One of the central challenges in synthetic chemistry is to master the control of free radicals. These highly reactive molecules, with unpaired electrons, are the ones we take antioxidant supplements to counteract oxidative stress.
In the world of synthetic chemistry, however, free radicals offer great potential. UC Santa Barbara chemistry professor Yang Yang and his colleagues believe that free radical chemistry can be very useful for synthesizing bioactive molecules and everyday polymers. The main obstacle they face is achieving stereocontrol, which involves controlling the three-dimensional orientation of atoms and molecules.
Stereochemistry is crucial as it affects the properties of organic molecules. For instance, (S)-carvone gives mint its distinct odor, while (R)-carvone, found in caraway seeds, has a different smell. Precise stereocontrol is a major goal for synthetic chemistry, and chemists have turned to catalysts to achieve this. Catalysts are substances that facilitate chemical reactions without being consumed themselves, making them reusable.
However, controlling the stereochemistry of free radicals is challenging. Free radicals don’t interact tightly with catalysts and can easily wander away from reactive sites. Yang and his team are exploring the use of metalloenzymes, naturally occurring proteins with a reactive metal center, to generate and control free radicals for selective transformations.
The researchers have managed to control the stereoselective addition of a radical species to an aromatic compound derived from racemic starting material (equal mixtures of left-handed and right-handed molecules). Usually, enzymes are very specific and recognize only one enantiomeric form of a chiral compound (mirror image molecules). But through engineered enzymes, they have successfully converted both the left-handed and right-handed forms of the starting material into the same major enantiomeric product with excellent selectivity.
In their study, they employed an iron-dependent enzyme for producing highly reactive radical species. By directed evolution, they engineered selective iron enzymes that produce either the left-handed or right-handed product with great selectivity. Additionally, they developed a “kinetic resolution” enzyme that selectively converts the left-handed starting material, leaving the right-handed one untouched.
These metalloenzymes offer a promising solution for controlling free radical selectivities, providing a toolbox of biocatalysts to enable various types of stereocontrol for radical functionalization of aromatic compounds. Yang hopes that these biocatalytic solutions will aid the synthesis and study of chiral compounds in both academic and industrial settings.