Allylic Amines as Key Building Blocks in the Synthesis of (E)-Alkene Peptide Isosteres.

Abstract

Nucleophilic imine additions with vinyl organometallics have developed into efficient, high yielding, and robust methodologies to generate structurally diverse allylic amines. We have used the hydrozirconation-transmetalation-imine addition protocol in the synthesis of allylic amine intermediates for peptide bond isosteres, phosphatase inhibitors, and mitochondria-targeted peptide mimetics. The gramicidin S-derived XJB-5-131 and JP4-039 and their analogs have been prepared on up to 160 g scale for preclinical studies. These (E)-alkene peptide isosteres adopt type II' β-turn secondary structures and display impressive biological properties, including selective reactions with reactive oxygen species (ROS) and prevention of apoptosis.