Synthesis of Chiral Alkenyl Cyclopropane Amino Acids for Incorporation into Stapled Peptides.

Abstract

α,α -Disubstituted amino acids serve as important non-proteinogenic amino acids in the construction of stabilised helical peptides. To expand the repertoire of α,α -disubstituted amino acids, chiral alkenyl-containing cyclopropane amino acids were synthesised via a two-step olefination and cyclopropanation procedure. Herein we report the first example of the use of alkenyl cyclopropane building blocks to constrain MDM2-targeting helical peptides. The increased potency and efficacy associated with C-terminal cyclopropane substitution is postulated to be driven by a combined effect of net hydrophobicity and enhanced protein association rates.