The Suzuki-Miyaura cross-coupling reaction has become extremely important in the area of industry and academia. The ability to cleanly cross-couple aryl, alkyl, or alkenyl boronic acids/esters with aryl, alkyl, or alkenyl halides to generate new C-C bonds has proven to be a versatile tool towards the synthesis of complex molecules. Over the past three decades, there has been an array of developments and accomplishments in this area of research including the joint awarding of the 2010 Nobel Prize in Chemistry to Suzuki, Heck, and Negishi. Our group published the first successful example of the cross-coupling of chiral secondary benzylic boronic esters. The key components in this reaction were the incorporation of silver oxide and excess triphenyl phosphine. Silver oxide was required for the transmetallation step to occur. Remarkably, the reaction was not only effective for the coupling of these challenging substrates; it was also selective for the branched benzylic species in the presence of a linear alkyl boronic ester. In order to further probe the selectivity of the aforementioned cross-coupling reaction, we have prepared a substrate that incorporates both an aryl and a secondary benzylic boronic ester. Since the secondary benzylic boronic ester requires specialized conditions for the cross-coupling to proceed, we have been able to employ this reaction to introduce two different substituents in place of the boron groups based solely on reaction conditions. Herein, we discuss the optimization and successful chemoselective/iterative Suzuki-Miyaura cross-coupling of a substrate that incorporates both an aryl and a secondary benzylic boronic ester without the need of protecting groups on the boron atoms. / Thesis (Master, Chemistry) -- Queen's University, 2012-10-13 21:20:42.541

Dendrimers are a unique class of macromolecules that present perfect branching on a molecular scale. The pattern of branching at the atomic scale is compared to the branching of trees, from whence dendrimers get their name. Dendrimers have been attractive synthetic targets for the past twenty years. The methods and building blocks used in the synthesis of dendrimers vary, but molecules of this class of polymeric materials all possess symmetrical branching emanating from the core. At each branch point the number of groups increases exponentially. Efforts directed toward the synthesis of dendrimers presenting multiple functional groups at the surface and within the dendrimer structure are described. Methods are described which provide access to dendrimers in a one-pot per generation fashion, with triazines as the common moiety. Chemoselective routes utilize the temperature dependant substitution of cyanuric chloride to construct dendrimers, obviating the use of protected monomers or the need to manipulate functional groups during the synthesis. These methods are atom economical, as the only by-products are HCl and a base to scavenge it. The methods are efficient, with typical isolated yields of product in the middle to high ninety percent range, often on a multi-gram scale. Methods are described for conducting three separate reactions in a single pot. Specific emphasis is placed on structural control of the interior and surface groups of the dendrimers. The synthesis of a G3 dendrimer of layered composition is described. The use of a different difunctional linkage group for each generation of dendrimer growth produced a G3 dendrimer with layered composition without the use of protecting groups or functional group interconversions. A G3 dendrimer was synthesized presenting five different functionalities at the periphery on a 10 gram scale, resulting in approximately 70% overall yield. The peripheral groups are composed of orthogonal functionality, which can be independently and selectively unmasked or manipulated in the presence of the other functionality. The syntheses of dendrimers incorporating the short linker hydrazine produce materials with interesting physical properties as well as a low ratio of carbon to nitrogen. The use of dendrimers in the construction of novel macromolecular constructs is also described.

The palladium-mediated cross-coupling of aryl electrophiles and amines (Buchwald-Hartwig amination) has become a widely used method of constructing arylamine frameworks. A crucial aspect of the advancement of this chemistry has been the design of ancillary ligands that are able to promote enhanced reactivity in challenging amination reactions. Despite significant ligand development within the field, challenges in this chemistry remain. Chemoselective aminations, wherein one amine substrate undergoes preferential arylation in the presence of multiple reactive amines has remained an underexplored area of Buchwald-Hartwig amination chemistry. This thesis describes the use of [Pd(cinnamyl)Cl]2 and N-[2-di(1-adamantylphosphino)phenyl]morpholine (Mor- DalPhos) in an extensive study of chemoselective Buchwald-Hartwig aminations, with 62 examples of structurally diverse di-, tri-, and tetraamines obtained in synthetically useful yields at reasonable catalyst loadings (1-5 mol % Pd). The coordination chemistry of [(Mor-DalPhos)Pd] species was also explored, as were complementary chemoselective aminations with the isomeric p-Mor-DalPhos ligand, leading to divergent product formation in some instances. The same [Pd(cinnamyl)Cl]2/Mor-DalPhos catalyst system used in the chemoselectivity study was also employed in a series of Buchwald-Hartwig aminations conducted under aqueous and solvent-free conditions, another underexplored area of this chemistry. A total of 52 amine products were isolated using these methodologies, moderate catalyst loadings (3 mol % Pd), and without the use of any additional additives, co-solvents, or rigorous exclusion of air. The synthesis of low-coordinate palladium complexes featuring both NHC and dialkylchlorophosphine ligands is also discussed herein. These complexes are prepared via a previously unreported and straightforward methodology involving an unusual net PCl bond reductive elimination, and represent a potential new class of pre-catalysts forpalladium-mediated reactions.

京都大学 / 0048 / 新制・課程博士 / 博士(薬科学) / 甲第19660号 / 薬科博第48号 / 新制||薬科||6(附属図書館) / 32696 / 京都大学大学院薬学研究科薬科学専攻 / (主査)教授 川端 猛夫, 教授 高須 清誠, 教授 竹本 佳司 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM

Le cancer est une cause majeure de mortalité dans le monde. Bien que les taux de décès aient fortement diminués grâce aux diagnostiques précoces et la mise au point de traitements multiples, les récidives sont fréquentes. Parmi les principaux traitements, la chimiothérapie présente une toxicité extrêmement élevée et la radiothérapie conduit souvent à la destruction de tissus sains, alors que des tumeurs errantes peuvent échapper à la chirurgie. L'immunothérapie offre une l'alternative particulièrement intéressante pour combattre le cancer. En particulier, le développement de vaccins thérapeutiques et/ou prophylactiques capables de traiter, et idéalement, protéger efficacement contre de tumeurs représente un objectif ambitieux. Notre équipe a décrit récemment une nouvelle génération de vaccins synthétiques qui incorporent dans la même molécule un cluster d'oligosaccharides (épitopes des cellules B), un peptide chimère (épitopes des cellules T) et un acide palmitique (adjuvant) lié à son extrémité N-terminale. Les études immunologiques ont révélé une régression tumorale et une augmentation spectaculaire du taux de survie chez la souris, sans administration d'adjuvants externes.Sur la base de ces travaux, notre objectif a été de développer une approche chimique qui permette d'accéder à des structures plus sophistiquées et plus immunogènes. Pour cela, nous avons mis au point des méthodologies de synthèse chimiosélectives telles que la ligation oxime (OL), la cycloaddition alcyne-azoture catalysée par le Cu(I) (CuAAc), le couplage thiol-chloroacétyle (TCC) et/ou le couplage thiol-ène (TEC) pour préparer des homoglycoclusters (4-, 16- ou 64-valent) ou d'hétéroglycocluster de combinaison variable (2+2, 3+1, 4+2, 8+8, 4x1 et 4x4) via différents types de liens chimiques (oxime, triazole, thioéther). Ces méthodes ont été appliquées à la synthèse de candidats vaccins portant les marqueurs osidiques Tn et/ou TF et un peptide immunostimulant. Des études biologiques avec des lectines bactériennes (LecB) ou végétale (UEA-I) ont été réalisées pour valoriser les composés glycosylés modèles (Fuc, Man, Gal) synthétisés au cours de cette thèse et ont permis de découvrir de ligands nanomolaires. Les études immunologiques actuellement en cours avec nos candidats vaccins permettront quant à elles de déterminer l'influence du linker, de la valence et de la composition en antigène sur la réponse immunitaire induite. / Cancer is a major cause of mortality worldwide. Even if the rate of deaths has decreased thanks to early diagnostics and the creation of a variety of treatments, reccurence happen frequently. Among the main treatments, chimiotherapy shows a very high toxicity and radiotherapy often leads to the destruction of healthy cells, while released tumors can be left around by surgery. Immunotherapy offers a very interesting alternative to fight cancer. The development of therapeutical and/or prophylactical vaccines, able to treat and protect against tumors, seems to be an ambitious goal. Our team has recently described a new generation of synthetical vaccines which involve in the same molecule an oligosaccharide cluster (B cells epitopes), a chimer peptide (T cells epitopes) and a palmitic acid (adjuvant), bound on its N-terminal end. Immunological studies have revealed a reduction of the tumor size and a spectacular increase of the survival rate on mice, without having to administrate any extern adjuvant. On the basis of these studies, our goal has been to develop a chemical approach which would give access to more sophisticated and more immunogenic structures. To do this, we have developed methodologies of chemoselective synthesis, such as oxime ligation, Cu(I) catalysed alkyne-azide cycloaddition, (CuAAc), the thiol-chloroacétyle (TCC) and/or the thiol-ène coupling (TEC), to prepare homoglycoclusters (4-, 16- or 64- valent) or heteroglycoclusters of variable combination (2+2, 3+1, 4+2, 4x1, 8+8, 4x4) via different kind of chemical links (oxime, triazole, thioéther). These methods have been applied to the synthesis of vaccine candidates having the same carbohydrate Tn and/or TF and an immunostimulating peptide. Some biological studies with bacterial (LecB) or vegetal (UEA-I) lectines have been realised to highlight the glycosylated compounds's templates (Fuc, Man, Gal) synthesized during this PhD and have revealed nanomolar ligands. The immunological studies currently in progress on our vaccine candidates will help to understand the influence of the linker, the valence and the antigen composition on the immune response created.

Dans l’optique de développer de nouveaux agents bio-inspirés pour la détection et/ou le traitement des cellules cancéreuses, nos travaux se sont tournés vers la synthèse de macromolécules peptidiques complexes ayant la capacité de reconnaître les cellules tumorales. Ces travaux visent à développer des molécules permettant de cibler des particularités cellulaires présentes sur les cellules tumorales dans le but d’obtenir un traitement personnalisé via une vectorisation active permettant une augmentation de l'efficacité thérapeutique et une réduction intrinsèque de la toxicité du traitement. Pour cela, ces biomolécules doivent posséder à la fois un site de reconnaissance pour la liaison avec des protéines présentes à la surface de la cellule cible et un ou plusieurs éléments utilisés pour détecter et/ou détruire la cible. Ces systèmes ont été élaborés à partir d'un châssis moléculaire cyclodécapeptidique présentant des propriétés conformationnelles particulières. Plusieurs approches ont été envisagées. La première a consisté à rechercher de nouveaux ligands de récepteurs tumoraux en s'inspirant du domaine de reconnaissance d'un anticorps monoclonal thérapeutique. Dans ce contexte, nous avons proposé la conception de mimes du Rituximab ciblant l'antigène CD20 utilisé dans le traitement des lymphomes Non-Hodgkinien. Dans la seconde approche, nous avons développé des vecteurs destinés à des applications d'imagerie tumorale. Pour cela, des châssis multivalents présentant des ligands peptidiques RGD ciblant l'intégrine alpha-v-beta-3 ont été conjugués avec différents agents de détection puis évalués par des techniques d'imagerie telles que la TEP, la TEMP et l’imagerie optique. Toujours dans un but de diagnostic des cellules tumorales, nous nous sommes par la suite tournés vers l’application à la capture cellulaire. Pour cela, une surface d’or à été modifiée via la formation d’une monocouche organisée SAM (« Self-assembled monolayer ») présentant des cyclodextrines. Un gabarit peptidique adéquat a ainsi permis la capture et le relargage sélectif de cellules tumorales mesurées par la technique de microbalance à quartz. Ces mêmes vecteurs, validés pour le diagnostic ont par la suite été couplés à des peptides cytotoxiques issus d’une protéine pro-apoptotique « Bax ». Enfin, une dernière partie a été consacrée à la recherche de nouveaux composés comportant plusieurs éléments de ciblage tumoraux. Ces molécules présentent deux ligands de ciblage des récepteurs surexprimés sur la membrane et peuvent ainsi permettre une meilleure sélectivité vis-à-vis des tissus tumoraux. / In order to develop new agents for cancer diagnosis and treatment, our work aims to synthesize complex peptide macromolecules that are able to specifically recognize cancer cells. Our goal is to increase the therapeutic efficiency and reduce the toxicity of currently available drugs using "targeted strategies". In this context, we designed sophisticated macromolecules encompassing a cell recognition domain and one or several components used to detect and/or destroy the target. This system was prepared starting from a cyclodecapeptidic scaffold presenting particular conformational properties. Different approaches were considered. First of all our work was to investigate new tumor receptor ligands based on the recognition domain of a therapeutics monoclonal antibody. We proposed the design of Rituximab mimics which targets the CD20 antigen used for the treatment of Non-Hodgkin lymphoma. In a second approach, we prepared new vectors for tumor imaging. For this purpose, multivalent scaffolds containing RGD peptide that targets alpha-v-beta-3 integrin were combined with several detection elements and evaluated by using PET, SPECT and optical imaging techniques. We also used this peptide vector for the selective cell capture and release from flowing suspensions, using a gold surface modified with a cyclodextrin-containing self-assembled monolayer (SAM). A scaffold containing ferrocenyl and -RGD- ligands permitted the selective capture and release of tumor cells. This experiment was monitored by QCM-D. This vector has been next grafted to a cytotoxic peptide that was discovered from a pro-apoptotic protein named “Bax”. Finally, we designed new molecules which include an additional ligand for the cell’s surface to increase the selectivity and the affinity of tumor tissue.

This thesis covers the development of catalytic methodologies for the mild and chemoselective hydrosilylation of amides. The first part describes the investigation of the Mo(CO)6-catalyzed reduction of carboxamides. It was found that the reduction could be controlled by tuning the reaction temperature and either amines or aldehydes could be obtained selectively. The system showed an unprecedented chemoselectivity and the amide reduction could take place in the presence of other reducible functional groups such as ketones, aldehydes, and imines. Moreover, the transformation could be performed on a preparative scale and was further employed in the synthesis of Donepezil, a pharmaceutical drug used in the treatment of Alzheimer´s disease. The third chapter concerns the development of the Mo(CO)6-mediated hydrosilylation protocol for the reduction of carboxamides containing acidic α-hydrogens. In this case, enamines were formed and a high level of chemoselectivity was observed. Enamines containing sensitive functional groups such as ketones, aldehydes and imines were generated. The enamines were not isolated but used in subsequent catalytic reductive functionalization of amides, which is described in the last part of the thesis (Chapters 4 – 7). The in situ formed enamines were reacted with a wide variety of electrophiles, generating heterocyclic compounds as triazolines, triazoles, 4,5-dihydroisoxazoles and pyrimidinediones. N-sulfonylformamidines as well as thioacrylamides could also be prepared with this approach. The protocols for the synthesis of triazolines, triazoles and N-sulfonylformamidines could additionally be performed on a preparative scale, showing the practicality of the methodology.

Depuis quelques décennies, l’étude de systèmes biologiques complexes est un domaine en plein essor. Ainsi, des outils de ligation des biomolécules avec des reporters chimiques ont été mis en place afin d’avoir une compréhension toujours fine du vivant. Les ligations sont des réactions chimiques biocompatibles permettant de lier deux entités synthétiques ou biologiques entre elles. On regroupe généralement ces ligations en deux catégories, les réactions de bioconjuguaison, qui font intervenir des fonctions chimiques naturellement présentes dans les biomolécules, et les réactions bio-orthogonales qui n’interfèrent pas avec les fonctions chimiques présentes dans ces milieux, mais nécessitent en amont une modification des partenaires de réaction. Cependant, il convient de faire la distinction avec une troisième catégorie, les réactions de conjugaison chimiosélectives, qui mettent en oeuvre des fonctions non naturellement présentes sur les biomolécules. En ce sens, elles se rapprochent donc des réactions bio-orthogonales, mais les fonctions ou conditions mises en jeu ne sont pas suffisamment bio-orthogonales ou les réactions ne sont pas suffisamment rapides pour pouvoir être réalisées dans les systèmes biologiques. Ces ligations sont toutefois très utilisées pour de la construction biomoléculaire allant de la petite molécule (par exemple oligopeptide modifié) à la biomacromolécule (type protéine modifiée) et se distinguent par une facilité de mise en oeuvre et purification des conjugués, ce qui n’est pas toujours réa lisable avec l’arsenal des réactions bio-orthogonales qui conduisent à la formation de multiple isomères. Ainsi, mes travaux de thèse se sont orientés vers la découverte et/ou l’étude de ligations chimiosélectives ainsi qu’à leur utilisation dans la préparation de sondes fluorescentes voire fluorogéniques. L’étude de la ligation Kondrat’eva préalablement développée au sein du laboratoire, a permis de mettre en évidence son caractère fluorogénique, et a été exploitée pour le marquage fluorescent de molécules via une étape unique de ligation fluorogénique. Puis, le développement d’une ligation utilisant le système tétrazine/pyrazolone a été développée afin de pallier le manque de sélectivité des réactions basées sur le motif tétrazine proposées jusqu’alors, qui conduisent aux bioconjugués sous la forme d’un mélange de produits. Cette approche a été illustrée par le marquage fluorescent d’une protéine humaine. Enfin, le développement d’une nouvelle voie d’accès aux quinoxalinones a permis leur étude photophysique et la mise en évidence de propriétés fluorogéniques utilisées notamment pour la synthèse d’une biosonde. / In recent decades, the study of complex biological systems has been a growing field. Thus, biomolecules ligation tools with chemical reporters were set up in order to have a better and fine understanding of the living. Ligations are biocompatible chemical reactions that link two synthetic or biological entities one antother. These ligations are generally gathered into two categories, bioconjugation reactions, using chemical functions naturally present in the biomolecules, and bio-orthogonal reactions which does not interfere with these function, but require a prior engineering of the biological partner. However, it is necessary to distinguish a third category, the chemoselective conjugation reactions, which implement functions not naturally present on biomolecules. In this sense, they are therefore closer to bio-orthogonal reactions, but the functions or conditions involved are not sufficiently bioorthogonal or the reactions are not fast enough to be carried out in any biological systems. These ligations are, however, widely used for biomolecular constructions ranging from the small molecule (for example modified oligopeptides) to the biomacromolecule (protein modification) and are distinguished by their ease of implementation and purification of the conjugates, which is not always feasible with the arsenal of bio-orthogonal reactions that leads to the formation of multiple isomers. Thus, my PhD work focused on the discovery and / or the study of chemoselective ligations as well as their use in the preparation of fluorescent or fluorogenic probes. The study of the Kondrat'eva ligation previously developed within the laboratory, highlighted its fluorogenic behaviour, and was exploited for the fluorescent labelling of molecules through a single fluorescence-ligation step. Then, the development of a ligation using the tetrazine / pyrazolone system was developed in order to overcome the lack of selectivity of the reactions based on the tetrazine scaffold which often lead to the formation of bioconjugates as a mixture of isomers. This approach has been illustrated by the fluorescent labelling of a human protein. Finally, the development of a new access route to quinoxalinones allowed to study their photophysical properties and to highlight their fluorogenic properties which were leveraged in particular for the synthesi s of a bioprobe.

The development of new strategies and associated reagents that enable previously inaccessible synthetic disconnections is largely attributing to the remarkable progress in exploring new chemical space for drug discovery and innovative complex molecule syntheses. In the Wengryniuk laboratory, we are devoted to discovering new synthetic methodologies that are based on umpolung or reverse polarity, strategies, enabled by Nitrogen-ligated (bis)cationic hypervalent iodine reagents (N-HVIs). I(III) N-HVIs represent an attractive new class of oxidant as they are environmentally benign, highly tunable, and have shown ability in enabling distinguished modes of reactivity. This dissertation focuses on demonstrating the synthetic utility of these N-HVI reagents towards C–O bond formation via a reverse polarity approach.In Chapter 1, a summary of the reactivity and characteristics of hypervalent iodine reagents is provided. Chapter 2 describes a mild and metal-free strategy for alcohol oxidation mediated by I(III) N-HVI reagents. This method demonstrates the first method for chemoselective oxidation of equatorial over axial alcohols and was the first in situ synthesis and application of N-HVIs for a simple one-pot procedure. Chapter 3 discusses a novel strategy for a dual C–H functionalization to access functionalized chroman scaffolds via an umpolung oxygen activation cyclization cascade. Computational studies in collaboration with Prof. Dean Tantillo (UC-Davis) along with experimental probes in our laboratory, support the formation of an umpoled oxygen intermediate as well as competitive direct and spirocyclization pathways for the key C–O bond forming event. The utility of the developed method is demonstrated through a downstream derivatization of the iodonium salt moiety to access C–H, C–X, and C–C substitution via established Pd-catalyzed cross couplings. Total synthesis of (±)-conicol natural product was performed in 8 steps and 23% overall yield, further demonstrating the synthetic utility of the developed method. Key synthetic steps include a smooth construction of the chroman core via N-HVI mediated C–H etherification of a pendant alcohol followed by a late-stage double bond installation. Overall, this dissertation summarizes the current state of research enabled by N-HVI reagents, with a focus on their utility in reverse polarity heteroatom activation strategies, and it serves as a practical guide for future development in the field. / Chemistry

京都大学 / 新制・課程博士 / 博士(エネルギー科学) / 甲第24252号 / エネ博第450号 / 新制||エネ||84(附属図書館) / 京都大学大学院エネルギー科学研究科エネルギー基礎科学専攻 / (主査)教授 森井 孝, 教授 片平 正人, 教授 佐川 尚 / 学位規則第4条第1項該当 / Doctor of Energy Science / Kyoto University / DFAM