- 2-(Halogenated Phenyl) acetamides and propanamides as potent TRPV1 antagonists
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A series consisting of 117 2-(halogenated phenyl) acetamide and propanamide analogs were investigated as TRPV1 antagonists. The structure–activity analysis targeting their three pharmacophoric regions indicated that halogenated phenyl A-region analogs exhibited a broad functional profile ranging from agonism to antagonism. Among the compounds, antagonists 28 and 92 exhibited potent antagonism toward capsaicin for hTRPV1 with Ki[CAP] = 2.6 and 6.9 nM, respectively. Further, antagonist 92 displayed promising analgesic activity in vivo in both phases of the formalin mouse pain model. A molecular modeling study of 92 indicated that the two fluoro groups in the A-region made hydrophobic interactions with the receptor.
- Ann, Jihyae,Bahrenberg, Gregor,Blumberg, Peter M.,Choi, Sun,Christoph, Thomas,Do, Nayeon,Frank-Foltyn, Robert,Ha, Heejin,Jeong, Jin Ju,Kang, Jin Mi,Kim, Changhoon,Kwon, Sun Ok,Lee, Jeewoo,Lee, Sunho,Lesch, Bernhard,Stockhausen, Hannelore,Vu, Thi Ngoc Lan,Yoon, Sanghee
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- Catalytic α-Deracemization of Ketones Enabled by Photoredox Deprotonation and Enantioselective Protonation
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This study reports the catalytic deracemization of ketones bearing stereocenters in the α-position in a single reaction via deprotonation, followed by enantioselective protonation. The principle of microscopic reversibility, which has previously rendered this strategy elusive, is overcome by a photoredox deprotonation through single electron transfer and subsequent hydrogen atom transfer (HAT). Specifically, the irradiation of racemic pyridylketones in the presence of a single photocatalyst and a tertiary amine provides nonracemic carbonyl compounds with up to 97% enantiomeric excess. The photocatalyst harvests the visible light, induces the redox process, and is responsible for the asymmetric induction, while the amine serves as a single electron donor, HAT reagent, and proton source. This conceptually simple light-driven strategy of coupling a photoredox deprotonation with a stereocontrolled protonation, in conjunction with an enrichment process, serves as a blueprint for other deracemizations of ubiquitous carbonyl compounds.
- Chen, Shuming,Gao, Anthony Z.,Ivlev, Sergei I.,Meggers, Eric,Nie, Xin,Ye, Chen-Xi,Zhang, Chenhao
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supporting information
p. 13393 - 13400
(2021/09/03)
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- Harnessing Applied Potential: Selective β-Hydrocarboxylation of Substituted Olefins
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The construction of carboxylic acid compounds in a selective fashion from low value materials such as alkenes remains a long-standing challenge to synthetic chemists. In particular, β-addition to styrenes is underdeveloped. Herein we report a new electrosynthetic approach to the selective hydrocarboxylation of alkenes that overcomes the limitations of current transition metal and photochemical approaches. The reported method allows unprecedented direct access to carboxylic acids derived from β,β-trisubstituted alkenes, in a highly regioselective manner.
- Alkayal, Anas,Buckley, Benjamin R.,Malkov, Andrei V.,Montanaro, Stephanie,Tabas, Volodymyr,Wright, Iain A.
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supporting information
(2020/02/13)
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- Preparation method of organic carboxylic acid
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The invention discloses a preparation method of organic carboxylic acid. The preparation method comprises the following steps that catalysts, olefins, water and solvents are added into a reaction container; CO is introduced; heating reaction is performed; after the reaction completion, separation is performed to obtain organic carboxylic acid; the catalysts comprise transition metal catalysts, ligands and catalysis assistants; the catalysis assistants comprise Lewis acid salt. The preparation method has the advantages that the dependency on protonic acid in the prior art is avoided; the Lewisacid salt is used as the catalysis assistant, so that the corrosion of a reaction system on equipment can be effectively prevented; the requirements on equipment are lowered. The preparation method has excellent substrate practicability; the operation steps are simple and fast; the reaction conditions are mild and are easy to control; the raw materials are cheap and can be easily obtained; the product yield and the product purity are high; the preparation method is suitable for large-scale industrial production; the normal/iso ratio of reaction products can be regulated and controlled throughthe catalysis assistants; the defects of regulating and controlling the normal/iso ratio of the reaction products by traditional phosphine ligands are overcome; the reaction progress of the reaction is simplified; the cost is favorably reduced.
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Paragraph 0068-0070
(2019/10/15)
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- Regioselectivity inversion tuned by iron(iii) salts in palladium-catalyzed carbonylations
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Impactful regioselectivity control is crucial for cost-effective chemical synthesis. By using cheap and abundant iron(iii) salts, the hydroxycarbonylations of both aromatic and aliphatic alkenes were significantly enhanced in both reactivity and selectivity (iso/n or n/iso up to >99:1). Moreover, Pd-catalyzed carbonylation selectivity can be switched from branched to linear by using different Fe(iii) salts. In addition, similar results were obtained for the carbonylation of secondary alcohols.
- Huang, Zijun,Cheng, Yazhe,Chen, Xipeng,Wang, Hui-Fang,Du, Chen-Xia,Li, Yuehui
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supporting information
p. 3967 - 3970
(2018/04/23)
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- Enantioselective Decarboxylative Cyanation Employing Cooperative Photoredox Catalysis and Copper Catalysis
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The merger of photoredox catalysis with asymmetric copper catalysis have been realized to convert achiral carboxylic acids into enantiomerically enriched alkyl nitriles. Under mild reaction conditions, the reaction exhibits broad substrate scope, high yields and high enantioselectivities. Furthermore, the reaction can be scaled up to synthesize key chiral intermediates to bioactive compounds.
- Wang, Dinghai,Zhu, Na,Chen, Pinhong,Lin, Zhenyang,Liu, Guosheng
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supporting information
p. 15632 - 15635
(2017/11/14)
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- Reducing versus basic properties of 1,2-diaryl-1,2-disodioethanes
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The outcome of the reaction between halogenated arylacetic acids and 1,2-diaryl-1,2-disodioethanes strongly depends on the nature of both reaction partners, and it can be rationalized in terms of a competition between reducing and basic properties of the vic-diorganometals, as well as of the ease of the reductive cleavage of the different carbon-halide bonds. As an application of these findings, we developed a particularly mild approach to the synthesis of halogenated and non halogenated α-substituted arylacetic acids.
- Azzena, Ugo,Dettori, Giovanna,Pisano, Luisa,Pittalis, Mario
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experimental part
p. 3470 - 3475
(2011/06/17)
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- Synthesis of chiral N-heterocyclic carbene ligands with rigid backbones and application to the palladium-catalyzed enantioselective intramolecular α-arylation of amides
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Chiral N-heterocyclic carbene (NHC) ligands having a 2,2′- bisquinoline-based C2 symmetric skeleton were developed. The ligands exhibited good enantioselectivity in palladium-catalyzed intramolecular α-arylation of amides to give 3,3-disubsituted oxindoles.
- Liu, Lantao,Ishida, Naoki,Ashida, Shinji,Murakami, Masahiro
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supporting information; scheme or table
p. 1666 - 1669
(2011/05/11)
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- Nickel-catalyzed reductive carboxylation of styrenes using CO2
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A nickel-catalyzed reductive carboxylation of styrenes using CO2 has been developed. The reaction proceeds under mild conditions using diethylzinc as the reductant. Preliminary data suggests the mechanism involves two discrete nickel-mediated catalytic cycles, the first involving a catalyzed hydrozincation of the alkene followed by a second, slower nickel-catalyzed carboxylation of the in situ formed organozinc reagent. Importantly, the catalyst system is very robust and will fixate CO2 in good yield even if exposed to only an equimolar amount introduced into the headspace above the reaction. Copyright
- Williams, Catherine M.,Johnson, Jeffrey B.,Rovis, Tomislav
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supporting information; experimental part
p. 14936 - 14937
(2009/03/12)
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- Microbial deracemization of α-substituted carboxylic acids: Substrate specificity and mechanistic investigation
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A new enzymatic method for the preparation of optically active α-substituted carboxylic acids is reported. This technique is called deracemization reaction, which provides us with a route to obtain the enantiomerically pure compounds, theoretically in 100% yield starting from the racemic mixture. This means that the synthesis of a racemate is almost equal to the synthesis of the optically active compound, and this concept is entirely different from the commonly accepted one in the asymmetric synthesis. Using the growing cell system of Nocardia diaphanozonaria JCM3208, racemates of 2-aryl- and 2-aryloxypropanoic acid are deracemized smoothly and (R)-form-enriched products are recovered in high chemical yield (>50%). In addition, using optically active starting compounds and deuterated derivatives as well as inhibitors, we have disclosed the fact that a new type of enzyme takes part in this biotransformation, and that the reaction proceeds probably via the same mechanism as that in rat liver.
- Kato, Dai-Ichiro,Mitsuda, Satoshi,Ohta, Hiromichi
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p. 7234 - 7242
(2007/10/03)
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- Presynaptic cholinergic modulators as potent cognition enhancers and analgesic drugs. 1. Tropic and 2-phenylpropionic acid esters
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Previous studies have shown that (R)-(+)-hyoscyamine has analgesic activity as a consequence of increased ACh release following antagonism of central muscarinic autoreceptors. Since the enhancement of central cholinergic transmission could be beneficial for cognitive disorders, we manipulated (R)-(+)-hyoscyamine, synthesizing several derivatives of tropic and 2-phenylpropionic acids, with the aim of obtaining drugs which are able to increase ACh release and consequently to show analgesic and nootropic activities. The results showed that several new compounds are indeed potent analgesics (with an analgesic efficacy comparable to that of morphine) and that the most potent one ((±)-19, PG9) also has remarkable cognition- enhancing properties. Our study confirmed that the mechanism of action involves ACh release even if it is still unclear whether only muscarinic autoreceptors or, also, heteroreceptors are involved.
- Gualtieri,Conti,Dei,Giovannoni,Nannucci,Romanelli,Scapecchi,Teodori,Fanfani,Ghelardini,Giotti,Bartolini
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p. 1704 - 1711
(2007/10/02)
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