Synthesis of S-linked thiooligosaccharide analogues of Nod factors: Synthesis of new protected thiodisaccharide and thiotrisaccharide intermediates

Article abstract of DOI:10.1016/S0008-6215(03)00149-6

We are investigating the synthesis of thioanalogues of nodulation factors that will be resistant to degradation by chitinases. To study the influence of our protecting group strategy, the glycosylation of 1,6-anhydro-2-azido-3-O-benzyl-2-deoxy-β-D-glucopyranoside (7) with two trichloroacetimidate glycosyl donors carrying an azido group at C-2 and either benzyl or benzoyl protecting groups on O-3 and O-4 was first attempted under catalysis with BF₃·Et₂O in toluene. While glycosylation with the benzoylated glycosyl donor gave only a poor yield (27%) of the disaccharide, a similar reaction with the benzylated donor gave the corresponding disaccharide in good yield (77%). Although both products were obtained as anomeric mixtures, the benzylated donor led to improved stereoselectivity in favor of the desired β-anomer (α:β 3:7). Based on these results, a novel thiotrisaccharide was synthesized via the coupling of 7 with 6-O-acetyl-4-S-(3,4,6-tri-O-acetyl-2-benzyloxycarbonylamino-2-deoxy-β- D-glucopyranosyl)-2-azido-3-O-benzyl-2-deoxy-4-thio-α-D-glucopyranosyl trichloroacetimidate (25) also newly synthesized. After optimization of the reaction conditions, the desired thiotrisaccharide 4-O-[6-O-acetyl-4-S-(3,4,6-tri-O-acetyl-2-benzyloxycarbonylamino-2-deoxy- β-D-glucopyranosyl)-2-azido-3-O-benzyl-2-deoxy-4-thio-β-D- glucopyranosyl]-1,6-anhydro-2-azido-3-O-benzyl-2-deoxy-β-D- glucopyranoside (26β) was obtained in 57% yield. These conditions led to an anomeric mixture in favor of the desired β-anomer (α:β 1:4.7) that was separated from the α-anomer by normal-phase HPLC on a PrepNova Pack silica gel cartridge. The work described here shows that thiodisaccharide glycosyl donors behave quite differently from the analogous O-disaccharide used previously to synthesize nodulation factors.