Allylic Amines as Key Building Blocks in the Synthesis of (E)-Alkene Peptide Isosteres.
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.
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Erin M
EM
Skoda
Gary C
GC
Davis
Peter
P
Wipf