Click chemistry as a route to cyclic tetrapeptide analogues:: Synthesis of cyclo-[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.