京都大学 / 新制・課程博士 / 博士(理学) / 甲第23029号 / 理博第4706号 / 新制||理||1675(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 加納 太一, 教授 依光 英樹, 教授 時任 宣博 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

京都大学 / 新制・課程博士 / 博士(工学) / 甲第23432号 / 工博第4887号 / 新制||工||1764(附属図書館) / 京都大学大学院工学研究科合成・生物化学専攻 / (主査)教授 杉野目 道紀, 教授 村上 正浩, 教授 大江 浩一 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

Radical reactions play central roles in regulating regional air quality and global climate. Some potentially important gas phase radical reactions are being investigated in this research project, including Cl reactions with acetone, butanone, 3-pentanone, pyridine, and dimethyl selenide (DMSe), HO2 complex formation and dissociation with formic and acetic acids, and reactive and non-reactive quenching of O(1D) by the potent greenhouse gases SO2F2, NF3, and SF5CF3. The involved radicals are generated by laser flash photolysis (LFP). Temporal profiles of either the radical reactant or a product are monitored in "real time" using atomic resonance fluorescence spectroscopy (RF), time-resolved UV-visible absorption spectroscopy (TRUVVAS), or tunable diode laser absorption spectroscopy (TDLAS), allowing kinetic and mechanistic information of these reactions to be obtained. These studies provide new knowledge of the investigated radical reactions and facilitate a better understanding of their significance in atmospheric chemistry.

Le squelette indolo[2,3-b]quinoléique est une cible synthétique attrayante car il est présent notamment dans la néocryptolépine, alcaloïde aux propriétés cytotoxiques et antipaludéennes. Nous proposons ici une approche originale pour accéder à ce tétracycle, qui combine dans une réaction radicalaire en cascade une cyclisation à un réarrangement de Smiles. La mise au point des conditions expérimentales et l'étude mécanistique de cette voie ont constitué le premier objectif de ce travail. Outre les produits attendus, les études structurales approfondies ont mis en évidence la formation de composés inédits résultant d'étapes radicalaires supplémentaires. En parallèle, l'application de la méthode à un substrat judicieusement fonctionnalisé a conduit au 3-(2'-aryl-N-alkylacétamido)oxindole, un intermédiaire clé vers le système indolo[2,3-b]quinoléique 6 et 11 disubstitué ciblé. / The indolo[2,3-b]quinoline ring system is an attractive synthetic target present in neocryptolepine, an antiplasmodial and cytotoxic alkaloid. We proposed an original pathway toward this squeleton, combining as key step a 5-exo-trig cyclisation to a Smiles rearrangement in a domino radical process. We first focused on scope and limitations studies and mechanistic investigations. Apart from the cyclised-rearranged products we isolated new original structures resulting from supplementary radical reactions. The application of the developed method to a conveniently functionalised substrate led to 3-(2'-aryl-N-alkylacetamido)indolinone, a key intermediate which was further converted to the aimed 6,11-disubstituted indolo[2,3-b]quinoline tetracycle.

Project I. Cinchona alkaloid-derived quaternary ammonium salts have been successfully used as phase-transfer catalysts, particularly in asymmetric alkylations. Our group applied this type of catalyst in the synthesis of β-hydroxy α-amino acids via aldol reactions and discovered that the Park-Jew catalyst afforded good yields and good enantiomeric excess of the syn diasteromers, but negligible diastereoselectivity. This project was therefore focused on the synthesis of novel cinchonidine-derived catalysts with the Park-Jew catalyst as the lead structure. The C3 position of cinchonidine nucleus was modified to achieve dimers and catalysts possessing electron-deficient alkyne and alkene moieties. Synthesized catalysts were tested in the asymmetric aldol reactions, with some of them yielding improvements relative to the Park-Jew catalyst. Project II. Celogentin C is a natural product that was isolated from the seeds of Celosia argentea by Kobayashi in 2001. It is the most potent inhibitor of the polymerization of tubulin from among the celogentin family. The novel bicyclic octapeptide structure contains unusual linkages between leucine β-carbon and indole C-6 of tryptophan and between tryptophan indole C-2 and imidazole N-1 of histidine. The project culminated in the first total synthesis of celogentin C. Reaction conditions were developed by synthesizing the left-hand ring and the right-hand ring separately, and the total synthesis was accomplished via a left to right strategy. Key transformations in the construction included intermolecular Knoevenagel condensation, radical conjugate addition, macrolactamization, and oxidative coupling.

Chemoselektive Peptidfragmentverknüpfungsmethoden sind ein zentrales Element der chemischen Peptid- und Proteinsynthese. Auf der Suche nach einem „universellen Werkzeug für die Peptidligation“ wurde in den vergangenen zwei Jahrzenten eine Vielzahl unterschiedlicher Hilfsmolekülen (Auxiliare) entwickelt. Trotz des enormen Forschungaufwandes blieben bisher verfügbare Nα-Auxiliare jedoch in ihrer Anwendung auf glycinhaltige Ligationsstellen beschränkt. Im Fall der häufig verwendeten säurelabilen Nα-Auxiliare müssen zudem starke Säuren oder Supersäuren eingesetzt werden, um das Hilfsmolekül nach der Peptidligation zu entfernen. Dabei wurde häufig die Spaltung der zuvor aufgebauten Amidbindung als unerwünschte Nebenreaktion beobachtet. In der vorliegenden Arbeit wurde die Synthese von acht Nα-Auxiliaren erarbeitet und deren Anwendung in der erweiterten nativen chemischen Ligation untersucht. Dabei konnten sechs Hilfsmoleküle identifiziert werden, welche die Auxiliar-Abspaltung unter mild-basischen Bedingungen ermöglichten. Von besonderer Bedeutung war das 2-Mercapto-2-phenethyl-Grundgerüst, welches im Gegensatz zu bisher beschriebenen Nα-Auxiliaren erstmals den Zugang zu sterisch anspruchsvollen Verknüpfungstellen, jenseits von Glycin, gestattete. Der Nutzen des Auxiliars wurde in die chemische Totalsynthese zweier antimikrobieller Peptide demonstriert. Durch die Verwendung eines 13C-markierten Hilfsmoleküls konnte der Mechanismus der radikalischen Auxiliar-Abspaltungsreaktion in NMR-Experimenten detailliert untersucht werden. Zusätzlich wurde das 2-Mercapto-2-phenethyl-Auxiliar in einer neuen Methode der chemischen Proteinsynthese eingesetzt, welche die gewünschten Proteine ohne eine einzige HPLC-Reinigung in reiner Form lieferte. Im letzen Teil der Arbeit wurde mit dem 2-Selenol-2-phenethyl-Grundgerüst erstmals die Anwendung eines Selenol-funktionalisierten Nα-Auxiliars beschrieben. Das Hilfsmolekül ermöglichte besonders schnelle Verknüpfungsreaktionen und konnte zudem rasch mit hoher Selektivität entfernt werden. / Chemoselective ligation methods are an essential element of chemical peptide and protein synthesis. The search of a „universal tool for peptide ligation“ led to a range of different ligation auxiliaries over the last two decades. Despite the intense research in this field established Nα-auxiliaries remained limited to glycine-containing ligation sites. Furthermore, the application of frequently used acid-labile Nα-auxiliaries requires strong acids or superacids to remove the auxiliary after the ligation reaction. Under these harsh acidic conditions the cleavage of the established amide bond has been observed as an undesired side-reaction. This work describes the synthesis of eight Nα-auxiliaries and their application in extended native chemical ligation. Six helping molecules were identified enabling auxiliary cleavage under mild-basic conditions. Perhaps most important and in contrast to previously reported Nα-auxiliaries, the 2-mercapto-2-phenethyl group facilitated access to sterically demanding ligation sites, beyond glycine. The synthetic utility of the auxiliary was demonstrated by the chemical total synthesis of two antimicrobial peptides. The application of a 13C-labelled scaffold allowed a detailled study oft the radical auxiliary cleavage reaction by NMR-spectroscopy. Additionally, the 2-mercapto-2-phenethyl auxiliary was utilised for a novel method of chemical protein synthesis, which delivered the desired proteins without a single HPLC-purification in high purity. Finally, a selenol-functionalized Nα-auxiliary is described for the first time by introducing the 2-selenol-2-phenethyl mojety. This scaffold enabled execptionally rapid peptide ligations and is readily removed with high selectivity.