京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第19725号 / 工博第4180号 / 新制||工||1645(附属図書館) / 32761 / 京都大学大学院工学研究科材料化学専攻 / (主査)教授 松原 誠二郎, 教授 中尾 佳亮, 教授 杉野目 道紀 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第21779号 / 工博第4596号 / 新制||工||1716(附属図書館) / 京都大学大学院工学研究科材料化学専攻 / (主査)教授 松原 誠二郎, 教授 中尾 佳亮, 教授 杉野目 道紀 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

No description available.

Photoredox catalysis applications for the purpose of new synthetic routes in organic and sustainable chemistry are hot topics in organic synthesis today. In the present study, the synthesis of a chiral proline-based organocatalyst functionalized with 10-phenyl-10H phenothiazine (PTH) photocatalytic moietiesis investigated and attempted for the first time. PTH, an organic photocatalyst, isstudied for its photocatalytic activity in different organic reactions, such as dehalogenation of aromatic halides and the pinacol coupling reaction between aromatic aldehydes. These transformations are otherwise difficult to achieve without a suitable catalyst and the reactions were performed with moderate to high yields. / Applikationer av photoredox-katalys med syftet att generera nya syntetiska vägar inom organisk och hållbar kemi är populära ämnen i organisk syntes idag. I denna studien undersöktes för första gången syntesen av en kiral prolinbaserad organokatalysator som är funktionaliserad med fotokatalytiska enheter (10-fenyl-10H-fenotiazin (PTH)). Den fotokatalytiska aktiviteten av PTH studerades för olika organiska reaktioner, såsom t.ex. dehalogenering av aromatiska halider och pinacolkopplingar mellan aromatiska aldehyder. Dessa transformationer är annars svåra att uppnå utan en lämplig fotokatalysator och reaktionerna utfördes med måttliga till höga utbyten.

A new phosphineoxy aziridiniyl phosphonates POAP were synthesized as potential organocatalysts and used for silicon based asymmetric Abramov-type phosphonylation of aldehydes with triethyl phosphite. Besides POAP organocatalyst, known chiral phosphineoxy ferrocenyl substituted aziridinyl methanol (POFAM) and aziridinyl phosphonates (AP) were also used for the same reaction. The product &alpha / -hydroxy phosphonates were obtained in good yields up to 99% but with poor enantioselectivities. Highest enantioselectivity (%34) was obtained with POAP organocatalyst. Optimization studies were done with different solvents, ligands, aldehydes, and concentrations.

Three-dimensional (3D) printing has an important role for fabrication of degradable scaffoldsfor soft tissue regeneration. Among the 3D printing techniques, photopolymerization-based 3Dprinting is one of fastest growing, offering environmental benefits and high precision of 3Dobjects. In this approach, photocurable macromonomers/monomers are cross-linked layer bylayer in the presence of photoinitiators under visible or UV light to fabricate 3D designedobjects. However, a limited biomedical material selection has prevented it from spreading overclinical application. Furthermore, poly(ε-caprolactone), a common degradable polymer usedfor 3D printing, shows not satisfactory physical properties for soft tissue regeneration. Thedearth of materials with proper properties raises the need for novel degradable materials,which should be not only compatible for photopolymerization-based 3D printing but alsosuitable for soft and gel-like scaffold fabrication. Here, the aim was to design photocurable macromonomers consisting of oligo(ε-caprolactoneran-p-dioxanone), oCLDX, with acrylate chain-end groups. A metal-free synthetic strategy wasdeveloped for the bulk ring-opening of ε-caprolactone (CL) and p-dioxanone (DX) at roomtemperature using diphenyl phosphate (DPP) as organocatalyst and multifunctional initiators. The oligomers had low dispersity (<1.2) and targeted molecular weight around 2000 g mol-1.The random sequence and the control over chain growth of oCLDXs were confirmed byreactivity ratios using 1D and 2D NMR analysis. Kinetics study of co-oligomerizationdemonstrated that within DPP-catalysed reaction, DX possessed higher reactivity than CL andthe ring-opening co-oligomerization followed an activated monomer mechanism (AMM). Thetopology of the co-oligomers could also be varied by using different alcohol initiators. The co-oligomers possessed lower degree of crystallinity than homopolymers of DX or CL and,depending on the composition, they were liquid at room temperature. The lower melting pointand gel-like appearance make them good candidates for photopolymerization-based 3Dprinting. The suitability toward photopolymerization was proven for the ethylene glycol-initiatedco-oligomer containing 30 mol% of DX. The cross-linked gels were soft but brittle and showedgood water uptake capacity. / Tredimensionell (3D)-utskrift har en viktig roll vid tillverkning av nedbrytbara matriser förregenerering av mjukvävnad. Bland 3D-utskriftteknikerna är fotopolymerisationsbaserad 3Dutskriften av de snabbast växande, och erbjuder miljöfördelar och hög precision hos 3Dobjekten.För att tillverka 3D-designade objekt med denna teknik är fotohärdandemakromonomerer/ monomerer tvärbundna lager på lager i närvaro av fotoinitiatorer och synligteller UV-ljus. Emellertid har ett begränsat urval av biomedicinska material hindrat tekniken frånatt spridas till kliniska applikationer. Vidare har poly(ε-kaprolakton), en vanlig nedbrytbarpolymer som används för 3D-utskrift, inte tillfredsställande fysikaliska egenskaper förregenerering av mjukvävnad. Bristen på material med rätt egenskaper ökar behovet av nyanedbrytbara material, som inte bara ska vara kompatibla för fotopolymerisationsbaserad 3Dutskriftutan också lämplig för mjuk och gelliknande matristillverkning.Här var syftet att designa fotohärdande makromonomerer bestående av oligo(ε-kaprolaktonsam-p-dioxanon), oCLDX, med akrylatkedjeändgrupper. En metallfri syntetisk strategiutvecklades för bulkringöppning av ε-kaprolakton (CL) och p-dioxanon (DX) vidrumstemperatur genom att använda difenylfosfat (DPP) som organisk katalysator ochmultifunktionella initiatorer. Oligomererna hade den förutbestämda molekylvikten, omkring2000 g mol-1, och en låg dispersitet (<1,2). Den slumpmässiga sekvensen och kontrollen avkedjans tillväxt, till oCLDX, bekräftades genom reaktivitetsförhållanden med hjälp av 1D och2D NMR-analys. Kinetikstudie av samoligomeriseringen visade att med DPP-katalyseradreaktion hade DX högre reaktivitet än CL och att den ringöppnande samoligomeriseringenföljde en aktiverad monomermekanism (AMM). Topologin hos samoligomererna kunde ocksåvarieras genom att använda olika alkoholinitiatorer. Samoligomererna hade lägre grad av kristallinitet än homopolymerer av DX eller CL ochberoende på kompositionen var de flytande vid rumstemperatur. Den lägre smältpunkten ochgelliknande utseendet gör dem till bra kandidater för fotopolymerisationsbaserad 3D-utskrift. Lämpligheten för fotopolymerisation bevisades för den etylenglykolinitierade samoligomerensom innehöll 30 mol% DX. De tvärbundna gelerna var mjuka men spröda och uppvisade godvattenupptagningskapacitet.

Notre étude porte sur le développement de réactions énantiosélectives organocatalysées de type aza-Morita-Baylis-Hillman (azaMBH). Nous avons commencé par synthétiser de nouveaux catalyseurs bifonctionnels dérivés de la β-isocupréidine. Nous avons ensuite utilisé ces catalyseurs pour mettre au point une version multi-composants monotope séquentielle de la réaction d’azaMBH à partir d’aldéhydes aliphatiques.Une méthode de synthèse efficace d’adduits d’azaMBH N-Boc protégés a ensuite été développée, à partir d’imines, d’amidosulfones, ainsi qu’en version multi-composants.Afin de mieux comprendre le processus réactionnel, nous nous sommes ensuite intéressés en détail aux études mécanistiques réalisées sur les réactions de MBH et d’azaMBH, avant de réaliser une étude de modélisation moléculaire avec le Dr Elise Tran.Puis nous avons utilisé des allènoates en tant qu’accepteurs de Michael, ce qui nous a conduit à la formation de deux produits : l’adduit d’azaMBH et une azétidine, issue d’une cyclisation [2+2]. Une nouvelle série d’organocatalyseurs dérivés de la quinidine ont alors été synthétisés, ce qui a permis de former exclusivement le produit azétidine avec d’excellents rendements et énantiosélectivités / This study is about the development of enantioselective, organocatalyzed aza-Morita-Baylis-Hillman’s type reactions (azaMBH). First, new bifunctionnal catalysts derived from the β-isocupreidin ewere synthetized. They were used to elaborate a one-pot multi-component aza-MBH reaction, involving aliphatic aldehydes.A new synthetic method for N-Boc protected azaMBH adducts has then been developed, starting from imines and amidosulfones.In order to better understand the transformation process, the mechanistic studies on the MBH and azaMBH reactions were examined. Then, we carried out a molecular modeling study with Dr Elise Tran.Finally, we disclosed abnormal aza-Baylis-Hillman reactions of imines with allenoates as Michael acceptors providing an easy access to azaMBH adducts and azetidines. A new series of organocatalysts derived from the quinidine was synthetized. Those were used to obtain exclusively the azetidine compounds, with excellent yields and enantioselectivities.

Chapter one; “(-)-Rhazinilam and (-)-Rhazinal: Alkaloids with Anti-mitotic Properties Derived from Kopsia teoi”, provides the background information behind the motives that initiated this research project. The plant alkaloid (-)-rhazinilam [(-)-1] and its naturally-occurring derivative (-)-rhazinal [(-)-13] both exhibit potent anti-mitotic activities and, as such, are interesting targets for total synthesis. Chapter one is a review of the literature regarding these two compounds and discusses the occurrence, proposed biosynthetic origins, structural elucidation and biological activites of compound (-)-1 and that of its analogues including alkaloid (-)-13. Previous total syntheses of these two compounds are then examined, concluding with the only reported total synthesis of compound (-)-13. Developed within the Banwell research group, this total synthesis produced the racemic modification of alkaloid (-)-13 due to a lack of any stereocontrol in the key intramolecular Michael addition step. This unprecedented key step, involving cyclisation of the C2 of pyrrole onto an N-tethered and ?,?-disubstituted acrylate to produce a quaternary-carbon stereogenic centre, would be of greatly enhanced utility if it could be achieved in a catalytic-enantioselective fashion. The realisation of this goal is the central aim of the research conducted within this thesis. ¶ Chapter two; “Investigating Asymmetric Induction in the Intramolecular Michael Addition of pyrrole to N-Tethered Acrylates and Related Species”, introduces the model study used to direct research towards achieving the goal of asymmetric induction in the title process. The model is a somewhat simplified version of the original process used in the total synthesis of compound (-)-13 involving cyclisation of the C2 of pyrrole onto an N-tethered and ?-monosubstituted Michael acceptor, to produce a tertiary-carbon stereogenic centre. This simplification allows the rapid synthesis of a broad range of potential substrates for use in the title process, thus enabling the investigation of various different approaches to inducing asymmetry therein. High levels of asymmetric induction are observed with the use of chiral substrates or catalysts, facilitating the synthesis of both 6- and 7-membered rings annulated to pyrrole with construction of the relevant tertiary-carbon stereogenic centre in enantio-enriched form. For the reactions producing a 6-membered ring annulated to pyrrole, unambiguous proof of the absolute sense of asymmetric induction observed in the intramolecular Michael addition event is established using a chemical correlation study involving elaboration of a key indolizine-type cyclisation product, to the plant alkaloid of known absolute stereochemistry, (-)-tashiromine [(-)-75]. For the reaction producing a 7-membered ring annulated to pyrrole, the same information is obtained via X-ray crystallographic analyses of a dibrominated derivative of a key pyrroloazepine-type cyclisation product. ¶ Chapter three “An Enantioselective Total Synthesis of the Alkaloid (-)-Rhazinal: An Anti-mitotic Agent Isolated from Kopsia teoi.”, focuses on the application of methodology developed in the previous chapter, to the original goal of inducing asymmetry in the intramolecular Michael addition reaction, involving cyclisation of the C2 of pyrrole onto an N-tethered and ?,?-disubstituted acrylate to produce a quaternary-carbon stereogenic centre. This is ultimately achieved in a catalytic-enantioselective fashion, resulting in the first such total synthesis of the anti-mitotic alkaloid (-)-rhazinal [(-)-13]. ¶ Chapter four “Extending the Reaction Manifold to the Syntheses of Related Natural Products: A Formal Total Synthesis of (+)-Aspidospermidine and Syntheses of (-)-Rhazinilam and (-)-Leuconolam from (-)-Rhazinal”, describes three extensions to the reaction manifold used in the enantioselective total synthesis of alkaloid (-)-13: The acquisition in an enantioselective manner, of an intermediate previously obtained in racemic form, en route to the racemic modification of the natural product (±)-aspidospermidine [(±)-134], constitutes a formal and enantioselective total synthesis of (+)-aspidospermidine [(+)-134]. The direct deformylation of (-)-rhazinal [(-)-13], is carried out, to produce the parent alkaloid (-)-rhazinilam [(-)-1]. The pyrrole ring present in (-)-rhazinilam [(-)-1] is oxidised, to produce the related natural product (-)-Leuconolam [(-)-12] which has not, hitherto, been prepared by total synthesis. ¶Chapter five contains the experimental procedures and characterisation data associated with compounds described in chapters two to four.

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The aim of this D.Phil was to develop a range of cyclisation cascades, which initially form a reactive iminium intermediates that can then be attacked by a pendant nucleophile resulting in novel polycyclic structures. This concept has been applied to the development of three methodologies and has resulted in the discovery of new reactivity as well as the synthesis of a wide range of interesting novel structures <b>Chapter 1: Enantioselective chiral-BINOL-phosphoric acid catalysed reaction cascade</b> A highly enantioselective hydroamination / N-sulfonyliminium cyclisation cascade using a combination of Au(I) and chiral phosphoric acid catalysts has been developed. Proceeding by an initial 5-exo-dig hydroamination and a subsequent phosphoric acid catalysed Pictet- Spengler cyclisation, the reaction provides access to complex sulfonamide scaffolds in excellent yields and with high levels of enantiocontrol. The scope can be extended to lactam derivatives, with excellent yields and enantiomeric excesses of up to 93&percnt; ee. <b>Chapter 2: Iridium catalysed nitro-Mannich cyclisation</b> A new chemoselective reductive nitro-Mannich cyclisation reaction sequence of nitroalkyltethered lactams has been developed. An initial rapid and chemoselective iridium(I) catalysed reduction of lactams to the corresponding enamine is subsequently followed by intra molecular nitro-Mannich cyclisation. This methodology provides direct access to important alkaloid, natural product-like structures in yields up to 81&percnt; and in diastereoselectivities that are typically good to excellent. An in-depth understanding of the reaction mechanism has been gained through NMR studies and characterisation of reaction intermediates. The new methodology has been applied to the total synthesis of (&plusmn;)-epi-epiquinamide in 4 steps. <b>Chapter 3: Iridium catalysed reductive interrupted Pictet-Spengler cyclisation</b> A novel reductive interrupted Pictet-Spengler cyclisation reaction cascade has been created. An iridium(I) catalyzed partial reduction of lactams/amides to the corresponding iminium is subsequently trapped by a pendant indole nucleophile. Interruption of the Pictet-Spengler reaction by indolium reduction provides a wide range of novel spirocyclic indoline moieties in excellent yield and diastereoselectivity.