Stereoselective Synthesis of [<SCP>l</SCP>-Arg-<SCP>l</SCP>/<SCP>d</SCP>-3-(2-naphthyl)alanine]-Type (E)-Alkene Dipeptide Isosteres and Its Application to the Synthesis and Biological Evaluation of Pseudopeptide Analogues of the CXCR4 Antagonist FC131

<SCP>l</SCP>,<SCP>l</SCP>-Type and <SCP>l</SCP>,<SCP>d</SCP>-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-S<INF>N</INF>2‘ 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 <SCP>l</SCP>-Arg-<SCP>l</SCP>/<SCP>d</SCP>-3-(2-naphthyl)alanine (Nal) that is contained in a small CXCR4 antagonist FC131 [cyclo(-<SCP>d</SCP>-Tyr-Arg-Arg-Nal-Gly-)]. Furthermore, a (Nal-Gly)-type EADI was synthesized by samarium diiodide (SmI<INF>2</INF>)-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.