Abstract
The effective induction of high levels of stereocontrol for free radical-mediated transformations represents a notorious challenge in asymmetric catalysis. Herein, we describe a novel metalloredox biocatalysis strategy to repurpose natural cytochromes P450 to catalyse asymmetric radical cyclisation to arenes through an unnatural electron transfer mechanism. Empowered by directed evolution, engineered P450s allowed diverse radical cyclisation selectivities to be accomplished in a catalyst-controlled fashion: P450arc1 and P450arc2 facilitated enantioconvergent transformations of racemic substrates, giving rise to either enantiomer of the product with excellent total turnover numbers (up to 12,000). In addition to these enantioconvergent variants, another engineered radical cyclase, P450arc3, permitted efficient kinetic resolution of racemic chloride substrates (S factor = 18). Furthermore, computational studies revealed a proton-coupled electron transfer (PCET) mechanism for the radical-polar crossover step, suggesting the potential role of the haem carboxylate as a base catalyst. Collectively, the excellent tunability of this metalloenzyme family provides an exciting platform for harnessing free radical intermediates for asymmetric catalysis.