title: Nickel-catalyzed stereoselective glycosylation with C(2)-N-substituted benzylidene D-glucosamine and galactosamine trichloroacetimidates for the formation of 1,2-cis-2-amino glycosides. Applications to the synthesis of heparin disaccharides, GPI anchor pseudodisaccharides, and α-GalNAc.
abstract: The 1,2-cis-2-amino glycosides are key components found within a variety of biologically important oligosaccharides and glycopeptides. Although there are remarkable advances in the synthesis of 1,2-cis-2-amino glycosides, disadvantages of the current state-of-the-art methods include limited substrate scope, low yields, long reaction times, and anomeric mixtures. We have developed a novel method for the synthesis of 1,2-cis-2-amino glycosides via nickel-catalyzed α-selective glycosylation with C(2)-N-substituted benzylidene D-glucosamine and galactosamine trichloroacetimidates. These glycosyl donors are capable of coupling to a wide variety of alcohols to provide glycoconjugates in high yields with excellent levels of α-selectivity. Additionally, only a substoichiometric amount of nickel (5-10 mol %) is required for the reaction to occur at 25 °C. The current nickel method relies on the nature of the nickel-ligand complex to control the α-selectivity. The reactive sites of the nucleophiles or the nature of the protecting groups have little effect on the α-selectivity. This methodology has also been successfully applied to both disaccharide donors and acceptors to provide the corresponding oligosaccharides in high yields and α-selectivity. The efficacy of the nickel procedure has been further applied toward the preparation of heparin disaccharides, GPI anchor pseudodisaccharides, and α-GluNAc/GalNAc. Mechanistic studies suggest that the presence of the substituted benzylidene functionality at the C(2)-amino position of glycosyl donors is crucial for the high α-selectivity observed in the coupling products. Additionally, the α-orientation of the C(1)-trichloroacetimidate group on glycosyl donors is necessary for the coupling process to occur.
authors.affiliation: Department of Chemistry, University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Enoch A
authors.initials: EA
authors.lastname: Mensah
authors.forename: Fei
authors.initials: F
authors.lastname: Yu
authors.forename: Hien M
authors.initials: HM
authors.lastname: Nguyen
mesh_terms: D000116:Acetylgalactosamine / Q000138:chemical synthesis*; D001597:Benzylidene Compounds / Q000737:chemistry*; D002384:Catalysis; D005688:Galactosamine / Q000737:chemistry*; D005944:Glucosamine / Q000737:chemistry*; D006031:Glycosylation; D017261:Glycosylphosphatidylinositols / Q000737:chemistry*; D006493:Heparin / Q000138:chemical synthesis*; D009532:Nickel / Q000737:chemistry*
chemical_list: D001597:Benzylidene Compounds; D017261:Glycosylphosphatidylinositols; D005688:Galactosamine; D009532:Nickel; D006493:Heparin; D000116:Acetylgalactosamine; D005944:Glucosamine