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

Significance 

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.

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

About the author

Gérard GUILLAMOT started his career in Industry in 1984 after a PhD in organic chemistry. He worked first for Merrell Dow Pharmaceuticals for 10 years, as a research engineer in Chemical Development, then for Schwarz Pharma for 5 years as an R&D manager, after that he moved to PCAS (a French CDMO) as an R&D Director for 17 years. Since 2017, he acts as a Scientific Director within SEQENS (a French CRDMO). As a senior fellow, he is collaborating with Academy and CNRS (French National Agency for Research) in France, monitoring the PhD thesis financed  both by SEQENS and a government agency (ANRT). Recently, he participated to develop a common technical platform between Academy & SEQENS. His main interests in the last decade are focused towards ‘Flow Chemistry’ and ‘H.T.E.’ in Chemical development. He is also part of the Scientific Council of SEQENS and a member of the French Chemical Society and the American Chemical Society.

About the author

Phannarath Phansavath was born in Vientiane (Laos). She received her PhD from Pierre & Marie Curie University in 1997 under the supervision of Prof. M. Malacria and Dr C. Aubert. After postdoctoral studies in the group of Prof. C. Bolm at the Institut für Organische Chemie, RWTH Aachen (Germany), she was appointed assistant professor in 1999 in the group of Prof. J.-P. Genêt at Ecole Nationale Supérieure de Chimie de Paris (Chimie ParisTech). Her current research interests include total synthesis of biologically relevant natural products and transition metal-catalyzed asymmetric reactions.

About the author

Virginie Vidal was born in Paris (France). She completed her PhD at Paris-Sud University under the supervision of Prof. H.P. Husson and Dr. J. Royer (Gif, France) and was a FRM post-doctoral fellow at the University of Montreal with Prof. S. Hanessian (Canada, 1989-1990), and in 1991 with Prof. P. Potier and Dr. R. H. Dodd (Gif). She was appointed as a CNRS Associate Researcher with Prof. J. P. Genêt at Ecole Nationale Supérieure de Chimie de Paris. She is currently CNRS Research Director at Chimie ParisTech (Paris, France). Her research interests focus on the development of transition-metal catalysis and the design of atropisomeric ligands (Synphos and Difluorphos). The synthesis of biorelevant targets is also a focus in her research group. She was Chair of the Division of Organic Chemistry of the French Chemical Society (2009−2012).

Reference

Molina Betancourt, R., Bacheley, L., Karapetyan, A., Guillamot, G., Phansavath, P., & Ratovelomanana-Vidal, V. (2022). An Environmentally Sustainable Synthesis of Enantioenriched CF3-Chromanol, Indanol and Tetralol Derivatives by Rh-Catalyzed Asymmetric Transfer Hydrogenation. ChemCatChem, 14(15), E202200595.

Go To ChemCatChem

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