Communications
selection of the imines was probably responsible for the
Int. Ed. 2001, 40, 4377 – 4379; d) J.-A. Ma, Angew. Chem. 2003,
15, 4426 – 4435; Angew. Chem. Int. Ed. 2003, 42, 4290 – 4299;
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Chem. Int. Ed. 2003, 42, 5794 – 5795.
1
relative stereochemistry. When such an iminium ion is
involved, it has been proposed that the reaction proceeds
[
17,18]
through an open transition-state model.
Thus, we spec-
[
3] a) E. Hagiwara, A. Fujii, M. Sodeoka, J. Am. Chem. Soc. 1998,
ulate that CÀC bond-formation in our Mannich-type reaction
occurs with the appropriate geometry as described in Figure 1
to minimize steric interactions.
120, 2474 – 2475; b) A. Fujii, E. Hagiwara, M. Sodeoka, J. Am.
Chem. Soc. 1999, 121, 5450 – 5458; c) A. Fujii, M. Sodeoka,
Tetrahedron Lett. 1999, 40, 8011 – 8014.
In summary, we have developed a highly enantioselective
catalytic Mannich-type reaction of b-ketoesters. The reaction
was applicable to a variety of imines derived from glyoxylate,
as well as simple aromatic and a,b-unsaturated aldehydes.
This method affords stereochemically elaborated b-amino
carbonyl compounds in up to 99% ee, thus indicating that
such addition reactions of b-ketoesters to various imines
would be useful to provide versatile intermediates for the
synthesis of chiral nitrogen-containing compounds. In this
reaction, the protic acid generated during the formation of the
Pd enolate would play a role in activating the imine. Since
protic acids are good catalysts for the nonenantioselective
Mannich reaction, it is surprising that our Mannich reaction is
highly enantioselective. We think that simultaneous activa-
tion of both reactants is the key to success, and this distinctive
reaction mechanism could be an important guide to the design
of novel reaction systems. Further studies to elucidate the
mechanism and extend the scope of the reaction are under
way.
[4] For recent examples of the catalytic enantioselective Mannich
reactions using preformed metal enolates: a) H. Fujieda, M.
Kanai, T. Kambara, A. Iida, K. Tomioka, J. Am. Chem. Soc.
1997, 119, 2060 – 2061; b) H. Ishitani, M. Ueno, S. Kobayashi, J.
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[
5] S. Kobayashi, M. Ueno in Comprehensive Asymmetric Catalysis,
Supplement 1 (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto),
Springer, Berlin, 2003, chap. 29.5, p. 143.
[
6] Recent examples of direct catalytic asymmetric Mannich
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Experimental Section
Representative procedure for the synthesis of 8aa: b-Ketoester 3a
(20 mL, 108.6 mmol) and palladium complex 1a (2.9 mg, 2.5 mol%)
were added successively to a solution of 5a (33.4 mg, 162.8 mmol) in
THF (110 mL) at 08C. The reaction mixture was stirred for 5 hours at
the same temperature. The reaction was monitored by TLC (hexane/
ethyl acetate, 3:1) and after completion was quenched by addition of
ethyl acetate (5 mL) and brine (3 mL). The aqueous layer was
extracted with ethyl acetate (3 ꢀ 5 mL). The combined organic layers
were washed with water and brine then dried over Na SO , and the
2
4
solvent was evaporated under reduced pressure. At this stage, the
1
diastereomeric ratio was determined by H NMR spectroscopic
analysis of the crude products. Further purification was performed
by medium pressure liquid chromatography on silica gel (hexane/
ethyl acetate, 4:1; major: 35.0 mg, 82%; minor: 4.6 mg, 11%). The ee
values of the diastereomers were determined by chiral high perform-
ance liquid chromatography analysis.
2
1
583 – 2591; i) B. M. Trost, L. R. Terrell, J. Am. Chem. Soc. 2003,
25, 338 – 339; j) S. Matsunaga, T. Yoshida, H. Morimoto, N.
Kumagai, M. Shibasaki, J. Am. Chem. Soc. 2004, 126, 8777 –
8
5
785; k) D. Uraguchi, M. Terada, J. Am. Chem. Soc. 2004, 126,
356 – 5357; l) W. Zhuang, S. Saaby, K. A. Jørgensen, Angew.
Received: October 5, 2004
Published online: January 31, 2005
Chem. 2004, 116, 4576 – 4578; Angew. Chem. Int. Ed. 2004, 43,
4476 – 4478; m) A. J. A. Cobb, D. M. Shaw, S. V. Ley, Synlett
2
004, 558 – 560; n) A. Cꢁrdova, Chem. Eur. J. 2004, 10, 1987 –
1997; see also, o) A. Cꢁrdova, Acc. Chem. Res. 2004, 37, 102 –
12.
7] a) Y. Hamashima, D. Hotta, M. Sodeoka, J. Am. Chem. Soc.
002, 124, 11240 – 11241; b) Y. Hamashima, K. Yagi, H. Takano,
Keywords: asymmetric catalysis · enolates · Mannich reaction ·
palladium · Schiff bases
.
1
[
2
L. Tꢂmas, M. Sodeoka, J. Am. Chem. Soc. 2002, 124, 14530 –
14531; c) Y. Hamashima, H. Takano, D. Hotta, M. Sodeoka, Org.
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Rec. 2004, 4, 231 – 242.
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528
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2005, 44, 1525 –1529