Studies in derivatisation and direct arylation of heterocycles

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Hickey, Aobha
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University College Cork
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Quorum sensing (QS) is a complex form of communication employed by bacterial species to coordinate group behaviours through the biosynthesis, secretion and detection of small molecules known as autoinducers (AIs). Understanding the mechanism via which these sophisticated networks operate could allow for the development of non-traditional therapies for the treatment of multi-drug resistant infections. Heerman and co-workers recently identified a group of 2-pyrones as AIs in the QS network of Photorhabdus luminescens. In Chapter 1, we synthesised 30 2-pyrone analogues, and explored whether these compounds could induce an interspecies response on a co-inhabiting microorganism, Bacillus atropheaus. One naturally occurring derivative dramatically enhanced the biofilm biomass of B. atropheaus. Contrastingly, all other natural and synthetic derivatives exhibited biofilm-inhibiting effects. Swarming motility was repressed by several analogues, with carbon chains between six and 10 units at the C-3 position proving optimal. In Chapter 2 the palladium‐catalysed, phosphine‐free direct arylation of 4-phenoxyquinolines in air is described. Diverse benzofuroquinolines were synthesised with excellent yields. Further expansions of this reaction using multi-halogenated substrates allowed for two, mechanistically distinct reactions to occur in one-pot using the same pre-catalyst. Investigations employing 1H-15N HMBC spectroscopy led us to propose that the quinoline motif may be acting as an N-ligand to palladium in these transformations. The photophysical characteristics of the scaffolds constructed are reported. Attempts to build on recent breakthroughs in the area of reversible oxidative addition to preserve C-Br bonds are also described. The quinoline nucleus is a versatile, nitrogen-based heterocycle which is found in numerous synthetic and naturally occurring pharmacologically active compounds. Structurally similar 6-fluoroquinolones account for a large portion of the antibiotic market. Chapter 3 involves the use of an iridium-catalysed C-H functionalisation/borylation strategy to selectively synthesise C-7 substituted 6-fluoroquinolines. The borylations proceed with very good yields and various important transformations utilising the installed boron group are demonstrated. Finally, the ubiquitous 6-fluoroquinolone moiety can be revealed through hydrolysis or hydrogenolysis of the 6-fluoro-4-substituted quinolines.
Borylation , Quinolone , Pyrone , Bacillus atropheaus , Autoinducers , Benzofuroquinoline , 1H-15N HMBC , Quorum sensing , C-H activation , Palladium catalysis , Iridium catalysis , Direct arylation , C-H functionalisation
Hickey, A. 2022. Studies in derivatisation and direct arylation of heterocycles. PhD Thesis, University College Cork.