Dissertations / Theses on the topic 'Organocatalysis'

Catalyse et repliement sont deux notions intimement liées dans la Nature à travers les protéines et les enzymes, puis par extension, avec les catalyseurs synthétiques conçus par les chimistes. Des briques élémentaires artificielles ont été développées depuis deux décennies afin de synthétiser de nouvelles architectures moléculaires ayant une forte propension à se replier, appelées foldamères. Dans de nombreux systèmes biomimétiques inspirés par les biopolymères, la stabilisation d’une forme repliée résulte de la formation d’un fort réseau de liaisons H. Ces squelettes repliés apportent plusieurs avantages pour une application en catalyse : ils peuvent offrir un effet coopératif lors de la coordination d’un ligand, une meilleure stabilisation des intermédiaires chargés ainsi qu’une minimisation du coût entropique de la formation de l’état de transition. Ils constituent une nouvelle classe d’organocatalyseurs méritant de plus amples investigations. L’organocatalyse présente un fort intérêt dans la recherche actuelle, dû la simplicité de mise en œuvre des systèmes et l’absence de métaux conduisant à une moindre toxicité. Cependant, des charges importantes (5-20 mol%) en catalyseur sont souvent nécessaires pour réaliser des transformations chimiques avec de bons rendements et de bonnes stéréosélectivités. L’effet synergique apporté par la structure bien définie des foldamères via leur fort réseau de liaisons hydrogène peut jouer en faveur d’une diminution de la charge catalytique du système.Les foldamères à base de motifs oligo(thio)urées sont des analogues des peptides, avec une structure secondaire hélicoïdale, 2.5 résidus par tour et un réseau de liaisons hydrogène fermant des pseudo-cycles à 12 et 14 atomes, et ils présentent un macrodipôle pouvant être renforcé par l’activation avec un groupe électroattracteur au niveau du pôle positif. La liaison d’anions avec des oligourées a été démontrée comme étant site-spécifique et n’ayant aucune influence sur la structure hélicoïdale, illustrant leur fort potentiel de liaison d’espèces chargés négativement. Les urées et les thiourées ont été largement utilisées comme donneurs de liaisons hydrogène pour l’organocatalyse avec des résultats très satisfaisants. Ces concepts posent les bases pour développer un organocatalyseur innovant avec des foldamères oligo(thio)urées, interagissant par activation des substrats par formation de liaisons H. Une étude autour de la relation structure-activité, accompagnée de l’élaboration d’une réaction modèle avec un large panel de substrats, ainsi que des études mécanistiques via des mesures RMN, vont permettre d’établir les principes gouvernant la catalyse avec des foldamères oligo(thio)urées
Catalysis and folding are two closely interwoven notions in Nature particularly among enzymes, and by extension can be applied to synthetic catalysts designed by chemists. Artificial monomers have been created for two decades to synthesize new oligomeric molecular architectures with a high propensity to fold, which are called foldamers. In many systems, folded structure is stabilized by a strong hydrogen-bonding network, in a similar way to biopolymer structures. These folded backbones may provide significant advantages as catalyst as they could offer cooperativity in ligand binding, a greater stabilization of charged intermediates and then a minimization of entropic cost of the transition state binding. They constitute a class of potential organocatalysts which deserves more investigation. Organocatalysis is an area of strong interest nowadays because of the lower toxicity of the catalysts and meta free procedures, their modularity and easiness to handle them. But generally high loading (5-20 mol%) are needed to perform chemical transformations with good yields and good stereoselectivities. The synergistic effect brought by the well-defined structures of foldamers through the strong hydrogen-bonding network can be in favour of a decrease of the catalyst loading.Oligo(thio)urea foldamers are peptides analogues, with a helical secondary structure, 2.5 residues per turn and 12- and 14-membered H-bond ring and present a macrodipole which can be reinforced through activation with electro-withdrawing group at the positive pole. Binding of anions to oligourea has been studied and was shown to be site specific and not to have any impact on the helical structure thus illustrating the high potential of coordination of negatively charged species to oligourea foldamers. Urea and thiourea small molecules have been widely used as H-bond donors for organocatalysis with very satisfying results. These concepts are the basis of the development of an innovative organocatalyst with oligo(thio)urea foldamers, acting through H-bond activation. A structure-activity relationship study combining an extended substrate scope and NMR mechanistic studies was performed allowing delineation of the principles governing oligourea foldamer-based catalysis

Durant molt temps, catàlisi homogènia ha estat gairebé sinònim amb catàlisi amb met¬alls de transició, amb un petit espai reservat a la biocatàlisi. Les coses han canviat molt en els últims anys. Des d'aproximadament l'any 2000, l'organocatàlisi, on el catalitzador és una molècula orgànica petita, sovint amb propietats quirals, ha crescut ràpidament fins a esdevenir un dels camps més importants de la química orgànica. A mesura que el camp de la investigació s'expandeix, el coneixement mecanístic esdevé més crítica per entendre les subtileses de la reacció i ajudar en el desenvolupament de processos més eficients. La química teòrica, amb la seva capacitat per localitzar els intermedis i estats de transició, pot ser molt útil en aquesta direcció. Aquesta tesi tracta de l'estudi com¬putacional del mecanisme de tres reaccions organocatalítiques representatives. 1. Hidroxialquilació Friedel-Crafts asimètrica d'indoles catalitzada per àcids de Brønsted quirals La catàlisi per àcids de Brønsted quirals és una àrea de ràpid creixement en organocatàlisi. L'aigua és una de les molècules més simples que pot actuar com a àcid de Brønsted. La coordinació de les molècules d'aigua a la funció carbonil en reaccions de Diels¬Alder i reordenaments de Claisen resulta en un increment de la velocitat de reacció. Carmona i col•laboradors van utilitzar una molècula d'aigua unida a un fragment d'iridi quiral com a catalitzador àcid de Brønsted per produir una reacció Friedel¬Crafts (FC) entre acetat de 3,3,3-trifluoromethylpyruvat i indole a baixa temperatura. Basant¬se en els seus resultats experimentals, hem dut a terme un estudi computacional en el mecanisme d'aquesta reacció i avaluat el paper catalític del complex de l'aigua amb iridi en aquesta reacció. La primera etapa de la reacció és la formació d'un enllaç C¬C juntament amb la transferència d'un protó de la molècula d'aigua al substrat, el segon pas és la l'etapa determinant, consistent en la transferència d'un protó de l'indole cap al grup OH provinent de la molècula d'aigua. El paper catalític del complex metàl.lic és la modulació de les propietats àcid / base de l'aigua coordinada, ja que la molècula d'aigua actua com a donador i acceptor de protons en les diferents etapes. Hem estat també capaços d'explicar l'origen de la l'estereoselectivitat del procés, que és el resultat d'una combinació subtil de les interaccions no covalents, tant atractives com repulsives, entre el catalitzador i el substrat. 2. Mecanisme de la síntesi enantioselectiva d'una cetona de Wieland-Miescher La cetona Wieland¬Miescher (WM) és un intermedi clau per a moltes reaccions. La preparació eficaç dels compostos de tipus cetona Wieland¬Miescher amb alta enantioselectivitat és per tant un desafiament en química orgànica. En un intent d'abordar aquest problema, el grup de Bonjoch ha dut a terme una síntesi enantioselectiva d'alta eficiència d'una cetona WM utilitzant N¬Ts¬(Sa)¬binam¬L¬prolinamida com a organocatalitzador, sota condicions lliures de dissolvent amb l'assistència d'àcid benzoic. El pas clau és una reacció d'anul • lació de Robinson, el procés requereix un 1% en mols de trietilamina com a base per a la reacció de Michael inicial i un 1% en mols de N¬Ts¬(Sa)¬Binam¬L¬prolinamida i 2,5% en mols d'àcid benzoic per a la reacció aldòlica intramolecular. Es va estudiar el mecanisme de la reacció aldòlica intramolecular en col • laboració amb el grup experimental. Hem estat capaços d'aclarir el mecanisme de la reacció amb prolinamida. Segueix les tendències generals del mecanisme amb prolina, amb l'important matís que la presència d'un àcid carboxílic com a co¬catalitzador és necessària en els passos inicials de la reacció, en particular per a la formació del intermedi imini. En contrast, l'àcid carboxílic no té cap efecte sobre la enantioselectivitat, perquè surt del sistema després de la formació de l'enamina, i està absent en l'estat de transició que condueix a la formació d'enllaços C¬C, on es decideix la enantioselectivitat de la reacció. L'origen de l'enantioselectivitat de la reacció també s'ha aclarit. Es basa en la rigidesa del catalitzador, que té dos punts d'ancoratge per al substrat, el doble enllaç C = N format a l'intermedi enamina, i els enllaços d'hidrogen NH ... O entre el catalitzador i el substrat. El substrat s'ha de distorsionar per unir¬se adequadament a aquest punts d'ancoratge, i aquesta distorsió és menor per a l'estat de transició que condueix a l'enantiòmer afavorit. 3. Mechanisme de la reacció de cicloaddició [4+2] catalitzada per derivats quirals de l'àcid fosfòric Els compostos heterocíclics amb àtoms de nitrogen i oxigen són abundants en la naturalesa i exhibeixen una àmplia gamma de propietats biològiques interessants, incloent comportament antihipertensiu i anti¬isquèmic. Els grups piranobenzopirà i furanobenzopirà, amb tres anells fusionats, són particularment interessants. Un enfocament atractiu per a la síntesi d'aquests compostos és una cicloaddició [4 +2] entre una hidroxibenzaldimina i un furà. Aquesta reacció és catalitzada per derivats d'àcid fosfòric. Hem analitzat en detall els resultats contradictoris publicats recentment pels grups de Fochi i Rueping. Fochi i col • laboradors van publicar el 2010 la síntesi de furanobenzopirans fusionats en cis mitjançant la cicloaddició [4 +2] amb demanda electrònica inversa (IED) de ο¬hidroxibenzaldimines amb 2,3¬dihidro¬2H-furà (DHF) catalitzada per derivats d'àcid fosfòric amb (S)¬BINOL. En el mateix any, Rueping i Lin van publicar la síntesi de furanobenzopirans fusionats en trans a partir dels mateixos reactius però amb un catalitzador del tipus (S)¬BINOL derivat de la N-triflilfosforamida. Els mateixos reactius i catalitzadors lleugerament diferents produeixen diferents diastereòmers del producte. L'estat de transició per a l'atac del furà a l'adducte entre hidroxibenzldimina i catalitzador controla la selectivitat del procés. Els enllaços d'hidrogen juguen un paper crític en l'estructura de l'estat de transició, però la seva força no decideix la selectivitat. Els estats de transició d'energia més baixa tenen un enllaç d'hidrogen, mentre que alguns estats de transició d'energia més alta en tenen dos de força similar. La selectivitat està controlada per interaccions atractives anell¬anell entre catalitzador i substrats. Els estats de transició d'energia afavorits tenen més interaccions, o les tenen amb distàncies més curtes (i per tant, probablement més fortes). La diferència entre el derivat de l'àcid fosfòric amb (S)¬BINOL (sistema de Fochi), que porta a un furanobenzopirà fusionat en cis, i el derivat de N¬triflylfosphoramida amb S)¬BINOL (sistema de Rueping), que porta a un furanobenzopirà fusionat en trans, va poder ser reproduida i explicada. La presència del substituent triflil sobre l'àtom de nitrogen del sistema de Rueping limita les possibles orientacions de l'àtom d'hidrogen sobre el mateix centre, i com a resultat impedeix l'orientació òptima de l'anell de furà clau per estabilitzar l'estat de transició que condueix al producte fusionat en cis. Com a resultat, el catalitzador de Rueping porta al producte fusionat en trans. Aquest impediment no existeix en el sistema de Fochi, que per això dóna lloc al producte fusionat en cis. 4. Observacions generals Hem estudiat tres processos organocatalíticas diferents que condueixen a productes quirals amb mètodes del funcional de la densitat (DFT) i amb mètodes híbrids funcional de la densitat / mecànica molecular (DFT / MM), i hem estat capaços d'obtenir un acord raonable amb els resultats experimentals, i de donar explicacions qualitatives per l'origen de l'enantioselectivitat en cadascun dels casos. L'estudi computacional de l'organocatàlisi enantioselectiva s'assembla molt a la de la catàlisi enantioselectiva amb metalls de transició, però hi ha alguns matisos significatius. En primer lloc, la descripció electrònica del sistema organocatalític és, en principi, més fàcil, tot i que la introducció de les correccions de dispersió és obligatori, com en qualsevol procés en què les interaccions estèriques poden tenir un paper important. En segon lloc, els problemes relacionats amb la complexitat isomèrica i conformacional són molt més crítics en organocatàlisi. La densitat dels isòmers conformacionals d'energia baixa és molt més gran, i això planteja una complicació en l'esforç que ha de ser fet per obtenir barreres d'energia quantitativament precises. El conjunt del treball d'aquesta tesi es confirma poder de la química computacional per a l'estudi de l'organocatàlisi quiral. També dóna una idea dels diferents mecanismes pels quals la enantioselectivitat es pot transmetre en organocatàlisi: des de les interaccions estèriques habituals entre catalitzador i el substrat, fins al paper clau de la rigidesa catalitzador observada en el sistema prolinamida. El camp de l'organocatàlisi enantioselectiva computacional està tot just començant, i podem esperar nous resultats interessants en el futur pròxim.
For a long time, homogeneous catalysis was almost synonymous with transition metal catalysis, with a small niche reserved to biocatalysis. Things have changed very much in recent years. Since about the year 2000, organocatalysis, where the catalyst is a small organic molecule, often with chiral properties, has grown rapidly to become one of the most important fields in organic chemistry. As the research field is expanding its role, mechanistic knowledge becomes more critical to understand the reaction modes and as¬sist in the development of more efficient processes. Theoretical chemistry, with its abil¬ity to locate intermediates and transition states, can be very helpful in this concern. This thesis is devoted to the computational study of the mechanism of three representative organocatalytic reactions. 1. Asymmetric Friedel-Crafts hydroxyalkylation of indoles catalyzed by chiral Brønsted-acids Chiral Brønsted¬acid catalysis is a rapidly growing area of organocatalysis. Water is one of the simplest molecules with Brønsted–acid capabilities. The coordination of water molecules to the carbonyl function in Diels–Alder reactions and Claisen rearrangements results in the enhancement of the reaction rate. Carmona and co¬workers used a water molecule attached to a chiral iridium fragment as a Brønsted–acid catalyst to yield the Friedel–Crafts (FC) reaction between ethyl 3,3,3 trifluoromethylpyruvate and indole at the low temperature. Based on their experimental results, we have carried out a computational study on the mechanism of this reaction and evaluated the catalytic role of the metal complex and water in this reaction. The mechanism of this reaction is stepwise, the first step is the formation of a C¬C bond together with the transfer of a proton from water molecule to the substrate; the second step is the rate determining one, which is the transfer of a proton from indole to the ¬OH moiety of the water molecule. The catalytic role of the metal complex is the modulation of the acid/base properties of the coordinated water, and the water molecule acts as a proton donor and acceptor. We have been also able to explain the origin of the the stereoselectivity of the process, which is a result of a subtle combination of the non¬covalent interactions, both attractive and repulsive, between catalyst and substrate. 2. Mechanism for the enantioselective synthesis of a Wieland-Miescher ketone The Wieland¬Miescher (W¬M) ketone is a key intermediate for many reactions. The efficient preparation of Wieland¬Miescher ketone¬type compounds with high enantioselectivity is thus a challenging problem in organic chemistry. In an attempt to address this issue, the Bonjoch group reported a highly efficient and enantioselective synthesis of a W¬M ketone using N¬Ts-(Sa)¬Binam¬L¬prolinamide as the organocatalyst, under solvent¬free conditions and the assistance of benzoic acid. The key step is a Robinson annulation reaction; it requires 1 mol% triethylamine as the base in the initial Michael process and 1 mol% of N¬Ts¬(Sa)¬binam¬L-prolinamide and 2.5 mol% of benzoic acid in the intramolecular aldol process. We studied the mechanism of the intramolecular aldol process in collaboration with the experimental group. We were able to clarify the mechanism of the reaction with prolinamide. It follows the general trends of the mechanism with proline, with the important caveat that the presence of a carboxylic acid as co¬catalyst is mandatory in the initial steps of the reaction, in particular for the formation of the iminium intermediate. In contrast, the carboxylic has no effect on the enantioselectivity, as it departs the system after enamine formation, and is absent in the transition state leading to C¬C bond formation, where the enantioselectivity of the reaction is decided. The origin of the enantioselectivity of the reaction has been also clarified. It is based on the rigidity of the catalyst, which has two anchoring points for the substrate, the C=N double bond in the enamine intermediate, and the N¬H...O hydrogen bonds between catalyst and substrate. The substrate has to distort to bind properly to this anchoring points, and this distortion is smaller for the transition state leading to the favored enantiomer. 3. Mechanism of [4+2] cycloaddition reaction catalyzed by chiral phosphoric acid derivatives N¬ and O¬containing heterocyclic compounds are prominent in nature and exhibit a wide range of interesting biological properties, including antihypertensive and anti¬ischemic behavior. Pyranobenzopyran and furanobenzopyran frameworks, containing three fused rings are particularly interesting. An appealing approach to the synthesis of these compounds is a [4+2] cycloaddition between a hydroxybenzaldimine and a furan. This reaction is catalyzed by phosphoric acid derivatives. We have analyzed in detail the recent puzzling results by the groups of Fochi and Rueping. Fochi and co¬workers reported in 2010 the synthesis of cis¬fused furanobenzopyrans obtained through inverse¬electron¬demand (IED) [4+2] cycloaddition of ο-hydroxybenzaldimines with 2,3¬dihydro¬2H¬furan (DHF) catalyzed by (S)¬BINOL¬derived phosphoric acid. In the same year, Rueping and Lin reported the synthesis of the trans¬fused furanobenzopyrans from the same reactants but with a (S)¬BINOL¬derived N-triflylphosphoramide catalyst. The same reactants and slightly different catalysts produced different diastereomers of the product. The transition state for the attack of DHF on the adduct between hydroxybenzldimine and catalyst controls the selectivity of the process. Hydrogen bonds play a critical role on the structure of the transition state, but their strength does not rule the selectivity. The lowest energy transition states have one hydrogen bond, while some higher energy transition states have two hydrogen bonds of similar strength. The selectivity is instead controlled by attractive ring¬ring interactions between catalysts and substrates. The lower energy transition states have more interactions, or shorter (thus likely stronger) ones. The difference between the (S)¬BINOL¬derived phosphoric acid (Fochi system), leading to a cis¬fused furanobenzopyran, and the (S)¬BINOL¬derived N¬triflylphosphoramide system (Rueping system), leading to a trans¬fused furanobenzopyran, could be reproduced and explained. The presence of the triflyl substituent on the nitrogen atom of the Rueping system constrains the possible orientations of the hydrogen atom on this same atom, and as a result precludes the optimal orientation of the furan ring that led to the stabilization of the key transition state in the Fochi system leading to the cis¬fused product. The cis¬fused product being disfavored because of this constraint, the trans¬fused product is formed with the Rueping catalyst. 4. General observations We have studied three different organocatalytic processes leading to chiral products with density functional theory (DFT) and density functional theory / molecular mechan¬ics (DFT/MM) methods and we have been able to obtain a reasonable agreement with experimental results, and to provide qualitative explanations for the origin of enantiose-lectivity in each of the cases. The computational study of enantioselective organocatalysis closely resembles that of enantioselective transition metal catalysis, but there are some significant nuances. In first place, the electronic description of the organocatalytic system is in principle easier, although the introduction of dispersion corrections is mandatory, as in any process where steric interactions may play an important role. In second place, the problems re¬lated to isomeric and conformational complexity are much more critical in organocatal¬ysis. The density of available isomers, conformational or not, available at low energy is much higher, and this poses a severe strain in the effort that has to be made to obtain quantitatively accurate energy barriers. The whole body of work in this thesis confirms the power of computational chemistry for the study of chiral organocatalysis. It also gives insight into the different mechanisms by which enantioselectivity can be transmitted in organocatalysis, from the usual steric interactions between catalyst and substrate to the less frequent key role of catalyst rigidity observed in the prolinamide system. The field of computational enantioselective organocatalysis is just starting, and we can expect new exciting results in the foreseeable future.

This thesis is divided into two sections. In Section I, the desymmetrisation of a meso-cyclic anhydride was described. However, the transformation requires extremely low temperatures (-55°C) and a long reaction time (96 h) in order to achieve high enantioselectivity, which is not feasible for transfer into a continuous flow system. Later on, the work turned to investigation of its application towards the synthesis of chiral cyclopentanes using new enabling technologies. In Section II, the enantioselective Michael addition of aldehydes to nitroethylene in flow was described. The process was successfully incorporated into a flow system (R2+ and R4 unit). Key to this organocatalytic process is the use of catalytic amounts of a diphenylprolinol silyl ether catalyst with acetic acid as co-catalyst. This is an efficient catalytic system that enables faster transformation (1-3 h) with high enantioselectivities (up to 98% ee). A study on a proposed enol mechanism for this catalytic process was also discussed. Both sections provide full experimental procedures as well as characterisation in support of the results described within this thesis.

New applications of organocatalysis, in particular the use of the bicyclic amidine DBN (1,5-diazabicyclo[4.3.0]non-5-ene) and then iodide as nucleophilic catalysts for Friedel-Crafts reactions, have been investigated. Firstly, the use of amidines and guanidines as nucleophilic catalysts is reviewed. Amidines and guanidines are traditionally thought of as strong, non-nucleophilic bases. However, there is increasing evidence to suggest that amidines and guanidines are actually strong nucleophiles and can act as catalysts in a number of reactions. The development of the first organocatalytic Friedel-Crafts acylation reaction is then described. It was found that DBN catalyses the regioselective C2-acylation of pyrroles and C3-acylation of indoles using acyl chlorides. The protocol was shown to work for a wide range of aromatic and alkyl acyl chlorides, as well as for a number of protected pyrroles and substituted indoles. The synthetic utility of the methodology was demonstrated with the synthesis of the non-steroidal anti-inflammatory drug Tolmetin. Detailed mechanistic studies have confirmed that DBN acts as a nucleophilic catalyst in the reaction, forming an N-acyl DBN intermediate with the acyl chloride. The structure of the intermediate has been confirmed by X-ray crystallographic analysis of an N-acyl DBN species as its tetraphenylborate salt. As the N-acyl DBN tetraphenylborate salt was found to be bench stable, the use of such salts as alternatives to acyl chlorides was investigated. A number of crystalline and air stable N-acyl DBN tetraphenylborate salts were synthesised and were shown to act as acylating agents towards a wide range of nucleophiles, including primary and secondary amines, sulfonamides, and alcohols. The DBN hydrotetraphenylborate side-product could be conveniently removed from the reaction mixtures by filtration, allowing pure acylated products to be isolated without the need for column chromatography. Finally, whilst investigating the Friedel-Crafts acylation of pyrroles, it was found that lithium iodide was a highly active catalyst for the process. Preliminary mechanistic studies suggest that the iodide acts as a nucleophilic catalyst towards acyl chlorides to form an acyl iodide intermediate in the reaction

With a resurgence of interest at the turn of the millennium, organocatalysis has become an established field in chemical research. Proline, in particular, has played a central role in the profusion of research. As the archetypal organocatalyst, proline mediated transformations have acted as a point of reference against which the performance of new developments in the field are benchmarked and compared. The field as a whole has benefited from a timely merging of complementary experimental, kinetic, and computational studies, through which a comprehensive picture of reaction mechanisms has been drawn. The research documented in this thesis attempts to build on this successful multi-faceted approach to elucidate further mechanistic insights into organocatalysis. The proline mediated conjugate addition of aldehydes to nitroalkenes has been investigated via a 'kinetics first' approach, through the use of Reaction Progress Kinetic Analysis (RPKA) methodology. It was discovered that proline is irreversibly removed from the catalytic cycle via initiation of a polymerisation reaction of the nitrostyrene substrate. Additionally, it was found that this off-cycle pathway was not limited to proline alone, but also occurs with a number of secondary amine compounds, including other organocatalysts. The synthesis of two constrained bicyclic proline analogues was carried out in order to experimentally verify their computationally predicted behaviour in a benchmark aldol reaction. Excellent agreement between the experimentally determined and computationally predicted product enantioselectivity was found. Kinetic investigation of these bicyclic proline analogues revealed deactivation of the catalyst to be interfering with the catalytic cycle and so critically impairing their activity as compared to proline. The catalytic capability of these catalysts was explored, revealing universally poor behaviour in all but the reaction for which they were designed. An intriguing case of a lack of selectivity in the HPESW reaction was explored computationally and the decrease in stability of the anti transition state relative to the syn was determined as the cause. A brief exploration of the application of modern DFT functionals, M062X and ωB97XD, in a synthetically relevant setting was conducted and their extremely poor performance noted, compared to the excellent and highly accurate performance of the B3LYP functional. With the recent description of a new stereochemical and mechanistic regime for organocatalysts lacking a directing group, termed Curtin-Hammett kinetics, a kinetic investigation of the diphenylprolinol silyl ether mediated α-selenation reaction was undertaken to generalise this regime across a further carbonyl α-functionalisation reaction. A kinetic profile for the reaction was observed through the use of the RPKA methodology. The shape, an initial spike followed by zero order kinetics, closely resembles that of the conjugate addition and α-chlorination reactions. Further exploration revealed product selectivity to be a function of both the reaction solvent, correlated to dielectric constants, and the electronic properties of the aryl rings of the catalyst. An in-depth computational investigation of the conformational preferences of two important species on the catalytic cycle, the starting material and product selenoenamines, was undertaken in order to probe the underlying cause of the solvent-dependent reversal on selectivity. In agreement with experimental findings in the literature, the starting material enamine was found to have a high energetic preference for the anti E enamine in a number of solvents, dependent on the both the conformation of the pyrrolidine ring and the exocyclic CPH2OTMS group for each enamine C-N rotamer. This implies a solvent-dependent change in starting material enamine conformational preference is unlikely to explain the effect of solvent on product selectivity. Study of the product selenoenamine in various solvents found the relative thermodynamic stabilities of the E and Z enamines to change with solvent, with the Z enamine more stable in the gas-phase and non-polar solvents but little-to-no difference in stability between the E and Z enamines in polar solvents. This suggests that the experimental observation of the E enamine only in toluene is not thermodynamically preferred but is rather the result of an inherent kinetic preference. The above evidence supports the proposed hypothesis that solvent dependent product selectivity is the result of the erosion of kinetic preferences due to equilibration of relative intermediates in the catalytic cycle, as opposed to a change of enamine conformation in the stereogenic carbon-carbon bond forming step.

In the following chapters new methods in organocatalysis are described. The design of new catalysts is explored starting from the synthesis and the study of ion tagged prolines to their applications and recycle, then moving to the synthesis of new bicyclic diarylprolinol silyl ethers and their use in organocatalytic transformations. The study of new organocatalytic reaction is also investigated, in particular bifunctional thioureas are employed to catalyse the conjugate addition of nitro compounds to 3-yilidene oxindoles in sequential and domino reactions. Finally, preliminary results on photochemical organocatalytic atom transfer radical addition to alkenes are discussed in the last chapter.

In the following chapters new methods in organocatalysis are described. The design of new catalysts is explored starting from the synthesis and the study of ion tagged prolines to their applications and recycle, then moving to the synthesis of new bicyclic diarylprolinol silyl ethers and their use in organocatalytic transformations. The study of new organocatalytic reaction is also investigated, in particular bifunctional thioureas are employed to catalyse the conjugate addition of nitro compounds to 3-yilidene oxindoles in sequential and domino reactions. Finally, preliminary results on photochemical organocatalytic atom transfer radical addition to alkenes are discussed in the last chapter.

Depuis des dizaines d’années, les chimistes organiciens ont accru leurs capacités à synthétiser des molécules complexes de manière exponentielle par le développement de nouvelles méthodes toujours plus élaborées. Malgré ces accomplissements, le challenge de synthétiser de nouvelles molécules toujours plus complexes de manière sélective et efficace reste toujours d’actualité. Dans le premier chapitre, nous introduirons la notion de chiralité de manière générale. Ensuite, les différentes stratégies pour contrôler la chiralité en synthèse organique seront exposées, en se focalisant plus particulièrement sur l’organocatalyse énantiosélective. Ensuite, dans le deuxième et troisième chapitre, le contrôle de la chiralité centrale sera étudié d’une part dans une synthèse de tetrahydropyranes et d’autre part dans l’addition de Michael impliquant les 1,3-cetoamides α,β-insaturés. Dans le quatrième chapitre, d’autres types de chiralité moins conventionnelles seront examinées. Tout d’abord, une étude portant sur la racemization des furanes atropisomères sera menée. Ensuite, des stratégie innovantes seront mises en œuvre pour la synthèse [4]- et [5] helicènes via notamment des phénomènes de conversion de chiralité
In the last century, the ability of organic chemists to build complex molecules has grown exponentially. Despite these achievements, the challenge of synthesizing new molecules efficiently and selectively remains open. In the first chapter, we will discuss the definition of chirality as a transversal topic in science. Subsequently we will discuss the different strategies to control chirality in organic synthesis, with a special attention to organocatalysis. In the second and third chapter we will focus on the attempt to control central chirality for the synthesis of substituted tetrahydropyrans and the investigation of the reactivity of α,β-unsaturated 1,3-ketoamides in Michael addition. In the fourth chapter, other less conventional types of chirality will be examined. First, a study on the racemization of atropisomer furans will be conducted. Then, innovative strategies will be implemented for the synthesis [4] - and [5] helicenes via, in particular, chirality conversion approaches

Sur la base des travaux antérieurs du laboratoire, nous avons développé une nouvelle approche synthétique énantiosélective, en deux étapes, pour l’accès à des glutarimides fonctionnalisés à partir de cyclobutanones facilement accessibles, selon deux directions: une stratégie impliquant une extension de cycle à deux atomes et une stratégie basée sur une contraction de cycle à deux atomes. En parallèle, nous avons démontré que les arynes porteurs de la chiralité axiale en position ortho de la triple liaison réactive peuvent être générés à partir des précurseurs iodo/triflate de type Suzuki et réagissent in situ avec divers substrats. Leur stabilité configurationnelle et leur grande réactivité nous ont permis de proposer une nouvelle méthode de synthèse pour introduire un fragment biaryle à chiralité axiale au sein de pratiquement toutes molécules organiques réactives vis-à-vis des arynes
Based on the previous work in our laboratory, we have developed a new enantioselective two-step synthetic approach to access functionalized glutarimide derivatives using readily available cyclobutanones following two directions: a two-atom ring expansion strategy and a two-atom ring contraction strategy. Meanwhile, we have demonstrated that arynes bearing axial chirality ortho to their reactive triple bond can be generated from the corresponding iodo/triflate Suzuki-type precursors and trapped in situ by various substrates. Their configurational stability and high reactivity allow us to propose a new synthetic method for the facile introduction of an axially chiral biaryl unit onto virtually any organic molecule reacting with arynes

A l’inverse des carbocations dont l’existence a pu être prouvée dès le début des années 60, les ions silyliums (R3Si+) ont longtemps été supposés comme étant des intermédiaires de nombreuses transformations .impliquant des organosilanes. Ce n’est qu’en 2002 que la première preuve structurale (diffraction de rayons X) a permis de lever le doute sur l’existence des cations silylés tricoordinés en phase condensée. Les ions silyliums sont extrêmement acides de Lewis, ils sont capables de se coordiner à de faibles nucléophiles et des solvants tels que le benzène. La possibilité de stabiliser cette acidité de Lewis par une coordination labile ouvre le champ d’application de ces espèces réactives afin de permettre leur utilisation en catalyse organique. L’objectif de cette thèse a été de synthétiser de nouveaux ions silyliums stabilisés par différentes bases de Lewis et de rationnaliser l’effet de celles-ci sur la réactivité. Dans une première partie, nous nous sommes concentrés sur l’utilisation de dérivés azotés encombrés pour stabiliser le centre silylé. La nature et la force de l’interaction résultante a pu être évaluée par des analyses de spectroscopie RMN et des calculs théoriques. Dans une seconde partie, l’introduction d’une chiralité sur le cation silylé a été étudiée. Une série de silyliums supportés par un squelette binaphtyle comportant une base de Lewis intramoléculaire a été synthétisée. Selon la force de la stabilisation, l’information chirale présente sur le silicium peut être maintenue et utilisée pour effectuer de la catalyse asymétrique
In contrast with carbocations which existence was unambiguously proven in the early 60’s, silylium ions (R3Si+) have remained for a long time elusive species and putative intermediates in many transformations involving organosilicon compounds. It was only in 2002 that the first structural proof (X-ray crystallography) dispelled any doubt about the existence of tricoordinated silicon cations in the condensed phase. Silylium ions are extremely electrophilic, able to coordinate to weak Lewis bases including solvent molecules such as benzene. The possibility to tame this acidity through an appropriate labile coordination even widens the scope of applications of these reactive species and allows their use as catalysts for organic synthesis. The aim of this thesis was to synthesize new stabilized silyliums ions and rationalize the impact of this stabilization onto the reactivity. In a first part, we focused on the use of hindered nitrogen derivatives to stabilize the silicon center. The nature and the strength of the interaction were assessed by NMR spectroscopy and theoretical calculations. In a second part, the introduction of chirality onto the silicon cation has been studied. A series of binaphtyl templated silyliums bearing an intramolecular Lewis base were synthesized. According to the strength of the stabilization, the chiral information present on the silicon can be persistent and used for asymmetric catalysis

El treball descrit en aquesta dissertació es centra en la implementació d’estratègies organocatalítiques per superar les limitacions de processos fotoquímics establerts. Específicament, dues transformacions impulsades per la llum han estat estudiades: (i) la fotoenolizació de 2-alquilbenzofenones per accedir a intermedis enòlics transitoris (fotoenols), i (ii) la ruptura homolítica fotoinduïda de derivats ditiocarbonílics per produir radicals. Per un costat, el procés de fotoenolizació acoblat amb la reactivitat de tipus Diels-Alder (seqüència fotoenolizació/ Diels-Alder) és una reacció fotoquímica històrica amb aplicacions conegudes en síntesi total. Malgrat això, una variant asimètrica d’aquest procés no ha estat encara reportada. Els Capítols II i III demostren com l’organocatàlisi asimètrica proporciona eines simples i efectives per fer participar a les espècies fotoenòliques en processos de tipus Diels-Alder i aldòlics altament estereoselectius. Per un altre costat, la ruptura fotolítica de espècies ditiocarboníliques capaces d’absorbir la llum visible, és un mètode conegut per la generació de radicals sota condicions suaus de reacció. Aquesta tecnologia fa ús de quantitats estequiomètriques de compostos ditiocarbonílics fàcilment accessibles. Encara que aquesta estratègia ha millorat considerablement les condicions per accedir a la reactivitat de tipus radicalària, aquesta requereix la síntesi prèvia de compostos que continguin la funcionalitat ditiocarbonílica. El Capítol IV detalla com aquest mètode de generació de radicals pot ser realitzat catalíticament, mitjançant el disseny d’un catalitzador
El trabajo descrito en esta disertación se centra en la implementación de estrategias organocatalíticas para superar las limitaciones de procesos fotoquímicos establecidos. Específicamente, dos transformaciones promovidas por la luz han sido estudiadas: (i) la fotoenolización de 2-alquilbenzofenonas para acceder intermedios enólicos transitorios (fotoenoles), y (ii) la ruptura homolítica fotoinducida de derivados ditiocarbonílicos para producir radicales. Por un lado, el proceso de fotoenolización acoplado con la reactividad de tipo Diels-Alder (secuencia fotoenolización/ Diels-Alder) es una histórica reacción fotoquímica con aplicaciones conocidas en síntesis total. Sin embargo, una variante asimétrica de este proceso no ha sido reportada. Los Capítulos II y III demuestran cómo la organocatálisis asimétrica proporciona herramientas simples y efectivas para hacer participar a las especies fotoenólicas en procesos de tipo Diels-Alder y aldólicos altamente esteroselectivos. Por otro lado, la ruptura fotolítica de especies ditiocarbonílicas capaces de absorber luz visible, es un conocido método para la generación de radicales bajo condiciones suaves de reacción. Esta tecnología hace uso de cantidades estequiométricas de compuestos ditiocarbonílicos fácilmente accesibles. Aunque esta estrategia ha mejorado considerablemente las condiciones para acceder a la reactividad de tipo radicalaria, ésta requiere la síntesis previa de compuestos que contentan la funcionalidad ditiocarbonílica.
The work described in this dissertation focuses on the implementation of organocatalytic strategies to overcome limitations of established photochemical processes. Specifically, two known light-driven transformations have been studied: (i) the photoenolization of 2-alkyl-benzophenones to access transient enol-intermediates (photoenols), and (ii) the photoinduced homolytic cleavage of stoichiometric dithiocarbonyl derivatives to produce radicals. On the one hand, the photoenolization process coupled with classical Diels-Alder chemistry (photoenolization/Diels- Alder sequence) is an historical photochemical reaction with known applications in total synthesis. However, an asymmetric catalytic variant of this light-driven transformation has remained elusive over the years. Chapter II and Chapter III demonstrate how asymmetric organocatalysis provides simple but effective catalytic tools to engage photoenols in highly stereoselective Diels-Alder and Aldol-type processes, respectively. On the other hand, the photolytic cleavage of visible-light-absorbing dithiocarbonyl-based compounds is a known effective method for the mild generation of radicals. This technology uses stoichiometric amounts of easy-to make dithiocarbonyl-based substrates, capable of triggering the formation of open-shell intermediates upon direct light-excitation. Although this strategy has greatly enhanced the conditions to access radical-type reactivity, it still relies on purposely designed stoichiometric reagents.

The main aim of my PhD project was the design and the synthesis of new pyrrolidine organocatalysts. New effective ferrocenyl pyrrolidine catalysts, active in benchmark organocatalytic reactions, has been developed. The ferrocenyl moiety, in combination with simple ethyl chains, is capable of fixing the enamine conformation addressing the approach trajectory of the nucleophile in the reaction. The results obtained represent an interesting proof-of-concept, showing for the first time the remarkable effectiveness of the ferrocenyl moiety in providing enantioselectivity through conformational selection. This approach could be viably employed in the rational design of ligands for metal or organocatalysts. Other hindered secondary amines has been prepared from alkylation of acyclic chiral nitroderivatives with alcohols in a highly diastereoselective fashion, giving access to functionalized, useful organocatalytic chiral pyrrolidines. A family of new pyrrolidines bearing sterogenic centers and functional groups can be readily accessible by this methodology. The second purpose of the project was to study in deep the reactivity of stabilized carbocations in new metal-free and organocatalytic reactions. By taking advantage of the results from the kinetic studies described by Mayr, a simple and effective procedure for the direct formylation of aryltetrafluoroborate salts, has been development. The coupling of a range of aryl- and heteroaryl- trifluoroborate salts with 1,3-benzodithiolylium tetrafluoroborate, has been attempted in moderate to good yields. Finally, a simple and general methodology for the enamine-mediated enantioselective α-alkylation of α-substituted aldehydes with 1,3-benzodithiolylium tetrafluoroborate has been reported. The introduction of the benzodithiole moiety permit the installation of different functional groups due to its chameleonic behaviour.

The main aim of my PhD project was the design and the synthesis of new pyrrolidine organocatalysts. New effective ferrocenyl pyrrolidine catalysts, active in benchmark organocatalytic reactions, has been developed. The ferrocenyl moiety, in combination with simple ethyl chains, is capable of fixing the enamine conformation addressing the approach trajectory of the nucleophile in the reaction. The results obtained represent an interesting proof-of-concept, showing for the first time the remarkable effectiveness of the ferrocenyl moiety in providing enantioselectivity through conformational selection. This approach could be viably employed in the rational design of ligands for metal or organocatalysts. Other hindered secondary amines has been prepared from alkylation of acyclic chiral nitroderivatives with alcohols in a highly diastereoselective fashion, giving access to functionalized, useful organocatalytic chiral pyrrolidines. A family of new pyrrolidines bearing sterogenic centers and functional groups can be readily accessible by this methodology. The second purpose of the project was to study in deep the reactivity of stabilized carbocations in new metal-free and organocatalytic reactions. By taking advantage of the results from the kinetic studies described by Mayr, a simple and effective procedure for the direct formylation of aryltetrafluoroborate salts, has been development. The coupling of a range of aryl- and heteroaryl- trifluoroborate salts with 1,3-benzodithiolylium tetrafluoroborate, has been attempted in moderate to good yields. Finally, a simple and general methodology for the enamine-mediated enantioselective α-alkylation of α-substituted aldehydes with 1,3-benzodithiolylium tetrafluoroborate has been reported. The introduction of the benzodithiole moiety permit the installation of different functional groups due to its chameleonic behaviour.

Sur la base des travaux antérieurs du laboratoire, nous avons développé une nouvelle approche synthétique énantiosélective, en deux étapes, pour l’accès à des glutarimides fonctionnalisés à partir de cyclobutanones facilement accessibles, selon deux directions: une stratégie impliquant une extension de cycle à deux atomes et une stratégie basée sur une contraction de cycle à deux atomes. En parallèle, nous avons démontré que les arynes porteurs de la chiralité axiale en position ortho de la triple liaison réactive peuvent être générés à partir des précurseurs iodo/triflate de type Suzuki et réagissent in situ avec divers substrats. Leur stabilité configurationnelle et leur grande réactivité nous ont permis de proposer une nouvelle méthode de synthèse pour introduire un fragment biaryle à chiralité axiale au sein de pratiquement toutes molécules organiques réactives vis-à-vis des arynes
Based on the previous work in our laboratory, we have developed a new enantioselective two-step synthetic approach to access functionalized glutarimide derivatives using readily available cyclobutanones following two directions: a two-atom ring expansion strategy and a two-atom ring contraction strategy. Meanwhile, we have demonstrated that arynes bearing axial chirality ortho to their reactive triple bond can be generated from the corresponding iodo/triflate Suzuki-type precursors and trapped in situ by various substrates. Their configurational stability and high reactivity allow us to propose a new synthetic method for the facile introduction of an axially chiral biaryl unit onto virtually any organic molecule reacting with arynes

Ce manuscrit traite de la synthèse d'aldols mono- et difluorés à partir de précurseurs stables d'éthers d'énol silylés. En premier lieu, la synthèse et la réactivité de synthons de type RCF2Li sont abordées. Cette étude a notamment permis d'obtenir des alpha-trialkylsilylcarbinols stables par addition sur des acylsilanes. Ces composés nous sont apparus comme des précurseurs stables de fluoroénolates, capables de générer in situ ces nucléophiles après réarrangement de Brook et élimination d'un fluorure sous l'action d'une base. La deuxième partie de ce manuscrit traitera ainsi de deux méthodologies monotopes permettant d'aboutir à des aldols monofluorés comportant un centre tétrasubstitué fluoré directement à partir de ces précurseurs: soit en utilisant un équivalent de t-BuOK, soit avec une quantité catalytique de p-MeOPhONBu4 en présence d'une base relais. Dans un troisième temps, en se basant sur une séquence similaire, une synthèse monotope racémique d'aldols difluorés à partir du réactif de Ruppert-Prakash, d'acylsilanes et d'aldéhydes a été mise au point. Cette réaction étant catalysée par le TBAT, une version asymétrique organocatalysée a ensuite été explorée grâce à l'utilisation de paires d'ions chiraux coopératifs
This manuscript deals with the synthesis of mono- and difluorinated aldols starting from stables precursors of silylated enol ethers. First, the synthesis and the reactivity of RCF2Li synthons has been investigated. A preparation of alpha-trialkylsilylcarbinols, which can be seen as fluoroenoxysilane precursors, has been developed. A sequence involving a Brook rearrangement followed by a fluoride elimination from these stable precursors has then been exploited in a second part to set up a one-pot preparation of monofluorinated aldols featuring a fluorinated tetrasubstituted center. Two methodologies were developped : one relying on the addition of a stoichiometric amount of t-BuOK and the second involving a catalytic amount of p-MeOPhONBu4 and a stoichiometric amount of a pro-base. Finally, a one-pot synthesis of difluorinated aldols starting from Ruppert-Prakash reagent, acylsilanes and aldehydes is described in a third part. This sequence, similar to the previous one, is catalyzed by TBAT and an asymmetric version relying on the use of chiral cooperative ion pairs has also been explored

Aquesta tesi es centra en organocatalitzadors de tipus tiourea amina primària (PAT). L’addició de Michael d’acetona a nitroestiré catalitzada per tiourees amina primària va ser estudiada en detall. Els efectes sinergístics de múltiples additius (aigua i àcid acètic) en aquesta reacció varen ser determinats mitjançant anàlisi espectroscòpica de 1H NMR. Els nostres estudis mecanístics van mostrar que l’àcid acètic facilita la hidròlisi dels intermedis d’imina, donant lloc a la catàlisi, i minimitza la formació del subproducte de doble addició. Per la seva banda, l’aigua alenteix la reacció però minimitza la desactivació del catalitzador per nitroestiré, fornint finalment rendiment més elevats. A més a més, vam explorar efectes de concentració en la mateixa reacció: en diluir la reacció, l’enantioselectivitat del producte augmentava de forma significativa, mentres que els rendiments aïllats es mantenien elevats. D’aquesta manera, l’estereoselectivitat de varis organocatalitzadors PAT va poder ser millorada fàcilment. Finalment, la immobilització d’organocatalitzadors quirals PAT ha estat duta a terme sobre resines poliestirèniques per primera vegada a tarvés d’usa estratègia “click” que forneix el grup tiourea i la unió a la resina simultàniament. Els polímers catalítics obtinguts han estat aplicats a les reaccions asimétriques d’addicó de Michael i de Mannich de cetones. Es van obtenir elevades enantioselectivitats en la reacció de Mannich, mentres que van ser moderades per l’addició de Michael.
Esta tesis se centra en organocatalizadores de tipo tiourea amina primaria. La adición de Michael de acetona a nitroestireno catalizada por tioureas amina primaria (PAT) fue estudiada en detalle. Los efectos sinergísticos de múltiples aditivos (agua y ácido acético) en esta reacción fueron determinados por análisis espectroscópico de 1H NMR. Nuestros estudios mecanísticos mostraron que el ácido acético facilita la hidrólisis de los intermedios de imina, conduciendo a la catálisis, y minimiza la formación del subproducto de doble adición. El agua, por su parte, ralentiza la reacción pero minimiza la desactivación del catalizador por nitroestireno, conduciendo finalmente a rendimientos más elevados. Además, exploramos efectos de concentración en la misma reacción: al diluir la reacción, la enantioselectividad del producto se incrementa significativamente. Atribuímos este comportamiento a la minimización de la desactivación del catalizador durante la dilución. De esta manera, la estereoselectividad de varios organocatalizadores PAT pudo ser fácilmente mejorada. Finalmente, la immobilización de organocatalizadores quirales PAT ha sido llevada a cabo sobre resinas poliestirénicas por primera vez a través de una estrategia “click” que permite la formación del grupo tiourea y su sunión a la resina simultáneamente. Los polímeros catalíticos así obtenidos han sido aplicados a las reacciones asimétricas de adición de Micheal y de Mannich de cetonas. Se obtuvieron elevadas enantioselectividades en la reacción de Mannich, mientras que los resultados fueron moderados para las adiciones de Michael.
This thesis focuses on primary amine thiourea organocatalysis. The Michael addition reaction of acetone to nitrostyrene catalyzed by primary amine thioureas (PAT) was studied in detail. The synergistic effects of multiple additives (water and acetic acid) in this reaction were determined by 1H NMR spectroscopic analysis. Our mechanistic studies showed that acetic acid facilitates hydrolysis of the imine intermediates, thus leading to catalysis, and minimizes the formation of the double addition side product. Water on the other hand, slows down the reaction but minimizes catalyst deactivation by nitrostyrene leading to higher yields. Moreover, we explored the concentration effects on the same reaction: upon reaction dilution, product enantioselectivity increases significantly whereas isolated yield can be kept high. We attribute this behavior to the minimization of catalyst deactivation upon dilution. In this way, the stereoselectivity of several PAT organocatalysts could be easily improved. Finally, the immobilization of chiral PAT organocatalysts has been performed on polystyrene-based resins for the first time through a “click” strategy that renders the thiourea group and the linkage simultaneously. The as-synthesized catalytic polymers have been applied to the asymmetric Michael addition and Mannich reaction of ketones. High enantioselectivities were recorded for the Mannich reaction, whereas moderate ee’s were obtained for the Michael addition reaction.

Jorgensen and List introduced enantioselective α-amination of an aldehyde with an azodicarboxylate as the electrophile using L -proline enamine catalysis in 2002. Following borohydride reduction, the α-hydrazino alcohol was obtained in high yield (93-99%) and enantioselectivity (86-97%). Application of the enantioselective α-amination reaction to an acetal as a masked aldehyde was developed in our group recently, and in part I of this thesis results on extending this chemistry to the α-amination of N-protected hemiaminals from N-heterocycles are reported, in which it was found that the reaction only worked with the carbonyl group exo to the ring. In the case of the hemiaminal derived from N-Boc or N-CBz 2-pyrrolidinone an amination with proline catalyst in acetonitrile over 3 days gave α-aminated products in high ee (77-84%). N-N bond hydrogenolysis using Raney Nickel and hydrogen, followed by oxidation to the lactam afforded the N -protected α-amino lactam in high enantioselectivity (78% and 8 6 %). In part II the development of a mild reduction of the N-N bond of the α-hydrazino amination products of straight-chain aldehydes is reported. The corresponding oxazolidinone- hydrazides are reduced to their oxazolidinones via a modified E1cB elimination using ethyl bromomalonate and potassium carbonate in acetonitrile. The reactions gave high yields (76-96%) and ees (83-95%) with a good chemoselectivity profile.

In this work the development of new organocatalytic protocols is reported. After a brief introduction on Organocatalysis in Chapter 1, The study of a sustainable Direct Enantioselective Proline-catalysed aldol reaction is described in Chapter 2. The organocatalysed alpha-fluorination of chiral gamma nitroaldehydes is studied in Chapter 3. Finally, the functionalization of nanomaterials for organocatalytic application is described in Chapter 4.

This thesis is concerned with two sections: the first deals with the synthesis of quinolinones via a tandem VNS reaction. The second examines the aminocatalysis of the Baylis-Hillman reaction Chapter 1: Provides an overview of aromatic chemistry. Focus is on the separate mechanisms of the substitution of aromatic compounds. An overview of VNS chemistry is also included to provide a basis for the investigations carried out. Chapter 2: Describes the synthesis of a small library of 6/s-rutroaromaric compounds using the VNS reaction. An investigation into the cyclisation of the &w-nitroaromatic compounds to a range of biologically interesting quinolinones is also described. Chapter 3: Introduces the concept of aminocatalysis and gives an overview of recent developments in the field including the Baylis-Hillman reaction, the reaction chosen for asymmetric catalyst development. Chapter 4: Is split into three sections the first describes an interesting solvent effect encountered during the course of the investigation. The second investigates the effect of the structure of secondary amines on the enantioselectivity of the reaction via iminium ion formation. The third section describes the investigation of the structure of Lewis bases on the enantioselectivity of the reaction.

The scope of this thesis covered three main areas of this emerging area of chemistry. A reaction pathway is proposed for the formation of iminium ion intermediates from the reaction of secondary amines with carbonyl compounds. This suggests the deprotonation of the amine as the rate-determining step. The effect of modification of amine structure on this pathway was studied, and rationalised using Atoms-in-Molecules analysis. Molecular properties were used to describe a range of secondary amines with an aim to find a relationship between composition and reactivity. A number of catalytic candidates were suggested for synthesis. Two reaction types that directly and indirectly utilise iminium ions as catalysts or intermediates were covered. This included studies of model amines, as well as those in current use as asymmetric catalysts. The Diels-Alder reaction was studied in depth for a number of iminium ions. The alpha-acyloxylation of enamines was also studied, and reaction profiles in gas-phase and solvent identified, and possible mechanisms of asymmetric induction explored.

The task of creating an all carbon quaternary centre, bearing an alkyl moiety with differentiated functionalities and substituents is a desired key step in organic synthesis. A variety of endeavours by research groups have lead to the construction of stereogenic quaternary centres, albeit with narrow scope of substrate. Despite the repertoire of transition metals/ligand, chiral auxiliaries and reagents available at hand, efficient enantioselective and organocatalytic methodologies for the construction of all carbon quaternary centres still remains a daunting challenge for synthetic chemists. One of the most popular methods to install a quaternary centre is via a conjugate addition, the addition of a chiral tertiary enolate to an electron deficient alkene or carbonyl compound has led to high levels of synthetic accomplishment over generations. Our strategy to assemble such quaternary centres focused on an organocatalytic tandem. Michael-aldol reaction, as an efficient one-pot strategy to install vicinal quaternary centres with good levels of enantioselective induction. Initial 1, 4-conjugate addition of the nucleophile with a-acrolein type Michael acceptors generates the enolate, which is now set up to undergo an intramolecular aldol reaction providing the desired molecules. Molecular complexes of this class are also amenable to further catalytic transformations and synthetic elaborations. This thesis presents our investigations towards organocatalytic enantioselective strategies for the assembly of fully substituted quaternary centres.

The field of organocatalysis has grown rapidly in the last 20 years. Moreover it is a big challenge in modern chemistry due to the rewards that can be gained from its efficiency, low cost and low toxicity. In addition, organocatalysis has many advantages in industrial chemistry it can save time and money by avoiding the use of large amounts of solvents and thus minimizing waste. This Thesis is broken down into three chapters, the first one presents a review of organocatalysis including recent updates and developments, and introduces the different organocatalyst classes, their modes of activation, and a number of examples which show the selectivity improvements obtained. The second chapter is divided into two parts. The first part descries the synthesis of certain binaphthyl organocatalysts and a description of the key steps of their synthesis: a diastereoselective Reformatsky addition and asymmetric lithiation and chloroformate/carboxylation addition steps. The second part focuses on the applications and the results obtained when these catalysts were used in aldol and Mannich reactions. The third chapter contains the experimental data for the products that are discussed in chapter two.

En chimie macromoléculaire, les polymères optiquement actifs, qu'ils soient naturels ou synthétiques, ont fait l'objet de beaucoup d'attention, compte tenu de leurs stéréochimies, du fait que leurs propriétés mécaniques, thermiques et physiques sont fortement affectées par leur stéréorégularité. Parmi ceux-ci, le polylactide (PLA), qui constitue une excellente alternative aux polymères classiques à base de pétrole, est devenu l'un des polymères les plus utilisés, formé à partir de ressources naturelles renouvelables. Il est désormais accepté comme un « polymère d'origine biologique». En raison de la diversité des structures diastéréoisomères du lactide (LA), de nombreuses chaînes de PLA peuvent être obtenues dans diverses stéréérégularités. Par exemple, des chaînes de PLA isotactiques peuvent être formées à l'aide de L ou D-LA énantiopures en l'absence de réactions d'épimérisation et montrent une transition vitreuse (Tg) à 50 ° C et une température de fusion (Tm) d'environ 160 à 180 °C. Les propriétés thermiques du PLA peuvent être encore améliorées par la formation de structures de PLA stéréocomplexes à partir de méso- et rac-LA en présence d'initiateurs/catalyseurs chiraux ou achiraux appropriés dans des conditions appropriées (des conditions cryogéniques peuvent être appliquées) entrainant une augmentation significative de la Tm autour de 230 - 240 oC. Au cours des deux dernières décennies, de nombreux catalyseurs métalliques ont été signalés dans ce but. Cependant, il n'y a que peu d'organocatalyseurs capables de préparer du PLA stéréorégulier à partir d'une matière première de rac-LA. Dans cette thèse, nous avons étudié la (thio) urée organique chirale, les dérivés de carbène N-hétérocycliques et le dérivé de guanidine 1,5,7-triazabicyclo [4.4.0] déc-5-ène (TBD) en tant qu'organocatalyseurs pour la ROP stéréosélective D-LA. Les activations catalytiques, les propriétés stéréosélectivites et les mécanismes de stéréocontrôle de ces catalyseurs ont été étudiés. Dans chaque cas, des isosélectivités élevées ont été favorisées même à des températures élevées, ce qui a été prouvé par RMN 1H homonucléaire, RMN 13C quantitative, analyse thermique et études cinétiques
Have received great deal of attention considering their stereochemistries due to the fact that their mechanical, thermal and physical properties are strongly affected by their stereoregularity. Among them, polylactide (PLA) as an outstanding alternative to the conventional petroleum-based polymers, has become one of the most widely used polymers, which is formed by renewable natural resources are now being accepted as “bio-based polymer”. Due to the variety of diastereomeric structures of lactide (LA), numerous of PLA chains can be obtained in diverse stereregularities. As an example, isotactic PLA chains can be formed using enantiopure L- or D-LA, and show glass transition (Tg) at 50 oC, melting temperature (Tm) at 160-180 oC. The thermal properties of the PLA can be further enhanced by the formation of stereocomplex PLA from meso- or rac-LA in the presence of appropriate chiral or achiral initiators/catalysts under appropriate conditions, which displays a significantly increased Tm around 230–240 oC. Many metal catalysts have been reported to this end. However, there are only few organocatalysts able to prepare stereoregular PLA from rac-LA. In this thesis, we studied chiral organic (thio)urea, N-heterocyclic carben derivatives, and 1,5,7-triazabicyclo-[4.4.0]dec-5-ene (TBD) organocatalysts for stereoselective ROP of rac-LA. Catalytic activations, stereoselectivite properties and stereocontrol mechanisms of these catalysts were investigated. In each case, high isoselectivities were promoted even sometimes at high temperatures, proved by homonuclear decoupled 1H NMR, quantitative 13C NMR, thermal analysis and kinetic studies

Recently, during the past10 years, with the intensified attention paid to the environment and industrial development, there has been growing interest in organocatalysis. One important area of the organocatalysis is the development of new designs of chiral catalysts for the synthesis of optically pure products. Another important area is to develop methods to simplify the purification of multi-component reactions. A chiral spirobiindane-based bisphosphine oxide catalyst was synthesized and employed in various reactions including Abramov-type phosphonylation reactions, reductive aldol reactions, direct aldol reactions, allylations, reductive cyclizations and C=N reduction reactions. The rigid and axially chiral spirobiindane skeleton of the bisphosphine oxide introduces steric hindrance and results in moderate to good enantioselectivity in Abramov phosphonylation and reductive cyclization reactions. However, the great steric hindrance of the catalyst also imposes negative effects on catalyst activity and yields of reactions. The observed slow reaction rates may possibly have led to the undesired, non-selective background reactions and therefore a lowered enantioselectivity. Secondly, the success of polymer-supported reagents in facilitating product purification prompted our attempt to prepare and examine two different types of polymer-supported benzothiazolines for hydrogen transfer reduction. An in situ generated self-supported polybenzothiazoline proved to be a rapidly formed polymer under mild conditions and could be applied to hydrogenation transfer reduction reactions with active alkenes. A rasta resin-supported benzothiazoline was also synthesized and examined in similar transformations. Both of the two polymer reagents afforded the desired reduction products, but further optimizations may be required to suppress the formation of byproducts and to improve their reactivity.
published_or_final_version
Chemistry
Master
Master of Philosophy

Chemistry
Ph.D.
This thesis research presents the synthesis and first application of bis-amino acid-based spiroligomers towards the development of organocatalysis, from small molecules to moderate size spiroligomers, and to macromolecules. By synthesizing a toolbox of cyclic monomers called "bis-amino acids", the Schafmeister group has developed an approach to construct both small and macromolecules named "Spiroligomers". These molecules arrange catalytic functional groups in a shape-persistent and programmable backbone. Unlike proteins and small peptides, spiroligomers do not fold; rather, their polycyclic backbone structures are controlled by the sequence and stereochemistry of the component monomers. Firstly, we demonstrated a structure/catalytic activity relationship together with computational modeling that suggests that a specific hydrophobic interaction between the modified pro4 catalyst and the aldehyde substrate is responsible for an observed rate enhancement in the aldol reaction. For the moderate size molecules, several spiroligomer libraries were prepared through solid phase or solution phase synthesis and screened for either the alcohol kinetic resolution reaction or the aldol reaction. The poor activity and selectivity suggest that the scaffolds involved cannot create the necessary chiral environment for asymmetric catalysis. Finally, a synthetic method of macromolecules using cross metathesis coupling was developed and a series of tetra-functionalized macrocyclic spiroligomers were synthesized. Three of these macromolecules were examined as asymmetric catalysts in the aldol reaction and gave moderate activity and selectivity. The NMR analysis of these macromolecules indicates their dynamic nature. As the first application of bis-amino acid based macromolecules in organocatalysis area, although these catalysts only generated moderate activity and selectivity, they provided evidence that changing the configuration of one stereocenter of the fourteen available within these macromolecules can alter the selectivity. This synthetic methodology also provides an effective way to create more complicated pocket like spiroligomer macromolecules for the future applications in catalysis and molecular recognition.
Temple University--Theses

Se ha estudiado la actividad catalítica de materiales derivados de grafeno como soporte de nanopartículas de paladio así como de complejos de paladio(II) en reacciones de acoplamiento carbono-carbono y carbono-heteroátomo. Así mismo, se ha llevado a cabo su actividad catalítica como carbocatalizador en diversas transformaciones orgánicas.

Depuis de nombreuses années, les phosphines chirales multifonctionnelles se sont révélées être des outils synthétiques puissants en organocatalyse asymétrique. Ces catalyseurs qui contiennent un site de base de Lewis et un site d'acide de Bronsted, ont reçu une attention particulière en raison de leur efficacité pour créer des liaisons C-C avec de très bonnes énantiosélectivités. A notre connaissance, la synthèse d'organocatalyseurs de type thiourée-phosphine dérivés de la (L)-proline n'a jamais été décrite dans la littérature. Ce sujet de thèse concerne la synthèse d'une nouvelle famille d'organocatalyseur chiral de type thiourée-phosphine dérivée de (L)-proline, un produit naturel, disponible et peu coûteux. Nous avons mis au point plusieurs méthodes de synthèse efficaces qui nous ont permis de préparer trois familles de phosphines-thiourées à partir de la (L)- proline. Ainsi, sept nouveaux composés énantiopurs ont été préparés au cours de ce travail. Ces composés ont été utilisés comme catalyseurs dans des réactions asymétriques catalysées par des phosphines. Ces réactions incluent la cyclisation [3+2], la réaction de Baylis-Hillman, la réaction de Friedel-Crafts, la réaction de substitution nucléophile
For many years, multifunctional chiral phosphines have proven to be powerful synthetic tools in asymmetric organocatalysis. These catalysts, containing Lewis basic and Brnsted acidic sites, have received considerable attention owing to their highly efficiency to create C-C bond by asymmetric organocatalysis. To our knowledge, the synthesis of organocatalysts type thiourea-phosphine derivatives (L) -proline have never been described in the literature. In this work, we wish to report the synthesis of new family of bifunctional chiral thiourea-phosphine organocatalyst derived from L-proline, a natural available product. We developed efficient methods to prepare three families of phosphine thiourea derived from L-proline. Thus, Seven new enantiopure compounds were synthesized in this study. They were used as catalyst asymmetric reaction catalyzed by phosphines: [3+2] cyclisation, Baylis-Hillman reaction, Friedel-Crafts reaction and nucleophilic substitution

Développement de méthodes d'α,β-fonctionnalisation d'amines et formation d'hétérocycles optiquement actifs via l'utilisation de l'organocatalyse et de la catalyse photoredox
Development of methods α,β-functionalization of amines andformation of optically active heterocycles via the use of the organocatalysis and thephotoredox catalysis

Les phosphines jouent un rôle central dans la chimie organique moderne. Dans le domaine de la catalyse, les composés organophosphorés peuvent être appliqués soit en tant qu’organocatalyseurs dans de nombreuses transformations, soit en tant que ligands en catalyse organométallique. Au cours de cette thèse, nous avons utilisé les phosphines dans ces deux applications : en organocatalyse et en catalyse asymétrique à l’or(I). Dans la première partie, nous avons développé une réaction d’addition de Michael/réaction de Wittig intramoléculaire. Nous avons judicieusement choisi la phosphine utilisée ainsi que l’agent réducteur afin de permettre la réduction in situ de l’oxyde de phosphine correspondant. De nombreux dérivés 1,2-dihydroquinolines diversement fonctionnalisés ont pu être isolés avec de bons rendements. Parallèlement à cela, une nouvelle réaction d’oléfination a pu être découverte, donnant accès à des dérivés succinates. Un mécanisme réactionnel a pu être proposé, en se basant notamment sur des expériences de deutération. Dans un deuxième temps, nous nous sommes intéressés au développement de réactions énantiosélectives catalysées par des complexes chiraux d’or(I), et utilisant des substrats énynes. Une première réaction de cyclisation d’énynes-1,5, suivie d’une addition nucléophile a été développée en utilisant des complexes d’or de structure TADDOL-phosphoramidite-AuCl. Ce catalyseur a permis l’obtention de vingt dérivés cyclopentènes avec de bons rendements et des excès énantiomériques atteignant 94% ee. Finalement, des substrats énynes-1,6 correctement substitués ont été utilisés dans une réaction de cyclisation, suivie d’un piégeage intramoléculaire, afin de donner accès à des composés tétracycliques et pentacycliques complexes. Les composés racémiques ont été isolés avec de bons rendements et la version asymétrique a également été développée, par l’utilisation de complexes chiraux d’or(I)
Phosphines play a major role in modern organic chemistry. In the field of catalysis, organophosphorus derivatives can be applied as catalysts in numerous transformations by itself, as organocatalysts, or as ligands in organometallic catalysis. This thesis focused on the application of phosphines both in phosphine organocatalysis and in asymmetric gold(I) catalysis. In the organophosphorus catalysis part, we have developed a phosphine-catalyzed Michael addition/Wittig reaction by using a well-chosen cyclic phosphine catalyst. In this process, silane was used as reducing agent to selectively reduce in situ the phosphine oxide. A series of highly functionalized 1,2-dihydroquinolines were prepared. Besides, a new olefination process was discovered for the synthesis of succinate derivatives. Detailed mechanism research was carried out with H/D exchange experiments. In the asymmetric gold(I) catalysis part, we have developed two new methodologies based on cyclization reactions of 1,n-enyne substrates. A 1,5-enyne cyclization/nucleophilic addition reaction was first developed with an acyclic TADDOL-derived phosphoramidite-Au(I) complex. Twenty examples were carried out with good to excellent yields and up to 94% enantiomeric excess. For the 1,6-enyne cyclization/intramolecular nucleophilic addition sequence, we have synthesized a range of racemic tetracyclic and pentacyclic compounds in high yields. The enantioselective version of this transformation was carried out successfully with both high reactivity and enantioselectivity

La lumière visible, reconnue pour être une source d'énergie abondante et économique, est devenue récemment un élément crucial dans l'avancement des processus chimiques catalytiques durables. Les importantes contributions de la communauté scientifique ont mis en lumière un large éventail de transformations, comme décrit dans le premier chapitre. Malgré les diverses applications synthétiques développées à ce jour, la réalisation de réactions photocatalysées de manière asymétrique demeure un défi considérable. Dans ce contexte, nous visons non seulement à développer de nouvelles méthodologies durables et efficaces basées sur la lumière, mais aussi à innover dans le développement de processus asymétriques. Le deuxième chapitre de ce manuscrit est consacré à l'introduction d'une nouvelle catégorie de catalyseurs organocatalytiques chiraux sensibles à la lumière visible. Ces catalyseurs sont caractérisés par un squelette covalent dérivé du BINOL lié à divers photosensibilisateurs, tels que les cétones aryles et la phénothiazine. Plusieurs CPAs, intégrant un ou deux groupes photosensibilisateurs, ont été synthétisés facilement en quelques étapes à partir du BINOL. Les propriétés photophysiques et électrochimiques de ces catalyseurs photocatalytiques chiraux symétriques C1 et C2 ont été étudiées. Les catalyseurs chiraux à base de cétones ont été appliqués avec succès dans un processus tandem multicomposant énantiosélectif, permettant la synthèse efficace de 1,2-diamines entièrement substituées avec d'excellentes énantiosélectivités. Le troisième chapitre expose une approche alternative pour le développement de processus asymétriques à travers la photocatalyse, en exploitant des auxiliaires chiraux. Il met en lumière la création d'une méthodologie photocatalysée durable et efficace spécifiquement conçue pour l'alkylation radicalaire stéréosélective de sulfinyl-imines chirales. En utilisant des précurseurs radicaux non préfonctionnalisés et du TBADT comme photocatalyseur pour générer des radicaux par transfert direct d'atome d'hydrogène (HAT), cette méthode a permis d'obtenir diverses amines chirales avec des rendements et d'excellentes diastéréosélectivités dans des conditions douces. Cette approche s'avère efficace pour l'accès à une gamme variée de composés médicalement pertinents, incluant à la fois des acides α-aminés naturels et synthétiques ainsi que d'autres composés α-aminés couramment présents dans les produits pharmaceutiques approuvés et les produits naturels. Le quatrième chapitre décrit un couplage électrophile croisé déoxygénant entre des esters redox actifs dérivés d'acides carboxyliques facilement disponibles et des sulfonylhydrazones d'aldéhyde avec l'utilisation de l'Eosine Y comme organophotocatalyseur sous irradiation de lumière visible. Ce couplage C(sp3)−C(sp3) croisé, sans métaux, se présente comme une plateforme polyvalente. Son utilité synthétique a été démontrée en mettant au point par une homologation C1 d'acides carboxyliques, offrant ainsi une alternative plus sûre et largement applicable à la réaction traditionnelle d'Arndt-Eistert. De plus, cette approche permet la synthèse directe d'amines β-aryléthylcycliques et acycliques en utilisant diverses sulfonylhydrazones d'aldéhyde. Il convient de noter que cette méthode est parfaitement compatible avec la fonctionnalisation en fin de phase des peptides en phase solide, simplifiant ainsi la modification de peptides complexes sans nécessiter de longues et fastidieuses synthèses de novo
Visible light, known for being an abundant and economical energy source, has recently become crucial in advancing sustainable catalytic chemical processes. The scientific community's substantial contributions have disclosed a broad spectrum of transformations, as outlined in the initial chapter. Among the various synthetic applications developed so far, achieving photocatalysed reactions in an asymmetric fashion remains a considerable challenge. In this specific context, our focus extends beyond the creation of new sustainable and efficient light-mediated methodologies; we are also dedicated to pioneering innovative asymmetric processes. Within this manuscript, the second chapter is dedicated to introducing a novel category of visible-light-sensitive chiral organocatalysts. These catalysts feature a covalently linked backbone of BINOL-derived Chiral Phosphoric Acids (CPAs) with various photosensitizers, such as aryl ketones and phenothiazine. Several CPAs, incorporating one or two photosensitizer moieties, were easily synthesized in a few steps from BINOL. The photophysical and electrochemical properties of these C1- and C2-symmetric chiral photocatalysts were investigated. The ketone-based chiral photocatalysts were applied in an enantioselective multicomponent tandem process, enabling the efficient synthesis of fully substituted 1,2-diamines with excellent enantioselectivities. The third chapter presents an alternative strategy for the development of asymmetric processes through photocatalysis, exploiting chiral auxiliaries. It highlights the needs of a sustainable and efficient photocatalysed methodology specifically designed for the stereoselective radical alkylation of chiral sulfinyl-imines. By utilizing readily available non-prefunctionalized radical precursors and TBADT as a photocatalyst to generate radicals through direct hydrogen atom transfer (HAT), this method has enabled the synthesis of diverse chiral amines with high yields and excellent diastereoselectivities under mild conditions. This approach proves to be effective for accessing a varied range of medically relevant compounds, encompassing both natural and synthetic α-amino acids and other α-amino compounds commonly present in approved pharmaceuticals and natural products. The fourth chapter describes a deoxygenative cross-electrophile coupling technique that combines readily available carboxylic acid-derived redox-active esters (RAEs) with aldehyde derived sulfonyl hydrazones, employing Eosin Y as an organophotocatalyst under visible light irradiation. This methodology serves as a versatile, metal-free C(sp3)−C(sp3) cross-coupling platform. Its synthetic utility as a safer and widely applicable C1 homologation of carboxylic acids was demonstrated, providing an alternative to the traditional Arndt-Eistert reaction. Furthermore, the approach allows for the direct synthesis of cyclic and acyclic β-arylethylamines using various aldehyde-derived sulfonyl hydrazones. Notably, the method is compatible with late-stage functionalization of peptides on solid-phase, simplifying the modification of intricate peptides without the need for time demanding de novo synthesis

Depuis des dizaines d’années, les chimistes organiciens ont accru leurs capacités à synthétiser des molécules complexes de manière exponentielle par le développement de nouvelles méthodes toujours plus élaborées. Malgré ces accomplissements, le challenge de synthétiser de nouvelles molécules toujours plus complexes de manière sélective et efficace reste toujours d’actualité. Dans le premier chapitre, nous introduirons la notion de chiralité de manière générale. Ensuite, les différentes stratégies pour contrôler la chiralité en synthèse organique seront exposées, en se focalisant plus particulièrement sur l’organocatalyse énantiosélective. Ensuite, dans le deuxième et troisième chapitre, le contrôle de la chiralité centrale sera étudié d’une part dans une synthèse de tetrahydropyranes et d’autre part dans l’addition de Michael impliquant les 1,3-cetoamides α,β-insaturés. Dans le quatrième chapitre, d’autres types de chiralité moins conventionnelles seront examinées. Tout d’abord, une étude portant sur la racemization des furanes atropisomères sera menée. Ensuite, des stratégie innovantes seront mises en œuvre pour la synthèse [4]- et [5] helicènes via notamment des phénomènes de conversion de chiralité
In the last century, the ability of organic chemists to build complex molecules has grown exponentially. Despite these achievements, the challenge of synthesizing new molecules efficiently and selectively remains open. In the first chapter, we will discuss the definition of chirality as a transversal topic in science. Subsequently we will discuss the different strategies to control chirality in organic synthesis, with a special attention to organocatalysis. In the second and third chapter we will focus on the attempt to control central chirality for the synthesis of substituted tetrahydropyrans and the investigation of the reactivity of α,β-unsaturated 1,3-ketoamides in Michael addition. In the fourth chapter, other less conventional types of chirality will be examined. First, a study on the racemization of atropisomer furans will be conducted. Then, innovative strategies will be implemented for the synthesis [4] - and [5] helicenes via, in particular, chirality conversion approaches

Les dérivés ambiphiles, possèdant un site acide de Lewis (B ou Al) et un site base de Lewis (P), sont connues pour activer les petites molécules, stabiliser des espèces hautement réactives, mais aussi pour se comporter comme des catalyseurs non-métalliques. Dans la mesure où ils présentent différents modes de coordination, ils possèdent des comportements variables en tant que ligands des métaux de transition. Cette thèse porte sur deux aspects des composés ambiphiles. Le premier concerne l'interaction avec les petites molécules et l'organocatalyse, et le second la coordination et la réactivité des complexes métalliques avec des ligands ambiphiles. Le premier chapitre aborde la synthèse et la réactivité de phosphines-boranes possédant un espaceur de type ortho-phénylène. Dans une première partie, des composés possédant des sites base et acide de Lewis de nature différente ont été synthétisés. Dans une seconde partie, les propriétés catalytiques de ces dérivés ont été évaluées lors de la réduction du dioxyde de carbone en présence de boranes. Ces dérivés ambiphiles se sont révélés être des organocatalyseurs efficaces pour cette réaction. Dans une troisième partie, une étude mécanistique a été réalisée. Lors de cette étude, un intermédiaire réactionnel a pu être isolé et caractérisé. Cette espèce, possédant une molécule de formaldéhyde pontante entre les atomes de phosphore et de bore, s'est montrée plus efficace en catalyse que les catalyseurs précédents. En effet, aucune période d'induction n'est observée lors de la réduction du dioxyde de carbone avec ce dernier. Le second chapitre aborde la réactivité d'un complexe de Pt possédant un ligand ambiphile de type phosphine-alane (PAl). Ce complexe comportant une interaction Pt-->Al, avait déjà montré une réactivité intéressante vis-à-vis de l'hydrogène. Dans ce chapitre, sa réactivité vis-à-vis d'autres substrats a été étudiée. Dans une première partie, la capacité du complexe PAl-Pt à activer une liaison N-H polaire a, en particulier, été évaluée. Un complexe issu de l'addition oxydante de PhC(O)NH2 sur le platine a pu être isolé et entièrement caractérisé. Dans une seconde partie, le complexe PAl-Pt a été mis en présence de petites molécules de type CE2 (E = O, S) et différents modes de coordination ont pu être mis en évidence aussi bien en solution et qu'à l'état solide. En particulier, un complexe n1 de CO2 a été isolé. Au cours de ce travail, l'accent a été mis sur la coopérativité d'action métal/acide de Lewis
Ambiphilic derivatives, which possess a Lewis acid (B or Al) and a Lewis base (P), are known for activating small molecules, stabilizing highly reactive species, but also to be used as metal-free catalyst. Because of their different coordination modes, they show different behaviour as ligand for transition metals. This thesis addresses two aspects of ambiphilic derivatives. The first one is about the interaction with small molecules and the organocatalysis, and the second one the coordination and the reactivity of metallic complexes with ambiphilic ligands. The first chapter deals with the synthesis and the reactivity of phosphine-borane which possess an ortho-phenylene backbone. In the first part, compounds with different kind of Lewis base and acid have been synthesized. In a second part, catalytic properties of these derivatives have been evaluated for the reduction of carbon dioxide in presence of borane. These ambiphilic derivatives have revealed themselves as effective organocatalyst for this reaction. In a third part, a mechanistic study have been realised. During this study, a reaction intermediate has been isolated and characterized. This species, which possess a molecule of formaldehyde bridging between the atoms of phosphorus and boron, revealed itself more effective in catalysis that the previous catalyst. Indeed, no induction period has been observed during the reduction of carbon dioxide with this compound. The second chapter relates the reactivity of a Pt complex which possess a phosphine-alane (PAl) type ambiphilic ligand. This complex involving a Pt-->Al interaction, has already shown an interesting reactivity toward dihydrogene. In this chapter, his reactity toward other kind of substrate has been studied. In a first part, the capacity of the PAl-Pt complex to activate a polar N-H bond has been evaluated. A complex coming from the oxidative addition of PhC(O)NH2 over the platinum has been isolated and fully characterized. In a second part, the PAl-Pt complex has been set to react with CE2 (E = O or S) type small molecules, and different coordination modes have been highlighted both in solution and in solid state. In particular a n1 CO2 coordinated complex has been isolated. During this work, the cooperativity of action metal/Lewis acid has been emphases

L'organocatalyse, et plus particulièrement l'organocatalyse par les phosphines, est devenu au cours de ces dernières décennies un domaine incontournable en chimie organique. De nombreux groupes ont montré le potentiel des phosphines dans diverses transformations chimiques. Par exemple, on peut noter le développement des réactions de Rauhut-Currier, Morita-Baylis-Hillman, d'additions de Michael ou encore de cyclisations. Dans le cadre de cette thèse, nous nous sommes intéressés aux réactions de cyclisations organocatalysées par les phosphines, pour la synthèse de molécules contenant le squelette spirooxindole. En effet, ce motif est présent dans de nombreux composés bioactifs et naturels. Une réaction de cyclisation [3+2] entre une oléfine activée et un allénoate a ainsi été mise au point, permettant l'accès à une nouvelle famille de spirooxindoles hautement fonctionalisés. Ces composés étant des analogues d'inhibiteurs de l'interaction MDM2-p53, leurs propriétés anticancéreuses ont ensuite été évaluées. Un composé possédant une constante d'inhibition (IC50) de 13 nM, similaire aux inhibiteurs précédemment décrits, a pu être mis en évidence.Lors de l'extension de cette réaction de cylisation [3+2], une nouvelle réactivité a pu être découverte. En effet, l'utilisation d'un allénoate substitué en position gamma par un groupement benzylique a permis de réaliser des cylisations [4+2] et ainsi former une nouvelle famille de spirocyclohexane-oxindoles.Au cours de cette thèse, nous avons également developpé l'utilisation d'une phosphine chirale, portant une chiralité hélicoïdale. Ces phosphahélicènes ont permis de réaliser des réactions de cyclisations [3+2] entre une oléfine et un alléne activé, avec des excès énantiomériques atteignant 97%. Ces cyclisations constituent les premiers exemples en organocatalyse utilisant une phosphine hélicoïdale et illustrent le potentiel des phosphahélicènes en organocatalyse énantiosélective
This last decades, phosphine organocatalysis became an important field in organic chemistry. Various groups showed the potential of phosphines to promote a lot of reactions. For example, Rauhut-Currier reaction, Morita-Baylis-Hillman reaction, Michael addition or cyclizations can be promoted by phosphines. During this thesis, we were particularly interested by cyclization reactions. Moreover, spirooxindole scaffold being present in many bioactive and natural compounds, we focused our attention on this scaffold. A [3+2] cyclisation methodology between electron poor olefins and allenoates has been developed to have access to a new family of highly functionalized spirooxindoles. These compounds being analogs of well know MDM2-p53 interaction inhibitors, we then evaluated them as anticancer agents. One of these compounds showed an inhibition constant (IC50) of 13 nm, which is similar to inhibitors previously describe. During the scope of the [3+2] cyclization methodology, a new reactivity of allenoate has been discovered. Indeed, allenoates bearing benzyl group on gamma position are able to induce [4+2] cylizations. With this new reactivity in hand, a family of highly susbtituted spirocyclohexane-oxindoles have been synthesized. This manuscript also reports the use of new family of chiral phosphines bearing a helical chirality and named phosphahelicenes. These helical catalysts were able to promote [3+2] cyclizations between electron poor olefins and activated allenes with enantiomeric excesses up to 97%. These cyclizations are the first examples of the use of helical phosphines in organocatalysis with high level of enantioselectivity

L’organocatalyse est une méthodologie qui connait un développement rapide, permettant de réaliser des transformations chimiques complexes dans le contexte général de la chimie durable (procédés sans métaux, recyclage des catalyseurs…). Les applications potentielles incluent l'élaboration rapide d'éléments de base avancés et utiles pour le développement pharmaceutique. Malgré de grandes réalisations, les organocatalyseurs souffrent généralement de certaines limitations comme une faible accélération de la réaction, d'un taux de rotation catalytique faible et de la nécessité de quantités importantes de catalyseur pour obtenir une bonne conversion et sélectivité. Afin de répondre à ces limitations, des catalyseurs incorporant de plus en plus de fonctions d'interaction afin d'exercer un contrôle plus important sur l'état de transition de réactions ont été des axes de recherche populaires. Un second axe consistant à utiliser des catalyseurs pré-structurés, analogues simplifiés des enzymes à également commencé à être étudié. Les foldamères d'oligourées développées par notre laboratoire ont précédemment démontré la capacité de catalyse dans le cadre de la réaction d'additions de composés 1,3-dicarbonylés aux nitroalcènes avec de très faibles charges catalytiques et d'excellentes stéréosélectivités. Les travaux présentés font suite à ces résultats et ont pour but d'étudier le mécanisme d'interaction du catalyseur, puis d'explorer de nouvelles réactions catalysées par nos foldamères
Organocatalysis is a rapidly expanding methodology enabling challenging chemical transformations to be performed in the broad context of sustainable chemistry (metal-free procedures, catalyst recycling…). Potential applications include the rapid elaboration of advanced and useful building blocks for pharmaceutical development. Despite major achievements, organocatalysts generally suffer from low rate acceleration and turnover and the need for relatively high amounts to achieve good conversion and selectivity. In order to address these limitations, catalyst structures incorporating increasing numbers of interacting functions to better control the transitions state of reactions have been a popular axis of research. A second, more recent approach has been the use of pre-organised catalysts, which can be viewed as simplified enzyme analogues. In this context, the oligourea foldamers developed by our group have previously been shown to catalyse the addition of 1,3-dicarbonyl compounds to nitroalkenes with low catalyst loading and excellent stereoselectivities. The works presented hereby come in continuation of these previous results with the main objectives being the study of the mechanism of interaction between the catalyst and substrates, and the exploration of new potential reactions catalysed by our foldamers

We have studied the mechanism of the reaction of N-Boc imines and acetylacetone in the presence and absence of chiral phosphoric acid catalysts. In order to gain mechanistic insight into the asymmetric Mannich reaction, a structurally homologous series of N-Boc imines and BINOL-derived phosphoric acid and thiophosphoric acid catalysts were synthesised. The degree of asymmetric catalysis was evaluated by chiral HPLC analysis of the products of catalysed Mannich reactions. Knowledge of the acidity difference between the phosphoric acid catalysts and the iminium ions is essential in order to determine the likely extent of proton transfer, full or partial, between these two species in the course of the Mannich reaction. The determination of aqueous pKa values of iminium ions was attempted by construction of pH-rate profiles for hydrolysis using UV-Vis spectrophotometry. Estimates of the second-order rate constant for acid-catalysed hydrolysis (kH, M-1s-1) and the first-order rate constant for the solvent reaction (k0, s-1) for each imine were extracted from the rate-profiles, however, pKa values could not be obtained for reasons that will be discussed. Iminium ion pKa values were determined in dimethyl sulfoxide by adopting a bracketing indicator method with use of UV-Vis spectrophotometry and pKa values in the range 0.65-1.61 were observed for the series of N-Boc aryl iminium ions. The pKa values of (thio)phosphoric acid catalysts were also estimated in dimethyl sulfoxide using this approach and values in the range 2.21-3.86 were obtained. The determination of pKa values of phosphoric acids in water and acetonitrile was unsuccessful due to the poor solubility of the catalyst in these media. Rate constants for the uncatalysed Mannich reaction of each imine with acetylacetone have been quantified using 1H NMR spectroscopy in CD2Cl2, CDCl3 and CD3CN. It was found that the solvent effect on the rate of the Mannich reaction was small, with the fastest reaction occurring in CD3CN. Altering the imine substituent was found to have a larger effect on the rate. We also aimed to determine rate constants for the catalysed Mannich reaction using 1H NMR spectroscopy. However, in all cases complete hydrolysis of the imine substrate occurred before the first time-point could be obtained. All efforts to suppress hydrolysis proved unsuccessful. Azolium ion organocatalysts were also investigated. These are the conjugate acids of N-heterocyclic carbenes, a class of highly successful nucleophilic/Brønsted base organocatalysts. As these carbenes are generated in situ from azolium ions during organocatalytic reactions, knowledge of the acidity of the parent ion is much sought after. This thesis describes the determination of aqueous pKa values of imidazolium and triazolium ions using a kinetic approach. Second-order rate constants for the deprotonation of these azolium ions by deuterioxide ion (kDO, M-1s-1) in D2O at 25 C were determined by 1H NMR spectroscopy. These kDO values could be used to calculate values for kHO (M-1s-1), the second-order rate constant for deprotonation of the azolium ion by hydroxide ion to give the carbene/ylide in water. Evidence is presented that the reverse rate constant for carbene protonation by solvent water is limited by solvent reorganisation and occurs with a rate constant of kHOH = kreorg = 1011 s-1. Values for kHO and kHOH permitted the calculation of reliable carbon acid pKa values for ionisation of the azolium ions in water. The effects of the N-substituents and counter ion on kHO and pKa values are discussed. Of the triazolium ions studied, kDO values of 3.66 × 107- 6.47 × 108 M-1s-1 were observed with corresponding pKa values of 16.6-17.8. For N,N-dialkylated imidazolium ions, kDO values of 1.03 × 102 - 1.07 × 102 M-1s-1 were obtained which yielded pKa values of 23.3-23.4.