Macrocyclization of ω-Isocyano Aldehydes

Medium-sized rings and macrocycles constitute a privileged class of scaffolds in medicinal chemistry, providing unique access to challenging biological targets through their preorganized, semi-rigid architectures. However, their synthesis remains challenging due to the unfavorable kinetic and thermodynamic constraints during ring closure. Herein, we report the efficient cyclization of ω-isocyano aldehydes via Passerini and Ugi multicomponent reactions (MCRs), alongside related variants. These transformations provide rapid access to structurally diverse medium-sized and macrocyclic α-acyloxy, α-hydroxy, α-acetamido, and α-keto lactams, as well as tetrazole-fused macrocycles, under mild conditions. Notably, this macrocyclization strategy relies on C(sp³)─C(sp²) bond formation while simultaneously generating α-functionalized amide motifs. By avoiding the need to pre-synthesize α-functionalized carboxylic acids, this approach offers a complementary alternative to traditional macrolactamization.