Les travaux rapportés dans ce mémoire concernent le développement de la réactivité de N-tosylhydrazones dans la création de liaisons carbone-carbone et carbone-azote ainsi que leurs applications à la synthèse des analogues de l’isocombrétastatine A-4 (isoCA-4), aux propriétés antivasculaires.Au cours de ce travail, des molécules de type 1,1-diaryléthylène furent synthétisées par un couplage pallado-catalysé entre des N-tosylhydrazones et des aryles halogénés. Ainsi, des oléfines polysubstituées avec un motif alcoxyle, analogues de l’isoCA-4, ont présenté des activités biologiques intéressantes. De même, les N-tosylhydrazones constituent des intermédiaires pour la synthèse de 1,5-énynes aromatiques. La cyclisation de ces derniers a pu être contrôlée selon la nature du catalyseur utilisé. En effet, en présence de l’or comme catalyseur, une cyclisation 6-endo-dig majoritaire est obtenue alors qu’en présence du palladium, une cyclisation 5-exo-dig exclusive est observée. Cette méthode permettrait de synthétiser des analogues contraints de l’isoCA-4. Le couplage réducteur, catalysé au cuivre, entre des N-tosylhydrazones et des amines et conduisant à des motifs arylalkylamines fut développé. Enfin, un processus cascade entre des 2’-halogéno-biaryl- N-tosylhydrazones et des amines fournit des dérivés du fluorène par la création d’une liaison CN et d’une liaison CC sur le même atome carbénique. / This manuscript reports the development of new metal-catalyzed reactions using N-tosylhydrazones as coupling partners for the creation of carbon-carbon and carbon-nitrogen bonds. These reactions are applied in the synthesis of analogues of isocombretastatine A-4 (isoCA-4), a vascular disrupting agent.First, a palladium-catalyzed cross-coupling reaction between N-tosylhydrazones and aryl halides was developed. By this means, polysubstituted olefins with an alkoxy motif were synthesized and presented good biological activities. Then, aromatic 1,5-enynes were synthesized by a multi-step approach using N-tosylhydrazones as intermediates. The regioselectivity of the cyclisation of these enynes was controlled depending on the reaction conditions. Under gold catalysis, a major 6-endo-dig cyclisation pattern leads to naphthalene derivatives while under palladium catalysis; an exclusive 5-exo-dig cyclisation furnishes benzofulvène derivatives. Conformationnally restricted isoCA-4 analogues could be synthesized by applying this method. A copper-catalyzed reductive coupling between N-tosylhydrazones and amines leading to -branched amine derivatives was also developed. Finally, a cascade reaction between 2’-halo-biaryl-N-tosylhydrazones and amines furnished fluoren scaffold by the formation of CC and CN bonds on the same carbenic atom.

Dans le cadre de cette thèse nous nous intéressons à la découverte de nouveaux ligands originaux de la tubuline ayant une activité inhibitrice de sa polymérisation. Pour ce faire, une étude rationnelle in silico est effectuée afin d’obtenir des molécules actives in vitro sur cette protéine. Lors de cette première année de thèse nous avons mis en place en collaboration avec l’équipe de modélisation de BioCIS – CNRS (Dr. G. Bernadat et Pr. T. Ha-Duong) un criblage virtuel sur une chimiothèque de plus de 3 millions de structures chimiques présentes dans la base de données ZINC en fonction de descripteurs structuraux. Ce criblage nous a permis de faire ressortir une trentaine de molécules potentiellement actives. Nous avons déjà synthétisé un quart de ces molécules qui sont actuellement en cours d’évaluation biologique en collaboration avec l’équipe de Biochimie et Chimie structurale des substances naturelles (Dr. J. Bignon et Dr. J. Dubois) de L’Institut de Chimie et des Substances Naturelles. Pour cette année, nous allons continuer la synthèse des molécules issues de ce criblage afin de pouvoir évaluer leurs activités sur la tubuline. En fonction des résultats biologiques, nous pourrons également effectuer des pharmacomodulations afin d’améliorer l’activité d’éventuelles touches. / As part of this work we are interested in discovering new ligands original tubulin inhibitory activity having its polymerization. To do this, rational in silico study is performed to obtain the active molecules in vitro that protein. During this first year of thesis we have developed in collaboration with the modeling team BioCIS - CNRS (Dr. G. Bernadat and Prof. T. Duong Ha.) A virtual screening a chemical library of more than 3 million chemical structures in the ZINC database according to structural descriptors. This screening allowed us to bring out thirty of potentially active molecules. We have already synthesized a quarter of these molecules that are currently being biological evaluation in collaboration with the team of Biochemistry and Structural chemistry of natural substances (Dr. J. Bignon and Dr. J. Dubois) of The Institute Chemistry and Natural Products. For this year, we will continue the synthesis of molecules from this screening in order to assess their activities on tubulin. Depending on the laboratory results, we can also perform pharmacomodulations to improve any potential ligands.

Ce document de thèse est divisé en deux parties indépendantes, la première partie décrit la synthèse et l'évaluation biologique de nouveaux analogues du composé anti-vasculaire, l'isocombretastatine A-4. Ce travail se situe à l'interface entre la chimie et la biologie.Des réactions séquentielles monotopes mettant en œuvre des réactions de couplage pallado-catalysées entre des N-tosylhydrazones et divers bromure de nitro-aryles et bromure de nitro-biaryles suivies d'une cyclisation réductrice ont conduit à la synthèse d’une chimiothèque d'indoles C2-, C3-, N-aryles et des carbazoles de vinyle avec une variété de substrats. De plus, cette méthodologie a permis d'explorer un nouveau mécanisme de synthèse inattendue d’indoles.L'étude biologique de ces nouvelles séries a montré que huit molécules sont dotées d’activités antiprolifératives intéressantes de l'ordre du nanomolaire contre les cellules humaines de cancer du côlon. Deux molécules ont présenté des activités très prometteuses, ayant des IC50 similaires à celle de l'isoCA-4.Par conséquent, cette partie a contribué à développer de nouvelles approches permettant l’accès rapide et simple à des molécules hautement fonctionnalisées, dont certaines possèdent une activité biologique prometteuse.Par ailleurs, la deuxième partie est liée à la synthèse de nouveaux analogues de thiazole et de benzothiazole de MIM-1 (molécule d'inhibition de Mcl-1) grâce à une série de réactions connues. Plusieurs analogues de benzothiazole ont été obtenus en une seule ou deux étapes, et les composés thiazole ont été obtenus en cinq étapes. La modification des structures des deux séries d'analogues est en cours, afin d’évaluer leur activité antitumorale, but principal de cette partie. / This thesis document is divided into two unrelated parts, the first part reported the synthesis and the biological evaluation of new analogs of the anti-vascular compound, isocombretastatin A-4. This work lies at the chemistry-biology interface.One-pot sequential reactions implementing palladium-catalyzed cross-coupling between N-tosylhydrazones and various nitro-aryl bromides and nitro-biaryl bromides followed by reductive cyclization led to the synthesis of a broad library of C2-, C3-, N-aryl indoles and vinyl carbazoles with vast substrate scope. Moreover, this methodology allowed to explore a new mechanism for the synthesis of indoles through unexpected pathways.Interestingly, the biological evaluation of these new series had identified eight molecules with antiproliferative activities in the nanomolar range against human colon carcinoma, with two molecules showing very promising results by having IC50 similar to that of isoCA-4.Hence, this part contributed to develop new processes for an easy access of highly substituted compounds which could possess promising biological activity.On the other hand, the second part is related to the synthesis of original thiazole and benzothiazole analogs of MIM-1 (Mcl-1 inhibition molecule) through a series of known reactions. Several benzothiazole analogs were obtained in one or two steps, and the thiazole compounds were obtained in five steps. More structural modifications of the two series of analogs is ongoing to achieve the innate goal of this part, which is to evaluate their antitumor activity.

Allenes are very important chemical reagents in organic synthesis. Due to their high reactivity, they have been extensively used to carry out a variety of unique and effective chemical transformations including but not limited to ionic and free radical additions and transition metal catalyzed cyclizations. As the chemistry of this group of compounds is explored further and their applications expanded there is a need to develop alternative and cost effective methods for their synthesis. Our approach involves the synthesis of allenes from oxa-bicyclo-alkan-2-ones by methyllithium induced Eschenmoser fragmentation of the bicyclotosylhydrazone derivatives.

Chapter 1: Metal carbenoids in organic synthesis The chapter describes the phenomena of metal carbenoid insertion reactions in two parts: Part A, and Part B. The study of N-tosylhydrazones as diazo precursor was commenced by Jose Barluenga in 2007,1 which demonstrated an in-situ generation of diazo species and trapping of that with low valent palladium catalyst (Scheme 1). Later, this palladium-carbenoid assumption was supported by few reports. Some of these discoveries were by D. F. Taber in 1986 followed by van Vranken in 1999 & 2001.2 These studies of palladium carbenes were supplemented by several groups in subsequent years. The consequent developments with N-tosylhydrazones as diazo source were very fruitful and produced exceptional chemical transformations in recent years. Though the precursor is also vastly customary for other metals such as Cu, Ni, Rh and Co, the primary focus has been given to Pd catalysis due to its wide utility and applicability. 1) Barluenga, J.; Moriel, P.; Valdes, C.; Aznar, F. Angew. Chem., Int. Ed. 2007, 46, 5587. 2) (a) Taber, D. F.; Amedio, J. C., Jr.; Sherrill, R. G. J. Org. Chem. 1986, 51, 3382. (b) Hoye, T. R.; Dinsmore, C. J.; Johnson, D. S.; Korkowski, P. F. J. Org. Chem. 1990, 55, 4518. (c) Greenman, K. L.; Carter, D. S.; Van Vranken, D. L Tetrahedron 2001, 57, 5219. 3) Palladium catalysed coupling of tosylhydrazones with aryl and heteroaryl halides in the absence of external ligands: synthesis of substituted olefins, Ojha, D. P.; Prabhu, K. R. J. Org. Chem., 2013, 78, 12136. Modes of reactivity of a metal-carbene Scheme 1 Cascade carbene migratory insertion process Part A: Ligand-free coupling of tosylhydrazones with aryl & heteroaryl halides In this part, Palladium catalysed cross-coupling reaction of hydrazones with aryl halides in absence of an external ligand is reported. The versatility of this coupling reaction has been demonstrated by showcasing the selectivity of coupling reaction in presence of hydroxyl and amine functional groups. This method allows synthesizing a variety of heterocyclic compounds, which are otherwise difficult to access from traditional methods. Application of the present methodology is validated in tandem reaction of ketones to the corresponding substituted olefins in a single pot experiment. Few examples are illustrated below in Scheme 2.3 Scheme 2: Scope of aryl halide coupling with tosylhydrazones Part B: Pd-catalysed Synthesis of Highly Branched Dienes The regioselective formation of highly branched dienes is a challenging task. Design and exploration of alternative working models to achieve such a regioselectivity to accomplish highly branched dienes is considered to be a historical advancement of Heck reaction to construct branched dienes. On the basis of the utility of carbene transfer reactions, in the reaction of hydrazones with Pd(II) under oxidative conditions, we envisioned obtaining a Pd-bis-carbene complex with α-hydrogens, which can lead to branched dienes. Herein, we report a novel Pd catalyzed selective coupling reaction of hydrazones in presence of tert-BuOLi and benzoquinone oxidant to form corresponding branched dienes (Scheme 3).4 The utility of the Pd catalyst for cross-coupling reactions for synthesizing branched conjugated dienes are rare. The reaction is very versatile and compatible with a variety of functional groups and is useful in synthesizing heterocyclic molecules. We anticipate that this Pd-catalyzed cross-coupling reaction will open new avenues for synthesizing useful compounds. 4) Pd-catalyzed cross-coupling reactions of hydrazones: regioselective synthesis of highly branched dienes, Ojha, D. P.; Prabhu, K. R. J. Org. Chem., 2012, 77, 11027. 5) Furrow, M. E.; Myers, A. G. J. Am. Chem. Soc. 2004, 126, 5436. 6) Taber, D. F.; Guo, P.; Guo, N. J. Am. Chem. Soc. 2010, 132, 11179. Scheme 3: diene synthesis via bis-carbene insertion process Chapter 2: Tosylhydrazones: Role in modern day organic synthesis In recent days, hydrazone based reactions are focused on the donor-acceptor ability of the hydrazones or the in-situ generated diazo species (Scheme 4). This commenced with the Myers’s report in 2004,5 which simplifies the Barton vinyl halide preparation with a remarkable revision on synthesis of alkyl-silyl-hydrazones and its applications. Improved methods of using tosylhydrazones were demonstrated by Aggarwal in successive years. Cycloadditions were implemented by Douglass F. Taber. 6 This study was enriched in a quite fascinating way by several groups such as Jose Barluenga, with many reductive coupling reactions and 1, 3-dipolar reactions. Thomson, in a very interesting report shows the traceless petasis reaction with hydrazones and also worked in many other prospects such as three component reactions and the acid catalysed [3+3] sigmatropic reactions of hydrazones. 7 Wang has also impressed with very attractive transformations in the past decade. 8 7) Thomson, R. J. et al. Nat. Chem. 2009, 1, 494. 8) Xiao, Q.; Zhang, Y.; Wang, J. Acc. Chem. Res. 2012, 46, 236. 9) Regioselective Synthesis of vinyl halides, vinyl sulfones, and alkynes: A tandem intermolecular nucleophilic and electrophilic vinylation of tosylhydrazones, Ojha, D. P.; Prabhu, K. R. Org. Lett. 2015, 17, 18. Scheme 4: Trapping diazo species in intermolecular fashion Part A: Synthesis of vinyl halides Trapping diazo species in an intermolecular fashion by attack of two independent ions (a cation followed by an anion) in tandem at the carbene center is unprecedented. As part of our efforts on the utility of tosylhydrazones, herein we report a novel approach of using ambiphilic diazo species to perform a tandem attack of a nucleophile followed by an electrophile in an intermolecular fashion for synthesizing various types of vinyl halides. A few representative examples are shown in Scheme 5.9 Scheme5: Synthesis if vinyl halides Part B: Synthesis of vinyl sulfones Vinyl sulfones are potential synthetic targets due to their presence in biologically and pharmaceutically important molecules ranging from small natural metabolites to proteins, and have found widespread applications in biological research as covalent protease inhibitors. Vinyl sulfones represent one of the important sulfur containing functional groups in organic chemistry, which are generally synthesized through elimination reactions, oxidation of vinyl sulfides or witting reactions using multistep sequence. Following this technique, we were able to synthesize a variety of vinyl sulfones with rich mechanistic features in a single step. A few such examples are documented in Scheme 6.9 Scheme 6: synthesis of vinyl sulfones Part C: Synthesis of alkynes The functional group conversion to achieve alkyne frameworks are generally a difficult transformation. There are very few limited and tedious processes are available in literature, mainly containing multi-step procedures. Additionally these reactions are require harsh conditions. Considering all these factors, there is a need for developing methods to synthesize alkynes from common functional groups under mild reactions conditions. In a similar way, to introduce different halogens at the same carbon, we expected the eliminations of the leaving groups in tandem formed alkynes. After extensive screening studies, it was pleasing to find that the reaction of tosylhydrazones with NCS−BTEAC, NBS−TBAB, or NIS−TBAI combination in presence of K2CO3 in dioxane as solvent at 110 °C can furnish corresponding acetylene derivatives in good yields. Few examples are shown in Scheme 7.9 Scheme 7: Trapping diazo species in intermolecular fashion Chapter 3: Pd catalysed hydroboration This chapter shows a hydroboration study of terminal alkynes in a highly regioselective manner (Scheme 8). Organoboron derivatives have become essential intermediates in organic and medicinal chemistry. Pioneering contributions are made by Brown and Akira Suzuki, who both instigated the development of new synthetic tools for the introduction of boron atoms onto organic molecules. 10 10) (a) Barbeyron, R.; Benedetti, E.; Cossy, J.; Vasseur, J.-J.; Arseniyadis, S.; Smietana, M. Tetrahedron 2014, 70, 8431. (b) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. 11) Pd-Catalysed regioselective borylation of alkynes: A ligand controlled synthesis of α- and β vinyl boronates (manuscript submitted). Scheme 8: possibility of site selectivity in hydroboration Part A: Pd-catalysed regioselective borylation of alkynes: A ligand controlled synthesis of α and β – vinyl boronates The metal catalyzed borylations of alkynes proceeds in a two-step process. Initially M-Bpin species undergo an addition onto the alkynes to generate organometallic species followed by quenching of the organometallic species with electrophiles. The addition M-Bpin species is regioselective governed by the steric and electronics factors of both metal complex as well as alkyne substituents. In this direction, a palladium catalysed α-selective borylation was achieved for terminal alkynes. A broad range of substrates were successfully borylated under optimized reaction conditions with very high selectivity. Interestingly, the selectivity was reversed to terminal site by using a NHC ligand. A few examples are shown in Scheme 9.11 Scheme 9: α & β-vinyl boronates Chapter 4: Pd/borane unit: Behavior towards isomerization vs reduction of alkenes This study presents a unique behaviour of palladium-boronate unit responsible for olefin chain walking and olefin reduction reactions (Scheme 10). The catalytic system stands efficient against both functionalized and unfunctionalized olefin isomerization as well as reductions. This study has been presented in two parts. Scheme 10: isomerization vs reduction Part A: Pd/ boronates or borane unit as efficient catalytic systems for olefin chain walk This study presents the behaviour of palladium-boronate unit responsible for olefin chain walking. The catalytic system is efficient for both functionalized and unfunctionalized olefin isomerizations (Scheme 11). Cycloisomerization of transient conjugated alkenes to synthesize heterocycles are prominent applications of this technique. The system describes a concept of olefin activation by coordination with Pd-borane complex, this complex assists in a facile [1,3]-hydride shift. This technique allows us to facilitate an isomerization in functionalized as well as unfunctionalized olefinic systems. Considering the substrates scope, the catalytic cycle tolerates various sensitive functional groups and shows good selectivity. In the following Scheme 11 few examples are depicted.12 12) Palladium/boron catalytic unit for olefin chain-walk (manuscript under preparation). Scheme 11: chain-walking of olefins. Part B: Palladium catalysed boronate promoted alkene reduction in water In this work, water has been employed as a source of hydrogen. The reduction of alkenes was achieved using Pd catalyst in presence of bis(pinacolato)diboron and H2O. In this aspect, the utility of water as hydrogen equivalent is the pertinent as well as beneficial with many advantages. Few representative examples are shown in Scheme 12.13 13) Pd-Catalysed homogeneous hydrogenation of olefins by using water as hydrogen source (manuscript under preparation). Scheme 12: synthesis of alkenes reduced products.