A series of new cobalt(II) beta-keto iminato complexes and cobalt(II) salens have been made and the effect of chirality in the northern, southern and peripheral quadrants of these catalysts, with respect to induced enantiomeric excess, during the ring-opening of 1,2-dioxines has been determined. Synthesis of a series of cobalt beta-keto iminato complexes was achieved after modification of literature procedures used for the synthesis of manganese beta-keto iminato complexes and this procedure was applied to generate ligands with ethyl, t-butyl, (-)-bornyl, (+)-menthyl and (-)-menthyl esters and a methyl side chain. Synthesis of the cobalt salens was also achieved using a modified literature procedure, in respect to the more complex aldehydes made. It was ascertained that chirality in the northern quadrant of these catalysts, obtained by the use of optically pure diamines, was of greatest importance in introducing enantiomeric excess into the products of ring-opening of 1,2-dioxines; namely gamma-hydroxy enones, and chirality in the southern and peripheral quadrants was of lesser, although still significant, importance. The reaction conditions were optimised and the conditions under which the highest enantiomeric excess was introduced were determined. The ideal solvent for the ring-opening was found to be THF with a catalyst concentration between 5 and 10 mol% at a temperature of -15oC. These conditions were found to be applicable to all catalysts and 1,2-dioxines tested. Enantiomeric excess as high as 76 % could be introduced when the optimised reaction conditions were used in large scale syntheses of cyclopropane (61). LC-MS studies indicate the presence of a solvent chelated species present in the reaction mixture when the solvent used is THF, however, the use of non-chelating solvents, such as dichloromethane, did not exhibit this same solvent chelated species. Catalyst dimers were also present in the mixture when analysed by LC-MS. The presence of oxygen in the reaction mixture was found to inhibit rearrangement of the dioxine with catalyst oxygen dimers (two molecules of catalyst bound to a single molecule of oxygen) present when analysed by LC-MS, however, the catalyst could be 're-activated' by de-aeration of the solution and was able to introduce the same enantiomeric excess, as prior to the addition of oxygen was unaffected. It was found that not only cobalt(II) tetradentate complexes were useful in the ring-opening of meso 1,2-dioxines. Achiral iron(II) salen and ruthenium(II) salen were also made and shown to be capable of ring-opening the dioxine. A purchased chiral manganese(III) salen was also shown to be capable of ring-opening the 1,2-dioxine, however, the time taken for the rearrangement to occur led to ring closure of the gamma-hydroxy enone and dehydration of the cyclic hemiacetal. The catalysts were also applied to the enantioselective ring-opening of epoxy-1,2-dioxines for the first time with a high level of success with enantiomeric excesses of between 60 and 90 % introduced with most of the catalysts. To show that these catalysts have the potential for use in the synthesis of potentially bioactive cyclopropyl amino acids, amines, acids and alcohols a small number were prepared, including both racemic and optically enriched or optically pure cyclopropanes. / Thesis (Ph.D.)--School of Chemistry and Physics, 2003.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1939. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaf [15]).

Les cyclopropanes sont rencontrés dans de nombreux produits naturels ou synthétiques bioactifs. Les travaux exposés dans ce manuscrit portent sur le développement de réarrangements sigmatropiques [3,3] impliquant des dérivés de cyclopropénylcarbinols pour accéder à des alkylidènecyclopropanes fonctionnalisés, précurseurs de cyclopropanes diversement substitués. Le réarrangement des cyanates de cyclopropénylcarbinyle a permis d'obtenir des dérivés N-acylés d'alkylidène(aminocyclopropanes). Une méthode efficace et stéréosélective, impliquant le réarrangement d'Ireland-Claisen des glycolates et glycinates de cyclopropénylcarbinyle, a également été mise au point pour synthétiser des alkylidènecyclopropanes possédant un motif α-hydroxy ou α-amino acide. Le champ d'application de ce réarrangement a été étendu avec succès à des gem-difluorocyclopropènes. L'hydrogénation diastéréosélective des alkylidènecyclopropanes diversement substitués issus de ces rérrangements sigmatropiques a ensuite permis d'obtenir des cyclopropanes fonctionnalisés. / The cyclopropane ring is ubiquitous in natural and biologically active compounds. [3,3]-Sigmatropic rearrangements of cyclopropenylcarbinol derivatives have been developed to access functionalized alkylidenecyclopropanes, which are useful precursors of diversely substituted cyclopropanes. We have shown that the rearrangement of cyclopropenylcarbinyl cyanates could be accomplished under mild conditions to obtain N-acyl alkylidene(aminocyclopropanes). The Ireland–Claisen rearrangement of glycolates or glycinates derived from secondary cyclopropenylcarbinols has been developed as an efficient and stereoselective method for the synthesis of alkylidenecyclopropanes possessing an α-hydroxy or α-amino acid moiety. The scope of this transformation was successfully extended to gem-difluorocyclopropenes. The alkylidenecyclopropanes resulting from these latter sigmatropic rearrangements are valuable precursors of substituted cyclopropanes by diastereoselective hydrogenation of the exocyclic olefin.

Cette thèse est centrée sur le développement de méthodologies d’halocyclopropanations énantiosélectives et sur l’étude des mécanismes de formation de carbénoïdes de zinc ainsi que de leur comportement. Nous avons tout d’abord développé une méthodologie de bromocyclopropanation énantiosélective d’alcools allyliques en modifiant les conditions précédemment décrites par notre groupe pour la synthèse d’iodo- et de chlorocyclopropanes. Désirant améliorer cette réaction -notamment en termes de déchêts générés- nous avons mené plusieurs expériences RMN nous permettant d’élucider la nature de l’espèce carbénoïde active ainsi que le mécanisme de sa formation. Grâce à ces informations, nous avons alors développé plusieurs jeux de conditions menant à de meilleurs résultats tout en limitant les ressources utilisées. Nous avons alors réalisé qu’il était possible d’améliorer les réactions d’halocyclopropanation décrites précédemment par notre groupe de la même façon. Nous nous sommes donc penchés sur la réaction d’iodocyclopropanation dans un premier temps, et avons réussi à augmenter son efficacité générale tout en caractérisant le carbénoïde actif. L’amélioration de la chlorocyclopropanation s’est quant à elle révélée plus ambitieuse : l’association de réactifs devant normalement générer le carbénoïde a mené à l’obtention d’un mélange de composés organométalliques selon des mécanismes d’échanges d’halogènes jusqu’à présent peu étudiés. Afin de contrer ces chemins réactionnels non désirés, un sel de zinc organique a été utilisé et a finalement permis l’amélioration de la réaction de chlorocyclopropanation. Nous avons par la suite décidé d’investiguer ces mécanismes d’échanges d’halogènes sur un large panel de carbénoïdes afin d’en comprendre les raisons et de potentiellement pouvoir les prévoir. / This thesis is focused on the development of enantioselective halocyclopropanation methodologies and the study of both the formation and behaviors of zinc carbenoids. Initially, we developed an enantioselective bromocyclopropanation reaction of allylic alcohols by modifying previous conditions described by our group for the synthesis of iodo- and chlorocyclopropanes. To further improve this reaction with particular regard to mitigating wate production, we performed several NMR experiments that elucidated both the active zinc carbenoid structure and the mechanism of its formation. Based on these findings, we developed modified conditions, providing improved yields without the need for excess reagents. Cognizant of a similar mechanistic pathway for previously developed halocyclopropanations, we applied these mechanistic findings towards improving both the iodocyclopropanation and chlorocyclopropanation reactions. Much to our delight, we successfully improved the efficiency of the iodocyclopropantion and characterized the active zinc carbenoid species. In contrast, the chlorocyclopropanation presented more challenges due to the complex mixture of various organometallic species obtained from the mixing of carbenoid reagents. These results suggested scrambling mechanisms were occuring, which were not really understood until now. In order to avoid those mechanisms, an organic zinc salt was used, providing access to an improved, more efficient chlorocyclopropanation reaction. Finally, we conducted an in-depth investigation into the observed scrambling mechanisms using a wide panel of carbenoids to both understand the causes of such scramblings and to potentially predict when they will occur.

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.

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.

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

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 cyclopropanes sont rencontrés dans de nombreux produits naturels ou synthétiques bioactifs. Les travaux réalisés portent sur le développement de couplages catalysés par le palladium permettant d'accéder à des cyclopropanes diversement substitués. Des couplages de Suzuki-Miyaura impliquant les cis- et trans-2-benzyloxy-cyclopropyltrifluoroborates de potassium ont pu être mis au point après un important travail d'optimisation. L'accès à des aminocyclopropanes par des couplages de type Hartwig Buchwald impliquant des iodures cyclopropaniques s'est révélé beaucoup plus difficile à mettre en œuvre. Leur faisabilité a été démontrée avec un exemple, en version intramoléculaire, mais les résultats n'ont pas pu être généralisés. Les premiers exemples de couplages de Sonogashira entre des iodures cyclopropaniques diversement substitués et des alcynes terminaux ont été décrits. Les alcynylcyclopropanes correspondants sont obtenus avec d'excellents rendements et rétention de configuration. Les cis-2-alcynylcyclopropanecarboxamides préparés par cette méthode peuvent subir une cyclisation 5 exo-dig en milieu basique et conduire à des énamides incorporant un motif 3-azabicyclo[3.1.0]hexane. En milieu acide, ces composés engendrent des ions N-acyliminiums bicycliques pouvant être impliqués dans des réductions ioniques ou des cyclisations de Pictet-Spengler menant à une grande diversité de composés hétérocycliques azotés originaux de manière totalement diastéréosélective.

The thesis entitled "Synthesis of Novel Chalcogenides using Acyloxyphosphonium Intermediates and Doubly Activated Cyclopropanes" is divided into six chapters. Chapter 1: Part 1: Synthesis of thioesters from carboxylic acids and alkyl halides using benzyltriethylammonium tetrathiomolybdate In this chapter, we describe the synthesis of thioesters from carboxylic acids and alkyl halides. Aryl carboxylic acids are first activated using PPh3 and NBS to form the corresponding acyloxy phosphonium intermediates which then on further reaction with reagent, 1generate thioaroylate ions in situ. These thioaroylates on further reaction with various electrophiles such as alkyl halides / dihalides in the same pot gives the corresponding functionalized thioesters. This methodology was then extended to carbohydrate based thioesters as they are important synthetic intermediates in various transformations and also they could be deprotected later to synthetically more valuable thiols. For this study, we took 1,2,3,4tetra-O-acetyl-β-D-glucopyranuronic acid which on treatment with PPh3,NBS, reagent, 1 and I-bromo propane (CHCl3, 28°C, 2h) afforded the corresponding thioester in 55% yield. An intramolecular version of the reaction was then performed on a compound containing both anomeric bromide and carboxylic acid functionality. This was achieved by treating tetra acetyl glucuronic acid, with HBr/AcOH to form α-D-bromo-glucopyranuronic acid which on further treatment with PPh3, NBS and reagent, 1 gave the corresponding bicyclic thiolactone in 55% yield. Chapter 1: Part 2: Synthesis of Thioesters by Simultaneous Activation of Carboxylic Acids and Alcohols using PPh3/NBS In this chapter, we have shown the synthesis of thioester from carboxylic acids and alcohols. Both carboxylic acids and alcohols are first activated using PPh3 and NBS to form the corresponding phosphonium salts. Reagent, 1 then reacts selectively with acyloxyphosphonium intermediates to generate thioaroylate ions in situ which then react either with alkoxy phosphonium salts or the corresponding alkyl bromide to give thioesters in good yield. The same methodology was then used for a one pot conversion of N-Boc serine ester to s-protected cysteine using reagent 1 as the key sulfur transfer reagent. Chapter 2: Part 1: Tetrathiomolybdate mediated Michael addition of thioaroylates generated from acyloxyphosphonium salts In this chapter, we have reported an easy and alternative protocol for the Michael addition of thioacids to various Michael acceptors. Acyloxyphosphonium salts and tetrathiomolybdate reacts to generate thioaroylate ions which then undergo Michael additionto givethe corresponding Michael adducts. This methodology was then extended for the synthesis carbohydrate based thiolactone by an intramolecular Michael addition reaction to show the applicability of the methodology. Chapter 2: Part 2: Regioselective and chemoselective ring opening of aziridines and epoxides using thioaroylate ions In this chapter, we have demonstrated nucleophilic ring opening of Aziridines and epoxides using thioaroylate ions generated from acyloxyphosphonium salts and tetrathiomolybdate as a sulfur transfer reagent. We have also demonstrated chemoselective ring opening of azirdines in the presence of an epoxide and tosylate to show the novelty of our method. Chapter 3: Synthesis of bromo esters and bromo thioesters by ring opening of cyclic ethers and thiiranes via acyloxyphosphonium intermediates In this chapter, we report the synthesis of bromo esters and thioesters by the ring opening of epoxides, tetrahydrofuran, and thiiranes with bromide ion to form the corresponding bromo alcohols and thiols followed by the nucleophilic displacement of triphenylphosphine oxide from acyloxyphosphonium salts. At first THF and epoxides were subjected for the ring opening reactions to give the corresponding bromo esters. The methodology was then extended to thiiranes to synthesis bromo thioesters in good to moderate yield. Chapter 4: Synthesis of doubly activated cyclopropranes and their applications to the synthesis of dihydrothiophenes and thiophenes In this chapter we discuss the synthesis and ring opening of doubly activated cyc1opropanes using tetrathiomolybdate and their applications towards the formation of dihydrothiophenes and other bioactive molecules. At first, we synthesized a number of doubly activated cyc1opropanes from dimethyl-α-arylsulfonium bromide,24 a protocol developed by Chow and others. With the doubly activated cyclopropanes in hand, we then attempted the ring opening of cyclopropanes containing a cyano group with tetrathiomolybdate to give the corresponding dihydrothiophene derivatives. Also we have used our methodology for the synthesis of HIV-1 reverse transcriptase inhibitor Chapter 5: Synthesis of unsymmetrical sulfide and disulfide derivatives via ring opening of doubly activated cyclopropanes Here, we describe the synthesis of various monosulfides and mixed disulfides by doubly activated cyclopropane ring opening mediated by tetrathiomolybdate in one pot. Tetrathiomolybdate is known for the reduction of disulfides while diaryl disulfides gives monosulfide, dialkyl disulfides give mixed disulfides with the corresponding doubly activated cyclopropane. Thus diaryl disulfide cleaves readily as the resultant thiolate ion is stable and opens the cyclopropane ring to give a monosulfide. Dibenzyl disulfide on the other hand being less reactive gave a mixed disulfide instead of a monosulfide. We also extended this ring opening reactions for the synthesis of symmetrical disulfides Using tetrathiomolybdate as the key sulfur transfer reagent. Chapter 6: A mild protocol for the nucleophilic ring opening of doubly activated cyclopropanes using selenolates generated in situ Nucleophilic ring opening of doubly activated cyc1opropanes with selenolate ions generated by the reduction of diselenides using NaB14 is discussed in this part of the work. A variety of doubly activated cyc1opropanes have been tested for this reaction giving the corresponding selenium compounds in good yield. This methodology was then extended to other diselenides using nitroester cyclopropane as standard and also to other substituted nitroester cyclopropanes using diphenyl diselenide as standard. This methodology was also then extended to the synthesis of homoselenocysteines by the reduction of nitro group using Sn/HCI for the reduction. (For structural formula pl refer the hard copy)