ORGANIC
LETTERS
2002
Vol. 4, No. 17
2933-2936
Enantioselective Conjugate Addition of
Silylketene Acetals to
â-Enamidomalonates. Synthesis of
â-Amino Acid Derivatives
Mukund P. Sibi* and Jianxie Chen
Department of Chemistry, North Dakota State UniVersity, Fargo, North Dakota, 58105
Received June 10, 2002
ABSTRACT
Conjugate addition of silylketene acetals or enolsilanes to enamidomalonates proceeds with excellent chemical efficiency and good selectivity
using Cu(OTf)2 and a chiral bisoxazoline. The effect of the Lewis acid, ligand, the N-acyl substituent, and the nucleophile on yield and selectivity
for the addition product have been evaluated.
New protocols for enantioselective conjugate addition con-
tinue to attract interest.1 In this context, several recent reports
have underscored the utility of malonate-type acceptors in
these reactions. These systems not only provide a new
structural motif for acceptors but also show enhanced
reactivity toward nucleophiles. The addition of chiral ionic
nucleophiles to malonates has been reported by Beak2 and
Alexakis.3 Evans and co-workers reported a highly selective
addition of neutral silyl ketene acetals to alkylidene and
arylidene malonates using catalytic amounts of chiral Lewis
acids.4 Additionally, Jørgensen has shown that indoles add
conjugatively to malonates using chiral Lewis acids.5 The
use of proline as a catalyst in the addition of ketones to
alkylidene malonates has also been demonstrated.6 The
addition of silyl ketene acetals to enamido methylene-
oxobutanoate has been reported by Saito and co-workers.7
A single example of silyl ketene acetal addition to enami-
domalonates in a racemic fashion was also reported in Saito’s
work. We have recently shown8 that chiral ionic nucleophiles
add to enamido malonates with high selectivity, thus provid-
ing a new route for accessing â-amino acid derivatives.9
Analogously, addition of neutral nucleophiles to enamidoma-
(1) For a recent review, see: Sibi, M. P.; Manyem, S. Tetrahedron 2000,
56, 8033. For other reviews in the area, see: Krause, N.; Hoffmann-Ro¨der,
A. Synthesis 2001, 171. Tomioka, K. In Modern Carbonyl Chemistry, Otera,
J., Ed.; Wiley-VCH: Weinheim, Germany, 2000; p 491. Leonard, J.; Diez-
Barra, E.; Merino, S. Eur. J. Org. Chem. 1998, 2051.
(2) (a) Park, Y. S.; Weisenburger, G. A.; Beak, P. J. Am. Chem. Soc.
1997, 119, 10537. (b) Curtis, M. D.; Beak, P. J. Org. Chem. 1999, 64,
2996.
(5) Zhuang, W.; Hansen, T.; Jørgensen, K. A. Chem. Commun. 2001,
347. For other examples, see: Maas, S.; Stamm, A. Kunz, H. Synthesis
1999, 1792. Cahiez, G.; Alami, M. Tetrahedron 1989, 43, 4163. For the
addition of hydroxylamines to alkylidene malonates, see: Cardillo, G.;
Gentilucci, L.; Gianotti, M.; Kim, H.; Perciaccante, R.; Tolomelli, A.
Tetrahedron: Asymmetry 2001, 12, 2395.
(6) Betancort, J. M.; Sakthivel, K.; Thayumanavan, R.; Barbas, C. F.,
III. Tetrahedron Lett. 2001, 42, 4441.
(3) (a) Alexakis, A.; Benhaim, C. Tetrahedron: Asymmetry 2001, 12,
1151. (b) Alexakis, A.; Rosset, S.; Allamand, J.; March, S.; Guillen, F.;
Benhaim, C. Synlett 2001, 1375.
(4) (a) Evans, D. A.; Rovis, T.; Kozlowski, M. C.; Downey, C. W.;
Tedrow, J. S. J. Am. Chem. Soc. 2000, 122, 9134. Also see: (b) Evans, D.
A.; Willis, M. C.; Johnston, J. N. Org. Lett. 1999, 1, 865. (c) Evans, D. A.;
Scheidt, K. A.; Johnston, J. S.; Willis, M. C. J. Am. Chem. Soc. 2001, 123,
4480. (d) Kitajima, H.; Ito, K.; Katsuki, T. Tetrahedron 1997, 53, 17015.
(e) Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325.
(7) Saito, S.; Uedo, E.; Kato, Y.; Murakami, Y.; Ishikawa, T. Synlett
1996, 1103. For Diels-Alder reactions with ketene acetals and enamido
substrates, see: Nishiuchi, M.; Honda, K.; Nakai, T. Chem. Lett. 1996,
321. Ray, C. A.; Wallace, T. W.; Ward, R. A. Tetrahedron Lett. 2000, 41,
3501.
(8) Sibi, M. P.; Asano, Y. J. Am. Chem. Soc. 2001, 123, 9708.
(9) For synthesis and biology of â-amino acids, see: EnantioselectiVe
Synthesis of â-Amino Acids; Juaristi, E., Ed.; Wiley-VCH: New York, 1997.
For a review, see: Cole, D. C. Tetrahedron 1994, 50, 9517.
10.1021/ol026333d CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/02/2002