Synthesis of Variously Functionalized Azabicycloalkane Scaffolds by Domino Metathesis Reactions

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.