Chapter one; “(-)-Rhazinilam and (-)-Rhazinal: Alkaloids with Anti-mitotic Properties Derived from Kopsia teoi”, provides the background information behind the motives that initiated this research project. The plant alkaloid (-)-rhazinilam [(-)-1] and its naturally-occurring derivative (-)-rhazinal [(-)-13] both exhibit potent anti-mitotic activities and, as such, are interesting targets for total synthesis. Chapter one is a review of the literature regarding these two compounds and discusses the occurrence, proposed biosynthetic origins, structural elucidation and biological activites of compound (-)-1 and that of its analogues including alkaloid (-)-13. Previous total syntheses of these two compounds are then examined, concluding with the only reported total synthesis of compound (-)-13. Developed within the Banwell research group, this total synthesis produced the racemic modification of alkaloid (-)-13 due to a lack of any stereocontrol in the key intramolecular Michael addition step. This unprecedented key step, involving cyclisation of the C2 of pyrrole onto an N-tethered and ?,?-disubstituted acrylate to produce a quaternary-carbon stereogenic centre, would be of greatly enhanced utility if it could be achieved in a catalytic-enantioselective fashion. The realisation of this goal is the central aim of the research conducted within this thesis. ¶ Chapter two; “Investigating Asymmetric Induction in the Intramolecular Michael Addition of pyrrole to N-Tethered Acrylates and Related Species”, introduces the model study used to direct research towards achieving the goal of asymmetric induction in the title process. The model is a somewhat simplified version of the original process used in the total synthesis of compound (-)-13 involving cyclisation of the C2 of pyrrole onto an N-tethered and ?-monosubstituted Michael acceptor, to produce a tertiary-carbon stereogenic centre. This simplification allows the rapid synthesis of a broad range of potential substrates for use in the title process, thus enabling the investigation of various different approaches to inducing asymmetry therein. High levels of asymmetric induction are observed with the use of chiral substrates or catalysts, facilitating the synthesis of both 6- and 7-membered rings annulated to pyrrole with construction of the relevant tertiary-carbon stereogenic centre in enantio-enriched form. For the reactions producing a 6-membered ring annulated to pyrrole, unambiguous proof of the absolute sense of asymmetric induction observed in the intramolecular Michael addition event is established using a chemical correlation study involving elaboration of a key indolizine-type cyclisation product, to the plant alkaloid of known absolute stereochemistry, (-)-tashiromine [(-)-75]. For the reaction producing a 7-membered ring annulated to pyrrole, the same information is obtained via X-ray crystallographic analyses of a dibrominated derivative of a key pyrroloazepine-type cyclisation product. ¶ Chapter three “An Enantioselective Total Synthesis of the Alkaloid (-)-Rhazinal: An Anti-mitotic Agent Isolated from Kopsia teoi.”, focuses on the application of methodology developed in the previous chapter, to the original goal of inducing asymmetry in the intramolecular Michael addition reaction, involving cyclisation of the C2 of pyrrole onto an N-tethered and ?,?-disubstituted acrylate to produce a quaternary-carbon stereogenic centre. This is ultimately achieved in a catalytic-enantioselective fashion, resulting in the first such total synthesis of the anti-mitotic alkaloid (-)-rhazinal [(-)-13]. ¶ Chapter four “Extending the Reaction Manifold to the Syntheses of Related Natural Products: A Formal Total Synthesis of (+)-Aspidospermidine and Syntheses of (-)-Rhazinilam and (-)-Leuconolam from (-)-Rhazinal”, describes three extensions to the reaction manifold used in the enantioselective total synthesis of alkaloid (-)-13: The acquisition in an enantioselective manner, of an intermediate previously obtained in racemic form, en route to the racemic modification of the natural product (±)-aspidospermidine [(±)-134], constitutes a formal and enantioselective total synthesis of (+)-aspidospermidine [(+)-134]. The direct deformylation of (-)-rhazinal [(-)-13], is carried out, to produce the parent alkaloid (-)-rhazinilam [(-)-1]. The pyrrole ring present in (-)-rhazinilam [(-)-1] is oxidised, to produce the related natural product (-)-Leuconolam [(-)-12] which has not, hitherto, been prepared by total synthesis. ¶Chapter five contains the experimental procedures and characterisation data associated with compounds described in chapters two to four.

<p>This thesis is divided into three separate parts with amino alcohols as the common feature. The first part describes the development of a novel three-component approach to the synthesis of α-hydroxy-β-amino esters. Utilizing a highly diastereoselective Rh(II)-catalyzed 1,3-dipolar cycloaddition of carbonyl ylides to various aldimines, syn-α-hydroxy-β-amino esters formed in high yields and excellent diastereoselectivities. This methodology was also applied in a short enantioselective synthesis of the C-13 side-chain of Taxol.</p><p>The second part of the thesis describes a total synthesis of D-erythro- Sphingosine based on a cross-metathesis approach to assemble the polar head group and the aliphatic chain.</p><p>The last part deals with the application of amino alcohols as scaffolds in a diversity-oriented protocol for the development of libraries of small polycyclic molecules. The design of the libraries is based on the iterative use of two powerful ring-forming reactions; a ring-closing metathesis and an intramolecular Diels-Alder reaction, to simultaneously introduce structural complexity and diversity.</p>

Le système spirocyclique [6.4] est un motif récurrent dans un certain nombre de produits naturels tels que les Lancifodilactones, les Micrandilactones ou les Rubriflordilactones. Ces structures polycycliques représentent un défi synthétique pour les chimistes organiciens puisqu’elles présentent au moins neuf centres stéréogènes dont plusieurs sont quaternaires. L’objectif principal de ce travail était de développer de nouvelles réactions métallo-catalysées, et de les utiliser comme étape clé afin d’obtenir rapidement et efficacement le squelette polycyclique de ces composés. La première partie de ces travaux a été consacrée au développement d’une nouvelle réaction domino pallado-catalysée donnant accès, selon les conditions employées, à différents cœurs polycycliques de nortriterpénoïdes issus d’une même famille, de manière totalement diastéréosélective. Cette séquence domino de trois réactions en un seul pot permet donc la synthèse unifiée de différents squelettes de produits naturels isolés du genre Schisandra, en une seule étape. Une approche au squelette tétracyclique ABCD de la Lancifodilactone F appliquant cette méthodologie pour la construction du motif spirolactone a été envisagée. Un cycle D hautement fonctionnalisé a ainsi été synthétisé de manière diastéréosélective via un réarrangement d’Ireland-Claisen et une réaction de métathèse cyclisante. Une réaction de cyclopropanation intramoléculaire et la réaction domino devraient permettre d’obtenir, par la suite, le squelette complet de la Lancifodilactone F. Dans une deuxième partie, deux approches aux coeurs CDEF et ACDE de la Rubriflordilactone A ont été développées autour d’une même réaction clé, c’est-à-dire une cycloaddition [2+2+2] d’un composé triynique permettant d’accéder en une seul étape au squelette tricyclique CDE. Le motif tétracyclique ACDE devrait être rapidement accessible après quelques aménagements de la voie de synthèse initiale. / The spiro [6.4] ring system is a recurring structural motif in numerous natural products such as Lancifodilactones, Micrandilactones and Rubriflordilactones. These polycyclic structures represent a synthetic challenge for organic chemists. Indeed, these molecules present at least nine stereogenic centers including several quaternary ones. The main goal of this work was to develop new metal-catalyzed reactions as key steps to obtain quickly and efficiently the polycyclic core of those natural products. The first part of these studies was dedicated to the development of a new palladium-catalyzed domino reaction leading to, depending on the conditions used, different polycyclic cores of nortriterpenoids coming from the same family, in a totally diastereoselective manner. This domino sequence of three reactions allowed the collective synthesis of various skeletons of natural products isolated from the Schisandra genus, in one pot. An approach to the tetracyclic core of Lancifodilactone F applying this methodology for the construction of the spirolactone moiety was then envisaged. A highly functionalized cycle D was synthetized in a diastereoselctive way via an Ireland-Claisen rearrangement and a ring closing metathesis reaction. Afterwards, an intramolecular cyclopropanation followed by the domino reaction should allow an access to the ABCD skeleton of Lancifodilactone F. In the last part, two approaches to the CDEF and ACDE cores of Rubriflordilactone A were developed around the same key reaction: a [2+2+2] cycloaddition of an acyclic triynic compound. The tricyclic skeleton CDE was reached at once in a single step. The ACDE tetracyclic moiety should be quickly accessible after few modifications of the initial strategy.

Made available in DSpace on 2015-05-14T13:21:22Z (GMT). No. of bitstreams: 1 ArquivoTotal.pdf: 18195512 bytes, checksum: 6229ab5e9f367190d5f7b4336c07dfec (MD5) Previous issue date: 2013-08-30 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / This study was designed based on the concept of achiral / meso compound. The importance of preparing achiral compounds is based on their structural simplification, leading to new molecules which require no further investigations pharmacodynamics and pharmacokinetics of the enantiomers. Therefore, it is proposed to the synthesis of analogues tetrahydropyrans achiral/meso using the Prins cyclization reaction. The homoallylic alcohols synthesized in this work were derived from the Barbier reaction obtained in great yields, wherein these products are used as a synthesis intermediate for the preparation of tetrahydropyrans proposed. The Prins cyclization reaction is an efficient method for the preparation of tetrahydropyrans therefore proved to be a powerful tool for synthesis and versatile for the preparation of substituted tetrahydropyrans to give all the compounds synthesized in satisfactory yields. Through spectroscopic and crystallographic studies were possible to determine in detail the relative configuration of the molecules 40a, 41a, 44a, 45a, 46a, 46b and 48b. Furthermore, a theoretical study was developed using the density functional theory to obtain the molecular geometries optimized in the gas phase, making it possible to compare these preferred conformations with geometries defined by crystals. The tetrahydropyrans bioevaluated were synthesized in the leukemic cell line K562 and two types of normal L929 cells and PBMC. The results were very promising in cancer in vitro assays, highlighting the hydrazones 42a-c and the 43a-c aminoguanidines they were the only compounds that were active against resistant cell line K562, highlighting the tetrahydropyran 42c which showed higher activity series counterpart (present value of IC50 7.59 μM) and the tetrahydropyran 42b with an excellent IC50 (8.97 μM) value and a good selectivity index (2.2 in L929 and 1.6 in PBMC). / Este trabalho foi idealizado baseado no conceito de compostos aquirais/meso. A importância da preparação de compostos aquirais está baseada na sua simplificação estrutural, conduzindo a novas moléculas que não necessitam de posteriores investigações farmacodinâmicas e farmacocinéticas dos enantiômeros. Sendo assim, propomos neste trabalho a síntese de análogos tetraidropirânicos aquirais/meso utilizando a reação de ciclização de Prins. Os álcoois homoalílicos sintetizados foram provenientes da reação de Barbier obtidos em ótimos rendimentos, no qual estes produtos foram utilizados como intermediário de síntese para a preparação dos tetraidropiranos propostos. A reação de ciclização de Prins é um método eficiente na preparação dos tetraidropiranos, pois mostrou-se ser uma ferramenta de síntese poderosa e versátil para a preparação dos tetraidropiranos substituídos, obtendo-se todos os compostos sintetizados em rendimentos satisfatórios. Através de estudos espectroscópicos e cristalográficos foi possível determinar detalhadamente a configuração relativa das moléculas 40a, 41a, 44a, 45a, 46a, 46b e 48b. Além disso, foi desenvolvido um estudo teórico utilizando a teoria do funcional densidade para se obter as geometrias moleculares otimizadas em fase gasosa, tornando possível comparar estas conformações preferenciais com as geometrias definidas pelos cristais. Os tetraidropiranos sintetizados foram bioavaliados na linhagem de células leucêmicas K562 e dois tipos de células normais L929 e PBMC. Os resultados em câncer foram bastante promissores nos ensaios in vitro, dando destaque para as hidrazonas 42a-c e as aminoguanidinas 43a-c que foram os únicos compostos que se mostraram ativos contra a linhagem celular resistente K562, destacando-se o tetraidropirano 42c que apresentou maior atividade da série congênere (apresentando valor de CI50 7.59 μM) e o tetraidropirano 42b que apresentou excelente valor de IC50 (8.97 μM) e um bom índice de seletividade (2.2 em L929 e 1.6 em PBMC).

Les travaux présentés dans ce mémoire décrivent une nouvelle voie de synthèse d'aminoalcools 1,2 à partir de γ-bromo-β-cétosulfoxydes, dans lesquels seul le centre stéréogène du soufre est défini. Cette synthèse s'appuie sur deux processus hautement stéréocontrôlés dirigés par le groupement sulfoxyde : le dédoublement cinétique dynamique lors de la substitution nucléophile du brome par la dibenzylamine et la réduction diastéréosélective du carbonyle. Les syn-γ-N,N-dibenzylamino-β-hydroxysulfoxydes correspondants ont été obtenus avec des excès diastéréoisomériques supérieurs à 95%. Les syn-γ-N,N-dibenzylamino-β-hydroxysulfoxydes se sont avérés être des intermédiaires très intéressants pour la synthèse de produits comportant le motif aminoalcool 1,2. Ainsi, nous avons décrit la préparation d'un 3-N,N-dibenzylamino-1,2-diol et son utilisation dans une nouvelle stratégie de déprotection régiodivergente d'acétals cycliques. Nous avons également décrit un nouvel accès aux cis-2-méthyl-6-alkylpipéridin-3-ols, via l'ouverture de cycle d'un 3-N,N-dibenzylamino-1,2-époxyde par l'azaénolate dérivé d'une hydrazone, et l'avons appliqué à la synthèse d'un alcaloïde, la (+)-déoxocassine. Parallèlement, nous avons débuté une étude de synthèse d'aminoalcools 1,3 par la réduction diastéréosélective d'une oxime dérivée d'un δ-céto-β-hydroxysulfoxyde. / In this thesis manuscript, we report on a new pathway to 1,2-aminoalcohols starting from chiral nonracemic γ-bromo-β-ketosulfoxides. This two-step approach, where the stereo control is provided by the sulfoxide group, relies on a highly stereocontrolled nucleophilic substitution of the bromine by dibenzylamine, combined with a dynamic kinetic resolution process, and the reduction of the carbonyl group. The corresponding syn-γ-N,N-dibenzylamino-β-hydroxysulfoxides were obtained with more than 95% diasteroisomeric excess. These syn-γ-N,N-dibenzylamino-β-hydroxysulfoxides turned out to be very useful intermediates for the synthesis of aminoalcohol containing products. Thus, we described the preparation of a 3-N,N-dibenzylamino-1,2-diol, and its use in an original strategy of regiodivergent cyclic acetals deprotection. We also developed a new access to "all cis"-2-methyl-6-alkylpiperidin-3-ols, by the mean of a 3-N,N-dibenzylamino-1,2-epoxide ring opening reaction with the azaenolate derived from an hydrazone. We applied this methodology to the synthesis of an alkaloid, (+)-deoxocassine. In addition, we studied a synthesis of 1,3-aminoalcohols using a diasteroselective reduction of a δ-keto-β-hydroxysulfoxyde-derived oxime.

This thesis is divided into three separate parts with amino alcohols as the common feature. The first part describes the development of a novel three-component approach to the synthesis of α-hydroxy-β-amino esters. Utilizing a highly diastereoselective Rh(II)-catalyzed 1,3-dipolar cycloaddition of carbonyl ylides to various aldimines, syn-α-hydroxy-β-amino esters formed in high yields and excellent diastereoselectivities. This methodology was also applied in a short enantioselective synthesis of the C-13 side-chain of Taxol. The second part of the thesis describes a total synthesis of D-erythro- Sphingosine based on a cross-metathesis approach to assemble the polar head group and the aliphatic chain. The last part deals with the application of amino alcohols as scaffolds in a diversity-oriented protocol for the development of libraries of small polycyclic molecules. The design of the libraries is based on the iterative use of two powerful ring-forming reactions; a ring-closing metathesis and an intramolecular Diels-Alder reaction, to simultaneously introduce structural complexity and diversity. / QC 20101222

No description available.

[pt] Neste trabalho foi desenvolvida a síntese de novos análogos do tipo N-tosil-aza-carbapterocarpanos com potencial ação antiproliferativa em linhagens de leucemia e mama.Os compostos aza-carbapterocarpanos e espiro-iso-indolinas, foram preparados através de abordagens sintéticas distintas e classificadas em Grupo I e II respectivamente. A etapa chave para obtenção dos compostos do grupo I foi a reação de aza-arilação do tipo Heck catalisada por paládio a partir de tetralonas comerciais e N-tosil-iodoanilinas substituídas previamente sintetizadas. Três moléculas deste grupo foram avaliadas quanto a sua ação antiproliferativa em linhagens de leucemia e mama. Dentre estas, o composto N-tosil-aza-carbaptercarpeno apresentou IC50 = 1,93 (mais ou menos) 0,88 micrômetros, 2,18 (mais ou menos) 1,47 micrômetros e 2.89 (mais ou menos) 0,92 micrômetros nas linhagens de leucemia K562, lucena-1 e FEPS, respectivamente, e na linhagem de mama MDA-MB-231 IC50=33.37 (mais ou menos) 3.98 micrômetros. Por outro lado, o composto aza-carbapterocarpeno foi inativo nestas mesmas linhagens, indicando que na ausência do grupo arilsulfonamida a ação antileucêmica não ocorre. Os compostos do grupo II, denominados espiro iso-indolinas, foram sintetizados através da adição diastereosseletiva de organomagnesío às N-terc-butano-sulfiniliminas quirais, seguida de uma aminação de Buchwald-Hartwig intramolecular catalisada por paládio. As N-terc-butano-sulfiniliminas foram obtidas através de tetralonas, cromanonas e tiocromanonas comerciais em uma reação de condensação com as N-tert-butanosulfinamidas comerciais em micro-ondas em uma abordagem livre de solvente utilizando tetraetóxido de titânio. Após as reações de adição nucleofílica com organomagnésio, remoção do auxiliar quiral e ciclização intramolecular, os compostos forma obtidos enantiomericamente puros e foram avaliados em linhagens de leucemia K562 e FESP. Embora estes compostos tenham apresentado baixa potência frente às linhagens testadas (IC50 entre 31,85 mais ou menos 3.0 micrômetros e 77,58 (mais ou menos) 5.76 micrômetros), pôde-se observar que há diferenças relevantes entre os enantiômeros, assim o como apresentam sensibilidade colateral, atuando em linhagens multiresitentes. / [en] In this work, the synthesis of new N-tosyl aza-carbapterocarpane analogues with potential antiproliferative action in leukemia and breast cell lines was developed. The aza-carbapterocarpanes and spiro-isoindolines compounds were prepared using different synthetic approaches and classified in Group I and II respectively. The key step for obtaining group I compounds was the palladium catalyzed Heck-type azaarylation reaction from commercially synthesized substituted tetralones and substituted N-tosyl iodoanilines. Three compounds of this group were evaluated for their antiproliferative action in leukemia cell lines and breast cancer cells lines. The compound N-tosyl-aza-carbaptercarpene presented IC50 = 1,93 0,88 , 2,18 (plus or minus) 1,47 micrometers e 2.89 (plus or minus) 0,92 micrometers. On the other hand, the aza-carbapterocarpene compound was inactive in these same lines, suggesting the role of the absence of the arylsulfonamide group for the antileukemic activity does not occur .The group II, denominated spiroisoindolines, were synthesized by diastereoselective addition of organomagnesium to chiral N-tert-butane sulfinylimines, followed by a palladium catalyzed intramolecular Buchwald-Hartwig amination. The N-tert-butane sulfinylimines were obtained through commercial tetralones, chromanones and thiochromanones by the condensation reaction with commercial N-tert-butanesulfinamides in a solvent free sistem using titanium tetraethoxide. After nucleophilic addition reactions with organomagnesium, chiral auxiliary removal and intramolecular cyclization, the compounds were obtained enantiomerically pure and were evaluated in K562 and FESP leukemia lines. Although these compounds presented low potency compared to the tested lines (IC50 between 31.85 (plus or minus) 3.0 micrometers and 77.58 (plus or minus) 5.76 micrometers), it was observed that there of them present relevant differences between enantiomers as soon as collateral sensitivity, acting in leukemia multiresistent cell lines.

Les iminosucres, analogues de sucres dans lesquels l'oxygène endocyclique a été remplacé par un atome d'azote, constitue une classe importante de mimes de sucres. Aujourd'hui, leurs applications se limitent au domaine biologique car ces composés ont montré un potentiel thérapeutique prometteur. Il serait intéressant d'élargir le domaine d'application de ces iminosucres, et la combinaison de ces structures présentant un azote endocyclique pourrait conduire à de nouveaux macrocycles inédits présentant des propriétés de chélation innovantes. Pour cela, l'introduction d'une chaîne alkyle en position pseudoanomérique donne accès à une nouvelle classe de composés, les iminosucres C-glycosides dont la fonctionnalisation en positions C-5 et C-1 est nécessaire.La première partie de ce travail se focalise sur le développement d'une voie de synthèse rapide et efficace d'iminosucres C-glycosides à six et sept chaînons au moyen d'une réaction tandem de Staudinger aza-Wittig. Pour accéder à ces composés de choix, notre stratégie se base sur des réactions de fonctionnalisation diastéréosélectives et stéréocontrollées. La seconde partie de cette thèse a été consacrée à la synthèse d'iminosucres aza-couronnes, dont les structures constituent un nouveau type de récepteurs moléculaires. L'étude des propriétés de chélation de ces nouveaux macrocycles des cations métalliques a montré des premiers résultats prometteurs et encourageants grâce à des analyses par RMN et par fluorimétrie. / Iminosugars, sugar analogs in which the endocyclic oxygen has been replaced by nitrogen, constitute a major class of sugar mimetics. Their application has been limited to the biological field so far as these compounds have shown promising therapeutic properties[1]. Interestingly, their structural analogy with sugars combined with the presence of an endocyclic nitrogen atom could deliver innovative macrocycles that could display chelation properties as well as catalytic potential when bound to metals and associated as duplex or higher multiplicity scaffolds. For this purpose, efficient introduction of an alkyl chain at the pseudoanomeric position of the iminosugar to yield an iminosugar C-glycoside[2] displaying two arms at C-5 and C-1 position is necessary. The first part of this work focused on the development of an efficient and convergent synthesis of seven and six membered iminosugars C-glycosides using a highly diastereoselective tandem Staudinger-Aza-Wittig reaction is presented. To access to these new compounds, our strategy is based on a highly diastereoselective and stereocontrolled functionalization. The second part of this work is based on the use of these structures to build up unprecedented iminosugar-aza-crowns, a new type of molecular receptors, using the strategy way developed in the first part. These news sweet aza-crowns displaying with various linkages showed promising results through their preliminary chelation properties by NMR and fluorimetric techniques.

Although α-keto carbocations have been demonstrated to be viable intermediates in solvolysis reactions, their applications in synthesis are scarce. These species can be considered to be equivalent to “reversed polarity” enolates and, as such, could be useful for the asymmetric formation of carbon-carbon and carbon-heteroatom bonds. In principle, facial selectivity in additions to α-keto carbocations may be induced using easily removed ester, amide, or imide chiral auxiliaries. Efforts to achieve such diastereoselective SN1 reactions of α-keto carbocations are described herein.