Nucleosides. 120. Syntheses of 2'-Deoxy-ψ-isocytidine and 2'-Deoxy-1-methyl-ψ-uridine from ψ-Uridine

Akira Matsuda, Chung K. Chu, U. Reichman, Krzysztof Pankiewicz, Kyoichi A. Watanabe, Jack J. Fox

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Abstract

2'-Deoxy-ψ-isocytidine (9, R = H) and 2'-deoxy-l-methyl-ψ-uridine (6), C-nucleoside isosteres of deoxycytidine and thymidine, were synthesized by two different procedures. Treatment of ψ-uridine (1) with α-acetoxyisobutyryl chloride gave a mixture containing the 2'-chloro-2'-deoxyribosyl (2) and 3'-chloro-3'-deoxyxylosyl (3) C-nucleosides. After hydrodehalogenation of the mixture with n-Bu3SnH, a mixture was obtained from which 2'-deoxy-ψ-uridine (4) and its 3'-deoxy isomer 5 were isolated. Compound 4 was converted into 2'-deoxy-l-methyl-ψ-uridine (6) by trimethylsilylation followed by treatment with methyl iodide. The mixture containing 4 and 5 was directly treated with DMF dimethyl acetal. 2'-Deoxy-l,3-dimethyl-ψ-uridine (7) and the 3'-deoxy analogue (8) were obtained from the mixture. Treatment of 7 with guanidine gave an α,β mixture of 2'-deoxy-ψ-isocytidine from which the β isomer (9, R = H) was isolated in low yield. Compound 8 was converted into 3'-deoxy-ψ-isocytidine (10) by treatment with guanidine. In the second procedure, 1 was converted into 1-methyl-ψ-uridine (11) which was tritylated to 12 and then thiocarbonylated to give the cyclic thionocarbonate 13. Upon treatment of 13 with n-Bu3SnH, three products, the 2',3'-olefinic nucleoside 14, 2'-deoxy-l-methyl-5,-0-trityl-ψ-uridine (15), and the 3'-deoxy C-nucleoside 16, were obtained in 18%, 45%, and 25% yields, respectively. De-O-tritylation of 15 and 16 afforded the 2'-deoxy (6) and 3'-deoxy (17) analogues of l-methyl-ψ-uridine, respectively, in good yield. Compound 15 was further methylated to 2'-deoxy-1,3-dimethyl-5'-0-trityl-ψ-uridine (18), and subsequent treatment with guanidine afforded an α,β mixture of the 2'-deoxy-ψ-isocytidine derivatives. The components were readily separated into pure isomers by chromatography. 2'-Deoxy-ψ-isocytidine (9, R = H) was obtained in high yield after de-O-tritylation of the β isomer 9 (R = Tr).

Original languageEnglish (US)
Pages (from-to)3603-3609
Number of pages7
JournalJournal of Organic Chemistry
Volume46
Issue number18
DOIs
StatePublished - Aug 1981

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