Stereoselective photometallobiocatalytic radical C–C coupling of organoboron reagents and diazo compounds via an outer-sphere mechanism

Designing and developing synthetically useful biocatalytic reactions that operate via novel mechanisms represent a central challenge in modern biocatalysis research. By coupling photoredox catalysis and metalloenzyme catalysis, we harness cooperative photometallobiocatalysis to merge enzymatically generated, open-shell iron carbenoids with reactive radical intermediates formed via excited-state chemistry. This strategy enables a new class of intermolecular radical C–C coupling reactions with excellent enantio- and diastereoselectivities. Central to the successful implementation of this design is the directed evolution of a small metalloprotein catalyst, derived from a thermophilic cytochrome c, to achieve challenging stereocontrol in radical C–C coupling via an outersphere mechanism. These photobiocatalytic, formal metal carbenoid-radical coupling reactions advance a new form of stereoselective outer-sphere metal carbenoid chemistry, providing a powerful strategy to design and evolve biocatalytic C–C bond forming reactions through otherwise challenging intermolecular asymmetric radical couplings.