Reação viníloga-aldol estereosseletiva de tetronamidas e síntese de rubrolídeos e butenolídeos beta-substituídos

Butenolides are α, -unsaturated lactone and are found in many natural and unnatural products with diverse biological properties. Owing to the prevalence of the substituted butenolides, much effort has been directed towards developing efficient methodologies for their synthesis and transformations. Among them, stereoselective access of the -substituted butenolide derivatives by utilizing the concept of vinylogy, which usually involves the carbon– carbon formation with an appropriate electrophile at the -position of butenolides, has triggered increasing interest. This thesis presents an efficient, simple, scalable and direct stereoselective vinylogous aldol reaction (VAR) of -aminosubstituted butenolides (tetronamides) with aldehydes. In addition, this thesis also describes the total syntheses of butenolide core bearing marine natural metabolites, rubrolides by using a highly regioselective late-stage bromination from appropriate intermediates, and apprises a facile reductive dehalogenation of α-halo- -substituted butenolides. An introduction to the general background, including versatile synthetic strategies, total syntheses, and biological properties of substituted butenolides is documented in Chapter 1. It is followed by an illustration of selected methods for construction of the butenolide core. Also discussed are the various methods for preparation of some selected natural products which either possess a butenolide core or synthesized from butenolide building blocks. Finally, some synthetic butenolide derivatives are described which are recently marketed as either medicines or agrochemicals. The results of the stereoselective VAR of tetronamides are compiled in Chapter 2. The described procedure, is simple and scalable, works well with both aromatic and aliphatic aldehydes, and affords mainly the corresponding syn-aldol adducts. In many cases, the latter are obtained essentially free of their anti-isomers in high yields. A detailed computational study was also carried out to establish the reaction mechanism. The experimental and computational studies suggest that the observed diastereoselectivity arises through anti–syn isomer interconversion, enabled by an iterative retro-aldol/aldol reaction. In Chapter 3, the crystal structures of several tetronamide aldol products with two stereocenters are described. Those compounds revealed conformational and supramolecular trends with the substitution pattern of a side aromatic/ heteroaromatic ring. The major contribution of this study concerns the control over the molecular conformation of tetronamide aldolates bearing several rotatable bonds and the high conformational freedom through the substitution pattern of a single ring. The first total syntheses of the marine natural products rubrolides I and O and some of their unnatural congeners are reported in Chapter 4. A versatile late-stage bromination strategy allowed functionalization of the aromatic rings in a highly regioselective fashion, enabling rapid access to the target rubrolides from common precursors. Next, the regioselective chlorination was also applied to the preparation of biologically important synthetic analogous of rubrolides from easily accessible precursors. In Chapter 5, a binary palladium catalyzed reductive dehalogenation of α-halo- -substituted butenolides is documented. The synthetic procedure allowed rapid access to the -substituted butenolides under mild conditions with high yields and excellent regioselectivity. In addition, a protecting group free step-economical synthesis of rubrolides E, F and γ”-bromorubrolide F has been reported by employing this protocol.Os butenolídeos, que apresentam em sua estrutura o núcleo lactona α, -insaturada, são encontrados em produtos naturais e não naturais com diversas propriedades biológicas. Devido à prevalência dos butenolídeos substituídos, muitos esforços têm sido direcionados para explorar metodologias eficientes para suas sínteses e transformações. Entre elas, o acesso estereosseletivo dos derivados de butenolídeos -substituídos utilizando o conceito de vinilogia, o qual envolve a formação de ligação carbono-carbono com um eletrófilo apropriado na posição do butenolídeo, tem provocado um interesse crescente. Portanto, esta tese apresenta uma reação aldólica viníloga estereosseleva (VAR) eficiente, simples, escalável e diretamente estereosseletiva de butenolídeos -amino-substituídos (tetronamidas) com aldeídos. Esta tese também descreve as sínteses totais de butenolídeos contendo metabólitos naturais marinhos rubrolídeos pela bromação altamente regiosseletiva de fase tardia a partir de intermediários apropriados. Além disso, a tese inclui uma desalogenação redutiva de butenolídeos α-halo- -substituídos sob condições suaves com rendimentos elevados e regiosseletivos. Uma introdução ao contexto geral, incluindo estratégias sintéticas versáteis, sínteses totais e propriedades biológicas dos butenolídeos substituídos estão documentadas na seção: Capítulo 1. Sendo seguida por uma ilustração dos métodos selecionados para a construção do núcleo de butenolídeos. São também discutidos os vários métodos para a preparação de alguns produtos naturais selecionados que possuem o núcleo de butenolídeo ou sintetizados a partir de butenolídeos que atuam como “building blocks”. Finalmente, foram descritos alguns butenolídeos sintéticos que são comercializados como medicamentos ou agroquimicos recentemente. Os resultados da VAR estereosseletiva de tetronamidas estão apresentatos no Capítulo 2. O procedimento descrito, simples e escalável, funciona bem com aldeídos aromáticos e alifáticos, proporcionando principalmente os adutos correspondentes de syn-aldol. Em muitos casos, estes últimos são obtidos isentos dos seus isômeros anti com rendimentos elevados. Foi também realizado um estudo computacional detalhado. Os estudos experimentais e computacionais sugerem que a diastereosseletividade observada surge através da interconversão do isômero anti-syn, através da reação reversível retro-aldólica. No Capítulo 3, as estruturas cristalinas de alguns produtos aldólicos de tetronamida com dois estereocentros foram descritos. Os compostos relacionados revelaram tendências conformacionais e supramoleculares com padrões de substituição do anel aromático/heteroaromático. Tais tendências foram racionalizadas com base nos perfis energéticos dos principais confôrmeros. A principal contribuição deste estudo refere-se ao controle sobre a conformação molecular de tetronamidas que apresentam várias ligações que permitem giros, além da elevada liberdade conformacional através do padrão de substituição de um único anel. As primeiras sínteses totais de produtos naturais marinhos, os rubrolídeos I e O e alguns de seus derivados não naturais são relatadas no Capítulo 4. Uma versátil estratégia de bromação na última etapa permitiu a funcionalização dos anéis aromáticos de maneira altamente regiosseletiva, permitindo o acesso rápido aos alvos, rubrolídeos, a partir de precursores comuns. Posteriormente, a cloração regiosselectiva foi também aplicada à preparação de análogos sintéticos biologicamente importantes a partir de precursores facilmente acessíveis. No Capítulo 5, foi relatado a desalogenação redutiva catalisada por paládio binário de butenolídeos α-halo- -substituídos. O procedimento sintético permitiu o acesso rápido aos butenolídeos substituídos sob condições suaves, com rendimentos elevados e excelente regiosseletividade. Além disso, uma nova proposta para a síntese dos rubrolídeos E, F e composto com a estrutura correspondente à descrita para 3"-bromorubrolídeo F de ocorrência natural utilizando este mesmo protocolo.Coordenação de Aperfeiçoamento de Pessoal de Nível Superio

Palladium-catalyzed hydrodehalogenation of butenolides: An efficient and sustainable access to β-arylbutenolides

Several α-unsubstituted β-arylbutenolides have been prepared in 69–92% yield by reductive dehalogenation of α-halo-β-arylbutenolides. The latter were assembled in a single-step from α,β-dihalobutenolides, which are accessible on a large-scale from biomass-derived furfural. Our dehalogenation protocol is illustrated by a new synthesis of the marine antibiotics rubrolide E and F, and 3″-bromorubrolide F

Thermodynamically driven: Syn -selective vinylogous aldol reaction of tetronamides

A stereoselective vinylogous aldol reaction of N-monosubstituted tetronamides with aldehydes is described. The procedure is simple and scalable, works well with both aromatic and aliphatic aldehydes, and affords mainly the corresponding syn-aldol adducts. In many cases, the latter are obtained essentially free of their anti-isomers (dr > 99:1) in high yields (70-90%). Experimental and computational studies suggest that the observed diastereoselectivity arises through anti-syn isomer interconversion, enabled by an iterative retro-aldol/aldol reaction.Fil: Karak, Milandip. Universidade Federal de Viçosa; Brasil. Universidade Federal de Minas Gerais; BrasilFil: Barbosa, Luiz C. A.. Universidade Federal de Minas Gerais; Brasil. Universidade Federal de Viçosa; BrasilFil: Acosta, Jaime A. M.. Universidade Federal de Minas Gerais; BrasilFil: Sarotti, Ariel Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; ArgentinaFil: Boukouvalas, John. Laval University; Canad

Optimizations of lipid II synthesis: an essential glycolipid precursor in bacterial cell wall synthesis and a validated antibiotic target

Lipid II is an essential glycolipid found in bacteria. Accessing this valuable cell wall precursor is important both for studying cell wall synthesis and for studying/identifying novel antimicrobial compounds. Herein, we describe optimizations to the modular chemical synthesis of lipid II and unnatural analogues. In particular, the glycosylation step, a critical step in the formation of the central disaccharide unit (GlcNAc-MurNAc), was optimized. This was achieved by employing the use of glycosyl donors with diverse leaving groups. The key advantage of this approach lies in its adaptability, allowing for the generation of a wide array of analogues through the incorporation of alternative building blocks at different stages of synthesis

Thiobarbiturates as potential antifungal agents to control human infections caused by Candida and Cryptococcus species

Hospitalized patients can suffer from Candida and Crytptococcus infections, aggravating underlying health conditions. Due to the development of drug-resistant microorganisms, we report here on the potential of some arylidene-thiobarbiturate to control five Candida spp. and one Cryptococcus species of medical interest. Initially, a bismuth nitrate catalyzed Knoevenagel condensation with thiobarbituric acid and aromatic aldehydes was developed. This new procedure generated seven new and thirteen known arylidene-thiobarbiturate derivatives (1–20) with excellent yields (81–95%), with a reaction time within 20 min. The antimicrobial activities of all compounds were evaluated against Candida albicans, C. tropicalis, C. parapsilosis, C. lusitaniae, C. dubliniensis, and Cryptococcus neoformans. Several compounds were as active as the commercially available drugs (IC50 < 1.95 µg mL−1) towards at least one microbial strain. The results suggest that some of the new compounds can serve as leads for new antimicrobial agents for the treatment of human fungal infections

Substituent-Modulated Conformation and Supramolecular Assembly of Tetronamides

The crystal structures of nine compounds (1-9) bearing the 4-aminofuran-2(5H)-one scaffold (commonly known as tetronamide, C4H5NO2) and two decorating aromatic/heteroaromatic moieties with two stereocenters have been determined. Tetronamides bearing at the 5-position a phenyl moiety (1 and 2, 3-chloro derivatives with either a 4-p-tolylamino or 4-p-bromophenylamino substituent), an o-bromopyridyl moiety (3, a 3-bromo-4-p-tolylamino derivative), or an o-tolyl moiety (4, a 3-bromo-4-p-tolylamino derivative) adopt a U-shaped conformation. This conformation is stabilized by an intramolecular contact involving either the phenyl o-CH moiety (1 and 2) or the substituent at the ortho position (3 and 4) and the π system of the N-phenyl ring. The other five tetronamides (5-9) are not present with such an intramolecular contact. In fact, these last five compounds are not U-shaped and feature the presence at the 5-position of a p-biphenyl moiety (5 and 7, 3-bromo-4-p-tolylamino diastereomers differing as 5R and 5S), a p-methoxyphenyl moiety (6, a 3-chloro-4-p-bromophenylamino derivative), or a 5-chlorofuran-2-yl moiety (8 and 9, 3-chloro-4-p-tolylamino diastereomers differing as 5R and 5S). Crystal structures of a 5,5-disubstituted tetronamide bearing m-nitrophenyl moieties (10) and a parent tetronamide without a substituent at the 5-position (11d) reinforce the conformational trend found in 1-9. Furthermore, OH···O centrosymmetric dimers are formed only in the crystal structures of the U-shaped tetronamides. Chain motifs assembled through OH···O and NH···O hydrogen bonds are preferred in the line-shaped tetronamides. Furthermore, the conformer energies were calculated in both the gas and solution phases (B3LYP/6-31G∗). The lowest-energy conformations feature an intramolecular N-H···O hydrogen bond as in the crystal structure of 7. In the U-shaped tetronamides, the crystal structure conformations are similar to the third or fourth energetically ranked stable calculated conformer. Therefore, it is concluded that the substitution pattern in the U-shaped tetronamides allows for accessible secondary minimum-energy conformations that are easily adopted in the crystal structure as a result of their compatibility with the robust centrosymmetric O-H···O dimer formation.Fil: Karak, Milandip. Universidade Federal de Minas Gerais; Brasil. Universidade Federal de Viçosa; BrasilFil: Acosta, Jaime A. M.. Universidade Federal de Minas Gerais; BrasilFil: Barbosa, Luiz C. A.. Universidade Federal de Minas Gerais; Brasil. Universidade Federal de Viçosa; BrasilFil: Sarotti, Ariel Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; ArgentinaFil: Da Silva, Cameron C.. Universidade Federal de Goiás; BrasilFil: Boukouvalas, John. Universite Laval; FranciaFil: Martins, Felipe T.. Universidade Federal de Goiás; Brasi