Molar scale synthesis of enantiopure stilbene oxide

Full text of DOI:10.1021/jo960718q

6456
J . Org. Chem. 1996, 61, 6456-6457
Sch em e 1
Mola r Sca le Syn th esis of En a n tiop u r e
Stilben e Oxid e
Han-Ting Chang and K. Barry Sharpless*
Department of Chemistry, The Scripps Research Institute,
10666 N. Torrey Pines Road, La J olla, California 92037
Received April 18, 1996
The enantiomerically pure stilbene oxides (R,R and
S,S) are useful precursors to the various heterosubsti-
tuted stilbene derivatives1 which have found uses as
chiral ligands,2 chiral building blocks,3 and chiral aux-
iliaries.4 Previous methods of preparation of enantio-
merically enriched stilbene oxide include catalytic epoxi-
dation of stilbene by chiral manganese and chromium
salen complexes,5 epoxidation of stilbene with chiral
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sulfonyloxaziridines or with chiral perborates,6 condensa-
tion of benzaldehyde with chiral sulfonium and arsonium
ylides,7 and several enzymatic kinetic resolutions of
appropriate racemic precursors.8 Each of these methods
was only described on a small scale and most of them
also gave modest enantioselectivities. In our continuing
efforts to develop practical applications for the asym-
metric dihydroxylation (AD) of olefins,9 we report here a
1 mol scale synthesis of enantiomerically pure (R,R)-
stilbene oxide (3) from (R,R)-hydrobenzoin (1). The latter
is readily available by AD of stilbene in a process
described on a 1 kg scale and needing only a 5-L reaction
vessel.10
The conversion of diol 1 to epoxide 3 is achieved in two
simple steps: first, the cyclic carbonate 2 is prepared by
transesterification with dimethyl carbonate; and second,
LiCl catalyzes nucleophilic opening of carbonate 2 to give
an intermediate which collapses to epoxide 3 with loss
of CO2. Both steps are very easy to perform and neither
involves extraction or chromatography.
The efficient large-scale formation of cyclic carbonate
2 relies on NaOH-catalyzed transesterification of hy-
drobenzoin by dimethyl carbonate with distillative re-
moval of the methanol produced.11 The workup proce-
dure simply requires dilution with THF, filtration through
Celite to remove the solids, and concentration. Carbon-
ate 2 was both chemically and enantiomerically pure by
1H NMR and HPLC, respectively, and was subjected
directly to epoxide formation.
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1994, 94, 2483.
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Hampton, A.; Nichol, A. W. Biochemistry 1966, 5, 2076. (c) Chang, H.-
T.; Sharpless, K. B. Tetrahedron Lett. 1996, 37, 3219.
(5) (a) Zhang,W.; Loebach, J . L.; Wilson, S. R.; J acobsen, E. N. J .
Am. Chem. Soc. 1990, 112, 2801. (b) Hatayama, A.; Hosoya, N.; Irie,
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A.; Yanai, K.; Fujii, H.; Irie, R.; Katsuki, T. Synlett, 1993, 641. (d)
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Tetrahedron 1994, 50, 11827. (g) Chang, S.; Galvin, J . M.; J acobsen,
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S0022-3263(96)00718-9 CCC: $12.00 © 1996 American Chemical Society

Notes
In our previous study on the nucleophilic opening of
J . Org. Chem., Vol. 61, No. 18, 1996 6457
Å molcular sieves, LiCl (Aldrich) was dried in a vacuum oven
at 150 °C overnight before use. Other reagents were purchased
from commercial sources and used without further purification.
1H and 13C NMR spectra were recorded in CDCl3 at 400 and
100 MHz, respectively. Melting points are uncorrected. Infrared
spectra were recorded using KBr pellets. Enantiomeric excesses
were determined by HPLC on Chiralcel AS and OD-H columns
(25 cm length × 4.6 mm i.d.).
(+)-(R,R)-1,2-Dip h en yleth ylen e Ca r bon a te (2). A 500 mL
flask, fitted with a distillation apparatus and a magnetic stir
bar, was charged with (R,R)-hydrobenzoin 1 (214 g, 1 mol),
catalytic NaOH (3 g, pellets) and 300 mL of dimethyl carbonate.
While being stirred under nitrogen, this solution was heated to
60 °C for 0.5 h and then the bath temperature was raised to 90
°C, whereupon distillative removal of a mixture of methanol and
dimethyl carbonate began and was continued until ca. 200-250
mL of distillate was collected. The remaining suspension was
diluted with 200 mL of THF, filtered through Celite, and
concentrated to dryness, leaving 240 g (quantitative yield) of the
crude carbonate 2, which was used directly in the next step.
[Crude 2 is a solid and may be recrystallized from methanol (1
g/2 mL) to give white crystalline 2, mp 110-112 °C]: 1H NMR
δ 5.44 (s, 2H), 7.30-7.33 (m, 4H), 7.43-7.45 (m, 6H); 13C NMR
δ 85.35, 126.05, 129.20, 129.73, 134.70; IR (KBr): 1810, 1275,
1167, 1034 cm-1; MS FAB calcd for C15H12O3 (M+ + H) 241,
found 241; mp 110-112 °C; [R]D +286° (c 1.0, EtOH); >99% ee
(Chiralcel AS, 10% i-PrOH/hexane, 0.5 mL/min; 22.9, 26.5).
cyclic carbonates for the synthesis of 1,2-amino alcohols,11c
epoxide is the predominant byproduct under anhydrous
conditions. This observation indicates that, especially in
the absence of a proton source, the intermediate azido
carbonate salt can extrude CO2 and azide, leading to
formation of the epoxide. Indeed, Shapiro reported in
1969 that ethylene oxide is obtained by pyrolysis of
ethylene carbonate in the presence of alkali metal
halides,12 and several Texaco patents have reported that
monosubstituted ethylene carbonates, such as propylene
carbonate, undergo the analogous transformation.13 Here,
we have extended this methodology to show that the
process can be stereoselective (i.e. threo-carbonate 2 gives
threo-epoxide 3).
In contrast to the high temperatures (>200 °C) em-
ployed in the earlier pyrolysis,12,13 we have found that
use of DMF as solvent facilitates the reaction, so that
useful rates are achieved in the 130-155 °C temperature
range. In a typical reaction, carbonate 2 was treated
with 5% of dry LiCl in refluxing DMF for 7 to 8 h.
Lithium chloride is a better catalyst than LiBr or Et4NCl,
which gave more byproducts. Sodium chloride, KCl, and
LiF were almost inactive as catalysts (<5% conversion).
The effect of water is notable in that reactions using the
commercial ACS grade DMF (which contains e0.15%
water) were ca. 3 times slower than those using the
commercial anhydrous DMF (which contains e0.005%
water). During the course of a 1 mol scale reaction, the
enantiomeric excess of the crude stilbene oxide (3)
dropped to 97%, whereas early in the reaction epoxide 3
was present in >99% ee. This slight epimerization is
thought to result from Lewis acid-catalyzed processes
involving the meso-epoxide.14a In addition, deoxybenzoin,
a major byproduct from the LiCl-catalyzed rearrange-
ment of 3,15 is produced rapidly after the starting
carbonate 2 has been consumed. The workup procedure
consists simply of removal of excess DMF followed by
filtration to give the crude epoxide 3 in 98% yield (97%
ee). After one recrystallization from hot MeOH (1 g/1
mL), the pure product was obtained in 77% overall yield
(151 g, >99.5% ee). Two further recrystallizations of the
mother liquor from methanol gave an additional 13.5 g
of enantiopure 3, for a combined yield of 84%.
(+)-(R,R)-Stilben e Oxid e (3). A 500 mL flask, equipped
with a condenser and a magnetic stir bar (all equipment oven
dried), was charged with (+)-(R,R)-1,2-diphenylethylene carbon-
ate 2 (240 g, 1 mol), predried LiCl (2.12 g, 0.05 mol), and 250
mL of anhydrous DMF (stored over 3 Å molecular sieves). The
mixture was refluxed under nitrogen in an oil bath for 7 h. It
is important to monitor the reaction carefully since the desired
epoxide starts to decompose rapidly when all the carbonate
starting material is consumed.14 A vacuum distillation ap-
paratus is then used for removal of the DMF under reduced
pressure (ca. 20 mmHg) at a bath temperature of ca. 50 °C. The
oily residue was diluted with 400 mL of EtOAc and filtered
through a 1 in. pad of silica gel16 topped by 0.5 in. of Celite (in
a 2.5 in. diameter sintered-glass funnel) and concentrated to
afford 202 g (theory ) 196 g) of crude epoxide 3 as a solid (ca.
97% ee). Recrystallization of crude 3 from hot methanol (1 g/mL)
gave 151 g (>99.5% ee, 77% yield)17 and 48.75 g (84% ee) from
the concentrated mother liquor. The 84% ee material was
recrystallized again from methanol to give 23.2 g (94% ee).
Another recrystallization of the preceding 23.2 g gave 13.5 g
(>99.5% ee, 7% yield). This 13.5 g sample was combined with
the original 151 g to give 164.5 g (84% overall yield from the
diol (1), >99.5% ee): 1H NMR δ 3.87 (s, 2H), 7.15-7.37 (m, 10H);
13C NMR: δ 62.83, 125.54, 128.30, 128.55, 137.08; IR (KBr):
In conclusion, we have developed a practical synthesis
of enantiomerically pure stilbene oxide. This simple
preparation should make the useful derivatives of 3 more
available. Only the (R,R)-epoxide is described here, but
the (S,S)-epoxide is of course equally accessible from the
(S,S)-diol.10
1455, 1283, 866, 847, 837, 695 cm-1; MS FAB calcd for C14H12
O
(M+ + H) 197, found 197; mp 68-69 °C;18 [R]D +361° (c 2.05,
PhH) [lit.18 mp 69 °C, [R]D +374° (c 0.5, PhH)]; >99% ee
(Chiralcel OD-H, 10% i-PrOH/hexane, 0.5 mL/min; 11.3, 18.1).
Exp er im en ta l Section
Gen er a l. (R,R)-hydrobenzoin was prepared by AD as de-
scribed earlier.10 Anhydrous DMF (Aldrich) was stored over 3
Ack n ow led gm en t. We thank the National Insti-
tutes of Health (GM 28384) and the W. M. Keck
Foundation for financial support.
(12) Shapiro, A. L.; Leven, S. Z.; Chekhovskaya, V. P. Zh. Org. Kh.
1969, 5, 207; J . Org. Chem. USSR, 1969, 5, 200.
(13) McEntire, E. E.; Gipson, R. M. US Patent 4 265 821, 1981; UK
Patent GB 2 092 126 A, 1981; US Patent 4 371 704, 1983.
(14) (a) The following control experiment was performed: a sample
of stilbene oxide (3) (99% ee) was subjected to the reaction conditions
overnight, whereupon ca. 90% of the epoxide had rearranged to
deoxybenzoin, the major byproduct in the actual process. The enan-
tiopurity of recovered 3 was reduced to 75% ee, and traces of the meso-
epoxide and diphenylacetaldehyde were also detected. (b) We find that
it is best to monitor the reaction by 1H NMR. Since the DMF
resonances do not interfere with the carbonate and epoxide methine
resonances, a ca. one drop aliquot is added directly to the NMR tube
followed by CDCl3. The reaction should be stopped when the epoxide
to carbonate ratio is about 20:1.
J O960718Q
(16) This silica gel filtration is very important. It removes the LiCl
which otherwise causes decomposition of the epoxide during recrys-
tallization from boiling MeOH.
(17) The recrystallization is performed in an Erlenmeyer flask with
a magnetic stir bar. The epoxide is added followed by the appropriate
volume of MeOH and the mixture is heated to boiling while being
stirred. The hot solution is then allowed to cool gradually to room
temperature and the crystalline product is collected by filtration.
(18) Epoxide 3 appears to be a racemic compound for which the
enantiopure substance and the racemate have coincidentally the same
melting point. Read, J .; Campbell, I. G. M. J . Chem. Soc. 1930, 2377.
(15) (a) Parker, R. E.; Isaacs, N. S. Chem. Rev. 1959, 737. (b) Pocker,
Y.; Ronald, B. P. J . Am. Chem. Soc. 1970, 92, 3385.