An approach to acyclo-1-deazathymidine c-nucleosides via 3,5-dichloro-6-methyl-2H-1,4-oxazin-2-one.

An approach to the synthesis of acyclo-1-deazathymidine nucleosides is described. Diels-Alder reaction of 3,5-dichloro-6-methyl-2H-1,4-oxazin-2-one with acetylenic compounds 4 and 5 yielded the 3-(tetrahydropyran-2-yl)oxy]-methyl- and 3-bromomethyl-5-methyl-2,6-dichloropyridine intermediates 7 and 8. The bromomethyl group of compound 8 underwent easy substitution with the appropriate nucleophiles, permitting the introduction of acycLo sugar moieties. The resulting 3-substituted 2,6-dichloro-5-methyl pyridines 9a,b - precursors for some acyclo pyridine-C-nucleosides - were treated with sodium phenylmethoride to afford 2,6-dibenzyloxypyridines 10a,b. Debenzylation using a palladium-strontium carbonate catalyst gave the unstable C-nucleosides 2a,b of the 6-hydroxy-1H-pyridin-2-one type. A stable 6-hydroxy-1H-pyridin-2-one 2c, exempt from benzylic oxygen, was obtained via cycloaddition of THP-protected 6-hydroxy-1-hexyne.