Benzophenone semicarbazone protection strategy for synthesis of aza‐glycine containing aza‐peptides

Aza‐glycine has been incorporated into peptide mimics as a tool for studying the active conformation and characterizing structure‐function relationships for activity. Side reactions, such as intramolecular cyclizations to form hydantoins and oxadiazalones, have, however, inhibited efforts to make activated aza‐Gly residues in solution using carbamate protection. Herein, we describe efficient incorporation of aza‐glycine into aza‐peptides using diphenyl hydrazone protection. Hydrazone acylation with p‐nitrobenzyl chloroformate provided the protected aza‐Gly activated ester, which was used to acylate a set of amino ester and amino acids to provide aza‐Gly‐Xaa aza‐dipeptide fragments for peptide synthesis. Removal of the hydrazone protection was performed under acidic conditions to provide the hydrochloride salt of the aza‐Gly residue for subsequent elongation of the aza‐peptide chain using standard coupling conditions. A proof of concept for the use of benzophenone protection has been established by the synthesis of an aza‐peptide analog of a potent activator of caspase 9 in cancer cells. © 2008 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 90: 824–831, 2008. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com