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1.
J Chromatogr A ; 1611: 460574, 2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31591039

RESUMO

Sixteen pairs of enantiomeric dipeptides were separated on four chiral ion-exchanger-type stationary phases based on Cinchona alkaloids. Anion-exchangers (QN-AX, QD-AX) and zwitterionic phases [ZWIX(+)™ and ZWIX(-)™] were studied in a comparative manner. The effects of the nature and concentrations of the mobile phase solvent components and organic salt additives on analyte retention and enantioseparation were systematically studied in order to get a deeper insight into the enantiorecognition mechanism. Moreover, experiments were performed in the temperature range 10-50 °C to calculate thermodynamic parameters like changes in standard enthalpy, Δ(ΔH°), entropy, Δ(ΔS°), and free energy, Δ(ΔG°) on the basis of van't Hoff plots derived from the ln α vs. 1/T curves. Elution sequences of the dipeptides were determined in all cases and, with a few exceptions, they were found to be opposite on the pseudoenantiomeric stationary phases as of QN-AX/QD-AX and of ZWIX(+) and ZWIX(-). The stereoselective retention mechanism is based on electrostatically driven intermolecular interactions supported by additional interaction increments mainly determined by the absolute configuration of the chiral C8 and C9 atoms of the quinine and quinidine moieties.


Assuntos
Alcaloides de Cinchona/química , Cinchona/química , Dipeptídeos/química , Extratos Vegetais/química , Cromatografia Líquida de Alta Pressão/instrumentação , Cromatografia Líquida de Alta Pressão/métodos , Estereoisomerismo , Temperatura , Termodinâmica
2.
J Chromatogr A ; 1609: 460498, 2020 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-31526638

RESUMO

Liquid chromatographic (LC) and subcritical fluid chromatographic (SFC) resolution of the basic natural and synthetic Cinchona alkaloid analogues has been studied. Focus has been placed on the employment of four enantiomerically structured chiral strong cation-exchangers and four chiral diastereoisomeric Cinchona alkaloid and cyclohexyl aminosulfonic acid-based zwitterionic ion-exchangers. Except for the novel, recently synthesized racemic quinine the other investigated pairs of basic analytes are diastereomeric, but often called "pseudoenantiomeric" compounds of quinine and quinidine, cinchonidine and cinchonine, 9­epi­quinine and 9­epi­quinidine. As expected, the elution order of the resolved racemic quinine was reversed for all the eight investigated enantiomeric and (pseudo)enantiomeric pairs of chiral stationary phases, whereas this was not necessarily the case for the diastereomeric pairs of the Cinchona alkaloid related analytes. Varying the type and composition of the protic (methanol) and non-protic (acetonitrile) but polar bulk solvents in combination with organic salt additives in the mobile phase the overall retention and stereoselectivity characteristics could be triggered, leading to well performing LC and SFC systems. Thus the retention behavior of the basic analytes on both the chiral cation-exchangers and the diastereomeric zwitterionic ion-exchangers, used as cation-exchangers, could be described by the stoichiometric displacement model related to the counter-ion effect of the mobile phase additives. In addition, it became obvious that the non-protic acetonitrile compared to methanol as bulk solvent lead to a significant increase in retention, which can be associated with an increased electrostatic interaction of the charged sites due to a smaller solvation shell of the solvated cationic and anionic species. Based on the chromatographic results of the systematically selected chiral analytes and stationary phases attempts were undertaken to interpret qualitatively the observed stereoselectivity phenomena.


Assuntos
Alcaloides de Cinchona/química , Alcaloides de Cinchona/isolamento & purificação , Cátions , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida , Troca Iônica , Estereoisomerismo
3.
Biophys Chem ; 257: 106280, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31877450

RESUMO

High pressure acts as a mild and non-destructive activation mode for chemical reactions. However, in the context of organo-/biocatalysis, high pressure activation, has not been investigated systematically, although there are significant benefits such as rate acceleration, increased selectivity and the possibility of suppressing side product formation. The influence of hydrostatic pressure in solution on the catalytic performance of enzymes and small molecule organocatalysts such as amino acids, peptides, amines, cinchona alkaloids and thioureas is evaluated in this review, taking reactivity and selectivity as a probe to identify pressure effects on biomolecules.


Assuntos
Aminoácidos/química , Alcaloides de Cinchona/química , Peptídeos/química , Pressão , Catálise , Reação de Cicloadição , Enzimas/química , Enzimas/metabolismo , Soluções/química , Tioureia/análogos & derivados
4.
Molecules ; 24(17)2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31480402

RESUMO

The current chemotherapy of Chagas disease needs to be urgently improved. With this aim, a series of 16 hybrids of Cinchona alkaloids and bile acids were prepared by functionalization at position C-2 of the quinoline nucleus by a radical attack of a norcholane substituent via a Barton-Zard decarboxylation reaction. The antitrypanosomal activity of the hybrids was tested on different stages and strains of T. cruzi. In particular, eight out of 16 hybrids presented an IC50 ≤1 µg/mL against trypomastigotes of the CL Brener strain and/or a selectivity index higher than 10. These promising hybrids yielded similar results when tested on trypomastigotes from the RA strain of T. cruzi (discrete typing unit-DTU-VI). Surprisingly, trypomastigotes of the Y strain (DTU II) were more resistant to benznidazole and to most of the hybrids than those of the CL Brener and RA strains. However, the peracetylated and non-acetylated forms of the cinchonine/chenodeoxycholic bile acid conjugate 4f and 5f were the most trypanocidal hybrids against Y strain trypomastigotes, with IC50 values of 0.5 and 0.65 µg/mL, respectively. More importantly, promising results were observed in invasion assays using the Y strain, where hybrids 5f and 4f induced a significant reduction in intracellular amastigotes and on the release of trypomastigotes from infected cells.


Assuntos
Antiparasitários/farmacologia , Ácidos e Sais Biliares/farmacologia , Alcaloides de Cinchona/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Chlorocebus aethiops , Concentração Inibidora 50 , Espaço Intracelular/parasitologia , Ratos , Células Vero
5.
Bratisl Lek Listy ; 120(8): 576-580, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31379180

RESUMO

AIM: Quinine, a frequently used anti-malaria alkaloid isolated from the Cinchona bark, possesses numerous toxic properties, the majority of which arrive from a dysfunction of the gastrointestinal tract. Similarly, cinchonine, another alkaloid from the Cinchona bark, displays a great potential for treating malaria (especially the resistant forms). METHODS: In this work, we aimed to evaluate the effects of cinchonine on spontaneous and induced Wistar rat ileum contractions in order to uncover potential side effects that might arise after its application. RESULTS: Cinchonine produced a concentration-dependent spasmolytic activity, which was found to be reversible (i.e. disappeared after tissue wash-up), with an IC50 value of 273 µM. Furthermore, the mechanism of action of cinchonine at IC50 elucidated through experiments with acetylcholine and Ca2+-induced ileum contractions. The applied IC50 concentration of cinchonine statistically significantly prevented the occurrence of contractions after the application of specific agonist. The obtained results are in a range with the effects seen with standard receptor antagonists, i.e. atropine and verapamil. CONCLUSIONS: The obtained results showed that cinchonine inhibited both types of induced contractions, suggesting a Ca2+-channels mediated modus operandi (Fig. 4, Ref. 19).


Assuntos
Alcaloides/farmacologia , Alcaloides de Cinchona/farmacologia , Cinchona/química , Íleo/efeitos dos fármacos , Contração Muscular/efeitos dos fármacos , Parassimpatolíticos/farmacologia , Animais , Ratos , Ratos Wistar
6.
Molecules ; 24(15)2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31366138

RESUMO

Decarboxylative aldol reaction of aliphatic carboxylic acids is a useful method for C-C bond formation because carboxylic acids are an easily available class of compounds. In this study, we found that the decarboxylative aldol reaction of tertiary ß-ketocarboxylic acids and trifluoropyruvates proceeded smoothly to yield the corresponding aldol products in high yields and with high diastereoselectivity in the presence of a tertiary amine catalyst. In this reaction, we efficiently constructed a quaternary carbon center and an adjacent trifluoromethylated carbon center. This protocol was also extended to an enantioselective reaction with a chiral amine catalyst, and the desired product was obtained with up to 73% enantioselectivity.


Assuntos
Aldeídos/química , Ácidos Carboxílicos/química , Alcaloides de Cinchona/química , Ácido Pirúvico/análogos & derivados , Aminas/química , Catálise , Fluoretos/química , Estrutura Molecular , Estereoisomerismo
7.
Molecules ; 24(15)2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31366139

RESUMO

The organo-catalyzed enantioselective benzylation reaction of α-trifluoromethoxy indanones afforded α-benzyl-α-trifluoromethoxy indanones with a tetrasubstituted stereogenic carbon center in excellent yield with moderate enantioselectivity (up to 57% ee). Cinchona alkaloid-based chiral phase transfer catalysts were found to be effective for this transformation, and both enantiomers of α-benzyl-α-trifluoromethoxy indanones were accessed, depended on the use of cinchonidine and cinchonine-derived catalyst. The method was extended to the enantioselective allylation reaction of α-trifluoromethoxy indanones to give the allylation products in moderate yield with good enantioselectivity (up to 76% ee).


Assuntos
Derivados de Alilbenzenos/química , Fluoretos/química , Indanos/química , Catálise , Alcaloides de Cinchona/química , Estrutura Molecular , Estereoisomerismo
8.
Methods Mol Biol ; 1985: 251-277, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31069739

RESUMO

For the early 2000s, chromatographic methods applying chiral stationary phases (CSPs) became the most effective techniques for the resolution of chiral compounds on both analytical and preparative scales. High-performance liquid chromatography (HPLC) employing various types of chiral selectors covalently bonded to silica-based supports offers a state-of-the-art methodology for "chiral analysis." Although a large number of CSPs are available nowadays, the design and development of new "chiral columns" are still needed since it is obvious that in practice one needs a good portfolio of different columns to face the challenging task of enantiomeric resolutions. The development of the unique chiral anion, cation, and zwitterion exchangers achieved by Lindner and his partners serves as an expansion of the range of the efficiently applicable CSPs.In this context this overview chapter discusses and summarizes direct enantiomer separations of chiral acids and ampholytes applying zwitterionic ion exchangers derived from Cinchona alkaloids. Our aim is to provide comprehensive information on practical solutions with focus on the molecular recognition and methodological variables.


Assuntos
Cromatografia Líquida/métodos , Alcaloides de Cinchona/química , Alcaloides de Cinchona/isolamento & purificação , Resinas de Troca Iônica/química , Modelos Químicos , Estereoisomerismo , Água/química
9.
Biosci Biotechnol Biochem ; 83(6): 1011-1026, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31074699

RESUMO

TRAF6 is highly expressed in many tumors and plays an important role in the immune system. The aim of this study is to confirm anti-tumor activities of all naturally occurring Cinchona alkaloids that have been screened using computational docking program, and to validate the accuracy and specificity of the RING domain of TRAF6 as a potential anti-tumor target, and to explore their effect on the immune system. Results reported herein would demonstrate that Cinchona alkaloids could induce apoptosis in HeLa cells, inhibit the ubiquitination and phosphorylation of both AKT and TAK1, and up-regulate the ratio of Bax/Bcl-2. In addition, these compounds could induce apoptosis in vivo, and increase the secretion of TNF-α, IFN-γ, and IgG, while not significantly impacting the ratio of CD4+T/CD8+T. These investigations suggest that the RING domain of TRAF6 could serve as a de novo biological target for therapeutic treatment in cancers.


Assuntos
Apoptose/efeitos dos fármacos , Alcaloides de Cinchona/metabolismo , Alcaloides de Cinchona/farmacologia , Domínios Proteicos , Fator 6 Associado a Receptor de TNF/metabolismo , Animais , Ligação Competitiva , Proliferação de Células/efeitos dos fármacos , Ativação Enzimática , Células HeLa , Humanos , Imunoglobulina G/sangue , Marcação In Situ das Extremidades Cortadas , Interferon gama/sangue , Contagem de Linfócitos , MAP Quinase Quinase Quinases/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Linfócitos T/efeitos dos fármacos , Fator 6 Associado a Receptor de TNF/química , Fator de Necrose Tumoral alfa/sangue , Enzimas de Conjugação de Ubiquitina/metabolismo , Ubiquitinação , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína X Associada a bcl-2/metabolismo
10.
Chem Pharm Bull (Tokyo) ; 67(4): 393-396, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30930443

RESUMO

In order to develop an efficient organocatalyst for the enantioselective N-H insertion reaction via carbene/carbenoid, the catalytic core of the cinchona alkaloids was investigated. According to our working hypothesis of an eight-membered ring transition state in the N-H insertion reaction, two pairs of enantiomers related to 2-amino-1-phenylethanol were investigated for their chiral inducing potential. Since both (1R,2S)-isomers gave the N-phenyl-1-phenylglycine derivative enriched in the R-form, while their enantiomers gave the S-form, the 2-amino-1-phenylethanol structure is concluded to be the catalytic core of the cinchona alkaloid in the enantioselective N-H insertion reaction via rhodium(II) carbenoid.


Assuntos
Amino Álcoois/química , Alcaloides de Cinchona/química , Álcoois Benzílicos/química , Catálise , Complexos de Coordenação/química , Hidrogênio/química , Nitrogênio/química , Ródio/química , Estereoisomerismo
11.
Alkaloids Chem Biol ; 82: 29-145, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30850032

RESUMO

Major Cinchona alkaloids quinine, quinidine, cinchonine, and cinchonidine are available chiral natural compounds (chiral pool). Unlike many other natural products, these alkaloids are available in multiple diastereomeric forms which are separated on an industrial scale. The introduction discusses in short conformational equilibria, traditional separation scheme, biosynthesis, and de novo chemical syntheses. The second section concerns useful chemical applications of the alkaloids as chiral recognition agents and effective chiral catalysts. Besides the Sharpless ethers and quaternary ammonium salts (chiral PTC), the most successful bifunctional organocatalysts are based on 9-amino derivatives: thioureas and squaramides. The third section reports the main transformations of Cinchona alkaloids. This covers reactions of the 9-hydroxyl group with the retention or inversion of configuration. Specific Cinchona rearrangements enlarging [2.2.2]bicycle of quinuclidine to [3.2.2] products are connected to the 9-OH substitution. The syntheses of numerous esterification and etherification products are described, including many examples of bi-Cinchona alkaloid ethers. Further derivatives comprise 9-N-substituted compounds. The amino group is introduced via an azido function with the inversion of configuration at the stereogenic center C9. The 9-epi-amino-alkaloids provide imines, amides, imides, thioureas, and squaramides. The syntheses of 9-carbon-, 9-sulfur-, and 9-selenium-substituted derivatives are discussed. Oxidation of the hydroxyl group of any alkaloid gives ketones, which can be selectively reduced, reacted with Grignard reagents, or subjected to the Corey-Chaykovsky reaction. The alkaloids were also partially degraded by splitting C4'-C9 or N1-C8 bonds. In order to immobilize Cinchona alkaloids the transformations of the 3-vinyl group were often exploited. Finally, miscellaneous functionalizations of quinuclidine, quinoline, and examples of various metal complexes of the alkaloids are considered.


Assuntos
Alcaloides de Cinchona/química , Compostos Organometálicos/química , Alcaloides de Cinchona/isolamento & purificação , Alcaloides de Cinchona/metabolismo , Estrutura Molecular , Compostos Organometálicos/isolamento & purificação , Compostos Organometálicos/metabolismo , Quinolinas/química , Quinuclidinas/química
12.
J Med Chem ; 62(5): 2305-2332, 2019 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-30779564

RESUMO

Optochin, a cinchona alkaloid derivative discovered over 100 years ago, possesses highly selective antibacterial activity toward Streptococcus pneumoniae. Pneumococcal disease remains the leading source of bacterial pneumonia and meningitis worldwide. The structure-activity relationships of optochin were examined through modification to both the quinoline and quinuclidine subunits, which led to the identification of analogue 48 with substantially improved activity. Resistance and molecular modeling studies indicate that 48 likely binds to the c-ring of ATP synthase near the conserved glutamate 52 ion-binding site, while mechanistic studies demonstrated that 48 causes cytoplasmic acidification. Initial pharmacokinetic and drug metabolism analyses of optochin and 48 revealed limitations of these quinine analogues, which were rapidly cleared, resulting in poor in vivo exposure through hydroxylation pendants to the quinuclidine and O-dealkylation of the quinoline. Collectively, the results provide a foundation to advance 48 and highlight ATP synthase as a promising target for antibiotic development.


Assuntos
Antibacterianos/farmacologia , Alcaloides de Cinchona/farmacologia , ATPases Mitocondriais Próton-Translocadoras/antagonistas & inibidores , Streptococcus pneumoniae/enzimologia , Antibacterianos/química , Antibacterianos/metabolismo , Sítios de Ligação , Alcaloides de Cinchona/química , Alcaloides de Cinchona/metabolismo , Resistência Microbiana a Medicamentos , Testes de Sensibilidade Microbiana , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Relação Estrutura-Atividade
13.
J Nat Med ; 73(2): 431-438, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30552602

RESUMO

New eight endophytic filamentous fungi were isolated from the young stems of Cinchona ledgeriana (Rubiaceae) cultivated in Japan. They were classified into four genera based on phylogenetic analysis of the nucleotide sequences of the internal transcribed spacers (ITS1 and ITS2), including the 5.8S ribosomal DNA region. Of the eight fungi isolated, there were five genera Cladosporium, one Meira sp., one Diaporthe sp. and one Penicillium sp. Genus of Cladosporium and Meira were first isolated fungi from Cinchona plant. In a previous study, we applied the same process to the same plant cultivated in Indonesia. The endophyte compositions for the two cultivation regions were found to differ at the genera level. The ability of Cinchona endophytes cultivated in Japan to produce Cinchona alkaloids was also assessed. We found that three isolates have producing ability of Cinchona alkaloids. However, the amount produced was very small compared to that produced by the endophytes of Indonesian Cinchona ledgeriana. In addition, the total content amount of Cinchona alkaloids, especially quinine, produced by the extract of Cinchona cultivated in Japan was much smaller than that from Indonesia. These finding indicate that endophyte composition has an influence on the Cinchona alkaloid content amount in the Cinchona ledgeriana host.


Assuntos
Alcaloides de Cinchona/metabolismo , Cinchona/microbiologia , Endófitos/isolamento & purificação , Fungos/isolamento & purificação , Alcaloides de Cinchona/isolamento & purificação , Endófitos/classificação , Endófitos/genética , Endófitos/metabolismo , Fungos/classificação , Fungos/genética , Fungos/metabolismo , Indonésia , Japão , Filogenia , Quinina/isolamento & purificação , Quinina/metabolismo , Rubiaceae
14.
Org Biomol Chem ; 17(1): 151-155, 2018 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-30525178

RESUMO

A highly enantio- and diastereoselective method for the synthesis of functionalized chroman-2-ones and chromanes was achieved by using an organocatalytic domino Michael/hemiacetalization reaction of aliphatic aldehydes and (E)-2-(2-nitrovinyl)phenols followed by a PCC oxidation and dehydroxylation, respectively. Using the modularly designed organocatalysts (MDOs) self-assembled from cinchona alkaloid derivatives and amino acids in the reaction media, the title products were obtained in good to high yields (up to 97%) and excellent diastereoselectivities (up to 99 : 1 dr) and enantioselectivities (up to 99% ee).


Assuntos
Cromanos/síntese química , Cromonas/síntese química , Aldeídos/química , Aminoácidos/química , Catálise , Alcaloides de Cinchona/química , Oxirredução , Fenóis/química , Estereoisomerismo
15.
Toxins (Basel) ; 10(12)2018 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-30477182

RESUMO

This article describes the discovery and use of the South American cinchona bark and its main therapeutic (and toxic) alkaloids, quinine and quinidine. Since the introduction of cinchona to Europe in the 17th century, it played a role in treating emperors and peasants and was central to colonialism and wars. Over those 400 years, the medical use of cinchona alkaloids has evolved from bark extracts to chemical synthesis and controlled clinical trials. At the present time, the use of quinine and quinidine has declined, to a large extent due to their toxicity. However, quinine is still being prescribed in resource-limited settings, in severe malaria, and in pregnant women, and quinidine made a limited comeback in the treatment of several cardiac and neurological syndromes. In addition, the article presents more recent studies which improved our understanding of cinchona alkaloids' pharmacology. The knowledge gained through these studies will hopefully lead to a wider use of these drugs in precision medicine and to design of new generation, safer quinine and quinidine derivatives.


Assuntos
Alcaloides de Cinchona/uso terapêutico , Cinchona , Malária/tratamento farmacológico , Doenças do Sistema Nervoso/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Antiarrítmicos/uso terapêutico , Antimaláricos/uso terapêutico , Humanos , Casca de Planta/química
16.
PLoS One ; 13(10): e0205193, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30289893

RESUMO

This paper describes the synthesis and anticholinesterase potency of Cinchona-based alkaloids; ten quaternary derivatives of cinchonines and their corresponding pseudo-enantiomeric cinchonidines. The quaternization of quinuclidine moiety of each compound was carried out with groups diverse in their size: methyl, benzyl and differently meta- and para-substituted benzyl groups. All of the prepared compounds reversibly inhibited human butyrylcholinesterase and acetylcholinesterase with Ki constants within nanomolar to micromolar range. Five cinchonidine derivatives displayed 95-510 times higher inhibition selectivity to butyrylcholinesterase over acetylcholinesterase and four were potent butyrylcholinesterase inhibitors with Ki constants up to 100 nM, of which N-para-bromobenzyl cinchonidinium bromide can be considered a lead for further modifications and optimizations for possible use in the treatment of neurodegenerative diseases.


Assuntos
Butirilcolinesterase/química , Inibidores da Colinesterase/farmacologia , Alcaloides de Cinchona/química , Desenho de Fármacos , Doenças Neurodegenerativas/tratamento farmacológico , Acetilcolinesterase/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/uso terapêutico , Cinchona/química , Ensaios Enzimáticos , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/química , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade
17.
J Am Chem Soc ; 140(42): 13913-13920, 2018 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-30252465

RESUMO

Cinchona alkaloid-derived chiral catalysts represent one of the most widely applied classes of organocatalysts, which have been successfully utilized in the promotion of a wide variety of asymmetric reactions. Cinchona alkaloids exist in nature as pseudoenantiomers, which allow cinchona alkaloid-catalyzed reactions to provide high enantioselectivities and yields toward both enantiomers of interest in many reactions. On the other hand, the subtle structural difference between pseudoenantiomeric cinchona alkaloids could also lead to uneven efficiency that severely limits the applicability of some cinchona alkaloid-catalyzed reactions. We describe here the elucidation of the origin of and the consequent development of novel modified cinchona alkaloids to address such a problem in asymmetric imine umpolung reactions by cinchonium salts.


Assuntos
Alcaloides de Cinchona/química , Catálise , Iminas/química , Modelos Moleculares , Sais/química , Estereoisomerismo
18.
Angew Chem Int Ed Engl ; 57(38): 12299-12302, 2018 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-30084528

RESUMO

The development of efficient syntheses of complex natural products has long been a major challenge in synthetic chemistry. Designing cascade reactions and employing bioinspired transformations are an important and reliable means of achieving this goal. Presented here is a combination of these two strategies, which allow efficient asymmetric synthesis of the cinchona alkaloid (+)-cinchonidine. The key steps of this synthesis are a controllable, visible-light-induced photoredox radical cascade reaction to efficiently access the tetracyclic monoterpenoid indole alkaloid core, as well as a practical biomimetic cascade rearrangement for the indole to quinoline transformation. The use of stereoselective chemical transformations in this work makes it an efficient synthesis of (+)-cinchonidine.


Assuntos
Alcaloides de Cinchona/síntese química , Alcaloides de Cinchona/química , Radicais Livres/química , Indóis/química , Luz , Oxirredução , Quinolinas/química , Estereoisomerismo
19.
J Pharm Biomed Anal ; 159: 127-152, 2018 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-29980014

RESUMO

As the understanding of the various biological actions of compounds with different stereochemistry has grown, the necessity to develop methods for the analytical qualification and quantification of chiral products has become particularly important. The last quarter of the century has seen a vast growth of diverse chiral technologies, including stereocontrolled synthesis and enantioselective separation and analysis concepts. By the introduction of covalently bonded silica-based chiral stationary phases (CSPs), the so-called direct liquid chromatographic (LC) methods of enantiomer separation became the state-of-the-art methodology. Although a large number of CSPs is available nowadays, the design and development of new chiral selectors and CSPs are still needed since it is obvious that in practice one needs a good portfolio of different CSPs and focused "chiral columns" to tackle the challenging tasks. This review discusses and summarizes direct enantiomer separations of chiral acids and ampholytes applying anionic and zwitterionic ion-exchangers derived from Cinchona alkaloids with emphasis on literature data published in the last 10 years. Our aim is to provide an overview of practical solutions, while focusing on the integration of molecular recognition and methodological variables.


Assuntos
Técnicas de Química Analítica/métodos , Alcaloides de Cinchona/análise , Alcaloides de Cinchona/química , Animais , Cromatografia por Troca Iônica/métodos , Cromatografia Líquida/métodos , Humanos , Estereoisomerismo
20.
Molecules ; 23(6)2018 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-29895754

RESUMO

A practical synthesis of both enantiomers of unnatural phenylalanine derivatives by using two pseudoenantiomeric phase transfer catalysts is described. Through asymmetric α-alkylation of glycine Schiff base with substituted benzyl bromides and 1-(bromomethyl)naphthalene under the catalysis of O-allyl-N-(9-anthracenmethyl) cinchoninium bromide (1f) and O-allyl-N-(9-anthracenylmethyl)cinchonidium bromide (1i), respectively, a series of both (R)- and (S)-enantiomers of unnatural α-amino acid derivatives were obtained in excellent yields and enantioselectivity. The synthetic method is simple and scalable, and the stereochemistry of the products is fully predictable and controlled: the cinchonine-type phase transfer catalyst 1f resulted in (R)-α-amino acid derivatives, and the cinchonidine-type phase transfer catalyst 1i afforded (S)-α-amino acid derivatives.


Assuntos
Aminoácidos/síntese química , Alcaloides de Cinchona/química , Fenilalanina/análogos & derivados , Compostos de Amônio Quaternário/química , Alquilação , Aminoácidos/química , Catálise , Glicina/química , Estrutura Molecular , Sais , Bases de Schiff/química , Estereoisomerismo
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