RESUMO
Visible-light-promoted radical (phenylsulfonyl)methylation reactions of electron-rich heteroarenes and N-arylacrylamides have been developed starting from bromomethyl phenyl sulfone derivatives. This method provides a mild and efficient access to various (phenylsulfonyl)methylated compounds.
RESUMO
A simple and efficient visible-light-promoted method for the C-3 thiocyanation of indoles has been developed. The transformation uses Rose Bengal as the photocatalyst and air as the terminal oxidant. The reaction is mild, high-yielding, and environmentally benign.
Assuntos
Indóis/química , Oxidantes/química , Tiocianatos/química , Ar , Luz , Metais/química , Processos FotoquímicosRESUMO
The synthesis of 2-substituted benzothiazoles has been achieved via cyclization of o-iodothiobenzanilide derivatives using Pd/C as the catalyst at room temperature. The protocol is ligand-free, additive-free, and high-yielding and involves very mild conditions.
RESUMO
Secondary enaminones were oxidized by photochemically generated singlet oxygen, followed by nucleophilic addition of alcohol and an unexpected 1,2-acyl migration to afford quaternary amino acid derivatives. An ene-type reaction pathway is proposed. It is distinctively different from the typical [2+2] addition of singlet oxygen to a C=C bond pathway.
RESUMO
Radical chemistry! A visible-light-promoted, tin/boron-free intermolecular [3+2] atom-transfer radical cyclization reaction was developed by using iridium polyphenylpridinyl complex as the sensitizer. 2-(Iodomethyl)cyclopropane-1,1-dicarboxylate reacted with various alkenes and alkynes to form cyclopentane and cyclopentene derivatives.
RESUMO
A visible light-promoted atom transfer Ueno-Stork reaction was developed using Ir(ppy)2(dtb-bpy)PF6 as the sensitizer. 2-Iodoethyl propargyl ethers or 2-iodoethyl allyl ethers were used as the radical precursors to construct tetrahydrofuran-containing fused [6,5] and [5,5] bicyclic frameworks.
Assuntos
Éteres/química , Furanos/síntese química , Luz , Fármacos Fotossensibilizantes/química , Cristalografia por Raios X , Ciclização , Furanos/química , Modelos Moleculares , Estrutura Molecular , Oxirredução , Processos FotoquímicosRESUMO
Ustiloxins A-F are antimitotic heterodetic cyclopeptides containing a 13-membered cyclic core structure with a synthetically challenging chiral tertiary alkyl-aryl ether linkage. The first total synthesis of ustiloxin D was achieved in 31 linear steps using an S(N)Ar reaction. An NOE study of this synthetic product showed that ustiloxin D existed as a single atropisomer. Subsequently, highly concise and convergent syntheses of ustiloxins D and F were developed by utilizing a newly discovered ethynyl aziridine ring-opening reaction in a longest linear sequence of 15 steps. The approach was further optimized to achieve a better macrolactamization strategy. Ustiloxins D, F, and eight analogues (14-MeO-ustiloxin D, four analogues with different amino acid residues at the C-6 position, and three (9R,10S)-epi-ustiloxin analogues) were prepared via the second-generation route. Evaluation of these compounds as inhibitors of tubulin polymerization demonstrated that variation at the C-6 position is tolerated to a certain extent. In contrast, the S configuration of the C-9 methylamino group and a free phenolic hydroxyl group are essential for inhibition of tubulin polymerization.
Assuntos
Micotoxinas/síntese química , Peptídeos Cíclicos/síntese química , Moduladores de Tubulina/síntese química , Isomerismo , Modelos Moleculares , Ressonância Magnética Nuclear BiomolecularRESUMO
An unprecedented stereo- and regioselective trisubstituted aziridine ring-opening by phenol derivatives was discovered. The reaction features very mild reaction conditions and broad functional group compatibility, which provides a good method for the stereoselective formation of tertiary alkyl-aryl ethers in highly functionalized systems. [reaction: see text]
Assuntos
Aziridinas/química , Éteres/síntese química , Fenóis/química , Catálise , Estrutura Molecular , EstereoisomerismoRESUMO
[reaction: see text] The ustiloxins are a family of heterodetic cyclopeptides that have been isolated from the water extracts of false smut balls on the panicles of rice plants caused by the fungus Ustilaginoidea virens. A concise total synthesis of ustiloxin D has been achieved via an unprecedented ethynyl aziridine ring-opening of phenol derivatives. The longest linear sequence of the synthesis is 15 steps from commercially available compounds.
Assuntos
Cobre/química , Micotoxinas/síntese química , Peptídeos Cíclicos/síntese química , Aziridinas/química , Catálise , Ciclização , Estrutura Molecular , Fenóis/químicaRESUMO
A mild and high-yielding visible-light-promoted conversion of alkyl benzyl ethers to the alkyl esters or alkyl alcohols was developed. Mechanistic studies provided evidence for a radical chain reaction involving the homolytic cleavage of O-α-sp(3) C-H bonds in the substrate as one of the propagation steps. We propose that α-bromoethers are key intermediates in the transformation.
RESUMO
[reaction: see text] Reaction of 1,4-dilithio-1,3-diene derivatives with 2 equiv of aldehydes affords polysubstituted 2,5-dihydrofurans in good to high yields with perfect regio- and stereoselectivities. Hexa-2,4-diene-1,6-dialcoholates are proposed as the first intermediates, which undergo a cyclization and subsequent elimination of Li(2)O to generate the 2,5-dihydrofuran derivatives.
Assuntos
Furanos/síntese química , Fatores Biológicos/síntese química , Butadienos/química , Cristalografia por Raios X , Ciclização , Lítio/química , Estrutura Molecular , Compostos Organometálicos/química , EstereoisomerismoRESUMO
Direct arylation of unactivated arenes or heteroarenes with aryl halides could be carried out in the presence of potassium tert-butoxide and dimethyl sulfoxide under visible-light irradiation. Ir(ppy)3 was found to be an effective photoredox catalyst for this reaction. The reactions of aryl iodides occurred at room temperature. Elevated temperature was required for aryl bromides. Homolytic aromatic substitution was proposed to be the operative reaction pathway.
Assuntos
Hidrocarbonetos Halogenados/química , Paládio/química , Catálise , Luz , Processos Fotoquímicos , TemperaturaRESUMO
A visible-light photoredox synthesis of α-amino amide or α-amino thioamide from N,N-dimethylaniline derivatives and aryl isocyanate or aryl isothiocyanate was developed. Bis[2-(4,6-difluorophenyl)pyridinato-C(2),N](picolinato)iridium(III) (FIrpic) was found to be the effective catalyst among six catalysts screened. The reaction involves generation of α-aminoalkyl radicals from tertiary amines, followed by radical addition to the electron-deficient carbon of isocyanate and isothiocyanate.
RESUMO
Rho kinases (ROCK1 and ROCK2) belong to serine/threonine (Ser/Thr) protein kinase family, and play the central roles in the organization of the actin cytoskeleton. Therefore, Rho kinases have become attractive targets for the treatments of many diseases, such as cancer, renal disease, hypertension, ischemia, and stroke. In order to develop small-molecule inhibitors of ROCK1, molecular docking was utilized to virtually screen two chemical databases and identify molecules that interact with ROCK1. A small set of virtual hits was purchased and submitted to a series of experimental assays. The in vitro enzyme-based and cell-based assays reveal that 12 compounds have good inhibitory activity against ROCK1 in the micro molar regime (IC50 values between about 7 and 28 µM) and antitumor activity against lung cancer, breast cancer or/and myeloma cell lines. The structural analysis shows that two active compounds present novel scaffolds and are potential leads for the development of novel anti-cancer drugs. We then characterized the interaction patterns between ROCK1 and two inhibitors with novel scaffolds by molecular dynamics (MD) simulations and free energy decomposition analysis. In addition, the pharmacological effect of the two ROCK1 inhibitors with novel scaffolds on atorvastatin-induced cerebral hemorrhage was evaluated by using zebrafish model, and one compound candidate is able to prevent atorvastatin-induced cerebral hemorrhage effectively.
Assuntos
Antineoplásicos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/farmacologia , Quinases Associadas a rho/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Atorvastatina , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Hemorragia Cerebral/induzido quimicamente , Hemorragia Cerebral/tratamento farmacológico , Feminino , Células HeLa , Ácidos Heptanoicos/farmacologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Modelos Moleculares , Simulação de Dinâmica Molecular , Estrutura Molecular , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Pirróis/farmacologia , Peixe-Zebra , Quinases Associadas a rho/metabolismoRESUMO
An aerobic visible-light driven photoredox catalytic formation of 2-substituted benzothiazoles through radical cyclization of thioanilides has been accomplished. The reaction features C-H functionalization and C-S bond formation with no direct metal involvement except the sensitizer. The reaction highlights the following: (1) visible-light is the reaction driving force; (2) molecular oxygen is the terminal oxidant, and (3) water is the only byproduct.
RESUMO
A thorough investigation of a regio- and stereospecific aziridine ring opening reaction presents new synthetic technology for the construction of a variety of quaternary beta-substituted-alpha-amino functional groups. Mild, metal-free reaction conditions allow for application in highly functionalized systems. This reaction has been applied to the challenging stereoselective formation of tertiary alkyl-aryl ethers. The strategy for the formation of these hindered ethers has been investigated using a variety of functionalized aziridines and phenols to determine the scope of the reaction. Other nucleophiles, such as thiolate, azide, and chloride, have also been examined to encompass the synthesis of a broader range of functionalities. This aziridine ring opening reaction manifold has demonstrated utility in assembling: beta-substituted-alpha-amino carboxamides, beta-substituted-alpha-amino esters, beta-substituted-alpha-amino silyl ethers, beta-thio-alpha-amino carboxamides, beta-azido-alpha-amino carboxamides, and beta-halo-alpha-amino carboxamides. Studies to probe the effect of the aziridine substitution patterns show that alkyl aziridines display similar reactivity to alkynyl aziridines, giving insight into mechanistic possibilities.
Assuntos
Amidas/síntese química , Aziridinas/química , Éteres/síntese química , Alcanos/química , Alcinos/química , Aminas/química , Azidas/química , Hidrocarbonetos Halogenados/química , Modelos Químicos , Silanos/química , Estereoisomerismo , Compostos de Sulfidrila/químicaRESUMO
Synthetic investigations of ustiloxin natural products are described. The first total synthesis of ustiloxin F was completed in 15 steps via ethynyl aziridine ring-opening by a phenol derivative. The results of biological tests of synthetic ustiloxins D and F, and two analogs, O-Me-ustiloxin D and 6-Ile-ustiloxin, demonstrated that the free hydroxyl group ortho to the ether linkage is critical for activity and variations at the Val/Ala site produce changes in the biological activity suggesting the need for further perturbations at this site to more extensively study the tubulin binding.
Assuntos
Produtos Biológicos/síntese química , Produtos Biológicos/farmacologia , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/farmacologia , Produtos Biológicos/química , Linhagem Celular Tumoral , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Micotoxinas/química , Peptídeos Cíclicos/química , Tubulina (Proteína)/metabolismoRESUMO
One-pot procedures for the preparation of highly substituted indenes, tetrahydroindenes, and cyclopentadienes have been developed by using a combination of zirconocene-mediated Cbond;C-bond-forming reactions with Lewis acid mediated activation of carbonyl groups. The carbonyl groups of aldehydes were deoxygenated in the reaction and behaved formally as a one-carbon unit. A variety of Lewis acids were checked and showed different reactivities in this reaction.