Understanding reaction mechanisms and structure/reactivity relationships in the electrophilic fluorination of enol esters

Wood, Susanna Helen

Thesis

Understanding reaction mechanisms and structure/reactivity relationships in the electrophilic fluorination of enol esters

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Creator

Wood, Susanna Helen

Rights statement

Strathclyde Thesis Copyright

Awarding institution

University of Strathclyde

Date of award

2019

Thesis identifier

T15959

Person Identifier (Local)

201569021

Qualification Level

Doctoral (Postgraduate)

Qualification Name

Doctor of Philosophy (PhD)

Department, School or Faculty

Department of Pure and Applied Chemistry

Abstract

Since the invention of the first fluorinated drug molecule in 1954 fluorinated pharmaceutical compounds have improved the health of many people throughout the world. This is due to the many ways in which fluorine can influence the behaviour, structure and physical properties of organic molecules. An essential aspect of ensuring the access to drug molecules by those who need them is the ability for these compounds to be synthesised efficiently and safely. The near complete lack of natural organofluorine molecules has necessitated the invention of a number of synthetic methods for the introduction of fluorine atom(s) into organic molecules, including nucleophilic and electrophilic fluorinating methods. A complete understanding of the mechanisms in operation in any given synthetic methodology is of high importance in ensuring that the synthetic procedures can be carried out in the most efficient manner possible. Enol esters have been widely utilised in electrophilic fluorination reactions using the SelectFluor reagent in order to synthesise 6α-fluorosteroid drug molecules. Despite the prevalence of this procedure in the patent literature the reaction mechanism of the electrophilic fluorination of enol esters was hitherto unexplored. Particularly, the addition of acidic and basic compounds to the fluorination reaction is commonplace in order to achieve high α/β ratios however the source of this high diastereoselectivity is unknown. Investigations into the reaction mechanism of the electrophilic fluorination of simple cyclic enol esters using SelectFluor have been undertaken. Once a feasible mechanistic rationale for the fluorination of these simple substrates had been established a number of steroid-like and steroidal substrates were examined in order to determine whether the mechanism is conserved throughout the different substrate classes. Finally, the role of the additives was examined to determine whether they allow the reaction to proceed via a divergent reaction mechanism or if their role is purely to aid crystallisation of the desired 6α-product from the reaction mixture in high purity.

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