Pyranonaphthoquinone lactones have been recently found to be selective inhibitors of the serine-threonine kinase AKT/PKB. AKT/PKB plays a major role in tumorigenesis, hence these compounds have a great potential to act as anti-cancer agents. They act by a novel bioreductive alkylation mechanism of inhibition of AKT/PKB. In this work, 7-deoxykalafungin, a pyranonaphthoquinone lactone and its deconstruction analogs were synthesized. The structural features of the compounds necessary to inhibit AKT1 potently and selectively were determined. It was observed that compounds with a pyran ring were more potent in inhibiting AKT1. Conversely, flexible compounds were found to be weak inhibitors of AKT1. Also, presence of a lactone ring was found to be favorable in inhibiting AKT1. Of the compounds tested, 7-deoxykalafungin was the most potent inhibitor of AKT1 (IC50 = 0.28 µM against AKT1) and compound 4-61 was the most potent inhibitor of PKA (IC50 = 0.43 µM against PKA).

Plus de la moitié des médicaments mis sur le marché entre 1981 et 2014 sont des produits naturels ou des dérivés. Ainsi, les structures des produits naturels sont une excellente source d'inspiration pour la découverte de nouveaux médicaments. L'introduction de cette thèse met en lumière le rôle important joué par les produits naturels en chimie médicinale. De plus, la préparation de produits naturels peut déboucher sur le développement de nouvelles méthodes de synthèse. Ainsi, au cours de cette thèse une approche synthétique de plusieurs produits naturels a été réalisée. Ces composés présentent des motifs clés tels que des amino-alcools 1,3, des diamines 1,3 ou un tétrahydropyrane. Les études synthétiques réalisées comprennent le développement de nouvelles méthodes pour accéder à ces structures. D'autre part, une réaction de Heck permettant l'accès à des précurseurs de tri-aryl éthylènes a été mise au point. / It has been estimated that more than half of all approved drugs, from the period 1981 to 2014, are either natural products or their derivatives. This, thus, indicates that natural products (NP), together with natural product derived and natural product inspired structures are significant as sources for potential leads towards the discovery of new drugs. The introduction of this thesis thereby highlights the importance of natural products in the field of drug discovery. In addition, the introduction emphasizes on the importance of natural products as a field of research. This is as the synthesis of natural products can result in the development of new synthetic methods which can then be applied to a broader range of applications across the field of chemistry. This new information, thus, bridges a gap in the scientific knowledge and allows for progress in science. Therefore the content of this thesis describes the syntheses and development of new synthetic methods towards bioactive natural products containing 1,3-amino alcohol, 1.3-diamine, THP-ring as well as tri-aryl ethylene unit which represent the key themes of (+)-negamycin (Chapter 1), (-)-cernuine and (+)-cermizine D (Chapter 2), enigmazole A (Chapter 3) and tamoxifen (Chapter 4), respectively.

<p>The palladium-catalysed Heck-reaction has been utilised in organic synthesis, where the introduction of aryl groups at the internal, β<i>-</i>carbon of different allylic substrates has been achieved with high regioselectivity.</p><p>The β<i>-</i>stabilising effect of silicon enhances the regiocontrol in the internal arylation of allyltrimethylsilane, while a coordination between palladium and nitrogen induces very high regioselectivities in the arylation of <i>N,N-</i>dialkylallylamines and the Boc-protected allylamine, producing β-arylated arylethylamines, which are of interest for applications in medicinal chemistry. Phthalimido-protected allylamines are arylated with poor to moderate regioselectivity.</p><p>Single-mode microwave heating can reduce the reaction times of Heck-, Stille- and radical mediated reactions drastically from approximately 20 hours to a few minutes with, in the majority of cases, retained, high regioselectivity.</p><p>The use of heavily fluorinated tin reagents, which proved to be unreactive under thermal heating, is shown to be applicable with microwave-heating and the high fluorous content of the products is utilised with the aim of improving and simplifying the work-up procedure.</p>

Palladium-catalysed coupling reactions have been embraced by synthetic chemists as one of the preferred means for smooth formation of new carbon-carbon bonds: a truly ubiquitous methodology of synthesizing complex molecules. This thesis describes the study of a series of palladium(0)-catalysed C2-arylations of a 1-cyclopentenyl ether, equipped with a chiral (S)-N-methyl-pyrrolidine auxiliary. The investigated olefin was demonstrated to undergo Si-face insertion, providing (R)-configuration of the arylated C2-carbon. In addition, the mild and novel palladium(II)-catalysed dominoHeck/Suzuki β,α-diarylation-reduction of a dimethylaminoethyl-substituted chelating vinyl ether was developed using arylboronic acids as arylating agents in combination with 1,4-benzoquinone (BQ). Further, highly regioselective palladium(II)-catalysed α-and β-monoarylation of the chelating vinyl ether was achieved using either a bidentate ligand or by employing ligand-less conditions. These studies demonstrate that the choice of ligands has a profound effect on the reaction outcome, as productive β,α-diarylation could only be obtained by suppressing the competing β-hydride elimination using BQ as the stabilising ligand and terminal reoxidant. The pivotal role of BQ in the reaction was studied using computer-aided density functional theory calculations. The calculations highlight the crucial role of BQ as a Pd(II)-ligand. In addition of serving as an oxidant of palladium, the calculations support the view that the coordination of BQ to the Pd(II)-centre in the key σ-alkyl complex leads to a low-energy pathway, aided by a strong η2 Pd-BQ donation-back-donation interaction. Furthermore, an investigation of the scope and limitations of novel stereoselective and BQ-mediated palladium(II)-catalysed domino Heck/Suzuki β,α-diarylation reactions, involving metal coordinating cyclic methylamino vinyl ethers and a number of electronically diverse arylboronic acids, conducted. In addition, a set of 4-quinolone-3-carboxylic acids, structurally related to elvitegravir and bearing different substituents on the condensed benzene ring, was designed and synthesized as potential HIV-1 integrase inhibitors. Finally, in an effort to identify a new class of HIV-1 protease inhibitors, four different stereopure β-hydroxy γ-lactam-containing inhibitors were synthesized, biologically evaluated, and co-crystallized with the enzyme. / The time 12:05 for the public defense mentioned in the thesis is incorrect. It will take place at 09:15, 2012-06-08.

The palladium-catalysed Heck-reaction has been utilised in organic synthesis, where the introduction of aryl groups at the internal, β-carbon of different allylic substrates has been achieved with high regioselectivity. The β-stabilising effect of silicon enhances the regiocontrol in the internal arylation of allyltrimethylsilane, while a coordination between palladium and nitrogen induces very high regioselectivities in the arylation of N,N-dialkylallylamines and the Boc-protected allylamine, producing β-arylated arylethylamines, which are of interest for applications in medicinal chemistry. Phthalimido-protected allylamines are arylated with poor to moderate regioselectivity. Single-mode microwave heating can reduce the reaction times of Heck-, Stille- and radical mediated reactions drastically from approximately 20 hours to a few minutes with, in the majority of cases, retained, high regioselectivity. The use of heavily fluorinated tin reagents, which proved to be unreactive under thermal heating, is shown to be applicable with microwave-heating and the high fluorous content of the products is utilised with the aim of improving and simplifying the work-up procedure.

It is widely accepted that palladium is one of the most useful catalysts in organic chemistry, and many palladium(0)-catalysed carbon–carbon bond-forming reactions have been developed over the years. In addition, the ever-growing need for more environmentally benign processes in the chemical industry has driven scientists to look for greener options while developing new methodologies for organic synthesis. This thesis describes a series of studies on Suzuki and Heck coupling reactions in water and the application of palladium(0) catalysis to the development of new HIV-1 integrase inhibitors. The previously described 'transition-metal-free Suzuki-type coupling' reaction was shown to take place due to sub-ppm levels of palladium contaminants present in the commercially available sodium carbonate base. Based on this finding, a new, microwave-assisted Suzuki protocol utilizing ppb/ppm levels of palladium in water was developed. This methodology was adapted to terminal Heck coupling, although the scope of the protocol was found to be rather limited. Finally, both Suzuki and Heck reaction processes were successfully scaled up to 100 mmol using an automated batch stop-flow microwave apparatus. As the methodologies utilizing ultralow palladium concentrations were not applicable to aryl chlorides, attention was shifted towards palladium on carbon. This simple catalyst, together with microwave heating employing simultaneous cooling, was found to be beneficial in the Suzuki coupling of aryl chlorides with phenylboronic acid in water. Ligand-controlled internal arylation of ethylene glycol vinyl ether with aryl halides was shown to be possible in water alone without any additives. Reactions were run under air, using conventional heating and the products formed were isolated as aryl methyl ketones in good to excellent yields. The electron-rich (dippp)2Pd complex was shown to be beneficial for the microwave-assisted internal arylation of some aryl chlorides. Furthermore, the active role of the hydroxyl group of ethylene glycol vinyl ether in the formation of a cationic intermediate leading to internal Heck coupling product was elucidated. Finally, to demonstrate the usefulness of palladium(0) catalysis in the development of new pharmaceutical entities, a series of HIV-1 integrase inhibitors was synthesised and evaluated in strand transfer assays and in vitro. Based on the results and docking studies performed, valuable information related to the structure–activity relationship was obtained.

This thesis describes synthesis of new chiral N,P ligands and their evaluation in two types of asymmetric transition-metal catalyzed reactions. The first part of the thesis describes studies in iridium-catalyzed asymmetric hydrogenation. A new class of chiral N,P ligands, imidazole-phosphines, was synthesized and evaluated in the Ir-catalyzed asymmetric hydrogenation of olefins (Paper I). The new ligands proved to be highly efficient and enantioselective in the reaction. Because the substrate scope of Ir-catalyzed asymmetric hydrogenation is still limited to certain types of test substrates, new substrate classes with importance in medicinal and materials chemistry were investigated. Vinyl fluorides were efficiently hydrogenated to fluorine-containing chiral centers by the iridium catalysts with imidazole-phosphine ligands (Paper I). To obtain CF3-bearing chiral centers, we hydrogenated CF3-substituted olefins (Paper II). Ir-catalyzed asymmetric  hydrogenation was highly enantioselective for the functionalized CF3-substituted olefins and the resulting chiral products can be valuable in design of materials such as LCD screens. Ir-catalyzed asymmetric hydrogenation was also evaluated as a route to diarylmethine chiral centers (Paper III). A wide range of new chiral compounds possessing a diarylmethine chiral center was obtained. The second part of the thesis deals with asymmetric intermolecular Heck reaction utilizing N,P ligands. The N,P ligand class of thiazole-phosphines was evaluated in the Heck reaction (Paper IV) and gave high enantioselectivity. Further, the intermolecular Heck reaction was examined using computational and experimental studies (Paper V). This study led to a better understanding of the enantioselectivity in the reaction.

Sustainable chemical processes are becoming increasingly important in all fields of synthetic chemistry. Catalysis can play an important role in developing environmentally benign chemical processes, and transition metals have an important role to play in the area of green chemistry. In particular, palladium(II) catalysis includes many key features for successful green chemistry methods, as demonstrated by a number of eco-friendly oxidation reactions catalyzed by palladium(II). The aim of the work presented in this thesis was to develop novel and greener palladium(II)-catalyzed coupling reactions. In striving to achieve this aim, the first open-vessel, room-temperature palladium(II)-catalyzed oxidative Heck reaction, using oxygen from the air as the reoxidant of palladium, was developed. In a further investigation of the palladium(II)-catalyzed oxidative Heck reaction, base-free conditions for the transformation were identified and suitable conditions for microwave-assisted oxidative Heck reactions were established. A convenient and low-cost palladium(II)-catalyzed method for the synthesis of styrene derivatives, by coupling arylboranes with vinyl acetate, was developed. The reaction mechanism was studied using ESI-MS, which enabled the detection of cationic palladium intermediates in ongoing productive reactions, and a plausible catalytic cycle was proposed. In an attempt to make the oxidative Heck and the styrene synthesis reactions more attractive from an industrial point of view, conditions for continuous flow synthesis were identified. The results were generally good and rapid synthesis of the desired products was obtained. The first palladium(II)-catalyzed C–P bond-forming Hirao-type reaction, employing arylboranes instead of the commonly used aryl halides, was developed. An ESI-MS study was performed, and a plausible catalytic pathway was suggested. Finally, a novel method for synthesizing aryl ketones from benzoic acids and nitriles, via palladium(II)-catalyzed decarboxylation of the benzoic acids, was established. Further, the reaction mechanism was studied by ESI-MS and a plausible catalytic route presented.

Im Rahmen der vorliegenden Arbeit wurden Studien zur Modifizierung und Immobilisierung mono- und bidentater Ferrocenylphosphane an Carbosilan-Trägermolekülen durchgeführt. Erstere wurden in die entsprechenden (p-Cymen)RuCl2-Komplexe überführt und als (Prä)Katalysatoren für die Oxopropylester-Synthese eingesetzt. Dabei wurden sowohl der Einfluss unterschiedlicher Ferrocenylphosphan-Liganden als auch der Effekt der Immobilisierung auf die katalytische Umsetzung herausgearbeitet. Im Weiteren konnte eine neuartige Klasse funktionalisierter zweizähniger Diphosphane des dppf-Typs erschlossen und ihre Identität eindeutig belegt werden. Geeignete Vertreter dieser Verbindungsklasse wurden wie die entsprechenden monodentaten Ferrocenylphosphane an Carbosilan-Grundgerüste angebunden und, nach Überführung in die entsprechenden PdCl2-Komplexe, als (Prä)Katalysatoren für Heck-Kreuzkupplungsreaktionen verwendet. Auch hier konnte der Effekt der Immobilisierung sowie der Einfluss der unterschiedlichen Phosphanliganden auf die katalytische Reaktion ermittelt werden. Abschließend wurden Untersuchungen zur Verwendung monomerer Mesitylphosphan-substituierter Ferrocenyldiphosphane als Liganden in der Heck-Reaktion unterschiedlicher Arylhalogenide mit Acrylaten zu den entsprechenden Zimtsäureestern durchgeführt. Zur Bestimmung der katalytischen Leistungsfähigkeit wurde neben Reaktionstemperaturen und Katalysatorkonzentrationen insbesondere die verwendete Halogenkomponente variiert.

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