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

Peptoids
that are oligomers of N-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 cis and trans conformations of their backbone amides is the major hurdle to overcome
for the construction of discrete folded structures, particularly for
the development of all-cis polyproline type I (PPI)
helices, as tools for modulating biological functions. The prominent
role of backbone to side chain electronic interactions (n → π*) and side chains bulkiness in promoting cis-amides was essentially investigated with peptoid aromatic
side chains, among which the chiral 1-naphthylethyl (1npe) 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
(S)-N-(1-tert-butylethyl)­glycine
(Ns1tbe) peptoid homo-oligomers. The X-ray crystal
structure of an Ns1tbe pentamer revealed an all-cis PPI helix, and the CD curves of the Ns1tbe 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 NtBu and Ns1tbe monomers. Strikingly,
the solid state structure of the mixed oligomer Ac-(tBu)2-(s1tbe)4-(tBu)2-COOtBu, 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.