Imidazolidinone‐Tethered α‐Hydrazidopeptides – Synthesis and Conformational Investigation

Abstract

Nα‐acylated β2,3‐3‐azapeptides, or α‐hydrazidopeptides, of different lengths were synthesized starting from a conformationally restricted imidazolidinone‐tethered monomer. The preferential conformations of the oligomers were investigated by NMR and CD spectroscopy, supported by computational analysis. The experimental data clearly confirmed the tendency of these α‐hydrazidopeptides to fold into a zig‐zag (Z8) 8‐helix conformation, whose stability is length‐dependent, stabilized by the C=O(i)···H–N(i + 2) and N(i)···H–N(i + 1) intramolecular H‐bonding pattern, as well as by non‐standard C=O···H‐C hydrogen bonds.

The Diverse World of Foldamers: Endless Possibilities of Self-Assembly

“…The secondary structures of foldamers based on higher homologues of α-amino acids (e.g., γ- and δ-amino acids), and the rationale at the basis of their formation and stability, have not been studied at the same level of detail than those of β-peptides [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 ] and aromatic foldamers [ 2 , 6 , 10 , 11 , 12 , 18 , 19 ]. The same usually applies to the knowledge and comprehension of the folding propensities of foldamers based on peptide analogs [ 15 ] and oligomers with heterogeneous backbones, either in the sense of peptidic skeletons featuring different types of aliphatic amino acids [ 16 ] or mixed aliphatic–aromatic structures [ 17 ]. In addition, intramolecular arrangements of many particular classes of foldamers have often been studied by a single research group.…”

“…In addition, remarkable variations in β-peptide foldamers folding could easily be obtained by exploiting apparently very small structural modifications, as demonstrated for the simple methylation at C α of a trans 5-membered cyclic β-amino acid monomer, that shifted the natural preference toward the rare 8-helix [ 13 , 14 ]. The formal substitution of C β with oxygen or nitrogen atoms in β-peptide analogues (i.e., α-aminoxy or α-hydrazino acids), as shown in Figure 1 f, also had a deep impact on their secondary structures [ 15 ]. The incorporation of structurally diverse monomers in foldamers with heterogeneous backbones led to a further impressive widening of the attainable conformations [ 16 , 17 ].…”

Controlling the conformational stability of coiled-coil peptides with a single stereogenic center of a peripheral β-amino acid residue

“…11 It was soon proved that a very useful approach for the development of foldamers is the introduction of unnatural amino acids into a-peptides in the process called foldamerization. 12,13 In terms of peptidomimetics, apart from widely studied foldamers based on higher homologues of a-amino acids, 14 there have been also studied the sequences containing a-aminoisobutyric acid (Aib), [15][16][17] oligoureas, 18 azapeptides, 19 a-hydrazido-peptides, 20 polyamides, 21 and others. [22][23][24] Foldamerization of sequences using b-amino acids shows two main advantages, namely, it improves both the conformational and proteolytic stability of peptides.…”