Limitations, mechanism and understanding of the origins of stereocontrol in (S)-dimethylsulfonium-(p-tolylsulfinyl)methylide-mediated epoxidation reactions

Article abstract of DOI:10.1016/j.tetasy.2010.01.012

The reaction of the (S)-dimethylsulfonium-(p-tolylsulfinyl)methylide with aldehydes gave α,β-epoxy sulfoxides with high enantioselectivity and diastereoselectivity dependent on the aldehyde. The mechanism of the 'model' reactions [ylide substituted with M

Full text of DOI:10.1016/j.tetasy.2010.01.012

Tetrahedron: Asymmetry 21 (2010) 177–186
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Tetrahedron: Asymmetry
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Limitations, mechanism and understanding of the origins of stereocontrol
in (S)-dimethylsulfonium-(p-tolylsulfinyl)methylide-mediated
epoxidation reactions
*
Wanda H. Midura , Marek Cypryk
Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, 90-363 Lodz Sienkiewicza 112, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 November 2009
Accepted 21 January 2010
The reaction of the (S)-dimethylsulfonium-(p-tolylsulfinyl)methylide with aldehydes gave
a,b-epoxy
sulfoxides with high enantioselectivity and diastereoselectivity dependent on the aldehyde. The mecha-
nism of the ‘model’ reactions [ylide substituted with Me S(O) or Ph S(O) with MeCHO or PhCHO] has been
studied in detail using density functional theory.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
ally, all the asymmetric conversions of aldehydes into oxiranes are
mediated by sulfur ylides, in which chirality is located in the sulfo-
Enantiopure sulfoxides have become an important class of chi-
ral auxiliaries due to their ease of preparation, synthetic versatility
and straightforward removal.1 The sulfinyl group acts as an elec-
tron-withdrawing group and activates carbon–carbon double
nium moiety.10
2. Results
bonds for conjugate addition and stabilizes the corresponding
a-
Continuing our work on the utilization of optically active sulfi-
nyl compounds in asymmetric synthesis,11 we designed a new type
of chiral sulfur ylide, containing an enantiopure sulfinyl group
bonded to the ylidic carbon atom.12 The sulfonium salt required
for the generation of the title ylide 1a was obtained by methylation
of (ꢀ)-(S)-p-tolyl methylthiomethyl sulfoxide with methyl iodide
in the presence of equimolar amount of silver tetrafluoroborate
in dry ethyl ether, followed by addition of acetone/water 1:1 mix-
ture, filtration of the precipitated AgI and evaporation of the sol-
vents. The crystalline salt (2) formed in quantitative yield was
fully characterized. The starting optically active thioacetal mono-
sulfoxide was prepared by treatment of optically active (+)-(S)-bro-
momethyl p-tolyl sulfoxide with sodium methanethiolate13 or
preferably by the substitution of (ꢀ)-menthyl (ꢀ)-(S)-p-toluene-
sulfinate by methylthiomethyl-lithium as described by Gennari.14
Treatment of the sulfonium salt 2 with sodium hydride in DMSO
solution at room temperature afforded dimethylsulfonium p-toly-
lsulfinylmethylide 1a in quantitative yield, as evidenced by 1H
NMR.12 Dimethylsulfonium p-tolylsulfinylmethylide 1a was also
prepared by deprotonation with sodium hydride in another polar
solvent MeCN to provide homogeneity of the reaction and also un-
der heterogenous conditions: in THF solution using BuLi as a base.
Later on, we determined that the ylide is generated in situ when
the reaction of sulfonium salt 2 with the electrophile is performed
in CH2Cl2 solution in the presence of potassium carbonate or potas-
sium hydroxide.
carbanion. To date, a large number of asymmetric syntheses using
chiral sulfoxides2 have been investigated in a wide range of reac-
tions such as the reduction of b-ketosulfoxides,3 the Michael addi-
tion of nucleophiles to the activated
the Diels–Alder reaction of vinyl sulfoxides3 and C–C bond forma-
tion using sulfoxide-stabilized carbanions.5 The reaction of
-sulfi-
a
,b-unsaturated sulfoxides,4
a
nyl carbanions with aldehydes and ketones, leading to
b-hydroxyalkyl sulfoxides, is generally known to be highly diaste-
reoselective with respect to the
a-sulfinyl carbon, but poorly
diastereofacially selective with respect to attack on the carbonyl
component. While simple optically active sulfoxides, such as
methyl p-tolyl sulfoxide, give products with poor diastereoselec-
tivity, those containing another functional group such as an ester,
sulfide or amide, which exert a chelating effect in the transition
state, led to the formation of optically active
a-sulfinyl esters,
sulfides or amides, which are very useful reagents in asymmetric
aldol-type condensations. When a halogen substituent is intro-
duced to a sulfoxide moiety as a good leaving group, ring closure
can be accomplished to give an epoxide.
There are two main ways of preparing an epoxide enantioselec-
tively: by enantioselective oxidation of the prochiral double
bond6,7 and by enantioselective alkylidenation of carbonyls using
either a carbene or Darzens type reagent.8,9 In addition to
a-chlo-
rosulfoxides, sulfonium ylides can be used for this purpose. Gener-
To demonstrate the utility of the sulfinylmethylide 1a in asym-
metric synthesis we first applied it to the conversion of aldehydes
* Corresponding author. Tel.: +48 42 6803202; fax: +48 42 6847126.
E-mail address: whmidura@cbmm.lodz.pl (W.H. Midura).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.01.012

178
W. H. Midura, M. Cypryk / Tetrahedron: Asymmetry 21 (2010) 177–186
to epoxides. In the first attempt, the ylide 1a generated in DMSO
solution at room temperature was in situ treated with benzalde-
hyde affording 3-phenyl-2-(p-tolylsulfinyl)-oxirane 4a as a mix-
ture of two diastereomers in a 1.5:1 ratio. This promising result
prompted us to check all the other conditions that the ylide could
be generated and their influence on the stereochemical results. In
order to determine the scope and limitation of the epoxidation
we performed the reaction with different types of aldehydes. The
results are shown in Table 1.
Table 1 reveals that the results of epoxidation depends on the
aldehyde used as well as on the base and the solvent. The ratio
of trans versus cis diastereomers formed was about 1 to 1, when al-
kyl aldehydes were used, but for aryl aldehydes it was slightly dif-
ferent and varied from 1.5:1 to 8:1. This was probably caused by
the bulkiness of the aryl group, since the best results were ob-
served for 1-naphthaldehyde. A lower trans/cis selectivity was ob-
served when the reaction was carried out in DMSO but was slightly
higher in an acetonitrile solution, as well in a non-polar solvent
(CH2Cl2). At this point it is necessary to underline the very high fa-
cial stereoselectivity observed during the addition of the ylide 1a
to the carbonyl group for all the reactions examined. The third dia-
stereomer (2R,3R,SS) was formed in very small amount (2–8.5%)
and under some reaction conditions this product was not even de-
tected. The fourth possible diastereomer was not observed. This
means that the stereochemistry on the ylidic carbon (C-2 in oxi-
rane) is completely controlled by the chirality of the sulfinyl
center.15
tional stabilization of the conformations is due to the intramolec-
ular hydrogen bonding between the sulfinyl oxygen atom and
the vinyl hydrogen atom.11c
Assuming the planar configuration on ylidic carbon atom as
proposed earlier for sulfonium ylides17 we can consider conforma-
tions A or B for ylide 1a (Fig. 1). Conformer B should be strongly
favored, since A suffers from non-bonded steric interactions be-
tween the methyl group on the sulfonium sulfur atom and the aryl
sulfinyl substituent. Additionally, conformation B can be stabilized
by a dipole–dipole interaction (sulfinyl group and ylidic carbon-
sulfonium sulfur atom).
Me
Me
S
Me
S
Me
S
S
O
H
H
O
A
B
Figure 1. Possible conformers of ylide 1—rationale for selectivity.
What could be the explanation of this high stereoselectivity?
The major problem for an acyclic auxiliary, such as a sulfinyl group,
is the stability of its conformation. The high stereocontrol achieved
3. Calculations
using b-ketosulfoxides was due to a chelation effect.16 For
a-phos-
To gain a better understanding of the factors controlling the ste-
reoselectivity of the cyclopropanation reactions of 1-phosphorylvi-
nyl sulfoxides 1, density functional theory (DFT) calculations were
performed.
phoryl-unsaturated sulfoxides the spatial location of the sulfinyl
group is forced by a dipole–dipole interaction, where both polar
sulfinyl and phosphoryl groups adopt an anti orientation. Addi-
Table 1
Epoxidation of aldehydes using ylide 1a
O
O
O
O
Me
R1
+
S
S
R1
SOTol-p
3
R1
SOTol-p
(2S,3S,SS)-4
p-Tol
Me
(2S,3R,SS)-4
(S)-1a
Entry
Aldehyde
R1
Methoda
(2S,3S,SS) (%)
2S,3R,SS (%)
2R,3R,SS (%)
Yieldb (%)
1
2
3
4
5
6
7
8
3a
3a
3a
3a
3a
3b
3b
3b
3c
3c
3d
3d
3d
3e
3f
Ph
Ph
Ph
Ph
Ph
p-BrC6H4
p-BrC6H4
p-BrC6H4
o-ClC6H4
o-ClC6H4
m-NO2C6H4
m-NO2C6H4
2,4-(NO2)2C6H3
2,4-(NO2)2C6H3
A
B
C
D
E
A
B
D
C
D
D
E
C
D
D
E
C
B
A
B
60
71
68
80.5
72
59
71
73
68.5
78.5
72.5
64
85.5
73.5
91.5
84
55
55
46
52
40
29
26
14.0
28
39.5
27
21
23
19.5
24
36
14.5
20
8.5
12
45
45
54
48
—
—
6
5.5
—
1.5
2
6
8.5
2
3.5
—
—
6.5
—
4
—
—
—
—
69
70
56
78
67
65
72
87
53
86
83
68
74
76
73
64
43
76
64
70
9
10
11
12
13
14
15
16
17
18
19
20
a
a
-Nphth
-Nphth
3f
3g
3h
3i
C4H9
C5H11
C9H19
C9H19
3i
a
Reaction conditions (A) NaH/DMSO, rt. (B) NaH/MeCN, rt. (C) BuLi/THF, 0 °C–rt. (D) K2CO3/CH2Cl2, rt. (E) KOH/CH2Cl2, rt.
Yield of purified two major diastereomers.
b

W. H. Midura, M. Cypryk / Tetrahedron: Asymmetry 21 (2010) 177–186
179
Ylides MeS(O)CHSMe2 1b and PhS(O)CHSMe2 1c and aldehydes
MeCHO and PhCHO were used as model compounds for the
epoxidation reaction. Detailed calculations were performed for
the MeS(O)CHSMe2 + MeCHO reaction. Calculations of the
PhS(O)CHSMe2 + PhCHO reaction were carried out to examine the
steric effect of larger phenyl groups but only for the limited number
of structures, because of the high computational cost.
S
H
H
S
O
O
C
D
Calculations indicate that the starting ylides are not planar
which implies the diastereomerism of the reactant. They appear
in a pyramidal form with the ylide carbon having a configuration
close to sp3 with the C-ylide and S-sulfoxide lone pairs in gauche
position [for MeS-ylide 1b the dihedral angle between S–C–S plane
and a C–H bond is 128° in the (SS,S)-isomer and 136° in the (SS,R)-
isomer]. The Gibbs free energy of the (1S,SS)-diastereomer is about
1.0 kcal/mol lower than that of the (1R,SS)-diastereomer, and the
inversion free energy barrier in the gas phase is ca. 3.9 kcal/mol.
For PhS-ylide 1c the Gibbs free energy difference is 0.3 kcal/mol
in favour of the (1S,SS)-diastereomer, while the inversion barrier
Figure 2. Stable conformers of ylide 1c (1S,SS) according to DFT calculations.
Taking this into account, we have calculated four diastereo-
meric pathways regarding both transoid and cisoid modes, of the
reaction of acetaldehyde with MeS-ylide 1b which lead to the
(2S,3S,SS) and (2S,3R,SS) (Scheme 1), (2R,3R,SS) and (2R,3S,SS)
(Scheme 2) configurations of the epoxides 6, respectively.
In the gas phase, the most favourable is the gauche or cisoid ap-
proach (in terms of dihedral angle Me2S–C–C@O), as it has a
slightly lower (1.4–5.8 kcal/mol) free energy barrier (i.e., lower
Gibbs free energy of the transition state) than the transoid ap-
proach in the diastereomeric pathways shown in Schemes 1 and
2. The gauche (cisoid) approach leads to the cisoid betaine 5, which
may reversibly dissociate to the substrates or rotate around the C–
C bond to a trans conformation and subsequently undergo cycliza-
tion. We were unable to locate any transition state for the cycliza-
tion in the gas phase, since geometry optimisation always led to
dissociation of Me2S. Therefore we assumed that the cyclization
occurs spontaneously (without energy barrier) once the transoid
arrangement is achieved.
is
D
Gà = 5.1 kcal/mol. The relatively low inversion barriers indicate
that a rapid inversion may take place in solution. Small differences
in the free energies of opposite configurations suggest that both
enantiomeric forms are represented in significant amounts. Thus,
it does not appear to be a factor determining stereochemistry.
Pyramidality may be explained by electronic effects: (i) hypeconju-
gation pC
!
rꢁS—O, which is more efficient in sp3 than in sp2 config-
uration on a C atom and (ii) reduction of the C–O lone pair
repulsion.18
For the above reasons, we considered different conformers of
ylide 1 to rationalize the selectivity (Fig. 2).
Me
S(O)Me
Me
S(O)Me
26.8 (solv)
27.2
H
H
18.1 (solv)
22.7
H
H
O
O-
S
S
cisoid betaine 5
Me
H
cisoid approach TS
O
25.9 (solv)
O
MeS-CH-SMe2
O-
O
S(O)Me
S(O)Me
H
S(O)Me
H
H
H
O
O
(1S,SS)-1b
O
H
Me
Me
MeS
S
S
H
S
Me
Me
Me
Me
28.6
-20.8
-18.1 (solv)
26.3 (solv)
20.8 (solv)
(1R,2S,SS) anti betaine 5
25.6 (solv)
transoid approach TS
epoxidation TS
(2S,3S,SS) trans-6
H
H
25.5 (solv)
26.1
S(O)Me 17.0 (solv)
19.8
H
S(O)Me
H
Me
Me
O-
O
S
S
cisoid approach TS
H
cisoid betaine 5
29.6 (solv)
O
O
Me
MeS-CH-SMe2
O-
S
O
S(O)Me
O
S(O)Me
O
H
S(O)Me
Me
H
H
O
(1S,SS)-1b
MeS
Me
Me
Me
H
H
S
S
Me
Me
H
25.8 (solv)
30.6
-19.6
-17.9 (solv)
(2S,3R,SS) cis-6
22.7 (solv)
(1R,2R,SS) syn betaine 5
23.3 (solv)
epoxidation TS
transoid approach TS
Scheme 1. Diastereomeric pathways of the reaction of acetaldehyde with MeS-ylide 1b leading to epoxide (2S,3S,SS)-6 and (2S,3R,SS)-6; numbers shown at structures are the
corresponding relative Gibbs free energies in kcal/mol.

180
W. H. Midura, M. Cypryk / Tetrahedron: Asymmetry 21 (2010) 177–186
cisoid approach TS
cisoid betaine 5
24.3 (solv)
24.1
20.4 (solv)
H
H
S(O)Me
H
H
Me(O)S
Me
Me
O-
O
S
S
H
solv 27.4
O-
O
O
Me
O
S
MeS-CH-SMe2
H
H
H
O
Me(O)S
Me(O)S
Me(O)S
O
Me
(1R,SS)-1b
Me
H
Me
H
S
MeS
Me
S
Me
Me
H
O
-17.7
-15.1 (solv)
29.9
28.8 (solv)
transoid approach TS
27.7 (solv)
epoxidation TS
25.1 (solv)
(1S,2R,SS) anti betaine 5
(2R,3R,SS) trans-6
cisoid approach TS
cisoid betaine 5
H
H
H
Me(O)S
26.6 (solv)
25.9
20.8 (solv)
H
Me(O)S
Me
-O
Me
O
S
S
Me
35.9 (solv)
O
O
H
O-
H
H
MeS-CH-SMe2
O
Me(O)S
Me
O
H
Me(O)S
Me
Me(O)S
Me
O
(1R,SS)-1b
H
H
S
Me
MeS
O
H
Me
S
S
Me
-17.7
31.0
28.8 (solv)
-16.3 (solv)
27.4 (solv)
24.5 (solv)
(1S,2S,SS) syn betaine 5
transoid approach TS
(2R,3S,SS) cis-6
Scheme 2. Diastereomeric pathways of the reaction of acetaldehyde with MeS-ylide 1b leading to epoxide (2R,3R,SS)-6 and (2R,3S,SS)-6 numbers shown at structures are the
corresponding relative Gibbs free energies in kcal/mol.
In the acetonitrile solution, the solvation effect compensates the
energy differences and similar values regarding the free energy
barriers of cisoid and transoid approach transition states were ob-
tained where (1R,2S,SS) and (1R,2R,SS) transoid transition states
(Scheme 1) are more stable than (1S,2R,SS) and (1S,2S,SS) transoid
transition states (Scheme 2) by about 2–3 kcal/mol. Moreover,
the SCRF calculations revealed additional transition states leading
to cyclization as well as the intermediates resulting from a transoid
approach (betaines 5). We can therefore conclude that solvation
stabilizes the intermediates in the reaction. Indeed, the charge in
the betaines is separated to a greater extent than in the transition
states leading to cyclization and therefore better stabilized by po-
lar acetonitrile. As a consequence, elimination of dimethylsulfide
dence of the relative enthalpy as a function of the h angle is pre-
sented in Figures 3–6.
Figure 3 shows that rotation around the C–C bond without dis-
sociation in the reaction pathway leading to (1R,2S,SS)-betaine is
possible. For (1R,2R,SS)-betaine a rotation is possible only in one
now requires passing through a
DG barrier of 0.7–4.8 kcal/mol rel-
ative to the betaine intermediates (Schemes 1 and 2).
Elimination occurs from the transoid betaines, in which the O–
C–C–S dihedral angle is near 180° which is consistent with the ste-
reochemical course of the SN2 substitution involving the back-at-
tack of a nucleophile. To reach this rotamer starting from the
cisoid betaines, it is necessary to pass over a torsional rotational
barrier as was postulated by Aggarwal.19 To examine whether
the rotation from cis- to trans-conformation is possible without
dissociation of the C–C bond, we performed a relaxed potential en-
ergy scan changing the (Me2S–C–C–O) angle h from ꢀ180 to 180°
for all diastereomers in MeCN searching the structures of station-
ary points. We found a number of complex rotamers (energy min-
ima) as well as rotational and dissociation–formation transition
states. There is a considerable number of stationary points hence
we are uncertain whether we have found all of them. The depen-
Figure 3. (a) Relative enthalpy profile in MeCN as a function of the dihedral Me2S–
C–C@O angle (rotation around C–C) in the MeS-ylide 1b-MeCHO (1R,2S,SS)-betaine
[maxima on enthalpy curve corresponds to rotational transition states]; (b) relative
enthalpy profile as a function of dihedral Me2S–C–C@O angle in dissociation–
complexation transition states MeS-ylide + MeCHO (1R,2S,SS)-betaine configura-
tion, see Scheme 1. Points are calculated, spline curves are for eye-drawing only.

W. H. Midura, M. Cypryk / Tetrahedron: Asymmetry 21 (2010) 177–186
181
Figure 4. (a) Relative enthalpy profile in MeCN as a function of dihedral Me2S–C–
C@O angle (rotation around C–C) in the MeS-ylide–MeCHO (1R,2R,SS)-betaine
(maxima on enthalpy curve corresponds to rotational transition states); (b) relative
enthalpy profile as a function of dihedral Me2S–C–C@O angle in dissociation–
complexation transition states MeS-ylide + MeCHO (1R,2R,SS)-betaine configuration
see Scheme 1. Points are calculated, spline curves are for eye-drawing only.
Figure 6. (a) Relative enthalpy profile in MeCN as a function of dihedral Me2S–C–
C@O angle (rotation around C–C) in the MeS-ylide–MeCHO (1S,2S,SS) betaine
(maxima on enthalpy curve corresponds to rotational transition states); (b) relative
enthalpy profile as a function of dihedral Me2S–C–C@O angle in dissociation–
complexation transition states MeS-ylide + MeCHO (1S,2S,SS)-betaine configuration
see Scheme 2. Points are calculated, spline curves are for eye-drawing only.
and we were not able to find some important stationary points
such as rotational transitions states, due to dissociation to the sub-
strates or in some cases to the lack of convergence of the mathe-
matical procedures. Therefore the Gibbs free energies of some
structures are only estimated, based on the observation that the
SCRF relative free energies in most cases are by 1–1.5 kcal/mol
lower than the corresponding free energies in the gas phase.
The general difference between Ph- and Me-substituted model
systemsis thatthefreeenergybarriersforPh-substituted modelsys-
tem are higher and the thermodynamic exothermic effect upon
epoxide formation is smaller. There are also smaller differences
between the barriers of the cisoid and transoid approaches of benzal-
dehyde. The stability order of epoxides in the gas phase is: trans-
(2S,3S,SS)-8 > cis-(2S,3R,SS)-8 ꢂ trans-(2R,3S,SS)-8 > cis-(2R,3R,SS)-8.
Calculations carried out in the gas phase as well as SCRF calculations
showed that the free energy barrier for the reaction pathway leading
to trans-(2S,3S,SS) epoxide is the lowest
D
Gà = 30.5 kcal/mol
(28.4 kcal/mol in acetonitrile), which is in agreement with the ob-
served domination of this diastereomer. The barrier of the reaction
Figure 5. (a) Relative enthalpy profile in MeCN as a function of dihedral Me2S–C–
C@O angle (rotation around C–C) in the MeS-ylide 1b-MeCHO (1S,2R,SS) betaine
(maxima on enthalpy curve corresponds to rotational transition states); (b) relative
enthalpy profile as a function of dihedral Me2S–C–C@O angle in dissociation–
complexation transition states ylide 1b + MeCHO (1S,2R,SS)-betaine configuration
see Scheme 2. Points are calculated, spline curves are for eye-drawing only.
pathway leading to cis-(2S,3R,SS) epoxide (
acetonitrile) is the same as the barrier of the reaction pathway lead-
ing to trans-(2R,3R,SS) epoxide (
Gà = 31.1 kcal/mol), which sug-
D
Gà = 31.1 kcal/mol in
D
gests that both directions of the reaction are feasible. The least
probable seems the formation of the cis-(2R,3R,SS) epoxide since
the barrier is significantly higher (D
Gà = 39 kcal/mol).
direction. At h ꢂ 60° dissociation of the C–C bond occurs (Fig. 4).
Analogous plots for (1S,2R,SS)- and (1S,2S,SS)-stereoisomers are
shown in Figures 5 and 6. In the pathway leading to (1S,2S,SS), rota-
tion in both direction results in dissociation (Fig. 6). Interestingly,
all betaines are higher in energy than the isolated substrates.
Thermodynamically, epoxidation in all cases is favourable (has
negative enthalpyand Gibbsfreeenergy). Thestabilityorder of epox-
In the case of the phenyl substituted reagents, the rotation
around the C–C bond in betaine is expected to be associated with
much higher torsional energy barrier than in the case of methyl
derivatives, because of the steric hindrance of the phenyl groups.
Inspection of rotation around the C–C bond in the molecular model
indicated a large congestion when both phenyl rings are in a
syn-position; there is also a considerable hindrance between phe-
nyl group in benzaldehyde and the methyl at the sulfonium centre,
when the rotation in the opposite direction is assumed (see
Fig. 6).Thus, the dissociation–addition mechanism of exchange be-
tween cisoid and transoid approaches is likely to dominate over the
rotation around the C–C bond.
ides
is
as
follows:
trans-(2S,3S,SS) > cis-(2S,3R,SS) > trans-
(2R,3R,SS) > cis-(2R,3S,SS). In our opinion, it is difficult to distinguish
between the cyclization occurring by cisoid addition and rotation
around the C–C bond to transoid position according to the Aggarval
concept from reversible addition–dissociation at random positions
with cyclization following the transoid addition since the free energy
barrierscorrespondingtobothreaction mechanismsareverysimilar.
Calculations for the PhS(O)CHSMe2 1c + PhCHO model system
were limited to the most important stationary points as the calcu-
lations were much more time-consuming (Schemes 3 and 4).
Moreover, the SCRF geometry optimizations in many cases failed,
4. Discussion
According to the generally accepted mechanism of S-ylide pro-
moted reactions, the key steps consist of the addition of the ylide

182
W. H. Midura, M. Cypryk / Tetrahedron: Asymmetry 21 (2010) 177–186
31.4 (solv)
32.8
21.6 (solv)
31.5
Ph
S(O)Ph
Ph
H
S(O)Ph
O-
H
H
H
O
S
S
Ph
H
cisoid betaine 7
cisoid approach TS
O
O
O-
O
S(O)Ph
PhS-CH-SMe2
O
O
S(O)Ph
H
H
S(O)Ph
H
H
H
O
-Me2S
PhS
(1S,SS)-1c
Ph
Ph
S
Ph
H
S
Me
Me
S
Ph
30.5
28.4 (solv)
-17.6
-15.3 (solv)
25.6 (solv)
28.1 (solv)
anti betaine 7
(2S,3S,SS) trans-8
transoid approach TS
epoxidation TS
H
H
21.6 (solv)
22.7
27.2 (solv)
28.6
S(O)Ph
H
S(O)Ph
H
Ph
Ph
O-
O
S
S
H
>29.6*
cisoid approach TS
cisoid betaine 7
O
O
Ph
O-
O
PhS-CH-SMe2
S(O)Ph
O
S(O)Ph
Ph
H
S(O)Ph
H
H
H
O
O
(1S,SS)-1c
PhS
H
Ph
S
- Me2S
Ph
S
S
H
Me
Ph
Me
32.5
31.1 (solv)
-15.6
-15.0 (solv)
24.0 (solv)
28.6 (solv)
transoid approach TS
syn betaine 7
(2S,3R,SS) cis-8
epoxidation TS
*
Scheme 3. Gibbs free energies relative to substrates (in kcal/mol) of cisoid and transoid approach of the reaction of benzaldehyde with PhS-ylide 1c. free energy barrier of
cisoid–transoid transition of (1R,2R,SS)-5; taking into account a bigger spatial requirement for Ph, this value for (1R,2R,SS)-7 should be much higher.
O
H
O
Ph(O)S
H
H
O
O
Ph
Ph
PhS-CH-SMe2
Ph
-Me2S
S
PhS
O
(1R,SS)-1c
33.5
-15.5
31.1 (solv)
-13.7 (solv)
(2R,3R,SS) trans-8
Ph
H
O
H
O
O
Ph(O)S
H
O
PhS-CH-SMe2
Ph
S
-Me2S
PhS
Ph
(1R,SS)-1c
O
40.3
-8.8
~39 (solv)
-7.5(solv)
(2R,3S,SS) cis-8
Scheme 4. Gibbs free energies relative to substrates (in kcal/mol)of transoid approach of the reaction of benzaldehyde with PhS-ylide 1c.
to an electrophile to generate a betaine intermediate, rotation
around the newly formed C–C bond to achieve the desired antiperi-
planar arrangement, and finally the elimination of the sulfur re-
agent, which generates the three membered ring. The trans-
epoxide is derived directly from the irreversible formation of the
anti-betaine. The cis-epoxide is derived from the partially revers-
ible formation of the syn betaine.
Based on calculations for the model system we tried to explain
the stereoselectivity of the epoxidation reaction using (S)-dimeth-
ylsulfonium-(p-tolylsulfinyl)methylide taking into consideration
the above mentioned mechanism. Certain differences have arisen
from the special structure of the ylide, where the bulky and polar
chiral sulfinyl group is bonded to the ylidic carbon atom. The re-
sults obtained show that the creation of the transoid betaine is

W. H. Midura, M. Cypryk / Tetrahedron: Asymmetry 21 (2010) 177–186
183
the trans conformation of the betaine. syn Betaine 5 is less stable
but the low free energy barrier of ring closure (0.6 kcal/mol) allows
for easy conversion to epoxide cis-(2S,3R,SS)-6. This explains the
lack of E/Z selectivity for aliphatic aldehydes (Table 1, entries
17–20).
Although these free energy differences are not large, one could
expect that upon going to the more bulky substituents, these dif-
ferences will increase and consequently the ratio of products will
change. This prediction corresponds well to the experimental
observations for the more bulky systems, where epoxides 4e and
4f are formed with the E/Z ratio being higher than 4–1.
The second trans-isomer epoxide (2R,3R,SS)-6 was formed in a
very low quantity (under certain reaction conditions this product
was not detected at all), which is probably related to the reversibil-
ity of this reaction. The highest energy barrier in this case, is attrib-
uted to the ring closure step, (Scheme 2) while the less stabilized
transoid betaine preferentially undergoes the reverse dissociation
to substrates. The activation barrier to the ring closure is higher
than reversion to the starting materials (relative rates: k2 kꢀ1).
The free energy of the (1R,2S,SS)-transition state [for (2R,3S,SS)-
cis-6 ]is higher by 2.5–3.0 kcal/mol than that of the others, this
direction is expected to be disfavoured.
Figure 7. Betaine structure (1R,2R,SS) for the addition of PhS(O)CHSMe2 to PhCHO.
The results for the phenyl-substituted model compared to the
methyl-substituted one show close analogies. However, the differ-
ence might be that the steric factor associated with the phenyl
groups prevents rotation around the C–C bond in the complex,
hence the addition–dissociation mechanism seems more likely in
this case. Unfortunately, we failed to obtain conclusive data from
calculations and this idea is based on qualitative molecular model-
ling (see Fig. 7).
The high facial stereoselectivity observed in all cases can be
attributed to the differences of free energy of betaine formation. It
seems to be a consequence of the steric hindrance occurring in the
corresponding TS structures. Additionally also the ring closure free
energy barrier could also have some influence on the stereochemical
outcome of epoxidation since their values of (2S,3S,SS)-6 and
(2S,3R,SS)-6 are lower than (2R,3R,SS)-6 and (2R,3S,SS)-6. The steric
factor is also responsible for this difference (Fig. 9).
the rate-limiting step for all diastereomeric pathways, however it
can be achieved in different ways. It has been shown that for this
reaction involving highly polar intermediates, analogously to
Aggarval’s conclusions,18 continuum solvation models need to be
used throughout in order to obtain reasonable results.
In the case of the diastereomeric pathway leading to epoxide
trans-(2S,3S,SS)-6 there is almost no difference in energy between
the cisoid and transoid approach (Scheme 1), hence both conform-
ers can be formed with the same probability. Moreover, the barrier
to torsional rotation is lower compared to the values obtained for
other diastereomers, which means that (1R,2S,SS)-anti-betaine 5
can be achieved quite easily. This betaine is the most stable
(DG = 20.8 kcal/mol, relative to substrates) of all transoid betaines.
The barrier of ring closure is smaller than that of dissociation.
The energy required for the cisoid approach to achieve
(1R,2R,SS)-syn betaine 5 (Scheme 1) is even smaller than in the for-
mer case, but only the transoid approach seems to be effective. It
was found that the highest activation barrier along this reaction
pathway was for the torsional rotation step, from the gauche to
The E/Z stereoselection depends on the dimension of the alde-
hyde substituent and the differences of free energies are mani-
fested for a model reaction using ylide 1c.
Figure 8. Computed potential enthalpy profile for the model epoxidation reaction in acetonitrile. B3LYP calculated enthalpies of intermediates and transition states are given
in kcal/mol. Purple and black curves correspond to cisoid and transoid addition of acetaldehyde, respectively (see Schemes 1 and 2).

184
W. H. Midura, M. Cypryk / Tetrahedron: Asymmetry 21 (2010) 177–186
5.2. Procedure for preparation of sulfonium salt 2
O-
Ar
O-
H
To 3 mmol (0.6 g) of (ꢀ)-(S)-p-tolyl methylthiomethyl sulfoxide,
an excess of MeI (0.5 mL) was added under an argon atmosphere
and the mixture was cooled to 0 °C. Next, 0.65 g of AgBF4 was
added in small portions and with vigorous stirring. Temperature
was maintained for 0.5 h, 5 mL of ethyl ether was added and stir-
ring was continued at rt overnight. After evaporation of ethyl ether
the residue was treated with 20 mL of water/acetone mixture (1/1)
and filtrated. Then acetone was evaporated, water solution was ex-
tracted with 2 ꢃ 3 mL of CHCl3 to remove impurities and water
was evaporated affording 9 g of crystalline salt 2: mp 114–116 °C
H
Ar
S
O
H
S
H
+
S
O
S+
Me
Me
Me
Me
(2S,3S,SS)-5
(2R,3R,SS)-5
Figure 9. Transition states of ring closure of transoid betaines.
½
a 2D2
ꢄ
¼ ꢀ285:9 (c 1.2, acetone); 1H NMR (200 MHz, CD3COCD3) d:
Our investigations suggest a big influence caused by the sulfinyl
2.43 (3H, s, CH3S); 3.05 (3H, s, CH3C6H4S); 3.16 (3H, s, CH3S);
4.83 and 5.10 (2H, AB system, J = 13.2 Hz, SCH2S); 7.49 and 7.73
(4H, AB system J = 8.4 Hz, Ar); 13C NMR (50 MHz) d: 22.0; 27.3:
27.5; 64.0; 126.0; 131.9; 139.3; 144.9. Anal. Calcd for
C10H15BF4OS2: C, 39.75; H, 5.00. Found: C, 39.64; H, 4.96.
substituent on the sulfonium ylide properties and the mechanism
of the epoxidations. First, the non-planar configuration of ylidic
carbon atom was established, although energy differences between
diastereomers of ylide are very small. Furthermore the barriers of
inversion are small, which suggests fast interconversion in solu-
tion. From a kinetic point of view of kinetics the epoxidation reac-
tion with sulfinylmethylide is a two-step process, when occurring
via transoid approach and three-step one assuming a cisoid ap-
proach followed by rotation around a C–C bond. According to cal-
culations, all four reaction pathways in MeCN solution are probable
since differences between energy barriers are relatively small
(<5 kcal/mol). However the routes leading to more stable products
(transoid approaches in Scheme 1, continuous black lines in Fig. 8)
seem to be favoured since the overall energy barriers (i.e., the ener-
gies of the highest points along the reaction coordinate) are lower
than those for routes shown in Scheme 2.
Considering the mechanism of the process, in the case of the
pathways leading to both trans (2S,3S,SS)-6 and (1R,2R,SS)-6 epox-
ides (Schemes 1 and 2), the transoid approach as well as the cisoid ap-
proach involving subsequent rotation (proposed by Aggarval) have
very similar energy barriers (Fig. 8) and are equally probable. In all
the other cases presented in Schemes 1 and 2, the overall energy bar-
riers for the cisoid approach/rotation are higher than the transoid
routes. It is difficult to exclude the cisoid approach in the pathway
shown in Scheme 1 on the basis of the calculations, because of the
small energy differences between the pathways. This is reasonable
since the steric hindrance provided by Me groups upon rotation is
small. It should be much larger in the case of phenyl substituents
and in this case transoid approach is expected to be favourable in for-
mation of epoxides. Unfortunately, calculations were too expensive
to perform a full conformational search. In particular, optimizations
of rotational transition states failed hence we do not know the en-
ergy barriers of rotation from cisoid to transoid conformations for
the Ph model. However, it is reasonable to assume that these barriers
should be considerably higher than the corresponding barriers for
the Me model. Thus the mechanism involving transoid approach
seems more likely in the case of steric substituents.
5.3. 3-Phenyl-2-(p-tolylsulfinyl)-oxirane 4a
Method A. To a solution of 1 mmol (0.3 g) of (S)-dimethylsulfo-
nium-(p-tolylsulfinyl)methylide in 5 mL of dry DMSO, 0.52 g
(1.1 mmol) of NaH was added at rt under an argon atmosphere.
The resulting mixture was stirred for 30 min. Then the precipitate
was filtered off and 1 mmol (0.11 g) of benzaldehyde in 1 mL of
DMSO was added. After stirring at rt for 2 h, the reaction was
quenched with aq NH4Cl solution (20 mL), extracted with hexane
(4 ꢃ 5 mL) and dried over MgSO4. After filtration, the solvent was
evaporated under reduced pressure to afford 4b in 82% of yield as a
mixture of trans/cis isomers in a ratio 1.5/1 (DMSO). Separation of
the isomers was achieved by chromatography on basic alumina
(hexane–acetone, 50:1).
Method B. To a solution of 1 mmol (0.3 g) of (S)-dimethylsulfo-
nium-(p-tolylsulfinyl)methyl tetrafluoroborate in 4–5 mL of dry
MeCN, 0.52 g (1.1 mmol) of NaH was added at rt under an argon
atmosphere. The resulting mixture was stirred for 30 min. Then
the precipitate was filtered off and 1 mmol (0.11 g) of benzalde-
hyde in 1 mL of dry MeCN was added. After stirring at rt for 2 h,
the reaction was quenched with aq NH4Cl solution (20 mL), ex-
tracted with hexane (4 ꢃ 5 mL) and dried over MgSO4. After filtra-
tion, the solvent was evaporated under reduced pressure to afford
3b in 90% of yield as a mixture of trans/cis isomers in a 2.5/1 ratio
(MeCN). Separation of isomers was achieved by chromatography
on basic alumina (hexane–acetone, 50:1).
Method C. To a suspension of 0.5 mmol (0.15 g) of (S)-dimethyl-
sulfonium-(p-tolylsulfinyl) methyl tetrafluoroborate in 15 mL of
dry THF, 2.75 mL (0.55 mmol) of BuLi was added at 0 °C. The mix-
ture was stirred at this temperature for 1 h and 0.5 mmol (0.055 g)
of benzaldehyde in 1 mL of dry THF was added.
Method D. In the round bottom flask equipped with magnetic stir-
rer 1 mmol(0.3 g) of (S)-dimethyl sulfonium-(p-tolylsulfinyl)methyl
tetrafluoroborate, 1 mmol (0.11 g) of benzaldehyde and 0.2 g of
K2CO3 was placed. 10 mL of CH2Cl2 was added and the mixture was
stirred vigorously overnight. Filtration and evaporation of solvent
afforded crude product, which was purified by chromatography.
Method E. The mixture of 1 mmol (0.3 g) of (S)-dimethyl sulfo-
nium-(p-tolylsulfinyl)methyl tetrafluoroborate, 1 mmol (0.11 g)
of benzaldehyde and 0.1 g of KOH in 10 mL of CH2Cl2 was stirred
vigorously overnight. Filtration and evaporation of solvent afforded
crude product, which was purified by chromatography.
5. Experimental
5.1. General
1H, 13C and 31P NMR spectra were recorded on a Bruker MSL 300
and Bruker AC 200 Spectrometer, using deuterochloroform as sol-
vent. Mass spectra were recorded on Finnigan MAT95. IR spectra
were recorded on Ati Mattson FTIR Spectrometer. The optical rota-
tions were measured on a Perkin–Elmer 241 MC photopolarimeter
in acetone solution. The microanalyses were performed on Ele-
mental Analyzer EA 1108. TLC was carried out on silica gel plates
(Merck F254) and Silica Gel 60 (70–230 ASTM) was used for chro-
matography. THF was freshly distilled over potassium/
benzophenone.
5.3.1. (2S,3S,SS)-3-Phenyl-2-(p-tolylsulfinyl)-oxirane 4a
[a]
D = +62.0 (c 0.8, acetone). 1H NMR (200 MHz) d: 2.40 (3H, s,
CH3C6H4S); 4.00 (1H, d, J = 1.6 Hz, CHPh); 4.58 (1H, d, J = 1.6 Hz,

W. H. Midura, M. Cypryk / Tetrahedron: Asymmetry 21 (2010) 177–186
185
CHS); 7.16–7.45 (7H, Ar); 7.59 (2H, d, J = 8.2 Hz). 13C NMR
(50 MHz) d: 21.4; 54.4; 75.6; 124.4; 125.9; 128.5; 129.0; 130.2;
133.8; 137.1; 142.5. Anal. Calcd for C15H14O2S: C, 69.74; H, 5.46.
Found: C, 69.61; H, 5.76
7.63 (m, 4H, Ar); 8.15 (br s, 1H, Ar); 8.17 (m, 1H, Ar). 13C NMR
(50 MHz) d: 21.4; 53.1; 75.6; 121.9; 124.1; 124.7; 130.1; 130.6;
132.4; 133.0; 136.5; 142.5;148.5. Anal. Calcd for C15H13NO4S: C,
59.39; H, 4.32. Found: C, 59.61; H, 4.46.
5.3.2. (2S,3R,SS)-3-Phenyl-2-(p-tolylsulfinyl)-oxirane 4a
5.6.2. (2S,3R,SS)-3-m-Nitrophenyl-2-(p-tolylsulfinyl)-oxirane
cis-4d
[
a]
D = ꢀ198.0 (c 0.5, acetone) mp 136–137 °C; 1H NMR
(200 MHz) d: 2.43 (3H, s, CH3C6H4S); 4.08 (1H, d, J = 3.4 Hz, CHPh);
4.52 (1H, d, J = 3.4 Hz, CHS); 7.26–7.45 (7H, Ar); 7.61 (2H, d,
J = 8.3 Hz). 13C NMR (50 MHz) d: 21.4; 60.7; 74.9; 124.5; 126.6;
128.5; 129.0; 130.1; 131.9; 138.4; 142.2.
½
a 2D2
ꢄ
¼ ꢀ39:2 (c 0.6, acetone) 1H NMR (200 MHz, CDCl3) d: 2.46
(3H, s, CH3C6H4S); 4.17 (1H, d, J = 3.4 Hz, CHAr); 4.60 (1H, d,
J = 3.4 Hz, CHS); 7.40–7.76 (5H, m, Ar); 7.82–7.85 (1H, m, Ar);
8.27–8.32 (2H, m, Ar).
5.4. (p-Bromophenyl)-2-(p-tolylsulfinyl)-oxirane method A, B,
and D
5.6.3. Partial data for (2R,3R,SS)-3-m-Nitrophenyl-2-(p-tolyl-
sulfinyl)-oxirane trans-4d
1H NMR (200 MHz, CDCl3) d: 4.14 (1H, d, J = 1.7 Hz, CHAr); 4.48
(1H, d, J = 1.7 Hz, CHS).
5.4.1. (2S,3S,SS)-3-(p-Bromophenyl)-2-(p-tolylsulfinyl)-oxirane
trans-4b
½
a 2D2
ꢄ
¼ þ52:1 (c 0.6, acetone); mp 136–137 °C 1H NMR
5.7. 3-2,4-Dinitrophenyl-2-(p-tolylsulfinyl)-oxirane—method C
and D
(200 MHz, CDCl3) d: 2.42 (3H, s, CH3C6H4S); 3.94 (1H, d,
J = 1.6 Hz, CHPh); 4.54 (1H, d, J = 1.6 Hz, CHS); 7.11 and 7.45 (4H,
AB system J = 8.4 Hz, Ar); 7.36 and 7.59 (4H, AB system J = 8.2 Hz,
Ar). 13C NMR (50 MHz) d: 21.5; 53.8; 75.7; 123.1; 124.6; 127.5;
130.3; 131.9; 133.0; 137.0; 142.7. Anal. Calcd for C15H13BrO2S: C,
53.42; H, 3.89. Found: C, 53.61; H, 3.76.
5.7.1. (2S,3S,SS)-3-2,4-Dinitrophenyl-2-(p-tolylsulfinyl)-oxirane
trans-4e
1H NMR (200 MHz, CDCl3) d: 2.42 (3H, s, CH3C6H4S); 3.99 (1H, d,
J = 1.4 Hz, CHAr); 5.23 (1H, d, J = 1.5 Hz, CHS); 7.30–7.82 (4H, m,
Ar); 8.57–8.62 (2H, m, Ar); 8.95 (1H, d, J = 2.2 Hz, Ar). 13C NMR
(50 MHz) d: 21.4; 62.6; 79.4; 121.4; 124.8; 128.8; 129.8; 130.1;
130.9; 141.5; 144.6; 148.7. Anal. Calcd for C15H12N2O6S: C, 51.72;
H, 3.47. Found: C, 51.61; H, 3.76.
5.4.2. (2S,3R,SS)-3-(p-Bromophenyl)-2-(p-tolylsulfinyl)-oxirane
cis-4b
½
a 2D2
ꢄ
¼ ꢀ117:1 (c 0.4, acetone); 1H NMR (200 MHz, CDCl3) d:
2.45 (3H, s, CH3C6H4S); 4.08 (1H, d, J = 3.3 Hz, CHPh); 4.4 (1H, d,
J = 3.3 Hz, CHS); 7.35 and 7.59 (4H, AB system J = 8.4 Hz, Ar); 7.39
and 7.62 (4H, AB system J = 8.2 Hz, Ar).
5.7.2. (2S,3S,SS)-3-2,4-Dinitrophenyl-2-(p-tolylsulfinyl)-oxirane
cis-4e
1H NMR (200 MHz, CDCl3) d: 2.45 (3H, s, CH3C6H4S); 4.39 (1H, d,
J = 3.9 Hz, CHAr); 5.05 (1H, d, J = 3.9 Hz, CHS); 7.38–8.04 (4H, m,
Ar); 8.65–8.69 (2H, m, Ar); 9.14 (1H, d, J = 2.2 Hz, Ar).
5.4.3. Partial data for 2R,3R,SS-3-(p-bromophenyl)-2-(p-
tolylsulfinyl)-oxirane trans-4b
1H NMR (200 MHz, CDCl3) d: 4.04 (1H, d, J = 1.6 Hz, CHAr); 4.30
(1H, d, J = 1.6 Hz, CHS).
5.7.3. Partial data for 2R,3R,SS-3-2,4-dinitrophenyl-2-(p-tolyl
sulfinyl)-oxirane trans-4e
1H NMR (200 MHz, CDCl3) d: 4.24 (1H, d, J = 1.3 Hz, CHAr); 5.00
(1H, d, J = 1.3 Hz, CHS).
5.5. o-Chlorophenyl-2-(p-tolylsulfinyl)-oxirane—method C and D
5.5.1. (2S,3S,SS)-3-o-Chlorophenyl-2-(p-tolylsulfinyl)-oxirane
trans-4c
5.8. 3-a-Naphthyl-2-(p-tolylsulfinyl)-oxirane—method D and E
½
a 2D2
ꢄ
¼ þ38:9 (c 0.75, acetone) 1H NMR (200 MHz, CDCl3) d: 2.42
(3H, s, CH3C6H4S); 3.87 (1H, d, J = 1.5 Hz, CHAr); 4.92 (1H, d,
J = 1.5 Hz, CHS); 7.19–7.45 (6H, m, Ar); 7.65 (2H, d, J = 8.1 Hz, Ar).
13C NMR (50 MHz) d: 21.4; 54.8; 75.4; 124.7, 127.2; 128.5:
129.2; 129.6; 130.1, 132.1; 141.7. Anal. Calcd for C15H13ClO2S: C,
61.53, H, 4.48. Found: C, 61.61; H, 4.56.
5.8.1. (2S,3S,SS)-3-a-Naphthyl-2-(p-tolylsulfinyl)-oxirane trans-
4f
½
a 2D2
ꢄ
¼ þ52:1 (c 0.6, acetone); 1H NMR (200 MHz, CDCl3) d: 2.40
(3H, s, CH3C6H4S); 4.02 (1H, d, J = 1.6 Hz, CHAr); 5.14 (1H, d,
J = 1.5 Hz, CHS); 7.25–7.90 (m, 11H, Ar); 13C NMR (50 MHz) d:
21.4; 55.8; 75.6; 124.1; 124.7; 127.5; 128.5; 129.4; 130.3; 131.3;
132.0; 132.4; 134.0; 137.0; 141.7. Anal. Calcd for C19H16O2S: C,
74.00; H, 5.23. Found: C, 73.81; H, 5.36.
5.5.2. (2S,3R,SS)-3-o-Chlorophenyl-2-(p-tolylsulfinyl)-oxirane
cis-4c
1H NMR (200 MHz, CDCl3) d: 2.44 (3H, s, CH3C6H4S); 4.19 (1H, d,
J = 3.4 Hz, CHAr); 4.65 (1H, d, J = 3.4 Hz, CHS); 7.11–7.67 (8H, m, Ar).
5.8.2. (2S,3R,SS)-3-a-Naphthyl-2-(p-tolylsulfinyl)-oxirane cis-4f
½
a 2D2
ꢄ
¼ ꢀ211:2 (c 0.4, acetone) 1H NMR (200 MHz, CDCl3) d: 2.44
5.5.3. Partial data for (2R,3R,SS)-3-o-chlorophenyl-2-(p-tolyl
sulfinyl)-oxirane trans-4c
(3H, s, CH3C6H4S); 4.32 (1H, d, J = 3.2 Hz, CHAr); 4.96 (1H, d,
J = 3.2 Hz, CHS); 7.31–7.39 (3H, m, Ar); 7.51–7.67 (5H, m, Ar);
7.91–7.95 (2 H, m, Ar); 8.12–8.16 (1H, m, Ar).
1H NMR (200 MHz, CDCl3) d: 3.95 (1H, d, J = 1.5 Hz, CHAr); 4.76
(1H, d, J = 1.5 Hz, CHS).
5.9. 3-Butyl-2-(p-tolylsulfinyl)-oxirane—method B
5.6. 3-m-Nitrophenyl-2-(p-tolylsulfinyl)-oxirane—method D
and E
5.9.1. (2S,3S,SS)-3-Butyl-2-(p-tolylsulfinyl)-oxirane trans-4g
½
a 2D2
ꢄ
¼ þ103:2 (c 0.75, acetone). 1H NMR (200 MHz) d: 0.87 (3H,
5.6.1. (2S,3S,SS)-3-m-Nitrophenyl-2-(p-tolylsulfinyl)-oxirane
trans-4d
t, J = 7.0 Hz, CH3CH2); 1.25–1.41 (4H, m); 1.58–1.65 (2H, m) 2.40
(3H, s, CH3C6H4S); 3.58 (1H, dt, J = 1.8, 5.7 Hz, CHCH2); 3.66 (1H,
d, J = 1.8 Hz, CHS); 7.33 and 7.53 (4H, AB system J = 8.4 Hz, Ar);
13C NMR (50 MHz) d: 13.7, 21.5; 22.2, 27.8, 30.2, 56.8; 72.7;
½
a 2D2
ꢄ
¼ þ55:4 (c 0.6, acetone); 1H NMR (200 MHz, CDCl3) d: 2.43
(3H, s, CH3C6H4S); 4.01 (1H, d, J = 1.4 Hz, CHAr); 4.68 (1H, d,
J = 1.4 Hz, CHS); 7.38 (2H, 1/2 AB system J = 8.1 Hz, Ar); 7.48–

186
W. H. Midura, M. Cypryk / Tetrahedron: Asymmetry 21 (2010) 177–186
Oxford, 1991; pp 148–170. Chapter 3; (c) Khiar, N.; Fernandez, I.; Alcudia, A.;
Alcudia, F.. In Advances in Sulfur Chemistry; Rayner, C. M., Ed.; JAI: Stanford, CT,
2000; Vol. 2, p 57. Chapter 3; (d) Rayner, C. M. Contemp. Org. Synth. 1994, 1,
191–203; (e) Procter, D. J. Chem. Soc., Perkin Trans. 1 2001, 335–354.
3. Solladie, G.; Carreno, M. C. In Organosulfur Chemistry. Synthetic Aspects; Page, P.
C. B., Ed.; Academic: New York, NY, 1995; pp 1–47. Chapter 1.
124.5; 130.1; 137.9; 142.2. Anal. Calcd for C13H18O2S: C, 65.51; H,
7.61. Found: C, 65.61; H, 7.76
5.10. 3-Pentyl-2-(p-tolylsulfinyl)-oxirane—method B
_
4. Some recent papers: (a) Gulea, M.; Kwiatkowska, M.; Łyzwa, P.; Legay, R.;
5.10.1. (2S,3S,SS)-3-Pentyl-2-(p-tolylsulfinyl)-oxirane trans-4h
Gaumont, A.-C.; Kiełbasin´ ski, P. Tetrahedron: Asymmetry 2009, 20, 293–297; (b)
Mikolajczyk, M.; Midura, W. H.; Ewas, A. M.; Perlikowska, W.; Mikina, M.;
Jankowiak, A. Phosphorus, Sulfur Silicon 2008, 183, 313–325; (c) Brebion, F.;
Goddard, J. P.; Fensterbank, L.; Malacria, M. Synthesis 2005, 2449–2452.
5. (a)Asymmetric Synthesis; Solladie, G., Morrison, J. D., Eds.; Academic: New York,
NY, 1983; Vol. 2, pp 157–199; (b) Cinquini, M.; Cozzi, F.; Montanari, F. In
Organic Sulfur Chemistry, Theoretical and Experimental Advances; Bernardi, F.,
Csizmadia, G., Mangini, A., Eds.; Elsevier: Amsterdam, 1985; (c) Hua, D. H.. In
Advances in Carbanion Chemistry; Snieckus, V., Ed.; JAI: London, 1992; Vol. 1, pp
249–281; (d) Hua, D. H. Adv. Heterocycl. Nat. Prod. Synth. 1996, 3, 151–177.
6. Finn, M. G.; Sharpless, K. B.. In Asymmetric Synthesis; Morrison, J. D., Ed.;
Academic Press: Orlando, FL, 1985; Vol. 5, p 247.
7. (a) Katsuki, T. In Comprehensive Asymmetric Catalysis II; Jacobsen, E. N., Pfaltz,
A., Yammoto, H., Eds.; Springer: Berlin, 1999; pp 621–648; (b) Jacobsen, E. N.;
Wu, M. H. In Comprehensive Asymmetric Catalysis II; Jacobsen, E. N., Pfaltz, A.,
Yammoto, H., Eds.; Springer: Berlin, 1999; pp 649–677; (c) Wang, Z.-X.; Tu, Y.;
Frohn, M.; Zhang, J. R.; Shi, Y. J. Am. Chem. Soc. 1997, 119, 11225; (d) Enders, D.;
Zhu, J.; Raabe, G. Angew. Chem., Int. Ed. 1996, 35, 1725.
½
a 2D2
ꢄ
¼ þ84:5 (c 1.1, acetone); 1H NMR (200 MHz) d: 0.85 (3H, t,
J = 6.8 Hz, CH3CH2); 1.21–1.39 (6H, m); 1.55–1.65 (2H, m) 2.42 (3H,
s, CH3C6H4S); 3.59 (1H, dt, J = 1.7, 5.7 Hz, CHCH2); 3.67 (1H, d,
J = 1.7 Hz, CHS); 7.35 and 7.56 (4H, AB system J = 8.2 Hz, Ar); 13C
NMR (50 MHz) d: 13.9, 21.5; 22.4, 25.3, 30.5, 31.2; 56.8; 72.8;
124.4; 130.0; 137.7; 142.3. Anal. Calcd for C14H20O2S: C, 66.63;
H, 7.99. Found: C, 66.61; H, 7.76.
1H NMR (200 MHz) d: 0.86 (3H, t, J = 6.8 Hz, CH3CH2); 1.22–1.43
(6H, m); 1.58–1.70 (2H, m) 2.42 (3H, s, CH3C6H4S); 3.37 (1H, dt,
J = 3.4, 5.7 Hz, CHCH2); 3.82 (1H, d, J = 3.4 Hz, CHS); 7.35 and 7.60
(4H, AB system J = 8.2 Hz, Ar).
5.11. 3-Nonyl-2-(p-tolylsulfinyl)-oxirane—method A and B
8. (a) Li, A.-H.; Dai, L.-X.; Aggarwal, V. K. Asymmetric Ylide Reactions:
Epoxidation, Cyclopropanation, Aziridination, Olefination, and Rearrangement
Chem. Rev. 1997, 97, 2341–2372; (b) Aggarwal, V. K.. In Comprehensive
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer:
Berlin, 1999; Vol. 2, pp 679–693.
9. (a) Satoh, T.; Taguchi, D.; Kurabayashi, A.; Kanoto, M. Tetrahedron 2002, 58,
4217; (b) Satoh, T.; Kaneko, Y.; Yamakawa, K. Tetrahedron Lett. 1986, 27, 2379.
10. (a) Furukawa, N.; Sugihara, Y.; Fujihara, H. J. Org. Chem. 1989, 54, 4222–4224;
(b) Julienne, K.; Metzner, P.; Henyron, V. J. Chem. Soc., Perkin Trans. 1 1999, 731–
735; (c) Zanardi, J.; Leriverend, C.; Aubert, D.; Julienne, K.; Metzner, P. J. Org.
Chem. 2001, 66, 5620–5623; (d) Winn, C. L.; Bellanie, B.; Goodman, J. M.
Tetrahedron Lett. 2002, 43, 5427–5430; (e) Li, A.-H.; Dai, L.-X.; Hou, X.-L.; Li, Y.-
Z.; Huang, F.-W. J. Org. Chem. 1996, 61, 489–493; (f) Hayakawa, R.; Shimizu, M.
Synlett 1999, 1328–1330; (g) Saito, T.; Akiba, D.; Sakairi, M.; Kanazawa, S.
Tetrahedron Lett. 2001, 42, 57–59.
5.11.1. (2S,3S,SS)-3-Nonyl-2-(p-tolylsulfinyl)-oxirane trans-4i
½
a 2D2
ꢄ
¼ þ66:4 (c 0.5, acetone); 1H NMR (200 MHz) d: 0.87 (3H, t,
J = 6.8 Hz, CH3CH2); 1.25–1.41 (14H, m); 1.58–1.65 (2H, m) 2.40
(3H, s, CH3C6H4S); 3.59(1H, dt, J = 1.8, 5.7 Hz, CHCH2); 3.68 (1H,
d, J = 1.8 Hz, CHS); 7.33 and 7.53 (4H, AB system J = 8.4 Hz, Ar);
13C NMR (50 MHz) d: 13.9, 21.5; 22.2, 22.4, 25.3, 27.8, 30.2, 30.5,
31.2; 31.4, 56.8; 72.8; 124.4; 130.0; 137.7; 142.3. Anal. Calcd for
C18H28O2S: C, 70.08; H, 9.15. Found: C, 70.21; H, 9.16.
5.12. Theoretical methods
11. (a) Midura, W. H.; Krysiak, J.; Wieczorek, M. W.; Filipczak, A. D. Pol. J. Chem.
2007, 81, 211–223; (b) Mikołajczyk, M.; Midura, W. H.; Michedkina, E.;
Filipczak, A.; Wieczorek, M. W. Helv. Chim. Acta 2005, 88, 1769–1775; (c)
Midura, W. H.; Krysiak, J. A.; Cypryk, M.; Mikołajczyk, M.; Wieczorek, M. W.;
Filipczak, A. D. Eur. J. Org. Chem. 2005, 653–662; (d) Garcia Ruano, J. L.; Fajardo,
C.; Martin, M. R.; Midura, W. H.; Mikołajczyk, M. Tetrahedron: Asymmetry 2004,
15, 2475–2482.
All calculations were performed using the density functional
theory methods with the GAUSSIAN 03 program.20 Equilibrium geom-
etries in the gas phase were optimized with the B3LYP/6-31G(d)
method. All potential energy minima and transition states were
identified by the frequency analysis. Transition states were further
verified by the IRC calculations. Final electronic energies for the
stationary points were calculated at the B3LYP/6-311+G(2d,p) level
for the B3LYP/6-31G(d) geometries (this level of theory is denoted
as 1B3LYP/6-311+G(2d,p)//B3LYP/6-31G(d)). Thermal corrections
to the enthalpy and entropy at 298.15 K were scaled by 0.98.
Geometries and energies in acetonitrile solution were calculated
using a continuum solvation model and the SCRF–PCM method21
as implemented in GAUSSIAN 03 at the B3LYP/6-31+G(d) level of
theory. Final electronic energies for the stationary points were cal-
culated at the B3LYP/6-311+G(2d,p) level (SCRF-B3LYP/6-
311+G(2d,p)//B3LYP/6-31+G(d)). UAHF atomic radii have been
used for cavity definition.
12. Midura, W. H. Synlett 2006, 733–736.
13. Numata, T.; Oae, S. Bull. Chem. Soc. Jpn. 1972, 45, 2794–2796.
14. Colombo, L.; Gennari, C.; Narisano, E. Tetrahedron Lett. 1978, 40, 3861–3862.
15. Addition of (S)-dimethylsulfonium-(p-tolylsulfinyl)methylide to N-tosyl
imines afforded the corresponding sulfinyl aziridines with full enantio- and
diastereoselectivity: Midura, W. H. Tetrahedron Lett. 2007, 48, 3907–3910.
16. (a) Garcia Ruano, J. L.; Martin Castro, A. M.; Roddguez, J. H. J. Org. Chem. 1992,
57, 7235–7241; (b) Posner, G. H. Acc. Chem. Res. 1987, 20, 72–78; (c) Solladie,
G.; Greck, C.; Demailly, G.; Solladie-Cavallo, A. Tetrahedron Lett. 1982, 23, 5047–
5051.
17. (a) Eades, R. A.; Gassman, P. G.; Dixon, D. A. J. Am. Chem. Soc. 1981, 103, 1066–
1068; (b) Aggarwal, V. K.; Schade, S.; Taylor, B. J. Chem. Soc., Perkin Trans. 1
1997, 2811–2813.
18. Non-planar configuration at the anionic
a-carbon atom was suggested
previously based on NMR studies and ab initio calculations of
a-
sulfinylcarbanion. [Chassaing, G.; Marquett, A.; Tetrahedron, 1978, 34, 1399;
Wolfe, S.; Rauk, A.; Csizmadia, I. G. J. Am. Chem. Soc. 1967, 89. 5710].
19. (a) Aggarwal, V. K.; Harvey, J. N.; Richardson, J. J. Am. Chem. Soc. 2002, 124,
5747–5756; (b) Aggarwal, V. K.; Richardson, J. Chem. Commun. 2003, 2644–
2651.
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