Cis–Trans Amide Bond Rotamers in β-Peptoids and Peptoids: Evaluation of Stereoelectronic: Effects in Backbone and Side Chains

Jonas Striegler Laursen, Jens Engel-Andreasen, Peter Fristrup, Pernille Harris, Christian Adam Olsen

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Abstract

Non-natural peptide analogs have significant potential for the development of new materials and pharmacologically active ligands. One such architecture, the β-peptoids (N-alkyl-β-alanines), has found use in a variety of biologically active compounds, but has been sparsely studied with respect to folding propensity. Thus, we here report an investigation of the effect of structural variations on the cis–trans amide bond rotamer equilibria in a selection of monomer model systems. In addition to various side chain effects, which correlated well with previous studies of α-peptoids, we present the synthesis and investigation of cis–trans isomerism in the first examples of peptoids and β-peptoids containing thioamide bonds as well as trifluoroacetylated peptoids and β-peptoids. These systems revealed an increase in the preference for cis-amides as compared to their parent compounds, and thus provide novel strategies for affecting the folding of peptoid constructs. By using NMR spectroscopy, X-ray crystallographic analysis, and density functional theory calculations, we present evidence for the presence of thioamide–aromatic interactions through Csp2-HSamide hydrogen bonding, which stabilize certain peptoid conformations.

Original languageEnglish
JournalJournal of the American Chemical Society
Volume135
Issue number7
Pages (from-to)2835-2844
ISSN0002-7863
DOIs
Publication statusPublished - 2013

Keywords

  • Amino acids
  • Bioactivity
  • Density functional theory
  • Hydrogen bonds
  • Nuclear magnetic resonance spectroscopy
  • X ray crystallography
  • Amides

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