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Synthesis 2008(12): 1918-1932  
DOI: 10.1055/s-2008-1067038
PAPER
© Georg Thieme Verlag Stuttgart · New York

Modular Synthesis of 4-Aryl- and 4-Amino-Substituted Benzene C-2′-Deoxyribonucleosides

Nicolas Joubert, Milan Urban, Radek Pohl, Michal Hocek*
Gilead & IOCB Research Center, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nám. 2, 16610 Prague 6, Czech Republic
Fax: +420(2)20183559; e-Mail: hocek@uochb.cas.cz;
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Publication History

Received 7 February 2008
Publication Date:
29 April 2008 (online)

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Abstract

A modular methodology for the syntheses of various 4-substituted-phenyl C-2′-deoxyribonucleosides has been developed. Coupling of toluoylated halogenose 1 with 4-bromophenylmagnesium bromide afforded the desired bis(toluoyl)-protected 1β-(4-bromophenyl)-1,2-dideoxyribofuranose 2a, which was deprotected under Zemplen conditions to give the unprotected 1β-(4-bromophenyl)-1,2-dideoxyribofuranose 3, and reprotected to give the bis(tert-butyldimethylsilyl)-protected 1β-(4-bromophenyl)-1,2-dideoxyribofuranose 4. Alternatively, addition of 1-lithio-4-bromobenzene on tert-butyldimethylsilyl-protected lactone 5, followed by reduction of the hemiketal 6, also gave bis(tert-butyldimethylsilyl)-protected bromophenyl nucleoside 4. Intermediates 2a and 4 were then subjected to a series of palladium-catalyzed cross-coupling reactions, aminations, and C-H activation to give 1β-[4-(aryl-, alkyl-, or amino)phenyl]-1,2-dideoxyribofuranoses 8a-n after deprotection. Finally, other types of 4-arylphenyl C-nucleosides 8o-u were prepared directly by aqueous-phase Suzuki cross-coupling reactions of unprotected 3 with boronic acids under microwave irradiation.

Key words

nucleosides - C-nucleosides - cross-coupling reactions - amination reactions - benzenes