- Mild Darzens Annulations for the Assembly of Trifluoromethylthiolated (SCF3) Aziridine and Cyclopropane Structures
-
We report mild new annulation approaches to trisubstituted trifluoromethylthiolated (SCF3) aziridines and cyclopropanes via Darzens inspired protocols. The products of these anionic annulations, rarely studied previously, possess attractive features rendering them valuable building blocks for synthesis platforms. In this study, trisubstituted acetophenone nucleophiles bearing SCF3 and bromine substituents in their α position were shown to undergo [2 + 1] annulations with vinyl ketones and tosyl-protected imines under mild reaction conditions.
- Delost, Michael D.,Njardarson, Jon T.
-
p. 6121 - 6125
(2021/08/16)
-
- Design and synthesis of Mannich base-type derivatives containing imidazole and benzimidazole as lead compounds for drug discovery in Chagas Disease
-
The protozoan parasite Trypanosoma cruzi is the causative agent of Chagas disease, the most important parasitic infection in Latin America. The only treatments currently available are nitro-derivative drugs that are characterised by high toxicity and limited efficacy. Therefore, there is an urgent need for more effective, less toxic therapeutic agents. We have previously identified the potential for Mannich base derivatives as novel inhibitors of this parasite. To further explore this family of compounds, we synthesised a panel of 69 new analogues, based on multi-parametric structure-activity relationships, which allowed optimization of both anti-parasitic activity, physicochemical parameters and ADME properties. Additionally, we optimized our in vitro screening approaches against all three developmental forms of the parasite, allowing us to discard the least effective and trypanostatic derivatives at an early stage. We ultimately identified derivative 3c, which demonstrated excellent trypanocidal properties, and a synergistic mode of action against trypomastigotes in combination with the reference drug benznidazole. Both its druggability and low-cost production make this derivative a promising candidate for the preclinical, in vivo assays of the Chagas disease drug-discovery pipeline.
- Atherton, Richard L.,Kelly, John M.,Olmo, Francisco,Sanz-Serrano, Julen,Alcolea, Verónica,Beltran-Hortelano, Iván,Pérez-Silanes, Silvia,Rubio-Hernández, Mercedes
-
-
- Manganese-Catalyzed Ring-Opening Coupling Reactions of Cyclopropanols with Enones
-
A manganese-catalyzed ring-opening coupling reaction of cyclopropanols with enones for the facile and efficient preparation of 1,6-diketones is described. A wide array of synthetically important 1,6-diketones bearing manifold functional groups are obtained with up to 93% yield. These reactions feature broad substrate scopes, environmentally benign conditions, inexpensive catalyst, and operational simplicity.
- Zhang, Yong-Hui,Zhang, Wen-Wei,Zhang, Ze-Yu,Zhao, Kai,Loh, Teck-Peng
-
p. 5101 - 5105
(2019/07/03)
-
- Structural Modification of Natural Product Ganomycin i Leading to Discovery of a α-Glucosidase and HMG-CoA Reductase Dual Inhibitor Improving Obesity and Metabolic Dysfunction in Vivo
-
It is a great challenge to develop drugs for treatment of metabolic syndrome. With ganomycin I as a leading compound, 14 meroterpene derivatives were synthesized and screened for their α-glucosidase and HMG-CoA reductase inhibitory activities. As a result, a α-glucosidase and HMG-CoA reductase dual inhibitor ((R,E)-5-(4-(tert-butyl)phenyl)-3-(4,8-dimethylnona-3,7-dien-1-yl)furan-2(5H)-one, 7d) with improved chemical stability and long-term safety was obtained. Compound 7d showed multiple and strong in vivo efficacies in reducing weight gain, lowering HbAlc level, and improving insulin resistance and lipid dysfunction in both ob/ob and diet-induced obesity (DIO) mice models. Compound 7d was also found to reduce hepatic steatosis in ob/ob model. 16S rRNA gene sequencing, SCFA, and intestinal mucosal barrier function analysis indicated that gut microbiota plays a central and causative role in mediating the multiple efficacies of 7d. Our results demonstrate that 7d is a promising drug candidate for metabolic syndrome.
- Wang, Kai,Bao, Li,Zhou, Nan,Zhang, Jinjin,Liao, Mingfang,Zheng, Zhongyong,Wang, Yujing,Liu, Chang,Wang, Jun,Wang, Lifeng,Wang, Wenzhao,Liu, Shuangjiang,Liu, Hongwei
-
p. 3609 - 3625
(2018/05/01)
-
- Indium(III)-Catalyzed Hydration and Hydroalkoxylation of α,β-Unsaturated Ketones in Aqueous Media
-
The hydration of α,β-unsaturated ketones with water proceeded efficiently in the presence of In(OTf)3 (20 mol%) in aqueous media to afford synthetically versatile β-hydroxyketones in moderate to good yields with good functional group compatibility. The method also can be extended to the hydroalkoxylation of α,β-unsaturated ketones with various alcohols for the efficient synthesis of β-alkoxyketones as well as tetrahydrofuran derivatives. (Figure presented.).
- Yun, Jin-Jin,Zhi, Man-Ling,Shi, Wen-Xiao,Chu, Xue-Qiang,Shen, Zhi-Liang,Loh, Teck-Peng
-
supporting information
p. 2632 - 2637
(2018/05/30)
-
- Chromium(III)-Catalyzed Addition of Water and Alcohol to α,β-Unsaturated Ketones for the Synthesis of β-Hydroxyl and β-Alkoxyl Ketones in Aqueous Media
-
An efficient chromium(III) chloride-catalyzed Michael-type reaction of water or alcohol with α,β-unsaturated ketones is developed. A variety of α,β-unsaturated ketones effectively reacted with either water or alcohols to give the corresponding β-hydroxyl ketones or β-alkoxyl ketones in modest to high yields with excellent compatibility to various functional groups. The approach was further utilized for the preparation of synthetically useful compounds containing tetrahydrofuran skeleton.
- Yun, Jin-Jin,Liu, Xuan-Yu,Deng, Wei,Chu, Xue-Qiang,Shen, Zhi-Liang,Loh, Teck-Peng
-
p. 10898 - 10907
(2018/09/06)
-
- The Pharmacological Heterogeneity of Nepenthone Analogs in Conferring Highly Selective and Potent κ-Opioid Agonistic Activities
-
To develop novel analgesics with no side effects or less side effects than traditional opioids is highly demanded to treat opioid receptor mediated pain and addiction issues. Recently, κ-opioid receptor (KOR) has been established as an attractive target,
- Li, Wei,Long, Jian-Dong,Qian, Yuan-Yuan,Long, Yu,Xu, Xue-Jun,Wang, Yu-Jun,Shen, Qing,Wang, Zuo-Neng,Yang, Xi-Cheng,Xiao, Li,Sun, Hong-Peng,Xu, Yu-Long,Chen, Yi-Yi,Xie, Qiong,Wang, Yong-Hui,Shao, Li-Ming,Liu, Jing-Gen,Qiu, Zhui-Bai,Fu, Wei
-
p. 766 - 776
(2017/04/26)
-
- Morita-Baylis-Hillman Reaction of α,β-Unsaturated Ketones with Allylic Acetates by the Combination of Transition-Metal Catalysis and Organomediation
-
An intermolecular Morita-Baylis-Hillman (MBH) reaction of α,β-unsaturated ketones with allylic acetates under the catalysis of 10 mol % of tetrakis(triphenylphosphine)palladium(0) and mediation of tributylphosphine has been developed in the presence of acetic acid, affording the desired α-coupling products. The MBH reaction has the advantages of good tolerance to many functional groups, excellent regioselectivity and E-stereoselectivity, and moderate to good yields.
- Li, Ya-Qiong,Wang, Hai-Jun,Huang, Zhi-Zhen
-
p. 4429 - 4433
(2016/07/06)
-
- Fluorine-containing three-membered ring compound, preparation method of fluorine-containing three-membered ring compound and preparation method of fluoroalkyl sulfonium salt
-
The invention discloses a fluorine-containing three-membered ring compound shown in the formula V-a, V-b or V-c and a preparation method thereof. The preparation method comprises that in an organic solvent, fluoroalkyl sulfur ylide shown in the formula II
- -
-
Paragraph 0172; 0173; 0174; 0175; 0180; 0181
(2016/10/08)
-
- Diastereoselective Johnson-Corey-Chaykovsky trifluoroethylidenation
-
(2,2,2-Trifluoroethyl)diphenylsulfonium triflate was found to be an efficient ylide reagent for the Johnson-Corey-Chaykovsky reaction to afford trifluoromethyl epoxides, cyclopropanes and aziridines. Interestingly, excellent but different diastereoselectivity was observed for these transformations. Both trifluoromethyl epoxides and cyclopropanes were obtained with trans-selectivity, whereas aziridines were obtained with cis-selectivity.
- Duan, Yaya,Zhou, Bin,Lin, Jin-Hong,Xiao, Ji-Chang
-
supporting information
p. 13127 - 13130
(2015/08/18)
-
- New pyridin-3-ylmethyl carbamodithioic esters activate pyruvate kinase M2 and potential anticancer lead compounds
-
Pyruvate kinase M2 (PKM2) is a key protein responsible for cancer's Warburg effect. Activation of PKM2 may alter aberrant metabolism in cancer cells, which suggests PKM2 as a tumor selective therapeutic target. In this paper, the lead compound 8 was first discovered as a new kind of PKM2 activator from a random screening of an in-house compound library. Then, a series of lead compound 8 analogs were designed, synthesized and evaluated for their activation of PKM2 and anticancer activities. 7-Azaindole analog 32 was identified as the most potent PKM2 activator. Compounds with potent enzyme activity also exhibited selective anti-proliferation activity on cancer cell lines HCT116, Hela and H1299 compared with non-tumor cell line BEAS-2B. The structure-activity relationships of these compounds were supported by molecular docking results. Preliminary pharmacological studies also showed that compound 32 arrests the cell cycle at the G2/M phase in HCT116 cell line.
- Zhang, Yu,Liu, Bin,Wu, Xingyu,Lei, Ridong,Ning, Xianling,Liu, Yu,Liu, Zhenming,Ge, Zemei,Li, Runtao,Yin, Yuxin
-
p. 4815 - 4823
(2015/08/03)
-
- Desulfonylative Methenylation of β-Keto Sulfones
-
A one-step strategy for the synthesis of α-methenyl ketones from β-keto sufones is reported. Success of the methodology is elaborated for the synthesis of chromanones and isoflavanones in one-step.
- Pandey, Ganesh,Vaitla, Janakiram
-
supporting information
p. 4890 - 4893
(2015/10/12)
-
- Enantioselective synthesis of 3-substituted 1,2-oxazinanes via organocatalytic intramolecular aza-Michael addition
-
A highly enantioselective intramolecular 6-exo-trig aza-Michael addition was developed to afford chiral 3-substituted 1,2-oxazinanes in high yields (up to 99% yield) and good enantioselectivities (up to 98/2 er). These reactions were enabled by a quinine-derived primary-tertiary diamine as a catalyst and pentafluoropropionic acid (PFP) as a co-catalyst.
- Cheng, Shuanghua,Yu, Shouyun
-
p. 8607 - 8610
(2014/12/10)
-
- Boron-trihalide-promoted regioselective ring-opening reactions of gem-difluorocyclopropyl ketones
-
Boron trihalide-promoted ring-opening reactions of gem-difluorocyclopropyl ketones to give the corresponding β-trifluoromethyl ketones and β-halodifluoromethyl ketones were described. It was found that boron trihalides act as both Lewis acids and nucleophiles and the proximal bond prefers to cleave in this transformation.
- Yang, Tang-Po,Li, Qiang,Lin, Jin-Hong,Xiao, Ji-Chang
-
supporting information
p. 1077 - 1079
(2014/01/17)
-
- Facile 1,3-diaza-Claisen rearrangements of tertiary allylic amines bearing an electron-deficient alkene
-
(Chemical Equation Presented) Tertiary allylic amines with an electron-deficient alkene react with isocyanates and isothiocyanates to give highly substituted ureas and thioureas arising from formal 1,3-diaza-Claisen rearrangements. Isocyanates and isothiocyanates with strong electron-withdrawing groups are more reactive. Similarly, the data suggest that a stronger electron-withdrawing substituent on the alkene favors a faster reaction, but this may be offset by sterlcs in the cyclic transition state.
- Aranha, Rachel M.,Bowser, Amy M.,Madalengoitia, Jose S.
-
supporting information; experimental part
p. 575 - 578
(2009/07/18)
-
- 7-PHENYL-ISOQUINOLINE-5-SULFONYLAMINO DERIVATIVES AS INHIBITORS OF AKT (PROTEINKINASE B)
-
The present invention relates to compounds Formula (I) as inhibitors of AKT activity, which are useful for the treatment of susceptible neoplasms and viral infections.
- -
-
Page/Page column 35
(2010/02/12)
-
- Non-steroid and non-prostanoid inhibitors of steroid and prostaglandin transforming enzymes
-
Compounds such as 1-(4'-nitrophenyl)-2-propen-1-ol are disclosed which are non-steroidal mechanism-based inactivators of rat liver 3α-hydroxysteroid dehydrogenase. The corresponding ketones are time dependent inactivators of cyclooxygenase (PGH2 -synthase).
- -
-
-
- KETONE SYNTHESIS VIA PALLADIUM-CATALYZED CARBONYLATION OF ORGANOALUMINIUM COMPOUNDS
-
Arylaluminium compounds react with aryl iodides and carbon monoxide in the presence of palladium complex to produce unsymmetrical ketones.
- Bumagin, N. A.,Ponomaryov, A. B.,Beletskaya, I. P.
-
p. 4819 - 4822
(2007/10/02)
-
- Synthetic Utility of the Palladium-Catalyzed Coupling Reaction of Acid Chlorides with Organotins
-
The palladium coupling of acid chlorides with unsymmetrical organotin reagents R''3SnR' can be carried out in chloroform under mild conditions in high yields to give the ketone RCOR'in which only one of the four organic groups on tin appears in the ketone product.Alkyl partners (R''= methyl or butyl) on tin serve as anchoring groups and do not transfer.When R' is acetylenic, vinyl, aryl, methoxymethylene, allyl, or benzyl, transmetalation takes place preferentially, resulting in coupling with the acyl group from the acid chloride.The reaction is tolerant of functional groups both on the acid chloride and the tin reagent.A palladium-catalyzed coupling reaction of an organotin reagent bearing acrylate functionality with an acid chloride serves as a method to introduce both a ketone and an acrylate functionality into a carbon framework.The coupling reaction of 4-(tert-butyldiphenylsiloxy)pentanoyl chloride with benzyl 3-(tributylstannyl)acrylate gave a 71percent yield of benzyl 7-(tert-butyldiphenylsiloxy)-4-oxo-2-octenoate, a precursor to the macrolide antibiotic pyrenophorin.
- Labadie, Jeff W.,Tueting, David,Stille, J. K.
-
p. 4634 - 4642
(2007/10/02)
-
- REACTION OF ORGANOMETALLIC COMPOUNDS CATALYZED BY TRANSITION METAL COMPLEXES. III. THE ACYLDEMETALLATION OF ORGANOTIN COMPOUNDS CATALYZED BY BIS(?-ALLYLPALLADIUM CHLORIDE)
-
A study was carried out on the reaction of organotin compounds RSnMe3 with carboxylic acid chlorides R'COCl (R'=Me, PhCH2, PhCH=CH, Ph, o-FC6H4, p-ClCOC6H4, p-NO2C6H4) catalyzed by bis(?-allylpalladium chloride) in hexametapol and acetone.The reaction proceeds at room temperature and gives high yields of asymmetrical ketones RCOR'.The stoichiometry of the reaction of PhCOPdCl(PPh3)2 with PhSnMe3 was studied.A possible mechanism for the catalytic acyldemetallation reaction was discussed.
- Bumagin, N. A.,Bumagina, I. G.,Kashin, A. N.,Beletskaya, I. P.
-
p. 977 - 981
(2007/10/02)
-
- The Acid-catalyzed Decomposition of α-Diazo β-Hydroxy Ketones
-
The proton acid-catalyzed decomposition of 3-aryl-2-diazo-3-hydroxy-1-phenylpropanone (1) gave aryl and hydrogen migration products.The former was the enol-form (2) of 2-aryl-3-phenyl-1,3-propanedione and the latter was the enol- (3) and keto-form (4) of 1-aryl-3-phenyl-1,3-propanedione.The product ratios, 2/(3+4), were affected by the catalysts and solvents used.More polar solvents favored the formation of aryl migration products (2).On the other hand, the BF3-catalyzed decomposition of 1 gave acetylenic ketones as main products along with 2, 3, 4.The TsOH-catalyzed decomposition of 2-diazo-3-hydroxy-3-phenyl-1-indanone, (cyclic α-diazo β-hydroxy ketone), gave 2-phenyl-1,3-indandione quantitatively through phenyl migration.
- Miyauchi, Kazuo,Hori, Kimiaki,Hirai, Tsuguji,Takebayashi, Matsuji,Ibata, Toshikazu
-
p. 2142 - 2146
(2007/10/02)
-