Multiplicative Stereocontrol in the Light-Driven Deracemization of Benzylic Nitriles

Abstract Light-driven deracemization has emerged as a powerful strategy for the optical enrichment of chiral organic molecules. In numerous cases, a single chiral catalyst promotes both stereoselective cleavage and re-formation of a C–H bond at the stereogenic center. However, methods to establish the mechanisms of these processes and quantify their individual contributions to overall deracemization enantioselectivity remain limited. Here we report a light-driven deracemization of benzylic nitriles with up to 99% yield and 98% ee enabled by cooperative photoredox and chiral phosphate catalysis that achieves high overall enantioselectivity through the combination of two moderately stereoselective steps. The reaction proceeds through a stereoablative sequence of oxidation and deprotonation, followed by stereoselective C–H bond formation to establish the α-nitrile stereocenter. Competition between back electron transfer and deprotonation of a key arene radical cation intermediate results in selective processing of the minor enantiomer in the reaction. The deprotonation step exhibits a primary kinetic isotope effect, enabling the extent of deracemization to be improved upon solvent isotopic substitution. The stereoselectivity of the C–H bond-forming step correlates with the ground-state reduction potential of the photocatalyst, consistent with the involvement of an enantioselective reductive proton-coupled electron transfer. The participation of a single chiral catalyst in two cooperative stereoselective steps produces a non-classical nonlinear effect that is shown to arise from the proposed mechanistic model. More broadly, these studies provide a set of diagnostic tools for analyzing the origins of enantioselectivity in deracemization reactions.