α-Aminoxy Peptoids: A Unique Peptoid Backbone with a Preference for cis-Amide Bonds

α-Peptoids, or N-substituted glycine oligomers, are an important class of peptidomimetic foldamers with proteolytic stability. Nevertheless, the presence of cis/trans-amide bond conformers, which contribute to the high flexibility of α-peptoids, is considered as a major drawback. A modified peptoid backbone with an improved control of the amide bond geometry could therefore help to overcome this limitation. Herein, we have performed the first thorough analysis of the folding propensities of α-aminoxy peptoids (or N-substituted 2-aminoxyacetic acid oligomers). To this end, the amide bond geometry and the conformational properties of a series of model α-aminoxy peptoids were investigated by using 1D and 2D NMR experiments, X-ray crystallography, natural bond orbital (NBO) analysis, circular dichroism (CD) spectroscopy, and molecular dynamics (MD) simulations revealing a unique preference for cis-amide bonds even in the absence of cis-directing side chains. The conformational analysis based on the MD simulations revealed that α-aminoxy peptoids can adopt helical conformations that can mimic the spatial arrangement of peptide side chains in a canonical α-helix. Given their ease of synthesis and conformational properties, α-aminoxy peptoids represent a new member of the peptoid family capable of controlling the amide isomerism while maintaining the potential for side-chain diversity.