Synthesis of nitrogen-containing heterocycles

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Shanahan, Rachel
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University College Cork
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The sharp rise in antimicrobial resistance has been matched by a decline in the identification and clinical introduction of new classes of drugs to treat microbial infections. Thus new approaches are being sought to target pathogenic microorganisms. In that context, the use of non-biocidal small molecules, that target quorum sensing signalling networks in pathogens, has emerged as a solution with real clinical potential. Previous work has shown that two alkyl quinolone signal molecules (HHQ and PQS) from the nosocomial pathogen Pseudomonas aeruginosa have modulatory activity towards other microorganisms. Chapter 1 of this thesis outlines the synthesis of analogues of HHQ with the aim of learning more about the structure activity relationship of alkyl quinolone quorum sensing molecules. Chapter 2 of this thesis describes work carried out during a six month work placement at Syngenta Crop Protection in Stein, Switzerland. The project involved efforts towards a new total synthesis of pyridohomotropane (PHT), a synthetic alkaloid which has shown agonistic activity towards nicotinic acetylcholine receptors (nAChRs). Since they are found in the central nervous system of insects, nAChRs are a key target of insecticidal crop protection products. This chapter outlines the retrosynthetic analysis and synthesis of key intermediates towards the total synthesis of PHT. The formation of aryl aryl bonds is an important transformation in organic synthesis due to the abundance of aryl aryl moieties in natural products and pharmaceuticals. Direct arylation strategies aim to avoid the installation of one or both of the activating groups typically required for traditional cross coupling methods. The application of direct arylation protocols towards the synthesis of polycyclic benzofuroquinoline compounds is described in Chapter 3. Expansion of the methodology to facilitate a one pot tandem reaction combining Suzuki Miyaura and direct arylation transformations is also discussed. Finally, the retention of specific carbon bromide bonds of the quinoline substrates is achieved via a reversible oxidative addition protocol.
Synthesis , Direct arylation , Total synthesis , Quinolone , Quinoline
Shanahan, R. M. 2019. Synthesis of nitrogen-containing heterocycles. PhD Thesis, University College Cork.