Diversity-oriented photobiocatalytic synthesis via stereoselective three-component radical coupling

• 成果类型: Article
• 署名作者: Zhang, Chen; Zhou, Jun; Xie, Pei-Pei; Rivera, Silvia M.; Alturaifi, Turki M.; Finnigan, James; Charnock, Simon; Liu, Peng; Yang, Yang
• 署名单位: University of California System; University of California Santa Barbara; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; University of California System; University of California Santa Barbara
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-11333
• DOI: 10.1126/science.adx2935
• 发表日期: 2025-09-25
• 关键词: alpha-amino-acids; photoredox catalysis; enzyme

摘要

Enzymatic multicomponent carbon-carbon (C-C) bond-forming reactions for diversity-oriented synthesis remain rare. Using cooperative photobiocatalysis, we developed a stereoselective three-component radical-mediated C-C coupling previously unknown in both organic chemistry and biochemistry. Directed evolution of repurposed pyridoxal decarboxylases enabled full fragment variability in this three-component coupling, giving rise to six classes of valuable products, many of which were inaccessible with other methods, even in a racemic fashion. This enzymatic platform integrates a range of asymmetric catalysis principles, including remote stereocenter construction, stereodivergent catalysis, kinetic resolution, and parallel kinetic resolution, achieving excellent diastereo- and enantiocontrol over radical intermediates. The broad substrate scope and complementary specificities of evolved enzyme variants enabled combinatorial library synthesis, affording structurally and stereochemically diverse scaffolds for medicinal chemistry.