Academic literature on the topic 'Organocatalysis'

Background:The continuous increase in challenges associated with the effective treatment of life threatening diseases influences the development of drug therapies with suitable physicochemical properties, efficiency and selectivity. So, organocatalysis is a potential synthetic tool which is accelerating the development of new drug molecules.Methods:Organocatalysis reactions can be carried out at lower temperatures and in milder pH conditions as compared to metal based catalysed reactions. Due to ready availability of catalysts, stability, purity, low toxicity and easy in handling of the chemical reactions, it has become an attractive technique to synthesise complex molecules with diverse structures. Here, the impact of various catalysts in organic synthesis with methods is discussed.Results:Organic catalysts are used widely in various chemical reactions such as Michael Addition, aldol reaction, Diels-Alder reactions and Knoevenagal reactions. It was observed that the use of organocatalyst results in the formation of stereo active molecules with diverse biological activities.Conclusion:This review also focuses on the various scopes and limitations of organocatalytic reactions in the production of medicinally useful drug molecules. Organocatalysts possess several advantages over traditional metal catalysts because they are non-toxic, readily available, stable, efficient, and easy to handle which involves environmentally friendly reaction.

This paper purports to review catalysis, particularly the organocatalysis and its origin, key trends, challenges, examples, scope, and importance. The definition of organocatalyst corresponds to a low molecular weight organic molecule which in stoichiometric amounts catalyzes a chemical reaction. In this review, the use of the term heterogenized organocatalyst will be exclusively confined to a catalytic system containing an organic molecule immobilized onto some sort of support material and is responsible for accelerating a chemical reaction. Firstly, a brief description of the field is provided putting it in a green and sustainable perspective of chemistry. Next, research findings on the use of organocatalysts on various inorganic supports including nano(porous)materials, nanoparticles, silica, and zeolite/zeolitic materials are scrutinized in brief. Then future scope, research directions, and academic and industrial applications will be outlined. A succinct account will summarize some of the research and developments in the field. This review tries to bring many outstanding researches together and shows the vitality of the organocatalysis through several aspects.

Organocatalysts have become one of the three pillars in asymmetric reactions, along with metal catalysis and enzyme catalysis. Organocatalysis is widely acknowledged in both academia and industry as a practical and advantageous synthetic method owing to its operational ease, readily available catalyst, environmentally friendly, and minimal toxicity. Much attention has been focused on the organocatalyst for its superior properties as an efficient and clean catalyst. In this work, a series of green organocatalysts of trans-4-hydroxyprolineamide were efficiently obtained in a two-step reaction utilizing EDC.HCl and HOBT as coupling reagents via a condensation reaction. The yield furnished in 93% to 97% yields. These organocatalysts have big potential in asymmetric reactions such as aldol and Michael addition reactions.

Novel organocatalytic systems based on the recently developed (S)-proline derivative (2S)-[5-(benzylthio)-4-phenyl-(1,2,4-triazol)-3-yl]-pyrrolidine supported on mesoporous silica were prepared and their efficiency was assessed in the asymmetric aldol reaction. These materials were fully characterized by FT-IR, MS, XRD, and SEM microscopy, gathering relevant information regarding composition, morphology, and organocatalyst distribution in the doped silica. Careful optimization of the reaction conditions required for their application as catalysts in asymmetric aldol reactions between ketones and aldehydes afforded the anticipated aldol products with excellent yields and moderate diastereo- and enantioselectivities. The recommended experimental protocol is simple, fast, and efficient providing the enantioenriched aldol product, usually without the need of a special work-up or purification protocol. This approach constitutes a remarkable improvement in the field of heterogeneous (S)-proline-based organocatalysis; in particular, the solid-phase silica-bonded catalytic systems described herein allow for a substantial reduction in solvent usage. Furthermore, the supported system described here can be recovered, reactivated, and reused several times with limited loss in catalytic efficiency relative to freshly synthesized organocatalysts.

Organocatalysis is a very useful tool for the asymmetric synthesis of biologically or pharmacologically active compounds because it avoids the use of noxious metals, which are difficult to eliminate from the target products. Moreover, in many cases, the organocatalysed reactions can be performed in benign solvents and do not require anhydrous conditions. It is well-known that most of the above-mentioned reactions are promoted by a simple aminoacid, l-proline, or, to a lesser extent, by the more complex cinchona alkaloids. However, during the past three decades, other enantiopure natural compounds, the carbohydrates, have been employed as organocatalysts. In the present exhaustive review, the detailed preparation of all the sugar-based organocatalysts as well as their catalytic properties are described.

Efficient synthetic methods that avoid the extensive use of hazardous reagents and solvents, as well as harsh reaction conditions, have become paramount in the field of organic synthesis. Organocatalysis is notably one of the best tools in building chemical bonds between carbons and carbon-heteroatoms; however, most examples still employ toxic volatile organic solvents. Although a portfolio of greener solvents is now commercially available, only ethyl alcohol, ethyl acetate, 2-methyltetrahydrofuran, supercritical carbon dioxide, ethyl lactate, and diethyl carbonate have been explored with chiral organocatalysts. In this review, the application of these bio-based solvents in asymmetric organocatalytic methods reported in the last decade is discussed, highlighting the proposed mechanism pathway for the transformations.

Since the beginning of the millennium, organocatalysis has been gaining a predominant role in asymmetric synthesis and it is, nowadays, a foundation of catalysis. Synergistic catalysis, combining two or more different catalytic cycles acting in concert, exploits the vast knowledge acquired in organocatalysis and other fields to perform reactions that would be otherwise impossible. Merging organocatalysis with photo-, metallo- and organocatalysis itself, researchers have ingeniously devised a range of activations. This feature review, focusing on selected synergistic catalytic approaches, aims to provide a flavor of the creativity and innovation in the area, showing ground-breaking examples of organocatalysts, such as proline derivatives, hydrogen bond-mediated, Cinchona alkaloids or phosphoric acids catalysts, which work cooperatively with different catalytic partners.

Majority of drugs act by interacting with chiral counterparts, e.g., proteins, and we are, unfortunately, well-aware of how chirality can negatively impact the outcome of a therapeutic regime. The number of chiral, non-racemic drugs on the market is increasing, and it is becoming ever more important to prepare these compounds in a safe, economic, and environmentally sustainable fashion. Asymmetric organocatalysis has a long history, but it began its renaissance era only during the first years of the millennium. Since then, this field has reached an extraordinary level, as confirmed by the awarding of the 2021 Chemistry Nobel Prize. In the present review, we wish to highlight the application of organocatalysis in the synthesis of enantio-enriched molecules that may be of interest to the pharmaceutical industry and the medicinal chemistry community. We aim to discuss the different activation modes observed for organocatalysts, examining, for each of them, the generally accepted mechanisms and the most important and developed reactions, that may be useful to medicinal chemists. For each of these types of organocatalytic activations, select examples from academic and industrial applications will be disclosed during the synthesis of drugs and natural products.

In recent years, a plethora of synthetic methods that employ hypervalent iodine compounds donating an atom or a group of atoms to an acceptor molecule have been developed. Several of these transformations utilize organocatalysis, which complements well the economic and environmental advantages offered by iodine reagents. This short review provides a systematic survey of the organocatalytic approaches that have been used to promote group transfer from hypervalent iodine species. It covers both the reactions in which an organocatalyst is applied to activate the acceptor, as well as those that exploit the organocatalytic activation of the hypervalent iodine reagent itself.1 Introduction2 Organocatalytic Activation of Acceptor2.1 Amine Catalysis via Enamine and Unsaturated Iminium Formation2.2 NHC Catalysis via Acyl Anion Equivalent and Enolate Formation2.3 Chiral Cation Directed Catalysis and Brønsted Base Catalysis via Pairing with Stabilized Enolates3 Organocatalytic Activation of Hypervalent Iodine Reagent3.1 Brønsted and Lewis Acid Catalysis3.2 Lewis Base Catalysis3.3 Radical Reactions with Organic Promoters and Catalysts4 Summary and Outlook

The synthesis of aminobenzylnaphthols by organocatalysis has generated interest due to the mild reaction conditions and environmental benefits. It has been shown that (1,4-diazacyclo[2.2.2]octane) has demonstrated high efficiency as an organocatalyst for the three component condensation reaction. These reactions lead to the synthesis of a novel class of aminobenzylnaphthols under various solvent conditions offering remarkable advantages like: mild reaction conditions, high yields, selectivity and simplicity. This protocol is particularly appealing for the synthesis of complex organic molecules with potential applications in pharmaceuticals and material science. Overall, the use of organocatalysts in aminobenzylnaphthol synthesis presents a versatile approach with potential for the further development maintaining the guidelines of greener chemistry.

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