During the course of this work we have synthesized and evaluated a series of new enantiopure silyl triflmides as catalysts for asymmetric reactions. 3-Phenyl dialkylsilyl ketones, which were the key precursors to the target silyl triflmides were prepared by 1,4-addition of the corresponding silyl cuprate to enones, and resolved by chiral HPLC. Enantiopure trans silyl ketones were successfully reduced via the corresponding tosylhydrazones by the NaBH3CN/ZnCl2 system. However, due to an isomerization of the tosylhydrazone during the reaction, cis isomers (m = 0) were reduced via the corresponding dithioketals followed by desulfurization. The diastereoselective synthesis of enantiopure silyl triflimides from enantiomerically pure compounds has been also studied. The enantiopure trialkylsilyl triflimides were generated in situ by protodesilylation of the corresponding phenylsilanes with bis-(trifluoromethylsulfonyl)imide. The Diels-Alder reaction of methyl acrylate with cyclopentadiene was used as the model reaction for testing the new chiral catalysts : 1) Almost all silyl triflimides were efficient catalysts giving high yields and excellent diastereoselectivities in favour of the endo-isomer. 2) the best ee's (up to 56%) were obtained from catalysts carrying an aryl group directly attached to the cyclohexane ring (m = 0) which were much better than those obtained from catalysts carrying a benzyl-type group (m = 1). Interestingly catalysts of the same configuration carrying phenyl or naphthyl group gave cycloadducts of opposite configuration. 3) When m = 0, additional substituents at position-3 or 6 of the cyclohexyl ring had little influence on the ee. However, for m = 1, a methyl group at C2 increased the ee from 3% to 35%. 4) The replacement of the methyl groups connected to the silicon atom by bulkier ethyl groups decreased the ee (m = 0). 5) When m = 0, ee's for cycloaddition reactions of N,N-dimethyl acrylamide or acryloxazolidinone with cyclopentadiene were lower than those obtained with methyl acrylate.

Thesis (M.Sc.)--Memorial University of Newfoundland, 2005. / Bibliography: leaves 97-99.

Vinigrol was isolated in 1987 from the fungal strain Virgaria nigra F-5408 by Hashimoto and co-workers. This compound was identified as having antihypertensive and platelet aggregation properties as well as being recognized as a tumor necrosis factor inhibitor. Aside from its interesting biological activities, vinigrol also possesses a unique structural motif consisting in a decahydro-1,5-butanonaphthalene core decorated with 8 contiguous stereocenters. Despite synthetic efforts by many research groups since its isolation, it wasn’t until 2009 that the first total synthesis of vinigrol was reported by Baran and co-workers. Herein is presented a formal synthesis of this highly compact molecule which relies upon a highly diastereoselective ketal Claisen rearrangement as the stereodefining step and an intramolecular Diels-Alder reaction to access the tricyclic structure of the molecule. (+)-Digitoxigenin is a cardiac glycoside used in the treatment of many ailments such as congestive heart failure. It is a member of the cardenolides, a sub-type of steroid containing certain structural differences such as cis A/B and C/D ring junctions, a tertiary hydroxyl group at C14 and a butenolide substituent at C17. Although a few syntheses of this class of compounds have been reported, general strategies to access their framework is scarce. Herein we report our studies towards the total synthesis of digitoxigenin which rely upon a cascading gold-catalyzed cycloisomerization (or enyne metathesis)/Diels-Alder reaction.

The cyathins are a unique group of diterpenoids produced by the birds nest fungi <i>Cyathus helenae</i>, <i>C. africanus</i>, and <i>C. earlei</i>. Several of the cyathins show strong antibiotic activity. More recently, several fungal metabolites with structures closely related to those of the cyathins have been found to be potent inducers of nerve growth factor (NGF) synthesis. The structural complexity and the exciting biological activity of the cyathane family of diterpenes have prompted our efforts to develop an efficient and general synthetic approach.<p>To date, there have been seven total syntheses and six partial syntheses of cyathins. Most of these syntheses target allocyathin B2, which does not contain the common 6-7 trans ring fusion or the hydroxyl group within the seven member ring. Modifications of these routes to provide targets with these features have not been demonstrated and may be challenging. We have developed a concise asymmetric synthesis of cyathin A3, based on the enantioselective Diels-Alder reaction of quinone (106) and diene (105). Because the transformations of cyathin A3 into other cyathins are well documented, this synthesis provides a general approach to the cyathane diterpene family. In Section 2.2, the enantioselective Diels-Alder reaction of quinone 106 and diene 105 is presented. This reaction is effectively catalyzed by a carefully prepared Mikami catalyst. It was carried out on a preparative scale to give the chiral building block 108. The absolute configuration of the Diels-Alder adduct 108 was determined by NMR and X-ray analysis.<p>In Sections 2.3-5, the enantioselective total synthesis of (-)-cyathin A3 is described. This approach features the successful oxymercuration ring opening, a newly developed in situ configuration inversion, a much improved intramolecular aldol reaction and a radical cyclization. Now envisioned in our laboratory is the development of a new access to cyathin A4, which is surmised to be possible via the intermediate prepared in this synthesis.

We report a palladium-catalyzed, norbornene mediated synthesis of tetrahydroisoquinolines via a domino ortho-alkylation/Heck reaction sequence. The desired products are obtained in moderate to excellent yields starting from readily available aryl iodides. The reaction conditions can be extended to the formation of tetrahydroisoquinolinones and tetrahydrobenzo[c]azepines. The reaction allows for sequential intermolecular and intramolecular ortho-alkylations. However, the product yields are higher with ortho-blocked aryl iodides, which simplify the domino process to one intramolecular ortho-alkylation and a Heck reaction. The Lautens group has previously reported diastereoselective aryne Diels-Alder reactions of benzyne with dienes supporting a chiral auxiliary at its terminal carbon. In an effort to extend this work and allow access to a wider variety of 1,4-dihydronaphthalenes, we attempted the synthesis of dienes supporting a chiral auxiliary at a central carbon. Chiral pyridyne precursors were also synthesized, in an attempt to vary the source of chirality in diastereoselective cycloadditions.

We report a palladium-catalyzed, norbornene mediated synthesis of tetrahydroisoquinolines via a domino ortho-alkylation/Heck reaction sequence. The desired products are obtained in moderate to excellent yields starting from readily available aryl iodides. The reaction conditions can be extended to the formation of tetrahydroisoquinolinones and tetrahydrobenzo[c]azepines. The reaction allows for sequential intermolecular and intramolecular ortho-alkylations. However, the product yields are higher with ortho-blocked aryl iodides, which simplify the domino process to one intramolecular ortho-alkylation and a Heck reaction. The Lautens group has previously reported diastereoselective aryne Diels-Alder reactions of benzyne with dienes supporting a chiral auxiliary at its terminal carbon. In an effort to extend this work and allow access to a wider variety of 1,4-dihydronaphthalenes, we attempted the synthesis of dienes supporting a chiral auxiliary at a central carbon. Chiral pyridyne precursors were also synthesized, in an attempt to vary the source of chirality in diastereoselective cycloadditions.

This work was a kinetic study of the Diels-Alder reaction of isoprene with variously substituted benzalmalononitriles. Application of the Hammett equation, a linear free energy relationship, to the kinetic rate data yielded a value of 1.31 for rho. This was interpreted as meaning the transition state for this Diels-Alder reaction was probably of the concerted type, although the nonconcerted polar transition state could not be eliminated in one case by the data of this study.Ball State UniversityMuncie, IN 47306

Les analogues de nucléosides font partie de l'arsenal contre le cancer, principale cause de décès au pays. Ces dérivés synthétiques, qui empêchent la prolifération des cellules malignes via l'inhibition d'enzymes (ex. : kinases et polymérases) impliquées dans la réplication de l'ADN, possèdent une courte demi-vie in vivo. Notamment, les phosphorylases clivent facilement le lien N-glycosidique. Un autre obstacle que rencontrent les analogues est la compétition que leur livrent les nucléosides naturels. Le mémoire porte sur des améliorations à 2 niveaux: la synthèse d'analogues stabilisés et la synthèse d'inhibiteurs de la biosynthèse des nucléosides puriques. Pour la première partie, la préparation de composés ayant un méthylène entre les sous-unités furannose et base nucléique, appelés l'-homonucléosides, pourrait réduire l'instabilité métabolique. Aucune méthode stéréosélective n'existe pour préparer ces composés. La synthèse de l'-homocarbanucléosides a été amorcée, de façon stéréosélective, à partir du cycloadduit de Diels-Alder [4+2] endo issu du cyclopentadiène et de l'acrylate de méthyle. Ensuite, l'ozonolyse de l'alcène et la réduction in situ du dialdéhyde intermédiaire ont produit un diol, duquel un des hydroxyles a réagi par lactonisation sélective avec l'ester provenant du diénophile. L'autre hydroxyle (position 5') a été protégé sous forme d'éther silylé. Pour compléter la synthèse de l '-homocarbanucléosides, il fallait régénérer l'hydroxyle impliqué dans la lactone et l'activer pour faire le couplage avec une base nucléique. La lactone a donc été aminolysée mais il a été impossible d'isoler le mésylate dérivé de l'hydoxyamide obtenu. Alternativement, la lactone a été réduite en lactol, qui a été impliqué dans une réaction de Wittig, libérant ainsi l'alcool en position l'-homo, qui a été activé sous forme de sulfonate. Diverses tentatives de couplage entre cet intermédiaire et la thymine sont restées sans succès jusqu'à maintenant. Pour la deuxième partie du mémoire, la préparation d'inhibiteurs bifonctionnels de l'enzyme amidophosphoribosyltransférase (APRT), mimant à la fois le ribose et la glutamine, a été envisagée. La stéréochimie l,4-cis des dérivés tétrahydrofuranés serait assurée par une cycloaddition [4+2] impliquant un vinylphosphonate comme diénophile et le 3-méthoxyfurane comme diène. La préparation de ce dernier a été tentée de différentes manières. Deux méthodes connues de la littérature ont échoué. Une troisième méthode a été tentée, impliquant une cycloaddition [4+2] entre le furane et l'anhydride maléique, une éthérification suivie d'une rétrocycloaddition [4+2]. Après avoir rencontré de nombreuses difficultés, nous avons exploré la possibilité de synthétiser un intermédiaire requis pour les inhibiteurs, mais excluant le 3-méthoxyfurane. ______________________________________________________________________________ MOTS-CLÉS DE L’AUTEUR : Analogue de nucléosides, Nucléosides, L'-homonucléosides, Cycloaddition de Diels-Alder, Inhibiteurs bifonctionnels, Enzyme APRT, 3- méthoxyfurane.

Les recherches sur le cancer sont d'une grande nécessité étant donné l'étendue de la maladie et l'incapacité que nous avons à la traiter efficacement. En effet, dans les pays industrialisés, on estime que le cancer est la deuxième cause de mortalité. Une façon de combattre cette maladie est d'utiliser des agents qui pourraient entraver la prolifération des cellules infectées. À ce titre, les analogues de nucléosides font l'objet de recherches depuis les années 70. Présentement, les analogues de nucléosides sont largement utilisés à titre d'inhibiteur de la synthèse d'ADN dans les traitements contre le cancer et des infections virales. Cependant, la plupart possèdent la même faiblesse: leur rapide dégradation in vivo. En effet, le lien C-N glycosidique peut être facilement hydrolysé en condition acide ainsi que par l'action d'enzymes nucléosidases. Suivant l'hypothèse que l'ajout d'un méthylène entre le squelette ribosique et la base azotée produirait des analogues moins facilement dégradables, notre laboratoire développe une méthode synthétique vers ces 1'-homonucléosides. La stéréochimie 1',4'-cis, qui imite la configuration anomérique B normalement nécessaire pour l'activité biologique, est contrôlée par une réaction de Diels-Alder entre le furane et l'acrylate d'éthyle. Le cycloadduit formé subit ensuite un tandem de réactions d'ozonolyse et de réduction, fournissant une y-lactone, à partir de laquelle des transformations de groupes fonctionnels permettront l'ajout de diverses bases azotées. Subséquemment, les produits synthétisés seront testés pour leur activité anticancéreuse et antivirale. Jusqu'à maintenant deux principaux volets synthétiques ont été explorés afin de compléter la synthèse de 1'-homonucléosides. Le premier volet est la synthèse de 1'-homonucléosides substitués en position 2' a été tenté en protégeant la fonction alcool obtenue suite à la lactonisation, ensuite la lactone a été ouverte de façon à créer l'alcool en position 1'-homo. Cet alcool a ensuite été activé de différentes façons afin d'y tenter le couplage de la base azotée. Dans un autre volet, la démarche afin de construire des 1'-homonucléosides substitués en position 3' a été établie. L'alcool obtenu après lactonisation est directement activé en groupe partant (p-toluènesulfonate) afin d'y faire des couplages de bases azotées. Il semble que la réaction fonctionne avec un meilleur rendement par chauffage via micro-ondes. Il reste encore à améliorer les conditions afin d'appliquer la méthodologie à la plupart des bases azotées. ______________________________________________________________________________ MOTS-CLÉS DE L’AUTEUR : analogues de nucléosides; nucléosides; 1'-homonucléosides; cycloaddition de Diels-Alder; tandem ozonlyse et réduction; y-lactone; activation en groupe partant; couplage de bases azotée

The first comprehensive account of Diels-Alder reactions occurring by a simultaneous self-assembly of the components and catalysis of the reaction via a Lewis Acid (LA) is presented in this study. The synthetic usefulness of the intramolecularity achieved by temporary connection of DA reaction components has been combined with the benefits of LA catalysis to overcome the regio- and stereochemical diversities associated with DA reactions of unsymmetrically substituted dienes and dienophiles. LA's employed in this study act both as temporary connectors (by binding to LB sites of the diene and dienophile) and as catalysts (by complexation to oxygen of carbonyl moieties of the dienophiles). Formation of the tether, cycloaddition; and removal of the transient linker all occurs in a single operation.* To illustrate the high selectivity accomplished in this approach, an experimental model system consisting of unsymmetrically substituted dienol 6 and methoxy diene 397 and an unsymmetrically substituted dienophile (methyl acrylate, MAC) was designed. Thermal combination of either of these two dienes with MAC produces nearly equimolar mixtures of all four possible adducts illustrating the unselective nature of the reactions. Use of LA's to mediate the reaction between dienol 6 and MAC results in exclusive regio- and stereoselective formation of a single adduct. In contrast, application of the same LA's for the reaction between the methoxy diene and MAC either results in the formation of two 'endo' regioisomers in low yield or no reaction at all.* Exclusive formation of a single adduct for the reactions of 6 is attributed to a process in which the LA both pre-organizes the reactants and catalyzes the cycloaddition. This phenomenon is not expected to be observed in the reactions of the methoxy diene. The difference in the behavior of the two dienes is ascribed to the difference in their interactions with the LA's. Dienol 6 is able to bind covalently and irreversibly to the LA's while methoxy diene 397 is only able to co-ordinate to the LA's in a reversible manner. Mechanistic studies strongly support the self-assembled pathway and exclude other potential routes. Reactions of dienol 6 with other structurally suitable dienophiles under similar LA mediated conditions exhibit higher selectivities and reactivities in comparison with their uncatalyzed counterparts. Use of a structurally similar chiral dienol induces a highly diastereoselective cycloadditions with different dienophiles, whereas the thermal versions of the reactions again produce all possible adducts. The strategy has also been used for DA reactions of ' 2H'-thiopyran dienols with dienophiles 'N'-acroyl-2-oxazolidinone (NAO), ('E')-3-[3-(methoxycarbonyl)propenoyl]-1,3-oxazolidin-2 -one (MCPO), and 'N'-phenylmaleimide (NPM). Use of MgII is demonstrated to be effective to stereoselectively catalyze reactions which are unselective thermally or do not proceed at all. *Please refer to dissertation for diagrams.