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

We
report the synthesis of a series of bis-functionalized β-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 circular dichroism (CD) spectroscopy
and 1H-13C heteronuclear single quantum coherence
nuclear magnetic resonance (HSQC NMR) spectroscopy revealed robust
helical folding propensity in acetonitrile. CD analysis showed a solvent-dependent
degree of helical content in the structural ensembles when adding
different ratios of protic solvents including an aqueous buffer. These
studies were enabled by a substantial increase in solubility compared
to previously analyzed β-peptoid oligomers. This also allowed
for the investigation of the effect of pH on the folding propensity
of the amino- and carboxy-functionalized oligomers, respectively.
Interestingly, we could show 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.