Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

A direct and highly efficient synthesis has been developed for telmisartan, the active ingredient in the widely prescribed antihypertensive drug Micardis®. This approach brings together two functionalized benzimidazoles using a high-yielding Suzuki reaction that can be catalyzed by a homogeneous palladium source or palladium on a solid support. The ability to perform the cross-coupling reaction was facilitated by the regio-controlled preparation of a 2-bromo-1-methylbenzimidazole precursor. The method developed is the first reported selective bromination at the 2-position of a benzimidazole and produces the first major precursor in high yield (93%). The second precursor, potassium (4-methyl-2-propylbenzimidazol-6-yl) trifluoroborate, was prepared from commercially available 4-bromo-2-methyl-6-nitroaniline. An optimized preparation is described that provides a direct three-step process to prepare the benzimidazole and install the borate; this synthetic sequence yields the second precursor with a 90% yield and no isolated intermediates. The two prepared precursors were combined with a third, commercially available methyl-4’-(bromomethyl)-[1,1’-biphenyl]-2-carboxylate, utilizing a short sequence of high yielding reactions to produce the telmisartan with an 83% yield from these advanced intermediates. This new convergent approach provides the active drug ingredient with an overall yield of 74% while circumventing many issues associated with the previously reported processes. Additionally, a flow-based synthesis of telmisartan was achieved with no intermediate purifications or solvent exchanges. The continuous process utilizes a tubular reactor system coupled with a plug flow cartridge, ultimately delivering telmisartan in an 86% isolated yield.

Thesis advisor: James P. Morken / The first highly enantioselective diboration of unfunctionalized terminal alkenes has been developed using a platinum-phosphonite complex. This transformation produces versatile 1,2-bis(boronate)esters that can manipulated chemoselectively to generate a pletheroa of enantioenriched structural motifs. When combined with an appropriate palladium catalyst, the diboration product undergoes an efficient alkyl boron cross-coupling with aryl and vinyl electrophiles producing a wide range of enantioenriched homobenzylic and homoallylic boronates. Alternatively, when the 1,2-bis(boronate)ester diboration product contains an adjacent Z-olefin (derived from diboration of cis-1,3-dienes), allylation to aldehydes can be achieved delivering the syndiastereomer of product exclusively with excellent chirality transfer. Notably, the products obtained from the two described reactions contain an additional boronate moiety, which can be further functionalized through known carbon-boron bond transformations. / Thesis (PhD) — Boston College, 2014. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Lawrence T. Scott / The Scott lab is interested in the functionalization of corannulene as a building block for large polycyclic aromatic hydrocarbons and carbon nanotube end-cap precursors. Toward that end, a new approach to the direct five-fold borylation of corannulene with iridium (I) catalysts via C-H activation has been explored. It has been discovered that the addition of catalytic amounts of base to the reaction mixture promotes the formation of symmetrical penta-borylated corannulene in a good yield on a sizable scale. All byproducts can be easily removed with iterative methanol washes. The present work also provides proof of the reversibility of the direct borylation reaction under the conditions used. Furthermore, modified Suzuki-Miyaura conditions have been employed to synthesize pentakis(2,6-dichlorophenyl)corannulene, a precursor for a [5,5] carbon nanotube end-cap. The reported reactions provide good yields and are scalable. / Thesis (MS) — Boston College, 2011. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Since its discovery in 1979, the Suzuki-Miyaura (SM) reaction has become one of the most widely utilised tools for carbon-carbon bond formation. The palladium catalysed coupling of an organoboron and organohalide compounds proceeds through a three-stage mechanism of oxidative addition, transmetalation and reductive elimination. The transmetalation of boronic acids to a palladium(II) complex has been widely studied. However, very little is known about the transmetalation of boronic esters, which are commonly used as an alternative to unstable boronic acids. Whether these species undergo direct transmetalation or prior hydrolysis to the boronic acid under SM conditions remains unknown. This research aimed to elucidate the mechanism of this cross-coupling process. Initial results under typical SM conditions created a biphasic reaction, promoted by the inorganic base and solvent composition, and showed that the boronic esters and corresponding boronic acid couple at the same absolute rate. This is thought to be a consequence of the formation of a biphasic mixture, rendering phase transfer the turnover-limiting step. The conditions were thus adapted to maintain a monophasic system using an organic soluble base, 2-tert-butyl-1,1,3,3-tetramethylguanidine, enabling the focus to be transmetalation as the turnover-limiting step. These new conditions show a significant difference in both reaction rate and induction period when using a boronic ester compared to the corresponding boronic acid. The use of guanidine was also shown to have an interesting effect on the boronic acid/ester species by 19F and 11B NMR. Further studies found the use of guanidine to create a boronate species, with this species being an aryl trihydroxyboronate or the hydroxyl"ate"-complex of the boronic ester, depending on the presence of diol in the system. Formation of a boronate species was found to be crucial for efficient cross-coupling. When testing weaker bases, unable to form a boronate species, poor SM cross-coupling conversion was found using the newly developed phosphine-free guanidine conditions, showing the importance of the boronate species under these conditions. The results suggest that depending on the strength of base used, the pathway of transmetalation pathway can be switched, between the boronate pathway and the oxo-palladium pathway, under the specific conditions developed.

Palladium-catalyzed carbon-carbon cross-coupling reactions have emerged a broadly useful, selective and widely applicable method to synthesize pharmaceutical active ingredients. As currently practiced in the pharmaceutical industry, homogeneous Pd catalysts are typically used in cross-coupling reactions. The rational development of heterogeneous catalysts for cross-coupling reactions is critical for overcoming the major drawbacks of homogeneous catalysis including difficulties in the separation, purification, and quality control process in drug production. In order to apply heterogeneous catalysis to flow reactors that may overcome this limitation, the catalyst must be strongly bound to a support, highly stable with respect to leaching, and highly active. While the primary role of supports in catalysis has been to anchor metal particles to prevent sintering and leaching, supports can also activate catalytic processes. In this study, by using a xi combined theoretical and experimental method, we probed the effect of graphene as support in the complex reaction cycle of Suzuki reactions. The density functional theory study provides a fundamental understanding of how a graphene support strongly binds the Pd nanoparticles and act as both an efficient charge donor and acceptor in oxidation and reduction reaction steps. Theoretical investigations prove that the Pd-graphene interaction promotes electron flow between the metal cluster and the defected graphene to reduce reaction barrier. The ability for graphene to both accept and donate charge makes graphene an unusually suitable support for multi-step catalytic processes that involve both oxidation and reduction steps. The computer-aided catalyst design with the atomic precise accuracy demonstrates the Pd/graphene catalyst can be further optimized and the first-row transition metal nanoparticles have great potential to replace Pd to catalyze the Suzuki reaction. The corresponding experimental study shows that the method to immobilize the Pd nanoparticles on the graphene is crucial to increasing the reactivity and stability of the resulted catalyst. A comparison of the activation energy and turn over frequency for a series of supported and homogeneous catalysts indicates that exposing palladium-graphene to defect inducing microwave radiation results in dramatically lower activation energies and higher turnover frequencies. Furthermore, the heterogeneity tests demonstrate the Suzuki reactions are carried out on the surface of the immobilized Pd nanoparticle agreeing with the theoretical results. A method to engineer the 2-D graphene support to a 3-D structure to minimize the re-stacking and agglomeration of the graphene lattice will also be introduced in this study.

Living organisms are capable of producing novel terpenoids with both remarkable ease and great selectivity. Many of these natural products exhibit significant biological activity useful for treatment of human diseases, but isolation of highly sought chemicals often results in only minute quantities. Consequently, extraction of these potential therapeutics from natural sources becomes an unrealistic method for obtaining enough material for a thorough biological evaluation, and so synthesizing these compounds becomes essential. Synthesis of terpenoids as potential therapeutics requires exceptional selectivity, especially when corresponding isomers elicit a contrasting biological response. The necessity for such selective syntheses along with the inherent structural complexities of terpenoids, often presents a number of significant challenges for the synthetic chemist. Isolation of the terpenoids pawhuskins A–C and petalostemumol from Dalea purpurea was reported by Belofsky in 2004, and of the collected compounds pawhuskin A was found to exhibit the most significant activity in an opioid receptor assay in vitro. Natural pawhuskin A was extracted from “Purple Prairie Clover” in only a 39 mg quantity and therefore syntheses of the natural product along with several analogues were pursued. Two of the synthesized analogues demonstrated greater potency than pawhuskin A, and interestingly these two isomeric derivatives were found to be selective for two different opioid receptors. However, the synthetic route utilized to form these two derivatives was not very selective for either isomer, and thorough purification proved challenging. Ergo, an alternative approach was sought to ensure the purity of these potential therapeutics. Parallel syntheses affording high selectivity for the key isomeric intermediates as well as a third regioisomer have been developed. The new isomeric intermediate also allowed the synthesis of two new analogues. This work is described in this report along with the formation of additional pawhuskin derivatives. The activity of these analogues as opioid receptor modulators also will be discussed.

This thesis centres on a member of the rural elite, Suzuki Bokushi (1770-1842) of Echigo, and his social environment in Tokugawa Japan (1603-1868). Through a case study of the interaction between one individual’s life and his social conditions, the thesis participates in the ongoing scholarly reassessment of Tokugawa society, which had an apparently rigid political and social structure, yet many features that suggest a prototype of modernity. Bokushi’s life was multifaceted. He was a village administrator, landlord, pawnbroker, poet, painter, and great communicator, with a nation-wide correspondence network that crossed various social classes. His remote location and humble lifestyle notwithstanding, he was eventually able to publish a book about his region, Japan’s ‘snow country’. This thesis argues that Bokushi’s life epitomises both the potentiality and the restrictions of his historical moment for a well-placed member of the rural elite. An examination of Bokushi’s life and texts certainly challenges residual notions of the rigidity of social boundaries between the urban and the rural, between social statuses, and between cultural and intellectual communities. But Bokushi’s own actions and attitudes also show the force of conservative social values in provincial life. His activities were also still restrained by the external environment in terms of geographical remoteness, infrastructural limitation, political restrictions, cultural norms and the exigencies of human relationships. Bokushi’s life shows that in his day, Tokugawa social frameworks were being shaken and reshaped by people’s new attempts to cross conventional boundaries, within, however, a range of freedom that had both external and internal limits.

Abstract: To the history of development of violin pedagogy, the 20th century is a golden age. With the succession and development by various great educators and virtuosos, and through the matured influence by the whole educational realm and environment, many different points of view, theoretic pedagogical systems and pedagogical schools began to appear. Both ¡§Talent Education¡¨ proposed by Shinichi Suzuki(1898-1998) and the pedagogy of ¡§Mental¡VPhysical Theory¡¨ mentioned by Kato Havas(1920- ) belong to one of the main violin pedagogical schools developed in recent years. Today in the field of violin teaching, although various schools have their own space for development, there are many different background factors among them. For example, Suzuki¡¦s pedagogy was influenced by the Eastern and Western cultures, whereas Havas¡¦ pedagogy completely inherited the Western teaching ideas; the vocabulary concept in the linguistics system was employed by Suzuki¡¦s pedagogy as its foundation, whereas Havas¡¦ pedagogy absorbed the theories of psychology as the basis of its pedagogical studies; Suzuki¡¦s pedagogy emphasized teaching materials, environment and the external, reasonable and appropriate succession of experience, whereas Havas¡¦ pedagogy emphasizes the search for the nature of playing action and the coordinating development of physical and mental. Since these cultural and educational backgrounds are different, the teaching principles of these two pedagogies are very different. In view of this, this research paper is divided into seven chapters for detailed studies and analyses, and comparisons are made between the philosophical foundations, teaching ideas, teaching strategies and means of these two pedagogies in order to present the characteristics of these two pedagogies developed under different background factors, and also show the similarities and dissimilarities between them. After detailed comparisons and analyses, we can understand that these two pedagogies are very much different in various aspects. Suzuki¡¦s pedagogy emphasizes the learning development of children. From many places of teaching it appears to have been influenced by the traditional German school. But Havas¡¦ pedagogy focuses on the realm of playing action. Hitherto the ¡§Mental-Physical Theory¡¨ mentioned by her is still a very new pedagogy. From the analytical description of these comparisons, we can understand that although there is a certain extent of difference between them, they perhaps can adopt some parts of the other pedagogy, and supplement the insufficiency of each other so as to achieve better teaching qualities.

Thèse de doctorat : Chimie organique : Strasbourg 1 : 2006. / Titre provenant de l'écran-titre. Bibliogr. p. 179-184.