Hydrogen bonds (H-bonds) are ubiquitous in peptides and proteins and are central to the stabilization of their structures. Inter-residue H-bonds between non-adjacent backbone amide NH and C=O motifs lead to the well-known secondary structures of helices, turns and sheets, but it is recognized that other H-bonding modes may be significant, including the weak intra-residue H-bond (called a C5 H-bond) that implicates the NH and C=O motifs of the same amino acid residue. Peptide model compounds that adopt stable C5 H-bonds are not readily available and the so-called 2.05-helix, formed by successive C5 H-bonds, is an elusive secondary structure. Using a combination of theoretical chemistry and spectroscopic studies in both the gas phase and solution phase, we have demonstrated that derivatives of 3-amino-1-methylazetidine-3-carboxylic acid, Aatc(Me) can form sidechain–backbone N–H···N C6γ H-bonds that accompany—and thereby stabilize—C5 H-bonds. In the capped trimer of Aatc(Me), extended C5/C6γ motifs are sufficiently robust to challenge classical 310-helix formation in solution and the fully-extended 2.05-helix conformer has been characterized in the gas phase. Concurrent H-bonding support for successive C5 motifs is a new axiom for stabilizing the extended backbone secondary structure in short peptides.

Post-synthetic modification is a powerful technique allowing access to non-canonical peptide derivatives in a selective manner, but it has not so far been applied for the installation of multiple arrays of modified side chains. Here, we use this approach in solution phase to prepare short N- and C-capped homooligomers of 3-amino-1-methylazetidine-3-carboxylic acid with all the azetidine side chain functions in free amine form. The key step is the multiple reductive amination reaction of the corresponding post-synthetically deprotected secondary amines.