Making double bonds in a more selective and efficient way could open the door to a family of biologically active natural products.

Richard Taylor and James Robinson at the University of York, UK, used sulfur chemistry to make combretastatin A-4, which is a bioactive natural product isolated from the African tree Combretum caffrum. According to Taylor, the route is efficient and reliable and uses readily available starting materials.

Combretastatin A-4 is the most potent inhibitor of cancer cell growth in the combretastatin family and its phosphate derivative is currently in clinical trials as a potential drug to treat solid tumours.

The combretastatins are based on a stilbene structure - a double bond with a phenyl group on each carbon. The York team make the stilbene unit using the Ramberg-Bäcklund reaction, where an alkene forms from a sulfone group, on expulsion of sulfur dioxide.

According to Taylor, the Ramberg-Bäcklund reaction is widely used in natural product synthesis, but it had been thought that it could only be used to make (E)-stilbenes. However, Taylor and Robinson made both (Z)- and (E)-isomers of the stilbene structure using the reaction. In the (Z)-stilbene, the phenyl groups are on the same side of the double bond (or cis to each other) and in the (E)-stilbene, the phenyl groups are on opposite sides (or trans to each other).  

'As a result, the preparation of stilbenoid and related bioactive natural products should expand dramatically,' said Taylor.

The route is flexible and can be used to make several combretastatin analogues and an (E)-stilbene compound called DMU-212, which is a synthetic analogue of resveratrol. This is a naturally occurring compound found in red wine, and is known to have anticancer and cholesterol-lowering properties.

Taylor predicts that the Ramberg-Bäcklund route could be used for making other natural products. 'Currently, we are developing an efficient new route to the naturally occurring anticancer agent varitriol which was recently isolated from the fungus Emericella variecolor,' he said.

Alison Stoddart