Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, 214122, Wuxi, P. R. China.
School of Life Sciences and Health Engineering, Jiangnan University, 214122, Wuxi, P. R. China.
Angew Chem Int Ed Engl. 2023 Dec 11;62(50):e202311762. doi: 10.1002/anie.202311762. Epub 2023 Nov 9.
New-to-nature biocatalysis in organic synthesis has recently emerged as a green and powerful strategy for the preparation of valuable chiral products, among which chiral oxygen-containing benzo-fused heterocycles are important structural motifs in pharmaceutical industry. However, the asymmetric synthesis of these compounds through radical-mediated methods is challenging. Herein, a novel asymmetric radical-mediated photoenzymatic synthesis strategy is developed to realize the efficient enantioselective synthesis of oxygen-containing benzo-fused heterocycles through structure-guided engineering of a flavin-dependent 'ene'-reductase GluER. It shows that variant GluER-W100H could efficiently produce various benzoxepinones, chromanone and indanone with different benzo-fused rings in high yields with great stereoselectivities under visible light. Moreover, these results are well supported by mechanistic experiments, revealing that this photoenzymatic process involves electron donor-acceptor complex formation, single electron transfer and hydrogen atom transfer. Therefore, we provide an alternative green approach for efficient chemoenzymatic synthesis of important chiral skeletons of bioactive pharmaceuticals.
新型自然生物催化在有机合成中作为一种绿色且强大的策略，用于制备有价值的手性产物，其中手性含氧苯并稠合杂环是制药行业中的重要结构基序。然而，通过自由基介导的方法进行这些化合物的不对称合成具有挑战性。在此，开发了一种新颖的不对称自由基介导的光酶合成策略，通过黄素依赖性“ene”-还原酶 GluER 的结构导向工程，实现了含氧苯并稠合杂环的高效对映选择性合成。结果表明，变体 GluER-W100H 在可见光下能够高效地以高收率和优异的立体选择性生成具有不同苯并稠合环的各种苯并噁嗪酮、色满酮和茚满酮。此外，这些结果得到了机理实验的很好支持，表明该光酶过程涉及电子给体-受体复合物形成、单电子转移和氢原子转移。因此，我们为生物活性药物中重要手性骨架的高效化学酶法合成提供了一种替代的绿色方法。
