Enantioselective reduction of α,β-unsaturated acylsilanes by chiral lithium amides

Article abstract of DOI:10.1021/ol990574c

(equation presented) Reaction of β-substituted acryloylsilanes I with lithium amides II affords α-silyl allylic alcohols III in high enantiomeric excess (>99percent) via formal hydride transfer from the chiral lithium amide.

Full text of DOI:10.1021/ol990574c

ORGANIC
LETTERS
1999
Vol. 1, No. 2
237-239
Enantioselective Reduction of
r,â-Unsaturated Acylsilanes by Chiral
Lithium Amides
Kei Takeda,* Yuji Ohnishi, and Toru Koizumi
Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical UniVersity,
2630 Sugitani, Toyama 930-0194, Japan
takedak@ms.toyama-mpu.ac.jp
Received April 9, 1999
ABSTRACT
Reaction of â-substituted acryloylsilanes I with lithium amides II affords r-silyl allylic alcohols III in high enantiomeric excess (>99%) via
formal hydride transfer from the chiral lithium amide.
During our investigation of the mechanism of the Brook
rearrangement-mediated [3 + 4] annulation,1 we observed
that treatment of R-silyl-γ-keto alcohol 1 with LDA (1 equiv)
afforded R-silyl alcohol 2 in 16% yield in addition to
cycloheptenone 4 (37%) and 3-nonen-2-one (3) (36%).2 The
formation of 2 suggests that reduction of acryloylsilane 5, a
retro aldol product, by LDA via the hydride transfer of the
Meerwein-Ponndorf-Verley type occurred at -80 °C.
agent has attracted far less attention, and there has been no
report concerning the reduction of R,â-unsaturated acyl-
silanes by LDA. Therefore, we first examined the reduction
of acylsilanes by LDA. When acryloylsilanes 64 were treated
with 1 equiv of LDA in THF at -80 °C for 30-60 min, the
corresponding R-silyl alcohols 7 were obtained in yields
depending on the â-substituent. Thus, the substrates bearing
no γ-hydrogen being abstracted afforded better yields of 7
(Table 1, entries 5-9), whereas in the case of the substrate
with γ-hydrogen, significant amounts of the starting acry-
loylsilane were recovered, suggesting the competitive forma-
tion of dienolate in the latter cases.5
Scheme 1
On the basis of the above result, we envisioned that the
use of lithium amide of chiral secondary amines instead of
LDA would offer the possibility of enantioselective reduc-
tion. To the best of our knowledge, there are only two reports
(2) Takeda, K.; Nakajima, A.; Takeda, M.; Okamoto, Y.; Sato, T.; Yoshii,
E.; Koizumi, T.; Shiro, M. J. Am. Chem. Soc. 1998, 120, 4947-4959.
(3) For a review of reduction with lithium dialkylamides including LDA,
see: Majewski, M.; Gleave, D. M. J. Organomet. Chem. 1994, 470, 1-16.
(4) Compounds 6a-e and 6f-j were prepared according to the methods
of Danheiser and Reich, respectively. (a) Danheiser, R. L.; Nowick, J. S.
J. Org. Chem. 1989, 54, 2798-2802. (b) Reich, H. J.; Kelly, M. J.; Olson,
R. E.; Holtan, R. C. Tetrahedron 1983, 39, 949-960.
(5) The formation of 1,2- and/or 1,4-adducts of the amide to the R,â-
unsaturated acylsilanes leading to the recovery of the starting material cannot
be ruled out. (a) Kowalski, C.; Creary, X.; Rollin, A. J.; Burke, M. C. J.
Org. Chem. 1978, 43, 2601-2608. (b) Herrmann, J. L.; Kieczykowski, G.
R.; Schlessinger, R. H. Tetrahedron Lett. 1973, 2433-2436.
Although there have been reports about the reduction of
a carbonyl group by LDA,3 the ability of LDA as a reducing
(1) Takeda, K.; Takeda, M.; Nakajima, A.; Yoshii, E. J. Am. Chem. Soc.
1995, 117, 6400-6401.
10.1021/ol990574c CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/29/1999

Table 1. Reduction of Acryloylsilanes with LDA
Table 2. Enantioselective Reduction of 6e
a Sixty-three percent of 6e was recovered. b The enantiomeric purity was
determined by chiral HPLC assay (Daicel Chiralcel-OD).
Trost11 using O-methylmandelate and the modified Mosher
method.12 Changes in the solvent from THF to THF-HMPA
(3 equiv) or toluene caused a decrease in chemical yield and/
or ee.
Encouraged by these results, we examined the enantio-
selective reduction of some R,â-unsaturated acylsilanes,
including cycloalkenylcarbonylsilanes, by 12. The results are
summarized in Table 3. Although the chemical yield
in the literature about the enantioselective reduction of a
carbonyl group via formal hydride transfer from chiral
lithium amides. In 1969 Wittig and Thiele reported the
enantioselective reduction of phenyl R-naphthyl ketone by
lithium (R)-(-)-R-phenylethylanilide to give the correspond-
ing alcohol in 25% yield with an ee less than 60%.6 Cervinka
and co-workers used (S)-(+)-2-methylpiperidine as a chiral
source in the reaction with diaryl ketones with little success.7
Since R-hydroxysilanes have shown promise as versatile
synthons for synthetically useful transformations, the genera-
tion of such species in enantiomerically pure form would
be desirable.8,9
Table 3. Enantioselective Reduction of R,â-Unsaturated
Acylsilanes 6
We first examined the enantioselective reduction by known
lithium amides 8-1210 (Figure 1) using 6e as a substrate
a The absolute configuration was assigned by analogy with 13. b The
enantiomeric purity was determined by chiral HPLC assay (Daicel Chiralcel-
OD and Chiralcel-OJ). c The enantiomeric purity was determined by 1H
NMR spectra after conversion into the corresponding Mosher’s esters.
diminished upon the presence of an abstractable γ-hydrogen,
as was the case for LDA, R-silyl alcohol 14 was obtained in
Figure 1.
(Table 2). Among the five lithium amides that were
examined, 12 gave the best result in terms of chemical and
optical yields; that is, the reaction proceeded smoothly to
give alcohol 13 with excellent optical purity. Assignment
of absolute configuration of 13 was made by the method of
(8) For asymmetric reduction of acylsilanes, see the following. Microbial
reduction: (a) Linderman, R. J.; Ghannam, A.; Badej, I. J. Org. Chem.
1991, 56, 5213-5216. (b) Tacke, R. In Organosilicon and Bioorganosilicon
Chemistry; Sakurai, H., Ed.; Ellis Horwood: New York, 1985; pp 252-
262. Use of chiral borans: (c) Buynak, J. D.; Stickland, J. B.; Hurd, T.;
Phan, A. J. Chem. Soc., Chem. Commun. 1989, 89-90. (d) Buynak, J. D.;
Zhang, H.; Strickland, J. B.; Lamb, G. W.; Khasnis, D.; Modi, S.; Williams,
D. J. Org. Chem. 1991, 56, 7076-7083. (e) Soderquist, J. A.; Anderson,
C. L.; Miranda, E. L.; Rivera, I.; Kabalka, G. W. Tetrahedron Lett. 1990,
31, 4677-4680. Also, see: (f) Cirillo, P. F.; Panek, J. S. Org. Prep. Proced.
Int. 1992, 24, 553-582.
(6) Wittig, G.; Thiele, U. Liebigs Ann. Chem. 1969, 726, 1-12.
(7) Cervinka, O.; Dudek, V.; Scholzova, I. Collect. Czech. Chem.
Commun. 1978, 43, 1091-1092.
238
Org. Lett., Vol. 1, No. 2, 1999

excellent optical yield. Unfortunately, â-silyl derivatives 6f-i
produced a complex mixture in sharp contrast to the case of
LDA. Elevated reaction temperatures and/or longer reaction
times resulted in the Brook rearrangement and in some cases
was followed by allylic rearrangement of the generated
carbanion.
This method could be applied to benzoylsilanes 15a,b and
nonenolizable phenyl ketones 15c,d, albeit in lower chemical
and optical yields (Table 4).
In conclusion, we have found that the lithium amide of
chiral secondary amines can serve as the chiral source in
the enantioselective reduction of a carbonyl group, especially
R,â-unsaturated acylsilanes. In this method, R-silyl alcohols
can be obtained in an optically pure form. Although the
chemical yield is not good, the R-silyl alcohol is the only
product and it can be easily separated from the recovered
acylsilanes. Investigation of the potential application, espe-
cially the use of acryloylsilanes as a chiral homoenolate
equivalent using a tandem reaction sequence involving
enantioselective reduction, and Brook and allylic rearrange-
ments is underway.
Table 4. Enantioselective Reduction of Benzoylsilanes and
Phenyl Ketones
Acknowledgment. This research was partially supported
by a grant-in-aid for Scientific Research (10671986) from
the Japanese Ministry of Education, Sciences, Sports and
Culture, Japan, and the Ciba-Geigy Foundation (Japan) for
the Promotion of Science.
Supporting Information Available: Full experimental
details and characterization data for all new compounds
described in the text. This material is available free of charge
via the Internet at http://pubs.acs.org.
a The enantiomeric purity was determined by chiral HPLC assay (Daicel
Chiralcel-OD and Chiralcel-OJ). b The absolute configuration was assigned
by comparison of the sign of optical rotation with the reported value.14,15
c The absolute configuration was assigned by analogy with 16a. d Com-
mercially available.
OL990574C
(9) Cirillo, P. F.; Panek, J. S. J. Org. Chem. 1994, 59, 3055-3063. (b)
Sakaguchi, K.; Mano, H.; Ohfune, Y. Tetrahedron Lett. 1998, 39, 4311-
4312.
(10) Compounds 8 and 9 are commercially available. Compounds 10-
12 were prepared according to literature methods. (a) Sone, T.; Hiroi, K.;
Yamada, S. Chem. Pharm. Bull. 1973, 21, 2331-2335. (b) Shirai, R.; Aoki,
K.; Sato, D.; Kim, H.-D.; Murakata, T.; Koga, K. Chem. Pharm. Bull. 1994,
42, 690-693. For a review on the use of the chiral lithium amides in
asymmetric synthesis, see: (c) Cox, P. J.; Simpkins, N. S. Tetrahedron:
Asymmetry 1991, 2, 1-26.
(11) Trost, B. M.; Belletire, J. L.; Godleski, S.; McDougal, P. G.;
Balkovec, J. M.; Baldwin, J. J.; Christy, E. E.; Ponticello, G. S.; Varga, S.
L.; Springer, J. P. J. Org. Chem. 1986, 51, 2370-2374.
(12) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092-4096.
Although the enantioselectivity can be interpreted as being
the result of a process via a six-membered transition state
17 (Figure 2) in which the silyl and the chelated piperazi-
nylmethyl groups occupy an axial position, the precise
mechanism is not known and is now under investigation.13
(13) For a mechanistic discussion on the reduction with lithium amides,
see ref 3. Although the placement of the large silyl group at the axial position
seems unlikely, the preference for the axial conformation of the silyl group
relative to the methyl group, which was ascribed to the reduced steric
interactions due to the C-Si bond being longer than the C-C bond, was
reported: Cho, S.-G.; Rim, O.-K.; Kim, Y.-S. THEOCHEM 1996, 364,
59-68.
(14) Seebach, D.; Beck, A. K.; Roggo, S.; Wonnacott, A. Chem. Ber.
1985, 118, 3673-3682.
(15) Wright, A.; West, R. J. Am. Chem. Soc. 1974, 96, 3227-3232.
Figure 2.
Org. Lett., Vol. 1, No. 2, 1999
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