4'-Substituted nucleosides. 3. Synthesis of some 4'-fluorouridine derivatives

Abstract

The reaction of l-(5-deoxy-2,3-0-isopropylidene-i?-D-eryf/zro-pent-4-enofuranosyl)uracil (1) with iodine fluoride in methylene chloride leads to the stereospecific formation of 5'-deoxy-4'-fluoro-5'-iodo-2',3'-0-isopropylideneuridine (4a) in almost quantitative yield. The 5'-iodo function of 4a can be converted into the analogous 5'azido derivative (5a) by vigorous treatment with lithium azide in dimethylformamide. Treatment of 5a with nitrosyl tetrafluoroborate leads to the isolation of 2,5,-anhydro-4'-fluoro-2,,3,-0-isopropylideneuridine (6a) which can be readily hydrolyzed to 4'-fluoro-2,,3'-0-isopropylideneuridine (7a). The latter compound has been converted into 4'-fluoro-5,-0-sulfamoyluridine (8b), the uracil analogue of nucleocidin, by treatment with sulfamoyl chloride followed by mild acidic hydrolysis. The synthesis of 4'-fluorouridine '-phosphate (8d] has also been achieved via conversion of 7a to its bis(2,2,2-trichloroethyl)phosphate ester followed by careful removal of protecting groups. The unusual stabilities of 4'-fluorouridine derivatives are discussed. In addition, it has been shown that treatment of 2',3'-methoxymethylene-and 2',3'-methoxyethylideneuridine derivatives with nitrosyl tetrafluoroborate leads to the formation of 2,2'-anhydro-1 -ß-D-arabinofuranosyluracils, presumably via 2',3'-acyloxonium ions.Recent work from this laboratory has explored methods for the introduction of substituents at C4> of the furanose ring in both purine and pyrimidine nucleosides.3 While other types

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“…Non-stereoselective synthesis of 2′-F-4′-Cα-OMe U (6) and 2′-F-4′-Cβ-OMe U (18) building blocks. a a Reagents and conditions: (i) TBS-Cl, imidazole/pyridine, rt, overnight, 87%; (ii) mCPBA/MeOH, rt, overnight, 10: 53%, 11: 17%; (iii) DMTr-Cl/pyridine, 0 °C, 14 h, 12: 89%,…”

The evolution of antiviral nucleoside analogues: A review for chemists and non-chemists. Part II: Complex modifications to the nucleoside scaffold

“…14 ). ( Jenkins et al, 1971 , 1976 ; Morton et al, 1969 ; Owen et al, 1976 ) While this analogue was one of the first examples of a 4′-modified furanose sugar, it also possessed a novel 5′-sulfamoyl group ( Jenkins et al, 1971 , 1976 ; Morton et al, 1969 ; Owen et al, 1976 ). This unique structure endowed nucleocidin with a broad antiparasitic spectrum, particularly against trypanosomes, however, the practical use of this analogue as a therapeutic was severely limited due to its toxicity ( Thomas et al, 1956 ; Hewitt et al, 1956 ).…”

Recent advances in the synthesis of fluorinated nucleosides

“…In addition, the uracil analogue 340 and its corresponding phosphate ester analogue were also prepared by Moffatt's group using a similar route. 182 It should be noted that, in 1993, Maguire and co-workers modified the procedure of the Moffatt group to synthesize nucleocidin 339 …”