A Stereocontrolled Total Synthesis of C-Nucleosides

Abstract

Abstract A stereocontrolled, general synthesis of chiral C-nucleosides has been achieved through a common lactonic C-β-glycoside intermediate which is readily obtainable from non-carbohydrate materials. Osmium tetraoxide-catalyzed vic-dihydroxylation of 8-oxabicyclo[3.2.1]oct-6-en-3-one gives, after acetonidation, (1R*,5S*,6S*,7R*)-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-O-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 t-C4H9OCH[N(CH3)2]2 yields 2-(2,3-O-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 C-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 (C6H5)3PCHCONH2, and acid hydrolysis. The second entry makes use of 2-(2,3-O-isopropylidene-)3-d-ribofuranosyl)acetic acid lactone as the intermediate, which is converted to 2-(2,3-O-isopropylidene-)8-d-ribofuranosyl)-2-furfurylideneaceticacid lactone by the aldol reaction with furfural and dehydration. Methanolysis of the furfurylidene lactone and t-butyldimethylsilylation are followed by ozonolysis, Wittig condensation with (C6H5)3PCHCON2, and hydrolysis to give the maleimide C-nucleoside. In addition, 6-azapseudouridine and 6-aza-2-thiopseudouridine are obtainable via intramolecular ring closures of the semicarbazone and thiosemicarbazone of methyl 2-(2,3-O-isopropylidene-β-d-ribofuranosyl)glyoxylate followed by deprotections, respectively. These overall transformations are accomplishable under complete stereochemical control.