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. 2025 Jul 11;90(27):9549-9558.
doi: 10.1021/acs.joc.5c01024. Epub 2025 Jun 30.

Azapeptide Atropisomers From Late-Stage N-Alkylations

Molly E Helton  1 , Christopher S Howard  1 , Keisy Prieto Bruno  1 , Katelyn D Cartrette  1 , Maxwell O Bowles  1 , William A Hearne  2 , Caroline Proulx  1
Affiliations

Azapeptide Atropisomers From Late-Stage N-Alkylations

Molly E Helton et al. J Org Chem. .

Abstract

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.

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