骨架编辑~武汉大学闵昶JACS:通过形式羰基插入实现吡啶盐的发散性骨架编辑反应
Skeletal editing offers a powerful strategy for rapid diversification of molecular frameworks without requiring de novo synthesis, yet most existing methods enable only a single, unidirectional scaffold transformation from a given substrate. Here, we report a divergent skeletal editing platform for pyridinium salts that enables sequential ring expansion and contraction from a common heteroaromatic precursor. Formal carbonyl insertion into pyridines proceeds with good efficiency at either the para or ortho position to afford azepinones under mild conditions. Subsequent photochemical [2+2] cycloaddition triggers two-carbon exocyclic transposition, delivering pyrrolidinone scaffolds not readily accessible through direct pyridine editing. This sequence constitutes a rare example of bidirectional ring-size editing (6→ 7→5) from a single core structure. The method exhibits a broad substrate scope, excellent functional group tolerance, and compatibility with late-stage modifications of drug molecules. This work establishes pyridines as versatile substrates for divergent skeletal editing and provides a practical framework for scaffold hopping in medicinal chemistry.图4. 对位羰基插入反应底物拓展 (图片来源于JACS)图5. 邻位羰基插入反应底物拓展 (图片来源于JACS)图6. 氮杂卓酮的[2+2]光环加成反应合成吡咯烷酮底物拓展 (图片来源于JACS)图7. 合成应用和衍生化反应 (图片来源于JACS)In summary, we have developed a divergent skeletal-editing strategy that enables programmable ring expansion and contraction of pyridinium salts. Formal carbonyl insertion converts pyridines into azepinones under mild, one-pot conditions with broad functional-group tolerance and late stage applicability. The resulting azepinones serve as versatile relay intermediates that undergo photochemical [2 + 2] cycloaddition to effect formal two-carbon transposition, providing access to pyrrolidinone scaffolds through a rare bidirectional ring-size editing sequence (6 → 7 → 5). This work establishes pyridines as a privileged framework for divergent skeletal editing and offers a practical framework for scaffold diversification in medicinal chemistry.
