Abstract
A general and modular synthesis of substituted benzene and pyridine 2-C-methyl-C-ribonucleosides was developed. Benzyl-protected haloaryl-C-nucleoside intermediates were prepared by the addition of bromo(het)aryllithium reagents to a protected lactone, followed by acetylation and reduction.
These halogenated intermediates were further transformed by Pd-catalysed cross-couplings, aminations, or hydroxylations. The final deprotection was rather troublesome, and different procedures involving catalytic hydrogenation on Pd/C, or treatment with BCl3, were optimized for each derivative.
The final C-nucleosides were also all converted into the corresponding NTPs. None of the C-nucleosides showed any activity in the HCV replicon assay, and none of the NTPs showed any significant inhibition of the HCV polymerase.