High Yield Preparation Research Articles

The Nicholas Reaction: A Powerful Tool for the Stereoselective Synthesis of Bioactive Compounds

Polyether units are a frequent heterocyclic fragment present in numerous natural products of great biological importance and constitute significant synthons for the synthesis of pharmacologically relevant compounds. Likewise, compounds having ­stereochemically defined alkyl-branched hydrocarbon chains are widespread in nature and the development of new synthetic ­methodologies to achieve their preparation in high yields and levels of stereocontrol is currently a challenging endeavour in organic synthesis. In this account, we describe our own approach to the stereoselective synthesis of bioactive compounds using the Nicholas reaction, the discovery of unexpected reaction pathways as well as some unreported results. The scope of the title reaction, within our research interests, and its synthetic applications are outlined. ­Reference to important related work from others in the field is also included.

NG-Hydroxyguanidines from Primary Amines

A concise and general method for the preparation of N(G)-hydroxyguanidines from primary amines is reported. Using available and readily prepared materials, primary amines are converted to protected N(G)-hydroxyguanidines in a one-pot procedure followed by deprotection under nonreducing conditions. The method has been successfully applied to a number of examples including a high-yielding preparation of N(G)-hydroxy-L-arginine, the intermediate in the enzymatic conversion of L-arginine to nitric oxide and L-citrulline by nitric oxide synthase.

Expression, purification and characterization of individual bromodomains from human Polybromo-1

Computational analysis reveals six tandem bromodomains within the amino-terminal region of the human Polybromo-1 protein, a required subunit of the Polybromo, BRG1-associated factors chromatin remodeling complex. Bromodomains are acetyl-lysine binding modules found in many chromatin binding proteins and histone acetyltransferases. Recent in vivo studies suggest that bromodomains can both discriminate the presence of an acetyl group on a lysine side chain and locate the acetyl-lysine within a histone protein. Together, this implies that multiple bromodomains may be able to function cooperatively and recognize a specific acetylation pattern to localize remodeling complexes to specific chromatin sites. Here, the cloning, expression and bioactivity of recombinant bromodomains from the human Polybromo-1 protein is described. Individual bromodomains from Polybromo-1 were cloned from human cDNA into a pET30b expression vector enabling effective one-step purification by affinity chromatography. Due to complications, including the high number of rare codons found in the coding regions and the tendency of individually expressed domains to aggregate and misfold, bacterial expression was only achieved using a cell strain containing rare eukaryotic tRNAs. Fluorescence-based bioactivity assays were performed to determine if native binding features were retained. The present cloning, expression, and purification procedure enabled the preparation of large quantity and high yields of biologically active recombinant bromodomains from human Polybromo-1 for in vitro structure and function studies. This is the first report of recombinant active form of bromodomains obtained from PB1.

A High‐Yielding Preparation of β‐Ketonitriles.

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A simple, catalytic H2-hydrogenation method for the synthesis of fine chemicals; hydrogenation of protoporphyrin IX dimethyl ester

A conceptually simple H2-hydrogenation protocol is introduced for the high-yield preparation of a natural product derivative. Protoporphyrin IX dimethyl ester is hydrogenated to the mesoporphyrin analogue in N,N-dimethylacetamide under H2 (1atm) at 80°C within 30min. The reaction is catalyzed by commercial RuCl3, without the need for the use of phosphine- and/or carbene-based ligands.

SequentialO- andN-Acylation Protocol for High-Yield Preparation and Modification of Rotaxanes: Synthesis, Functionalization, Structure, and Intercomponent Interaction of Rotaxanes

A pseudorotaxane consisting of a 24-membered crown ether and secondary ammonium salt with the hydroxy group at the terminus was quantitatively acylated by bulky acid anhydride in the presence of tributylphosphane as catalyst to afford the corresponding rotaxane in high yield. Large-scale synthesis without chromatographic separation was easily achieved. The ammonium group in the resulting rotaxane was quantitatively acylated with excess electrophile in the presence of excess trialkylamine. Various N-functionalized rotaxanes were prepared by this sequential double-acylation protocol. 1H NMR spectra and X-ray crystallographic analyses of the rotaxanes showed that the crown ether component was captured on the ammonium group in ammonium-type rotaxane by strong hydrogen-bonding intercomponent interaction. The conformation around the ammonium group was fixed by the hydrogen-bonding interaction. Meanwhile, the conformation of the amide-type rotaxane was determined by the weak CH/pi interaction between the methylene group in crown ether and the benzene ring of the axle component. The N-acylation of ammonium-type rotaxane is useful for the preparation of both functionalized rotaxanes and weak intercomponent interaction-based rotaxanes.

Microwave-Assisted Three-Component Synthesis of 7-Aryl-2-alkylthio-4,7-dihydro-1,2,4-triazolo[1,5-a]-pyrimidine-6-carboxamides and Their Selective Reduction

Multicomponent reactions (MCRs) and microwave-assisted organic synthesis (MAOS) have been used as key methods for the synthesis of fused dihydropyrimidine derivatives. The three-component condensation of 3-amino-5-alkylthio-1,2,4-triazoles with aromatic aldehydes and acetoacetamides under microwave irradiation was developed as a rapid and efficient solution-phase method for the high-yielding preparation of 7-aryl-2-alkylthio-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine-6-carboxamide libraries. In addition, the selective reduction of the formed dihydrotriazolopyrimidines to trans-trans-2-alkylthio-7-aryl-4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]pyrimidine-6-carboxamides was established. The described synthetic protocols provide rapid access to novel and diversely substituted dihydroazolopyrimidine libraries.

Synthesis of Copper-Promoted CeO2 Catalysts

The urea method is explored for a high-yield preparation of CuO−CeO2 catalysts precursors. Solutions containing urea, Ce(NO3)3, and Cu(NO3)2 were aged at 363 K for 5 h, achieving a quantitative coprecipitation in the form of amorphous Cu(II)−Ce(III) basic carbonates, with Cu(II) contents up to 40%. The mixed precursors were characterized by PXRD, SEM, EDS, FTIR, and TG. Upon mild thermal treatment under air atmosphere, i.e., T = 723 K, powders were readily converted into CuO-promoted nanometric ceria. No Tenorite (CuO) segregation is observed after annealing at 873 K. The binary oxides were characterized by means of temperature-programmed reduction (TPR) and a test reaction for the preferential oxidation of carbon monoxide (CO-PROX), achieving the best performance with samples containing around 20% in copper atoms.

Genome-wide Transcriptional Profile of Escherichia coli in Response to High Levels of the Second Messenger 3′,5′-Cyclic Diguanylic Acid

Cyclic diguanylic acid (c-di-GMP; cGpGp) is a global second messenger controlling motility and adhesion in bacterial cells. Intracellular concentrations of c-di-GMP depend on two opposite activities: diguanylate cyclase, recently assigned to the widespread GGDEF domain, and c-di-GMP-specific phosphodiesterase, associated with proteins harboring the EAL domain. To date, little is known about the targets of c-di-GMP in the cell or if it affects transcriptional regulation of certain genes. In order to expand our knowledge of the effect of this molecule on the bacterial metabolism, here we report on the Escherichia coli transcriptional profile under high levels of c-di-GMP. We show that an important number of genes encoding cell surface and membrane-bound proteins are altered in their transcriptional activity. On the other hand, genes encoding several transcriptional factors, such as Fur, RcsA, SoxS, and ZraR, are up-regulated, and others, such as GadE, GadX, GcvA, and MetR, are down-regulated. Transcription of motility and cell division genes were altered, and consistent with this was the physiological analysis of cells overexpressing yddV, a diguanylate cyclase; these cells displayed an abnormal cell division process when high levels of c-di-GMP were present. We also show evidence that the diguanylate cyclase gene yddV is co-transcribed with dos, a heme base oxygen sensor with c-di-GMP-specific phosphodiesterase activity. A delta dos::kan mutation rendered the cells unable to divide properly, suggesting that dos and yddV may be part of a fine-tuning mechanism for regulating the intracellular levels of c-di-GMP.

A High-Yielding Preparation of β-Ketonitriles

[reaction: see text] beta-Ketonitriles are important precursors for a wide variety of biologically active heterocycles. A facile procedure for the high-yielding acylation of nitrile anions with unactivated esters to provide beta-ketonitriles is reported. The procedure is successful with enolizable and nonenolizable esters as well as hindered nitrile anions.

Synthesis and Electrochemistry of Undeca-substituted Metallo-benzoylbiliverdins

The high-yield preparation of metallo-benzoylbiliverdins 9, 10, and 11 from either oxidation of dodeca-substituted porphyrin 6 in the presence of NaNO2/TFA and air followed by metalation or by reaction of the Ni(II) or Cu(II) complexes of 6 with m-chloroperoxybenzoic acid in pyridine under air is reported. The X-ray structures of complexes 9 and 10 and the electrochemistry and spectroelectrochemistry of metallo-benzoylbiliverdins 9-11 are presented and discussed.

Synthetic and structural studies on C-ethynyl- and C-bromo-carboranes

A high-yield preparation of the C-monoethynyl para-carborane, 1-Me(3)SiC[triple bond]C-1,12-C2B10H11, from C-monocopper para-carborane and 1-bromo-2-(trimethylsilyl)ethyne, BrC[triple bond]CSiMe(3) is reported. The low-yield preparation of 1,12-(Me3SiC[triple bond]C)2-1,12-C2B10H10 from the C,C'-dicopper para-carborane derivative with 1-bromo-2-(trimethylsilyl)ethyne, BrC[triple bond]CSiMe3, has been re-investigated and other products were identified including the C-monoethynyl-carborane 1-Me3SiC[triple bond]C-1,12-C2B10H11 and two-cage assemblies generated from cage-cage couplings. The contrast in the yields of the monoethynyl and diethynyl products is due to the highly unfavourable coupling process between 1-RC[triple bond]C-12-Cu-1,12-C2B10H10 and the bromoalkyne. The ethynyl group at the cage carbon C(1) strongly influences the chemical reactivity of the cage carbon at C(12)-the first example of the "antipodal effect" affecting the syntheses of para-carborane derivatives. New two-step preparations of 1-ethynyl- and 1,12-bis(ethynyl)-para-carboranes have been developed using a more readily prepared bromoethyne, 1-bromo-3-methyl-1-butyn-3-ol, BrC[triple bond]CCMe2OH. The molecular structures of the two C-monoethynyl-carboranes, 1-RC[triple bond]C-1,12-C2B10H11 (R = H and Me3Si), were experimentally determined using gas-phase electron diffraction (GED). For R = H (R(G) = 0.053) a model with C(5v) symmetry refined to give a C[triple bond]C bond distance of 1.233(5) A. For R = Me3Si (R(G) = 0.048) a model with C(s) symmetry refined to give a C[triple bond]C bond distance of 1.227(5) A. Molecular structures of 1,12-Br2-1,12-C2B10H10, 1-HC[triple bond]C-12-Br-1,12-C2B10H10 and 1,12-(Me(3)SiC[triple bond]C)2-1,12-C2B10H10 were determined by X-ray crystallography. Substituents at the cage carbon atoms on the C2B10 cage skeleton in 1-X-12-Y-1,12-C2B10H10 derivatives invariably lengthen the cage C-B bonds. However, the subtle substituent effects on the tropical B-B bond lengths in these compounds are more complex. The molecular structures of the ethynyl-ortho-carborane, 1-HC[triple bond]C-1,2-C2B10H11 and the ethene, trans-Me3SiBrC=CSiMe3Br are also reported.

Vinylation of Aryl Bromides Using an Inexpensive Vinylpolysiloxane

[reaction: see text] A mild and general method for the palladium-catalyzed vinylation of aryl bromides has been developed. The use of tetrabutylammonium fluoride (TBAF) as the activator and an inexpensive and nontoxic vinyl donor, 1,3,5,7-tetramethyl-1,3,5,7-tetravinylcyclotetrasiloxane (D(4)(V), 1), allows for a general and high-yielding preparation of substituted styrenes.

Preparation of Azepinoindole Derivatives via Oxidative Palladium Couplings

Oxidative palladium couplings allow the preparation in high yields of different azepinoindole moieties. The use of CuCl2 as reoxidant leads to the formation of chloro derivatives instead of alkenes. Keywords: Indole, palladium, oxidative cyclisation, oxidant

A Green Protocol for the Easy Synthesis of Thiiranes from Epoxides Using Thiourea/Silica Gel in the Absence of Solvent.

The use of thiourea/silica gel provides a green protocol for the easy and high-yielding preparation of thiiranes from different classes of epoxides in the absence of solvent at room temperature. The high stereospecific conversion of (R)(+)-styrene oxide to (S)(+)-styrene sulfide is also reported using this reagent system.

Identification of an achiral analogue of J-113397 as potent nociceptin/orphanin FQ receptor antagonist

To date, J-113397 represents the most potent and selective non peptide NOP receptor antagonist widely used in pharmacological studies. However, the synthesis, purification, and enantiomer separation of this molecule, which contains two chiral centers, is rather difficult and low-yielding. Here, we synthesized and tested a series of simplified J-113397 analogues to investigate the importance of the stereochemistry and the influence of the substituents at position 3 of the piperidine nucleus and on the nitrogen atom of the benzimidazolidinone nucleus. The compound coded as Trap-101, an achiral analogue of J-113397, combines a pharmacological profile similar to that of the parent compound with a practical, high-yielding preparation.

High-Yield Preparation of Uniform Cobalt Hydroxide and Oxide Nanoplatelets and Their Characterization

Cobalt hydroxide nanoplatelets with a uniform hexagonal shape were prepared in high yield ( approximately 95%) by a facile hydrothermal route in the presence of poly(vinylpyrrolidone). This method provides a simple, low-cost, and large-scale route to produce beta-cobalt hydroxide nanoplatelets with an average diameter of 280 nm and a thickness of ca. 26 nm which show a predominant well-crystalline hexagonal brucite-like phase. Their thermal decomposition produced anisotropic nanoplatelets of cobalt oxides (CoO and Co3O4) under designed temperatures. The products were characterized by transmission electronic microscopy, selected-area electron diffraction, Fourier transform infrared spectroscopy, differential scanning calorimetric, and thermogravimetric analysis. The magnetic properties of the products were investigated by a superconducting quantum interference device magnetometer. Co3O4 nanoplatelets exhibit a superparamagnetic behavior, and they might be a promising material to study the magnetic tunneling effect as anisotropic nanostructures.

Soy protein reduces hepatic lipotoxicity in hyperinsulinemic obese Zucker fa/fa rats

Hepatic steatosis is commonly present during the development of insulin resistance, and it is a clear sign of lipotoxicity attributable in part to an accelerated lipogenesis. There is evidence that a soy protein diet prevents the overexpression of hepatic sterol-regulatory element binding protein-1 (SREBP-1), decreasing lipid accumulation. Therefore, the aim of the present work was to study whether a soy protein diet may prevent the development of fatty liver through the regulation of transcription factors involved in lipid metabolism in hyperinsulinemic and hyperleptinemic Zucker obese fa/fa rats. Serum and hepatic cholesterol and triglyceride levels, as well as VLDL-triglyceride and LDL-cholesterol, were significantly lower in rats fed soy protein than in rats fed a casein diet for 160 days. The reduction in hepatic cholesterol was associated with a low expression of liver X receptor-alpha and its target genes, 7-alpha hydroxylase and ABCA1. Soy protein also decreased the expression of SREBP-1 and several of its target genes, FAS, stearoyl-CoA desaturase-1, and delta5 and delta6 desaturases, decreasing lipogenesis even in the presence of hyperinsulinemia. Reduction in SREBP-1 was not associated with the presence of soy isoflavones. Finally, soy protein reduced SREBP-1 expression in adipocytes, preventing hypertrophy, which also helps prevent the development of hepatic lipotoxicity.

A Green Protocol for the Easy Synthesis of Thiiranes from Epoxides Using Thiourea/Silica Gel in the Absence of Solvent

The use of thiourea/silica gel provides a green protocol for the easy and high-yielding preparation of thiiranes from different classes of epoxides in the absence of solvent at room temperature. The high stereospecific conversion of (R)(+)-styrene oxide to (S)(+)-styrene sulfide is also reported using this reagent system.

New high-yield preparation procedure of Ln[Fe(CN) 6]· nH 2O (Ln = La, Gd, and Lu) and their thermal decomposition into perovskite-type oxides

The heteronuclear Ln[Fe(CN) 6]· nH 2O (Ln = La, Gd, and Lu) complexes were synthesized by the mixing of (NH 4) 3[Fe(CN) 6] and Ln(NO 3) 3 methanol solutions as a new method. Their thermal decomposition products were then investigated. Although the yield of the Ln[Fe(CN) 6]· nH 2O complexes was ca. 20% for the well-known method in a water solution, it was improved to ca. 90% using this new method. The X-ray diffraction (XRD) patterns of the complexes agreed with those of the Ln[Fe(CN) 6]· nH 2O single phase for all the examined Ln systems. The LnFeO 3 single phase was obtained by the thermal decomposition of the synthesized heteronuclear complexes for Ln = La, Gd, and Lu.