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

Research output: Contribution to journalArticle

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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 - Jan 1 1981

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Uridine
Nucleosides
Isomers
Guanidine
Deoxyuridine
Deoxycytidine
isocytidine
Chromatography
Thymidine
Chlorides
Derivatives

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Matsuda, A., Chu, C. K., Reichman, U., Pankiewicz, K., Watanabe, K. A., & Fox, J. J. (1981). Nucleosides. 120. Syntheses of 2'-Deoxy-ψ-isocytidine and 2'-Deoxy-1-methyl-ψ-uridine from ψ-Uridine. Journal of Organic Chemistry, 46(18), 3603-3609. https://doi.org/10.1021/jo00331a005

Nucleosides. 120. Syntheses of 2'-Deoxy-ψ-isocytidine and 2'-Deoxy-1-methyl-ψ-uridine from ψ-Uridine. / Matsuda, Akira; Chu, Chung K.; Reichman, U.; Pankiewicz, Krzysztof; Watanabe, Kyoichi A.; Fox, Jack J.

In: Journal of Organic Chemistry, Vol. 46, No. 18, 01.01.1981, p. 3603-3609.

Research output: Contribution to journalArticle

Matsuda, A, Chu, CK, Reichman, U, Pankiewicz, K, Watanabe, KA & Fox, JJ 1981, 'Nucleosides. 120. Syntheses of 2'-Deoxy-ψ-isocytidine and 2'-Deoxy-1-methyl-ψ-uridine from ψ-Uridine', Journal of Organic Chemistry, vol. 46, no. 18, pp. 3603-3609. https://doi.org/10.1021/jo00331a005
Matsuda, Akira ; Chu, Chung K. ; Reichman, U. ; Pankiewicz, Krzysztof ; Watanabe, Kyoichi A. ; Fox, Jack J. / Nucleosides. 120. Syntheses of 2'-Deoxy-ψ-isocytidine and 2'-Deoxy-1-methyl-ψ-uridine from ψ-Uridine. In: Journal of Organic Chemistry. 1981 ; Vol. 46, No. 18. pp. 3603-3609.
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title = "Nucleosides. 120. Syntheses of 2'-Deoxy-ψ-isocytidine and 2'-Deoxy-1-methyl-ψ-uridine from ψ-Uridine",
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).",
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AU - Matsuda, Akira

AU - Chu, Chung K.

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N2 - 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).

AB - 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).

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