Fluorine-containing molecules have desirable chemical, structural, pharmacological and biological properties and have made a fundamental paradigm shift in pharmaceutical, agrochemical, and materials science research over the last few decades. Notably, approximately 25% of marketed drugs and three out of the ten top-selling pharmaceuticals in 2011 as well as one-third of the top-performing drugs contain at least one fluorine atom in their structure. However, facile introduction of fluorine atom or fluorinated groups, especially trifluoromethoxy (OCF3), polyfluoroalkoxy (ORf) and pentafluorosulfanyl (SF5) groups, into organic molecules is recognized as a formidable challenge in synthetic chemistry. Most of the current methodologies either suffer from poor substrate scope or require use of highly toxic, difficult-to-handle, and/or thermally labile reagents. Therefore, there is a significant gap between the needs of the chemical and pharmaceutical industry and the efficiency of current strategies for installation of fluorinated groups into molecules of interest. Our long-term goal is to bridge the gap by inventing bench-stable and easy-to-handle reagents and establishing operationally simple, and scalable reactions to facilitate direct incorporation of the fluorinated groups into complex molecules. In the proposed funding period, we will develop a general intramolecular polyfluoroalkoxylation (ORf) reactions of arenes and heteroarenes. Due to their ubiquity in biologically active natural products, pharmaceuticals, and agrochemicals, arenes and heteroarenes bearing ORf groups (e.g. OCF3, OCF2H, and OCF2CF3) will serve as invaluable building blocks for all molecular screenings from medicinal chemistry to materials science. In addition, we will invent novel reagents and reactions for late-stage radical trifluoromethoxylation (OCF3) and pentafluorosulfanylation (SF5) of complex pharmaceuticals and natural products, which will allow rapid biological-activity assays of trifluoromethoxylated and pentafluorosulfanylated analogues. These reagents and synthetic methods could maximize structural diversity and provide insights for future rational property design. To complement these diversity-oriented synthetic approaches, we will also establish transition metal-catalyzed polyfluoroalkylation of phenols to achieve site-selective synthesis of polyfluoroalkoxylated compounds. Given that the fluorinated groups exhibit favorable properties for biological applications, our research program will allow access to and study of new fluorinated functional molecules to aid the discovery and development of new drugs, biocompatible materials, bioprobes, and imaging agents.

Public Health Relevance

Fluorine-containing compounds have favorable physical, chemical and biological properties, and are omnipresent in daily life. They can be found in pharmaceuticals, dyes, pesticides, lubricants, polymers, clothes, non-stick cookware and inhaler propellant, and are involved literally every aspect of life. Our ability to create new fluorinated functional molecules will have significant impact on a broad spectrum of technological applications. The work described herein focuses on the invention of novel chemical tools for creating new fluorine-containing molecules to accelerate drug discovery and development, improve the quality of health care products, and promote the development of new materials for biomedical applications.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Unknown (R35)
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Special Emphasis Panel (ZRG1)
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Yang, Jiong
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State University New York Stony Brook
Schools of Arts and Sciences
Stony Brook
United States
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Zheng, Weijia; Morales-Rivera, Cristian A; Lee, Johnny W et al. (2018) Catalytic C-H Trifluoromethoxylation of Arenes and Heteroarenes. Angew Chem Int Ed Engl 57:9645-9649
Zheng, Weijia; Lee, Johnny W; Morales-Rivera, Cristian A et al. (2018) Redox-Active Reagents for Photocatalytic Generation of the OCF3 Radical and (Hetero)Aryl C-H Trifluoromethoxylation. Angew Chem Int Ed Engl 57:13795-13799
Lee, Katarzyna N; Spiegowski, Dominique N; Lee, Johnny W et al. (2018) Transition-metal-free C-H amidation and chlorination: synthesis of N/N'-mono-substituted imidazopyridin-2-ones from N-pyridyl-N-hydroxylamine intermediates. Chem Commun (Camb) 54:6935-6938
Lee, Katarzyna N; Ngai, Ming-Yu (2017) Recent developments in transition-metal photoredox-catalysed reactions of carbonyl derivatives. Chem Commun (Camb) 53:13093-13112
Lee, Katarzyna N; Lei, Zhen; Ngai, Ming-Yu (2017) ?-Selective Reductive Coupling of Alkenylpyridines with Aldehydes and Imines via Synergistic Lewis Acid/Photoredox Catalysis. J Am Chem Soc :
Lee, Johnny W; Spiegowski, Dominique N; Ngai, Ming-Yu (2017) Selective C-O bond formation via a photocatalytic radical coupling strategy: access to perfluoroalkoxylated (ORF) arenes and heteroarenes. Chem Sci 8:6066-6070