Direct asymmetric aldol reaction co-catalyzed by l-proline and group 12 elements Lewis acids in the presence of water

An approach based on combinations of various water compatible Lewis acids and l-proline co-catalysts has been evaluated for the direct asymmetric aldol reaction. From this broad screening, chloride salts from group 12 elements (ZnCl2, CdCl2, HgCl2) lead to the highest stereoselectivities. Optimized catalytic conditions (catalytic system: l-proline: 20%/ZnCl2: 10%; solvent mixture: DMSO/H2O, 8:2) gave anti aldol products with improved enantioselectivity (>99% ee) compared to a moderately stereoselective procedure based on proline activation only.