New method for building carbohydrate molecules

Chemists at the California Institute of Technology have succeeded in devising a new method for building carbohydrate molecules in a simple and straightforward way that requires very few steps. The new synthesis strategy should be of benefit to scientists in the areas of chemistry and biology and in the pharmaceutical industry.

In an article published online August 12 by the journal Science on the Science Express Website, Caltech chemistry professor David MacMillan and his graduate student Alan Northrup describe their new method of making carbohydrates in two steps. This is a major improvement over current methods, which can require up to a dozen chemical steps.

"The issue with carbohydrate utilization is that, for the last 100 years, scientists have needed many chemical reactions to differentiate five of the six oxygen atoms present in the carbohydrate structure," explains MacMillan, a specialist in organic synthesis. "We simplified this to two steps by the invention of two new chemical reactions that are based on an old but powerful chemical transformation known as the aldol reaction. Furthermore, we have devised methods to selectively build oxygen differentiated glucose, mannose, or allose in just two chemical steps."

MacMillan has also demonstrated that this new method for carbohydrate synthesis allows easy access to unnatural carbohydrates for use in medicinal chemistry and glycobiology as well as in a number of diagnostic techniques. One application involves a rare form or carbon known as carbon-13, which is easier to identify with magnetism-based analytical methods.

By using the readily available and inexpensive 13C-labeled form of ethylene glycol, MacMillan and Northrup have been able to construct the all-13C-labeled versions of carbohydrates in only four chemical steps. For comparison, the previous total synthesis of this all-13C-labeled carbohydrate was accomplished in 44 chemical steps.

"Carbohydrates are essential to human biology, playing key roles in everything from our growth and development to our immune system and brain functions," says John Schwab, a chemist at the National Institute of General Medical Sciences, which supported the research. "They also play critical roles in plants, bacteria, and viruses, where they have huge implications for human health. But because they are so difficult to work with, carbohydrates are not nearly as well understood as DNA and proteins.

"MacMillan's technique will allow scientists to more easily synthesize and study carbohydrates, paving the way for a deeper understanding of these molecules, which in turn may lead to new classes of drugs and diagnostic tools," Schwab adds.

"One of the central goals of chemical synthesis is to design new ways to build molecules that will greatly benefit other scientific fields and ultimately society as a whole," MacMillan says. "We think that this new chemical sequence will help toward this goal; however, there is a bounty of new chemical reactions that are simply waiting to be discovered that will greatly impact many other areas of research in the biological and physical sciences."

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