Synthesis of a Fusion‐Isomeric Cellobionoimidazole and Its Evaluation against the syn‐Protonating Glycosidase Cel7A

Abstract

AbstractThe fusion‐isomeric cellobinoimidazole 2, a potential inhibitor of the syn‐protonating β‐glycosidase Cel7A, was synthesised by Koenigs–Knorr glycosylation of the α‐D‐arabinopyranoside 32, followed by selective hydrolysis. Glycosylation of 32 with acetobromoglucose 6 proceeded with poor diastereoselectivity, giving the desired 1,3‐linked β‐d‐disaccharide 35 as minor product, besides the major 1,3‐linked α‐d‐disaccharide 36. Hg2+‐Promoted glycosylation of 32 led predominantly to the 1,2‐ortho ester 33. Sequential removal of the silyl, acetyl, and allyl 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 α‐d‐glucosides 13–19, 33, 34, and 36 adopts a 4C1 conformation, while the arabinopyranosyl moiety of the β‐d‐glucosides 17 and 35 exists as a 1 : 3 mixture of 4C1 and 1C4 conformers, as a result of the combined preferred axial orientation of bulky vicinal substituents and the anomeric effect. MM3* Modelling evidences a preferred 4C1 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.