published_or_final_version / abstract / toc / Chemistry / Doctoral / Doctor of Philosophy

Although known since the 1930s, organogold chemistry has been dormant until recently, primarily due to preconceptions about the inertness of gold in transformations. However, this last decade has witnessed the emergence of a Golden Age with the development of a wealth of reports on gold in a plethora of reactions. In recent years, the drive for more atom- and step-economical and environmentally friendly reactions has become a field of intense research. In our on-going research on well-defined transition metal complexes bearing NHC ligands, our group recently discovered a new gold(I) hydroxide complex [Au(OH)(IPr)] (1a) that can be easily synthesised from the chloride precursor [AuCl(IPr)] (1b). A preliminary survey of the reactivity of this gold synthon has demonstrated interesting reactivity that holds great potential in bond activation reactions and the development of useful synthetic methods. Simplistically, this gold hydroxide complex can be seen as a strong Brønsted base. This thesis is dedicated to an in-depth examination of the reactivity of this complex in base-free bond activation reactions. Two themes predominate in the following chapters: the first part demonstrates the activity of gold(I) hydroxide as a bond activation agent to readily and efficiently access organogold complexes while the second part studies the reactivity of this compound in decarboxylation processes with carboxylic acids. Chapter 2 and 3 were dedicated to the development of new synthetic routes to access organogold complexes via base-free transmetalation reactions with organoborons and silanes using 1a. The combination of experimental and computational studies allowed identification and isolation of key intermediates in these reactions. Chapter 4 can be seen as a transition between the development of novel methodologies to synthesise aryl and heteroarylgold complexes and the first steps of gold hydroxide 1a as mediator in decarboxylation reaction. As a result, a novel mode of reactivity for gold was discovered and the synthetic route developed constitutes one of the greenest procedures to prepare organogold complexes with the generation of water and CO₂ as only side products. Chapter 5 and 6 venture further into the exploration of 1a in decarboxylation reactions and detail the development of a catalytic process for the protodecarboxylation reaction and subsequent mechanistic investigations of this reaction through stoichiometric experiments and kinetic and computational studies.

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Thesis advisor: Amir H. Hoveyda / Chapter 1 Enantioselective Conjugate Additions of Carbon Nucleophiles to Activated Olefins: Preparation of Enantioenriched Compounds Containing All-Carbon Quaternary Stereogenic Centers. Methods for enantioselective conjugate addition of nucleophiles to activated olefins generating products containing all-carbon quaternary stereogenic centers are critically reviewed. Enantioselective conjugate addition has been shown to be a powerful and concise approach to construct carbon-carbon bonds to prepare compounds containing sterically hindered stereogenic centers and has seen great advances in the past several years. Owing to the difficult nature of additions to relatively unreactive conjugate acceptors, compared to additions generating tertiary stereogenic centers, and construction of a sterically-hindered bond, in many cases, new and active catalysts had to be developed. The review discusses the areas where significant advances have been made as well as current limitations and future outlook. Chapter 2 Development of New and Active Catalysts for Cu-Catalyzed Enantioselective Conjugate Addition of Alkyl- and Arylzinc Reagent. Through development of new chiral catalysts, we have found an active and enantiodiscriminating bidentate, sulfonate-containing NHC-Cu catalyst that effects enantioselective conjugate addition of alkyl- and arylzinc reagents on notoriously difficult trisubstituted cyclic enones. Products are prepared with high levels of selectivity and participate in a variety of further functionalizations. The enantioselective additions are efficient and practical, not requiring rigorously anhydrous or oxygen-free conditions. Chapter 3 Cu-Catalyzed Enantioselective Conjugate Addition of Alkyl- and Arylaluminum Reagents to Trisubstituted Enones. Outlined in this chapter is the first effective solution for Cu-catalyzed enantioselective addition of alkyl and aryl nucleophiles to trisubstituted cyclopentenones generating products bearing a &beta;-all-carbon quaternary stereogenic center. Products are obtained in up to 97% yield and 99:1 er, only requiring 5 mol % of an in situ generated Cu-NHC catalyst. The methodology was highlighted as one of the key steps in the total synthesis of clavirolide C. Not only five-membered rings, but six- and seven-membered rings serve as proficient partners in the enantioselective process. Moreover, in cases for the enantioselective aryl addition, in situ prepared Me₂AlAr can be used without purification, filtration, or isolation, only requiring the corresponding aryl halides. The additions have also been extended to trisubstituted unsaturated lactones and chromones. Chapter 4 Cu-Catalyzed Enantioselective Conjugate Addition of Vinylaluminum Reagents to Cyclic Trisubstituted Enones. An enantioselective protocol for the formation of &beta;,&beta;-disubstituted cyclic ketones containing a synthetically versatile vinylsilane is disclosed. Enantioselective conjugate addition of in situ prepared silyl-substituted vinylaluminum reagents to &beta;,&beta;-unsaturated ketones promoted by 5 mol % of chiral Cu-NHC complexes delivers desired products with high efficiency (up to 95% yield after purification) and enantioselectivities (up to >98:<2 er). Several functionalizations utilizing the vinylsilanes, vicinal to an all-carbon quaternary stereogenic center, are shown, including an oxidative rearrangement, vinyl iodide formation and protodesilylation, accessing products not previously attainable. Furthermore, the enantioselective protocol is demonstrated as the key transformation in the total synthesis of riccardiphenol B. / Thesis (PhD) — Boston College, 2011. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Les nucléolipides sont des molécules hybrides amphiphiles de faible poids moléculaire composées de deux parties liées de façon covalente : la première est un acide nucléique, un nucléotide, un nucléoside ou une nucléobase et la seconde un lipide. En combinant les propriétés physicochimiques de deux des biomolécules parmi les plus représentées dans le vivant, les nucléolipides présentent la capacité à former des auto-assemblages supramoléculaires d’intérêt pour la conception de biomatériaux. L'étude des capacités d’auto-assemblage des GlycoNucléoLipides, qui possèdent un lien aromatique de type triazole, a démontré que la nature du lien covalent qui unit les deux parties du nucléolipide a un effet déterminant sur l’assemblage. Ce travail a porté sur l'utilisation et le développement d'une réaction de Stetter, organocatalysée par des carbènes N-hétérocycliques et bioinspirée, pour obtenir un lien de type dicétone-1,4 entre la thymidine et différents lipides. Ce motif, précurseur de cycles hétéroaromatiques, a notamment conduit à la formation de liens de type pyrrole par une réaction de type Paal-Knorr. Les propriétés gélatrices de ces nucléolipides originaux ont été comparées à celles de ceux portant un motif triazole. Parmi les nucléolipides obtenus, un composé particulièrement lipophile, porteur du lien 1,4- dicétone, a montré la capacité de former un gel dans des huiles (soit un oléogel). Une étude structurepropriétés a été effectuée pour comprendre le rôle de chaque partie de la molécule. Ce type de formulation présentant un intérêt tout particulier pour le développement de systèmes de délivrance contrôlée de substances actives lipophiles, les propriétés physicochimiques de cet oléogel ont par ailleurs été étudiées. La réaction de Stetter présentant la plupart des caractéristiques d'une réaction dite de "chimie click", des conditions de réaction plus éco-compatibles et adaptées à la fonctionnalisation d’autres biomolécules ont ensuite été développées en milieu aqueux. / Nucleolipids are hybrid amphiphilic low molecular weight molecules composed of two parts covalently linked: the first one being a nucleic acid, a nucleotide, a nucleoside or a nucleobase and the second a lipid. Combining the physico-chemical properties of two of the most widespread biomolecules, nucleolipids are capable of self-assemble as supramolecular structures of interest for application in the field of biomaterials. The study of the self-assembling properties of GlycoNucleoLipids, bearing a triazole moiety as a linker, demonstrated the crucial influence of the nature of the covalent linker bringing together the two parts of the nucleolipid onto the self-assembly. In this work, the synthesis of nucleolipids bearing a 1,4-diketone linker between thymidine and various lipids via the bioinspired and N-Heterocyclic Carbene organocatalyzed Stetter reaction is described. As an heteroaromatic cycle precursor, this moiety led to the formation of pyrrole skeletons via the classical Paal-Knorr reaction. The gelating properties of these original nucleolipids were evaluated and compared with the ones bearing a triazole link. Among these original synthetic nucleolipids, a lipophilic compound bearing a 1,4-diketone link exhibited the ability to form gels in oils (i.e. oleogels). A structure-properties study was realized to understand the role of each part of the molecule. This type of formulation being of particular interest for the development of lipophilic drug delivery systems, the physico-chemical properties of the oleogel were also extensively studied. The Stetter reaction exhibiting most of the « click chemistry » characteristics, eco-friendly reaction conditions were developed in aqueous media and applied to other biomolecules conjugation.

Thesis advisor: Amir H. Hoveyda / Formation of C-C bonds is an invaluable tool for the construction of materials, pharmaceuticals, natural products, and the building blocks of life. Although great strides in this area have been made, there remain several limitations in regio-, site-, and enantioselective additions of carbon-based nucleophiles. Solving these challenges by expanding the scope, efficiency, and selectivity of alkyl, aryl, heteroaryl, vinyl, and alkynyl additions to carbon-based electrophiles is the topic of this dissertation. / Thesis (PhD) — Boston College, 2013. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

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N-heterocyclic carbenes (NHCs) can be used as ligands for organometallics complexes, which can then facilitate numerous catalytic applications, such as, C-H activation, small molecule activation and numerous materials applications. The use of anionically-tethered NHCs for usage with electropositive metals has been pioneered by the Arnold group within the last decade. This thesis describes the synthesis of both aryloxide- and amide-tethered NHC organometallic complexes of s-, p-, d- and f-block metals to provide a platform for small molecule activation. Once synthesised, the reactivity of some of these complexes were tested by reaction with CO2 with the aim of turning a molecule considered a harmful (environmentally), waste product into value added products, potentially providing an alternative fuel source. Chapter One introduces the use of anionically-tethered NHCs for use in a number of organometallic complexes as well as their current potential as catalysts for a number of important small molecules. This chapter focuses upon the differences between complexes tethered with anionic O, N, P, S elements, f-element NHC complexes and the use of d-block NHC complexes for catalysis. Chapter Two contains the synthesis and characterisation of a number of aryloxy-tethered NHC p-, d- and f-block organometallic complexes using the ligand H2(LArO R)2. The synthesis of SnII complexes including the synthesis of new ‘normal’ ‘abnormal’ complexes given enough steric bulk around the Sn centre due to the lone pair present in Sn complexes, preventing one of the ligands binding through the classical carbene position and therefore binding through the backbone C4 carbon. The synthesis of MII (Zn, Co and Fe) complexes to compare the solid-state structure and binding mode of the carbenes. The synthesis and characterisation of MIII (Ce and Eu) complexes to assess the solid-state structure and binding modes within f-bock complexes. Chapter Three investigates the reactivity of the MII complexes (Sn, Zn, and Fe) with CO2. Successful reactions were characterised using NMR and further treated with alkynes to target catalytic reactions. Chapter Four contains reactions to target a number of amide-tethered bis (NHC) s-, p-, d- and f-block organometallic complexes using the proligand, H4(LN Mes)Cl3. Deprotonation studies undertaken with a number of bases to give the MI (Li and K) salts and MII (Mg) salts and proved to be unsuccessful upon isolation. Reactions to synthesise the p-, d- and f-block complexes were then undertaken using in situ free carbene production as well as the attempted isolation of the free carbene, both of which also proved unsuccessful. Chapter Five provides an overall conclusion to the work presented in Chapters Two, Three and Four within this thesis. Chapter Six gives the experimental and characterising data for the complexes and reactions.

Dans le cadre de ma thèse, nous avons développé des édifices moléculaires associant des hélicènes et des carbènes N-hétérocycliques (NHC) afin de développer les premiers complexes métalliques de NHC-hélicènes. Dans un premier temps, des premiers complexes cycloiridiés de ligands NHC-[4,6]hélicènes, de formule générale IrLCp*X, dans lesquels le ligand porte un hélicène et un NHC greffés par l’intermédiaire d’un pont méthylénique, ont été obtenus. Les propriétés chiroptiques de ces complexes ont été étudiées à la fois expérimentalement et théoriquement. Nous avons ainsi pu démontrer la bonne communication entre les deux unités hélicène et NHC par l’intermédiaire de l’iridacycle, et la contribution du NHC dans les propriétés chiroptiques. Dans un deuxième temps, des complexes monocoordinnés de formule IrL(COD)X, à base d'iridium(I) et de ligands dans lesquels l’hélicène et le NHC sont orthofusionnés, ont été développés. L’efficacité de ces complexes en catalyse énantiosélective a été évaluée dans une réaction de transfert d’hydrogène de l'acétophénone, révélant un excès énantiomérique (ee) assez modeste allant jusqu’à 36%. D'autre part, des complexes d'iridium(III) cyclométallés de formule IrL(dfppy)2 ont révélé des propriétés de phosphorescence dans le vert et des temps de vie très longs. La comparaison du spectre d’émission avec celui d’un complexe analogue sans unité hélicénique a permis de mettre en évidence l’implication à la fois des orbitales d du métal mais aussi de l’unité NHC-hélicénique. Enfin, d'autres voies d’obtention d’hélicène-NHC ont été explorées, parmi lesquelles la synthèse d'un [4]hélicène-benzimidazole à partir d'un hélicène-boronate, suivie de sa déprotonation in situ et de sa cycloiridation. / During my PhD work, I have developed new molecular architectures combining helicenes and N-heterocyclic carbenes (NHC). Firstly, a novel family of cycloiridiated complexes bearing NHC-[4,6]helicene ligands, of general formula IrLCp*X, in which the ligand bear a helicene and a NHC grafted through a methylene bridge, were obtained. The chiroptical properties of these complexes have been analyzed both experimentally and theoretically. In this way, we have demonstrated the good communication between the helicene and NHC units through the iridacycle, and the contribution of the NHC in the chiroptical properties. Secondly, monocoordinated iridium(I) complexes of general formula IrL(COD)X, in which the ligands are this time constituted of orthofused NHC-helicenes, were obtained. The efficiency of these complexes in enantioselective catalysis was evaluated in a hydrogen transfer reaction on acetophenone, and revealed rather modest enantiomeric excess (ee) up to 36%. Then, cyclometallated iridium(III) complexes of general formula IrL(dfppy)2 were prepared and have shown to be phosphorescent in the green region with very long lifetimes. The comparison of the emission properties with an analogous complex without helicenic unit enabled to highlight the contribution of both the d orbitals of the iridium metal and the helicoïdal-NHC unit. Finally, other methods for the development of new NHC-helicenes structures have been explored. Among them, the synthesis of a [4]helicene-benzimidazole by transformation of a helicene-boronate, and the subsequent in situ deprotonation and cycloiridation, have been performed.