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Chemical engineered extracts of Portuguese biorenewable resources to the synthesis of diverse natural products hybrids towards new bioactive entities
Get PDFNatural products (NPs) with biologically active pharmacophores are biologically validated starting points for the development of new drugs. Between 1981 and 2019, NPs and their derivatives represented 24% of all newly approved drugs. Cistus ladanifer is an aromatic plant from Mediterranean climates that exist in high quantity in Portugal. Cistus ladanifer essential oils have shown antimicrobial and antitumoral biological activities. An interesting methodology to access NPs derivatives is the preparation of chemically engineered extracts (CEEs). This approach focuses on the transformation of selected chemical functionalities, highly common in natural products extracts, into new chemical entities.
This work aims to develop a new and efficient methodology to prepare CEEs from Cistus ladanifer. To this end, light-mediated thiol-ene reaction, was applied to natural extracts of Cistus ladanifer, to took advantage of alkene functional groups and form thioether-CEEs.
The optimization of the reaction conditions was executed using limonene as model substrate (3 equiv. of N-acetylcysteine, 0.1 equiv. of DMPA, dry MeOH, 2.2 M limonene, for 1h at 365 nm in a FEP Tube). The optimized reaction conditions were applied to a basic fraction of the natural extract of Cistus ladanifer, however further optimization was needed. Cistus ladanifer profile was studied through UPLC/ESI-HR-MS and two approaches were used for the purification of the new CEEs. (i) Flash chromatography, where the best protocol was based in an initial MTBE acid/basic workup followed by 2 consecutives normal phase column chromatography’s (ii) semi-preparative HPLC that allowed the identification of 3 Peaks at 254 nm. The m/z identified correspond to 33 possible compounds in peak 1, 19 in peak 2, and 37 in peak 3.
The main compound of the acid fraction of Cistus ladanifer, labdanolic acid, was also studied. A methylation reaction followed by a dehydration allowed the introduction of alkenes in the molecule making it susceptible to thiol-ene reaction. Unfortunately, no conversion was obtained.Produtos naturais (NPs) com farmacóforos biologicamente ativos são pontos de partida interessantes para o desenvolvimento de novos fármacos. Entre 1981-2019, os NPs e derivados representam cerca de 24% de todos os novos fármacos aprovados. Cistus ladanifer é uma planta aromática que existe em alta quantidade em Portugal e que pode ser encontrada em climas mediterrâneos. Diversos estudos demonstram o seu alto potencial antimicrobiano e antitumoral. Uma metodologia interessante para aceder a derivados de NPs é a preparação de extratos quimicamente modificados (CEEs). Esta abordagem permite a transformação de determinadas funcionalidades químicas, altamente comuns, em extratos naturais.
O objetivo principal deste trabalho é de desenvolver uma nova metodologia eficiente que permita preparar CEEs a partir de um extrato de Cistus ladanifer. Reações tiol-ene mediadas pela luz UV foram aplicadas a este extrato, tirando partido de olefinas presentes, formando novas ligações tioeter-CEEs.
As otimizações das condições reacionais foram executadas usando limoneno como substrato modelo (3 equiv. N-acetilcisteína, 0.1 equiv. DMPA, MeOH, 2.2 M limoneno e luz UV a 365 nm num tubo FEP durante 1 h). As condições otimizadas foram aplicadas à fração básica do extrato de Cistus ladanifer, seguido de nova otimização. O perfil da Cistus ladanifer foi estudado por UPLC/ESI-HR-MS e foram utilizadas duas abordagens para purificar os novos CEEs: (i) Cromatografia Flash, onde o melhor protocolo utilizado foi baseado num workup ácido/base inicial com MTBE, seguido de duas cromatografias em coluna consecutivas (ii) HPLC Semi-Preparativo, que permitiu a identificação de três novas bandas a 254 nm. As m/z identificadas podem ser atribuídas a 33 possíveis compostos na banda 1, 19 na banda 2 e 27 na banda 3.
O composto maioritário da fração ácida da Cistus ladanifer, Ácido Labdanólico, foi também estudado. A esterificação e seguida desidratação deste composto permitiu a introdução de uma olefina na molécula que pode sofrer reação tiol-ene. Infelizmente nenhuma conversão foi obtida
C-H borylation of furfural derivatives
No full textTrabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2022, Universidade de Lisboa, Faculdade de Farmácia.Durante os últimos anos, as fontes de carbono fósseis, tais como carvão, petróleo bruto e gás
natural, têm sido a principal fonte não só de energia, como de químicos à base de carbono
também. No entanto, estas fontes apresentam algumas desvantagens, visto não serem
renováveis e estarem associadas a problemas ambientais, o que tem levado a um interesse
crescente, por parte da comunidade científica, no desenvolvimento de alternativas mais eco-compatíveis. Nesta perspetiva, a biomassa surgiu como fonte de carbono, podendo ser usada na
síntese de vários químicos de valor. Entre estes, pode-se distinguir o furfural, uma vez que
possui um grande potencial na produção de outras moléculas, sendo considerado um dos
químicos derivados da biomassa mais importantes. Uma área interessante, que permite a
funcionalização de derivados do furfural, é a ativação C–H catalisada por metais de transição.
A maioria deste tipo de reações funcionaliza a posição C5 do anel furânico, visto ser a posição
mais reativa, ao contrário das posições C3 e C4, que são muito mais difíceis de funcionalizar.
Neste projeto, estudamos um tipo de funcionalização C–H, a borilação C–H. Nesse sentido,
após uma reação de condensação entre furfural e aminas primárias, obtendo furfuril-iminas,
realizamos a borilação da posição C5 destas, usando bis(pinacolato)diboro como fonte de boro
e um catalisador de irídio, obtendo os respetivos produtos com bom rendimento e seletividade.
Subsequentemente, realizamos um acoplamento de Suzuki-Miyaura com sucesso, usando
diferentes haletos de aril, e determinamos que a utilização de um haleto de aril com um grupo
eletrodoador na posição ortho resultava em melhores rendimentos. Assim, com a inserção de
um grupo diretor na nossa molécula, foi possível realizar a funcionalização C4–H, que consistiu
numa reação de Fujiwara-Moritani catalisada por paládio, com um acrilato, o que resultou na
obtenção do respetivo produto com boa seletividade.For the past years, fossil carbon resources, such as coal, crude oil and natural gas, have been
the main source of not only energy, but carbon-based chemicals as well. However, these
resources present some disadvantages, since they are exhaustible and are related to
environmental issues. Therefore, recently, the scientific community has demonstrated an
increasing interest in the development of more eco-compatible solutions, and thus biomass
emerged as a carbon resource that can be used to synthetize several value-added chemicals.
Furfural is one of these platform chemicals, and it has a great potential for the production of
other molecules, being considered one of the most valuable biomass-derived initial platform
molecules. One interesting area in this field is the selective transition-metal-catalyzed C–H
activation of furfural derivatives, which allows the functionalization of these molecules. The
majority of this type of reactions perform the functionalization at the C5 position of the furan
ring, since it is the most reactive position, unlike the C3 and C4 positions, that are much more
difficult to functionalize.
One type of C–H functionalization is the C–H borylation, which is explored in this project.
After performing a condensation reaction between furfural and primary amines, affording
furfuryl-imines, we performed the iridium catalyzed C5-borylation of these molecules, using
bis(pinacolato)diboron as boron source, obtaining good yields and selectivity. Subsequently,
we performed the Suzuki-Miyaura cross coupling, with different aryl halides as coupling
partners. This reaction was also successfully accomplished, and we determined that using an
aryl halide with an electron donor group in ortho position resulted in better yields. Since this
reaction allowed the insertion of a directing group in our molecule, it was then possible to
perform the C4–H functionalization, which consisted in a palladium catalyzed Fujiwara Moritani coupling with an acrylate. This resulted in the respective alkenylation product with
good selectivity.Institut Parisien de Chimie Moléculaire, Sorbonne Université
Pd-catalyzed ring opening of bicyclic aziridines prepared by photochemical transformation of pyridinium salt under continuous flow
No full textTrabalho Final de Mestrado Integrado, Ciências Farmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2019O grupo funcional aziridina apresenta-se como uma das estruturas cíclicas mais pequenas com maior potencial como meio de síntese para novas moléculas de interesse químico. Devido à sua alta reatividade e tensão anelar, apresenta características que permitem a aplicação numa ampla gama de reações. Neste projeto, particularmente, retratamos as aziridinas bicíclicas. Estas moléculas foram já previamente estudadas no que diz respeito à abertura da estrutura recorrendo a nucleófilos baseados em heteroátomos. Neste contexto, durante este projeto quisemos estender o estudo no âmbito da abertura do ciclo das aziridinas bicíclicas com uso de nucleófilos baseados em ligação carbono-carbono e envolvendo catálise com paládio. Para tal, usando um sistema inovador de “flow”, sintetizamos inicialmente a aziridina bicíclica com o grupo hidroxilo [(1R,2R,5R)-6-butil-6-azabiciclo[3.1.0]hex-3-en-2-ol] em grande escala ( 8 gramas com 96% de rendimento). De seguida, a aziridina bicíclica com o grupo acetil [(1R,2R,5R)-6-butil-6-azabiciclo[3.1.0]hex-3-en-2-ol] também foi sintetizada. Posteriormente, a catálise com paládio foi testada com sucesso, na aziridina bicíclica hidroxilo e acetilo, com nucleófilos baseados em ligação carbono-carbono tais como: ácido de meldrum originando rendimentos isolados de 44% e 71%, respectivamente; ácido dimetil barbitúrico com rendimentos de 42% e 83%, respectivamente; acetoacetato de metilo com rendimento isolado de 60% para a aziridina bicíclica hidroxilo; e nitroacetato de etilo com rendimento isolado de apenas 24% para a aziridina bicíclica acetilo. Todos os produtos foram caracterizados por RMN (1H, 13C NMR e análise 2D), HRMS e por análise raio-X (para produtos obtidos com o ácido dimetil barbitúrico) que confirmou a regio e estéreo-seletividade desta reação. Outros nucleófilos como o malononitrilo, bis(fenilsulfonil)metano e metil 2-tosilacetato foram também testados, mas sem sucesso. De modo geral, alcançámos a síntese e caracterização de diversos novos compostos com abertura regio e estéreo-seletivamente controlada da aziridina bicíclica, demonstrando a importância desta química.The functional group aziridine is one of the smallest cyclic structures having a great potential for synthesis of new molecules of chemical interest. Due to its high reactivity and ring tension, it has characteristics that allow its application in a wide range of reactions and, therefore, applications in the construction of new and bigger molecules. In previous reports by our group, the potential of bicyclic aziridines in chemistry was studied, and specially the opening of the structure in the presence of heteroatom-based nucleophiles. In this context, during this project, we wanted to extend this study concerning the ring opening of bicyclic aziridines, to the use of carbon-based nucleophiles by involving palladium catalysis. For that, using an innovative continuous flow system, first of all we synthetized the bicyclic aziridine bearing a free hydroxyl group [(1R,2R,5R)-6-butyl-6-azabicyclo[3.1.0]hex-3-en-2-ol] in large scale (8 grams in total with 96% yield). Then, the corresponding acetylated bicyclic aziridine [(1R,2R,5R)-6-butyl-6-azabicyclo[3.1.0]hex-3-en-2-ol] was also synthetized by an acylation reaction. Thereafter, the Pd catalysis was successfully tested on the unprotected and the acetylated bicyclic aziridines, with some carbon-based-nucleophiles, such as: Meldrum’s acid leading to 44% and 71% isolated yields, respectively; dimethyl barbituric acid given 42% and 83% isolated yields, respectively; methyl acetoacetate leading to 60% only with the unprotected bicyclic aziridine; and ethyl nitroacetate furnishing only 24% yield with the acylated bicyclic aziridine. All the products were characterized by NMR (1H, 13C NMR and 2D analysis), HRMS and by X-ray analysis (for products obtained with barbituric acid) that confirmed the regioselectivity of this reaction. Other nucleophiles like malononitrile, dimedone, bis(phenylsulfonyl)methane and methyl 2-tosylacetate, were also tested, but without successful results. Overall, we were able to synthetize and characterized a variety of new compounds, with both controlled stereo and regioselectivity cleavage of the bicyclic aziridine, showing the high value of this particular chemistry.Instituto de Investigação do Medicamento, Faculdade de Farmácia da Universidade de Lisboa; Institut Parisien de Chimie Moléculaire, Sorbonne Universit
C-H borylation of furfural derivatives
No full textTrabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2022, Universidade de Lisboa, Faculdade de Farmácia.Durante os últimos anos, as fontes de carbono fósseis, tais como carvão, petróleo bruto e gás
natural, têm sido a principal fonte não só de energia, como de químicos à base de carbono
também. No entanto, estas fontes apresentam algumas desvantagens, visto não serem
renováveis e estarem associadas a problemas ambientais, o que tem levado a um interesse
crescente, por parte da comunidade científica, no desenvolvimento de alternativas mais eco-compatíveis. Nesta perspetiva, a biomassa surgiu como fonte de carbono, podendo ser usada na
síntese de vários químicos de valor. Entre estes, pode-se distinguir o furfural, uma vez que
possui um grande potencial na produção de outras moléculas, sendo considerado um dos
químicos derivados da biomassa mais importantes. Uma área interessante, que permite a
funcionalização de derivados do furfural, é a ativação C–H catalisada por metais de transição.
A maioria deste tipo de reações funcionaliza a posição C5 do anel furânico, visto ser a posição
mais reativa, ao contrário das posições C3 e C4, que são muito mais difíceis de funcionalizar.
Neste projeto, estudamos um tipo de funcionalização C–H, a borilação C–H. Nesse sentido,
após uma reação de condensação entre furfural e aminas primárias, obtendo furfuril-iminas,
realizamos a borilação da posição C5 destas, usando bis(pinacolato)diboro como fonte de boro
e um catalisador de irídio, obtendo os respetivos produtos com bom rendimento e seletividade.
Subsequentemente, realizamos um acoplamento de Suzuki-Miyaura com sucesso, usando
diferentes haletos de aril, e determinamos que a utilização de um haleto de aril com um grupo
eletrodoador na posição ortho resultava em melhores rendimentos. Assim, com a inserção de
um grupo diretor na nossa molécula, foi possível realizar a funcionalização C4–H, que consistiu
numa reação de Fujiwara-Moritani catalisada por paládio, com um acrilato, o que resultou na
obtenção do respetivo produto com boa seletividade.For the past years, fossil carbon resources, such as coal, crude oil and natural gas, have been
the main source of not only energy, but carbon-based chemicals as well. However, these
resources present some disadvantages, since they are exhaustible and are related to
environmental issues. Therefore, recently, the scientific community has demonstrated an
increasing interest in the development of more eco-compatible solutions, and thus biomass
emerged as a carbon resource that can be used to synthetize several value-added chemicals.
Furfural is one of these platform chemicals, and it has a great potential for the production of
other molecules, being considered one of the most valuable biomass-derived initial platform
molecules. One interesting area in this field is the selective transition-metal-catalyzed C–H
activation of furfural derivatives, which allows the functionalization of these molecules. The
majority of this type of reactions perform the functionalization at the C5 position of the furan
ring, since it is the most reactive position, unlike the C3 and C4 positions, that are much more
difficult to functionalize.
One type of C–H functionalization is the C–H borylation, which is explored in this project.
After performing a condensation reaction between furfural and primary amines, affording
furfuryl-imines, we performed the iridium catalyzed C5-borylation of these molecules, using
bis(pinacolato)diboron as boron source, obtaining good yields and selectivity. Subsequently,
we performed the Suzuki-Miyaura cross coupling, with different aryl halides as coupling
partners. This reaction was also successfully accomplished, and we determined that using an
aryl halide with an electron donor group in ortho position resulted in better yields. Since this
reaction allowed the insertion of a directing group in our molecule, it was then possible to
perform the C4–H functionalization, which consisted in a palladium catalyzed Fujiwara Moritani coupling with an acrylate. This resulted in the respective alkenylation product with
good selectivity.Institut Parisien de Chimie Moléculaire, Sorbonne Université
Photochemical synthesis and functional transformations of bicyclic vinyl aziridines
Get PDFAziridines, a class of organic compounds containing a three membered heterocycle with a nitrogen atom, are extremely valuable molecules in organic and medicinal chemistry. They are frequently used as versatile precursors in the synthesis of natural products, and many biologically active molecules possess the aziridine moiety.
The reactivity of aziridines has been studied, for example, in ring-opening reactions with thiols. However, not much interest seems to be given to reactions of aziridines in aqueous media, despite the numberless advantages of using water as solvent in organic chemistry.
The nucleophilic ring-opening reaction of aziridines in aqueous media was here explored. Following the Kaplan aziridine synthetic methodology, in which pyridinium salts undergo a photochemical transformation to give bicyclic vinyl aziridines, new aziridines were synthetized. Their nucleophilic ring-opening reaction in water under physiological conditions was investigated and a range of sulphur, nitrogen, carbon and oxygen nucleophiles tested. Thiols, anilines and azide proved to be good nucleophiles to react with the aziridines, giving the ring-opening product in moderate to good yields. The best results were obtained with thiols, more specifically with cysteine-derived nucleophiles. Preliminary results show that these bicyclic vinyl aziridines can modify calcitonin, a peptide containing two cysteine amino acids residues, grating them the potential to be used in bioconjugation as ligands to cysteine-containing proteins, or even as enzyme inhibitors of, for example, cysteine proteases.
Additionally, exploratory investigations suggest that the separation of both enantiomers of the bicyclic vinyl aziridine can be performed by taking advantage of an enzymatic methodology for the resolution of racemic secondary alcohols. Both enantiomers would be highly valuable as precursors in the synthesis of enantiomerically pure molecules, as no other method is currently reported for their separation
Pd-catalyzed ring opening of bicyclic aziridines prepared by photochemical transformation of pyridinium salt under continuous flow
No full textTrabalho Final de Mestrado Integrado, Ciências Farmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2019O grupo funcional aziridina apresenta-se como uma das estruturas cíclicas mais pequenas com maior potencial como meio de síntese para novas moléculas de interesse químico. Devido à sua alta reatividade e tensão anelar, apresenta características que permitem a aplicação numa ampla gama de reações. Neste projeto, particularmente, retratamos as aziridinas bicíclicas. Estas moléculas foram já previamente estudadas no que diz respeito à abertura da estrutura recorrendo a nucleófilos baseados em heteroátomos. Neste contexto, durante este projeto quisemos estender o estudo no âmbito da abertura do ciclo das aziridinas bicíclicas com uso de nucleófilos baseados em ligação carbono-carbono e envolvendo catálise com paládio. Para tal, usando um sistema inovador de “flow”, sintetizamos inicialmente a aziridina bicíclica com o grupo hidroxilo [(1R,2R,5R)-6-butil-6-azabiciclo[3.1.0]hex-3-en-2-ol] em grande escala ( 8 gramas com 96% de rendimento). De seguida, a aziridina bicíclica com o grupo acetil [(1R,2R,5R)-6-butil-6-azabiciclo[3.1.0]hex-3-en-2-ol] também foi sintetizada. Posteriormente, a catálise com paládio foi testada com sucesso, na aziridina bicíclica hidroxilo e acetilo, com nucleófilos baseados em ligação carbono-carbono tais como: ácido de meldrum originando rendimentos isolados de 44% e 71%, respectivamente; ácido dimetil barbitúrico com rendimentos de 42% e 83%, respectivamente; acetoacetato de metilo com rendimento isolado de 60% para a aziridina bicíclica hidroxilo; e nitroacetato de etilo com rendimento isolado de apenas 24% para a aziridina bicíclica acetilo. Todos os produtos foram caracterizados por RMN (1H, 13C NMR e análise 2D), HRMS e por análise raio-X (para produtos obtidos com o ácido dimetil barbitúrico) que confirmou a regio e estéreo-seletividade desta reação. Outros nucleófilos como o malononitrilo, bis(fenilsulfonil)metano e metil 2-tosilacetato foram também testados, mas sem sucesso. De modo geral, alcançámos a síntese e caracterização de diversos novos compostos com abertura regio e estéreo-seletivamente controlada da aziridina bicíclica, demonstrando a importância desta química.The functional group aziridine is one of the smallest cyclic structures having a great potential for synthesis of new molecules of chemical interest. Due to its high reactivity and ring tension, it has characteristics that allow its application in a wide range of reactions and, therefore, applications in the construction of new and bigger molecules. In previous reports by our group, the potential of bicyclic aziridines in chemistry was studied, and specially the opening of the structure in the presence of heteroatom-based nucleophiles. In this context, during this project, we wanted to extend this study concerning the ring opening of bicyclic aziridines, to the use of carbon-based nucleophiles by involving palladium catalysis. For that, using an innovative continuous flow system, first of all we synthetized the bicyclic aziridine bearing a free hydroxyl group [(1R,2R,5R)-6-butyl-6-azabicyclo[3.1.0]hex-3-en-2-ol] in large scale (8 grams in total with 96% yield). Then, the corresponding acetylated bicyclic aziridine [(1R,2R,5R)-6-butyl-6-azabicyclo[3.1.0]hex-3-en-2-ol] was also synthetized by an acylation reaction. Thereafter, the Pd catalysis was successfully tested on the unprotected and the acetylated bicyclic aziridines, with some carbon-based-nucleophiles, such as: Meldrum’s acid leading to 44% and 71% isolated yields, respectively; dimethyl barbituric acid given 42% and 83% isolated yields, respectively; methyl acetoacetate leading to 60% only with the unprotected bicyclic aziridine; and ethyl nitroacetate furnishing only 24% yield with the acylated bicyclic aziridine. All the products were characterized by NMR (1H, 13C NMR and 2D analysis), HRMS and by X-ray analysis (for products obtained with barbituric acid) that confirmed the regioselectivity of this reaction. Other nucleophiles like malononitrile, dimedone, bis(phenylsulfonyl)methane and methyl 2-tosylacetate, were also tested, but without successful results. Overall, we were able to synthetize and characterized a variety of new compounds, with both controlled stereo and regioselectivity cleavage of the bicyclic aziridine, showing the high value of this particular chemistry.Instituto de Investigação do Medicamento, Faculdade de Farmácia da Universidade de Lisboa; Institut Parisien de Chimie Moléculaire, Sorbonne Universit
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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