Dynamic Kinetic Resolution of Azlactones via Phase-Transfer Catalytic Alcoholysis

Phase-transfer catalytic asymmetric alcoholysis of azlactones via dynamic kinetic resolution proceeded for a wide range of alcohols and azlactones, affording the corresponding α-chiral amino acid esters in up to 98% yield and up to 99:1 er. In addition, this catalytic system was also applied to the asymmetric alcoholysis of N-benzoyl amino acid hexafluoroisopropyl ester providing the desired product in good yield with high stereoselectivity (71% yield, 98:2 er). The catalyst loading could be reduced to 0.1 mol % without significant loss of stereoselectivity (turnover number = 411). Furthermore, a gram-scale reaction and transformations of the enantioenriched products involving hydrogenolysis, LAH-reduction, and Suzuki–Miyaura coupling reactions were successfully achieved. Detailed computational studies using a pseudotransition state (pseudo-TS) conformational search with ConFinder and density functional theory (DFT) calculations indicated a TS model that accounted for the origin of the stereoselectivity. In this TS model, water or alcohol molecules activate the azlactone substrate by H-bonding with the nitrogen atom, and concomitant accumulated weak interactions, including H-bonding interactions, C–H−π, and π–π interactions, stabilize the TS, leading to the major enantiomer.