Cholesterol-based compounds: Recent advances in synthesis and applications

This review reports on the latest developments (since 2014) in the chemistry of cholesterol and its applications in different research fields. These applications range from drug delivery or bioimaging applications to cholesterol-based liquid crystals and gelators. A brief overview of the most recent synthetic procedures to obtain new cholesterol derivatives is also provided, as well as the latest anticancer, antimicrobial, and antioxidant new cholesterol-based derivatives. This review discusses not only the synthetic details of the preparation of new cholesterol derivatives or conjugates, but also gives a short summary concerning the specific application of such compoundsThanks are due to the University of Aveiro, Instituto Politécnico de Bragança, FCT/MEC for financial support of the QOPNA (FCT UID/QUI/00062/2013) and CIMO (UID/AGR/00690/2013) research units, through national funds, and where applicable cofinanced by the FEDER, within the PT2020 Partnership Agreement; and also to the Portuguese NMR Network. This work was also supported by the Integrated Programme of SR&TD “pAGE–Protein aggregation Across the Lifespan” (reference CENTRO-01-0145-FEDER-000003), co-funded by the Centro 2020 program, Portugal 2020, European Union, through the European Regional Development Fund. H. M. T. Albuquerque thanks the pAGE project for his Post-Doc grant (BPD/UI98/4861/2017).info:eu-repo/semantics/publishedVersio

Reações de cicloadição e adição conjugada de cromonas substituídas em C.2 com sistemas insaturados

Doutoramento em QuímicaO presente trabalho teve como principal objetivo estudar a reatividade de (E)-2-(4-arilbut-1-en-3-in-1-il)-4H-cromen-4-onas e 2-[(1E,3E)-4-arilbuta-A reatividade das 2-[(1E,3E)-4-arilbuta-1,3-dien-1-il]-4H-cromen-4-onas foi também testada em reações de adição conjugada com nucleófilos de carbono. A reação de nitrometano com as referidas cromonas catalisada por 1,8-diazabiciclo[5.4.0]undec-7-eno (DBU) originou β- (nitrometil)cromonas como produtos maioritários. Isolaram-se também (E)-5'-(nitrometil)-3'-estiril-[1,1'-bifenil]-2-óis e 3'-aril-2'-nitro-5'- (nitrometil)espiro[cromano-2,1'-ciclo-hexan]-4-onas como produtos minoritários, os quais resultam da adição de uma segunda molécula de nitrometano, por processos tandem. As adições de malononitrilo, acetilacetona, malonato de dietilo e cianoacetato de etilo originaram os respetivos produtos de adição conjugada 1,6, e no caso do malonato de dietilo, isolou-se um produto minoritário resultante de adições conjugadas 1,8/1,6. Estudos computacionais ajudaram a explicar a reatividade dos diferentes nucleófilos nas reações de adição às 2- [(1E,3E)-4-arilbuta-1,3-dien-1-il]-4H-cromen-4-onas. A funcionalização de alguns produtos de adição levou à síntese de estirilpirrolidinas e novos derivados de pirazol e bis-pirazol. Finalmente, a reação de DA intramolecular, sob radiação MW monomodo, de (E)-2-[2-(prop-2-in-1-iloxi)estiril]-4H-cromen-4-onas e 2- {(1E,3E)-4-[2-(prop-2-in-1-iloxi)fenil]buta-1,3-dien-1-il}-4H-cromen-4- onas originou 6H,8H-cromeno[3,4-b]xanten-8-onas e 2-(6Hbenzo[ c]cromen-8-il)-4H-cromen-4-onas, respetivamente. Todos os compostos sintetizados, intermediários e produtos finais, foram caracterizados por diversas técnicas analíticas, sobretudo por estudos espectroscópicos de ressonância magnética nuclear (RMN), incluindo espectros de 1H e 13C e bidimensionais de correlação espectroscópica homo e heteronuclear e de efeito nuclear de Overhauser (NOESY). 1,3-dien-1-il]-4H-cromen-4-onas em reações de cicloadição e adição conjugada. Sintetizaram-se díades do tipo xantona-1,2,3-triazol por duas rotas diferentes, partindo de (E)-2-(4-arilbut-1-en-3-in-1-il)-4H-cromen-4-onas. Na rota A, o núcleo de xantona foi sintetizado por reação de Diels-Alder (DA) das referidas cromonas com N-metilmaleimida (NMM), sob radiação micro-ondas (MW, do inglês microwaves), seguida de aromatização dos cicloadutos obtidos com 2,3-diciano-5,6-dicloro-1,4-benzoquinona (DDQ). O anel de 1,2,3-triazol foi incorporado através da reação de cicloadição 1,3-dipolar do alcino com azida de sódio, originando as díades xantona-1,2,3-triazol pretendidas. Por sua vez, a rota B envolveu a reação de cicloadição 1,3-dipolar das referidas cromonas com azida de sódio, seguida de metilação do grupo NH do triazol. A etapa seguinte consistiu na reação de DA, sob radiação MW, das díades 2-vinilcromona- 1,2,3-triazol com a NMM, seguida de aromatização dos cicloadutos, originando as díades xantona-1,2,3-triazol desejadas. Estudou-se também a reatividade das 2-[(1E,3E)-4-arilbuta-1,3-dien-1- il]-4H-cromen-4-onas como dienos em reações de DA com dienófilos pobres e ricos em eletrões, sob radiação MW. As melhores condições de reação foram obtidas usando a NMM como dienófilo, na presença de triflato de escândio, em condições de ausência de solvente. A presença deste ácido de Lewis melhorou os rendimentos da reação, na medida em que evita a ocorrência de uma segunda reação de DA nos cicloadutos obtidos. O dieno-α,β:γ,δ das 2-[(1E,3E)-4-arilbuta-1,3-dien-1-il]-4Hcromen- 4-onas mostrou ser o mais reativo, sendo este facto confirmado pelos estudos computacionais. Estes estudos explicaram ainda a inesperada falta de reatividade de alguns dienófilos. Os cicloadutos obtidos por reação com a NMM foram aromatizados a compostos do tipo arilflavona, usando DDQ como agente oxidante. AThe main goal of the present work was to study the reactivity of (E)-2-(4- arylbut-1-en-3-yn-1-yl)-4H-chromen-4-ones and 2-[(1E,3E)-4-arylbuta- 1,3-dien-1-yl]-4H-chromen-4-ones in cycloaddition and conjugate addition reactions. Xanthone-1,2,3-triazole dyads have been synthesized by two different approaches, both starting from (E)-2-(4-arylbut-1-en-3-yn-1-yl)-4Hchromen- 4-ones. In the first one (route A), the xanthone moiety was built by Diels-Alder (DA) reaction of the referred unsaturated chromones with N-methylmaleimide (NMM) under microwave irradiation, followed by oxidation of the obtained adducts with 2,3-dichloro-5,6-dicyano-1,4- benzoquinone (DDQ), whereas the 1,2,3-triazole ring results from the cycloaddition reaction of the acetylene moiety with sodium azide. In turn, the second strategy (route B) involved firstly the cycloaddition reaction with sodium azide to provide the 1,2,3-triazole ring, followed by methylation of the triazole NH group prior to DA reaction with NMM. The last step in this synthesis of novel xanthone-1,2,3-triazole dyads entailed the cycloadducts oxidation by DDQ. The reactivity of 2-[(1E,3E)-4-arylbuta-1,3-dien-1-yl]-4H-chromen-4-ones as dienes in DA reactions with several electron-poor and electron-rich dienophiles under microwave irradiation was studied. The optimized reaction conditions were achieved with NMM as dienophile and scandium triflate as Lewis acid, under microwave-assisted and solvent-free conditions. The Lewis acid improved the reaction yields by preventing the adducts obtained to undergo a second DA reaction. Computational studies confirmed the experimental findings that the α,β:γ,δ-diene of the starting chromones was the most reactive one. Theoretical calculations also provided a rationale for the unexpected lack of reactivity shown by some dienophiles. The adducts prepared with NMM were dehydrogenated to arylflavone derivatives with DDQ as oxidizing agent. The reactivity of 2-[(1E,3E)-4-arylbuta-1,3-dien-1-yl]-4H-chromen-4-ones in conjugate additions with carbon nucleophiles was also studied. The 1,6-conjugate addition of nitromethane to 2-[(1E,3E)-4-arylbuta-1,3-dien- 1-yl]-4H-chromen-4-ones was accomplished, leading mainly to the corresponding β-(nitromethyl)chromones. (E)-5'-(Nitromethyl)-3'-styryl- [1,1'-biphenyl]-2-ol and 3'-aryl-2'-nitro-5'-(nitromethyl)spiro[chromane- 2,1'-cyclohexan]-4-one derivatives were also isolated as minor products, which result from the addition of a second molecule of nitromethane, in tandem processes. The nucleophile scope with malononitrile, acetylacetone, ethyl cyanoacetate and diethyl malonate gave the expected 1,6-addition products, being also possible to isolate in the latest case, a minor product formed via 1,8-/1,6-addition sequence. Computational calculations provided a rationale for the experimental reactivity of carbon nucleophiles with 2-[(1E,3E)-4-arylbuta-1,3-dien-1-yl]-4H-chromen-4-ones. Further functionalizations of some adducts allowed the preparation of new nitrogen-containing heterocyclic compounds, such as novel styrylpyrrolidines and new pyrazole and bis-pyrazole derivatives. Finally, the intramolecular DA reaction of (E)-2-(2-(prop-2-yn-1- yloxy)styryl)-4H-chromen-4-ones and 2-{(1E,3E)-4-[2-(prop-2-yn-1- yloxy)phenyl]buta-1,3-dien-1-yl}-4H-chromen-4-ones, under MW irradiation, gave the desired 6H,8H-chromeno[3,4-b]xanthen-8-ones and 2-(6H-benzo[c]chromen-8-yl)-4H-chromen-4-ones, respectively. All the synthesized compounds, intermediates and final products, were characterized by several analytical techniques, especially by nuclear magnetic resonance (NMR) spectroscopy studies, including 1H and 13C, two-dimensional homo and heteronuclear correlated spectroscopy and nuclear Overhauser effect (NOESY) experiments

Chromones as versatile building blocks in cycloaddition reactions

4H-Chromen-4-ones commonly referred as chromones are a class of naturally occurring heterocyclic compounds implicated in a series of biological and pharmacological properties.[1] It is also an interesting scaffold involved in a range of chemical transformations for the preparation of novel and more complex oxygen-containing heterocyclic derivatives.[2] Following our interest in the chemistry of chromones, we design two different building blocks, 2- [(1E,3E)-4-arylbuta-1,3-dien-1-yl]-4H-chromen-4-ones 1 and (E)-2-(4-arylbut-1-en-3-yn-1-yl)-4Hchromen- 4-ones 2, and explore the reactivity of the unsaturated systems in cycloaddition reactions. In the former case, chromones 1 were used as dienes in microwave-assisted Diels–Alder (DA) reactions with various electron-poor and electron-rich dienophiles to provide flavone-type compounds 3.[3] In the latter case, the diene system of chromones 2 was involved in DA reactions with N-methylmaleimide whereas the acetylene moiety react with sodium azide, via 1,3-dipolar cycloaddition reaction, to afford xanthene-1,2,3-triazole dyads 4.[4] In this communication, we will present and discuss the synthetic details and spectroscopic characterization of the main products and some interesting byproducts, as well as the intermediate compounds isolated in each case.Thanks are due to University of Aveiro and FCT/MEC for the financial support of the QOPNA research unit (FCT UID/QUI/00062/2013) through national founds and, where applicable, co-financed by the FEDER, within the PT2020 Partnership Agreement, and to the Portuguese NMR Network, as well as to the Instituto Politécnico de Bragança. H.M.T.A. is grateful to FCT for their PhD grant (SFRH/BD/86277/2012).info:eu-repo/semantics/publishedVersio

Synthesis of xanthone-1,2,3-triazole dyads

Xanthones and 1,2,3-triazoles are known to exhibit several biological, pharmacological and biocidal properties[1]. The potential applications of these two classes of heterocycles led us to develop new strategies to synthesize xanthone-1,2,3-triazole dyads, aiming to get potentially improved therapeutic agents[2]. With this rational in mind we designed and synthesized novel chromone derivatives 1a-d to be used as building motifs and to explore the reactivity of the two unsaturated systems (the diene and the alkyne). In the present communication we will present a new synthetic route towards the synthesis of xanthone-1,2,3-triazole dyads 7a-d using consecutively the azide-alkyne Huisgen 1,3-dipolar cycloaddition and Diels-Alder reaction. Our approach involves the synthesis chromone-triazole derivatives 2a-d using the reaction of 1a-d with sodium azide, followed by the methylation of the NH of the triazole moiety. The methylation afforded three isomers 3a-d, 4a-d and 5a-d, as expected. The major isomers 3a-d were used in the Diels-Alder reaction with N-methylmaleimide, and the adducts obtained 6a-d were oxidized to afford the xanthone-1,2,3-triazole dyads 7a-d. All the synthetic details as well as the structural characterization (by 1D and 2D NMR studies) of the new synthesised compounds will be presented and discussed

Chalcones as versatile synthons for the synthesis of 5- and 6-membered nitrogen heterocylces

Chalcones belong to the flavonoid family which constitutes one of the major classes of naturally occurring oxygen heterocyclic compounds. The alpha,beta-unsaturated carbonyl system of chalcones possesses two electrophilic reactive centers allowing them to participate in addition reactions via attack to the carbonyl group (1,2-addition) or involving the beta-carbon (1,4-conjugate addition), leading to the synthesis of promising bioactive heterocyclic compounds. The purpose of this review is to present a systematic survey of the most recent literature that uses chalcones in the synthesis of biologically active 5- and 6-membered nitrogen heterocycles such as pyrroles, indoles, isoxazoles, imidazoles, pyrazoles, indazoles, triazoles, tetrazoles, pyridines and pyrimidines. Efficiency, easy-to-handle and cheap reagents, alternative heating conditions and greener protocols will be highlighted. In this review we will cover the literature since the beginning of the 21st century in more than 400 publications.PEst-C/QUI/UI0062/2013 FCOMP-01-0124-FEDER-03729

Synthesis of 2-{2-[5(4)-aryl-2H-[1,2,3]-triazol-4(5)-yl]vinyl}chromen-4-ones

Chromones are a family of oxygen-containing heterocyclic compounds that have been shown particular relevant biological activity. In what concerns to 2-methylchromones, their reactivity is well-known and allowed to exploit many different kinds of chemical reactions. The acidic character of the 2-methyl group, due to the low electron density at C-2 caused by carbonyl group enable this class of compounds to undergo oxidation, photolysis, cycloaddition and condensation reactionsUniversity of Aveiro, Funda9ao para a Ciencia e Tecnologia (FCT, Portugal), European Union, QREN, FEDER and COMPETE for funding the QOPNA Research Unit (project PEst-C/QUI/UI0062/2011) and the Portuguese National NMR Network. Hello Albuquerque also thanks FCT for his fellowship (SFRH/Bl/51556/2011 )

Nitromethane conjugate addition to 2-[(1E,3E)-4-arylbuta-1,3-dien-1-yl]-4Hchromen- 4-ones

Chromone are a group of oxygen-containing heterocycles, which are often associated to important biological activities.1 Chromone derivatives are also seen as interesting scaffolds to input further functionalizations,2 most of them through chemical transformations such as oxidation, condensation, Diels-Alder or conjugate addition. Conjugate addition of carbon nucleophiles to electron-deficient alkenes is one of the most important methods available for carbon–carbon bond-forming reactions. A wide range of carbon nucleophiles easily undergo conjugate addition with various substrates such as chalcones, cinnamylideneacetophenones or styrylchromones. Following previous work of our research group involving the 1,6-conjugate addition of nitromethane to (E)-2- styrylchromones,3 herein we report the first reactivity studies in the nitromethane conjugate addition to the extended unsaturated π-system of 2-[(1E,3E)-4-arylbuta-1,3-dien-1-yl]-4H-chromen-4-ones 1 (Scheme 1). The DBU catalyzed nitromethane addition reaction afforded the corresponding β-(nitromethyl)chromones 2 (1,6-conjugate addition) as major products. (E)-5'-(Nitromethyl)-3'-styryl-[1,1'-biphenyl]-2-ol 3 and 3'-aryl-2'-nitro-5'-(nitromethyl)spiro [chromane- 2,1'-cyclohexan]-4-one 4 derivatives were also isolated as minor products, which result from the addition of two nitromethane molecules, through tandem processes.info:eu-repo/semantics/publishedVersio

2-(4-Arylbuta-1,3-dien- or 1-en-3-yn-1-yl)chromones as synthons for the synthesis of other nitrogen and oxygen heterocyclic compounds

It is well known the great biological relevance of oxygen and nitrogen heterocycles. Herein, the reactivity of 2-(4-aryl-1,3-dien- and 1-en-3-yn-1-yl)chromones are explored in order to establish new synthetic routes towards the preparation of new heterocyclic compounds such as xanthones and triazoles. The reactive sites of the starting chromone derivatives (the double and triple bonds) allow them to be involved in reactions such as Diels-Alder and Huisgen cycloadditions. These reactions are used separately or subsequently in order to prepare new biologically active compounds emphasizing the synthetic potential of the referred chromone derivatives. Using these new synthetic routes we were able to develop new compounds, such xanthones bearing triazole moiety, which are expected to enclosure interesting biological properties

Conjugate additions of carbon nucleophiles to chromone derivatives towards nitrogen heterocycles

Conjugate additions of nitromethane to the extended π- system of chromone derivatives afforded the 1,6-conjugate addition products, together with structure complex oxygen heterocycles through tandem processes. Further functionalization of targeted adducts allowed the preparation of biological relevant nitrogen heterocycles such as styrylpyrrolidines, as well as pyrazole and bis-pyrazole derivatives.Thanks are due to FCT/MEC for the financial support of the QOPNA research unit (FCT UID/QUI/00062/2013) through national founds and, where applicable, co-financed by the FEDER, within the PT2020 Partnership Agreement, and to the Portuguese NMR Network. H.M.T.A. is grateful to FCT for his PhD grant (SFRH/BD/86277/2012).info:eu-repo/semantics/publishedVersio