104941-35-7Relevant academic research and scientific papers
α- And β-Functionalized Ketones from 1,3-Dienes and Aldehydes: Control of Regio- And Enantioselectivity in Hydroacylation of 1,3-Dienes
Parsutkar, Mahesh M.,Rajanbabu
supporting information, p. 12825 - 12835 (2021/08/30)
Ketones are among the most widely used intermediates in organic synthesis, and their synthesis from inexpensive feedstocks could be quite impactful. Regio- and enantioselective hydroacylation reactions of dienes provide facile entry into useful ketone-bearing chiral motifs with an additional latent functionality (alkene) suitable for further elaboration. Three classes of dienes, 2- or 4-monosubstituted and 2,4-disubstituted 1,3-dienes, undergo cobalt(I)-catalyzed regio- and enantioselective hydroacylation, giving products with high enantiomeric ratios (er). These reactions are highly dependent on the ligands, and we have identified the most useful ligands and reaction conditions for each class of dienes. 2-Substituted and 2,4-disubstituted dienes predominantly undergo 1,2-addition, whereas 4-substituted terminal dienes give highly enantioselective 4,1- or 4,3-hydroacylation depending on the aldehyde, aliphatic aldehydes giving 4,1-addition and aromatic aldehydes giving 4,3-addition. Included among the substrates are feedstock dienes, isoprene (US$1.4/kg) and myrcene (US$129/kg), and several common aldehydes. We propose an oxidative dimerization mechanism that involves a Co(I)/Co(III) redox cycle that appears to be initiated by a cationic Co(I) intermediate. Studies of reactions using isolated neutral and cationic Co(I) complexes confirm the critical role of the cationic intermediates in these reactions. Enantioselective 1,2-hydroacylation of 2-trimethylsiloxy-1,3-diene reveals a hitherto undisclosed route to chiral siloxy-protected aldols. Finally, facile syntheses of the anti-inflammatory drug (S)-Flobufen (2 steps, 92% yield, >99:1 er) and the food additive (S)-Dihydrotagetone (1 step, 83% yield; 96:4 er) from isoprene illustrate the power of this method for the preparation of commercially relevant compounds.
Highly Chemo- And Enantioselective Hydrogenation of 2-Substituted-4-oxo-2-alkenoic Acids
Chen, Weiping,Jiang, Ru,Liu, Xian,Nie, Huifang,Wen, Jialin,Yao, Lin,Zhang, Xumu
, (2020/07/02)
The highly chemo- and enantioselective hydrogenation of (E)-2-substituted-4-oxo-2-alkenoic acids was established for the first time using the Rh/JosiPhos complex, affording a series of chiral α-substituted-γ-keto acids with excellent results (up to 99% yield and >99% ee) and high efficiency (up to 3000 TON). In addition, the importance of this methodology was further demonstrated by a concise and gram-scale synthesis of the anti-inflammatory drug (R)-flobufen.
Nickel(0)-Catalyzed Hydroalkylation of 1,3-Dienes with Simple Ketones
Cheng, Lei,Li, Ming-Ming,Xiao, Li-Jun,Xie, Jian-Hua,Zhou, Qi-Lin
supporting information, p. 11627 - 11630 (2018/09/21)
We developed a highly regioselective addition of 1,3-dienes with simple ketones by nickel-hydride catalyst bearing DTBM-SegPhos ligand. A wide range of aromatic and aliphatic ketones directly coupled with 1,3-dienes, providing synthetically useful γ,δ-unsaturated ketones in high yield and regioselectivity. The asymmetric version of the reaction was also realized in high enantioselectivity by using novel chiral ligand DTBM-HO-BIPHEP. The utility of this hydroalkylation was demonstrated by facile product modification and enantioselective synthesis of (R)-flobufen.
Chiral forms of 4-(2′,4′-difluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic acid (flobufen) and its metabolite. Synthesis and basic biological properties
Kuchar, Miroslav,Poppova, Marie,Jandera, Antonin,Panajotovova, Vladimira,Zunova, Hana,Budesinsky, Milos,Tomkova, Hana,Jegorov, Alexandr,Taimr, Jan
, p. 498 - 509 (2007/10/03)
4-(2′,4′-Difluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic acid (1, flobufen) is subjected to clinical testing in the treatment of rheumatoid arthritis. Owing to the occurrence of a centre of chirality, the compound exists in two enantiomers, and its major human metabolite, viz. 4-(2′,4′-difluorobiphenyl-4-yl)-4-hydroxy-2-methylbutanoic acid isolated in the lactone form (2), possesses two chiral centres, making possible the existence of four stereoisomers. All of the optical isomers of the substances 1 and 2 were prepared. For flobufen (1), the racemate was separated into the stereoisomers by using the salts 3 with R-(+)-or S-(-)-1-phenylethylamine. The pairs of stereoisomers of 2, obtained by reduction of R-(+)-flobufen or the S-(-)-enantiomer, were separated by column chromatography. The physico-chemical parameters of the optical isomers were determined and some biological activities were evaluated in both in vitro and in vivo models.
4-(2',4'-DIFLUOROBIPHENYL-4-YL)-2-METHYL-4-OXOBUTANOIC ACID AND ITS DERIVATIVES
Kuchar, Miroslav,Poppova, Marie,Zunova, Hana,Knezova, Eva,Vosatka, Vaclav,Prihoda, Marek
, p. 2705 - 2713 (2007/10/02)
Friedel-Crafts reaction of itaconic anhydride (III) with 2,4-difluorobiphenyl (II) afforded unsaturated acid IV which was hydrogenated to give 4-(2',4'-difluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic acod (I).A series of functional derivatives and salts of the acid I has been prepared.The antiinflammatory effect of these compounds was compared with that of acid I using selected experimental inflammation models.The analgesic activity in the intraperitoneal iritation test was also evaluated.In the case of (R)-(+)-1-phenylethylamide Vf the ratio of the diastereisomers was determined by HPLC.
QUANTITATIVE RELATIONS BETWEEN STRUCTURE AND ANTIINFLAMMATORY ACTIVITY OF ARYLOXOALKANOIC ACIDS
Kuchar, Miroslav,Maturova, Eva,Brunova, Bohumila,Grimova, Jaroslava,Tomkova, Hana,Holubek, Jiri
, p. 1862 - 1872 (2007/10/02)
The antiinflammatory effect of a series of aryloxoalkanoic acids II and of their biphenyl derivatives III was examined by measuring the inhibition of the development of carageenan- and adjuvant-induced edemas.The quantitative relations between the antiinflammatory effect and physicochemical and structural parameters of the compounds tested were evaluated.The equations obtained by the method of regression analysis showed a significant linear dependence of both inhibitory activities on the lipophilicity of the compounds and a considerable effect of some structural changes as expressed by indicator variables.The antiinflammatory effect is especially enhanced in both tests by the presence of a cyclic substituent at the aromatic ring.The high antiinflammatory effect of biphenylyl derivatives III is paralleled by their prolonged action.The prolongation of the effect is most likely a result of a suitable biotransformation of acid III to an efficient metabolite.The structural requirements which resulted from both the regression analysis and from the hypothesis of biotransformation of acids III were utilized in the synthesis of suitably substituted biphenylyloxoalkanoic acids.By this approach derivatives IIIe-i were obtained some of which showed a high antiinflammatory and also protracted effect. 4-(2',4'-Difluorobiphenylyl)-4-oxo-2-methylbutanoic acid (VUFB 16066, Flobufen) was chosen for further preclinical development.
