Oral Presentation 8th Modern Solid Phase Peptide Synthesis & Its Applications Symposium 2022

Azapeptides typically possess at least one aza-amino acid residue embedded in a peptide sequence, where the a-carbon has been replaced by a nitrogen atom. These peptidomimetics tend to favor b-turns and polyproline type II helices while also altering hydrogen bonding, which can be used to modulate bioactivity and self-assembly. In contrast, fewer studies of azapeptoids have been reported, where the side chain is located on the adjacent (N1) nitrogen atom. Similarly, examples of highly substituted N1,N2-dialkylated azapeptides remain scarce in the literature, likely due to synthetic difficulties. Here, we report the late-stage N-alkylation of resin-bound azapeptides as a divergent strategy to install side chains selectively on the aza-amino acids. We demonstrate that minor modification of the alkylation conditions can yield either mono-alkylated azapeptoids or dialkylated azapeptides, and confirm the selectivity of the reaction using Edman degradation, tandem mass spectrometry, and NMR spectroscopy. This method provided access to underexplored peptidomimetics, and was used to rapidly synthesize >20 Leu-Enkephalin derivatives as a proof of concept.