The work presented in this thesis mainly describes the discovery and development of methodology for the synthesis of anthecularin and anthecotulides, a family of unusual sesquiterpene lactones. Firstly, two 1,3-dipolar cycloaddition approaches toward anthecularin have been evaluated, using either oxidopyrylium ylide chemistry (Path A) or carbonyl ylides, generated by rhodium-catalysed decomposition of diazo ketones (Path B). Synthesis of the key precursor for the diazo strategy was achieved but unfortunately no desired cycloadduct was isolated. Secondly, an experimentally straightforward method to stereoselectively synthesise β-hydroxymethyl-α-methylene-γ-butyrolactones was developed using chromium or zinc. The synthetic utility of this methodology was demonstrated in syntheses of (±)-methylenolactocin, (±)-hydroxymatairesinol and, ultimately, (±)-hydroxyanthecotulide using a gold-catalysed Meyer-Schuster rearrangement. Finally, the first asymmetric synthesis of (+)-anthecotulide has been achieved, in 6 steps from commercially available materials. During this synthesis the absolute configuration was established. Furthermore, a novel rhodium-catalysed enantioselective ene-yne cycloisomerisation was used to form the α-methylene-γ-butyrolactone core.

Introduction: The introduction provides a survey of the natural product and pharmaceutical targets accessible from dihydropyridines and dihydropyridones as well as an overview of previous work carried out towards the synthesis of these valuable intermediates. The mechanism, scope and limitations of the various approaches are covered, along with the goals of this project. Results and Discussion: A Regioselective Route to Dihydropyridones. The regioselective addition of nucleophiles to a range of disubstituted pyridinium salts has been achieved, with selectivity determined by hard/soft factors. Certain nucleophiles can be added with complete regioselectivity to either C-2 or C-6 of these salts, depending on the conditions employed. Addition at C-2 allows the generation of a quaternary centre in high yield. The conditions discovered can be applied to pyridinium salts with different substitution patterns and an effective procedure has been developed for the removal of the nitrogen protecting group post reduction. The Preparation of Enantiopure Dihydropyridones.After unsuccessful attempts to find a reagent-controlled asymmetric synthesis of dihydropyridones, a highly diastereoselective and non-chiral auxiliary based substrate-controlled procedure has been developed. By prompting an intramolecular hydride migration from a secondary silyl ether onto the pyridinium core, the corresponding dihydropyridones are available in high yield, with the diastereoselectivity being controlled by the minimization of 1,3-allylic strain between the N-allyl group and the hydride-bearing side chain. Thus, an enantiopure pyridyl alcohol may be converted to the corresponding dihydropyridone without loss of enantiomeric purity. Furthermore, the dihydropyridones can be easily converted to complex bicyclic systems via a ring closing metathesis reaction. Experimental: Full experimental procedures and spectroscopic characterization of compounds are provided.

This thesis describes investigations into the utility of boron fluorides and tetrafluoroborates as sources of nucleophilic fluorine. Chapter 1 discusses the history and importance of the field of organofluorine chemistry and outlines some of the principle motivations for the site-selective fluorination of organic molecules. Some of the most commonly useed methods of nucleophilic fluorination are briefly surveyed, with an emphasis on the formation of fluorinated stereogenic centres. Literature precedent for the use of tetrafluoroborates and boron trifluoride as nucleophilic fluorinating agents is also presented. Chapter 2 describes the development of a highly regio- and stereoselective S_Ni-type ring-opening fluorination of trans-β-substituted aryl epoxides using BF₃●OEt₂ as a nucleophilic fluorinating agent. This robust and scalable protocol grants efficient access to a variety of functionalised benzylic fluoride building blocks, and provides a solution to the problem of stereocontrol in the synthesis of this class of compounds. To highlight the utility of the resultant syn-fluorohydrins in the synthesis of stereodefined β-fluoro β-aryl amines, their elaboration to a range of aryl-substituted β-fluoroamphetamines is demonstrated. Chapter 3 introduces the concept of tuning the reactivity of BF₃ by replacing one or two of the fluoro ligands on boron for electron-donating alkoxy group(s). On this basis, pinacolatoboron fluoride (pinBF) [which may be prepared in situ by pre-mixing BF₃●OEt₂ and bis(O-trimethylsilyl)pinacol] is identified as a superior reagent to BF₃●OEt₂ for the ring-opening fluorination of trans-β-substituted aryl epoxides bearing electron-rich aryl groups. Chapter 4 details a highly regioselective and stereospecific S_N2-type ring-opening fluorination of 2,3- and 3,4-epoxy amines using HBF₄●OEt₂ as a nucleophilic flurine source. The reactions are both operationally simple to perform and readily scalable, and proceed to completion within 5 min at ambient temperature, providing a highly practical and economical route to stereodefined amino fluorohydrins. To highlight the synthetic utility of this reaction in the preparation of pharmaceutically-important β-fluoro amines, a concise de novo asymmetric synthesis of (S,S)-3-deoxy-3-fluorosafingol is performed. Chapter 5 chronicles the successful development of a protocol for the direct hydroxyfluorination of allylic amines to the corresponding amino fluorohydrins, using m--CPBA as the oxidant and HBF₄●OEt₂ in a dual role as both the Brønstead acid N-protecting agent and nucleophilic fluorine source. With chiral allylic amines which are conformationally biased or constrained, the diastereofacial selectivity of the reaction can be controlled by altering the concentration of HBF₄●OEt₂ employed in the reaction, allowing for a diastereodivergent hydroxyfluorination process. The synthetic utility of this methodology is demonstrated via its application to the diastereodivergent synthesis of 4-deoxy-4-fluoro-L-xylo-phytosphingosine and 4-deoxy-4-fluoro-L-lyxo-phytosphingosine, each in 5 steps from Garner's aldehyde. Chapter 6 contains full experimental procedures and characterisation data for all compounds synthesised in chapters 2, 3, 4 and 5.

In this thesis, the effect of fluorinating reagents on a selection of transition metal-mediated organic transformations was investigated. The first four chapters are focused on gold-catalysed nucleophilic addition processes performed in the presence of “F⁺” sources. Chapter 1 provides a general introduction to homogeneous gold catalysis and summarises the aims and objectives of the project. The effect of the electrophilic fluorinating reagent Selectfluor (82) on the gold-catalysed rearrangement of propargyl acetates 85 is discussed in Chapter 2. α-Fluoroenones 92 resulting from fluorodeacetylation of an allenyl acetate intermediate were delivered as the major products of these reactions (Scheme i). [Scheme i Gold-Catalysed Rearrangement-Fluorodeacetylation of Propargyl Acetates 85.] By contrast, performing the gold(I)-catalysed cyclisation of allenoates 102 in the presence of Selectfluor (82) led to products of oxidative coupling. The “F⁺” source in these processes most likely acts as an external oxidant in an Au<sup>I</sup</Au^III redox cycle. In Chapter 3, the cascade cyclisation-intramolecular arylation of benzyl-substituted substrates is discussed whilst the extension of the methodology towards intermolecular homocoupling and intermolecular alkynylation is presented in Chapter 4 (Scheme ii). [Scheme ii Gold-Catalysed Cyclisation-Oxidative Coupling of tert-Butyl Allenoates 102.] In Chapter 5, the feasibility of palladium-catalysed allylic [¹⁸F]radiofluorination was investigated using high-specific-activity [¹⁸F]fluoride. This study led to the development of the first transition metal-mediated C-¹⁸F bond-forming process of relevance for the preparation of radiotracers for PET imaging (Scheme iii). [Scheme iii Palladium-Catalysed Allylic [18F]Radiofluorination of Allylic Methyl Carbonate 227b.] Chapter 6 gives full experimental procedures and characterisation data for all compounds.

Caged compounds are biologically active molecules that are rendered inert by masking an important functionality with a photolabile protecting, ‘caging’, group. The caging group can be removed by irradiation with light to reveal the active compound with restored pharmacological activity with high spatial and temporal control. This technology provides an ideal tool for the study of many chemical, physiological and biological systems. This DPhil dissertation highlights several projects in which caging technology has been employed to address biological problems and questions. The first example of spatially controlled mitochondrial inactivation is reported - a tool for the study of the role of mitochondria in Ca2+ signalling. Caged TRPV1 agonists and antagonists have been developed to probe TRPV1, specifically the location of the agonist-binding site. T cell activation has been controlled with light as a tool to gain insight into the adaptive immune response. Caged sodium channel blockers have been investigated. Wavelength-orthogonal photolysis in a neuronal system has been demonstrated using the neurotransmitters glutamate and GABA - this represents a significant advancement in caging technology. This dissertation also includes investigations into the development of novel caging groups.

This thesis describes the development of new osmium-mediated methodologies providing novel applications through the use of a third generation of reoxidant for osmium. Chapter 1, The introduction: Summary of past and present methodologies towards the synthesis of the 1,2 amino alcohol motif. Chapter 2, Intramolecular processes: The studies of the tethered aminohydroxylation (TA) of amide and urea derivatives are being investigated. Chapter 3, Investigations towards an intermolecular process: The transposition of the TA methodology to an intermolecular process and the requirements involved are discussed. The role of acetamide is being investigated. Chapter 4, Successful transition to an intermolecular process: Amino acid derivatives became for the first time possible nitrogen sources and were efficiently employed through osmium-mediated reaction to afford interesting biological scaffolds. Chapter 5, Experimental: Full experimental procedures and characterisation of compounds are reported. References: A complete list of citations employed in the previous five chapters is provided. Appendix: Full documentation of X-ray crystal structures, key NMR spectra and HPLC traces is provided.

This thesis is concerned with the development and application of methods for the stereoselective cyclopropanation of allylic amines and derivatives. Firstly, a highly chemo- and stereoselective cyclopropanation of N,N-dibenzyl-protected allylic amines was developed using the highly reactive Shi’s carbenoid [CF₃CO₂ZnCH₂I]. Subsequent mechanistic studies revealed that the high diastereoselectivity of the reaction was likely to be due to coordination of the amine to the zinc carbenoid reagent. It is then shown that the reaction is general for a wide range of both cyclic and acyclic substrates giving the corresponding cyclopropanes in high yields and diastereoselectivities. Secondly, a novel stereodivergent cyclopropanation of allylic carbamates and amides was developed. It was found that reaction of cyclic allylic carbamates with the Wittig-Furukawa reagent [Zn(CH₂I)₂] typically gives the syn-diastereoisomer in high yields and diastereoselectivities, whilst treatment of the same substrates with Shi’s carbenoid [CF₃CO₂ZnCH₂I] gives the corresponding anti-diastereoisomers in high yields and diastereoselectivities. Mechanistic investigations suggested that reactions with the Wittig-Furukawa reagent proceed via a N-directed intramolecular cyclopropanation step whilst those with Shi’s carbenoid proceed via a sterically directed intermolecular cyclopropanation step. Unsuccessful investigations into an asymmetric variant of the cyclopropanation reaction utilising chiral carbamate protecting groups are then described. Finally, studies towards the total synthesis of the potential anti-obesity therapeutic trans-SCH-A and its epimer cis-SCH-A are described. A stereodivergent route towards the epimeric products was developed through the cyclopropanation of a common allylic carbamate intermediate with either the Wittig-Furukawa reagent or Shi’s carbenoid to give the corresponding trans-2-amino-5-arylbicyclo[3.10]hexane or cis-2-amino-5-arylbicyclo-[3.10]hexane intermediates respectively.

Small-molecule libraries with enhanced structural diversity are of value in drug discovery campaigns where novel biologically active hits are desired. As such, multicomponent reactions (MCRs) have proven fruitful to enhance the molecular diversity of chemical collections and expedite forward progression of the drug discovery chain. Bicalutamide (Casodex), an anticancer drug, and Telaprevir (Incivek), an antiviral, are two examples of marketed drugs that can be synthesized using an MCR. The research topic of this dissertation involves the design, discovery, and development of novel MCRs and new combinations of MCRs with post-condensation modifications to generate over twenty-five new drug-like scaffolds in an operationally friendly, atom-economical, time- and cost-effective fashion. The developed chemical methodologies possess inherent 'iterative efficiency','high exploratory power', and 'bond forming efficiency' that allow them to quickly explore chemical space and navigate the 'hypothesis-synthesis-screening' loop that is key for a medicinal chemistry project. The prepared molecules were submitted to the Community for Open Antimicrobial Drug Discovery (CO-ADD) for antimicrobial screening against pathogens that are known to cause drug-resistance infections.

This dissertation describes work towards two marine alkaloid natural products of the manzamine family. The total synthesis of (–)-nakadomarin A, via two conceptually different strategies is described along with the development of a novel nitro-Mannich-Mannich cascade reaction, which has been applied in a synthesis of the diazatricyclic core of the madangamines. A short and highly stereoselective synthesis of (–)-nakadomarin A has been developed. A sequential alkyne ring-closing metathesis/syn selective reduction strategy enabled the stereoselective construction of the Z-configured alkene in the fifteen-membered macrocycle of the molecule. ‘Matched’ catalyst and substrate control facilitated a highly diastereoselective nitro olefin Michael addition to fix two of the four stereocentres in one key step. Furthermore, a nitro-Mannich/lactamization cascade, furan N-acyl iminium ion cyclisation and alkene ring-closing metathesis enabled the total synthesis of the natural product in 19 steps. In collaboration with Prof. Amir Hoveyda and Prof. Richard Schrock, an alternative approach to a highly Z-selective macrocyclic ring closure in the synthesis of (–)-nakadomarin A has been developed. Three diene substrates were prepared and the Z-selectivity of alkene ring-closing metathesis investigated using a range of molybdenum MAP (monoaryloxide pyrrolide) catalysts. Initial studies using these catalysts produced promising results (Z:E = ~1.2:1), relative to commercially available ruthenium metathesis catalysts (Z:E = 2:3). Using a recently developed chiral tungsten MAP complex, alkene ring-closing metathesis was found to proceed in excellent yield (90%) with exceptional Z:E-selectivity (Z:E ~1.2:1) and requiring only low catalyst loadings (5 mol%). A novel nitro-Mannich-Mannich cyclisation cascade has been developed allowing access to highly functionalized piperidines. Application of this unprecedented mode of reactivity using a substrate derived from a Michael-addition of methylcyanoacetate to a functionalized cyclic nitro olefin allowed the preparation of a cis-fused 6,6’-bicycle in excellent yield. Further elaboration of this 6,6’-bicycle enabled the synthesis of the diazatricyclic core of the madangamine alkaloids to be achieved.

<strong>Chapters 1</strong> and <strong>2</strong> of this thesis focus on the application manganese(III) and copper(II)-mediated oxidative radical cyclisation of alkenyl amidomalonates to the formation of pyrrolidinone-lactones and their subsequent use in the total syntheses of highly bioactive natural products. A novel concise total synthesis of (-)-salinosporamide A based on the oxidative cyclisation previously developed in the group is presented in <strong>chapter 1</strong>. The second chapter discusses the work towards the pyrrolidinone core of the oxazolomycin. Each chapter contains its own introduction to set in context the presented results, which discusses the isolation and the biological activity of the two families of natural products. Previous synthetic work toward salinosporamide A and the oxazolomycin family achieved in the group and reported in the literature is also described in the introduction of each chapter. The third chapter of the thesis succinctly presents the extension of the scope of the manganese(III) and copper(II)-mediated oxidative radical cyclisation reaction. The optimisation, development and scope of the rapid access to fused THF-lactones via the cyclisation of alkenyl oxymalonates is described. Preliminary synthetic manipulations of the resultant bicyclic products to study the application possibilities of the new reaction in future complex molecules syntheses are also presented. The final conclusion gives a summary of the results obtained and introduces the proposed future work that may arise from these three areas.