Synthetic and mechanistic aspects of the reactions of α-diazosulfoxides

The research described in this thesis focuses, principally, on synthesis of stable α-diazosulfoxides and investigation of their reactivity under various reaction conditions (transition-metal catalysed, photochemical, thermal and microwave) with a particular emphasis on the reactive intermediates and mechanistic aspects of the reaction pathways involved. In agreement with previous studies carried out on these compounds, the key reaction pathway of α-diazosulfoxides was found to be hetero-Wolff rearrangement to give α-oxosulfine intermediates. However, a competing reaction pathway involving oxygen migration from sulfur to oxygen was also observed. Critically, isomerisation of α-oxosulfine stereoisomers was observed directly by 1H NMR spectroscopy in this work and this observation accounts for the stereochemical outcomes of the various cycloaddition reactions, whether carried out with in situ trapping or with preformed solutions of sulfines. Furthermore, matrix isolation experiments have shown that electrocyclisation of α-oxosulfines to oxathiiranes takes place and this verifies the proposed mechanisms for enol and disulfide formation. The introductory chapter includes a brief literature review of the synthesis and reactivity of α-diazosulfoxides prior to the commencement of research in this field by the Maguire group. The Wolff rearrangement is also discussed and the characteristic reactions of a number of reactive intermediates (sulfines, sulfenes and oxathiiranes) are outlined. The use of microwave-assisted organic synthesis is also examined, specifically, in the context of α-diazocarbonyl compounds as substrates. The second chapter describes the synthesis of stable monocyclic and bicyclic lactone derivatives of α-diazosulfoxides from sulfide precursors according to established experimental procedures. Approaches to precursors of ketone and sulfimide derivatives of α-diazosulfoxides are also described. The third chapter examines the reactivity of α-diazosulfoxides under thermal, microwave, rhodium(II)-catalysed and photochemical conditions. Comparison of the results obtained under thermal and microwave conditions indicates that there was no evidence for any effect, other than thermal, induced by microwave irradiation. The results of catalyst studies involving several rhodium(II) carboxylate and rhodium(II) carboxamidate catalysts are outlined. Under photochemical conditions, sulfur extrusion is a significant reaction pathway while under thermal or transition metal catalysed conditions, oxygen extrusion is observed. One of the most important observations in this work was the direct spectroscopic observation (by 1H NMR) of interconversion of the E and Z-oxosulfines. Trapping of the α-oxosulfine intermediates as cycloadducts by reaction with 2,3-dimethyl-1,3-butadiene proved useful both synthetically and mechanistically. As the stereochemistry of the α-oxosulfine is retained in the cycloadducts, this provided an ideal method for characterisation of this key feature. In the case of one α-oxosulfine, a novel [2+2] cycloaddition was observed. Preliminary experiments to investigate the reactivity of an α-diazosulfone under rhodium(II) catalysis and microwave irradiation are also described. The fourth chapter describes matrix isolation experiments which were carried out in Rühr Universität, Bochum in collaboration with Prof. Wolfram Sander. These experiments provide direct spectroscopic evidence of an α-oxosulfine intermediate formed by hetero-Wolff rearrangement of an α-diazosulfoxide and subsequent cyclisation of the sulfine to an oxathiirane was also observed. Furthermore, it was possible to identify which stereoisomer of the α-oxosulfine was present in the matrix. A preliminary laser flash photolysis experiment is also discussed. The experimental details, including all spectral and analytical data, are reported at the end of each chapter. The structural interpretation of 1H NMR spectra of the cycloadducts, described in Chapter 3, is discussed in Appendix I.

The corporate social responsibility movement and law's empire: Is there a conflict?

At the heart of corporate governance and social responsibility discourse is recognition of the fact that the modern corporation is primarily governed by the profit maximisation imperative coupled with moral and ethical concerns that such a limited imperative drives the actions of large and wealthy corporations which have the ability to act in influential and significant ways, shaping how our social world is experienced. The actions of the corporation and its management will have a wide sphere of impact over all of its stakeholders whether these are employees, shareholders, consumers or the community in which the corporation is located. As globalisation has become central to the way we think it is also clear that ‘community’ has an ever expanding meaning which may include workers and communities living very far away from Corporate HQ. In recent years academic commentators have become increasingly concerned about the emphasis on what can be called short-term profit maximisation and the perception that this extremist interpretation of the profit imperative results in morally and ethically unacceptable outcomes.1 Hence demands for more corporate social responsibility. Following Cadbury’s2 classification of corporate social responsibility into three distinct areas, this paper will argue that once the legally regulated tier is left aside corporate responsibility can become so nebulous as to be relatively meaningless. The argument is not that corporations should not be required to act in socially responsible ways but that unless supported by regulation, which either demands high standards, or at the very least incentivises the attainment of such standards such initiatives are doomed to failure. The paper will illustrate by reference to various chosen cases that law’s discourse has already signposted ways to consider and resolve corporate governance problems in the broader social responsibility context.3 It will also illustrate how corporate responsibility can and must be supported by legal measures. Secondly, this paper will consider the potential conflict between an emphasis on corporate social responsibility and the regulatory approach.4 Finally, this paper will place the current interest in corporate social responsibility within the broader debate on the relationship between law and non-legally enforceable norms and will present some reflections on the norm debate arising from this consideration of the CSR movement.

Synthetic and stereochemical aspects of intramolecular reactions of α-diazoketones catalysed by rhodium(II) carboxylates

Chapter 1 of this thesis is a brief introduction to the preparation and reactions of α-diazocarbonyl compounds, with particular emphasis on the areas relating to the research undertaken: C-H insertion, addition to aromatics, and oxonium ylide generation and rearrangement. A short summary of catalyst development illustrates the importance of rhodium(II)carboxylates for α-diazocarbonyl decomposition. Chapter 2 describes intramolecular C-H insertion reactions of α-diazo-β-keto sulphones to form substituted cyclopentanones. Rhodium(II) carboxylates derived from homochiral carboxylic acids were used as catalysts in these reactions and enantioselection achieved through their use is discussed. Chapter 3 describes intramolecular Buchner cyclisation of aryl diazoketones with emphasis on the stereochemical aspects of the cyclisation and subsequent reaction of the bicyclo[5.3.0]decatrienones produced. The partial asymmetric synthesis achieved through use of chiral rhodium(II) carboxylates as catalysts is discussed. The application of the intramolecular Buchner reaction to the synthesis of hydroazulene lactones is illustrated. Chapter 4 demonstrates oxonium ylide formation and rearrangement in the decomposition of an α-diazoketone. The consequences of the use of chiral rhodium(II) carboxylates as catalysts are described. Particularly significant was the discovery that rhodium(II) (S)-mandelate acts as a very efficient catalyst for α-diazoketone decompositions, in general. Moderate asymmetric induction was possible in the decomposition of α-diazoketones with chiral rhodium(II) carboxylates, with rhodium(II) (S)-mandelate being one of the more enantioselective catalysts investigated. However, the asymmetric induction obtained was very dependent on the exact structure of the α-diazoketone, the catalyst, and the nature of the reaction. Chapter 5 contains the experimental details, and the spectral and analytical data for all new compounds reported.

Molecular and cellular aspects of the SREBP pathway

The SREBP (sterol response element binding proteins) transcription factors are central to regulating de novo biosynthesis of cholesterol and fatty acids. The SREBPs are regulated by retention or escape from the ER to the Golgi where they are proteolytically cleaved into active forms. The SREBP cleavage activating protein (SCAP) and the INSIG proteins are essential in this regulatory process. The aim of this thesis is to further characterise the molecular and cellular aspects surrounding regulation of SREBP processing. SREBP and SCAP are known to interact via their carboxy-terminal regulatory domains (CTDs) but this interaction is poorly characterised. Significant steps were achieved in this thesis towards specific mapping of the interaction site. These included cloning and over expression and partial purification of tagged SREBP1 and SREBP2 CTDs and probing of a SCAP peptide array with the CTDs. Results from the SREBP2 probing were difficult to interpret due to insolubility issues with the protein, however, probing with SREBP1 revealed five potential binding sites which were detected reproducibly. Further research is necessary to overcome SREBP2 insolubility issues and to confirm the identified SREBP1 interaction site(s) on SCAP. INSIG1 has a central role in regulating SREBP processing and in regulating stability of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), a rate limiting enzyme in cholesterol biosynthesis. There are two protein isoforms of human INSIG1 produced through the use of two in-frame alternative start sites. Bioinformatic analysis indicated that the presence of two in-frame start sites within the 5-prime region of INSIG1 mRNA is highly conserved and that production of two isoforms of INSIG1is likely a conserved event. Functional differences between these two isoforms were explored. No difference in either the regulation of SREBP processing or HMGCR degradation between the INSIG1 isoforms was observed and the functional significance of the two isoforms is as yet unclear. The final part of this thesis focused on enhancing the cytotoxicity of statins by targeted inhibition of SREBP processing by oxysterols. Statins have significant potential as anti-cancer agents as they inhibit the activity of HMGCR leading to a deficiency in mevalonate which is essential for cell survival. The levels of HMGCR fluctuate widely due to cholesterol feedback of SREBP processing. The relationship between sterol feedback and statin mediated cell death was investigated in depth in HeLa cells. Down regulation of SREBP processing by sterols significantly enhanced the efficacy of statin mediated cell death. Investigation of sterol feedback in additional cancer cell lines showed that sterol feedback was absent in cell lines A- 498, DU-145, MCF-7 and MeWo but was present in cell lines HT-29, HepG2 and KYSE-70. In the latter inhibition of SREBP processing using oxysterols significantly enhanced statin cytotoxicity. The results indicate that this approach is valid to enhance statin cytotoxicity in cancer cells, but may be limited by deregulation of SREBP processing and off target effects of statins, which were observed for some of the cancer cell lines screened.

Nurses’ perceptions of nursing presence and the relationship between nursing presence and moral sensitivity in nurses working with people with dementia in residential care

Aim: The aim of this study was to measure nursing presence among nurses caring for people with dementia in residential care settings, and to investigate the relationship between nursing presence and moral sensitivity. Background: Nursing presence is a core relational skill in nursing and holds many benefits for nurses and their patients. Moral sensitivity is defined as how one recognises the moral elements of a situation, and how one’s moral or ethical decision making may impact on an individual. Methods: A descriptive, cross sectional quantitative methodology was used with a sample of 150 registered nurses. The Presence of Nursing Scale for Registered Nurses was used to investigate nursing presence, and the Moral Sensitivity Questionnaire for moral sensitivity. Results: Findings from the study demonstrated that participants agreed with the majority of elements of nursing presence, (mean 76.97, SD= 7.51). A mean score of 36.22 was evidence of a well developed level of moral sensitivity in participants. Nurses who perceived themselves to be highly present to their patients also scored highest on certain elements of moral sensitivity such as moral strength. Nursing presence was also found to be more developed in those participants that rated themselves as having higher levels of expertise based on Benner’s (1984) definitions. Older nurses also scored higher on nursing presence. There was a high level of agreement that factors such as lack of time (n=133), and heavy workload influenced nursing presence. Nurses, who were older and had longer clinical experience, were shown to have greater moral strength. There were differences in elements of moral sensitivity between groups of nurses who ranked themselves according to Benner’s (1984) competence framework with higher scores evident in the more expert groups. Conclusion: Overall, this study showed that participants had a well developed level of nursing presence, and certain elements of moral sensitivity are positively related to nursing presence. Nursing presence appears to be linked to the level of expertise of the nurse but factors such as time and workload do influence nursing presence.

Godwin, Fénelon, and the disappearing teacher

The connection between Godwin and Fénelon has traditionally been restricted to the famous and controversial moment in the first edition of Political Justice (1793) in which Godwin presents an example of the interdependence of rationality and ethical action. This paper argues, however, that Fénelon, and particularly his political and educational treatise Telemachus (1699), plays a significant role in a number of Godwin's subsequent fictional works. Employing Telemachus to explore the theories of education presented by Godwin in the various editions of Political Justice and The Enquirer (1797), this paper explores the manner in which Godwin's version of the Enlightenment transcendence of pedagogical power comes up against its limits. Reading this issue in relation to Godwin's argument, in ‘Of Choice in Reading’, that literature remains outside of socio-ethical corruption, three of Godwin's major novels are shown to demonstrate that Telemachus provides the chance for meta-textual moments in which the appeal to reason (the reader's rational capacity or ‘private judgement’) is at once reflected upon and produced. Reading educational theories and problems into Godwin's major fiction in this fashion helps to clarify aspects of the Godwinian (or ‘Jacobin’) novel.

The examination of the traditional femininity and women’s lives in ancient China

This thesis explores the evolution of the concept of traditional Chinese femininity in relation to women’s lives in ancient China (221 BCE – A.D.1840). It proposes that the traditional Chinese femininity had been trying to seek a balance between the permanent principles and contingency plans for the stability and development of the society, which caused women’s humiliation and freedom. In reality, politicians and thinkers in ancient China had been transforming the concept of femininity itself to make it more adaptable to the social conditions of that time. This may be discussed in terms of three aspects. Firstly, the traditional concept of Chinese human relationships, including the ethical order, always emphasised the influence of individual behaviour on others and the overall stability and linked development of family, society and nation. Thus, both men and women, must be placed within this interrelated, interacting and cooperating relationship. Secondly, the association of family and country created an overlap of family and public affairs, which, objectively, facilitated the movement of women from the inner to the public arena. Thirdly, the notions of political and ethical morality and of men’s virtues and women’s virtues were integrated because of the union of family and nation. Therefore, typically virtuous women could be a source of encouragement for men and, furthermore, men formulated their virtues in the public space by formulating women’s virtues in the private space. The shaping of the gender image and concept of women in ancient China reflected the country’s changing cultural and gender norms. Chinese femininity and lifestyles, like Chinese history, were a continuous presence in the society but were also constantly changing. Through this study, it could be noted that Chinese women were not hidden and that their subjectivity and the concepts motivating them were not merely devised by a male-dominated society and culture.