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2.
Science ; 377(6606): 673-678, 2022 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-35926016

RESUMO

Skeletal or concave polyhedral crystals appear in a variety of synthetic processes and natural environments. However, their morphology, size, and orientation are difficult to control because of their highly kinetic growth character. We report a methodology to achieve synchronous, uniaxial, and stepwise growth of micrometer-scale skeletal single crystals from planar-chiral double-decker molecules. Upon drop-casting of a heated ethanol solution onto a quartz substrate, the molecules spontaneously assemble into standing vessel-shaped single crystals uniaxially and synchronously over the wide area of the substrate, with small size polydispersity. The crystal edge is active even after consumption of the molecules and resumes stereoselective growth with successive feeding. The resultant morphology can be packed into polycyclic aromatic hydrocarbon-like microarchitectures and behaves as a microscopic container.


Assuntos
Microvasos , Cinética , Estereoisomerismo
3.
Environ Int ; 167: 107442, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35921772

RESUMO

The environmental impact of the chiral fungicide epoxiconazole and its chiral transformation products (TPs) on non-target organisms and the environment has become a significant concern due to its widespread use in agricultural practice. Enantioselectivity studies of parent contaminants cannot adequately assess the complexity of its chiral TPs in the environment. This study aimed to investigate the environmental behavior of epoxiconazole in an earthworm-soil system. 2S,3R-(-)-epoxiconazole was preferentially enriched in earthworms during the accumulation phase (p < 0.05), but no enantioselectivity was observed during the elimination phase. One methoxylated and four hydroxylated chiral TPs were identified in soil, earthworm, and excrement. The epoxy ring hydroxylated TP and methoxylated TP of epoxiconazole were discovered for the first time in the environment. The chemically specific enantioselectivity with enantiomer fraction (EF) > 0.8 was observed for the TPs in different matrices. The CYP450 monooxygenase of earthworm was significant activated. In vitro enzyme metabolism experiments (earthworm microsomes and recombinant CYP450 enzymes CYP2A6, CYP 2C9, and CYP 3A4) were carried out to further explain the biotransformation mechanism of epoxiconazole in earthworm. This study provides new evidence of enantiomeric biotransformation of chiral fungicide epoxiconazole in the earthworm-soil system and could provide valuable insights into their environmental risk assessment.


Assuntos
Fungicidas Industriais , Oligoquetos , Poluentes do Solo , Animais , Biotransformação , Compostos de Epóxi , Fungicidas Industriais/análise , Solo/química , Poluentes do Solo/análise , Estereoisomerismo , Triazóis
4.
Nat Commun ; 13(1): 4759, 2022 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-35963867

RESUMO

Amines and alcohols with a fully substituted α-carbon are structures of great value in organic synthesis and drug discovery. While conventional methods towards these motifs often rely on enantioselective carbon-carbon or carbon-heteroatom bond formation reactions, a desymmetric method is developed here by selectively hydrosilylating one of the esters of easily accessible α-substituted α-amino- and -oxymalonic esters. The desymmetrization is enabled by a suite of dinuclear zinc catalysts with pipecolinol-derived tetradentate ligands and can accommodate a diverse panel of heteroatom substituents, including secondary amides, tertiary amines, and ethers of different sizes. The polyfunctionalized reduction products, in return, have provided expeditious approaches to enantioenriched nitrogen- and oxygen-containing molecules, including dipeptides, vitamin analogs, and natural metabolites.


Assuntos
Álcoois , Ésteres , Álcoois/química , Aminas/química , Carbono/química , Estereoisomerismo
5.
Molecules ; 27(15)2022 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-35956825

RESUMO

A Knoevenagel based redox-reaction promoted by intramolecular phosphine sources is presented for the first time. The influence of different diketones, aldehydes, bases and acids was investigated. The effects of different substituents were evaluated based on their electronical influence on the diketone structure. With the obtained results a mechanism is proposed, giving information about transition states formed during the reaction, which can lead to different products. This type of an internal redox transformation with a phosphine oxide moiety remaining in the molecule after the redox reaction represents a new type of reaction.


Assuntos
Fosfinas , Catálise , Cetonas/química , Oxirredução , Fosfinas/química , Estereoisomerismo
6.
Molecules ; 27(15)2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35956942

RESUMO

Carvedilol (CAR), a racemic lipophilic aryloxy propanolamine, acts as a selective α1-adrenoreceptor antagonist and a nonselective ß-adrenoreceptor antagonist. CAR metabolism mainly produces three active metabolites: desmethyl carvedilol (DMC), 4'-hydroxy carvedilol (4'OHC) and 5'-hydroxy carvedilol (5'OHC). The oxidative S-(-)-metabolites contribute to the ß-antagonistic effect, yet not to the α-antagonistic effect to be observed after drug dosage. Therefore, the three ß-adrenoceptor blocking metabolites, which are structurally closely related to the parent CAR, are included into the development of a bioanalytical quantitative method for all major active species relevant with respect to adrenoceptor-blockade. Because of the given pharmacological profile, resolution of the enantiomers of carvedilol, of 4'- and 5'-hydroxy carvedilol as well as of DMC, is mandatory. The current study aims to determine the response surface for the enantiomer separation of the parent CAR as well as the major metabolites on a suitable chiral stationary phase. Design of experiment approach (DoE) was utilized in an initial screening phase followed by central-composite design for delimitation of the response surface for resolution of the four enantiomeric pairs in least run time. The impact of chromatographic variables (composition and percentage of organic modifier(s), buffer type, buffer pH, flow rate) on critical peaks resolution and adjusted retention time was evaluated, in order to select the most significant critical quality attributes. On this basis, a robust UHPLC-UV method was developed and optimized for the simultaneous, enantioselective determination of CAR along with its major active metabolites (4'OHC, 5'OHC, and DMC) on Chiralpak IBN-5. The optimized UHPLC-UV method (which includes metoprolol as the internal standard) was validated according to the ICH M10 guidelines for bioanalytical methods and proven to be linear, precise, accurate, and robust. The validated assay was applied to plasma samples from cardiovascular patients treated with rac-CAR (blood randomly drawn at different times after oral CAR intake). In order to provide more insight into the mechanism of the enantiomer separation of CAR and its metabolites on the CSP, docking experiments were performed. Molecular simulation studies suggest the chiral recognition to be mainly due to different binding poses of enantiomers of the same compound.


Assuntos
Antagonistas Adrenérgicos beta , Propanolaminas , Antagonistas Adrenérgicos beta/química , Carvedilol , Cromatografia Líquida de Alta Pressão/métodos , Humanos , Propanolaminas/química , Receptores Adrenérgicos , Estereoisomerismo
7.
Top Curr Chem (Cham) ; 380(5): 43, 2022 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-35951264

RESUMO

The Diels-Alder reaction (DAR) is found in myriad applications in organic synthesis and medicinal chemistry for drug development, as it is the method of choice for the expedient synthesis of complex natural compounds and innovative materials including nanomaterials, graphene expanses, and polymeric nanofibers. Furthermore, the greatest focus of attention of DARs is on the consistent reaction procedure with stimulus yields by highly stereo- and regioselective mechanistic pathways. Therefore, the present review is intended to summarize conventional solvent-free (SF) DARs for the expedient synthesis of heterocyclic compounds and materials. In particular, this review deals with the DARs of mechanochemical grinding, catalysis (including stereoselective catalysts), thermal, and electromagnetic radiation (such as microwave [MW], infrared [IR], and ultraviolet [UV] irradiation) in SF procedures. Therefore, this comprehensive review validates the application of DARs to pharmaceutical innovations and biorenewable materials through consistent synthetic approaches.


Assuntos
Solventes , Catálise , Técnicas de Química Sintética , Reação de Cicloadição , Solventes/química , Estereoisomerismo
8.
Nat Commun ; 13(1): 4718, 2022 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-35953485

RESUMO

Thousands of natural products are derived from the fused cyclopentane-pyran molecular scaffold nepetalactol. These natural products are used in an enormous range of applications that span the agricultural and medical industries. For example, nepetalactone, the oxidized derivative of nepetalactol, is known for its cat attractant properties as well as potential as an insect repellent. Most of these naturally occurring nepetalactol-derived compounds arise from only two out of the eight possible stereoisomers, 7S-cis-trans and 7R-cis-cis nepetalactols. Here we use a combination of naturally occurring and engineered enzymes to produce seven of the eight possible nepetalactol or nepetalactone stereoisomers. These enzymes open the possibilities for biocatalytic production of a broader range of iridoids, providing a versatile system for the diversification of this important natural product scaffold.


Assuntos
Produtos Biológicos , Iridoides , Biocatálise , Ciclopentanos , Estereoisomerismo
9.
Nat Commun ; 13(1): 4577, 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35931694

RESUMO

Axially chiral biaryl motifs possessing ortho-heteroatom-substituted functionalities exist widely in the structures of natural products and have served as foundation for constructing prominent chiral organocatalysts, ligands, functional materials, and even bioactive molecules. However, a general and enantioselective synthesis of such chiral structures with high synthetic value is rare. Taking advantage of the BaryPhos-facilitated asymmetric Suzuki-Miyaura cross-coupling, we have established a general, efficient and enantioselective construction of the ortho sulfur- or nitrogen-substituted axially chiral biaryls. The protocol shows excellent compatibility to various functional groups and structural features, delivering chiral biaryl structures with ortho-sulfonyl groups or with ortho-nitro groups at a broad range of molecular diversity and complexity. The immobilization of BaryPhos on polyethylene glycol (PEG) support has enabled homogeneous enantioselective cross-coupling in aqueous media and the palladium catalyst recycling for multiple times. The method has enabled a concise 10-step asymmetric synthesis of isoplagiochin D as well as the construction of chiroptical molecules with circularly polarized luminescence (CPL) properties.


Assuntos
Nitrogênio , Enxofre , Catálise , Ligantes , Estereoisomerismo
10.
Methods Mol Biol ; 2531: 211-225, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35941488

RESUMO

Capillary electrophoresis (CE) is a technique that has already proven its importance in the separation of enantiomers. The combination of CE with mass spectrometry (MS) detection further boosts the possibilities of CE in terms of achieving higher sensitivity with the possibility of an unambiguous assignment of analytes of interest. This chapter details four different examples using CE in the electrokinetic chromatography (EKC) mode coupled to MS with application to four different fields of analysis (pharmaceutical, biomedical, food, and agrochemical). The first two methods are based on the use of a single and a double chiral selector system, respectively, in which the partial filling technique (PFT) had to be used to avoid MS-source contamination. In the last two examples, PFT was not needed as they were based on the use of low concentrations of chiral selector but a derivatization step was necessary to allow proper enantiorecognition with the chiral selectors. Description of these protocols is fully explained.


Assuntos
Cromatografia , Eletroforese Capilar , Eletroforese Capilar/métodos , Espectrometria de Massas/métodos , Estereoisomerismo
11.
Org Lett ; 24(31): 5797-5801, 2022 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-35912453

RESUMO

A readily available and highly modular class of chiral P,N,N-ligands based on a structurally flexible nonchiral phosphine-amine framework with an optically active 1,2-diphenylethylenediamine unit bearing a tertiary amine terminus as the chiral source have been developed and successfully applied in the Ir-catalyzed asymmetric hydrogenation of o-amidophenyl ketones. These tridentate P,N,N-ligands exhibited excellent activity, enantioselectivity, and substrate tolerance, thus furnishing various optically active o-amidobenzhydrols in up to 99% yields and with >99% ee. The utility of this protocol has been proven by synthetically diverse product transformation and highly enantioselective production of a rice plant growth regulator, (S)-inabenfide.


Assuntos
Irídio , Cetonas , Aminas , Catálise , Etilenodiaminas , Hidrogenação , Ligantes , Estrutura Molecular , Estereoisomerismo
12.
Org Lett ; 24(31): 5812-5816, 2022 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-35912985

RESUMO

The first bioinspired, enantioselective, and protecting group free total synthesis of the antibacterial sesquiterpenoid (-)-antroalbocin A (1) has been achieved in 12 steps (5.4% overall yield) from dimedone. An organocatalytic Robinson annulation gave rapid access to the tricyclic enone (19) as starting material for the photochemical domino process of deconjugation and sigmatropic 1,3-acyl shift. Computational data of this process indicate that the 1,3-acyl shift benefits from the highly strained 1,3-enone 8. The transformation of 8 to its bridged isomer 5 is exergonic and, therefore, enables an increased conversion compared to unstrained substrates.


Assuntos
Sesquiterpenos , Ciclização , Estereoisomerismo
13.
Anal Methods ; 14(31): 3011-3020, 2022 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-35916141

RESUMO

Racemic mixtures of twelve common α-amino acids and three chiral drugs were tested for the separation of their enantiomers by drift tube ion mobility spectrometry (IMS)-quadrupole mass spectrometry (QMS) by introducing chiral selectors into the buffer gas of the IMS instrument. (R)-α-(Trifluoromethyl)benzyl alcohol, (L)-ethyl lactate, methyl (S)-2-chloropropionate, and the R and S enantiomers of 2-butanol and 1-phenyl ethanol were evaluated as chiral selectors. Experimental conditions were varied during the tests, including buffer gas temperature, concentration and type of chiral selectors, analyte concentration, electrospray (ESI) voltage, ESI solvent pH, and buffer gas flow rate. The individual enantiomers yielded the same drift times and the racemic mixtures could not be separated. Energy calculations of the chiral selector-ion interactions showed that these separations are unlikely using 2-butanol as a chiral selector but they might be theoretically feasible depending on the chiral selector nature and the type of enantiomers. Several plausible explanations for not achieving separations were analyzed. Recommendations for potential enantiomer separations by IMS are proposed.


Assuntos
Aminoácidos , Espectrometria de Mobilidade Iônica , Espectrometria de Massas/métodos , Estereoisomerismo
14.
J Org Chem ; 87(15): 10054-10061, 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35849546

RESUMO

Current models for oxazaborolidine-catalyzed transition-state structures are determined by C-H···O-B and C-H···O═S formyl hydrogen bonding between the electrophile and catalyst. However, selectivity in the oxazaborolidine-catalyzed Mukaiyama aldol cannot be fully rationalized using these models. Combined density functional theory and noncovalent interaction analyses reveal a new reaction model relying on C-H···O, C-H···π, and π-π interactions between the nucleophile, electrophile, and catalyst to induce selectivity.


Assuntos
Aldeídos , Hidrogênio , Aldeídos/química , Catálise , Ligação de Hidrogênio , Estereoisomerismo
15.
Org Lett ; 24(27): 4865-4870, 2022 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-35775729

RESUMO

Herein, we report the Pd(0)-catalyzed intermolecular asymmetric dearomative [3 + 2] annulation of phenols with vinyl cyclopropanes via in situ generated ortho-quinone methide intermediates. A series of highly functionalized spiro-[5,6] bicycles which bear three contiguous stereogenic centers including one all-carbon quaternary were obtained with excellent stereoselectivities. Density functional theory (DFT) calculations indicate that the reactions were controlled by thermodynamics.


Assuntos
Ciclopropanos , Paládio , Catálise , Estrutura Molecular , Fenóis , Estereoisomerismo
16.
J Chromatogr A ; 1676: 463216, 2022 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-35777138

RESUMO

The introduction of additives has revolutionized super/subcritical fluid chromatography (SFC) by expanding the range of compounds that could be analyzed by the technique. From being considered a mere extension of gas chromatography, incorporation of a modifier, and subsequently an additive has made SFC a workhorse for chiral separations. Additives are by far the smallest component of the SFC mobile phase but can result in changing the polarity and acidity of the mobile phase, suppression of ionization, deactivation of the stationary phase, and act as an ion pairing agent. A wide variety of compounds have been tested as additives including but not limited to diethylamine, trifluoroacetic acid, ammonium acetate, and water. This review summarizes the different role played by additives in the SFC mobile phase. Further this work aims to help the reader by critically evaluating different additives used in enantiomeric separations with packed column SFC.


Assuntos
Cromatografia com Fluido Supercrítico , Cromatografia Líquida , Cromatografia com Fluido Supercrítico/métodos , Estereoisomerismo , Ácido Trifluoracético/química , Água
17.
Org Lett ; 24(27): 4860-4864, 2022 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-35793545

RESUMO

A general and diastereoselective fluorination/glycosylation strategy for the synthesis of 2'-fluorinated nucleosides has been developed. Electrophilic fluorination of a glycal with NFSI provided the 1',2'-difunctionalized furanoside intermediate with high diastereoselectivity. The TBS-protected 2'-deoxyfluorosulfonimide sugar was prepared on an 80 g scale and isolated as a crystalline, bench-stable single diastereomer. This intermediate was found to undergo a subsequent glycosylation reaction with a variety of heteroaryl nucleophiles with generally good diastereoselectivities.


Assuntos
Halogenação , Nucleosídeos , Glicosilação , Estereoisomerismo
18.
J Chromatogr A ; 1676: 463285, 2022 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-35802964

RESUMO

Terbutaline is mainly metabolized by sulfoconjugation stereoselectively, favoring its (S)-(+) enantiomer. Reported chiral separations of Terbutaline enantiomers were achieved by various chromatographic methods. However, the simultaneous enantioseparation of Terbutaline and the monosulfate conjugate metabolites was never reported. This study aims at shedding light on the influential factors and interactions leading to successful enantioseparation of Terbutaline and its monosulfate conjugate pairs by Supercritical Fluid Chromatography (SFC) for the first time within a Quality by Design framework using Design of Experiments. The effect of molarity of mobile phase additive, mobile phase flow rate, column temperature and back pressure were evaluated. Compared to previous reports, the response surface interestingly revealed the favorability of high temperature and high flow rate up to 2.25 ml/min for resolution of the two pairs of enantiomers on polysaccharide chiral stationary phase CHIRALPAK IC. In addition, a switch in the elution order of Terbutaline and the sulfate conjugate peak pairs was observed upon elimination of the mobile phase additive where the sulfate conjugate underwent intra-molecular ionic interactions and the change in elution order was only due to TER behavior. The multifactorial interactions would not have been detected with the common one-factor-at-a-time approach during method development, demonstrating the superiority and importance of the Analytical Quality by Design frame in enantioseparation.


Assuntos
Cromatografia com Fluido Supercrítico , Cromatografia com Fluido Supercrítico/métodos , Polissacarídeos/química , Estereoisomerismo , Sulfatos , Terbutalina
19.
J Am Chem Soc ; 144(28): 12638-12641, 2022 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-35786918

RESUMO

Indolizidine alkaloids have been the target of chemical and biological studies for decades, most recently highlighted by the isolation of the curvulamine and bipolamine polypyrrole-containing subclass. Herein we report a stereoselective 15-step synthesis of bipolamine I, a distinct member of the broader family, and through this work develop an intermediate that will serve to access other polypyrrole natural products and key analogues going forward.


Assuntos
Alcaloides , Produtos Biológicos , Polímeros , Pirróis , Estereoisomerismo
20.
J Org Chem ; 87(15): 10523-10530, 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35895907

RESUMO

Recent years have witnessed significant achievements in the field of organic chemistry, which have led to new drugs and the discovery of new and biologically interesting molecules. Herein, we describe a practical and efficient approach to the synthesis of enantiomerically pure and diverse lysobisphosphatidic acid analogues. The key feature of the synthesis is a one-pot, sequential phosphorylation of a protected sn-2-O-oleoyl glycerol or sn-3-O-oleoyl glycerol with 2-cyanoethyl N,N-diisopropylchlorophosphoramidite, followed by oxidation.


Assuntos
Glicerol , Monoglicerídeos , Lisofosfolipídeos/química , Monoglicerídeos/química , Estereoisomerismo
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