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Stereoselective Synthesis of [l-Arg-l/d-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

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journal contribution
posted on 27.01.2005 by Hirokazu Tamamura, Kenichi Hiramatsu, Satoshi Ueda, Zixuan Wang, Shuichi Kusano, Shigemi Terakubo, John O. Trent, Stephen C. Peiper, Naoki Yamamoto, Hideki Nakashima, Akira Otaka, Nobutaka Fujii
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.