Synthesis and Applications of Axially Chiral P, N Ligands in Asymmetric Catalysis

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dc.contributor.authorBarker, James- the Authoren_US
dc.description.abstractThe development of tools used to access enantiomerically pure compounds is a task with particular relevance to the pharmaceutical industry and the greater area of modern medicine. As such, it garners great attention in the form of research from both academic and industrial settings alike. A synopsis of the synthetic tools available to perform asymmetric synthesis is described, outlining the advantages and limitations of each. Asymmetric A3 (aldehyde, amine, alkyne) couplings are well-studied reactions, involving the condensation of an aldehyde and amine before attack of an alkynyl nucleophile on the electrophilic imine/iminium ion. In this thesis, work is described towards accessing a protocol for an asymmetric A3 coupling system with dynamic kinetic resolution. Racemic chiral aldehydes were employed in asymmetric A3 coupling reactions with the intention of producing products with two contiguous stereocentres as a single diastereomer, with theoretical yields up to 100%. An initial substrate scope to synthesise eight different products was performed, before a subsequent investigation into the role of catalyst identity, catalyst loading, reaction temperature, and additives had on the diastereoselecitivity of the reaction. To date, poor yields persist regarding ¿-aryl aldehydes and poor diastereoselectivities regarding ¿-aliphatic aldehydes have been observed. Preliminary work towards accessing enantiopure aldehydes is also described. Secondly, work towards accessing novel imidazoline-based axially chiral P,N ligands and the synthesis of centrally chiral P,N ligands is presented. The synthesis of axially chiral P,N ligands previously reported by the Guiry is described, alongside investigations into a modular synthetic pathway for accessing novel imidazoline-based axially chiral P,N ligands. Numerous methodologies towards functionalising naphthalene systems are discussed, including a new undescribed palladium-catalysed C-H halogenation of naphthoic acid. A new route towards synthesising centrally chiral imidazoline-based P,N ligands employing established Cu-catalysed C-P bond formation chemistry is also presented. Four reported centrally chiral P,N ligands were synthesised over the novel three-step route, in yields ranging from 36 to 48%. Finally, a novel protocol for the heteroatom-directed borylation of hetereoaryl-alkenes is described. Four P,N ligands were tested in the reaction, before extensive optimisation regarding catalyst identity, solvent identity, base identity, temperature, alcohol additive and boron source equivalents. The asymmetric Cu-catalysed system furnished borylated intermediates, which were subsequently oxidised to the corresponding novel alcohols for characterisation purposes. The system boasts short reaction times of one hour, with yields up to 88% and enantioselectivities up to 76% ee reported in a substrate scope containing twelve heteroaryl-substituted products. The enantioenriched organoboron intermediates contain a versatile synthetic handle that is amenable to further synthetic transformations.en_US
dc.publisherUniversity College Dublin. School of Chemistryen_US
dc.titleSynthesis and Applications of Axially Chiral P, N Ligands in Asymmetric Catalysisen_US
dc.typeDoctoral Thesisen_US
dc.statusPeer revieweden_US
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