Macrocyclization of ω‐Isocyano Aldehydes

ABSTRACT 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(sp 3 )─C(sp 2 ) 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.