Synthesis of 2′-β-fluoro-substituted nucleosides by a direct approach

Krzysztof W. Pankiewicz, Kyoichi A. Watanabe

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28 Scopus citations

Abstract

Recent research activities directed toward the synthesis of 2′-β-fluoro-substitutednucleosides by nucleophilic displacement of an activated 2′-hydroxy group of preformedribonucleosides are reviewed. In the pyrimidine-C-nucleoside area, direct fluorination ofa 4,5′-anhydro-C-nucleoside triflate with TASF afforded the desired 2′-β-fluoro-1-methyl-ψ-uridine (C-FMAU). A similar strategy in regular pyrimidine series by using the corresponding2,5′-O-, 2,3′-O- and 5′,6-anhydro nucleoside derivatives did not give thedesired fluoro-containing products. An interesting triflyl migration was discovered whena triflate nucleoside was treated with LiCl in HMPA. The carbocyclic analog of theadenosine containing a fluorine in the 2′-β configuration was prepared from O5′, O3′, N6-tribenzoylaristeromycin in reaction with DAST. A similar treatment of purine nucleosidesled to decomposition. When, however, inosine, adenosine and guanosine were tritylatedat the 3′,5′ positions of the sugar moiety and suitably protected at the base, thecorresponding 2′-β-fluoro-substituted arabino-nucleosides were obtained by treatmentwith DAST in moderate to good yields. Deprotection afforded the desired F-ara-H,F-ara-A and F-ara-G. The role of the bulky trityl groups at the 3′,5′ positions of thesugar and the effect of C-3′-endo to C-2′-endo conformational shift on the reaction courseof 2′-hydroxyl group with DAST is discussed.

Original languageEnglish (US)
Pages (from-to)15-36
Number of pages22
JournalJournal of Fluorine Chemistry
Volume64
Issue number1-2
DOIs
StatePublished - Sep 1993

Bibliographical note

Funding Information:
The authors aclmowledge support of funds from the National Cancer Institute and in part from the National Institute of General Medical Sciences, National Institutes of Health, US Department of Health and Human Services (Grant Nos. CA-08748, 18601, 33907 and GM-42010). We thank Kyowa Hakko Kogyo, Ltd. for the gift of large amounts of $-uridine for our research. We thank Dr Barbara Nawrot, now at the Institute of Organic Chemistry, Technical University (Politechnika), Lodz, Poland and Dr Jacek Krzeminski, currently at the American Health Foundation, Valhalla, New York, for their invaluable contributions to the area of research described in this article.

Copyright:
Copyright 2014 Elsevier B.V., All rights reserved.

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