Novel methodology for the synthesis of a-indolyl-glycine containing peptide via direct asymmetric Friedel–Crafts reaction to peptidyl imine

Peptides which contain unnatural amino acids are attractive novel drug candidates due to their biological activity superior to those of the peptides consisting of only proteinogenic amino acids.[1] These peptides are conventionally prepared by two steps; (1) asymmetric synthesis of unnatural amino acid unit, and (2) installation of the unit by Fmoc or Boc Solid-phase peptide synthesis (Fig. 1-A).However, the present procedure requires multi-step of reaction, including removal of the protective groups of amino and carboxy groups and protection of the amine moiety by Fmoc group, to prepare diverse of peptide.To develop new methodology which addresses this problem, we envisioned an asymmetric construction of unnatural amino acid units in a growing peptide chain (Fig. 1-B).[3] If direct asymmetric 1,2-addition of α-iminopeptideis realized, changing of the nucleophiles enables easy access to a diverse range of unnatural amino acid-containing peptides.