Enzyme-controlled stereoselective radical cyclization to arenes enabled by metalloredox biocatalysis

Type
Journal Article
Year of Publication
2023
URL
https://doi.org/10.1038/s41929-023-00986-5
DOI
10.1038/s41929-023-00986-5
User Type
In-House
Facility
Characterization (UCSB)
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 metalloredox biocatalysis strategy to repurpose natural cytochromes P450 to catalyse asymmetric radical cyclization to arenes through an unnatural electron transfer mechanism. Directed evolution afforded a series of engineered P450 aromatic radical cyclases with complementary selectivities: 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\thinspace=\thinspace18). Furthermore, computational studies revealed a proton-coupled electron transfer 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.