Synthesis of 6 '-Methyl-2 '-O,4 '-C-methylene-alpha-L- ribofuranosyl-pyrimidine Nucleosides

摘要

abstract_textpHerein, we report the efficient synthesis of (6'R)- and (6'S)-6'-methyl-2'-O,4'-C-methylene-alpha-L-ribofuranosyl-thymine, and (6'R)- and (6'S)-6-methyl-2'-O',4'-C-methylene-alpha-L-ribofuranosyl-uracil starting from diacetone glucofuranose in overall yields of 6.3, 4.7, 5.4 and 4.0, respectively. The key step in the synthesis of stereochemically defined 6'-Me-bicyclic-nucleosides is the nucleophilic addition of methyl group at methylene carbon of 4-C-CH2OH moiety of the 4-C-tert-butyldiphenylsilyloxymethylated sugar precursor. Thus, the methyl group was added on the aldehyde obtained from Dess-Martin periodinane oxidation of the precursor alcohol employing AlMe3 in hexane. Both (6'R)- and (6'S)-stereoisomers of bicyclic nucleosides T and U were successfully synthesized following Vorbruggen nucleobase coupling of T and U with triacetylated glycosyl donor obtained from acetolysis of (5R)- and (5S)-4-C-(tert-butyldiphenylsilyloxymethyl)-5-C-methyl-1,2-O-isopropylidene-3-O-(2-naphthylmethyl)-alpha-D-xylofuranoses and further cyclization and deprotection of the resulted nucleoside. One of the nucleosides, (6'R)-6'-methyl-2'-O,4'-C-methylene-alpha-L-ribofuranosyl-uracil has been reported earlier in 1.8 yield, while the present methodology yielded the nucleoside in 5.4 yield. All the synthesized 6'-Me-bicyclic-nucleosides showed no significant anti-viral activity against H1N1 strain of influenza A virus (A/Puerto Rico/8/1934)./p/abstract_text