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.

The work described in this thesis is focused on the development of new bidentate iridium complexes and their applications in the asymmetric reduction of olefins, ketones and imines. Three new types of iridium complexes were synthesized, which included pyridine derived chiral N,P-iridium complexes, achiral NHC complexes and chiral NHC-phosphine complexes. A study of their catalytic applications demonstrated a high efficiency of the N,P-iridium complexes for asymmetric hydrogenation of olefins, with good enantioselectivity. The carbene complexes were found to be very efficient hydrogen transfer mediators capable of abstracting hydrogen from alcohols and subsequently transfer it to other unsaturated bonds. This hydrogen transferring property of the carbene complexes was used in the development of C–C and C–N bond formation reactions via the hydrogen borrowing process. The complexes displayed high catalytic reactivity using 0.5–1.0 mol% of the catalyst and mild reaction conditions. Finally chiral carbene complexes were found to be activated by hydrogen gas. Their corresponding iridium hydride species were able to reduce ketones and imines with high efficiency and enantioselectivity without any additives, base or acid. / <p>At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 5: Submitted. Paper 6: Manuscript.</p><p> </p>

Esta tese descreve a primeira síntese assimétrica do sesquiterpeno fenólico (+)-(1S, 3R)-mutisiantol, assim como de seu enantiômero não-natural. O (+)-mutisiantol foi obtido em 11 etapas a partir do 2-metil-anisol, em rendimento global de 14% e excesso enantiomérico de 90%. Estas sínteses permitiram determinar a configuração absoluta deste produto natural. A etapa-chave da síntese consistiu na hidrogenação assimétrica do 4,7-dimetil-6- metóxi-1,2-di-hidronaftaleno, utilizando-se catalisadores opticamente ativos de irídio, conhecidos como Ir-PHOX. Com esta reação foi possível obter tanto o (+)-(S)- quanto o ()- (R)-1,6-dimetil-7-metóxi-1,2,3,4-di-hidronafaleno em ótimos rendimentos e excessos enantioméricos. Uma outra etapa importante desta síntese foi a reação de contração de anel do 1,6- dimetil-7-metóxi-1,2-di-hidronaftaleno. Esta oxidação foi realizada através da reação do 1,2- di-hidronaftaleno com tálio(III) ou com iodo(III). Ambos oxidantes levaram exclusivamente ao trans-indano desejado em rendimentos que variaram de moderado a bom. Esta tese também descreve a preparação, em excelentes excessos enantioméricos, de uma série de 1-tetralóis opticamente ativos, através de dois tipos diferentes de biotransformações: a) a resolução cinética enzimática de 1-tetralóis mediada por CALB; e b) a biorredução de 1-tetralonas mediada por Daucus carota. / This thesis presents the first asymmetric synthesis of the phenolic sesquiterpene (+)- (1S, 3R)-mutisianthol, as well as its non-natural enantiomer. The (+)-mutisianthol was obtained in 11 steps from 2-methylanisole, with 14% overall yield and enantiomeric excess of 90%. This synthesis allowed to assign the absolute configuration of this natural product. The key-step was an asymmetric hydrogenation of 4,7-dimethyl-6-methoxy-1,2- dihydronaphthalene using optically active iridium catalysts, known as Ir-PHOX. This reaction led to the either (+)-(S) or ()-(R)-1,6-dimethyl-7-methoxy-1,2,3,4-dihydronaphthalene in good yields and enantiomeric excess. Another important step of the route was the ring contraction reaction of the 1,6- dimethyl-7-methoxy-1,2-dihydronaphthalene, which was performed using thallium(III) or iodine(III). Both oxidants led exclusively to the desired trans-indan in good to excellent yield. This thesis also describes the preparation of a series of optically active 1-tetralols in excellent enantiomeric excesses, using two different biotransformations: a) the kinetic enzymatic resolution of 1-tetralols mediated by CALB and b) the bioreduction of 1-tetralones mediated by Daucus carota.

<p>This thesis describes stereoselective syntheses of four amino acids, three of which are C-glycosidic analogues of glycosylated amino acids. The overall goal of the project was to probe the interactions between MHC molecules, glycopeptide antigens and T cell receptors, that are essential for development of collagen induced arthritis. Collagen induced arthritis is a frequently used mouse model for rheumatoid arthritis, an autoimmune disease that attacks joint cartilage and leads to a painful and eventually crippling condition.</p><p>The thesis is based on four studies. The first study describes the synthesis of hydroxylysine, an amino acid that is found in collagen and is an important constituent of the glycopeptide proposed as an antigen in collagen induced arthritis. During the synthesis of hydroxylysine some new insight into the mechanism of the reductive opening of <i>p</i>-methoxybenzylidene acetals was obtained.</p><p>The remaining three studies deals with the synthesis of C-glycosidic analogues of glycosylated amino acids, hydroxy norvaline, threonine and hydroxylysine.The synthesis of each amino acid required control of several stereogenic centra and utilizes a variety of approaches such as use of stereoselective reactions, chiral auxilaries, chiral templates and asymmetric catalysis.</p><p>The C-glycosidic analogues of galactosylated hydroxynorvaline and hydroxylysine were incorporated in glycopeptides from type II collagen and evaluated in T cell response assays. It was found that the T cells were stimulated by the C-glycopeptides, but that higher concentrations were required than for the native O-glycopeptide</p>

This thesis describes stereoselective syntheses of four amino acids, three of which are C-glycosidic analogues of glycosylated amino acids. The overall goal of the project was to probe the interactions between MHC molecules, glycopeptide antigens and T cell receptors, that are essential for development of collagen induced arthritis. Collagen induced arthritis is a frequently used mouse model for rheumatoid arthritis, an autoimmune disease that attacks joint cartilage and leads to a painful and eventually crippling condition. The thesis is based on four studies. The first study describes the synthesis of hydroxylysine, an amino acid that is found in collagen and is an important constituent of the glycopeptide proposed as an antigen in collagen induced arthritis. During the synthesis of hydroxylysine some new insight into the mechanism of the reductive opening of p-methoxybenzylidene acetals was obtained. The remaining three studies deals with the synthesis of C-glycosidic analogues of glycosylated amino acids, hydroxy norvaline, threonine and hydroxylysine.The synthesis of each amino acid required control of several stereogenic centra and utilizes a variety of approaches such as use of stereoselective reactions, chiral auxilaries, chiral templates and asymmetric catalysis. The C-glycosidic analogues of galactosylated hydroxynorvaline and hydroxylysine were incorporated in glycopeptides from type II collagen and evaluated in T cell response assays. It was found that the T cells were stimulated by the C-glycopeptides, but that higher concentrations were required than for the native O-glycopeptide

Transition metal catalysis is a powerful tool for the construction of biologically active and pharmaceutically relevant architectures. With the challenge of continually depleting resources that this generation of scientists faces, it is becoming increasingly important to develop sustainable technologies for organic synthesis that utilize abundant and renewable feedstocks while minimizing byproduct formation and shortening the length of synthetic sequences by removing unnecessary protecting group manipulations and functionalizations. To this end, we have developed four new methods that transform inexpensive starting materials to valuable products. This dissertation covers the following key areas: 1) activation of CO2 for a mild and functional group tolerant synthesis of carboxylic acids, 2) oxidative twofold C–H bond activations as a strategy toward biaryls, 3) migratory O- to N-rearrangements in pyridines and related heterocycles for the preparation of N-alkylated heterocycles, and 4) asymmetric hydrogenations of cyclic imines and enamines en route to chiral 1,2- and 1,3-diamines and macrocyclic peptides.

Transition metal catalysis is a powerful tool for the construction of biologically active and pharmaceutically relevant architectures. With the challenge of continually depleting resources that this generation of scientists faces, it is becoming increasingly important to develop sustainable technologies for organic synthesis that utilize abundant and renewable feedstocks while minimizing byproduct formation and shortening the length of synthetic sequences by removing unnecessary protecting group manipulations and functionalizations. To this end, we have developed four new methods that transform inexpensive starting materials to valuable products. This dissertation covers the following key areas: 1) activation of CO2 for a mild and functional group tolerant synthesis of carboxylic acids, 2) oxidative twofold C–H bond activations as a strategy toward biaryls, 3) migratory O- to N-rearrangements in pyridines and related heterocycles for the preparation of N-alkylated heterocycles, and 4) asymmetric hydrogenations of cyclic imines and enamines en route to chiral 1,2- and 1,3-diamines and macrocyclic peptides.

Durant les darreres dècades, el disseny de processos en el marc de la química sostenible ha anat creixent de forma exponencial. La recerca constant de processos mes benignes amb el medi ambient ha implicat un gran esforç per obtenir millors rendiments mitjançant l'activació de llocs específics, i possant especial èmfasi amb el control de la quimio-, la regio- i la enantioselectivitat, punts crucials per a l'economia atómica. En aquest sentit, els dissolvents juguen un paper crític, i com podrà veure's al llarg d'aquesta memòria..Aquesta Tesi s'enfoca en l'ús de mitjans de reacció alternatius i sostenibles, com són els líquids iònics (ILs), el diòxid de carboni supercrític (scCO2) i la barreja de ambdós dissolvents, amb l'objectiu de disminuir l'ús de dissolvents orgànics convencionals i la seva aplicació en els següents processos catalítics: hidrogenació asimètrica, reacció de Suzuki d'acoblament creuat C-C, reacció d'alquilació al·lílica asimètrica i la hidrogenació de arens. / In the last decades, the design of processes in the framework of the sustainable chemistry has been exponentially growing. The constant searching of cleaner processes has led to a lot of effort to obtain higher yields by activation of specific sites, and improving chemo-, regio- and enantio-selectivities, which are crucial from a point of view of an atom economy strategy. In this sense, solvents play a critical role. This PhD thesis focuses on the use of alternative sustainable reaction media such as ionic liquids (ILs), supercritical carbon dioxide (scCO2) and mixtures of both solvents in different catalytic processes, with the aim of decreasing the use of conventional organic solvents applied in the following catalytic reactions: homogeneous and supported rhodium catalysed asymmetric hydrogenation, biphasic palladium catalysed Suzuki C-C cross-coupling, homogeneous palladium catalysed asymmetric allylic alkylation, and ruthenium and rhodium nanoparticles catalysed arene hydrogenation were tested.

Esta tese descreve a primeira síntese assimétrica do sesquiterpeno fenólico (+)-(1S, 3R)-mutisiantol, assim como de seu enantiômero não-natural. O (+)-mutisiantol foi obtido em 11 etapas a partir do 2-metil-anisol, em rendimento global de 14% e excesso enantiomérico de 90%. Estas sínteses permitiram determinar a configuração absoluta deste produto natural. A etapa-chave da síntese consistiu na hidrogenação assimétrica do 4,7-dimetil-6- metóxi-1,2-di-hidronaftaleno, utilizando-se catalisadores opticamente ativos de irídio, conhecidos como Ir-PHOX. Com esta reação foi possível obter tanto o (+)-(S)- quanto o ()- (R)-1,6-dimetil-7-metóxi-1,2,3,4-di-hidronafaleno em ótimos rendimentos e excessos enantioméricos. Uma outra etapa importante desta síntese foi a reação de contração de anel do 1,6- dimetil-7-metóxi-1,2-di-hidronaftaleno. Esta oxidação foi realizada através da reação do 1,2- di-hidronaftaleno com tálio(III) ou com iodo(III). Ambos oxidantes levaram exclusivamente ao trans-indano desejado em rendimentos que variaram de moderado a bom. Esta tese também descreve a preparação, em excelentes excessos enantioméricos, de uma série de 1-tetralóis opticamente ativos, através de dois tipos diferentes de biotransformações: a) a resolução cinética enzimática de 1-tetralóis mediada por CALB; e b) a biorredução de 1-tetralonas mediada por Daucus carota. / This thesis presents the first asymmetric synthesis of the phenolic sesquiterpene (+)- (1S, 3R)-mutisianthol, as well as its non-natural enantiomer. The (+)-mutisianthol was obtained in 11 steps from 2-methylanisole, with 14% overall yield and enantiomeric excess of 90%. This synthesis allowed to assign the absolute configuration of this natural product. The key-step was an asymmetric hydrogenation of 4,7-dimethyl-6-methoxy-1,2- dihydronaphthalene using optically active iridium catalysts, known as Ir-PHOX. This reaction led to the either (+)-(S) or ()-(R)-1,6-dimethyl-7-methoxy-1,2,3,4-dihydronaphthalene in good yields and enantiomeric excess. Another important step of the route was the ring contraction reaction of the 1,6- dimethyl-7-methoxy-1,2-dihydronaphthalene, which was performed using thallium(III) or iodine(III). Both oxidants led exclusively to the desired trans-indan in good to excellent yield. This thesis also describes the preparation of a series of optically active 1-tetralols in excellent enantiomeric excesses, using two different biotransformations: a) the kinetic enzymatic resolution of 1-tetralols mediated by CALB and b) the bioreduction of 1-tetralones mediated by Daucus carota.

Ce mémoire de thèse est consacré au développement de nouveaux systèmes catalytiques dérivés de métallocyclodextrines. Les travaux qui y sont décrits ont trait à la mise au point de méthodes de fonctionnalisation régiosélective de la face primaire des cyclodextrines donnant accès à des ligands hétérodentés de type P,P’ à chiralité inhérente. Ces derniers forment quantitativement des complexes chélate de géométrie cis, dont les versions rhodiées ont été testées en hydrogénation eten hydroformylation asymétriques d’oléfines prochirales. L’étude des propriétés complexantes et catalytiques de deux phosphines confinantes dérivées d’α- et de β-cyclodextrine a également étér éalisée. L’ancrage rigide de l’atome de phosphore (III) au sein de la matrice cyclodextrine permet de confiner le centre métallique au coeur du macrocycle, ce qui se traduit par la formation exclusive de complexes mono-ligandés en phosphore. Les complexes monophosphine de rhodium (I) catalysent l’hydroformylation asymétrique du styrène avec une très forte sélectivité en produit branché et une énantiosélectivité très élevée. Le pontage de diaminocyclodextrines par l'acénaphtènequinone permet d’obtenir des ligands potentiellement confinants dans lesquels l’anse azotée de type N-(2-N’-alkylaminoacenaphthenyl)alkylimine est dissymétrique. L’oxydation du pont par voie chimique ou électrochimique conduit à une anse imidazole 1,2-disubstitué très courte qui provoque une forte déformation du squelette cyclodextrine. / This manuscript is concerned with the design of novel catalytic systems derived from metallocyclodextrins. The first part describes new ways of functionalising the cyclodextrin primary face regioselectively for accessing inherently chiral P,P’ chelators. These heterodentate ligands gavequantitatively cis-chelate complexes with various d8 cations. Their rhodium(I) complexes were assessed in the asymmetric hydrogenation and hydroformylation of prochiral olefins. Thecoordination and catalytic properties of two phosphines derived from a- and b-cyclodextrin are also reported. With their phosphorus lone pair pointing toward the CD core, these confining ligands force the coordinated metal centre to stay within the CD hollow and promote the formation of singly phosphorus-ligated complexes. Rhodium (I) monophosphine complexes of this type catalyse the asymmetric hydroformylation of styrene with both very high isoselectivity and enantioselectivity. Capping of diaminocyclodextrins with acenaphthenequinone resulted in the formation of a nonsymmetricN-(2-N’-alkylaminoacenaphthenyl)alkylimine handle with two intra-annular nitrogen atoms. A strong deformation of the cyclodextrin scaffold was shown to take place upon chemical or electrochemical oxidation of the bridging unit into the very short 1,2-disubstituted imidazole moiety.