Conformational restriction through C?i ? C?i cyclization: Ac12c, the largest cycloaliphatic C?,?- disubstituted glycine known

Crystal structure of a tripeptide containing aminocyclododecane carboxylic acid: a supramolecular twisted parallel β-sheet in crystals

“…The average values for the endocyclic torsion angles are close to 160, À70, À70, 160, À70, À70, 160, À70, À70, 160, À70, and À70, which correspond to the highly symmetrical lowest energy conformation of cyclododecane. The observed ring conformation is in agreement with that reported previously for the Ac 12 c residue [31]. This 12membered ring conformation, which is described as [3,3,3,3] according to Dale's nomenclature [46], was characterized in the crystal and electron diffraction studies of cyclododecane [47,48] and is the global minimum structure in the energy calculations of 12-membered rings [49,50].…”

Ac10c: a medium‐ring, cycloaliphatic Cα,α‐disubstituted glycine. Incorporation into model peptides and preferred conformation

“…This observation is common to Aib and Ac 10 c‐rich peptides (6). The average value for the conformationally sensitive N‐C α ‐C′ ( τ ) bond angle, external to the cyclic system, is 109.7°, comparable with that exhibited by the C α,α ‐disubstituted glycines forming regular bends and helices (110–111°) (6,9).…”

“…In summary, the 1 H NMR results allow us to conclude that in CDCl 3 solution at 1 m m concentration the N(3)H to N(5)H protons of the tri‐, tetra‐ and pentapeptides are almost inaccessible to perturbing agents and are therefore, most probably, intramolecularly H‐bonded. In view of these findings and by analogy with the conformational tendency of other cycloaliphatic C α,α ‐disubstituted glycines (3,6,9), it is reasonable to conclude that the most populated structures assumed in CDCl 3 solution by the N‐ and C‐protected Ac 10 c tri‐, tetra‐ and longer peptides are the β‐bend, two consecutive β‐bends (incipient 3 10 ‐helix) and the 3 10 ‐helix, respectively. These conclusions agree well with those extracted from the FT‐IR absorption investigation discussed above.…”

“…In this connection the prototypical α‐amino acid of this class (Aib) (4–6) is known to strongly favor β‐bend (7) and 3 10 /α‐helical structures (8). Similarly folded conformations are also typically observed in peptides rich in other α‐amino acids of this class, more specifically those with C α i ↔C α i cyclization (Ac n c, with n = 3–9, 11, 12) (3,6,9).…”

“…Recently, we proposed that the family of Ac n c ( n = 3–12) residues, having increasing effective volume and hydrophobicity, but possessing a similar conformational preference, may represent a sound basis for an ‘Ac n c scan’ (9). Indeed, we believe that the SAR data of analogs of relevant bioactive peptides, incorporating this whole series of Ac n c residues at a selected position, may be of great value in delineating the nature of the receptor‐bound conformation and in the production of highly active agonists and antagonists.…”