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1.
J Org Chem ; 88(15): 10682-10692, 2023 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-37440309

RESUMO

We report a simple and environmentally friendly method for synthesizing N-containing heterocycles via a visible-light-mediated aerobic dehydrogenation reaction. Using a nontoxic, stable, and inexpensive titanium dioxide catalyst, a variety of substituted quinoline, indole, quinoxaline, and 3,4-dihydroisoquinoline derivatives could be synthesized using the green oxidant molecular oxygen. Improved reactivity and scalability of this reaction were demonstrated by adapting the photochemical multiphasic reaction to a continuous flow system. To gain insight into the mechanism, we also conducted several mechanistic studies, including absorption analysis, light on-off testing, and NMR analysis. Especially, oxygen is reduced to hydrogen peroxide, and dimethyl sulfoxide is a critical scavenger of the oxidant byproduct for ensuring high yields.

2.
J Org Chem ; 88(1): 585-593, 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36538655

RESUMO

An efficient, tandem one-pot approach to synthesize multisubstituted 2-acylpyrroles from readily prepared N-tosyl triazoles and 2-hydroxymethylallyl carbonates is reported. The reaction proceeds via Rh(II)-catalyzed O-H insertion, [3,3]-sigmatropic rearrangement, Pd(0)-catalyzed oxidative addition, intramolecular cyclization, DBU-promoted E1cB elimination, double bond isomerization, and aromatization, enabling the disconnection and formation of multiple bonds in one reactor. The approach represents a highly regioselective way to access di-, tri-, and tetra-substituted NH pyrroles with high efficiency.

3.
Pharmaceutics ; 14(11)2022 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-36432671

RESUMO

L-α-Glycerylphosphorylcholine (L-α-GPC) has mainly been produced by two methods: extraction from plants rich in phosphatidylcholine and chemical synthesis. However, production through extraction involves difficult processes, such as fermentation, extractions and ripening, and conventional chemical synthesis methods with high-cost reactants and a batch reactor. These methods are not ideal for large-quantity production. Thus, it is important to develop a simple production method of L-α-GPC, which is suitable for mass production without the need for expensive reactants. Here, we studied synthetic L-α-GPC methods that are applicable to a flow synthesis system, which can provide selectivity, reproducibility, scalability, and a high yield in short reaction time using inexpensive starting materials. We developed a two-step synthetic route to produce L-α-GPC, including the synthesis of phosphoryl choline using choline chloride and phosphoryl oxychloride (POCl3) as a first step and synthesis of L-α-GPC by reacting phosphoryl choline with (R)-(-)-3-chloro-1,2-propanediol (CPD) as a second step under basic conditions. Both steps were separately performed in a customized flow reactor, and reaction conditions were optimized. Finally, phosphoryl choline and L-α-GPC, the products first and second reactions, were successfully synthesized with high conversion yields of 97% and 79%, respectively.

4.
Org Lett ; 23(19): 7467-7471, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34523938

RESUMO

Facile construction of a meta-(indol-3-yl)phenol framework with a wide substrate scope (a total of 25 compounds) via a palladium(II)-catalyzed oxidative Heck reaction and dehydrogenative aromatization in a one-step sequence is reported. This methodology affords a novel route for the privileged structures that are challenging to access via a direct link between indole and phenol, in a highly efficient and atom-economical manner.

5.
Chem Commun (Camb) ; 56(19): 2873-2876, 2020 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-32037420

RESUMO

This study presents a controllable one-pot synthesis for constructing valuable scaffolds (alcohols, 2,3-dihydrofurans, α-cyano-γ-butyrolactones, and γ-butyrolactones) via a visible-light photoredox-catalyzed Giese reaction and further transformation. This one-pot reaction can selectively synthesize the desired scaffold in excellent yields with good functional group tolerance. To further highlight the broad applicability of this controllable one-pot reaction, we have established flow reaction conditions with short reaction times for the scale-up of each scaffold and demonstrated the further transformation of 2,3-dihydrofurans and α-cyano-γ-butyrolactones to achieve scaffold diversity for applications in drug discovery.

6.
J Org Chem ; 85(5): 3234-3244, 2020 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-31895983

RESUMO

We report a visible light-mediated flow process for C-N cross-coupling of (hetero)aryl halides with a variety of amine coupling partners through the use of a photoredox/nickel dual catalyst system. Compared to the method in batch, this flow process enables a broader substrate scope, including less-activated (hetero)aryl bromides and electron-deficient (hetero)aryl chlorides, and significantly reduced reaction times (10 to 100 min). Furthermore, scale up of the reaction, demonstrated through the synthesis of tetracaine, is easily achieved, delivering the C-N cross-coupled products in consistently high yield of 84% on up to a 10 mmol scale.


Assuntos
Sais , Tetracaína , Aminação , Catálise , Luz
7.
J Org Chem ; 84(16): 10012-10023, 2019 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-31322349

RESUMO

A total of 47 flavanones were expediently synthesized via one-pot ß-arylation of chromanones, a class of simple ketones possessing chemically unactivated ß sites, with arylboronic acids via tandem palladium(II) catalysis. This reaction provides a novel route to various flavanones, including natural products such as naringenin trimethyl ether, in yields up to 92%.


Assuntos
Ácidos Borônicos/química , Cromonas/química , Flavanonas/síntese química , Paládio/química , Catálise , Flavanonas/química , Estrutura Molecular , Estereoisomerismo
8.
Eur J Med Chem ; 180: 253-267, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31310917

RESUMO

Herein, we address repurposing hybrids of mosloflavone or 5,6,7-trimethoxyflavone with amide analogs of resveratrol from anticancer leads to novel potent anti-inflammatory chemical entities. To unveil the potent anti-inflammatory molecules, biological evaluations were initiated in LPS-induced RAW 264.7 macrophages at 1 µM concentration. Promising compounds were further evaluated at various concentrations. Multiple proinflammatory mediators were assessed including NO, PGE2, IL-6, TNF-α and IL-1ß. Compound 5z inhibited the induced production of NO, PGE2, IL-6, TNF-α and IL-1ß at the low 1 µM concentration by 44.76, 35.71, 53.48, 29.39 and 41.02%, respectively. Compound 5z elicited IC50 values as low as 2.11 and 0.98 µM against NO and PGE2 production respectively. Compounds 5q and 5g showed potent submicromolar IC50 values of 0.31 and 0.59 µM respectively against PGE2 production. Reverse docking of compound 5z suggested p38-α MAPK, which is a key signaling molecule within the pathways controlling the transcription of proinflammatory mediators, as the molecular target. Biochemical testing confirmed these compounds as p38-α MAPK inhibitors explaining its potent inhibition of proinflammatory mediators' production. Collectively, the results presented 5z as a promising compound for further development of anti-inflammatory agents for treatment of macrophages-and/or immune mediated inflammatory diseases.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Flavonas/farmacologia , Flavonoides/farmacologia , Mediadores da Inflamação/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Resveratrol/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Relação Dose-Resposta a Droga , Descoberta de Drogas , Flavonas/química , Flavonoides/química , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Células RAW 264.7 , Resveratrol/química , Relação Estrutura-Atividade , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
9.
Prostaglandins Other Lipid Mediat ; 144: 106347, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31229523

RESUMO

We previously reported the strong inhibitory potency of N-phenyl-N'-(4- benzyloxyphenoxycarbonyl)-4-chlorophenylsulfonyl hydrazide (PBCH) on lipopolysaccharide (LPS)-induced prostaglandin E2 (PGE2) production in macrophages. Herein, we characterized PBCH as a microsomal prostaglandin E synthase-1 (mPGES-1) inhibitor and evaluated its anti-inflammatory effects using in vivo experimental models. PBCH inhibited PGE2 production in various activated cells in addition to inhibiting the mPGES-1 activity. In the ear edema and paw edema rat models, PBCH significantly reduced ear thickness and paw swelling, respectively. Besides, in adjuvant-induced arthritis (AIA) rat model, PBCH decreased paw swelling, plasma rheumatoid factor (RF), and receptor activator of nuclear factor kappa-B ligand (RANKL)/osteoprotegerin (OPG) ratio. Furthermore, while PBCH reduced the plasma prostaglandin E metabolite (PGEM) levels, it did not affect the plasma levels of prostacyclin (PGI2) and thromboxane A2 (TXA2). Our data suggest that PBCH downregulates PGE2 production by interfering with the mPGES-1 activity, thus reducing edema and arthritis in rat models.


Assuntos
Anti-Inflamatórios/farmacologia , Dinoprostona/metabolismo , Regulação para Baixo/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Hidrazinas/farmacologia , Prostaglandina-E Sintases/antagonistas & inibidores , Tiazóis/farmacologia , Células A549 , Animais , Anti-Inflamatórios/uso terapêutico , Dinoprostona/biossíntese , Modelos Animais de Doenças , Inibidores Enzimáticos/uso terapêutico , Humanos , Hidrazinas/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Camundongos , Células RAW 264.7 , Ratos , Ratos Sprague-Dawley , Tiazóis/uso terapêutico
10.
Science ; 354(6310)2016 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-27846504

RESUMO

α-Olefins are the most abundant petrochemical feedstock beyond alkanes, yet their use in commodity chemical manufacture is largely focused on polymerization and hydroformylation. The development of byproduct-free catalytic C-C bond-forming reactions that convert olefins to value-added products remains an important objective. Here, we review catalytic intermolecular reductive couplings of unactivated and activated olefin-derived nucleophiles with carbonyl partners. These processes represent an alternative to the longstanding use of stoichiometric organometallic reagents in carbonyl addition.

11.
J Org Chem ; 81(18): 8585-94, 2016 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-27580269

RESUMO

Osmium(0) complexes derived from Os3(CO)12 and XPhos (2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl) catalyze the C-C coupling of α-hydroxy esters 1a-1i, α-ketols 1j-1o, or 1,2-diols dihydro-1j-1o with ethylene 2a to form ethylated tertiary alcohols 3a-3o. As illustrated in couplings of 1-octene 2b with vicinally dioxygenated reactants 1a, 1b, 1i, 1j, 1k, 1m, higher α-olefins are converted to adducts 4a, 4b, 4i, 4j, 4k, 4m with complete levels of branched regioselectivity. Oxidation level independent C-C coupling is demonstrated by the reaction of 1-octene 2b with diol dihydro-1k, α-ketol 1k, and dione dehydro-1k. Functionalized olefins 2c-2f react with ethyl mandelate 1a to furnish adducts 5a-8a as single regioisomers. The collective data, including deuterium labeling studies, are consistent with a catalytic mechanism involving olefin-dione oxidative coupling to form an oxa-osmacyclopentane, which upon reductive cleavage via hydrogen transfer from the secondary alcohol reactant releases the product of carbinol C-alkylation with regeneration of the ketone. Single-crystal X-ray diffraction data of the dinuclear complex Os2(CO)4(O2CR)2(XPhos)2 and the trinuclear complex Os3(CO)11(XPhos) are reported. These studies suggest increased π-backbonding at the stage of the metal-olefin π-complex plays a critical role in facilitating alkene-carbonyl oxidative coupling, as isostructural ruthenium(0) complexes, which are weaker π-donors, do not catalyze the transformations reported herein.


Assuntos
Alcenos/química , Etilenos/química , Osmio/química , Catálise , Cristalografia por Raios X , Ésteres/química , Hidrogenação , Análise Espectral/métodos
12.
J Am Chem Soc ; 137(24): 7652-5, 2015 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-26066660

RESUMO

A strategy for catalytic vinyl transfer from enol carboxylates to activated secondary alcohol C-H bonds is described. Using XPhos-modified ruthenium(0) or osmium(0) complexes, enol carboxylate-carbonyl oxidative coupling forms transient ß-acyloxy-oxametallacycles, which eliminate carboxylate to deliver allylic ruthenium(II) or osmium(II) alkoxides. Reduction of the metal(II) salt via hydrogen transfer from the secondary alcohol reactant releases the product of carbinol C-H vinylation and regenerates ketone and zero-valent catalyst.


Assuntos
Álcoois/química , Ácidos Carboxílicos/química , Osmio/química , Rutênio/química , Compostos de Vinila/química , Catálise , Complexos de Coordenação/química , Hidrogenação
13.
J Am Chem Soc ; 136(34): 11902-5, 2014 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-25075434

RESUMO

The cationic ruthenium catalyst generated upon the acid-base reaction of H2Ru(CO)(PPh3)3 and 2,4,6-(2-Pr)3PhSO3H promotes the redox-triggered C-C coupling of 2-alkynes and primary alcohols to form (Z)-homoallylic alcohols with good to complete control of olefin geometry. Deuterium labeling studies, which reveal roughly equal isotopic compositions at the allylic and distal vinylic positions, along with other data, corroborate a catalytic mechanism involving ruthenium(0)-mediated allene-aldehyde oxidative coupling to form a transient oxaruthenacycle, an event that ultimately defines (Z)-olefin stereochemistry.


Assuntos
Alcinos/química , Compostos Alílicos/química , Compostos Organometálicos/química , Propanóis/química , Rutênio/química , Álcoois/química , Catálise , Estrutura Molecular , Oxirredução , Estereoisomerismo
14.
J Am Chem Soc ; 135(44): 16320-3, 2013 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-24156560

RESUMO

Heteroaromatic secondary alcohols react with isoprene to form products of hydrohydroxyalkylation in the presence of ruthenium(0) catalysts generated from Ru3(CO)12 and tricyclohexylphosphine, enabling direct conversion of secondary to tertiary alcohols in the absence of premetalated reagents or stoichiometric byproducts. The putative oxaruthenacycle intermediate has been isolated and characterized, and reversible metallacycle formation has been demonstrated.


Assuntos
Álcoois/química , Butadienos/química , Hemiterpenos/química , Compostos Organometálicos/química , Pentanos/química , Rutênio/química , Álcoois/síntese química , Alquilação , Catálise , Compostos Heterocíclicos/química , Hidrocarbonetos Aromáticos/química , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/isolamento & purificação
15.
J Am Chem Soc ; 134(27): 11100-3, 2012 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-22734694

RESUMO

Upon exposure of acrylic ester 1 to alcohols 2a-i in the presence of a cyclometalated iridium catalyst modified by (-)-TMBTP, catalytic C-C coupling occurs, providing enantiomerically enriched 5-substituted α-exo-methylene γ-butyrolactones 3a-i. Bromination of the methylene butyrolactone products followed by zinc-mediated reductive aldehyde addition provides the disubstituted α-exo-methylene γ-butyrolactones 6a and 6b with good to excellent levels of diastereoselectivity.


Assuntos
4-Butirolactona/análogos & derivados , Álcoois/química , Compostos Alílicos/química , Irídio/química , 4-Butirolactona/síntese química , 4-Butirolactona/química , Catálise , Hidrogenação , Estereoisomerismo
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