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$-UNSATURATED SULFINATE ESTERS
FOR THE PREPARATION OF POLY HYDROXYIMERCAPTO COMPOUNDS
Advisor:
Dr. Adrian L. Schwan
Dino Alberico
University of Guelph, 2001
This
thesis
examines
the
reactivity
of
ethyl
(E)-
and
(a-2-carbornethoxyethenesulfinates (24) in Diels-Alder chemistry with a variety
of dienes including cyclopentadiene, furan, anthracene, 2,3-dimethyl-1,3butadiene and 1,3-cyclohexadiene. Experiments were conducted under both
thermal, and Lewis acid catalyzed conditions. In most cases, Lewis acid
catalyzed reactions proceeded faster and demonstrated greater selectivity. Steric
evaluations of (E)-24 with cyclopentadiene were conducted in an effort to
improve endo:exo selectivity. lncreasing the size of the sulfinate ester
functionality lead to increased S-exo selectivity, as expected. lncreasing the size
of the carboxylic ester functionality resulted in the opposite expected selectivity.
Atternpts to create bis sulfinate containing dienophiles will also be reported.
An evaluation of the cycloadducts as a synthetic approach to poly
hydroxylmercapto compounds is also discussed. The cycloadducts were
subjected to a number of different reduction conditions employing LiAIH4 and
DIBAL. In some cases, benzyl bromide was added to trap the thiolate resulting in
the sulfide.
2.2.2
2.2.3
2.2.4
2.2.5
Reduction of Cis 2.3.Dimethyl4. 3.Butadiene Cycloadduct.........-55
Reduction of Anthracene Cycloadducts ...................................... -55
Reduction of Cyclopentadiene Cycloadducts.............................. 5 6
Reduction of Furan Cycloadducts ................................................ 57
2.3 Steric Evaluation of (E)-a$-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...............................................................................................
70
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
Eu(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-butylbiphenyl
enantiomeric excess
electron impact mass spectrometry
equivalents
triethylamime
ethyl 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
(1R,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 11: 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 SO2CI2and
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 11: 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: Dipole 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 dThis
. ~ ~ 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
A
diene dienophile
diene dienophile
diene dienophile
LUMO
HOMO
normal
inverse
neutral
In Diels-Alder reactions 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
compounds8and highly functionalized natural p r o d u c 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
EDG
--------KwG
"ortho"
-
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
. ' ~ example, the reaction of
dienophile are preserved in the ~ ~ c l o a d d u c tFor
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
Et2AICIwas used, an 88:12 mixture of 2:3 was obtained, while under the same
conditions, the use of EtAICI2 resulted in a 2 9 8 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 d e v e ~ o ~ e d . *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
O
Il
R-S-R'
II
R-S-R'
Il
O
O
R-S-OR'
R-S-OR'
II
II
O
6
II
O
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 la
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 nThe
. ~ ~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 Four
n e . ~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
\
s-cis
attack
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
12a
s-cis
12b
s-trans
Diastereoselectivity can also be enhanced with the use of Lewis acid
c a t a ~ y s t sThis
. ~ ~ 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
J
Catalyst (Equivalents)
None
E u ( f ~ d(1
) ~-2)
TiC14 (1-2)
ZnBr2 (1.2)
Product
n-Facial Selectivity
15a:15b
9.1:l
22: 1
6.4: 1
0.08: 1
exolendo
(15a+l5b):l5c
4.3:l
2.2:1
24: 1
1911
Scheme 6
I
I
C02Me
cat.
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
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-1Sa (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 nBr2and TiCI4
-0.
CI atom
s-O
CI
Me0
Me0
O BnO
fl
si
ToL.,~
j*
Br
Me0
\
O BnO
'
.
2
O'
Me0
\
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$-Unsaturated sulfoxides play an important role in the synthesis of
natural products and biologically active c o r n p o ~ n d s For
. ~ ~example.
~ ~ ~ ~ ~the
enantioselective total synthesis of glyoxalase I inhibitor 20, a compound of
interest due to its cytotoxic and cancerostatic activity, was achieved utilizing the
asymmetric Diels-Alder reaction of dienophile 18 and 2-methoxyfuran (Scheme
7).39
Scherne 7
/
7 steps
Men =
K,,
1.2.2 a$-Unsaturated Sulfones
a$-Unsaturated sulfones, both vinylic and acetylenic, are excellent
dienophiles mainly due to the electron withdrawing ability of the sulfur
functionality. The synthetic utility of these unsaturated sulfones in cycloadditions
The
is high, as they car: be transforrned into many other functional groups.30*41v42
use of aryl vinyl sulfones is of particular interest because they may serve as
ethylene or ketene equivalents. Cases in which a vinyl sulfone has been utilized
as an ethylene equivalent is in the preparation of syn- sesquinorbornene and
sesquinorbornadiene (Scherne 8).43 A disadvantage of sulfones is that unlike
sulfoxides, sulfones do not exist in optically active form, and therefore do not
impart chirality to the cycloadduct.
Scheme 8
1.2.3 a$-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-workersperformed 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
Diene
cyclopentadiene
1,3-cyclohexadiene
2-methyl-1,3-butadiene
2,3-dirnethyl-1,3-butadiene
1-(trimethylsilyloxy)-1,3-butadiene
1 Temperature (OC) Time (h)
1
25
60
50
60
130
5
8
12
12
6
Yield (%)
95
86
81
84
95
The Schwan group was the first to report the Diels-Alder reaction of
1-alkenesulfinic esters.45*46 It was shown that 1-alkenesulfinate esters bearing
tethered furans can undergo highly diastereoselective intramolecular Diels-Alder
reactions under the proper
condition^.^'
For example, a single isomer was
obtained from the intramolecular Diels-Alder reaction of 22 (Scheme 9).
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-Alkenesulfinate 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
~ cycloaddition reactions were performed under
reactions (Scheme 1I ) . ~The
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
14(1.1: l ) : l
None
98 (98)
1 h, 40°C
None
4h
18(1.3:1):1
(87)
45(11:1):1
1O0
5 min
BFTE~O
ZnBr2
30 min
38(0.90: 1): 1
100 (98)
1
EtpAiCI
1
30 min
1
23(1.9:11:1
1
90
Yb(0Tf)s
30 min
1
23(1.9:1):1
86
27c1.5:1): 1
94
30 min
MgBr2
49
TiCI4
100 min
25(0.67: 1):1
23(1.6: 1):1
hl2
94
40 min
34(1.O: 1): 1
1O0
5 min
SnC14
100
34(1.4: 1):1
ZnC12
15 min
aYieldswere determined by GC, isolated yields are in parenthesis.
-
1
1
1
1
C
Table 4: Diels-Alder Reactions of Cyclopentadiene and 24b
)
Lewis Acid
None
None
BFd37O
ZnBr2
Et2AICI
Y b(OTf)3
MgBr2
TiCI4
1
Time
1 h, 40°C
24 h
18 h
5 min
15 min
80 min
50 min
5.5 h
1
S-endo
1 S-exo (28)
(ratio)
(27)l(syn:antî)(27a:27b)
l(1.6:l)
1.6(1:1.4)
l(1.5:l)
1.7(1:1.3)
1(1.6:1)
1.6(1:1.4)
1(1.2:1)
28(A :l
-1)
1 1(1.3:1)
2.5(1:1 .O)
1(1.3:1)
1.4(1:l
.A)
1 1(1.6:1)
1.1(1:1.2)
OX(1:l.l)
l(2.0: 1)
1
Total Yield
(%)"
97
82
(85)
95 (83)
1O0
1O0
1O0
69
aYieldswere determined by GC, isolated yields are in parenthesis.
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
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 (11:1).
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
"0
Me0
a>
m
*
1
\
s
less
cycloaddition
hindered face
via *
h
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 12).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~
This
Menhanced
~ ~ . 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
cyclopentadiene
cyclopentadiene
1,3-cyclohexadiene
5,5-dimethoxy-l,2,3,4tetrachlorocvcio~entad
iene
Conditions
CH2&, 20°C, 168 h
toluene. 120°C. 4 h
toluene, 150°C, 18 h
xylene, reflux, 20 h
Ratio 1 Yield (%)
84: 16
100
73:27
i 95
endo only
96
endo only
72
1 endo:exo
Figure 15: Transition States of Cyclopentadiene and Cyclohexadiene
Approaching 38
One last example of a dienophile belonging to the sulfonate farnily is the
acetylenic s u l f ~ n a t e .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
RO-S
II
8
H
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
reduction
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
Disfavored by
sitting at the axia
position of the
S-B-O ring
51
'
\
re
Ar
sitting at the axial
position of the
B-O-% ring
52
54
most favored
I
Ar
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 TB5OTf, ETI N,
Me
THF, 78"C,Ih
..O" Me
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 oxabridge 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+
cyclOhexyloxy
adarnantoxy
+O+
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
Et2AICIwas 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
Reaction Conditions
CH2C12, r.t.
tofuene, 65°C
ZnBr2, CH2C12, r.t.
Et2AICI, CH2CI2, r-t.
aDecornpositionoccurred.
Time
24 h
24 h
6h
10 min
Ratio (A:B)
NR
Total Yield (%)
3.1:l
60
NRa
3.7:1
85
-
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 Et2AICIoccurred 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.
Scheme 23
O
1l
M e o p s h , E t
+
)
O
< - )"JE-"~t
24b
70
O
f
H
"'co~M~
Table 7: Diels-Alder Reactions of 24b with 2,3-Dimethyl-1,3-Butadiene
Ratio (A:B)
Total Yield (%)
Tirne
Reaction Conditions
24 h
NR
CH2CI2,r.t.
24 h
2.0: 1
55 a
toluene. 60°C
24 h
1.8:l
91 a
toluene, 100°C
24 h
48a*b
1.311
ZnBr2, CH2CI2,r.t.
10 min
94
1.8:l
Et2AICI,CH2CI2,r.t.
'Yields based on starting material recovered. b~ecomposition
occurred.
-
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.
Scheme 24
71
Table 8: Diels-Alder Reactions of 24a with Anthracene
Time
Reaction Conditions
Ratio (A:B)
24 h
CH2C12, r.t.
NR
24 h
NR
toluene, 80°C
ZnBr2, CHÎCI~,r-t.
24 h
NR
18 h
5.6: 1
Et2AICI, CH2CI2,r.t.
%elds based on starting material recovered.
Total Yield (%)
1
-
46a
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
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
Time
Ratio (A:B)
NR
24
h
CH7C17.
r.t.
- -2.13:l
5d
toluene, 60°C
NR
24 h
toluene, 100°C
24 h
NR
ZnBr2, CH2CI2,r.t.
2.65: 1
18 h
Et2AICI, CH2C12, r.t.
Yields based on starting material recovered.
Total Yield (%)
-
34=
-
-
44
2.1.3 Diels-Alder Reactions Of 24 with Furan
It is well known that furan can undergo Diels-Alder reactions, despite its
aromaticity and hence expected decreased reactivity. Depending on the nature of
the dieneophile, differences in yields, reaction times, and stereoselectivities are
often observed.69-7' The Diels-Alder reaction of furan with 24a is illustrated in
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 ~ r a n ; ~ * - ~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-
4.4 Hz, which correspond to the
coupling constants in 73a were found to be
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
Time
Reaction Conditions
24 h
CH2C12, r.t.
24 h
CH2CI2,40°C
1h
ZnBr2, CH2CI2,r.t.
1a Et2AICI, CH2CI2, r-t. 1 10 min
Decomposition occurred.
--
endo(A:B):exo(C:D)
NR
NR
NRa
1.1(2.2:1):1(2.4:1)
Total Yield (%)
-
1
46
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
reduction, elucidation of S-endo and S-exo products was possible (vide infra);
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
[
Time
S-endo(A:B):S-exo(C: D)
Reaction Conditions
NR
24 h
CH2CI2,r-t.
24 h
NR
CH2CI2,40°C
24 h
1.60(1.5:1):1(1.2:1)
ZnBr2, CH2CI2,r-t.
l(1.8: 1):2.3(1.8:1)
10 min
Et2AICI, CH2CI2,r.t.
v i e l d based on starting material recovered.
Total Yield (%)
-
45=
68
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.
p = 0.87D
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 Et2AICIto 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
observation^.^^
1,3-cyclohexadiene resulted in similar
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
~ienophile
24a
24a
24a
24b
1
1
Reaction Conditions
CH2C12, r.t.
Toluene. 80°C
Et2AICI, CH2C12,r.t.
Et2AICIl CH2C12,r.t.
1
1
1
Time
6d
24 h
24 h
24 h
Result
starting material
starting material
1
1
decomposition
decomposition
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.
1
1
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.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
2. benzvl bromide, r-t.. 24 h
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
.
.
1
Product
76
77
76
77
76
Yield (%)
22
75
starting material
82
13
36
6
68
-
1
starting material
starting material
starting material
-
-
The proposed rnechanism for the reduction of 70 and formation of 75 is
illustrated in Scheme 30. After 30 minutes, the reduction in THF contained one
spot on the TLC plate with an Rf value of 0.40(Rf of isolated mercapto alcohol is
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
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. DIBAL (6 equiv), THF, -78OC, 30 min
.
Product
75
78
75
77
78
- 75
77
76
1
.
2. benzyl bromide, -78OC+r.t., 3 h
1. DlBAL (6 equiv), THF, -78OC, 30 min
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
75
79
starting material
75
77
78
Yield (%)
38
11
54
1
3
7
14
33
61
97
62
12
53
3
6
Once the optimum reduction conditions were chosen, they were applied to
al1 other cycloadducts which are presented below.
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
25
S(0)OEt
1. LiAtH4, THF, r.t., 15 min
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
S-Endo:S-Ex0
Yield (%)
Cycloaddition 1 Reduction Cycloaddition 1 Reduction
Product
Product
Product
Product
endo only
90
23: 1
26
24a + cyclopentadiene 1
1O 0
2.5: 1
2.5:1
55
24b + cyclopentadiene
1.1 :l
2.6: 1
46
30
24a + furan
68
58
1:2.3
7 :3.5
24b + furan
aCycloadductsfomed from DielsAlder reactions employing Et2AICI.
Cycloaddud?
Scheme 37
S
os
27
'OEt
28
1. LiAIH4, THF, r.t., 15 min
2. benzyl bromide, 2 h
I
Yield = 55%
2.2.5 Reduction of Furan Cycloadducts 73 and 74
The reduction of cycloadducts 73 gave an inseparable mixture of 87
(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
s-trans
O
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
a)
ya01
H
..0
cycloaddition via
le- hindered side
O,/
+
C02Me
O
/
EtO,
S
s
O
cycloaddition via
less hindered side
C02C4Hg
S(0)OEt
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 l o h e x a n o2-adamantanol
l,~~
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 CH2CI2at 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-exoratios are given in Table 16.
Table 16: S-endo:S-exo Ratios and Yields for Cycloaddition Products and
Reduction Products for Steric Studies
Dienophile
24b
89
Cycloadduct
S-endo: S-exo
Yield (%)
2.5: 1
1O0
1.30:1
89
Reduction Products
S-endo:S-exo
Yield (%)
2.5: 1
55
1-43:1
37
'lsomeric ratio; can not distinguish beheen Szndo:S-exo isomers.
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-exoratio 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.
,
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-S
PMB-SH
/
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
41b). 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~ration.~~
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
O
II
+ Pm-sH
b) PMB"\
96
H
Et3N,CH2CI2, P M B - ~
O°C, 24 h
97
+ PMB-SH RhCI(PPh3)3(cat.),
d) PMB-'\
H
toluene, 80°C, 24 h
s-PMB
w
,
PMB-S
S-PMB
w
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 S02Clzand Capture
with a Number of Reagents
1
Conditions
Desired Producta
94a
1. SO2CI2(2 equiv), CH2C12. -78OC
2. EtOH (2 equiv), K2C03, -78OC
94a
1. S02C12(2 equiv), CH2C12, -78°C
2. EtOH (2 equiv), pyridine, -78°C
94ag6
1. SO2CI2(2 equiv), CH2CI2,-78°C
2. TMS-OEt (2equiv), -78°C
98'=
1. SO2CI2(2 equiv), CH2CI2,-78°C
2. TMS-NH-TMS (1 equiv), -78°C
9gg6
1. SO2CI2(2 equiv), CH2C12,-78°C
2. a-naphthylamine (1 equiv), -78°C
10og6
1. SO2CI2(2 equiv), CH2CI2,-78°C
2. TMS-O-TMS (1 equiv), -78°C
aDecornpositionoccurred in al1 cases after capture.
1
Sulfinyl chlorides are known to be very u n s t a b ~ eBy
. ~ ~creating bis sulfinyl
chlorides, it can be assurned that the instability of such compounds will
1
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.93One 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 a c e t y ~ e n e s ~ 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-'O6Also if chiral Lewis acids
are employed in the cycloadditions, pseudothiasugars can be made chiral.
Scheme 42
C02Me
S(0)OEt
- @
HO...,
CH20H
(H)R
""
sH
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 apparatus
and are uncorrected. 'H NMR and
13cNMR spectra were recorded on a Bniker
model Spectrometer at 400 MHz and 100.6 MHz. respectively, in CDCI3. 'H
chemical shifts are reported in parts per million 6 (ppm) referenced to interna1
tetramethylsilane (6 = 0.00 ppm) or CHCI3 (6 = 7.26 pprn). In some cases where
there is an inseparable mixture of isomers, the complete 'H spectrum for the
major isomer is reported. For the minor isomer, a partial 'H spectrum is reported
including only chemical shifts that could be observed or inferred.
13cchemical
shifts are reported in parts per million b (ppm) referenced to CDCI3 (6 = 77.00
ppm). lnfrared (IR) spectra were obtained on a Bornen FTlR spectrometer either
neat or in a solution cell with CH2&
or CDC13. Mass spectra (MS) were
performed by the McMaster Regional Center for Mass Spectrornetry, McMaster
University, on a Finnigan 4500 quadrupole mass spectrometer and recorded on a
low resolution EI/CI at unit resolution. Elemental Analysis were performed by
M.H.W Laboratories, Phoenix, AZ. Yields and isomer ratios are reported in the
Results and Discussion section.
All reactions were run under a positive pressure of argon or nitrogen in
flasks which were Rame or oven dried. Tetrahydrofuran (THF) and diethyl ether
were freshly distilled from sodium and benzophenone. Methylene chloride and
toluene were distilled from calcium hydride. Ethanol was distilled from
magnesium and iodine. Triethylamine was distilled from potassium hydroxide.
Toluene, ethanol and tnethylamine were stored over 4 A molecular sieves under
nitrogen or argon. Air and water sensitive reagents were transferred via ovendried, nitrogen or argon purged syringes.
Flash chrornatography was performed on virgin or recycled 200-245 rnesh
silica gel. Analytical thin-layer chromatography (TLC) was carried out on 0.25
mm Merck Kieselgel 60 Pz54 precoated glass-backed silica gel plates and
visualized through charring with anisaldehydelsulfuric acid solution.
3.2 Diels-Alder Reactions of 24 with Dienes
General Method for Diels-Alder Reactions of 24a and 24b with Dienes
A solution of sulfinate ester 24 (60.0 mg, 0.337mmol, 1.O equiv) and diene (1.3
equiv) in dry CH2CI2 or dry toluene was stirred until TLC showed the
disappearance of the sulfinate ester. The mixture was then washed with NaHC03
(aq), water, and bine and was dried with MgS04. Concentration under reduced
pressure (aspirator) provided crude products. Flash chromatography on silica gel
with EtOAdhexanes as eluent afforded pure cycloadducts. When Lewis acids
were employed, 1.2 equivalents were introduced to the mixture at the beginning.
Cycloadduct 69 from the Reaction of 24a with 2,3-Dimethyl-1,3-Butadiene
An inseparable mixture of sulfinyl epimers were obtained as a pale yellow solid,
mp = 4143°C.
TLC (25% EtOAdhexanes) Rf = 0.29. 'H NMR (400 MHz, CDC13) (major) 6
4.15-3.90 (m, 2H, S02CH2), 3.64 (S. 3H, C02CH3), 3.13 (m. 1H, CHS02), 3.01
(ml 1H, CHC02), 2.57-2.07 (m, 4H, 2 x CH2), 1-60 (s, 6H, 2 x CH3), 1.27 (t, J =
7.1 HZ, 3 H, CH2CH3). 13cNMR (100.6 MHz, CDCI3) 6 172.80, 124.75, 123.50,
65.77, 64.42, 51.64, 39.81, 31.46, 28.34, 18.81, 18.70, 15.69; 'H NMR (400
MHz, CDC$) (minor) 6 3.19 (m, I H , CHS02), 1.31 (t, J = 7.1 Hz, 3H. CH2Cti3)1
3
NMR
~
(100.6 MHz, CDCI3) 6 172.80, 124.64, 123.30, 65.15, 63.49, 51.91,
38.00, 32.57, 28.34, 18-90, 18.81, 15-98. IR (mixture) (cm-') 2984, 2918, 2860,
1736, 1400, i386, 1367, 1314, 1266, 1228, 1210, 1177,1127,892,882. Analysis
CI 55.36; HI 7.74. Found: C, 55.51; HI 7.60.
Calc'd for C12H2004S:
Cycloadduct 73 from the Reaction of 24a with Furan
73
Three products were isolated by flash column chromatography; one S-endo
sulfur epimer, one S-exo sulfur epimer, and a mixture of the other S-endo and
S-exo sulfur epimers.
S-endo epimer:
White solid, rnp = 6365°C. TLC (25% EtOAdhexanes) Rf = 0.21. 'H NMR (400
MHz, CDC13) 6 6.77 (dd, J = 5.8, 1.4 Hz, 1HIvinytic H), 6.66 (dd, J = 5.8, 1.4 Hz,
IH, vinylic H), 5.24-5.18 (m, 2H, bridgehead H), 4.05 (AB&, AVAB= 48.9 Hz, JAB
= 10.0 HZ, J,qX = 7.1, JBX= 7.1, 2 H I S02CH2),3.72 (dd, J = 9.2, 4.4 HZ, 1Hl CH),
3.67 (s, 3H, C02CH3), 3.52 (dd, J = 9.1, 4.4 HZ, IH, CH), 1.30 (t, J= 7.1, 3H,
CH2CH3). I3cNMR (100.6 MHz, CDCI3) 6 169.76, 136.34, 135.01, 80.72, 79.98,
69.59, 65.64, 52.14, 46.67, 15.78. IR (cm-') 3056, 2987, 2958, 1738, 1437, 1423,
1387, 1359, 1320, 1263, 1198, 1171, 1115, 1064, 1020, 879. Analysis Calc'd for
CI0Hl4O5S:CI 48.77; H, 5.73. Found: CI 48.57; H, 5.89.
Mixture of S-endo and S-exo sulfur epimers:
'
Pale yellow oil. TLC (25% EtOAdhexanes) Rf = 0.1 1. H NMR (400 MHz, CDCI3)
(S-endo epimer) 6 6.53 (s, 2H. vinylic H's), 5.20 (dl J = 4.2 Hz, IH, bridgehead
H), 5.10 (d, J = 4.2 Hz, 1H, bridgehead H), 4.15-3.93 (m. 2H, S02CH2),3.69 (s,
3H, C02CH3), 3.63 (dd, J = 9.1, 4.2 HZ, IH, CH), 3.56 (dd, J = 9.1, 4.2 HZ, l H ,
CH), 1.37 (t, J = 7.1, 3H, CH2CH3). 13cNMR (100.6 MHz, CDCI3) 6 171-23,
136.36, 134.23, 80.68, 79.99, 71.27, 64.59, 52.44, 46.32, 15.96; 'H NMR (400
MHz, CDCI3) (S-exo epimer) 6 6.47 (s, 2H, vinylic H's), 5.42 (s, IH, bridgehead
H), 5.18 (s, 1HI bridgehead H), 4.15-3.93 (m, 2H, SOÎCH2), 3.74 (S. 3H,
C02CH3),2.90 (d, J = 8.2, IH, CH), 2.83 (d, J = 8.2, I H , CH), 1.30 (t, J= 7.1, 3H,
CH2CH3).13cNMR (100.6 MHz, CDC13) 6 171-62, 136.80. l35.91, 81-85, 78.93,
69.04, 65.41, 52.27, 45.89, 15.68. IR (mixture of isomers) (cm-') 3057, 2986,
2954,2898, 1740, 1623, l 5 7 l , 1437,1388, 1356,1306,1272,1171, 1121,1020,
949, 922, 881, 808.
S-endo epimer:
Pale yellow oil. TLC (25% EtOAdhexanes) Rf = 0.06. 'H NMR (400 MHz, CDC13)
S 6.49 (S. 2H, vinylic H's), 5.22 (s, 1HI bridgehead H), 5.20 (s, 1HI bridgehead H),
4.18 (AB&, A V A ~= 21.8 HZ, JAB = 10.3 HZ, JAX= 7.1, JBX = 7.1, 2H, S02CH2),
3.74 (s, 3H. C02CH3), 2.95 (d. 5 = 8.2, 1HI CH), 2.87 (d, J = 8.2, 1H , CH), 1.40
(t, J= 7.1, 3H. CHzCH3).
I3cNMR (100.6 MHz, CDCIj) 6 171.62,
136.73, 135.84,
82.1 1, 78.95, 69.43, 65.46, 52.59, 45.42, 16.00. IR (cm-') 3056. 2987, 2958.
1723, 1428, 1314, 1286, 1256, 1209, 1189, 1120, 1046, 1008, 923, 897, 883,
811. Analysis Calc'd for CioH140sS: Cl48.77; Hl 5.73.Found: C, 48.79; HI 5.79.
Cycloadduct 71 from the Reaction of 24a with Anthracene
A mixture of sulfur epimers were obtained and separated by flash column
chrornatography.
Major isomer:
Pale yelllow solid, mp = 148-149°C. TLC (25% EtOAdhexanes) Rr = 0.24. 'H
NMR (400 MHz, CDCI3) 6 7.50-7.10 (ml 8H, Ar H), 4.87 (d, J = 2.2, AH,
bridgehead H), 4.50 (cf, J = 1.8, 1H, bridgehead H), 4.05-3.93 (m, 1HI S02CH2),
3.85-3.70 (m, 1HI SO2CH2).3.62 (s, 3H. C02CH3),3.33 (dd, J = 9.7, 1.8 Hz, 1HI
CH), 3.14 (dd, J = 9.7, 2.2 HZ, IH, CH), 1.19 (t, J = 7.1, 3H, CH2CH3).13cNMR
(100.6 MHz, CDC13) 6 171.11, 141.87, 141.24, 140.29, 138.75, 126.85, 126.72 (2
C's),126.64, 125.29. 124.84. 124.22, 123.59, 69.65, 65.37, 51.95, 48.15, 47.35.
44.13, 15.63. IR (cm") 2979, 2951, 1740, 1512, 1514, 1468, 1460, 1437, 1388.
1357, 1207, 1192, 1175, 1113, 1062, 1019, 910, 878. EIMS, mlz (%): 263 (1OO),
Minor isomer:
Pale yellow oil. TLC (25% EtOAdhexanes) Rr = 0.15. 'H NMR (400 MHz, CDCI3)
6 7.40-7.10 (m, 8H, Ar H), 4.73 (d, J = 2.3, IH, bridgehead H). 4.56 (d, J = 2.2,
1H. bridgehead H), 4.23-4.09 (m, 2H, S02CH2). 3.65 (s, 3H. C02CH& 3.37 (dd,
J = 10.0, 2.2 Hz, ?Hl CH), 3.20 (dd, J = 10.0, 2.3 Hz, IH, CH), 1.47 (t, J = 7.1,
3H, CH2CH3).I3cNMR (100.6 MHz, CDC13) 6 171.56, 141.79, 141.46, 140.35,
64.71, 52.27, 47.85, 46.71, 44-91, 16.14. IR (cm-') 2979, 2952, 1737, 1512,
Calc'd for C20H2004S:
CI 67.39; Hl 5.66. Found: CI 67.27; H, 5.80.
Cycloadduct 70 from the Reaction of 24b with 2,3-Dirnethyl-l,3-Butadiene
l c Y s ( o"'C
) o E
~et
70
An inseparable mixture of sulfur epimers were obtained, as a colourless oil:
TLC (25% EtOAcIhexanes) Rf = 0.33. 'H NMR (400 MHz, CDC13) (major) 6 4.12
3H, C02CH3), 3.28-3.16 (m, IH, CHCO?), 2.94 (app q, J = 7.4, IH, CHS02),
2.53-2.20 (m, 4H, 2 x CH2), 1.66 (s, 3H. CH3), 1.64 (S. 3H, CHs), 1.34 (t, J = 7.0,
3H, CH2CH3).I3cNMR (100.6 MHz, CDC13) S 173.85, 123.95, 123.06, 65.44,
61.49, 51.90, 39.37, 32.92, 26.35, 18.73, 18-53, 15.70; 'H NMR (400 MHz,
CDC13) (partial minor) S 3.73 (s, 3H, C02CH3),2.84 (ddd, J = 14.5, 7.9, 6.5,1H,
CHS02) 1.36 (t, J = 7.0, 3H, CH2CH3).13cNMR (100.6 MHz, CDC13) 6 173.85,
123.95, 123.33, 65.27, 61.11, 51.90, 39.19, 33.32, 25.29, 18-73, 18.46, 15.76. IR
(mixture of isomers) (cm-')2953, 2917, 2847, 1733, 1386, 1313, 1195, 1117,
1061, 1017 879. Analysis Calc'd for C12H2004S:CI55.36; HI 7.74. Found: C,
55.16; HI 7.56.
Cycloadduct 74 from the Reaction of 24b with Furan
A mixture of 4 inseparable isomers were obtained; 2 S-endo epimers and 2
S-exo epimers.
TLC (25% EtOAdhexanes) Rf = 0.13. 'H NMR (400 MHz, CDCI3) S 6.70-6.35 (m,
2H, vinylic H's), 5.40-5.12 (m, bridgehead H's), 4.25-4.05 (m, 2H, S02CH2),3.79
(s, 3H, C02CH3 of S-endo epimer), 3.78 ( s , 3H. C02CH3of S-endo epimer), 3.70
( s , 3H, C02CH3 of S-exo epimer), 3.69 (s, 3H, C02CH3of S-exo epirner), 3.27-
3.18, 3.57-3.50 (m, 1HI exo H's), 2.82 (d, J = 3.8 Hz, 1HI endo H in S-endo
isomers), 2.52 (d, J = 4.0 Hz, 1HI endo H in S-exo isomers), 1.43-1.29 (m, 3H,
CHzCii3).
13cNMR
(100.6 MHz, CDC13) (mixture of 4 isomers) 6 1il.
17, 170.11,
169.87, 137.11, 136.94, 135.93, 135.81, 135.64, 135.43, 134.94, 134.35, 82.54,
82.49, 79.68, 79.63, 79.51, 79.39, 78.58, 78.14, 68.88, 68.20, 68.07, 67.45,
65.01, 64.47, 64.18, 52.68, 52.64, 52.03, 45.30, 44.98, 44.84, 44.59, 1579,
15.68. IR (cm") 3021, 1742, 1650, 1640, 1357, 1315, 1193, 1124, 1016, 867.
Analysis Calc'd for CioHi4O5S: CI 48.77; H, 5.73. Found: C, 48.58; HI 5.52.
Cycloadduct 72 from the Reaction of 24b with Anthracene
72
A mixture of sulfur epimers were obtained and isolated by flash column
chromatography.
Major isomer:
Pale yellow oil. TLC (25% EtOAdhexanes) Rf = 0.25. 'h NMR (400 MHz, CDC13)
6 7.50-7.10 (m, 8H, Ar H), 4.78 (d, J
= 2.6, I H , bridgehead H), 4.68 (d, J = 2.6,
1HI bridgehead H), 4.1 8-4.03 (m, 2H, S02CH2),3.76 (dd, J = 4.5, 2.6 Hz, 1HI
CH), 3.65 (s, 3H, C02CH3),3.28 (dd, J = 4.5, 2.6 HZ, 1H, CH), 1.39 (t, J = 7.1,
3H. CH2CH3). 13cNMR (100.6 MHz, CDCI3) 6 171.57, 141.67, 140.83, 140.40,
139.44, 126.85, 126.72, 126.65, 126.48, 124.66, 124.56, 124.10, 123.91, 67.82,
64.68, 52.54, 46.88, 45.44, 44.28, 15.92. IR (cm") 3025, 2980, 2952, 1740,
1468,1459, l436,l387,l362, 1318, 1273,1215, 1169,1127,1114, 1061, 1017,
C ,67.39; H, 5.66. Found: CI67.12; H, 5.74.
880. Analysis Calc'd for C20H2004S:
Minor isomer:
Pale yellow solid, mp = 141-142°C. TLC (25% EtOAdhexanes) Rt = 0.14. 'H
NMR (400 MHz, COCI3 6 7.45-7.05 (m, 8H, Ar H), 4.81 (dl J = 2.7. IH,
bridgehead H), 4.73 (d, J = 2.6, I H , bridgehead H),(AB&, AVAB = 16.4 HZ, JAB=
7.1 HZ, JAX = 3.1, JBX = 3.1, 2H, SO2CH2),3.69 (dd, J = 4.5, 2.8 HZ, IH, CH),
, HZ, I H , CH), 1.18 (t, J = 7.1, 3H,
3.64 (s, 3H, C02CH3), 2.89 (dd, J ~ 4 . 5 2.6
CH2CH3). 13c NMR (100.6 MHz, CDCI3) 6 171.26, 141.85, 140.69, 140.05,
139.01, 126.97, 126.88, 126.70, 126.66, 125.29, 124.45, 124.13, 123.84, 67.59,
64.55, 52.46, 47.24, 46.1 6, 43.67, 15.68. iR (cm-') 3078, 30.27, 2954, 2897.
1739, 1468, 1460, 1437, 1387, 1361, 1318, 1216, 1194,1117, 1061, ?017,881.
Analysis Calc'd for C20H2004S:
CI 67.39; HI 5.66. Found: C, 67.27; H, 5.65.
3.3 Reduction of Cycloadducts
General Procedure for Cycloadduct Reductions with LiAIH4
Cycloadduct (1.O equiv) in dry solvent (3 mL) was added dropwise with stirring, to
a suspension of LiAIH4 (4.0 equiv) in the same dry solvent (7 mL). The mixture
was stirred at room temperature for 30 min. To the solution was added EtOAc
(10 m l ) and HCI (10 % aq, 10 mL). The layen were separated and the aqueous
layer washed with EtOAc (3 x 5 mL). The combined organic extracts were
washed with water to neutral pH, then washed with brine, dried with anhydrous
MgS04, and concentrated. The products were purified by flash chromatography
on silica gel with EtOAdhexanes.
General Procedure for Cycloadduct Reductions with LiAIH4 and Capture
with Benzyl Bromide
Cycloadduct (1.0 equiv) in dry solvent (3 mL) was added dropwise, with stirring,
to a suspension of LiAIH4 (4.0 equiv) in the same dry solvent (7 ml). The mixture
was stirred at room temperature for 30 min. Benzyl bromide (1.1 equiv) was
added dropwise. The mixture was stirred at room temperature until the TLC
showed the disappearance of the uncaptured intermediate. To the solution was
added EtOAc (10 mL) and HCI (10% aq, 10 ml). The layers were separated and
the aqueous layer was washed with EtOAc (3 x 5 mL). The combined organic
extracts were washed with water to neutral pH, then washed with brine, dried
with anhydrous MgS04, and concentrated. The products were purified by flash
chromatography on silica gel with EtOAdhexanes.
General Procedure for Cycloadduct Reductions with DlBAL
A solution of cycloadduct (1.O equiv) in dry solvent (10 mL) was cooled to -78°C.
DlBAL (1.0 M in THF, 3.0-6.0 equiv) was added dropwise and allowed to stir at
-78°C until the TLC showed the disappearance of cycloadduct (30 min - 1.5 h).
The mixture was warmed to room temperature for 30 min and then quenched by
adding NH&I (sat'd aq, 5 mL), followed by HCI (10% aq, 5 mL). The layers were
separated and the aqueous layer was washed with EtOAc (3 x 5 mL). The
combined organic extracts were washed with water to neutral pH, then washed
with brine, dried with anhydrous MgS04, and concentrated. The products were
purified by flash chromatography on silica gel with EtOAdhexanes.
General Procedure for Cycloadduct Reductions with DIBAL and Capture
with Benzyl Bromide
A solution of cycloadduct (1.O equiv) in dry solvent (10 mL) was cooled to -78°C.
DlBAL (1.0 M in THF, 4.4-6.0 equiv) was added dropwise and allowed to stir at
-78°Cuntil the TLC showed the disappearance of cycloadduct (30 min - 1.5 h).
Benzyl bromide (1.1 equiv) was added dropwise at -78OC. The mixture was
stirred for 10 min and allowed to warm to room temperature until the TLC showed
the disappearance of the uncaptured thiol intermediate. The mixture was
quenched with NH4CI (sat'd aq, 5 mL), followed by HCI (10 % aq, 5 mL). The
layers were separated and the aqueous layer was washed with EtOAc (3 x 5
mL). The combined organic extracts were washed with water to neutral pH, then
washed with brine, dried with anhydrous MgSO4 and concentrated. The products
were purified by flash chromatography on silica gel with EtOAdhexanes.
Reduction of Cycloadduct 70 with L i A I b
75
The reduction of cycloadduct 70 (70.0 mg, 0.269 mmol) with LiAIH4 (40.8 mg,
1.08 mrnol) in dry THF yielded rnercapto alcohol 75 (37.9 mg, 82%) as an oil
after flash column chromatography (10% EtOAdhexanes).
TLC (25% EtOAcIhexanes) Rt = 0.36. 'H NMR (400 MHz, CDCI3) 6 3.74 (ABX,
AvAB = 17.2 HZ, JAB= 11.1 HZ, JAX = 4.8, Jex = 4.8, 2H, CkOH), 2.90 (app ddt,
J
= 15.3, 10.0, 5.2, AH, H a to SH), 2.50-1.80 (m, 4H, 2 x CH2), 1.73 (app ddt, J =
15.3, 10.2, 5.2,1H, H P to OH), 1.59 (s, 6H, 2 x CH3), 1.52 (d, J = 8.3, IH, SH).
13cNMR
(100.6 MHz, CDCI3) 6 126.27, 125.72, 67.26, 45.56, 45.24, 39.70,
36.37, 20.06, 79.91. IR (cm-') 3373, 2916, 2859, 2832, 2560, 1727, 1435, 1379,
1261, 1097, 1051, 1020, 931, 801. Analysis Calc'd for C9HI60S: C, 62.74; H,
9.36. Found: C, 62.58; Hl 9.31.
Reduction of Cycloadduct 70 with LiAIH4and Capture with Benzyl Bromide
76
Cycloadduct 70 (70.0 mg, 0.269 mmol) was reduced with with LiAIH4 (40.8 mg,
1.08 mmol) in dry THF. Addition of benzyl bromide (35.2 PL, 0.296 mmol) with
stirring for 4 h afforded sulfide alcohol 76 (47.7 mg, 68%) as a white solid after
fiash column chromatography (10% EtOAckexanes), mp = 4647°C.
TLC (25% EtOAcIhexanes) Rr = 0.40. 'H NMR (400 MHz, CDCI3) 6 7.38-7.20 (m,
5H, Ar H's), 3.79 (AB, AvAe = 16.2 Hz, JAe = 13.1 Hz, 2H, benzylic H's), 3.63
(ABX, AVAB = 55.7 HZ, Jae = 11.3 HZ, JAX= 4.6, JBx = 4.6, 2H, CI&OH), 2.68 (dt,
J = 9.9, 5.5 Hz, 1H, H a to S), 2.38-1.85 (ml 4H, 2 x CHÎ), 1.82 (m, I H , H
OH), 1.59 (S. 6H, 2 x CH3).
I3cNMR
B to
(100.6 MHz, CDCI3) 6 128.79, 128.57,
127.06. 124.69, 124.14. 65.72, 43.07, 40.84, 39.53, 34.94, 18.60. IR (cm-') 3390,
3027, 2911, 2831, 1601, 1494, 1452, f434, 1381, 1236, 1071, 1049, 926.
Analysis Calc'd for C16H220S:CI 73.23; Hl 8.45. Found: C, 73.07; H, 8.19.
Formation of 77 via Reduction of Cycloadduct 70 with LiAIH4 and Capture
with Benzyl Bromide
Cycloadduct 70 (70.0 mg, 0.269 mrnol) was reduced with with LiAIH4 (40.8 mg,
1.08 mmol) in dry ether. Addition of benzyl bromide (35.2 PL, 0.296 rnmol) with
stirring for 2 h afforded two products after flash column chromatography (10-25%
EtOAc/hexanes, gradient), sulfide 76 (15.5 mg, 22%) and disulfide 77 (12.0 mg,
13%) as a pale yellow oil.
TLC (50% EtOAdhexanes) Rf = 0.25. 'H NMR (400 MHz, CDC13) G 3.76 (ABX,
AvAB = 104.6 HZ, JAB = 11.2 HZ, JAX= 4.6# JBX = 4.6, 2H, CbOH), 3.75 (ABX,
AvAB= 54.1 HZ, JAB= 11.3 HZ, JAX= 4.8, Jex
= 4.8, 2H, Cf-&OH), 3.02 (m, 2H, H's
a to S), 2.50-1 -99 (m, 8H14 x CHz), 1-92(m, 2H, H's
CH3).
B to OH). 1.61 (s, 12H, 4 x
NMR (100.6 MHz, CDC13 6 124.83, 124.77, 123.62, 123.42. 64.63,
64.23, 49.18, 48.61, 40.61, 40.51. 37.56, 37.25, 34.20. 34.02. 18.65. IR (cm-')
3404,2987,2915,2861,2834,1463, 1436,1383,1252,1233,1181,1122,1048,
908. EIMS, m h (%): 343 (66, [M+H]+), 171 (45)' 139 (80), 121 (1OO), 113 (Ag),
107 (49), 93 (54), 91 (47), 83 (14), 77 (20). HREIMS: Calc'd for C18H3102S2:
343.177. Found: 343.175.
Reduction of Cycloadduct 70 with DlBAL
Cycloadduct 70 (75.0 mg, 0.288 mmol) was reduced with DlBAL (1.0 M in THF,
1.73 m l , 1.73 mmol), in dry THF for 30 min. Mercapto alcohol 76 (48.1 mg, 97%)
was obtained affer flash column chromatography (10% EtOAcfhexanes).
Formation of 79 via Reduction of Cycloadduct 70 with DlBAL
Cycloadduct 70 (70.0 mg, 0.269 mmol) was reduced with DlBAL (1.O M in THF,
0.807 mL, 0.807 rnmol), in dry THF for 30 min. Thiol 79 (33.5 mg, 62%) was
obtained after flash column chromatography (10% EtOAdhexanes), as a pale
yellow oïl with a very potent stench. Starting material was also recovered (8.5
mg, 12% yield), making the chernical reaction yield 69%.
TLC (10% EtOAdhexanes) Rr = 0.14. 'H NMR (400 MHz, CDCI3) 6 3.73 (S. 3H,
C02CH3),3.16 (app dtd, J= 10.8, 7.5, 7.5, 5.5, IH, H a to SH), 2.60 (dt, J = 10.1,
6.2, 1H, CHC02CH3), 1.75 (d, 7.5 HZ, 1H, SH), 1.60 (s, 6H, 2 x CHo). 13cNMR
18.54, 18.39. IR (cm-') 2915, 2522, 1735, 1437, 1370, 1309, 1261, 1227, 1196,
1173, 1160, 1119, 1069, 1024, 911. EIMS, mlz (%): 200 (2. M'), 166 (29), 107
(91), 91 (22), 84 (100).
Formation of 78 via Reduction of Cycloadduct 70 with DlBAL
Cycloadduct 70 (100 mg, 0.384 mmol) was reduced with DlBAL (1.0 M in THF,
1.69 mL, 1.69 rnmol), in dry CH2CI2for 1.5 h. Addition of benzyl brornide (50 PL,
0.423 mmol) with stirring for 2 h afforded two products after flash coiumn
chromatography (1050% EtOAcIhexanes, gradient), mercapto alcohol 75 (25.1
mg, 38%) and sulfinate ester 78 (10.0 mg,11%) as a clear oil.
TLC (10% EtOAcIhexanes) Rr = 0.14. 'H NMR (400 MHz, CDCI3) 6 4.15 (AB&,
AVAB = 26.8 HZ, JAB= 10.2 HZ, JAX = 7.1, JBX= 7.1, 2H, S02CH2),3.71 (ABX,
AVAB = 98.4 HZ, JAB= 11-5HZ, JAX= 4.7, JBX= 4.7, 2H, ChOH), 2.94 (app dt, J =
8.4, 5.8, IH, CHS02), 2.40-1.95 (m. 5H, H
p to OH and 4 x CH2) 1.64 (S. 3H.
CH3), 1.62 (s, 3H, CHJ), 1.37 (t, J = 7.1, 3H. CH2Cl&).
13cNMR (100.6
MHz,
CDC13) 6 125.40, 122.51, 65.19, 63.98, 63.02, 36.40, 33.80, 28.93, 18.76. 18.68,
15.84. IR (cm-') 3431. 2984, 2927, 2861, 1640. 1468, 1443, 1386, 1289, 1108,
1049, 1016,890.
Reduction of Cycloadduct 70 with DIBAL and Capture with Benzyl Bromide
Cycloadduct 70 (70.0 mg, 0.269 rnmol) was reduced with DlBAL (1.0 M in THF,
0.807 mL, 0.807 mmol) in dry THF for 30 min. Addition of benzyl bromide (35 PL,
0.296 mmol), followed by triethylamine (41 pl, 0.296 mmol) with stirring for 4 h,
afforded sulfide 76 (43.0 mg, 61%) after flash column chromatography (10%
EtOAcIhexanes).
Synthesis of 82
82
A solution of cycloadduct 69 (62.8 mg, 0.241 mmol) in dry THF (3 rnL) was
added dropwise with stirring, to a suspension of LiAIH4 (36.6 mg, 0.965 mmol) in
dry THF (7 mL). The mixture was stirred at room temperature for 15 min. To the
solution was added EtOAc (70 mL) and HCI (10 % aq, 10 mL). The layers were
separated and the aqueous layer was washed with EtOAc (3 x 5 mL). The
combined organic extracts were washed with extracted to neutral pH, then
washed with brine, dried with anhydrous MgS04, and concentrated. Product 82
(40.2 mg, 97%) was obtained by fiash column chromatography (20%
EtOAckiexanes), as a pale yellow liquid.
TLC (25% EtOAdhexanes) Rr = 0.37. 'H NMR (400 MHz, CDCI3) 6 3.63 (ABX,
AvAB = 32.9 HZ, JAB = 10.7 HZ, JM = 6.6, Jex = 6.6, 2H, CI&OH), 3.36 (qd, J =
5.5, 2.8, i H , H a to SH), 2.65-2.55, 2.20-1.80 (m, 5H, H f3 to OH and 2xCHp),
1.63 (s, 3H, CH3), 1.61 (s, 3H, CH3), 1.43 (d, J = 9.3, IH, SH).
l3cNMR (100.6
MHz, CDCI3) 8 122.33 (2 C'S),63.04, 41-57, 40.41, 36.36, 30.16, 19.10, 18-82. IR
(cm-') 3417,2959,2927,2554,1727,1461, 1382,1277,1125, 1074, 1048,908.
Synthesis of 83
83
The reduction of cycloadduct 71 (82.2 mg, 0.231 mmol) with LiAIH4 (35.0 mg,
0.922 mmol) in dry THF yielded mercapto alcohol 83 (52.2 mg, 84%) as a solid
after flash column chromatography (20% EtOAclhexanes), rnp 128-12Q°C.
TLC (25% EtOAcIhexanes) Rr = 0.29. 'H NMR (400 MHz, CDC13) 8 7.40-7.00 (m,
8H, Ar H), 4.33 (dl J = 2.2, IH, bridgehead H), 4.21 (d, J = 1.5, I H , bridgehead
H), 3.47-3.25 (m, 3H, C h O H and H a to SH), 2.34 (m, 1H, H P to OH). 1.26 (br
s, I H , OH), 1.22 (d, J = 9.9, SH). l3cNMR (100.6 MHz, CDC13 6 143.07, 140.23,
126.58, 126.41 (2 C's), 126.07, 125.93, 125.06, 123.86, 123.38, 65.05, 54.01,
46.89, 43.75, 40.75, 29.64. IR (cm") 3515, 3025, 2929, 2446, 1737, 1608, 1467,
1459, 1193, 1079, 1036, 911. Analysis Calc'd for C17H160S: C, 76.08; H, 6.01.
Found: C, 75.23; Hl 6.60.
Synthesis of 84
84
The reduction of cydoadduct 72 (150.0 mg, 0.421 mmol) with LiAIH4 (63.9 mg,
1.68 mmol) in dry THF yielded mercapto alcohol 84 (78.5 mg, 69%) as a solid
after fiash column chromatography (20% EtOAdhexanes), mp 123-1%OC.
TLC (25% EtOAdhexanes) Rt = 0.25. 'H NMR (400 MHz, CDC13) 6 7.45-7.00 (ml
8H, Ar H), 4.32 (dl J = 2.2, IH, bridgehead H), 4.21 (dl J = 2.2, IH, bridgehead
H), 3.31 (AMX, AVAM = 167.1 HZ, JAM = 10.7 HZ, JAX = 5.7, JMx = 9.1, 2H,
Ct&OH), 2.49 (qd, J = 5.2, 2.2, I H , H a to SH), 1.93 (m, AH, H P to OH), 1.70 (br
s, 1Hl OH), 1.43 (dl J = 9.6, 1H, SH).
NMR (100.6 MHz, CDC13) 6 143.13,
142.74, 139.36, 139.22, 126.57, 126.55, 126.34 (2 C's), 125.79. 125.42. 123.62,
123.47, 64.56, 54.34, 53.45, 45.83, 40.85. IR (cm-') 3619, 3025, 2927, 2545,
1733, 1466, 1458, 1193, 1020, 1011. Analysis Calc'd for C17H160S: Ci 76.08; H,
6.01. Found: C, 75.98; Hl 5.97.
Synthesis of 85
A mixture of cycloadducts 25 and 26 (74.0 mg, 0.303 mmol) was reduced with
with LiAIH4(46.0 mg, 1.21 mmol) in dry THF. Addition of benzyl bromide (39 PL,
0.333 mmol) with stirring for 2 h afforded sulfide 85 (19.5 mg, 26%) as an oil after
flash column chromatography (20% EtOAdhexanes).
TLC (25% EtOAcIhexanes) Rf = 0.31. 'H NMR (400 MHz, CDCI3) 6 7.40-7.20 (ml
5H, Ar H), 6.17 (dd, J = 5.6, 3.0, 1H. vinylic H), 6.12 (dd, J = 5.6, 3.0. I H , vinylic
H), 3.77 (s, 2H, benzylic H's), 3.42 (ABX, AVAB = 35.0 Hz, JAB= 11.5 HZ, J A =~
8.7, Jex = 5.7, 2H, CkOH), 3.19 (dd, J = 9.0, 3.3, IH, H a to S), 2.89 (br s, 1H,
bridgehead H), 2.85 (br s, IH, bridgehead H), 2.51 (app ddt, J = 9.0, 5.7,3.3,
1H. H P to OH), 1.48 (dt, J = 8.5, 1.6, IH, CH2), 1.30 (d, J = 8.5, I H , CH2). 13c
NMR (100.6 MHz, CDCI3) 6 135.49, 135.25, 128.73, 128.56, 127.10, 64.1 1,
Synthesis of 86
86a
86b
A mixture of cycloadducts 27 and 28 (65.0 mg, 0.266 mmol) was reduced with
with LiAIH4 (40.4 mg, 1.O6 mrnol) in dry THE Benzyl bromide (34 PL, 0.293
rnmol) was added with stirring for 2 h. An inseparable 2.5:1 mixture of S-endo
86a and S-exo 86b sulfides (36.0 mg, 55%), were obtained as an oil after flash
column chromatography (20% EtOAdhexanes).
TLC (25% EtOAc/hexanes) Rf (mixture) = 0.30. 'H NMR (400 MHz, CDC13) (86a)
6 7.38-7.20 (m. 5H, Ar H), 6.08 (dd, J = 5.6, 2.7, 1H. vinylic H), 6.04 (dd, J = 5.6,
2.7, IH, vinylic H), 3.80 (s, 2H, benzylic H's), 3.34 (ABX, AVAB = 48.3 Hz, JnB =
10.7 Hz, JAX= 8-1, JBX = 6.0, 2HI CBOH), 2.89 (br s, 1H, bridgehead H), 2.69 (br
s, 1HI bridgehead H), 2.65, 2.02-1.35 (m, 4H, CH2, H p to OH, H a to S).
j3c
NMR (100.6 MHz, CDCI3) 6138.45, 136.25, 134.76, 128.75, 128.48, 126.93,
65.56, 50.86, 47.96, 47.12, 46.28, 45.67, 43.55, 37.20.
'H NMR (400 MHz, CDCI3) (86b) 6 6.29 (dd, J = 5.9, 3.2, I H , vinylic H), 6.09
(dd, J = 5.9, 3.2, 1H, vinylic H), 3.77 (s, 2H, benzylic H's), 3.61 (ABX, AVAB= 72.6
Hz, JAB= 10.6 HZ, JAX= 8.2, J B =~ 6.4, 2H, C&OH), 2.85 (br s, 1HI bridgehead
H), 2.71 (br s, IH, bridgehead H), 2.65, 2.02-1.35 (m. 4H, CH2, H p to OH, H a to
S).
13c NMR
(100.6 MHz, CDC13 6 138.45, 137.89, 134.66, 128.75, 128.48,
126.93, 65.78, 51.23, 47.38, 47.1 1, 46.28, 45.67, 44.10, 36.98.
IR (mixture of isomers) (cm") 3427, 3030, 2969, 2929, 1602, 1494, 1466, 1453,
1383, 1336, 1297, 1072, 1028, 908. Analysis Calc'd for CI5Hl8OS:
CI73.13; Hl
7.36. Found: C, 73.14; Hl 7.11.
Synthesis of 87
87a
87b
Cycloadduct 73 (89.7 mg, 0.364 mmol) was reduced with with LiAIH4 (55.3 mg,
1.46 mmol) in dry THF. Benzyl bromide (47.6 PL, 0.401 mmol) was added with
stirring for 2 h. An inseparable 2.64:l mixture of endo 87a and exo 87b sulfides
(30.5 mg, 34%), were obtained as an oil after flash column chromatography (2050% EtOAc/hexanes, gradient).
TLC (50% EtOAcIhexanes) Rf = 0.27. 'H NMR (400 MHz, CDCI3) (87a) 6 7.367.25 (m, 5H, Ar H), 6.40 (dd, J = 5.9, 1.5, I H , vinylic H), 6.36 (dd, J = 5.9, 1.5,
AH, vinylic H), 4.91 (d, J = 4.2, l H , bridgehead H), 4.65 (dl J = 4.2,
1HI
bridgehead H), 3.76 (s, 2H1s,benzylic H's), 3.37 (dl J = 7.3, 2H1s,CH;IOH), 3.23
(dd, J = 9.0, 4.4, 1H, H a to S ) , 2.65 (ml IH, H f%to OH); (87b) 6 7.36-7.25 (ml
5H, Ar H), 6.37 (dd, J = 5.8, 1.4, IH, vinylic H), 6.21 (dd, J = 5.8, 1.4, I H , vinylic
H), 4.77 (br s, IH, bridgehead H), 4.57 (br s, I H , bridgehead H), 3.83 (s, 2H1s,
benzylic H's), 3.82-3.71 (m. 2H1s,CbOH), 2.70 (d, J = 7.9, I H , H a to S), 2.00
(dd, J = 14.0, 7.4, I H , H
P
to OH).
13cNMR (100.6
MHz, CDCI3) (mixture of
isomers) 6 135.75, 135.66, 134.56, 128.80, 128.76, 128.75, 127.42, 127.41,
80.94, 80.40, 80.39, 62.53, 45.90. 44.84, 37.98. IR (cm-') 3412, 2925, 1494,
1453, 1320, 1071, 1027, 902. EIMS, m h (%): 180 (14), 91 (100), 65 (89).
Synthesis of 88
88a
88b
Cycloadduct 74 (70.0 mg, 0.284 mmol) was reduced with with LiAIH4 (43.1 mg,
1.14 mmol) in dry THF. Addition of benzyl bromide (35.2 PL, 0.296 mmol) with
stirring for 2 h afforded two products after flash column chromatography (10-25%
EtOAclhexanes, gradient), S-endo sulfide 88a (10.6 mg, 15%) and S-exo sulfide
88b (35.5 mg, 50%) both as a pale yellow oils.
Sulfide 88a: TLC (50% EtOAclhexanes) Rf = 0.32. 'H NMR (400 MHz, CDCI3) 6
7.39-7.22 (m, 5H, Ar H), 6.43 (dd, J = 5.8, 1.6, AH, vinylic H), 6.31 (dd, J = 5.8,
1.4, 1H, vinylic H), 4.80 (s, 1H, bridgehead H), 4.59 (d, J = 3.8, 1HI bridgehead H
p to S), 3.77 (s, 2H, benzylic H's), 3.67 (ABXI AVAB= 53.4 HZ, Jns = 10.5 Hz, JAX
= 5.2, Jsx=7.6, 2H, Ct&OH), 2.71 (appt, J =4.0, 1H, H a t o S ) , 1.56(m1IH, H p
to OH). 13cNMR (100.6 MHz, CDC13) 6 135.74, 134.89, 128.72, 128.65, 127.29,
80.80, 80.40, 63.92, 50.23, 44.23, 37.66. IR (cm-') 3412, 2919, 1494, 1453,
1078, 1029, 908, 871. E M S , rnh (%): 180 (14), 91 (100), 65 (89).
Sulfide 88b: TLC (50% EtOAclhexanes) Rf = 0.26. 'H NMR (400 MHz, CDCI3) 6
7.37-7.22 (m, 5H, Ar H), 6.34 (dd, J = 5.9, 1.O 1HI vinylic H), 6.31 (dd, J = 5.9,
1.3 I H , vinylic H), 5.00 (ci, J = 4.3, IH, bridgehead H), 4.53 (s, AH, bridgehead H
p to S), 3.84 (s, 2H, benzylic H's), 3.58 (dd, J = 10.6. 6.2, 1Hl Ci&OH), 3.24 (t, J
= 10.6. I H , ChOH), 2.21 (m. I H , H P to OH), 2.11 (d, J = 4.3, I H , H a t o S).
13c
NMR (100.6 MHz, CDCI3) 6 138.23, 135.74, 134.14, 128.82, 128.60, 127.15.
83.32, 79.54, 64.12, 49.85, 45.46, 36.82. IR (cm-') 3412, 3027, 2923, 1601,
1494, 1453, 1317, 1257, 1199, 1089, 1027, 1001, 908, 872. Analysis Calc'd for
Cq4HI6o2S: Ci 67.71; H, 6.49. Found: C, 67.58; H, 6.29.
Reduction of Cycloadduct 70 with LiAIH4 in the Presence of Benzyl
Mercaptan to Form Disulfide 81
81
A solution of cycloadduct 70 (100 mg, 0.384 mmol) in dry THF (15 mL) was
cooled to -78°C. DIBAL (1.0 M in THF, 2.30 mL, 2.30 mmol) was added
dropwise followed by benzyl mercaptan (54.1 PL, 0.461 mmol), and allowed to
stir at -78°C for 1 h. The mixture was warmed to room temperature for 8 h and
then quenched by adding NH4CI (sat'd aq, 7mL), followed by HCI (10 % aq, 7
mL). The layers were separated and the aqueous layer was extracted with EtOAc
(3 x 5 mL). The combined organic extracts were washed with water to neutral pH.
then washed with brine, dried with anhydrous MgS04, and concentrated.
Purification by flash column chromatography (10-50% EtOAdhexanes, gradient)
afforded mercapto alcohol 75 (18.8 mg, 28%) and recovery of benzyl mercaptan
(49.0 mg).
3.4 Steric Evaluation of Cycloaddition Reactions
Synthesis of p-Methoxybenzyl (E)-2-t-Butoxycarbonylethenyl Sulfide (102)
102
Triethylamine
O
LI5.09 mmol) was added to a solution Of PMB thiol (71.3
mg, 4.63 mmol) and t-butyl propiolate (0.698 mL, 5.09 mmol) in CH2CI2at O°C.
The solution was stirred for 10 min and warrned to roorn temperature for 15 min.
NH&I (sat'd aq. 20 mL) was added and the layen were separated. The aqueous
layer was washed with EtOAc (3 x 5 mL) and the combined organic extracts were
washed with water and brine, dried with anhydrous MgS04, and concentrated.
Purification by flash column chromatography (100% hexanes) resulted in (E)and (3-102 isomers (1-28 g, 99%), in a 1.3:l ratio.
TLC (10% EtOAdhexanes) Rr = 0.37. 'H NMR (400 MHz, CDCI3) ((E)-101) 6
7.57 (d, J = 15.1, AH, vinylic H), 7.24 (d, J = 8.3, 2H, Ar H), 6.86 (dl J = 8.3, 2H,
Ar H), 5.73 (d, J = 15.1, 1H, vinylic H), 3.95 (s, 2H, benzylic H's), 3.78 (s, 3H,
0CH3), 1.46 (s, 9H, C(CH&).
13cNMR (100.6 MHz, CDCI3) 6
164.52, 159.01,
144.71, 129.91, 127.35, 116.05, 114.11, 80.08, 55.17, 38.77, 28.17; ((2)-101) 6
7.24 (d, J = 8.1, 2H, Ar H), 6.95 (d, J = 10.1, AH, vinylic H), 6.85 (d, J = 8.4, 2H,
Ar H), 5.72 (dl J = 10.1, 1HI vinylic H). 3.89 (s, 2H. benzylic H's), 3.78 (s, 3H,
0CH3), 1.46 (s, 9H, C(CH&).
13cNMR (100.6 MHz, CDC13 6
166.07, 158.83,
146.92, 130.05, 129.05, 115.26, 114.04, 80.08, 55.17, 35.92, 28.17. IR (mixture
of isomers) (cm") 3002, 2977, 2836, 1731, 1610, 1512, 1441, 1391, 1366, 1304,
1251, 1147, 1034,969,948,878.
Synthesis of p-Methoxybenzyl (E)-2-t-Butoxycarbonylethenyl Sulfoxide
(103)
rnCPBA (84% active, 730 mg, 5.02 mmol) in CH2C12 (20 mL) was added
dropwise over 30 min to a solution of sulfide 102 (1.27 g, 4.53 mmol) in CH2CI2
(25 rnL) at -78°C. The mixture was stirred for 3 h at -78°C. Once the solution
warmed to room temperature it was quenched with Na2C03 (aq, 35 mL). The
layers were separated, and the aqueous layer was extrated with EtOAc (3 x 10
mL). The cornbined organic layers were washed with brine, dried over MgS04,
and
concentrated.
Two
products
were
obtained
after
Rash
column
chromatography (20-50% EtOAclhexanes. gradient), (2)-103 (411 mg, 30%),
TLC (25% EtOAclhexanes) Rf = 0.1 7, and (E)-103 (480 mg, 35 %), TLC (25%
EtOAclhexanes) Rf = 0.08, mp = 108-1Og°C.
(E)-102: 'H NMR (400 MHz, CDC13) 6 7.43 (d, J = 15.0, I H , vinylic H), 7.20 (d, J
= 8.5, 2H. Ar H's), 6.90 (d, J = 8.5, 2H, Ar H's), 6.47 (d, J = 15.0, I H , vinylic H),
4.05 (s, 2H, benzylic H's), 3.81 (s, 3H. 0CH3), 1.49 (s, 9H, C(CH3)3). 13cNMR
(100.6 MHz, CDCI3) 6 163.56, 159.76, 155.87, 131.66, 126.88, 122.16, 114.07,
82.86, 59.30, 55.25, 28.00. IR (cm-') 3009, 1713, 1611, 1513, 1390, 1305, 1192,
1178, 1104, 1141, 1062, 1034, 960. Analysis Calc'd for C15H2004S: CI 60.78; H,
6.80. Found: C, 60.54; HI 6.69.
General Procedure for Oxidative Fragmentation Reactions of Alkenyl
Sulfoxides
To a solution of sulfoxide (1.0 equiv) in dry CHzC12 at -78OC was added SO1Cl2
(1.O M in CH2C12, 1.O7 equiv) via syringe. The mixture was stirred for 10 min and
allowed to warm to room temperature over 1 h. Upon cooling to -78°Cfor 10 min,
the alcohol (1.0 equiv) was added via syringe immediately followed by the
addition of K2C03 (5.0 equiv). Stirring continued for another 10 min, followed by
warming to room temperature for the next 2 h. Filtration through Celite and
concentration under reduced pressure (aspirator) provided crude product. The
product was purified by two consecutive flash chromatography colums on silica
gel with 10% EtOAdhexanes.
Synthesis
of
Ethyl
(E)-2-t-Butoxycarbonylethenesulfinate
(92)
via
Fragmentation Reaction
To a solution of sulfoxide 103 (480 mg, 1.62 mmol) in CH2C12 (25 mL) was added
S02CIî (1.73 mL, 1.73 mmol). Addition of ethanol (96.0 PL, 1.62 mmol) and
K2C03 (1.i 2 g18.09 mmol) afforded sulfinate 92 (230 mg, 65%) as an oil after
chromatography.
TLC (10% EtOAdhexanes) Rf = 0.29.
IH
NMR
(400 MHz, CDCI3) 6 7.30 (dl J =
15.4, AH, vinylic H), 6.53 (d, J = 15.4, I H , vinylic H), 4.08 (AB&, AvAB = 72.58
HZ, JAB= 10.0 HZ, JAX= 7.1, JBX= 7.0, 2H, S02CH2), 1.49 (s, 9H, C(CH3)3), 1-35
(t, J = 7.1, 3H, CH3). I3cNMR (100.6 MHz, CDCI3) 6 162.88, 147.77, 131.25,
82.37, 62.95, 27.90, 15.68. IR (cm-') 2981, 2937, 1721, 1623, 1476, 1459, 1394,
1370, 1302, 1235, 1303, 1235, 1148,1013,968,886.
Synthesis of 2-Adamantyl (0-2-Carbomethoxyethenesulfinate (90) via
Fragmentation Reaction
To a solution of sulfoxide 24b (600 mg, 2.36 mmol) in CH2C12(35 mL) was added
SO2CI2(2.60 mL, 2.60 rnmol). Addition of 2-adamantanol (359 mg, 2.60 mmol)
and K2CO3(1.63 g, 11.8 mmol) afforded sulfinate 90 (535 mg, 80%) as a white
solid after chromatography, mp = 57-58 O C (recrystallized from hexanes).
TLC (10% EtOAdhexanes) Rf = 0.15. 'H NMR (400 MHz, CDCI3) 6 7.48 (d, J =
15.4, AH, vinylic H), 6.62 (d, J = 15.4, l H , vinylic H), 4.51 (s, l H l SOICH), 3.82
(s, 3H, COÎCH3), 2.23-1.45 (ml 14H, adamantane H's).
I3cNMR (100.6
MHz,
CDCI3) 6 164.48, 149.94, 127.94, 83.72, 52.50, 37.16, 36.50, 36.41, 33.75,
33.43, 31.13, 27.05, 26.70. IR (cm~')291Il2858, 1731, 1452, 1300, 1225, 1192,
S:
H, 7.09. Found:
1131, 1101, 970, 926. Analysis Calc'd for C I ~ H ~ ~ OC,~ 59.13;
Synthesis
of
t-Butyl
(E)-2Carbomethoxyethenesulfinate
(91)
via
Fragmentation Reaction
To a solution of sulfoxide 24b (500 mg, 1.97 rnmol) in CH2CI2(25 mL) was added
S02C12 (2.16 mL, 2.16 mmol). Addition of 2-rnethyl-2-propanol (146 mg, 1.97
mmol) and K2CO3(1.36 g, 9.83 mmol) afforded sulfinate 91 (238 mg, 53%) as an
oïl after chromatography.
TLC (25%EtOAc/hexanes) Rf = 0.40. 'H NMR (400 MHz, CDC13) 6 7.38 (dl J =
15.4, I H , vinylic H), 6.57 (dl J = 15.4, I H , vinylic H), 3.81 (s, 3H, C02CH3),1.49
(s, 9H, C(CH3)3). 13cNMR (100.6 MHz, CDC13 6 164.52, 150.28. 127.09, 83.97,
52.42, 29.62. IR (cm-') 2981, 1732, 1437, 1396, 1298, 1275, 1226, 1149, 1030,
962, 866. Currently awaiting elemental analysis results.
General
Method
for
DieIs-Alder
Reactions
of
Sterically
Modified
Dienophiles and Cyclopentadiene
To a solution of sulfinate ester (60.0 mg, 1.0 equiv) and cyclopentadiene (1.3
equiv) in dry CH2CI2(5 mL) was added with stirring, Et2AICI (1-8 M in toluene, 1.2
equiv). The mixture was allowed to stir for 15 min and was quenched with
NaHC03 (aq, I O mL). The layers were separated, and the aqueous layer was
extracted with CH2C12(3 x 5 mL). The combined organic layers were washed with
water, brine, dried over MgS04, and concentrated.
In the cases of
carbomethoxyethenesuIfinates, the S-endo:S-exo isomer ratios of the crude
mixture were deterrnined by the integration values of the methoxy peaks in the
'H NMR spectrum. lsomer ratio for t-butoxycarbonylethenesulfinatecycloaGsuct
were deterrnine by the t-butyl peak ratios. However, S-endo:S:exo could not be
distinguished for the latter cycloadduct.
General Method for Reduction of the Sterically Modified Dienophile
Cycloadducts
Cycloadduct (1.O equiv) in dry THF (3 mL) was added dropwise, with stirring, to a
suspension of LiAIH4 (4 equiv) in dry THF (7 mL). The mixture was stirred at
room temperature for 30 min. Benzyl bromide (1.1 equiv) was added dropwise,
and the mixture was stirred at room temperature for an additional 2 h. To the
solution was added EtOAc (10 mL) and HCI (10 % aq, 10 mL). The layers were
separated and the aqueous layer washed with EtOAc (3 x 5 mL). The combined
organic extracts were washed with water to neutral pH, then washed with brine,
dried with anhydrous MgS04, and concentrated. The isomer mixtures were
purified by flash chromatography on silica gel (20% EtOAclhexanes). The S-
endo:S-exo ratios were determined by the integration values of the methylene
protons a to the sulfur in the 'H NMR spectrum.
3.5 Bis Ethenesulfinate Ester Studies
Synthesis of (2)-1,2-Bis@-methoxybenzyIsulfinyl)ethylene
Me0
OMe
(21-93
mCPBA (84% active, 1.92 g, 13.2 mmol) in CH2CI2(25 m l ) was added dropwise
via dropping funnel, over 30 min to a solution of (2)-95 (2.00 g, 6.01 mmol) in
CH2CIâ(60 mL) at -78°C.The mixture was stirred for 30 min -78OC, then warrned
to 0°C for 1.5 h. Once the solution was warmed to room temperature it was
quenched with Na2C03 (aq, 50 mL). The layers were separated, and the
aqueous layer was extracted with EtOAc (3 x 30 mL). The combined organic
layers were washed with brine, dried over anhydrous MgS04, and concentrated.
Purification by flash chromatography on silica gel (50% EtOAdhexanes silica gel
slurry was prepared and a 45:45:10 EtOAdhexaneslMeOH eluent was used)
resulted in a mixture of two diastereomen of (3-93,in a 2.51:l ratio (1.53 g,
70%) as a yellow solid, mp = 92-93°C.
TLC (45:45:10% EtOAdhexaneslMeOH) Rr = 0.17. 'H NMR (400 MHz, CD&)
(major isomer) 6 7.15 (dl J = 8.4, 4H, Ar H), 6.89 (dl J = 8.4 Hz, 4H. Ar H), 6.58
(s, 2H, vinylic), 3.90 (AB, AVAB= 21.4 HZ, JAB= 13.1 HZ, 4H, benzylic H's), 3.77
(S.
6H. 2 x 0CH3).
13cNMR
(100.6 MHz, CDC13 6 160.00, 143.43, 131.70,
120.70, Il4.22, 60.1 5, 55.28;'H NMR (400 MHz, CDC13) (rninor isomer) 6 7.12
(dl J = 8.4, 2H, Ar H), 6.90 (d, J = 8.4 Hz, 2H, Ar H), 6.62 (s, 2H, vinylic), 3.77
(AB, AVAB= 15.7 Hz, JAB= 13.0 HZ, 4H, benzylic H's), 3.77 (s, 6H, 2 x 0CH3). 13c
NMR (100.6 MHz, CDCI3) S 160.00, 143.83, 131.70, 120.36, 114.40, 59.27,
55.29. IR (mixture of isomen) (cm") 2839, 1610, 1583, 1514. 1465, 1304, 1192,
1179, 1035, 836. Analysis Calc'd for C18H2004S2:
Cl 59.31 ; H, 5.53.Found: Cl
59.50; H, 5.70.
Attempts at the Synthesis of (0-95
Attempt 1: Michael Addition of PM9 Thiol to PMB Thioacetylene
Triethylamine (1.98 mL, 14.3 mmol) was added to a solution of PMB thiol (2.0 g,
13.0 mmol) and PMB thioacetylene (2.53 rnL, 14.3 mmol) in CH2C12 (30 ml) at
0°C. The solution was stirred for 10 min and warmed to room temperature for 24
h. NH&I (sat'd aq, 80 mL) was added and the layers were separated. The
aqueous layer was washed with EtOAc (3 x 40 m l ) and the combined organic
extracts were washed with brine.
dried with
anhydrous MgS04, and
concentrated. Purification by fiash chromatography on silica gel (20%
EtOAdhexanes), afforded (4-95 (2.10 g, 50%).
Attempt 2: Michael Addition of PM9 Thiol to PMB Sulfinylacetylene
Triethylamine (36.0 PL, 2.59 mmol) was added to a solution of PMB thiol (363
mg, 2.35 mmol) and PMB sulfinylacetylenegO(500 mg, 2.59 mmol) in CH2C12(15
mL) at 0°C. The solution was stirred for 10 min and warmed to room temperature
for 1 h. Saturated NH&I (aq, 20 mL) was added and the layers were separated.
The aqueous layer was washed with EtOAc (3 x 10 mL) and the combined
organic extracts were washed with brine, dried with anhydrous MgS04, and
concentrated. Purified by fiash chromatography on silica gel (20-80%
EtOAclhexanes, gradient), afforded (2)-95 ethylenegO(600 mg, 77%).
Attempt 3: Rhodium-Catalyzed Addition of of PMB Thiol to PMB
Sulfinylacetylene
To a soution of RhCI(PPh3)3(47.0 mg, 50.5 pmol) in EtOH (2 mL) was added
PMB thioacetylene (300 mg, 1.68 mmol). PM8 thiol (280 mg, 1.85 mmol) was
added dropwise over 1 h at room temperature and allowed to stir for an
additional 24 h. The mixture was concentrated and purified by flash
chromatography on silica gel (10% EtOAcIhexanes) resulting in (2)-95 (150 mg,
27%). The product was oxidized with 1.O equiv mCPBA in order to verify that it
was in fact the cis product and not the trans.
Attempt
4:
Rhodium-Catalyzed Addition
of
PMB
Thiol
to
PMB
Sulfinylacetylene at an Elevated Temperature
To a soution of RhCI(PPh3)3 (31.2 mg, 33.7 pmol) in toluene (2 mL) was added
PMB thioacetylene (300 mg, 1.68 mmol). PMB thiol (0.273 g, 1.76 rnmol) was
added dropwise over 1 h at room temperature and then refiuxed at 80°C for 16 h.
The mixture was concentrated and purified by fiash chromatography on silica gel
(10% EtOAc/hexanes) resulting in (2)-95 (140 mg, 25%).
The product was
oxidized with 1.O equiv mCPBA in order to verify that it was in fact the cis product
and not the t r a m
Attempted Fragmentation of 93a and Capture with EtOH in the Presence of
K2C03to Forrn 94a
To a solution of bis sulfoxide (1-00 g, 2.74 mmol) in dry CH2CI2(60 mL) at -78°C
was added S02Cln (1.0 M in CH2CI2, 6.04 mL, 6.04 mmol) via syringe. The
mixture was stirred for 10 min and allowed to warm to room temperature over 1
h. TLC indicated consumption of sulfoxide and appearance of the characteristic
sulfinyl chloride. A sample was taken for IR analysis, IR (CH2CI2),cm": 2839,
1611, 1586, 1536, 1515, 1465, 1369, 1338, 1197, 1176, 1155, 1033. Upon
cooling to -78°C for 10 min, EtOH (0.340 mL, 5.49 mmol) was added via syringe
immediately followed by K2C03 (1.90 g, 14.0 mmol). Stirring continued for
another 10 min, followed by warming to room temperature for the next 2 h.
Mixture was filtered through Celite and concentrated under reduced pressure
(aspirator). No evidence of formation of new product or remaining starting
sulfoxide was evident by TLC or 'H NMR analysis of the crude mixture.
Attempted Fragmentation of (a83and Capture with EtOH in the Presence
of Pyridine to Forrn 94a
To a solution of bis sulfoxide (300 mg, 0.823 mmol) in dry CH2CI2(20 mL) at
-78°C was added S02C12(1.O M in CH2CI2, 1.81 mL, 1.81 mmol) via syringe. The
mixture was stirred for 10 min and allowed to warm to room temperature over 1
h. TLC indicated consumption of sulfoxide and appearance of the characteristic
sulfinyl chloride. Upon cooling to -78OC for 10 min, EtOH (0.1 12 mL, 1.81 mmol)
was added via syringe immediately followed by pyridine (0.150 mL, 1.81 mmol).
Stirring continued for another 10 min, followed by warming to room temperature
for the next 2 h. Mixture was washed with NH4CI (sat'd aq, 20 mL), water, and
brine and was dried with anhydrous MgS04 and concentrated under reduced
pressure (aspirator). No evidence of formation of new product or remaining
starting sulfoxide was evident by TLC or 'H NMR analysis of the crude mixture.
Atternpted Fragmentation of (2)-93 and Capture with TMS-OEt to Form 94a
To a solution of bis sulfoxide (1.O0 g, 2.74 mmol) in dry CH2C12(60 mL) at -78OC
was added SO2CI2 (1.0 M in CH2C12, 6.04 mL, 6.04 mmol) via syringe. The
mixture was stirred for 10 min and allowed to w a m to room temperature over 1
h. TLC indicated consumption of sulfoxide and appearance of the characteristic
sulfinyl chloride. Upon cooling to -78OCfor 10 min, TMS-OEt (0.71 g, 6.04 mmol)
was added. Stirring continued for another 10 min, followed by warming to room
temperature for 48 h. Mixture was concentrated under reduced pressure
(aspirator). No evidence of formation of new product or remaining starting
sulfoxide was evident by TLC or 'H NMR analysis of the crude mixture.
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