Ce travail de thèse porte sur la synthèse de nouveaux composés chiraux à partir de l’isosorbide et de l’isomannide en vue de leurs applications en catalyse asymétrique. Dans une première partie, de nouvelles monophosphines ont été synthétisées et appliquées en tant que ligands dans la réaction d'hydrogénation asymétrique d’oléfines. Des excès énantiomériques jusqu’à 96% ont été observés. Elles ont également été employées en tant que catalyseurs organiques dans les réactions de cyclisation [3 +2]. De bonnes activités catalytiques et des excès énantiomériques modestes sont obtenus. Dans une deuxième partie, une série de composés azotés chiraux a été synthétisée en 3 à 4 étapes avec de bons rendements globaux. Ils ont été testés en tant que ligands dans la réaction de réduction de cétones aromatiques par transfert d’hydrogène. Des excès énantiomériques jusqu’à 73% ont été obtenus. La réaction d’addition de phénylacétylène sur d’imines a également été étudiée. Les complexes formés se sont montrés actifs mais pas très énantiosélectifs. Ces composés azotés ont également été utilisés en tant que catalyseurs organiques dans la réaction d’addition de Michael de cétones aromatiques sur le nitrostyrène. Toutefois, ils n’ont permis de conduire qu’à de faibles énantiosélectivités. Dans une dernière partie, des composés de type thiourée ont été synthétisés en 5 étapes. Ces thiourées ont été appliquées en catalyse organique dans la réaction d’alkylation de type Friedel-Crafts entre différents substrats indoliques et nitrooléfines, et dans la réaction d’addition conjuguée des hydroxylamines sur des pyrazoles pour la synthèse de dérivés β-aminoacides. Ces catalyseurs se sont révélés actifs mais peu énantiosélectifs. / The Thesis deals with the synthesis of new chiral compounds derived from isosorbide and isomannide and their applications to asymmetric catalysis. The first part of this work consisted in perfecting the chemical and enantioselective hydrogenation conditions of olefins using chiral monophosphines as ligands (up to 96% ee). These phosphines were also used as organocatalysts for [3+2] cyclisation reactions showing good catalytic activity and moderate enantioselectivity. The second part turned to the synthesis of a series of chiral nitrogen compounds which were evaluated in the asymmetric transfer hydrogenation of aromatic ketones giving good enantioselectivity (up to 73% ee). The complexes formed with amine ligands were also applied to the addition reaction of phenylacetylene to imines. Good catalytic activity but low enantioselectivity were observed. These nitrogen compounds were also used as organocatalysts in the Michael addition reaction of aromatic ketones to the nitrostyrene. Again, low enantiomeric excess was obtained. The last part of this work consisted in preparing new chiral thiourea compounds which were applied as organocatalysts to the Friedel-Crafts alkylation reaction of different indoles with nitroolefines, and to the conjugate addition reaction of hydroxylamines to pyrazoles derivatives for the synthesis of β-amino acids. In two cases, these catalysts have proved active but not enantioselective.

Les Tirosina Cinases (TKs) són un grup de Proteïna Cinases claus en la senyalització cel·lular. Aquestes Cinases estan implicades, entre d'altres, en processos de creixement tumoral, fet que fa que la recerca d'inhibidors de TKs sigui una àrea d'investigació molt important en química mèdica.En aquest context es desenvolupa el present treball en el qual es pretenen sintetitzar inhibidors potencials de Tirosina Cinases amb estructura 4-hidrogenpirido[2,3-d]pirimidínica. Molècules amb aquesta estructura han presentat elevada activitat com inhibidors de TKs pel que en primer lloc s'aborda la síntesis de la 6-(2,6-diclorofenil)-2-(4-(2-(dietilamino)etoxi)fenilamino)-8-metil-5,6-dihidropirido[2,3-d]pirimidin-7(8H)-ona. Aquest compost és anàleg a una de les estructures piridopirimidíniques que ha presentat millors resultats d'activitat inhibidora de TKs. D'altra banda, es desenvolupa un nou procediment per a l'obtenció de sistemes 5,6 dihidropirido[2,3-d]pirimidínics 4-hidrogen substituïts basat en una addició de Michael inusual. S'utilitza com metilè actiu el 3,3-dimetoxipropionitril, no utilitzat prèviament en addicions d'aquest tipus. L'esmenta't nitril, per addició sobre un acrilat de metil 2-aril substituït rendeix èsters 4-cianopentanoics o 4-cianopentenoics en funció de la temperatura de reacció. La posterior reacció d'aquests adductes de Michael amb guanidines desemboca en els sistemes 6 aril-5,6 dihidropirido[2,3-d]pirimidínics 4-hidrogen substituïts desitjats. Aprofitant l'experiència obtinguda amb el 3,3-dimetoxipropionitril es desenvolupa un procediment d'obtenció de pentanodioats substituïts per addició de Michael de 3,3 dimetoxipropionat de metil sobre èsters -insaturats. La posterior reacció d'aquests pentanodioats amb guanidina rendeix 3-(2-amino-1,6-dihidro-6-oxo-pirimidin-5-il)propanoats de metil que poden ser considerats com anàlegs de cadena oberta dels sistemes pirido[2,3-d]pirimídinics. / Las Tirosina Quinasas (TKs) son un grupo de Proteína Quinasas claves en la señalización celular. Dichas quinasas están implicadas, entre otros, en procesos de crecimiento tumoral, por lo que la búsqueda de inhibidores de TKs es un área de investigación muy importante en química médica.En este contexto se desarrolla el presente trabajo en el que se pretenden sintetizar inhibidores potenciales de Tirosina Quinasas con estructura 4-hidrógenopirido[2,3-d]pirimidínica. Moléculas con dicha estructura han presentado elevada actividad como inhibidores de TKs por lo que en primer lugar se aborda la síntesis de la 6-(2,6-diclorofenil)-2-(4-(2-(dietilamino)etoxi)fenilamino)-8-metil-5,6-dihidropirido[2,3-d]pirimidin-7(8H)-ona. Dicho compuesto es análogo a una de las estructuras piridopirimidínicas que ha presentado mejores resultados de actividad inhibidora de TKs.Por otro lado se desarrolla un nuevo procedimiento para la obtención de sistemas 5,6 dihidropirido[2,3-d]pirimidínicos 4-hidrógeno sustituidos basado en una adición de Michael inusual. Se utiliza como metileno activo el 3,3-dimetoxipropionitrilo, no usado previamente en adiciones de este tipo. Dicho nitrilo, por adición sobre un acrilato de metilo 2-aril sustituido rinde ésteres 4-cianopentanoicos o 4-cianopentenoicos en función de la temperatura de reacción. La posterior reacción de estos aductos de Michael con guanidinas desemboca en los sistemas 6 aril-5,6 dihidropirido[2,3-d]pirimidínicos 4-hidrógeno sustituidos deseados.Aprovechando la experiencia obtenida con el 3,3-dimetoxipropionitrilo se desarrolla un procedimiento de obtención de pentanodioatos sustituidos por adición de Michael de 3,3 dimetoxipropionato de metilo sobre ésteres -insaturados. La posterior reacción de dichos pentanodioatos con guanidina rinde 3-(2-amino-1,6-dihidro-6-oxo-pirimidin-5-il)propanoatos de metilo que pueden ser considerados como análogos de cadena abierta de los sistemas pirido[2,3-d]pirimidínicos. / Tyrosine Kinases (TKs) are a group of Protein Kinases key in cell signaling. These kinases are involved in tumor growth processes, so the search for TK inhibitors is a very important research area in medicinal chemistry. Present work is developed in this context, so the aim of the work is to synthesize potential inhibitors of TKs with a 4-unsubstituted pyrido[2,3-d]pyrimidinic structure. Molecules with this structure have presented high activity as TKs inhibitors. Therefore the synthesis of 6-(2,6-dichlorophenyl)-2-(4-(2-(diethylamino)ethoxy)phenylamino)-8-methyl-5,6-dihydropyrido[2,3-d] pyrimidin-7(8H)-one is addressed. This is an analogous compound to a one of the most active pyridopyrimidine systems described as TK inhibitors. On the other hand, a new procedure for obtaining 4-unsubstituted 5,6 dihydropyrido[2,3-d]pyrimidinic systems is described. Such process is based on an unusual addition in which 3,3 dimethoxypropanenitrile is used as an active methylene compound. This compound had not previously been used in this kind of additions. The reaction of this nitrile with methyl 2-arylacrylates yields 4-cyanopentanoic esters or 4-cyanopentenoic esters depending on the reaction temperature. The subsequent reaction of these Michael adducts with guanidines leads to desired 4-unsubstituted 6-aryl-5,6-dihydropyrido[2,3-d]pyrimidine systems. Using the experience obtained with 3,3-dimethoxypropionitrile a procedure for obtaining new substituted alkyl pentanedioates by Michael addition of methyl 3,3 dimethoxypropionate on -unsaturated esters has been developed. The subsequent reaction with guanidine yields methyl 3-(2-amino-1,6-dihydro-6-oxo-pyrimidin-5-yl)propanoates that can be considered as open-chain analogues of pyrido[2,3-d]pyrimidines.

Block copolymers can self-assemble into a variety of periodic nanostructures and therefore, are promising candidates for a diverse range of applications. While self-assembly of block copolymers has been widely studied and exploited, graft copolymers have remained far less explored in this context. One of the primary reasons for this is that the most commonly used methods to prepare graft copolymers leads to polymers that do not have precisely defined structures; specifically, controlling the precise location of the grafted segments is a synthetically difficult challenge. In typical chain polymerization processes, statistically random incorporation of monomers takes place and consequently, the periodicity of the grafted segment along the backbone is very difficult to control precisely; therefore, such methods cannot be utilized to prepare periodically grafted copolymers. Some recent efforts towards the preparation of sequence regulated copolymers using controlled radical polymerization in conjunction with periodic dosing of a commoner could provide an alternative to better regulate the periodicity, although this will also not be perfectly periodic. The only approach to control the periodicity perfectly is to utilize condensation polymerization approaches, wherein one of the monomers serve as a spacer whereas the other provides the opportunity to install the graft segment, as depicted in Scheme 1. One of the earliest examples of the utilization of a condensation approach to locate desired units at periodic intervals was reported by Wagener and co-workers using Acrylic Diene Metathesis (ADMET) process.1 ]n periodicity ]n graft segment Scheme 1. Synthetic scheme for the preparation of periodically grafted copolymers using condensation polymerization. From our lab, Roy et al. developed periodically grafted amphiphilic copolymers (PGAC), based on a readily available starting material, diethyl malonate;2 melt trans-esterification between diethyl malonate, containing a pendant hexaethylene glycol monomethyl ether (HEG) segment and 1,22-docosane diol resulted in PGAC wherein the hydrophilic oligo ethylene glycol units were placed on every 27th atom along the backbone (Scheme 2). Such PGAC underwent self-segregation and adopted a folded zigzag conformation, which was driven by the intrinsic immiscibility of the alkylene and HEG segments and was reinforced by the strong tendency for long chain alkylene segments to crystallize in a paraffinic lattice. However, one of the drawbacks of the above approach was that the hydrophilic pendant unit was installed at the monomer stage and consequently, the synthetic approach does not allow easy variation of the hydrophilic grafted segment; this limits the flexibility and any structural variation of the pendant segment would be synthetically tedious. 150 oC DBTDL 5 20 DBTDL = Dibutyltin dilaurate Scheme 2. Synthesis of PGAC, based on diethyl malonate, and immiscibility-driven folding of such PGACs. Mandal et al. developed a more general strategy for the synthesis of such periodically grafted systems; they prepared periodically clickable polyesters carrying propargyl groups at regular intervals, by the solution polycondensation of 2-propargyl-1,3-propanediol or 2,2-dipropargyl-1,3-propanediol and the acid chloride of 1,20-eicosanedioic acid. Such periodically clickable polyesters were shown to react quantitatively with a fluoroalkyl azide3 and PEG 350 azide4, thus allowing them to place different kinds of functionalities precisely along the backbone, as shown in Scheme 3. The immiscibility of the alkylene and fluoroalkyl/PEG segments caused the polymer chains to fold in a zigzag fashion, thereby facilitating the segregation of these segments, as observed earlier in the study by Roy et al.2 The objective of this study was to place various desired functionalities along the polymer backbone and examine their effect on the self-assembly behaviour and morphology of such periodically clicked systems. Scheme 3. Synthetic scheme for the generation of periodically clickable polyesters and their subsequent functionalization via Cu-catalysed click chemistry. In Chapter 2, we describe an alternative general strategy for the scalable synthesis of periodically graftable polyesters and their subsequent functionalization to generate a wide variety of periodically grafted systems. The importance of our approach lies in our choice of the monomer, which is based on itaconic acid, an inexpensive and bio-sourced molecule. We demonstrated that dibutyl itaconate can be melt-condensed with aliphatic diols to generate unsaturated polyesters (Scheme 4); importantly, we showed that the double bonds in the itaconate moiety remain unaffected during the melt polymerization. A particularly useful attribute of these polyesters is that the exo-chain double bonds are conjugated to the ester carbonyl and therefore, can serve as excellent Michael acceptors. A variety of organic thiols, such as alkane thiols, MPEG thiol, thioglycerol, derivative cysteine etc., were shown to quantitatively Michael-add to the exo-chain double bonds and generate interesting functionalized polyesters; similarly, organic amines, such as N-methylbenzylamine, diallyl amine and proline also underwent Michael addition across the double bond (Scheme 4). Thus, such poly(alkylene itaconate)s could be utilized to place diverse functionalities at regular intervals along the polymer backbone. Scheme 4. Preparation of periodically graftable polyesters, based on itaconic acid, and their subsequent modification by Michael addition. In Chapter 3, we examined a series of periodically grafted polyesters carrying long crystallizable alkylene (C-20) segments along the backbone and pendant polyethylene glycol monomethyl ether (MPEG) segments grafted at periodic intervals. Such periodically grafted amphiphilic copolymers (PGAC) having MPEG graft segments of varying lengths were prepared by utilizing the activated exo-chain double bonds in poly(icosyl itaconate) (PII) that carries a 20-carbon alkylene segment; MPEG thiols of varying lengths (TREG, 350, 550 and 750) were quantitatively grafted under standard Michael addition conditions to yield the required graft copolymers, as shown in Scheme 5. Scheme 5. Synthesis of a series of periodically grafted amphiphilic copolymers (PGAC) utilizing post-polymerization modification via Michael addition with MPEG thiols of varying lengths. The immiscibility of the backbone alkylene and pendant MPEG segments, and the strong propensity of the alkylene segments to crystallize in a paraffinic lattice, drive these systems to fold in a zigzag fashion and subsequently organize into a lamellar morphology, as shown in Scheme 6. Interestingly, all the graft copolymers exhibited a clear and invariant melting transition at ~44°C that suggested the crystallization of the backbone C-20 segment; the MPEG segments were, however, amorphous except in the case of polymers carrying MPEG 550/MPEG-750 segments, wherein a second melting transition corresponding to the independent crystallization of the PEG segment was also seen. SAXS studies indicated that all of the samples exhibited lamellar morphologies wherein more importantly, the inter-lamellar spacing was seen to increase linearly with the MPEG length (Scheme 6). This study provides a new design for controlling the dimensions of the microphase-separated nanostructures at significantly smaller length scales (sub-10 nm) than is typically possible using block copolymers. Scheme 6. Schematic representation of formation of lamellar morphology in PGACs and control of interlamellar spacing in such systems. In order to understand the influence of having a mixture of MPEG lengths on the self-assembled morphology, in Chapter 4 we prepared a series of PGACs by co-grafting the parent poly(icosyl itaconate) with a mixture of two different MPEG thiols, namely MPEG-350 and MPEG-750; the mole-ratios of these two PEGs were varied to generate co-grafted PGACs, carrying different amounts of the two MPEG segments randomly distributed along the chain (Scheme 7). Parallely, we also examined the behaviour of physical mixtures of two different PGACs, one bearing MPEG-350 and the other MPEG-750 grafts; keeping the total MPEG content constant, we sought to examine the differences in the behaviour of randomly co-grafted polymers and physical mixtures. Scheme 7. Preparation of co-grafted PGACs and physical mixtures of two different PGACs. The co-grafted PGACs also exhibited a lamellar morphology; interestingly, the inter- lamellar spacing increased linearly with the total volume of PEG domain. This suggested that despite the presence of MPEG segments of two different lengths in the co-grafted samples, there occurred a reorganization of the PEG chains within the amorphous domain ensuring that the condition of incompressibility is not violated, thereby giving rise to a weighted average interlamellar spacing, as shown in Scheme 8. In contrast, the SAXS patterns of the physical mixtures revealed the presence of two distinct lamellar domains in the sample; this indicated that the two homo-grafted samples do not mix and form separate lamellar domains. The self- segregation induced folding and subsequent crystallization of the central alkylene segments clearly appeared to dominate the final morphology. Scheme 8. Schematic depiction of the possible scenarios that could arise when MPEG segments of two different lengths, namely MPEG350 and MPEG750, are present in the PGACs; top panel depicts the co-grafted PGACs, whereas the bottom panel shows the case of mixtures of PGACs with two different MPEG lengths. In Chapter 5, we have dealt with the design and synthesis of chain-end functionalizable polyalkylene itaconates. Changing the monomer from dibutyl itaconate to dipropargyl itaconate and using it in controlled excess allowed us to generate chain-end functionalizable polymers containing propargyl groups at the chain ends, in addition to the exo-chain double bonds along the backbone, thereby providing the opportunity for orthogonal functionalization. In order to obtain three different telechelic polymers with target DPs (degree of polymerization) of 5, 10 and 20 respectively, 3 different mole ratios of the two monomers (dipropargyl itaconate and 1,20-eicosanediol) were used (Scheme 9). Scheme 9. Synthetic scheme for the generation of chain-end functionalizable polyalkylene itaconates. Orthogonal functionalization of the resultant polymers was carried out using thiol-Michael addition and Cu(I)-catalysed alkyne-azide cycloaddition (AAC), without interference between the functional handles present along the polymer backbone and the chain-end, respectively. Michael addition with triethylene glycol thiol and subsequent Cu-catalysed click reaction with MPEG 750 azide led to the generation of ABA type triblock copolymers where the middle block is a periodically grafted amphiphilic block and the two linear end blocks are hydrophilic in nature. Furthermore, such propargyl-terminated polyalkylene itaconates were used as macromonomers to prepare multiblock copolymers. The telechelic polymers were first treated with PEG 600 diazide, resulting in the formation of alternating multiblock copolymers; these multiblock copolymers were further reacted with thioglycerol to generate amphiphilic multiblock copolymers where one of the blocks is a periodically functionalized amphiphilc block, as depicted in Scheme 10. In both these amphiphilic block copolymer systems, a key feature is that the periodically functionalized amphiphilic block folds into a zigzag form, as evident from the presence of a nearly invariant melting peak corresponding to the crystallization of the alkylene segment. Scheme 10. Preparation of multiblock copolymers utilizing propargyl-terminated polyalkylene itaconates as a macromonomer. In summary, the thesis has demonstrated the design and synthesis of a series of novel amphiphilic copolymers using a bio-sourced monomer, wherein the driving theme is the immiscibility driven self-segregation that leads to the folding of the chain; these have been thoroughly examined using DSC, SAXS, WAXS, variable temperature FT-IR and AFM measurements. References (1) Berda, E. B.; Lande, R. E.; Wagener, K. B. Macromolecules 2007, 40, 8547. (2) Roy, R. K.; Gowd, E. B.; Ramakrishnan, S. Macromolecules 2012, 45, 3063. (3) Mandal, J.; Krishna Prasad, S.; Rao, D. S. S.; Ramakrishnan, S. Journal of the American Chemical Society 2014, 136, 2538. (4) Mandal, J.; Ramakrishnan, S. Langmuir 2015, 31, 6035.

Dans ce travail, de nombreux hétérocycles porteurs d’un groupement CF3 ou C2F5 ont été décrits : des cétals, des benzo[1,3]dixoles, des pyran-2H-ones, des isocoumarines, des benzofuranes et des indolo[2,3-c]pyran-1-ones. Ces hétérocycles représentent une classe importante de produits biologiquement actifs. L’hydroalkoxylation intermoléculaire des dérivés du 4,4,4-perfluorobut-2-ynoate d’éthyle en présence d’une quantité catalytique de sodium métallique dans des conditions simples et douces a permis la synthèse de cétals fluorés d’une manière totalement régiosélective. La méthodologie a été étendue par la suite aux dérivés phénols pour préparer ,dans un premier temps, stériosélectivement des éthers d’énols. Des benzofuranes fluorées ont été synthétisées par la suite par cyclisation de quelques éthers vinyliques dans les conditions de Heck. Dans les mêmes conditions et en utilisant des dérivés du catéchol, nous avons réalisé des synthèses totalement régiosélective des hétérocycles de type : benzo[1,3]dioxoles, benzo[1,3]oxazoles et benzo[1,3]oxothiazoles. l’hydrocarboxylation du 4,4,4-perfluorobut-2-ynoate d’éthyle en utilisant des dérivés de l’acide 2-iodobenzoïque suivi d’une cyclisation intramoléculaire de manière ‟one-potˮ utilisant des sels de cuivres (II) nous a permis d’accéder régiosélectivement aux isocoumarines porteuses d’un groupement fluoroalkyle. Cette réaction a été étendue par la suite à la série hétéroaromatique faisant appel aux dérivés indoliques porteurs d’une fonction acide en positions 2 et d’un atome d’iode en position 3. Cette approche a permis de synthétiser de nouveaux hétérocycles fluorés à savoir des indolo[2,3-c]pyran-1ones. Nous avons exploité aussi une partie de potentiel offert par les structures énynoates synthétisées pour synthétiser des pyran-2H-ones originales porteuses d’un groupement fluoroalkyle par une stratégie d’iodolactonisation. Les réactions du couplage de type Sonogashira ont permis la synthèse d’une diversité d’alpha pyrones. / Fluorinated heterocyclic compounds can be found among potent pharmaceuticals,crop protection agents, and products of technical importance. This mergingarea of organic, heterocyclic, and fluoroorganic chemistry is still rapidly growing andin the past decades a large number of fluorinated heterocyclic materials have been discovered. In this work, an efficient and original method was developed for the synthesis of 3,3-dialkoxy propionate bearing a perfluoroalkyl group in b-position from fluorinated alkyne and alcohols using base-catalyzed double Michael addition reaction. This method provides easy access to a-perfluoro ketals with reasonable to good yields with total regioselectivity. This procedure was extended to the phenol derivatives, and a fluorinated enol ether derivatives were selectively synthesized. The use of catechol and derivative allowed the synthesis of fluorinated heterocycles such as benzo[1,3]dioxoles, benzo[1,3]oxazoles and benzo[1,3]oxothiazoles. Copper-catalyzed annulation of aromatic and heteroaromatic b-iodo-a,b-unsaturated carboxylic acids with fluorinated alkyne 1 was developed. This strategy offers a simple and efficient route for the synthesis of isocoumarins and indolo[2,3-c]pyrane-1-ones. This family of compounds are known to have various biological properties; indolo[2,3-c]pyrane-1-one derivatives exhibit anti-cancer potential towards human cervix adenocarcinoma and antinociceptive and anti-inflammatory activity. Fluorinated pyrane-2H-ones bearing an iodine atom in position 5 have been also described. The a-pyrones constitute an important class of biologically active compounds.