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Discovery of remogliflozin etabonate: A potent and highly selective SGLT2 inhibitor
We optimized the structure of an active metabolite (1) of WAY-123783, which was obtained from mouse urine after oral administration, to improve selectivity for SGLT2 and oral bioavailability. O-glucoside derivative 24 (remogliflozin etabonate) was subsequently identified as a potent, highly selective, and orally available SGLT2 inhibitor.
Shimizu, Kazuo,Fujikura, Hideki,Fushimi, Nobuhiko,Nishimura, Toshihiro,Tatani, Kazuya,Katsuno, Kenji,Fujimori, Yoshikazu,Watanabe, Shinjiro,Hiratochi, Masahiro,Nakabayashi, Takeshi,Kamada, Noboru,Arakawa, Koichi,Hikawa, Hidemasa,Azumaya, Isao,Isaji, Masayuki
(2021/02/16)

Reductive Knoevenagel Condensation with the Zn-AcOH System
An efficient gram-scale one-pot approach to 2-substituted malonates and related structures is developed, starting from commercially available aldehydes and active methylene compounds. The technique combines Knoevenagel condensation with the reduction of the C=C bond in the resulting activated alkenes with the Zn-AcOH system. The relative ease with which the C=C bond reduction occurs can be traced to the accepting abilities of the substituents in the intermediate arylidene malonates.
Ivanov, Konstantin L.,Melnikov, Mikhail Ya.,Budynina, Ekaterina M.
p. 1285 - 1291
(2020/11/13)

REDUCTION METHOD AND REDUCTION PRODUCT OF ALKENYL ACTIVE METHYLENE COMPOUND
Disclosed are a reduction method and reduction product of an alkenyl active methylene compound. The reduction reaction comprises the following steps: taking an alkenyl active methylene compound as a substrate, a metal hydride as a reducing agent, and a palladium compound as a catalyst, performing a reduction reaction to obtain a reduction product, and then reducing the alkenyl active methylene compound. The reduction system is a simple method for reducing the alkenyl active methylene compound, and the used hydride and palladium compound catalyst are both reagents that could easily be obtained in a laboratory. Compared with conventional hydrogen hydrogenation methods and reduction methods of reducing agents, the method is easier to operate, higher in safety, mild in conditions, and high in reaction yield, a reaction in a one-pot two-step manner can be achieved, and high atom economy and step economy can be obtained.
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Paragraph 0022-0023

(2021/07/02)

Identification of new 3-phenyl-1H-indole-2-carbohydrazide derivatives and their structure–activity relationships as potent tubulin inhibitors and anticancer agents: A combined in silico, in vitro and synthetic study
Virtual screening of commercially available molecular entities by using CDRUG, structure-based virtual screening, and similarity identified eight new derivatives of 3-phenyl-1H-indole-2-carbohydrazide with anti-proliferative activities. The molecules were tested experimentally for inhibition of tubulin polymerisation, which revealed furan-3-ylmethylene-3-phenyl-1H-indole-2-carbohydrazide (27a) as the most potent candidate. Molecule 27a was able to induce G2/M phase arrest in A549 cell line, similar to other tubulin inhibitors. Synthetic modifications of 27a were focussed on small substitutions on the furan ring, halogenation at R1 position and alteration of furyl connectivity. Derivatives 27b, 27d and 27i exhibited the strongest tubulin inhibition activities and were comparable to 27a. Bromine substitution at R1 position showed most prominent anticancer activities; derivatives 27b-27d displayed the strongest activities against HuCCA-1 cell line and were more potent than doxorubicin and the parent molecule 27a with IC50 values 50 = 0.34 μM), while 27d displayed stronger activity against A549 cell line (IC50 = 0.43 μM) compared to doxorubicin and 27a. Fluorine substitutions at the R1 position tended to show more modest anti-tubulin and anticancer activities, and change of 2-furyl to 3-furyl was tolerable. The new derivatives, thiophenyl 26, displayed the strongest activity against A549 cell line (IC50 = 0.19 μM), while 1-phenylethylidene 21b and 21c exhibited more modest anticancer activities with unclear mechanisms of action; 26 and 21c demonstrated G2/M phase arrest, but showed weak tubulin inhibitory properties. Molecular docking suggests the series inhibit tubulin at the colchicine site, in agreement with the experimental findings. The calculated molecular descriptors indicated that the molecules obey Lipinski's rule which suggests the molecules are drug-like structures.
Saruengkhanphasit, Rungroj,Butkinaree, Chutikarn,Ornnork, Narittira,Lirdprapamongkol, Kriengsak,Niwetmarin, Worawat,Svasti, Jisnuson,Ruchirawat, Somsak,Eurtivong, Chatchakorn
(2021/03/17)

Pyrazole-Thiazole Core-Containing Analogs Exhibit Adjunctive Activity with Meropenem against Carbapenem-Resistant Enterobacteriaceae (CRE)
Pyrazole-thiazole core-containing compound KP-40 and 20 novel derivatives were designed and synthesized through traditional SAR analysis. These molecules displayed adjunctive activity with meropenem against Gram-negative bacteria evidenced by a range of fractional inhibitory concentration (FIC=0.5–0.25) and minimum adjunctive concentration (MAC=128–32 μM) values. Of this series of molecules, four compounds displayed notable adjunctive potential, with FIC and MAC values of 0.25 and 32 μM, respectively. Moreover, the solubility of these compounds was improved to an acceptable range. Further analysis using our “in house” permeation and efflux multi parameter optimization (PEMPO) algorithm revealed key physicochemical properties that may be critical for the development of active Gram-negative antibacterials. Taking PEMPO scores into consideration prior to executing synthesis of analogs may be a simple, yet rapid and effective strategy that can be used in conjunction with traditional SAR approaches to aid in the design of potent Gram-negative antibacterials.
Kim, Chungsik,Kassu, Mintesinot,Smith, Kenneth P.,Kirby, James E.,Manetsch, Roman
supporting information
p. 2775 - 2780
(2021/07/02)

Catalytic Asymmetric Homologation of Ketones with α-Alkyl α-Diazo Esters
The homologation of ketones with diazo compounds is a useful strategy to synthesize one-carbon chain-extended acyclic ketones or ring-expanded cyclic ketones. However, the asymmetric homologation of acyclic ketones with α-diazo esters remains a challenge due to the lower reactivity and complicated selectivity. Herein, we report the enantioselective catalytic homologation of acetophenone and related derivatives with α-alkyl α-diazo esters utilizing a chiral scandium(III) N,N′-dioxide as the Lewis acid catalyst. This reaction supplies a highly chemo-, regio-, and enantioselective pathway for the synthesis of optically active β-keto esters with an all-carbon quaternary center through highly selective alkyl-group migration of the ketones. Moreover, the ring expansion of cyclic ketones was accomplished under slightly modified conditions, affording a series of enantioenriched cyclic β-keto esters. Density functional theory calculations have been carried out to elucidate the reaction pathway and possible working models that can explain the observed regio- and enantioselectivity.
Tan, Fei,Pu, Maoping,He, Jun,Li, Jinzhao,Yang, Jian,Dong, Shunxi,Liu, Xiaohua,Wu, Yun-Dong,Feng, Xiaoming
supporting information
p. 2394 - 2402
(2021/02/16)

Complementing Pyridine-2,6-bis(oxazoline) with Cyclometalated N-Heterocyclic Carbene for Asymmetric Ruthenium Catalysis
A strategy for expanding the utility of chiral pyridine-2,6-bis(oxazoline) (pybox) ligands for asymmetric transition metal catalysis is introduced by adding a bidentate ligand to modulate the electronic properties and asymmetric induction. Specifically, a ruthenium(II) pybox fragment is combined with a cyclometalated N-heterocyclic carbene (NHC) ligand to generate catalysts for enantioselective transition metal nitrenoid chemistry, including ring contraction to chiral 2H-azirines (up to 97 % ee with 2000 TON) and enantioselective C(sp3)?H aminations (up to 97 % ee with 50 TON).
Li, Long,Han, Feng,Nie, Xin,Hong, Yubiao,Ivlev, Sergei,Meggers, Eric
supporting information
p. 12392 - 12395
(2020/06/10)

Development of coumarine derivatives as potent anti-filovirus entry inhibitors targeting viral glycoprotein
Filoviruses, including Ebolavirus (EBOV), Marburgvirus (MARV) and Cuevavirus, cause hemorrhagic fevers in humans with up to 90% mortality rates. In the 2014–2016 West Africa Ebola epidemic, there are 15,261 laboratory confirmed cases and 11,325 total deaths. The lack of effective vaccines and medicines for the prevention and treatment of filovirus infection in humans stresses the urgency to develop antiviral therapeutics against filovirus-associated diseases. Our previous study identified a histamine receptor antagonist compound CP19 as an entry inhibitor against both EBOV and MARV. The preliminary structure-activity relationship (SAR) studies of CP19 showed that its piperidine, coumarin and linker were related with its antiviral activities. In this study, we performed detailed SAR studies on these groups with synthesized CP19 derivatives. We discovered that 1) the piperidine group could be optimized with heterocycles, 2) the substitution groups of C3 and C4 of coumarin should be relatively large hydrophobic groups and 3) the linker part should be least substituted. Based on the SAR analysis, we synthesized compound 32 as a potent entry inhibitor of EBOV and MARV (IC50 = 0.5 μM for EBOV and 1.5 μM for MARV). The mutation studies of Ebola glycoprotein and molecular docking studies showed that the coumarin and its substituted groups of compound 32 bind to the pocket of Ebola glycoprotein in a similar way to the published entry inhibitor compound 118a. However, the carboxamide group of compound 32 does not have strong interaction with N61 as compound 118a does. The coumarin skeleton structure and the binding model of compound 32 elucidated by this study could be utilized to guide further design and optimization of entry inhibitors targeting the filovirus glycoproteins.
Gao, Yinyi,Cheng, Han,Khan, Sameer,Xiao, Gaokeng,Rong, Lijun,Bai, Chuan
(2020/07/23)

Anti-filamentous virus small molecule compound and application thereof
The invention discloses an anti-filamentous virus small molecule compound and application thereof. The small molecule compound has a structural formula shown as a formula I, and an R group of the small molecule compound is selected from structural formulas II-V. The four new compounds all have higher anti-filamentous virus activity and excellent filamentous virus treatment index, and the use of compounds with similar structures finds that the new compounds have better antiviral activity by 6-glycerol branched chain substitution on the basis of the original compounds; and the structural framework can become a basic skeleton of an anti-filamentous virus inhibitor.
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Paragraph 0047; 0050; 0053-0054

(2021/01/04)

Method for synthesizing beta-keto ester through copper catalysis
The invention relates to a method for synthesizing beta-keto ester by copper catalysis, which comprises the following steps of dissolving ethyl acylacetate and halogenated hydrocarbon in an organic solvent, adding a copper catalyst and alkali, reacting at 60-90 DEG C for 12-18 hours, and separating and purifying to obtain the beta-keto ester. Compared with the prior art, the method has the advantages of simple and green synthesis process, excellent selectivity, higher yield and wide substrate range, and has the wide application value in the fields of biology, pharmaceutical chemistry industryand the like.
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Paragraph 0037-0039

(2019/12/02)

The Employment of Sodium Hydride as a Michael Donor in Palladium-catalyzed Reductions of α, β-Unsaturated Carbonyl Compounds
Sodium hydride was employed as a Michael donor under the catalysis of PdCl2 for 1,4-conjugate reductions of α, β-unsaturated carbonyl compounds, which features operational simplicity, mild conditions and high atom-economy. The merits of NaH as a reductant were demonstrated by the one-pot or cascade reactions for the syntheses of complex molecules. (Figure presented.).
Liu, Ye,Mao, Yujian,Hu, Yanwei,Gui, Jingjing,Wang, Liang,Wang, Wei,Zhang, Shilei
supporting information
p. 1554 - 1558
(2019/02/16)

Reduction method and reduction product of alkenyl active methylene compound
The invention discloses a reduction method and reduction product of an alkenyl active methylene compound. The reduction reaction comprises the following steps: taking the alkenyl active methylene compound as a substrate, a metal hydride as a reducing agent, a palladium compound as a catalyst, performing a reduction reaction to obtain the reduction product, and then reducing the alkenyl active methylene compound. The reduction system of the invention is a simple method for reducing the alkenyl active methylene compound, used hydride and a palladium compound catalyst are all easily obtained reagents in the laboratory, compared with the conventional hydrogen hydrogenation method and the reduction method of the reducing agent, the method is easier to operate, higher in safety, mild in conditions and high in reaction yield, and can be reacted in a one-pot two-step manner, thereby having very high atom economy and step economy.
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Paragraph 0019

(2019/01/16)

Enantioselective and Diastereoselective Ir-Catalyzed Hydrogenation of α-Substituted β-Ketoesters via Dynamic Kinetic Resolution
An iridium/f-amphol catalytic system for the enantioselective hydrogenation of α-substituted β-ketoesters via dynamic kinetic resolution is reported. The desired anti products were obtained in high yields (up to 98%) with good diastereoselectivity (up to 96:4 diastereometic ratio (dr)) and excellent enantioselectivity (up to >99% enantiomeric excess (ee)). A catalytic model is proposed to explain the stereoselectivity.
Gu, Guoxian,Lu, Jiaxiang,Yu, Ouran,Wen, Jialin,Yin, Qin,Zhang, Xumu
supporting information
p. 1888 - 1892
(2018/04/16)

Interrupted Baeyer–Villiger Rearrangement: Building A Stereoelectronic Trap for the Criegee Intermediate
The instability of hydroxy peroxyesters, the elusive Criegee intermediates of the Baeyer–Villiger rearrangement, can be alleviated by selective deactivation of the stereoelectronic effects that promote the 1,2-alkyl shift. Stable cyclic Criegee intermediates constrained within a five-membered ring can be prepared by mild reduction of the respective hydroperoxy peroxyesters (β-hydroperoxy-β-peroxylactones) which were formed in high yields in reaction of β-ketoesters with BF3?Et2O/H2O2.
Vil', Vera A.,dos Passos Gomes, Gabriel,Bityukov, Oleg V.,Lyssenko, Konstantin A.,Nikishin, Gennady I.,Alabugin, Igor V.,Terent'ev, Alexander O.
supporting information
p. 3372 - 3376
(2018/02/28)

Five Roads That Converge at the Cyclic Peroxy-Criegee Intermediates: BF3-Catalyzed Synthesis of β-Hydroperoxy-β-peroxylactones
We have discovered synthetic access to β-hydroperoxy-β-peroxylactones via BF3-catalyzed cyclizations of a variety of acyclic precursors, β-ketoesters and their silyl enol ethers, alkyl enol ethers, enol acetates, and cyclic acetals, with H2O2. Strikingly, independent of the choice of starting material, these reactions converge at the same β-hydroperoxy-β-peroxylactone products, i.e., the peroxy analogues of the previously elusive cyclic Criegee intermediate of the Baeyer-Villiger reaction. Computed thermodynamic parameters for the formation of the β-hydroperoxy-β-peroxylactones from silyl enol ethers, enol acetates, and cyclic acetals confirm that the β-peroxylactones indeed correspond to a deep energy minimum that connects a variety of the interconverting oxygen-rich species at this combined potential energy surface. The target β-hydroperoxy-β-peroxylactones were synthesized from β-ketoesters, and their silyl enol ethers, alkyl enol ethers, enol acetates, and cyclic acetals were obtained in 30-96% yields. These reactions proceed under mild conditions and open synthetic access to a broad selection of β-hydroperoxy-β-peroxylactones that are formed selectively even in those cases when alternative oxidation pathways can be expected. These β-peroxylactones are stable and can be useful for further synthetic transformations.
Vil, Vera A.,Gomes, Gabriel Dos Passos,Ekimova, Maria V.,Lyssenko, Konstantin A.,Syroeshkin, Mikhail A.,Nikishin, Gennady I.,Alabugin, Igor V.,Terent'Ev, Alexander O.
p. 13427 - 13445
(2018/11/02)

Asymmetric Aza-Wacker-Type Cyclization of N-Ts Hydrazine-Tethered Tetrasubstituted Olefins: Synthesis of Pyrazolines Bearing One Quaternary or Two Vicinal Stereocenters
We have developed an asymmetric aza-Wacker-type cyclization of N-Ts hydrazine-tethered tetrasubstituted olefins, affording optically active pyrazolines bearing chiral tetrasubstituted carbon stereocenters. This reaction is tolerant to a broad range of substrates under mild reaction conditions, giving the desired chiral products with high enantioselectivities. Generation of two vicinal stereocenters on the C=C double bonds was also achieved with high selectivities, a process which has been rarely studied for Wacker-type reactions. A mechanistic study revealed that this aza-Wacker-type cyclization undergoes a syn-aminopalladation process. It was also found that for substrates bearing two linear alkyl substituents on the outer carbon atom of the olefin, both of which are larger than a methyl group, the alkyl substituent that is cis to the intranucleophilic group participates more readily in β-hydride elimination. When one of the two alkyl substituents on the outer carbon atom of the olefin is a methyl group, β-hydride elimination proceeds selectively at the methylene side, thus both diastereomers can be prepared via switching the configuration of the olefin. Furthermore, the product can be converted to a pharmaceutical compound in high yields over three steps.
Kou, Xuezhen,Shao, Qihang,Ye, Chenghao,Yang, Guoqiang,Zhang, Wanbin
supporting information
p. 7587 - 7597
(2018/06/04)

Catalytic Enantioselective Protonation/Nucleophilic Addition of Diazoesters with Chiral Oxazaborolidinium Ion Activated Carboxylic Acids
A new chiral Br?nsted acid derived from carboxylic acid and a chiral oxazaborolidinium ion (COBI), as an activator, is introduced. This acid was successfully applied as a catalyst for the highly enantioselective protonation/nucleophilic addition of diazoesters with carboxylic acids.
Kang, Ki-Tae,Kim, Seung Tae,Hwang, Geum-Sook,Ryu, Do Hyun
supporting information
p. 3977 - 3981
(2017/03/27)

Thiourea catalysed reduction of α-keto substituted acrylate compounds using Hantzsch ester as a reducing agent in water
The first method for the reduction of α-keto substituted acrylate compounds by Hantzsch ester in water under the catalysis of thiourea has been developed. The products were isolated in moderate to high yields (38-95%). These products are important intermediates in the synthesis of a series of natural products and other biologically active molecules.
Weng, Guanglin,Ma, Xiaobo,Fang, Dongmei,Tan, Ping,Wang, Lijiao,Yang, Linlin,Zhang, Yuanyuan,Qian, Shan,Wang, Zhouyu
p. 22909 - 22912
(2017/07/10)

PYRAZOLOPYRIMIDINE DERIVATIVES AND THE COMPOSITIONS AND METHODS OF TREATMENT REGARDING THE SAME
The present disclosure is directed to pyrazolo[1,5-a]pyrimidine compounds of formula (I), pharmaceutical compositions thereof and methods for modulating or activating a Parkin ligase The present disclosure is also directed to methods of treating and/or reducing the incidence of diseases or conditions related to the activation of Parkin ligase. R21, R22, R23, R24 and R25 are as defined herein.
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Paragraph 492; 493

(2018/01/17)

Tunable Aerobic Oxidative Hydroxylation/Dehydrogenative Homocoupling of Pyrazol-5-ones under Transition-Metal-Free Conditions
A practical and tunable transition-metal-free aerobic oxidation of pyrazol-5-ones preparing either 4-hydroxypyrazoles (via C-H hydroxylation) or bispyrazoles (via dehydrogenative homocoupling) is described. The K2CO3/dioxane reagent system predominately promoted hydroxylation to deliver the α-hydroxylated pyrazoles. In contrast, the formation of bispyrazoles was overwhelmingly preferred with CH3CN as the reaction medium without any additives.
Sheng, Xuguang,Zhang, Jinlong,Yang, Huameng,Jiang, Gaoxi
supporting information
p. 2618 - 2621
(2017/05/24)

Antischistosomal Activity of Pyrido[1,2-a]benzimidazole Derivatives and Correlation with Inhibition of β-Hematin Formation
The extensive use of praziquantel against schistosomiasis raises concerns about drug resistance. New therapeutic alternatives targeting critical pathways within the parasite are therefore urgently needed. Hemozoin formation in Schistosoma presents one such target. We assessed the in vitro antischistosomal activity of pyrido[1,2-a]benzimidazoles (PBIs) and investigated correlations with their ability to inhibit β-hematin formation. We further evaluated the in vivo efficacy of representative compounds in experimental mice and conducted pharmacokinetic analysis on the most potent. At 10 μM, 48/57 compounds resulted in >70% mortality of newly transformed schistosomula, whereas 37 of these maintained >60% mortality of adult S. mansoni. No correlations were observed between β-hematin inhibitory and antischistosomal activities against both larval and adult parasites, suggesting possible presence of other target(s) or a mode of inhibition of crystal formation that is not adequately modeled by the assay. The most active compound in vivo showed 58.7 and 61.3% total and female worm burden reduction, respectively. Pharmacokinetic analysis suggested solubility-limited absorption and high hepatic clearance as possible contributors to the modest efficacy despite good in vitro activity. The PBIs evaluated in this report thus merit further optimization to improve their efficacy and to elucidate their possible mode of action.
Okombo, John,Singh, Kawaljit,Mayoka, Godfrey,Ndubi, Ferdinand,Barnard, Linley,Njogu, Peter M.,Njoroge, Mathew,Gibhard, Liezl,Brunschwig, Christel,Vargas, Mireille,Keiser, Jennifer,Egan, Timothy J.,Chibale, Kelly
p. 411 - 420
(2017/06/14)

Bioreduction of α-Acetoxymethyl Enones: Proposal for an SN2′ Mechanism Catalyzed by Enereductase
(Z)-3-Acetoxymethyl-4-R-3-buten-2-ones (R=aryl, alkyl) and (Z)-3-methyl-4-R-3-buten-2-ones (R=aryl) were synthesized and submitted to reduction by the yeast Saccharomyces cerevisiae producing the (R)- and (S)-4-R-3-methybutan-2-ones, respectively. This stereochemistry control strategy was applied in the syntheses of (R)- and (S)-Tropional with moderate to high enantiomeric excesses. Other (Z)-3-acyloxymethyl-4-phenyl-3-buten-2-ones showed similar behavior to the (Z)-3-acetoxymethyl counterpart, and the acylated Morita–Baylis–Hillman adduct 1-acetoxy-2-methylene-1-phenylbutan-3-one produced a mixture of products, with and without the acetoxy group, via three different reaction pathways. In addition to experiments employing whole cells, those in which isolated enereductases were used suggested that the main pathway through which the loss of the acetoxy group occurs during the biocatalytic cascade is an SN2′-type reaction, rather than formal hydrogen addition followed by acetic acid elimination. Finally, related ethyl enones were reduced enantioselectively by the yeast Candida albicans, producing both (R)- and (S)-reduction products, depending on the presence of the acetoxy group in the starting material. (Figure presented.).
Paula, Bruno R. S.,Zampieri, Davila,Rodrigues, J. Augusto R.,Moran, Paulo J. S.
p. 3555 - 3571
(2016/11/25)

A pharmaceutical intermediate relieves a cough the alkone method for synthesis of benzyl acetone (by machine translation)
A pharmaceutical intermediate relieves a cough the alkone method for synthesis of benzyl acetone, comprising the following steps: in is provided with an agitator, reflux condenser, dropping funnel, thermometer in the reaction container, add cyclonexane 320 ml, the batch is added stannous chloride 1.3mol, adding acetyl ethyl acetate 2.3mol, control the stirring speed of the 130 [...] 160rpm, reaction of the 60 [...] 90 min, the temperature of the solution elevated to 65 - - 70°C, reflux 3 the [...] 5h, instillment phenmethyl amine (3) the 2.6 [...] 2.8mol, dropping time control in the 3 [...] 4h, reflux reaction the 3 [...] 4h, to form intermediate product, reducing the temperature of the solution to 10 - - 15°C, adding 330 ml potassium sulfite solution, keep the backflow 4 the [...] 5h, generating oily, the pH of the solution is adjusted with oxalic acid to the 4 [...] 5, to continue to return the 4 [...] 6h, vacuum distillation, collecting 95 - - 105 °C fraction, salt solution washing, acetonitrile washing, recrystallization of the nitromethane in, to obtain crystal benzyl acetone. (by machine translation)
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Paragraph 0014; 0015

(2016/11/07)

Enantioselective intramolecular cyclization of alkynyl esters catalyzed by a chiral Br?nsted base
An enantioselective intramolecular cyclization reaction of alkynyl esters was developed, which employs a Br?nsted base catalyst generated in situ from a chiral Schiff base and t-BuOK. This reaction is a rare example of the enantioselective intramolecular addition of simple ester enolates to alkynes under Br?nsted base catalysis.
Kondoh, Azusa,Tran, Hoa Thi Quynh,Kimura, Kyoko,Terada, Masahiro
supporting information
p. 5726 - 5729
(2016/05/19)

Copper-Mediated Deuterotrifluoromethylation of α?Diazo Esters
A copper-mediated deuterotrifluoromethylation of α?diazo esters under the promotion of deuterium oxide (D2O) has been developed for the synthesis of deuterium-labeled trifluoromethyl compounds. This deuterotrifluoromethylation reaction is of broad scope and can afford the deuterated products with higher than 99% isotopic purity. Moreover, the results of this investigation also provide some experimental evidences to support our previously proposed trifluoromethylation mechanism.
Hu, Mingyou,Xie, Qiqiang,Li, Xinjin,Ni, Chuanfa,Hu, Jinbo
supporting information
p. 469 - 472
(2016/05/24)

Construction of All-Carbon Quaternary Centers through Cu-Catalyzed Sequential Carbene Migratory Insertion and Nucleophilic Substitution/Michael Addition
A Cu-catalyzed three-component cross-coupling reaction of terminal alkyne, α-diazo ester, and alkyl halide has been developed. This transformation involves sequent migratory insertion of copper-carbene and nucleophilic substitution, in which a C(sp)-C(sp3) bond and a C(sp3)-C(sp3) bond are formed successively on a carbenic center. Michael addition acceptors can also be employed instead of alkyl halides that enable Michael addition to be an alternative way to build C(sp3)-C(sp3) bond. This transformation represents a highly efficient method for the construction of all-carbon quaternary centers.
Wang, Chengpeng,Ye, Fei,Wu, Chenggui,Zhang, Yan,Wang, Jianbo
p. 8748 - 8757
(2015/09/15)

Cascade engineered synthesis of ethyl benzyl acetoacetate and methyl isobutyl ketone (MIBK) on novel multifunctional catalyst
A novel trifunctional catalyst with basic, acidic and metal sites was synthesized by nanocolloidal method and used in industrially important reactions. in the laboratory. The synthesized catalyst consisted of palladium and hydrotalcite supported on transition metal modified hexagonal mesoporous silica (HMS) and was characterized in virgin and reused states using a number of techniques such as elemental analysis, FTIR, NH3- TPD, CO2- TPD, H2- TPR, XRD and BET surface area. The activity of particular catalytic site was engineered so that a desired reaction pathway was followed in spite of possibility of multiple series and parallel or complex reactions. One pot cascade engineered synthesis of ethyl benzyl acetoacetate from benzaldehyde and ethyl acetoacetate was studied in solvent free condition in a batch reactor. The effects of various parameters on the rates of reaction were analysed to establish instantaneous selectivity. Reaction mechanism and kinetic modelling was studied to validate the experimental results. The reaction follows Langmuir-Hinshelwood-Hougen-Watson mechanism involving weak adsorption of reactants and products. The apparent activation energy was found to be 13 kcal/mol and intrinsic kinetic constant 33 cm6 mol-1 gcat-1 s-1. This study was further extended to synthesis of methyl isobutyl ketone (MIBK) from acetone in solvent free condition. Similar experimental and theoretical analysis was done for MIBK synthesis for which the activation energy and intrinsic kinetic constant were found to be 12 kcal/mol and 4 cm6 mol-1 gcat-1 s-1, respectively.
Patankar, Saurabh C.,Dodiya, Sanjay K.,Yadav, Ganapati D.
p. 171 - 182
(2015/09/15)

Regioselective catalytic asymmetric C-alkylation of isoxazolinones by a base-free palladacycle-catalyzed direct 1,4-addition
Isoxazolinones constitute a class of heterocycles utilized for the development of novel drug candidates. The cyclic oxime ester motif is also synthetically useful as it contains functional handles which have previously been used to provide access to an assortment of valuable compound classes not easily accessible by alternative approaches. However, asymmetric methods towards isoxazolinones are notoriously scarce. Herein we report the first catalytic asymmetric alkylations of isoxazolinones forming all-C-substituted quaternary stereocenters. The present studies were driven by the question of how to control the regioselectivity in the competition of different nucleophilic positions. The investigation of a direct 1,4-addition uncovered that a sterically demanding palladacycle catalyst directs the reactivity in the absence of a base nearly exclusively to the nucleophilic C atom, while at the same time it allows for high enantioselectivity and TONs up to 1900.
Hellmuth, Tina,Frey, Wolfgang,Peters, Ren
supporting information
p. 2788 - 2791
(2015/03/04)

Alkynylation of heterocyclic compounds using hypervalent iodine reagent
The alkynylation of various nitrogen- and/or sulphur-containing heterocyclic compounds using hypervalent iodine TMS-EBX by utilization of tertiary amines under mild conditions is described. The developed metal-free methodology furnishes the corresponding alkynylated heterocycles bearing quaternary carbon in high yields.
Kamlar,Císa?ová,Vesely
supporting information
p. 2884 - 2889
(2015/04/27)

gem-Difluoroolefination of Diazo Compounds with TMSCF3 or TMSCF2Br: Transition-Metal-Free Cross-Coupling of Two Carbene Precursors
A new olefination protocol for transition-metal-free cross-coupling of two carbene fragments arising from two different sources, namely, a nonfluorinated carbene fragment resulting from a diazo compound and a difluorocarbene fragment derived from Ruppert-Prakash reagent (TMSCF3) or TMSCF2Br, has been developed. This gem-difluoroolefination proceeds through the direct nucleophilic addition of diazo compounds to difluorocarbene followed by elimination of N2. Compared to previously reported Cu-catalyzed gem-difluoroolefination of diazo compounds with TMSCF3, which possesses a narrow substrate scope due to a demanding requirement on the reactivity of diazo compounds and in-situ-generated CuCF3, this transition-metal-free protocol affords a general and efficient approach to various disubstituted 1,1-difluoroalkenes, including difluoroacrylates, diaryldifluoroolefins, as well as arylalkyldifluoroolefins. In view of the ready availability of diazo compounds and difluorocarbene reagents and versatile transformations of 1,1-difluoroalkenes, this new gem-difluoroolefination method is expected to find wide applications in organic synthesis.
Hu, Mingyou,Ni, Chuanfa,Li, Lingchun,Han, Yongxin,Hu, Jinbo
supporting information
p. 14496 - 14501
(2015/11/27)

Fe(HSO4)3 : An efficient, heterogeneous and reusable catalyst for C-alkylation of β-dicarbonyl compounds
Fe(HSO4)3(FHS) was used as an efficient catalyst for the heterogeneous addition of a series of benzylic and allylic alcohols to various β-dicarbonyl compounds, which afforded moderate to excellent yields of C-alkylated products in 1,2-dichloroethane. In comparison with the previous methods, the present research surprisingly exhibited higher reaction yields without formation of any by-products which could be formed by self-condensation of alcohols. Moreover, the catalyst can be readily recovered and reused up to five times with almost maintained reactivity and yields.
Khafajeh, Samaneh,Akhlaghinia, Batool,Rezazadeh, Soodabeh,Eshghi, Hossein
p. 1903 - 1912
(2015/02/05)

Catalytic asymmetric insertion of diazoesters into Aryl-CHO bonds: Highly enantioselective construction of chiral all-carbon quaternary centers
This paper describes a catalytic enantioselective route to synthesize functionalized all-carbon quaternary acyclic systems via a boron Lewis acid-promoted formal C-C insertion of diazoesters into aryl-CHO bonds. In the presence of chiral (S)-oxazaborolidinium cation 1d as a catalyst, the reaction proceeded in good yield (up to 83%) with good regioselectivity (up to 88:12) and excellent enantioselectivity (up to 99% ee). The synthetic potential of this method was illustrated by conversion of the products to both α-and β-amino esters.
Gao, Lizhu,Kang, Byung Chul,Ryu, Do Hyun
supporting information
p. 14556 - 14559
(2013/10/22)

First iodine-catalyzed deallylation of reactive allyl methylene esters
C-Allyl cleavage has been developed using the inexpensive and mild reagent iodine in dimethylsulfoxide. A variety of compounds with active methylene groups were C-deallylated using this reagent. This method is efficient and operationally simple in comparison to the methods using transition-metal complexes. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications to view the free supplemental file.
Nawghare, Beena R.,Lokhande, Pradeep D.
p. 1955 - 1963
(2013/06/05)

Substituted 3-benzylcoumarins as allosteric MEK1 inhibitors: Design, synthesis and biological evaluation as antiviral agents
In order to find novel antiviral agents, a series of allosteric MEK1 inhibitors were designed and synthesized. Based on docking results, multiple optimizations were made on the coumarin scaffold. Some of the derivatives showed excellent MEK1 binding affinity in the appropriate enzymatic assays and displayed obvious inhibitory effects on the ERK pathway in a cellular assay. These compounds also significantly inhibited virus (EV71) replication in HEK293 and RD cells. Several compounds showed potential as agents for the treatment of viral infective diseases, with the most potent compound 18 showing an IC 50 value of 54.57 nM in the MEK1 binding assay.
Wang, Chao,Zhang, Hao,Xu, Fengrong,Niu, Yan,Wu, Yun,Wang, Xin,Peng, Yihong,Sun, Jing,Liang, Lei,Xu, Ping
p. 6057 - 6091
(2013/06/27)

Enantioselective synthesis of α-alkyl-β-ketoesters: Asymmetric Roskamp reaction catalyzed by an oxazaborolidinium ion
Breaking kamp: A catalytic route toward chiral α-alkyl-β- ketoesters using the title reaction of α-alkyl diazoester with aldehydes has been developed (see scheme). The reaction proceeds with high to excellent enantioselectivities and this methodology was applied to a concise two-step synthesis of the natural pheromone sitophilate. Copyright
Gao, Lizhu,Kang, Byung Chul,Hwang, Geum-Sook,Ryu, Do Hyun
supporting information; experimental part
p. 8322 - 8325
(2012/09/08)

H5CoW12O40 supported on nano silica from rice husk ash: A green bifunctional catalyst for the reaction of alcohols with cyclic and acyclic 1,3-dicarbonyl compounds
Rice husk ash (RHA) is an abundant agricultural by-product. The present research work deals with the production of nano silica powders, with high surface area and in amorphous form, from RHA using optimized technique. 12-Tungestocobaltic acid, H5CoW12O40 (CoW), was supported on silica from RHA to produce silica supported CoW (CoW/NSiO 2) as a nano catalyst. The characterization data derived from FT-IR reveal that the Keggin structure of CoW remains intact in CoW/NSiO2. TEM image showed that the catalyst had spherical shape with an average particle size of 10 nm. The acidity of the catalyst was measured by potentiometric titration with n-butylamine. To our surprise, this very strong solid acid catalyst showed an excellent distribution of acid sites, suggesting that the catalyst possesses a higher number of surface active sites compared to CoW supported on commercial silica (CoW/SiO2), CoW and K 5CoW12O40. A high catalytic activity was found over CoW/NSiO2. Finally, CoW/NSiO2 has been used as a highly effective catalyst for benzylation of linear 1,3-dicarbonyl compounds with benzylic alcohols and synthesis of β-keto enol ethers from cyclic 1,3-dicarbonyl compounds. The present methodology offers a practical, simple, mild, environmentally friendly, and timesaving method under solvent-free conditions.
Rafiee, Ezzat,Khodayari, Maryam,Kahrizi, Masoud,Tayebee, Reza
experimental part
p. 121 - 128
(2012/06/01)

Different products in the reaction of the alcohols with cyclic and acyclic 1,3-dicarbonyl compounds: K5CoW12O40 as an electron transfer nano catalyst
K5CoW12O40 was used as a highly effective catalyst for the benzylation of 1,3-dicarbonyl compounds. β-Keto enol ethers were obtained when cyclic 1,3-dicarbonyl compounds used in this conditions instead of linear ones. The present methodology offers a practical, simple, mild, environmentally friendly, and time-saving method for etherification. Very low loading of catalyst, ease of workup, ease of handling, and reusability of catalyst are other advantages of this catalyst.
Rafiee, Ezzat,Kahrizi, Masoud,Joshaghani, Mohammad
p. 1363 - 1366
(2013/02/22)

Substrate range of the titanium TADDOLate catalyzed asymmetric fluorination of activated carbonyl compounds
The substrate range of the [TiCl2(TADDOLate)] (TADDOL=α,α,α′,α′-tetraaryl-1,3-dioxolane-4, 5-dimethanol)-catalyzed asymmetric α-fluorination of activated β-carbonyl compounds has been investigated. Optimal conditions for catalysis are characterized by using 5 mol-% of TiCl2(naphthalen-1- yl)-TADDOLate) as catalyst in a saturated (0.14 mol/l) MeCN solution of F-TEDA (1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis- [tetrafluoroborate]) at room temperature. A series of α-methylated β-keto esters (3-oxobutanoates, 3-oxopentanoates) with bulky benzyl ester groups (60-90% ee) or phenyl ester (67-88% ee) have been fluorinated readily, whereas α-acyl lactones were also readily fluorinated, but gave lower inductions (13-46% ee). Double stereochemical differentiation in β-keto esters with chiral ester groups raised the stereoselectivity to a diastereomeric ratio (dr) of up to 96.5:3.5. For the first time, β-keto S-thioesters were asymmetrically fluorinated (62-91.5% ee) and chlorinated (83% ee). Lower inductions were observed in fluorinations of 1,3-diketones (up to 40% ee) and β-keto amides (up to 59% ee). General strategies for preparing activated β-carbonyl compounds as important model substrates for asymmetric catalytic α-functionalizations are presented (>60 examples). Copyright
Bertogg, Andreas,Hintermann, Lukas,Huber, Dominique P.,Perseghini, Mauro,Sanna, Maria,Togni, Antonio
experimental part
p. 353 - 403
(2012/05/07)

12-Tungstophosphoric acid supported on nano silica from rice husk ash as an efficient catalyst for direct benzylation of 1,3-dicarbonyl compounds in solvent-free condition
Nano silica has been prepared from rice husk, which is an agricultural waste, with high surface area and in amorphous form. 12-Tungstophosphoric acid, H3PW12O40 (PW) has been supported on this silica to produce nano silica supported PW (NPW/SiO2) as a nano catalyst. Characterization of this catalyst has been investigated by TEM, FTIR, and ICP, also, acidic properties have been studied by potentiometric titration method. 40% NPW/SiO2 has been used as a high effective catalyst for benzylation of 1,3-dicarbonyl compounds with benzylic alcohols. The present methodology offers a clean, practical, simple, mild, environmentally friendly, green and time-saving method under solvent free condition. Also, the catalyst is a good candidate for large-scale in direct benzylation of 1,3-dicarbonyl compounds.
Rafiee, Ezzat,Khodayari, Maryam,Shahebrahimi, Shabnam,Joshaghani, Mohammad
experimental part
p. 204 - 209
(2012/02/03)

Direct benzylation of 1,3-dicarbonyl compounds catalyzed by Cs 2.5H0.5PW12O40 in solvent-free conditions
Various 1,3-dicarbonyl compounds reacted readily with benzylic alcohols in the presence of Cs2.5H0.5PW12O40 salt to produce 2-benzylic-1,3-dicarbonyl compounds in high yields. It was found that this catalyst could be completely recovered and reused without loss of its catalytic activities and is thus environmentally conscious especially in solvent-free conditions. The use of this method provides improved modification of the direct benzylation of 1,3-carbonyl compounds in terms of low reaction times, solvent-free conditions, usage of a small amount of the catalyst, and a clean reaction profile. Furthermore, the use of this catalyst is feasible because of its easy preparation, its easy handling, its stability, its easy recovery, its reusability, being environmentally green, its excellent activity, and its selectivity.
Rafiee, Ezzat,Khodayari, Maryam,Joshaghani, Mohammad
experimental part
p. 1533 - 1538
(2012/01/12)

Catalytic asymmetric roskamp reaction of α-Alkyl-α-diazoesters with aromatic aldehydes: Highly enantioselective synthesis of α-Alkyl-β-keto esters
The first catalytic enantioselective Roskamp reaction of α-alkyl-α-diazoesters with aromatic aldehydes was realized using a simple chiral N, N′-dioxide-scandium(III) complex. Remarkably, with 0.05 mol % catalyst, the reaction was performed well over a series of substrates, giving the desired products chemoselectively in excellent yields (up to 99%) and enantioselectivities (up to 98% ee) under mild conditions. This protocol provides a promising method for the synthesis of chiral α-alkyl-β- keto esters and 1,3-diols.
Li, Wei,Wang, Jun,Hu, Xiaolei,Shen, Ke,Wang, Wentao,Chu, Yangyang,Lin, Lili,Liu, Xiaohua,Feng, Xiaoming
supporting information; experimental part
p. 8532 - 8533
(2010/08/06)

Endochin optimization: Structure-activity and structure-property relationship studies of 3-substituted 2-Methyl-4(1 H)-quinolones with antimalarial activity
Since the 1940s endochin and analogues thereof were known to be causal prophylactic and potent erythrocytic stage agents in avian models. Preliminary screening in a current in vitro assay identified several 4(1H)-quinolones with nanomolar EC50 against erythrocytic stages of multidrug resistant W2 and TM90-C2B isolates of Plasmodium falciparum. Follow-up structure-activity relationship (SAR) studies on 4(1H)-quinolone analogues identified several key features for biological activity. Nevertheless, structure-property relationship (SPR) studies conducted in parallel revealed that 4(1H)-quinolone analogues are limited by poor solubilities and rapid microsomal degradations. To improve the overall efficacy, multiple 4(1H)-quinolone series with varying substituents on the benzenoid quinolone ring and/or the 3-position were synthesized and tested for in vitro antimalarial activity. Several structurally diverse 6-chloro-2-methyl-7-methoxy-4(1H)-quinolones with EC50 in the low nanomolar range against the clinically relevant isolates W2 and TM90-C2B were identified with improved physicochemical properties while maintaining little to no cross-resistance with atovaquone.
Cross, R. Matthew,Monastyrskyi, Andrii,Mutka, Tina S.,Burrows, Jeremy N.,Kyle, Dennis E.,Manetsch, Roman
scheme or table
p. 7076 - 7094
(2010/12/25)

Coumarins as novel 17β-hydroxysteroid dehydrogenase type 3 inhibitors for potential treatment of prostate cancer
The synthesis and SAR studies of 3- and 4-substituted 7-hydroxycoumarins as novel 17β-HSD3 inhibitors are discussed. The most potent compounds from this series exhibited low nanomolar inhibitory activity with acceptable selectivity versus other 17β-HSD isoenzymes and nuclear receptors.
Harada, Koichiro,Kubo, Hideki,Tomigahara, Yoshitaka,Nishioka, Kazuhiko,Takahashi, Junya,Momose, Mio,Inoue, Shinichi,Kojima, Atsuyuki
scheme or table
p. 272 - 275
(2010/04/06)

Novel synthesis of 5-substituted-3-phenylindole-2-(1,2,4-triazole) derivatives
Various substituted 3-phenylindole 2-carboxylates (1a-c) were prepared according to the literature methods. These carboxylates (1a-c) on reaction with thiosemicarbazide yielded 5-substituted-3-phenylindol-2-(1,2,4-triazole-3- thione) (2a-c) on refluxing in pyridine for 8 h. The 5-substituted-3- phenylindole-2-[1,2,4-triazolo-3-thioacetic acid] (3a-c) were prepared from 5-substituted-3-phenyl indole-2-[1,2,4-triazole-3-thione] (2a-c) on reaction with an appropriate alkylating agent and sodium acetate in acetic acid. Further, (3a-c) were reacted with acetic anhydride to bring about a cyclocondensation reaction to yield 5-substituted-3-phenylindol-2-thiazolo(2,3-b)-triazole (4a-c). The 5-substituted-3-phenylindole-2-[1,2,4-triazolo-3-acetic acid] (3a-c) were reacted with o-phenylenediamino dihydrochloride in ethylene glycol to yield 5-substituted-3-phenylindole-1,2,4-triazolo-3′-yl-thiomethyl) benzimidazoles (5a-c). Copyright Taylor & Francis Group, LLC.
Sharma, P. M. Veeresha,Purohit
p. 1381 - 1388
(2008/09/20)

An unusual dianion equivalent from acylsilanes for the synthesis of substituted β-keto esters
The reaction of lithiated diazo esters with acylsilanes generates a remarkable intermediate en route to highly substituted β-keto esters. The Royal Society of Chemistry.
Galliford, Chris V.,Scheidt, Karl A.
p. 1926 - 1928
(2008/12/22)

Asymmetric synthesis of β2-amino acids: 2-substituted-3-aminopropanoic acids from N-acryloyl SuperQuat derivatives
Conjugate addition of lithium dibenzylamide to (S)-N(3)-acryloyl-4- isopropyl-5,5-dimethyloxazolidin-2-one (derived from l-valine) and alkylation of the resultant lithium β-amino enolate provides, after deprotection, a range of (S)-2-alkyl-3-aminopropanoic acids in good yield and high ee. Alternatively, via a complementary pathway, conjugate addition of a range of secondary lithium amides to (S)-N(3)-(2′-alkylacryloyl)-4-isopropyl-5,5- dimethyloxazolidin-2-ones, diastereoselective protonation with 2-pyridone, and subsequent deprotection furnishes a range of (R)-2-alkyl- and (R)-2-aryl-3-aminopropanoic acids in good yield and high ee. Additionally, the boron-mediated aldol reaction of β-amino N-acyl oxazolidinones is a highly diastereoselective method for the synthesis of a range of β-amino- β′-hydroxy N-acyl oxazolidinones. The Royal Society of Chemistry.
Beddow, James E.,Davies, Stephen G.,Ling, Kenneth B.,Roberts, Paul M.,Russell, Angela J.,Smith, Andrew D.,Thomson, James E.
p. 2812 - 2825
(2008/03/12)

Triketoacid inhibitors of HIV-integrase: A new chemotype useful for probing the integrase pharmacophore
Integrase is one of three enzymes expressed by HIV and represents a validated target for therapy. This study reports on the discovery of a new triketoacid-based chemotype that selectively inhibits the strand transfer reaction of HIV-integrase. SAR studies showed that the template binds to integrase in a manner similar to the diketoacid-based inhibitors. Moreover, comparison of the new chemotype to two different diketoacid templates led us to propose two aryl-binding domains in the inhibitor binding site. This information was used to design a new diketoacid template with improved activity against the enzyme.
Walker, Michael A.,Johnson, Timothy,Ma, Zhuping,Banville, Jacques,Remillard, Roger,Kim, Oak,Zhang, Yunhui,Staab, Andrew,Wong, Henry,Torri, Albert,Samanta, Himadri,Lin, Zeyu,Deminie, Carol,Terry, Brian,Krystal, Mark,Meanwell, Nicholas
p. 2920 - 2924
(2007/10/03)

Efficient synthesis of enantiomerically pure β2-amino acids via chiral isoxazolidinones
We report a practical and scalable synthetic route for the preparation of α-substituted β-amino acids (β2-amino acids). Michael addition of a chiral hydroxylamine, derived from α-methylbenzylamine, to an α-alkylacrylate followed by cyclization gives a diastereomeric mixture of α-substituted isoxazolidinones. These diastereomers are separable by column chromatography. Subsequent hydrogenation of the purified isoxazolidinones followed by Fmoc protection affords enantiomerically pure Fmoc-β2-amino acids, which are useful for β-peptide synthesis. This route provides access to both enantiomers of a protected β2-amino acid.
Lee, Hee-Seung,Park, Jin-Seong,Kim, Byeong Moon,Gellman, Samuel H.
p. 1575 - 1578
(2007/10/03)

Synthesis of optically pure (S)-2-acetylthio-3-benzenepropanoic acid via enzymatic resolution
A method of synthesizing optically pure (S)-2-acetylthio-3-benzenepropanoic acid has been developed and good to excellent enantiomeric excess achieved via enzymatic resolution.
Zhu, Jingyang,You, Li,Zhao, Shannon X,White, Brenda,Chen, Jason G,Skonezny, Paul M
p. 7585 - 7587
(2007/10/03)

Beta-ketoester compounds
The beta-ketoesters of formula I are useful as precursors for organoleptic compounds, especially for flavors, fragrances and masking agents and antimicrobial compounds.
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(2010/11/30)