The chemistry developed in Scheme 1 was next mapped onto a 2-deoxy-2,2-gem-difluoro ribose system to access 4'-thiogemcitabine and analogues thereof (Scheme 2). Commercially available lactone 7 was manipulated in six steps to deliver 2-deoxy-2,2-difluoro-1-(4-thio-D-ribofuranose) 10. Lactone 7 was first reduced using Li(O t Bu)3AlH to the hemiacetal in 95% crude yield and then converted directly to oxime 8 via reaction with O-methoxyhydroxylamine and Et3N in the presence of pyridinium p-toluenesulfonate. Interestingly, no reaction to convert the intermediate hemi-acetal was observed in the absence of the pyridinium salt. Oxime 8 then underwent successive derivatisation at C4, first to the sulfonate ester and then nucleophilic substitution to yield bromide 9. Finally, oxime The anomeric hydroxyl group in 10 was next converted to either mesylate 11 or acetate 12 as appropriate leaving groups to explore glycosylation of nucleobases. Treatment of 10 with MsCl and Et3N (Scheme 2) afforded 11 in 79% yield as a 1/4, α/β mixture. The β-anomer was isolated by crystallisation from hot Et2O and the resultant solid recrystallised by diffusion using CH2Cl2/hexanes to afford pure β-11. A sample of β-11 was analysed by X-ray crystallography and confirmed the double stereochemical inversion at C4, which retained a D-ribo configuration (Figure ). The anomeric mesylate and C5 were observed above the plane of the thiopentose ring, consistent with 1-β-D-ribo stereochemistry, with the ring adopting a C3-endo conformation in the solid state. Anomeric acetate 12 was accessed in 88% yield as a 3/2 mixture of anomers that, in our hands, proved inseparable by crystallisation or column chromatography.