RESUMO
Kinetic resolution of N-Boc-spirocyclic 2-arylpiperidines with spiro substitution at C-4 was achieved with high enantiomeric ratios using the chiral base n-BuLi/sparteine. Cyclopropanation or metallaphotoredox catalysis were used to access the piperidines, which could be further functionalised without loss of enantiopurity, highlighting their use as potential 3D fragments for drug discovery.
RESUMO
Highly enantiomerically enriched dihydrohydroquinolines were prepared in two steps from quinoline. Addition of aryllithiums to quinoline with tert-butoxycarbonyl (Boc) protection gave N-Boc-2-aryl-1,2-dihydroquinolines. These were treated with n-butyllithium and electrophilic trapping occurred exclusively at C-4 of the dihydroquinoline, a result supported by DFT studies. Variable temperature NMR spectroscopy gave kinetic data for the barrier to rotation of the carbonyl group (ΔG≠ ≈49â kJ mol-1 , 195â K). Lithiation using the diamine sparteine allowed kinetic resolutions with high enantioselectivities (enantiomer ratio up to 99 : 1). The enantioenriched 1,2-dihydroquinolines could be converted to 1,4-dihydroquinolines with retention of stereochemistry. Further functionalisation led to trisubstituted products. Reduction provided enantioenriched tetrahydroquinolines, whereas acid-promoted removal of Boc led to quinolines, and this was applied to a synthesis of the antimalarial compound M5717.
RESUMO
Piperazines are important heterocycles in drug compounds. We report the asymmetric synthesis of arylpiperazines by photocatalytic decarboxylative arylation (metallaphotoredox catalysis) then kinetic resolution using n-BuLi/(+)-sparteine. This gave a range of piperazines with very high enantioselectivities. Further functionalizations gave enantioenriched 2,2-disubstituted piperazines, and either N-substituent can be removed selectively. Late-stage functionalizations of enantioenriched piperazine derivatives were demonstrated, including synthesis of a drug compound with glycogen synthase kinase (GSK)-3ß inhibitor activity with potential for treating Alzheimer's disease.
Assuntos
Doença de Alzheimer , Piperazinas , Humanos , Cinética , Fosforilação , CatáliseRESUMO
The base n-BuLi with sparteine allows a kinetic resolution of N-Boc-2-aryl-4-methylenepiperidines. The 2,2-disubstituted products and recovered starting materials were isolated with high enantiomeric ratios. From VT-NMR spectroscopy and DFT studies, the rate of rotation of the N-Boc group is fast. Lithiation and trapping of the enantioenriched starting materials gave 2,2-disubstituted piperidines with retention of stereochemistry. Functionalization of the 4-methylene group led to a variety of 2,4-disubstituted piperidines without loss of enantiopurity that could be useful building blocks for drug discovery.
Assuntos
Esparteína , Cinética , Espectroscopia de Ressonância Magnética , Piperidinas/química , Esparteína/química , EstereoisomerismoRESUMO
Kinetic resolution of 2-arylindolines (2,3-dihydroindoles) was achieved by treatment of their N-tert-butoxycarbonyl (Boc) derivatives with n-butyllithium and sparteine in toluene at -78 °C followed by electrophilic quench. The unreacted starting materials together with the 2,2-disubstituted products could be isolated with high enantiomer ratios. Variable temperature NMR spectroscopy showed that the rate of Boc rotation was fast (ΔG≠ ≈57â kJ/mol at 195â K). This was corroborated by DFT studies and by inâ situ ReactIR spectroscopy. The enantioenriched N-Boc-2-arylindolines were converted to 2,2-disubstituted products without significant loss in enantiopurity. Hence, either enantiomer of the 2,2-disubstituted products could be obtained with high selectivity from the same enantiomer of the chiral ligand sparteine (one from the kinetic resolution and the other from subsequent lithiation-trapping of the recovered starting material). Secondary amine products were prepared by removing the Boc group with acid to provide a way to access highly enantioenriched 2-aryl and 2,2-disubstituted indolines.
Assuntos
Esparteína , Indóis , Cinética , EstereoisomerismoRESUMO
Janus kinases (JAKs) mediate responses to cytokines, hormones and growth factors in haematopoietic cells1,2. The JAK gene JAK2 is frequently mutated in the ageing haematopoietic system3,4 and in haematopoietic cancers5. JAK2 mutations constitutively activate downstream signalling and are drivers of myeloproliferative neoplasm (MPN). In clinical use, JAK inhibitors have mixed effects on the overall disease burden of JAK2-mutated clones6,7, prompting us to investigate the mechanism underlying disease persistence. Here, by in-depth phosphoproteome profiling, we identify proteins involved in mRNA processing as targets of mutant JAK2. We found that inactivation of YBX1, a post-translationally modified target of JAK2, sensitizes cells that persist despite treatment with JAK inhibitors to apoptosis and results in RNA mis-splicing, enrichment for retained introns and disruption of the transcriptional control of extracellular signal-regulated kinase (ERK) signalling. In combination with pharmacological JAK inhibition, YBX1 inactivation induces apoptosis in JAK2-dependent mouse and primary human cells, causing regression of the malignant clones in vivo, and inducing molecular remission. This identifies and validates a cell-intrinsic mechanism whereby differential protein phosphorylation causes splicing-dependent alterations of JAK2-ERK signalling and the maintenance of JAK2V617F malignant clones. Therapeutic targeting of YBX1-dependent ERK signalling in combination with JAK2 inhibition could thus eradicate cells harbouring mutations in JAK2.
Assuntos
Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Neoplasias/genética , Neoplasias/patologia , Proteína 1 de Ligação a Y-Box/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Células Cultivadas , Células Clonais/metabolismo , Células Clonais/patologia , Feminino , Xenoenxertos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Íntrons/genética , Janus Quinase 2/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Mutação , Transplante de Neoplasias , Neoplasias/tratamento farmacológico , Fosfoproteínas/análise , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteoma/análise , Proteômica , Splicing de RNA/genética , Indução de Remissão , Proteína 1 de Ligação a Y-Box/antagonistas & inibidores , Proteína 1 de Ligação a Y-Box/químicaRESUMO
Quinolinium salts, Q+-CH2-CO2Me Br- and Q+-CH2-CONMe2 Br- (where Q = quinoline), were prepared from quinolines. Deprotonation of these salts with triethylamine promoted the reaction of the resulting quinolinium ylides (formally azomethine ylides) with electron-poor alkenes by conjugate addition followed by cyclization or by [3 + 2] dipolar cycloaddition. The pyrroloquinoline products were formed as single regio- and stereoisomers. These could be converted to other derivatives by Suzuki-Miyaura coupling, reduction or oxidation reactions.
RESUMO
Hepatic stellate cells activate upon liver injury and help at restoring damaged tissue by producing extracellular matrix proteins. A drastic increase in matrix proteins results in liver fibrosis and we hypothesize that this sudden increase leads to accumulation of proteins in the endoplasmic reticulum and its compensatory mechanism, the unfolded protein response. We indeed observe a very early, but transient induction of unfolded protein response genes during activation of primary mouse hepatic stellate cells in vitro and in vivo, prior to induction of classical stellate cell activation genes. This unfolded protein response does not seem sufficient to drive stellate cell activation on its own, as chemical induction of endoplasmic reticulum stress with tunicamycin in 3D cultured, quiescent stellate cells is not able to induce stellate cell activation. Inhibition of Jnk is important for the transduction of the unfolded protein response. Stellate cells isolated from Jnk knockout mice do not activate as much as their wild-type counterparts and do not have an induced expression of unfolded protein response genes. A timely termination of the unfolded protein response is essential to prevent endoplasmic reticulum stress-related apoptosis. A pathway known to be involved in this termination is the non-sense-mediated decay pathway. Non-sense-mediated decay inhibitors influence the unfolded protein response at early time points during stellate cell activation. Our data suggest that UPR in HSCs is differentially regulated between acute and chronic stages of the activation process. In conclusion, our data demonstrates that the unfolded protein response is a JNK1-dependent early event during hepatic stellate cell activation, which is counteracted by non-sense-mediated decay and is not sufficient to drive the stellate cell activation process. Therapeutic strategies based on UPR or NMD modulation might interfere with fibrosis, but will remain challenging because of the feedback mechanisms between the stress pathways.
Assuntos
Estresse do Retículo Endoplasmático/genética , Células Estreladas do Fígado/metabolismo , Cirrose Hepática/metabolismo , MAP Quinase Quinase 4/metabolismo , Resposta a Proteínas não Dobradas/genética , Animais , Apoptose/genética , Linhagem Celular , Células Cultivadas , Retículo Endoplasmático/metabolismo , Células Estreladas do Fígado/efeitos dos fármacos , Cirrose Hepática/patologia , MAP Quinase Quinase 4/antagonistas & inibidores , MAP Quinase Quinase 4/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Degradação do RNAm Mediada por Códon sem Sentido/genética , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismo , Tunicamicina/farmacologiaRESUMO
A cascade or domino sequence of condensation of hydroxylamine and an aldehyde to give an oxime, cyclization to a nitrone, and intramolecular 1,3-dipolar cycloaddition has been successfully employed where there is branching at C-4 as a route to the iboga alkaloids. Cyclization occurs with displacement of chloride as a leaving group and intramolecular cycloaddition occurs with an alkene as a dipolarophile. The reaction gives an azabicyclo[2.2.2]octane product containing a fused isoxazolidine as a single stereoisomer and this was converted to an isoquinuclidine that completed a formal synthesis of the alkaloid (±)-19-hydroxyibogamine.
RESUMO
Treatment of N-Boc-2-aryl-1,2,3,4-tetrahydroquinolines with n-butyllithium in THF at -78 °C resulted in efficient lithiation at the 2-position and the organolithiums were trapped with a variety of electrophiles to give substituted products. Variable temperature NMR spectroscopy gave kinetic data that showed that the rate of tert-butoxycarbonyl (Boc) rotation was fast (ΔG ≈ 45 kJ mol-1 at -78 °C) and in situ ReactIR spectroscopy showed fast lithiation at -78 °C. By carrying out the lithiation in the presence of the chiral ligand sparteine, kinetic resolutions with very high levels of enantioselectivity were achieved. The resulting enantioenriched N-Boc-2-aryltetrahydroquinolines were converted to 2,2-disubstituted products without significant loss in enantiopurity. Most electrophiles add at the 2-position and the chemistry provides a way to access tetrahydroquinolines that are fully substituted alpha to the nitrogen atom. Notably, either enantiomer of the 2,2-disubstituted tetrahydroquinolines can be obtained with high selectivity from the same enantiomer of the chiral ligand. Unusually, when methyl cyanoformate was used as the electrophile, substitution occurred in the ortho position of the aryl ring attached at C-2. This change in regioselectivity on changing the electrophile was probed by deuterium isotope studies and by DFT calculations which suggested that the binding of the cyanoformate altered the structure of the intermediate organolithium. Secondary amine products can be prepared by removing the Boc group with acid or by inducing the Boc group to rearrange to the 2-position in the presence of triethylborane and this carbonyl N-to-C rearrangement occurs with retention of configuration from the intermediate enantiomerically enriched organolithium species.
RESUMO
We report the deprotonation of a chiral nitrile and reaction of the resulting chiral organometallic species with a variety of electrophiles to give highly enantiomerically enriched 2-substituted nitrile products. The nitrile was treated with TMPMgCl and the resulting anion, an asymmetric alpha cyano Grignard species, was found to be configurationally stable at low temperature for a short time (half-life several minutes at -104 °C).
RESUMO
Aliphatic ketones containing a chloride and alkene were heated with hydroxylamine to promote cascade, tandem condensation to oximes, cyclization to nitrones, and 1,3-dipolar cycloaddition to tricyclic isoxazolidines as single stereoisomers. Single regioisomers were obtained when three atoms linked the ketone and dipolarophile to give five-membered rings but mixtures resulted with four atoms in the tether unless a terminal ester was located on the alkene. The N-O bond in the products could be reduced to give spirocyclic amines and diamines.
RESUMO
Simple haloaldehydes, including enolisable aldehydes, were found to be suitable for the formation of cyclic products by cascade (domino) condensation, cyclisation, dipolar cycloaddition chemistry. This multi-component reaction approach to heterocyclic compounds was explored by using hydroxylamine, a selection of aldehydes, and a selection of activated dipolarophiles. Initial condensation gives intermediate oximes that undergo cyclisation with displacement of halide to give intermediate nitrones; these nitrones undergo in situ intermolecular dipolar cycloaddition reactions to give isoxazolidines. The cycloadducts from using dimethyl fumarate were treated with zinc/acetic acid to give lactam products and this provides an easy way to prepare pyrrolizinones, indolizinones, and pyrrolo[2,1-a]isoquinolinones. The chemistry is illustrated with a very short synthesis of the pyrrolizidine alkaloid macronecine and a formal synthesis of petasinecine.
Assuntos
Óxidos de Nitrogênio/química , Oximas/química , Oximas/síntese química , Alcenos/química , Ciclização , Reação de CicloadiçãoRESUMO
Substituted N-tert-butoxycarbonyl (Boc)-1,2,3,4-tetrahydroisoquinolines were prepared and treated with n-butyllithium in THF at -50 °C to test the scope of the metallation and electrophilic quench. The lithiation was optimised by using in situ ReactIR spectroscopy and the rate of rotation of the carbamate was determined. The 1-lithiated intermediates could be trapped with a variety of electrophiles to give good yields of 1-substituted tetrahydroisoquinoline products. Treatment with acid or reduction with LiAlH4 allows conversion to the N-H or N-Me compound. The chemistry was applied to the efficient total syntheses of the alkaloids (±)-crispine A and (±)-dysoxyline.
Assuntos
Lítio/química , Tetra-Hidroisoquinolinas/química , Tetra-Hidroisoquinolinas/síntese química , Técnicas de Química SintéticaRESUMO
During efforts to prepare the known compound , a new tetracyclic compound, called VG1, was prepared in six steps. This compound was found to have good activity as an inhibitor of nonsense-mediated mRNA decay.
Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Degradação do RNAm Mediada por Códon sem Sentido/efeitos dos fármacos , RNA Mensageiro/metabolismo , Relação Dose-Resposta a Droga , Compostos Heterocíclicos de 4 ou mais Anéis/química , Estrutura MolecularRESUMO
A method to prepare 1-substituted N-Boc-tetrahydro-ß-carbolines was developed by lithiation followed by electrophilic substitution. The deprotonation to give the organolithium was optimized by in situ IR spectroscopy and showed that the Boc group rotates slowly at low temperature. The chemistry was applied to the synthesis of 9-methyleleagnine (N-methyltetrahydroharman) and 11-methylharmicine.
Assuntos
Carbolinas/química , Harmina/análogos & derivados , Alcaloides Indólicos/síntese química , Lítio/química , Compostos Organometálicos/química , Harmina/síntese química , Harmina/química , Alcaloides Indólicos/química , Espectrofotometria Infravermelho , EstereoisomerismoRESUMO
An efficient synthetic approach to the core structure of the manzamine alkaloids is reported, particularly in relation to incorporating a one-carbon unit in ring B from which the aldehyde in ircinal A or the beta-carboline unit in manzamine A could potentially be generated. The key steps involve a Johnson-Claisen rearrangement, enolate alkylation, dithiane alkylation and a stereoselective intramolecular dipolar cycloaddition of an azomethine ylide, which provided the desired tricyclic ABC core structure.
Assuntos
Carbazóis/síntese química , Carbazóis/química , Cristalografia por Raios X , Modelos Moleculares , Estrutura MolecularRESUMO
The chiral base n-BuLi/(-)-sparteine or n-BuLi/(+)-sparteine surrogate promotes kinetic resolution of N-Boc-2-arylpiperidines by asymmetric deprotonation. The enantioenriched starting material was recovered with yields 39-48% and ers up to 97 : 3. On lithiation then electrophilic quench, 2,2-disubstituted piperidines were obtained with excellent yields and enantioselectivities.
Assuntos
Compostos Organometálicos/química , Piperidinas/síntese química , Esparteína/química , Cinética , Piperidinas/química , EstereoisomerismoRESUMO
Lithiation of N-Boc-1-phenyltetrahydroisoquinolines was optimized by in situ IR spectroscopy. The kinetics for rotation of the carbamate group and for the enantiomerization of the organolithium were determined. The organolithium is configurationally stable at low temperature, and the asymmetric synthesis of 1,1-disubstituted tetrahydroisoquinolines can be achieved with high yields and high enantiomer ratios. The chemistry was applied to the preparation of FR115427 and provides a way to recycle the undesired enantiomer in the synthesis of solifenacin.
Assuntos
Lítio/química , Espectrofotometria Infravermelho/métodos , Tetra-Hidroisoquinolinas/síntese química , Tetra-Hidroisoquinolinas/químicaRESUMO
The addition of BuLi, Bu3MgLi, Et2ZnBuLi, or Me2CuLi to α-arylthioalkanenitriles triggers an arylthio-metal exchange. NMR spectroscopic analyses implicate organometallic attack on sulfur forming a three-coordinate sulfidate as the key intermediate. Electrophilic trapping affords tertiary and quaternary nitriles in high yield. The method addresses the challenge of improving the functional group tolerance and preventing polyalkylations.