Orientador: Ronaldo Aloise Pilli / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Quimica / Made available in DSpace on 2018-08-10T13:11:39Z (GMT). No. of bitstreams: 1 Salvador_MayraBeloti_M.pdf: 2010457 bytes, checksum: 350e267c8a65621fe41d0da941852b62 (MD5) Previous issue date: 2007 / Resumo: Esta dissertação de mestrado trata da síntese da Criptomoscatona D2, uma lactona isolada pelo grupo de pesquisa dos Profs. Cavalheiro e Yoshida a partir da Cryptocarya moschata, planta encontrada em território brasileiro, cujas configurações relativa e absoluta ainda não foram determinadas. Além de auxiliar em sua elucidação estrutural a síntese desta molécula nos permitiria realizar estudos sobre sua atividade citotóxica, dando prosseguimento a estudos anteriores desenvolvidos em nosso laboratório com essa classe de compostos. Partindo-se do benziloxiacetaldeído obteve-se o álcool homoalílico quiral correspondente através de uma reação de alilação assimétrica com alilestanana e (S)-binaftol. Clivagem oxidativa da dupla ligação e reação de alilação mediada por InCl3 e estanho metálico na presença de brometo de alila forneceu uma mistura de álcoois homoalílicos sin/anti 1:1 cuja separação cromatográfica permitiu o prosseguimento da síntese racêmica com cada um dos diasteroisômeros. A reação de proteção das hidroxilas com o grupo TBS, seguida de clivagem oxidativa da dupla ligação e reação de alilação com BF3.Et2O e alilestanana forneceu o terceiro álcool homoalílico com mistura diastereoisomérica de cerca de 2:1 em ambas as rotas. Por fim, uma reação de esterificação do álcool remanescente na forma de acrilato seguida de reação de metátese de olefinas para formação do anel lactônico nos possibilitou o mapeamento de grande parte da rota sintética da Criptomoscatona D2 em sua forma racêmica / Abstract: This work describes the preliminary studies on the racemic and the asymmetric synthesis of Cryptomoscatone D2 based on sequential allylation reactions for the construction of its three stereogenic centers and ring-closing methatesis reaction to construct the lactone scaffold. Besides allowing the structure elucidation of the molecule isolated from a typical brazilian plant by the research groups of Profs. Cavalheiro and Yoshida, the synthesis of such a lactone would allow us to carry new cytotoxic studies which are being lately developed with this class of compound. The synthesis started with the allylation reaction of benzyloxyacetaldehyde under the conditions described by Keck and coworkers to furnish corresponding homoallylic alcohol. After an oxidative cleavage of the double bond, an InCl3 promoted allylation reaction allowed the preparation a 1:1 mixture of syn/anti homoallylic alcohols which were as the TBS ethers and submitted separately to double bond oxidative cleavages. These aldehydes were used as substrates for another allylation reaction with BF3.Et2O and allyltri-n-butyltin and the homolallylic alcohols (2:1 diatereoisomeric mixtures) were converted to the corresponding acrylates in order to carry out the planned RCM reaction. Several allylation reactions were tested and the homoallylic alcohols were prepared in 1:1 diasteroisomeric excesses. Efforts will be carried out in order to enhance the distereoselectivity of the allylation reactions for an efficient approach to Cryptomoscatone D2 (12) backbone / Mestrado / Quimica Organica / Mestre em Química

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Ce mémoire traite de l’utilisation d’allylmétaux chiraux, allylalanes et allylzincs, en synthèse asymétrique. Des stratégies adaptées à la stabilité configurationnelle intrinsèque de ces deux espèces ont été développées et appliquées à la synthèse d'alcools et d'amines homoallyliques énantioenrichis. La première partie de ce manuscrit est consacrée à la génération de cycloalkylèn-1-ylzincs à partir des alanes correspondants via une séquence hydroaluminationtitanocatalysée de diènes conjugués/transmétallation. Ces allylzincs, engagés dans l’allylmétallation d'imines non racémiques, conduisent aux amines homoallyliques correspondantes avec une bonne diastéréosélectivité selon un processus de résolution cinétique dynamique. La seconde partie vise à étudier l'influence des co-produits de transmétallation sur le cours stéréochimique de la réaction d'allylation d'imines. L'utilisation alternative d'allylzirconiums, qui libère un acide de Lewis inerte, se révèle bénéfique pour la stéréosélectivité de la réaction d’allylation d’imines. Le dernier volet de ce travail concerne l'utilisation directe d'allylalanes chiraux. Reposant sur la stabilité configurationnelle de ces alanes, un dédoublement cinétique des deux énantiomères, utilisant le camphre en tant que "piège chiral", permet d'enrichir le milieu réactionnel en un énantiomère. L'addition d'électrophiles prochiraux donne accès à des alcools et amines homoallyliquesénantio-enrichis. / This thesis deals with the use of chiral allylmetals, allylalanes and allylzincs, in asymmetric synthesis. Strategies adapted to the intrinsic configurational stability of these two species have been developed and applied to the synthesis of enantio-enriched homoallylic alcohols and amines.The first part of this manuscript is devoted to the generation of cycloalkylen-1-yl-zinc from the corresponding alanes via a titanium-catalyzed hydroalumination of conjugated dienes / transmetallation sequence. These allylzines, involved in the allylmetallation of non-racemic imines, provided the corresponding homoallylamines with good diastereoselectivity according to a dynamic kinetic resolution process.The first part of this memory discusses the generation of cycloalkylen-1-ylzincs from the corresponding alanes via a titanium-catalysed hydroalumination of cyclic conjugated dienes/transmetallation sequence. These allylzincs, involved in the allylmetallation of non-racemic imines, provided homoallylic amines with good diastereoselectivity according to a dynamic kinetic resolution process.The second part of this work aims at studying the influence of transmetallation co-products on the stereochemical course of the imine allylation reaction. The alternative use of allylzirconiums, which delivers a inert Lewis acid, was proven to benefit to the streoselectivity of the imine allylation.The last part of this work concerns the direct use of chiral allylalanes. Based on the configuration stability of these alanes, a kinetic resolution of the two enantiomers, using camphor as a "chiral trap", allowed to enrich the reaction medium with an enantiomer. The subsequent addition of prochiral electrophiles gives access to enantio-enriched homoallylic alcohols and amines.

L'utilisation des matières premières renouvelables dans la synthèse des molécules organiques ou les additifs alimentaires, les pesticides et les polymères a trouvé un intérêt croissant ces dernières années pour des raisons économiques aussi bien qu'écologiques. Au cœur des produits naturels on trouve les terpènes provenant essentiellement des bioressources et représentant une grande famille de molécules naturelles. Ils offrent un potentiel important pour l'accès à des produits à haute valeur ajoutée en utilisant des outils catalytiques sélectifs, tout en respectant le principe d'économie d'atomes. Les réactions cascades basées sur les processus d’(auto)transfert d'hydrogène, générant uniquement de l'eau et des sels non toxiques comme produits secondaires sont particulièrement propres, efficaces et attractives du point de vue de la valorisation durable des terpènes. Dans ce contexte, nous avons développé un nouveau système catalytique et efficace pour l’amination réductrice des alcools allyliques en présence de différentes amines en utilisant des complexes de ruthénium(II). Cette méthode a été appliquée à une large gamme d'alcools allyliques terpéniques tels que le géraniol, le nérol et le phytol, ce qui a permis leur valorisation d’une façon chimiosélective, ne générant que l’eau et le dioxyde de carbone comme sous produits bénins. La fonctionnalisation sp3 C-H des azaterpènes cycliques a été ensuite réalisée avec différents terpènes aldéhydes en présence de complexe de ruthénium(II). Ces transformations ont permis la production d'une petite librairie de N-et C-azaterpenes. Certains de ces terpènes alcaloïdes ont montré une bonne activité antibactérienne. Par la suite, la synthèse de nouveaux complexes chiraux [Ru(Cp’)] (IV) à partir de (+)-nopinone, un monoterpène issu de l’oxydation de β-pinène a été réalisée. L'application de ces complexes dans l'allylation asymétrique de carbonate de cinnamyle par le phénol a montré une bonne régio- et énantiosélectivité. / The use of renewable feedstock in the synthesis of organic molecules such as food additives, pesticides and polymers, has found increasing interest over recent years due to economic as well as ecological reasons. At the heart of natural products are terpenes derived essentially from bioresources and they represent a large family of natural molecules, which have a moderate cost. They offer a significant potential for the access to products with high added value using selective catalytic tools, respecting the principle of atom economy. Catalytic reactions involving hydrogen (auto)transfer, generating only water and non-toxic salts as byproducts are particularly clean, efficient and attractive methods from a sustainable point of view for the valorization of terpenes. In this context we have developed a new and efficient catalytic system for reductive amination of allylic alcohols in the presence of various amines using arene ruthenium(II) complex. The application of this method to a wide range of terpenic allylic alcohols like geraniol, nerol and phytol allowed the formation of new azaterpenes in good yield and high chemoselectivity generating only water and carbon dioxide as benign side products. The sp3 C–H functionalization of N-terpenylated cyclic amines was then performed with various terpenaldehydes without side alkene reduction in the presence of arene ruthenium(II) catalyst. These eco-friendly transformations enable the production of a small library of N- and C- terpenylated amines. Some of these terpene alkaloids showed good antibacterial activities. The synthesis of new chiral [Ru(Cp’)] (IV) complexes featuring a N,O chelate were successful, using a chiral ligand derived from commercially available (+)-nopinone, a monoterpene derived from oxidation of β-pinene. The application of these complexes in the asymmetric allylation of cinnamyl carbonate by phenol gave high regioselectivity and satisfactory enantioselectivity.

Les boranes vinyliques,les acides boroniques vinyliques et les boronates vinyliques sont des organoboranes où la différence d'électronégativité entre le carbone et le bore est très faible[C (2. 55)-B (2. 04)] et la liaison entre ces deux atomes est donc peu polaire. Les propriétés caractéristiques du bore permettent de réaliser une grande variété de réactions dans différentes conditions. Beaucoup de groupes de recherche ont exploré les applications synthétiques des organoboranes en synthèse organique. Par exemple les boranes vinyliques peuvent être transformés en les alcènes correspondants par protonolyse,ils peuvent être facilement oxydés avec H2O2 en présence de base(addition d'un groupe hydroxyle sur la double liaison) pour donner des produits cis-anti Markovnikov. Ils peuvent aussi subir des réactions d'addition pour donner des alcools allyliques ou des cycloadditions [4+2] pour former deux nouvelles liaisons carbone- carbone via des réactions de Diels-Alder. Les acides vinylboroniques peuvent être transformés en halogénures vinyliques via une halogénolyse,réagir via une réaction de cyclisation radicalaire utilisant la méthode catalytique de Corey en présence d'un initiateur de réaction radicalaire pour obtenir des diols 1,3- ou 1,4. Ils peuvent participer à des réactions de couplage au palladium de type Suzuki pour former de nouvelles liaisons carbone-carbone. Ils peuvent réagir avec des anhydrides pour donner différentes cétones insaturatées via des catalyses au palladium ou au rhodium . Les acides vinylboroniques ont aussi été utilisés pour la formation de nouvelles liaisons carbone-azote , carbone-oxygène , carbone-fluor via des réactions catalysées au palladium ou au cuivre. Les boronates vinyliques ont été employés pour former de nouvelles liaisons carbone-carbone via des couplages de Suzuki- Miyaura. Ils sont employés dans la réaction multicomposant de Petasis pour donner des hétérocycles azotés fonctionnalisés. Ils participent aux réactions de métathèse croisée pour donner des boronates vinyliques hautement fonctionnalisés , ils réagissent facilement avec des carbènes générés à partir de diazos pour donner des cyclopropanes et ceci à travers des catalyses au palladium et au rhodium. Les boronates vinyliques, en réaction avec des oxides de nitrile subissent des réactions de cycloaddition 1,3-dipolaire pour donner des isoxazoles . Les boronates vinyliques ont aussi été utilisés comme nucléophiles en réaction d'allylation avec catalyse au cuivre ou au palladium. Les transformations précédentes des organoboranes fournissent des précurseurs importants pour la synthèse totale de molécules bioactives complexes qui ont été utilisées dans les domaines de la médecine, de l'agrochimie, des composés pharmaceutiques et de la chimie fine. Les organoboranes peuvent être synthétisés facilement et ceci les rend particulièrement précieux comme intermédiaires clés en synthèse organique. / Vinylboranes, vinylboronic acids and vinylboronates are organoboranes where the electro negativity difference between carbon and boron bond is very low [C (2. 55)-B (2. 04)] and the bond between them is less polar. The characteristic features of borane allow performing wide range of reactions under different conditions. Several research groups explored the synthetic applications of organoboranes in organic synthesis. For example vinylboranes can be transformed to their corresponding alkenes via protonolysis,can be easily oxidized by hydrogen peroxide in presence of base(addition of hydroxy group at double bond)to result cis-,anti Markovnikov products also participate in addition reactions to give allylic alcohols,they undergo[4+2]cyclo adition reactions to form two new carbon- carbon bonds via Diels- Alder reaction. Vinylboronic acids can be transformed to vinylhalides via halogenolysis,react via boron-tethered radical cyclisation using Corey’s catalytic tributyl-stannane method in presence of radical initiator to afford 1,3- or 1,4-diols,participates in palladium catalyzed Suzuki cross coupling reactions to give characteristic carbon-carbon bond,react with anhydrides to result various unsaturated ketones via palladium and rhodium catalysis,vinylboronic acids were also used for the synthesis of new carbon-nitrogen,carbon- oxygen, carbon-fluoine bonds via palladium and copper catalysis. Vinylboronates were used to synthesize new carbon-carbon bonds via Suzuki- Miyaura cross coupling reaction under palladium catalysis, participates in Petasis multicomponent reaction to give functionalized nitrogen based heterocycles, they undergo olefin cross-metathesis to afford highly functionalized vinylboronate deivaives, readily react with carbene generated from diazo compounds to afford cyclopropane derivatives under palladium and rhodium catalysis. Vinylboronates on treatment with arylnitrile oxides undergo 1,3-dipolar cyclo addition reaction to give isoxazole derivatives, vinylboronates were also used as nucleophiles in allylation with copper and palladium catalysisThe above transformations of organoboranes provide important precursors for building complex bioactive molecules which were developed as medicine, agrochemicals, pharmaceuticals and fine chemicals. Organoboranes can be easily synthesized and this easy access for preparation made them useful key intermediates for organic synthesis. Vinylboranes can be synthesized via hydroboration of alkynes with alkylboranes,vinylboronic acids can be synthesized via hydroboration of alkynes with alkoxyboranes followed by hydrolysis where as vinylboronates were synthesized from organometallic reagents by transmetallation with trimethyl orthoborate,also prepared from hydroboration of alkynes with alkoxyboranes. Grafting a substitution in the allylic position of vinyl boronates confers to these units a high degree of versatility to their use in organic synthesis. -substitue.

Chiral bisphosphinites are well-documented alternatives for chiral bisphosphines as ligands that can be exploited in various asymmpetric syntheses. Particularly, vicinal biarylphophinite ligands give a seven membered chelate ring similar to the successful DIOP on coordination to the metal. RajanBabu and coworkers have described asymmetric bisphosphinites obtained by functionalization of sugars and have shown their utility in enantioselective hydrogenation, hydrovinylation and hydrocynation reactions. Despite the interesting reactions demonstrated by bisphosphinites, not much attention has been paid to their synthesis and catalysis. This is probably due to the known moisture and oxygen sensitivity that makes their use limited. In the present thesis, a series of C1 an C2 symmetric bisphosphinite complexes of Pd(II) and Pt(II) have been synthesized directly from various naturally occurring chiral alcohols using a modified template method. A number of asymmetric catalytic reactions have been developed such as allylation of imines, allylation of aldehydes, allylic allylation, allylic alkylation, hydrosilylation of alkenes and regioselective allylation of oxiranes. Allylation of imines was carried out in essentially neutral conditions using Pd(II) catalysts and water was shown to accelerate the reaction. Interestingly acetic acid was required as a promoter in asymmetric allylation of cinnamaldehyde in the Pt(II) catalyzed reaction whereas water was a deterrent. Hydrosilylation reaction was carried out in solvent free conditions with high turnover numbers (.1000). Ascorbic acid based complexes produced the highest enantioselectivity for the asymmetric allylic alkylation reaction (97 % ee) and hydrosilylation of styrene (98% ee). These enantioselectivity results are the best obtained using ligands directly prepared from natural products.

Ion-binding organocatalysis is an emerging field that has the potential to control the stereochemical outcome of any transformation that goes via charged intermediates. The aim of this project was to explore how this concept could be applied to an asymmetric allylation reaction. Chapter 2 of this thesis discusses anion-binding catalysis and investigates a chiral cooperative thiourea catalyst that could bind to fluoride to control allylation using an allylsilane. Optimization using a non-chiral thiourea (Schreiner’s catalyst) demonstrated that the reaction proceeded in high yield with TBAT onto an N-benzoylhydrazone. A chiral cooperative thiourea catalyst library was then synthesized but unfortunately, although the allylation using these catalysts proceeded in excellent yield, the product was isolated as the racemate (Scheme 1). Scheme 1: Anion-binding catalysis gave allylated products in high yields but gave no stereocontrol. Chapter 3 examines a chiral quaternary ammonium fluoride as an example of chiral cation-directed catalysis. We hypothesized that an allylsilane activated by fluoride would generate an allyl anion species that would associate with the chiral quaternary ammonium cation through electrostatic interactions. Extensive optimization found that the allylation reaction proceeded in good yield in chloroform at reflux with N-benzoylhydrazones. Different fluoride catalysts were prepared using an ion-exchange resin, and cinchonidine-derived catalysts performed the best. This methodology was extended to a phase-transfer catalyzed process, where solid cesium fluoride exchanged with chloride in situ, removing the need to synthesize and isolate ammonium fluoride catalysts (Scheme 2). Scheme 2: Cation-directed asymmetric allylation. In Chapter 4 cation-directed asymmetric catalysis was extended to an intramolecular allylation reaction. Substrate synthesis was attempted by cross metathesis but the reaction was capricious and yields were low. Intramolecular allylation with these materials gave promising results (Scheme 3) but a lack of material prevented optimization. Scheme 3: Intramolecular allylation results.

The work presented in this thesis mainly describes the discovery and development of methodology for the synthesis of anthecularin and anthecotulides, a family of unusual sesquiterpene lactones. Firstly, two 1,3-dipolar cycloaddition approaches toward anthecularin have been evaluated, using either oxidopyrylium ylide chemistry (Path A) or carbonyl ylides, generated by rhodium-catalysed decomposition of diazo ketones (Path B). Synthesis of the key precursor for the diazo strategy was achieved but unfortunately no desired cycloadduct was isolated. Secondly, an experimentally straightforward method to stereoselectively synthesise β-hydroxymethyl-α-methylene-γ-butyrolactones was developed using chromium or zinc. The synthetic utility of this methodology was demonstrated in syntheses of (±)-methylenolactocin, (±)-hydroxymatairesinol and, ultimately, (±)-hydroxyanthecotulide using a gold-catalysed Meyer-Schuster rearrangement. Finally, the first asymmetric synthesis of (+)-anthecotulide has been achieved, in 6 steps from commercially available materials. During this synthesis the absolute configuration was established. Furthermore, a novel rhodium-catalysed enantioselective ene-yne cycloisomerisation was used to form the α-methylene-γ-butyrolactone core.

Development of new asymmetric processes is one of the objectives of catalysis in organic chemistry. These processes can provide access to chiral building blocks applicable in syntheses of various natural substances that can be used for medical purposes. One such process is the preparation of chiral homoallyl alcohols, which have been used for syntheses of variety of biologically active compounds. In view of the aforementioned, suitably substituted homoallyl alcohols could be used as intermediates in syntheses of koibacins A-D, which have a number of interesting biological properties. Natural koibacins A-D are metabolites isolated from the marine cyanobacterium Oscillatoria sp. that exhibits selective antileishmanial activity and potent antïinflammantory properties. Our synthetic plan is focused on an approach through the allylation of aldehydes, esterification, ring closing metathesis and finally cross metathesis with different lipophilic fragments. Key words: enantioselective allylation, asymmetric synthesis, natural compounds, coibacins.

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