京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第21776号 / 工博第4593号 / 新制||工||1716(附属図書館) / 京都大学大学院工学研究科材料化学専攻 / (主査)教授 中尾 佳亮, 教授 松原 誠二郎, 教授 杉野目 道紀 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

La tesis doctoral describe estrategias útiles y sencillas para las síntesis de 2-oxindoles 3,3'-disustituídos y alcoholes homoalílicos. La memoria se divide en dos grandes bloques: el primero referido a la alquilación desacilativa como método para la síntesis de 2-oxindoles 3,3'-disustituídos que engloba la introducción I, el capítulo I titulado alquilación desacilativa para la síntesis de 2-oxindoles 3,3'-disustituídos y capítulo II titulado bromación desacilativa para la síntesis de 3,3'-bioxindoles y aislamiento de 3-bromooxindoles. La segunda parte se refiere a fotocatálisis y metalofotocatálisis como nuevos métodos de síntesis orgánica y engloba la introducción II, capítulo III titulado fotocatálisis para la síntesis de 3,3'-bioxindoles y capítulo IV titulado catálisis dual para la alilación de aldehídos.

The purpose of this investigation is to examine reactions of anions of oximes, oxime ethers and imines with acylating agents and other electrophiles. It is also an attempt to utilize the phenomenon of geometrical enantiomeric isomerism, in which absolute configuration is determined by double bond geometry, and the concept of regiospecific anion formation, also determined by double bond geometry, for stereospecific synthesis of tropinone derivatives.

Geldanamycin possesses various biological activities as seen in the NCI 60 cell line panel (13 nM avg., 70 nM SKBr-3 cells). The predominant mode of action providing these unique results arises from the ability of geldanamycin (GA) to bind to the chaperone heat shock protein 90 (Hsp90). Despite its complicated functionality, the first total synthesis of GA was accomplished, which included two new reactions developed specifically to address the stereochemical features. The final step in the synthesis of GA was a demethylation-oxidation sequence to generate the desired para-quinone. This step could only be accomplished with HNO3/AcOH, producing GA in 5% yield. A GA model study, which closely resembled the aromatic core, was extensively investigated to solve this critical oxidation issue. A protected hydroquinone model compound was determined to be the optimum choice. Using Pd in the presence of air with a 1,4-hydroquinone provided the desired para-quinone quickly and nearly quantitatively in 98% yield. This study formulated the recipe of success for para-quinone formation of GA and future synthetic analogs. Asymmetric glycolate alkylation has been developed using phase-transfer-catalysis (PTC). Diphenylmethoxy-2,5-dimethoxyacetophenone with trifluorobenzyl cinchonidinium catalyst and cesium hydroxide provided alkylation products at —35 °C in high yield (80-99%) and with excellent enantioselectivity (up to 90% ee). Useful α-hydroxy products were obtained using bis-TMS peroxide Baeyer—Villiger conditions and selective transesterification. The intermediate aryl esters can be obtained with >99% ee after a single recrystallization. The newly developed PTC glycolate alkylation was applied to the asymmetric syntheses of ragaglitazar and kurasoin A. Ragaglitazar is a potent antihyperglycemic and lipid modulator, currently in phase II clinical trials. Kurasoin A is a relatively potent protein farnesyltransferase (PFTase) inhibitor with an IC50 value of 59.0 micromolar. PTC glycolate alkylation was optimized to provide 4-benzyloxy glycolate intermediates in excellent overall yield and with 96% ee after recrystallization. Ragaglitazar was then synthesized after considerable experimentation to provide the potent lipid modulator with yields and enantiopurity rivaling the best-known routes produced by industry standards. Kurasoin A was produced through an α-triethylsiloxy Weinreb amide to provide the highest overall yielding route to this PFTase inhibitor currently disclosed.

Brief explanation and history of cinchona based Phase Transfer Catalysis (PTC). Studied aryl acetates in PTC, encompassing napthoyl, 6-methoxy napthoyl, phenyl and protected 4-hydroxy phenyl acetates. Investigated means of controlling the selectivity of the PTC reaction by changing the electrophile size, the ether side group size or by addition of inorganic salts. Found that either small or aromatic electophiles increased enantioselectivity more than aliphatic electrophiles, and that increasing the size of ether protecting group also increased selectivity. Positive effects of salt addition included either decreasing reaction time or increasing enantiomeric excess. Applied findings towards the synthesis of S-equol. Computational experiments working towards deducing the transition state between PTC and aryl acetate substrates.

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The legibility of the digitized copy is limited due to the quality of the original document. McMaster Digitization Centre. March 26, 2019. / The object of the program was to develop general guidelines for the art of simulation, and then to show how simulation could be used in practice. A digital computer simulation was assembled to describe the operation of the Shell alkylation plant at Bronte, Ontario. The solution of the steady-state mass and energy balances provided a working simulation on which to demonstrate the modeling and simulation techniques which are presented. The simulation was used to predict the operating costs and to asses the technical feasibility of five plant case studies. / Thesis / Master of Engineering (ME)

Les produits synthétisés à partir du même halogénure de départ sont numérotés en chiffres arabes dans l'ordre d'apparition et affecté du même indice (la, 2a, .lb, 2b, Les numéros des composés cités pour mémoire sont mentionnés entre parenthèses ( (1), (2), ...) . En ce qui concerne la nomenclature, nous nous sommes efforcés de respecter la version française des règles de 1957 de l'Union Internationale de Chimie Pure et Appliquée (N.Lozach, Bull. Soc. Chim. Fr., 1957, 55; 1958, 1206). Nous avons employé le terme "alkylation" à la place d"'alcoylation" et fait précéder du préfixe cyclo- toute réaction impliquant la création d'un cycle : cycloalkylation, cycloacylation, cyclodéshydratation. / Montréal Trigonix inc. 2018