The efficient construction of complex organic molecules mandates that an assortment of methods for forming C-C bonds be available to the practicing synthetic chemist. The addition of carbon based nucleophiles to carbonyl compounds represents a broad class of reactions used to achieve this goal. Traditional methodology requires the use of stoichiometrically preformed organometallic reagents as nucleophiles in this type of reaction. However, due to the moisture sensitivity, excessive preactivation and inevitable generation of stoichiometric waste required for the use of these reagents, alternative methods have become a focus of the synthetic organic community. The research presented in this dissertation describes a new class of C-C bond forming reactions enabled through catalytic transfer hydrogenation. Here, the development and implementation of efficient green methods for carbonyl addition employing π-unsaturates as surrogates to preformed organometallic reagents is described. Additionally, this research describes the first systematic studies toward using alcohols as electrophiles in carbonyl allylation, propargylation and vinylation reactions. / text

Carbonyl allylation and propargylation reactions have been an important tool for the stereocontrolled formation of carbon-carbon bonds for synthetic chemists. The chiral homoallylic and homopropargylic alcohols obtained from these reactions serve as versatile intermediates for the synthesis of natural and pharmaceutical products. Over the past three decades and continuing on, various synthetic groups around the globe have directed their research towards the efficient synthesis of these chiral moieties. In spite extensive research, asymmetric allylation and propargylation reactions remain an enduring challenge in organic chemistry. Chapter 1 of this thesis describes the first phosphoric acid catalyzed asymmetric allylboration of aldehydes. We found that the BINOL-derived phosphoric acids can efficiently catalyze the allylation reaction under specific conditions. Homoallylic alcohols were obtained in high yields and enantioselectivities from a wide variety of substrates. The optimized conditions were also found to be effective towards crotylboration of aldehydes. Chapter 2 describes the extension of the Br[o/]nsted acid catalyzed allylboration methodology to the propargylation of aldehydes. Homopropargylic alcohols were obtained with high selectivities with TRIP-PA as the catalyst. Synthesis of various important synthetic scaffolds from these chiral alcohols is also presented. The mechanistic insights studied by research groups of Kendall Houk and Jonathan Goodman have been outlined in chapter 3. These studies show that the major isomer is formed via a transition state involving the hydrogen bonding interaction between the hydroxyl group of the catalyst and the pseudoaxial oxygen of the boronate, with a stabilizing interaction of the phosphoryl oxygen to the formyl hydrogen. These insights helped us in developing new and highly efficient boronates that are described in the next chapter.

Environmental concerns have birthed an awareness of how we conduct ourselves as citizens of this planet. To reduce environmental impact, we have learned that we must be responsible stewards in all ranges of life: from buying locally grown food to how scientific research and industrial processes are executed. In the realm of chemical research, "green chemistry" has initiated the development of new, sustainable methods that make use of atom economy, step economy, and utilize renewable materials to minimize waste and production of toxic by-products. The formation of carbon-carbon bonds lies at the very heart of organic synthesis, and traditional methods for forming such bonds generally require the use of at least one stoichiometrically preformed organometallic reagent. This corresponds to at least one equivalent of metallic waste byproduct. The in situ formation of alkyl metal nucleophiles for carbonyl additions via hydrogenation of [pi]-unsaturates represents an alternative to use of preformed organometallic reagents. Comprising nearly 90% of the atoms in the universe, hydrogen is vastly abundant and very cheap. The Krische group seeks to contribute new technologies which make use of catalytic hydrogenation and transfer hydrogenation in the reductive coupling of basic chemical feedstocks. / text

Submitted by Fabio Sobreira Campos da Costa (fabio.sobreira@ufpe.br) on 2016-08-31T13:18:33Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Tese-Jucleiton-5.pdf: 12633477 bytes, checksum: a9581d3a8bca6762bb7a3d370f0ca74d (MD5) / Made available in DSpace on 2016-08-31T13:18:33Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Tese-Jucleiton-5.pdf: 12633477 bytes, checksum: a9581d3a8bca6762bb7a3d370f0ca74d (MD5) Previous issue date: 2016-02-15 / CNPq / Neste trabalho quatro diferentes métodos para a síntese de álcoois homopropargílicos obtidos a partir de aldeídos e compostos de boro foram desenvolvidos. A primeiro método foi baseado na utilização da resina Amberlyst A-31 como promotora. Os melhores rendimentos (70-95%) foram obtidos quando foi empregado uma quantidade de 200% m/m da Amberlyst A-31 em CH2Cl2, sob atmosfera aberta, com tempos reacionais que variaram de 1,5-7,0 horas. A resina pôde ser recuperada e reutilizada até três vezes em outras reações de propargilação sem perdas no rendimento. O segundo método desenvolvido baseou-se na utilização da argila Tonsil como promotora. Neste caso, os compostos desejados foram obtidos em bons rendimentos (60-96%) quando uma quantidade de 150% m/m de Tonsil em CH2Cl2, sob atmosfera aberta e temperatura ambiente foi utilizada. Quando os dois métodos usando promotores heterogêneos foram comparados frente a reações de propargilação de aldeídos contendo grupos protetores sensíveis em meio ácido, o melhor resultado foi obtido utilizando Tonsil onde o produto desejado foi obtido em bom rendimento juntamente com uma pequena quantidade do produto de desproteção. O terceiro método desenvolvido foi baseado na utilização do BF3•Et2O como promotor. Novamente, os produtos foram obtidos em bons rendimentos (75-91%) após um tempo reacional de 30 minutos. A melhor condição reacional foi observada quando uma quantidade de 4 equivalentes de BF3•Et2O em THF, sob atmosfera de argônio e temperatura ambiente foi utilizada. As tentativas de reação de propargilação assimétrica de aldeídos empregando-se BF3Et2O e diferentes ligantes quirais levaram aos álcoois homoalílicos desejados em bom rendimento, no entanto, em nenhuma das reações testadas foi observado excesso enantiomérico. Por fim, quando foi empregado a irradiação de micro-ondas, a melhor condição encontrada para a propargilação de aldeídos pelo ácido alenilborônico pinacol éster foi utilizando a temperatura de 100ºC e uma potência de 300 W. Os álcoois homopropargílicos correspondentes foram obtidos em bons rendimentos (51-98%) após 20 minutos. Através dos quatros métodos os produtos foram obtidos em rendimentos elevados de maneira regio- e quimiosseletivo. Foram obtidos vinte sete álcoois homopropargílicos e todos os compostos foram caracterizados por RMN de 1H e 13C. / In this work, four different methods for the synthesis of homopropargylic alcohols from aldehydes and boron compounds were developed. The first method was based on the use of the Amberlyst A-31 resin as the promoter. Best yields (70- 95%) were observed when an amount of 200% m/m of Amberlyst A-31 was used in CH2Cl2 under open atmosphere after 1,5 to 7,0 hours. The resin could be recovered and reused for three times in other reactions without looses in the yield. The second method was based on the use of tonsil clay as promoter. In this case, the desired compounds were obtained in good yields (60-96%) when an amount of 150% m/m of tonsil in CH2Cl2 under open atmosphere at room temperature was used. When the two methods using heterogeneous promoters were compared using aldehydes containing protecting groups sensitives to acidic medium, the best result was observed when tonsil was used, where the desired product was obtained in good yield together with a small amount of deprotected product. The third method was based on the use of BF3•Et2O as promoter. Again, the products were obtained in good yields (75-91%) after 30 minutes. The best condition was observed when 4 equivalents of BF3•Et2O in THF under argon atmosphere at room temperature was used. Attempts for the asymmetric propargylation reaction using BF3Et2O and different chiral ligands gave the corresponding products in good yields without any enantiomeric excess. Finally, when microwave irradiation was used to promote the propargylation of aldehydes, the best condition was found when allenylboronic acid pinacol ester was used at 100ºC using a 300 W potency. The homopropargylic alcohols were obtained in good yields (51-98%) after 20 minutes. Using the four developed methods, the products were obtained in high yields in a regio- and chemoselective way. Twenty seven homopropargylic alcohols were synthesized and all compounds were characterized by 1H and 13C NMR.

La thapsigargine (Tg) est une lactone sesquiterpène polyoxygénée appartenant à la famille des guaianolides, isolée de Thapsia (Apiacae), une plante poussant communément dans le basin méditerranéen. Son intérêt dans le traitement du cancer de la prostate est basé sur son potentiel inhibiteur de l’enzyme endo/sarcoplasmique calcium ATPase (SERCA). Ce phénomène conduit à une augmentation de la concentration du calcium dans le lumen du réticulum endoplasmique et engendre une apoptose cellulaire. Dans un premier temps, un modèle 8-desoxy-bicyclo[5.3.0]decadiénone, de structure proche du squelette de la Tg, a été synthétisé par le biais d’une réaction clé de Pauson-Khand allène-yne catalysée par un complexe de rhodium. L’approche directe développée est robuste avec de hautes sélectivités et rendements. Cette voie a ensuite été appliquée à la synthèse du produit naturel. A partir d’un époxyde optiquement enrichi, la partie Sud de la Tg (le motif lactonique) est tout d’abord mise en place. Les centres C6 et C8 sont ensuite construits respectivement par alcynylation/réduction asymétrique et par propargylation énantiosélective. Cette première approche a permis d’isoler un produit énantiopure possédant les centres chiraux C6, C7 et C8 ainsi que du motif lactonique en dix-sept étapes. Une seconde voie a été initiée permettant la mise en place plus rapide de la partie Sud de la molécule incluant les centres asymétriques C6, C7, C8 et C11 par le biais d’une réaction de dihydroxylation. Cette seconde voie a permis d’isoler un produit racémique possédant les centres chiraux C6, C7, C8 et C11 ainsi que du motif lactonique en dix étapes. Parallèlement, une étude méthodologique a été menée sur la réaction de Pauson-Khand allénol-yne intramoléculaire. Treize composés bicycliques ont été synthétisés en série acétal et NTs. / Thapsigargin (Tg) is a highly oxygenated sesquiterpene lactone belonging to the guaianolide family, isolated from the Mediterranean plant species Thapsia (Apiaceae). Its interest towards treatment of prostate cancer is based on the potency of this compound as an inhibitor of the endo/sarcoplasmic calcium ATPase (SERCA) inducing an increase in cytosolic calcium concentration and leading to apoptotic cell death. A straightforward approach to a highly functionalized 8-desoxy-bicyclo[5.3.0]decadienone model close to the Tg framework has been achieved through a key Rh(I) allenic Pauson-Khand reaction (APKR). The synthetic route developed therein is robust and the yields and selectivities are high. This approach was used in the synthesis of the natural compound. Starting from the same chiral epoxide, the bottom portion of the Tg (lactone core) is first built, then C6 and C8 carbons are functionalized respectively by asymmetric reduction and enantioselective propargylation. This first way allowed to synthesize a seventeen steps-enantiopure product with C6, C7, C8 chiral centers and the lactone core. A second way is performed to set up faster the bottom part of the molecule included C6, C7, C8 and C11 asymmetric centers through a dihydroxylation step. This second approach allowed to synthesize a ten steps-racemic product with C6, C7, C8, C11 chiral centers and the lactone core. Meanwhile, a methodological study was conducted on the intramolecular allenol-yne Pauson-Khand reaction. Thirteen bicyclic compounds were synthesized in acetal and NTs series.

Vu l’importance des molécules fluorées dans différents domaines et vu la réactivité engendrée par le 4,4,4-trifluorobut-2-ynoate d’éthyle 1 lors des travaux antérieurs réalisés au laboratoire, nous avons décidé d’étudier le comportement de dérivé fluoré 1 vis-à-vis d’hydrure tributylétain sans l’emploi de catalyseurs ou d’additifs. Le but est d’accéder à de nouveaux synthons fluorés par voies originales.Après une étude préliminaire pour effectuer cette réaction d’hydrostannation dans les meilleures conditions, nous avons réalisé pour la première fois la synthèse totalement régio- et stéréosélective des vinylétains (Z)-2α et (Z)-2β par un simple choix de solvant et sans l’utilisation d’aucun additif. Ces résultats inédits et très encourageants, nous ont conduis à étendre cette stratégie à d’autres hydrures comme l’hydrure de diphénylphosphine et l’hydrure de triphénylgermane..Les vinylétains (Z)-2α et (Z)-2β- de configurations bien définies sont des réactifs de choix pour élaborer de nouvelles structures fonctionnelles trifluorométhylées. En effet, le couplage cupro-catalysé de ces vinylétains en présence d’une quantité catalytique de CuI (10 moles%) avec une variété de bromures d’allyles, de propargyles, d’aryles, de benzyles et d’alcynyles conduisent à une grande variété de composés fluorés jamais décrits dans la littérature.Les méthodes de synthèse développées dans ce travail sont originales et permettent la synthèse d’une grande famille de composés fluorés avec un moindre coût. / The development of a simple method to obtain perfluoroalkylated building blocks for their subsequent utilization in the synthesis of Rf-containing compounds is therefore essential to organofluorine chemistry. Perfluoroalkylated vinyl metals constitute an important class of these building blocks.In order to prepare a new perfluoroalkylated bulding blocks, we investigated transition metal-catalyzed-free hydrostannylation of ethyl 4,4,4-trifluorobut-2-ynoate 1. The hydrostannylation took place smoothly in the absence of additive, providing regioselectively high yields of the corresponding α or β stannylated alkenoates depending on the nature of the solvent used. Indeed, we have demonstrated that the hydrostannylation of 1 in hexane provided the β-stannylated product with high regioselectivity (>95%) and excellent yield (>97%). Using methanol as solvent, total α-regioselectivity of the hydrostannylation of 1 was observed, providing α -tributylstannylacrylate as the sole regioisomer in a nearly quantitative yield.Theses new vinyltins reagents readily undergo copper (I) catalyst coupling reactions with various electrophiles as allyl, propargyl, benzyl and alkynyl bromides to provide good yields of the new corresponding acrylates esters bearing a β-trifluoromethyl group.This method provided a new efficient entry to this important class of compounds