New Approach to Glycosylation

SYNTHESIS

A solution to a long-standing problem of oligosaccharide synthesis--the introduction of 1,2-cis-glycoside linkages between some types of sugars--appears to be at hand.

When two sugars are linked, mixtures of anomers (glycoside diastereomers) often result. The anomers must be separated after each coupling step to avoid the formation of complex mixtures. One type of anomer, 1,2-trans-glycosides, can be obtained in pure form by exploiting a phenomenon called the neighboring-group effect, but this hasn't worked for the other type of product, 1,2-cis-glycosides.

The lack of a straightforward route to pure 1,2-cis-glycosides, including common oligosaccharides such as -glucosides and -galactosides, has been a major stumbling block to one-pot multistep glycosylations and automated polymer-supported oligosaccharide syntheses. "The stereoselective formation of 1,2-cis-glycosides is the principal challenge of complex-oligosaccharide synthesis," says chemistry professor Geert-Jan Boons of the Complex Carbohydrate Research Center at the University of Georgia, Athens.

Boons and coworkers have now solved this problem for some sugars by finding a neighboring group that induces the exclusive formation of 1,2-cis-glycoside products (J. Am. Chem. Soc. 2005, 127, 12090)

The directing group is an (S)-phenylthiomethylbenzyl moiety that's placed on the glycosyl donor's carbon-2, adjacent to the reactive anomeric carbon. Boons and coworkers demonstrated the technique by using one-pot synthesis to combine three monosaccharides, without a separation step that would normally be required. The product was the Galili trisaccharide, an immunoactive oligosaccharide that includes one 1,2-cis linkage.

The technique "is so simple and so obvious; why didn't I think of it myself?" says professor of chemistry and biochemistry Alexei V. Demchenko of the University of Missouri, St. Louis, who specializes in glycosylation. The paper is a milestone, he says.

The study shows that "use of a protective group that also serves as a chiral auxiliary can be used to control the stereochemical outcome of a glycosylation reaction," says chemistry professor Peter H. Seeberger of the Swiss Federal Institute of Technology, Zurich, whose interests include automated carbohydrate synthesis. "This relatively simple idea allows in some cases for much improved stereocontrol of a reaction that is over 100 years old but remains challenging. It is the simplicity that may be the greatest strength of this method." The study "demonstrates that methodological improvements are still needed, and a seemingly mature field is an exciting playing field for practitioners of organic synthesis."

"This is an important conceptual advance based on a sound understanding of the principles of conformational analysis," adds chemistry professor David Crich of the University of Illinois, Chicago, an expert in the synthesis of complex oligosaccharides.

In the reaction, steric and electronic factors cause the donor's (S)-phenylthiomethylbenzyl group to form a trans-decalin sulfonium intermediate. Attack on the sulfonium by a hydroxyl group of the glycoside acceptor opens the decalin ring, forming 1,2-cis-glycosides exclusively. Boons and coworkers report that the approach is effective with glucose and galactose donors, and they are currently testing it on other sugars as well.

"The authors seem to have taken care of every aspect of the method," Demchenko says--"efficient synthesis of glycosyl donors, excellent yields, complete stereoselectivity of glycosylations, and easy deprotection [removal of the (S)-phenylthiomethylbenzyl group], with the possibility of recycling the participating moiety. Critical readers will note that only trichloroacetimidates have been used as glycosyl donors, mostly reactive acceptors have been tried, and gluco- and galactopyranose products are the only examples given. But these are just pilot studies that will stimulate other related investigations. This is a nonorthodox approach to a long-standing challenge in the field."