英国曼彻斯特大学Green Anthony P.团队报道了对映选择性亲核芳香族取代工程酶。相关研究成果发表在2025年1月15日出版的《自然》。

亲核芳香取代（SNAr）是制药和农用化学工业中使用最广泛的过程之一，能够通过C-C和C-X（X=O，N，S）键形成复杂分子的会聚组装。SNAr反应通常使用强制条件进行，包括不允许控制反应选择性的极性非质子溶剂、化学计量碱和高温。尽管SNAr化学很重要，但据报道，只有少数选择性催化方法依赖于小型有机氢键或相转移催化剂。

该文中，研究人员通过揭示设计的一种具有活化精氨酸的设计酶中混杂的SNAr活性，建立了一种立体选择性SNAr化学的生物催化方法。该活性在连续几轮定向进化中进行了优化，以提供一种工程生物催化剂SNAr1.3，其效率比母体高160倍，并促进缺电子芳烃与碳亲核试剂的偶联，具有近乎完美的立体控制（>99%e.e.）。

SNAr1.3可以以0.15 s^-1的速率运行，进行>4000次转换，可以接受广泛的亲电和亲核偶联伴侣，包括那些能够构建具有挑战性的1,1-二芳基季铵盐立体中心的偶联伴侣。生化、结构和计算研究为SNAr1.3的催化机制提供了见解，包括由关键催化残基Arg124和Asp125形成的卤化物结合口袋的出现。

研究将具有里程碑意义的合成反应带入生物催化领域，为催化SNAr化学提供了一个高效且通用的平台。

附：英文原文

Title: Engineered enzymes for enantioselective nucleophilic aromatic substitutions

Author: Lister, Thomas M., Roberts, George W., Hossack, Euan J., Zhao, Fei, Burke, Ashleigh J., Johannissen, Linus O., Hardy, Florence J., Millman, Alexander A. V., Leys, David, Larrosa, Igor, Green, Anthony P.

Issue&Volume: 2025-01-15

Abstract: Nucleophilic aromatic substitutions (SNAr) are amongst the most widely used processes in the pharmaceutical and agrochemical industries1–4, allowing convergent assembly of complex molecules through C–C and C–X (X = O, N, S) bond formation. SNAr reactions are typically carried out using forcing conditions, involving polar aprotic solvents, stoichiometric bases and elevated temperatures, which do not allow for control over reaction selectivity. Despite the importance of SNAr chemistry, there are only a handful of selective catalytic methods reported that rely on small organic hydrogen-bonding or phase-transfer catalysts5–11. Here we establish a biocatalytic approach to stereoselective SNAr chemistry by uncovering promiscuous SNAr activity in a designed enzyme featuring an activated arginine12. This activity was optimized over successive rounds of directed evolution to afford an engineered biocatalyst, SNAr1.3, that is 160-fold more efficient than the parent and promotes the coupling of electron-deficient arenes with carbon nucleophiles with near-perfect stereocontrol (>99% e.e.). SNAr1.3 can operate at a rate of 0.15 s-1, perform >4000 turnovers and can accept a broad range of electrophilic and nucleophilic coupling partners, including those that allow construction of challenging 1,1-diaryl quaternary stereocentres. Biochemical, structural and computational studies provide insights into the catalytic mechanism of SNAr1.3, including the emergence of a halide binding pocket shaped by key catalytic residues Arg124 and Asp125. This study brings a landmark synthetic reaction into the realm of biocatalysis to provide an efficient and versatile platform for catalytic SNAr chemistry.

DOI: 10.1038/s41586-025-08611-0

Source: https://www.nature.com/articles/s41586-025-08611-0