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

Oct 03, 2012
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: Producing biodegradable plastic just got cheaper and greener

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 04, 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, ...

A new way to prepare fluorinated pharmaceuticals

Aug 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

Jun 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'

Aug 02, 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

Dec 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

Aluminum clusters shut down molecular fuel factory

Jul 06, 2015

Despite decades of industrial use, the exact chemical transformations occurring within zeolites, a common material used in the conversion of oil to gasoline, remain poorly understood. Now scientists have ...

New catalyst does more with less platinum

Jul 06, 2015

Platinum is a highly reactive and in-demand catalyst across the chemical and energy industries, but a team of University of Wisconsin-Madison and Georgia Institute of Technology scientists could reduce the ...

Learning from biology to accelerate discovery

Jul 06, 2015

A spider's web is one of the most intricate constructions in nature, but its precious silk has more than one use. Silk threads can be used as draglines, guidelines, anchors, pheromonal trails, nest lining, ...

User comments : 1

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.