Non‐native Intramolecular Radical Cyclization Catalyzed by a B₁₂‐Dependent Enzyme**

Abstract

Despite the unique reactivity of vitamin B12 and its derivatives, B12‐dependent enzymes remain underutilized in biocatalysis. In this study, we repurpose the B12‐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 via either redox‐neutral or reductive ring closure with marked enhancement of reactivity and selectivity relative to the free B12 cofactor. CarH* also catalyzes an unusual spirocyclization via 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 B12 and expanding the synthetic utility of B12‐dependent enzymes.

Visible-Light-Driven α-C(sp3)–H Bond Functionalization of Glycine Derivatives

“…Secondly, while electron donor-acceptor (EDA) complexes hold promise as alternatives to external photocatalysts, their efficiency relies heavily on the structural features and visible light absorption properties of the substrates. Developing a designable heterogeneous photocatalyst or collaborating with the enzyme catalysis [155][156][157][158] may provide a more sustainable solution. Thirdly, the restricted availability of aryl sources for C-H bond arylation, primarily limited to nucleophilic heterocycles like indoles, calls for developing a universal aryl source to expand the scope of this transformation.…”

A New Age of Biocatalysis Enabled by Generic Activation Modes

“…This includes imine/enamine catalysis, which allows activation of (α,β-unsaturated) carbonyl groups to either yield efficient electrophilic , or nucleophilic , intermediates. Similarly, amine groups can be activated by pyridoxal 5-phosphate (PLP)-dependent enzymes. − Further, radical processes through either selective HAT using high-valent iron oxo species, or cobalamin activation of C–Cl bonds have recently attracted attention. , Hydrogen bonding and Lewis acid activation are additional areas being investigated, , and there are many more reactive sites in enzymes just waiting to be explored. Much of this research had a strong chemomimetic focus, producing enzymes that mimic chemical catalysts.…”

“… 120 − 123 Further, radical processes through either selective HAT using high-valent iron oxo species, or cobalamin activation of C–Cl bonds have recently attracted attention. 124 , 125 Hydrogen bonding and Lewis acid activation are additional areas being investigated, 22 , 126 and there are many more reactive sites in enzymes just waiting to be explored. Much of this research had a strong chemomimetic 13 focus, producing enzymes that mimic chemical catalysts.…”