Wu Licheng, Xia Hanyu, Bai Jiahao, Xi Yang, Wu Xianqing, Gao Li, Qu Jingping, Chen Yifeng
Key Laboratory for Advanced Materials and Joint International Research Laboratory of Precision Chemistry and Molecular Engineering, Feringa Nobel Prize Scientist Joint Research Center, Frontiers Science Center for Materiobiology and Dynamic Chemistry, School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai, China.
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
Nat Chem. 2024 Dec;16(12):1951-1959. doi: 10.1038/s41557-024-01668-w. Epub 2024 Nov 21.
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 C‒C 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.
饱和氮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，开发构建氮杂环的合成方法在合成领域具有重要意义。通过分子编辑技术将这些基序的环系改变为具有不同环大小的类似物，在药物化学中极具吸引力。我们在此展示了将甘氨酸衍生物作为双碳合成子直接插入到无张力的五元或六元饱和环状胺的可预测位点，通过钌催化的碳-碳键形成、逆氮杂-Michael加成和内酰胺化过程，实现了具有合成挑战性的中等大小氮杂环的构建。经过进一步衍生，我们利用这个同系化平台实现了一碳或两碳单元在脂肪环中的模块化插入。将单个氮杂环转化为多达五个其他氮杂环，为使现有候选药物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。
