Synthesis of 2,4-Disubstituted Pyrimidin-5-yl C-2′-Deoxyribonucleosides by Sequential Regioselective Reactions of 2,4-Dichloropyrimidine Nucleosides

Authors

  • Tomáš Kubelka,

    1. Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences & IOCBResearch Center, Flemingovo nam. 2, 16610 Prague 6, Czech Republic, Fax: +420-220183559
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  • Lenka Slavětínská,

    1. Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences & IOCBResearch Center, Flemingovo nam. 2, 16610 Prague 6, Czech Republic, Fax: +420-220183559
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  • Blanka Klepetářová,

    1. Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences & IOCBResearch Center, Flemingovo nam. 2, 16610 Prague 6, Czech Republic, Fax: +420-220183559
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  • Michal Hocek

    1. Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences & IOCBResearch Center, Flemingovo nam. 2, 16610 Prague 6, Czech Republic, Fax: +420-220183559
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Abstract

A new modular synthesis of diverse 2,4-disubstituted pyrimidin-5-yl C-2′-deoxyribonucleosides by sequential regioselective reactions of 2,6-dichloropyrimidin-5-yl C-nucleosides was developed. The intermediate was prepared by the Heck coupling of 2,6-dichloro-5-iodopyrimidine with glycal followed by desilylation and reduction. Its mild nucleophilic substitutions or Fe-catalyzed cross-coupling with MeMgCl proceeded regioselectively at position 4, whereas at elevated temperatures or with excess of MeMgCl, double substitution occurred. The 2-chloro-4-substituted intermediates undergo another substitution or coupling to afford 2,4-disubstituted derivatives.

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