Asymmetric direct aldol reaction of α-keto esters and acetone catalyzed by bifunctional organocatalysts

A type of C-2-symmetrical bisprolinamide has been developed for the asymmetric aldol reaction between acetone and a-keto esters, which furnishes the chiral tertiary alcohols in high yields (up to 99%) with high enantioselectivities (up to 94% ee). Aliphatic, heteroaromatic and aromatic a-keto esters including those with electron-donating or electron-withdrawing group substituents were found to be suitable substrates in the presence of bisprolinamide 2a (15 mol%) and AcOH (150 mol%) with reaction times of no more than 16 h. This process is easily manipulated with readily available reagents. The geometry of catalyst 2a was fully optimized at the B3LYP/6-31G(d) level with all electron calculations. Based on the experimental investigations and DFT calculations of catalyst 2a, a possible transition state A has been proposed to explain the origin of the activation and asymmetric inductivity.