Peptoids are proteolytically stable peptidomimetics composed of N-substituted glycine monomers, with applications ranging from medicinal chemistry to nanomaterials. They can be easily synthesized using a two-step submonomer method that alternates between 1) acylation of a resin-bound peptoid with bromoacetic acid, and 2) bromide displacement with amines. However, peptoids are typically more flexible than their peptide counterparts due to their tertiary amide backbone composition, as well as the absence of a stereocenter at the α-carbon and the lack of a backbone hydrogen bond donor (NH). Here, we introduce the use of hydrazones as new submonomers in solid phase peptoid synthesis. Hydrazones are easily accessible through simple condensation reactions between hydrazine and carbonyl compounds, and can be used in standard submonomer synthesis procedures to introduce N-iminoglycine residues. Moreover, by simply changing the resin cleavage conditions, we show that N-alkylamino-glycine-containing peptoids can also be obtained. Using a combination of NMR spectroscopy, X-ray crystallography, and computational studies, we demonstrate that both N-imino- and N-alkylamino-glycines have a strong preference for the trans-amide bond geometry, expanding the toolbox of available structure-inducing peptoid monomers.

Submonomer synthesis of peptoids containing trans-inducing N-imino- and N-alkylamino-glycines

ACS Fall 2021

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