Non‐native Intramolecular Radical Cyclization Catalyzed by a B<sub>12</sub>‐Dependent Enzyme**
Jianbin Li, Amardeep Kumar, Jared C. Lewis
Abstract
Abstract 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 γ‐ and δ‐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.