To date, the Nazarov cyclization of a pentadienone has not been a proven methodology towards the construction of the core of the rocaglate natural products. It has been found that this conversion can be achieved using acetylbromide in excellent yield. This represents the first time acetylbromide has been employed in this manner. This methadology provides a very effective and direct route to the core structures of this class of molecules. / text

The use of a Nazarov cyclization for the diastereoselective synthesis of rocaglamide was studied. Chapter 1 discusses the biological activity of the rocaglamide family of natural products and details the previous synthetic work on these compounds. Chapter 2 discusses the approaches taken in the Magnus group for the total synthesis of rocaglamide. Several approaches to the natural product were undertaken. Using a novel acid bromide induced Nazarov cyclization, construction of the C-ring of the natural product was achieved. Attempts to construct the remainder of rocaglamide were ultimately unsuccessful. / text

För en handfull år sedan, i februari 2012, blev en imam och politisk flykting skjuten i Strömsund av en uzbekisk torped. Gärningsmannen dömdes till livstid i mars 2016 och de senare åren har inneburit betydande ökning av flyktingar till Sverige, många med politiska anledningar att fly, och sina egna orsaker att vara oroliga för att bli utsatta för attentat. Detta gjorde idag till den bästa tiden att berätta denna historia, och vi satte oss på att läsa in oss på artiklarna och beställa de dokument som vi skulle kunna behöva. Domar, förundersökningar, rapporter om situationen i Uzbekistan, och internetforum, för att även få en bild av vad de "riktigt kritiska" tyckte om saken. Snart visade det sig att den komiska bild vi haft inte stämde, av torpeden som står på ett tomt torg mitt emot sågverket och stoppar en förbiåkande sparkförare för att fråga om det går några fler bussar mot Östersund den dagen. Som tur var visade sig den riktiga historien vara ännu mer spektakulär.  I denna rapport reflekterar vi över arbetet. De källor vi valde, de källor vi valde bort, hur vi resonerade kring valet av radiodokumentär som genre för berättandet, hur vi arbetade med källkritik och, sist men inte minst, redovisar vi hur vi arbetade med dramaturgi och stilistik. Vi redovisar hur vi använt oss av olika källor och hur vi redovisar även våra resonemang om hur vi ska framställa de personer som medverkar i dokumentären..  Efteråt följer en arbetsdagbok, där processen redovisas dag-för-dag, samt en line-by-line enligt Nils Hansons modell, där varje sakpåstående styrks med källhänvisningar, reportaget helhetsbild bedöms, och extra hänsyn tas till om eventuella kritiserade parter har fått chans att besvara kritiken.

Ce travail a été consacré à l’utilisation d’un sulfoxyde chiral pour effectuer une réaction de cyclisation polarisée de Nazarov asymétrique. Une méthodologie mettant en jeu une condensation de Knoevenagel a été mise au point pour la synthèse de divinylcétones portant un sulfoxyde chiral en position α. Cet auxiliaire a mené à une sélectivité du sens de rotation, appelée torquosélectivité, des orbitales π impliquées dans l’électrocyclisation. Une diastéréodivergence de la pentannelation a pu être développée à partir de substrats dihydropyraniques qui ont mis en évidence une inversion de torquosélectivité selon l’acide de Lewis employé. La cyclisation de différents substrats (hétéro)-aromatiques a aussi montré des torquosélectivités importantes, ceci ayant permis de réaliser la première synthèse non-racémique d’une indanone dérivée de l’acide gallique, composé anticancéreux. Par la suite, une réduction stéréodivergente du carbonyle de la cyclopenténone formé a pu conduire aux carbinols épimères correspondants. Parallèlement, l’oxydation de l’inducteur chiral en sulfone a donné lieu à une allylation avec une totale diastéréosélectivité. Enfin, le clivage de la liaison C-S sous forme de sulfure ou de sulfone a permis d’élaborer, avec un excellent stéréocontrôle, des bicycles dihydropyrane-cyclopentane fusionnés à substituants fonctionnalisés. / This work was devoted to the use of a chiral sulfoxide to perform an asymmetric polarized Nazarov cyclization. A methodology involving a Knoevenagel condensation has been developed for the synthesis of divinylketones bearing a chiral sulfoxide in α-position.This auxiliary led to a rotation direction selectivity, called torquoselectivity, for the orbitals involving during the electrocyclization. A pentannelation diastereodivergence could be developed from dihydropyran-containing substrats that showed a torquoselectivity switch depending to the used Lewis acid.(Hétéro)-aromatic substrates cyclization also showed significant torquoselectivities, this allowed the first non-racemic synthesis of a gallic acid-based indanone, an anticancer agent.Thereafter, stereodivergente reduction of the cyclopentenone carbonyl gave the two corresponding carbinolic epimers. In parallel, the chiral inductor oxidation into sulfone allowed a total diastereoselective allylation. Finally, C-S bond cleavage, as sulfide or sulfone, afforded dihydropyran-fused-cyclopentane rings bearing functionalized substituents with excellent stereocontrol.

Les molécules polycycliques représentent un défi en synthèse organique en raison de leur complexité moléculaire. Elles sont contenues dans de nombreux produits naturels et font l'objet d'intenses recherches pour la découverte de nouveaux principes actifs. L'objectif du projet est de synthétiser de nouvelles architectures polycycliques à partir de substrats facilement accessibles grâce au développement de séquences domino débutant par une réaction d'iso-Nazarov. Cette approche permet d'accéder à des structures complexes très diversifiées avec la création de plusieurs cycles, plusieurs liaisons et plusieurs centres stéréogènes en une seule étape. / Polycyclic molecules represent a challenge in organic synthesis due to the complexity of their backbone. Their presence in many bioactive natural products makes them valuable in drug discovery. The objective of the PhD work deals with the synthesis of polycyclic architectures from easily available substrates via different iso-Nazarov-initiated domino sequences. This one-step method leads to complex and diverse structures with the creation of several cycles, several bonds and several stereocenters.

Le stress électrophile et oxydant est un souci grandissant pour la santé avec l'évolution de nos modes de vie. L'exposition aux ultraviolets, à la pollution, aux substances carcinogènes, à la fumée de cigarette et la pratique intensive d'activités sportives sont autant de causes de stress oxydant pour l'organisme. Ces dommages sont associés à plusieurs maladies et conditions pathologiques telles que cancers, diabètes, infections pulmonaires et maladies neurodégénératives. L'élément de réponse antioxydant (ARE) est un des composants principaux des défenses de la cellule contre ce phénomène. Ce promoteur agit sous le contrôle de Nrf2 (Nuclear factor erythroid 2-related factor 2). Une stratégie populaire pour l'activation de ce mécanisme est l'utilisation d'inducteurs covalents. Ces molécules agissent par la formation de liens covalents avec les nombreux résidus cystéine de Keap1 (Kelch-like ECH-associated protein 1), une protéine chaperonne qui contrôle l'activité de Nrf2. Cette thèse présente la synthèse, les propriétés biologiques et l'étude des relations structure-activité d'une librairie d'électrophiles capables d'induire la transcription des gènes cibles de la voie de signalisation Keap1/Nrf2/ARE. Le premier volet fait état de la comparaison d'une variété d'électrophiles simples pour étudier les préférences de la cible. Le deuxième volet montre que la présence d'une seconde fonction capable de piéger un résidu cystéine fournit des analogues très puissants.

Philosophiae Doctor - PhD / Zeolites are widely used as environmentally friendly solid catalysts or catalyst supports in the refining and petrochemical industries. ZSM-5 zeolite is composed of a three-dimensional medium pore structure (openings of 5-5.5 Å) with high silica content, high temperature stability and strong acidity making it a well-known and an established catalyst for several petroleum derived chemical processes such as cracking, aromatic alkylation, disproportionation, Methanol-to-Gasoline, isomerisation, etc. Nowadays, the synthesis of ZSM-5 zeolite from silica, alumina sources and structure directing agents (templates) is well known. Its synthesis is possible from fly ash, which is a low cost source of both silica and alumina. Fly ash is an inorganic residue resulting from the combustion of coal in electricity generating plants, consisting mostly of SiO₂ and Al₂O₃. ZSM-5 zeolite has not been synthesised from South African coal fly ash and the literature reports that fly ash-based ZSM-5 zeolite was synthesised only with tetrapropylammonium (TPA+) as structure directing agent and required an excessive amount of additional silica. The final ZSM-5 product was reported to still contain fly ash mineral phases after synthesis. This prevents the use of fly ash as a ZSM-5 zeolite precursor. Moreover, the synthesis of a high purity ZSM-5 zeolite from fly ash without additional silica has not been yet reported. This study aimed to synthesise high purity ZSM-5 zeolite from South African coal fly ash without additional silica, and with tetrapropylammonium bromide (TPABr), 1,6- hexanediamine (HDA) or 1-propylamine (PA) as structure directing agent. This aim was achieved by first optimising the synthesis of ZSM-5 zeolite from South African coal fly ash based on a formulation reported in the literature with fumed silica and TPABr as additional source of silica and structure directing agent respectively. Thereafter, the obtained optimum conditions were used to synthesise other fly ash-based ZSM-5 zeolite products by substituting TPABr with HDA or PA. Two routes of treating the as-received fly ash prior to the hydrothermal synthesis were applied in order to improve the quality of the final products or reduce the amount of the fumed silica that was used. The first route consisted of treating the as-received fly ash with concentrated H₂SO₄ in order to remove a certain amount of aluminium and increase the Si/Al in the acid treated fly ash solid residue but also remove some other elements such as Fe, Ca, Mg, and Ti which might have an undesirable effect on the product quality. The acid treated fly ash solid residue was used as ZSM-5 precursor with fumed silica as additional silica source and TPABr, HDA or PA as structure directing agent. The ZSM-5 zeolite products that were synthesised from the as-received fly ash as well as from the H₂SO₄ treated fly ash were treated with oxalic acid solution in order to reduce the aluminium content in the final products. The second route consisted of fusing the as-received fly ash with NaOH and treating the powder fused fly ash extract with oxalic acid solution. The obtained fused and oxalic acid treated fly ash extracts were used as ZSM-5 precursors without additional fumed silica and with TPABr, HDA or PA as structure directing agent. ZSM-5 zeolite was synthesised from the as-received South African coal fly ash not only with the commonly used structure directing agent TPABr but also with two other, lower cost structure directing agents, HDA and PA. The synthesis process did not generate any solid waste as fly ash was used as bulk, which could be a way of valorising South African coal fly ash. However, the final products contained some fly ash mineral phases such as mullite and quartz, and had poor physical and chemical properties compared to a commercial H-ZSM-5 zeolite. The treatment of the as-received fly ash with H₂SO4 resulted in fly ash-based ZSM-5 zeolite products with better physical and chemical properties than those of ZSM-5 zeolite products that were synthesised from the as-received fly ash. Moreover, the post-synthesis treatment of the fly ash-based ZSM-5 zeolite products with oxalic acid resulted in an increase in the Si/Al ratio, offering a post-synthesis route to adjust the acidity of the catalysts. However, mullite and quartz phases were still present in the synthesised products. Alternatively, high purity ZSM-5 zeolite was synthesised from the fused and oxalic treated fly ash extracts without additional silica and with TPABr, HDA or PA as structure directing agent. Moreover, these synthesised fly ash-based ZSM-5 zeolite products had similar physical and chemical properties to the commercial H-ZSM-5 zeolite. The synthesised fly ash-based ZSM-5 zeolite products were used as solid catalysts in the Methanol-to-Olefins (MTO) and Nazarov reactions. The ZSM-5 zeolite products that were synthesised from the H₂SO4 treated fly ash as well as fused and oxalic treated fly ash were successfully used as solid catalysts in the MTO and Nazarov reactions. The ZSM-5 zeolite products that were synthesised from the H₂SO₄ treated fly ash presented a similar trend in MTO and Nazarov reactions depending on the structure directing agent that was used, and the ZSM-5 zeolite that was synthesised with HDA as structure directing agent had the highest MTO and Nazarov conversion. However these catalysts deactivated more quickly compared to the commercial H-ZSM-5 zeolite. On the other hand, the zeolites that were synthesised from the fused and oxalic acid treated fly ash had a high initial MTO conversion equivalent to the commercial H-ZSM-5 zeolite. However, they deactivated after 5 h of time on stream due to diffusional constraints, because of their large crystal sizes. This study developed novel routes in the synthesis of high value zeolites from fly ash. ZSM-5 zeolite was synthesised from fly ash with structure directing agents other that TPA+ cation and had acceptable Brønsted acidity and high initial conversion in MTO and Nazarov reactions. This has not been yet reported in the literature. Moreover, for the first time a high purity ZSM-5 zeolite was synthesised from fly ash without additional silica and had similar properties to a commercial H-ZSM-5 zeolite. This constituted a breakthrough in the fly ash-based ZSM-5 zeolite synthesis procedure, which will promote the valorisation of fly ash through ZSM-5 synthesis due to avoiding the addition of silica source in the hydrothermal gel and preventing the presence of fly ash mineral phases in the final products. This study can have a significant economic and environmental impact in South Africa if the synthesis process is scaled up as it provides a potentially cheap and innovative way of using waste for making a high value green and acid catalyst, namely ZSM-5 zeolite that has several catalytic applications; and it promotes the valorisation of South African coal fly ash that is considered by many as waste material. / National Research Foundation (NRF)

Nous avons développé trois accès synthétiques performants à des cyclopentènones fonctionnalisées en exploitant des réactivités inattendues que nous avons découvertes. Nous avons aussi effectué la première synthèse d’isostères des flavaglines substitués par un groupement formylamino ou mésylamino en position 1b et ainsi démontré l’importance de l’hydroxyl en cette position pour la cytotoxicité de ces composés. De plus, nous avons aussi contribué à l’exploration du potentiel thérapeutique des flavaglines et d’un autre ligand des prohibitines, la fluorizoline, dans le traitement des cancers et de l’inflammation chronique des intestins, ainsi que dans la prévention des effets adverses des chimiothérapies au niveau cardiaque. / We have developed three novel synthetizes of functionalized cyclopentenones based on unexpectedreactivities that we discovered.We also developed the first synthesis of flavaglines isostere substituted by a formylamino or mesylaminogroup on the position of 1b, and demonstrated the importance of a hydroxyl group on this position forcytotoxicity.Moreover, we contributed to the exploration of the therapeutic potential of flavaglines and another ligand ofprohibitins, fluorizoline, in the treatment of cancers and intestinal chronic inflammation, and also in theprevention of the cardiac adverse effects in anticancer treatments.

Over the past decades, functional group manipulation of aromatic precursors has been a common strategy to access new aromatic compounds. However, these classical methods, such as Friedel-Crafts alkylations and electrophilic/nucleophilic aromatic substitutions, have shown lack of regioselectivity besides the use of activators in excess amounts. To this end, numerous benzannulations to form benzo-fused substrates via Diels-Alder (DA), ring-closing metathesis (RCM), cycloaddition, and transition-metal-promoted processes have been reported. Appending a benzene ring directly onto a pre-existing ring is preferable to many classical methods due to the likely reduction of reaction steps and superior regiocontrol. However, many of these benzannulation reactions require air- and/or moisture- sensitive reaction conditions, a last oxidation step, or the use of highly functionalized precursors. Here we disclose three ‘complementary’ intramolecular ring-opening benzannulations to access a large array of functionalized (hetero)aromatic scaffolds utilizing cyclopropenes-3,3-dicarbonyls, alkylidene cyclopropanes-1,1-diesters, and 2,3-dihydrofuran O,O- and N,O- acetals as building blocks. More than 70 benzo-fused aromatic compounds were synthesized using this complementary approach with yields up to 98% and low catalyst loadings. With these benzannulation reactions in hand, we aim to open the synthetic door to a handful of bioactive natural products.

The ability of gold(I) to activate many types of unsaturated bonds toward nucleophilic attack was not widely recognized until the early 2000s. One major challenge in gold catalysis is the control over regioselectivity when there are two or more possible products as a result of complicated mechanistic pathways. It is well know that the choice of ligand can have dramatic effects on which pathway is being followed but very rarely are the reasons for this selectivity understood. The synthesis of new acyclic diaminocarbenes was developed and a study of the ligand effects on the regioselectivity of a gold-catalyzed domino enyne cyclization hydroarylation reaction and a Nazarov cyclization was undertaken. New chiral acyclic diaminocarbenes were also developed and tested along side new C3-symmetric phosphite ligands in an asymmetric intramolecular hydroamination of allenes. Structure activity correlations were developed for the potential use in further rational ligand design. The synthesis of 6a,7-dihydro-5-amino-dibenzo[c,g]chromene derivatives via a gold-catalyzed domino reaction of alkynylbenzaldehydes in the presence of secondary amines was developed. These were sent to be screened for biological activity.