Modular assembly of indole alkaloids enabled by multicomponent reaction

Jiaming Li, Zhencheng Lai, Weiwei Zhang, Linwei Zeng and Sunliang Cui ()
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Jiaming Li: Zhejiang University
Zhencheng Lai: Zhejiang University
Weiwei Zhang: Zhejiang University
Linwei Zeng: Zhejiang University
Sunliang Cui: Zhejiang University

Nature Communications, 2023, vol. 14, issue 1, 1-10

Abstract: Abstract 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(sp3)–C(sp3) 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.

Date: 2023
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DOI: 10.1038/s41467-023-40598-y

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