Thèse diffusée initialement dans le cadre d'un projet pilote des Presses de l'Université de Montréal/Centre d'édition numérique UdeM (1997-2008) avec l'autorisation de l'auteur.

Since the discovery that diazomethane, CH2N2, can effect the cyclopropanation of alkenes under palladium catalysis in the 1960s, this reaction has been used to great effect in synthesis. However, the necessity of preparing and handling diazomethane, a toxic and explosive reagent, is unappealing. The substitution of diazomethane for a commercially-available and thermally-stable silylated congener, namely trimethylsilyldiazomethane (TMSDAM), has been investigated. Under optimised conditions, designed to promote protodesilylation, use of this reagent affords the same products as would be obtained with the more hazardous diazomethane, with no trace of the corresponding silylated cyclopropanes. NMR spectroscopy has revealed that the protodesilylating agent employed in the reaction, tetrabutylammonium bifluoride (n-Bu4N+ HF2 -, TBABF), reacts cleanly with TMSDAM to generate diazomethane. Under catalytic conditions, the consumption of the desilylated diazo reagent by palladium is sufficiently rapid to prevent the accumulation of this hazardous reagent in solution. Spectroscopic titration studies also revealed a “hidden” mode of TBABF catalysis, whereby adventitious water drives the regeneration of the bifluoride salt. This observation was exploited by the development of an EtOH-driven reaction variant in which catalytic amounts (20 mol%) of TBABF could be employed. The ability to effect the in situ generation of diazomethane has allowed for mechanistic studies into the course of the cyclopropanation reaction to be undertaken. These reveal a partitioning in the consumption of nascent diazomethane between the desired cyclopropanation reaction and a side reaction. The product of the side reaction was identified as cyclopropane (C3H6), the product of formal methylene cyclotrimerisation, by employing EtOD in TBABF-catalysed deuterodesilylative cyclopropanation. The partitioning between the two pathways is dependent on the nature of the substrate, with efficient cyclopropanation dominating with electrondeficient alkenes. For an electronically-varied range of styrenes, the relative rate of productive diazomethane consumption correlates well with the energy of the frontier molecular orbitals (as determined by DFT calculations). These results are consistent with an initial, substrate-dependent partitioning of the palladium pre-catalyst between species able to effect alkene cyclopropanation, and those (likely higher-order) species which promote only the cyclotrimerisation of diazomethane.

Thèse diffusée initialement dans le cadre d'un projet pilote des Presses de l'Université de Montréal/Centre d'édition numérique UdeM (1997-2008) avec l'autorisation de l'auteur.

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第21126号 / 工博第4490号 / 新制||工||1698(附属図書館) / 京都大学大学院工学研究科合成・生物化学専攻 / (主査)教授 村上 正浩, 教授 杉野目 道紀, 教授 松田 建児 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DGAM

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.

Over the past decades, functional group manipulation of aromatic precursors has been a common strategy to access new aromatic compounds. However, these classical methods, such as Friedel-Crafts alkylations and electrophilic/nucleophilic aromatic substitutions, have shown lack of regioselectivity besides the use of activators in excess amounts. To this end, numerous benzannulations to form benzo-fused substrates via Diels-Alder (DA), ring-closing metathesis (RCM), cycloaddition, and transition-metal-promoted processes have been reported. Appending a benzene ring directly onto a pre-existing ring is preferable to many classical methods due to the likely reduction of reaction steps and superior regiocontrol. However, many of these benzannulation reactions require air- and/or moisture- sensitive reaction conditions, a last oxidation step, or the use of highly functionalized precursors. Here we disclose three ‘complementary’ intramolecular ring-opening benzannulations to access a large array of functionalized (hetero)aromatic scaffolds utilizing cyclopropenes-3,3-dicarbonyls, alkylidene cyclopropanes-1,1-diesters, and 2,3-dihydrofuran O,O- and N,O- acetals as building blocks. More than 70 benzo-fused aromatic compounds were synthesized using this complementary approach with yields up to 98% and low catalyst loadings. With these benzannulation reactions in hand, we aim to open the synthetic door to a handful of bioactive natural products.

Over the past decades, functional group manipulation of aromatic precursors has been a common strategy to access new aromatic compounds. However, these classical methods, such as Friedel-Crafts alkylations and electrophilic/nucleophilic aromatic substitutions, have shown lack of regioselectivity besides the use of activators in excess amounts. To this end, numerous benzannulations to form benzo-fused substrates via Diels-Alder (DA), ring-closing metathesis (RCM), cycloaddition, and transition-metal-promoted processes have been reported. Appending a benzene ring directly onto a pre-existing ring is preferable to many classical methods due to the likely reduction of reaction steps and superior regiocontrol. However, many of these benzannulation reactions require air- and/or moisture- sensitive reaction conditions, a last oxidation step, or the use of highly functionalized precursors. Here we disclose three ‘complementary’ intramolecular ring-opening benzannulations to access a large array of functionalized (hetero)aromatic scaffolds utilizing cyclopropenes-3,3-dicarbonyls, alkylidene cyclopropanes-1,1-diesters, and 2,3-dihydrofuran O,O- and N,O- acetals as building blocks. More than 70 benzo-fused aromatic compounds were synthesized using this complementary approach with yields up to 98% and low catalyst loadings. With these benzannulation reactions in hand, we aim to open the synthetic door to a handful of bioactive natural products.

Small rings are frequently found in natural products as well as incorporated into drugs and agrochemicals in which they impart valuable properties on the biological activity of these compounds. Cyclopropanes are also extremely useful as reagents in organic synthesis, in particular as “umpolung” reagents, allowing access to products which would otherwise be more difficult to synthesise. This thesis will describe forays into the synthesis and further substitution of small rings as well as the iminium-catalysed ring-opening of cyclopropanes. The introduction will outline the uses and properties of cyclopropanes, and will also describe some of the more common ways for incorporating cyclopropanes into larger structures. This will include the Horner–Wadsworth–Emmons procedure which has previously been developed by the group. The second chapter describes efforts towards the iminium-catalysed nucleophilic ring-opening of cyclopropanes. This is followed by Chapter 3, in which the Horner–Wadsworth–Emmons methodology for the synthesis of the cyclopropanes used in Chapter 2 is investigated as a procedure for the synthesis of 4-membered heterocycles. Chapter 4 describes the development of a decarboxylative method for the protodecarboxylation of cyclopropanecarboxylic acids. This was developed as the first step towards decarboxylative cross-coupling of cyclopropanes. Decarboxylative cross-couplings have been extensively developed as environmentally friendly and facile alternatives to the current cross-coupling methods. In Chapter 5 the attempted development of a decarboxylative cross-coupling reaction of cyclopropanes is described. Conclusions and future work are outlined in Chapter 6, followed by the experimental details in Chapter 7.

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.

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