Les motifs 1,3-polyols sont fréquemment rencontrés dans de nombreuses molécules naturelles biologiquement actives. Cependant, à ce jour, il n'existe que peu de méthodes générales et efficaces permettant d'accéder à ces motifs de manière stéréocontrôlée. Nous nous sommes particulièrement intéressés à la synthèse de 1,3,5,7-tétraols et une méthode a été mise au point pour former ces composés en utilisant deux cyclisations de Prins successives suivies d'une coupure réductrice du bis-tétrahydropyrane obtenu. Cette méthode permet d'accéder à tous les diastéréoisomères des tétraols efficacement et elle a été appliquée avec succès à la synthèse du (+)-cryptocaryol A, un composé polyhydroxylé stabilisant PdCd4, qui est une protéine inhibant le développement cellulaire. Par ailleurs, nous avons développé une approche synthétique de la filipine III, un macrolide naturel possédant des propriétés antibiotiques et antifongiques, et comportant un fragment 1,3-polyol et un fragment pentaénique. Plusieurs stratégies ont été envisagées afin d'accéder à ces deux fragments, qui ont été synthétisés de manière convergente. Leur assemblage a été réalisé grâce à une réaction d'aldolisation diastéréosélective et nous avons pu accéder au squelette carboné complet de la filipine III. / 1,3-Polyols are present in a large variety of biologically active natural products. However, right now only a few general and efficient methods have been described to access these compounds in a stereocontrolled manner. We were particularly interested in the synthesis of 1,3,5,7-tetraols and a method has been developed to prepare these compounds, using two successive Prins cyclizations followed by a reductive cleavage of the resulting bis-tetrahydropyran. This efficient method allows the access to all the diastereomers of these tetraols and has successfully been applied to the synthesis of (+)-cryptocaryol A, a polyhydroxylated compound which stabilizes PdCd4, a protein inhibiting the cellular growth. We have also developed a synthetic approach toward filipin III, an antibiotic and antifungal macrolide, which possesses a 1,3-polyol part and a pentaenic part. Several strategies have been envisaged to construct these fragments, which have been synthesized in a convergent manner. These fragments were then coupled using a diastereoselective aldolisation and we were able to access the complete carbon skeleton of filipin III.

L'acide alpha-linolénique (ALA, C18:3 n-3) est présent dans les membranes lipidiques des végétaux. Lors d'un stress oxydant, l'oxydation radicalaire non-enzymatique de cet acide gras polyinsaturé pourrait conduire à la formation de métabolites tétrahydrofuraniques nommés phytofuranes (PhytoFs). Souhaitant mettre en évidence leur existence et étudier leurs potentielles activités biologiques, nous avons développé une stratégie de synthèse divergente et flexible permettant d'accéder à ces métabolites de type PhytoFs. / Alpha-linolenic acid (ALA, C18:3 n-3) is the major polyunsaturated acid in plant membranes. During an oxidative stress, the non-enzymatic radical peroxidation of this acid would lead to tetrahydrofuran metabolites called phytofurans (PhytoFs). In order to bring into light their existence and to study their biological activities, we develop a divergent and flexible strategy to access to these metabolites.

Intramolecular hydroamination represents a potentially general, simple strategy to access various nitrogen heterocycles. While important progress has been accomplished in recent years, six-membered ring formation via alkene hydroamination is typically difficult and limited to terminal alkenes, suggesting that only 2-methylpiperidines can be accessed reliably with current methods. As part of the Beauchemin group efforts on metal-free concerted hydroamination methods, the first part of this thesis describes the development of a Cope-type hydroamination-Meisenheimer rearrangement (CHMR) sequence that is applicable in inter- and intramolecular reactions. Data acquired from optimization on a difficult substrate (coniine) and the successful application of the CHMR sequence to the syntheses of N-norreticuline and 10-desbromoarborescidine are reported. The amination of alkenes is surprisingly scarcely used in the synthesis of complex alkaloids despite its potential for the construction of structurally challenging molecules while avoiding functional group interconversions. Hence, the second part of this thesis describes the studies on a novel amination sequence, consisting of an intermolecular Diels-Alder followed by an intramolecular hydroamination reaction, in the efforts towards the synthesis of biologically active and structurally complex Manzamine A. As such, the synthesis of the model substrates, including the development of a novel family of aminodienes, as well as the assessment of their reactivity towards [4+2] cycloadditions is reported.

This is a thesis in two parts. Part A examines two potential routes towards the synthesis of the communesin family of alkaloids, as well as an overview of some of the successful synthetic routes to date. Our first proposed route involves the gold catalyzed isomerization of an o-amino aryallene to a vinyl imine and subsequent (formal) cycloaddition with an indole. This would have allowed quick access to the pentacyclic core of the communesins; however, the unexpected 5-endo-dig product was exclusively obtained in good to excellent yields. The second route involves the use of a Meerwein- Eschenmoser Claisen rearrangement. This route was successful in affording the C, D, E and F rings of the communesin alkaloids, however future work is required for completion of the synthesis. Also discussed in these sections is an alternative endgame approach involving a novel Pictet-Spangler reaction to afford the G ring, and the possibility of an asymmetric variation to the proposed route. Part B examines the use of alkyl aluminum sesquichlorides in the catalysis of Diels-Alder cycloadditions of sterically hindered systems, a current obstacle in organic chemistry. Previously developed methods are discussed and preliminary results are presented. Ethyl aluminum sesquichloride is compared to other alkyl aluminum catalyst, and the effects of temperature, catalysts loading, choice of solvent, the use of additives, and the use of chiral oxazolidinones are reported and what these result can tell us about the mechanism of catalysis are discussed.

Polycyclic Polyprenylated Acylphloroglucinols (PPAPs) are a vast family of natural products, which includes more than 200 members. They contain a stunningly complex molecular architecture which in most cases includes a bicyclo[3.3.1]nonane core. PPAPs have been of interest to the scientific community for their intricate structure, their powerful aid in treating many ailments and large portfolio of biological activities. More particularly, they have been of synthetic interest since 1999 with the first report of an approach to these complicated cores by Nicolaou. Herein, we present the first total synthesis of papuaforin A, papuaforin B, papuaforin C, hyperforin and the formal synthesis of nemorosone following a report by Simpkins and co-workers. We relied on a gold(I)-catalyzed carbocyclization for the construction of the core of this family of natural products. Ginkgolides are isolated from the ginko tree, Ginkgo biloba, a living fossil with records of its existence dating back 280 million years. For centuries, the plant and its extracts have been used extensively for their beneficial properties, especially in China, Japan and India. For example, extract Egb761, one of the most potent fraction, generates over $500 million a year alone. The ginkgolides possess a truly unique compact diterpene framework of six 5-membered rings with a high content oxygen. Eleven oxygens can be found in ginkgolide C for a core containing only 23 carbons. The ginkgolides also include a very unique feature: a tert-butyl group located on the most convoluted ring system: the B ring. Few groups have found success in limning a synthetic route to ginkgolides. Corey’s group was the first to achieve the total synthesis of ginkgolide B in 1987. He was also able to complete ginkgolide A a year later. Crimmins and co-workers also achieved the total synthesis of ginkgolide B a decade later in 1999. Herein, we present our new approach toward ginkgolides through a newly developed methodology for the α-allylation of ketones and the creation of highly hindered contiguous quaternary centers. The synthesis is still at an early stage but a synthetic pathway giving access to the ring B with all the key moieties has been extensively investigated.

Orientador: Ronaldo Aloise Pilli / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-26T20:06:35Z (GMT). No. of bitstreams: 1 Sant'Ana_CarolinaMartinsAvilade_D.pdf: 25003165 bytes, checksum: deb5835cc499985cdc35e9f74c89025a (MD5) Previous issue date: 2014 / Resumo: No capítulo 1 estudou-se uma rota sintética inédita para a obtenção da fostriecina e seus análogos, a qual possui como etapa chave a adição aldólica 1,4-anti, mediada por enolato de boro, para instalar o centro estereogênico em C11. Neste contexto, foi avaliada a influência do substituinte em ? nas reações aldólicas envolvendo enolatos de boro de metilcetonas quirais, que contêm em sua estrutura um centro estereogênico quaternário em C-8. Explorou-se seu escopo reacional, utilizando aldeídos que diferem entre si no que se refere aos aspectos estéreo e eletrônico. Obteve-se adutos com excelente diastereoseletividade (rd 1,4-anti versus 1,4-syn > 90:10). Esta metodologia foi aplicada na síntese do fragmento C5-C13 da fostriecina sendo obtido em 10 etapas e 8,4% de rendimento global a partir do (2E)-2-metil-2-buten-1-ol, disponível comercialmente. Este fragmento foi utilizado por G. A. O¿Doherty e colaboradores na síntese total mais recente da fostriecina, sendo preparado em 15 etapas a partir do (2E)-pent-2-en-4-in-1-ol (Org. Lett., 12, 3752, 2010). No capítulo 2, foi desenvolvida uma rota sintética flexível utilizando-se uma abordagem modular que permitiu a preparação de quatro estereoisômeros do produto natural coibacina A a fim de determinar a configuração absoluta do produto natural. Esta rota sintética possui como etapas chave olefinações de Wittig e Julia e ciclopropanação assimétrica de Charette. Após comparação por HPLC, utilizando coluna quiral, dos tempos de retenção destes quatro estereoisômeros com uma amostra da coibacina A de origem natural, foi possível estabelecer inequivocamente a configuração absoluta deste policetídeo como sendo 5R,16S,18S. A estereoquímica do centro estereogênico em C-5 da lactona ?-? insaturada, previamente assinalada como S, foi corrigida para R e a estereoquímica dos centros em C-16 e C-18 foi estabelecida como sendo S e S, respectivamente. Dessa forma concluímos a primeira síntese total do policetídeo insaturado coibacina A em 13 etapas (etapa linear mais longa) e 3,4% de rendimento global a partir do (S)-glicidol, obtido comercialmente. Adicionalmente, sintetizamos o isômero 5R,14S,16S da coibacina B em 13 etapas (etapa linear mais longa) e 5,7% de rendimento global / Abstract: In chapter 1, a new synthetic route for fostriecin and analogues was studied with the 1,4-anti boron-mediated aldol reaction as the key step in the formation of the stereogenic center at C11. In this context, the influence of the ?-alkoxy substituent in the aldol reaction involving the boron enolate of the chiral methyl ketones with a quaternary stereogenic center at C-8 was evaluated. The reaction scope was explored by using aldehydes with different steric and electronic patterns. Products were obtained in excellent diastereoselectivity (rd 1,4-anti versus 1,4-syn > 90:10). This methodology was applied to the synthesis of C5-C13 fragment of fostriecin in 10 steps and 8.4% overall yield from commercially available (2E)-2-methyl-2-buten-1-ol. This intermediate was used by G. A. O¿Doherty and co-workers in the most recent total synthesis of fostriecin and it was prepared in 15 steps from (2E)-pent-2-en-4-yn-1-ol (Org. Lett., 12, 3752, 2010). In chapter 2, a flexible synthetic route for four stereoisomers of the natural product coibacin A was developed based on a modular approach in order to establish the absolute configuration of this natural product. This synthetic strategy possesses as key steps the Wittig and Julia olefination reactions and Charette asymmetric cyclopropanation reaction. After comparison by chiral HPLC chromatography of the retention time of the four synthetic stereoisomers with a sample of coibacin A obtained from natural sources, the absolute configuration of the natural product was unequivocally established as 5R,16S,18S. The stereochemistry of the stereogenic center at C-5 of the ?,?-unsaturated ?-lactone, that had been previously assigned as S, was corrected to R and the absolute configurations at C-16 and C-18 were assigned as S and S, respectively. Therefore, we accomplished the first total synthesis of the unsaturated polyketide coibacin A in 13 steps (longest linear sequence) and 3.4% overall yield from commercially available (S)-glycidol. Additionally, we synthesized the 5R,14S,16S isomer of coibacin B in 13 steps (longest linear sequence) and 5.7% overall yield / Doutorado / Quimica Organica / Doutor em Ciências

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

Orientador: Luiz Carlos Dias / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-27T15:23:27Z (GMT). No. of bitstreams: 1 Polo_EllenChristine_D.pdf: 34484354 bytes, checksum: 4caa49b48c6b6c122794cf9e1e497292 (MD5) Previous issue date: 2015 / Resumo: A nhatrangina A foi isolada em 2010, por Orjala e colaboradores, a partir de uma coleção vietnamita da cianobactéria marinha Lyngbya majuscula. Este policetídeo apresenta seis centros estereogênicos e sua determinação estrutural foi realizada através da análise conjunta dos espectros de RMN 1D e 2D. O objetivo principal deste trabalho foi investigar uma rota sintética convergente e flexível para a obtenção deste produto natural e checar o assinalamento estrutural proposto pelos autores do isolamento. A estrutura proposta para a nhatrangina A foi sintetizada em 19 etapas, considerando a rota linear mais longa, e rendimento global de 6,7%. As etapas chave envolveram reação aldólica, reação de Corey-Fuchs, acoplamento entre alcino e amida de Weinreb mediado por lítio, redução estereosseltiva de Noyori e reação de esterificação de Yamaguchi. Além disso, sintetizamos seis diastereoisômeros da estrutura proposta para o produto natural, utilizando a mesma estratégia sintética empregada na síntese da estrutura proposta para a nhatrangina A, no entanto nenhum destes isômeros corresponderam ao produto natural / Abstract: The nhatrangin A was isolated in 2010 by Orjala and co-workers, from a Vietnamese collection of marine cyanobacterium Lyngbya majuscula. This polyketide containing six stereogenic centers and its structure was assigned based on spectrometric and spectroscopic methods including 1D and 2D NMR experiments. The aim of this work was to investigate the convergent and flexible synthetic route for obtaining this natural product and check the structural assignment proposed by the authors of isolation. The proposed structure of nhatrangin A was synthesized in 19 steps, considering the longest linear route, and overall yield of 6.7%. The key steps involved aldol reaction, Corey-Fuchs reaction, lithium-mediated coupling between alkyne and Weinreb amide, Noyori stereoselective reduction and Yamaguchi esterification. In addition, we synthesized six diastereoisomers of the proposed structure for the natural product, using the same synthetic strategy employed in the synthesis of the proposed structure of nhatrangin A, however none of these isomers correspond to the natural product / Doutorado / Quimica Organica / Doutora em Química

Thesis advisor: James P. Morken / This dissertation details three main projects that focus on stereoselective synthesis of organoboron reagents and their application to total synthesis studies. The first chapter describes the development of an enantioselective palladium-catalyzed conjuntive cross-coupling of bis(alkenyl)borates to access chiral allylboron reagents. These reagents are of high synthetic value that is demonstrated through various applications. The second chapter describes the development of a diastereoselective amine-modified boron-Wittig reaction with ketone electrophiles to access trisubstituted alkenyl boronic esters. The synthetic utility of these trisubstituted alkenyl boronic esters is demonstrated through a novel palladium-catalyzed cross-coupling reaction. The third chapter encompassess studies toward the total synthesis of natural products amphidinolides C and F. It highlights the application of methods developed in the Morken laboratory in the context of challenging total synthesis. It also highlights the potential for newly developed conjunctive cross-coupling and boron-Wittig reactions to solve problems in total synthesis. / Thesis (PhD) — Boston College, 2020. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

京都大学 / 0048 / 新制・課程博士 / 博士(薬学) / 甲第22405号 / 薬博第843号 / 新制||薬||241(附属図書館) / 京都大学大学院薬学研究科薬学専攻 / (主査)教授 大野 浩章, 教授 高須 清誠, 教授 竹本 佳司 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM