Olefin metathesis is a valuable synthetic tool, widely used in several fields of science. Due to the importance of this transformation several contributions have been made in this field in order to understand mechanistic aspects, reactivity and applicability of this process. In this topic, ruthenium indenylidene complexes have shown great activity and stability in metathesis, making them very valuable pre-catalysts. However, several aspects of these pre-catalysts have not been evaluated yet. For example, even though reports of active second generation ruthenium indenylidene complexes bearing bulky N-heterocyclic carbenes are present in the literature, no studies have been done to understand how steric hindrance affects the process. For these reasons, [RuCl₂(IPr*)(PPh₃)(3-phenylindenylidene)] (IPr*-PPh₃) and [RuCl₂(IPr*)(Py)(3-phenylindenylidene)] (IPr*-Py), bearing the very bulky ligand, IPr* have been synthesised and compared with [RuCl₂(IPr)(PPh₃)(3-phenylindenylidene)] (IPr-PPh₃) and the new [RuCl₂(IPr)(Py)(3-phenylindenylidene)] (IPr-Py). Another important aspect, presented in this thesis, is the investigation of the stability of indenylidene pre-catalysts in alcohol solvents. Surprisingly, several different decomposition processes occur depending on the starting complex and the alcohol used. Mechanistic investigation into this decomposition, allowed us to develop a better understanding of this process, and to predict the decomposition product based on the environment. In particular, this study revealed that [RuCl(η⁵-3-phenylindenyl)(PPh₃)₂] (Eta-5) is accessed from [RuCl₂(3-phenylindenylidene)(PPh₃)₂] (M₁₀) via a novel indenylidene to η⁵-indenyl rearrangement. This formal decomposition product has been found to be active in at least 20 different catalytic transformations, rendering it a versatile catalytic tool.

Thesis (MSc (Chemistry and Polymer Science))--Stellenbosch University, 2008. / N,N-dialkyl-N-acyl(aroyl)thiourea ligands form stable chelated complexes in a cis configuration with the platinum group metals. Such chelated complexes are generally considered substitutionally “inert” in solution, however, it was found that cis-bis(N,Ndialkyl- N-acyl(aroyl)thioureato)M(II) complexes (M = Ni(II), Pd(II) or Pt(II)) readily undergo facile chelate metathesis reactions in solution at room temperature. Upon mixing two different parent complexes, a mixed-ligand product formed in solution, with an equilibrium, or steady state, between the two parent complexes and the mixed-ligand product being attained after a period of time: M(LA)2 + M(LB)2 M(LA)(LB). All three complexes remained in solution even with a ten-fold excess of one parent complex. The presence of the mixed-ligand products in solution was confirmed by liquid chromatography-mass spectrometry (LC-MS), nuclear magnetic resonance (NMR) spectra and a crystal structure of the mixed-ligand complex cis-Pd(L3-S,O)(L4-S,O). Though a number of attempts were made, it was not possible to either isolate or synthesise the mixed-ligand complexes exclusively. The equilibrium distribution and the rate of the metathesis reaction were influenced by a number of factors, including the central metal ion, the substituents on the complexed ligands and the reaction medium. In addition to these, a number of other factors, some unexpected, also played a role in the rate of the reaction. Initial concentration of the parent complexes, the age of the solutions upon mixing and the presence of impurities or additives all contributed to the overall rate of reaction. The results from these rate studies highlighted the necessity for extensively purified compounds. In addition to chelate metathesis reactions, the exchange between a cis-Pd(L-S,O)2 complex and an unbound HL ligand in solution was also investigated. Again, even with an excess of unbound ligand, all three possible complexes were present in solution. It has been shown previously that these complexes undergo a photoinduced cis-trans isomerisation under intense light, and it has been proposed that the reverse trans-cis process, which occurs in the dark, may be a metathesis reaction. In light of this, the relationship between these chelate metathesis reactions and the reverse trans-cis reaction was briefly investigated. Though the metathesis reactions were a general phenomenon in the Ni(II), Pd(II) and Pt(II) complexes of the aforementioned ligands, the experiments focused mainly on the cis-Pd(L-S,O)2 complexes due to the favourable timescales of their metathesis reactions. The primary technique to observe these reactions was reversed-phase high-performance liquid chromatography (rp-HPLC). The timescales involved in the cis-Pd(L-S,O)2 metathesis reactions as well as the stability of the Pd(II) complexes under the HPLC conditions made this technique ideal.

The Germanic initial sound combination wr (e.g. in *wrītan 'write') has not been preserved in any standard language. In the Scandinavian languages the development of this sound combination has resulted in five different initial sounds or sound combinations, namely rw, r, w, br and vr. The aim of this study is to describe the occurrence of these sound combinations, and to explain their age and origin. A limited number of words, mainly from Swedish dialects, has been investigated. The Swedish material has been assembled in a collection that has largely also been mapped, and so has a collection of Norwegian dialect material. The result shows that br is frequent in the Swedish dialects and that it also occurs in Trøndelagen and Østlandet in Norway, and on Jutland. R is widespread in Norway and occurs in Sweden in some words in Norrland, Dalarna, Värmland, Dalsland, Uppland and on the island of Gotland. Rw has been documented in Upper Dalarna, and w in the same area, as well as in the Kalix dialect in northernmost Sweden. The author demonstrates that the Norwegian loss of w might have started already in the 6th century in western Norway. The loss on Gotland is independent and can be demonstrated in Old Gutnish. The metathesis rw is found in Swedish and Norwegian 13-14th century sources from Uppland, Västmanland, Östergötland and southeastern Norway. The developments wr &gt; r and wr &gt; rw probably have their roots in a difference between the west Norwegian wr and the east Norwegian and Swedish war which is documented from PrimScand times. W is a secondary development of rw. The change wr &gt; br can be dated by place-name material to the early 15th century. The change wr &gt; vr appears to have taken place at approximately the same time. The author demonstrates that the result, wr &gt; br or wr &gt; yr, is apparently governed by certain phonetic factors. The failure of the Germanic wr to survive depends on the combination being phonetically complex. The risk that w would be lost was therefore considerable. However, differentiating forces worked for its retention. All developments emanating from wr, apparently disparate, can be seen as features of a larger process where a general linguistic tendency towards a weakening of sounds is confronted by conservative forces, with the above results as a consequence. / <p>Doktorsavhandling vid Uppsala universitet 1991</p>

Cardanols are more and more used in the industry of polymers, resins, coatings, friction materials, etc. At right conditions, these lipid-like chemicals can undergo metathesis reaction. The main aim of the diploma thesis is an analysis of products of cardanol metathesis by HPLC-MS/MS. Standard 3,3'-hexadec-8-en-1,16-diyldiphenol, one of the main products of cardanol metathesis, was prepared for quantitative HPLC analysis. The standard was prepared in two steps. The first step was cardanol ethenolysis to give 3-(non-8-enyl)phenol. The second step was self-metathesis of 3-(non-8- enyl)phenol to give 3,3'-hexadec-8-en-1,16-diyldiphenol. The standard was characterised by HPLC/MS, MS/MS, EI-MS, UV/VIS, IR, Raman a NMR spectroscopy. The second part of the thesis is dedicated to the study of a mechanism of double-bond localization method in long chain hydrocarbons by acetonitrile APCI-MS. The formation of adducts [M + 55]+ , which are the key substances of this method, was studied using simple alkene models by MS and MS/MS. At the end, the structure and the mechanism of the formation of adducts [M + 55]+ were suggested. Key words: Cardanol, olefin metathesis, HPLC-MS, double-bond localization, APCI, acetonitrile

Les synthèses par sol-gel non-hydrolytique (SGNH) d'oxydes mixtes Re-Si-Al et Mo-Si-Al sont présentées comme une voie innovante pour la préparation en une étape de catalyseurs hétérogènes de métathèse. Les catalyseurs supportés à base d'oxyde de molybdène sont intéressants du fait de leur faible coût d'achat, de leur résistance mécanique et de leur bonne activité à température modérée. Les catalyseurs supportés à base d'oxyde de rhénium sont connus pour être très actifs et sélectifs même à température ambiante. Cependant ils sont chers et la sublimation de l'oxyde de rhénium pose problème lors de leur synthèse. La synthèse utilisée est basée sur la réaction en une étape des précurseurs chlorés (ReCl5 ou MoCl3, SiCl4, AlCl3) avec du diisopropyléther (iPr2O) à 110 °C dans le dichloromethane. Le faible coût des précurseurs, l'absence de modificateurs de réactivité et de templates ainsi que la simplicité de synthèse rendent le procédé SGNH particulièrement attractif. Les catalyseurs oxydes mixtes obtenus présentent des compositions bien contrôlées, des textures mésoporeuses et avec des densités en sites acides élevées. La caractérisation par DRX, XPS et ToF-SIMS montre que les catalyseurs peuvent être décrits comme une matrice silice-alumine amorphe avec des espèces de surface Mo et Re bien dispersées. Pour les catalyseurs à base de Re, dans les compositions riches en silice, des pertes de rhénium ont été observées durant la calcination. Cette perte de rhenium peut être évitée en augmentant le taux d'alumine dans la composition. De plus, nous avons montré que la sublimation de Re, au cours de la calcination dans les compositions riches en silice, n'a pas lieu quand toutes les étapes du procédé (synthèse, lavage, séchage et calcination) sont réalisées en l'absence d'humidité. Nous avons étudié l'influence de la composition sur la texture, la structure, l'acidité et les propriétés de surface, qui sont corrélées aux performances catalytiques. Les performances des catalyseurs Re-Si-Al et Mo-Si-Al ont été évaluées en métathèse du propène et en métathèse croisée de l'éthène et du trans-2-butène. Les catalyseurs SGNH sont comparés à des catalyseurs avec des compositions similaires préparés par d'autres méthodes (imprégnation, thermal spreading, flame spray pyrolysis). Les catalyseurs préparés par SGNH présentent une très bonne activité spécifique en métathèse. / The non-hydrolytic sol-gel synthesis (NHSG) of Re-Si-Al and Mo-Si-Al mixed oxides was proposed as an innovative one step route to heterogeneous olefin metathesis catalysts. Supported molybdenum oxide catalysts are receiving much attention as a result of their relatively low price, robustness and good activity at low temperature. Supported rhenium oxide catalysts are known to be highly active and selective even at room temperature. However, they are expensive and moderately stable because of the sublimation of the rhenium oxide. The NHSG synthesis used in this work is based on the one pot reaction of chloride precursors (ReCl5 or MoCl3, SiCl4, AlCl3) with diisopropylether (iPr2O) at 110 °C in dichloromethane. The simplicity of NHSG makes it attractive: multi-step procedures, expensive precursors, or reactivity modifiers are not needed. The mixed oxide catalysts exhibited well-controlled compositions and mesoporous textures, with high acid site densities. XRD, XPS and ToF-SIMS showed that the catalysts could be described as an amorphous silica-alumina matrix with well-dispersed Re or Mo surface species. In the case of Re-based catalysts, rhenium losses by sublimation during calcination were observed for the silica-rich formulations. The loss of rhenium could however be avoided by increasing the Al content. More importantly we demonstrate that Re sublimation during calcination of silica-rich formulations is suppressed when the whole preparation procedure (synthesis, washing, drying and calcination) is carried out in the absence of water. Particular attention was devoted to the study of the influence of the composition on texture, structure, acidity and surface properties, which were correlated with the catalytic performances. The performance of selected Re-Si-Al and Mo-Si-Al catalysts was evaluated in the metathesis of propene and in the cross-metathesis of ethene and trans-2-butene. The NHSG catalysts were compared to catalysts of similar compositions prepared by other more methods (impregnation, thermal spreading, flame spray pyrolysis). The catalysts prepared by NHSG have a high specific activity in the metathesis reaction.

Thesis advisor: Amir H. Hoveyda / Chapter 1. Mechanistic Insights and Factors Influencing Polytopal Rearrangements in Stereogenic-at-Ru Carbenes. Herein, the mechanistic elucidation of the stereochemical inversion in stereogenic-at-Ru carbene complexes through olefin metathesis (OM) and non-olefin metathesis (non-OM) based polytopal rearrangements is provided. Our investigations involve the isolation and characterization of previously hypothesized higher-energy (e.g., endo-anti) and lower-energy (e.g., exo-anti) diastereomers, and their interconversion under thermal and/or acid-catalyzed conditions is demonstrated. Furthermore, our computational efforts highlighting the importance of the anionic ligands, due to their critical role in trans influence, dipolar interactions, and e-e repulsions, in polytopal rearrangements are reported. Finally, the positive influence of H-bonding in OM and non-OM processes is also rationalized. (a) Khan, R. K. M.; Zhugralin, A. R.; Torker, S.; O'Brien, R. V.; Lombardi, P. J. and Hoveyda, A. H. "Synthesis, Isolation, Characterization, and Reactivity of High-Energy Stereogenic-at-Ru Carbenes: Stereochemical Inversion Through Olefin Metathesis and Other Pathways," J. Am. Chem. Soc. 2012, 134, 12438-12441. (b) Torker, S.; Khan, R. K. M. and Hoveyda, A. H. "The Influence of Anionic Ligands on Stereoisomerism of Ru Carbenes and Their Importance to Efficiency and Selectivity of Catalytic Olefin Metathesis Reactions," J. Am. Chem. Soc. 2014, 136, 3439-3455. Chapter 2. Highly Z- and Enantioselective Ring-Opening/Cross-Metathesis of Enol Ethers Through Curtin-Hammett Kinetics. The first instances of Z- and enantioselective Ru-catalyzed olefin metathesis are presented. Ring-opening/cross-metathesis (ROCM) reactions of oxabicyclic alkenes and enol ethers and a phenyl vinyl sulfide are promoted by 0.5-5.0 mol % of enantiomerically pure stereogenic-at-Ru complexes with an aryloxy chelate tethered to the N-heterocyclic carbene. Products are formed efficiently and with exceptional enantioselectivity (up to >98:2 enantiomer ratio). Surprisingly, the enantioselective ROCM reactions proceed with high Z selectivity (up to >98% Z). Moreover, reactions proceed with the opposite sense of enantioselectivity versus aryl olefins, which afford E- isomers exclusively. DFT calculations and deuterium-scrambling experiments, indicating fast interconversion between endo- and exo-Fischer carbene diastereomers, support a Curtin-Hammett situation. On this basis, models accounting for the stereoselectivity levels and trends are provided. Furthermore, the correlation of Fischer carbene character to the observed chemoselectivity in ROCM with enol ethers is also disclosed. Finally, a general proposal for the substrate-controlled Z selectivity in OM is also discussed. (a) Khan, R. K. M.; O'Brien, R. V.; Torker, S.; Li, B. and Hoveyda, A. H. "Z- and Enantioselective Ring-Opening Cross-Metathesis with Enol Ethers Catalyzed by Stereogenic-at-Ru Carbenes: Reactivity, Selectivity, and Curtin-Hammett Kinetics," J. Am. Chem. Soc. 2012, 134, 12774-12779. (b) Torker, S.; Koh, M. J.; Khan, R. K. M. and Hoveyda, A. H. "Origin of Z selectivity in Olefin Metathesis Reactions of Certain Terminal Alkenes Catalyzed by Typically E-Selective Ru Carbenes," manuscript submitted. Chapter 3. A New Class of Highly Efficient Ru Catalysts for Z-Selective Olefin Metathesis. Herein, we outline a general design for Z-selective OM, which led to the development of a new class of stereogenic-at-Ru carbene complexes (Ru4-9). Furthermore, we demonstrate that the newly developed dithiolate complexes Ru4b and Ru5 efficiently promote high activity and selectivity in ROMP reactions of norbornene and cyclooctene. Notably, the catechothiolate Ru4b catalyzes Z-selective ROCM with a broad scope of alkenes involving various functional groups (e.g., alcohols, enol ethers, vinyl sulfides, amides, heterocycles, and conjugated 1,3-dienes). More importantly, we disclose that the catecholate complex Ru4a is kinetically non-selective in OM and readily decomposes in the presence of mildly acidic moieties (e.g., alcohols and CDCl3). Subsequently, Ru9 is developed to efficiently promote highly Z-selective CM of a diol cross-partner with a wide range of alkene substrates. Most remarkably, the aforementioned protocol is employed in two natural product syntheses and the OM-based Z-selective cracking of oleic acid, which is unprecedented with existing Ru-carbenes and Mo/W-alkylidenes. (a) Khan, R. K. M.; Torker, S. and Hoveyda, A. H. "Readily Accessible and Easily Modifiable Ru-Based Catalysts for Efficient and Z-Selective Ring-Opening Metathesis Polymerization and Ring-Opening Cross-Metathesis," J. Am. Chem. Soc. 2013, 135, 10258-10261. (b) Koh, M. J.; Khan, R. K. M.; Torker, S. and Hoveyda, A. H. "Broadly Applicable Z- and Diastereoselective Ring-Opening/Cross-Metathesis Catalyzed By a Dithiolate Ru Complex," Angew. Chem., Int. Ed. 2014, 53, 1968-1972. (c) Khan, R. K. M. ; Torker, S. and Hoveyda, A. H. "Reactivity and Selectivity Differences Between Catecholate and Catechothiolate Ru Complexes. Implications Regarding Design of Stereoselective Olefin Metathesis Catalysts," J. Am. Chem. Soc. 2014, 136, 14337-14340. (d) Koh, M. J.; Khan, R. K. M.; Torker, S.; Yu, M.; Mikus, M. S. and Hoveyda, A. H. "Synthesis of High-Value Alcohols, Aldehydes and Acids by Catalytic Z-Selective Cross-Metathesis" manuscript submitted. / Thesis (PhD) — Boston College, 2014. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

La thapsigargine, lactone sesquiterpénique de type guaïanolide d’origine naturelle, est un puissant inhibiteur des enzymes ubiquitaires SERCAs (Sarco-Endoplasmic Reticulum Ca2+-ATPases) et est actuellement en phase clinique pour le traitement du cancer de la prostate non-hormono dépendant. Au cours de cette thèse, nous avons développé une nouvelle approche pour la synthèse de cette molécule, suffisamment flexible pour permettre de préparer des analogues ayant un bon degré de diversité structurale. Cette voie met en jeu une métathèse cyclisante d’ényne pour former le squelette bicyclique [5-7] de cette molécule. La préparation du précurseur de métathèse a nécessité le développement de deux voies différentes. La première utilise le ditertbutylacétylène dicarboxylate comme matière de départ et met en jeu un procédé original Michael-Wittig en un pot. Malgré une étude approfondie de cette étape ayant permis d’optimiser les conditions opérationnelles avec un rendement de 65%, cette voie s’est finalement avérée non applicable pour la synthèse envisagée ceci en raison d’un manque de chimiosélectivité au niveau d’une étape décisive. Une deuxième voie a donc été développée. Elle utilise la 2-méthylcyclopentane-1,3-dione comme produit de départ et offre le précurseur de métathèse en série racémique en 10 étapes et un rendement de 8%. Les quatre centres stéréogènes C1, C3, C10 et C6 sont mis en place grâce à des réactions diastéréosélectives (d.r ≥ 80%). La dernière étape de cette voie est une réaction d’alkynylation d’un aldéhyde conjugué avec piégeage in-situ de l’alcool secondaire obtenu. La configuration relative du centre C-6 de ce précurseur de métathèse s’est avéré par la suite épimère de celui de la thapsigargine (nOe mesurés après RCEYM). Des essais de métathèse cyclisante ont ensuite été réalisés sur l’ényne obtenue dans différentes conditions incluant l’utilisation de catalyseurs originaux fournis par le Pr. Marc Mauduit (université de Rennes). Ces réactions se sont montrées concluantes, fournissant le squelette bicyclique [5,7] de la thapsigargine avec de bons rendements (de 61 à 89%).A la suite de cette étape, un ensemble de réactions a été réalisé afin de mettre en place les groupements fonctionnels nécessaires à la transformation de la plateforme bicyclique obtenue en thapsigargine. De nombreuses difficultés ont été rencontrées : les tentatives d’épimérisation du centre C-6, d'époxydation de l'adduit de cyclisation ou encore de formation de -lactone se sont révélées infructueuses ou ont conduit à des résultats inattendus. L’idée d’exploiter la présence du centre stéréogène C-6 de configuration non naturelle pour installer le centre C-8 crucial pour l’activité biologique de la thapsigargine, via un réarrangement sigmatropique [1,3] de type suprafacial catalysé à l’or (catalyseur de Nolan), a été également testée. De manière inattendue, le produit de réarrangement est obtenu avec inversion faciale, indiquant le passage probable par un cation allylique.Ainsi, au cours de ce travail, deux composés bicycliques [5,7] oxygénées en C8, précurseurs raisonnables de la thapsigargine et analogues, ont été synthétisés par deux voies qui diffèrent au niveau du réarrangement final des produits de cyclisation hydroxylés en C6obtenu après métathèse cyclisante. A partir de de la 2-méthylcyclopentan-1,3-dione commerciale l’un est obtenu en 13 étapes avec 3% de rendement et l’autre en 12 étapes avec 5% de rendement. L’ensemble des essais de réactions effectuées sur les adduits de métathèse permettent de mieux cerner leur réactivité. / Thapsigargin, a guaianolide sesquiterpene lactone of natural origin is a potent inhibitor of ubiquitous SERCA enzymes (Sarco-Endoplasmic Reticulum Ca2+-ATPase) and is currently in clinical trial phase 1 for the treatment of non-hormono dependent prostate cancer. In this work a new approach for the synthesis of thapsigargin has been developed, flexible enough to allow the elaboration of analogues with a high degree of structural diversity. The strategy developed involves an enyne metathesis cyclization reaction (RCEYM) to form the bicyclic [5,7] scaffold of these molecules. For the synthesis of the required precursor of RCEYM, two successive routes have been explored. The first one uses tert-butylacetylene dicarboxylate as starting material and involves a one-pot Michael-intramolecular Wittig reaction. Conditions have been found to allow an efficient synthesis of trisubstituted cyclopentenones. Unfortunately this route has proved difficult to use for the programmed synthesis because of the lack of chemoselectivity at a decisive strategic level. A second approach was developed starting from commercial 2-methyl-cyclopentane-1,3-dione, providing the required racemic precursor of the metathesis reaction in 10 steps and 8% yield. The four C1, C3, C6 and C10 stereogenic centers are set up through diastereoselective reactions (dr ≥ 80%). The final step of the synthesis of this precursor involves an alkynylation reaction of an aldehyde combined with in-situ trapping of the secondary alcohol obtained. The relative configuration of center C6 was shown to be the inverse of that of thapsigargin. Metathesis cyclization assays were then carried out on this intermediate enyne under different conditions, including the use of original catalysts provided by Prof. Marc Mauduit (University of Rennes). These reactions provided the expected [5,7] bicyclic core of thapsigargin with good yields (61 to 89%). In the third part of the thesis, a set of reactions have been attempted to put in place the necessary functional groups for the achievement of the synthesis of thapsigargin. Many difficulties were encountered: attempted epimerization of the C6 center, epoxidation of the RCEYM cyclization adduct or attempts to form a  -lactone either were unsuccessful or led to unexpected results. The idea of using the presence of the stereogenic center of unnatural configuration at C6 to install the hydroxyl group at C8, crucial for the biological activity of thapsigargin, via a gold-catalyzed (Nolan catalyst) suprafacial sigmatropic [1,3] rearrangement was experimented. Unexpectedly, the rearranged acetate adduct was obtained with facial inversion, indicating a probable allyl cation intermediate. Thus, in this work, two [5,7] bicyclic oxygenated compounds at C8 have been synthesized from commercial 2-methylcyclopentane-1,3-dione through two pathways that differ in the conditions leading to the final rearrangement of the cyclic C6-hydroxylated RCEYM adducts. One of them is obtained in 13 steps with 3% yield and the second in 12 steps with 5% yield. Both compounds appear to be suitable intermediates for the syntesis of thapsigargin and its analogues. All tests performed on the adducts, obtained after RCEYM, helps us to identify their reactivity.

Different catalytic approaches have been applied to new -lactams preparations. olefin metathesis has been successfully performed with 3--methylidene--lactams. It was verified that 3--methylidene--lactams olefin metathesis is applicable to preparation of biologically active -lactam of Ezetimibe-type.

Le travail présenté dans ce manuscrit consiste à développer une voie de synthèse originale visant les alcaloïdes de type Lycorine, composés naturels isolés de plantes de la famille des Amaryllidaceae, possédant des activités anticancéreuses prometteuses. La réaction clé de métathèse tandem ène-yne-ène a été explorée avec succès, permettant un accès rapide au cœur hexahydroindole des Lycorines. Le développement de nouvelles méthodes synthétiques autour de composés de type N-sulfinylthioimidate a été réalisé ; leur synthèse efficace en trois étapes, leur fonctionnalisation en position α par des halogénures d'alkyles ou des aldéhydes, ainsi que leur réduction ménagée en aldimines α-chirales hautement fonctionnalisées ont été étudiés. Ces aldimines représentent des intermédiaires clés avancés pour la synthèse de divers membres de la famille des Lycorines : la synthèse totale des α et γ-Lycorane a donc été réalisée ; la synthèse de composés mono-hydroxylés tels que la Fortucine et la Kirkine est en cours d'étude. / The work reported in this manuscript concerns the development of an original synthetic strategy towards Lycorine-type alkaloids, natural products isolated from the plants of the Amaryllidaceae family, owning promising antitumoral activities. The tandem metathesis key step ene-yne-ene was explored with success, offering a quick access to the Lycorine hexahydroindole core. The development of new synthetic methods around N-sulfinylthioimidates was performed: the settings up of their efficient synthesis in three steps, their α-functionalization with halide alkyles or aldehydes, as well as their reduction in α-chiral aldimines highly functionalised were studied. These aldimines represent advanced key intermediates for the synthesis of several members of the Lycorine family: we achieved the total synthesis of α and γ-Lycorane; the synthesis of mono-hydroxylated compounds such as Fortucine and Kirkine is on going.

<p>This thesis describes the design and synthesis of compounds that are</p><p>intended to inhibit serine and aspartic proteases. The first part of the text deals with preparation of inhibitors of the hepatitis C virus (HCV) NS3 serine protease. Hepatitis C is predominantly a chronic disease that afflicts about 170 million people worldwide. The NS3 protease, encoded by HCV, is essential for replication of the virus and has become one of the main targets when developing drugs to fight HCV. The inhibitors discussed here constitute surrogates for the widely used <em>N</em>-acyl-hydroxyproline isostere designated 4-hydroxy-cyclopentene. The stereochemistry of the 4-hydroxy-cyclopentene scaffold was determined by nuclear overhauser effect spectroscopy (NOESY) and the regiochemistry by heteronuclear multiple bond correlation (HMBC). The scaffold was decorated with different substituents to obtain both linear and macrocyclic HCV NS3 protease inhibitors that display low nanomolar activity. The second part of the thesis describes the design and synthesis of potential aspartic protease inhibitors. The hydroxyethylene motif was used as a noncleavable transition state isostere. The synthetic route yielded a pivotal intermediate with excellent stereochemical control, which was corroborated by NOESY experiments. This intermediate can be diversified with different substituents to furnish novel aspartic protease inhibitors.</p> / Report code: LIU-TEK-LIC-2006:45