Expanding Macrocyclic Chemical Space through Ugi-Tetrazole-Based Macrocyclization

A multicomponent strategy for the synthesis of fused tetrazolo macrocycles is described. Isocyanoalkyl tosylates serve as bifunctional building blocks in the Ugi-tetrazole reaction, enabling spontaneous intramolecular macrocyclization without an external base to furnish 9-and 10-membered macrocycles in a single operation. The approach allows the rapid generation of structurally diverse scaffolds from simple aldehydes and amines. Cheminformatic analysis reveals that the resulting macrocycles occupy physicochemical space consistent with orally bioavailable macrocycles while expanding accessible macrocyclic chemical space.