南京大学黄小强团队报道了对映选择性三自由基分选的协同光生物催化。相关研究成果于2024年11月21日发表在国际顶尖学术期刊《自然》。

三种或三种以上底物结合成一种产物的反应的多组分反应，在快速构建复杂度增加的化学构建块方面非常有用，但通过酶法实现这一点仍然很少见。这种局限性主要是因为酶的活性位点通常不用于处理多种底物，特别是在涉及多种自由基中间体的情况下。

最近，化学催化自由基分选已成为各种有用反应的一种使能策略。然而，由于自由基立体化学控制的固有困难，使这些过程具有对映选择性是极具挑战性的。

该文中，研究人员通过定向反应重新利用硫胺素依赖酶，将其与光氧化还原催化结合，实现光生物催化的对映选择性三组分自由基交叉偶联。这种方法结合了三种现成的起始材料——醛、α-溴羰基和烯烃，以获得富集对映体的酮产品。

机制研究提供了对这种双光/酶系统如何精确引导参与转化的三个不同自由基的见解，从而释放新的酶反应性。该方法实现了卓越的立体选择性，33个实例中有25个实现了≥97%的对映体过量。

附：英文原文

Title: Synergistic photobiocatalysis for enantioselective triple radical sorting

Author: Xing, Zhongqiu, Liu, Fulu, Feng, Jianqiang, Yu, Lu, Wu, Zhouping, Zhao, Beibei, Chen, Bin, Ping, Heng, Xu, Yuanyuan, Liu, Aokun, Zhao, Yue, Wang, Chuanyong, Wang, Binju, Huang, Xiaoqiang

Issue&Volume: 2024-11-21

Abstract: Multicomponent reactions – those where three or more substrates combine into a product – have been highly useful in rapidly building chemical building blocks of increased complexity4, but achieving this enzymatically has remained rare.5 This limitation primarily arises because an enzyme’s active site is not typically set up to address multiple substrates, especially in cases involving multiple radical intermediates6. Recently, chemical catalytic radical sorting has emerged as an enabling strategy for a variety of useful reactions7,8. However, making such processes enantioselective is highly challenging due to the inherent difficulty in the stereochemical control of radicals9. Here, we repurpose a thiamine-dependent enzyme10,11 through directed evolution, combine it with photoredox catalysis, to achieve a photobiocatalytic enantioselective three-component radical cross-coupling. This approach combines three readily available starting materials — aldehydes, α-bromo-carbonyls and alkenes — to give access to enantioenriched ketone products. Mechanistic investigations provide insights into how this dual photo-/enzyme system precisely directs the three distinct radicals involved in the transformation, unlocking new enzyme reactivity. Our approach has achieved exceptional stereoselectivity, with 25 out of 33 examples achieving ≥97% enantiomeric excess.

DOI: 10.1038/s41586-024-08399-5

Source: https://www.nature.com/articles/s41586-024-08399-5