Traditionally, access to structurally defined complex carbohydrates has been very laborious. Although recent advancements in solid-phase synthesis have made the construction of complex oligosaccharides less tedious, a high level of technical expertise is still necessary to obtain the desired structures. We describe the automated chemical synthesis of several oligosaccharides on a solid-phase synthesizer. A branched dodecasaccharide was synthesized through the use of glycosyl phosphate building blocks and an octenediol functionalized resin. The target oligosaccharide was readily obtained after cleavage from the solid support. Access to certain complex oligosaccharides now has become feasible in a fashion much like the construction of oligopeptides and oligonucleotides.
Described is an efficient one-pot synthesis of alpha- and beta-glycosyl phosphate and dithiophosphate triesters from glycals via 1,2-anhydrosugars. Glycosyl phosphates function as versatile glycosylating agents for the synthesis of beta-glucosidic, beta-galactosidic, alpha-fucosidic, alpha-mannosidic, beta-glucuronic acid, and beta-glucosamine linkages upon activation with trimethylsilyl trifluoromethanesulfonate (TMSOTf). In addition to serving as efficient donors for O-glycosylations, glycosyl phosphates are effective in the preparation of S-glycosides and C-glycosides. Furthermore, the acid-catalyzed coupling of glycosyl phosphates with silylated acceptors is also discussed. Glycosyl dithiophosphates are synthesized and are also used as glycosyl donors. This alternate method offers compatibility with acceptors containing glycals to form beta-glycosides. To minimize protecting group manipulations, orthogonal and regioselective glycosylation strategies with glycosyl phosphates are reported. An orthogonal glycosylation method involving the activation of a glycosyl phosphate donor in the presence of a thioglycoside acceptor is described, as is an acceptor-mediated regioselective glycosylation strategy. Additionally, a unique glycosylation strategy exploiting the difference in reactivity of alpha- and beta-glycosyl phosphates is disclosed. The procedures outlined here provide the basis for the assembly of complex oligosaccharides in solution and by automated solid-phase synthesis with glycosyl phosphate building blocks exclusively or in concert with other donors.
[formula: see text] A beta-(1-->4)-linked trisaccharide was prepared in 53% yield on a polymer support using glycosyl phosphates and released by cross-metathesis of a novel linker to reveal the anomeric n-pentenyl glycoside. Heptasaccharide 33 was prepared in 9% yield in 14 steps.
Differentially protected glycosyl phosphates prepared by a straightforward synthesis from glycal precursors are used as powerful glycosyl donors. Activation of beta-glycosyl phosphates by TMSOTf at -78 degrees C achieves the selective formation of beta-glycosidic linkages in excellent yields with complete stereoselectivity. Reaction with thiols results in the conversion of glycosyl phosphates into thioglycosides in nearly quantitative yield. An orthogonal coupling strategy using glycosyl phosphate donors and thioethyl glycoside acceptors allows for the rapid synthesis of a trisaccharide.
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