The terpene and terpenoid family of compounds is considered to be the largest group of natural products. These compounds not only display great diversity in their structural features but are also known to have a multitude of biological activities including but not limited to anti-bacterial, anti-cancer, anti-inflammatory, and anti-HIV properties. Remarkably, all the terpenoids formed in nature come from two molecules viz. isopentenyl pyrophosphate and its isomer, dimethylallyl pyrophosphate both consisting of just five carbons but assembled in many ways. Nature utilizes highly efficient, enzyme-mediated cascade reactions to transform simple linear molecules to more complex cyclic scaffolds. Cascade or domino reactions are organic chemistry’s most powerful tools that, if executed correctly, mimic the extreme complexity of reactions occurring in nature. Our group has successfully utilized cationic cascade cyclization reactions, to prepare a large library of natural products along with their analogues. It was during the synthesis of one such natural product that it was discovered that a methoxymethyl (MOM) “protecting group” had been transferred within the same molecule. The optimization of this process not only allowed the synthesis of the desired tricyclic framework but also resulted in the liberated MOM group doing an EAS reaction which gave a new C-C bond. This transferred MOM group was further elaborated to different functional groups. Use of the tandem reaction sequence in an attempt to prepare radulanin E has been described. Total syntheses of two chalcone-based analogous meroterpenoids have been successfully completed using the aforementioned sequence. An advanced intermediate for an entire new class of acridine-based schweinfurthins has been elaborated. The results will be discussed in detail.

京都大学 / 0048 / 新制・課程博士 / 博士(薬科学) / 甲第18928号 / 薬科博第42号 / 新制||薬||5(附属図書館) / 31879 / 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

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This thesis documents the development of rhodium-catalyzed traceless chelation-controlled hydroacylation reactions for the synthesis of a variety of ketone products. <strong>Chapter 1</strong> provides an overview of rhodium-catalyzed hydroacylation chemistry, focusing on the origin of chelation-controlled strategies and the benefits thereof. <strong>Chapter 2</strong> describes a sequential reaction involving alkene hydroacylation, sulfide elimination and boronic acid conjugate addition, which affords products with the initial sulfide coordinating group replaced by a stereochemically defined aryl group. <strong>Chapter 3</strong> demonstrates a sequential process involving alkyne hydroacylation, boronic acid conjugate addition and sulfide elimination, which provides enantioenriched β'-arylα,β-unsaturated ketones in a highly efficient and selective manner. <strong>Chapter 4</strong> illustrates a versatile chelating group, triazene, for hydroacylation reactions. Subsequent functionalization of aromatic C-H bonds, promoted by the same chelating unit, offers highly substituted phenyl ketone products. <strong>Chapter 5</strong> documents experimental procedures and data.

Ces travaux de thèse nous ont permis de mettre au point différentes voies de synthèse de systèmes polycycliques complexes tels que des fenestradiènes et des cyclooctatriènes, par réactions en cascades palladocatalysées. Celles-ci débutent par une réaction de cyclocarbopalladation 4-exo-dig et est suivie par un couplage de Sonogashira. Dans des conditions adéquates, une réaction d'addition d'alcyne sur une triple liaison a ensuite lieu et [permet] d'accéder à un intermédiaire de type tétraène, dont les quatre doubles liaisons conjuguées permettent au système de subir spontanément une électrocyclisation à huit électrons. Sous contrôle des conditions d'irradiation, une réaction supplémentaire d'élecrocyclisation à six électrons re s'effectue alors. Plusieurs exemples de [4.6.4.6] fenestradiènes, ainsi que des cyclooctatriènes 6-4-8 et 7-4-8 comportant des différents substituants ont ainsi été synthétisés, en partant du même substrat de départ de structure relativement simple et en utilisant des réactifs et catalyseurs courants. Notre étude souligne notamment la remarquable régiosélectivité de la réaction d'addition d'alcyne qui se déroule lors de cette cascade réactionnelle catalysée au palladium. / This PhD thesis focuses on the study of methodologies employing cascade reactions and allowed access to a large variety of highly tense and functionalized polycyclic structures as fenestradienes and cyclooctatrienes. Those cascades reactions are initiated by a 4-exo-dig cyclocarbopalladation followed by a Sonogashira cross-coupling. Under appropriate conditions, an alkyne addition reaction on a triple bond allow to access a tetraene intermediate, Those four conjugated double bonds realize a conrotatory Sn electrocyclization. Under microwave irradiation conditions control, a supplementary 6n lectrocyclization can be performed. Several examples of [4.6.4.6] fenestradienes, 6-4-8 and 7-4-8 cyclooctatrienes have been synthesized, employing the same starting material and widely used catalysts and reactants. A particular attention is paid to alkyne addition reaction, which is carried out in the studied palladocatalyzed cascade reaction.

The emerging potential of miRNA molecules as diagnostic biomarkers calls for the development of a new quantification method. Current approaches usually require time-consuming and costly miRNA isolation for proper sample analysis. In this thesis, a new, isolation-free, oligonucleotide- modified gold nanoparticle (AuNP/DNA) system is proposed and designed for miRNA detection and quantification in living cells. This cascade, entropy-driven, and enzyme-free amplification system provides fluorescence signal upon selective interaction with the target miRNA. For this purpose, citrate-stabilized gold nanoparticles were synthesized, and their diameters were determined by dynamic light scattering and transmission electron microscopy. The AuNP/DNA conjugates were prepared following a recently published "freezing method". Their reaction kinetics with the target miRNA and selectivity to various miRNAs were compared with those of an analogous DNA system without AuNPs in a series of fluorescence measurements. Furthermore, stability experiments in glutathione environment were conducted, as well as DNA electrophoresis, demonstrating the mechanistic aspects of the reaction. The reaction yields and selectivity to target miRNA of 42.31 ± 2.91 nm AuNP/DNA constructs, containing approximately 25 DNA complexes per AuNP,...

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

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京都大学 / 新制・課程博士 / 博士(エネルギー科学) / 甲第23437号 / エネ博第424号 / 新制||エネ||81(附属図書館) / 京都大学大学院エネルギー科学研究科エネルギー基礎科学専攻 / (主査)教授 森井 孝, 教授 佐川 尚, 教授 片平 正人 / 学位規則第4条第1項該当 / Doctor of Energy Science / Kyoto University / DFAM

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