O-Glycosylation in the Solid to Solid State

Abstract

Glycosylation in the solid to solid state produced glycosides in a simple, mild and stereoselective fashion, and this methodology could serve as an addition to existing glycosylation procedures. A large number of efficient glycosylation procedures have been developed; most of these protocols are being carried out in solution. However, there is still a continuing demand for an appreciable process in terms of mildness, efficacy and stereocontrol. In our earlier work, we demonstrated that N-glycosylation in the solid to solid state provided glycopyranosyl-uracil or -thymine with an enhancement in selectivity, and that this method could serve as a viable alternate to existing solutions and/or fusion procedures. Extending of this methodology, we now report that O-glycosylation in the solid to solid state produced glycoside with excellent stereoselectivity. The glycosylation was simply produced by grinding the glycosyl donor and acceptor in the presence of the promoter with a mortar and pestle for 30 min under argon atmosphere in a glove box. When necessary, the reaction mixture was further ground in a ball mill for 24 hr. The results of O-glycosylation obtained from the solution, and present methods for the comparison between the two are summarized in the Table 1. Tetra-O-acetyl-α-D-glucopyranosyl bromide 1a, 1,2anhydro-3,4,6-tri-O-benzyl-α-D-glucopyranose 1b and 1,2anhydro-3,4,6-tri-O-benzyl-β-D-mannopyranose 1c used as glycosyl donors, and methanol 2a, 1,2;3,4-di-O-isopropylidene-α-D-galactopyranose 2b and methyl 2,3-di-Omethyl-α-D-glucopyranoside 2c used as the glycosyl acceptor are shown in the following Scheme 1. Because of its high hygroscopic nature and the difficulty of handling of 1a due to moisture present in the air, we also tested 1b and 1c as the glycosyl donor instead of 1a in this study. We found these 1,2-anhydrosugars gave better results in the formation of a disaccharide with greatly reduced reaction times and enhanced yields of product. Thus, the reaction of 1b with 2c in the solid to solid state for 30 min produced 43% of glucoside, while the same reaction in solution for 20 hr produced only 35% of the product. In the presence of Amberlite IRC-50, a cationic form of ionic exchange resin, and in the absence of promoter, 1b also reacted with 2c and formed the corresponding disaccharide, producing 32% and 18% of product, respectively. When liquid acceptor 2a and a solution of 2b in CHCl3 were added to the ground mixture of 1b and an activator, glycosylation also proceeded. These observations clearly demonstrate that solid to solid state methodology could be widely extended in glycosylation. In summary, although there is still room for improvement in yield of the product, the solid to solid state reaction methodology could effectively serve as a simple, mild, and stereoselective procedure in glycosylation.