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Chlorine as an auxiliary in asymmetric aldol reactions and photocatalytic fluorination of C-H bonds

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Thesis type
(Thesis) Ph.D.
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Organohalides are ubiquitous in organic chemistry, with broad utility ranging from their use as building blocks in multistep syntheses, to fluoropharmaceuticals that can oftentimes provide more favourable properties to drug molecules. In this regard, two new synthetic methods have been developed that involve the use or preparation of organohalides: chlorine as an auxiliary for asymmetric aldol reactions, and the photocatalytic fluorination of C-H bonds. The aldol reaction is an important carbon-carbon bond forming reaction in organic chemistry, the product of which is a β-hydroxyketone, which is a functionality often encountered in drugs and natural products. As many pharmaceuticals, agrochemicals and bioactive compounds have increased activity as single enantiomers, asymmetric variants of aldol reactions are sought. Herein, an auxiliary strategy is demonstrated for the stereoselective addition of lithium enolates to aldehydes in which the auxiliary itself is not chiral, but a single chlorine atom introduced via organocatalytic asymmetric α-chlorination. The stereodirecting influence of the chloromethine is then exploited prior to its removal by radical reduction. This strategy is demonstrated in the synthesis of various optically enriched β-hydroxyketones (92-99% ee), as well as the natural products (+)-dihydroyashabushiketol and (+)-solistatin. Fluorination reactions are essential to modern medicinal chemistry, and can provide a means to block site-selective metabolic degradation of drugs and access radiotracers for positron emission tomography imaging. Despite current sophistication in fluorination reagents and processes, the fluorination of unactivated C-H bonds remains a significant challenge. Reported herein is a convenient and economic process for direct fluorination of C-H bonds that exploits the hydrogen abstracting ability of a decatungstate photocatalyst in combination with the mild fluorine atom transfer reagent N-fluorobenzenesulfonimide. This operationally straightforward reaction provides direct access to a wide range of fluorinated organic molecules, including structurally complex natural products, acyl fluorides, and fluorinated amino acid derivatives.
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Thesis advisor: Britton, Robert
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