Precision indole skeletal editing for single-carbon replacement

• 成果类型: Article
• 署名作者: Zhang, Ling; Lang, Yatao; Luo, Zhen; Han, Xinlong; Zeng, Huiying; Li, Chao-Jun
• 署名单位: Lanzhou University; McGill University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aec3587
• 发表日期: 2026-04-30
• 页码: 512-518
• 关键词: RETRO-MANNICH FRAGMENTATION; ASYMMETRIC TOTAL-SYNTHESIS; molecular-orbital methods; NITROGEN-ATOM INSERTION; gaussian-type basis; enantioselective synthesis; formal synthesis; basis-sets; QUEBRACHAMINE; heterocycles

摘要

Indole is widely present in pharmaceuticals and natural products. In this work, we report an intramolecular skeletal editing reaction of tryptamine derivatives enabled by photoreaction of a pendant amide that simultaneously achieves regioselective single-carbon replacement and substitution at the C2 position of indoles. This strategy facilitates deuteration, alkylation, arylation, and acylation at the indole C2 position while also enabling the incorporation of 13C-labeled carbon into the scaffold. We highlighted the practical applicability of this method through a concise four-step total synthesis of quebrachamine, a complex monoterpene indole alkaloid. Experimental studies and density functional theory (DFT) calculations revealed a reaction pathway involving cascade [2+2] cycloaddition, retro-[2+2] ring opening, decarbonylation, and cyclization, elucidating the sequence at an atomic level.