07-Aug-2018 - China State Institute of Pharmaceutical Industry

Two new ways to fluorinated structures

Chemo-enzymatic synthesis of fluorinated antibiotics

Fluorinated structures make up more than 20 percent of modern drugs, but benign and fast fluorination schemes are scarce. In a study scientists have now combined dynamic kinetic resolution and nucleophilic fluorination for the asymmetric synthesis of florfenicol, a veterinary antibiotic. After enzymatic resolution of the racemate, two different fluorination strategies both proved effective and fast. One is especially interesting for industrial production.

Fluorine substituents have many welcomed effects in drugs. Often, fluorinated compounds are more lipophilic, penetrate more easily in the cells, and enzymes may find it harder to degrade them. For example, the fluorinated antibiotic florfenicol is more active than thiamphenicol, to which it is related by a terminal fluorine instead of a hydroxy group. Florfenicol and thiamphenicol, which are both variants of chloramphenicol, are used against conjunctivitis and respiratory diseases in cattle.

Despite the relevance of fluorination, many industrial fluorination strategies still involve aggressive and harmful reagents. In the case of florfenicol, not only is the fluorinating agent expensive and corrosive, but the preparation of the two stereocenters also produces a high amount of waste. These issues prompted Fuli Zhang from China State Institute of Pharmaceutical Industry, Shanghai, China, and his colleagues, to look for more environmentally benign processes. To synthesize florfenicol, they had to construct two adjacent stereocenters of the cis-1,2-amino alcohol and introduce a terminal fluorine atom.

The scientists chose to install the fluorine as a last, separate step because the two asymmetric carbon atoms can be conveniently prepared by dynamic kinetic resolution. Kinetic resolution means that two enantiomers can be separated according to their different reactivity. The process is called “dynamic” when the two enantiomers can racemize, that is, interconvert. Then, the faster reacting enantiomer can be isolated with maximal yield.

Zhang and his colleagues designed a dynamic reductive kinetic resolution using ketoreductase enzymes as biocatalysts and glucose as the hydride source. Having established the two stereocenters by this bioenzymatic route, they explored possible fluorination reactions. Two routes of nucleophilic fluorination proved especially convincing, and both routes use amine hydrofluoride as the fluorinating reagent, which is mild and selective and can be handled in glass equipment.

For industrial manufacture, the authors also have a favorite. The route involving a cyclic sulfate intermediate outcompeted the other one containing an intermediate aziridine, a three-membered nitrogen-containing ring. The chemo-enzymatic sulfate route produced florfenicol in only five steps and showed high yield and flexibility as well as acceptable environmental and health safety. The next step will be the further exploration of the reductase enzymes in other dynamic bioreduction syntheses, the authors remark.

Facts, background information, dossiers
  • Asymmetric Synthesis
  • antibiotics
  • florfenicol
More about Wiley-VCH
  • News

    Chemical hydrogen storage system

    Hydrogen is a highly attractive, but also highly explosive energy carrier, which requires safe, lightweight and cheap storage as well as transportation systems. Scientists at the Weizmann Institute of Science, Israel, have now developed a chemical storage system based on simple and abundant ... more

    For a Better Contrast

    Magnetic resonance imaging (MRI) has emerged as one of the most powerful clinical imaging tools because of its superb spatial resolution and soft tissue contrast, especially when using contrast agents. In the European Journal of Inorganic Chemistry, scientists have presented a new kind of n ... more

    A Successful Coupling

    Coupled oxygen transfer and electron transfer reactions that use cofactors are enzymatic reactions of crucial significance to all lifeforms from bacteria to vertebrates. In the European Journal of Inorganic Chemistry, scientists have introduced a model for the enzyme sulfite oxidase. It is ... more

  • Companies

    Wiley-VCH Verlag GmbH & Co. KGaA

    Wiley-VCH publishes monographs, textbooks, major references works and journals in print or online. Wiley-VCH can look back on over 80 years of publishing in chemistry, materials sciences, physics and the life sciences. more