Treatment with 2 -fluorinated nucleosides

An interesting regioselective deaminative fluorination of a purinc-2.6-diamine derivative 12 has been reported. The nucleoside is selectively fluorinated in the 2-position of the purine moiety by treatment with tert-butyl nitrite in 60% hydrogen fluoride/ pyridine at — 20 C for 10 minutes.149 The hydrogen fluoride concentration of the reagent should not be higher than 65% (suitable 45-65%). 

A unique method for the introduction of fluorine via an ester-type linkage has been used for the preparation of fluorinated nucleosides.It consi.sts of the treatment of 2,3 -anhydro nucleosides with hydrogen fluoride in the presence of aluminum trifluoride in dioxane at temperatures between 150 and 200 The yields are in the range of 30-40%. With potassium... 

Purines or purine nucleosides that have been fluorinated at multiple positions are of great interest in medicinal chemistry. Most techniques currently available for the synthesis of difluorinated purines rely on combining several fluorination techniques. The first examples of difluorinating purines came from subjecting 2-amino-9-(2,3,5-tri-0-acetyl-p-D-xylofuranosyl)adenine derivative 12 to a modified Schiemann reaction (Scheme 42). In this case, treatment with NaN02 and 48 % fluoroboric acid afforded a mixture of the 2-fluoroadenine 120 and the 2,6-difluoroadenine derivative 121, which were isolated in 13 % and 16 %, respectively [3]. The fact that no 6-fluoroadenine derivative was isolated led to the hypothesis that under the reaction conditions, diazotization-fluorodediazonation at the 2-position occurred before fluorination at the 6-position could take place. 

Since TASF and DAST were reported as efficient reagents in fluorination of sugars and nucleosides we studied if a good leaving group at C-2 of a purine nucleoside such as 8 could be displaced with fluorine by these reagents. Thus, we thesized 3, 5 -di-0-benzyl-2 -0-triflyl-l-benzylinosine for TASF treatment As depicted in Scheme 3 the 3, 5 -0-(l,l,3,3-tetraisopropyl)disiloxanyl-l-benzylinosine (17) was treated with dihydropyran (DHP)/TsOH and then desilylated with EtjNHF-THF to obtain 19. Ben lation of 19 followed by 2 -0-deprotection and triflylation afforded 20-22. Finally, when 22 was treated with TASF, only elimination products 23 and 24 were isolated. No traces of F-ara-H were detected in the reaction mixture. 

Fluorinated analogues of nucleosides are drugs that interact with enzymes involved in the synthesis of DNA and RNA (cf. Chapter 7). They are developed for treatment of cancer and viral infections. Fluorine atoms can be present either on the base moiety or on the sugar one. 

Trifluridine (trifluorothymidine) is a fluorinated pyrimidine nucleoside that inhibits viral DNA synthesis in HSV-1, HSV-2, CMV, vaccinia, and some adenoviruses. It is phosphorylated intracellularly by host cell enzymes, and then competes with thymidine triphosphate for incorporation by the viral DNA polymerase (Figure 49-3). Incorporation of trifluridine triphosphate into both viral and host DNA prevents its systemic use. Application of a 1% solution is effective in treating keratoconjunctivitis and recurrent epithelial keratitis due to HSV-1 or HSV-2. Cutaneous application of trifluridine solution, alone or in combination with interferon alfo, has been used successfully in the treatment of acyclovir-resistant HSV infections. 

Thus, 1-benzylinosine was directly tritylated with TrCl in pyridine, and the 2, 5 - and 3, S -regioisomers were separated on a silica gel colmnn. The relatively large J,2 value of 7.1 Hz for the 3, 5 -di-0-tr%l derivative 26 versus small 1, 2 coupling of 2.5 Hz for 22 indicates that trityl groups did cause the desired conformational change in 26 toward the C-2 endo conformer. When 26 was treated with TASF, the desired 2 -fi-fluorinated arabino nucleoside 27 was obtained in 30% yield. Treatment of nucleoside 25 with DAST afforded the same F-ara-H derivative 27 in 79% yield. Detritylation of 27 with CFsCOjH/CHClj, followed by hydrogenotysis with Pd(OH)2, afforded a good yield of F-ara-H (lc). ... 

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