SULFINYL CHLORIDES AS A SOURCE OF ENANTIOENRICHED

a#-UNSATURATED SULFINATE ESTERS AND SULFOXIDES

A Thesis

Presented to

The Faculty of Graduate Studies

of

The University of Guelph

In partial tùlfillment of the requirements

for the degree of

Doctor of Philosophy

September, 2000

O Ricky R. Strickler, 2000

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ABSTRACT

SULFINYL CELORIDES AS A SOURCE OF ENANTIOENRICEED a$-UNSATURATED SULFINATE ESTERS AND SULFOXIDES

Ricky R. Strickler University of Guelph, 2000

Advisor: Dr. Adrian L. Schwan

Recent work has shown that a group of 1-alkenyl sulfoxides possessing

diphenylrnethyl (DPM), p-methoxybenzyl or 2-(trirnethylsily1)ethyl groups could be

prepared and subsequently converted to 1 -alkenesulfinyl chlorides using SOzClz to induce

oxidative cleavage. As part of a continuing investigation into the preparation and organic

transformation of 1 -alkenesulfinyl chlorides, this thesis has been divided into two main

components. The first portion of the thesis will examine the preparation of a number of

highly substituted 1-alkenyl 2-(trimethylsi1yl)ethyl sulfoxides and their subsequent

conversion into highly substituted I-alkenesulfinyl chlorides. Owing to their inherent

instability, the 1-alkenesulfinyl chorides were captured as their corresponding I -

alkenesulfinate esters and tùlly characterized. This portion of the thesis will also examine

the achiral transformation of 1-alkenesulfinyl chlorides to prepare a,P unsaturated B-keto

sulfoxides.

The major portion of this study will examine efforts to prepare 1-alkenesulfinate

esters with homochirality at the sulfitr centre. This was accomplished by capturing the 1-

alkenesulfinyl chlorides with cholesterol and a chiral amine base. Following one to two

crystallizations, several 1-alkenesulfinate esters were isolated in an enantiopure form. The

1-alkenesulfinate esters were also treated with several different Grignard reagents to

prepare a large variety of new enantioenriched aralkyl 1-alkenyl sulfoxides. The

determination of enantiorneric excess, as well as the absolute configuration of the sulfinate

esters and sulfoxides, was done by 'H NMR spectroscopy using an anthryl ethanol chiral

solvating agent. Circular dichroism curves were also obtained for the enantiopure 1-

alkenesulfi nate esters and a cornparison was made of the relative configurations.

............................................................................................................ Acknowledgments i

List of Abbreviations ....................................................................................................... ii

List of Tables .................................................................................................................. iv

List of Figures ........................................................................................................... v

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

2 . Sulfinyl Chlorides ......................................................................................................... 3

.......................................................................... 2.1. Preparation of Sulfinyl Chlorides 3

.......................................................... 2.2. Synthetic Usefulness of Sulfinyl Chlorides 10

3 . Asymmetnc Synthesis of Sulfinate Esters, Sulfinamides and Sulfoxides ...................... 15

......................................................... 3.1. Synthetic Value of Enantiopure Sulfoxides 16

3.2. Preparations of Enantiopure Sulfoxides via Asymmetric Oxidations .................... 29

3.3. Preparation of Sutfinic Acid Derivatives for Asymmetric Synthesis of ........................................................................................................ Sulfoxides 34

3.3.1. Sulfinate Esters ........................................................................................... 34

..................................................................................................... 3.4. Project Goals 54

4 . Results and Discussion: Preparation and Achiral Transformations of 1- ..................................................................................... Alkenesulfinyl Chlorides 57

4.1. Preparation and Oxidative Fragmentation of 1-Alkenyl 2-(Trimethylsilyl)ethyl ........................................................................................................ Sulfoxides 57

.................................................... 4.2. Carbon Capture of 1-Alkenesulfinyl Chlorides 71

....................................................................................................... 4.3. Conclusions 77

5 . Results and Discussion: Targeting the Stereogenic a, B Sulfinyl Group ....................... 79

.......................................... 5.1 . Preparation of Enantiopure 1-Alkenesulfinate Esters 79

5.1.1. Determination of Enantiopurity and Absolute Configuration of 1- .............................................................................. Aikenesulfinate Esters 9 8

5.1.2. Analysis of 1-Aikenesulfinate Esters Using Circular Dichoism ................... 103

....................................................... 5.2. Preparation of 1 -Aikenylaralkyl Sulfoxides 109

5.2.1. Determination of Enantiomeric Excess and Absolute Configuration of 1- .......................................................................... Alkenyl Aralkylsulfoxides 119

...................................................................................................... 5.3. Conclusions 126

.................................................................................................... 5.4. Future Work 128

............................................................................................................ . 6 Experimental 131

........................................................... 6.1. General Procedures and Instrumentation 131

6.2. Preparation and Oxidative Fragmentations of 1-Alkenyl 2-(Trimethy1silyl)ethyl ...................................................................................................... Sulfoxides 132

6.2.1. General Method for the Synthesis of 1-Aikenyl 2-(Trimethylsilyl)ethyl ................................................................................................. Sulfoxides 132

6.2.2. General Method for the Desilylation of 1-Alkenyl 2-(Trimethylsilyl)ethyl ................................................................................................. Sulfoxides 136

6.2.3. General Method for the Oxidative Fragmentation of 1-Alkenyl 2- (Trimethylsi1yl)ethyl Sulfoxides ................................................................. 140

6.3. Synthesis of p-Keto Vinyl Sulfoxides ............................................................. 147

6.3.1. General Method for the Synthesis of P-Keto Vinyl Sulfoxide .................... 147

6.4. Asymmetric Synthesis of (-)-Cholesteryl 1-Alkenesuffinate Esters ..................... 154

6.4.1. General Method for the Oxidative Fragmentation of 1-Aikenyl @PM or ............................................... ........................ PMB) Sulfoxides .........-.. 154

6.5. Asymmetnc Synthesis of Enantioenriched Aralkyl 1 -Aikenyl Sulfoxides ........... 164

6.5.1. General Method for the Synthesis of Enantioenriched Aralkyl 1-Alkenyl ................................................................................................. Sulfoxides 164

6.5.2. Description of Experimental Trials Involving n-BuMgBr and Suffinate .......................................................................................................... 136b 167

Acknowledeents

It has been an interesting and busy four years. 1 would first like to thank my

advisor Adrian Schwan for his support and encouragement over the course of this project.

His helpful advice and never ending ideas have given me the opportunity to explore

various aspects of research. Thank you Adrian for your friendship.

1 would like to thank the additional members of my advisory cornmittee, Dr.

Gordon Lange, Dr. Nigel Bunce and Dr. Monica Barra for their advice and support

throughout the course of my PhD. program. Thank you to Dr. Rick Yada and Masimo

Marcone for their assistance in obtaining the circular dichroism curves, My gratitude, as

well, to Valerie Robinson for her assistance with the NMR's obtained for this project,

without which most of this project would not have been possible.

l'd like to thank ail the past and present members of the Schwan lab group. Thank

you for making the lab a fun place to work. A special thanks to Jenn Snelgrove and

Yvonne Lear for their continuing fiiendship and support.

I'd like to thank NSERC for a PGS-A scholarship and the Ontano government for

two graduate scholarships.

Finally, and most importantly, I'd iike to thank my wife, Krystina. Over the last

four years she's had to endure countless replies like ". . . I can't go to the movie tonight,

I've got the NMR booked.. . ." I want her to know that without her support 1 wouldn't be

where 1 am today. Thanks Krys.

Abbreviations

AcOH .................................... acetic acid

Bn ......................................... benzyl

CD ........................................ circular diciuoism

CE ......................................... Cotton effect

Chol ...................................... cholesteryt

CKP ...................................... cumene hydroperoxide

CS A . . .................................... chiral solvating agent

CSR ...................................... chiral shifl reagent

D AG ..................................... diacetone-D-glucose

DBU .................................... .1,8-diazabicyclo[5.4.O]undec-7-ene

de.. ........................................ diastereomeric excess

DET ...................................... diethyl tartrate

DiBAL-H.. ........................... diisobutyiaîuminum hydride

DPM ..................................... diphenylmethyl

ee .......................................... enantiomenc excess

GC ...................................... . . a ctuomatography

HRMS. .................................. high resolution mass spectroscopy

iR.. ........................................ intiareci

............................... mCPB A. . m-chloroperbenzoic acid

........................................ MS mass spectroscopy

MsCl ..................................... mesityl chloride

...................................... NBS N-bromosuccinimide

................................... NMR.. nuclear magnetic resonance

..................................... ORD optical rotatory dispersion

PMI3 .................................... .p-rnethoxybenzyl

pyr ........................................ pyridine

RaNi ...................................... Raney nickel

.................................. TBHP.. t-butyl hydrogen peroxide

TEA ...................................... triethylamine

. . ...................................... TFA trifluoroacetic acid

THF ...................................... tetrahydrofuran

TLC ...................................... thin layer chromatography

TMS.. .................................... trimethylsilyl

tol ......................................... toiyl

Table 1: Preparative Methods for Sulfinyl Chlorides ...................................................... 4

Table 2: New Sulfinyl Chlorides Using Established Procedures ....................................... 5

Table 3: Preparation of 1-Alkenyl2-(TRmethylsilyl)ethyl Sulfoxides ............................. 59

Table 4: Preparation of I -Alkenyl2-(Trimethylsi1yl)ethyi Sulfoxides via ........................................................................................... Protiodesilylation 61

Table 5: Oxidative Fragmentations of 1-AIkenyl2-(Trimethylsilyl)ethyl Sulfoxides ....... 66

Table 6: Preparation of 1 -AikenylsulfinylrnethyI Ketones .............................................. 75

Table 7: Preparative Approaches to Cholesteryl Ethenesulfinate Using Various Bases. ............................................................ Solvents and Temperature Conditions 82

Table 8: Preparative Approaches to Cholesteryl Ethenesulfinate Using Quinine and . . . Quinidine ....................................................................................................... 84

Table 9: Preparative Approaches to Enantioenriched Ethenesulfinate Using Various .............................................................................................. Chiral Alcohols 85

Table 10: Preparative Approaches to Cholesteryl Suifinate 136f ................................... 87

Table 11: Preparative Approaches to Cholesteryl Sulfinate 136b ................................... 89

.................. Table 12: Preparative Approaches to Cholesteryl Sulfinates 136d and 136g 91

Table 13: Preparative Approaches to Various Cholesteryl Sulfinate Esters .................... 92

Table 14: Grignard Reactions of [RIs-136C .............................................................. 112

Table 15: Preliminary Grignard Reactions of [RIS-136b .............................................. 114

Table 16: Grignard Reactions of [RIs and [SJs-136b .................................................. 115

Table 17: Grignard Reactions of [RIs and [S]~-136ri .................................................. 117

......................................... Table 18: Grignard Reactions of [RIs-136d and 14s-136g 118

Table 19: Comparison of Opticai Rotations of Several Reported SuWoxides ................ 125

List of Fieures

..................................................................... Figure 1: Tricoordinate Sulfur Compounds 1

Figure 2: Stereoselective Control by the Suüinyl Centre ............................................... 17

........................ Figure 3: Facial Selectivity Model for Intramolecular Michael Addition 21

................................. Figure 4: Stereoselectivity in Diels-Alder Reactions of Sulfoxides 24

........................................................ Figure 5: NOE Irradiation of Vinyl Sulfinate Ester 68

................................................. Figure 6: Stabilizing Influence of Silicon-Carbon Bond 68

........................................................ Figure 7: Chiral Alcohols Examined for Reactivity 80

Figure 8: Chiral Amine Bases: Quinine and Quinidine ................................................... 83

Figure 9: Sulhrane Interactions .................................................................................... 96

Figure 10: Steric Crowding in Sulfurane 143 ............................................................... 97

I .......................................................... Figure 11: H NMR Spectrum for Sulfinate 136f 99

Figure 12: Coordination Model for CSA and Sulfinate Ester ....................................... 101

Figure 13: Differential Shielding Observed for CSA and Sulfinate Ester ...................... 102

Figure 14: 'H NMR Spectrum for Sulfinate 136f with CSA ........................................ 103

Figure 15: Circular Dichroism Curve for [RIs and [as-136b ....................................... 105

Figure 16: Circular Dichroism Cuwe for [RIs and [4~-136f ........................................ 106

Figure 17: Circular Dichroism Curve for [4~-136g ................................................... 107

Figure 18: Circular Dichroism Curve for [RIS-136d ................................................. 108

Figure 19: 'H NMR Spectrum for Enantioenriched Sulfoxide 158c ............................. 120

Figure 20: 'H NMR Spectrum for Enantioenriched Sulfoxide 161a ............................. 121

Figure 21: Coordination Model for CSA and Sulfoxide .............................................. 122

Figure 22: Differential Shielding Observed for CSA and Sulfoxide .............................. 122

Figure 23: Circular Dichoism Curves for [RIs Sulfinate Versus [SJS Suifoxide ............. 123

Figure 24: Circular Dichoism Curves for [SIs Sulfinate Versus [qs Sulfoxide ............. 124

1. Introduction

Organosulfùr compounds have an important role in organic synthesis.' Of

particular interest to the organic chemist are the tricoordinate sulfbr compounds,

specifically sulfinate esters and sulfoxides (Figure 1). Chiral sulfoxides are often used to

intraduce chirality into a target molecule of interest, by controlling the stereochemistry of

a reaction.13 As a result they are increasingly being used for natural product synthesis and

the preparation of biologically active molecules."

Sul foxide Sulfinate Ester Sulfinyl Chlonde

Figure 1: Tricoordimte mlfirr compotrncis.

Tricoordinate sulhr compounds such as sulfoxides and sulfinate esters adopt a

triganal pyramidal structure.' However, the presence of an electron lone pair gives the

sulfur centre a tetrahedral fiamework. Hence, by definition, unsymmetrical sulfoxides and

sulfinate esters are enantiomeric as there is no plane of symmetry and their mirror images

are non-superimposable. Uniike amines containing three different ligands, chiral

sulfoxides and sulfinate esters are contigurationally stable at ambient temperatures. It has

been found, however, that interconversion between sulfoxide enantiomers will occur at

elevated temperatures5 The mechanism of this thermal racemization has been h n d to be

pyramidal inversion, not carbon-sulfiir bond cleavage.

As a result of their synthetic uselùlness numerous methods for the asyrnmetric

synthesis of sulfinate esters and sulfoxides have been developed, many of them involving

sulfinyl chlorides (Figure 1). While possessing the tetrahedral geometry comparable to

sulfinates and sulfoxides, they have not been isolated in an enantiopure fonn6

Nevertheless, sulfinyl chlorides have demonstrated their usefulness in a variety of synthetic

situations,

In the following introductory chapters the synthesis and synthetic usefulness of

sulfinyl chiorides will be exarnined. This will also include an in-depth look at the

asyrnmetric synthesis of sulfinate esters and sulfoxides, and the important capacity these

compounds oEer to the organic synthetic chemist.

2. Introduction to Sulfinyl Chlorides

One of the rnost important roles of sulfinyl chlorides involves the synthesis of

homochiral sulfinate esters, which in tum leads to the generation of enantiopure sulfoxides

via the well known Andersen chemistrY."* They have also been used to prepare a number

of sulfonarnide and sulfinamide peptidomimetics.g These compounds are used to uncover

the mode of activity of enzyme inhibitors.

2.1. Preparation of Sulfinyl Chlorides.

The pioneering work of ~ o u ~ l a s s l ~ has led to the development of a large variety of

rnethods for the preparation of sulfinyl chlorides (Table I).'~"' The lower rnolecular

weight sulfinyl chlorides, such as the alkanesulfinyl chlorides and simple arenesulfinyl

chlorides are liquids, and many of these have been purified via vacuum distillation. Care

6 must be taken, however, as a number of explosions have been reported. Substituted

arenesulfinyl chlorides are typically so~ids.~

While older rneth~dsl"~ have been used to prepare some novel sulfinyl

ch lori de^^'^'^ (Table 2) a significant drawback of these procedures is their use of Cl2 gas

and/or the generation of acidic by-products. To overcome these drawbacks a number of

researchers have used SOzC12 instead of gaseous Cl2 in their sulfinyl chloride preparations.

For example Scherne 1 shows the preparation of arenesulfinyl chlorides from the

corresponding thio~acetate.~' This procedure was originally proposed in 1978~' but only in

the paper's experimental section, and went unnoticed for several years before

Table 1: Preparative Methods for Sulfinyl Chlorides

Syntheîic Mdhod Reference

MeSSMe + 3 Cl2 - 2MeSCS 10

O MeSC13 + ROH - II + HCI + RCI S

~ e ' 'CI

R: H; Me; MeC(0) additional alkyl groups: Et; i-Pr; n-Pr; !-Bu; Ph; n-CjHl 1

RSSR + O II + AcCl + 3 S02 + 2 HCl 12 2AcOH + 3 Ch - 2

ROS'~I

O RSSR + 2 Ac@ + 3Cb - 2 II + 4 AcCl 13

R' 'CI

M e / ' y M e Ch; Ac20 O II

____C) S O ~ e ' 'CI

O RSSR + 3 So2Cl2 + 2 AcOH - 2 + 2 AcCl 15

R' 'CI R: Me; i-Pr; /-Bu; Bz; Ph;

p-tol y 1; MeC(0)OCH2CH2- + 3 S 0 2 + 2HCI

O RSH - 2 SOzCb_ AcOH - II

+ AcCl 16 S

CI R: Et; i-Pr; s-Bu; Bn; Ph; p-tolyl; -CHzC(0)OMe; -CHzC(0)OCH2Me 2 S02 - 2HCI

Table 2: New Sulfinyl Chlorides using Established Procedures.

Surfinyl Chloride Starting Sitbstrate ReagentsO Synthetic Reference

thiolacetate

sulfinic acid

disulfide

thiolacetate

thiolacetate

thiolacetate

disulfide

thiolacetate

thiolacetate

sodium sulfinate

magnesium suhate

a Original or usual protocol for suiiïnyi chlonde generation. with the corresponding reference.

being redi~covered.~~ Using this procedure alkyl and aryl thiolacetates have been

convened to the corresponding sulfinyl chlorides in high yields (86-97%). The advantages

of this modification are that the formation of large arnounts of gaseous HCI is avoided and

only the volatile reaction by-products SOz and acetyl chIoride are formed. This protocol

also avoids the use of thiols since the alkyl or aryl thiolacetates can be prepared from the

corresponding alcohol.

Scheme 1

Another modification to this procedure makes use of tnmethylsilyl acetate as an

alternative to acetic anhydride.= This reagent simultaneously serves as both the oxygen

donor and the chloride ion acceptor. The reaction can be used for the preparation of

aIkane- and arenesulfinyl chlorides from either thiols, thiolacetates, or disulfides in 80-

100% yield (Scheme 2). Again the process is advantageous in that only relatively mild

reaction by-products are generated. The method is not ideal for benzyl sulfinyl chloride

(50% yield) and r-butyl sulfinyl chloride does not form at d l .

Schwan and coworkers have also found that a variety of aliphatic and aromatic

sulfinyl ~ h l o r i d e s ~ ~ ~ ' could be prepared via an oxidative fragmentation of aliphatic and aryl

2-(trimethylsilyi)ethyl sulfoxides (L), respectively, using S&C12. The key to this chemistry

is that in most cases the normally observed a-oxidation of the sulfoxides is precluded by

the presence of the 2-(trimethylsily1)ethyl functionality which promates

O II + 2 AcCl + 3 S02 RSSR - 2 MeC02SiM~ - 3 S02CS - 2

R' 'CI 2 Me3SiCI

Scheme 2

C-S bond cleavage and sulfinyl chloride generation (Scheme 3). For aliphatic sulfinyl

chlorides, the method is most effective when by-product 2 can be removed under reduced

pressure pnor to distillation of the sulfinyl chiorides; this is not a problem for the arornatic

~ o n ~ e n e r s . ~ ~ Starting fiom sulfoxides 3 or 4, similar methodology could also be applied

for the preparation of 2-(trimethylsilyI)ethanesulfinyl chloride (5) (Scheme 4).

Interestingly, the oxidative Fragmentation mode of 3 has a notable solvent dependence: I-

butanesulfinyl chloride becomes a significant product if the reaction is perforrned in

C H ~ C I ~ . ~ '

R: Ph; p-Mec&; p-CIC6& 2-napthyl; n-Pr; PhCH?; TMS(CH&; CH?=CHC&; c-C6Hi 1; n-C 12H23

Scheme 3

Scheme 4

The oxidative fiagmentation method was considered a possible procedure for the

first preparation of 1-alkenesulfinyl chlorides. The concept was that the conjugated double

bond of a s-rrlfoxiùe starting substrate should have reduced nucleophilic character and

would be less reactive toward electrophilic chlorine reagents. To test this theory, 1-alkenyl

2-(trimethylsilyl)ethyl sulfoxides (6a-d) were prepared and subjected to the oxidative

fragmentation conditions (Scheme 5). In the case of 6a and 6b the corresponding sulfinyl

chlorides (7alb) were observed via TLC and IR spectroscopy, and were isolated as their

cycloheqd 1-alkenesulfinate esters (8dby5, owing to the inherent reactivity of the sulfinyl

chloride, as a means to complete characterization. When compounds 6c and 6d were

treated under identical reaction conditions, formation of the corresponding sulfinyl

chlorides was not observed. Instead, a$-dichlorination products 9c and 9d were isolated.

Products 9cld are presumed to form as a result of an additive Pummerer r e a ~ t i o n . ~ ~

Prompted by the partial success of the 2-(trimethylsilyI)ethyl group, Schwan and

coworkers investigated other groups and found the diphenylmethyl @PM) and

p-methoxybenzyl (PMB) units to be rnost usefiil for achieving facile C-S bond cleavage.

Several 1-alkenyl sulfoxides bearing these groups 'were prepared and treated under

Scheme 5

similar reaction conditions (Scheme 6).35.37 In each case the presence of 1-alkenesulfinyl

chlorides couId be inferred through TLC and solution cell IR analysis (sulfinyl stretching

frequency * 1140-1 150 cm-[) of the reaction mixture. The sulfinyl chlorides were again

R' O ROH

R' O SOlCk

' -78 O C to n -78 O C to rt

C = diphenylmethyl @PM); p-methoxybenzyl (PMB) R I ; R'; R3: various alkyl, aryl and ester p u p s ROH: cy clohexanol or 3-pheny l- 1 -propanol

Scheme 6

isolated as 1-alkenesulfinate esters. Lower molecular weight sulfinyl chlorides 10 and II,

prepared from the corresponding DPM sulfoxide were isolated (90% purity) when

subjected to flash di~tillation.~'

The oxidative fiagmentation procedure suggested by Schwan and coworkers is

advantageous in that it can be used to prepare a variety of aliphatic, aryl and now vinylic

sulfinyl chlorides without any of the acidic by-products such as HCI, acetic acid or acetyl

chlorides, which are normally associated with some of the earlier procedures found in

Table 1.

2.2. Synthetic Usefulness of Sulfinyl Chlondes

Sulfinyl chlorides are generally used as intermediates in the synthesis of other

compounds. They readily participate in substitution reactions due to the electrophilicity of

the sulfinyl groups and the good leaving ability of chloride. They have been used in the

synthesis of a large number of compounds and an exainination of al1 these cornpounds and

methods is beyond the scope of this introductory section. As such, selected examples are

described below that highlight their synthetic utility. A notable exception to these

examples is their role in the asymmetric synthesis of sulfinic acid derivatives, whch will be

elaborated upon in greater detail in the next chapter. The more common substitution

reactions involving sulfinyl chloides are those with oxygen and nitrogen nudeophiles.

The nucleophilic substitution of sulfinyl chlondes with an alcohol leads to sulfinate ester

formation, a class of compounds that demonstrate increased stability over their sulfinyl

chloride precursors. This allows for the suffinates to be easily isolated and undergo fd l

spectroscopic analysis. This was illustrated by Schwan and coworkers when they isolated

1-alkenesulfinyl chlorides, generated in an oxidative Fragmentation reaction, as 1-

alkenesulfinate esters.37

An example of a nucleophilic substitution of a sulfinyl chloride is found in the

biomimetic synthesis of the sesquiterpene agelasidine A (12) from sulfinyl chloride 13

(Scheme 7).27 This synthetic strategy also dernonstrates the conversion of the allylic

Scheme 7

sulfinate ester to the therrnodynarnically more stable sulfone. Following formation of

sulfinate 14 from sulfinyl chloride 13, the reaction is heated to induce a 2,3-sigmatropic

rearrangement to form sulfone 15. Subsequent steps lead to the desired sesquiterpene

The reaction of sulfinyl chlorides with nitrogen nucleophiles afFords a class of

compounds called sulfinamides. Weinreb and coworkers have made use of this chemistry

in protecting group methodology for amines (Scheme 8)1' Due to the insufficient

reactivity of sulfonyl chlorides, t-butyl sulfinyl chloride was reacted with a series of

primary and secondary amines. Oxidation of the sulfinamide 16 leads to the sulfonyl

protected amine: sulfonamide 17, which is stable under a variety of reaction conditions.

Deprotection is accomplished using trifluotoacetic acid.

Peptidomimetics are referred to as transition state isoteres. They are designed

with hnctionality that is stericaIly comparable to the tetrahedral intermediates involved in

the hydrolysis of the amide bond of proteins and peptides. As peptides contain

hnctionality similar to sultinarnides or sulfonamides these groups can be used a transition

state isoteres leading towards the development of HLV (Human lmmunodeficiency Virus)

protease inhibitors and catalytic antibodies. As shown in Scheme 9, reaction of sulfinyl

chloride 18 with amine 19 generated sulfinamide peptidomimetic isotere 20.~' Subsequent

oxidation afforded sulfonamide 21. Sulfonamide 21 was subsequently used for the

production of monoclonal antibodies and investigated for possible amidase and esterase

activity. While no activity was observed in this particular example, various sulfinyl

chlorides (Table 2, 22-24) can be captured using additional a-amino acids lending

considerable promise to this methodology.

O H II O

l -2yI 4 l9

NHMe BocN b

NMM 18

O H

BocN

NHMe

NHMe

Scheme 9

Typically it is more conservative to first convert a sulfinyl chloride to a sulfinate

ester or sulfinarnide prior to substitution with an organometallic reagent to generate a

sulfoxide. However, the direct conversion of sulfinyl chloride to a sulfoxide has been

achieved in a nurnber of cases.a For example, reaction bewen phosphorus ylides 25 and

26 with a sulfinyl chloride leads to sulfoxides 27 and 28 respectively. Sulfoxides 27 and

28 can also be classed as sulfinyl ylides (Scheme 10). ".'*

Scheme 10

Jung and coworkers have also prepared sulfoxides directly via an electrophilic

aromatic substitution reaction. Diaryl sulfoxide 29 was prepared in a Lewis acid induced

sulfinylation reaction between benzenesulfinyl chloride and p-methylphenol 30 (Scheme

Scheme 11

3. Introduction to the Asymmetric Synthesis of Sulfinate Esters, Sulfinamides and Sulfoxides

Perhaps the most important synthetic role sulfinyl chlorides play is in the

preparation of homochiral sulfinate esters and sulfinarnides, with the eventual target for

this chemistry being the generation of enantioenriched sulfoxides. As a result of the

chirality at the sulfinyl centre, sulfoxides have been used in a number of synthetic schemes

to induce stereochemistry into a target mo~ecule.~.' As such, a great deal of effort has

gone into developing reliable, efficient methods for the synthesis of enantiopure sulfoxides

because of the important role they have in asymmetric synthesis.

At this point four general methods are available for the preparation of sulfoxides

with homochirality at the sultiir centre. These include: optical and kinetic resolution,

asymmetric oxidation and stereospecific synthesis." Optical and kinetic resolutions

involve taking a racemate of the sulfoxide and separating a single isomer based upon a

preferential crystallization or a chemical reaction. While there are many examples of these

older methods in the literatureu7 low optical purities are generally obtained and these

methods are not otlen employed. Recent efforts have examined optical resolution of

sulfoxides using lattice inclusion compounds. This technique has been reported effective

for the enantioselective inclusion of alkyl aryl sulfoxides with a high degree of

e f f i c i e n ~ ~ . ' ~ . ~ The major methods for generating enantiopure sulfoxides are asymmetric

oxidation and syntheses.

The following sections will examine the synthetic importance of sulfoxides in

asymmetric synthesis. From a synthetic viewpoint the emphasis will be placed upon the

synthesis of diastereomeric sulfinate esters and sulfinamides and their subsequent

conversion to enantiopure sulfoxides. A brief examination of asymmetric oxidation of

sulfides to afFord sulfoxides will also be included.

3.1. Synthetic Value of Eoantiopure Sulfoxides

The role of sulfoxides in asymmetric synthesis is quite diverse. They can

participate in a variety of different types of stereoselective reactions such as conjugate

addition and Diels-Alder reactions. In these reactions it is the chirality at the sulfùr centre

that pIays a pivotal role in controlling the stereochemical outcome of the reaction. Oflen,

the sulfoxide serves simply as a chiral auxiliary which can be readily removed following

the induction of the stereochemistry. In the following section several recent examples are

examined in an attempt to outline their synthetic utility. In several cases, examples of

natural products that have been prepared using enantiopure sulfoxides are reviewed to

iùrther demonstrate the usetiiiness of sulfoxides to the synthetic chemist.

One of the earliest papers demonstrating the role of enantiomeric sulfoxides was

presented by Goldberg and ~ahli." Their experiments involved the pyrolysis of each

enantiomer of (+)-[RIS and (-)-[SIS-trans-4-methylcyclohexyl p-tolyl sulfoxide. The

resulting 4-methylcyclohexene isomers were isolated with enantiomeric excesses (ee's) as

high as 70% (Scheme 12).

The stereoselectivity is controlled by the configuration at the sulfinyl centre

(Figitrt? 2) . For each case the transition state is configured such that the bulkier p-tolyl

group lies away from the ring system so that a single isomer is formed. For the second

isomer to form simultaneously the p-tolyl group would be in a sterically hindered

position.50

Me Me-? S... ,,,,,,

\ P- toi - 6

Scheme 12

[RIs isomer [SIs Isomer

Figure 2: Stereoselective control by the sirlfnyl grolrp.

In a similar it was show that cyclohexene derivatives can be prepared in

an enantiomerically pure form through a radical fragmentation of a-bromophenyl

suifoxides (31) (Scheme 13). Starting with the cis isomer of 31, enantioenriched

cyclohexene 32 could be isolated in 65 to 70% yields (70-80% ee). These results are much

better compared to the corresponding thermal elimination (ee's 54%), and involve

significantly milder conditions (i.e. 10 O C versus 200 O C ) . Unfortunately, use of the pans

isomer of 31 (not shown) resulted in a racemic mixture.

Bu3SnH - AIBN

Scheme 13

Enantiopure vinyl sulfoxides can participate in a number of different types of

reactions. For example, Carretero and coworkers have recentiy shown their participation

in an intramolecular Heck reaction (Scheme 1 4 . ~ ~ The chemistry was initially done using

a racemic sulfoxide 33, however, the cyciization reaction was Found to occur with tùll

regio- and diastereoselective control. Furthermore, the authors found that starting

O + S-R

Scheme 14

with enantiopure [SIS-33, no racemizatian at sulfbr occurs during the reaction. The origin

of the high stereochemical control is still under investigation.

Analogous to a$-unsaturated carbonyl compounds, a$-unsaturated sulfoxides

can also participate in Michael additions. The advantage of the sulfinyl functionality is the

presence of the chiral centre which can direct the stereochemistry of the addition. The

work of Tsuchihashi and coworkers outlines some of the early research done on this

r e a ~ t i o n . ~ ~ They found that in the presence of sodium ethoxide, ethyl acetoacetate reacted

with sulfoxide 34 to form the Michael adduct 35 (Scheme 1.5). To study the

stereochemistry of the reaction, the authors examined a Michael addition of &am-P-styryl

p-tolyl sulfoxide (36), as it could be isolated in an enantiopure form (Scheme 16). They

found that Michael adduct 37a could be isolated in an 82% yield and a de of 95%. The

stereochemistry is based upon the formation of anions 38. It is generally accepted5' that

the more stable carbanion conformation would be 38a whereby the lone pair orbital is

f~.or~s to the sulfinyl oxygen. As a result, stereoisomer 38a is preferentially formed.

EtONa 1 EtOH

Scheme 15

Michael additions have also been camed out using enolates as the nucle~phile.~~"~

Takeda and coworkers examined the cyclization of sulfoxide 39 with L-selectride (Scheme

17). The reaction proceeds with complete x-facial diastereoselectivity to afford 40 in a

50% yield. While the origin of the truns selectivity is not known, the facial selectivity can

be accounted for by enolate attack fiom the less hindered side in the chelated structure

(Figure 3). This mode1 is supported by the reduction in facial selectivity when HMPA is

present, as it disrupts the chelation show in Figure 3.

Scheme 16

Scheme 17

Figure 3: Facial seiectivity mode1 for iritramolecirlar Michael aditiori.

Michael additions to enantiopure vinyl sulfoxides are not limited to carbon

nucleophiles. Conjugate addition of amines has been investigated by several groups' and

has been shown to proceed with good stereoselectivity. For example. Pyne and

coworkers examined the conjugate addition of benzylamine with isobornyl vinyl sulfoxide

4 1 (Scheme 18)." Depending upon temperature and solvent conditions the reaction

proceeds in excellent yield and with good stereoselectivity.

P ~ ~ N H , ___II_)

EtOH 30°C 1 8 days $OH ,,,/ + &OH *f) se

R "".- NHCH2P h NHCH2P h H

R = CHzOTBMS 95% (93:7)

Scheme 18

Conjugate addition reactions to vinyl sulfoxides have also been used to prepare a

nurnber of natural productsl as well as a number of biologically active precursors such as

the chroman ring of a - t o ~ o ~ h e r o l , ~ ~ An example cif a natural product prepared via a

conjugate addition is show in Scheme 19. Following the preparation of vinyl sulfoxide

42 the sulfoxide was treated with NaH to undergo an intramolecular conjugate addition to

afford sulfoxide 43. Sulfoxide 43 could then be treated with p-TsOWMeOH to induce

isomerization to 44. Both sulfoxides 43 and 44 underwent desulfiirization using Raney Ni

to form the corresponding enantiomers of 45, the sex pheromone of an olive f l ~ . ~ '

Scheme 19

a, P-Unsaturated sulfoxides can also participate in [4+2] cycloaddition reactions in

which up to four new chiral centres can be generated, Since the sulfinyl tiinctional group

can exert high asymmetric induction in carbon-carbon bond formation, vinyl sulfoxides are

an idcal choice for use in the synthesis of complex products, such as cycloadducts, with

several chiral centres.

Carreho and coworkers have recently examined Diels-Alder reactions of sulfinyl

quinone 46 with cyclopentadiene (Scheme 20).~' They observed that the introduction of

either electron donating or electron withdrawing substituents in the aryl sulfoxides, as well

as the choice of catalyst could be used to control the reactivity, chemoselectivity and x-

facial diastereoselectivity. In the absence of a Lewis acid, C& chemoselectivity

47 46a Ar = p-tolyl

48

b Ar = p-methoxyphenyl c Ar = p-nitrophenyl

+

Scheme 20

was observed to give cycloadducts 47 and 48, respectively. In each case it-facial

selectivity was shown to afford 47 as the major diastereomer, which could be separated by

chromatography. The use of Eu(fod)3 as a Lewis acid enhanced the facial selectivity but

decreased the chemoselectivity with cycloaddition occurring to d o r d a mixture of

cycloadducts 47-49 (80: 10: 10 ratio). A reversal of the facial selectivity was observed with

BF3.Et20 as the Lewis acid, aording 48 as the major cycloadduct. In each case 46c was

proven to be the most reactive starting matenal (Le.: 16 hours for 46a versus 2 hours for

46c).

The x-facial diastereoselectivity is explained using the rnodels drawn in Figure 4.

In structure 1 for Eu(fod)3 the diene approaches from the lower electron density face of

the s-tram conformation to give 47 as the major product. For BF3.Et20 the s-cis

conformation (n) is adopted and the diene approaches fiom the top face to give 48 as the

major product. In each case the lower electron density is the result of an interaction of the

sulfùr lone pair and the quinone's ~r cloud.

Figure 4: Stereochemistry in Diels-Alder Reaction.

sc is

In addition to [4+2] cycloaddition, vinyl suIfofides have also been shown to

participate in [3+2] cycloaddition (Scheme 21). The resulting cycloadducts 50, which

were isolated in good chemical yields as a mixture of two diastereomers (only one shown),

were separated by flash c h r o m a t ~ ~ r a ~ h ~ . ~ '

Scheme 21

Finally, Diels-Alder reactions of vinyl sulfoxides have been used to prepare a

number of natural products.' For example, both enantiomers of 45, which were show to

be prepared using a Michael addition (Scheme 19), can also be prepared using a

cycloaddition reaction with 51 (Scheme 22).62 While there is no chiral induction in the

actual formation of cycloadducts 52, the diastereomers can be easily separated using flash

chromatography. Removai of the sultiir tiinctionality is easily accomplished using Raney

Ni, which also serves to hydrogenate the double bond. The chemistry is interesting to

note for two reasons: (i) the sulfinyl compound serves as the diene rather than the olefin

source and (ii) the reaction demonstrates the incorporation of a heteroatom in the Diels-

Alder reaction of an unsaturated sulfoxide.

Sulfoxide 51 has also been used to prepare the natural product 53, a pheromone cf

the house mouse, M m rntm~111s.~~ As in the previous example, while the initial

stereoselectivity is low (70:30 mixture), the isomers can be readily separated using

chrornatography. What is noteworthy about the preparation of 53 is that it utilizes not

only Diels-Alder chemistry, but a Michael addition as well (Scheme 23).

Scheme 22

Scheme 23

A class of enantiopure sulfoxides which have been used extensively in asymmetric

synthesis are P-keto sulfoxides. One of the most important transformations these

suifoxides undergo is their conversion to P-hydroxy sulfoxides. 1.6366 Depending upon the

choice of the reducing agent the transformation proceeds with high diastereoselectivity.

Of the reducing reagents examinai DIBAL-H and DLBAL-iUZnCI2 provide the greatest

stereoselectivity, affording complementary diastereomers with good to excellent yields.

The stereoselectivity that is observed can be explained using the various conformations

shown in Scheme 24. For DIBAL abne, coordination chair

Ar

C 1, zx- CI' s, - I

Cl .. R

Scheme 24

conformation A is preferred because of a steric interaction between the i-Bu group and the

sulfinyl substituent in the B conformation. In the presence of ZnClz the metal coordinates

to both the sulfinyl and carbonyl oxygen. Again, owing to a steric interaction, chair

conformation C is preferred over conformation D. Following hydride transfer

diastereorners 54 were obtained separately. Similar results have also been obtained with

the stereoselective reduction of a y-keto sulfoxide, although the selectivity is not as

g ~ ~ d . 6 7

P-Keto sulfoxides and their resultant B-hydroxy reduction products have been used

to prepare a number of natural products. Some recent examples include: (-)-(5s. 7R)

tarchonanthuslactone (5516', both D-erythro and L-threo sphingosine, 56 and 57

respe~tively~~ and the pheromone [RIS-(-)-sulcatol (58)." In each of these synthetic

routes a key step for introducing the stereochemistry in the Anal molecule is the

stereoselective reduction of the B-keto group.

3.2. Preparations of Enantiopure Sulfoxides via Asymmetric Oxidation

The asymmetric oxidation of unsymmetrical sulfides is one of the two major

methods for preparing enantiopure sulfoxides. The tint reported asymmetric oxidation

were published separately by ont ana ri" and ~a l enov i c~~ in the early 1960's. The

reported method involved the use of chiral peracids, with the configuration of the

sulfoxide product being dependent upon the absolute configuration of the peracid.73 A

significant drawback of this method is the low de's (less than 10%) that are obtained.

ln 1984 ~ a ~ a n ~ ' and ode na'^ independently reported that high enantiomenc

excesses could be obtained using a modified Sharpless reagent for the asymmetric

oxidation of unsymmetrical sulfides (59). The Sharpless reagent (Tito-i-Pr)d: (R,R)-

diethyl tartrate @ET): t-BuOOH (TBHP) is used for the asymmetric epoxidation of allylic

alcohols. Using the standard Sharpless reagent the oxidation of sulfides leads to a

racemate of the sulfoxides. It was discovered, however, that by adding a specific amount

of water to the system, enantiosetective oxidation of sulfides can be achieved (Scheme

~ j ) . ~ ' It was shown that the oxidation was not a combination of asymmetric synthesis

and kinetic resolution as treatment of racemic 60 did not afford the corresponding

~ulfone.'~

R'; R2 : various alkyl and aryl groups

It was determined that the amount of water used as well as the reaction

temperature play a pivotal role in the stereoselectivity of the oxidation. As indicated with

the unmodified Sharpless reagent, in the absence of water a racemate is observed. By

increasing the amount of water present a steady increase in the ee's is obtained, reaching a

maximum when 1 equivalent of water is used. When additional water is added, however,

a significant decrease in the stereoselectivity is observed. A similar effect is observed for

the temperature of the reaction with optimal ee's being obtained when the reaction is

carried out at -20

It was also discovered that the enantioselectivity of the oxidation was very

dependent upon the nature of the sulfide substituents. Good to excellent ee's were

obtained for methyl aryl sulfides and most alkyl aryl sulfides (ee's 70-95%). The

stereoselectivity was not as good, however, for the preparation of dialkyl sulfoxides (ee's

42-71%). It was also generally observed that as the size differential between the two

substituents was reduced the selectivity decreased. 74. 76 The relationship between the

absolute configuration of the sulfoxide generated and the absolute configuration of the

DET Iigand was determined. Based upon sulfide 59 (Scheme 25) if R' is large (Le. aryl)

and R* is small (i.e. small alkyl groups) then (R,R)-DET affords the [RIS sulfoxides while

(S,S)-DET leads to the [SJs sulfoxide.

Since the initial work was introduced, Kagan and coworkers have reported a

number of modifications which have shown significant improvements to the

enantioselectivity. By carrying out the reaction in methylene chioride or 1,2-

dichloroethane optimal ee's and yields are ~bse rved .~ The use of cumene hydroperoxide

(Cm) has also been found to greatly improve the ee's. The added benefit of using CHP

over TBHP is that it allows for a reduction in the amount of titaniurn complex required.n

Kagan and coworkers have also found that by replacing water with 2-propanol and

carrying out the reaction in the presence of molecular sieves, significant increases to the

enantioselectivities were obtained. Ee's as high as 95% (for aliq~l aryl sulfoxides) were

observed using a 1:4:4 ratio of Ti(O-i-Pr)4 / (R,R )-DET I i-PrOH in the presence of

molecular sieves and with CHP as the oxidant."

Other groups have also examined modifications to the reagents proposed by

Kagan. The use of di01 61 instead of DET has been show to provide good ee's for the

oxidation of rnethyl aryl sulfides. The yields obtained were much lower (40-60%),

however, due to the formation of sulfone. It was found that sulfone formation could be

limited by decreasing the reaction time. This was accompiished by doubiing the amount of

oxidant (TBW; 2 equiv.) and raising the temperature. Only methyl aryl sulfides were

examined and the [RIS sulfoxide was obtained in each case.n Greater selectivity was

achieved using Binol derivative 62 and TBHP as the oxidant. In this case the di01 leads to

the preferential formation of the [S]S sulfoxide enanti~mer.~

While no kinetic resolution has been show to take place with the simple sulfides

oxidized by Kagan and coworkers, Phillips and coworkers have found that the Kagan

reagent preferentially oxidized the (+) enantiomer of 63 faster than the (-) enantiomer

allowing for the isolation of (-)-5 and for the formation of sulfoxide 63 in high ee (Scheme

26). ''

Scheme 26

A similar effect was also observed by Uemura and coworkers." They took a

racemate of a methyl aryl sulfoxide and treated it with the Kagan reagent to isolate the

[RIs sulfoxide in high ee's (>99%), as well as the sulfone. The drawback of these various

kinetic resolution techniques is that the enantiopure sulfoxides are isolated in less than

50% yield.

While the reagent proposed by Kagan and coworkers is highly efficient for the

oxidation of methyl aryl sulfides (ee's > 90%), it is lirnited in terms of other alkyl aryl and

dialkyl sulfides (ee's 20 to 60 %). This prompted Davis and coworkers to develop a

suifide oxidation technique using various chiral N-sulfonyl oxaziridine substrates

( 6 ~ - 6 8 ) ' ~ - ~ ~ The compounds have also been found to be usefiil for the enantioselective

epoxidations of alkenes."

67 68 X = CI, H, F, Br X=CI,H,F,Br

R = Ph, p-tolyl, O-MeOPh

It has been established that the contiguration at the three membered oxaziridine

ring controls the stereochemistry of the product. For example (3'R, 25')-(+)-68 in every

case studied afTorded the [RIs suüioxide, while (3'S, 2R)-(-)-68 gave the [SJS sulfoxide in

every case.86 It has been proposed that the observed stereoselectivity arises due to steric

interactions between the substituents present on the sulfide as well as the substituents on

the oxaziridine.

Analogous to the results obtained by Kagan and coworkers, higher ee's are

obtained when there is a larger size differential between the substituents present on the

~ulfide.'~ Of the various oxaziridines studied, 68 (X = CI) appears to be the most usefiil

with the majority of ee's reported in excess of those reported by ~ a g a n . ' ~ An additional

advantage of this method is the recovery of oxidation by-product 69 (>90% recovery).

Sulfonylimine 69 can be recycled and used in the preparation of 68.

3.3. Preparation of Sulfinic Acid Derivatives for Asymmetric Synthesis of Sulfoxides

3.3.1. Sulfinate Esters

The general method for preparing diastereomeric sulfinate esters involves reacting

a sulfinyl chloride with a chiral aliphatic or aromatic alcohol in the presence of base (Le.,

KzCO3, pyridine). This reaction, once thought to proceed via an SN2 me~hanism,~' is now

çenerally theotized to involve a sulfùrane intermediate." This new mechanistic

understanding has allowed researchers to advance the original Andersen strategy7.' for the

preparation of diastereomerically enriched or pure sulfinate esters which in turn have

proved to be a usefiil source of enantiopure sulfoxides.

Sulfinyl chlorides were originally used by ~ h i l l i ~ s ~ ~ to prepare sulfinate ester 70.

This involved a reaction betweenptolyl suffinyl chloride 71 and menthol in the presence

of pyridine to form a diastereomeric mixture of 70 (Sckme 27). This synthetic approach

is general in scope and has been used to prepare a large number of diastereomeric sulfinate

esters.' A number of modifications to this approach have been proposed with varying

degrees of success and will be presented later in this section.

O O II

O II II S + (-)-menthol PYr _ :11.....s, toi + D,,i....S,

p-tol' 'CI MenthylO / P- p- tol D / OMenthyl

Scheme 27

The stereoselective synthesis of enantiopure sulfoxides fiom diastereomeric

sulfinate esters was first reported by Andersen in the 1960's." It involves reacting the

sulfinate ester, with geometric purity or enrichment at the sulfiir centre, with a Grignard

reagent or other organometallic reagents. In the original report Andersen reacted sulfinate

(-)-[SIS-70 with ethylmagnesium iodide (Scheme 28) to afford the corresponding [RIS-

suifoxide. Andersen showed that this nucleophilic substitution occurred with inversion of

configuration at the sulfbr centre. This will be discussed in greater detail later in this

section.

Scheme 28

Organolithium reagents have also been applied in Andersen chemistry. For

example, Marino and coworkers reacted monolithiated 72 with (-)-[SJs-70 to generate

sulfoxide 73. Further conversion to 74 was achieved by treating 73 with NBS (Scheme

29).'" A dificulty encountered with this reaction are the low yields, believed to be the

result of deprotonation of the vinyl product by the lithiated nucleophile. This quenches the

nucleophile before the reaction can go to completion. This problem was overcome by

adding 72 to a solution of [SIs-70 as rapidly as possible.g0

Scheme 29

The synthesis of a$-unsaturated sulfoxides can also be accomplished by utilizing a

Wittig or Horner-Wadsworth-Ernrnons rea~t ion .~ ' '~ Early attempts at this chemistry

reacted phosphorus compound 75 with [SJs-70 to afford 76. Sulfinyl phosphonium ylide

76 was then treated with an aldehyde to afford the desired enantiopure vinyl sulfoxide 36.

The drawback to this procedure is the formation of a mixture of EL7 isomers (Scheme

30).~' Mikolajczyk and coworkers have found, however, that switching to phosphonium

ylide, generated from 77, affords almost fiilly (E) stereoselecti~it~.~~

O O O O II r1Bui.i II II II

@M'Me - (R)2Py %.....: PKHO -Sc*...: (-)-[SJs-70 ptol - Ph p-tol

75: R = Me0 76 36 77: R = Ph

E:Z 1: 1.7 87% yield with 77 E:Z 100:O 75% yield

Scheme 30

While the Andersen procedure is general in scope for the preparatim of

enantiopure diaryl and alkyl aryl sulfoxides, it is Iirnited in terms of the preparation of

dialkyl sulfoxides because of the unavailability of the corresponding diastereomerically

pure or enriched sulfinate esters. Diastereomerk mixtures of menthyl alkanesulfinates are

often found as oils, which are difficult to separate through chromatography or

crystallization. Due to the synthetic significance of sulfinate esters a great deal of effort

has çone into improving the synthetic methodology for their preparation.

One method for improving the synthesis of (-)-[SIS-70 has been proposed by

Solladié and coworker~ .~ It involves the addition of HCI to an acetone solution of both

diastereomers which promotes epimerization of (+)-[RIS-70 to (-)-[SIS-70 (Scheme 31).

This technique is a modification to an earlier procedure.9s Unfortunately, this method has

been shown to not always provide consistent resuks.

Perhaps the most significan! modification to the preparation of diastereomeric

sulfinate esters involves the use of chiral alcohols other than (-)-menthol. In 1984

Andersen and coworkers% found that substituting cholesterol for menthol led to

cholesteryl methanesulfinates (78) (Scheme 32). Unlike menthyl methanesulfinates,

Scheme 3 1

O O O II TE A II + II s + cholesterol ,,l,,,..S, :,lv,s,

~ e ' 'CI Me OChol ChoK) Me

C ho1 : cholestery l Isomers separated through crystallization

Scheme 32

which are oils, the cholesteryl sulfinates (78) can be separated through crystallization.

This was an important discovery as it allowed Cor the preparation of dialkyl sulfoxides

utilizing the Andersen chernistry. Upon treatment of 78 with alkyl or aryl Grignard

reagents, alkyl or aryl methyl sulfoxides can be prepared with high enantiorneric purity

(Scherne 33).

One of the drawbacks of this strategy are the low yields obtained for both

diastereomeric forms of 78 ([&: 3.5 %; [RIS: 0.7%). This presurnably is the result of the

multiple recrystalIizations (up to 7) required to isolate the diastereomers in a pure fonn. It

was suggested that improvements to the recrystallization techniques might increase the

yields.96

O II O

.,,,A, II 1 OChal + R'M@ - .,l,~*..s.

Me * J Me R [SIS-78

R' = ri-Bu; 52% (95% ee) = PhCH2; 36% (100% ee)

R' =p-tolyl; 3 5% (95% ee) = ri-Pr, 32% (1 00% ee)

Scheme 33

One of the most synthetically useful adaptations to the Andersen strategy has been

the use of diacetone-D-glucose @AG, 79) as the chiral alcohol (Scheme 34).". 97*99 The

unique facet of this chemistry is that either configuration of sulfinate is available simply by

choosing the correct base and solvent combination. For instance, the researchers found

that addition of racemic meihanesulfinyl chloride in toluene to a solution of DAG in the

presence of iPr2EtN, showed only a single diastereomer (de 2 95 %) by IH NMR analysis

of the crude reaction mixture. Purification by recrystallization afEorded the [SJs-DAG

methanesulfinate 80. When the base was changed fiom rPrzEtN to pyridine under the

same reaction conditions, [RIS-DAG methanesulfinate 81 was isolated (Scheme 3 4 . As

described above for the cholesteryl methanesdfinates, either sulfinate 80 or 81 can be

treated with a variety of alkyl or aryl Grignard reagents to afford the corresponding

sulfoxides (Scheme 35). W,88,97sS This method is advantageous since access to either

epimeric sulfinate is possible, hence either sulfoxide isomer is accessible.

79, DAG - -

THF

Scheme 34

Upon closer examination of the reaction conditions (i.e., base and solvent) Alcudia

and coworkers were able to demonstrate a relationship between the base and solvent used

and the stereoselectivity of the reaction." Pyridine-like bases, including DMAP and

imidazole, afford the [RIS-sulfinate (de's 56-86%). The [SJs-sulfinates (de's = 16 - 95%)

can be prepared using iPr2EtN or comparable bulky bases such as TEA. collidine and

N,N-dimethylaniline @MA). Choice of solvent is also important, with the highest de's

obtained using THF for pyridine-like bases and toluene for i-Pr2EtN like bases. The

sulfinates are isolated using colurnn chromatography or recrystallization.

ee > 98% for R=p-tolyl

ee > 87% for R=p-tolyl

Scheme 35

More recent work has been done to examine wheiher this badsolvent effect is due

to the nature of the chiral alcohol or if it is applicable to al1 chiral secondary a l c o h o ~ s . ~ ~

Several different chiral secondary alcohols were examined, such as dicycloheqlidene-D-

glucose @CG-82), menthol, and cholesterol, and a basehotvent effect was again

observed. However, except for DCG, which is structurally similar to DAG, the de's were

significantly lower.

The mechanism proposed to account for the diastereoselectivity has as its basis the

geometry of the substituents in various sutfùrane intermediates. The mechanism requires

that the reaction does not proceed through a sultine intermediate and that it is kinetically

~ontrolled.~' Another assumption is that the alcohol reacts with both sulfinyl chioride

enantiomers. In the first step of the proposed mechanism (Scheme 36), an

R OH ' DAG R DAG HO ... ,,.S. e +-

R -.; Y - tl..o + ..

R N@ OH A I DAG 's' - @+-y- .( "'.O Fi- !.

83b 85

-: R [RI Sulfinate

90 I N = Py or related

89 N = nitrogen base

8 N = quatemary nitrogen

Y = pseudorotation

Scheme 36

equilibrium reaction occurs between the sulfinyl chloride and the base afliording a racemic

pair of sulfinyl ammonium (or pyridinium) enantiomers 83. intermediate 83 then reacts

with the chiral alcohol to generate diastereomeric sulfùrane intermediates. When a bulky

iPrzEtN-type base is used, the approaching alcohol and the base assume apical positions,

generating sulfuranes 84 and 85. The [SIS-sulfinate can be directly forrned fiom 84, while

sulfurane 85 requires a series of pseudorotations to form sulfùrane 86 and eventually the

[qs-sulfinate. The formation of 85 may be less favorable due to a destabilizing interaction

between the R group and the C-5 of the sugar ring. When the smaller pyridine-type bases

are used the base occupies the equatorial position while the alcohol takes on an apical

position, generating sulfuranes 87 and 88. Both sulhranes 87 and 88 undergo 1 or 2

pseudorotations forrning sulfùranes 89 and 90, respectively, which then form the [RIS-

sulfinate. tt is possible that the formation of sulfùrane 88 is preferred, with sulfiirane 87

being less stable because of an unfavorable interaction between the R group and the C-5 of

the sugar.

When diastereomeric sulfinates are treated with organometallic reagents,

purification difficulties are sometimes observed in separating the resulting sulfoxide and

chiral alcohol, particularly on a larger scale. These difficulties can be overcome when

using the DAG sulfinates by treating the DAGlsulfoxide mixture with a TFNwater

solution. This solution serves to selectively hydrolyte one of the two acetal groups in the

DAG molecule. The hydrolyzed DAG is water soluble and can be easily separated fiom

the sulfoxide. 'Ou

The DAG alcohol has aiso been used in a modified Sharpless preparation of

sulfinates (Scheme 37).1°' The Sharpless procedure involves the reduction of a sulfonyl

chIoride to a sulfinyl chloride with trimethyl phosphite followed by the irr situ esterification

with menthol. Tom and coworker~'~' have found that when using DAG as the chiral

alcohol and triphenylphosphine as the reducing reagent the resulting sulfinate can be

isolated in high yields with good diastereomeric ratios. Furthermore, like Alcudia and

coworkers, they observed stereoselective control dependent upon the choice of base.

Separation of the diastereomers was again achieved through column chromatography.

O II

DAG

baseholvent Me Ph3P

Me

Scheme 3 7

Since they were first reported, enantiopure DAG sulfinates have been used to

prepare a number of chiral compounds. Some examples include 2-sulfinyl thioacetamides

(91),Io2 alkyl methylthiomethyl sulfoxides (92)'03 and chiral N-sulfinylimines (93).'04

Many of these compounds can then be used to generate other chiral species. For example,

sulfinylimine 93 can be used to prepare chiral aziridines (Scheme 38) which in tum can be

used to prepare various biologicaily important molecules such as aikaloids, amino acids

and p-lactam antibiotics.

H H H C H~=S(O)MQ ' N . , . ~ g N .+.oc -

p- tol MeLi 93 Ar H

Ar = Ph; (E)PhCH=CH

Scheme 38

Whitesell and Wong have investigated the use of chiral alcohol trans-2-

phenylcyclohexanol (94) as a chiral auxiliary (Scheme 39).1°' The diastereomeric sulfinate

esters 95 are prepared in good yield with better selectivity [(4-10): 11 than observed with

menthol [(2-3):1].'06 More importantly, the diastereomers can be separated via

chromatography andlot recrystallization. The latter is possible as the major diastereorners

are crystalline in the cases e~amined.'~' Each of these sulfinates reacts cleanly with

Grignard reagents to afford the corresponding enantiopure sulfoxide.

R=p-tolyl, 2-naphthyl, Me, i-Pr

Scheme 39

In each of the above synthetic methods, the diastereomeric sulfinates were

prepared using either a sulfinyl or sulfonyl chioride. In a related study Whitesell and

Wong have examined sulfinate ester preparation using 94, without the use of a sulfinyl

chloride (Scheme JO).''' When chiral alcohol 94 was reacted with thionyl chloride the

resulting diastereomeric (1:l at rt and 2: 1 at -78 OC) chiorosulfinate esters 96 were

suficiently stable that full characterization was possible. When chlorosulfinates 96 were

treated with Grignard and organolithium reagents the diastereomeric ratio observed for

the resulting sulfinate esters (95) minored that observed for the chlorosulfinates. When

treated with 0.9 equiv. of dimethylzinc the sulfinate esters were generated in a

diastereomeric mixture of 98:2 and in good chemical yield.

O O O II

=fH +

II S...,, S.. 1 ' .-*=O/ \Cl + -00 y%,.

S 94 CI' 'CI Ph .. Ph clm

As indicated earlier in this section, when Andersen reported his original work on

the Grignard reactions of diastereomeridly pure sulfinate esters he was able to

dernonstrate that the reaction proceeded with inversion of config~ration.~~ He was able

to demonstrate tfiis using optical rotatory dispersion (ORD) measurements of both [Sjs-70

and [RIs-ethyl p-tolyl sulfoxide (97). An ORD is a measure of a compound's specific

rotation as a hnction of wavelength. In the absence of any absorption by the substrate

monotonie changes in the specific rotation are observed. If there is electronic absorption,

an anomaly occurs at the wavelength (k) of the absorption. This anomaly is referred to

as a Cotton effect (CE). A positive CE refers to an increase in the optical rotation as the

wavelength decreases on the ORD curve while a negative CE shows the opposite

behavior. The sign of the CE is a reflection of the configuration of the chromophore that

caused the anomaly.

Using an ORD curve of [SJs-70, Andersen observed a strongly negative CE. He

was able to assign the correct configuration to 70 by examining the CE for [SJs-98. An

exchange of the Me group ofptolyl for iodine was not expected to significantly change

the ORD curve. tt was demonstrated that they have similar CE's, suggesting that the

configurations at the sulfinyl group were identical. Andersen then compared the ORD

curve of [J)s-70 to the ORD curve of the Grignard product 97. Sulfoxide 97 was found

to çive a strongly positive CE. These opposing CE's imply that the suifinyl centres have

opposite configurations. To add fiirther evidence, 97 was prepared through the

asymmetric oxidation of the corresponding sulfide using (+)-ch monopercamphoric acid.

While the enantiopunty was low, 97 prepared througti the Andersen method and the

enantioenriched suifoxide prepared through the oKidation method had the same sign of

optical rotation. The onIy way 97 could be prepared through a Grignard reaction with the

assigned configuration was if the nucleophilic substitution proceeded with inversion of

configuration.

Although work done in the early 1990's suggested that the reaction of homochiral

sulfinate esters with bulky Grignard reagents proceeded with retention of configuration, it

was Iater shown that these reactions proceeded with inversion of configuration. Alcudia

and coworkers initially reported that the reaction of sulfinate 80 and 81 with bulky

Grignard reagents (Le. t-BuMgCI) proceeded with retention of configuration at the sulfur

centre.97 This was further supported with evidence reported by Mikolajczyk and

coworkers who examined the reaction of sulfinate 99 with bulky Grignard reagents. A

cornparison of the CE'S for the various sulfoxides prepared suggested that in the case of

the s-Bu and t-Bu Grignard reagents, retention of configuration was obse r~ed . '~~ Because

of the conflicting opinions as to whether or not the reaction proceeded with inversion or

retention of configuration, Drabowict and coworkers decided to determine the absolute

configuration of the sulfoxide using a combined chernical-crystallographic method.'Og This

was accomplished by converting sulfoxide 100 to 101 (Scheme JI). Following several

recrystaIlizations 101 was isolated in a diastereomerically pure form and an X-ray crystai

structure was obtained. This crystal structure unequivocally showed that inversion of

configuration had occurred.

Scheme 41

3.3.2. Sulfinamides

Complementary and sometimes improved access to homochiral sulfinic acid

derivatives and hence sulfoxides can be achieved through the use of homochiral

sultïnarnides. Analogous to sulfinate esters, diastereomerically pure sulfinamides are

prepared through a substitution reaction between a sulfinyl chloride and a chiral nitrogen

cornpound. Also in keeping with the chemistry of sulfinate esters, the reaction between a

diastereomerically pure sulfinamide and an organometallic reagent proceeds with inversion

of configuration at the sulfbr centre to generate optically active sulfoxides. For a number

of years the oxazolidinone class of chiral auxiliaries has garnered considerable attention

and two members of the oxazolidinone farnily (102 and 103) have been used by Evans and

coworkers as auxiliaries to generate a new class of chiral sulfinyl transfer reagents.'IO

When lithiated oxazolidinones 102 and 103 are reacted with a sultinyl chloride two

diastereomers are formed, with de's of 4.6: 1 (104) and 2: 1 (los), respectively (Scheme

2 ) The major diastereomer is isolated &er a single recrystallization in excellent optical

purity (104allOSa; each > 99% de by HPLC). Depending upon the choice of the chiral

oxazolidinone, access to both epimers at sulfiir can be achieved. The [RIS-sulfinamide can

be prepared using IO2 while the [SIS-sulfinamide arises through the use of 103.

Scheme 42

Experimental evidence has shown that an equilibrium is established between the

diastereomeric products (Schemr 43) and it is this equilibrium which accounts for the

observed diastereoselectivity. This was tested in a control experiment with each of the

sulfinamide diastereomers 105. When [SJs-1OSa was treated with 1 .O or 0.1 equiv. of

lithiated 103 at -78 OC. a 71:29 mixture of lO5a and b was obtained after fess than 1

minute. The same ratio was observed when the reaction started with [RIS-1OSb. In an

additional experiment, when [RIS-t04a was treated with a mixture of lithiated 102 and 103

a randomized set of sulfinamide diastereomers was obtained.

lO5a Rh4 = MeLi (low ee)

= MeMgX (99% ee)

Scheme 43

The rate at which the equilibrium is established is dependent on the identity of the

metal ion present. Equilibrium is established quickly with lithiated oxazolidinones (1

minute at -78 OC), but takes more time with magnesium conjugates. This has important

consequences during nucleophilic substitutions at sulhr as the nature of the metal

counterion could influence the sulfinyl stereochemistry. For example, when sulfinamide

[qs-1OSa was treated with methyllithium the optical purity of the isolated sulfoxide was

significantly reduced, while reaction with a methyl Grignard yielded the same sulfoxide in

high optical purity (99% ee) (Scheme 43). Using [SJs-lOSa, Evans and coworkers have

been able to prepare several alkyl aryl sulfoxides (82-87% yield; 90-91% ee) and dialkyl

sulfoxides (78-92% yield; 93->97% ee). An additional advantage to using 104 and 105 is

that they have been shown to be at least two orders of magnitude more reactive than

sulfinate esters. ''O

The Oppolzer group has subsequently show the use of 2-10-camphorsultam (106,

Oppolzer's sultam) as a new chiral sulfinyl transfer agent."' When sultam 106 is reacted

with a sulfinyi chloride, gram scale amounts of sulfinyl sultam 107 are generated as a 6.2: 1

mixture of diastereomers (Scheme 44). Subsequent recrystallization from hexanedether

provided access to the [RIS-sulfinyl suitam in good yield (72%).lU Unlike the Evans chiral

auxiliaries, however, the [Sjs suhr epimer is not accessible.

DMAP, p- tolS(0)CI TM;, r.t., 77%

1 O7

Scheme 44

Subsequent reaction of the Oppolzer sulfinyl sultam 107 with a variety of Grignard

or Reformatsky reagents proceeds with inversion of configuration at the sulfur centre,

affording the corresponding suifoxide in high yield (79-97%) and enantiopurity (96-299%

ee). In addition, the chiral auxiliary can be recovered in 9 1 to 98% yield. Sulfinyl sultam

107 can also react with enolizable and non-enolizable aldehydes to a o r d enantiopure

~ulfinirnines,~'~ a class of compounds with broad synthetic utility. 112 113

Other chiral auxiliaries can be used to prepare diastereomerically pure

sulfinamides. When chiral pyrrolidine derivative 108 was treated with

bromobenzenesulfinyl chloride, suffinamide 109 was obtained in optically pure fonn in

good yield (71-91%, Scheme 45).llJ Acidic alcoholysis in the presence of TFA and

octanol provided the corresponding sulfinate ester in good yield and high enantiomeric

purity (ee>95%).

Scheme 45

An alternative preparation of enantiomerically pure sulfinamides avoids the use of

sulfinyl chlorides by using a diastereomerically pure sulfinate ester as the chiral transfer

agent. Treatment of menthyl sulfinate 70 (which is commercially available in both

enantiomeric forms) with a lithium amide affords the enantio-enriched sulfinamide 110

(Schrme 46).lI5 As in similar reactions of sulfinarnides, this transformation occurs with

inversion of configuration at the sulfbr centre. Chiral sulfinamide 110 can be converted to

acylated sulfinamide 111, which in tum is a source of enantiopure sulfoxides via

organometallic substitution. This latter reaction is advantageous as the nucleophilic

substitution occurs faster with 111 than the corresponding reaction with 70.

O O I I

O O I I 1. n-BSi I I

.iiiii..-S, n-BuLi HN/St.l: 2. acyl agent R' omenhyl RNH2) '

~ . N ~ ? H P O ~ I p-tol p40I R R

R = Bn; t-Bu; R'= Et; Me; (l+MeCH=CH; CF3

Scheme 46

In some cases, progression to chiral sulfinic acids is achieved through sulfenic acid

derivatives For instance, Evans and coworkers were able to show that sulfinarnide 105

could be prepared through an oxidation of the sulfiir, avoiding the use of any sulfinyl

ch~ondes."~ To pursue this strategy, the reaction of arenethiosulfonate 1 12 and

RS-S- Ph I I O

+ N

112 u Bn,..*s*

R = Ph; Me; /-Bu

+ .a

..< ,..- ~ n " ' Bn"'

1OSb (major) 1 0 5

Scheme 47 lithiated 103 leads to sulfenamide 113 (Scheme 47). Unfortunately. the oxidation of 113

occurred wi th low diastereoselectivity (2.5: 1) and the resulting sultinamides (105) had to

be separated by chromatography.

3.4. Project Goals

With the availability of 1-alkenesulfinyl chlorides using the oxidative fragmentation

approach developed by Schwan and coworkers, it was considered that it should be

possible to capture them as sulfinic acid derivatives using a chiral auxiliary. Once isolated

in an enantiopure form, the l-alkenesulfinic acid derivative could then be treated with

vanous organometallic reagents, following the well established Andersen methodology, to

prepare enantiopure l-alkenyl sulfoxides. This method woutd be advantageous as it

would allow for a greater variety of enantiopure a$-unsaturated sulfoxides to be

generated than are currently available using the established methods.

To achieve these goals the project was divided into two main parts. The first

objective was to expand upon the number of I-alkenesulfinyl chlorides that are available

and to examine their capture using achiral alcohols and trimethylsilyl enol ethers. To

realize this goal, several highly substituted I-alkenyl sulfoxides were prepared bearing the

2-(trimethylsilyl)ethyl group. As indicated earlier, the 2-(tnmethylsilyl)ethyl group has

been found, in most cases, to induce C-S bond cleavage to afTord the sulfinyl chlonde

under certain oxidative fragmentation conditions. The second objective was to examine

the capture of available I-alkenesulfinyl chlorides using either chiral alcohols or amides to

afford enantiopure a,P-unsaturated sulfinate esters or sulfinamides, respectively. The

sulfinic derivatives would then be treated with several organometallic reagents to examine

the preparation of enantiopure a$-unsaturated sulfoxides.

As will be discussed in detail in the foltowing two chapters, several, new, highly

substituted I-alkenyl 2-(trimethylsilyl)eihyl sulfoxides were prepared. These compounds

readily underwent oxidative fragmentation to afEord the corresponding sulfinyl chloride

and sequentially the formation of l-alkenesulfinate esters. It was also found that in a

number of cases l-alkenesulfinyl chlorides showed a predisposition to be captured as an

diastereomerically enriched suifinate ester using a chiral alcohol and could then be isolated

in an enantiopure form by crystalliation. Most of these sulfinates readily undenvent

nucleophilic substitution at sultiir to afford a vatiety of enantioenriched a,&unsaturated

sulfoxides.

4. Results and Discussion: Preparation and Achiral Transformations of 1-Alkenesulfinyl Chlorides.

As indicated in the preceding chapters, sulfinyl chlorides can be used in a number

of synthetic strategies. Recent efforts for preparing novel 1-alkenesulfinyl chlorides" have

provided an avenue to tiirther expand the synthetic utility of sulfinyl chlorides. On this

basis, this chapter is divided into two sections. The first section will outline the

preparation and oxidative fragmentation of 1-alkenyl 2-(trimethylsilyl)ethyl sulfoxides to

afford a group of highly substituted 1-atkene suifinyl chlorides. The second section will

examine the capture of a$-unsaturated sulfinyl chlorides as P-keto sulfoxides. The next

chapter will explore the preparation of enantiopure vinyl sulfinate esters fiom l -

alkenesulfinyl chlorides and their subsequent conversion to enantioenriched vinyl

sulfoxides using the well known Andersen methodology.

4.1. Preparation and Oxidative Fragmentation of 1-Alkenyl 2- (Trimethylsilyl)ethyI Sulfoxides

In order to lùlly explore the oxidative fragmentation method to generate highiy

tunctionalized vinyl sulfinyl chiorides it was necessary to prepare a nurnber of highîy

tunctionalized vinyl sulfoxides bearing the 2-(trimethylsiiyi)ethyl functionality. The

methods used for the preparation of the sulfoxides were dependent upon the degree of

double bond functionality required. One set of sulfoxides was prepared with full

substitution on the double bond, a second set was prepared with three substituents and the

final set with only two substituents. The sulfoxide bearing sirnply a vinyl group has been

previously prepared. When it was treated with S02C12, however, no sulfinyl chloride was

obtained, but instead the a,P-dichlorination product resulted (Scheme 5).35

The first set of sulfoxides was prepared starting tiom disulfide 114 (Scheme -18).

The disulfide was chosen because it was previously found that its treatment with SOzC12

affords the corresponding sulfenyl chloride 1 1s3' that can, in tum, be readily added across

the triple bond of an alkyne to generate the vinyl sulfide. Subsequent oxidation with

mCPBA affords the desired 1-alkenyl 2-(tnmethylsilyl)ethyl sulfoxides (1 16). The yields

of several sulfoxides prepared in this manner are s h o w in Table 3.

114 -78°C 115

1 TMSCGCR' (or R'> -78°C (or RT)

R'

1 16i: RI; R' = CI; Ph e: R'; R' = H; CI b: R'; R' = 11-Bu; CI d: R'; R' = CI; H

Scheme 48

The initiai preparations were carried out such that the vinyl sulfides were oxidized

in silir immediately following formation of the sulfide. Formation of the sulfide could be

monitored through TLC and GC analysis of the reaction. It was found, however, that

yields could be improved by as much as 10-20 % if the crude sulfide was isolated pnor to

oxidation. Sulfide isolation simply involved concentrating the reaction mixture to remove

I solvent and any volatile by-products. H NMR spectra of the cmde sulfides generally

showed very little contamination. The sulfoxide was then prepared by dissolving the

sulfide in CH2CI2 and adding mCPBA as the oxidant.

Table 3: Preparation of 1-Alkenyl2-(Trimethylsilyl)ethyl Sulfoxides

TMS

Structure Yield ( O h )

a: Warmed IO RT afîer addition of S02C12

The addition of sulfenyl chlorides to alkynes generally lads to the formation of the

tram adduct. 116.117.118 This conclusion is partly based upon the tram addition of sulfenyl

chlorides across olefins to generate the tram-B-halo sulfides."' The addition to olefins

proceeds through an episulfonium salt intermediate 117 (Scheme 49) followed by

predominant or exclusive attack of the chloride anion at the more positively polarized

carbon. The addition of sulfenyl chlorides across alkynes (Scheme 49) has been shown to

proceed in a similar manner through an unsaturated thiirenium ion (l18).lL8 In certain

instances the sulfenyl chloride addition yields the cis adduct as the isolated product. While

this contradicts the evidence indicating the stereospecificity of the addition, in these cases

the cis adducts are the result of the isomerization of the primary tram adduct."' Certain

isolated trms adducts, upon standing in a solution containing 5% HCI.

Scheme 49

have been shown to isomerize to their cis isomers. To generate sulfoxide 116c, the

addition of sulfenyl chloride across the triple bond was camed out at - 78 O C . For the

preparation of 1164 however, the addition was done at room temperature. In this case

the sulfenyl chloride adds cis to the alkyne to form the geometric isomer of 116c. It is

believed that at the elevated temperature the TMS tunctionality overrides the need for a

bridging S atom in the thiirenium ion, allowing formation of the cis adduct. Sulfoxides

116c and 116d were difficult to isolate with good reproducibility and as such the yields are

presented as a range (Table 3; Entries 3 &4).

Sulfoxides I l9 were readily prepared fiom their corresponding silylated precursors

by employing a chemoselective protiodesilylation (Scheme 50; Table 4). Sulfoxide 1 19d

could not be prepared in this manner, however, as it was found that 116d decomposed

under the protiodesilylation conditions. This is presumably due to the fruns

R ' I ~ / S * ~ S - K2C03 MeOH R2 % '\/\rnS TMS H

120: R'; R2 = CI; H

R' O R' O II - K2c03 R2+s\/\MS

MeOH TMS H

119r: R'; R2 = CI; Ph e: R'; R2 = H; CI b: R I ; R2 = ,,-Bu; CI d: RI; R' = Cl; H

Scheme JO

Table 4: Preparation of 1-Alkenyl 2-(Trimethylsilyl)ethyl Sulfoxides via Protiodesilylation.

Structure Yield (%)

o: Protiodesilylation done prior to oxidation of sulf~de.

6 1

disposition of the chloride and the targeted silyl group. Preparation of sulfoxide ll9d was

achieved through protiodesilylation of sulfide 120 prior to oxidation (Scheme 50).

An analysis of the vinyl hydrogen coupling constants for 119c indicates fruns

geometry of the double bond confirming the tram addition of sulfenyl chloride to form

116c. In a similar manner the cis addition of sulfenyl chloride to form 116d is recognized

through the cis coupling constants observed for 119d. Evidence for the geometry

assigned to t 16b and 119b can be found through the appearance of the allylic CH2 group

(in the 'H NMR spectrum) for both sulfoxides. In each case the CH2 is part of an ABX2

system with the chemical shift difference of the gerninal AB hydrogens the result of the

asymmetry of the cis sulfinyl group.

The assignment of the double bond geometry to 116a and 119a provided a more

interesting challenge. Based upon the evidence presented below and later in this section,

the suIfoxides have been assigned the Z geometry. Using the alkene additivity rule on

119a was not particularly informative as the actual chemical shift of the vinyl hydrogen

falls about halhay between the predicted chemical shift values for the E and Z isomers.

The predicted values, however, for the E and (2)-2-phenylethenyl sulfoxides, previously

reported by the Schwan group, are of a higher ppm value than those actually ob~erved.~'

Using these values a correction can be applied to the chemical shitl observed for 119a

which favours the assigned Z geometry. As well, by heating the sulfide formed through

the addition of 115 to phenylacetylene, no change in the geometry was observed. This

suggests that the thermodynamic product had probably already formed. To explain the loss

of the usual stereoselectivity of the sulfenyl chloride addition reaction it is suggested that

the mechanism does not involve a thiirenium ion like the one shown in Scheme 49.

Instead, through a combination of the p-silicon effect and benzylic stabiiization, the

geometry directing influence of the bridging sulfiir is overcome, allowing isomerization to

occur. It has been found that Br2 adds across (0-2-(trimethylsi1yI)styrene to afford the

~ t r adduct. This exemplies that the strength of the p-silicon effect and benzylic

stabilization can overcome the stabilization offered by the bridged bromonium ion, lending

support for the proposed mode of addition described above.

An alternative procedure was followed to generate sulfoxide 121 using suifinate

122. Sulfinate 122 was prepared using a previously reported procedure (Scheme fil)."

The last step of the preparation of 122 is of interest. In order to achieve preferential

fragmentation of the t-BU-S bond, to generate the corresponding sulfinyl chloride (S), the

reaction was canied out in diethyl ether rather than CH2C12, the solvent typically used for

an oxidative Fragmentation. When the reaction was camed out in CH2C12, several

Scheme 51

contaminants were observed, including 2-(trimethylsi1yl)ethyl chloride (2) and 2-methyl-2-

propenesulfinyl chloride, the latter indicating scission of the C-S bond of the 2-

(trimethylsilyl)ethyI grotip.3J In diethyl ether the reaction proceeded cleanly to generate 2-

(trimethy1silyl)ethanesulfinyl chloride (S), which is subsequently captured as 122 using

MeOH and pyridine. Sulfinate 122 was then treated with methyl acetylide anion, prepared

according to the method reported by Suffert and to afford 123. Sulfoxide 121

was finally generated through DIBAL-H reduction of the triple bond to give the tram

isomer.

With a suitable collection prepared, sutfoxides 116, 119, and 121 were then treated

with S02Clz. As discovered for aryl and alkyl 2-(trimethyIsi1yl)ethyl su l f~x ides ,~~~~" the 2-

(trimethylsilyl)ethyl group generally induced cleavage of the C-S bond to afford the

conesponding sulfinyl chloride. Upon warming to room temperature, analysis by TLC

indicated consumption of the staning sulfoxide and the appearance of a significantly more

polar compound, which moved and then stalled on the TLC plate, a behavior consistent

with sulfinyl chlorides. In each case where TLC analysis indicated the formation of the

sulfinyl chloride, an IR of the crude reaction mixture was obtained. The S=O stretches

observed were typically in the 1160-1 143 cmmL range, which is also consistent for sulfinyl

ch lori de^.^'

The mechanism proposed for the oxidative fragmentation is s h o w in Scheme 52.

The first step involves electrophilic addition of chlorine to the sulfûr centre to generate the

pentacoordinated chlorosulfoxonium sait 124. With the probable assistance fiom the

silicon, the chlotide ion then attacks the a-carbon, displacing the suIfUr moiety. This

results in the formation of the sulfinyl chforide and the 2-(trimethylsilyl)ethyI chloride (2)

by-product, which has k e n consistently observed by 'H NMR analysis of the crude

sulfinyl chloride mixture. The sulfinyl chlorides were subsequently captured as their

corresponding cyclohexane or 3-phenyl-l-propanesulîinate esters, which were tùlly

characterized to determine the structure of the sulfinyl chloride. The results of the

oxidative fragmentation experirnents are presented in Table 5.

Scheme 52

The oxidative fragmentation of the more substituted sulfoxides 116(a,b,d) and

119(a,b) proceeded cleanly to afford sulfinates 125(a-c), 126(a,b) respectively (Scheme

53 and 54). In the case of suifoxide 116c isomerization of the double bond was observed,

affording the same reaction product as that obtained fiom 116d, sulfinate 125c (Scheme

54). To determine when the isomerization of lldc occurs, a 'H NMR spectrum of the

crude reaction mixture was obtained for each of the sulfinyl chlorides generated fiom 1 l6c

and 116d, respectively. For each sulfinyl chioride the chemical shift of the vinyl hydrogen

was identical suggesting that the double bond geometry was the same in

Table 5 : Oxidative Fragmentation of 1-Alkenyl2-(Trimet hy1silyl)ethyl Sulfoxides

Strrting Sulhate Structure Alcohol S=O Stretch Yield of Sulfoxide R* ~2 ~3 (R~OH) (cm-')' Sulfinate (%)b

I 116a Cl Ph TMS

2 t16b il-Bu CI TMS

3 116c Cl H TMS

4 1 l6d Cl H TMS

5 1 19a CI Ph H

6 119b IFBU Cl H

7 119c H Cl H

8 1196 Cl H FI

9 12 1 H Me H

Cyclohexanol

Ph(CH2)3OH

Ph(CH2)30H

Ph(CH2)iOH

Cyclohexanol

Ph(CH&OH

Ph(CHî)30H

P h(CH2)30H

P h(CH2)30H

n IR strctching frcquency of S=O of conesponding M ~ n y l chlaridc. b Uscd 1.2 eq of SO:CI2 to generate sulfinyl chloride unlcss othenvise indicated. c Uscd 0.7 q of SO2CIi to gcneratc sulfinyl chloride. d Usc of 1.2 cq of S02C12 to gcneraic sultinyl chloride lead to reduced yields (33%) e Usc of 1.2 cq of S02C12 afforded 33% tram isomer, 0.7 q gavc 27% cis and 32% watts.

1251: R' ; RI; R~ = CI; Ph; TMS; R~ = c-C6Hi

1 2 6 ~ R'; R'; R~ = Cl; Ph; H; R~ = C-C~H,

125b: R' ; R'; d = +Bu; Cl; TMS; R~ = -(CH2),Ph

126b: RI; R'; R3 BU; Cl; H; R~ = -(CH&Ph

Scheme 53

TMS 116cord

TMS l25d

Scheme 54

each case. This implies that the isomerization of the double bond of 1 l6c occurs prior to

the formation of the sulfinyl chloride. It is believed that the isomerization is the result of

the chlonde anions present in the reaction mixture. The chloride anion would be available

to add to the double bond and then subsequently eliminate to afford the more stable

isomer. This addition most likely occurs to the chloro sulfoxonium intermediate (124),

due to the greater electrophilicity of the double bond. The absence of any additional

peaks, with the exception of the 2-(trimethylsilyl)ethyl chloride (2; see Scheme 3) by-

product. indicates that the isornerization was cornplete prior to the 'H NMR analysis.

To determine the double bond geometry of 125d an NOE difference spectrum was

obtained. Irradiation of the methyl protons of the vinylic TMS group detectably enhances

the vinyl hydrogen (Figure 5) indicating that the vinyl H and vinyl TMS groups are cis to

each other. Further evidence for the double bond geometry is provided by

protiodesilylation attempts of 125d. While substantiai decomposition was observed, the

coupling constants in the 'H NMR spectrum of the crude reaction mixture indicated a cis

geornetry of the double bond of the desilylated product. Assurning that desilylation occurs

without isomerization of the double bond, this confirms the (2) geometry assigned to

sulfinate 125d.

enhancement O observed I I

L irradiated protons

Figure 3: NOE irradiation of the vinyI suifinate ester.

The stability of the isolated cis chloro product (125d) over that of the tram chloro

product can be explained in tems of a hyperconjugation efTect between the silyl group and

the anti-bonding orbital of the Cl (Figure 6). The stabilizing influence of electron

donation from the silicon-carbon bond into the a* orbital of the chlorine-carbon bond can

only occur if these fimctional groups are tram to each other.

Figure 6: Slabiliring irflt~ence of the Si-C botd

Prompted by the double bond isomerization during sulfinyl chloride formation, a

reexamination of the double bond geometry assigned to sulfinates 125(a,b) and 126(a,b)

was performed. As in the case of the starting sulfoxides 116b and 119b, the AB pattern

exhibited by the allylic CH2 group of l2Sb and 126b is again indicative of the close

proximity of the cis asymmetric sulfinyl group, confirming the assigned geometry of the

double bond. To confinn the structure assigned to l2Sa and l26a, a protiodesilylation of

125a was carried out in order to convert it to 126a. This contirmed that both l25a and

126a have the same relative positioning of sulibr and chlorine. Next, the chemical stiifis of

the vinyl hydrogens of sulfinate 126a, sulfoxide 119a, and the intermediate sulfinyl

chloride were compared. The trend of increasing chernical shifts in the order of sulfoxide

< sulfinate < sulfinyl chloride is consistent with the trend previously e~tablished.~'

Furthemore, the S=O stretch of the sulfinyl chiorides generated from 1 l6a and 119a

(1 153 and I 154 cm" respectively) agrees with the higher S=O stretching fiequency

previously detennined for the (E)-2-phenylethenyl sulfinyl chioride (1 145 For the

(2)-2-phenylethenyl sulfinyl chloride (S=O, II30 cm'') the stretching fieqcency is

considerably srna~ler.~~ Both of these pieces of evidence support the Z geornetry assigned

to 1251 and 126a.

The oxidative lragmentation of the cis and tram chloro sulfoxides 119c and d

proved to be more challenging (Scheme Sj). Fragmentation of 119c using established

conditions (i.e. f .2 equiv. of SOzCI2) afforded the sulfinate product 126c, but in low yield

(33%). Decreasing the amount of S02Clz to 0.7 equiv. provided an improvement to the

yield (Table 5). As in the case of sulfoxide 116c, the oxidative fiagrnentation of cis chloro

sulfoxide 119d led to isomerization of the double bond. When treated with 1.2 equiv. of

SO2CI2 the unexpected t m s chloro sulfinate 126e was isoiated in a 33% yield. Upon

decreasing the amount of S02Clz to 0.7 equiv. a mixture of both frans (126c) and cis

(126d) sulfinates was generated (27% cis; 32% m s ) . The 'H NMR spectrum of the

cnide reaction mixture indicateà sulfinyl chloride was present in the cis configuration. This

suggests that the isomerization observed in sulfinate l26d occurred following the

formation of the sulfinyl chloride.

CI O 1. S0,Ck; O -7S°C

II

LSoTMS 2. PUCH&OH; C I - S ' O v P h 1 19d 126c - Iruns: 32%

K$03 126d - cis: 27%

Formation of the vinyl sulfinate was not observed in the fragmentation of sulfoxide

121. Instead, the a$-dichlorination product 127 was isolateci in 26% yield (Scheme 56).

Although the crude sulfinyl cMoride was observed by TLC and IR (S=O stretch 1145 cm'

1 ), frorn the 'H NMR spectrum of the crude sulfinyl chloride it cuuld not

Scheme 56

be determined whether chlorination of the double bond had occurred. Confirmation of the

rnolecular formula of 127 was done using high resolution mass spectroscopy.

4.2. Carbon Capture of 1-Alkenesulfinyl Chlorides

To tiirther evaluate the synthetic utility of 1-alkenesulfinyl chlorides, several

sulfinyl chlorides were prepared and treated with TMS enol ethers to form aJ-

unsaturated B-ketosulfoxides. As reviewed in the introductory chapter (section 3.1), P-

ketosulfoxides have a variety of uses in organic synthesis. With a procedure to prepare l-

akenesulfinyl chlorides readily available, the method used by Meanwell and ~ o h n s o n ~ for

the reactions of methane- and benzenesulfinyl chlorides with TMS enol ethers was adapted

and the subsequent capture examined. The sulfinyl chlorides were prepared through an

oxidative fragmentation of a series of 1-alkenyl sulfoxides (129-130) bearing either a

diphenylrnethyl (DPM) or p-methoxybenzyl (PMB) functionality as the leaving group.

Both the DPM and PMB groups have demonstrated a propensity to facilitate cleavage of

the C-S bond and generate the desired sulfinyl chloride3' in a method analogous to the one

outlined for 2-(trimethylsilyl)ethyl sulfoxides.

The preparation of sulfoxides 129 and 130 has been previously rq~orted.~'

Sulfoxides 129a-e and 130a-e were prepared via a stereoselective ring opening of the

corresponding ariti-thiirane S-oxide. The ring opening is achieved, through a L W S

mediated regioselective deprotonation to generate the (E)-1-alkenesulfenate anions,'*l

which were then captured with either DPM-Br or PMB-Br to &ord the desired sulfoxide

(Scheme 57). Good yields of the sulfoxides are typically achieved with the exception of

129d1130d. The ring opening reaction in these cases gave rise to both of the possible

isomers with the Ph group in either a trans or geminal position.

DPM DPM-Br

Scheme 57

An alternative route to 129d130a involved an acid induced reaction between

PMB-OH (or DPM-OH) and 2-mercaptoethanol (Scheme 58). The resulting hydroxyethyl

PMI3 sulfide was then oxidized with mCPBA. The hydroxysulfoxide was mesylated, and

an elimination reaction completed the ~ynthesis.~'

0"

HS II O

-OH B F & O II + -

2. DBU J ' . C PMB-OH HO

(or DPM-OH) n=O C = PMB; 129a, 71% mCPBA C = DPM; 130a, 65%

Scheme 58

The final sulfoxide examined, 129f, was prepared through an addition of PMB-SH

across the triple bond of methyl propiolate (Scheme 59). Under the established conditions

the thiol adds tram across the triple bond. The resulting (4-sulfide was then oxidized

with mCPBA to afford sulfoxide 1291.

PMB-SH

Scheme 59

A selection of oxidative fragmentations was carried out using 129 and 130 to

afford sulfinyl chlorides 10 and 131, and the desired P-ketosulfoxides (132) were

generated using silyl ethers 133a-c with or without the use of a Lewis acid catalyst

(Scheme 60; Table 6). Tic14 was found to be the most effective Lewis acid catalyst.

Stoichiometric amounts of Tic& or other Lewis acids were less effective and substantial

decomposition was observed. In the case of 132d, the use of K2C03 as the additive

proved to be the most efficient. In each case the isolation of the product proved to be

difficult due to decomposition dunng the purification. The best conditions for purification

were rapid chromatography on neutral alumina. The best yields were achieved using a-

styryl trimethylsilyl ether 133a while products from propenyl trimethylsilyl ether 133b and

1-cyclohexenyl trimethylsilyl ether 133c were less accommodating. The nucleophile 133b

was found to be very sluggish in the reaction with sulfinyl chlonde and moreover the

resulting products were particularly predisposed to decomposition during the purification.

OTMS

'Cl

132 (see Table 6 for structures)

133i: R ~ ; R' = Ph; H 4. ' l33b: R , R =Me; H 4 5 133~: R ; R = -(CH2)j-

Scheme 60

Substantial decomposition was observed in the reactions involving the sulfinyl

chlorides derived from 129f. For both silyl ethers (133(a,b)) examined, 'H NMR analysis

of the crude reaction mixture allowed the detection of the corresponding P-ketosulfoxides.

Upon chromatography, however, formation of rearrangement products 134a,b was

evident. Spectral data collected for 134 were consistent with the assigned structures. In

particular. the ABX pattern in the 'H NMR spectra and the absence of a ketone stretching

frequency in the IR spectrum were very informative. 1,4-Oxathiin S-oxides 134 are

believed to form through enol or enolate addition to the highly electrophilic double bond

(Scheme 61).

Table 6: Preparation of 1-Alkenylsulfinylmethyl Ketoaes

OTMS Starting Product Y ield Sulforide 4

Et5

R' R'

6 116b Ph H R' O R' = CI; R2 = ri-Bu

133a R 2 + ~ J Ph 9%; 132e TMS R' = n-Bu; R' = CI

9%; 132ee

a Could not be isolated in a pure fonn, observai traces of 0-keto suifoxide

Scheme 61

The reverse of the type of reaction shown in Scheme 61 has been recently utilized

in the preparation of P-keto suifoxides (Scheme 62). Starting fiom 135 Caputo and

coworkers reported that treatment with LDA deprotonates the a-alkyl h~dr0gens.I~~ The

Scheme 62

76

resulting anion then rearranges to the enolate, which upon protonation, affords the ethenyl

P-keto sulfoxide 132a.

An attempt was made to generate P-keto sulfoxides via the oxidative

fragmentation of 2-(tnmethylsilyl)ethyl sulfoxide 116b. Isomers 132e and 132ee were

isolated following chrornatography. tt is believed that isomerization of the double bond

occurs as a result of the excess chloride ions present, not only from the SOzCl2, but fiom

the titanium catalyst as well. This is inconsistent because, as shown in the previous

section, the double bond of tldb does not isomerize when captured as sulfinate 125b.

The geometry of 132e and l32ee was assigned by examining the splitting pattern of the

vinyl CH2 group. For 132ee, a distinct MX2 pattern is observed. arising from its

proximity to the sulfinyl group, while for 132e a multiplet is obsewed. The latter implies

that the tram sulfinyl group does not significantly influence the magnetic environment of

the allylic methylene protons.

4.3. Conclusions and Future Work

In conclusion a group of highly substituted 1-alkenyl 2-(trimethylsi1yl)ethyl

sulfoxides have been prepared in moderate to goad yields and subsequently treated with

SOZC12 to afford the corresponding sulfinyl chlorides. They were then captured as their

corresponding sulfinate esters using either 3-phenylpropanol or cyclohexanol in moderate

to good yields, comparable to the earlier results obtained for the preparation of sulfinate

ester 8(a,b). For several sulfoxides not bearing an alkyi or aryl substituent on the double

bond, isomerization of the double bond geometry was observed during or shortly

following the oxidative fragmentation. The double bond geometry was assigned using L~

NMR analysis of the sulfinate product. In one example, in addition to the formation of the

sulfinyl chloride and ultimately the sulfinate ester, dichlorination of the double bond was

also observed. This contrasts with previously reported r e ~ u l t s ~ ~ for less substituted 1-

alkenyl 2-(trimethylsi1yl)ethyl sulfoWdes whereby oxidative fragmentation did not occur.

tn those examples only dichlorination of the starting material was o b s e r ~ e d . ~ ~ In each

case, IR analysis of the cmde sutfinyl chloride was obtained, confirming the formation of

the sulfinyl chloride.

This methodology for preparing 1-alkenesulfinyl chlorides, together with previous

Schwan efforts for preparing alkyl and aryl sulfinyl chlorides, affords access to most types

of sulfinyl chlorides. As indicated in the introductory chapters, sulfinyl chiorides can be

utilized in a number of synthetic strategies for the preparation of a large variety of

compounds, rnost notably sulfinate esters. These compounds can then undergo funfier

transformations to provide a large number of compounds. Future work in this area will

examine extending this methodology to the preparation of 1-alkynesulfinyl chiorides.

Several 1-alkynyl sulfoxides bearing either 2-(trimethylsilyl)ethyl, DPM or PMB

Functionalities will be prepared and treated with S02C12 to determine if the preparation of

I -alkynesulfiny l chlorides can be achieved.

it has also been shown that P-keto sulfoxides can be prepared directly fiom a$-

unsaturated sulfinyl chiorides. These compounds, however, were found to be difficult to

purify and seemed to undergo enolization quite readily. In two instances the P-keto

sulfoxides could not be isolated, but instead rearranged during chromatography to f iord

1 .cl-oxathiin S-oxidas.

5. Results and Discussion: Targeting the Stereogenic a,P- Unsaturated Sulfinyl Group.

As outlined in Section 3.3.1 the Andersen methodology is one of the most

important routes available to the synthetic chemist for the preparation of enantiopure

sulfoxides. One of the main limitations of this chemistry is the availability of the requisite

sulfinyl chlorides. With a practical method established for the synthesis of 1-alkenesulfinyl

chlorides it was perceived that application of the Andersen methodology might provide a

useful rneans for the preparation of homochiral vinylic sulfoxides.

5.1. Preparation of Enantiopure 1-Alkenesulfinate Esters.

The initial experiments of the project were designed to examine a wide range of

conditions to determine which sulfinate esters would provide optimal results. To

accomplish this goal an array of small scale experiments was carried out in which sulfinyl

chlorides 10 and 131 b-f were treated with K2C03 and various chiral alcohols (Scheme 63),

chosen on the basis of established synthetic procedures as well as their availability and

cost. These alcohols were: menthol,' cholestero~,~ diacetone-D-glucose (DAG),~* (IR,

2~)-(-)-1rn~~s-2-~hen~lc~lcohexanol,'~~ borneol, and fenchyi alcohol (Figure 7). From

these experiments three important pieces of information were gathered: (i) use of the

established procedure for 1-alkenesulfinate formation exhibited very little kinetic

stereoselectivity; (ii) the diastereomers could not be separated using silica gel

chromatography; and (iii) with the exception of cholesterol, ail alcohols led to an oily,

inseparable mixture of sulfinate diastereomers. It was hoped that crystallization of the

cholesteryl sulfinates, which were consistently a solid mixture of diastereomers, would

provide access to enantiopure 1-alkenesulfinate esters.

II (chiral alcohols) II

C l - K2C03 R ~ ~ ' ' o R *

R' -78" C to RT R-

10 and 131

10 R'; R' = H; H 131 R1 = (b) t-Bu; (d) Ph; (e) PhCH2CH2; (O C02Me

R ~ = H

131 (e) R I ; R' = -(CH&

Scheme 63

HO'''''' 9 menthol

OH bomeol

cholesterol

OH tram-2-phenylcyclohexanol fenchyl alcohol

Figure 7: Chiral alcohols exami~ted for reactivity wiih I-alkenesir,finyl chlorides.

Starting with the simplest system, larger scale reactions using sulfinyl chloride 10

were examined (Scheme 6 4 with cholesterol as the chiral auxilliary. As shown in Table 7,

when KzC03 was used as the base both low yields and de's of sulfinate 136a were

observed (Entries 1 and 2). The determination of the de and the absolute configuration

will be discussed in a later section. The reproducibility of these results was also poor;

possibly resulting from solubility problems encountered with the cholesteroV KzC03

suspension at -78 O C .

Crystallization of the diastereomeric mixture did not result in any improvement to

the de. Various experiments were carried out in an attempt to optimize both the yield and

de of the cholesteryl sulfinate. Pyridine, (iPr)lEtN and sparteine were examined as bases

under several temperature and solvent conditions. Unlike the DAG rnethodology reponed

by Alcudia and coworkers 88. 97-100 the achiral amine bases did not fiord high yields nor

high stereoselectivity (Table 7). It was suggested, based upon the work reported by

Mikolajczyk and cow~rke r s , ' ~ that switching to the chiral amine bases quinine and

quinidine might provide a means to improving both yields and de's. Quinine and quinidine

are isomeric alkaloids with the difference between thern arising fiom the stereochemistry

at the labeled carbons (Figure 8).

O cholesterol O I I 1 I

reaction conditio; ~ S \ O C h o l

10 136a Chol: (-)-cholesteryl

Scheme 64

Table 7: Preparative Approaches to Cholesteryl Ethenesulfinate Using Various bases, Solvents and Temperature Conditions.

Conditions' Yield / deb

Base Temp (OC) Solvent

1 KzC03

2 KzC03

3 pyridine

J pyridine

5 pyridine

6 pyridine

7 (IPr)*EtN

8 (?r)2EtN

9 (iPr),EtN

10 sparteine

I f sparteine

CHiC12

CH2Cll

CHzC12

CH2C12/ toIuenec

CH2Cl2

THF

CH2Ch

toluene

CH~CI.L

CHzC12

CH2Clz

n Addition inode: alcohol and base added to suKnyl chloride sol'n b Sufinate 136a was obtained as a mixture of diastenomers; de refen to initiai de afîer cluomatognphy; yields and de's as determined from 'H NMR (U10 MHz) of sample containing sulfinatc and either PMB or DPM aicohol. c SoIubility problems were encountered in pure tolwnc.

Quinine Quinidine

Figure 8: Chiral mitie bases: qtrinine and pririidine.

Using the chiral amine base, sulfinyl chloride 10 was again treated with cholesterol

to afford sulfinate 136a (Scheme 65;Table 8). Under these conditions improvements to

both the yield and de, as well as access to either sulfiir epimer, were achieved. Using

quinine, sulfinate 136a was enriched in the [RIS isomer while quinidine afforded

enrichment of the [SIS isomer. Again, in an effort to achieve higher de's and yields,

various conditions were manipulated including temperature, solvent and mode of addition

of the reactants. As shown in Table 8 (Entries 7 and 14) the best yields and de's were

achieved using CH2CI~ as the solvent, increasing and then holding the temperature from - 78 O C to -20 O C until completion of the reaction and finally, transfemng the cmde sulfinyl

chloride solution to a precooled solution of cholesterol and base. Unfortunately, all

attempts to isolate either sulfur epimer in an enantiopure form met with little success.

Atternpts to isolate [RIs-136a through crystallization fiom various solvents such as

acetone, hexanes, pentanes and ethanol, resulted in a decrease in the de, while atternpts to

isolate [SJs-136a showed no improvement (Table 8).

cholesterol

quinidine 1 O reaction conditions 136a

Scheme 65

Table 8 Preparative Approaches to Cholesteyl Ethcnesullinate Using Quinine or Quinidine.

- - --- -

Conditions" Yield / deb Recrystallizationsc

Base Temp ("C) ~dd 'n ' de yield

2 quinine -78 A 3%

6 quinine -78 to n B 48% / 40% [RIs 24%[RIs 19%

7 quinine -78 to -20 B 57% / 47%[R]~ - - 8 quinidine -78 A 49% 1 25%[S]s 26%[SIs 6%

9 quinidine' -78 A 340/6/ 7%[SIs - - 10 quinidine' -78 B 27?d/ 30%[S]~ - - 11 quinidine -78 to rt A 16% / 17%[S]s - - 12 quinidine -78 to n B 10% 1 3O%[S]s - - 13 quinidine -78 to -20 A 11% / 19%[S]~ - - J quinidine -78 to -20 B 55% / 22%[S]s - -

a Solvent was CH2C12 unless othemise noted. b Sulfinate 136a was obiained as a mixture of diasteremers; de refcrs to initial de afler chrornatography. c Rccrystallization solvent was hemes. d Addition mode A: alcohol and base added to d i n y l chloride sol'n: addition mode B: suEnyl chloride added IO alcohot and base sol'n. e Rcaction run in THF. f Yield detennined from 'H NMR (MO MHz) of sample containhg suifînate and DPM alcohol. g Rcaction run in totuene.

With improved yields and de's observed in the preparation of cholesteryl sulfinate

136a. it was then decided to reexamine the sulfinate capture of 10 using other chiral

alcohols with Our new set of reaction conditions (Table 9). With the exception of

menthol, low yields and de's were observed in each case. For menthol, a moderate yield

of the sulfinate was obtained. Unfortunately, as was observed in Our preliminary

investigation, the diastereomeric mixtures of sulfinates were oily, precluding crystallization

as a means of separating the iwmers. With the inability of cholesterol or other chiral

alcohols to afford an enantiopure ethenesulfinate ester, a series of experiments were

undertaken in an attempt to capture 10 using chiral amides.

Table 9: Preparative Approaches to Chiral Ethenesulfinates Using Various Chiral Alcohols.

- - -

Conditions' Y icld 1 deb

Alcohol Base Temp ( O C )

1 menthol quinine -78 47% 1 15%

2 borneol quinidine -78 10% / 20%

3 fenchyl alcohol quinidine -78 7% 1 33%

4 DAG quinidine -78 4 % ' 1 40%

5 pantolactone quinidine -78 to rt <5%'/ 41%

a Addition mode: alcohol and base added to sulfinyl chloride sol'n; ail reactions run in CH2CI2. b Sulfinaies were obiaineci as an oiiy mi.vture of diastemmen; de refen to initial de after cliromatography; yields and de's as detcnnined from 'H NMR (JO0 MHz) of sample containing sulfinate and either PMB or DPM aicohol. c 'H NMR (400 MHz) very messy. noi much product obscrved.

The first amide examined was Evans' chiral auxiliary 103 (Schrme 66)."O

Following the formation of 10, it was transferred to a prepared solution of lithiated 103.

M e r slowly warming to rt, consumption of 10 was observed by TLC. Unfortunately, the

formation of sulfinamide 137 was not observed. Similar results were obtained when 10

was treated with lithiated Opppoizer's Sultam 106 (Scheme 66).11' These results are

surprising as diastereomerically enriched sulfinamides can be readily prepared from alkyl

or aryl sulfinyl chlorides. Il0, l l l

N u

O n,f-** (fiom 103)

(from 104)

Scheme 66

Based upon this lirnited success for the l-ethenesulfinyl chloride system, attention

was turned to other 1-alkenesulfinyl chlorides. When sulfinyl chloride 131f was treated

with cholesterol and &Co3, sulfinate ester 136t was isolated in good yields and enriched

in the [RIs isomer (Scheme 67; Table IO). As observed for 136a, consistent yields and

de's were difficult to achieve resulting from a solubility problem encountered with the

cholesteroVK2C03 solution. Unlike the earlier sulfinate, however, enantiopure [Rs]-1361

could be isolated after a single crystallization fiom hexanes in 26% yield. Subsequent

crystallization of the mother liquor afforded a total 39% recovery of the [RIS sulfinate. In

l l cholesterol

O E-"Ci base s-. I I

131f reaction conditions E OChol 136f

E: COzMe

Scheme 6 7

Table 10: Preparative Approaches to Cholesteryl Sulfinate (1369.

Conditions' Yield / deb Rec ystallizationsc

Base Temp ('C) ~ d d ' n ' de yield

1 KzC03 -78 to -20 A 63% 156%[R]s 100%[RIs 26%'

2 quinine -78 A 75% 1 1 6%[SIs - 3 quinine -78 to -20 B 89% 1 6%[S]s 86%[RIs 20%

4 quinidine -78 A 71%/20%~]s - - 5 quinidine -78 to -20 B 80% 1 12%[R]s 64%FJs 3 8%

a Solvcnt was CH2Clz. b Sulfinate 1361 was obtaincd as a mixture of diastereomers; de refen Io initial de after chromatography. c Values in parentheses refer to a 2* recrystailization. Ciymllization solvent was he.uanes. d Addition mode A: alcohol and base ad&d Co sulf~nyl chioride sol'n; addition mode B: sulfinyl chloride added to alcohol and base sol'n. e An overall yield of 39% was observeci d e r additional recqstallizations of the mother liquor.

an attempt to improve the reproducibility of the results, the information gathered during

the 1-ethenesulfinyl chloride experirnents was applied to the preparation of 136f. As

shown in Tabk IO, the use of quinine or quinidine significantly irnproved the yield of 136f,

albeit with a much reduced de. Subsequent crystallization, however, afforded the

enantiopure sulfinate. Again, access to either sulfur epimer was possible depending upon

the choice of base. Interestingly, whereas quinine provided access to [RIS enriched 136a.

the use of quinine for this system resulted in enrichment of the [SIS isomer of 136f.

Simiiariy, the use of quinidine in the preparation of 136a affords the [SJs isorner, whereas

the use of quinidine in the preparation of 136f aRords the [RIS isomer. Also, regardless of

the isomeric enrichment of 136f. preferential crystallization of the [RIS isomer is observed.

Following the initial crystaliization the mother liquor was generally slightly enriched in the

[SIs isomer. Further crystallizations of [RIs could be achieved which, in turn, resulted in a

increased ratio favouring the [SJs isomer in the rnother liquor and, in the end, provided

access to [4~-136f(66% de).

Simitar success was a l r ~ achieved for the preparation of sulfinate 136b fiom

sulfinyl chloride t31b (Scheme 68). For reactions using KzC03 moderate yields were

observed for the generation of the sulfinate, but very little stereoselectivity was measured

(kblr? Il). Application of the quinine or quinidine methodology led to excellent yieids, as

observed for t36f, as well as significant improvements to the selectivity (Table II). Again

access to either sulfir epimer was possible, but with opposite selectivity to that observed

for f36f. White low to moderate de's were initially achieved for al1 examples, enantiopure

[R]s-L36b could be isolated, following one to two crystallizations fiom hexanes. Access

to diastereomencally e ~ c h e d [qs136b (70-75% de) was possible following one to two

crystallizations of the [SJs enriched sulfinate fiom acetone.

O I I cholesterol

O II

[-BU base reaction conditions * r-Bu+S\OChol 131b 136b

Scheme 68

Table I l : Preparation of Cholesteryl (E)-2-t-Butylethenesulfinate (136b).

Conditionsm Yield / deb Recrystallizationse

Base Temp ~dd 'n" de y ield ( O C )

2 KzC03 -78 to rt

3 pyridine -78 to -20

4 quinine -78 to -20

5 quinine -78

6 quinine -78 to -20

7 cpinind -78 to -20

8 quinine -78 to rt

9 quinidine -78

10 quinidine -78

If quinidine -78 to -20

a SoIvcnt \vas CH2C12 unless othenvise noted. b Sulfinate 136b was obtained as a mi.uture of diasiereomers: de refers to initial de ailer chromatography. c Values in parentheses rekr to a lDd recrystallization. Crydization solvent was hexanes unless othenvise noted. ri Addition mode A: alcohol and base added to suUinyl chlonde sol'n; addition mode B: sdiïnyl chlonde added to alcohol and base sol'n. e Wien run in THF these conditions aordecl suüinate in 98% chemical yield: de = l%[Sls. ISolvcnt %vas 5050 toluene: CH2C12 miunire. g C~stailized from aceione.

Sulfinyl chloride 131d exhibited results comparable to sulfinyl chioride 131b.

Treatment of 131d with quinine or quinidine and cholesterol (Scheme 69) aKorded

sulfinate 136d in good yietd and moderate de's, with access to either sulkr epimer being

dependent upon the choice of base (Table 12). Following crystallization from 15%

EtOAcIhexanes enantiopure [RIs-136d could be isolated in yields lower than those

observed for 136b. Atternpts to isolate [q~-136d did not rneet with any success. It was

found that as the diastereomeric mixture became more enriched in the (5'1s isomer its

composition went from being a solid to being a semisolid, with irace impurities that could

not be removed. tn addition, the identity of the sulfoxide From which sulfinyl chloride

131d was generated had important consequences to the purity of 136d. Starting fiom

PMB sulfoxide 129d the sulfinate product contained traces of PMB-OH. which possesses

an Rf value vinually identical to 136d. As such, the PMB-OH could not be effectively

removed during chrornatography. It also co-crystallized with 136d during attempts at

puri@ng the sulfinate through crystallization. Starting from DPM sulfoxide 1306, similar

problems wcre not encountered as DPM-OH and 136d have Rf values that are sufficiently

different to allow for full separation after one or two columns. DPM-OH and PMB-OH

arise frorn hydrolysis of the DPM-CI or PMB-CI co-products, respectively, during

c hromatography.

Access to the [S]s sulfbr epimer with a tram phenyl group and a cis cfiloro group

was possible starting From sulfoxide 119a. Oxidative Fragmentation of 119a generated the

corresponding sulfinyl chloride which was subsequently captured using quinine or

quinidine and cholesteroI to fiord sulhate ester 136g in excellent yietd (Scheme 69;

cholesterol R

base R1= ph; R2 = H : 13ld reaction conditions Ph; R' = H : 136d

R'= Ph; R~ = CI : l31g R'= Ph; R2 = Cl : 1361

Scheme 69

Table 12: Preparative Approaches to Cholesteryl Sulfinates 136d and 136g.

Conditions' Y ield 1 dec ~ecrystallizations'

sullinateb Base Temp de yicld ("Cl

2 136d quinine -78 to -20 73% 1 43%[RIs 100%[R]s 21%

3 136d quinine -78 to -20 35%'1 34%[RIs 100%[RIs 13%

4 136d quinine -78 to n 4 1% 1 14%[RIs IOO%[RIs 16%

5 136d quinidine -78 to -20 82% 1 43%[SJs 86%[R]s 14%

6 136g quinine -78 to rt 88% 1 lO%[R]s 52%[~lsf 23%

7 136g quinidine -78 to n 89% / 9%[Sls 82%[fll 11%

n Solvent wvas CH& sullinyl chloride added to alcohol and base sol'n. b See Schenre 69 for sulfinate suuctw. c Sulfinatc 1361 and 136g were obtained as a mixture of diastereomen; de refers to initial de &er chrornntography. d Values in parcnlheses refer to a 2"' recrystailization; Crystailization solvent \vas 85% he.uanes : 15% EtOAc unless othenvise noted. e Sulfinyl chloride generated from the corresponding PMB sulfoxide. fcrystallized from hesanes.

Tabit! 12). Despite the lower de's observed, one to two crystallization tiorn hexanes

afforded diastereornerically enriched [&]-136s in yields comparable to those observed for

136d. Unfortunately, recombining the mother liquor in an attempt to isolate additional

sulfinate was unsuccessfiil because of the semi-solid/oily nature of the isomeric mixture.

Note that for this example the [SIS isomer was preferentially crystallized.

Other systems were examined, but met with very little success (Table 13). While

sulfinates 136e and 136h could be isolated enriched in the [RIS isomer, subsequent

crystallization failed to improve the enantiopurity to any notable degree and in the case

Table 13: Preparative Approaches to Various Cholesteryl Sulfinates Esters.

136e: R'; R ~ ; R3 = (CH&Ph; H; H

136h: RI; R'; R3 = CI; IFBU; H

Structure Conditions' Yield / deb Recrystallizationsc

R' R2 R3 Base Temp (OC) de yield

2 Cl nBu H quinine -78 to -20 96% 1 19%[R]s 25% [RIs 21%

3 (CH2)$h H H quinine -78 to rt 45% / 40%[R]s 12%[S]s 15%

n Solvent was CH?CI? unless othenvise noted. Sulfinyl chloride added to alcohoVbase sol'n unless otlienvise indicated. b Sulfinatcs were obtained as a mixture of diastereomers; de refers to initial de after chromatography. c Values in parcntheses refer to a 2"d recrystaiiization. Recrystailization solvent was he.wes unless othenvise noted. d Alcohol and base added to the cmde sulfinyl chloride reaction mimut. e Recornbincd crystals and mother liquor and recrystallized from acetone.

of 136e crystallization actually resulted in a significant loss of stereochemistry. As a result

of the difficulties encountered with these substrates they were not pursued tùrther.

The proposed mechanism for the oxidative fiagrnentation of sulfoxides 129 and

130 (as shown in Scheme 70 for the PMB sulfoxide) to afford sulfinyl chlorides 131 is

essentially identical to the mechanism outlined for 1-alkenyl 2-(trimethylsilyl)ethyl

sulfoxide (see Scheme 52). The first step involves electrophilic addition of chlorina to

geneiate the pentacoordinated chlorosulfoxonium salt. As a result of the electron

donating properties of the p-methoxyphenyl group or.the two phenyl groups, the chloride

ion displaces the sulfir moiety through attack at the a carbon. An alternative to this

approach would be the unimolecular scission of the C-S bond to form the DPM or PMB

benzylic cation and the corresponding sulfinyl chloride. The cation would then be

captured by the chloride anion. There is no evidence which favours either of these

proposed mechanisms.

OMe

The mechanism for capturing sulfinyl chlorides 131 with cholesterol to afford the

various sulfinate esters is less clear. In the proposed mechanism by Alcudia and

coworkersgg an amine displaces the chloride to generate a racemic pair of sulfinyl

ammonium enantiomers which then react with the chiral alcohol to generate

diastereomeric sulfùrane intemediates, which may or may not undergo pseudorotations to

afford the enantiopure sulfinate (Scheme 36). The selectivity anses fiom differences in the

size of the amine base and differences in the stability of the various sulfùrane intermediates

(see Scheme 36).

The application of Alcudia's proposed rnechanism for the explanation of some of

the results obtained for the u,P-unsaturated sulfinyl chlorides is difficdt. The low

selectivity observed using KzC03 is understandable as the base would not be expected to

react with the sulfinyl chloride in the s m e manner predicted for amine bases. This does

not explain. however, the low selectivity observed using pyridine or (iPr)zEtN, bases

shown by Alcudia and coworkers to provide a significant degree of seiectivity when DAG

is used as the chiral alcohol. Recall that the differences in sulfitane stability were

predicted to anse from the interaction between the DAG group and the alkyl group. With

cholesterol and the alkenyl group those destabilizing interactions must be reduced

suggesting that with achiral bases there is little difference between the sultùrane

intermediates.

Using various models a proposed explanation for the selectivity observed using

quinine or quinidine can be invoked. A reaction between sulfinyl chlorides 131 and the

chiral amine would generate a racemic pair of suffinyi ammonium enantiomers (83,

Schrrne 71) as predicted by the Alcudia model. Following this reaction cholesterol

141 [Sj Sulfinate 144 1

% HO

l -OCM Y R-..IIIS S HO<= \ A -

.i R * w

1 39 143

quinine

IR] Sulfinate

N = quinine or quinidine

8 N = quaternary nitrogen

Y = pseudorotation

R = olefin group

Scheme 71

would approach 83 to generate sulfbranes 138-141 (Scheme 71). In each case hydrogen

bonding can occur between the sulfinyl oxygen and the base's hydroxyl group (Figure 9).

For the DAG chemistryss the stability difference berneen the various sulfiiranes anses

from destabilizing interactions between the R group and the DAG substituent. For quinine

and quinidine the differences arise from interactions between the alkenyl group and the

base, a result of the configurational difference between quinine and quinidine. When

quinine is used as the base sulhrane 141 is tess stable than 138 due to steric interactions

between quinine's bicyclic ring system and the alkenyl group (Figwe 9). For the same

reason, sulhrane 139 is more stable than sultiirane 140. Following one to two

pseudorotations sulhranes 142 and 143 can be generated from 138 and 139 respectively,

Destabilizing Interaction

M e 0

Hydrogen Bonding

Figure 9: Siïlfïrane interactions.

which can then evolve to afford the [RIs sulfinate, which is typically observed when

quinine is used as the base.

In the case of quinidine, suifiiranes 138-141 are sirnilar in stability. The

destabilizing interaction observed for quinine in sultiiranes 140 and 141 (Figure 9) is not

observed with quinidine due to the contigurational differences between the chiral bases.

The observed selectivity for quinidine is the result of differences in stability between

sulfùranes 141-144. Sultùranes 142 and 143 are less stable resulting fiom steric

interactions between quinidine, cholesteryl and the 1-alkenyl group (Figrrre 10). As such,

for quinidine, sulfuranes 141 and 144 are more stable and can evolve to fiord the

observed [ J ~ s sulfinate.

destabilizing interactions > Figure 1 O: Steric crowding in strlfiratre 243.

The opposing selectivity that is observed for 136f could arise due to possible

hydrogen bonding between the carboxylic ester and the base's hydroxyl group. This could

result in changes in the stability of the various sultùranes. For both quinine and quinidine

the differences in the stability of the various sulfiiranes are very subtle. As a result the

observed selectivity is not as great as that which is observed for the DAG chemistry.

5.1.1. Determination of Enantiopurity and Absolute Configuration of I- Alkenesulfinate Esters

Following the preparation of the homochiral 1-alkenesulfinate esters it was

necessary to determine the diastereomeric excess of each sulfinate isomer. Measurement

of the optical rotation of the sulfinate and cornparison of the rotation to known literature

values was inappropriate for this research for a number of reasons: (i) the rotation of the

enriched enantiomer must be known along with the determined ee; (ii) the magnitude of

the rotation must be greater than zero to ensure accuracy; and (iii) there must be sufficient

amount of the isomer to measure. As the optical rotation of the 1-alkenesulfinates was

unknown, poiarimetry was only used empirically and 'H NMR analysis was used to

determine the de's.

When the 'H NMR spectra of the vinyl sulfinates were obtained, examination of

the vinyl hydrogen peaks indicated the presence of two isomers, but the chemicat shift

differences between the two peaks were not sufficient to accurately measure the de. Using

CGDs as the NMR so~ven t '~~ a significant chernical shifi difference was observed for the

cholesteryl 1-alkenesulfinate esters (Figure II). To determine the diastereomeric excess,

the area of each peak was determined by carefiilly measuring both height and width (at 1/2

height) for each diastereomer and then calculating the relative difference.

Figure I I : Spectmrn for a-vinyl hydrogeji 0 paks for mlftiate l36f iri C A (a) mivl~rra of hvo isorners; (b) isolated enaniiopwee

There are two possible methods available for determining the absolute

configuration of the cholesteryl sulfinates: (i) converting the sulfinate into a known

sulfoxide via a Grignard reaction and comparing their optical rotations; and (ii) the use of

chiral solvating agents (CSA) or chiral shifi reagents (CSR) and correlating the absolute

configuration on the basis of the relative positions of the isomeric resonances. As the

cholesteryl sulfinates are new compounds and their behavior in organometallic reactions

was unknown, it was decided to assign the absolute configuration using the more direct

method of a CSA or CSR. The conversion of the sulfinates to known sulfoxides was also

examined and those results will be presented in a later section.

There are several CSA's and CSR's available for 'H NMR analysis of enantiornerk

excess and the elucidation of the absolute configuration. 125.126 Many of the compounds

that arc available, however, are often used for the analysis of sulfoxides rather than

sulfinate esters. For example, chiral lanthanide shiA reagents 145 ( E ~ ( h f c ) ~ ) ~ ~ and chiral

solvating agent l4tin have been used for simple methyl aryl and alkyl aryl sulfoxides. For

sulfoxides with more complex spin systems a-methoxyphenylacetic acid 147 has been

fouiid to be s u c ~ e s s f ù l . ~ ~ ~ While these reagents have proven usehl for sulfoxide analysis,

they have not been reported for the analysis of sulfinate esters.

For this group of compounds the use of chiral 1-aryl-2,2,2-trifluoroethols has been

found to be successfùl for not only de determination, but for the assignment of absolute

configuration. 127,[2B On this bais [RI-(-)-2,2,2-trüiuoro-1-(9-anthryl)ethanol (148) was

Çound to be quite successfiil in separating the vinyl hydrogen peaks of the cholesteryl 1-

alkenesulfinate esters.

The nature of the diastereomeric interaction between 148 and the 1-alkenesuffinate

127.128 esters was proposed by Pirkle and coworkers (Figure 12) to involve two hydrogen

bonding interactions. A primary hydrogen bonding interaction occurs between the

hydroxyl hydrogen and the sulfinyl oxygen, while a secondary stabilizing effect occurs

between the electron poor carbinyl hydrogen of 148 and the cholesteryl oxygen. Using

this model the chemicai shifl of the a-vinyl hydrogens can be correlated with the absolute

configuration. To illustrate this correlation the model drawn in Figure 13, using an [RIS

and [SIS sulfinate will be utilized. The configurations were designated based upon the

Cahn-Ingold-Prelog (CiP) mles, with the cholesteryl oxygen being given a higher priority

than the lone sulfur oxygen. This precedent is well established in the literature."*

Figure 12: Dinstereomeric inleractiot~s bîweeti s11Hnates and CSA 148.

Complex 149 demonstrates the interaction between CSA 148 and an [SJs sulfinate.

The vinyl hydrogens are directly above the arornatic ring in CSA 148, resulting in an

upfield shifi. Conversely, in complex 150 between 148 and an [RIs sulfinate, the vinyl

hydrogens are not shielded by the anthryl group and appear tiirther downfield (Figure 14).

150: IR], sulfinate

Figure 13: Demonstruting d~flerential shieldirig eficts of CSA 148.

Applying this methodology to the homochiral vinyl sulfinates it was possible to

assign the absolute configurations. As show in Figure I4a for an isomeric mixture of

suKnate 136f two sets of peaks are observed for the a-vinyl hydrogen (H,). The

downfield peak represents the [RIS isomer and the upfield peak represents the [SIS isomer.

Upon comparing the spectrum of the mixture (Figirre I4a) to the spectrum obtained for

the enantiopure sulfinate (Figrre Iqb), the absolute configuration of enantiopure 136f is

[&]. Furthennore, if one inspects the CaD6 spectrum (Figure I I ) the chemical shiîl

induced by C a 6 is analogous to the shift induced by 148. This allows for detennination

of both the de and the configuration using C6Da rather than the expensive solvating agent.

Analogous results were obtained for each of the 1-alkenesulfinates prepared.

Figure 14: Spectrum for a-vityi hydroge~i (HJ peaks for sirlfiiate l36f irsitg CSA 148 (ci) mixtirrt! of two isomers; (i31 isolated enar~tiop~re.

5.1.2. Analysis of Cholesteryl 1-Alkenesulfinate Esten Using Circular Dichmism.

There are three optical methods that can be used to differentiate enantiomeric

compounds: (i) polarimetry; (ii) optical rotatory dispersion (ORD); and (iii) circular

dichroism (CD).'~' Each of these methods is based upon the interaction between the chiral

centre and plane polarized light. Plane polarized light is generated by passing ordinary

light (monochromatic or polychromatic), which vibrates in an infinite number of planes at

right angles to the direction the light is traveling, through a polarizing filter such that the

vibrations take place in only one of these possible planes. Plane polarized light also

consists of a pair of orthogonal polarization States: left and right circularly polarized light.

All chiral compounds are capable of rotating the plane of polarized light in either a

clockwise or counterclockwise direction, but for racemates the contributions are equal and

no effect is observed. It has been found that for enantiopure or enriched compounds the

plane of poiarized light is rotated by a specific amount. It is the measurement of this

rotation which fonns the basis of polarimetry. In 18 17, Biot discovered that the eiutent of

optical rotation changes as the wavelength of the light used for measurement decreases.

This change is referred to as ORD. CD is the differential absorption of lefi and nght

circularly polarized light with changes in the wavelength. ORD or CD methods cm be

used for the determination of absolute configuration.

To lend fùrther support to Our configurational assignments to sulfinate esters 136,

CD spectra were obtained for 136b,d, f and g and their Cotton effects (CE) analyzed.

The CE observed for CD spectra generally takes place in spectral regions in which

absorption bands are observed in the isotropie UV spectmm for the compound being

a r ~ a l ~ z e d . ~ ~ Because a single compound can have more than one absorption band, a CD

curve may have more than one Cotton effect. Since CD's are difference spectra (the

difference in absorption of lefi and right circularily polarized light), the Cotton effects

observed for the CD curves can be assigned a positive or negative sign. Generally, the CE

of interest is one that occurs at the LN absorption for the compound being exarnined.

By analyzing the various CD spectra of 136b,d, f and g, a cornparison can be made of

their relative configurational assignments.

The CD curves shown in Figure 15 are representative of [RIs and [&]-136b. For

[Rs]-136b (Figirrcr 15a) there is a slight positive CE around 278 nm followed by a strongiy

negative CE around 254 nm. This strong CE corresponds to the of 252.0 nm

ohtained frorn the UV absorption spectrum of 136b. Examining [Ss]-136b (Figiire 15b)

there is a slight negative CE followed by a strong CE around 254 nrn. As the [ q s isomer

is enriched (70% de) and the [RIs isorner is enantiopure the intensity of the CE for [S&

136b is not as great. Notice also that the two curves in Figure I S are mirror images of

each ot her, suggesting that they have opposite configurations at sulfur.

1.5 -

&, = 252.0 nm (UV absorption)

b'

Wavelength (nrn)

Figure 15: Circrrlar dichroism etme for (a) [RIs-136b; (b

The CD obtained for [RIs and [SJs-136f are slightly different than those obtained

for 136b (Flgrre 16). For the major isomer isolated (Figiire 164 there is a strong

negative CE around 298 nrn followed by a slightly smaller positive CE around 254 nm.

The two CE'S are likely the result of the different chromophores present in the molecule.

The CE at 298 nm is close to the UV absorption A.- (290.2 nm) observed for 136f and is

the one that should be comparable to 136b. As indicated in Figure 16a, the negative CE

at the observed W A.,- matches the CE at the W absorption Lx observed for [Rs]-

136b. This suggests that both sulfinates have the same relative configuration and hence

the curve in Figrire Ma is representative of [RIS -136f. Similarly, the CD curve in Figitre

166 is the mirror image of Figure 16a indicating the opposite configuration: [SIS-1361.

Figirre 16c is representative of a racernic mixture of 136f and as such very little CE is

observed.

1 -0.06 - 1 L, = 290.2 nm (UV absorption) -0.08

Wavelength (nm)

Figure 16: Circtilar dichroisrn curves for (a) [RIrl36fi (ô) 66% de [Sls136fl (c) racemate of 136f

The configuration assigned to 136g by 'H NMR, based upon the Pirkle model, is

[SIS. An examination of the CD curve (Figure 17) shows a moderate CE around 270 nm

and a stronger CE around 239 nm foltowed by a slightly smaller CE at 220nm. The

stronger CE occurs at the UV absorption & for 136g (239.4 nm). Upon comparison to

the CD curves for W b , the CD cume for 136g more closely resembles that for

[SIS -136b. The correlation implies similar configurations, confirming the configuration

assigned using CSA 148.

-0.3 i

Wavelength

Figure 17: Cirmlar dichroim cime for di&reomericaIiy ewiched (94% de) [qs- 136g

A comparison of the CD curve for 136d (Figure 18) to those obtained for 136b

implies that the configuration of 136d should be assigned [SIS, opposite to that predicted

and assigned by the Pirkle model. To be assigned the [RIS configuration the CD curve

should show a strong negative CE around the UV absorption Lx for 136d. Instead the

Lx for the CD curve (278 nrn) is significantly different than the h- observed fiorn the

UV absorption spectrum of 136d (258.2 nm).

A,,,, = 258.2 nm (üV absorption)

Wavelength (nm)

Figure 18: Circirlar dichroism ct1rve for erwniiopure [RIS-136d.

What is likely being obsewed for 1366 are oppositely signed overlapping CE's

which essentially appear as the algebraic sum of the component CE's. Depending upon

their magnitudes and relative proximity to each other, the observed CE's can be shified in

position and diminished in intensity compared to the CE's that are distinctly ~epa ra t ed . ' ~

On this basis a direct cornparison of the CD curves for 136b and 136d cannot be made for

the assignment of the relative configuration. As will be discussed in a later section,

conversion of enantiopure 136d to an known enantioenriched sulfoxide allows for the

absolute configuration of 136d to be assigned [RIS, as' predicted by the Pirkle rnodel using

CSA 148.

5.2. Preparation of Aralkyl 1-Alkenylaralkyl Sulfoxides

With a suitabie collection of 1-alkenesulfinate esters available, it was decided to

continue the Andersen approach and treat them with a variety of organometallic reagents

to prepare enantiopure or enriched aJ3-unsaturated sulfoxides. Of the various sulfinate

esters prepared it was expected that 1361 could be troublesome resulting fiom two

possible reactiori sites: the sulfinyl ester and the carbonyl ester. To test the likely

reactivity of 136f, the model compound 151 was prepared and treated with MeMgBr

(Scheme 72) under the established Andersen conditions." While the sulfoxide product

(152) was observed, the major product was identified as vinyl ether 153.

Scheme 72

A variety of reaction conditions and reagents were examined in an attempt to

influence the reactivity of 151. Vanous organometallic reagents were examined including

additional organomagnesium reagents, as well as organolithiums and organoceriums.

With the exception of n-BuMgCl, Iittle or no sulfoxide was generated, and 153 was

çenerally isolated in approxirnately 20% yield. With ri-BuMgCl, however, the

corresponding sulfoxide was generated in 17% yield dong with a 17% yield of 153.

It is proposed that 153 is forrned via a Michael addition P to the carboxylic ester of

152 using the alkoxide anion expelleci during the conversion of 151 to 152 (Scheme 73).

The addition product then undergoes an elimination reaction to generate the vinyl ether

product along with methanesulfenate anion. To gain a better understanding of the

Scheme 73

chemistry taking place, an experiment was designed to confirm the formation of the

sulfenate anion. Starting with a solution of sulfoxide 129f in ether, cyclohexanol and n-

BuLi were added (Scheme 74). After an hour at O O C , formation of 153 was observed by

TLC. M e r cooling the reaction mixture to -78 O C , benzyl bromide was added and the

reaction mixture was allowed to warrn to room temperature. Following workup and

chromatography sulfoxide 154 was isolated in a 47% yieid Sulfoxide 154 forms as a result

of a reaction between the sulfenate anion and BnBr in a manner analogous to the reaction

used to prepare sulfoxides 129 and 130 (Scheme 57).

O II

HOC6Hll E ~ o c s H l l

s, EN PMB - + PMBSO~ n-BuLi 153

129f

Scheme 74

Despite the low sulfoxide yield it was decided to proceed with the Andersen

chemistry on 1361 (Scheme 75). As expected fiom the model compound study, the

sulfoxide yields, while higher than those observed for 151, were low (Table II), and the

side product, cholesteryl vinyl ether 156, was isolated in approxirnately 20% yield.

Completely unexpected, however, was the substantial loss of stereochemistry. Starting

with enantiopure [RIs-1361, the sulfoxides isolated had ee's of no more than 5 1% and in

most cases lower.

Scheme 75

Tablc 14: Grignard Reactions of Sulfinate Ester 136f.

Grignard Initial Temp. ( O C ) / Sulfoxide Reagent de of 136f "Ivent Structure %yield %ee

n The obtention of the R-isomer is consistent wilh an inversion mechanism. The apparent configuration cliangc from carlicr cntries in the table is a conxqucnrx of differences in atomic prioritics of the groups surrounding the sulfur.

As a result of its poor reactivity with conventional organometallic reagents, 136f

was treated with nucleophiles that might prevent the subsequent Michael addition of the

alkoxide anion. To accomplish this 136f was reacted i t ~ situ with dianions 157(a,b)

130.131 (Scheme 76), prepared using established methods. it was hoped that, following the

Scheme 76

initial nucleophilic substitution at sulfiir, the second anion would add to the double bond

faster than the alkoxide anion, decreasing the electrophilicity of the double bond.

Unfortunately, in both examples, several different products were observed and the

expected product(s) were not obtained.

While highly stereoselective preparation of a$-unsaturated sulfoxides could not

be achieved from 136f, it was believed that the other vinyl sulfinates prepared would react

similarly to the original Andersen results. To that end, enantiopure or enriched forms of

L36b were subjected to a series of sulfinate substitution reactions with 11-BuMgCl

(Scherne 77) to detennine the optimal conditions for sulfoxide formation (Table 15). It

was found that reactions carried out in benzene with 11-BuMgCl aiTorded the sulfoxide in

higher yields while maintaining the stereochemical integrity of the sulfinyl centre. This

effect has been noted before in the literature. lJ2 Utilizing these conditions [RS]-136b was

treated with a variety of commercially available Grignard reagents (Scheme 78; Table 16)

to afford, in most cases, enantioenriched sulfoxides in good yield and ee, which were

readily separated from cholesterol by flash chromatography. Experiments with MeMgBr

were camed out several times and the yields were consistently near 85%. A couple of

examples using [SS]-136b were also exarnined and the results presented in Tabk 16

demonstrate the high stereospecificity of the sulfinate substitution reactions. The results

presented in Table 16 also suggest that the Grignard substitution with the vinyl sulfinates

proceeds with inversion of configuration. The determination of ee's, as well as the

absolute configuration assigned to the sulfoxides, will be discussed in the next section.

Sckeme 77

Table 15: Prelirninary Grignard Reactians of [Rl~-136b

Grignard Initial de Temp. (OC)/ Sulfoxide Chol.'

Reagent of 136b solvent Structure %yield %ee

1 rrBuMgCl 100%[RIs -78 to rt/Et2O 158a 6 1 83[qs 89

a Yield of rccovered cholesterol.

The preparation of sulfoxide 158g presented more of a challenge. Treatment of

[RIs-136b with the lithiated anion of furan afforded the furanyl sulfoxide in low yield and

low ee. It was reasoned that these results could be partially explained by deprotonation of

the a vinyl hydrogen of the sulfoxide product. It is possible that the lithiated tùran is

basic enough to deprotonate the sulfoxide product as it is fonned, effectively quenching

the nucleophile and preventing funher r e a c t i ~ n . ~ The ability of the sulfinyl group to

stabilize a anions is well known and has been exploited to prepare a number of

compounds including enantiopure ~-hydroxysulfoxides."3 trisubstituted, enantiopure vinyl

~ulfoxides,'~' and di and trisubstituted al le ne^.'^^

Scheme 78

Table 16: Grignard Reactions of Sulfinate 136b.

Grignard Initial de Temp.(OC)/ Sulfoxide ~ h o l . ~

Reagenta of 136b solvent Structure %yield %ee

a Uscd 2 cq of Grignard ragent unless othenvise noted. b Yield of rccovercd cholesterol. c Eqxriment !vas done with one equiv. of Grignard ragent. d The obteniion of ihe R-isomer is consistent with an invcaion mechanism. The apparent configurational change from earlier entries in the table is a consequenœ af differenccs in atomic priorities of the p u p s surrounding the sulfur. e Prepared from Iithiated lùranyl anion; see t e s for deuils. /Amount of cholesterol recovered not obtained.

By converting the anion fiom an organolithium to an organomagnesium reagent

(Scheme 79) the difficulty mentioned above can be overcome. This is accomplished by

treating the hranyl anion, generated using n-BuLi, with MgBr2.Et20 (Scheme 79). 136.137

followed by the in sittr addition of [RIs-136b. Using this method the sulfoxide was

generated in good yield and high ee. Sulfoxides bearing the furanyl group are important in

organic ~~nthes is '~* and have been used in the synthesis of naturally occuning

cornpo~nds.~~"he unique feature of 158g is that, in addition to the diene functional

group. it also possesses the vinyl moiety.

Scheme 79

While the ethenesulfinate system 136a could not be isolated in an enantiopure

form, Grignard reactions (Scheme 80) were carried out on both the [RIs and [qs enriched

systems (Table 17). For those reactions where the sulfinate was treated with aryl

Grignard reagents, moderate to good yields of a$-unsaturated sulfoxide were achieved,

and the stereochernical integrity of the sulfinyl centre was maintained, implying that

inversion of configuration had taken place during the substitution. Treatment of 136a

with alkyl Grignard reagents, though, showed significantly poorer reactivity. Preparation

of 159c and 159d proceeded in lower yields and in the case of 159d a loss of the

stereochemical integrity was also observed. Several experirnents with i-PrMgBr failed to

generate the desired sulfoxide.

Scheme 80

Tnble 17: Grignard Reactions of Cholesteryl Ethenesulfinate 136a.

Grignard' Initial Temp. (OC)/ Sulfoxide Reagent de of 136a sO'vent Structure % Yield %ee

n Espcrinicnt )vas done Mth one equiv. of Grignard reagent. b. The obtention of the configurational assignment is consistent with an inversion mechanism. The apparent configurational change from earlier entries in the table is a conspquence of differences in atomic priontics of the groups surrounding the sulfur. c Yield in brackets based upon recovered stariing material.

The conversion of 136d to sulfoxides 160 proceeded in an analogous marner to

136b (Scheme 81). For each Grignard reagent examined the sulfoxides were prepared in

good yields and ee's (Table 18). Again in each case the reaction proceeded with inversion

of configuration at the sulfinyl centre. Sulfinate 136s was also treated with a couple of

Grignard reagents and in each of those reactions the sulfoxide product was isolated in

good yield. Determination of ee ais0 demonstrated that the sulfinyl centre of 136g

rnaintained its stereochernical integrity.

136d: R'; R' = Ph; H +6a / C6H6 160: R' = ph; H

136g: R'; R' = Ph; CI 161: R1; R' = Ph; CI

Scheme 81

Table 28: Grignard reactions of Cholesteryl 1-Alkenesulfinates 136d or 136s.

Grignard Initial De Temp. (OC)/ Sulfoxide

Reagent' of 136d or solvent Structure % Yield %ee 136g

I i-PrMgBr 1OO%[Rls +6 /C& 160a 87 9 1 [SIS

a Two equiv. of Grignard nagent were used unless othenvise noted. b Esperiment was done with one equiv. of Grignard reagent c The obtention of the configurational assignment is consistent with an inversion mechmism. The apparent configurational change from earlier enuies in the table is a conseqwnce of ditkences in atomic prioritics of the groups surrounding the sulfur

Each of the p-tolyl 1-alkenyl sulfoxides prepared above has been previously

reported in the literature. The method which has previously been used for synthesis

involves a Wittig type reaction using sulfinate 70 (Scheme 30), 92-93.140 both isomers of

which are commercially available in an enantiopure forrn. The p-tolyl sulfoxides can also

be prepared fiom 70 using a vinyl Grignard reagent. However, the sulfoxides are typically

prepared as a mixture of (E) and (Z) isomers and the yields are low.'" There are several

advantages for using the method presented in this paper: (i) there are significantly fewer

steps (starting fiom sulfoxides 129 or 130) involved than using a Wittig type reaction; (ii)

the geometry of the double bond is maintained, hence only the (E) isomer is generated;

and (iii) most importantly, our method provides access to a much larger variety of

enantioenriched a,P-unsaturated sulfoxides. Furthemore, the method presented in this

paper is not limited only to the preparation of those sulfoxides bearing the p-tolyi group.

For example, racemic sulfoxide 160a has been previously prepared'JO using the Wittig

chemistry. However, using the method presented here ,it can be isolated with an ee of

9 1%. Furthemore, the alkyl I-alkenyl sulfoxides prepared herein could possibly undergo

Michael addition chemistry or hydrogenation reactions to a o r d highly enantioenriched

dialkyl sulfoxides; a class of compounds that has been elusive to prepare in high

enantiomeric excess.

5.2.1. Determination of Enantiomeric Excess and Absolute Configuration of Aralkyl l-Alkenyl sulfoxides.

The enantiomeric excess of the various sulf'oxides prepared was deterrnined using

CSA 148. This solvating agent has been reported for the analysis of not only sulfinate

esters, but sulfoxides as we11.~*' For 5-10 mg of sulfoxide, 1-3 equiv. of 148 in CDCh was

typically required to separate the chemical resonances of the enantiomers. As the peaks

for the solvating agent sometimes overlap with the vinyl hydrogen peaks, a resonance

representative of a hydrogen on the alkyl or aryl group was examined to determine the ee.

As in the case of the sulfinates, ee's were detennined by measuring the area beneath the

enantiomer peaks and determining the relative amounts. As shown in Figure 19 and

Figirre 20 the presence of both enantiomers can be clearly observed for

Figure 19: ' H M R spectra of sulfoxide 115c for vinyl hydrogen HL,: (a) in the absence of CSA 148; (b) with 1 e p i v . of CSA 148 (in CDClJ

sulfoxides 158c and Idla.

The mode1 used to describe the diastereomeric interaction that occurs between 148

and the sulfoxide (Figure 2 I ) is somewhat similar to the complexes proposed for the

suifinates (see Figire 12). The solvating agent hydrogen bonds to the sulfinyl oxygen and

this complex is ttnher enhance by a secondary stabilizing interaction between the carbinol

hydrogen and the suliür electron lone pair. As was observed for the sulfinate complexes,

the observed separation of the proton resonances is caused by the non-equivalence

induced by the differential shielding of the anthryl ring system.

Figure 20: 'H NMR ~pectra of mlfoxide l6la, a-vinyi hyàrogn H. with leq of C'SA 148 ( irr C'ad.

Figure 21: Diostereomeric i~~/eraction between a; ~rrrrsatzrrared surfoxides and CSA 1 48.

Solvating agent 148 can also be used to determine the absolute configuration of

the sulfoxides in a manner comparable to the sulfinate system descnbed earlier. Using

suifoxide 158c, the [RIS isomer interacts with 148 to f iord cornplex 162 while the [SJs

isomer affords complex 163 (Figure 22). In complex 162 the vinyl protons are shielded

by the anthryl aromatic ring resulting in an upfield shifi of the [RIS sulfoxide vinyl

hydrogens. In complex 163 the vinyl hydrogens do not experience the shielding effect and

therefore the vinyl hydrogen resonances for the [SIS sulfoxide remain downfield. In the

spectrum for 158c in Figure 19 the downfield resonances would be representative of the

[SIs isorner and the upfield peaks would be representative of the [RIS isomer. Therefore

the major enantiomer present in Figure 19 would be [SIS-1SSc.

Figure 22: Drj4erential shielding observed for [RIs and [S]s-ISBc tising CSA f 48.

Circular dichroism curves were obtained for sulfoxides lS8e and 16Lb and

compared to the corresponding sulfinates from which they were prepared. The CD curves

in Figrre 23 are shown for 158e and [Rs]-136b. The sulfoxide shows a srnaIl negative CE

around 274 nm followed by a strong, broad CE around 234 m (Figure 23a). This is the

opposite to the CE'S shown for [Rs]-136b, which has a small positive CE followed by a

strong negative CE. These curves imply that 158e has the opposite configuration to [Rs]-

t36b, indicating that inversion of configuration occurred during the nucleophilic

substitution. This also corroborates the [Sjs geometry assigned to 158e using the Pirkle

model.

(a) - Sul foxi de 1 OOO/o IR] Sulfinate

+ -

Wavelength (nm)

Figure 23: Circiilar dichroism ctiwes for (a) mrfoxide N e (A- =244.2 rrm); and (6) [RIs-I36b (A,,,, =ZX. O nm).

The CD curve for sulfoxide 161b is very similar to the one obtained for [Ss]-136g

(Figtrc! 24). It shows a strong negative CE around 248 nm followed by a strong positive

CE around 228 nm (Figure 24~) . Each of these corresponds to absorption shoulders

observed in the absorption spectrum. The sulfinate curve (Figure 2Jb) also shows a

negative CE followed by a positive CE. The similarities between the CD curves suggest

that retention of configuration is being observed. This would contradict al1 the evidence

that has been presented indicating that the nucleophilic substitution occurs with inversion

of c ~ n f i ~ u r a t i o n . ' ~ ~ h i s also contradicts the [SIs configuration assigned to 161b using

CSA 148 (Figzrre 20). The [SIS sulfoxide can only fonn from [5'Is-136g if inversion of

configuration occurs. Mikolajczyk and coworkers, based upon the results of their CD

experiments, inaccurately concluded that certain Grignard reactions with bulky alkyl

groups (i.e. s-Bu; [-Bu) proceeded with retention of configuration.lo8 With this in mind,

I t (b) 96% [SI sulfinate

(c sulfoxide

Wavelength

Figure 24: Cirmlar dichroism nrwes for (a) mlfxide l6lb; and (3) sulfiriae 136g.

it is believed that the preparation of 161b proceeds with inversion of configuration and

that the CD analysis is inconclusive because of the difficulty in accurately extrapolating

from the üV spectrum of 161b. This serves to demonstrate the limitations of CD

analysis for assigning and correlating the relative configurations.

Another rneans of determining the enantiomeric purity would be a cornpanson of

the measured optical rotations with those reported in the literature for known sulfoxides.

As indicated earlier, the vanous p-tolyl sulfoxides have been previously prepared and a

cornparison of the optical rotations is presented in Table 19. For each sulfoxide prepared

the sign of the measured optical rotation matches that reported in the literature,

confirming the absolute configuration determined using solvating agent 148. Furthennore,

as shown in Table 19, this confirms the configuration assigned to corresponding sulfinate

ester. For example, sulfoxide [RIs-36 can only be prepared from the corresponding [RIs-

136d if inversion of configuration occurs at the sulfinyl centre.

Table 19: Cornparison of Optical Rotations of Several Reported Sulfoxides.

Sulfinate' Sulfoxide Optical Rotation Configuration Ref. Measurcd Literature Measured Literature

[RIs- 136d 160a +116.7" O 9 I%[SJs racemate 1-10

a Suifinate that the sulfoxide was prepared hm. b Enantiomeric excess not reporied

5.3. Conclusions

In conclusion, it has been show that a number of 1-alkenesulfinyl chlorides can be

successfully employed to prepare several new cholesteryl l-alkenesulfinate esters

possessing enantiopurity or enantioenrichment at the sulfinyl centre. This was

accomplished using the chiral amine bases quinine and quinidine, followed by one to two

crystallizations, usually fiom hexanes. The use of quinine and quinidine generally allowed

access to either sultiir epimer. In certain instances the diastereornerically enriched

sulfinate esters could be prepared, but upon crystallization little or no improvement to the

enantioselectivity was observed The enantiopurity could be determined using [H NMR

spectral analysis of the vinyl sulfinate in CaDtj. The use of CSA 148 allowed for the

detennination of the absolute configuration.

Of the various chiral alcohols exarnined, only cholesterol provided a consistently

solid mixture of diastereomers which could be separated using crystallization. For al1

other alcohols an inseparable, oily mixture of diastereomers was obtained. The use of

DAG was exarnined thoroughly and not only was there no selectivity observed, but

generally very little product formation took place. This is surprising considering the high

yields and selectivity achieved when using methanesulfinyl ch~orides.~~ Almost identical

reactivity was observed for trans-2-phenylcyclohexanol. Uniike Whitesell and coworkers,

who utilized this alcohol to afford both sulfinate esters and chlorosulfinates, 105.107 , reaction was observed between 1-alkenesulfinyl chlorides and ~~~~~~~2-phenylcyclohexanol.

Following the preparation of l-alkenesuffinate esters the Andersen protocol was

successfiilly utilized to prepare a variety of enantioenriched l-alkenyl sulfoxides. With a

couple of exceptions, the reactions proceeded cleanly to afford the vinyl sulfoxides in high

yield and with high stereoselectivity. For sulfinate 136f substantial decomposition was

observed, affording a cholesteryl vinyl ether as the major product. Various expenments

were attempted to change the reactivity of the sulfhate by modifj4ng the organometallic

used as well as the temperature and solvent conditions. However, little change in the

sulfinate's reactivity was observed. For 136a reactions with alkyl Grignard reagents

afforded the sulfoxides in low yield. The enantiomeric excess of al1 sulfoxides was

determined using CSA 148.

Circular dichroism curves were obtained for several of the sulfinate esters and a

comparison could be made of the relative configurations. With one exception, this

comparison corroborated the configurational assignments made using the chiral solvating

agent. In the case of the trar~s-phenylethenewlfinate the CD comparison was

inconclusive. A comparison of the sulfinate CD curves to CD curves obtained for selected

sulfoxides indicated opposing sulfûr configurations, implying that the nucleophilic

substitution occurred with inversion of configuration at the sulfinyl centre in both

instances.

This thesis presents the first reported preparation of l-alkenesulfinate esters with

homochirality at the sultùr centre. This methodology offers a number of advantages to the

synthetic chemist: (i) the reactions are easy to carry out; (ii) the sulfinates are stable and

easy to handle; (iii) enantiopure or diastereomerically enriched l-alkenesulfinates cm be

easily obtained following one to two crystallizations; and (iv) the de can be easily

determined using 'H NMR in C a s . Furtherrnore, this group of sulfinate esters readily

undergo nucleophilic substitution with Grignard reagents to afTord a number of new

enantioenriched vinyl sulfoxides, which have proven to be very valuable for inducing

chirality into a target molecule. Vinyl sulfoxides can be utilized in Diels-Alder reactions

as well as Michael addition chemistry, steps that are &en used in the synthesis of natural

products and biologically active molecules.

5.4. Future Efforts

A number of directions for both the a,P-unsaturated sulfinate esters and sulfoxides

are available for this research to continue. The determination of a preferred chiral

auxiliary would prornote the isolation of a greater number of 1-alkenesulfinate esters with

increased selectivity. This could involve directly capturing the sulfinyl chlorides with the

preferred auxiliary, and then separating the isomers using either chromatography or

crystallization. An alternative would be to convert the various 1-alkenesulfinate esters

that proved difficult to isolate in an enantiopure form into a sulfinic acid derivative that

can be isolated in an enantiopure form. For example, the parent ethenyl system (136a)

could not be isolated in an enantiopure form and the corresponding sulfinyl chloride (10)

showed no reactivity towards the Evans or Oppoizer amide auxiliaries. Tt may be possible

to treat 136r with the lithiated amide or some other chiral auxiliary to afford a sulfinamide

whereby the sulfur epimers can be isolated in an enantiopure fom (Scheme 82).

N A0 u f

8n - (or other chiral

auxiliary )

Scheme 82

128

By finding a preferred chiral auxiliary, and hence expanding the number of

homochiral sulfinate esters available, this will provide access to an even larger number of

enantioenriched vinyl sulfoxides that can be prepared.

Additional chernistry c m also be examined with the available 1-alkenesulfinate

esters. For example, previous work examined various Diels-Alder reactions involving

racernic vinyl sulfinates bearing the carboxyl ester substituents. Future work will look at

Diels-Aider chemistry with 136f to examine not only the stereoselectivity of the reaction,

but the preparation of polyhydroxylmercapto compounds (Scheme 83). Using various

enantiapure l-alkenesulfinates, the first enantiopure or enriched doubiy unsaturated

sulfoxides will be explored. This will involve treating the sulfinate esters with Mnylic or

acetylenic Grignard reagents (Schemr 84).

Scheme 83

Hydrogenation reactions of various I-alkenyl sulfoxides can be examined. This

would provide access to a large number of dialkyl sulfoxides, which have proven difficult

to isolate in an enantiopure fom.

6. Experimental

6.1. General Procedures and Instnrmentatioa

Melting points were detennined using a MEL-TEMP melting point apparatus and

are uncorrected. Infiared (IR) spectra were obtained on a Bornen FTIR spectrometer

either neat or in a solution cell (CH2CI2 or CDC13). NMR spectra for 'H NMR and 13c

NMR were recorded on a Bruker mode1 Spectrometer at 400 and 100.6 MHz,

respectively, in CDCI3 and C a 6 (for enantiopure or enantioenriched sulfinates).

Additional 'H MIR spectra were recorded on a Vanan Gemini Spectromerer (200 MHz)

1 in CDCI3. H NMR and NMR chernical shifis are reported in parts per million 6 (ppm)

referenced to intemal tetramethylsilane or to the solvent peak. Mass spectra (MS) were

recorded on a Kratos 890 using chernical ionization and electron impact techniques. CD

Spectra were recorded on a Jasço J-600 Spectropolarimeter. Diethyl ether and

tetrahydrofuran (Tm) were fieslily distilled From sodium and benzophenone. Methylene

chloride, benzene, toluene, pyridine and (1-Pr)*EtN were distilted fiom calcium hydride.

Benzene, toluene, pyridine and (i-PrhEtN were then stored over molecular sieves. Air

and water sensitive reagents were transferred via oven-dried Ntrogen-purged syringes.

Flash chromatography was performed on virgin or recycled 200-425 mesh Type 60 A

silica gel. Analytical thin-layer chrornatography (TLC) was perforrned using 0.25 mm

Merck Kieselgel 60 F254 precoated siiica gel plates. Analflical GC was performed on a

Varian 3400 capillary gas chromatograph. Sulfiiryl chloride was purchased fiom Aldrich

as a 1.0 M solution in CH& Older solutions were discarded before complete

consumption of their contents. Various organomagnesium reagents were purchased fkom

Aldrich as 0.5 to 2.5 M solutions. mCPBA was obtained from Acros and was calibrated

before use. Elemental analyses were performed by MHW Labs of Phoenix, Ai!. Spectral

data are presented for those compounds which have not been previously characterized in

the literature or by the Schwan group.

6.2. Preparation and Oxidative Fragmentations of 1-Alkenyl 2- (Trimethylsilyl)ethyI Sulfoxides

6.2.1. General Method for the Synthcsis of 1-Alkenyl 2-(Trimcthylsilyl)tthyl Sulfoxides

A solution of 2-(trimethylsily1)ethyl disulfide 114 (1 equiv) was prepared in dry

CHiCI2 (10 mL/mmol) and cooled to -7R°C under N2. While stirring SO2CI2 (1.2 equiv;

as a 1M solution in CH2C12) was added via syringe. The mixture was stirred for 15

minutes at -78 O C followed by the addition of alkyne (2 equiv). The reaction was stirred

until complete by TLC andor G.C. analysis and was then concentrated under reduced

pressure. The crude sulfide was dissolved in CH2C12 (2.5 mWmmol) and cooled to -78°C

followed by the dropwise addition of mCPBA in CH2CI2 (4 mL/nunol). The oxidation

reaction was stirred 3-4 hours until compleie by TLC and then was filtered through a bed

of Celite.M The solution was washed (3 x 100 mL) with Na2C03 then brine, dried with

MgS04, filtered and then concentrated under reduced pressure. The sulfoxide product

was isolated using flash chromatography through silica gel with EtOAchexanes as the

eluent. Sulfoxide yields were calculated from the disuifide.

Synthesis o f (Z)-2-Chloro-2-PhcnyI-l-Trimethylsilylethenyl2-(TrimethylJilyl)ethyl Sulfoxide (116a):

TMS

Disulfide 114 (1.22 g, 4.59 mmol) in dry CH2C12 (40 mL) was treated with SO2C12 (5.96

mL, 5.96 mmol) followed by the addition of 1-(trimethylsilyl)-2-phenylacetylene (1.60 g,

9.17 mmol). The crude sulfide was concentrated under reduced pressure and oxidized

with mCPBA (2.2 1 g, 7.80 mmol) in CH2C12 (40 mL). Sulfoxide ll6a (2.67 g, 70%, 2

steps) was isolated as a solid afler flash chromatography (EtOAchexanes). Mp: 6 1-63 OC

(recrystallized); 'H NMR (400 MHz), 8: 7.50-7.47 (m, 3H), 7.36-7,32 (rn, 2H), 2.60 (m.

lH), 2.40 (m, IH), 0.82 (dt, J=14.0 & 4.0 Hz, lH), 0.57 (dt, J=14.0 & 4.0 Hz, lH), 0.51

(s, 9H), 0.00 (s, 9H); '3~NMR(100.6 MHz),S: 152.7, 150.5, 130.5, 129.4, 128.9, 128.2,

47.0, 9.8, 1.2, 0.0; iR (CH2C12), cmm': 303 1, 2953, 2899, 14 14, 1252, 1 156, 1050, 955,

850; MS (CI, NH3) mlz (%): 359 ((M+H)', 14), 241 (13), 177 (15), 175 (48), 134 (13).

103 (Sl), 93 (24), 91 (100), 75 (26), 61 (37), 59 (17), 57 (43), 56 (17); Analysis calc'd

for C I ~ H ~ ~ C ~ O S S ~ ~ : C, 53.52; H, 7.58; found: C, 53.95; H, 7.72.

Synthesis of (E)-2-Chloro-2-(l-ButyI)-l-trimethylsilylethenyl2-(Trimethylsilyl)ethyl Sulfoxide (1 l6b):

Disulfide 114 (1.04 g, 3.91 mmol) in dry CH2C12 (40 mL) was treated uith SO2Clz (5.08

mL, 5.08 mmol) followed by the addition of 1-(trimethylsi1yl)-1-hexyne (1.20 g, 7.82

mmol). The crude sulfide was concentrated under reduced pressure and oxidized with

mCPBA (2.10 g, 7.41 mrnol) in CH2C12 (40 mL). Sulfoxide l l6b (1.59 g, 60%, 2 steps)

was isolated as an oil afier flash chromatography (20% EtOAchexanes). 'H NMR (400

MHz). 6: 2.83 (dt, J=13.8 & 4.0 Hz, l m , 2.71 (dt, J=L3.8 & 4.0 Hz, lH), 2.74-2.42 (m,

2H), 1.71 (m, lH), 1.58-1.32 (m, 3H), 0.93 (m. 3H), 0.59 (dt, J=13.8 & 4.0 Hz, IH), 0.31

(s, 9H), 0.04 (S. 9H); I3c NMR (100.6 MHz), 6: 155.6, 146.3, 48.6, 3 1.1, 26.0, 23.2,

13.7, 10.6, 0.94, -1.9; IR (neat), cm": 2957, 2937, 1460, 1415, 1252, 1156,1093, 938;

MS (EI), m/z (%): 3 10 ((M)', 4), 275 (8), 196 ( 1 1), 147 (37), 10 1 (25), 93 (26). 85 (46),

74 (48), 73 (39), 72 (100), 69 (33), 36 (46); Anatysis calc'd for Cl*H3~CIOSSi2: C, 49.59;

H, 9.2 1; found: C, 49.50; H, 9.00.

Synthesis of (E)-2-Chloro-l-trimethylsilylethenyl2-(Trimethylsilyl)ethyl Sulfoxide (1 1 oc):

Disulfide 114 (1.01 g, 3.79 mrnol) in dry CH2Cl2 (40 mL) was treated with SOzC12 (4.93

mL, 4.93 mmol) followed by the addition of 1-(trimethylsilyl)acetylene (1.07 mi,, 7.58

mmol). The crude sulfide was concentrated under reduced pressure and oxidized with

mCPBA (2.26 g, 7.98 mmol) in CH2Ch (40 mL). Sulfoxide 116c (1.14 g, 53%, 2 steps)

was isolated as an oil afler flash chromatography (10% EtOAchexanes). 'H NMR (400

MHz), 6: 7.00 (s, IH), 2.80 (m, IH), 2.65 (m, lH), 0.87 (dt, J=13.9 & 4.3 Hz, IH), 0.71

(dt, k13 .9 & 4.3 Hz, IH), 0.32 (s, 9H), 0.04 (S. 9H); 13c NMR (100.6 MHz), 6: 153.2,

145.6, 50.3, 8.9, -0.19, -2.0; IR (neat), cm": 2955, 2895, 1414, 1252, 1045, 849, 761;

MS (CI, NH,), rn/z (%): 283 (o., 74), 219 (19); 165(13), 147 (29), 105 (lm), 101

(18), 91 (34), 73 (27), 65 (71); Analysis calc'd for Cid&IOSSi2 : C, 42.45; H, 8.19;

found: C, 42.59; H, 8.21,

Synthesis of ~Z)-2-Chlor~l-trimethylsiiyIethenyl2-(Trimethylsilyl)ethyl Sulfoxide (1 l6d):

Disulfide 114 (430 mg, 1.62 mmol) in dry CHzClz (40 mL) was treated with SOlClz (2.83

rnL, 2.83 mmol), warmed to room temperature, followed by the addition of

(trimethylsilyl)acetylene (456 pL, 3.23 mmol). The crude sulfide was concentrated under

reduced pressure and oxidized with mCPBA (837 mg, 2.96 mmol) in CH2Clz (40 mL).

Sulfoxide 116d (466 mg, 5 1%, 2 steps) was isolated as a solid dter flash chromatography

(1 0% EtOAchexanes). Mp: 36-39 O C (recrystallized); 'H NMR (400 MHz), 6: 6.58 (s,

IH), 2.82 (m, 2H), 1.05-0.95 (m, 2H), 0.24 (s, 9H), 0.05 (s, 9H); 'y C (100.6 MHz),

6: 148.1, 143.9, 48.9, 8.6, -1.9, -2.7; IR (CDCI,), cm": 2954, 2892, 1559, 125 1, 1043,

921; MS (CI, NI-&), m/z (%):283 ((M+H)*, 33), 91 (13). 90 (100), 74 (IO), 73 (21);

Analysis calc'd for CIOHDCIOSS~~: C, 42.44; H, 8.49; found: C, 42.55; H, 7.94.

6.2.2. General Method for the Desiiylation of 1-Alkenyl 2-(Trimethylsilyl)ethyl Sulfoxides

The vinyl TMS group was removed by preparing a solution of the silylated

sulfoxide 116 in MeOH (5 mL/mrnol) followed by the inunediate addition of &CO3 (1 to

5.5 equiv). The reaction was stirred for 1 hour then tiltered and concentrated under

reduced pressure. The desilylated product was isolated using flash chromatography

through silica gel with EtOAchexanes as the eluent.

Synthesis of (Z)-2-Chloro-2-phenylethenyl2-(Trimethylsilyl)ethyl Sulfoxide (1 l9a):

Sulfoxide (520 mg, 1.45 mrnol) was treated with K2C03 (200 mg, 1.45 mmol) in

methanol to aford sulfoxide 119a (333 mg, 80%) as an oil d e r chromatography (10%

EtOAcIhexanes). 'H NMR (400 MHz), 6: 7.49 (m, 3H), 7.39 (m, 2H), 6.8 1 (s, 1 H), 2.70

(dt, J=14.0 & 4.0 Hz, lH), 2.30 (dt, J=14.0 & 4.0 Hz, lH), 0.96 (dt, J=14.0 & 4.2 Hz,

lH), 0.73 (dt, 5-14.0 & 4.2 Hz, IH), 0.00 (s, 9H); I3c NMR (100.6), 6:143.5, 129.8,

129.6, 129.0, 128.3, 122.7,46.2, 5.5,O.O; IR (neat), cm": 3060, 2953, 29 14, 2895, 1627,

1594, 1489, 1443, 1412, 1294, 1250, 1158, 1094, 1063, 1001; MS (CI, NH3); rnlz (%):

287 ((M+H)*, 33), 171 (37), 169 (100), 15 1 (28), 101 (25), 91 (65), 73 (39); Analysis

calc'd for Ci3H19ClOSSi: C, 54.42; H, 6.68; found: C, 54.22; H, 6.46.

Synthesis of (E)-t-Chloro-2-(l-bu~l)ethenyl 2-(Trimethylsily1)ethyl Sulfoxidc (1 19b):

Sulfoxide 116b (538 mg, 1.59 mrnol) was treated with K2C03 (1.2i gy 8.74 rnmol) in

methanol to afford sulfoxide lt9b (331 mg, 78%) as an oil aAer chromatography

(EtOAc/hexanes). 'H NMR (400 MHz), 6: 6.6 1 (s, IH), 2.8 1 (dt, J= 13.6 & 4.0 Hz, 1 H),

2.59(dt, J=13.6&4.0Hz, IH), 2.49(ddd, J=14.6, 8.8 &6.4Hz, IH), 2.09(ddd, J=14.6,

8.8 & 6.4 Hz, 1 H), 1.57-1.50 (m, 2H), 1.39 (sextet, J=7.4 Hz, 2H), 0.93 (t, J=7.4 Hz,

3H), 0.86 (dt, 3=13.8 & 4.4 Hz, IH), 0.73 (dt, J=13.8 & 4.4 Hz, IH), 0.04 (s, 9H); I3c

NMR ( 100.6 MHz), 6: 144.8, 122.8,47.5, 29.5, 25.7, 22.5, 13.5,6.9, .-2.0; IR (neat), cm*

': 2946, 2869, 162 1, 146 1, 1414, 1254, 1 159, 1095, 1050; MS (EI), d z (%): no Mc

peak, 238 (9) , 196 (17), 124 (1 l), 101 (34), 85 (45), 75 (34), 74 (32), 73 (100), 59 (40);

Analysis calc'd for CIIHUCIOSS~: C, 49.50; H, 8.69; found: C, 49.71; H, 8.57.

Syn t hesis o f (E)-2-Chloroeihenyl2-(Trimethylsilyl)ethyl Sulfoxide (1 19c):

Sulfoxide 116c (571 mg, 2.02 mmol) was treated with & C a (280 mg, 2.02 mmol) in

methanol to a o r d suifoxide t19c (206 mg, 49%) as an oil afler chromatography

(EtOAchexanes). 'H NMR (400 MHz), 6: 6.80 (dl J=l3.2 Hz, lH), 6.62 (d, J=13.2 Hz,

IH), 2.75 (m, 2H), 0.86 (m, 2H), 0.05 (s, 9H); I3c NMR (100.6 MHz), 6: 134.8, 128.3,

49.7, 7.6, -1.9; IR (neat), cm-': 2956, 1583, 1265, 1251, 1050, 920; MS (CI, Ni+), m/z

(%): 283 ((M+TMS)*, 76), 2 1 1 ((M+H)I, 9). 167 (17), 149 (29), 147 (29), 102 (IO), 101

(87), 93 (16), 75 (19), 74 (15), 73 (100); Analysis calc'd for CiH15CIOSSi: C, 39.89; H,

7.17; found: C, 39.00; H, 7.18.

Synthesis of (Z)-2-Chloroethenyl t-(Trimethylsilyl)ethyl Sulfoxide (1 19d):

Disulfide 114 (553 mg, 2.08 mmol) in dry CH2CI2 (40 rnL) and was cooled to -78 OC and

treated with S02C12 (2.49 mL, 2.49 mmol) followed by the addition of

trimethylsilylacetylene (590 pi-, 4.15 mmol) aller 15 minutes. The cmde sulfide was

concentrated under reduced pressure then redissolved in MeûH (10 mL) and treated with

K2C03 (390 mg, 2.82 mmol) at rt. M e r 1 hour the reaction mixture was filtered and

concentrated under reduced pressure. The crude sulfide was oxidized with mCPBA (445

mg, 2.32 mmol) in CH2CI2 (40 rnL) at -78 O C to fiord sulfoxide 119d (172 mg, 20%) as

an oil after flash chromatography. I l i NMR (400 MHz), 6: 6.63 (d, J=7.0 Hz, lH), 6.47

(d, J=7.0 Hz, IH), 2.85-2.30 (m, ZH), 0.94-0.79 (m, 2H), -0.03 (s, 9H); I3c NMR (100.6

MHz). 8: 138.0, 127.2, 49.3, 8.35, -1.91; CR (mat), cm": 2954, 2899, 1575, 1251, 1161,

1043; MS (CI, NHJ), mlz (%): 21 1 ((M+H)', 151, 9 1 (IO), 90 (100), 73 (1 8); Analysis

calc'd for CiH15CIOSSi: C, 39.89; H, 7.17; found: C, 39.68; H, 6.99.

Syn thesis of 1-Propynyl t-(Trimethylsilyl)ethyl Sulfoxide (1 23):

A solution of 1-bromo-1-propene (700 pL, 8.05 mmol) in dry THF was cooled to -78 O C

under Nz. tr-BuLi (4.72 mL, 11.8 mrnol) was added dropwise and then stirred for 2 hours

at -78 O C . Sulfinate 122 (966 mg, 5.37 rnmol) was added and the solution was stirred

until the reaction was judged complete by TLC analysis (1-2 hours). The reaction was

quenched with W C 1 (aq) and the organic layer was separated. The aqueous layer was

extracted with EtOAc and the organic layers combined. The organic layer was then

washed (3 x 50 mL) with NtkCI, and brine, and dried with MgSO4, filtered and

concentrated under reduced pressure. Sulfoxide 123 (612 mg, 61%) was isolated as an oil

after flash chromatography (25% EtOAchexanes). 'H NMR (400 MHz), 6: 2.95 (m, 2H),

2.09 (s, 3H), 1.01 (m, 2H), 0.06 (s, 9H); "C NMR (100.6 MHz), 8: 101.1, 76.4, 52.5,

8.6, 4.8, -1.9; [R(neat), cm-': 2954,2896, 2192, 1418, 1160, 1096, 1062, 1032, 886.

Synthesis of (E)-1-Propenyl2-(Trimethylsilyl)ethyl Sulfoxide (121):

To a THF (10 mL) solution of sulfoxide 123 (732 mg, 3.89 mmol), DiBAL (4.7 mL, 4.67

mmol; 1 M solution in heptanes) was added dropwise at -78 OC under Nz. M e r 1 hour the

reaction was quenched with NttCI. The organic layer was separated, washed with brine,

dried with MgS04,filtered and concentrated under reduced pressure. Sulfoxide 121 (676

mg, 91%) was isolated as an oil d e r flash chromatography (25% E!OAc/hexanes). 'H

NMR (400 MHz), 6: 6.44 (dq, J=15.0 & 6.8 Hz, IH), 6.16 (dq, J=15.0 & 1.4 Hz, IH),

2.65 (m, 2H), 1.92 (dd, J=6.8 & 1.4 Hz, 3H), 0.82 (m, 2H), 0.03 (s, 9H); 13c NMR

(100.6 MHz), 6: 137.1, 133.0, 49.3, 17.9, 8.0, -1.9; IR (neat), cm-': 2952, 2915, 2857,

1635, 1441, 1417, 1294, 1159, 1099, 1051, 1016, 954; MS ( ), m/z (%): submitted;

Analysis calc'd for CJilsOSSi: C, 50.47; H, 9.53; found: C, 50.61; H, 9.67

6.2.3. General Method for the Oxidative Fragmentation of t-Alkenyl 2- (Trimethylsilyl)ethyI Sulfoxides

A solution of l-alkenyi 2-(trimethy1silyl)ethyl sulfoxide (1.0 equiv) was prepared in dry

CH2C12 (1 0 mi,) and cooled to -78 O C under N2. While stimng, SOzClz (usuatiy 1.1 - 1.3

equiv, as a IM solution in CH2CI2) was added via syringe. The mixture was stirred for 10

minutes then allowed to warrn to room temperature over 60 minutes, and a sample (500-

900 BL) was taken for IR analysis. Upon cooling to -78 O C , 3-phenyl-l-propanol or

cyclohexanol (0.9-1.0 equiv) was added, followed by the immediate addition of &CO3

(2.5 to 4 equiv). The reaction mixture was stirred for 10 min., followed by warming

slowly to room temperature for 2 to 3 hours. When complete by TLC analysis, the

reaction mixture was filtered through a bed of CeliteTM and concentrated under reduced

pressure. The vinyl sulfinate product was then isolated using flash chromatography

through silica gel with EtOAc and hexanes as the eluent. Sulfinate yields were calculated

fiom the alcohol limiting reagent.

Synthesis of Cyclohexyl (E)-2-Chloro-2-phenyI-l-(trimethylsilyl)ethenesulfinate (125a):

Ph

TMS

The reaction of sulfoxide 116a (3 17 mg, 0.885 mmol) with S02C12 (1.2 mL, 1.15 mmol)

provided sulfinyl chloride (S=O stretch 1153 cm*'). Addition of cyclohexanol (100 PL.

0.84 1 mmol) and KK03 (306 mg, 2.21 mmol) afforded sulfinate ester 125a, as a pair of

rotational isomers (273 mg, 87%), as an oil afier flash chromatography (8%

EtOAcIhexanes). 'H NMR (400 MHz), 6: 7.48-7.43 (m, 3H), 7.35-7.32 (m, 2H), 4.27 (m,

IH -major isomer), 4.19 (m. 1H -minor isomer), 2.1 1 (rn 1 H), 1.85- 1.47 (m, SH), 1.45-

1.26 (m, 4H), 0.41 (s, 9H); I3c NMR (100.6 MHz), 6: major isomer: 130.3, 129.2, 128.6,

128.8, 77.9, 33.4, 32.9, 25.1, 23.5, 0.77; rninor isorner that can be observed: 78.7, 33.5,

33.0; IR (neat), cm": 3056, 2937, 2859, 1414, 1369, 1266, 1252, 1135, 961, 845; MS

(CI, NH3), m/z (%): 429 ((M+TMS)', 19), 357 ((M+H)', 100), 303 (1 7), 277 (28). 275

(64), 257 (14). 175 (3 L), 121 (38), 83 (18), 73 (15); Analysis calc'd for Ci1H25C102SSi:

C, 57.20; H, 7.06; found: C, 56.97; H, 6.92.

Synthesis of IPhenylpropyl (E)-2-Chloro-2-(l-butyI~l-(trimcthylsilyl)ethen~ sulfinate (125b):

The reaction of suifoxide 116b (279 mg, 0.825 mmol) with SOzClz (1.07 rnL, 1.07 mmol)

provided sulfinyl chloride (S=O stretch 1149 cm -'). Addition of 3-phenyl-1-propanol

(100 PL, 0.743 mmol) and K2C03 (456 mg, 3.30 mmol) afTorded sulfinate ester l2Sb

(168 mg, 59%) as an oil afier flash chromatography (% EtOAcIhexanes). 'H NMR (400

Hz); 6: 7.31-7.28 (m, 2H), 7.22-7.17 (m, 3H), 3.99 (t of AB,, J=10.0 & 6.4 Hz, 2H),

2.77-2.69 (m, 3H), 2.60 (ddd, J=13.3, 10.0 & 6.0 Hz, IH), 2.06-1.99 (m, 2H), 1.68-1.58

(m, ZH), 1.43 (sextet. J=7.2 Hz, 2H), 0.95 (t, J=7.2 Hz, 3H), 0.34 (s, 9H); 13c NMR

(100.6 MHz), 6: 159.9, 148.0, 140.8, 128.5, 128.4, 126.1, 67.2, 31.9, 31.7, 30.9, 25.5,

23.1, 12.8, 0.8; IR (mat), cm": 3027, 2957, 2932, 2872, 1497, 1466, 1455, 1252, 1 139,

1042, 1010; MS (EI), m/z (%): 372 (M', 2), 357 (IO), 239 (17), 139 (17), Il9 (441, 118

(76), 1 17 (17), 105 (1 7), 95 (1 S), 93 (2 l), 92 (18), 91 (86), 8 1 (20), 79 (20), 77 (1 7), 75

(18), 74 (19), 73 (IOO), 65 (18); Analysis calc'd for Ci7H&IOSSi: C, 59.18; H, 8.47;

found: C, 58.97; H, 8.57

Synthesis of 3-Phenylpropyl (E)-2-Chloro-1-(trimtthylsilyl)ethenesulnate (125~):

ius

The reaction of sulfoxide 116c (448 mg, 1.59 mmol) with S02C12 (1.91 mi,, 1.91 mmol)

provided sulfinyl chloride ( S 4 stretch 1137 cm"). Addition of 3-phenyl- 1-propanol (194

PL, 1.43 mmol) and K2C03 (880 mg, 6.37 mmol) afforded sulfinate ester l2Sc (238 mg,

52%) as an oil afier flash chromatography (7% EtOAchexanes). 'H NMR (400 MHz), 6:

7.21-7.16 (m, 2H), 7.12-7.08(m, 3H), 6.59(s, lH), 4.00(t ofAb,, J=IO & 6.4 Hz, 2H),

2.64 (t, J=7.2 Hz, 2H), 1.99- 1.9 1 (m, 2H), 0.16 (s, 9H); 13c NMR (1 00.6 MHz), 6: 149.8,

144.8, 140.8, 128.4 (2 Cs), 126.0, 66.7, 31.7, 3 i.5, -2.7; IR (neat), cm-': 3027, 3004,

2956, 1604, 1568, 1497, 1455, 1382, 1252, 1188, 1124, 1121, 1006, 920; MS (EI), m/z

(%): 3 17 (M*, 14), 1 19 (59, 1 18 (84), 1 17 (36), 105 (28), 104 (1 7), 103 (30), 91 (IOO),

83 (25), 79 (25), 78 (22), 77 (31), 75 (22), 74 (23), 73 (88), 65 (38), 63 (17), 51 (18);

Analysis calc'd for ClJH21CI 4SS i : C, 53.06; H, 6.68; found: C, 52.87; H, 6.67.

The reaction of suifoxide 116d (223 mg, 0.791 mmol) with SO2CI2 (0.950 mL,

0.950 mmol) provided sulfinyl chloride (S=O stretch 1 139 cm-'). Addition of 3-phenyl- 1 - propanol (100 pi, 0.752 mmol) and &CO3 (438 mg, 3.17 mmol) afforded sulfinate ester

12% (1 37 mg, 57%) as an oil d e r flash chromatography (7% EtOAchexanes).

Synthesis of Cyclohexyl (Z)-2-Chloro-2-phenylethcnesulFinste (126a):

The reaction of sulfoxide 119a (182 mg, 0.634 mmol) with SOzCI2 (760 pi-, 0.762 mmol)

provided sulfinyl chloride (S=O stretch 1154 cm-'). Addition of cyclohexanol (57 mg,

0.571 mrnol) and K2CO3 (351 mg, 2.53 mmol) afforded sulfinate ester l26a ( 1 17 mg,

65%) as an oil afier flash chromatography (10% EtOAchexanes). 'H NMR (400 MHz), 6:

7.46-7.36 (m, SH), 7.14 (s, IH), 4.21 (mi l m , 1.80 (m, IH), 1.63 (m, 2H), 1.47 (m, 3H),

1.21 (m, 4H); I3c NMR (100.6 MHz), 6: 148.1, 129.8, 129.2, 128.9, 128.6, 126.5, 79.4,

33.3, 32.9, 24.9, 23.5, 23.3; IR (neat), cm": 3063, 3033, 3005, 2959, 291 1, 2836, 1610,

15 13, 1455, 1303, 125 1, 1 178, 1032, 909; MS (EI), mh (%): 284 (bf, 3), 205 (41), 204

(20), 203 (go), 185 (21), 139 (33). 138 (32), 137 (77), 102 (IOO), 101 (28), 83 (97),

77(21), 67 (SI), 55 (85), 51 (20); Analysis calc'd for Cid1~ClOzS: C, 59.04; H, 6.02;

found: C, 58.83; Hi 5.92,

Synthesis of 3-Phenylpropyl(&2-Chloro-2-(l-butyl)ethencsulfinate (126b):

The reaction of sulfoxide 119b (1 16 mg, 0.433 mmol) with S02C12 (521 pL, 0.521 mmol)

provided sulfinyl chloide (S=O stretch 1154 cm-'). Addition of 3-phenyl-1-propanoi

(59.3 pi,, 0.439 mmol) and K2CO3 (152 mg, 1.10 rnrnol) afforded sulfinate ester 126b (87

mg, 67%) as an oil after flash chromatography (7% EtOAc/hexanes). *H NMR (400

MHz), 6: 7.35-7.30 (m,2H), 7.26-7.21 (m, 3H), 6.90 (s, lH), 3.95 (t of AB,, J=9.8 & 6.4

2H), 2.75 (t, J=7.6 Hz, 2H), 2.62-2.54 (m, 1H), 2.42-2.34 (m, IH), 2.08-2.01 (m,

2H), 1.64-1.57 (m, 2H), 1.44 (sextet, J=7.4 Hz, 2H), 0.98 (t, J=7.4 Hz, 3H); "C NMR

22.6, 13.7; tR (neat), cm-': 3027,2957, 2932, 2873, 2863, 1625, 1601, 1466, 1454, 1 139,

1007; MS (CI, NHJ); mlz (%): 301 ((M+H)', 32), 183 (29), 165 (SS), 119 (IOO), 118

(45), 117 (26), 91 (79), 81 (21). 57 (25), 59 (45); Analysis calc'd for CI5H2&1O1S: C,

59.89; H, 7.04; found: C, 59.70; H, 6.94.

Synthesis of 3-Phenylpropyl(J!+2-Chloroethenesulfinate (126c):

The reaction of sulfoxide I19c (200 mg, 0.95 mmol) with SO2CI2 (670 pL, 0.670 mmol)

provided sulfinyl chloride (S=O svetch Il33 cm"). Addition of 3-phenyl-1-propanol(120

PL, 0.9 1 mmol) and &CO3 (33 1 mg, 2.39 mmol) aorded sulfinate ester l26c (1 33 mg,

57%, from sulfoxide) as an oil after flash chromatography (7% EtOAc / hexanes). 'H

NMR (400 W), 6: 7.32- 7.29 (m, 2H), 7.23 - 7.18 (m, 3H), 6.97 (d, J= 13.2 Hz, IH),

6.68 (d, b13.2, IH), 4.01 (t of AB,, F10.0 & 6.4 Hz, lH), 2.73 (t, J=7.6 Hz, 2H), 2.03

(m, 2H); I3c NMR (100.6 MHz), 6: 140.7, 137.9, 132.3, 128.5, 128.4, 126.1, 65.0, 31.8,

3 1.3; IR (neat), cm": 3062, 3027, 2950, 2886, 1603, 158 1, 1497, 1454, 1 168, 1 125,

1004, 90 1, 834, 772; MS (Cl, NH3), mlz (%): no (M+H)' peak, 183 (2), 1 19 (I4), 1 18

(27), 105 (7). 92 ( 9 , 91 (IOO), 77 (14), 65 (10) Anaivsis calc'd for C11H~3C102S: C,

53.98; H, 5.35; found: C, 53.70; H, 5.09

Synthesis of 3-Phenylpropyl(2')-2-chloroethenesulfin~te (126d):

The reaction of sulfoxide 119d (383 mg, 2.04 mmol) with SOzClz (1.28 mL, 1.28 rnmol)

provided sulfinyl chloride (S=O stretch 1 165 cm-'). Addition of 3-phenyl-1-propanol(280

PL, 2.04 mmol) and KzC03 (704 mg, 5.09 mrnol) afforded siilfinate ester l26c (143 mg,

32%, from sulfoxide) as an oil and 126d (123 mg, 27%, from sulfoxide) as an oil which

could not be completely purified using flash chromatography (7% EtOAdhexanes). 'H

NMR (400 MHz), 6: 7.22-7.16 (m, 2H), 7.12-7.08 (m, 3H), 6.64 (d, 5=7.0 Hz, IH), 6.53

(d, J=7.0 Hz, IH), 4.06 (m, IH), 3.95 (m, IH), 2.64 (t, J=7.2 Hz, 2H), 1.99-1.92 (rn, 2H);

'" NMR ((100.6 MHz), 8: 140.7, 139.9, 128.4 (2 C's), 128.2, 126.1, 66.6, 31.7, 31.5; IR

(neat), cm": 3085, 3028, 2% 1, 2884, 1574, 1497, 1454, 1249, 1 15 1, 1006; HRMS FI),

Calcd. For C ~ ~ H ~ ~ ~ ~ C I O ~ S : 245.040; found: 245.040.

NOTE The reaction of sulfoxide 119d (153 mg, 0.734 mmol) with SOzC12 (0.770 mL,

0.770 mmol) provided sulfinyl chloride. Addition of 3-phenyl-1 -propanol ( 100 PL, 0.770

mmol) and &Co3 (406 mg, 2.94 mmol) afforded the pans isomer sulfinate ester 126c (60

mg, 34%, frorn sulfoxide) as an oil(7% EtOAchexanes).

Synthesis of 3-Phenylpropyl 1,2-Dichloropropanesulfinate (127):

The reaction of sulfoxide 121 (132mg, 0.694 mmol) with SOzC12 (902 pL, 0.902 mmol)

provided sulfinyl chloride (S=O stretch 1 145 cm"). Addition of 3-phenyl-1 -propanol (89

PL, 0.659 mmol) and K2C03 (192 mg, 1.39 mmol) afîorded sulfinate ester 127 (52 mg,

27%) as an oil afier flash chromatography (15% EtOAcIhexanes). 'H NMR (400 MHz),

6: 7.27-7.24 (m, 2H), 7.21-7.14 (m, 3H), 4.59-4.54 (m, 2H), 4.14-4.08 (m, 2H), 2.71 (t,

J=7.2 Hz, 2H), 2.06- 1.99 (m, 2H), 1.66- 1.6 1 (m, 3H); I3c NMR (100.6 MHz), 6: 140.5,

128.5, 128.4, 126.2, 81.5, 69.2, 54.5, 31.6, 31.5, 20.5; IR, (neat), cm": 3027, 2953, 2867,

1604, 1497, 1497, 1464, 1455, 1383, 1249, 1136, 1051, 1016; HRMS (EI), Calcd. For

~ 1 ~ ~ 1 7 ~ ~ ~ 1 2 0 2 s : 295.0323; found: 295.0308.

6.3. Synthesis of f3-Keto Vinyl Sulfoxides

6.3.1. General Method for the Synthesis of P-Keto Vinyl Sulfoxides

To a solution of 1-alkene DPM (or PMB) sulfoxide (1 .O equiv) in dry CH2C12 (10

mi,) at -78 OC was added SOzCI2 (1.1 to 1.3 equiv, as a 1M solution in CH2C12) via

syringe. The mixture was stirred for 10 minutes then allowed to warm to room

temperature over 1 hour. Upon cooling to -78 OC, a solution of trimethylsilyl vinyl ether

(1.0 equiv) in dry CHzClz was added via syringe, followed by the imrnediate addition of

TiCI, (0.1 equiv, as a LM solution in CH2Ch). The reaction was allowed to stir at

-78 O C for 30 to 60 minutes. The reaction mixture was then quenched with the addition of

1 mL of deionized water and was warrned to room temperature. The layers were

separated and the aqueous layer was washed with CHzClz (2 x 10 mL). The combined

organic layers were washed with bnne, dried with MgSOd, filtered and concentrated under

reduced pressure. The P-keto sulfoxide product was then isolated using a shon neutral

alumina plug with 20 to 80% EtOAc and hexanes (gradient).

Synthesis of Ethenesulfinylmethyl Phenyl Ketone (132a):

Sulfinyl chloride 131c generated fiom ethenyl PMB sulfoxide l29a (606 mg, 3.09 mmol)

was treated with 1-(trimethylsiloxy)styrene (594 mg3.07 mrnol) and TiCI, (3 10 a, 0.3 1

mmol) to afford P-keto sulfoxide 132a (356 mg, 59%) as a solid after a neutral alurnina

plug. Mp.: 54-55 O C (recrystallized from hexanes); 'H NMR (400 MHz), 6: 7.95 (m,

2H), 7.64 (rn, lH), 7.5 (m, lH), 6.92 (dd, J= 9.8 & 16.47 Hz, l m , 6.19 (d, J=16.5 Hz,

1H), 6.01 (d, 5-9.8 Hz, IH), 4.40 (AB,, J=14.5 Hz, 2H); 13c NMR (100.6 MHz), 6:

191.7, 140.5, 135.8, 134.3, 128.9, 128.8, 122.4, 62.3; IR (CDCb), cm": 3062, 3005,

2950, 2903, 1673, 1596, 1580, 1449, 1369, 1278, 1 197, 1057, 990; MS (El), dz (%):

194 (MF, SS), 146 (1 6), 105 (1 OO), 1 O3 (1 l), 9 1 (72) 77 (72) 65 (22); Analysis calc'd for

CioHioO~S : C, 61.78; H, 5.15; found: C, 61.74; H, 5.13.

Synthesis of (E)-3,3 Dimethyt-1-butenesulfinylmcthyl Phtnyl Ketone (132b):

Sulfinyl chloride 131b generated fiom 3,3-dirnethyl-1-butenyl PMB sulfoxide l29b (223

mg; 0.75 mmol) was treated with 1-(t~methylsiloxy)styrene (143 mg; 0.75 mmol) and

Tic14 (75 PL; 0.07 mmol) to afford P-keto sulfoxide 132b (135 mg; 72%) as a solid afier

a neutral alumina plug. Mp: 59-61 O C (recrystallized fiom hexanes). 'H NMR (400 MHz),

8: 7.96 (m, 2H), 7.62 (m, IH), 7.51 (m, lH), 6.45 (d, J=15.4 Hz, lH), 6.28 (d, J=15.4 Hz,

IH), 4.37 (AB,, J=13.7 Hz, 2H), 1.03 (s, 9H); I3c NMR (100.6 MHz), 6: 191.4, 151.3,

136.2, 134.2, 128.9, 128.8, 127.6, 62.4, 34.2, 28.6; iR(CH2Cld, cm": 3067, 2961, 2906,

2867, 1674, 1597, 1580, 1449, 1364, 1277, 1197, 1054, 992, 973; MS FI), m/z (%):

250 (M', 33), 13 1 (18), 120 (20), 105 (IOO), 99 (16), 9 1 (57), 83 (20), 8 1 (24). 79 (20),

77 (61), 69 (20), 67 (16), 65 (26), 57 (31), 55 (30); Analysis calc'd for Ci&tigO2S: C,

67.21; H, 7.19; found: C, 67.23; H, 7.40.

Synthesis of (E)-3,3-Dimethybt-butenesulfinylmtthyl Ketone (132bb):

Sulfinyl chloride 131 b generated tiom 3,3-dimethyl- 1-butenyl DPM sulfoxide

130b (3 70 mg, 1.29 mmol ) was treated with 2-(trimethylsiloxy)propene (207 pL, 1.24

mmol) and Tic& (124 pl.,, 0.12 mmol) to afford B-keto sulfoxide 132bb (38.9 mg, 17%)

as an oil after a neutral alumina plug. 'H NMR (400 MHz), 6: 6.49 (d, J=15.4 Hz, lH),

6.18 (d, J=15.4 Hz, IH), 3.73 (AB,, 5=13.4 Hz, 2H), 2.29 (s, 3H), 1.09 (s, 9H); I3c NMR

(100.6 MHz) 6: 199.5, 151.4, 130.0, 62.4, 34.2, 32.4, 28.9; IR (neat), cm-': 3054, 2965,

2907, 2869, 1713, 1623, 1421, 1363, 1265, 1058,971; MS (El), m/z (%): 188 (M', 71),

140 (20), 13 1 (94), 113 (53), 101(22), 99 (do), 98 (21), 85 (57), 83 (79, 81 (87), 79

(93), 69 (39, 67 (53), 65 (74), 59 (32), 57 (84), 55 (IOO), 53 (42); Analysis calc'd for

C9H,&S: C, 57.41; H, 8.57; Found: C, 58.00; H, 8.03

Synthesis of 1-Cyclohexenesulfinylmethyl Phenyl Ketone (132~):

Sulfinyl chlotide 131c generated fiom cyclohexyl PMI3 sulfoxide 129c (283 mg;

0.96 mmol) was treated with 1-(trimethy1siloxy)styrene (184 mg; 0.96 mmol) and TiC14

(100 pi.,; 0.10 mmol) to afford P-keto sulfoxide 132c (98 mg; 41%) as a semi-solid after a

neutral alumina plug. 'H NMR (400 MHz), 6 : 7.97 (m, 2H), 7.63 (m, lH), 7.54 (m, LH),

6.37 (m, lH), 4.31 (AB,, J=13.1 Hz, 2H), 2.42 (m, IH), 2.15 (m, 3H), 1.73 (m, 3H), 1.56

(m, IH); ''c NMR (100.6 MHz), 6: 191.4, 140.6, 136.4, 134.0, 133.9, 128.9, 128.8,

59.9, 24.5, 2 1.9, 2 1.7, 20.3; IR (neat), cm-': 3059, 2935, 2861, 1676, 1596, 1579, 1448,

13 15, 1275, 1055, 992; MS (EI) mlz (%): 248 v, 12), 129 (72), 120 (24), 105 (IOO),

103 (37), 91 (56), 84 (46), 80 (28), 79 (79), 78 (20), 77 (85), 65 (28), 53 (32); Analysis

calc'd for C l ~ l 6 0 2 S : C, 67.74; H, 6.45; found: C, 67.98; H, 6.65.

Synthesis of 2-([a-2-Phenyltthenesufinyl) cyclohexanone (132d):

Sulfinyl chloride 131d generated fiom 2-phenylethenyl DPM sulfoxide 130d (274

mg, 0.80 mmol) was treated with 1-cyclohexenyloxytrimethylsilane (25 1 pi, 1.29 mmoi)

and K2C03 (595 mg, 4.3 1 mmol) to afFord P-keto sulfoxide 132d (76 mg, 35%) as an oil

afier a neutral alumina plug. 'H NMR (400 MHz), 6: 7.45 (m, 2H), 7.36 (m. 3H), 7.28 (d,

J=l5.5 Hz, IH), 7.05 (d, J=15.5 Hz, IH), 3.51 (dd, J 4 . 9 & 10.1 Hz, IH), 2.56-2.37 (m,

3H). 2.25-2.06 (m, 3H), 1.91-1.70 (m, 2H); "C NMR (100.6 MHz), 6: 206.2, 137.5,

129.6, 129.5, 128.8, 127.6, 73.1, 42.4, 27.2, 26.4; IR (neat), cm-': 3057, 2935, 2891,

1703, 16 14, 1446, 1330, 1294, 1 125, 1045, 965; MS (EI), d z (%): 248 (M. 62), 152

(581, 13 1 (IO()), 135 ((je), 134 (46), 123 (91), 104 (44), 102 (39), 97 (36), 91 (91), 77

(841, 69 (72),68 (70), 55 (go), 5 1 (57); Analysis calc'd for Ci&OzS: C, 67.71; H 6.49;

Found: C, 67.54; H, 6.21.

Synthesis of (2) and (E)-2-Chloro-2-(1-butyl)ethenylsulfinylmethyl Phenyl Ketone (132e and 132ee):

Sulfinyl chloride generated fiom (E)-2-chloro-2-n-butylethenyl 2-(trimethylsi1yl)ethyl

sulfoxide 119b (393 mg, 1.16 mmol) was treated with 1-(trimethylsi1oxy)styrene (245 mg,

1.28 rnmol) and TiCk (120 pL, 0.116 mmol) to afEord a mixture of the (EIZ) isomers: (2)-

132e (35 mg, 9%) and (E)-132ee (33 mg, 9%) as a separable oii afler a neutral alumina

plug. (Zb132e: 'H NMR (400 MHz), 6: 8.01-7.94 (m, 2H), 7.63 (m, lH), 7.51 (m, 2H),

4.35 (Ab,, J=13.8, 2H), 2.79 (dddd, J=13.4, 11.6 & 5.2 Hz, IH), 2.62 (dddd, k13.4,

1 1.6, 5.2 Hz, l m , 1.76- 1.30 (m. 4H), 0.93 (t, J=7.2 Hz, ZH), 0.30 (s, 9H); "C NMR

(100.6 MHz), 6: 191.0, 155.2, 135.9, 134.3, 128.9, 128.8, 61.2, 31.2, 26.7, 23.2, 13.7,

0.51; IR (neat), cm-': 3056, 2935, 2890, 1705, 1613, 1447, 1330, 1295, 1126, 1045, 996;

IEI-132ee: 'H NMR (400 MHz), 6: 8.01-7.92 (m, 2H), 7.63-7.59 (m, lH), 7.50 (m, 2H),

4.3 9 (Ab,, J= 13.2 Hz, 2H), 2.54-2.40 (m, 2H), 1.55- 1 .JO (m, 4H), 0.90 (t, J=7.2 Hz, 2H),

0.51 (S. 9H); "C NMR (100.6 MHz), 6: 191.1, 156.3, 136.3, 133.9, 128.9, 128.8, 60.4,

33.9, 27.1, 22.9, 13.8, -0.7; IR (neat), cm": 3056, 2934, 2989 1710, 1614, 1445, 1329,

Attempted Synthesis of (E)-2-Carbomethoxyethenesulfinylmethyl Phenyl Ketone (L32f):

Sulfinyl chloride 131f generated from (E)-2-carbomethoxyethenyl PMI3 sulfoxide 1291

(388 mg; 1.53 mmol) was treated with 1-(trimethylsiloxy)styrene (345 pL, 1.79 mrnol)

and Tic14 (150 &, 0.15 mmol) to aiEord f3-keto sulfoxide 132f. 'H NMR (400 MHz,

partial spectmm from crude reaction mixture), 6: 7.90-7.84 (m, 2H), 7.81 (d, J =15.4 Hz,

1H), 7.77-7.34 (m, 3H), 6.66 (d, J=15.4 Hz, lH), 4.44 (AB,, J=15.0, 2H), 3.80 (s, 3H).

Chromatography on a neutral alumina plug afforded the cyclized product, oxathiin S-oxide

134a (189 mg, 49%) as a partially separable 6: 1 ratio of diastereomers, which could not

be türther purified. Maior Isomer. 'H NMR (400 MHz), 6: 7.70 (m, 2H), 7.5 1-7.41 (m,

3H), 6.62 (s, lH), 5.39 (dd, J=8.8 & 5.3 Hz, lH), 3.82 (s, 3H), 3.32 (center of ABX

pattern, J ~ ~ 1 7 . 6 Hz, J ~ 1 3 . 8 Hz, Je1~5.3 Hz, 2H), I3c MUR (100.6 MHz), 6: 169.5,

167.0, 13 1.8, 128.8, 127.8, 127.3, 102.0,94.1, 52.5, 30.4. Minor Isomer. 'H NMR (400

MHz), 6: 7.70 (m, 2H), 7.51-7.41 (m, 3H), 6.52 js, 3H), 5.88 (dd, 1- 8.0 & 6.6 Hz, IH),

3.79 (s, 3H), 2.85 (center of ABX pattern, J,~=16.5 Hz, JAk=8.0 fi, Jah=6.6 Hz, 2H).

13 C NMR (100.6 MHz), assignable signals only, 6: 13 1.9, 127.4, 100.9, 100.1, 52.5, 34.8.

HRMS (EI), mi' (mixture of isorners): calcd for Ci&OJS 252.0456, found 252.0458.

Attempted Synthesis of (E)-2-carbomethoxyethenesulfinylmethyl Methyl Ketone (132fî):

Sulfinyl chloride 131f generated fiom [El-2-carbomethoxyethenyl PMI3 sulfoxide

129f (23 1 mg; 0.9 1 mmol) was treated with 2-(trirnethylsiloxy)propene (1 78 pL, 1 .O7

mmol) and TiClJ (100 pL, 0.09 mmol) to atTord B-keto sulfoxide 132ff. 'H NMR (200

MHz, crude reaction mixture) 6: 7.69 (d, J=15.0 Hz, lH), 6.66 (d, J=15.0 Hz. IH), 3.95

(AB,, J=14.7 Hz, 2H), 3.78 (s, 3H), 2.29 (s, 3H). Chromatography on a neutral alurnina

pluç afforded the cyclized product, oxathiin S-oxide 134b (20 mg 12%) as a 20: 1 ratio of

diastereomers which could not be fiirther purified. Data for major isomer only: 'H NMR

(400 MHz), 6: 6.02 (s, LH), 5.18 (dd, H . 8 & 5.7 Hz, lH), 3.94 (s, 3H), 3.18 (center of

ABX pattern, JI\B = 17.6 Hz, Jr~y = 8.1 & J B ~ = 5-7 Hz, 2H), 2.1 1 (s, 3H); I3c NMR

(100.6 MHz), 6:169.6, 168.8, 104.8, 94.0, 52.5, 30.3, 15.2; iR, cm-': 3104, 2955, 2925,

2853, 1734, 1623, 15 12, 1456, 1374, 13 17, 1 166, 1096, 1042, 996; MS (CI, NH3), mz

(96): 219 (11); 192 (13), 191 (IOO), 159 (l2), 103 (17).

6.4. Asymmetric Synthesis o f (-)-Cbolesteryl LAlkenesulfinate Esters.

6.4.1. General Method for the Oxidative Fragmentation of 1-Alkenyl (DPM or PMB) Sulfoxides

To a solution of 1-alkene DPM (or PMB) sulfoxide (1.0 equiv) in dry CH2CI2 (5

mL/mmol) at -78 O C under Nz was added S@Cl2 (1.1 to 1.3 equiv, as a 1M solution in

CH2CI2) via syringe. The mixture was stirred for 10 minutes then allowed to warm to

room temperature over 1 hour. Upon recooling to -78 O C for 10 minutes the sulfinyl

chloride solution was transferred via syringe to a -78 O C solution of cholesterol and base in

CH2C12 (7.5 mL/mmol). The reaction mixture was allowed to warm siowly to -20°C and

stirred overnight. When complete by TLC analysis, the reaction mixture was concentrated

under reduced pressure. The vinyl sulfinate product was then isolated using silica gel flash

chromatography with EtOAchexanes as the eluent. Sulfinate ester yields were calculated

from the amount of cholesterol added.

Synthesis of (-)-Cholesteryl (-)-[RlsEthenesulfinate (136a):

The reaction of sulfoxide 130a (700 mg, 2.89 mmol) with SOzClz (3.76 mL, 3.76 mmol)

yielded sulfinyl chloride 10. Upon transfemng the sulfinyl chloride to a solution of

cholesterol (950 mg, 2.46 mmol) and quinine (1.13 g, 3.47 mmol) in CH2Cl2 at -78 OC the

reaction mixture was warmed to -20 OC and stirred ovemight. Diastereomerically

enriched sulfinate 136a (650 mg, 57%, 42% [RIS) was isolated as a solid &er flash

chromatography (2 columns, 10% EtOAcIhexanes). Mp (Diastereomerically enriched [RIS

23 sulfinate): 83-84 O C ; [a],: -26.3' (c 2.16, acetone). 'H NMR (400 MHz). 6: 6.67 (dd,

P16.8 & 10.0 Hz, lH), 6.11 (d, J=16.8 Hz, IH), 5.94 (d, J=10.0 Hz, IH), 5.37 (m IH),

4.15 (m, IH), 2.47-2.41 (m, 2H), 1.00 (s, 3H), 0.90 (d, J=6.5 Hz, 3H), 0.85 (d, J=6.6 Hz,

3H), 0.85 (d, J=6.6 Hz. 3H), 0.66 (s, 3H), 2.01-1.03 (m, remaining peaks for cholesteryl

skeleton, 26H); 13c NlMR (100.6 MHz), 6: 143.6. 139.4, 123.9, 123.0, 79.4, 56.6, 56.1,

49.9, 42.2, 40.2, (40.l), 39.6, 39.5, 37.1, (37.1), 36.4, 36.1, 35.7, 31.8,. 31.8, 29.9,

(39.7), 28.2, 28.0, 24.2, 2..8, 22.8,. 22.5, 21.0, 19.2, 18.7, 11.8 (bracketed values are

representative of the [Sjs isomer); 1R (CH2C12), cm-': 2930, 2907, 2868, 2855, 1606,

1468, 1382, 1375, 1368, 1 127, 1027, 1005,970,946; MS (CI, NH3), m/x (%): 386 (33),

370 (24), 369 (87), 368 (100); Analysis calc'd for C&a02S: C, 75.60; H, 10.50; found:

C, 75.54, ; H, 10.35

Synthesis of (-)-Cholesteryl (-)-[SlsEthenesulfinate (136a):

The reaction of sulfoxide 130a (376 mg, 4.03 mmol) with SO2CI2 (5.24 mL, 5.24 mmol)

yielded sulfinyl chloride 10. Upon transfemng the sulfinyl chloride to a solution of

choIesterol(l.33 g.3.43 mmol) and quinidine (1.57 g, 4.84 mmol) in CHzClz at -78 OC the

reaction mixture was warmed to -20 O C and stirred overnight. Diastereomericaily

enriched sulfinate 136a (658 mg, 42%, 17% [SIS) was isolated as a solid d e r flash

chromatography (2 columns. 10% EtOAchexanes). Mp (Diastereomerically enriched [SIs a

sulfinate): 8 1-83 O C ; [a], : - 18.2" (c 2.42, acetone).

Synthesis of (-)-Cholesteryl (-)-[RI&)-(3,3)-Dimethyl-1-butenesullinate (136b):

The reaction of sulfoxide 130b (1.12 g, 3.75 mmol) with SO2CI2 (4.9 mL, 4.88 m o i )

yielded sulfinyl chloride 131b. Upon transferring the sulfinyl chloride to a solution of

cholesterol (1.24 g, 3.19 m o l ) and quinine (1.22 g, 3.75 m o l ) in CH2C12 at -78 OC the

reaction mixture was warmed to rt and s h e d overnight. Diastereomerically enriched

sulfinate 136b (1.36 g, 83%, 39% de [RIS) was isolated as a solid d e r flash

chromatography (3-5% EtOAchexanes). Following crystallization fiom hexanes, the

enantiopure [RIS sulfinate was isolated in a 42% yield (89% [RIS). Following a second

crystallization from hexanes the [RIS sulfinate was obtained diastereomerically pure in a

25 36% yield. Mp (enantiopure [RIs sulfinate): 153-154 OC; [a], : -23.2' (c 1.33, CHC13).

1 HNMR(400MHz): 6: 6.48 (d, k15.7 Hz, IH), 6.22 (d, J=15.7 Hz, lH), 5.37(m, LEI),

4.14 (m, lH), 2.48-2.41 (m, 2H), 1.10 (s, 9H), 1.01 (s, 3H), 0.91 (d, J=6.5 Hz, 3H), 0.87

(d, J=6.6 Hz, 3H), 0.86 (d, J=6.6 Hz, 3H), 0.67 (s, 3H), 0.85-2.02 (remaining peaks for

cholesteryl skeleton, 26 H); ' 3 ~ NMR (100.6 MHz), 6: 152.0, 139.6, 13 1.8, 122.8, 78.7,

56.6, 56.1, 49.9, 42.3, 40.3, 39.7, 39.5, 37.2, 36.5, 36.2, 35.8, 34.0, 31.9, 31.8, 29.7,

28.7, 28.2, 28.0, 24.3, 23.8, 22.8, 22.5, 21.0, 19.3, 18.7, 11.8; IR (CH2C12), cm": 3041,

2944, 2898, 1667, 1623, 1465, 1367, 1129, 1 115, 996,976; MS (CI, NH,), d z (%) CI:

5 16(M', 1 ), 386(8), 37 l(29), 3ïO( 100), 369(7), 368(22), 354(7), 149(10), l33(8), 13 l(5),

115(8), 83(2), 57(12); Anal. Calcd for: C33H5602S: C, 76.68; H, 10.92; found: C, 76.85;

H, 10.68.

The reaction of sulfoxide 130b (902 mg, 3.03 rnmol) with SOzClz (3.63 rnL, 3.63 rnrnol)

yielded sulfinyl chloride 13lb. Upon transfemng the sulfinyl chloride to a solution of

cholesterol (994 mg, 2.57 mmol) and quinidine (1.18 g, 3.63 mmol) in CH2CI2 at -78 O C

the reaction mixture was warmed to -20 O C and stirred overnight. Diastereomerically

enriched sulfinate 136b (1 193.2 mg, 82%, 63% de [SIs) was isolated as a solid &er flash

chromatography (3-5% EtOAdhexanes). Following crystallization fiom acetone the [S]S

sulfinate was isolated in a 3 1% yield (70% [SIS). Following a second crystallization fiom

acetone the diastereomerically eiiriched [SJs sulfinate was isolated in a 12% yield (75% de

25 [SIs). Mp. (Diastereomerically enriched 70% [SIs): 130-132 O C ; [alD: -16.6' (c 1.14,

CHCIj).

The reaction of sulfoxide 130d (457 mg, 1.68 mrnol) with SOzCI2 (2.02 rnL, 2.02 mmol)

yielded sulfinyl chloride 131d. Upon transferring the sulfinyi chloride to a solution of

cholesterol (552 mg, 1.43 mmol) and quinine (654 mg, 2.02 mmol) in CHzClz at -78 OC

the reaction mixture was warmed to -20 O C and stirred overnight. Diastereomerically

enriched sulfinate 136d (562 mg, 73%, 43% [RIS) was isolated as a solid after flash

chromatography (34% EtOAchexanes). Following crystallization fiom hexanes the

enantiopure [RIS sulfinate was isolated in a 21% yield (lOO%[R]s). Mp (Enantiopure [RIS

sulfinate): 158-160 O C ; [a]:: +14.3' (c 2.65. CHCI,). 'H NMR (400 MHz), 6: 7.5 1-7.49

(m, 2H). 7.42-7.38 (m, 3H), 7.27 (d, J=16.0 Hz, IH), 6.92 (d, J=16.0 Hz, l m , 5.37 (m,

IH), 4.21 (m, IH), 2.51-2.45 (rn, 2H), 1.01 (s, 3H), 0.91 (d, J= 6.6 Hz, 3H), 0.87 (d,

J=6.6 Hz, 3H), 0.86 (d, J=6.6 Hz, 3H), 0.67 (s, 3H). 2-02- 1.03 (m, remaining peaks for

choIesteryl skeleton, 26H); 13c NMR (100.6 MHz), 6: 139.5, 138.5, 133.4, 133.2, 130.2,

218.9, 128.0, 123.0, 56.6, 56.1, 49.9, 42.3, 39.7, 39.5, 37.1, 36.5, 36.L, 35.8, 31.9, 31.8,

29.8, 28.2, 28.0, 24.2, 23.8, 22.8, 22.5, 21.0, 19.2, 18.7, 11.8; IR (CH2CIS, cm-': 3050,

291 1,2909,2869,2855, 1614, 1124,973,946; MS (EI), rn/z (%): 369 (2), 119 (12), 118

(24), 9 1 (38), 79 (16), 76 (13), 59 (38), 58 (62), 43 (IOO), 42 (15); MS (positive ion ESI):

537; Analysis calc'd for C35HszOzS: C, 78.30; H, 9.76; found: C, 78.19; H, 9.53.

Synthesis of (-)-Cholesteryl (-)-[RIS-@)-4-Phenyl-l-butenesulfinate (136e):

The reaction of sulfoxide 130e (784 mg, 2.25 mmol) with S02Cl2 (2.70 mL, 2.70 mmol)

yielded sulfinyl chloride 131e. Upon transferring the sulfinyl chloride to a solution of

cholesterol (739 mg, 1.91 mmol) and quinine (875 mg, 2.70 mmol) in CH2C12 at -78 O C

the reaction mixture was warmed to rt and stirred overnight. Diastereomerically enriched

sulfinate 136e (487 mg, 45%, 40% [RIs) was isolated as a solid afler flash

chromatography (34% EtOAchexanes). M e r crystallization from acetone the [qs

sulfinate was isolated in a 7% yield (10% [SIs). Mp @iastereomerically enriched [SIs

25 sulfinate): 108-109 OC; [a], : -1 1.8' (c 1.02. CHCli). 'H NMR (400 MHz). 6: 7.3 1-7.28

(m, 2H), 7.22-7.17 (m, 3H). 6.56 (dt, J=15.6 & 6.8 Hz, Hz, IH), 6.35 (dt, J=15.6 Hz,

IH), 5.37 (m, IH), 4.12 (m, IH), 2.81-2.77 (m, 2H), 2.59-2.38 (m, 4H), 1.01 (s, 3H),

0.91 (d, J=6.6 Hz, 3H). 0.87 (d, 5 4 . 6 Hz, 3H), 0.86 (d, J=6.6 Hz, 3H), 0.67 (s, 3H),

2.03-0.87 (m, remaining peaks for cholesteryl skeleton, 26 H); 13c NMR (100.6 MHz), 6:

141.1, 140.5, 139.5, 136.3, 178.5, 128.3, 126.2, 122.9, 79.1, 56.6, 56.1, 50.0, 42.3, 40.3,

39.7, 39.5, 37.1, 36.4, 36.1, 34.2, 33.4, 31.9, 31.8, 29.7, 28.2, 28.0, 24.2, 73.8, 23.0,

22.5, 2 1 .O, 19.2, 18.7, 1 1.8; IR (CH2CI$, cm-': 3030, 294 1, 2909, 2868, 2855, 1604,

1497, 1468, 1 123,973,946.

Sy nthesis of (-)-Cholesteryl (-)-[R~r(E)-2-Carbomethonyethenes~Ifinate (1361):

The reaction of sulfoxide 129f (721 mg, 2.84 mmol) with SO2CI2 (3.69 mL, 3.69 mmol)

yielded sulfinyl chloride 131f. Upon transferring the sulfinyl chloride to a solution of

cholesterol (933 mg, 2.4 1 mmol) and quinidine (1.1 l g, 3.4 1 mmol) in CHI CI^ at -78 "C

the reaction mixture was warmed to -20 "C and stirred for several hours.

Diastereomerically enriched sulfinate 136f (1 .O 1 g, 8 1%, 12% [RIs) was isolated as a solid

after flash chromatography (3-5% EtOAc/hexanes). Following crystallization from

hexanes the [RIS sulfinate was isolated in a 38% yield (64% [RIs). Following a second

crystallization from hexanes the enantiopure [RIs sulfinate was obtained in a 27% yield

2s Mp (Enantiopure [RIS sulfinate): 130-132 OC; [a],: -25.6' (c 1.06, acetone). 'H NMR

(400 MHz), 6: 7.44 (d, J=15.4 Hz, lH), 6.61 (d, J=15.4 Hz, lH), 5.38 (m, lH), 4.81 (in,

IH), 3.82 (s, 3H), 2.42 (m, 2H), 1.00 (s, 3H), 0.91 (d, J=6.4 Hz, 3H), 0.86 (d, J=6.4 Hz,

3H), 0.85 (d, J=6.8 Hz, 3H), 0.67 (s, 3H), 2.05 - 0.85 (m, remaining peaks for cholesteryl

skeIeton, 26H); 13c NMR (100.6 MHz), 6: 164.3, 149.7, 139.1, 128.0, 123.3, 80.6, 56.6,

56.1, 52.5, 49.9, 42.3, 40.1, 39.7, 39.5, 37.0, 36.4, 36.1, 35.7, 31.8, 31.8, 29.8, 28.2,

28.0, 24.2, 23.8, 22.8, 22.5, 19.3, 18.7, 12.5; IR (CDCb), cm": 3054, 2953, 2865, 1729,

1617, 1467, 1439, 1384, 1371, 1294, 1269, 1222, 1137, 1120, 1027, 994, 971; MS (Cl,

NF&), d z (%): 386 (23), 371 (29), 370 (IOO), 368 (19), 135 (12), 119 (1 l), 103 (23),

87 (13), 65 (18); Analysis calc'd for CJrHsoOsS: C, 71.77; H, 9.71; found: C, 71 SO; H,

9.48

Synthesis of (-)-Cholesteryl (-)-[SIS-(E)-2-Carbomethoxyethenesulfinate (1360:

After multiple crystallizations from hexanes the [SIs sulfinate was isolated

diastereomerically enriched (66% de), Mp @iastereomerically enriched [SIS sulfinate):

25 108- 1 10 O C ; [a],: -1 1.8' (c 1.36, acetone).

Synthesis of (-)-Cholesteryl (-)-[&-(Z)-2-Chlo~2-phenylcthcncsullinte (136g):

The reaction of sulfoxide 119a (55 1 mg, 1.92 mrnol) with S02C12 (2.3 1 mL, 2.3 1 mmol)

yielded sulfinyl chloride 131s. Upon transferring the sulfinyl chloride to a solution of

cholesterol (632 mg, 1.63 mrnol) and quinidine (749 mg, 2.3 1 mmol) in CH2C12 at -78 O C

the reaction mixture was warmed to rt and stirred overnight. Diastereomerically enriched

sulfinate 136g (823 mg, 88%, 100/a [RIS) was isolated as a solid atler flash

chromatography (3-5% EtOAdhexanes). Following crystallization from hexanes the [SIS

sulfinate was isolated in a 23% yield (52% [SIS). Following a second crystallization fiom

hexanes the diastereomerically enriched [SIS sulfinate was isolated in a 12% yield (94%

25 [SIS). Mp. (Diastereomerically enriched [SJs sulfinate): 14 1- 142 O C ; [a], : -43.6" (c 2.22,

CHC13). 'H NMR (400 MHz), 6: 7.47-7.43 (m, 3H), 7.42-7.37 (m, 2H), 7.14 (s, lH), 5.27

(m. IH), 4.06 (m, IH), 0.93 (s, 3H), 0.90 (d, J=6.8 Hz, 3H), 0.86 (d, J=6.4 Hz, 3H), 0.86

(d, J=6.8 Hz, 3H), 0.65 (s, 3H), 2.2-0.69 (m. remaining peaks for cholesteryl skeleton,

28H); I3c NMR (100.6 MHz), 6: 147.9, 139.2, 129.7, 129.2, 128.9, 126.6, 113.0, 80.5,

56.6, 56.0, 49.8, 42.2, 39.7, 39.6, 39.4, 37.0, 36.4, 36.1, 35.7, 31.8, 31.7, 29.6, 28.2,

28.0, 24.2, 23.8, 22.8, 22.5, 20.9, 19.1, 18.7, 1 1.8; IR (CH2C12), cm": 3062, 2943, 2868,

2852, 1490, 1467, 1444, 1382,1367, 1136, 992; Analysis calc'd for C,5H5iCISO2: C,

73.58; H, 9.00; found: C, 73.63; H, 8.88.

Synthesis of (-)-Cholesteryl (-)-[RIS-(E)-2-Chlord-hexenesulfinate (136h):

The reaction of sulfoxide 119b (388 mg, 1.45 mmol) with Sac12 (1.89 mi,, 1.89 mmol)

yielded sulfinyl chlonde. Upon transfemng the sultinyl chloride to a solution of

cholesterol ( 478 mg, 1.24 mmol) and quinine (566 mg, 1.75 mmol) in CH2C12 at -78 OC

the reaction mixture was warmed to rt and stirred overnight. Diastereomerically enriched

sulfinate 136h (653 mg, 96%, 19% [RIs) was isolated as a solid f i e r flash

chromatography (3-5% EtOAchexanes). Following crystallization from hexanes the

diastereomerically enriched [RIS sulfinate was isolated in a 21% yield (25% [RIS). Mp

25 (Diastereomerically ennched [RIS sulfinate): 82-84 'C; [a],: -10.2' (c 2.65, CHCI>). 'H

NMR (400 MHz), 6: 6.86 (s, IH), 5.39 (m, IH), 4.12 (m, IH), 2.57-2.45 (m, 2H), 2.45-

2.35(m,3H), 1.01 (s,3H),0.94(t,J=7.3Hz,3H),0.91(d, J=6.5Hz,3H),0.87(d, J=6.6

Hz, 3H), 0.86 (d, .I=6.6 Hz, 3H), 0.67 (s, 3H), 2.02-0.97 (m, remaining peaks for

cholesteryl skeleton and n-Butyl group, 29 H); I3c NMR (100.6 MHz), 6: 149.0, 139.3,

126.0, 123.1, 79.9, 56.6, 56.1, 50.0, 42.3, 40.1, 39.7, 39.5, 37.1, 37.1, 36.5, 36.1, 35.8,

31.9, 31.8, 29.6, 28.2, 28.0, 25.4, 24.2, 233.8, 22.8, 22.6, 22.5, 21.0, 19.2, 18.7, 13.7,

1 1.8; IR (CH2C12), cm-': 3054, 2949, 2869, 1626, 1467, 1439, 138 1, 1367, 1265, 1 136,

1026,992; MS (CI, NH,), m/z (%): 385 (7), 371 (6), 370 (29), 369 (100), 368 (13), 367

(20), 353 (8). 55 (10); Analysis calc'd for C33H55C102S: C, 7 1.89; H, 10.06; found: C,

71.62; H, 9.96.

6.5. Asy mmetric Synthesis of Enantioenriched Aralkyl 1-Alkenyl Sulfoxides.

6.5.1. General Method for the Synthesis of Enantioenriched Aralkyl 1-Alkenyl Sulfoxides.

Diastereomerically pure cholesteryl 1-alkenesulfinate ester (1 equiv) was dissolved

in benzene ( I O mL) and cooled to 6°C under N2. M e r 10 minutes the Grignard reagent

(cornrnercially available stock sotution; 1 to 2 equiv) was added dropwise. The reaction

mixture was s h e d until complete by TLC analysis (1-2 hours) and then quenched with

W C 1 (10rnL). The solution was diluted with EtOAc and the organic layer separated,

washed with brine, dried with MgSOs, filtered and concentrated under reduced pressure.

The enantioenriched sulfoxides were isolated using silica gel flash chromatography, with

EtOAchexanes as the eluent.

Synthesis of (E)-[SIS-2-Carbomethoxyethenyl 1-butyl Sulfoxide (Ma):

The reaction of sulfinate 136f(336 mg, 0.65 mmol, 100% [RIs) with n-BuMgCI (388 @,

0.78 mmol; as a 2M solution in &O) in anhydrous ether at -78 "C generated vinyl ether

byproduct 156 (1 17 mg, 38%) as a solid afler chromatography (20% EtOAcihexanes)

Enantioenriched sulfoxide lSSa was isolated as a sotid (37 mg, 30%, 51% [SIs) afier

25 additional chromatography (80% EtOAchexanes). Mp: 53-54 O C . [a], : + 120.6' (c 0.73,

acetone). 'H NMR (400 MHz), 6: 7.58 (d, J=15.0 Hz, IH), 6.66 (d, J=15.0 Hz, IH), 3.8 1

(s, 3H), 2.87 (ddd, J=13.2, 10.0 & 5.8 Hz, lH), 2.74 (ddd, J=13.2, 10.0, 5.8 Hz, IH),

1.81 (m, IH), 1.69 (m, IH), 1.48 (m, 2H), 0.96 (t, J=7.2 Hz, 3H); I3c NMR (100.6

MHz), 6: 164.3, 149.7, 126.0, 52.6, 52.3, 24.0, 21.9, 6.6; IR, cm": 3030, 2959, 2932,

17 19, 162 1, 1292, 1223, 1 146, IO4 1; MS (CI, NH3), m/z (%): 191 ((M+I)*, IOO), 175

(5.6), 151 (12), 141 (9), 135 (B), 121 (161, 107 (M), 57 (33); Analysis caic'd for

CiH1~02S: C, 50.66; H, 7.42; found: C, 50.50; H, 7.42

Synthesis of (E)-[RlsZ-Carbomethoxyethenyl QMethylphenyl Sulfoxide (155b)'":

The reaction of sulfinate 136f (471.5 mg, 0.91 mmol, 100% [RIS with p-tolMgBr (1 .O9

mL, 1.09 mmol; as a 1M solution in EtzO) in anhydrous ether warming fiom -78 OC to

-40 OC generated vinyl ether byproduct 156 (76 mg, 18%) as a solid afler chromatography

(20% EtOAcIhexanes). Enantioenriched sulfoxide lSSb was isolated as a solid (50.5 mg,

25%, 21% [RIS) after additional chromatography (80% EtOAc/hexanes). Mp: 5 1-53 "C.

25 [a],: +62.4' (c 0.22, acetone; ~it."' +42i0, (acetone), >98% [RIS). 'H NMR (400

MHz), S:7.52 (d, J=8.0 Hz, 2H), 7.48 (d, J=15.O Hz, IH), 7.33 (d, J=8.0 Hz, 2H), 6.73

(d, J=15.0 Hz, IH), 3.77 (s, 3H), 2.47 (s, 3H); I3c NMR (100.6 MHz), S: 164.4, 151.5.

142.7, 138.2, 130.5, 125.1, 123.5, 52.3, 21.7; IR (CDCb), cm-': 3036, 1720, 1621, 1299,

1233, 1 148, 1087, 1060, 967; MS (EI), m/z (%): 224 ((M+l)', 1 l), 177 (3 l), 176 (100),

175 (2 1 ), 148 (22), 145 (77), 139 (4 l), 123 (43), 1 17 (27), 92 (24), 9 1 (4 1 ), 89 (20), 79

(24), 77 (30), 65 (37), 63 (22), 59 (26); Anaiysis calc'd for CIIHIZO~S : C, 58.91; H, 5.39;

found: C, 58.98; H, 5.43

Characterization Data for (-)-Cholesteryl (-)-(E)-2-Carbomethoxyethenyl ether (156):

I H NMR (400 MHz), 6: 7.55 (d, J=12.4 Hz, Ili) , 5.40-5.39 (m, IH), 5.26 (d, J=12.4 Hz,

IH), 3.84-3.76(mi lH), 3.69(~,3H),2.38-2.35(rn,2H), 1.01 (s,3H),0.91 (d, J=6.5,

3H), 0.86 (d, J=6.6 Hz, 3H), 0.68 (s, 3H), 2.09-0.80 (remaining peaks for cholesteryl

skeleton, 26H); I3c NMR (100.6 MHz), 6: 168.6, 16 1.7, 139.3, 123.1, 97.0, 82.3, 56.7,

56.1, 51.0, 50.0, 42.3, 39.7, 39.5, 38.5, 36.8. 36.6, 36.2, 35.8, 31.9, 31.8, 28.2, 28.1,

28.0, 24.3, 23.8, 22.8, 22.6, 2 1 .O, 19.3, 18.7, 1 1.8; IR (CH2CI2), cm-': 2946, 2906, 2868,

2851, 1715, 1643, 1133, 959; MS (CI, W), m/z (%): 471((M+H)*, 37), 370 (29), 369

(100). 61 (13); Analysis calc'd for C3,H5003: C, 79.10; H, 10.71; found: C, 79.21; H,

10.60.

6.5.2. Description of Experimtntal Trials Involving n-BuMgBr and Sulfinate 136b.

Sulfinate 136b was dissolved in an anhydrous solvent (EtzO; Et20/CsH12; Cs&)

and cooled to the desired temperature (-78 OC for EtzO; -6 OC for Et2OlCaH12; +6 OC for

C6H6) for 10 minutes under Nz. ri-BuMgBr was then added dropwise with stimng. The

temperature was then maintained or warmed slowly. M e r complete by TLC analysis (1

to 4 hours), the reaction was quenched with Wl and the organic layer was separated.

The aqueous layer was washed with EtOAc and the organic layers were combined,

washed with bine, dned with MgSOJ, filtered and concentrated under reduced pressure.

Chromatography (20% EtOAchexanes to eiute cholesterol; 80% to elute the sulfoxide)

afforded sulfoxide 158a (see Table 15 for results).

Synthesis of (S)~-(E)-3,3-Dimethyl-l-Butenyl 1-Butyl Sulfoxide (1SSa):

The reaction of suifinate 1364 (353.3 mg, 0.684 mmol, 100 % [RIS) with nBuMgJ3r (684

PL, 1.368 mmol; as a 2.0 M solution in &O) in anhydrous benzene at 5-7 OC afforded

enantioenriched sulfoxide 158a (109.9 mg, 86%, >97% [Sjs) as a clear oil afier flash

chrornatography (25 O/o EtOAcihexanes to elute cholesterol, 80 % to elute sulfoxide).

25 [a],. +l30.7" (c 1.57, acetone). '~NMR(400hIHz),6: 6.45 (d, J=15.4 HZ, IH), 6.09

(d, J=15.4 Hz, IH), 2.70 (t, J=7.7 Hz, 2H), 1.68(m, 2H), 1.48 (m, 2H), 1.1 1 (s, 9H), 0.96

(t, J=7.3 Hz, 3H); I3c NMR (100.6 MHz) 6: 151.1, 128.1, 53.8, 34.2, 28.8, 24.1, 22.0,

13.7; iR (neat), cm": 2959,2932,2906, 2870, 1625, 1465, 1364, 1265, 1074, 1039, 97 1;

MS (EI), m/z (%): 1118 (M-, 7.7), 172 (12.5), 171 (39), 132 (39, 13 1 (13), 119 (14), 118

(21). 117 (lOO), 115 (34), 101 (40), 99 (33), 97 (25), 85 (32), 84 (20), 83 (86), 81 (20),

79 (1 8), 74 (29), 71 (22), 69 (27), 67 (29), 65 (26), 63 (17), 59 (71), 57 (78)- 56 (18), 55

(70), 53 (28), 51 (17); Analysis calc'd for CI&OOS: C. 63.78; H, 10.70; found: C,

63.83; H, 10.45.

Synthesis of (S)s(E)-3,3-Dimethyl-1-butenyl Methyl Sulfoxide (158b):

The reaction of sulfinate 136b (405.0 m g 0.784 mm& 100 % [RIS) with MeMgBr (160

PL, 1.57 mmol; as a 1.0 M solution in butyl ether) in anhydrous benzene at 5-7 O C

afforded enantioenriched sulfoxide 158b (77.2 mg, 67%, 86% [qs) as a clear oil after

chromatography (25 % EtOAchexanes to elute cholesterol, 80 % to elute sulfoxide).

25 [a], : +238.2' (c 2.90, acetone). 'H NMR (400 MHz), 6: 6.47 (d, J= 15.4 Hz, IH). 6.17

(d, J=15.4 Hz, IH), 2.61 (s, 3H), 1.1 1 (s, 3H); I3c NMR (100.6) 6: 150.5, 129.9, 40.8,

34.0, 28.8; IR (neat) cm-': 296 i , 2909, 2868, 1626, 1474, 1465, 1364, 1047, 1028; MS

(EI), m/z(%): 146 (w, 201, 131 (28), 130 (32), 117 (12), 115 (IOO), 83 (47), 81 (21), 71

(20), 58 (2 l ) , 57 (62). 53 (29), 5 1 (22); Anal. Calcd for: CiHi40S: C, 57.49; Hl 9.65;

Found: C, 57.45; H, 9.52.

Synthesis of (S)S-(E)-3,3-Dimethyl-1-buttnyl 1-Methylethyl Sulfoxide (158~):

The reaction of sulfinate 136b (334.4 mg, 0.647 mmol, 100% [RIS) with i-PrMgCI (650

PL, 1.29 mmol; as a 2.0 M solution in EtzO) in anhydrous benzene at 5-7 O C afl'orded

enantioenriched sulfoxide l58c (96.0 mg, 85%, 98% [SIS) as a clear oil f i e r flash

chromatography (25 % EtOAdhexanes to elute cholesterol, 80 % to elute sulfoxide).

25 [a],: +150.3' (c 1.95, acetone). 'H NMR (400 MHz), 6: 6.43 (d, J=15.6 Hz, IH), 6.01

(d, k15.6 Hz, IH), 2.78 (m, J=6.8 Hz, lH), 1.24 (d, h6.8 Hz, 3H), 1.22 (d, J=6.8 Hz,

3H), 1.10 (s, 9H); I3c NMR (100 MHz), 6: 152.3, 125.4, 51.7, 34.3, 28.9, 15.2, 14.6; IR

(neat), cm-': 2961, 2932, 2905, 2868, 1628, 1475, 1463, 1365, 1266, 1062, 1024, 973;

MS (EI), m/z (%): 174 (M', IS), 158 (20)- 143 (38). 132 (90), 117 (IOO), 1 1 5 (42), 101

(591, 99 (39), 83 (81), 74 (30), 67 ( 3 9 , 65 (311, 59 (85), 57 (27); Analysis calc'd for

C9HlgOS: C, 62.02; H, 10.41; Found: C, 61.82; H, 10.25

Synthesis of (R)s-(0-3,3-Dimethyl-l-butenyl L-MethyLthyl Sulfoxidc (1SSc):

The reaction of sulfinate 136b (324.0 mg, 0.627 mrnol, 71% [SJs) with i-PrMgC1 (630

PL, 1.25 mmol; as a 2.0 M solution in EtzO) in anhydrous benzene at 5-7 OC afforded

enantioenriched sulfoxide lS8c (83.0 mg, 76%, 71% [RIS) as a clear oil afler flash

chromatography (25 % EtOAc/hexanes to elute cholesterol, 80 % to elute sulfoxide).

25 [a], : - 1 12.3' (c 1 S3, acetone).

Synthesis of (S)s(E)-3,3-Dimcthyl-1-buttnyl Cyclohesyl Sulfoxidc (158d):

The reaction of sulfinate L36b (324.0 mg, 0.627 mmol, 100% [RIS) cC&MgCI (627 pL,

1.254 mmol; as a 2.0 M solution in Et2O) in anhydrous benzene at 5-7 OC afforded

enantioenriched sulfoxide l58d (1 15.4 mg, 86%, >97% [SIS) as a solid aller flash

chromatography (25 % EtOAchexanes to e1ute cholesterol, 80 % to elute sulfoxide).

Mp.: 39 - 40 OC; [a$: +61.1' (c 2.38, acetone). 'H NMR (400 MHz): 6: 6.42 (d, 1=15.6

Hz, IH), 6.04 (d, J-15.6 Hz, lH), 2.54 (m, lH), 2.04 (m, l m , 1.88 (m, 3H), 1.67 (m,

lH), 1.31 (m, SH), 1.11 (s, 9H); I3c NMR (100.6 MHz): 6: 152.2, 126.1, 60.5, 34.3,

28.9, 26.0, 25.6, 25.5, 25.3, 24.8; IR (CH2CI2), cm": 3029, 2935, 2855, 1622, 1474,

1463, 145 1, 1365, 1264, 1055, 971; MS (El), mh (%): 214 (M', 8), 198 (19), 183 (32),

132 (loo), 1 17 (7% 1 15 (27) 101 (48), 83 (88), 81 (19), 74 (20), 67 (26), 59 (4 11, 53

(17), 55 (85). Anal. Calc'd For C~~HUOS: C, 67.23; H, 10.34; Found: C, 67.08; H, 9.93.

Synthesis of IRIS-(E)-3,3-Dimethyl-1-butenyl Cyclohexyl Sulfoxide (lS8d):

The reaction of sulfinate 136b (330.7 mg, 0.640 mmol, 71% [SIS) c C ~ H ~ ~ M ~ C I (600 @,

1.28 mmol; as a 2.0 M solution in EtzO) in anhydrous benzene at 5-7 "C afforded

enantioenriched sulfoxide 158d (108.7 mg, 79%, 71% [RIs) as a solid &er flash

chrornatography (25 % EtOAchexanes to elute cholesterol, 80 % to elute sulfoxide).

[a];: -4 1 4 " (C 2.30. acetone).

Synthesis of [SIS-(E)-3,3-Dimethyl-1-butenyl Benzyl Sulfoxide (158e)'~:

The reaction of sulfinate 136b (305.5 mg, 0.591 mmol, 100% [RIS) BnMgCl (600 a,

0.59 1 mmol; as a 2.0 M solution in THF) in anhydrous benzene at 5-7 "C aîTorded

enantioenriched sulfoxide lS8e (101.7 mg, 78%, 91% [SIs) as a solid after flash

chromatography (25 % EtOAdhexanes to elute cholesterol, 80 % to elute sulfoxide).

25 Mp.: 42-43 O C ; [a],: +142.0° (c 1.3 1, acetone). L~ NhlR (400 MHz): 6: 7.25-7.23 (m.

3H), 7.16-7.13 (m, ZH), 6.12 (d, J = 15.5 Hz, 1H), 5.89 (d, J = 15.4 Hz, lH), 3.89 (AB,,

J=12.6 Hz, ZH), 0.90 (s, 9H).

Syn thesis of [RIS-(4-3,3-Dimethyi-i-butenyl CMethylphenyl ~ulfoxidc( 1 5 8 ~ ~ ' :

The reaction of sulfinate 136b (306.8 mg, 0.594 mmol, 100% [RIS) p-tolMgBr (1.20 mL,

1.19 mmol; as a LM solution in Et20) in anhydrous benzene at 5-7 "C afforded

enantioenriched sulfoxide 1581 (1 11.6 mg, 85%, 94% [RIS) as a solid afler flash

chromatography (25 % EtOAdhexanes to elute cholesterol, 80 % to elute sulfoxide).

?3 Mp,: 58-59 O C ; [a], : +Il6.6' (c 1.4 1, acetone; ~ i t . ~ ' : +33"). 'H NMR (400 MHz): 6:

7.49 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 6.59 (d, J= 15.4 iiz, iH), 6.1 1 (d, J=

15.4 Hz, IH), 2.41 (s, 3H), 1.08 (s, 9H); I3c NlMR(100.6): 6: 150.7, 141.3, 14L.1, 13 1.0,

130.0, 124.6, 34.2, 28.7, 21.4; IR (neat). cm-': 3036, 2962, 2905, 2868, 1621, 1494,

1475, 1463, 1365, 1265, 1085, 1047, 10 16, 968, 920; MS (El), m/z (%): 222 (M', 18),

174 (67), 173 (ZO), L 59 (lOO), 124 (23), 123 (32), 92 (28), 9 1 (33), 65 (20), 57 (321, 55

(22); Anal. Calcd For: C13HiaOS: C, 70.22; H, 8.16; Found: C, 69.98; H, 7.95.

Synthesis of (S)s-(E)-3,3-Dimethyl-l-butenyl 2-Furanyl Sulfoxide (158g):

The Grignard reagent was prepared 111 silu by slowly adding n-BuLi (34 1 pL, 0.68 mmol)

to a solution of fiiran (40 pL, 0.57 mmol) in dry ether (5 mL) at -20 O C . After stirring for

20 minutes, MgBrz (125.8 mg, 0.68 mmol) dissolved in dry ether (5 rnL) was added

slowly with vigorous stirring for 20 minutes followed by the addition of enantiopure

sulfinate [RIS-136b in dry ether (5 mL). After 60 minutes the reaction was complete by

TLC and was quenched with W C I . The organic layer was separated, and the aqueous

later was extracted with EtOAc. The combined organic layers were washed with brine,

dried with MgSOJ and the mixture was concentrated under reduced pressure. Following

chromatography (20% EtOAchexanes to elute cholesterol, 80% to elute sulfoxide)

23 enantioenriched sulfoxide 158g was isolated as an oil ( 114.2 mg, 78%, >97% [RIS). [alD :

1- 125.8' (c 1.69, acetone). 'H (400 MHz), 6: 7.63 (m, I H), 6.88 (d, J=?.6 Hz, 1 H), 6.66

(d, J=15.4 Hz, 1H), 6.51 (dd, J=3.6 & 1.6 Hz, IH), 6.35 (d, J=15.4 Hz, IH), 1.13 (s, 9H);

I3c NMR (100.6 MHz), 6: 152.7, 151.7, 146.8, 125.9, 115.2, 11 1.3, 34.3, 28.7; IR (neat),

cm": 3 1 14,296 1,2905,2868, 1625, 1475, 1366, 1266, 1218, 1 128, 1066, 1008,970; MS

(EI), m/z (%):I99 ((M+l)+, 6), 150 (51), 135 (69), 107 (1 i), 99 (15), 91 (IO), 83 (17),

8 1 (16), 79 (19, 71 (14), 67 (1 l), 59 (22), 57 (57), 55 (821, 53 (17), 45 (32), 43 (37), 41

(100); Analysis calc'd for CIOHI~O~S: C, 60.57; H, 7.12; found: C, 60,69; H, 7.06,

Synthesis of [R~r4-Fluoro-3-methylphenyl Ethenyl Sulfoxide (159a):

The reaction of sulfinate 136a (254 mg, 0.551 mmol; 42% [RIs) with 4-Buoro-3-

methylphenylmagnesium bromide (0.6 rnL, 0.551 mmol; as a 1 M solution in THF) in

anhydrous benzene at 5-7 O C generated enantioennkhed sulfoxide 159a (80.7 mg, 80%,

4 1% [RIS) as an oil after chromatography (25% EtOAchexanes to elute cholesterol, 80%

25 to elute sulfoxide). [a],: +153.4 (c 1.09, acetone). 'H NMR (400 MHz). 6: 7.48 (dd.

J=6.8 & 1.6 Hz, IH), 7.42 (m, IH), 7.14 (t, J=8.8 Hz, IH), 6.57 (dd, J=16.4 & 9.6 Hz,

IH), 6.20 (d, J=16.4 Hz, lH), 6.91 (d, J=9.6 Hz, IH), 2.33 (s, 3H); I3c NMR (100.6

MHz), 6: 162.9 (d, J=250 Hz), 142.8, 138.1, 128.0 (d, J=6.0 Hz), 126.9 (d, J=18.5 Hz),

124.3 (d, 5 4 . 9 Hz), 120.6, 1 16.1 (d, J=23.7 Hz), 14.5 (d, J=3.2 Hz); IR (neat), cm":

3064, 3032, 2928, 1597, 1577, 1485, 1449, 1395, 1384, 1368, 1240, 1183, 1120, 1085,

1055, I O 1 5, 986; MS FI), m h (%): 184 W. 1 l), 157 (21), 141 (18), 137 (1 l), 136

(loo), 135 (21), 110 (18), 109 (33), 108 (IO), 107 (12), 97 (I l ) , 83 (20), 59 (IO), 57

(13), 45 (19); Analysis calc'd for CgHgFOS: C, 58.68; H, 4.92; found: C, 58.77; H, 5.02.

Synthesis of [Sj~4-Fluoro-3-mtthylphenyl Ethenyl Sulfoxide (159a):

The reaction of sulfinate 13611 (250 mg, 0.540 m o l , 22%[S]s) with 4-fluoro-3-

methylphenylrnagnesium bromide (542 PL, 0.540 rnmol; as a 1 M solution in THF) in

anhydrous benzene at 5-7 O C generated enantioe~ched sulfoxide 159a (83mg, 83%, 22%

[SIS) as an oil after chrornatography (25% EtOAchexanes to elute cholesterol, 80% to

25 elute sulfoxide). [alD : -79.9O (c 1.42, acetone).

Sy n thesis of [RlsEthenyl CMet hylphenyl Sulfoxide (34)lM:

The reaction of sulfinate 134a (225 mg, 0.490 mmol, 42% [RIS) with p-toiMgBr (490 pL,

0.490 mmol; as a IM solution in &O) in anhydrous benzene at 5-7 OC generated

enantioenriched sulfoxide 34 (62 mg, 77%, 42 %[RIS) as an oil after chromatography

23 (20% EtOAcIhexanw to elute cholesterol, 8û?A to elute sulfoxide). [a],: +136.3" (c, 1.08

acetone; lit.'4o: 386'; (c, 0.98 ethanol), 94% [RIs). 'H NMR (400 MHz), 6: 7.52 (d, J=8.0

Hz, 2H), 7.32 (d, J=8.4 Hz, 2H), 6.58 (dd, 5=16.4 & 9.6 Hz, lH), 6.19 (d, J=16.4 Hz,

lH), 6.18 (d, J=9.6 Hz, IH), 2.41 (s, 3H).

Synthesis of (R)sZFuranyl Ethenyl Sulforide (159b):

The Grignard reagent was prepared in situ by slowly adding rt-BuLi (360 pL, 0.73 mmol)

to a solution of tùran (50 fi, 0.65 mmol) in dry ether (5 rnL) at -20 O C under N2. M e r

stirring for 20 minutes MgBr2 (180 mg, 0.98 mmol) dissolved in dry ether (5 mL) was

added slowly with vigorous stimng for 20 minutes followed by the addition of sulfinate

[RIs-136a (301 mg, 0.65 mmol) in dry ether (5 mL). M e r 60 minutes the reaction was

complete by TLC and was quenched with WCI. The organic layer was separated, and

the aqueous layer was extracted with EtOAc. The combined organic layers were washed

with brine, dried with MgSO, and concentrated under reduced pressure. Following

chrornatography (20% EtOAchexanes to elute cholesterol, 80% to elute sulfoxide)

25 enantioenriched sulfoxide 159b was isolated as an oil (42 mg, 59%, 41% ee [RIs). [alD:

+72.3" (c 0.83, acetone) 'H NMR (400 MHz), 6: 7.64 (m, lH), 6.95 jdd, J=3.8 & 0.4 Hz,

lH), 6.76 (dd, J=16.4 & 9.6 Hz, lH), 6.53 (dd, k3 .8 & 2.0 Hz, lH), 6.34 (d, J=16.4 Hz,

IH), 6.1 1 (d, J=9.6 Hz, IH); NMR (100.6 MHz), 6: 137.4, 130.5, 130.2, 122.3,

116.4, I I 1.3; IR (neat), cm": 31 17, 3039, 3010, 2952, 1600, 1550, 1456, 1453, 1370,

1220, 1165, 1066, 1051.

Sy n thesis of [qs Cyclohexyl Et henyl Sulfoxide (159~):

The reaction of sulfinate 13th (275 mg, 0.600 mrnol, 22% [SIs) with cC6HllMgCI (300

PL, 0.600 mmol; as a 2.0 M solution in Et20) in anhydrous benzene at 5-7 O C generated

enantioenriched sulfoxide 159c (40 mg, 42%, 23% [RIs) as a solid afler chromatography

U (20% EtOAclhexanes to elute cholesterol, 80% to elute sulfoxide). Mp: 48-50 OC. [a], :

-5 1.6" (c 0.32, acetone). 'H NMR (400 MHz), 6: 6.57 (dd, 1=16.5 & 10.0 Hz, IH), 6.07

(d, J= 16.5, IH), 6.00 (d, J=10.0 HZ, lH), 2.57 (tt, b l t . 6 & 3.6, lH), 2.02-1.87 (III, 3H),

1.80-1.60 (m, 2H), 1.50-1.15 (m, 5H); 13c NMR (100.6 MHz), 8: 138.6, 122.9, 60.2,

26.0, 25.5, 25.3, 24.2; IR (CH~CII), cm": 3043, 2933, 2856, 1452, 1055; MS (CI, NH3),

m/z (%): 1 59 ((M+ 1)-, 2 L), IO8 (24), 9 1 (100), 90 (3 S), 74 (28), 73 ( 14); Analysis calc'd

for CsHlJOS: C, 60.71; H, 8.92; found: C, 60.92; H, 8.70.

Synthesis of [SIS 2-Methyi-2-phenylpropyl Ethcnyl Sulfoxide (159d):

Ph The reaction of sulfinate 136a (253 mg, 0.549 mmol, 36% [RIs) with 2-methyl-2-

phenylpropylmagnesium chioride (1.10 mL, 0.549 mmol; as a 0.5 M solution in Et20) in

anhydrous benzene at 5-7 OC generated enantioenriched sulfoxide 159d (45 mg, 39%,

28%[51~) as an oil afier chromatography (20 % EtOAdhexanes to elute cholesterol, 80%

25 to elute sulfoxide). [a], : +43.0° (c 1.96, acetone). NMR (400 MHz), 6:7.3 1-7.24 (m,

3H), 7.17-7.14 (m, ZH), 6.25 (dd, k16.4 & 9.6 Hz, lH), 5.92 (d, J=16.4 Hz, 1H), 5.73

(d, k 9 . 6 Hr, IH). 2.89 (AB,,, J-13.4 Hz, 2H), 1.16 (s, 3H), 0.78 (s, 3H); 13c NMR

(100.6 MHz), 6: 146.7, 141.5, 128.5. 126.6, 125.6, 120.7, 70.0, 37.8, 29.9, 27.2; IR

(neat), cm": 3089, 3034, 2967, 2932, 1497, 1444, 1370, 1047; MS (El), m/z (%): 209

w, 8 3 133 (91), 91 (100), 55 (20); Analysis calc'd for C ~ I H ~ ~ O S : C, 69.19; H, 7.74;

found: C, 69.38; H, 7.53.

Synthesis of [SI&)-2-Phenylethenyl 1-Methylethyl Sulfoxide (160a)'~:

The reaction of sulfinate 136d (223 mg, 0.416 mmol, 100% [RIS) with iPrMgBr (0.42 mL,

0.83 1 mmol; as a 2.0 M solution in EtzO) in anhydrous benzene at 5-7 O C generated

enantioenriched sulfoxide 160a (70.1 mg, 87%, 91% [SIs) as a solid after chromatography

2s (20 % EtOAdhexanes to elute cholesterol, 80% to elute sulfoxide). Mp: 50-52 OC. [a], :

+ 1 16.7 (c 1.69, acetone). 'H NMR (400 MHz), 6: 7.49-7.47 (m, 2H), 7.4 1-7.34 (rn, 3H),

7.23 (d, J=15.6 Hz, IH), 6.78 (d, J=15.6 Hz, IH), 2.92 (septet, J=6.8 Hz, IH), 1.33 (d,

J=6.8 Hz, 3H), 1.30 (d, J=6.8 Hz, IH); 13c NMR (100.6 MHz), 6: 137.9, 134.0, 129.6,

128.9, 127.9, 127.5, 52.3, 15.4, 14.5; IR (CDC13), cm-': 3056, 2973, 2932, 1625, 1449,

1262, 1255, 1 167, 1 159, 1148, 1121, 1032, 1014, 967; MS (EI), m/z (%): i94 (Ad+, 6),

152 (IOO), 135 (55), 134 (16), 104 (59, 91 (34), 77 (27), 73 (39), 5 1 (15), 45 (34), 43

(45),41 (21); Analysis calc'd for ClIHI~OS: C, 68.00; H, 7.26; found: C, 67.77; H, 6.75

Synthesis of [SIs -(E)-2-Phtnylethcnyl Cyclohcxyl Sulfoxide (160b):

The reaction of sulfinate 136d (23 1 mg, 0.430 mmol, 100% [RIS) with c-CsH~dMgBr

(0.42 mL, 0.859 mmol; as a 2.0 M solution in EtzO) in anhydrous benzene at 5-7 OC

generated enantioenriched sulfoxide 160b (61.9 mg, 62%. 92% [SIS) as a solid &er

chromatography (20% EtOAchexanes to elute cholesterol, 80% to elute sutfoxide). Mp.:

25 90-91 O C. [a], : +62.3' (c 1.61, acetone). IH NMR (400 MHz), 6: 7.50-7.47 (m. 2H).

7.41-7.33 (m, 3H), 7.22 (di J=15.4 Hz, IH), 6.81 (d, J=l5.4 Hz, IH), 2.68 (tt, J=11.8 &

3.5 Hz, IH), 2.09-1.96 (m, 2H), 1.91-1.87 (m, 2H), 1.73-1.70 (mi lH), 1.55-1.40 (rn,

ZH), 1.40-1.15 (m, 3H); I3c NMR (100.6 MHz), 6: 137.7, 134.0, 129.6, 128.9, 128.6,

127.5, 61.1, 26.1, 25.5 (2 C's), 25.3, 24.6; IR (CDC13), cm*': 3088, 3055, 2936, 2857,

1449, 1263, 1253, 1234, 1 167, 1 159, 1032, 1015, 967; MS (EI), m/z (%): 234 (M', 21,

152 (IOO), 135 (25), 104 (22). 91 (12), 83 (13). 77 (12), 73 (22), 55 (SO), 45 (SO), 41

(28); Analysis calc'd for CIJ-ilsOS: Ci 71.75; H, 7.74; found: C, 71.73; Ii, 7.32

Synthesis of [RIs-(E)-2-Phenylcthenyl 4-Fhoro-3mrthylphenyl Sulfoxide (160~):

The reaction of sulfinate 136d (177 mg, 0.33 mmol, 100% [RIS) with 4-fluoro-3-

methy1phenyl magnesium bromide (330 pi.,, 0.33 mmol; as a 1 M solution in THF) in

anhydrous benzene at 5-7 OC generated enantioenriêhed sulfoxide 160c (70 mg, 82%,

95% [ R I S ) as a solid afler chromatography (20% EtOAchexanes to elute cholesterol, 8%

25 to elute sulfoxide). Mp: 58-59 OC. [a],: il52.O (c 1.11, acetone). 'H NMR (400 MHz),

6: 7.55-7.45 (m, lH), 7.49-7.45 (m, 3H), 7.40-7.37 (m, 4H), 7.37 (d, J=15.6 Hz, IH),

7.14 (t, J 4 . 8 Hz, IH), 6.80 (d, J-15.6 Hz, lH), 2.33 (s, 3H); I3c NMR (100.6 MHz), 6:

162.9 (d, J=250 Hz), 138.8 (broad), 136.2, 133.6, 132.7, 129.8, 128.9, 128.0 (d, J=5.9

Hz), 127.3, 126.9 (d, J=18.4 Hz), 124.3 (d, J=9.0 Hz), 116.1 (d, J=23.6 Hz), 14.6; ER

(CDCh), cm-': 3063, 3023, 301 1, 2925, 1488, 1447, 1239, 1079, 105 1, 1034; MS (Cl,

M3), d z (%): 261 ((M+H)', 100), 212 (23), 91 (6); Analysis calc'd for C15H13SOF: C,

69.21; H, 5.03; found: C, 69.40; H, 5.07.

Synthesis of [RIS-@)-2-Phenylethenyl CMethylphenyl Sulfoxide (36)'":

The reaction of sulfinate 134d (284 mg, 0.530 mmol, 100% [RIs) with p-tolMgBr (1.05

pL, 1.05 mmol; as a 1M solution in Et20) in anhydrous benzene at 5-7 OC generated

enantiomerically enriched sulfoxide 36 (97 mg, 76%, >97% [RIS) as an solid der

chromatography (20% EtOAchexanes to elute cholesterol, 80% to elute sulfoxide). Mp.:

2s 76-77 OC. [a],: +176.9' (c, 1.03, acetone; lit.": +172.g0; (CHCC), 100% [RIS). 'H

NMR (400 MHz), 6: 7.58 (d, P 6 . 8 Hz, 2H), 7.47-7.44 (m, 2H), 7.39-7.32 (m, 6H), 6.82

(d, J=15.6 Hz, IH), 2.41 (s, 3H).

Synthesis of [Rls(Z)-2-Chloro-2-Phenylethenyi Cyciohexyl Sulfoxide (161a):

The reaction of sulfinate 136s (147 mg, 0.258 m o l , 85% [qs) with c-CsHllMgBr (260

PL, 0.5 16 mmol; as a 2.0 M solution in EtzO) in anhydrous benzene at 5-7 "C generated

enantioenriched sulfoxide 161a (51 mg, 73%, 79% [RIS) as a oil afler chromatography

25 (20% EtOAdhexanes to elute cholesterol, 80% to elute sulfoxide). [a], : -28.0" (c 1.17,

acetone). 'H NMR (400 MHz), 6: 7.49-7.41 m, 3H), 7.39-7.36 (m, 2H), 6.73 (s, IH),

2.18 (tt, J=3.5 Hz, IH), 1.90-1.32 (m, 7H), 1.28-1.1 1 (m, 3H); 13c NMR (100.6 MHz), 6:

142.4, 130.0, 129.5, 129.0, 128.4, 122.8, 56.7, 27.3, 25.7, 25.2 (2 C's), 21.5; IR (neat),

cm-': 3058, 2933, 2855, 1625, 1594, 1489, 1454, 1296, 1066, 1063, 1030, 992; MS (EI),

miz (%): 27 1 (50), 269 (M', IOO), 188 (14), 186 (36), 185 (2 l), 83 (18), 55 (89), 54 (20),

41 (77); Analysis calc'd for Ci+HI$30S: C, 62.55; H, 6.38; found: C, 63.01; H, 6.33.

Synthesis of [Sls(Z)-2-Chloro-2-Phtnyltthenyl 4-Fluoro-3-Methylphenyl Sulfoxide (161b):

The reaction of sulfinate 136g (223 mg, 0.391 mmol, 86% [SIS) with 4-fluoro-3-

methylphenylmagnesium bromide (390 pL, 0.391 rnmol; as a 1 M solution in THF) in

anhydrous benzene at 5-7 OC generated enantioenriched sulfoxide l6 lb (70 mg, 61%,

89% [SJs) as a oil &er chromatography (20% EtOAcniexanes to elute cholesterol, 80%

to elute sulfoxide). [a]:: -49.5" (c 2.52, acetone). 'H NMR (400 MtIz), 6: 7.35-7.28 (m,

3H), 7.20 (dd, F6.8 & 1.6 HZ, IH), 7.1 1 (s, IK), 7.10-7.01 (III, 3K), 6.94 (t, J=8.8 Hz,

1H); 13c NMR (100.6 MHz), 6:; IR (neat), cm-': 3060, 2927, 1580, 1488, 1444, 1239,

1 184, 1 O8 1, 1060 Analysis calc'd for CISH~~CLFOS: C, 6 1.12; H, 4.10; found: C, 6 1.32;

H. 4.24.

7.

1.

2.

3 .

4.

5 .

6.

7.

S.

9.

1 o.

I I .

12.

13.

14.

15.

16.

17.

18.

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