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trichloroacetimidate-mediated glycosylation, since the analogous reaction proceeds smoothly once the N-acetyl group has been replaced by an azide.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/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)