Mechanistic and enantioselectivity analysis of amino acid-catalyzed asymmetric aldol reactions: a theoretical study

In this work, we theoretically studied the asymmetric aldol reactions between acetone and p-NO2PhCHO catalyzed by (S)-proline, (S)-azetidine-2-carboxylic acid, (S)-pipecolic acid, L-hisdine, L-phenylalanine, L-valine and N-methyl-L-valine. For all reactions, the potential Gibbs energy surfaces are drawn after DFT calculations, and the rate-determining steps are determined. Both thermodynamics and kinetics can influence the yield of the main reactions, the side reactions are suppressed by either thermodynamics or kinetics, and the enantioselectivity difference between the (S)-proline- and (S)-azetidine-2-carboxylic acid-catalyzed reactions is determined by the difference in the entropy effect between the stereo-determining transition states, which is investigated by different DFT-D methods.