Esta tese teve por principal objetivo o estudo de algumas reações envolvendo os grupos alquilselenolato e alquiltelurolato, preparados a partir dos elementos Se e Te e alquillítio comercial. A primeira parte desta tese é dedicada ao estudo da utilização de butiltelurolato e butilselenolato como ligantes não transferíveis em organocupratos, especialmente na adição conjugada a sistemas carbonílicos α,β-insaturados. Na segunda parte deste trabalho, é apresentado um estudo envolvendo a hidroteluração e hidrosselenilação de olefinas ativadas, geradas pela adição de alquilcalcogenatos em enonas, ésteres, aldeídos e nitrilas α,β insaturadas. / This thesis has the main purpose of studying some on reactions involving alkylselenolate and alkyltellurolate groups obtained from elemental Se and Te and commercial alkyllithiums. The first part of this thesis deals with the study of the use of butyltellurolate and butylselenolate as non-transferible ligands in the chemistry of cuprates, in special conjugated addition to α,β-unsaturated carbonylic systems. In the second part of this work, a study involving the hydrotelluration and hydroselenilation of activated olefins prepared by addition of alkylcalcogenates in enones. esteres, aldehydes and α,β unsaturated nitriles, is presented.

Depuis une vingtaine d’années, l’utilisation massive des antibiotiques a provoqué l’apparition de souches bactériennes résistantes contre la plupart des familles d’antibiotiques disponibles sur le marché pharmaceutique. L’apparition de souches multirésistantes voire totorésistantes notamment dans le milieu hospitalier, pose de manière croissante des difficultés thérapeutiques et constitue un grave problème de santé publique. Lors de mon doctorat, deux approches ont été abordées.La première approche consiste à inhiber les enzymes DapF et MurE impliquées dans la voie de biosynthèse du peptidoglycane, composant principal de la paroi des cellules bactériennes. Nous avons donc préparé des acides aminés comportant des groupes fonctionnels triazolyle ou alcynyle, analogues stériquement contraints de l’acide 2,6-diaminopimélique (méso-DAP).La deuxième approche développée au laboratoire repose sur le développement d’adjuvants d’antibiotiques, permettant de cibler spécifiquement les protéines responsables des mécanismes de résistances (Histidines kinases, HKs). Ce travail a permis l’obtention de trente-trois molécules dérivées du thiophène, dont huit présentent une activité biologique contre trois HKs différentes (1,63 < CI50 (μM) < 243,9). De plus, sur les huit molécules biologiquement actives, deux ont présenté une inhibition de la croissance bactérienne contre des bactéries à gram-positif et/ou à gram-négatif (B. subtilis, S. aureus, B. anthracis, E. coli…) et une restaure la sensibilité de souches bactériennes (E. coli productrice de β-lactamases à spectre large (BLSE) et S. aureus résistant à la méticilline (SARM)) à l’antibiotique approprié (céfotaxime). / Over the two past decades, the massive use of antibiotics has led to the emergence of resistant bacterial strains against most families of antibiotics available on the pharmaceutical market. The emergence of multiresistant and totoresistant bacterial strains particularly in hospitals, which create increasing problem in the development of new therapeutics and constitutes serious public health threat problems. During my PhD, two approaches were discussed.The first approach of this project consist in targeting the DapF and MurE enzymes, which are implicated in the biochemical pathway for peptidoglycan biosynthesis, a key component of the bacterial cell wall. Consequently, we prepared amino acids derivatives with triazolyl and alkynyl groups, sterically hindered analogs of 2,6-diaminopimelic acid (meso-DAP).The second approach is the development of antibiotic adjuvants, to target specific proteins implicated in the development of bacterial resistance mechanisms (Histidine kinases, HKs). This work has enabled the development of thirty-three thiophene derivatives, eight of them have biological activity against three HKs (1.63 < IC50 (μM) < 243.9). In addition, among the eight molecules with biological activity, two of them present inhibition of bacterial growth (bactericide) against both gram-positive and/or gram-negative bacteria (B. subtilis, S. aureus, B. anthracis, E. coli…) and one of them restores the sensibility of bacterial strains (E. coli producing extended spectrum of β-lactamases (ESBL) and S. aureus resistant to methicillin (MRSA)) to the appropriate antibiotic (cefotaxim).

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This thesis is concerned with the application of the conjugate addition of enantiopure lithium amides in the asymmetric syntheses of (−)-martinellic acid. Chapter 1 introduces the importance of the quinoline motif in a wide variety of natural products and pharmaceuticals. The natural products (–)-martinellic acid and (+)-martinelline are introduced and previous methods for their synthesis are described. Chapter 2 introduces the conjugate addition reaction of lithium N-benzyl-N-α-methylbenzylamide as a means of synthesising β-amino esters from α,β-unsaturated esters. Both “tandem” and “stepwise” enolate functionalisation pathways to introduce an α-substituent are discussed, and the products are cyclised to the corresponding quinolin-2-ones. Modification of this strategy allowed the development of a double cyclisation reaction to form the pyrroloquinoline core found within (–)-martinellic acid and (+)-martinelline. Initial attempts at elaborating the tricyclic core to the natural products are described. Chapter 3 addresses the difficulties encountered in the initial synthetic route by the use of lithium (R)-N-allyl-N-(α-methyl-4-methoxy-benzyl)amide as an alternative enantiopure ammonia equivalent. A key Wittig and intramolecular Michael reaction is used to introduce the remaining stereogenic centre, allowing access to either epimeric series. Full optimisation of the synthetic sequence is described resulting in the synthesis of a simplified triamine core, lacking only the ester functionality required for (–)-martinellic acid and (+)-martinelline. Chapter 4 presents an asymmetric synthesis of (–)-martinellic acid and the first asymmetric synthesis of 4-epi-martinellic acid using the methodology developed in chapter 3, by incorporation of an ester functionality into substrate. Chapter 5 contains full experimental procedures and characterisation data for all compounds synthesised in Chapters 2, 3 and 4.

One area of natural product synthesis which has been heavily investigated in the last eight decades is the total synthesis of terpenoids. Among terpenoids, the presence of a great deal of stereochemical complexity in combination with a variety of functionalities makes sesquiterpenes challenging targets to the synthetic chemists. As a result synthetic activity in this area continues to flourish. The thesis entitled “Enantiospecific Synthesis of Guaianes and Tricyclic Ring Systems of Elisabethins and Dumsins’’ describes the studies directed towards the synthesis of the guaiane sesquiterpenes and exploratory studies towards elisabethins and dumsin diterpenoids. For convenience, the results are presented in two chapters; viz (1) Enantiospecific Total Synthesis of Guaiane Sesquiterpenes; and (2) Enantiospecific Synthesis of ABC Ring System of the Diterpenoids Elisabethins and Tetranortriterpenoids Dumsins. In each chapter of the thesis, the compounds are sequentially numbered (bold) and references are marked sequentially as superscripts and listed at the end of the chapter. All the spectra included in the thesis were obtained by xeroxing the original NMR spectra. Clavukerin A, the first member of the trisnorguaianes, was simultaneously isolated in 1983 by the research groups of Kitagawa from the Okinawan soft coral Clavularia koellikeri (stolonifer), and Bowden from the Australian soft coral Cespituloria sp. In 1992, Kakisawa and his research group reported the isolation of isoclavukerin A from the Okinawan soft coral Clavularia sp. In the present thesis, formal total syntheses of clavukerin A and isoclavukerin A have been described in the first part of the first chapter. To begin with, (R)-limonene has been transformed into 1-[5-isopropenyl-2-methylcyclopent-1-en-1-yl]pent-4-en-1-one via the 5-isopropenyl-2-methyl-cyclopent-1-en-1-carboxaldehyde. RCM reaction of the enone produced 6,10-dimethylbicyclo[5.3.0]deca-1(10),5-dien-2-one, which on epoxidation generated 1-[(1S,2S,5R) and (1R,2S,5S)-2-isopropenyl-5-methyl-6-oxabicyclo[3.1.0]hex-1yl]pent-4-en-1-ones. These epoxy ketones were then transformed into (6S,7S) and (6R,7S)6,10-dimethylbicyclo[5.3.0]dec-1(10)-en-2-ones, thus completing the formal total synthesis of clavukerin A and isoclavukerin A. In the subsequent parts of the first chapter, enantiospecific total syntheses of the guaiane sesquiterpenes, aciphyllenes A and B, isocalamusenone and 6-epiisocalamusenones, and (6S)- and (6R)-11-hydroxyguaiadienes have been described. Aciphyllene A was isolated in 1983 by Kubota and co-workers from the essential oil of the roots of Lindera glauca. Aciphyllene B was isolated by Konig et al. in 1998 from the liverwort D. hirusta. In 1979, Rohr and co-workers reported the isolation of isocalamusenone from the plant Acorus calamus L, In 2000, Nkunya and colleagues isolated (6R)-11-hydroxyguaiadiene from the root bark of Lettowianthus stellatus, whereas (6S)-11-hydroxyguaiadiene was isolated in 1977 by Bohlmann et al. from the roots of Parthenium hysterophorus. The 5isopropenyl-2-methyl-cyclopent-1-en-1-carboxaldehyde derived from (R)-limonene has been converted into the (3R,4S,6S,7S)- and (3R,4S,6R,7S)-3-acetyl-6,10 dimethylbicyclo[5.3.0]dec1(10)-en-4-ols employing a type II carbonyl ene reaction and Wilkinson’s hydrogenation as the key steps, which have been further converted into aciphyllenes A and B along with their C-6 epimers, (+)-isocalamusenone, 6-epi-isocalamusenone, and (6S)- and (6R)-11-hydroxyguaiadienes. In the second chapter of the thesis, enantiospecific synthesis of the ABC-ring systems of elisabethin group of diterpenoids and tetranortriterpenoids dumsins have been described, starting from the readily available monoterpene (R)-carvone. To begin with, (R)-carvone has been transformed into 1,6,6-triallylcarveol, which on two simultaneous RCM reactions generated the ABC-ring system of the elisabethin group of diterpenoids. An alternative synthetic strategy was also developed for the same compound. Thus, first (R)-carvone has been transformed into 6-allyl-10-isopropenyl-7-methylspiro[4.5]deca-2,7-dien-6-ol, which on ROM-RCM reaction generated the requisite tricyclic alcohol, which on oxidation generated 4,8-dimethyltricyclo[7.4.0.01,5]trideca-3,8,11-trien-7-one, which represents the ABC ring system of elisabethins. Introduction of the second allyl group at the C-7 position of 6-allyl-10isopropenyl-7-methylspiro[4.5]deca-2,6-dien-8-one followed by RCM reaction resulted in the formation of the tricyclic ketones (1S,4S,6R) and (1R,4S,6R)-4-isopropenyl-1-methylbicyclo[4.4.0]decanespiro[5,1']-cyclopenta-3',8-diene-2-ones, which represents the ABC ring system of tetranortriterpenoids dumsins.

One of the largest problems in current medicine is the shortage of organs for transplant due to technological limitations in the storage of organs for any length of time. A possible solution to this problem would involve cryopreservation. However, current cryopreservatives such as sucrose or DMSO have concerning cytotoxic issues that limit their possible applications. A major cause of cryoinjury is the uncontrolled recrystallization of inter and intra-cellular ice crystals that occurs during the thawing process leading to mechanical damage and dehydration. The Ben lab has thus been interested in the design of compounds that are capable of inhibiting this process but do not possess other undesirable properties found in the native compounds. These synthetic analogues have been shown to increase cellular viability post-thaw. A series of mixed α/β glycopeptides are prepared and analyzed for antifreeze properties. The results of this study imply that it is not the gross conformation of the glycopeptide that is responsible for activity, but rather that intramolecular relationships may be responsible for disrupting the reorganization of ice. A technique was devised for the incorporation of triazoles into the analogues to investigate the importance of the linker and to greatly simplify the synthesis of a library of glycoconjugates. It was found that the IRI activity of glycopeptides is very sensitive to the distance between carbohydrate and peptide backbone. The electron density at the anomeric oxygen is an important parameter with respect to intramolecular networks. A series of substituted galactosides is presented that modify the electronics of the anomeric oxygen. The results demonstrate that decreasing electron density at this position appears to improve IRI activity in a predictable manner. To better understand the remarkable IRI activity of a key analogue, it was systematically truncated. This study led to the serendipitous discovery of a series of very highly IRI active analogues that do not contain a peptide backbone. These compounds represent the first non-glycopeptides that can show very significant IRI activity even at very low concentrations. The final portion of the thesis reports the efforts towards the preparation of a carbasugar analogue of AFGP-8.

Reductive electron transfer has been successfully utilized to facilitate the first enantioselective desymmetrisation of malonate derivatives. Selective monoreduction of cyclic 1,3-diesters through the combined use of SmI2-Et3N and chiral non-racemic diols has granted rapid access to enantioenriched β-hydroxy acids containing challenging quaternary centres – an abundant motif in many drug molecules. Unique radical anions generated from the single electron reduction of cyclic 1,3-diesters have been exploited in cyclisation cascades. Capture of acyl-type radical anions by both alkene and alkyne acceptors have permitted the construction of complex bicyclic architectures in a single synthetic operation. The reductive cyclisation cascade of lactones has also been demonstrated, using SmI2-H2O to achieve a challenging domino 5-exo-trig/6-exo-trig cyclisation event. This process generates highly decorated carbo[5.4.0]bicyclic scaffolds with complete diastereocontrol.

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第22663号 / 工博第4747号 / 新制||工||1742(附属図書館) / 京都大学大学院工学研究科合成・生物化学専攻 / (主査)教授 杉野目 道紀, 教授 村上 正浩, 教授 大江 浩一 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DGAM

Ces dernières années ont été témoin de l'énorme développement de la chimie organique du fluor. Notamment, l'introduction de groupements fluorés émergents sur des « briques » moléculaires variées a attiré l'attention de la communauté scientifique en raison de leurs propriétés particulières. De plus, la stratégie de fonctionnalisation dirigée de la liaison C-H par catalyse par les métaux de transition, a conduit à une révolution dans le développement de méthodologies synthétiques originales. Par conséquent, la conception de nouvelles approches synthétiques pour l'introduction de groupements fluorés par fonctionnalisation de la liaison C-H catalysée par les métaux de transition est particulièrement attirante. Dans cette thèse, nous nous sommes concentrés sur le développement de nouvelles méthodologies d'introduction directe des groupements fluorés sur des arènes et des oléfines par fonctionnalisation directe de liaison C(sp2)-H catalysée par les métaux de transition. En particulier, nous avons tourné notre attention sur le 2-bromo-3,3,3-trifluoropropène (BTP), un réactif fluoré bon marché et provenant de déchets de l'industrie. Ce dernier est utilisé comme agent de remplacement de halon pour la suppression des incendies et, utilisé comme « brique » moléculaire en synthèse organique (Chapitre 1). La première partie de cette thèse est dédiée au développement de nouvelles méthodologies pour l'introduction directe du groupement CF3-vinyl sur des arènes et des oléfines par fonctionnalisation de la liaison C(sp2)-H catalysée par le palladium. Ensuite, cette approche a été étendue à la fonctionnalisation d'esters α,β- insaturés, bien qu'un mécanisme différent soit probablement impliqué (Chapitre 2). Dans la seconde partie de cette thèse, nous avons développé une nouvelle méthodologie pour l'introduction directe du groupement SCF3 sur des arènes et des oléfines par fonctionnalisation de la liaison C(sp2)-H catalysée par le palladium, utilisant le réactif de Munavalli (Chapitre 3). / Recent years have witnessed a great development of the organofluorine chemistry field. In particular, the introduction of emergent fluorinated moieties onto various scaffolds has attracted attention of the scientific community because of their special properties. Besides, transition metal-catalyzed directed C-H bond functionalization strategy has brought a revolution in the development of original synthetic methodologies, since it allows straightforward and more atom-economical processes. Thus, the design of new synthetic approaches for the introduction of fluorinated moieties by transition metal-catalyzed C-H bond functionalization pathway is particularly appealing. Therefore, in this Ph.D. thesis, we focused on the development of new methodologies for the direct introduction of fluorinated moieties onto arenes and olefins by transition metal catalyzed directed C(sp2)-H bond functionalization. In particular, we turned our attention to the 2-bromo-3,3,3-trifluoropropene (BTP), an inexpensive fluorinated reagent coming from industry waste, used as a potential halon replacement for fire suppression and as a fluorinated building block in organic synthesis (Chapter 1). The first part of this Ph.D. thesis was dedicated to the development of new methodologies for the direct introduction of a CF3- vinyl moiety onto arenes and olefins by a Pd-catalyzed directed C(sp2)-H bond functionalization with BTP. Then, this approach was extended to the functionalization of α,β-unsaturated esters, although a different reaction pathway is probably involved (Chapter 2). In the second part of this Ph.D. thesis, we developed a new methodology for the direct introduction of the SCF3 group onto arenes and olefins by Pd-catalyzed directed C(sp2)-H bond functionalization using the Munavalli reagent (Chapter 3).