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

In 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glycosylation, since the analogous reaction proceeds smoothly once the N ‐acetyl group has been replaced by an azide.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/Et 2 O (9:1) system, we obtained the GlcUA‐β‐(1→4)‐GlcN 3 ‐α‐(1→4)‐GlcUA‐β‐(1→4)‐GlcN 3 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 CH 2 Cl 2 was used. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)