Le sujet de cette thèse porte sur la synthèse d'inhibiteurs spécifique de la Sérine-Thréonine phosphatase I (PP1). Un criblage de la chimiothèque de l'institut Curie, réalisé par l'équipe du Dr. Popov a permis d'identifier une 3-aryl-1(2H)isoquinolone, qui perturbe la dynamique des microtubules et qui s’est ensuite avéré être un inhibiteur sélectif de PP1. Dans une première partie, nous avons mis au point une nouvelle méthodologie de synthèse de ces composés hétérocycliques par une réaction tandem d’aminocarbonylation-cyclisation pallado catalysée. L’étude d’une seconde voie de synthèse de ces composés a été étudié par réaction d'arylation direct d'une 1(2H)isoquinolone. Dans le but de trouver d’autres hit, ligand de cette phosphatase, nous avons tenté de développer un test de triple hybride chimique, en collaboration avec la société Hybrigenics. Ce test est basé sur l’interaction de notre inhibiteur hit avec la phosphatase PP1. Pour cela, nous avons synthétisé une sonde à partir de la molécule hit initiale. La deuxième partie a trait à un développement de chimie médicinal pour optimiser le hit initial. Des dérivés de très bonne sélectivité pour l’enzyme cible ont été préparés. / This PhD thesis deals with the synthesis of serine threonine phosphatase I (PPI) inhibitors. This project started with the screening of the Institut Curie’s Library carried out by Dr. Popov team. They identified a 3-aryl-1(2H)isoquinolone (hit molecule) which strongly disturbs the microtubules dynamics. In the first part, we designed an original methodology to prepare those heterocycles, though a tandem palladium catalyzed aminocarbonylation/cyclization reaction. Then, we studied the direct arylation reaction to obtain the desired scaffold. In collaboration with Hybrigenics, we synthesize a probe for a triple hybrid system, based on the specific interaction of the hit molecule with its target PPI. Thanks to this system, one could identify new inhibitors of the targeted phosphatase protein. Eventually, a library of isoquinolones derivatives was synthesized. During the invitro tests, some of those molecules proved to be very specific for the serine threonine phosphatase I.

The thesis is composed of three chapters. The aim of this thesis is to apply the novel dirhodium perfluorobutyrate-catalyzed intramolecular aromatic C-H insertion methodology to the enantioselective total synthesis of praziquantel and synthetic model studies on ecteinascidin 743, which belongs to the important tetrahydroisoquinoline family. The first introductory chapter deals with the biological significance and previous synthetic methodologies. Our novel methodology is based on dirhodium perfluorobutyrate-catalyzed intromolecular aromatic C-H insertion reaction, which is crucial in the pivotal carbon-carbon bond formation when constructing isoquinolone moiety, which is ubiquitous in numerous natural products of significant biological and pharmacological activities. The second chapter takes on the first enantioselective total synthesis of praziquantel, an antihelmintic drug. Praziquantel is used worldwide to treat schistosomiasis, which has tremendous impact on the global fight on this disease affecting 150 million people. We believe this is the first asymmetric total synthesis to date, which is distinct from previous racemic syntheses reported. We also shed light on the mechanistic aspect of this key reaction to rationalize the superb regioselectivity and stereoselectivity achieved. The third chapter explores the synthetic model studies on ecteinascidin 743, a tetrahydroisoquinolone family natural product with significant antitumor and antimicrobial activities. Several different synthetic routes were attempted, including the N-Methyl and the N-Boc routes, and the results achieved contributed significantly to our final synthetic plan of the target molecule.

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.

We use stepwise [3+3] annulation to prepare the asymmetric glutarimides, and then establish a new approach to isoquinolone skeleton starting from glutarimides via regioselective nucleophilic addition and ring-closing metathesis reaction. Finally, we applied this method to the synthetic studies toward (¡Ó)-Xylopinine.

ABSTRACT DEVELOPMENT OF NEW SYNTHETIC METHODOLOGIES FOR ISOQUINOLONE AND ISOINDOLINONE DERIVATIVES M&uuml / jde, Berk M.Sc., Department of Chemistry Supervisor: Prof. Dr. Metin Balci July 2010, 146 pages Due to the wide range of physiological activities, heterocycles containing nitrogen and oxygen have always attracted the interest of chemists. The objective of this research is to develop new synthetic routes to the synthesis of isoquinolone and isoindolinone derivatives starting from 2-(2-carboxyethyl)benzoic acid and homophthalic acid, respectively. The half ester produced from 2-(2-carboxyethyl)benzoic acid was an important key compound for the synthesis of new isoquinolone derivatives which are expected to be biologically active. The corresponding acyl azides and isocyanates were generatedwhich might be used as a precursors to construct a variety of isoquinolone derivatives. Transformation of acyl azides into urea derivatives followed by ring-closure under the basic conditions provided isoquinolones. Bromo- and methoxyhomophthalic acid derivatives were synthesized to increase in variety of isoindolinone derivative. Then corresponding anhydrides were generated to further reactions for synthesis of isoindolinone derivatives. Surprisingly, tetrazolinone derivatives are also formed by 1,3 dipolar cycloaddition. Whole products were conscientiously purified and characterized. In addition, the similar methodology which was used for the synthesis of isoquinolone derivatives, was applied to 2-(carboxymethyl)furan-3-carboxylic acid to synthesize new nitrogen and oxygen containing heterocycles.

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.

Le développement de plans synthétiques de molécules de complexité variable qui utilise des réactifs aisés d’accès et qui sont économes en atomes et en étapes est constamment au cœur des préoccupations du chimiste organicien pour accroître la diversité moléculaire de façon efficace et éco-responsable. La catalyse par les métaux de transition a permis de faire des progrès considérables dans la construction et la fonctionnalisation combinées d’hétérocycles d’intérêt à valeur ajoutée dans les sciences des produits naturels et les industries pharmaceutiques et phytosanitaires. Le principe synthétique consiste en l’enchaînement de processus standards élémentaires de transformations chimiques en un seul pot au sein de la sphère catalytique métallique. Un axe de progrès contemporain repose en particulier sur l’incorporation de processus de métallation catalytique de liaisons C-CO2H et C-H. Les travaux de thèse s’inscrivent dans ce jeune domaine de recherche initié au cours de la dernière décennie par plusieurs équipes de recherche dont celle de Jieping Zhu de l’école polytechnique fédérale de Lausanne compte parmi les pionnières et les plus actives. Ils ont visé notamment à implémenter consécutivement aux processus standards de carbopalladation intramoléculaire d’ortho-halogéno allénamides de Grigg de construction d’hétérocycles azotés très variés, d’une part des réactions d’allylation directe de la liaison C-H d’hétérocycles et d’énamides et d’autre part d’allylation décarboxylante d’acides propioliques. Après avoir évalué la réactivité des complexes pi-allypalladium conjugués à un atome d’azote dans la réaction, l’allylation directe de la laison C-H d’oxadiazoles et de 1,3-diazoles à fort caractère acide ainsi que des énamides, des séquences originales de construction et d’hétéroarylation combinées pallado-catalysées d’isoquinolinones et d’indoles ont été établies. Un protocole séquencé conduit en un seul pot et basé sur la génération in situ des allénamides, qui ne sont plus isolées, suivie de la réaction de construction et d’hétéroarylation combinées pallado-catalysée a ensuite été mis au point. Il a été exploité pour la préparation d’indoles, 1(2H)-isoquinoléïnones, isoquinoléïnes mais également des hétérocycles de taille supérieure, benzo-(2H)-azépine et benzo-(2H)-azocine intégrant des oxadiazoles et oxa(thia)zoles. Une première étude d’extension du concept synthétique a finalement été ciblée sur la construction et la propargylation combinée de la large gamme d’hétérocycles azotés obtenus précédemment en utilisant les acides propioliques comme partenaire de couplage. / The design of efficient and eco-friendly atom and step-economical synthetic plans of molecules using highly available starting materials is one of major objectives of organic chemist. Transition metal catalysis has allowed a bold step to build and functionalize consecutively, through a one-pot reaction, major nitrogen-containing heterocycles which are broadly present into numerous natural products, pharmaceutics and agrochemicals. The catalysis is based upon tandem inner-sphere elemental chemical transformations and one of major current challenge is to implement catalytic metallation of C-CO2H and C-H bonds. Involved in this young field of research initiated since the past decade from sevaral groups including pioneering and high active Jieping Zhu team of the Polytechnic School of Lausanne, the present study has been directed towards the design of innovative palladium-catalyzed domino Grigg nitrogen-containing heterocycles building through ortho-halogeno allenamides intramolecular carbopalladation process followed by direct C-H allylation of heterocycles and enamides or direct decarboxylative allylation of propiolic acids. After demonstrating the reactivity of nitrogen-conjugated pi-allypalladium complex in direct C-H allylation of acidic heterocycles, first palladium-catalyzed tandem build and heteroarylation of 1(2H)-isoquinoleinone and indole from ortho-halogeno allenamides was first envisaged. Efforts were next directed to the setting up of a one-pot protocol including in situ generation of allenamide followed by palladium-catalyzed domino building and functionalization of heterocycles. It was then hugely evaluated to the preparation of indole, 1(2H)-isoquinoleinones, isoquinolins as well as high-membred ring heterocycles such as benzo-(2H)-azepine and benzo-(2H)-azocine embedding with oxadiazoles and oxa(thia)zoles. An first extended synthetic concept towards the palladium-catalyzed tandem build and propargylation of nitrogen-containing heterocycles using sevral propiolic acids as coupling partners.

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