Synthesis of Asialo GM1. New Insights in the Application of Sulfonamidoglycosylation in Oligosaccharide Assembly: Subtle Proximity Effects in the Stereochemical Governance of Glycosidation

The total synthesis of asialo GM 1 ( 1a ) has been accomplished. Using related chemistry, the methyl glycoside of the asialo compound ( 1b ) has also been synthesized. These kinds of compounds have been identified as potential ligands for bacterial and viral infection sites. A simpler structure, which has also been identified for its infection attracting structure in the context of glycopeptides and glycolipids (methyl glycoside 2 ), has also been synthesized. The key common phase in the syntheses involves the sulfonamidoglycosidation reaction which is used to create a β-linkage leading to a galNAc residue joined to the C 4 hydroxyl group of a galactose unit either as a monosaccharide (see compound 2 ) or as C 4 ‘ in the context of a lactosyl moiety. During the course of these studies there was encountered an unusual “proximal hydroxyl” directing effect. Thus, when C 4 on the galactose ring of an azaglycosylating donor bears a free hydroxyl (see, for instance, compound 13 ), β-glycoside formation predominates. When this hydroxyl group is blocked, the process tends in the direction of α-glycoside formation (see compound 32 ). These findings were explained as arising from a critical intramolecular hydrogen bond between the C 4 axial hydroxyl of the galactose donor and its proximal pyranosidal ring oxygen. This interaction stabilizes conformations from which β-glycosidation predominates.