Thèse diffusée initialement dans le cadre d'un projet pilote des Presses de l'Université de Montréal/Centre d'édition numérique UdeM (1997-2008) avec l'autorisation de l'auteur.

Metal-catalyzed cyclopropanation of olefins with diazo reagents has attracted research interest because of its fundamental and practical importance. The resulting cyclopropyl units are recurrent motifs in biologically important molecules and can serve as versatile precursors in organic synthesis. Since they were first introduced in 2004, Co(II) complexes of D2-symmetric chiral amidoporphyrins [Co(D2-Por*)] have emerged as a new class of catalysts for asymmetric cyclopropanation. These metalloradical catalysts have been shown to be highly effective for asymmetric intermolecular cyclopropanation of a broad scope of substrates with different classes of carbene sources, particularly including electron-deficient olefins and acceptor/acceptor-substituted diazo reagents, with excellent diastereoselectivity and enantioselectivity. This dissertation focuses on exploring the Co(II)-based metalloradical catalyzed enantioselective cyclization reactions. It includes expanding families of catalysts, types of reactions and classes of substrates. With the developed novel approach for chiral porphyrin ligands, a new family of catalysts bearing different electronic and steric characters was synthesized. They turned out to be better catalysts for metalloradical cyclization in many cases, for instance, enantioselectivity of intramolecular cyclopropanation reached up to 99% with new catalyst. Besides the catalyst synthesis, more challenging diazo reagents were successfully employed in both intra- and intermolecular cyclopropanation for direct synthesis of highly functionalized cyclopropanes. Moreover, a tandem radical cyclization process beyond cyclopropanation was discovered, dihydrofuran was generated in a highly selective manner. Last but not least, we developed some novel applications of cyclopropane products, which could potentially lead to more exciting works.

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Typescript (Photocopy) / Includes bibliographies / x, 157, A.xxxi : ill ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Summary: Studies the complexation of various monovalent metal ions by the diaza-crown ether C21 and the cryptands, C211 and C22C5 to form cryptates in various solvents, and investigates the kinetics for the interaction of the pendant arm ligand 1,4,8,11-tetrakis (2-hydroxyethyl)-1,4,8,11-tetraazacyclotetradecane (THEC) with the divalent metal ions Cd2+, Hg2+ and Pb2 / Thesis (Ph.D.)--Dept. of Physical and Inorganic Chemistry, University of Adelaide, 1993

Thesis (Ph. D.)--Ohio State University, 2007. / Title from first page of PDF file. Includes bibliographical references (p. 440-459).

Thesis (doctoral)--Westfälische Wilhelms-Universität zu Münster, 1973. / Vita. Includes bibliographical references (p. 183-191).

Thesis (Ph.D.)--McMaster University, 2003. / Advisor: N. Werstiuk. Includes bibliographical references (leaves 148-156). Also available via World Wide Web.

In recent years, the exploitation of flow technologies as an enabling tool to access unique chemical reactivity has flourished. This dissertation describes the utilisation of these flow methods to access new sets of highly versatile, unstable diazo compounds and their application in coupling reactions. In the first chapter, an introduction into the structure and reactivity of diazo compounds is provided, as well as a discussion of currently available methods for their generation. The second chapter describes the coupling of flow-generated, semi-stabilised diazo compounds with terminal alkynes for the synthesis of racemic di- and trisubstituted allenes, using copper(I) catalysis. The third chapter follows with an account of creating chiral disubstituted allenes by asymmetric coupling of flow-generated, semi-stabilised aryl aldehyde-derived diazo compounds with terminal alkynes, using a copper(I) catalyst and a newly developed pyridine(bisimidazoline) ligand. The fourth chapter describes the generation of new, highly reactive non-stabilised diazo compounds and their reaction with arylboronic acids to allow metal-free ‘protodeboronative’ and ‘oxidative’ C(sp2)-C(sp3) cross-couplings. Finally, the fifth chapter describes the experimental procedures relevant for the results described in Chapters 2-4.

Diazoxide, a non-diuretic benzothiadiazlne antihypertensive agent, is thought to act directly upon the vascular smooth muscle of the resistance vessels to exert its therapeutic effects in hypertension. Diazoxide may exert its antihypertensive action by antagonizing calcium in vascular smooth muscle. Wohl et al. (1967 and 1968) have suggested such an interaction based on experiments conducted with isolated rabbit aortae. The present experiments were designed to investigate the possible cellular locus of the postulated interaction of diazoxide with calcium using the isolated anterior mesenteric vein of the rabbit as a model of vascular smooth muscle. This vein is spontaneously motile and possesses characteristics similar to those observed for vessels of the microcirculation. Diazoxide at 10ˉ⁴ M inhibited spontaneous motility and its associated membrane electrical activity, and caused hyperpolarization in rabbit anterior mesenteric veins examined with a sucrose gap apparatus. Diazoxide also inhibited spontaneous electrical and contractile activity in guinea-pig taenia coli and in estrogen dominated rabbit uterus. In all these tissues, calcium is believed to play an important role in spontaneous electrical membrane activity. Diazoxide failed to affect contractility, rate of spontaneous contractions, or action potential configurations in isolated rabbit heart, even though the action potential in heart tissues possesses a definite calcium current component. Diazoxide reduced contractions induced in the mesenteric vein by electrical stimulation of the smooth muscle itself or by excitation of the nerve endings within the vein. Various drugs were chosen for their ability to contract the mesenteric vein in different ways. Noradrenaline contracts vascular smooth muscle even when the tissue Is depolarized with ouabain Diazoxide failed to inhibit noradrenaline contractions in the depolarized vein, but showed the characteristics of a competitive inhibitor of noradrenaline in normally polarized veins. Diazoxide was also capable of inhibiting contractions to serotonin and procaine, agents which require membrane polarization to initiate contraction. The inhibitory effect of diazoxide was not observed to be modified in solutions containing high concentrations of calcium. Diazoxide was tested upon the contractile responses to calcium In veins depolarized in K⁺ Ringer solution. Examination of the resultant dose response curves showed that diazoxide inhibited calcium contractions ln a reversible, non surmountable manner. Hydrochlorothiazide had no effect upon calcium induced contractions. Diazoxide antagonizes drug induced contractions only if a polarized membrane is present. Calcium Induced contractions in depolarizing solutions were inhibited in an apparently Insurmountable manner, while drug responses in polarizing solutions were inhibited by diazoxide in a surmountable manner. In addition, action potentials from rabbit heart were unchanged whereas, the apparently calcium spike mediated electrical activity of certain smooth muscles is inhibited. It is concluded that diazoxide affects the membrane of vascular smooth muscle to reduce excitability of the tissue to drugs or electrical stimuli. It is possible that cell membrane bound calcium could be the locus of action of diazoxide and that this agent modifies membrane calcium to cause increased membrane stability. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Graduate

This thesis is centered around the use of flow chemistry to enable cycles in order to increase reaction or process efficiency. Chapter two describes the development of a pseudo-catalytic cycle in space; a strategy to achieve formal sub-stoichiometric loading of a chiral auxiliary. By telescoping auxiliary attachment, asymmetric transformation and auxiliary cleavage into one continuous flow process, coupled with separation of product and recovery of auxiliary, the reuse of the auxiliary can be automated by returning the recovered auxiliary back to the start of the process to achieve ‘turn-over.’ An asymmetric hydrogenation mediated by Oppolzer’s sultam is used to demonstrate this concept. In order to achieve cycles such as the one discussed in Chapter two, the ability to telescope reactions in flow is paramount. However, solid handling challenges are frequent when transitioning to flow, leading to limitations in potential solvents or conditions in order to achieve homogeneity. This complicates the ability to telescope reactions, and to address this challenge the work in Chapter three focuses on the development of a general and simple solution to negate precipitation problems arising from precipitation of base·HX salts, a frequent reaction by-product of common reactions. By using bases that form low- to moderate-melting salts upon protonation, precipitation is precluded while reactions are performed above the melting point of the base·HX salt. This is shown to be applicable for a wide variety of substitution reactions and allow facile reaction telescoping. Chapter four focus on overcoming severe scope limitations in palladium catalyzed transformations that result when rapid background reactions deplete the nucleophilic coupling partner faster than catalyst turnover. This work starts with real-time MS investigations to investigate why slow addition of Grignard or organolithium nucleophiles facilitates substantial scope expansion in Kumada-Corriu or Murahashi cross-couplings, and then uses the information gleaned from these studies to significantly expand the accessible scope of palladium catalyzed aryl halide–diazo cross-coupling, through controlled addition of the diazo reagent at a rate that approximates aryl halide oxidative addition, in combination with on-demand flow synthesis of non-stabilized diazo reagents. Chapter five focuses on improving efficiency in the collection of kinetic data in flow, by developing a reaction cycling reactor. Conversion over time data is obtained by passing a discrete reaction slug back-and-forth between two residence coils, with analysis performed each time the solution passes from one coil to the other. In contrast to a traditional steady state flow system, which requires >5 X the total reaction time to collect data, this reactor design collects all the data during a single reaction. Multiple reactions can also be monitored at the same time by performing multiple reactions as sequential slugs in the reactor. The reactor is demonstrated by application to a wide variety of transformations and different methods of kinetic analysis.