Les hétérocycles azotés chiraux représentent une classe importante de composés biologiquement actifs. L’hydroamination asymétrique intramoléculaire correspond parfaitement au concept d’économie d’atomes et permet l’accès direct à la formation de nouvelles liaisons carbone-azote. Le développement de catalyseurs pour la formation de pyrrolidines et piperidines reste cependant une tâche importante. Le thème de cette thèse est l’étude de nouveaux complexes chiraux binaphthylamide d’yttrium facilement accessibles et leur application pour promouvoir la réaction d’hydroamination/cyclisation des amines primaires liées à des alcènes stériquement encombrés.Des complexes chiraux binaphthylamidure alkyl ate d’yttrium ont été développés. Ces systèmes catalytiques ont été préparés in situ par une réaction simple stœchiométrique en présence d’un précurseur d’yttrium [Li(THF)4][Y(CH2SiMe3)4] connu et d’une variété de ligands chiraux binaphthyldiamine substitués. Les complexes chiraux hétéroleptiques obtenus se sont révélés actifs et énantiosélectifs pour la réaction d’hydroamination asymétrique intramoléculaire des aminoalcènes 1,2-disubstitués conduisant à la formation d’hétérocycles azotés avec cinq et six châinons. Les catalyseurs d’yttrium préparés à partir du ligand (R)-N-anthrylmethyl-binaphthylamine H2L13 et des ligands (R)-benzyl N-para-substitués H2L4 or H2L6 se sont révélés les plus énantiosélectifs à 70-110°C pour la réaction d’hydroamination/cyclisation des aminoalcènes encombrés. Un excès énantiomérique de 77% a été obtenu comme valeur la plus élevée décrite jusqu’à présent pour l’hydroamination asymétrique intramoléculaire des amines comportant des alcènes 1,2-disubstitués. Les premiers exemples de la réaction d’hydroamination intramoléculaire asymétrique des aminoalcènes 1,1,2-trisubstitués ont été rapportés. Les complexes ate alkyl d’yttrium ont fourni les produits hétérocycliques avec des centres quaternaires énantiomériquement enrichis dans des conditions réactionelles plus sévères que la cyclisation des aminoalcènes 1,2-disubstitués et avec des énantiosélectivités prometteuses atteignant 55%. Les complexes alkyl d’yttrium contenant une molécule de chlorure de lithium [{(R)-C20H12(NSiMe3)2}Y{CH2SiMe3}{LiCl(THF)2}] and [{(R)-C20H12(NC5H9)2}Y{CH2SiMe3}{LiCl(THF)2}] ont été préparés et comparés aux mêmes complexes sans LiCl. Ils se sont révélés être des catalyseurs efficaces pour la réaction d’hydroamination intramoléculaire des aminoalcènes terminaux. / Chiral nitrogen-containing heterocycles represent an important class of biologically active compounds. The asymmetric intramolecular hydroamination perfectly matches the concept of sustainable chemistry and allows the formation of new nitrogen-carbon bonds in an ideal atom efficiency and economy, starting from non activated substrates. The development of catalysts for formation of enantioenriched pyrrolidines and piperidines derivatives remains however a challenging task. The topic of this dissertation is the study of new easily accessible chiral yttrium binaphthylamide complexes and their application for promoting the hydroamination/cyclisation of primary amines tethered to sterically demanding alkenes. Chiral binaphthylamido alkyl ate yttrium complexes have been investigated. These catalytic systems have been prepared by a facile in situ stoichiometric reaction of a well-known yttrium precursor [Li(THF)4][Y(CH2SiMe3)4] with a variety of chiral substituted (R)-binaphthylamine ligands. These chiral heteroleptic complexes are shown to be efficient catalysts for the enantioselective intramolecular hydroamination of 1,2-disubstituted aminoalkenes leading to the formation of five and six-membered N-heterocycles. Yttrium catalysts prepared from (R)-N-anthrylmethyl-binaphthylamine ligand H2L13 and (R)-N-para-substituted benzyl ligands H2L4 or H2L6 proved to be the most enantioselective catalysts at 70-110°C for the hydroamination/cyclisation of challenging aminoalkenes. An enantiomeric excess value of 77 % was indeed disclosed as the highest value reported so far for the asymmetric intramolecular hydroamination of amines tethered to 1,2-disubstituted alkenes. The first examples of asymmetric intramolecular hydroamination of 1,1,2-tri-substituted aminoalkenes have been reported. The alkyl ate yttrium complexes produced the heterocyclic compounds with enantioenriched quaternary centres under harsher reaction conditions than the cyclisation of the corresponding 1,2-disubstituted alkenes, and with promising enantioselectivities of up to 55 %.The neutral alkyl yttrium complexes containing one molecule of lithium chloride [{(R)-C20H12(NSiMe3)2}Y{CH2SiMe3}{LiCl(THF)2}] and [{(R)-C20H12(NC5H9)2}Y{CH2SiMe3}{LiCl(THF)2}] have been prepared and compared with the same complexes lacking LiCl. They have been revealed as efficient catalysts for intramolecular hydroamination of terminal aminoalkenes.

Les complexes salen chiraux ont été intensément étudiées. En effet, Ils constituent l'une des familles de catalyseurs principaux qui peuvent être utilisés pour préparer des synthons très précieux, énantioenrichies. En accord avec l'idée de la chimie verte, l'un des principaux objectifs consiste maintenant à établir des procédures efficaces pour la récupération et la réutilisation de ces catalyseurs. Plusieurs procédures d'hétérogénéisation ont été décrits qui impliquent la modification des structures salen par des interactions covalentes greffage ou non covalente avec différents supports. Une autre approche consiste à la préparation de polymères à partir de salen modifiés ou les complexes correspondants. Dans ce contexte, la procédure la plus courante consiste à établir des réactions de polycondensation entre diamines correctement modifiés et produits dérivés disalicylaldéhyde. Nous avons ainsi développé une méthodologie polymère synthétique par polycondensation de divers dérivés disalicylaldéhydes modifiés avec différentes diamines chirales. Les analyses Maldi-Tof ont montré que les polymères ciblés possèdent une structure macrocyclique, nommé calix-salen, dans un mélange de 2-, 3-, 4- et 5-mères. Ces nouveaux dérivés chiraux calix-salens ont été complexés avec des sels de chrome et cobalt pour être testés comme catalyseurs hétérogènes dans les réactions asymétriques (réaction de Henry, dédoublement cinétique hydrolytique). Après réduction des fonctions imines, les catalyseurs réduits correspondants sont complexés avec des sels de cuivre et testés dans la réaction de Henry asymétrique transformation pour une comparaison de l'efficacité de deux catalyseurs. Leur recyclage a été examiné. / Chiral salen complexes have been intensively studied because they constitute one of the main catalyst families that can be used to prepare valuable, highly enantioenriched synthons. In line with the idea of green chemistry, one major goal is now to establish efficient procedures for the recovery and reuse of such catalysts. Several heterogenization procedures have been described that involve the modification of the salen structures through covalent grafting or non-covalent interactions with various supports. Another approach consists in the preparation of polymers from appropriately modified salen or corresponding complexes. In this context, the most common procedure involves polycondensation reactions between properly modified diamines and disalicylaldehyde derivatives.We have thus developed a polymer synthetic methodology by polycondensation of various modified disalicylaldehyde derivatives with different chiral diamines. Maldi-Tof analyses showed that the targeted polymers possessed a macrocyclic structure, named calix-salen, in a mixture of 2-, 3-, 4- and 5-mers. These new chiral calixsalen derivatives have been complexed with chromium and cobalt salts and tested as heterogeneous catalysts in asymmetric reactions (Henry Reaction, Hydrolytic Kinetic Resolution). After reduction of the imine functions, the corresponding reduced catalysts will be complexed with copper salts and tested to promote the Henry reaction for a comparison of the efficiency of both catalysts type. Their recyclability was examine.

Ce manuscrit présente le développement de nouvelles réactions de cycloaddition [3+2] palladocatalysées entre des vinylcyclopropanes électro-appauvris et diverses espèces dipolarophiles. La première partie de ces travaux a porté sur la désaromatisation de composés nitroaromatiques tels que les 3-nitroindoles ou les 2-nitrobenzofuranes par le biais d'un procédé de cycloaddition impliquant les vinylcyclopropanes. Une seconde méthodologie de cycloaddition [3+2] énantiosélective entre des aldéhydes ?,?-insaturés et des vinylcyclopropanes a été développée. En tirant parti du concept de catalyse synergique métallo-organique, divers cyclopentanes hautement fonctionnalisés ont été obtenus, avec notamment des énantiosélectivités très élevées. Dans une troisième partie de ces travaux, l'extension de cette méthodologie à la synthèse de composés hétérocycliques a été étudiée ; une première approche impliquant la formation in situ de dipôles-1,3 et -1,4 azotés n'ayant pas abouti à la réactivité désirée, nous avons alors développé une méthodologie de cycloaddition de vinylcyclopropanes et d'imines électro-déficientes par catalyse au palladium(0) menant à des dérivés de pyrrolidine. / This manuscript presents the development of novel palladium-catalysed [3+2] cycloaddition reactions between vinylcyclopropanes and various dipolarophiles. The first part of this work focused on the dearomatization of nitroaromatic compounds such as 3-nitroindoles and 2-nitrobenzofurans through a cycloaddition process with vinylcyclopropanes. In a second time, an enantioselective [3+2] cycloaddition of vinylcyclopropanes with α,β-unsaturated aldehydes under a synergistic metal-organocatalytic activation manifold was developed, leading to highly substituted cyclopentane scaffolds with very high enantioselectivity. In a third part of this work, the extension of this methodology towards the synthesis of heterocyclic compounds was investigated. A first approach dealing with the in situ generation of nitrogen-containing 1,3- and 1,4-dipoles did not lead to the desired reactivity, which prompted us to develop a palladium(0)-catalysed cycloaddition of vinylcyclopropanes and electron-deficient imines to synthesize pyrrolidine derivatives.

This thesis deals with the preparation and use of chiralbispyridylamides as ligands in metal-catalyzed asymmetricreactions. The compounds were prepared by amide formation usingdifferent coupling reagents. Bispyridylamides havingsubstituents in the 4- or 6- positions of the pyridine ringswere prepared by functional group interconversion of the 4- or6- halopyridine derivatives. These synthetic approaches provedto be useful for various types of chiral backbones. Pseudo C2-symmetric bispyridylamides were also synthesizedby means of stepwise amide formation. The compounds were used as ligands in themicrowave-accelerated Mocatalyzed asymmetric allylic alkylationreaction. Ligands having ð-donating substituents in the4-positions of the pyridine rings gave rise to products withhigher branched to linear ratio. The catalytic reaction, whichproved to be rather general for allylic carbonates with anaromatic substituent, was used as the key step in thepreparation of (R)-baclofen. The Mo-bispyridylamide catalystprecursor was studied by NMR spectroscopy. Bispyridylamide complexes of metal alkoxides were alsoevaluated in the asymmetric addition of cyanide to aldehydesand the metal complexes involved were studied by NMRspectroscopy and X-ray crystallography. Chiral diamines wereused as additives to study the ring opening of cyclohexeneoxide with azide, catalyzed by Zr(IV)-bispyridylamidecomplexes. Various bispyridylamides were attached to solid supports oforganic or inorganic nature. The solid-supported ligands wereused in Mo-catalyzed asymmetric allylic alkylation reactionsand in the asymmetric addition of cyanide to benzaldehyde. Keywords:asymmetric catalysis, chiral ligand, pyridine,amide, allylic alkylation, enantioselective, cyanation,ring-opening, chiral Lewis acid.

This thesis deals with the design and synthesis of chiralenantiopure nitrogencontaining ligands and the use of theseligands in asymmetric catalysis. A modular synthetic approachto enantiopure nitrogen-containing ligands was developed. Thesynthetic method is based on the ring-opening of activatedchiral aziridines by nitrogen nucleophiles. The aziridines areconveniently prepared from amino alcohols. The structure oftheaziridine and of the nucleophile can be extensively varied andlibraries of ligands are easily prepared. The use of primaryamines affords C2-symmetric bis(sulfonamides), whereas the use ofammonia affords C3-symmetric tris(sulfonamides) that can beelaborated into the corresponding tetra-amines. The C2- and C3-symmetric ligands were used in the asymmetrictitaniummediated addition of diethylzinc to benzaldehyderesulting in modest enantioselection, 76% ee. A thoroughinvestigation of the reaction conditions revealed that theamount of Ti(OiPr)4has a decisive effect on the reaction rate and thestereochemical outcome of the reaction. The reaction timedecreased from about 90 hours to 15 minutes and theenantioselectivity changed from 26% of the (R)- enantiomer to72% of the (S)-enantiomer when the Ti(OiPr)4:benzaldehyde ratio was increased from 0.125:1 to1.48:1. Moreover, the titanium-mediated addition of diethylzincto benzaldehyde was studied in the presence of chiraladditives. The bis(sulfonamides) were also used in thecyclopropanation of cinnamyl alcohol. However, only lowenantioselection was observed, 27% ee. The C3-symmetric tetra-amines were reacted to formazaphosphatranes. These weak acids were only partiallydeprotonated by the strong base KOtBu to form the correspondingproazaphosphatranes. The unexpectedly strong basicity of theproazaphosphatranes was believed to be due to steric effects assuggested by DFT calculations. The tetra-amines and thesulfonamides were used for the preparation of metal complexesof Lewis acidic metals such as titanium(IV) andzirconium(IV). <b>Keywords:</b>asymmetric catalysis, aziridine, benzaldehyde,diethylzinc, enantioselective, ligand, proazaphosphatrane,ring-opening, sulfonamide, symmetry, titanium, zirconium

Palladium-catalyzed reactions for carbon-carbon bond formation have had a significant impact on the field of organic chemistry in recent decades. Illustrative is the 2010 Nobel Prize, awarded for “palladium-catalyzed cross couplings in organic synthesis”, and the numerous applications of these transformations in industrial settings. This thesis describes recent developments in C(sp2)-C(sp3) bond formation, focusing on alkane arylation reactions and arylative dearomatization transformations. In the first part, our contributions to the development of intramolecular C(sp3)-H arylation reactions from aryl chlorides are described (Chapter 2). The use of catalytic quantities of pivalic acid was found to be crucial to observe the desired reactivity. The reactions are highly chemoselective for arylation at primary aliphatic C-H bonds. Theoretical calculations revealed that C-H bond cleavage is facilitated by the formation of an agostic interaction between the palladium centre and a geminal C-H bond. In the following section, the development of an alkane arylation reaction adjacent to amides and sulfonamides is presented (Chapter 3). The mechanism of C(sp3)-H bond cleavage in alkane arylation reactions is also addressed through an in-depth experimental and theoretical mechanistic study. The isolation and characterization of an intermediate in the catalytic cycle, the evaluation of the roles of both carbonate and pivalate bases in reaction mechanism as well as kinetic studies are reported. Our serendipitous discovery of an arylation reaction at cyclopropane methylene C-H bonds is discussed in Chapter 4. Reaction conditions for the conversion of cyclopropylanilines to quinolines/tetrahydroquinolines via one-pot palladium(0)-catalyzed C(sp3)-H arylation with subsequent oxidation/reduction are described. Initial studies are also presented, which suggest that this transformation is mechanistically unique from other Pd catalyzed cyclopropane ring-opening reactions. Preliminary investigations towards the development of an asymmetric alkane arylation reaction are highlighted in Chapter 5. Both chiral carboxylic acid additives and phosphine ligands have been examined in this context. While high yields and enantiomeric excesses were never observed, encouraging results have been obtained and are supported by recent reports from other research groups. Finally, in part two, the use of Pd(0)-catalysis for the intramolecular arylative dearomatization of phenols is presented (Chapter 7). These reactions generate spirocyclohexadienones bearing all-carbon quaternary centres in good to excellent yields. The nature of the base, although not well understood, appears to be crucial for this transformation. Preliminary results in the development of an enantioselective variant of this transformation demonstrate the influence of catalyst activation on levels of enantiomeric excess.

A synthetic approach to produce lysergic acid by virtue of an asymmetric ring opening (ARO) of symmetrical 3,6-disubstituted-7,10-hydroxymethyl bridgehead substituted oxabicycles is described. The use of a Rhodium(I)/JosiPhos(R,S) catalyst system to effect an ARO using an amine nucleophile furnishes an enantiopure tetrahydronapthalene intermediate with the amine conveniently installed at the 6 position as in lysergic acid, with appropriate stereochemistry; further which, two subsequent annulations are necessary to form the fused 3,5-substituted indole and tetrahydropyridine to complete the synthesis. Progress of this work is described herein along with future directions. The second chapter in this thesis describes the modular and stereoselective synthesis of tetrasubstituted helical alkenes via a palladium-catalyzed domino reaction under Catellani conditions. These helical alkenes possess potentially interesting photochemical properties as molecular motors / switches, and can be applicable in the materials sciences as molecular machines.

Asymmetric catalysis is one of the most effective ways to control a target molecule’s stereochemistry. Through the development of a wide variety of chiral transition metal complexes, synthetic chemists are given the tools they need to synthesize the desired enantiomer of numerous compounds. This work focuses on exploiting the non-innocent ligand reactivity of metal bis-dithiolenes with multiple conjugated π systems in order to synthesize chiral ligands. Recent work has shown that platinum bis-dithiolene reacts with dienes stereoselectively to form a racemic mix of C2 -chiral thioether ligands. The present contribution will show approaches to synthesizing chiral dienes and organometallic complexes with potential applications for asymmetric allylic substitution reactions. Dienes with various chiral auxiliaries were reacted with platinum dithiolene and monitored through NMR spectroscopy. Attempts to synthesis palladium bis-dithiolene complexes, not previously seen in the literature were made, and the reaction of α-β unsaturated ketones with metal bis-dithiolenes was explored.

A synthetic approach to produce lysergic acid by virtue of an asymmetric ring opening (ARO) of symmetrical 3,6-disubstituted-7,10-hydroxymethyl bridgehead substituted oxabicycles is described. The use of a Rhodium(I)/JosiPhos(R,S) catalyst system to effect an ARO using an amine nucleophile furnishes an enantiopure tetrahydronapthalene intermediate with the amine conveniently installed at the 6 position as in lysergic acid, with appropriate stereochemistry; further which, two subsequent annulations are necessary to form the fused 3,5-substituted indole and tetrahydropyridine to complete the synthesis. Progress of this work is described herein along with future directions. The second chapter in this thesis describes the modular and stereoselective synthesis of tetrasubstituted helical alkenes via a palladium-catalyzed domino reaction under Catellani conditions. These helical alkenes possess potentially interesting photochemical properties as molecular motors / switches, and can be applicable in the materials sciences as molecular machines.

Asymmetric catalysis is one of the most effective ways to control a target molecule’s stereochemistry. Through the development of a wide variety of chiral transition metal complexes, synthetic chemists are given the tools they need to synthesize the desired enantiomer of numerous compounds. This work focuses on exploiting the non-innocent ligand reactivity of metal bis-dithiolenes with multiple conjugated π systems in order to synthesize chiral ligands. Recent work has shown that platinum bis-dithiolene reacts with dienes stereoselectively to form a racemic mix of C2 -chiral thioether ligands. The present contribution will show approaches to synthesizing chiral dienes and organometallic complexes with potential applications for asymmetric allylic substitution reactions. Dienes with various chiral auxiliaries were reacted with platinum dithiolene and monitored through NMR spectroscopy. Attempts to synthesis palladium bis-dithiolene complexes, not previously seen in the literature were made, and the reaction of α-β unsaturated ketones with metal bis-dithiolenes was explored.