95 mmol) Ph3P in 6 mL THF
was added 4 A MS followed by 192 mg (0.95 mL) DIAD at 0 °C. After about 3 min,
large amounts of white precipitation formed. To this milky suspension was quickly
added a premixed solution of 94 mg (0.48 mmol) V-78 and 201 mg (E)-V-14 (0.95
mmol) in 3 mL THF. Shortly after the addition the solution turned clear. The reaction
was stirred at 0 °C for 15 min before the ice bath was removed. The reaction was stirred
overnight and was diluted with diethyl ether and washed with 1M HCl, water, and brine.
The organic phase was dried over MgSO4 and concentrated. Silica gel chromatography
(2% EtOAc in hexanes) furnished 141 mg V-79 (78%) as a colorless oil. [0160 -11.4° (c
0.55, CHCl3); IR (neat) 3306, 2961, 1724, 1616, 1334, 1176, 1074 cm", 1H NMR (300
MHz, CDCl;;) 6 6.88-6.71 (m, 1H), 4.79 (t, J = 6.2 Hz, 1 H), 2.98-3.05 (m, 3 H), 2.92 (dd,
J= 2.3, 6.4 Hz, 1 H), 2.70 (dd, J = 2.2, 7.2 Hz, 1 H), 2.31 (ABd, A = 30.4 Hz, J= 17.0
Hz, J= 2.6, 5.5 Hz, 2 H), 2.10 (p, J= 5.8 Hz, 1 H), 2.01-2.06 (m, l H), 1.20-1.55 (series
ofm, 5 H), 1.14 (d, J= 6.8 Hz, 3 H), 0.95 (d, J= 6.7 Hz, 3 H), 0.91 (t, J= 7.0 Hz, 3 H);

107

”C NMR (75 MHz, CDCl3) 8 163.2, 130.8, 121.8, 81.5, 75.9, 70.4, 61.6, 56.6, 36.6, 35.2,

34.9, 31.1, 22.2, 19.9, 15.7, 15.1, 14.2; HRMS (FAB) m/z 405.0918 [(M+H)+, calcd for
C(7H26103, 405.0928].

Preparation of V-80. To a solution of 266 mg V-77 (1.37 mmol) in 10 mL THF
was added 1.94 mL (1.6 M in Et20, 3.1 mmol) n-BuLi at -55 °C and the solution was
stirred for 15 min during which time the temperature warmed to -38°C. The temperature
was cooled to -55 0C before 0.19 mL TMSCI (1.5 mmol) was added. The solution was
stirred for 20 min during which time the temperature warmed to rt. The reaction was

quenched with 6 mL 1 N HCl and the mixture was stirred for 4 h at rt. TLC indicated

 

only one product had formed. The mixture was diluted with 20 mL diethyl ether, washed

with 1 M HCl, water and brine. The organic phase was dried over MgSOa and

concentrated. Silica gel chromatography (hexanes) furnished 330 mg V-80 (86%), with
39 mg of a mixture of V-77 and V-80, all as oils. 1611123o +32.4° (c 0.94, CHC13); IR (neat)
3366, 2961, 2175, 1458, 1377, 1250, 1026 cm"; 1H NMR (300 MHz, CDC13) 6 5.47
(ABd, A = 43.6 Hz, J= 15.3, 7.6 Hz, 2 H), 3.97 (t, J= 7.1 Hz, 1 H), 2.31 (ABd, A = 28.0
Hz, J= 16.8, 7.0 Hz, 2 H), 2.09-2.21 (m, 1H), 1.81 (p, J= 6.8 Hz, 1 H), 1.60 (br s, 1 H),
1.21-1.38 (m, 4 H), 1.00 (d, J= 6.7 Hz, 3 H), 0.98 (d, J= 6.7 Hz, 3 H), 0.90 (t, J= 6.8
Hz, 3 H), 0.17 (s, 9 H); 13C NMR (75 MHz, CDC13) 6 139.7, 128.7, 106.0, 85.9, 76.4,

39.1, 38.2, 36.3, 23.3, 20.6, 20.4, 15.5, 14.0, 0.1; HRMS (FAB) m/z 267.2140 [(M+H)+,
calcd for C16H3108i, 267.2144].

Preparation of V-8l. Molecular sieves (4 A) were added to a 25 mL round

bottom flask that was then flame dried under vaccum for 5 min. After cooling under N2,
340 mg (1.2 mmol) Ti(0-iPr)4 was added followed by 6 mL CH2Cl2. The temperature

was lowered to -40 °C before 351 mg (1.5 mmol) (+)-diethyl L-tartrate in 3 mL CH2C12

was added dropwise. The solution was stirred for 40 min during which time the

temperature slowly warmed to —5 °C. The temperature was lowered to —-25 °C and a

108

50111
1110;
330

0161

111.
C01
llR‘

 

 

 

solution of 0.38 mL tert-butyl hydroperoxide (4.2 M in toluene, 1.6 mmol) was added
dropwise. Upon complete addition the solution was stirred for 15 min at —25 °C. Then
330 mg V-80 (1.24 mmol) in 3 mL CH2C12 was added, and the mixture was stirred

overnight at -20 °C before it was quenched with 0.5 mL saturated Na2S03 aqueous

solution and 0.5 mL saturated Na2804 aqueous solution. The reaction mixture was

diluted with 10 mL diethyl ether and one drop of glycerol was added via a pipette. The
mixture was then stirred for 3 h and washed with 1 M HCl, water, and brine. The organic
phase was dried over MgS04 and concentrated. Silica gel chromatography (10% EtOAc
in hexanes) furnished 237 mg V-81 (68%) as a colorless oil. 1a16° -20 (c 0.2, CHCh); IR

(neat) 3458, 2963, 2175, 1459, 1250, 1032 cm", ‘H NMR (300 MHz, CDC13) 6 3.69 (dd,

 

J = 3.1, 6.9 Hz, 1 H), 2.91 (t, J= 3.0 Hz, 1 H), 2.82 (dd, J: 2.4, 7.4 Hz, 1 H), 2.41 (ABd,
A = 30.2 Hz, J: 16.8, 7.2 Hz, 2 H), 2.05 (br s, 1 H), 1.80-1.95 (m, 1 H), 1.22-1.57 (m, 5
H), 1.13 (d, J = 6.9 Hz, 3 H), 0.89-1.00 (m, 6 H), 0.17 (s, 9 H); ”C NMR (75 MHz,
CDC13) 8 105.3, 86.4, 71.3, 59.5, 58.0, 36.7, 36.5, 35.1, 23.4, 20.0, 15.9, 15.2, 14.2, 0.1;
HRMS (FAB) m/z 283.2096 [(M+H)*, calcd for C16H3102Si, 283.2093].

Preparation of V-82. To a solution of 325 mg (1.24 mmol) Ph3P in 10 mL THF
was added 4 A MS followed by 250 mg (1.24 mL) DIAD at 0°C. Upon complete
addition, large amounts of white precipitate formed. To this milky suspension was
quickly added a premixed solution of 219 mg (0.77 mmol) V-81 and 210 mg (E)-V-14 1
(1.0 mmol) in 6 mL THF. Shortly after the addition the solution turned clear. The I
reaction was stirred at 0 °C for 15 min before the ice bath was removed. The reaction was
stirred overnight and was diluted with diethyl ether and washed with 1 M HCl, water, and
brine. The organic phase was dried over MgS04 and concentrated. Silica gel
chromatography (2% EtOAc in hexanes) furnished 278 mg V-82 (75%) as colorless oil.
1411230 -7.3° (c 1.55, CHC13); IR (neat) 2961, 2175, 1726, 1616, 1458, 1332, 1250, 1176,

1074 cm]; 1H NMR (300 MHz,_CDCl3) 6 6.62-6.70 (m, 1 H), 4.70 (t, J = 6.3 Hz, 1 H),

109

 

2.7 (s, 3 H), 2.88 (dd, J: 1.5, 6.6 Hz, 1 H), 2.66 (dd, J: 1.5, 6.9 Hz, 1 H), 2.31 (ABd, A
= 33.9 Hz, J: 17.1, 6.6 Hz, 2 H), 2.04 (p, J: 6.3 Hz, 1 H), 1.15-1.55 (m, 5 H), 1.08 (d, J
= 6.9 Hz, 3 H), 0.93 (d, J = 6.6 Hz, 3 H), 0.89 (t, J = 6.9 Hz, 3 H), 0.13 (m, 9 H); ”C
NMR (75 MHz, CDC13) 8 163.1, 130.9, 121.4, 104.1, 86.9, 76.4, 61.7, 56.5, 36.6, 35.2,
35.0, 31.1, 23.5, 19.9, 15.7, 15.2, 14.1, 0.0; HRMS (FAB) m/z 477.1320 [(M+H)*, calcd
for C20H341038i, 477.1324].

110

REFERENCES

111

REFERENCES

CHAPTER 1
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2. (a) Nakai, T.; Mikami, K. Chem. Rev. 1986, 86, 885-902. (b) Marshal, J. A., in
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3. (a) Schéifer, H.; Schéllkopf, U.; Walter, D. Tetrahedron Lett. 1968, 2809-2812, and
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(e) Tomooka, K.; Yamamoto, H.; Nakai, T. J. Am. Chem. Soc. 1996, 118, 3317-3318. (1)
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4. (a) Schreiber. S. L.; Goulet, M. T. Tetrahedron Lett. 1987, 28, 1043-1046. (b) Verner,
E. J.; Cohen, T. J. Am. Chem. Soc. 1992, 114, 375-337. (c) Hoffmann, R; Brfickner, R.
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50, 5927-5932.

5. (a) Kobayashi, J .; Ishibashi, M.; Nakamura, H.; Ohizumi, Y. Tetrahedron Lett. 1986,
27, 5755. (b) Kobayashi, J.; Ishibashi, M.; Hirota, H. J. Nat Prod. 1991, 54, 1435-1439.
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6. For the synthesis of other members of amphidinolides, see: Amphidinolide J: (a)
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Amphidinolide K: (b) Williams, D. R.; Myers, K. G. Org. Lett. 1999, 1, 1303-1305. (c)
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Williams, D. R.; Myers, B. J. J. Am. Chem. Soc. 2001, 123, 765-766. Amphidinolide B:
(e) Lee, D-H.; Rho, M-D. Tetrahedron Lett. 2000, 41, 2573-2576. (1) Pattenden, G.; Cid,
M. B. Tetrahedron Lett. 2000, 41 , 7373-7378. (g) Ishiyama, H.; Takemura, T.; Tsuda,
M.; Kobayashi, J. Tetrahedron 1999, 55, 4583-4594.

7. (a) Terrell, L. R.; Ward, J. S., III; Maleczka, R. E., Jr. Tetrahedron Lett. 1999, 40,
3097-3100. (b) O’Connor S. J .; Williard P. G. Tetrahedron Lett. 1989, 30, 4637-4640. (c)
Boden, C.; Pattenden, G. Synlett 1994, 181. (d) Hollingworth, G. J.; Pattenden, G.
Tetrahedron Lett. 1998, 39, 703-706.

8. (a) Stille, J. K.; Groh, B. L. J. Am. Chem. Soc. 1987, 109, 813-817. (b) Mitchell, T.
Synthesis 1992, 803-815.

112

9. Klaps, E.; Schmid, W. J. Org. Chem. 1999, 64, 7537—7546.

10. (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450. (b) Schuster, M.;
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CHAPTER 2

1. (a) Nakai, T.; Mikami, K. Chem. Rev. 1986, 86, 885-902. (b) Marshal, J. A., in
Comprehensive Organic Synthesis, Pattenden, G., Ed.; Pergamon: London, 1991; Vol. 3,
975-1014.

2. (a) Schafer, H.; Schollkopf, U.; Walter, D. Tetrahedron Lett. 1968, 2809-2812, and
references cited therein. (b) Evans, D. A.; Baillargeon, D. J. Tetrahedron Lett. 1978,
3315-3318. (c) Garst, J. F.; Smith, C. D. J. Am. Chem. Soc. 1976, 98, 1526-1537. ((1)
Azzena, U.; Denurra, T.; Melloni, G.; Piroddi, A. M. J. Org. Chem. 1990, 55, 5532-5535.
(e) Tomooka, K.; Yamamoto, H.; Nakai, T. J. Am. Chem. Soc. 1996, 118, 3317-3318. (1)
Tomooka, K.; Yamamoto, H.; Nakai, T. Liebigs Ann. 1997, 1275-1281.

3. (a) Schreiber. S. L.; Goulet, M. T. Tetrahedron Lett. 1987, 28, 1043-1046. (b) Goulet,
M. T. Ph.D. Dissertation, Yale University, 1988.

4. Verner, E. J .; Cohen, T. J. Am. Chem. Soc. 1992, 114, 375-337.
5. Hoffmann, R.; Briickner, R. Chem. Ber. 1992, 125, 1957-1963.

6. (a) Tomooka, K.; Igarashi, T.; Nakai, T. Tetrahedron Lett. 1993, 34, 8139-8142. (b)
Tomooka, K.; Igarashi, T.; Nakai, T. Tetrahedron 1994, 50, 5927-5932.

7. Nakai has reported chelation-controlled rearrangements of racemic lithio species (see
ref 2e).

8. Tomooka, K.; Igarashi, T.; Watanabe, M.; Nakai, T. Tetrahedron Lett. 1992, 33, 5795-
5798.

9. Matteson, D. S.; Tripathy, P. B.; Sarkar, A.; Sadhu, K. M. J. Am. Chem. Soc. 1989,
1 11, 4399-4402, and references cited therein.

10. (a) Ohgo, Y.; Yoshimura, J.; Kono, M.; Sato, T. Bull. Chem. Soc. Jpn. 1969, 42,
295 7-2961. (b) Mulzer, J .; Angennann, A. Tetrahedron Lett. 1983, 24, 2843-2846.

1 1. Schollkopf, U. Angew. Chem. Int. Ed. Engl. 1970, 9, 763-773.

12. (a) Hoffmann, R.; Brfickner, R. Chem Ber. 1992, 125, 1471-1484. (b) Priepke, H.;
Bruckner, R. Chem. Ber. 1990, 123, 153-168.

CHAPTER 3
1. (a) Nakai, T.; Tomooka, K. Pure Appl. Chem. 1997, 69, 595-600. (b) Nakai, T.;
Mikami, K. Organic Reactions 1994, 46, 105-209. (c) Marshall, J. A., in Comprehensive

113

Organic Synthesis, Pattenden, G., Ed.; Pergamon: London, 1991; Vol. 3, 975-1014. ((1)
Brfickner, R. In Comprehensive Organic Synthesis, Pattenden, G., Ed; Pergamon:
London, 1991; Vol. 6, 873-908.

2. Still, W. C.; Mitra, A. J. Am. Chem. Soc. 1978, 100, 1927-1928.

3. (a) Chemistry of Tin; Smith, P. J ., Ed.; Blackie Academic & Professional: New York,
1998. (b) Davies, A. G. In Organotin Chemistry, VCH: New York, 1997. (c) Pereyre, M.;
Quintard, J.-P.; Rahm, A. In Tin in Organic Synthesis; Butterworth: Toronto, 1987.

4. (a) Hoffmann, R.; Brfickner, R. Chem. Ber. 1992, 125, 1471-1484. (b) Kruse, B.;
Brfickner, R. Tetrahedron Lett. 1990, 31, 4425-4428. (c) Kruse, B.; Bruckner, R. Chem.
Ber. 1989, 122, 2023-2025. (d) Broka, C. A.; Shen, T. J. Am. Chem. Soc. 1989, 111,
2981-2984.

5. Hioki, K.; Kono, K.; Tani, S.; Kunishima, M. Tetrahedron Lett. 1998, 39, 5229-5232.

6. Kunishima, M.; Hioki, K.; Kono, K.; Kato, A.; Tani, S. J. Org. Chem. 1997, 62, 7542-
7543.

7. Maleczka, R. E. Jr.; Gallagher, W. P.; Terstiege, I. J. Am. Chem. Soc. 2000, 122, 384-
385, and references cited therein.

8. Reetz, M. T.; Greif, N. Chem. Ber. 1977, 110, 2958-2959.
9. Takahashi, 0.; Maeda, T.; Mikami, K.; Nakai, T. Chem. Lett. 1986, 1355-1358.
10. Adam, S. Tetrahedron 1989, 45, 1409-1414.

11. (a) Tomooka, K.; Yamamoto, H.; Nakai, T. Liebigs Ann. Chem. 1997, 1275-1281. (b)
Maleczka, R. E., Jr.; Geng, F. J. Am. Chem. Soc. 1998, 120, 8551-8552, and references
Cited therein.

12. Carey, F. A.; Court, A. S. J. Org. Chem. 1972, 37, 939-943.

13. (a) Mulzer, J .; List, B. Tetrahedron Lett. 1996, 37, 2403-2404. (b) Magnus, R; Roy,
G. Organometallics 1982, 1, 553-559. (c) For a general review see Weber, W. P. In
Silicone Reagents for Organic Synthesis; Springer-Verlag: New York, 1983.

14. (a) Lindennan, R. J.; Ghannam, A. J. Am. Chem. Soc. 1990, 112, 2392-2398. (b)
Brook, A. G.; Bassendale, A. R. In Rearrangements in Ground and Excited States; de
Mayo, P., Ed.; Academic Press; New York, 1980; Vol. 2, 149-227.

15. For examples of the directed deprotonation and rearrangement of vinylogous 01-

alkoxysilanes see: (a) Mikami, K.; Kishi, N.; Nakai, T. Chem. Lett. 1989, 1683-1686. (b)
Greeves, N.; Lee, W.-M. Tetrahedron Lett. 1997, 38, 6445-6448.

114

16. The [1.2]-Wittig rearrangement of (aryloxy)methylsilanes has been initiated by

deprotonation and affords a-silylbenzyl alcohols. See Eisch, J. J .; Galle, J. B.;
Piotrowski, A.; Tsai, M.-R. J. Org. Chem. 1982, 47, 5051-5056.

17. (a) Suga, S.; Miyamoto, K.; Watanabe, M.; Yoshida, J. Appl. Organomet. Chem.
1999, 13, 469-474. (b) Mulzer, J.; List, B. Tetrahedron Lett. 1996, 37, 2403-2404, and

references cited therein

18. For a retro [1,4]-Brook rearrangement approach to a-alkoxysilanes see: Hoffmann,
R.; Bri'lckner, R. Chem. Ber. 1992, 125, 1471-1484.

19. (a) Brook, A. G.; Pascoe, J. D. J. Am. Chem. Soc. 1971, 93, 6224-6627. (b) Brook, A.
G. Acc. Chem. Res. 1974, 7, 77-84.

20. For successful examples of an in situ methylation and silylation see: Murai, A.;
Abiko, A.; Shimada, N.; Masamune, T. Tetrahedron Lett. 1984, 25, 4951-4954.

21. For examples of some common side reactions under Williamson ether conditions see
(a) Kreeger, R. L.; Menard, P. R.; Sans, E. A.; Shechter, H. Tetrahedron Lett. 1985, 26,
1115-1118. (b) Sans, E. A.; Shechter, H. Tetrahedron Lett. 1985, 26, 1119-1122. (c)
Chakraborty, T. K.; Reddy, G. V. J. Chem. Soc., Chem. Commun. 1989, 251-253.

22. Tsuge, 0.; Kanemasa, S.; Nagahama, H.; Tanaka, J. Chem. Lett. 1984, 1803-1806.

23. Wessel, H. P., Iversen, T., Bundle, D. R. J. Chem. Soc., Perkin Trans. 1 1985, 2247-
2250.

24. Varied regioselectivity was observed with trichloroacetimidates prepared from allyic
alcohols. For example, etherification of III-01a with the trichloroacetimidate of
crotylalcohol gave a separable mixture of III-02a (67%) and III-02b (25%), while
reaction of III-01b with the trichloroacetimidate of cinnamyl alcohol gave III-02d
exclusively,

25. Gingras, M. Tetrahedron Lett. 1991, 32, 7381-7384.
26. Schdllkopf, U.; Fellenberger, K.; Rizk, M. Liebigs Ann. Chem. 1970, 734, 106-115.

27. (a)Fujimoto, K.; Sakai, H.; Nakai, T. Chem. Lett. 1993, 1397-1400. (b)
Rautenstrauch, V. J. Chem. Soc., Chem. Commun. 1970, 4-6.

28. Kruse, B.; Bruckner, R. Tetrahedron Lett. 1990, 31, 4425-4428.
29. Chuit, C.; Corriu, R. J. P.; Reye, C.; Young, J. C. Chem. Rev. 1993, 93, 1371-1448.

30. Wu, Y.-D.; Houk, K. N.; Marshall, J. A. J. Org. Chem. 1990, 55, 1421-1423.

115

31. [2,3]-Wittig rearrangement of the dessilyl analog of III-02a proceeds with similar
(2:1) preference for the erythro product (Schdllkopf, U.; Fellenberger, K.; Rizk, M.
Liebigs Ann. Chem. 1970, 734, 106-115).

32. The same reaction sequence applied to III-12b provided analogous results.

33. (a) ref. 19b. (b) Biembaum, M. S.; Mosher, H. S. J. Am. Chem. Soc. 1971, 93, 6221-
6223.

34. Iseki, K.; Kuroki, Y.; Takahashi, M.; Kishimoto, S.; Kobayashi, Y. Tetrahedron
1997, 53, 3513-3526.

35. Biellmann, J .-F .; d'0rchymont, H. J. Org. Chem. 1982, 4 7, 2882-2886.

36. While the retro-Brook sequence only gave 21% of the desired a-hydroxysilane, 67%
of the silylether was also recovered. Presumably this material could be recycled,
however no attempt to optimize the process was made.

37. Lowry, T. H.; Richardson, K. S. In Mechanism and Theory in Organic Chemistry;
Harper & Row: New York, 1987; Chapter 2.

38. Although we have no direct evidence of any O-silyl products, the 1,3-silyl migration
probably takes place via Brook rearrangement (ref. 19) of 111-24 followed by
rearrangement of the resulting homoenolate. For similar examples see (a) Kuwajima, I.
J. Organomet. Chem. 1985, 285, 137-148. (b) Still, W. C. J Org. Chem. 1976, 41, 3063-
3064.

39. (a) Bonini, B. F.; Comes-Franchini, M.; Fochi, M.; Mazzanti, G.; Ricci, A. J.
Organometal. Chem. 1998, 567, 181-189. (b) Maleczka, R. E., Jr.; Geng, F. Tetrahedron
Lett. 1999, 40, 3113-3114, and reference cited therein.

40. (a) Fleming, 1.; Mandal, A. K. J. Chem. Soc., Chem. Commun. 1999, 923-924. (b)
Furin, G. G.; Vyazankina. 0. A.; Gostevsky, B. A.; Vyazankin, N. S. Tetrahedron 1988,
44, 2675-2749. (c) Hsiao, C. N.; Shechter, H. J. Org. Chem. 1988, 53, 2688-2699, and
references cited therein.

CHAPTER 4

1. For reviews on the chemistry of acylsilanes see: (a) Bonini, B. F .; Comes-Franchini,
M.; Fochi, M.; Mazzanti, G.; Ricci, A. J. Organometal. Chem. 1998, 567, 181-189. (b)
Page, P. C. B.; Klair, S. S.; Rosenthal, S. Chem. Soc. Rev. 1990, 19, 147-195. (c) Ricci,
A.; Degl’lnnocenti, A. Synthesis 1989, 647-660. (d) Fleming, 1. In Comprehensive
Organic Chemistry; Barton, D. H. R.; Ollis, W. D. Eds; Pergamon: Oxford, 1979; Vol. 3,
647-653. (e) Magnus, P. D.; Sarkar, T.; Djuric, S. In Comprehensive Organometallic
Chemistry; Wilkinson, G.; Stone, F. G. A.; Abel, E. W., Eds; Pergamon: Oxford, 1982;
Vol. 7, 631-639.

116

2. For methods involving acyl anion equivalents see: (a) Brook, A. G.; Duff, J. M.; Jones,
P. F.; Davis, V. R. J. Am. Chem. Soc. 1967, 89, 431-434. (b) Corey, E. J.; Seebach, D.;
Freedman, R. J. Am. Chem. Soc. 1967, 89, 434-436. (c) Yoshida, J.; Matsunaga, S.;
Ishichi, Y.; Maekawa, T.; Isoe, S. J. Org. Chem. 1991, 56, 1307-1309. (d) Katritzky, A.
R.; Wang, Z.; Lang, H. Organometallics 1996, 15, 486-490, and cited references.

3. For methods involving tn'alkylsilylaluminum species: (a) Kang, J .; Lee, J. H.; Kim, K.
S.; Jeong, J. U.; Pyun, C. Tetrahedron Lett. 1987, 28, 3261-3262. For the use of
silylcuprates, see: (b) Capperucci, A.; Degl’Innocenti, A.; Faggi, C.; Ricci, A. J. Org.
Chem. 1988, 53, 3612-3614. (c) Bonini, B. F.; Franchini, M. C.; Mazzanti, G.;
Passamonti, U.; Ricci, A.; Zani, P. Synthesis 1995, 92-96. For an efficient approach to
TIPS acylsilanes, see: (d) Lipshutz, B. H.; Lindsley, C.; Susfalk, R.; Gross, T.
Tetrahedron Lett. 1994, 35, 8999-9002.

4. (a) Yamaoto, K.; Suzuki, 8.; Tsuji, J. Tetrahedron Lett. 1980, 21, 1653-1656. (b)
Yamaoto, K.; Hayashi, A.; Suzuki, S.; Tsuji, J. Organometallics 1987, 6, 974-979.

5. Rich, J. D. J. Am. Chem. Soc. 1989, 111, 5886-5893.

6. Hatanaka, Y.; Hiyama, T. Synlett 1991, 845-853.

7. Ritter, K. Synthesis 1989, 218-221.

8. Peddle, G. J. D. J. Organometal. Chem. 1968, 14, 139-147.
CHAPTER 5

1. (a) Kobayashi, J .; Ishibashi, M.; Nakamura, H.; 0hizumi, Y. Tetrahedron Lett. 1986,
27, 5755. (b) Kobayashi, J.; Ishibashi, M.; Hirota, H. J. Nat Prod. 1991, 54, 1435. (c) For
a review: Kobayashi, J .; Ishibashi, M. Heterocycles 1997, 44, 543.

2. For the synthesis of other members of amphidinolides, see: Amphidinolide J: (a)
Williams, D. R.; Kissel, W. S. J. Am. Chem. Soc. 1998, 120, 11198-11199.
Amphidinolide K: (b) Williams, D. R.; Myers, K. G. Org. Lett. 1999, I, 1303-1305. (c)
Williams, D. R.; Myers, K. G. J. Am. Chem. Soc. 2001, 123, 765-766. Amphidinolide P:
(d) Williams, D. R.; Myers, B. J .; Mi, L. Org. Lett. 2000, 2, 945-948.

3. (a) Terrell, L. R.; Ward, J. S., III; Maleczka, R. E., Jr. Tetrahedron Lett. 1999, 40,
3097-3100. (b) O’Connor S. J .; Williard P. G. Tetrahedron Lett. 1989, 30, 4637-4640. (c)
Boden, C.; Pattenden, G. Synlett 1994, 181-182. (d) Hollingworth, G. J.; Pattenden, G.
Tetrahedron Lett. 1998, 3 9, 703-706.

4. Klaps, E.; Schmid, W. J. Org. Chem. 1999, 64, 7537-7546.

5. (a) Trost, B. M.; Indolese, A. F.; Muller, T. J. J .; Treptow, B. J. Am. Chem. Soc. 1995,
117, 615-623. (b) Trost, B. M.; Toste, F. D. Tetrahedron Lett. 1999, 40, 7739-7743. (c)
Trost, B. M.; Machacek, M.; Schnaderbeck, M. J. Org. Lett. 2000, 2, 1761-1764.

117

6. (a) Stille, J. K.; Groh, B. L. J. Am. Chem. Soc. 1987, 109, 813-817. (b) Mitchell, T.
Synthesis 1992, 803-815.

7. (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450. (b) Schuster, M.;
Blechert, S. Angew. Chem, Int. Ed. Engl. 1997, 36, 2037-2056. (c) Hyldtoft, L.; Madsen,
R. J. Am. Chem. Soc. 2000, 122, 8444-8452.

8. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483.

9. (a) Mitsunobu, 0. Synthesis 1981, 1-28. (b) Castro, B. R. Organic Reactions 1983, 29,
1-162.

10. (a) Raban, M.; Mislow, K. Top. Stereochem. 1967, 1, 1-38. (b) Dale, J. A.; Mosher,
H. S. J. Am. Chem. Soc. 1973, 95, 512-519. (c) Trost, B. M.; Belletire, J. L; Godleski, S.;
McDougal, P. G.; Balkovec, J. M. J. Org. Chem. 1986, 51 , 2370-2374. (d) Latypov, Sh.
K.; Seco, J. M.; Quinoa, E.; Riguera, R. J. Org. Chem. 1996, 61, 8569-8577.

11. Evans, D. A.; Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stout, T. J. J. Am. Chem. Soc.
1990, 112, 7001-7031.

12. Smith, W. N.; Beumel, O. F., Jr. Synthesis 1974, 441-442.

13. Pfenninger, A. Synthesis 1985, 89-116.

14. (a) Liu, J .; Abiko, A.; Pei, Z.; Buske, D.C.; Masamune, S. Tetrahedron Lett. 1998, 39,
1973-1976. (b) Abiko, A.; Liu, J.; Masamune, S. J. Am. Chem. Soc. 1997, 119, 2586-
2587.

15. Ward, J. S. PhD. Dissertation, Michigan State University.

16. (a) Wessel, H. P.; Iversen, T.; Bundle, D. R. J. Chem. Soc., Perkin Trans. 1 1985,
2247-2250. (b) Nakajima, N.; lHorita, K.; Abe, R.; Yonamitsu, O. Tetrahedron Lett. 1988,
33, 4139-4142.

17. Terrell, L. R. PhD. Dissertation, Michigan State University, 2001.

18. Lombardo, L. Tetrahedron Lett. 1982, 41, 4293-4296.

19. (a) Valle, L. D.; Stille, J. K.; Hegedus, L. S. J. Org. Chem 1990, 55, 3019-3023. (b)
Echavarren, A. M.; Castano, A. M. Tetrahedron Lett. 1996, 36, 6587-6590.

20. Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118, 2748—2749.

21. Hoye, T. R.; Zhao, H. Org. Lett. 1999, I, 1123-1125.

118

APPENDICES

119

APPENDIX 1

NMR SPECTRA OF NEW COMPOUNDS

120

 

 

 

 

 

 

 

 

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191

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194

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194

APPENDIX 2

ORTEP REPRESENTATION OF COMPOUND II-22

195

ORTEP representation of II-22

' t T. 3 RTE-L!
:ABU :1 K“;
,1;

196

   

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