Les travaux décrits dans ce manuscrit de thèse ont porté d'une part sur le développement de nouvelles méthodes de spirocyclisation de céto-ynamides et d'autre part sur la réactivité de spiroénamides tertiaires. Les céto-sulfonamides en présence de bromoalcynes et de carbonate de césium conduisent à la formation de spiro-énamides par réaction de spirocyclisation via un intermédiaire céto-ynamide activé. Une grande variété de cycloalcanones et de bromoalcynes électroattracteurs sont tolérés.Les céto-ynamides conduisent à la formation de dérivés spiro-énamides par traitement avec du Triton B. La spirocyclisation tolère de nombreuses cycloalcanones et différents substituants aryles sur l'ynamide, et opère avec un bon stéréocontrôle de l'énamide. Une version en milieu micellaire aqueux de cette spirocyclisation a également été développée. Deux réactions dominos assistées par l'énamide tertiaire spirocyclique ont ensuite été développées. En présence de tétrachlorure de zirconium, la réaction domino permet d'obtenir des tétracycles de façon diastéréosélective tandis qu'avec le tétrachlorure de titane des pentacycles sont obtenus à partir du spiro-énamide avec un excellent régio- et diastéréocontrôle. / The work described in this manuscript involved the development of new spirocyclization methods starting from keto-ynamides, and the reactivity of tertiary spiro-enamides.Keto-sulfonamides led to spiro-enamides in the presence of cesium carbonate by spirocyclization reaction via an activated keto-ynamide intermediate. A wide range of cycloalkanones and electronwithdrawing bromoalkynes are tolerated. The spirocyclization reaction starting from keto-ynamides afforded spiro-enamide by treatment with Triton B. Various cycloalkanones, as well as a wide range of aryl substituents on the ynamide moiety, were suitable and provided good stereocontrol of the enamide formed. The spirocyclization reaction was also studied in aqueous micellar media. Two domino reactions assisted by the spirocyclic tertiary enamide were next developed. In the presence of zirconium tetrachloride, the domino reaction provided tetracyclic fused ring systems in a diastereoselective manner, whereas in the case of titanium tetrachloride, pentacyclic systems were obtained starting from the spiro-enamide with excellent regio- and diastereocontrol.

Este trabalho apresenta: 1) Duas revisões bibliográficas sendo uma sobre a síntese de α-ceto-tioésteres e -ésteres e a outra sobre a decomposição de sulfóxidos e sulfonas sulfeniladas; 2) Investigações prévias indicando a viabilidade da decomposição térmica e a estabilidade relativa dos derivados bissulfenilados de tioésteres de diferentes estados de oxidação Ia-e, obtidos a partir do α-ceto-tioéster; 3) O estudo de síntese de precursores de α-ceto-tioésteres II e α-ceto-ésteres III, a saber: α - metilsulfonil- α - metiltio tioésteres IVa-c, -éster V e α, α - dimetiltio - ésteres VIa-c; 4) Decomposição térmica de α-metilsulfonil-α-metiltio-tioésteres Iva, b e c e -éster V sintetizados aos α-ceto-tioésteres e ésteres correspondentes, pelo emprego do método elaborado anteriormente por Wladislaw e col. e sugestão do mecanismo da mesma. A síntese de α metilsulfonil α metiltio tiopropionato de etila (Ivb), foi efetuada a partir do ácido α-cloro propiônico através de quatro passos reacionais, a saber: sulfenilação por substituição, oxidação à sulfona , tioesterificação e sulfenilação pelo emprego de NaH/MeS02SMe em DMSO. A obtenção do α - benzil - α - metilsulfonil - α - metiltio - tioacetato de etila (Ivc) foi efetuada a partir de ácido α-cloro acético através de reações de sulfenilação por substituição oxidação à sulfona tioesterificação alquilação com brometo de benzila e NaH em DMSO e, finalmente, a sulfenilação que só foi possível com o emprego de N-metiltioftalimida. A síntese de α-metilsulfonil-α-metiltio-propionato de etila (V) foi efetuada a partir do α-metilsulfonil malonato VIIa pelo eemprego do método de descarbetoxilação sulfenilativa usando 1,4 diazabiciclo [2,2,2] octano (DABCO) em tolueno sob refluxo e MeSO2SMe. Os compostos VIIa,b e c foram preparados a partir dos malonatos de dietila alquil - substituidos, seguido de sulfenilação e oxidação à sulfona. É de interesse a inédita reação de α - metilsulfonil fenilmalonato de dietila (VIIb), com DABCO em benzeno sob refluxo e MeSO2SMe, que conduziu à dessulfonilação sulfenilativa fornecendo o α - metiltio - fenilmalonato de dietila. É apresentada uma discussão mecanística tanto sobre descarbetoxilação, como sobre dessulfonilação sulfenilativas. A síntese de α,α-dimetiltio-ésteres VIa-c foi efetuada pela reação de sulfenilação com descarboxilação dos mono-ácidos malônicos correspondentes. O acompanhamento da descarboxilação e experimentos de deuteração permitiram esclarecer a sequência dos passos reacionais nestas novas reações. Cabe ressaltar que são compostos ainda não descritos na literatura os precursores IVa, IVb, IVc, V e Vib e 11 intermediários envolvidos nas reações efetuadas. Os resultados apresentados neste trabalho, além de importância sintética, trazem uma contribuição para a Química de Compostos Orgânicos de Enxofre. / This work presents: 1) Two literature reviews, one about the synthesis of α-keto thioesters and esters and the other on the decomposition of sulfenylated sulfoxides and sulfones; 2) Previous investigations indicating the viability of thermal decomposition and the relative stability of the dithioderivatives of different oxidation states Ia-e,which were obtained from the α-keto thioester; 3) The study of synthesis of α-keto thioesters II and esters III precursors, which are the following: α-methylsulfonyl-α-methylthio-thioesters IVa-c and -ester V, and α, α - dimethylthio esters VIa-c; 4) Thermal decomposition of the synthesized α - methylsulfonyl- α -methylthio- thioesters Iva,b e c and ester V, to the corresponding α-keto thioesters and α-keto ester, through the method developed by Wladislaw et al., with the suggestion of the mechanism. α-Methylsulfonyl-α-methylthio ethyl thiopropionate (Ivb) was synthesized from α-chloro-propionic acid in four steps: sulfenylative substitution, oxidation to sulfone, thioesterification and sulfenylation using NaH/MeSO2SMe in DMSO. α-Benzyl-α-methylsulfonyl-α-methylthio ethyl thioacetate (,i>Ivc) was obtained from α-chloro acetic acid through the following steps: sulfenylative substitution, oxidation to sulfone, thioesterification, alkylation with benzylbromide and NaH in DMSO, and finally, the sulfenylation which was successful only with the use of N-methylthiophtalimide. α-Methylsulfonyl-α-methylthio ethyl propionate (V) was synthesized through the sulfenylative decarbethoxylation of α methylsulfonyl diethyl malonate VIIa employing DABCO (1,4-diazabicyclo [2.2.2.]octane), in refluxing toluene, and MeSO2Sme. The compounds VIIa,b e c were obtained by the alkylation of malonates, followed by sulfenylation and oxidation to sulfones. An interesting and novel reaction, the sulfenylative desulfonylation, was observed when α-methylsulfonyl phenyldiethyl malonate (VIIb) was treated with DABCO, in refluxing benzene and MeSO2SMe, which led to the α-methylthio diethyl malonate. A mechanistic discussion about the sulfenylative decarbethoxylation and sulfenylative desulfonylation is presented. α, α-dimethylthio esters VIa-c were synthesized by sulfenylation and decarboxylation of the corresponding malonic half-esters. The sequence of the steps of this new reaction could be determined by deuteration experiments and by following the evolution of CO2. The precursors IV, IVb, IVc, V e Vib and 11 intermediates were unknown compounds. This work, besides the synthetical importance, presents some contribution to the Organosulfur Chemistry.

No description available.

Despite comprehensive studies addressing the chemical kinetics of butanol isomers, relevant uncertainties associated with the emissions of relevant pollutants persists. Also, a lack of chemistry knowledge of processes designed to produce biofuels limits their implementation at industrial scales. Therefore, the first objective of this thesis was to use cutting-edge kinetic theories to calculate rate constants of propen-2-ol, 1-pronenol, and vinyl alcohol keto-enol tautomerizations, which account for the production of the harmful carbonyl species. The second objective was to use the predictive capabilities of dynamic theories to reveal new chemistry of syngas oxy-combustion in supercritical CO2 and complexities of the zeolite dealumination, two processes involved in coal and biomass conversion. Rate constants computations considered transition state theory with variational effects, tunneling correction, and multistructural torsional anharmonicity. The study also included pressure effects by using and improving the system-specific quantum Rice-Ramsperger-Kassel/modified strong collision model. The atomistic simulations used ReaxFF force fields in hydrogen/oxygen/carbon monoxide/ carbon dioxide mixtures to represent the syngas system and an MFI zeolite with different water loading to model the dealumination. The results show that the studied assisted tautomerizations have much lower energy barriers than the unimolecular process. However, the “catalytic” effect is efficient only if the partner molecule is at high concentrations. Pressure effects are pronounced in the chemically activated tautomerizations, and the improved algorithm to compute pressure-dependent rate constants overcomes the initial difficulties associated with its application to C3 or larger molecules at temperatures above 800-1000 K. Reactive molecular dynamics simulations revealed the role of CO2 as an initiator in the syngas oxy-combustion and a new step involving the formation of formic acid. Those simulations for the zeolite dealumination process also showed that proton transfer, framework flexibility, and aluminum dislodging mediated by silicon reactions are complex dynamic phenomena determining the process. These aspects complement the dealumination theory uncovered so far and establish new paths in the study of water-zeolite interactions. Overall, the rate constants computed in this work reduce relevant uncertainties in the chemical kinetic mechanisms of alcohol oxidation, and the molecular dynamics simulations broaden the chemical knowledge of processes aimed at the utilization of alternative energy resources.

Yes / The aldo-keto reductase 1C3 (AKR1C3) isoform plays a vital role in the biosynthesis of androgens and is considered an attractive target in prostate cancer (PCa). No AKR1C3-targeted agent has to date been approved for clinical use. Flufenamic acid and indomethacine are non-steroidal anti-inflammatory drugs known to inhibit AKR1C3 in a non-selective manner as COX off-target effects are also observed. Recently, we employed a scaffold hopping approach to design a new class of potent and selective AKR1C3 inhibitors based on a N-substituted hydroxylated triazole pharmacophore. Following a similar strategy, we designed a new series focused around an acidic hydroxybenzoisoxazole moiety, which was rationalised to mimic the benzoic acid role in the flufenamic scaffold. Through iterative rounds of drug design, synthesis and biological evaluation, several compounds were discovered to target AKR1C3 in a selective manner. The most promising compound of series (6) was found to be highly selective (up to 450-fold) for AKR1C3 over the 1C2 isoform with minimal COX1 and COX2 off-target effects. Other inhibitors were obtained modulating the best example of hydroxylated triazoles we previously presented. In cell-based assays, the most promising compounds of both series reduced the cell proliferation, prostate specific antigen (PSA) and testosterone production in AKR1C3-expressing 22RV1 prostate cancer cells and showed synergistic effect when assayed in combination with abiraterone and enzalutamide. Structure determination of AKR1C3 co-crystallized with one representative compound from each of the two series clearly identified both compounds in the androstenedione binding site, hence supporting the biochemical data. / University of Turin (Ricerca Locale grant 2015-2017) and Prostate Cancer UK grant S12-027.

A highly regio- and diastereoselective approach towards complex 6-membered lactones was developed using allyl/propargyl benzyl ethers and delta keto esters. Crucially, the classical ET reagent SmI2 gave unsatisfactory results and it was necessary to develop and screen new Sm(II) cyclopentadienyl complexes to deliver high selectivity in the transformation. The methodology was extended to a one-pot approach to complex cycloheptanols using SmI2-H2O in a second stage of the process. Samarium(II) folding cascades were developed where simple, linear starting materials are converted to complex polycyclic architectures bearing multiple stereocentres. It was found that, depending on the sidechain in the starting material, it was possible to achieve four different pathways from the common radical intermediate. Crucially, transannular 1,5-HAT from tertiary and benzylic positions was observed to give diverse products. A proposed 1,5-HAT facilitated SmI2-mediated 6-membered lactone radical cyclisations for the first time without an activating proton donor additive. Enantioselective samarium(II) mediated cyclisation cascades were achieved, where simple beta keto esters are converted to complex polycyclic architectures bearing up to five contiguous stereocentres with high diastereo- and enantiocontrol. In the process, a simple and easy to prepare chiral aminodiol was employed which could be recycled after the reaction. Unprecedented, enantioselective transannular radical cascades allowed access to unique 3- dimensional scaffolds inaccessible by other synthetic methods.

Les glycoconjugués constituent une classe de molécules organiques importante car ils sont impliqués dans de nombreux processus biologiques à savoir l'inflammation, la transmission du signal, la fécondation, l'adhérence cellule-cellule et bactérie-cellule, la reconnaissance virus-cellule et la défense immunitaire… L'utilisation de ce type de molécules comme principe actif peut être limitée par l'instabilité de la liaison glycosidique en milieu physiologique et de ce fait la préparation de C-glycoconjugués plus stables, non sensibles aux hydrolyses acides et enzymatiques constitue un enjeu en synthèse organique. Cette thèse décrit un nouvel accès à des C-glycoconjugués via des précurseurs céto-C-glycosides. La majeure partie du travail a consisté à la mise au point d’une nouvelle voie d’accès à des céto-C-glycosides à partir de glyconitriles issus du glucose, du galactose ou du mannose. Dans un premier temps, la réactivité de glyconitriles totalement protégés sous forme d’éthers benzyliques vis-à-vis d’organozinciques activés a été étudiée permettant d’isoler différentes cétones fonctionnalisées C-glycosylés. Lorsque ces substrats sont opposés à des organomagnésiens, un mélange de composé attendu et de glycal issu de l’élimination du benzyloxy en position 2 est observé. Afin de limiter la formation des glycals, des glyconitriles comportant un groupe hydroxyle en position 2 ont été préparés. L’addition de réactifs de Grignard ou d’organolithiens sur ces glyconitriles ont conduit à divers céto-C-glycosides. Ainsi, il a été montré que l’addition des organolithiens était plus efficace en termes de rendement.Ayant en main ces dérivés cétoniques, une étude de fonctionalisation de la fonction cétonique (formation de méthylène, de gem-difluoré, réduction en alcool…) a été entreprise, sur un substrat modèle, acquis qui pourra être transposé aux acyl-C-glycosides plus complexes. De plus, l’application de la méthodologie de synthèse à des C-glycoconjugués originaux appartenant à trois familles de composés différentes, inhibiteurs potentiels de SGLT-2 ou de glycogène phosporylase, nouvelles cibles thérapeutiques dans le traitement du diabète de type 2, a été validée. / Glycoconjugates, an important series of organic molecules, are fundamental to many important biological processes such as inflammation, signal transduction, fertilization, bacterial-cell or cell-cell adhesion, virus-cell recognition and immune response…The use of such compounds as drug is limited by the significant hydrolysis occurring in physiological medium or in acidic conditions. Thus, more stable C-glycoconjugates syntheses have to be developed.A new strategy for the synthesis of C-glycoconjugates via acyl-C-glycosides precursors is described from gluco-, galacto- or manno-nitriles. First, the reactivity of O-perbenzylated glyconitriles towards various activated organozinc reagents led to various functionalized keto-C-glycosides. However, with Grignard reagents, a mixture of the corresponding compound along with glycal occurring from the elimination of benzyloxy group located in position 2 is observed. To prevent such elimination, 2-hydroxyglyconitrile was prepared. With organomagnesium or organolithium reagents, these glyconitriles led to various glyconitriles in good yieds. It is noteworthy that organolitium reagents were more efficient, leading to better yields in glucose and galactose series.With these keto derivatives in hands, the transformation of the keto group into methylene, gem-difluorine, alcool…. was performed on a galatose-derived ketone as a model for the preparation of more complex C-glycosides. Moreover, the application of the methodology was applied to the synthesis of original C-glycoconjugates as potential SGLT-2 or glycogen phosphorylase inhibitors, thereby validating the synthetic strategy.

This thesis presents a new developed method for first intermolecular aldehyde/ketone cross benzoin coupling. Protected &amp / #945 / -keto tertiary alcohols are synthesized starting from easily available acyl phosphonates and ketones via Brook rearrangement in the presence of catalytic amount of cyanide ion. The scopes and the limitations of the methods for the synthesis of tertiary alcohols with &amp / #945 / -keto group are discovered.

This thesis describes a computational investigation of the mutagenicity of 5-bromouracil (BrU). In Chapter 1, three models of spontaneous and BrU-induced base mispairing (rare tautomer, wobble pair, and ion) are reviewed. Chapter 2 presents the computational techniques used: electronic structure methods (Hartree–Fock-based and density functional theory) and molecular dynamics. Chapter 3 presents optimisations of the keto and enol tautomers of BrU and uracil (U) in water clusters. The enol tautomer of BrU is found to be more stable than that of U. Chapter 4 is a molecular dynamics study of the keto-enol tautomerism of BrU and U in a periodic water box. The pKₐ of BrU at N3 is found to be lower than that of U. Chapter 5 is a study of stacked base dimers containing BrU, U, or thymine (T) stacking with natural bases. Some structures were taken from the Protein Data Bank, while others were generated using an in-house methodology. BrU is found to stack more strongly than T in vacuo, but solvation and thermal effects nullify this difference. Chapter 6 discusses the significance of the results in Chapters 3–5 in terms of BrU-induced mutagenesis. Appendices A and B–D provide supplementary material to Chapters 2 and 5, respectively. Appendix E is an investigation of the “base flipping” pathway of 2-aminopurine (2AP). Both 2AP/N and A/N dinucleosides (N = thymine or guanine) are found to adopt a wide range of energy-minimum conformations – not only stacked and “flipped”, but also intermediate – and the stacked are not the most favourable by free energy. Appendix F is a list of publications and papers in preparation. One publication concerns BrU stacking. The other is a conformational study of the dipeptide tyrosine-glycine: the theoretical results are shown to be consistent with experiment (R2PI spectra) if thermal effects are taken into account.

CoordenaÃÃo de AperfeÃoamento de Pessoal de NÃvel Superior / A Tese Brincando no (Canto-que-DanÃa) do Ijexà com o Bumba-meu-Boi: Teatro do Encantamento da Ancestralidade Africana em Fortaleza A Cidade Tan-Tan, tem por objetivo aprofundar estudos da minha dissertaÃÃo de mestrado. No referido trabalho movimentÃvamos uma discussÃo na intenÃÃo de fazer o pensamento cantar e danÃar como festivamente ensina a cultura tradicional africana de matriz ioruba, a fim de elencar possibilidades para a construÃÃo de uma EducaÃÃo Teatral assentada na Ancestralidade Africana e na AfrodescendÃncia. Agora, no doutorado, a proposta à focar-se na ritualÃstica de saberes do Candomblà Ketu. Daà fazer batucar o Movimento (Canto-que-DanÃa) do IjexÃ: Exu-Oxum-Logun com o Brinquedo Afro Ancestral do Bumba-meu-Boi. Quando o Ijexà Movimenta o Bumba-meu-Boi, c@ntando a histÃria da minha descendÃncia, dessa conexÃo nasce meu feto-filho â Teatro do Encantamento da Ancestralidade Africana â parido no meu Ãtero negro. Nosso projeto, orientado pelos conceitos da Ancestralidade Africana e da AfrodescendÃncia quer plantar os Fundamentos Afrodescendentes de uma EducaÃÃo Teatral, tendo por base uma oralidade toda minha. O que desejamos à nos emprenhar com uma experiÃncia outra no sentido de mobilizar e desenvolver o corpo para uma expressividade teatral orgulhosamente afrodescendente. Ao final dos trabalhos instituir uma alternativa de EducaÃÃo em Teatro que nÃo nos oprima nem nos agrida por sermos as pessoas que somos. / La tesis Jugando con el (Canto-que-baila) del Ijexà con el Bumba-meu-boi: teatro del encantamiento de la ancestralidad africana en Fortaleza, la ciudad alocadaâ, tiene como meta profundizar estudios de mi disertaciÃn de maestrÃa. En este trabajo habÃamos creado una discusiÃn con el intento de hacer el pensamiento cantar y bailar como festivamente enseÃa la cultura tradicional africana de origen iorubà con el objetivo de elencar posibilidades para la construcciÃn de una EducaciÃn Teatral asentada en la Ancestralidad africana y Afrodescendencia. Ahora, en el doctorado, la propuesta es enfocar la ritualÃstica de saberes del Candomblà Ketu. De ahà el batuque con el Movimiento (Canto-que-baila) del IjexÃ: Exu-Oxum-Logun con el Juguete Afro Bumba-meu-Boi. Cuando el Ijexà mueve el Bumba-meu-boi, c@antando la historia de mi descendencia, de esta conexiÃn nace mi feto-hijo â Teatro del encantamiento de la Ancestralidad africana â parido en mi Ãtero negro. Nuestro proyecto, orientado por los conceptos de la Ancestralidad africana y de la Afrodescendencia, busca plantar los fundamentos afrodescendientes de la educaciÃn teatral basado en una oralidad completamente mÃa. Lo que deseamos es empreÃarnos con una experiencia otra en el sentido de mover y desarrollar el cuerpo hacia una expresividad teatral orgullosamente afrodescendiente. Al final de los trabajos instituir una alternativa de educaciÃn en el teatro que no nos oprima tampoco nos enoje por ser quienes somos.