Dissertations / Theses on the topic 'Enantioselective synthesi'

Helicenes are ortho-annulated polycyclic aromatic or heteroaromatic compounds, endowed with inherent chirality owing to the helical shape of their π-conjugated system. Carbohelicenes only include benzene rings in their structure, while in heterohelicenes one or more heterocycles are present. Interestingly, the introduction of heteroatoms into the fused polycyclic frameworks adds remarkable changes to the electronic structures of helicenes, and additional chemical and physical properties. Their unique structural features and physicochemical properties have stimulated manifold studies in several fields, including optoelectronics, material science, asymmetric catalysis, and chiral recognition. Many of these applications require the use of enantiomerically pure helicenes, although the resolution of racemates by means of analytical methods as well as the separation of diastereomers still remain the most common ways to obtain non-racemic helicenes, whose peculiar geometry makes them extremely difficult targets for stereoselective synthesis. This Ph.D. thesis was intended to provide a meaningful contribution in the development of innovative and versatile syntheses of heterohelicenes, also in enantiopure form, and has focused on the following main goals: 1. Study of methodologies for the synthesis of functionalised tetrathia[7]helicenes (7-THs). 2. Synthesis of different classes of thiahelicenes through methodologies set up for the preparation of 7-THs. 3. Enantioselective synthesis of thia[5]helicenes via Au-catalysed alkyne hydroarylation. In the course of this thesis, a sub-topic has also been developed: 4. Functionalisation of benzo[1,2-b:4,3-b']dithiophenes by Suzuki reactions in Deep Eutectic Solvents (DESs).

Benzylic fluorides are attractive target molecules for medicinal chemistry, agrochemicals and materials chemistry. The enantioselective synthesis of benzylic fluorides is challenging and few general methods exist. This thesis describes several approaches to the synthesis of benzylic fluoride targets, including enantioselective processes. Chapter 1: Reviews the properties, uses and synthetic approaches to fluorinated molecules, with a particular focus on benzylic fluorides and enantioselective syntheses. Chapter 2: Describes the fluorination cyclisation of prochiral indole precursors. The use of catalytic amounts of a bis-cinchona alkaloid gave good enantioselectivities for the cyclisation. Alcohol, tosylamine, amide and carbamate pendant nucleophiles all cyclised successfully to give quaternary benzylic fluorides in moderate yields and with enantioselectivities up to 92%. The substrate scope of the reaction is described, as well as methodology for deprotection of cyclised nitrogen nucleophiles. Chapter 3: Details an investigation of the Pd catalysed substitution of polycyclic benzylic fluorides by a range of nucleophiles and their relative reactivity in comparison to oxygen leaving groups. Modification of the methodology to enable reaction of monocyclic substrate substitution was enabled by the use of a protic solvent. Chemoselective reaction conditions were identified for selective reaction of Bn-F or Ar-Cl bonds and comparative reactivity studies were undertaken. The feasibility of Pd(0)/(II) catalysed nucleophilic C-F bond formation was examined. Chapter 4: The development of the defluorination methodology from Chapter 3 for secondary substrates is described. The stereochemical course of defluorination was probed, showing that displacement of fluoride is mechanistically similar to that of oxygen leaving groups. A kinetic resolution with a low selectivity was developed for access to enantioenriched benzylic fluorides.

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.

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.

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.

Nous avons développé de nouveaux accès pour la construction de molécules comportant les motifs Csp3-CF3 et Csp3-SCF3. Deux réactions de transfert d'hydrure sur des composés trifluorométhylés par catalyse avec des métaux de transition ont été réalisées : 1) l'isomérisation catalytique d'alcools allyliques trifluorométhylés par des complexes de fer (II); 2) le transfert d'hydrogéne énantiosélectif de céto-imines trifluorométhylées par des complexes chiraux de ruthénium en utilisant l'isopropanol comme source d'hydrure pour obtenir des amines trifluorométhylées optiquement actives avec de hauts rendements et de hautes énantiosélectivités. La trifluorométhylthiolation allylique nucléophile de dérivés de Morita-Baylis-Hillman a été étudiée. L'accès régio- et stéréosélectif aux produits SCF3 thermodynamiques a été réalisé par la combinaison de S8/CF3SiMe3/KF/DMF avec de bons rendements. Le produit cinétique a été obtenu en utilisant le réactif de Zard
We have developed new accesses for the construction of molecules featuring Csp3-CF3 and Csp3-SCF3 motifs. Two atom-economical hydride transfer reactions of trifluoromethylated compounds by transition-metal catalysis were realized: 1) the isomerization of trifluoromethylated allylic alcohols by iron (II) complexes; 2) the enantioselective transfer hydrogenation of trifluoromethylated ketimines by a chiral complex of ruthenium and isopropanol as hydride source for the preparation of optically pure trifluoromethylated amines in high yields and high enantioselectivities. The nucleophilic allylic trifluoromethylthiolation of Morita-Baylis-Hillman derivatives was investigated. The regio- and stereoselective access to thermodynamic trifluoromethylthiolated products has been achieved by combination of S8/KFfMe3SiCF3/DMF in good yields. The kinetic trifluoromethylthiolated products were obtained by using Zard's trifluoromethylthiolating reagent

Thesis (M.S.)--East Tennessee State University, 2003.
Title from electronic submission form. ETSU ETD database URN: etd-0715103-013825. Includes bibliographical references. Also available via Internet at the UMI web site.

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.

Luminacin D, isolated from the fermentation broth of soil bacterium Streptomyces sp. Mer-VD1207, has angiogenesis inhibitory activity. In vivo studies have shown this activity derives from a novel mode of action, thus making luminacin D an interesting target for synthesis. Previous syntheses have not enabled the preparation of the spiro-epoxypyran moiety in a stereoselective manner, and luminacin D has been isolated as a mixture with the 6’,8’ – epimer as a result. This has been overcome by early, stereospecific introduction of the epoxide in our synthesis and we have constructed the natural product skeleton with the correct absolute stereochemistry, by chelation controlled diastereoselective additions. This has enabled possibly the first enantioselective and diastereoselective synthesis of this natural product to be completed. The allylation of α-heteroatom substituted aldehydes was of significance to the synthesis as the key step in the synthesis involved allylation of an α-epoxyaldehyde. These allylation reactions have been investigated by DFT calculations to unambiguously assign the Evans-Conforth and Polar Felkin-Ahn models in these additions.

Ce travail decrit la synthese enantioselective d'analogues tricycliques simplifies de l'artemisinine, principe actif isole d'une plante (artemisia annua l. ) utilisee en medecine traditionnelle chinoise pour ses proprietes antimalariques. Ces analogues possedent le systeme 5-alcoxy-1,2,4-trioxane, qui est considere comme le pharmacophore minimal necessaire a l'activite biologique, mais different de l'artemisinine par l'absence du cycle d lactonique, et par le deplacement du methyle porte par le carbone c-6 vers le carbone c-5a en jonction des cycles a et c. L'etape cle de la synthese de ces analogues est l'elaboration du noyau trioxane. Deux voies d'acces potentielles a ce systeme ont ete explorees. La premiere approche qui repose sur la reaction de photoxydation des ethers d'enol, s'est averee ne fournir le trioxane attendu qu'en tres faible rendement, le produit majoritaire resultant d'une ene-reaction. En revanche la seconde voie consistant en l'ozonation d'un vinylsilane, suivie du rearrangement acide du dioxetane intermediaire, nous a permis de preparer le trioxane desire avec un rendement satisfaisant. Le ceto-vinylsilane precurseur des trioxanes necessaire a cette etude a ete prepare a partir du cetonitrile resultant d'une reaction de michael entre l'acrylonitrile et l'imine chirale derivee de la 2-methylcyclohexanone et de la (s)-1-phenylethylamine. L'adduit optiquement actif obtenu a ete transforme en 4 etapes en ceto-vinylsilane, par une sequence dont le point le plus notable est une nouvelle methode de desoxygenation des epoxysilanes. Les structures des analogues de l'artemisinine obtenus ont ete determinees par diffraction des rayons x, et leurs proprietes biologiques ont ete evaluees in vitro.

Thesis (Ph. D.)--University of California, San Diego, 2009.
Title from first page of PDF file (viewed June 18, 2009). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references.

Ce travail concerne la synthese asymetrique et l'etude de la reactivite de composes 1-formylcyclopropanes. Dans une premiere partie, nous avons presente les eicosanoides produits naturels provenant de diverses sources, nous avons mis l'accent sur ceux qui renferment au sein de leurs structures un motif cyclopropanique et appartenant au regne marin, puis nous avons rappele les differentes methodes d'acces a des cyclopropanes substitues asymetriques. La seconde partie comprend deux phases. Nous avons dans un premier temps, etudie les additions nucleophiles sur des 1-formylcyclopropanes 2-substitues et dans un deuxieme temps nous avons applique cette etude dans une approche globale pour la synthese de produits naturels possedant dans leurs structures des motifs cyclopropaniques. Lors des additions nucleophiles sur des formylcyclopropanes trans-1,2-di-substitues, aucune diastereoselectivite n'a ete observee. Par contre, dans le cas des formylcyclopropanes cis-1,2-disubstitues, les resultats que nous avons obtenus montrent que le diastereoisomere syn est majoritairement obtenu. Grace a des isomerisations de formylcyclopropanes cis en formylcyclopropanes trans, l'acces diastereoselectif a des derives cyclopropaniques trans possedant aussi des centres asymetriques hydroxyles dans les positions adjacentes a ete rendu possible. En modifiant les conditions, et notamment en ajoutant des acides de lewis, nous avons pu augmenter cette diastereoselectivite. Ces resultats sont interessants dans la mesure ou un certain nombre de produits naturels, essentiellement d'origine marine, renferment des cyclopropanes possedant des carbones asymetriques hydroxyles au niveau des positions adjacentes. Ces produits naturels seraient ainsi accessibles via cette methode. Nous avons ensuite tente d'appliquer ces resultats dans une approche de la synthese totale de constanolactones, produits naturels d'origine marine appartenant a la famille des oxylipines et possedant dans leurs structures le cycle a trois chainons dans une configuration trans. La voie synthetique que nous avons choisie est generale grace a ces additions nucleophiles diastereoselectives. Cependant une des etapes finales de cette synthese n'a pour l'instant pas pu etre maitrisee

Thesis advisor: James P. Morken
Described herein are three distinct projects centered on the formation and use of carbon-boron bonds. In the first, the enantioselective platinum-catalyzed 1,4-diboration of trans-1,3-dienes is advanced in both selectivity and scope through the development of a novel class of electron rich chiral monodentate phosphines. Under the action of the new ligands, highly selective diboration is maintained at reduced loadings of catalyst. Secondly, enantioenriched 1,2-bis(pinacol boronates) are engaged in regioselective Suzuki-Miyaura cross-coupling with aryl and vinyl electrophiles. A tandem diboration cross-coupling sequence is successfully implemented to afford homobenzylic and homoallylic pinacol boronates directly from terminal olefins, which subsequently undergo oxidation, amination or homologation of the remaining carbon-boron bond to arrive at a range of enantioenriched products. Lastly, aryl electrophiles containing tethered allylboronate units undergo efficient intramolecular coupling in the presence of a chiral palladium catalyst to give enantioenriched carbocyclic products
Thesis (PhD) — Boston College, 2014
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Chemistry

Thesis advisor: Amir H. Hoveyda
Chapter 1. Part A: N-Heterocyclic Carbenes Catalyzed Enantioselective Boryl Conjugate Additions to α,β-Unsaturated Ketones, Esters, Weinreb Amides and Aldehydes. The first broadly applicable enantioselective boryl conjugate addition reactions to a variety of α,β-unsaturated carbonyls are reported. Transformations are promoted by 5.0 mol % of a chiral Lewis basic N-heterocyclic carbene. The distinctive feature of the reactions in chemoselectivity of the method compared to the Cu-catalyzed variants has been illustrated. Part B: Enantioselective Synthesis of Boron-Substituted Quaternary Carbon Stereogenic Centers through N-Heterocyclic Carbenes Catalyzed Boryl Conjugate Additions to Cyclic and Acyclic Enones The first examples of Lewis base catalyzed enantioselective boryl conjugate additions that afford products containing boron-substituted quaternary carbon stereogenic centers are presented. The carbon–boron bond forming reactions are promoted by 1.0–5.0 mol % of a chiral N–hererocyclic carbene. Cyclic or linear α,β–unsaturated ketones can be used as suitable substrates and the desired products are obtained in 63–95% yield and 91:9 to >99:1 enantiomeric ratio. The utility of the Lewis base-catalyzed approach is demonstrated in the context of an enantioselective formal synthesis of antifungal natural product crassinervic acid. Chapter 2. Enantioselectivity Fluctuations in Phosphine–Cu-Catalyzed Enantioselective Boron-Allyl Addition to Aryl-Substituted Olefins. Catalytic enantioselective multicomponent processes involving B2(pin)2, aryl or heteroaryl monosubstituted olefins, and allylic phosphates or carbonates are disclosed. Transformations promoted by a chiral Cu–phosphine complex afford products that contain a primary C–B(pin) bond and an allyl-substituted tertiary carbon stereogenic center in up to 84% yield and 98:2 enantiomeric ratio. The utility of the approach is showcased in the enantioselective formal synthesis of biologically active heliespirones A and C. Based on mechanistic and computational studies, we show that enantioselectivities variations can depend on electronic and/or steric factors of the alkene substrate and the allyl electrophile as well as their concentration. In most cases, selectivity loss can be minimized and that the resulting insights are also applicable to reactions involving Cu–H species. Chapter 3. Synthesis of Vicinal Diboronate Compounds through Practical Phosphine–Copper Catalyzed Three-Component Processes. The phosphine–Cu-catalyzed multicomponent processes have been developed for a practical and direct synthesis of vicinal diboronate compounds. Reactions of alkenyl–boronates, allylic phosphates, and diboron reagents are promoted by 2.5–10 mol % of a Cy3P–Cu complex affording a wide range of desirable vicinal diboronate products. The ability for easy access to either regioisomers of the products with a C–B(pin) and an adjacent C–B(dan) bond that can be site-selectively functionalized is a noteworthy feature of the method
Thesis (PhD) — Boston College, 2016
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Chemistry

Atropisomerism is a property exhibited by molecules where rotation about one or more bonds is restricted. Along with biaryls, which are widely utilised in asymmetric catalysis, several other classes of compounds display atropisomerism. These molecules have applications in enantioselective synthesis, asymmetric catalysis and have been used to relay stereochemical information. There are, however, a number of challenges associated with their asymmetric synthesis (Chapter 1). This thesis describes research carried out on the synthesis and asymmetric synthesis of atropisomeric diaryl ethers. Chapter 2.1 explains how these ethers are synthesised in multi-gram quantities and to allow the incorporation of large ortho substituents. Having a number of diaryl ethers with suitable substitution patterns to achieve atropisomerism, Chapter 2.2 goes on to report two novel and complimentary biocatalytic approaches to the enantioselective synthesis of diaryl ethers by desymmetrisation. This chapter also describes a possible route towards the synthesis of a diaryl ether based ligand. Chapter 2.3 reports the lateral lithiation of meso diaryl ethers to yield diastereomeric atropisomers stereoselectively. Our attempts to use (-)-sparteine in lateral lithiations to desymmetrise a diaryl ether enantioselectively is also described. We go on to determine the configurational integrity of our organolithiums and the reaction pathway that exists in lithium substitution. Finally, the diastereoselective synthesis of both a diaryl ether (via a stereoselective reduction of a pro-chiral ketone) and a diaryl sulfide (via an addition reaction) is described in chapter 2.4. This chapter also reports the conformational behaviour of a diaryl amide in solution.

Thesis advisor: Amir H. Hoveyda
Chapter 1 Mechanism-Based Enhancement of Scope and Enantioselectivity for Reactions Involving a Copper-Substituted Stereogenic Carbon Center: Organoborons are important building blocks of complex natural products, functional materials, and pharmaceutically relevant compounds due to their prevalent utility in C–C and C–hetero atom bond transformations. Using a readily accessible copper catalyst, we have developed highly site- and enantioselective allylic substitution by way of a threecomponent, single-vessel, and sustainable catalytic protocol. Detailed mechanistic studies revealed valuable insights which led us to develop copper–boron and copper–hydride additions to olefins with broader substrate scope, higher efficiency, and higher enantioselectivity. In addition, the method can be applied to the synthesis of biologically active molecules such as preclamol and heliespirone A and C. Chapter 2 Versatile Homoallylic Boronates by Chemo-, SN2’-, Diastereo- and Enantioselective Catalytic Sequence of Cu–H Addition to Vinyl-B(pin)/Allylic Substitution: To achieve an efficient multicomponent reaction, high chemoselectivity between a starting material and a reagent must be accomplished during the first catalytic transformation to generate an intermediate which then selectively reacts with another substrate to furnish the product in a site-, and/or stereoselective fashion. Development and application of efficient multicomponent reactions involving allylic substitution can provide alternative solutions for difficult synthetic problems in organic chemistry. Our group has developed a sulfonate-containing chiral NHC–Cu catalyzed chemo-, SN2’-, diastereo-, and enantioselective multicomponent reaction through Cu–H addition to readily available vinyl–B(pin) followed by allylic substitution to deliver homoallylic boronates. The derived homoallylic alcohols can be used as building blocks of biologically active molecules. Chapter 3 Enantioenriched Halogen-Substituted Alkenes through NHC–Cu-Catalyzed Borylation/Dehalogenation and Their Applications: Because of their unique properties, mono- and difluoroalkenes have received attention as an important class of compounds as building blocks for fluorine-containing monomers for functional polymers and biologically active molecules in medicine and agriculture. However, reported methods to prepare enantioenriched difluoroalkenes are scarce and often require undesirable amounts of precious transition metals and very high/low temperatures. To solve these challenges, we have developed a highly efficient, regio-, and enantioselective boron allylic substitution to CF3-alkenes and other halogen-substituted olefins by using an abundant copper-based catalyst
Thesis (PhD) — Boston College, 2017
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Chemistry

Une methode d'alkylation reductrice enantioselective de naphtalenes portant un auxiliaire chiral de type l-prolinol a ete developpee. Cette methode a ete appliquee a la synthese d'une octalone chirale, synthon permettant d'acceder a des clerodanes de jonction de cycle trans- ou cis. Le controle de la stereochimie de la jonction de cycle a partir d'un alcool allylique via une reaction radicalaire utilisant l'agrafe silylee de g. Stork a ete etudie et a permis l'obtention de decalines polyoxygenees de jonction de cycle trans- et cis

Une synthese asymetrique efficace de mono et diphosphines tertiaires ou l'atome de phosphore est porteur de la chiralite est decrite en serie complexee. Son principe repose sur: 1) la separation diastereoselective d'un complexe borane d'oxazaphospholidine derive de l'ephedrine; 2) l'ouverture regio et stereospecifique de l'heterocycle complexe par les organometalliques. L'aminophosphine-borane obtenue est transformee en chlorophosphine ou en phosphinite-borane, respectivement par reaction avec l'acide chlorhydrique ou par methanolyse. Les phosphinites-borane reagissent avec les organolithiens pour conduire aux phosphines-borane avec des e. E. De 85 a 100% et des rendements globaux atteignant 70%. Les methyles phosphines-borane conduisent aux diphosphines-borane par couplage oxydant ou reaction avec un dichlorosilane. Les mono et diphosphines sont isolees quantitativement sans perte de chiralite par decomplexations avec la diethylamine

Includes bibliographical references (leaves 198-203).
A study has been carried out on the enantioselective total synthesis of the indolizidine alkaloid (+)-castanospermine. The aim was to develop a convergent synthesis based on a C-8/C-8a disconnection. A distinguishing feature of this method is that it is non-carbohydrate-based.

La mise au point de systemes hautement fluores utilisables dans le domaine biomedical ou celui des materiaux moleculaires implique la conception et la synthese de nouvelles molecules hautement fluorees si possible de stereochimie controlee. Notre objectif a ete de developper une famille de dihydropyrenones f-alkylees chirales preparees par synthese enantioselective. Dans une premiere partie nous decrivons la synthese des precurseurs : les aldehydes f-alkyles de type r#f(ch#2)#ncho. Ils sont obtenus par oxydation des alcools primaires f-alkyles correspondants par trois methodes differentes : oxydation de swern, oxydation par le chlorochromate de pyridinium et oxydation par le periodinane de dess-martin. La deuxieme partie de ce memoire concerne la mise au point de la lacdac (lewis acid catalyzed diene aldehyde cyclocondensation) en serie fluoree. Les dihydropyrenones f-alkylees sont obtenues selon la litterature pour les aldehydes possedant une chaine methylenique. Par contre pour les aldehydes perfluores, cette reaction s'effectue sans catalyseur et a temperature ambiante. Dans ce dernier cas, l'intermediaire de la reaction a ete isole et decrit. Enfin la derniere partie decrit la synthese des dihydropyrenones f-alkylees asymetriques. La lacdac enantioselective est alors realisee en utilisant un catalyseur chiral : le complexe r(+) ou s() binol/ti(oipr)#4. Les composes asymetriques ainsi obtenus sont des synthons potentiellement utilisables dans le domaine biomedical ou comme dopant dans des systemes nematiques ou smectiques pour l'obtention de nouveaux cristaux liquides.

The enantioselective chlorination of alcohols by the menthyldipheny1-phosphine/carbon tetrachloride reagent previously reported in the literature was investigated and quantified. Further examples were found. A new enantioselective reaction of menthyldipheny1phosphine/carbon tetrachloride was discovered. This was the synthesis of aziridines by ring closure of ? amino alcohols. Other optically active phosphines in conjunction with carbon tetrachloride were found to react in a similar manner to menthy1dipheny1phosphine/carbon tetrachloride with a variety of ? amino alcohols. Menthy1dipheny1phosphine was found to react enantioselectively with a ? amino alcohol in the presence of chlorine.

Dans le cadre de la synthèse totale de la leucophyllidine, un alcaloïde bis-indolique, des réactions de carbo- et sulfonyl-cyanation radicalaires sans étain ont été développées. Les cyanures de sulfonyle RSO2CN, préparés à partir des thiocyanates correspondant par une nouvelle méthode d’oxydation, sont utilisés comme pièges radicalaires. Ces réactifs fragmentent en présence d’initiateur thermique (carbo-cyanation) ou par le biais de la catalyse photoredox (sulfonyl-cyanation). Dans ce dernier cas, une étude mécanistique approfondie sur le cycle photo-catalytique a été accomplie. Ces méthodologies introduisent un nitrile sur une chaîne carbonée insaturée par voie radicalaire, fournissant des intermédiaires avancés pour la synthèse totale d’alcaloïdes. Pour la synthèse asymétrique de l’eucophylline, le fragment sud de la leucophyllidine, la sulfonyl-cyanation de cyclobutènes énantioenrichis a montré d’excellentes diastéréosélectivités. Différentes stratégies d’ouverture de cycle ont ensuite été examinées
During our efforts directed toward the total synthesis of leucophyllidine, a bis-indole alkaloid, the tin-free radical carbo-cyanation and sulfonyl-cyanation of olefins were developed. The sulfonyl cyanides, acting as radical traps, were synthesized through a new oxidation of the corresponding thiocyanate. These reagents were found to fragment under thermal initiation (carbo-cyanation) or using the photoredox catalysis (sulfonyl-cyanation). A thorough mechanistic study was accomplished for the sulfonyl-cyanation. These methodologies install a nitrile onto an olefin backbone, furnishing advanced intermediates for the total synthesis of alkaloids. For the asymmetric synthesis of eucophylline, the south fragment of leucophyllidine, the sulfonyl-cyanation of optically pure cyclobutenes showed excellent diastereoselectivities. Different ring-opening reactions of the corresponding cyclobutane were then examined