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Carbon-carbon bond formation is one the fundamental reactions in organic synthesis. The quest for the development of new and more efficient processes for the construction of this bond has been an ongoing focus for years. The transformations that permit the use of simple precursors to access complex structural architectures in the absence of stoichiometric quantities by-products are highly desirable. Hydrogen is a cheapest and cleanest reductant available to the mankind. The catalytic hydrogenation has been widely utilized in the industry, however the construction of the carbon-carbon bond under hydrogenative conditions has been achieved only for alkene hydroformylations and Fisher-Tropsh process and limited to the use of carbon monoxide. The extension of the hydrogenative carbon-carbon bond formations beyond aforementioned processes would be of a great significance to the synthetic community. The overview of allene use in the metal catalyzed reactions to achieve carbonyl and imine allylation and vinylation is presented in Chapter 1. The following chapter vii discusses the development of metal catalyzed hydrogenative and transfer hydrogenative coupling of allenes and carbonyl compounds to afford allylation products. These studies have resulted in the development of the first carbonyl allylation from the alcohol oxidation level. Chapter 3 discusses efforts towards achieving highly enantioselective hydrogenative coupling of alkynes to carbonyl compounds. / text

Lors de son développement, une tumeur ne peut survivre sans passer par une étape invasive afin de subvenir à ses besoins en nutriment et en oxygène. Cette étape, appelé angiogénèse tumorale, conduit à la formation de vaisseaux sanguins dits « tumoraux », différents des vaisseaux sanguins normaux. Afin de stopper la croissance de la tumeur, il est possible de détruire les vaisseaux sanguins tumoraux formés pendant l’angiogénèse tumorale grâce à des molécules antivasculaires. Ces molécules vont désorganiser la structure du vaisseau et diminuer le flux sanguin au sein de la tumeur pour mener à la nécrose de cette dernière. Parmi ces molécules antivasculaires,la prodrogue phosphate de la combrétastatine A-4 naturelle (CA-4) est le composé actuellement le plus efficace(en développement clinique de phase III contre le cancer de la thyroïde). L’isocombrétastatine A-4 (isoCA-4),possédant une structure de type 1,1-diaryléthylène, est un analogue très puissant développé au laboratoire. Cette molécule est isomère de la CA-4 et permet d’obtenir les mêmes activités biologiques que la CA-4. L’objectif de cette thèse est d’étudier ce motif 1,1-diaryléthylène dans le cadre de molécules cytotoxiques en synthétisant et en évaluant in vitro plusieurs séries de molécules de type « iso ». L’autre partie de cette thèse est dédiée à la synthèse d’analogues hétérocycliques de l’isoCA-4, qui permettront de réaliser les premières études de relation structure-activité sur l’isoCA-4, où son cycle B a été remplacé par un hétérocycle. Ce travail nous a permis de confirmer que la structure de l’isoCA-4 peut servir de base de travail pour développer d’autres agents antivasculaires. / For a tumor, the angiogenesis is a vital step for its development. The spread of the tumor is necessary characterized by an extension of the surrounding vasculature, in order to provide the nutriments and the oxygen required to the growth of the tumor. Resulting from the angiogenesis, the new tumorous blood vessels formed represent an excellent target to treat cancer by aiming specifically at the heart of the tumor. By means of vascular disrupting agents (VDA), it is possible to cut the tumor off the blood flow to trigger the necrosis within the tumor. Among the current VDA, the natural combretastatin A-4 (CA-4) is a strong compound that exhibits excellent antitumoral activities. An isomer of the CA-4, the isocombretastatin A-4 (isoCA-4), was developed inour laboratory to propose an alternative and a new family of VDA. The isoCA-4 is characterized by a 1,1-diarylethylene core, which we studied in this thesis, through 3 series of molecules related to this new structure inmedicinal chemistry. We also synthesized heterocyclic analogues of the isoCA-4, in order to explore the capacity of the isoCA-4 to serve as a basis for developing new antimitotic compounds.

The synthesis and reactions of hydrotris(pyrazolyl)borate, (TpR,R) supported ytterbium(II) borohydride and lanthanide(III) dialkyl (Ln = Yb, Lu) complexes were investigated. The lanthanide(III) dialkyl complexes were found to undergo both hydrogenolysis reaction and protonolysis reaction with terminal alkynes. Reaction of [(TptBu,Me)YbH]2 (1) with NH3BH3 and (TptBu,Me)YbI(THF) (2) with NaBH4 afforded the corresponding mono-ligand complexes, (TptBu,Me)Yb(BH4) (3) and (TptBu,Me)Yb(BH4)(THF) (4), respectively. Compounds 3 and 4 represent rare examples of lanthanide(II) tetrahydroborate complexes. IR spectroscopy data, in the B-H stretching region are consistent with the 3-BH4 bonding mode found in the solid state of compound 4 and the corresponding deuterium labelled BD4 analogue of 4 shows the expected IR isotope shifts. Mono-ligand lanthanide dialkyl complexes, (TpR,R)Ln(CH2SiMe2R)2(THF)0/1 (5-9) were synthesized from the homoleptic Ln(CH2SiMe2R)3(THF)2 (Ln = Yb, Lu; R = Me, Ph) complexes by two alternative and complementary methods: alkyl abstraction with the thallium salts of the ligands, TlTpR,R and protonolysis using the acid form of the ligands, HTpR,R. Hydrogenolysis of the dialkyl complexes (TpMe2)Ln(CH2SiMe3)2(THF) (7a, Yb; 8a, Lu) afforded the corresponding tetranuclear hydride complexes, [(TpMe2)LnH2]4 (11, Yb; 12, Lu). Similarly, hydrogenolysis of (Tp)Yb(CH2SiMe3)2(THF) (9) afforded the hexanuclear hydride [(Tp)YbH2]6 (13). When treated with a variety of terminal alkynes, the dialkyl complexes, (TpR,Me)Ln(CH2SiMe3)2(THF) (14a, Y; 8a, Lu), gave the corresponding bis-alkynide complexes, (TpR,Me)Ln(CCR)2 (15-27). The structures of the complexes depend on the steric size of both the alkyne substituents and the substituent on position 3 of the pyrazolyl ring. Except for the bulkiest substituents, the compounds are dimeric with two asymmetric 2-alkynide bridging groups and a coupled alkynide unit bridging the two lanthanide centers via an unusual enyne bonding motif. The synthesis of Lu(CH2Ph-4-R)3(THF)3 (R = H, 28a; R = Me, 28b) was achieved by salt metathesis reactions between KCH2Ph-4-R and LuCl3. Variable temperature NMR studies in THF shows that the formation of these complexes is accompanied by a small amount of the anionic ate K[Lu(CH2PH-4-R)4(THF)n] (30) complexes, which can be prepared independently by reaction of pure Lu(CH2Ph-4-R)3(THF)3 with one equiv. of KCH2Ph-4-R. One of the coordinated THF of 28a could be removed by trituration with toluene to give Lu(CH2Ph-4-R)3(THF)2 (29a). Protonolysis reaction with HTpR,R afforded the corresponding dibenzyl complexes, (TpR,R)Ln(CH2Ph-4-R)2(THF)n (31-33). X-ray crystal structures of complex 4, the dialkyl complexes 5b, 6b, 7 and 8; dihydride complexes 11, 12 and 13; bis-alkynide complexes 15, 16, 17, 21, 22 and 24 as well as the tribenzyl compounds 28a and 29a and dibenzyl complexes 31-33 were determined. The solution behaviour, solid state structures and structural diversity of these complexes are discussed.

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This thesis describes synthetic studies directed towards the total synthesis of the nakafuran and florlide marine natural products. Chapter One provides an overview of the importance of natural products to current medicinal chemistry and describes how the "supply issue" associated with these biologically derived compounds can be resolved through the process of total synthesis. Two families of marine natural products, the nakafurans and the florlides, are introduced as synthetic targets and strategies utilising a type II intramolecular Diels-Alder (IMDA) reaction to achieve their total synthesis are delineated. The efficient preparation of regio- and stereodefined vinyl coupling fragments via hydrostannylation and hydrohalogenation methodology is described in Chapter Two. The palladium-catalysed cross-coupling of these fragments, via Stille or Negishi coupling methodology, yielded dienes which were successfully advanced to IMDA triene precursors. Chapter Three describes investigation of the type II IMDA reaction to give bicyclo[4.3.1]decene carbocyclic skeletons. A facile acid-catalysed 6,7-alkene to 7,8-alkene olefinic isomerisation, via a proposed oxonium intermediate, and the inability to appropriately functionalise the desired adducts impeded progress along the synthetic route. Molecular modelling was conducted to investigate the causes of this unexpected reactivity. Investigations in Chapter Four describe the successful synthesis and cyclisation of homomethyl triene analogues prepared via application of enyne metathesis chemistry. The use of an exo-cyclopropylcarbinyl fragmentation was found to be unsuccessful as a means of installing the desired 6-methyl-bicyclo[4.3.1]decan-2-one core with a competing endo-ring expansion giving rise to a bicyclo[4.4.1]undecane ring system. Chapter 5 summarises the above results and gives a brief discussion of the future potential of this research to provide for a total synthesis of the nakafuran and florlide natural products.

This thesis deals with the development of transition metal-catalyzed silaborations of 1,3-dienes and 1,6-enynes. The first part of the thesis describes the development of the enantioselective 1,4-silaboration of 1,3-cyclohexadiene. A number of chiral metal-ligand complexes were evaluated. Up to 82% enantiomeric excess was obtained using a catalyst system derived from Pt(acac)2 and a phosphoramidite ligand. The product formed was employed in allylborations of aldehydes, giving homo-allylic alcohols in good yields with good to moderate diastereoselectivity. In attempts to widen the scope of silaborations to include acyclic, terminally substituted 1,3-dienes, products from H-B exchange with, and H-Si addition to, the dienes were obtained. The second part describes the development of silaborative carbocyclization of 1,6-enynes. A Pd N-heterocylic carbene complex was found to be effective for the silaborative carbocyclization of unsubstituted enynes, giving the products in good to excellent yields. Employing terminally substituted enynes resulted in low or no yields. The last part describes investigations into the reaction mechanisms of the processes developed in the first part. It was found that the silylborane undergoes oxidative addition to a Pt(0) complex generated from Pt(acac)2 and DIBALH. After insertion of 1,3-cyclohexadiene into the Pt-B bond a π-allyl complex was observed experimentally. In the addition of silylborane to acyclic, terminally substituted, 1,3-dienes it was shown by deuterium labeling experiments that one diene loses a hydride via H-B exchange and that this hydride is then added to another diene via H-Si addition. A reaction mechanism was proposed for this process. / QC 20100924

This thesis describes synthetic studies directed towards the total synthesis of the nakafuran and florlide marine natural products. Chapter One provides an overview of the importance of natural products to current medicinal chemistry and describes how the "supply issue" associated with these biologically derived compounds can be resolved through the process of total synthesis. Two families of marine natural products, the nakafurans and the florlides, are introduced as synthetic targets and strategies utilising a type II intramolecular Diels-Alder (IMDA) reaction to achieve their total synthesis are delineated. The efficient preparation of regio- and stereodefined vinyl coupling fragments via hydrostannylation and hydrohalogenation methodology is described in Chapter Two. The palladium-catalysed cross-coupling of these fragments, via Stille or Negishi coupling methodology, yielded dienes which were successfully advanced to IMDA triene precursors. Chapter Three describes investigation of the type II IMDA reaction to give bicyclo[4.3.1]decene carbocyclic skeletons. A facile acid-catalysed 6,7-alkene to 7,8-alkene olefinic isomerisation, via a proposed oxonium intermediate, and the inability to appropriately functionalise the desired adducts impeded progress along the synthetic route. Molecular modelling was conducted to investigate the causes of this unexpected reactivity. Investigations in Chapter Four describe the successful synthesis and cyclisation of homomethyl triene analogues prepared via application of enyne metathesis chemistry. The use of an exo-cyclopropylcarbinyl fragmentation was found to be unsuccessful as a means of installing the desired 6-methyl-bicyclo[4.3.1]decan-2-one core with a competing endo-ring expansion giving rise to a bicyclo[4.4.1]undecane ring system. Chapter 5 summarises the above results and gives a brief discussion of the future potential of this research to provide for a total synthesis of the nakafuran and florlide natural products.

La synthèse asymétrique d’aza-hétérocycles (tétrahydro-isoquinoléines et naphtodiazépines) a été réalisée grâce à la mise en œuvre d’un processus faisant intervenir des réactions radicalaires et polaires en cascade à partir des ènediynes portant un centre stéréogène. Ce processus implique successivement : la formation d’un ényne-allène (via une migration-1,3 de proton, une réaction d’un alcyne terminal avec un carbénoïde de cuivre, ou encore une réaction d’homologation de Crabbé)/ la cyclisation de Saito-Myers/ le transfert-1,5 d’un atome d’hydrogène/ la recombinaison du biradical résultant. Les deux dernières étapes élémentaires de ce réarrangement étaient idéalement adaptées à l’application d’une stratégie basée sur le phénomène de mémoire de chiralité. Des études mécanistiques basées sur des expériences de marquage isotopique et des calculs théoriques ont permis de mieux comprendre les paramètres qui contrôlent la régio- et la stéréosélectivité de la réaction. L’ambition de contrôler par cette voie, via une double mémoire de chiralité, deux centres stéréogènes nous a conduits à étudier le transfert de la chiralité axiale d’un motif allénique judicieusement substitué. Cette étude a permis de découvrir une cycloisomérisation originale catalysée par le cuivre (I) conduisant à des fulvènes chiraux via un double transfert de chiralité (centrique-axial-centrique). / The asymmetric synthesis of azaheterocycles (tetrahydorisoquinolines and naphthodiazepines) was successfully achieved via the polar/radical cross-over rearrangement of enediynes bearing a stereogenic center. This process involves successively : enyne-allene formation (via 1,3-proton shift, reaction of a terminal alkyne group with carbenoids or Crabbé homologation)/Saito-Myers cyclization/1,5-hydrogen atom transfer/biradical recombination. It was ideally suited to apply a strategy based on the memory of chirality phenomenon. Mechanistic studies based on isotopic labelling and theoretical calculations enabled to go deeper into the understanding of the parameters controlling the regio- and the stereoselectivity of the reaction. The ambition to control two stereogenic centers via double memory of chirality, led us to investigate the transfer of the axial chirality of a designed allenic moiety. This study led to the discovery of an original copper (I)-mediated cycloisomerization leading to chiral fulvenes and proceeding via central-to-axial-to-central double chirality transfer.

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