Aromatic rings are privileged structures found in a diverse range of natural and synthetic compounds, thus synthetic methods for their functionalisations are important in organic synthesis. Despite significant advancements made, especially in the field of transition metal catalysis, work still continues for the development of milder, more efficient, and more atom economical reactions. We describe here our efforts towards the development of decarboxylative/direct C(aryl)–N and C(aryl)–C bond forming reactions using aromatic carboxylic acids and unfunctionalised arenes as cheap and widely available aromatic sources. The investigations into copper-catalysed and copper/palladium-catalysed intermolecular and copper/silver/palladium-catalysed intramolecular decarboxylative amination of aromatic carboxylic acids are reported. A new approach to decarboxylation of benzoic acids is also described. The reaction uses silver (I) catalyst and peroxydisulfate salt to generate aryl radicals via oxidative decarboxylation. The applications of this approach in intra- and intermolecular decarboxylative C–H arylation, and protodecarboxylation are described. Also described is the development of silver-catalysed trifluoromethylation of simple arenes and heteroarenes. The reaction proceeds via radical trifluoromethylation using trimethyl(trifluoromethyl)silane as the trifluoromethyl radical source. This method has been applied to the trifluoromethylation of complex agrochemical molecules, proving its synthetic utility in late-stage functionalisation. Furthermore, we describe the exploitation of trifluoroacetate derivatives as cheap trifluoromethylating reagents in copper-mediated decarboxylative C–H trifluoromethylation of 2-phenylpyridine.

The thesis entitled “Copper-Catalyzed Novel Oxidative Transformations: Construction of Carbon-Hetero Bonds” is divided into two main sections. Section A deals with the utility of azide as a nitrogen source for C-N bond formation, which is further divided into 4 chapters, and section B presents decarboxylative radical coupling reaction for C-heteroatom bond formation which is further divided in to two chapters. Section A Chapter 1 describes an approach for the direct synthesis of nitrile from the corresponding alcohols using azide as a nitrogen source. Nitrile functionality is a versatile and ubiquitous which occurs in a variety of natural products. Nitrile functionality can be easily transformed into a variety of functional groups and products such as aldehydes, ketones, acids, amines, amides and nitrogen-containing heterocycles, such as tetrazoles and oxazoles. In this chapter a successful attempt for developing a novel methodology to oxidize benzylic and cinnamyl alcohols to their corresponding nitriles in excellent yields has been described. This strategy uses DDQ as an oxidant and TMSN3 as a source of nitrogen in the presence of a catalytic amount of Cu(ClO4)2·6H2O. A few representative examples are highlighted in Scheme 1.1 Scheme 1. Oxidative conversion of alcohols to nitriles Second chapter represents a protocol for the synthesis of 1,5-disubstituted tetrazoles from the corresponding secondary alcohols. Among heterocyles, tetrazole and its derivatives are important class of nitrogen containing molecules. Due to their well-known biological activities as well as vast applications in pharmaceuticals and material science, they are potential targets for synthetic organic chemists. Therefore, a simple and user-friendly method for the synthesis of tetrazole is desirable. In this chapter, a mild and convenient method to synthesize 1,5-disubstituted tetrazoles using easily accessible secondary alcohols by employing TMSN3 as a nitrogen source is developed. This reaction is performed in the presence of a catalytic amount of Cu(ClO4)2·6H2O using DDQ as an oxidant under ambient conditions (Scheme 2).2 Scheme 2. Oxidative conversion of secondary alcohols to tetrazoles Third chapter presents a method for synthesizing amides from their corresponding secondary alcohols. Amide functionality is a crucial backbone in peptide chemistry, it also serve as an important precursor or intermediate for variety of organic transformations. In this contention, a mild and convenient method to synthesize amides using easily accessible secondary alcohols by employing TMSN3 as a nitrogen source is developed. This reaction is performed in the presence of a catalytic amount of Cu(ClO4)2·6H2O using DDQ as an oxidant under ambient conditions (Scheme 3).3 Scheme 3. Oxidative conversion of secondary alcohols to amides Additionally, the application of this methodology has also been revealed for the synthesis azides directly from their alcohols. Some of the representative examples are shown in the Scheme 4.3 Scheme 4. Direct conversion of alcohols to their azides. Fourth chapter describes highly chemoselective Schmidt reaction. The classical Schmidt reaction involves the formation of new carbon-nitrogen bonds in a reaction of a carbon-centred electrophile with hydrazoic acid followed by loss of nitrogen, which usually occurs via a rearrangement. It is well known that under the Schmidt reaction conditions, ketones and carboxylic acids are converted into their corresponding amides and amines respectively, whereas aldehydes furnish a mixture of formanilides and nitriles. In this chapter, Schmidt reaction of aldehydes to obtain their nitriles without formation of the corresponding formanilide is presented (Scheme 5).4 It was also observed that aromatic ketones and acids functionalities were intact under the reaction condition, unlike the conventional Schmidt reaction. Scheme 5. Highly chemoselective Schmidt reaction Section B It is divided into two chapters, describes a copper catalyzed decarboxylative radical coupling for the synthesis of vinyl sulfones and nitroolefins (Scheme 6). Scheme 6. General strategy for the second part First chapter narrates a strategy for synthesizing nitroolefins from the α,β-unsaturated carboxylic acids. Nitroolefins represent a unique class of nitro compounds, which have multifaceted utility in organic synthesis. They possess antibacterial, rodent-repelling, and antitumor activities. They serve as important intermediates in organic synthesis. Nitroolefins also react with a variety of nucleophiles, and their electron-deficient character renders them as a powerful dienophiles in Diels-Alder reactions. In our attempt to use the decarboxylative strategy, this chapter describes a method for the nitrodecarboxylation of substituted cinnamic acid derivatives to their corresponding nitroolefins. This nitrodecarboxylation reaction is performed using catalytic amount of CuCl in the presence of air using TBN as a nitrating source (Scheme 7).5 Besides, the reaction provides a useful method for the synthesis of β,β-disubstituted nitroolefin derivatives which are generally difficult to access from other conventional methods. Scheme 7. Decarboxylative nitration Second chapter presents a new protocol for the synthesis of vinyl sulfones from the α,β-unsaturated carboxylic acid. Vinyl sulfones are versatile building blocks, which find their utility as Michael acceptors and used in cycloaddition reactions. This functional group has also been shown to potently inhibit a variety of enzymatic processes, and thus provides unique properties for drug design and medicinal chemistry. Vinyl sulfones are prominent in medicinal chemistry owing to their wide presence in pharmaceutically active molecules, such as enzyme inhibitors and biological activity. In this chapter, we report a method for the construction of C-S bonds via ligand promoted decarboxylative radical sulfonylation of ,-unsaturated carboxylic acids to synthesize vinyl sulfones using Cu catalysis (Scheme 8).6 This is the first report for this particular conversion. Scheme 8. Decarboxylative sulfonation

La fonctionnalisation des hétéroaromatiques suscite grand intérêt tant en chimie supramoléculaire qu’en chimie pharmaceutique. Parmi les techniques les plus employées, la chimie organométallique catalysée par les métaux de transition est une méthode de choix et apporte depuis plus d’un siècle une contribution majeure notamment depuis l’avènement des couplages croisés. Les défis méthodologiques contemporains reposent en grande partie sur le concept du ‘mieux avec moins’ et visent notamment au développement de couplages croisés directs catalytiques impliquant des liaisons C-CO₂H et C−H avec le souci (i) d’éviter la préparation et/ou l’isolement d’intermédiaires organométalliques hautement réactifs souvent préparés dans des conditions drastiques et/ou sensibles à l’humidité et parfois instables, (ii) de réduire la production massive de sels; (iii) d’éviter les étapes de protection/déprotection des fonctions sensibles aux attaques nucléophiles. Ce travail de thèse s’inscrit dans ce contexte et a pour objectif le développement de nouveaux couplages croisés directs décarboxylants de type CCO₂H/C-X et C-CO₂H/C-H impliquant deux partenaires de couplages inédits, les acides carboxyaziniques N-oxydés et les acides cinnamiques α-méthoxylés, traités dans deux parties distinctes. Un premier travail a conduit au développement d’une méthodologie générale de couplage décarboxylant,catalysée au palladium (0) et assistée par l’argent (I), d’acides quinaldiques et picoliniques N-oxydés ainsi que de l’acide isoquinoline 3-carboxylique avec des halogéno(hétéro)arènes. En effet, bien que le cuivre (I) se soit révélé plus performant par calculs DFT pour conduire l’ipso-décarboxylation-métallation, seul l’argent favorise la catalyse conventionnelle coopérative Pd(0)/Ag(I) assurant la sélectivité en lieu et place de la fonction acide carboxylique. Ayant montré un large spectre de réactivité, la méthodologie tolère en particulier la présence de substituants sur le noyau azinique. Elle représente également une alternative synthétique à l’arylation directe de la liaison C−H des azines N-oxydées pour accéder aux azines 2-hétéroarylées ainsi qu’aux pyridines 2,5-disubstituées et aux isoquinoléïnes 3-arylées. Comme application, une approche modulable et flexible a été développée pour la synthèse d’une isoquinoline fonctionnalisée en position 1 et 3 connue comme agent antitumoral. Le second travail a porté sur la mise au point des premiers couplages croisés décarboxylants oxydants de type CCO₂H/C−H pallado-catalysés et assistés par le cuivre (II) d’acides cinnamiques α-méthoxylés sur une large gamme d’hétérocycles pour conduire à la formation stérécontrollée d’éthers d’enol héteroarylés en position géminale. L’introduction directe et inédite de la fonction éther vient enrichir le panel des méthodologies de fonctionnalisation des liaisons C−H des hétérocycles. Leur haut potentiel d’aménagement fonctionnel permet de diversifier consécutivement et très largement la nature de la fonctionnalisation pour accéder en particulier aux hétéroarylalkyl cétones et aux alcènes poly-fonctionnalisés. / The functionalization of heterocycles arouse an interest both in supramolecular chemistry and in pharmaceuticals. Based on the so-called concept better with less, the development of direct functionalization methodologies of heterocycles involving C–H and C–CO₂H bonds has emerged as an efficient, modern alternative and complementary process to traditional cross coupling methods, avoiding thus the use of stoichiometric organometallic reagents that are often air and moisture sensitive. In this context, the aim of this PhD work was to develop new decarboxylative cross couplings, CO₂H / C-X and CO₂H / C−H, using substituted 2-carboxyazine N-oxides and α-methoxyacrylic acids as new coupling partners.The first part of this work has been focused on the development of the versatile Pd-catalyzed and Ag-assisted decarboxylative coupling of quinaldic and picolonic acids N-oxides as well as 3-carboxyisoquinoline acids with (hetero)aryl halides. Although copper (I) appeared to be more efficient by DFT calculations to perform ipsodecarboxylation-metallation step, only silver catalysis revealed to be much more adequate to achieve the conventional decarboxylative coupling and this was then pointed out with the high regioselectivity observed at the carboxy function site. This reaction showed a large reactivity spectrum and tolerated for the first time substituents on azinic core. It is also a synthetic alternative to the direct C−H arylation on azine N-oxides for the regioselective synthesis of 2-arylated substituted pyridines and 3-arylated isoquinolines. As application, a modular and flexible approach has been developed for the synthesis of the highly functionalized 1,3-substitute disoquinoline 5, shown as an antitumor agent.In the second part, the first Pd-catalyzed and Cu-assisted decarboxylative / C-H alkenylation of heterocycleswith various α−methoxyacrylic acids was reported offering general stereocontrolled access to heteroarylated enol ethers in geminal position. The direct introduction of vinyl ether allows to expand the panel of C-H bond functionalizations methodologies of heterocycles. The high potential for subsequent post-functional adjustment of the vinyl ether moiety enable thus the synthesis of heteroarylated α,β-enolizable ketones and polysusbituted alkenes.

Les travaux présentés dans ce manuscrit de thèse concernent la mise au point de nouvelles méthodologies de synthèse asymétrique en organocatalyse promues par des phénolates d’ammoniums quaternaires, catalyseurs de type paires d’ions coopératifs chirales, et des dérivés de l’acide de Meldrum comme substrats. Dans un premier temps, nous avons utilisé l’acide de Meldrum comme un précurseur de cétène via une cycloréversion induite par O-silylation grâce à une probase silylée, afin de réaliser une réaction de cycloaddition [2+2] avec un aldéhyde ou une imine catalysée par un phénolate d’ammonium chiral, permettant de former des β-lactones et des β-lactames. Les travaux effectués n’ont cependant pas permis d’obtenir le produit désiré. Dans un secont temps, nous avons exploité le caractère électrophile des dérivés disubstitués de l’acide de Meldrum et leur capacité à fragmenter suite à l’addition nucléophile d’un phénolate. Une première partie a été consacrée au développement d’une réaction monotope de désymétrisation de l’acide de Meldrum pour former des malonates dissymétriques après une étape d’alkylation in situ du carboxylate intermédiaire. Bien que de bons rendements isolés aient été obtenus, un maximum de 21% ee a pu seulement être atteint. Dans une seconde partie, nous avons mis au point une séquence originale, catalysée par un phénolate d’ammonium quaternaire chiral, qui est constituée (1) d’une addition nucléophile de phénolate suivie (2) d’une fragmentation avec perte d’acétone qui permet, après (3) une étape de décarboxylation de générer un acétal de cétène acyclique qui va subir (4) une réaction de protonation énantiosélective. Cette méthode a pu être appliquée à un large panel de substrats avec de bons rendements et des excès énantiomériques allant jusqu’à 70% ee. / The work developed in this PhD thesis deals with the development of new asymmetric organocatalytic methodologies implying cooperative chiral ion pairing catalysis, by using chiral ammonium phenoxides as catalysts and Meldrum’s acid derivatives as substrates. First, we used the ability of Meldrum’s acid to generate acylketenes after cycloversion triggered by O-silylation thanks to a silylated probase in the presence of a chiral ammonium phenoxide. Such an approach was applied to the synthesis of β-lactones and β-lactames following a [2+2] cycloaddition reaction with aldehydes or imines respectively. Unfortunately, the desired products have never been observed. Then, we focused on disubstitued derivatives of Meldrum’s acids and their propensity to fragment after a nucleophilic addition of phenoxide. In a first part, we have developed a one-pot desymmetrization reaction of Meldrum’s acid derivatives to form dissymmetric malonates after an in-situ alkylation of the transient carboxylate. However, despite high isolated yields, only an unsatisfactory 21% ee could be reached. In a second part, we have developed an unprecedented sequence consisting of (1) a nucleophilic addition of phenol derivatives to Meldrum’s acid followed by (2) a fragmentation with loss of acetone, leading after (3) decaboxylation to the formation of an acyclic ketene acetal which is involved in (4) an enantioselective protonation reaction to provide a wide range of enantioenriched phenolic esters with moderate to excellent yield and up to 70% ee.

No description available.

Les molécules aromatiques se retrouvent dans de nombreux produits de la chimie fine ou de spécialité. Aujourd'hui toutes sont obtenues par voie pétrochimique ; il est donc nécessaire de trouver des ressources alternatives renouvelables. Dans le cadre de cette thèse, nous nous sommes intéressés à des méthodologies applicables en chimie fine et mettant en oeuvre la transformation de molécules aromatiques issues de la biomasse soit pour obtenir des synthons équivalents à ceux de la filière pétrochimique, soit pour synthétiser des composés de chimie fine sans recourir à des fonctionnalisation intermédiaires. Ainsi, une nouvelle voie d'obtention de styrènes fonctionnels à partir d'acides cinnamiques par décarboxylation cuprocatalysée dans le PEG a été mise au point. Cette stratégie a été étendue à la préparation de composés aromatiques et hétéroaromatiques à partir des acides correspondants, et aux amines à partir d'aminoacides biosourcés. Un second axe a concerné le développement d'un système catalytique [Pd/Cu] homogène, et en partie hétérogène, pour la synthèse de biaryles par couplage décarboxylant de deux acides benzoïques. Appliqué aux acides 2-Nitrobenzoïque et 2,6- diméthoxybenzoïque, le système permet l'obtention du biaryle visé avec un rendement de 70%. Des études supplémentaires sont nécessaires pour lever les verrous technologiques limitant l'utilisation en termes de substrats. Le dernier axe traite de la synthèse de stilbènes par couplage d'un acide cinnamique et d'un halogénure d'aryle. L'étude a permis la mise au point d'une palladocatalyse très efficace qui permet d'obtenir la molécule cible avec un rendement allant jusqu'à 78%. La méthodologie a été transposée en catalyse hétérogène par l'utilisation de PdO/SiO2 et Pd/C ; le PdO/SiO2 s'est avéré stable sur au moins 4 cycles. Comme pour la synthèse de biaryles, le système nécessite d'autres développements pour étendre son champ d'action aux dérivés d'acides cinnamiques peu réactifs / Aromatic molecules are present in a large field of products in fine chemistry. Nowadays, all are obtained by petrochemical way ; Thus, it’s necessary to find alternative renewable resources. As part of this thesis, we are interested in the fine chemical methodologies and implementing the transformation of aromatic molecules from biomass either to obtain building blocks equivalent to those from the petrochemical industry, or to synthesize fine chemicals compounds without the necessity of intermediate functionalization. Thus, a new way to obtain functionalized styrenes from cinnamic acids by decarboxylation copper catalyzed into PEG was developed. This strategy has been extended to the preparation of aromatic and heteroaromatic compounds from the corresponding acids and amines from biosourced amino acids. A second axis concerned the development of a homogeneous catalytic system [Pd/Cu], and partly heterogeneous, for the synthesis of biaryls by decarboxylating coupling of two benzoic acids. Applied to 2-Nitrobenzoic acid and 2,6 dimethoxy acid, the system allows the production of biaryl covered with a yield of 70%. Further studies turn out to be necessary to remove technological barriers in terms of limited substrates. The last axis deals with the synthesis of carbons by coupling a cinnamic acid and an aryl halide. The study development allowed a very efficient palladocatalyse that achieves the target molecule with a yield up to 78%. The methodology has been implemented in heterogeneous catalysis using PdO/SiO2 and Pd/C; PdO / SiO2 was stable for at least 4 turnover. As for the synthesis of biaryls, the system requires further development to expand its scope to derivatives cinnamic acids less reactive

Les gymnodimines, les spirolides, les pinatoxines et les ptériatoxines constituent une famille de toxines d’origine marine de structures complexes, produites en faibles quantités par des microorganismes marins appelés dinoflagellés. Ces toxines sont connues pour bloquer les récepteurs nicotiniques de l’acétylcholine (nAChR) sans que leurs modes d’action ne soient connus avec précision. D’après les différents tests biologiques réalisés à ce jour, il semblerait que le motif spiroimine, commun à toutes ces molécules, soit le pharmacophore principal, indispensable pour toute activité inhibitrice. Le travail réalisé au cours de cette thèse s’est focalisé sur la synthèse du fragment spiroimine de la (–)-gymnodimine A, dans l’optique d’une étude pharmacologique de ces structures. Dans un premier temps, la création du centre quaternaire a été développée en utilisant la réaction Tsuji-Trost qui nous a donné de bons résultats en termes de rendement et d’excès énantiomérique. Au cours d’une approche sur des substrats modèles, une stratégie de fonctionnalisation originale de la chaîne allylique, mettant en jeu une métathèse croisée puis une oxydation, nous a permis d’atteindre l’intermédiaire spirolactone désiré. Après quelques étapes d’aménagements fonctionnels, une réaction de Staudinger nous a permis d’isoler les spiroimines attendues. Puis, dans la perspective d’une future synthèse totale, la réaction de Tsuji-Trost a été appliquée à des substrats plus fonctionnalisés. Dans un second temps, une allylation décarboxylante asymétrique à partir de Beta-cétoesters, nous a aussi permis de former le centre stéréogénique avec de bons rendements et excès énantiomériques. Une séquence rapide et efficace a été mise au point pour la synthèse de motifs spiroimines. Après une étape d’isomérisation, les composés ont été engagés dans une réaction de cycloaddition 1,3-dipolaire entre un alcène et une fonction azoture pour former les spiroimines souhaitées. La généralisation de la méthode a alors pu être débuté. Les trois spiroimines isolées au cours de ces travaux ont été évalués biologiquement sur les nAChRs, montrant un effet antagoniste, voire bloquant, selon les structures, de ces récepteurs. Leurs structures est beaucoup plus simple que celle de la GYM A et l’activité biologique est plus faible que la molécule naturelle. Toutefois, ces résultats montrent bien que le motif spiroimine est l’un des pharmacophore de la GYM A. / Gymnodimines, spirolides, pinatoxines and pteriatoxines constitute a family of marine toxins with complex structures. They are produced in small quantities by marine microorganisms called dinoflagelles. These toxins are known to block the nicotinic acetylcholine receptors (nAChR), but the exact mode of action remains to be determined. Different biological tests showed that the spiroimine moiety, common feature to all these molecules, is the main pharmacophore, indispensable for the inhibitive activity. This Ph.D. work has been focused on the synthesis of the spiroimine fragment of the (–)-gymnodimine A, for pharmacological studies of these structures. In a first part, the formation of the quaternary carbon was developped around the Tsuji-Trost reaction. Good yield and enantiomeric excess were obtained. During our work with modele substrate, an original approach was used to functionnalize the allyl chain. We realized a cross metathesis followed by an oxidative cleavage to form an aldehyde used to synthezise the wished spirolactone. After some functional arrangements, a Staudinger cyclisation has been involved to isolate the expected spiroimines. Then, Tsuji-Trost reaction was applied to more functionnalized substrates for a future total synthesis. In a second time, an asymmetric decarboxylative allylation from Beta-cétoesters, was used to form the stereogenic center with good yield and enantiomeric excess. A short synthetic route was developped for the synthesis of the spiroimine moiety. After an isomerisation of the allylic chain, compounds were involved in a 1,3-cycloaddition between an alcene and an azide to form the wished spiroimines. The generalization of the method was just begun. Three spiroimines were isolated and biologically evaluated on nAChRs. Their structure were simpler than GYM A but they show an antagonist effect and even a blocking effect according to the molecule. Their biological activities were lower than the natural product but these results show that spiroimine moiety is one of the pharmacophore of the GYM A.

Les gymnodimines, les spirolides, les pinnatoxines et les ptériatoxines constituent une famille de toxines d’origine marine de structures complexes, produites en faibles quantités par des microorganismes marins appelés dinoflagellés. Ces toxines sont connues pour bloquer les récepteurs nicotiniques de l’acétylcholine (nAChRs) sans que leurs modes d’action ne soient connus avec précision. D’après les différents tests biologiques réalisés à ce jour, il semblerait que le motif spiroimine, commun à toutes ces molécules, soit le pharmacophore principal, indispensable pour toute activité antagoniste. Le 13 dem SPX est un composé qui appartient à la famille des toxines à imines cycliques. Sa structure complexe présente un cœur à imine cyclique original, un macrocycle possédant un motif bis-spiroacétal et un buténolide. Actuellement aucune synthèse totale de ce composé n’a été publiée. L’ensemble du travail présenté dans ce manuscrit a été consacré à des études pour synthétiser, d’une part, le cœur imine spirocyclique et d’autre part, à la préparation d’un intermédiaire avancé pour parvenir à la synthèse totale de ce composé.Dans un premier temps une étude méthodologique pour synthétiser des spiroimines simplifiées optiquement actives a été réalisée. Une approche originale et convergente à été développée reposant sur des réactions d’ADc asymétrique, d’isomérisation et de cycloaddition-[3+2] 1,3-dipolaire, à partir de substrats facilement accessibles.Dans un second temps nous avons exploré deux voies synthétiques pour parvenir à un intermédiaire avancé pour la synthèse du 13 SPX C. Pour ce faire, deux approches ont été envisagées. Seule la stratégie reposant sur des étapes d’addition-1,2 d’un nucléophile, suivie d’une cyclisation pour obtenir les composés spirocycliques puis hydrogénation par l’iridium(I) cationique a été abordée au cours de ces travaux. / Gymnodimines, spirolides, pinnatoxines and pteriatoxines constitute a family of marine toxins with complex structures. They are produced in small quantities by marine microorganisms called dinoflagellates. These toxins are known to block the nicotinic acetylcholine receptors (nAChR), but the exact mode of action remains to be determined. Biological tests have showed that the spiroimine moiety, the common feature of these molecules, is the main pharmacophore, essential for the antagonist activity. 13-dem SPX C belongs to the cyclic imine toxin family. Its complex structure shows an original cyclic imine core, a macrocycle that bears bis spiroketal moiety and a butenolide. Currently, no total synthesis of this toxin has been achieved. This Ph.D. work has been focused on methodological studies to synthesize cyclic imine core of 13-dem SPX C and on the synthesis of a very functionalized compound to reach 13-dem SPX C.In the first part, a methodological work to synthesize simple optically active spiroimines was achieved. This original 3 steps sequence was based on asymmetric ADc reactions, isomerization and 1,3-dipolar [3+2]-cycloaddition from easily accessible cycloketones.In the second time we imagined two synthetic ways to reach a highly functionalized moiety of 13-dem SPX C. Only the way that relies on 1,2-addition of nucleophile followed by a cyclization to get spirocyclic patterns and an iridium(I) catalyzed hydrogenation of endo alkene was tested.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2017-10-20T14:28:20Z No. of bitstreams: 1 eloahpereiraavila.pdf: 19264165 bytes, checksum: c322eb3e55e26c89546b4e9982d62ba3 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-10-21T13:12:18Z (GMT) No. of bitstreams: 1 eloahpereiraavila.pdf: 19264165 bytes, checksum: c322eb3e55e26c89546b4e9982d62ba3 (MD5) / Made available in DSpace on 2017-10-21T13:12:18Z (GMT). No. of bitstreams: 1 eloahpereiraavila.pdf: 19264165 bytes, checksum: c322eb3e55e26c89546b4e9982d62ba3 (MD5) Previous issue date: 2017-08-18 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / As reações de adição 1,2 às iminas são uma ferramenta sintética de grande interesse para a obtenção de blocos de construção contendo grupos aminas e aminoácidos em seus esqueletos estruturais. Os compostos obtidos por esta via são de grande interesse farmacológico, industrial e demais produtos de química fina. Desta forma, é possível acessar não apenas substratos para a síntese de moléculas complexas, mas também compostos com propriedades biológicas relevantes. Assim, propusemos duas vertentes para obtenção de estruturas análogas: em um primeiro momento, o desenvolvimento de uma metodologia para a obtenção de triclorometilaminas a partir da inserção do triclorometil carbânion gerado pela descarboxilação do sal tricloroacetato de potássio em um solvente aprótico em condições brandas e economicamente viável. Uma versão diastereosseletiva foi apresentada para a obtenção de um derivado enantiomericamente puro. Para uma melhor compreensão do mecanismo, cinética de descarboxilação, e formação de espécies envolvidas, foi utilizada a espectroscopia no Infravermelho por Transformada de Fourier com Reflexão Total Atenuada (ATR-FTIR) em tempo real, sendo possível medir a velocidade de decomposição, importância na adição dos reagentes e inferir a formação do ânion -CCl3. Em um segundo momento, propõe-se a síntese de derivados de α,β-diaminoácidos via catálise por ácido de Brønsted assimétrica a partir de uma reação do tipo Mannich entre azalactonas e iminas. Vários derivados de α,β-diaminácidos quirais foram preparados em bons rendimentos e alto controle da estereosseletividade. / 1,2-addition reactions to imines are a synthetic tool of great interest for obtaining building blocks containing amine and amino acid scaffolds with pharmacological interest, agrochemical industry and other fine chemicals. Therefore, it is possible to access not only substrates for the synthesis of complex molecules but also compounds of relevant biological properties. Thus, we proposed two strategies for preparation of those compounds: first, the development of a methodology to obtain trichloromethylamines from the addition of the trichloromethyl anion generated by the decarboxylation of the potassium trichloroacetate salt under mild and economically viable conditions was presented. A diastereoselective version was presented to obtain an enantiomerically pure derivative. For a better understanding of the mechanism, kinetics of decarboxylation, and the formation of involved species, Fourier Transform Infrared spectroscopy with real attenuated Total Reflection (ATR-FTIR) was used. The data indicated the kinetics behavior, importance of the addition of the reagents as well as the formation of the -CCl3 anion. Second, the synthesis of α,β-diamino acid derivatives via asymmetric Brønsted acid catalyzed Mannich type reaction between azalactones and imines is also described. The chiral α,β-diamino acid derivatives were prepared in good yields and with near perfect diastereo- and enantioselectivities.