Conformational restriction through C-i(alpha)<-> C-i(alpha) cyclization: Ac(12)c, the largest cycloaliphatic C-alpha,C-alpha-disubstituted glycine known

Two complete series of N-protected, monodispersed oligopeptide esters to th e pentamer level from 1-aminocyclododecane-1-carboxylic acid (Ac(12)c), an alpha-amino acid conformationally constrained through C-i(alpha) <-> C-i(al pha) cyclization, and either L-Ala or Aib residues, along with the N-protec ted Ac(12)c homopeptide alkylamide series from monomer to trimer, have been synthesized by solution methods and fully characterized The solution-prefe rred conformations of these peptides have been assessed by Fourier transfor m ir absorption and H-1-nmr techniques. Moreover, the molecular structures of one derivative (Z-Ac(12)c-OH) and three peptides [the tripeptide ester Z -L-Ala-Ac(12)c-L-Ala-OMe, the tripeptide alkylamide Z-(Ac(12)c)(3)-NHiPr, a nd the tetrapeptide ester Z-(Aib)(2)-Ac(12)c-Aib-OtBu (Aib, alpha-aminoisob utyric acid)] have been determined in the crystal state by x-ray diffractio n. The results obtained point to the conclusion that beta-bends and 3(10)-h elices are preferentially adopted by peptides based on Ac(12)c, the largest cycloaliphatic C-disubstituted glycine known. A comparison with the struct ural tendencies extracted from published works on peptides from Aib, the pr ototype of C-disubstituted glycines, and the other extensively studied memb ers of the class of 1-aminocycloalkane-1-carboxylic acids (Ac(n)c, with n = 3-9), is made and the implications for the use of the Ac(12)c residue in t he Ac(n)c scan approach of conformationally restricted analogues of bioacti ve peptides are briefly discussed. (C) 2000 John Wiley & Sons, Inc.