Towards the enantioselective synthesis of Plakortide P and its application to the development of drugs for the treatment of Chagas disease

The primary focus of this thesis was the asymmetric peroxidation of α,β-unsaturated aldehydes and the development of this methodology to include the synthesis of bioactive chiral 1,2-dioxane and 1,2-dioxalane rings. In Chapter 1 a review detailing the new and improved methods for the acyclic introduction of peroxide functionality to substrates over the last decade was discussed. These include a detailed examination of metal-mediated transformations, chiral peroxidation using organocatalytic means and the improvements in methodology of well-established peroxidation pathways. The second chapter discusses the method by which peroxidation of our various substrates was attempted and the optimisation studies associated with these reactions. The method by which the enantioselectivity of our β-peroxyaldehydes was determined is also reviewed. Chapters 3 and 4 focus on improving the enantioselectivity associated with our asymmetric peroxidation reaction. A comprehensive analysis exploring the effect of solvent, concentration and temperature on enantioselectivity was examined. The effect that different catalytic systems have on enantioselectivity and reactivity was also investigated in depth. Chapter 5 details the various transformations that β-peroxyaldehydes can undergo and the manipulation of these transformations towards the establishment of several routes for the formation of chiral 1,2-dioxane and 1,2-dioxalane rings. Chapter 6 details the full experimental procedures, including spectroscopic and analytical data for the compounds prepared during this research.

Access to modified geiparvarins using Pd(0)-mediated C-C bond forming reactions

Geiparvarin is a natural product which contains both a 3(2H)-furanone and a coumarin moiety in its structure. The aim of this project was to investigate the use of Pd(0)-mediated C–C bondforming reactions to produce structurally modified geiparvarins. Chapter 1 consists of a review of the relevant literature, including that pertaining to the syntheses of selected naturally occurring 3(2H)-furanones. The known syntheses of geiparvarin and closely related analogues are examined, along with the documented biological activity of these compounds. The synthetic routes which allow access to 4-substituted-3(2H)-furanones are also described. Chapter 2 describes in detail the synthesis of a variety of novel structurally modified geiparvarins by two complementary routes, both approaches utilising Pd(0)-mediated crosscoupling reactions, and discusses the characterisation of these compounds. The preparation of 5-ethyl-3(2H)-furanones is described, as is their incorporation into geiparvarin and the corresponding 5″-alkylgeiparvarin analogues via formation and dehydration of intermediate alcohols. Halogenation of 5-ethyl-3(2H)-furanones and the corresponding geiparvarin derivatives is discussed, along with further reactions of the resulting halides. Preparation of 3″-arylgeiparvarins involving both Suzuki–Miyura and Stille reactions, using the appropriate intermediate iodides and bromides, is described. The application of Stille and Heck conditions to give 3″-ethenylgeiparvarin analogues and Sonogashira conditions to produce 3″-ethynylgeiparvarin analogues, using the relevant intermediate iodides, is also extensively outlined. Chapter 3 contains all of the experimental data and details of the synthetic methods employed for the compounds prepared during the course of this research. All novel compounds prepared were fully characterised using NMR spectroscopy, IR spectroscopy, mass spectrometry and elemental analysis; the details of which are included.

Cooperation between adsorbates accounts for the activation of atomic layer deposition reactions

Atomic layer deposition (ALD) is a technique for producing conformal layers of nanometre-scale thickness, used commercially in non-planar electronics and increasingly in other high-tech industries. ALD depends on self-limiting surface chemistry but the mechanistic reasons for this are not understood in detail. Here we demonstrate, by first-principle calculations of growth of HfO2 from Hf(N(CH3)2)4–H2O and HfCl4–H2O and growth of Al2O3 from Al(CH3)3–H2O, that, for all these precursors, co-adsorption plays an important role in ALD. By this we mean that previously-inert adsorbed fragments can become reactive once sufficient numbers of molecules adsorb in their neighbourhood during either precursor pulse. Through the calculated activation energies, this ‘cooperative’ mechanism is shown to have a profound influence on proton transfer and ligand desorption, which are crucial steps in the ALD cycle. Depletion of reactive species and increasing coordination cause these reactions to self-limit during one precursor pulse, but to be re-activated via the cooperative effect in the next pulse. This explains the self-limiting nature of ALD.

Quantum chemical study of the effect of precursor stereochemistry on dissociative chemisorption and surface redox reactions during the atomic layer deposition of the transition metal copper

Using quantum chemical calculations, we investigate surface reactions of copper precursors and diethylzinc as the reducing agent for effective Atomic Layer Deposition (ALD) of Cu. The adsorption of various commonly used Cu(II) precursors is explored. The precursors vary in the electronegativity and conjugation of the ligands and flexibility of the whole molecule. Our study shows that the overall stereochemistry of the precursor governs the adsorption onto its surface. Formation of different Cu(II)/Cu(I)/Cu(0) intermediate complexes from the respective Cu(II) compounds on the surface is also explored. The surface model is a (111) facet of a Cu55 cluster. Cu(I) compounds are found to cover the surface after the precursor pulse, irrespective of the precursor chosen. We provide new information about the surface chemistry of Cu(II) versus Cu(I) compounds. A pair of CuEt intermediates or the dimer Cu2Et2 reacts in order to deposit a new Cu atom and release gaseous butane. In this reaction, two electrons from the Et anions are donated to copper for reduction to metallic form. This indicates that a ligand exchange between the Cu and Zn is important for the success of this transmetalation reaction. The effect of the ligands in the precursor on the electron density before and after adsorption onto the surface has also been computed through population analysis. In the Cu(I) intermediate, charge is delocalized between the Cu precursor and the bare copper surface, indicating metallic bonding as the precursor densifies to the surface.

Strategies to prevent potentially inappropriate prescribing and adverse drug reactions in older patients

INTRODUCTION: Potentially inappropriate prescribing (PIP) is a major contributor to adverse drug reactions and overall increased healthcare costs. The aim of this thesis was to identify, develop and implement strategies with the potential to prevent PIP and ADRs in older patients. METHODS: A systematic review of the qualitative literature (Meta-synthesis); A qualitative study in Irish hospitals; A randomised controlled trial (RCT) to assess the impact of an online educational module on doctors’ prescribing knowledge and confidence; Exploration of the potential for a frailty index score to enable doctors identify patients at increased risk of PIP and ADRs; Exploration of the potential for the SHiM tool to enable doctors to optimise prescribing for older patients. RESULTS: The meta-synthesis identified four key concepts: (i) Desire to please the patient; (ii) Feeling of being forced to prescribe; (iii) Tension between experience and guidelines; (iv) Prescriber fear. Similar themes also emerged from the qualitative study. In the RCT, the online educational module resulted in a highly significant 22% difference in test scores between intervention and control groups. The studies exploring the frailty index score showed a significant positive relationship between a patient’s frailty status and their likelihood of experiencing PIP/ADRs. Patients above a frailty threshold of 0.16 were at least twice as likely to experience PIP/ADRs. SHiM was found to be a useful tool in terms of reconciling patients’ medications. However, the evidence for it being capable of preventing clinically relevant adverse events was poor. CONCLUSION:Qualitative research in this thesis has proposed novel theories relating to the causative factors of PIP in older patients. In doing so, it has identified several areas for intervention and laid down a road map for future research.