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Treballs Finals de Grau de Química, Facultat de Química, Universitat de Barcelona, Any: 2022, Tutors: Antoni Riera Escalé, Marina Bellido Muñoz, The synthesis of chiral natural products has long been the focal point in the field of asymmetric catalysis since both stereoisomers usually have different bioactivity. Within all the catalytic asymmetric methodologies, homogeneous transition-metal catalyzed hydrogenation plays a pivotal role. Our group has been working in the Ir-catalyzed asymmetric hydrogenation reactions of several substrates such as sulfones, which are versatile building blocks in synthetic chemistry. In this respect, the group recently developed a methodology to synthesize homoallylic sulfones through a highly selective process which has set the stage for the synthesis of different natural products. The previously mentioned methodologies have established the framework for the synthesis and the Ir-catalyzed asymmetric hydrogenation of homoallylic sulfones. In the present work, the applicability of these methodologies has been demonstrated through the synthesis of (+)-⍺-curcumene 1 and an advanced intermediate of (−)-curcuquinone 2.

[spa] La industria vitivinícola genera una gran cantidad de subproductos. Entre ellos el subproducto más abundante son los sarmientos de vid originados durante la temporada de poda. Los sarmientos de vid poseen una mezcla compleja de compuestos fenólicos los que incluyen ácidos fenólicos, flavonoides, y estilbenos, que a su vez están asociados con una amplia gama de beneficios para la salud. El perfil fenólico de los sarmientos es altamente dependiente del tipo de cultivar, la zona geográfica de cultivo, y de las condiciones de almacenamiento posteriores a la poda. Los procesos y sistemas de extracción también influyen fuertemente en el perfil de los compuestos fenólicos. Aunque existen numerosos estudios de recuperación e identificación de compuestos fenólicos obtenidos desde sarmientos de vid, muy pocos de ellos se han centrado en el estudio del escalamiento de los procesos de extracción y en el efecto sobre el perfil fenólico. Por otro lado, los compuestos fenólicos son reconocidos por ser inestables y sensibles a altas temperaturas, la luz, el pH y las enzimas oxidativas y degradantes. Estas variables afectan al perfil fenólico tanto en los procesos de producción como en la estabilidad de los productos finales. Una opción viable a escala industrial que permite solucionar estos problemas es la encapsulación de estos compuestos en ciclodextrinas, que les proporcionan una matriz protectora y les ayuda a preservar sus actividades biológicas. Por todas estas razones, esta tesis tiene por objetivo estudiar los cambios en el perfil fenólico de un extracto de sarmientos durante su producción y encapsulación, mediante cromatografía de líquidos acoplada a espectrometría de masas de alta resolución. La espectrometría de masas de alta resolución basada en LC-ESI-LTQ-Orbitrap-MS ha demostrado ser una poderosa herramienta de identificación y caracterización de compuestos fenólicos. El uso de este equipo nos permitió identificar nuevos compuestos en los extractos de sarmientos de vid producidos a escala de laboratorio. También fue útil para estudiar los cambios en el perfil fenólico durante la extracción a escala piloto y posterior encapsulación de estos compuestos en ciclodextrinas. Los resultados de esta tesis doctoral permitieron ampliar el conocimiento del perfil fenólico de los extractos de sarmientos de vid, analizar las diferencias de los extractos desde la extracción de laboratorio, a la extracción piloto hasta su posterior encapsulación en ciclodextrinas, permitiendo el desarrollo de un producto de alto valor agregado y con futuras aplicaciones en las industrias alimentaria y farmacéutica., [eng] The wine industry produces many by-products. The most common by-product is the grape canes (or vine shoots) that are produced during the pruning season. Grape canes contain a complex mixture of phenolic compounds, including phenolic acids, flavonoids, and stilbenes, which in turn have been linked to several health benefits. The phenolic profile of grape canes is highly dependent on the variety, the geographical area of cultivation, and the storage conditions after pruning. Extraction methods and systems also strongly influence the profile of phenolic compounds. Although there are numerous studies on the extraction and identification of phenolic compounds from grape canes, very few of them have focused on the study of the scaling-up of the extraction process and the effects on the phenolic profile. On the other hand, phenolic compounds are known to be unstable and sensitive to high temperature, light, pH, and oxidative and degradative enzymes. These variables affect the phenolic profile both in the production processes and in the stability of the final products. A viable way to address these issues on an industrial scale is to encapsulate these compounds in cyclodextrins, which allows them to obtain a protective matrix and retain their biological activities. For all these reasons, this PhD aims to study the changes in the phenolic profile of a grape cane extract during its production and encapsulation using liquid chromatography coupled with high-resolution mass spectrometry. High-resolution mass spectrometry-based on LC-ESI-LTQ-Orbitrap-MS has proven to be a powerful tool for the identification and characterization of phenolic compounds. The use of this equipment allowed us to identify new compounds in extracts of grape canes. It was also useful to study the changes in phenolic profile during pilot-scale extraction and subsequent encapsulation of these compounds in cyclodextrins. The results of this PhD allowed to increase the knowledge of the phenolic profile of extracts from grape canes, to analyze the differences of the extracts from laboratory extraction to pilot extraction and their encapsulation in cyclodextrins, leading to the development of a product with high added value and with future applications in the food and pharmaceutical industries.

[spa] En esta Tesis doctoral se ha abordado la síntesis total de la Anfidinolida B2, un macrociclo de 25 miembros aislado por primera vez por Shimizu y colaboradores en 1994 en Brewer’s Bay, Santo Tomás, una de las Islas Vírgenes de los Estados Unidos de América. Posee una estructura compleja y una importante toxicidad. Aunque actualmente se acepta la propuesta de estructura de Carter (2013), esta no ha sido confirmada todavía, por lo que su síntesis total es un objetivo muy atractivo. Nuestra retrosíntesis se basa en la desconexión del macrólido en cuatro fragmentos más sencillos, cuya síntesis, optimización y unión son los objetivos de este trabajo. En el capítulo 2 se ha optimizado la preparación del Fragmento I, ya que la síntesis desarrollada anteriormente en el grupo presentaba ciertos inconvenientes. Por ello, decidimos optimizar la preparación de la cetona 10, un intermedio clave. Se investigaron seis rutas, concluyendo que más adecuada para preparar el Fragmento I transcurría en seis etapas a partir del metil-malonato de dietilo y con un rendimiento del 44%. En el capítulo 3 abordamos la optimización de la síntesis del Fragmento II. Inicialmente optimizamos una síntesis anterior, obteniendo el Fragmento II en 11 etapas y con un 17% de rendimiento a partir del (S)-lactato de metilo. Debido al elevado número de etapas de esta síntesis, exploramos dos alternativas. Pese a los prometedores resultados iniciales, ninguna de las dos rutas resultó factible. Una cuarta vía alternativa, no ha podido ser explorada por falta del material necesario. El Fragmento III se preparó en el capítulo 4 siguiendo una retrosíntesis anteriormente descrita en nuestro grupo. No obstante, obtuvimos resultados desalentadores en las transformaciones iniciales, por lo que se optó por modificar esta parte problemática de la ruta, preparando los mismos intermedios a partir de otros materiales de partida. De esta manera obtuvimos el Fragmento III en seis etapas y con un 52% de rendimiento a partir del butano-1,4-diol. Debido a que el Fragmento IV presenta ciertos grupos lábiles, en el capítulo 5 se estudió la preparación del Fragmento IV acortado, una versión más sencilla del fragmento inicial. Para ello se prosiguió una retrosíntesis anterior. Debido a que una etapa intermedia transcurría con rendimientos moderados y poco reproducibles, se estudió una aproximación alternativa. No obstante, los resultados eran peores que los de la ruta inicialmente propuesta, por lo que esta se descartó, preparando finalmente el Fragmento IV en tres etapas con un 44% de rendimiento a partir del 2,3-dibromopropeno. Una vez obtenidos los distintos Fragmentos, se procedió a su unión en el capítulo 6. En primer lugar, unimos el Fragmento I con el IV a través de un acoplamiento cruzado de Negishi. El compuesto obtenido se transformó en el yoduro correspondiente, que se sometió a un segundo acoplamiento de Negishi. Este transcurrió con rendimientos bajos y, además, era muy poco reproducible. Por ello, estudiamos una ruta alternativa que evitase esta transformación. Así pues, desarrollamos una nueva vía que promete ser una mejor alternativa que la originalmente propuesta. Solo se pudo llevar esta ruta a escala reducida, por lo que estos resultados aún no son concluyentes. El compuesto así obtenido, resultante de la unión de los Fragmentos I y IV, se sometió a la desprotección del hidroxilo terminal y se introdujo el grupo epoxialdehído deseado mediante una oxidación de Dess–Martin y una epoxidación de Jørgensen. Más tarde, se añadió el Fragmento III mediante una olefinación de Julia–Kocienski y se hidrolizó el éster con trimetilsilanoato de potasio. A continuación, una esterificación de Shiina permitió unir el último Fragmento, el Fragmento II. Estas etapas transcurrieron con rendimientos bajos, por lo que se optimizaron. Pese a nuestros intentos, solo se pudieron obtener rendimientos moderados. En estos momentos estamos llevando a cabo la siguiente etapa, la metátesis de cierre de anillo, y esperamos los resultados correspondientes., [eng] In this Thesis we have undertaken the total synthesis of Amphidinolide B2, a 25-membered macrolide. It was first isolated by Shimizu and coworkers in 1994, from Brewer’s Bay, Saint Thomas, one of USA’s Virgin Islands. This molecule has a very interesting structure and an important cytotoxicity. Carter’s proposal of the structure of Amphidinolide B2 has yet to be confirmed, so that the total synthesis of this macrolide becomes an attractive goal. Our proposal for the synthesis of this molecule is based on the disconnection of the macrocycle into four, more simple, Fragments. In Chapter 2 the preparation of Fragment I was optimized, as the previously developed syntheses were relatively unsuccessful. Six different routes were studied for the preparation of ketone 10, a key intermediate in our synthesis. Finally, Fragment I was obtained in six steps, in a 44% yield starting from methyl-diethyl malonate. In Chapter 3 we approached the synthesis of Fragment II. Originally, we optimized a previous synthesis developed in group for this Fragment, obtaining the desired compound in 11 steps and a 17% yield starting from (S)-methyl lactate. Due to the high number of steps of this route, we explored two alternatives. However, both were unsuccessful. Fragment III was prepared in Chapter 4, following a retrosynthesis previously described in our group. However, discouraging results were obtained in the initial transformations, which made us search for a new route. In the end, Fragment III was obtained in six steps and in a 52% yield starting from butane-1,4-diol. The preparation of a shortened version of Fragment IV is described in Chapter 5, following a previous retrosynthesis. Because an intermediate step proved troublesome, a new approximation was studied, with no success. Finally, Fragment IV was prepared in three steps and in a 44% yield starting from 2,3-dibromopropene With the different Fragments in our hands, their coupling was investigated. Initially, we joined Fragment I with Fragment IV via a Negishi cross coupling. The obtained product was then transformed into the corresponding iodide, which was used in a second Negishi cross coupling. Despite our efforts, low yields were obtained in this transformation which also showed little reproducibility. Therefore, an alternative, promising route was investigated. After functional group manipulation, the desired epoxyaldehyde was prepared. Then, Fragment III was introduced via a Julia–Kocienski olefination. Hydrolysis of the ester, followed by a Shiina esterification was used to link Fragment II. At this moment, we are exploring the next step, the ring closing metathesis for the formation of the macrocycle.

[spa] La industria vitivinícola genera una gran cantidad de subproductos. Entre ellos el subproducto más abundante son los sarmientos de vid originados durante la temporada de poda. Los sarmientos de vid poseen una mezcla compleja de compuestos fenólicos los que incluyen ácidos fenólicos, flavonoides, y estilbenos, que a su vez están asociados con una amplia gama de beneficios para la salud. El perfil fenólico de los sarmientos es altamente dependiente del tipo de cultivar, la zona geográfica de cultivo, y de las condiciones de almacenamiento posteriores a la poda. Los procesos y sistemas de extracción también influyen fuertemente en el perfil de los compuestos fenólicos. Aunque existen numerosos estudios de recuperación e identificación de compuestos fenólicos obtenidos desde sarmientos de vid, muy pocos de ellos se han centrado en el estudio del escalamiento de los procesos de extracción y en el efecto sobre el perfil fenólico. Por otro lado, los compuestos fenólicos son reconocidos por ser inestables y sensibles a altas temperaturas, la luz, el pH y las enzimas oxidativas y degradantes. Estas variables afectan al perfil fenólico tanto en los procesos de producción como en la estabilidad de los productos finales. Una opción viable a escala industrial que permite solucionar estos problemas es la encapsulación de estos compuestos en ciclodextrinas, que les proporcionan una matriz protectora y les ayuda a preservar sus actividades biológicas. Por todas estas razones, esta tesis tiene por objetivo estudiar los cambios en el perfil fenólico de un extracto de sarmientos durante su producción y encapsulación, mediante cromatografía de líquidos acoplada a espectrometría de masas de alta resolución. La espectrometría de masas de alta resolución basada en LC-ESI-LTQ-Orbitrap-MS ha demostrado ser una poderosa herramienta de identificación y caracterización de compuestos fenólicos. El uso de este equipo nos permitió identificar nuevos compuestos en los extractos de sarmientos de vid producidos a escala de laboratorio. También fue útil para estudiar los cambios en el perfil fenólico durante la extracción a escala piloto y posterior encapsulación de estos compuestos en ciclodextrinas. Los resultados de esta tesis doctoral permitieron ampliar el conocimiento del perfil fenólico de los extractos de sarmientos de vid, analizar las diferencias de los extractos desde la extracción de laboratorio, a la extracción piloto hasta su posterior encapsulación en ciclodextrinas, permitiendo el desarrollo de un producto de alto valor agregado y con futuras aplicaciones en las industrias alimentaria y farmacéutica. [eng] The wine industry produces many by-products. The most common by-product is the grape canes (or vine shoots) that are produced during the pruning season. Grape canes contain a complex mixture of phenolic compounds, including phenolic acids, flavonoids, and stilbenes, which in turn have been linked to several health benefits. The phenolic profile of grape canes is highly dependent on the variety, the geographical area of cultivation, and the storage conditions after pruning. Extraction methods and systems also strongly influence the profile of phenolic compounds. Although there are numerous studies on the extraction and identification of phenolic compounds from grape canes, very few of them have focused on the study of the scaling-up of the extraction process and the effects on the phenolic profile. On the other hand, phenolic compounds are known to be unstable and sensitive to high temperature, light, pH, and oxidative and degradative enzymes. These variables affect the phenolic profile both in the production processes and in the stability of the final products. A viable way to address these issues on an industrial scale is to encapsulate these compounds in cyclodextrins, which allows them to obtain a protective matrix and retain their biological activities. For all these reasons, this PhD aims to study the changes in the phenolic profile of a grape cane extract during its production and encapsulation using liquid chromatography coupled with high-resolution mass spectrometry. High-resolution mass spectrometry-based on LC-ESI-LTQ-Orbitrap-MS has proven to be a powerful tool for the identification and characterization of phenolic compounds. The use of this equipment allowed us to identify new compounds in extracts of grape canes. It was also useful to study the changes in phenolic profile during pilot-scale extraction and subsequent encapsulation of these compounds in cyclodextrins. The results of this PhD allowed to increase the knowledge of the phenolic profile of extracts from grape canes, to analyze the differences of the extracts from laboratory extraction to pilot extraction and their encapsulation in cyclodextrins, leading to the development of a product with high added value and with future applications in the food and pharmaceutical industries.

[spa] La presente Tesis versa acerca de estudios sintéticos en el campo de los alcaloides Daphniphyllum, una familia de productos naturales con estructuras de un elevado interés sintético debido a su complejidad estructural y las propiedades biológicas que presentan. En primer lugar se han sintetizado building-blocks que contengan sistemas cis-azabicíclicos de 3- metiloctahidroindol, 3a-metiloctahidrociclohepta[b]pirrol y 9b-metilbenzo[e]indol, para su posterior aplicación a aproximaciones de novo de ciertos alcaloides Daphniphyllum. El nexo de unión del trabajo metodológico para acceder a los building-blocks elegidos, reside en la utilización de ciclaciones radicalarias 5-endo-trig para el acceso a gamma-lactamas a partir de haloenamidas y eninos, obtenidos mediante procesos de acetilación de iminas y enaminas. Utilizando como sustrato de partida la 1,4-ciclohexanodiona protegida, y mediante un proceso estereocontrolado de 3 etapas: formación de la enamida, ciclación radicalaria bajo condiciones reductoras y finalmente una hidrogenación, permitió la obtención de 3-metiloctahidrondoles funcionalizados en C-5 y con una estereoquímica trans entre el grupo metilo y los protones de la posición de fusión. La formación de octahidrociclohepta[b]pirroles se llevó a cabo mediante el mismo proceso radicalario con previa expansión de anillo tanto de un derivado de N-cicloalquenil tricloroacetamida como mediante la expansión de anillo de un sistema octahidroindólico sintetizado en el grupo de investigación, obteniéndose, en ambos procedimientos, gamma-lactamas polifuncionalizadas con una fusión cis y un estereocentro cuaternario carbonado en la fusión del anillo. Por otra parte, se ha desarrollado una nueva ruta sintética hacia el alcaloide dafenilina, el único miembro de los alcaloides Daphniphyllum que contiene un anillo bencénico en su estructura. Además, consta de un esqueleto reordenado de tipo 22-norcalicifilina A que incluye un sistema hexacíclico [6.6.5.7.6.5] y seis centros estereogénicos, uno de ellos cuaternario. Hasta el presente, se han descrito cinco síntesis totales, la primera de ellas en 2013. La síntesis se inició con 1-metil-2-tetralona en su forma racémica. Aplicando la misma metodología radicalaria, se generó un 9b-metilbenzo[e]indol a partir de la correspondiente tricloroacetilenamida, así como la formación del único centro cuaternario. La estereoestructura de este sistema azatricíclico fue la clave para la génesis diastereoselectiva de los centros estreogénicos requeridos para acceder al sistema pentacíclico. La introducción de una cadena lateral en C(6), controlada por efectos estéricos debidos a la disposición del grupo metilo en C(5), y reducción diastereoselectiva de una enamida con posterior ciclación de Friedel Crafts intramolecular, permitieron la formación del sistema tertacíclcio ACDE con un grupo carbonilo bencílico que presentaba una reactividad muy baja. Este hecho determinó que la reacción de alquilación en C(10) se llevase a cabo mediante una alfa-alquilación de un enolato generado a partir de un producto resultante de una transposición carbonílica 1,2 cuya regioselectividad está controlada por su carácter bencílico. La instalación de las cadenas precursoras de los anillos D y F en C(6) y C(10) fue controlada por la topología molecular de los intermedios sintéticos, en los que la cara cóncava es más accesible que la convexa. Finalmente, una ciclación de Friedel Crafts intramolecular permitió la obtención del fragmento ACDEF de la dafenilina después de 21 etapas con un rendimiento global del 6.5%., [eng] The Daphniphyllum alkaloids comprise more than 320 natural compounds having almost 20 different polycyclic frameworks and diverse biological activities. The work developed in this PhD thesis is focused mainly on developing new synthetic approaches to access three different azapolycyclic building blocks, which can be useful to explore new synthetic pathways to synthesize some structural types of Daphniphyllum alkaloids. The common key carbon−carbon bond-forming step in our synthetic approach is a stereocontrolled 5-endo-trig radical cyclization of an N-(2-methylcycloalkenyl) trichloroacetamide derivative involving a tetrasubstituted enamide to achieve polyfunctionalized gamma-lactams. The first building block investigated was a 3-methyl-cis-octahydroindole with a relative configuration, in which the methyl group was trans to the hydrogen atoms in the cis-ring fusion. This bicyclic structure is found in yuzurimine- and daphniglaucine-types alkaloids and only one stereoselective procedure was previously reported for its synthesis. Starting from 1,4.cyclohexanedione monoethylene acetal, a three-steps sequence (enamide formation, radical cyclization, and hydrogenation) either from dichloroacetamides or propargylamines, provided the 3-methyl-cis-octahydroindole motif with a functionalized C-5 and the right stereochemical pattern for the methyl group in acceptable to good yields. The second building block studied, 3a-metil- cis-octahidrociclohepta[b]pyrrole, present in 2-deoxymacropodumine A and daphnicyclidin A, was also achieved using the same radical procedure on the corresponding trichloroacetamide after a ring expansion in a 1,4-cyclohexanedione derivative through a homologation process using ethyl diazoacetate. The main part of the research carried out was focused in the development of a new synthetic strategy toward daphenylline, which is the only Daphniphyllum alkaloid having a benzene ring in its structure. A 5-endo-trig radical cyclization of a bicyclic trichloroenamide available from 1- methyl-2-tetralone was successfully used for the preparation of a benzo[e]indole intermediate. In this process, our approach allowed to elaborate the fully substituted stereogenic center during a lactam ring closure. Stereocontrolled processes were used to generate the three stereogenic methine carbons in the pyrrolidine C ring, including the all-carbon quaternary stereocenter at C5. Ring closure to build both seven- and five-membered rings was achieved by Friedel-Crafts reactions. An azapentacyclic octahydro-7,8-(epiminomethano)naphto [2,1,8-cde]azulene system, which constitutes the ACDEF fragment of daphenylline has been synthesized for the first time, providing an interesting precursor to this alkaloid. The overall process implies 21 steps and the targeted compound was achieved in 6.5% overall yield.

Oleanolic acid (OA) and maslinic acid (MA) are pentacyclic triterpenic compounds that abound in industrial olive oil waste. These compounds have renowned antimicrobial properties and lack cytotoxicity in eukaryotic cells as well as resistance mechanisms in bacteria. Despite these advantages, their antimicrobial activity has only been tested in vitro, and derivatives improving this activity have not been reported. In this work, a set of 14 OA and MA C-28 amide derivatives have been synthesized. Two of these derivatives, MA-HDA and OA-HDA, increase the in vitro antimicrobial activity of the parent compounds while reducing their toxicity in most of the Gram-positive bacteria tested, including a methicillin-resistant Staphylococcus aureus-MRSA. MA-HDA also shows an enhanced in vivo efficacy in a Galleria mellonella invertebrate animal model of infection. A preliminary attempt to elucidate their mechanism of action revealed that these compounds are able to penetrate and damage the bacterial cell membrane. More significantly, their capacity to reduce antibiofilm formation in catheters has also been demonstrated in two sets of conditions: a static and a more challenged continuous-flow S. aureus biofilm., This study was partially supported by grants from the Ministerio de Economiá , Industria y Competitividad, MINECO, and Agencia Estatal de Investigación, AEI, Spain, cofunded by Fondo Europeo de Desarrollo Regional, FEDER, European Union (BIO2015−63557-R, FIS2017−85954-R and RTI2018−098573-B-100)

The expedient assembly of complex, natural product-like small molecules can deliver new chemical entities with the potential to interact with biological systems and inspire the development of new drugs and probes for biology. Diversity-oriented synthesis is a particularly attractive strategy for the delivery of complex molecules in which the 3-dimensional architecture varies across the collection. Here we describe a folding cascade approach to complex polycyclic systems bearing multiple stereocentres mediated by reductive single electron transfer (SET) from SmI2. Simple, linear substrates undergo three different folding pathways triggered by reductive SET. Two of the radical cascade pathways involve the activation and functionalization of otherwise inert secondary alkyl and benzylic groups by 1,5-hydrogen atom transfer (HAT). Combination of SmI2, a privileged reagent for cascade reactions, and 1,5-HAT can lead to novel complexity-generating radical sequences that unlock access to diverse structures not readily accessible by other means.

[spa] El presente trabajo se centra en los alcaloides del grupo de las madangaminas, un pequeño grupo de alcaloides diaminopentacíclicos, aislados de esponjas marinas pertenecientes al orden Haplosclerida y derivados biogenéticamente de precursores con estructura de 3-alquilpiperidina. Estructuralmente, las madangaminas se caracterizan por la presencia de un núcleo diazatricílico (anillos ABC), sin precedentes entre los productos naturales, y dos puentes de carbono lineales que conectan el nitrógeno N-7 al carbono de la posición C-9 (anillo D) y el nitrógeno N-1 al carbono de la posición C-3 (anillo E). El anillo macrocíclico D varía en cada madangamina, tanto en tamaño (de 13 a 15 miembros) como en posición y grado de insaturación, mientras que el anillo E es idéntico en las madangaminas A-E (dos insaturaciones y 11 miembros) pero es diferente en la madangamina F (cuatro insaturaciones; 13 miembros). Además, la madangamina F incorpora una función hidroxilo en la posición C-4. Tras alcanzar la primera síntesis total de un alcaloide del grupo de las madangaminas, llevada a cabo por nuestro grupo en el 2014,1 en la presente Tesis Doctoral nos propusimos abordar la síntesis de otros alcaloides de esta familia. Para ello, centramos nuestra atención en las madangaminas A, B, C y E, para las que, al inicio de la presente Tesis Doctoral, no se había descrito ninguna síntesis total. Nuestra estrategia sintética se basa en la construcción enantioselectiva de un núcleo diazatricíclico altamente funcionalizado a partir de una lactama quiral derivada del R- fenilglicinol y en la posterior formación de los macrociclos D y E. La síntesis del sistema tricíclico 16 se ha logrado de forma satisfactoria y a gran escala (multigramos) mediante una secuencia sintética de 13 etapas con un rendimiento global del 15% a partir de la lactama derivada del feniglicinol 1a. A partir de este intermedio se ha estudiado la construcción del sistema ABCE común a las madangaminas A-E. En concreto, la estrategia basada en una reacción de Wittig con el iluro derivado de la sal de fosfonio 47 con posterior macrolactamización ha mostrado ser la más eficiente para la construcción del anillo macrocíclico E común a todas las madangaminas. De esta manera se ha sintetizado el tetraciclo ABCE de forma satisfactoria. Por otro lado, también a partir del compuesto tricíclico 16 se ha explorado la construcción de los macrociclos D de las madangaminas A, B, C y E. Un proceso de ring closing metathesis altamente eficiente (90% de rendimiento) ha permitido la construcción del anillo D de la madangamina C de trece miembros, aunque como mezcla inseparable de isómeros. Por hidrogenación del anterior se ha podido acceder al sistema tetracíclico ABCD de la madangamina E. Por otra parte, una estrategia basada en una reacción de coupling entre un alquino terminal y un ioduro diinico y posterior reducción del triple enlace resultante a trans- alqueno ha permitido por primera vez alcanzar la construcción del complejo macrociclo D de la madangamina B en una piperidina modelo. Finalmente, se ha descrito una nueva aproximación enantioselectiva a la síntesis de la madangamina A. La síntesis del sistema pentacíclico 111 representa la síntesis formal del alcaloide., [eng] Madangamines alkaloids constitute a small group of complex pentacyclic alkaloids isolated from marine sponges of the order Haposclerida. Structurally, these alkaloids have an unprecedented skeletal type, characterized by a diazatricyclic core (ABC rings) and two linear carbon bridges. The peripheral macrocyclic ring D is different in each madangamine, in size as well as in degree and position of unsaturation, whereas ring E is identical in madangamines A-E. In the context of our studies on the enantioselective synthesis of complex piperidine-containing natural products from phenylglycinol- derived bicyclic lactams, we have developed a unified strategy to access the variety of alkaloids of this group. Appling this strategy, that involves the formation of the macrocyclic rings after the construction of the highly functionalized central core, recently in our group was carried out the enantioselective synthesis of madangamine D, which represents the first total synthesis of an alkaloid of the madangamine group.1 In this Doctoral Thesis we focused our attention in the total synthesis of other members of the family: madangamines A, B, C and E. Starting from tricyclic intermediate 16, which was prepared by 13 steps, we performed the construction of the complex E ring, common to madangamines A-E. The construction of the different D rings was explored in model compounds as well in the tricyclic and tetracyclic intermediates; these studies allowed to accomplish the synthesis of the ring of madangamine B in a piperidine derivative, the ABCD system of madangamines C and E and the pentacyclic system of madangamine A, which represent the formal synthesis of this alkaloid.

A convergent and stereoselective approach for the synthesis of marine natural product (MNP) phormidolide D (PM D) is proposed. Two main disconnections divided PM D in three molecular fragments: the macrocyclic core 4, the stapling iodoalkene 9 corresponding to the central part of PMs, and the east fragment 5 that includes the unusual bromo-methoxy-diene moiety and a tetradecanoic acid ended with a (E)-dichloro-ene functionality. Procedures for the preparation of compounds 5, 9, and the never-reported fatty acids 7 and 8, present in PMs C and D, respectively, have been afforded with good yields and high degree of stereoselectivity. The absolute configuration of all of the generated stereocenters has been established. The reaction to link iodoalkene 9 and formylmacrolactone 4, using the Nozaki− Hiyama−Takai−Kishi coupling, gave an advanced synthetic intermediate with total stereocontrol. Finally, a deeper study of protecting groups and reaction conditions for the last step of the synthesis is needed. All the information gathered in this publication will be of great value to continue performing synthetic studies for the preparation of these NPs. The versatility and the presence of a common polyol chain in oscillariolide and PMs A− C would allow applying the same retrosynthesis for the synthesis of the mentioned MNP.

Natural products play an important role in the development of new drugs. In this context, the Amaryllidaceae alkaloids have attracted considerable attention in view of their unique structural features and various biological activities. In this study, twenty-three alkaloids were identified from; Crinum amabile; by GC-MS and two new structures (augustine; N; -oxide and buphanisine; N; -oxide) were structurally elucidated by NMR. Anti-parasitic and cholinesterase (AChE and BuChE) inhibitory activities of six alkaloids isolated from this species, including the two new compounds, are described herein. None of the alkaloids isolated from; C. amabile; gave better results than the reference drugs, so it was possible to conclude that the; N; -oxide group does not increase their therapeutic potential.

BACKGROUND & AIMS: Soraphen A (SorA) is a myxobacterial metabolite that inhibits the acetyl-CoA carboxylase, a key enzyme in lipid biosynthesis. We have previously identified SorA to efficiently inhibit the human immunodeficiency virus (HIV). The aim of the present study was to evaluate the capacity of SorA and analogues to inhibit hepatitis C virus (HCV) infection. METHODS: SorA inhibition capacity was evaluated in vitro using cell culture derived HCV, HCV pseudoparticles and subgenomic replicons. Infection studies were performed in the hepatoma cell line HuH7/Scr and in primary human hepatocytes. The effects of SorA on membranous web formation were analysed by electron microscopy./nRESULTS:/nSorA potently inhibits HCV infection at nanomolar concentrations. Obtained EC50 values were 0.70 nM with a HCV reporter genome, 2.30 nM with wild-type HCV and 2.52 nM with subgenomic HCV replicons. SorA neither inhibited HCV RNA translation nor HCV entry, as demonstrated with subgenomic HCV replicons and HCV pseudoparticles, suggesting an effect on HCV replication. Consistent with this, evidence was obtained that SorA interferes with formation of the membranous web, the site of HCV replication. Finally, a series of natural and synthetic SorA analogues helped to establish a first structure-activity relationship./nCONCLUSIONS:/nSorA has a very potent anti-HCV activity. Since it also interferes with the membranous web formation, SorA is an excellent tool to unravel the mechanism of HCV replication. The authors are supported by grants BFU2013-44629-R (to JD, GK and GPV), SAF2013-46077-R (to/nAM and JM), both from the Spanish Ministry of Economy and Competitiveness and FEDER, and from the German Centre for Infection Research (DZIF, to MB and RM)

Liquid chromatography-electrospray-tandem mass spectrometry (LC-ESI-MS/MS) was applied to the analysis and authentication of fruit-based products and fruit-based pharmaceutical preparations. A Kinetex C18 reversed-phase column under gradient elution with 0.1 % formic acid aqueous solution and methanol mobile phases was used for the simultaneous determination of 26 polyphenols, allowing an acceptable separation in less than 22 min. Instrumental quality parameters such as limits of detection (LOD, values between 12 and 14 μg/L for 19 of the 26 analyzed polyphenols), linearity (r (2) 0.991), run-to-run and day-to-day precisions (relative standard deviation (RSD) values lower than 9.9 and 13.5 %, respectively), and accuracy (relative errors lower than 8 %) were established. A simple extraction method, consisting of a sample sonication with acetone/water/hydrochloric acid (70:29.9:0.1 v/v/v) and centrifugation, was proposed. Two calibration procedures, external calibration using standards prepared in water and standard addition, were evaluated for polyphenol quantification in several grape and cranberry fruits and processed fruit products. For a 95 % confidence level, no statistical differences were observed between the two calibration methods (p values between 0.06 and 0.95), denoting that external calibration was suitable enough for the quantitative analysis of polyphenols in fruit-based products. The proposed LC-ESI-MS/MS method was then applied to the analysis of polyphenols in 23 grape-based and cranberry-based natural products and pharmaceutical preparations. Polyphenolic concentration data was then analyzed by principal component analysis (PCA) to extract information of the most significant profile data contributing to authentication of natural extracts according to their fruit of origin.

[eng] Chiral amino alcohol derived lactams are a valuable scaffold for the enantioselective synthesis of alkaloids. In the present thesis the potential of this methodology was expanded and to demonstrate the synthetic utility of chiral tricyclic lactams obtainedthe enantioselective total synthesis complex cis-decahydroquinoline alkaloids was carried out. The alkaloids that were targeted for synthesis using the developed methodology were the lepadin alkaloids (marine alkaloids) and tricyclic cis-decahydroquinoline alkaloids such as cermizine B (Lycopodium alkaloids). To accomplish these objectives further studies on the functionalization of the decahydroquinoline system were required in order to install the appropriate substituents and functionalities for the synthesis of each target. During the present PhD thesis it was possible to complete the total synthesis of (+)-gephyrotoxin 287C, (−)-cermizine B, (−)-lepadin B and (+)-lepadin D and the formal total synthesis of (−)-lepadins A and C.

Chiral amino alcohol derived lactams are a valuable scaffold for the enantioselective synthesis of alkaloids. In the present thesis the potential of this methodology was expanded and to demonstrate the synthetic utility of chiral tricyclic lactams obtainedthe enantioselective total synthesis complex cis-decahydroquinoline alkaloids was carried out. The alkaloids that were targeted for synthesis using the developed methodology were the lepadin alkaloids (marine alkaloids) and tricyclic cis-decahydroquinoline alkaloids such as cermizine B (Lycopodium alkaloids). To accomplish these objectives further studies on the functionalization of the decahydroquinoline system were required in order to install the appropriate substituents and functionalities for the synthesis of each target. During the present PhD thesis it was possible to complete the total synthesis of (+)-gephyrotoxin 287C, (−)-cermizine B, (−)-lepadin B and (+)-lepadin D and the formal total synthesis of (−)-lepadins A and C.

Some natural products, known sources of bioactive compounds with a wide range of properties, may have therapeutic values in human health and diseases, as well as agronomic applications. The effect of three compounds of plant origin with well-known dietary antioxidant properties, astaxanthin (ATX), caffeic acid (CA) and hydroxytyrosol (HT), on zebrafish (Danio rerio) larval adiposity and rainbow trout (Onchorynchus mykiss) adipocytes was assessed. The zebrafish obesogenic test (ZOT) demonstrated the anti-obesogenic activity of CA and HT. These compounds were able to counteract the obesogenic effect produced by the peroxisome proliferator-activated receptor gamma (PPARγ) agonist, rosiglitazone (RGZ). CA and HT suppressed RGZ-increased PPARγ protein expression and lipid accumulation in primary-cultured rainbow trout adipocytes. HT also significantly reduced plasma triacylglycerol concentrations, as well as mRNA levels of the fasn adipogenic gene in the adipose tissue of HT-injected rainbow trout. In conclusion, in vitro and in vivo approaches demonstrated the anti-obesogenic potential of CA and HT on teleost fish models that may be relevant for studying their molecular mode of action. Further studies are required to evaluate the effect of these bioactive components as food supplements for modulating adiposity in farmed fish.

Several natural peptides have a biaryl or biaryl ether motif in their biologically active structures. A model bicyclic pentapeptide containing a biaryl bridge has been synthesized by solid-phase peptide synthesis combining on-resin Suzuki and Miyaura cross-coupling reactions. Its biological properties in terms of permeability, stability and cytotoxicity have been studied, demon-strating the positive contribution of the biaryl bridge, excellent membrane penetration and serum stability

Aquesta Tesi Doctoral cobreix tres camps de la química orgànica sintètica dedicats a la síntesi de nous materials basats en hidrocarburs aromàtics policíclics (HAPs), el desenvolupament de noves metodologies sintètiques catalitzades per complexos metàl·lics, i la síntesi de derivats de productes naturals. El desenvolupament de noves estratègies per a la síntesi de nous fragments de grafè amb estructures ben definides és un camp de gran interès donada la seva potencial implementació en dispositius d’electrònica molecular. Els fragments de grafè amb estructures circulars resulten particularment interessants degut a les seves extraordinàries propietats optoelectròniques i d’autoassemblatge. En aquest context es va desenvolupar la síntesi d’un nou fragment circular de grafè d’elevada simetria C54H20, tetrabenzocircumpirè, les propietats electròniques del qual van ser examinades mitjançant microscòpia d’efecte túnel (STM). Els acens estan constituïts per anells de benzè fusionats en línia i representen un atractiu tipus de HAPs degut a les seves propietats semiconductores. Tanmateix, la seva aplicació en dispositius electrònics està limitada per la seva baixa solubilitat i la seva inherent inestabilitat. Una possible solució per salvar aquestes limitacions és preparar derivats parcialment saturats més estables, els quals poden emprar-se com precursors dels sistemes conjugats. Així doncs, va establir-se un nou mètode per a la preparació d’acens parcialment saturats basat en una ciclació catalitzada per or(I) d’1,7-enins que deriven d’un precursor comú. Aquest mètode va resultar ser general i va permetre la preparació de diversos dihidrotetracens funcionalitzats, així com d’hidroacens amb fins a nou anells linealment fusionats. L’excepcional habilitat dels complexos d’or(I) per a construir estructures policícliques complexes va ser examinada també en el marc de la síntesi de productes naturals. L’alcoxiciclació d’1,6-enins catalitzada per or(I) va permetre un ràpid assemblatge de l’esquelet tetracíclic [3,5,5,7] de les echinopines, fet què va donar lloc a un mètode per a la preparació de derivats funcionalitzats d’aquests productes naturals., Esta Tesis Doctoral cubre tres campos de la química orgánica sintética dedicados a la síntesis de nuevos materiales basados en hidrocarburos aromáticos policíclicos (HAPs), el desarrollo de nuevas metodologías sintéticas catalizadas por complejos metálicos, y la síntesis de derivados de productos naturales. El desarrollo de nuevas estrategias para la síntesis de nuevos fragmentos de grafeno con estructuras bien definidas es un campo de gran interés dada su potencial implementación en dispositivos de electrónica molecular. Los fragmentos de grafeno con estructuras circulares resultan particularmente interesantes debido a sus extraordinarias propiedades optoelectrónicas y de autoensamblaje. En este contexto se desarrolló la síntesis un nuevo fragmento circular de grafeno de elevada simetría C54H20, tetrabenzocircumpireno, cuyas propiedades electrónicas fueron examinadas mediante microscopía de efecto túnel (STM). Los acenos están constituidos por anillos de benceno fusionados en línea, y representan otra atractiva clase de HAPs debido a sus propiedades semiconductoras. Sin embargo, su aplicación en dispositivos electrónicos está limitada por su baja solubilidad y su inherente inestabilidad. Una posible solución para salvar estas limitaciones es preparar derivados parcialmente saturados más estables, los cuales pueden usarse como precursores de los sistemas conjugados. Así, se estableció un nuevo método para la preparación de acenos parcialmente saturados, el cual está basado en una ciclación catalizada por oro(I) de 1,7-eninos que derivan de un precursor común. Este método resultó ser general y permitió la preparación de diversos dihidrotetracenos funcionalizados, así como de hidroacenos con hasta nueve anillos linealmente fusionados., This PhD covers three fields of synthetic organic chemistry devoted to the synthesis of new materials based on polycyclic aromatic hydrocarbons (PAHs), the development of new metal-catalyzed synthetic methodology, and the synthesis of natural product derivatives. The development of new strategies for the precise synthesis of structurally well-defined novel graphene cutouts is a field of great interest due to their potential implementation in molecular electronic devices. Particularly interesting PAHs are disc-shaped fragments of graphene because of their unique optoelectronic and self-assembly properties, which are predicted to be enhanced for expanded systems. In this context, an efficient synthesis of a new discotic highly symmetric C54H20 graphene fragment – tetrabenzocircumpyrene – was developed and the electronic properties of this new graphene fragment were examined by scanning tunneling microscopy (STM). Acenes consist of planar sets of linearly fused benzene rings and represent another appealing class of PAHs due to their semiconducting properties. Nonetheless, their applicability in electronic devices is limited by their poor solubility and their inherent instability. One approach to circumvent these limitations is the preparation of more stable partially saturated derivatives, which can be used as precursors of the conjugated systems. Thus, a selective method for the preparation of partially saturated acenes under mild reaction conditions was developed based on a gold(I)-catalyzed cyclization of suitable 1,7-enynes that were assembled from a common precursor. The method proved to be general and allowed the preparation of functionalized dihydrotetracenes, as well as larger hydroacenes with up to nine linearly fused rings. The outstanding ability of gold(I) complexes to construct complex polycyclic frameworks was also examined in the context of the synthesis of natural products. Thus, the gold(I)-catalyzed alkoxycyclization of cyclopropyl-tethered 1,6-enynes allowed the ready assembly of the [3,5,5,7] tetracyclic skeleton of Echinopines, which opened an entry for the preparation of functionalized derivatives of these natural products.

Tumor metastasis is a complex process in which cells detach from the primary tumor and colonize a distant organ. Metastasis is also the main process responsible for cancer-related death. Despite the enormous efforts made to unravel the metastatic process, there is no effective therapy, and patients with metastatic tumors have poor prognosis. In this regard, there is an urgent need for new therapeutic tools for the treatment of this disease. Small molecules with the capacity to reduce cell migration could be used to treat metastasis. Migrastatin-core analogs are naturally inspired macrocycles that inhibit pathological cell migration and are able to reduce metastasis in animal models. Migrastatin analogs can be synthesized from a common advanced intermediate. Herein we present a review of the synthetic approaches that can be used to prepare this key intermediate, together with a review of the biological activity of migrastatin-core analogs and current hypotheses concerning their mechanism of action.

[eng] Mayotlide is a marine peptide isolated by PharmaMar S.A. from Spongia sp.. The sequence of the aminoacids were achieved by MS-MS spectrometry, where two of them were tryptophans. The NMR spectroscopy revealed the presence of N1-C3a bond between the tryptophans, which means that one of them was cyclized. On the first structure proposal, the aminoacids were forming two macrocyclic rings: on the ring B, all the aminoacids of molecule were tied by amide bond, remarking the presence of the cyclized tryptophan as a hexahydropyrroloindole unit (HPI). The ring A was established by three aminoacids of the ring B: one tryptophan, one isoleucine and the HPI, which became closed by the N1-C3a bond between the two tryptophans. The aminoacid analysis demonstrated the L configuration of all of them, just remaining the HPI with unknown stereochemistry. Due to the configuration of the HPI system, there can be four diasteromers. To the best of our knowledge, there were not empirical evidences about which one could be more favorable. Hence, a computational study of the ring A through the MOE program was performed, evidencing that the rings A with the exo HPI adducts (L and D) were more stable than the endo ones. Among the exo ones, another computational study with the whole molecule revealed that the mayotlide with the exo-L adduct of the HPI was more stable. Once that there was established a starting point with the HPI, it was necessary to find out a synthetic strategy that could fulfill the necessary requirements. A methodology developed by Baran and coworkers for the synthesis of the Trp-HPI fragment on molecules related to mayotlide was adapted to our proposal. On the first step of this strategy, under reaction conditions, the starting tryptophan cyclizes, providing exclusively the HPI with the exo configuration, at the same time that the N1-C3a bond between the HPI and 2-iodoaniline is formed. The 2-iodoaniline, along with a disubstituted alkyne, condense together yielding the upper tryptophan without loss of the former stereochemistry, reaching the Trp-HPI framework in two steps with high yields. Taking advantage of this methodology and an appropriate use of the protecting groups in order to perform the corresponding cyclizations of the two macrocyclic rings, the mayotlide with the exo-L HPI was accomplished. Nevertheless, nor the NMR neither the MS-MS fragmentation pattern of the final compound coincided with the natural product ones. Thus, the next alternative would consist on repeating the synthesis but with the exo-D adduct of the HPI instead. During the last synthesis, the bibliography and the analytical data of the natural product were extensively revised. There were no documented precedents of natural peptides with the Trp- HPI motif, and the initial structure did not justify the most important data extracted from the MS-MS spectrometry. the main fragmentation concerned to the isoleucine, and on the first proposal such aminoacid was not forming part of a conflictive scaffold. Likewise, among the eight proposed linear sequences for the ring B, the isoleucine just appear in one as C-terminus of the b-ions, when it is one of the aminoacids that forms part of both macrocycles. The most related family of peptides to mayotlide are the kapakahines. Kapakahines, instead of having a Trp-HPI moiety as the central part of the molecule, exhibit a Trp-α carboline, with an aminoacid establishing the bridge for a very tensioned tetracyclic system. Such structure may justify the isoleucine fragmentation pattern, but on the other hand the sequence of the aminoacids did not fix. It was necessary to invert the central sequence of the aminoacids to reach out a final structure proposal which justifies all the requirements, relabeled as “kapakahine H”., [spa] La mayotlida es un producto natural de origen marino aislado por PharmaMar. SA.. En la primera propuesta que se hizo, se elucidó como un péptido con dos anillos macrocíclicos: en el anillo B estaban contenidos todos los aminoácidos de la molécula, destacando la presencia de una unidad de HPI, que procede de la ciclación intramolecular del extremo amino de un triptófano con el C2 del anillo de indol. El anillo A está formado por tres aminoácidos del anillo B: un triptófano, una isoleucina y el HPI, quedando cerrado por la formación de un enlace entre el N1 del triptófano y el C3a del HPI. El análisis de aminoácidos demostró la configuración L de todos ellos, quedando desconocida la estereoquímica del HPI. El HPI posee tres estereocentros: los C3a y C8a, que siempre están en cis por la propia configuración del anillo y se pueden considerar como un conjunto, y el estereocentro del Cα. Por tanto, son cuatro el número total de diasterómeros posibles. El anillo A con las cuatro posibilidades de HPI fue estudiado energéticamente con el programa MOE, llegando a la conclusión que los aductos exo son más estables que los endo, y que el aducto exo-L es más estable que el exo-D. Para abordar la síntesis de la mayotlida exo-L se adaptó una metodología desarrollada por Phil Baran y colaboradores para moléculas con una estructura relacionada a la mayotlida. Tras conseguir la síntesis de la mayotlida con el aducto exo-L del HPI, se comprueba que los espectros de RMN y de MS-MS presentan grandes divergencias. Ante la incapacidad de interpretar las diferencias existentes entre el producto natural y la mayotlida exo-L, se tomó la decisión de abordar la síntesis de la mayotlida con el aducto exo-D del HPI. En el transcurso de la síntesis exo-D se revisó extensivamente la bibliografía y los datos analíticos relacionados con la mayotlida: no existían antecedentes de productos naturales peptídicos con estructura Trp-HPI, y la estructura no encajaba con los datos más transcendentales del MS-MS. La estructura fue revisada, llegando a la conclusión de que podía pertenecer a la familia de las kapakahines, con una estructura central Trp-α carbolina y con la secuencia central de los aminoácidos invertida, rebautizada como kapakahina H.

Molecules derived from plants make up a sizeable proportion of the drugs currently available on the market. These include a number of secondary metabolite compounds the monetary value of which is very high. New pharmaceuticals often originate in nature. Approximately 50% of new drug entities against cancer or microbial infections are derived from plants or micro-organisms. However, these compounds are structurally often too complex to be economically manufactured by chemical synthesis, and frequently isolation from naturally grown or cultivated plants is not a sustainable option. Therefore the biotechnological production of high-value plant secondary metabolites in cultivated cells is potentially an attractive alternative. Compared to microbial systems eukaryotic organisms such as plants are far more complex, and our understanding of the metabolic pathways in plants and their regulation at the systems level has been rather poor until recently. However, metabolic engineering including advanced multigene transformation techniques and state-of-art metabolomics platforms has given us entirely new tools to exploit plants as Green Factories. Single step engineering may be successful on occasion but in complex pathways, intermediate gene interventions most often do not affect the end product accumulation. In this review we discuss recent developments towards elucidation of complex plant biosynthetic pathways and the production of a number of highvalue pharmaceuticals including paclitaxel, tropane, morphine and terpenoid indole alkaloids in plants and cell cultures. VTT and UdL gratefully acknowledge support from European Union Framework 7 Program Integrated Project 222716 SmartCell; European Union Framework 7 European Research Council IDEAS Advanced Grant (to PC) Program-BIOFORCE; COST Actions FA0804 Molecular farming: plants as a production platform for high value proteins and FA1006 Plant Metabolic Engineering for High Value Products.

[eng] The first objective of this Thesis was the study of the preparation of octhydro-1H-cyclopenta[b]pyridines and octahydro-1H-indoles, through the synthesis of (R)-phenylglycinol derived tricyclic lactams. Following the previous reported methodology a carbon substituent would be present at the carbocyclic ring and we planned to find the conditions for controlling its absolute configuration. Unfortunately, the reaction of ketoester 4 and ketoacid 7, provided undesired enamines 8 and 9. On the other hand, the reaction of ketoacid derivatives 16 and 17 with (R)-phenylglycinol led to a mixture of epimeric amides 18. With the aim to extend the methodology, we planned to study the cyclocondensation reaction of (R)-phenylglycinol and (1S, 2R)-aminoindanol with C-3 and C-5 substituted cyclohexanepropionate derivatives. These reactions provided enantiopure tricyclic or pentacyclic lactams: in every run, a major lactam was isolated or identified, and a minor one was detected. The use of (1S, 2R)-aminoindanol resulted in better results. These tricyclic and pentacyclic lactams are precursors of C-8 (and C-6,8) substituted cis-decahydroquinolines. The conversion required the stereoselective reductive cleavage of C-O oxazolidine bond with simultaneous reduction of lactam carbonyl group, and debenzylation. A library of enantiopure cis-decahydroquinolines was obtained. To illustrate the usefulness of our method, we decided to undertake the synthesis of some alkaloids of Myrioneuron nutans family, which contain an 8-substituted cis-decahydroquinoline core. In particular, we prepared the enantiopure alcohol 82, which was described to be a common intermediate in the synthesis of various Mirioneuron nutans alkaloids. Our synthetic procedure greatly improved the previous results reported for the synthesis of this alcohol. The cyclocondensation reaction of (R)-phenylglycinol and (1S,2R)-aminoindanol with 3-alkyl-2-oxo-cyclohexane-1-acetate derivatives was finally considered. Reaction of (R)-phenylglycinol and 3-alkyl-2-oxocyclohexaneacetate derivatives 97-100 and 107 provided with high yield and stereoselectivity tricyclic lactams 110, 112a, 114, 116 and 118, which incorporate an alkyl or aryl substituent at C-10, while (1S,2R)-aminoindanol did not furnish so good outcomes. These reactions stereoselectively provided an additional minor hexahydroindole by-product. The absolute configuration of these compounds 111a, 113a, 115a and 117a was confirmed by X-ray crystallography. In the case of any or aryl substituent at C-10 of the tricyclic lactam, no by products were detected. We demonstrated that these unsaturated products derived from the opening of the oxazolidine ring of the minor lactams, which are epimers at C-10 of the major lactams, in the presence of acids. The stereoselective opening of the oxazolidine ring of the major lactams, in the presence of strong acids provided unsaturated compounds 111b, 113b, 115b and 117b, in which H-7 and H-7a resulted in cis relative disposition. In the case of lactam 118, with an aryl substituent at C-10, provided the unsaturated compound 125, in which H-7 and H-7a are in relative trans disposition. This different relative configuration can be accounted for by considering the structure rigidity of this system. Major tricyclic lactams were converted into C-7 exo substituted cis-octahydroindoles and cis-octahydroindolones, by selection of the appropriate reductive conditions. Hexahydroindolones 111b, 113b, 115b and 117b were converted stereoselectively into the corresponding enantiopure C-7 endo substituted cis-octahydroindolones, by catalytic hydrogenation of the carbon-carbon double bond, followed by elimination of the chiral inductor through reaction with sodium radical. Moreover, these hexahydroindolones and 125 were transformed into the corresponding trans-octahydroindolones 146c-149c and 126b by simultaneous reduction and debenzylation in sodium ammonia. The presence of the amide function allowed the stereoselective insertion of a new substituent by a-alkylation and a-amidoalkylation. Finally, in order to demonstrate the utility of this methodology, (+)-a-Lycorane was synthesized in only four steps, starting from easily available ketone 171, in 35% of overall yield, which resulted an improvement with respect to previously reported synthesis., [spa] El primer objetivo de esta Tesis Doctoral ha sido el estudio de la preparación de octahidro-1H-ciclopentapiridinas y octahidro-1H-indoles, a través de la síntesis de lactamas tricíclicas derivadas del (R)-fenilglicinol. Desafortunadamente, la reacción del ceto-éster 4 y del ceto-ácido 7, proporcionó solamente las eniminas 8 y 9. Por otro lado, la reacción de los derivados de ceto-ácidos 16 y 17 con (R)-fenilglicinol rindió únicamente una mezcla de productos 18, amidas conjugadas epímeras en la posición C-7a. Se ha sido estudiado la reacción de ciclocondensación de derivados de 2-oxociclohexano propionato convenientemente sustituidos en C-3 o en C-3 y C-5 con (R)-fenilglicinol y (1S,2R)-aminoindanol. Esta reacción conduce estereoselectivamente a lactamas tricíclicas o pentacíclicas quirales: se aisló mayoritariamente una lactama y se detectó la presencia de otra minoritaria. Al utilizar (1S,2R)-aminoindanol se obtuvieron mejores resultados. Estas lactamas son precursoras de cis-decahidroquinolinas, con sustituyentes en la posición 8 o en la posición 6 y 8. Las etapas clave de esta transformación son la reducción con alano y la eliminación del inductor quiral. Con esta metodología se ha preparado la decahidroquinolina 82, precursor de numerosos alcaloides de la familia Mirioneuron nutans. Además, presentamos el estudio de las reacciones de ciclocondensación con (R)-fenilglicinol a partir de ciclohexanonas que poseen una cadena de acetato en la posición C-1 y diversos sustituyentes alquilo o arilo en la posición C-3. Esta reacción conduce estereoselectivamente a una sola lactama tricíclica de las ocho posibles. A partir de las cetonas con un sustituyente alquilo en la posición C-3 aislamos una cantidad variable de enamida. Las lactamas mayoritarias, fueron convertidas en cis-octahidroindoles y cis-octahidroindolonas, que presentan un sustituyente en la posición 7 o en las posiciones 7 y 7a del anillo carbocíclico. Además, estudiamos la reactividad de las lactamas tricíclicas en medio ácido: la reacción con TiCl4 en THF, proporciona lactamas insaturadas con elevada estereoselectividad y buen rendimiento. La presencia de la función enamida, nos permitió preparar selectivamente nuevas cis y trans octahidroindolonas. Esta metodología nos permitió sintetizar el (a)-Licorano, un metabolito de la familia de las Amaryllidaceae.

[cat] En el present treball es descriu la millora més important realitzada en el procés de la síntesi de les formidolides B i C. Aquesta millora es basa en un canvi d'estratègia per sintetitzar el nucli macrocíclic d'aquesta família de compostos. Els canvis principals han estat la utilització d'una metodologia diastereoselectiva per a la formació del nucli de tetrahidrofuran (THF), l'addició d'un al·lilstannà a un aldehid per donar exclusivament l'isòmer desitjat (Z)-1,5-anti i la millora en les condicions finals de ciclació. Tot això va suposar multiplicar per deu el rendiment descrit anteriorment., [eng] This paper describes the most important optimization carried out in the phormidolides B and C synthetic process. It consists in a change of strategy in order to synthesize the macrocyclic core of this family of compounds. The main changes have been the use of a diastereoselective methodology to construct the tetrahydrofuran (THF) core, a (Z)-1,5-anti allylstannane addition where the synthesis converges, and a notable improvement in the cyclization conditions. All this work has supposed a 10-fold increment in the overall yield of the synthesis.

Treballs Finals de Grau de Química, Facultat de Química, Universitat de Barcelona, Any: 2016, Tutor: Fèlix Urpí Tubella, Peperomins A – E are a class of novel and unusual type of secolignans with a common structure except for the different substituents of the aromatic rings. Extracted from different Peperomia type plants found in Taiwan, Venezuela or India, these molecules present a broad range of significant biological activities, from antitumor to anti-HIV, and therefore they are considered as potential chemotherapeutic agents. Thus, it is highly desirable any efficient synthesis of these natural compounds. From all types of peperomins, peperomin D has been described in the literature as the most complicated to synthesize. Therefore, it is an excellent target to challenge new synthetic methods. Keeping in mind this idea, the key step of our approach, and the major improvement compared to other syntheses, involves a catalytic nickel(II) reaction recently developed in our research group.The strength of this reaction is the use of a nickel(II) complex, which is structurally simple, robust, and commercially available. The reaction is highly stereoselective and efficient, as only one of the two possible diastereomers is observed and isolated in excellent yields. After some studies with an N-acyl thioimide containing an ester group, the removal of the chiral auxiliary turned out to be too difficult and, as a consequence, we were forced to modify our synthetic plan. Instead, a new approach based on the reaction of an N-acyl thioimide possessing a terminal olefin was assessed. Preliminary results have been promising. Double bonds are much more resistant to hydride reagents and thus DIBAL-H can be used to reduce the chiral auxiliary. The synthetic approach shown in the former scheme has provided alcohol 19 in an overall yield of 84% over 3 steps. Moreover, it was possible to avoid chromatographic purification of product 6, as well as in the reaction of 18 to give 19. In order to complete the synthesis, further steps involving ozonolysis, cyclization and substrate-controlled α-methylation will be applied. By completing the synthesis with the most complicated peperomin among all of them, the synthetic pathway might also be applied to synthesize all other peperomins. Work is in process.

[cat] En el present treball es descriu la millora més important realitzada en el procés de la síntesi de les formidolides B i C. Aquesta millora es basa en un canvi d'estratègia per sintetitzar el nucli macrocíclic d'aquesta família de compostos. Els canvis principals han estat la utilització d'una metodologia diastereoselectiva per a la formació del nucli de tetrahidrofuran (THF), l'addició d'un al·lilstannà a un aldehid per donar exclusivament l'isòmer desitjat (Z)-1,5-anti i la millora en les condicions finals de ciclació. Tot això va suposar multiplicar per deu el rendiment descrit anteriorment., [eng] This paper describes the most important optimization carried out in the phormidolides B and C synthetic process. It consists in a change of strategy in order to synthesize the macrocyclic core of this family of compounds. The main changes have been the use of a diastereoselective methodology to construct the tetrahydrofuran (THF) core, a (Z)-1,5-anti allylstannane addition where the synthesis converges, and a notable improvement in the cyclization conditions. All this work has supposed a 10-fold increment in the overall yield of the synthesis.

Resumen: La síntesis total de productos naturales ha entrado en una nueva era en la que la eficiencia del proceso asume un papel preponderante, a fin de poder acceder de manera escalable a moléculas con potencial impacto en la sociedad. Se presenta un panorama general de propuestas para alcanzar una síntesis ideal, tales como las estrategias de diseño de síntesis (uso de reacciones tándem, reducción de etapas no productivas) y nuevos procedimientos operacionales (uso de reactivos anclados, agentes secuestradores y economía de recipiente / poteconomy). Palabras clave: eficiencia sintética, diseño de síntesis, economía de recipiente, síntesis total, productos naturales.

Corynantheine alkaloids with a tetracyclic indole[2,3-a]-quinolizidine motif are an important issue in academia and in the life science industries due to their broad bioactivity profile. In particular, the main biological effects described for indoloquinolizidines include analgesic, anti-inflammatory, antihypertensive, and antiarrhythmic activities, as well as inhibition of multiple ion channels, affinity for opioid receptors, and activity against Leishmania. For that reason, in the last decades, numerous efforts have been invested in the development of novel synthetic strategies to obtain the indole[2,3-a]-quinolizidine system. This review focuses on the synthetic methodologies developed to target the most important alkaloids of this family, and highlights the potential use of these alkaloids or analogs to treat several diseases, ranging from cancer to neurodegenerative disorders.

Podeu consultar el llibre complet a: http://hdl.handle.net/2445/67430, Oxylipins are a family of natural compounds that are reported to perform a variety of biological functions. Besides the biological properties of such compounds, interest in hydroxy fatty acids is increasing, due to the industrial applications of these renewable compounds as a starting material for resins, emulsifiers, plastics or polyesters. Hydroxy fatty acids are used as thickeners in a new generation of emulsifiers and lubricants, to reach new levels of performance. When grown in submerged culture with oleic or linoleic acid, Pseudomonas aeruginosa 42A2 produced several oxylipins. In this study, oxylipin production and its applications are examined.

A unified strategy for the synthesis of the cis-phlegmarine group of alkaloids is presented, leading to the first synthesis of serratezomine E (1) as well as the putative structure of huperzine N (2). A contrasteric hydrogenation method was developed based on the use of Wilkinson’s catalyst, which allowed the facial selectivity of standard hydrogenation to be completely overturned. Calculations were performed to determine the mechanism, and structures for huperzines M and N are reassigned.

El presente trabajo está centrado en la síntesis enantioselectiva de la cadena polihidroxílica presente en los productos marinos oscillariolida y formidolidas. Estas moléculas se pueden dividir en tres fragmentos; la cadena polihidroxílica, el macrociclo y el ácido graso. El presente trabajo está centrado en la síntesis enantioselectiva de la cadena polihidroxílica y el estudio en la unión del poliol y el macrociclo. La parte central del poliol se construye utilizando diferentes estrategias basadas en adiciones aldólicas. En la primera etapa se estudian auxiliares quirales como oxazolidinonas. El mejor resultado se observa con la (R)-4­benciloxazolidinona consiguiendo el aldol deseado con un exceso diatereomérico excelente y con buenos rendimientos. En la siguiente adición aldólica la inducción asimétrica es dirigida por los sustratos y se elabora un estudio para conseguir los aldoles de interés con excesos diasteroméricos y rendimientos satisfactorios. Se realizan adiciones aldólicas tipo acetato utilizando diferentes ácidos de Lewis como derivados de B o Ti, se aplica la variación de la las adiciones aldólicas tipo Mukaiyama y se prueba la adición de ácidos de Lewis quirales. Los mejores resultados se obtuvieron con el ácido de Lewis quiral DIP (bis(isopinocanfenil)cloroborano) rindiendo el aldol deseado con un excelente exceso diasteomérico y rendimientos moderados. La configuración absoluta del nuevo estereocentro se realiza utilizando el modelo de Mosher. A continuación, se lleva a cabo la reducción estereoselectiva de ß­hidroxicetonas a un compuesto dihidroxílico utilizando el catecolborono y se llega al intermedio 1,3-sin dihidroxílico con rendimientos y excesos diatereoméricos excelentes. De esta manera se sintetiza el fragmento central de la cadena polihidroxílica. En todo el proceso sintético cabe destacar la importancia de la ortogonalidad de los grupos protectores ya que es imprescindible la buena planificación para las desprotecciones selectivas y compatibilidad con las reacciones futuras. Partiendo del fragmento central de la cadena polihidroxílica, en un extremo se adiciona un derivado de la acroleína mediante la reacción de Barbier para conseguir un intermedio precursor al bromoéter de enol derivado. En el otro extremo, se estudia la adición de derivados organometálicos sobre aldehídos para poder dar como finalizada la síntesis total de la cadena polihidroxílica. Adicionalmente, se ha estudiado la unión del poliol con el macrociclo utilizando substratos modelo. La investigación se basa en la adición de un vinil metal derivado a un formil THF derivado. Se estudian tres metodologías diferentes: control por quelación con metales, carboaluminación y Nozaki­Hiyama-Kishi (NHK). En el estudio se consiguen identificar las mejores condiciones para obtener el producto de la adición con buenos rendimientos y excesos diastereoméricos. En todo este proceso sintético han sido imprescindibles técnicas como RMN (1D y 2D), HPLC, MS e IR., There are an important number of marine origin molecules with promising bioactivity. The group of polyketide macrolides is an interesting family of molecules where oscillariolide and phormidolide are included. These two molecules contain a common polyhydroxy chain linked to a THF ring. First, oscillariolide was isolated from Oscillatoria sp. which allowed the structural elucidation of the polyhydroxy chain. After that, phormidolide was isolated and that permit the determination of the absolute configuration of the eight polyol stereocenters, which was not achieved until that moment. Although the structure of the polyol has been known during several years, the molecule has not been synthesized yet. The aim of this work is the asymmetric synthesis of the chain. Our target molecules can be separated in three different fragments: a polyhydroxy chain, a macrocycle and a fatty acid. One of the objectives of this work is the synthesis of the polyhydroxy chain and the study of the bond formation between the polyol and the macrocycle. Firstly, aldol condensations using different chiral auxiliaries were studied. Evans auxiliaries such as oxazolidinones and oxazolinthiones were studied. The reactions were performed using different chelating metals, bases, aldehyde protecting groups, and with different reaction times and temperatures. On the other hand, a metal based aldol condensation was carried out between a chiral aldehyde and a ketone. An important influence of the protecting group in the ß-position of the aldehyde on the stereochemical outcome of this transformation is suspected. The elongation of the chain was achieved using strategies bases on addition of organometallic reagents, as Barbier reaction and Reformatsky type reaction. Finally, the bond formation between the polihidroxy chain and the macrocycle of the natural products was studied. This study was carried out using model molecules. Three main methodologies were applied to study the vinylorganometilic reagents additions to chiral 2-formylTHF: chelated controlled organometallic addition, carboalumination and Nozaki-Hiyama-Kishi (NHK) reaction.

(S)-2-(4-Bromo-2,4′-bithiazole)-1-(tert-butoxycarbonyl)pyrrolidine ((S)-1) was obtained as a single enantiomer and in high yield by means of a two-step modified Hantzsch thiazole synthesis reaction when bromoketone 3 and thioamide (S)-4 were used. Further conversion of (S)-1 into trimethyltin derivative (S)-2 broadens the scope for further cross-coupling reactions.

Research on natural products containing hexahydropyrrolo[2,3-b]indole (HPI) has dramatically increased during the past few years. Newly discovered natural products with complex structures and important biological activities have recently been isolated and synthesized. This review summarizes the structures, biological activities, and synthetic routes for natural compounds containing HPI, emphasizing the different strategies for assembling this motif. It covers a broad gamut of molecules, from small alkaloids to complex peptides.

Thiopeptides, or thiazolyl peptides, are a relatively new family of antibiotics that already counts with more than one hundred different entities. Although they are mainly isolated from soil bacteria, during the last decade, new members have been isolated from marine samples. Far from being limited to their innate antibacterial activity, thiopeptides have been found to possess a wide range of biological properties, including anticancer, antiplasmodial, immunosuppressive, etc. In spite of their ribosomal origin, these highly posttranslationally processed peptides have posed a fascinating synthetic challenge, prompting the development of various methodologies and strategies. Regardless of their limited solubility, intensive investigations are bringing thiopeptide derivatives closer to the clinic, where they are likely to show their veritable therapeutic potential.

La Tesis Doctoral se articula alrededor de dos objetivos: a) desarrollo de metodología de síntesis basada en química radicalaria y b) aplicación de los métodos en estudio a procesos encaminados a la síntesis total de productos naturales específicamente alcaloides. La reacción de ciclación radicalaria con transferencia de átomo (ATRC) a partir de tricloroacetamidas transcurre satisfactoriamente en substratos con alquenos neutros, con grupos electrón-atrayentes y grupos electrón-donadores, como aceptores radicalarios, en procesos 6-exo-trig para sintetizar 2-azabiciclo[3.3.1]nonanos polifuncionalizados. El proceso es catalizado por Cu(I) y la descomposición de un iniciador radicalaria convencional como es el AIBN interacciona con la forma oxidada para regenerar satisfactoriamente la especie activa. La extensión del proceso (CuCl, TPMA, AIBN) a dicloroetoxicarbonilacetamidas para la síntesis de morfanos polifuncionalizados con grupos aceptores radicalarios del tipo alquenos, nitrilos alfa-, beta-insaturados y acetatos de enol, presenta ciertas variaciones. En el caso de que los productos azabicíclicos contengan una unidad de 1,3-dicloalcano con estereoquímica antiperiplanar, éstos continúan evolucionando para generar un sistema ciclopropánico incrustado en el anillo de morfano. La reacción de desaromatización de bencenos no activados es posible mediante una ipso-ciclación de N-tricloroacetilbencilaminas en un procesos de ciclación radicalaria con transferencia de átomo catalizada por CuCl conduciendo a 2-azaespiro[4.5]decadienos, en los que los cloruros alílicos inicialmente formados son lábiles y sufren sustitución en los procesos de quenching utilizando agua (alcoholes), metanol (éteres) o alilamina (aminas). La reacción de desaromatización radicalaria transcurre también de manera exitosa utilizando análogos de tipo anisol, utilizando el catalizador de Grubbs II para inducir el proceso de espirociclación, seguido de la transferencia del átomo de cloro. En estas condiciones de reacción se aíslan ciclohexandienonas. La metodología sintética radicalaria desarrollada se aplicó a la preparación de “building-blocks” nitrogenados tri- y tetracíclicos de interés para la síntesis del inmunosupresor FR901483, alcaloides Daphniphyllum y madangaminas. La ciclación radicalaria de N-tricloroacetil-1-azaespiro[4.5]decanos procede con rendimiento aceptables utilizando un método ATRC. Así utilizando el catalizador de Grubbs II (5%) es factible el proceso ya que el radical carbamoildiclorometilo en ausencia de un dador de hidrógeno puede evolucionar de manera productiva para generar el sistema azatricíclico característico del inmunosupresor FR901483. Se describe una nueva aproximación para la síntesis del fragmento ABC de los alcaloides Daphniphyllum del grupo de la calicifilina A, en la que la sulfona azabicíclica, precursora del cierre final, se obtiene con excelentes rendimientos mediante la ciclación con transferencia de átomo, descrita en esta tesis, de tricloroacetamidas sobre acetatos de enol. La reacción de Michael clave, a partir de un carbanión estabilizado por un grupo sulfona sobre un aceptor de tipo enona alfa-, beta- -substituida, transcurre mediante el uso de una base débil K2CO3 o Cs2CO3. El proceso es estereodivergente, ya que según la base empleada se puede obtener un epímero u otro de manera preferente. Los cálculos computacionales sugieren que el proceso no es en ningún caso de control termodinámico ya que ambos epímeros son isoenergéticos. La ciclación radicalaria de (etoxicarbonil)dicloroacetamidas frente a nitrilos alfa, beta-insaturados transcurre de manera sintéticamente útil utilizando el método reductivo, lo que permite la formación con rendimientos superiores al 70% de un compuesto azabicíclico polifuncionalizado, que permite el acceso de manera rápida y eficiente a los sistemas diazatetracíclicos de las madangaminas D, E y F. La reacción de alilación para generar el centro cuaternario de las madangaminas transcurre de manera totalmente diastereoselectiva. El control en la formación de los centros estereogénicos permite el cierre del sistema diazatricíclico de las madangaminas, que es intermedio común para una síntesis divergente mediante procesos de RCM de los sistemas tetracíclicos de las madangaminas D, E y F., This Thesis is organized around two objectives: a) development of synthetic methodology based on radical chemistry and b) application of the studied radical cyclization procedures to the search of new routes in the total synthesis of some types of alkaloids. The atom transfer radical cyclization (ATR) from trichloroacetamides tethered to electron-deficient, -neutral, and –rich alkenes proceeds satisfactorily in 6-exo-trig processes leading to 2-azabicyclo[3.3.1]nonanes. The reaction is catalyzed by Cu(I) using AIBN as additive. Extension of the chlorine atom transfer radical cyclizations process (CuCl, TPMA, AIBN) to carbamoyldichloroacetate-tethered alkenes, enol acetates and alpha-, beta-unsaturated nitriles also lead morphan compounds but there was some variations. Cyclopropane ring formation was observed from the resulting 1,3-dichlorides in some morphan substrates using either Cu(I), Pd, or Zn. An atom transfer radical dearomatizing spirocyclization from N-benzyltrichloroacetamides using CuCl regioselectively leads to 2-azaspiro[4.5]decadienes, in which the labile allylic chlorine atom is easily replaced by a hydroxyl group in aqueous medium or by quenching with methanol or allylamine. Intramolecular Kharasch-type additions of trichloroacetamides on anisole and enol acetates catalyzed by Grubbs’ ruthenium carbenes are described. This protocol provides access to highly functionalized 2-azaspiro[4.5]decanes, morphan compounds, and the azatricyclic core of FR901483. The radical synthetic methodology developed was applied to the preparation of nitrogen-containing building blocks useful for the synthesis devoted to Daphniphyllum and madangamine alkaloids. The ABC-ring system of calyciphylline A-type alkaloids has been synthesized. The key steps of the synthetic approach are an atom transfer radical cyclization of a trichloroacetamide upon an enol acetate to generate the B ring, and a sulfone-based conjugated addition upon a beta-methyl- alpha-, beta-unsaturated ketone to give the target azatricyclic ketone. Selecting the cation (K+ or Cs+) of the carbonate in the C ring-forming intramolecular Michael addition gives stereodivergent access to both epimers of the cyclized product. Synthesis of the tetracyclic cores of madangamines D, E, and F featured a reductive radical process from an ethoxycarbonyldichloroacetamide to build the morphan nucleus, a Mitsunobu-type aminocyclization toward the common diazatricyclic intermediate, and ring-closing metathesis reactions for the macrocyclization step leading to the 13- to 15-membered rings.

The efficient and selective oxidation of secondary C-H sites of alkanes is achieved by using low catalyst loadings of a non-expensive, readily available iron catalyst [Fe(II)(CF3SO3)2(mcp)], {Fe-mcp, [mcp=N,N'-dimethyl-N,N'-bis(2-pyridylmethyl)cyclohexane-trans-1,2-diamine]}, and hydrogen peroxide (H2O2) as oxidant, via a simple reaction protocol. Natural products are selectively oxidized and isolated in synthetically amenable yields. The easy access to large quantities of the catalyst and the simplicity of the C-H oxidation procedure make this system a particularly convenient tool to carry out alkane C-H oxidation reactions on the preparative scale, and in short reaction times We would like to thank European Research Foundation for Project ERC-2009-StG-239910, MICINN for projects CTQ2012-37420-C02-01/BQU and CSD2010-00065. Generalitat de Catalunya for an ICREA Academia Award (X. R. and M. C.) and PhD grant (M. Canta). X. R. thanks financial support from INNPLANTA project INP-2011-0059-PCT-420000-ACT1

Los tratamientos considerados para el dolor y la inflamación han demostrado efectos colaterales, por ello, el descubrimiento e investigación de nuevos fármacos de origen natural son considerados como alternativa favorable. Los flavonoides comprenden un grupo de compuestos del tipo fenólico que abarcan una gran variedad de sustancias dentro de los Productos Naturales. Es por ello que en el presente trabajo se asilaron cuatro flavanonas isoprenílicas: 5, 7-dihidroxi-6-metil-8-prenilflavanona (I), 5, 7-dihidroxi-6-metil-8-prenil-4’-metoxi-flavanona (II), 5, 7-dihidroxi-6-prenilflavanona (III) y 5-hidroxi-7-metoxi-6-prenilflavanona (IV) a partir del extracto metanólico del las hojas de la especie vegetal Eysenhardtia platycarpa. A estas flavanonas se les evaluó su eficacia antiinflamatoria en un modelo de TPA en oreja de ratón, su capacidad antioxidante utilizando DPPH como radical libre y finalmente se hicieron pruebas de citotoxicidad frente a Artemia salina. Posteriormente, se elaboraron nanoformulaciones, en específico nanoemulsiones (NEs) y nanopartículas (NPs) a partir de las cuatro flavanonas Las NPs fueron del tipo polimérico preparadas mediante el método del desplazamiento del disolvente descrito por Fessi utilizando como polímero el PLGA 50/50 a la concentración de 1.5 mg/mL de principio activo. Estas NPs mostraron un tamaño de partícula medio de 156 - 202 nm con una carga negativa entre -25 and -30 mV. Los estudios de microscopía de transmisión electrónica (TEM) evidencian que las NPs tienen forma esférica obteniéndose de esta manera nanoesferas con un patrón denso uniformemente distribuido. Para el caso de las NEs se eleboraron empleando el método de pesada directa a una concentración de 0.5 % de principio activo. Los estudios de TEM y DLS (Dynamic light scattering) indican que se obtuvieron NEs del tipo W/O, de forma esférica y una estructura micelar de las gotas que oscilaban entre 60 y 70 nm; obteniéndose un menor tamaño de gotícula que en el caso de las NPs. A partir de las NPs y NEs se realizaron ensayos de liberación donde se encontró que los compuestos vehiculizados en nanopartículas liberan más rápido que en naoemulsiones; a las 2 h y a las 10 h. respectivamente y en ambos casos, las flavanonas (I) y (III) son las que mayor cantidad de fármaco liberan a esos tiempos. De los ensayos de permeación se observó que la constante de permeación y la cantidad retenida en piel se ven incrementados para las flavanonas (I), (II) y (IV) cuando son vehiculizadas en NPs. Con base a los resultados de la presente investigación se considera que la flavanona 5-hidroxi-7-metoxi-6-prenil flavanona (III) vehiculizada en nanoemulsión y nanopartículas poliméricas presenta los mejores resultados de permeación y actividad antiinflamatoria por lo que puede ser considerado un potencial agente alternativo antiinflamatorio de uso tópico., The clinically used antiinflammatory drugs suffer from the disadvantage of side effects, though the discovery and research of new natural drugs are a better alternative. Flavonoids are a wide group of natural phenolic compounds. In the present research, some nanoformulations were elaborated, specifically nanoemulsions (NEs) and nanoparticles (NPs), from four isoprenylic flavanones: 5, 7-dihydroxy-6-metil-8-prenylflavanone (I), 5, 7-dihydroxy-6-metil-8-prenyl-4’-methoxy-flavanone (II), 5, 7-dihydroxy-6-prenylflavanone (III) y 5-hydroxy-7-methoxy-6-prenylflavanone (IV) for using them as topical antiinflamatory drugs. The NPs were polimerycal compounds prepared by the solvent displacement technique described by Fessi using the PLGA 50/50 as a polymer (Concentration of active: 1.5 mg/mL). These NPs showed an average particle size of 156-202 nm with a negative charge between -25 and -30 mV. Microscopical studies (TEM) reveal that the NPs have a spherical shape, getting then nanospheres with a dense pattern homogeneously distributed. In the case of the NEs, they were prepared using the direct weighing method at a 0.5 % concentration of active. The TEM and DLS (Dynamic light scattering) studies confirmed that all W/O NEs were obtained, in round shape and a micellar structure of the drops between 60 and 70 nm; whereas in the NPs droplets of smaller size were obtained. Release studies revealed that the NPs vehiculized compounds release rate is higher than the one in the NEs (at 2 and 10 hours, respectively) and in both cases, flavanones (I) and (III) are the ones with the highest amount of drug released. Permeation studies showed that the permeation constant and the retained amount in skin are increased in flavanones (I), (II) and (IV) when they are vehiculized in NPs. According to the present research results we confirm that flavanone 5-dihydroxy-6-methoxy-6-prenylflavanone (III) vehiculized in NEs and polymeric NPs shows the best permeation and anti-inflammatory activity results; therefore it may be considered a potential alternative anti-inflammatory topical agent.

vegeu pdf

Since the late 1980s, a large number of depsipeptides that contain a new topography, referred to as “head-to-side-chain” cyclodepsipeptides, have been isolated and characterized. These peptides present a unique structural arrangement that comprises a macrocyclic region closed through an ester bond between the C-terminus and a β-hydroxyl group, and terminated with a polyketide moiety or a more simple branched aliphatic acid. This structural pattern, the presence of unique and complex residues, and relevant bioactivity are the main features shared by all the members of this new class of depsipeptides, which are reviewed herein.

An enantioselective approach to (-)-isoavenaciolide was achieved starting from 1- undecyn-3-ol. The synthesis relied upon the preparation of a chiral 4-silyloxy-2-alkenylborane by hydroboration of a protected 2,3-allenol and subsequent stereoselective addition to 2- thiophenecarboxaldehyde

The present doctoral thesis has been devoted to the development of a new synthetic strategy to obtain a new member of the thiopeptide, or thiazolyl peptide, family of antibiotics. This new member, baringolin, was isolated and characterized by the Spanish pharmaceutical company Instituto Biomar S.A. Although a structure was proposed, no stereochemical information was provided. Thus, this thesis has several objectives; first, a novel modular and straightforward strategy must be developed to achieve its total synthesis, but also to facilitate the preparation of analogues. The achievement of the total synthesis of baringolin should serve as the final confirmation of its structure and stereochemistry. The strategy developed herein is based in cross-coupling reactions and required the preparation of suitable building blocks and optimization of the required methodology. Moreover, L –series amino acids were chosen as the sole source of chirality to be introduced in the molecule, which is presumably synthesized in the ribosome of the producing bacteria. Once the synthetic methodology was set up and building blocks were ready, condensation of all fragments and final steps gave rise to synthetic baringolin, which was identical to its natural counterpart, confrming its structure and stereochemistry. Comparison of both products was made by spectroscopic methods and biological function assessment. Given the successful outcome of our synthetic plan, a small library of analogues was designed. Two different moieties of the molecule were modified: the thiazoline ring and the peptidic tail. As a result of minimum inhibitory concentration of Gram positive bacteria growth assessment of the library, different conclusions could be drawn from the results thus obtained. First, thiazoline was shown to be crucial to keep a broad activity profile against many strains; its substitution for a more rigid thiazole ring resulted in loss of activity towards most strains, while potency was only maintained against S. aureus. On the other hand, shortening of the peptidic tail had almost no effect in either activity or potency. Substitution of the peptidic tail with a cyclohexanoic acid moiety in the thiazole series resulted in recovery of activity against all strains and a potency increase against most of them. The good results obtained are good evidence of the efficiency of the synthetic strategy developed during this thesis and demonstrate that chemical synthesis is a useful tool for both structure determination and structure-activity relationship studies., En la presente tesis doctoral se ha llevado a cabo el desarrollo de una nueva estrategia sintética para la obtención de un nuevo miembro de la familia de antibióticos conocida como tiopéptidos, o tiazolil péptidos. Este nuevo miembro, la baringolina, fue aislado y caracterizado por la empresa farmacéutica española Biomar S.A., la cual no elucidó la estereoquímica del compuesto. Así, el propósito inicial de esta tesis es múltiple; por un lado se pretende desarrollar una estrategia que permita su obtención de forma directa y modular, facilitando la futura síntesis de análogos; por otro lado, la obtención de la baringolina sintética debe ofrecer una confirmación definitiva de su estructura y su estereoquímica. La estrategia desarrollada se basó en reacciones de acoplamiento cruzado, lo cual requería la preparación de los fragmentos necesarios y la optimización de la metodología a utilizar. Además, se escogió utilizar amino ácidos de la serie L como única fuente de quiralidad en la molécula, la cual presumiblemente está formada a partir de estos, dado el origen ribosomal de los tiopéptidos. Con la metodología puesta a punto y los fragmentos correspondientes preparados, se pudo llevar a cabo su ensamblaje, dando lugar a la baringolina sintética, la cual resultó ser idéntica a la natural, confirmándose así su estructura y estereoquímica. Dado el éxito de la síntesis total, se procedió a la síntesis de una pequeña librería de análogos, en la cual se modificaron dos zonas diferentes de la molécula, el anillo de tiazolina y la cola peptídica. Como resultado de la evaluación de la capacidad de inhibición de cultivos de bacterios Gram positivo, se extrajeron diversas conclusiones relativas a las relaciones estructura-actividad de las partes modificadas. En primer lugar, la tiazolina demostró ser necesaria para mantener un amplio espectro de actividad frente a diversas cepas, ya que su substitución por un anillo de tiazol, más rígido, prácticamente solo mantuvo el mismo nivel de potencia frente a S.aureus. Por otro lado, el papel de la cola peptídica resultó ser limitado, ya que su acortamiento no causó grandes diferencias de actividad y potencia. Por último, se substituyó la cola por un grupo de ácido ciclohexanoico en la versión que poseía un anillo de tiazol en lugar de tiazolina, lo cual resultó en el restablecimiento de la actividad frente a todas las cepas y un aumento de potencia frente a la mayoría de estas.

[spa] El filo Porifera (Grant, 1836) está compuesto por metazoos sésiles con un sistema acuífero diferenciado del que forman parte los coanocitos que generan un flujo de agua unidireccional. A pesar de no presentar auténticos tejidos, las esponjas pueden llegar a desarrollar dos regiones bien definidas, el ectosoma (capa externa) y el coanosoma (región interna). Estos organismos representan un grupo ecológicamente importante del bentos marino con gran capacidad de adaptación y dispersión en muchos hábitats, contribuyendo así en la organización y funcionamiento a nivel de comunidad y ecosistema. Una de las claves del éxito evolutivo de las esponjas yace en la relación estrecha que presentan desde el Precámbrico con microorganismos a través de la cual desarrollaron una protección química. Muchas esponjas habrían utilizado los metabolitos secundarios de origen microbiano como defensa química. A día de hoy se han desarrollado dos áreas de investigación, la ecología química y la microbiana de esponjas, de las que realmente desconocemos su origen o su impacto. Dado el vacío existente de estudios que evalúen la comunidad bacteriana de esponjas como fuente de compuestos bioactivos, teníamos la oportunidad de integrar estos dos campos de la ecología de esponjas investigando la relación entre productos naturales y microorganismos simbiontes, con el fin de entender la funcionalidad de la comunidad bacteriana en el huésped. Esta tesis fue concebida para estudiar la ecología química y microbiana de la esponja Aplysina aerophoba (Nardo, 1833), cuya química y comunidad bacteriana asociada han sido objeto de muchos estudios previos. El principal objetivo fue explorar las fuentes de variación tanto de los productos naturales adscritos a Aplysina como de su estructura microbiana e inferir una posible relación entre comunidad de microorganismos y la producción de metabolitos secundarios. La aproximación que utilizamos consistía en explorar la variabilidad natural de los compuestos bioactivos y de la estructura microbiana de la esponja Aplysina aerophoba a distintas escalas espaciales (desde pocos centímetros hasta miles de kilómetros) y temporales (meses, años), y evaluar el efecto de factores ambientales, como la luz, en los perfiles químicos y microbianos. Posteriormente, correlacionar ambos patrones de variación e inferir alguna asociación potencial entre productos naturales y simbiontes microbianos. Resumiendo, la producción de metabolitos secundarios en esponjas y la composición filogenética de la microbiota asociada depende esencialmente de la especie de esponja, de los factores ecológicos con variación espacial y temporal, como también del estado del huésped (si presenta o no estrés). La combinación entre factores abióticos y bióticos determinará en última instancia la abundancia de defensas químicas y la diversidad microbiana debido a una autorregulación entre ambos tipos de factores, [eng] Phylum Porifera (Grant, 1836) are sessile metazoans with a differentiated inhalant and exhalant aquiferous system with external pores. Lacking a tissue grade of construction, sponges can reach two well-differentiated regions, the ectosome (external layer free of choanocytes) and the choanosome (internal region with choanocytes). As the most likely primitive metazoans, their challenging structural organization, physiology for biocalcification and trophic requirements allowed sponges to rapidly colonize distinct environments and built important sponge reefs during the Paleozoic and Mesozoic eras, making them an ecologically relevant group principally in marine benthic communities. To date, sponges are still ecologically important among benthic fauna although the role as reef builders in modern coral reefs has changed in favor of scleractinian corals. Nonetheless, sponges have demonstrated a huge capacity to adapt and spread in many habitats contributing to organization and functioning at both community and ecosystem levels. One of the keys of the evolutionary success of this group lies in the close association between sponges and microbes that dates back to the Precambrian era. The need to be defended may have arisen from the lack of motility of sponges and several mechanisms emerged to fulfill their demand including a chemical protection. Many sponges would have taken advantage of associated microbes to use their metabolites as a defense barrier against predators, competitors or foulers. This particular symbiosis has consequently become a key factor in biotic interactions within the sponge research. To date, chemical ecology and microbial ecology are two independent areas of the sponge research with ecological implications that occasionally converge at the same point. We want to analyze the evolution of the sponge chemical and microbial ecology from the very beginning, to quantify their impact on the scientific community, and to compare both research areas. This PhD dissertation has been conceived to study the chemical and microbial ecology of sponges using the demosponge Aplysina aerophoba (Nardo, 1833) as a model species because its secondary chemistry and its associated microbial community are well studied and it is quite abundant in our study area (Northwestern Mediterranean and Canary Islands). Beyond the knowledge achieved about the major chemistry and bacterial assemblages in A. aerophoba, we have been able to explore the variation sources of the natural products and the sponge microbial consortium. Additionally, we have assessed the putative relationships between the host bacterial community and the production of secondary metabolites in this species. We explored changes in the abundance of secondary metabolites and the relative composition of bacterial assemblages in A. aerophoba at multiple spatial (from few centimeters to thousand kilometers) and temporal (months and years) scales. The approach used allowed us to investigate which is the magnitude of the variance attributable to the distinct spatial and temporal scales and the most relevant scale at which the abundance of secondary metabolites and bacterial symbionts varied. We also investigated the relationship between natural products and microbial community structure by assessing whether both parameters covary at multiple scales. Finally, we experimentally addressed whether different light exposures can modify chemical and microbial profiles in the external and internal regions of A. aerophoba. In summary, the production of natural products in sponges and the abundance and phylogenetic composition of the host-associated microbial community mainly depend to a large extent on the sponge-species and the ecological factors with spatial and temporal variations (e.g., light, predation, competition, fouling). The host state (i.e., stress) is also a key factor that may be the main driver of symbiotic shifts causing a breakdown in the sponge health and making the symbiont communities unstable and likely the sponge chemical defense. The combination between abiotic and biotic factors may finally determine the concentration of bioactive compounds and associated microbial diversity as the abiotic environmental context can control the outcomes of biotic interactions, and biotic interactions often moderate the effect of abiotic factors. For that reason, it is not an easy task to actually figure out the factors that limit or enhance chemical and microbial variability. Further experiments and time-series observations are needed to reveal the underlying processes hidden.

L'agent de control biològic (ACB) Candida sake CPA-1 és un llevat que ha demostrat reduir la podridura per B. cinerea (PBC) en collita quan va ser aplicada a camp amb l'additiu Fungicover® (FC) en estudis previs. Objectius: 1) estudiar l'eficàcia dels tractaments de C. sake amb FC, comparant amb altres productes comercials per al control de la PBC i de fonts d'inòcul secundari de B. cinerea (cap. 1, 2, 4 i 6), 2) Avaluar l'efecte d'aquests tractaments biològics sobre la podridura àcida del raïm (Cap. 3); 3) Investigar l'epidemiologia de la PBC en vinyes de climatologia mediterrània (Lleida), determinant els moments més importants durant la campanya per al desenvolupament de B. cinerea (Cap. 2, 5); 4) Avaluar l'efecte dels factors que redueixen la supervivència de C. sake CPA-1 en camp (Cap. 6, 7). Els resultats presentats en aquesta tesi doctoral demostren l'alta eficàcia dels tractaments amb C. sake CPA-1 i FC (82-90% de reducció de la severitat comparat amb el control sense tractar en assaigs à camp), que va ser similar o major que la d'altres productes registrats i en ús, confirmant la fiabilitat i el potencial d'aquests mètodes de control biològics per al control de la PBC en vinya. D’altra banda, s'han obtingut noves dades sobre la supervivència de C. sake i l'epidemiologia de B. cinerea, important per a futurs estudis de control biològic d'aquesta malaltia. Aquesta informació també aporta importants aplicacions pràctiques per optimitzar els tractaments amb C. sake i altres mitjans de control alternatius als fungicides de síntesi., El agente de control biológico (ACB) Candida sake CPA-1 es una levadura que ha demostrado reducir la podredumber por B. cinerea (PBC) en cosecha cuando fue aplicada en campo junto con el aditivo Fungicover® (FC) en estudios previos. Objetivos: 1) estudiar la eficacia de los tratamientos de C. sake con FC, comparando con otros productos comerciales para el control de la PBC y de fuentes de inóculo secundario de B. cinerea (Cap. 1, 2, 4 y 6); 2) Evaluar el efecto de estos tratamientos biológicos sobre la podredumbre ácida del racimo (Cap. 3); 3) Investigar la epidemiología de la PBC en viñedos de climatología mediterránea (Lleida), determinando los momentos más importantes durante la campaña para el desarrollo de B. cinerea (Cap. 2, 5); 4) Evaluar el efecto de los factores que reducen la supervivencia de C. sake CPA-1 en campo (Cap. 6, 7). Los resultados presentados en la presente tesis doctoral demuestran la alta eficacia de los tratamientos con C. sake CPA-1 y FC (82-90% de reducción de la severidad respecto al control sin tratar en ensayos de campo), que fue similar o mayor que la de otros productos registrados y en uso, confirmando la fiabilidad y el potencial de estos métodos de control biológicos para el control de la PBC en viña. Además, se han obtenido nuevos datos sobre la supervivencia de C. sake y la epidemiología de B. cinerea, importantes para futuros estudios de control biológico de esta enfermedad. Esta información también revela importantes aplicaciones prácticas para optimizar los tratamientos con C. sake y otros medios de control alternativos a los fungicidas de síntesis., The biocontrol yeast Candida sake CPA-1 had demonstrated to be effective to control BBR applied in combination with Fungicover in previous studies. Objectives: 1) to study and compare the efficacy of C. sake plus FC with other biologically-based treatments against BBR and secondary B. cinerea inoculum sources (Chapters 1, 2, 4 and 6); 2) to test the effect of biologically-based treatments on sour rot of grapes (Chapter 3). Moreover, 3) the epidemiology of B. cinerea in Mediterranean climate vineyards (Lleida) was also studied (Chapters 2, 5), in order to determine the most important phenological stages along the season for B. cinerea development; and lastly, 4) to investigate the effect of the abiotic factors determining the survival of C. sake CPA-1 after field applications (Chapters 6, 7). The results of the present PhD thesis demonstrated the high efficacy of C. sake CPA-1 plus FC treatments (82-90% severity reduction compared to the untreated control in field experiments), which was similar or higher than other commercialised products, confirming the reliability and potential of biologically-based strategies to control BBR. In addition, new data on survival of C. sake and B. cinerea epidemiology have been obtained, important for future research on BCAs and BBR. This information also provided important practical outcomes to optimise field treatments with C. sake and other biologically-based products.

A chemoselective indole-templated ring-closing metathesis is used to assemble the cyclohepta[b]indole substructure of the indole alkaloid ervitsine. A subsequent intramolecular Heck coupling of the resulting alkene functionality with an amino-tethered vinyl halide accomplishes the closure of the unique 2- azabicyclo[4.3.1]decane framework of the alkaloid with concomitant incorporation of the exocyclic Eethylidene substituent.

[cat] La present Tesi Doctoral es centra en l'estudi de l'efecte de diferents compostos d'origen natural sobre el càncer de còlon. La Tesi s'estructura en dues parts: la primera in vitro basada en estudis amb cèl•lules HT29 d’adenocarcinoma de còlon humà, on s'han avaluat la pentagaloilglucosa (PGG), l’hamamelitanin (HT) i la fracció polifenòlica F800H4 provinents de la planta Hamamelis virginiana (Capítol 1) i l’epicatequina (EC), l’epigal•locatequin gal•lat (EGCG) (Capítol 2) i l’epicatequin gal•lat (ECG) (Capítol 3) presents en té verd i raïm. D'altra banda, s'ha estudiat in vivo (en un model murí de càncer de còlon conegut com a ratolí ApcMin/+) la resposta al compost X, pendent de patent (Capítol 4) i a l'àcid maslínic (MA - Maslinic Acid) (Capítol 5), provinent de l'oliva. Finalment, l’últim capítol s’ha basat en la determinació de noves dianes anti-angiogèniques a nivell metabòlic. En el capítol l, diferents tècniques corresponents a la citòmica ens van permetre demostrar que el taní hidrolitzable PGG i la fracció F800H4 rica en tanins condensats extrets d'H. virginiana inhibeixen de manera semblant el creixement de les cèl•lules HT29 i dels colonòcits normals NCM460. En canvi, el taní hidrolitzable HT actua específicament contra les cèl•lules tumorals HT29 induint apoptosi i produint un arrest en la fase S del cicle cel•lular. En el capítol 2, utilitzant diferents tècniques proteòmiques es va determinar que els polifenols majoritaris en té verd, EC i EGCG, inhibeixen l'entrada de butirat en cèl•lules HT29 i la subsegüent diferenciació induïda per aquest. Aquest efecte no es deu a la modulació de les histones deacetilases ni a canvis en l'expressió del Transportador Monocarboxílic 1 (MCT1) encarregat del transport intestinal de butirat. Tanmateix, l’EC i l’EGCG disminueixen l'activitat del MCT1 mitjançant el seu posicionament en zones de la membrana plasmàtica no corresponents a rafts lipídics. En el capítol 3, es va caracteritzar l’ECG com a potencial inhibidor del metabolisme tumoral. El tractament de les cèl•lules HT29 amb ECG, present en té verd i raïm, redueix l'entrada de diferents substrats metabòlics com són la glucosa i la glutamina i també la producció de lactat. A més, l’ECG disminueix l'ús del cicle dels àcids tricarboxílics, de la síntesi de lípids i de la via de les pentoses fosfat. La reducció en aquesta última via es deu a la inhibició de l'activitat dels seus enzims clau glucosa-6-fosfat deshidrogenasa i transcetolasa. En el capítol 4 diferents tècniques pertanyents a la transcriptòmica ens van permetre determinar que el tractament dels ratolins ApcMin/+ amb el compost X disminueix la poliposi intestinal mitjançant la modulació de l'expressió gènica relacionada amb una inducció d'apoptosi i d'arrest del cicle cel•lular en la fase G1. Així mateix, el compost X també va infraregular gens relacionats amb la resposta immune i la inflamació, la qual cosa contraresta la inflamació crònica present en ratolins ApcMin/+. El capítol 5 mostra que l’MA inhibeix la poliposi intestinal en ratolins ApcMin/+. El mecanisme bàsic pel qual es dóna aquesta inhibició és la inducció d'apoptosi i d'arrest en la fase G1 del cicle cel•lular. A més, el tractament amb MA produeix un perfil metabòlic protector caracteritzat per una disminució en els nivells sèrics de glucosa i un augment en els nivells de cossos cetònics. Finalment, el capítol 6 caracteritza els canvis metabòlics associats a l’activació angiogènica. A manera de resum, els resultats obtinguts en aquesta Tesi Doctoral donen a conèixer nous mecanismes d'acció i noves dianes terapèutiques associats a l'efecte dels polifenols en càncer de còlon. A més, les dades obtingudes aporten llum al coneixement sobre algunes interferències entre diferents productes bioactius. Finalment, es mostra una adaptació metabòlica característica de les cèl•lules endotelials activades que pot esser explotada per al tractament efectiu del càncer., [eng] The present Doctoral Thesis is based on the study of the effect of different natural compounds on colon cancer. The Thesis is structured in two parts: the first in vitro part is based on studies with human colon adenocarcinoma HT29 cells, where we have evaluated the pentagalloylglucose (PGG), the hamamelitannin (HT) and the polyphenolic fraction F800H4 from Hamamelis virginiana bark (Chapter 1) and the epicatechin (EC), the epigallocatehin gallate (EGCG) (Chapter 2) and the epicatechin gallate (ECG) (Chapter 3) present in green tea and grape. On the other hand, we have investigated in vivo (in a mouse model of colon cancer known as ApcMin/+) the effect of a compound X, pending of patent (Chapter 4) and the effect of the maslínic acid (MA) (Chapter 5), from olive pomace. Finally, chapter 6 is based on the determination of new antiangiogenic targets at metabolic level. In summary, the results obtained in this Doctoral Thesis show novel mechanisms of action and new therapeutic targets associated to the effect of different polifenols, derivatives and triterpenes in colon cancer. Besides, the obtained data contribute to the knowledge on some interferences between different bioactive products which have to taken into account in future chempopreventive interventions. Finally, we show a characteristic metabolic adaptation underlying angiogenic activation that can be used to inhibit cancer growth.

[eng] The inhabitants of marine benthos must combat the ecological pressure caused by predation, competition and fouling through a series of mechanisms, one of which is chemical defense. This type of protection is particularly extended among sessile and/or sluggish organisms, such as sponges, soft corals or ascidians. The strategies to prevent predation are related to bad taste rather than to toxicity. Moreover, they must be considered along with nutritional quality, since the more nutritious the prey, higher quantities or more potent repellents are needed to gain protection. The production of defensive secondary metabolites is energetically expensive. For this reason, the Optimal Defense Theory (ODT) predicts that defenses must be allocated in the most valuable or more exposed structures or body-regions. In Antarctic communities, the main predators are asteroids, and defensive agents are hence expected to accumulate in superficial layers of potential prey. But dense populations of amphipods, which associate opportunistically with biosubtrata, obtaining both refuge and direct or indirect sources of nutrition, are also very influencing on these bottoms. It has been reported that chemical defenses are very common in Antarctic organisms, in accordance with our results. However, the research effort has not been the same for all the groups, and there are still many aspects to learn on the chemical ecology, like the identification of the implicated products, their mode of functioning or their localization and origin. This PhD has focused on three relevant groups of the Antarctic benthos, quite understudied: hexactinellid sponges, soft corals and colonial ascidians. Two influencing sympatric predators were selected, the sea star Odontaster validus, which is a known model predator, and for the first time, the amphipod Cheirimedon femoratus, used to perform feeding experiments for the detection of repellent chemical defenses. We designed a new protocol which provided numerous methodological profits, as well as a remarkable discriminatory potential for unpalatable activities. In a survey with 31 species of Antarctic organisms, a larger incidence of unpalatable activities was recorded towards C. femoratus than against the asteroid, especially in algae and sponges, in which amphipods may particularly influence defenses distribution for representing potential host-preys. Some organisms instead, seemed to exploit alternative defensive strategies. The ecological success of the three studied groups is probably related to the presence of chemical defenses. In hexactinellid sponges these are weak, yet compensated with a low energetic content, and derive from primary metabolites, such as steroid derivates. Some glucosphingolipids instead, could have a chemotaxonomical value as chemical markers in rossellid sponges. In soft corals, chemical protection is obtained from products originating from both, primary (wax esters) and secondary metabolism (sesquiterpenoids), which seem to cooperate in an additive way, and are likely exuded within the coral mucus in living specimens. The use of primary metabolites for defense represents an effective energy saving strategy. In colonial ascidians, defensive secondary metabolites of terpenoid and alkaloid nature with potent bioactivities predominate, and in some species these are accumulated in internal tissues. Presumably, this distribution is related to the production of chemically defended lavae. Some bioactive secondary metabolites isolated from various sources, like the meridianins, may suggest a broad evolutionary retention, or a symbiotic origin. Regarding bacterial antifouling, ascidians exhibited poor activity, while some soft corals did display inhibition. With this work we provide the identification, localization, and possible origin of several defensive agents in three relevant groups of Antarctic benthic invertebrates., [spa] Los habitantes del bentos antártico combaten la depredación, la competencia y el recubrimiento desarrollando mecanismos como la defensa química. Ésta estrategia está particularmente extendida entre organismos sésiles y organismos de cuerpo blando. Las defensas repelentes contra depredadores han de considerarse junto con la calidad nutricional, pues las dietas muy energéticas enmascaran la repelencia. La producción de metabolitos secundarios defensivos es costosa. Por ello, la Teoría de Defensa Optimizada (ODT) prevé que han de localizarse en las regiones corporales más valiosas o expuestas. En las comunidades antárticas los principales depredadores son las estrellas de mar y se postula la concentración de defensas en áreas superficiales en las presas. Pero también influyen las poblaciones de anfípodos asociados a los biosustratos, obteniendo en ellos refugio y fuente de alimentación. Esta tesis se centra en las defensas químicas de tres grupos relevantes del bentos antártico relativamente poco estudiados: esponjas hexactinélidas, corales blandos y ascidias coloniales. Se seleccionaron dos depredadores simpátricos, la estrella Odontaster validus y, por primera vez, fue utilizado el anfípodo Cheirimedon femoratus. Diseñamos un nuevo protocolo con numerosas ventajas metodológicas además de un gran potencial discriminatorio, y observamos que en 31 especies hubo mayor repelencia hacia el anfípodo que hacia la estrella, sobretodo en algas y esponjas, que podrían representar potenciales huéspedes-presa. A partir de aquí estudiamos muestras de los tres grupos seleccionados. En hexactinélidas, las defensas químicas son más débiles y derivadas del metabolismo primario, pero compensadas con un bajo valor nutricional. Algunos glucoesfingolípidos, podrían tener valor quimiotaxonómico como marcadores de la familia Rossellidae. En corales blandos existen metabolitos de defensa primarios y secundarios operando sinérgicamente, y probablemente forman parte del mucus superficial. En ascidias coloniales, los metabolitos defensivos son secundarios y muy potentes; además, en algunas especies éstos tienden a acumularse en tejidos internos, presumiblemente para producir larvas protegidas químicamente. Las ascidias mostraron poca actividad antibacteriana, pero algunos corales exhibieron respuestas inhibitorias. Esta Tesis proporciona la estructura, distribución y posible origen de los metabolitos responsables de las actividades defensivas en tres grupos relevantes de invertebrados antárticos.

[cat] L’estudi d’espècies marines (micro- i macroorganismes) és interessant perquè ha conduit a l’aïllament de substàncies amb una estructura química totalment diferent de les trobades en productes naturals aïllats d’organismes terrestres i a més amb una amplia gama de activitat biològica força interessant. La mayotlida és un producte natural d’origen marí aïllat per la empresa Pharmamar d’una mostra de Spongia sp. La mayotlida presenta activitat inhibidora del creixement (GI50) del ordre nanomolar. Des del punt de vista estructural, la mayotlida és un sistema octapeptídic i té la peculiaritat de la unió entre dos triptòfans (Trps), mitjançant l’enllaç entre el N indòlic d’un i el C3a de l’altre, que es troba ciclat constituint una unitat hexahidropirroloindole (HPI). Aquesta estructura triptòfan-pirroloindole ha sigut detectada, fins el moment en pocs productes naturals, i la mayotlida és el primer exemple d’un compost bis-macrocíclic amb aquest enllaç. En el capítol 1 de la memòria s’estudia la formació del sistema triptòfan-pirroloindole, per a lo qual s’ha assajat la reacció entre un Trp i un anàleg halogenat de l’HPI en diferents condicions experimentals a fi de trobar les més adients. Estàn descrites dues rutes sintètiques que condueixen a la formació de l’HPI halogenat en la posicióo 3a, conduint cadascuna a un diastereòmer distint. A més, en la formació de l’enllaç entre el C3a de l’HPI i el N indòlic del Trp, s’han escollit els grups protectors més adients i amb ortogonalitat entre ells per al creixement ordenat i selectiu del sistema Trp-HPI. En el capítol 2 s’inicia la síntesis de la mayotlida. En primer lloc, s’ha estudiat la formació de l’anell A, que és l’anell petit de la mayotlida. L’anell A és un macrocicle de tretze puntes format per tres aminoàcids: un Trp, l’HPI i l’Ile. S’han assajat tres posicions de macrociclació per a comprovar el punt idoni per tancar l’anell. S’ha determinat l’estereoquímica relativa dels estereocentres d’aquest anell mitjançant experiments de RMN mono i bidimensionals. La segona part d’aquest capítol es dedica a la formació del segon macrocicle, que anomenem anell B. S’ha sintetitzat, en fase sòlida, la cadena lineal pentapeptídica que unida als grups àcid i amina de l’anell A conduirà a l’anell B de la mayotlida. S’ha acoblat aquesta cadena amb l’anell A i s’ha realitzat la macrociclació de l’anell B per fornir la mayotlida. S’ha comparat la mayotlida sintètica amb la natural, coeluint ambdues al mateix temps. En el capítol 3 s’ha plantejat la síntesi de dos anàlegs de la mayotlida, els quals tenen la mateixa seqüència peptídica que l’anell B de la mayotlida i es diferèncien en que no tenen l’enllaç Trp-HPI, és a dir, no contenen l’anell A en la seva estructura; a més, un d’ells té un Trp enlloc de l’HPI. Endemés, s’ha assajat l’activitat de l’anell A de la mayotlida i d’un dels anàlegs sintetitzats., [eng] Marine natural products research is interesting because marine species (micro- and macroorganisms) biosynthesize compounds with different chemical structures and bioactivities from terrestrial natural products. Mayotlide is a marine natural product; it was isolated by Pharmarmar from a sample of Spongia sp. Mayotlide shows a nanomolar GI50 activity. Structurally, mayotlide is an octapeptidic system and it has the characteristic trait: the bond between Trp’s – the N-indole of a Trp and the C3a of a cycled Trp: a hexahydropyrroloindole unit (HPI). Few natural products contain this Trp-HPI system in their structures until the moment, and mayotlide is the first example of a bis-macrocyclic compound with this bond. The chapter 1 of the manuscript studies the synthesis of tryptophan-pyrroloindole system, which requires the reaction between a Trp and a halogenated HPI. Two synthetic routes have been reported to afford the halogenated HPI at C3a, each of which afford one mainly different diastereomer. In addition, the most suitable orthogonal protecting groups have been selected to allow the selective growing from the Trp-HPI system. The chapter 2 is about the beginning of the synthesis of mayotlide. First, the synthesis of the A ring has been studied, which is the small ring of mayotlide. The A ring is composed of three amino acids: Trp, Ile, and HPI. Three closing points of macrocycle have been tested. Several mono and bidimensional NMR experiments have made relative stereochemistry of stereocenters possible. The second half of this chapter is about the second macrocycle formation. The elongation of peptide chain of mayotlide has been synthesized on solid phase. Then, the couplings between the peptide chain and the A ring have been performed, affording the synthetic mayotlide. The natural and synthetic mayotlide have coeluted at the same time in a HPLC. The syntheses of two analogues of mayotlide have been studied in chapter 3. The structures of these analogues are one cycle which contain the same peptide sequence of the B ring of mayotlide; one of them has change the HPI for a Trp. In addition, the activities of the A ring and one analogue have been tested.