Azapeptides are unnatural peptide mimics in which one or more α-carbon center is substituted for a nitrogen. This substitution has been shown to restrict the conformation of the peptide backbone as well as perturb the pKa’s of the surrounding nitrogen atoms. In this work, we take advantage of the variations in acidity to introduce diverse side chains onto internal azaglycine residues. Through a combination of MS/MS sequencing, Edman degradation and NMR, we demonstrate that the installation of these side chains is highly selective for the azaglycine over any other backbone nitrogen. This late-stage functionalization of azaglycine-containing peptides allows for the expeditious creation of a library of substituted azapeptides from a single compound.

Late-stage fucntionalization of azaglycine-containing peptides

ACS Spring 2022

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