Homogeneous and Robust Polyproline Type I Helices from Peptoids with Nonaromatic α‑Chiral Side Chains

Peptoids that are oligomers of <i>N</i>-substituted glycines represent a class of peptide mimics with great potential in areas ranging from medicinal chemistry to biomaterial science. Controlling the equilibria between the <i>cis</i> and <i>trans</i> conformations of their backbone amides is the major hurdle to overcome for the construction of discrete folded structures, particularly for the development of all-<i>cis</i> polyproline type I (PPI) helices, as tools for modulating biological functions. The prominent role of backbone to side chain electronic interactions (<i>n</i> → π*) and side chains bulkiness in promoting <i>cis</i>-amides was essentially investigated with peptoid aromatic side chains, among which the chiral 1-naphthylethyl (<i>1npe</i>) group yielded the best results. We have explored for the first time the possibility to achieve similar performances with a sterically hindered α-chiral aliphatic side chain. Herein, we report on the synthesis and detailed conformational analysis of a series of (<i>S</i>)-<i>N</i>-(1-<i>tert</i>-butylethyl)­glycine (<i>N</i>s1tbe) peptoid homo-oligomers. The X-ray crystal structure of an <i>N</i>s1tbe pentamer revealed an all-<i>cis</i> PPI helix, and the CD curves of the <i>N</i>s1tbe oligomers also resemble those of PPI peptide helices. Interestingly, the CD data reported here are the first for any conformationally homogeneous helical peptoids containing only α-chiral aliphatic side chains. Finally we also synthesized and analyzed two mixed oligomers composed of <i>Nt</i>Bu and <i>N</i>s1tbe monomers. Strikingly, the solid state structure of the mixed oligomer Ac-(<i>t</i>Bu)₂-(<i>s1tbe</i>)₄-(<i>t</i>Bu)₂-COO<i>t</i>Bu, the longest to be solved for any linear peptoid, revealed a PPI helix of great regularity despite the presence of only 50% of chiral side chain in the sequence