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1.
Nat Commun ; 11(1): 4371, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32873790

RESUMO

Pentacyclic triterpenoids (PTs) constitute one of the biggest families of natural products, many with higher oxidation state at the D/E rings possess a wide spectrum of biological activties but are poorly accessible. Here we report a site-selective C-H hydroxylation at the D/E rings of PTs paving a way toward these important natural products. We find that Schönecker and Baran's Cu-mediated aerobic oxidation can be applied and become site-selective on PT skeletons, as being effected unexpectedly by the chirality of the transient pyridine-imino directing groups. To prove the applicability, starting from the most abundant triterpenoid feedstock oleanane, three representative saponins bearing hydroxyl groups at C16 or C22 are expeditiously synthesized, and barringtogenol C which bears hydroxyl groups at C16, C21, and C22 is synthesized via a sequential hydroxylation as the key steps.


Assuntos
Produtos Biológicos/química , Técnicas de Química Sintética , Triterpenos Pentacíclicos/química , Química Farmacêutica , Hidroxilação , Relação Estrutura-Atividade
2.
Nat Commun ; 11(1): 4874, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32978395

RESUMO

Organic synthesis methodology enables the synthesis of complex molecules and materials used in all fields of science and technology and represents a vast body of accumulated knowledge optimally suited for deep learning. While most organic reactions involve distinct functional groups and can readily be learned by deep learning models and chemists alike, regio- and stereoselective transformations are more challenging because their outcome also depends on functional group surroundings. Here, we challenge the Molecular Transformer model to predict reactions on carbohydrates where regio- and stereoselectivity are notoriously difficult to predict. We show that transfer learning of the general patent reaction model with a small set of carbohydrate reactions produces a specialized model returning predictions for carbohydrate reactions with remarkable accuracy. We validate these predictions experimentally with the synthesis of a lipid-linked oligosaccharide involving regioselective protections and stereoselective glycosylations. The transfer learning approach should be applicable to any reaction class of interest.


Assuntos
Carboidratos/química , Aprendizado de Máquina , Oligossacarídeos/química , Metabolismo dos Carboidratos , Técnicas de Química Sintética , Glicosilação , Estrutura Molecular , Oligossacarídeos/metabolismo
3.
Nat Commun ; 11(1): 4443, 2020 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-32895371

RESUMO

Aryl azole scaffolds are present in a wide range of pharmaceutically relevant molecules. Their ortho-selective metalation at the aryl ring is challenging, due to the competitive metalation of the more acidic heterocycle. Seeking a practical access to a key Active Pharmaceutical Ingredient (API) intermediate currently in development, we investigated the metalation of 1-aryl-1H-1,2,3-triazoles and other related heterocycles with sterically hindered metal-amide bases. We report here a room temperature and highly regioselective ortho-magnesiation of several aryl azoles using a tailored magnesium amide, TMPMgBu (TMP = 2,2,6,6-tetramethylpiperidyl) in hydrocarbon solvents followed by an efficient Pd-catalyzed arylation. This scalable and selective reaction allows variation of the initial substitution pattern of the aryl ring, the nature of the azole moiety, as well as the nature of the electrophile. This versatile method can be applied to the synthesis of bioactive azole derivatives and complements existing metal-mediated ortho-functionalizations.


Assuntos
Azóis/química , Técnicas de Química Sintética/métodos , Estereoisomerismo , Catálise , Estrutura Molecular , Triazóis/química
4.
Nat Commun ; 11(1): 4761, 2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32958762

RESUMO

Chemical synthesis based on the skeletal variation has been prolifically utilized as an attractive approach for modification of molecular properties. Given the ubiquity of unstrained cyclic amines, the ability to directly alter such motifs would grant an efficient platform to access unique chemical space. Here, we report a highly efficient and practical strategy that enables the selective ring-opening functionalization of unstrained cyclic amines. The use of difluorocarbene leads to a wide variety of multifaceted acyclic architectures, which can be further diversified to a range of distinctive homologative cyclic scaffolds. The virtue of this deconstructive strategy is demonstrated by successful modification of several natural products and pharmaceutical analogues.


Assuntos
Aminas/química , Aminas/síntese química , Hidrocarbonetos Fluorados/química , Técnicas de Química Sintética , Estrutura Molecular , Bibliotecas de Moléculas Pequenas , Estereoisomerismo
5.
Nat Commun ; 11(1): 4170, 2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32820174

RESUMO

Sulfur-sulfur motifs widely occur in vital function and drug design, which yearns for polysulfide construction in an efficient manner. However, it is a great challenge to install desired functional groups on both sides of sulfur-sulfur bonds at liberty. Herein, we designed a mesocyclic bilateral disulfurating reagent for sequential assembly and modular installation of polysulfides. Based on S-O bond dissociation energy imparity (mesocyclic compared to linear imparity is at least 5.34 kcal mol-1 higher), diverse types of functional molecules can be bridged via sulfur-sulfur bonds distinctly. With these stable reagents, excellent reactivities with nucleophiles including C, N and S are comprehensively demonstrated, sequentially installing on both sides of sulfur-sulfur motif with various substituents to afford six species of unsymmetrical polysulfides including di-, tri- and even tetra-sulfides. Life-related molecules, natural products and pharmaceuticals can be successively cross-linked with sulfur-sulfur bond. Remarkably, the cyclization of tri- and tetra-peptides affords 15- and 18-membered cyclic disulfide peptides with this reagent, respectively.


Assuntos
Dissulfetos/química , Indicadores e Reagentes/química , Peptídeos/química , Sulfetos/química , Enxofre/química , Produtos Biológicos/química , Técnicas de Química Sintética/métodos , Ciclização , Indicadores e Reagentes/síntese química , Modelos Químicos , Estrutura Molecular , Oxirredução , Preparações Farmacêuticas/química
6.
Nat Protoc ; 15(9): 2980-3008, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32839575

RESUMO

High-surface-area mesoporous materials expose abundant functional sites for improved performance in applications such as gas storage/separation, catalysis, and sensing. Recently, soft templates composed of amphiphilic surfactants and block copolymers have been used to introduce mesoporosity in various materials, including metals, metal oxides and carbonaceous compounds. In particular, mesoporous metals are attractive in electrocatalysis because their porous networks expose numerous unsaturated atoms on high-index facets that are highly active in catalysis. In this protocol, we describe how to create mesoporous metal films composed of gold, palladium, or platinum using block copolymer micelle templates. The amphiphilic block copolymer micelles are the sacrificial templates and generate uniform structures with tunable pore sizes in electrodeposited metal films. The procedure describes the electrodeposition in detail, including parameters such as micelle diameters, deposition potentials, and deposition times to ensure reproducibility. The micelle diameters can be controlled by swelling the micelles with different solvent mixtures or by using block copolymer micelles with different molecular weights. The deposition potentials and deposition times allow further control of the mesoporous structure and its thickness, respectively. Procedures for example applications are included: glucose oxidation, ethanol oxidation and methanol oxidation reactions. The synthetic methods for preparation of mesoporous metal films will take ~4 h; the subsequent electrochemical tests will take ~5 h for glucose sensing and ~3 h for alcohol oxidation reaction.


Assuntos
Ouro/química , Paládio/química , Platina/química , Álcoois/química , Catálise , Técnicas de Química Sintética , Eletroquímica , Interações Hidrofóbicas e Hidrofílicas , Micelas , Modelos Moleculares , Conformação Molecular , Oxirredução , Polímeros/química
7.
Food Chem ; 332: 127150, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32659696

RESUMO

We report an optical biosensor using imine, 5-((anthrcene-9-ylmethylene) amino)-2,3dihydrophthalazine) 1-4-dione (ADD) for direct detection of ascorbic acid (AA) via FRET quenched. The ADD was successfully prepared by using simple ultra - sonication method, which was characterized by various spectroscopic techniques. The fluorescence intensity of ADD probe was drastically quenched in presence of AA, and shown excellent selectivity towards the detection of AA in presence of possible biological active interferences. A wide linear range from 0.25 to 190 µM was achieved towards the detection of AA with a LOD of 10 nM. The occurrence of FRET mechanism is due to intermolecular hydrogen bonding between ADD and AA, which was confirmed by Density Functional Theory calculations. Moreover, the biosensor was successfully applied for the detection of AA in real samples such as fruits and vegetables to demonstrate the practicability. In addition, the developed biosensor could be a simple and economically cheap platform for the detection of AA in food samples.


Assuntos
Ácido Ascórbico/análise , Técnicas Biossensoriais/métodos , Frutas/química , Luminol/análogos & derivados , Fenômenos Ópticos , Sonicação , Verduras/química , Técnicas de Química Sintética , Limite de Detecção , Luminol/síntese química , Luminol/química
8.
PLoS One ; 15(6): e0229891, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32497076

RESUMO

A facile method has been developed for the synthesis of Schiff bases derived from substituted and unsubstituted 3-amino- and 4-amino-1,2,4-triazoles. Condensation of the aminotrizoles with a variety of aromatic aldehydes afforded desired Schiff bases in excellent yields in 3-5 minutes of exposure to ultra-sound. The synthesized compounds were characterized by means of IR, 1HNMR and Mass spectrometry. The synthesized compounds were also screened for their antibacterial potential against Gram-negative (Escherichia coli, Shigella sonnei, Pseudomonas aeruginosa and Salmonella typhi) and two Gram-positive (Staphylococcus aureus and Bacillus subtilis) strains.


Assuntos
Amitrol (Herbicida)/síntese química , Amitrol (Herbicida)/farmacologia , Antibacterianos/síntese química , Antibacterianos/farmacologia , Triazóis/síntese química , Triazóis/farmacologia , Ondas Ultrassônicas , Amitrol (Herbicida)/química , Antibacterianos/química , Bactérias/efeitos dos fármacos , Técnicas de Química Sintética , Testes de Sensibilidade Microbiana , Bases de Schiff/química , Triazóis/química
9.
Nat Commun ; 11(1): 2756, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32488003

RESUMO

Trifluoroethanol and difluoroethanol units are important motifs in bioactive molecules, but the methods to direct incorporate these units are limited. Herein, we report two organosilicon reagents for the transfer of trifluoroethanol and difluoroethanol units into molecules. Through intramolecular C-Si bond activation by alkoxyl radicals, these reagents were applied in allylation, alkylation and alkenylation reactions, enabling efficient synthesis of various tri(di)fluoromethyl group substituted alcohols. The broad applicability and general utility of the approach are highlighted by late-stage introduction of these fluoroalkyl groups to complex molecules, and the synthesis of antitumor agent Z and its difluoromethyl analog Z'.


Assuntos
Etanol/análogos & derivados , Etanol/química , Compostos de Organossilício/química , Trifluoretanol/química , Álcoois/química , Alquilação , Técnicas de Química Sintética , Indicadores e Reagentes/química , Estrutura Molecular
10.
Science ; 368(6494): 1007-1011, 2020 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-32467391

RESUMO

Bryostatins are a family of 21 complex marine natural products with a wide range of potent biological activities. Among all the 21 bryostatins, bryostatin 3 is structurally the most complex. Whereas nine total syntheses of bryostatins have been achieved to date, bryostatin 3 has only been targeted once and required the highest number of steps to synthesize (43 steps in the longest linear sequence and 88 total steps). Here, we report a concise total synthesis of bryostatin 3 using 22 steps in the longest linear sequence and 31 total steps through a highly convergent synthetic plan by the use of highly atom-economical and chemoselective transformations in which alkynes played a major role in reducing step count.


Assuntos
Produtos Biológicos/síntese química , Briostatinas/síntese química , Macrolídeos/síntese química , Alquinos/química , Produtos Biológicos/química , Briostatinas/química , Técnicas de Química Sintética , Macrolídeos/química
11.
Nat Commun ; 11(1): 2431, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32415161

RESUMO

Chemical desymmetrization reactions of meso-diols are highly effective for the precise and efficient synthesis of chiral molecules. However, even though enzyme-catalyzed desymmetric glycosylations are frequently found in nature, there is no method for highly diastereoselective desymmetric chemical glycosylation of meso-diols. Herein, we report a highly diastereoselective desymmetric 1,2-cis-glycosylation of meso-diols found in myo-inositol 1,3,5-orthoesters using a boronic acid catalyst based on predictions of regioselectivity by density functional theory (DFT) calculations. The enantiotopic hydroxyl groups of the meso-diols are clearly differentiated by the stereochemistry at the C2 position of the glycosyl donor with excellent regioselectivities. In addition, the present method is successfully applied to the synthesis of core structures of phosphatidylinositolmannosides (PIMs) and glycosylphosphatidylinositol (GPI) anchors, and common ß-mannoside structures of the LLBM-782 series of antibiotics.


Assuntos
Antibacterianos/síntese química , Técnicas de Química Sintética , Desenho de Fármacos , Manosídeos/química , Antibacterianos/química , Carboidratos/química , Glicosilação , Espectroscopia de Ressonância Magnética , Fosfatidilinositóis/química , Estereoisomerismo
12.
Nat Commun ; 11(1): 2569, 2020 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-32444828

RESUMO

Methods for direct C-H trifluoromethoxylation of arenes and heteroarenes are rare, despite the importance of trifluoromethoxylated compounds for pharmaceuticals, agrochemicals, and material sciences. Especially selective C-H trifluoromethoxylation of pyridines remains a formidable challenge. Here we show a general late-stage C-H trifluoromethoxylation of arenes and heteroarenes as limiting reagent with trifluoromethoxide anion. The reaction is mediated by silver salts under mild reaction conditions, exhibiting broad substrate scope and wide functional-group compatibility. In addition, ortho-position selective C-H trifluoromethoxylation of pyridines is observed. The method is not only applicable to the gram-scale synthesis of trifluoromethoxylated products but also allows efficient late-stage C-H trifluoromethoxylation of marketed small-molecule drugs, common pharmacophores and natural products.


Assuntos
Hidrocarbonetos Fluorados/química , Técnicas de Química Sintética , Piridinas/química , Compostos de Prata/química
13.
Nature ; 581(7808): 288-293, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32433618

RESUMO

The hydrogen isotopes deuterium (D) and tritium (T) have become essential tools in chemistry, biology and medicine1. Beyond their widespread use in spectroscopy, mass spectrometry and mechanistic and pharmacokinetic studies, there has been considerable interest in incorporating deuterium into drug molecules1. Deutetrabenazine, a deuterated drug that is promising for the treatment of Huntington's disease2, was recently approved by the United States' Food and Drug Administration. The deuterium kinetic isotope effect, which compares the rate of a chemical reaction for a compound with that for its deuterated counterpart, can be substantial1,3,4. The strategic replacement of hydrogen with deuterium can affect both the rate of metabolism and the distribution of metabolites for a compound5, improving the efficacy and safety of a drug. The pharmacokinetics of a deuterated compound depends on the location(s) of deuterium. Although methods are available for deuterium incorporation at both early and late stages of the synthesis of a drug6,7, these processes are often unselective and the stereoisotopic purity can be difficult to measure7,8. Here we describe the preparation of stereoselectively deuterated building blocks for pharmaceutical research. As a proof of concept, we demonstrate a four-step conversion of benzene to cyclohexene with varying degrees of deuterium incorporation, via binding to a tungsten complex. Using different combinations of deuterated and proteated acid and hydride reagents, the deuterated positions on the cyclohexene ring can be controlled precisely. In total, 52 unique stereoisotopomers of cyclohexene are available, in the form of ten different isotopologues. This concept can be extended to prepare discrete stereoisotopomers of functionalized cyclohexenes. Such systematic methods for the preparation of pharmacologically active compounds as discrete stereoisotopomers could improve the pharmacological and toxicological properties of drugs and provide mechanistic information related to their distribution and metabolism in the body.


Assuntos
Benzeno/química , Técnicas de Química Sintética , Cicloexenos/química , Cicloexenos/síntese química , Deutério/química , Preparações Farmacêuticas/química , Preparações Farmacêuticas/síntese química , Bases de Dados de Compostos Químicos , Cinética , Estrutura Molecular , Estereoisomerismo , Tetrabenazina/análogos & derivados , Tetrabenazina/síntese química , Tetrabenazina/química , Tungstênio/química
14.
PLoS One ; 15(4): e0231147, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32287324

RESUMO

This paper reports the synthesis, characterization, anticancer screening and quantum chemical calculation of a tetradentate Schiff base 2,2'-((1E,1'E)-((2,2-dimethylpropane-1,3-diyl)bis- (azanylylidene))bis(methanylylidene))bis(4-fluorophenol) (L2F) and its Pd (II) complex (PdL2F). The compounds were characterized via UV-Visible, NMR, IR spectroscopy and single crystal x-ray diffraction. Density Functional Theory (DFT) and time-dependent DFT calculations in gas and solvent phases were carried out using B3LYP, B3P86, CAM-B3LYP and PBE0 hybrid functionals combined with LanL2DZ basis set. Complexation of L2F to form PdL2F was observed to cause a bathochromic shift of the maximum absorption bands of n-π* from 327 to 410 nm; an upfield shift for δ (HC = N) from 8.30 to 7.96 ppm and a decreased wavenumber for ν(C = N) from 1637 to 1616 cm-1. Overall, the UV-Vis, NMR and IR spectral data are relatively well reproduced through DFT and TD-DFT methods. L2F and PdL2F showed IC50 of 90.00 and 4.10 µg/mL, respectively, against human colorectal carcinoma (HCT116) cell lines, signifying increased anticancer activity upon complexation with Pd (II).


Assuntos
Complexos de Coordenação/farmacologia , Paládio/farmacologia , Bases de Schiff/farmacologia , Técnicas de Química Sintética/métodos , Complexos de Coordenação/química , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Concentração Inibidora 50 , Ligantes , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Paládio/química , Bases de Schiff/química , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier
15.
Nature ; 581(7809): 415-420, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32268340

RESUMO

The ubiquity of tertiary alkylamines in pharmaceutical and agrochemical agents, natural products and small-molecule biological probes1,2 has stimulated efforts towards their streamlined synthesis3-9. Arguably the most robust method for the synthesis of tertiary alkylamines is carbonyl reductive amination3, which comprises two elementary steps: the condensation of a secondary alkylamine with an aliphatic aldehyde to form an all-alkyl-iminium ion, which is subsequently reduced by a hydride reagent. Direct strategies have been sought for a 'higher order' variant of this reaction via the coupling of an alkyl fragment with an alkyl-iminium ion that is generated in situ10-14. However, despite extensive efforts, the successful realization of a 'carbonyl alkylative amination' has not yet been achieved. Here we present a practical and general synthesis of tertiary alkylamines through the addition of alkyl radicals to all-alkyl-iminium ions. The process is facilitated by visible light and a silane reducing agent, which trigger a distinct radical initiation step to establish a chain process. This operationally straightforward, metal-free and modular transformation forms tertiary amines, without structural constraint, via the coupling of aldehydes and secondary amines with alkyl halides. The structural and functional diversity of these readily available precursors provides a versatile and flexible strategy for the streamlined synthesis of complex tertiary amines.


Assuntos
Aminas/química , Aminas/síntese química , Técnicas de Química Sintética/métodos , Aldeídos/química , Alquilação , Aminação , Loratadina/análogos & derivados , Loratadina/síntese química , Loratadina/química
16.
Nat Commun ; 11(1): 1956, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32327665

RESUMO

The dehydrogenative alkenylation of C-H bonds with alkenes represents an atom- and step-economical approach for olefin synthesis and molecular editing. Site-selective alkenylation of alkanes and aldehydes with the C-H substrate as the limiting reagent holds significant synthetic value. We herein report a photocatalytic method for the direct alkenylation of alkanes and aldehydes with aryl alkenes in the absence of any external oxidant. A diverse range of commodity feedstocks and pharmaceutical compounds are smoothly alkenylated in useful yields with the C-H partner as the limiting reagent. The late-stage alkenylation of complex molecules occurs with high levels of site selectivity for sterically accessible and electron-rich C-H bonds. This strategy relies on the synergistic combination of direct hydrogen atom transfer photocatalysis with cobaloxime-mediated hydrogen-evolution cross-coupling, which promises to inspire additional perspectives for selective C-H functionalizations in a green manner.


Assuntos
Aldeídos/química , Alcanos/química , Alcenos/química , Alcenos/síntese química , Catálise , Técnicas de Química Sintética , Química Verde , Estrutura Molecular , Compostos Organometálicos/química , Processos Fotoquímicos , Estereoisomerismo
17.
Nat Protoc ; 15(5): 1707-1741, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32269381

RESUMO

Here, we provide a protocol to generate synthetic nanobodies, known as sybodies, against any purified protein or protein complex within a 3-week period. Unlike methods that require animals for antibody generation, sybody selections are carried out entirely in vitro under controlled experimental conditions. This is particularly relevant for the generation of conformation-specific binders against labile membrane proteins or protein complexes and allows selections in the presence of non-covalent ligands. Sybodies are especially suited for cases where binder generation via immune libraries fails due to high sequence conservation, toxicity or insufficient stability of the target protein. The procedure entails a single round of ribosome display using the sybody libraries encoded by mRNA, followed by two rounds of phage display and binder identification by ELISA. The protocol is optimized to avoid undesired reduction in binder diversity and enrichment of non-specific binders to ensure the best possible selection outcome. Using the efficient fragment exchange (FX) cloning method, the sybody sequences are transferred from the phagemid to different expression vectors without the need to amplify them by PCR, which avoids unintentional shuffling of complementary determining regions. Using quantitative PCR (qPCR), the efficiency of each selection round is monitored to provide immediate feedback and guide troubleshooting. Our protocol can be carried out by any trained biochemist or molecular biologist using commercially available reagents and typically gives rise to 10-30 unique sybodies exhibiting binding affinities in the range of 500 pM-500 nM.


Assuntos
Técnicas de Química Sintética/métodos , Anticorpos de Domínio Único/química , Bacteriófagos/química , Ribossomos/química
18.
Nat Protoc ; 15(5): 1742-1759, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32269382

RESUMO

[18F]6-fluoro-L-DOPA ([18F]FDOPA) is a diagnostic radiopharmaceutical for positron emission tomography (PET) imaging that is used to image Parkinson's disease, brain tumors, and focal hyperinsulinism of infancy. Despite these important applications, [18F]FDOPA PET remains underutilized because of synthetic challenges associated with accessing the radiotracer for clinical use; these stem from the need to radiofluorinate a highly electron-rich catechol ring in the presence of an amino acid. To address this longstanding challenge in the PET radiochemistry community, we have developed a one-pot, two-step synthesis of high-molar-activity [18F]FDOPA by Cu-mediated fluorination of a pinacol boronate (BPin) precursor. The method is fully automated, has been validated to work well at two separate sites (an academic facility with a cyclotron on site and an industry lab purchasing [18F]fluoride from an outside vendor), and provides [18F]FDOPA in reasonable radiochemical yield (2.44 ± 0.70 GBq, 66 ± 19 mCi, 5 ± 1%), excellent radiochemical purity (>98%) and high molar activity (76 ± 30 TBq/mmol, 2,050 ± 804 Ci/mmol), n = 26. Herein we report a detailed protocol for the synthesis of [18F]FDOPA that has been successfully implemented at two sites and validated for production of the radiotracer for human use.


Assuntos
Ácidos Borônicos/química , Técnicas de Química Sintética/métodos , Cobre/química , Di-Hidroxifenilalanina/análogos & derivados , Glicóis/química , Di-Hidroxifenilalanina/síntese química , Radioisótopos de Flúor , Halogenação
19.
Nat Protoc ; 15(5): 1760-1774, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32296151

RESUMO

The direct cleavage of otherwise inert C-H bonds has emerged as a sustainable approach for organic synthesis; in contrast to other approaches, these reactions result in the formation of fewer undesired by-products and do not require pre-functionalization steps. In recent years, oxidative C-H/N-H alkyne annulations and C-H oxygenations were realized by 3d metals. Unfortunately, most of these reactions require stoichiometric amounts of often toxic chemical oxidants. This protocol provides a general method for cobaltaelectro-catalyzed C-H activations of benzamides. Here, anodic oxidation obviates the need for a chemical oxidant and uses 10-20% of a more environmentally benign, inexpensive catalyst. We outline a detailed and precise description of the designed electrolytic cell for metallaelectrocatalysis, including readily available electrode materials and electrode holders. The custom-made device is further compared with the commercially available and standardized ElectraSyn 2.0 electrochemistry kit. As example applications of this approach, we describe cobaltaelectro-catalyzed C-H activation protocols for the direct C-H oxygenation of benzamides and resource-economical synthesis of isoquinolones. The cobaltaelectrocatalysis setup and reaction take about 17 h, while an additional 5 h have to be anticipated for workup and chromatographic purification. The methods described herein feature broad functional group tolerance, operational simplicity, low waste-product formation and an overall exceptional level of resource economy.


Assuntos
Benzamidas/química , Técnicas de Química Sintética/métodos , Cobalto/química , Técnicas Eletroquímicas/métodos , Catálise , Oxirredução
20.
Nat Protoc ; 15(4): 1525-1541, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32111986

RESUMO

Positron emission tomography (PET) is a diagnostic nuclear imaging modality that relies on automated protocols to prepare agents labeled with a positron-emitting radionuclide (e.g., 18F). In recent years, new reactions have appeared for the 18F-labeling of agents that are difficult to access by applying traditional radiochemistry, for example those requiring 18F incorporation into unactivated (hetero)arenes. However, automation of these new methods for translation to the clinic has progressed slowly because extensive modification of manual protocols is typically required when implementing novel 18F-labeling methodologies within automated modules. Here, we describe the workflow that led to the automated radiosynthesis of the poly(ADP-ribose) polymerase (PARP) inhibitor [18F]olaparib. First, we established a robust manual protocol to prepare [18F]olaparib from the protected N-[2-(trimethylsilyl)ethoxy]methyl (SEM) arylboronate ester precursor in a 17% ± 5% (n = 15; synthesis time, 135 min) non-decay-corrected (NDC) activity yield, with molar activity (Am) up to 34.6 GBq/µmol. Automation of the process, consisting of copper-mediated 18F-fluorodeboronation followed by deprotection, was achieved on an Eckert & Ziegler Modular-Lab radiosynthesis platform, affording [18F]olaparib in a 6% ± 5% (n = 3; synthesis time, 120 min) NDC activity yield with Am up to 319 GBq/µmol.


Assuntos
Técnicas de Química Sintética/métodos , Cobre/química , Radioisótopos de Flúor/química , Ftalazinas , Piperazinas , Inibidores de Poli(ADP-Ribose) Polimerases , Automação , Ftalazinas/síntese química , Ftalazinas/química , Piperazinas/síntese química , Piperazinas/química , Inibidores de Poli(ADP-Ribose) Polimerases/síntese química , Inibidores de Poli(ADP-Ribose) Polimerases/química , Tomografia por Emissão de Pósitrons , Radioquímica , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química
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