A general synthetic approach to various isoxanthopterin-nucleosides starting from 6-methyl-2-methylthio-4(3H),7(8H)-pterdinedione (1) has been developed. Ribosylation with 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-D-ribofuranose via the silyl-method led to 2 and reaction with 1-chloro-2-deoxy-3,5-di-O-p-toluoyl-alpha-D-ribofuranose using the DBU-method afforded 28. Protection of the amide function at O4 by benzylation to 5 and by a Mitsunobu reaction with 2-(4-nitrophenyl)ethanol to 29 gave soluble intermediates which can be oxidized to the corresponding 2-methylsulfonyl derivatives 8 and 30, respectively. Nucleophilic displacement reactions of the highly reactive 2-methylsulfonyl functions by various amines proceeded under mild conditions to isoxanthopterin-N8-ribo- (11-17) and 2'-deoxyribomucleosides (31-33). Debenzylation can be achieve by Pd-catalyzed hydrogenation (9 to 19) and cleavage of the npe-protecting group (31, 32 to 34, 35) works well with DBU by beta-elimination.

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Wie funktionieren retentive Glycosyltransferasen? Bei der Beantwortung dieser Frage muss berücksichtigt werden, dass von den Disubstratanaloga 1 überraschenderweise 1β und nicht 1α die α(1-3)-Galactosyltransferase sehr gut hemmt. Das Verständnis dieser Hemmung ist ein wichtiger Schritt für die pharmakologische Vermeidung hyperakuter Abstoßungsreaktionen bei der Xenotransplantation von Schweineorganen auf Primaten. In den Verbindungen 1 sind die Enzymsubstrate, UDP-Gal und Galactose, kovalent verknüpft.

How do retaining glycosyltransferases function? To answer this question, UDP-Gal and galactose were covalently linked to form disubstrate analogues 1, of which surprisingly 1β and not 1α inhibited α(1-3)-galactosyltransferases very well. An understanding of this inhibition is a key to the pharmacological prevention of hyperacute rejection in pig to primate xenotransplantation.

A general strategy toward the synthesis of C-ketosides of N-acetylneuraminic acid (Neu5Ac) has been developed and successfully applied to the synthesis of methylene-bridged Neu5Ac-alpha-(2,3)-Gal C-disaccharide 2. The key strategic element of this novel approach is a stereoselective, 6-exo-trig selective, electrophilic cyclization of the appropriate open chain precursor 4 by means of phenylselenyl triflate. The open chain precursor was formed by the addition of lithiated iodide 18 accessible from D-galactose to open chain aldehyde 5a obtained from D-glucono-delta-lactone by chain elongation. Subsequent C1-incorporation using Tebbe-reagent, formation of a cyclic carbonate, and deprotection of the two isopropylidene ketals afforded tetrol 4 which, upon treatment with phenylselenyl triflate, was stereoselectively cyclized in a 6-exo-trig selective manner. A selena-Pummerer rearrangement, oxidation, and esterification readily led to methyl ester 37 which, after deacetylation, could be regioselectively tetrabenzoylated with benzoyl cyanide. Triflate activation of the axial hydroxyl group in 40 and nucleophilic displacement by azide ion with inversion of configuration afforded azide 41, which was reduced with hydrogen and Pearlman's catalyst. Concomitant removal of the benzyl ethers and subsequent saponification of all ester moieties successfully completed the de novo synthesis of the desired methylene bridged Neu5Ac-alpha-(2,3)-Gal C-disaccharide 2.