Synthesis and Application of (Z)-Alkene- and (E)-Fluoroalkene-Dipeptide Isosteres as cis-Amide Equivalents

Abstract

Introduction dipeptide isosteres have been developed as nonhydrolyzable peptide-bond bio-isosteres that mimic the planar structure of peptide bonds. Restricted peptide bond (ω-angle) rotations in alkene-type isosteres enable one to investigate the cis or trans conformation of the peptide bonds. The precedented synthetic methods reported for alkene-type dipeptide isosteres preferentially provide trans-amide bond mimics, such as (E)-alkene dipeptide isosteres (ADIs) and (Z)fluoroalkene dipeptide isosteres (FADIs). On the other hand, there have only been a few reports on the synthesis of cis-amide bond mimics possessing (Z)-alkene or (E)fluoroalkene, which limits their application. Recently, we established a widely applicable synthetic method for the synthesis of (Z)-ADI and (E)-FADI using organocopper-mediated reduction of certain α,βunsaturated-δ-lactams possessing a leaving group(s) at the γ-position, followed by ring-opening of the lactams [1]. Herein, we report the use of Phe-Gly-type (Z)-ADI and (E)-FADI in the Fmocbased solid-phase peptide synthesis (SPPS) of peptide derivatives of a GPR54 agonist 1 [H-Amb-Phe-Gly-Leu-Arg-Trp-NH2; Amb = 4-(aminomethyl)benzoic acid], to probe the conformational requirement of its Phe-Gly peptide bond.