Part A. A number of constituents isolated from the ethanol extracts of the leaves of the neotropical species Hernandia Didymantha Donn. These include series of ethyl esters of common C14, C16, and C18 saturated and unsaturated fatty acides. The presence of the ethyl ester of the CI7 fatty acid was indicated by GC-MS. The major non polar component was shown to be nerolidol, 4, an open chain sesquiterpene. Ethnobotanical reports indicate that this sesquiterpene can be used as a natural pesticide and as a transdermal carrier. It is also reported to have anti-malarial activity. The major more polar component was shown to be the tryptamine derivative phenethyl cinnamide, 1. The structure identification was based on comparison of literature data and a two step synthesis (80%) from cinnamic acid and tryptamine. Part B. Chenopodium ambrosioides has been known for centuries as an antifungal and vermifuge remedie. As an infusion, Chenopodium ambrosioides is safe and an effective treatment. The essential oil has been investigated as an organic insecticide by Codena Inc, (St Charles sur Richelieu, Quebec). Registration was initially rejected by the U.S. Environmental Protection Agency because of the known toxicity of one of the components, the monoterpene endoperoxide ascaridol, compound 26. The selective removal of ascaridol was achieved without affecting the other constituents present in the essential oil using either the reaction with zinc in acetic acid or Lindlar Catalyst poisoned with quinoline and hydrogen at room temperature under several atmospheres of pressure. In each case the reduction product is the diol 27. The treated oil still showed excellent insecticidal properties and was approved for use as an organic pesticide by the U.S. Environmental Protection Agency. Considerable efforts were made to optimize the zinc/acetic acid. Unfortunately the optimized procedure still required considerable excess amounts of both reagents. This procedure, although successful from a chemistry and safety point of view, was not economically viable. The second method using the poisoned Lindlar Catalyst and H2 a gave clean reduction of ascaridol without causing reduction of any of the many olefinic components present in the oil. We showed that the catalyst could be recycled at least five times without significant loss of activity. Finally to give a reduced essential oil free of any quinoline, we prepared catalyst in hexane and removed the excess quinoline by washing several times with hexanes. Metallic contaminants in the oil such as lead and palladium which are components of the Lindlar catalyst were effectively removed by stirring the final product with 1% silica gel followed by filtration. This method appears to be inexpensive and thus suitable for commercial production of the safe "Codena Oil". Part C. Literature reports have shown that ursolic acid, a triterpene acid has a positive effect on the elimination of biofilms without any damage to the bacteria function. Since ursolic acid and canophyllol are both pentacyclic triterpenes a series of analogues of canophyllol have been synthesized and characterized by 1H NMR, 13C NMR, MS and their melting points. These compounds in which we made relatively simple changes in the functionality at C-3 and C-28 of the canophyllol molecule, together with a variety of similar betulinic acid compounds are now available for testing as potential controls of biofilm formation. These test will be carried out by the research group of Dr. R. Sattar of the University of Ottawa, Faculty of Medicine. Canophyllol was obtained as the major triterpene component in the bark of Ruptilliocarpon caracolito collected in the Osa Penninsula, Costa Rica.

Part A. Asymmetric synthesis is a growing field in synthetic and medicinal chemistry. Investigations into the use of organocatalysts to engender chirality into organic molecules is of particular interest. Herein we present the study of the efficiency of camphor-based hydrazide organocatalysts in the asymmetric Friedel-Crafts alkylations of N-methylindole with alpha,beta-unsaturated aldehydes. In addition, the applicability of newly designed second-generation camphor-based hydrazide catalysts will be examined.* Part B. The synthesis of trisubstituted olefins represents an intriguing target in organic chemistry. However, the stereocontrolled synthesis of trisubstituted olefins can prove to be difficult, as mixtures of isomers are often obtained. A new methodology is presented herein that allows for the synthesis of single isomer trisubstituted olefins by a palladium catalyzed reaction of alkynyl esters with aryl and vinyl boronic acids under mild reaction conditions by using the simple phosphine ligand Et3P. The process provides alpha,beta-unsaturated esters with complete control of the stereochemistry and regiochemistry at the newly formed the double bond.* *Please refer to dissertation for diagrams.

Antifreeze glycoproteins (AFGPs) are biological antifreezes which are found in the blood serum of arctic fish to help them living in the subzero temperature environments. AFGPs have a common structure composed with a carbohydrate and a peptide moiety by alpha O-linkage and can inhibit ice recrystallization which is useful in medical and commercial applications. The alpha O-linkage is very sensitive to acidic, basic and enzymatic conditions, therefore design and synthesizing AFGP analogues are more attractive. Thermal hysteresis (TH) and IRI activities of AFGPs have no relationship with one another and antifreeze analogues having good IRI and no TH will be good candidates for cryopreservation. Recent reports suggested that hydration numbers and hydration indices of carbohydrates are important factors for its antifreeze activity. Antifreezes having saccharides with high hydration number and hydration index show good IRI activities which are in accordance with antifreeze activities of the saccharides. My research goal was to synthesize 53 which is a truncated version of compound 52 (originally synthesized by Nishimura group) and test its IRI activity. Lactose has a high hydration number and hydration index in disaccharides and shows a good recrystallization inhibition. If compound 53 has good IRI activity, we can then conclude that the IRI activities of AFGP analogues which have disaccharides as their carbohydrate moiety are in accordance with the recrystallization inhibition activities of their carbohydrate moiety themselves. The compound 53 was synthesized through a convergent method. In its carbohydrate component synthesis, the glycosyl donor, benzyl ether protected lactose fluoride 55 was prepared starting from commercially available lactose. The synthesis of peptide component 56 was started from commercially available N-Fmoc-O-t-butyl-L-threonine 61. Coupling reaction between 55 and 56 and then deprotecting the allyl ether to obtain the building blocks 54 and 65. The glycopeptides 68 and 72 were obtained from standard SPPS. Following cleaved 68 and 72 from the solid support, the final products should be obtained from removing their benzyl groups. Unfortunately, the debenzylation could not be achieved, and the final polymer 69 and 73 were not obtained.

L'hydroamination d'alcènes est l'une des méthodologies les plus simples pour la formation de liens carbone-azote. Cependant, l'hydroamination d'alcènes est une transformation difficile peu développée dans la littérature scientifique. L'objectif vise des recherches présentées dans cette thèse était de développer des méthodologies efficaces pour les hydroaminations inter- et intramoléculaires.* Le chapitre 2 présente la tentative de synthèse de la dioscorine à l'aide d'une hydroamination intramoléculaire d'un haut niveau de difficulté pour former le squelette de l'isoquinuclidine, un bicycle tendu (équation 1). Suite à l'échec des différentes méthodologies testées et à la démonstration de la quasi thermoneutralité des hydroaminations d'alcènes intermoléculaires par le groupe de Hartwig, nous nous sommes penchés sur la conception d'une nouvelle stratégie d'hydroamination qui favoriserait thermodynamiquement la formation des produits d'hydroamination. Pour réaliser cette objectif ambitieux, nous avons entreprit le développement d'une séquence tandem, ou la deuxième réaction serait irréversible et produirait un produit plus stable. Avec une telle séquence tandem, les hydroaminations seraient sous contrôle cinétique, une condition essentielle pour le développement d'une méthodologie efficace et générale. Le chapitre 3 présente le développement de la séquence tandem hydroamination de type Cope/réarrangement de Meisenheimer (équation 2). Cette séquence tandem utilise la réactivité des hydroxylamines, préalablement développée par notre groupe de recherche, pour les hydroaminations de type Cope. La séquence tandem développée utilise la réactivité de l'intermédiaire N-oxide 2 pour induire une seconde réaction, soit le réarrangement de Meisenheimer. Il a été démontré que la séquence tandem était efficace pour l'hydroamination intermoléculaire d'alcènes tendus ou actives par un groupe fonctionnel. Des travaux effectués en parallèle ont également démontré la viabilité de la séquence tandem pour des hydroaminations intramoléculaires. *Please refer to dissertation for diagrams.

Intramolecular hydroamination and aminocarbonylation of alkenes are highly desirable synthetic transformations providing access to structures frequently used in medicinal chemistry. Most research efforts currently focus on achieving this reactivity through transition metal catalysis. Our approach involves using hydrazides under thermal (metal-free) conditions to achieve hydroamination or aminocarbonylation upon selection of the appropriate hydrazide substituent (R). Upon substitution when R=Ph, various different compounds were synthesized and isolated in moderate to excellent yields (39 to 98%). Primary and secondary hydrazides pyrrolidines were cyclized and terminal or internal substituted double bonds were tolerated. Morpholine, piperazine, piperidine and azepane moieties were also cyclised with increased heat. This methodology was also consistent with hydroamination on a benzylic olefin. Aminocarbonylation products were obtained in good to excellent yields (52--86%), when R=NH2 and O-tBu. Substituted terminal bonds are obtained with retention of alkene stereochemistry, suggesting a novel concerted reaction pathway. Such reactions are very practical: the starting materials are accessed readily, and both starting materials and products are easy to handle and purify. Such products are also remarkably stable at high temperatures.* *Please refer to dissertation for diagrams.

In this dissertation, two distinct asymmetric reaction types are described: [5 + 2] pyrylium cycloadditions and aldehyde α-functionalizations. Both reactions are mediated by simple, organic primary amine catalysts bearing bulky meta-terphenyl moieties. The main text of this thesis is divided into five chapters outlining the relevant background and the original research. Chapter 1 provides a thorough historical overview of [5 + 2] oxidopyrylium cycloadditions and related asymmetric [3 + 2] cycloadditions. Early discoveries of intermolecular and intramolecular processes, asymmetric precedents, and pertinent frontier molecular orbital considerations are examined. The application of these transformations to the synthesis of natural products and bioactive compounds is also discussed. In Chapter 2, a new method for effecting catalytic enantioselective intramolecular [5 + 2] cycloadditions based on oxidopyrylium intermediates is presented. The development and employment of a dual catalyst system—consisting of a chiral m-terphenyl-containing primary aminothiourea and a second achiral thiourea—are described. Experimental evidence points to a new type of cooperative catalysis with each species being necessary to generate a reactive pyrylium ion pair that undergoes subsequent cycloaddition with high enantioselectivity. Chapter 3 details the successful expansion of the enantioselective [5 + 2] methodology to intermolecular reactions. Highly enantioselective intermolecular [5 + 2] cycloadditions of pyrylium ion intermediates with electron-rich alkenes are promoted by the same dual catalyst system as in Chapter 2. The observed enantioselectivity is highly dependent on the substitution pattern of the 5π component, and the basis for this effect is analyzed in detail using experimental and computational evidence. The resultant 8-oxabicyclo[3.2.1]octane derivatives possess a scaffold common in natural products and medicinally active compounds and are also versatile chiral building blocks for further manipulations. Several stereoselective complexity-generating transformations of the 8-oxabicyclooctane products are described. In Chapter 4, we transition into a literature survey of catalytic asymmetric α-functionalizations of α-branched aldehydes. First, the challenges associated with the efficient functionalization of such substrates, relative to their unbranched counterparts, are detailed. This introduction is followed by a comprehensive overview of catalytic, enantioselective α-heterofunctionalizations: aminations, oxygenations, sulfenylations, and fluorinations. Advantages and drawbacks to previously described methods are analyzed in detail. Chapter 5 recounts our own contributions to this area. A new chiral m-terphenyl-containing primary amine catalyst for the asymmetric α-hydroxylation and α-fluorination of α-branched aldehydes is reported. The products of the title transformations are isolated in high yields and exceptional enantioselectivities within short reaction times. Both processes can be performed at high concentrations and on gram scale. The remarkable similarity between the procedures, combined with computational evidence, implies a possible general catalytic mechanism for α-functionalizations. Promising initial results for α-amination and α-chlorination support this hypothesis. / Chemistry and Chemical Biology

Part one of this thesis describes the production of C4-modified tetracycline derivatives. Our synthetic strategy originally targeted SF2575, a C4-oxygenated tetracycline analog with antiproliferative properties, but was later amended to target antibacterial C4-oxygentaed minocycline analogs. The C4-modified tetracyclines were accessed utilizing a strategy based on the Myers’ platform to 6-deoxytetracyclines (Michael–Claisen cyclization between AB enone 71 and D-ring phenyl esters 44 or 84) in addition to the 4th generation route to tetracycline key AB enone (Michael–Claisen cyclization between B-ring enone 8 and isoxazole 21). The crucial enabling step along this route was the C4-epimerization of Boc bis-carbonate 82 to Boc bis-carbonate 83. Five C4-modified tetracyclines were synthesized and their antibiotic properties were assessed. Part two of this thesis describes the development of a new chiral glycine equivalent for aldol reactions, pseudoephenamine glycinamide ((R,R)-179), and an application of this methodology toward the production of C4-disubstituted monocyclic β-lactam antibiotics. Asymmetric aldolization of pseudoephenamine glycinamide with aldehydes and ketones produces syn-β-hydroxy-α-amino amides 180 with high diastereoselectivities and without the use of protecting groups. These aldol adducts can be transformed into enantiomerically enriched alcohols, ketones, and carboxylates, many of which enable powerfully simplified syntheses of various antibiotics. Utilization of the newly developed methodology enabled access to β,β’-disubstituted-β-hydroxy-α-amino acids. Elaboration of these substrates provided novel C4-disubstitued monobactam analogs, an underrepresented class of β-lactam antibiotics. Four C4-disubstituted monocyclic β-lactam antibiotic candidates were synthesized and their antibiotic activities were assessed. / Chemistry and Chemical Biology

5-Fluorouracil is a broad-spectrum chemotherapeutic for cancer treatment. [18F]5-Fluorouracil, which contains the radioactive isotope fluorine-18, is a tracer for positron emission tomography (PET) imaging and has been applied for determining the location over time of 5-fluorouracil in the bodies of human cancer patients. Potential applications of [18F]5-fluorouracil are for personalized chemotherapy and the development of new cancer treatments. All reported preparations of [18F]5-fluorouracil for human PET imaging have used [18F]F2 gas, which is challenging to produce and handle, and is less desired as a starting material in comparison to [18F]fluoride. This dissertation describes the development and translation of new chemical reactions to produce human doses of [18F]5-fluorouracil from [18F]fluoride. The first preparation of nickel(II) σ-aryl complexes by transmetalation from arylboronic acids was developed. This transmetalation reaction was applied to produce a nickel(II) σ-aryl complex that undergoes oxidative fluorination with [18F]fluoride for the synthesis of [18F]5-fluorouracil. This oxidative fluorination reaction was translated for production of human doses of [18F]5-fluorouracil. Although numerous transition metal-mediated fluorination reactions have been developed, none have previously been translated to enable human PET imaging. / Chemistry and Chemical Biology

Quinones are organic oxidants that play important roles in biological contexts and find wide application in organic synthesis. They are known to be activated toward electron transfer through hydrogen bonding, which has largely been observed for Lewis basic, weakly oxidizing quinones. Comparable activation through H-bonding is more difficult to achieve when more reactive, electron-deficient quinones are used, as these intrinsically weaker Lewis bases are less prone to engage in H-bonding interactions. Herein, we describe the successful application of HBD-coupled electron transfer as a strategy to activate electron-deficient quinones. A systematic investigation of several small-molecule HBDs allowed examination of the effects of H-bonding on electron transfer to o-chloranil, an electron-deficient quinone that lacks the intrinsic reactivity necessary to oxidize many organic substrates of synthetic interest. This study has led to the discovery that dicationic HBDs have an exceptionally large effect on the rate and thermodynamics of these electron transfer reactions. Favorable modulation of the thermodynamics occurs as a result of the stabilization provided to the reduced quinone (Q•–) by the HBD. Electrochemical experiments have allowed quantification of the binding affinity for Q•– to each of the HBDs, as well as elucidation of the binding stoichiometry of the resulting ground-state complex. Monocationic HBDs bind to Q•– with 2:1 stoichiometry, whereas dicationic HBDs bind in a 1:1 complex. Dicationic bis-amidinium salts exhibit significantly improved binding to Q•–, offering more thermodynamic stabilization to this reduced state. The effects of HBDs on the kinetics of electron transfer have also been evaluated under homogenous conditions. Reactions between o-chloranil and ferrocene derivatives exhibit pronounced HBD-dependent rate enhancements, with dicationic HBDs displaying the greatest effect. Relative to neutral dual HBDs, the bis-amidinium salts accelerate the rate of electron transfer by > 1012. Binding stoichiometries within the rate-limiting transition states corroborate the results determined electrochemically, and binding affinity correlates with rate enhancement was observed across the series of HBDs evaluated. Application of HBD-coupled electron transfer in an oxidative lactonization illustrates that this strategy is applicable to catalysis of organic reactions. A dicationic HBD catalyst affords the lactone product in nearly quantitative yield within 24 h, whereas o-chloranil alone was ineffective (< 5% yield). The rates of lactonization with several HBD catalysts correlate well with the thermodynamic and kinetic trends described above. This trend indicates that the rate of the oxidative lactonization is related to the ability of the HBD to promote an electron transfer step. Potential strategies for application in enantioselective transformations and possibilities for future mechanistic investigation are presented. / Chemistry and Chemical Biology

Anion-binding catalysis by dual hydrogen-bond donors such as ureas and squaramides has been demonstrated as a powerful strategy for the development of highly enantioselective transformations involving prochiral cationic intermediates, such as iminium ions, oxocarbenium ions, carbenium ions, and episulfonium ions. The research described in this dissertation explores the ability of dual H-bond donor catalysts to engage chiral cationic intermediates and to induce enantioselectivity in transformations involving such intermediates. In Chapters 1, we provide an overview of the progress and challenges in the development of enantioselective halo- and seleno-functionalization reactions, which proceed via three-membered ring cationic halonium or seleniranium ions. In Chapter 2, we report a highly enantioselective selenocyclization reaction that is promoted by the combination of a chiral squaramide catalyst, a mineral acid, and an achiral Lewis base. Mechanistic studies reveal that the enantioselectivity originates from the dynamic kinetic resolution of seleniranium ions through anion-binding catalysis. Chapter 3 details our discovery of a squaramide-catalyzed enantioselective iodoisocyanation reaction, which represents a rare example in asymmetric intermolecular halofunctionalization of simple olefins. Kinetic studies reveal that [I(NCO)2]–1 anion is the counterion of iodonium intermediate and the dual H-bond donor catalyst aggregates in the resting state. Hammett analysis indicates that the degree of stabilization by catalyst to the iodonium intermediate accounts for both catalysis and enantioselectivity. The reactions developed in Chapter 2 and 3 have therefore extended anion-binding catalysis to reactions involving chiral and stereochemically labile halonium and seleniranium cations. Knowledge learned in these studies will provide valuable guidance to the development of asymmetric transformations involving other chiral cationic intermediates. / Chemistry and Chemical Biology