京都大学 / 0048 / 新制・課程博士 / 博士(薬学) / 甲第18550号 / 薬博第812号 / 新制||薬||238(附属図書館) / 31450 / 京都大学大学院薬学研究科医療薬科学専攻 / (主査)教授 佐治 英郎, 教授 橋田 充, 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

Two series of stable palladium and silver complexes ligated to hemilabile ligands were prepared. The stability and applicability of these well-defined complexes in promoting various reactions (cycloaddition, hydroamination, cross-coupling reactions, etc.) was investigated. Structure-activity studies with a series of related ligands led us to find a pronounced ligand effect on these reactions. The dichotomous reactivity of triethyl phosphonium hydrobromide salt with dialkyl acetals was used for the synthesis of alkoxy phosphonium salts. Reactivity and applications of these phosphonium salts were described for the synthesis of the biologically active cinnamyl triazoles and ethyl indole-2-carboxylates. Total synthesis of the natural product nostodione A, was developed in eight chemical steps and with 21.6% overall yield from ethyl-2-indolecarboxylates. The synthesis of a mini-panel of structural analogs allowed for the discovery of anti-parasitic biological activity of nostodione A and its analogues for the first time. / Thesis / Doctor of Science (PhD)

Transition metal catalysis is a necessary branch of organic synthesis. Both monometallic and bimetallic catalysts can reduce reaction times, improve regio- and enantioselectivity, and minimize byproducts. Additionally, bimetallic catalysts can cooperatively activate substrates, which can enable new reactions and mechanistic pathways. The first half of this work will describe the synthesis and catalytic ability of our novel Pd(I) and Pd(II) dimers. Both dimers use a 2-phosphinoimidazole ligand scaffold to bring the metal centers in close proximity. The Pd(II) dimer can catalyze the synthesis of 1,3-disubstituted naphthalene rings from commercially available aryl iodides and methyl ketones with high regioselectivity and yields. Mechanistic and theoretical studies suggest the mechanism undergoes a Pd(III)–Pd(III) like intermediate. Additionally, we studied the impact of precatalyst oxidation state on C–N bonding reactions. We found that our Pd(I) dimer performed better in Buchwald-Hartwig aminations, while our Pd(II) dimer was shown to be extremely active in aminocarbonylation reactions. Both reactions gave C–N bonding products in good to excellent yield. The second portion of this work describes our novel Pd N–H NHC complex and its application in Suzuki-Miyaura cross couplings. In the presence of methanol, a Pd(II) salt will insert into the C–P bond of a 2-phosphinoimidazole ligand to give a protic NHC complex. The acidic hydrogen can be deprotonated under reaction conditions to give an anionic complex, which further increases the electron density on palladium as shown in Tolman Electronic Parameter studies. Application of the catalyst in Suzuki-Miyaura and Sonogashira coupling reactions gave product in high yield. Since our Pd N–H NHC complex with a diphenylphosphine ligand could not activate aryl chlorides, we then applied 2-dialkylphopshinoimidazole ligands. When the dialkyl ligands were stirred with Pd(II) salts in methanol, an equilibrium was observed between N–H NHC and P–N coordination complexes. When the catalytic mixture was applied to Suzuki-Miyaura cross-couplings, (hetero)aryl chlorides gave high yields with low catalyst loadings.

Thesis advisor: Jeffery A. Byers / This dissertation will discuss the development of Suzuki-Miyaura cross-coupling reactions catalyzed by iron-based complexes with an emphasis on addressing limitations to their practical application in industrial contexts. Chapter 1 will provide an overview of the development of the palladium-catalyzed Suzuki-Miyaura cross-coupling reaction and key factors which have enabled its prevalent use in various industries, with a comparison to how those factors have limited similar development of iron-catalyzed analogues. Chapter 2 will discuss the initial discovery and subsequent development of a series of iron-based precatalysts for the cross-coupling reaction of unactivated aryl boronic esters and alkyl halides. Chapter 3 will discuss the development and validation of a bench-stable iron(III)-based complex capable of catalyzing the Suzuki-Miyaura cross-coupling reaction between unactivated aryl boronic esters and alkyl halides. To conclude, Chapter 4 will discuss the ability of iron-based complexes to participate in the Suzuki-Miyaura cross-coupling reaction with alkyl tosylate electrophiles and its implications for harnessing the ability of iron catalysis to operate under different mechanistic manifolds. / Thesis (PhD) — Boston College, 2021. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Syftet med denna studie är att undersöka de musikpedagogiska idéer som utvecklades av Jaques-Dalcroze, Kodály, Orff och Suzuki för att se hur de väletablerade metoderna kan användas i pianoundervisning med förskolebarn i syfte att främja deras motoriska, språkliga och socioemotionella utveckling. Som metod i min studie har jag valt att analysera de fyra musikpedagogernas idéer och principer kartlagda i deras ursprungliga texter och övningsböcker. Den teorin som jag har använt mig av i min analys är från det traditionella utvecklingspsykologiska perspektivet. Jag väljer att begränsa mig till tre områden i förskolebarns utveckling: motorik, socioemotionell kompetens och språk. Analysen har visat att alla fyra metoder innehåller didaktiska medel som kan användas med förskolebarn. Min slutsats är dock att ingen av de fyra pedagogiska metoderna kan gynna barns utveckling i alla tre utvecklingsområden i lika hög utsträckning. Det är i stället en kombination av metoderna som på bästa vis kan hjälpa lärare att organisera pianoundervisning med förskolebarn.

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Organometallic chemistry is highly dependent upon the ligands which are employed on a metal's surface. These ligands control steric bulk and electronics of the metal center which can change the reactivity of the organometallic complex. Ligands that are standard in organometallic chemistry include phosphine ligands. These phosphine ligands have been utilized in the field since the 1960's and have shaped the development of many key organometallic catalysts. Phosphine ligands are easily functionalized and highly reactive. This increased reactivity, however, causes severe limitations as phosphine ligands are often unstable under standard benchtop conditions and must be handled both air and moisture free environments. To combat some of these issues new ligand types have emerged such as N-heterocyclic carbene ligands. These ligands are found to possess similar reactivity in terms of electron and steric influences but can be prepared and used on the benchtop. In this work we highlight a dual N-heterocyclic carbene/phosphine ligand which is obtained from an accessible 2-phosphinoimidazole. These 2-phsophinoimidazole ligands can undergo a transformation in the presence of a proton source. The proton source will cause the disassociation of the C-P bond forming a NHC-phosphine complex. Addition of a metal source to the NHC-phosphonium complex causes a NHC/phosphine metal complex, which upon further investigation was found to be catalytically active. This activity was tested in various cross coupling reactions which include Suzuki, Heck, and Sonogashira. Highlights of these results include the extreme functionalization of these 2-phosphinioimidazole ligands which can produce new aryl groups on the NHC, a free N-H bond on the imidazole which can be deprotonated or influence intermolecular forces with substrates, replacing the moieties on the phosphine, and finally the ability to transform in situ with the addition of a common alcohol. Each of these functionalization's are explained below along with their reactivity to isolate a wide variety of substrates. In addition to the work above a collaboration with Rio Tinto and the Madsen Lab at BYU is discussed. This work involves the concerns of land managers and their ability to restore landscapes that have been destroyed through a variety of issues including fire, mining, and invasive species. These ecological pressures cause land managers to search for native plants to seed on a landscape. Issues arise when using natives, however, because of their inability to quickly germinate and establish on a landscape. This is caused by dormancy issues where an antagonistic relationship between gibberellic acid and abscisic acid where the overproduction of one over the other results in dormant native plants. We have invented a methodology to use slow releasing polymers to hijack this system and deliver gibberellic acid to a seed causing it to germinate regardless of external stimuli. Our results show significant improvement in native Penstemon species with no side effects to the plant growth and establishment.

Le 21e siècle est le berceau d’une conscientisation grandissante sur les impacts environnementaux des processus utilisés pour synthétiser des molécules cibles. Parmi les avancées qui ont marqué ces dernières décennies, il est également question de réduction de déchets, de conservation de l’énergie et de durabilité des innovations. Ces aspects constituent les lignes directrices de la chimie verte. De ce fait, il est impératif de développer des stratégies de synthèse dont les impacts environnementaux sont bénins. Dans ce mémoire nous présentons la synthèse, la caractérisation et l’étude des propriétés catalytiques en milieu aqueux d’un ligand composé d’une unité -cyclodextrine native, d’une unité imidazolium et d’une chaine alkyle à 12 carbones. Ce ligand hybride s’auto-assemble dans l’eau sous forme de micelles, permettant ainsi d’effectuer en sa présence des couplages de Suzuki-Miyaura dans l’eau, avec de bons rendements. La fonctionnalisation de la face primaire de la -cyclodextrine par un noyau alkyl-imidazolium, précurseur de ligand de type carbène N-hétérocyclique, a permis le développement d’un système catalytique vert et hautement recyclable. Dans un deuxième temps, nous présentons l’utilisation du même ligand hybride dans des couplages de Heck dans l’eau, démontrant ainsi la versatilité du ligand. / Chemistry keeps evolving in new directions. Research has provided improved methodologies for the design and synthesis of targeted molecules. At the same time, the 21st century is witnessing increasing concern about the environmental impacts of chemical wastes. A new philosophy of chemical research and engineering has emerged, known as «Green chemistry». This concept encourages the design of products, processes and technologies that minimize the use and generation of hazardous substances. Therefore, there is an urge to develop environmentally friendly process to convert molecules into product of interest. In the present thesis, we describe the synthesis, characterization and catalytic properties of a novel alkylimidazolium-modified β-cyclodextrin (-CD). Our strategy was to construct a single amphiphilic bimodal ligand by the combination of a mass transfer unit (-CD), covalently bound to a ligand moiety (alkylimidazolium, an N-heterocyclic carbene (NHC) precursor) for aqueous catalysis. First, we demonstrated that the introduction of a dodecyl chain on the imidazolium moiety attached to the primary face of a native β-CD allows the formation of a highly active micellar self-assembled catalytic system in neat water with remarkable recyclable properties for the Suzuki–Miyaura coupling. In addition, we studied the versatility of this self-assembled bimodal system by performing Heck coupling in neat water.