Malonic Ester Synthesis Research Articles

Enantiospecific Total Synthesis and Absolute Configuration Assignment of Chabrolobenzoquinone H.

Chabrolobenzoquinone H (1), a meroditerpene metabolite with cytotoxic activity, is synthesized via a stereoselective Julia-Kocienski olefination between a chiral pool derived aliphatic PT-sulfone and a benzoquinone aldehyde partner. The latter was obtained via consecutive chain extension steps involving a Stille coupling and a stereospecific olefin cross-metathesis reaction followed by malonic ester synthesis and a Krapcho decarboxylation. Furthermore, this total synthesis securely determined the absolute configuration of the targeted natural product.

Catalyst: Is the Amino Acid a New Frontier for Biorefineries?

Prof. Ning Yan obtained his BS and PhD degrees from Peking University in 2004 and 2009, respectively. Thereafter, he worked as a Marie-Curie research fellow at Ecole Polytechnique Federale de Lausanne, Switzerland. He joined the National University of Singapore (NUS) as an assistant professor, established the Lab of Green Catalysis in 2012, and was promoted to the position of associate professor in 2018. Yunzhu Wang received her BE degree from NUS in 2014. She joined Prof. Yan’s group in the same year and is currently pursuing her PhD. Her research interests include nanoscale metal catalysts and their applications in producing renewable nitrogen-containing chemicals.

Asymmetric Synthesis of (+)‐Aspicilin

AbstractAspicilin (1), an eighteen membered macrolide with four stereocenters, was synthesized using (3R,4R)‐1,5‐hexadiene‐3,4‐diol and (S)‐propylene oxide as the starting materials. Sharpless epoxidation on the protected dienediol generated the required three consecutive stereocenters, and malonic ester synthesis added the acetyl unit. Yamaguchi protocol was applied to form the key ester with two terminal olefins ready for the ring‐closing metathesis. RCM, hydrogenation, selenylation, oxidation and deprotections gave aspicilin with 4.7% total yield.

A facile synthesis of dispersable NaCl nanocrystals

During the classical malonic ester synthesis, sodium chloride is eliminated. Sodium diethyl malonate was reacted either with phenacyl chloride or acetyl chloride, both in toluene solution and without solvent. NaCl nanocrystals with a size of 100-300 nm were obtained that could be easily redispersed in organic solvents if phenacyl chloride was used as reagent. The dispersion in dichloromethane was stable for at least two weeks without sedimentation or agglomeration.

An improved procedure for the synthesis of labelled fatty acids utilizing diethyl malonate

An improved procedure for the preparation and purification of labeled fatty acids by malonic ester synthesis has been developed. This method uses the different hydrolysis rates of the monoalkylmalonic ester intermediate and its dialkylmalonic ester side product. A convenient GC–MS monitoring technique allows performing this 3-step procedure without isolation of intermediates and gives a good yield. Copyright © 2006 John Wiley & Sons, Ltd.

Preparation of Resin-Bound Bismethylene Cyclic Malonic Acid Ester and Facile Solid-Phase Synthesis of 2-Alkylthio-4(1H)-quinolone and 2-Alkyl-4(1H)-quinolone

The resin-bound bismethylthiomethylene cyclic malonic acid ester 3 was built up efficiently. Resin 3 can react with arylamines and subsequent thermal cyclizations give 2-alkylthio-4-(1H)-quinolones. Furthermore, conjugate addition of Grignard reagents to the resin 3 forms the resin 6 which was reacted with aryl amines and subsequent thermal-cyclization-cleavages afford the 2-alkyl-4-(1H)-quinolones.

Synthesis of 4‐hydroxyquinolin‐2(1H)‐one analogues and 2‐substituted quinolone derivatives

AbstractA versatile synthetic method for preparing 4‐hydroxyquinolone and 2‐substituted quinolone compounds from simple benzoic acid derivatives was demonstrated. The synthetic strategies involve the use of well known ethyl acetoacetate synthesis, malonic ester synthesis and reductive cyclization. The key intermediates were keto esters 4a‐e, which could be transformed to 4‐hydroxyquinolones 5a,b or 2‐substituted quinolone ethyl esters 6a‐c depending on the reaction conditions. 4‐Hydroxyquinolone analogues were prepared and investigated for N‐methyl‐D‐aspartate (NMDA) activity in vitro. Among these derivatives, 6,7‐difluoro‐3‐nitro‐4‐hydroxyquinolin‐2(1H)‐one (9) exhibited moderate activity.

Synthesis of Phosphatidylcholine Having a Very Long Chain Polyunsaturated Fatty Acid

Abstract A phosphatidylcholine 9 bearing icosadienoyl and docosahexaenoyl groups at the 1- and 2-positions respectively was synthesized. The synthetic route involves carbon chain elongation of linoleic acid via malonic ester synthesis, preparation of lyso-phosphatidylcholine via lipase-catalyzed mon-acylation of 2-O-methoxyethoxymethylglycerol and phosphodiester synthesis, and finally DCC-mediated esterification.

Malonic ester and acetoacetic ester synthesis of 2-[ 11,14C]methyl-fatty acids

Suitable conditions were sought for the synthesis of various 2-[ 11,14C]methyl-fatty acids by malonic ester synthesis and acetoacetic ester synthesis, both involving radio-methylation with [ 11,14C]Ch 3I. The malonic ester synthesis gave 2-[ 11C]methyl-fatty acids with over 60% decay-corrected yields in about 40 min and the [ 14C]products with somewhat higher yields at a longer time. In the acetoacetic ester synthesis, several 2-[ 14C]methyl-fatty acids were synthesized in 50–70% yields by the hydrolysis of the radio-methylated acetoacetates with a concentrated potassium hydroxide solution, together with by-prodcut ketones. This hydrolysis was completed in 5 min at 70°C, whereas rather drastic conditions or a longer time were needed for the thermal decarboxylation in the malonic ester synthesis.

A general and stereoselective synthesis of the capsaicinoids via the orthoester Claisen rearrangement

Capsaicin, a main pungent principle of hot pepper, and its 15 analogs have been efficiently synthesized. The key step of this synthetic sheme is the orthoester Claisen rearrangement, which transformed allylic alcohols 2A-C to ( E)-alkenoates 3A-C ( E Z > 100 ) in a highly stereoselective manner. The subsequent carbon chain elongations on 3 based on the cyanation or the malonic acid ester synthesis afforded ( E)-alkenoic acids 8, which were converted to the corresponding acid chloride and then coupled with vanillylamine to give capsaicinoids. HPLC and CE (capillary electrophoresis) analyses of these capsaicinoids were also carried out.

ChemInform Abstract: CsF in Organic Synthesis. Malonic Ester Synthesis Revisited for Stereoselective Carbon‐Carbon Bond Formation.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 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.

CsF in Organic Synthesis. Malonic Ester Synthesis Revisited for Stereoselective Carbon-Carbon Bond Formation

CsF in Organic Synthesis. Malonic Ester Synthesis Revisited for Stereoselective Carbon-Carbon Bond Formation

Determination of the absolute configuration of annonin I, a bioactive natural acetogenin from Annona squamosa

The absolute configuration of annonin I 1, a bioactive natural acetogenin with a bis(tetrahydrofuran) moiety, containing eight chiral centres has been determined by analysis of its circular dichroism (CD). The Cotton effects of the natural appearing annonin I 1 have been compared with a reference substance 2 synthesized by a malonic ester synthesis.

A facile preparation of enantiomers of ethyl 4,4,4-trifluoro-3-(indole-3-)butyrate, a novel plant growth regulator

Malonic ester synthesis combined with lipase-catalyzed enantioselective partial hydrolysis was used to prepare enantiomers of ethyl 4,4,4-trifluoro-3-(indole-3-)butyrate, a novel plant growth regulator. Among six commercially available enzymes, lipase AK (a lipase from Pseudomonas sp.) showed high enantioselectivity and moderate reactivity. The hydrolysis of racemic diethyl 2,2,2-trifluoro-1-(indole-3-)ethylmalonate (DTFIE) with lipase AK gave, following usual treatment of the products, S-(+)-4,4,4-trifluoro-3-(indole-3-)butyric acid (TFIBA) ethyl ester having 95% e.e. and R-(−)-TFIBA ethyl ester having >99% e.e. The optimized conditions for lipase AK hydrolysis were 0.1 M phosphate buffer (pH 6.0) containing 10% hexane at 45°C.

Syntheses of 5-fluoro- d/ l-dopa and [ 18F]5-fluoro- l-dopa

This paper describes the synthesis of 5-fluoro- d/ l-dopa and the corresponding [ 18F]5-fluoro- l-dopa starting from 5-nitrovanillin via malonic ester synthesis, the Balz-Schiemann reaction and the separation of the racemic mixture [ 18F]5-fluoro- d/ l-dopa with a chiral HPLC system. The inactive 5-fluoro- d/ l-dopa was obtained in an eight-step synthesis with an overall yield of 10%. For a reliable synthesis, the nitro group was reduced with hydrazine hydrate and ruthenium on charcoal.

Stereoisomeric flavour compounds LXVII. 2‐, 3‐, and 4‐Alkyl‐branched acids, part 1: General approach to the synthesis of the enantiopure acids

AbstractA general approach to the synthesis of 2‐, 3‐, and 4‐alkyl‐branched acids of high enantiomeric purity is described. The enantiopure 2‐alkyl‐branched acids are prepared via liquid chromatographic resolution of diastereomeric phenylglycinol amides and their absolute configuration is deduced from the 1H‐NMR data of the separated diastereomers. Chain elongation methods, by Arndt–Eistert synthesis, via 2‐alkylated alkyl carbonitrile or by malonic ester synthesis, are used to prepare 3‐ and 4‐alkyl‐branched acids of high configurational purity and known absolute configuration starting from the enantiomeric 2‐alkyl‐branched acids. © 1994 Wiley‐Liss, Inc.

Synthesis and 29- 14C-labeling of 3α,7α,12α-trihydroxy-27-carboxymethyl-5β-cholestan-26-oic acid. A bile acid occurring in peroxisomal diseases

The synthesis and 14 -labeling of 3α,7α,12α-trihydroxy-27-carboxymethyl-5-β-cholestan-26-oic acid by two different approaches is described. One of them involves chain elongation of cholic acid via Wittig-Horner condensation of its formylated 24-aldehyde with tetraethyl phosphonoglutarate. The resulting cholestenoate, on deprotection and hydrogenation, affords the unusual C 29 bile acid in good yield. An alternative procedure consists in a malonic ester synthesis starting from the formulated 24-alcohol which, after conversion into a mesylate, is reacted with sodium salt of 2-carboethoxy-γ-butyrolactone. Alkaline hydrolysis, decarboxylation, esterification with diazomethane and selective tosylation of the newly introduced primary hydroxyl function give a C 28 precursor, which is easily chain-elongated into a labeled or unlabeled C 29 bile acid by reaction with cyanide and hydrolysis. Due to easy lactonization of some of the C 28 intermediates, the latter method provides a better way for introducing a C-29 label than the sequence usually employed for carboxyl labeling of bile acids and consisting in a decarboxylative halogenation of the parent acid followed by substitution of the norhalogenide with [ 14C]cyanide and hydrolysis. The structure of the synthesized acid or its dimethyl ester is confirmed by 13C nuclear magnetic resonance spectroscopy and mass spectrometry, and is also shown by gas liquid chromatography to be identical with an authentic sample of biosynthesis C 29 dioic bile acid extracted from body fluids of Zellweger patients.

The malonic ester synthesis in the undergraduate laboratory

The versatile reactions of diethyl malonate represent an important lecture topic in introductory organic courses, but are only rarely performed in the lab because of several problems associated with performing these reactions. These authors present a lab the circumvents some of the typical problems.

Analogs of carbamyl aspartate as inhibitors of dihydroorotase: preparation of boronic acid transition-state analogs and a zinc chelator carbamylhomocysteine

Dihydroorotase (DHO) catalyzes the conversion of carbamyl aspartate (CA) to dihydroorotate (DO) in the de novo pyrimidine biosynthetic pathway. Few effective inhibitors of DHO have been reported, and thus blockade of this reaction has not been widely pursued as a strategy for development of antitumor agents. Utilizing two mechanism-based strategies, we have designed and prepared potential DHO inhibitor analogues of CA. One strategy replaced the gamma-carboxyl moiety of CA with a boronic acid. This substitution yields compounds which form stable charged tetrahedral intermediates and mimic the enzyme-substrate transition state. Preparation of the boronic acid analogues of CA and its carboxylic acid esters focused on a Curtius rearrangement as a key step following a malonic ester synthesis. This was followed by carbamoylation of the free amine under nonaqueous neutral conditions with Si(NCO)4. The ethyl ester was a competitive inhibitor of DHO with an apparent Ki of 5.07 microM, while the nonesterified analogue and the methyl ester were not effective inhibitors. None of the compounds were cytotoxic against L1210 cells in culture. An active-site-directed sulfhydryl-containing zinc chelator was also prepared. This analogue irreversibly inhibited the enzyme, but it also was ineffective in L1210 growth inhibition.

Design and applications of a solid‐phase oxidizing reagent consisting of a crosslinked polystyrene matrix and a t‐butyl hypochlorite function separated by a trimethylene spacer

AbstractA crosslinked polystyrene–supported solid‐phase analogue of t‐butyl hypochlorite containing a trimethylene spacer group between the polymer matrix and the t‐butyl hypochlorite function was prepared and used as a recyclable oxidizing reagent for alcohols. The synthetic route to this new polymeric reagent involved a seven‐step polymer‐analogous reaction starting from styrene‐divinyl benzene 2%‐crosslinked polymer. A β‐ketopropionic acid function was introduced into the polystyrene matrix by Friedel–Crafts reaction with succinic anhydride. The keto function in the resulting polymer (2) (capacity, 3.57 meq of COCH2CH2COOH/g) was converted to the methylene group by Clemmensen reduction using zinc amalgam and HCl. The carboxyl function in the product polymer (3) was converted to the acylmalonic ester function by malonic ester synthesis through the reaction of the polymeric acid chloride (4) with ethoxymagnesium diethylmalonate. The polymeric acyl malonic ester (5) was decarboxylated to yield the 2‐oxopentyl polystyrene resin (6). This on Grignard reaction with methyl magnesium iodide followed by hydrolysis afforded the polystyrene derivative with the t‐butyl alcohol function separated by three methylene groups (7). The t‐butyl alcohol resin (7) was converted to the corresponding hypochlorite resin (8) by reaction with sodium hypochlorite. The resin was found to have a capacity of 2.84 mmol Cl/g by iodometric analysis. The capacities of the resins 2–8 were determined from the weight changes in the corresponding conversions and verified by quantitative determination of the functional groups. This new hypochlorite was found to oxidize alcohols to carbonyl compounds in 85–98% yield. The oxidizing efficiency of this new reagent was found to be significantly greater than those of the reagents containing only one spacer and no spacer between the reagent function and the polymer support. The presence of a 3‐methylene spacer also facilitated the hypochlorite formation step significantly.