The inclusion of fluoride in organic molecules has a significant impact on the molecular conformation, acidity of neighboring heteroatoms, and reactivity of the organic molecule. Consequently, the addition of fluorine in biologically active molecules increases the lipophilicity, bioavailability, and oxidative stability, making fluorine-bearing molecules attractive drug targets. Methods for synthesizing ?-fluorinated carbonyl compounds generally proceed through electrophilic addition to an activated enolate. These techniques, however, suffer from harsh reactions and unselective fluorinations, which restrict the overall scope and utility of the methods. Another approach to obtaining fluorinated compounds is nucleophilic fluorination, which benefits from the low cost and abundance of fluoride sources such as anhydrous HF or KF. Nevertheless, nucleophilic fluorination reactions are notorious for requiring harsh and operationally challenging reaction conditions due to the low solubility, poor nucleophilicity, and high hydroscopicity of fluoride. Furthermore, very few catalytic, let alone asymmetric, methods have been realized for nucleophilic fluorination. In this proposal we will develop a mild, dual-catalytic approach to the enantioselective synthesis of ?-fluoro carbonyl derivatives by nucleophilic fluorination with diazo compounds. This strategy will allow for highly functionalized carbonyl substrates to be selectively fluorinated with a readiy available, inexpensive, and stable fluoride source. The in situ formation of an HF-amine species from the combination of benzoyl fluoride, an alcohol, Lewis base catalyst and transition metal catalyst will afford a mild, robust, site-specific fluorination technique. We propose that with a diazo moiety present in the molecule, the intermediate metal-stabilized carbene will be preferentially fluorinated, regardless of the additional functionalities.
Specific aim 1 addresses reaction design and optimization of the fluorination of diazoesters through a dual-catalytic approach, and specific aim 2 explores the use of the mild fluorination system to carry out radiofluoriations for the development of PET tracers. The development of this method will provide a new catalytic technique for the mild asymmetric, site-specific fluorination of diazo compounds.

Public Health Relevance

Installing a fluorine atom into biologically-active molecules increases the potency and efficiency of many drug targets. Current methods for fluorination often require harsh reaction conditions, or simple starting materials, making it challenging to add fluorine into a molecule with drug-like functionality. The strategy proposed will allow for highly functionalized substrates to be stereoselectively fluorinated with a readily available, inexpensive, and stable fluoride source using mild laboratory procedures.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1)
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Lees, Robert G
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Princeton University
Schools of Arts and Sciences
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Gray, Erin E; Nielsen, Matthew K; Choquette, Kimberly A et al. (2016) Nucleophilic (Radio)Fluorination of ?-Diazocarbonyl Compounds Enabled by Copper-Catalyzed H-F Insertion. J Am Chem Soc 138:10802-5