This thesis describes synthetic applications of α-keto carbocations, which represent potentially useful, but poorly studied, reversed polarity equivalents of enolates. In the first chapter, a Ag(I) – mediated method for the nucleophilic displacement of α-halocarbonyl compounds to construct carbon-carbon bonds is described. The highly electrophilic nature of the putative α-keto carbocation intermediates enables the use of relatively unreactive nucleophiles in both intra- and intermolecular contexts. Such intermediates also present interesting opportunities for stereocontrol: our efforts to carry out diastereoselective additions to chiral α-keto carbocations are described. Oxazoles are an important class of heterocycles, and several syntheses are addressed in Chapter 2. Our approach to this class of compounds employs a TMSOTf mediated Ritter reaction to construct the carbon-nitrogen bond. Cycloaddition of 2-alkoxyoxazoles with alkynes presents a facile route for furan synthesis. The final chapter describes our attempts to apply anion-π interaction in organocatalysis. These interactions between anions and electron-deficient arenes have been characterized in some detail and have recently been applied in ion transport. Applications of prolinol-based secondary amines incorporating electron-deficient aromatic groups are described.

This thesis describes synthetic applications of α-keto carbocations, which represent potentially useful, but poorly studied, reversed polarity equivalents of enolates. In the first chapter, a Ag(I) – mediated method for the nucleophilic displacement of α-halocarbonyl compounds to construct carbon-carbon bonds is described. The highly electrophilic nature of the putative α-keto carbocation intermediates enables the use of relatively unreactive nucleophiles in both intra- and intermolecular contexts. Such intermediates also present interesting opportunities for stereocontrol: our efforts to carry out diastereoselective additions to chiral α-keto carbocations are described. Oxazoles are an important class of heterocycles, and several syntheses are addressed in Chapter 2. Our approach to this class of compounds employs a TMSOTf mediated Ritter reaction to construct the carbon-nitrogen bond. Cycloaddition of 2-alkoxyoxazoles with alkynes presents a facile route for furan synthesis. The final chapter describes our attempts to apply anion-π interaction in organocatalysis. These interactions between anions and electron-deficient arenes have been characterized in some detail and have recently been applied in ion transport. Applications of prolinol-based secondary amines incorporating electron-deficient aromatic groups are described.

Grâce à leurs fortes acidités, les milieux superacides permettent d’accéder par polyprotonation à des intermédiaires superélectrophiles polycationiques, capables d’être piégés par des nucléophiles très faibles. Ces espèces très réactives ont permis de développer des méthodologies de synthèse sans équivalent en conditions « classiques ».Dans la première partie de ce travail, le comportement de composés organophosphorés dans le milieu HF/SbF5 a été évalué et les sites de protonation de différentes fonctions phosphorées ont pu être observés par RMN in situ à basse température. La réactivité d’oxydes de phosphines insaturés a également été évaluée et des composés organophosphorés cycliques et/ou fluorés ont été synthétisés avec de bons rendements. Des expériences de RMN in situ à basse température ont permis de mettre en évidence un intermédiaire superélectrophile de type phosphonium-carbénium inédit dont l’implication a été confirmée par des calculs théoriques.La deuxième partie est consacrée à l’exploitation de la contrainte benzylique d’espèces superélectrophiles. A partir d’éphédrines tosylées, des benzosultames cycliques ont été obtenus par cyclisation intramoléculaire diastéréospécifique dans l’acide trifluorométhanesulfonique. L’analyse des intermédiaires réactionnels par RMN a permis de révéler l’implication d’une contrainte benzylique contrôlant la spécificité de la réaction. Les benzosultames chiraux N-F obtenus après fluoration ont été utilisés comme réactifs de fluoration électrophile énantiosélective et la synthèse de dioxydes de méthanodibenzothiazocines chiraux inédits a également été envisagée. / Thanks to their exceptional acidity, superacid allow access to polycationic superelectrophiles by polyprotonation. These highly reactive species are capable of being trapped by very weak nucleophiles and can be used to develop new synthetic methodologies without equivalents under “classical” conditions. In the first part of this work, the behavior of organophosphorus compounds in HF/SbF5 was evaluated and the protonation sites of different phosphorus functions have been observed by low temperature NMR spectroscopy. The reactivity of unsaturated phosphine oxides has also been evaluated and cyclic and/or fluorinated organophosphorus compounds have been synthetized in good yields. In situ low-temperature NMR experiments revealed a phosphonium-carbenium superelectrophilic intermediate whose implication was confirmed by theoretical calculations. The second part deals with the study of the benzylic strain applied to superelectrophilic species. From tosylated ephedrines, cyclic benzosultams were obtained by diastereospecific intramolecular process in trifluoromethanesulfonic acid. Analysis of the reaction intermediates by NMR revealed the implication of a benzylic strain controlling the specificity of the reaction. After fluorination, the obtained N-F chiral benzosultams were used as enantioselective electrophilic fluorination reagents and the synthesis of new chiral methanodibenzothiazocine dioxides was also considered.

No description available.

Asymmetric synthesis is most significant method to generate chiral compounds from prochiral substrates. It usually involves a chiral catalysis, which can be either metal based or organo-catalysis. Both of these systems have their own advantages and disadvantages. In recent times, organocatalysts are gathering widespread attention due to their low toxicity and inexpensive nature. Organocatalysts can replace traditional metal based Lewis acid catalysts in several useful organic transformations like the Diels-Alder reactions. Carbocations are compounds with positively charged carbon atoms and they can activate the substrate by pulling its electrons thus making it more electrophilic. Though carbocations are well-known in literature, they are not well explored in catalysis despite their tremendous potential. The aim of this project is to synthesize new chiral carbocations, derived from different chiral auxiliaries and substitution on aromatic moiety and to investigate them in asymmetric Diels- Alder reactions. We envisioned the final product to be enantio-enriched as the carbocations are chiral in nature. We have synthesized several chiral secondary and tertiary alcohols as a precursor of carbenium salts. These alcohols were mainly synthesized by addition of Grignard reagent or organolithium reagents to the carbonyl compounds. Though, we have synthesized several chiral alcohols, only three carbocations could be isolated those having methoxy group in the aromatic ring. The methoxy group was found to be crucial for the stabilization of the carbocation. All the isolated carbocations were able to catalyze the Diels-Alder reactions, however it was found that carbocation 4with BF4 as a counter ion was better reactive than others. Unfortunately, we could not get any chiral induction with the use of these catalysts. We believe that with better tuning in catalysts structure and the reaction conditions these carbocations might able to produce chiral induction in the product.

Lewis acids can be used as catalysts in different reactions, but the term Lewis acid catalysts often refers to metal salts. Metal complexes have been widely used for asymmetric catalysis. Asymmetric synthesis can however be performed in a metal-free way by using organocatalysis. New Lewis acid catalysts that are more effective, enantioselective and environmental friendly is of interest. This new type of Lewis acid catalysts could for example be of carbocation based character. The aim of this project was to synthesize chiral carbocations with different degree of sterical hindrance and investigate their catalytic ability in Diels-Alder reactions. It was presumed that the Diels-Alder reactions were going to be performed in an asymmetric way since the carbocation catalysts were achiral. Two chiral carbocations were synthesized successfully. The first synthesized carbocation, the less sterical hindered compound 8, was formed as a racemic mixture. The second carbocation, compound 16, could be formed as an enatiomeric pure compound. Both carbocations showed catalytic ability in Diels-Alder reactions and compound 8 was comparable with some common Lewis acid catalysts. In general, when using compound 8 as catalyst, higher catalyst amount gave higher conversions. Higher concentrations also gave higher conversions, but up to a certain level. No trend between polarity of different solvents and conversions could be seen. However, an increased temperature leads to faster reactions. The more rigid and sterical hindered compound 16 catalyzed the reactions slower than compound 8. The longer reaction time may indicate that the reaction occurs with higher selectivity, but no method to measure the ee of the product was found. An attempt to synthesize a third even more sterical hindered chiral carbocation, compound 19, resulted in a product contaminated by impurities that showed a catalytic ability lower than compound 8 and compound 16 in Diels-Alder reactions. The synthesis and the use of carbocations as Lewis acid catalysts in Diels-Alder reactions seem promising as a new type of catalysts even though there are questions that are still unanswered, e.g. counter ions effects, possible side reactions, selectivity etc.

京都大学 / 新制・論文博士 / 博士(工学) / 乙第13542号 / 論工博第4205号 / 新制||工||1984(附属図書館) / (主査)教授 杉野目 道紀, 教授 大江 浩一, 教授 松原 誠二郎 / 学位規則第4条第2項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

Préalablement, une synthèse de l’aliskiren, un inhibiteur de la rénine développé pour le traitement de l’hypertension, a été réalisée auprès du groupe Hanessian. Durant cette synthèse, une réaction clé de cyclisation par métathèse, menant à la formation de lactone à neuf membres, a été réalisée. Durant cette réaction, nous avons observé une différence de réactivité entre les diastéréomères, menant à la formation de monolactones et de dilactones, générant ainsi de l’intérêt pour l’étude des facteurs en cause. Le présent mémoire rapporte et détaille les résultats de cette analyse quant à la formation de monomères versus celle de dimères par cyclisation à l’aide de catalyseurs de Grubbs et l’impact de différentes conditions réactionnelles et la diastéréochimie relative sur la réaction. Un intérêt pour la formation de liens benzyliques nous a incité à approfondir notre compréhension d’une méthodologie de substitution nucléophile diastéréosélective catalysée par des acides. Le rationnel mit de l’avant par les groupes Bach et Olah a procuré une compréhension du mécanisme réactionnel sur lequel nous avons basé nos observations subséquentes. Nous avons porté notre attention sur l’alkylation d’arènes, de phénols et de sulfonamides. Diverses régiosélectivités et diastéréosélectivités ont pu être observées en présence de substrats dérivés de la synthèse de l’aliskiren, de nitroalcools ainsi que de azidoalcools en utilisant plusieurs acides de Lewis et de Brønsted. / Previously, a synthesis of aliskiren, a renin inhibitor developed for the treatment of hypertension, was developed in the Hanessian group. As part of that synthesis, they used a ring-closing metathesis which led to the formation of a nine-membered lactone, a key intermediate of the synthesis. During the reaction, we observed a difference in reactivity between the various diastereoisomers leading to the formation of mono- and dilactones, inciting us to study the various factors involved. The present master’s thesis reports and details the results of the study of monomers versus dimers formation by cyclization using Grubbs’s catalysts and the effect of various reaction conditions and relative configuration on the reaction. An interest for the formation of benzylic bonds drove us to deepen our comprehension of a methodology of diastereselective nucleophilic substitution catalysed by acids. The rational brought forth by the Bach and Olah groups served as a basis for our understanding of the mechanism involved upon which we based our following observations. We focused our attention on the alkylation of arenes, phenols and sulfonamides. Various regioselectivities and diastereoselectivities were observed on substrates derived from the aliskiren’s synthesis, nitroaocohols and azidoalcohols while using various Lewis and Brønsted acids.

Although α-keto carbocations have been demonstrated to be viable intermediates in solvolysis reactions, their applications in synthesis are scarce. These species can be considered to be equivalent to “reversed polarity” enolates and, as such, could be useful for the asymmetric formation of carbon-carbon and carbon-heteroatom bonds. In principle, facial selectivity in additions to α-keto carbocations may be induced using easily removed ester, amide, or imide chiral auxiliaries. Efforts to achieve such diastereoselective SN1 reactions of α-keto carbocations are described herein.

Although α-keto carbocations have been demonstrated to be viable intermediates in solvolysis reactions, their applications in synthesis are scarce. These species can be considered to be equivalent to “reversed polarity” enolates and, as such, could be useful for the asymmetric formation of carbon-carbon and carbon-heteroatom bonds. In principle, facial selectivity in additions to α-keto carbocations may be induced using easily removed ester, amide, or imide chiral auxiliaries. Efforts to achieve such diastereoselective SN1 reactions of α-keto carbocations are described herein.