Esta dissertação apresenta um estudo de diferentes metodologias de imobilização (fisissorção, quimissorção com carboxibenzaldeído e quimissorção com glutaraldeído) da lipase de Burkholderia cepacia em nanopartículas magnéticas e sua aplicação na resolução cinética de alcoóis secundários racêmicos. O método de imobilização por fisissorção resultou na imobilização de 0,21 mg de proteína em 20 mg de nanopartículas magnéticas. Para a mesma quantidade de nanopartículas magnéticas, o método de quimissorção com carboxibenzaldeído imobilizou 0,26 mg de proteína contra 0,28 mg de proteína pelo método de quimissorção com glutaraldeído, a melhor relação encontrada neste trabalho. A atividade enzimática foi avaliada na resolução cinética de alcoóis secundários racêmicos [(RS)-2-bromo-1-(fenil)etanol, (RS)-2-bromo-1-(4-nitrofenil)etanol, (RS)-1-(4-nitrofenil)etanol e (RS)-1-(fenil)-1,2-etanodiol] via reação de transesterificação enantiosseletiva. O efeito de diferentes parâmetros reacionais para a resolução cinética foi estudado, como agente acilante, quantidade de substrato, solvente, quantidade de nanopartículas magnéticas (suporte), velocidade de agitação, tempo e temperatura reacionais. Os melhores parâmetros encontrados foram acetato de vinila como agente acilante, tolueno como solvente e sob agitação de 800 rpm. Observou-se que após 30 dias de estocagem da lipase imobilizada por fisissorção sua atividade foi mantida. Além disso, estudou-se a reciclagem da enzima imobilizada, durante a resolução cinética. A melhor temperatura e tempo reacional foram determinados para cada método de imobilização. A quimissorção com glutaraldeído foi o melhor método de imobilização para a reciclagem da enzima, pois durante 8 ciclos de resolução cinética a conversão (50 %) e a enantiosseletividade (>99 %) foram mantidas. Com base nesses resultados, pode-se concluir que o processo de imobilização permite um aumento da estabilidade da enzima quando comparada com a enzima livre, permitindo sua reutilização por vários ciclos reacionais. / This dissertation describes studies about different immobilization methodologies (physisorption, chemisorption with carboxibenzaldehyde and chemisorption with glutaraldehyde) of the Burkholderia cepacia lipase on magnetic nanoparticles and its application in the enzymatic kinetic resolution of chiral secondary alcohols. The physisorption method immobilized 0.21 mg of protein per 20 mg of magnetic nanoparticles. Using the same amount of magnetic nanoparticles, the chemisorption method with carboxibenzaldehyde immobilized 0.26 mg of protein against 0.28 mg for the chemisorption with glutaraldehyde, the best result found in this work. The enzymatic activity was determined in the enzymatic kinetic resolution of chiral secondary alcohols [(RS)-2-bromo-1-(phenyl)ethanol, (RS)-2-bromo-1- (4-nitrophenyl)ethanol, (RS)-1-(4-nitrophenyl)ethanol and (RS</I<)-1-(phenyl)- 1,2-ethanodiol] via enantioselective transesterification reaction. The effect of several reaction parameters for the kinetic resolution was studied, such as acetyl donor, substrate concentration, solvent, amount of magnetic nanoparticles (support), agitation speed, reaction time and temperature. The best results were obtained using vinyl acetate as acetyl donor, toluene as solvent, and 800 rpm as agitation speed. Regarding the physisorption method, after 30 days as storing time the enzymatic activity remained the same. Besides, the reusability of immobilized lipase was evaluated. The best temperature and reaction time in the kinetic resolution were determined for each immobilization method. The chemisorption with glutaraldehyde was the best immobilization method for the enzyme reusability, because even after 8 cycles of the kinetic reaction, the conversion (50 %) and enantioselectivity (>99 %) remained the same. Based on these results, it is possible to conclude that the immobilization process increased the enzyme stability when compared to the free enzyme, allowing its reusability for many reaction cycles.

Nesta dissertação estão descritos os resultados obtidos sobre a preparação de nanocascas funcionalizadas (nanopartículas ocas) de ouro/prata de diâmetro de 50 nm e imobilização de diferentes lipases (Burkholderia cepacia (BCL) e pâncreas de porco (PPL)). [Obs.: A imagem do esquema pode ser visto no arquivo PDF] Inicialmente as nanocascas de ouro/prata (NSs AgAu) foram sintetizadas e caracterizadas, através de imagens de MEV e MET. Através destas imagens algumas características das NSs AgAu foram elucidadas, como seu tamanho e sua característica oca. Em seguida, a funcionalização das NSs AgAu com diferentes moléculas mercapto-alcanóicas e uma molécula mercapto-amina foi realizada. Depois de funcionalizadas as NSs-funcionalizadas foram ativadas, com glutaraldeído ou EDC, para que assim elas ficassem aptas à imobilização das lipases, via ligação covalente. Para a BCL foi possível imobilizar 0,155-0,282 mg de proteína/3 mg do suporte. No caso da PPL uma menor quantidade de enzima foi imobilizada (0,035-0,048 mg/3 mg do suporte). A atividade da enzima imobilizada foi testada frente à reação de acetilação enantiosseletiva do (R,S)-1-feniletanol com acetato de vinila (RCE, resolução cinética enzimática). Excelentes resultados de conversão (50%) e seletividade (E > 200) foram conseguidos com a BCL imobilizada em todos os suportes. A PPL livre não catalisava a acetilação deste substrato e quando esta enzima foi imobilizada nas diferentes NSs-funcionalizadas, os resultados apresentados para acetilação enantiosseletiva do (R,S)-1-feniletanol com acetato de vinila foram interessantes. Nesse caso conseguimos alcançar conversões de até 4% do substrato R à sua forma acetilada com excelente enantiosseletividade ( > 99% e.e. do produto). Como uma alternativa de demonstrar a atividade enzimática da BCL imobilizada em reação tradicional de hidrólise, o teste da hidrólise do palmitato de p-Nitrofenila pela BCL livre e imobilizada foi realizado. Este teste revelou que a BCL imobilizada nas NSs-funcionalizadas catalisavam a hidrólise do palmitato de p-Nitrofenila mais rápido que a enzima livre, comprovando os bons resultados obtidos na RCE, mostrando que os sistemas onde tínhamos a BCL imobilizada foram mais eficientes que a enzima livre. As NSs AgAu, NSs-funcionalizadas e até as nanocascas contendo as lipases imobilizadas foram caracterizadas por de imagens de MEV e MET, análises de FT-IR e método de Bradford. Outros estudos com os sistemas contendo a BCL imobilizada foram elucidados. Diferentes funcionalizadores de diferentes tamanhos foram utilizados e a influência de cada um deles sobre a atividade enzimática foi estudado. Por exemplo, quando as NSs AuAg foram funcionalizadas com moléculas mercapto-alcanóicas menores, como por exemplo, o ácido mercapto acético, melhores resultados para a RC do (R,S)-1-feniletanol foram conseguidos. As diferentes formas de ativação da NSs-funcionalizadas utilizando glutaraldeído ou EDC, para consequente imobilização da BCL não resultaram em alterações da atividade enzimática na RC, apresentando valores idênticos para RCE. Experimentos para testar a estabilidade dos sistemas contendo a BCL imobilizada também foram feitos. Descobrimos que é possível armazenar a BCL imobilizada nos diferentes sistemas à - 4 °C por até 28 dias. O estudo da reciclagem destes sistemas revelou que por até 3 ciclos os sistemas conseguiram manter 90% da atividade enzimática. / This dissertation presents the results achieved on the preparation of functionalized gold/silver nanoshells (hollow nanoparticles, 50 nm) and immobilization of different lipases (Burkholderia cepacia (BCL) and porcine pancreatic (PPL)). Initially Gold/Silver nanoshells (NSs Ag Au) were synthesized and characterized through SEM and TEM pictures. By these images some characteristics of NSs AgAu were elucidated, as its size and hollow feature. The functionalization NSs AgAu with different mercapto-alkanoic molecules and mercapto-amine molecule was next step performed. After the functionalized NSs-functionalized were activated with glutaraldehyde or EDC, after that they remained suitable for the immobilization of lipases via covalent bond. BCL was possible immobilized 0.155-0.282 mg protein/3 mg of support. And the PPL a smaller amount of enzyme was immobilized (from 0.035-0.048 mg / 3 mg of support). The activity of the immobilized enzyme was assayed by the reaction enantioselective acetylation of (R,S)-1-phenylethanol with vinyl acetate (KR, kinetic resolution). Excellent conversion results (50%) and selectivity (E > 200) were achieved with the immobilized BCL. The free PLP did not catalyzed acetylation of the substrate and when this enzyme was immobilized on NSs-functionalized the results for enantioselective acetylation of (R,S)-1-phenylethanol with vinyl acetate were interesting. In this case we achieve conversions of 4% of the substrate (R) to acetylated form with excellent enantioselectivity (> 99% e.e. of the product). As alternative to demonstrate the enzymatic activity of BCL immobilized on traditional hydrolysis reaction, the hydrolysis of p-nitrophenyl palmitate by free and immobilized BCL was performed. This test revealed BCL immobilized on NSs-functionalized catalyzed hydrolysis of p-nitrophenyl palmitate faster than free enzyme, confirming the good results obtained in KR, showing that systems which had immobilized BCL were more efficient than the enzyme free. The NSs AgAu, NSs-functionalized and Nanoshells containing the immobilized lipases were characterized by SEM and TEM images , FT-IR analysis , the Bradford method. Other studies with systems containing immobilized BCL were elucidated. Different spacers with different sizes were used for functionalized the nanoshells, and the influence of each of the enzymatic activity was studied. For example, when the NSs were functionalized with smaller molecules mercapto-alkanoic and cysteamine best results for the KR (R,S)-1-(phenyl)ethanol were obtained. The different forms of activation of NSs-functionalized using glutaraldehyde or EDC, for subsequent immobilization of BCL did not result in changes in enzyme activity in the KR . Experiments to test the stability of systems containing immobilized BCL were also made . We found it possible to store the BCL immobilized on different systems at - 4 ° C for 30 days. The study of the recycling of these systems was made and by 3 cycles systems maintain 90% of the enzyme activity.

Apresenta-se, nesta tese, a síntese total do alcaloide marinho (+)-trans-triquentrina A. Três abordagens foram investigadas como estratégias sintéticas: uma adição conjugada assimétrica, um acoplamento arílico com um complexo de ferro e uma resolução cinética enzimática. Esta última permitiu finalizar a síntese do produto natural em 20 etapas e com 0,6% de rendimento global. A síntese tem como etapas-chave a resolução cinética de um éster racêmico, mediada pela lipase da Pseudomonas cepacia - que forneceu o (S)-ácido correspondente em excelente excesso enantiomérico - e a contração de anel de um ciclo-hexeno substituído promovida por um sal de tálio(III), fornecendo seletivamente o composto trans-1,3-dimetilciclopentano correspondente. Efetuaram-se testes visando à síntese total da (+)-cis-triquentrina A a partir de um intermediário obtido da etapa de resolução cinética enzimática, que seria comum à síntese das duas moléculas-alvo. Investigou-se a atividade antiproliferativa da (+)-trans-triquentrina A, bem como a de intermediários da síntese e de produtos relacionados. Estes estudos permitiram descobrir compostos com atividade potente frente a linhagens de células tumorais humanas de ovário (GI50=0,31-0,42 &#181;g.mL-1) e de cólon (GI50=0,25 &#181;g.mL-1). / The total synthesis of marine alkaloid (+)-trans-trikentrin A is presented in this thesis. Three approaches were investigated as synthetic strategies: an asymmetric conjugate addition, an aryl coupling with an iron complex and an enzymatic kinetic resolution. The latter allowed the synthesis of the natural product to be achieved in 20 steps and 0.6% overall yield. The synthesis features as key steps a kinetic resolution of a racemic ester, which was mediated by the lipase from Pseudomonas cepacia, leading to the corresponding (S)-acid in excellent enantiomeric excess, as well as a thallium(III)-mediated ring contraction of a cyclohexene derivative that selectively afforded the corresponding trans-1,3- dimethylcyclopentanic compound. Studies toward the total synthesis of (+)-cis-trikentrin A were performed aiming to achieve both natural products from a common intermediate, obtained from the enzymatic kinetic resolution. The antiproliferative activity of (+)-trans-trikentrin A as well as that of intermediates and related products was investigated. Compounds with potent activity against ovarian (GI50=0.31- 0.42 &#181;g.mL-1) and colon (GI50=0.25 &#181;g.mL-1) tumor cell lines were discovered during these studies.

A obtenção de moléculas enantiomericamente puras ou enriquecidas tem se demonstrado um desafio em química orgânica sintética. Nesse âmbito, a biocatálise aparece como uma importante ferramenta sintética. Neste trabalho, desenvolveu-se uma metodologia para a obtenção de 6-hidróxioct-7-inoato de metila, 5-hidróxihept-6-inoato de metila, e 4-hidróxihex-5-inoato de metila enantiomericamente enriquecidos via resolução cinética enzimática. Primeiramente foram investigadas variáveis como temperatura, tempo, quantidade de doador de acila, solvente e enzima adequada para a reação. Em uma segunda etapa do trabalho, foram desenvolvidas seqüências reacionais onde os hidroxiésteres originariam moléculas bioativas Utilizando o 5-hidróxihept-6-inoato de metila, após três etapas reacionais, foi possível sintetizar intermediários sintéticos avançados das moléculas bioativas goniotalamina e argentilactona. De maneira análoga, após algumas etapas reacionais, o 4-hidróxihex-5-inoato de metila originou os feromônios buibuilactona, japonilura e 4-hexanolida / The synthesis of enantiomerically pure or enriched molecules has been an important challenge in synthetic organic chemistry. Among a variety of disciplines dedicated to achive this goal, biocatalysis appears as an important synthetic tool. Herein, we developed a methodology to obtain methyl 6-hydroxyoct-7-ynoate, methyl 5-hydroxyhept-6-ynoate and methyl 4-hydroxyhex-5-ynoate enantiomerically enriched by an enzymatic kinetic resolution. Reaction conditions such as temperature, reaction time, amount of acyl donor, solvent and enzyme were screened, in order to obtain high yields and enantioselectivities. In the second part of our work, synthetic pathways were developed where the hydroxyesters lead to bioactive molecules. Using methyl 5-hydroxyhept-6-ynoate, after three steps, advanced synthetic intermediates for the synthesis of the bioactive molecules, such as goniothalamine and argentilactone, were prepared. In the same way, methyl 4-hydroxyhex-5-ynoate was submitted to a reaction sequence leading the pheromones buibuilactone, japonilure and 4-hexanolide.

Cette thèse traite de dédoublement cinétique, de fonctionnalisation et d’utilisation de composés chiraux dérivés de polyoxométalates lacunaires de structure Dawson [α1-P2W17O61]10¬-. La première partie traite de l’utilisation de complexes organosolubles TBA5K[α1-Hf-P2W17O61] pour catalyser l’addition de nucléophiles comme des ethers d’énol ou des acétals de cétènes silylés mais également des pronucléophiles sur des hémiaminals. La seconde partie détaille l’étude sur la préparation et l’utilisation de trichlorostannanes énantiopures en vue du dédoublement cinétique des composés chiraux lacunaires [α1-P2W17O61]10-¬. La fonctionalisation diastéréosélective de derive chiraux organosoluble TBA7[α2-RSnP2W17O61] est également présentée. Le dernier chapitre décrit des hybrides chiraux POM-imidazolidinones dont la chiralité est uniquement apportée par le polyanion. Utilisé avec succès pour catalyser de manière énantiosélective des réactions de Diels Alder, ces composés sont les premiers POM de structure chirale a transféré la chiralité de manière aussi efficace vers des composés organiques. / This manuscript deals with the kinetic resolution, the functionalization and the use of chiral lacunary Dawson α1-POM [α1-P2W17O61]10-¬. The first part deals with the racemic organo-soluble TBA5K[α1-Hf-P2W17O61] complex used to catalyze the nucleophilic addition of silyl enol ethers, ketene-acetals and activated methylene C-nucleophiles onto hemiaminals. The second part describes the synthesis of enantiopure trichlorostannane complexes as resolving agents for the kinetic resolution of chiral [α1-P2W17O61]10-¬. The diastereoselective functionalization of organosoluble chiral TBA7[α2-RSnP2W17O61] is also reported. The final chapter describes chiral POM imidazolidinones hybrids based on the known chiral α1-Dawson POM. Successfully applied as asymmetric catalysts in Diels-Alder reactions, these compounds are the first intrinsically chiral POM to efficiently transfer chirality to organic products.

Les 1,3-diols acycliques sont des motifs ubiquitaires, essentiels dans la structure de nombreux produits naturels. Le développement d’approches permettant leur obtention de manière énantiosélective se révèle donc d’un grand intérêt synthétique. Dans ce contexte, notre équipe a envisagé une stratégie reposant sur des transferts d’acyle énantiosélectifs organocatalysés multiples. Cette approche a abouti à la mise en oeuvre d’une méthodologie de désymétrisation énantiosélective organocatalysée de 1,3-diols méso acycliques. Les composés ainsi obtenus constituent des briques moléculaires aisément valorisables en synthèse totale. Une approche similaire a permis de décrire, dans un second temps, une méthode inédite de double dédoublement cinétique de 1,3-diols anti. Générale et pratique, ce procédé fournit des diols énantiopurs de structures variées. La particularité de ces méthodologies réside dans l’exploitation du principe de Horeau se traduisant par une amplification de l’énantiosélectivité déployée par le catalyseur chiral. Les isothiourées employés dans ces réactions constituent une famille de bases de Lewis azotées dont la capacité à promouvoir les réactions d’acylation énantiosélectives n’a été découverte que récemment. Bien que leur utilisation en catalyse énantiosélective se soit rapidement démocratisée, les éléments structuraux responsables de leur sélectivité n’ont pas été totalement identifiés. Avec le nouvel objectif d’établir une relation entre structure, réactivité et sélectivité de ces molécules, des isothiourées originales ont été synthétisées et leur potentiel catalytique étudié en détail. / Acyclic 1,3-diols are ubiquitous scaffolds, essential in the structure of numerous natural products. The developpment of innovative pathways allowing their enantioselective obtention is of first interst in organic synthesis. In this context, our team envisaged a strategy of multiple organocatalyzed enantioselective acyl transfers. This approach led to the implement of a methodology based on the organocatalyzed desymmetrization of meso 1,3-diols. The desymmetrized compounds were obtained with high level of enantioselectivity and were used as useful building blocks easily valorizable in total synthesis. In a second time, we developed an organocatalyzed method of double kinetic resolution (DoCKR) of anti 1,3-diols. Very general, practicable and useful, this process allows the preparation of enantiopur diols with a large structural diversity. The particularity of these methods reside in the exploitation of the Horeau principle leading to the amplification of the enantioselectivity. These phenomons of kinetic amplification, often anecdotic, were used in this study as a powerful tool.The employed isothioureas belong to the nitrogenated Lewis bases family which were discovered only very recently to promote enantioselective acyl transfer. Although their uses in enantioselective catalysis were rapidly democratized, the structural feature responsible of their selectivity are not all clearly identified. To establish a relationship between structure, reactivity and selectivity of theses molecules, new isothioureas were synthesized and evaluated in enantioselective catalysis.

Devant l’intérêt grandissant pour le développement de stratégies innovantes applicables à la synthèse de molécules complexes, notre groupe s’est orienté vers la construction de motifs présents dans un grand nombre de produits biologiquement actifs : les tétrahydropyranes (THP) et les polypropionates. Notre stratégie, basée sur la formation diastéréosélective de diols méso primaires, fait intervenir une étape inédite de désymétrisation organocatalysée par transfert d’acyle asymétrique. Cette approche permet la synthèse énantiosélective de THP pentasubstitués qui par la suite peuvent être valorisés par l’obtention de polypropionates fonctionnalisés, possédant quatre centres stéréogènes contigus. Par ailleurs, cette nouvelle méthodologie de désymétrisation donne accès à des motifs cycliques et acycliques comportant plusieurs centres stéréogènes quaternaires. Elle constitue, de plus, l’unique exemple de désymétrisation énantiosélective de diols méso primaires catalysée par une dialkylaminopyridine chirale. Bien que le transfert d’acyle asymétrique organocatalysé ait été très largement étudié depuis la fin des années 90, de nombreuses études sont en cours pour accéder à des catalyseurs plus sélectifs et plus nucléophiles. Inspiré des récents travaux de Steglich et Vedejs, notre deuxième objectif s’est porté sur la synthèse énantiosélective et modulaire d’une nouvelle famille d’organocatalyseurs chiraux plus polyvalents dérivés de la 1,6-naphtyridine. Leur application, en catalyse nucléophile, a pu être évaluée dans des réactions de dédoublement cinétique d’alcools et dans les réarrangements de Steglich. / Alongside metallocatalysis and biocatalysis, organocatalysis has emerged as a complementary and powerful tool that can circumvent limitations associated to the use of metals or enzymes. Because of the growing interest for new innovative methodologies useful for complex molecules synthesis, we get interested in the preparation of versatile building blocks present in many bioactive molecules: tetrahydropyrans (THP) and polypropionates. Based on the diastereoselective formation of primary meso diols, our strategy involves an original organocatalyzed desymmetrization of these compounds by asymmetric acyl transfer. This approach allows the enantioselective synthesis of pentasubstituted THP which were valorized through the synthesis of polypropionates bearing four consecutive stereogenic centers. In addition, this new methodology provides cyclic and acyclic scaffolds with several all carbon quaternary stereogenic centers. It represents the first example in organocatalyzed asymmetric desymmetrization by acyl transfer using a chiral dialkylaminopyridine. Although asymmetric organocatalyzed acyl transfer has been widely studied since the late 90s, several investigations are currently underway to access to new chiral nucleophilic catalysts. Following the recent work of Steglich and Vedejs, we were interested in the development of new chiral organocatalysts derived from 1,6-naphthyridine. Their applications in nucleophilic catalysis have then been evaluated in kinetic resolutions of alcohols and in asymmetric Steglich rearrangements.

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.

Im Rahmen dieser Arbeit wird eine neuartige Deoxygenierungskaskade von Flavanonen bzw. Isoflavanonen via asymmetrischer Transferhydrierung (ATH) beschrieben. Diese Methodik ermöglicht einen einstufigen Zugang zu enantiomerenreinen Flavanen bzw. Isoflavanen aus entsprechenden racemischen Ketonen. Unter Verwendung der ATH-Deoxygenierungskaskade werden hoch enantioselektive Naturstoffsynthesen elaboriert. So erfolgt eine effiziente Darstellung der Flavane Brosimin A, Brosimin B, Brosimacutin L, Kazinol U und 7,3‘-Dihydroxy-4‘-methoxyflavan. Darüber hinaus wird mittels dynamischer kinetischer Racematspaltung die Totalsynthese der Isoflavane Equol, Manuifolin K und Eryzerin D beschrieben.

Die Desymmetrisierung eines p-Benzochinon-Monoacetals durch organokatalytische Sulfa-Michael-Addition stellte den C-Ring-Baustein für eine Formalsynthese von (-)-Codein bereit. Mittels diastereoselektiver 1,2-Addition zur A/C-Ringverknüpfung, intramolekularer Nitron-Cycloaddition zur Konstruktion des Phenanthren-Gerüsts und Sulfoxid-Eliminierung konnte das Schlüsselintermediat einer früheren racemischen Codeinsynthese über 12 Stufen ausgehend von Isovanillin in enantiomerenreiner Form verfügbar gemacht werden.