美国加州理工学院Frances H. Arnold研究小组近日取得一项新成果。经过不懈努力，他们开发出通过生物催化叠氮化非活化烯烃的手性恶唑烷酮。相关论文于2026年9月23日发表于国际顶尖学术期刊《自然》杂志上。

手性噁唑烷酮是广泛用于不对称合成和药物发现的优势杂环。传统合成路线依赖“手性池”策略，需要以对映纯的氨基醇作为关键中间体。尤其重要的是一类5-(S)-氨甲基噁唑烷酮，它们是靶向耐多药和广泛耐药结核分枝杆菌的下一代抗生素的关键骨架。尽管存在许多构建4位（氮的α位）手性的策略，但安装所需5位立体中心（氧的α位）的方法仍不发达。在此，研究人员报道了一种血红素蛋白催化的氮丙啶化/扩环级联反应，能够从简单烯烃直接、对映选择性地合成临床相关和发现阶段的噁唑烷酮。这项工作通过实现未活化烯烃的功能化，推进了血红素蛋白催化的氮宾转移，而此前这种反应性仅限于苯乙烯等共轭体系。计算分析进一步揭示，通过定向进化引入的关键突变负责这些产物的对映选择性形成。

附：英文原文

Title: Chiral oxazolidinones via biocatalytic aziridination of unactivated alkenes

Author: Li, Zi-Qi, Hanley, Deirdre, Zhang, Yu, Xie, Pei-Pei, Wu, Sophia J., Qin, Zi-Yang, Zhang, Chi, Alfonzo, Edwin, Li, Francesca-Zhoufan, Brinkman-Chen, Sabine, Liu, Peng, Arnold, Frances H.

Issue&Volume: 2026-09-23

Abstract: Chiral oxazolidinones are privileged heterocycles broadly used in asymmetric synthesis (1) and drug discovery (2–3). Conventional synthetic routes rely on a “chiral pool” strategy, where enantiopure amino alcohols are required as key intermediates. Of particular importance are a class of 5-(S)-aminomethyl oxazolidinones that are key scaffolds in next-generation antibiotics targeting multidrug- and extensively drug-resistant Mycobacterium tuberculosis (4–6). While many strategies exist to construct chirality at the 4-position (α-to-nitrogen), methods to install the desired 5-stereocentre (α-to-oxygen) remain underdeveloped. Here we report a haemprotein-catalysed aziridination/ring-expansion cascade that enables direct, enantioselective synthesis of clinically relevant and discovery-stage oxazolidinones from simple alkenes. This work advances haemprotein-catalysed nitrene transfer by enabling functionalisation of unactivated alkenes, a reactivity previously limited to conjugated systems such as styrenes. Computational analysis further reveals that key mutations introduced through directed evolution are responsible for the enantioselective formation of these products.

DOI: 10.1038/s41586-026-11169-0

Source: https://www.nature.com/articles/s41586-026-11169-0