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Photoexcitation of flavoenzymes enables a stereoselective radical cyclization

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Science  21 Jun 2019:
Vol. 364, Issue 6446, pp. 1166-1169
DOI: 10.1126/science.aaw1143

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Light teaches (co)enzymes new tricks

Light is widely used in organic synthesis to excite electrons in a substrate or catalyst, opening up reactive pathways to a desired product. Biology uses light sparingly in this way, but coenzymes such as flavin can be driven to excited states by light. Biegasiewicz et al. investigated this reactivity and found a suite of flavoenzymes that catalyze asymmetric radical cyclization when exposed to light. “Ene”-reductases, when reduced and illuminated, converted starting materials containing an α-chloroamide and an alkene into five-, six-, seven-, or eight-membered lactams. Different enzymes furnished different stereochemistry in the products, likely because of changes in active-site pocket geometry.

Science, this issue p. 1166

Abstract

Photoexcitation is a common strategy for initiating radical reactions in chemical synthesis. We found that photoexcitation of flavin-dependent “ene”-reductases changes their catalytic function, enabling these enzymes to promote an asymmetric radical cyclization. This reactivity enables the construction of five-, six-, seven-, and eight-membered lactams with stereochemical preference conferred by the enzyme active site. After formation of a prochiral radical, the enzyme guides the delivery of a hydrogen atom from flavin—a challenging feat for small-molecule chemical reagents. The initial electron transfer occurs through direct excitation of an electron donor-acceptor complex that forms between the substrate and the reduced flavin cofactor within the enzyme active site. Photoexcitation of promiscuous flavoenzymes has thus furnished a previously unknown biocatalytic reaction.

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