Synthesis of oligosaccharide libraries using ionically-tagged glycosyl donors

Increasing awareness of the important biological roles oligosaccharides play in living organisms has given birth to a renaissance in carbohydrate chemistry. The synthesis of oligosaccharides and the screening of their biological activities are therefore of crucial importance for better understanding their roles in Nature.; Combinatorial chemistry is well-suited to the rapid generation of a large number of chemicals (libraries) in a short time. However, the preparation of oligosaccharide libraries through combinatorial chemistry is much more challenging than that of other biopolymers because of their inherent chemical complexity. Specifically, oligosaccharide libraries present special difficulties in terms of their isolation from the complex reaction mixtures and identification of the individual positional isomers.; One of the most useful procedures for the combinatorial synthesis of oligosaccharide is “random glycosylation” strategy developed by Hindsgaul and his coworkers. In the random glycosylation approach, a suitably protected glycosyl donor is reacted with an unprotected acceptor of defined structure under conditions where all possible positional isomers are hopefully produced. This procedure suffers, however, from the low yield of product formation due to limited solubility of the unprotected glycosyl acceptor, as well as the extensive purification required for product isolation from a complex reaction mixture consisting of the remaining oligosaccharide acceptor and over-glycosylated oligosaccharides. In addition, the identification of the positional isomers present in such mixtures is obviously extremely challenging.; In order to circumvent these problems, we have developed a new procedure based on the reaction of a partially benzoylated glycosyl acceptor with an ionically-tagged glycosyl donor. In this approach, the ion tag serves a protecting group suitable for the isolation of products having only one additional glycosyl residue using ion-exchange chromatography. Such a procedure allows for the easy removal of unreacted glycosyl acceptor as well as over-glycosylated oligosaccharides.; In order to demonstrate the feasibility of this strategy, a 4,6- O-(4-methoxy-carbonylbenzylidene) protecting group was introduced into the glycosyl donor and several oligosaccharide libraries were prepared by the random glycosylation strategy.; The individual positional isomers present in the libraries prepared and isolated in this way were readily identified using the reductive-cleavage method.