Increasing the Functional Group Diversity in Helical β-Peptoids: Achievement of Solvent- and pH-Dependent Folding

Abstract

We report the synthesis of a series of bis-functionalized <i>b</i>-peptoid oligomers of the hexamer length. This was achieved by synthesizing and incorporating protected amino- or azido-functionalized chiral building blocks into precursor oligomers by a trimer segment coupling strategy. The resulting hexamers were readily elaborated to provide target compounds displaying amino groups, carboxy groups, hydroxy groups, or triazolo-pyridines, which should enable metal ion binding. Analysis of the novel hexamers by CD spectroscopy and HSQC NMR spectroscopy revealed robust helical folding propensity in acetonitrile. CD analysis showed solvent-dependent degree of helical content in the structural ensembles when adding different ratios of protic solvents including aqueous buffer. These studies were enabled by the substantial increase in solubility compared to previously analyzed <i>b</i>-peptoid oligomers. This also allowed for investigation of the effect of pH on folding propensity of the amino- and carboxy-functionalized oligomers, respectively. Interestingly, we could demonstrate a reversible effect of sequentially adding acid and base, resulting in a switching between compositions of folded ensembles with varying helical content. We envision that the present discoveries can form the basis for the development of functional peptidomimetic materials responsive to external stimuli.