Using a novel cobalt-based catalyst, scientists are now able to introduce C-F chiral centres in the desired position with higher efficiency.
In Chemistry, a molecule is chiral if it cannot be superimposed on its mirror image by any translation or rotation. Chirality is important in the synthesis and development of pharmaceutical drugs as the pharmacological activity of drugs greatly rely on these chiral centres for interaction with biological targets. While one enantiomer of a chiral drug could reap therapeutic effects, another enantiomer of the molecule could be inactive or even toxic. Therefore, synthesising compounds as a single enantiomer is vital in the design and manufacture of drugs. However, introducing a chiral centre in the alkyl backbone remains difficult.
While past attempts involved either tailor-made auxiliary groups in the alkyl backbone or highly active reagents, a recent study published in Nature Catalysis has unveiled a novel cobalt-based catalyst to conduct C(sp3)-C(sp<sup”>3) coupling reaction to introduce a C-F chiral centre in the desired position.</sup”>
Building on their earlier work on nickel-based catalysis, a research team led by Dr. Lu Xi and Professor Fu Yao from the University of Science and Technology of China (USTC) of the Chinese Academy of Sciences constructed a few chiral ligands and found that the catalyst performed the best when the ligand was combined with cobalt. Furthermore, an approximately higher yield and chirality (enantioselectivity) were obtained with or without auxiliary groups or directing groups.
To explain the chiral selectivity of the catalyst, the team carried out a few experiments and density functional theory calculations. The data obtained suggest that the chiral selectivity of the catalyst comes from both the stabilising electrostatic interaction and destabilising repulsion between the substrate and the ligand of the catalyst.
From this, the scientists synthesised several products with C-F chiral centre. Most noteworthy is desaturase inhibitors, which are often used in pest control, where the team was able to obtain a high yield of the product in fewer steps compared to previous methods.
This novel cobalt-based catalyst makes traditional auxiliary groups and harsh experimental conditions irrelevant, presenting us with a new strategy to introduce chiral centres in the alkyl backbone with relative ease and higher efficiency. [APBN]
Source: Li et al. (2021). Cobalt-catalysed enantioselective C (sp3)–C (sp3) coupling. Nature Catalysis, 4(10), 901-911.