Photoexcitation of flavoenzymes enables a stereoselective radical cyclization

• Published in: Science (American Association for the Advancement of Science) Vol. 364; no. 6446
• Main Authors: Biegasiewicz, Kyle F., Cooper, Simon J., Gao, Xin, Oblinsky, Daniel G., Kim, Ji Hye, Garfinkle, Samuel E., Joyce, Leo A., Sandoval, Braddock A., Scholes, Gregory D., Hyster, Todd K.
• Format: Journal Article
• Language: English
• Published: United States AAAS 21.06.2019
• DOI: 10.1126/science.aaw1143
• ISSN: 0036-8075

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. As a result, photoexcitation of promiscuous flavoenzymes has thus furnished a previously unknown biocatalytic reaction.