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Sweeter hookups between sugars using a macrocyclic catalyst

Bis-thiourea compound helps stereospecifically build β-glycoside sugar linkages

by Bethany Halford
January 16, 2017 | A version of this story appeared in Volume 95, Issue 3

Assembling oligosaccharides and polysaccharides can be tricky business. The steric and electronic elements that come into play when hooking one sugar onto another makes the synthesis of these molecules unpredictable. Now, inspired by the enzymes that connect sugars to one another in cells, Eric N. Jacobsen and coworkers at Harvard University have developed a macrocyclic catalyst that predictably and reliably builds certain types of sugar linkages—known as β-glycosidic bonds—in a stereospecific manner (Science 2017, DOI: 10.1126/science.aal1875).

Jacobsen’s group was hoping to use its expertise in chiral catalysts to influence the stereochemical outcome of a substitution reaction of a glycosyl chloride to create oligosaccharides. But the team discovered that when using a macrocyclic bis-thiourea catalyst, both enantiomers of the catalyst led to the same stereochemical outcome in the product.

Instead of the catalyst controlling the stereochemistry of the reaction, the stereochemistry of the sugar controls the reaction, Jacobsen explains. The reaction takes place via an SN2 mechanism: The thiourea groups in the catalyst make hydrogen bonds to the chloride on the sugar to make it a better leaving group, while an amide side chain in the catalyst activates an alcohol to make it a better nucleophile. The team used the catalyst to assemble a wide variety of trans-1,2-, cis-1,2-, and 2-deoxy-β-glycosides.

“There’s no reliable, general way to attach any two sugars together in a predictable way,” Jacobsen says. “That’s key if we’re going to help advance the field of oligosaccharide synthesis, including automated methods, for biological applications.” This new catalyst, he says, is a step in that direction.

“This is a fascinating study that links concepts from numerous parts of chemistry to define a new approach to selective carbohydrate synthesis,” says Scott J. Miller, an expert in organic synthesis at Yale University. “Achieving catalyst control with nonenzymatic catalysts, through the use of the reported bis-thioureas, opens up new doors and leverages the physical organic chemistry of the catalytic mechanisms in powerful new ways.”

Carbohydrate connection

Reaction scheme showing glycosyl chloride electrophile and glycosyl nucleophile producing β-glycoside using a bis-thiourea catalyst.
A macrocyclic bis-thiourea catalyst allows the Jacobsen group to create a ß-glycoside.


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