Click Chemistry as a Route to Cyclic Tetrapeptide Analogues:  Synthesis ofcyclo-Pro-Val-ψ(triazole)-Pro-Tyr

Despite the plethora of techniques to cyclize small peptides, a synthesis of cyclo-(L)Pro-(L)Tyr-(L)Pro-(L)Val, a potent tyrosinase inhibitor, remains elusive because of the unfavorable transition state leading to the cyclic product. Herein, we report the successful synthesis of its triazole analogue, cyclo-(L)Pro-(L)Val-psi(triazole)-(L)Pro-(L)Tyr. Attempted cyclization via peptide bond formation at room temperature fails to provide the desired product, but Cu(I)-catalyzed alkyne-azide coupling at 110 degrees C affords the triazole tetrapeptide in 70% yield, demonstrating the utility of "click" chemistry.