Skeletal editing of pyrrolidines by nitrogen-atom insertion

• 成果类型: Article
• 署名作者: Li, Jinghao; Tang, Pengcheng; Fan, Yang; Lu, Hongjian
• 署名单位: Guizhou University; Nanjing University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9512
• DOI: 10.1126/science.adl4755
• 发表日期: 2025-07-17
• 页码: 275-281
• 关键词: deletion

摘要

Given the prevalence of nitrogen-containing heterocycles in bioactive molecules, inserting a nitrogen atom into a saturated ring offers a powerful yet underdeveloped scaffold-hopping strategy for expanding drug-like chemical space. In this study, we present a skeletal editing method that directly inserts a nitrogen atom into pyrrolidine rings, converting them into tetrahydropyridazine scaffolds under mild, operationally simple conditions with readily available O-diphenylphosphinyl hydroxylamine. This method features broad substrate scope and functional group compatibility, enabling late-stage editing of complex molecules. Furthermore, simple redox manipulation of the tetrahydropyridazines grants access to saturated piperidazines and aromatic pyridazines-nitrogen-rich scaffolds that are highly valued in medicinal chemistry but typically difficult to synthesize. Overall, this work establishes a versatile platform for nitrogen-based skeletal editing of saturated pyrrolidines, expanding the synthetic toolkit for medicinal chemistry.