Tese (doutorado)–Universidade de Brasília, Instituto de Química, Programa de Pós-Graduação em Química, 2015. / Neste trabalho, foi desenvolvida uma estratégia convergente para a síntese de peptóides lineares e cíclicos via reações multicomponente de Ugi e cicloadição azida/alcino catalisada por cobre em regime de fluxo contínuo. Todas as condições experimentais para a reação de Ugi quatro componentes aplicadas à síntese dos peptóides lineares foram primeiramente estabelecidas por meio do uso da técnica de micro-ondas, o que permitiu o preparo em excelentes rendimentos de diferentes estruturas de peptóides.Tanto a etapa de formação da isonitrila como de preparação do ácido azido acético foram realizadas in situ, sem a necessidade de isolamento e purificação desses compostos. Estas etapas foram combinadas diretamente em uma mesma plataforma de fluxo contínuo com a reação de Ugi, gerando em três etapas, de forma eficiente, um peptóide linear com tempo reacional total de 25 min. A transposição das condições experimentais estabelecidas em micro-ondas para o fluxo contínuo foi realizada sem otimizações adicionais. A realização da reação de ciclização de CuAAC em fluxo contínuo por meio de um reator de cobre possibilitou o preparo de oito ciclopeptóides contendo o núcleo triazólico com rendimentos que variaram de bons a excelentes, sem a necessidade da utilização de nenhum tipo de aditivo. / In this work, a convergent strategy for the synthesis of linear and cyclic peptoids via the Ugi multicomponent reaction and copper-catalyzed azide/alkyne cycloaddition under continuous flow system was developed. All conditions for the Ugi four component reaction applied to the synthesis of linear peptoids were first established by using the microwave technique, which allowed the preparation of different peptoid structures in excellent yields.The steps of the isonitrile formation and the azido acetic acid preparation were both conducted in situ without any isolation or purification of these compounds. Later, these steps were directly combined in the same continuous flow platform with the Ugi reaction, yielding in three steps, in an efficient manner, a linear peptoid in a total reaction time of 25 min. Thus, the transposition of the experimental conditions established in microwave for continuous flow was accomplished without additional optimizations. The CuAAC cyclization reaction in continuous flow through a copper reactor enabled the preparation of eight ciclopeptoids containing the triazole nucleus in good to excellent yields avoiding the use of any additive.

Dissertação (mestrado)—Universidade de Brasília, Instituto de Química, Programa de Pós-Graduação em Química, 2016. / Reações multicomponentes (RMC`s) são amplamente conhecidas como processos em que três ou mais substratos são combinados de forma direta, ou seja, sem a necessidade de isolamento de intermediários, para a preparação de uma única estrutura. A reação de Ugi multicomponente é considerada a mais importante reação multicomponente baseada em isocianetos existente, pela sua versatilidade e pela simplicidade experimental em formar uma molécula relativamente complexa e pela economia de átomos. Cumarinas são consideradas uma das mais importantes moléculas heterocíclicas existentes por causa da sua versatilidade de aplicações em vários segmentos da ciência e tecnologia, devido às suas características fluorescentes, sua ótima solubilidade e sua razoável estabilidade, além da sua fácil preparação. Ao longo do projeto, foi possível sintetizar e caracterizar um acervo de quatorze peptóides fluorescentes utilizando cumarinas substituídas como substrato da reação. Estudo metodológico de síntese de isocianetos, um substrato essencial para que ocorra reação, também foi realizado através de uma síntese alternativa, mais rápida e simples quando comparadas com as usuais. Estudos das propriedades também foram feitos a fim de se elucidar efeitos solvatocrômicos desses peptóides, bem como seus mecanismos de estabilização no seu estado excitado. Por último, alguns peptóides foram utilizados como marcadores em células vivas, a fim de compreender como esses produtos se comportam no interior dessas células. Um dos peptóides se mostrou um excelente marcador específico para mitocôndrias. / Multicomponent Reactions (RMC`s) are widely known as processes in which three or more substrates are combined directly, without isolation of intermediates, for preparing a single structure. The Ugi reaction is considered the most important multicomponent reaction based on isocyanides by their versatility, the experimental simplicity to form a relatively complex molecule and atoms eficiency. Coumarins are considered one of the most important existing heterocyclic molecules for their versatility of application in various segments of science and technology due to their fluorescent characteristics, optimal solubility and reasonable stability, in addition to easy preparation. Throughout the project, it was possible to synthesize and characterize a collection of fourteen fluorescent peptoids using substituted coumarins as reaction substrates. Methodological study of isocyanides synthesis, essential substrates for reactions to occur, was also accomplished through an alternate, quicker and simpler synthesis when compared to usual. Procedures of the optical properties were also made to elucidate solvatochromic effects of peptoids as well their stabilization mechanisms in the excited state. Finally, some peptoids were used as markers in living cells in order to understand how these products behave within these cells. One of peptoids showed an excellent specific marker for mitochondria.

In 2006, an amphoteric molecule containing both an aldehyde and an unprotected amine was reported in the Yudin group by Dr. Ryan Hili. The unprotected aziridine aldehyde exists as homochiral dimers. Furthermore, due to the reversibility of the hemiacetal formation, the free aldehyde is available to undergo a wide array of reactions including an Ugi multicomponent reaction to give the final peptide macrocycle. Thus far, the mechanistic pathway involved in the Ugi reaction between S-trans aziridine aldehyde dimer and L-amino acids in the presence of tert-butyl isocyanide has given high diastereoselectivity whereas low diastereoselectivity is observed if the aziridine dimer is of the opposite stereochemistry. Herein, preliminary results show that a S-cis aziridine aldehyde with either a D or L-secondary amino acid gives high diastereoselectivity showing that the reaction is under Felkin-Ahn control.

In 2006, an amphoteric molecule containing both an aldehyde and an unprotected amine was reported in the Yudin group by Dr. Ryan Hili. The unprotected aziridine aldehyde exists as homochiral dimers. Furthermore, due to the reversibility of the hemiacetal formation, the free aldehyde is available to undergo a wide array of reactions including an Ugi multicomponent reaction to give the final peptide macrocycle. Thus far, the mechanistic pathway involved in the Ugi reaction between S-trans aziridine aldehyde dimer and L-amino acids in the presence of tert-butyl isocyanide has given high diastereoselectivity whereas low diastereoselectivity is observed if the aziridine dimer is of the opposite stereochemistry. Herein, preliminary results show that a S-cis aziridine aldehyde with either a D or L-secondary amino acid gives high diastereoselectivity showing that the reaction is under Felkin-Ahn control.

Dissertação (mestrado)—Universidade de Brasília, Instituto de Química, Programa de Pós-Graduação em Química, 2017. / Submitted by Raquel Almeida (raquel.df13@gmail.com) on 2017-11-09T18:53:32Z No. of bitstreams: 1 2017_JorgePatryckSantos.pdf: 5629659 bytes, checksum: f2b8b5b43101e0703cc7c515a8cf8b99 (MD5) / Approved for entry into archive by Raquel Viana (raquelviana@bce.unb.br) on 2017-11-23T12:03:20Z (GMT) No. of bitstreams: 1 2017_JorgePatryckSantos.pdf: 5629659 bytes, checksum: f2b8b5b43101e0703cc7c515a8cf8b99 (MD5) / Made available in DSpace on 2017-11-23T12:03:20Z (GMT). No. of bitstreams: 1 2017_JorgePatryckSantos.pdf: 5629659 bytes, checksum: f2b8b5b43101e0703cc7c515a8cf8b99 (MD5) Previous issue date: 2017-11-21 / De modo geral, estruturas cíclicas ocupam um lugar de destaque na química orgânica e rotas sintéticas para a obtenção desta classe de moléculas são altamente desejáveis. É crescente o número de publicações em que reações multicomponente de Ugi são utilizadas visando à síntese de compostos macrocíclicos e heterocíclicos. Desta forma, neste trabalho foram propostas duas estratégias sintéticas distintas, ambas baseadas na reação de Ugi, para a construção de um acervo de compostos cíclicos. A primeira delas, baseada nos preceitos da MiBs (Multiple Multicomponent Macrocyclizations Including Bifunctional Building Blocks), em que componentes bifuncionais são necessários, visou a síntese de compostos macrocíclicos via reações consecutivas de Ugi empregando diácidos carboxílicos preparados a partir de reações de Ugi do tipo U-5C-4CR. A segunda estratégia buscou empregar um aldeído polifuncionalizado, produto de um rearranjo de Claisen em adutos de Morita-Baylis-Hillman, como um dos componentes em reações multicomponentes de Ugi. Esta abordagem permitiu a obtenção de compostos heterocíclicos estruturalmente distintos pela utilização de diferentes estratégias de ciclização. / In general, cyclic structures occupy a prominent place in organic chemistry and synthetic routes for obtaining this class of molecules are highly desirable. There is a growing number of publications in which Ugi multi-component reactions are used for the synthesis of macrocyclic and heterocyclic compounds. In this work, two different synthetic strategies were proposed, both based on the Ugi reaction, for the construction of a collection of cyclic compounds. The first one, based on the precepts of the MiBs (Multiple Multicomponent Macrocyclics Including Bifunctional Building Blocks), in which bifunctional components are required, aimed the synthesis of macrocyclic compounds via consecutive Ugi reactions using carboxylic diacids prepared from U- 5C-4CR Ugi variant. The second strategy employ a polyfunctionalized aldehyde, product of a Claisen rearrangement in Morita-Baylis-Hillman adducts, as one of the components in Ugi multicomponent reactions. This approach allowed structurally distinct heterocyclic compounds readly obtained by the use of different cyclization strategies.

The current 'gold standard method' of detecting cancer relies on microscopic examination by specialised pathologists. However, there are risks associated with surgery and biopsies and so the ability to diagnose cancer and other diseases in a non-invasive manner is highly attractive. There are many imaging techniques suitable for this, each with their own advantages and disadvantages, which can be improved by the use of contrast agents. The incorporation of targeting vectors allows for the specific imaging of desired tissues. Further to this, the incorporation of more than one contrast agent into one imaging agent allows for multi-modal imaging of cancerous tissue and other diseases. This allows for the advantages of different techniques to be used simultaneously and is an emerging field. The methods for the synthesis of these drugs can be synthetically demanding and low yielding due to linear synthetic strategies. The use of multi-component reactions would be a major benefit and the Ugi reaction is particularly attractive due to the incorporation of four components and the biocompatible bis-amide motif of Ugi products. This work serves as an extension to previous work based on Ugi reactions of metal complexes, which showed that amine and carboxylic acid appended lanthanide and carboxylic acid appended d-metal complexes can be used as stable building blocks in the formation of mono-metallic complexes. This work presents the synthesis of aldehyde appended lanthanide complexes and their use in Wittig and Ugi chemistry in the synthesis of mono-metallic complexes. The previously synthesised amine appended lanthanide complexes 1, 3, 4 were also synthesised to be used as a feedstock in subsequent Ugi reactions. A number of carboxylic acid appended d-metal complexes and cyanine dyes were synthesised according literature procedures. Both the bis-acid appended d-metal complexes and cyanine dyes were used unsuccessfully in the Ugi reaction. However, the mono-acid d-metal complexes were used successfully in the Ugi reaction in keeping with previous reports. These were used as the third feedstock for the synthesis of trimetallic complexes along with the aldehyde and amine appended lanthanide complexes via the Ugi reaction. In addition, a number of Ugi reactions were performed on organic compounds. The use of p-toluic acid gave five Ugi compounds, which were characterised and gave the expected results. However, the use of biotin as the carboxylic acid component gave four compounds that were complex to characterise and suggested that the incorporated biotin may not serve as a viable targeting vector. One of the p-toluic acid Ugi products was reacted further and a biotin moiety was incorporated with a (CH2)6 spacer. Spectroscopic evidence suggested that the biotin would still act as a viable targeting vector. Overall, this work serves to set the scene for the synthesis of targeted tri-metallic multi-modal imaging agents using stable metal complexes as building blocks in the Ugi reaction.

Les réactions multicomposant à base d'isonitrile (I-MCR) combinées à des transformations de post-condensation constituent des outils de synthèse extrêmement puissants pour la préparation de structures moléculaires complexes et diverses avec de nouvelles propriétés pharmacologiques.Dans un premier temps, nous nous sommes intéressés à l'extension du couplage de Ugi-Smiles aux dérivés de purines, en utilisant la 6-mercaptopurine comme partenaire de couplage. Cette méthodologie permet un accès direct et rapide aux dérivés d'adénine avec des rendements modérés à bons à partir de précurseurs simples et facilement accessibles.Par la suite, nous avons démontré que les produits d'addition Ugi dérivés d'aldéhydes aromatiques peuvent être convertis en 2-pyrrolines par addition d'accepteurs de Michael, sous irradiation par micro-ondes. La réaction peut se dérouler via la formation inhabituelle d’ylures azométhines suivie d'une cycloaddition [3 + 2] avec des accepteurs de Michael.Enfin, nous avons montré que les adduits Passerini issus de cinnamaldéhyde peuvent être efficacement convertis en α-cétoamides lorsqu'ils sont traités en milieu basique et dans des conditions de chauffage sous irradiations micro-ondes. / The isocyanide based multicomponent reactions (I-MCRs) with subsequent post-condensation transformations constitute extremely powerful synthetic tools for the preparation of structurally diverse complex molecules with novel properties.In this context, we first investigated the extension of Ugi-Smiles coupling to purines, by using 6-mercaptopurine as coupling partner. This methodology allows direct access to adenine derivatives in moderate to good yields starting from readily available precursors.Then, we demonstrated that Ugi adducts derived from aromatic aldehydes may be converted to pyrrolines via addition of Michael acceptors under microwave irradiation. The reaction may proceed via unusual formation of azomethine ylides followed by a [3+2] cycloaddition using Michael acceptors.Finally, we described that the Passerini adducts of cinnamaldehyde and analogues may be efficiently converted into α-ketoamides when heated with a base under microwave conditions.

Na primeira parte deste trabalho apresentamos uma forma eficiente para sintetizar quinze novos compostos α-amino-1,3-dicarbonílicos através da reação multicomponente de Ugi. Para estas sínteses foi utilizado o microrreator de fluxo contínuo, um aparelho que possibilita uma excelente transferência de calor, de massa e alta relação superfície / volume. Algumas das vantagens em se utilizar um microrreator de fluxo contínuo na síntese são: redução do tempo de reação, aumento de rendimento, seletividade das reações e menor geração de resíduos. Foi possível assim estudar as reações químicas em condições inéditas, variando parâmetros como: temperatura, pressão, tempo de residência e relação estequiométrica. Um comparativo de rendimento da síntese de quatro moléculas foi realizado e pôde-se notar a eficiência do equipamento utilizado, pois os rendimentos obtidos foram superiores quando as mesmas moléculas foram sintetizadas através da reação one-pot. Um scale-up da reação de Ugi também foi realizado e apresentou um resultado satisfatório. Na segunda parte alguns destes compostos foram utilizados como intermediários na formação de uma ligação amídica e também aplicamos a metodologia relacionada à cicloadição catalisada por cobre entre alquinos e azidas na síntese de cinco novos compostos 1,2,3-triazóis. Este foi o primeiro trabalho realizado no Laboratório de Compostos Heterocíclicos da Faculdade de Ciências Farmacêuticas utilizando o microrreator de fluxo contínuo e este equipamento atendeu as necessidades deste trabalho com efetividade. / The first part of this work we present an efficient way to synthesize fifteen new α-amino-1,3-dicarbonyl compounds through the multicomponent Ugi reaction. For these syntheses was used the continuous flow micro-reactor, an equipment that allows an excellent transfer of heat, mass and high surface / volume ratio. Some of the advantages of using a continuous flow micro-reactor in the synthesis are: reduction of reaction time, increase of yield, selectivity of reactions and less generation of residues. It was possible to study the chemical reactions under new conditions, varying parameters such as: temperature, pressure, residence time and stoichiometric ratio. A yield comparison of the synthesis of four molecules was carried out and it was possible to note the efficiency of the equipment used, because the obtained yields were superior when the same molecules were synthesized through the one-pot reaction. A scale-up of the Ugi reaction was also performed and presented a satisfactory result. In the second part some of these compounds were used as intermediates in the formation of an amide bond and we also apply the methodology related to the copper catalyzed cycloaddition between alkynes and azides in the synthesis of five new 1,2,3-triazoles compounds. It was the first work performed in the Laboratory of Heterocyclic Compounds of the Faculty of Pharmaceutical Sciences using the continuous flow micro-reactor and this equipment met the needs of this work with effectiveness.

Na primeira parte deste trabalho apresentamos uma forma eficiente para sintetizar quinze novos compostos α-amino-1,3-dicarbonílicos através da reação multicomponente de Ugi. Para estas sínteses foi utilizado o microrreator de fluxo contínuo, um aparelho que possibilita uma excelente transferência de calor, de massa e alta relação superfície / volume. Algumas das vantagens em se utilizar um microrreator de fluxo contínuo na síntese são: redução do tempo de reação, aumento de rendimento, seletividade das reações e menor geração de resíduos. Foi possível assim estudar as reações químicas em condições inéditas, variando parâmetros como: temperatura, pressão, tempo de residência e relação estequiométrica. Um comparativo de rendimento da síntese de quatro moléculas foi realizado e pôde-se notar a eficiência do equipamento utilizado, pois os rendimentos obtidos foram superiores quando as mesmas moléculas foram sintetizadas através da reação one-pot. Um scale-up da reação de Ugi também foi realizado e apresentou um resultado satisfatório. Na segunda parte alguns destes compostos foram utilizados como intermediários na formação de uma ligação amídica e também aplicamos a metodologia relacionada à cicloadição catalisada por cobre entre alquinos e azidas na síntese de cinco novos compostos 1,2,3-triazóis. Este foi o primeiro trabalho realizado no Laboratório de Compostos Heterocíclicos da Faculdade de Ciências Farmacêuticas utilizando o microrreator de fluxo contínuo e este equipamento atendeu as necessidades deste trabalho com efetividade. / The first part of this work we present an efficient way to synthesize fifteen new α-amino-1,3-dicarbonyl compounds through the multicomponent Ugi reaction. For these syntheses was used the continuous flow micro-reactor, an equipment that allows an excellent transfer of heat, mass and high surface / volume ratio. Some of the advantages of using a continuous flow micro-reactor in the synthesis are: reduction of reaction time, increase of yield, selectivity of reactions and less generation of residues. It was possible to study the chemical reactions under new conditions, varying parameters such as: temperature, pressure, residence time and stoichiometric ratio. A yield comparison of the synthesis of four molecules was carried out and it was possible to note the efficiency of the equipment used, because the obtained yields were superior when the same molecules were synthesized through the one-pot reaction. A scale-up of the Ugi reaction was also performed and presented a satisfactory result. In the second part some of these compounds were used as intermediates in the formation of an amide bond and we also apply the methodology related to the copper catalyzed cycloaddition between alkynes and azides in the synthesis of five new 1,2,3-triazoles compounds. It was the first work performed in the Laboratory of Heterocyclic Compounds of the Faculty of Pharmaceutical Sciences using the continuous flow micro-reactor and this equipment met the needs of this work with effectiveness.

De nouvelle réactions multicomposants ont été mises au point. Une nouvelle ouverture de furane a par ailleurs été développée.