Durante o último século, diversas transformações envolvendo diazocompostos foram descobertas. Diazocompostos em presença de um átomo metálico como Rh, Cu, Au, entre outros, dão origem a um carbenóide o qual pode ser utilizado em diversos tipos de transformações. Dentre estas, podem ser destacadas as reações de ciclopropanação, rearranjos de Wolff, formação de ilídeos, reações de inserção C-H e reações de inserção X-H (sendo X= N, O, S, Se, halogênios, etc). As reações de inserção X-H, em especial as inserções de nitrogênio e oxigênio, tem sido muito estudadas nos últimos anos. Para se ter ideia do tamanho da importância dessas reações, as inserções N-H são atualmente usadas como etapa chave do processo da síntese do antibiótico Tienamicina, desenvolvido pela Merck. Recentemente, a primeira síntese total do Maecristal V, um produto natural muito promissor no combate ao câncer, evolveu em uma das etapas chave a reação de inserção O-H. Entretanto, a maior parte das metodologias para reações de inserção são descritas com a utilização de catálise metálica ou por reações fotoquímicas. A organocatálise tem se destacado nos últimos anos, o que pode ser notado pelo crescente número de publicações na área. Além das vantagem como, por exemplo, o menor custo, menor geração de resíduos, menor toxicidade, maior tolerância ao ar e umidade, entre outras. O presente trabalho demonstra uma nova metodologia para reações de inserção O-H, utilizando-se ácidos de Brønsted como organocatalisadores, especificamente um ácido fosfórico. Foram desenvolvidas duas metodologias, uma sem solvente com excesso de um álcool e outra utilizando solvente na presença de uma menor quantidade de álcool, fornecendo rendimentos entre 19-91%. Essas metodologias foram avaliadas em outras substâncias hidroxiladas, tais como, água, fenóis e silanóis, porém sem sucesso nesses casos. Por último, foram realizadas reações de inserção de metanol em alguns exemplos de um exemplo de α-aril-diazoéteres e em α-diazocetona, com rendimentos entre 50-96%, sendo possível mostrar a aplicabilidade do método. Por fim, foi estudada a inserção de metanol em β-ceto-α-diazoésteres, mas não houve sucesso nessa reação. / Over the last century, several transformations involving diazocompounds were discovered. Diazocompounds in the presence of metallic atoms such as Rh, Cu, Au, among others, lead to a carbenoid, which may be used in many kinds of transformations. Among them, we may hightlight cyclopropanation reactions, the Wolff rearrangement, formation of ylides, C-H and X-H insertion reactions (being X= N, O, S, Se, halogen, etc). The X-H insertion reactions, in special insertions of nitrogen and oxygen, have been extensively studied in the last years. To mention the importance of these reactions, a N-H insertion was used as the key step for the preparation of the antibiotic Tienamicene, developed by Merck. Recently, the first total synthesis of Maecristal V, a very promising natural product for cancer treatment, involved an O-H insertion reaction. Despite of that, most methodologies for insertion reactions are still described by metal catalysis or photochemistry reactions. Organocatalisys has been very popular in recent years, as may be seen by the growing number of publications in the area. Beyond this advantage, lower cost, less waste, less toxicity, increased tolerance to air and moisture are also encountered in organocatalysis. The present work demonstrates a new methodology for O-H insertion reaction, using Brønsted acids as the catalyst, specifically a phosphoric acid. Two methodologies were developed, one without solvent and with an excess of alcohol and other using solvent in presence of small amount of alcohol. Insertion reactions were performed in different alcohols, furnishing yields between 19-91%. These methodologies were evaluated with other hydroxylated substances, such as, water, phenols and silanols, but without success. Insertion reactions in the presence of methanol were carried out for some examples of α-aril-diazoesthers and with one example of a α-diazoketone (yields between 50-96%), showing the applicability of this method. Finally, the insertion of methanol in a β-keto-α-diazoesther was studied, but without success in this reaction.

Durante o último século, diversas transformações envolvendo diazocompostos foram descobertas. Diazocompostos em presença de um átomo metálico como Rh, Cu, Au, entre outros, dão origem a um carbenóide o qual pode ser utilizado em diversos tipos de transformações. Dentre estas, podem ser destacadas as reações de ciclopropanação, rearranjos de Wolff, formação de ilídeos, reações de inserção C-H e reações de inserção X-H (sendo X= N, O, S, Se, halogênios, etc). As reações de inserção X-H, em especial as inserções de nitrogênio e oxigênio, tem sido muito estudadas nos últimos anos. Para se ter ideia do tamanho da importância dessas reações, as inserções N-H são atualmente usadas como etapa chave do processo da síntese do antibiótico Tienamicina, desenvolvido pela Merck. Recentemente, a primeira síntese total do Maecristal V, um produto natural muito promissor no combate ao câncer, evolveu em uma das etapas chave a reação de inserção O-H. Entretanto, a maior parte das metodologias para reações de inserção são descritas com a utilização de catálise metálica ou por reações fotoquímicas. A organocatálise tem se destacado nos últimos anos, o que pode ser notado pelo crescente número de publicações na área. Além das vantagem como, por exemplo, o menor custo, menor geração de resíduos, menor toxicidade, maior tolerância ao ar e umidade, entre outras. O presente trabalho demonstra uma nova metodologia para reações de inserção O-H, utilizando-se ácidos de Brønsted como organocatalisadores, especificamente um ácido fosfórico. Foram desenvolvidas duas metodologias, uma sem solvente com excesso de um álcool e outra utilizando solvente na presença de uma menor quantidade de álcool, fornecendo rendimentos entre 19-91%. Essas metodologias foram avaliadas em outras substâncias hidroxiladas, tais como, água, fenóis e silanóis, porém sem sucesso nesses casos. Por último, foram realizadas reações de inserção de metanol em alguns exemplos de um exemplo de α-aril-diazoéteres e em α-diazocetona, com rendimentos entre 50-96%, sendo possível mostrar a aplicabilidade do método. Por fim, foi estudada a inserção de metanol em β-ceto-α-diazoésteres, mas não houve sucesso nessa reação. / Over the last century, several transformations involving diazocompounds were discovered. Diazocompounds in the presence of metallic atoms such as Rh, Cu, Au, among others, lead to a carbenoid, which may be used in many kinds of transformations. Among them, we may hightlight cyclopropanation reactions, the Wolff rearrangement, formation of ylides, C-H and X-H insertion reactions (being X= N, O, S, Se, halogen, etc). The X-H insertion reactions, in special insertions of nitrogen and oxygen, have been extensively studied in the last years. To mention the importance of these reactions, a N-H insertion was used as the key step for the preparation of the antibiotic Tienamicene, developed by Merck. Recently, the first total synthesis of Maecristal V, a very promising natural product for cancer treatment, involved an O-H insertion reaction. Despite of that, most methodologies for insertion reactions are still described by metal catalysis or photochemistry reactions. Organocatalisys has been very popular in recent years, as may be seen by the growing number of publications in the area. Beyond this advantage, lower cost, less waste, less toxicity, increased tolerance to air and moisture are also encountered in organocatalysis. The present work demonstrates a new methodology for O-H insertion reaction, using Brønsted acids as the catalyst, specifically a phosphoric acid. Two methodologies were developed, one without solvent and with an excess of alcohol and other using solvent in presence of small amount of alcohol. Insertion reactions were performed in different alcohols, furnishing yields between 19-91%. These methodologies were evaluated with other hydroxylated substances, such as, water, phenols and silanols, but without success. Insertion reactions in the presence of methanol were carried out for some examples of α-aril-diazoesthers and with one example of a α-diazoketone (yields between 50-96%), showing the applicability of this method. Finally, the insertion of methanol in a β-keto-α-diazoesther was studied, but without success in this reaction.

Transition metal catalysis has emerged as one of the most versatile methods for the selective formation of carbon–carbon and carbon–heteroatom bonds. In particular, oxidative carbon–carbon bond forming reactions have been widely studied due to their atom economic feature. This thesis has been focused on the development of new palladium(II)-catalyzed carbocyclization reactions under oxidative conditions. The first part of the thesis describes the palladium(II)-catalyzed oxidative carbocyclization-borylation and -arylation of enallenes. In these reactions, the (σ-alkyl)palladium(II) intermediate, which was shown previously to undergo β-hydride elimination, could be trapped in situ by organoboron reagents (B2pin2 and arylboronic acids) to form new carbon–boron and carbon–carbon bonds. Through these two protocols, a range of borylated and arylated carbocycles were obtained as single diastereomers in high yields. The second part deals with a palladium(II)-catalyzed oxidative diarylative carbocyclization of enynes. The reaction was proposed to start with a syn-arylpalladation of an alkyne, followed by insertion of the coordinated alkene. Subsequent arylation afforded a series of valuable diarylated tetrahydrofuran and tetrahydropyran products. The final part of the thesis advances the previously developed palladium(II)-catalyzed oxidative carbocyclization-borylation of enallenes in an enantioselective manner. C2-symmetric chiral phosphoric acids were used as the novel co-catalyst to trigger the enantioselective formation of intramolecular carbon–carbon bonds. By using this chiral anion strategy, a number of enallenes were converted to the borylated carbocycles with high to excellent enantioselectivity. / <p>At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.</p>

Depuis les années 2000 le domaine de l’organocatalyse asymétrique est en plein développement comme le montre le nombre croissant de publications sur le sujet. Durant cet essor un grand nombre d’organocatalyseurs a été développé, ils se classent en quatre catégories : les catalyseurs de transfert de phase, les bases de Lewis, les bases de Brønsted et les acides de Brønsted. Appartenant à cette dernière catégorie, les acides phosphoriques chiraux font partie des acides de Brønsted les plus populaire. Leurs premières utilisations en organocatalyse asymétrique remontent à 2004 où des acides phosphoriques dérivés du BINOL furent utilisés par Terada et Akiyama pour catalyser des réactions de Mannich de manière hautement énantiosélective. Depuis le champ d’application des acides phosphoriques s’est considérablement étendu et aujourd’hui environ 90 réactions différentes peuvent être catalysées efficacement par ces acides. En parallèle de ce développement des équipes ont commencé à apporter des modifications structurales aux acides phosphoriques dans le but d’étendre encore leur champ d’application. L’une des approches consiste à modifier le squelette carboné afin de modifier l’organisation spatiale de l’encombrement stérique chiral autour du phosphore. Le travail présenté dans ce manuscrit décrit l’élaboration et l’utilisation en catalyse d’une nouvelle famille d’acides phosphoriques à chiralité planaire basée sur un motif [3,3]paracyclophane. L’étude commence par la modélisation par calculs DFT de différents paracyclophanes dans le but d’évaluer la tension de cycle et la barrière de rotation imprimer à la structure en fonction de l’espaceur utilisé. Trois espaceurs sont sélectionnés pour des essais en synthèse : le -CH2-NTs-CH2-, le 1,8-naphtalènediyle et le 1,1’-ferrocènediyle. Les synthèses de trois bisphénols comportant les motifs précédents sont réalisées. Les bisphénol comportant les espaceurs -CH2-NTs-CH2-, le 1,8-naphtalènediyle n’ont pas pu être transformés en acides phosphoriques. En revanche il a été possible d’obtenir une nouvelle famille d’acides phosphoriques à chiralité planaire comportant le motif 1,1’-ferrocènediyle.Par la suite une méthode de synthèse permettant la variation facile des substituants aromatiques a été mise en place ainsi qu’une méthode de séparation de diastéréoisomères à l’aide d’un auxiliaire chiral afin d’obtenir des acides phosphoriques énantiopurs. Une famille de 6 acides phosphoriques a ainsi pu être synthétisée. Ces nouveaux acides ont ensuite été testés en organocatalyse asymétrique. La réaction de réduction par des esters de Hantzsch de quinoléines substituées en position 2 a servi de réaction test. Après sélection du meilleur acide, une étude sur l’influence de l’ester de Hantzsch a été menée conduisant à une forte augmentation de l’énantiosélectivité de la réaction. Enfin le champ d’application de la réaction a été explorer et des excès énantiomériques atteignant 92% ont pu être atteints. D’autres modifications structurales peuvent être apportées à cette nouvelle structure comme par exemple le remplacement du motif 1,1’-ferrocènediyle par le motif 1,8-dibromobiphénylènyl. Une influence non négligeable de l’espaceur sur les performances du catalyseur a pu être ainsi observée.L’étude a montré le potentiel de cette nouvelle famille d’acide phosphorique en organocatalyse asymétrique. Cette nouvelle famille va donc pouvoir être utilisée pour développer de nouvelle réaction énantiosélectives et ce dans le domaine de l’organocatalyse ou bien dans celui de la catalyse organométallique en utilisant le phosphate comme contre-ion chiral. / During the first decade of the century the organocatalysis has known an intense development shown by the increasing number of publications on the subject. This development led to the apparition of a wide number of different organocatalysts. These catalysts can be sorted in three categories: the phase transfer catalysts, the Lewis bases, the Brønsted bases and the Brønsted acids. One of the most used types of organocatalysts belonging to the latter category are the chiral phosphoric acids (CPA). The first use of these CPAs as organocatalysts was published in 2004 by Terada and Akiyama. They independently reported two Mannich-type reactions catalysed by BINOL-derived CPAs with high levels of enatioselectivity. Since then CPAs appeared as versatile catalysts and to this date more than 90 different reactions can be catalysed in a highly énantiosélective manner by these acids. Meanwhile some researchers began to modify the original BINOL-based phosphoric acids so as to broaden their scope. One possible approach consists in changing the chiral backbone to change the spatial organisation of the chiral environment. The work reported in this manuscript describe the design, the synthesis and the use in organocatalysis of a new planar chiral phosphoric acids based on a [3,3]paracyclophanes scaffold. This study begins with the DFT modelling of a series of paracyclophanes in order to evaluate the ring strain and rotation barrier induced by the nature of different tethering units. Three tethers have been selected for synthesis trials: the -CH2-NTs-CH2-, the 1,8-naphtalenediyl and the 1,1’-ferrocenediyl. Three different bisphenols each one embedding one of the three tethers mentioned above have been synthesised. It was not possible to turn the -CH2-NTs-CH2- and the 1,8-naphtalenediyl-based bisphenols into the corresponding phosphoric acids. But the 1,1’-ferrocenediyl-based bisphenol was successfully cyclised into the desired planar chiral phosphoric acid. Subsequently a synthetic pathway allowing an easy variation of the aryl substituents has been developed together with the use of a chiral auxiliary to obtain the planar CPAs in an enantiopure way. By this method 6 different CPAs have been synthesised. The efficiency in asymmetric organocatalysis of these new planar CPAs was investigated. The reduction of 2-substituted quinolines by Hantzsch esters was used as a benchmark reaction. After having identified the best CPA, the role of the Hantzsch ester has been investigated leading to an important improvement of the enantioselectivity of the reaction. Eventually, the scope of the reaction has been explored and e.e.’s up to 92% have been reached. Some other structural modifications of the structure can be made such as the replacement of the 1,1’-ferrocenediyl unit by a 1,8-dibromobiphenylenyl. A non-negligible influence of the tether has been observed on the catalyst behaviour. The study has demonstrated the potential of this new class of organocatalyst in asymmetric catalysis. These planar CPAs will then be used in the developpement of new énantiosélective reaction in the domain of organocatalysis or in the domain of organometallic catalysis by using the phosphate as a chiral counter-ion