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

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–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 Vorbrüggen nucleobase coupling of T and U with triacetylated glycosyl donor obtained from acetolysis of (5R)‐ 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).

Chemical and chemoenzymatic routes to bridged homoarabinofuranosylpyrimidines: Bicyclic AZT analogues

“…Following this trend, we assigned the same stereochemistry for the C5′ centre of nucleoside 9b . Interestingly, we noticed that the stereochemistry of the C5′ centre was unaltered in the dimesylated allofuranosyl nucleosides 16a , b or 22a , b and the corresponding bridged homoarabinofuranosylpyrimidine nucleosides 9a , b , whereas we expected an inversion of stereochemistry as it was noticed in earlier literature [ 30 – 31 ]. Depending on this observation, we postulated a mechanistic pathway for this cyclization process, where two consecutive inversions of configuration at the C5′ centre enabled the retention of stereochemistry.…”

Double-headed nucleosides: Synthesis and applications

“…Modified nucleosides are a class of organic compounds which are unnatural and have an altered/substituted nucleobase and/or a modified pentose sugar [3,4]. The synthe-tic accessibility of these organic molecules encouraged researchers to prepare sugar-modified nucleosides [5,6] and nucleobase-modified nucleosides [7,8]. Modified nucleoside monomers comprising more than one nucleobase are called double-headed nucleosides [9,10].…”

Chemoenzymatic Synthesis of arabino-Configured Bicyclic Nucleosides

“…In the past few years, our research group has aimed and successfully executed the synthesis of various sugar modified nucleosides following chemical and biochemical pathways. 6′-Methyl-2′-O,4′-C-methylene--L-ribofuranosylpyrimidines, 36 -L-ribofuranosylnucleosides, 37 C-4′spiro-oxetano--L-ribonucleosides 38 were synthesized following chemical pathway, whereas 2′-O,4′-C-methyleneribonucleosides C, 39 C-4′-spiro-oxetanoribonucleosides, 40 homolyxofuranosylpyrimidines D 41 were synthesized following chemoenzymatic pathway. Herein, a facile and efficient methodology has been described for the synthesis of LNA nucleosides 8a,b following a chemoenzymatic pathway (Figure 1).…”