Synthesis of Variously Functionalized Azabicycloalkane Scaffolds by Domino Metathesis Reactions.

Abstract

7,5-Fused azabicycloalkane scaffolds, carrying a quaternary stereocenter at C3 position of the lactam ring, can act as effective reverse-turn mimics and have proven to be useful intermediates for the preparation of Arg-Gly-Asp (RGD)-based cyclopentapeptides (cRGD) with nanomolar activity as αvβ3/αvβ5 integrin antagonists. Here, we report the synthesis of new azabicycloalkane scaffolds endowed at the C6 position with a para-substituted phenethyl side chain, which could be exploited to obtain cRGD-based bioconjugates that may find promising applications in anticancer therapy. By performing a domino cross enyne metathesis/ring-closing metathesis (CEYM/RCM) in the presence of styrene derivatives, followed by catalytic hydrogenation of the diene system, we easily converted a dipeptide precursor into the desired C6-functionalized azabicycloalkane scaffolds. The presence of a suitably protected p-amino group on the styrene moiety could be exploited, after deprotection, either to directly conjugate a bioactive compound or to introduce a suitable spacer between the cRGD unit and the bioactive compound.