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.

Chemistry and synthesis of 3(2H)-furanones and 4,5-dihydro analogues: mechanistic investigations and stereochemical control

The subject matter of this thesis relates to the chemistry of the five-membered oxygen heterocycles – 3(2H)-furanones and their 4, 5-dihydro analogues. Chapter one of the thesis is a review of the relevant chemistry of the compounds: their synthesis and key transformations. In chapter two, new research on 3(2H)-furanones is outlined in two parts. The first describes an investigation into the cyclisation of α'-trialkylsilyloxyenone adducts with arenesulfenyl and selenenyl chlorides into the corresponding sulfur and selenium substituted 3(2H)-furanones without the involvement of a Lewis acid catalyst. The study, largely involving in situ NMR techniques, identified key features associated with the formation and reaction of the chlorosulfide and chloroselenide intermediates, including operation of the Thorpe-Ingold effect. The knowledge gained in this study was applied (the second part) to the synthesis of vinyl substituted furanone systems from α'-trialkylsilyloxydienones where choice of the reaction conditions and electrophilic reagent was a key feature. An important difference in the behaviour of arenesulfenyl and selenenyl halides towards conjugated dienes emerged from this work. This phase of the research concluded with a new synthesis of geiparvarin, a natural product possessing anti-tumour properties.

Chemoenzymatic routes to enantiopure hydroxytetrahydrofurans: muscarine and its analogues

Muscarine was identified as an active principle of the poisonous mushroom Amanita muscaria over 170 years ago and has been identified as an agonist of acetylcholine. The synthesis of all stereoisomers of muscarine have been accomplished at this stage by chemical methods and the biological activity of these compounds tested. A number of synthetic routes to enantiomerically pure muscarine and its analogues have been published. In this work, we are focussed on the use of a novel biotransformation strategy to access these compounds. Asymmetric synthesis involves targeting a synthetic pathway leading to one enantiomer of a compound and biocatalysis is one strategy used in asymmetric synthesis. Chapter 1 consists of a review of the relevant literature pertaining to the synthesis and stereoselective transformations of 3-hydroxytetrahydrofuranss. A review of synthetic routes to these compounds is presented, with a particular focus on routes to the natural product muscarine and its analogues. Chapter 2 discusses the preparative routes to the 3-hydroxytetrahydrofurans via 3(2H)- furanones. Steps amongst which include Rh(II) mediate cyclisation and kinetic resolution via baker’s yeast mediated carbonyl reduction, resulting in enantioenriched 3- hydroxytetrahydrofuran derivatives. Finally, application of this methodology to the preparation of all four enantiomers of an analogue of desmethylmuscarine and the synthesis of epimuscarine is described. Chapter 3 consists of a detailed experimental section outlining the synthetic procedures employed.

The Barretstown experience

The thesis was prompted by a simple clinical observation. Seriously ill children returning from Barretstown Holiday Camp appeared changed. Barretstown ‘magic’ confuses the issue but indicates real and clinically evident transformations. The project sought to understand the experience and place it in a recognisable framework. The data was collected by interviews, observations as camp Paediatrician, memberships of the Child Advisory Committee and the Association’s criteria assessment team, participation in volunteer training and visits to international camps. The research presents evidence that the concepts of rite of passage, graceful mimesis and salutogenesis clarify operative social processes. The passage stages of separation, transition and reaggregation can be identified. Passage rites reorder personal and social upsets to fresh arrangements that facilitate change. Interviews confirm the reordering impact of achievements in play activities. These are challenging experiences closely guided by their Masters of Ceremonies – the Caras. The Cara/camper relationship is crucial and compatible with Girard’s theory of external mimesis. Visits to four camps confirm an inspirational process in contrast to a reported camp with a predetermined formative influence. Charismatic Caras/Councillors inspire playful mimesis and salutogenic transformations. Health is more than correction of pathogenic deficits and restoration of homeostasis. Salutogenic health promotes heterostasis – a desire for optimal experiences underpinned by a sense of coherence and adequate resources. Some evidence is presented that children have an improved sense of coherence after camp, which enables them to cope better with the demands of ill health. The camps enable sick children to up regulate risk taking towards more heterostatic experiences rather than down regulate their expectations. The heterostatic impulse can explain the disability paradox of good quality of life in the presence of severe disability. The salutogenic power of Barretstown can trump the pathogenic effects of childhood cancer and other serious illnesses.

Engineering design of a bioprocess for the production of natural red colourants by submerged fermentation of the thermophilic fungus Penicillium purpurogenum GH2

The development of a new bioprocess requires several steps from initial concept to a practical and feasible application. Industrial applications of fungal pigments will depend on: (i) safety of consumption, (ii) stability of the pigments to the food processing conditions required by the products where they will be incorporated and (iii) high production yields so that production costs are reasonable. Of these requirements the first involves the highest research costs and the practical application of this type of processes may face several hurdles until final regulatory approval as a new food ingredient. Therefore, before going through expensive research to have them accepted as new products, the process potential should be assessed early on, and this brings forward pigment stability studies and process optimisation goals. Only ingredients that are usable in economically feasible conditions should progress to regulatory approval. This thesis covers these two aspects, stability and process optimisation, for a potential new ingredient; natural red colour, produced by microbial fermentation. The main goal was to design, optimise and scale-up the production process of red pigments by Penicillium purpurogenum GH2. The approach followed to reach this objective was first to establish that pigments produced by Penicillium purpurogenum GH2 are sufficiently stable under different processing conditions (thermal and non-thermal) that can be found in food and textile industries. Once defined that pigments were stable enough, the work progressed towards process optimisation, aiming for the highest productivity using submerged fermentation as production culture. Optimum production conditions defined at flask scale were used to scale up the pigment production process to a pilot reactor scale. Finally, the potential applications of the pigments were assessed. Based on this sequence of specific targets, the thesis was structured in six parts, containing a total of nine chapters. Engineering design of a bioprocess for the production of natural red colourants by submerged fermentation of the thermophilic fungus Penicillium purpurogenum GH2.