In this thesis, two rather different types of problems were investigated. The first was a case of anomalous reactivity in the area of carbohydrate synthesis. Hexopyranosides having the galacto configuration (i.e. C-4?OR axial) display very low SN2 reactivities towards anionic nucleophiles, whereas the corresponding gluco-configured C-6 sulfonates (C-4?OR equatorial) react at rates typical of primary centers. The accepted explanation for this difference involves the repulsive interaction of local dipoles in the transition structure of the galacto compound. This interaction is thought to destabilize the transition structure, making this reaction difficult. However, there are numerous inconsistencies in the application of this simple model (cases where the model fails to predict the observed behavior). Thus, a computational project was undertaken to examine six model systems of this type. The energetics and equilibria of the reactants were determined, including solvation. Reaction pathways and kinetics for various displacements were computed. Analyses of the calculated charge densities allowed for evaluation of any electrostatic interactions. This study revealed a number of important factors affecting the rates of reaction, while clearly showing that dipole-dipole interactions are very limited in these systems. The second project was in the related areas of molecular polarizability and vibrational spectroscopy. Descriptive models have been sought relating the structure and connectivity of molecules to their electronic properties. Researchers in the areas of non-linear optics and of conducting polymers require a better understanding of the effects of structural variations on electronic properties. The 4 simplest models of molecular polarizability and its derivatives with respect to molecular vibrations are grossly inadequate. The highest-level calculations are generally reliable but are not applicable to even moderately sized systems. Thus trends in these properties were investigated for a large series of molecules. Calculations were performed at a variety of theoretical levels in order to determine the ranges of predicted behavior. Since these calculations predicted unusual properties in bicyclo-[1.1.1]-pentane, an experimental project was completed on this molecule. The results of Raman scattering intensity experiments on bicyclo-[1.1.1]-pentane allowed for evaluation of the performance of various computational methods. More importantly, it allowed for the confirmation of some qualitative structure/property relationships. / October 2004

In this thesis, two rather different types of problems were investigated. The first was a case of anomalous reactivity in the area of carbohydrate synthesis. Hexopyranosides having the galacto configuration (i.e. C-4?OR axial) display very low SN2 reactivities towards anionic nucleophiles, whereas the corresponding gluco-configured C-6 sulfonates (C-4?OR equatorial) react at rates typical of primary centers. The accepted explanation for this difference involves the repulsive interaction of local dipoles in the transition structure of the galacto compound. This interaction is thought to destabilize the transition structure, making this reaction difficult. However, there are numerous inconsistencies in the application of this simple model (cases where the model fails to predict the observed behavior). Thus, a computational project was undertaken to examine six model systems of this type. The energetics and equilibria of the reactants were determined, including solvation. Reaction pathways and kinetics for various displacements were computed. Analyses of the calculated charge densities allowed for evaluation of any electrostatic interactions. This study revealed a number of important factors affecting the rates of reaction, while clearly showing that dipole-dipole interactions are very limited in these systems. The second project was in the related areas of molecular polarizability and vibrational spectroscopy. Descriptive models have been sought relating the structure and connectivity of molecules to their electronic properties. Researchers in the areas of non-linear optics and of conducting polymers require a better understanding of the effects of structural variations on electronic properties. The 4 simplest models of molecular polarizability and its derivatives with respect to molecular vibrations are grossly inadequate. The highest-level calculations are generally reliable but are not applicable to even moderately sized systems. Thus trends in these properties were investigated for a large series of molecules. Calculations were performed at a variety of theoretical levels in order to determine the ranges of predicted behavior. Since these calculations predicted unusual properties in bicyclo-[1.1.1]-pentane, an experimental project was completed on this molecule. The results of Raman scattering intensity experiments on bicyclo-[1.1.1]-pentane allowed for evaluation of the performance of various computational methods. More importantly, it allowed for the confirmation of some qualitative structure/property relationships.

In this thesis, two rather different types of problems were investigated. The first was a case of anomalous reactivity in the area of carbohydrate synthesis. Hexopyranosides having the galacto configuration (i.e. C-4?OR axial) display very low SN2 reactivities towards anionic nucleophiles, whereas the corresponding gluco-configured C-6 sulfonates (C-4?OR equatorial) react at rates typical of primary centers. The accepted explanation for this difference involves the repulsive interaction of local dipoles in the transition structure of the galacto compound. This interaction is thought to destabilize the transition structure, making this reaction difficult. However, there are numerous inconsistencies in the application of this simple model (cases where the model fails to predict the observed behavior). Thus, a computational project was undertaken to examine six model systems of this type. The energetics and equilibria of the reactants were determined, including solvation. Reaction pathways and kinetics for various displacements were computed. Analyses of the calculated charge densities allowed for evaluation of any electrostatic interactions. This study revealed a number of important factors affecting the rates of reaction, while clearly showing that dipole-dipole interactions are very limited in these systems. The second project was in the related areas of molecular polarizability and vibrational spectroscopy. Descriptive models have been sought relating the structure and connectivity of molecules to their electronic properties. Researchers in the areas of non-linear optics and of conducting polymers require a better understanding of the effects of structural variations on electronic properties. The 4 simplest models of molecular polarizability and its derivatives with respect to molecular vibrations are grossly inadequate. The highest-level calculations are generally reliable but are not applicable to even moderately sized systems. Thus trends in these properties were investigated for a large series of molecules. Calculations were performed at a variety of theoretical levels in order to determine the ranges of predicted behavior. Since these calculations predicted unusual properties in bicyclo-[1.1.1]-pentane, an experimental project was completed on this molecule. The results of Raman scattering intensity experiments on bicyclo-[1.1.1]-pentane allowed for evaluation of the performance of various computational methods. More importantly, it allowed for the confirmation of some qualitative structure/property relationships.

Targeted covalent inhibitors (TCIs) are irreversible enzyme inhibitors that are designed to first bind to a targeted enzyme’s active site reversibly using non-covalent interactions between the molecular scaffold of the inhibitor and the surrounding amino acid residues of the enzyme’s binding site. They then form a covalent bond between the inhibitor’s electrophilic warhead and a nucleophilic amino acid residue located inside of the binding pocket. Cysteine (Cys), a redox-sensitive thiol, is found in many enzyme active sites and is used as the target for many current TCIs in clinical application. Electrophilic warheads such as acrylamides and chloroacetamides are known to readily undergo thiol-addition, and although they are commonly used in the development of enzyme inhibitors, few previous studies have explored the mechanism of thiol-addition and the intrinsic reactivities of these moieties. In this work, a robust kinetic assay was developed to perform mechanistic studies of thiol-addition to the electrophilic warhead derivatives N-phenylacrylamide (NPA), N-acryloylpiperidine (AcrPip), and N-phenylchloroacetamide (NPC). By reacting these warhead derivatives with thiol nucleophiles having various pKa values, we were able to construct Brønsted-type plots, resulting in shallow positive βNucRS- values for NPA, AcrPip and NPC (βNucRS- = 0.07 ± 0.04, 0.11 ± 0.03, and 0.21 ± 0.07, respectively), meaning that these electrophiles are relatively insensitive to thiolate nucleophilicity. However, while the trend in their reactivity across thiolate nucleophilicity is similar, their intrinsic reactivity was found to be vastly different. In conjunction with the Brønsted-type plot, temperature, ionic strength, and kinetic isotope effects were studied to afford information about the rate-limiting transition state and elucidate the mechanism of thiol-addition. NPA and AcrPip were found to undergo very similar thiol-additions, consistent with the microscopic reverse of the E1cbrev elimination, whereas NPC follows an SN2 type addition, consistent with the intuitive mechanism of addition to a haloacetamide.

Les transformations photochimiques sont des outils puissants pour créer de la diversité moléculaires à partir de substrats facilement accessibles; elles requièrent le réactif le plus simple : un photon. Les réactions de cycloaddition [2+2] photochimiques de composés carbonylés ou carboxylés α,β-insaturés avec des oléfines sont les réactions photochimiques les plus largement utilisées en synthèse organique. Les photoadduits cyclobutaniques sont très appliqués en synthèse multi-étapes de produits naturels ou dérivés et sont également prisés comme intermédiaires de synthèse du fait de la grande réactivité intrinsèque liée à leur tension de cycle. Dans la première partie de cette thèse, nous nous sommes intéressés à une approche photochimique pour la synthèse de β-acides aminés cyclobutaniques substitués. Notre objectif était de mettre en place une synthèse robuste et efficace sur l’échelle du gramme des acides cis- et trans-2-aminocyclobutane-1-carboxyliques (cis- et trans-ACBC) diversement substitués en position 3 ou 4. La construction du cycle à quatre chaînons a été réalisée via une réaction de cycloaddition [2+2] photochimique entre le tert-butoxyéthène et le maléimide ou l’anhydride maléique. Les fonctions amine et acide carboxylique ont ensuite été générées par des processus consécutifs ou “one-pot” impliquant un réarrangement de Hofmann. Les mélanges racémiques des 3- et 4-cis-syn-hydroxy-ACBCs ont été dédoublés via l’utilisation d’une oxazolidinone chirale, donnant accès aux β-acides aminés énantiopures ciblés sur grande échelle, sous la forme déprotégée ou protégée orthogonalement. Le contrôle d’une procédure d’épimérisation cis-trans a permis l’accès aux composés trans-syn-3-hydroxy-ACBC à partir des substrats cis-syn-3-hydroxy-ACBC. Enfin, les composés ACBCs diversement substitués en position 3 et de configuration cis-anti ou trans-anti ont pu être préparés grâce à une réaction de Mitsunobu ou d’autres transformations de type SN2, à partir des réactifs cis-syn- ou trans-syn-3-hydroxy-ACBC correspondants. Dans la seconde partie de cette thèse, nous avons étudié des processus photochimiques tandem et cascade initiés par une réaction de cycloaddition [2+2] photochimique. En collaboration avec un chercheur post-doctorant, nous avons réalisé la synthèse contrôlée d’une librairie d’acétals cyclobuténiques et d’oxétanes polycycliques, via des photoréactions tandem et cascade entre des cyclopent-2-énones et des partenaires alcènes. Le processus tandem résulte d’une réaction de cycloaddition [2+2] photochimique suivie d’une fragmentation de type Norrish I et d’un transfert d’hydrogène en position γ, conduisant aux aldéhydes cyclobuténiques protégés in situ sous la forme de dérivés acétals stables. La triple cascade réactionnelle a permis l’accès à de nouveaux oxétanes tricycliques angulaires par le biais d’une réaction de Paternò-Büchi intramoléculaire à partir des aldéhydes cyclobuténiques précédemment cités. La généralisation de ces deux processus domino a été étudiée à partir d’un panel de cyclopent-2-énones et de trois partenaires alcènes représentatifs. La formation de certains des composés obtenus a pu être expliqué par à une réaction supplémentaire de type SN’. Une étude préliminaire de cette transformation non-attendue a été réalisée. / Photochemical transformations are powerful tools for the creation of molecular diversity from simple and readily available starting materials; they employ the simplest of reagents, a photon. Photochemical [2+2] cycloaddition reactions of α,β-unsaturated carbonyl or carboxyl compounds with olefins are one of the most widely applied photochemical reactions in organic synthesis. The cyclobutane photoadducts have been used ubiquitously in multi-step syntheses of a wide array of natural products or related derivatives, and they have also been used as intermediates in other synthetic procedures which exploit their strained molecular skeletons and their resulting intrinsic chemical reactivity.In the first part of this thesis, we focused on a photochemical approach for the synthesis of ring-substituted cyclobutane β-amino acids. Our objective was to establish a robust, large-scale and efficient synthesis of cis- and trans-2-aminocyclobutane-1-carboxylic acids (cis- and trans-ACBC) diversely substituted at the 3- or 4-positions. The cyclobutane ring was constructed using a photochemical [2+2] cycloaddition reaction between tert-butyl vinyl ether and either maleimide or maleic anhydride. The amine and carboxylic acid functions were subsequently installed through consecutive or one-pot protocols including a Hofmann rearrangement. The protected racemates of 3- and 4-cis-syn-hydroxy-ACBCs obtained in this way were resolved using a chiral oxazolidinone auxiliary to provide a large scale access to enantiomerically pure samples of the target β-amino acids in either free or orthogonally protected form. A controlled cis-to-trans epimerization procedure from cis-syn-3-hydroxy-ACBC substrates permitted facile access to target trans-syn-3-hydroxy-ACBCs. Finally, diversely substituted 3-ACBCs with cis-anti or trans-anti relative configurations were synthesized using Mitsunobu or other SN2-type reactions, starting from corresponding cis-syn- or trans-syn-3-hydroxy-ACBC derivatives.In the second part of the thesis, we investigated photochemical tandem and cascade processes which began with a photochemical [2+2] cycloaddition reaction. In collaboration with a post-doctoral researcher, we reacted cyclopent-2-enones and alkenes to afford libraries of cyclobutene acetals and polycyclic oxetanes, in a controlled manner, via tandem and triple cascade photoreactions. The tandem process consisted of a photochemical [2+2] cycloaddition followed by Norrish I/γ-H transfer which led to cyclobutene aldehydes; these reactive photoadducts were trapped in situ as stable acetal derivatives. The triple cascade process provided access to unprecedented angular tricyclic oxetanes via an intramolecular Paternò-Büchi reaction of the above-mentioned cyclobutane aldehydes. The scope of these two domino processes was investigated using panels of 2- and 4-substituted cyclopent-2-enones and three representative alkene partners. The formation of some of the compounds obtained during this study was attributed to an additional SN’ reaction. Preliminary investigations on this unexpected transformation were performed.

En la presente memoria se aborda el estudio de la reactividad de dianiones de hidrocarburos aromáticos policíclicos (HAPs). En el capítulo I se llevó a cabo una síntesis eficaz del fluorometilciclopropano y posterior estudio como sonda de radicales. Se estudió el mecanismo de reacción a través del cual tiene lugar la alquilación de dianiones de HAP (bifenilo y naftaleno) con fluoruros de alquilo primarios, con el fin de elucidar si este mecanismo transcurre vía TE, o si existe competencia con la sustitución nucleófila bimolecular SN2. En el capítulo II se ha conseguido establecer una ruta eficaz para la síntesis asimétrica del 2,7,10,15-tetra-terc-butiltetrafenileno, obteniendo ambos enantiómeros con excelentes excesos enantioméricos. Se ha llevado a cabo un estudio cinético para el cálculo de la energía de racemización del 2,7,10,15-tetra-terc-butiltetrafenileno.

Plusieurs analogues de nucléosides thérapeutiques (Ara-C, Clofarabine), utilisés pour le traitement de leucémies, présentent un arrangement 1’,2’-cis entre la nucléobase reliée au centre anomère et le substituant (électroattracteur) en C-2’. Récemment, notre laboratoire a développé une approche synthétique pour former sélectivement des analogues de nucléosides et de thionucléosides 1’,2’-trans et 1’,2’-cis à partir de précurseurs acycliques. Ce mémoire présente une nouvelle méthodologie pour accéder efficacement aux analogues de nucléosides 1’,2’-cis à partir de furanosides. Différents groupements en position anomérique ont été examinés, sous conditions cinétiques en utilisant le bromure de diméthylbore pour générer sélectivement des produits acycliques ou cycliques. Les intermédiaires cinétiques de différents furanosides de méthyle formés en présence de Me2BBr ont été piégés in situ par un thiol pour générer des thioacétals acycliques avec de bonnes voire d’excellentes diastéréosélectivités. Les produits générés sont en accord avec une rétention globale de l’information stéréochimique du centre acétal et deux déplacements SN2 consécutifs ont été suggérés pour rationaliser ces résultats. Toutefois, l’objectif de synthétiser des analogues de nucléosides à partir de furanosides de méthyle a échoué. Tel que démontré par le Dr Michel Prévost, l’activation par Me2BBr des lactols des quatres différents furanosides suivie d’une addition in situ d’une base silylée a permis de former diastéréosélectivement les analogues de nucléosides 1’,2’-cis correspondants avec d’excellents rendements. Nous avons démontré que d’autres substrats peuvent être employés et que l’induction stéréochimique est sous contrôle du substituant électroattracteur en C-2. D’autres acides de Lewis, tel que TMSBr, peuvent également être utilisés. Cette méthodologie a également été étendue à d’autres nucléophiles tels que des Grignards ou des éthers d’énols silylés, conduisant à de bonnes sélectivités. / Many therapeutically relevant nucleoside analogs (Ara-C, Clofarabine) for the treatment of leukemia have a 1’,2’-cis arrangement between the nucleobase attached at the anomeric center and the non-hydrogen substituent at C-2’. Recently, our laboratory has developed a versatile approach to the synthesis of 1’,2’-trans and 1’,2’-cis nucleoside and thionucleoside analogues from acyclic scaffolds. This work will present a new methodology to access efficiently 1’,2’-cis nucleoside analogues from cyclic furanoside. Activation of various anomeric groups by Me2BBr was investigated, and under kinetic control acyclic substrates or cyclic ones could be generated selectively. Trapping the kinetic product of methyl furanoside formed in presence of Me2BBr by thiol in the presence of base led to the formation of acyclic thioacetal in good to excellent diastereoselectivity. The results obtained are in accordance with total retention of the stereochemical information of the acetal moiety and thus suggested that the mechanism of these two reactions is two successive SN2 displacements. The objective of synthesizing nucleoside analogs from methyl furanoside was unsuccessful. As shown recently by Dr Michel Prévost, activation of all four furanoside lactol scaffolds by Me2BBr with an in situ addition of silylated nucleobase afforded 1’,2’-cis pyrimidine nucleoside analogues in very good yields and with diastereoselectivities greater or equal to 20:1. Expending this methodology to other scaffolds provided evidence of stereoelectronic control of the C-2 electron-withdrawing substituent. Other Lewis acids such as TMSBr can be used. This methodology was also applied to other nucleophiles such as allyl Grignard and silylated enols ethers, which were successfully alkylated in good yield and 1,2-cis diastereoselectivity.

Le présent mémoire a pour sujet le développement d’une méthode rapide et efficace vers la production d’allènes hautement substitués à partir de dérivés cyclopropaniques électrophiles énantioenrichis. L’avancement de méthodes synthétiques intéressantes pour la production asymétrique de ces dérivés de cyclopropane-1,1-diesters sera également présenté. Dans un premier temps, les différentes méthodes de synthèses des cyclopropanes activés seront abordées, ainsi que leur utilisation dans la préparation de molécules plus complexes. Par la suite, les techniques précédentes de préparation asymétrique des allènes seront introduites, démontrant ainsi la difficulté de leur accessibilité. Le développement d’une méthode fiable pour la synthèse de cyclopropane-1,1-diesters utilisant les ylures d’iodonium sera présenté. Finalement, l’accessibilité à plusieurs types d’allènes hautement substitués par l’utilisation de cuprates sera détaillée. Dans une seconde partie, il sera davantage question de l’accessibilité des cyclopropane-1,1-diesters énantioenrichis. Ces derniers sont d’un intérêt particulier, car ils constituent le point de départ de notre méthodologie précédente. Le développement d’une méthode pouvant être utilisée à grande échelle et à faible coût a donc été explorée. Les deux derniers chapitres présenteront donc les tentatives de générer ces cyclopropanes activés par résolution cinétique ou encore par l’hydrogénation asymétrique des cyclopropènes correspondants. / The subject of this present M.Sc. thesis is the developpement of an efficient and fast methodology toward the production of highly substituted allenes using enantioenriched cyclopropanes derivatives. The development of new synthetic methodologies in the production of these enantioenriched cyclopropan-1,1-diesters will be presented. First, the various methodologies for the preparation of activated cyclopropanes will be discussed along with their uses in the synthesis of more complex molecules. Then, the precedents in the field of asymmetric allenes synthesis will be introduced. The developpement of a viable method for the synthesis of cyclopropane-1,1-diesters using iodonium ylides will be presented. Finally, the accessibility of different highly substituted allenes by the used of cuprates will be detailed. In a second part, we will elaborate on the accessibility of the enantioenriched cyclopropane-1,1-diesters derivatives. These compounds are interesting, because they are used as starting materials in the previous methodology of allenes synthesis. This methodology has to be usable in large scale and at small cost. The last two chapters of this thesis will present the alternatives strategies for the preparation of these activated cyclopropanes by either kinetic resolution or the asymmetric hydrogenation of cyclopropenes.

Plusieurs analogues de nucléosides thérapeutiques (Ara-C, Clofarabine), utilisés pour le traitement de leucémies, présentent un arrangement 1’,2’-cis entre la nucléobase reliée au centre anomère et le substituant (électroattracteur) en C-2’. Récemment, notre laboratoire a développé une approche synthétique pour former sélectivement des analogues de nucléosides et de thionucléosides 1’,2’-trans et 1’,2’-cis à partir de précurseurs acycliques. Ce mémoire présente une nouvelle méthodologie pour accéder efficacement aux analogues de nucléosides 1’,2’-cis à partir de furanosides. Différents groupements en position anomérique ont été examinés, sous conditions cinétiques en utilisant le bromure de diméthylbore pour générer sélectivement des produits acycliques ou cycliques. Les intermédiaires cinétiques de différents furanosides de méthyle formés en présence de Me2BBr ont été piégés in situ par un thiol pour générer des thioacétals acycliques avec de bonnes voire d’excellentes diastéréosélectivités. Les produits générés sont en accord avec une rétention globale de l’information stéréochimique du centre acétal et deux déplacements SN2 consécutifs ont été suggérés pour rationaliser ces résultats. Toutefois, l’objectif de synthétiser des analogues de nucléosides à partir de furanosides de méthyle a échoué. Tel que démontré par le Dr Michel Prévost, l’activation par Me2BBr des lactols des quatres différents furanosides suivie d’une addition in situ d’une base silylée a permis de former diastéréosélectivement les analogues de nucléosides 1’,2’-cis correspondants avec d’excellents rendements. Nous avons démontré que d’autres substrats peuvent être employés et que l’induction stéréochimique est sous contrôle du substituant électroattracteur en C-2. D’autres acides de Lewis, tel que TMSBr, peuvent également être utilisés. Cette méthodologie a également été étendue à d’autres nucléophiles tels que des Grignards ou des éthers d’énols silylés, conduisant à de bonnes sélectivités. / Many therapeutically relevant nucleoside analogs (Ara-C, Clofarabine) for the treatment of leukemia have a 1’,2’-cis arrangement between the nucleobase attached at the anomeric center and the non-hydrogen substituent at C-2’. Recently, our laboratory has developed a versatile approach to the synthesis of 1’,2’-trans and 1’,2’-cis nucleoside and thionucleoside analogues from acyclic scaffolds. This work will present a new methodology to access efficiently 1’,2’-cis nucleoside analogues from cyclic furanoside. Activation of various anomeric groups by Me2BBr was investigated, and under kinetic control acyclic substrates or cyclic ones could be generated selectively. Trapping the kinetic product of methyl furanoside formed in presence of Me2BBr by thiol in the presence of base led to the formation of acyclic thioacetal in good to excellent diastereoselectivity. The results obtained are in accordance with total retention of the stereochemical information of the acetal moiety and thus suggested that the mechanism of these two reactions is two successive SN2 displacements. The objective of synthesizing nucleoside analogs from methyl furanoside was unsuccessful. As shown recently by Dr Michel Prévost, activation of all four furanoside lactol scaffolds by Me2BBr with an in situ addition of silylated nucleobase afforded 1’,2’-cis pyrimidine nucleoside analogues in very good yields and with diastereoselectivities greater or equal to 20:1. Expending this methodology to other scaffolds provided evidence of stereoelectronic control of the C-2 electron-withdrawing substituent. Other Lewis acids such as TMSBr can be used. This methodology was also applied to other nucleophiles such as allyl Grignard and silylated enols ethers, which were successfully alkylated in good yield and 1,2-cis diastereoselectivity.

Le présent mémoire a pour sujet le développement d’une méthode rapide et efficace vers la production d’allènes hautement substitués à partir de dérivés cyclopropaniques électrophiles énantioenrichis. L’avancement de méthodes synthétiques intéressantes pour la production asymétrique de ces dérivés de cyclopropane-1,1-diesters sera également présenté. Dans un premier temps, les différentes méthodes de synthèses des cyclopropanes activés seront abordées, ainsi que leur utilisation dans la préparation de molécules plus complexes. Par la suite, les techniques précédentes de préparation asymétrique des allènes seront introduites, démontrant ainsi la difficulté de leur accessibilité. Le développement d’une méthode fiable pour la synthèse de cyclopropane-1,1-diesters utilisant les ylures d’iodonium sera présenté. Finalement, l’accessibilité à plusieurs types d’allènes hautement substitués par l’utilisation de cuprates sera détaillée. Dans une seconde partie, il sera davantage question de l’accessibilité des cyclopropane-1,1-diesters énantioenrichis. Ces derniers sont d’un intérêt particulier, car ils constituent le point de départ de notre méthodologie précédente. Le développement d’une méthode pouvant être utilisée à grande échelle et à faible coût a donc été explorée. Les deux derniers chapitres présenteront donc les tentatives de générer ces cyclopropanes activés par résolution cinétique ou encore par l’hydrogénation asymétrique des cyclopropènes correspondants. / The subject of this present M.Sc. thesis is the developpement of an efficient and fast methodology toward the production of highly substituted allenes using enantioenriched cyclopropanes derivatives. The development of new synthetic methodologies in the production of these enantioenriched cyclopropan-1,1-diesters will be presented. First, the various methodologies for the preparation of activated cyclopropanes will be discussed along with their uses in the synthesis of more complex molecules. Then, the precedents in the field of asymmetric allenes synthesis will be introduced. The developpement of a viable method for the synthesis of cyclopropane-1,1-diesters using iodonium ylides will be presented. Finally, the accessibility of different highly substituted allenes by the used of cuprates will be detailed. In a second part, we will elaborate on the accessibility of the enantioenriched cyclopropane-1,1-diesters derivatives. These compounds are interesting, because they are used as starting materials in the previous methodology of allenes synthesis. This methodology has to be usable in large scale and at small cost. The last two chapters of this thesis will present the alternatives strategies for the preparation of these activated cyclopropanes by either kinetic resolution or the asymmetric hydrogenation of cyclopropenes.