A Novel Proline-Valinol Thioamide Small Organic Molecule for a Highly Enantioselective Direct Aldol Reaction

A new prolinethioamide compound 4, prepared from readily available natural amino acid L-proline and amino alcohol L-valinol, has been found to be an active catalyst for the direct aldol reaction of various aldehydes with acetone, cyclohexanone or cyclopentanone at 0 degrees C. Using only 2 mol% loading of this organocatalyst, the reaction could give high enantioselectivity with up to 96% enantiomeric excess for the reaction of 2-nitrobenzaldehyde with acetone. And as for the cyclohexanone, the excellent diastereoselectivity (anti/svn: 99/1) and enantioselectivity (99% ee) could be achieved when reacted with 3-nitrobenzaldehyde in water in the presence of this thioamide 4. This structurally simple catalyst is a highly efficient prolinethioamide derivative, and the terminal hydroxy group in this catalyst is a primary alcohol which is different from the previously reported prerequisite secondary or tertiary alcohol of prolinamides. Our results suggest a new strategy in the design of diversiform organic catalysts for direct asymmetric aldol reactions and related transformations.