Novel small organic molecules for a highly enantioselective direct Aldol reaction

Novel organic molecules containing an l-proline amide moiety and a terminal hydroxyl for catalyzing direct asymmetric aldol reactions of aldehydes in neat acetone are designed and prepared. Catalyst 3d, 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. A theoretical study of transition structures demonstrates the important role of the terminal hydroxyl group in the catalyst in the stereodiscrimination. Our results suggest a new strategy in the design of new organic catalysts for direct asymmetric aldol reactions and related transformations because plentiful chiral resources containing multi-hydrogen bond donors, for example, peptides, might be adopted in the design. Copyright © 2003 American Chemical Society.