Environmentally friendly insecticides have long been desired in the production of food. Pyrethiod compounds not only decompose under light and heat, but they are highly toxic to insects while having effectively no toxicity to mammals. The cis-cyclopropane ring in pyrethiod insecticides is the most challenging component to synthesize. We are exploring the best parameters for the most effective cis-Cyclopropanation reactions. An alkene and a diazo compound react together in the presence of a dirhodium catalyst to produce cyclopropanes. First however, the starting materials must be pure. My part of the project is to purify ethyl diazoacetate(EDA). Column chromatography has been used, but yielded no fraction containing EDA as determined by Gas chromatography/Mass spectrometry. Extraction of EDA with sodium carbonate solution yielded similar results. Thus, I turned to distillation at reduced pressure. This method produced EDA in high enough purity to be used in cyclopropanation reactions. The purity of EDA was determined by H-1 nuclear magnetic resonance spectroscopy.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Dans ce manuscrit, nous avons décrit l'accès aux dérivés bicyclo[2.1.0]pentanes via deux réactions métalo-Catalysées, à savoir une cycloisomérisation d’énynes-1,6 catalysée par le platine et la cyclopropanation de cyclobutènes catalysée par le ruthénium à l’aide carboxylates propargyliques tertiaires. Tout d'abord, nous avons développé la formation, catalysée par Pt(II), de cyclobutènes à partir d’énynes-1,6 reliés par un hétéroatome (azote ou oxygène) pour former les aza- et oxa-Bicyclo[3.2.0]hept-6-Ènes respectivement. Il est montré que la présence de substituant(s) alkyle(s) en position propargylique et l'utilisation de solvants faiblement coordonnés, tels que le DMA sont les caractéristiques principales favorisant la formation de cyclobutènes. Ensuite, la disponibilité de cyclobutènes issus de la cycloisomérisation des 1,6-Énynes a permis leur utilisation pour la construction de systèmes bicyclo[2.1.0]pentanes par la mise en œuvre d’une cyclopropanation catalysée par le ruthénium utilisant les carboxylates propargyliques tertiaires. Ces composés sont obtenus sous la forme d’un diastéréomère unique avec des rendements bons à excellents. Cette réaction fournit une alternative sûre aux méthodes utilisant les dangereux composés diazo précurseurs de carbène pour générer les bicyclo[2.1.0]pentanes fonctionnalisés dans des conditions douces et avec des rendements élevés. / In this manuscript, we have described an access to bicyclo[2.1.0]pentanes via two metal-Catalyzed reactions, namely a platinum-Catalyzed cycloisomerization of heteroatom-Tethered 1,6-Enynes and the subsequent ruthenium-Catalyzed cyclopropanation of cyclobutenes with tertiary propargyl carboxylates.First, we have developed the Pt(II)-Catalyzed formation of cyclobutenes from nitrogen and oxygen-Tethered 1,6-Enynes to form aza- and oxabicyclo[3.2.0]hept-6-Enes respectively. It is shown that the presence of alkyl substituent(s) at propargyl position and the use of weakly coordinating solvents such as DMA are the key elements favoring the formation of cyclobutenes.Second, the availability of cyclobutenes from the cycloisomerization of 1,6-Enynes has allowed their utilization for the construction of strained bicyclo[2.1.0]pentane structures as single diastereomers in good to excellent yield through a ruthenium-Catalyzed cyclopropanation. It provides a safe method which avoid the use of the hazardous diazo compounds precursors of carbenes to generate functionalized bicyclo[2.1.0]pentane frameworks in high yields under mild conditions.

Le premier chapitre de cette thèse fait état d'études modèles pour une réaction de métathèse d'alcènes avec fermeture de cycle avec clivage d'un auxiliaire chiral en tandem particulièrement défavorisée. La synthèse des substrats modèles amides et amines y est décrite et les résultats de métathèse y sont présentés. Ces résultats ont mené au développement d'une stratégie de métathèse d'alcènes à relais qui est discutée et appliquée sur un substrat modèle amide.Le second chapitre présente dans un premier temps l'application de la métathèse d'alcènes à relais sur un substrat possédant les chaînes latérales appropriées pour nos efforts synthétiques vers la daphniphylline. Une séquence synthétique mettant en vedette une réaction de cyclopropanation d'un énamide par un diazoacétate est présentée, d'abord sur un substrat modèle puis sur le système menant à la daphniphylline. Une stratégie d'iodoétherification-cyclisation radicalaire est aussi abordée.Le troisième chapitre traite de nos efforts dans le but de développer une cascade de biscyclisation radicalaire particulièrement ambitieuse. Une modification de la stratégie impliquant une fragmentation d'un lien C-Sn comme force motrice est aussi discutée. Nos travaux visant à dénicher un dérivé cristallin afin de déterminer la stéréochimie de nos substrats y sont également présentés. Finalement, le quatrième chapitre expose les résultats préliminaires obtenus dans le cadre du développement d'une nouvelle cascade radicalaire impliquant une cyclisation 5-exo-trig dans un premier temps suivie d'une allylation ou d'une diénylation intermoléculaire. Une étude modèle est décrite avant de passer à une discussion quant à l'application de cette approche sur un système menant à la daphniphylline.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

This thesis describes the development of chiral auxiliary based methodologies for the asymmetric synthesis of hydroxylated !-lactones and "-lactones containing multiple contiguous stereocentres. The first chapter introduces the concept of chirality and provides a general overview of the range of strategies available for the preparation of chiral molecules in enantiomerically pure forms. The second chapter critically reviews the range of synthetic methodology that is currently available for the asymmetric synthesis of chiral #-lactones that are either natural products or useful chiral building blocks for synthesis. The third chapter describes the development of novel methodology for the epoxidation/lactonisation of a range of $-vinyl-syn-aldols to directly afford !-lactones containing up to four contiguous stereocentres in high de. These reactions were shown to proceed via a mechanism whereby hydroxyl-directed diastereoselective epoxidation is followed by intramolecular attack of their !-acyl-oxazolidin-2- one fragment, to directly afford the desired chiral !-lactone. The ‘self-cleavage’ aspect of these reactions was exploited to enable this methodology to be transferred to polymer-support using an immobilised Evans’-oxazolidin-2-one for asymmetric synthesis. Chapter 4 describes the development of a complementary methodology for the asymmetric synthesis of this type of hydroxylated !-lactone based on a strategy involving dihydroxylation of N-acyl-oxazolidin-2-one-$-vinyl-syn-aldols using catalytic amounts of osmium tetroxide. This methodology was developed as part of a reinvestigation of previously reported dihydroxylation reactions by Dias and coworkers, where we have clearly shown that the stereochemistry of thelactones reported in their paper have been incorrectly assigned. This diastereoselective dihydroxylation methodology has been successfully applied to the asymmetric synthesis of the natural product deoxyribonolactone. Finally, Chapter 5 describes the development of methodology for the asymmetric synthesis of chiral "-lactones containing four contiguous stereocentres of use as potential chiral building blocks for the synthesis of polyketide natural products. In this approach, cyclopropanation of N-acyl-oxazolidin-2-one-$-vinyl-syn-aldols occurs under the sterodirecting effect of the $- hydroxyl group to afford cyclopropyl-aldols in very high de. These cyclopropyl-aldols are then ring opened in the presence of mercuric ions, with their N-acyl-oxazolidin-2-one fragment acting as an internal nucleophile, to afford highly functionalised alkyl-mercury species that may be subsequently reduced to afford their corresponding "-lactones in high de.

O (-)-?-bisabolol é um produto natural abundante no Brasil. É extraído de várias espécies de plantas. Possui atividades biológicas reconhecidas, que o torna extremamente interessante para as indústrias de cosméticos e fármacos. O trabalho de pesquisa tem como objetivo principal sua modificação buscando, com isso, melhorar as atividades biológicas ou agregar novas potencialidades biológicas. Durante estas transformações procura-se, principalmente, empregar metodologias ecologicamente corretas (Green Chemistry). O trabalho foi dividido em 3 (três) partes principais: Aminoredução, oxidação e cicloadição. A primeira parte consiste na preparação da imina (N-benzilfenilmetanoamina) e transformação, da mesma, em uma amina secundária, através de aminação redutiva. Na segunda, oxidação das aminas secundárias e do bisabolol e, na terceira, estudo das reações de cicloadições. As oxidações das aminas secundárias (dibenzilamina e 1,2,3,4-tetraidroisoquinolina) forneceram as nitronas correspondentes (N-óxido de N-benzilidenobenzilamina e N-óxido de 3,4-diidroisoquinolina). A oxidação (epoxidação) do Bisabolol forneceu uma mistura de óxidos de Bisabolol: Óxido de Bisabolol - B: 1-metil-1-[5-(4-metil-3-cicloexenil)tetraidro-2-furanil]etil álcool e Óxido de Bisabolol - A: (3S)-2,2,6-trimetil-6-(4-metil-3-cicloexenil)tetraidro-2H-3-piranol. A oxidação alílica do Bisabolol, forneceu o tetraidro-2,2,6-trimetil-6-(4-metil-3-cicloexen-1-il)-4H-piran-4-ona. A cicloadição [1+2] entre diclorocarbeno e o bisabolol originou o 4-(2,2-dicloro-3,3-dimetilciclopropil)-2-(7,7-dicloro-6-metilbiciclo [4.1.0]hept-3-il)-2-butanol. A reação de cicloadição [2+3] entre a nitrona (N-óxido de 3,4-diidroisoquinolina) e o dipolarófilo (butil vinil éter) forneceu a isoxazolidina 1,5,6,10b-tetraidro-2H-isoxazolol[3,2-a]isoquinolina-2-il butil éter. / The (-)-?-bisabolol is a natural product available in a large quantity in Brazil. It is extracted of several specimens of trees and has recognized biological activity that made it a so interesting product for cosmetic and pharmaceutic industries. The research has as mean goal the modification of (-)-?-bisabolol a natural product. The modification has intended, improve the biological activity or create new biological activity. The methods applied always consider condition to protect the environment (Green Chemistry). The research has three main parts: amino reduction, oxidation and cycloaddition. The first part based on the reaction to synthesize the imines (N-benzylphenilmethanoamine) and with the amine reduction synthesis the secondary amine. A second part was oxidizing the secondary amines and bisabolol. The third part is a research about cycloaddition. The amines oxidation (dibenzylamine e 1,2,3,4-tetrahydroisoquinoline) gave the nitrones [N-benzylidenebenzylamine N-oxide and 3,4-dihydroisoquinoline N-oxide] respectively. The Bisabolol oxidation (epoxidation reaction) gave a mix of bisabolol oxide: The Bisabolol oxide B, 1-methyl-1-[5-(4-methyl-3-ciclohexenyl)tetrahydro-2-furanyl]ethyl alcohol and The Bisabolol oxide A, (3S)-2,2,6-trimethyl-6-(4-methyil-3-ciclohexenyl) tetrahydro-2H-3-piranol. The alilic oxidation from Bisabolol also was achieved and gave the tetrahydro-2,2,6-trimethyl-6-(4-methyl-3-cyclohexen-1-yl)-4H-pyran-4-one. The cycload-dition [1+2] between diclorocarbene and bisabolol gave, 4-(2,2-dicloro-3,3-dimethylciclopropil)-2-(7,7-dicloro-6-methylbiciclo[4.1.0]hept-3-yl)-2-butanol. The cycloaddition [2+3] with nitrones (3,4-dihydroisoquinoline N-oxide) and dipolarophile (butyl vinyl ether) gave the isoxazolidine 1,5,6,10b-tetrahydro-2H-isoxazolol[3,2-a]isoquinoline-2-yl butyl ether.

O (-)-?-bisabolol é um produto natural abundante no Brasil. É extraído de várias espécies de plantas. Possui atividades biológicas reconhecidas, que o torna extremamente interessante para as indústrias de cosméticos e fármacos. O trabalho de pesquisa tem como objetivo principal sua modificação buscando, com isso, melhorar as atividades biológicas ou agregar novas potencialidades biológicas. Durante estas transformações procura-se, principalmente, empregar metodologias ecologicamente corretas (Green Chemistry). O trabalho foi dividido em 3 (três) partes principais: Aminoredução, oxidação e cicloadição. A primeira parte consiste na preparação da imina (N-benzilfenilmetanoamina) e transformação, da mesma, em uma amina secundária, através de aminação redutiva. Na segunda, oxidação das aminas secundárias e do bisabolol e, na terceira, estudo das reações de cicloadições. As oxidações das aminas secundárias (dibenzilamina e 1,2,3,4-tetraidroisoquinolina) forneceram as nitronas correspondentes (N-óxido de N-benzilidenobenzilamina e N-óxido de 3,4-diidroisoquinolina). A oxidação (epoxidação) do Bisabolol forneceu uma mistura de óxidos de Bisabolol: Óxido de Bisabolol - B: 1-metil-1-[5-(4-metil-3-cicloexenil)tetraidro-2-furanil]etil álcool e Óxido de Bisabolol - A: (3S)-2,2,6-trimetil-6-(4-metil-3-cicloexenil)tetraidro-2H-3-piranol. A oxidação alílica do Bisabolol, forneceu o tetraidro-2,2,6-trimetil-6-(4-metil-3-cicloexen-1-il)-4H-piran-4-ona. A cicloadição [1+2] entre diclorocarbeno e o bisabolol originou o 4-(2,2-dicloro-3,3-dimetilciclopropil)-2-(7,7-dicloro-6-metilbiciclo [4.1.0]hept-3-il)-2-butanol. A reação de cicloadição [2+3] entre a nitrona (N-óxido de 3,4-diidroisoquinolina) e o dipolarófilo (butil vinil éter) forneceu a isoxazolidina 1,5,6,10b-tetraidro-2H-isoxazolol[3,2-a]isoquinolina-2-il butil éter. / The (-)-?-bisabolol is a natural product available in a large quantity in Brazil. It is extracted of several specimens of trees and has recognized biological activity that made it a so interesting product for cosmetic and pharmaceutic industries. The research has as mean goal the modification of (-)-?-bisabolol a natural product. The modification has intended, improve the biological activity or create new biological activity. The methods applied always consider condition to protect the environment (Green Chemistry). The research has three main parts: amino reduction, oxidation and cycloaddition. The first part based on the reaction to synthesize the imines (N-benzylphenilmethanoamine) and with the amine reduction synthesis the secondary amine. A second part was oxidizing the secondary amines and bisabolol. The third part is a research about cycloaddition. The amines oxidation (dibenzylamine e 1,2,3,4-tetrahydroisoquinoline) gave the nitrones [N-benzylidenebenzylamine N-oxide and 3,4-dihydroisoquinoline N-oxide] respectively. The Bisabolol oxidation (epoxidation reaction) gave a mix of bisabolol oxide: The Bisabolol oxide B, 1-methyl-1-[5-(4-methyl-3-ciclohexenyl)tetrahydro-2-furanyl]ethyl alcohol and The Bisabolol oxide A, (3S)-2,2,6-trimethyl-6-(4-methyil-3-ciclohexenyl) tetrahydro-2H-3-piranol. The alilic oxidation from Bisabolol also was achieved and gave the tetrahydro-2,2,6-trimethyl-6-(4-methyl-3-cyclohexen-1-yl)-4H-pyran-4-one. The cycload-dition [1+2] between diclorocarbene and bisabolol gave, 4-(2,2-dicloro-3,3-dimethylciclopropil)-2-(7,7-dicloro-6-methylbiciclo[4.1.0]hept-3-yl)-2-butanol. The cycloaddition [2+3] with nitrones (3,4-dihydroisoquinoline N-oxide) and dipolarophile (butyl vinyl ether) gave the isoxazolidine 1,5,6,10b-tetrahydro-2H-isoxazolol[3,2-a]isoquinoline-2-yl butyl ether.

Metalloporphyrins have been shown to catalyze many fundamental and practically important chemical transformations, some of which represent the first demonstrations of these catalytic processes. The most notable examples include an assortment of atom/group transfer reactions, such as oxene, nitrene, and carbene transfers. Atom/group transfer reactions allow for the direct conversion of abundant and inexpensive alkenes and alkanes into value-added functional molecules. Previous reports from our group have shown that cobalt-porphyrin based carbene and nitrene transfer reactions are some of the most selective and practical catalytic systems developed for cyclopropanation and aziridination. Backed by a family of D2-symmetric chiral cobalt porphyrins our group continues the development of stereoselective carbene and nitrene transfer reactions. Metal-catalyzed cyclopropanation of olefins with diazo reagents has attracted great research interest because of its fundamental and practical importance. The resulting cyclopropyl units are recurrent motifs in biologically important molecules and can serve as versatile precursors in organic synthesis. Supported by a family of D2-symmetric chiral cobalt porphyrins, we have demonstrated the use of succimidyl diazoacetate as carbene source for a highly diastereo- and enantioselective cyclopropanation process. The resulting cyclopropyl succinimdyl esters are highly reactive and serve as valuable synthons for generating cyclopropylcarboxamides. We have also developed the first cobalt-porphyrin based intramolecular cyclopropanation, which is able to produce the resulting bicyclic lactones in high yields and enantioselectivity. Nitrene transfer reactions are also an attractive route to produce biologically and synthetically important molecules such as amines and aziridines. Although much progress has been made in nitrene transfer reactions utilizing [N-(p-toluenesulfonyl) imino]phenyliodinane (PhI=NTs) the nitrene source suffers from several drawbacks. Consequently, there has been growing interest in developing catalytic nitrene transfer reactions using alternate nitrene sources. To this end, we have utilized arylsulfonyl azides as nitrene source to explore their use in the development of a cobalt-porphyrin catalyzed enantioselective aziridination system. The cobalt catalyzed process can proceed under mild and neutral conditions in low catalyst loading without the need of other reagents, while generating nitrogen gas as the only byproduct. We have also explored the use of arylsulfonyl azides as nitrene source in a cobalt-catalyzed intramolecular C-H amination process.