Synthesis of 9-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)hypoxanthine. the first direct introduction of a 2'-β-fluoro substituent in preformed purine nucleosides. studies directed toward the synthesis of 2'-deoxy-2'-substituted arabinonucleosides. 8

Jacek Krzeminski, Barbara Nawrot, Krzysztof W. Pankiewicz, Kyoichi A. Watanabe

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13 Scopus citations

Abstract

The 3'-di-O-acetyl-,3''-di-O-benzyl-, 3'- O- trityl- and 3',5'-di-O-trityl-2' -O-triflyl-1-benzylinosine (8c, 15, 20c, and 27, respectively) were prepared and subjected to nucleophilic reaction with TASF. Thus, 3',5' -O-(1,1,3,3-tetraisopropyldisiloxanyl)-1-benzylinosine (5c) was triflylated, desilylated, and then acetylated to give 8c. Also, 5c was converted into the 2'-O-tetrahydropyranyl (THP) derivative 11 which was desilylated and then benzylated to give 2'-O-tetrahydropyranyl-O3, O5, N1-tribenzylinosine (13). Removal of the THP group from 13 followed by triflylation afforded 2'-O-trif lyl-O3',O5', N1-tribenzylinosine (15). 3'-O-Acetyl-2' -O-triflyl-5'-O-trityl-1-benzylinosine (20) was prepared from 5'-O-trityl-1-benzylinosine (18c) by conversion into the 2',3' -O- (di-n-butylstannylene) derivative which was treated with triflyl chloride and then acetylated. Treatment of 1-benzylinosine (4c) with trityl chloride in pyridine containing p-dimethylamino-pyridine afforded a mixture of 2',5'- and 3', 5'-di-O-trityl-1-benzylinosine (25 and 26, respectively). These regioisomers were chromatographically separated. Triflylation of 26 gave 2'-O-triflyl-3',5'-di-O-trityl-1-benzyl inosine (27). The triflates 8c and 15 only afforded elimination products upon treatment with TASF. However, the triflate group in 20c and 27 was displaced by fluoride with formation of the 2'-fluoro-arabino nucleosides, 21c and 28, in 10 and 30% yield, respectively. After deprotection of 28, 9- (2-deoxy-2-fluoro-β-D-arabinofuranosyl) hypoxanthine (1, F-ara-H) was obtained in good yield. The conformational influence of the sugar protecting groups on the rate of nucleophilic substitution against elimination is discussed.

Original languageEnglish (US)
Pages (from-to)781-798
Number of pages18
JournalNucleosides and Nucleotides
Volume10
Issue number4
DOIs
StatePublished - Jun 1 1991

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