Deciphering the role of acid additives in chiral diamine-catalyzed asymmetric aldol reactions of cyclohexanones with aldehydes

Abstract

Density functional theory (DFT) calculations were performed to rationalize the influence of additive acids on chiral vicinal diamine-catalyzed asymmetric aldol reactions of cyclohexanones with aldehydes. Three TS models are explored. The computations reveal that with TFA as additive, the acid anion-containing nine-membered cyclic TS model is preferred to the other two models. While with succinic acid or HAc, the preferred TS model involves an acid anion-containing ten-membered ring. Acid additive-induced conformational changes are responsible for the pronounced changes in the experimentally observed stereoselectivity. With TFA as addictive, the lowest-energy TS exhibits an almost perfect staggered conformation along the forming C－C bond, which is stabilized by weak non-covalent interactions and less steric repulsion affording (R,S) anti isomer, whereas using HAc as additive, the (S,S) syn-selectivity stems primarily from less steric strain and conformational distortion in the favored transition structures, while in the case of succinic acid, the preferred transition structure has more extended conformation and softer low-frequency vibrational mode than other TSs, which induce more vibrational entropy contributions to Gibbs free energy and more stability of the transition state. The theoretical results reproduce the experimental findings and provide a reasonable explanation for highly varied stereoselectivities by different acid additives.