3 years ago

Synthesis of Variously Functionalized Azabicycloalkane Scaffolds by Domino Metathesis Reactions

Synthesis of Variously Functionalized Azabicycloalkane Scaffolds by Domino Metathesis Reactions
Elena Giulia Peviani, Massimo Serra, Eric Bernardi, Lino Colombo
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 αvβ3vβ5 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.

Publisher URL: http://dx.doi.org/10.1021/acs.joc.7b02047

DOI: 10.1021/acs.joc.7b02047

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