Peptide helices with pendant cycloalkane rings. Characterization of conformations of 1-aminocyclooctane-1-carboxylic acid (Ac₈c) residues in peptides

Abstract

A pentapeptide, Boc-Leu-Ac₈c-Ala-Leu-Ac₈c-OMe 1, an octapeptide, Boc-Leu-Ac₈c-Ala-Leu-Ac8c-Ala-Leu-Ac₈c-OMe 2 and a tripeptide, Boc-Aib-Ac₈c-Aib-OMe 3 containing the 1-aminocyclooctane-1-carboxylic acid residue (Ac₈c) were synthesized and conformationally characterized by x-ray diffraction studies in the crystal state. Peptides 1 and 2 were also studied by NMR in CDCl₃ solution. Peptide 1 adopts a purely 3₁₀-helical conformation in crystals, stabilized by three intramolecular 1← 4 hydrogen bonds. Peptide 2 in crystals is largely 3₁₀-helical with distortion in the backbone at the N-terminus by the insertion of a water molecule between Ac₈c (2) CO and Ala (6) NH groups. Peptide 3 forms a C₁₀-ring structure, i.e. a type III (III′) β-turn conformation stabilized by an intramolecular 1 ← 4 hydrogen bond. Five cyclooctane rings assume boat-chair conformations, whereas the sixth [Ac₈c(8) in 2] is appreciably distorted, resembling a chiral intermediate in the pseudorotational pathway from the boat-chair to the twisted boat-chair conformation. Internal bond angles of the cyclooctane rings are appreciably distorted from the tetrahedral value, a characteristic feature of the cyclooctane ring. Peptide 1 crystallized in the space group P2₁2₁2₁ with a = 11.900(4) Å, b = 18.728(6) Å, c = 20.471(3) Å and Z = 4. The final R₁ and wR₂ values are 0.0753 and 0.2107, respectively, for 3901 observed reflections [F_o ≥ 3(F_o)]. Peptide 2 crystallized in space group P2₁ with a = 12.961(5) Å, b = 17.710(10) Å, c = 15.101(7) Å, β = 108.45(4)° and Z = 2. The final R₁ and wR₂ values are 0.0906 and 0.1832, respectively, for 2743 observed reflections [F_o ≥ 3σ(F_o)]. ¹H-NMR studies on both the peptides strongly suggest the persistence of 3₁₀-helical conformations in solution. Peptide 3 crystallized in the space group P2₁/n, with a = 10.018(1) Å, b = 20.725(1) Å, c = 12.915(1) Å and Z = 4. The final R₁ and wR₂ values are 0.0411 and 0.1105, respectively, for 3634 observed reflections [F_o ≥ 4σ(F_o)].