Non‐Native Intermolecular Radical Addition Reactions Catalyzed by B ₁₂ ‐Dependent Enzymes

Intermolecular CC bond formation via radical intermediates poses a formidable challenge in biocatalysis, primarily due to the difficulty in suppressing thermodynamically favored reductive quenching pathways such as hydrogen atom transfer (HAT). Here, we report a photoenzymatic platform that leverages an engineered vitamin B 12 ‐dependent photoreceptor, CarH, to catalyze the non‐native intermolecular radical alkylation of activated alkenes. Through rational protein engineering, specifically the removal of the axial histidine ligand (H132A), we disrupted the inhibitory bis‐histidine coordination and expanded the active‐site cavity, thereby enhancing catalytic efficiency (up to 67.9% yield) relative to the wild‐type enzyme. This strategy enables the highly selective synthesis of functionalized alkenes from a diverse array of N‐substituted α‐haloamides and a broad scope of activated alkenes—smoothly accommodating electron‐rich, electron‐deficient, sterically hindered styrenes, and heteroaryl olefins—under mild visible‐light irradiation. This study illustrates how modulation of metallocofactor coordination within a protein scaffold can unlock non‐natural radical reactivity.