(Re)emerging RNA viruses such as Severe Acute Respiratory Syndrome (SARS), Zika, Dengue, Chikungunya, H1N1 influenza and Ebola have been major threats to public health in the past years, for which only few drugs are available. Among them, nucleoside analogues are still at the cornerstone of the antiviral therapy. On one hand, the replacement of the oxygen in the furanose ring with methylene group led to carbanucleosides which are chemically more stable towards the enzymatic cleavage of the N-glycosidic bond and have an increased cell permeability because of its higher lipophilicity than their nucleoside parents. On the other, C-nucleosides, in which the ribofuranosyl moiety is linked to a heterocyclic non-canonical base through a C-C bond, have been reported for their antiviral and/or anticancer potential. Herein, we report the synthesis of rare carbocyclic C-nucleosides bearing non-canonical nucleobase through a cobalt-assisted-route as key step. In fact, if several efforts towards the synthesis of enantioenriched carbocyclic nucleosides have been reported in the past years, the multi-step sequences combined with the difficulty associated with the installation of stereocenters make these approaches long, tedious, and not suitable for the pharmaceutical industry. We use a methodology previously reporting by P. Knochel, based on Co-catalyst to obtain a stereo controlled and efficient synthesis of diverse carba-C-nucleosides without the use chiral catalyst, but taking advantage of stereocenters previously set in the molecule. The cyclopentenone 1 was converted into the halohydrine 2, on which several non-canonical aromatic aryl nucleobases were installed using a freshly prepared CoCl2.2LiCl solution in THF and (aryl)MgBr. A radical mechanism of the magnesium insertion into organic halides is generally accepted. Yields range from 40-85%. The aryl derivatives include electron-donating and electron-withdrawing substituents, heteroaryl derivatives, in order to maintain the required hydrophobicity, π-stacking and Watson-Crick hydrogen bond interactions.

Cobalt-assisted route to rare carbocyclic C-nucleosides

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