DIELSALDER REACTIONS OF a,B-UNSATURATED SULFINATE ESTERS

FOR THE PREPARATION OF POLY HYDROMMERCAPTO COMPOUNDS

A Thesis

Presented to

The Faculty of Graduate Studies

of

The University of Guelph

In partial fulfillment of requirements

for the degree of

Masters of Science

August, 2001

O Dino Alberico, 2001

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ABSTRACT

DIELS-ALDER REACTIONS OF a$-UNSATURATED SULFINATE ESTERS

FOR THE PREPARATION OF POLY HYDROXYIMERCAPTO COMPOUNDS

Dino Alberico University of Guelph, 2001

Advisor: Dr. Adrian L. Schwan

This thesis examines the reactivity of ethyl (E)- and

(a-2-carbornethoxyethenesulfinates (24) in Diels-Alder chemistry with a variety

of dienes including cyclopentadiene, furan, anthracene, 2,3-dimethyl-1,3-

butadiene and 1,3-cyclohexadiene. Experiments were conducted under both

thermal, and Lewis acid catalyzed conditions. In most cases, Lewis acid

catalyzed reactions proceeded faster and demonstrated greater selectivity. Steric

evaluations of (E)-24 with cyclopentadiene were conducted in an effort to

improve endo:exo selectivity. lncreasing the size of the sulfinate ester

functionality lead to increased S-exo selectivity, as expected. lncreasing the size

of the carboxylic ester functionality resulted in the opposite expected selectivity.

Atternpts to create bis sulfinate containing dienophiles will also be reported.

An evaluation of the cycloadducts as a synthetic approach to poly

hydroxylmercapto compounds is also discussed. The cycloadducts were

subjected to a number of different reduction conditions employing LiAIH4 and

DIBAL. In some cases, benzyl bromide was added to trap the thiolate resulting in

the sulfide.

2.2.2 Reduction of Cis 2.3.Dimethyl4. 3.Butadiene Cycloadduct ......... -55 ...................................... 2.2.3 Reduction of Anthracene Cycloadducts -55

.............................. 2.2.4 Reduction of Cyclopentadiene Cycloadducts 5 6 ................................................ 2.2.5 Reduction of Furan Cycloadducts 57

..................... 2.3 Steric Evaluation of (E)-a$-Unsaturated Sulfinate Ester 59

.................................................................. 2.4 Bis Ethenesulfinate Esters 6 3 ........................ 2.4.1 Oxidative Fragmentation of Bis Ethenesulfoxides 65

............................................................ 2.5 Conclusions and Future Work 6 7

............................................................................................... 3 . Experirnental 7 0

............................................ 3.1 General Procedures and Instrumentation 70

.............................................. 3.2 Diees-Alder Reactions of 24 with Dienes 71

................................................................ 3.3 Reductions of Cycloadducts -78

....................................... 3.4 Steric Evaluation of Cycioaddition Reactions 92

....................................................... 3.5 Bis Ethenesulfinate Ester Studies 9 7

................................................................................................. 4 . References 103

Acknowledgements

The last two years have been sorne of the most challenging and rewarding

times of rny life. I would iike to thank many people for supporting and assisting

me throughout this time.

First I would like to thank my supervisor, Dr. Adnan L. Schwan. Adrian's

wisdom, guidance and enthusiasm have made this time a valuable and

entertaining learning experience. He truly is a great role model.

I would like to thank the other members of my advisory comrnittee, Dr.

Gordon L. Lange and Dr. William Tarn for their advice and support. In addition, I

would wish to express my gratitude to Valerie Robinson for her assistance.

I would like to thank the long list of past and present members of the

Schwan lab group and the Lange lab group - Colin Race, John Motto, Jen O'Donnell, Craig Humber, Nadia Corelli, Rick Strickler, Laura, McConachie,

Marjolaine Doux, Rob Faragher, Luke Lairson, Greg Byme and Qu Long - for helping me achieve this Masters, as well as supporting my addiction to Tim

Horton's coffee. I would also like to thank al1 the other friends that have made my

stay at the University of Guelph an enjoyable one.

I give special thanks to my parents, my sister Linda, my brother Sandro,

and my friends and family from home for their unconditional love and support.

Especially Sandro, who has been the greatest positive influence in my life.

iii

List of Abbreviations

aPP aq BHT cat. COD DIAD DIBAL DME DTBB ee ElMS equiv Et3N EtOAc EtOH E u ( f ~ d ) ~

FM0 HOMO HREIMS IR LDA LUMO mCPBA MeOH MerCO mP MPV MS NMR NR Ph PMB PPm rt sat'd TBS THF TLC TMS Ts

apparent aqueous 2,6-di-tert-butyl-4-methylphenol catalytic cyclooctadiene diisopropyl diazodicarboxyiate diisobutylaluminum hydride 1,2-dimethoxyethane 4,4'-di-tert-butyl biphenyl enantiomeric excess electron impact mass spectrometry equivalents triethylamime et h yl acetate ethanol tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato) europium frontier molecular orbital highest occupied molecular orbital high resolution electron impact mass spectrometry infrared lithium diisopropylamide lowest unoccupied molecular orbital m-chloroperoxybenzoic acid methanol (1 R,2S,3R)-3-mercaptocamphan-2-ol melting point Meenivein-Ponndoif-Verley mass spectrometry nuclear magnetic resonance no reaction phenyl p-methoxybenzyl parts per million room temperature saturated tert-butyldimethylsilyl tetrahydrofuran thin-layer chromatography trimethylsilane p-toluenesulfonyl

List of Tables

Table 1 : Diels-Alder Reaction 14 and Cyclopentadiene Using Various Lewis ................................................................................................... Acids 14

................................ Table 2: Diels-Alder Reactions of Acetylenic Sulfinate 21 19

.............................. Table 3: Diels-Alder Reaction of Cyclopentadiene and 24a 23

Table 4: Diels-Alder Reaction of Cyclopentadiene and 24b .............................. 23

..................................................... Table 5: Diels-Alder Reaction of Sultone 38 28

.......... Table 6: Diels-Alder Reactions Of 24a with 2.3.Dimethyl.l. 3.Butadiene 40

.......... Table 7: Diels-Alder Reactions Of 24b with 2.3.Dimethyl.l. 3.Butadiene 41

Table 8: Dîels-Alder Reactions Of 24a with Anthracene ................................... 42

Table 9: Diels-Alder Reactions Of 24b with Anthracene ................................... 43

Table 10: Diels-Alder Reactions Of 24a with Furan .......................................... 46

Table 1 1 : Diels-Alder Reactions Of 24b with Furan .......................................... 47

...................... Table 12: Diels-Alder Reactions Of 24 with 1. 3.Cyclohexadiene 49

.............................................................. Table 13: Reduction of 70 with LiAIH4 -51

.............................................................. Table 14: Reduction of 70 with DIBAL 54

Table 15: Endo:Exo Ratios of Cycloaddition and Reduction Products of Bicyclic Systems ............................................................................... 57

Table 16: S-endo:S-exo Ratios and Yields for Cycloaddition Products and Reduction Products for Steric Studies .............................................. 62

Table 17: Oxidative Fragmentation Reactions of 93 with SO2CI2 and Capture with a Number of Reagents ................................................. 66

List of Figures

Figure 1 : Reaction Types Based on Different HOMO-LUMO Arrangements ..... 2

Figure 2: Regioselectivity in Diels-Alder Cycloadditions ..................................... 3

.................................................................... Figure 3: Endo vs . Exo Interactions 5

Figure 4: Lewis Acid Complex Conformations .................................................... 6

Figure 5: Lewis Acid Complexes with Chiral Dieneophile 1 ............................... -8

Figure 6: Chiral Lewis Acid Complex .................................................................. 9

Figure 7: Types of Sulfur Containing Functionalities ......................................... 10

Figure 8: Syn vs . Anti ............... .... ................................................................ Il

Figure 9: Diene Approach Towards Vinyl Sulfoxides ...................................... 12

Figure 10: Diene Approach Towards Vinyl Sulfoxide 12 ................................... 13

........................ Figure 1 1 : rr-Facial Selectivity of 14 with Different Lewis Acids 15

Figure 12: n-Facial Selectivity of 14 with Different Zn& and TiCI4 .................. 16

Figure 13: Spatial Arrangement of 24a in Diels-Alder Reactions ...................... 24

Figure 14: lntramolecular Diels-Alder Transitions States of 33 ......................... 27

Figure 15: Transition States of Cyciopentadiene and Cyclohexadiene Approaching 38 ................................................................................ 29

Figure 16: Di pole Interaction Between Furan Oxygen and Sulfinyl Group ........ 48

Figure 17: s-cis and s-trans Conformations of 24b ........................................... 59

Figure 18: Steric Evaluations of 24b ................................................................. 60

Figure 19: Double Caged Metal Ion Capturing Compound ............................... 69

1. Introduction

1.1 Diels-Alder Reactions - General Aspects The Diels-Alder reaction is one of the most important reactions in the field

of organic synthesis. In a single synthetic step, two a bonds are formed in a

potentially stereo- and regioselective manner at the expense of two rc bonds from

the starting material. Since its discovery in 1928', an extensive understanding of

the reactivity, and regio- and stereoselectivity of this reaction has been

d e ~ e l o p e d . ~ ~ This section will give a brief oveMew on the general aspects of the

Diels-Alder reaction including discussions on reactivity, stereoselectivity,

regioselectivity, and Lewis acid catalysts both chiral and achiraL4*=

1 .l .l Reactivity

The reactivity of Diels-Alder reactions can be explained by considering

frontier molecular orbital interactions (FMO).'~~ The rate is primarily determined

by the interactions between the highest occupied molecular orbital (HOMO) of

one reactant and the lowest unoccupied molecular orbital (LUMO) of the other.

Any factors that decrease the difference in HOMO-LUMO energies will increase

the reaction rate. One major contributing factor is the effect that substituents

have on the diene and dienophile. Electron-withdrawing substituents lower both

HOMO and LUMO energies, whereas electron-donating substituents have the

opposite effect.

There are three general types of reactions depending on the three

possible HOMO-LUMO arrangements (Figure 7).3*7 ln the normal electron

demand reaction, the main interaction is between the HOMO of an electron-rich

diene and the LUMO of an electron-deficient dienophile. Therefore,

electron-donating substituents on the diene facilitate the reaction by raising the

HOMO, thus contributing to a decrease in HOMO-LUMO energy separation.

Likewise, electron-withdrawing substituents on the dienophile accelerate the

reaction by lowering the LUMO.

Figure 1 : Reaction Types Based on Different HOMO-LUMO Arrangements

diene dienophile diene dienophile diene dienophile

LUMO

HOMO

normal

A

In Diels-Alder reactions

inverse neutral

with inverse electron demand, the opposite

HOMO-LUMO interaction occurs; that is between the LUMO of an

eiectron-deficient diene and the HOMO of an electron-rich dienophile. Therefore,

dienophiles bearing electron-donating substituents and dienes bearing

electron-withdrawing substituents facilitate inverse electron demand reactions.

This type of reaction is commonly used in the synthesis of heterocyclic

compounds8 and highly functionalized natural p roduc t~ .~ - '~

In neutral Diels-Alder reactions, the least common of the three types, the

reactivity is similarly influenced by both possible HOMO-LUMO interactions,

regardtess of the substituents on the diene andlor dienophile. One such example

involves the Diels-Alder reaction of substituted tetraphenylcyclopentadienones

with substituted styrenes3

1.1.2 Regioselectivity

The extensive use of Diels-Alder reactions in synthesis can be attributed

to the ability of controlling regio- and stereoselectivity. A cycloaddition reaction

involving an unsymmetrical diene with an unsymmetrical dienophile could in

principle result in two regioisorneric adducts. The position of the substituents on

the diene and dienophile counterparts govern which regioisomeric adduct

predominates. The terms ortho, meta, and para used for disubstituted benzene

nomenclature are commonly used to describe the relative positions of

substituents in the cycloadducts.

Figure 2: Regioselectivity in Diels-Alder Cycloadditions

J "ortho"

EDG

--------KwG -

EWG

Frontier rnolecular orbital theory can be used to explain and predict

regioselectivity." The atomic orbital coefficients of the atoms where sigma bonds

will form govern the regiochemistry of the cycloadduct. That is, the larger

coefficient of one reactant will preferentially bond with the larger coefficient of the

other reactant- Therefore, in normal Diels-Alder reactions, the addition of a

1-substituted diene with a dienophile will generally favor the ortho product,

whereas the 2-substituted diene favors the para product (Figure 2).3-9

1 .1.3 Stereoselectivity

Another valuable feature of the Diels-Alder reaction is its high

stereoselectivity. In the reaction between a diene and a dienophile, up to four

new chiral centers may be formed. However, in many cases only one

diastereomeric product predominates. Two rules that generally govern the

stereoselective outcome of the major products are the cis rule and the endo rule.

The cis rule states that the relative configuration of substituents in the diene and

dienophile are preserved in the ~~cloadduct . '~ For example, the reaction of

1,3-butadiene with the cis compound dimethyl maleate and trans compound

dimethyl fumarate results in the cis- and trans-cyclohexene-4,5-

dimethyldicarboxylic ester, respectively (Scherne 1). Likewise, the reaction of

(E,E)-hexadiene with rnaleic anhydride gives rise to the product with the methyl

groups in the cis configuration (Scherne

The endo rule, which applies only to the kinetic products of the reaction, is

based on how the reactants arrange themselves during the reaction. The diene

and dienophile approach each other in parallel planes. Either endo or exo

cycloadducts form depending on the methods of interaction as shown in the

reaction between cyclopentadiene and maleic anhydride (Figure 3).3 The endo

rule states that the reactants approach each other in parallel planes where the

most stable transition state is that in which there is the maximum possibility of

orbital overlap.* Therefore, a dienophile bearing substituents with x bonds will

preferentially adopt the endo orientation in the transition state.

Scheme 1

Figure 3: Endo vs. Exo Interactions

1 .i -4 Lewis Acid Catalysts

Diels-Alder reactions that are catalyzed with a Lewis acid are known to

exhibit remarkable improvements in reactivity, regio-, stereo-, and

diastereoselectivity when compared to uncatalyzed reactions. The kinetic effects

are attributed to the Lewis acid fomiing a complex with the polar groups of the

dienophile. 13-15 This complex induces a lowering of the dienophile LUMO that

results in a decreased HOMO-LUMO energy separation. Therefore in normal

electron demand Lewis acid catalyzed cycloadditions, stabilization in the

transition state is increased resulting in the reaction proceeding more rapidly.

Exarnples of the use of Lewis acids to increase regio-, stereo-, and

diastereoselectivity are extensive. 16-22 In the case of enantioselectivity, the

outcome is based on the facial selectivity of the addition. In most cases, the

Lewis acid is complexed with a functionalized vinyl derivative. The Lewis acid

complex can adopt an s-cis or s-trans conformation, and can be either syn or anti

to the double bond (Figure 4)." The resulting enantioselectivity is a consequence

of the effective steric shielding of one face of the complex.

Figure 4: Lewis Acid Cornplex Conformations

anti s-cis anti s-&ans syn s-cis syn s- trans

In general, selectivity is controlled by the choice of the catalyst used. For

example, in a study involving the Diels-Alder reaction of the chiral oxazoline

(R)-(-)-rnethyl (2)-3-(4,5-dihydro-2-phenyl4-oxazolyl)-2-prope~ 1 ) with

cyclopentadiene in the presence of one equivalent of diethylaluminum chloride

gave opposite diastereoselective results compared to when one equivalent of

ethylaluminurn dichloride was used (Scheme 2).23

Scheme 2

Lewis acid

In both reactions, only the endo product was observed. However, when

Et2AICI was used, an 88:12 mixture of 2:3 was obtained, while under the same

conditions, the use of EtAICI2 resulted in a 298 mixture. The proposed

complexes that form between the Lewis acids and the chiral dienophile can

explain these results (Figure 5). The complex of diethylaluminum chloride with 1

is tetrahedral at aluminum and involves a single association of the aluminum with

the nitrogen (4). In this orientation the upper face of the alkene in 4 is open for

the reaction with cyclopentadiene, and results in cycloadduct 2 as the major

diastereorner. The complex of ethylaluminum dichloride with 1 is a trigonal

bipyramid in which the nitrogen and the carbonyl oxygen are associated with the

aluminum equatorially and the two chlorines are axial. In this complex, the upper

face of the alkene in 5 is exposed to the reaction with cyclopentadiene, and

results in cycloadduct 3 as the major diastereomer.

Figure 5: Lewis Acid Complexes with Chiral Dieneophile 1

H H H H

1.1.5 Chiral Lewis Acids

A strategy used to control the absolute configuration of the desired

product in Diels-Alder reactions is by employing chiral catalysts. A number of

chiral Lewis acid catalysts for asymmetric Diels-Alder reactions have been

developed. 2e26 The chiral Lewis acid coordinates to the dienophile thereby

activating it, as well as providing a chiral environment that affects facial

selectivity. One example involves the reaction of methyl crotonate and

cyclopentadiene using 10% alkyldichloroborane catalyst, which resulted in only

endo product with a 97% ee (Scheme 3).27

Scheme 3

- -

endo: 97% ee

This chiral catalyst foms a complex with methyl crotonate that is favored

due to electrostatic and n-71: interactions behrveen the Lewis acid activated

carboxyl group and the electron rich arene. In this conformation. the edge of the

naphthalene group blocks the botîom face of the dienophile allowing the top face

to be approached by the diene (Figure 6).

Figure 6: Chiral Lewis Acid Complex

1.2 Sulfur Functionalities on Dienophiles

Over the past decades, a substantial number of dienophiles bearing

different activating groups have been deve~o~ed.*~"~ Dienophiles bearing sulfur

functionalities have shown to be an important class of useful substituents for

several reasons including their excellent electron-withdrawing abilities, as well as

their capability of undergoing a variety of synthetically useful transformations. In

cases where an optically active sulfur group activates the dienophile, the

cycloaddition may occur with high diastereoselectivity, which makes these

groups attractive in asymmetric synthesis. Some of the sulfur-containing

functionalities on dienophiles utilized in cycloaddition reactions include sulfoxides

(6), sulfones (7). sulfinate esters (8). and sulfonate esters (9). 28-3 I

Figure 7: Types of Sulfur Containing Functionalities

O Il

O II

O II

O I I

R-S-R' R-S-R' R-S-OR' R-S-OR' Il II O O

6 7 8 9

1.2.1 a,p-Unsaturated Sulfoxides

a$-Unsaturated sulfoxides are efficient compounds in asymmetric

Diels-Alder reactions since the sulfoxide can be prepared enantiomerically pure.

Furthermore, the chiral center is directly bonded to one of the reactive carbon

atoms, allowing a significant effect on the type stereochemical result of the

cycl~addition.~~ Four diastereomeric products are possible upon the Diels-Alder

reaction of an optically active a$-unsaturated sulfoxide and a diene, such as

cyclopentadiene (Scheme 4).32

Scheme 4

endo-l l a

Two terms used to describe the diastereosetectivity of these reactions are

endo/exo-selectivity and n-facial selectivity. The first term, which was described

in Section 1 .i .3, is used to describe the mode of approach of the reactants, endo

or exo. For the purpose of this thesis, the terms endo and exo will refer to the

orientation of the sulfur substituent, regardless of other functional groups having

priority, unless otherwise stated.

The second term is used to describe the diastereofacial outcome of the

cycloaddition. n-Facial selectivity is mainly governed by steric factors. Therefore,

the favored approach of the reactants will occur at the least hindered face of the

sulfinylated substrate. The terms syn and anti will be to used describe the

outcome of the r e a ~ t i o n . ~ ~ The term syn is used when the S-R bond is positioned

parallel to the bridgehead C-H bond on the same side of the rnolecule, and when

the S=O bond is below the bicyclic skeleton. The term anïi is used when the S-R

bond is positioned parallel to the bridgehead C-H bond on the same side of the

molecule, resulting in the S=O bond being extended away from the molecule

(Figure 8).

Figure 8: Syn vs. Anti

R anti

The first study of Diels-Alder cycloadditions involving optically active

sulfoxides was carried out by Maignao, who utilized (R)-vinyl ptolyl sulfoxide and

~ ~ c l o ~ e n t a d i e n e . ~ ~ Four diastereomers were obtained with poor selectivity as

shown in Scheme 4. The poor diastereoselectivity is due to the small energy

difference between the two ground state conformations of 10a and ?Ob.

Therefore, there is no preference for attack by cyclopentadiene (Figure 9).

Figure 9: Diene Approach Towards Vinyl Sulfoxides

upper face /-- attack

\ attack

s-cis s-trans

In order to enhance the reactivity and diastereoselectivity in Diels-Alder

cycloadditions, a$-unsaturated sulfoxides can be modified by the addition of

electron-withdrawing groups in the position P to the sulfinyl moiety. For example,

when ( - and (a-ester substituted vinyl sulfoxides were reacted with

cyclopentadiene under mild conditions, a much higher endolexo and a-facial

diastereoselectivity were obtained (Scheme 5, only (3-sulfoxide shown, the

configuration at sulfur is maintained)?

The higher observed diastereoselectivity is due to the difference in stability

of the two conformers illustrated in Figure 10. The s-tram conformer (12b)

contains the sulfinyl oxygen remote from the ethoxycarbonyl rnoiety. This results

in lower dipole-dipole repulsion, relative to the s-cis conformer (12a), making it

the more stable conformer. Since cyclopeniadiene wll prefer to approach the

less hindered lone pair side of the more stable 12b conformer, the resulting

product is 13c. 3034

Scherne 5

Figure 10: Diene Approach Towards Vinyl Sulfoxide 12

7

1 2a s-cis

12b s-trans

Diastereoselectivity can also be enhanced with the use of Lewis acid

c a t a ~ y s t s . ~ ~ ~ ~ This was demonstrated in a study of the effect of different Lewis

acids on the cycloaddition reaction of p-toluenesulfinyl maleate 14 with

cyclopentadiene (Scheme 6). These results are summanzed in Table 1 .37

Table 1: Diels-Alder Reaction of 14 and Cyclopentadiene Using Various Lewis Acids

Scheme 6

Catalyst (Equivalents)

None E u ( f ~ d ) ~ (1 -2)

TiC14 (1 -2) ZnBr2 (1.2)

II cat. C02Me

In the absence of a catalyst the rnost stable conformation of 14 is

conformation 14a (Figure I l ) , which contains the sulfinyl oxygen in the s-cis

J

Product n-Facial Selectivity

15a:15b 9.1:l 22: 1 6.4: 1 0.08: 1

exolendo (1 5a+l5b):l5c

4.3:l 2.2:1 24: 1 1911

arrangement. Regardless of relative stabilities of 14a and 14b, conformation 14a

is the more reactive conformer because of steric interaction that exists between

the arornatic ring in conformation 14b and cyclopentadiene. This interaction

strongly destabilizes both endo and exo approaches. Therefore, the favored

approach of cyclopentadiene takes place from the less hindered face of 14a (si

face). This is in agreement with the stereochemistry of the major product adduct

endo-1 Sa (carboxyl group being endo) (Scheme 6).

Figure il: x-Facial Selectivity of 14 with Different Lewis Acids

The formation of endo-15a adduct is also favored with the use of Eu(fod)3

catalyst. The high n-facial selectivity is explained by assuming the E ~ ( f o d ) ~

catalyst, which exhibits a low chelating ability, coordinates with the sulfinyl

oxygen (16). The s-cis conformation is more stable since the bulky Eu(fod)3

imposes large steric restrictions with any other possible conformation.

Figure 12: n-Facial Selectivity of 14 with Z nBr2 and TiCI4

O BnO

fl si

-0.

CI atom s-O CI

Me0 Me0

ToL.,~ j*

Br Me0 Me0

\ 2.' \

O BnO O' Br

Me

When ZnBr2 or TiCI4 catalysts are used, the reaction takes place with the

chelated species 17 (Figure I l ) , which is a result of the sirnultaneous

coordination of the sulfinyl and carbonyl oxygens with the rnetal. However, their

spatial arrangements reveal differences in preferred approach by

cyclopentadiene. In the case of ZnBr2 chelate, the re face is more accessible in

the approach of cyclopentadiene since the si face is sterically and electronically

hindered by the sulfinyl oxygen (Figure 12). The opposite is tnie for the TiC14

chelate. The octahedral substituent arrangement around the titanium atom

results in directing one of the chlorine atoms towards the re face, thereby

hindering it. Therefore the preferred approach of the diene is to the si face

(Figure 12).

1.2.1.1 Applications of a$-Unsaturated Sulfoxides

a$-Unsaturated sulfoxides play an important role in the synthesis of

natural products and biologically active c o r n p o ~ n d s . ~ ~ ~ ~ ~ ~ ~ For example. the

enantioselective total synthesis of glyoxalase I inhibitor 20, a compound of

interest due to its cytotoxic and cancerostatic activity, was achieved utilizing the

asymmetric Diels-Alder reaction of dienophile 18 and 2-methoxyfuran (Scheme

7). 39

Scherne 7

Men =

7 steps / K,,

1.2.2 a$-Unsaturated Sulfones

a$-Unsaturated sulfones, both vinylic and acetylenic, are excellent

dienophiles mainly due to the electron withdrawing ability of the sulfur

functionality. The synthetic utility of these unsaturated sulfones in cycloadditions

is high, as they car: be transforrned into many other functional groups.30*41v42 The

use of aryl vinyl sulfones is of particular interest because they may serve as

ethylene or ketene equivalents. Cases in which a vinyl sulfone has been utilized

as an ethylene equivalent is in the preparation of syn- sesquinorbornene and

sesquinorbornadiene (Scherne 8).43 A disadvantage of sulfones is that unlike

sulfoxides, sulfones do not exist in optically active form, and therefore do not

impart chirality to the cycloadduct.

Scheme 8

1.2.3 a$-Unsaturated Sulfinates

Recently, the synthesis of a,&unsaturated sulfonate and sulfinate esters

and their subsequent use in both inter- and intrarnolecular Diels-Alder reactions

have generated much interest. Lee and CO-workers performed a study comparing

the activating powen in dienophiles of a sulfinate group with those of sulfoxide

and sulfone functions." Acetylenic sulfinate 21 undenvent cycloaddition

reactions with a number of different dienes (Table 2). For a reactive diene such

as cyclopentadiene, the cycloaddition took place at roorn temperature and

resulted in excellent yields. For less reactive dienes, the reactions were carried

out at elevated temperatures and afforded good to excellent yields of adducts.

When cornpared to the sulfoxide or sulfone counterparts, the acetylenic sulfinate

was found to be as reactive or substantially more reactive.

O II

Table 2: Diels-Alder Reactions of Acetylenic Sulfinate 21

The Schwan group was the first to report the Diels-Alder reaction of

1 -al kenesulfinic esters. 45*46 It was shown that 1-alkenesulfinate esters bearing

Yield (%) 95 86 81 84 95

tethered furans can undergo highly diastereoselective intramolecular Diels-Alder

Time (h) 5 8 12 12 6

Diene 1 Temperature (OC) cyclopentadiene 1 25

reactions under the proper condition^.^' For example, a single isomer was

1,3-cyclohexadiene

obtained from the intramolecular Diels-Alder reaction of 22 (Scheme 9).

60 2-methyl-1, 3-butadiene

2,3-dirnethyl-1, 3-butadiene 1 -(trimethylsilyloxy)-1,3-butadiene

50 60 130

Scheme 9

- 7 7 O ~ , CHZC12, 9h 0.1 eqv. of BHT

The results obtained from the study indicate the value of adding an ester

fundionality to the double bond of the sulfinate. That is, there is a substantial rate

increase without sacrificing stereoselectivity, and also the presence of the ester

unit contributes one more diastereoisomeric center in the adduct thereby

increasing its synthetic diversity.

1.2.3.1 1 -Al kenesulfinate Esters

The Schwan group were the fint to synthesize 1-alkenesulfinate esters

24." The synthesis begins with the Michael addition of PMB thiol to methyl

propiolate. Either the cis or tram isomer is obtained depending on which solvent

is used. When methanol is used the cis isomer is obtained, and in the presence

of CH2C12, the trans isomer is obtained. The sulfides are then oxidized with

mCPBA to form the corresponding sulfoxide. The final step involves an oxidative

fragmentation reaction with sulfuryi chloride to form the corresponding sulfinyl

chloride, which is captured with ethanol to form the sulfinate ester (Scherne 10).

60th (2)- and (E)-isomers, 24a and 24b respectively were reacted with

cyclopentadiene in order to determine their reactivity in interrnolecular Diels-Alder

reactions (Scheme 1 I ) . ~ ~ The cycloaddition reactions were performed under

thermal conditions, and also in the presence of several Lewis acids (Tables 3

and 4).

Scheme 10

Scheme 11

Table 3: DielsAlder Reactions of Cyclopentadiene and 24a

1 Lewis Acid Time 1 endo(25a:25b)/exo 1 Total Yield (%)a 1

ZnBr2 30 min 38(0.90: 1 ): 1 100 (98) 1

None None

BFTE~O

1 EtpAiCI 1 30 min 1 23(1 .9:11:1 1 90 1 Yb(0Tf)s 30 min 1 23(1.9:1):1 86 1

1 h, 40°C 4 h

5 min

Table 4: Diels-Alder Reactions of Cyclopentadiene and 24b

-

14(1.1 : l) : l 18(1.3:1):1 45(11:1):1

MgBr2 TiCI4 h l 2

SnC14 ZnC12

C

) Lewis Acid 1 Time 1 S-endo 1 S-exo (28) 1 Total Yield 1

98 (98) (87) 1 O0

aYields were determined by GC, isolated yields are in parenthesis.

30 min 100 min 40 min 5 min 15 min

None None

BFd37O

27c1.5: 1): 1 25(0.67: 1): 1 23(1.6: 1): 1 34(1 .O: 1): 1 34(1.4: 1): 1

ZnBr2

aYields were determined by GC, isolated yields are in parenthesis.

94 49 94 1 O0 100

1 h, 40°C 24 h 18 h

Et2AICI Y b(OTf)3

MgBr2 TiCI4

The cycloaddition of the (2)-isomer 24a, resulted in three out of four

possible diastereorners, with 25a and 25b being the major products (Scherne

11). It was found that the sulfinate group, like the sulfoxide, demonstrated a

stronger preference for the endo position than does the carboxylic ester moiety.

The use of Lewis acids resulted in substantially faster reactions and also

5 min

(27)l(syn:antî)(27a:27b) 1.6(1 :1.4) 1.7(1:1.3) 1.6(1 :1.4)

15 min 80 min 50 min 5.5 h

28(A :l -1)

(ratio) l(1.6:l) l(1.5:l) 1(1.6:1)

(%)" 97 82

(85) 1(1.2:1)

1 O0 1 O0 1 O0 69

2.5(1:1 .O) 1 1(1.3:1) 95 (83)

1.4(1 :l .A) 1(1.3:1) 1.1(1:1.2) 1 1(1.6:1)

OX(1:l . l ) l(2.0: 1)

demonstrated greater selectivity. The most effective of the Lewis acids used was

BF3Ef20, providing the largest 2526 ratio (453). and also the greatest endo

adduct ratio, 25a:25b (1 1 : 1 ).

The high stereoselectivity of 25a with BF3-Et20, relative to 25b is

explained by invoking an s-trans arrangement of sulfinate 24a (Figure 13a). The

s-trans arrangement is preferred since the unfavorable steric and dipole-dipole

interactions of the two polar functionalities are minimized. The BF3-Et20, being a

monodentate Lewis acid, enhances both dipolar and steric repulsions by

coordinating to one of the two ester groups, thereby ensuring that 24a assumes

the s-trans orientation. In the case of titanium and zinc based catalysts, both

being bidentate Lewis acids, coordination to both sulfinyl and carbonyl oxygens

results in an s-cis conformation of 24a (Figure 13b) leading to little preference

during the cycloaddition reaction.

Figure 13: Spatial Arrangement of 24a in DielsAlder Reactions

O h

Me0 "0 1 less cycloaddition hindered face via

a> m * \ s ~

* QLzMe

~t0"'& OflS,O~t

25a

The cycloaddition of the (E)-isomer 24b. was less successful in terms cf

selectivity. Four diastereomers were isolated with very little selectivity, under both

thermal conditions and in the presence of a Lewis acid.

1.2.3.2 Identification of Cycloadducts

In order to aid in the determination of the cycioadduct structures, products

25-28 underwent iodocyclization reactions with either the carboxylic ester. or the

sulfinate ester participating in the formation of a polycyclic iactone or sultine,

respectively (Scheme 1 2).46

Scheme 12

AgOC02CF3. b, DME, rt

AgOC02CF3, b, DME, rt

In the iodosultinization reaction, the sulfinyl oxygen of 25a attacks the

activated carbon atom on the opposite side of the ring. This occurs because the

alignment of the sulfinyl oxygen necessary for iodosultinization leads to the

ethoxy group positioned anti to the bicyclic structure, thereby minimizing steric

barriers to cyclization. In the case of 25b, the sulfinate group can not be

positioned in a conformation suitable for iodosultinization because of severe

steric interactions between the ethoxy group and the carboxylic ester moiety.

Therefore, cyclization of 25b proceeds by participation of the carboxylic ester.

1.2.4 a$-Unsaturated Sulfonates

The sulfonate functionality has evolved as a powerful dienophile

substituent due to its electron-withdrawing nature and high stereoselectivity in

intramolecular Diels-Alder reactions. The Metz group has demonstrated several

examples of intramolecular Diels-Alder reactions of cyclic and acyclic diene

tethered 1 -alkenesulfonic esters. For example, the Diels-Alder reactions of vinyl

sulfonate 31 proceeded with high diastereoselectivity, and with the endo sultone

32 as the major product (Scheme 13).48

The Metz group has also utilized vinyl sulfonates possessing an acyclic

diene moiety (33).49 The intramolecular reaction of 33 resulted in high

stereoselective formation of 6 sultones 34 and 35 out of four possible

diastereomeric products (Scheme 14).

Scheme 13

Scheme 14

Sultones 34 and 35 arise via a chair-like transition state with R' assuming

an equatorial position. When substituent R2 is larger than hydrogen, there is

notable preference for the formation of the exo product 34 relative to 35, as

shown by virtually complete diastereoselectivity in favor of sultone 34 when

RLS~M~~. This enhanced tram selectivity can be explained by the sterically

unfavorable interaction between R~ and the axial hydrogen (Hr) at the carbinol

center in 37, the transition state leading to 35 (Figure 14).

Figure 14: lntramolecular DielsAlder Transition States of 33

Another interesting dienophile containing a sulfonate functionality is the

sultone. Diels-Alder studies of prop-1-ene-1.3-sultone (38) with a variety of

dienes resulted in good chernical yields and excellent endo selectivity, proving it

to be an efficient dienophi~e.'~ Results of the reaction of 38 with cyclopentadiene,

1,3-cyclohexadiene and 5,5-dirnethoxy-l,2,3,4-tetrachlorocyclopentadiene are

tabulated in Table 5. In ail cases the stereoselectivity towards the formation of

endo adducts is mainly attributed to secondary orbital interactions in the

transition state (Figure 15). It is evident that the steric hindrance of 40 is greater

than that of 39 (when R = H) (Figure 15). This is due to the two allylic rnethylene

groups of cyclohexadiene are located on the top of the S02 and CH2 groups of

the sultone, causing steric hindrance and therefore resulting in only endo

product. In the case of cyclopentadiene, the methylene group is on the top of the

center of the sultone, adapting an orientation with less steric hindrance than

cyclohexadiene, hence the minor exo product. When two bulky methoxy groups

replace the rnethylene protons in cyclopentadiene (39, R = OCH3), the steric

hindrance prevented the formation of the exo product.

Table 5: Diels-Alder Reactions of Sultone 38

Diene Conditions 1 endo:exo Ratio 1 Yield (%) cyclopentadiene cyclopentadiene

1,3-cyclohexadiene 5,5-dimethoxy-l,2,3,4-

tetrachlorocvcio~entad iene

CH2&, 20°C, 168 h toluene. 120°C. 4 h

toluene, 150°C, 18 h xylene, reflux, 20 h

84: 16 100

endo only endo only

73:27 i 95 96 72

Figure 15: Transition States of Cyclopentadiene and Cyclohexadiene Approaching 38

One last example of a dienophile belonging to the sulfonate farnily is the

acetylenic su l f~nate .~~ Like the sulfinate, the sulfonate has proven to be an ideal

activator of an acetylenic dienophile. For example, the Diels-Alder reaction of

sulfonate 41 with cyclopentadiene took place readily at 0°C ta afford cycloadduct

42 is almost quantitative yield (Scheme 15).

Scheme 15

O II

RO-S H

8 CH2C12, O°C, 8h

1.3 Applications of Poly HydroxylMercapto Compounds and Diels-Alder Cycloadducts

1.3.1 Auxiliary Ligands

Poly hydroxy/mercapto compounds are those that contain one or more

thiol groups as well as one or more alcohol groups. There are many occurrences

of these cornpounds in organic chemistry. One area where such compounds are

used is in catalytic asymmetric synthesis. There is a necessity for developing

efficient enantioselective catalysts applicable to a wide range of carbon-carbon

bond foming reactions.=* Auxiliary ligands, based on a camphor sulfonic acid

backbone, possessing thiol and alcohol fuctionalitites have been shown to be

efficient in asymmetric synthesis. For example, the asymmetric reduction of

a$-unsaturated ketones to saturated secondary alcohols or allylic alcohols was

done using an optically active mercapto alcohol as a chiral reagent via a tandem

Michael additionlMeerwein-Ponndorf-Verley reduction (Scheme 16). 53-54

Scheme 16

intramolecular MPV red uction

Micheal addition of 43 to 44, using a Lewis acid formed sulfide 45

containing ketone and chiral alcohol moieties. The intramolecular

Meewein-Ponndorf-Verley reduction (1,7-hydride shift) of 45 resulted in 48 with

high stereoselectivity. Desulfurization of 48 afforded the optically active allylic

alcohol46 or saturated alcohol 47.

Another mercapto alcohol chiral catalyst successfully used in asymmetric

synthesis is MerCO (49).55 The borane reduction of aryl methyl ketones

catalyzed by MerCO produced 1 -aryl ethyl alcohols 50 in 92% ee (Scheme 17).

Scheme 17

The transition states in Scheme 18 show why the S configuration of the

alcohol is obtained. Transition states 52 and 54 being more favorable than 51

and 53 can be explained by the fact that boron is a hard Lewis acid. and would

prefer to coordinate with oxygen. When cornparhg 52 and 54, spatial

arrangements favor transition state 54. The bulky camphor backbone is oriented

at the axial position of the six-membered ring ligand-borane-ketone complex in

52. In 54, the 2-hydroxyl group of the camphor skeleton is set at the equatorial

position in the ligand-borane-ketone complex. Since the aryl group prefers to

remain in the equatorial position, the borohydride approaches the re-face of the

ketone, thereby leading to the S-alcohol according to the spatial arrangement of

transition state 54.

Scheme 18

1 ' \ H re

Disfavored by Ar sitting at the axia position of the S-B-O ring 51

sitting at the axial I Ar position of the B-O-% ring 52

54 most favored

1.3.2 Homologation of 2-Mercapto Benzylic Alcohols

Another example involving interesthg chemistry of poly hydroxy/mercapto

compounds is a homologation reaction of 2-mercaptobenzylic alcohol (55)

(Scheme 19). 1,3-Oxathiane 56 was prepared from 55 by reaction with

2,2-dimethoxypropane and ptoluenesulfonic acid as catalyst. A DTBB-rnediated

lithiation of 56, followed by hydrolysis with water, resulted in

2-mercaptohomobenzylic alcohol 57. Lastly, 57 was able to cyclize under

Mitsunobu-type reaction conditions resulting in the sulfur containing heterocycle

Scheme 19

(CH3)2C(OCH3)2, pTSOH cat., acetone, 40°C w

1. Li, DTBB cat., / THFJ8OC

1.3.3 Stereoselective RingOpening

Oxabicyclic compounds are valuable intermediates in the preparation of

carbohydrates and biologically active compounds, arising from their ability to be

stereoselectivly ring-opened to highly fuctionalized cyclohexane derivatives.

Therefore, the development of new strategies which efficiently form

multifunctional and stereochemically rich polycyclic systems in a limited number

of steps is of great value to organic s~nthesis."

Scheme 20

1. Bu3SnH, Pd(OH), 2. RLi *

Various regio- and stereoselective ring opening processes are known. 58.59

For exarnple, oxabicyclic compound 59 (Scheme 20), derived from a Diels-Alder

reaction involving furan, underwent nucleophilic ring-opening reactions, 60.61

reductive nickel-catalyzed hydroalumination-fragmentation ~equence,~* and

palladium-catalyzed hydrostannationltin-lithium exchange fragmentation

Another valuable ring opening method is the regio- and stereocontrolled

alkylative bridge cleavage of oxabicyclic vinyl s u ~ f o n e s . ~ ~ ~ ~ ~ Highly functionalized

cyclohexenyl sulfones bearing up to four neighboring chiral centers are produced

in high yields (Scheme 21). The phenylsulfonyl functionality is an appealing

substituent due to vinyl sulfones being synthetically versatile4* and since the

regiochemistry of the process can be readily controlled.

Scheme 21

PhS02 - 1. MeLi, THF. 78"C, 1 hm , 2 TB 5 OTf, ETI N , ..O " Me

Me THF, 78"C, I h OTBS

Oxabicyclic vinyl sulfones 66 are formed from optically pure Diels-Alder

endo adducts (63) of furan and acrylic acid?& Tricyclic sulfide 64 is obtained in

two steps from 63. Treatment of 64 with n-BuLi leads to the cleavage of the more

strained tetrahydrofuran ring and in situ addition of p-toluenesulfonyl chloride

forming tosylate 65. Vinyl sulfone 66 is fomed by chemoselective reduction of

the tosylate function and then sulfide oxidation. The MeLi induced alkylative oxa-

bridge opening of 66 produced regio- and stereoselective cyciohexenyl sulfone

67. Sulfone 67 was isomerized by reaction with LDA affording allyl isomer 68 as

the single product (Scheme 21).

2. Results and Discussion

Two main objectives were associated with this project. The first objective

was to further evaluate the Diels-Alder chemistry of a$-unsaturated sulfinate

esters 24. There are few studies involving Diels-Alder reactions with dienophiles

bearing sulfinate ester functionalities. Such dienophiles are thought to be

synthetically useful for several reasons. For example, wmpetition reactions

involving a$-unsaturated sulfoxides and a$-unsaturated sulfinate esters

resulted in 2.5 times more sulfinate a d d ~ c t . ~ ~ This indicates that sulfinate

substituents on dienophiles enhance the rate of Diels-Alder reactions, cornpared

to sulfoxide substituents, a phenornenon that is presumably due to the sulfinate

being a better electron-withdrawing substituent than the su~foxide.~~ Another

valuable quality of the sulfinate ester functionality is its ease of transformation

into a sulfoxide, sulfone or thiol, after the cycloaddition. The fact that a

cycloadduct containing a thiol can be formed suggests that a$-unsaturated

sulfinate esters are able to act as an enethiol equivalent. This is beneficial since

the thiol is an electron-donating substituent, which are norrnally not very reactive

with electron-rich dienes. Furthemore, only a few papers report the passing

existence of enethio~s.~~

Broad selections of dienes having different reactivitites were chosen for

the reaction with a$-unsaturated sulfinate esters 24; mainly based on availability

and cost. The dienes selected included furan, 2,3-dirnethyl-1,3-butadiene,

1,3-cyclohexadiene, and anthracene. The reactions were carried out under both

thermal and Lewis acid catalyzed conditions. The Lewis acids were chosen

based on the best results obtained from the DieIs-Alder reactions of 24 with

cyc~opentadiene,~~ as well as avalibility. In most cases, mixtures of sulfur epimers

were formed in the cycloadducts. Since the ultimate goal is to achieve poly

hydroxylmercapto compounds via reduction of cycloadducts, no further effort was

made to distinguish the epimers.

Another facet of this first objective was to explore the steric evaluation of

(E)-a$-unsaturated sulfinate ester 24b. Recall that the cycloaddition of 24b with

cyclopentadiene resulted in 4 isomers with poor selectivity (Section 1.2.3.1). In

order to increase S-exo selectivity, 24b bearing different larger sulfinate ester

substituents were synthesized and used in cycloaddition reactions with

cyclopentadiene. The bulkier groups chosen to replace the ethoxy group are

shown below.

flo+ +O+ cycl O hexy loxy adarnantoxy t-butoxy

Similarly, in an attempt to irnprove S-endo selectivity, 24b bearing a

bulkier t-butoxycarbonyl substituent was synthesized and subjected to

cycloaddition reactions with cyclopentadiene.

The third approach in evaluating the Diels-Alder chemistry of

a$-unsaturated sulfinate esters was to increase the dienophilicity of 24 by

replacing the carboxylic ester group with a sulfinate ester. A description of the

requisite attempts to create bis sulfinate containing dienophiles will be reported.

The second main objective of this project was to evaluate the

cycloadducts as synthetic precunors to poly hydroxylmercapto compounds. The

2.3-dimethyl-l ,J-butadiene cycloadducts were subjected to a number of different

reduction conditions employing LiAIH4 and DIBAL. In some cases, benzyl

bromide was added during the reduction in order to capture the thiolate as a

sulfide and also to avoid the potent stench produced by the thiol. The best

reduction conditions were then applied to the remaining cycloadducts.

2.1 Diels-Alder Reactions of 24

2.1 -1 Diels-Alder Reactions of 24 with 2.3-Dimethyl-l,3-Butadiene

The cycloaddition reactions of 24a with 2,3-dimethyl-l,3-butadiene were

carried out at room temperature, elevated temperatures and in the presence of

Lewis acids ZnBr2, and Et2AICI. The reaction is illustrated in Scheme 22 and the

results are shown in Table 6. The best result in terrns of rate and yield was when

Et2AICI was employed. When ZnBr2 was used, the reaction mixture turned black

and the TLC contained an elongated spot that moved with the solvent front. The

'H NMR spectrum showed what appeared to be extensive polymerization. At

increased temperature, in the absence of a Lewis acid, the reaction did proceed

over a longer period of time and resulted in a lower yield.

For the successful reactions, two isomers were identified by NMR

analysis; however the two could not be distinguished. The epirner with the methyl

protons from the sulfinate ester group at 1.27 ppm is designated isomer A. The

epimer with the methyl protons from the sulfinate ester group at 1.31 ppm is

designated isomer B.

Scheme 22

Table 6: Diels-Alder Reactions of 24a with 2.3-Dimethyl-l,3-Butadiene

The cycloaddition reactions of 24b with 2,3-dimethyl-l,3-butadiene were

also carried out at room temperature, elevated temperatures and in the presence

of ZnBr2, and Et2AICI. The reaction is illustrated in Scheme 23 and the results are

shown in Table 7. Reactions catalyzed with Et2AICI occurred almost instantly and

resulted in a high yield. The yields were also improved by increasing the

temperature for the uncatalyzed reactions. Two isomers were identified by 'H

NMR analysis; however, once again the two could not be distinguished. The

epimer with the methyl protons from the carboxylic ester group at 3.72 ppm is

designated isomer A. The epimer with the methyl protons from the carboxylic

ester group at 3.73 ppm is designated isomer B.

Reaction Conditions CH2C12, r.t.

tofuene, 65°C ZnBr2, CH2C12, r.t. Et2AICI, CH2CI2, r-t.

aDecornposition occurred.

Time 24 h 24 h 6 h

10 min

Ratio (A:B) NR 3.1:l NRa 3.7: 1

Total Yield (%) -

60 -

85

Scheme 23

O O f 1 l

M e o p s h , E t + ) < - )"JE-"~t H O " ' c o ~ M ~

24b 70

Table 7: Diels-Alder Reactions of 24b with 2,3-Dimethyl-1,3-Butadiene

Reaction Conditions CH2CI2, r.t.

toluene. 60°C

2.1.2 Diels-Alder Reactions of 24 with Anthracene

Sulfinate esters 24 underwent cycloaddition reactions with anthracene at

room ternperature, elevated temperatures and in the presence of ZnBr2, and

Et2AICI. In al1 cases, the successful reactions required extended time to achieve

cornpletion cornpared to other dienes.

The reaction with 24a is illustrated in Scheme 24 and the results are

tabulated in Table 8. The only successful reaction was when Et2AICI was

employed. All other attempts resulted in recovery of starting material. Two

epimers (71) where found and separated by flash chromatography on silica gel.

However the isomers could not be distinguished. The isorner bearing the methyl

protons from the sulfinate addend at 1.19 ppm is designated isomer A. The

isomer bearing the rnethyl protons from the sulfinate addend at 1.47 ppm is

designated isomer B.

toluene, 100°C ZnBr2, CH2CI2, r.t. Et2AICI, CH2CI2, r. t.

Tirne 24 h 24 h

'Yields based on starting material recovered. b~ecomposition occurred.

24 h 24 h

10 min

Ratio (A:B) NR

2.0: 1

Total Yield (%) -

55 a 1.8:l 1.311 1.8:l

91 a 48a*b 94

Scheme 24

71

Table 8: Diels-Alder Reactions of 24a with Anthracene

Reaction Conditions CH2C12, r.t.

toluene, 80°C

The cycloaddition of 24b was less successful in terms of epimer selectivity

compared to 24a. Scheme 25 illustrates the reaction and the results are shown in

Table 9. It is interesting to note that cycloadditions that took place at 60°C were

successful, however at 80°C only starting material was recovered. Furthermore,

reactions of 24a with anthracene at 80°C resulted in starting material recovery.

This may suggest the retro-Diels-Aider reaction is occurring at elevated

temperature above 60°C. It is known that anthracene undergoes retro-Diels-Alder

reactions at elevated tempe rature^.^^

Once again two epimers (72) where formed and separated by flash

chromatography. However the isomers could not be distinguished. The isomer

bearing the methyl protons from the sulfinate addend at 1.18 ppm is designated

Time 24 h 24 h

ZnBr2, CHÎCI~, r-t.

%elds based on starting material recovered. Et2AICI, CH2CI2, r.t.

1

Ratio (A:B) NR NR

24 h 18 h

NR 5.6: 1

Total Yield (%) - - -

46a

isomer A. The isomer bearing the methyl protons from the sulfinate addend at

1.40 ppm is designated isomer B.

Scheme 25

Table 9: Diels-Alder Reactions of 24b with Anthracene

Reaction Conditions CH7C17. r.t.

2.1.3 Diels-Alder Reactions Of 24 with Furan

- -- toluene, 60°C toluene, 100°C

ZnBr2, CH2CI2, r.t. Et2AICI, CH2C12, r.t.

It is well known that furan can undergo Diels-Alder reactions, despite its

Time 24 h

aromaticity and hence expected decreased reactivity. Depending on the nature of

Yields based on starting material recovered.

the dieneophile, differences in yields, reaction times, and stereoselectivities are

Ratio (A:B) NR

34= - -

44

5 d 24 h 24 h 18 h

often observed. 69-7' The Diels-Alder reaction of furan with 24a is illustrated in

Total Yield (%) -

2.13:l NR NR

2.65: 1

Scheme 27 and the results are shown in Table 10. The only successful reaction

occurred when Et2AICI was employed. This reaction resulted in poor endolexo

(1.l:l) selectivity, when compared to the reaction of 24a and cyclopentadiene

(endolexo ratio of 23:l). This cornparison is commonly reported. That is, there

are many examples involving low endolexo selectivities in reactions involving a

number of dienophiles with f~ran;~*-~' even direct comparisons with

cyc~opentadiene.~"~~ There are also many explanations suggested to account for

the observed results. One study involving the reaction of furan with phenyl

ethene sulfonate (Scheme 26a) resulted low enddexo selectivity. The major

isomer produced at room temperature had endo selectivity, while the exo isomer

was the predominant product resulting from elevated tempe rature^.^' The

observed results suggested that the kinetically controlled endo product

isomerizes to the thermodynamically more stable exo product via

retro-Diels-Alder reactions under the influence of solvent and temperature.

Scheme 26

Similar explanations were reported for the Diels-Alder reaction of diethyl

ketovinylphosphonate and furan (Scheme 26b).76 Another study involving the

Diels-Alder reaction of (E)-1 , l ,1-trichloro-3-nitro-2-propene with furan reported

that the low CC13 endolexo selectivity (1.1 : 1 ) is a consequence of the steric

interaction of the trichloromethyl group and the oxygen lone pairs of the furan

(Scheme 26~)~~' Therefore, potential retro-Diels-Alder reactivity, or possible

steric interactions between 24a and the oxygen lone pairs of furan may account

for the observed low endolexo selectivity.

Four products were obtained in the cycloaddition reaction of 24a and furan

(Scheme 27); two sulfur epirners in the endo adduct and two sulfur epirners in the

exo adduct. Upon flash chromatography on silica gel, three products were

isolated; one endo sulfur epimer, one exo sulfur epimer, and a mixture of the

other endo and exo sulfur epimers. The endo and exo structures were assigned

by 'H NMR analysis. The and J- coupling constants in 73a were found to be

4.4 Hz, which correspond to the endo product. 32180 The and J31-# coupling

constants in 73b were found to be O Hz, which correspond to the exo product.

The epimers could not be distinguished. Therefore, the isolated endo product

bearing methoxy protons at 3.67 ppm is designated isomer B. The endo product

in the mixture bearing methoxy protons at 3.69 pprn is designated isomer A. The

exo product in the mixture bearing methoxy protons at 3.74 ppm is designated

isorner C. The isolated exo product bearing methoxy protons at 3.74 ppm is

designated isomer D.

Scheme 27

Table 10: Diels-Alder Reactions of 24a with Furan

-- 1 Et2AICI, CH2CI2, r-t. 1 10 min 1 .1(2.2:1):1(2.4:1) 1 46 a Decomposition occurred.

Total Yield (%) - - -

Reaction Conditions CH2C12, r.t.

CH2CI2, 40°C ZnBr2, CH2CI2, r.t.

The reaction of 24b and furan resulted in a mixture of 4 inseparable

isomers; two S-endo epirners and two S-exo epirners (Scheme 28). Following

Time 24 h 24 h 1 h

reduction, elucidation of S-endo and S-exo products was possible (vide infra);

endo(A: B):exo(C:D) NR NR N Ra

however distinguishing pairs of epirners was not. The methyl protons from the

sulfinate group of the S-endo epimer at 3.79 ppm are designated isomer A. The

methyl protons from the sulfinate group of the S-endo epimer at 3.78 ppm are

designated isomer B. The methyl protons frorn the sulfinate group of the S-exo

epimer at 3.70 ppm are designated isomer C and the methyl protons from the

sulfinate group of the S-exo epimer at 3.69 ppm are designated isomer D.

Scheme 28

Table 11 : Diels-Alder Reactions of 24b with Furan

The outcome of these reactions resulted in unusual findings. The

cycioaddition reaction with Et2AICI resulted in an unexpected endolexo ratio of

1:2.3 (Table 11). One proposal that can account for such a result involves

electrostatic forces. One report on possible alternatives to secondary orbital

overlap explanations provides an example in which there exists an electrostatic

interaction between the furan oxygen and the carbonyl carbon of

cyclopropenone.81~82 This strong electrostatic stabilization accounted for the exo

preference.

Electrostatic interactions could be applied to the reaction of 24b with

furan. The dipole moments of dimethyl sulfite, diethyl sulfite, dimethyl carbonate

and diethyl carbonate are indicated b e ~ o w . ~ ~ In al1 cases the sulfite dipole

moments are greater than the carbonate dipole moments. Therefore it can be

inferred that the dipole moment of the sulfinate group in 24b is greater than that

of the carboxylic group. By considering this, it may be possible that an

electrostatic stabilization between the furan oxygen and the sulfur in 24b can

result is a preferred orientation in which the sulfinate functionality exists in the

exo position (Figure 16). Of course, sufficient interaction between the furan

oxygen and the sulfur must exist in order for this proposal to be viable.

Total Yield (%) - -

45= 68

[ Reaction Conditions CH2CI2, r-t.

CH2CI2, 40°C ZnBr2, CH2CI2, r-t. Et2AICI, CH2CI2, r.t.

v ie ld based on starting material recovered.

Time 24 h 24 h 24 h

10 min

S-endo(A:B):S-exo(C: D) NR NR

1.60(1.5:1):1(1.2:1) l(1.8: 1):2.3(1.8:1)

p = 0.87 D p = 2.61 D

p = dipole moment in Debye units (D)

The endolexo ratio obtained when ZnBrz was employed was 1.6:l. By

considering the explanation given for the Et2AICI outcome, one would assume

the exo product would predominate. Lewis acid strength can offer a possible

explanation to these strange results. If considering Lewis acid strengths, Et2AICI

is stronger Lewis acid than ~ n ~ r z . " Therefore, coordination of the Et2AICI to the

sulfinyl oxygen would render a stronger interaction between the furan oxygen

and the sulfinyl group; more so than that with ZnBr2. Therefore ZnBr2 may still

contribute to an electrostatic stabilization (explaining the low endo:exo ratio), but

not to the extent of Et2AICI, bearing in minci that the endo:exo ratio when 24b

reacts with cyclopentadiene is (2.5-2.8): 1, regardless of the Lewis a ~ i d . ~ ~

Figure 16: Dipole Interaction Between Furan Oxygen and the Sulfinyl Group

8 dipole interaction

2.1.4 Diels-Alder Reactions of 24 with 1,3tyclohexadiene

The cycloaddition reactions of 24 with 1,3-cyclohexadiene were

unsuccessful (Table 12). Reactions in absence of a Lewis acid resulted in

recovery of starting material. When Lewis acids were employed, extensive

polymerization occurred. Other studies involving Diels-Alder reactions with

1 ,3-cyclohexadiene resulted in similar observation^.^^ One successful study

involved the use of catalytic amounts of Lewis acids under ultrahigh pressuresa5

An alternative reaction condition would be to utilize ultrahigh pressure if a

cycloadduct of 24 and 1,3-cyclohexadiene is desired.

Table 12: DielsAlder Reactions of 24 with 1.3-Cyclohexadiene

1 24a 1 Et2AICI, CH2C12, r.t. 1 24 h 1 decomposition 1

~ienophile 24a 24a

24b 1 Et2AICIl CH2C12, r.t. 1 24 h 1 decomposition 1

2.2 Reduction of Cycloadducts

The next step en route to the formation of polylhydroxy mercapto

cornpounds is reduction of the sulfinate and carboxylate groups in the

cycloadducts. Reductions of cyclic sulfinate esters to the corresponding

mercapto alcohols have been carried out with LiAIH4. In order to determine

the most efficient reduction conditions, cycloadduct 70 underwent a variety of

reductions with LiAIH4 and DIBAL. From these results, the best conditions were

applied to al1 other cycloadducts.

Result starting material starting material

Reaction Conditions 1 Time CH2C12, r.t.

Toluene. 80°C 6 d 24 h

2.2.1 Reduction of Cycloadduct 70

The best condition for the formation of the rnercapto thiol 75 from 70

involved 4 equivalents of LiAIH4 treatment in THF at room temperature (Table

13). The reactions were not successful in methylene chloride or toluene. After

allowing the reduction reaction to stir for 30 minutes in THF or ether, a potent

thiol odour was detected when spotting the TLC plate. At this point, the reaction

was either quenched with acid to form 75 or alkylated with benzyl bromide to

form 76.

Scheme 29

1 reduction conditions

Table 13: Reduction of 70 with LiAIH,

Reaction Conditions 1. LiAIH4 (4 equiv), ether, r.t-, 30 min

2. benzvl bromide, r-t.. 24 h 1 1

. .

2. benzyl bromide, r-t., 2 h 1. LiAlH4 (4 equiv), ether, 3S°C, 30 min 2. benzyl bromide, r-t., 2 h I . LiAIH4 (4 equiv), THF, r.t., 30 min 2. benzyl bromide, r.t., 4 h 1. LiAIH4 (4 equiv), THF, r.t., 30 min 1. LiAIH4 (4 equiv), toluene, r-t., 30 min

Product 76

The proposed rnechanism for the reduction of 70 and formation of 75 is

Yield (%) 22

77 76 77 76

75 starting material

1. LiAIH4 (4 equiv), toluene, r-t., 24 min 1. LiAIH4 (4 equiv), CH2& r.t., 30 min 2. benzyl bromide, r.t., 24 h

( 1. LiAIH4 (4 equiv), CH2C12, r-t., 30 min

illustrated in Scheme 30. After 30 minutes, the reduction in THF contained one

13 36 6 68

82 -

spot on the TLC plate with an Rf value of 0.40 (Rf of isolated mercapto alcohol is

starting material starting material

starting material

0.36). When the reaction took place in ether, two spots were observed; one with

- -

-

an Rf at 0.40 and the other at 0.25. The lower Rf species was isolated and

spectroscopic analysis indicated that it was the disulfide product 77.

Scheme 30

76

R = HS-R 75

A proposed mechanism for the formation of 77 is depicted in Scheme 31.

In this mechanism, a thiolate anion is formed and reacts with sulfenic acid 80

resulting in 77. In an effort to help assess the feasibility of this mechanistic

offering, benzyl mercaptan was introduced at the beginning of the reaction. It was

anticipated the thiolate anion of benzyl mercaptan, as a foreign species would

intercept 80 forming mixed disulfide 81 (Scheme 32). However, the reaction

resulted in the formation of 77 and recovery of benzyl mercaptan, reducing the

likelihood of this mechanism.

Scheme 31

Scheme 32

Another possible mechanism is proposed in Scherne 33.'* ln this

mechanism, sulfenic acid is formed and reacts with itself to lose water, a reaction

that results in the formation of a thiosulfinate, which is further reduced to 77. It is

interesting to note that at elevated temperatures in ether (35OC), the relative

amounts of 76 to 77 was greater compared to the reaction conducted at room

temperature. This suggests that elevated temperatures are required to effect S-S

bond redu~tion.~'

Scheme 33

O II

R-S-S-R

R-S-S-R

77

Like LiAIH4, the use of DIBAL as a reducing agent for 70 proved to be

efficient (Table 14). The best condition for the formation of 75 involves 6

equivalents of DIBAL in THF at -78OC. When benzyl bromide was added to these

conditions, the major product after 3 hours was 77. However when one molar

equivalent of triethylamine was added imrnediately following benzyl bromide, 75

was the only product obtained. When toluene or methylene chloride were used

as solvents, 75 was the major product obtained. DisuIfide 77 was also produced,

along with a product in which only the carboxylic ester was reduced, and not the

sulfinate (78). Conditions of 3 equivalents of DIBAL in THF resulted in a product

in which oniy the sulfinate was reduced, and not the carboxylic ester. These

results suggest that the choice of solvent rnay effect selective reduction of

carboxylic esters vs. sulfinate esters when DIBAL is employed. Further studies

rnay be worthwhile to organic synthesis.

fable 14: Reduction of 70 with DlBAL

Yield (%) 38 11 54 3 7

Reaction Conditions 1. DIBAL (4.4 equiv), CH2CI2, -78OC, 1.5 h 2. benzyl bromide, -78OC+r.t., 2 h 1. DIBAL (4.4 equiv), CH2CI2, -78OC, 1.5 h

1 - - / 1. DIBAL (6 equiv), THF, -78OC, 30 min 1

Product 75 78 75 77 78 75

. .

2. benzyl bromide, -78OC+r.t., 3 h 1. DlBAL (6 equiv), THF, -78OC, 30 min

Once the optimum reduction conditions were chosen, they were applied to

14

2. benzyl bromide, Et3N-78OC+r.t., 1.5 h 1. DIBAL (6 equiv), THF, -78OC, 30 min 1. DlBAL (3 equiv), THF, -78OC, 30 min

1. DIBAL (6 equiv), toluene, -78OC, 1.5 h

al1 other cycloadducts which are presented below.

77 76

33 61

75 79

starting material 75 77 78

97 62 12 53 3 6

2.2.2 Reduction of Cycloadduct 69

Scheme 34

m L - O E t LAIHA. THF

2.2.3 Reduction of Anthracene Cycloadducts 71 and 72

The reduction of anthracene cycloadducts 71 and 72 proceeded with ease

in 15 minutes using LiAIH4 in THF (Scheme 35).

Scheme 35

LiAIH,, THF, r.t., 15 min

O f

LiAIH4, THF, r.t., 15 min

2.2.4 Reduction of Cyclopentadiene Cycloadducts 25, 26, 27 and 28

The reduction and alkylation of a mixture cycloadducts endo 25 and exo

26 resulted in only the endo product in a low 26% yield (Scheme 36). Reductions

without the addition of benzyl bromide were successful by TLC anaylsis.

However, the product could not be found after several different trials of

purification by flash chromatography on silica gel as well as on alumina. Similar

occurrences were observed for other cyclopentadiene and furan cycloadducts.

Therefore, al1 bicyclic cycloadduct reductions were captured with benzyl brornide.

Scheme 36

I 1. LiAtH4, THF, r.t., 15 min S(0)OEt

25 2. benzyl bromide t

The reduction and capture of a mixture of 27 and 28 cycloadducts

afforded an inseparable mixture of 86 (Scheme 37). The S-endo:S-exo ratio was

found to be 2 - 5 3 , and was deterrnined by the ratio of the benzylic protons in the

'H NMR spectra. This ratio is identical to that reported for the cycloadduct

precursor. A comparison of S-endo:S-exo ratios for bicyclic cycloaddition

products and reduction products is tabulated in Table 15.

Table 15: Endo:Exo Ratios of Cycloaddition and Reduction Products of Bicyclic Systems

Scheme 37

Yield (%) Cycloaddition 1 Reduction

Cycloaddud?

S os ' OEt 27

S-Endo: S- Ex0 Cycloaddition 1 Reduction

Product 24a + cyclopentadiene 1 23: 1

28

I 1. LiAIH4, THF, r.t., 15 min 2. benzyl bromide, 2 h

aCycloadducts fomed from DielsAlder reactions employing Et2AICI.

Product endo only

2.5:1 2.6: 1 7 :3.5

24b + cyclopentadiene 24a + furan 24b + furan

Yield = 55%

2.5: 1 1.1 :l 1 :2.3

2.2.5 Reduction of Furan Cycloadducts 73 and 74

Product 90 1 O 0 46 68

The reduction of cycloadducts 73 gave an inseparable mixture of 87

Product 26 55 30 58

(Scheme 38). The endo and exo structures were assigned by 'H NMR analysis

and the ratio was found to be of 2.6:1 (endo:exo). The Jiz and Jw coupling

constants in 87a were found to be 4.1 Hz, which correspond to the endo product.

The JI-, and J3'-4' coupling constants in 87b were found to be O Hz, which

correspond to the exo product. The endo product still remains the dominant one

but more so than its cycloadduct precunor, which contained an endo:exo ratio of

1.1:1.

In the reduction of cycloadducts 74, a mixture of S-endo to S-exo products

were obtained and separated by flash chromatography on silica gel (Scheme 39).

The structures were detemined by 'H NMR analysis. An endo:exo ratio of t3.5

was obtained and remained consistent with that of the cycloaddition product

ratio of 1 :2.3.

Scheme 38

1 1. LiAIH4, THF, r.t., 15 min ! 2. benzyl bromide, 2 h +

Yield = 30%

Scheme 39

s os ' OEt

LiAIH4, THF, r-t., 15 min benzyl bromide, 2 h

Yield = 58%

2.3 Steric Evaluation of ( E ) a , p-Unsaturated Sulfinate Ester 24b

The cycloaddition of 24b with cyclopentadiene resulted in 4 isomers with

poor selectivity (Section 1.2.3.1). This may be due to the small energy

differences between the s-cis and s-trans conformations depicted in Figure 17,

which would lead to little preference of attack by cyclopentadiene.

Figure 17: s-cis and s-tmns Conformations of 24b

O O

s-trans s-cîs

In an effort to increase S-endo and S-exo sefectivity, the bulkiness of

either the sulfinate group or carboxyiic ester group was increased. If a bulky

substituent, such as an adamantoxy group, replaces the ethoxy group in 24by

there should be a higher occurrence for an orientation in which sulfinate group

assumes the exo position (Figure 18a). This is due to steric hindrance between

the larger substituent and the approaching diene. Likewise,'if a bulky substituent,

such as a t-butoxy group replaces the methoxy group in 24b. there should be a

higher occurrence for an orientation in which sulfinate group assumes the endo

position (Figure 18b).

Figure 18: Steric Evaluations of 24b

1 cycloaddition via + a) ya 0 H 0.. le- hindered side

O,/ C02Me

O

cycloaddition via C02C4Hg less hindered side

EtO, / S s S(0)OEt O

Three dienophiles containing a larger sulfinate ester group were

synthesized. The synthesis involves an oxidative fragmentation reaction,

discussed in Section 1.2.3.1 of the introduction, followed by capture with an

alcohol. The alcohols chosen included; ~~c lohexano l , ~~ 2-adamantanol and

t-butanol. The structures of the corresponding a$-unsaturated sulfinate esters

are shown below. Compound 92 was synthesized the same way in which 24b

was synthesized (Scheme 10). The difference being PMB thiol underuvent a

Michael addition to t-butyl propiolate rather than methyl propiolate.

Dienophiles 89-92 undement Diels-Alder reactions with cyclopentadiene

in the presence of Et2AICI. The reactions were carried out in CH2CI2 at room

temperature and were complete in 20 minutes. The cycloadducts were purified

by flash chromatography on silica gel. The yields and the S-endo:S-exo ratios

are given in Table 16. The cycloadducts were then subjected to reduction

conditions (with the exception of 91) with LiAIH4 in THF at room temperature for

15 minutes. The yields and the S-endo:S-exo ratios are given in Table 16.

Table 16: S-endo:S-exo Ratios and Yields for Cycloaddition Products and Reduction Products for Steric Studies

'lsomeric ratio; can not distinguish beheen Szndo:S-exo isomers.

Dienophile

24b 89

For the reactions involving 24b and 89-91, the general trends expected

were indeed observed. That is, by increasing the bulkiness of the sulfinate group,

from ethoxy, the S-endo:S-exo ratio decreased. Upon reduction of the

cycloadducts, the S-endo:S-exo ratio remained consistent with the cycloaddition

ratio.

The steric evaluation of 92 afforded unusual results. An isomeric ratio of

1.45:l was observed. The ratio was determined by 'H NMR analysis of the

t-butoxy protons. However, the isomen could not be distinguished by this

method. The reduction of the cycloaddducts did not aid isomer determination.

That is, a ratio of 1:l was obtained by considering the ratio of the benzylic

protons. In any case, a ratio of 1.45:l for either S-endo:S-exo or S-exo:S-endo

contradicted expectations. That is, an increase in S-endo:S-exo greater than

2.5:l was expected. This suggests that substituent changes on the carboxylic

end have created an undesired and at this point unexplained variation in the

experimental trends. Additional studies with different substituents would assist in

understanding the observed ratios.

Cycloadduct Reduction Products S-endo: S-exo

2.5: 1 1 .30:1

S-endo:S-exo 2.5: 1 1 -43: 1

Yield (%) 1 O0 89

Yield (%) , 55 37

2.4 Bis Ethenesulfinate Esters

Further attempts at evaluating the Diels-AIder chemistry of

a$-unsaturated sulfinate esters was to increase the dienophilicity of 24 by

replacing the carboxylic ester group with a sulfinate ester, thereby synthesizing a

dienophile containing two sulfinate ester functionalities.

Me0 OMe 94a

93a (2); 93b (E);

The goal was to synthesize both (E)- and (2)-93 and subject them to

oxidative fragmentation conditions followed by capture with ethanol to form (E)-

and (2)-94. The synthesis of bis thio ethene 95 was previously synthesized by

the Schwan group (Scheme 40)." Oxidation of 95 with 2 equivalents of mCPBA

at -78°C resulted in 93a.

Scheme 40

PMB-SH PMB-S S-PMB LJ

2 equiv mCPBA, CH2CI2, -78"C, 2 h /

O O \\

PMB-s S-PMB w

Several attempts to synthesize 93b were not very successful (Scheme

41). By changing the solvent from methanol to methylene chloride in the Michael

addition of PM6 thiol to PM6 thioacetylene (Scheme 41a), it was anticipated that

(E)-95 would be generated, which is the case for the formation of

(6-1-alkenesulfinates. However, the result was only (2)-95. The second atternpt

involved the Michael addition of PMB thiol to PMB sulfinylacetylene (Scheme

41 b). The Schwan group has shown that addition of a number of nucleophiles to

ethynyl sulfoxide 96 proceeds to give the formation of trans produ~ts.~"

Therefore, it was anticipated that a trans product would result from the addition of

PMB thiol. Unfortunately, only (2)-97 was produced; however in a fairly good

yield (77%).

Another potential route to 95 was to undergo transition-metal-catalyzed

hydrothiolation.g' It has been shown that the use of RhCI(PPh& in the addition of

benzenethiol to a variety of terminal alkynes yields anti-Markovnikov-type vinylic

sulfides with trans config~rat ion.~~ These reported conditions were applied to the

addition of PMB thiol to PMB thioacetylene at room temperature (Scheme 41c)

and at elevated temperature (Scheme 41d). In both cases, only cis

anti-Markovnikov products were produced.

It is evident that the cis product predominates in bis sulfide formation.

There have been other reported cases in which the synthesis of bis substituted

thio ethylenes resulted in only cis product. For example, the reactions of several

thiols with vinyl chloride, vinylidene chloride and (a- and (E)-dichloroethylenes resulted in only cis bis sulfides; even when trans product was anticipated. 93-95

Scheme 41

II O

b) PMB"\ + P m - s H Et3N,CH2CI2, P M B - ~ s-PMB O°C, 24 h

H w

96 97

d) PMB-'\ + PMB-SH RhCI(PPh3)3 (cat.), , PMB-S S-PMB toluene, 80°C, 24 h w

H 95

2.4.1 Oxidative Fragmentation of Bis Ethenesulfoxides

Compound 93 proceeded to oxidative fragmentation studies. The intended

results are tabulated in Table 17. In ail cases similar results were observed. That

is upon oxidative fragmentation with two equivalents of sulfuryl chloride, the TLC

indicated consumption of the sulfoxide and formation of a new polar component

that moves, then stalls on the TLC plate leaving an elongated streak. An aliquot

was removed from the reaction mixture of a) in Table 17 and infrared analysis

was conducted on it. lnfrared analysis is consistent with the formation of a sulfinyl

chloride. That is, a distinctive S=O stretch at 1155 cm-' was observed, which is

characteristic of a sulfinyl chloride, and there was no evidence of S=O stretch for

Upon addition of the capturing agent and monitoring by TLC, it was

evident in al1 cases that decomposition was occurring. In many cases the mixture

formed a thick black solution. Further analysis by 'H NMR supported this

observation. Some intended products are depicted below.

Table 17: Oxidative Fragmentation Reactions of 93 with S02Clz and Capture with a Number of Reagents

1 Conditions Desired Producta 1 1. SO2CI2 (2 equiv), CH2C12. -78OC 2. EtOH (2 equiv), K2C03, -78OC 1. S02C12 (2 equiv), CH2C12, -78°C

94a

94a 2. EtOH (2 equiv), pyridine, -78°C 1. SO2CI2 (2 equiv), CH2CI2, -78°C 94ag6 2. TMS-OEt (2 equiv), -78°C 1. SO2CI2 (2 equiv), CH2CI2, -78°C 98'= 2. TMS-NH-TMS (1 equiv), -78°C 1. SO2CI2 (2 equiv), CH2C12, -78°C

1 2. TMS-O-TMS (1 equiv), -78°C aDecornposition occurred in al1 cases after capture.

9gg6 2. a-naphthylamine (1 equiv), -78°C 1. SO2CI2 (2 equiv), CH2CI2, -78°C

Sulfinyl chlorides are known to be very unstab~e.~~ By creating bis sulfinyl

1 0og6

chlorides, it can be assurned that the instability of such compounds will

drarnatically increase, which may account for the decomposition of products in

these studies.

2.5 Conclusions and Future Work

Much of the project was successful in ternis of accomplishing the main

objectives. The Diels-Alder reactions of 24 proved to be a valuable addition to the

vast array of sulfur containing dienophiles. Dienophile 24 underwent successful

cycloaddition reactions with furan, 2,3-dimethyl-1,3-butadiene, and anthracene.

Different isorner ratios were obtained depending on the reaction conditions.

However, in rnany cases the yields were substantially low, and irnprovements to

these yields would be beneficial.

The endolexo ratios of furan cycloadducts were poor. Future attempts to

selectively increase this ratio, would be to employ chiral Lewis acids. There are a

large number of chiral Lewis acids available for such studies. 24-26 Another

rnethod to improve furan cycloadduct selectivity would be to sterically rnodify 24.

A desired selectivity can probably be achieved by increasing the size of the

sulfinate substituent or carboxylic substituent or both.

The steric evaluation of 24b with cyclopentadiene resulted in expected, as

well as unusual results. By increasing the sulfinate ester functionality, the. S-exo

selectivity increased as expected. By increasing the size of the carboxylic ester

functionality, the unexpected was observed. That is, an increase in S-endo

selectivity did not occur. In order to understand this observation, further studies

with different carboxylic substituents should be conducted. Also calculations

using software such as PC Spartan may aid in determining the most

therrnodynamically stable produd, and hence give insight as to what is occurring.

Synthesis of (E)-bis sulfide 95 could not be accomplished. It has been

shown that a (4-bis sulfide will isomerize to the trans at elevated temperatures

over a long period of time.93 One simple trial to obtain a trans isomer would be to

heat 93 or 94 over a longer period of time. Another rnethod would be to

synthesize a bis acetylenyl sulfide followed by reduction of the triple bond. There

are several exarnples reported for bis thio ace t y~enes~~ - ' ~~ and triple bond

reductions to trans ethylenes. 101-103

It is unfortunate that oxidative fragmentation of 93 could not be

accomplished. Such a dienophile would benefit the formation of poly mercapto

compounds. Compounds containing two thiol functionalities have be used as

chiral auxiliaries in asymmetric synthesis.lo4 One way to synthesize such

compounds is to react 93 with a diene. This cycloadduct can then be subject to a

one-pot oxidative fragmentation reaction followed by reduction.

The synthesis of poly hydroxyhercapto compounds was fortunately

successful. Accomplishment of these studies opens up a large number of

possible targets. For instance, ring ~ p e n i n g ~ ' ~ ~ of furan cycloadducts followed by

reduction, organometallic addition, andfor double bond reduction steps can result

in rarely reported pseudothiasugars (Scheme 42).lo5-'O6 Also if chiral Lewis acids

are employed in the cycloadditions, pseudothiasugars can be made chiral.

Scheme 42

C02Me HO. .., CH20H - - (H)R @ "" s H

S(0)OEt OH

The reduction studies can also be utilized in the synthesis of double caged

compounds such as 101 (Figure 19). Compound 101 and other versions of it can

be used to enclose and capture a series of metals. In the long term, it may be

possible to then apply these compounds to the removal of toxic rnetals from

untreated manure.

Figure 19: Double Caged Metal Ion Capturing Compound

3. Experimental

3.1 General Procedures and Instrumentation

Melting points were detemined on a MEL-TEMP melting point a