Novel Small Organic Molecules Catalysts For Asymmetric Direct Aldol Reaction

Novel organic molecules, derived from L-proline and amines or amino alcohols, were found to catalyze the asymmetric direct Aldol reaction with high efficience. Especially those containing L-proline amide moiety and terminal hydroxyl group could catalyze direct asymmetric aldol reactions of aldehydes in neat acetone with better result. Catalyst 25, 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.Theoretical study of transition structures demonstrates the important role of the terminal hydroxyl group in the catalyst in the stereo-discrimination. Our results, which refute the conventional wisdom that the carboxylic acid group of proline is a requirement for high enantioselectivity, suggest a new strategy in the design of new organic catalysts for direct asymmetric aldol reactions and related transformations because plentiful chiral amino alcohol and other compounds containing multi-hydrogen bond donors, for example, peptides, might be adopted in the design. This make it possible to mimic the enzyme and help us understand the catalytic mechanism of Aldolase.