Ac10c: a medium-ring, cycloaliphatic C-alpha,alpha-disubstituted glycine. Incorporation into model peptides and preferred conformation

Two complete series of N-protected oligopeptide esters to the pentamer level from 1-amino-cyclodecane-1-carboxylic acid (Ac(10)c), an alpha -amino acid conformationally constrained through a medium-ring C-i(alpha)<---->C-i(alpha) cyclization, and either the L-Ala or Aib residue, along with the N-protected Ac(10)c monomer and homo-dimer alkylamides, were synthesized using solution methods and fully characterized. The preferred conformation of these model peptides was assessed in deuterochloroform solution using FT-IR absorption and H-1 NMR techniques. Furthermore, the molecular structures of two derivatives (Z-Ac(10)c-OH and Fmoc-Ac(10)c-OH) and two peptides (the dipeptide ester Z-Ac(10)c-L-Phe-OMe and the tripeptide ester Z-Aib-Ac(10)c-Aib-OtBu) were determined in the crystal state using X-ray diffraction. The experimental results support the view that P-bends and 3(10)-helices are preferentially adopted by peptides rich in Ac(10)c, the third largest cycloaliphatic C-alpha,C-alpha-disubstituted glycine known. This investigation allowed us to complete a detailed conformational analysis of the whole 1-amino-cycloalkane-1-carboxylic acid (Ac(n)c, with n =3-12) series, which represents the prerequisite for our recent proposal of the 'Ac(n)c scan' concept.