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

J Org Chem. 2020 Feb 7;85(3):1556-1566. doi: 10.1021/acs.joc.9b02659. Epub 2019 Dec 26.

Abstract

α,α'-Disubstituted amino acids serve as important non-proteinogenic amino acids in the construction of stabilized helical peptides. To expand the repertoire of α,α'-disubstituted amino acids, chiral alkenyl-containing cyclopropane amino acids were synthesized 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.

Publication types

  • Research Support, Non-U.S. Gov't