Enantiomeric molecules resemble each other like right and left hands. Both variants normally arise in chemical reactions. But frequently only one of the two forms is effectual in biology and medicine. Hitherto, completely converting this mixture into the desired enantiomer was deemed impossible. Deploying a photochemical method, a team of researchers has now achieved this feat.
Producing active ingredients with very specific properties - antibacterial characteristics, for example - is not always so easy. The reason: many of these organic compounds are chiral. They have two mirror-image forms, so-called enantiomers.
This small difference can be consequential because the two enantiomers can have different properties. While one has a healing effect, the other might be ineffective or even cause unwanted side effects.
"For a long time, researchers around the world have been seeking ways to selectively synthesize only the desired enantiomer from a racemate," explains the senior author. However, this has been very difficult, since chemical reactions usually produce both molecule variants.
The team has now developed a method with which the desired enantiomer can be obtained from a racemate, the mixture of both enantiomers, in high concentrations of up to 97 percent. They show that it is possible to photochemically deracemize chiral compounds with high enantioselectivity using irradiation with visible light (wavelength of 420 nanometres) in the presence of catalytic quantities (2.5 mole per cent) of a chiral sensitizer. They converted an array of 17 chiral racemic allenes into the respective single enantiomers with 89 to 97 per cent enantiomeric excess.
Rather than painstakingly extracting the unwanted mirror-molecules from the mixture, the researchers use a photochemical reaction to transform them into the desired end product. "That saves time, energy and resources because all the molecules are used and you do not need to throw away half of them," explains the senior author.
The secret of the transformation is a special photochemical catalyst. Originally, the thioxanthone sensitizer was developed for [2 + 2] photocycloadditions. The dye is itself chiral and therefore specifically converts only one of the enantiomers to the other. In the span of a few minutes, the equilibrium shifts in favor of the desired molecule. The undesirable mirror images disappear. The sensitizer is postulated to operate by triplet energy transfer to the allene, with different energy-transfer efficiencies for the two enantiomers. It thus serves as a unidirectional catalyst that converts one enantiomer but not the other, and the decrease in entropy is compensated by light energy.
The chemists have successfully tested their new method on various molecular mixtures from the allene structural class. "We could thus demonstrate that selective and efficient catalysis to prepare enantiopure compounds from racemates is fundamentally possible," said the senior author.
https://www.nature.com/articles/s41586-018-0755-1
