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.

The framework for REVIEWS: an exploration into design principles for an electronic medical early warning system observation chart

The observation chart is for many health professionals (HPs) the primary source of objective information relating to the health of a patient. Information Systems (IS) research has demonstrated the positive impact of good interface design on decision making and it is logical that good observation chart design can positively impact healthcare decision making. Despite the potential for good observation chart design, there is a paucity of observation chart design literature, with the primary source of literature leveraging Human Computer Interaction (HCI) literature to design better charts. While this approach has been successful, this design approach introduces a gap between understanding of the tasks performed by HPs when using charts and the design features implemented in the chart. Good IS allow for the collection and manipulation of data so that it can be presented in a timely manner that support specific tasks. Good interface design should therefore consider the specific tasks being performed prior to designing the interface. This research adopts a Design Science Research (DSR) approach to formalise a framework of design principles that incorporates knowledge of the tasks performed by HPs when using observation charts and knowledge pertaining to visual representations of data and semiology of graphics. This research is presented in three phases, the initial two phases seek to discover and formalise design knowledge embedded in two situated observation charts: the paper-based NEWS chart developed by the Health Service Executive in Ireland and the electronically generated eNEWS chart developed by the Health Information Systems Research Centre in University College Cork. A comparative evaluation of each chart is also presented in the respective phases. Throughout each of these phases, tentative versions of a design framework for electronic vital sign observation charts are presented, with each subsequent iteration of the framework (versions Alpha, Beta, V0.1 and V1.0) representing a refinement of the design knowledge. The design framework will be named the framework for the Retrospective Evaluation of Vital Sign Information from Early Warning Systems (REVIEWS). Phase 3 of the research presents the deductive process for designing and implementing V0.1 of the framework, with evaluation of the instantiation allowing for the final iteration V1.0 of the framework. This study makes a number of contributions to academic research. First the research demonstrates that the cognitive tasks performed by nurses during clinical reasoning can be supported through good observation chart design. Secondly the research establishes the utility of electronic vital sign observation charts in terms of supporting the cognitive tasks performed by nurses during clinical reasoning. Third the framework for REVIEWS represents a comprehensive set of design principles which if applied to chart design will improve the usefulness of the chart in terms of supporting clinical reasoning. Fourth the electronic observation chart that emerges from this research is demonstrated to be significantly more useful than previously designed charts and represents a significant contribution to practice. Finally the research presents a research design that employs a combination of inductive and deductive design activities to iterate on the design of situated artefacts.

Synthesis and reactivity of alpha-thio-beta-chloroacrylamides and alpha-thio-beta-chloroenones

Development of novel synthetic methodology for selective transformation of organic compounds is a central element underpinning organic synthesis with control of chemo-, regio- and stereoselectivity a very high priority. Reactions which can be conducted under mild reaction conditions and, ideally in an environmentally attractive manner, are particularly advantageous. The principal objective of this thesis was to explore the synthesis, reactivity and synthetic utility of a series of α,β-thio-β-chloroenones. The stereochemical features of these transformations and the potential of this novel series of compounds in the synthesis of bioactive compounds were of particular interest. In exploring the reactivity of these compounds, the key transformations included nucleophilic additions and Stille cross-coupling at the β-carbon. Chapter 1 reviews the literature relevant to the research conducted, and focuses in particular on the synthesis of β-chloroenones and related unsaturated carbonyl compounds. The synthesis of chalcone compounds from various precursors is also discussed, with particular emphasis on the use of palladium cross-coupling reactions in the preparation of these compounds. The biological activity of chalcones is also summarised in this chapter. The second chapter delineates the stereoselective synthesis of the novel α-thio-β-chloroenones from the corresponding α-thioketones in a multistep reaction cascade initiated by a NCS-mediated chlorination. A range of both alkyl and aryl β-chloroenones were prepared in this work and the oxidation of these compounds to the corresponding sulfoxides and sulfones is also outlined. The electrophilicity of the β-carbon of the enones was examined in nucleophilic addition/substitution reactions with successful access to a variety of synthetically useful novel adducts including acetals and enaminoketones. Investigation of the synthetic potential of the Stille cross-coupling reaction with the novel α-thio-β-chloroenones was explored and provided an efficient route for the synthesis of a novel series of chalcones. Most importantly this new methodology provided a new and synthetically powerful approach for carbon-carbon bond formation at the β-carbon under mild neutral conditions. A preliminary investigation into the use of these β-chloroenones as dienophiles in Diels-Alder cycloaddition reactions is also discussed in this chapter. Chapter 2 also reports the nucleophilic addition of N, O, S and C nucleophiles to previously described β-chloroacrylamides and their corresponding sulfoxide derivatives. This work builds on previous research carried out in this programme and the reactivity of these β-chloroacrylamides at the sulfide and sulfoxide level is compared. Comparison of the reactivity of the β-chloroacrylamides, in nucleophilic substitution and Stille-coupling, with that of the novel β-chloroenones is of interest. Finally, the biological activity of both the β-chloroenones and the β-chloroacrylamides in terms of cytotoxicity is summarised in Chapter 2. The final chapter, Chapter 3, details the full experimental procedures, including spectroscopic and analytical data for the compounds prepared during this research.