Oxyanion Hole Stabilization by C–H···O Interaction in a Transition StateA Three-Point Interaction Model for Cinchona Alkaloid-Catalyzed Asymmetric Methanolysis of meso-Cyclic Anhydrides

Oxyanion holes are commonly found in many enzyme structures. They are crucial for the stabilization of high-energy oxyanion intermediates or transition states through hydrogen bonding. Typical functionalities found in enzyme oxyanion holes or chemically designed oxyanion-hole mimics are N–H and O–H groups. Through DFT calculations, we show that asymmetric methanolysis of meso-cyclic anhydrides (AMMA) catalyzed by a class of cinchona alkaloid catalysts involves an oxyanion hole consisting of purely C–H functionality. This C–H oxyanion hole is found to play a pivotal role for stabilizing the developing oxyanion, via C–H···O hydrogen bonds, in our newly proposed three-point interaction transition-state model for AMMA reactions, and is the key reason for the catalyst to adopt the gauche-open conformation in the transition state. Predicted enantioselectivities of three cinchona alkaloid catalysts, namely DHQD-PHN, DHQD-MEQ, and DHQD-CLB, based on calculations of our transition-state model, agree well with experimental findings.