Neste trabalho realizou-se uma triagem com os fungos de origem marinha Trichoderma sp Gc1, Penicillium miczynskii Gc5, Penicillium raistrickii Ce16 e Aspergilus sydowii Gc12 para catalisar a abertura do (RS)-2-(benziloximetil)oxirano (2). O melhor resultado foi obtido com o fungo Trichoderma sp Gc1, pois forneceu o (R)-(-)-2-(benziloximetil)oxirano (2) com excesso enantiomérico de 60 % e rendimento isolado de 39 %; o diol (S)-(+)-1,2-propanodiol-3-fenilmetóxi (2a) com excesso enantiomérico de 32 % e rendimento de 19 %. Posteriormente otimizou-se as condições experimentais com o epóxido 2 e o fungo Trichoderma sp Gc1, variando-se a massa de biocatalisador, o meio de cultura e o tempo de reação. Os melhores resultados sob essas condições foram aplicadas para os epóxidos 3-5 fornecendo o (S)-(+)-2-[4-metoxifenoxi)metil]oxirano (3a), (S)-(+)-2-(propeniloxi)oriano (4), (R)-(+)-1-alilóxi-2,3-propanodiol (4a) e o (-)-9-deceno-1,2-diol (5a). Nesses estudos embora ocorreu a abertura seletiva dos epóxidos com as células totais do fungo Trichoderma sp Gc1, não obteve-se altas purezas enantioméricas dos produtos. Ainda nesse trabalho realizou-se a síntese das cloroidrinas racêmicas, a (RS)- 1-cloro-2-propanol- 3-fenilmetóxi (2b), (RS)- 1-cloro-2-propanol- 3-(4-metoxifenóxi) (3b) e (RS)- 1-alilóxi-3-cloro-2-propanol (4b) em bons rendimentos e uma metodologia sintética ambientalmente apropriada, pois os compostos foram preparados em meio aquoso na presença de íons cloreto. Em seguida realizou-se uma resolução enzimática da (RS)-1-alilóxi-3-cloro-2-propanol (4b) com a lipase de Candida antarctica onde obteve-se a clorodrina 4a (e.e. 72 %) e o seu correspondente produto acetilado 4c (e.e. 82 %) em bons excessos enantioméricos. Conclui-se que os fungos de origem marinha utilizados neste trabalho são potenciais fontes de epóxido-hidrolases para promover a abertura seletiva de epóxidos. / In this work carried out itself the first study biocatalytic involving reactions of reduction of cetonas with fungi of marine origin. They were utilized 7 cetonas commercial as substratos and 8 fungi derived little seas like biocatalisadores. The fungi were isolated of the sponges little seas Geodia corticostylifera (Trichoderma sp Gc1, Penicillium miczynskii Gc5, Aspergillus sydowii Gc12) and Chelonaplysylla erect (Bionectria sp Ce5, Aspergillus sydowii Ce15, Penicillium raistrickii Ce16 and Aspergillus sydowii Ce19). The reduction 2-chloro-1-phenylethanone (1) was studied under several conditions of reaction (changes of pH, addition or absence of glucose) and the best result was with fungus P. miczynskii Gc5, therefore itself obteve an isolated performance of 60% and excess enantiomeric of 50% for the (S)- 2-chloro-1- phenylethanol (1a). The interesting one in these studies was that all of the fungi utilized in the selection with the 2-chloro-1-phenylethanone (1) presented selectivity anti- Prelog. In the literature is common obtain reduction enzymatic with selectivity Prelog. To 2-bromo-1-phenylethanone (2) was biotransformaded by the fungus A. sydowii Ce19 you correspond composed: (S)-2-bromo-1-phenylethanol (2a), (S)-2-cloro-1- phenylethanol (1a), whereas to (2c), 2-chloro-1-phenylethanone (1) and the 2- phenyloxirane (2b) were obtained by reactions not enzymatic. To 2-bromo-1-(4- bromophenyl)ethanone (3) and to 2-bromo-1-(4-nitrophenyl)ethanone (4) were entirely biodegradadas by the fungus A. sydowii Ce19. The reduction biocatalytic of the 1-(2- iodophenyl)ethanol (5) and 1-(3-iodophenyl)ethanol (6) with the fungus Trichoderma sp Gc1 supplied the 1-(2-iodophenyl)ethanol (5a) and the 1-(3-iodophenyl)ethanol (6a) with excellent excesses enantiomeric (e.e. > 99%). It stayed verified also that the fungi derived little seas for promote the reactions of reduction by biocatalysis are going to be cultivated in water of the artificial sea.

Catalytic enantioselective desymmetrization of meso-epoxides is widely used in many areas of chemistry. Such process is usually catalyzed by a transition metal complex with a chiral ligand. Recently, a synthesis of an analogue of Bolm's 2,2'-bipyridine ligand was developed and its combination with metal salts were tested in various reactions. In this master's thesis, a catalytic system composed of Sc(OTf)3/Bolm's ligand analogue was studied in alcoholysis and aminolysis of the meso- epoxides. The reaction has been extended to a broad range of alcohols providing 1,2-diol monoethers in excellent enantioselectivity up to 99% ee. The aminolysis of meso-epoxides has been optimized, as well. The catalyst loading could be lowered to 1 mol% with only marginal effects on the enantioselectivity. Key words: epoxides, enantioselective catalysis, chiral ligands.

No description available.

This thesis describes investigations into the utility of boron fluorides and tetrafluoroborates as sources of nucleophilic fluorine. Chapter 1 discusses the history and importance of the field of organofluorine chemistry and outlines some of the principle motivations for the site-selective fluorination of organic molecules. Some of the most commonly useed methods of nucleophilic fluorination are briefly surveyed, with an emphasis on the formation of fluorinated stereogenic centres. Literature precedent for the use of tetrafluoroborates and boron trifluoride as nucleophilic fluorinating agents is also presented. Chapter 2 describes the development of a highly regio- and stereoselective S_Ni-type ring-opening fluorination of trans-β-substituted aryl epoxides using BF₃●OEt₂ as a nucleophilic fluorinating agent. This robust and scalable protocol grants efficient access to a variety of functionalised benzylic fluoride building blocks, and provides a solution to the problem of stereocontrol in the synthesis of this class of compounds. To highlight the utility of the resultant syn-fluorohydrins in the synthesis of stereodefined β-fluoro β-aryl amines, their elaboration to a range of aryl-substituted β-fluoroamphetamines is demonstrated. Chapter 3 introduces the concept of tuning the reactivity of BF₃ by replacing one or two of the fluoro ligands on boron for electron-donating alkoxy group(s). On this basis, pinacolatoboron fluoride (pinBF) [which may be prepared in situ by pre-mixing BF₃●OEt₂ and bis(O-trimethylsilyl)pinacol] is identified as a superior reagent to BF₃●OEt₂ for the ring-opening fluorination of trans-β-substituted aryl epoxides bearing electron-rich aryl groups. Chapter 4 details a highly regioselective and stereospecific S_N2-type ring-opening fluorination of 2,3- and 3,4-epoxy amines using HBF₄●OEt₂ as a nucleophilic flurine source. The reactions are both operationally simple to perform and readily scalable, and proceed to completion within 5 min at ambient temperature, providing a highly practical and economical route to stereodefined amino fluorohydrins. To highlight the synthetic utility of this reaction in the preparation of pharmaceutically-important β-fluoro amines, a concise de novo asymmetric synthesis of (S,S)-3-deoxy-3-fluorosafingol is performed. Chapter 5 chronicles the successful development of a protocol for the direct hydroxyfluorination of allylic amines to the corresponding amino fluorohydrins, using m--CPBA as the oxidant and HBF₄●OEt₂ in a dual role as both the Brønstead acid N-protecting agent and nucleophilic fluorine source. With chiral allylic amines which are conformationally biased or constrained, the diastereofacial selectivity of the reaction can be controlled by altering the concentration of HBF₄●OEt₂ employed in the reaction, allowing for a diastereodivergent hydroxyfluorination process. The synthetic utility of this methodology is demonstrated via its application to the diastereodivergent synthesis of 4-deoxy-4-fluoro-L-xylo-phytosphingosine and 4-deoxy-4-fluoro-L-lyxo-phytosphingosine, each in 5 steps from Garner's aldehyde. Chapter 6 contains full experimental procedures and characterisation data for all compounds synthesised in chapters 2, 3, 4 and 5.

Direct generation of enantioenriched mono-α-alkylated aldehydes by intermolecular nucleophilic substitution is a general and long-standing problem in synthesis, and is of importance due to the diverse reactions such aldehydes undergo for introducing asymmetry into molecules. The work described in this thesis initially details the development of the first lithium amide capable of efficiently converting terminal epoxide into enamine functionality, where the latter also demonstrates effective C-alkylation activity. Not only addition to Michael acceptors, but more notably substitution using activated organohalides (α-bromoacetates, benzyl, allyl and propargyl bromide) gave the corresponding α-substituted aldehydes in good to excellent yields. Alkylation with propargyl bromide yielded only the propargyl-substituted aldehyde with none of the corresponding allene observed; this result shows that N-alkylation followed by [3,3] sigmatropic rearrangement is not occuring. Importantly, a range of short-, longer-chain and secondary unactivated alkyl iodides also proved viable. Significantly, with chiral lithium amides, the corresponding chiral enamines could be alkylated with strongly electrophilic benzyl, allyl and propargyl (no allene seen) bromides in very good yields, and with short chain alkyl iodides – MeI and EtI in satisfactory yields, to provide the first direct access to α-alkylated aldehydes with high asymmetric induction by intermolecular nucleophilic substitution.

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.

The work leading to this thesis has provided additional information and novel knowledge concerning structure-function relationship in the potato epoxide hydrolase. Epoxide hydrolases are enzymes catalyzing the hydrolysis of epoxides to yield the corresponding vicinal diols. The reaction mechanism proceeds via a nucleophilic attack resulting in a covalent alkylenzyme intermediate, which in turn is attacked by a base-activated water molecule, followed by product release. Epoxides and diols are precursors in the production of chiral compounds and the use of epoxide hydrolases as biocatalysts is growing. The promising biocatalyst StEH1, a plant epoxide hydrolase from potato, has been investigated in this thesis. In paper I the active site residue Glu35, was established to be important for the formation of the alkylenzyme intermediate, activating the nucleophile for attack by facilitated proton release through a hydrogen bond network. Glu35 is also important during the hydrolytic half reaction by optimally orienting the hydrolytic water molecule, aiding in the important dual function of the histidine base. Glu35 makes it possible for the histidine to work as both an acid and a base. In paper II a putative proton wire composed of five water molecules lining a protein tunnel was proposed to facilitate effective proton transfer from the exterior to the active site, aiding in protonation of the alkylenzyme intermediate. The protein tunnel is also proposed to stabilize plant epoxide hydrolases via hydrogen bonds between water molecules and protein. Enzyme variants with modified enantiospecificity for the substrate (2,3-epoxypropyl)benzene have been constructed by in vitro evolution using the CASTing approach. Residues lining the active site pocket were targeted for mutagenesis. From the second generation libraries a quadruple enzyme variant, W106L/L109Y/V141K/I155V, displayed a radical shift in enantioselectivity. The wild-type enzyme favored the S-enantiomer with a ratio of 2:1, whereas the quadruple variant showed a 15:1 preference for the R-enantiomer.

Both clan CA and clan CD proteases have a variety of physiological and pathological roles. In particular, both clans have members who have been implicated in cell death pathways, including apoptosis. Caspases are members of clan CD. Many of the caspase inhibitors used in apoptotic studies have shown cross reactivity with clan CA proteases. Thus, the anti-apoptotic effect of these inhibitors could be due to the broad-spectrum inhibition of a variety of cysteine proteases. Recently, the Powers laboratory designed a new class of inhibitors highly specific for clan CD proteases, aza-peptide epoxides. Initial data showed that this high selectivity could be due to the presence of the aza-residue, and not simply an artifact of substrate specificities. E-64c, an epoxysuccinyl inhibitor, is known to be a highly potent inhibitor of cathepsin B and calpain I. Thus, to determine if these clan CA proteases could tolerate an aza-residue, aza-E-64c and its analogues were synthesized. These inhibitors, termed epoxysuccinyl aza-peptides, were found to be significantly less potent for cathepsin B, calpain I, and papain than their non-aza counterparts, including E-64c. Previous findings have shown that the reactivity and selectivity of aza-peptide epoxides with caspases were significantly influenced by epoxide stereochemistry and the prime side substituent. Thus, this second project involved the systematic study of epoxide stereochemistry effects, prime side substituent effects, and the combined effect of these two variables. All inhibitors were tested with the seven apoptotic caspases: caspases-2, -3, -6, -7, -8, -9, and -10. We found that epoxide stereochemistry, prime side substituent, and also the peptidyl sequence have combined effects on potency and selectivity. In general, the (S,S) stereoisomer is the most potent relative to the (R,R) and (cis) stereochemistries. Modeling studies were done to determine why this is true. Aza-peptide epoxides were also briefly compared to aza-peptide Michael acceptors, another class of inhibitors highly specific for clan CD proteases

Benzimidazole and benzotriazole derivatives, 4-(2,3-Dihydrothieno[3,4-b][1,4] dioxin-5-yl)-7-(2,3-dihydrothieno[3,4b][1,4]dioxin-7-yl)-2-benzyl-1H-benzo[d] imidazole (BIm-Ed), 2-benzyl-4,7-di(thiophen-2-yl)-2H-benzo[d] [1,2,3] triazole (BBTS), and 2-benzyl-4,7-bis(2,3-dihydrothieno[3,4-b][1,4]dioxin-5-yl)-2Hbenzo[ d] [1,2,3] triazole (BBTES) were employed as photosensitizers for diaryliodonium salt photoinitiators in cationic photopolymerization of various epoxide and vinyl ether monomers. Diphenyliodonium hexafluorophosphate (Ph2I+PF6&macr / ) salt was used as the photoinitiator in this study. Extended conjugation and electron-rich moieties of the photosensitizers enabled the use of long wavelength UV and visible light emitting light sources in cationic photopolymerizations. Polymerizations were achieved at room temperature and monitored by optical pyrometry. Photopolymerization of a diepoxide monomer with ambient solar irradiation was examined.

Made available in DSpace on 2014-10-09T12:52:34Z (GMT). No. of bitstreams: 0 / Made available in DSpace on 2014-10-09T14:02:31Z (GMT). No. of bitstreams: 0 / Dissertação (Mestrado) / IPEN/D / Instituto de Pesquisas Energeticas e Nucleares - IPEN/CNEN-SP