Orientador: Ronaldo Aloise Pilli / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Quimica / Made available in DSpace on 2018-08-04T07:48:41Z (GMT). No. of bitstreams: 1 Rosso_GiovanniBernardi_D.pdf: 15549651 bytes, checksum: c4309cb39642c602d7b5b33d48fe1565 (MD5) Previous issue date: 2005 / Doutorado / Quimica Organica / Doutor em Quimica

Extractos de plantas de la familia Stemonoacea son ricos en compuestos conocidos como alcaloides de Stemona y han sido ampliamente utilizados dentro de la medicina natural de China y Japón para el tratamiento de enfermedades respiratorias tales como la bronquitis y la tuberculosis, así como contra enfermedades parasitarias. Los alcaloides de Stemona son policíclicos y la gran mayoría incorporan en su estructura un esqueleto de 1-azabiciclo[5.3.0]decano así como uno o más anillos de alfa-metil-gamma-butirolactona. Hasta el momento se han sintetizado 13 de ellos, pero la mayoría de síntesis son largas, complejas y con bajos rendimientos. En nuestro grupo de investigación se inició hace algunos años un proyecto dirigido a la síntesis de algunos alcaloides de Stemona, utilizando como paso clave una reacción de cicloadición 1,3-dipolar entre una nitrona cíclica de 5 miembros y un éster alfa,beta-insaturado de 6 átomos de carbono convenientemente funcionalizado. A partir de un intermedio azabicíclico común se pretende llegar a distintos alcaloides del grupo Stemoamida (que presentan un anillo de lactona fusionado al sistema azabicíclico) y Tuberostemospiromina (que presentan un anillo de lactona unido de forma espiránica). Con este objetivo se ha sintetizado una nueva nitrona enantioméricamente pura y a escala multigramo como intermedio clave para la síntesis de los alcaloides. A partir de esta nitrona se han obtenido intermedios azabicíclicos sobre los que se ha ensayado la formación del anillo de lactona espiránico presente en los alcaloides del grupo Tuberostemospironina, y más concretamente los alcaloides stemospironina y stemonidina. La síntesis de stemospironina continúa actualmente en estudio, habiéndose obtenido intermedios cuyos centros estereogénicos presentan la misma configuración relativa que el alcaloide. Paralelamente, teniendo en cuenta la disyuntiva patente en la literatura sobre la existencia del alcaloide stemonidina, se han llevaron a cabo estudios dirigidos a la síntesis de este alcaloide. Tanto la lactona espiránica como la que se encuentra como sustituyente del anillo de pirrolina se construyeron mediante una reacción tipo Reformasky sobre una cetona y un aldehído, respectivamente. A partir de los resultados obtenidos podemos concluir que la estructura asignada a stemonidina es equívoca y que, muy probablemente, el alcaloide es en realidad stemospironina. / Extracts of plants of the Stemonoacea family are rich in compounds known as alkaloids Stemona and widely have been used within the natural medicine of China and Japan for the treatment of respiratory diseases such as the bronchitis and the tuberculosis as well as against parasitic diseases.The alkaloids of Stemona are polyciclic and the great majority incorporates in their structure a skeleton of 1-azabicyclo[5.3.0]decane as well as one or more ring of alpha-metil-gamma-butirolactona. Until the moment the total synthesis of 20 of them has been published, but most of synthesis they are long, complex and with low yields. In our group of investigation a project directed to the synthesis of some alkaloids of Stemona began some years ago, using like step nails a reaction of 1,3-dipole cicloaddicion between one nitrone of 5 members and a ester alpha, beta-insaturate of 6 carbon atoms properly functionalised. From an azabicyclic intermediate it is tried to arrive at different alkaloids from the group Stemoamide (that presents a ring of lactona fused to the azabicyclic system) and Tuberostemospiromine (that present a united ring of spiro-lactona form). With this objective nitrona enantiomeric pure and on scale has been synthesized how intermediate key for the synthesis of the alkaloids. From this nitrone intermediate azabicyclic have been obtained on which the formation of the ring of spiro-lactone has been tried present in the alkaloids of the Tuberostemospironina group. We carried out the preparation of the precursory epoxide of the ring of lactone with good diastereoselectivity, being stated that the conformation adopted by the oxirane makes difficult the formation of corresponding lactone. Considering the greater accessibility of the convex face of the azabicyclic system, we decided to modify the synthetic strategy taking advantage of this characteristic, obtaining itself intermediate advanced whose estereogenic centers present the same relative configuration that the stemospironine alkaloid. Parallelly, considering the disjunctive patent in Literature on the existence of the stemonidina alkaloid, directed studies were carried out to the synthesis of this alkaloid. As much spiro-lactona as the one that is as group of the pirrolina ring were constructed by means of a reaction of Reformasky on a ketone and an aldehyde, respectively. From the obtained results we can conclude that the assigned structure to stemonidina is ambiguous and that, more likely, the alkaloid is in fact stemospironina.

Natural products continue to influence society at large as many drugs are of natural product origin. Consequently, the development and study of new chemical reactions that lead to the efficient preparation of natural products is a central goal in organic chemistry today. To this end, we have investigated the reactivity and stereoselectivity of cyclic 2-(N-acylamino)-1,3-dienes toward a total synthesis of stenine. Chapter I describes the isolation and characterization of stenine, in addition to comparing five published total syntheses of stenine. Chapter II discusses synthetic and theoretical investigations of cyclic 2-(Nacylamino)- 1,3-dienes. We have shown that vinylazepenes react with Nphenylmaleimide to afford exo cycloadducts exclusively. Previous studies of vinylpiperidenes revealed a preference for endo selectivity. We confirmed the contrasting stereoselectivity by X-ray analysis of compounds i and ii. The stereoselectivity of vinylazepenes, vinylcycloalkenes, and vinyl piperidenes in Diels-Alder reactions varies depending on the detailed structure of the diene. In collaboration with Dr. Daniel Singleton and Jennifer Hirschi, DFT calculations were utilized to study model reactions of these dienes to provide insight into controlling the stereochemistry of this class of Diels-Alder reactions. Chapter III describes the synthesis of compounds such as iv and v that were utilized in intra and intermolecular Diels-Alder approaches toward the synthesis of stenine. We demonstrated that intermediate viii could be constructed from vinyl stannane vii in ten steps via an intermolecular Diels-Alder reaction of v and dimethyl fumarate (vi). Finally, we propose a synthetic plan for the completion of stenine from advanced intermediate viii.

Orientador: Ronaldo Aloise Pilli / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-26T22:32:16Z (GMT). No. of bitstreams: 1 BritoJunior_GilmarAraujo_D.pdf: 17782870 bytes, checksum: 5c94657b3c62d85cdf49bb3535c55ecb (MD5) Previous issue date: 2014 / Resumo: Os alcaloides Estemona são um grupo de cerca de 170 substancias com características estruturais intrínsecas. Dentro desses compostos o alcaloide Parviestemoamida (11a/11b) foi isolado em 1991, mas não teve sua estrutura tridimensional elucidada. Através de estudos prévios no nosso grupo de pesquisa, um possível epímero para a estrutura 11b proposta foi sintetizado, mas a não exatidão das análises espectroscópicas não permitiu a conclusão da elucidação estrutural para esse composto. Diversas metodologias foram testadas visando à preparação da lactama de 10 membros em 48, 52 e 57, mas esses produtos nunca foram obtidos. Mudança no plano sintético foi feito baseado em construir inicialmente o anel de 10 membros e por fim o de 5 membros. Dessa maneira, através da reação de ciclização radicalar foi possível sintetizar o composto 92, já contendo todos os átomos de carbono presentes na estrutura proposta 11a/11b, porém não foi possível a funcionalização da ligação dupla nesse composto, por nenhuma das metodologias testadas. Utilizando-se de ferramentas computacionais e análises comparativas com o produto natural Estemoamida (17), sugerimos que o produto natural isolado por Xu e colaboradores é a própria Estemoamida (17) ou algum isômero. O outro alcaloide, Estemoamida (17) já teve sua estrutura tridimensional elucidada bem como foi objeto de várias sínteses totais. A hidrogenólise seguido de ciclização em cascata do intermediário 51a levou favorecidamente à estrutura tricíclica presente no alcaloide 9a-epi-Estemoamida (96b) com razão de 5:1. Através desses resultados variações nas condições reacionais, como pressão e solvente, buscamos uma condição para que o triciclo presente no produto natural (17) fosse favorecido. A hidrogenólise seguido de ciclização em cascata do intermediário 51b sob 10 atm de pressão de hidrogênio e trifluoretanol como solvente, levou ao isômero desejado 96a com razão de 10:1. Cálculos computacionais foram utilizados buscando uma explicação para essa diferença de seletividade. A conversão dos triciclos 96a e 96b nos alcaloides (±)-Estemoamida e (±)-9a-epi-Estemoamida, já se encontra presente na literatura. Dessa maneira, realizamos uma síntese formal, curta e bastante eficiente para esses alcaloides / Abstract: The Stemona alkaloids are a group of about 170 substances that possess unique structural features. Among those compounds, Parviestemoamide (11a/11b) was isolated in 1991, but its tridimensional structure was not elucidated. Through previous studies in our research group, a possible epimer of the proposed structure 11b was synthetized, but the spectroscopic analysis did not match with the reported data, preventing an unambiguous structural elucidation of this compound. Several synthetic approaches toward the 10 membered lactam in 48, 52 and 57 were tested, but the desired products were never obtained in any condition tested. A alternative synthetic strategy to initially prepare the 10 membered ring and then the 5 membered lactone was planned. In this way, compound 92 was prepared by the radical cyclization reaction, already having all the carbon atoms present in the proposed structure 11a/11b, but unfortunately it was not possible to conduct the double bond functionalization in this bicyclic compound using the tested methodologies. Employing computational tools and by comparative analysis with the natural product Stemoamide (17), we suggest that the natural product isolated by Xu and coworkers is Stemoamide (17) itself or an isomer of 17. On the other hand, Stemoamide (17) already has had its tridimensional structure elucidated through syntheses by many research groups. The hydrogenolysis followed by cascade cyclization on intermediate 51a led to the core 96b present in 9a-epi-Estemoamida (98) and its 9a epimer in a 5:1 ratio, respectively. Inspired by this result, we sought a condition that could provide the other diastereomer, 96a, present in the natural Stemona alkaloid, Stemoamide (17). Based on this, the intermediate 51b was submitted to a similar condition, with 10 atm of H2 pressure and trifluoroethanol as solvent. In this way, the desired isomer 96a was obtained with 10:1 diastereoisomeric ratio. Computational calculations have been employed to explain this facial selectivity. The conversion of compounds 96a and 96b in the alkaloids (±)-Stemoamide (17) and (±)-9a-epi-Stemoamide (98) is already reported in the literature, so we could perform a short and efficient synthesis of these alkaloids / Doutorado / Quimica Organica / Doutor em Ciências

<div> Carbon monoxide is a useful carbon linchpin to construct complex molecules of natural products by stitching different pieces of target molecules together. Recently, our group reported a novel and efficient palladium-catalyzed spirolactonization by Dr. Dexter Davis to construct oxaspirolacones from esters or lactones. As an essential motif, oxaspirolactone structures in natural products exhibit diverse and exciting structures and biological activities. The first part of this thesis mainly describes the total synthesis of stemoamide alkaloids in the stemona family and the application of our palladium-catalyzed spirolactonization, which was developed by our group to complete total synthesis of bisdehydroneostemoninine and bisdehydrostemoninine with Prof. Kaiqing Ma. The total synthesis features a one-pot ring-closing cross-metathesis, Lewis acid-mediated Friedel-Crafts reaction and lactonization, and accomplished bisdehydrostemonine in 15 steps. The total synthesis of stemoamide, tuberostemoamide, and sessilifoliamide A were finished, and the critical step features an mCPBA oxidation to convert pyrrole to lactam in one step without destructing other functional groups. </div><div> In the second part of this thesis, we developed a novel and efficient palladium-catalyzed cascade amino-carbonylative lactonization to streamline the synthesis of dihydropyrrole-fused furanones in collaboration with Prof. Seleem’s lab for biological activities. Using this method, we quickly expanded this method to construct different ring structures, such as β-lactone and dihydropyrrole-fused pyrrolone. This method was applied to the total synthesis study towards stemofoline alkaloids. Our palladium-catalyzed spirolactonizaiton was also used in this total synthesis study for target molecules. </div><div><br></div>

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