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京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第20388号 / 工博第4325号 / 新制||工||1670(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 吉田 潤一, 教授 中尾 佳亮 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

The last decade has been marked by a large increase of demand for green chemistry processes. Consequently, chemists have focused their efforts on the development of more direct routes toward different classes of targets. In that regard catalysis has played a crucial role at enabling key bond formations that were otherwise inaccessible or very energy and resources consuming. The central theme of this body of work concerns the formation of C–N bonds, either through transition metal catalysis or organocatalysis. These structural units being highly recurrent in biologically active molecules, the establishment of more efficient routes for their construction is indispensable. The first part of this thesis describes a new method for the synthesis of isoquinolines from the oxidative coupling/annulation of alkynes with N-tert-butyl benzaldimines via Rh(III) catalysis (Chapter 2). Preliminary mechanistic investigations of this system pointed to the involvement of Rh(III) in the C–H bond cleavage step as well as in the C–N bond reductive elimination that provides the desired heterocycle. Following this oxidative process, a Rh(III)-catalyzed redox-neutral approach to isoquinolones from the reaction of benzhydroxamic acids with alkynes is presented (Chapter 3). The discovery that an N–O bond contained in the substrate can act as an internal oxidant was found to be very enabling. Indeed, it allowed for milder reaction conditions, broader scope (terminal alkyne and alkene compatible) and low catalyst loadings (0.5 mol%). Mechanistic investigations on this system were also conducted to identify the nature of the C–N bond formation/N–O bond cleavage as well as the rate-determining step. The second part of this work presents mechanistic investigations performed on a recently developed intermolecular hydroamination reaction catalyzed through tethering organocatalysis (Chapter 4). This transformation operates via the reversible covalent attachment of two reactants, a hydroxylamine and an allylamine, to an aldehyde catalyst by the formation of a mixed aminal. This allows a difficult intermolecular Cope-type hydroamination to be performed intramolecularly. The main kinetic parameters associated with this reaction were determined and they allowed the generation of a more accurate catalytic cycle for this transformation. Attempts at developing new families of organocatalysts are also discussed.

The last decade has been marked by a large increase of demand for green chemistry processes. Consequently, chemists have focused their efforts on the development of more direct routes toward different classes of targets. In that regard catalysis has played a crucial role at enabling key bond formations that were otherwise inaccessible or very energy and resources consuming. The central theme of this body of work concerns the formation of C–N bonds, either through transition metal catalysis or organocatalysis. These structural units being highly recurrent in biologically active molecules, the establishment of more efficient routes for their construction is indispensable. The first part of this thesis describes a new method for the synthesis of isoquinolines from the oxidative coupling/annulation of alkynes with N-tert-butyl benzaldimines via Rh(III) catalysis (Chapter 2). Preliminary mechanistic investigations of this system pointed to the involvement of Rh(III) in the C–H bond cleavage step as well as in the C–N bond reductive elimination that provides the desired heterocycle. Following this oxidative process, a Rh(III)-catalyzed redox-neutral approach to isoquinolones from the reaction of benzhydroxamic acids with alkynes is presented (Chapter 3). The discovery that an N–O bond contained in the substrate can act as an internal oxidant was found to be very enabling. Indeed, it allowed for milder reaction conditions, broader scope (terminal alkyne and alkene compatible) and low catalyst loadings (0.5 mol%). Mechanistic investigations on this system were also conducted to identify the nature of the C–N bond formation/N–O bond cleavage as well as the rate-determining step. The second part of this work presents mechanistic investigations performed on a recently developed intermolecular hydroamination reaction catalyzed through tethering organocatalysis (Chapter 4). This transformation operates via the reversible covalent attachment of two reactants, a hydroxylamine and an allylamine, to an aldehyde catalyst by the formation of a mixed aminal. This allows a difficult intermolecular Cope-type hydroamination to be performed intramolecularly. The main kinetic parameters associated with this reaction were determined and they allowed the generation of a more accurate catalytic cycle for this transformation. Attempts at developing new families of organocatalysts are also discussed.

The last decade has been marked by a large increase of demand for green chemistry processes. Consequently, chemists have focused their efforts on the development of more direct routes toward different classes of targets. In that regard catalysis has played a crucial role at enabling key bond formations that were otherwise inaccessible or very energy and resources consuming. The central theme of this body of work concerns the formation of C–N bonds, either through transition metal catalysis or organocatalysis. These structural units being highly recurrent in biologically active molecules, the establishment of more efficient routes for their construction is indispensable. The first part of this thesis describes a new method for the synthesis of isoquinolines from the oxidative coupling/annulation of alkynes with N-tert-butyl benzaldimines via Rh(III) catalysis (Chapter 2). Preliminary mechanistic investigations of this system pointed to the involvement of Rh(III) in the C–H bond cleavage step as well as in the C–N bond reductive elimination that provides the desired heterocycle. Following this oxidative process, a Rh(III)-catalyzed redox-neutral approach to isoquinolones from the reaction of benzhydroxamic acids with alkynes is presented (Chapter 3). The discovery that an N–O bond contained in the substrate can act as an internal oxidant was found to be very enabling. Indeed, it allowed for milder reaction conditions, broader scope (terminal alkyne and alkene compatible) and low catalyst loadings (0.5 mol%). Mechanistic investigations on this system were also conducted to identify the nature of the C–N bond formation/N–O bond cleavage as well as the rate-determining step. The second part of this work presents mechanistic investigations performed on a recently developed intermolecular hydroamination reaction catalyzed through tethering organocatalysis (Chapter 4). This transformation operates via the reversible covalent attachment of two reactants, a hydroxylamine and an allylamine, to an aldehyde catalyst by the formation of a mixed aminal. This allows a difficult intermolecular Cope-type hydroamination to be performed intramolecularly. The main kinetic parameters associated with this reaction were determined and they allowed the generation of a more accurate catalytic cycle for this transformation. Attempts at developing new families of organocatalysts are also discussed.

A number of privileged starting materials based on aryl halide frameworks have emerged that allow access to a variety of different heterocyclic scaffolds through judicious choice of reaction conditions. This work describes efforts to develop and extend the utility of two of these general heterocycle precursors - ortho-(haloalkenyl)aryl halides A and α-(ortho-haloaryl) ketones B - in conjunction with cascade reactions involving the construction of key carbon-heteroatom bonds via palladium or copper catalysis. Chapter 1 entails an overview of the development of palladium- and copper-catalysed carbon-heteroatom bond forming processes. The application of these processes in heterocycle synthesis using ortho-(haloalkenyl)aryl halide and ortho-haloacetanilides/ α-(ortho-haloaryl) ketone precursors is also described. Chapter 2 focuses on the development of a two-step synthesis of cinnolines using ortho-(haloalkenyl)aryl halides via intermediate protected dihydrocinnoline derivatives C. Chapter 3 demonstrates how the inherent reactivity of protected dihydrocinnoline derivatives C can be harnessed to provide access to functionalised products. A brief target synthesis of a pharmaceutically-relevent cinnoline is also described. Chapter 4 details attempts to develop a novel synthesis of benzothiophenes D from both ortho-(haloalkenyl)aryl halide and α-(ortho-haloaryl) ketone precursors.

Les LIMKs sont deux protéines kinases responsables de la régulation de la dynamique du cytosquelette d’actine et des microtubules. Leur dérégulation peut jouer un rôle prépondérant dans l’apparition de certaines maladies telles que la neurofibromatose de type 1, le cancer ou la sclérose latérale amyotrophique.Au cours de ce projet collaboratif, nous avons cherché à concevoir des inhibiteurs à la fois puissants et sélectifs des LIMKs en nous inspirant du composé le plus performant de l’époque développé par Lexicon Pharmaceuticals.Nous avons, dans un premier temps, travaillé sur la base hétérocyclique en remplaçant la pyrrolo[2,3-d]pyrimidine par différentes pyridopyrimidines et une triazolopyridopyrimidine. Cette dernière modification a ouvert la voie à un sujet de méthodologie autour du réarrangement de Dimroth. Nous avons ensuite modifié le cycle central pipérazine par une 3,6-dihydropyridine ou une pipéridine différemment substituée et avons fait varier la substitution au niveau de l’arylurée. Enfin, nous sommes revenus apporter quelques modifications structurales à la pyrrolo[2,3-d]pyrimidine de départ.Finalement, nous avons créé, à l’aide de méthodologies de synthèse efficaces, un large panel de composés originaux qui ont été testés in vitro et in cellulo sur nos cibles.Au travers de ce projet de chimie médicinale, nous avons pu approfondir les relations structure-activité afin de concevoir des inhibiteurs des LIMKs très prometteurs. / LIMKs are two protein kinases involved in regulating cytoskeleton and microtubule actin dynamics. Their deregulation can play a major role in the onset of several diseases such as neurofibromatosis type 1, cancer or amyotrophic lateral sclerosis.During this collaborative project, we have sought to design both potent and selective LIMKs inhibitors based on one of the most efficient compounds of the day developed by Lexicon Pharmaceuticals.We first worked on the heterocyclic base by replacing the pyrrolo[2,3-d]pyrimidine by different pyridopyrimidines and a triazolopyridopyrimidine. This last modification lead to a directed synthetic methodology study around the Dimroth rearrangement. We then modified the piperazine central ring with a differently substituted 3,6-dihydropyridine or piperidine and varied the substitution at the arylurea. Lastly, we made some further structural changes to the starting pyrrolo[2,3-d]pyrimidine.In conclusion, we have created, using effective synthetic methodology, a wide range of original compounds that have been tested in vitro and in cellulo on our targets.Through this medicinal chemistry project, we now have a better understanding of the structure-activity relationships needed in order to design very promising LIMK inhibitors.