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 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社区中具有重要意义。通过采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，这在药物化学中将非常有吸引力。我们在此介绍了甘氨酸衍生物作为双碳合成子在可预测位点直接插入未应变的五元或六元饱和环胺中，从而能够通过连续 Ru 催化的 C\u2012C 键形成、逆氮杂-Michael 加成和内酰胺化过程构建合成具有挑战性的中等大小氮杂环。在进一步推导后，我们利用这个认证平台实现将一碳或双碳单元模块化插入脂肪环中。将单个 azacycle 转换为多达五个其他 azacycle 为实现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途的工具箱。