Tropische Infektionskrankheiten sind noch immer die Haupttodesurache in vielen Ländern der Dritten Welt. Unter ihnen ist Malaria neben der Immunschwächekrankheit AIDS und Tuberkulose am weitesten verbreitet. Laut WHO erkrankten allein im Jahr 2016 rund 216 Millionen Menschen an Malaria und weltweit verstarben 445.000 Menschen an den Folgen dieser Infektion. Solange die Wirksamkeit des Impfstoffs RTS,S/AS01 gegen Malaria noch Schwachstellen aufweist und andere Impfstoff-Kanditaten sich noch in präklinischen Testphasen befinden, ist vor allem die Entwicklung neuer Wirkstoffe, auch im Hinblick auf die rasante Ausbreitung von Resistenzen gegen herkömmliche Medikamente, weiterhin eine dringende Aufgabe. Eine vielversprechende Wirkstoffklasse mit interessanten strukturellen Eigenschaften und einer ungewöhnlichen Biosynthese aus Acetat-Einheiten sind die Naphthylisochinolin-Alkaloide aus den beiden paläotropischen Pflanzenfamilien der Dioncophyllaceae und Ancistrocladaceae. Die Naphthylisochinolin-Alkaloide sind hervozuheben aufgrund ihrer exzellenten Aktivität gegen Plasmodium falciparum, den Erreger der Malaria tropica, sowie wegen ihrer Wirksamkeit gegen Erreger weiterer Krankheiten wie beispielsweise AIDS, Leishmaniose und Afrikanische Trypanosomiasis. Auch im Kampf gegen maligne Erkrankungen wie Leukämie und pankreatischen Krebs werden sie aufgrund ihrer cytotoxischen Eigenschaften als vielversprechende Leitstrukturen betrachtet. Die strukturell beeindruckendsten Naphthylisochinolin-Alkaloide sind die dimeren Mbandakamine, die von unserer Arbeitsgruppe vor einiger Zeit aus einer kongolesischen Ancistrocladus-Liane isoliert wurden. Sie besitzen sieben stereogene Elemente und sind die ersten natürlich vorkommenden Dimere mit einer höchst unsymmetrischen 6',1''-gekuppelten zentralen Biarylachse. Diese impliziert eine außergewöhnlich hohe sterische Hinderung an der zentralen Achse, wie sie noch in keinem anderen dimeren Naphthylisochinolin-Alkaloid gefunden wurde. Verbunden mit ihren bemerkenswerten und vielseitigen pharmakologischen Wirkeigenschaften sind sie ausgesprochen interessante Moleküle für eine synthetische Erschließung. Ziel dieser Arbeit war die erstmalige Totalsynthese von Mbandakamin A und B sowie die Synthese ihrer monomeren Hälften 5-epi-Korupensamin E und 8-O-Methylkorupensamin A. Zudem sollten weitere Naphthylisochinolin-Dimere, die bei der Synthese der Mbandakamine anfallen, isoliert und charakterisiert werden. Alle neuen mono- und dimeren Naphthylisochinoline sollten abschließend am Schweizerischen Tropen- und Public-Health-Institut auf ihre biologische Aktivität getestet werden. Zusätzlich gelang im Rahmen eines Kooperationsprojekts erstmals die stereochemische Charakterisierung des strukturell ganz neuartigen, inhärent chiralen Wolframbiscorrols durch online HPLC-ECD-Analyse in Kombination mit quantenchemischen Rechnungen. / Tropical infectious diseases are still the leading cause of death in developing countries. Among them, malaria is the most widespread one, besides the immunodeficiency syndrome AIDS and tuberculosis. According to the WHO about 216 million people were diagnosed with malaria in 2016, and it was estimated that 445 000 deaths due to malaria occurred globally. As long as vaccinations still show weaknesses in their efficacy or are only in the pre-clinical phase, the development of new drugs is inevitable because of the rapid spread of drug resistance. A promising class of agents with interesting structural properties and an unusual biosynthesis are the naphthylisoquinoline alkaloids from the two palaeotropic plant families of Dioncophyllaceae and Ancistrocladaceae, because not only the naphthalene parts but also the isoquinoline moieties originate from acetate- units. The naphthylisoquinoline alkaloids have attracted attention due to their high activities against Plasmodium falciparum, the pathogen causing malaria tropica, and for their effectiveness against the pathogens of further tropical diseases such as AIDS, leishmaniasis, schistosomiasis and trypanasomiasis. In the fight against malignant diseases such as leukemia and pancreatic cancer, they are also considered as promising lead structures, because of their cytotoxic properties. Structurally most impressive naphthylisoquinoline alkaloids are the dimeric mbandakamines, recently isolated by our group from a Congolese Ancistrocladus liana. The mbandakamines possess seven stereogenic elements and are the first naturally occurring dimers with a highly unsymmetric 6',1''-coupled central biaryl axis. This implies an exceptionally high steric hindrance that has not been found in any other dimeric naphthylisoquinoline alkaloid so far. In combination with their remarkable pharmacological activities, they are extremely interesting synthetic goals. The aim of of the present work was the first synthesis of 5-epi-korupensamine E and 8-O- methylkorupensamine A, which are the two molecular halves of mbandakamines A and B, followed by their phenol-oxidative coupling to give rise to the mbandakamines. Additionally, further mono- and dimeric naphthylisoquinolines obtained en route to the mbandakamines were to be isolated and characterized. Moreover, all new mono- and dimeric naphthylisoquinolines were to be tested for their antiprotozoal activities at the Swiss Tropical and Public Health Institute. In addition,in a cooperation project the stereochemical characterization of an inherently chiral tungsten biscorrole by online-HPLC-ECD analysis in combination with quantum-chemical calculations was achieved for the very first time.

High-valent transition metal-oxo intermediates are of fundamental importance because of their central role as active oxidizing species in enzymatic and synthetic catalytic oxidations. Many transition metal catalysts have been extensively studied as models of the ubiquitous cytochrome P450 enzymes to probe the sophisticated oxygen atom transfer mechanism as well as to invent enzyme-like oxidation catalysts. In this work, photolysis of highly photo-labile corrole-manganese(IV) bromates or nitrites by visible light was studied in two corrole systems with different electronic environments. The corrole systems under studied include 5,10,15- tris(pentafluorophenyl)corrole (TPFC) and 5,10,15-triphenylcorrole (TPC). As observed in both systems, homolytic cleavage of O-Br or O-N bonds in the ligands resulted in one-electron photo-oxidation to generate corrrole-manganese(V)-oxo species, as determined by their distinct UV-vis spectra and kinetic behaviors. The kinetic of oxygen atom transfer (OAT) reactions with various substrates by these photogenerated [MnV(Cor)(O)] were studied in CH3CN and CH2Cl2 solutions. [MnV(Cor)(O)] exhibits remarkable solvent and ligand effects on its reactivity and spectral behaviors. In the more electron-deficient TPFC system and in the polar solvent CH3CN, MnV-oxo corrole returned MnIII corrole in the end of oxidation reaction. However, in the less polar solvent CH2Cl2 or in the less electron-deficient TPC systems, MnIV product was formed instead of MnIII. With the same substrates and in the same solvent, the order of reactivity of MnV-oxo corrole was inverted as TPC > TPFC. The spectra and kinetic results are rationalized by a multiple oxidation model, where the electron-demand MnVoxo species may serve as direct two-electron oxidation for oxygen atom transfer reactions; and less electron-demand systems undergo a disproportionation reaction to form a putative manganese(VI)-oxo corrole as the true oxidant. The choice of pathways is strongly dependent on the nature of the solvent and corrole ligand. Furthermore, porphyrin-manganese(V)-oxo were produced in organic solvents by visible light irradiation of the corresponding porphyrin-manganese(III) nitrite complexes. The porphyrin systems studied were 5,10,15,20-tetrakispentafluoro phenylporphyrin (TPFPP), 5,10,15,20-tetrakis(2,6-difluorophenyl)porphyrin (TDFPP) and 5,10,15,20-tetrakis(2,6-dichlorophenyl)-porphyrin (TDCPP). Heterolytic cleavage of O-N bond of nitrite ligand results in two-electrons photo-oxidation. Under visible light irradiation, MnV-oxo porphyrins quickly returned to MnIII product. However, in absence of light, MnIV-oxo species were formed, as determined by their distinct UV-vis spectra, which permitted direct kinetic studies. The apparent rate constants for reaction of [MnIV(Por)(O)] species show inverted reactivity order with (TPFPP) < (TDFPP) < (TDCPP) in reactions with ethylbenzene. A model for oxidation under catalytic condition was presented.

Boron complexes of porphyrin analogues are rare and typically difficult to prepare. The possibility of extending this chemistry further to include corroles was intriguing and provided the main motivation for this work. The coordination chemistry of boron with corroles was explored. The aim was to see whether boron could be coordinated within the corrole N4 core and if so whether novel or similar structural types resulted, relative to the closely related porphyrin system. Boron halides and aryl halides were reacted with free base corroles in the presence of diisopropylethylamine. The methodology employed was similar to that used for boron porphyrin systems. As well as free base corrole, an N-methyl corrole and trilithiated corrole were also used as starting materials. Several boron corrole structural types were obtained. The reaction of free base corrole with boron trifluoroetherate led to the first structurally characterised corrole with boron bound within the N4 core, B2OF2(corrole). From this reagent a mono-boron species, BF2(corrole) was also obtained. With dichlorophenylborane, several boron corrole complexes were prepared including PhB2O(corrole), PhB2(corrole) and B2Ph2H(corrole). The latter species was structurally characterised and the bridging hydride is proposed to form through a reductive coupling process. Use of N-methyl corrole effectively blocked one boron binding site and subsequently mono-boron corroles BF2(N-methyl- corrole), BPh(OH)(N-methyl corrole) and BPhF(N-methyl corrole) were prepared in good yields. The reaction of lithiated corrole and dichloroplenylborane afforded B2Ph2Cl(corrole). Overall, several new boron corrole species were prepared, significantly extending the library of known boron complexes with ligands related to the porphyrin system.

Boron complexes of porphyrin analogues are rare and typically difficult to prepare. The possibility of extending this chemistry further to include corroles was intriguing and provided the main motivation for this work. The coordination chemistry of boron with corroles was explored. The aim was to see whether boron could be coordinated within the corrole N4 core and if so whether novel or similar structural types resulted, relative to the closely related porphyrin system. Boron halides and aryl halides were reacted with free base corroles in the presence of diisopropylethylamine. The methodology employed was similar to that used for boron porphyrin systems. As well as free base corrole, an N-methyl corrole and trilithiated corrole were also used as starting materials. Several boron corrole structural types were obtained. The reaction of free base corrole with boron trifluoroetherate led to the first structurally characterised corrole with boron bound within the N4 core, B2OF2(corrole). From this reagent a mono-boron species, BF2(corrole) was also obtained. With dichlorophenylborane, several boron corrole complexes were prepared including PhB2O(corrole), PhB2(corrole) and B2Ph2H(corrole). The latter species was structurally characterised and the bridging hydride is proposed to form through a reductive coupling process. Use of N-methyl corrole effectively blocked one boron binding site and subsequently mono-boron corroles BF2(N-methyl- corrole), BPh(OH)(N-methyl corrole) and BPhF(N-methyl corrole) were prepared in good yields. The reaction of lithiated corrole and dichloroplenylborane afforded B2Ph2Cl(corrole). Overall, several new boron corrole species were prepared, significantly extending the library of known boron complexes with ligands related to the porphyrin system.

Boron complexes of porphyrin analogues are rare and typically difficult to prepare. The possibility of extending this chemistry further to include corroles was intriguing and provided the main motivation for this work. The coordination chemistry of boron with corroles was explored. The aim was to see whether boron could be coordinated within the corrole N4 core and if so whether novel or similar structural types resulted, relative to the closely related porphyrin system. Boron halides and aryl halides were reacted with free base corroles in the presence of diisopropylethylamine. The methodology employed was similar to that used for boron porphyrin systems. As well as free base corrole, an N-methyl corrole and trilithiated corrole were also used as starting materials. Several boron corrole structural types were obtained. The reaction of free base corrole with boron trifluoroetherate led to the first structurally characterised corrole with boron bound within the N4 core, B2OF2(corrole). From this reagent a mono-boron species, BF2(corrole) was also obtained. With dichlorophenylborane, several boron corrole complexes were prepared including PhB2O(corrole), PhB2(corrole) and B2Ph2H(corrole). The latter species was structurally characterised and the bridging hydride is proposed to form through a reductive coupling process. Use of N-methyl corrole effectively blocked one boron binding site and subsequently mono-boron corroles BF2(N-methyl- corrole), BPh(OH)(N-methyl corrole) and BPhF(N-methyl corrole) were prepared in good yields. The reaction of lithiated corrole and dichloroplenylborane afforded B2Ph2Cl(corrole). Overall, several new boron corrole species were prepared, significantly extending the library of known boron complexes with ligands related to the porphyrin system.

Boron complexes of porphyrin analogues are rare and typically difficult to prepare. The possibility of extending this chemistry further to include corroles was intriguing and provided the main motivation for this work. The coordination chemistry of boron with corroles was explored. The aim was to see whether boron could be coordinated within the corrole N4 core and if so whether novel or similar structural types resulted, relative to the closely related porphyrin system. Boron halides and aryl halides were reacted with free base corroles in the presence of diisopropylethylamine. The methodology employed was similar to that used for boron porphyrin systems. As well as free base corrole, an N-methyl corrole and trilithiated corrole were also used as starting materials. Several boron corrole structural types were obtained. The reaction of free base corrole with boron trifluoroetherate led to the first structurally characterised corrole with boron bound within the N4 core, B2OF2(corrole). From this reagent a mono-boron species, BF2(corrole) was also obtained. With dichlorophenylborane, several boron corrole complexes were prepared including PhB2O(corrole), PhB2(corrole) and B2Ph2H(corrole). The latter species was structurally characterised and the bridging hydride is proposed to form through a reductive coupling process. Use of N-methyl corrole effectively blocked one boron binding site and subsequently mono-boron corroles BF2(N-methyl- corrole), BPh(OH)(N-methyl corrole) and BPhF(N-methyl corrole) were prepared in good yields. The reaction of lithiated corrole and dichloroplenylborane afforded B2Ph2Cl(corrole). Overall, several new boron corrole species were prepared, significantly extending the library of known boron complexes with ligands related to the porphyrin system.

京都大学 / 新制・課程博士 / 博士(理学) / 甲第23021号 / 理博第4698号 / 新制||理||1674(附属図書館) / 京都大学大学院理学研究科化学専攻 / (主査)准教授 齊藤 尚平, 教授 時任 宣博, 教授 依光 英樹 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

Résumé Ce travail de thèse en cotutelle a été réalisé à l’Institut de Chimie Moléculaire de l’Université de Bourgogne (France) ainsi qu’au département de Chimie de l’Université de Sherbrooke (Québec). Ces travaux sont consacrés à la modification de la structure des BODIPY en vue d'une application in vivo pour l'imagerie bimodale optique/TEP ou TEMP. Ces modifications concernent l'hydrosolubilisation des fluorophores, mais aussi le décalage des domaines d’absorption et d’émission vers la fenêtre thérapeutique, zone dans laquelle la lumière est moins atténuée par les tissus biologiques. Des solutions permettant la bioconjugaison des fluorophores sur un dérivé de la bombésine, peptide permettant de cibler des récepteurs membranaires surexprimés dans certains types de cellules cancéreuses, sont également présentées. Enfin, une stratégie d’introduction d’un radioélément sur le BODIPY est décrite. Elle implique l’introduction sur l’atome de bore d’un groupe partant permettant sa radiofluoration. Différents dérivés de BODIPY ont également été utilisés pour la construction d’édifices multichromophoriques à transfert d’énergie. Ces travaux sont décrits dans la seconde partie de cette thèse. Ils comprennent notamment des études photophysiques permettant de mettre en évidence le transfert d’énergie photoinduit donneur-accepteur entre différents chromophores Dans les différents système élaborés, de type BODIPY-pophyrine et BODIPY-corolle, le BODIPY est alternativement donneur, ou accepteur d’énergie.

Résumé Ce travail de thèse en cotutelle a été réalisé à l’Institut de Chimie Moléculaire de l’Université de Bourgogne (France) ainsi qu’au département de Chimie de l’Université de Sherbrooke (Québec). Ces travaux sont consacrés à la modification de la structure des BODIPY en vue d'une application in vivo pour l'imagerie bimodale optique/TEP ou TEMP. Ces modifications concernent l'hydrosolubilisation des fluorophores, mais aussi le décalage des domaines d’absorption et d’émission vers la fenêtre thérapeutique, zone dans laquelle la lumière est moins atténuée par les tissus biologiques. Des solutions permettant la bioconjugaison des fluorophores sur un dérivé de la bombésine, peptide permettant de cibler des récepteurs membranaires surexprimés dans certains types de cellules cancéreuses, sont également présentées. Enfin, une stratégie d’introduction d’un radioélément sur le BODIPY est décrite. Elle implique l’introduction sur l’atome de bore d’un groupe partant permettant sa radiofluoration. Différents dérivés de BODIPY ont également été utilisés pour la construction d’édifices multichromophoriques à transfert d’énergie. Ces travaux sont décrits dans la seconde partie de cette thèse. Ils comprennent notamment des études photophysiques permettant de mettre en évidence le transfert d’énergie photoinduit donneur-accepteur entre différents chromophores Dans les différents système élaborés, de type BODIPY-pophyrine et BODIPY-corolle, le BODIPY est alternativement donneur, ou accepteur d’énergie.

Catalytic oxidation plays a crucial role in current chemical and pharmaceutical industries which is also a leading technology for green chemical processes. In Nature, the ubiquitous cytochrome P450 enzymes can catalyze a wide variety of oxidation reactions with high efficiency and selectivity. Many transition metal catalysts are designed as the biomimetic model of cytochrome P450 enzymes. In this work, series of metalloporphyrins and metallocorroles have been successfully synthesized to investigate and develop catalytic selective oxidation of sulfides to sulfoxides. Manganese(III) porphyrin complexes (2) and manganese(III) corrole complexes (6) with iodobenzene diacetate [PhI(OAc)2] as a mild oxygen source exhibited remarkable catalytic activity toward selective oxidation of sulfides to sulfoxides under mild conditions. Conspicuous is the fact that readily soluble PhI(OAc)2 in the presence of a small amount of water is more efficient than the commonly used PhIO and other oxygen sources under identical conditions. It was found that the reactivity of manganese(III) porphyrin catalysts was greatly affected by axial ligand and the weakly binding chlorate gave the highest catalytic activity in the oxidation of sulfide. Both porphyrin-manganese and corrole-manganese catalysts catalyzed the highly selective oxidation of para-substituted thioanisoles with PhI(OAc)2 in the presence of a small amount of water. Complete conversion and of sulfide and excellent selectivities for sulfoxide were achieved within 120 min. We discovered that photo-disproportionation of a bis-porphyrin-diruthenium(IV)- μ-oxo dimer gave a porphyrin-ruthenium(III) species and a putative poprhyrinruthenium( V)-oxo species that can be detected and studied in real time using laser flash photolysis methods. As determined by its spectral and kinetic behavior, the same oxo transient was also formed by photolysis of a porphyrin-ruthenium(III) N-oxide adduct. Second-order rate constants for reactions with several substrates at 22 °C were determined; representative values of rate constants were kox = 6.6 × 103 M-1 s-1 for diphenylmethanol, kox = 2.5 × 103 M-1 s-1 for styrene, and kox = 1.8 × 103 M-1 s-1 for cyclohexene.