Exploring the Aldol Reaction using Catalytic Antibodies and “On Water” Organocatalysts from QM/MM Calculations

The aldol reaction between benzaldehyde and acetone has been investigated using QM/MM Monte Carlo calculations and free-energy perturbation theory to determine the origin of the enhanced rates and enantioselectivities (% ee) derived from an enamine-based catalytic antibody 33F12 and a chiral organocatalyst. Electrostatic stabilization of the general acid/base TyrL36 by TrpH103, SerH100, and AsnL34 enabled the 33F12 active site to exclusively adopt an <i>si</i>-face benzaldehyde orientation for C–C bond formation with the LysH93-enamine. Whereas preorganization was responsible for the exclusive (<i>S</i>)-aldol product in the antibody, the organocatalyst featuring a chiral diphenyl amino alcohol moiety instead derived its preferred (<i>R</i>)-aldol product from an interplay between sterics and electronic stabilization. The <i>si</i>-face benzaldehyde conformation had unfavorable interactions with the organocatalyst in contrast to the <i>re</i>-face. Gas-phase calculations predicted a 73% ee; however, solution boosted the % ee values despite similar reaction geometries. An “on water” environment, defined as a reaction that proceeds in an aqueous organic emulsion, yielded a computed 94% ee (exptl 93% ee) compared to a calculated 87% ee in “neat” acetone (exptl 85% ee). Specific hydrogen bonding between the interfacial waters and an amide oxygen on the catalyst was found to control the % ee. A more compact <i>si</i>-face transition structure reduced solvent accessibility to the amide oxygen with a “closed state” steric barrier compared to an “open state” for the <i>re</i>-face. New insight into the synthetically important aldol reaction and state-of-the-art methodology is presented herein