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Thesis (Ph. D.)--University of Wisconsin--Madison, 1937. / Typescript. Includes abstract and vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references: leaf [52].

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An efficient and expedient synthetic method was developed for the preparation of chiral poly-substituted morpholine and oxazepine derivatives. The method was designed in the objective of applying the synthesis to the preparation of Cyclophilin A inhibitors. / The stereo- and regioselective method involves the reaction of enantiopure beta-amino alcohols with alpha,beta-unsaturated aldehydes. The synthesis proceeds through three steps; i) Reductive amination, ii) N-alkylation/ N-tosylation and iii) intramolecular-haloetherification. Stereoselectivity of this last step was controlled by N-alkyl/ N-tosyl groups and substitution across the double bond, and was enhanced by the addition of Bronsted acids. Substitution across the double bond of the starting material controlled the regioselectivity of the method. Morpholines were obtained through 6- exo cyclization and oxazepines were obtained through 7-endo cyclization. / A small library of morpholine-based derivatives was designed in-silico. Affinity and binding modes to the Cyclophilin A were investigated through a docking-based virtual screening study.

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La Nature est une source quasi inépuisable de molécules possédant des propriétés biologiques souvent remarquables. Ainsi, les plantes fournissent chaque jour de nouvelles structures dont les chimistes s’inspirent afin de créer de façon synthétique des molécules similaires ou dérivées pouvant avoir de potentielles applications en tant qu’agents thérapeutiques par exemple.L’émergence de la catalyse organométallique a permis d’améliorer considérablement les méthodes de synthèse de molécules complexes. La catalyse homogène à l’or, dont le potentiel n’a été exploité qu’à partir des années 2000, a prouvé son efficacité pour effectuer de nombreuses réactions permettant de créer plusieurs liaisons carbone-carbone ou carbone-hétéroatome en une étape. Les conditions douces et la grande tolérance des catalyseurs d’or vis-à-vis de groupements fonctionnels divers ont naturellement mené à l’application de la catalyse à l’or à la synthèse de produits naturels. Ces études s’inscrivent dans cette dynamique et exploitent la réactivité d’azacycles contraints et d’alcynes en présence d’or(I) pour former des squelettes hétérocycliques couramment rencontrés au sein de produits naturels. La réactivité particulière des groupements sulfonyles protecteurs de l’azote a également été étudiée pour synthétiser différentes molécules azabicycliques. Les méthodes de synthèse mises au point ont finalement été appliquées à la synthèse de molécules cibles. / Nature is a nearly endless source of molecules, often possessing remarkable biological properties. Thus, plants provide new structures every day, inspiring chemists to synthetically create similar molecules or analogs, which are potential therapeutic agents for example. The emergence of organometallic chemistry allowed for considerable improvement of synthetic methods to make complex molecular scaffolds. Homogeneous gold catalysis, whose potential has only been explored starting from 2000, proved its efficiency to make numerous reactions. Most of them can generate several carbon-carbon or carbon-heteroatom bonds in one step. Soft conditions as well as good tolerance of gold catalysts toward multiple functional groups naturally led to the application of gold-catalyzed steps in various total syntheses of natural products.The present study evolves in this context and explores the reactivity of strained azacycles and alkynes in the presence of gold(I) to form heterocyclic skeletons that are commonly found in natural products. The specific reactivity of sulfonyl nitrogen-protecting groups has also been studied to synthesize azabicyclic compounds. The application of those various new methodologies to the synthesis of target molecules has finally been studied.

The topic of this thesis is the design and synthesis of biaryl-based self adaptableligands for asymmetric metal catalysis. The results discussed in papers I-III are covered, together with some unpublished results concerning substrate-adaptable catalysts. A general survey of self-adaptable catalysts is presented first. The second chapter of this thesis starts with a survey of inversion barriers in biphenyl-based ligands and catalysts. Thereafter, the determination of barriers to conformational adaptation in dibenzoazepines and dibenzophosphepines is described. Palladium complexes with a diphosphine ligand or a diamine ligand, as well as the free diamine ligand, were studied. Entropies and enthalpies of activation were determined with variable temperature NMR spectroscopy. The mechanism of conformational change in the metal complexes was elucidated. The third chapter describes the synthesis of semiflexible and rigid phosphinite ligands, as well as their application in rhodium-catalysed asymmetric hydrogenation. Modest enantioselectivities (up to 63% ee) were obtained. The semiflexible ligand was found to behave like the most active rigid diastereomer. The fourth chapter describes the behaviour of amine and phosphoramidite ligands in model complexes relevant to the palladium-catalysed asymmetricallylic alkylation of benchmark substrates. Diphosphoramidite and aminephosphoramiditeligands were designed and synthesised. Pd(olefin) complexesof diamine and diphosphoramidite ligands were studied, and their symmetry determined. It was found that both types of ligands are able to adapt their conformation to the substrate. / QC20100630

This thesis deals with the design and synthesis of ligands for asymmetric catalysis: palladium catalyzed allylic alkylations, and rho-dium and iridium catalyzed hydrogenations of olefins. Chirally flexible phosphepine ligands based on biphenyl were synthesized and their properties were studied. The rotation barrier for configurationally flexible phosphepines was determined by NMR spectroscopy. The ratio of the atropisomers was shown to depend on the group bound to phosphorus. Only complexes with two homochiral ligands bound to the metal center were observed upon complexation with Rh(I). It was shown that one diastereomer of the flexible ligand exhibits higher activity but lower selectivity than its diastereomer in the rhodium catalyzed hydrogenation of methyl alfa-acetamidocinnamate. These ligands were also tested in nickel catalyzed silabora-tions. Chiral P,N-ligands with pseudo-C2 and pseudo-CS symmetry based on pyrrolidines-phospholanes or azepines-phosphepines were synthesized and studied in palladium catalyzed allylic alkylations. Semi-flexible azepine-phosphepine based ligands were prepared and their ability to adopt pseudo-C2 or pseudo-CS symmetry depending on the substrate in allylic alkylations was studied. It was shown on model allyl systems with flexible N,N-ligands that the ligand prefers CS-symmetry in compexes with anti-anti as well as syn-syn allyl moieties, but that for the latter type of complexes, according to computations, the configuration of the ligand is R*,R* in the olefin complexes formed after addition of a nucleophile to the allylic group. A preliminary investigation of the possibilities to use a su-pramolecular approach for the preparation of P,N-ligands with pseudo-C2 and pseudo-S symmetry was made. An N,N-ligand with C2 symmetry was prepared and its activity in palladium catalyzed ally-lic alkylation was studied. Pyridine-based P,N-ligands were tested in iridium catalyzed hy-drogenations of unfunctionalized olefins with good activities and se-lectivities. In order to attempt to improve the selectivity, ligands with a chirally flexible phosphepine fragment were prepared and applied in catalysis with promising results. / QC 20100929