Carbonyl-to-sulfur swap enabled by sequential double carbon-carbon bond activation

• 成果类型: Article
• 署名作者: Zhang, Zining; Dong, Guangbin
• 署名单位: University of Chicago
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-12782
• DOI: 10.1126/science.adx2723
• 发表日期: 2025-06-26
• 页码: 1436-1440
• 关键词: molecular-orbital methods; organic-synthesis; single-atom; ketones; thiasteroids; derivatives; chemistry; biology; potent

摘要

In drug development, replacement of a skeletal carbon with a sulfur atom can result in analogs of bioactive compounds with improved properties. Currently, the sulfur analogs are almost exclusively prepared by de novo synthesis; the existing approach to swap carbon with sulfur is inefficient and involves stoichiometric mercury reagents. In this study, we report a two-step carbonyl-to-sulfur (CO-to-S) atom swap approach, enabled by a rationally designed N '-alkyl-hydrazonamide (NAHA) reagent that promotes forming pre-aromatic intermediates twice sequentially by different mechanisms, thereby achieving homolytic cleavage of both alpha-C-C bonds of the ketone substrates. A Ts-S-Ts (Ts, p-toluenesulfonyl) reagent mediates this process through successive intermolecular and intramolecular alkyl radical trapping by the central sulfur. This method shows a broad substrate scope and excellent chemoselectivity, providing a streamlined route to sulfur-containing scaffolds from readily available ketones.