Synthesis of a fusion-isomeric cellobionoimidazole and its evaluation against the syn-protonating glycosidase Cel7A

The fusion-isomeric cellobinoimidazole 2, a potential inhibitor of the syn-protonating beta-glycosidase Cel7A, was synthesised by Koenigs-Knorr glycosylation of the alpha-(D)-arabinopyranoside 32, followed by selective hydrolysis. Glycosylation of 32 with acetobromoglucose 6 proceeded with poor diastereoselectivity, giving the desired 1,3-linked beta-(D)-disaccharide 35 as minor product, besides the major 1,3-linked alpha-(D)-disaccharide 36. Hg2+-Promoted glycosylation of 32 led predominantly to the 1,2-ortho ester 33. Sequential removal of the silyl, acetyl, and ally] groups of 35 led to a 45:55 equilibrium mixture 2 and the manno-configured isomer 39. Similarly, deprotection of 36 gave a mixture of the maltonoimidazole 42 and the manno-configured isomer 43. According to a known protocol, the glycosyl acceptor 32 was synthesised in eleven steps and an overall yield of 8-13% from (D)-lyxose. The silylated arabinopyranosyl moiety of the a-D-glucosides 13-19, 33, 34, and 36 adopts a C-4(1) conformation, while the arabinopyranosyl moiety of the beta-(D)-glucosides 17 and 35 exists as a I : 3 mixture of C-4(1) and C-1(4) conformers, as a result of the combined preferred axial orientation of bulky vicinal substituents and the anomeric effect. MM3* Modelling evidences a preferred C-4(1) conformation of 35 and 36, and stronger steric interactions between the pyranosyl moieties of 35. The equilibrium mixture 2/39 proved a poor inhibitor of Cel7A with an IC50 value of ca. 4 mm.