related compounds, trimethylsilyl derivatives, do not. Tri-
methoxysilyl enol ethers,8 which are easily prepared from
the corresponding lithium enolate with chlorotrimethoxysi-
lane9 or enone with trimethoxysilane, are so stable that they
survive the aqueous workup or silica gel column chroma-
tography. However, examples of base-catalyzed aldol reac-
tions of trimethoxysilyl enol ether have yet to be reported
and the reactivity of hypervalent silicate derived from the
trimethoxysilyl enol ether remains unknown. In our pursuit
of developing base-mediated reactions involving hypervalent
silicate,5,10 we investigated the enantioselective aldol reaction
of trimethoxysilyl enol ethers catalyzed by Lewis bases.
Table 1. Effect of Water as an Additive in Enantioselective
Aldol Reaction of Trimethoxysilyl Enol Ether
entry H2O (equiv) yield, %a syn:antib ee, % (syn, anti)b
1
2
3
4
5
0
97
93
97
93
94
1:3.7
1:1.1
1.7:1
3.2:1
3.1:1
8, 51
15, 46
60, 44
77, 52
80, 50
0.1
0.5
1.0
1.5
Our initial studies examined the addition of trimethoxysilyl
enol ether 2a derived from cyclohexanone (1.5 equiv) to
benzaldehyde using a variety of bases (10 mol %) in THF.
Among the various chiral bases surveyed, the corresponding
aldol adduct was obtained in high yield (98%) by employing
10 mol % lithium binaphtholate11 as a catalyst, which was
prepared in situ from the corresponding binaphthol and BuLi,
but diastereo- and enantioselectivity were not observed or
were barely observed. Screening binaphthol derivatives
revealed that the dilithium salt of 3,3′-dibromobinaphthol (1)
predominantly gave the anti adduct in high yield (97%, syn:
anti ) 1:3.7), with moderate enantioselectivity (8% ee (syn),
51% ee (anti)).12 When optimizing the reaction conditions,
we were surprised to find that adding water (1.5 equiv to
aldehyde, i.e., 1.0 equiv to silyl enol ether) as an additive
predominantly resulted in the syn adduct (syn:anti ) 3.2:1)
and dramatically increased the ee of the syn adduct (80% ee
(syn), 51% ee (anti))13-15 Stoichiometric studies revealed that
equimolar amounts of water to silyl enol ether were sufficient
a Combined isolated yield. b Determined by HPLC (Daicel chiralcel OD-
H).
to optimize diastereo- and enantioselectivity (Table 1), which
suggests that water (or hydroxy ion) may strongly coordinate
to the silicon atom of silyl enol ether. The trimethoxysilyl
enol ether, which is stable under anhydrous conditions even
in the presence of lithium binaphtholate, quickly decomposed
to the corresponding ketone in aqueous solutions in the
presence of lithium binaphtholate. This suggests that the
coordination of water (or hydroxy ion) to silicon atom may
increase the nucleophilicity of the silicate complex to afford
the syn adduct predominantly via an acyclic transition state,
while under anhydrous conditions the reaction proceeds via
a cyclic chairlike transition state4,5 to predominantly yield
the anti adduct, although the details are unclear.
(5) Nakajima, M.; Yokota, T.; Saito, M.; Hashimoto, S. Tetrahedron Lett.
2004, 45, 61-64.
(6) Chuit, C.; Corriu, R. J. P.; Reye, C.; Young, J. C. Chem. ReV. 1993,
93, 1371-1448.
(7) (a) Schiffers, R.; Kagan, H. B. Synlett 1997, 1175-1178. (b)
Yanagisawa, A.; Kageyama, H.; Nakatsuka, Y.; Asakawa, K.; Matsumoto,
Y.; Yamamoto, H. Angew. Chem., Int. Ed. 1999, 38, 3701-3703. (c)
Yamasaki, S.; Fujii, K.; Wada, R.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 2002, 124, 6536-6537. (d) Aoyama, N.; Hamada, T.; Manabe, K.;
Kobayashi, S. Chem. Commun. 2003, 676-677.
Table 2 shows select results of the aldol reaction of
trimethoxysilyl enol ethers with benzaldehyde under hydrous
conditions. (E)-Enolates (entries 1, 2) and enolate without
substituents on the R-position (entry 3) gave good results,
while (Z)-enolate afforded low diastereo- and enantioselec-
tivities (entry 4). Triethoxysilyl enol ether18 gave similar
selectivities, though the reaction proceeded slowly (entry 5).
The aldol reactions of other aldehydes with 2a or 2c were
investigated (Table 3). The reaction of aliphatic aldehydes
proceeded smoothly with high enantioselectivities of over
90% ee, although the diastereoselectivities decreased (entries
3-5). The best enantioselectivity (97% ee) was obtained for
the reaction of cyclohexanecarboxaldehyde (entry 4). It is
noteworthy that the aldol reaction of aliphatic aldehydes,
which often gives inferior results under Lewis base-catalyzed
(8) Yamamoto has reported an aldol reaction of trimethoxysilyl enol ether
catalyzed by Lewis acid.7b
(9) Corriu, R. J. P.; Moreau, J. J. E.; Thepot, P.; Man, M. W. C. Chem.
Mater. 1992, 4, 1217-1224.
(10) (a) Nakajima, M.; Saito, M.; Shiro, M.; Hashimoto, S. J. Am. Chem.
Soc. 1998, 120, 6419-6420. (b) Nakajima, M.; Saito, M.; Uemura, M.;
Hashimoto, S. Tetrahedron Lett. 2002, 43, 8827-8829.
(11) Kagan reported an enantioselective reduction of ketones with
trimethoxysilane catalyzed by lithium binaphtholate.7a
(12) Monolithium salt of 3,3′-dibromobinaphthol gave syn adduct
predominantly in moderate yield (42%, syn:anti ) 1.8:1) with low
enantioselectivity (27% ee (syn), 14% ee (anti)).
(13) Experimental Procedure. To a solution of 3,3′-dibromobinaphthol
(21 mg, 0.047 mmol) in THF (3 mL) was added H2O (5% sol in THF, 0.26
mL, 0.70 mmol) and BuLi (0.19 M in hexane, 0.54 mL, 0.094 mmol) at
-23 °C under an Ar atmosphere, and the mixture was stirred for 5 min.
Benzaldehyde (10% sol in THF, 0.50 mL, 0.47 mmol) and trimethoxysilyl
enol ether 2a (0.15 mL, 0.70 mmol) were successively added to the resulting
yellow solution, and the mixture was stirred for 30 min. The reaction was
quenched with KF/KH2PO4 buffer, and entire mixture was extracted with
EtOAc. The organic layer was washed with brine and dried over Na2SO4.
Evaporation followed by SiO2 column chromatography afforded the
corresponding aldol adduct (90 mg, 94%) as a mixture of diastereomers.
(14) Initial product under anhydrous conditions is the silyl ether of the
corresponding aldol adduct, whereas silyl ether was not observed under
aqueous conditions. The reaction with 0.5 equiv (to silyl enol ether) of
water gave a 1:1 mixture of the silyl ether and the alcohol.
(15) Among various binaphthol derivatives screened, the 3,3′-dibromo
derivative gave the best result. R on 3,3′-position, % yield, syn:anti, % ee
(syn,anti): R ) H, 76, 1.2:1, (24, 5); R ) Me, 98, 2.3:1, (55, 15); R )
CO2Me, 76, 1:1.1, (17, 46); R ) CF3,16 95, 2.6:1, (69, 38); R ) Cl, 98,
3.0:1, (78, 48); R ) I, 98, 2.9:1, (73, 35).
3764
Org. Lett., Vol. 6, No. 21, 2004