<i>Cis</i>–<i>Trans</i> Amide Bond Rotamers in β‑Peptoids and
Peptoids: Evaluation
of Stereoelectronic Effects in Backbone and Side Chains
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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 <i>cis</i>–<i>trans</i> 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 <i>cis</i>–<i>trans</i> 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 <i>cis</i>-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 C<sub>sp<sup>2</sup></sub>–H···S<sub>amide</sub> hydrogen bonding, which stabilize certain peptoid conformations