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Identification of a common Diels-Alder pattern in three classes of bioactive natural products led us to study the synthesis and cycloaddition of a new class of cyclic dienes readily available from β,γ-unsaturated lactams. A practical and readily scalable route to the parent p-methoxybenzyl-protected 6- and 7-membered β,γ-unsaturated lactams was developed. These were readily transformed into the corresponding O-silylated dienes, which were reacted with dimethyl and diethyl fumarate to yield stereoselectively highly functionalized bicyclic adducts. These exhibited unexpected and versatile transformations upon acid hydrolysis depending on the nature of the dienophile substituents and the acid catalyst. All reactions have been performed on multigram quantities. These transformations provide a convenient, economical, and easily scalable pathway for the rapid construction of functionally and stereochemically dense privileged scaffolds for the construction of libraries of natural products-inspired molecules of pharmacological relevance.

26 p.-8 fig.-2 tab.-1 graph. abst.-+9 p. mat. supl.-10 fig.-2 tab., Common copathogenic factors, including oxidative stress and neuroinflammation, are found to play a vital role in the development of neurodegenerative disorders, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). Nowadays, owing to the multifactorial character of the diseases, no effective therapies are available, thus underlying the need for new strategies. Overexpression of the enzyme GSK-3β and downregulation of the Nrf2/ARE pathway are responsible for a decrease in antioxidant defense effects. These pieces of evidence underline the usefulness of dual GSK-3β inhibitors/Nrf2 inducers. In this regard, to design a dual modulator, the structures of a curcumin-based analogue, as GSK-3β inhibitor, and a diethyl fumarate fragment, as Nrf2 inducer, were combined. Among the hybrids, 5 and 6 proved to effectively inhibit GSK-3β, while 4 and 5 showed a marked ability to activate Nrf2 together to increase the neuronal resistance to oxidative stress. These last pieces of evidence translated into specific neuroprotective effects of 4 and 5 against PD pathological events including neurotoxicity elicited by α-synuclein aggregates and 6-hydroxydopamine. Hybrid 5 also showed neuroprotective effects in a C. elegans model of PD where the activation of GSK-3β is intimately involved in Nrf2 regulation. In summary, 5 emerged as an interesting multitarget derivative, valuable to be exploited in a multitarget PD perspective., This work was supported by the University of Bologna (RFO funds), MCIU (grant no. SAF2016-76693-R), and ISCiii CIBERNED (CB18/05/00040) and EDS, partially funded by the CNR project NUTR-AGE (FOE-2019, DSB.AD004.271).

The oxidative stress response (OSR) in yeast is under the control of oxidation-sensitive cysteines in the Yap1p transcription factor, and fusion of the Yap1p-dependent OS-induced promoter of the YKL071w gene (OSI1) to a luciferase coding sequence makes a sensitive reporter for OS induced by electrophiles. In mammalian cells, the OSR induced by electrophiles is coordinated in a mechanistically similar way via oxidation-sensitive cysteines in the kelch-like ECH-associated protein 1 (Keap1)&ndash, nuclear factor erythroid 2-related factor 2 / antioxidant response element ( Nrf2/ARE) system. Many electrophilic oxidants have already been independently shown to trigger both the Yap1 and Keap1 systems. Here, we investigated the responses of Yap1 and Keap1 reporters to sulforaphane (SFN), allyl isothiocyanate (AITC), phenylethyl isothiocyanate (PEITC), previously known to stimulate Keap1&ndash, Nrf2/ARE but not known to activate Yap1, and as a positive control, allicin, previously reported to stimulate both Yap1 and Nrf2. We have compared the reciprocal responsiveness of the respective reporter systems and show that the yeast reporter system can have predictive value for electrophiles that stimulate the mammalian Keap1&ndash, Nrf2/ARE system.

Pyrazole molecules are in the forefront of organic chemistry due to their various encompass substituents, which have many biological activity sequence. The biological and medicinal activities of pyrazolo[1,5-a]pyrimidines have received considerable interest in this regard. We reported here a comparison between reaction of 4-phenylazo-3,5-diaminopyrazole (4) with ethyl propiolate (15), dimethylacetylene dicarboxylate (20), diethyl fumarate (25) and benzylidenemalononitrile (11) in the presence of catalytic amount of piperidine. We initially followed literature procedure (method A), then utilizing ultrasound irradiation (method B), microwave heating (method C) and in a Q-tube (method D). We confirmed the structure of the product by analytical spectroscopic methods. Method (D) gave a good yield with a record reaction time.

High-pressure liquid–vapor phase equilibrium data (P–T–x–y) for the binary mixture of the ester diethyl fumarate with CO2 have been measured at temperatures of (373.2, 398.2, 423.2, and 453.2) K over the pressure range from (2.5 to 23) MPa using a static-analytic method. The results show that the molar fraction of CO2 in the liquid phase increases with increasing pressure at the studied temperatures and decreases with increasing temperature at constant pressure, while the composition of the light phase remains more or less unchanged. The experimental results were correlated using the Peng–Robinson equation of state in combination with one fluid mixing rule with two adjustable parameters, and the binary interaction parameters were calculated as functions of temperature. Overall, the absolute average relative deviations of the model from the data obtained for the light and heavy phases ranged from (8 to 10) % and (4 to 12) %, respectively.

A synthetic method for novel 4-unsubstituted 2-phenyldihydropyrimidines having acyl and alkoxycarbonyl groups at the 5- and 6-positions was developed. The cyclization of 4-dimethylamino-1,3-diaza-1,3-butadiene having N-protecting groups (Boc, Cbz) with 1,2-disubstituted ethylenes, such as diethyl maleate, diethyl fumarate, (Z)-hex-3-ene-2,5-dione, (E)-1,4-diphenylbut-2-ene-1,4-dione, and unsymmetrical (E)-ethyl 4-oxo-4-phenylbut-2-enoate, following the elimination of a dimethylamino group proceeded smoothly, producing the corresponding dihydropyrimidines in good overall yield. The N-protecting group (Boc) could be easily removed to obtain N-unsubstituted dihydropyrimidines as a mixture of tautomers, and their tautomeric behavior was analyzed by 1H NMR spectroscopy.

International audience; ESI mass spectrometry was used together with other analytic methods for studying the mechanism of the free-radical donor-acceptor copolymerization of diethyl fumarate with simple vinylether or allylether model monomers. The polymerization of various monomer mixtures was achieved by photo-initiation under soft 365 nm UV light. Diluted solutions as well as solvent-free blends of monomers were reacted in stoichiometric amounts. The obtained copolymers were analyzed, particular attention being paid to their composition in co-monomers and to the nature of the end-groups. ESI mass spectrometry provided detailed information allowing for a semi-quantitative evaluation of the different mechanisms taking place during the initiation, propagation and termination steps of the free radical process. The prime importance of transfer reactions was evidenced for copolymerization involving allyl ethers. Different transfer mechanisms are proposed accordingly.

We report the synthesis and characterization of a variety of trans-3,4-substituted cyclopentanones and the corresponding tosylhydrazone derivatives starting with diethyl fumarate. Protection of the keto group followed by selective monohydrolysis of esters was achieved, resulting in cyclopentanones with different substituents at positions 3 and 4. The tosylhydrazone derivative of each cyclopentanone intermediate was prepared in moderate to good yields. These compounds are potential precursors for functionalized methanofullerenes.

Pd(OAc) 2 -catalyzed aerobic alkenylation and dienylation of ferrocene with electron-poor olefins and dienes (ethyl acrylate, methyl ( E )-cinnamate, diethyl fumarate and maleate, ethyl sorbate and sorbic acid) is reported. In the case of acrylate and cinnamate the reaction leads to mixtures of mono- and dialkenylated ferrocenes. In other cases the products of mono alkenylation and dienylation are formed in low yield. The relatively slow (∼1 week) reaction takes place in AcOH solutions at room temperature.

International audience; Dimethylzinc-mediated addition of acyloxymethyl radicals to diethyl fumarate led to the highly stereoselective formation of disubstituted gamma-lactones in mean to good yields; this cascade provides a new example of a one-pot process mediated by dimethylzinc involving a tandem radical-anionic reaction; the chemoselectivity of the reaction was totally modified by additional Lewis acids.

This protocol describes the synthesis of 500-4,000 Da poly(propylene fumarate) (PPF) by a two-step reaction of diethyl fumarate and propylene glycol through a bis(hydroxypropyl) fumarate diester intermediate. Purified PPF can be covalently cross-linked to form degradable polymer networks, which have been widely explored for biomedical applications. The properties of cross-linked PPF networks depend upon the molecular properties of the constituent polymer, such as the molecular weight. The purity of the reactants and the exclusion of water from the reaction system are of utmost importance in the generation of high-molecular-weight PPF products. Additionally, the reaction time and temperature influence the molecular weight of the PPF product. The expected time required to complete this protocol is 3 d.

Dosimetric characterization of diethyl fumarate DEF in dimethyl formamide DMF solution was studied spectrophotometrically for possible application at high dose dosimetry in the range 1–125 kGy. The absorption spectra of irradiated solutions showed broad absorption bands between 325 and 400 nm with a shoulder at 350 nm. The absorbance increases with increasing the dose. Absorbance at 350, 360 and 370 nm was measured and plotted versus absorbed dose. Good response and linear relationship were found between absorbed dose and absorbance of DMF solution 20% in DEF in the range 1–60 kGy at the three measured wavelengths; in addition, a good linear absorbance response up to 125 kGy was found at 370 nm. Good dose rate independence was observed in the range 1–40 kGy/h, sufficient post-irradiation stability over a period of 800 h after irradiation and temperature independence within the range 0–60 °C was also observed.

Esterification of maleic anhydride with ethanol over Al-MCM-41 (Si/Al = 50,100 and 150) and Hβ zeolite was investigated in the liquid phase at 80, 100 and 120 °C. Monoesterification of maleic anhydride to monoethyl maleate (MEM) was found to be fast and independent of the presence of catalyst but subsequent esterification to diethyl maleate (DEM) was catalyst dependent. The absence of isomerisation of diethyl maleate to diethyl fumarate (DEF) over Al-MCM-41 molecular sieves is a significant advantage. Al-MCM-41 (50), Al-MCM-41 (100) and Hβ are convenient replacement for hazardous sulphuric acid used in the industrial esterification of maleic anhydride with ethanol.

Although tissue engineering is an area with great potential, it still has few applications due to the lack of biocompatible, biodegradable materials with suitable mechanical properties. Recently, several biodegradable materials were developed, of which poly(propylene fumarate (PPF) is one of the most notable. It degrades into fumaric acid and propylene glycol, which are both biocompatible products. Microstereolithography is a new technology that can be used to fabricate free-form 3-D microstructures by dividing a desired shape into many slices of a given horizontal thickness. This technology requires a low-viscosity resin to fabricate fine structures. However, the viscosity of PPF is too high to fabricate 3D structures using microstereolithography. Therefore, we reduced the viscosity of the resin by adding diethyl fumarate (DEF). Then, we added a photoinitiator to photo-crosslink the DEF/PPF resin, and fabricated 2.5-D scaffolds using our system. We confirmed that microstereolithography technology is effective in scaffold fabrication. The fabricated 2.5-D scaffolds were seeded with fibroblasts and the cells attached well after seeding.

Current studies on scaffold fabrication have focused on overcoming the limitations imposed by the mechanical properties of existing biodegradable materials and the irregular structures they produce. Recently, several promising biodegradable materials were introduced, including poly(propylene fumarate) (PPF). In addition, the development of micro-stereolithography allows the fabrication of free-form 3D microstructures by dividing a desired shape into several slices of a given thickness. This technology, however, requires a low-viscosity resin to fabricate fine structures, which excludes the use of PPF. To fabricate precise 3D scaffolds using micro-stereolithography, we created a system in which the viscosity of PPF was reduced by adding diethyl fumarate. The fabricated scaffold was sterilized, and fibroblasts in cell culture medium were seeded onto the structure. Cells were fixed and freeze-dried after 4, 7, and 28 days of culture. Under scanning electron microscopy, we observed that the cells were able to attach to the scaffold surface and grow.

The reactions of a series of substituted 5-aminoindoles with diethyl oxaloacetate were studied. A synthesis was developed for 5-indolylamino derivatives of diethyl fumarate as well as 7-ethoxycarbonyl-6,9-dihydro-3H-pyrrolo[3,2-f]quinolin-9-ones.

Diplomsko delo obsega raziskave faznega ravnotežja za sistem dietil fumarat, etanol in ogljikov dioksid, pri konstantnem tlaku 150 bar in pri temperaturah 125 in 180 °C. Kadar je stisljiv medij izpostavljen visokemu tlaku in temperaturi in dosežemo kritično točko, govorimo o superkritičnih fluidih (supercritical fluid – SCF). Značilne lastnosti superkritičnega fluida sta zelo visoka stisljivost in gostota. V prvem delu smo pripravili vzorec dietil fumarata in etanola ter ga aplicirali v rezervoar visokotlačne optične celice, dodali še tekoči CO2 ter vzpostavili konstanten tlak in temperaturo. Raztopino v celici smo najprej mešali, nato smo pustili, da se fazno ravnotežje vzpostavi, sledilo je vzorčenje. Preučevali smo, kako vplivajo na topnost CO2 v tekoči fazi različna razmerja etanola in dietil fumarata. Določili smo porazdelitveni koeficient in separacijski faktor. Na koncu smo izračunali še standardno napako meritev in jo argumentirali. Za izris faznega diagrama ternarnega sistema smo uporabili program OriginPro. Ugotovili smo, da se z višajem temperature topnost CO2 v tekoči fazi pri konstantnem tlaku zniža. Na podlagi dobljenih rezultatov smo ugotovili, da pri temperaturi 125 °C večina meritev vsebuje večjo napako, saj ravnotežje ni bilo povsem vzpostavljeno. Zato smo drugi set meritev izvajali pri temperaturi 180 °C. Rezultate diplomskega dela smo prikazali v obliki tabel in grafov. Thesis comprises the research of phase equilibrium for system diethyl fumarate, ethanol, carbon dioxide, at constant pressure of 150 bar at temperatures from 125 °C to 180 °C. When a compressible (media) is exposed to high pressure and high temperature and a critical point is reached, this fluid is called supercritical fluid (SCF). Characteristic properties of SCF are very high density and compressibility. In first part of the thesis a sample of diethyl fumarate in ethanol has been prepared and injected into a high pressured optical cell. Afterwards liquid CO2 was added and constant pressure and temperature have been established. The solution in the cell has been mixed in order to establish phase equilibrium, and afterwards the sampling has been performed. We studied how the ratio of ethanol and diethyl fumarate influences the solubility of CO2 in the liquid phase. Based on the solubility data the distribution coefficients and separation factors have been determined. Furthermore, standard error of measurements has been calculated and commented. For constructing a phased diagram of ternary system we used the program OriginPro. We came to the conclusion that the solubility of CO2 decreases with increasing temperature at constant pressure. Based on obtained results we observed that standard error of measurements which were made at temperature of 125 °C is high because equilibrium between phases wasn’t completely established, therefore the second set of measurements was performed at temperature of 180 °C. Results obtained have been presented in the form of graphs and tables.

The Diels-Alder reactions of the ortho-quinodimethane (o-QDM) thermally generated from 2,4-diphenylciclobutapyrimidine with the dienophiles diethyl maleate, diethyl fumarate and dimethyl acetylenedicarboxylate have been investigated. The reaction afforded 5,6,7,8-tetrahydroquinazoline and quinazoline derivatives. While diethyl maleate formed a mixture of cis- and trans-adducts, diethyl fumarate gave only the trans-adduct. The reaction with methyl acetylenedicarboxylate formed a mixture of 5,8-dihydroquinazoline and quinazoline derivatives. © 2006 Bentham Science Publishers Ltd.

The RuCl2(PPh3)3-catalyzed diazo coupling of ethyl diazoacetate was manipulated to generate either diethyl fumarate (DEF) or diethyl maleate (DEM) with high stereoselectivity. A mechanism was proposed which contained separate pathways for DEM and DEF formation and explained how reaction conditions were controlled to favor either pathway.

Treatment of 3-methylamino-5-phenylthiophene with α,β-unsaturated esters, i.e., methyl acrylate, (E)-methyl crotonate, diethyl fumarate, diethyl maleate and ethyl propiolate, in tetrahydrofuran for several days at reflux gave 1-methyl-3,4-dihydrothieno[2,3-e]pyridin-2-ones 4 and/or 1-methylthieno[2,3-e]pyridin-2-ones 5, depending on the structure of the esters. On the other hand, the same reactions with α,β-unsaturated nitriles such as acrylonitrile and tetracyanoethene, gave the corresponding thiophenes 7 and 10 bearing 2-cyanoethyl and 1,2,2-tricyanoethenyl groups at C-2, respectively. The reaction with (Z)-1,2-dicyanoethene under the same conditions produced the corresponding thiophene 9 bearing the 1,2-dicyanoethenyl group and 1,2-dicyano-5-methylaminobiphenyl.

3-(Fluoroalkyl)isoxazolidines 6 and -2,3-dihydroisoxazoles 8 have been obtained in enantiomerically pure form with good diastereoselectivity by 1,3-dipolar cycloaddition of diethyl fumarate and dimethylacetylene dicarboxylate, respectively, to the chiral fluorinated nitrone (R)-5. The latter has been prepared from the β-fluoromethyl-β-oxo sulfoxide (RS)-1, by a synthetic sequence where the chiral and enantiomerically pure sulfinyl function acts as a removable source of chirality. Reductive opening of isoxazolidines 6 then afforded amino fluoromethyl diols 7 in good yields.

The first examples of Diels-Alder reactions of chiral, C 2 -symmetric ( E , E )-1,4-dialkoxy-1,3-butadienes are described. The cycloadditions with maleic anhydride lead in all instances to the exclusive formation of the endo adducts. C 24 -Symmetric dienophiles such as fumaronitrile and diethyl fumarate react with variable diastereoselectivities; best results are obtained with the camphor-derived diene 1d , whose reaction with diethyl fumarate takes place with complete facial selectivity. A theoretical analysis, using the SCF-MO procedure AM1, of the conformations of the dialkoxydienes has been used to rationalize the steric course of the cycloadditions.

The rhenium dimer complex Cp*(CO)2ReRe(CO)2Cp* (1) (Cp*=C5Me5) reacted in THF with diethyl fumarate in a fragmentation reaction to form Cp*Re(CO)3 (3) and Cp*Re(CO)(η2-(E)-EtO2CCHCHCO2Et)(THF) (6). Reaction of 6 with CO resulted in substitution of the THF ligand with CO to form the alkene complex Cp*Re(CO)2(η2-(E)-EtO2CCHCHCO2Et) (7). Variable temperature 1H-NMR spectroscopy of 7 showed that rotation of the alkene ligand is slow below −50°C.

Steroidal alkenyl iodides (17-iodo-androsta-16-ene and 17-iodo-4-methyl-4-aza-androsta-16-ene-3-one) were reacted with conjugated unsaturated esters (ethyl acrylate, diethyl fumarate, diethyl maleate, diethyl acetylene dicarboxylate) in Heck-reaction and consecutive Diels-Alder reaction resulting in facile formation of pentacyclic derivatives. All steroidal esters possessing two, three and four ester functionalities on the E-ring were formed by the α-side addition of the dienophile.

Deuterated isopropyl vinyl sulfides and diethyl fumarate were synthesized and employed in a re-investigation of the mechanism of initiation of spontaneous polymerization of these comonomers by means of spin-trapping/ESR spectroscopy. Previous radical spin-trapping studies had been interpreted as indicating the involvement of vinyl radicals. While our studies produced data substantially in agreement with the previous study, it must be noted that the data are not consistent with literature data for other vinyl radicals. Accordingly, results from both spin-trapping/ESR studies are inconsistent with involvement of vinyl radical intermediates, but are consistent with initiation by tetramethylene diradicals.

A variety of Diels-Alder reactions have been performed in supercritical water as a reaction medium. The rapid reaction of Diels-Alder reactions of cyclopentadiene and various electron poor dienophiles such as diethyl fumarate and acrylonitrile is observed in supercritical water, and leads to high yields of clean products without added catalysts.

The title compound was synthesized via 1,3-dipolar cycloaddition of diazoacetonitrile and diethyl fumarate.

A synthesis of 2-substituted-1,3-dienes is reported which uses silicon as a control element: Eight aldehydes were converted into α-silyl ketones by treatment with trimethylsilylmethylmagnesium chloride and rapid Collins oxidation. Addition of vinylmagnesium bromide to the resulting α-silyl ketones, followed by Peterson elimination, gave a series of dienes. The route was used to make (4S)-3-methylene-t-[(phenylmethoxy)methoxy]pent-1-ene from (–)-ethyl lactate; low asymmetric induction was observed in the Diels–Alder reactions of this diene with diethyl fumarate and N-phenylmaleimide.

The photochemical reaction between 9-vinyladenine (2) and diethyl fumarate (4) gave an unusual photoadduct, epimers 4 and 5, probably derived from attack of the vinyl group on N-3 and reaction of diethyl fumarate on N-9 and N-6.

A synthetic pathway to 5,6-dihydrovaltrate (I) is described using an asymmetric Diels—Alder reaction between diethyl fumarate and cyclopentadiene as key step (catalyst and product configuration are not specified, yield quant., 95% e.e.).

A variety of Diels-Alder reactions have been performed in supercritical water as a reaction medium. The rapid reaction of Diels-Alder reactions of cyclopentadiene and various electron poor dienophiles such as diethyl fumarate and acrylonitrile is observed in supercritical water, and leads to high yields of clean products without added catalysts.

Aromatic and heteroaromatic aldehydes react with diethyl fumarate or diethyl maleate and tri-n-butylphosphine at room temperature to afford good yields of diethyl arylidenesuccinates. Unsaturated and saturated aldehydes afford cognate products.

Bony defects have been three-dimensionally (3D) created in many clinical circumstances; however, many defects cannot be reconstructed because most of the current bony substitutes cannot provide the necessary exact 3D structure. Therefore, to overcome this limitation, a 3D scaffold with embedded growth factor-delivering microspheres was developed by solid free-form fabrication (SFF) technology using computer-aided design/manufacturing (CAD/CAM). In this study, BMP-2-loaded poly(DL-lactic-co-glycolic acid) (PLGA) microspheres were incorporated into a 3D scaffold that was fabricated using a microstereolithography (MSTL) system with a suspension of microspheres and a poly(propylene fumarate) (PPF)/diethyl fumarate (DEF) photopolymer. By measuring release profiles in vitro, we verified that the fabricated microsphere-containing 3D scaffold could gradually release growth factor. The effects of BMP-2 were also assessed in vitro by observing cell differentiation using MC3T3-E1 pre-osteoblasts. Finally, we confirmed that SFF scaffolds created by MSTL were superior to traditional scaffolds produced using a particulate leaching/gas foaming method. In addition, based on in vivo tests, the scaffolds that released BMP-2 promoted bone formation. Based on these results, we concluded that our 3D scaffold might be a useful tool for enhancing reconstruction quality in many complex bony defects that should be reconstructed using a customized 3D scaffold.

3-(Fluoroalkyl)isoxazolidines 6 and -2,3-dihydroisoxazoles 8 have been obtained in enantiomerically pure form with good diastereoselectivity by 1,3-dipolar cycloaddition of diethyl fumarate and dimethylacetylene dicarboxylate, respectively, to the chiral fluorinated nitrone (R)-5. The latter has been prepared from the β-fluoromethyl-β-oxo sulfoxide (RS)-1, by a synthetic sequence where the chiral and enantiomerically pure sulfinyl function acts as a removable source of chirality. Reductive opening of isoxazolidines 6 then afforded amino fluoromethyl diols 7 in good yields.

A practical method for the multigram scale selective cis-dihydroxylation of electron deficient alkenes such as diethyl fumarate and N-alkyl and N-aryl-maleimides using H(2)O(2) is described. High turnovers (1000) can be achieved with this efficient manganese based catalyst system, prepared in situ from a manganese salt, pyridine-2-carboxylic acid, a ketone and a base, under ambient conditions. Under optimized conditions, for diethyl fumarate at least 1000 turnovers could be achieved with only 1.5 equiv. of H(2)O(2) with d/l-diethyl tartrate (cis-diol product) as the sole product. For electron rich alkenes, such as cis-cyclooctene, this catalyst provides for efficient epoxidation.

The structures of the cycloadducts formed in the (2+2) cycloaddition reactions of 1,3-dimethylallene (13DMA) with 1,1-dichloro-2,2-difluoroethene (1122), acrylonitrile (ACN), methyl acrylate (MAC), N-phenylmaleimide (NPMI), and diethyl fumarate (DEF) and maleate (DEM) and the product disitributions have been interpreted on the basis of favored conformations for diradical formation and ring closure to the cycloadducts