RESUMO
Cyclopropane fusion of the only rotatable carbon-carbon bond in furanosyl nucleosides (i.e., exocyclic 4'-5') is a powerful design strategy to arrive at conformationally constrained analogues. Herein, we report a direct stereodivergent route toward the synthesis of the four possible configurations of 4-spirocyclopropane furanoses, which have been transformed into the corresponding 4'-spirocyclic adenosine analogues. The latter showed differential inhibition of the protein methyltransferase PRMT5-MEP50 complex, with one analogue inhibiting more effectively than adenosine itself, demonstrating the utility of rationally probing 4'-5' side chain orientations.
Assuntos
Adenosina , Nucleosídeos , CatáliseRESUMO
The stereoselective reduction of carbonyls is of key importance in the total synthesis of natural products and in medicinal chemistry. Nevertheless, models for rationalizing the stereoselectivity of the hydride reductions of cyclobutanones toward cyclobutanols are largely lacking, unlike cyclohexanone reductions. In order to elucidate the factors that control the stereoselectivity of these reductions, we have investigated the effect of the reaction temperature, solvent, substituent, and type of reducing agent using a synergistic experimental-computational approach. On the experimental side, the hydride reduction of 3-substituted cyclobutanones was proven to be highly selective for the formation of cis alcohol (>90%), irrespective of the size of the hydride reagent. The pronounced selectivity can be further enhanced by lowering the reaction temperature or decreasing the solvent polarity. On the computational side, density functional theory and noncovalent interaction analysis reveal that torsional strain plays a major role in the preference for the antifacial hydride approach, consistent with the Felkin-Anh model. In the presence of the benzyloxy substituent, the high selectivity for the cis isomer is also driven by repulsive electrostatic interactions in the case of a syn-facial hydride attack. The computed cis/trans ratios are in good agreement with the experimental ones and thus show the potential of computational chemistry for predicting and rationalizing the stereoselectivity of hydride reductions of cyclobutanones.
RESUMO
A novel class of substituted spiro[3.4]octanes can be accessed via a [2 + 2]-cycloaddition of dichloroketene on a readily prepared exo-methylene cyclopentane building block. This reaction sequence was found to be robust on a multigram scale and afforded a central spirocyclobutanone scaffold for carbocyclic nucleosides. The reactivity of this constrained building block was evaluated and compared to the corresponding 4'-spirocyclic furanose analogues. Density functional theory calculations were performed to support the observed selectivity in the carbonyl reduction of spirocyclobutanone building blocks. Starting from novel spirocyclic intermediates, we exemplified the preparation of an undescribed class of carbocyclic nucleoside analogues and provided a proof of concept for application as inhibitors for the protein methyltransferase target PRMT5.
Assuntos
Ciclopentanos , Nucleosídeos , Reação de CicloadiçãoRESUMO
The importance of axially chiral biaryls has risen steeply in the recent decades. This structural motif proved to be successful in catalytic asymmetric synthesis and the configuration of the biaryl axis is decisive for the biological activity. A new approach for the atroposelective synthesis of biaryls would be through a cycloaddition between an enantiopure phenyl-substituted thiophene S-oxide and an alkyne. Importantly, the chiral center of the thiophene S-oxide needs to be stable enough to avoid pyramidal inversion during the cycloaddition. Considering that the racemization of thiophene monoxides has been scarcely investigated so far, we perform a thorough quantum chemical study on the inversion barriers of a large number of chiral thiophene S-oxide derivatives. Our main goal is to identify substitution patterns leading to stable atropisomers at room temperature. Appealingly, the role of stereoelectronic effects and the position of the substituents as well as the importance of aromaticity on the pyramidal inversion barrier are elucidated for the first time.
RESUMO
Despite the large variety of modified nucleosides that have been reported, the preparation of constrained 4'-spirocyclic adenosine analogues has received very little attention. We discovered that the [2+2]-cycloaddition of dichloroketene on readily available 4'-exo-methylene furanose sugars efficiently results in the diastereoselective formation of novel 4'-spirocyclobutanones. The reaction mechanism was investigated via density functional theory (DFT) and found to proceed either via a non-synchronous or stepwise reaction sequence, controlled by the stereochemistry at the 3'-position of the sugar substrate. The obtained dichlorocyclobutanones were converted into nucleoside analogues, providing access to a novel class of chiral 4'-spirocyclobutyl adenosine mimetics in eight steps from commercially available sugars. Assessment of the biological activity of designed 4'-spirocyclic adenosine analogues identified potent inhibitors for protein methyltransferase target PRMT5.
Assuntos
Adenosina/química , Nucleosídeos/análogos & derivados , Nucleosídeos/síntese química , Carboidratos/química , Reação de Cicloadição , Teoria da Densidade Funcional , Dicloroetilenos/química , Glicosilação , Metais/química , Estrutura Molecular , Oxirredução , Estereoisomerismo , TermodinâmicaRESUMO
Short alphahelical peptide sequences were stabilized through Glaser-Hay couplings of propargylated l- and/or d-serine residues at positions i and i+7. NMR analysis confirmed a full stabilization of the helical structure when a d-Ser (i), l-Ser (i+7) combination was applied. In case two l-Ser residues were involved in the cyclization, the helical conformation is disrupted outside the peptide's macrocycle.
Assuntos
Di-Inos/química , Peptídeos/química , Sequência de Aminoácidos , Conformação Proteica em alfa-Hélice , Estabilidade Proteica , EstereoisomerismoRESUMO
The Mycobacterium tuberculosis rv2466c gene encodes an oxidoreductase enzyme annotated as DsbA. It has a CPWC active-site motif embedded within its thioredoxin fold domain and mediates the activation of the prodrug TP053, a thienopyrimidine derivative that kills both replicating and nonreplicating bacilli. However, its mode of action and actual enzymatic function in M. tuberculosis have remained enigmatic. In this study, we report that Rv2466c is essential for bacterial survival under H2O2 stress. Further, we discovered that Rv2466c lacks oxidase activity; rather, it receives electrons through the mycothiol/mycothione reductase/NADPH pathway to activate TP053, preferentially via a dithiol-disulfide mechanism. We also found that Rv2466c uses a monothiol-disulfide exchange mechanism to reduce S-mycothiolated mixed disulfides and intramolecular disulfides. Genetic, phylogenetic, bioinformatics, structural, and biochemical analyses revealed that Rv2466c is a novel mycothiol-dependent reductase, which represents a mycoredoxin cluster of enzymes within the DsbA family different from the glutaredoxin cluster to which mycoredoxin-1 (Mrx1 or Rv3198A) belongs. To validate this DsbA-mycoredoxin cluster, we also characterized a homologous enzyme of Corynebacterium glutamicum (NCgl2339) and observed that it demycothiolates and reduces a mycothiol arsenate adduct with kinetic properties different from those of Mrx1. In conclusion, our work has uncovered a DsbA-like mycoredoxin that promotes mycobacterial resistance to oxidative stress and reacts with free mycothiol and mycothiolated targets. The characterization of the DsbA-like mycoredoxin cluster reported here now paves the way for correctly classifying similar enzymes from other organisms.
Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/metabolismo , Modelos Moleculares , Mycobacterium tuberculosis/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Pró-Fármacos/farmacologia , Isomerases de Dissulfetos de Proteínas/metabolismo , Pirimidinas/farmacologia , Ativação Metabólica , Antibacterianos/química , Antibacterianos/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Biocatálise , Domínio Catalítico , Cristalografia por Raios X , Cisteína/metabolismo , Testes de Sensibilidade a Antimicrobianos por Disco-Difusão , Drogas em Investigação/química , Drogas em Investigação/metabolismo , Drogas em Investigação/farmacologia , Deleção de Genes , Conformação Molecular , Simulação de Acoplamento Molecular , Mycobacterium tuberculosis/enzimologia , Mycobacterium tuberculosis/crescimento & desenvolvimento , Oxirredução , Filogenia , Pró-Fármacos/química , Pró-Fármacos/metabolismo , Conformação Proteica , Isomerases de Dissulfetos de Proteínas/química , Isomerases de Dissulfetos de Proteínas/genética , Pirimidinas/química , Pirimidinas/metabolismo , Proteínas Recombinantes/metabolismo , Especificidade por SubstratoRESUMO
An efficient metal-free cascade reaction between 1-dibromovinyl-2-nitro-substituted arenes and secondary amines results in the formation of polycyclic pseudoindoxyls in a single step. The reaction mechanism leading to these fused ring systems was investigated, and is believed to involve the initial formation of nitroarylated ynamines/ynamides. These intermediates cycloisomerize towards N-alkenyl-tethered 2-aminoisatogens via a carbene intermediate as demonstrated by QTAIM (quantum theory of atoms in molecules) and ELF (electron localization function) analysis. A subsequent intramolecular dipolar cycloaddition afforded the title compounds.
RESUMO
N-Benzoyl ß,ß-difluoroenamides and N-benzoyl fluoroynamides are novel structural units which have been explored as precursors in heterocyclic synthesis. The presence of two fluorine atoms at the ß-position of the enamide moiety endows unique electrophilic reactivity. Treatment of these enamides with oxygen nucleophiles gives rise to a nucleophilic vinylic substitution (S(N)V) reaction, which was directed toward 2-fluoro-1,4-benzoxazines and 2-fluoro-1,4-benzoxazepin-5-ones. Furthermore, fluorinated ynamides, a new type of building block, were prepared in excellent yields for the first time. In this case, ß-addition of nucleophiles across the triple bond is observed also.
Assuntos
Benzoxazinas/síntese química , Flúor/química , Oxazepinas/síntese química , Benzoxazinas/química , Estrutura Molecular , Fenômenos de Química Orgânica , Oxazepinas/químicaRESUMO
A five-step procedure for the synthesis of cis-1-tosyl-2-tosyloxymethyl-3-(trifluoromethyl)aziridine was developed, starting from 1-ethoxy-2,2,2-trifluoroethanol, involving imination, aziridination, ester reduction, hydrogenation, and N-,O-ditosylation steps. Further synthetic elaborations revealed a remarkable difference in the reactivity of cis-1-tosyl-2-tosyloxymethyl-3-(trifluoromethyl)aziridine with respect to aromatic sulfur and oxygen nucleophiles, thus enabling the selective deployment of this versatile substrate as a building block for the synthesis of functionalized aziridines, azetidines, and benzo-fused dithianes, oxathianes, dioxanes, and (thio)morpholines.
Assuntos
Azetidinas/síntese química , Aziridinas/síntese química , Dioxanos/síntese química , Compostos Heterocíclicos/química , Hidrocarbonetos Fluorados/química , Hidrocarbonetos Fluorados/síntese química , Morfolinas/síntese química , Oxigênio/química , Quinolizinas/síntese química , Compostos de Enxofre/síntese química , Enxofre/química , Trifluoretanol/análogos & derivados , Trifluoretanol/química , Azetidinas/química , Aziridinas/química , Dioxanos/química , Morfolinas/química , Quinolizinas/química , Estereoisomerismo , Compostos de Enxofre/químicaRESUMO
A convenient approach toward nonactivated 1-alkyl-2-(trifluoromethyl)azetidines as a new class of constrained azaheterocycles was developed starting from ethyl 4,4,4-trifluoroacetoacetate via imination, hydride reduction, chlorination, and base-induced ring closure. Furthermore, the reactivity profile of these 2-CF(3)-azetidines was assessed by means of quaternization and subsequent regiospecific ring opening at C4 of the azetidinium intermediates by oxygen, nitrogen, carbon, sulfur, and halogen nucleophiles, pointing to a clear difference in reactivity compared to azetidines bearing other types of electron-withdrawing groups at C2.
Assuntos
Aminas/síntese química , Azetidinas/síntese química , Aminas/química , Azetidinas/química , Estrutura Molecular , Sais/química , EstereoisomerismoRESUMO
Fluorinated pyrazoles bearing additional functional groups that allow further functionalization are of considerable interest as building blocks in medicinal chemistry. The developed synthetic strategy for new 3-amino-4-fluoropyrazoles consists of a monofluorination of ß-methylthio-ß-enaminoketones using 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor) toward the corresponding monofluorinated enaminoketones, followed by condensation with different hydrazines.
Assuntos
Pirazóis/química , Pirazóis/síntese química , HalogenaçãoRESUMO
An efficient and straightforward approach towards the synthesis of 1-alkyl-2-(trifluoromethyl)aziridines starting from 1,1,1-trifluoroacetone via imination, α-chlorination, hydride reduction and ring closure was developed. In addition, novel primary ß-iodo amines were obtained by regioselective ring opening of these 2-(trifluoromethyl)aziridines using alkyl iodides, and their synthetic potential was demonstrated by converting them into novel α-CF(3)-ß-phenylethylamines upon treatment with lithium diphenylcuprate.
Assuntos
Acetona/análogos & derivados , Aziridinas/síntese química , Compostos de Flúor/síntese química , Acetona/química , Alquilação , Metilação , Estrutura MolecularRESUMO
Novel C-4',C-5' cyclobutane-fused spirocyclic ribonucleoside analogues were prepared. Thermal [2 + 2] cycloaddition between dichloroketene and readily derived 4'-exo-methylene furanoses afforded a first entry to the required constrained ribofuranoses, relying on a carbonyl transposition sequence. Alternatively, an unusual stereoselective ionic [2 + 2] cycloaddition using methyl propiolate promoted by methylaluminoxane gave a complementary, more direct approach to such ribofuranoses. Further conversion to the constrained adenosine analogues revealed promising structure-dependent inhibition of the protein methyltransferase PRMT5:MEP50 complex in the (sub)micromolar range.
Assuntos
AdenosinaRESUMO
3,4,5-Trimethyl-2(5H)-furanone, a new seed germination inhibitor with very promising agrochemical applications, was efficiently synthesized from 2,3-dimethylmaleic anhydride via nucleophilic addition of methyllithium followed by reduction using sodium borohydride. This two-step synthesis is straightforward and high-yielding and permits the large-scale preparation of the seed germination inhibitor.
Assuntos
Furanos/síntese química , Furanos/química , Furanos/farmacologia , Estrutura Molecular , Sementes/efeitos dos fármacos , Sementes/crescimento & desenvolvimento , EstereoisomerismoRESUMO
ABC analogues of the antitumor antibiotic lavendamycin, which contain the key metal chelation site and redox-active quinone unit essential for biological activity, were prepared via the palladium(0)-catalyzed cross-coupling reaction of various 2-haloheteroaromatics with 2-stannylated pyridines and quinolines. Using the Stille reaction, 2-bromo substituted quinolines and 1-bromoisoquinolines were found to undergo efficient coupling with 2-pyridinylstannanes to provide unsymmetrical heterobiaryl derivatives. While the Stille reaction using the reverse coupling partners (i.e., 2-quinolinylstannanes and haloheteroaromatics) had not received much attention in the literature, we found that this alternative coupling reaction efficiently provided several new heterobiaryl derivatives. The gold-catalyzed intramolecular cycloisomerization of N-(prop-2-ynyl)-1H-indole-2-carboxamide smoothly afforded a beta-carbolinone derivative that was subsequently used for a Pd(0)-catalyzed cross-coupling directed toward the synthesis of lavendamycin analogues.
Assuntos
Antibióticos Antineoplásicos/síntese química , Indóis/síntese química , Paládio/química , Quinolinas/química , Estreptonigrina/análogos & derivados , Antibióticos Antineoplásicos/química , Catálise , Reagentes de Ligações Cruzadas , Indóis/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Estereoisomerismo , Estreptonigrina/síntese química , Estreptonigrina/químicaRESUMO
A practical methodology to obtain alpha-diazoketones through an improved Arndt-Eistert synthesis is described. The method allows the efficient transformation of acid halides using a stoichiometric amount of diazomethane in the presence of calcium oxide, without concomitant ketene or haloketone formation. The obtained alpha'-brominated-alpha-diazoketones were employed as suitable substrates for the synthesis of interesting alpha-arylamino-alpha'-halomethylketones.
Assuntos
Compostos de Cálcio/química , Diazometano/química , Cetonas/síntese química , Óxidos/química , Cetonas/química , Estrutura Molecular , EstereoisomerismoRESUMO
Synthetic strategies toward 4-substituted 3,3-difluoropiperidines were evaluated. 4-Alkoxymethyl- and 4-aryloxymethyl-3,3-difluoropiperidines were synthesized via 1,4-addition of ethyl bromodifluoroacetate to 3-substituted acrylonitriles in the presence of copper powder, followed by borane reduction of the cyano substituent, lactamization, and reduction of the lactam. This method was applied to establish the synthesis of N-protected 3,3-difluoroisonipecotic acid, a fluorinated gamma-amino acid. 4-Benzyloxy-3,3-difluoropiperidine was prepared using an analogous methodology and was converted to N-protected 3,3-difluoro-4,4-dihydroxypiperidine, a compound with high potential as a building block in medicinal chemistry.
Assuntos
Hidrocarbonetos Fluorados/síntese química , Piperidinas/síntese química , Aminoácidos/química , Cobre/química , Hidrocarbonetos Fluorados/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Piperidinas/química , EstereoisomerismoRESUMO
Synthetic routes toward new 5-amino- and 5-hydroxy-3,3-difluoropiperidines, which are of high interest as building blocks in medicinal chemistry, are described. The key step involves the N-halosuccinimide-induced cyclization of 2,2-difluoro-4-pentenylamines toward 5-halo-3,3-difluoropiperidines, which were used to synthesize 5-amino-3,3-difluoropiperidine. In a second strategy, iodolactonization of 2,2-difluoro-4-pentenoic acid gave the corresponding γ-lactone, which was transformed into 5-hydroxy-3,3-difluoropiperidine.
Assuntos
Hidrocarbonetos Fluorados/síntese química , Piperidinas/síntese química , Ciclização , Hidrocarbonetos Fluorados/química , Lactonas/química , Ácidos Pentanoicos/química , EstereoisomerismoRESUMO
A short and efficient synthesis of 4-aminomethyl-4-fluoropiperidines and 3-aminomethyl-3-fluoropyrrolidines is described. These fluorinated azaheterocycles are of specific interest as bifunctional building blocks for fluorinated pharmaceutical compounds. The key step of the synthetic pathway involves the regioselective bromofluorination of N-Boc-4-methylenepiperidine and 3-methylenepyrrolidine using Et(3)N.3HF and NBS.