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1.
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
2.
Proc Natl Acad Sci U S A ; 119(28): e2204765119, 2022 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-35787048

RESUMO

Life as we know it is homochiral, but the origins of biological homochirality on early Earth remain elusive. Shallow closed-basin lakes are a plausible prebiotic environment on early Earth, and most are expected to have significant sedimentary magnetite deposits. We hypothesize that ultraviolet (200- to 300-nm) irradiation of magnetite deposits could generate hydrated spin-polarized electrons sufficient to induce enantioselective prebiotic chemistry. Such electrons are potent reducing agents that drive reduction reactions where the spin polarization direction can enantioselectively alter the reaction kinetics. Our estimate of this chiral bias is based on the strong effective spin-orbit coupling observed in the chiral-induced spin selectivity (CISS) effect, as applied to energy differences in reduction reactions for different isomers. In the original CISS experiments, spin-selective electron transmission through a monolayer of double-strand DNA molecules is observed at room temperature-indicating a strong coupling between molecular chirality and electron spin. We propose that the chiral symmetry breaking due to the CISS effect, when applied to reduction chemistry, can induce enantioselective synthesis on the prebiotic Earth and thus facilitate the homochiral assembly of life's building blocks.


Assuntos
Elétrons , Óxido Ferroso-Férrico , DNA/química , Planeta Terra , Estereoisomerismo
3.
Int J Mol Sci ; 23(13)2022 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-35806433

RESUMO

Chiral metabolomics is starting to become a well-defined research field, powered by the recent advances in separation techniques. This review aimed to cover the most relevant advances in indirect enantioseparations of endogenous metabolites that were published over the last 10 years, including improvements and development of new chiral derivatizing agents, along with advances in separation methodologies. Moreover, special emphasis is put on exciting advances in separation techniques combined with mass spectrometry, such as chiral discrimination by ion-mobility mass spectrometry together with untargeted strategies for profiling of chiral metabolites in complex matrices. These advances signify a leap in chiral metabolomics technologies that will surely offer a solid base to better understand the specific roles of enantiomeric metabolites in systems biology.


Assuntos
Pesquisa Biomédica , Metabolômica , Espectrometria de Massas/métodos , Metabolômica/métodos , Estereoisomerismo
4.
J Chem Phys ; 157(3): 034304, 2022 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-35868921

RESUMO

We present a comprehensive study of enantioselective orientation of chiral molecules excited by a pair of delayed cross-polarized femtosecond laser pulses. We show that by optimizing the pulses' parameters, a significant degree (∼10%) of enantioselective orientation can be achieved at 0 and 5 K rotational temperatures. This study suggests a set of reasonable experimental conditions for inducing and measuring strong enantioselective orientation. The strong enantioselective orientation and the wide availability of the femtosecond laser systems required for the proposed experiments may open new avenues for discriminating and separating molecular enantiomers.


Assuntos
Lasers , Luz , Estereoisomerismo
5.
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
6.
J Am Chem Soc ; 144(28): 12970-12978, 2022 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-35792599

RESUMO

3,5-Dimethylorsellinic acid (DMOA)-derived spiromeroterpenoids are a unique natural product family with attractive structures, unconventional stereochemistry, and potent biological activities. Herein, we report the first asymmetric total syntheses of the asnovolins, DMOA-derived spiromeroterpenoids. The spirocyclic skeleton was efficiently assembled through a sterically hindered bis-neopentyl 1,2-addition coupling/oxidative Michael addition sequence. The unusual axial C12-methyl stereochemistry was established via metal hydrogen atom transfer (MHAT) reduction involving a chair-to-boat conformational change. The mechanism of the HAT process was studied through both deuterium labeling and computational studies. Attempted late-stage alkene isomerization of an exocyclic enone proved to be challenging and resulted in hetero-Diels-Alder dimerization, which ultimately led to development of an alternative desaturation/coupling sequence. Endgame core modifications including orthogonal desaturation, Sc(III)-promoted regioselective Baeyer-Villiger oxidation, and Meerwein-Ponndorf-Verley reduction enabled collective syntheses of five asnovolin-related natural products. This study demonstrates the utility of anionic fragment coupling to assemble a sterically congested molecular framework and provides a foundation for the synthesis of spiromeroterpenoid congeners with higher oxidation states for biological studies.


Assuntos
Produtos Biológicos , Ânions , Dimerização , Oxirredução , Estereoisomerismo
7.
Org Lett ; 24(27): 4971-4976, 2022 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-35796493

RESUMO

Two strategies are described en route to an enantioselective total synthesis of gelsenicine. One approach centers on a chirality transfer cycloisomerization that ultimately fell short. Separately, an asymmetric catalysis route utilizing bisphosphine-gold-catalyzed cycloisomerization was pursued. A catalytic system was identified that provided a synthetic intermediate in our Gelsemium alkaloid syntheses in high enantiopurity and with absolute configuration determined by electronic circular dichroism, thus representing an enantioselective formal total synthesis of (+)-gelsenicine.


Assuntos
Alcaloides Indólicos , Catálise , Estrutura Molecular , Estereoisomerismo
8.
J Am Chem Soc ; 144(28): 12619-12626, 2022 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-35802534

RESUMO

Chiral organophosphorous compounds are very important in catalysis, organic syntheses, and medicinal chemistry. However, catalytic enantioselective protocols for the axially chiral allenyl phosphorus compounds have never been reported. Herein, a palladium-catalyzed enantioselective carbon-phosphorus bond formation reaction affording axially chiral allenyl phosphonates has been developed. The reaction enjoys high yields and ees accommodating a wide range of functional groups. Mechanistic studies have unveiled an overwhelming kinetic resolution process.


Assuntos
Paládio , Catálise , Técnicas de Química Sintética/métodos , Paládio/química , Estereoisomerismo
9.
Acta Chim Slov ; 69(2): 316-321, 2022 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-35861083

RESUMO

A series of novel tridentate Schiff bases is synthesized from piperazine-amine and substituted salicylaldehydes, and characterized by spectroscopic methods. These chiral ligands were used to catalyze the addition of nitromethane to various aldehydes in the presence of Cu(II) ions under ambient conditions in good yields (98%) and high enantioselectivities (9:91 er).


Assuntos
Compostos Heterocíclicos , Bases de Schiff , Catálise , Ligantes , Piperazinas , Bases de Schiff/química , Estereoisomerismo
10.
Org Biomol Chem ; 20(28): 5510-5514, 2022 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-35788245

RESUMO

An efficient enantioselective Michael addition reaction of 2,3-dioxopyrrolidine with indole in aqueous media was developed by virtue of a chiral copper complex. This reaction features air tolerance, a broad substrate scope and mild reaction conditions. Furthermore, a gram-scale synthesis was conducted to afford the corresponding products with a high yield and excellent enantioselectivity. Moreover, the proposed mechanism was supported by control experiments, XPS investigation and DFT calculations.


Assuntos
Indóis , Lactamas , Catálise , Cobre , Estereoisomerismo , Água
11.
Org Biomol Chem ; 20(28): 5566-5574, 2022 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-35792054

RESUMO

A concise manganese(III)-promoted stereoselective ß-phosphorylation of acyclic tertiary enamides and diverse H-phosphine oxides was achieved. This reaction proceeds with absolute E-selectivity in contrast to Z-selectivity obtained in other previous works and affords various E-selective ß-phosphorylated tertiary enamides in high efficiency. To the best of our knowledge, this is the first case of E-selective ß-phosphorylation of tertiary enamides through C-H functionalization. In addition, the method features broad substrate scope, good functional group compatibility and efficient scale-up.


Assuntos
Amidas , Manganês , Humanos , Estrutura Molecular , Fosforilação , Estereoisomerismo
12.
Org Biomol Chem ; 20(28): 5515-5519, 2022 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-35796246

RESUMO

The method for the synthesis of complex alkaloid-like aza-heterocycles has been developed through the Povarov reaction of in situ generated 2-oxoimidazolium cations. The reaction lead to the formation of 2 C-N, 2 C-C bonds and three stereocentres, and features excellent regio- and diastereoselectivity. Based on the controlled experiments and quantum chemistry data, the mechanism of the reaction cyclization was proposed and diastereoselectivity origins were rationalized. Additionally, a straightforward synthesis of hardly accessible 4,4'-bi(imidazol-2-one) derivatives has been achieved using the same methodology.


Assuntos
Alcaloides , Quinolinas , Alcaloides/química , Ciclização , Quinolinas/química , Estereoisomerismo
13.
Org Biomol Chem ; 20(28): 5582-5588, 2022 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-35796306

RESUMO

A class of o-sulfonylaminostyryl isoxazole synthons were designed and demonstrated to be useful building blocks in asymmetric cascade aza-Michael/Michael reaction with 3-olefinic oxindoles. This squaramide-catalysed cascade reaction afforded structurally complex isoxazole-containing spirooxindole tetrahydroquinolines bearing three contiguous stereocenters in good to excellent yields (up to 99%) with high diastereoselectivities (up to >20 : 1 dr) and enantioselectivities (up to 88% ee). Moreover, the gram-scale synthesis and synthetic transformations were also demonstrated.


Assuntos
Isoxazóis , Estrutura Molecular , Quinina/análogos & derivados , Quinolinas , Estereoisomerismo
14.
Org Biomol Chem ; 20(28): 5624-5637, 2022 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-35796681

RESUMO

In this work, the classical "isoxazoline route" toward aldols involving the [3 + 2]-cycloaddition of nitrile oxide to alkenes and hydrogenolysis of the oxime group was revisited. To avoid regioselectivity issues, [4 + 1]-annulation of nitroalkenes with sulfonium ylides was used to construct the isoxazoline ring bearing an N-oxide moiety. Subsequent deoxygenative C-H functionalization using the Boekelheide rearrangement and hydrogenolysis of the isoxazoline ring afforded α'-acyloxy-substituted aldols, which are difficult to access both by the classical aldol reaction and the "isoxazoline route". The products are formed in good to high overall yields and as single diastereomers in most cases. The synthetic use of these aldols was showcased by their smooth transformation into diastereomerically pure triols and a 2,3-diaryl-4-hydroxy-substituted tetrahydrofuran derivative, which is structurally related to cinncassin B.


Assuntos
Cetonas , Óxidos , Alcenos , Reação de Cicloadição , Estereoisomerismo
15.
Molecules ; 27(15)2022 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-35897858

RESUMO

Difenoconazole is a chemical entity containing two chiral centers and having four stereoisomers: (2R,4R)-, (2R,4S)-, (2S,4R)- and (2S,4S)-difenoconazole, the marketed product containing a mixture of these isomers. Residues of difenoconazole have been identified in many agricultural products and drinking water. A computational approach has been used to evaluate the toxicological effects of the difenoconazole stereoisomers on humans. It integrates predictions of absorption, distribution, metabolism, excretion and toxicity (ADMET) profiles, prediction of metabolism sites, and assessment of the interactions of the difenoconazole stereoisomers with human cytochromes, nuclear receptors and plasma proteins by molecular docking. Several toxicological effects have been identified for all the difenoconazole stereoisomers: high plasma protein binding, inhibition of cytochromes, possible hepatotoxicity, neurotoxicity, mutagenicity, skin sensitization potential, moderate potential to produce endocrine disrupting effects. There were small differences in the predicted probabilities of producing various biological effects between the distinct stereoisomers of difenoconazole. Furthermore, there were significant differences between the interacting energies of the difenoconazole stereoisomers with plasma proteins and human cytochromes, the spectra of the hydrogen bonds and aromatic donor-acceptor interactions being quite distinct. Some distinguishing results have been obtained for the (2S,4S)-difenoconazole: it registered the highest value for clearance, exposed reasonable probabilities to produce cardiotoxicity and carcinogenicity and negatively affected numerous nuclear receptors.


Assuntos
Quimioinformática , Citocromos , Dioxolanos , Humanos , Simulação de Acoplamento Molecular , Estereoisomerismo , Triazóis
16.
Molecules ; 27(15)2022 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-35897866

RESUMO

Piperidine and pyrrolidine derivatives are important nitrogen heterocyclic structures with a wide range of biological activities. However, reported methods for their construction often face problems of requiring the use of expensive metal catalysts, highly toxic reaction reagents or hazardous reaction conditions. Herein, an efficient route from halogenated amides to piperidines and pyrrolidines was disclosed. In this method, amide activation, reduction of nitrile ions, and intramolecular nucleophilic substitution were integrated in a one-pot reaction. The reaction conditions were mild and no metal catalysts were used. The synthesis of a variety of N-substituted and some C-substituted piperidines and pyrrolidines became convenient, and good yields were obtained.


Assuntos
Amidas , Pirrolidinas , Catálise , Piperidinas/química , Pirrolidinas/química , Estereoisomerismo
17.
Molecules ; 27(15)2022 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-35897907

RESUMO

(Ph3C)[BPh(F)4]-catalyzed Hosomi-Sakurai allylation of allylsilanes with ß,γ-unsaturated α-ketoesters has been developed to give γ,γ-disubstituted α-ketoesters in high yields with excellent chemoselectivity. Preliminary mechanistic studies suggest that trityl cation dominates the catalysis, while the silyl cation plays a minor role.


Assuntos
Estereoisomerismo , Alcenos , Catálise , Cátions , Estrutura Molecular , Silanos
18.
J Chromatogr A ; 1677: 463306, 2022 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-35810641

RESUMO

Capillary electrokinetic chromatography (CEKC) and liquid chromatography (LC) methods were explored for the enantiomeric separation of six unsymmetrically disubstituted ferrocene derivatives. In normal-phase mode liquid chromatography, the use of n-heptane, ethanol or isopropanol with 1% n-butylamine as mobile phase on six polysaccharide-based columns, allowed to fully separate the enantiomers of three compounds out of the six (i.e 7-chloro-N-(2-((dimethylamino)methyl)ferrocenyl)quinolin-4-amine (ferroquine) (compound 1), 1-[(1S)-(1-Aminoethyl)]-2-(diphenylphosphino)ferrocene (compound 5) and 1-[(1R)-1-(Dicyclohexylphosphino)ethyl]-2-(diphenylphosphino)ferrocene (compound 6). Among the columns used, the Lux i-Cellulose-5 was the most effective. In capillary electrokinetic chromatography, a phosphate buffer of 25 mM concentration and pH equal to 2.5 was chosen as background electrolyte, leading to cationic ferrocene derivatives. The addition of neutral cyclodextrins was undertaken first and native ß- or γ-cyclodextrins were found to resolve the enantiomers of two derivatives. Then, 15 mM of anionic cyclodextrins were added to the background electrolyte. The use of SBE-ß-CD, S-ß-CD or S-γ-CD have allowed the separation of the enantiomers for most of the ferrocene derivatives studied with high resolution values in short migration time. For instance, for 1-(R)-2-(Diphenylphosphino)ethyldi-tert-butylphosphine ferrocene (compound 2), the migration times were less than 2 minutes and the resolution value was equal to 3.52 in short-end mode with 15 mM S-ß-CD, at 25 kV and 25°C. Finally, a dual cyclodextrins system was tested using 15 mM of S-ß-CD plus 15 mM HP-γ-CD in the phosphate buffer. This system allowed the improved separation of two ferrocene derivatives with an unusual resolution value equal to 41.5 in long-end mode. Overall, CEKC showed better enantioseparating power of the six chiral ferrocenes studied than liquid chromatography.


Assuntos
Ciclodextrinas , Cromatografia Líquida , Ciclodextrinas/química , Indicadores e Reagentes , Metalocenos , Fosfatos , Estereoisomerismo
19.
J Am Chem Soc ; 144(29): 13344-13355, 2022 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-35830682

RESUMO

New-to-nature radical biocatalysis has recently emerged as a powerful strategy to tame fleeting open-shell intermediates for stereoselective transformations. In 2021, we introduced a novel metalloredox biocatalysis strategy that leverages the innate redox properties of the heme cofactor of P450 enzymes, furnishing new-to-nature atom-transfer radical cyclases (ATRCases) with excellent activity and stereoselectivity. Herein, we report a combined computational and experimental study to shed light on the mechanism and origins of enantioselectivity for this system. Molecular dynamics and quantum mechanics/molecular mechanics (QM/MM) calculations revealed an unexpected role of the key beneficial mutation I263Q. The glutamine residue serves as an essential hydrogen bond donor that engages with the carbonyl moiety of the substrate to promote bromine atom abstraction and enhance the enantioselectivity of radical cyclization. Therefore, the evolved ATRCase is a bifunctional biocatalyst, wherein the heme cofactor enables atom-transfer radical biocatalysis, while the hydrogen bond donor residue further enhances the activity and enantioselectivity. Unlike many enzymatic stereocontrol rationales based on a rigid substrate binding model, our computations demonstrate a high degree of rotational flexibility of the allyl moiety in an enzyme-substrate complex and succeeding intermediates. Therefore, the enantioselectivity is controlled by the radical cyclization transition states rather than the substrate orientation in ground-state complexes in the preceding steps. During radical cyclization, anchoring effects of the Q263 residue and steric interactions with the heme cofactor concurrently control the π-facial selectivity, allowing for highly enantioselective C-C bond formation. Our computational findings are corroborated by experiments with ATRCase mutants generated from site-directed mutagenesis.


Assuntos
Sistema Enzimático do Citocromo P-450 , Simulação de Dinâmica Molecular , Biocatálise , Sistema Enzimático do Citocromo P-450/metabolismo , Heme/metabolismo , Estereoisomerismo
20.
J Chromatogr A ; 1677: 463325, 2022 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-35853420

RESUMO

Fluindapyr and penthiopyrad are two new succinate-dehydrogenase-inhibitor fungicides both employed as racemic mixtures of enantiomers to control various fungal pathogens. In the present work, a robust and highly-sensitive method for simultaneous determination of fluindapyr and penthiopyrad enantiomers in plant-origin foods (cereals, fruits and vegetables) was developed using UPLC-MS/MS combined with a chiral stationary phase. Rapid baseline chiral separation of four stereoisomers of fluindapyr and penthiopyrad was obtained within 4.2 min on chiral MX(2)-RH column under reversed-phase conditions (with the eluent of acetonitrile/0.1% formic acid in water =70/30 (V:V) and column temperature maintained at 30 °C). The plant-origin samples were extracted quickly with acetonitrile and purified with multi-walled carbon nanotubes. Excellent linearity for the target analytes was observed in the concentration ranging from 1 to 250 µg/L with regression coefficient no less than 0.9967. The mean recoveries of fluindapyr and penthiopyrad enantiomers from six matrices were 77.1-107.2%, with all relative standard deviations values lower than 9.1%. The limit of quantification of four stereoisomers of two target chiral fungicides was 5 µg/kg. The analysis of real samples reveal that the developed method is suitable for the simultaneous chiral determination of fluindapyr and penthiopyrad residues in cereals, fruits and vegetables samples at enantiomeric level and can support their further investigation on enantioselective environmental behaviors and residue surveillance.


Assuntos
Fungicidas Industriais , Nanotubos de Carbono , Acetonitrilas/análise , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida/métodos , Fungicidas Industriais/análise , Estereoisomerismo , Ácido Succínico , Espectrometria de Massas em Tandem/métodos , Verduras/química
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