The research presented herein is concerned with the exploration of tandem processes initiated by the conjugate reduction of Michael acceptors, encompassing the asymmetric reductive Dieckmann reaction and the two-carbon homologation of aldehydes by two complementary methodologies. Chapter 1 introduces the area of transition metal catalysed tandem reductive processes as a tool for carbon-carbon bond formation. An extensive discussion of this methodology is included and recent advances in the area are highlighted. Chapter 2 discusses the initial study into the asymmetric reductive Dieckmann condensation. 3,3’-Disubstituted 4-oxopyrrolidines were synthesised in up to 93% ee using both molybdenum and copper catalysis. Chapter 3 describes the novel molybdenum-catalysed two-carbon homologation of aldehydes by the reduction of alkylidene Meldrum’s acid derivatives. No over reduction to the corresponding alcohol is observed, as the aldehyde functionality remains protected until hydrolysis. Chapter 4 discusses the mild, expeditious amine promoted reduction of cyclic malonates to β-substituted propionaldehydes. The synthetic utility of the methodology is demonstrated by the synthesis of γ-substituted propylamines in a one-pot hydrosilylation/reductive amination process. Chapter 5 describes the synthesis and characterisation for the compounds discussed in chapters 2, 3 and 4.

The construction of benzylic quaternary stereocentres via the enantioselective copper-catalyzed 1,4-addition of dialkylzinc reagents to Meldrum’s acid acceptors in the presence of a phosphoramidite ligand is reported. Meldrum’s acid acceptors can be easily accessed and numerous derivatives have been prepared to investigate the scope of the enantioselective 1,4-addition. The reaction is tolerant to a wide range of heteroaromatic and functional groups. The significance of substituting the position para, meta, and ortho to the electrophilic centre is also highlighted. Primary and secondary organozinc reagents are shown to be compatible in this reaction. A highly enantioselective synthesis of carboxylic acid derivatives having an -quaternary centre through copper-catalyzed 1,4-addition of dialkylzinc reagents to aryl acetate derivatives is also described. This method employs a commercially available phosphoramidite ligand and readily accessible Meldrum’s acid acceptors. A brief insight into the observed selectivity is also discussed. The significance of this method was established by the expedient preparation of chiral diesters, succinimides, γ-butyrolactones, and isocyanates from highly functionalized benzyl Meldrum’s acids. In addition to 1,4-addition, the enantioselective asymmetric synthesis of benzylic tertiary and quaternary stereogenic centres via 1,6-addition of dialkylzinc reagents to Meldrum’s acid acceptors is outlined. This work represents one of the early examples of 1,6-asymmetric conjugate addition reactions and discussions on the regioselectivity of the process are disclosed. On a different subject matter, the occurrence and persistence of C–H•••X (O, S, Br, Cl, and F) bond in solution using 1H NMR spectroscopy is discussed for a large number of benzyl Meldrum’s acids. The latter are novel and reliable probes for the evaluation of this type of non-classical interactions in solution. The persistence of the C–H•••X bond in solution is demonstrated to be dependent upon structural features present on the aromatic moiety and the benzylic position of the benzyl Meldrum’s acid derivatives. The observations presented highlight the large potential of Meldrum’s acid in developing an understanding of the function and nature of C–H•••X interactions.

The construction of benzylic quaternary stereocentres via the enantioselective copper-catalyzed 1,4-addition of dialkylzinc reagents to Meldrum’s acid acceptors in the presence of a phosphoramidite ligand is reported. Meldrum’s acid acceptors can be easily accessed and numerous derivatives have been prepared to investigate the scope of the enantioselective 1,4-addition. The reaction is tolerant to a wide range of heteroaromatic and functional groups. The significance of substituting the position para, meta, and ortho to the electrophilic centre is also highlighted. Primary and secondary organozinc reagents are shown to be compatible in this reaction. A highly enantioselective synthesis of carboxylic acid derivatives having an -quaternary centre through copper-catalyzed 1,4-addition of dialkylzinc reagents to aryl acetate derivatives is also described. This method employs a commercially available phosphoramidite ligand and readily accessible Meldrum’s acid acceptors. A brief insight into the observed selectivity is also discussed. The significance of this method was established by the expedient preparation of chiral diesters, succinimides, γ-butyrolactones, and isocyanates from highly functionalized benzyl Meldrum’s acids. In addition to 1,4-addition, the enantioselective asymmetric synthesis of benzylic tertiary and quaternary stereogenic centres via 1,6-addition of dialkylzinc reagents to Meldrum’s acid acceptors is outlined. This work represents one of the early examples of 1,6-asymmetric conjugate addition reactions and discussions on the regioselectivity of the process are disclosed. On a different subject matter, the occurrence and persistence of C–H•••X (O, S, Br, Cl, and F) bond in solution using 1H NMR spectroscopy is discussed for a large number of benzyl Meldrum’s acids. The latter are novel and reliable probes for the evaluation of this type of non-classical interactions in solution. The persistence of the C–H•••X bond in solution is demonstrated to be dependent upon structural features present on the aromatic moiety and the benzylic position of the benzyl Meldrum’s acid derivatives. The observations presented highlight the large potential of Meldrum’s acid in developing an understanding of the function and nature of C–H•••X interactions.

Dans le cadre de cette thèse, nous nous sommes tournés vers l'utilisation de l'acide de Meldrum en tant que plateforme pour la synthèse d'hétérocycles chiraux par organocatalyse. De nouvelles voies d'accès, diastéréo- et/ou énantiosélectives, à des pyrazolidinones, pyrimidinones et isoxazolidinones ont été mises au point, via une réaction domino de type Knoevenagel/aza Michael/Cyclocondensation. La problématique du contrôle de la stéréochimie au sein de ces molécules a été d'autant plus étudiée que ce type de structures peut être retrouvé dans des composés d'intérêt biologique. Un intérêt tout particulier a été porté à l'étude des mécanismes réactionnels. Notamment dans le cadre d'une collaboration entre notre groupe et l'équipe « Analyse et Modélisation » du laboratoire COBRA pour l'étude de la réaction d'annélation [3+2] entre l'acide de Meldrum et des nitrones, par spectrométrie de masse / In the course of this thesis, we focused our efforts on developing the use of Meldrum's acid as a platform for the organocatalyzed synthesis of chiral heterocycles. In the end, we managed to access various pyrazolidinone, pyrimidinone and isoxazolidinone moieties in a diastero- and/or enantioselective fashion. We found these reactions to proceed via a navel domino Knoevenagel/aza Michael/Cyclocondensation reaction. The stereocontrol issue was particularly studied, as our final compounds can be found as part of biologically relevant structures. We also put much effort in probing reaction mechanisms. In the latter, we worked in collaboration with the "Analyse et Modélisation" team of laboratoire COBRA to get insights on the [3+2] annulation reaction between Meldrum's and nitrones, using mass spectrometry

The intramolecular Friedel-Crafts acylation of aromatics with Meldrum?s acid derivatives catalyzed by metal trifluoromethanesulfonates and other Lewis acids is reported. Meldrum?s acids are easily prepared, functionalized, handled, and purified. The synthesis of polysubstituted 1-indanones from benzyl Meldrum's acids was investigated thoroughly, and it was shown that a variety of catalysts were effective, whilst accommodating a diversity of functional groups under mild conditions. The scope, limitations, and functional group tolerance (terminal alkene and alkyne, ketal, dialkyl ether, dialkyl thioether, aryl methyl ether, aryl TIPS and TBDPS ethers, nitrile- and nitro-substituted aryls, alkyl and aryl halides) for a variety of 5-benzyl (enolizable Meldrum?s acids) and 5-benzyl-5-substituted Meldrum?s acids (quaternarized Meldrum?s acids), forming 1-indanones and 2-substituted-1-indanones respectively, are delineated. <br ><br /> This method was further applied to the synthesis of 1-tetralones, 1-benzosuberones, and the potent acetylcholinesterase inhibitor donepezil. <br ><br /> Mechanistic investigations were undertaken to determine the rate-determining step in the acylation sequence using Meldrum?s acid, as well as to examine the role of the Lewis acid catalyst. Enolizable Meldrum?s acid derivatives can react via an acyl ketene intermediate under thermal conditions, while quaternarized Meldrum?s acid derivatives are thermally stable and only act as effective Friedel-Crafts acylating agents in the presence of a Lewis acid catalyst. <br ><br /> The total synthesis of (??)-Taiwaniaquinol B was completed. This natural product was the first ever isolated containing an unusual 6-5-6 fused ring system, and it also contains a hexasubstituted aromatic ring, and two all-carbon quaternary centers. This synthesis was accomplished via an intramolecular Friedel-Crafts acylation/carbonyl a-<em>tert</em>-alkylation reaction that exploits the unique chemistry of Meldrum?s acid. This novel methodology can be used to access a variety of highly substituted fused ring systems of various sizes.

The intramolecular Friedel-Crafts acylation of aromatics with Meldrum?s acid derivatives catalyzed by metal trifluoromethanesulfonates and other Lewis acids is reported. Meldrum?s acids are easily prepared, functionalized, handled, and purified. The synthesis of polysubstituted 1-indanones from benzyl Meldrum's acids was investigated thoroughly, and it was shown that a variety of catalysts were effective, whilst accommodating a diversity of functional groups under mild conditions. The scope, limitations, and functional group tolerance (terminal alkene and alkyne, ketal, dialkyl ether, dialkyl thioether, aryl methyl ether, aryl TIPS and TBDPS ethers, nitrile- and nitro-substituted aryls, alkyl and aryl halides) for a variety of 5-benzyl (enolizable Meldrum?s acids) and 5-benzyl-5-substituted Meldrum?s acids (quaternarized Meldrum?s acids), forming 1-indanones and 2-substituted-1-indanones respectively, are delineated. <br ><br /> This method was further applied to the synthesis of 1-tetralones, 1-benzosuberones, and the potent acetylcholinesterase inhibitor donepezil. <br ><br /> Mechanistic investigations were undertaken to determine the rate-determining step in the acylation sequence using Meldrum?s acid, as well as to examine the role of the Lewis acid catalyst. Enolizable Meldrum?s acid derivatives can react via an acyl ketene intermediate under thermal conditions, while quaternarized Meldrum?s acid derivatives are thermally stable and only act as effective Friedel-Crafts acylating agents in the presence of a Lewis acid catalyst. <br ><br /> The total synthesis of (±)-Taiwaniaquinol B was completed. This natural product was the first ever isolated containing an unusual 6-5-6 fused ring system, and it also contains a hexasubstituted aromatic ring, and two all-carbon quaternary centers. This synthesis was accomplished via an intramolecular Friedel-Crafts acylation/carbonyl a-<em>tert</em>-alkylation reaction that exploits the unique chemistry of Meldrum?s acid. This novel methodology can be used to access a variety of highly substituted fused ring systems of various sizes.

The development of selective SmI2-H2O-mediated mono-reductions of cyclic-1,3-diesters to the corresponding 3-hydroxy acids is described. The reaction proceeds with complete selectivity for cyclic-1,3-diesters over acyclic esters. Sequential one-pot conjugate reduction-ester reduction of alkylidene cyclic-1,3-diesters is also reported. Furthermore, we describe the exploitation of the unusual ketyl radical intermediates formed via single electron reduction of the ester carbonyl in unprecedented 5-exo-trig cyclisations providing access to highly substituted, stereo-defined, cyclopentanols and cyclopentanones. Also described is the use of a silicon control element to direct the stereochemical outcome of the SmI2-MeOH-mediated conjugate reduction-intramolecular aldol cyclisations of α,β-unsaturated lactones. These cyclisations generate two contiguous quaternary centres with complete diastereocontrol; the utility of the silicon-directing group as a synthetic handle for derivatisation of the cyclisation products has also been demonstrated. These cyclisations have been applied in a model approach to the anti-mitotic natural product pseudolaric acid B.

The selective transformation of carbon-carbon and carbon-hydrogen bonds represents an attractive approach and rapidly developing frontier in synthesis. Benefits include step and atom economy, as well as the ubiquitous presence in organic molecules. Advances to this exciting realm of synthesis are described in this thesis with an emphasis on the development of catalytic, selective reactions under mild conditions. Additionally some applications of the methodologies are demonstrated. In Chapter 1, the first examples of inter-and intramolecular enantioselective conjugate alkenylations employing organostannanes are reported. A chiral, cationic Rh(I)-diene complex catalyzed the enantioselective conjugate addition of alkenylstannanes to benzylidene Meldrum’s acids in moderate enantiomeric ratios and yields. Notably, the cationic and anhydrous conditions required for the asymmetric alkenylation are complementary to existing protocols employing other alkenylmetals. In Chapter 2, a domino, one-pot formation of tetracyclic ketones from benzylidene Meldrum’s acids using Sc(OTf)3 via a [1,5]-hydride shift/cyclization/Friedel-Crafts acylation sequence is described. Respectable yields were obtained in accord with the ability to convert to the spiro-intermediate, and considering the formation of three new bonds: one C-H and two C-C bonds. An intriguing carbon-carbon bond cleavage was also serendipitously discovered as part of a competing reaction pathway. In Chapter 3, the pursuit of novel C-H bond transformations led to the development of non-carbonyl-stabilized rhodium carbenoid Csp3-H insertions. This methodology enabled the rapid synthesis of N-fused indolines and related complex heterocycles from N-aziridinylimines. By using a rhodium carboxamidate catalyst, competing processes were minimized and C-H insertions were found to proceed in moderate to high yields. Also disclosed is an expedient total synthesis of (±)-cryptaustoline, a dibenzopyrrocoline alkaloid, which highlights the methodology. In Chapter 4, the Lewis acid promoted substitution of Meldrum’s acid discovered during the course of the domino reaction was explored in detail. The protocol transforms unstrained quaternary and tertiary benzylic Csp3-Csp3 bonds into Csp3-X bonds (X = C, N, H) and has even shown to be advantageous with regards to synthetic utility over the use of alternative leaving groups for substitutions at quaternary benzylic centers. This reaction has a broad scope both in terms of suitable substrates and nucleophiles with good to excellent yields obtained (typically >90%).

The selective transformation of carbon-carbon and carbon-hydrogen bonds represents an attractive approach and rapidly developing frontier in synthesis. Benefits include step and atom economy, as well as the ubiquitous presence in organic molecules. Advances to this exciting realm of synthesis are described in this thesis with an emphasis on the development of catalytic, selective reactions under mild conditions. Additionally some applications of the methodologies are demonstrated. In Chapter 1, the first examples of inter-and intramolecular enantioselective conjugate alkenylations employing organostannanes are reported. A chiral, cationic Rh(I)-diene complex catalyzed the enantioselective conjugate addition of alkenylstannanes to benzylidene Meldrum’s acids in moderate enantiomeric ratios and yields. Notably, the cationic and anhydrous conditions required for the asymmetric alkenylation are complementary to existing protocols employing other alkenylmetals. In Chapter 2, a domino, one-pot formation of tetracyclic ketones from benzylidene Meldrum’s acids using Sc(OTf)3 via a [1,5]-hydride shift/cyclization/Friedel-Crafts acylation sequence is described. Respectable yields were obtained in accord with the ability to convert to the spiro-intermediate, and considering the formation of three new bonds: one C-H and two C-C bonds. An intriguing carbon-carbon bond cleavage was also serendipitously discovered as part of a competing reaction pathway. In Chapter 3, the pursuit of novel C-H bond transformations led to the development of non-carbonyl-stabilized rhodium carbenoid Csp3-H insertions. This methodology enabled the rapid synthesis of N-fused indolines and related complex heterocycles from N-aziridinylimines. By using a rhodium carboxamidate catalyst, competing processes were minimized and C-H insertions were found to proceed in moderate to high yields. Also disclosed is an expedient total synthesis of (±)-cryptaustoline, a dibenzopyrrocoline alkaloid, which highlights the methodology. In Chapter 4, the Lewis acid promoted substitution of Meldrum’s acid discovered during the course of the domino reaction was explored in detail. The protocol transforms unstrained quaternary and tertiary benzylic Csp3-Csp3 bonds into Csp3-X bonds (X = C, N, H) and has even shown to be advantageous with regards to synthetic utility over the use of alternative leaving groups for substitutions at quaternary benzylic centers. This reaction has a broad scope both in terms of suitable substrates and nucleophiles with good to excellent yields obtained (typically >90%).

Les travaux présentés dans ce manuscrit de thèse concernent la mise au point de nouvelles méthodologies de synthèse asymétrique en organocatalyse promues par des phénolates d’ammoniums quaternaires, catalyseurs de type paires d’ions coopératifs chirales, et des dérivés de l’acide de Meldrum comme substrats. Dans un premier temps, nous avons utilisé l’acide de Meldrum comme un précurseur de cétène via une cycloréversion induite par O-silylation grâce à une probase silylée, afin de réaliser une réaction de cycloaddition [2+2] avec un aldéhyde ou une imine catalysée par un phénolate d’ammonium chiral, permettant de former des β-lactones et des β-lactames. Les travaux effectués n’ont cependant pas permis d’obtenir le produit désiré. Dans un secont temps, nous avons exploité le caractère électrophile des dérivés disubstitués de l’acide de Meldrum et leur capacité à fragmenter suite à l’addition nucléophile d’un phénolate. Une première partie a été consacrée au développement d’une réaction monotope de désymétrisation de l’acide de Meldrum pour former des malonates dissymétriques après une étape d’alkylation in situ du carboxylate intermédiaire. Bien que de bons rendements isolés aient été obtenus, un maximum de 21% ee a pu seulement être atteint. Dans une seconde partie, nous avons mis au point une séquence originale, catalysée par un phénolate d’ammonium quaternaire chiral, qui est constituée (1) d’une addition nucléophile de phénolate suivie (2) d’une fragmentation avec perte d’acétone qui permet, après (3) une étape de décarboxylation de générer un acétal de cétène acyclique qui va subir (4) une réaction de protonation énantiosélective. Cette méthode a pu être appliquée à un large panel de substrats avec de bons rendements et des excès énantiomériques allant jusqu’à 70% ee. / The work developed in this PhD thesis deals with the development of new asymmetric organocatalytic methodologies implying cooperative chiral ion pairing catalysis, by using chiral ammonium phenoxides as catalysts and Meldrum’s acid derivatives as substrates. First, we used the ability of Meldrum’s acid to generate acylketenes after cycloversion triggered by O-silylation thanks to a silylated probase in the presence of a chiral ammonium phenoxide. Such an approach was applied to the synthesis of β-lactones and β-lactames following a [2+2] cycloaddition reaction with aldehydes or imines respectively. Unfortunately, the desired products have never been observed. Then, we focused on disubstitued derivatives of Meldrum’s acids and their propensity to fragment after a nucleophilic addition of phenoxide. In a first part, we have developed a one-pot desymmetrization reaction of Meldrum’s acid derivatives to form dissymmetric malonates after an in-situ alkylation of the transient carboxylate. However, despite high isolated yields, only an unsatisfactory 21% ee could be reached. In a second part, we have developed an unprecedented sequence consisting of (1) a nucleophilic addition of phenol derivatives to Meldrum’s acid followed by (2) a fragmentation with loss of acetone, leading after (3) decaboxylation to the formation of an acyclic ketene acetal which is involved in (4) an enantioselective protonation reaction to provide a wide range of enantioenriched phenolic esters with moderate to excellent yield and up to 70% ee.