Carbonyl compounds are of central importance to organic chemistry and their reactions have been described as the ‘backbone of organic synthesis’. Over recent decades, palladium-catalysed C–H carbonylation reactions have emerged as a powerful means of introducing carbonyl motifs to organic molecules. This thesis describes the development of a general C–H carbonylation reaction of secondary aliphatic amines, which provides facile access to synthetically useful β-lactam products. The first part of the thesis explores the scope and limitations of this reaction. Whilst previous C(sp3)–H carbonylation methodologies were restricted to ‘Type F’ secondary aliphatic amines, the reaction described in this thesis was found to be broadly applicable all structural sub-classes of secondary aliphatic amine. Furthermore, the reaction was found to be remarkably tolerant of functional groups, even those that commonly cause issues in palladium-catalysed C–H activation reactions such as heteroaromatics and thioethers. The second part of this thesis investigates the mechanism of this C–H carbonylation reaction. Interestingly, the reaction was found not to proceed via a traditional C–H carbonylation mechanism comprising of C–H activation, 1,1-migratory carbon monoxide insertion and reductive elimination. Instead, a new mechanistic paradigm for palladium-catalysed C–H carbonylation is proposed, which invokes a putative ‘palladium anhydride’ intermediate. A series of DFT calculations and experiments were conducted in order to support this mechanistic proposal. The work described within this PhD thesis was published in Science.

This thesis is centred around sequential C-C bond forming processes using oxygenated electrophiles. A major part of this research focuses on the constructive deoxygenation of 2-methoxyphenol (guaiacol), a major breakdown product of the renewable feedstock, lignin. 1,2-dielectrophiles are known to be challenging substrates for catalysis if both leaving groups are of similar reactivity, however high selectivity was observed in the palladium- catalysed Grignard cross-coupling of 2-methoxyphenyl-1H-imidazole-1-sulfonate. The previously untested Grignard cross-coupling catalyst, [PdCl₂(Xylyl-Phanephos)], was found to be highly active. A 2-benzoxazolyl functionality was shown to be an excellent directing group for the chelation-controlled nucleophilic aromatic substitution of aryl methyl ethers. However, this modified Meyers reaction is limited to aryl ethers containing an ortho-chelating group. To expand the ether scope, nickel-catalysed Grignard cross-coupling was studied. [NiCl₂(PⁿBu₃)2] showed increased activity in the Grignard cross-coupling of challenging ortho-substituted anisoles compared to the well-renowned [NiCl₂(PCy₃)2] and several Ni0 -NHC systems, with a ligand steric effect demonstrated. The success of [NiCl₂(PⁿBu₃)2] was extended to more activated methoxynaphthalene substrates, in which the lowest reported catalyst loadings (0.1-0.25 mol%) were reported. Induction periods at 0.1 mol% suggested the requirement of inorganic Lewis-acidic magnesium salts to be formed in situ before any considerable activity was observed. Further work is required to increase reaction and ether scope, but this work provides a basis for exploiting lignin- derived phenols as a framework in the synthesis of functionalised chemicals of higher value. The final results chapter concerns an alternative sequential C-C bond forming process using another oxygenated electrophile. [PdCl₂((S)-Xylyl-Phanephos)] was used to accomplish a Grignard cross-coupling of vinyl tosylate, with the product then subjected to a highly enantioselective methoxycarbonylation using the same catalyst. This lead to a concise synthesis of (S)-Flurbiprofen.

<div> Carbon monoxide is a useful carbon linchpin to construct complex molecules of natural products by stitching different pieces of target molecules together. Recently, our group reported a novel and efficient palladium-catalyzed spirolactonization by Dr. Dexter Davis to construct oxaspirolacones from esters or lactones. As an essential motif, oxaspirolactone structures in natural products exhibit diverse and exciting structures and biological activities. The first part of this thesis mainly describes the total synthesis of stemoamide alkaloids in the stemona family and the application of our palladium-catalyzed spirolactonization, which was developed by our group to complete total synthesis of bisdehydroneostemoninine and bisdehydrostemoninine with Prof. Kaiqing Ma. The total synthesis features a one-pot ring-closing cross-metathesis, Lewis acid-mediated Friedel-Crafts reaction and lactonization, and accomplished bisdehydrostemonine in 15 steps. The total synthesis of stemoamide, tuberostemoamide, and sessilifoliamide A were finished, and the critical step features an mCPBA oxidation to convert pyrrole to lactam in one step without destructing other functional groups. </div><div> In the second part of this thesis, we developed a novel and efficient palladium-catalyzed cascade amino-carbonylative lactonization to streamline the synthesis of dihydropyrrole-fused furanones in collaboration with Prof. Seleem’s lab for biological activities. Using this method, we quickly expanded this method to construct different ring structures, such as β-lactone and dihydropyrrole-fused pyrrolone. This method was applied to the total synthesis study towards stemofoline alkaloids. Our palladium-catalyzed spirolactonizaiton was also used in this total synthesis study for target molecules. </div><div><br></div>

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Ce travail est centré sur la synthèse de complexes du rhodium contenant un ligand azoté et leur mise en œuvre dans la réaction catalytique de carbonylation du méthanol en acide acétique. Dans une première partie, nous nous intéressons à la préparation de complexes neutres de formule générale [RhI2(CO)(L)] (L = amines, imidazoles et pyrazoles) et à quelques homologues chlorés. Ces complexes plans carrés manifestent une réactivité directement liée à l’encombrement stérique du ligand azoté L dans la réaction d’addition oxydante de l’iodomethane suivie de la cis-migration du groupement méthyle pour former l’espèce acétyle. Dans une deuxième partie, les complexes précédents ont été engagés dans des essais catalytiques de carbonylation du méthanol dans les conditions du procédé industriel. Comme il s’est avéré que les complexes neutres se transforment en espèce [RhI2(CO)2]- pour laquelle les contre-cations associés sont constitués du ligand azoté protoné ou methylé, nous avons effectué la préparation et la caractérisation des complexes [HNR3][RhI2(CO)2] ou [MeNR3][RhI2(CO)2]. Par IR, RMN et électrochimie, nous nous sommes intéressés aux phénomènes d’appariement d’ions et nous montrons qu’il s’agit dans le meilleur des cas d’interactions hydrogènes. Celles-ci influent la vitesse de la réaction oxydante de CH3I. Dans la dernière partie, nous avons complété une étude, précédemment initiée au laboratoire, sur le mécanisme, qui dans la dernière étape du cycle catalytique permet de passer de l’espèce acétyle [RhI3(COCH3)(CO)2]- à l’espèce active [RhI2(CO)2]- avec production de l’iodure d’acyle. A l’inverse du concept admis d’élimination réductrice de CH3COI suivie de son hydrolyse immédiate en CH3COOH et HI, nous montrons, avec l’appui de calculs théoriques (DFT) qu’en fait un ligand I- est substitué par un ligand acetate pour conduire à l’espèce [RhI2(OAc)(COCH3)(CO)2]-. L’élimination réductrice produit alors l’anhydride acétique qui est hydrolysé en CH3COOH régénérant [RhI2(CO)2]-. Un tel mécanisme opère en présence d’ions acetate dans les milieux faiblement hydratés visés par l’industriel. / This study focuses on the synthesis and reactivity of rhodium complexes bearing N- containing ligands or counter-cations for the [Rh]-catalyzed methanol carbonylation reaction to produce acetic acid under the industrial Celanese Acid Optimization (AO) process conditions. In a first part, full synthesis and characterization of neutral Rh(I) square planar cis- [RhX(CO)2(L)] (X = Cl or I) complexes have been described, for which L is an N-ligand belonging to the amine, imidazole or pyrazole family. For the [RhI(CO)2(L)] complexes, variable-temperature 13C{1H} NMR spectroscopy has put in evidence a fluxional behavior for the different sized L ligands involved. The rate of this fluxional process reveals to be related to both electronic and steric contributions brought by L to the Rh center. These parameters (mainly steric), supported by single-crystal X-ray analyses in the solid state, also influence significantly the kinetics of the methyl iodide oxidative addition reaction followed by rapid CO migratory insertion, the overall being the rate determining step of the [Rh]-catalyzed methanol carbonylation cycle. In absence of CO, this reaction gives rise to the corresponding neutral Rh(III) acetyl complex, which immediately dimerizes to afford [Rh(μ- I)I(COMe)(CO)(L)]2 complex, for which several X-ray crystal structures have been obtained and studied. In addition, the surprising C-H activation in the case of a tBu-pyrazole ligand giving rise to a cyclometalated Rh dimer is reported. In a second part, the reactivity of the latter neutral Rh(I) [RhI(CO)2(L)] complexes as potential precursors has been investigated by batch experiments for the methanol carbonylation reaction. Mechanistic understanding via VT-HP-NMR experiments enabled to detect mainly anionic Rh(I) [RL][RhI2(CO)2] (R = H or CH3 according to the working conditions) complexes formed by decoordination followed by quaternization of the L ligand. Despite this result, the pyrazole family ligands showed better stability under the harsh process conditions. Thus, it cannot be ruled out that equilibrium between neutral and anionic species co-exist in the reaction medium at high temperatures and that [RL]I salt dissociation occurs, restoring the L ligand into the Rh coordination sphere. At this stage we focused on the anionic Rh(I) complex and prepared a series of [XNR3][RhI2(CO)2] (X = H or CH3) species, which have been fully characterized. Infrared, NMR, conductivity experiments and DFT model calculations together put in evidence ion interactions according to the nature of the ammonium counter-cation. Protonated cations significantly impact on the kinetics of the methyl iodide oxidative addition presumably due to H-interactions with the Rh square plane. The final part deals with the mechanism of the reductive elimination reaction, the last step of the [Rh]-catalyzed methanol carbonylation cycle, which from complex [RhI3(COCH3)(CO)2]-, regenerates [RhI2(CO)2]-. In contrast to the classically admitted mechanism of reductive elimination of CH3COI followed by subsequent hydrolysis to form AcOH and HI, we demonstrate from experimental DFT calculation that substitution of an iodo ligand by an acetate ion occurs to give rise to the [RhI2(OAc)(COCH3)(CO)2]- species. Thus, reductive elimination regenerates [RhI2(CO)2]- and produces acetic anhydride, which after hydrolysis affords two molecules of acetic acid. Such a mechanism operates under process conditions at low water content with a significant amount of acetate ions.

La photocatalyse est un procédé d'oxydation avancée qui consiste en l'activation du dioxyde de titane sous UV pour générer des espèces oxydantes. Ces dernières sont capables d'inactiver les cellules vivantes. Nos travaux ont porté sur l'analyse des mécanismes antimicrobiens de la photocatalyse à l'échelle cellulaire et moléculaire sur le modèle eucaryote Saccharomyces cerevisiae, champignon unicellulaire. Le traitement photocatalytique affecte de manière drastique la cultivabilité de cette levure. La diminution de la cultivabilité a été reliée à la perte de l'intégrité membranaire et à la perte de l'activité enzymatique intracellulaire, analysées par cytométrie en flux. L'exposition des levures à la photocatalyse provoque des dommages à toutes les macromolécules (acides nucléiques, lipides membranaires, protéines) et par conséquent aux structures cellulaires ce qui engendre la libération de constituants cellulaires (ions, acides aminés), de même que la formation de produits de dégradation (malondialdéhyde, acides organiques). Ces dommages peuvent être liés à un stress oxydant intracellulaire suggéré par l'accumulation des ions superoxyde dans les cellules traitées et l'augmentation de la résistance pour les souches surexprimant des enzymes de dégradation des ROS. Enfin, l'étude de l'impact de la photocatalyse sur des organismes fongiques ayant un impact environnemental ou sur la santé, a révélé l'existence de cellules ou de structures fongiques résistantes. Ces résultats ont apporté des éléments de connaissance inédits sur l'impact de la photocatalyse sur les cellules eucaryotes fongiques et ouvrent de nouvelles perspectives notamment dans la compréhension du phénomène de résistance / Photocatalysis is an advanced oxidative process that generates reactive oxygen species (ROS) and inactivates living cells. The aim of this work was to have a better understanding of the antimicrobial mechanisms generated by photocatalytic treatment. The cellular impact was monitored using the unicellular fungal model, Saccharomyces cerevisiae yeast. Photocatalysis reduces drastically the cultivability of yeast cells. Flow cytometry analyses revealed that the decrease of cell cultivability was related to both damages in plasma membrane and loss of intracellular enzymatic activity. During exposure to photocatalysis, multiple cellular macromolecules are damaged (lipids, proteins, nucleic acids). These damages are responsible for cellular structure dysfunction leading to a release of intracellular compounds (ions, amino acids) and the formation of by-products and pollutant (carboxylic acids, malondialdéhyde). The increase of intracellular superoxide ions amounts and the higher resistance of yeast strains overexpressing ROS detoxifying enzymes suggested an intracellular oxidative status responsible for described macromolecular damages. Finally, exploring photocatalytic treatment on other environmental and health impact fungi revealed the presence of resistant cells or structures. For the first time, an interdisciplinary work focusing on cellular impacts of photocatalysis was monitored leading to a better understanding and to new perspectives

La Tomographie par Emission de Positrons (TEP) constitue l’une des techniques d’imagerie moléculaire les plus novatrices pour la visualisation in vivo des processus biologiques. Elle intervient comme technique de choix pour le diagnostic dans de nombreux domaines. La conception et l’élaboration de nouveaux radiotraceurs sont en perpétuel développement. Dans ce contexte une méthode d’introduction du radioisotope 11C a été développée pour le marquage de composés bioconjugées. Les conditions particulièrement douces de l’alcoxycarbonylation intramoléculaire mise au point ont permis un marquage en dernière étape de synthèse. La diversification des structures des précurseurs a également été envisagée grâce à un nouveau couplage biarylique catalysé à l’or sous conditions photorédox. Enfin la fonctionnalisation de motifs BODIPY a conduit à de premières avancées pour l’obtention de sondes bimodales innovantes. / Positron Emission Tomography (PET) is a powerful molecular-imaging technique for physiological andbiological investigations in various areas. Due to the increasing need of this technique for in vivoapplications, there is always a demand for the development of new tracers and radiolabelingstrategies. In this context an original method was developed to introduce the 11C-radioisotope for thelabeling of bioconjugated compounds. The extremely mild conditions of this intramolecular Pdcatalyzedalcoxycarbonylation allowed to label these structures in the last step of the synthesis.Diversification of the available precursors was investigated by a novel biaryl cross coupling using goldcatalisis under photoredox conditions. Finally, preliminary studies for the functionalization of BODIPYcores were realized to obtain innovative bimodal probes.

<p>This thesis describes how radical cyclization chemistry can be applied for the construction of heterocyclic compounds.</p><p>In the first part, a series of electron deficient α-phenylselenenylalkenes were prepared <i>via</i> a PhSeCl-addition/HCl-elimination sequence. Allyl- and propargylamines readily underwent conjugate addition to these species to produce pyrrolidines or dihydropyrrol derivatives, after triethylborane initiated reductive radical cyclization in the presence of tris(trimethylsilyl)silane.</p><p>The second part describes a convergent synthesis of the pineal hormone melatonin. The indole nucleus is secured <i>via</i> a tris(trimethylsilyl)silane mediated<i> 5-exo</i> radical cyclization. The protocol provides convenient and simple access to compounds useful for studies of biological activity and structure activity relationships.</p><p>The third part describes construction of substituted tetrahydrofuran-3-ones and pyrrolidin-3-ones. Regioselective ring-opening of epoxides or aziridines with benzeneselenolate/tellurolate, followed by Michael addition to electron deficient alkynes afforded the corresponding O/N-vinylated compounds. The tetrahydrofuran-3-ones and pyrrolidin-3-ones were secured <i>via </i>radical carbonylation/reductive cyclization using pressurized carbon monoxide (80 atm).</p><p>The fourth part is concerned with the effect of an N-protecting group on the cyclization of 2-substituted-3-aza-5-hexenyl radicals. Relative energies for reactants and transition states were determined using density functional calculations. Reactant and transition state conformers leading to <i>cis</i>-product were lower in energy than those leading to<i> trans</i>-product. The results can be explained by the unfavorable 1,2-strain present in chair-equatorial and boat-equatorial conformers.</p>

<p>Methods for the ¹¹C-labeling of carbonyl compounds applicable in the preparation of radiotracers for Positron Emission Tomography (PET) are described. To this end [¹¹C]carbon monoxide at low concentration was used in transition metal- mediated reactions.</p><p>Stille couplings were employed in the synthesis of [<i>carbonyl-</i>¹¹C]ketones from methyl and aryl halides with [¹¹C]carbon monoxide. The synthesized [<i>carbonyl-</i>¹¹C]ketones were obtained from the corresponding organostannanes with analytical radiochemical yields up to 98%.</p><p>A number of synthetic routes were designed using [¹¹C]carbon monoxide and rhodium complexes. Nitrene intermediates were generated from azides and reacted via a rhodium-mediated carbonylation reaction as a general synthetic route to [<i>carbonyl-</i>¹¹C]isocyanates, versatile precursors. [<i>carbonyl-</i>¹¹C]Isocyanate reacted via nucleophilic attack of an amine to form <i>N,N’</i>-diphenyl[¹¹C]urea in 82% analytical radiochemical yield, ethyl phenyl[¹¹C]carbamate was synthesized by the same route, using ethanol as the nucleophile, in 70% radiochemical yield. [¹¹C]Isocyanate was also able to react in a [2+3] cycloaddition with ethylene oxide to form 3-phenyl[<i>carbonyl-</i>¹¹C]oxazolidin-2-one in over 80% analytical radiochemical yield. This method was applied to the synthesis of a potential efflux system tracer [¹¹C]hydroxyurea in 38% isolated radiochemical yield and the derivative 1-hydroxy-3-phenyl[¹¹C]urea in 35% isolated radiochemical yield. Carbene intermediates, generated from diazo compounds, were reacted with [¹¹C]carbon monoxide in the rhodium-mediated synthesis of [<i>carbonyl-</i>¹¹C]ketenes. [<i>carbonyl-</i>¹¹C]Ketene intermediates were utilised in the synthesis of diethyl[<i>carbonyl</i>-¹¹C]malonate, from ethyl diazoacetate and ethanol. The product was obtained with a 20% isolated radiochemical yield. Alkylation of diethyl[<i>carbonyl</i>-¹¹C]malonate, with ethyliodide and tetrabutylammonium fluoride, was successfully accomplished and diethyl diethyl[<i>carbonyl</i>-¹¹C]malonate was synthesized in 50% analytical radiochemical yield. Several (<i>carbonyl-</i>¹³C)compounds were also synthesized using the described methods as a way of characterizing the position of the label using ¹³C-NMR.</p>