Leveraging lessons learned in organizations through implementing practice-based organizational learning and performance improvement - An opportunity for context-based intelligent assistant support (CIAS)

Organizations that leverage lessons learned from their experience in the practice of complex real-world activities are faced with five difficult problems. First, how to represent the learning situation in a recognizable way. Second, how to represent what was actually done in terms of repeatable actions. Third, how to assess performance taking account of the particular circumstances. Fourth, how to abstract lessons learned that are re-usable on future occasions. Fifth, how to determine whether to pursue practice maturity or strategic relevance of activities. Here, organizational learning and performance improvement are investigated in a field study using the Context-based Intelligent Assistant Support (CIAS) approach. A new conceptual framework for practice-based organizational learning and performance improvement is presented that supports researchers and practitioners address the problems evoked and contributes to a practice-based approach to activity management. The novelty of the research lies in the simultaneous study of the different levels involved in the activity. Route selection in light rail infrastructure projects involves practices at both the strategic and operational levels; it is part managerial/political and part engineering. Aspectual comparison of practices represented in Contextual Graphs constitutes a new approach to the selection of Key Performance Indicators (KPIs). This approach is free from causality assumptions and forms the basis of a new approach to practice-based organizational learning and performance improvement. The evolution of practices in contextual graphs is shown to be an objective and measurable expression of organizational learning. This diachronic representation is interpreted using a practice-based organizational learning novelty typology. This dissertation shows how lessons learned when effectively leveraged by an organization lead to practice maturity. The practice maturity level of an activity in combination with an assessment of an activity’s strategic relevance can be used by management to prioritize improvement effort.

The quality of diabetes care in the community: practice, policy and culture

Aim: Diabetes is an important barometer of health system performance. This chronic condition is a source of significant morbidity, premature mortality and a major contributor to health care costs. There is an increasing focus internationally, and more recently nationally, on system, practice and professional-level initiatives to promote the quality of care. The aim of this thesis was to investigate the ‘quality chasm’ around the organisation and delivery of diabetes care in general practice, to explore GPs’ attitudes to engaging in quality improvement activities and to examine efforts to improve the quality of diabetes care in Ireland from practice to policy. Methods: Quantitative and qualitative methods were used. As part of a mixed methods sequential design, a postal survey of 600 GPs was conducted to assess the organization of care. This was followed by an in-depth qualitative study using semi-structured interviews with a purposive sample of 31 GPs from urban and rural areas. The qualitative methodology was also used to examine GPs’ attitudes to engaging in quality improvement. Data were analysed using a Framework approach. A 2nd observation study was used to assess the quality of care in 63 practices with a special interest in diabetes. Data on 3010 adults with Type 2 diabetes from 3 primary care initiatives were analysed and the results were benchmarked against national guidelines and standards of care in the UK. The final study was an instrumental case study of policy formulation. Semi-structured interviews were conducted with 15 members of the Expert Advisory Group (EAG) for Diabetes. Thematic analysis was applied to the data using 3 theories of the policy process as analytical tools. Results: The survey response rate was 44% (n=262). Results suggested care delivery was largely unstructured; 45% of GPs had a diabetes register (n=157), 53% reported using guidelines (n=140), 30% had formal call recall system (n=78) and 24% had none of these organizational features (n=62). Only 10% of GPs had a formal shared protocol with the local hospital specialist diabetes team (n=26). The lack of coordination between settings was identified as a major barrier to providing optimal care leading to waiting times, overburdened hospitals and avoidable duplication. The lack of remuneration for chronic disease management had a ripple effect also creating costs for patients and apathy among GPs. There was also a sense of inertia around quality improvement activities particularly at a national level. This attitude was strongly influenced by previous experiences of change in the health system. In contrast GP’s spoke positively about change at a local level which was facilitated by a practice ethos, leadership and special interest in diabetes. The 2nd quantitative study found that practices with a special interest in diabetes achieved a standard of care comparable to the UK in terms of the recording of clinical processes of care and the achievement of clinical targets; 35% of patients reached the HbA1c target of <6.5% compared to 26% in England and Wales. With regard to diabetes policy formulation, the evolving process of action and inaction was best described by the Multiple Streams Theory. Within the EAG, the formulation of recommendations was facilitated by overarching agreement on the “obvious” priorities while the details of proposals were influenced by personal preferences and local capacity. In contrast the national decision-making process was protracted and ambiguous. The lack of impetus from senior management coupled with the lack of power conferred on the EAG impeded progress. Conclusions: The findings highlight the inconsistency of diabetes care in Ireland. The main barriers to optimal diabetes management center on the organization and coordination of care at the systems level with consequences for practice, providers and patients. Quality improvement initiatives need to stimulate a sense of ownership and interest among frontline service providers to address the local sense of inertia to national change. To date quality improvement in diabetes care has been largely dependent the “special interest” of professionals. The challenge for the Irish health system is to embed this activity as part of routine practice, professional responsibility and the underlying health care culture.

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.

Carbon nanotubes as materials in nanotechnology

Carbon nanotubes (CNTs) are hollow tubes of sp2-hybridised carbon with diameters of the order of nanometres. Due to their unique physical properties, which include ballistic transport and high mechanical strength, they are of significant interest for technological applications. The electronic properties of CNTs are of particular interest for use as gas sensors, interconnect materials in the semi-conductor industry and as the channel material in CNT based field effect transistors. The primary difficulty associated with the use of CNTs in electronic applications is the inability to control electronic properties at the growth stage; as grown CNTs consist of a mixture of metallic and semi-conducting CNTs. Doping has the potential to solve this problem and is a focus of this thesis. Nitrogen-doped CNTs typically have defective structures; the usual hollow CNT structure is replaced by a series of compartments. Through density functional theory (DFT) calculations and experimental results, we propose an explanation for the defective structures obtained, based on the stronger binding of N to the growth catalyst in comparison to C. In real electronic devices, CNTs need to be contacted to metal, we generate the current-voltage (IV) characteristics of metal-contacted CNTs considering both the effect of dopants and the structure of the interface region on electronic properties. We find that substitutionally doped CNTs produce Ohmic contacts and that scattering at the interface is strongly influenced by structure. In addition, we consider the effect of the common vacancy defects on the electronic properties of large diameter CNTs. Defects increase scattering in the CNT, with the greatest scattering occurring for the largest defect (555777). We validate the independent scattering approximation for small diameter CNTs, which enables mean free paths in large diameter CNTs to be calculated, with a smaller mean free paths found for larger defects.

A king for the queene: Samuel Sheppard's the faerie king and his reception of Spenser's epic authority

This thesis is the study of the use and abuse of Edmund Spenser as an authority in native English epic literature of the early seventeenth century, within fifty years of his death. It focuses on attempts to emulate or adapt his seminal text, The Faerie Queene (1596), and offers a comparative analysis of two such approaches by the liminal authors, Ralph Knevet and Samuel Sheppard. The former, a tutor to the wealthy Norfolk Paston family, produced his A Supplement of the Ferie Queene in the pre-Civil War period (c.1630-1635), while the latter wrote The Faerie King at the very end of the social upheaval of the war (c.1648-54). The thesis privileges the study of the holograph manuscripts (Cambridge University Library, MS Ee.3.53 and Bodleian Library MS Rawl. Poet. 28 respectively) over the basic editions of these neglected texts. It argues for the need to re-evaluate the significance of such texts within the Spenserian canon and, through new readings of the texts' structures and contexts, the thesis questions the legitimacy of canon formation and continuation, as well as the influence editorial policies and decision making can have on subsequent readers and receptions of the text

Biodiversity change in the Irish uplands - the effects of grazing management

As a prominent form of land use across much of upland Europe, extensive livestock grazing may hold the key to the sustainable management of these landscapes. Recent agricultural policy reform, however, has resulted in a decline in upland sheep numbers, prompting concern for the biodiversity value of these areas. This study quantifies the effects of varying levels of grazing management on plant, ground beetle and breeding bird diversity and assemblage in the uplands and lowlands of hill sheep farms in County Kerry, Ireland. Farms represent a continuum of light to heavy grazing, measured using a series of field indicators across several habitats, such as the internationally important blanket bog, home to the ground beetle, Carabus clatratus. Linear mixed effects modelling and non-metric multidimensional scaling are employed to disentangle the most influential management and environmental factors. Grazing state may be determined by the presence of Molinia caerulea or Nardus stricta, and variables such as % traditional ewes, % vegetation litter and % scrub prove valuable indicators of diversity. Measures of ecosystem functioning, e.g. plant biomass (nutrient cycling) and % vegetation cover (erosion rates) are influenced by plant diversity, which is influenced by grazing management. Levels of the ecosystem service, soil organic carbon, vary with ground beetle abundance and diversity, potentially influencing carbon sequestration and thereby climate change. The majority of species from all three taxa are found in the lowlands, with the exception of birds such as meadow pipit and skylark. The scale of measurement should be determined by the size and mobility of the species in question. The challenge is to manage these high nature value landscapes using agri-environment schemes which enhance biodiversity by maintaining structural heterogeneity across a range of scales, altitudes and habitats whilst integrating the decisions of people living and working in these marginal areas.

High speed nonlinear optical components for next-generation optical communications

Electronic signal processing systems currently employed at core internet routers require huge amounts of power to operate and they may be unable to continue to satisfy consumer demand for more bandwidth without an inordinate increase in cost, size and/or energy consumption. Optical signal processing techniques may be deployed in next-generation optical networks for simple tasks such as wavelength conversion, demultiplexing and format conversion at high speed (≥100Gb.s-1) to alleviate the pressure on existing core router infrastructure. To implement optical signal processing functionalities, it is necessary to exploit the nonlinear optical properties of suitable materials such as III-V semiconductor compounds, silicon, periodically-poled lithium niobate (PPLN), highly nonlinear fibre (HNLF) or chalcogenide glasses. However, nonlinear optical (NLO) components such as semiconductor optical amplifiers (SOAs), electroabsorption modulators (EAMs) and silicon nanowires are the most promising candidates as all-optical switching elements vis-à-vis ease of integration, device footprint and energy consumption. This PhD thesis presents the amplitude and phase dynamics in a range of device configurations containing SOAs, EAMs and/or silicon nanowires to support the design of all optical switching elements for deployment in next-generation optical networks. Time-resolved pump-probe spectroscopy using pulses with a pulse width of 3ps from mode-locked laser sources was utilized to accurately measure the carrier dynamics in the device(s) under test. The research work into four main topics: (a) a long SOA, (b) the concatenated SOA-EAMSOA (CSES) configuration, (c) silicon nanowires embedded in SU8 polymer and (d) a custom epitaxy design EAM with fast carrier sweepout dynamics. The principal aim was to identify the optimum operation conditions for each of these NLO device configurations to enhance their switching capability and to assess their potential for various optical signal processing functionalities. All of the NLO device configurations investigated in this thesis are compact and suitable for monolithic and/or hybrid integration.

The analytical approach of the European Court of Human Rights in surveillance cases—the implications, justifications, and future of the Court’s reasoning, with a focus on the legislative impact in Ireland

A notable feature of the surveillance case law of the European Court of Human Rights has been the tendency of the Court to focus on the “in accordance with the law” aspect of the Article 8 ECHR inquiry. This focus has been the subject of some criticism, but the impact of this approach on the manner in which domestic surveillance legislation has been formulated in the Party States has received little scholarly attention. This thesis addresses that gap in the literature through its consideration of the Interception of Postal Packets and Telecommunications Messages (Regulation) Act, 1993 and the Criminal Justice (Surveillance) Act, 2009. While both Acts provide several of the safeguards endorsed by the European Court of Human Rights, this thesis finds that they suffer from a number of crucial weaknesses that undermine the protection of privacy. This thesis demonstrates how the focus of the European Court of Human Rights on the “in accordance with the law” test has resulted in some positive legislative change. Notwithstanding this fact, it is maintained that the legality approach has gained prominence at the expense of a full consideration of the “necessary in a democratic society” inquiry. This has resulted in superficial legislative responses at the domestic level, including from the Irish government. Notably, through the examination of a number of more recent cases, this project discerns a significant alteration in the interpretive approach adopted by the European Court of Human Rights regarding the application of the necessity test. The implications of this development are considered and the outlook for Irish surveillance legislation is assessed.

Simplified decoding techniques for linear block codes

Error correcting codes are combinatorial objects, designed to enable reliable transmission of digital data over noisy channels. They are ubiquitously used in communication, data storage etc. Error correction allows reconstruction of the original data from received word. The classical decoding algorithms are constrained to output just one codeword. However, in the late 50’s researchers proposed a relaxed error correction model for potentially large error rates known as list decoding. The research presented in this thesis focuses on reducing the computational effort and enhancing the efficiency of decoding algorithms for several codes from algorithmic as well as architectural standpoint. The codes in consideration are linear block codes closely related to Reed Solomon (RS) codes. A high speed low complexity algorithm and architecture are presented for encoding and decoding RS codes based on evaluation. The implementation results show that the hardware resources and the total execution time are significantly reduced as compared to the classical decoder. The evaluation based encoding and decoding schemes are modified and extended for shortened RS codes and software implementation shows substantial reduction in memory footprint at the expense of latency. Hermitian codes can be seen as concatenated RS codes and are much longer than RS codes over the same aphabet. A fast, novel and efficient VLSI architecture for Hermitian codes is proposed based on interpolation decoding. The proposed architecture is proven to have better than Kötter’s decoder for high rate codes. The thesis work also explores a method of constructing optimal codes by computing the subfield subcodes of Generalized Toric (GT) codes that is a natural extension of RS codes over several dimensions. The polynomial generators or evaluation polynomials for subfield-subcodes of GT codes are identified based on which dimension and bound for the minimum distance are computed. The algebraic structure for the polynomials evaluating to subfield is used to simplify the list decoding algorithm for BCH codes. Finally, an efficient and novel approach is proposed for exploiting powerful codes having complex decoding but simple encoding scheme (comparable to RS codes) for multihop wireless sensor network (WSN) applications.

Synthesis and reactivity of α-diazo-β-keto sulfoxides: scope and synthetic potential

The research described in this thesis focuses on the design and synthesis of stable α-diazosulfoxides and investigation of their reactivity under a variety of conditions (transition-metal catalysis, thermal, photochemical and microwave) with a particular emphasis on the synthesis of novel heterocyclic compounds with potential biological activity. The exclusive reaction pathway for these α-diazosulfoxides was found to be hetero-Wolff rearrangement to give α-oxosulfine intermediates. In the first chapter, a literature review of sulfines is presented, including a discussion of naturally occurring sulfines, and an overview of the synthesis and reactivity of sulfines. The potential of sulfines in organic synthesis and recent developments in particular are highlighted. The second chapter discusses the synthesis and reactivity of α-diazosulfoxides, building on earlier results in this research group. The synthesis of lactone-based α-diazosulfoxides and, for the first time, ketone-based benzofused and monocyclic α-diazosulfoxides is described. The reactivity of these α-diazosulfoxides is then explored under a variety of conditions, such as transition-metal catalysis, photochemical and microwave, generating labile α-oxosulfine intermediates, which are trapped using amines and dienes, in addition to the spontaneous reaction pathways which occur with α-oxosulfines in the absence of a trap. A new reaction pathway was explored with the lactone based α-oxosulfines, involving reaction with amines to generate novel 3-aminofuran-2(5H)-ones via carbophilic attack, in very good yields. The reactivity of ketone-based α-diazosulfoxides was explored for the first time, and once again, pseudo-Wolff rearrangement to the α-oxosulfines was the exclusive reaction pathway observed. The intermediacy of the α-oxosulfines was confirmed by trapping as cycloadducts, with the stereochemical features dependant on the reaction conditions. In the absence of a diene trap, a number of reaction fates from the α-oxosulfines were observed, including complete sulfinyl extrusion to give indanones, sulfur extrusion to give indanediones, and, to a lesser extent, dimerisation. The indanediones were characterised by trapping as quinoxalines, to enable full characterisation. One of the overriding outcomes of this thesis was the provision of new insights into the behaviour of α-oxosulfines with different transition metal catalysts, and under thermal, microwave and photolysis conditions. A series of 3-aminofuran-2(5H)-ones and benzofused dihydro-2H-thiopyran S-oxides were submitted for anticancer screening at the U.S. National Cancer Institute. A number of these derivatives were identified as hit compounds, with excellent cell growth inhibition. One 3-aminofuran-2(5H)-one derivative has been chosen for further screening. The third chapter details the full experimental procedures, including spectroscopic and analytical data for the compounds prepared during this research. The data for the crystal structures are contained in the attached CD.

Users & use: An exploration of the interaction between the user and the digital archive

This thesis will examine the interaction between the user and the digital archive. The aim of the study is to support an in-depth examination of the interaction process, with a view to making recommendations and tools, for system designers and archival professionals, to promote digital archive domain development. Following a comprehensive literature review process, an urgent requirement for models was identified. The Model of Contextual Interaction presented in this thesis, aims to provide a conceptual model through which the interaction process, between the user and the digital archive, can be examined. Using the five-phased research development framework, the study will present a structured account of its methods, using a multi-method methodology to ensuring robust data collection and analysis. The findings of the study are presented across the Model of Contextual Interaction, and provide a basis on which recommendations and tools for system designers have been made. The thesis concludes with a summary of key findings, and a reflective account of how the findings and the Model of Contextual Interaction have impacted digital provision within the archive domain and how the model could be applied to other domains.

Nuove intersezioni: crimine e storia nella narrativa Italiana al cambio di millennio

My research investigates a recent tendency in Italian literature, characterized by elements of renewal within the novel-writing tradition and of discontinuity with postmodern culture. It proposes an interpretation of the genres of the historical novel and crime fiction in the last fifteen years, in order to underline the important role played by these types of narrative in revitalizing contemporary Italian literature. These modalities of writing are considered both individually and in their connections beyond a traditional notion of genre, emphasizing those characteristics which may be assumed as irreconcilable with a postmodern approach to fiction and those which, furthermore, seem to indicate attempts to take a new course. In particular, my study analyses the recent literary tendency to combine the elements of ‘crime’ and ‘history’ in order to represent political and social reality, and how the works examined relate to postmodern narrative. For this reason, I pay particular attention to the relationship between literature and the past and to the socio-political aspects connected with the praxis of narrating, offering an original interpretation of the way in which the authors studied engage with these characteristics.

Vascular calcification and mineral bone disorder in chronic kidney disease

Chronic Kidney Disease (CKD), osteoporosis and mild hyponatremia are all prevalent chronic conditions that may coexist and are often under-recognized. Mineral-Bone Disorder begins early in the natural history of CKD and results in complex abnormalities of bone which ultimately confers a well-established increased risk of fragility fractures in End Stage Kidney Disease. Hyponatremia is a novel, usually renal mediated metabolic perturbation, that most commonly occurs independently of the stage of renal dysfunction but which may also predispose to increased fracture risk. The extent -if any- to which either early stages of renal dysfunction or the presence of hyponatremia contribute to fracture occurrence in the general population, independently of osteoporosis, is unclear. Renal transplantation is the treatment of choice for ESKD and although it restores endogenous renal function it typically fails to normalize either the long term cardiovascular or fracture risk. One potential mechanism contributing to these elevated long-term risks and to diminished Health Related Quality of Life is persistent, post-transplant hyperparathyroidism. In this study we retrospectively examine the association of renal function and serum sodium with Bone Mineral Density and fracture occurrence in a retrospective cohort of 1930 female members of the general population who underwent routine DXA scan. We then prospectively recruited a cohort of 90 renal transplant recipients in order to examine the association of post transplant parathyroid hormone (PTH) level with measures of CKD Mineral Bone Disorder, including, DXA Bone Mineral Density, Vascular Calcification (assessed using both abdominal radiography and CT techniques, as well as indirectly by carotid-femoral Pulse Wave Velocity) and Quality of Life (using the Short Form-12 and a PTH specific symptom score). In the retrospective DXA cohort, moderate CKD (eGFR 30-59ml/min/1.73m2) and hyponatremia (<135mmol/L) were associated with fracture occurrence, independently of BMD, with an adjusted Odds Ratio (95% Confidence Interval), of 1.37 (1.0, 1.89) and 2.25 (1.24, 4.09) respectively. In the renal transplant study, PTH was independently associated with the presence of osteoporosis, adjusted Odds Ratio (95% Confidence Interval), 1.15 (per 10ng/ml increment), (1.04, 1.26). The presence of osteoporosis but not PTH was independently associated with measures of vascular calcification, adjusted ß (95% Confidence Interval), 12.45, (1.16, 23.75). Of the eight quality-of-life domains examined, post-transplant PTH (per 10ng/ml increment), was only significantly and independently associated with reduced Physical Functioning, (95% Confidence Interval), 1.12 (1.01, 1.23). CKD and hyponatremia are both common health problems that may contribute to fracture occurrence in the general population, a major on-going public health concern. PTH and decreased Bone Mineral Density may signal sub-optimal long-term outcomes post renal transplantation, influencing bone and vascular health and to a limited extent long term Health Related Quality of Life

Infected vision in the works of Thomas Middleton

This thesis investigates the extent and range of the ocular vocabulary and themes employed by the playwright Thomas Middleton in context with early modern scientific, medical, and moral-philosophical writing on vision. More specifically, this thesis concerns Middleton’s revelation of the substance or essence of outward forms through mimesis. This paradoxical stance implies Middleton’s use of an illusory (theatrical) art form to explore hidden truths. This can be related to the early modern belief in the imagination (or fantasy) as chief mediator between the corporeal and spiritual worlds as well as to a reformed belief in the power of signs to indicate divine truth. This thesis identifies striking parallels between Middleton’s policy of social diagnosis and cure and an increased preoccupation with knowledge of interior man which culminates in Robert Burton’s Anatomy of Melancholy of 1621. All of these texts seek a cure for diseased internal sense faculties (such as fantasy and will) which cause the raging passions to destroy the individual. The purpose of this thesis is to demonstrate how Middleton takes a similar ‘mental-medicinal’ approach which investigates the idols created by the imagination before ‘purging’ the same and restoring order (Corneanu and Vermeir 184). The idea of infection incurred through the eyes which are fixed on vice (or error) has moral, religious, and political implications and discovery of corruption involves stripping away the illusions of false appearances to reveal the truth within whereby disease and disorder can be cured and restored. Finally, Middleton’s use of theatrical fantasy to detect the idols of the diseased imagination can be read as a Paracelsian, rather than Galenic, form of medicine whereby like is ‘joined with their like’ (Bostocke C7r) to restore health.

Catalyst, additive and substrate effects in intramolecular aromatic additions of alpha-diazoketones

This thesis is focused on transition metal catalysed reaction of α-diazoketones leading to aromatic addition to form azulenones, with particular emphasis on enantiocontrol through use of chiral copper catalysts. The first chapter provides an overview of the influence of variation of the substituent at the diazo carbon on the outcome of subsequent reaction pathways, focusing in particular on C-H insertion, cyclopropanation, aromatic addition and ylide formation drawing together for the first time input from a range of primary reports. Chapter two describes the synthesis of a range of novel α-diazoketones. Rhodium and copper catalysed cyclisation of these to form a range of azulenones is described. Variation of the transition metal catalyst was undertaken using both copper and rhodium based systems and ligand variation, including the design and synthesis of a novel bisoxazoline ligand. The influence of additives, especially NaBARF, on the enantiocontrol was explored in detail and displayed an interesting impact which was sensitive to substituent effects. Further exploration demonstrated that it is the sodium cation which is critical in the additive effects. For the first time, enantiocontrol in the aromatic addition of terminal diazoketones was demonstrated indicating enantiofacial control in the aromatic addition is feasible in the absence of a bridgehead substituent. Determination of the enantiopurity in these compounds was particularly challenging due to the lability of the products. A substantial portion of the work was focused on determining the stereochemical outcome of the aromatic addition processes, both the absolute stereochemistry and extent of enantiopurity. Formation of PTAD adducts was beneficial in this regard. The third chapter contains the full experimental details and spectral characterisation of all novel compounds synthesised in this project, while details of chiral stationary phase HPLC and 1H NMR analysis are included in the appendix.