New asymmetric synthesis method

Article by Neil Clark

A HIGHLY enantioselective method for the decarboxylative halogenation of carboxylic acids has been described by researchers in Japan, who say it could help develop new pharmaceutical compounds.

Many pharmaceuticals are chiral, whereby two mirror image forms of a molecule exist, but only one of these enantiomers has a medicinal use. Organohalides – molecules in which a halogen such as chlorine is bonded to carbon – are one such important class of compounds. They can be produced from carboxylic acids by simply replacing an acid with a halogen; but if the target compound is chiral, this substitution produces left- and right-handed isomers in equal amounts.

Now, a research group from the Toyohashi University of Technology has described a new catalytic reaction to produce such molecules in isomerically pure form. As described in Nature Communications, they did this by using a catalyst which itself was chiral.

Lead author Kazutaka Shibatomi said: “We screened a diverse array of chiral catalysts, such as Lewis acid, Brønsted acid, and Lewis base catalysts. Finally, we found an amine that gave us organohalides with up to 98% enantiomeric purity – even though our starting material was a 50/50 mixture.”

The researchers were able to demonstrate the chiral production of a range of chlorinated products, called chloroketones. These compounds can be applied as building blocks for pharmaceuticals, as the chlorine can be easily substituted by another atom to make a new molecule. Using one of their reaction products, the research team demonstrated the synthesis of Cathinone, a central nervous system stimulant.

Shibatomi said: “The substitution proceeds in a simple, classic way. While chlorine leaves the molecule on one side, the incoming group approaches from the opposite side. The product's chirality just depends on the arrangement of these atoms – so if you begin with a pure enantiomer, you retain that purity.

“This could open up a whole class of compounds that were previously a major challenge to produce as pure enantiomers."

In their paper, the authors state that studies are ongoing into applying the method to enantioselective fluorination reactions, and to reactions with other types of aliphatic carboxylic acids bearing electron-withdrawing substituents.

Nature communications:

Article by Neil Clark

Staff Reporter, The Chemical Engineer

Recent Editions

Catch up on the latest news, views and jobs from The Chemical Engineer. Below are the four latest issues. View a wider selection of the archive from within the Magazine section of this site.