Trimethyl Ester Research Articles

Reaction of organozinc reagents formed in reaction of dibromomalonic acid dialkyl esters and zinc, with 2-arylmethylenemalonic acid dinitriles and 3-aryl-2-cyanopropenoic acid methyl esters

Organozinc compounds, obtained from dibromomalonic acid dialkyl esters and zinc, react with 2-arylmethylmalonic acid dinitriles and 3-aryl-2-cyanopropenoic acid methyl esters forming 3-aryl-2,2-dicyanocyclopropane-1,1-dicarboxylic acid dialkyl esters and 3-aryl-2-cyanocyclopropane-1,1,2-tricarboxylic acid trimethyl esters. 1H and 13C NMR, 3 J CH constants are considered.

Synthesis of ent‐Thallusin.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Synthesis ofent-Thallusin

[reaction: see text] A three-step route from sclareol oxide (6) to bromo ester 4 in 53% overall yield was achieved using the efficient oxidation of an allylic bromide to an enal with bis(2,4,6-trimethylpyridine)silver(I) hexafluorophosphate in DMSO. Stille coupling of bromo ester 4 with stannylpyridine 5 gave the trimethyl ester of ent-thallusin in 54-92% yield by the stoichiometric conversion of 4 to a vinyl palladium intermediate prior to the addition of 5 to the reaction.

New pyrrolopyridazine derivatives as blue organic luminophors

New pyrrolopyridazine derivatives were synthesized as potential blue organic luminophors. Three different classes of pyrrolopyridazine derivatives were made, for example, aryl groups directly connected to the core PPY (pyrrolo[1,2- b]pyridazine-5,6,7-tricarboxylic acid trimethyl ester) moiety, aryl groups connected to the PPY via a vinylene linker and aryl groups connected to the PPY via an acetylene linker. Their optical and electrochemical properties were productively compared. One of the derivatives 2 showed a relative quantum yield as high as 0.9. Compound 8 in the vinyl bridged pyrrolopyridazine series has been characterized by its X-ray crystal structure analysis.

Unexpected formation of new chiral 3-amino-5-alkyl-2,5-dihydro-1 H-pyrrolin-2-ones from N-Boc-α-amino esters

We describe a one-pot process involving the DiBAl-H reduction of the ester moiety of N-protected α-amino esters, followed by Horner–Wadsworth–Emmons olefination in the presence of the trimethyl ester phosphonoglycinate carbanion allowing the formation of new chiral 3-amino-5-alkyl-2,5-dihydro-1 H pyrrolin-2-one 5 . The Z-enoate 4b , which is formed during this reaction, could be converted into the corresponding lactam 5b under UV irradiation with the presence of BuLi.

New Water-Soluble Phosphines as Reductants of Peptide and Protein Disulfide Bonds: Reactivity and Membrane Permeability

Tris(2-carboxyethyl)phosphine (TCEP) is a widely used substitute for dithiothreitol (DTT) in the reduction of disulfide bonds in biochemical systems. Although TCEP has been recently shown to be a substrate of the flavin-dependent sulfhydryl oxidases, there is little quantitative information concerning the rate by which TCEP reduces other peptidic disulfide bonds. In this study, mono-, di-, and trimethyl ester analogues of TCEP were synthesized to evaluate the role of carboxylate anions in the reduction mechanism, and to expand the range of phosphine reductants. The effectiveness of all four phosphines relative to DTT has been determined using model disulfides, including a fluorescent disulfide-containing peptide (H(3)N(+)-VTWCGACKM-NH(2)), and with protein disulfide bonds in thioredoxin and sulfhydryl oxidase. Mono-, di-, and trimethyl esters exhibit phosphorus pK values of 6.8, 5.8, and 4.7, respectively, extending their reactivity with the model peptide to correspondingly lower pH values relative to that of TCEP (pK = 7.6). At pH 5.0, the order of reactivity is as follows: trimethyl- > dimethyl- > monomethyl- > TCEP >> DTT; tmTCEP is 35-fold more reactive than TCEP, and DTT is essentially unreactive. Esterification also increases lipophilicity, allowing tmTCEP to penetrate phospholipid bilayers rapidly (>30-fold faster than DTT), whereas the parent TCEP is impermeant. Although more reactive than DTT toward small-molecule disulfides at pH 7.5, all phosphines are markedly less reactive toward protein disulfides at this pH. Molecular modeling suggests that the nucleophilic phosphorus of TCEP is more sterically crowded than the thiolate of DTT, contributing to the lower reactivity of the phosphine with protein disulfides. In sum, these data suggest that there is considerable scope for the synthesis of phosphine analogues tailored for specific applications in biological systems.

Efficient Synthesis of Pyropheophorbide-a and Its Derivatives

A process for the preparation of pyropheophorbide a and its derivatives, including 3-devinyl-3-(1'-hexyloxy)ethyl-­pyropheophorbide-a, otherwise known as HPPH, is provided. The process involves treating chlorin e6, in the form of its trimethyl ester, with a base, followed by heating to give pyropheophorbide a, which is converted to HPPH by treatment with acid, followed by hexyl alcohol under basic conditions.

Strategies for the Preparation of (1-Acetyloxyethylidene)-1,1-bisphosphonic Acid Derivatives

The novel strategies for the synthesis of acetylated etidronic acid derivatives were investigated. (1-Acetyloxyethylidene)-1,1-bisphosphonic acid and its P,P'-dimethyl, trimethyl and tetramethyl esters were prepared in high 81-100% yields.

Determination of organophosphorus pesticides and related compounds in water samples by membrane extraction and gas chromatography.

A membrane extraction-gas chromatography method was developed for determination of organophosphorus pesticides and related compounds including methamidophos, DDVP, dimethoate, methyl parathion, parathion, thiophosphoric acid trimethyl ester, and thiophosphoramidic acid dimethyl ester in water samples. In this method, surface-modified acetic cellulose membranes were used to extract the target analytes in water samples, the extracted analytes were back-extracted into a small amount of methanol, and gas chromatography with pulsed flame photometric detector (GC-PFPD) was used to determine the concentrations of target analytes in the extracts. The recoveries obtained for the target analytes spiked into the water samples ranged from 66 to 94%. The method detection limit for each target analyte was 0.05 microg L(-1). The method developed in this study had shown the advantages of being cheap, simple, fast, and reliable. It had been used successfully to determine the concentrations of target analytes in river water samples.

Carbonylbisphosphonate and (diazomethylene)bisphosphonate analogues of AZT 5 ′-diphosphate

A novel nucleotide analogue is described, in which the α,β-phosphoric anhydride oxygen of a nucleoside 5 ′-diphosphate is replaced by a carbonyl group: the carbonylbisphosphonate analogue 5 of 2 ′,3 ′-dideoxy-3 ′-azidothymidine 5 ′-diphosphate (AZT 5 ′-diphosphate). 5 was synthesized from tetramethyl (diazomethylene)bisphosphonate 1 via the trimethyl ester 4 of the corresponding AZT 5 ′-(diazomethylene)bisphosphonate 6, which is also a new type of nucleotide analogue. The ultimate product 5 was isolated by reverse-phase HPLC, and characterized by 31 P , 13 C , and 1 H NMR; and by high-resolution mass spectrometry. The ketone group of 5 is a visible chromophore (yellow) and reversibly forms a colorless hydrate. The ketone hydrate ‘pK’ is about 4.2 when excess of magnesium ion is present. The potential of such analogues as novel inhibitors of enzymes mediating nucleotide-dependent biochemical processes is discussed.

Antitumor agents. Part 209: Pheophorbide- a derivatives as photo-Independent cytotoxic agents

A methanolic crude extract of the plant Garuga pinnata Roxb. (Burseraceae) showed promising cytotoxic activity against a panel of human tumor cell lines in vitro, including KB and its drug-resistant sublines (Ferguson et al. Cancer Res. 1988, 48, 5956). Pheophorbide- a and- b methyl esters ( 3, 4) were isolated as active principles with broad photo-dependent cytotoxic activities in the micromolar range. These findings prompted SAR studies of known and novel pheophorbide- a derivatives as photo-dependent and photo-independent cytotoxic agents. The results showed that zinc-protoporphyrin IX ( 10), zinc 13 2 ( R)-hydroxypheophorbide- a methyl ester ( 22), and zinc chlorin- e6 trimethyl ester ( 13) possessed photo-independent cytotoxic activity. Compounds 13 and 22 were the most active cytotoxic agents of the series (mean ED 50 4.6±1.0 μM and 5.7±0.7 μM, respectively) against KB cells incubated in the dark.

The chemisorption of organophosphorus compounds at an Al(1 1 1) surface

The reactive chemisorption of three organophosphorus compounds have been investigated at clean and oxidised Al(1 1 1) surfaces using X-ray photoelectron spectroscopy (XPS). Phosphoric acid, trimethyl ester (or trimethylphosphate, TMP, OP(OCH 3) 3), and methyl phosphonic acid and dimethyl ester (or dimethylmethylphosphate, DMMP, OP(CH 3)(OCH 3) 2,) were adsorbed from the gas phase, but this approach proved unsuccessful for methyl phosphonic acid (MPA, OP(CH 3)(OH) 2) due to decomposition in the gas phase. MPA was therefore adsorbed from either an aqueous or an ether solution placed onto the aluminium sample in a helium atmosphere. Core binding energies for the POCH 3, PCH 3, PO and PO groups are reported and the decomposition pathways for the three compounds discussed. The PCH 3 bond is stable at both clean and oxidised aluminium surfaces up to temperatures of 570 K, whereas the POCH 3 bond can be broken even at room temperature. Decomposition of all three molecules requires clean aluminium sites and is hindered by high concentrations of adsorbed species.

Pyrolysis/gas chromatography/mass spectroscopy analysis of the surface film formed on graphite negative electrode

The chemical constituents of the protective surface film formed on graphite negative electrode in ethylene carbonate (EC)-based electrolyte solutions were analyzed by pyrolysis/gas chromatography/mass spectroscopy (Pyro/GC/MS). Oligomers that consist of oxyethylene units, such as ethylene glycol, di(ethylene glycol), and tri(ethylene glycol) methyl ester, were detected. These oligomers were formed by reductive decomposition of EC, and their presence suggested that the surface film contained polymer-like substances that have repeated oxyethylene units.

A Conformational Study of Cyclohexane‐1,3,5‐tricarbonitrile Derivatives

AbstractCyclohexane‐1,3,5‐tricarbonitrile reached equilibrium having 1,3‐cis‐1,5‐cis and 1,3‐cis‐1,5‐trans isomers in a ratio of 3:7. The cis, cis‐isomer preferred the conformation with three equatorial cyano groups, where as the cis, trans‐isomer displayed two cyano groups on equatorial positions and another cyano group on axial position. Condensation of cis, cis‐cyclohexane‐1,3,5‐tricarbonitrile with L‐(S)‐valinol by the catalysis of ZnCl2 in refluxing 1,2‐dichlorobenzene afforded two isomeric cyclohexane‐1,3,5‐trioxazolines in favor of the 1,3‐cis‐1,5‐trans isomer. Metalation of cis, cis‐cyclohexane‐1,3,5‐tricarbonitrile, followed by alkylations with dimethyl sulfate, benzyl bromide or allyl bromide, gave the cor responding trialkylation products with predominance of 1,3‐cis‐1,5‐trans isomers. The cis, trans‐isomer showed two cyano groups on axial positions and another cyano group on equatorial position, where as the cis, cis‐isomer exhibited three axial cyano groups. Treatment of trimethyl cis, cis‐cyclohexane‐1,3,5‐tricarboxylate with lithium diisopropylamide and dimethyl sulfate afforded mainly the trimethyl ester of Kemp's triacid, which showed three axial carboxylate groups. Two competitive factors, i.e. the steric effect of in coming electrophiles and the dipole‐dipole inter actions of the cyano or carboxylate groups, might inter play to give different stereoselectivities in these reaction systems.

Bisphosphonate Prodrugs. Selective Synthesis of (1-Hydroxyethylidene)-1,1-bisphosphonate Partial Esters

Selective methods for the synthesis of (1-hydroxyeth- ylidene)-1,1-bisphosphonate tri-, P,P -di-, P,P-di- and mono esters have been developed. Preparation is started from selected symmet- ric or unsymmetric tetraesters of etidronate using alkalimetal salts or trimethylsilyl iodide as dealkylating agents. Synthesis of H3CC(OH)(P(O)(OH)2)(P(O)(OH)(OHex)) starting from trimethyl ester of etidronate is also described. 1 H, 13 C and 31 P NMR data are reported including 1 JCP, 2 JCP and 2 JPP couplings. The solid state structure is given for (1-(dimethoxyphosphinyl)-1-hydroxyethyl)- 1-phosphonic acid monomethyl ester monopotassium salt (1a).

Synthesis of pentenoic acid analogs as potential anti-influenza agents

The synthesis of (2Z,4RS)-5-acetamido-4-guanidino-2-benzamidopent-2-enoic acid (sodium salt) 5 is reported. Wittig–Horner olefination of diamino protected propionaldehyde 8 with phosphonoglycine trimethyl ester 11 provided (Z)-olefin methyl ester 12. The methyl ester was converted to allyl ester 15 by initial hydrolysis with lithium hydroxide followed by reaction with allyl bromide. Target compound 5 was prepared from allyl ester 15 by initial formation of bis(Boc)guanidino ester 16 followed by treatment with tetrakis(triphenylphosphine)palladium(0). The product was evaluated for activity against influenza neuraminidase and was found to be weakly active.

Photochemical Reactions of Coenzyme PQQ (Pyrroloquinolinequinone) and Analogues with Benzyl Alcohol Derivatives via Photoinduced Electron Transfer

Photochemical redox reactions of the trimethyl ester of coenzyme PQQ (PQQTME) with benzyl alcohol derivatives (ArCH2OH), tetrahydrofuran, and 1,4-cyclohexadiene occur efficiently under visible light irradiation in MeCN to yield PQQTMEH2 (reduced PQQTME in the quinol form) and the corresponding dehydrogenated products (ArCHO, furan, and benzene) quantitatively. A similar photochemical oxidation of benzyl alcohols also occurs with phenanthrolinequinone derivatives (PTQ), benzoquinolinequinone derivatives (BQQ), and phenanthrenequinone (PQ). PQQTME and the analogues are essentially nonfluorescent in MeCN, and the photochemical reaction of the o-quinones is retarded significantly in the presence of molecular oxygen. Transient absorption spectra of the triplet excited states of the o-quinones were detected in laser flash photolysis of the MeCN solutions. From the decay of T−T spectra were determined the lifetimes of the triplet excited states of the o-quinones. The quenching rate constants of the triplet excited states by benzyl alcohols agree with the observed rate constants of the photochemical reduction of the o-quinones with the same substrates determined from the saturated dependence of quantum yields on the benzyl alcohol concentrations. Such an agreement confirms that the photochemical reaction proceeds via the triplet excited state of the quinones. Dependence of the observed rate constants kobs of the photochemical redox reaction on the one-electron oxidation potential Eoox of the substrates as well as the results of kinetic deuterium isotopic study indicates that the photochemical redox reactions between the o-quinones and the substrates proceed via photoinduced electron transfer from the substrate to the triplet excited state of the o-quinone, followed by proton and hydrogen atom transfer to yield the quinol and the corresponding oxidation products. The transient absorption spectra of the radical ion pair formed in the photoinduced electron transfer have been detected successfully in laser flash photolysis of the o-quinone−benzyl alcohol systems.

NH tautomerism in the natural chlorin derivatives.

The NH tautomerism of five Mg-free chlorophyll a and b derivatives 2-6 was studied utilizing NMR spectroscopy and molecular modeling. The results from the dynamic NMR measurements of the chlorins revealed that substituent effects contribute crucially to the free energy of activation (DeltaG(double dagger)) in the NH tautomeric processes. An intermediate tautomer for the total tautomeric NH exchange in a chlorin was observed for the first time, when the (1)H NMR spectra of chlorin e(6) TME (3) and rhodin g(7) TME (4) (TME = trimethyl ester) were measured at lower temperatures. The lower energy barriers (DeltaG(1)(double dagger)) obtained for the formation of the intermediate tautomers of 3 and 4, assigned to the N(22)-H, N(24)-H trans-tautomer, were 10.8 and 10.6 kcal/mol, respectively. The energy barrier (DeltaG(2)(double dagger) value) for the total tautomeric NH exchange in the five chlorins was found to vary from 13.6 kcal/mol to values higher than 18 kcal/mol. The lowest DeltaG(2)(double dagger) value (13.6 kcal/mol) was obtained for rhodochlorin XV dimethyl ester (2), which was the only chlorophyll derivative lacking the C(15) substituent. In the case of chlorins 4 and 5, the steric crowding around the methoxycarbonylmethyl group at C(15) raised the DeltaG(2)(double dagger) activation free-energy to 17.1 kcal/mol. However, the highest energy barrier with DeltaG(2)(double dagger) > 18 kcal/mol was observed for the NH exchange of pyropheophorbide a methyl ester (6), possessing the macrocycle rigidifying isocyclic ring E. Our results demonstrate that the steric strain, arising either from the steric crowding around the bulky substituent at C(15) or the macrocycle rigidifying isocyclic ring E, slows down the NH tautomeric process. We suggest that deformations in the chlorin skeleton are closely connected to the NH tautomeric exchange and that the exchange occurs by a stepwise proton-transfer mechanism via a hydrogen bridge.

Bisphosphonate prodrugs: unusual dimerisation of clodronic acid trimethyl ester to a cyclic bis(bisphosphonate)

Cl2C[P(O)(OMe)2P(O)(OMe)(O− Z+)] selectively reacts with acetyl chloride to provide a new enzymatically stable heterocyclic bis(bisphosphonate); the structure is confirmed by X-ray crystallography.

Analysis of Methylcitric Acid by Enantioselective Multidimensional Gas Chromatography-Mass Spectrometry

Methylcitric acid (2-hydroxybutane-1,2,3-tricarboxylic acid–MCA) is a structural analogue of citric acid, but due to an additional methyl group it is a chiral molecule with two stereogenic centers and thus four stereoisomers are conceivable. MCA occurs naturally as prominent metabolite in body fluids of patients with inherited metabolic diseases such as propionic acidemia, methylmalonic aciduria, or holocarboxylase synthetase deficiency. Therefore methylcitric acid is considered to be an important diagnostic marker for these diseases. MCA is most likely produced from accumulated propionyl-CoA in these diseases by the enzyme si-citrate synthase from the citric acid cycle; however, there are other enzymes known which could catalyze the same reaction with different stereoselectivity, such as re-citrate synthase or the more specific enzyme methylcitrate synthase, found in microorganisms. Almost all methods dealing with MCA in the literature are non-enantioselective. For that reason there is no information about occurrence of MCA enantiomers in healthy people, patients with propionic acidemia, methylmalonic aciduria, or holocarboxylase synthetase deficiency and about value of enantiomeric distribution for diagnosis and long-term treatment. The enantioselective analysis of MCA as corresponding trimethyl ester was achieved by enantioselective multidimensional gas chromatography coupled with mass spectrometry using heptakis-(2,3-di-O-methyl-6-O-tert-butyl-dimethylsilyl)-β-cyclodextrin as chiral stationary phase. The described method allows a reliable screening of MCA in complex matrices like urine without time consuming sample preparation and with mass selective detection. During this investigation urine samples from various patients and healthy controls were analyzed. As concluded, MCA is a good diagnostic marker and can be easily measured by the method presented. Only the two stereoisomers (2S,3R) and (2S,3S) were detectable in patients and healthy controls. The varying ratios of these stereoisomers cannot presently be correlated with the health status of patients, although there are some indications that this might be possible. However, the quantitative levels of MCA, determined as the ratio of MCA absolute peak area divided by 1,000 to the creatinine contents of urine samples in this investigation, showed a dependence on the state of health and MCA would thus also be a possible marker for long-term treatment. Such a substance is of major interest nowadays since there are different studies searching for such a long-term marker in propionic acidemia or methylmalonic aciduria.