Chirality is a universal phenomenon in nature. Take the conches below for example: each conch is the mirrored image of the other, but the two conches shall never overlap, introducing a case of chirality. The two different conchs are sometimes described as "left hand" conch and "right hand" conch, because hands also stand for chirality.
Recently, a research team led by Dr. LU Xi and Prof. FU Yao from University of Science and Technology of China (USTC) of the Chinese Academy of Sciences developed a novel cobalt-based catalyst to conduct C(sp3)-C(sp3) coupling reaction and successfully introduced a C-F chiral center in the desired position. The catalytic system requires no auxiliary groups or harsh experimental conditions. The work was published in Nature Catalysis.
Chirality can be extremely important in pharmaceuticals in that chiral centers are usually the biochemically active sites for medicine. However, it remains challenging to introduce a chiral center in organic compound. With the need of developing medicine based on alkyl backbone, this problem has become even harder. Previous approaches almost always involve either tailor-made auxiliary groups in the alkyl backbone or highly active reagents.
Based on their previous research experience on nickel-based catalysts, the researchers designed several chiral ligands and discovered that the catalyst achieved the best performance when the ligand was combined with cobalt. Relatively high yield and chirality (enantioselectivity) were both achieved with or without auxiliary groups or directing groups.
In order to understand the chiral selectivity of the catalyst, the researchers conducted a number of experiments and density functional theory (DFT) calculations. The result suggested that the chiral selectivity of the catalyst derives from both the stabilizing electrostatic interaction and destabilizing repulsion between the substrate and the ligand of the catalyst.
A number of products with C-F chiral center were synthesized in this research. Notably, desaturase inhibitory, the medicine that assists pest control, was synthesized with both fewer steps and higher yield than previous methods. More importantly, as the figure below implies, the product in this research has much higher chirality: the "left hand" and "right hand" products are separated. It suggests that the product has higher biochemical value.
The cobalt-based catalyst introduced in this research makes traditional auxiliary groups and harsh experimental conditions unnecessary, revealing a new approach to introducing chiral centers in the alkyl backbone. Moreover, with the help of the catalyst, medicine with chiral centers was successfully synthesized, which sheds light on its application in pharmaceuticals.