Design of sulfides with a locked conformation as promoters of catalytic and asymmetric sulfonium ylide epoxidation

Article abstract of DOI:10.1021/jo0479260

A new generation of 2,5-dimethylthiolanes with a locked conformation was developed to promote the asymmetric addition of chiral sulfonium ylides to aldehydes. The novel chiral sulfur derivative 4 succeeded the synthesis of trans-stilbene oxide derivatives with enantiomeric ratios ranging from 95:5 to 98:2. This user-friendly organocatalytic process proved to be efficient with 20-10% of sulfide 4 in 1 or 2 days of reaction. An insight into the ylide intermediate conformation is given on the basis of a computational ab initio study.

Full text of DOI:10.1021/jo0479260

SCHEME 1. C2-Symmetrical Thiolanes as
Asymmetric Mediators
Design of Sulfides with a Locked
Conformation as Promoters of Catalytic
and Asymmetric Sulfonium Ylide
Epoxidation
Marion Davoust, Jean-Franc¸ois Brie`re,
Paul-Alain Jaffre`s, and Patrick Metzner*
Laboratoire de Chimie Mole´culaire et Thio-organique (UMR
CNRS 6507), ENSICaen-Universite´ de Caen, 6 Boulevard
du Mare´chal Juin, 14050 Caen, France
a transition-metal-free one-pot protocol.7 This user-friend-
ly and economically reliable method is based on the de-
protonation in the presence of a mineral base of the in
situ formed nonracemic sulfonium salt from benzyl bro-
mide. In this context, Goodman et al. have recently show-
ed that a readily available C2 symmetrical sulfide8 allow-
ed the reaction to reach up to 99:01 er.6b Unfortunately,
a slow reaction rate usually occured with such a protocol,
and a sluggish sulfonium salt formation is often invoked.9
Our group developed simple and readily available C2-
symmetric 2,5-disubstituted thiolanes10 easily used in
open reaction vessel (Scheme 1). These sulfonium ylide
mediators11 effected the bis-arylepoxide formation on the
order of days.6c The trans-stilbene oxide was then obtain-
ed with up to 96:04 er by means of 0.1 equiv of the di-
ethylthiolane derivative 3. However, as one can expect, the
improved selectivities with the sterically more hindered
sulfide 3 led to longer reaction times (1 vs 2 and 2 vs 3).
In this paper, we disclose a second generation of C2
symmetrical thiolanes featuring a controlled topology
with the aim to improve the efficiency of this process
(Scheme 2). The presence of an acetal bridge at the 3,4
positions of the derivatives 4 and 5 constrains the five-
patrick.metzner@ensicaen.fr
Received November 23, 2004
A new generation of 2,5-dimethylthiolanes with a locked
conformation was developed to promote the asymmetric
addition of chiral sulfonium ylides to aldehydes. The novel
chiral sulfur derivative 4 succeeded the synthesis of trans-
stilbene oxide derivatives with enantiomeric ratios ranging
from 95:5 to 98:2. This user-friendly organocatalytic process
proved to be efficient with 20-10% of sulfide 4 in 1 or 2 days
of reaction. An insight into the ylide intermediate conforma-
tion is given on the basis of a computational ab initio study.
The catalytic asymmetric addition of chiral sulfonium
ylides to aldehydes has emerged as an efficient approach
toward nonracemic epoxides (Scheme 1).1 The oxirane
ring is constructed in a one-step process via a C-C and
a C-O bond formation, along which a subtle control of
both diastereo- and enantioselectivities is involved.2
Although the synthesis of nonracemic aromatic epoxide
intermediates making use of this ylide methodology has
met with some successful elaboration of biologically
important targets,1,3,5a the number of chiral sulfur deriva-
tives4 reaching at least 95:5 er in a catalytic approach5
is thus far limited.1,2b,6 Aggarwal et al. described a
bridged bicyclic sulfide yielding trans-stilbene oxide as
model substrate with 97:03 er.6a An elegant catalytic cycle
based on the sulfonium ylide formation by means of
rhodium-mediated carbenoid transfer led to a reaction
completed within a day with only 0.2-0.05 equiv of
sulfide on a large range of aldehyde precursors. On the
other hand, Furukawa et al. originally developed in 1989
(4) For recent chiral sulfur reagents promoting bis-arylepoxides
synthesis, see: (a) Minie`re, S.; Reboul, V.; Metzner, P.; Fochi, M.;
Bonini, B. F. Tetrahedron: Asymmetry 2004, 15, 3275-3280. (b) Saito,
T.; Akiba, D.; Sakairi, M.; Ishikawa, K.; Otani, T. Arkivoc 2004, (ii),
152-171. (c) Ishizaki, M.; Hoshino, O. Chirality 2003, 15, 300-305.
(d) Aggarwal, V. K.; Angelaud, R.; Bihan, D.; Blackburn, P.; Fieldhouse,
R.; Fonquerna, S. J.; Ford, G. D.; Hynd, G.; Jones, E.; Jones, R. V. H.;
Jubault, P.; Palmer, M. J.; Ratcliffe, P. D. J. Chem. Soc., Perkin Trans.
1 2001, 2604-2622. This last reference describes an impressive piece
of work toward the elaboration of chiral sulfur derivatives.
(5) For efficient stoichiometric approaches as alternatives, see: (a)
Aggarwal, V. K.; Bae, I.; Lee, H.-Y.; Richardson, J.; Williams, D. T.
Angew. Chem., Int. Ed. 2003, 43, 3274-3278. (b) Solladie´-Cavallo, A.;
Roje, M.; Isarno, T.; Sunjic, V.; Vinkovic, V. Eur. J. Org. Chem. 2000,
1077-1080.
(6) (a) Aggarwal, V. K.; Alonso, E.; Bae, I.; Hynd, G.; Lydon, K. M.;
Palmer, M. J.; Patel, M.; Porcelloni, M.; Richardson, J.; Stenson, R. A.;
Studley, J. R.; Vasse, J.-L.; Winn, C. L. J. Am. Chem. Soc. 2003, 125,
10926-10940. (b) Winn, C. L.; Bellenie, B. R.; Goodman, J. M.
Tetrahedron Lett. 2002, 43, 5427-5430. (c) Zanardi, J.; Leriverend, C.;
Aubert, D.; Julienne, K.; Metzner, P. J. Org. Chem. 2001, 66, 5620-5623.
(7) Furukawa, N.; Sugihara, Y.; Fujihara, H. J. Org. Chem. 1989,
54, 4222-4224.
(8) For early attempts to use C2-symmetrical sulfides, see: Breau,
L.; Ogilvie, W. W.; Durst, T. Tetrahedron Lett. 1990, 31, 35-38. For
an intramolecular version: Kim, H.-H.; Metobo, S.; Jimenez, L. S.
Phosphorus, Sulfur, Silicon 2001, 176, 29-47.
(9) A lack of reactivity of the sulfur derivatives, due to the presence
electron-withdrawing groups nearby, can also be detrimental to the
reaction rate; see: Durst, T. Phosphorus, Sulfur Silicon Relat. Elem.
1993, 74, 215-232.
(10) 2,5-Dialkylthiolanes are synthesized in two steps from the
commercially available chiral 1,4-diols, which are available in bulk
from JFC-Juelich Fine Chemicals GmbH Co.: Haberland, J.; Hummel,
W.; Daussmann, T.; Liese, A. Org. Proc. Res. Dev. 2002, 6, 458-462.
(11) A recent review on organocatalysis including sulfur ylides,
see: Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138-
5175.
* To whom correspondence should be addressed. Tel: Int. code
+3323145-2885. Fax: Int. code +3323145-2865.
(1) For a recent review, see: Aggarwal, V. K.; Winn, C. L. Acc. Chem.
Res. 2004, 8, 611-620.
(2) For recent contributions on getting insight in the reaction
mechanisms, see: (a) Silva, M. A.; Bellenie, B. R.; Goodman, J. M.
Org. Lett. 2004, 6, 2559-2562. (b) Aggarwal, V. K.; Richardson, J.
Chem. Commun. 2003, 2644-2651. (c) Aggarwal, V. K.; Harvey, J. N.;
Richardson, J. J. Am. Chem. Soc. 2002, 124, 5747-5756.
(3) (a) Aggarwal, V. K.; Imhyuck, B.; Leeb, H.-Y. Tetrahedron 2004,
60, 9725. (b) Lupattelli, P.; Bonini, C.; Caruso, L.; Gambacorta, A. J.
Org. Chem. 2003, 68, 3360-3362. (c) Solladie´-Cavallo, A.; Diep-
Vohuule, A. J. Org. Chem. 1995, 60, 3494-3498.
10.1021/jo0479260 CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/09/2005
4166
J. Org. Chem. 2005, 70, 4166-4169

TABLE 1. Stilbene Oxide Synthesis with Various
SCHEME 2. C2-Symmetrical Thiolanes with a
Locked Conformation
C2-Symmetrical Chiral Thiolanes
drd
ere
(S,S/
R,R)
thiolane
(20%)
time convb yieldc (trans/
entry
conda (h)
(%)
(%)
cis)
1
2
3
4
5
6
2
2
4
4
5
5
A
B
A
B
A
B
48f
24
100
69
100
92
<20
52
80
62
88
75
90:10 92.5:7.5g
91:9
91.5:8.5
2:98
24
83:17
90:10
80:20
24
168
96
5:95
SCHEME 3. Synthesis of the Chiral Thiolanesa
nd
27
82:18 74.5:25.5
a Conditions A: The reaction mixture of benzaldehyde (1 equiv),
benzyl bromide (2 equiv), NaOH (2 equiv), n-Bu4NI (1 equiv),
catechol (0,005 equiv) in a mixture of t-BuOH/H2O (9/1) was stirred
at rt. Conditions B: the reaction mixture of with benzaldehyde (1
equiv), benzyl bromide (2 equiv), n-Bu4NHSO4 (0.2 equiv), and
NaOH (2 equiv) in a mixture of MeCN/H2O (9/1) was stirred at rt.
b Determined by 1H NMR of the crude product with respect to the
aldehyde. c Isolated yield after column chromatography. d Deter-
mined by 1H NMR of the crude product. e Determined by enantio-
selective HPLC. f A conversion of 86% was measured after 24 h.
g Our previous results with conditions A without catechol additive,
ref 6c.
a Key: (a) MsCl, Et3N, CH2Cl2, 0 °C to rt; (b) Na2S‚9H2O (4
equiv), DMSO, 50 °C.
membered-ring conformation. Interestingly, the two meth-
yl groups of 4 and 5 are fixed in a different position with
respect to the trans or the cis relationship with the acetal
moiety. The 3D-models revealed, on one hand, that the
methyl groups of 4 occupy a pseudo-axial position. With
structure 5, these CH3 groups are forced in a pseudo-
equatorial position. The impact upon selectivities would
stem from a conformational control of the ring backbone
instead of steric hindrance as with 2,5-diethylthiolane
3.12 It is expected that maintaining the methyl groups
at the C2 and C5 positions would both minimize the
shielding of the sulfur lone pair and keep a reasonably
rapid rate for the formation of the sulfonium salt. We
wish to describe herein the success of such an approach.
The synthesis of new sulfides 4 and 5 was envisaged via
diols 6 and 7 (Scheme 3), which were easily obtained in
few steps from cheap D-mannitol according to literature
procedures.13 The cyclization step of the known mesylates14
of 6 and 7 required an excess of sodium sulfide nonahy-
drate under optimized conditions (see the Supporting In-
formation). The sulfide 4 was thus formed smoothly, in
71% isolated yield over two steps, as a colorless and heavy
oil. Under similar conditions, however, the mesylated diol
7 yielded a mixture of products requiring tedious puri-
fications on column chromatography to isolate the sulfide
5 in poor yield. It is believed that the difficult intramo-
lecular substitution reaction by sodium sulfide illustrates
the ring strain dictated by the acetal bridge.
the sulfonium ylide was performed in the presence of
benzyl bromide, a mineral base, i.e., NaOH and the help
of an ammonium salt (vide infra). This one-pot protocol
is simply performed without exclusion of air or humidity.
Under these conditions, an efficient organocatalysis took
place with only 0.2 equiv of 4, leading to 100% conversion
in 24 h (Table 1, entry 3). Pleasingly, we measured a high
enantiomeric ratio of 98:02 for the formed oxirane in 88%
isolated yield. This result constitutes a marked improve-
ment in comparison with the previous generation of
dimethylthiolane 2, which afforded a 92.5:7.5 ratio in
favor of the S,S epoxide (entry 1). Although an erosion
of the diastereoselectivity could be observed in protic
solvents (entries 1 and 3), the use of acetonitrile allowed
us to obtain a 90:10 trans/cis ratio with a slight decrease
of the enantiomeric purity of the oxirane (entries 3 and
4).2c Moreover, the configurationally locked sulfide 4
succeeded in the epoxide formation somewhat faster than
the flexible thiolane 2 (entries 1-4). The transformation
can be completed within 24 h in a catalytic manner. It is
worth mentioning that usually several days of reaction
are required for such a protocol.15 Those results place the
sulfide 4 as one of the most effective promoter used so
far in sulfonium ylide epoxidation.1 To pursue the study
of the remote acetal bridge effects, we carried on the same
reaction with the sulfide 5 featuring a trans relationship
between methyl and ether groups. Whatever the condi-
tion A or B (entries 5 and 6), both selectivities and
conversions were decreased. The thiolane 5 gave the
oxirane enantiomer of the one obtained with 4, i.e., the
major S,S enantiomer. This demonstrates that the meth-
yl groups at the 2 and 5 positions control the sense of
the enantioselectivity.8
Then, we carried out the model synthesis of trans-
stilbene oxide from benzaldehyde promoted by a catalytic
amount of the previous 2 and the new C2 symmetrical
thiolanes 4 and 5 in polar solvents (see the Supporting
Information for optimization).6c The in situ formation of
(12) For computer-assisted modelisation of chiral sulfur reagents,
see: (a) Aggarwal, V. K.; Charmant, J. P. H.; Dudin, L.; Porcelloni, M.;
Richardson, J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5467-5471.
(b) Myllyma¨ki, V. T.; Lindvall, M. K.; Koskinen, A. M. P. Tetrahedron
2001, 57, 4629-4635. The described chiral sulfide, in this latter paper,
allowed the synthesis of trans-stilbene oxide with 95:5 er, but in poor
yield.
Moving a step forward to other aldehydes, we were
struck by the behavior of the new chiral sulfide 4. First
of all, reproducible results in tert-butyl alcohol were
obtained for the synthesis of stilbene oxide only with the
(13) For an excellent review on chiral phospholanes describing the
use of diol precursors, see: Clark, P. C.; Landis, C. R. Tetrahedron:
Asymmetry 2004, 15, 2123-2137.
(14) (a) Yan, Y.-Y.; RajanBabu, T. V. J. Org. Chem. 2000, 65, 900-
906. (b) Li, W.; Zhang, X. J. Org. Chem. 2000, 65, 5871-5874.
(15) Dai already described that 20% of a camphor-derived sulfide
allowed stilbene oxide synthesis within a day without the need of any
transition metal but a maximum of 80:20 er was obtained; see: Li,
A.-H.; Dai, L.-X.; Hou, X.-L.; Huang, Y.-Z.; Li, F.-W. J. Org. Chem.
1996, 61, 489-493.
J. Org. Chem, Vol. 70, No. 10, 2005 4167

TABLE 2. Additive Effects upon Ylide Addition to
4-chlorobenzaldehyde after 24 ha
TABLE 3. Asymmetric Synthesis of Epoxides from
Various Aldehydes
n-Bu4NX
dr
er
(S,S/
R,R)
dr
er
conv yield (trans/
solvent
(90/10)
conv yield (trans/ (S,S/
entry
ArCHO
conda (%)
(%)
cis)
entry
X
(equiv)
(%)
(%)
cis)
R,R)
1
2
3
4
5
6
2-NaphthylCHO
2-NaphthylCHO
4-F3CC6H4CHO
4-F3CC6H4CHO
4-FC6H4CHO
A
B
A
B
B
B
100
72
92
65
58
53
61
66
83:17
92:8
90:10
95:5
88:12
4:96
5:95
1
2
3
4
5
6
7
Ib
(1)
t-BuOH/H2O
MeCN/H2O
t-BuOH/H2O
t-BuOH/H2O
t-BuOH/H2O
MeCN/H2O
27
30
4
15
83:17 5:95
Ib
(1)
84:16
nd
nd
nd
nd
nd
Ib
Br
(0.2)
(0.2)
100
100
100
5:95
4.5:95.5
5:95
6
HSO4 (0.2)
HSO4 (0.2)
45
100
79
38
71
64
81:19 4:96
89:11 5:95
90:10 4:96
4-MeC6H4CHO
84b,c
90:10 2.5:97.5
HSO4 (0.2)c MeCN/H2O
a Refer to condition A or B of Table 1. b Result after 48 h of
reaction. c Conversion of 46% after 24 h.
a The reaction mixture of aldehyde (1 equiv), benzyl bromide
(2 equiv), NaOH (2 equiv) and the sulfide 4 (0.2 equiv) was stirred
at rt for 24 h. b 0,5% of catechol was used with respect to the
aldehyde. c 0.1 equiv of sulfide 4 was used.
SCHEME 4. Asymmetric Induction with the
Locked Chiral Sulfide 8
presence of both a small amount of catechol and 1
equivalent of n-Bu4NI.6c Next, even though this procedure
proved to be robust for benzaldehyde itself, it turned out
to be chemically aldehyde dependent.16 For instance,
p-chlorobenzaldehyde (Table 2) furnished the correspond-
ing enantioenriched oxirane in 95:5 er, but with only 15%
yield after 24 h (entry 1). No improvement was obtained
in acetonitrile (entry 2), the alternative polar solvent for
this reaction.17 Then, we undertook an investigation of
ammonium additives with 0.2 equiv of sulfide 4 and
found a beneficial effect of the counteranion (Table 2).
As expected, decreasing the amount of n-Bu4NI to 20%
slowed dramatically the reaction rate probably by de-
creasing the I-Br exchange rate (entry 3). No effect was
observed with n-Bu4NBr (entry 4). However, the use of
bisulfate as counterion showed an acceleration of the
reaction rate in tert-butyl alcohol (entry 5). Eventually,
the reaction was smoothly performed in acetonitrile in
24 h with only 20% of n-Bu4NHSO4 (entry 6) and afforded
good selectivities for the trans-epoxide (without the need
of catechol as additive). Furthermore, the loading of the
sulfide could be reduced to 0.1 equiv, giving rise to a
respectable conversion of 79% (entry 7, 64% yield) after
24 h of reaction without decreasing the selectivity. It is
worthy of note that these conditions also provided good
reaction rates with dimethylthiolane derivative 2 in
acetonitrile (Table 1, entry 2). Although the effect of this
ammonium salt is not clear at the moment, we suppose
that it behaves as a phase transfer catalyst18 in this
heterogeneous mixture.19 It would support both the
extraction of the hydroxide anion into the organic phase
and/or the deprotonation of the sulfonium salt. In fact,
1
we were able to check by H NMR that the formation of
the sulfonium salt between 2 equiv of benzyl bromide and
1 equiv of sulfide 4 in a mixture of CD3CN/D2O (9/1)20 is
nicely completed within 3 h.4a The subsequent addition
of 2 equiv of NaOD and benzaldehyde revealed a slow
formation of the epoxide even after several days without
any other additives. This first experiment points out that
the ylide formation or the ylide addition to the aldehyde
seems to be sluggish for the corresponding sulfide 4 in
the absence of an ammonium salt.
Having established robust experimental conditions for
an enantioselective addition of sulfur ylide to aldehyde
with 0.2 equiv of the thiolane 4, we were interested in
probing the generality of this process with a set of para-
substituted aromatic aldehydes and 2-naphthaldehyde
(Table 3). In almost all cases a complete conversion was
obtained after 24 h with moderate to good yields. We were
able to measure excellent levels of selectivity for the
major trans-oxirane (at least 95:05 er). In the case of
tolualdehyde (entry 6) a slower reaction rate required 2
days of reaction but a high enantiomeric ratio of 97.5:
2.5 was obtained. In general, the diastereoselectivity2c
was better in acetonitrile than in t-BuOH (entries 1-4)
without affecting the enantioselectivity. Those results
bring confidence to the usefulness of such a constrained
C2-symmetrical 2,5-dimethylthiolane structure 4.
It is now well recognized2 that ylide reagent intermedi-
ates would adopt two conformations featuring a mini-
mum of energy, i.e., exo and endo conformations, as seen
in Scheme 4 (ylide 8 from sulfide 4 as an exemple), so
that the filled p orbital of the sp2-hybridized ylide carbon
is perpendicular to the sulfur lone pair in order to
minimize the electronic repulsions. The incoming aryl-
aldehyde would then approach the ylide moiety following
a cisoid or gauche addition (Scheme 4).2c A very recent
theorical study by Goodman,2a at the DFT level with C2-
(16) It was found that a complete and reproducible conversion
occurred in 24 h when distilled benzaldehyde was stabilized with a
small amount of catechol. Although catechol is a well-known anti-
oxidant of aldehydes, such behavior in our process is not completely
understood. Moreover, this effect was aldehyde dependent. For in-
stance, no difference was observed with 2-naphthaldehyde whatever
catechol was used or not.
(17) Julienne, K.; Metzner, P.; Henryon, V. J. Chem. Soc., Perkin
Trans. 1 1999, 731-735.
(18) n-Bu4NHSO4 has been used as PTC for sulfur ylide epoxidation
in a racemic approach, see: Solladie´-Cavallo, A.; Lupattelli, P.; Marsol,
C.; Isarno, T.; Bonini, C.; Caruso, L.; Maiorella, A. Eur. J. Org. Chem.
2002, 1439-1444.
-
(19) The ability of HSO4 or SO42-, in basic conditions, to perform
a counterion exchange with the sulfonium bromide cannot be ruled
out, as has been also suggested by a reviewer. This exchange would
promote the nonreversible formation of the sulfonium salt due to the
non-nucleophilic caracter of the sulfate anions. The ammonium ion
would facilitate the sulfate anion extraction from the aqueous phase.
(20) This equilibrium proved to be finely balanced with regard to
the solvent polarity. In pure CD3CN without D2O, we did not observe
any sulfonium salt formation by 1H NMR even after 24 h; see the
Supporting Information.
4168 J. Org. Chem., Vol. 70, No. 10, 2005

TABLE 4. Ab Initio Computational Studies on Sulfur
The ylides 9 and 10 are characterized by the two 2,5-
methyl groups located in a pseudoequatorial position. The
dihedral angles are positive (Table 4, entries 2 and 3).
Since the ylides 9 and 10 feature reverse absolute config-
urations at C2 and C5 of the thiolane ring, the obtained
conformation is different as can be seen in Scheme 5.
Indeed, the downward CH3 is pushed forward to the
methylene ylide carbon. This conformation would mini-
mize the 1,3 nonbonding interactions of the endo-ylides
9 and 10 and decrease the endo/exo equilibrium constant.
Having this in mind, we assume that the pseudoaxial
methyl groups could account for the selectivity of sulfide
4, giving the corresponding ylide 8. They could destabilize
the TS8-endo transition state by 1,3 nonbonding inter-
actions between the phenyl moiety and the downward
CH3 group (Scheme 4). It is also supposed that the
pseudoaxial methyl group of 8 shields one of the ylide
faces better than the pseudoequatorial methyl groups in
analogues 9 and 10. The difference in selectivity between
5 and 2 was not expected, according to the closely related
structure of the corresponding ylide intermediates 9 and
10. The derivative 2 is more flexible than 5 and likely
features a different conformation in the transition state.
Ylides 8-10
b,c
b,c
benzylidene corresponding ∆Eendo-exo θendo
θexo
(deg)
entry
ylidesa
sulfide
(kJ/mol)a
(deg)
1
2
3
8
4
5
2
3.54
1.62
0.99
+20.1 +11.6
+13.9 +24.8
+17.0 +25.5
9
10
a Exo or endo conformation as described in Scheme 5 and see
comment in ref 21. b Dihedral angle measured between the carbon
atom of the methyl group at the R position of the sulfur atom and
the ylide carbon atom. c A positive sign means a counterclockwise
rotation of the dihedral angle.
SCHEME 5. Conformation of the Ylide
Intermediates from ab Initio Calculation
In summary, this work has provided insight into the
importance of the conformation of C2 symmetrical 2,5-
dimethylthiolanes for the asymmetric synthesis of ep-
oxides from chiral sulfonium ylide reagents. We have
designed a locked chiral sulfide 4 with C2 and C5 methyl
groups located in a pseudoaxial position. This original
sulfur derivative promoted the synthesis of trans-aryl-
epoxides with excellent enantiomeric ratios ranging from
95:05 to 98:02 via the catalytic transfer of benzylidene
to a range of aromatic aldehydes. Moreover, under
optimized conditions, making use of a phase transfer
catalyst, n-Bu4NHSO4, the reaction was carried out with
only 10-20% of chiral thiolane in 1 or 2 days in transition
metal-free conditions. The novel chiral sulfur 4 is there-
fore one of the most selective and catalytically active
promoter developed so far for the asymmetric synthesis
of trans-stilbene oxide.1 Although we do not reach the
scope23 of the recently developed metal-catalyzed car-
benoid transfer toward chiral sulfonium ylide formation,6a
our organocatalytic process constitutes an efficient one-
pot procedure, which is easily performed in open reaction
vessel with readily available and usually cheap materials.
symmetrical thiolanes such as 2, revealed that the enan-
tioselectivy of the trans-epoxide is controlled in the trans-
ition state of this carbon-carbon bond formation step
(TS8-exo vs TS8-endo). Accordingly, we assume that the
carbonyl derivative undergoes the Re face ylide addition
(TS8-exo), following the lowest energetic pathway, to give
the major (R,R)-stilbene oxide. For this explanation, it is
supposed that the downward methyl group of 8 shields
the back face of these intermediates (Scheme 4). As far as
the other dimethylthiolanes 2 and 5 are concerned, bear-
ing a reverse absolute configuration at the R-position of
the sulfur atom, they led to the opposite stereochemistry.
We desired to get insight in the relative position of the
methyl groups at C2 and C5 of the thiolanium ring, with
respect to the remote acetal bridge. We examined the
optimized geometries of the most populated exo and endo
ylides 8, 9,21 and 10 (Table 4 and Scheme 5) by means of
an ab initio computational study12 at the HF/6-31G* level
(see the Supporting Information for more details).22
The exo ylide species, having the phenyl pointing away
from the bulky thiolane ring (the RR groups in Scheme
5), are slightly preferred conformations and the exo ylide
8 is the most stable. To have an indicator of the methyl
position at C2, we took into account the dihedral angle θ
(Table 4) between the downward methyl group at C2 and
the methylene carbon of the ylides 8-10 as depicted in
Scheme 5. The ylide 8, having a pseudoaxial methyl
group, features positive dihedral angles (Table 4, entry
1). As a consequence, the CH3 is pulled backward from
the methylene ylide carbon, lying underneath the five-
membered ring. This conformation would therefore in-
crease the 1,3 nonbonding interactions between the
phenyl ring and the methyl group in the endo-ylide struc-
ture 8 and drive the equilibrium toward the exo-ylide 8.12b
Acknowledgment. We gratefully acknowledge fi-
nancial support from the “Ministe`re de la Recherche”,
CNRS, the “Re´gion Basse-Normandie”, and the Euro-
pean Union (FEDER funding). We also warmly thank
Nicolas Bracq, Thomas No¨tzel, Elyse Mariette, and
Pierre Donnat for their contribution in the synthesis of
thiolane precursors.
Supporting Information Available: Experimental pro-
cedures and characterization datas. Reproduction of 1H NMR
spectra for the sulfides 4 and 5, the sulfonium salt derived
from 4, and the epoxides. Computational data for ylides 8-10.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(21) For computational convenience, we replaced the gem-dimethyl
group present on the acetal bridge of the sulfonium ylides 8 and 9 by
a methylene group, given the lack of influence expected on the
conformations.
JO0479260
(22) For discussion of such a computational method for sulfonium
ylides, see: Lindvall, M. K.; Koskinen, A. M. P. J. Org. Chem. 1999,
64, 4596-4606.
(23) Under our conditions no epoxide was obtained from 3-pyridyl
carboxaldehyde. 2-Thienyl carboxaldehyde underwent epoxidation in
20% yield after 3 days of reaction.
J. Org. Chem, Vol. 70, No. 10, 2005 4169