La recherche de nouvelles molécules à visée thérapeutique est un enjeu majeur pour la communauté scientifique et actuellement, 60% des médicaments utilisés cliniquement sont des produits naturels ou leurs analogues. Dans ce contexte, afin d'être capable de générer rapidement une bibliothèque de composés, le développement d'outils de synthèse efficaces est fondamental et c'est dans cette optique que s'inscrit le travail mené au cours de cette thèse. Les produits d'origine marine sont une source d'inspiration considérable dans le domaine de la création de nouveaux médicaments. Lors de ce travail, une attention particulière a été accordée à la ningaline B et à ses analogues avec pour objectif de mettre au point une voie d'accès simple et efficace. En effet, si la capacité de la forme hexaméthyléther à reverser la résistance aux anticancéreux par inhibition de la glycoprotéine-P a déjà été rapportée dans la littérature, l'étude d'analogues n'a été que peu exploitée.Dans ce contexte, une voie de synthèse reposant sur une étape clé de double couplage de Suzuki-Miyaura sur un dérivé (pseudo)dihalogéné symétrique a été proposée. Cette étape a fait l'objet d'une étude approfondie en envisageant deux approches. La première approche, basée sur des travaux antérieurs réalisés au laboratoire, a été de type simultané. Ainsi, à la manière d'une réaction multicomposante, tous les réactifs sont introduits dès le départ dans le milieu réactionnel. Cette méthode a montré des résultats intéressants dans le cas où deux dérivés borés électroniquement différents sont employés. En revanche, il a été montré que l'utilisation d'espèces borés électroniquement similaires était peu viable avec l'obtention d'un mélange statistique en produits de dicouplage. Toutefois, la préparation des cibles visées requérant l'utilisation d'aryles borés riches en électrons, une autre approche, séquentielle, a été envisagée. Après un travail d'optimisation sur des substrats simplifiés, avec pour objectif de disposer de conditions efficaces, adaptables, faciles avec des réactifs standards, une méthode de monoarylation de dérivés (pseudo)dihalogénés symétriques a été mise en place. Le champ d'application a ensuite été élargi en incluant les noyaux pyrroles nécessaires à la synthèse de la ningaline B et de ses dérivés. Ces travaux ont permis d'accéder aux molécules ciblées. En effet, une fois, les teraryles préparés, quelques étapes de manipulations fonctionnelles permettront d'avoir rapidement accès à de nombreux analogues. D'autre part, les motifs pouvant être obtenus par ce type de séquence réactionnelle pourraient être facilement dérivatisables afin de générer une bibliothèque d'analogues.

Ordered mesoporous silicas have been shown to have a variety of useful applications ranging from adsorbents for containments to supports for catalysts. While these materials have received a good deal of attention in the literature there is still much opportunity for new technologies. We present research describing a novel approach to incorporate functionality onto the pore surfaces of these materials as well as a highly active catalyst for the Suzuki-Miyaura reaction. Our approach to selectively graft functionality on to the pore walls of the mesoporous silicas SBA-15 and MCM-41 involves treating the materials loaded with a structure directing agent (SDA), with hexamethyldisilazane that passivates the external surface through silylation. Once the SDA is removed the mesopores can be functionalized selectively using standard methods. A test designed to look at the passivation layer is also described. The catalyst developed is designated Pd-SBA-15-SH(g) and it is active for the Suzuki-Miyaura reaction. The activity, recyclability and leaching of Pd-SBA-15-SH(g) was found to be superior to related materials. A mechanistic analysis suggests the catalyst is a reservoir for soluble Pd metal. A key challenge that is holding back wide scale application of ammonia borane (NH3BH3) as a hydrogen storage material for mobile applications is the dearth of regeneration strategies. Presented are our forays into the development of an organic hydride based regeneration strategy. The first phase of the project focused on the reaction between Hantzsch esters and B(C6F5)3. N-substituted Hantzsch esters were found to transfer hydride to boron in >90 % yield. Mechanistic analysis of the reaction suggests either a SET mechanism or a highly asynchronous transition state. A novel hydride transfer equilibrium promoted by B(C6F5)3 was observed and it operated at temperatures below -10 ºC. N,N-ditertbutyl-dihydroimidazole is also an effective hydride donor to B(C6F5)3 as well as other Lewis acids that are more relevant mimics to those invoked in regeneration schemes. When the redistribution of B(SPh)3 is carried out with N,N-ditertbutyl-dihydroimidazole in the presence of NEt3 and CH2Cl2 at 50 ºC, BH2(NEt)3(SPh) is formed. CH2Cl2 functions as a thiol scavenger under the reaction conditions. 1-Octene trapping experiments provided indirect evidence for the formation of diborane, a critical component in the regeneration of NH3BH3. / Thesis (Ph.D, Chemistry) -- Queen's University, 2011-09-09 14:51:54.697

No description available.

This thesis describes the combination of non-stabilized nucleophiles and prochiral/racemic electrophiles in transition metal catalyzed asymmetric transformations. These enantioselective reactions have tremendous potential for the formation of chiral building blocks and new structural motifs that can be found in a variety of natural products and their derivatives. The first part of the thesis focuses on the synthetic approach towards anti-cancer active diterpenoid structures. The two key steps involve a Cu-catalyzed asymmetric conjugate addition of alkylzirconocenes to enones and an intramolecular oxidative cyclisation. Particular investigations into the cyclisation are made with organocatalysis, transition metal catalysis and electrochemistry for the formation of these tricyclic scaffolds. In the second part this work builds on the Rh-catalyzed asymmetric Suzuki-Miyaura coupling of benzeneboronic acids and cyclic allyl chlorides, which has been developed in our group. Here, the main point is to use more challenging coupling partners, such as heteroaromatic boronic acids, which are coupled to racemic cyclic allyl halides. The utility of this method is demonstrated by performing further transformations and an asymmetric synthesis of the natural product (+)- isoanabasine. The last chapter describes the development of a new asymmetric Hiyama coupling of arylsiloxanes with racemic cyclic allyl chloride. Attempts are made to generate substrates that are not accessible via the asymmetric Suzuki - Miyaura reaction. After extensive optimisation a variety of arylsiloxanes is generated and tested with the best conditions to prove its utility in comparison to the asymmetric Suzuki-Miyaura coupling.

The 2-aryl-2,3-dihydroquinolin-4(1H)-ones were prepared via acid-catalyzed cyclization of the corresponding 2-aminochalcones, which were in turn, prepared by base-promoted Claisen-Schmidt aldol condensation of 2-aminoacetophenone and benzaldehyde derivatives. The 2-aryl-6,8-dibromo-2,3-dihydroquinolin-4(1H)-ones were prepared by reacting 2-aryl-2,3-dihydroquinolin-4(1H)-ones with N-bromosuccinimide (NBS) in carbon tetrachloride-chloroform mixture at room temperature. The 2-aryl-6,8-dibromo-2,3-dihydroquinolin-4(1H)-ones were subjected to palladium-catalyzed Suzuki-Miyaura cross-coupling reaction with arylboronic acid using dichlorobis(triphenylphosphine)palladium(II)-tricycohexylphosphine as catalyst mixture and potassium carbonate as a base in dioxane-water under reflux to afford the corresponding novel 2,6,8-triaryl-2,3-dihydroquinolin-4(1H)-ones in a single-pot operation. The latter were subjected to thallium(III) p-tolylsulfonate in dimethoxyethane under reflux to yield the 2,6,8-triarylquinolin-4(1H)-ones. The 2,6,8-triaryl-2,3-dihydroquinolin-4(1H)-ones were treated with molecular iodine in refluxing methanol to afford the corresponding 2,6,8-triaryl-4-methoxyquinolines. All the new compounds were characterized using a combination of 1H NMR & 13C NMR spectroscopy, IR and mass spectroscopic techniques. / Chemistry / M.Sc. (Chemistry)

Orientador: Nelson Henrique Morgon / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Quimica / Made available in DSpace on 2018-08-04T16:59:18Z (GMT). No. of bitstreams: 1 Silva_MauricioChagasda_M.pdf: 1448929 bytes, checksum: 5e8a626133912c0e72a209eeccbbfd34 (MD5) Previous issue date: 2005 / Mestrado / Físico-Química / Mestre em Química

Ce manuscrit présente une approche synthétique de deux produits naturels, la Dasyscyphine D et le Laingolide A. En ce qui concerne la Dasysyphine D, nous avons étudié une étape-clé de cycloaddition de Diels-Alder entre un diène et un diénophile, préparés par des réactions de couplage pallado-catalysées et/ou de métathèse cyclisante. Pour le Laingolide A, plusieurs isomères ont été synthétisés dans le but de déterminer la configuration relative des trois centres stéréogènes. Cette synthèse fait intervenir une réaction tandem dimérisation croisée/oxonia-Cope et une macrocyclisation finale formant un motif énamide. / This manuscript presents the synthetic approach of two natural products, Dasyscyphin D and Laingolide A. Concerning Dasysphin D, the key step of the synthesis is a Diels-Alder cycloaddition between a diene and a dienophile, which were prepared by palladium-catalyzedcross coupling and/or metathesis reactions. For Laingolide A, several isomers have been synthesized in order to determine the relative configuration of the three stereogenic centers.This synthesis involves a tandem cross dimerization/oxonia-Cope reaction, and a final macrocyclization to install the enamide moiety.

No description available.

Two series of stable palladium and silver complexes ligated to hemilabile ligands were prepared. The stability and applicability of these well-defined complexes in promoting various reactions (cycloaddition, hydroamination, cross-coupling reactions, etc.) was investigated. Structure-activity studies with a series of related ligands led us to find a pronounced ligand effect on these reactions. The dichotomous reactivity of triethyl phosphonium hydrobromide salt with dialkyl acetals was used for the synthesis of alkoxy phosphonium salts. Reactivity and applications of these phosphonium salts were described for the synthesis of the biologically active cinnamyl triazoles and ethyl indole-2-carboxylates. Total synthesis of the natural product nostodione A, was developed in eight chemical steps and with 21.6% overall yield from ethyl-2-indolecarboxylates. The synthesis of a mini-panel of structural analogs allowed for the discovery of anti-parasitic biological activity of nostodione A and its analogues for the first time. / Thesis / Doctor of Science (PhD)

Transition metal catalysis is a necessary branch of organic synthesis. Both monometallic and bimetallic catalysts can reduce reaction times, improve regio- and enantioselectivity, and minimize byproducts. Additionally, bimetallic catalysts can cooperatively activate substrates, which can enable new reactions and mechanistic pathways. The first half of this work will describe the synthesis and catalytic ability of our novel Pd(I) and Pd(II) dimers. Both dimers use a 2-phosphinoimidazole ligand scaffold to bring the metal centers in close proximity. The Pd(II) dimer can catalyze the synthesis of 1,3-disubstituted naphthalene rings from commercially available aryl iodides and methyl ketones with high regioselectivity and yields. Mechanistic and theoretical studies suggest the mechanism undergoes a Pd(III)–Pd(III) like intermediate. Additionally, we studied the impact of precatalyst oxidation state on C–N bonding reactions. We found that our Pd(I) dimer performed better in Buchwald-Hartwig aminations, while our Pd(II) dimer was shown to be extremely active in aminocarbonylation reactions. Both reactions gave C–N bonding products in good to excellent yield. The second portion of this work describes our novel Pd N–H NHC complex and its application in Suzuki-Miyaura cross couplings. In the presence of methanol, a Pd(II) salt will insert into the C–P bond of a 2-phosphinoimidazole ligand to give a protic NHC complex. The acidic hydrogen can be deprotonated under reaction conditions to give an anionic complex, which further increases the electron density on palladium as shown in Tolman Electronic Parameter studies. Application of the catalyst in Suzuki-Miyaura and Sonogashira coupling reactions gave product in high yield. Since our Pd N–H NHC complex with a diphenylphosphine ligand could not activate aryl chlorides, we then applied 2-dialkylphopshinoimidazole ligands. When the dialkyl ligands were stirred with Pd(II) salts in methanol, an equilibrium was observed between N–H NHC and P–N coordination complexes. When the catalytic mixture was applied to Suzuki-Miyaura cross-couplings, (hetero)aryl chlorides gave high yields with low catalyst loadings.