A Simple C2 Symmetrical Sulfide for a One-Pot Asymmetric Conversion of Aldehydes into Oxiranes

Full text of DOI:10.1021/jo980269p

4532
J . Org. Chem. 1998, 63, 4532-4534
Sch em e 1
A Sim p le C2 Sym m etr ica l Su lfid e for a
On e-P ot Asym m etr ic Con ver sion of
Ald eh yd es in to Oxir a n es
Karine J ulienne and Patrick Metzner*,†
Laboratoire de Chimie Mole´culaire et Thio-organique
(UMR CNRS 6507), ISMRA-Universite´, 6, boulevard du
Mare´chal J uin, 14050 Caen, France
from camphoric acid. Recently the groups of Solladie´-
Cavallo,12-14 Aggarwal,15-17 and Dai18 have reported
major advances in terms of chemical efficiency and ee’s,
based on chiral sulfonium ylides derived from pulegone
or camphor with various reaction conditions. We report22
a simple chiral auxiliary, which can be prepared in two
steps and has C2 symmetry and low molecular weight
(only 6 carbons) tending toward the principle of atom
economy.23 It can be used in a simple one-pot procedure,
and it leads to epoxides in high yields and diastereoiso-
meric and enantiomeric excesses (de and ee).
Vivien Henryon and Alfred Greiner
Rhoˆne Poulenc Industrialisation, Centre de Recherches des
Carrie`res, 85, avenue des Fre`res Perret, 69192 Lyon, France
Received February 17, 1998
Epoxides are versatile intermediates used to a very
large extent in short or multistep syntheses. One of the
most important reactions1,2 is their opening with amines,
providing 1,2-amino alcohols of major biological interest,
such as adrenergic â-blockers3,4 or inhibitors of ergosterol
synthesis.5,6 Access to enantiopure oxiranes by Sharpless
and J acobsen type oxidations of alkenes has been the
focus of several studies.7-9 Alternative starting sub-
strates are carbonyl compounds using the reaction of
sulfur ylides developed in the 1960s. Initial attempts10
to achieve an asymmetric epoxidation were disappointing
until the advances11-18 of the 1990s. A pioneering work
by Furukawa showed the feasibility of an approach based
on chiral sulfides.19 It was rapidly followed20,21 by
breakthroughs of Durst who reported the first ee’s
reaching 90%, with a chiral sulfide,20 obtained in six steps
The principle of C2 symmetry24 has been applied to
chiral sulfides by Durst and co-workers with three
thiolanes,21 prepared in five steps with unspecified yields.
The reaction of the corresponding sulfur ylides with
benzaldehyde as a typical example led to stilbene oxide
with yields ranging from 27 to 53% (calculated from the
sulfonium salt) and enantiomeric excesses from 15 to
64%. We decided to investigate the use of the very simple
enantiopure trans 2,5-dimethylthiolane 1. It is only
mentioned25,26 in a meeting report in which it was
indicated briefly that it did not lead to any asymmetric
induction. We have prepared26 thiolane 1 easily in only
two steps from commercially available (2S,5S)-hex-
anediol. This diol27-29 can also be obtained by the
enzymatic reduction of the cheap 2,5-hexanedione with
baker’s yeast.27 Activation of hydroxyl groups into me-
sylates30 and subsequent cyclization with sodium sulfide,
by two nucleophilic substitutions with inversion, fur-
nished the C2 symmetrical sulfide 1 in 95% yield.
The asymmetric benzylidene transfer on aldehydes was
investigated. We intended to use a simple epoxidation
procedure18,19 involving a mineral base and mixing all
reagents together in one pot at room temperature (Scheme
2). The reaction of benzaldehyde (1 equiv) with benzyl
bromide (2 equiv) and thiolane 1 (1 equiv) was carried
out with potassium or sodium hydroxide (2 equiv) in
various solvents. Experiments in nonpolar or moderately
polar solvents, under heterogeneous (toluene/aqueous
NaOH, CH2Cl2/aqueous NaOH) or homogeneous (THF/
aqueous NaOH) conditions, furnished poor yields or
† E-mail: Patrick.Metzner@ismra.fr. Fax: (33) 2 31 45 28 77.
(1) Gorzynski Smith, J . Synthesis 1984, 629-653.
(2) Rao, A. S.; Paknikar, S. K.; Kirtane, J . G. Tetrahedron 1983,
39, 2323-2367.
(3) Main, B. G. Comprehensive Medicinal Chemistry; Hansch, C.,
Sammes, P. G., Taylor, J . B., Emmett, J . C., Eds.; Pergamon: Oxford,
1990; Vol. 3, pp 187-228.
(4) Ganellin, C. R.; Roberts, S. M. Medicinal Chemistry: The Role
of Organic Chemistry in Drug Research; Academic Press: London,
1993.
(5) Schwin, F. J . Pestic. Sci. 1983, 15, 40-47.
(6) Siegel, M. R. Plant Disease 1981, 65, 986-989.
(7) Aube´, J . Comprehensive Organic Synthesis; Trost, B. M., Flem-
ing, I., Schreiber, S. L., Eds.; Pergamon Press: Oxford, 1991; Vol. 1,
pp 819-842.
(8) Besse, P.; Veschambre, H. Tetrahedron 1994, 50, 8885-8927.
(9) Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1-299.
(10) Trost, B. M.; Hammen, R. F. J . Am. Chem. Soc. 1973, 95, 962-
964.
(11) Li, A.-H.; Dai, L.-X.; Aggarwal, V. K. Chem. Rev. 1997, 97,
2341-2372. Aggarwal, V. K. Synlett 1998, 329-336.
(12) Solladie´-Cavallo, A.; Adib, A. Tetrahedron 1992, 48, 2453-2464.
(13) Solladie´-Cavallo, A.; Diep-Vohuule, A. J . Org. Chem. 1995, 60,
3494-3498.
(22) Communicated at the 4th ANORCQ meeting, Southampton
(U.K.), April 17, 1997.
(23) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259-281.
(24) Whitesell, J . K. Chem. Rev. 1989, 89, 1581-1590.
(25) Durst, T. Phosphorus Sulfur Silicon Relat. Elem. 1993, 74, 215-
232.
(14) Solladie´-Cavallo, A.; Diep-Vohuule, A. Tetrahedron: Asymmetry
1996, 7, 1783-1788.
(15) Aggarwal, V. K.; Kalomiri, M.; Thomas, A. P. Tetrahedron:
Asymmetry 1994, 5, 723-730.
(16) Aggarwal, V. K.; Thompson, A.; J ones, R. V. H.; Standen, M.
C. H. Tetrahedron: Asymmetry 1995, 6, 2557-2564.
(17) Aggarwal, V. K.; Ford, J . G.; Thompson, A.; J ones, R. V. H.;
Standen, M. C. H. J . Am. Chem. Soc. 1996, 118, 7004-7005.
(18) Li, A.-H.; Dai, L.-X.; Hou, X.-L.; Huang, Y.-Z.; Li, F.-W. J . Org.
Chem. 1996, 61, 489-493.
(26) After this note was submitted for publication, a preparation of
thiolane 1 was reported according to the same method as the one used
here. Otten, S.; Fro¨hlich, R.; Haufe, G. Tetrahedron: Asymmetry 1998,
9, 189-191.
(27) Lieser, J . K. Synth. Commun. 1983, 13, 765-767.
(28) Burk, M. J .; Feaster, J . E.; Harlow, R. L. Tetrahedron: Asym-
metry 1991, 2, 569-592.
(19) Furukawa, N.; Sugihara, Y.; Fujihara, H. J . Org. Chem. 1989,
54, 4222-4224.
(20) Breau, L.; Durst, T. Tetrahedron: Asymmetry 1991, 2, 367-
(29) Ikeda, H.; Sato, E.; Sugai, T.; Ohta, H. Tetrahedron 1996, 52,
8113-8122.
370.
(21) Breau, L.; Ogilvie, W. W.; Durst, T. Tetrahedron Lett. 1990,
31, 35-38.
(30) Short, R. P.; Kennedy, R. M.; Masamune, S. J . Org. Chem. 1989,
54, 1755-1756.
S0022-3263(98)00269-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/05/1998

Notes
J . Org. Chem., Vol. 63, No. 13, 1998 4533
Sch em e 2
from the thiolane ring. Attack of the si face of the ylide
4a would be preferred; the re face is indeed hindered by
the methyl group cis to the benzylidene group.
A
classical 109° approach of the aldehyde, leading to the
trans epoxide, avoids the gauche interaction between the
ylide and aldehyde phenyl groups. This model results
in the formation of the trans (S,S) enantiomer, as
observed experimentally. It contrasts with the models
proposed by Solladie´-Cavallo13 and Dai18 with the attack
of the aldehyde carbonyl being respectively either or-
thogonal or opposite to ours to provide a coordination
with an oxygen atom absent in our inductor.
Ta ble 1. Asym m etr ic Syn th esis of Stilben e Oxid e 2a in
Va r iou s Solven ts w ith KOH
time
(days) (%)a
yield de (trans) ee (S,S)c
entry
solvent
(%)b
(%)d
The excellent data obtained in a mixture of tert-butyl
alcohol and water (9:1) for the synthesis of stilbene oxide
from benzaldehyde (Table 1, entry 2), in terms of yield
(92%) and de and ee values (86 and 88%), led us to prefer
this solvent for further investigations. The nature of the
base (KOH or NaOH) was shown to have no influence
on the yield and the stereocontrol. The epoxidation of
various aromatic aldehydes and an aliphatic one was
then achieved in 9:1 t-BuOH:H2O with NaOH, in 2 days
and in yields of about 90% (Table 2, Scheme 2). Trans
oxiranes 2 were formed with 85% de for aromatic alde-
hydes (entries 1-3), and the reduced diastereoselectivity
observed for an aliphatic aldehyde (entry 4) was not
unexpected according to recent studies.35 Enantioselec-
tivities from 86 to 94% were observed for the trans
isomers. Starting from cyclohexanecarboxaldehyde, we
were able to analyze the cis oxirane and measured a 82%
ee (entry 4).
1
2
3
4
5
9:1 CH3CN:H2O
9:1 t-BuOH:H2O
9:1 i-PrOH:H2O
9:1 EtOH:H2O
H2O
1
2
8
3
4
92
92
59
15
90
88
86
86
84
74
84
88
90
94
86
a
b
Yield after purification on a silica gel column. Diastereoiso-
meric excess determined on 1H NMR measurements from the
crude product. c The major enantiomer (S,S) is eluted first by
chiral HPLC.17 Enantiomeric excess determined by chiral HPLC
d
using a Chiralsep Chirose-Bond or OD column.
Sch em e 3. Asym m etr ic In d u ction Mod el
An attractive feature of this ylide chemistry is that the
initial sulfide is recovered after epoxidation and usable
in a catalytic amount.17-19 The feasibility of a catalytic
process was here demonstrated by the use of 0.1 equiv
of thiolane 1 for the epoxidation of benzaldehyde (1 equiv)
with benzyl bromide (2 equiv) in 9:1 t-BuOH:H2O with
NaOH. The reaction was slow as expected (1 month to
complete the reaction), but an excellent yield of 2a (94%)
was obtained, and de and ee values were maintained (85
and 90%). Thus the thiolane 1 is robust under the basic
conditions which we have used.
In conclusion, we have introduced a very simple sulfide
for the asymmetric ylide mediated epoxidation of carbo-
nyl compounds. Thiolane 1 is prepared in a straightfor-
ward manner (two steps) and in excellent yield. Attrac-
tive conditions have been found for a one-pot procedure,
potentially feasible for scaling up. They do not require
a strong base, anhydrous solvent, inert atmosphere,
preformation of the sulfonium salt,13,20 or harsh electro-
philes (phenyldiazomethane17 or triflates13). Our chiral
auxiliary, by its simplicity, efficiency, and robustness, is
thus attractive. In the category of one-pot procedures
using simple reagents,18,19 our procedure is excellent: for
stilbene oxide the yield is 92% and the ee 88% with a
sulfide prepared in two steps and 95% yield. The
opposite enantiomer of 1 appears accessible from the
known (2R,5R)-hexanediol.28,36,37 Extension of this reac-
selectivities. In more polar solvents (DMF, DMSO,
MeCN, alcohols) with powdered KOH, we observed
various predominant side reactions (Cannizzaro reaction,
benzyl bromide solvolysis, Williamson alkylation, solvent
reactivity). These could be largely avoided by the addi-
tion of 10% of water in the case of MeCN31 and t-BuOH;
under these conditions, stilbene oxide was obtained in
excellent yields, in 1 or 2 days at ambient temperature
(Table 1, entries 1-2). Very remarkable is our observa-
tion that this reaction could even be carried out in water
(Table 1, entry 5). In all cases, the trans isomer of
stilbene oxide 2a was formed preferentially and the major
enantiomer was identified17 by chiral HPLC as the trans-
(2S,3S)-diphenyloxirane. The best enantiomeric excesses
(from 84 to 94%) were achieved with MeCN:H2O, alcohol:
H2O, and H2O (Table 1).
The high asymmetric induction can be rationalized as
shown in Scheme 3. The C2 symmetry of 1 dictates the
formation of the single sulfonium salt 3 by reaction with
benzyl bromide. Deprotonation affords the ylide 4 with
a planar carbon and a tetrahedral sulfur, the sulfur
doublet lying in the plane of the ylide carbon substitu-
ents to avoid repulsive interaction with the carbanion
doublet.25,32-34 Out of two possible conformations (4a and
4b), the former is favored as the phenyl group is away
(33) Fava, A. Organic Sulfur Chemistry. Theoretical and Experi-
mental Advances; Bernardi, F., Csizmadia, I. G., Mangini, A., Eds.;
Elsevier: Amsterdam, 1985; pp 299-354.
(34) Aggarwal, V. K.; Schade, S.; Taylor, B. J . Chem. Soc., Perkin
Trans. 1 1997, 2811-2813.
(31) The reaction reported by Dai and Huang18 with a camphor-
derived sulfide in acetonitrile (from the bottle) could not be reproduced
unless we added a few percent of water.
(32) Wolfe, S. Organic Sulfur Chemistry. Theoretical and Experi-
mental Advances; Bernardi, F., Csizmadia, I. G., Mangini, A., Eds.;
Elsevier: Amsterdam, 1985; pp 133-190.
(35) Aggarwal, V. K.; Calamai, S.; Gair Ford, J . J . Chem. Soc., Perkin
Trans. 1 1997, 593-599.
(36) Kim, M.-J .; Lee, I. S.; J eong, N.; Choi, Y. K. J . Org. Chem. 1993,
58, 6483-6485.
(37) Nagai, H.; Morimoto, T.; Achiwa, K. Synlett 1994, 289-290.

4534 J . Org. Chem., Vol. 63, No. 13, 1998
Ta ble 2. Asym m etr ic Syn th esis of 1,2-Dia lk yloxir a n es 2 in 9:1 t-Bu OH:H2O w ith Na OH
Notes
entry
aldehyde
benzaldehyde
4-chlorobenzaldehyde
4-tolualdehyde
time (days)
oxirane
yield (%)a
de (trans) (%)b
ee (trans) (%)d
ee (cis) (%)d
1
2
3
4
2
2
2
2
2a
2b
2c
2d
92
89
88
87
86
84
84
30
88 (S,S)c
86 (S,S)c
88 (S,S)c
94
meso
e
e
82
cyclohexanecarboxaldehyde
a
Yield after purification on a silica gel column. b Diastereoisomeric excess determined on 1H NMR measurements from the crude product.
c The major enantiomer (S,S) is eluted first by chiral HPLC.17 Enantiomeric excess determined by chiral HPLC using a Chiralsep Chirose-
d
Bond or OD column. e The enantiomers could not be separated by chiral HPLC.
yellow liquid (3.28 g, 95%) was obtained with an unpleasant odor
(storing in the cold in a carefully closed vial and manipulation
under hood avoided any discomfort). It appeared unnecessary
to further purify (2R,5R)-2,5-dimethylthiolane 1. Bp12 ) 37 °C.
tion to a variety of substrates for alkylidenation, cyclo-
propanation, and aziridination will be reported in due
course.
[R]25 ) +119° (c ) 4,0; pentane). 1H NMR δ: 1.30 (d, J ) 6.5
D
Exp er im en ta l Section
Hz, 6H), 1.49-1.57 (m, 2H), 2.13-2.24 (m, 2H), 3.52-3.65 (m,
2H). 13C NMR δ: 22.8, 39.6, 44.5. HRMS: calcd for C6H12
116.06597, found 116.0659.
S
Preparative flash liquid chromatography was performed with
Merck 60 silica gel (63-200 µm) in the eluting solvents indicated
below. 1H NMR (250 MHz) spectra were recorded on a Bruker
AC 250 spectrometer. Data appear in the following order:
chemical shift in ppm, multiplicity (s, singlet; d, doublet; t,
triplet; q, quartet; m, multiplet), coupling constant in hertz,
number of protons, assignment. 13C NMR spectra were deter-
mined at 62.9 MHz with the same spectrometer, operating with
(2S,3S)-Dip h en yloxir a n e 2a . To a solution of (2R,5R)-
dimethylthiolane 1 (24 mg, 0.2 mmol) in a 9:1 mixture of tert-
butyl alcohol and water (0.8 mL) were added benzyl bromide
(48 µL, 0.4 mmol), benzaldehyde (20 µL, 0.2 mmol), and
powdered NaOH (16 mg, 0.4 mmol). The reaction mixture was
stirred for 2 days at room temperature. Water was added. The
aqueous phase was extracted with dichloromethane; the com-
bined organic layers were dried over MgSO4 and then concen-
trated to dryness. NMR analysis38 of the crude product revealed
a 93:7 trans:cis ratio. The crude product was submitted to
column chromatography (silica gel, 70:30 petroleum ether/
dichloromethane) to afford 36 mg of 2,3-diphenyloxirane 2a
(92%). HPLC analysis17 (OD column, 99:1 n-hexane/2-propanol)
showed that the product was a 94:6 ratio of (S,S):(R,R) enanti-
omers [retention times: 5.1 min for the meso oxirane, 6.5 for
the (S,S) enantiomer, and 10.0 for the (R,R) one].
1
broad band H decoupling. The solvent used is CDCl3, and TMS
is the internal standard. (2S,5S)-Hexane-2,5-diol is commer-
cially available (Aldrich) and was also prepared27 by baker’s
yeast reduction of 2,5-hexanedione.
(2R,5R)-2,5-Dim eth ylth iola n e (1). According to ref 30 a
solution of (2S,5S)-hexane-2,5-diol (3.5 g, 29.6 mmol), and
triethylamine (10 mL, 72 mmol) in dichloromethane (60 mL) was
cooled at -18 °C. Methanesulfonyl chloride (5 mL, 65 mmol)
was added dropwise while the temperature was maintained
between -20 and -15 °C. After addition the mixture was
allowed to warm to 0 °C. A 1 N HCl solution (10 mL) was added.
The extraction was carried out with dichloromethane (2 × 30
mL). The organic layer was separated, washed with a saturated
NaHCO3 aqueous solution (30 mL), and dried over MgSO4. After
filtration and evaporation of the solvent, a colorless oil of (1S,4S)-
4-methanesulfonyloxy-1-methylpentyl methanesulfonate was
obtained (8.2 g, quantitative yield). 1H NMR δ: 1.44 (d, J )
6.3 Hz, 6H), 1.75-1.84 (m, 4H), 3.02 (s, 6H), 4.84-4.90 (m, 2H).
13C NMR δ: 21.3, 32.1, 38.8, 78.9.
Sodium sulfide (Na2S‚9H2O, 14.4 g, 60 mmol) was added to a
solution of the preceding dimesylate (8.2 g, 29.6 mmol) in ethanol
(75 mL). The mixture was stirred at ambient temperature for
15 days. A milky suspension of sodium methanesulfonate was
formed. It was poured into water (50 mL) and extracted with
pentane (4 × 25 mL). The combined organic phase was washed
with brine (2 × 50 mL) and dried over MgSO4. After filtration,
pentane was evaporated with the evaporator water bath being
kept at 0 °C to avoid any loss of the volatile thiolane 1. A pale
Oxir a n es 2b-d . They are known compounds whose struc-
tures (trans and cis) were assigned by comparison with the
literature spectroscopic data.38
Ack n ow led gm en t. We thank CNRS and Rhoˆne
Poulenc for their generous support of this study.
Su p p or t in g In for m a t ion Ava ila b le: Chromatographic
analysis of the enantiomers of epoxides 2a -d (6 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
J O980269P
(38) Aggarwal, V. K.; Abdel-Rahman, H.; Fan, L.; J ones, R. V. H.;
Standen, M. C. H. Chem. Eur. J . 1996, 2, 1024-1030.