Diversified ring expansion of saturated cyclic amines enabled by azlactone insertion

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. Saturated N-heterocycles are ubiquitous structures among natural products and biologically active compounds, but methods to edit the ring size of these substructures are scarce. Now the ring expansion of unactivated cyclic amines has been achieved via sequential Ru-catalysed C‒C bond formation, retro-aza-Michael addition and a lactamization process to construct synthetically challenging medium-sized azacycles.