Stereo-controlled Synthesis of [L-Arg, L/D-3-(2-Naphthyl)alanine]-type (E)-Alkene Dipeptide Isosteres and its Application to the Preparation and Biological Evaluation of Peptidomimetic Analogs of the CXCR4 Antagonist FC131

Abstract

l,l-Type and l,d-type (E)-alkene dipeptide isosteres (EADIs) that have unnatural side chains at the α-position were synthesized by the combination of stereoselective aziridinyl ring-opening reactions and organozinc−copper-mediated anti-SN2‘ reactions toward a single substrate of γ,δ-cis-γ,δ-epimino (E)-α,β-enoate. The utility of this methodology was demonstrated by the stereoselective synthesis of a set of diastereomeric EADIs of l-Arg-l/d-3-(2-naphthyl)alanine (Nal) that is contained in a small CXCR4 antagonist FC131 [cyclo(-d-Tyr-Arg-Arg-Nal-Gly-)]. Furthermore, a (Nal-Gly)-type EADI was synthesized by samarium diiodide (SmI2)-induced reduction of a γ-acetoxy-α,β-enoate. Several FC131 analogues, in which these EADIs were inserted for reduction of their peptide character, were synthesized with analogues containing reduced amide-type dipeptide isosteres to investigate the importance of these amide bonds for anti-HIV and CXCR4-antagonistic activity.