Synthesis of Glycosaminoglycan Oligosaccharides − An Unexpected Inhibitory Effect of a Remote N‐Acetyl Group upon Trichloroacetimidate‐Mediated Couplings

Abstract

AbstractIn order to prepare biologically relevant heparan sulfate (HS) tetrasaccharide fragments containing an N‐acetylated glucosamine at the reducing end, we studied the glycosylation reaction between the 2‐azidoglucose trichloroacetimidate disaccharide donor 1 and a range of 4′‐OH‐uronyl disaccharide acceptors with an N‐acetylglucosamine at the reducing terminus. Although we tried several condensation conditions, no tetrasaccharide was formed. We show that the failure of these reactions is due to the presence of the N‐acetyl group, which inhibits the trichloroacetimidate‐mediated glycosylation, since the analogous reaction proceeds smoothly once the N‐acetyl group has been replaced by an azide. In the latter case, we show that the careful optimisation of the solvent system is a powerful way to obtain high yields and α‐stereoselectivity in coupling reactions of 1 with the 4‐OH of a GlcUA acceptor. Thus, in a THF/Et2O (9:1) system, we obtained the GlcUA‐β‐(1→4)‐GlcN3‐α‐(1→4)‐GlcUA‐β‐(1→4)‐GlcN3 tetrasaccharide 16α/β in 90% isolated yield and 92:8 α/β ratio, as compared to 57% yield and 70:30 α/β ratio when CH2Cl2 was used. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)