Methylboronic Acid Research Articles

A Facile Synthetic Method for Conversion of Chlorophyll-ato Bacteriochlorophyll-c

A simple synthetic route for converting chlorophyll(Chl)-a to bacteriochlorophyll(BChl)-c is described. Methyl bacteriopheophorbide(MBPhe)-d, easily obtained from Chl-a, was selectively brominated at the 20-position with pyridinium tribromide, and the following Suzuki-coupling with methylboronic acid afforded ca. a 4:1 mixture of desired MBPhe-c (20-Me) and debrominated MBPhe-d (20-H) in quantitative yield. Separation of MBPhe-c, transesterification of the 17-propionate group (Me --> farnesyl), and magnesium insertion successfully led to naturally occurring BChl-c.

Palladium-Catalyzed Methylation and Arylation of sp2 and sp3 C−H Bonds in Simple Carboxylic Acids

The use of preformed sodium carboxylates as substrates led to the first observation of facile Pd-insertions into sp3 β-C−H bonds in simple aliphatic acids. Consequently, Pd-catalyzed methylation and arylation of o-C−H bonds in benzoic acids and β-C−H bonds in aliphatic acids using either a phenylboronate, methylboronic acid, or ArI have been achieved via a C−H activation/C−C coupling sequence.

Stereoisomer-differentiating esterification of diols with methylboronic acid. A simple method for the separation of cis- and trans-1,2-diols

A simple procedure for the separation of cis–trans-stereoisomeric 1,2-diols by the selective esterification of cis-isomer with methylboronic acid is described.

Dimeric boronates derived from the reaction of schiff bases and boronic acids

The one-pot synthesis of dimeric boron complexes is reported. The compounds were obtained by reaction of Schiff bases (tridentate ligands) with trans-beta-phenylvinylboronic acid, 3-thiopheneboronic acid and methylboronic acid. Building of the dimeric structures is favored by the presence of intramolecular N-> B coordination bonds, resulting in the formation of ten-membered ring heterocycles. An X-ray crystallographic analysis for one of them confirmed the dimeric nature of these compounds.

Stability of β-agonist methyl boronic derivatives before gas chromatography–mass spectrometry analysis

A method for the confirmatory analysis of clenbuterol, mabuterol and salbutamol in bovine urine and feeds by gas chromatography–mass spectrometry (GC–MS) is described. β-Agonist residues were extracted and further purified and concentrated by immunoaffinity chromatography. Methyl boronic acid (MBA) was used for the derivatisation of β-agonist residues and time and temperature of derivatisation were optimised. These derivatives allowed the use of shorter columns while improving the chromatographic resolution. Methyl boronic derivatives were stored either at room temperature or at −20 °C and then injected into the gas chromatograph–mass spectrometer at specific time intervals. Methyl boronic derivatives showed a slight decrease for clenbuterol and a more marked loss for mabuterol when stored at −20° C up to 3 days and then remained stable up to 7 days. However, the stability for salbutamol was poorer as it rapidly decreased at 2 days. When derivatives were stored at room temperature, clenbuterol and internal standard (IS) showed good stability up to 6 h while the stability of mabuterol was progressively reduced. Salbutamol dropped to very low values at just the first hour. Under these conditions it is clear that the analysis should be performed as soon as possible after derivatisation. The combination of immunoaffinity chromatography, MBA derivatisation and gas chromatography–mass spectrometry has shown a high sensitivity, good reproducibility and short chromatography time for the control of the studied β-agonists.

Minimization of carbon addition during derivatization of monosaccharides for compound‐specific δ13C analysis in environmental research

Little is known about the delta13C composition of monosaccharides representing the largest carbon reservoir in the biosphere. The main reason for this might be that monosaccharides have to be derivatized prior to gas chromatography/combustion/isotope ratio mass spectrometry (GC/C/IRMS) analyses and that a large isotopic correction is necessary for the carbon that has to be added to the original molecule during derivatization, resulting in large uncertainty of the calculated delta13C values of individual monosaccharides. The amount of added derivatization carbon is twice (alditol acetates) or even three times (trimethylsilyl (TMS) derivatives) as high as the amount of the original monosaccharide carbon. In addition, isotope fractionation occurs during acetylation. Therefore, the objectives of this study were (i) to minimize carbon addition during derivatization for GC/C/IRMS measurements of monosaccharides in soil and sediment samples and (ii) to quantify improvements in accuracy and precision of the final results. Minimization of carbon addition was accomplished by derivatization with methylboronic acid (MBA) and TMS thereafter (MBA method). Monosaccharides derivatized with the MBA method instead of TMS reduced the number of added carbon atoms from 2.2-2.7 to 0.3-0.8 per sugar carbon atom. Although the precision of GC/C/IRMS measurements with both methods is comparable (about 0.3 per thousand), delta13C values of an internal standard indicated that the newly developed MBA method is about 2 per thousand more accurate than the TMS method. delta13C comparison between soil samples that differed only slightly in their bulk carbon isotope signature showed that the MBA method is better in proving these small differences on a significant level. Total precision of the whole MBA method including all analytical and calculation steps is better by a factor of almost three than the TMS method.

Synthesis of [11C]/(13C)amines via carbonylation followed by reductive amination.

Twelve 11C-labelled amines were prepared via 11C-carbonylation followed by reductive amination. The 11C-carbonylation was performed in the presence of tetrakis(triphenylphosphine)palladium using aryl iodides or aryl triflates, [11C]carbon monoxide and phenyl-/methylboronic acid. The [11C]ketones formed in this step were then transformed directly into amines by reductive amination using different amines in the presence of TiCl4 and NaBH3CN. The 11C-labelled amines were obtained with decay-corrected radiochemical yields in the range 2-78%. The radiochemical purity of the isolated products exceeded 98%. (13C)Benzhydryl-phenyl-amine was synthesised and analysed by NMR spectroscopy for confirmation of the labelling position. Specific radioactivity was determined for the same compound. The reference compounds were prepared by reductive amination of ketones using conventional reaction conditions and three of the compounds were novel. The presented approach is a new method for the synthesis of [11C]/(13C)amines.

Overexpression and enzymatic characterization of Neisseria gonorrhoeae penicillin-binding protein 4.

The penicillin-binding proteins (PBPs) are ubiquitous bacterial enzymes involved in cell wall biosynthesis, and are the targets of the beta-lactam antibiotics. The low molecular mass Neisseria gonorrhoeae PBP 4 (NG PBP 4) is the fourth PBP revealed in the gonococcal genome. NG PBP 4 was cloned, overexpressed, purified, and characterized for beta-lactam binding, DD-carboxypeptidase activity, acyl-donor substrate specificity, transpeptidase activity, inhibition by a number of active site directed reagents, and pH profile. NG PBP 4 was efficiently acylated by penicillin (30,000 m-1.s-1). Against a set of five alpha- and epsilon-substituted l-Lys-D-Ala-D-Ala substrates, NG PBP 4 exhibited wide variation in specificity with a preference for N epsilon-acylated substrates, suggesting a possible preference for crosslinked pentapeptide substrates in the cell wall. Substrates with an N epsilon-Cbz group demonstrated pronounced substrate inhibition. NG PBP 4 showed 30-fold higher activity against the depsipeptide Lac-ester substrate than against the analogous peptide substrate, an indication that k2 (acylation) is rate determining for carboxypeptidase activity. No transpeptidase activity was apparent in a model transpeptidase reaction. Among a number of active site-directed agents, N-chlorosuccinimide, elastinal, iodoacetamide, iodoacetic acid, and phenylglyoxal gave substantial inhibition, and methyl boronic acid gave modest inhibition. The pH profile for activity against Ac2-l-Lys-D-Ala-d-Ala (kcat/Km) was bell-shaped, with pKa values at 6.9 and 10.1. Comparison of the enzymatic properties of NG PBP 4 with other DD-carboxypeptidases highlights both similarities and differences within these enzymes, and suggests the possibility of common mechanistic roles for the two highly conserved active site lysines in Class A and C low molecular mass PBPs.

Regiospecific Suzuki Coupling of 3,5‐Dichloroisothiazole‐4‐carbonitrile.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Regiospecific Suzuki coupling of 3,5-dichloroisothiazole-4-carbonitrile

3,5-Dichloroisothiazole-4-carbonitrile 1 react with aryl- and methylboronic acids to give in high yields the 3-chloro-5-(aryl and methyl)-isothiazole-4-carbonitrile 2 regiospecifically. The reaction was optimized with respect to base, phase transfer agent and palladium catalyst. Suzuki coupling at C-5 was also achieved in high yield using potassium phenyltrifluoroborate. The regiospecificity of either coupling method is maintained with 3,5-dibromoisothiazole-4-carbonitrile 4 to give exclusively 3-bromo-5-phenylisothiazole-4-carbonitrile 5. Suzuki cross-coupling conditions applied to 3-chloro-5-phenylisothiazole-4-carbonitrile 2a gave 3-phenoxy-5-phenylisothiazole-4-carbonitrile 6, which was prepared independently, and not the 3-phenyl derivative. All isothiazole products were fully characterized.

Coupling of Isoprenoid Triflates with Organoboron Nucleophiles: Synthesis and Biological Evaluation of Geranylgeranyl Diphosphate Analogues

The Suzuki coupling reaction has been used to introduce a methyl group derived from commercially available methylboronic acid into a vinyl triflate. This has led to a concise synthesis of all-trans-geranylgeraniol (10), with the key step being the palladium-catalyzed, silver-mediated methylation of triflate 8 to give ethyl geranylgeranoate 9. This coupling protocol has also been used to produce the novel geranylgeranyl diphosphate (GGPP) analogue 3-phenyl-3-desmethylgeranylgeranyl diphosphate (3-PhGGPP, 2d). Our previously developed organocuprate coupling protocol has been used to introduce the cyclopropyl and tert-butyl moieties into the 3-position of vinyl triflate 8. The four GGPP analogues 3-vinyl-3-desmethylgeranylgeranyl diphosphate (3-vGGPP, 2a), 3-cyclopropyl-3-desmethylgeranylgeranyl diphosphate (3-cpGGPP, 2b), 3-tert-butyl-3-desmethyl-geranylgeranyl diphosphate (3-tbGGPP, 2c), and 2d were then evaluated as potential inhibitors of recombinant yeast protein-geranylgeranyl transferase I (PGGTase I). The potential mechanism-based inhibitors 3-vGGPP and 3-cpGGPP did not exhibit time-dependent inactivation of PGGTase I. Instead, both analogues were alternative substrates, in accord with the interaction of the corresponding farnesyl analogues 3-vFPP and 3-cpFPP with PFTase. The tert-butyl and phenyl analogues were not substrates, but were instead competitive inhibitors of PGGTase I. Note that all four of the GGPP analogues were bound less tightly by the enzyme than the natural substrate, in contrast to the behavior of the 3-substituted FPP analogues.

Generation and characterization of ionic and neutral (CH 3OBH) +/· and (CH 3BOH) +/· in the gas phase by tandem mass spectrometry

The isomeric dicoordinated borinium ions CH 3O–B–H + and CH 3–B–OH + are generated upon electron ionization of trimethylborate and methyl boronic acid, respectively. The connectivity of the ions is confirmed by collision-induced dissociation experiments on magnetic deflection type tandem mass spectrometers. Neutralization–reionization experiments on these structurally characterized ions indicate that the neutral radicals CH 3O–B–H · and CH 3–B–OH · are viable species in the gas phase. Calculations at the G2 level of theory were performed to obtain thermochemical data on the title isomers and their main dissociation products. The calculations also provide a rationale for the moderate yield of the neutrals generated in the experiments: the vertical electron transfer processes for both systems are associated with particularly unfavourable Franck-Condon factors.

Synthesis, Structure, and Reactions of Triaryl(methyl)bismuthonium Salts

Treatment of triarylbismuth difluorides 2 (Ar3BiF2; a, Ar = Ph; b, Ar = 4-MeC6H4; c, Ar = 4-MeOC6H4; d, Ar = 2-MeOC6H4) with methylboronic acid (3) in the presence of BF3·OEt2 in CH2Cl2 afforded th...

Generation and characterization of ionic and neutral dihydroxy boron B(OH) 2+/0 in the gas phase

The dicoordinated borinium ion, dihydroxyborinium, B(OH) 2 + is generated from methyl boronic acid CH 3B(OH) 2 by dissociative electron ionization and its connectivity confirmed by collisional activation. Neutralization–reionization (NR) experiments on this ion indicate that the neutral B(OH) 2 radical is a viable species in the gas phase. Both vertical neutralization of B(OH) 2 + and reionization of B(OH) 2 in the NR experiment are, however, associated with particularly unfavorable Franck-Condon factors. The differences in adiabatic and vertical electron transfer behavior can be traced back to a particular π stabilization of the cationic species compared to the sp 2-type neutral radical. Thermochemical data on several neutral and cationic boron compounds are presented based on calculations performed at the G2 level of theory.

A Remarkable Effect of Cationic Micelles on Stereospecific Hydrolysis of p-Nitrophenyl D-Glucopyranoside by Boronic Acid

The hydrolysis rate of p-nitrophenyl α-D-glucopyranoside was greatly enhanced in cationic micelles of hexadecyltrimethylammonium chloride (HTAC) by using phenylboronic acid (PBA) in pH 11.0 phosphate buffer. Stereospecific acceleration of hydrolysis toward the α-anomer over the β-anomer then increased to a high extent. The effect of the type of boronic acid in micelles of HTAC was examined in order to clarify the mechanism of the enhancement of the hydrolysis rate of the α-glucoside and the α/β selectivity in the presence of HTAC by the addition of PBA. The more hydrophobic boronic acid afforded the higher α/β selectivity. p-Decyloxyphenylboronic acid (C10PBA) gave the highest selectivity (kα/kβ=64) in the presence of cationic micelles. The enhancement of selectivity by the addition of 1mM C10PBA was comparable to that by 7mM methylboronic acid (MBA), which is the highest selectivity obtained in the absence of cationic micelles.

Stereoselective Hydrolysis of p-Nitrophenyl Glycoside by Boronic Acid

Abstract The alkaline hydrolysis of p-nitrophenyl α-D-glucoside, α-D-galactoside, and β-D-mannoside was selectively accelerated by addition of methyl boronic acid, as compared to that of the corresponding β-D-glucoside, β-D-galactoside, and α-D-mannoside. In the case of p-nitrophenyl α (or β)-D-glucoside, the α/β selectivity was increased up to 110 when four molar equivalents of methyl- or phenylboronic acid were added.

Synthesis of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP)

Palladium-catalyzed cross-coupling of methylboronic acid with 2-chloro-3-nitropyridine produced 2-methyl-3-nitropyridine 4 in one step in high yield. Oxidation of 4 with selenium dioxide gave aldehyde 5. Alternatively, condensation of 4 with DMFDMA followed by oxidation gave 5 in a two step higher yielding conversion. Subsequent direct coupling of 5 with thiosemicarbazide followed by reduction of the nitro group using stannous chloride or sodium sulfide provided 3-AP (3). Reduction with sodium hydrosulfite gave 3-HAP (8). Finally a route which avoids the reduction of a nitro function was devised. Thus direct coupling of styrene with 2-chloro-3-aminopyridine 9 under Heck reaction conditions gave 16 which was converted to 17, oxidized to the aldehyde 18 and converted to 3-AP (3) with in situ deblocking of the t-Boc functionality.

An 11B NMR study of the kinetics of methylboronic acid–methylboronate interchange in aqueous solution

Methylboronic acid–methylboronate interchange has been studied kinetically by the band shape analysis of 11B NMR signals. The system was analyzed as two-site exchange CH 3B(OH) 2⇌CH 3B(OH) 3 − for a self-buffered aqueous solution in pH 9.5–11.4 at 24–55°C. The exchange rate was expressed as: rate=( k ex[CH 3B(OH) 3 − ]+ k X2)[CH 3B(OH) 2]=( k ex[CH 3B(OH) 2]+ k Y2)[CH 3B(OH) 3 − ]. The second-order rate constant, k ex (dm 3 mol −1 s −1) (24.2°C)=7.03×10 5, is independent of pH, and the kinetic parameters obtained at I=0.10 M are Δ H ≠ (kJ mol −1)=17.5±1.9 and Δ S ≠ (J mol −1 K −1)=−74.3±6.2. A dimeric transition state is suggested for the path similarly to the interchange between boric acid and borate. The first-order rate constants k X2 and k Y2 depend on the hydroxide ion concentration indicating alternative routes for the interchange.

Determination of beta 2-agonists in hair by gas chromatography/mass spectrometry.

A method is described for the determination of the beta 2-agonists clenbuterol and salbutamol in hair. The method involves washing hair in sodium dodecyl hydrogensulphate solution, chemical digestion of the hair matrix in alkaline medium, solid-phase extraction, derivatization with methylboronic acid and analysis by gas chromatography/electron impact mass spectrometry in either the selected-ion monitoring or the scan mode. the effects of chemical digestion and of extraction on the recovery of the analytes were evaluated. Derivatization with methyl-boronic acid was compared with trimethylsilylation for GC/MS analysis of hair extracts, and was found to give mass spectra which showed more structural information with less chemical noise and better sensitivity. The proposed method was tested on real hair samples obtained from guinea pigs treated with growth-promoting doses of clenbuterol and salbutamol. Both compounds could be detected in hair of treated animals.

BATO complexes derived from dimethoxy dioximes: Synthesis, characterization and biodistribution

To prepare less lipophilic BATO complexes, two new methoxy-substituted dioximes were synthesized: cis-4,5-dimethoxycyclohexane-1,2-dione dioxime (DMCDO) and 1,4-dimethoxybutane-2,3-dione dioxime (DMDMG). 99mTcCl(DMCDO) 3BMe (BMe = methylboronic acid) was prepared and characterized. Reversed-phase HPLC analyses of 99mTcCl(DMCDO) 3BMe and 99mTcCl(DMCDO) 3- p-TBA ( p-TBA = p-tolylboronic acid) indicated that both of these complexes were mixtures of four enantiomeric pairs of diastereomers. Attempted preparation of a BATO complex from DMDMG gave a mixture of products. In rats, 99mTcCl(DMCDO) 3BMe displayed more rapid liver and renal clearance than 99mTcCl(CDO) 3BMe, but 99mTcCl(DMCDO) 3BMe and 99mTcCl(DMCDO) 3- p-TBA displayed low uptake in both heart and brain.