Synthesis of 6′‐Methyl‐2′‐ O ,4′‐ C ‐methylene‐ α ‐L‐ ribofuranosyl‐pyrimidine Nucleosides

Herein, we report the efficient synthesis of (6′ R )‐ and (6′ S )‐6′‐methyl‐2′‐ O ,4′‐ C ‐methylene‐ α ‐L‐ribofuranosyl‐thymine, and (6′ R )‐ and (6′ S )‐6′‐methyl‐2′‐ O ,4′‐ C ‐methylene‐ α ‐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– CH 2 OH 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 AlMe 3 in hexane. Both (6′ R )‐ and (6′ S )‐stereoisomers of bicyclic nucleosides T and U were successfully synthesized following Vorbrüggen nucleobase coupling of T and U with triacetylated glycosyl donor obtained from acetolysis of (5 R )‐ and (5  S )‐4‐ C ‐( tert ‐butyldiphenylsilyloxymethyl)‐5‐ C ‐methyl‐1,2‐ O ‐isopropylidene‐3‐ O ‐(2‐naphthylmethyl)‐ α ‐D‐xylofuranoses and further cyclization and deprotection of the resulted nucleoside. One of the nucleosides, (6′ R )‐6′‐methyl‐2′‐ O ,4′‐ C ‐methylene‐ α ‐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 H1 N1 strain of influenza A virus (A/Puerto Rico/8/1934).