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Title: Catalytic strategies for asymmetric nucleophilic fluorination using a latent HF source: development and mechanistic investigations
Authors: Kalow, Julia Ann
Advisors: Doyle, Abigail G
Contributors: Chemistry Department
Keywords: asymmetric catalysis
Subjects: Organic chemistry
Issue Date: 2013
Publisher: Princeton, NJ : Princeton University
Abstract: Fluorinated organic molecules display broad utility as pharmaceuticals, radiotracers, performance materials, and agrochemicals. In particular, the development of new synthetic methods for C&ndash;F bond formation furthers the discovery of bioactive small molecules and PET tracers necessary to study, diagnose, and treat human disease. While catalytic asymmetric methods using electrophilic "F<super>+</super>" equivalents have been identified, complementary strategies for enantioselective C&ndash;F bond formation using abundant, inexpensive nucleophilic fluoride sources are scarce. We have developed catalytic methods for the synthesis of &beta;-fluoroamines and alcohols using benzoyl fluoride as a soluble, latent source of fluoride anion. The combination of benzoyl fluoride and an alcohol generates HF in situ, allowing catalyst-controlled C&ndash;F bond formation. Under Lewis base catalysis, an amine&ndash;HF reagent is generated that shows excellent reactivity and broad substrate scope in aziridine hydrofluorination. The use of a chiral auxiliary enables the practical asymmetric synthesis of enantioenriched fluoroamines. This latent HF source has also been applied to the asymmetric catalytic ring opening of epoxides to provide &beta;-fluoroalcohols. Both the desymmetrization of meso epoxides and the kinetic resolution of terminal epoxides were achieved under mild conditions. A dual-catalyst system, consisting of a chiral Lewis acid and an amine, was found to be optimal; cooperative effects between the cocatalysts were observed. Detailed mechanistic studies have shed light on the origin of cooperativity and enabled synthetic improvements. Additionally, these studies revealed that the active nucleophilic species is a chiral transition-metal fluoride formed from the Lewis acid catalyst and the latent HF source. To demonstrate the utility of this nucleophilic fluoride source in other asymmetric transformations, we developed an enantioselective heterobimetallic fluoride ring opening of aziridines.
Alternate format: The Mudd Manuscript Library retains one bound copy of each dissertation. Search for these copies in the library's main catalog
Type of Material: Academic dissertations (Ph.D.)
Language: en
Appears in Collections:Chemistry

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