Copper(I)-Mediated Denitrogenative Macrocyclization for the Synthesis of Cyclic α3 β-Tetrapeptide Analogues

Abstract

A copper(I)-mediated denitrogenative reaction has been successfully developed for the preparation of cyclic tetrapeptides. The key reactive intermediate, ketenimine, triggers intramolecular cyclization through attack of the terminal amine group to generate an internal β-amino acid with an amidine linkage. The chemistry developed herein provides a new synthetic route for the preparation of cyclic α₃ β-tetrapeptide analogues that contain important biological properties and results in rich structural information being obtained for conformational studies. With the success of this copper(I)-catalyzed macrocyclization, two histone deacetylase inhibitor analogues consisting of the cyclic α₃ β-tetrapeptide framework have been successfully synthesized.

Keywords: copper; inhibitors; macrocycles; peptides; synthesis design.