- Preparation of mono-substituted malonic acid half oxyesters (SMAHOs)
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The use of mono-substituted malonic acid half oxyesters (SMAHOs) has been hampered by the sporadic references describing their preparation. An evaluation of different approaches has been achieved, allowing to define the best strategies to introduce diversity on both the malonic position and the ester function. A classical alkylation step of a malonate by an alkyl halide followed by a monosaponification gave access to reagents bearing different substituents at the malonic position, including functionalized derivatives. On the other hand, the development of a monoesterification step of a substituted malonic acid derivative proved to be the best entry for diversity at the ester function, rather than the use of an intermediate Meldrum acid. Both these transformations are characterized by their simplicity and efficiency, allowing a straightforward access to SMAHOs from cheap starting materials.
- Condon, Sylvie,Le Gall, Erwan,Pichon, Christophe,Presset, Marc,Xavier, Tania
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supporting information
p. 2085 - 2094
(2021/09/02)
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- Xanthenylacetic Acid Derivatives Effectively Target Lysophosphatidic Acid Receptor 6 to Inhibit Hepatocellular Carcinoma Cell Growth
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Despite the increasing incidence of hepatocellular carcinoma (HCC) worldwide, current pharmacological treatments are still unsatisfactory. We have previously shown that lysophosphatidic acid receptor 6 (LPAR6) supports HCC growth and that 9-xanthenylacetic acid (XAA) acts as an LPAR6 antagonist inhibiting HCC growth without toxicity. Here, we synthesized four novel XAA derivatives, (±)-2-(9H-xanthen-9-yl)propanoic acid (compound 4 – MC9), (±)-2-(9H-xanthen-9-yl)butanoic acid (compound 5 – MC6), (±)-2-(9H-xanthen-9-yl)hexanoic acid (compound 7 – MC11), and (±)-2-(9H-xanthen-9-yl)octanoic acid (compound 8 – MC12, sodium salt) by introducing alkyl groups of increasing length at the acetic α-carbon atom. Two of these compounds were characterized by X-ray powder diffraction and quantum mechanical calculations, while molecular docking simulations suggested their enantioselectivity for LPAR6. Biological data showed anti-HCC activity for all XAA derivatives, with the maximum effect observed for MC11. Our findings support the view that increasing the length of the alkyl group improves the inhibitory action of XAA and that enantioselectivity can be exploited for designing novel and more effective XAA-based LPAR6 antagonists.
- Gnocchi, Davide,Cavalluzzi, Maria M.,Mangiatordi, Giuseppe F.,Rizzi, Rosanna,Tortorella, Cosimo,Spennacchio, Mauro,Lentini, Giovanni,Altomare, Angela,Sabbà, Carlo,Mazzocca, Antonio
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p. 2121 - 2129
(2021/06/07)
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- Synthesis of Cyclopentenones through Rhodium-Catalyzed C-H Annulation of Acrylic Acids with Formaldehyde and Malonates
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An efficient rhodium-catalyzed protocol for the synthesis of cyclopentenones based on a three-component reaction of acrylic acids, formaldehyde, and malonates via vinylic C-H activation is reported. Exploratory studies showed that 5-alkylation of as-prepared cyclopentenones could be realized smoothly by the treatment of a variety of alkyl halides with a Na2CO3/MeOH solution. Excess formaldehyde and malonate led to a multicomponent reaction that afforded the multisubstituted cyclopentenones through a Michael addition.
- Yu, Shuling,Hong, Chao,Liu, Zhanxiang,Zhang, Yuhong
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supporting information
p. 5054 - 5059
(2021/07/20)
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- Macrolactam Synthesis via Ring-Closing Alkene-Alkene Cross-Coupling Reactions
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Reported herein is a practical method for macrolactam synthesis via a Rh(III)-catalyzed ring closing alkene-alkene cross-coupling reaction. The reaction proceeded via a Rh-catalyzed alkenyl sp2 C-H activation process, which allows access to macrocyclic molecules of different ring sizes. Macrolactams containing a conjugated diene framework could be easily prepared in high chemoselectivities and Z,E stereoselectivities.
- Goh, Jeffrey,Loh, Teck-Peng,Maraswami, Manikantha
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supporting information
p. 9724 - 9728
(2020/12/21)
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- Iodonium Ylides as Carbene Precursors in Rh(III)-Catalyzed C-H Activation
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The rhodium(III)-catalyzed coupling of C-H substrates with iodonium ylides has been realized for the efficient synthesis of diverse cyclic skeletons, where the iodonium ylides have been identified as efficient and outstanding carbene precursors. The reaction systems are applicable to both sp2 and sp3 C-H substrates under mild and redox-neutral conditions. The catalyst loading can be as low as 0.5 mol % in a gram-scale reaction. Representative products exhibit cytotoxicity toward human cancer cells at nanomolar levels.
- Jiang, Yuqin,Li, Pengfei,Li, Xingwei,Liu, Bingxian,Zhao, Jie
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supporting information
p. 7475 - 7479
(2020/10/12)
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- Exploring the Promiscuous Enzymatic Activation of Unnatural Polyketide Extender Units in Vitro and in Vivo for Monensin Biosynthesis
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The incorporation of new-to-nature extender units into polyketide synthesis is an important source for diversity yet is restricted by limited availability of suitably activated building blocks in vivo. We here describe a straightforward workflow for the biogenic activation of commercially available new-to-nature extender units. Firstly, the substrate scope of a highly flexible malonyl co-enzyme A synthetase from Streptomyces cinnamonensis was characterized. The results were matched by in vivo experiments in which the said extender units were accepted by both the polyketide synthase and the accessory enzymes of the monensin biosynthetic pathway. The experiments gave rise to a series of predictable monensin derivatives by the exploitation of the innate substrate promiscuity of an acyltransferase and downstream enzyme functions.
- Grote, Marius,Schulz, Frank
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p. 1183 - 1189
(2019/03/11)
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- Copper-catalyzed intermolecular chloro- and bromotrifluoromethylation of alkenes
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A highly practical copper-catalyzed intermolecular halotrifluoromethylation of alkenes has been developed under mild reaction conditions. A variety of Cl/Br-containing trifluoromethyl derivatives were directly synthesized from a wide range of alkenes, including electron-deficient and unactivated alkenes.
- Fu, Mingyang,Chen, Long,Jiang, Yongpeng,Jiang, Zhong-Xing,Yang, Zhigang
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supporting information
p. 348 - 351
(2016/02/19)
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- Synthesis, antibacterial activity, and biological evaluation of formyl hydroxyamino derivatives as novel potent peptide deformylase inhibitors against drug-resistant bacteria
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Peptide deformylase (PDF) has been identified as a promising target for novel antibacterial agents. In this study, a series of novel formyl hydroxyamino derivatives were designed and synthesized as PDF inhibitors and their antibacterial activities were evaluated. Among the potent PDF inhibitors (1o, 1q, 1o′, 1q′, and 1x), in vivo studies showed that compound 1q possesses mild toxicity, a good pharmacokinetic profile and protective effects. The good in vivo efficacy and low toxicity suggest that this class of compounds has potential for development and use in future antibacterial drugs.
- Yang, Shouning,Shi, Wei,Xing, Dong,Zhao, Zheng,Lv, Fengping,Yang, Liping,Yang, Yushe,Hu, Wenhao
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p. 133 - 152
(2014/10/15)
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- Organocatalytic enantioselective transient enolate protonation in conjugate addition of thioacetic acid to a-substituted n-acryloyloxazolidinones
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Organocatalytic conjugate addition of thioacetic acid to a series of a-substituted N-acryloyloxazolidin-2- ones followed by enantioselective protonation has been studied in the presence of thiourea catalysts derived from cinchona alkaloids. Conjugate addition/protonation adducts have been obtained up to 97% ee and high yields. The methodology could serve as an easy and practical route to the syntheses of useful biologically active molecules.
- Unhale, Rajshekhar A.,Rana, Nirmal K.,Singh, Vinod K.
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supporting information
p. 1911 - 1915
(2013/05/23)
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- Production of peroxycarboxylic acids
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Provided are various methods, systems and reactors for producing peroxycarboxylic acid compositions, such as non-equilibrium compositions of peracetic acid, for example. The methods and systems relate to electrolytic generation of hydrogen peroxide or peroxide ions in a reactor, wherein the generated materials are reacted with an acetyl donor to form peracetic acid. In an embodiment, a source of alkali metal ions is provided to an anode chamber such that the ratio of concentrations of the alkali metal ions to protons in the anode chamber of a reactor is greater than 1.
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Page/Page column 27-28
(2012/12/13)
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- Expanding the utility of Bronsted base catalysis: Biomimetic enantioselective decarboxylative reactions
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As a result of the low reactivity of simple esters, the use of them as nucleophiles in direct asymmetric transformations is a long-standing challenge in synthetic organic chemistry. Nature approaches this difficulty through a decarboxylative mechanism, which is used for polyketide synthesis. Inspired by nature, we report guanidine-catalyzed biomimetic decarboxylative C-C and C-N bond-formation reactions. These highly enantioselective decarboxylative Mannich and amination reactions utilized malonic acid half thioesters as simple ester surrogates. It is proposed that nucleophilic addition precedes decarboxylation in the mechanism, which has been investigated in detail through the identification of intermediates by using electrospray ionization (ESI) mass-spectrometric analysis and DFT calculations. Copyright
- Pan, Yuanhang,Kee, Choon Wee,Jiang, Zhiyong,Ma, Ting,Zhao, Yujun,Yang, Yuanyong,Xue, Hansong,Tan, Choon-Hong
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supporting information; experimental part
p. 8363 - 8370
(2011/09/13)
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- Design, synthesis, and antibacterial activity of 2,5-dihydropyrrole formyl hydroxyamino derivatives as novel peptide deformylase inhibitors
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The synthesis and antibacterial activity of 2,5-dihydropyrrole formyl hydroxyamino derivatives are reported. The antibacterial activities of these derivatives were evaluated, and some of these derivatives showed better in vitro antibacterial activity than existing drugs, including penicillin, ciprofloxacin, vancomycin, and linezolid.
- Shi, Wei,Duan, Yuejiao,Qian, Yu,Li, Ming,Yang, Liping,Hu, Wenhao
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scheme or table
p. 3592 - 3595
(2010/09/06)
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- Peptide deformylase inhibitors of Mycobacterium tuberculosis: Synthesis, structural investigations, and biological results
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Bacterial peptide deformylase (PDF) belongs to a subfamily of metalloproteases catalyzing the removal of the N-terminal formyl group from newly synthesized proteins. We report the synthesis and biological activity of highly potent inhibitors of Mycobacterium tuberculosis (Mtb) PDF enzyme as well as the first X-ray crystal structure of Mtb PDF. Structure-activity relationship and crystallographic data clarified the structural requirements for high enzyme potency and cell based potency. Activities against single and multi-drug-resistant Mtb strains are also reported.
- Pichota, Arkadius,Duraiswamy, Jeyaraj,Yin, Zheng,Keller, Thomas H.,Alam, Jenefer,Liung, Sarah,Lee, Gladys,Ding, Mei,Wang, Gang,Chan, Wai Ling,Schreiber, Mark,Ma, Ida,Beer, David,Ngew, Xinyi,Mukherjee, Kakoli,Nanjundappa, Mahesh,Teo, Jeanette W.P.,Thayalan, Pamela,Yap, Amelia,Dick, Thomas,Meng, Wuyi,Xu, Mei,Koehn, James,Pan, Shi-Hao,Clark, Kirk,Xie, Xiaoling,Shoen, Carolyn,Cynamon, Michael
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scheme or table
p. 6568 - 6572
(2009/09/30)
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- A simple method for the alkaline hydrolysis of esters
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A very mild and rapid procedure for the efficient alkaline hydrolysis of esters in non-aqueous conditions has been developed, by the use of dichloromethane/methanol (9:1) as solvent. This method conveniently provides both carboxylic acids and alcohols from the corresponding esters and sodium hydroxide in a few minutes at room temperature. A plausible reaction mechanism is proposed.
- Theodorou, Vassiliki,Skobridis, Konstantinos,Tzakos, Andreas G.,Ragoussis, Valentine
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p. 8230 - 8233
(2008/03/14)
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- Microwave assisted hydrolysis of Meldrum's acid derivatives and decarboxylation of derived malonic acids
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Microwave induced hydrolysis of alkyl Medrum's acids and decarboxylation of derived malonic acids using poly-4-vinylpyridine as a catalyst gives high yields of carboxylic acids in a short time.
- Helavi,Solabannavar,Desai,Mane
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p. 174 - 175
(2007/10/03)
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- 1,1-Alkanediol dicarboxylate linked antibacterial agents
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Useful antibacterial agents in which a penicillin and/or a beta-lactamase inhibitor are linked via 1,1-alkanediol dicarboxylates are of the formula STR1 where A is the residue of certain dicarboxyic acids, R3 is H or (C1 -C3), n is zero or 1 such that when n is zero R is P or B and R1 is the residue of certain esters, H or a salt thereof; and when n is 1, one of R and R1 is P and the other is B, and P is STR2 where R2 is H or certain acyl groups, and B is the residue of a beta-lactamase inhibiting carboxylic acid; a method for their use, pharmaceutical compositions thereof and intermediates useful in their production.
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- Bis-esters of dicarboxylic acids with amoxicillin and certain hydroxymethylpenicillanate 1,1-dioxides
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Antibacterial bis-esters of 1,4-cyclohexanedicarboxylic acids and alkane dicarboxylic acids wherein the ester moieties are derived from different alcohols; one alcohol being hydroxymethylpenicillanate 1,1-dioxide, or the 6-beta-hydroxymethyl or the 6-alpha-aminomethyl derivative thereof; and the other being 6-[D-(2-amino-2-(p-hydroxyphenyl)acetamido)]penicillanic acid (amoxicillin); and pharmaceutically acceptable salts thereof; a method for the use of said esters and their salts, and methods for their preparation.
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