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Synthesis of 6′‐Methyl‐2′‐ O ,4′‐ C ‐methylene‐ α ‐L‐ ribofuranosyl‐pyrimidine Nucleosides
Author(s) -
Mangla Priyanka,
Maity Jyotirmoy,
Rungta Pallavi,
Verma Vineet,
Sanghvi Yogesh S.,
Prasad Ashok K.
Publication year - 2019
Publication title -
chemistryselect
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.437
H-Index - 34
ISSN - 2365-6549
DOI - 10.1002/slct.201900809
Subject(s) - methylene , chemistry , thymine , bicyclic molecule , uracil , moiety , pyrimidine , stereochemistry , nucleoside , methyl group , formylation , medicinal chemistry , organic chemistry , catalysis , group (periodic table) , dna , biochemistry
Abstract 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).