Precision indole skeletal editing for single-carbon replacement.

Abstract

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.