This thesis describes research conducted since September 2006 in Prof. Robert Batey’s laboratory. The thesis is divided into four chapters. Chapter one presents a general introduction of domino reactions, sigmatropic rearrangements, and the allylic azide rearrangement. Several factors affecting the allylic azide rearrangement along with some respective examples are presented. Chapter two describes an efficient synthesis of azido unsaturated ester compounds using a microwave-assisted domino allylic azide / Johnson-Claisen rearrangement. The domino rearrangement reaction proceeds to give the azido ester compounds in good yield and excellent diastereoselectivity. The synthesis of vinyl epoxides and hydroxy allylic azides starting materials are also presented. In addition, other variants of Claisen rearrangements are briefly discussed. Chapter three describes a microwave-assisted domino allylic azide / Overman rearrangement process. The scope of the domino rearrangements, including an example involving an enantioenriched compound, is presented. The product of the domino rearrangements can be used as precursors to 1,2-vicinal diamines. Several functional group transformations and potential application of the product of the domino rearrangement are also described. Chapter four provides the synthesis of cis-2,5-disubstituted pyrrolidines from domino reduction / cyclization of γ-azido-α,β-unsaturated ketones. The overall process involves hydrogenation of the alkene and the azido group, followed by intramolecular cyclization and loss of H2O to form an imine, which is further reduced to give cis-2,5-disubstituted pyrrolidines. The reaction proceeds cleanly to give the products in high yield and with a very high diastereoselectivity ratio. In addition, the formation of pyrrolidinones via domino reduction / cyclication of γ-azido esters are also reported

Thesis (B.S.) Magna Cum Laude--Butler University, 2007. / Includes bibliographical references (leaves 26-27).

Submitted by Irene Nascimento (irene.kessia@ufpe.br) on 2016-07-28T18:13:32Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Dissertação de Mestrado Emmanuel Dias - ver Biblioteca 3.pdf: 5438340 bytes, checksum: 493d14db263ba9635f4d797c2d7f26cf (MD5) / Made available in DSpace on 2016-07-28T18:13:32Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Dissertação de Mestrado Emmanuel Dias - ver Biblioteca 3.pdf: 5438340 bytes, checksum: 493d14db263ba9635f4d797c2d7f26cf (MD5) Previous issue date: 2016-02-12 / CNPQ / Compostos orgânicos contendo dióis alílicos com configuração trans são substancias orgânicas muito úteis na área de síntese orgânica. Além disso, esses compostos podem ser encontrados na natureza, apresentando importantes atividades biológicas. Estes compostos também podem ser empregados como building blocks na preparação de moléculas bioativos de interesse. Dentre as várias metodologias existentes para preparar estes compostos, muitas empregam reagentes nocivos ao meio ambiente e/ou catalisadores metálicos, em rotas de síntese contendo numerosas etapas reacionais. Com isso, tivemos o interesse de desenvolver um método alternativo, visando à síntese destes compostos, em um processo mais limpo, de enantiosseletividade. A metodologia proposta consistiu no uso de lipases para obtenção dos compostos de forma seletiva. Com isso, após submeter os compostos em sua forma racêmica à resolução na presença de lipases, mono e diacetatos poderiam ser obtidos com alto grau de pureza óptica. A rota quimioenzimática proposta levou a preparação de uma biblioteca de (E)-dióis alílicos, com elevado excesso enantiomérico. / Organic compounds containing trans allylic diols are useful substances in organic synthesis. Furthermore, these compounds can be find in nature showing a wide range of biological activity. In addition, these compounds can be employed as building blocks in the preparation of bioactive compounds as target substances. Among several methodologies to prepare these compounds, the majority employs toxic reagents and/or metallic catalysts, in multistep pathway. Thereby, our interest was develop an alternative method aiming at the synthesis of these compounds, in a greener and enantioselective process. This proposal has consisted in employ lipases as a manner to achieve the related compounds selectively. Thus, after subjecting the racemic compounds to an enzymatic resolution, mono and bis acetates could be generated in high optical purity. The proposal chemo-enzymatic approach lead to the preparation of an enantioenriched library of (E)-allylic diols.

La mise au point de nouvelles méthodes de synthèse permettant d'accéder à des produits biologiquement actifs en utilisant réactifs peu onéreux dans des conditions respectueuses de l'environnement est un enjeu majeur. Le motif 2H-chromène est présent dans un grand nombre de molécules naturelles, et notamment dans plusieurs métachromines. Les métachromines sont des méroterpénoïdes naturels possédant des propriétés biologiques intéressantes. Notre étude s'est portée sur le développement d'une méthode de synthèse permettant d'accéder à des 2H-chromènes hautement fonctionnalisés par une réaction de cyclisation catalysée par des complexes de fer(III) à partir d'alcools allyliques phénoliques ainsi que l'application de cette méthode à la synthèse de produits naturels.Dans une première partie, cette méthode a été appliquée à des alcools allyliques phénoliques mono-, di-, tri-, ou tétra-substitués, pour conduire aux 2H-chromènes de manière efficace. L'étude de cette méthode a montré qu'un grand nombre de fonctionnalités étaient tolérées et qu'il était possible de moduler la réactivité des alcools allyliques phénoliques par la substitution du cycle aromatique et de la double liaison allylique. Cette méthode a été utilisée efficacement comme étape-clé dans la première synthèse totale de la téphrowatsine B, un 2H-chromène naturel issu d'une plante équatoriale présentant des propriétés insecticides. Dans une seconde partie, la première synthèse totale des métachromines J et T a été abordée. Notre méthode a été utilisée comme étape-clé pour accéder à un fragment 2H-chromène, précurseur commun de ces molécules. La synthèse totale de la métachromine C a également été étudiée. / The development of new synthetic methods, which could be used in the synthesis of biologically active compounds using inexpensive reactants and environmentally friendly conditions, is a major challenge in modern chemistry. 2H-Chromenes are present in a large number of biologically active compounds and especially in metachromins. Metachromins are natural marine meroterpenoids that present interesting biological activities. With these objectives in mind, our investigations were focused on the development of a synthetic method to access highly functionalised 2H-chromenes from readily accessible phenolic allylic alcohols, catalysed by iron(III) complexes as well as applications to the synthesis of various natural products. At the beginning, this method was applied to mono-, di-, tri- and tetra-substituted phenolic allylic alcohols to efficiently access the corresponding 2H-chromenes. This method tolerated a large number of functionalities and it was possible to modulate the reactivity of the substrates by substituting the aromatic ring and/or the allylic double bond. This method was applied as a key step in the first total synthesis of tephrowatsin B, a natural 2H-chromene isolated from an equatorial plant having insecticidal activities. On the other hand, the first total synthesis of metachromin J and T was investigated. Our method was used as a key step to access their 2H-chromene fragment, a common precursor of these molecules. The total synthesis of metachromin C was also studied.

This thesis deals with the copper-catalyzed substitution of allylic substrates. In the first part of this thesis, the synthesis of a series of metallocenethiolates is described. The thiolates were examined as ligands in the enantioselective copper(I)-catalyzed γ-substitution of allylic acetates. The second part describes a study on copper-catalyzed α-substitution of enantiomerically pure secondary allylic esters. It was observed that the degree of chirality transfer is strongly dependent on the reaction temperature. The loss of chiral information is consistent with an equilibration of the allylCu(III) intermediates prior to product formation, which is essential in order to realize a copper-catalyzed dynamic kinetic asymmetric transformation process. The third part describes a study on copper-catalyzed stereoselective α-substitution of enantiopure acyclic allylic esters. This method, when combined, with ruthenium and enzyme catalyzed dynamic kinetic resolution of allylic alcohols, provides a straightforward route to pharmaceutically important α-methyl carboxylic acids. The fourth part is a mechanistic study on the reaction of perfluoroallyl iodide with organocuprates. Experimental studies as well as theoretical calculations were used to explain the contrasting reactivity of perfluoroallyl iodide vs. allyl iodide in cuprate allylation reactions. In the fifth part, the development of a practical and useful method for the preparation of pentasubstituted acylferrocenes is presented.

Depuis Juillet 2008, l'union européenne bannit une grande partie des retardateurs de flamme halogénés actuellement sur le marché pour des problèmes environnementaux. Les produits phosphorés s'avèrent une alternative prometteuse. Dans le cadre de ma thèse, nous décrivons la synthèse de monomères allyliques phosphonés cycliques, leur télomérisation, polymérisation et copolymérisation en solution par voie radicalaire mais aussi les premiers « essais feu» effectués. Les monomères allyliques phosphonés cycliques sont synthétisés par transestérification entre un glycol possédant une double liaison et un hydrogénophosphonate. La présence de diastéréoisomères nous a permis de faire une étude poussée en RMN pour comprendre la structure de ces composés. L'homopolymérisation radicalaire du dioxaphosphorinane hydrogéné faite en présence d'AIBN comme amorceur nous a permis d'obtenir des polymères avec 2 distributions chromatographiques composées d'oligomères et de polymères de haute masse moléculaire respectivement. Cette deuxième espèce présente une structure hyperbranchée avec des solubilités faibles qui nuisent aux futures applications. Des solutions alternatives ont été proposées comme la télomérisation de ce même monomère avec l'hydrogénophosphonate de diméthyle comme agent de transfert donnant une seule population d'oligomères. Le remplacement de l'hydrogène lié au phosphore par un groupement alkyle ou aryle simplifient le mécanisme de polymérisation pour former des chaînes macromoléculaires où les groupements phosphonés sont situés dans les chaînes latérales. La copolymérisation Accepteur/Donneur entre l'anhydride maléique et les allyl éthers phosphonés a été envisagée pour produire des copolymères alternés avec la possibilité d'introduire des groupements différents comme les acides carboxyliques, potentiellement intéressants pour la résistance au feu. Une dernière solution, utilisant la synergie des atomes d'azote et de phosphore, a été mise en oeuvre par la synthèse d'oligomères allyl amine phosphonés par polymérisation radicalaire en solution aqueuse. Un bilan de tous les polymères phosphonés a été réalisé dans le but de tester leurs performances en tant que retardateurs de flamme. Les caractérisations en analyse thermogravimétrique et en microcalorimètre ont montré une bonne thermostabilité des télomères comme des copolymères et une chaleur dégagée équivalente au produit de référence. Les essais feu sur textile au cône calorimètre montrent que des résultats encourageants sur les polymères synthétisés. / Since July 2008, a wide rnage of halogenated flame retardants was withdrawed from the market for environmental problems by the European Union. The phosphorous products turn out to be promising candidates. Within the framework of my thesis, the synthesis of allyl cyclic phosphonated monomers is described as well as their telomerization, polymerization and copolymerization in solution using a radical process). Their flame retardant behavior was also evaluated. Allyl cyclic phosphonated monomers are synthesized by transesterification between a glycol with a double bond and hydrogenophosphonate. An NMR study of the obtained diastereoisomers allowed us to fully understand the structure of these compounds. Radical homopolymerization of hydrogenated dioxaphosphorinane, in the presence of AIBN as initiator, allowed us to obtain polymers with two molar mass distributions: one for oligomers and one for polymers of higher molar mass. This second species is due to a hyperbranched structure showing poor solubility in common solvents, which damage the future applications. The telomerization of the same monomer was carried out using dimethyl hydrogenophosphonate as chain transfer agent leading only one population of oligomers. Furtehrmore, the replacement of the hydrogen linked to phosphorus by an alkyl or aryl group simplify the mechanism of polymerization since only linear oligomers are obtained. Acceptor-donor copolymerization of maleic anhydride and phosphonated allyl ethers, allowed producing alternated copolymers with the opportunity to introduce different reactive groups such as carboxylic acids. Then, oligomers were produced by radical polymerization of phosphonated allyl amine in order to potentially use the nitrogen-phosphorus synergy. An overview of all the phosphonated polymers previously synthesized, was done with the aim of testing their flame retardant performances. Thermogravimetric analysis showed a good thermal behavior of the telomers and the copolymers, similar heat release rate was observed by microcalorimeter compare to commercial product. High efficiency of these phosphorus-containing flame retardants polymers was finally evidenced by using the cone calorimeter on textile.

Dans le cadre de nos travaux, nous avons développé une méthode extrêmement douce et particulièrement efficace d’accès à des γ-butyrolactones possédant un centre stéréogène quaternaire en α à partir d’énols carbonates d’allyle cycliques et exocycliques en utilisant la réaction d’alkylation allylique asymétrique décarboxylante pallado-catalysée (Pd-DAAA). Remarquablement, cette méthode a permis d’étendre l’utilisation de l’allylation asymétrique décarboxylante à des substrats sans précèdent dans la littérature, tels que les énols carbonates allyliques exocycliques. Cette réaction a été utilisée comme étape clé dans la synthèse des spirolactones chirales qui ont été obtenues avec de bons rendements et d’excellentes énantiosélectivités. Une nouvelle méthode catalytique robuste et hautement énantiosélective permettant d’accéder à des isoxazolidinones possédant un centre stéréogène quaternaire en α a été développée. Ce protocole repose sur une alkylation allylique asymétrique catalysée par des complexes de palladium chiraux (Pd-AAA) et amène aux produits désirés avec de bons rendements et d’excellents excès énantiomériques. Par ailleurs, nous avons également mis au point des conditions permettant de convertir ces isoxazolidinones α,α-disubstituées en acides β2,2 aminés et en β-lactames. / The development of a palladium-catalyzed decarboxylative allylic alkylation protocol (Pd DAAA) applied to cyclic and exocyclic allyl enol carbonates has allowed a highly enantioselective access to a range of γ butyrolactones bearing an all-carbon α quaternary stereogenic center. Remarkably, this approach allowed the extension of this reaction to substrates with no precedent in the literature, such as the exocyclic allyl enol carbonates. The Pd-DAAA process was eventually used for the synthesis of chiral spirolactones, which were readily obtained in high yields and in high optical purity. The synthesis of different isoxazolidin-5-ones bearing highly stereodefined all carbon α quaternary center was accomplished by palladium-catalyzed asymmetric allylic alkylation (Pd-AAA) of 4 substituted isoxazolidin-5-ones with an array of 2 substituted allyl acetates. The reaction proceeded in both excellent enantioselectivity and yield with isoxazolidin-5-ones containing an α-aryl substituents or an α heteroaryl moieties. This robust and highly enantioselective method allowed the access to valuable β2,2-amino acids and β lactams.

Bimetallic Catalysis is an emerging field of study that uses two metals to cooperatively perform organic transformations. These metals can serve to activate or bind substrates in order to increase the rate and selectivity of reactions. This work first describes the synthesis and utilization of six new chiral, titanium-containing phosphinoamide ligands. These Lewis acidic ligands withdraw electron density from an active palladium center to induce chirality and increase the rate of allylic amination of hindered, secondary N-alkyl amines. X-ray quality crystals were grown for each ligand and completed the allylic amination of hindered secondary amines in minutes whereas other non-titanium-containing ligands produced trace product. Although enantioselectivity was low initially, through a dynamic kinetic resolution enantioselectivity was increased over time, reaching 53% enantioselectivity. The second type of bimetallic catalysis discussed is dinuclear Pd(II) and Pd(I) catalysis. These dimers were built on a 2-phosphinoamide ligand scaffold and present interesting molecular structure and unique reactivity. These dimers were found to perform tandem arylketone coupling to produce disubstituted naphthalene products under oxidative conditions. It is proposed that the Pd(II) dimer undergoes oxidative addition to produce a Pd(III) dimer which subsequently produces an aryl-ketone intermediate. This process is made possible by the cooperativity of the two palladium centers which enable the formation of a Pd(III) dimer, circumventing the need for the high energy Pd(IV) oxidation state. Oxidative conditions then allows coupling and cyclization of a second ketone to form the naphthalene product.

Lignin is the most abundant source of naturally occurring aromatic compounds but has mainly been considered as waste material or energy source in the pulp and paper industry. However, due to the drive to find new material applications derived from renewable resources, there are extensive research activities aiming to develop new routes to utilize this source toward novel polymer materials. In this project, cinnamyl alcohol was used as a benchmark substrate in determining the most favorable reaction conditions for the optimal dehydrative etherification of allylic alcohols. The optimal reaction conditions determined for cinnamyl alcohol aimed to be applied to the etherification of the structurally similar, lignin-derived coniferyl alcohol to produce a bio-based allylic ether of relevance for biomaterial applications. However, due to the COVID-19 pandemic, the investigation of the etherification of coniferyl alcohol could not be conducted and the project had to be limited to the synthesis of 2-phenylethyl cinnamyl ether. Thus, this project serves as a pre-study for the sustainable etherification of lignin-derived allylic alcohols of relevance for biomaterials. The optimal reaction conditions for the synthesis of 2-phenylethyl cinnamyl ether was concluded to be 0.25 M cinnamyl alcohol and 1.00 M 2-phenylethanol as initial concentration of the reactants, 0.02 M Zr(Cp)2(OTf)2 ∙ THF as initial concentration of the catalyst, benzotrifluoride as solvent, a reaction mixture temperature of 60 °C, and a reaction time of four hours. Using optimized reaction conditions, coniferyl alcohol, a lignin-derived allylic alcohol, could in further research be evaluated as a sustainably sourced allylating agent with potential for biomaterial purposes.

京都大学 / 0048 / 新制・課程博士 / 博士(理学) / 甲第18093号 / 理博第3971号 / 新制||理||1572(附属図書館) / 30951 / 京都大学大学院理学研究科化学専攻 / (主査)教授 大須賀 篤弘, 教授 丸岡 啓二, 教授 時任 宣博 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM