A γ‑Amino Acid That Favors 12/10-Helical Secondary Structure in α/γ‑Peptides

H-bonded helices in conventional
peptides (containing exclusively
homochiral α-amino acid residues) feature a uniform H-bonding
directionality, N-terminal side CO to C-terminal side NH.
In contrast, heterochiral α-peptides can form helices in which
the H-bond directionality alternates along the backbone because neighboring
amide groups are oriented in opposite directions. Alternating H-bond
directions are seen also in helices formed by unnatural peptidic backbones,
e.g., those containing β- or γ-amino acid residues. In
the present study, we used NMR spectroscopy and crystallography to
evaluate the conformational preferences of the novel γ-amino
acid (1R,2R,3S)-2-(1-aminopropyl)-cyclohexanecarboxylic acid (APCH), which is constrained by a
six-membered ring across its Cα–Cβ bond. These
studies were made possible by the development of a stereoselective
synthesis of N-protected APCH. APCH strongly enforces the α/γ-peptide
12/10-helical secondary structure, which features alternating H-bond
directionality. Thus, APCH residues appear to have a conformational
propensity distinct from those of other cyclically constrained γ-amino
acid residues.