Malonate Addition Research Articles

Stereoselective mechanochemical synthesis of thiomalonate Michael adducts via iminium catalysis by chiral primary amines.

The study presents a novel approach utilizing iminium salt activation and mild enolization of thioesters, offering an efficient and rapid synthesis of Michael adducts with promising stereoselectivity and marking a significant advancement in mechanocatalysis. The stereoselective addition of bisthiomalonates 1-4 to cyclic enones and 4-chlorobenzylideneacetone proceeds stereoselectively under iminium activation conditions secured by chiral primary amines, in contrast to oxo-esters as observed in dibenzyl malonate addition. Mild enolization of thioesters allows for the generation of Michael adducts with good yields and stereoselectivities. Reactions in a ball mill afford product formation with similar efficacy to solution-phase reactions but with slightly reduced enantioselectivity, yet they yield products in just one hour compared to 24 or even 168 hours in solution-based reactions. It is noteworthy that this represents one of the early reports on the application of iminium catalysis using first-generation chiral amines under mechanochemical conditions, along with the utilization of easily enolizable thioesters as nucleophiles in this transformation.

The proceeded ammonia release from ammonium nitrate owing to sodium malonate addition: Dependence of RH, acidity and surfactant

The gas-particle partition of ammonia has strong effect on size, composition and hygroscopic property of atmospheric aerosols. However, how chemical reaction drives ammonia evaporation from particle is not well known. In this work, ammonium depletion is used to characterize the ammonia liberation from aqueous ammonium nitrate and sodium malonate/ammonium nitrate aerosols. The addition of sodium malonate promotes more ammonia liberation owing to inter-ingredients reaction. As the relative humidity (RH) decreases, ammonia release is enhanced. Moreover, NH3 evaporation is also impacted by aerosol acidity. At pH 1.93, malonate is directly converted into hydrogen malonate and malonic acid via protonation. Under the neutral/alkaline condition, higher pH is beneficial for component reactions. When cetyltrimethylammonium bromide is added into mixed aerosols, NH3 evaporation becomes slow. These results can provide a new perspective on the evolution mechanism of NH3–NH4+ buffer pairs for multicomponent aerosols.

Three-Component Reaction of Dimethyl Malonate with α,β-Acetylenic Aldehydes and Amines. Synthesis of Push–Pull Buta-1,3-dienes

Three-component reaction of dimethyl malonate with α,β-acetylenic aldehydes and cyclic secondary amines (pyrrolidine, piperidine, morpholine, and piperazine) under mild conditions afforded dimethyl 2-(3-aminoprop-2-en-1-ylidene)malonates in 50–91% yields. The products were formed preferentially as E isomers, and the described reaction provides a convenient method for the synthesis of push–pull buta-1,3-dienes that are interesting as fluorescent, solvatochromic, and nonlinear optical materials and starting compounds in the synthesis of carbo- and heterocycles. A plausible reaction mechanism involves Knoevenage condensation of dimethyl malonate with α,β-acetylenic aldehyde to give dimethyl 2-(prop-2-yn-1-ylidene)malonate and subsequent nucleophilic addition of cyclic amine to the latter.

Thiourea-Catalyzed Enantioselective Malonate Addition onto 3-Sulfonyl-3'-indolyl-2-oxindoles: Formal Total Syntheses of (-)-Chimonanthine, (-)-Folicanthine, and (+)-Calycanthine.

A general approach to bispyrroloindolines via a key thiourea-catalyzed addition of malonates to 3-sulfonyl-3'-indolyl-2-oxindoles is reported. The enantioselelective process is found to be highly effective (up to 94% ee), where a C-C bond formation leads to the synthesis of a number of 2-oxindoles with an all-carbon quaternary stereocenter.

Lewis Acid-Catalyzed Malonate Addition onto 3-Hydroxy-2-oxindoles: Mechanistic Consideration and Synthetic Approaches to the Pyrroloindoline Alkaloids.

Metal triflate-catalyzed reactions of 3-hydroxy-2-oxindoles with a variety of malonates have been developed under mild conditions. The reaction afford a variety of 2-oxindoles sharing a C-3 quaternary center at the pseudobenzylic position in an operationally simple procedure. Control experiments using enantioenriched 3-hydroxy/methoxy 2-oxindoles (91% ee) afforded a malonate addition product in racemic form, clearly suggesting that the reaction proceeds through an in situ generated 2 H-indol-2-one intermediate (4a). Synthetic potential of this methodology has been shown by approaching the cyclotryptamine alkaloids linked with the aryl group at the pseudobenzylic position.

Cu(ii)-tBu-PHOX catalyzed enantioselective malonate addition onto 3-hydroxy 2-oxindoles: application in the synthesis of dimeric pyrroloindoline alkaloids.

An efficient Cu(ii)-PHOX-catalyzed malonate addition onto 3-hydroxy 3-indolyl-2-oxindoles is envisioned to afford excellent enantioselectivities (up to >99% ee) in high chemical yields. Detailed characterization techniques including X-ray, NMR, CV and EPR experiments suggest that a Cu(ii)-complex is involved as an active species in this process. Applying this strategy, an advanced intermediate of cyclotryptamine alkaloids has been synthesized in few steps for a general approach to bis-cyclotryptamine alkaloids.

ChemInform Abstract: Asymmetric Oxidative Lewis Base Catalysis—Unifying Iminium and Enamine Organocatalysis with Oxidations.

AbstractA novel domino oxidation—asymmetric malonate addition reaction is presented, which affords chiral aryl(formyl)cyclopropanedicarboxylates (III) or linear aldehydes (VII) in moderate to high enantioselectivity (up to 98% e.e.).

Immobilization of Chiral Bifunctional Organocatalysts on Poly(methylhydrosiloxane)

Takemoto promotes: Enantiomerically pure bifunctional chiral catalysts are immobilized on poly(methylhydrosiloxane). A supported Takemoto-type catalyst promoted the diethyl malonate addition to nitrostyrene in fair to good yields and up to 83 % ee, and its recyclability is demonstrated.

Stereoselective diversity-oriented syntheses of functionalized saccharides from bicyclic carbohydrate 1,2-lactones

Bicyclic carbohydrate 1,2-lactones have been synthesized in only two steps and high yields by saponification and subsequent cyclization from known malonate addition products to glycals. The gluco-configured lactone serves as an important precursor for diversity-oriented syntheses. Thus, stereoselective opening of the lactone ring was realized with various nucleophiles in the presence of Sc(OTf) 3. This enabled the introduction of different substituents at the anomeric position, to afford a broad variety of 1-functionalized carbohydrates. On the other hand, stereoselective α-substitution of the gluco-configured lactone with different electrophiles and subsequent ring opening gives a collection of 2-functionalized saccharides. More than 30 products have been isolated in analytically pure form, and their configurations were unequivocally established by various NMR methods. Thus, carbohydrate 1,2-lactones are attractive precursors for the stereoselective synthesis of diverse saccharides.

Unexpected fullerene dimerizationvia [5,6]-bond upon functionalization of Cs-C70(CF3)8by the Bingel reaction

The Bingel reaction of the C(s) isomer of C(70)(CF(3))(8) has been found to yield two C(70)(CF(3))(8)[C(CO(2)Et)(2)] monoadducts and one C(70)(CF(3))(8)[C(CO(2)Et)(2)](2) bisadduct as its major products. Malonate addition occurs at those [6,6]-bonds that radiate from the polar pentagons of the C(70)(CF(3))(8) cage. Unexpectedly, X-ray single crystal analysis reveals dimerization of the above substances during crystallization, providing two isomers of {C(70)(CF(3))(8)[C(CO(2)Et)(2)]}(2), one isomer of {C(70)(CF(3))(8)[C(CO(2)Et)(2)](2)}(2) and {C(70)(CF(3))(8)}(2). This dimerization represents [2+2]-cycloaddition via [5,6]-bonds and results in functionalization patterns resembling several known C(70)X(10) derivatives.

Asymmetric Catalysis in Confined Space Provided by l-Proline Functionalized Mesoporous Silica with Plugs in the Pore

Mesoporous silica having l-proline functionality and plugged pore structure was synthesized by direct microwave synthesis under acidic condition using Pluronic P123 as template and sodium metasilicate nonahydrate as silica source. The direct synthesis resulted in the prismatic or disk types with short channels and plugs in the pore structure. Due to the presence of plugs, dual mesoporosities with 7 and 3 nm pore diameter were generated leading to an existence of cavitation. Tri-functionality of this materials i.e. chiral organofunctional group, plugs, and short channel, would be useful for the asymmetric diethyl malonate addition reaction and asymmetric epoxidation reaction of α,β-unsaturated aldehydes. We proved that the formation of plugs in the mesoporous silica governs the formation of dual mesoporosities providing an enhancement of enantiomeric excess in the asymmetric catalysis. This finding might open an important application of the amino-acid organo multifunctionalized mesoporous silica for asymmetric reactions.

Asymmetric Synthesis of Tetrabenazine and Dihydrotetrabenazine

The enantioselective synthesis of (+)-tetrabenazine (TBZ) and (+)-dihydrotetrabenazine (DTBZ), agents of significant interest for therapeutic and molecular imaging applications, has been completed in 21% (TBZ) and 16% (DTBZ) overall yield and in >97% ee from the starting dihydroisoquinoline. The synthesis utilizes Sodeoka's palladium-catalyzed asymmetric malonate addition to set the initial stereocenter followed by a number of diastereoselective transformations to incorporate the remaining asymmetric centers.

Overexpression of isocitrate lyase—glyoxylate bypass influence on metabolism in Aspergillus niger

In order to improve the production of succinate and malate by the filamentous fungus Aspergillus niger the activity of the glyoxylate bypass pathway was increased by over-expression of the isocitrate lyase ( icl) gene. The hypothesis was that when isocitrate lyase was up-regulated the flux towards glyoxylate would increase, leading to excess formation of malate and succinate compared to the wild-type. However, metabolic network analysis showed that an increased icl expression did not result in an increased glyoxylate bypass flux. The analysis did show a global response with respect to gene expression, leading to an increased flux through the oxidative part of the TCA cycle. Instead of an increased production of succinate and malate, a major increase in fumarate production was observed. The effect of malonate, a competitive inhibitor of succinate dehydrogenase (SDH), on the physiological behaviour of the cells was investigated. Inhibition of SDH was expected to lead to succinate production, but this was not observed. There was an increase in citrate and oxalate production in the wild-type strain. Furthermore, in the strain with over-expression of icl the organic acid production shifted from fumarate towards malate production when malonate was added to the cultivation medium. Overall, the icl over-expression and malonate addition had a significant impact on metabolism and on organic acid production profiles. Although the expected succinate and malate formation was not observed, a distinct and interesting production of fumarate and malate was found.

Organocatalytic Application of Direct Organo-Functionalized Mesoporous Catalysts Prepared by Microwave

The organic functional groups such as primary and quaternary amine, sulfonic acid, and amino acid, especially l-proline, have been tried to immobilize onto mesoporous materials by the direct synthesis method using microwave. Microwave induced direct functionalization enabled to get well ordered mesoporous structures and stable organic tethered groups with enhanced hydrothermal stability due to more hydrophobic surfaces as well as enhanced activity. The method is also useful for overcoming several shortcomings in the post-synthesis grafting method which suffers from pore blocking at the aperture, and difficulties in controlling the as obtained from the direct co-condensation method had their functional groups spatially loadings, as well as the dispersion of active sites. The organo-functionalized mesoporous silica dispersed on the surface which could play roles as single site catalysts. Direct tethering of organic functional groups was preferably synthesized by microwave, gave morphological control and illustrated superiority in some organocatalytic application such as Knoevenagel and Henry reactions base catalytic reaction, Claisen–Schmidt condensation, and diethyl malonate addition reactions.

ChemInform Abstract: A General Organocatalytic Enantioselective Malonate Addition to α,β‐Unsaturated Enones.

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 of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Chiral Enhancement in Diethyl Malonate Addition by Morphosynthesized L‐Proline Mesoporous Silica.

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 of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A General Organocatalytic Enantioselective Malonate Addition to α,β‐Unsaturated Enones

A general enantioselective organocatalytic conjugate addition procedure of a variety of malonates to alpha,beta-unsaturated enone systems is presented. The reaction is efficiently catalysed by the pyrrolidinyl tetrazole catalyst 1. Cyclic, acyclic and aromatic enones can be used and the reaction with ethyl malonates 3 b provides the Michael addition products in high yields with good to excellent enantioselectivities. Since only 1.5 equivalents of malonate are used as a reagent, the reaction is readily scaled and practical to operate. Furthermore, the malonate addition products can be easily mono decarboxylated without loss in enantiomeric excess by enzymatic or sodium hydroxide mediated methods.

Chiral enhancement in diethyl malonate addition by morphosynthesized l-proline mesoporous silica

l-Proline was immobilized onto mesoporous silica through direct synthesis method via morphosynthesis possessing short channels and plugs in the pore structure which provided chiral enhancement in the diethyl malonate addition reaction.

Nucleophilic Addition to (3-Methylpentadienyl)iron(1+) Cations: Counterion Control of Regioselectivity; Application to the Enantioselective Synthesis of 4,5-Disubstituted Cyclohexenones

The regioselectivity of malonate addition to (3-methylpentadienyl)Fe(CO)3+ is controlled by the malonate-counterion association. The Li+ salt of malonate proceeds via C1 nucleophilic attack to afford the 1,3Z-diene complex 4a, while reaction of highly dissociated ion pair (i.e., Na+ or Li+/12-crown-4) salt proceeds at the C2 internal carbon to eventually afford cyclohexenone products 6. Reaction of 1a with the sodium salt of bis(8-phenylmenthyl)malonate proceeds with excellent diastereocontrol to afford a single diastereomeric cyclohexenone.

Malonate induces cell death via mitochondrial potential collapse and delayed swelling through an ROS‐dependent pathway

1. Herein we study the effects of the mitochondrial complex II inhibitor malonate on its primary target, the mitochondrion. 2. Malonate induces mitochondrial potential collapse, mitochondrial swelling, cytochrome c (Cyt c) release and depletes glutathione (GSH) and nicotinamide adenine dinucleotide coenzyme (NAD(P)H) stores in brain-isolated mitochondria. 3. Although, mitochondrial potential collapse was almost immediate after malonate addition, mitochondrial swelling was not evident before 15 min of drug presence. This latter effect was blocked by cyclosporin A (CSA), Ruthenium Red (RR), magnesium, catalase, GSH and vitamin E. 4. Malonate added to SH-SY5Y cell cultures produced a marked loss of cell viability together with the release of Cyt c and depletion of GSH and NAD(P)H concentrations. All these effects were not apparent in SH-SY5Y cells overexpressing Bcl-xL. 5. When GSH concentrations were lowered with buthionine sulphoximine, cytoprotection afforded by Bcl-xL overexpression was not evident anymore. 6. Taken together, all these data suggest that malonate causes a rapid mitochondrial potential collapse and reactive oxygen species production that overwhelms mitochondrial antioxidant capacity and leads to mitochondrial swelling. Further permeability transition pore opening and the subsequent release of proapoptotic factors such as Cyt c could therefore be, at least in part, responsible for malonate-induced toxicity.