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Late-Stage Aromatic C-H Difluoroalkylation and Amination via Arylthianthrenium Salts and 18F-labeling of Peptide via Ruthenium-Mediated Deoxyfluorination


Halder,  Riya
Research Department Ritter, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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Halder, R. (2024). Late-Stage Aromatic C-H Difluoroalkylation and Amination via Arylthianthrenium Salts and 18F-labeling of Peptide via Ruthenium-Mediated Deoxyfluorination. PhD Thesis, Rheinisch-Westfälische Technische Hochschule, Aachen.

Cite as: https://hdl.handle.net/21.11116/0000-000F-58F7-8
This thesis addresses the pressing need for methodologies facilitating late-stage aromatic C–N and C–CF2 bond formations, crucial in the realm of drug discovery. The significance of aromatic C–N bonds in pharmaceutical compounds underscores the demand for diversification at advanced stages. Aromatic C–H functionalization, a strategy involving the conversion of carbon-bound hydrogen atoms into functional groups, offers an avenue to enhance aromatic molecule complexity. Challenges in C–H functionalization include positional selectivity and tolerance towards reactive functional groups. The Ritter group's work on selective C–H thianthrenation paved the way for constructing aryl electrophiles, utilized in subsequent transformations like fluorination, amination, and oxygenation.
Part I of this thesis showcases the novel use of arylthianthrenium salts for C(sp2)–CF2 bond construction via palladium-catalyzed Negishi cross-coupling, enabling late-stage incorporation of difluoroalkyl groups. The method extends to generate even fluorolkylated arenes. Part I also demonstrates Ni(I)-catalyzed amination of arylthianthenium salts, broadening substrate scope and offering an alternative to dual Ni/photoredox-catalyzed amination, particularly for electron-rich substrates.
Part II of this thesis shifts the focus to positron-emission tomography (PET)-tracer development. As of 2023, the U.S. Food and Drug Administration (FDA) has approved just seventeen PET-tracers, of which seven have been developed in the last five years and only one was developed in last two years. Beyond factors like regulatory requirements, high costs, need for specialized expertise etc., the scarcity of approved tracers results from complications in research and development as identifying compounds that can effectively target specific biological processes or diseases in animals can be challenging. Moreover, introducing short-lived radionuclides in the final or penultimate step of the synthesis adds up to the challenge. Complex molecular structures can hinder reactivity, necessitating innovative strategies. Peptides, due to selective binding and rapid clearance, are promising for PET-tracer design. The second part introduces a method for radio-deoxyfluorination, yielding peptide with 4-[18F]fluoro-phenylalanine side chain, preserving biological function and enabling versatile labeling.
This thesis tackles critical challenges in late-stage bond formations and PET-tracer development, contributing valuable methods to advance drug discovery and molecular imaging.