RESUMO
Convenient synthesis of stereochemically dense 5-oxo-pyrrolidines was obtained from succinic anyhdride and imines by combining the Castagnoli-Cushman reaction with directed Pd-catalyzed C(sp3)-H functionalization, taking advantage of the developing carboxylic group properly derivatized with 8-aminoquinoline as a directing group. These fully substituted 5-oxopyrrolidines were found to be able to inhibit BACE-1 enzyme with sub-micromolar activity, thanks to the interaction of the key aryl appendage introduced by C(sp3)-H activation within BACE-1 S2' subsite.
RESUMO
Dibenzocyclooctynes have emerged as promising scaffolds for bioorthogonal ligation. An important structural aspect that has not been addressed so far relates to their chirality. Herein, we explore, by theoretical and experimental methods, this structural aspect that has been neglected so far. First, computational analysis is conducted, and the results are used as a guide for the experimental investigation. Next, an array of different experiments (high-performance liquid chromatography (HPLC) on chiral columns, chiroptical spectroscopy, and X-ray diffraction) for structure elucidation is scrutinized in concert. Finally, this work demonstrates the chirality and the stereodynamic behavior of dibenzocyclooctynes and their triazole derivatives with simple azides and also uncovers their conformational behavior.
RESUMO
Six- and seven-membered ring-fused, functionalized cyclopentadienes can be obtained in moderate to excellent yields by a cascade process entailing the Au(I)-catalyzed propargyl Claisen rearrangement/Nazarov cyclization of propargyl vinyl ethers, the hetero-Diels-Alder reaction with dialkylazodicarboxylates, and the spontaneous conversion of cycloaddition products into cyclopentadienes by a highly regioselective cleavage of a C-N bond. Depending on the treatment of the crude reaction mixtures, two types of products can be obtained: cyclopentadienes with pendant hydrazine and aldehyde moieties that intramolecularly react to form hemiaminals are obtained in 43-52% overall yields when the crude reaction mixtures are left over K2CO3 in a DCM solution. Instead, by reducing in situ the aldehyde group just after addition of the heterodienophile, the regioselective C-N bond cleavage generates the corresponding cyclopentadienes bearing a hydrazine and an alcohol appendage in excellent yields (66-82%) over four steps, all in one pot. Two examples from the latter class of compounds were also converted into ring-fused, functionalized cyclopentadienes, bearing a protected amino group, by the selective N-N cleavage of the hydrazine moiety.
Assuntos
Ciclopentanos , Ouro , Aldeídos/química , Catálise , Reação de Cicloadição , Ciclopentanos/química , Hidrazinas , EstereoisomerismoRESUMO
The first total synthesis of the natural product bruceolline I, isolated in small quantities from the ethanol extract of Brucea mollis stems, was achieved in 29% yield over nine steps and with high enantiomeric purity (>98%). The key step of the process is the tandem gold-catalyzed rearrangement/Nazarov reaction of a propargylic acetate derivative. This synthesis provides a sufficient amount of synthesized bruceolline I for further bioassays.
Assuntos
Brucea/química , Ciclopentanos/síntese química , Indóis/síntese química , Caules de Planta/química , Produtos Biológicos , Catálise , Ciclopentanos/química , Ciclopentanos/isolamento & purificação , Indóis/química , Indóis/isolamento & purificação , Estrutura Molecular , EstereoisomerismoRESUMO
Three new and easily accessible chiral compounds, containing the pharmacophore 1,3,4-thiadiazoline nucleus joined by a spiro center to a monoalkyl (methyl or t-butyl) substituted cyclohexyl fragment, have been synthesized and fully characterized from the structural and stereochemical point of view. The formation of a spiro-cyclohexyl-thiadiazoline system (sCT) offered the rare opportunity to generate at room temperature both anancomeric structures, displaying alkyl groups bound to the cyclohexyl ring in equatorial position, and other quite stable stereoisomers in which the same alkyl moieties are, instead, inserted in axial position, even for the extreme case represented by the really bulky t-butyl group. DFT calculations led to a clear rationalization of such stereochemical behaviors, pointing out that in all cases they arise from the unexpected strong anancomeric character possessed by the sCT framework in its 4-acetyl substituted version. In consideration of the large number of substances in which the 1,3,4-thiadiazoline heterocycle has been found as the active pharmacophore, the results discussed in this work may provide solid bases to allow a rational design of new chiral bioactive spiro-thiadiazolines characterized by well-defined stereochemical structures and single anancomeric geometries.
RESUMO
The synthesis of the uncommon dihydropyrazinone ring was accomplished by a two-step one pot process taking advantage of the ring rearrangement of N-acylated morpholine acetal derived from serine under acidic treatment in the presence of 2,6-lutidine. The mechanism involves an N-acyl iminium intermediate resulting from morpholine acetal ring opening, which occurs after a nucleophilic attack of the amino acid nitrogen atom to the acetal carbonyl atom. X-Ray diffraction analysis of the dihydropyrazinone, which may be exploited as a constrained Xaa-Ser dipeptide isostere, showed a planar assembly and the internal side-chain in axial orientation with respect to the cyclic molecular scaffold.
Assuntos
Acetais/química , Dipeptídeos/química , Morfolinas/química , Pirazinas/química , Acetais/síntese química , Acilação , Cristalografia por Raios X , Dipeptídeos/síntese química , Modelos Moleculares , Morfolinas/síntese química , Pirazinas/síntese química , Piridinas/síntese química , Piridinas/química , Serina/síntese química , Serina/químicaRESUMO
A two-step one purification access to dichloronaphtho[1,2-b:8,7-b'] and [1,2-b:5,6-b']dithiophenes using bis-alkylnaphthyl alkynes and phthalimidesulfenyl chloride as starting materials has been developed. The functionalization of the carbon-chlorine bonds allowed further modification of NDT core, broadening the potential of the methodology.
Assuntos
Alcinos/química , Naftóis/síntese química , Tiofenos/síntese química , Estrutura Molecular , Naftóis/química , Estereoisomerismo , Tiofenos/químicaRESUMO
The synthesis of three racemates and the corresponding non-chiral analogues of a C5-methyl pyridazine series is described here, as well as the isolation of pure enantiomers and their absolute configuration assignment. In order to obtain optically active compounds, direct chromatographic methods of separation by HPLC-UV were investigated using four chiral stationary phases (CSPs: Lux Amylose-2, Lux Cellulose-1, Lux Cellulose-2 and Lux Cellulose-3). The best resolution was achieved using amylose tris(5-chloro-2-methylphenylcarbamate) (Lux Amylose-2), and single enantiomers were isolated on a semipreparative scale with high enantiomeric excess, suitable for biological assays. The absolute configuration of optically active compounds was unequivocally established by X-ray crystallographic analysis and comparative chiral HPLC-UV profile. All compounds of the series were tested for formyl peptide receptor (FPR) agonist activity, and four were found to be active, with EC50 values in the micromolar range.
Assuntos
Piridazinas/química , Piridazinas/farmacologia , Receptores de Formil Peptídeo/agonistas , Técnicas de Química Sintética , Cromatografia Líquida de Alta Pressão , Cristalografia por Raios X , Células HL-60 , Humanos , Piridazinas/síntese química , Piridazinas/isolamento & purificação , EstereoisomerismoRESUMO
A novel stereoselective synthetic approach to pentahydroxyazepane iminosugars is described. The strategy relies on a key osmium-catalyzed aminohydroxylation reaction of allylic alcohols obtained via addition of vinylmagnesium bromide to a d-mannose-derived aldehyde, which forms the new C-N bond with complete regio- and stereocontrol according to the tethering approach. Subsequent intramolecular reductive amination afforded the desired azepanes. This method represents the first application of the osmium-catalyzed tethered aminohydroxylation reaction to the synthesis of iminosugars.
RESUMO
1-(2-Pyridyl)-2-propen-1-ol, obtained by vinylation of commercially available picolinaldehyde, resulted a good starting material for the synthesis of the indolizidine skeleton. In particular, a simple process involving bromination, reduction, and nucleophilic substitution (via elimination and addition) allowed an easy conversion of the starting material into (±)-lentiginosine in ~27% overall yield.
Assuntos
Alcaloides/síntese química , Propanóis/química , Piridinas/química , Alcaloides/química , Estrutura Molecular , EstereoisomerismoRESUMO
A direct semipreparative HPLC enantioseparation of two chiral thiazolidinone derivatives having cyclooxygenase-2 inhibition activity was performed on the Chiralpak IA chiral stationary phase. Semipreparative amounts of enantiopure forms were collected using acetonitrile-ethanol-trifluoroacetic acid mixtures as mobile phase. The absolute configuration of both compounds was unequivocally established by single-crystal X-ray diffraction method and correlated to the chiroptical properties of isolated enantiomers.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Ciclo-Oxigenase 2/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase/isolamento & purificação , Cristalografia por Raios X , Inibidores de Ciclo-Oxigenase/química , Inibidores de Ciclo-Oxigenase/farmacologia , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Espectrofotometria Ultravioleta , EstereoisomerismoRESUMO
The [3,3]-sigmatropic allyl cyanate/isocyanate rearrangement of glycals in the presence of O-, N-, and C-nucleophiles afforded ß-N-glucosyl and galactosyl carbamates, ureas, and amides in good yields. The unsaturated products were elaborated to N-glycosides by dihydroxylation, to 1,3-diaminosugars by tethered aminohydroxylation, or to 1,2-diaminosugars by iteration of the sigmatropic rearrangement. This metal-free methodology represents an excellent and general method for the stereoselective synthesis of N-glycosides and diamino sugars with complete transmission of stereochemical information.
RESUMO
Chiral 2-(sec-butylthio)-6-[1-(2,6-dichlorophenyl)propyl]-5-methylpyrimidin-4(3H)-one (compound 1) was synthesized to serve as a model compound for structural elucidation of novel S-DABO (dihydroalkoxybenzyloxopyrimidine) derivatives endowed with potential HIV-1 reverse transcriptase inhibitory activity. Stereochemical characterization of four stereoisomers of 1 was achieved by an experimental approach based on the following steps: (a) direct HPLC enantio- and diastereoseparation at semipreparative scale; (b) determination of elution order of stereomeric mixture by using chiroptical detection (polarimeter or circular dichroism (CD)); (c) X-ray crystallography of two diastereoisomers isolated at semipreparative scale. The CD analysis of 1 and its two analogues (compounds 2 and 3), both having a single stereogenic center located in two different alkyl side chains of the dihydropyrimidinone structure, was carried out. The results of this study indicated a correlation between the absolute configuration at C-1 of alkyl side chain of the dihydropyrimidinone structure and the sign of the CD band at around 245 nm.
Assuntos
Pirimidinas/química , Cromatografia Líquida de Alta Pressão , Dicroísmo Circular , Cristalografia por Raios X , Pirimidinas/síntese química , Espectrofotometria Ultravioleta , EstereoisomerismoRESUMO
We have designed and synthesized a series of new imidazole-based compounds structurally related to an antiprotozoal agent with nanomolar activity which we identified recently. The new analogues possess micromolar activities against Trypanosoma brucei rhodesiense and Leishmania donovani and nanomolar potency against Plasmodium falciparum. Most of the analogues displayed IC50 within the low nanomolar range against Trypanosoma cruzi, with very high selectivity toward the parasite. Discussion of structure-activity relationships and in vitro biological data for the new compounds are provided against a number of different protozoa. The mechanism of action for the most potent derivatives (5i, 6a-c, and 8b) was assessed by a target-based assay using recombinant T. cruzi CYP51. Bioavailability and efficacy of selected hits were assessed in a T. cruzi mouse model, where 6a and 6b reduced parasitemia in animals >99% following intraperitoneal administration of 25 mg/kg/day dose for 4 consecutive days.
Assuntos
Antiprotozoários/química , Antiprotozoários/farmacologia , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Imidazóis/química , Imidazóis/farmacologia , Trypanosoma/efeitos dos fármacos , Animais , Antiprotozoários/síntese química , Inibidores das Enzimas do Citocromo P-450/farmacologia , Humanos , Imidazóis/síntese química , Testes de Sensibilidade ParasitáriaRESUMO
In previous studies, Okamoto et al. described the results of the exceptionally large chiral recognition of 2-(benzylsulfinyl)benzamide onto a coated-type chiral stationary phase based on cellulose tris(3,5-dichlorophenylcarbamate). As a continuation and deepening of those studies, here the sulfoxide and a small set of its structural analogues were analyzed on the commercially available Chiralpak IC-3 chiral stationary phase based upon the same polysaccharide derivative as the chiral selector but immobilized onto silica support. The chromatographic results obtained using different mobile phases consisting of pure methanol, ethanol and 2-propanol or binary mixtures n-hexane-2-propanol, which are prohibited with the progenitor coated-type chromatographic support, permitted to identify the NH2 of the amide group as the key structural element of the (S)-enantiomer of 2-(benzylsulfinyl)benzamide for obtaining a very high affinity for the IC-3 chiral stationary phase.
Assuntos
Benzamidas/química , Celulose/análogos & derivados , Cromatografia Líquida de Alta Pressão/métodos , Fenilcarbamatos/química , Benzamidas/análise , Celulose/química , Cristalografia por Raios X , Conformação Molecular , Polissacarídeos/química , Solventes/química , Estereoisomerismo , Sulfóxidos/química , TermodinâmicaRESUMO
With the aim to identify new, potent and selective monoamine oxidase B (MAO-B) inhibitors, molecular interaction field analysis has been applied to a MAO-B complex with 3-acetyl-2,5-diaryl-2,3-dihydro-1,3,4-oxadiazole chemical structure, known as a privileged scaffold for this target. Several compounds displayed potent in vitro activity, exhibiting IC50 values in the medium to low nanomolar range. The enantiomers of most promising derivatives were separated by enantioselective HPLC and in vitro evaluated. Experimental results, according to theoretical drug design, clearly indicated a key role of the ligand stereochemistry in the target recognition/inhibition. In particular the (R)- enantiomers showed the best activity with respect to the (S)- stereoisomer. Finally, docking experiments coupled to molecular dynamics (MD) simulations, were applied for understanding the putative MAO -B binding modes of the new compounds providing detailed information for further structural optimization.
Assuntos
Desenho de Fármacos , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Oxidiazóis/farmacologia , Simulação por Computador , Relação Dose-Resposta a Droga , Humanos , Simulação de Dinâmica Molecular , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Oxidiazóis/síntese química , Oxidiazóis/química , Relação Estrutura-AtividadeRESUMO
[Reaction: see text] C-Phenyl-N-erythrosylnitrone 3 behaves as a C1,C1' bis-electrophile, undergoing a double addition of Grignard reagents in a domino fashion to afford acyclic hydroxylamines 4. The reaction proceeds at 0 degrees C with variable degrees of diastereoselectivity, from moderate to good, mainly depending on the organomagnesium reagent used. The usefulness of compounds 4 has been exemplified with the synthesis of pyrroloazepine 12 through a ring closing metathesis key step.
Assuntos
Compostos Aza/síntese química , Carbono/química , Compostos Heterocíclicos/síntese química , Magnésio/química , Óxidos de Nitrogênio/química , Ânions , Compostos Aza/química , Glicosilação , Compostos Heterocíclicos/química , Estrutura Molecular , Compostos Organometálicos/química , EstereoisomerismoRESUMO
Six new atropisomeric heteroarenes were synthesized by connecting two 2-alkylbenzimidazole fragments via N-N junction. They differ by the substituent nature (methyl, ethyl, propyl, butyl, pentyl and hexyl) of the aliphatic function. The novel atropisomeric compounds were used as chiral probes to study the chromatographic behavior of the amylose tris(3,5-dimethylphenyl carbamate) (Chiralpak AD-3) chiral stationary phase (CSP) under normal phase mode. The pivotal role of the length and flexibility of the 2,2'-alkyl groups on retention, enantioselectivity and enantiomer elution order was demonstrated by enantioselective HPLC analysis. Additional information on the chiral recognition mechanism was obtained from the evaluation of the correlated thermodynamic data.
Assuntos
Carbamatos/química , Cromatografia Líquida de Alta Pressão/métodos , Estereoisomerismo , TermodinâmicaRESUMO
A set of ten C5-chiral 4,5-dihydro-(1H)-pyrazole derivatives was synthesized and analyzed by high-performance liquid chromatography (HPLC) on the polysaccharide-based Chiralcel OJ-H chiral stationary phase (CSP). The enantioseparations were carried out using pure ethanol as eluent. Different structural elements of the investigated compounds were recognized for obtaining a very high enantioselectivity. In order to clarify some aspects of the chiral discrimination process, the thermodynamic parameters associated to the enantiorecognition and the enantiomer elution order were established.
Assuntos
Benzoatos/química , Celulose/análogos & derivados , Cromatografia Líquida de Alta Pressão/instrumentação , Pirazóis/química , Adsorção , Celulose/química , Cromatografia Líquida de Alta Pressão/métodos , Estrutura Molecular , EstereoisomerismoRESUMO
Ugi four-component condensation (Ugi-4CC) between 2-formylbenzoic acid, phenacylamine dimethyl acetal, and isocyanides afforded 1H-isochromen-1-ones (isocoumarins). These products, where structure corresponds to the tautomeric enediamine form of the Ugi-4CC primary adducts, were stable enough to allow their isolation and characterization. Stable isocoumarins were also obtained by employing anilines as the amino component in the Ugi four-component condensation.