Chiral building blocks needed for the preparation of pharmaceutical preparations and drugs in large quantities

Scientists from Germany have succeeded in synthetically producing large amounts of isocitric acid, one step before the production of citric acid. So far, these substances have only been able to be produced synthetically in small quantities

Using a combination of a biotechnological and a chemical step, and starting from sunflower oil, researchers from the University of Leipzig have developed a synthetic process for the preparation of large quantities of (2R,3S)-isocitric acid, the last intermediate in the preparation of citric acid (citric acid).

The citric acid cycle, one of the most important metabolic processes in our body, was formulated back in 1937. Since then, all its intermediates have been produced in industrial quantities, except for one exception - (2R,3S)-isocitric acid. A research team at the University of Leipzig succeeded in this, in the end.

Their process, a combination of a biotechnological and a chemical stage, begins with sunflower oil, a renewable natural starting material. Thanks to this process isocitric acid and its chemical derivatives are available in quantities of kilograms. In the citric acid cycle, acetyl-coenzyme-A, obtained from the breakdown of fats, sugars and amino acids, is used to create energy that is biochemically available for animal production.
Carbon dioxide and water are released during this process. This reaction mechanism is named after one of the intermediates, the anion of citric acid. In nature, isocitric acid always occurs with its isomer, citric acid. The only difference between these two compounds is that the hydroxyl group is attached to a different carbon atom in each of them.

Efficient separation in industrial quantities of the two isomers has been impossible until now. Preparation of the pure isomer in biotechnological fermentation processes also failed. The research team succeeded in this, thanks to very tiny helpers - a yeast called "Yarrowia lipolytica", which produces isocitrate from refined sunflower oil in a process where the utilization and the ratio of the isomers are unpromising. After removal of the by-products, electrodialysis is used to obtain the two acids cleanly. The researchers use a chemical trick to separate the two isomers: they use methanol to convert the acids into their corresponding methyl esters.

Why does it work correctly? While the methyl ester of citric acid crystallizes, the methyl ester of isocitric acid is a liquid. In this situation the separation between the two is extremely simple. Why was isocitric acid so important to these researchers? The acid is a compound with chiral centers - carbon atoms that carry four different substituent groups. Naturally, there are always two types of isomers with chiral centers - enantiomers - each is the mirror image of the other. Commonly available small chiral compounds are building blocks for the synthesis of complex natural materials and extremely important starting materials for the pharmaceutical industry. Obtaining the isocitric acid with such ease in the modern method allows an available, convenient, efficient and cheap reservoir for such chiral building blocks.

to the researchers' press release