No description available.

The first part of this thesis presents a novel approach for synthesising enantioenriched cyclic allylsilanes via asymmetric ring-closing metathesis (ARCM). The second part of this thesis focuses on the reactivity of allylsilanes in electrophilic trifluoromethylation under transition metal and photoredox catalysis. <strong>Chapter 1</strong> provides a general introduction to existing methods for preparing compounds containing Si-stereogenic centres. The motivation for using ARCM to form Si-stereogenic centres is discussed. To set the stage for this work, the development of olefin metathesis as a tool in organic synthesis is briefly summarised. <strong>Chapter 2</strong> describes the synthesis of various prochiral silicon-containing trienes and their reactivity in Ru-, Mo- and W-catalysed ring-closing metathesis. . Following extensive screening of chiral catalysts, few catalysts were identified that enabled selective ARCM to access Si-stereogenic products in up to 98% ee. A systematic investigation of the relationship between the structure of the starting material (i.e., hydrocarbon chain length, steric and electronic properties of the silicon substituents) and the resulting efficacy in ARCM was undertaken, the results from these experiments are discussed. Importantly, this study represents the first example in which ARCM has been successfully used to desymmetrise prochiral substrates to form a new chiral Si centre (Scheme 1). <strong>Chapter 3</strong> provides a general introduction to the field of trifluoromethylation, with a special focus on recent applications of transition metal catalysts in Csp²–CF₃ and Csp³–CF₃ bond formation. A myriad of effective nucleophilic, electrophilic and radical trifluromethylating reagents have been developed during the past several years; the properties of these reagents and their compatibility with various modes of catalysis are summarised to provide a context for the second part of this thesis research. <strong>Chapter 4</strong> presents two novel methods for effecting trifluoromethylation of allylsilanes . First, it was discovered that the combination of an electrophilic trifluoromethlyating reagent and a copper catalyst effectively mediated trifluoromethylation of allylsilanes. The silicon substituent was crucial for improving the nucleophilicity of the substrate and dictating the regioselectivity of the Csp³–CF₃ bond-forming step. With this method, alkyl or aryl substitution at the &beta;-position of the allylsilane was critical for reactivity. Second, in a complementary study, it was found that copper could be replaced by a ruthenium photocatalyst and visible light. This latter method allowed for trifluoromethylation of substrates that were ineffective with copper catalysis. Mechanistic studies of both reaction systems were undertaken, and plausible reaction pathways for both reactions are proposed. <strong>Chapter 5</strong> gives full experimental procedures and characterisation data for all compounds.

Asymmetric phase-transfer catalysis is a powerful technique that enables a wide range of transformations under mild conditions, often using inexpensive and environmentally benign reagents. By extending the applications of phase-transfer catalysis we have developed a highly diastereo- and enantioselective synthesis of functionalized indolines bearing two contiguous stereocentres, one of which is quaternary and all carbon, in a single synthetic step. The reaction proceeds with complete diastereoselectivity and with high levels of enantioselectivity (up to 99% ee). Despite the development of phase-transfer catalysis as a primary synthetic tool in organic synthesis, the mechanistic understanding of these reactions still remains a challenge, due mainly to the difficulty of studying the complex multi-phase systems. Therefore, a further aim of this project was to understand the reaction mechanism of our phase-transfer catalysed transformation. Investigations into the mechanism of our phase-transfer catalysed reaction have been carried out by studying the reaction kinetics. These have shown that the reaction follows a sigmoidal curve with an induction period present. A detailed kinetic investigation was carried out which demonstrated that an autocatalytic mechanism is operational.

Rhodium-catalysed hydroacylation provides a highly atom economic synthesis of ketone products from the combination of aldehydes and multiple bond systems by C-H bond activation. This work evaluates the combination of intermolecular hydroacylation for the synthesis of classical heterocycle precursors and their dehydrative cyclisation to give rise to a range of substituted heterocyclic compounds. Chapter 1 outlines recent developments in the chemistry of hydroacylation. Particular attention is paid to the various chelation strategies employed in intermolecular hydroacylation. Chapter 2 discusses some relevant and recent developments in the field of pyridine and pyrrole synthesis. Having established that β-sulphur chelation controlled hydroacylation can be used to synthesise pyridines in Chapter 3; attention was turned to hydroacylation of propargyl amines in Chapter 4. The methodology was expanded to provide a synthesis of γ-amino enones. The hydroacylation reaction and cyclisation is combined in a procedure that utilises thermal Boc-deprotection and cyclisation to give a range of highly-substituted pyrroles. The regioselectivity of the hydroacylation of propargyl amines is investigated in Chapter 5 by application of statistical Design of Experiments methodology. Optimised conditions were identified with minor improvements in the selectivity of the reaction.

<strong>Chapter 1. Introduction</strong> Scientific background on the development of homogeneous palladium-catalysed cross coupling reactions, focusing on the &alpha;-arylation reaction of enolates and its application to the synthesis of heteroaromatic compounds. The classical syntheses of isoquinolines are discussed, followed by an account of modern methods for their synthesis, including the recent &alpha;-arylation-based methodology developed by the Donohoe group. <strong>Chapter 2. Results and Discussion</strong> 2.1 Studies towards the development of a palladium-catalysed, C–H activation-based &alpha; arylation reaction of ketones, resulting in a C–H bromination/&alpha;-arylation sequence for the synthesis of isoquinolines and isoquinoline N-oxides. 2.2 The one-pot, four component coupling of a ketone, an acetal protected ortho-bromobenzaldehyde or ketone, an electrophile, and an ammonia source is described. This protocol, which ultimately provides C4 functionalised isoquinolines, is later extended to a novel &alpha;,&alpha; heterodiarylation protocol to furnish C4-aryl isoquinolines. 2.3 It is shown that the synthesis of 3 aminoisoquinolines can be achieved via the &alpha; arylation of nitriles. tert-Butyl cyanoacetate can act as a substitute for primary alkyl nitriles, with sequential &alpha;-arylation, in situ functionalisation, decarboxylation and cyclisation reactions provide C4 functionalised 3 aminoisoquinolines. 2.4 The synthetic utility of the &alpha; arylation based methodology for isoquinoline synthesis is exemplified by the total synthesis of the alkaloid berberine in 68% yield over five steps. This is followed by syntheses of pseudocoptisine, palmatine, dehydrocorydaline, and an unnatural fluorine containing analogue, in yields of 46%, 73%, 60% and 37%, respectively. 2.5 Finally, preliminary investigations demonstrate the utility of palladium-catalysed enolate arylation in the synthesis of &beta;-carbolines.