The synthesis of C‐4′‐(1,5‐disubstituted)‐triazole‐spiro‐α‐L‐arabinofuranosyl nucleosides has been achieved in a regio‐ and stereospecific manner by using intramolecular Huisgen 1,3‐dipolar cycloaddition reaction. The synthesis of these nucleosides necessitates the possession of azide and alkyne moieties in the same molecule, which is being employed as the precursor. Thus, the crucial step in the synthesis of targeted compound is the preparation of 1,2,3‐tri‐O‐acetyl‐5‐azido‐5‐deoxy‐4‐C‐propynyl‐α,β‐L‐arabinofuranose and its conversion to corresponding nucleosides via nucleobase coupling. The microwave heating of such tailor made nucleoside precursors furnishes the targeted spironucleosides, which combines conformational‐restriction concept with a triazole structural feature highly sought in drug design.
The biocatalytic synthesis of C-4′-hydroxyl-tetrahydrofurano-spironucleosides where the tetrahydrofuranospirocyclic ring at C-4′ position locks the furanose ring of nucleosides in the NE-conformation (C4′-exo).
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).
Three triazole-linked nonionic xylo-nucleoside dimers T(L)-t-T(xL), T(L)-t-A(BzxL) and T(L)-t-C(BzxL) have been synthesized for the first time by Cu(I) catalyzed azide-alkyne [3 + 2] cycloaddition reaction (CuAAC) of 1-(3'-azido-3'-deoxy-2'-O,4'-C-methylene-β-D-ribo-furanosyl)thymine with different alkynes, i.e., 1-(5'-deoxy-5'-C-ethynyl-2'-O,4'-C-methylene-β-D-xylofuranosyl)thymine, 9-(5'-deoxy-5'-C-ethynyl-2'-O,4'-C-methylene-β-D-xylo-furanosyl)-N6-benzoyladenine and 1-(5'-deoxy-5'-C-ethynyl-2'-O,4'-C-methylene-β-D-xylofuranosyl)-N4-benzoylcytosine in 90%-92% yields. Among the two Cu(I) reagents, CuSO4.5H2O-sodium ascorbate in THF:(t)BuOH:H2O (1:1:1) and CuBr.SMe2 in THF used for cycloaddition (click) reaction, the former one was found to be better yielding than the latter one.
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