Aniline catalysis has allowed oxime ligations between α-oxo aldehydes or ketones with aminooxy functional group to proceed at pH 7, which has increased their utility in bioconjugation reactions. While formation of an aniline Schiff base intermediates is critical for reactivity, high concentrations of aniline can be toxic to cells and selectivity in the presence of endogenous ketones and aldehydes can be problematic. Additionally, methods to install α-oxo-carbonyl functional groups on peptide substrates typically require NaIO4 exposure, which may lead to side-reactions with sensitive residues (e.g. Met, Trp), or the use of excess pyridoxal 5’-phosphate (PLP). We recently reported that aerobic oxidation of certain N-phenylglycinyl peptides to give α-imino amide intermediates in situ was possible, which reacted with aminooxy groups to yield oxime products in the absence catalysts. Here, we demonstrate that N-aryl peptides, possessing diverse substituents at the α-carbon, can also undergo tandem aerobic oxidation/oxime ligation reactions at neutral pH to afford substituted oxime bonds. The scope of this work will be discussed, and mechanistic insight will be provided.

Ketoxime peptide ligations by employing tunable N-aryl peptide substrates

ACS Fall 2021

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