Carbofunctionalization of alkenyl and vinyl thianthrenium salts and $^{18}$f-labeling of borussertib via ruthenium mediated deoxyfluorination

  • Carbofunktionalisierung von Alkenyl- und Vinylthianthreniumsalzen und $^{18}$F-Markierung von Borussertib über Ruthenium-vermittelte Desoxyfluorierung

Breen, Nicola Bridget; Ritter, Tobias (Thesis advisor); Patureau, Frédéric (Thesis advisor); Leitner, Walter (Thesis advisor)

Aachen : RWTH Aachen University (2022)
Dissertation / PhD Thesis

Dissertation, RWTH Aachen University, 2022

Abstract

Direct C-H functionalization is one of the most desirable reactions in organic chemistry, but remains a challenging feat. The main challenge is controlling regioselectivity, because organic molecules tend to contain multiple C-H bonds, and complex molecules often have C-H bonds of varying reactivity due to different hybridizations of the C-H bonds. Established methods can typically target C-H bonds with different hybridizations (e.g. Csp2 vs. Csp3), but site selectivity remains an issue if there is more than one C-H bond exhibiting the same hybridization. In 2019, the Ritter group published a report on the highly selective C-H thianthrenation of arenes to prepare aryl electrophiles. These electrophiles have been used in many subsequent transformations, such as fluorination, amination, and hydroxylation. Additionally, in 2020 the Ritter group published a report on applying thianthrenation to alkenes to regio- and stereoselectively prepare alkenyl electrophiles. These electrophiles were then used either with photoredox catalysis or palladium catalysis to form new carbon-heteroatom bonds.Part I of this thesis focuses on using these alkenyl electrophiles in Giese type reactions and photoredox mediated radical/polar crossover. Alkenyl thianthrenium salts have already been shown to react with nucleophiles in substitution reactions; the goal of this work was to determine if these electrophiles are also able to react with alkyl radicals in the β position to the thianthrenium group. Part I also focuses on using vinyl thianthrenium salts, a special case of an alkene (C2H3), in cross coupling reactions with alkyl halides. This transformation currently only exists to form new C-C bonds between alkyl halides and monosubstituted olefins, yielding a disubstituted olefin as the final product. The goal of this project was to instead introduce the vinyl group to a broad scope of alkyl halides with palladium catalysis. Both of these transformations can be summed up as a type of carbofunctionalization, because the work with both the alkenyl and vinyl thianthrenium salts attempts to form new C-C bonds, specifically new C(sp2)-C(sp3) bonds. In addition to direct C-H functionalization, carbon-heteroatom bonds can be formed by a substitution reaction if an organic molecule contains a suitable leaving group. When the nucleophile attacks at an aromatic carbon, the mechanism is typically through a nucleophilic aromatic substitution, although the Ritter group has published substitution reactions of phenols with fluoride via a concerted nucleophilic aromatic substitution mechanism. This reactivity works with both fluoride-19 and fluoride-18, and the Ritter group has published several reports on this work. However, deoxyfluorination of electron rich phenols initally proved challenging and had to be modified to obtain the desired reactivity. Preparing a ruthenium phenol complex makes the arene electron deficient enough to undergo deoxyfluorination with both fluoride-19 and fluoride-18. In 2018, the Ritter group showed the ruthenium mediated deoxyfluorination of peptides using this chemistry and have also applied this chemistry to medically relevant molecules. Part II of this thesis focuses on the radio deoxyfluorination of borussertib, a covalent-allosteric Akt inhibitor used to treat cancer. Borussertib exhibits remarkable selectivity and introducing the fluorine-18 isotope would allow for the opportunity to use PET imaging to study the mechanism of how this molecule acts in the body. 18F-borussertib was successfully prepared via ruthenium mediated deoxyfluorination of a ruthenium phenol precursor and the successful synthesis and purification of this molecule allowed for imaging studies in mice to be done.  

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