- Mechanistic studies on metabolic chiral inversion of 4-(4-methylphenyl)-2-methylthiomethyl-4-oxobutanoic acid (KE-748), an active metabolite of the new anti-rheumatic agent 2-acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic acid (KE-298), in rats
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The chiral inversion properties of 4-(4-methylphenyl)-2-methylthiomethyl-4-oxobutanoic acid (KE-748), an active metabolite of 2-acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic acid (KE-298), were compared with those of ibuprofen in rats. After administration of R(-)-[2α-2H]KE-748, S(+)-KE-748 was present in the rat plasma, and the deuterium atoms of the S(+)-enantiomer were almost all replaced by hydrogen atoms. After administration of S(+)-[2α-2H]KE-748, the deuterium content of S(+)-KE-748 in the plasma remained intact. In the in vitro study, using a cell-free system and rat liver homogenates, the chiral inversion of ibuprofen was apparent when both CoA and ATP were present; however, KE-748 was not inverted. In the study on isolated rat hepatocytes, the unidirectional chiral inversion from R(-)- to S(+)-enantiomer was observed for both ibuprofen and KE-748. When R(-)-ibuprofen was incubated with medium and long chain fatty acids (carbon chain length C6 to C16), using isolated hepatocytes, the chiral inversion decreased significantly. On the other hand, when R(-)-KE-748 was incubated with short and medium chain fatty acids (carbon chain length C3 to C8), chiral inversion was inhibited markedly. To induce hepatic microsomal long chain fatty acid CoA ligase, rats were treated with clofibric acid (CF rats). In both in vitro and in vivo experiments on CF rats, chiral inversion from R(-)- to S(+)-ibuprofen was enhanced significantly compared with that in controls, whereas the enhancement was not observed in the case of R(-)-KE-748. There was no influence of benzoic acid, a typical substrate on medium chain fatty acid CoA ligase in the mitochondrial matrix, on chiral inversion of R(-)-ibuprofen, using isolated hepatocytes. In contrast, the chiral inversion from R(-)- to S(+)-KE-748 was strongly inhibited in the presence of benzoic acid. These results indicate that chiral inversion of R(-)-KE-748 may proceed via formation of the CoA-thioester intermediate with loss of the 2α-methine proton, in a manner similar to that seen with R(-)-ibuprofen. However, the enzymes needed to form CoA-thioester of R(-)-KE-748 differ from those for R(-)-ibuprofen.
- Yoshida, Hideo,Kohno, Yoshiro,Endo, Hiromi,Yamaguchi, Jun-Ichi,Fukushima, Kiyomi,Suwa, Toshio,Hayashi, Masahiro
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- Asymmetric Alkoxy- and Hydroxy-Carbonylations of Functionalized Alkenes Assisted by β-Carbonyl Groups
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As a fundamental type of carbonylation reaction, the alkoxy- and hydroxy-carbonylation of unsaturated hydrocarbons constitutes one of the most important industrial applications of homogeneous catalysis. However, owing to the difficulties in controlling multi-selectivities for asymmetric hydrocarbonylation of alkenes, this reaction is typically limited to vinylarenes and analogues. In this work, a highly efficient asymmetric alkoxy- and hydroxy-carbonylation of β-carbonyl functionalized alkenes was developed, providing practical and easy access to various densely functionalized chiral molecules with high optical purity from broadly available alkenes, CO, and nucleophiles (>90 examples, 84–99 % ee). This protocol features mild reaction conditions and a broad substrate scope, and the products can be readily transformed into a diverse array of chiral heterocycles. Control experiments revealed the key role of the β-carbonyl group in determining the enantioselectivity and promoting the activity, which facilitates chiral induction by coordination to the transition metal as rationalized by DFT calculations. The strategy of utilizing an innate functional group as the directing group on the alkene substrate might find further applications in catalytic asymmetric hydrocarbonylation reactions.
- Dong, Kaiwu,Ji, Xiaolei,Ren, Xinyi,Shen, Chaoren,Tang, Lin,Tian, Xinxin,Wang, Zhen
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supporting information
p. 17693 - 17700
(2021/07/10)
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- Enzyme-Inspired Chiral Secondary-Phosphine-Oxide Ligand with Dual Noncovalent Interactions for Asymmetric Hydrogenation
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Inspired by the unique character of enzymes, we developed novel chiral SPO (secondary-phosphine-oxide) ligand (SPO-Wudaphos) which can enter into both ion pair and H-bond noncovalent interactions. The novel chiral SPO-Wudaphos exhibited excellent results
- Chen, Caiyou,Zhang, Zhefan,Jin, Shicheng,Fan, Xiangru,Geng, Mingyu,Zhou, Yan,Wen, Songwei,Wang, Xinrui,Chung, Lung Wa,Dong, Xiu-Qin,Zhang, Xumu
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supporting information
p. 6808 - 6812
(2017/06/06)
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- Synthesis and hypotensive activity of some 6-(substituted aryl)-4-methyl-2,3-dihydropyridazin-3-ones
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6-(Substituted aryl)-4-methyl-2,3-dihydropyridazin-3-ones are synthesized by cyclisation of appropriate β-(substituted aroyl)-2-methylene propionate with hydrazine hydrate in the presence of sodium acetate. The title compounds are tested for hypotensive activity, non-invasively, by tail-cuff method and are found to possess significant hypotensive activity in normotensive rats.
- Siddiqui, Anees A.,Wani, Sachin M.
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p. 1574 - 1579
(2007/10/03)
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- A practical procedure for the synthesis of Esonarimod, (R,S)-2-acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic acid, an antirheumatic agent. II
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An efficient large-scale synthesis of Esonarimod, (R,S)-2-acetylthio-methyl-4-(4-methylphenyl)-4-oxobutanoic acid (1), a new antirheumatic drug, was established. A small amount of water increased the yield of the Michael addition of thioacetic acid (4) to
- Noguchi, Toshiya,Onodera, Akira,Ito, Masato,Yoshida, Mamoru,Yokomori, Sadakazu
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p. 2657 - 2670
(2007/10/03)
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- A practical procedure for the synthesis of esonarimod, (R,S)-2-acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic acid, an antirheumatic agent (part 1).
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An efficient and practical procedure for the synthesis of esonarimod, (R,S)-2-acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic acid (1), a new antirheumatic drug, has been developed. The intermediate, 2-methylene-4-(4-methylphenyl)-4-oxobutanoic acid (2), was prepared by Friedel-Crafts acylation of toluene with itaconic anhydride (3) in the presence of aluminum trichloride and nitrobenzene in 63% yield without silica gel column purification. Compound 1 was prepared by Michael addition of 2 with thioacetic acid (4) in 74% yield. Overall, 1 was obtained in 47% yield from 3. The structures and synthetic mechanisms of by-products (five compounds) of 2 were also clarified.
- Noguchi, Toshiya,Onodera, Akira,Tomisawa, Kazuyuki,Yokomori, Sadakazu
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p. 1407 - 1412
(2007/10/03)
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- Benzoylpropionic acid derivatives
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Benzoylpropionic acid derivatives represented by the general formula STR1 (wherein R1 represents a hydrogen atom, a lower alkyl group or a benzyl group, R2 represents a lower alkyl group or a phenyl group, X represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a phenoxy group or a halogenophenoxy group, and Y represents a hydrogen atom or a lower alkyl group). The compounds have immunomodulative function and are effective for treatment of diseases caused by abnormal immunofunction.
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