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Chiral phosphoric acids are bifunctional catalysts that have the ability to activate electrophiles and nucleophiles through hydrogen bonding, and they have been successful in catalysing highly enantioselective additions of a wide range of nucleophiles to imines. In most literature reports it is not frequently revealed how these catalysts impart enantioselectivity. Thus, the vast majority of time required for reaction development is expended on the optimisation of the catalyst features. The research described here explores the ability of relating computational derived catalyst parameters to enantioselectivity as a means to assess the catalyst features important for enantioinduction. The proposed features are evaluated computationally and summarised into simple qualitative models to understand and predict outcomes of similar reactions. In Chapter 1, I provide an overview of the progress and challenges in the development of chiral phosphoric acid mediated reactions. I highlight leading computational studies that have enabled a greater understanding of how the catalyst imparts reactivity and selectivity. In general, the studies focus on the most effective catalyst and do not do a detailed investigation into the effects of changing the substituents at the 3,3’ positions. Implicating steric effects from reasonably large groups as a key component in imparting enantioselectivity. However, it is clear that they have a more subtle effect. A large group is required but if it is too large poor or unusual results are obtained, making the correct choice of reaction conditions challenging. In Chapter 2, I develop a quantitative assessment of the substituents at the 3,3’ positions. I show in Chapters 3 and 4 that I can use rotation barriers in combination with a novel steric parameter, AREA(θ), to correlate enantioselectivity. By exploiting this finding, the catalyst features important for enantioselectivity can be identified, and this is validated by QM/MM hybrid calculations. Summarising these detailed calculations into a single qualitative model, guides optimal catalyst choice for all seventy-seven literature reactions reporting over 1000 transformations. These mechanistic studies have guided the design of a new catalyst with increased versatility, which is discussed in Chapter 5. Chapter 6 details my study into the effect of the hydroxyl group on the mechanism of transfer hydrogenation of imines derived from ortho-hydroxyacetophenone. I show, using detailed DFT and ONIOM calculations, that transition states of these reactions involve hydrogen bonding from both the hydroxyl group on the imine and the nucleophile’s proton to the phosphate catalyst. In Chapter 7, computational analysis is used to provide insight into the origins of enantioselectivity in chiral phosphoric acid catalysed Friedel-Crafts and Mannich reactions proceeding through monoactivation mechanisms. The final chapter contains an in-depth look into the stereoelectronic effects altering enantioselectivity in the silver-phosphate mediated spirocyclisation reaction involving aromatic ynones. In this study I show that enantioselectivity is governed by the non-covalent interactions between the aromatic group of the ynone and the 3,3’ substituent. I was able to propose synthetic modifications to the substrate used in this reaction, resulting in an improvement in enantioselectivity.

Synthesis of optically active dendrimers based on 1,1'-bi-2-naphthol enantiomers and their derivatives as core units is growing rapidly due to the unique behavior and properties of the new compounds and their various valuable applications in several fields such as asymmetric catalysts, enantioselective fluorescent sensors and in chiral molecular recognition. To the best of our knowledge, the synthesis of binaphthyl-based symmetrical and asymmetrical axially chiral dendrimers via 1,3-cycloaddition reactions ["Click" chemistry] using Fréchet-type dendrons and their azido-analogues has not been studied yet. The principal aim of this project was the synthesis and characterization of a novel series of binaphthyl-based symmetrical and asymmetrical axially chiral dendrimers via "Click" and etherification reactions, and then determination of the specific and molar rotation of the new dendrimers to investigate the influence of linkage nature between the dendritic wedges and the core units on the optical properties in presence of the triazole ring by comparing of the properties of the new dendrimers with the dendrimers reported in literature, in addition to study the influences of different chemical groups near the dendritic wedges on the optical properties of the novel synthesized dendrimers. In conclusion, several families of novel BINOL-based symmetrical and asymmetrical axially chiral dendrimers have been synthesized by the reaction of well-known BINOL derivatives as core units with Fréchet-type dendrons and their azido-analogues via "Click" and etherfication reactions for the first time. All new dendrimers were obtained in very good yields which confirm the effectiveness of "Click" reaction in this type of synthesis. The new dendrimers were fully characterized by 1H, 13C and HMQC NMR spectroscopy, mass spectrometry, IR spectroscopy and UV-Vis spectrometry. All new dendrimers show moderate optical activity. Changes in the specific and molar rotation are characterized by a general decrease in the specific rotation and a general increase in the molar rotation with the increase in the dendritic wedges generation in each series of the synthesized dendrimers. By our current knowledge, the increase in the specific rotation as generation increases of (S)-358, (S)-359 and (S)-360 observed in this research is the first such observation. The presence of the triazole ring in the linkage between the core unit and the dendritic wedges plays an important role in reducing of the steric repulsion between the two naphthyl units and in reducing of the effect of the dendritic wedges generation on the torsional angle by making the wedges far away from the attachment point of the two naphthyl units.

La presente Tesis Doctoral se encuentra dividida en dos Capítulos. En el Capítulo 1 se presentan los estudios realizados sobre la síntesis de ésteres insaturados derivados de BINOL, TADDOL y TTFOL y su aplicación en reacciones de hidroestannación radicalaria. El empleo de TFAA/H3PO4 no sólo provocó la apertura del diacetónido sino que además se observó una reorganización estructural selectiva, con retención de la configuración. Los nuevos diésteres obtenidos con simetría C2 lograron sintetizarse bajo condiciones suaves de reacción, con excelentes rendimientos y tiempos cortos. Asimismo, teniendo en cuenta antecedentes previos junto con un estudio por RMN dinámica, se realizó un estudio del mecanismo involucrado. La ruta sintética desarrollada resulta atractiva para la generación de derivados del tetrahidrofuran-3,4-diol, importantes en síntesis estereoselectiva. También, dada la importancia de los diésteres de BINOL en diversos campos, se buscó una ruta sintética adecuada para la generación de los mismos. Se estableció nuevamente que el uso de TFAA/H3PO4 dio los mejores resultados en lo que respecta a tiempos y rendimientos de reacción. Este mismo método se utilizó para la síntesis de ésteres del ácido cafeico, los cuales son de interés por su actividad biológica. En relación a los estudios de hidroestannación sobre diésteres insaturados derivados de TADDOL, se desarrollaron dos nuevos métodos que permitieron la síntesis estereoselectiva de macrolidos con variaciones en las condiciones de reacción respecto al método de referencia. Se observó que, según el diéster y el hidruro utilizado, se produjeron cambios sustanciales en la diasteroselectividad, los tiempos de reacción y los rendimientos obtenidos. La misma reacción fue estudiada para los nuevos diésteres insaturados de BINOL. En este caso, la hidroestannación radicalaria no tuvo lugar con ciclación intramolecular sino que se observó la existencia de aductos de mono y diadición. Asimismo, debido a la actividad catalítica que presentan ciertos haluros de trialquilestaño o dialquilestaño, se generaron los derivados bisiododifenilestannilados y bisclorodialquilestannilados, ambos con excelentes rendimientos y moderada diastereoselectividad. Finalmente, dada la importancia biológica de los -amino derivados, se estudió la generación de los mismos por reacción de Aza-Michael sobre los diésteres enantioméricamente puros derivados de TADDOL, BINOL y TTFOL. En el Capítulo 2, los estudios que se presentan se desarrollaron bajo el marco de una Beca para Jóvenes Docentes de la UNS en el Instituto de Investigaciones Biomédicas (IRB, Barcelona, España). Se realizaron reacciones de hidrogenación y Pauson-Khand asimétricas catalizadas por el complejo Rh-MaxPHOS. Se hicieron medidas cinéticas de la 2 velocidad de hidrogenación sobre los sustratos MAA y Z-MAC las cuales dieron resultados comparables a los obtenidos con el catalizador de referencia. Además, se logró disminuir la carga de catalizador para MAA. Así, la hidrogenación asimétrica de una serie de N-acil enamidas ocurrió con excelente grado de conversión y enantioselectividad. Posteriormente, se estudió el catalizador frente a reacciones de Pauson-Khand intramoleculares, siendo eficaz para la ciclización de varios 1,6-eninos con excesos enantioméricos de buenos a muy buenos. En ambos casos los productos generados son de potencial importancia biológica. / The present Doctoral Thesis is divided in two chapters. In Chapter 1, the studies about the synthesis of unsaturated esters derived from BINOL, TADDOL and TTFOL and their application in radical hydrostannation reactions is presented. The use of TFAA/H3PO4 caused not only the opening of the diacetonide but a selective structural reorganization with retention of the configuration too. The new diesters with C2 symmetry were synthesized under mild reaction conditions, excellent yields and in short time. The involved mechanism is proposed taking into account previous results together with a dynamic NMR study. The synthetic developed route is attractive for the generation of derivatives of tetrahydrofuran-3,4-diol, important in stereoselective synthesis. Also, and given the increasing interest in BINOL diesters in many fields, the search of new synthetic routes was studied. It was stablished that, again, the system TFAA/H3PO4 gave the best results in relation to yields and reaction time. Following with the esterification procedures, the excellent results obtained with the employment of this system, for the synthesis of caffeic acid esters due to the wide scope of biological applications. In the research about hydrostannation reactions of unsaturated esters of TADDOL, two new methods were developed that allowed the stereoselective synthesis of macrolides with variations on the reaction conditions in comparison with the reference method. It was observed that, according with the diester and the hydride used, substantial changes occurred related with diastereoselectivity. The same procedure was used for the new BINOL unsaturated diesters. In this case, the radical hydrostannation did not take place with intramolecular cyclization but the existence of mono- and diaddition products was determined. Also, and due to the catalytic activity that some trialkyl- and dialkyltin halides present, the corresponding bis-iododiphenylstannyl and bis-chlorodialkylstannyl derivatives were obtained, with both excellent yields and moderate diastereoselectivity. Finally, and 3 because of the potential biological applications of the -amino derivatives, the synthesis of this type of compounds by means of the Aza-Michael reaction was accomplished. In Chapter 2 are presented the studies made in the Biomedical Research Institute, (IRB, Barcelona, Spain) under a Young Researchers Fellowship (UNS). The asymmetric hydrogenation and Pauson-Khand reactions catalyzed by Rh-MaxPHOS complex were achieved. Kinetic measures on the rate of the hydrogenation reaction over MAA and Z-MAC substrates were done. The results observed here were comparative to those obtained with the reference catalyst. Besides, it was possible to reduce the catalyst charge for MAA. Thus, the asymmetric hydrogenation of a variety of N-acyl enamides happened with excellent conversion and enantioselectivity. Afterwards, the catalyst was studied in the intramolecular Pauson-Khand reactions and probed to be very efficient for the cyclization of some 1,6- enynes with good to very good enantiomeric excess.

La fonctionnalisation sélective de BINOL en position 6 ou 6 et 6' par des groupements 3 - (diméthylamino)prop-1-yn-1-yl est décrite. Cette méthode constitue une stratégie prometteuse pour le développement de nouveaux ligands recyclables. Les complexes de La et Yb correspondants ont été testés dans la réaction d’époxydation des cétones α, β-insaturées. Les complexes d’ytterbium sont les plus efficaces, fournissant les époxydes chiraux attendus avec 90 ou 93% d’excès énantiomérique en conditions homogène et hétérogène, respectivement.Dans le cadre de nos études, nous avons également évalué de nouveaux catalyseurs comportant un ion de manganèse penta-coordinnée [LMn(III)OH]ClO4 et [LMnCl](MnCl4)0,5. Ces complexes ont été testés dans la réaction d’époxydation des oléfines terminales utilisant H2O2/NaHCO3 et PhIO comme oxydant. Il s'avère que le complexe [LMn(III)OH]ClO4 est le catalyseur le plus efficace de la série. Une autre approche également été envisagée : oxyder une molécule d’eau présente dans la sphère de coordination du métal par le Cerium Ammonium Nitrate (CAN) et utiliser l’espèce oxydante ainsi générée pour oxyder des substrats. Nos études ont montré que cette stratégie était possible et permettait d’oxyder des substrats organiques. / The selective functionalization of BINOL in position 6 or 6 and 6’ with 3-(dimethylamino)prop-1-yn-1yl is described, and it constitutes a promising strategy for the development of a recyclable ligands. The corresponding La and Yb complexes were evaluated towards the epoxidation of α,β-unsaturated ketones. The Yb-complexes displayed an efficient activity, affording the expected chiral epoxides in up to 90 or 93% ee in homogeneous and heterogenous catalysis, respectively.As part of our studies, we also evaluated new catalysts with a penta-coordinated manganese ion [LMn(III)OH]ClO4 and [LMnCl](MnCl4)0.5. These complexes were tested in the epoxidation reaction of terminal olefins using H2O2/NaHCO3 and PhIO as an oxidant. It turns out that the complex [LMn (III) OH] ClO4 is the most efficient catalyst of the series. Another approach was also considered: oxidize a molecule of water present in the coordination sphere of the metal by Cerium Ammonium Nitrate (CAN) and use the generated oxidizing species to oxidize substrates. Our studies have shown that this strategy was feasible and allowed to oxidize organic substrates.

The 2,2'-disubstituated 1,1'-binaphthyls (BINOLs) are important ligands in enantioselective synthesis . The major approach for their preparation is based on transition-metal-mediated oxidative C-C coupling of 2-substituted naphtalenes. This diploma thesis examined the mechanism of the coupling reaction in the gas phase using mass spectrometry with electrospray ionization. The aim of this thesis was to compare the selectivity of the copper(II)- catalyzed coupling reaction of 2-naphthol and its derivative with an electron-withdrawing group, to detect possible reaction intermediates, and to determine the origin of the preference of the cross-coupling. The electron-withdrawing group of naphthol slows down the coupling reaction which enabled us to detect the reaction intermediates. The intermediates in the reaction of 2-naphthol were not observed, because the coupling reaction proceeds too quickly. Hence, we have observed only complexes of the coupling products. The preferential cross coupling was explaned on the basis of an interplay between the probability of the formation of binuclear copper complexes and the reactivity of such complexes.

The synthesis of new molecules is often initiated with the desire to create unique materials that have specific functions and/or properties. The materials are often used in areas such as pharmaceuticals, medical imaging, and energetics. Preparation of these materials utilizes fundamental rules that define how molecules interact with each other in a solid. My research focuses on employing the established concepts to predict how certain molecules interact and assessing the solid form that results (crystal structure) from these interactions. The solids investigated in my research are composed of two different molecules that can combine in various ways based on complementary interactions. Once the two molecules interact to form a crystal structure, external stimuli, such as heat, can cause the atoms within the crystal to move in specific directions to allow for events such as water loss, or it can initiate atoms to rearrange completely to form a new molecule. My work evaluates how the crystal structure changes when the atoms move and how the interactions between the molecules are impacted. The results of my research indicate the crystal structure can be controlled by aspects such as physical size and the properties of the individual molecules within the crystal. Additionally, my work involves assessing new ways to synthesize the described molecules by using technology that avoids the use of harmful solvents. My research has demonstrated a new mixing method that can prepare molecules in the lab and production facilities that reduces the amount of solvent needed and improves sustainability through chemistry.

Le BINOL est un inducteur chiral largement utilisé dans les réactions asymétriques. Le travail de ce mémoire porte sur la synthèse d'un nouveau dérivé du BINOL, porteur de groupements triflyles (CF3SO2) fortement électroattracteurs et présente ses premières applications en catalyse asymétrique.<br />La première partie constitue une mise au point bibliographique sur le BINOL et ses dérivés substitués par des groupements électroattracteurs en position 3,3' et/ou 6,6'. Ces derniers ont montré que la présence de ce type de groupements induit de fortes augmentations de stéréosélectivité et s'est révélée bénéfique pour le turnover.<br />La deuxième partie présente la synthèse et la caractérisation du nouveau (R)-6,6'–bis(trifluorométhanesulfonyl)-1,1'-bi-2-naphtol. Au regard de la difficulté de la trifluorométhanesulfonylation aromatique, cette synthèse a nécessité de nombreuses tentatives que nous citons avant de détailler la voie de synthèse originale de ce ligand que nous avons mise au point.<br />La troisième partie décrit les premières applications du (R)-6,6'-Tf2BINOL en catalyse asymétrique. Les résultats que nous avons obtenus indiquent clairement que ce ligand, complexé à des métaux oxophiles tels que le zirconium ou le titane, conduit à des catalyseurs organométalliques très actifs.<br />Lors de la caractérisation et des essais de cristallisation du complexe du zirconium, nous avons isolé un produit dont la structure correspond à un cluster organométallique. Ce dernier s'est avéré stable à l'air et plus performant dans la catalyse de la réaction type-Mannich que le complexe préparé in situ.

Les ligands de carbènes N-hétérocycliques (NHC) qui possèdent une symétrie C1 attirent beaucoup l’attention dans la littérature. Le présent projet de recherche propose de synthétiser une nouvelle série de ligands NHC C1-symétriques avec deux groupements N-alkyles qui exploitent un relais chiral. Un protocole modulaire et efficace pour la synthèse des sels d’imidazolium chiraux qui servent comme préligands pour les NHC a été développé. Quelques-uns de ces nouveaux ligands ont été installés sur le cuivre et de l’or, créant de nouveaux complexes chiraux. Les nouveaux complexes à base de cuivre ont été évalués comme catalyseurs pour le couplage oxydatif de 2-naphthols. Les ligands C1-symmétriques ont fourni des meilleurs rendements que les ligands C2-symmétriques. Au cours de l’optimisation, des additifs ont été évalués; les additifs à base de pyridine ont fourni des énantiosélectivités modérées tandis que les additifs à base de malonate ont donné des meilleurs rendements de la réaction de couplage oxydatif. Ultérieurement, les additifs à base de malonate ont été appliqués envers l’hétérocouplage de 2-naphthols. Le partenaire de couplage qui est riche en électrons est normalement en grand excès à cause de sa tendance à dégrader. Avec le bénéfice de l’additif, les deux partenaires de couplage peuvent être utilisés dans des quantités équivalentes. La découverte de l’effet des additifs a permis le développement d’un protocole général pour l’hétérocouplage de 2-naphthols. / A new class of C1-symmetric N-heterocyclic carbene (NHC) ligands has been developed. The new ligands exploit a biaryl methyne as a chiral relay, and an N-methyl group as a reactivity controlling element. The precursors for the new ligands were synthesized via a modular scheme that allows for facile diversification. Several of the new ligands were installed onto both copper and gold, generating mono N-heterocyclic carbene transition metal complexes. The new C1-symmetric copper complexes were tested as catalysts for the synthesis of binaphthols via the oxidative coupling of electron poor 2-naphthols. The new C1-symmetric ligands afforded higher yields than their C2-symmetric counterparts. During the course of the optimization, small molecule additives were found to modulate the reactivity of the copper catalyst. Pyridine additives, such as 2-picoline, were found to induce low to moderate enantioselectivity in the oxidative coupling reaction, while diethylmalonate was found to improve the reaction yield without affecting the selectivity. The malonate additive was employed in the catalytic oxidative heterocoupling of electronically dissimilar 2-naphthols. The electron-rich coupling partner is normally added in a large excess due to its tendency to degrade. When the malonate additive is used, the coupling partners can be used in equimolar quantities. The discovery resulted in the development of a general protocol for the additive assisted aerobic oxidative heterocoupling of electronically dissimilar 2-naphthols.

Die Mukaiyama-Aldolreaktion ist die Umsetzung eines Silylenolethers mit einer Carbonylverbindung in Gegenwart einer Lewis-Säure. Diese Reaktion ist eine wichtige Methode zur Knüpfung einer Kohlenstoff-Kohlenstoff-Bindung in der Organischen Chemie. In der vorliegenden Arbeit wird mittels quantenchemischer Methoden ein Einblick in den Mechanismus der Reaktion und die Ursachen der Enantioselektivität gegeben. Ausgehend von der unkatalysierten Reaktion wurde der Mechanismus der von kleineren achiralen Lewis-Säuren wie BF3 und TiCl4 katalysierten bzw. vermittelten Reaktion bearbeitet. Mit dem NEB-Verfahren zur Berechnung des Reaktionsmechanismus der enantioselektiv katalysierten Reaktion kam eine neuartige Möglichkeit zur Optimierung von Reaktionswegen zum Einsatz. Es konnte gezeigt werden, dass die Optimierung auch sehr komplexer Reaktionswege möglich ist. So wurde der gesamte katalytische Cyclus der Ti-BINOL katalysierten Reaktion berechnet, wobei sich der Einsatz der DFTB-Methode (density-functional based tight-binding method) zur Berechnung des Systems als sehr gut geeignet erwies. Die Leistungsfähigkeit der DFTB Methode konnte im Vergleich mit den geometrischen Daten aus Röntgenkristallstrukturanalysen nachgewiesen werden. Die Richtung der stereochemischen Differenzierung konnte in Übereinstimmung mit den experimentellen Ergebnissen bestimmt werden. Aus diesem Ergebnis war es möglich, ein schematisches Modell zu entwickeln, das die Ursache der Selektivität veranschaulicht.