<p>Carbon–carbon bond-forming reactions comprise the most important class of synthetic transformations. The development of improved and simplified approaches to these reactions will make important and useful contributions not only to the field of synthetic organic chemistry, but also to the many other areas of science that rely on it. Enolate based carbon–carbon bond formation is fundamental to synthetic organic chemistry and has provided the foundation for advancement to its present state. Herein, an important aspect of enolate chemistry is explored: the development of direct methods for carbon–carbon bond formation based on soft enolization of thioesters. Both metal-mediated and organocatalytic approaches to soft enolization are described.</p><p>MgBr₂·OEt₂-promoted soft enolization conditions were developed and successfully applied to the aldol addition and Mannich reactions, resulting in a mild and efficient direct reaction that is inexpensive and can be used under atmospheric conditions. A conjugate addition approach to chemoselective deprotonation was also explored and applied to the aldol. In addition, the first organocatalytic Mannich reaction based on proximity-accelerated intramolecular soft enolization of thioesters was developed. Given the advantages of soft enolization, including the inherent operational simplicity, and the accessibility of thioesters, we expect these methods to meet with wide application.</p> / Dissertation

The syntheses of aflastatin A and its C3-C48 degradation fragment are described. The syntheses feature several complex diastereoselective fragment couplings, including a C35-C36 anti-Felkin-selective boron-mediated oxygenated aldol reaction, a C15-C16 Felkin-selective trityl-catalyzed Mukaiyama aldol reaction, and a C26-C27 chelate-controlled aldol reaction involving soft enolization with magnesium. Careful comparison of the spectroscopic data for the synthetic aflastatin A C3–C48 degradation fragment (2) to that reported by the isolation group revealed a structural misassignment in the lactol region of the naturally derived degradation product. The cause of the mismatch was initially believed to be stereochemical in origin. Ultimately, the data reported for the naturally derived aflastatin A C3–C48 degradation lactol (2, R = H) was attributed to its derivative lactol trideuteriomethyl ether \((R = CD_3)\). Further, the absolute configurations of six stereogenic centers (C8, C9 and C28–C31) in aflastatin A (1) were formally revised by the isolation group prior to completion of its total synthesis. The synthesis of the aflastatin A C3–C48 lactol trideuteriomethyl ether and its spectroscopic match to the naturally derived C3–C48 degradation fragment confirm the stereochemical revision. The synthesis of a degradation product containing the tetramic acid and two overlapping stereocenters (C4 and C6) was also achieved. Its spectroscopic match to the corresponding naturally derived degradation fragment verified the absolute configuration of the aflastatin A C5' stereocenter. When combined with previous degradation fragment syntheses, and eventually the total synthesis of aflastatin A, the revised stereochemical assignment of aflastatin A was fully affirmed. / Chemistry and Chemical Biology

This thesis involves the synthesis of two main classes of triaminocyclopropenium (tac) Ionic Liquids (ILs) (i) Amino Acid Ionic Liquids (AAILs) and (ii) reduced-symmetry cations. [C₃(NEt₂)₂(NRR’)]X (X = TFSA and MeSO₄) were prepared, whereby NHR is derived from amino acids. Optically pure AAILs, [E₄AminoAcid]X (X = TFSA and MeSO₄) were obtained as a mixture of the IL and its zwitterion. The ratios of these mixtures were determined by pH titration and microanalysis. The AAILs specific rotations and pKa values were determined. AAILs can be used for chiral discrimination and form diasterreomeric salts with the entioenriched sodium salt of Mosher’s acid. The AAILs were also successfully used as a solvent and/or catalyst in an aldol reaction and a Diels-Alder reaction. The low-molecular weight series, [C₃(NMe₂)₂(NRR’)]X and [C₃(NMe₂)₂(NR’2)]X was synthesized and characterized: protic ILs NRR’, where R = ethyl, propyl, allyl, butyl, - CH2CH2OCH₃ and pentyl, R’ = H and X = TFSA: and aprotic ILs NRR’, where R = Me, R’ = ethyl, allyl, propyl, butyl, -CH2CH2OCH₃ and hexyl and X = TFSA and DCA. ILs with C2v symmetry [C₃(NEt₂)₂(NH2)]X (X = TFSA and MeSO₄), [C₃(NEt₂)₂(NBu2)]I, [C₃(NEt₂)₂(NHex₂)]I and [C₃(NEt₂)₂(NHex₂)]OTf were also synthesized and characterized. The C₃h cations, [C₃(NMeR)₃]X (R = ethyl, allyl, -CH2CH2OCH₃ and phenyl, X = TFSA and DCA) were successfully prepared as well. The D₃h cation salts [C₃(NEt₂)₃]X (X = MeC6H4SO₃, OTf, I and F5C6O) and [C₃(NBu2)₃]X (X = B(CN)4 and FAP) were also prepared. The tac-based ILs [C₃(NEt₂)₃]+ and [C₃(NBu2)₃]+ were also complexed with metal halides - - 2- 2- forming salts with FeCl₄ , SnCl₃ , CuCl₄ and ZnCl₄ . Reaction of pentachlorocyclopropane (C₃Cl5H) with BuNH2 gave the open ring allylium product [H2C₃(NBuH)4]2+. This was characterized as Cl- and TFSA- salt. During the synthesis of [C₃(NMe₂)₃]Cl, the open ring cation [HC₃(NMe₂)4]+ was also isolated and was characterized as the TFSA- salt. XX Abstract The TGA, DSC, density, viscosity, conductivity, and molar conductivity properties for the ILs were measured where possible. The viscosity and conductivity data was fitted for the Arrhenius and Vogel-Fulcher Tamman equations. The entire tac-based ILs lie below the KCl ideal line in Walden plot. A fragility plot was obtained by fitting the viscosity data and all the tac-based ILs were fragile. The crystal structures of [C₃(NPhH)₃]TFSA, [C₃(NEt₂)₃]FeCl₄ and [HC₃(NMe₂)4]Cl.2CH₃Cl were determined.

Les travaux présentés dans ce manuscrit s’inscrivent dans le contexte général de l’essor de la biocatalyse et de son utilisation en synthèse organique. Le thème principal porte sur l’étude et le développement de différentes voies d’accès stéréosélectives à des acides alpha-aminés bêta-hydroxylés substitués. L’utilisation d’un biocatalyseur permettant d’accéder à des acides alpha-aminés bêta-hydroxylés par une aldolisation entre la glycine et divers aldéhydes, en présence de phosphate de pyridoxal, a été étudiée. Des aldéhydes aliphatiques, aromatiques et hétéroaromatiques ont pu être impliqués avec succès comme partenaires électrophiles dans ces réactions qui permettent un excellent contrôle de la configuration du carbone asymétrique créé en alpha du groupe carbonyle mais s’effectuent généralement avec des diastéréosélectivités plus modestes. Par ailleurs, un dédoublement cinétique enzymatique d’esters alpha,bêta-dihydroxylés, précurseurs d’acides alpha-aminés bêta-hydroxylés substitués en alpha, a été étudié. La méthode développée repose sur la monoacylation d’esters alpha,bêta-dihydroxylés, acycliques ou cycliques, en présence d’une lipase et d’un donneur d’acyle. De façon indépendante, la mise au point de séquences réactionnelles monotopes faisant intervenir une étape d’oxydation biocatalytique a été étudiée pour accéder à des composés aminés hautement fonctionnalisés. / The research work presented in this manuscript pertains to the field of biocatalysis and some applications in organic synthesis. The main subject is the development of stereoselective synthetic methods allowing access to substituted alpha-amino beta-hydroxy acids. The use of a biocatalyst enabling the preparation of optically enriched alpha-amino beta-hydroxy acids in a single step from glycine by an aldol reaction, in the presence of pyridoxal phosphate, was investigated. Aliphatic, aromatic and heteroaromatic aldehydes could be successfully used as electrophilic partners in such reactions that allow an excellent control of the stereocenter created at the alpha position of the carbonyl group whereas moderate levels of diastereoselectivity were generally observed. The enzymatic kinetic resolution of acyclic or cyclic alpha,beta-dihydroxy esters, which are precursors of alpha-substituted alpha-amino beta-hydroxy acids, was also achieved by monoacylation in the presence of a lipase and an acyl donor. Independently, a one-pot sequence involving a biocatalytic oxidation was developed to access highly functionalized nitrogen containing compounds.

Orientador: Luiz Carlos Dias / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-16T16:04:10Z (GMT). No. of bitstreams: 1 Pinheiro_SavioMoita_D.pdf: 9633814 bytes, checksum: c4c7b0ac3175d0a710829278dbc19423 (MD5) Previous issue date: 2010 / Resumo: As reações aldólicas com enolatos de boro de metilcetonas quirais contendo o protetor p-metóxi- benzilideno cetal (105 e 106) levaram a obtenção do diastereoisômero com indução 1,5-anti em boas seletividades. A avaliação do processo de dupla-diastereosseletividade da metilcetona 105 mostrou que existe uma influência parcial por parte do aldeído no nível de seletividade. Reações aldólicas com metilcetonas acíclicas 1,2-syn-dissubstituídas contendo os grupos protetores PMB (108) e TBS (107) levaram ao isômero 1,5-anti em baixa seletividade. O emprego das metilcetonas contendo a relação 1,2-anti entre os seus estereocentros mostrou baixos níveis de indução 1,5-anti para a metilcetona 109 e 1,5-syn, para a metilcetona 110, eliminando a possibilidade de competição entre as induções 1,4-syn e 1,5-anti. Com o objetivo de compreender os fatores que controlam a reação aldólica, outros estudos estão em andamento no nosso grupo de pesquisas. / Abstract: We report herein that good to excellent levels of 1,5-anti stereoinduction are obtained in boron enolate aldol reactions of 1,2-syn -alkoxy methyl ketones with achiral aldehydes, when the b-alkoxy protecting group is part of a benzylidene ketal. The strong internal stereoinduction of the b-alkoxy stereocenter of the boron enolates dominates the overall stereochemical outcome of the corresponding aldol addition reactions, leading to the 1,5-anti products with good levels of diastereoselectivities. Even with the use of acyclic a-methyl-b-alkoxy methyl ketones, the b-stereocenter plays a dominant role in determining the sense of 1,5-anti asymmetric induction, although lower levels of diastereoselectivities were obtained. Due to the lower energy difference observed between transition states, it looks like a mismatched relationship case as a competition between 1,4-syn induction from the a-methyl stereocenter and 1,5-anti induction from the b-alkoxy stereocenter. The results showed a predominance of 1,5-induction in competition with 1,4-induction. / Doutorado / Quimica Organica / Doutor em Ciências

Orientador: Fernando Antonio Santos Coelho / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Quimica / Made available in DSpace on 2018-08-07T03:08:23Z (GMT). No. of bitstreams: 1 Ferreira_BrunoRicardoVilacha_M.pdf: 1423792 bytes, checksum: 7de8ab5e57971637382e0a11e87dbdf0 (MD5) Previous issue date: 2005 / Resumo: Napalilactona e Patilactona A são dois sesquiterpenóides espirolactônicos isolados de fontes marinhas. Esses sesquiterpenos, biogeneticamente derivados de um esqueleto carbônico do tipo aristoleno, apresentam em suas estruturas quatro centros estereogênicos contínuos e diferem apenas na substituição do heteroátomo (Cl versus OH) vizinho à unidade espiro g-butirolactônica. Como parte de um programa de pesquisa direcionado à síntese de alguns produtos naturais, descrevemos, nesse trabalho, um estudo focado no desenvolvimento de um método direto, que permitiria a preparação de um alceno funcionalizado, opticamente ativo. Esse intermediário pode ser usado para a síntese assimétrica dos dois sesquiterpenos. Devido ao elevado custo da (S)-(-)-pulegona, iniciamos esse trabalho com a (R)-(+)-pulegona, como um sistema modelo. O nosso objetivo principal era estabelecer uma estratégia sintética que mais tarde pudesse ser extrapolada para a síntese dos sesquiterpenos citados. Baseado nos dados anteriormente descritos pelo nosso laboratório para a síntese racêmica da Patilactona A, realizamos uma seqüência de reações na tentativa de se formar esse alceno funcionalizado. De acordo com a rota sintética partindo da (R)-(+)-pulegona, o intermediário seleneto foi preparado em 9 etapas com um rendimento global de 12%. Em vista do sucesso na síntese de intermediários avançados a partir da (R)-(+)-pulegona, esta mesma sequência sintética pôde ser usada na síntese assimétrica da (+)-Napalilactona, usando como material de partida a (S)-(-)-pulegona / Abstract: Napalilactone and Pathylactone A are two sesquiterpenoids spirolactones isolated from marine corals. These sesquiterpenes, biogenetically derivable from an aristolene carbon skeleton, show in their structures four contiguous stereocenters and differ only in the nature of heteroatom substituent (Cl versus OH) adjacent to the spirolactone ring junction. As part of a research program directed toward the total synthesis of some marine natural products, we describe in this work a study focused on the development of a straightforward method, which would allow the preparation of an optically active functionalized alkene. This key intermediate could be used for the asymmetric synthesis of both sesquiterpenes. Owing to the high cost of (S)-pulegone, we began this work using (R)-pulegone as a model system. Our aim was to establish a synthetic strategy that later could be surpassed for the synthesis of the sesquiterpenes cited. Based on data previously described from our laboratory for the racemic synthesis of Pathylactone-A, we carried out a sequence of reactions in an attempt to form the functionalized alkene. According to the synthetic route from (R)-(+)-pulegone, the intermediate selenide was prepared in 9 steps with overall yield of 13%. In view of the success in the synthesis of advanced intermediates from (R)-pulegone, this same synthetic sequence could be used for the asymmetric synthesis of (+)-Napalilactone, using as starting material the (S)-(-)-pulegone / Mestrado / Quimica Organica / Mestre em Química

Orientador: Luiz Carlos Dias / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Quimica / Made available in DSpace on 2018-08-13T21:30:59Z (GMT). No. of bitstreams: 1 Finelli_FernandaGadini_D.pdf: 6560101 bytes, checksum: 5eb9e7f25248bb940dd29d8af3e505ed (MD5) Previous issue date: 2009 / Resumo: O capítulo 1 relata as sínteses da macrolactona da migrastatina 11 e da macrolactona análoga 62a. A macrolactona da migrastatina é o composto que apresenta a maior atividade de inibição de migração de células tumorais in vitro dentre os compostos da família da migrastatina até hoje sintetizados. A macrolactona 62a, ainda inédita na literatura, é epímero em C8 da macrolactona 62b sintetizada pelo grupo do Professor Danishefsky em 2004 e apresenta atividade de inibição semelhante à macrolactona 11. Além disso, foram realizados estudos visando à síntese da macrolactona 124, epímero da macrolactona 11. Paralelamente, em colaboração com a Farmoquímica Cristália e o grupo do Professor Adriano Andricopulo, do IF/USP de São Carlos, foram realizados testes de avaliação biológica de diversos compostos sintetizados neste trabalho com o intuito de gerar novas substâncias químicas bioativas candidatas a novos fármacos no tratamento do câncer de mama. O capítulo 2 relata a síntese e aplicação de alguns substratos contendo grupos funcionais que ainda não haviam sido testados frente à reação de metátese de alcinos utilizando um novo catalisador de molibdênio. Este projeto foi desenvolvido no laboratório do Professor Alois Fürstner, no Instituto Max-Planck, em Mülheim an der Ruhr ¿ Alemanha. Além disso, um precursor do fragmento B das Latrunculinas A e B foi sintetizado em grande escala, fornecendo material para subsequentes estudos químicos e biológicos / Abstract: Chapter 1 describes the syntheses of macrolactones 11 and 62a. Macrolactone 11 presents the best tumor cell migration inhibitory effect among the compounds of the migrastatin family synthesized so far. Macrolactone 62a, not described in the literature, is the C8-epimer of macrolactone 62b, which was synthesized by Professor Danishefsky¿s group in 2004 and shows similar antitumor activities when compared to macrolactone 11. Studies aiming at the synthesis of macrolactone 124, epimer of macrolactone 11, were also performed. Besides, in collaboration with Farmoquímica Cristália and Professor Andricopulo¿s group (IF/USP, São Carlos), biological assays of several compounds synthesized in this work were carried out, with the purpose of developing new bioactive chemical substances which may soon be employed in the manufacturing of novel drugs in the treatment of breast cancer.Chapter 2 describes the syntheses of new substrates for applications in Mo-catalyzed RCAM. This project was carried out in Professor Fürstner¿s laboratory, at Max-Planck Institute, in Mülheim an der Ruhr ¿ Germany. In this part of the work, a Latrunculin A and B fragment precursor was also synthesized in large scale to provide further material for new biological and chemical studies / 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

No description available.

Die Mukaiyama-Aldolreaktion ist die Umsetzung eines Silylenolethers mit einer Carbonylverbindung in Gegenwart einer Lewis-Säure. Diese Reaktion ist eine wichtige Methode zur Knüpfung einer Kohlenstoff-Kohlenstoff-Bindung in der Organischen Chemie. In der vorliegenden Arbeit wird mittels quantenchemischer Methoden ein Einblick in den Mechanismus der Reaktion und die Ursachen der Enantioselektivität gegeben. Ausgehend von der unkatalysierten Reaktion wurde der Mechanismus der von kleineren achiralen Lewis-Säuren wie BF3 und TiCl4 katalysierten bzw. vermittelten Reaktion bearbeitet. Mit dem NEB-Verfahren zur Berechnung des Reaktionsmechanismus der enantioselektiv katalysierten Reaktion kam eine neuartige Möglichkeit zur Optimierung von Reaktionswegen zum Einsatz. Es konnte gezeigt werden, dass die Optimierung auch sehr komplexer Reaktionswege möglich ist. So wurde der gesamte katalytische Cyclus der Ti-BINOL katalysierten Reaktion berechnet, wobei sich der Einsatz der DFTB-Methode (density-functional based tight-binding method) zur Berechnung des Systems als sehr gut geeignet erwies. Die Leistungsfähigkeit der DFTB Methode konnte im Vergleich mit den geometrischen Daten aus Röntgenkristallstrukturanalysen nachgewiesen werden. Die Richtung der stereochemischen Differenzierung konnte in Übereinstimmung mit den experimentellen Ergebnissen bestimmt werden. Aus diesem Ergebnis war es möglich, ein schematisches Modell zu entwickeln, das die Ursache der Selektivität veranschaulicht.