Synthesis of conformationally restricted amino acids and their use in the preparation of biologically active peptides and peptidomimetics

The synthesis of two new diastereomeric 6-amino-3-azabicyclo[3.2.1]octane-6-carboxylic acids exo- and endo-8,9 is reported using exo- and endo-norbornene amino acids as chiral building blocks. This method provides a fast access to optically pure amino acids 8 and 9 which can be considered both alfa, gamma- and alfa,delta-diamino acids containing sterical constraints and characterized by alfa,alfa-disubstitution. A single step synthesis on the gram scale of four pure stereoisomers of the 6-amino-3-aza-bicyclo[3.2.1]octane-6-carboxylic acid was carried out using (R)-1-phenylethylamine to confer chirality. The phenylethyl group, and the p-methoxy group linked to the N-atom, are easily removed by hydrogenolysis affording the corresponding NH-3 derivatives. A series of N-3-alkyl compounds were prepared by way of a "one-pot" deprotection-alkylation procedure starting from the above key compounds. Their biological activity has been evaluated on the GABA receptor. The features of these compounds, i.e. the presence of constraints and heterosubstitution, as well as the α,α-disubstitution made these amino acids interesting compounds for the preparation of peptidomimetic models containing a constrained ornitine-like amino acid. The availability of four diastereoisomers has been an added value since different orientation to peptide sequence were obtained.