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. / Minutes originally posted on Dec. 3rd, 2013; correction made to minutes and reposted on Feb. 3rd, 2014.

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.

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.

La tesis doctoral que nos acontece, muestra las premisas básicas acerca de la investigación que se realiza sobre la implantación de Mantenimiento Preventivo y Predictivo en industrias de Proceso, gracias al desarrollo y personalización de la metodología RCM a partir del AMFEC. La metodología RCM, sirve para determinar las actividades de mantenimiento reactivas y proactivas, con objeto de optimizar la fiabilidad de los activos industriales. Como antecedentes de la tesis doctoral se comenta que la metodología RCM, sirve para determinar las actividades de mantenimiento reactivas y proactivas, con objeto de optimizar la fiabilidad de los activos industriales. Se basa en la obra de John Moubray, donde se basa la implantación del RCM en 7 preguntas. Los métodos de cálculo de criticidades que actualmente se reflejan en los estudios actuales, denotan la oportunidad de desarrollo de métodos de cálculo donde se tengan en cuenta multitud de variables. El número de ponderación del riesgo (NPR) para cada modo de fallo, viene calculándose en función de tres parámetros gravedad, frecuencia de fallos y detectabilidad, siendo habitualmente valorados de 1 a 10, pero invariantes ante variaciones de parámetros técnicos y de operación. Los planes de mantenimiento, aunque bien definidos por las obras de expertos, se vislumbra la oportunidad de desarrollarlos en función de tipos de equipo, tipos de mantenimiento y criticidad de NPR de modos de fallos. Los estudios de indicadores de gestión, son amplios y muy bien desarrollados, aunque para la detección de repeticiones de incidencias en el Mantenimiento Correctivo, se requiere de una definición o desarrollo. El objetivo principal del presente estudio es ayudar a la implantación de un método de gestión técnica y económica de activos, basado en la actual implantación de RCM, Mantenimiento Peventivo e indicadores de gestión y definir un método para implantar Mantenimiento Preventivo y Predictivo, controlar las incidencias, costes y aplicar soluciones técnico-económicas. / Gardella González, M. (2010). Mejora de metodología RCM a partir del AMFEC e implantación de mantenimiento preventivo y predictivo en plantas de procesos [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/9686 / Palancia

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. 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. 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. / QC 20101130

En el Capítulo I se describe la preparación del esqueleto fenantroindolizidínico quiral. La síntesis se apoya en la aminoalilación estereoselectiva de derivados del 2-(fenantren-9-il)acetaldehído, usando reactivos de alilindio y terc-butilsulfinilamida como inductora quiral. Transformaciones quimioselectivas de la correspondiente sulfinamina homoalílica, permitieron la síntesis de los compuestos deseados en sólo tres operaciones sintéticas. Siguiendo este procedimiento, fue posible preparar la (R)-Tiloforina natural. En el Capítulo II se detallan dos metodologías para la síntesis de la 7-Metoxicriptopleurina quiral. Mientras uno de los procedimientos hace uso de una hidroformilación lineal con un catalizador de rodio como etapa clave, el segundo método se apoya en una metátesis de cierre de anillo (RCM). Por otro lado, en este capítulo se describe la preparación de fenantroquinolizidinas quirales con un centro cuaternario en C14a, así como de sus derivados bencilados en C9 a través del reordenamiento de Stevens. Además, se detalla la citotoxicidad frente a diferentes líneas celulares tumorales de las fenantroquinolizidinas preparadas. Por último, en el Capítulo III se presentan dos metodologías alternativas para la síntesis de fenantridinas 6-sustituidas. El primer método emplea persulfato de amonio y carbonato de potasio, permitiendo la adición deshidrogenante de 1,4-dioxano a 2-isocianobiarilos. El segundo método utiliza perbenzoato de terc-butilo y carbonato de potasio, favoreciendo la adición de diversos éteres. Los estudios mecanísticos realizados sugieren que la cascada radicalaria es un ejemplo de sustitución homolítica aromática promovida por una base en medio acuoso (BHAS).

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. 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. 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. / QC 20101125

La synthèse énantiosélective de la (+)-ambruticine S, un produit naturel antifongique a été effectuée au sein de notre groupe. Trois approches ont été développées pour la synthèse du fragment lactone (cycle A). Ces trois voies d’accès au cycle A ont pour intermédiaire commun le methyl α-D-glycopyranoside déjà porteur du diol requis et disponible commercialement à bon prix. Une désoxygénation de l’hydroxyle en C-4 et l’homologation d’un carbone de la chaine latérale en C-6 ont permis l’obtention du cycle lactonique A. Le deuxième projet est une collaboration entre le groupe Hanessian et ISIS Pharmaceuticals afin de développer de nouveaux oligonucléosides antisens. Les nucléosides antisens [4.3.0]-bicycliques cis et trans ont été synthétisés avec succès à partir d’un monosaccharide naturel commun, L-arabinose, porteur des stéréocentres requis. Un réaction clé d’allylation de Sakurai a permis d’obtenir les diastéréoisomères cis et trans dans des conditions de contrôle de type Felkin-Ahn et de contrôle par chélation respectivement. Les composés bicycliques finaux cibles ont été obtenus par une réaction d’aldol intramoléculaire catalyzéé par la proline, par métathèse de fermeture de cycle et par l’application de la méthode de Vorbrüggen pour la synthèse de nucléosides. / An enantioselective synthesis of the antifungal natural product (+)-ambruticin S has been accomplished in our group. For the synthesis of a ring A lactone fragment, three approaches were developed. They all started from commercially available and inexpensive methyl α-D-glycopyranoside, which already possesses the required diol unit. A deletion of the hydroxyl group at C-4 and a one-carbon homologation of the C-6 side chain furnished the ring A lactone. The second project is an ongoing collaboration between the Hanessian group and ISIS pharmaceuticals to develop new antisense oligonucleosides. The cis- and trans-[4.3.0]bicyclic antisense nucleosides were successfully synthesized from a common natural monosaccharide, L-arabinose, which bears the required stereocenters. A key Sakurai allylation led to the cis- and trans diastereomers under Felkin-Ahn and chelation-controlled conditions respectively. The final bicyclic targets were achieved by a practical proline-catalyzed intramolecular aldol reaction and ring-closing metathesis (RCM) strategy, and application of the Vorbrüggen method for nucleoside synthesis.

Le nouveau contexte de planification du Grand Montréal engendré par la Loi modifiant la Loi sur l’aménagement et l’urbanisme et d’autres dispositions législatives concernant les communautés métropolitaines (L.Q. 2010, c. 10) soulève un grand nombre de questions en matière d’aménagement, notamment par rapport à la gestion de l’urbanisation et plus spécifiquement en ce qui a trait à la notion de périmètre d’urbanisation. Ce nouveau contexte de planification est donc l’élément déclencheur de la présente recherche qui vise à examiner la conception du périmètre métropolitain définie dans le Plan métropolitain d’aménagement et de développement (PMAD) adopté par la Communauté métropolitaine de Montréal (CMM) et qui est entré en vigueur le 12 mars 2012, suite à l’avis favorable du gouvernement du Québec. Cette recherche vise également à examiner l’encadrement du périmètre métropolitain en fonction du contenu des schémas d’aménagement et de développement (SAD) en vigueur des cinq municipalités régionales de compté (MRC) de la Couronne Nord. Plus précisément, il s’agit d’examiner ces documents en ce qui a trait à quatre outils de planification complémentaires, soit les seuils minimaux de densité, les programmes de phasage, les plans de développement de la zone agricole et les demandes à portée collective, ceci afin d’évaluer leur présence et leur contribution à l’atteinte des objectifs poursuivis par le concept de périmètre d’urbanisation. La présente recherche a permis de conclure qu’en matière de conception, le périmètre métropolitain est un outil nettement plus stratégique, comparativement au rôle attribué à cette notion au préalable dans les schémas régionaux, et ce, même considérant le peu de complémentarité entre les périmètres régionaux et ce dernier. En matière d’encadrement, il est possible de conclure que le contexte de planification révèle une situation régionale hautement variable qui illustre le besoin d’une approche de planification commune afin d’atteindre les objectifs du périmètre métropolitain. / The new planning framework created by The Act to amend the Act respecting land use planning and development and other legislative provisions concerning metropolitan communities (S.Q. 2010, c. 10) raises a number of questions about land use issues, notably with regards to growth management and more specifically with the concept of urban growth boundaries. In light of the new planning framework, the aim of this research is to assess the design of Greater Montreal’s Metropolitan Growth Boundary as defined in The Metropolitan Land Use and Development Plan (PMAD) adopted by the Communauté métropolitaine de Montréal (CMM) and which came into effect on March 12, 2012, following approval of the Québec government. This paper will also look at the management of the Metropolitan Growth Boundary within the new planning framework by focusing on the content of The Land Use and Development Plan (SAD) in force in the five Regional County Municipalities (RCM) of Greater Montreal’s North Shore. The regional planning documents will be examined with regards to four complementary planning tools (Minimum Density Thresholds, Phased Growth Programs, Agricultural Development Plans and Demands of Collective Scope) in order to ascertain whether the tools were used and if so, whether they contribute to supporting the Metropolitan Growth Boundary objectives. This research finds that, in terms of its design, even considering the lack of synchronization between regional growth boundaries and the Metropolitan Growth Boundary, the Metropolitan Growth Boundary is now a much more strategic tool than the previous regional incarnations within the regional Land Use and Development Plans. As well, in terms of the management of the Metropolitan Growth Boundary, it is possible to conclude that due to a highly variable planning situation, the regional planning framework highlights the need for a common planning approach in order to achieve the objectives of the Metropolitan Growth Boundary.

Wind power presently plays a minor role in Western Canada as compared to hydroelectric power in British Columbia and coal and natural gas thermal power generation in Alberta. However, ongoing reductions in the cost of wind power generation facilities and the increasing costs of conventional power generation, particularly if the cost to the environment is included, suggest that assessment of the present and future wind field in Western Canada is of some importance. To assess present wind power, raw hourly wind speeds and homogenized monthly mean wind speeds from 30 stations in Western Canada were analyzed over the period 1971-2000 (past). The hourly data were adjusted using the homogenized monthly means to attempt to compensate for differences in anemometer height from the standard height of 10m and changes in observing equipment at stations. A regional reanalysis product, the North American Regional Reanalysis (NARR), and simulations conducted with the Canadian Regional Climate Model (CRCM) driven with global reanalysis boundary forcing, were compared to the adjusted station wind-speed time-series and probability distributions. The NARR had a better temporal correlation with the observations, than the CRCM. We posit this is due to the NARR assimilating regional observations, whereas the CRCM did not. The NARR was generally worse than the CRCM in reproducing the observed speed distribution, possibly due to the crude representation of the regional topography in NARR. While the CRCM was run at both standard (45 km) and fine (15 km) resolution, the fine grid spacing does not always provide better results: the character of the surrounding topography appears to be an important factor for determining the level of agreement. Multiple simulations of the CRCM at the 45 km resolution were also driven by two global climate models (GCMs) over the periods 1971-2000 (using only historic emissions) and 2031-2060 (using the A2 emissions scenario). In light of the CRCM biases relative to the observations, these simulations were calibrated using quantile-quantile matching to the adjusted station observations to obtain ensembles of 9 and 25 projected wind speed distributions for the 2031-2060 period (future) at the station locations. Both bias correction and change factor techniques were used for calibration. At most station locations modest increases in mean wind speed were found for most of the projected distributions, but with a large variance. Estimates of wind power density for the projected speed distributions were made using a relationship between wind speed and power from a CRCM simulation for both time periods using the 15km grid. As would be expected from the wind speed results and the proportionality of wind power to the cube of wind speed, wind power at the station locations is more likely than not to increase in the 2031-2060 period from the 1971-2000 period. Relative changes in mean wind speeds at station locations were found to be insensitive to the station observations and choice of calibration technique, suggesting that we estimate relative change at all 45km grid points using all pairs of past/future mean wind speeds from the CRCM simulations. Overall, our results suggest that wind energy resources in Western Canada are reasonably likely to increase at least modestly in the future. / Graduate / 0725 / 0608 / jtdaines@uvic.ca