Evidence of covalent interaction of fumaric acid esters with sulfhydryl groups in peptides

Fumaric acid esters, namely dimethylfumarate, have been used for the treatment of psoriasis for many years. Still, their mode of action is not fully clear. Because addition of nucleophiles to the double bonds of fumarates can occur (Michael analogous addition), a study of the interaction of fumarates with cysteine and cysteine-containing peptides possessing nucleophilic sulfhydryl group was carried out. Experiments were performed in aqueous medium at pH 7.4 and at 37 degrees C to simulate physiological conditions. It was proven by mass spectrometric measurements using an ion-trap and time-of-flight instrument that a covalent bond can form between fumarates and the sulfhydryl group of cysteine or cysteinyl residues in peptides. Structures of the interaction products were elucidated by multistage mass spectrometry applying collision-induced dissociation. Higher reactivity of dimethylfumarate in comparison to monomethylfumarate and fumaric acid was observed.     

Spin trapping of propagating radicals derived from dialkyl fumarates

Propagating radicals of dialkyl fumarates (DRFs) and deuterated fumarate were trapped by admitting a 2-methyl-2-introsopropane (BNO) solution to the polymerization mixture containing the active radicals or by the polymerizations initiated with di-t-butyl hyponitrite in the presence of BNO. Although ESR spectra of the propagating radicals were appreciably changed with the size of the ester alkyl groups, all the nitroxyl radicals resulting from the spin trapping exhibited similar six-line spectra. The hyperfine splitting constant for the α-hydrogen of the radical moiety showed a slight dependence on the chain length, and the bulkiness of the ester alkyl group did not affect splitting of the spectra. These findings indicate that a substituted methylene radical is produced by addition of the primary radical to DRF followed by propagation throughout the polymerization and that poly(DRF) radical does not encounter severe hindrance in the reaction with BNO.     

A convenient synthesis of functionalized pyrazolones bearing a highly twisted 1,3-butadiene moiety with skew geometry

Abstract

The four-component reaction among arylhydrazine, alkyl acetoacetate derivatives, alkyl isocyanides, and dialkyl acetylenedicarboxylates, leading to the formation of dialkyl 2-[(Z)-(alkylamino)(3-alkyl-5-oxo-1-phenyl-1,5-dihydro-4H-pyrazol-4-ylidene)methyl] fumarates is described. The structure of target compounds was confirmed using X-ray diffraction study. These pyrazolone derivatives contain a highly twisted exocyclic 1,3-butadiene moiety with skew (??=?87°) geometry.     

The synthesis of 2-ketopiperazine acetic acid esters and amides from ethylenediamines with maleates and maleimides

The reaction of substituted ethylenediamines with various fumarates, maleates, and maleimides to form substituted ketopiperazine acetic acid esters and amides was investigated. This method affords a straightforward, high yield approach to a variety of potential peptidomimetics and can yield surprising results with regard to regio- and stereoselectivity.     

Kinetic study of radical polymerization of dialkyl fumarates using electron spin resonance spectroscopy

The radical polymerization of dialkyl fumarates (DRF) bearing various ester alkyl groups was kinetically studied. The propagation and termination rate constants were determined using electron spin resonance (ESR) spectroscopy. The introduction of the bulky ester alkyl groups such as a tert-butyl group decreased the termination rate constant as expected. However, it has also been revealed that the bulky groups promote propagation despite the steric repulsion. The propagation rate and mechanism are discussed in relation to the propagation manner, i.e., tacticity of the polymer. © 1996 John Wiley & Sons, Inc.     

Radical polymerization and copolymerization reactivities of fumarates bearing different alkyl ester groups

Radical polymerization of fumarates bearing different alkyl ester groups (DRF) on the same molecules was investigated. In bulk polymerization of DRF at 60°C initiated with 2,2′-azobis(isobutyronitrile), it was confirmed that the polymerization reactivity depended on the structures of both alkyl ester groups. The introduction of bulky alkyl groups increased the polymerization rate and molecular weight of the polymer because of retardation of bimolecular termination rates. The effect of the ester substituents on the termination was examined by electron spin resonance spectroscopy. The copolymerization reactivities of DRF with styrene were also investigated. © 1993 John Wiley & Sons, Inc.     

有机磷化合物的研究 X:五价膦(磷)酸酯与卤代烷在卤化钠存在下的酯烷基交换反应

A detailed study on the ester alkyl exchange reaction of various types of quinique-valent phosphorus esters with alkyl halide in the presence of sodium bromides was reported. This ester alkyl exchange reaction was evidently influenced by the structure of phosphorus esters and alkyl halides as well as by the nature of the halides of metal ions. In contrast with the reaction without sodium hadlide, the alkyl phosphinmate is more reactive than phosphonate and phosphate by treatment with alkyl halide in the presence of sodium halide. This is consistent with the high nucleophilicity of >P(CO)O- as leaving group. The reactivity of butyl halides was decreased in the following order: n-BuBr>i-BuBr=s-BuBr>t-BuBr. Alkyl iodide was proved to be more reactive than the corresponding bromide and chloride. However, the use of iodioe is limited by the formation of alkene resulted from the elimination of HI. These structural effects show the general characteristics of a nucleophilic substitution reaction. A reaction mechanism involving the formation of sodium salt intermecutiate was proposed based on the concept of HSAB principle. This reaction may, however, be used as a convenient method for the preparation of mixed esters of quinque-valent phosphorus acids.     

Fungicidal activity of tributyltin alkylsulfate esters

Tributyltin alkyl sulfate esters, e.g. tributyltin dodecyl sulfate, tributyltin hexadecyl sulfate and tributyltin octadecyl sulfate, were synthesized from the reaction of bis(tributyltin) oxide and appropriate alkyl hydrogen sulfates. The resulting tributyltin alkyl sulfate esters were found to exhibit fungicidal activity on Penicillium, Aspergillus and Syncephalustrum species.     

Highly selective trifluoroacetic ester/ketone metathesis: an efficient approach to trifluoromethyl ketones and esters

A highly selective and atom efficient ‘trifluoroacetic ester/ketone metathesis’ has been sincerely witnessed. Enolizable alkyl (at least two non-hydrogen atoms) aryl ketones were found to react readily with ethyl trifluoroacetate under the promotion of NaH to afford trifluoroacetic ester/ketone exchange products, trifluoromethyl ketones (TFMKs), and aromatic acid esters, which were quite different from the general Claisen condensation products, 1,3-diketones. The outcome of the reaction between ketone and ethyl trifluoroacetate is strongly related to the structures of substrates, the steric congestion caused by alkyl group is in favor of the C–C bond cleavage. DFT investigation further disclosed that the metathesis reaction was a kinetically favored pathway. Using only a slight excess of cheap trifluoromethylation reagent, simple operation and mild conditions make it a practical method for preparation of TFMKs on large scale, as well as a new choice of converting aryl alkyl ketones to aromatic acid esters.     

Conjugate addition/Ireland-Claisen rearrangements of allyl fumarates: simple access to terminally differentiated succinates

The conjugate addition of dialkylzinc reagents to allyl fumarates with subsequent Ireland-Claisen rearrangement has been accomplished yielding substituted unsymmetrical succinic acid derivatives. This one-pot reaction creates two new carbon-carbon bonds at contiguous stereogenic centers. The reaction proceeds for several alkylzinc reagents and substituted allyl fumarates. The products contain distinguishable functional handles for further manipulation.     

Selective formal transesterification of fluorinated 2-(trimethylsilyl)ethyl alpha-imino esters mediated by TBAF

The scope of the transesterification reaction between beta-fluorinated alpha-imino esters and various electrophiles in the presence of TBAF as fluorine source is described. The reaction is highly selective for alkyl iodides, bromides, and mesylates, while alkyl chlorides react at a significantly slower rate and tosylates do not react under the reaction conditions. This methodology represents a simple and useful alternative for the preparation of a wide variety of fluorinated alpha-imino esters.     

Regioselective synthesis of isochromenones by iron(III)/PhSeSePh-mediated cyclization of 2-alkynylaryl esters

A series of 4-Se-(Te, S)-isochromenones and 3-substituted isochromenones were synthesized in good yields via FeCl(3)-mediated cyclization of alkynylaryl esters with different diorganyl dichalcogenides. This methodology was carried out at room temperature, using inexpensive and environmentally friendly iron salts as metallic source and under air atmosphere. The reaction showed to be tolerant to a range of substituents bonded into the aromatic ring of the diorganyl dichalcogenides as well as to alkyl groups directly bonded to the chalcogen atom. Alternatively, the cyclization reaction of 2-alkynylaryl esters with FeCl(3), in the absence of diorganyl dichalcogenide, gave the isochromenones without the chalcogen moiety in the structure. This approach proved to be highly regioselective, providing only six-membered ring products, once the possible five-membered products were not observed in any experiments.     

Organophosphorus esters—IV : Novel approach to monoalkyl hydrogen phosphites

Tetramethylammonium t-butyl hydrogen phosphite (2), readily available from the reaction between di-t-butyl phosphite and aqueous tetramethylammonium hydroxide, was found to be a convenient phosphorylating agent for organic halides. It reacts easily with alkyl iodides and some alkyl bromides in boiling acetone affording the corresponding alkyl t-butyl phosphites (3). On treatment with trifluoroacetic acid at room temperature these compounds can be readily converted into monoalkyl hydrogen phosphites (1), isolated and characterized as S-p-chlorobenzylthiouronium derivatives (4).     

Effects of L-tyrosine esters on quenching and photosensitized charge separation using polymers containing ruthenium(II) complex

A series of ruthenium(II) complex-containing partially quaternized poly(1-vinylimidazole)s with various alkyl side chains such as hexyl (C₆RuQPIm), dodecyl (C₁₂RuQPIm), and hexadecyl (C₁₆RuQPIm) were synthesized. The effects of L -tyrosine esters with hexyl (C₆Tyr), octyl (C₈Tyr), and dodecyl (C₁₂Tyr) on the quenching with methylviologen and photosensitized charge separation reactions were investigated using these metallopolymers as polymer photosensitizers. The quenching reaction took place through both a dynamic quenching process and a static quenching one mediated by the L -tyrosine esters. The kinetic parameters for these processes were obtained from a computed curve fitting using a Stern–Volmer equation derived from a combination of dynamic quenching and static quenching. The parameters had a significant dependence on the lengths of the alkyl groups in the L -tyrosine esters and the alkyl side chains on these metallopolymers. During photosensitized charge separation, the reaction proceeded through these quenching processes, referred to as direct and mediated processes. The initial rates of methylviologen radical formation also depended on these lengths; they increased when the lengths of the alkyl side chain on these metallopolymers and alkyl groups in the L -tyrosine esters were long. Such a dependence was caused by a change in the balance of some effects such as the electrostatic and steric effects. © 1999 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 37: 4360–4367, 1999     

Alkyl vinyl esters of brassylic (tridecanedioic) acid

Brassylic acid was partially esterified at 77°C. in toluene solution with ethyl, 2-methylpentyl, or nonyl alcohol and with p-toluenesulfonic acid used as catalyst. Half-esters were isolated from the respective reaction mixtures in yields of 28, 34, and 32% after reaction times of 2,6, and 8 hr. Both recovered brassylic acid and byproduct dialkyl ester were successfully used as starting materials in subsequent esterifications. Consequently, conversion of starting materials to half-ester would be increased in a process that involved continuous recycling of byproducts. Alkyl hydrogen brassylates were vinylated at 165°C. for 8 hr. with acetylene at 360 psig. The zinc salt generated in situ from zinc oxide served as catalyst and toluene as solvent. Yields were 80–88% and purities of products were 94–95%. Samples of 2-methylpentyl vinyl brassylate and nonyl vinyl brassylate of much higher purity were obtained by preparative gas–liquid chromatography or molecular distillation. Physical properties and experimental conditions for gas–liquid chromatographic analyses of both the alkyl hydrogen and alkyl vinyl brassylates are reported.     

Palladium-catalyzed coupling of thiol esters with aryl and primary and secondary alkyl organoindium reagents

Thiol esters and organoindium reagents undergo palladium-catalyzed cross-coupling under mild conditions to give ketones in moderate to excellent yields. Aryl and primary/secondary alkyl organoindium reagents can be used as coupling partners. This method has two advantages over the cross-coupling of thiol esters with boron and tin reagents: (1) no added copper reagent is required to mediate the reaction and (2) for the case of alkyl transfer, no added base is required to activate organoindium reagents for cross-coupling as is required for the coupling of alkyl boron reagents with thiol esters.     

Synthesis of alkyl-H-phosphinic acid alkyl esters from red phosphorus and alkyl bromides

Alkyl-H-phosphinic acid alkyl esters are synthesized in 65–71% yield via chemoselective reaction of alkyl bromides with available alkyl-H-phosphinic acids (60–65 °C, Et3N). The latter are prepared, in turn, by direct phosphorylation of alkyl bromides with red phosphorus under phase-transfer conditions.     

Simple method for the preparation of esters from Grignard reagents and alkyl 1-imidazolecarboxylates

The reaction of Grignard reagents with alkyl imidazolecarboxylates, which were prepared from alcohols with carbonyl diimidazole, gave the corresponding esters in good to excellent yields. This method conveniently provides esters from alkyl halides and alcohols by C1-carbon chain extension.     

Synthesis of esters of 3-fluoro-3-nitroacrylic acid

Conclusions The reaction of 1,3-difluoro-1,1,3,3-tetranitropropane with alkanols was used for the preparation of alkyl esters of 3-fluoro-3-nitroacrylic acid. 1,3-Difluoro-1,3,3-trinitro-1- propene and 1,3-difluoro-1,3-dinitro-2-alkoxy-1-propene were also isolated as intermediates.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 3, pp. 709–711, March, 1989.     

Sugar-amide surfactant micelles as effective reaction fields for enantioselective hydrolysis of alpha-amino acid esters

The enantioselective hydrolysis of p-nitrophenyl esters of alpha-amino acids (Phe, Leu, Ala) was accomplished in micelles formed with the surfactants bearing one or two sugar-amide headgroups. The effect of structural variations in such sugar-amide surfactants on the rates and enantioselectivity (kD/kL) for hydrolysis of p-nitrophenyl esters of D- and L-phenylalanine hydrogen bromides (D- and L-PheONp) was studied. Both the hydrolysis rate of D-PheONp and the enantioselectivity increased with an increase in the alkyl chain length as well as an increase in the number of the alkyl chains in the maltobionamide-type surfactants. Enantioselectivity also increased with an increase in the sugar chain length from bisgluconamide to bismaltobionamide (by one glucose unit per each sugar chain) in the double-sugar-chain surfactants, but enantioselectivity was no longer influenced by a further increase to bismaltotrionamide. The stereochemistry of the linkage between the sugar units in the sugar chain remarkably affected the enantioselectivity: the maltobionamide-type surfactant, in which the two sugar units are connected by an alpha-1,4-glucosidic linkage, showed high enantioselectivity (kD/kL = 5.5), whereas the surfactant bearing cellobionamide headgroups (beta-1,4-glucosidic linkage) showed no enantioselectivity. Similar trends were observed when p-nitrophenyl esters of D- and L-leucine hydrogen bromides were used as substrates. On the other hand, the rates and enantioselectivity for hydrolysis of p-nitrophenyl esters of D- and L-alanine hydrogen bromides were not so largely affected by the structural variations in the sugar-amide surfactants. Additionally, the effects of the surfactant concentration and the reaction temperature on the rates and enantioselectivity for the hydrolysis of D- and L-PheONp were examined.