The Role of N‐Methyl Squaramides in a Hydrogen‐Bonding Strategy to Fold Peptidomimetic Compounds

Small peptides and peptomimetic compounds are valuable tools to probe and study biological systems. Small synthetic peptide analogues adopt a given secondary structure driven by structural modules that organize the compound architecture. Among them, β‐ and α‐turn mimetics are widely used. This work reports SQ4 and SQ5 squaramido‐based turn modules that combine tertiary and secondary squaramide bonds in their structure to control their conformational properties. The efficacy of this combination has been evaluated to promote folding in peptide‐like compounds to obtain parallel and antiparallel‐hairpin model compounds in hydrogen‐bonding competitive media. Crystallographic structures of model compounds and conformational studies based on NMR spectroscopic analysis of the squaramido‐peptides confirm that secondary‐tertiary squaramides are more prone to adopt the E,Z‐conformation than di‐secondary squaramides, and consequently are more suitable to gain conformational control over foldable peptidomimetic compounds. Another way to turn: N‐Methylation of squaramides promotes the conformational control of peptidomimetic‐based squaramides (see figure). The combination of tertiary and secondary squaramide bonds in their structure efficiently folds peptide‐like compounds to give parallel and antiparallel‐hairpin analogues. The process is driven by hydrogen bond and C−H⋅⋅⋅O interactions in hydrogen‐bonding competitive media.