Precision indole skeletal editing for single-carbon replacement
Summary
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 s
Content
# Precision indole skeletal editing for single-carbon replacement
*Published: 2026 Apr 30*
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.
DOI: 10.1126/science.aec3587