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

Abstract

Two complete series of N-protected oligopeptide esters to the pentamer level from 1-amino-cyclodecane-1-carboxylic acid (Ac10c), an alpha-amino acid conformationally constrained through a medium-ring Calphai <--> Calphai cyclization, and either the L-Ala or Aib residue, along with the N-protected Ac10c 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 1H NMR techniques. Furthermore, the molecular structures of two derivatives (Z-Ac10c-OH and Fmoc-Ac10c-OH) and two peptides (the dipeptide ester Z-Ac10c-L-Phe-OMe and the tripeptide ester Z-Aib-Ac10c-Aib-OtBu) were determined in the crystal state using X-ray diffraction. The experimental results support the view that beta-bends and 3(10)-helices are preferentially adopted by peptides rich in Ac10c, the third largest cycloaliphatic C(alpha,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.