Dissertations / Theses on the topic 'Enantioselective'

La tesi descriu noves estratègies per implementar reaccions fotoquímiques enantioselectives promogudes per llum visible. La primera part se centra en el desenvolupament de transformacions químiques que depenen de la formació de complexos donadors-acceptors d'electrons (EDA). Específicament, es desenvolupa la perfluoroalquilació fotoquímica enantioselectiva de β-cetoésters intervinguda per enolats quirals. Aquest estudi estableix la capacitat dels enolats quirals, generats mitjançant transferència de fase (PTC), per actuar com a donadors en la formació de complexos fotoactius EDA amb iodurs de perfluoroalquil, alhora que per proporcionar inducció asimètrica en la generació de centres quaternaris estereogènics de perfluoroalquil. La segona part de la tesi detalla una nova estratègia per dissenyar processos organocatalítics asimètrics en cascada. El nou enfoc combina la diferent reactivitat de dos intermedis organocatalítics quirals; la reactivitat de l'estat excitat d'ions imini quirals amb la reactivitat de l'estat fonamental de les enamines. Aquestes reaccions organofotoquímiques en cascada ens condueixen a la formació de ciclopentanols estereoquímicament densos, compostos als quals no es pot accedir per altres mètodes, amb elevats rendiments i excel·lents selectivitats. Les excel·lents selectivitats observades s'originen mitjançant un mecanisme d'amplificació asimètrica, que es deu a un procés de resolució cinètica operatiu en la segona etapa del procés en cascada
La tesis describe novedosas estrategias para implementar reacciones fotoquímicas enantioselectivas promovidas por luz visible. La primera parte se centra en el desarrollo de transformaciones químicas que dependen de la formación de complejos dadores-aceptores de electrones (EDA). Específicamente, se desarrolla la perfluoroalquilación fotoquímica enantioselectiva de β-cetoésteres mediada por enolatos quirales. Este estudio establece la capacidad de los enolatos quirales, generados mediante transferencia de fase (PTC), para actuar como dadores en la formación de complejos fotoactivos EDA con yoduros de perfluoroalquilo, a la vez que para proporcionar inducción asimétrica en la generación de centros cuaternarios estereogénicos de perfluoroalquilo. La segunda parte de la tesis detalla una nueva estrategia para diseñar procesos organocatalíticos asimétricos en cascada. El nuevo enfoque combina la distinta reactividad de dos intermedios organocatalíticos quirales; la reactividad del estado excitado de iones iminio quirales con la reactividad del estado fundamental de las enaminas. Estas reacciones organofotoquímicas en cascada nos conducen a la formación de ciclopentanoles estereoquímicamente densos, compuestos a los que no se puede acceder por otros métodos, con elevados rendimientos y excelentes selectividades. Las excelentes selectividades observadas se originan mediante un mecanismo de amplificación asimétrica, que se debe a un proceso de resolución cinética operativo en la segunda etapa del proceso en cascada
The thesis describes novel strategies to implement enantioselective photochemical reactions promoted by visible light. The first part focuses on the development of chemical transformations that rely on the formation of electron-donor acceptor (EDA) complexes. Specifically, the enantioselective photochemical perfluoroalkylation of β-ketoesters mediated by a chiral enolate was developed. This study established the ability of chiral enolates, generated under phase transfer (PTC) conditions, to act as suitable donors in the formation of photoactive EDA complexes with perfluoroalkyl iodides, while providing effective asymmetric induction in the generation of quaternary perfluoroalkyl stereogenic centers. The second part of the thesis details a new strategy to design organocatalytic asymmetric cascade processes. The new approach combines the distinct reactivity of two chiral organocatalytic intermediates, namely the excited-state reactivity of chiral iminium ions with the ground-state reactivity of enamines. The photochemical organo-cascade reaction leads to stereochemically dense cyclopentanols with high yields and excellent selectivity, compounds that cannot be accessed by other methods. The observed excellent selectivity originated by an asymmetric amplification mechanism, which is due to a kinetic resolution process operative in the second step of the cascade process.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2007.
Vita.
Includes bibliographical references.
Chapter 1 describes the development of an asymmetric nucleophile-catalyzed [2+2] cycloaddition of ketenes with aldehydes. This is the first report of a catalytic enantioselective synthesis of trisubstituted [beta]-lactones. Two enantioselective phosphine-catalyzed [3+2] cycloadditions of allenoates are detailed in Chapter 2. A method for the asymmetric synthesis of cyclopentenes via a [3+2] cycloaddition of allenoates with enones is first discussed. This is followed by a report of our efforts to extend this [3+2] methodology to imine electrophiles. We conclude, in Chapter 3, with an account of the development of a novel phosphine-catalyzed synthesis of bicyclo[3.3.0]octanones and bicyclo[4.3.0]nonanones. Preliminary results for an enantioselective variant of this method are also disclosed.
by Jonathan E. Wilson.
Ph.D.

A brief overview of why it is important to prepare a chiral compound as a specific enantiomer rather than as a racemate is discussed along with several general strategies on how they maybe prepared. The area of research into the preparation of racemic and enantiomerically pure arylpropanoic acids is briefly reviewed by reference to some of the more important synthons. Some of the more general procedures that have been developed for the construction of arylpropanoic acids are discussed. The preparation of substituted alkyl aryl ketones and their subsequent two step conversion into diastereomerically enriched dimethyl tartrate (S)-bromoalkyl aryl acetals is described. An investigation into the effects of solvent, source of anhydrous acid, workup procedure, source of bromine and temperature upon the bromination of these dimethyl tartrate acetals is discussed. Direct conversion of these diastereomerically enriched dimethyl tartrate (S)-bromoalkyl aryl acetals into enantiomerically pure (S)-bromoalkyl aryl ketones and their subsequent conversion into (S)-bromoalkyl aryl esters via a Baeyer-Villiger reaction is described. Hydrolysis of these (S)-bromoalkyl aryl esters followed by treatment with diazomethane afforded the corresponding methyl (S)-bromoalkyl esters with minimal racemisation, while treatment of these (S)-bromoalkyl aryl esters with an amine gave the corresponding amide with minimal racemisation. Reduction with sodium borohydride at low temperature of a (S)-bromoalkyl aryl ketone afforded exclusively the corresponding (1S,2S) alkyl aryl bromohydrin as predicted using the Felkin-Anh model. Stereospecific conversion of our diastereomerically enriched dimethyl tartrate (S)-bromoalkyl aryl acetals into (S)-arylcarboxylic acids using a silver promoted or solvent promoted rearrangement is discussed. Subsequent conversion of these (S)-arylcarboxylic acids into the corresponding Boc amide via a modified Curtius rearrangement is described. Possible further uses of dimethyl tartrate bromoacetals leading to the synthesis of highly functionalised lactones, lactols, epoxides, chiral diacids, diamines, chiral ligands, resolving agents etc are also discussed.

Au cours de ce travail, nous avons effectue l'irradiation d'un ester alpha,beta-insature a temperature variable, pour rechercher les points isocinetique et d'iso-inversion de la reaction de protonation asymetrique du photodienol. Nous avons aussi developpe une nouvelle voie de synthese asymetrique permettant d'acceder en milieu neutre a des cetones chirales. Selon cette methode, un photoenol est genere a partir d'une cetone aromatique ayant un hydrogene en gamma suivant la reaction de norrish ii. L'induction asymetrique est obtenue par tautomerie de l'enol intermediaire, en presence d'une quantite catalytique d'un inducteur chiral. L'enantioselectivite depend fortement de l'enol, du choix de l'inducteur chiral et des conditions experimentales. Pour acceder a certains inducteurs utilises au cours de ce travail, nous avons propose une methode de synthese efficace permettant d'obtenir l'aminobornanol-endo-endo enantiomoeriquement pur. Differentes methodes developpees dans la litterature ont toujours permis de l'obtenir plus ou moins contamine par ses diastereoisomeres

El objetivo general del trabajo presentado es investigar nuevas metodologías para la síntesis de: a) nectrisina, un inhibidor de α-glucosidasas y α-mannosidasas, b) del fragmento oligosacarídico del antibiótico AT2433-A1, un antibiótico utilizado en el tratamiento de numerosos tipos de cánceres y, c) de análogos del cidofovir o HPMPC, nucleósido acíclico que incorpora una unidad de fosfonato, y que se utiliza en el tratamiento del citomegalovirus (CMV) en pacientes con SIDA. Síntesis enantioselectiva de nectrisina Retrosintéticamente la síntesis de la nectrisina puede llevarse a cabo por ciclación del aminoaldehído 2 (R4=CHO), el cual puede proceder del alqueno trans 3 mediante una reacción de dihidroxilación estereoselectiva. La síntesis de 3 puede llevarse a cabo a partir de 4 mediante elongación de la cadena utilizando la reacción de metatesis cruzada catalizada por rutenio. Finalmente, el intermedio clave 4 procede de una aminación alílica asimétrica catalizada por Pd del monepóxido de butadieno racémico 5, reacción ya descrita por Trost. La aminación alílica asimétrica del monepóxido de butadieno racémico catalizada por Pd (η3-C3H5)PdCl/DACH-naftilo transcurrió con elevado rendimiento y enantioselectividad para dar el compuesto 4. La elongación de la cadena de 4 se realizó mediante una metatesis cruzada catalizada por el catalizador de Grubbs-Hoveyda con diferentes alquenos como acroleína, 2-vinil-1,3-dioxolano, y con acrilato de etilo. Sólo en este último caso se obtuvieron resultados relevantes del compuesto 3 (R4=COOEt) como para continuar la síntesis. La reacción de dihidroxilación estereoselectiva del alqueno trans 3 (R4=COOEt) condujo al diol deseado 2 (R4=COOEt) con buena selectividad utilizando OsO4/TMEDA. La hidrólisis del benzoato con LiOH y la ciclación in situ condujo a la lactama, a partir de la cual se siguió una secuencia sintética descrita en la bibliografía, consistente en la sililación de los grupos hidroxilo, protección del grupo amino en forma de terc-butil carbamato, reducción del carbonilo y eliminación con desprotección concomitante de los grupo sililo para dar la imina, que en nuestras manos no logró llevarse a fin debido a problemas en la última etapa de eliminación para dar la imina. Síntesis enantioselectiva de análogos de Cidofovir HPMPC La síntesis de los análogos del cidofovir se planteó siguiendo un esquema sintético similar al de la nectrisina, en el que la síntesis del intermedio 7 se llevó a cabo mediante la aminación alílica asimétrica del monoepóxido del butadieno y posterior reacción de metátesis cruzada como pasos clave. En primer lugar se realizó la aminación alílica asimétrica catalizada por Pd (η3-C3H5)PdCl/DACH-naftil del monepóxido de butadieno racémico, con adenina y citosina la cual se optimizó hasta conseguir rendimientos y excesos enantioméricos superiores al 90%. Seguidamente se optimizó la reacción de metátesis cruzada de los compuestos obtenidos (6) con un alil fosfonato convenientemente protegido, obteniendo 7 con buen rendimiento. La síntesis de los análogos de cidofovir insaturados 8 y 9 se completó tras la desprotección de todos los grupos protectores con TMSBr. La síntesis del derivado saturado 10 se realizó mediante la hydrogenación (3 bares de hidrógeno, Pd/C durante 5h) y la eliminación de los grupos protectores. Síntesis enantioselectiva del fragmento oligosacarídico del antibiótico AT2433-A1 La retrosíntesis de 18 se planteó por ciclación electrófila inducida por yodo de 15, donde X debiera ser un grupo activador del doble enlace que a su vez se pudiera comportar como grupo saliente en la subsiguiente reacción de glicosilación a partir de 15. La síntesis del intermedio 15 se planteó por diferentes procedimientos y en particular a partir del sulfato 14, el cual provendría del diol 13, que a su vez provendría de la dihidroxilación de 12. El compuesto 12 debería poder obtenerse a partir de 5 por la secuencia clásica de DYKAT y metatesis cruzada. Así, a partir del compuesto 11 (R=Boc) se realizó la metatesis cruzada con diferentes alquenos y en particular con el alil fenil tioéter. Las limitaciones se encontraron en la reacción de dihidroxilación, ya que en casi todos los casos ensayados se produjo la oxidación del azufre, lo que conduciría al cambio de la selectividad en posteriores etapas como la ciclación. Se consiguió evitar la oxidación utilizando ligandos quirales en la dihidroxilación, pero con rendimientos muy bajos no compatibles con un esquema de síntesis por etapas.
The present thesis deals with the development of methodology for the syntheses of several organic molecules that were selected by their interesting biological properties: the antibiotic AT2433-A1, the glycosidase inhibidor nectrisine and analogs of the anti-viral Cidofovir (Figure 1.1) . Although apparently structurally unrelated, they were envisaged to be synthesized through common high-efficient key steps that involve metal-catalyzed process. Enantioselective Synthesis of nectrisine We explore an enantioselective synthesis of nectrisine based on Pd-catalyzed asymmetric allylic amination, cross-metathesis and dihydroxylation as key steps. Scheme 1 shows the retrosynthesis proposed, where the key synthon is the allylamine 4 which is obtained in high enantiomeric purity by a deracemization process using Pd/DACH as a catalytic system. Cross-metathesis will allow increasing the chain length, and at the same time would provide the aldehyde functionality necessary for formation of the cyclic imine moiety in the final nectrisine. Besides, configuration of double bond resulting from cross-metathesis must be E in order to provide the correct configuration of hydroxyl groups in 2 after the dihydroxylation reaction. The stereoselectivity of this reaction will be controlled by the stereocenter in the molecule, which could be also be enhanced by chiral ligands in a matched double stereodifferentiation process. The asymmetric allylic amination from racemic butadiene monoepoxide using (η3-C3H5)PdCl/DACH-naphtyl system and t-Butyl-benzoyl-imido carboxylate as a N-nucleophile proceeded with excellent yield (98%) and enantioselectivity (97%) to obtain the chiral allylic amine synthon 4. Elongation of the chain of the key chiral allylic imide with ethyl acrylate through cross metathesis using Hoveyda-Grubbs catalyst (5 mol %), proceeded quatitatively to obtain the trans alkene intermediates 3. The installation of the syn diol moiety via dihydroxylation of the alkene proceeded with high yield and good diastereoselectivity with OsO4/TMEDA. Hydrolysis of benzoate group in 2 with LiOH and in situ cyclization led to the lactam. Whose hydroxyl functionalities were fully protected by treatment with TBSCl. Subsequent protection with di-t-butyl dicarbonate (Boc) 2O and Et3N in CH2Cl2 gave desired product in 50% yield. The increased carbonyl electrophilicity resulting from NBoc protection should facilitate the smooth reduction of the lactam, which proceeded by reaction with Super Hydride® at −78°C to give lactol. Enantioselective Synthesis of Cidofovir Analogues In this context, the retrosynthetic proposal is shown in Scheme 2. Cidofovir (HPMPC) analogues could be obtained by double bond reduction of product 7 followed by protecting group cleavage on compound 11. Compound 7 in turn can be synthesized from compound 6 via chain elongation mediated by cross-metathesis reaction. Lastly, chiral synthon 6 could be obtained by a palladium-catalyzed dynamic kinetic asymmetric transformation (DYKAT) from racemic butadiene monoepoxide (5). The asymmetric allylic amination of racemic butadiene monoepoxide with cytosine as N-nucleophile was carried out with (η3-C3H5)PdCl/DACH-naphtyl system to obtain chiral allylic cytosine in 85% yield and 72% ee. The reaction was successfully expanded to other pyrimidine and purine bases, among which adenine afforded chiral allyl adenine in 90% yield and 92% ee. Chain elongation via Ru-cross metathesis of key allylic nucleobases and diethyl allylphosphonate with second generation Grubbs catalyst (5 mol%), produced desired compounds in 92% and 90% yield, respectively. Deprotection of all protecting groups with TMSBr afforded the desired unsaturated acyclic nucleosides 8 and 9 in good yields. Hydrogenation with (H2, /Pd/C) at 3 bar rendered the saturated Cidifovir analogues 10. Approaches to the Enantioselective Synthesis of AT2433-A1 The objective of this work was to explore a new enantioselective method to obtain AT2433-A1 with special focus on the synthesis of the 2, 4-dideoxy-4-amino-xyloside moiety. The retrosynthetic proposal is shown in Scheme 5.6. The aminodeoxysugar (19) could be obtained from 16 by eletrophile-induced cyclization. A key point is the selection of group X, since it must control the regioselectivity of the cyclization to an endo-mode and eventually must behave as a leaving group in a future glycosylation reaction. Amino alcohol 16 could be prepared from allylic amine 13 by dihydroxylation, sulphate formation and elimination. Compound 13 can be synthesized from allyl amine 12 via chain elongation mediated by cross-metathesis reaction. Lastly, chiral allyl amine 12 could be obtained, similarly to the previous chapters, by a palladium-catalyzed dynamic kinetic asymmetric transformation (DYKAT) from the racemic butadiene monoepoxide 5. On the other hand, the intermediate 15 could be also obtained by addition to the Garner aldehyde (18) followed by deprotection of the protecting groups in 17. The asymmetric allylic amination from racemic butadiene monoepoxide using (η3-C3H5)PdCl/DACH-naphtyl system and imide as a nitrogen nucleophile proceeded with good yield (96%) and enantioselectivity (90%). Chain elongation of key chiral allylic amine 12 was carried out by cross metathesis with allyl phenyl sulphide with Hoveyda-Grubbs catalyst (5 mol%) to obtain the corresponding trans alkene 13 in 80% yield. The installation of the diol moiety with OsO4 was unsuccesful, due to the competitive oxidation of sulfur, preventing the completion of the synthesis.

The tandem oxy-Cope/ene reaction allows the rapid construction of complex structures in a few steps. It was notably used in the total synthesis of (+)-arteannium M where the cascade revealed to be highly diastereoselective and enantioselective. The hypothesis that the retention of chirality based on the rigidity of an intermediate atropisomer devoid of stereogenic centers was proposed. This document presents a study of the enantioselectivity of the tandem oxy-Cope/ene reaction and provides an explanation for the decrease in chirality observed during the cascade. Different variables of the reaction and of the starting material were analyzed to explain the retention of chirality.* The efforts of our group in the development of tandem reactions led to the discovery of a novel cascade that involves 4 pericyclic reactions: the oxa-Cope/Claisen/ene/Claisen cascade. This sequence of reactions was briefly investigated to determine its scope and limitations, notably by changing the substituent on the alkyne and on the tertiary alcohol of 150*. *Please refer to dissertation for diagrams.

This thesis studies the novel enantioselective of nitrocycloalkanes with multiple stereocentres via inter and/or intramolecular Michael addition using a variety of organocatalytic approaches. A novel nitro-Michael/Michael domino reaction catalysed by a quinine-derived bifunctional thiourea catalyst has been developed. This methodology has been applied to generate a variety of nitrocyclohexane derivatives, containing up to five contiguous stereocentres, with very high enantioselectivity and good diastereoselectivity. We have hypothesized that the reaction proceeds through the dual coordination of thiourea catalyst to both the nitronate and the conjugated ester. Finally the application of these compounds was demonstrated in the synthesis of a tetracyclic alkaloid a-lycorane-like compound. We have also successfully devised an enantioselective organocatlytic Michael addition to vinyl cyanosulfones catalysed by quinine-derive bifunctional thiourea catalyst. A variety of highly functionalised cyclohexyl derivatives containing one quaternary stereocentre in nature were synthesised with high yield and good enantioselectivity and diastereoselectivity. Finally, the synthetic application was demonstrated through the synthesis of and amino acid precursors.

Au laboratoire, la reaction de carbolithiation enantioselective de l'alcool cinnamique a ete bien etudiee. L'addition de n-butyllithium dans l'hexane ou le cumene en presence d'une quantite stoechiometrique de (-)-sparteine comme inducteur chiral permettait d'obtenir le produit de carbometallation desire avec un bon exces enantiomerique (82%) et un bon rendement de 82%. Au cours de notre travail, nous avons tout d'abord cherche a ameliorer l'exces enantiomerique lors de la reaction de carbolithiation enantioselective de l'alcool cinnamique. L'addition d'un alkyllithien primaire ou secondaire en presence d'une quantite catalytique ou stoechiometrique de (-)-sparteine sur l'alcool cinnamique (e) protege sous forme d'ether de 1-(1-methoxy-1-methylethyl) conduit au produit de carbometallation avec d'excellents exces enantiomeriques (85-95%) et de bons rendements (50-77%). De plus, l'organolithien benzylique intermediaire, ainsi forme, peut conduire a des cyclopropanes chiraux trans disubstitues grace a une reaction de substitution nucleophile intramoleculaire et ce, par simple rechauffement du milieu reactionnel a l'ambiante. La partie la plus importante de notre travail a consiste en la generalisation de la reaction de carbolithiation enantioselective a d'autres substrats que l'alcool cinnamique. Nous nous sommes d'abord interesse au remplacement du groupement hydroxymethyle de l'alcool cinnamique et nous nous avons pu montrer que la presence d'un heteroatome sur la molecule n'etait pas necessaire pour que l'addition de l'organolithien ait lieu. La reaction de carbolithiation a pu etre generalisee a divers beta-akylstyrenes et de bons exces enantiomeriques (76-85%) ainsi que de bons rendements (73-92%) ont ete obtenus pour les produits de carbometallation. En ce qui concerne le cas du remplacement du phenyle de l'alcool cinnamique par divers groupements c'est le remplacement par un reste vinyle qui nous a donne le plus de satisfaction. En effet, nous avons pu obtenir l'addition d'un organolithien de facon totalement regioselective sur le pole 2 du diene avec des exces enantiomeriques allants de 55 a 74%. De plus, nous avons mis en evidence une reaction generale d'addition d'organolithiens primaires sur des dienes 1,3 terminaux, conduisant avec de bons rendements a l'allyl lithien correspondant et non decrite a notre connaissance.

On the instigation of A/Prof C. S. P. McErlean I have investigated asymmetric approaches for the synthesis of strigolactone analogues. Strigolactones are an emergent class of phytohormone whose biological importance is only beginning to be elucidated. As our understanding of these phytohormones expands, the importance of stereochemistry on their biological action becomes increasingly apparent. As such, methodologies which allow access to strigolactones or their analogues, in a stereocontrolled fashion are of paramount importance. In the first chapter we discuss the discovery of strigolactones and the roles they play in nature. Previous approaches to the synthesis of strigolactones, as well as the development of synthetic analogues and mimics are also discussed. In chapter two, we describe our enantioselective approach for the synthesis of the key strigolactone analogue GR24. Our approach utilised a Noyori asymmetric transfer hydrogenation to install the chiral centres in a dynamic, and catalytic manner. Chapter three describes the application of our developed methodology for the synthesis of bromo-GR24 analogues. These molecules were further functionalised with a water solubilising group, or a fluorescent tag, to enable further biological studies. We also discuss a formal synthesis of the strigolactone (−)-solanacol. Finally, we discuss work undertaken at the University of Oxford, under the supervision of A/Prof Jonathan W. Burton. Here we developed synthetic approaches toward the synthesis of the inthomycin family of natural products, utilising a highly convergent strategy and environmentally benign organoboronates.

Enantioselective Nickel-catalysed anti-Carbometallative Cyclisations of Alkynyl Electrophiles Enabled by Reversible Alkenylnickel E/Z Isomerisation. Highly enantioselective anti-carbometallations of alkynes bearing tethered ketones is described using a Ni(II) salt and a commercially available chiral phosphinooxazoline ligand. Due to the syn-selective nature of alkyne-migratory insertion, many examples of carbometallative processes giving the cyclised syn-products have been reported, however, anti¬-carbometallative processes are rare. The mechanism of this anti-carbometallation is thought to occur via an alkenylnickel E/Z-isomerisation of the organometallic species formed after initial alkyne migratory insertion. Although a number of examples of such isomerisaions have been reported, the utilisation of the phenomina in ring-forming reactions to give anti-carbometallation products is much less well explored. Further reaction development for the nickel-catalysed anti-carbometallative cyclisations of alkynyl electrophiles has allowed for the synthesis of enantioenriched cyclopentenones using malonates as electrophiles. The use of the trifloroethanol leaving group on a malonate electrophile is important for efficient reactivity and allows the previously unreactive ester electrophile to be used. However, inorder to obtain high enantioselectivities and aryl group at the quaternaty centre of the substrate is required.

Aquesta tesi descriu el disseny i la síntesi d’una nova classe de lligands basats en ferrocè, i la seva aplicació a la catàlisi enantioselectva amb Au(I). Aquests lligands han estat específicament implementats per superar les dificultats de la catàlisi enantioselectiva amb Au(I) a causa de la separació espacial entre la informació quiral del lligand i el centre actiu localitzat a la cara oposada del metall. S’ha desenvolupat una síntesi modular d’1-(2’-dialquilarilfosfina)-3-arilferrocè, permetent l’accés a una família de complexes quirals d’Au(I) amb diferents propietats estèriques i electròniques. S’ha identificat un complex quiral d’Au(I) com a catalitzador per la cicloaddició [4+2] formal d’1,6-arilenins amb elevats rendiments i bones enantioselectivitats. El mode d’acció del catalitzador ha estat estudiat computacionalment, trobant-se que una interacció atractiva no covalent entre el lligand i el substrat és crucial per assolir una elevada inducció enantiomèrica. Així mateix, hem aplicat un complex d’Au(I), amb un lligand fosfina que inclou una pirrolidina quiral 2,5-disustituida amb simetria C2 a una posició remota, a la síntesi de ferrocens amb quiralitat planar mitjançant una reacció d’hidroarilació de (2-alquinilaril)ferrocens.
La presente tesis describe el diseño y la síntesis de una nueva clase de ligandos basados en ferroceno, y su aplicación en catálisis enantioselectiva con Au(I). Estos ligandos han sido específicamente implementados para superar las dificultades de la catálisis enantioselectiva con Au(I) debido a la separación espacial entre la información quiral en el ligando y el centro activo localizado en la cara opuesta del metal. Se ha desarrollado una síntesis modular de 1-(2’-dialquilarilfosfina)-3-arilferroceno, permitiendo el acceso a una familia de complejos quirales de Au(I) con diferentes propiedades estéricas y electrónicas. Se identificó un complejo quiral de Au(I) como catalizador para la cicloadición [4+2] formal de 1,6-arileninos con elevados rendimientos y buenas enantioselectividades. El modo de acción de nuestro catalizador quiral se ha estudiado computacionalmente, encontrándose que una interacción atractiva no covalente entre el ligando y el sustrato es crucial para lograr una elevada inducción enantiomérica. Asimismo, hemos aplicado un complejo de Au(I), cuyo ligando fosfina incluye una pirrolidina quiral 2,5-disustituida con simetría C2 en posición remota, a la síntesis de ferrocenos con quiralidad planar mediante una reacción de hidroarilación de (2-alquinilaril)ferrocenos.
This thesis describes the design and synthesis of a new class of ferrocene-based ligands applied to enantioselective gold(I) catalysis. These ligands have been specifically implemented to overcome difficulties of enantioselective gold(I) catalysis due to the spatial separation between the chiral information on the ligand and the catalytic site located on the opposite side of the metal center. A modular synthesis of 1-(2’-dialkylarylphosphine)-3-arylferrocene was developed allowing to access a family of chiral gold(I) complexes bearing various steric and electronic properties. One chiral gold(I) complex was identified to catalyze the formal [4+2] cycloaddition of 1,6-arylenynes in high yields and good enantioselectivities. The working mode of our chiral catalysts was studied computationally. An attractive non-covalent interaction between the ligand and the substrate was found to be crucial to achieve high enantioinduction. Additionally, we applied a phosphine-supported gold(I) complex containing a chiral remote C2-symmetric 2,5-disubstituted pyrrolidines to the enantioselective synthesis of planar chiral ferrocenes by hydroarylation of (2-alkynylaryl)ferrocenes.

Hydrometalation of α,β-unsaturated carbonyl compounds provides access to reactive metal enolates, which can then be trapped by a suitable electrophile. The coppercatalysed reductive aldol reaction involves hydrometalation of an α,β-unsaturated carbonyl compound, followed by an inter- or intramolecular aldol reaction. While there have been numerous examples of copper-catalysed reductive aldol reactions reported in the literature, the corresponding reductive Michael reaction has been relatively understudied. Herein, the copper-catalysed reductive Michael cyclisation of substrates containing two α,β-unsaturated carbonyl moieties is described. A range of structurally and electronically diverse substrates were prepared by various different methods. Both α,β-unsaturated ketones and esters underwent cyclisation, in the presence of a copper catalyst, a bisphosphine ligand, and a stoichiometric reductant, to afford 5- and 6- membered carbocyclic and heterocyclic products, with good-to-excellent levels of diastereo- and enantiocontrol. Furthermore, the diastereochemical outcome of these reactions is dependent on the specific reaction conditions used.

Chapter One gives an introduction to the key concepts of bridgehead alkene formation and its relevance to the formation of bridgehead enolates of ketones including a review of bridgehead enolates in synthesis. The review is limited to the generation of bridgehead carbanions alpha to a carbonyl group and does not cover bridgehead cations, radicals or any anions except those already mentioned. In addition, a brief introduction to chiral base methodology and a review of the latest developments is included. Chapter Two describes the generation of bridgehead enolates in various bridged bicyclic ketones using chiral and achiral lithium amide bases and their subsequent interception with chlorotrimethylsilane. The chiral bridgehead silanes resulting from enantioselective deprotonation were shown to undergo silyl exchange reactions with TBAT as fluoride source in the presence of various electrophiles. Chapter Three describes a review of bridgehead enolates of imides and describes the extension of the developed methodology in Chapter Two to the generation and trapping of bridgehead enolates in bridged bicyclic imides and lactams. In addition bridgehead enolates are shown to react in the presence of non-classical in situ electrophiles such as methyl iodide, allyl bromide, benzyl bromide, prenyl bromide and pivaloyl chloride in high yield and enantioselectivity. The secondary bridgehead deprotonation of monosubstituted imides was also achieved resulting in double bridgehead functionalised products with high ee. The bridgehead silanes are shown to undergo silyl exchange reactions and display silyl directed regioselective reduction and thionation reactions. The mechanism of deprotonation, comparison to known examples and the origin of bridgehead carbanion stability are discussed. Chapter Four contains the experimental procedures and analytical data for the preparation of the novel compounds described herein followed by the appendix of selected NMR and X-ray data.

The diketopiperazine scaffold can be found in a large number of natural products and commercialised drugs. Conversely, the triketopiperazine one is far less common in Nature and scarce research has been conducted to determine its utility. The project goal was to develop enantioselective organocatalysis on these two frameworks. Chapter 1 gives an introduction on their presence in Nature and the pharmaceutical industry, the most relevant synthetic advances as well as an overview of the organocatalysis tools previously reported. Although diketopiperazines have been the subject of intense research, no asymmetric methods have been previously reported despite the myriad of available methodologies. Chapter 2 discusses the particular organocatalytic precedents that motivated this project and the initial efforts devoted to develop such methodology. Unfortunately, diketopiperazines showed complete lack of reactivity under a wide range of conditions. Our interest in developing this enantioselective method in heterocycles related to diketopiperazines made us turn our attention to the triketopiperazine scaffold. The successful application of a cinchona alkaloid derived catalysed Michael addition on this scaffold is described in Chapter 3. Progresses made in the manipulation of the chiral products are also included. An extension of the previously developed methodology, where selected Michael acceptors afford bicycle[2.2.2]diazaoctane derived products via a tandem Michael–ring-closure process, is discussed in Chapter 4.

The total synthesis of the 3-polyenoyltetramic acid antibiotic altamycin A has been attempted via a novel method of preparing enantiomerically pure tetramic acids. Thus two target fragments were identified: (a) the tetramic acid and (b) the polyenal fragment. The chirality present in the latter was introduced (enantioselectively) through the catalytic Sharpless epoxidation of an isomerically pure allylic alcohol. This epoxide was then elaborated, using Wittig technology, into the aforementioned polyenal unit. The chiral acid was readily available through reaction of an ester enolate with an oxazolidine-2,5-dione of desired stereochemistry. The coupling of these fragments was studied - several methods being tried then evaluated according to their expediency. This approach to altamycin A is sufficiently flexible to allow the preparation of other members of this interesting class of naturally occurring compounds.