The Click Triazolium Peptoid Side Chain: A Strong <i>cis</i>-Amide Inducer Enabling Chemical Diversity

Abstract

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).