A synthetic investigation on the chemistry of cyclotryptamine derived natural products, with a particular focus on the synthesis of the trimeric-alkaloid, hodgkinsine. Methodology has been developed to tackle this complex natural product which utilises a desymmetrization approach; this strategy hinges on the development and applications of asymmetric C-N bond forming reactions. Chapter one examines elements of symmetry in natural products, looking in particular at the synthesis of compounds which contain cyclotryptamine functionality. Chapter two contains a brief review of enantioselective desymmetrization paying attention, if possible, on its application in the synthesis of natural products. In the remaining chapters we discuss our own progress and results in our pursuit of an efficient enantioselective total synthesis of hodgkinsine.

<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.

Elatenyne, a brominated C₁₅ acetogenin isolated from the red Laurencia elata marine algae, was originally assigned a pyranopyran structure. Previous total synthesis of the pyranopyran structure has found this assignment to be incorrect. During this work the revised 2,2’-bifuranyl skeleton of elatenyne was suggested, but this skeleton has 32 possible diastereomers. The most likely diastereomer of elatenyne was predicted using computational ¹³C NMR chemical shift calculation in combination with the possible stereochemical outcomes from the proposed biosynthesis. Chapter 1 introduces the structural misassignment of natural products and describes the misassignment of elatenyne as well as a related chloro enyne. The use of computational methods and biosynthetic postulates to aid structure elucidation are also discussed. Chapter 2 describes the first generation synthesis of cross metathesis coupling partners required for the synthesis of elatenyne from D-mannitol. Chapter 3 describes the completed total synthesis of elatenyne, along with three derivatives and the (E)-isomer of elatenyne; itself a natural product. A comparison of the synthetic data with the isolation data for the natural products is presented, as well as comparison with the synthetic material of Kim and co-workers whose concurrent biomimetic total synthesis is also presented. Chapter 4 describes the modular nature of the devised synthetic route to access any diastereomer of elatenyne and its application to related 2,2’-bifuranyl natural products.

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.

The development of drugs and therapeutic agents for combating infections and human malignancies continues to be a forefront area in both academic and industrial research. This is driven by the rapid emergence of multi-drug resistant bacterial strains and accumulating mutations in cancer targets that is quickly rendering our current arsenal of drugs ineffective for these therapies. Unless new drugs with novel mechanisms of action are identified and developed at a faster pace, we face a losing battle in managing these diseases. The first part of this work concerns with the natural product Simocyclinone D8 (SD8). Simocyclinone D8 is an angucyclinone antibiotic that inhibits DNA gyrase with a novel mechanism of action that has been termed competitive inhibition. Simocyclinone D8 was found to inhibit the growth of both Gram-(+ve) and Gram-(–ve) organisms and also inhibit a fluoroquinolone resistant mutant of DNA gyrase. Inspired by the structure and novel mechanism of action that SD8 displays, we synthesized analogues based on the co-crystal structure of SD8 with DNA gyrase. These compounds were found to inhibit DNA gyrase, albeit by a different mechanism of action than that of SD8. We also conducted studies towards the total chemical synthesis of SD8 and made three out of the four fragments in SD8 in decent yields. The second part of this work is focused on the development of a substrate-competitive covalent inhibitor for protein kinase B (AKT). AKT is a valid target for cancer research with two compounds currently in late stage clinical trials. Developing substrate- competitive inhibitors for kinases is a novel approach in targeting them, with very few examples in the literature. This mechanism has been postulated to overcome common resistance mutations that cancer targets harbor. A major drawback in this approach is the low binding affinity for peptide substrates by kinases. We circumvented this problem of affinity by utilizing a covalent mode of binding and synthesized a potent non-peptide active-site directed irreversible compound that inhibits AKT. Further studies on this compound are underway and are expected to yield a compound that can be used as a therapeutic agent or as a probe for AKT.

Ce mémoire décrit les travaux qui ont été réalisés sur la synthèse de l’hodgsonox, un sesquiterpène tricyclique comportant un éther diallylique dans un cycle tétrahydropyranique. Les approches envisagées sont la formation du cycle à cinq puis la formation du tétrahydropyrane et une autre plus convergente qui implique la synthèse des deux cycles en une seule étape. La première partie du mémoire discute de la synthèse d’un précurseur acyclique du cycle à cinq membres, afin de réaliser une réaction de métathèse de fermeture de cycle. Toutefois, les essais n’ont pas été concluants et cette voie a été abandonnée. Dans la deuxième partie, une nouvelle approche impliquant la synthèse d’un bicycle par une réaction de Pauson-Khand a été étudiée. Le précurseur de la réaction de Pauson- Khand a été préparé en 9 étapes (30% de rendement global) à partir du diéthyle tartrate. Le produit de cyclisation a été également obtenu mais il n’a pas été possible par la suite d’introduire le groupement isopropyle. Dans la dernière partie de ce mémoire, les travaux de Lise Brethous sur la synthèse de l’hodgsonox ont été repris. Celle-ci avait montré que le cycle à 5 membres pouvait être obtenu à partir de l’a-acétyl g-butyrolactone et que la formation du bicycle pouvait être réalisée par une réaction catalytique d’insertion d’un composé diazoïque dans un lien O-H. Certaines de ces étapes ont été optimisées et différents tests ont été effectués pour réaliser les dernières étapes de la synthèse de l’hodgosonox, mais sans succès. / This master thesis describes various strategies towards the total synthesis of (+)- and (-)-hodgsonox, a tricyclic sesquiterpene containing a diallylic ether functionality fused into a tetrahydropyran ring. The first synthetic approach involved the formation of the fivemembered ring followed by the formation of the tetrahydropyran moiety. The second approach consisted in the synthesis of both carbon cycles in a single stage. In the first part, is described the synthesis of an acyclic precursor to assemble the fivemembered ring via a ring-closing metathesis reaction. This approach proved unsuccessful and was not pursued. In the second part, is reported a Pauson-Khand cyclization to produce the bicyclic compound. The Pauson-Khand precursor was synthesized in 9 steps (30% overall yield) from diethyl tartarate. The cyclization was successful, but the isopropyl moiety could not be introduced. A former Lebel’s PhD student, Lise Brethous had also worked on the total synthesis of hodgsonox. She established that the 5-membered ring could be prepared from a-acetyl gbutyrolactone and observed the formation of the tetrahydropyran moiety via an OH-insertion reaction with a diazo intermediate. In the last part of this master thesis, some steps from Brethous’s approach were optimized. Unsuccessful attempts to tackle the last steps of the synthesis are also described.

This diploma thesis deals with the use of organocatalysis in an asymmetric allylic substitution reaction of Morita-Baylis-Hillman carbonates by aniline derivatives leading to enantiomerically enriched allylic amines. The first part of the thesis is focused on optimizing the reaction conditions in the organocatalytic reaction with respect to the yields and enantiomeric excesses of the products. In the second part of the thesis prepared enantiomerically enriched allylic amines are used in the cyclization step to give β-lactame cycles that serve as the key intermediates in the total synthesis of Ezetimib as is demonstrated in the final part of the diploma thesis.

Herein is reported the synthesis of molecular probes for action of neuroactive steroids in vitro and in living organisms. In the first part, preparation of enantiomeric pregnane steroids is investigated, ultimately resulting into the total synthesis of ent-progesterone. The chirality of the target molecule is introduced by a highly effective organocatalytic asymmetric Robinson annulation. A new method for the sequential construction of five-membered carbocyclic ring is introduced as the key step. This is composed of substrate-controlled copper-catalyzed conjugate addition followed by radical oxygenation and subsequent thermal cyclization employing the persistent radical effect. The synthesis of truncated neurosteroid analogs is described and their biological activity at the NMDA receptor is compared with the native hormone. In the second part, methodology for specific deuterium labeling of both angular methyls of the 5β-pregnane steroid core is explored. Special attention was paid to the Barton-McCombie deoxygenation as the tool for introduction of the last deuterium atom into the methyl group. Both positions were labelled with total of three deuterium atoms in high isotopic purity.

Limiter la perte d'atomes, privilégier l'usage de catalyseurs, s'abstenir de l'utilisation de réactifs toxiques et éviter les étapes de purifications sont certains des challenges de la chimie moderne. De nombreuses recherches ont donc été consacrées au développement de réactions dites ''tandems''. La réaction d'isomérisation d'alcène permet dans certains cas de générer une toute nouvelle réactivité au sein d'une molécule, en déplaçant une double liaison. Cette réaction requiert souvent un catalyseur de type hydrure avec un métal de transition. Ce mémoire décrit la mise au point de nouvelles réactions ''tandems'' dont l'une des composantes mise en jeu est une réaction isomérisation d'oléfine. Une attention toute particulière a été adressée à la synthèse de vinylboronates notamment par métathèse croisée. Outre les nombreuses applications en synthèse organique qui sont présentées dans ce mémoire, ces intermédiaires peuvent être isomérisés en allylboronates. Ces derniers peuvent réagir avec un aldéhyde pour donner des alcools homoallyliques avec une complète diastéréosélectivité. Ces alcools ont, entre autres, été utilisés en synthèse totale de plusieurs molécules naturelles complexes présentant un motif 2,3-dihydrobenzofurane. / Some of the new challenges of modern synthetic chemistry are: atom economy, employment of catalytic processes, avoidance of toxic reactants and limitation of purification steps. A lot of work has been devoted to the development of tandem reactions. A new reactivity could be generated in a molecule thanks to an isomerisation (or migration) reaction of an alkene. This reaction often needs an hydride specie which comes from a transition metal catalyst. This PhD thesis is about the development of new tandem reactions in which at least one step is an isomerisation of an olefin. A great attention has been dedicated to the synthesis of vinylboronates especially with a cross-metathesis strategy. These intermediates are of great importance in organic chemistry and can be useful in a wide range of reactions. One of those reactions is the transformation of vinylboronates to allylboronates thanks to an isomerisation step. Allylboronates can then react with aldehydes to generate homoallylic alcohols with total diastereoselectivity. These new reactions have found applications in total synthesis of natural molecules with a 2,3-dihydrobenzofuran core.

L'acide arachidonique (AA, C20 :4, n-6) et l'acide docosahexaènoïque (DHA, C22 :6, n-3) sont présents en quantités importantes dans les membranes phospholipidiques. Lors d'un stress oxydant, ces acides gras polyinsaturés sont métabolisés en composés de structure tetrahydrofuranique appelés isofuranes (IsoFs) pour l'AA et neurofuranes (NeuroFs) pour le DHA. Nous nous sommes intéressés à la synthèse de ce type de composés afin d'accéder à de nouveaux biomarqueurs du stress oxydant. Dans ce même objectif, nous nous sommes également penchés sur la synthèse de potentielles structures analogues dérivant de l'acide adrénique (AdA, C22 :4, n-6), que nous avons nommées dihomo-isofuranes (dihomo-IsoFs). / Arachidonic acid (AA, C20 :4, n-6) and docosahexaenoïc acid (DHA, C22 :6, n-3) are phospholipidic membranes polyinsaturated fatty acids. During and oxidative stress, these are metabolized into tetrahydrofuran-containing compounds, known as isofurans (IsoFs) for AA and neurofurans (NeuroFs) for DHA. We were interested in the total synthesis of these compounds in the aim of getting access to novel biomarkers of the oxidative stress. Towards the same goal, we envisaged the total synthesis of potential analog structures coming from adrenic acid (AdA, C22 :4, n-6), that we named dihomo-isofurans (dihomo-IsoFs).