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 γ-aldehyde, which reacts with β-keto phosphonates to generate the Horner-Wadsworth-Emmons product.  In the presence of H2 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 addnl. orthogonal chem. handle for readily generating diversity on the cyclic amino acid scaffold by using a β-keto phosphonate derived from amino acids.  A cyclic RGD (Arg-Gly-Asp) pentapeptide analog contg. this new class of noncoded amino acids was also prepd. by microwave-assisted cyclization, showing a promising activity as αvβ3 integrin inhibitor.