Scanning nitrogen in sp3-rich scaffolds enabled by carbonyl-to-nitrogen atom swap

• 成果类型: Article
• 署名作者: Zhang, Zining; Liang, Zhehan; Ye, Rong; Dong, Guangbin
• 署名单位: University of Chicago
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aef0610
• 发表日期: 2026-04-30
• 页码: 536-542
• 关键词: PHARMACOLOGICAL EVALUATION; binding; potent; affinity; DESIGN; isomerization; substitution; PROPIVERINE; metabolites; derivatives

摘要

Medicinal chemistry campaigns routinely require access to series of saturated nitrogen heterocycle (SNH)-based analogs that place nitrogen at different positions to probe structure-activity relationships. However, systematic preparation of N-positional variants remains synthetically burdensome. In this work, we report a strategy for nitrogen scanning in sp3-rich scaffolds enabled by the exchange of a carbonyl group with an amine moiety, formally achieving a carbonyl-to-nitrogen (CO-to-N) atom swap. Because ketone positional isomers can be readily obtained through carbonyl transposition or carbon-hydrogen oxidation from a common carbocyclic precursor, the CO-to-N atom swap greatly streamlines the preparation of SNH positional analogs and obviates the need for multiple de novo syntheses. The CO-to-N reaction exhibits exceptional functional group compatibility and generality, which makes it well suited for late-stage modification of complex bioactive molecules and for isotopic labeling.