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

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Abstract
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

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