Gemcitabine analogues with a lipophilic 4-N-alkyl chain bearing a terminal β-keto sulfonate moiety suitable for fluorination compatible with F-radiolabeling have been explored. Displacement of p-toluenesulfonylamino in protected 4-N-tosylgemcitabine with 1-amino-10-undecene gave 4-N-(10-undecenyl)-3',5'-di-O-benzoyl-2'-deoxy-2',2'-difluorocytidine. Oxidation of the terminal double bond in the latter with OsO/NMO afforded 4-N-(10,11-dihydroxyundecanyl) derivative. Regioselective sulfonation of primary hydroxyl followed by oxidation of secondary hydroxyl with Collin's reagent yielded desired β-keto sulfonate analogues 8 or 9. Subsequent displacement of the mesylate or tosylate group with KF in the presence of Kryptofix 2.2.2. or 18-crown-6 ether followed by deprotection with NH/MeOH gave 4-N-(11-fluoro-10-oxoundecanyl)-2'-deoxy-2',2'-difluorocytidine 11.
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