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

01 September 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


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.


non-native enzyme catalysis
radical cyclization

Supplementary materials

Supporting information for Non-native Radical Cyclization Enabled by a B12-dependent Enzyme
Supporting information, including all relevant protocols and characterization.


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Comment number 1, Jared Lewis: Sep 06, 2023, 19:45

Found this excellent perspective when thinking about next steps for this project. Will definitely be cited in a revised draft: DOI: 10.1039/d0sc04112b