Non-native Intramolecular Radical Cyclization Catalyzed by a B₁₂-Dependent Enzyme

Despite the unique reactivity of vitamin B(12 )and its derivatives, B-12-dependent enzymes remain underutilized in biocatalysis. In this study, we repurposed the B-12 -dependent transcription factor CarH to enable non-native radical cyclization reactions. An engineered variant of this enzyme, CarH*, catalyzes the formation gamma- and delta-lactams through either redox-neutral or reductive ring closure with marked enhancement of reactivity and selectivity relative to the free B-12 cofactor. CarH* also catalyzes an unusual spirocyclization by dearomatization of pendant arenes to produce bicyclic 1,3-diene products instead of 1,4-dienes provided by existing methods. These results and associated mechanistic studies highlight the importance of protein scaffolds for controlling the reactivity of B-12 and expanding the synthetic utility of B-12-dependent enzymes.