Photochemical Deracemization of Chiral Compounds Assists Drug Development

Deploying a photochemical method, a team from the Technical University of Munich (TUM) has achieved deracemization of chiral compounds for use in biology and medicine. The advance could make it easier for chemists and drug developers to produce active ingredients with very specific properties — antibacterial characteristics, for example — even when working with compounds that are chiral.

Chiral compounds exist as enantiomers that are nonsuperimposable mirror images of each other. Although enantiomeric molecules — molecule pairs that are mirror images of each other — resemble each other like right and left hands, frequently only one of the two forms is effectual. The difference in enantiomers can be significant; while one has a healing effect, the other could be ineffective or even cause unwanted side effects.

First authors Alena Hoelzl-Hobmeier and Andreas Bauer as well as professor Thorsten Bach (center) with the two enantiomers of one of the allenes studied. Courtesy of Uli Benz/TUM.

The research team, led by professor Thorsten Bach, developed a method for obtaining the desired enantiomer from a racemate (i.e., a mixture of both enantiomers) in concentrations of up to 97 percent by using a photochemical catalyst. The dye itself was chiral and therefore specifically converted only one of the enantiomers to the other.

The team demonstrated that it was possible to deracemize chiral compounds with high enantioselectivity using irradiation with visible light (420 nm), in the presence of catalytic quantities (2.5 mole percent) of a chiral sensitizer. It converted an array of 17 chiral racemic allenes into the respective single enantiomers with 89 to 97 percent enantiomeric excess. The sensitizer served as a unidirectional catalyst that converted one enantiomer but not the other. The decrease in entropy was compensated by light energy.

The allenic group of the unwanted enantiomer is much closer to the thioxanthone sensitizer and is therefore converted to the desired form. Courtesy of S. M. Huber and A. Bauer/TUM.

“For a long time, researchers around the world have been seeking ways to selectively synthesize only the desired enantiomer from a racemate,” Bach said. His team has successfully tested its 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,” he said.

The research was published in Nature (https://doi.org/10.1038/s41586-018-0755-1).