Azapeptide Atropisomers From Late-Stage N-Alkylations

We evaluate peptide sequence compatibility during late-stage azapeptide N-alkylation reactions and describe the atropisomeric properties of the azapeptoid and N1,N2-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 N1,N2-dialkylated azapeptides, respectively.