Conformational characterization of the 1-aminocyclobutane-1-carboxylic acid residue in model peptides

A series of N- and C-protected, monodispersed homo-oligopeptides (to the dodecamer level) from the small-ring alicyclic C-alpha,C-alpha-dialkylated glycine 1-aminocyclobutane-1-carboxylic acid (Ac4c) and two Ala/Ac(4)c tripeptides were synthesized by solution methods and fully characterized. The conformational preferences of all the model peptides were determined in deuterochloroform solution by FT-IR absorption and H-1-NMR The molecular structures of the amino acid derivatives Z-Ac(4)c-OH and Z(2)-Ac(4)c-OH, the tripeptides Z-(Ac(4)c)(3)-OtBu, Z-Ac(4)c-(L-Ala)(2)-OMe and Z-L-Ala-Ac(4)c-L-Ala-OMe, and the tetrapeptide Z-(Ac(4)c)(4)-OtBu were determined in the crystal state by X-ray diffraction. The average geometry of the cyclobutyl. moiety of the Ac(4)c residue was assessed and the tau(N-C-alpha-C') bond angle was found to be significantly expanded from the regular tetrahedral value. The conformational data are strongly in favour of the conclusion that the Ac(4)c residue is an effective beta-turn and helix former. A comparison with the structural propensities of alpha-aminoisobutyric acid, the prototype of C-alpha,C-alpha-dialkylated glycines, and the other extensively investigated members of the family of 1-aminocycloalkane-1-carboxylic acids (Ac(n)c, with n=3, 5-8) is made and the implications for the use of the Ac(4)c residue in conformationally constrained peptide analogues are briefly examined. (C) 1997 European Peptide Society and John Wiley Br Sons, Ltd.