Denmark et al.
control the stereochemical outcome.9,10 High diastereo-
selectivities have been obtained in the additions of achiral
enolates to chiral ketones bearing an R-sulfinyl9a or car-
bohydrate auxiliary.10d Significant progress has also been
made in the development of various chiral enolates for
the aldol addition to ketones. Excellent diastereoselec-
tivities are observed in the additions of in-situ generated,
chiral, titanium or zinc enolates to achiral ketones.10b-e
Recently, the use of chiral amino alcohol additives has
reported for stereocontrol in Reformatsky-type reac-
tions.11 Through large-scale screening, Ojida and co-
workers discovered that cinchonin is highly effective in
controlling the stereochemical outcome of Reformatsky-
type reactions with heteroaromatic ketones.11c
SCHEME 1
were to explore the scope of this reaction with regard to
ketone partners and to design highly selective chiral
Lewis base catalysts for this process. This report details
in full our investigations of both the catalyzed and
uncatalyzed additions of methyl trichlorosilyl ketene
acetal to ketones.13
Results
1. Synthesis of Methyl Trichlorosilyl Ketene
Acetal. Burlachenko and co-workers first described the
preparation of methyl trichlorosilyl ketene acetal 1 by
transmetalation of R-stannyl ester 4 with SiCl4 (Scheme
2).14 In Burlachenko’s original report, stannyl ester 4 was
obtained in low yield after fractional distillation at high
temperature. A modification developed in these labora-
tories improved the preparation of the stannyl ester 4
and the procedure for the metathesis reaction.12 The new
procedure afforded 4 in higher yield and purity through
purification by preparative HPLC.
Background
In recent years, we have been engaged in the develop-
ment of catalytic asymmetric aldol addition reactions
through application of Lewis base catalysis. In these
reactions, chiral Lewis base activators promote the
addition of enoxytrichlorosilane reagents derived from
aldehydes, ketones, and esters to a wide variety of
aldehydes with high diastereo- and enantioselectivity.
Although ketone- and aldehyde-derived enoxytrichlorosi-
lanes do not react with ketones, the trichlorosilyl ketene
acetal of methyl acetate 1 was shown to be sufficiently
reactive in early studies of this aldol process.12 Silyl
ketene acetal 1 reacts slowly with acetophenone 2a at
room temperature, but in the presence of a catalytic
amount of HMPA, a rapid addition takes place affording
a high yield of aldol product 3a (Scheme 1). This
preliminaryresult showed that additions of 1 to ketones
were thermodynamically favorable and also susceptible
to Lewis base catalysis.
SCHEME 2
It was subsequently discovered, however, that the
transmetalation step was not reproducible using the
material purified by preparative HPLC. Depending on
the batch, the complete consumption of 4 required hours
to days. When 4 was further purified by vacuum distil-
lation after column chromatography, the transmetalation
proceeded to only 60% conversion even after 3 days.
We surmised that the decrease in the reaction rate
with highly purified materials was likely the result of
removing a catalytically active contaminant. To identify
that component, the impurities removed during purifica-
tion were subject to closer examination. A small amount
of tributyltin methoxide was isolated from one run, and
its influence on the reaction rate of transmetalation was
investigated. In the presence of 5 mol % of this agent,
the exchange was complete within minutes. Unfortu-
nately, this reagent also caused the rapid decomposition
of 1.
We next investigated the use of a hindered tin oxide
and selected commercially available and inexpensive bis-
(tributyltin) oxide. Gratifyingly, as little as 10 mol % of
(Bu3Sn)2O was found to significantly accelerate the
transmetalation without destroying the product (Scheme
3). The reaction was reproducibly complete within 4 h,
and the trichlorosilyl ketene acetal 1 was obtained in
consistently higher yields (74-82%).
We therefore embarked on a program to develop a
general catalytic, enantioselective method for aldol ad-
ditions to ketones with 1. The primary goals of this study
(7) (a) Evans, D. A.; Burgey, C. S.; Kozlowski, M. C.; Tregay, S. W.
J. Am. Chem. Soc. 1999, 121, 686-699. (b) Evans, D. A.; Kozlowski,
M. C.; Burgey, C. S.; MacMillan, D. W. C. J. Am. Chem. Soc. 1997,
119, 7893-7894.
(8) Shibasaki has recently described a catalytic aldol addition of
trialkylsilyl ketene acetals to ketones. One example of an enantiose-
lective addition to 3-pentanone was reported. Oisaki, K.; Suto, Y.;
Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 5644-5.
(9) For additions of achiral enolates to ketones with chiral auxilia-
ries, see: (a) Ruano, J. L. G.; Barros, D.; Carmen Maestro, M.; Slawin,
A. M. Z.; Bulman, P. C. J. Org. Chem. 2000, 65, 6027-6034. (b)
Mioskowski, C.; Solladie, G. Tetrahedron 1980, 36, 227-237. (c) Ojima,
I.; Yoshida, K.; Inaba, S.-i. Chem. Lett. 1977, 429-432. (d) Akiyama,
T.; Ishikawa, K.; Ozaki, S. Synlett 1994, 275-276. (e) Sakito, Y.; Asami,
M.; Mukaiyama, T. Chem. Lett. 1980, 455-457. (f) Reetz, M. T.;
Hullmann, M. J. Chem. Soc., Chem. Commun. 1986, 1600-1602. (g)
Guanti, G.; Riva, R. Tetrahedron Lett. 1995, 36, 3933-3936.
(10) For additions of chiral enolates to ketones, see: (a) Bartroli,
J.; Turmo, E.; Belloc, J.; Forn, J. J. Org. Chem. 1995, 60, 3000-3012.
(b) Judge, T. M. et al. J. Am. Chem. Soc. 1997, 119, 3627-3628. (c)
Takagi, R.; Kimura, J.; Shinohara, Y.; Ohba, Y.; Takezono, K.; Hiraga,
Y.; Kojima, S.; Ohkata, K. J. Chem. Soc., Perkin Trans. 1 1998, 689-
699. (d) Jacobson, I. C.; Reddy, G. P. Tetrahedron Lett. 1996, 37, 8263-
8267. (e) Basavaiah, D.; Bharathi, T. K. Tetrahedron Lett. 1991, 32,
3417-3420. (f) Soloshonok, V. A.; Avilov, D. V.; Kukhar, V. P.
Tetrahedron 1996, 52, 12433-12442.
(11) For chiral amino alcohol mediated enantioselective Refor-
matsky-type reactions with ketones, see: (a) Soai, K.; Oshio, A.; Saito,
T. J. Chem. Soc., Chem. Commun. 1993, 811-812. (b) Andre´s, J. M.;
Mart´ın, Y.; Pedrosa, R.; Pe´rez-Encabo, A. Tetrahedron 1997, 53, 3787-
3794. (c) Ojida, A.; Yamano, T.; Taya, N.; Tasaka, A. Org. Lett. 2002,
4, 3051-3054.
(13) A preliminary account of this work has already appeared.
Denmark, S. E.; Fan, Y. J. Am. Chem. Soc. 2002, 124, 4233-4235.
(14) Burlachenko, G. S.; Khasapov, B. N.; Petrovskaya, L. I.; Baukov,
Y. I.; Lutsenko, I. F. J. Gen. Chem. USSR (Engl. Transl.) 1966, 36,
532-536.
(12) Denmark, S. E.; Winter, S. B. D.; Su, X.; Wong, K.-T. J. Am.
Chem. Soc. 1996, 118, 7404-7405.
5236 J. Org. Chem., Vol. 70, No. 13, 2005