The true structure and synthesis of edaxadiene - a molecule thought to be crucial for the virulence of the tuberculosis pathogen - has been revealed by US scientists. This could pave the way for better understanding and treatment of the disease.

Tuberculosis kills over 1.5 million people each year, but details about its virulence and how it spreads are only partly understood, which has slowed progress towards new drugs to combat it. The structure of a chemical produced only by pathogenic strains of the organism involved, Mycobacterium tuberculosis, was proposed previously but now Erik Sorensen and colleagues at Princeton University, US, have synthesised it and discovered that the proposed structure was incorrect.

Edaxadiene was isolated and its structure proposed in 2009 but was only available in tiny quantities. The proposed structure contained a tricyclic core with five adjacent stereocentres- a particularly challenging synthetic target which Sorensen and colleagues wanted to produce in sufficient quantities for further investigation. After trying several methods to construct the core unit, they finally succeeded using an oxidative cyclisation of a ketone-alkene system.

At this point in the synthesis, Sorensen noticed that the spectroscopic data of their material different dramatically from that reported for edaxadiene. The team suspected that the original structure for edaxadiene was wrong, and that the correct structure was bicyclic, with a larger side chain. A molecule with this structure had in fact been isolated in 2004 from a Red Sea sponge, and had been given the name nosyberkol.

Nosyberko (right) retains the (red) bicyclic core of edaxadiene (left), but the third ring is opened out to a chain.

Sorensen's team confirmed their hypothesis by adjusting their synthesis to make nosyberkol instead. They found that the data for synthetic nosyberkol matched exactly with that reported for edaxadiene. The hydroxy group in nosyberkol easily falls off during mass spectrometry, which could have led to the erroneous conclusion that edaxadiene did not contain a hydroxy group, speculates Sorenson.

Knowledge of the correct structure, says Sorensen, should help them 'to establish the biomolecular target of nosyberkol and define its role in the progression of tuberculosis infections.' He concludes that their synthesis 'should provide sufficient quantities of this compound to elucidate its role in the infectivity and virulence of M. tuberculosis.'

Pauline Chiu, at the University of Hong Kong, China, emphasises the role that total syntheses such as this play in the structural revision of natural products, saying 'this is a very nice piece of work that is going to make an impact on the understanding and treatment of tuberculosis.'

David Barden

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