(Health Korea News / Yu Ji-in) A domestic research team has developed a method to effectively synthesize difluoromethylated compounds in vicinal (adjacent) positions, which is expected to lead to new applications in the synthesis of new drug candidates and library construction.
The National Research Foundation of Korea announced on the 5th that Professor Hyunwoo Kim’s research team at POSTECH developed a new method to synthesize doubly difluoromethylated compounds at the vicinal position using an electrocatalytic method.
The difluoromethyl (CF2H) functional group is a compound with unique isosteric properties, including polarized carbon-hydrogen bonds and lipophilicity. An isostere is a substance that is placed in the same place as another compound due to similarity in structure, composition, and other molecular parameters.
The difluoromethyl group has emerged as a central strategy in chemical development because it can improve the physicochemical and biochemical properties of drug candidates simply by replacing the corresponding functional group in the hydrogen bond donor. In particular, there is a growing interest in the approach of difluoromethylated compounds with a novel skeletal structure as an isostere of the vicinal position hydrogen bond donor.
However, despite these advantages, there were limitations such as the occurrence of unwanted side reactions due to the various synthetic possibilities of the reactive intermediate, and the low efficiency in producing the desired structure due to the kinetic barrier of the radical intermediate, making development difficult. Radicals are independently existing chemical species with unshared unpaired electrons.
The research team developed an effective method for synthesizing double difluoromethylated compounds at the vicinal position by combining electrical oxidation and copper catalyst. The method is to install a difluoromethyl group at the terminal of the substrate using an electrically oxidized difluoromethyl radical, and to combine the generated carbon radical intermediate with an expensive copper catalyst.
The research team elucidated the reaction mechanism using various experimental techniques, including electrochemistry and computational chemistry. The synthetic method can also be applied to complex substances containing existing pharmaceutically active structures, which is expected to expand the library for deriving new drug candidates.
Professor Kim Hyun-woo said, “This study is significant in that it presents a synthetic method that combines the dual roles of a difluoromethylation reagent as a radical/anion precursor with a copper electrocatalytic system to overcome the kinetic limitations of the existing double difluoromethylation reaction at the vicinal position,” adding, “This synthetic method can be applied as a breakthrough measure to increase the structural diversity of new drug substances.”
The results of this study were published on July 30 in the Journal of the American Chemical Society, an international academic journal in the field of chemistry.
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