近日，美国加州大学圣巴巴拉分校Yang Yang团队研究了立体选择性三组分自由基偶联的多样性导向光生物催化合成。2025年7月31日出版的《科学》杂志发表了这项成果。

酶法多组分C-C键形成反应的多样性取向合成仍然罕见。

利用协同光生物催化，研究组开发了一种立体选择性三组分自由基介导的C-C偶联，这在有机化学和生物化学中都是未知的。定向进化的重组吡哆醛脱羧酶使这种三组分偶联的完整片段可变性成为可能，从而产生六类有价值的产物，其中许多是通过其他方法无法获得的，即使是以外消旋的方式。

该酶平台集成了一系列不对称催化原理，包括远程立体中心构建、立体发散催化、动力学分辨和平行动力学分辨，实现了对自由基中间体的优异非立体和对映控制。广泛的底物范围和进化的酶变体的互补特异性实现了组合文库合成，为药物化学提供了结构和立体化学多样化的支架。

附：英文原文

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

Author: Chen Zhang, Jun Zhou, Pei-Pei Xie, Silvia M. Rivera, Turki M. Alturaifi, James Finnigan, Simon Charnock, Peng Liu, Yang Yang

Issue&Volume: 2025-07-31

Abstract: Enzymatic multicomponent 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 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 by 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.

DOI: adx2935

Source: https://www.science.org/doi/10.1126/science.adx2935