华东理工大学陈宜峰团队报道了氮杂内酯的插入实现饱和环胺的多样化扩环。相关研究成果发表在2024年11月21日出版的《自然—化学》。

饱和N-杂环是天然产物和生物活性化合物中普遍存在的结构。因此，开发构建N-杂环的合成方法在合成界具有重要意义。通过使用分子编辑技术将这些基序的环系统，改变为具有不同环大小的类似物在药物化学中具有很高的吸引力。

该文中，研究人员介绍了甘氨酸衍生物作为两个碳合成子，在可预测的位点直接插入未受应变的五元或六元饱和环胺中，通过连续的钌催化CC键形成、反氮杂迈克尔加成和内酰胺化过程，能够构建具有合成挑战性的中等氮杂环。

经过进一步推导，利用这个同源平台实现了将一个或两个碳单元模块化插入脂肪环。将单个氮杂环转化为多达五个其他氮杂环，为现有候选药物的多样化和增加临床成功的前景，提供了一个有前景的工具箱。

附：英文原文

Title: Diversified ring expansion of saturated cyclic amines enabled by azlactone insertion

Author: Wu, Licheng, Xia, Hanyu, Bai, Jiahao, Xi, Yang, Wu, Xianqing, Gao, Li, Qu, Jingping, Chen, Yifeng

Issue&Volume: 2024-11-21

Abstract: Saturated N-heterocycles are ubiquitous structures among natural products and biologically active compounds. Therefore, the development of synthetic methods for the construction of N-heterocycles is of great importance in the synthetic community. Altering the ring system of these motifs to analogues with different ring sizes by employing molecular editing techniques would be highly appealing in medicinal chemistry. We present herein the direct insertion of glycine derivatives as two-carbon synthons into unstrained five- or six-membered saturated cyclic amines at predictable sites, enabling the construction of synthetically challenging medium-sized azacycles through sequential Ru-catalysed CC bond formation, retro-aza-Michael addition and a lactamization process. Upon further derivation, we leverage this homologation platform to realize modular insertion of one- or two-carbon units into the aliphatic rings. The conversion of a single azacycle into up to five others provides a promising toolbox for diversifying existing drug candidates and increasing the prospects for clinical success.

DOI: 10.1038/s41557-024-01668-w

Source: https://www.nature.com/articles/s41557-024-01668-w