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)-(s1tbe)-(tBu)-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.

The synthesis and conformational preferences of a set of new synthetic foldamers that combine both the α,β-peptoid backbone and side chains that alternately promote cis- and trans-amide bond geometries have been achieved and addressed jointly by experiment and molecular modeling. Four sequence patterns were thus designed and referred to as cis-β- trans-α, cis-α- trans-β, trans-β- cis-α, and trans-α- cis-β. α- and β NtBu monomers were used to enforce cis-amide bond geometries and α- and β NPh monomers to promote trans-amides. NOESY and molecular modeling reveal that the trans-α- cis-β and cis-β- trans-α tetramers show a similar pattern of intramolecular weak interactions. The same holds for the cis-α- trans-β and trans-β- cis-α tetramers, but the interactions are different in nature than those identified in the trans-α- cis-β-based oligomers. Interestingly, the trans-α- cis-β peptoid architecture allows establishment of a larger amount of structure-stabilizing intramolecular interactions.