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Faculty of Science School of Chemistry 0100505x jzeevaart@csir.co.za / The application of homogenous transition metal catalysis to the arylation of enolates to develop new synthetic procedures which are more environmentally benign, atomefficient and economically viable than current methods was the motivation behind the current work. The specific choice of molecules with an aromatic group in the a- position of a ketone, carboxylic acid, amide or other electron-withdrawing group arose from the fact that many natural products, pharmaceutical actives and synthetic intermediates contain such a substructure while the syntheses of these substructures are often cumbersome. The application of homogenous catalysis to various types of enolates was explored and in the process several developments were achieved and discoveries made. These included the use of inorganic bases under phase transfer conditions for the Heck reaction of acrylic acid as well as the synthesis and application of phosphine and phosphite ligands in the Heck reaction of acrylic acid esters. The successful use of low palladium loadings (as low as 0.01mol%) in the arylation of diethyl malonate using aryl chlorides and the application to the synthesis of ketoprofen and phenobarbital was demonstrated. The novel application of palladium catalysis to the arylation of methanesulfonamides and the first example of a bromoindole derivative as the aryl halide partner in an enolate arylation reaction was demonstrated. Ligand-free palladium catalysed phenylation of pinacolone followed by Baeyer Villiger oxidation led to a proposed novel synthetic route to tert-butyl esters of 2-arylacetic acids. The palladium and copper catalysed arylation of acetoacetate esters, with in situ decarbonylation, provided a different route to 2-arylacetic acid esters which are useful in the preparation of non-steroidal anti-inflammatory compounds.

Orientador: Luiz Carlos Dias / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-18T09:00:14Z (GMT). No. of bitstreams: 1 LuccaJunior_EmilioCarlosde_M.pdf: 5948258 bytes, checksum: 406eb38fa953e871cd9581138b7bc85d (MD5) Previous issue date: 2011 / Resumo: As reações aldólicas envolvendo os enolatos de boro 71 (P = TBS, R = t-Bu), 72 (P = PMB, R = t-Bu) e 96 (P = TPS, R = t-Bu) levaram à formação de adutos de aldol com seletividades de moderadas a boas em favor do isômero 1,5-syn. As reações aldólicas envolvendo os enolatos de boro 90 (P = Tr, R = t-Bu), 91 (P = Tr, R = Me) e 97 (P = TPS, R = Me) levaram à formação de adutos de aldol em uma proporção equimolar de 1,5-anti e 1,5-syn. A reação aldólica envolvendo o enolato de boro 131 (P = TBS, R = Ph3C) levou à obtenção de excelentes níveis de seletividade em favor do aduto de aldol 1,5-syn / Abstract: The aldol reactions involving boron enolates 71 (P = TBS, R = t-Bu), 72 (P = PMB, R = t-Bu) and 96 (P = TPS, R = t-Bu) led to the formation of aldol adducts with moderate to good levels of diastereoselectivity, favouring the 1,5-syn isomer. The aldol reactions involving boron enolates 90 (P = Tr, R = t-Bu), 91 (P = Tr, R = Me) and 97 (P = TPS, R = Me) led to the formation of aldol in a 50:50 mixture. The aldol reactions of boron enolate 131 (P = TBS, R = Ph3C) led to excellent levels of diastereoselectivity, favouring the 1,5-syn adduct / Mestrado / Quimica Organica / Mestre em Química

Orientador: Luiz Carlos Dias / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-18T09:04:21Z (GMT). No. of bitstreams: 1 Polo_EllenChristine_M.pdf: 6602828 bytes, checksum: d42e742a7de09597441836d6ade5c8bf (MD5) Previous issue date: 2011 / Resumo: As reações aldólicas com o enolato de boro da metilcetona 44, com protetor cíclico de acetonídeo e relação trans entre os centros quirais, levaram à obtenção de adutos de aldol com níveis de seletividade variando de moderados a bons, em favor do isômero 1,5-anti. Reações aldólicas envolvendo enolatos de boro da metilcetona 45, com protetor cíclico de acetonídeo e relação cis entre os centros quirais, levaram à formação de adutos de aldol com excelentes níveis de seletividade em favor do isômero 1,5-anti. As reações aldólicas entre o enolato de boro da metilcetona 46, com protetor cíclico de silício e relação trans entre os centros quirais, levaram a obtenção de adutos de aldol com níveis de seletividade variando de moderados a bons em favor do isômero 1,5-anti. A reação aldólica entre o enolato de boro da metilcetona 47, com protetor cíclico de silício e relação cis entre os centros quirais, e pivalaldeído levou à formação do aduto de aldol em bom nível de seletividade em favor do isômero 1,5-anti / Abstract: The aldol reactions of the boron enolate generated from methylketone 44 (containing a trans-acetonide), led to aldol adducts with moderate to good levels of diastereoselectivity, favoring the 1,5-anti adduct. The aldol reactions involving the boron enolate of methylketone 45 (containing a cis-acetonide) gave the corresponding aldol adducts with excellent levels of diastereoselectivity, favoring the 1,5-anti adduct. The aldol reactions of the boron enolate generated from methylketone 46 (containing a cyclic silicon protecting group and trans relationship between the chiral centers), led to the formation of aldol adducts with moderate to good levels of diastereoselectivity favoring the 1,5-anti isomer. The aldol reaction between the boron enolate prepared from methylketone 47 (containing a cyclic silicon protecting group and cis relationship between the chiral centers), led to the formation of aldol adduct with good level of diastereoselectivity favoring the 1,5-anti isomer / Mestrado / Quimica Organica / Mestre em Química

Yes / The use of methylmalonyl-CoA epimerase (MCEE) to improve stereoselectivity in crotonase-mediated biocatalysis is exemplified by the coupling of MCEE, crotonyl-CoA carboxylase reductase and carboxymethylproline synthase in a three-enzyme one-pot sequential synthesis of functionalised C-5 carboxyalkylprolines starting from crotonyl-CoA and carbon dioxide. / Biotechnology and Biological Sciences Research Council, The Wellcome Trust, and CONACyT and FIDERH (Mexico, RGC) The Structural Genomics Consortium is a registered charity (number 1097737) that receives funds from AbbVie, Boehringer Ingelheim, the Canada Foundation for Innovation, the Canadian Institutes for Health Research, Genome Canada, GlaxoSmithKline, Janssen, Lilly Canada, the Novartis Research Foundation, the Ontario Ministry of Economic Development and Innovation, Pfizer, Takeda, and the Wellcome Trust (092809/Z/10/Z).

Na primeira parte desta tese são apresentados os resultados referentes ao desenvolvimento de uma metodologia de α-alquinilação eletrofílica de aldeídos com o reagente de iodo hipervalente TMS-EBX, empregando NaHMDS como base e TBAF. Aldeídos acíclicos foram submetidos a esta transformação e 9 exemplos de álcoois homopropargílicos foram obtidos em rendimentos de 50-81%, após uma etapa de redução com NaBH4. A transformação desenvolvida revelou-se aplicável também com o reagente de iodo hipervalente Ph-EBX e 2 exemplos foram obtidos em 24 e 40% de rendimento. O álcool homopropargílico precursor de um inibidor da bactéria que produz a toxina botulínica foi preparado em uma escala de 5 mmol sem a necessidade de alterar as condições reacionais já otimizadas. Na segunda parte desta tese são apresentados os resultados referentes ao desenvolvimento de uma metodologia para a síntese de cetonas cíclicas e 2-cromanonas α-alquinil-β-substituídas por meio de uma sequência de adição 1,4/alquinilação eletrofílica empregando cumarinas e enonas como material de partida, utilizando o reagente de iodo hipervalente TMS-EBX. Os enolatos foram gerados com sucesso a partir de uma reação de adição 1,4 catalisada por cobre utilizando complexos de alumínio e reagentes de Grignard como fontes nucleofílicas. No total foram obtidos 17 exemplos em 34-89% de rendimento e em alta diastereosseletividade. Realizamos três modificações estruturais visando aumentar a complexidade estrutural dos produtos sintetizados. A reação Click, rea- ção de Sonogashira e redução mediada por NaBH4 foram aplicadas com sucesso. Por fim, na terceira parte desta tese são apresentados os resultados preliminares referentes ao desenvolvimento de uma metodologia de síntese de furanos a partir da acetofenona e do reagente de iodo hipervalente Ph-EBX, empregando NaHMDS comoviii base. A acetofenona foi submetida a esta transformação e uma mistura de furanos di- e trissubstituídos foram obtidos em 49% de rendimento. Um experimento controle demonstrou que a alquinilação do ânion terc-butóxido, em uma reação extremamente rápida, é a principal via de consumo do Ph-EBX e o composto (terc-butoxietinil)benzeno foi obtido em 92% de rendimento. Esta reação lateral é a principal responsável pelo baixo rendimento da reação de síntese dos furanos. / In the first part of this work are presented the results relative to the development of a methodology of α-electrophilic alkynylation of aldehydes with the hypervalent iodine reagent TMS-EBX, employing NaHMDS as base and TBAF. Acyclic aldehydes were submitted to this transformation and 9 examples of homopropargylic alcohols were obtained in 50-81% yield, after a reduction step with NaBH4. The developed transformation proved to be works also with the hypervalent iodine reagent Ph-EBX and 2 examples were obtained in 24 and 40% yield. The homopropargylic alcohol precursor of an inhibitor of bacteria that produces a botulinic toxin was prepared at a 5 mmol scale without change the reaction condition already optimized. In the second part of the thesis are presented the results relative to the development of a methodology for the synthesis of cyclic ketones and 2-chromanones α-alkynyl-β-substituted by the1,4-addition/electrophilic alkynylation sequence using coumarins and enones as a starting material and the hypervalent iodine reagent TMS-EBX. The enolates were generated with success from a Cu-catalyzed 1,4 addition using aluminum complexes and Grignard reagents as nucleophilic source. In total 17 examples were obtained in 34-89% yield and high diastereoselectivity. We carried out three structural modification aiming to increase the complexity of the products synthesized. Click reaction, Sonogashira reaction and reduction promoted by NaBH4 were applied with success. Finally, in the third part of the thesis are presented the preliminary results relative to the development of a methodology for synthesis of furans from acetophenone and the hypervalent iodine reagent Ph-EBX, using NaHMDS as a base. Acetophenone was submitted to this transformation and only one example was obtained in 49% yield in a mixture of di- and trisubstituted furans. A control experimentx showed that the alkynylation of tert-butoxide anion, in an extremely fast reaction, is the main path of consumption of the Ph-EBX reagent and the compound (tert-butoxyethynyl)benzene was obtained in 92% yield. This side reaction is the main responsible for the low yield of the reaction of synthesis of furans.

A variety of protected enolic forms of 1, 2-cyclohexanedione was prepared as substrates for conjugate addition studies using organocopper reagents. The sequence involved the enol ether preparation via the enolate, alkylation with an organometalic reagent, and oxidative rearrangement with pyridinium chlorochromate followed by the conjugate addition reactions. Protection of 1, 2-cyclohexanedione was achieved by reacting with chloro tert-butyldimethyl silane and subjected to alkylation. Steric problems were encountered and so an alternative protective group the methoxymethyl acetal was prepared and studied. Alkylation of these derivatives was successful; however, the oxidation was problematic and although evidence for rearrangement was observed in one case, it did not provide the desired ketone.

Memory of chirality (MOC) is an emerging strategy in asymmetric synthesis. It has been applied to enolate chemistry, reactions involving carbocation intermediates, and to radical systems. In this strategy the chirality of an enantiopure reactant is transferred to the dynamic chirality of a reactive intermediate to produce stereospecific product. 1,4-Benzodiazepin-2-ones have been described as a "privileged" structure in medicinal chemistry. In addition to their uses as anxiolytics (Valium ®) and anti-epileptic agents (Clonopin ®), they have shown activity as HIV Tat antagonist, ras farnesyltransferase inhibitors in cancer cells, and antiarrhythmic agents. Because of the utility of this scaffold in the area of medicinal chemistry, it has served as a template in libraries for tens of thousands of compounds. Despite the vast diversity of 1,4-benzodiazepin-2-ones, there are few routes to enantiomerically enriched 3,3-disubstituted benzodiazepines containing a "quaternary" stereogenic center. This research will discuss the stereochemical properties of 1,4-benzodiazepin-2-ones, and provide a novel approach to synthesize enantiomerically enriched "quaternary" benzodiazepines with stereogenic centers through MOC, without the use of external chiral sources. / Ph. D.

Yes / The crotonases comprise a widely distributed enzyme superfamily that has multiple roles in both primary and secondary metabolism. Many crotonases employ oxyanion hole-mediated stabilization of intermediates to catalyze the reaction of coenzyme A (CoA) thioester substrates (e.g., malonyl-CoA, α,β-unsaturated CoA esters) both with nucleophiles and, in the case of enolate intermediates, with varied electrophiles. Reactions of crotonases that proceed via a stabilized oxyanion intermediate include the hydrolysis of substrates including proteins, as well as hydration, isomerization, nucleophilic aromatic substitution, Claisen-type, and cofactor-independent oxidation reactions. The crotonases have a conserved fold formed from a central β-sheet core surrounded by α-helices, which typically oligomerizes to form a trimer or dimer of trimers. The presence of a common structural platform and mechanisms involving intermediates with diverse reactivity implies that crotonases have considerable potential for biocatalysis and synthetic biology, as supported by pioneering protein engineering studies on them. In this Perspective, we give an overview of crotonase diversity and structural biology and then illustrate the scope of crotonase catalysis and potential for biocatalysis. / Biotechnology and Biological Sciences Research Council, the Medical Research Council, and the Wellcome Trust