Noncovalent interactions as a solution for the metal-free one-pot asymmetric synthesis of (S)-2-aryl-2,3-dihydro-4(1H)-quinolones.

4-Quinolones compose a remarkable class of compounds that show various pharmacological applications. In particular, the activities of both (S) and (R) enantiomers of 2-aryl-2,3-dihydro-4(1H)-quinolones have made them an object of befitting interest for asymmetric synthesis. Although readily yielded as a racemic mixture from an one-pot reaction between 2-aminoacetophenone and benzaldehyde, a pathway for the metal-free enantioselective one-pot synthesis of the (S) isomer is not completely clear. In the present work, guided by the burgeoning role of organocatalysis in asymmetric synthesis and recent experimental insight into the most likely reaction mechanism, we report the in silico screening for a roster of MacMillan chiral imidazolidinones through quantum mechanics calculations. Two stereopredictive models yielding similarly high expected ee (up to 97%) were proposed. The role of aromatic interactions for the control of enantioselectivity was systemically studied, as well as the Pro-S si-enantiofacial attack activation energies, which were found to correlate well (R = 0.75) with the reported Bürgi-Dunitz angle for the expected intramolecular Mannich reaction mechanism.