The use of heterogeneous catalysts containing Au nanoparticles supported on TiO2 has been explored for oxidative aqueous phase transformations of sustainable phenolic and benzoic acid derivatives that can be obtained from lignin. Au/TiO2 catalysts were chosen because of their high activity for ambient pressure oxidations of gas phase species, and because their synthesis is facile and reproducible through a modified deposition-precipitation method. The aerobic oxidation of syringic, vanillic, and ferulic acid as well as of guaiacol, eugenol and anisole was investigated at temperatures up to 70°C under (i) atmospheric air sparging in an open reactor and (ii) at 10 atm air pressure in a closed reactor system. The catalysts were characterised by Transmission Electron Microscopy (TEM), Inductively Coupled Plasma (ICP) Optical Emission Spectroscopy and the reproducibility of their catalytic activity independently monitored by determining their activity for carbon monoxide oxidation in a gas flow reactor. The oxidation of syringic acid, vanillic acid, ferulic acid over Au/TiO2 resulted in the formation of 2,6-dimethoxy benzoquinone, guaiacol, and vanillin, respectively, indicating high selectivity for decarboxylation followed by selective oxidation at the position releasing the leaving group. Guaiacol was found to form tetraguaiacol, while eugenol produced quinone methide. Generally, higher air pressure strongly accelerated the transformations, indicating that availability of oxidants formed from O2 is the rate limiting step in the observed transformations. No transformations took place when O2 was excluded from the systems. Overall, guaiacol was found to react fastest, followed by syringic acid, ferulic acid, then vanillic acid. Anisole was found to be unreactive, even at elevated air pressure. The overall reaction pattern emerging from these studies is that the aerobic oxidation in the presence of Au/TiO2 mimics known biotransformations, for example peroxidase-catalysed oxidations involving H2O2.To assess how the functional groups on the aromatic ring influence reactivity the oxidation of p-hydroxybenzoic acid and of 2,6-dimethoxybenzoic acid was also assessed. It was found that decarboxylation of p-hydroxybenzoic acid proceeds, albeit rather slowly, forming phenol, with no further oxidation to hydroquinone or benzoquinone. Taken together these results indicate that the methoxy moieties influence reactivity through both their inductive and resonance effects: leaving of the carboxylic acid group appears to be enhanced through the inductive effect, while further oxidation at the phenolic site seems to be activated through the resonance effect in ortho-position. In line with this hypothesis, it was recently found that dimethoxybenzoic acid converts fast.

Gold catalysts have the characteristic of promoting nucleophilic reaction. The cyclization reaction of enediynes catalyzed by gold activated by silver in toluene at 100oC to give 6H-dibenzo[c,h]chromen-6-ones (63), 6H-benzo[c]chromen-6-one (66) and Arnottin I (10) is described. Treatment of enediynes (61¡B65) with 5 mol% of Ph3PAuCl and 10 mol% of AgSbF6 in toluene at 100oC gave 6H-dibenzo[c,h]chromen-6-ones (63) and 6H-benzo[c]chromen-6-one (66) in good yield. In addition to using gold catalyst, electrophilic reagents employed in the reaction caused one cyclization instead of two cyclization. Furthemore, a mechanistic study and GC-MS data showed that the toluene could participate in the reaction. Enediynes (73) can be synthesized by a series of organic synthesis with few steps. Treatment of enediynes (73) with 5 mol% of Ph3PAuCl and 10 mol% of AgSbF6 in toluene at 100oC gave natural product-Arnottin I (10).

京都大学 / 0048 / 新制・課程博士 / 博士(薬学) / 甲第22405号 / 薬博第843号 / 新制||薬||241(附属図書館) / 京都大学大学院薬学研究科薬学専攻 / (主査)教授 大野 浩章, 教授 高須 清誠, 教授 竹本 佳司 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(薬科学) / 甲第19669号 / 薬科博第57号 / 新制||薬科||7(附属図書館) / 32705 / 京都大学大学院薬学研究科医薬創成情報科学専攻 / (主査)教授 大野 浩章, 教授 高須 清誠, 教授 竹本 佳司 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM

Une nouvelle approche pour la synthèse de l’aliskiren, un puissant inhibiteur de la rénine pour le traitement de l’hypertension chez l’homme, a été développée. De cette approche, des étapes clés tels qu’une allylation avec un des catalyseurs de MacMillan, une cyclisation par métathèse (RCM) pour la préparation d’une lactone à neuf membres et une séquence de réactions d’aziridination diastéréosélective/réarrangement de cycle par une catalyse acide donnant un produit aminohydroxylé ont permis de compléter la synthèse de l’aliskiren en 11 étapes. Durant l’élaboration de la séquence de réactions pour la préparation de l’aliksiren, il a été noté que la lactone à neuf membres avait une facilité à se réarranger via des intermédiaires quinonoïdaux et les produits issus de cette tendance ont été analysés. De plus, une étude sur la réaction de RCM, donnant la lactone à neuf membres, a montré une dépendance envers la nature diastéréomérique du substrat de départ. Une méthodologie d’alpha-allylation asymétrique de cétones catalysée au palladium, tirant avantage d’un ligand chiral PHOX, a été explorée et utilisée en vue de la synthèse de l’aliskiren. De cette méthode, une étude pour la synthèse de produits alpha-allylcétones acycliques a été démontrée et un effet d’additif sur la sélectivité et la vitesse de réaction a été découvert. De plus, la production d’un intermédiaire avancé d’un produit d’intérêts a été accomplie et la nature de la contribution de l’additif a été investiguée. Les produits obtenus depuis la méthodologie d’allylation catalysée au palladium et la formation d’intermédiaire cationique des certains dérivés de la synthèse de l’aliskiren ont inspirés une nouvelle approche faisant appel à des techniques d’alkylation en catalyse acide pour la formation de produits diaryliques. Il a été trouvé que le catalyseur de chlorure d’or(III) et de triflate de bismuth(III) étaient particulièrement efficaces, démontrant une différence de cinétique pour la réactivité d’un mélange diastéréoisomériques d’alcools alpha-substitués de départ. / A new synthetic route toward aliskiren, a potent renin inhibitor for the treatment of hypertension in man, was achieved. In this approach, the use of key steps such as an asymmetric allylation catalyzed by one of MacMillan’s catalysts, a ring closing metathesis for the formation of a 9-membered lactone and a catalytic aziridination/diastereoselective acid-catalyzed ring rearrangement reaction sequence leading to an aminohydroxylated product permitted us to achieve an 11-step synthesis of aliskiren. While elaborating the sequence towards the inhibitor, the tendency of the cyclic intermediate to rearrange through a quinonoid intermediate was observed. The products of the rearrangement were analyzed. Furthermore, studies exploring the formation of the nine-membered ring lactone demonstrated a dependency on the diastereomeric nature of the substrates. A new allylation methodology was explored for the preparation of aliskiren, in which a palladium catalyzed decarboxylative asymmetric alkylation took place in the presence of a chiral PHOX ligand. The scope of the reaction was studied varying substituents on acyclic alpha-allylketones and an additive effect was noticed with respect of the reaction rate and selectivity. In addition to the preparation of molecules with pharmaceutical interest, few experiments to elucidate the role of the additive in the allylation reaction were investigated. Inspired by our observation of quinonoid formation and our use of the palladium asymmetric allylation method to generate an alpha-stereogenic center, we anticipated that a diastereoselective synthesis of a key intermediate for the synthesis of aliskiren could be accomplished by introducing a nucleophile on a quinonoid intermediate from the least hindered face, under catalytic and acidic conditions. Gold(III) chloride and bismuth(III) triflate were found to be especially efficient as catalysts, showing kinetically controlled differentiation in the reactivity of diastereomeric alpha-substituted benzyl alcohols.