Introduction of fluorine atoms into organic molecules could have applications for synthesis of pharmaceuticals

October 3, 2012, RIKEN
A schematic representation of the four different stereoisomers of the fluorinated amino acid derivatives that can be synthesized using the fluorination and hydroxy/amino derivative technique. Credit: 2012  Mikiko Sodeoka et al., RIKEN Advanced Science Institute

Despite its small size, the fluorine atom has had a vast impact on the pharmaceutical industry. More often than not, introducing fluorine to a drug molecule improves the drug's biological activity, earning it a reputation as a 'magic element'.

Amino acids—comprising an amino group and a carboxylic acid group—are also important to the medicinal chemist. Amino acids are not only the building blocks of proteins, they are commonly found in . Now, Mikiko Sodeoka and colleagues at the RIKEN Advanced Science Institute, Wako, have developed a that can selectively and efficiently combine and into the same .

The starting materials are alpha-keto esters that contain a carbonyl group and an ester group. The first reaction of the team's technique is the substitution of a hydrogen atom, on the carbon atom adjacent to the carbonyl group, for a fluorine atom. As there are two that could be replaced, two mirror images, or enantiomers could result. Sodeoka and colleagues use a palladium catalyst that preferentially forms one of these enantiomers. This renders the reaction enantioselective; that is, one enantiomer is selectively formed over the other. The carbon atom to which the fluorine attaches becomes a stereogenic center as it has four different substituents. The interchange of any two substituents gives a pair of enantiomers. In the wider picture, these enantiomers are stereoisomers—molecules that differ only by their 3D orientation of the atoms. 

Next, the carbonyl group of the fluorinated alpha-keto ester transforms to a hydroxyl group. Again, two possible stereoisomers of the molecule could form. By exploiting the existing stereogenic center and using different reagents, the researchers could synthesize one stereoisomer in preference to the other. Hence, the technique not only introduces fluorine, but two stereogenic centers to the molecule. The formation of two stereogenic centers creates the possibility of four different stereoisomers (Fig. 1). By tuning the reagents, the team isolated all four stereoisomers in separate reaction sequences. 

Overcoming the chemical instability of the intermediate, however, is challenging. "The fluorinated alpha-keto esters easily convert to their hydrated form, so care is required to exclude water from the reaction mixture," Sodeoka explains. "However, the hydroxy and amino acid derivatives are stable and easy to handle." 

In the future, Sodeoka and colleagues hope to widen the scope of the fluorination reaction to other starting materials. This would create the possibility of making numerous biologically active compounds.

Explore further: Organic chemistry: Amino acids made easy

More information: Suzuki, S., Kitamura, Y., Lectard, S., Hamashima, Y. & Sodeoka, M. Catalytic asymmetric mono-fluorination of α-keto esters: Synthesis of optically active β-fluoro-α-hydroxy and β-fluoro-α-amino acid derivatives. Angewandte Chemie International Edition 51, 4581–4585 (2012).

Related Stories

Organic chemistry: Amino acids made easy

May 4, 2011

Amino acids are the building blocks of proteins. There are 22 different amino acids and they can combine in a myriad ways to form a vast array of proteins. All amino acids except glycine are chiral molecules, meaning they ...

A new way to prepare fluorinated pharmaceuticals

August 13, 2009

( -- A team of MIT chemists has devised a new way to add fluorine to a variety of compounds used in many drugs and agricultural chemicals, an advance that could offer more flexibility and potential cost-savings ...

Taming the molecule's Dr. Jekyll and Mr. Hyde

June 14, 2011

Many organic molecules are non-superimposable with their mirror image. The two forms of such a molecule are called enantiomers and can have different properties in biological systems. The problem is to control which enantiomer ...

Eliminating the 'Twin'

August 2, 2006

A University of Arkansas researcher has received a grant to study the dynamics of synthesizing molecules with the same "handedness."

From rare bugs to test tube drugs

December 23, 2008

( -- Scientists at the University of St Andrews have created exotic biological compounds in a test tube by uncovering some of Nature's chemical secrets.

Recommended for you

Saving lives with platypus milk

March 15, 2018

A breakthrough by Australian scientists has brought the introduction of an unlikely hero in the global fight against antibiotic resistance a step closer; the humble platypus.

Turbocharging fuel cells with a multifunctional catalyst

March 14, 2018

Powering clean, efficient cars is just one way fuel cell technology could accelerate humanity into a sustainable energy future, but unfortunately, the technology has been a bit sluggish. Now, engineers may be able to essentially ...

The element of surprise

March 14, 2018

Many of us are often told we bear a resemblance to another member of our family—for instance, that we have our mother's nose or our father's eyes.

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

1 / 5 (2) Oct 09, 2012
What's new?
Many pharmaceutical drugs already have fluoride incorporated in their molecules.
Most of them are damaging to health.
Let's not forget that fluoride is a poison. Despite being added to the water supply in some places, fluoride is highly toxic.
Fluorinated aminoacids - mmmmh

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.