Exploring the effect of bioisosteric replacement of carboxamide by a sulfonamide moiety on N-glycosidic torsions and molecular assembly: Synthesis and x-ray crystallographic investigation of n-(β- D -glycosyl)sulfonamides as n-glycoprotein linkage region analogues

N-Glycoprotein linkage region constituents, 2-acetamido-2-deoxy-β-D- glucopyranose (GlcNAc) and asparagine (Asn) are conserved among all the eukaryotes. To gain a better understanding for nature's choice of GlcNAcβAsn as linkage region constituents and inter- and intramolecular carbohydrate-protein interactions, a detailed systemic structural study of the linkage region conformation is essential. Earlier crystallographic studies of several N-(β-glycopyranosyl)alkanamides showed that N-glycosidic torsion, φN, is influenced to a larger extent by structural variation in the sugar part than that of the aglycon moiety. To explore the effect of the bioisosteric replacement of a carboxamide group by a sulfonamide moiety on the N-glycosidic torsions as well as on molecular assembly, several glycosyl methanesulfonamides and glycosyl chloromethanesulfonamides were synthesized as analogues of the N-glycoprotein linkage region, and crystal structures of seven of these compounds have been solved. A comparative analysis of this series of crystal structures as well as with those of the corresponding alkanamido derivatives revealed that N-glycosidic torsion, φN, does not alter significantly. Methanesulfonamido and chloromethanesulfonamido derivatives of GlcNAc display a different aglycon conformation compared to other sulfonamido analogues. This may be due to the cumulative effect of the direct hydrogen bonding between N1 and O1′ and C-H×××O interactions of the aglycon chain, revealing the uniqueness of the GlcNAc as the linkage sugar. Unique molecular assembly motif of GlcNAc: The different aglycon conformations of methanesulfonamido and chloromethanesulfonamido derivatives of GlcNAc as compared to other sulfonamido analogues is a unique feature of their molecular assembly. This could be due to the cumulative effect of the direct hydrogen bonding between N1 and O1′ and C-H×××O interactions of the aglycon chain. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.