Synthesis of alkyne-bridged cyclic tripeptides toward constrained mimics of vancomycin

The synthesis of a range of highly constrained cyclic tripeptides has been performed using either an intramolecular Sonogashira coupling or a macrolactamization as the final ring-closing reaction. Our approach gives access to rigidified 15-membered peptidic macrocycles based on the central ring system of vancomycin. Tripeptides 3a-c and dipeptide 11 were cyclized via an intramolecular Sonogashira reaction, and the cyclic peptides 4a-c and 15a were obtained in 6-23% yield. In contrast, macrolactamization of 12 and 17 resulted in the desired peptidic macrocycles 15b and 18 with 54-61% yield. Modeling studies hint at a distorted triple bond, which explains the low yield of the Sonogashira-based cyclization. Moreover, modeling data also showed that this class of peptidic macrocycles formed a cavity-like structure in which guest molecules may bind.