Enantioselective direct aldol reactions catalyzed by L-prolinamide derivatives

L-Prolinamides 2, prepared from L-proline and simple aliphatic and aromatic amines, have been found to be active catalysts for the direct aldol reaction of 4-nitrobenzaldehyde with neat acetone at room temperature. They give moderate enantioselectivities of up to 46\% enantiomeric excess (ee). The enantioselectivity increases as the amide N-H becomes a better hydrogen bond donor. L-Prolinamides 3, derived from the reaction Of L-proline with alpha,beta-hydroxyamines such that there is a terminal hydroxyl group, show more efficient catalysis and higher enantioselectivities. In particular, catalyst 3h, prepared from L-proline and (1S,2S)-diphenyl-2-aminoethanol, exhibits high enantioselectivities of up to 93\% ee for aromatic aldehydes and up to >99\% ee for aliphatic aldehydes under -25degreesC. Model reactions of benzaldehyde with three enamines derived from the condensation of prolinamides with acetone have been studied by quantum mechanics calculations. The calculations reveal that the amide N-H and the terminal hydroxyl groups form hydrogen bonds with the benzaldehyde substrate. These hydrogen bonds reduce the activation energy and cause high enantioselectivity. Our results suggest a new strategy in the design of new organic catalysts for direct asymmetric aldol reactions and related transformations.