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Within the last few years, a significant contribution to the discovery of sp2C−H activation processes and useful applications for cross-coupling C−C bond formation has been achieved by the use of ruthenium(II) arene catalysts. The aim of this thesis is to describe a modular approach for the synthesis of several ruthenium(II) arene complexes with the potential for C−H activation. Another cutting-edge field, catalytic enantioselective functionalization of C−H bonds by transitional metal catalysts, has also been realized within the last few years. It represents a highly atom- and step-economic approach toward the generation of structural complexity. However, the majority of current methodologies rely on the usage of late third- row transition metals such as pallidum, iridium and rhodium. There is a need that motivates the search for cheaper, relative earth abundant metals that could have similar catalytic ability. Herein is also represented a preliminary study of a ruthenium(II)-catalyzed enantioselective access to chromane moiety enabled by chiral transient directing group.

In Michael J. Krische research group we are developing new transition metal catalyzed Carbon-Carbon (C-C) forming reactions focusing on atom economy and byproduct free, environmental friendly approaches. We have developed a broad family of C-C bond forming hydrogenations with relative and absolute stereocontrol which provide an alternative to stoichiometric organometallic reagents in certain carbonyl and imine additions. Inspiring from the group work my goal was to develop new reactions, extend the scope of our group chemistry and their application towards synthesis of biologically active natural products. I have been part of enantioselective Rh catalyzed Aldol reaction of vinyl ketones to different aldehydes. Also, we have found that iridium catalyzed transfer hydrogenation of allylic acetates in the presence of aldehydes or alcohols results in highly enantioselective carbonyl allylation under the conditions of transfer hydrogenative. Based on this reactivity a concise enantio- and diastereoselective synthesis of 1,3-polyols was achieved via iterative chain elongation and bidirectional iterative asymmetric allylation was performed, which enables the rapid assembly of 1,3-polyol substructures with exceptional levels of stereocontrol. The utility of this approach stems from the ability to avoid the use of chirally modified allylmetal reagents, which require multistep preparation, and the ability to perform chain elongation directly from the alcohol oxidation level. This approach was utilized for the total synthesis of (+)-Roxaticin from 1,3-propanediol in 20 longest linear steps and a total number of 29 manipulations. Further, advancements were made in iridium catalyzed C-C bond formation under transfer hydrogenation. While methallyl acetate does not serve as an efficient allyl donor, the use of more reactive leaving group in methallyl chloride compensate for the shorter lifetime of the more highly substituted olefin π-complex. Based on this insight into the requirements of the catalytic process, highly enantioselective Grignard-Nozaki-Hiyama methallylation is achieved from the alcohol or aldehyde oxidation levels. Also, a catalytic method for enantioselective vinylogous Reformatsky- type aldol addition was developed in which asymmetric carbonyl addition occurs with equal facility from the alcohol or aldehyde oxidation level. Good to excellent levels of regioselectivity and uniformly high levels of enantioselectivity were observed across a range of alcohols and aldehydes. / text

This thesis describes the development and mechanistic studies of carbocyclization reactions of allene-substituted olefins and 1,3-dienes, catalyzed by palladium(0) and palladium(II). These reactions results in the formation of [n,3,0] bicyclic systems (n = 3-5) with high stereoselectivity and in good to excellent yields. The first carbocyclization presented is a novel palladium(0)-catalyzed cyclo- isomerization of allene-substituted olefins. Secondly an efficient aerobic biomimetic system has been developed for a Pd(II)-catalyzed allylic oxidative carbocyclization of allene-substituted olefins. Additionally, during the studies of palladium-catalyzed carbocyclizations of allene-substituted olefins, it was found that in the absence of palladium a mild thermal ene-reaction occurs. In this manner stereodefined, functionalized bicyclic compounds are obtained with good regioselectivity and in high yields. The third and fourth carbocyclization developed are a palladium(II)-catalyzed oxidation and a palladium(0)-catalyzed intramolecular telomerization of allene-substituted 1,3-dienes. A mechanistic study of the palladium(II)-catalyzed oxidation of allene-substituted 1,3-dienes was made, and reaction intermediates could be isolated. The stereochemistry of the reaction intermediates was assigned, and this made it possible to suggest a mechanism for the reaction. The presented mechanism is a trans carbopalladation of the 1,3-diene, where the allene act as the carbon nucleophile. Due to different stereochemical outcomes of the stoichiometric and catalytic reactions, this mechanism could only explain the stoichiometric reaction. Another mechanism for the catalytic reaction was suggested, which rationalizes both the regio- and stereochemistry of the products.

N-phenylpyridin-2-amine , treated with stochiometric amount of palladium(II) acetate in dichloromethane at 65-70¢J for 4 h, to give high yield palladacycle 53. The reaction of palladacycle 53 with potassium aryltrifluoroborates in 1,4-dioxane at 140¢J for 24 h, could give a variety of N-(2-pyridinyl)carbazoles 55a-55m via sequential C-H bond activation. Carbazole derivative 55a reacted with irdium chloride gave iridium dimer, which followed by addition of picolinic acid via ligand exchange will form iridium complexes, which can further be utilized as OLEDs materials.

Under the conditions of transfer hydrogenation utilizing chromatographically purified ortho-cyclometallated iridium C,O-benzoate precatalysts, enantioselective carbonyl crotylation and methallylation can be performed in the absence of stoichiometric metallic reagents and stoichiometric chiral modifiers. In the case of carbonyl crotylation, use of a preformed precatalyst rather than an in situ generated catalyst results in lower reaction temperatures, providing generally higher diastereoselectivity and yields. By utilizing a more reactive leaving group in chloride over acetate on our methallyl donor, the inherently shorter lifetime of the olefin π-complex is compensated for, giving our group’s first report of reactivity utilizing 1,1-disubstituted allyl donors. / text

Esta tesis doctoral se centró en la síntesis y la caracterización de nanopartículas metálicas (Pd, Ni, Pt) estabilizadas por varios tipos de ligandos y el uso de estas nanopartículas en reacciones de formación de nuevos C-C o C-heteroatomo: a) Reacción de substitución alílica catalizadas por Pd; b) Reacción de acoplamiento asimétrico de Suzuki-Miyaura; c) Reacción de acoplamiento de Suzuki-Miyaura; d) reacción de adición 1,4 de ácidos borónicos a cetonas. En cada una de estas reacciones se llevó a cabo la síntesis y caracterización de nanoparticulas metálica y complejos moleculares usando muchos tipos de ligandos en los sistemas moleculares y los sistemas análogos cataliazados por nanopartículas. Excelentes actividades y enatioselectividades fueron obtenidas en la reacción de alquilación y aminación alílica. Además, estos sistemas fueron reciclados usando líquidos iónicos. También, nuevos y selectivas nanoparticulas fueron sintetizadas y caracterizadas. Estas nanopartículas fueron usadas exitosamente en varias reacciones de formación de nuevos enlaces C-C. / This doctoral thesis focuses on the synthesis and characterization of metal nanoparticles (Pd, Ni, Pt) stabilized by several types of ligands and the used of these nanoparticles in new C-C or C-heteroatom bond formation reactions: a) Pd-catalysed asymmetric allylic substitution reactions; b) Pd-catalysed asymmetric Suzuki-Miyaura coupling reactions; c) Ni-catalysed Suzuki-Miyaura coupling reactions; d) Pt-catalysed 1,4-addition of phenylboronic acid to 2-cyclohexen-1-one reaction. For each reaction, the synthesis and characterization of metal nanoparticles and molecular complexes using several types of ligands were performed and both types of catalytic systems were tested in the appropriate reactions. Remarkably, excellent enantioselectivities using Pd/phosphite ligand were obtained in allylic substitution reaction. An efficient recovery of the catalytic system was carried out using ionic liquids as reaction medium. New active and selective nanoparticles were synthesized and characterized. These nanoparticles were applied successfully in various C-C bond formation reactions.

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Diverse biological activities of polyketide natural products are often associated with specific structural motifs, biosynthetically introduced after construction of the polyketide core. Therefore, investigation of such "post-polykektide synthase (PKS)" modifications is important, and the accumulated knowledge on these processes can be applied for combinatorial biosynthesis to generate new polyketide derivatives with enhanced biological activities. In addition to the practical value, a lot of unprecedented chemical mechanisms can be found in the enzymes involved therein, which will significantly advance our understanding of enzyme catalysis. The works described in this dissertation focus on elucidating a number of post-PKS modifications involved in the biosynthesis of an insecticidal polyketide, spinosyn A, in Saccharopolyspora spinosa. First, three methyltransferases, SpnH, SpnI, and SpnK, responsible for the modification of the rhamnose moiety, have been investigated to verify their functions and to study how they are coordinated to achieve the desired level of methylation of rhamnose. In vitro assays using purified enzymes not only established that SpnH, SpnI, and SpnK are the respective rhamnose 4ʹ-, 2ʹ-, and 3ʹ-O-methyltransferase, but also validated their roles in the permethylation process of spinosyn A. Investigation of the order of the methylation events revealed that only one route catalyzed by SpnI, SpnK, and SpnH in sequence is productive for the permethylation of the rhamnose moiety, which is likely achieved by the proper control of the expression levels of the methyltransferase genes involved in vivo. The key structural feature of spinosyn A is the presence of the unique tetracyclic architecture likely derived from the monocyclic PKS product. To elucidate this "cross-bridging" process, which had been hypothesized to involve four enzymes, SpnF, SpnJ, SpnL, and SpnM, the presumed polyketide substrate was chemically synthesized using Julia-Kocienski olefination, Stille cross-coupling, and Yamaguchi macrolactonization as key reactions. Incubation of the synthesized substrate with SpnJ produced a new product where the 15-OH group of the substrate is oxidized to the ketone. Next, it was demonstrated that incubation of this ketone intermediate with SpnM produces a tricyclic compound, via a transient monocyclic intermediate with high degree of unsaturation. Whereas it was initially thought that SpnM catalyzes both dehydration and [4+2] cycloaddition in sequence, detailed kinetic analysis revealed that SpnM is only responsible for the dehydration step, and the [4+2] cycloaddition step is indeed catalyzed by SpnF. Finally, successful conversion of the tricyclic intermediate to the tetracyclic core was demonstrated using SpnL. Proposed chemical mechanisms of SpnF and SpnL, Diels-Alder and Rauhut-Currier reactions, respectively, are interesting because enzymes capable of catalyzing these reactions have yet to be characterized in vitro. This work not only establishes the biosynthetic pathway for constructing the spinosyn tetracyclic core, but also epitomizes the significance of the post-PKS modification as a rich source of new enzyme catalysis. / text

The functionalisation of C-H bonds has been widely studied in organic synthesis. This work presents the results of investigation into two areas of current research, copper-catalysed aromatic C-H functionalisation and rhodium-catalysed hydroacylation. Chapter 1 presents the development of palladium- and copper-catalysed aromatic C-H functionalisation with particular attention paid to regiocontrol. Chapter 2 describes the development of copper-catalysed cross-coupling of perfluorinated arenes and alkenyl halides along with efforts to expand this methodology to a more general reaction. In Chapter 3 the development of chelation-controlled rhodium-catalysed hydroacylation is discussed. Chapter 4 outlines the utilisation of amino acid derived N-methylthiomethyl aldehydes in rhodium-catalysed hydroacylation methodology.