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.
Department of Medicinal Chemistry, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, P.O. Box 80082, 3508 TB Utrecht, The Netherlands.
Hefziba T
HT
ten Brink
Dirk T S
DT
Rijkers
Rob M J
RM
Liskamp
D000480:Alkynes / Q000737:chemistry*; D000900:Anti-Bacterial Agents / Q000737:chemistry*; D003500:Cyclization; D010456:Peptides, Cyclic / Q000138:chemical synthesis*; D014640:Vancomycin / Q000737:chemistry*
D000480:Alkynes; D000900:Anti-Bacterial Agents; D010456:Peptides, Cyclic; D014640:Vancomycin