De novo synthesis of a methylene-bridged Neu5Ac-alpha-(2,3)-gal C-disaccharide.
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.
Notz
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Fachbereich Chemie, Universität Konstanz, Fach M 725, D-78457 Konstanz, Germany.
Hartel
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C
Waldscheck
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B
Schmidt
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RR
D000475:Alkenes / Q000138:chemical synthesis* / Q000737:chemistry; D002240:Carbohydrate Sequence; D004187:Disaccharides / Q000138:chemical synthesis* / Q000737:chemistry; D006838:Hydrocarbons; D009682:Magnetic Resonance Spectroscopy; D008697:Methane / Q000031:analogs & derivatives* / Q000737:chemistry*; D008969:Molecular Sequence Data
D000475:Alkenes; D004187:Disaccharides; D006838:Hydrocarbons; C431204:N-acetylneuraminic acid-(2,3)-Gal C-disaccharide; C030011:carbene; D008697:Methane