Azapeptide Atropisomers From Late-Stage <i>N</i>-Alkylations

We evaluate peptide sequence compatibility during late-stage azapeptide <i>N</i>-alkylation reactions and describe the atropisomeric properties of the azapeptoid and <i>N</i>1,<i>N</i>2-dialkylated azapeptide products. Our findings indicate that almost all protected amino acid side chains are compatible with the late-stage alkylation conditions on resin, with the exception of methionine. Using variable temperature NMR and dynamic HPLC, N-N rotational energy barriers of 15-16 and 20-24 kcal/mol are reported for a series of azapeptoids (monoalkylated) and <i>N</i>1,<i>N</i>2-dialkylated azapeptides, respectively.