The catalytic enantioselective tandem reaction is an efficient synthetic methodology in which optically active compounds are assembled from simple prochiral substrates via two (or more) distinct catalytic processes taking place under the same conditions. The synthetic efficiency is enhanced by avoiding the time-intensive and yield-reducing isolation and purification of synthetic intermediates and by decreasing the amounts of chemicals and solvents used. The asymmetric catalytic reductive aldol reaction is an efficient tandem transformation involving conjugate reduction of a,b-unsaturated carbonyl compounds followed by aldol reaction of the enolate intermediate with aldehydes or ketones. Chiral transition-metal catalysts have been used to control the stereochemistry of these transformations. We recently reported that achiral phosphorus oxides function as Lewis base organocatalysts to promote both the conjugate reduction of enones with trichlorosilane and the reductive aldol reaction of enones with aldehydes. Herein we report that enantioselective catalysis of this tandem reaction by chiral Lewis bases provides good to high diastereoand enantioselectivities. Scheme 1 outlines the current catalytic method. Our previous study had shown that the Lewis base catalyzed conjugate reduction with trichlorosilane proceeds via a six-membered transition state with an enone in the s-cis conformation to give the (Z)-trichlorosilyl enolate exclusively. Therefore, high syn selectivity is expected for the subsequent aldol process, assuming that the reaction proceeds through a chair-like cyclic transition state. Moreover, high enantioselectivity could also be achieved by judicious selection of chiral Lewis base catalysts (LB*). We first examined various chiral Lewis base catalysts (Figure 1) for the reductive aldol reaction of chalcone (1a) and benzaldehyde (2a) with trichlorosilane at 78 8C (Table 1). With (S)-BINAPO, the reaction in dichloromethane gave aldol adduct 3a with respectable stereoselectivities (Table 1, entry 1). By simply changing the solvent from dichloromethane to propionitrile, both the stereoselectivities and chemical yield dramatically improved (Table 1, entry 2). Other Lewis base catalysts were then examined using this solvent (Table 1, entries 3–6). (R,R)-DIOPO showed a comparable activity to BINAPO to afford similar enantioselectivity with a slight loss of diastereoselectivity (Table 1, entry 3). Although structurally similar to BINAPO, (S)[a] Prof. Dr. M. Sugiura, N. Sato, Y. Sonoda, Prof. Dr. M. Nakajima Graduate School of Pharmaceutical Sciences Kumamoto University 5-1 Oe-honmachi, Kumamoto 862-0973 (Japan) Fax: (+81)96-362-7692 E-mail : msugiura@kumamoto-u.ac.jp (M. Sugiura) nakajima@gpo.kumamoto-u.ac.jp (M. Nakajima) [b] Prof. Dr. S. Kotani Priority Organization for Innovation and Excellence Kumamoto University 5-1 Oe-honmachi, Kumamoto 862-0973 (Japan) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/asia.200900450. Scheme 1. The enantioselective reductive aldol reaction with trichlorosilane catalyzed by a chiral Lewis base catalyst.