RESUMO
Several natural products containing a 1,4-oxazepane-2,5-dione-core are known. One example is serratin, isolated from Serratia marcescens. Because of the presence of a carboxylic amide, which has a preference for a trans-conformation, and the presence of a labile lactone in this core, many synthetic methodologies commonly used for the cyclization toward medium-sized heterocycles cannot be applied. As N-acyl amino acids lacking a third substituent at nitrogen failed to undergo ring-closure, several N-protecting groups were evaluated. With the use of the removable PMB-group, an N-unsubstituted 1,4-oxazepane-2,5-dione was synthesized. Via the application of pseudoprolines (i.e. serine-derived oxazolidines as another type of protecting group), a compound with the presumed structure of the natural product serratin was obtained. As a result of the differences in spectral data, the incorrect structural assignment of the natural product serratin was identified. Instead of the predicted seven-membered heterocycle, a symmetrical serratamolide analogue is proposed to be the correct structure of serratin.
Assuntos
Aminoácidos/química , Oxazepinas/química , Triterpenos/química , Ciclização , Estrutura Molecular , Rotação , EstereoisomerismoRESUMO
Two edible plants in Southeast Asia, Gynura bicolor and G. divaricata, are not only known to be nutritive but also useful as medicinal herbs. Previous phytochemical investigation of Gynura species showed the presence of hepatotoxic pyrrolizidine alkaloids (PAs), indicating the toxic risk of using these two plants. The present study was designed to analyze the distribution of PA components and tried to evaluate the preliminary toxicity of these two Gynura species. Eight samples of G. bicolor and G. divaricata from five different Chinese locations were collected and their specific PAs were qualitatively characterized by applying an UPLC/MS/MS spectrometry method. Using a pre-column derivatization HPLC method, the total retronecine ester-type PAs in their alkaloids extracts were quantitatively estimated as well. Finally, their genotoxicity was investigated with an effective high-throughput screening method referred to as Vitotox™ test and their potential cytotoxicity was tested on HepG2 cells. It was found that different types of PAs were widely present in Gynura species collected from south of China. Among them, no significant genotoxic effects were detected with serial concentrations through the present in vitro assay. However, the cytotoxicity assay of Gynura plants collected from Jiangsu displayed weak activity at the concentration of 100 mg/ml. It is important to note that this research validates in part the indication that the use of Gynura species requires caution.
Assuntos
Asteraceae/química , Sobrevivência Celular/efeitos dos fármacos , Plantas Medicinais/química , Alcaloides de Pirrolizidina/toxicidade , China , Cromatografia Líquida de Alta Pressão , Células Hep G2 , Ensaios de Triagem em Larga Escala , HumanosRESUMO
2-(2-Cyanoethyl)aziridines and 2-aryl-3-(2-cyanoethyl)aziridines were deployed as substrates for an In(OTf)3 -mediated regio- and stereoselective ring rearrangement upon treatment with LiAlH4, affording a variety of novel 2-(aminomethyl)pyrrolidines and 3-aminopiperidines, respectively. Further synthetic elaboration of the obtained 3-aminopiperidines resulted in the formation of a peculiar and unexplored conformationally constrained imidazolidinone and diketopiperazine scaffold.
RESUMO
α-Halomethyllithium carbenoids are useful homologating reagents which - reacting under proper reaction conditions as carbanions - enable the installation via nucleophilic addition of a reactive halomethyl fragment onto a preformed carbon-heteroatom bond. The pronounced thermolability represented - since seminal studies by Köbrich - the Achilles' heel of these reagents: the use of Barbier-type methodologies (i.e., the electrophile should be present in the reaction mixture prior to the formation of the carbenoid) was pivotal in order to suppress decomposition through α-elimination processes. Nowadays, the use of low temperatures (-78 °C) guarantees reliable procedures and, significantly, the employment of microreactor technologies allows external trapping to be performed even at higher temperatures as reported by Luisi. We will discuss the α-halomethyllithium-mediated homologations of a series of carbon electrophiles such as carbonyl compounds, imines, esters, Weinreb amides, and isocyanates.
RESUMO
N-Benzoyl ß,ß-difluoroenamides and N-benzoyl fluoroynamides are novel structural units which have been explored as precursors in heterocyclic synthesis. The presence of two fluorine atoms at the ß-position of the enamide moiety endows unique electrophilic reactivity. Treatment of these enamides with oxygen nucleophiles gives rise to a nucleophilic vinylic substitution (S(N)V) reaction, which was directed toward 2-fluoro-1,4-benzoxazines and 2-fluoro-1,4-benzoxazepin-5-ones. Furthermore, fluorinated ynamides, a new type of building block, were prepared in excellent yields for the first time. In this case, ß-addition of nucleophiles across the triple bond is observed also.
Assuntos
Benzoxazinas/síntese química , Flúor/química , Oxazepinas/síntese química , Benzoxazinas/química , Estrutura Molecular , Fenômenos de Química Orgânica , Oxazepinas/químicaRESUMO
Gynura bicolor and G. divaricata are not only known to be nutritive as cultured vegetables, but also beneficial as folk medicines in East Asia. As demonstrated by the current phytochemical knowledge, the genus Gynura is a promising source of phenolics with multiple medicinal activities. To expand this phytochemical knowledge, the phenolic secondary metabolites of G. bicolor and G. divaricata were studied. From the aerial parts of these two species, collected in five different Chinese locations, two fractions of phenolic compounds with different polarity were obtained by extraction and chromatographic separation. Using UPLC/MS/MS analysis, a total of 53 phenolics were either identified by comparison with respective reference compounds or tentatively characterized by their chromatographic behavior, UV-absorption patterns, and MS fragmentations. Some naturally existing positional isomers of O-caffeoylquinic acid, O-p-coumaroylquinic acid, O-feruloylquinic acid, and dicaffeoylquinic acid as well as their methyl esters were qualitatively characterized by their specific fragmentation patterns in targeted MS/MS. In addition, the aerial parts of the two Gynura species contained kaempferol, quercetin oligoglycosides, and a variety of derivatives of benzoic acid, hydroxycinnamic acid, and caffeic acid. Furthermore, the distribution of phenolic compounds in the two species from different Chinese origins was discussed. Finally, an investigation of the total phenolic content and in vitro antioxidant activity of the various phenolic fractions was completed, to evaluate the potential of the extracts of these species for medicinal development. The free-radical-scavenging activities of the extracts derived from plants originating from Nanjing were proven to be higher than those of the other extracts, which correlated well with their total phenolic content.
Assuntos
Asteraceae/classificação , Fenóis/análise , China , Cromatografia Líquida de Alta Pressão , Espectrometria de Massas , Fenóis/química , Especificidade da EspécieRESUMO
This paper reports on the generation and alkylation of the 1-tosyl-2-(trifluoromethyl)aziridin-2-yl anion with ω,ω'-dihaloalkanes, followed by a novel ring-expansion protocol toward 2-CF3-pyrrolidines, 2-CF3-piperidines, and 3-CF3-azepanes. A variety of halogen, oxygen, nitrogen, sulfur, and carbon nucleophiles was used to trigger this ring rearrangement, resulting in CF3-azaheterocycles bearing different types of functionalized side chains.
Assuntos
Azepinas/química , Aziridinas/química , Piperidinas/química , Pirrolidinas/química , Alquilação , Azepinas/síntese química , Cristalografia por Raios X , Flúor/química , Conformação Molecular , Piperidinas/síntese química , Pirrolidinas/síntese químicaRESUMO
A convenient and stereoselective approach toward cis- and trans-1-alkyl-2-(methyl/phenyl)-3-(trifluoromethyl)aziridines was developed starting from the corresponding α,α,α-trifluoroketones via imination, α-chlorination, and hydride-induced ring closure. The reactivity of these newly synthesized nonactivated α-CF3-aziridines was evaluated by applying N-protonation or N-alkylation to effect regio- and stereospecific aziridine ring opening by oxygen, halogen, sulfur, and nitrogen nucleophiles. Furthermore, nonactivated α-CF3-aziridines were easily transformed into their activated analogues by replacing the N-benzyl protecting group with a N-tosyl group, rendering these α-CF3-aziridines much more susceptible to nucleophilic ring opening.
Assuntos
Aziridinas/síntese química , Hidrocarbonetos Clorados/síntese química , Alquilação , Aziridinas/química , Hidrocarbonetos Clorados/química , Estrutura Molecular , EstereoisomerismoRESUMO
Mannich-type reactions of O-Boc glycolic esters across chiral N-sulfinyl-α-chloroaldimines resulted in the efficient and syn-stereoselective synthesis of new γ-chloro-α-hydroxy-ß-amino esters (dr > 99 : 1). The α-coordinating ability of the chlorine atom was of great importance for the diastereoselectivity of the Mannich-type reaction and overruled the chelation of the sulfinyl oxygen with the lithium ion of the incoming E-enolate in the transition state model. These novel chloroisothreonine derivatives proved to be excellent building blocks in asymmetric synthesis of novel syn-ß,γ-aziridino-α-hydroxy esters and biologically relevant trans-oxazolidinone carboxylic esters.
Assuntos
Hidrocarbonetos Clorados/química , Iminas/química , Bases de Mannich/química , Treonina/análogos & derivados , Treonina/síntese química , Cristalografia por Raios X , Ésteres/síntese química , Ésteres/química , Modelos Moleculares , Estereoisomerismo , Treonina/químicaRESUMO
Diatoms are known to produce a variety of halogenated compounds, which were recently shown to have a role in allelopathic interactions between competing species. The production of these compounds is linked to haloperoxidase activity. This research, has shown that this system may also be involved in diatom-bacteria interactions via the H2O2 dependent inactivation of a type of quorum sensing (QS) molecule, i.e., N-ß-ketoacylated homoserine lactones (AHLs), by a natural haloperoxidase system from the benthic diatom Nitzschia cf pellucida. The AHL degradation pathway towards corresponding halogenated derivatives was elucidated via HPLC-MS analysis and the synthesis of a broad series of novel halogenated AHL analogues as reference compounds. Furthermore, their biological activity as quorum sensing modulators was directly compared and evaluated against a series of naturally occurring ß-keto-AHLs. It has been demonstrated that the loss of the QS activity results from the final cleavage of the halogenated N-acyl chain of the signal molecules.
Assuntos
Diatomáceas/química , Diatomáceas/metabolismo , Homosserina/metabolismo , Lactonas/metabolismo , Peroxidases/química , Percepção de Quorum/efeitos dos fármacos , Bioensaio , Catalase/química , Cromatografia Líquida de Alta Pressão , Chromobacterium/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Escherichia coli/metabolismo , Proteínas de Fluorescência Verde , Lactonas/síntese química , Extração Líquido-Líquido , Espectrometria de Massas , FenolsulfonaftaleínaRESUMO
Novel N-α-haloacylated homoserine lactones, in which a halogen atom was introduced at the α-position of the carbonyl function of the N-acyl chain, have been studied as quorum sensing (QS) modulators and compared with a library of natural N-acylated homoserine lactones (AHLs). The series of novel analogues consists of α-chloro, α-bromo and α-iodo AHL analogues. Furthermore, the biological QS activity of the synthetic AHL analogues compared to the natural AHLs was evaluated. Halogenated analogues demonstrated a reduced activity in the Escherichia coli JB523 bioassay, with the α-iodo lactones being the less active ones and the α-chloro AHLs the most potent QS agonists. Most of the α-haloacylated analogues did not exhibit a significant reduction when tested in the QS inhibition test. Therefore, these novel analogues could be utilized as chemical probes for QS structure-activity studies.
RESUMO
The reactivity of 3-hydroxy-4-(1,2-dihydroxyethyl)-ß-lactams with regard to the oxidant sodium periodate was evaluated, unexpectedly resulting in the exclusive formation of new 2-hydroxy-1,4-oxazin-3-ones through a C3C4 bond cleavage of the intermediate 4-formyl-3-hydroxy-ß-lactams followed by a ring expansion. This peculiar transformation stands in sharp contrast with the known NaIO(4)-mediated oxidation of 3-alkoxy- and 3-phenoxy-4-(1,2-dihydroxyethyl)-ß-lactams, which exclusively leads to the corresponding 4-formyl-ß-lactams without a subsequent ring enlargement. In addition, this new class of functionalized oxazin-3-ones was further evaluated for its potential use as building blocks in the synthesis of a variety of differently substituted oxazin-3-ones, morpholin-3-ones and pyrazinones. Furthermore, additional insights into the mechanism and the factors governing this new ring-expansion reaction were provided by means of density functional theory calculations.
Assuntos
Azetidinas/química , Oxazinas/síntese química , beta-Lactamas/síntese química , Estrutura Molecular , Oxazinas/química , Oxirredução , Ácido Periódico/química , Estereoisomerismo , beta-Lactamas/químicaRESUMO
A five-step procedure for the synthesis of cis-1-tosyl-2-tosyloxymethyl-3-(trifluoromethyl)aziridine was developed, starting from 1-ethoxy-2,2,2-trifluoroethanol, involving imination, aziridination, ester reduction, hydrogenation, and N-,O-ditosylation steps. Further synthetic elaborations revealed a remarkable difference in the reactivity of cis-1-tosyl-2-tosyloxymethyl-3-(trifluoromethyl)aziridine with respect to aromatic sulfur and oxygen nucleophiles, thus enabling the selective deployment of this versatile substrate as a building block for the synthesis of functionalized aziridines, azetidines, and benzo-fused dithianes, oxathianes, dioxanes, and (thio)morpholines.
Assuntos
Azetidinas/síntese química , Aziridinas/síntese química , Dioxanos/síntese química , Compostos Heterocíclicos/química , Hidrocarbonetos Fluorados/química , Hidrocarbonetos Fluorados/síntese química , Morfolinas/síntese química , Oxigênio/química , Quinolizinas/síntese química , Compostos de Enxofre/síntese química , Enxofre/química , Trifluoretanol/análogos & derivados , Trifluoretanol/química , Azetidinas/química , Aziridinas/química , Dioxanos/química , Morfolinas/química , Quinolizinas/química , Estereoisomerismo , Compostos de Enxofre/químicaRESUMO
2H,3'H-Spiro[benzofuran-3,2'-naphthoquinones], constituting a new spiroheterocyclic skeleton, were synthesized starting from 2-aryloxymethyl-1,4-naphthoquinones by means of a palladium(II)-catalyzed reaction, which is a new spirocyclic transformation. Under optimal conditions, i.e. 10 mol % of palladium(II) acetate, 15 mol % of 3,5-dichloropyridine, and 5 mol % of trifluoroacetic acid in acetic acid at 110 °C, various 2H,3'H-spiro[benzofuran-3,2'-naphthoquinones] were synthesized in yields strongly dependent on the substitution pattern of the aryloxy group. Unsubstituted or ortho-substituted 2-aryloxymethyl-1,4-quinones were found to rearrange toward the corresponding 2-(4-hydroxyaryl)-1,4-quinones upon treatment with trifluoroacetic acid.
Assuntos
Benzofuranos/síntese química , Naftoquinonas/síntese química , Compostos Organometálicos/química , Paládio/química , Compostos de Espiro/síntese química , Benzofuranos/química , Catálise , Estrutura Molecular , Naftoquinonas/química , Compostos de Espiro/químicaRESUMO
A variety of 5-, 6- and 8-(4-aminobutyloxy)quinolines as novel oxygen analogues of known 4- and 8-(4-aminobutylamino)quinoline antimalarial drugs was generated from hydroxyquinolines through a three-step approach with a rhodium-catalyzed hydroformylation as the key step. Antiplasmodial assays of these new quinolines revealed micromolar potency for all representatives against a chloroquine-sensitive strain of Plasmodium falciparum, and three compounds showed submicromolar activity against a chloroquine-resistant strain of P. falciparum with IC(50)-values ranging between 150 and 680 nM.
Assuntos
Antimaláricos/síntese química , Cloroquina/análogos & derivados , Animais , Antimaláricos/química , Antimaláricos/toxicidade , Células CHO , Catálise , Sobrevivência Celular/efeitos dos fármacos , Cloroquina/síntese química , Cloroquina/toxicidade , Cricetinae , Cricetulus , Avaliação Pré-Clínica de Medicamentos , Plasmodium falciparum/efeitos dos fármacos , Ródio/químicaRESUMO
2-(4-Chloro-2-cyano-2-phenylbutyl)aziridines were employed for the one-step stereoselective construction of both endo- and exo-2-aminomethyl-4-phenyl-1-azabicyclo[2.2.1]heptanes as new azaheterobicyclic scaffolds via a double LiAlH(4)-induced reductive cyclization protocol. Antiplasmodial assessment of these 1-azabicyclo[2.2.1]heptanes revealed moderate to good activities in the micromolar range, with the exo-isomers being the most promising structures. Furthermore, the proposed mode of action was supported by ligand docking studies, pointing to a strong binding interaction with the enzyme plasmepsin II.
Assuntos
Antimaláricos/síntese química , Antimaláricos/farmacologia , Aziridinas/química , Heptanos/síntese química , Heptanos/farmacologia , Compostos de Alumínio/química , Antimaláricos/química , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacologia , Ciclização , Heptanos/química , Humanos , Ligantes , Compostos de Lítio/química , Simulação de Acoplamento Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
In this critical review, the ring opening of non-activated 2-substituted aziridines via intermediate aziridinium salts will be dealt with. Emphasis will be put on the relationship between the observed regioselectivity and inherent structural features such as the nature of the C2 aziridine substituent and the nature of the electrophile and the nucleophile. This overview should allow chemists to gain insight into the factors governing the regioselectivity in aziridinium ring openings (81 references).
Assuntos
Aziridinas/química , Alquilação , Ácidos de Lewis/química , Prótons , EstereoisomerismoRESUMO
Reaction of N-tert-butanesulfinyl α-halo imines with alkoxides afforded new N-tert-butanesulfinyl 2-amino acetals in good to excellent yield. These N-tert-butanesulfinyl 2-amino acetals are convenient precursors for the TMSOTf-promoted synthesis of the corresponding N-protected α-amino aldehydes and ketones, as well as for the HCl-promoted synthesis of 2-amino acetal hydrochlorides and α-amino ketone and α-amino aldehyde hydrochlorides in high yield. Via this method, an asymmetric synthesis of (S)-cathinone hydrochloride (er 94:6) was achieved.
Assuntos
Acetais/síntese química , Iminas/química , Cetonas/síntese química , Óxidos/química , Acetais/química , Cetonas/química , Estrutura MolecularRESUMO
A convenient approach toward nonactivated 1-alkyl-2-(trifluoromethyl)azetidines as a new class of constrained azaheterocycles was developed starting from ethyl 4,4,4-trifluoroacetoacetate via imination, hydride reduction, chlorination, and base-induced ring closure. Furthermore, the reactivity profile of these 2-CF(3)-azetidines was assessed by means of quaternization and subsequent regiospecific ring opening at C4 of the azetidinium intermediates by oxygen, nitrogen, carbon, sulfur, and halogen nucleophiles, pointing to a clear difference in reactivity compared to azetidines bearing other types of electron-withdrawing groups at C2.
Assuntos
Aminas/síntese química , Azetidinas/síntese química , Aminas/química , Azetidinas/química , Estrutura Molecular , Sais/química , EstereoisomerismoRESUMO
Zincated 3-chloro-3-methyl-1-azaallylic anions undergo a stereoselective aldol addition across aromatic aldehydes and subsequent mesylation to produce syn α-chloro-ß-mesyloxyketimines, which were isolated in 80-84% yield and high diastereomeric excess (dr > 97/3) after purification via flash chromatography. The syn α-chloro-ß-mesyloxyketimines were further stereoselectively reduced to give stereochemically defined 3-aminopropyl mesylates, which were cyclized to 1,2,3,4-tetrasubstituted 3-chloroazetidines containing three contiguous stereogenic centers. DFT calculations on the key aldol addition revealed the presence of a highly ordered bimetallic six-membered twist-boat-like transition state structure with a tetra-coordinated metal cyclic structure. DFT calculations revealed that chelation of both zinc and lithium cations in the transition state structure leads to the experimentally observed high syn diastereoselectivity of aldol reactions.