Tian Di, He Yu-Ping, Yang Lu-Sen, Li Zhuo-Chen, Wu Hua
Shanghai Frontiers Science Center for Drug Target Identification and Delivery, Laboratory of Innovative Immunotherapy, and Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, China.
Department of Chemistry, College of Sciences, Shanghai University, Shanghai, China.
Nat Chem. 2025 Apr 7. doi: 10.1038/s41557-025-01793-0.
The rapid diversification of core ring structures in complex molecules through switchable skeletal editing is valuable in the drug discovery process. However, controllable methods for chemically divergent modifications of azaarene frameworks using common substrates are challenging, despite the potential to maximize structural diversity and complexity. Here we report the tunable skeletal editing of quinolines through Brønsted acid-catalysed multicomponent reactions of quinoline N-oxides, dialkyl acetylenedicarboxylates and water to generate nitrogen-containing heteroaromatic compounds together with linear compounds in a modular fashion. Specifically, in a one-pot procedure, after cyclization and sequential rearrangement processes, the quinoline N-oxides are easily converted into unique 2-substituted indolines. These then undergo acid-promoted fragmentation to give indoles, base-facilitated ring-opening to afford 2-alkenylanilines and oxidative cyclization to yield isoquinolinones. Catalytic asymmetric skeletal editing of quinolines is also realized, providing enantioenriched benzazepines bearing quaternary stereocentres, and late-stage skeletal modification of quinoline cores in several drugs is demonstrated.
通过可切换的骨架编辑实现复杂分子中核心环结构的快速多样化，在药物发现过程中具有重要价值。然而，尽管利用常见底物对氮杂芳烃骨架进行化学发散修饰具有最大化结构多样性和复杂性的潜力，但可控的方法仍具有挑战性。在此，我们报道了通过喹啉 N-氧化物、乙炔二羧酸二烷基酯和水的布朗斯特酸催化多组分反应，以模块化方式对喹啉进行可调谐的骨架编辑，生成含氮杂环芳烃化合物以及线性化合物。具体而言，在一锅法中，经过环化和连续重排过程后，喹啉 N-氧化物可轻松转化为独特的 2-取代吲哚啉。这些吲哚啉随后进行酸促进的碎片化反应生成吲哚，碱促进的开环反应得到 2-烯基苯胺，以及氧化环化反应生成异喹啉酮。喹啉的催化不对称骨架编辑也得以实现，提供了带有季立体中心的对映体富集苯并氮杂卓，并展示了几种药物中喹啉核心的后期骨架修饰。
