意大利博洛尼亚大学Paolo Melchiorre课题组的一项最新研究，利用非天然光脱羧酶实现了立体特异性自由基偶联。相关论文于2024年9月10日发表于国际顶尖学术期刊《自然》杂志上。

据介绍，光酶是一种光能生物催化剂，其催化活性通常依赖于辅因子或非天然氨基酸的激发。一个显著的自然例子是脂肪酸光脱羧酶(FAP)，它利用光能将脂肪族羧酸转化为非手性烃。

研究人员报道了一种基于酶结合催化中间体的激发，而不是依赖于辅因子激发的非天然光脱羧酶的设计方法。由工程化I类醛缩酶活性位点内的羟醛瞬间产生的微量烯胺离子，能吸收紫光并起单电子氧化剂的作用。

手性羧酸的活化，随后是脱羧，产生两个自由基，经过立体特异性交叉偶联，产生具有两个立体中心的产物。使用适当的对映纯手性底物，可选择性地以完全对映控制获得所需的非对映异构体产物。

这一发现强调了活性位点能够将立体化学信息，从手性自由基前体转移到产物中，有效地解决了手性自由基快速外消旋的长期问题。由此产生的“手性记忆”场景在对映选择性自由基化学中是罕见的。

附：英文原文

Title: Stereospecific radical coupling with a non-natural photodecarboxylase

Author: Tseliou, Vasilis, Kqiku, Laura, Berger, Martin, Schiel, Florian, Zhou, Hangyu, Poelarends, Gerrit J., Melchiorre, Paolo

Issue&Volume: 2024-09-10

Abstract: Photoenzymes are light-powered biocatalysts that typically rely on the excitation of cofactors or unnatural amino acids for their catalytic activities. A notable natural example is the fatty acid photodecarboxylase (FAP), which uses light energy to convert aliphatic carboxylic acids to achiral hydrocarbons. Here, we report a way to design a non-natural photodecarboxylase based on the excitation of enzyme-bound catalytic intermediates, instead of relying on cofactor excitation. Iminium ions, transiently generated from enals within the active site of an engineered class I aldolase, can absorb violet light and function as single-electron oxidants. Activation of chiral carboxylic acids, followed by decarboxylation, generates two radicals that undergo stereospecific cross-coupling, yielding products with two stereocenters. Using the appropriate enantiopure chiral substrate, the desired diastereoisomeric product is selectively obtained with complete enantiocontrol. This finding underscores the active site's ability to transfer stereochemical information from the chiral radical precursor into the product, effectively addressing the longstanding problem of rapid racemization of chiral radicals. The resulting ‘memory of chirality’ scenario7 is a rarity in enantioselective radical chemistry.

DOI: 10.1038/s41586-024-08004-9

Source: https://www.nature.com/articles/s41586-024-08004-9