Li Jiaming, Lai Zhencheng, Zhang Weiwei, Zeng Linwei, Cui Sunliang
Institute of Drug Discovery and Design, National Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
Nat Commun. 2023 Aug 9;14(1):4806. doi: 10.1038/s41467-023-40598-y.
Indole alkaloids are one of the largest alkaloid classes, proving valuable structural moiety in pharmaceuticals. Although methods for the synthesis of indole alkaloids are constantly explored, the direct single-step synthesis of these chemical entities with broad structural diversity remains a formidable challenge. Herein, we report a modular assembly of tetrahydrocarboline type of indole alkaloids from simple building blocks in a single step while showing broad compatibility with medicinally relevant functionality. In this protocol, the 2-alkylated or 3-alkylated indoles, formaldehyde, and amine hydrochlorides could undergo a one-pot reaction to deliver γ-tetrahydrocarbolines or β-tetrahydrocarbolines directly. A wide scope of these readily available starting materials is applicable in this process, and numerous structural divergent tetrahydrocarbolines could be achieved rapidly. The control reaction and deuterium-labelling reaction are conducted to probe the mechanism. And mechanistically, this multicomponent reaction relies on a multiple alkylamination cascade wherein an unusual C(sp)-C(sp) connection was involved in this process. This method could render rapid access to pharmaceutically interesting compounds, greatly enlarge the indole alkaloid library and accelerate the lead compound optimization thus facilitating drug discovery.
吲哚生物碱是最大的生物碱类别之一，在药物领域是有价值的结构部分。尽管人们不断探索吲哚生物碱的合成方法，但直接一步合成这些具有广泛结构多样性的化学实体仍然是一项艰巨的挑战。在此，我们报告了从简单的构建模块一步模块化组装四氢咔啉型吲哚生物碱，同时显示出与药物相关功能具有广泛的兼容性。在该方案中，2-烷基化或3-烷基化吲哚、甲醛和胺盐酸盐可进行一锅反应，直接生成γ-四氢咔啉或β-四氢咔啉。这些容易获得的起始原料中有很大一部分适用于此过程，并且可以快速获得大量结构不同的四氢咔啉。进行了对照反应和氘标记反应以探究其机理。从机理上讲，该多组分反应依赖于多烷基胺化级联反应，其中该过程涉及一个不寻常的C(sp)-C(sp)连接。该方法可以快速获得具有药学意义的化合物，极大地扩展吲哚生物碱库并加速先导化合物的优化，从而促进药物发现。
