Synthesis of 5'-deoxy-5'-difluoromethyl phosphonate nucleotide analogs

Article abstract of DOI:10.1021/jo00113a040

A synthetic route to nucleoside 5'-deoxy-5'-difluoromethyl phosphonates from ribofuranosyl 5-deoxy-5-difluoromethyl phosphonate precursors is described. Methyl 5,6-dideoxy-6-(diethoxyphosphinyl)-6,6-difluoro-2,3-O- isopropylidene-β-D-ribo-hexofuranoside (7) was converted, under mild conditions, to the suitable glycosylating agent 1-O-acetyl-2,3-di-O-benzoyl-5,6-dideoxy-6-(diethoxyphosphinyl) -6,6-dif luoro-β-D-ribo-hexofuranoside (10). 1,2-Di-O-acetyl-3-O-benzyl-5,6-dideoxy-6-(diethoxyphosphinyl)- 6,6-difl uoro-β-D-ribo-hexofuranoside (16) was also prepared as a versatile building block for nucleotide synthesis. Condensation of 10 with silylated nucleobases, followed by complete deprotection, afforded 5',6'-dideoxy-6'-(dihydroxyphosphinyl)-6',6'-difluoro nucleoside analogs 22a-c. In the case of the glycosylation of adenine, a considerable quantity of N-7 regioisomer 19 was formed. 5',6'-Dideoxy-6'-(dihydroxyphosphinyl)-6',6'-difluoro adenosine analog 22c was converted into the triphosphate analog 23 using 1,1'-carbonyldiimidazole activation followed by condensation with pyrophosphate. The adenosine 3',5'-cyclic monophosphate analog 24 was obtained through the DCC promoted intramolecular cyclization of 22c. Dinucleoside phosphate analog 27 was prepared by DCC-catalyzed coupling of 1-[2,3-di-O-benzoyl-5,6-dideoxy-6-(dihydroxyphosphinyl)-6,6- di fluoro-β-D-ribo-hexofuranosyl]uracil (21a) with 2',5'-bis(O-tert-butyldimethylsilyl)-N⁴-acetyl-cytidine (25), followed by deprotection.