A stereocontrolled total synthesis of C-nucleosides.

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概要

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• A stereocontrolled, general synthesis of chiral <I>C</I>-nucleosides has been achieved through a common lactonic <I>C</I>-β-glycoside intermediate which is readily obtainable from non-carbohydrate materials. Osmium tetraoxide-catalyzed <I>vic</I>-dihydroxylation of 8-oxabicyclo[3.2.1]oct-6-en-3-one gives, after acetonidation, (1<I>R</I><SUP>*</SUP>,5<I>S</I><SUP>*</SUP>,6<I>S</I><SUP>*</SUP>,7<I>R</I><SUP>*</SUP>)-6,7-isopropylidenedioxy-8-oxabicyclo[3.2.1]octan-3-one as a single stereoisomer. Baeyer-Villiger oxidation of the ketone affords the key intermediate, 2-(2,3-<I>O</I>-isopropylidene-β-ribofuranosyl)acetic acid lactone. The optically pure lactone having the natural D configuration is obtained through optical resolution of the seco acid by the Pirkle's method followed by relactonization. α-Aminomethylenation of the lactone with <I>t</I>-C<SUB>4</SUB>H<SUB>9</SUB>OCH[N(CH<SUB>3</SUB>)<SUB>2</SUB>]<SUB>2</SUB> yields 2-(2,3-<I>O</I>-isopropylidene-β-D-ribofuranosyl)-2-(dimethylaminomethylene)acetic acid lactone, which undergoes base-assisted condensation with urea followed by deprotection to furnish naturally occurring pseudouridine. Analogously, construction of heterocycles using thiourea and guanidine converts the aminomethylene lactone to unnatural pyrimidine <I>C</I>-nucleosides, 2-thiopseudouridine and pseudoisocytidine, respectively. Showdomycin in natural form can be prepared by two schemes. One approach consists of ozonolysis of the α-dimethylaminomethylene lactone, Wittig reaction using (C<SUB>6</SUB>H<SUB>5</SUB>)<SUB>3</SUB>PCHCONH<SUB>2</SUB>, and acid hydrolysis. The second entry makes use of 2-(2,3-<I>O</I>-isopropylidene-)3-D-ribofuranosyl)acetic acid lactone as the intermediate, which is converted to 2-(2,3-<I>O</I>-isopropylidene-)8-D-ribofuranosyl)-2-furfurylideneaceticacid lactone by the aldol reaction with furfural and dehydration. Methanolysis of the furfurylidene lactone and <I>t</I>-butyldimethylsilylation are followed by ozonolysis, Wittig condensation with (C<SUB>6</SUB>H<SUB>5</SUB>)<SUB>3</SUB>PCHCON<SUB>2</SUB>, and hydrolysis to give the maleimide <I>C</I>-nucleoside. In addition, 6-azapseudouridine and 6-aza-2-thiopseudouridine are obtainable <I>via</I> intramolecular ring closures of the semicarbazone and thiosemicarbazone of methyl 2-(2,3-<I>O</I>-isopropylidene-β-D-ribofuranosyl)glyoxylate followed by deprotections, respectively. These overall transformations are accomplishable under complete stereochemical control.

• 公益社団法人 日本化学会の論文

著者

• Noyori Ryoji

  Department Of Chemistry And Molecular Chirality Research Unit Nagoya University

• Sato Tsuneo

  Department Of Life Science Kurashiki University Of Science And The Arts

• Hayakawa Yoshihiro

  Chemical Instrument Center, Nagoya University

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