Orientador: Maria Isabel Felisberti / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-17T19:50:50Z (GMT). No. of bitstreams: 1 Trinca_RafaelBergamo_M.pdf: 2663870 bytes, checksum: 36c96b7a317207cfd922f61029873b60 (MD5) Previous issue date: 2011 / Resumo: Neste trabalho foram sintetizados copolímeros bi (triblocos) e tricomponentes (penta blocos) constituídos de poli(etileno glicol) (PEG), l-lactídeo (3,6-Dimetil-1,4-dioxano-2,5-diona - LLA) e glicolídeo (1,4-dioxano-2,5-diona - GL). A síntese foi realizada pelo método de polimerização por abertura de anel (Ring-Opening Polymerization ¿ ROP) utilizando o 2-etilhexanoato de estanho e o PEG, como catalisador e iniciador, respectivamente. No que diz respeito às contribuições do projeto, foram estabelecidas as condições reacionais para a polimerização por abertura de anel em solução de tolueno, método até então não descrito na literatura. Além disso, o estudo de ação catalítica realizado mostrou que o provável mecanismo de ação do catalisador 2-etilhexanoato de estanho envolve etapas de coordenação/inserção, sendo que eventos de transferência de cadeia são minimizados. Dessa forma, apenas os grupos iniciadores previamente coordenados ao catalisador irão participar da reação, sendo necessário o uso de razões estequiométricas entre catalisador e iniciador para se garantir a manutenção das proporções entre monômeros e iniciadores utilizadas no meio reacional. O emprego das condições catalíticas estabelecidas garante elevada conversão dos monômeros e elevado rendimento reacional. Os copolímeros sintetizados foram caracterizados por técnicas de DSC, TGA, RMN, GPC e ensaios de degradação hidrolítica e intumescimento. A cristalização dos diferentes blocos dos copolímeros foi parcial ou totalmente suprimida por razões conformacionais e de impedimento estéreo, sendo dependente da composição, arquitetura e massa molar. Copolímeros ricos em PEG são hidrossolúveis e os demais são passiveis de intumescimento em água, demonstrando o caráter anfifílico. A degradação hidrolítica ocorre preferencialmente pela cisão de ligações unindo blocos hidrofóbicos e hidrofílicos / Abstract: Copolymers and terpolymers based on poly(ethylene glycol) (PEG), l-lactide (3,6-dimethyl-1,4-dioxane-2,5-dione - LLA) and glycolide (1,4-dioxane-2,5-dione - GL) were synthesized, producing a series of triblock and pentablock polymers with different architecture and composition. The synthesis was performed by the Ring-Opening Polymerization (ROP) method, using tin(II) 2-ethylhexanoate and PEG as catalyst and initiator, respectively. Regarding to the project contributions, the reaction conditions for Ring-Opening Polymerization in toluene solution were established, method so far not described in the literature. Moreover, the study of catalytic action showed that the probable action mechanism of the catalyst tin(II) 2-ethylhexanoate involves steps of coordination-insertion, and that chain transfer events are minimized. Thus, only the initiators previously coordinated to the catalyst will participate in the reaction, being necessary the use of stoichiometric ratios between catalyst and initiator to ensure the high reaction yield and a conversion of lactones to copolymers. The copolymers were characterized by DSC, TGA, NMR and GPC techniques and by swelling and hydrolytic degradation tests. The crystallization of different blocks of the copolymers were partially or totally suppressed for conformational and steric hindrance reasons, being dependent on the composition, architecture and molecular mass. PEG-rich copolymers are water soluble and others are capable of swelling in water, showing the amphiphilic character of the copolymers. The hydrolytic degradation occurs preferentially by scission of ester bonds linking hydrophobic and hydrophilic blocks / Mestrado / Físico-Química / Mestre em Química

A doença de Chagas é uma doença endêmica causada pelo protozoário Trypanosoma cruzi que assola cerca de 15 milhões de pessoas na América Latina. Na busca de uma alternativa mais econômica e eficiente para o tratamento desta doença, Kiushi e colaboradores isolaram da planta Darcocephalum komarovi, a komaroviquinona. Após estudos \"in vitro\" de células humanas contaminadas com tripomastigotos do Trypanosoma cruzi, a komaroviquinona mostrou ser 15 a 300 vezes mais eficiente que os tratamentos atualmente disponíveis. Mesmo com este resultado animador, pouco se tem relatado sobre a síntese da komaroviquinona, existindo apenas 4 rotas sintéticas descritas na literatura, sendo duas delas enantiosseletivas. Baseado neste fato, o presente trabalho visa estudar uma forma de se obter a komaroviquinona de forma rápida e eficaz, utilizando, para tal fim, a estratégia de abertura de epóxidos por um aril-magnésio ou aril-lítio, como etapa chave. Pretende-se com esta estratégia sintetizar a komaroviquinona em 9 etapas, partindo de reagentes disponíveis comercialmente. Cabe ressaltar que esta estratégia possibilita a síntese de outros produtos naturais como o brussonol, que apresentou citotoxidade moderada em células de ovários do inseto Spodoptera frugiperda (Sf9) e células de ovário do mamífero hamster chinês (CHO), além de atividade citotoxicológica às células P388 leucêmicas de camundongo. Alguns resultados promissores foram obtidos como a preparação \"one pote\" da cetona 2-alil-3,3-dimetil-cicloexanona com rendimento na faixa entre 54-65 % e a preparação do respectivo epóxido com rendimento de 89 %. Além destes resultados, a reação de abertura de epóxido se mostrou eficiente quando utilizados organometálicos modelo (disponíveis comercialmente), sendo que os rendimentos foram de 53 % e 62%, dependendo do reagente de Grignard utilizado. Entretanto ainda se faz necessário otimizar as condições reacionais para aplicação dos organometálicos reais, precursores da komaroviquinona e do brussonol. / Chagas\'s disease is an endemic infection caused by the protozoan Trypanosoma cruzi, affecting near 15 milion of people in Latin America. In a search of an economical and efficient alternative for the treatment of this disease, Kiushi and colleagues isolated Komaroviquinone from the plant Darcocephalum komarovi. After in vitro studies of human cells (infected with trypomastigotes of Trypanosoma cruzi), komaroviquinone proved to be 15 to 300 times more efficient than the currently available prescriptions. Even with this encouraging result, little has been reported on the synthesis of komaroviquinone, and only four synthetic routes are described in the literature (two being enantioselective). Based on this fact, the present work deals with the study of a new strategy to synthesize komaroviquinone quickly and effectively, employing an epoxide ring-opening approach with aryl-magnesium and aril-lithium compounds as the key step. Using this strategy, komaroviquinone may be synthesized in 9 steps, starting from commercially starting materials. It should be noted that this strategy enables the synthesis of other natural products such as brussonol, which showed moderate cytotoxicity on insect-derived Spodoptera frugiperda pupal ovarian cells (Sf9), mammalian Chinese hamster ovary cell (CHO), and P388 murine leukemia cells. Some promising results were already obtained as the preparation one pote of ketone with yield in range of 54-65 % and the preptaration of the corresponding epoxide with 89 % yield. Besides this, the epoxide ring-opening approach could be applied with some aromatic model compounds (commercially available) with 53 % and 62 % yield, depending on the Grignard reagents employed. However, in order to prepare komaroviquinone, it is still necessary to optimize the reaction conditions so that the real aromatic derivatives (precursors of komaroviquinone and brussonol) may be used.

Common biodegradable polyesters such as poly(lactic acid) (PLA), poly(lactic-co-glycolic acid) (PLGA) and poly(ε-caprolactone) (PCL) are used as drug delivery vehicles for tissue regenerative applications. However, they are typically bioinert, with drug loading limitations. Polymerizing the active agent or precursor into its respective biodegradable polymer would control drug loading via molar ratios of drug to initiator used for synthesis. Simvastatin was chosen due to its favorable anti-inflammatory, angiogenic, and osteogenic properties. In addition, its lactone ring lends itself to ring-opening polymerization and, consequently, the synthesis of poly(simvastatin) with controlled simvastatin release. Simvastatin was first polymerized with a 5kDa methyl-terminated poly(ethylene glycol) (mPEG) initiator and catalyzed via stannous octoate to form poly(simvastatin)-block-poly(ethylene glycol). Molecular weights ranged from 9.5kDa, with a polydispersity index (PDI) of 1.1 at 150 °C, to 75kDa with a PDI of 6.9 at 250 °C. First-order propagation rates were seen. Infrared spectroscopy showed carboxylic and methyl ether stretches unique to simvastatin and mPEG in the copolymer, respectively. Slow degradation was seen in neutral and alkaline conditions, with simvastatin, simvastatin-incorporated macromolecules, and mPEG identified as degradation products. Alternatively, triazabicyclodecene (TBD) was used to mediate simvastatin polymerization. A lower temperature of 150°C led to successful polymerization using 5kDa mPEG, compared to at least 200 °C via stannous octoate. TBD was also successful for reactions using 2 or 0.55kDa mPEG. The biodegradability of poly(simvastatin)-block-poly(ethylene glycol) via TBD improved, losing twice more mass in phosphate-buffered saline, pH 7.4, than the copolymer synthesized via stannous octoate. Release rates of three different copolymers synthesized demonstrated tunable simvastatin release. To further modulate degradation, poly(simvastatin)-block-poly(ethylene glycol) was blended with 5, 2, or 0.55kDa mPEG-initiated PLA copolymers. The blends showed a compressive elastic modulus ranging from 26 to 44MPa, within the magnitude of trabecular bone (approximately 50MPa). Tunability in mass loss and release was also seen due to varied ratios of incorporated PLA copolymers. Lastly, copolymer degradation byproducts inhibited HMG-CoA reductase and showed possible enhancement of osteoblastic activity in vitro. A pilot study using a rodent calvarial onlay model showed tolerability of the polymers and potential for long-term evaluations of bioactivity. Poly(simvastatin) may be useful in regenerative applications.

The synthesis and characterization of a series of chiral indium complexes bearing a tridentate NNO ligand are reported. The ligand 2-[[[(dimethylamino)cyclohexyl]amino]methyl]- 4,6-bis(tert-butyl) phenol (H₂NNO) was synthesized via a previously published procedure and bound to indium by both a protonolysis and salt metathesis route. A dimethylated indium complex (NNO)InMe₂ (1) was isolated by reaction of InMe₃ with H₂NNO. A one-pot saltmetathesis route was used to produce a unique mixed-bridge dinuclear indium complex [(NNO)InCl] ₂(μ-OEt)(μ-Cl) (3) from a mixture of indium trichloride, potassium ethoxide and the monopotassiated salt of the ligand, KH(NNO). Direct reaction of KH(NNO) and indium trichloride resulted in the formation of (NNO)InCl₂ (4) which was carried forward to 3 by reaction with sodium ethoxide. The complex 3 is active for the ROP of β-butyrolactone ε-caprolactone and lactide and is the first reported indium-based catalyst for lactide or β-butyrolactone ROP. Kinetic studies of 3 for ROP of LA revealed that catalyst was well-behaved, and that the rate was first order with regard to lactide and catalyst. The enthalpy and entropy of activation for the ROP were experimentally determined. Polymer produced by ROP by 3 has narrow molecular weight distribution and a good correlation is seen between the observed moleular weight and monomer loading. A mechanism was proposed for 3 acting as a catalyst for the ROP of lactide; however further experiments are required to confirm this mechanism. Polymer samples isolated from the ROP of rac-lactide by rac-3 show isotactic enrichment. It is postulated that the chiral catalyst 3 is exerting stereocontrol via an enantiomorphic site control mechanism. / Science, Faculty of / Chemistry, Department of / Graduate

Compounds containing multiple metal-carbon bonds are now widely used as catalysts for organic and materials synthesis. Among such transformations, olefin metathesis (OM) occupies a position of pre-eminent significance. Alkyne metathesis holds great promise, but remains in a much lower state of development. The OM-directed work in this thesis sought to advance the state of the art in living, Ru-catalyzed ringopening metathesis polymerizations (ROMP). Currently, the first- and third-generation Grubbs initiators, which exhibit the ease of handling characteristic of the late metal ruthenium, dominate ROMP applications. These initiators are characterized by extremes of reactivity, however. We describe the first ruthenium initiator capable of living ROMP at RT, irrespective of monomer bulk. Polydispersity indices as low as 1.03 are routinely attainable, and excellent control is maintained in synthesis of diblock copolymers from sterically demanding and sterically unencumbered monomers. Work on alkyne metathesis sought to expand existing understanding of the features that influence stability and reactivity in ruthenium carbynes. A classification system was developed in which Class A carbynes were defined as those that readily undergo conversion into an M=C entity (e.g. vinylidene, allenylidene, or alkylidene); Class B carbynes those that have a stable carbyne functionality. Four Ru carbyne complexes, all initially regarded as prospective Class B carbynes, were selected for study. Investigation of their reactivity resulted in categorization of several as Class A species, and development of design criteria that may open the door to assembly of stable, well-defined carbyne complexes of ruthenium.

Usage of complexes in homogeneous catalysis for synthesis functional materials with defined properties is one of the most significant areas of research organometallic compounds of lanthanides in the last decade. One of the way became polymers with defined properties is for example ring opening polymerization. Aliphatic polyesters, which are biodegradable and biocompatible (useful for biomedicine), can be prepared by this method. Theoretical part of this work includes preparation of lanthanidocenes, their characterization and possibilities of their use for polymer synthesis. The aim of experimental part was performance and optimizing synthesis of series lanthanocen chlorides complex (Sm, Nd a Pr) and new monopentamethylcyklopentadienyl complexes. Introduced structural types were chosen for their possibility of polymerization activity or their activation by adding alkyl reagents. The complexes were spectral characterized by 1H NMR, and IR spectroscopy. Structure was defined by roentgen structural analysis. Catalytic activities for polymerization of ?-caprolacton in toluen (laboratory temperature) were performed for selected complexes. Polycaprolactone was characterized by gel permeation chromatography and NMR.

Syntéza polylaktidu (PLA) polymerací za otevření kruhu cyklického monomeru (ROP) může být uskutečněna různými způsoby. Literatura uvádí více než 100 katalytických systémů, jejichž pomocí lze polylaktid a jiné biodegradabilní alifatické polyestery získat. Například organokovové katalyzátory na bázi Sn, Zn, Al atd. se po splnění své polymerační funkce stávají kontaminanty a pro humánní implantáty je použití takového materiálu diskutabilní. V současné době jsou v centru výzkumné pozornosti nové N-heterocyklické karbenové katalyzátory. Tyto „metal-free“ katalytické struktury jsou schopné reprodukovatelně řídit syntézu polymerů předem definované molekulové hmotnosti s definovanými koncovými skupinami a nízkou polydisperzitou, která je charakteristická pro živý průběh polymerace. Nabízí se možnost syntézy blokových kopolymerů a různorodých makromolekulárních architektur. Předložená diplomová práce se zabývá studiem polymerace cyklického monomeru D,L-laktidu katalyzované N-heterocyklickým karbenem. Polymerace byly vedeny v přítomnosti benzylalkoholu jako iniciátoru v roztoku THF. Byl sledován vliv složení reakčního systému monomer – iniciátor – katalyzátor. Dále byly připraveny polymery opticky čistého L-laktidu s makroiniciátory PEG s Mn = 1000 a 2000 g/mol. Střední číselná molekulová hmotnost (Mn) a polydisperzita (PDI) byly stanoveny pomocí GPC. Definovatelnost koncových skupin vybraných polymerů byla prokázána pomocí 1H NMR.

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På senare tid har forskning syftat till att främja miljövänligare teknik inom alla fält. Det visar sig inom materialframställningen som en önskan att använda material som inte är beroende av olja, inte tillverkade med tungmetaller samt nedbrytbara med en minimal miljöpåverkan. Detta har bland annat gett organiska katalysatorer en större plats inom forskningen. En av dessa är cyclodextrin, en cyklisk oligosackarid som har påvisats bilda makromolekylara komplex med andra molekyler. En aspekt av detta är att den kan hydrolysera polymerer då den bildar komplex med hydrofila molekyler och kan aktivera dessa genom vätebindning. Vilket Harada et. al. visade kunde utnyttjas for att polymerisera cycliska estrar. Detta examensarbete utforskar en del av det arbetet genom att dels verifiera polymerisationstekniken som ar en lösningsmedelsfri polymerisation dels försök till att framstalla en ny dimer av cyclodextrin som ska effektivt kunna polymerisera cycliska estrar mer effektivt an tidigare. Den nya dimern bygger på en thiourea-länk. Aven om polymerisation med vanlig cyclodextrin har visats fungera sa kan den föreslagna  dimern inte polymerisera lika effektivt. Syntesen ar problematisk och annars åtråvarda egenskaper hos cyclodextrin, som makromolekylär komplexbildning, kan inhibera polymerisationen och tidigare uppreningssteg.

<p>  </p> <p>Tetrahydrofurans (THFs) and tetrahydropyrans (THPs) are important core scaffolds frequently found in many bioactive natural products and important drug molecules. Regardless of the recent advances, achieving high stereoselective disubstituted or polysubstituted THFs and THPs still remains a synthetic challenge especially via metal catalyzed direct intramolecular Csp³-O bond formation for the ring closure. Cyclopropanols are important and useful building blocks in synthetic chemistry, and due to the intrinsic ring strain, they are prone to undergo ring opening process under transition metal catalyst to produce homoenolates. Herein, we have developed a novel Cu(II)-catalyzed hydroxyl tethered cyclopropanol ring-opening cyclization to diastereoselective syntheses of THF and THP rings. The reaction features a broad substrate scope, scalability, and good functional-group tolerability. Further mechanism study has revealed that the 7-membered metallocycle intermediate generated by Cu and hydroxycyclopropanol plays an important role in reaction pathway. It also enabled us to complete the shortest enantioselective total synthesis of hyperione A and B.</p> <p>The gibberellins contain a family of nearly 130 highly functionalized diterpenoids in the plant world. Gibberellic acids (GAs) are produced by plants and microorganisms to regulate the cell growth and development. We have developed a comprehensive synthesis strategy for the natural product GA₁₈ that includes the ene reaction, one-pot ozonolysis cascade aldol condensation, photocatalyzed [2+2] reaction, and Sm-induced rearrangement to build the critical tetracyclic skeleton.  Additionally, efforts also have been made in functional group interconversion to finalize the end game. </p>