京都大学 / 0048 / 新制・課程博士 / 博士(薬科学) / 甲第22753号 / 薬科博第127号 / 新制||薬科||14(附属図書館) / 京都大学大学院薬学研究科薬科学専攻 / (主査)教授 二木 史朗, 教授 中山 和久, 教授 髙倉 喜信 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM

<div><br></div><div><p>Noble metal nanoparticles have been studied extensively as heterogeneous catalysts for electrocatalytic and thermal reactions. In particular, the support material for the catalytic species is known to play a role in influencing the geometric and electronic properties of the active site as well as its catalytic performance. Polycrystalline gold electrodes have been used as a support to modify the electrocatalytic behavior of adsorbed molecular species. Here, we have studied two electrocatalytic processes- the hydrogen evolution reaction (HER) and the oxygen reduction reaction (ORR), using Au nanoparticle-based catalysts.</p> <p>Transition metal dichalcogenides are well-known HER catalysts that show structure-sensitive catalytic activity. In particular, undercoordinated sulfur sites at the edges of bulk materials as well as amorphous clusters and oligomers tend to show the highest reactivity. The hydrogen adsorption energy of MoS_x nanoclusters can be further tuned through the metallic support. Here, we synthesize colloidal Au@MoS₄^2-, Au@WS₄^2-and Au@MoS₄^2--WS₄^2- using a biphasic ligand-exchange method. The MoS₄^2- and WS₄^2- complexes show higher HER activity when supported on Au nanoparticles than on to a carbon control, illustrating the electronic role played by the support material.</p> <p>In the second project, Au nanoparticle cores are utilized as supports for Pd submonolayer and monolayer surfaces in order to catalyze the two-electron reduction of O₂ to generate hydrogen peroxide. Bulk surfaces of Pt and Pd are excellent catalysts for the four-electron reduction of O₂ to H₂O. In order to achieve high selectivity for H₂O₂, we postulate that the ensemble geometry of the Pd surface must be reduced to small islands or single atoms based on literature studies that have shown that large Pd ensembles are required for O–O bond cleavage. In this study, we synthesize several submonolayers surface coverages of Au@Pd core-shell nanoparticles using a biphasic ligand-exchange method. As the Pd coverage decreases from monolayer to submonolayer, the peroxide selectivity rises but is accompanied by an increase in catalytic overpotential. The highest peroxide selectivity was observed for 0.1 layers of Pd on Au, which likely exhibits the highest fraction of isolated atom and small cluster geometric ensembles of Pd.</p><br></div>

京都大学 / 0048 / 新制・課程博士 / 博士(薬科学) / 甲第18918号 / 薬科博第32号 / 新制||薬||4(附属図書館) / 31869 / 京都大学大学院薬学研究科薬科学専攻 / (主査)教授 松﨑 勝巳, 教授 加藤 博章, 教授 石濱 泰 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DGAM

Thesis advisor: Jia Niu / O-Sulfation is an important chemical code existing widely in nature, participating in a variety of biological activities including immune response, hemostasis, hormone regulation, cell signaling, and viral invasion. The heterogeneous nature, high polarity with negative charge, and the chemical lability of the sulfate modification have created significant challenges in the synthesis and structure-function studies of O-sulfated biomolecules. It is therefore highly desirable to achieve caging and selective release of the O-sulfated biomolecules. Inspired by sulfur (VI) fluoride exchange reaction, our group developed a series of general approaches to caged O-sulfated biomolecules and their selective deprotection. First, an O-sulfation strategy is developed by coupling aromatic fluorosulfate with silylated target molecules. Scalable synthesis was demonstrated on monosaccharides, disaccharides, amino acid, and steroid. Selective hydrolytic and hydrogenolytic removal of the aryl masking groups yielded the corresponding O-sulfated products in excellent yields. Furthermore, a complete knowledge gap was noted in biocompatible caging of sulfate. With the rational design and systematic optimizations, we discovered that fluorosulfotyrosine in peptides and proteins was an ideal precursor for sulfotyrosine (sY), which can be efficiently converted into the anionic active form by hydroxamic acid activators under physiologically relevant conditions. Photocaging the hydroxamic acid activators further allowed for light-controlled activation of functional sulfopeptides. This system featuring fast kinetics, high selectivity, excellent robustness, and on-demand release provides a valuable tool for probing functional roles of sulfation in the peptides and proteins. / Thesis (PhD) — Boston College, 2023. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Yes / In a competitive coformer exchange reaction, a recent topic of interest in pharmaceutical research, the coformer in a pharmaceutical cocrystal is exchanged with another coformer which is expected to form a cocrystal that is more stable. There will be a competition between coformers to form the most stable product through formation of hydrogen bonds. Thus, to monitor each and every step of such reactions, employing a very sensitive technique is crucial. 1H nuclear magnetic resonance (NMR) is a very powerful technique that is very sensitive to the hydrogen bond interactions. In this study, an in situ monitoring of a coformer exchange reaction is carried out by 1H magic angle spinning (MAS) solid-state NMR (SSNMR) at a spinning frequency of 60 KHz. The changes in caffeine maleic acid cocrystals on addition of glutaric acid, and caffeine glutaric cocrystal on addition of maleic acid were monitored. In all the reactions, it has been observed that caffeine glutaric acid Form I is formed. When glutaric acid was added to 2:1 caffeine maleic acid, the formation of metastable 1:1 caffeine glutaric acid Form I was observed, at the start of the experiment, indicating that the centrifugal pressure is enough for the formation. The difference in the end product of the reactions with similar reaction pathway of 1:1 and 2:1 reactant stoichiometry indicate that a complete replacement of maleic acid has only occurred only in the 1:1 stoichiometry of the reactants. The polymorphic transition of caffeine glutaric acid Form II to Form I at higher temperature was crucial reason which triggers the exchange of glutaric acid with maleic acid in the reaction of caffeine glutaric acid and maleic acid. Based on these results, new reaction pathways in competitive coformer exchange reactions could be distinguished, and the remarkable role of stoichiometry, polymorphism, temperature and centrifugal pressure could be established. / C.H. acknowledges Department of Science and Technology, India (DST), for the grant of Inspire Fellowship. T.G.A. acknowledges Council of Scientific and Industrial Research, India (CSIR) for research grants under the 12th 5 year plan project (Grant No. CSC0405). / The full-text of this article will be released for public view at the end of the publisher embargo on 19 Feb 2025.

Cette thèse décrit une méthodologie innovante d’extraction et d’hémisynthèse simultanée, dénommée SECheM (Simultaneous Extraction and Chemical Modification) sur une plante mauritanienne le Cienfuegosia digitata Cav. Cette méthodologie présente plusieurs avantages : (a) elle permet d’éviter les étapes critiques au niveau de la séparation et de la purification du gossypol, un polyphénol instable isolé de la plante ciblée (b) elle permet de stabiliser le gossypol thermiquement en le transformant en base de Schiff beaucoup plus stable. (c) elle présente un avantage en termes de réduction du nombre d’étapes et de temps. La même méthodologie a été utilisée pour accéder à des analogues bases de Schiff énantiomériquement pures du gossypol seulement en 2 étapes. Ces dernières transformées efficacement en complexes métalliques énantiomériquement purs se sont montrés être intéressants d’un point de vue catalytique. / This PhD work describes an innovative methodology for simultaneous extraction and semisynthesis, named SECheM (Simultaneous Extraction and Chemical Modification) on a Mauritanian plant: Cienfuegosia digitata Cav. This methodology offers many advantages: (a) It is a perfect solution to circumvent critical steps in the extraction, separation and purification processes of gossypol that is unstable polyphenol isolated from the targeted plant (b) It allows an in-situ preparation of more stable gossypol Schiff base derivatives (c) It shows an important reduction of step number and also the time needed for the process. The same SECheM methodology was used to access enantiomerically pure Schiff base derivatives of gossypol in only two steps. The latters were efficiently transformed into enantiomerically pure metallic complexes that appear to be very interesting in a catalytic reaction.

Despite the unfavorable pharmacokinetic properties associated with peptides, they are still of great interest in drug development due to a multitude of interesting biological functions. The development of peptidomimetics strives to maintain or improve the biological activity of a peptide concurrently with removing the unwanted properties. This thesis describes two synthetic approaches to peptidomimetics with particular emphasis on secondary structure mimetics. First the design, synthesis and evaluation of two beta-turn mimetics incorporated in the endorphin Leu-enkephalin is presented. The beta-turn mimetics were stabilized by replacement of the intramolecular hydrogen bond with an ethylene bridge, and the amide bond between Tyr and Gly was replaced with an ether linkage. Linear analogues of the two mimetics were also synthesized. The peptidomimetics and their linear analogues were evaluated in a competitive binding assay at two opiate receptors, my and delta. One of the cyclized beta-turn mimetics was found to be a delta receptor antagonist with an IC50 value of 160 nM. Second a synthetic strategy to a beta-strand mimetic using 2-fluoro-4-iodopyridine as scaffold is described. The synthesis involved a Grignard exchange reaction on the pyridine scaffold using an amino acid derivative as electrophile followed by an SNAr reaction using an amine as nucleophile. The synthesis of a tripeptidomimetic of Leu-Gly-Gly and attempts to introduce chiral building blocks at the C-terminal, as well as studies towards elongated mimetics are presented. Two additional studies deal with the synthesis of two classes of potential thrombin inhibitors based on the pyridine scaffold. The first class contain pyridine as central fragment (P2 residue) substituted with a para-amidinobenzylamine group as P1 residue and various benzoyl groups as P3 residues. Three potential thrombin inhibitors were synthesized and found to be microM inhibitors in an enzymatic assay. In the second class, the pyridine ring serves as P3 residue. This class also lacks a strongly basic group in the P1 position. A small library of eight compounds were synthesized and evaluated in the enzymatic assay. Unfortunately, these compounds lacked inhibitory activity.

A presente tese de doutorado descreve a integração de metodologias sintéticas da química de organoteluretos desenvolvidas nos últimos anos pelo grupo. Especialmente a hidroteluração de cetonas &#945;,&#946;-insaturadas, a resolução cinética enzimática de hidróxi-teluretos e a reação de troca Te/Li. Tais metodologias, empregadas em sequência, possibilitaram a obtenção de blocos sintéticos versáteis na preparação de reagentes organometálicos funcionalizados e enantiomericamente enriquecidos. Esse protocolo mostrou-se eficiente na preparação de uma variedade de produtos naturais, como por exemplo, feromônios de insetos-praga e butirolactonas com atividades biológicas relevantes. O trabalho foi dividido em duas partes. Estudou-se a reatividade e o emprego de organoteluretos alquílicos (sp3) e vinílicos (sp2) O-funcionalizados, na síntese dos produtos naturais citados acima. Na primeira parte do trabalho estudou-se a utilização de organoteluretos vinílicos. Esta classe de compostos foi preparada a partir da hidroteluração de alquinonas, os intermediários carbonílicos foram reduzidos com NaBH4, fornecendo uma mistura racêmica de hidróxi-teluretos vinílicos. Esses compostos foram submetidos à resolução cinética enzimática, empregando a lipase, disponível comercialmente, Novozyme® 435. Os resultados, quanto à excessos enantioméricos e rendimentos foram bons, possibilitando a obtenção de hidróxi-teluretos vinílicos enantiomericamente enriquecidos em até 96% e.e. Na etapa seguinte, efetuou-se a reação de troca Te/Li, gerando um reagente organometálico funcionalizado, denominado 1,4-(C,O) diânion vinílico de lítio. Pela eletronegatividade do átomo de lítio possibilitar vários tipos de transmetalações, esse intermediário é de grande valia em síntese orgânica. Na presença de eletrófilos, como CO2, esse diânion apresentou boa reatividade, gerando &#945;-alquil-&#947;-butenolidas, após hidrólise em meio ácido. Tais butenolidas, constituíram-se como esqueleto avançado na síntese da (+)-Blastimicinona, (-)-Blastimicinolactol, (+)-Antimicinona, (-)-NFX-2 e todos os isômeros da Acaterina, em bons rendimentos globais. Esses compostos apresentam atividades antifúngicas, antitumorais e inibitórias de enzimas relacionadas à Arteriosclerose, respectivamente. Na segunda parte do trabalho estudou-se a utilização de um organotelureto alquílico em particular. Obtido a partir da hidroteluração da metil-vinil-cetona e redução in situ, do intermediário carbonílico. A mistura racêmica obtida foi resolvida através de resolução cinética enzimática, empregando a lipase, disponível comercialmente, Novozyme® 435. Os resultados, quanto a excessos enantioméricos e rendimentos foram bons, possibilitando a obtenção dos dois enantiômeros do respectivo hidróxi-telureto alquílico em excessos enantioméricos de até 99%. Na etapa seguinte, efetuou-se a reação de troca Te/Li, gerando um reagente organometálico funcionalizado, denominado 1,4-(C,O) diânion alquílico de lítio que foi transmetalado para uma série organocupratos. Ao reagi-lo com tosilatos específicos e realizar work-up com Ac2O, obteve-se uma série de feromônios de insetos-praga (C. pisi, M. destructor e D. mulleri) em bons rendimentos. / This PhD thesis describes the integration of synthetic methodologies involving organotellurides chemistry developed in recent years by the group, especially hydrotelluration of &#945;,&#946;-unsaturated ketones, enzymatic kinetic resolution of hydroxytellurides and Te/Li exchange reaction. These methods, used together, made it possible to obtain versatile synthetic blocks which were used in the preparation of functionalized and enantiomerically enriched organometallic reagents, featuring a synthetic key step in preparing a variety of natural products, such as Insect Pheromones and Butyrolactones with relevant biological activities. This work was divided into two parts. We studied the reactivity and the application of alkyl (sp3) and vinyl (sp2) O-functionalized organotellurides, in the synthesis of natural products cited above. In the first part of the work we studied the use of vinyl organotellurides. This class of compounds was prepared from hydrotelluration of alkynones, carbonyl intermediates were reduced with NaBH4 giving a racemic mixture of hydroxy-vinyl tellurides. These compounds were subjected to enzymatic kinetic resolution, using the lipase NovozymeTM 435. The results, as the yields and enantiomeric excesses were good yielding hydroxy-vinylic tellurides with enantiomeric excesses up to 96%. In the next step we performed the Te/Li exchange reaction, generating a functionalized organometallic reagent, known as lithium 1,4-(C,O) vinyl dianion. According to the characteristics of the electronegative atom of lithium, this intermediate is of great value in organic synthesis. In the presence of electrophiles such as CO2 showed good reactivity generating &#945;-alkyl-&#947;-butenolides after acid hydrolysis. Such Butyrolactones constituted themselves as a skeleton for the synthesis of advanced (+)-Blastmycinone, (-)-Blastmycinolactol, (+)-Antimycinone, (-)-NFX-2 and all isomers of Acaterin in good overall yields. These compounds have antifungal and antitumor activity and inhibitory enzymes related to arteriosclerosis, respectively. In the second part of the work we studied the use of a specific alkyl organotelluride obtained by hydrotelluration of methyl vinyl ketone and in situ reduction of carbonyl intermediate by NaBH4. The racemic mixture was submitted to enzymatic kinetic resolution using the lipase NovozymeTM 435. The results, as the yields and enantiomeric excesses were good, allowing to obtain the two enantiomers of the corresponding hydroxy-alkyl telluride with enantiomeric excess of up to 99%. In the next step we performed the Te/Li exchange reaction, generating a functionalized organometallic reagent, known as lithium 1,4- (C,O) alkyl dianion that was used for the transmetallation for several organocuprate which when reacted with tosylates and perform specific work-up provided a number of pheromones of pest insects (C. pisi, M. destructor and D. mulleri) in good yields.

A presente tese de doutorado descreve a integração de metodologias sintéticas da química de organoteluretos desenvolvidas nos últimos anos pelo grupo. Especialmente a hidroteluração de cetonas &#945;,&#946;-insaturadas, a resolução cinética enzimática de hidróxi-teluretos e a reação de troca Te/Li. Tais metodologias, empregadas em sequência, possibilitaram a obtenção de blocos sintéticos versáteis na preparação de reagentes organometálicos funcionalizados e enantiomericamente enriquecidos. Esse protocolo mostrou-se eficiente na preparação de uma variedade de produtos naturais, como por exemplo, feromônios de insetos-praga e butirolactonas com atividades biológicas relevantes. O trabalho foi dividido em duas partes. Estudou-se a reatividade e o emprego de organoteluretos alquílicos (sp3) e vinílicos (sp2) O-funcionalizados, na síntese dos produtos naturais citados acima. Na primeira parte do trabalho estudou-se a utilização de organoteluretos vinílicos. Esta classe de compostos foi preparada a partir da hidroteluração de alquinonas, os intermediários carbonílicos foram reduzidos com NaBH4, fornecendo uma mistura racêmica de hidróxi-teluretos vinílicos. Esses compostos foram submetidos à resolução cinética enzimática, empregando a lipase, disponível comercialmente, Novozyme® 435. Os resultados, quanto à excessos enantioméricos e rendimentos foram bons, possibilitando a obtenção de hidróxi-teluretos vinílicos enantiomericamente enriquecidos em até 96% e.e. Na etapa seguinte, efetuou-se a reação de troca Te/Li, gerando um reagente organometálico funcionalizado, denominado 1,4-(C,O) diânion vinílico de lítio. Pela eletronegatividade do átomo de lítio possibilitar vários tipos de transmetalações, esse intermediário é de grande valia em síntese orgânica. Na presença de eletrófilos, como CO2, esse diânion apresentou boa reatividade, gerando &#945;-alquil-&#947;-butenolidas, após hidrólise em meio ácido. Tais butenolidas, constituíram-se como esqueleto avançado na síntese da (+)-Blastimicinona, (-)-Blastimicinolactol, (+)-Antimicinona, (-)-NFX-2 e todos os isômeros da Acaterina, em bons rendimentos globais. Esses compostos apresentam atividades antifúngicas, antitumorais e inibitórias de enzimas relacionadas à Arteriosclerose, respectivamente. Na segunda parte do trabalho estudou-se a utilização de um organotelureto alquílico em particular. Obtido a partir da hidroteluração da metil-vinil-cetona e redução in situ, do intermediário carbonílico. A mistura racêmica obtida foi resolvida através de resolução cinética enzimática, empregando a lipase, disponível comercialmente, Novozyme® 435. Os resultados, quanto a excessos enantioméricos e rendimentos foram bons, possibilitando a obtenção dos dois enantiômeros do respectivo hidróxi-telureto alquílico em excessos enantioméricos de até 99%. Na etapa seguinte, efetuou-se a reação de troca Te/Li, gerando um reagente organometálico funcionalizado, denominado 1,4-(C,O) diânion alquílico de lítio que foi transmetalado para uma série organocupratos. Ao reagi-lo com tosilatos específicos e realizar work-up com Ac2O, obteve-se uma série de feromônios de insetos-praga (C. pisi, M. destructor e D. mulleri) em bons rendimentos. / This PhD thesis describes the integration of synthetic methodologies involving organotellurides chemistry developed in recent years by the group, especially hydrotelluration of &#945;,&#946;-unsaturated ketones, enzymatic kinetic resolution of hydroxytellurides and Te/Li exchange reaction. These methods, used together, made it possible to obtain versatile synthetic blocks which were used in the preparation of functionalized and enantiomerically enriched organometallic reagents, featuring a synthetic key step in preparing a variety of natural products, such as Insect Pheromones and Butyrolactones with relevant biological activities. This work was divided into two parts. We studied the reactivity and the application of alkyl (sp3) and vinyl (sp2) O-functionalized organotellurides, in the synthesis of natural products cited above. In the first part of the work we studied the use of vinyl organotellurides. This class of compounds was prepared from hydrotelluration of alkynones, carbonyl intermediates were reduced with NaBH4 giving a racemic mixture of hydroxy-vinyl tellurides. These compounds were subjected to enzymatic kinetic resolution, using the lipase NovozymeTM 435. The results, as the yields and enantiomeric excesses were good yielding hydroxy-vinylic tellurides with enantiomeric excesses up to 96%. In the next step we performed the Te/Li exchange reaction, generating a functionalized organometallic reagent, known as lithium 1,4-(C,O) vinyl dianion. According to the characteristics of the electronegative atom of lithium, this intermediate is of great value in organic synthesis. In the presence of electrophiles such as CO2 showed good reactivity generating &#945;-alkyl-&#947;-butenolides after acid hydrolysis. Such Butyrolactones constituted themselves as a skeleton for the synthesis of advanced (+)-Blastmycinone, (-)-Blastmycinolactol, (+)-Antimycinone, (-)-NFX-2 and all isomers of Acaterin in good overall yields. These compounds have antifungal and antitumor activity and inhibitory enzymes related to arteriosclerosis, respectively. In the second part of the work we studied the use of a specific alkyl organotelluride obtained by hydrotelluration of methyl vinyl ketone and in situ reduction of carbonyl intermediate by NaBH4. The racemic mixture was submitted to enzymatic kinetic resolution using the lipase NovozymeTM 435. The results, as the yields and enantiomeric excesses were good, allowing to obtain the two enantiomers of the corresponding hydroxy-alkyl telluride with enantiomeric excess of up to 99%. In the next step we performed the Te/Li exchange reaction, generating a functionalized organometallic reagent, known as lithium 1,4- (C,O) alkyl dianion that was used for the transmetallation for several organocuprate which when reacted with tosylates and perform specific work-up provided a number of pheromones of pest insects (C. pisi, M. destructor and D. mulleri) in good yields.

Dry etching is an important technique for pattern transferin fabrication of most opto-electronic devices, since it canprovide good control of both structure size and shape even on asub-micron scale. Unfortunately, this process step may causedamage to the material which is detrimental to deviceperformance. It is therefore an objective of this thesis todevelop and investigate low damage etching processes for InPbased devices. An ion beam system in combination with hydrocarbon (CH4) based chemistries is used for etching. At variousion energies and gas flows the etching is performed in twomodes, reactive ion beam etching (RIBE) and chemical assistedion beam etching (CAIBE). How these conditions affect both etchcharacteristics (e.g. etch rates and profiles, surfacemorphology and polymer formation) and etch induced damage (onoptical and electrical properties) is evaluated and discussed.Attention is also paid to the effects of typical post etchingtreatments such as annealing on the optical and electricalproperties. An important finding is the correlation betweenas-etched surface morphology and recovery/degradation inphotoluminescence upon annealing in PH3. Since this type of atmosphere is typical forcrystal regrowth (an important process step in III/Vprocessing) a positive result is imperative. A low ion energy N2/CH4/H2CAIBE process is developed which not onlysatisfies this criteria but also exhibits good etchcharacteristics. This process is used successfully in thefabrication of laser gratings. In addition to this, the abilityof the ion beam system to modify the surface morphology in acontrollable manner is exploited. By exposing such modifiedsurfaces to AsH3/PH3, a new way to vary size and density of InAs(P)islands formed on the InP surfaces by the As/P exchangereaction is presented. This thesis also proposes a new etch chemistry, namelytrimethylamine ((CH3)3N or TMA), which is a more efficient methyl sourcecompared to CH4because of the low energy required to break the H3C-N bond. Since methyl radicals are needed for theetching it is presumably a better etching chemistry. A similarinvestigation as for the CH4chemistry is performed, and it is found that bothin terms of etch characteristics and etch induced damage thisnew chemistry is superior. Extremely smooth morphologies, lowetch induced damage and an almost complete recovery uponannealing can be obtained with this process. Significantly,this is also so at relatively high ion energies which allowshigher etch rates. <b>Keywords:</b>InP, dry etching, ion beam etching, RIBE,CAIBE, hydrocarbon chemistry, trimethylamine, As/P exchangereaction, morpholoy, low damage, AFM, SCM, annealing