<strong>Chapter 1. Introduction</strong> Scientific background on the development of homogeneous palladium-catalysed cross coupling reactions, focusing on the &alpha;-arylation reaction of enolates and its application to the synthesis of heteroaromatic compounds. The classical syntheses of isoquinolines are discussed, followed by an account of modern methods for their synthesis, including the recent &alpha;-arylation-based methodology developed by the Donohoe group. <strong>Chapter 2. Results and Discussion</strong> 2.1 Studies towards the development of a palladium-catalysed, C–H activation-based &alpha; arylation reaction of ketones, resulting in a C–H bromination/&alpha;-arylation sequence for the synthesis of isoquinolines and isoquinoline N-oxides. 2.2 The one-pot, four component coupling of a ketone, an acetal protected ortho-bromobenzaldehyde or ketone, an electrophile, and an ammonia source is described. This protocol, which ultimately provides C4 functionalised isoquinolines, is later extended to a novel &alpha;,&alpha; heterodiarylation protocol to furnish C4-aryl isoquinolines. 2.3 It is shown that the synthesis of 3 aminoisoquinolines can be achieved via the &alpha; arylation of nitriles. tert-Butyl cyanoacetate can act as a substitute for primary alkyl nitriles, with sequential &alpha;-arylation, in situ functionalisation, decarboxylation and cyclisation reactions provide C4 functionalised 3 aminoisoquinolines. 2.4 The synthetic utility of the &alpha; arylation based methodology for isoquinoline synthesis is exemplified by the total synthesis of the alkaloid berberine in 68% yield over five steps. This is followed by syntheses of pseudocoptisine, palmatine, dehydrocorydaline, and an unnatural fluorine containing analogue, in yields of 46%, 73%, 60% and 37%, respectively. 2.5 Finally, preliminary investigations demonstrate the utility of palladium-catalysed enolate arylation in the synthesis of &beta;-carbolines.

<strong>Introduction – Dearomatisation of Heteroaromatic Compounds</strong> The introduction provides a survey of dearomatisation reaction of heteroaromatics, with a particular focus on pyridines/pyridinium salts and furans. The mechanism, scope, and limitations of various approaches are covered, along with the goals of this project. <strong>Results and Discussion – Dearomatisation of Electron-Deficient Heteroaromatics</strong> This chapter initially explores the asymmetric addition of organometallic nucleophiles to pyridinium salts bearing a chiral counterion. Unfortunately, this approach ultimately proved unsuccessful, due to low observed enantioselectivities, and the low solubility of such salts. The second part of this chapter concerns the attempted asymmetric addition of dicarbonyl nucleophiles to electron-deficient furans, under conditions of chiral phase-transfer catalysts, affording bicyclic products in moderate enantioselectivity. Various alternative routes were also explored for the dearomatisation of furans and benzenoid systems. <strong>Introduction – Hydrogen Borrowing Alkylation Reactions with Alcohols</strong> The introduction surveys the range of methods available for the alkylation of various nucleophiles with alcohols under transition metal-catalysed conditions. Related methodologies are also explored, along with methods for the dehydrogenation of methanol. <strong>Results and Discussion - Rhodium-catalysed Methylation of Ketones Using Methanol</strong> This chapter describes the development of a novel ketone α-methylation using methanol. The development of reaction conditions is explored, followed by expansion of the substrate scope, including limitations of the methylation reaction. Mechanistic investigations support a methanol oxidation, aldol reaction/elimination, conjugate reduction pathway. Investigations into the role of O2 in the methylation reaction proved inconclusive. The utility of the reaction was also expanded via one-pot dialkylation reactions (work by Di Shen), Baeyer-Villiger oxidation of the products, and an attempted asymmetric transfer-hydrogenation. <strong>Results and Discussion - Interrupted Hydrogen Borrowing Reactions of Methanol</strong> This chapter looks to intercept intermediates from the α-methylation reaction. The selective methylenation of ketones is described, and a range of nucleophiles are screened for further functionalisation of ketones. Finally, a number of nucleophiles, including nitroalkanes, amines, peroxides and boronic acids are applied to one pot methylenation/conjugate addition protocols, affording complex products after two steps in one reaction vessel. <strong>Experimental</strong> Full experimental procedures and spectroscopic characterisation of compounds are provided.

The thesis describes synthesis and reactions of allene azides tethered to various functional groups and the application of the discovered cascade transformations towards the synthesis of radianspene J model system. Chapter 1 covers reactions of simple allene azides containing alkyl and cycloalkyl substituents. Thermal rearrangements of these substrates delivered isocyanides and azadienes via the proposed azatrimethylenemethane (ATMM) intermediates. On the other hand, vinylidenecyclopropanes (VDCPs) gave dramatically different products, as described in Chapter 2. A phenyl-substituted VDCP was transformed into an unstable polycyclic compound by a divinylcyclopropane rearrangement. Chapter 3 discusses allene azides tethered to furan, N-substituted pyrroles, and E- and Z-dienes. Depending on the structure of the starting material, products of formal (3+4)- or (2+3)-cycloaddition were formed. Finally, an application of the discovered cyclisation cascade towards total synthesis is described in Chapter 4. A model system of radianspene J was assembled using a key transannular cycloaddition of a macrocyclic allene.

A class of linear diamidines was synthesized for the evaluation as a treatment of Human African Trypanosomiasis. These fused heterocyclic compounds are thiazole[5,4-d]thiazoles and are of interest because the parent compound, 2,5-Bis(4-amidinophenyl)-thiazolo[5,4-d]thiazole HCl salt, which is also called DB 1929, has exhibited a low nanomolar IC50 value against Trypanosoma brucei rhodesiense and has shown selectivity for binding to the human telomere G-quadruplex over that of DNA duplex. A fluoro and a methoxy derivative have been synthesized and are currently undergoing testing for activity and binding affinity. In addition, fluorescence studies of selected diamidines were done to study the effect of structural variation on fluorescence. This data is useful since it can determine what types of moieties are needed to yield a compound that will fluoresce in the higher wavelengths (500 nm and above) of the visible spectrum, which would be advantageous in determining the uptake of the drug in the trypanosome within the endemic areas of Africa with a simple microscope.

During the attempts to carry out Suzuki coupling reactions, the σ-bonded Pd−Caryl benzochalcogenadiazolyl complexes trans-[ClPd(PPh3)2(C6H2BrN2E)] (E = S, Se) were isolated. The corresponding bromo derivatives were also synthesized on purpose to investigate their activity in Stille coupling reactions. A head-to-tail dimer trans- [{ClPd(PPh3)(μ-C6H2BrN2Se)}2] was synthesized from the thermolysis of trans- [ClPd(PPh3)2(C6H2BrN2Se)] in the presence of SeO2. The reduction potentials of the mononuclear and dinuclear complexes were measured by cyclic voltammetry (CV) and square wave voltammetry (SWV). 4,7-bis(2/4-pyridyl)benzochalcogenadiazole ligands were synthesized by Stille coupling reactions and the 1,5-bis(4-pyridyl)naphthalene ligand was prepared by a Suzuki coupling reaction. Reactions of the labile complex [BrRe(CO)4(NCMe)] with 4,7-bis(4- pyridyl)benzochalcogenadiazole ligands in a 2:1 ratio afforded self-assembled molecular rods [{ReBr(CO)4}2(μ-4,7-bis(4-pyridyl)benzochalcogenadiazoles)]. Palladium directed molecular squares [(enPd)(μ-4,7-bis(4-pyridyl)benzochalcogenadiazole)]4[PF6]8 were prepared by reactions of enPd(PF6)2 and 4,7-bis(4-pyridyl)benzochalco-genadiazoles in a 1:1 ratio. The optoelectronic properties of the ligands and the molecular rods were investigated by CV and SWV, and by luminescence spectroscopy. The optical properties of the square complexes were also studied by luminescence spectroscopy. / xvii, 152 leaves : ill. (some col.) ; 29 cm

La situation épidémiologique des maladies infectieuses et parasitaires a eu un impact considérable sur de nombreux changements globaux importants. Ce type de maladies offre continuellement, encore aujourd’hui, de nouveaux défis à la recherche scientifique ; on peut notamment citer l’épidémie du virus ebola, responsable de plus de 11 000 morts en 2015, l'émergence du virus zika au Brésil, les cas de schistosomiase en Corse en 2014, en plus des différents cas d'exposition des patients dans les zones endémiques des pays tropicaux. L’émergence rapide de nombreuses épidémies est notamment due à certains changements sociaux observés au niveau global depuis quelques décennies, caractérisés entre autre par une urbanisation rapide et une communication facilitée entre les continents. Ces différents facteurs ont par conséquent contribué à la conception du profil épidémiologique des maladies infectieuses et parasitaires dans le monde entier. Parmi ces maladies, la schistosomiase est une maladie parasitaire grave causée par trématode Schistosoma mansoni. Actuellement, le praziquantel (PZQ) est le seul médicament capable de traiter toutes les différentes formes de la schistosomiase. Néanmoins, une nouvelle classe de molécule, les imidazolidines, hétérocycles pentagonaux possédants diverses activités biologiques, se sont également révélés actifs contre les Schistosoma. Le premier objectif de cette étude sera donc de déterminer l'activité schistosomicide de nouveaux dérivés thioxo-imidazolidínicos. Dans ce contexte, 24 nouveaux composés 5-arylidène-3-(2-chloro,6-fluoro)-benzyl-2-thioxo-imidazolidin-4-one (PTS) ont été obtenus. Après analyse en composantes principales (ACP), les 11 dérivé les plus (dis)-similaires ont été évalués biologiquement. L’un d’eux, le dérivé indole-imidazolidine LPSF-PTS-14, a montré des résultats supérieurs à la PZQ. En effet, la mort de 100% des vers a été observée après 24 heures à une concentration de 5 g/ml de ce composé, ainsi qu’une cytotoxicité inférieure à 5 ug/ml pour des cellules humaines. Ces résultats ont stimulé le développement d'un modèle de pharmacophore en utilisant le logiciel FLAP. Une évaluation sur le mode d’action de la molécule, ainsi que le développement d’un modèle de prédiction sur la cytotoxicité de ces composés, ont également été développés. Le deuxième objectif portait sur la réalisation d'une étude bibliographique sur le PZQ, permettant d’amener une proposition de modèle sur la relation structure-activité entre les composés chimiques actifs et leur activité biologique. Ensuite, dans une partie qui présente des travaux encore en cours, a été abordé un modèle de pharmacophore et de prédiction d'activité par les méthodes chimiométriques. En ce qui concerne l'infection bactérienne, l'apparition de super bactéries comme par exemple une souche d’Escherichia coli résistante à tous les antibiotiques disponibles, a recentré l'attention sur le développement de nouveaux antibiotiques. Les aminoglycosides, comme la neamine, sont une famille de molécules d’origine naturelle ou semi-synthétique, efficaces contre les bactéries Gram (+) et Gram (-). Le dernier objectif de cette thèse était donc de réaliser la synthèse d'analogues de Neamina, un aminoglycosides, à partir de la N-acétyl-D-glucosamine par l'utilisation de réactions de métathèse. Bien que la synthèse de ces composés n’ai pas pu être menée jusqu’au bout, des progrès importants ont été réalisés sur les voies de synthèse proposées et certains intermédiaires clés ont été obtenus. Une évaluation de la compatibilité de certains groupes protecteurs avec les conditions de métathèse utilisées a également été réalisée, permettant ainsi de proposer une nouvelle voie de synthèse, entamée dans ce travail, mais qui devra être achevée par la suite. / The epidemiological situation of infectious and parasitic diseases has presented significant changes worldwide. This group of diseases continues to pose challenges to prevention programs, such as the ebola virus epidemic, which is responsible for more than 11,000 deaths in 2015, the emergence of the zika virus in Brazil, the cases of schistosomiasis in the region of Corsica, France, in 2014, not including the exposure of patients to endemic areas in tropical countries. This scenario reflects the social transformations that have occurred in the last decades, characterized by accelerated urbanization, communication between continents, among other factors that contributed to the delineation of the current epidemiological profile of infectious and parasitic diseases worldwide. Schistosomiasis mansoni is a severe parasitosis caused by the Schistosoma mansoni trematode. Currently, praziquantel (PZQ) is the only drug capable of treating all the different forms of schistosomiasis. The imidazolidines are represented by a group of pentagonal heterocyclic substances possessing diverse biological activities, among them the schistosomicidal activity. The first objective of this work is the investigation of the schistosomicidal activity of new thioxoimidazolidine derivatives. In this context, 24 new arylidene-3-(2-chloro, 6-fluoro)-benzyl-imidazolidin-2-thioxo-4-one derivatives of (PTS) were obtained. After principal component analysis (PCA), the most dissimilar derivatives were evaluated biologically. The indolyl-imidazolidinic derivative, LPSF / PTS-14, presented greater results than PZQ, 100% death of worms in 24 h at 5 μg / mL, and a toxicity below 5 μg / mL against BALB splenocytes / C mice. These results, combined with low cytotoxicity, stimulated the development of a pharmacophor model using FLAP software, as well as the evaluation of the mode of action by the Michael Addition reaction, and the development of a prediction model for cytotoxicity. The second objective of this work was the accomplishment of a bibliographic study about the PZQ, making it possible to propose a model relating chemical structure and biological activity. Then, in works still under development, a model of pharmacophores will be proposed, and prediction of activity through chemometric methods made. In relation to bacterial infections, the appearance of superbugs, such as the Escherichia coli strain resistant to all antibiotics available in the clinic in 2016, again calls attention to the development of new antibiotics. Aminoglycosides, such as Neamine, are a family of substances of natural or semi-synthetic origin that are effective against Gram (+) and Gram (-) bacteria. The third objective of this work was the synthesis of analogues of Neamine from N- Acetyl-D-glucosamine and the use of metathesis reactions. Although none of the proposed derivatives were synthesized in the allotted time, important advances were made in the proposed routes, and key intermediaries were obtained. It was also possible to develop an evaluation study between the compatibility of protective groups used in derivatives and the occurrence of metathesis reactions. These studies led to the proposition of a synthetic route compatible with the protective groups, initiated at the end of this work, and to be concluded in the future.

The initial aim of this project was to investigate ways of synthesising fused, spirocyclic and linked bicyclic amines. We built on methodology previously developed within our group, employing cyclic dienamides, prepared using the reductive cyclisation of bromoenynamides, as key structural building blocks for further annulation. In the course of investigating the reactivity of these cyclic dienamides, we discovered a new efficient and general route to their synthesis, by employing palladium- or ruthenium-catalysed enynamide cycloisomerisation. A wide range of attractive dienamide scaffolds were synthesised from simple enynamide precursors in rapid, high yielding and operationally simple reactions, underlining their potential utility as an atom-economical source of azacycles. Chiral enynamide substrates were used to generate 1,4-dienamides as a single diastereomer at the newly formed (quaternary) stereocentre. This relay of stereochemistry was exploited not only in the formation of monocyclic dienamides, but even in the formation of a spirocyclic product, and this bodes well for further stereocontrolled synthesis of polysubstituted azacycles. Finally the palladium- and ruthenium-catalysed cycloisomerisation of enynamides was discussed and investigated mechanistically, utilising ¹H NMR spectroscopy, timecourse and deuterium-labelling experiments.

This thesis describes the development of nitro-Mannich/hydroamination cascade reactions for the synthesis of N-heterocycles, which are important motifs found in a variety of biologically active natural products and pharmaceuticals, such as atorvastatin (Lipitor®). Chapter 2 outlines the development of an efficient synthesis of 2,5-disubstituted pyrroles using a nitro-Mannich/hydroamination cascade. Starting from easily prepared N-protected imines and nitroalkyne substrates, a compatible combination of KOtBu (10 mol%) and AuCl3 (5 mol%) was used to afford the desired pyrrole products, after an alkene isomerisation/HNO2 elimination reaction sequence. Chapter 3 describes the extension of this methodology to the diastereo- and enantioselective synthesis of 1,2,3,4-tetrahydropyridine derivatives using a nitroalkyne substrate with an extended carbon chain. The sequential addition of a bifunctional Brønsted base/H-bond donor organocatalyst and a gold complex was found to facilitate the desired cascade reaction affording substituted 1,2,3,4-tetrahydropyridine products. We then established that highly substituted pyrrolidine compounds could be prepared by replacing the nitroalkyne substrate with a nitroallene substrate (Chapter 4). The combination of KOtBu (5 mol%) and a gold catalyst derived from Au(PPh3)Cl (10 mol%) and AgSbF6 (20 mol%) was found to give an efficient diastereoselective synthesis of pyrrolidine derivatives after an additional nitro group epimerisation step. In addition, the nitro-Mannich/hydroamination cascade using nitroallene substrates was developed into an enantioselective variant using the previously employed bifunctional Brønsted base/H-bond donor organocatalyst. This afforded enantioenriched pyrrolidine derivatives.

Iminosugars, carbohydrate analogues in which nitrogen replaces the endocyclic oxygen, have attracted much interest due to their biological activity. Iminosugars inhibit carbohydrate-processing enzymes, thereby affecting many biological processes. Several iminosugars are licensed drugs, with many more compounds undergoing clinical trials. The main subject of this thesis is the synthesis and evaluation of novel iminosugars, particularly the effects of structural modifications on the biological activity of these compounds. Chapter 1 describes the role of carbohydrate-processing enzymes in the body, and explores the therapeutic applications of iminosugars that arise from their activity against these enzymes. Examples of substituted iminosugars are reviewed, and the effects of substituents on enzyme inhibition are described. Chapter 2 concerns methyl-branched swainsonine derivatives. Swainsonine has shown potential as a cancer treatment through its inhibition of &alpha;-mannosidase. The synthesis of (6R)- and (6S)-C-methyl D-swainsonine is described; both compounds were potent and selective &alpha;-mannosidase inhibitors (IC₅₀ 3.8 &mu;M, 14 &mu;M). Although less active than the parent compound, their selectivity for Golgi mannosidase over lysosomal mannosidase may be more important than the absolute value against the model enzyme. Chapter 3 describes the synthesis of a 2-C-methyl L-fucose derivative. A diastereoselective Kiliani reaction allowed the formation of a single lactone bearing a new quaternary centre. The utility of this intermediate in accessing di-branched iminosugars was explored; however, attempts to introduce nitrogen to the lactone lacked the necessary stereoselectivity. Chapter 4 relates to the synthesis of pyrrolidine iminosugars, specifically methyl amides. Two enantiomeric dihydroxyproline amides were synthesised; the D-proline derivative was a potent &beta;-N-acetylhexosaminidase inhibitor (IC₅₀ values of up to 3.6 &mu;M), but the L-enantiomer was completely inactive. Inhibition of N-acetylhexosaminidases is relevant to the treatment of cancer and lysosomal storage diseases, and this work contributed to a wider project investigating the effects of altered stereochemistry on the biological activity of pyrrolidine amides.

Analogues of Antibacterial Natural Products Elizabeth Anne Heaviside, St Catherine’s College, University of Oxford DPhil Thesis, Trinity Term 2012 This thesis is concerned with the synthesis and biological evaluation of structural mimics for the natural products 16-methyloxazolomycin and lemonomycin which display potent biological activity including antibacterial and antitumour activity. Chapter 1 explores methods and approaches to the discovery of new antibacterial drugs and the challenges faced in this respect. It also gives an overview of the properties of the natural products investigated in the following chapters and summarises previous synthetic approaches to these molecules published in the scientific literature. Chapter 2 describes the work carried out towards the synthesis of the diazabicyclo[3.2.1]octane unit of the tetrahydroisoquinoline antitumour antibiotic lemonomycin. The intended retrosynthesis of the natural product led to a 2,5-disubstituted pyrrolidine bearing a 1ʹ-amino functional group; a series of routes were explored for the synthesis of this unit. Using (S)-pyroglutamic acid, strategies using Eschenmoser and thiolactim ether coupling reactions were investigated. A sequence based on the formation of a pyrrolidine ring from the cyclisation of an appropriately substituted oxime ether derived from L-phenylalanine was then implemented but a competing Beckmann rearrangement/Grob fragmentation prevented access to the desired heterocycle. Preliminary investigations were also carried out on the modification of cyclic imines derived from oxime ethers which did not undergo Beckmann rearrangement. Chapter 3 describes the synthesis of a library of densely functionalised tetramic acid and pyroglutamate mimics for the right-hand fragment of 16-methyloxazolomycin, and their coupling with a gem-dimethylamide unit mimicking the middle fragment of the natural product. Tetramates were accessed through the Dieckmann cyclisation of N-acyloxazolidines and were derivatised with various alkyl halides. The pyroglutamates were accessed via the highly diastereoselective aldol cyclisation of N-acyloxazolidines formed by the amide coupling of a threonine derived oxazolidine and β-keto-acids. A series of β-keto-acids were synthesised through the acylation and subsequent ring-opening/decarboxylation reaction of Meldrum’s acid. The formation of right-hand/middle fragment adducts was explored using cycloaddition, alkylation and Sonogashira chemistry before a Wittig protocol led to the formation of adducts (E)- and (Z)- 402 and 403. Biological evaluation of the compounds synthesised in this chapter was carried out using both broth and hole-plate bioassays and active compounds were identified. Of particular note was that the Wittig adducts displayed a higher level of activity against Gram-negative E. coli than either the pyroglutamate or amide motifs alone.