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Modular Synthesis of 5-Substituted Thiophen-2-yl C-2′-Deoxyribonucleosides

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journal contribution
posted on 16.05.2008, 00:00 by Jan Bárta, Radek Pohl, Blanka Klepetářová, Nikolaus P. Ernsting, Michal Hocek
A new modular methodology of preparation of 5-substituted thiophene-2-yl C-nucleosides was developed. A Friedel−Crafts-type of C-glycosidation of 2-bromothiophene with toluoyl-protected methylglycoside 2 gave the desired protected 1β-(5-bromothiophen-2-yl)-1,2-dideoxyribofuranose 4a in 60%. The key intermediate 4a was then subjected to a series of palladium-catalyzed cross-coupling reactions. The cross-coupling reactions with alkyl organometallics gave β-(5-alkylthiophen-2-yl)-2-deoxyribonucleosides 4 and 7 in moderate yields accompanied by side-products of reduction. On the other hand, cross-couplings with arylstannanes proceeded smoothly to give a series of β-(5-arylthiophen-2-yl)-2-deoxyribonucleosides 4 in good yields. Deprotection of toluoylated nucleosides by NaOMe in MeOH and silylated nucleosides by Et3N·3HF gave a series of free C-nucleosides 6. Alternatively, other types of 5-arylthiophene C-nucleosides 6 were prepared in one step by the aqueous-phase cross-coupling reactions of unprotected 1β-(5-bromothiophen-2-yl)-1,2-dideoxyribofuranose with boronic acids. Title 5-arylthiophene C-nucleosides 6 exhibit interesting fluorescent properties with emission maxima varying from 339 to 396 nm depending on the aryl group attached.