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

摘要

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-c/s-2-amino glycosides via nickel-catalyzed a-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 a-selectivity. Additionally, only a substoichiometric amount of nickel (5-10 mol %) is required for the reaction to occur at 25 ℃. The current nickel method relies on the nature of the nickel-ligand complex to control the a-selectivity. The reactive sites of the nucleophiles or the nature of the protecting groups have little effect on the a-selectivity. This methodology has also been successfully applied to both disaccharide donors and acceptors to provide the corresponding oligosaccharides in high yields and a-selectivity. The efficacy of the nickel procedure has been further applied toward the preparation of heparin disaccharides, GPI anchor pseudodisaccharides, and a-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 a-selectivity observed in the coupling products. Additionally, the a-orientation of the C(1)-trichloro-acetimidate group on glycosyl donors is necessary for the coupling process to occur.