In the last century, no less than five nobel prizes have been awarded for the construction of carbon-carbon bonds : The Grignard reaction (1912), the Diels-Alder reaction (1950), the Wittig reaction (1979), Olefin metathesis (2005) and palladium cross-coupling reactions (2011). The latter two are transition metal catalyzed transformations and their impact on the synthesis of pharmaceutically active compounds, bulk chemicals, fine chemicals, high tech materials as well as agricultural chemicals has been phenomenal. These reactions have changed the way the scientific community views the science of synthesis. Unlike palladium, gold has long been considered to be an expensive and inert metal and therefore, research on Au catalysis was scarse until the begining of the new millenium. Once the scientific community realized the treasure trove of reactivity that gold had to offer, the number of chemical transformations as well as total syntheses involving Au(I)/Au(III) catalysis has sky rocketed. A methodology initially developped by Toste and coworkers has shown that intramolecular addition of a silyl enol ether on alkynes proceeds via a 5-exo¬-dig¬ process. In the first part of this thesis, we will discuss how the ancilary ligand on Au(I) species can influence pathway selectivity for these cyclizations, therefore opening the door to selective 6-endo-dig cyclizations to generate fused carbocycles. With biological processes as well as other competing processes becoming ever more efficient, the future of chemical synthesis is threatened. If it is to survive, the focus of new chemical transformations will have to be on the cost and the greeness of the process. In the second part of this thesis, we will demonstrate how Ag(I) and Cu(I) complexes can offer even better 6-endo-dig¬ selectivity than analogous Au(I) complexes. Silver is about 56 times less expensive than gold, and copper is about 453 times less expensive than gold. Due to the greatly increased selectivity as well as the diminished cost of the catalysts, we have provided access to an attractive 6-endo-dig¬ cyclization process.

Neste trabalho foi sintetizada e caracterizada uma série de porfirinas e FeP correspondentes contendo substituintes NO2 nas posições orto- ou grupos COOH nas posições para- dos anéis meso-fenis, e a atividade catalítica destes compostos na oxidação de hidrocarbonetos foi investigada, tanto em sistemas homogêneos quanto em sistemas suportados. As porfirinas H2(TNMCPP), H2(DNDCPP) e H2(MNTCPP) foram sintetizadas pela reação de pirrol com a mistura de 2-nitrobenzaldeído e 4-carboxibenzaldeído, em meio de ácido propiônico e nitrobenzeno, sendo em seguida isoladas e purificadas através de cromatografia preparativa em sílica gel tendo como eluente a mistura DCM : ACT : HAc (8 : 2 : 0,1). A inserção de ferro nas porfirinas bases livre foi feita pela reação com FeBr2.2H2O em meio de DMF. A caracterização das porfirinas bases livre e das correspondentes FeP envolveu diferentes técnicas como: TLC, eletroforese em gel de agarose, análise elementar, UV/Vis, IV, RMN 1H, FAB MS, susceptibilidade magnética e EPR. Utilizou-se as porfirinas H2(TNPP) e H2(TCPP) e FeP correspondentes como padrões de comparação, tornando a série completa. A purificação e caracterização destas porfirinas mostraram-se bastante complexas devido à presença de grupos ionizáveis resultando em grandes diferenças de solubilidade na série e efeitos de agregação. Estes efeitos foram mais pronunciados para as porfirinas contendo maior número de grupos COOH. O estudo da atividade catalítica da série de FeP foi desenvolvido inicialmente em meio homogêneo, utilizando diferentes substratos como: (Z)-cicloocteno, cicloexeno, cicloexano e adamantano. As FeP sintetizadas mostraram-se catalisadores eficientes e seletivos para a hidroxilação de alcanos e epoxidação de alcenos. A estabilidade da Fe(TNMCPP)Cl foi investigada em reações com múltiplas adições de oxidante. Observou-se uma alta estabilidade para este catalisador em solução, com bons rendimentos em epóxido para até sete ciclos consecutivos, e um alto número de turnover (1142). A Fe(TNMCPP)Cl foi ancorada na APS através de ligação covalente (peptídica) entre o grupo COOH da FeP e o grupo NH2 da sílica funcionalizada. Esta FeP foi selecionada por possuir apenas um grupo capaz de reagir com a sílica e, ao mesmo tempo, a proteção estérica de três grupos NO2 substituintes nas posições orto-, constituindo um sistema interessante do ponto de vista catalítico. Este sistema mostrou-se bastante eficiente na oxidação do (Z)-cicloocteno. O número máximo de turnover catalítico para esta FeP suportada foi de 595 após três adições sucessivas de oxidante. A Fe(TNMCPP)Cl foi ancorada na APS também por atração eletrostática, porém este sistema mostrou-se menos eficiente como catalisador na oxidação do (Z)-cicloocteno. / In this work, a series of porphyrins and corresponding FeP containing NO2-substituents in the ortho- or COOH-groups in the para- meso-phenyl rings were synthesized and the catalytic activities of such compounds were investigated in both homogeneous and heterogeneous systems. H2(TNMCPP), H2(DNDCPP) and H2(MNTCPP) porphyrins were synthesized through the mixed co-condensation of pyrrole and different benzaldehydes (2-nitrobenzaldehyde and 4-carboxybenzaldehyde) in propionic acid and nitrobenzene media. The porphyrins were then isolated and purified through silica gel chromatography, having a solvent mixture DCM : ACT : HAc (8 : 2 : 0,1). The characterization of the free-base porphyrins and the corresponding FeP was carried out through TLC, electrophoresis on agarose gel, elemental analysis, UV/Vis, infra red, RMN 1H, FAB MS, magnetic susceptibility and EPR. H2(TNPP) and H2(TCPP) and corresponding FeP were used for comparison, thus completing the porphyrin series. The purification and characterization of these porphyrins proved to be very complex due the presence of ionic groups. This resulted in different solubilities throughout the series, as well as aggregation effects. Such effects were more pronounced with porphyrins containing a greater number of COOH groups. The study of the catalytic activities of the FeP was initially carried out in homogeneous system, by using various substrates: (Z)-cyclooctene, cyclohexene, cyclohexane and adamantane. The synthesized FeP were efficient and selective catalysts for alkane hydroxilation and alkene epoxidation. The stability of Fe(TNMCPP)Cl was investigated by multiple oxidant addition. A high stability was observed for this catalyst in homogeneous system, since it led to good epoxide yields up to the seventh cycle and an excellent turnover number of 1142. Fe(TNMCPP)Cl was supported on APS through covalent binding of the peptidic type between COOH groups in the FeP and NH2 group on the funcionalized silica. This FeP was chosen for the study since it has only one group that is capable of reacting with the silica, at the same time that it presents sterical hindrance confered by the three NO2 groups in the ortho-position. This is a very interesting system from the catalytical point of view. Such system proved to be very efficient in the oxidation of (Z)-cyclooctene. The maximum catalytic turnover attained with this supported FeP was of 595, after three sucessive additions of oxidant. Fe(TNMCPP)Cl was also supported on APS though electrostatic binding, but this system was a less efficient catalyst for (Z)-cyclooctene oxidation.

The use of enamines continues to be an important tool in organic syntheses as both a catalyst and reactant. The addition of metal catalysts coupled with enamine catalysis has generated many reactions that normally would not occur separately. However, catalysts' incompatibility is an issue that we wish to solve allowing new chemistry to occur without hindrance. The use of enamines has continued to be a well-studied area of organic chemistry, but the field is ripe for different types of enamines to gain the spotlight. Enaminones are enamines with both nucleophilic and electrophilic properties. They allow reactions that are normally not possible with enamines to become obtainable. Chapter 1 is a brief introduction on enamines and the reason they gained so much attention. Then ends with enaminones and what makes them interesting reactants. Chapter 2 described a new synthesis for the tricyclic synthesis of chromanes using a novel bifunctional catalyst system of enamine-metal Lewis acid giving great yields (up to 87 %yield) and excellent stereoselectivity (up to 99 % ee). Chapter 3 covered new reactions for ring-open cyclopropane (up to 94% yield), tetrahydroquinolinones (up to 84% yield) and enantiospecific tetrahydroquinolinones (up to 84% yield and 97% ee) using α-enaminone and donor-acceptor cyclopropanes. Finally, Chapter 4 focused a new method for synthesizing benzobicyclo[3.2.1]octanes with an added sterically bulky quaternary center and imine functionalization giving yields between 36-73% yield using α-enaminone with alkylidene malonates.

In the last century, no less than five nobel prizes have been awarded for the construction of carbon-carbon bonds : The Grignard reaction (1912), the Diels-Alder reaction (1950), the Wittig reaction (1979), Olefin metathesis (2005) and palladium cross-coupling reactions (2011). The latter two are transition metal catalyzed transformations and their impact on the synthesis of pharmaceutically active compounds, bulk chemicals, fine chemicals, high tech materials as well as agricultural chemicals has been phenomenal. These reactions have changed the way the scientific community views the science of synthesis. Unlike palladium, gold has long been considered to be an expensive and inert metal and therefore, research on Au catalysis was scarse until the begining of the new millenium. Once the scientific community realized the treasure trove of reactivity that gold had to offer, the number of chemical transformations as well as total syntheses involving Au(I)/Au(III) catalysis has sky rocketed. A methodology initially developped by Toste and coworkers has shown that intramolecular addition of a silyl enol ether on alkynes proceeds via a 5-exo¬-dig¬ process. In the first part of this thesis, we will discuss how the ancilary ligand on Au(I) species can influence pathway selectivity for these cyclizations, therefore opening the door to selective 6-endo-dig cyclizations to generate fused carbocycles. With biological processes as well as other competing processes becoming ever more efficient, the future of chemical synthesis is threatened. If it is to survive, the focus of new chemical transformations will have to be on the cost and the greeness of the process. In the second part of this thesis, we will demonstrate how Ag(I) and Cu(I) complexes can offer even better 6-endo-dig¬ selectivity than analogous Au(I) complexes. Silver is about 56 times less expensive than gold, and copper is about 453 times less expensive than gold. Due to the greatly increased selectivity as well as the diminished cost of the catalysts, we have provided access to an attractive 6-endo-dig¬ cyclization process.

This thesis is focused on the development of new palladium and copper- mediated reactions for functionalization of alkenes and propargylic alcohol derivatives. The synthetic utility of the 1,2-diborylated butadienes synthesized in one of these processes has also been demonstrated. We have developed an efficient procedure for the synthesis of allenyl boronates from propargylic carbonates and acetates. This was achieved by using a bimetallic system of palladium and copper or silver as co-catalyst. The reactions were performed under mild conditions for the synthesis of a variety of allenyl boronates. Furthermore, the synthesis of 1,2-diborylated butadienes was achieved with high diastereoselectivity from propargylic epoxides. The reactivity of the 1,2-diborylated butadienes with aldehydes was studied. It was found that the initial allylboration reaction proceeds via an allenylboronate intermediate. The allenylboronate reacts readily with an additional aldehyde to construct 2-ethynylbutane-1,4-diols with moderate to high diastereoselectivity. We have also studied the copper-mediated trifluoromethylation of propargylic halides and trifluoroacetates. It was also shown that a transfer of chirality occurred when an enantioenriched starting material was used. In the last part of the thesis, we have described a method for palladium-catalyzed functionalization of allylic C-H bonds for the selective synthesis of allylic silanes. The protocol only works under highly oxidative conditions which suggest a mechanism involving high oxidation state palladium intermediates. / <p>At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 1: Accepted.</p>

Neste trabalho foi sintetizada e caracterizada uma série de porfirinas e FeP correspondentes contendo substituintes NO2 nas posições orto- ou grupos COOH nas posições para- dos anéis meso-fenis, e a atividade catalítica destes compostos na oxidação de hidrocarbonetos foi investigada, tanto em sistemas homogêneos quanto em sistemas suportados. As porfirinas H2(TNMCPP), H2(DNDCPP) e H2(MNTCPP) foram sintetizadas pela reação de pirrol com a mistura de 2-nitrobenzaldeído e 4-carboxibenzaldeído, em meio de ácido propiônico e nitrobenzeno, sendo em seguida isoladas e purificadas através de cromatografia preparativa em sílica gel tendo como eluente a mistura DCM : ACT : HAc (8 : 2 : 0,1). A inserção de ferro nas porfirinas bases livre foi feita pela reação com FeBr2.2H2O em meio de DMF. A caracterização das porfirinas bases livre e das correspondentes FeP envolveu diferentes técnicas como: TLC, eletroforese em gel de agarose, análise elementar, UV/Vis, IV, RMN 1H, FAB MS, susceptibilidade magnética e EPR. Utilizou-se as porfirinas H2(TNPP) e H2(TCPP) e FeP correspondentes como padrões de comparação, tornando a série completa. A purificação e caracterização destas porfirinas mostraram-se bastante complexas devido à presença de grupos ionizáveis resultando em grandes diferenças de solubilidade na série e efeitos de agregação. Estes efeitos foram mais pronunciados para as porfirinas contendo maior número de grupos COOH. O estudo da atividade catalítica da série de FeP foi desenvolvido inicialmente em meio homogêneo, utilizando diferentes substratos como: (Z)-cicloocteno, cicloexeno, cicloexano e adamantano. As FeP sintetizadas mostraram-se catalisadores eficientes e seletivos para a hidroxilação de alcanos e epoxidação de alcenos. A estabilidade da Fe(TNMCPP)Cl foi investigada em reações com múltiplas adições de oxidante. Observou-se uma alta estabilidade para este catalisador em solução, com bons rendimentos em epóxido para até sete ciclos consecutivos, e um alto número de turnover (1142). A Fe(TNMCPP)Cl foi ancorada na APS através de ligação covalente (peptídica) entre o grupo COOH da FeP e o grupo NH2 da sílica funcionalizada. Esta FeP foi selecionada por possuir apenas um grupo capaz de reagir com a sílica e, ao mesmo tempo, a proteção estérica de três grupos NO2 substituintes nas posições orto-, constituindo um sistema interessante do ponto de vista catalítico. Este sistema mostrou-se bastante eficiente na oxidação do (Z)-cicloocteno. O número máximo de turnover catalítico para esta FeP suportada foi de 595 após três adições sucessivas de oxidante. A Fe(TNMCPP)Cl foi ancorada na APS também por atração eletrostática, porém este sistema mostrou-se menos eficiente como catalisador na oxidação do (Z)-cicloocteno. / In this work, a series of porphyrins and corresponding FeP containing NO2-substituents in the ortho- or COOH-groups in the para- meso-phenyl rings were synthesized and the catalytic activities of such compounds were investigated in both homogeneous and heterogeneous systems. H2(TNMCPP), H2(DNDCPP) and H2(MNTCPP) porphyrins were synthesized through the mixed co-condensation of pyrrole and different benzaldehydes (2-nitrobenzaldehyde and 4-carboxybenzaldehyde) in propionic acid and nitrobenzene media. The porphyrins were then isolated and purified through silica gel chromatography, having a solvent mixture DCM : ACT : HAc (8 : 2 : 0,1). The characterization of the free-base porphyrins and the corresponding FeP was carried out through TLC, electrophoresis on agarose gel, elemental analysis, UV/Vis, infra red, RMN 1H, FAB MS, magnetic susceptibility and EPR. H2(TNPP) and H2(TCPP) and corresponding FeP were used for comparison, thus completing the porphyrin series. The purification and characterization of these porphyrins proved to be very complex due the presence of ionic groups. This resulted in different solubilities throughout the series, as well as aggregation effects. Such effects were more pronounced with porphyrins containing a greater number of COOH groups. The study of the catalytic activities of the FeP was initially carried out in homogeneous system, by using various substrates: (Z)-cyclooctene, cyclohexene, cyclohexane and adamantane. The synthesized FeP were efficient and selective catalysts for alkane hydroxilation and alkene epoxidation. The stability of Fe(TNMCPP)Cl was investigated by multiple oxidant addition. A high stability was observed for this catalyst in homogeneous system, since it led to good epoxide yields up to the seventh cycle and an excellent turnover number of 1142. Fe(TNMCPP)Cl was supported on APS through covalent binding of the peptidic type between COOH groups in the FeP and NH2 group on the funcionalized silica. This FeP was chosen for the study since it has only one group that is capable of reacting with the silica, at the same time that it presents sterical hindrance confered by the three NO2 groups in the ortho-position. This is a very interesting system from the catalytical point of view. Such system proved to be very efficient in the oxidation of (Z)-cyclooctene. The maximum catalytic turnover attained with this supported FeP was of 595, after three sucessive additions of oxidant. Fe(TNMCPP)Cl was also supported on APS though electrostatic binding, but this system was a less efficient catalyst for (Z)-cyclooctene oxidation.

In the last century, no less than five nobel prizes have been awarded for the construction of carbon-carbon bonds : The Grignard reaction (1912), the Diels-Alder reaction (1950), the Wittig reaction (1979), Olefin metathesis (2005) and palladium cross-coupling reactions (2011). The latter two are transition metal catalyzed transformations and their impact on the synthesis of pharmaceutically active compounds, bulk chemicals, fine chemicals, high tech materials as well as agricultural chemicals has been phenomenal. These reactions have changed the way the scientific community views the science of synthesis. Unlike palladium, gold has long been considered to be an expensive and inert metal and therefore, research on Au catalysis was scarse until the begining of the new millenium. Once the scientific community realized the treasure trove of reactivity that gold had to offer, the number of chemical transformations as well as total syntheses involving Au(I)/Au(III) catalysis has sky rocketed. A methodology initially developped by Toste and coworkers has shown that intramolecular addition of a silyl enol ether on alkynes proceeds via a 5-exo¬-dig¬ process. In the first part of this thesis, we will discuss how the ancilary ligand on Au(I) species can influence pathway selectivity for these cyclizations, therefore opening the door to selective 6-endo-dig cyclizations to generate fused carbocycles. With biological processes as well as other competing processes becoming ever more efficient, the future of chemical synthesis is threatened. If it is to survive, the focus of new chemical transformations will have to be on the cost and the greeness of the process. In the second part of this thesis, we will demonstrate how Ag(I) and Cu(I) complexes can offer even better 6-endo-dig¬ selectivity than analogous Au(I) complexes. Silver is about 56 times less expensive than gold, and copper is about 453 times less expensive than gold. Due to the greatly increased selectivity as well as the diminished cost of the catalysts, we have provided access to an attractive 6-endo-dig¬ cyclization process.

Peptide secondary structure provides an exceptional scaffold on which to design highly reactive and selective enzyme-like catalysts. This work describes the rational design and synthesis of a suite of helical peptide catalysts that are capable of achieving proximity-induced rate enhancement in Diels-Alder cycloadditions and indole alkylations. Microwave assisted synthesis of resin-supported polypeptides enables incorporation of non-natural amino acid residues that induce helicity (Aib) or provide functional handles on which organic catalytic residues can be attached. These small peptide catalysts exhibit binding-driven selectivity rather than relying on the inherent reactivity of substrates, which allows access to products that are not obtainable with traditional catalysts in solution. Catalyst efficiency reached up to 28,000 turn overs, which mimics natural enzymatic systems. Studies were also conducted into the stabilization of peptide secondary structure via covalent linking of nucleophilic amino acid side chains with squaric acid residues. Under mild conditions, stapling of nitrogen, sulfur and oxygen residues can readily be achieved in either organic or aqueous media. Squaric acid staples display pH selectivity for specific side chains and selective removal of diester staples (diserine staple) is demonstrated with methylamine. This new method for peptide stapling is shown to dramatically increase the proteolytic stability of eIF4E cancer inhibitor proteins, which typically are prone to quick degradation. Tyrosidine and RGD peptide analogues were synthesized and cyclized on resin in order to provide a new pathway to macrocyclization of antibacterial and integrin binding cyclic peptides.

The ability of gold(I) to activate many types of unsaturated bonds toward nucleophilic attack was not widely recognized until the early 2000s. One major challenge in gold catalysis is the control over regioselectivity when there are two or more possible products as a result of complicated mechanistic pathways. It is well know that the choice of ligand can have dramatic effects on which pathway is being followed but very rarely are the reasons for this selectivity understood. The synthesis of new acyclic diaminocarbenes was developed and a study of the ligand effects on the regioselectivity of a gold-catalyzed domino enyne cyclization hydroarylation reaction and a Nazarov cyclization was undertaken. New chiral acyclic diaminocarbenes were also developed and tested along side new C3-symmetric phosphite ligands in an asymmetric intramolecular hydroamination of allenes. Structure activity correlations were developed for the potential use in further rational ligand design. The synthesis of 6a,7-dihydro-5-amino-dibenzo[c,g]chromene derivatives via a gold-catalyzed domino reaction of alkynylbenzaldehydes in the presence of secondary amines was developed. These were sent to be screened for biological activity.

No description available.