
Seeds from Chinese star anise are the source of a compound critical to the production of Tamiflu using current methods. A new method can produce this drug synthetically using a low-cost and naturally occurring sugar.
© 2010 iStockphoto/KAppleyard
Large-scale production of oseltamivir phosphate, or Tamiflu, during a global influenza A (H1N1) pandemic—as occurred in 2009—hinges on the seasonal availability of seeds from a plant called Chinese star anise. From this traditional cooking spice, manufacturers—under pressure from governments stockpiling the drug—must extract large quantities of an important synthetic precursor called shikimic acid.
Tamiflu can now be synthesized efficiently using a readily available and naturally occurring sugar, D-ribose, thanks to a novel process developed by Anqi Chen, Christina Chai and co-workers from the A*STAR Institute of Chemical and Engineering Sciences in Singapore, in collaboration with the Japanese pharmaceutical company Shionogi. Because D-ribose can be produced abundantly on a multi-thousand tonne scale, this method provides a feedstock for Tamiflu at a fraction of the cost of other techniques.
To chemists, the molecular structure of Tamiflu is deceptively simple. Because it is composed of a six-membered hydrocarbon ring with four different chemical units—known as functional groups—around its exterior, dozens of methods already exist to produce this compound. However, because three of the functional groups on the central ring are chiral—chemical sites that can produce mirror-image isomers during a reaction—industrial chemists have struggled to find an economic manufacturing route that maintains the correct orientations of the functional groups.
According to Chen and Chai, good starting candidates for Tamiflu production should have chiral geometries that are as close as possible to the target molecule to avoid unnecessary experimental steps. An extensive search revealed that D-ribose, with its pentagonal sugar ring and pendant alcohol groups, could match and induce the chirality of Tamiflu. The team successfully transformed D-ribose into a derivative of the shikimic acid precursor using four high-yielding reactions.
The next steps in the synthesis were more challenging. After their initial attempt to cleave a functional group known as a ketal failed to yield the correct intermediate, the researchers had to develop new procedures to generate intermediates with appropriately positioned functional groups. One step in particular was challenging—with two possible reaction sites on the ring, there were potential competing reactions—but geometric interactions ensured formation of only the correct product. In total, Chen, Chai and co-workers synthesized Tamiflu from D-ribose in just 12 steps.
“There is a continual need to develop affordable methods for the synthesis of Tamiflu,” say Chen and Chai. “Our route has the advantage of using D-ribose as a much cheaper, more abundant and reliable feedstock.”
The A*STAR-affiliated researchers mentioned in this highlight are from the Institute of Chemical and Engineering Sciences.