Les peptides Cα-thioester jouent un rôle central dans la synthèse de protéines par voie chimique : ils sont des partenaires clés dans la ligation chimique native (NCL), réaction qui a révolutionné ce domaine. L’accès à ces peptides par Fmoc-SPPS, méthode largement utilisée dans les laboratoires, est encore restreint à des experts. Cette limitation représente à l’heure actuelle un frein à la démocratisation de la synthèse de protéines par NCL. Le premier volet de cette thèse décrit la conception et le développement d’une nouvelle méthode bioinspirée de synthèse de précurseurs de peptides thioester, fondée sur un dispositif de thioestérification intramoléculaire de type N-(2-hydroxy-5-nitrobenzyl)-cystéine (N-Hnb-Cys). La synthèse des peptides portant ce dispositif a été totalement automatisée à partir de réactifs peu couteux et ne requière pas d’étapes post-SPPS avant la NCL. La conception biomimétique du dispositif –ce dernier opérant via un réarrangement par transfert d’acyle N→S–, résulte en des cinétiques de NCL rapides à pH neutre. Un large éventail de précurseurs de thioester a été synthétisé, ceci nous a permis d’explorer le potentiel et les limites de la méthodologie, tout en soulignant son efficacité même pour des « séquences difficiles » et de longs peptides. Cette approche a été appliquée à la synthèse par ligation d’une gamme représentative de peptides naturels riches en cystéines, issus du venin d’un serpent, de mollusques, de primates ou encore de plantes. En particulier, nous avons décrit la première synthèse d’une Big-défensine (93 acides aminés), issue de l’huitre et dont l’activité biologique est en cours d’évaluation. Par ailleurs, une voie synthétique originale pour accéder à des peptides comprenant une cystéine C-terminale a été proposée. Elle repose sur l’introduction de cet acide aminé par NCL, évitant les réactions secondaires inhérentes aux approches existantes. Nous avons également appliqué notre approche à la synthèse par NCL intramoléculaire du squelette peptidique cyclique de plusieurs produits naturels, avec des rendements remarquables. L’ensemble de nos résultats est extrêmement encourageant pour la généralisation de notre approche. / Peptide Cα-thioesters play a prominent role in the chemical synthesis of proteins: they are key partners in native chemical ligation (NCL), a reaction that has revolutionized the field. Nonetheless, access to such peptides via the widely used Fmoc-SPPS is still limited to experts. This limitation is currently an obstacle to further popularization of NCL-based protein synthesis. The first part of this thesis describes the design and optimization of a new bio-inspired methodology for the synthesis of peptide thioester precursors, based on an N-(2-hydroxy-5-nitrobenzyl)-cysteine intramolecular thioesterification device (N-Hnb-Cys). Synthesis of peptides bearing this device was fully automated, starting from inexpensive materials. Importantly, no post-SPPS steps are required prior to NCL. The biomimetic design of the device –that operates through an N→S acyl shift–, results in fast NCL kinetics at neutral pH. A broad range of thioester precursors has been synthesized; this allowed us to explore the scope and limitation of the methodology, while stressing its efficiency even for demanding sequences and long peptides. This approach has been applied to the ligation-based synthesis of a representative variety of naturally occurring disulfide-rich peptides (DRP) sequences, from snake venom, molluscs, primates and plants. In particular, we have described the first synthesis of a Big-defensin (93 amino acids), discovered in oyster and whose biological activity is currently under evaluation. Furthermore, an original method for the synthesis of C-terminal cysteine-containing DRP has been proposed. It is based on the introduction of this amino acid through NCL, avoiding side reactions inherent to existing approaches. We have also applied our approach to the intramolecular NCL-based synthesis of the cyclic backbone of several DRP, with remarkable yields. Altogether, our results are extremely encouraging for the generalization of this methodology.

The thesis entitled "Synthesis of Novel Chalcogenides using Acyloxyphosphonium Intermediates and Doubly Activated Cyclopropanes" is divided into six chapters. Chapter 1: Part 1: Synthesis of thioesters from carboxylic acids and alkyl halides using benzyltriethylammonium tetrathiomolybdate In this chapter, we describe the synthesis of thioesters from carboxylic acids and alkyl halides. Aryl carboxylic acids are first activated using PPh3 and NBS to form the corresponding acyloxy phosphonium intermediates which then on further reaction with reagent, 1generate thioaroylate ions in situ. These thioaroylates on further reaction with various electrophiles such as alkyl halides / dihalides in the same pot gives the corresponding functionalized thioesters. This methodology was then extended to carbohydrate based thioesters as they are important synthetic intermediates in various transformations and also they could be deprotected later to synthetically more valuable thiols. For this study, we took 1,2,3,4tetra-O-acetyl-β-D-glucopyranuronic acid which on treatment with PPh3,NBS, reagent, 1 and I-bromo propane (CHCl3, 28°C, 2h) afforded the corresponding thioester in 55% yield. An intramolecular version of the reaction was then performed on a compound containing both anomeric bromide and carboxylic acid functionality. This was achieved by treating tetra acetyl glucuronic acid, with HBr/AcOH to form α-D-bromo-glucopyranuronic acid which on further treatment with PPh3, NBS and reagent, 1 gave the corresponding bicyclic thiolactone in 55% yield. Chapter 1: Part 2: Synthesis of Thioesters by Simultaneous Activation of Carboxylic Acids and Alcohols using PPh3/NBS In this chapter, we have shown the synthesis of thioester from carboxylic acids and alcohols. Both carboxylic acids and alcohols are first activated using PPh3 and NBS to form the corresponding phosphonium salts. Reagent, 1 then reacts selectively with acyloxyphosphonium intermediates to generate thioaroylate ions in situ which then react either with alkoxy phosphonium salts or the corresponding alkyl bromide to give thioesters in good yield. The same methodology was then used for a one pot conversion of N-Boc serine ester to s-protected cysteine using reagent 1 as the key sulfur transfer reagent. Chapter 2: Part 1: Tetrathiomolybdate mediated Michael addition of thioaroylates generated from acyloxyphosphonium salts In this chapter, we have reported an easy and alternative protocol for the Michael addition of thioacids to various Michael acceptors. Acyloxyphosphonium salts and tetrathiomolybdate reacts to generate thioaroylate ions which then undergo Michael additionto givethe corresponding Michael adducts. This methodology was then extended for the synthesis carbohydrate based thiolactone by an intramolecular Michael addition reaction to show the applicability of the methodology. Chapter 2: Part 2: Regioselective and chemoselective ring opening of aziridines and epoxides using thioaroylate ions In this chapter, we have demonstrated nucleophilic ring opening of Aziridines and epoxides using thioaroylate ions generated from acyloxyphosphonium salts and tetrathiomolybdate as a sulfur transfer reagent. We have also demonstrated chemoselective ring opening of azirdines in the presence of an epoxide and tosylate to show the novelty of our method. Chapter 3: Synthesis of bromo esters and bromo thioesters by ring opening of cyclic ethers and thiiranes via acyloxyphosphonium intermediates In this chapter, we report the synthesis of bromo esters and thioesters by the ring opening of epoxides, tetrahydrofuran, and thiiranes with bromide ion to form the corresponding bromo alcohols and thiols followed by the nucleophilic displacement of triphenylphosphine oxide from acyloxyphosphonium salts. At first THF and epoxides were subjected for the ring opening reactions to give the corresponding bromo esters. The methodology was then extended to thiiranes to synthesis bromo thioesters in good to moderate yield. Chapter 4: Synthesis of doubly activated cyclopropranes and their applications to the synthesis of dihydrothiophenes and thiophenes In this chapter we discuss the synthesis and ring opening of doubly activated cyc1opropanes using tetrathiomolybdate and their applications towards the formation of dihydrothiophenes and other bioactive molecules. At first, we synthesized a number of doubly activated cyc1opropanes from dimethyl-α-arylsulfonium bromide,24 a protocol developed by Chow and others. With the doubly activated cyclopropanes in hand, we then attempted the ring opening of cyclopropanes containing a cyano group with tetrathiomolybdate to give the corresponding dihydrothiophene derivatives. Also we have used our methodology for the synthesis of HIV-1 reverse transcriptase inhibitor Chapter 5: Synthesis of unsymmetrical sulfide and disulfide derivatives via ring opening of doubly activated cyclopropanes Here, we describe the synthesis of various monosulfides and mixed disulfides by doubly activated cyclopropane ring opening mediated by tetrathiomolybdate in one pot. Tetrathiomolybdate is known for the reduction of disulfides while diaryl disulfides gives monosulfide, dialkyl disulfides give mixed disulfides with the corresponding doubly activated cyclopropane. Thus diaryl disulfide cleaves readily as the resultant thiolate ion is stable and opens the cyclopropane ring to give a monosulfide. Dibenzyl disulfide on the other hand being less reactive gave a mixed disulfide instead of a monosulfide. We also extended this ring opening reactions for the synthesis of symmetrical disulfides Using tetrathiomolybdate as the key sulfur transfer reagent. Chapter 6: A mild protocol for the nucleophilic ring opening of doubly activated cyclopropanes using selenolates generated in situ Nucleophilic ring opening of doubly activated cyc1opropanes with selenolate ions generated by the reduction of diselenides using NaB14 is discussed in this part of the work. A variety of doubly activated cyc1opropanes have been tested for this reaction giving the corresponding selenium compounds in good yield. This methodology was then extended to other diselenides using nitroester cyclopropane as standard and also to other substituted nitroester cyclopropanes using diphenyl diselenide as standard. This methodology was also then extended to the synthesis of homoselenocysteines by the reduction of nitro group using Sn/HCI for the reduction. (For structural formula pl refer the hard copy)

<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

No description available.

Le contexte de ce projet de thèse était d’approfondir la compréhension du métabolisme de Trypanosoma brucei. Les trypanosomes utilisent différents types de sources de carbone, des hydrates de carbone ainsi que des acides aminés pour alimenter leurs besoins énergétiques et biosynthétiques (conditions imitant réellement l'environnement dans la mouche tse-tse). Les différences de thioesters d'acyl-CoA sont encore inconnues dans ces conditions. Une telle élucidation est essentielle pour comprendre les adaptations métaboliques de l'organisme au cours de son cycle de vie. Cet objectif pourrait être complété par une combinaison d'analyses sensibles de divers groupes de métabolites, de délétions dirigées de gènes ou de régulations négatives. Ces derniers développements intègrent un flux de travail complet d'analyse des flux métaboliques par 13C à l’état-instationnaire. Ce flux de travail combine les méthodes existantes pour la collecte d'échantillons, la métabolomique quantitative basée sur MS et l'analyse isotopique d'acides organiques, d'acides aminés, de composés phosphorylés en plus des thioesters d'acyl Coenzyme A (acyl-CoAs), qui représentent un point central entre le métabolisme central du carbone et les voies anaboliques. Ce flux de travail a d'abord été évalué et validé sur l'organisme modèle Escherichia coli et a fourni de nouvelles idées sur son fonctionnement métabolique. Par la suite, ce flux de travail a ensuite été exploité pour étudier le métabolisme de T. brucei, pour lequel les résultats préliminaires sont décrits et discutés dans cette thèse. / Unusual metabolism of protozoan parasite causing deadly sleeping sickness, Trypanosoma brucei, has been enigmatic for many years. In the past decades, targeted genetic perturbations combined with metabolic analysis have advanced the view on complex compartmentalized metabolism of this organism, but acyl-CoA metabolism on the crossroad between catabolic and anabolic pathways, remains largely uncharacterized. Present work aims at clarifying mitochondrial operation and topology of acyl-CoA network of T. brucei, as well as its interconnections with the rest of metabolism. This has required the development of a complete framework for investigation of acyl-CoA metabolism in T. brucei integrating isotope labeling experiments with metabolite quantification. Sensitive LC-MS method for identification and quantification of acyl-CoAs based on high-resolution mass spectrometry (HRMS) with LTQ-OrbiTrap has been established and applied to investigate acyl-CoA metabolism in the protozoan parasite, as well as in the model organism in systems and synthetic biology, Escherichia coli. Complete workflow from cell cultivation, measurement of extracellular fluxes and analysis of isotopic profile which is result of enzyme-specific incorporation of isotopic tracer allowed modelling of metabolic network and calculation of metabolic fluxes. The entire workflow has been biologically validated and has clarified the link between acyl-CoA and central carbon metabolism in E. coli. The proposed framework has been adapted to T. brucei, for which several sample collection methods have been evaluated thoroughly. It was possible to extract, identify and quantify main acyl-CoA species produced from glucose catabolism. This optimised setup for acyl-CoA analysis will allow collection of data for NMR-based analysis of metabolic end products as well as collection of intracellular metabolites from same sample.

A presente Dissertação relata o estudo conformacional e das interações eletrônicas dos &#945;-(etilsulfonil)-tioacetatos de fenila-para-substituídos X-&#934;-S-C(O)-CH2-SO2-Et, sendo X substituintes atraentes, hidrogênio e doadores de elétrons, isto é, X= NO2 (1), Cl (2), Br (3), H (4), Me (5) e OMe (6) através da espectroscopia no Infravermelho, apoiada por cálculos ab initio e difração de Raio-X. Os dados obtidos indicaram a existência dos confôrmeros gauche1(s-trans) e um gauche2(s-cis), sendo este último bem mais estável do que o primeiro. Assim sendo, pode-se concluir que o componente de menor freqüência de maior intensidade da banda de carbonila corresponde ao confôrmero mais estável s-cis e o de maior freqüência de menor intensidade da banda da carbonila corresponde ao confôrmero s-trans menos estável. Diferentemente do que ocorre na maioria dos compostos carbonílicos &#945;-heterossubstituídos, pode-se constatar que o aumento da polaridade do solvente origina uma população relativa gauche2(s-cis)/gauche1 (s-trans) praticamente constante em todas a série dos tioésteres estudados (1 )-(6). Este comportamento está de acordo com a menor basicidade dos tioésteres em relação às outras classes de compostos carbonílicos. Os dados dos cálculos ab initio indicam que: a) As interações orbitalar e eletrostática O&#947;-(SO2)...........C&#947;+(CO) estabilizam as conformações gauche2(s-cis) e gauche1(s-trans) praticamente na mesma extensão; b) A interação O&#947;-(CO)...........S&#947;+(SO2) estabiliza a conformação gauche2 (s-cis) em maior extensão do que a gauche1 (s-trans); c) A interação por ponte de hidrogênio O&#947;-(CO)...........H&#947;+(SO2Me)...........é mais forte no rotâmero gauche2(s-cis) do que no rotâmero gauche1 (s-trans). Os dados no Infravermelho indicam um aumento progressivo da população relativa gauche2(s-cis)/gauche1(s-trans) para os compostos de (1)-(6) em todos os solventes indo-se na posição para do grupo fenilsulfonila de substituintes atraentes a doadores de elétrons. Adicionalmente, constata-se no Infravermelho a ocorrência em CCl4 de deslocamentos de freqüência (&#916;&#957;) mais negativos para o rotâmero gauche2(s-cis) do que o rotâmero gauche1(s-trans) dos compostos de (1)-(6), em relação aos tioacetatos de fenila correspondentes. Os dados no I.V. apoiam fortemente nos &#945;-(etilsulfonil)-tioacetatos de fenila-para-substituídos (1)-(6) a ocorrência das interações orbitalares e eletrostáticas acima mencionados que estabilizam a conformação gauche2(s-cis) em maior extensão do que a gauche1(s-trans). Contrariamente ao nosso estudo anteriores de &#946;-ceto-sulfonas, este comportamento pode ser atribuído à predominância das interações O&#947;-(CO)...........S&#947;+(SO2) e O&#947;-(CO)...........H&#947;+(SO2Me) sobre O&#947;-(SO2)...........C&#947;+(CO). De fato substituintes doadores de elétrons aumentam a densidade eletrônica sobre o átomo de oxigênio carbonílico, e desta forma facilitam as interações O&#947;-(CO)...........S&#947;+(SO2) e a O&#947;-(CO).........H&#947;+(SO2Me). Contrariamente, os substituintes em para atraente de elétrons diminuem a densidade eletrônica no átomo de oxigênio da carbonila e deste modo fazem com que a referida interação toma-se mais difícil de ocorrer. A análise por difração de Raio-X mono cristal dos &#945;-etilsulfoniltioacetatos de fenila-(4) e de -para-metilfenila-(5) indicou que estes compostos no estado sólido encontram-se na conformação gauche2(s-cis), porém, ligeiramente distorcida em relação à mesma conformação presente no estado gasoso e em solução. A cela unitária do cristal é estabilizada pelo ganho de energia obtido tanto pelo acoplamento dos momentos de dipolos como também pela formação de ligações de hidrogênio intermoleculares H&#947;+(orto)..........O&#947;-(CO) e H&#947;+(CH2CH3)...........O&#947;(CO). / This thesis reports the conformational and electronic interaction studies of some p-substituted S-phenyl &#945;-(ethylsulfonyl)-thioacetates Ph-SC(O)CH2SO2Et, being X electron-attracting, hydrogen and electron-donating para-substituents [X= NO2 (1), Cl (2), Br (3), H (4), Me (5) and OMe (6)], through IR spectroscopy supported by ab initio calculations and X-ray diffraction. The obtained data indicated the occurrence of two stable conformations i.e. the gauche2(s-cis) and the gauche1 (s-trans), being the former the most stable one. Therefore it may be concluded that the lower frequency more intense carbonyl doublet component is the most stable gauche2(s-cis) conformer while the higher frequency less intense doublet component is the least stable gauche1(s-trans) conformer. Differently from the majority of the &#945;-heterosubstituted carbonyl compounds, the increasing polarity of the solvent effect originates an almost constant gauche2(s-cis)/gauche1(s-trans) population ratio for the whole series (1)-(6). This behaviour seems to be in line with the smaller basicity of the thioesters in comparison with the other classes of carbonyl compounds. The ab initio data indicate that: a) the O&#947;-(SO2)..........C&#947;+(CO) orbital and Coulombic interactions stabilise both the gauche2(s-cis) and gauche1 (s-trans) conformations almost to the same extent; b) the O&#947;-(CO)..........S&#947;+(SO2) interaction stabilises gauche2(s-cis) conformer into a greater extent than the gauche1(s-trans) conformer; e) the hydrogen bond interaction H&#947;+(SO2Me)..........O&#947;-(CO)) is slightly stronger for the gauche2(s-cis) conformer than that for the gauche1(s-trans) conformer. The IR data indicate that there is a progressive increase of the gauche2(s-cis)/gauche1(s-trans) population ratio for the whole series (1)-(6), on going at the para position of the phenylsulfonyl group, from electron attracting to electron donating substituents. Moreover there is, in carbon tetrachloride, a larger negative carbonyl frequency shifts (&#916;&#957;) for the gauche2(s-cis)conformer of the title compounds (1)-(6) with respect to the gauche1(s-trans) conformer relative to the corresponding parent S-phenyl thioacetates (7)-(12). Therefore the IR data strongly support for the p-substituted S-phenyl &#945;-(ethylsulfonyl)-thioacetate series the occurrence of the orbital and electrostatic interactions which stabilise the gauche2(s-cis) conformer into a larger extent than the gauche1(s-trans)conformer. Differently from the previously studied &#946;-carbonyl-sulfones, this behaviour can be mainly ascribed to the predominance of the summing up of the O&#947;-(CO)..........S&#947;+(SO2) and H&#947;+(SO2Me)..........O&#947;-(CO) interactions over the O&#947;-(SO2)..........C&#947;+(CO) interaction. In fact, the electron donating para substituents increases the electron density on the carbonyl oxygen atom, and thus facilitates both the O&#947;-(CO)..........S&#947;+(SO2) and H&#947;+(SO2Me)..........O&#947;-(CO) interactions. On the other hand the electron attracting para substituents decreases the electron density on the carbonyl oxygen atom and thus make the referred interactions more difficult to occur. X-ray single crystal diffraction analyses for the S-phenyl-(4) and S-p-methylphenyl-(5), &#945;-(ethylsulfonyl)-thioacetates indicated that these compouns exist in the solid state in a geometry which is reasonably close to the more stable gas and solution gauche2(s-cis) conformation. Furthermore in order to obtain the larger energy gain from the crystal packing, the slightly distorted gauche2(s-cis) geometry of compounds ( 4) and (5) is stabilised in the solid though dipole moment coupling along with the intermolecular H&#947;+(o-&#934;)..........O&#947;-(CO) and H&#947;+(CH2CH3)..........O&#947;-(CO) hydrogen bond interactions.

A presente Dissertação relata o estudo conformacional e das interações eletrônicas dos &#945;-(etilsulfonil)-tioacetatos de fenila-para-substituídos X-&#934;-S-C(O)-CH2-SO2-Et, sendo X substituintes atraentes, hidrogênio e doadores de elétrons, isto é, X= NO2 (1), Cl (2), Br (3), H (4), Me (5) e OMe (6) através da espectroscopia no Infravermelho, apoiada por cálculos ab initio e difração de Raio-X. Os dados obtidos indicaram a existência dos confôrmeros gauche1(s-trans) e um gauche2(s-cis), sendo este último bem mais estável do que o primeiro. Assim sendo, pode-se concluir que o componente de menor freqüência de maior intensidade da banda de carbonila corresponde ao confôrmero mais estável s-cis e o de maior freqüência de menor intensidade da banda da carbonila corresponde ao confôrmero s-trans menos estável. Diferentemente do que ocorre na maioria dos compostos carbonílicos &#945;-heterossubstituídos, pode-se constatar que o aumento da polaridade do solvente origina uma população relativa gauche2(s-cis)/gauche1 (s-trans) praticamente constante em todas a série dos tioésteres estudados (1 )-(6). Este comportamento está de acordo com a menor basicidade dos tioésteres em relação às outras classes de compostos carbonílicos. Os dados dos cálculos ab initio indicam que: a) As interações orbitalar e eletrostática O&#947;-(SO2)...........C&#947;+(CO) estabilizam as conformações gauche2(s-cis) e gauche1(s-trans) praticamente na mesma extensão; b) A interação O&#947;-(CO)...........S&#947;+(SO2) estabiliza a conformação gauche2 (s-cis) em maior extensão do que a gauche1 (s-trans); c) A interação por ponte de hidrogênio O&#947;-(CO)...........H&#947;+(SO2Me)...........é mais forte no rotâmero gauche2(s-cis) do que no rotâmero gauche1 (s-trans). Os dados no Infravermelho indicam um aumento progressivo da população relativa gauche2(s-cis)/gauche1(s-trans) para os compostos de (1)-(6) em todos os solventes indo-se na posição para do grupo fenilsulfonila de substituintes atraentes a doadores de elétrons. Adicionalmente, constata-se no Infravermelho a ocorrência em CCl4 de deslocamentos de freqüência (&#916;&#957;) mais negativos para o rotâmero gauche2(s-cis) do que o rotâmero gauche1(s-trans) dos compostos de (1)-(6), em relação aos tioacetatos de fenila correspondentes. Os dados no I.V. apoiam fortemente nos &#945;-(etilsulfonil)-tioacetatos de fenila-para-substituídos (1)-(6) a ocorrência das interações orbitalares e eletrostáticas acima mencionados que estabilizam a conformação gauche2(s-cis) em maior extensão do que a gauche1(s-trans). Contrariamente ao nosso estudo anteriores de &#946;-ceto-sulfonas, este comportamento pode ser atribuído à predominância das interações O&#947;-(CO)...........S&#947;+(SO2) e O&#947;-(CO)...........H&#947;+(SO2Me) sobre O&#947;-(SO2)...........C&#947;+(CO). De fato substituintes doadores de elétrons aumentam a densidade eletrônica sobre o átomo de oxigênio carbonílico, e desta forma facilitam as interações O&#947;-(CO)...........S&#947;+(SO2) e a O&#947;-(CO).........H&#947;+(SO2Me). Contrariamente, os substituintes em para atraente de elétrons diminuem a densidade eletrônica no átomo de oxigênio da carbonila e deste modo fazem com que a referida interação toma-se mais difícil de ocorrer. A análise por difração de Raio-X mono cristal dos &#945;-etilsulfoniltioacetatos de fenila-(4) e de -para-metilfenila-(5) indicou que estes compostos no estado sólido encontram-se na conformação gauche2(s-cis), porém, ligeiramente distorcida em relação à mesma conformação presente no estado gasoso e em solução. A cela unitária do cristal é estabilizada pelo ganho de energia obtido tanto pelo acoplamento dos momentos de dipolos como também pela formação de ligações de hidrogênio intermoleculares H&#947;+(orto)..........O&#947;-(CO) e H&#947;+(CH2CH3)...........O&#947;(CO). / This thesis reports the conformational and electronic interaction studies of some p-substituted S-phenyl &#945;-(ethylsulfonyl)-thioacetates Ph-SC(O)CH2SO2Et, being X electron-attracting, hydrogen and electron-donating para-substituents [X= NO2 (1), Cl (2), Br (3), H (4), Me (5) and OMe (6)], through IR spectroscopy supported by ab initio calculations and X-ray diffraction. The obtained data indicated the occurrence of two stable conformations i.e. the gauche2(s-cis) and the gauche1 (s-trans), being the former the most stable one. Therefore it may be concluded that the lower frequency more intense carbonyl doublet component is the most stable gauche2(s-cis) conformer while the higher frequency less intense doublet component is the least stable gauche1(s-trans) conformer. Differently from the majority of the &#945;-heterosubstituted carbonyl compounds, the increasing polarity of the solvent effect originates an almost constant gauche2(s-cis)/gauche1(s-trans) population ratio for the whole series (1)-(6). This behaviour seems to be in line with the smaller basicity of the thioesters in comparison with the other classes of carbonyl compounds. The ab initio data indicate that: a) the O&#947;-(SO2)..........C&#947;+(CO) orbital and Coulombic interactions stabilise both the gauche2(s-cis) and gauche1 (s-trans) conformations almost to the same extent; b) the O&#947;-(CO)..........S&#947;+(SO2) interaction stabilises gauche2(s-cis) conformer into a greater extent than the gauche1(s-trans) conformer; e) the hydrogen bond interaction H&#947;+(SO2Me)..........O&#947;-(CO)) is slightly stronger for the gauche2(s-cis) conformer than that for the gauche1(s-trans) conformer. The IR data indicate that there is a progressive increase of the gauche2(s-cis)/gauche1(s-trans) population ratio for the whole series (1)-(6), on going at the para position of the phenylsulfonyl group, from electron attracting to electron donating substituents. Moreover there is, in carbon tetrachloride, a larger negative carbonyl frequency shifts (&#916;&#957;) for the gauche2(s-cis)conformer of the title compounds (1)-(6) with respect to the gauche1(s-trans) conformer relative to the corresponding parent S-phenyl thioacetates (7)-(12). Therefore the IR data strongly support for the p-substituted S-phenyl &#945;-(ethylsulfonyl)-thioacetate series the occurrence of the orbital and electrostatic interactions which stabilise the gauche2(s-cis) conformer into a larger extent than the gauche1(s-trans)conformer. Differently from the previously studied &#946;-carbonyl-sulfones, this behaviour can be mainly ascribed to the predominance of the summing up of the O&#947;-(CO)..........S&#947;+(SO2) and H&#947;+(SO2Me)..........O&#947;-(CO) interactions over the O&#947;-(SO2)..........C&#947;+(CO) interaction. In fact, the electron donating para substituents increases the electron density on the carbonyl oxygen atom, and thus facilitates both the O&#947;-(CO)..........S&#947;+(SO2) and H&#947;+(SO2Me)..........O&#947;-(CO) interactions. On the other hand the electron attracting para substituents decreases the electron density on the carbonyl oxygen atom and thus make the referred interactions more difficult to occur. X-ray single crystal diffraction analyses for the S-phenyl-(4) and S-p-methylphenyl-(5), &#945;-(ethylsulfonyl)-thioacetates indicated that these compouns exist in the solid state in a geometry which is reasonably close to the more stable gas and solution gauche2(s-cis) conformation. Furthermore in order to obtain the larger energy gain from the crystal packing, the slightly distorted gauche2(s-cis) geometry of compounds ( 4) and (5) is stabilised in the solid though dipole moment coupling along with the intermolecular H&#947;+(o-&#934;)..........O&#947;-(CO) and H&#947;+(CH2CH3)..........O&#947;-(CO) hydrogen bond interactions.

Thio metallates are known for many years for their utility in many processes. They have been established as versatile reagents in organic synthesis. However the heavier metal chalcogenides, though known for many years, have been ignored for a long time. In this thesis the results of the development of tetraethylammonium tetraselenotungstate [EttN]2Wse4 1 as a new class of selenium transfer reagent have been described. The thesis also deals with the chemistry of benzyltriethylammonium tetrathiomolybdate, [BnEt3N]2MoS4,2 in the synthesis of diselenides and thio esters. The thesis entitled "Chemistry of Thio and Seleno Metallates in Organic Synthesis" is divided into four Chapters. Chapter 1 In this chapter a detailed studies of alkylation of tetraethylammonium tetraselenotungstate (EuN)2WSe4,1 with a variety of alkyl halides, benzylic halides and acyl halides to yield the corresponding diselenides in excellent yields are described. (structural Formula) Scheme 1 Various carbohydrate-derived diselenides were also prepared by treating the sugar bromides with tetraethylammonium tetraselenotungstate 1 (Scheme 2). An attempt was made to synthesize seleno lactones from co- bromo acyl halides. This reaction mainly furnished the corresponding diacyl diselenides (Scheme 3). The reaction of 1 with aryldiazonium tetrafluoroborates led to the formation of corresponding diselenides or mono selenides depending on the substitution on the aromatic ring (Scheme 4). (structural formula) Scheme 2 (structural formula) Scheme 3 (structural formula) Scheme 4 Chapter 2 In this chapter a general methodology for the formation of the diselenide bond has been extended to the synthesis of a number of redox- switched crown ethers of various ring size using the reagents tetraethylammonium tetraselenotungstate (Et4N)2WSe4 t 1 and benzyltriethylammonium tetrathiomolybdate, [BnEt3NJ2MoS4,2 (Scheme 5). (structural formula) Scheme 5 The association constants for the binding of silver and potassium ions with the diselena crown ethers were determined. This methodology is very useful for obtaining selenacrown ethers under very mild conditions and also without using high dilution conditions. Chapter 3 In this chapter a general methodology for the facile conversion of amides and lactams to the corresponding seleno amides and selenolactams is described. A number of amides and lactams were converted into their selenocarbonyl derivatives in excellent yield via the formation of Vilsmeier intermediates followed by treatment with tetraethylammonium tetraselenotungstate (EuN^WSe4,1 (Scheme .6). (structural formula( Scheme 6 Chapter 4 In this chapter, a general method for the synthesis of thioesters is described. The reaction of p- nitrophenyl esters and disulfides with benzyltriethylammonium tetrathiomolybdate (PhCH2NEt3)2MoS4,2 furnished the corresponding thio esters in good yield (Scheme (7). The intramolecular version of this reaction furnished dimeric thiolactones as the major product (Scheme 8) (structural formula) Scheme 7 (structural formula) Scheme 8 (for structural formula pl see the original document)

Les fonctions catalytiques de l'intégrase (IN) du Virus de l'Immunodéficience humaine (VIH-1) sont strictement nécessaires pour l'intégration du génome viral dans les cellules hôtes. Aujourd'hui, trois inhibiteurs anti-IN appartenant à la famille des dikétoacides sont utilisés en thérapie : le raltegravir, l'elvitegravir et le dolutegravir. Cependant, les patients traités par ces médicaments développent des mutations de résistance. Dans ce travail, nous cherchons à mieux comprendre le mécanisme d'interaction de ces drogues avec l'ADN viral. Ce travail a également contribué à la conception de molécules qui devraient être dotées d'une affinité augmentée pour l'ADN, permettant de surmonter le problème de la résistance virale. La compréhension du mécanisme d'inhibition de IN s'est poursuivie par l'étude de deux anticorps monoclonaux anti-K159 (peptide 147-175 du coeur catalytique de IN), 4C6 et 4F4. Les résultats montrent que les anticorps reconnaissent leurs épitopes dans l'IN. D'autre part, du fait de son implication dans de nombreuses étapes du cycle du VIH-1, nous ciblons la protéine 7 de la nucléocapside (NCp7). Pour ce faire, nous avons étudié la structure de nos systèmes (NCp7 et NCp7-ADN) et nous avons pu déterminer les interactions clés responsables de la structuration, ainsi que des fonctions, de ces systèmes. Dans un second temps, nous avons évalué les interactions de NCp7 avec un inhibiteur éjecteur de zinc (C247) de la famille des thioesters. Enfin, sur le plan méthodologique, nous avons raffiné dans le potentiel SIBFA (Sum of Interaction Between Fragments Ab initio computed) la représentation des doublets libres de type sp et sp2 dans les molécules conjuguées. / The catalytic functions of integrase (IN) of Human Immunodeficiency Virus (HIV-1) are strictly necessary for the integration of the viral genome into the host cells. To this day, three anti-IN inhibitors belonging to the diketoacids are used in therapy: raltegravir, elvitegravir and dolutegravir. However, under treatments with these drugs, patients develop resistance mutations. In this work, we seek to better understand the interaction of the three drugs with viral DNA. This work also contributed to the design of novel molecules. These should be endowed with increased DNA binding affinities as a step towards overcoming viral resistance. The understanding of the inhibition mechanism of IN was pursued by the study of two monoclonal antibodies, 4F4 and 4C6, which are directed against sequence 147-175 of the catalytic core of HIV-1 IN, a peptide denoted K159. The results show that the antibodies recognize their epitopes in IN. We also aim to target an HIV-1 nucleocaspid protein NCp7 involved in many stages of the viral cycle. We have thus studied the structure of NCp7 and its viral DNA complex. We were able to determine the interactions responsible for the structuring and thus the functions of these complexes. Then, we evaluated the interactions of NCp7 with an inhibitor of the thioester family, C247, which acts as a zinc ejector. Finally, from the methodological standpoint, we have refined in SIBFA (Sum of Interaction Between Fragments Ab initio computed) the representation of the sp2 and sp lone pairs in conjugated molecules.

Este trabalho apresenta: 1) Duas revisões bibliográficas sendo uma sobre a síntese de &#945;-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 &#945;-ceto-tioéster; 3) O estudo de síntese de precursores de &#945;-ceto-tioésteres II e &#945;-ceto-ésteres III, a saber: &#945; - metilsulfonil- &#945; - metiltio tioésteres IVa-c, -éster V e &#945;, &#945; - dimetiltio - ésteres VIa-c; 4) Decomposição térmica de &#945;-metilsulfonil-&#945;-metiltio-tioésteres Iva, b e c e -éster V sintetizados aos &#945;-ceto-tioésteres e ésteres correspondentes, pelo emprego do método elaborado anteriormente por Wladislaw e col. e sugestão do mecanismo da mesma. A síntese de &#945; metilsulfonil &#945; metiltio tiopropionato de etila (Ivb), foi efetuada a partir do ácido &#945;-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 &#945; - benzil - &#945; - metilsulfonil - &#945; - metiltio - tioacetato de etila (Ivc) foi efetuada a partir de ácido &#945;-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 &#945;-metilsulfonil-&#945;-metiltio-propionato de etila (V) foi efetuada a partir do &#945;-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 &#945; - metilsulfonil fenilmalonato de dietila (VIIb), com DABCO em benzeno sob refluxo e MeSO2SMe, que conduziu à dessulfonilação sulfenilativa fornecendo o &#945; - metiltio - fenilmalonato de dietila. É apresentada uma discussão mecanística tanto sobre descarbetoxilação, como sobre dessulfonilação sulfenilativas. A síntese de &#945;,&#945;-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 &#945;-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 &#945;-keto thioester; 3) The study of synthesis of &#945;-keto thioesters II and esters III precursors, which are the following: &#945;-methylsulfonyl-&#945;-methylthio-thioesters IVa-c and -ester V, and &#945;, &#945; - dimethylthio esters VIa-c; 4) Thermal decomposition of the synthesized &#945; - methylsulfonyl- &#945; -methylthio- thioesters Iva,b e c and ester V, to the corresponding &#945;-keto thioesters and &#945;-keto ester, through the method developed by Wladislaw et al., with the suggestion of the mechanism. &#945;-Methylsulfonyl-&#945;-methylthio ethyl thiopropionate (Ivb) was synthesized from &#945;-chloro-propionic acid in four steps: sulfenylative substitution, oxidation to sulfone, thioesterification and sulfenylation using NaH/MeSO2SMe in DMSO. &#945;-Benzyl-&#945;-methylsulfonyl-&#945;-methylthio ethyl thioacetate (,i>Ivc) was obtained from &#945;-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. &#945;-Methylsulfonyl-&#945;-methylthio ethyl propionate (V) was synthesized through the sulfenylative decarbethoxylation of &#945; 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 &#945;-methylsulfonyl phenyldiethyl malonate (VIIb) was treated with DABCO, in refluxing benzene and MeSO2SMe, which led to the &#945;-methylthio diethyl malonate. A mechanistic discussion about the sulfenylative decarbethoxylation and sulfenylative desulfonylation is presented. &#945;, &#945;-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.