Highly Sterically Hindered Peptide Bond Formation between α,α-Disubstituted α-Amino Acids and N-Alkyl Cysteines Using α,α-Disubstituted α-Amidonitrile

Abstract

Peptides and proteins attract enormous attention in many fields of academia and industry. The introduction of unusual amino acids such as α,α-disubstituted α-amino acids or N-alkyl α-amino acids into normal peptide backbones is a well-utilized and useful tool for the modification of properties such as conformation, biological activity, and pharmacological profile. Despite the significant interest in sterically hindered peptides, research on peptides bearing an amide bond between an α,α-disubstituted α-amino acid and an N-alkyl α-amino acid remains underexplored because of the lack of an efficient synthetic approach. Herein, we describe a high-yielding synthetic method to access such extremely sterically hindered peptide bonds between amino acids. The reaction takes place between a peptide with an α,α-disubstituted α-amidonitrile and a second peptide bearing an N-alkyl cysteine, without a coupling reagent.