An Environmentally Sustainable Access to CF3-Substituted Alcohols as Valuable Fluorinated Motifs for the Synthesis of Bioactive Compounds

The trifluoromethyl group (CF₃) is a functional group consisting of three fluorine atoms bonded to a single carbon atom. It has unique physicochemical properties, which make it an important and versatile group in both medicinal and synthetic chemistry. There are many important applications of the trifluoromethyl group for instance CF₃ group has been widely used in drug design and discovery, as it can enhance the potency and selectivity of drugs by altering their physicochemical properties. For example, adding a trifluoromethyl group to a drug molecule can increase its lipophilicity, metabolic stability, and binding affinity to target proteins. This has led to the development of several successful drugs that contain a trifluoromethyl group, such as celecoxib (a COX-2 inhibitor), efavirenz (an HIV-1 reverse transcriptase inhibitor), and sitagliptin (a DPP-4 inhibitor). CF₃ group is also commonly used in the design of agrochemicals, such as herbicides, fungicides, and insecticides. These compounds are used to protect crops and enhance their yield. The CF₃ group can improve the bioavailability, stability, and activity of these compounds, making them more effective against pests and diseases. Moreover, CF₃ group can also be used in the synthesis of advanced materials with unique properties. For example, the CF₃ group can be incorporated into polymers, surfactants, and liquid crystals to modify their structure and properties. This has led to the development of exciting new materials with improved thermal stability, hydrophobicity, and optical properties. Furthermore, CF₃ group can be used as a derivatizing agent in analytical chemistry to enhance the detection and quantification of analytes. This has led to the development of sensitive and selective analytical methods for the detection of various compounds, such as drugs, pesticides, and environmental pollutants. Nevertheless, despite the practical importance of trifluoromethyl group, an environmentally sound pathway for synthesis and access to enantioenriched trifluoromethyl-containing building blocks is still lacking.

To this account, Chimie-ParisTech-PSL University researchers: Ricardo Molina Betancourt, Lucas Bacheley, Anzhela Karapetyan, Dr. Gérard Guillamot (Scientific Director of Seqens) Dr Phannarath Phansavath and Dr Virginie Ratovelomanana-Vidal developed an efficient pathway for accessing nitrogen and oxygen-containing fluorinated heterocycles. They focused on using a Rh-catalyzed asymmetric transfer hydrogenation/dynamic kinetic resolution (ATH/DKR) for the synthesis of enantioenriched cistrifluoromethyl alcohols under mild conditions. Their work is currently published in the research peer-reviewed journal, ChemCatChem.

The research team reported the successful ATH/DKR of α-CF₃-substituted CF₃-chromanol, indanol and tetralol derivatives to obtain the corresponding enantioenriched β-CF₃-substituted alcohols. The reaction was successfully and efficiently performed in an open flask in a green solvent 2-MeTHF at room temperature using low Rh(III) complex catalyst loading and HCO₂H/Et₃N (1:1) as the hydrogen source. The asymmetric reduction delivered a high yield of up to 98% of the desired cis-alcohols as well as excellent diastereo- and enantioselectivities. It was possible to transpose the reaction to the gram-scale without significant effects. Furthermore, the reduced compounds could be post-functionalized on benzene ring or hydroxyl functional group.

Overall, the trifluoromethyl group has a wide range of applications in medicinal and synthetic chemistry, materials science, agrochemicals, and analytical chemistry. Its unique physicochemical properties make it a versatile tool for modifying the properties of molecules and materials, and for enhancing their biological, chemical, and physical properties. In summary, Chimie-ParisTech-PSL University scientists in collaboration with the Scientific Director of Seqens described a practical and environmentally friendly synthesis of enantioenriched β-trifluoromethyl alcohols. The adopted ATH/DKR process was based on an easy-to-handle and air-stable complex capable of operating under environmentally sound conditions. It is also an atom-economic transformation process, which obeys the green chemistry principles. In a statement to Advances in Engineering, Dr Virginie Ratovelomanana-Vidal, Research Director at the CNRS (The French National Centre for Scientific Research) and corresponding author of the study explained that the proposed new method is sustainable, environmentally benign and suitable for accessing valuable fluorinated motifs that would advance the synthesis of bioactive compounds.