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Synthesis

Key Oligosaccharide of Cell Wall Prepared

Reagent matching enables rapid first synthesis of a lipomannan from tuberculosis-causing bacterium

by Stu Borman
September 19, 2005 | A version of this story appeared in Volume 83, Issue 38

LIPOMANNAN
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Fraser-Reid and coworkers synthesized this component of the tuberculosis bacterium's cell wall by a synthetic approach that avoided most protecting-group manipulations.
Fraser-Reid and coworkers synthesized this component of the tuberculosis bacterium's cell wall by a synthetic approach that avoided most protecting-group manipulations.

A complex oligosaccharide that makes up part of the cell wall of the tuberculosis-causing bacterium has been prepared by total synthesis. The work makes the cell-wall component--a lipomannan--available in pure form for studies of its role in the disease. It also demonstrates the growing practicality of a long-recognized way to accelerate carbohydrate synthesis by omitting some protection and deprotection steps.

The work was carried out by carbohydrate chemist Bert Fraser-Reid and postdocs K. N. Jayaprakash and Jun Lu at the Natural Products & Glycotechnology Research Institute, a nonprofit organization with labs at North Carolina State University's Centennial Campus (Angew. Chem. Int. Ed. 2005, 44, 5894).

The researchers created the lipomannan component from simple precursors by using "donor-acceptor matching." This technique can eliminate many of the tedious protecting-group manipulations that make carbohydrate synthesis difficult and time-consuming.

The lipomannan unit of the tuberculosis bacterium's cell wall has been shown to exhibit strong inflammatory and apoptosis-inducing activities and is most likely responsible for some of the clinical symptoms of the disease. The synthetic availability of the component could now aid studies of its effects.

"The determination of inflammatory properties of material isolated from natural sources is difficult because trace amounts of other cell-wall components may also induce these effects," comments chemistry professor Geert-Jan Boons of the Complex Carbohydrate Research Center at the University of Georgia, Athens. "These problems can be addressed by chemically synthesizing putative active compounds followed by biological testing. A synthetic approach will also allow for structure-activity relationship studies" on the lipomannan component.

The standard synthetic approach to oligosaccharides like lipomannan would involve extensive use of protecting groups. These are put onto carbohydrate reactants to ensure that they react only at specific positions, and they later have to be removed as well.

"The real time-consuming aspect of oligosaccharide synthesis is preparation of the monomers with their protecting groups," Fraser-Reid says. "It takes the same amount of time to install a benzyl protecting group on the monomer whether you are using old-fashioned synthetic methods" or more recently developed solid-phase or automated oligosaccharide syntheses, he says.

To synthesize lipomannan, Fraser-Reid and coworkers adopted a less daunting approach--the use of donor-acceptor matching to minimize protecting-group manipulations in the glycosylation reactions used to create linkages between sugars. In glycosylation reactions, the donor is the sugar whose ring gets connected to a hydroxyl on another sugar, the acceptor. The idea of donor-acceptor matching is that donor functional groups that are poorly "matched" chemically (for any number of reasons) to an acceptor's reactive hydroxyl are unlikely to react with that hydroxyl. They therefore don't necessarily have to be protected from it and deprotected later.

THE TRICK is finding the proper matches and mismatches, a trial-and-error process that takes time. But with a complex oligosaccharide like lipomannan, whose assembly involves a number of similar mannose-to-mannose glycosylations, the donor-acceptor matching approach can be much faster than the conventional protecting-group approach.

"Our matching strategy dispenses with a lot of, but unfortunately not all, protecting and deprotecting operations, speeding up the process going in and coming out," Fraser-Reid says. Instead of using many of the protecting groups that would normally have been used in the lipomannan synthesis, he and his coworkers activated donor sugars chemoselectively with Lewis acid salts to nudge reactants along the desired glycosylation pathways.

The donor-acceptor matching concept was developed in the mid-1980s by chemistry professor Hans Paulsen of the University of Hamburg, Germany, and coworkers. "At that time, we did not have all the new coupling reagents" available today, so the approach was initially less useful than it currently can be, Paulsen says. The study by Fraser-Reid and coworkers "demonstrates that this concept can be used to simplify oligosaccharide synthesis using modern reagents that are generally applicable," he says.

The power of the technique is exemplified by the synthesis of lipomannan: One person, using common lab glassware and equipment, assembled the oligosaccharide's dodecasaccharide skeleton in three weeks, an unusually short time for a synthesis of that scale. "The strategy is nicely designed and avoids extensive protecting-group manipulations during oligosaccharide synthesis," Boons comments. "This is the approach by which oligosaccharides should be synthesized."

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