A direct asymmetric Mannich reaction using a novel axially chiral amino trifluoromethanesulfonamide (S)-3 has been developed in highly anti-selective and enantioselective manners. Thus, in the presence of a catalytic amount of (S)-3, the reactions between aldehydes and the alpha-imino ester 4 proceed smoothly to give the functional beta-amino aldehydes with significantly higher anti/syn ratio and enantioselectivity than previously possible.

The direct catalytic asymmetric aldol reaction is one of the most fundamental transformations in organic synthesis, and several efficient asymmetric methodologies for this reaction using chiral metal catalysts [1] and organocatalysts [2][3][4] have recently been developed, of which catalysis by proline [2, 3] and its derivatives [4] have been extensively explored. However, the reactivity and selectivity of some of these prolinecatalyzed aldol reactions have serious limitations because of the difficulty in structurally modifying proline. Furthermore, a substoichiometric amount of proline is often necessary to achieve reasonable yields in the direct aldol reaction of aldehydes with acetone. Also, proline is known to react with electron-deficient aromatic aldehydes to form iminium salts, which undergo decarboxylation, even at room temperature. [5] Such degradation may induce the significant retardation of the proline-catalyzed aldol reactions. In this context, we were interested in designing an artificial amino acid catalyst 1 that would not undergo undesirable degradation through decar-

A novel and robust binaphthyl-based amino acid was designed and successfully applied to the direct asymmetric aldol reaction. In some cases, this catalyst leads to higher yields and selectivities than the well-known proline catalyst. For instance, the direct asymmetric aldol reaction of acetone with 4-nitrobenzaldehyde in the presence of the binaphthyl-based amino acid catalyst proceeded smoothly to give the aldol adduct in 82% yield with 95% ee. This catalyst was also found to catalyze effectively the reactions of cyclic or unsymmetrical ketones to give the corresponding aldol adducts with excellent diastereo- and enantioselectivities.

[reaction: see text] A concise and enantioselective synthesis of (S)-2-cyclohexyl-2-phenylglycolic acid as a key intermediate for (S)-oxybutynin is reported. The crucial asymmetric tetrasubstituted carbon center was constructed with excellent stereoselectivity through the proline-catalyzed direct asymmetric aldol reaction between cyclohexanone and ethyl phenylglyoxylate under mild conditions.