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Title: Development of new catalytic processes for organic chemistry
Author: Muir, Calum W.
ISNI:       0000 0004 5991 7120
Awarding Body: University of Strathclyde
Current Institution: University of Strathclyde
Date of Award: 2016
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Chapter 1 - Brønsted Acid-catalysed Enantioselective Conjugate Addition to Vinyl NHeterocycles This chapter details work towards the development of a new catalytic and enantioselective carbon-carbon and carbon-heteroatom bond forming method to enable access to desirable heterocyclic motifs containing functionalised stereocentres. Chiral Brønsted acid-catalysed conjugate addition to vinyl N-heterocycles was predicted to facilitate enantiocontrolled access to heterocycles containing a chiral benzylic and/or homobenzylic functionality (Scheme 1). Scheme 1. Brønsted acid-catalysed conjugate addition to substituted vinyl N-heterocycles [see thesis for details] From initial investigations, it became apparent that the most competent nucleophile was aniline which was selected as the nucleophile for optimisation studies. Vinyl pyridine systems displayed poor reactivity towards the conjugate addition, whereas a vinyl quinoline compound was found to be significantly more reactive and was chosen as a more competent Michael acceptor (Scheme 2).Scheme 2. Reactivity of vinyl quinoline system compared to vinyl pyridine system [see thesis for details] Optimisation of the process showed high selectivity could be achieved at the expense of conversion (33% conversion, 80% ee) and, conversely, high conversion could be achieved at the expense of selectivity (72% conversion, 64% ee). The rate of proton transfer in asymmetric protonations is an important factor in their success and controlling this will be key to developing the current methodology towards high selectivity at an appropriate degree of reactivity. Efforts to reconcile these have, so far, proved unsuccessful and work towards doing so will be undertaken within the group in the future. Chapter 2 - One-pot Formal Homologation of Boronic Acids: A Platform for Diversity-oriented Synthesis This chapter details methodology in which chemoselective formal homologation of boronic acids has been developed. Chemoselective Suzuki-Miyaura cross-coupling between a boronic acid and a haloaryl MIDA boronate (BMIDA) followed by controlled BMIDA hydrolysis reveals the formally homologated boronic acid product (Scheme 3). The chemoselectivity in this process arises from the selective cross-coupling of the haloarene with one boron species preferentially over the other. Scheme 3. Chemoselective formal homologation of boronic acids [see thesis for details] The process was immediately validated and efficiently optimised through the careful control of the reaction media (Scheme 4). Scheme 4. Validation and optimisation of homologation reaction [see thesis for details] Once optimised, the process was applied to a wide range of substrates which were successfully delivered in good to excellent yields (46-95%), a significant proportion of which are novel boronic acids (Scheme 5). Scheme 5. Scope of the developed boronic acid homologation reaction [see thesis for details] With the reaction scope firmly established, the next step would be to utilise the proven ability of the reaction to tolerate a range of substrates to synthesise a boronic acid which could act as a valuable precursor to a biologically relevant molecule. This boronic acid would then act as the platform for diversification in a display of the value of the methodology towards drug discovery programmes. Application of this procedure was successfully achieved in the synthesis of a range of bromodomain binding inhibitors (Scheme 6).Scheme 6. Application of the methodology towards diversity oriented synthesis [see thesis for details].
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral