Epilepsy drug created from greener catalytic process

A NEW method has been developed for drug production that avoids the use of expensive precious metals as catalysts.

Some molecules have left and right-handed forms so that their structures appear as mirror images of one another. The two forms can react differently, and certain medications require one specific form of a molecule, known as single-enantiomer drugs. Synthesising only one enantiomer for drug production is challenging and typically requires precious metals, such as platinum and rhodium, as catalysts. Not only are these catalysts expensive, but they are environmentally unfriendly as they require intensive mining. They also often require the use of toxic solvents such as dichloromethane, which are harmful to the environment and are difficult to dispose of on an industrial scale.

A method for the asymmetric synthesis of drugs, such as the epilepsy drug levetiracetam, has now been developed that uses Earth-abundant cobalt as a catalyst as it is more accessible and requires less energy to extract. The new method also uses methanol as a ‘green’ solvent which is less harmful to the environment than dichloromethane.

"We started this program maybe ten years ago, and it was really motivated by cost,” said lead researcher Paul Chirik, a professor of chemistry at Princeton University. “Metals like rhodium and platinum are really expensive, but as the work has evolved, we realised that there's a lot more to it than simply pricing. There are huge environmental concerns, if you think about digging up platinum out of the ground. Typically, you have to go about a mile deep and move 10 t of earth. That has a massive carbon dioxide footprint."

Catalysts based on precious metals operate via two-electron oxidation and have tunable ligands – the molecule or ion that binds to the central metal atom. However, transition metals such as cobalt use one-electron oxidation and have limitations likely due to loss of ligands, which posed a challenge for the researchers to overcome.

“One-electron oxidation or reduction is a common chemical property of the first-row transition metals such as cobalt and iron,” said Chirik. “This is also known as ‘radical chemistry’ and is the chemical origin of a rusting car. Heavier metals tend to operate by two-electron changes and are less prone to oxidation. It is why metals like silver, gold, platinum and rhodium are used for jewellery and hardly lose their lustre. Using one-electron chemistry with iron or in this case, cobalt, in a productive way is an underexplored frontier. Typically, one electron chemistry has been thought to lead to catalyst deactivation. Here we show that cobalt, undergoing one-electron chemistry, provides a new opportunity in catalysis.”

The team used zinc to perform two sequential single-electron reductions of Co(II) to create a more robust catalyst. “We have shown that Co(II) is an unfavourable oxidation state in methanol, our preferred solvent, because the ligand falls off,” said Chirik. “How Zn activation solved this problem is that it brings Co(II) to Co(I) or Co(0), where the ligand will stay on the cobalt in methanol.”

The reduced cobalt functions well as a catalyst to perform the asymmetric synthesis of epilepsy medicine and the new reaction is faster than the conventional method using expensive catalysts.

"We're working in an area of the periodic table where people haven't, for a long time, so there's a huge wealth of new fundamental chemistry," said Chirik. "By learning how to control this electron flow, the world is open to us."

Science http://doi.org/gdmfnd