A chiral analog of the bicyclic guanidine TBD: synthesis, structure and Brønsted base catalysis

• Mariano Goldberg,
• Denis Sartakov,
• Jan W. Bats,
• Michael Bolte and
• Michael W. Göbel

Beilstein J. Org. Chem. 2016, 12, 1870–1876, doi:10.3762/bjoc.12.176

• ][16][17] or from their reduction products, chiral α-amino alcohols [9][18]. In contrast, our approach used the racemic ester rac-12 of β-phenylalanine, easily accessible in a Knoevenagel-type condensation of benzaldehyde 11, ammonium acetate and malonic acid, followed by esterification (Scheme 1) [20

Catalytic asymmetric synthesis of biologically important 3-hydroxyoxindoles: an update

• Bin Yu,
• Hui Xing,
• De-Quan Yu and
• Hong-Min Liu

Beilstein J. Org. Chem. 2016, 12, 1000–1039, doi:10.3762/bjoc.12.98

• reaction was performed under mild conditions using PTSA·H2O as the additive. Subsequently, the asymmetric aldol reaction of aliphatic aldehydes with isatins was achieved by the same group by using a structurally slightly modified organocatalyst (cat. 5, Scheme 18) [34]. Malonic acid as the additive and

• anhydrous EtOH as the solvent were found to be critical for achieving high yields and enantioselectivities. However, only 33% ee was obtained for 5-methylisatin under the same conditions. A plausible transition-state model was proposed and examined by DFT calculations, in which malonic acid formed two

Bifunctional phase-transfer catalysis in the asymmetric synthesis of biologically active isoindolinones

• Antonia Di Mola,
• Maximilian Tiffner,
• Francesco Scorzelli,
• Laura Palombi,
• Rosanna Filosa,
• Paolo De Caprariis,
• Mario Waser and
• Antonio Massa

Beilstein J. Org. Chem. 2015, 11, 2591–2599, doi:10.3762/bjoc.11.279

• recovered methyl ester of 9 (60% ee), although high yields were observed (Table 3, entry 1). Then, in another attempt, the malonic acid 10 was subjected to the reaction with carbonyldiimidazole (CDI) under different conditions but also in combination with a piperazine. This method has been reported for a

An economical and safe procedure to synthesize 2-hydroxy-4-pentynoic acid: A precursor towards ‘clickable’ biodegradable polylactide

• Quanxuan Zhang,
• Hong Ren and
• Gregory L. Baker

Beilstein J. Org. Chem. 2014, 10, 1365–1371, doi:10.3762/bjoc.10.139

• sequential hydrolysis of amide and esters, and decarboxylation of the resulting malonic acid. The resulting intermediate 6 was not isolated and used directly for the subsequent reaction. Notably, basic treatment of 5 as discussed in literature [31][33] would not allow conversion of 5 to 6 in a convenient one

A convenient enantioselective decarboxylative aldol reaction to access chiral α-hydroxy esters using β-keto acids

• Zhiqiang Duan,
• Jianlin Han,
• Ping Qian,
• Zirui Zhang,
• Yi Wang and
• Yi Pan

Beilstein J. Org. Chem. 2014, 10, 969–974, doi:10.3762/bjoc.10.95

• did not improve in the cases of methyl, isopropyl or benzyl esters (Table 2, entries 2–4). The mechanism of the reaction was proposed based on the kinetic studies of the malonic acid half thioester system by Shair [33]. Essentially β-keto acids can undergo decarboxylation or deprotonation to generate

• enolates. Though in the case of enzymatic reactions, decarboxylation occurs first to form the enolates, followed by condensation with esters; it is believed that in the scandium-catalysed aldol process of β-keto acid, similar to the case of malonic acid half thioesters, decarboxylation happens after the

Use of activated enol ethers in the synthesis of pyrazoles: reactions with hydrazine and a study of pyrazole tautomerism

• Denisa Tarabová,
• Stanislava Šoralová,
• Martin Breza,
• Marek Fronc,
• Wolfgang Holzer and
• Viktor Milata

Beilstein J. Org. Chem. 2014, 10, 752–760, doi:10.3762/bjoc.10.70

• University, Althanstrasse 14, A-1090 Vienna, Austria 10.3762/bjoc.10.70 Abstract Activated enol ethers derived from esters or the dinitrile of malonic acid, or from pentane-2,4-dione were treated with hydrazine hydrate. The structures of the obtained products – pyrazoles 5 – were studied with a focus on

• ]. Electron-accepting groups can include ester, cyano, acetyl, nitro and trifluoroacetyl moieties. Thus, the simplest way to obtain activated enol ethers 3 is the condensation of active methylene components 2 such as malonic acid derivatives (esters, nitrile), (trifluoro)acetoacetic acid derivatives (esters

• active methylidene compounds such as diesters, dinitriles of malonic acid or pentane-2,4-dione are excellent three-carbon synthons. They act as trifunctional electrophiles for the syntheses of tautomeric pyrazoles when reacted with hydrazine thereby obtaining 3,4-disubstituted pyrazoles, namely 3-amino

Quantification of N-acetylcysteamine activated methylmalonate incorporation into polyketide biosynthesis

• Stephan Klopries,
• Uschi Sundermann and
• Frank Schulz

Beilstein J. Org. Chem. 2013, 9, 664–674, doi:10.3762/bjoc.9.75

• Polyketides are biosynthesized through consecutive decarboxylative Claisen condensations between a carboxylic acid and differently substituted malonic acid thioesters, both tethered to the giant polyketide synthase enzymes. Individual malonic acid derivatives are typically required to be activated as coenzyme

• A-thioesters prior to their enzyme-catalyzed transfer onto the polyketide synthase. Control over the selection of malonic acid building blocks promises great potential for the experimental alteration of polyketide structure and bioactivity. One requirement for this endeavor is the supplementation of

• methylmalonate is studied and quantified, showing a surprisingly high and transferable activity of these polyketide synthase substrate analogues in vivo. Keywords: biosynthesis; coenzyme A; malonic acid; polyketide; polyketide synthase; Introduction Polyketides are ubiquitous natural products and find

From bead to flask: Synthesis of a complex β-amido-amide for probe-development studies

• Kevin S. Martin,
• Cristian Soldi,
• Kellan N. Candee,
• Hiromi I. Wettersten,
• Robert H. Weiss and
• Jared T. Shaw

Beilstein J. Org. Chem. 2013, 9, 260–264, doi:10.3762/bjoc.9.31

• studies of this compound as a biological probe [14][15]. The synthesis of 1 emanates from a one-pot, three-component reaction (3CR) of an arylaldehyde, malonic acid (5), and ammonium acetate, which assembles the β-amino acid core (Figure 2) [14][15][18]. In the reported synthesis of 1, a protected β-amino

• difficulty from acid 7, this route was unsuccessful at a late stage for a reason that we describe below. We next envisioned benzimidazole 3 emanating from β-amino ester 10, which could be accessed in a few steps starting with an early stage 3CR of aldehyde 11, malonic acid (5), and ammonium acetate (Figure 2

• variants of the 3CR with malonic acid (5) and ammonium acetate. Tan and Weaver demonstrated previously that the β-amino acid forming 3CR works best for electron-rich aldehydes and poorly for electron-deficient aldehydes [18]. Thus, we suspected that aldehyde 4 may be too electron poor for the 3CR to work

Total synthesis and biological evaluation of fluorinated cryptophycins

• Christine Weiß,
• Tobias Bogner,
• Benedikt Sammet and
• Norbert Sewald

Beilstein J. Org. Chem. 2012, 8, 2060–2066, doi:10.3762/bjoc.8.231

• be employed in the Knoevenagel condensation without purification. Reaction of 9 with malonic acid in the presence of piperidine/acetic acid gave the β,γ-unsaturated carboxylic acid 10. The latter compound was transformed into the methyl ester by treatment with SOCl2 in methanol. The resulting ester

• : (a) SOCl2, MeOH, 0 °C → rt, 16 h; (b) DIBAL-H, CH2Cl2, −78 °C, 3.5 h; (c) malonic acid, piperidine, AcOH, DMSO, 65 °C, 1.5 h; (d) SOCl2, MeOH, 0 °C → rt, 1 h; (e) K2CO3, K2OsO4∙2H2O, K3[Fe(CN)6], (DHQD)2-PHAL, CH3SO2NH2, t-BuOH/H2O, 0 °C, 42 h; (f) LDA, MeI, THF, −78 °C, 3 d; (g) (CH3)2C(OCH3)2, MeOH

A novel asymmetric synthesis of cinacalcet hydrochloride

• Veera R. Arava,
• Laxminarasimhulu Gorentla and
• Pramod K. Dubey

Beilstein J. Org. Chem. 2012, 8, 1366–1373, doi:10.3762/bjoc.8.158

• of 73:27 (chiral HPLC analysis). From this crude mixture, 4a was isolated in pure form by recrystallization from 10% ethyl acetate–hexanes in 68% yield with 99.94% ee (Scheme 3). Malonic acid (13) was condensed with 8 and a catalytic amount of piperidine in pyridine under reflux to yield 3-(3

• )acrylic acid (9): Aldehyde 8 (50.0 g, 0.287 mol) was dissolved in pyridine (100.0 mL) and piperidine (0.5 mL) at rt. Malonic acid (13, 80.0 g, 0.768 mol) was added to this solution at rt and it was stirred for 15 min. Then, the reaction mixture was heated to 115–120 °C and stirred for another 4 h. After

Asymmetric organocatalytic decarboxylative Mannich reaction using β-keto acids: A new protocol for the synthesis of chiral β-amino ketones

• Chunhui Jiang,
• Fangrui Zhong and
• Yixin Lu

Beilstein J. Org. Chem. 2012, 8, 1279–1283, doi:10.3762/bjoc.8.144

• unsatisfactory and the enantioselectivities were modest [20]. In recent years, inspired by the enzymatic synthesis of polyketides and fatty acids in biological systems, the enantioselective decarboxylative reactions of malonic acid half thioesters (MAHTs) have received much attention. In this regard, various

• alternative decarboxylation–addition pathway at this stage. In fact, in sharp contrast to the popular use of malonic acid half thioesters (MAHTs) as an ester enolate equivalent in enantioselective decarboxylative additions [39], the employment of β-keto acids as a reaction partner in decarboxylative processes

Synthesis of novel 5-alkyl/aryl/heteroaryl substituted diethyl 3,4-dihydro-2H-pyrrole-4,4-dicarboxylates by aziridine ring expansion of 2-[(aziridin-1-yl)-1-alkyl/aryl/heteroaryl-methylene]malonic acid diethyl esters

• Satish S. More,
• T. Krishna Mohan,
• Y. Sateesh Kumar,
• U. K. Syam Kumar and
• Navin B. Patel

Beilstein J. Org. Chem. 2011, 7, 831–838, doi:10.3762/bjoc.7.95

• -[(aziridin-1-yl)-1-alkyl/aryl/heteroaryl-methylene]malonic acid diethyl esters in very good to excellent yields under mild reaction conditions. The electronic and steric impact of the substituents on the kinetics of ring expansion of N-vinyl aziridines to pyrrolines has been studied. Various diversely

• /heteroaryl substituted 3,4-dihydro-2H-pyrrole-4,4-dicarboxylates. The synthesis of 2-[(aziridin-1-yl)-1-alkyl/aryl/heteroaryl-methylene]malonic acid diethyl esters was carried out by nucleophilic displacement by aziridine of the chloro atom from electron-poor activated 2-(1-alkyl/aryl/heteroaryl-1

• yields (81–93%). The schematic representation of this methodology is shown in Scheme 2. The details of the synthesis of various 2-[(aziridin-1-yl)-1-alkyl/aryl/heteroaryl-methylene]malonic acid diethyl esters are shown in Table 1. During the studies of iodide ion mediated ring expansion of N

An easy assembled fluorescent sensor for dicarboxylates and acidic amino acids

• Xiao-bo Zhou,
• Yuk-Wang Yip,
• Wing-Hong Chan and
• Albert W. M. Lee

Beilstein J. Org. Chem. 2011, 7, 75–81, doi:10.3762/bjoc.7.11

• solutions (5 mM) of the tetrabutylammonium salts of phthalatic acid, isophthalic acid, terephthalic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, D- and L-aspartic acid, and D- and L-glutamic acid in CH3CN were prepared. Stock solutions of hosts (1 mM) were prepared in DMSO. Test solutions

A new and facile synthetic approach to substituted 2-thioxoquinazolin-4-ones by the annulation of a pyrimidine derivative

• Nimalini D. Moirangthem and
• Warjeet S. Laitonjam

Beilstein J. Org. Chem. 2010, 6, 1056–1060, doi:10.3762/bjoc.6.120

• active methylene compounds, such as, malononitrile and ethylcyanoacetate. Results and Discussion DTBA are among the simplest synthetic intermediates and can be easily prepared in a one-pot reaction by treating 1,3-diaryl thioureas with malonic acid in the presence of acetyl chloride. DTBA undergoes

Hydroxyapatite supported caesium carbonate as a new recyclable solid base catalyst for the Knoevenagel condensation in water

• Monika Gupta,
• Rajive Gupta and
• Medha Anand

Beilstein J. Org. Chem. 2009, 5, No. 68, doi:10.3762/bjoc.5.68

• Monika Gupta Rajive Gupta Medha Anand Department of Chemistry, University of Jammu, Jammu 180 006, India 10.3762/bjoc.5.68 Abstract The Knoevenagel condensation between aromatic aldehydes and malononitrile, ethyl cyanoacetate or malonic acid with hydroxyapatite supported caesium carbonate in

• water is described. HAP–Cs2CO3 was found to be a highly active, stable and recyclable catalyst under the reaction conditions. Keywords: ethyl cyanoacetate; hydroxyapatite supported caesium carbonate; Knoevenagel condensation; malonic acid; malononitrile; Introduction An area of recent intense

• caesium carbonate (HAP–Cs2CO3) and its effective application to the Knoevenagel condensation between different aromatic aldehydes and malononitrile or ethyl cyanoacetate or malonic acid by stirring in water at 80–100 °C. The products were obtained in high yield and purity. Results and Discussion