Azabicycloalkenes as synthetic intermediates - Synthesis of conformationally constrained glutamate analogues

As a part of our study of the cancer-specific protease PSMA (prostate-specific membrane antigen) we present a stereoselective synthesis of conformationally constrained glutamate mimetics. Key intermediates are azabicycloalkenes which are synthesized via diastereoselective or enantio selective imino-Diels-Alder protocols. The versatility of the route is demonstrated with the preparation of Asp, Glu and HGlu-mimetics based on proline or pipecolic acid scaffolds. These scaffolds are assembled by an oxidative cleavage of azabicycloalkenes and subsequent conversions of the resulting dialdehydes via chlorite oxidation or Wittig olefination. The resulting cyclic amino acids are obtained as Cbz-protected derivatives or free amines ready for further manipulation at their N-terminus and are useful as building blocks for the assembly of conformationally rigid PSMA ligands. ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007).