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1.
Org Lett ; 2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33428416

RESUMO

Ir-catalyzed asymmetric tandem allylation/iso-Pictet-Spengler cyclization of arylidenaminomalonates with indolyl allylic methyl carbonates was successfully developed, which provided a direct and practical approach to access synthetically useful and biologically active tetrahydro-γ-carboline derivatives bearing multiple functional groups and stereogenic centers in good to high yields and excellent stereoselective control (44%-96% yields, >20:1 dr, 94% → 99% ee). A wide range of substrate generality, easily available substrates, and simple chiral catalytic system displayed great potential practicality of this efficient protocol.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33219607

RESUMO

An unprecedented radical cross-coupling reaction was achieved between glycine esters and racemic α-bromoketones catalyzed by synergistic Brønsted acid/photoredox catalysis, thus serving as an efficient platform for the synthesis of highly valuable enantioenriched unnatural α-amino acid derivatives. This dual catalysis provides a powerful capability to control the reactive radical intermediate and iminium ion, thereby enabling enantioconvergent bond-formation in a highly stereochemical manner. An array of valuable enantioenriched unnatural α-amino acid derivatives bearing two contiguous stereogenic centers are readily accessible with high diastereoselectivity and excellent enantioselectivity, which include α-amino acids with a unique ß-fluorinated quaternary stereocenter or its ß-all-carbon counterpart. A strong chiral amplification effect was observed in this dual catalytic system.

3.
Chem Commun (Camb) ; 56(67): 9691-9694, 2020 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-32697814

RESUMO

Here, we developed an expedient access route to highly functionalized pyrroles from readily available α-amino acid ester hydrochlorides and alkynals via a cascade condensation/intramolecular cyclization followed by a unique C-N ester migration process. A variety of 1,2,3-trisubstituted pyrroles, which were difficult to acquire with the common methodologies, were successfully prepared in good yields under mild conditions.

4.
Org Lett ; 22(12): 4852-4857, 2020 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-32506915

RESUMO

A stereodivergent preparation of α-quaternary serine/cysteine derivatives incorporating two adjacent stereogenic centers has been developed through Cu/Ir-catalyzed asymmetric allylation of 2-oxazoline-4-carboxylates and 2-thiazoline-4-carboxylates. Tuning the electronic effect is the key to enhancing the reactivity of 2-oxazoline-4-carboxylates and suppressing the undesired ß-elimination. The salient feature of this protocol is that all four stereoisomers of α-quaternary serine and cysteine derivatives could be achieved from the identical starting materials through pairwise combination of two distinct chiral catalysts.

5.
Acc Chem Res ; 53(5): 1084-1100, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32320206

RESUMO

Optically active nitrogen-containing compounds have attracted substantial attention due to their ubiquity in the cores of natural products and bioactive molecules. Among the various synthetic approaches to nitrogenous frameworks, catalytic asymmetric 1,3-dipolar cycloadditions are one of the most attractive methods because of their powerful ability to rapidly construct various chiral N-heterocycles. In particular, N-metallated azomethine ylides, common and readily available 1,3-dipoles, have been extensively applied in dipolar cycloaddition reactions. Despite the fact that asymmetric transformations of azomethine ylides have been investigated for decades, most of the efforts have been directed toward the preparation of pyrrolidines using glycinate-derived α-unsubstituted aldimine esters as the precursors of the azomethine ylides. While α-substituted azomethine ylides derived from amino esters other than glycinate have seldom been harnessed, the construction of non-five-membered chiral N-heterocycles via 1,3-dipolar cycloadditions remains underexplored. In addition, the asymmetric α-functionalization of aldimine esters to prepare acyclic nitrogenous compounds such as α-amino acids, in which an in situ-generated N-metallated azomethine ylide serves as the nucleophile, has not been sufficiently described.In this Account, we mainly discuss the achievements we have made in the past decade toward broadening the applications of N-metallated azomethine ylides for the preparation of nitrogen-containing compounds. We began our investigation with the design and synthesis of a new type of chiral ligand, TF-BiphamPhos, which not only coordinates with Lewis acids to activate dipolar species but also serves as an H-bond donor to increase the reactivity of dipolarophiles with significantly enhanced stereochemical control. Using the Cu(I) or Ag(I)/TF-BiphamPhos complex as the catalyst, we achieved highly stereoselective (3+2) cycloadditions of glycinate and non-glycinate-derived azomethine ylides with diverse dipolarophiles, producing a variety of enantioenriched pyrrolidines with multiple stereocenters in a single step. To further expand the synthetic utility of N-metallated azomethine ylides, we successfully developed higher order cycloadditions with fulvenes, tropone, 2-acyl cycloheptatrienes, and pyrazolidinium ylides serving as the reaction partner, and this reaction provides straightforward access to enantioenriched fused piperidines, bridged azabicyclic frameworks, and triazines via (3+6)- and (3+3)-type cycloadditions. Using N-metallated azomethine ylides as the nucleophile, we realized Cu(I)-catalyzed asymmetric 1,4-Michael additions with α,ß-unsaturated bisphosphates/Morita-Baylis-Hillman products, furnishing an array of structurally diverse unnatural α-amino acids. Based on the strategy of synergistic activation, we achieved highly efficient dual Cu/Pd and Cu/Ir catalysis for the α-functionalization of aldimine esters via the asymmetric allylic/allenylic alkylation of N-metallated azomethine ylides. Notably, Cu/Ir catalysis allowed the stereodivergent synthesis of α,α-disubstituted α-amino acids via a branched allylic alkylation reaction, in which the two distinct chiral metal catalysts independently have full stereochemical control over the corresponding nucleophile and electrophile. Furthermore, an expedient and stereodivergent preparation of biologically important tetrahydro-γ-carbolines was realized through a Cu/Ir-catalyzed cascade allylation/iso-Pictet-Spengler cyclization. In addition, when the steric congestion in the allylation intermediates was increased, the combined Cu/Ir catalysts provided an asymmetric cascade allylation/2-aza-Cope rearrangement, producing various optically active homoallylic amines with impressive results.

6.
Chem Commun (Camb) ; 56(22): 3333-3336, 2020 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-32090227

RESUMO

Facile access to quaternary α-trifluoromethyl α-amino acids has been developed. This sequential reaction involves an Ir-catalyzed asymmetric allylation of α-trifluoromethyl aldimine esters followed by an unprecedented kinetic resolution.


Assuntos
Aminoácidos/química , Irídio/química , Aminoácidos/síntese química , Catálise , Cristalografia por Raios X , Iminas/química , Cinética , Conformação Molecular , Estereoisomerismo
7.
Org Lett ; 22(2): 569-574, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31895576

RESUMO

Pd-phosphinooxazoline (Pd-PHOX)-catalyzed asymmetric hydroalkylation of 1,3-dienes with azlactones was successfully developed for the first time, affording various enantioenriched α-quaternary α-amino acid derivatives bearing contiguous quaternary and tertiary stereogenic centers in good yields with exclusive regioselectivity and excellent stereoselective control (up to 92% yield, >20:1 dr, and >99% ee). The scale-up catalytic asymmetric hydroalkylation was performed well without loss of reactivity and stereoselectivities, which exhibited great potential application. The synthetic utility of the current methodology was demonstrated through product transformations to access other biologically important compounds such as chiral ß-amino alcohol and α-quaternary cyclic α-amino acid derivatives.


Assuntos
Alcadienos/química , Aminoácidos/síntese química , Paládio/química , Alquilação , Aminoácidos/química , Catálise , Estrutura Molecular , Estereoisomerismo
8.
Pediatr Infect Dis J ; 39(3): 177-183, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31738328

RESUMO

BACKGROUND: Mycoplasma pneumoniae pneumonia is generally a self-limiting disease, but it can develop into severe Mycoplasma pneumoniae pneumonia (SMPP). Immunologic mechanisms are thought to play an important role in the pathogenesis of SMPP. Therefore, the use of systemic glucocorticoids may have beneficial effects. However, to date, the use of glucocorticoid therapy in SMPP is limited to small case series, and the glucocorticoid dosage for children with SMPP has not been established. METHODS: Here, we used a meta-analysis method to collect data from randomized control trials of different doses of methylprednisolone in SMPP to assess the safety and efficacy of treatment with low- versus high-dose methylprednisolone in children with SMPP. RESULTS: We included 13 Chinese randomized control trials that included 1049 children. The high- and low-dose groups were comprised of 524 and 525 children, respectively. The high-dose group was significantly more effective than the low-dose group in clinical efficacy [risk ratio = 1.30, 95% confidence interval (CI) (1.23, 1.38), P < 0.05]. In addition, compared with low-dose methylprednisolone, high-dose methylprednisolone significantly shortened hospital stays and antipyretic therapy, pulmonary rales disappearance, cough disappearance and pulmonary shadow absorption times. There was no significant difference in adverse events between the high- and low-dose groups: risk ratio= 0.85, 95% CI (0.53, 1.36), P > 0.05. CONCLUSIONS: We conclude that high-dose methylprednisolone is effective in the treatment of SMPP without increasing the incidence of adverse reactions.


Assuntos
Anti-Inflamatórios/administração & dosagem , Metilprednisolona/administração & dosagem , Mycoplasma pneumoniae/efeitos dos fármacos , Pneumonia por Mycoplasma/tratamento farmacológico , Pneumonia por Mycoplasma/microbiologia , Anti-Inflamatórios/efeitos adversos , Criança , Glucocorticoides/administração & dosagem , Glucocorticoides/efeitos adversos , Humanos , Tempo de Internação , Metilprednisolona/efeitos adversos , Pneumonia por Mycoplasma/diagnóstico , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Avaliação de Sintomas , Resultado do Tratamento
9.
Nat Commun ; 10(1): 5553, 2019 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-31804483

RESUMO

Enantiomerically enriched indole-containing heterocycles play a vital role in bioscience, medicine, and chemistry. As one of the most attractive subtypes of indole alkaloids, highly substituted tetrahydro-γ-carbolines are the basic structural unit in many natural products and pharmaceuticals. However, the syntheses of tetrahydro-γ-carbolines with high functionalities from readily available reagents are significant challenging. In particular, the stereodivergent syntheses of tetrahydro-γ-carbolines containing multi-stereogenic centers remain quite difficult. Herein, we report an expedient and stereodivergent assembly of tetrahydro-γ-carbolines with remarkably high levels of stereoselective control in an efficient cascade process from aldimine esters and indolyl allylic carbonates via a synergistic Cu/Ir catalyst system. Control experiments-guided optimization of synergistic catalysts and mechanistic investigations reveal that a stereodivergent allylation reaction and a subsequent highly stereoselective iso-Pictet-Spengler cyclization are the key elements to success.


Assuntos
Carbolinas/química , Ciclização , Alcaloides Indólicos/química , Indóis/química , Carbolinas/síntese química , Catálise , Cromatografia Líquida de Alta Pressão , Sinergismo Farmacológico , Alcaloides Indólicos/síntese química , Indóis/síntese química , Modelos Químicos , Estrutura Molecular , Espectroscopia de Prótons por Ressonância Magnética , Estereoisomerismo
10.
Clin Lab ; 65(8)2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31414767

RESUMO

BACKGROUND: The C-reactive protein to albumin ratio (CAR) is a novel inflammation index that has recently been used as a marker for poor prognosis or mortality in various patient groups. This study aimed to evaluate the association between the CAR and 30-day mortality in patients with hepatitis B virus-related decompensated cirrhosis (HBV-DeCi). METHODS: This was a retrospective cohort study of 113 patients who had been diagnosed with HBV-DeCi. Univariate and multivariate regression models were used to determine risk factors for mortality. RESULTS: The CAR was observed to be significantly higher in the non-surviving patients compared to the surviving patients. Moreover, the CAR was positively correlated with the model for end-stage liver disease (MELD) score and Child-Pugh score. In multivariate analysis, the CAR and the MELD score were independent prognostic factors for HBV-DeCi patients. CONCLUSIONS: A high CAR value at admission can serve as an independent predictor of 1-month mortality in patients with HBV-DeCi.


Assuntos
Proteína C-Reativa/análise , Hepatite B Crônica/complicações , Cirrose Hepática/complicações , Albumina Sérica/análise , Adulto , Idoso , Feminino , Hepatite B Crônica/mortalidade , Humanos , Cirrose Hepática/mortalidade , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida
11.
Org Lett ; 21(17): 6940-6945, 2019 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-31424222

RESUMO

A general protocol for the preparation of enantioenriched α-tetrasubstituted α-trifluoromethyl homoallylic amines is disclosed. Despite the significant challenge in stereoselectivity control, Ir-catalyzed asymmetric cascade umpolung allylation/2-aza-Cope rearrangement of trifluoromethylated fluorenone imines with allylic carbonates was realized with excellent efficiency and remarkable stereoselectivity. These were enabled by the suitable protective imino moiety and an unexpectedly exclusive E-geometrical imine of the allylation intermediate. This methodology is also applicable to facile access to chiral α-trisubstituted α-trifluoromethyl homoallylic amines in similarly high yield and stereoselectivity.

12.
Chem Commun (Camb) ; 55(47): 6672-6684, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31134230

RESUMO

Chiral multi-nitrogen-containing heterocycles, such as pyrazole, imidazole and pyridazine, are widely found in naturally occurring organic compounds and pharmaceuticals, and hence, their stereoselective and efficient synthesis is an important issue in organic synthesis. Out of the variety of methods that have been developed over the past century, the catalytic asymmetric cyclization and cycloaddition reactions are recognized as the most synthetically useful strategies due to their step-, atom- and redox-economic nature. In particular, the recently developed annulation reactions using azoalkenes as key intermediates show their great ability to construct diverse types of multi-nitrogen-containing heterocycles. In this feature article, we critically analyse the strategic development and the efficient transformation of azoalkenes to chiral heterocycles and α-functionalized ketone derivatives since 2010. The plausible mechanism for each reaction model is also discussed.

13.
Org Lett ; 21(12): 4842-4848, 2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31145631

RESUMO

An unprecedented Ir-catalyzed asymmetric cascade umpolung allylation/2-aza-Cope rearrangement of trifluoroethylisatin ketimines has been realized. The current method provides a facile access to biologically important α-trifluoromethyl-containing homoallylic amines in high yields with excellent enantioselectivity. Notably, umpolung reactivity of trifluoroethylisatin ketimine was discovered for the first time. Mechanism studies revealed the key intermediates in the initial umpolung allylation and the stereospecific chirality transfer in the subsequent 2-aza-Cope rearrangement.

14.
Chemistry ; 25(37): 8681-8685, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31054197

RESUMO

An unprecedented asymmetric allenylic alkylation of readily available imine esters, which was enabled by a synergistic Cu/Pd catalysis, has been developed. This dual catalytic system possesses good substrate compatibility, delivering a diverse array of nonproteinogenic α-allenylic α-mono- or α,α-disubstituted α-amino acids (α-AAs) with high yields and generally excellent enantioselectivities. Furthermore, the scalability and practicability of the current synthetic protocol were proven by performing gram-scale reactions and by the first catalytic asymmetric synthesis of naturally occurring (S)-γ-allenic α-amino acid, respectively.

15.
Nat Commun ; 10(1): 1594, 2019 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-30962429

RESUMO

The efficient construction of enantiomerically enriched molecules from simple starting materials via catalytic asymmetric synthesis strategies is a key challenge in synthetic chemistry. Metallated azomethine ylides are commonly-used synthons for the preparation of N-heterocycles and α-amino acids. Remarkably, to date, the utilization of azomethine ylides for the facile access to chiral amines has proven elusive. Here, we report that a synergistic Cu/Ir-catalytic system combined with careful tuning of the steric congestion can be used to convert aldimine esters to a variety of chiral homoallylic amines via a cascade allylation/2-aza-Cope rearrangement. The elucidation of the distinct effects of each stereogenic center of the allylation intermediates on the stereochemical outcome and chirality transfer in the rearrangement further guided the selection of catalysts combination.

16.
Org Lett ; 21(4): 1191-1196, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30707591

RESUMO

The first example of highly efficient kinetic resolution of exo-3-oxodicyclopentadienes and endo-3-oxodicyclopentadiene has been developed by means of Cu(I)-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylide. Compared with the existing methodologies for those synthetically important optically active convex molecules, the current protocol provides an alternative but more practical approach from the readily available racemic starting materials, which is free from the repetitive reduction/oxidation steps in the enzymatic resolution or the indispensable stoichiometric amount of chirality-induction reagents.

17.
iScience ; 11: 146-159, 2019 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-30612034

RESUMO

Development of a general catalytic and highly efficient method utilizing readily available precursors for the regio- and stereoselective construction of bioactive natural-product-inspired spiro architectures remains a formidable challenge in chemical research. Transition metal-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides produces numerous N-heterocycles, but reaction control with the regioselectivity opposite to the conventional fashion has rarely been demonstrated. Herein, we report a unique ligand-controlled Cu(I)-catalyzed umpolung-type 1,3-dipolar cycloaddition of azomethine ylide to realize efficient kinetic resolution of racemic alkylidene norcamphors with the concomitant construction of previously inaccessible spiro N-heterocycles with high levels of regio- and stereoselectivity. The success of this methodology relies on the strategy of kinetic resolution, and the serendipitous discovery of a unique ligand-enabled regiospecific cycloaddition, which not only provides evidence for the existence of the minor zwitterionic resonance form in metallated azomethine ylide but also diversifies the existing chemistry of azomethine ylide-involved 1,3-dipolar cycloadditions with rare polarity inversion.

18.
J Org Chem ; 83(19): 11814-11824, 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30149707

RESUMO

The mechanism of the Cu(I)/( S, Rp)-PPFOMe-catalyzed 1,3-dipolar cycloaddition of azomethine ylides with fluorinated aldimines has been studied using labeling experiments, control experiments, and linear effect experiments, which clearly ruled out the 1,3-DC/epimerization pathways and explained the unusal exo'-selective stereochemistry. This protocol allows for the preparation of a series of highly functionalized fluorinated imidazolidines in good yields with excellent stereoselectivities. Moreover, the current methods have been successfully extended to synthesize more challenging imidazolidines bearing a CF3-containing quaternary stereogenic center via the endo-selective 1,3-DC of azomethine ylides with trifluorinated ketimine under identical reaction conditions.

19.
Org Lett ; 20(12): 3482-3486, 2018 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-29846076

RESUMO

An efficient kinetic resolution of readily available racemic cyclopentene-1,3-diones has been developed via a Ag(I)-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides. This methodology shows good functional-group tolerance, delivering an array of synthetically valuable cyclopentene-1,3-diones with excellent stereoselectivity and generally high resolution efficiency ( s = 48-226) accompanied by the biologically important fused pyrrolidine derivatives. Notably, this strategy allows facile access to the key intermediates for the synthesis of (+)-madindolines A and B.

20.
Org Biomol Chem ; 16(15): 2591-2601, 2018 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-29560980

RESUMO

Spirocyclic pyrrolidines are structural motifs frequently found in a wide variety of natural products, pharmaceuticals and biologically significant compounds. In the past few years, catalytic asymmetric 1,3-dipolar cycloaddition reactions of azomethine ylides have shown to be one of the most straightforward methods for the stereoselective preparation of diverse biologically important spiropyrrolidine heterocycles in high yields with excellent enantioselectivities under mild reaction conditions. In this review, we will discuss the recent major developments in the catalytic enantioselective synthesis of chiral spiropyrrolidine derivatives since 2009.

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