Es wird die enantioselektive Synthese eines substituierten Cyclopentanfragmentes beschrieben, welches zur Synthese einer Vielzahl von Diterpenen aus Euphorbiaceae genutzt werden kann. Schlüsselschritt hierbei ist eine intramolekulare Carbonyl-En-Reaktion. In zwei verschiedenen Syntheseansätzen wurde versucht, dieses zu einem Jatrophan-Diterpen umzusetzen. Versuche hinsichtlich einer Nozaki-Hiyama-Kishi-Kupplung werden beschrieben. Im zweiten Ansatz, wurde über eine Ringschlussmetathese bzw. eine Relay-Ringschlussmetathese versucht entsprechende Jatrophane herzustellen. Dies gelang bei einem Substrat, welches eine zweifach substituierte Doppelbindung beinhaltet. Somit konnte ein nichtnatürliches 17-Norjatrophan enantioselektiv synthetisiert werden. / The enantioselective synthesis of a highly substituted cyclopentan, useful for the synthesis of diterpenes from Euphorbiaceae is described. Key step is a intramolecular carbonyl-en reaction. Two different approaches towards Jatrophanes were examined. The first one envisioning a Nozaki-Hiyama-Kishi coupling didn´t work. The second one employed a ring-closing-metathesis which was successful in the case of a disubstituted double bond formed. The use of an relay-ring-closing-metathesis was also examined. The enantioselective synthesis of a nonnatural 17-Norjatrophane is described in all details.

This item contains the agenda, minutes, and attachments for the Faculty Senate meeting on this date. There may be additional materials from the meeting available at the Faculty Center.

Es wird die enantioselektive Synthese eines substituierten Cyclopentanfragmentes beschrieben, welches zur Synthese einer Vielzahl von Diterpenen aus Euphorbiaceae genutzt werden kann. Schlüsselschritt hierbei ist eine intramolekulare Carbonyl-En-Reaktion. In zwei verschiedenen Syntheseansätzen wurde versucht, dieses zu einem Jatrophan-Diterpen umzusetzen. Versuche hinsichtlich einer Nozaki-Hiyama-Kishi-Kupplung werden beschrieben. Im zweiten Ansatz, wurde über eine Ringschlussmetathese bzw. eine Relay-Ringschlussmetathese versucht entsprechende Jatrophane herzustellen. Dies gelang bei einem Substrat, welches eine zweifach substituierte Doppelbindung beinhaltet. Somit konnte ein nichtnatürliches 17-Norjatrophan enantioselektiv synthetisiert werden. / The enantioselective synthesis of a highly substituted cyclopentan, useful for the synthesis of diterpenes from Euphorbiaceae is described. Key step is a intramolecular carbonyl-en reaction. Two different approaches towards Jatrophanes were examined. The first one envisioning a Nozaki-Hiyama-Kishi coupling didn´t work. The second one employed a ring-closing-metathesis which was successful in the case of a disubstituted double bond formed. The use of an relay-ring-closing-metathesis was also examined. The enantioselective synthesis of a nonnatural 17-Norjatrophane is described in all details.

<p>Maximum asset performance is one of the major goals for electric power system managers. To reach this goal minimal life cycle cost and maintenance optimization become crucial while meeting demands from customers and regulators. One of the fundamental objectives is therefore to relate maintenance and reliability in an efficiently and effectively way, which is the aim of several maintenance methods such as the Reliability Centered Maintenance method (RCM). Furthermore, this necessitates the determination of the optimal balance between preventive and corrective maintenance to obtain the lowest total cost.</p><p>This thesis proposes methods for defining the importance of individual components in a network with respect to total interruption cost. This is a first step in obtaining an optimal maintenance solution. Since the methods consider several customer nodes simultaneously, they are especially suitable for network structures that serve many purposes/customers e.g. transmission and distribution networks with more than one load point. The major results are three component reliability importance indices, which are applied in two case studies. The first case study is based on a network in the Stockholm area. The second case study is performed for one overhead line system in the rural parts of Kristinehamn. The application studies demonstrate that the indices are possible to implement for existing electrical networks and that they can be used for maintenance prioritization. Consequently these indices constitute a first step in the overall objective of a maintenance optimization method.</p><p>The computations of the indices are performed both with analytical and simulation based techniques. Furthermore, the indices can be used to calculate the component contribution to the total system interruption cost. The approach developed for the importance indices can be utilized in any multi-state network that can be measured with one performance indicator.</p>

Chapter 1 gives background information on proteases and discusses the concept of protease inhibition as a therapeutic strategy for humans. It introduces the key concept that conformation defines biological activity. It also outlines how proteases almost universally bind their substrate/inhibitors in an extended β-strand conformation. The use of calpain as a prototype protease for the testing of β-strand mimics synthesised later in the thesis is also discussed. Chapter 2 describes how molecular modeling was used to rationalise the structure based activity relationships (SAR) of known calpain inhibitors. Molecular modeling was then used to successfully design a number of acyclic β-strand mimics. The synthesis and testing of eight such inhibitors is described. The most potent β-strand mimic prepared was 2.13. This was determined to have an IC₅₀ of 30 nM against calpain II. Chapter 3 outlines the history and application of ring closing metathesis (RCM) to the synthesis of cyclic compounds. The attempted synthesis of an eight membered cyclic nitrogen to nitrogen conformationally constrained dipeptide is described. The synthesis of a conformationally constrained β-amino acid calpain inhibitor (3.73) is also described. A novel calpain inhibitor motif was designed in Chapter 4. On the basis of this an in-silico combinatorial library of two hundred and eighty eight possible β-strand templates was prepared. Conformational analysis of this library was performed and from this a number of excellent β-strand templates were identified and selected for synthesis. The preparation of ten β-strand templates is described. New microwave irradiation methodology was developed to achieve this. vii The formation of a six-membered catalyst deactivating chelate is also proposed to explain why some dienes fail to undergo RCM. Two methods to circumvent the formation of such a chelate are outlined. The addition of Lewis acid chloro-dicyclohexyl borane to the RCM reaction mixture and chain length alteration are investigated. Chapter 5 describes the design of macrocyclic β-strand mimics using induced fit molecular modelling. The physicochemical properties of these were calculated in-silico. From this analysis a number of Tyr-XX-Gly based and Tyr-XX-Cys based macrocyclic calpain inhibitors were selected for synthesis. The preparation and testing of these are described. In the Tyr-XX-Gly macrocyclic system a number of variables were investigated and numerous SAR implications concluded. Aldehyde 5.14 was identified as the best electrophilic warhead macrocyclic calpain inhibitor with an IC₅₀ against calpain II of 27 nM. The best non-electrophilic warhead macrocycle (5.13) had an IC₅₀ against calpain II of 704 nM. Chapter 6 describes synthetic optimisation for the preparation of calpain inhibitors 2.13, 5.14 and 5.17. Multi-gram quantities of each were prepared. Aldehydes 2.13 and 5.14 were evaluated as anti-cataract agents using in-vivo cataract sheep model. Both of these β-strand mimics were demonstrated to retard cataract development. Macrocycle 5.14 was found to be the most effective, decreasing the rate of cataract development between forty four and forty nine per cent relative to control. Chapter 7 outlines the attempted development of RCM methodology for the chiral synthesis of α-α disubstituted amino acid lactams. In addition, methodology for the stereoselective incorporation of a C-N constrained β-amino acid carbocycle into a peptide or peptidomimetic is described.

L’intérêt pour les hélicènes s’est accru au fur et à mesure que de nouvelles applications pour ce genre de molécules ont été découvertes. Par contre, la recherche dans ce domaine a été limitée par le petit nombre de voies de synthèse de ces molécules, la plupart nécessitant une étape de résolution ou de séparation des énantiomères par HPLC à la fin de la synthèse. Le présent projet de recherche propose d’utiliser la réaction de fermeture de cycle asymétrique par métathèse d’oléfines (asymmetric ring closing metathesis, ARCM) pour effectuer une synthèse d’hélicène à la fois catalytique et énantiosélective. La synthèse énantiosélective du [7]hélicène a été effectuée à l’aide d’une résolution cinétique du précurseur racémique. Au cours de cette synthèse, nous avons été en mesure de démontrer l’efficacité de différents catalyseurs de métathèse chiraux en plus de démontrer l’effet de l’ajout de simples oléfines comme additifs à la réaction. De plus, nous avons formulé une hypothèse expliquant cet effet à l’aide du mécanisme de la réaction. Finalement, nous avons aussi montré l’effet du changement de solvant sur la sélectivité de la réaction. Au cours de ces travaux, nous avons également développé une nouvelle méthode de synthèse de binaphtols à l’aide d’une réaction de couplage oxydatif impliquant un catalyseur de cuivre. À l’aide d’études de réactivité, nous avons été en mesure de démontrer que le métal portait deux ligands N-hétérocycliques (NHC). Nous avons aussi observé que le catalyseur favorisait la formation de binaphtol non symétrique avec un groupement naphtol avec une densité électronique élevée et un autre groupement naphtol avec une faible densité électronique. / The interest in helicenes has increased as new potential applications have been proposed for these twisted conjugated aromatics. However, further research is limited by the lack of methods for the enantioselective synthesis of helicenes. The current traditional syntheses often conclude with a resolution, most often via separation on a chiral stationary phase. This thesis describes the development of new catalytic method for the synthesis of helicenes using ring closing metathesis (RCM) employing highly reactive Ru-based catalysts or commercially available catalysts and microwave heating. Furthermore, an enantioselective variant of the asymmetric ring closing metathesis (ARCM) reactions was developed for the synthesis of enantioenriched [7]helicene via a kinetic resolution protocol. The development of the kinetic resolution involved the preparation and screening of a number of novel chiral Ru-based olefin metathesis catalysts. During these studies, the beneficial effect of simple olefins additives on the selectivity of the reaction was observed and a hypothesis to explain these effects has been proposed. In addition, intriguing solvent effects were also observed. Lastly, this thesis describes the investigation of a new method for the preparation of binaphthol via an oxidative coupling with a novel copper catalyst bearing two N-heterocyclic carbene (NHC) ligands. It was demonstrated that the cationic catalyst allowed for the formation of mixed oxidative couplings between electron rich and electron poor 2-naphthols to form C1-symmetric binaphthol derivatives.

Maximum asset performance is one of the major goals for electric power distribution system operators (DSOs). To reach this goal minimal life cycle cost and maintenance optimization become crucial while meeting demands from customers and regulators. One of the fundamental objectives is therefore to relate maintenance and reliability in an efficient and effective way. Furthermore, this necessitates the determination of the optimal balance between pre¬ventive and corrective maintenance, which is the main problem addressed in the thesis. The balance between preventive and corrective maintenance is approached as a multiobjective optimization problem, with the customer interruption costs on one hand and the maintenance budget of the DSO on the other. Solutions are obtained with meta-heuristics, developed for the specific problem, as well as with an Evolutionary Particle Swarm Optimization algorithm. The methods deliver a Pareto border, a set of several solutions, which the operator can choose between, depending on preferences. The optimization is built on component reliability importance indices, developed specifically for power systems. One vital aspect of the indices is that they work with several supply and load points simultaneously, addressing the multistate-reliability of power systems. For the computation of the indices both analytical and simulation based techniques are used. The indices constitute the connection between component reliability performance and system performance and so enable the maintenance optimization. The developed methods have been tested and improved in two case studies, based on real systems and data, proving the methods’ usefulness and showing that they are ready to be applied to power distribution systems. It is in addition noted that the methods could, with some modifications, be applied to other types of infrastructures. However, in order to perform the optimization, a reliability model of the studied power system is required, as well as estimates on effects of maintenance actions (changes in failure rate) and their related costs. Given this, a generally decreased level of total maintenance cost and a better system reliability performance can be given to the DSO and customers respectively. This is achieved by focusing the preventive maintenance to components with a high potential for improvement from system perspective. / QC 20100810

Examinations administered by the Royal Conservatory of Music (RCM) play a major role in the musical education of many individuals across Canada. The evaluative process needs to be a constructive one in order to ensure its positive impact on students’ musical education. Examiners who are confident and comfortable in their roles as assessors are more likely to provide this ideal environment for the students. Individuals at the dawn of their examining careers are prone to lower confidence and comfort levels due to their inexperience. Yet all music students deserve an optimal examination situation, even from new examiners. Ensuring that an examiner receives proper training will help to increase their confidence and comfort levels while assessing students. This study examined the elements of an examiner’s education, experience and preparation which contributed to higher confidence and comfort levels as they participated in the RCM evaluative process. Ten individuals participated in surveys and interviews. Seven were recent apprentices of the examiner training program and three were senior examiners. Their experiences and insights given in a narrative form shed light on which elements of their background and training benefited them as examiners. According to the participants, varied and extensive pedagogical training, taking exams as students and intensive performance education gave them the most advantages during their early careers as examiners. Regarding the examiner apprenticeship program, participants felt that they would have benefited from more practical experience during the early classroom seminar, additional opportunities to observe students at varying performing levels and more time for discussion with their mentors. These recommendations for background preparation and enhanced training are intended to give examiners greater confidence in their evaluative roles early in their careers, enabling them to provide constructive and effective assessments for students and their teachers.

Examinations administered by the Royal Conservatory of Music (RCM) play a major role in the musical education of many individuals across Canada. The evaluative process needs to be a constructive one in order to ensure its positive impact on students’ musical education. Examiners who are confident and comfortable in their roles as assessors are more likely to provide this ideal environment for the students. Individuals at the dawn of their examining careers are prone to lower confidence and comfort levels due to their inexperience. Yet all music students deserve an optimal examination situation, even from new examiners. Ensuring that an examiner receives proper training will help to increase their confidence and comfort levels while assessing students. This study examined the elements of an examiner’s education, experience and preparation which contributed to higher confidence and comfort levels as they participated in the RCM evaluative process. Ten individuals participated in surveys and interviews. Seven were recent apprentices of the examiner training program and three were senior examiners. Their experiences and insights given in a narrative form shed light on which elements of their background and training benefited them as examiners. According to the participants, varied and extensive pedagogical training, taking exams as students and intensive performance education gave them the most advantages during their early careers as examiners. Regarding the examiner apprenticeship program, participants felt that they would have benefited from more practical experience during the early classroom seminar, additional opportunities to observe students at varying performing levels and more time for discussion with their mentors. These recommendations for background preparation and enhanced training are intended to give examiners greater confidence in their evaluative roles early in their careers, enabling them to provide constructive and effective assessments for students and their teachers.

<p>The Swedish electricity market was de-regulated in 1996, followed by new laws and a new regulation applied to the natural monopolies of electrical distribution systems (EDS). These circumstances have motivated distribution systems operators (DSOs) to introduce more comprehensive analysis methods. The laws, the regulation and additional incentives have been investigated within this work and results from this study can be valuable when developing risk methods or other quantitative methods applied to EDS. This tendency is not unique for Sweden, the results from a comparative study of customer outage compensation laws between Sweden and UK is for example included.</p><p>As a part of investigating these incentives, studies of the Swedish regulation of customer network tariffs have been performed which provide valuable learning when developing regulation models in different countries. The Swedish regulatory model, referred to as the Network Performance Assessment Model (NPAM), was created for one of the first de-regulated electricity markets in the world and has a unique and novel approach. For the first time, an overall presentation of the NPAM has been performed including description of the underlying theory as a part of this work. However, the model has been met by difficulties and the future usage of the model is uncertain. Furthermore, the robustness of the NPAM has been evaluated in two studies with the main conclusion that the NPAM is sensitive toward small variations in input data. Results from these studies are explained theoretically investigating algorithms of the NPAM.</p><p>A pre-study of a project on developing international test systems is presented and this ongoing project aims to be a useful input when developing risk methods. An application study is included with the approach to systematically describe the overall risk management process at a DSO including an evaluation and ideas of future developments. The main objective is to support DSOs in the development of risk management, and to give academic reference material to utilize industry experience. An idea of a risk management classification has been concluded from this application study. The study provides an input to the final objective of a quantitative risk method.</p>