Synthesis of a Fusion-Isomeric Cellobionoimidazole and Its Evaluation against the syn-Protonating Glycosidase Cel7A
✍ Scribed by Narinder Mohal; Bruno Bernet; Andrea Vasella
- Book ID
- 102253286
- Publisher
- John Wiley and Sons
- Year
- 2005
- Tongue
- German
- Weight
- 372 KB
- Volume
- 88
- Category
- Article
- ISSN
- 0018-019X
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✦ Synopsis
Abstract
The 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. Hg^2+^‐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 ^4^C~1~ conformation, while the arabinopyranosyl moiety of the β‐d‐glucosides 17 and 35 exists as a 1 : 3 mixture of ^4^C~1~ and ^1^C~4~ conformers, as a result of the combined preferred axial orientation of bulky vicinal substituents and the anomeric effect. MM3* Modelling evidences a preferred ^4^C~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 IC~50~ value of ca. 4 mM.