Incorporation of a cis-Amide Bond Isostere in the Synthesis of Cyclic Tetrapeptides

Abstract

Cyclic tetrapeptides are an exciting class of molecules showing a wide range of biological activities. They are very difficult to synthesize due to the inherent strain of the 12 membered ring. Our initial experiments on the inclusion of backbone substituents to increase the propensity for cis conformations of the amide bond [1] resulted in significant improvements in yields for cyclizing these linear precursors. To support the hypothesis on the role of cis amide bonds in reducing ring strain within cyclic tetrapeptides, and to provide a simple synthetic method in accessing these molecules we have been evaluating cis-amide bond surrogates. We initially decided on the synthesis of a pyrrole as a conformational isostere and to incorporate this into a cyclic motif to examine its effect on cyclization. Herein, we report on a simple preparation of an unprotected H-Gly-Tyr-OH dipeptide surrogate which contains a 1,2-pyrrole Ψ[C₄H₃N] moiety designed to mimic a cis amide bond (Figure 1).