Operationally friendly protocols to produce libraries of novel small molecules with high molecular complexity are in huge demand for the interrogation of biological systems. As such, development of new MCRs and post-condensation modification of the MCR products have proven fruitful in the quest for new molecular probes and their expedited progression along the drug discovery value chain. The products thereof have found their way into numerous corporate compound collections. Crixivan (Indinavir), an antiretroviral, and Xylocaine (Lidocaine), a local anesthetic, are two examples of drugs derived from an MCR that have been marketed. The research topic of this dissertation encompasses the design and development of fifteen novel drug-like chemotypes in an operationally friendly, green, and expedited (≤ 3 synthetic operations) manner involving the Ugi MCR coupled with MAOS and high-throughput purification platforms. Over 500 drug-like small molecules (purity > 90% based on UV 214 nm and ELSD) have been synthesized, purified, and submitted to the NIH MLSMR for further biological evaluation against protein targets of interest. Furthermore, non-electrochemical carbamate oxidations enabling formation of N-acyliminium ion precursors, which are reactive intermediates that form the basis of a multitude of synthetic routes to natural products, have also been developed.

La tesis doctoral describe estrategias útiles y sencillas para las síntesis de 2-oxindoles 3,3'-disustituídos y alcoholes homoalílicos. La memoria se divide en dos grandes bloques: el primero referido a la alquilación desacilativa como método para la síntesis de 2-oxindoles 3,3'-disustituídos que engloba la introducción I, el capítulo I titulado alquilación desacilativa para la síntesis de 2-oxindoles 3,3'-disustituídos y capítulo II titulado bromación desacilativa para la síntesis de 3,3'-bioxindoles y aislamiento de 3-bromooxindoles. La segunda parte se refiere a fotocatálisis y metalofotocatálisis como nuevos métodos de síntesis orgánica y engloba la introducción II, capítulo III titulado fotocatálisis para la síntesis de 3,3'-bioxindoles y capítulo IV titulado catálisis dual para la alilación de aldehídos.

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This dissertation demonstrates the preparation of blocky brominated syndiotactic polystyrene (sPS-co-sPS-Br) copolymers with tailored chain sequences using a simple, post-polymerization functionalization method conducted in the heterogeneous gel state, and investigates the effect of sPS reaction state and sPS/solvent gel morphology on the copolymer microstructure and thermal properties. Gel-state (Blocky) brominated copolymers were prepared from a 10 w/v% sPS/carbon tetrachloride (CCl4) gel and a 10 w/v% sPS/chloroform (CHCl3) gel in a matched set containing 6−32 mol% p-bromostyrene (Br-Sty) units. For comparison, a matched set of randomly brominated copolymers was prepared using a homogeneous solution-state (Random) reaction method and a set of brominated copolymers was prepared using a heterogenous powder-state (Powder) reaction method. The degree of bromination was evaluated using 1H nuclear magnetic resonance (NMR) spectroscopy. Powder-state bromination produced copolymers with a limited degree of functionalization of up to 12 mol% Br and required a threefold longer reaction time than the gel-state method conducted on the sPS/CHCl3 gel, demonstrating that the powder-state method is time-consuming and the dense sPS powder is incapable of producing copolymers with high Br-content. Microstructural characterization provided by 13C NMR spectroscopy, showed that bromination of sPS produces multiple peaks in the quaternary carbon region of the NMR spectrum, signifying through-bond communication between neighboring styrene and Br-Sty monomers. This work provides the first high-resolution comonomer sequencing of brominated sPS copolymers. Characterization of the quaternary carbon spectrum, assisted by band selective gradient heteronuclear multiple bond correlation (bsgHMBC) spectroscopy, electronic structure calculations, and simulated statistically random copolymer chains, revealed that each resonance peak could be assigned to a styrene or Br-Sty unit that exists in the center of a unique sequence of five monomers (i.e., a pentad) along the copolymer chain (e.g., ssssb where s = styrene and b = brominated styrene). Our comonomer sequencing method demonstrated that the Blocky and Powder copolymers have block-like character. Remarkably, the Blocky copolymers exhibit notably higher degrees of blockiness and larger fractions of sssss and bbbbb pentads at low Br contents (i.e., 32 mol% Br), relative to the Powder copolymers, confirming their blocky microstructure. Quenched films of the Blocky copolymers, analyzed using ultra-small-angle (USAXS) and small-angle X ray scattering (SAXS), show micro-phase separated morphologies that are reminiscent of conventional block copolymer phase behavior, supporting that the Blocky copolymers contain distinct segments of pure sPS and segments of randomly brominated sPS. Crystallization behavior of the copolymers, examined using differential scanning calorimetry (DSC), demonstrates that the Blocky copolymers are more crystallizable and crystallize faster at lower supercooling compared to their Random analogs. Simulations of blocky copolymers were developed based on the semicrystalline gel morphology to rationalize the effect of gel-state functionalization on copolymer microstructure and crystallization behavior. The simulations confirm that restricting the accessibility of the brominating reagent to monomers well removed from the crystalline fraction of the gel network produces copolymers with a greater prevalence of long runs of pure sPS that is advantageous for preserving desired crystallizability of the resulting blocky copolymers. To investigate the effect of sPS/solvent gel morphology on copolymer microstructure and crystallization behavior, the sPS/CCl4 and sPS/CHCl3 copolymers were compared directly. Characterization of the sPS/solvent gels using USAXS/SAXS, revealed that the gels exhibit different morphologies and average lamella thicknesses. Microstructural analysis showed that the sPS/CHCl3 copolymers contain larger fractions of sssss pentad and a greater degree of blockiness. The sPS/CHCl3 copolymers contain larger phase domains, supporting that these copolymers contain longer distinct segments of pure sPS and randomly brominated sPS in a multiblock-like microstructure. In addition, the sPS/CHCl3 copolymers are more crystallizable during conditions of rapid cooling and crystallize faster at low supercooling relative to their sPS/CCl4 analogs. Simulated average chains of the Blocky copolymers, generated from the empirical pentad sequence distributions, provide strong evidence that the runs of pure sPS in the Blocky copolymers originate from the crystalline stems within the crystalline lamellae. Thus, the simulations support that semicrystalline blocky brominated copolymers with tailored chain sequences, phase behavior, and crystallization properties and can be prepared simply by changing the gelation solvent. / Doctor of Philosophy / Block copolymers are a class of large molecules (polymers) that are made up of two or more chains (blocks) of different smaller units (monomers) linked together at one of each of the chain ends. When the monomers that make up each block have distinctly different chemical properties, the blocks may be capable of self-assembling into well-ordered physical structures, which give the block copolymer unique material properties that are different, and often better than the properties of the individual blocks alone (homopolymers). Block cop olymers have thus received tremendous attention with respect to controlled preparation, tailored structure development, and customized physical properties, for their potential use in self-assembled, nanostructured materials. Nevertheless, the generally difficult procedures and conditions required to make (polymerize) block copolymers with controlled sequences limits the scope of their commercial application. As an alternative to conventional polymerization methods, this dissertation demonstrates a comparatively simple physical method to make copolymers that contain significantly non-random (blocky) monomer sequences, starting with a homopolymer and using a reagent to modify units along the polymer chain. This post-polymerization method is conducted in the homopolymer’s gel state, in which segments of the homopolymer chains are effectively shielded from the reagent. The homopolymer, syndiotactic polystyrene (sPS), was used as a model to conduct a fundamentical investigation into the effects of the polymer reaction state, i.e., gel, solution, or powder, and the gel structure (morphology) on the copolymer structure and properties. The gel-state was found to produce copolymers with a high degree of modification and a greater degree of blockiness than the solution-state and powder-state. Copolymers prepared from the gel state exhibited properties that are characteristic of conventional block copolymers. Furthermore, using the gel-state method, blocky copolymers with tailored chain sequences and properties were prepared by simply changing the gel morphology. Thus, reaction in the gel-state is demonstrated as a simple physical approach to polymer design and synthesis that will be useful in the development of next-generation functionalized materials through the modification of lowcost commodity polymers. As an advancement to the manner in which nanostructured materials are created, these tailored materials will greatly enhance the convenience of block copolymers for a wide variety of applications including structural and biomechanical materials, and polymeric membranes for energy conversion and water purification systems.

ABSTRACT FUNCTIONALIZATION OF SATURATED HYDROCARBONS: HIGH TEMPERATURE BROMINATION G&uuml / nbaS, Duygu Deniz M.S., Department of Chemistry Supervisor: Prof. Dr. Metin Balci June 2006, 174 pages Although saturated hydrocarbons are readily available and extremely cheap starting materials, they can not be used in synthetic chemistry without prior activation. Efficient functionalization of alkanes leading to the production of useful organic chemicals in an industrial scale is of considerable interest for the chemical and pharmaceutical industries and remains a long-term challenge for chemists. In this respect, halogenations of hydrocarbons which leads to a variety of useful synthetic intermediates is an open avenue which deserves special attention. It is also noteworthy to mention that efficient methods for selective functionalization of saturated bicyclic hydrocarbons still remains elusive, albeit a number of methods employing various reagents have been developed for the C&amp / #8211 / H bond activation of open chain and monocyclic alkanes. Herein, we will investigate the high temperature bromination reactions as a method for functionalization of saturated bicyclic hydrocarbons such as octahydropentalene (1), octahydro-1H-indene (2) and 1a,2,7,7a-tetrahydro-1H-cyclopropa[b]naphthalene (3). The scope and the limitations of the reaction will reveal the regio-and stereoselectivity. Furthermore, formation mechanism of the products will be discussed and the chemistry of these compounds will be extended for further functionalization

Le paludisme est une maladie parasitaire qui présente une problématique de santé majeure, touchant actuellement plus de 200 millions de personnes dans le monde. Le développement de nouveaux médicaments est nécessaire pour succéder aux traitements existants qui perdent progressivement leur efficacité suite à l’émergence des résistances. Les produits naturels constituent une source d’inspiration inépuisable pour la recherche de nouveaux médicaments. Dans le cadre de cette thèse, nous nous sommes intéressés à deux familles de produits à propriétés antipaludiques : les mallotojaponines et les bromophycolides. Dans la première partie du projet, nous avons effectué la première synthèse totale de la mallotojaponine C. Nous avons également synthétisé une bibliothèque de ses analogues. Tous ces composés ont été testés contre Plasmodium falciparum responsable du paludisme et contre Trypanosoma brucei responsable de la maladie du sommeil. Nous avons confirmé l’activité antipaludique des mallotojaponines et découvert leur activité trypanocide. Dans la deuxième partie de ce projet, nous avons mis au point une méthode sélective et chimiodivergente de bromation des terpènes qui pourrait ensuite être appliquée à la synthèse des bromophycolides. En utilisant des réactifs d’iode(III) hypervalent pour générer des espèces bromonium électrophiles in situ à partir des bromures, nous avons réussi à mettre au point des conditions de bromocarbocyclisation, d’oxybromation et de dibromation des chaînes terpéniques. Dans tous les cas, les réactions sont rapides et faciles à mettre en œuvre. / Malaria is a parasitic disease affecting more than 200 million people in the world. The development of new antimalarial drugs is necessary in order to replace the existing treatments that are progressively becoming less efficient due to resistance phenomena. Natural products are an inexhaustible source of inspiration for the discovery of new drugs. In this project, we focused our attention on two natural products families exhibiting antimalarial properties: mallotojaponins and bromophycolides. In the first part of this project, we carried out the first total synthesis of mallotoajaponin C. We also synthesised a library of its analogues. All of these compounds were tested against Plasmodium falciparum responsible for malaria and against Trypanosoma brucei responsible for African sleeping sickness. We have confirmed the antimalarial activity of mallotojaponins and discovered their trypanocidal activity. In the second part of the project, we developed a chemodivergent and selective method of bromination of terpenes that could later be applied to the synthesis of bromophycolides. Using simple bromides and hypervalent iodine(III) reagents to generate electrophilic bromonium species in situ, we have shown that the reaction can be steered selectively towards the bromocarbocyclisation, the oxybromination or the dibromination of terpene chains. In all cases, the reactions are fast and easy to perform.

ABSTRACT FUNCTIONALIZATION OF SATURATED BICYCLIC HYDROCARBONS: HIGH TEMPERATURE BROMINATION &Ouml / zer, Melek Sermin M.Sc., Department of Chemistry Supervisor: Prof. Dr. Metin Balci January 2011, 139 pages Although hydrocarbons are readily available and extremely cheap starting materials, they cannot be used in synthetic chemistry without prior activation. The selective functionalization of saturated hydrocarbons under mild conditions is of both biochemical and industrial importance. Initially, saturated hydrocarbons such as octahydro-1H-indene 80, octahydro-1H-4,7-methanoindene 81 and bicyclo[4.2.0]octan-7-one 82 were synthesized as starting materials. Then high temperature bromination reactions of these saturated hydrocarbons as a method for C-H bond activation have been investigated and the synthetic application of the formed intermediates has been searched. Furthermore, the role of the alkyl substituents in tricyclic systems and the effect of carbonyl group in bicyclo[4.2.0] octan-7-one 82 have been studied and the mechanism for the formation of the products have been discussed. Finally, whole products were conscientiously purified and characterized.

The first part of study describes an investigation aimed at the incorporation of an allene unit into a natural compound, being alpha-pinene, by using Doering-Moore-Skatteboel method. DFT computations show that both allene product and insertion product can be isolated if the reaction of methyllithium with 3,3-dibromo-2,7,7-trimethyl-tricyclo[4.1.1.02,4]octane is carried out at either low or high temperatures. One insertion product resulting from the intramolecular C-H insertion at the bridge and three allene dimers were isolated when this reaction was carried out at room temperature. In the second part of study, exo- and endo-cyclopropylidene incorporated into benzonorbornadiene were investigated by using theoretical and experimental methods. Theoretical calculations show that the endo-carbene would be stable and undergo some kind of insertion and addition reactions. On the contrary, the exo-carbene is not stable and isomerizes to the corresponding allene structure during the optimization process. For this purpose, the reaction of dibromocarbene and dichlorocarbene with 7-methoxybenzonorbornadiene was achieved to afford gem-dibromocyclopropane and gem-dichlorocyclopropane adducts, respectively. However, they suffer stereoelectronically-controlled ring opening under the reaction conditions to give the ring-expanded allylic dihalides, respectively. On the other hand, gem-bromofluorocyclopropane, obtained by the treatment of 7-methoxybenzonorbornadiene with bromofluorocarbene, provided one of the four possible [2+4] allene adducts upon treatment with MeLi in furan. The exact structure of the adduct has been elucidated on the basis of NMR spectral data. This result confirms the formation of the bicyclic allene as an reactive intermediate. No products were isolated derived from the endo-carbene.

Les carbapénèmes occupent actuellement une place centrale dans la lutte contre les bactéries résistantes aux antibiotiques classiques de type pénicilline. Notre thèse a pour objectif de développer une synthèse de leurs intermédiaires dans l'optique d'une application à l'échelle industrielle. Nous avons exploité, comme stratégie de fermeture de l'hétérocycle, la formation du lien C-3/C-4 par attaque nucléophile intramoléculaire sur un époxyde. Celui-ci est obtenu à partir de la L thréonine qui fournit deux stéréocentres et permet d'induire le troisième carbone asymétrique. Nous avons utilisé le groupe benzhydryle comme groupe protecteur, nouveau dans cette chimie, pour remplacer le groupe para-anisyle habituel qui pose des problèmes industriels. Ce nouveau groupe change fortement la réactivité de l'époxyamide impliquant une optimisation délicate des conditions et un choix judicieux des substituants. De plus, une nouvelle méthode de déprotection par bromation photochimique a été mise au point, complètement compatible avec la fragilité du cycle beta-lactame. Enfin, pour générer le groupe partant en C-4, nous avons utilisé une oxydation de Baeyer-Villiger. La régiosélectivité de cette étape dépend fortement des substituants et apparaît contradictoire avec les exigences de la fermeture de cycle. L'étude de l'influence des substituants sur ces deux étapes nous a permis de sélectionner le substituant optimal. Dans la seconde partie de cette thèse, nous nous intéressons à l'introduction du 4e centre asymétrique caractéristique des carbapénèmes. Nous avons étudié la possibilité de l'effectuer avec des dérivés de l'acide de Meldrum pour substituer la position C-4 de l'intermédiaire-clef, suivi d'une décarboxylation asymétrique. Nous clôturons ce travail par une évaluation économique de notre synthèse d'un précurseur équivalent à l'acétoxyazétidinone. /Carbapenems occupy a central role in the fight against bacteria that are resistant to classical antibiotics such as penicillins. Our thesis has the aim to develop a synthesis of their principal intermediates with the objective to apply it at the industrial scale. We have explored, as strategy of the heterocycle closing, the formation of the C-3/C-4 bond by a nucleophilic attack on an epoxide. This one was obtained from L-threonine which brings two stereocenters and allows the induction for the creation of the third asymmetric carbon. We used the benzhydryl group as protecting group, new in this chemistry, to replace the usual para-anisyl group which causes industrial problems. This new group strongly affects the reactivity of the epoxyamide imposing a fine optimization of the conditions and an adequat choice of substituents. Furthermore, a new deprotection method by photochemical bromination was developed, entirely compatible with the fragility of the beta-lactam ring. Finally, to create the leaving group in C-4, we used a Baeyer-Villiger oxidation. Regiochemistry of this step strongly depends on substituents and appears contradictory with the requirements of the ring closing. The study of the influence of the substituents on these two steps permits us to choose the optimal substituent. In a second part of the work, we were interested in the introduction of the fourth asymmetric center of carbapenems. We studied the feasibility to perform it with Meldrum's acid derivatives by substituting the C-4 position of the key-intermediate, followed by an asymmetric decarboxylation. We ended this work by an economic evaluation of the synthesis of our precursor similar to acetoxyazetidinone.

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