Side Reaction of Significance in Preparation of Peptide- or Peptidomimetic-Based Hydroxamate Enzyme Inhibitors

Peptidic and peptidomimetic hydroxamates are increasingly
being developed as potential pharmaceutical agents in
targeting metalloenzymes. For a number of practical considerations, the hydroxamate moiety is often introduced in
the synthesis onto valuable advanced synthetic precursors.
The approach entails activation of the carboxylate of the
synthetic precursor by any number of methods for the
preparation of the hydroxamate. We report herein that this
widely used approach in preparation of an entire class of
enzyme inhibitors is problematic as documented by the
formation of an undesirable cyclization product (characterized in this report), which could at times be the exclusive
outcome of the carboxylate activation process.