Malonic Diesters Research Articles

Dual-Way-Switchable Ester Rotaxanes Constructed Using the Recognition of Malonate Diesters.

Malonate diesters can thread into the cavity of a di(ethylene glycol)-containing macrocycle under the templating effect of a Na+ ion; the corresponding rotaxanes can be synthesized with good efficiency by applying several stoppering reactions. A molecular switch, in which the interlocked macrocycle was moved between two rarely used stations (i.e., malonate and TAA) through the addition of acid/base and the presence/absence of Na+ ions, was constructed using this new recognition system.

Front Cover: Asymmetric Construction of All‐Carbon Quaternary Stereocenters via Organocatalytic α‐Hydroxymethylation of Malonic Diesters Using Aqueous Formaldehyde (Asian J. Org. Chem. 8/2022)

Formaldehyde is a potent one-carbon electrophile for organic synthesis. However, there are few synthetic approaches using aqueous formaldehyde (formalin). This paper describes an organocatalyzed enantioselective α-hydroxymethylation of malonic diesters with aqueous formaldehyde. Formaldehyde would react catalytically by transferring from the aqueous phase to the organic phase, providing chiral versatile malonic diester derivatives which contain a quaternary stereogenic center. More information can be found in the Research Article by Takuya Kanemitsu et al.

Asymmetric Construction of All‐Carbon Quaternary Stereocenters via Organocatalytic α‐Hydroxymethylation of Malonic Diesters Using Aqueous Formaldehyde

AbstractAn organocatalyzed α‐hydroxymethylation of α‐monoalkyl malonic diesters using 37% aqueous formaldehyde (formalin) as a one‐carbon electrophilic unit to generate all‐carbon substituted quaternary stereocenters has been developed. In the course of our exploration of catalytic methodologies, a metal‐free cooperative catalytic approach with cinchonidine and squaramide co‐catalysts was found to improve both reactivity and enantioselectivity in this transformation. Our organocatalytic method represents the first example of an enantioselective α‐hydroxymethylation of a malonic diester. The enantioenriched α‐hydroxymethyl products could be recrystallized with high recovery, yielding optically pure materials. Moreover, to demonstrate the utility of this methodology, the all‐carbon substituted α‐quaternary stereogenic malonate was converted to both (S)‐ and (R)‐4,4‐disubstituted oxazolidin‐2‐ones without loss of optical purity.

Lewis acid triggered N-alkylation of sulfoximines through nucleophilic ring-opening of donor-acceptor cyclopropanes: synthesis of γ-sulfoximino malonic diesters.

Scandium triflate (Sc(OTf)3) catalyzed, mild, and regioselective ring-opening reaction of donor-acceptor (D-A) cyclopropanes has been developed using sulfoximines for the synthesis of γ-sulfoximino malonic diesters. This protocol allows the synthesis of different N-alkyl sulfoximines in good to excellent yields (up to 94%) with broad functional group tolerance. In this process, N-H and C-C bonds are cleaved to form new C-N and C-H bonds. The feasibility of this method is supported by a gram-scale reaction and synthetic elaboration of the obtained product.

Asymmetric synthesis of intermediate for (1R,2S)-ethyl 1-amino-2-vinylcyclopropanecarboxylate by desymmetrization using engineered esterase from Bacillus subtilis

(1R,2S)-Ethyl 1-amino-2-vinylcyclopropanecarboxylate (VCPA), is a key intermediate for anti-hepatitis C virus drugs. In this study, we developed an efficient manufacturing method of intermediate for (1R,2S)-VCPA by enzymatic desymmetrization of a malonate diester derivative. In synthesis scheme of VCPA (1S,2S)-1-(ethoxycarbonyl)-2-vinylcyclopropanecarboxylic acid (VCPME) is the monoester intermediate, which is converted from 2-vinylcyclopropane-1,1-dicarboxylate diethyl ester (VCPDE). As a result of esterase screening for producing (1S,2S)-VCPME from VCPDE by enzymatic desymmetrization, p-nitrobenzyl esterase from Bacillus subtilis NBRC3027 (PNBE3027) showed high enantioselectivity (more than 90% e.e.). Based on the homology model of PNBE3027, a library of mutants with the substitution of L70, L270, L273, and L313 in substrate-binding pocket was created for improvement in enantioselectivity. (1S,2S)-VCPME produced by the best variant harboring L70D, L270Q, L273R, and L313M showed 98.9% e.e. of enanthiopurity. Furthermore, preparative scale production of (1S,2S)-VCPME using the quadruple mutant was achieved. Our investigations present a new efficient process for (1R,2S)-VCPA using esterase and diverse to be applied for the industrial scale production.

Expanding the Versatile Reactivity of Diazido Malonic Acid Esters and Amides: Decarboxylation and Imine Formation

Herein, we advance our understanding on the divergent reaction pathways that are possible, starting from diazido diethyl malonate (easily generated through the oxidative diazidation of diethyl malonate with iodine and sodium azide in DMSO at room temperature): when treated with amines, diazidated malonamides are rapidly formed, many of which then undergo a formal substitution reaction with alkylamines leading to imino malonamides under basic conditions. Using the established conditions of CuAAC click reactions with terminal alkynes, the diazidated malonamides are alternatively transformed into their corresponding bistriazole derivatives, a reaction that is also achievable with diazido diethyl malonate. We now demonstrate that the malonic diester bistriazoles undergo a smooth decarboxylation in the presence of amines, creating novel bistriazole variants derived from acetamides. All protocols presented herein are experimentally simple and enhance the variety of products obtainable from malonic acid derivatives.

Ester Prodrugs of Malonate with Enhanced Intracellular Delivery Protect Against Cardiac Ischemia-Reperfusion Injury In Vivo

PurposeMitochondrial reactive oxygen species (ROS) production upon reperfusion of ischemic tissue initiates the ischemia/reperfusion (I/R) injury associated with heart attack. During ischemia, succinate accumulates and its oxidation upon reperfusion by succinate dehydrogenase (SDH) drives ROS production. Inhibition of succinate accumulation and/or oxidation by dimethyl malonate (DMM), a cell permeable prodrug of the SDH inhibitor malonate, can decrease I/R injury. However, DMM is hydrolysed slowly, requiring administration to the heart prior to ischemia, precluding its administration to patients at the point of reperfusion, for example at the same time as unblocking a coronary artery following a heart attack. To accelerate malonate delivery, here we developed more rapidly hydrolysable malonate esters.MethodsWe synthesised a series of malonate esters and assessed their uptake and hydrolysis by isolated mitochondria, C2C12 cells and in mice in vivo. In addition, we assessed protection against cardiac I/R injury by the esters using an in vivo mouse model of acute myocardial infarction.ResultsWe found that the diacetoxymethyl malonate diester (MAM) most rapidly delivered large amounts of malonate to cells in vivo. Furthermore, MAM could inhibit mitochondrial ROS production from succinate oxidation and was protective against I/R injury in vivo when added at reperfusion.ConclusionsThe rapidly hydrolysed malonate prodrug MAM can protect against cardiac I/R injury in a clinically relevant mouse model.

Lewis Acid Catalyzed Ring-Opening 1,3-Aminothiolation of Donor-Acceptor Cyclopropanes Using Sulfenamides.

Yb(OTf)3 catalyzed mild and regioselective ring-opening 1,3-aminothiolation of donor-acceptor (D-A) cyclopropanes using sulfenamides has been demonstrated. The insertion of the C-C σ-bond of D-A cyclopropanes into the S-N σ-bond of sulfenamides allows the synthesis of diverse γ-aminated α-thiolated malonic diesters in moderate to good yields (up to 87%) with good functional group compatibility. The stereospecificity of the reaction was demonstrated using enantiomerically pure D-A cyclopropane.

Asymmetric Michael addition of malonic diesters to acrylates by phase-transfer catalysis toward the construction of quaternary stereogenic α-carbons

A highly enantioselective construction of an all-carbon quaternary stereogenic center at the α-position of malonic diesters has been achieved by Michael addition using phase-transfer catalysis. The reaction of α-monosubstituted malonates with acrylates in the presence of N-(9-anthracenylmethyl)quininium chloride as a phase-transfer catalyst afforded the corresponding α,α-disubstituted malonic diesters in high chemical yields (up to >95% yield) with high enantioselectivities (up to 95% ee). Furthermore, the product was amenable to chemoselective transformation and could be successfully converted to the corresponding α,α-disubstituted amino acid derivatives through Curtius rearrangement.

Chemoselective Catalytic Dehydrogenative Cross-Coupling of 2-Acylimidazoles: Mechanistic Investigations and Synthetic Scope

Chemoselective iron-catalyzed dehydrogenative cross-coupling using 2-acylimidazoles is described. The addition of a phosphine oxide ligand substantially facilitated the generation of tert-butoxy radicals from di-tert-butyl peroxide, allowing for efficient benzylic C–H bond cleavage under mild conditions. Extensive mechanistic studies revealed that the enolization of 2-acylimidazole proceeded through dual iron catalyst activation, followed by subsequent chemoselective cross-coupling with a benzyl radical over an undesired benzyl radical-derived homocoupling dimer that inevitably formed in earlier reported conditions. A variety of alkylarenes, aliphatic alkane, and functionalized 2-acylimidazoles were applicable, demonstrating the synthetic utility of the present catalysis. Contiguous all-carbon quaternary carbons were constructed through dehydrogenative cross-coupling. The catalytic chemoselective activation of 2-acylimidazole over bidentate coordinative and much more acidic malonate diester was particular noteworthy. Catalytic oxidative cross-enolate coupling of two distinct carboxylic acid equivalents was also achieved using acetonitrile as a coupling partner.

Stereospecific 1,3‐Aminobromination of Donor–Acceptor Cyclopropanes

AbstractSn(OTf)2‐catalyzed 1,3‐aminobromination of donor–acceptor cyclopropanes with various sulfonyl amides or electron‐poor anilines and N‐bromosuccinimide is reported. These experimentally straightforward reactions occurred with complete regio‐ and stereospecificity (for anilines) to give γ‐aminated α‐brominated malonic diesters in good to excellent yields (up to 98 %). These compounds served as valuable substrates for subsequent reactions to provide substituted azetidines and γ‐lactams in high yields.

Stereospecific 1,3-Aminobromination of Donor-Acceptor Cyclopropanes.

Sn(OTf)2 -catalyzed 1,3-aminobromination of donor-acceptor cyclopropanes with various sulfonyl amides or electron-poor anilines and N-bromosuccinimide is reported. These experimentally straightforward reactions occurred with complete regio- and stereospecificity (for anilines) to give γ-aminated α-brominated malonic diesters in good to excellent yields (up to 98 %). These compounds served as valuable substrates for subsequent reactions to provide substituted azetidines and γ-lactams in high yields.

Diastereoselective Hydrolysis of Branched Malonate Diesters by Porcine Liver Esterase: Synthesis of 5‐Benzyl‐Substituted Cα‐Methyl‐β‐proline and Catalytic Evaluation

Malonate diesters with highly branched side chains containing a preexisting chiral center were prepared from optically pure amino alcohols and subjected to asymmetric enzymatic hydrolysis by Porcine Liver Esterase (PLE). Recombinant PLE isoenzymes have been utilized in this work to synthesize diastereomerically enriched malonate half‐esters from enantiopure malonate diesters. The diastereomeric excess of the product half‐esters was further improved in the later steps of synthesis either by simple recrystallization or flash column chromatography. The diastereomerically enriched half‐ester was transformed into a novel 5‐substituted Cα‐methyl‐β‐proline analogue (3R,5S)‐1c, in high optical purity employing a stereoselective cyclization methodology. This β‐proline analogue was tested for activity as a catalyst of the Mannich reaction. The β‐proline analogue derived from the hydrolysis reaction by the crude PLE appeared to catalyze the Mannich reaction between an α‐imino ester and an aldehyde providing decent to good diastereoselectivities. However, the enantioselectivities in the reaction was low. The second diastereomer of the 5‐benzyl‐substituted Cα‐methyl‐β‐proline, (3S,5S)‐1c was prepared by enzymatic hydrolysis using PLE isoenzyme 3 and tested for its catalytic activity in the Mannich reaction. Amino acid, (3S,5S)‐1c catalyzed the Mannich reaction between isovaleraldehyde and an α‐imino ester yielding the “anti” selective product with an optical purity of 99 %ee.

Enantioselective α-Benzoyloxylation of Malonic Diesters by Phase-Transfer Catalysis.

A highly enantioselective α-benzoyloxylation of malonic diester has been achieved by phase-transfer catalysis. The reaction of α-monosubstituted tert-butyl methyl malonate with benzoyl peroxide in the presence of aqueous KOH and N-(9-anthracenylmethyl)cinchoninium chloride afforded the corresponding α,α-disubstituted products in generally excellent chemical yields (up to 99% yield) with high enantioselectivities (up to 96% ee). In addition, the utility of this methodology was exhibited by the synthesis of a mineralocorticoid receptor antagonist.

ChemInform Abstract: Temporary Generation of a Cyclopropyl Oxocarbenium Ion Enables Highly Diastereoselective Donor—Acceptor Cyclopropane Cycloaddition.

AbstractA novel formal [3+2] cycloaddition of cyclopropylacetals and aldehydes is developed.

ChemInform Abstract: Chemoselective Intramolecular Carbonyl Ylide Formation Through Electronically Differentiated Malonate Diesters.

AbstractTrapping of the carbonyl ylides by alkynes is examined, and depending on the ylides substituents either functionalized oxabicyclic compounds are produced in a chemo‐, regio‐ and diastereoselective manner or tetronic acids are obtained as mixtures of diastereomers.

Chemoselective Intramolecular Carbonyl Ylide Formation through Electronically Differentiated Malonate Diesters.

A method for chemoselective carbonyl ylide formation utilizing the Rh(II) catalyzed decomposition of electronically differentiated diazo malonates is disclosed. Treatment of ethyl, trifluoro ethyl diazo malonate with a Rh(II) catalyst selectively forms a carbonyl ylide from the relatively electron rich ethyl ester. This carbonyl ylide can be trapped by various alkynes giving highly functionalized oxabicyclic compounds in a chemo-, regio-, and diastereoselective fashion.

Substrate specificity of an esterase from the archaeon Sulfolobus tokodaii bearing a GGG(A)X motif

A GGG(A)X-type esterase (Est0071) from an archaeon catalyzes asymmetric hydrolysis of prochiral bulky malonic diesters in good enantioselectivity. The selectivity of Est0071 was for the opposite enantiomer to that previously shown for pig liver esterase, and the resulting enantiomeric excess of the products was higher. Est0071 could also catalyze the hydrolysis of various acetates of secondary alcohols, and showed moderate enantioselectivity in these reactions.

Application of asymmetric alkylation of malonic diester with phase-transfer catalysis: synthesis of LFA-1 antagonist BIRT-377

An efficient asymmetric synthesis of LFA-1 antagonist BIRT-377 using enantioselective phase-transfer catalytic alkylation has been developed. The alkylation of α-monosubstituted tert-butyl methyl malonate was catalyzed by a quaternary ammonium salt derived from a cinchona alkaloid to obtain the product with a quaternary stereogenic carbon in high yield and with high enantioselectivity. The chiral α,α-disubstituted product thus obtained was transformed into BIRT-377 through alternating chemoselective deprotection of the two ester groups followed by Curtius rearrangement.

Synthesis of a Series of Malonic Diester–Introduced Fullerene Derivatives

A facile preparation method for derivatization of fullerene through the Bingel reaction was introduced. A series of fullerene derivatives, to which malonic diester with different substituents were introduced, were systematically synthesized by Bingel reaction. Malonic diester could be added to fullerene at room temperature in the presence of iodine and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and various substituents such as phenyl, hexyl, thienyl, and pyrenyl were introduced into both sides of the malonic diester. As a result, 17 systematic variations were synthesized. The solubility parameters of the obtained fullerene derivatives calculated by the method reported by Fedors were in the range of 33 to 43 (J cm−3)1/2. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource(s): Full experimental and spectral details.]