Stereodivergent atom-transfer radical cyclization by engineered cytochromes P450

Naturally occurring enzymes can be a source of unnatural reactivity that can be molded by directed evolution to generate efficient biocatalysts with valuable activities. Owing to the lack of exploitable stereocontrol elements in synthetic systems, steering the absolute and relative stereochemistry of free-radical processes is notoriously difficult in asymmetric catalysis. Inspired by the innate redox properties of first-row transition-metal cofactors, we repurposed cytochromes P450 to catalyze stereoselective atom-transfer radical cyclization. A set of metalloenzymes was engineered to impose substantial stereocontrol over the radical addition step and the halogen rebound step in these unnatural processes, allowing enantio- and diastereodivergent radical catalysis. This evolvable metalloenzyme platform represents a promising solution to tame fleeting radical intermediates for asymmetric catalysis.

Automated summary

Naturally occurring enzymes can be evolved to generate efficient biocatalysts for unnatural reactions. By repurposing cytochromes P450, stereoselective atom-transfer radical cyclization can be catalyzed, allowing for enantio- and diastereodivergent radical catalysis with substantial stereocontrol. This evolvable metalloenzyme platform offers a promising solution for asymmetric catalysis involving fleeting radical intermediates.