New Methods for the Chemoselective Functionalization of Peptides

Chemoselective reactions that occur under mild conditions are required to synthesize and
functionalize biomolecules. To that end, ligation of a-nucleophiles with a-oxo-aldehydes
or ketones have been pursued; however, addition of superstoichiometric amounts of
aniline are typically required to construct oxime and hydrazone bonds at neutral
pH via formation of an aniline Schiff-base intermediate. Moreover, while starting from
ketone substrates instead of aldehydes would allow substitution at the site of ligation,
synthetic challenges to access ketone derivatives from common amino acid building
blocks and their slow reactivity in condensation reactions have precluded their
widespread use in peptide ligations. Here, we expand the utility of oxime and hydrazone
ligation reactions by providing direct access to reactive a-imino amide intermediates from
a site-selective, aerobic oxidation of N-aryl peptides. We demonstrate that the reactivity
of N-aryl peptides can be modulated by the electronics of the aryl ring, and that various
substitution at the a-carbon can be introduced at the site of ligation in high yield. Efforts
towards streamlining N-aryl peptide synthesis, as well as controlling the structural and
conformational properties of ketoxime and kethydrazone-linked peptides will also be
discussed.