No description available.

The first part of this dissertation is devoted to the study of an asymmetric [3+2] cycloaddition sequence developed in our laboratory. The cycloaddition sequence used a sulfonamide-based homoenolate equivalent which was cyclocondensed with a cyclic enone. The stereochemistry of the final product was fixed during the first step, the Michael addition to the enone. Our study focused thus on the Michael addition of sulfonamides to enones. We have synthesized a series of chiral and achiral sulfonamides. We then studied the regiochemistry and the stereochemistry of the addition of the anions derived from these sulfonamides to cyclohexenone. The presence of a heteroatom at the (gamma)-carbon of the sulfonamide was crucial for the regiochemical outcome of the reaction. The substituent on the sulfonamide also influenced the facial selectivity of the reaction with chiral sulfonamides, but had no influence on the diastereoselectivity with achiral sulfonamides. The sequence had been applied to various cyclenones. We were also able to apply the method to an acyclic enone with good enantioselectivities. However the method could not be applied to other Michael acceptors. Another part of the present work was devoted to search a new catalytic asymmetric cyclopentannulation sequence. Two different approaches were studied. Phase-transfer catalysis seemed the most appropriate strategy for our objective. We soon realized that sulfur-stabilized nucleophiles could not be used under these conditions. Ketals derived from 3-nitropropanal were thus chosen as potential annulation agents. The racemic version was quite efficient and could be applied to less active acceptors such as unsaturated lactams and lactones. Unfortunately we were not able to realize the reaction with good enantioselectivities. However two new catalysts, obtained by the reaction of cinchonine with 1- and 2-methylnaphthyl chloride, emerged as interesting candidates for the phase-transfer reactions. Organocatalysis was our second approach. The use of rubidium prolinate or the use of proline in the presence of a base proved to be very efficient and the Michael adducts could be obtained with good enantioselectivities. The Michael adducts were easily cyclized and the nitro group could be removed under mild conditions.

Hydrometalation of α,β-unsaturated carbonyl compounds provides access to reactive metal enolates, which can then be trapped by a suitable electrophile. The coppercatalysed reductive aldol reaction involves hydrometalation of an α,β-unsaturated carbonyl compound, followed by an inter- or intramolecular aldol reaction. While there have been numerous examples of copper-catalysed reductive aldol reactions reported in the literature, the corresponding reductive Michael reaction has been relatively understudied. Herein, the copper-catalysed reductive Michael cyclisation of substrates containing two α,β-unsaturated carbonyl moieties is described. A range of structurally and electronically diverse substrates were prepared by various different methods. Both α,β-unsaturated ketones and esters underwent cyclisation, in the presence of a copper catalyst, a bisphosphine ligand, and a stoichiometric reductant, to afford 5- and 6- membered carbocyclic and heterocyclic products, with good-to-excellent levels of diastereo- and enantiocontrol. Furthermore, the diastereochemical outcome of these reactions is dependent on the specific reaction conditions used.

Norzoanthamine is a complex heptacyclic marine alkaloid isolated from colonial zoanthids. It potently inhibits loss of bone weight and strength in a postmenopausal osteoporosis mouse model, but its mode-of-action remains unknown. The scarcity of this natural product from its natural source and the need to access analogs for structure-activity relationship (SAR) study make it necessary to chemically synthesize this compound. However, the complex molecular skeleton, especially the highly functionalized and stereochemically complex ABC core structure of the natural product poses a significant challenge. As part of our efforts to develop a practical synthetic route to norzoanthamine, we systematically explored a transannular Michael reaction cascade in the context of the synthesis of angular 6-6-6 tricyclic ring system, a mimic of the ABC core structure of norzoanthamine. Using 1,7-bis-enones in the form of 14-membered macrocyclic lactone as model substrates, we demonstrated that both E,Z- and E,E-macrocycles underwent facile transannular reactions to give cis-syn-cis and trans-anti-trans ring systems, respectively. However, Z,E- and Z,Z- macrocycles did not cyclize under similar reactions. The similarities and differences between transannular Diels-Alder reactions and this transannular cyclization process were also disclosed. Building upon these preliminary studies, we developed a 12-linear step synthesis of the ABC carbocyclic core of norzoanthamine. It features an organocatalytic asymmetric intramolecular aldolization to set the stereochemistry of the entire molecule, a fragment coupling based on selective alkylation of a bis-enolate, and a transannular Michael reaction cascade for rapid and stereoselective synthesis of the polycyclic core. Subsequent Claisen rearrangement enabled installation of a handle for introduction of the bottom piece to complete the total synthesis. Other efforts toward the total synthesis have also been discussed.

The indole alkaloids, a class of natural products, have received much synthetic attention for years due to their diverse structures and interesting biological properties. We are particularly interested in synthesizing some of the yohimbine alkaloids extracted from the bark of a tall evergreen African tree (Corynanthe yohimbe, commonly known as fringe tree). Yohimbine and its stereoisomers have been tempting targets for synthetic organic chemists for more than fifty years. These compounds feature a pentacyclic ring system with two heteroatoms and five stereogenic centers. Broadly, the fifteen different synthetic approaches that led to the successful completion of yohimbine alkaloids relied only on two basic synthetic strategies. In the first strategy, the last step almost always was the formation of the C(2)-C(3) bond by either Pictet-Spengler reaction or by Bischler-Napieralski reaction with the concomitant formation of the C ring. The second strategy involved the annulation of the D and E rings onto the intact ABC ring system. With our double annulation methodology, herein, we report a completely different synthetic approach to access the yohimbine alkaloids, and our disconnections are not even remotely close to the synthetic designs used in the past. Our key steps include double Michael reaction to construct the E ring, an intramolecular cyclization to construct the D ring, and finally, the functionality on the D ring can be elaborated to form the C ring of the yohimbine alkaloids.

Les fluoroalcènes sont employés pour préparer des mimes de peptides. Malgré de nombreuses études réalisées dans ce domaine, la préparation d'analogues de peptides comportant une proline modifiée en position C-terminale a été très peu explorée. Ce travail de thèse est consacré à la synthèse de pyrrolidine comportant un motif fluorovinylique. La préparation de sulfones fluorées comportant un cycle pyrrolidine a été réalisée, par réaction d'aza-Michael intramoléculaire. Ce réactif permet la formation de pyrrolines par réaction de Julia modifiée, là où la réaction de Horner-Wadworth-Emmons échoue. Cette étude a été étendue à la préparation de pipéridines fluorées. Cette méthode a été appliquée avec succès à la préparation de précurseurs de peptides Pro-Ψ[CF=CH]-Xaa, peu étudiés dans la littérature. / Fluoroalkenes are used to prepare peptide mimics. In spite of numerous studies carried out in this field, the preparation of peptide analogs comprising a modified proline in the C-terminal position has been very little explored. This thesis is devoted to the synthesis of pyrrolidine with a fluorovinyl unit. The preparation of fluorinated sulfones containing a pyrrolidine ring was carried out by reaction of intramolecular aza-Michael. This reagent allows the formation of pyrrolines by modified Julia reaction, where the Horner-Wadworth-Emmons reaction fails. This study was extended to the preparation of fluorinated piperidines. This method has been successfully applied to the preparation of pro-Ψ peptide precursors [CF = CH] -Xaa, which are poorly studied in the literature.

No / A new and convenient method for the acid-catalysed Michael addition reactions of alcohols, thiols and amines to methyl vinyl ketone has been developed using the ionic liquid ethyltri-n-butylphosphonium tosylate. The reaction conditions are mild and obviate the need for toxic and expensive Lewis acid catalysts, offering advantages over more commonly used systems.

No description available.

Organofluorine compounds constitute a large part of all the drugs, crop protection agents and advanced materials produced nowadays. Therefore, there is a great interest in developing the new methods of synthesis of organofluorine compounds. In this thesis we report a novel method of synthesis of monofluorinated cyclopropanes based on the Michael-initiating ring closure (MIRC) reaction. Our method allows obtaining polysubstituted monofluorinated cyclopropanes from ethyl dibromofluoroacetate and various Michael acceptors. We have also implemented the asymetric version of cyclopropanation using a novel oxazolodinone-derived chiral fluorinated reagent. In the final part of this thesis we report the synthesis of a fluorinated analog of L-FAP4, a potent agonist of group II metabotropic glutamate receptors (mGluR II). Incorporation of a fluorine atom is expected to increase the biological activity and bioavailabiblity of this compound.

Les composés organofluorés constituent une grande partie de produits pharmaceutiques, ainsi que pesticides, herbicides et matériaux fabriqués actuellement. Développement des méthodes sélectives de la synthèse des composés organofluorés est donc d'intérêt principal pour la chimie. Dans cette thèse, nous décrivons la nouvelle méthode de synthèse des cyclopropanes monofluorés basé sur la cyclisation initiée par la réaction de Michaël (MIRC). Notre méthode permet d'obtenir les cyclopropanes monofluorés polysubstitués à partir de dibromofluorocetate d'éthyle et différents accpteurs de Michaël. Nous avons aussi réalisé la cyclopropanation asymétrique en utilisant le nouveau réactif fluoré chiral à base d'oxazolidinone. Dans la partie finale de cette thèse nous décrivons la synthèse de l'analogue fluoré de L-FAP4, l'agoniste puissant des récepteurs métabotropiques de glutamate groupe II(mGluR II), afin d'augmenter l'activité biologique et la biodisponibilité de ce composé. / Organofluorine compounds constitute a large part of all the drugs, crop protection agents and advanced materials produced nowadays. Therefore, there is a great interest in developing the new methods of synthesis of organofluorine compounds. In this thesis we report a novel method of synthesis of monofluorinated cyclopropanes based on the Michael-initiating ring closure (MIRC) reaction. Our method allows obtaining polysubstituted monofluorinated cyclopropanes from ethyl dibromofluoroacetate and various Michael acceptors. We have also implemented the asymetric version of cyclopropanation using a novel oxazolodinone-derived chiral fluorinated reagent. In the final part of this thesis we report the synthesis of a fluorinated analog of L-FAP4, a potent agonist of group II metabotropic glutamate receptors (mGluR II). Incorporation of a fluorine atom is expected to increase the biological activity and bioavailabiblity of this compound.