Thiamine diphosphate (ThDP)-dependent enzymes are ubiquitously distributed in all domains of life. Typically, they catalyse a variety of C–C bond-forming (or bond-breaking) reactions through nucleophilic addition (or the reverse) of the umpolung carbanion-enamine (Breslow intermediate) with different electrophiles. These well-characterized biocatalysts have inspired the development of N-heterocyclic carbenes (NHCs). Although a few early studies revealed that pyruvate: ferredoxin oxidoreductase (PFOR)-catalysed acetylation of coenzyme A (CoA) through single-electron oxidation pathway, the ability of ThDP-dependent enzymes in stereocontrolled radical chemistry remains unknown.

Our group pioneered a dual-catalyst system consisting of a ThDP-dependent enzyme and an organophotoredox catalyst to achieve an unnatural enantioselective radical acylation. In this system, a ThDP-dependent BAL is repurposed to be an unprecedented radical acyl transferase (RAT) by merging green-light induced single-electron transfer and directed evolution, catalysing acylation of carboxylic-acid-derived prochiral radicals with a plethora of aldehydes in an enantioselective fashion. This work introduces a new class of radical enzymes and a distinct acyl radical-transfer mechanism, which not only expands the toolbox of biocatalysts but also represents an alternative superior to chemo-NHC catalysts for the stereocontrol of prochiral radicals.

Repurposing benzaldehyde lyase into an unnatural radical acyl transferase

Xiaoqiang Huang

Nanjing University

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