US team develops H-heterocyles production method with implications for Pharma
The process – a palladium-catalysed decarboxylative allylic alkylation detailed in an article in Nature Chemistry – creates complex structures – heterocycles – in which carbon-carbon bonds are formed even when atoms are hidden or blocked by other parts of the molecule.
The authors from the California Institute of Technology wrote that: “Given the prevalence of quaternaryN-heterocycles in biologically active alkaloids and pharmaceutical agents, we envisage that our method will provide a synthetic entry into thede novoasymmetric synthesis of such structures.”
This was reiterated by lead researcher Brian Stoltz - the Ethel Wilson Bowles and Robert Bowles Professor of Chemistry at the California Institute of Technology - who said the ability to form carbon-carbon bonds at ‘congested carbon centres’ could present new opportunities for drugmakers.
“There was essentially no way to make these compounds before, so to all of a sudden be able to do it and with perfect selectivity… that's pretty awesome."
Stoltz explained that while the majority of drugs made today do not include congested carbon centres, it is not because such structures are not therapeutically active it is because – prior to the development of the new process – they have been difficult to produce.
“We've made it very easy to make those very hindered centers, even in compounds that contain nitrogen. And that should give pharmaceutical companies new possibilities that they previously couldn't consider."
Enantiomeric Purity
The other advantage of the new method for drugmakers – according to Stoltz and his team – is that the catalytic method they developed is enantioselective – in other words it only produces one version - or enantiomer – of a particular molecule.
"So not only are we making tricky carbon-carbon bonds, we're also making them such that the resulting products have a particular, desired handedness," Stoltz said.
This is significant as different enantiomers of the same compound can have different biological effects – one may have a beneficial therapeutic effect while its mirror image could have at best no effect or, at worse, cause damage.
Regulators increasingly favour enantiomeric purity in active pharmaceutical ingredients (APIs).
For example, according to the most recently available data, over 65 per cent of the drugs approved by the US Food and Drug Administration (FDA) between 2004 and 2006 were single enantiomers.
