Carb Two-step

ORGANIC SYNTHESIS

A newly developed technique saves many steps formerly required in the chemical synthesis of simple sugars. The versatile approach provides an efficient route to carbohydrate building blocks that can be further elaborated and combined into a range of oligosaccharide structures.

Hexose sugars like galactose, glucose, and mannose play crucial roles in living organisms. But they each have multiple hydroxyl groups that are hard to distinguish chemically. Therefore, functionalizing them at specific positions generally requires eight to 14 reactions, including several protection and deprotection steps.

Alan B. Northrup and professor David W. C. MacMillan of Caltech have now devised a technique that requires only two steps [Science, published online Aug. 13, http://dx.doi.org/10.1126/science.1101710]. The first step, developed earlier, is a proline-catalyzed aldol addition of two -oxyaldehydes [Angew. Chem. Int. Ed., 43, 2152 (2004); C&EN, April 12, page 34]. The second is a "tandem Mukaiyama" aldol addition and cyclization in which a third -oxyaldehyde is added and the product cyclized.

With this approach, the starting materials can be derivatized prior to the synthesis, making protection and deprotection unnecessary. Since the method can yield both natural and nonnatural carbohydrates, medicinal chemists could use it "to rapidly study structure-activity relationships of important carbohydrate-containing medicinal agents," MacMillan says.

Simple sugars have been constructed before with enzymes, but the new chemical method offers greater synthetic flexibility, says Samuel J. Danishefsky of Memorial Sloan-Kettering Cancer Center, New York City. "It's really impressive," he says.

Benjamin List of Max Planck Institute for Coal Research, Mülheim, Germany, says that related aldol reactions have been developed by his group and others, but Northrup and MacMillan "have clearly taken this chemistry to the next level. This will likely be the shortest and most practical way to synthesize many differentially protected monosaccharides."