α,α-Disubstituted Glycines Bearing a Large Hydrocarbon Ring: Peptide Self-Assembly through Hydrophobic Recognition

Article abstract of DOI:10.1002/chem.200305492

A method was developed for synthesizing α,α-disubstituted glycine residues bearing a large (more than 15-membered) hydrophobic ring. The ring-closing metathesis reactions of the dialkenylated malonate precursors proceed efficiently, particularly when long methylene chains tether both terminal olefin groups. Surprisingly, the amino groups of these α,α-disubstituted glycines are inert to conventional protective reactions (e.g., N-tert-butoxycarbonyl (Boc) protection: Boc ₂O/4-dimethylaminopyridine (DMAP)/CH₂Cl₂; N-benzyloxycarbonyl (Z) protection: Z-Cl/DMAP/CH₂Cl₂). Curtius rearrangement of the carboxylic acid functionality of the malonate derivative after ring-closing metathesis leads to formation of an amine functionality and can be catalyzed by diphenylphosphoryl azide. However, only the intermediate isocyanates can be isolated, even in the presence of alcohols such as benzyl alcohol. The isocyanates obtained by Curtius rearrangement in an aprotic solvent (benzene) were isolated in high yields and treated with 9-fluorenylmethanol in a high-boiling-point solvent (toluene) under reflux to give the N-9-fluorenylmethoxycarbonyl (Fmoc)-protected aminomalonate derivatives in high yield. These hydrophobic amino acids can be incorporated into a peptide by Fmoc solid-phase peptide synthesis and the acid fluoride activation method. The stability of the monomeric α-helical structure of a 17-amino-acid peptide was enhanced by replacement of two alanine residues with two hydrophobic amino acid residues bearing a cyclic 18-membered ring. The results of sedimentation equilibrium studies suggested that the peptide assembles into hexamers in the presence of 100 mM NaCl.