Access to homogeneous and discrete folded peptoid structures primarily depends on control of the cis/trans isomerism of backbone tertiary amides. This can be achieved by designing specific side chains capable of forming local interactions with the backbone. This is often undertaken at the expense of side-chain diversity, which is a key advantage of peptoids over other families of peptidomimetics. We report for the first time a positively charged triazolium-type side chain that does not compromise diversity and exhibits the best ability reported to date for inducing the cis conformation. The cis-directing effect was studied in N-acetamide dipeptoid model systems and evaluated in terms of K(cis/trans) using NMR spectroscopy in aprotic and protic solvents. Computational geometry optimization and natural bond orbital analysis in combination with NOESY experiments were consistent with a model in which n → π*(Ar) electronic delocalization [from carbonyl (O(i-1)) to the antibonding orbital (π*) of the triazolium motif on residue i] may be operative. In the computational model (gas-phase) and experimentally in CDCl(3), H-bonding between the triazolium C-H proton and the C(i)═O(i) oxygen was also identified and may act cooperatively with the n → π*(Ar) delocalization, resulting in the absence of the trans rotamers in CDCl(3).

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.