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Fixation of carbon dioxide by oxalic amidinato magnesium complexes: Structures and reactions of trimetallic magnesium carbamato and related complexes
The reaction of oxalic amidines R1-N=C(NHR2)-C(NHR2)=N-R1 with CH3MgX followed by uptake of CO2 results in the formation of the trimeric carbamato complexes [R1-N=C(NR2-COO)-C(NR2-COO)-C(NR2COO)=N- R1]3Mg3(THF)6 (2a: R1 = R2 = Ph; 2b: R1 = R2 = p-tolyl) as the thermodynamically stable final products of the reaction. Their X-ray crystal structures show that the three metal centres are in a linear arrangement. The central magnesium ion is octahedrally surrounded by six O-donor atoms of the μ2-carbamato bridges, while both peripheral magnesium ions are facially coordinated by three O-donor atoms of the carbamato groups and three THF molecules. This coordination sphere can be considered as a structural model for the active centre in the ribulose-1,5-bisphosphate carboxylase/oxygenase enzyme. Compound 2a reacts with ZnCl2 or CoBr2, with CO2 elimination, to form dimeric complexes of the type [X2M(oxalamidinato)MX2][Mg(DMF)6] (M = Zn, Co; X = Cl, Br). X-ray crystal structure analyses show that the d-metals are tetrahedrally coordinated. The magnesium-bromide-containing intermediates in the formation of 2a and 2b are able to transfer CO2 to acetophenone, thus simulating the CO2 activation step in enzymatic biotin-dependent carboxylation reactions.
Ruben, Mario,Walther, Dirk,Knake, René,G?rls, Helmar,Beckert, Rainer
p. 1055 - 1064
(2000)
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Organocatalytic Asymmetric Decarboxylative Addition of β-Ketoacids to Methyleneindolinones Derivatives
The quinine squaramide-catalyzed enantioselective decarboxylative addition reaction of various β-keto acids with methyleneindolinones has been developed. Through this methodology, various oxindole derivatives were synthesized in good yields (up to 93 %) and excellent enantiomeric excess (up to 99 % ee) and moderate diastereoselectivity (up to 66:34).
Kumari, Anita,Kaur, Jasneet,Bhardwaj, Vimal K.,Chimni, Swapandeep Singh
p. 4081 - 4088
(2018)
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Enantioselective decarboxylative Mannich reaction of β-keto acids withC-alkynylN-BocN,O-acetals: access to chiral β-keto propargylamines
The chiral keto-substituted propargylamines are an essential class of multifunctional compounds in the field of organic and pharmaceutical synthesis and have attracted considerable attention, but the related synthetic approaches remain limited. Therefore, a concise and efficient method for the enantioselective synthesis of β-keto propargylaminesviachiral phosphoric acid-catalyzed asymmetric Mannich reaction between β-keto acids andC-alkynylN-BocN,O-acetals as easily availableC-alkynyl imine precursors has been demonstrated here, affording a broad scope of β-ketoN-Boc-propargylamines in high yields (up to 97%) with generally high enantioselectivities (up to 97?:?3 er).
Chen, Li-Jun,Li, Wei,Shen, Bao-Chun,Sun, Zhong-Wen,Xie, Hui-Ding,Zhang, Cong-Cong
p. 8607 - 8612
(2021/10/20)

Synthetic method of lobeline hydrochloride
The invention relates to the technical field of medicine synthesis, and particularly discloses a method for synthesizing lobeline hydrochloride. The method comprises the following steps: performing acylation reaction on ethyl acetoacetate and benzoyl chloride serving as raw materials in the presence of NaOH, NH4Cl and the like, performing hydrolysis reaction on the obtained ethyl benzoylacetate in water in the presence of potassium hydroxide to obtain benzoylacetic acid, carrying out a condensation reaction with glutaraldehyde and methylamine hydrochloride in a citric acid buffer solution, carrying out a reduction reaction on lobeline diketone hydrochloride obtained by the condensation reaction in a mixed solution composed of potassium borohydride, activated carbon, sodium hydroxide and methanol, quenching the reducing agent in the obtained reaction liquid by sulfuric acid, sequentially filtering, extracting, concentrating, cooling and crystallizing to obtain lobeline racemate, then adding L-DBTA, and sequentially performing resolution, dissociation and hydrochlorination to obtain lobeline hydrochloride. The synthesis method has the characteristics of few synthesis steps, simple synthesis conditions, convenience in operation and the like, and the used raw materials have the characteristics of wide source, low price and the like.
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(2021/06/09)

Double decarboxylative route to 3-substituted pyrrolidines: Reaction of monoalkyl malonates and related carboxylic acids with sarcosine and formaldehyde
Three-component reactions of monoalkyl malonates, cyanoacetic acids or 2-ketocarboxylic acids, N-methylglycine, and formaldehyde were developed to rapidly access 3-substituted pyrrolidines in 17–97% yield. These reactions represent a double decarboxylative domino-sequence promoted by pyrrolidine and involve N-methylazomethine ylide as the reactive intermediate.
Buev, Evgeny M.,Smorodina, Anastasia A.,Moshkin, Vladimir S.,Sosnovskikh, Vyacheslav Y.
supporting information

(2020/02/22)

Engineered Biosynthesis of Fungal 4-Quinolone Natural Products
Quinolone-containing natural products are widely found in bacteria, fungi, and plants. The fungal quinolactacins, which are N-methyl-4-quinolones, display a wide spectrum of biological activities. Here we uncovered a concise nonribosomal peptide synthetase pathway involved in quinolactacin A biosynthesis from Penicillium by using heterologous reconstitution and in vitro enzymatic synthesis. The N-desmethyl analog of quinolactacin A was accessed through the construction of a hybrid bacterial and fungi pathway in the heterologous host.
Liu, Mengting,Ohashi, Masao,Tang, Yi
supporting information
p. 6637 - 6641
(2020/09/02)

CO2-Folded Single-Chain Nanoparticles as Recyclable, Improved Carboxylase Mimics
Emulating the function of natural carboxylases to convert CO2 under atmospheric condition is a great challenge. Herein we report a class of CO2-folded single-chain nanoparticles (SCNPs) that can function as recyclable, function-intensified carboxylase mimics. Lewis pair polymers containing bulky Lewis acidic and basic groups as the precursor, can bind CO2 to drive an intramolecular folding into SCNPs, in which CO2 as the folded nodes can form gas-bridged bonds. Such bridging linkages highly activate CO2, which endows the SCNPs with extraordinary catalytic ability that can not only catalyze CO2-insertion of C(sp3)-H for imitating the natural enzyme's function, it can also act on non-natural carboxylation pathways for C(sp2 and sp)-H substrates. The nanocatalysts are of highly catalytic efficiency and recyclability, and can work at room temperature and near ambient CO2 condition, inspiring a new approach to sustainable C1 utilization.
Chen, Liang,Yan, Qiang,Zeng, Rongjin
supporting information
p. 18418 - 18422
(2020/08/21)

Expanding the repertoire of nitrilases with broad substrate specificity and high substrate tolerance for biocatalytic applications
Enzymatic conversion of nitriles to carboxylic acids by nitrilases has gained significance in the green synthesis of several pharmaceutical precursors and fine chemicals. Although nitrilases from several sources have been characterized, there exists a scope for identifying broad spectrum nitrilases exhibiting higher substrate tolerance and better thermostability to develop industrially relevant biocatalytic processes. Through genome mining, we have identified nine novel nitrilase sequences from bacteria and evaluated their activity on a broad spectrum of 23 industrially relevant nitrile substrates. Nitrilases from Zobellia galactanivorans, Achromobacter insolitus and Cupriavidus necator were highly active on varying classes of nitriles and applied as whole cell biocatalysts in lab scale processes. Z. galactanivorans nitrilase could convert 4-cyanopyridine to achieve yields of 1.79 M isonicotinic acid within 3 h via fed-batch substrate addition. The nitrilase from A. insolitus could hydrolyze 630 mM iminodiacetonitrile at a fast rate, effecting 86 % conversion to iminodiacetic acid within 1 h. The arylaliphatic nitrilase from C. necator catalysed enantioselective hydrolysis of 740 mM mandelonitrile to (R)-mandelic acid in 4 h. Significantly high product yields suggest that these enzymes would be promising additions to the suite of nitrilases for upscale biocatalytic application.
Rayavarapu, Pratima,Shah, Shikha,Sunder, Avinash Vellore,Wangikar, Pramod P.
p. 289 - 296
(2020/05/18)

Synthesis of novel proxyphylline derivatives with dual Anti-Candida albicans and anticancer activity
Three out of 16 newly synthesized 1,3-dimethylxanthine derivatives (proxyphylline analogues) exhibited consistencies between antifungal and anticancer properties. Proxyphylline possessing 1-(10H-phenothiazin-10-yl)propan-2-yl (6) and polybrominated benzimidazole (41) or benzotriazole moiety (42) remained selectively cidal against Candida albicans (lg R ≥ 3 at conc. of 31, 36 and 20 μM, respectively) however not against normal mammalian Vero cell line in vitro (IC50 ≥ 280 μM) and Galleria mellonella in vivo. These compounds also displayed moderate antineoplastic activity against human breast adenocarcinoma (MCF-7) cell line (EC50 = 80 μM) and high against peripheral blood T lymphoblast (CCRF-CEM) (EC50 = 6.3–6.5 μM). In addition, 6 and 42 exerted: (1) dual activity against fungal adhesion and damage mature biofilm; (2) necrosis of planktonic cells due to loss of membrane function and of structural integrity; (3) biochemical (inhibition of sessile cell respiration) and morphological changes in cell wall polysaccharide contents. Therefore, leading proxyphylline derivatives can be employed to prevent cancer-associated biofilm Candida infections.
Borowiecki, Pawe?,Wińska, Patrycja,Bretner, Maria,Gizińska, Ma?gorzata,Koronkiewicz, Miros?awa,Staniszewska, Monika
p. 307 - 333
(2018/03/21)

In situ generation of nitrile oxides from copper carbene and tert -butyl nitrite: Synthesis of fully substituted isoxazoles
Herein, we present a novel [3 + 2] cycloaddition reaction of β-keto esters with nitrile oxides, which were generated in situ from copper carbene and tert-butyl nitrite. This three-component reaction provides new methodology for the direct synthesis of fully substituted isoxazole derivatives, featuring mild reaction conditions, readily accessible starting materials and simple operation. The experimental studies and DFT calculations suggest that the reaction starts with the generation of the key intermediate nitrile oxides, followed by a [3 + 2] cycloaddition reaction of β-keto esters to give the final isoxazole products.
Chen, Rongxiang,Ogunlana, Abosede Adejoke,Fang, Shangwen,Long, Wenhao,Sun, Hongmei,Bao, Xiaoguang,Wan, Xiaobing
p. 4683 - 4687
(2018/07/06)

Mechanochemical electrophilic fluorination of liquid beta-ketoesters
An improved substrate scope for the mechanochemical electrophilic fluorination of dicarbonyls is reported. The applicable substrates have now been broadened to include liquid β-ketoesters. Key to this capability is the inclusion of a grinding auxiliary (NaCl) to improve mass transfer and prevent pasting or gumming of the reaction mixture. Notably, the use of a small amount of acetonitrile is critical to increasing the rate of reaction, ensuring complete consumption of starting materials during the short reaction times as well as improving the selectivity for the monofluorinated product in the mill.
Howard, Joseph L.,Sagatov, Yerbol,Browne, Duncan L.
p. 3118 - 3123
(2017/12/26)

Visible Light-Mediated Photocatalytic Metal-Free Cross-Coupling Reaction of Alkenyl Carboxylic Acids with Diarylphosphine Oxides Leading to β-Ketophosphine Oxides
A new visible light-mediated photocatalytic decarboxylative oxyphosphorylation of cinnamic acids with diarylphosphine oxides is described. This reaction is performed under mild conditions to afford the corresponding β-ketophosphine oxides.
Qian, Hai-Feng,Li, Cheng-Kun,Zhou, Zhi-Hao,Tao, Ze-Kun,Shoberu, Adedamola,Zou, Jian-Ping
supporting information
p. 5947 - 5951
(2018/09/21)

Switching Chemoselectivity: Using Mechanochemistry to Alter Reaction Kinetics
A reaction manifold has been discovered in which the chemoselectivity can be altered by switching between neat milling and liquid assisted grinding (LAG) with polar additives. After investigation of the reaction mechanism, it has been established that this switching in reaction pathway is due to the neat mechanochemical conditions exhibiting different kinetics for a key step in the transformation. This proof of concept study demonstrates that mechanochemistry can be used to trap the kinetic product of a reaction. It is envisaged that, if this concept can be successfully applied to other transformations, novel synthetic processes could be discovered and known reaction pathways perturbed or diverted.
Howard, Joseph L.,Brand, Michael C.,Browne, Duncan L.
supporting information
p. 16104 - 16108
(2018/11/23)

Palladium-Catalyzed [3 + 2]-C-C/N-C Bond-Forming Annulation
The synthesis of bi- and tricyclic structures incorporating pyrrolidone rings is disclosed, starting from resonance-stabilized acetamides and cyclic α,β-unsaturated-γ-oxycarbonyl derivatives. This process involves an intermolecular Tsuji-Trost allylation/intramolecular nitrogen 1,4-addition sequence. Crucial for the success of this bis-nucleophile/bis-electrophile [3 + 2] annulation is its well-defined step chronology in combination with the total chemoselectivity of the former step. When the newly formed annulation product carries a properly located o-haloaryl moiety at the nitrogen substituent, a further intramolecular keto α-arylation can join the cascade, thereby forming two new cycles and three new bonds in the same synthetic operation.
Liu, Yang,Mao, Zhongyi,Pradal, Alexandre,Huang, Pei-Qiang,Oble, Julie,Poli, Giovanni
supporting information
p. 4057 - 4061
(2018/07/15)

Translating solid state organic synthesis from a mixer mill to a continuous twin screw extruder
A study on the translation of a solid-state synthetic reaction from a mechanochemical mixer-mill to a continuous twin-screw extruder is discussed herein. The study highlights some considerations to be made and parameters to be tested in the context of a model fluorination reaction, which is the first organic fluorination to be attempted using extrusion. Upon optimization, which features the first use of grinding auxiliary solids to enable effective synthetic extrusion, the difluorination reaction was successfully translated to the extruder, leading to a 100-fold improvement in Space Time Yield (STY); 29 kg m-3 day-1 in a mixer mill to 3395 kg m-3 day-1 in a twin screw extruder.
Cao, Qun,Howard, Joseph L.,Crawford, Deborah E.,James, Stuart L.,Browne, Duncan L.
supporting information
p. 4443 - 4447
(2018/10/17)

Mannich-type Reactions of Cyclic Nitrones: Effective Methods for the Enantioselective Synthesis of Piperidine-containing Alkaloids
Even though there are dozens of biologically active 2-substituted and 2,6-disubstituted piperidines, only a limited number of approaches exist for their synthesis. Herein is described two Mannich-type additions to nitrones, one using β-ketoacids under catalyst-free conditions and another using methyl ketones in the presence of chiral thioureas, which can generate a broad array of such 2-substituted materials, as well as other ring variants, in the form of β-N-hydroxy-aminoketones. Both processes have broad scope, with the latter providing products with high enantioselectivity (up to 98 %). The combination of these methods, along with other critical steps, has enabled 8-step total syntheses of the 2,6-disubstituted piperidine alkaloids (?)-lobeline and (?)-sedinone.
Lisnyak, Vladislav G.,Lynch-Colameta, Tessa,Snyder, Scott A.
supporting information
p. 15162 - 15166
(2018/10/26)

Biomimetic synthesis of 2-substituted N-heterocycle alkaloids by one-pot hydrolysis, transamination and decarboxylative Mannich reaction
Heterocycles based on piperidine and pyrrolidine are key moieties in natural products and pharmaceutically active molecules. A novel multi-enzymatic approach based on the combination of a lipase with an α,ω-diamine transaminase is reported, opening up the synthesis, isolation and characterisation of a broad range of 2-substituted N-heterocycle alkaloids.
Galman, James L.,Slabu, Iustina,Parmeggiani, Fabio,Turner, Nicholas J.
supporting information
p. 11316 - 11319
(2018/10/24)

Characterization of a new nitrilase from Hoeflea phototrophica DFL-43 for a two-step one-pot synthesis of (S)-β-amino acids
A nitrilase from Hoeflea phototrophica DFL-43 (HpN) demonstrating excellent catalytic activity towards benzoylacetonitrile was identified from a nitrilase tool-box, which was developed previously in our laboratory for (R)-o-chloromandelic acid synthesis from o-chloromandelonitrile. The HpN was overexpressed in Escherichia coli BL21 (DE3), purified to homogeneity by nickel column affinity chromatography, and its biochemical properties were studied. The HpN was very stable at 30–40?°C, and highly active over a wide range of pH values (pH 6.0–10.0). In addition, the HpN could tolerate against several hydrophilic organic solvents. Steady-state kinetics indicated that HpN was highly active towards benzoylacetonitrile, giving a KM of 4.2?mM and a kcat of 170?s?1, the latter of which is ca. fivefold higher than the highest record reported so far. A cascade reaction for the synthesis of optically pure (S)-β-phenylalanine from benzoylacetonitrile was developed by coupling HpN with an ω-transaminase from Polaromonas sp. JS666 in toluene-water biphasic reaction system using β-alanine as an amino donor. Various (S)-β-amino acids could be produced from benzoylacetonitrile derivatives with moderate to high conversions (73–99%) and excellent enantioselectivity (> 99% ee). These results are significantly advantageous over previous studies, indicating a great potential of this cascade reaction for the practical synthesis of (S)-β-phenylalanine in the future.
Zhang, Zhi-Jun,Cai, Rui-Feng,Xu, Jian-He
p. 6047 - 6056
(2018/05/15)

Copper-Catalysed Decarboxylative Trifluoromethylation of β-Ketoacids
An efficient method for Cu-catalyzed decarboxylative trifluoromethylation of β-ketoacids to achieve α-trifluoromethyl ketones was developed. A wide variety of synthetically useful α-trifluoromethyl ketones were obtained in modest to good yields under mild reaction conditions. The present method also exhibits good functional-group compatibility.
Xu, Xiaolan,Chen, Huanhuan,He, Jianbo,Xu, Huajian
p. 1665 - 1668
(2017/10/05)

Chiral Squaramide-Catalyzed Enantioselective Decarboxylative Addition of β-Keto Acids to Isatin Imines
An efficient chiral squaramide-catalyzed enantioselective decarboxylative addition reaction of β-keto acids to isatin imines has been developed. The reaction proceeds smoothly using 20 mol% of organocatalyst to afford the chiral 3-aminooxindoles in high yield and excellent enantioselectivities. (Figure presented.).
Kaur, Jasneet,Kumari, Anita,Bhardwaj, Vimal K.,Chimni, Swapandeep Singh
p. 1725 - 1734
(2017/05/22)

Synthesis of γ-pyrones via decarboxylative condensation of β-ketoacids
Abstract: This manuscript describes the convergent synthesis of aryl- and alkyl-disubstituted γ-pyrones from β-ketoacids. The reaction proceeds in the presence of trifluoromethanesulfonic anhydride via an unprecedented decarboxylative auto-condensation of the starting material. Herein, the scope and limitations of this transformation are reported. Graphical abstract: [Figure not available: see fulltext.]
Merad, Jérémy,Maier, Thomas,Rodrigues, Catarina A. B.,Maulide, Nuno
p. 57 - 62
(2017/01/17)

Concert along the Edge: Dynamics and the Nature of the Border between General and Specific Acid-Base Catalysis
Reactions that involve a combination of proton transfer and heavy-atom bonding changes are normally categorized by whether the proton transfer is occurring during the rate-limiting step, as in the distinction between general and specific acid-base catalysis. The experimental and computational study here of a β-ketoacid decarboxylation shows how the distinction between the two mechanisms breaks down near its border due to the differing time scales for proton versus heavy-atom motion. Isotope effects in the decarboxylation of benzoylacetic acid support a transition state in which the proton transfer is complete. In quasiclassical trajectories passing through this transition state, the new O-H bond after proton transfer undergoes several vibrations before heavy-atom motion completes the reaction. The bonding changes are thus temporally separated at a "dynamic intermediate" structure that acts equivalently to an ordinary intermediate in the trajectories, including the reversal of trajectories at the intermediate when the second "step" fails, but the structure is not an energy minimum. The results define a border between mechanisms where the usual energetic definition of intermediates is not meaningful.
Aziz, Hannah R.,Singleton, Daniel A.
supporting information
p. 5965 - 5972
(2017/05/04)

Direct synthesis of γ-pyrones by electrophilic condensation of β-ketoesters
Triflic anhydride is a versatile electrophile that is able to activate poor nucleophiles. Herein, we show that readily available β-keto esters are activated by Tf2O furnishing γ-pyrones. Mechanistic studies suggest that this transformation proceeds via a double triflation, formation of an oxocarbenium intermediate and dealkylation promoted by a crucial nitrile additive.
Rodrigues, Catarina A. B.,Misale, Antonio,Schiel, Florian,Maulide, Nuno
supporting information
p. 680 - 683
(2017/01/25)

Method for activating and converting carbon dioxide
The invention relates to a method for activating and converting carbon dioxide. The method includes following steps: enabling secondary amine substances to react with terbium salt to obtain a terbium complex; feeding carbon dioxide into the terbium complex to obtain terbium carbamate; using terbium carbamate as a catalyst, and using ketone substances as raw materials for reaction under illumination to obtain carboxylic acid substances. The terbium complex having fluorescent effect is utilized as a catalyst for fixing and activating carbon dioxide. Terbium metal is similar to magnesium metal which belongs to a main group in chlorophyll and has high oxyphilic polarity, and the terbium metal and carbamate can form a complex. In addition, the photocatalyst having oxidation-reduction property can well simulate photosynthesis in nature, energy can be obtained in the subsequent photocatalysis process to generate carboxylation so as to obtain industrially-useful C-C bond product, so that carbon dioxide which is a C resource is utilized efficiently.
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(2017/12/29)

Catalytic Promiscuity of Ancestral Esterases and Hydroxynitrile Lyases
Catalytic promiscuity is a useful, but accidental, enzyme property, so finding catalytically promiscuous enzymes in nature is inefficient. Some ancestral enzymes were branch points in the evolution of new enzymes and are hypothesized to have been promiscuous. To test the hypothesis that ancestral enzymes were more promiscuous than their modern descendants, we reconstructed ancestral enzymes at four branch points in the divergence hydroxynitrile lyases (HNL's) from esterases ～100 million years ago. Both enzyme types are α/β-hydrolase-fold enzymes and have the same catalytic triad, but differ in reaction type and mechanism. Esterases catalyze hydrolysis via an acyl enzyme intermediate, while lyases catalyze an elimination without an intermediate. Screening ancestral enzymes and their modern descendants with six esterase substrates and six lyase substrates found higher catalytic promiscuity among the ancestral enzymes (P 0.01). Ancestral esterases were more likely to catalyze a lyase reaction than modern esterases, and the ancestral HNL was more likely to catalyze ester hydrolysis than modern HNL's. One ancestral enzyme (HNL1) along the path from esterase to hydroxynitrile lyases was especially promiscuous and catalyzed both hydrolysis and lyase reactions with many substrates. A broader screen tested mechanistically related reactions that were not selected for by evolution: decarboxylation, Michael addition, γ-lactam hydrolysis and 1,5-diketone hydrolysis. The ancestral enzymes were more promiscuous than their modern descendants (P = 0.04). Thus, these reconstructed ancestral enzymes are catalytically promiscuous, but HNL1 is especially so.
Devamani, Titu,Rauwerdink, Alissa M.,Lunzer, Mark,Jones, Bryan J.,Mooney, Joanna L.,Tan, Maxilmilien Alaric O.,Zhang, Zhi-Jun,Xu, Jian-He,Dean, Antony M.,Kazlauskas, Romas J.
p. 1046 - 1056
(2016/02/05)

A high-throughput screening method for determining the substrate scope of nitrilases
Nitrile compounds are intermediates in the synthesis of pharmaceuticals such as atorvastatin. We have developed a chromogenic reagent to screen for nitrilase activity as an alternative to Nessler's reagent. It produces a semi-quantifiable blue colour and hydrolysis of 38 nitrile substrates by 23 nitrilases as cell-free extracts has been shown. This journal is
Black, Gary W.,Brown, Nicola L.,Perry, Justin J. B.,Randall, P. David,Turnbull, Graeme,Zhang, Meng
supporting information
p. 2660 - 2662
(2015/03/05)

The synthesis of α-azidoesters and geminal triazides
Three simple methods for the synthesis of geminal triazides are described: Starting from 1) 3-oxocarboxylic acids, 2) iodomethyl ketones, or 3) terminal olefins, a range of triazidomethyl ketones can be constructed under mild oxidative reaction conditions by the use of IBX-SO3K, a sulfonylated derivative of 2-iodoxybenzoic acid (IBX), and NaN3 as an azide source. This is the first report of representatives of this novel class of triazide compounds: Despite their high nitrogen content, the geminal triazides are easy to handle, even when preparative-scale syntheses are performed. (Caution: These procedures still require protective measures!) The triazides are now broadly available for further studies regarding their properties and reactivity. Furthermore, we show how the method can be used to provide α-azidoesters, which are potential building blocks for amino acids. Either/or: Geminal triazides are rapidly constructed with broad scope by the use of oxocarboxylic acids, iodomethyl ketones, or terminal olefins as starting substrates in oxidative azidations with a mild derivative of 2-iodoxybenzoic acid and sodium azide. Along with this little-studied class of organic azides, α-azidoesters were also synthesized.
Klahn, Philipp,Erhardt, Hellmuth,Kotthaus, Andreas,Kirsch, Stefan F.
supporting information
p. 7913 - 7917
(2014/08/05)

Phenylimidazoles as potent and selective inhibitors of coagulation factor XIa with in vivo antithrombotic activity
Novel inhibitors of FXIa containing an (S)-2-phenyl-1-(4-phenyl-1H-imidazol-2-yl)ethanamine core have been optimized to provide compound 16b, a potent, reversible inhibitor of FXIa (Ki = 0.3 nM) having in vivo antithrombotic efficacy in the rabbit AV-shunt thrombosis model (ID50 = 0.6 mg/kg + 1 mg kg-1 h-1). Initial analog selection was informed by molecular modeling using compounds 11a and 11h overlaid onto the X-ray crystal structure of tetrahydroquinoline 3 complexed to FXIa. Further optimization was achieved by specific modifications derived from careful analysis of the X-ray crystal structure of the FXIa/11h complex. Compound 16b was well tolerated and enabled extensive pharmacologic evaluation of the FXIa mechanism up to the ID90 for thrombus inhibition.
Hangeland, Jon J.,Friends, Todd J.,Rossi, Karen A.,Smallheer, Joanne M.,Wang, Cailan,Sun, Zhong,Corte, James R.,Fang, Tianan,Wong, Pancras C.,Rendina, Alan R.,Barbera, Frank A.,Bozarth, Jeffrey M.,Luettgen, Joseph M.,Watson, Carol A.,Zhang, Ge,Wei, Anzhi,Ramamurthy, Vidhyashankar,Morin, Paul E.,Bisacchi, Gregory S.,Subramaniam, Srinath,Arunachalam, Piramanayagam,Mathur, Arvind,Seiffert, Dietmar A.,Wexler, Ruth R.,Quan, Mimi L.
p. 9915 - 9932
(2015/02/05)

Primary β-amino acid salt-catalyzed asymmetric Michael addition of benzoylacetates to cyclic enones and its application for the synthesis of enantioenriched 1,5-diketones
The asymmetric Michael addition of benzoylacetates to cyclic enones was successfully carried out by using a primary β-amino acid salt catalyst. The reactions proceeded under mild reaction conditions to produce Michael adducts in high yields and with high enantioselectivities. The obtained Michael adducts were converted into β-benzoylmethylated cyclic ketones by decarboxylation without a significant loss of enantiomeric excess.
Yoshida, Masanori,Kubara, Ami,Hara, Shoji
supporting information
p. 180 - 182
(2013/03/28)

Improved synthesis of 2-arylhydrazono-3-hydroxy-1-propanones and their utility in efficient synthesis of pyridazine derivatives
Reaction of 2-arylhydrazono-1-phenylethanones 2a-c with formaldehyde either in presence of montmorillonite K10 or by simply stirring in methanol and TEA leads to selective synthesis of 2-arylhydrazono-3-hydroxy-1-phenylpropan-1-one derivatives 3a-c in high yield. Heating 1a with N-phenylmaleimide in DPE/DABCO using microwave irradiation for 5 minutes at 200 °C results in a 73% yield of pyrrolo[3, 4-c]pyridazine 8. Compounds 2a-c react with benzylidenemalononitriles 9a or ethyl 2-cyanocinnamate 9b in refluxing ethanol and piperidine or β-chitosan to yield new pyridazine derivatives 10a-f which are converted into pyridazinones 11a-c upon reflux in acetic/hydrochloric acids mixture. ARKAT-USA, Inc.
Al-Awadi, Nouria A.,Ibrahim, Maher R.,Al-Etaibi, Alya M.,Elnagdi, Mohamed H.
experimental part
p. 310 - 321
(2011/05/11)

Biosynthesis of 2-Alkyl-4(1H)-Quinolones in Pseudomonas aeruginosa: Potential for Therapeutic Interference with Pathogenicity
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Pistorius, Dominik,Ullrich, Angelika,Lucas, Simon,Hartmann, Rolf W.,Kazmaier, Uli,Mueller, Rolf
body text
p. 850 - 853
(2012/02/04)

Kinetic resolution of aromatic β-amino acids by ω-transaminase
Racemic aromatic β-amino acids have been kinetically resolved into (R)-β-amino acids with high enantiomeric excess (>99%) by a novel ω-TA with ca. 50% conversion.
Bea, Han-Seop,Park, Hye-Jeong,Lee, Sang-Hyeup,Yun, Hyungdon
supporting information; experimental part
p. 5894 - 5896
(2011/06/23)

A stereoselective and practical synthesis of (E)-α,β-unsaturated ketones from aldehydes
α,β-Unsaturated ketones can be prepared by reaction of differently substituted β-keto acids and aldehydes. The reaction is carried out under organocatalysis (β-alanine, 0.5 equiv.) and generates the enones with high E selectivity (>95%). This version of the Verley-Doebner modification of the Knoevenagel reaction is a practical alternative to the classic Horner-Wadsworth-Emmons (HWE) reaction without the formation of high molecular weight byproducts. The process makes use of simple reagents and can be applied to large-scale synthesis under conditions compatible with atom-economy principles. Differently substituted aliphatic, aromatic, or heteroaromatic α,β-unsaturated ketones can be prepared. An example of a hydroformylation/Verley-Doebner Knoevenagel telescoped process is also described. The conditions used in the Knoevenagel reaction to prepare conjugated esters under amino acid organocatalysis can be applied also for the synthesis of α,β unsaturatedketones. β-Keto acids are prepared byhydrogenolysis of the corresponding benzyl ester and react easily with aldehydes to give the α,β-unsaturated ketones without formation of high molecular weight byproducts. Copyright
Balducci, Evita,Attolino, Emanuele,Taddei, Maurizio
experimental part
p. 311 - 318
(2011/02/28)

A PRODRUG COMPRISING BETA-KETO CARBOXYLIC ACID, BETA-KETO CARBOXYLIC ACID SALT OR BETA-KETO CARBOXYLIC ACID ESTER FOR DRUG DELIVERY
There is provided a prodrug of a pharmaceutically active agent, said prodrug comprising a beta-keto carboxylic acid, a beta-keto carboxylic acid salt or a beta-keto carboxylic acid ester functional group, to a pharmaceutical composition comprising the prodrug, and to the use of the prodrug or composition for treatment of a mammalian subject suffering from a condition which can be cured or alleviated by administration of said pharmaceutically active agent. There is further provided a method of inhibiting decarboxylation of a compound comprising a beta-keto carboxylic acid or a salt thereof with a monovalent cation, characterized in that a dry salt of said beta-keto carboxylic acid with a divalent or polyvalent cation is prepared.
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Page/Page column 74

(2010/11/04)

SILVER β-KETOCARBOXYLATE, MATERIAL COMPRISING THE SAME FOR FORMING SILVER METAL, AND USE THEREOF
A new material from which silver metal can be rapidly formed even at a temperature as low as about 210°C or below. The material for silver metal formation comprises a silver β-ketocarboxylate. Heating this forming material can rapidly form silver metal even at a temperature as low as about 210°C or below. Examples of the silver β-ketocarboxylate include silver isobutyrylacetate, silver benzoylacetate, silver acetoacetate, silver propionylacetate, silver α-methylacetoacetate, and silver α-ethylacetoacetate.
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Page/Page column 24-25

(2008/06/13)

Ir-catalyzed regio- and enantioselective decarboxylative allylic alkylations
[Ir(COD)Cl]2/phosphoramidite ligand 1a was found to be an efficient catalytic system, for the highly regio- and enantioselective decarboxylative alkylation of γ-substltuted allyl β-ketocarboxylates, affording the branched products with up to >99/1 branched-linear ratio and 96% ee.
He, Hu,Zheng, Xiao-Jian,Li, Yi,Dai, Li-Xin,You, Shu-Li
p. 4339 - 4341
(2008/03/12)

Scope and mechanism of enantioselective michael additions of 1,3-dicarbonyl compounds to nitroalkenes catalyzed by nickel(II)-diamine complexes
Readily prepared Ni(II)-bis[(R,R)-N,N′-dibenzylcyclohexane-1,2- diamine]Br2 was shown to catalyze the Michael addition of 1,3-dicarbonyl compounds to nitroalkenes at room temperature in good yields with high enantioselectivities. The two diamine ligands in this system each play a distinct role: one serves as a chiral ligand to provide stereoinduction in the addition step while the other functions as a base for substrate enolization. Ligand modification within the catalyst was also investigated to facilitate the reaction of aliphatic nitroalkenes, 1,3-diketones, and β-ketoacids. Ni(II)-bis[(R,R)-N,N′-di-p-bromo-benzylcyclohexane-1,2-diamine]Br 2 was found to be an effective catalyst in these instances. Furthermore, monodiamine complex, Ni(II)-[(R,R)-N,N′-dibenzylcyclohexane- 1,2-diamine]Br2, catalyzed the addition reaction in the presence of water. The proposed model for stereochemical induction is shown to be consistent with X-ray structure analysis.
Evans, David A.,Mito, Shizue,Seidel, Daniel
p. 11583 - 11592
(2008/03/15)

FIVE-MEMBERED HETEROCYCLES USEFUL AS SERINE PROTEASE INHIBITORS
The present invention provides a method for treating a thrombotic or an inflammatory disorder administering to a patient in need thereof a therapeutically effective amount of at least one compound of Formula (I) or Formula (V): (I) [INSERTCHEMICAL STRUCTURE HERE] (V)[INSERT CHEMICAL STRUCTURE HERE] or a stereoisomer or pharmaceutically acceptable salt or solvate form thereof, wherein the variables A, L, Z, R3, R4, R6, R11, X1, X2, and X3 are as defined herein. The compounds of Formula (I) are useful as selective inhibitors of serine protease enzymes of the coagulation cascade and/or contact activation system; for example thrombin, factor Xa, factor XIa, factor IXa, factor VIIa and/or plasma kallikrein. In particular, it relates to compounds that are selective factor XIa inhibitors. This invention also provides compounds within the scope of Formula I and relates to pharmaceutical compositions comprising these compounds.
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Page/Page column 132

(2008/06/13)

Nucleophilic benzoylation using a mandelic acid dioxolanone as a synthetic equivalent of the benzoyl carbanion. Oxidative decarboxylation of α-hydroxyacids
The synthesis of alkyl aryl ketones using a mandelic acid dioxolanone as a synthetic equivalent (Umpolung) of the benzoyl carbanion is reported. The methodology involves alkylation of the mandelic acid dioxolanone, hydrolysis of the dioxolanone moiety in the alkylated products and oxidative decarboxylation of the resulting α-hydroxyacids. The last step is carried out in a catalytic aerobic way using a Co (III) complex in the presence of pivalaldehyde under very mild conditions.
Blay, Gonzalo,Fernandez, Isabel,Monje, Belen,Pedro, Jose R.
p. 365 - 372
(2007/10/03)

Nucleophilic benzoylation using lithiated methyl mandelate as a synthetic equivalent of the benzoyl carbanion. Oxidative decarboxylation of α-hydroxyacids
The synthesis of alkyl aryl ketones using lithiated methyl mandelate as a synthetic equivalent of the benzoyl carbanion is reported (Umpolung). The methodology involves alkylation of methyl mandelate, hydrolysis of the ester group and oxidative decarboxylation of the resulting α-hydroxyacids. The last step is carried out in a catalytic aerobic way using a Co(III) complex in the presence of pivalaldehyde under very mild and advantageous conditions. The procedure is also applied to methyl mandelates substituted on the aromatic ring.
Blay, Gonzalo,Fernández, Isabel,Formentin, Pilar,Monje, Belén,Pedro, José R,Ruiz, Rafael
p. 1075 - 1081
(2007/10/03)

Ketone derivatives and medical application thereof
The present invention relates to ketone derivatives represented by the following formula and medical agents containing the ketone derivatives or pharmacologically acceptable salts thereof as an active ingredient, and in particular, relates to a hematopoietic agent; it is shown that the present invention increases blood cells, such as platelets, white blood cells, and red blood cells, and is effective in preventing and treating cytopenia caused by cancer chemotherapy, radiation therapy, and the like.
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(2008/06/13)

The reaction of β-ketoacids with allylboronates
Allylboronates react with β-ketoacids to yield tertiary homoallylic β-hydroxycarboxylic acids. The reaction presumably proceeds via a bicyclic transition state. The β-carboxylic substituent enhances the rate of the reaction.
Kabalka,Yang,Wang
p. 511 - 517
(2007/10/03)

Carboxylation of acetophenone with zinc(II) alkoxides/CO2 systems: A mechanistic study
The crystal structures of the homoleptic dimer zinc(II) 2,6-di- tert- butylphenoxide (1b) and of the corresponding monomer 1b/(DMSO)2 are presented. The structural motif of 1b is a Zn-O-Zn-O four-membered ring. The bulky phenoxide ligands led to a coordination number of only three for the zinc atom. Monomer 1b/(DMSO)2 crystallized as a four-coordinated monomer with a highly distorted tetrahedral geometry around the zinc center. 13C NMR investigations reveal details for the reaction of CO2 with a series of alkoxide zinc(II)/solvent systems [2,6-dimethylphenoxide zinc(II) (1a), zinc(II) 2,6-di-tert-butylphenoxide (1b), zinc(II) 2,6-diphenylphenoxide (1c), zinc(II) 4-tert-butylphenoxide (1d), and zinc(II) 2-pyrid-ylcarbinolato (2)]. The interpretation of the 13C NMR signals agree with ab initio calculations of a model zinc(II) phenoxide/CO2 system. Experimentally, the carboxylation of acetophenone as a representative for CH-acidic substrates was carried out with specific zinc(II) phenoxide/CO2 systems. The reactions resulted in yields of ca. 40% of benzoyl acetic acid. The role of the soluble zinc(II) phenylcarbonate intermediate is discussed with respect to the subsequent CO2 transfer reaction.
Kunert, Michael,Br?uer, Michael,Klobes, Olaf,G?rls, Helmar,Dinjus, Eckhard,Anders, Ernst
p. 1803 - 1809
(2007/10/03)

Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: Identification of 4-[5-(4-methylphenyl)- 3(trifluoromethyl)-1h-pyrazol-1-yl]benzenesulfonamide (sc-58635, celecoxib)
A series of sulfonamide-containing 1,5-diarylpyrazole derivatives were prepared and evaluated for their ability to block cyclooxygenase-2 (COX-2) in vitro and in vivo. Extensive structure-activity relationship (SAR) work was carried out within this series, and a number of potent and selective inhibitors of COX-2 were identified. Since an early structural lead (1f, SC- 236) exhibited an unacceptably long plasma half-life, a number of pyrazole analogs containing potential metabolic sites were evaluated further in vivo in an effort to identify compounds with acceptable pharmacokinetic profiles. This work led to the identification of 1i (4-[5-(4-methylphenyl)-3- (trifluoromethyl)-1H-pyrazol-1-y1]benzenesulfonamide, SC-58635, celecoxib), which is currently in phase III clinical trials for the treatment of rheumatoid arthritis and osteoarthritis.
Penning, Thomas D.,Talley, John J.,Bertenshaw, Stephen R.,Carter, Jeffery S.,Collins, Paul W.,Docter, Stephen,Graneto, Matthew J.,Lee, Len F.,Malecha, James W.,Miyashiro, Julie M.,Rogers, Roland S.,Rogier,Yu, Stella S.,Anderson, Gary D.,Burton, Earl G.,Cogburn, J. Nita,Gregory, Susan A.,Koboldt, Carol M.,Perkins, William E.,Seibert, Karen,Veenhuizen, Amy W.,Zhang, Yan Y.,Isakson, Peter C.
p. 1347 - 1365
(2007/10/03)

Contrast media synthesized from polyaldehydes
Microparticles comprising biodegradable polymers, characterized in that they are synthesized from polymerizable aldehydes, which optionally contain additives and/or crosslinkers capable of copolymerization, optionally surfactants or surfactant mixtures, gases and/or highly volatile liquids in free or bound form, coupling agents, optionally biomolecules or macromolecules bound by these coupling agents as well as optionally diagnostically or therapeutically effective components, are suitable as ultrasonic contrast media.
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(2008/06/13)

Carboxylation of Active Methylene Compounds Using Anilide, Potassium Carbonate, and Carbon Dioxide
Active methylene compounds were effectively carboxylated with carbon dioxide in the presence of anilide (acetanilide or formanilide) and potassium carbonate at 20-40 deg C for 0.5-10 h.In the carboxylation of fluorene, a high yield (48percent) was obtained at 20 deg C for 4 h.The yield of carboxylic acid using 2,6-dimethylacetanilide was 8.9percent, and smaller than 26.6percent when using acetanilide at 20 deg C for 2 h, indicating the interference of a methyl group for the carboxylation.
Chiba, Koji,Tagaya, Hideyuki,Karasu, Masa,Ishizuka, Masahiko,Sugo, Toshiyuki
p. 452 - 454
(2007/10/02)

NITROIMIDAZOLES XI. SYNTHESES OF SUBSTITUTED (1-METHYL-5-NITRO-2-IMIDAZOLYL)PYRAZOLES
The β-diketone derivatives of nitroimidazole were synthesized from the reaction of magnesium salt of β-keto acids (2) with imidazolide (3).The β-keto acids (1) were obtained from the hydrolysis of β-keto esters (5) or the reaction of magnesium methylcarbonate with the ketone (6).The reaction of β-diketones (4) with hydrazine afforded the pyrazoles (7), which were converted to N-methylpyrazoles (8) and (9).The latters could also be obtained from the reaction of β-diketones (4) with methylhydrazine.
Karimi-Khoozani, Rahim,Ghanbarpour, Alireza,Shafiee, Abbas
p. 503 - 510
(2007/10/02)

The Carboxylation of Active Methylene Compounds with Carbon Dioxide in the Presence of Diphenylcarbodiimide and Potassium Carbonate
Active methylene compounds were effectively carboxylated with carbon dioxide in the presence of diphenylcarbodiimide (DPC) as a biotin model and potassium carbonate.Fluorene was carboxylated even under a nitrogen atmosphere in the presence of DPC, indicating that a carbonate ion was the carbon source.The reaction occured even in the presence of water.It was considered that reaction intermediates are stable to water and that the concentration of the carbonate ion is important for carboxylation.
Chiba, Koji,Tagaya, Hideyuki,Karasu, Masa,Ono, Tsuyoyuki,Hashimoto, Kazumi,Moriwaki, Yasusi
p. 966 - 970
(2007/10/02)

β-Oxocarboxylic Acids by Carboxylation of Enamines
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Frenzel, Ralf,Domschke, Guenther,Mayer, Roland
p. 495 - 496
(2007/10/02)

The Carboxylation of Active Methylene Compounds with Diphenylcarbodiimide and Potassium Carbonate
Active methylene compounds were carboxylated by employing the reagent system, diphenylcarbodiimide and potassium carbonate, in dimethyl sulfoxide at room temperature and atmospheric pressure.The reaction proceeded even in the absence of carbon dioxide, but the carboxylation easily proceeded in carbon dioxide atmosphere.
Chiba, Koji,Tagaya, Hideyuki,Karasu, Masa,Ono, Tsuyoyuki,Kugiya, Masashi
p. 39 - 42
(2007/10/02)