All cis alpha and beta peptoid foldamers

Peptoids are N-substituted glycine oligomers which are similar to peptides with the side chains located on the amide nitrogen rather than the alpha-carbon. Peptoids are an interesting case of peptidomimetic foldamers. Since their backbones lack free NH amides, the capacity to form well-ordered structures is strictly related to the nature of the side chains. Peptoid residues are structurally related to proline as the coupling of residues gives tertiary amide bonds which can populate cis and trans conformations. While amide bonds in peptides and proteins are mainly in the transoid form, the polyproline type I (PPI) peptide helix featuring only cis amides is a typical peptoid secondary structure. Recently, great efforts have been devoted to controlling peptoid amide bond geometry in order to minimize backbone conformational heterogeneity. Herein we show a series of alpha and beta-peptoids characterized by an N-tBu side chain which locks the amide sites in the cis conformation in any solvent.[4] Synthesis of longer oligomers was optimized through a combination of the classical submonomer approach and coupling reaction of sterically hindered secondary amines. Conformational studies in solution were performed by bi-dimensional NOESY experiments and molecular modeling.