Synthesis of Enantiopure 7-Substituted Azepane-2-carboxylic Acids as Templates for Conformationally Constrained Peptidomimetics

The introduction of a cyclic amino acid in a peptide is one of the best methods to rigidify a strand. A general approach towards a new class of seven-membered ring amino acids is described starting from (S)-tribenzyl glutamic acid gamma-aldehyde, which reacts with beta-keto phosphonates to generate the Horner-Wadsworth-Emmons product. In the presence of H-2 and a Pd catalyst, a four-step process occurs involving double-bond hydrogenation, hydrogenolysis of three benzyl protecting groups, imine formation, and reductive amination to produce the 7-substituted azepane carboxylic acid in good overall yield and with good to excellent diastereomeric ratios. An amino function can be introduced in the 7-position as an additional orthogonal chemical handle for readily generating diversity on the cyclic amino acid scaffold by using a beta-keto phosphonate derived from amino acids. A cyclic RGD (Arg-Gly-Asp) pentapeptide analogue containing this new class of noncoded amino acids was also prepared by microwave-assisted cyclization, showing a promising activity as alpha(v)beta(3) integrin inhibitor.