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The first chapter of this thesis describes the development of a general method for indirectly effecting radical carbocyclization of an alkyl chain onto an aromatic ring. This process involves a Birch reductive alkylation of aromatic tert-butyl esters, chromium(VI)-mediated oxidation and radical cyclization. The cyclized products are easily aromatized by Saegusa oxidation and treatment with bismuth trichloride. This method forms five- and six-membered benzo-fused carbocycles. Modification allows both formation of non-phenolic products, and the introduction of an additional substituent on the original aromatic ring. The second chapter describes a method for converting tert-butyl benzoates or tert-butyl 1-naphthoates into derivatives having a substituted alkyl group in a 1,4-relationship to an alkyl, aryl, alkenyl or alkynyl group. Key steps in the process involve addition of an organometallic species to a cross-conjugated cyclohexadienone followed by treatment with bismuth trichloride, which results in spontaneous decarboxylative aromatization. The method was successfully applied to the synthesis of the antimicrobial fungal metabolite culpin. The last chapter of this thesis describes synthetic studies towards the marine antileukemic alkaloid, sorbicillactone A. Studies towards the core structure of sorbicillactone A have resulted in a new method of desymmetrization of cross-conjugated cyclohexadienones. The key step involves a highly diastereoselective iodoetherification and radical cyclization, which affords a product that can be elaborated into a -lactone.

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Cette thèse porte sur les réactions de cyclisation des 1,6-enynes impliquant des catalyseurs de ruthénium. Trois types différents de cyclisation ont été élaborés à partir de précurseurs facilement disponibles, tels que les 1,6-enynes et alcynes. Dans un premier temps, une nouvelle cyclisation hydroalcynylante des 1,6-enynes, à l'aide d'alcynes terminaux comme co-réactifs, catalysée par le ruthenium a été explorée. Cette réaction fournit une méthode de synthèse de cycles à cinq chaînons doté d'un motif 1,5-enyne exocyclique. Un complexe du ruthenium neutre et riche en électrons, Cp*Ru(cod)Cl, s'est avéré être le catalyseur de choix de ces transformations. Dans un deuxième temps, en utilisant le même complexe, la cycloaddition [2+2+2] des 1,6-enynes et alcynes catalysée par le ruthénium a été développée. Les alcynes internes et terminaux sont appropriés pour accéder en une seule étape aux bicyclohexadienes avec de hauts rendements. Une bicycloannulation inhabitelle des 1,6-enynes, intégrant un atome d’azote, catalysée par le ruthénium a également été élaborée. Pour ces cyclisations, seul un complexe du ruthénium électrophile et alkynophile tel que [RuCl2(CO)3]2 a été en mesure d'effectuer la réaction. La formation exclusive des 3-azabicylo[4.1.0]hept-1-enes a été observée avec les 1,6-enynes dotés d'une unité alcyne interne. Ces réactions de cyclisation, respectant le principe des réactions à économie d’atome, sont discutées et sur la base de leur mécanisme de formation. / This dissertation focuses on cyclization reactions of 1,6-enynes involving ruthenium catalysts. Three different types of cyclization were developed from readily available precursors, such as 1,6-enynes and alkynes. In one application, a novel ruthenium-catalyzed hydroalkynylative cyclization of 1,6-enynes using terminal alkynes as co-reactants was explored. This reaction provides and entry to five-membered rings featuring an exocyclic 1,5-enyne motif. A neutral electron-rich ruthenium complex Cp*Ru(cod)Cl proved to be the catalyst of choice for these transformations. In another application, using the same complex, the ruthenium-catalyzed [2+2+2] cycloaddition of 1,6-enynes and alkynes was developed. Both internal and terminal alkynes were suitable substrates to access bicyclohexadienes with high yields in a single step. An intriguing ruthenium-catalyzed bicycloannulation of nitrogen-tethered 1,6-enynes has also been developed. For these cyclizations, only the electrophilic and alkynophilic ruthenium complex [RuCl2(CO)3]2 was able to perform the reaction. The exclusive formation of 3-azabicylo[4.1.0]hept-1-enes was observed with 1,6-enynes featuring an internal alkyne unit. These cyclization reactions fulfil the atom-economical reactions principle and are discussed on the basis of their mechanisms of formation.

Natural products and small molecules play a major role in drug development. However, using natural products as a source of medicine comes with many challenges, such as lack of natural abundance and difficulty in isolation. Consequently, synthetic organic chemistry is a solution in order to access these compounds in usable quantities. However, synthetic chemisty comes with its own challenges such as efficiency, chemoselectivity, stereoselectivity and enantioselectivity. Therefore, synthetic tools that addresses these challenges are required solve these limitations. This thesis discusses new methodologies using strained carbocycles (cyclopropanes and cyclopropenes) as the reactive subunit for the construction of different carbocyclic and heterocyclic compounds. The homo-Nazarov cyclization of alkenyl and heteroaryl cyclopropyl ketones was used in order to construct cyclohexenones, cyclohexenols, heteroaryl ring-fused cyclohexenones, dihydrofurans, furans and furanones in a mild and efficient manner. Benzofused heteroaromatic compounds were achieved via the Lewis acid-catalyzed cycloisomerization of cyclopropene-3,3-dicarbonyls and furan-3-carboxylates. These heteroaromatic compounds can be applied to medicinal chemistry and material science.

Gold catalysis has become an important tool to achieve highly chemoselective p-acid activation. Exceptional reactivity and selectivity are often encountered under mild reaction conditions. These properties have made gold(I) complexes suitable catalysts for tremendous applications in the total synthesis of natural products. The first chapter will highlight a number of total syntheses using gold catalysis as a key step. The second chapter will cover our application of the gold(I)-catalyzed 6-endo-dig carbocyclization for the synthesis of bridgehead-substituted scaffolds and its use toward the synthesis of PPAP natural products. This research has opened our eyes to the utility of biphenylphosphine ligands, particularly JohnPhos, in gold(I)-catalysis. The reactivity and selectivity exhibited by gold(I) complexes is modulated by the nature of the ancillary ligand. Recent research rationalizes the impact of these ligands on the divergent reactivity observed between cationic and carbenoid intermediates. Our desire to favor the 6-endo-dig pathway has led us toward the discovery of another example of the diagonal reactivity that NHC carbene and biphenylphosphine ligands can bring to gold(I)-catalysis. Chapter three will explain the development of a selective gold-catalyzed synthesis of fused carbocycles . Our selective divergent synthesis of fused carbocycles, combined with the Diels–Alder reaction, has brought new synthetic opportunities. Chapter four will describe our approach toward the synthesis of various polycyclic diterpene-related frameworks. Starting with a unique linear precursor, we have developed a new “one-pot” process for the synthesis of three different polycyclic compounds related to the terpenoid family. The facile modulation of the linear precursor and the use of different dienophiles during the Diels–Alder reaction could enable the synthesis of diverse polycyclic analogues based on three principal frameworks. The gold(I)-catalyzed synthesis of fused carbocycles reached some limitations during our study. Regioselective control was found to be substantially more challenging, with terminal alkynes or alkynes bearing a sterically and electronically neutral methyl substituent. In chapter five, we will discuss how the complementarity of silver(I) catalysis to gold(I) catalysis enabled the selective divergent synthesis of three different fused carbocycles from a unique precursor. Moreover, copper(I) catalysis has given access to the 6-endo-dig pathway on terminal alkynes without the formation of a vinylidene intermediate.

Gold catalysis has become an important tool to achieve highly chemoselective p-acid activation. Exceptional reactivity and selectivity are often encountered under mild reaction conditions. These properties have made gold(I) complexes suitable catalysts for tremendous applications in the total synthesis of natural products. The first chapter will highlight a number of total syntheses using gold catalysis as a key step. The second chapter will cover our application of the gold(I)-catalyzed 6-endo-dig carbocyclization for the synthesis of bridgehead-substituted scaffolds and its use toward the synthesis of PPAP natural products. This research has opened our eyes to the utility of biphenylphosphine ligands, particularly JohnPhos, in gold(I)-catalysis. The reactivity and selectivity exhibited by gold(I) complexes is modulated by the nature of the ancillary ligand. Recent research rationalizes the impact of these ligands on the divergent reactivity observed between cationic and carbenoid intermediates. Our desire to favor the 6-endo-dig pathway has led us toward the discovery of another example of the diagonal reactivity that NHC carbene and biphenylphosphine ligands can bring to gold(I)-catalysis. Chapter three will explain the development of a selective gold-catalyzed synthesis of fused carbocycles . Our selective divergent synthesis of fused carbocycles, combined with the Diels–Alder reaction, has brought new synthetic opportunities. Chapter four will describe our approach toward the synthesis of various polycyclic diterpene-related frameworks. Starting with a unique linear precursor, we have developed a new “one-pot” process for the synthesis of three different polycyclic compounds related to the terpenoid family. The facile modulation of the linear precursor and the use of different dienophiles during the Diels–Alder reaction could enable the synthesis of diverse polycyclic analogues based on three principal frameworks. The gold(I)-catalyzed synthesis of fused carbocycles reached some limitations during our study. Regioselective control was found to be substantially more challenging, with terminal alkynes or alkynes bearing a sterically and electronically neutral methyl substituent. In chapter five, we will discuss how the complementarity of silver(I) catalysis to gold(I) catalysis enabled the selective divergent synthesis of three different fused carbocycles from a unique precursor. Moreover, copper(I) catalysis has given access to the 6-endo-dig pathway on terminal alkynes without the formation of a vinylidene intermediate.

Chiral molecules play a central role in our daily life and in nature, for instance the different enantiomers or diastereomers of a chiral molecule may show completely different biological activity. For this reason, it is a vital goal for synthetic chemists to design selective and efficient methodologies that allow the synthesis of the desired enantiomer. In this context, it is highly important that the concept of green chemistry is considered while designing new approaches that eventually will provide more environmental and sustainable chemical synthesis.The aim of this thesis is to develop the concept of combining transition metal catalysis and aminocatalysis in one process (dual catalysis). This strategy would give access to powerful tools to promote reactions that were not successful with either transition metal catalyst or the organocatalyst alone. The protocols presented in this thesis based on organocatalytic transformations via enamine or iminium intermediates or both, in combination with transition metal catalysis, describes new enantioselective organocatalytic procedures that afford valuable compounds with high chemo- and enantioselectivity from inexpensive commercial available starting materials. In paper I, we present a successful example of dual catalysis: the combination of transition metal activation of an electrophile and aminocatalyst activation of a nucleophile via enamine intermediate. In paper II, the opposite scenario is presented, here the transition metal activates the nucleophile and the aminocatalyst activates the electrophile via an iminium intermediate. In paper III,we present a domino Michael/carbocyclisation reaction that is catalysed by a chiral amine (via iminium/enamine activation) in combination with a transition metal catalysts activation of an electrophile. In paper IV, the concept of dual catalysis was further extended and applied for the highly enantioselective synthesis of valuable structural scaffolds, namely poly-substituted spirocyclic oxindoles. Finally, in paper V the concept of dual catalysis was expanded, by investigating more challenging and environmentally benign processes, such as the successful combination of a heterogeneous palladium and amine catalysts for the highly enantioselective synthesis of functionalised cyclopentenes, containing an all carbonquaternary stereocenter, dihydrofurans and dihydropyrrolidines.

In this thesis, carbohydrate mimicry is investigated through the syntheses of carbohydrate analogues and evaluation of their inhibitory effects on carbohydrate-processing enzymes. Galactofuranosides are interesting structures because they are common motifs in pathogenic microorganisms but not found in mammals. M.tuberculosis, responsible for the disease tuberculosis, has a cell wall containing a repeating unit of alternating (1→5)- and (1→6)-linked β-D-galactofuranosyl residues. Synthetic inhibitors of the enzymes involved in the biosynthesis of the cell wall could find great therapeutic use. The first part of this thesis describes the first synthesis of the hydrolytically stable carbasugar analogue of galactofuranose, 4a-carba-β-D-Galf, and the synthetic work of synthesising β-linked pseudodisaccharides containing carba-Galf, which were tested for glycosyltransferease inhibitory activity. The pseudodisaccharide carba-Galf-(β1→5)-carba-Galf was found to be a moderate inhibitor of the glycosyltransferase GlfT2 of M.tuberculosis. The thesis also describes how a general method towards biologically relevant α-linked carba-Galf ethers was developed. The final part of this thesis is focussed on the formation of nitrogen-linked monosaccharides without the participation of the anomeric centre. Such a mode of coupling is called tail-to-tail neodisaccharide formation. The couplings of carbohydrate derivatives via the Mitsunobu reaction are successfully reported herein. The method describes the key introduction of an allylic alcohol in the electrophile and the subsequent functionalisation of the alkene to obtain the neodisaccharide. Two synthesised neodisaccharides presented in this thesis have been sent to be tested for glycosidase inhibitory activity. / At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Manuscript. Paper 4: Manuscript. Paper 5: Manuscript. Paper 6: Manuscript.