114446-57-0Relevant articles and documents
Development of an Enzymatic Process for the Synthesis of (S)-2-Chloro-1-(2,4-dichlorophenyl) Ethanol
Wei, Teng-Yun,Tang, Jia-Wei,Ni, Guo-Wei,Wang, Hong-Yi,Yi, Dong,Zhang, Fu-Li,Chen, Shao-Xin
, p. 1822 - 1828 (2019)
(S)-2-Chloro-1-(2,4-dichlorophenyl) ethanol (3) is a chiral intermediate in the synthesis of luliconazole ((R)-E-1). Here, we report a novel biopreparation of 3 by bioreduction of 2-chloro-1-(2,4-dichlorophenyl) ethanone (2) using recombinant Escherichia
Chemoenzymatic Synthesis of Luliconazole Mediated by Lipases
Fonseca, Thiago de S.,Lima, Lara D.,de Oliveira, Maria da C. F.,de Lemos, Telma L. G.,Zampieri, Davila,Molinari, Francesco,de Mattos, Marcos C.
, p. 2110 - 2116 (2018)
A straightforward chemoenzymatic synthesis of luliconazole has been developed. The key step involved the preparation of the enantiomerically pure β-halohydrin (1S)-2-chloro-1-(2,4-dichlorophenyl)-1-ethanol through kinetic resolution of the corresponding racemic acetate. This was achieved by a hydrolytic approach, mediated by the lipase from Thermomyces lanuginosus or Novozym 435. The latter enzyme proved to be a robust biocatalyst for the kinetic resolution, and the (S)-β-halohydrin was obtained with high selectivity (ee > 99 %, E > 200) after just 15 min, at 45 °C. It could be reused five times with maintenance of high values of both conversion and enantioselectivity. Subsequently, the (S)-β-halohydrin was subjected to a mesylation reaction; the mesylated derivative reacted with 1-cyanomethylimidazole in the presence of CS2 to give luliconazole in 43 % yield with >99 % ee.
Efficient biosynthesis of (R)-2-chloro-1-(2, 4-dichlorophenyl) ethanol using a mutant short-chain dehydrogenase from Novosphingobium aromaticivorans
Li, Guifang,Que, Fandi,Tang, Yunping,Zhao, Qiaojun,Zhou, Shuyao,Zhou, Yafeng
, (2020)
(R)-2-chloro-1-(2, 4-dichlorophenyl) ethanol ((R)-CPEO) is an important chiral intermediate for antifungal drug synthesis. (R)-CPEO can be produced from 2-chloro-1-(2, 4-dichlorophenyl) ethanone (CPE) via a mutant short-chain dehydrogenase/reductase from Novosphingobium aromaticivorans (NaSDR). The Vmax of a mutant NaSDR-G145A/I199L toward CPE (6.32 U mg?1) was greater than that of wild-type NaSDR (2.58 U mg?). The Km of mutant NaSDR-G145A/I199L toward CPE (0.23 mM) was less than that of wild-type NaSDR (0.38 mM), indicating that the substrate affinity of mutant NaSDR-G145A/I199L was the greater of the two. Docking simulations were used to illustrate the mechanisms of the increased enzyme activity of NaSDR-G145A/I199L; these showed that NaSDR-G145A/I199L presented a more effective docking posture than that of the wild-type enzyme. Further, NaSDR-G145A/I199L and glucose dehydrogenase (GDH) were used to transform 120 g/L CPE into (R)-CPEO. After 6 h, the conversion rate and enantiomeric excess values were 99% and 99.95%, respectively. The present study provides a practical method for high substrate loading of (R)-CPEO for industrial-scale applications.
Aminoazabenzimidazoles, a Novel Class of Orally Active Antimalarial Agents
Hameed P, Shahul,Chinnapattu, Murugan,Shanbag, Gajanan,Manjrekar, Praveena,Koushik, Krishna,Raichurkar, Anandkumar,Patil, Vikas,Jatheendranath, Sandesh,Rudrapatna, Suresh S.,Barde, Shubhada P.,Rautela, Nikhil,Awasthy, Disha,Morayya, Sapna,Narayan, Chandan,Kavanagh, Stefan,Saralaya, Ramanatha,Bharath, Sowmya,Viswanath, Pavithra,Mukherjee, Kakoli,Bandodkar, Balachandra,Srivastava, Abhishek,Panduga, Vijender,Reddy, Jitender,Prabhakar,Sinha, Achyut,Jiménez-Díaz, María Belén,Martínez, María Santos,Angulo-Barturen, I?igo,Ferrer, Santiago,Sanz, Laura María,Gamo, Francisco Javier,Duffy, Sandra,Avery, Vicky M.,Magistrado, Pamela A.,Lukens, Amanda K.,Wirth, Dyann F.,Waterson, David,Balasubramanian,Iyer, Pravin S.,Narayanan, Shridhar,Hosagrahara, Vinayak,Sambandamurthy, Vasan K.,Ramachandran, Sreekanth
, p. 5702 - 5713 (2014)
Whole-cell high-throughput screening of the AstraZeneca compound library against the asexual blood stage of Plasmodium falciparum (Pf) led to the identification of amino imidazoles, a robust starting point for initiating a hit-to-lead medicinal chemistry effort. Structure-activity relationship studies followed by pharmacokinetics optimization resulted in the identification of 23 as an attractive lead with good oral bioavailability. Compound 23 was found to be efficacious (ED90 of 28.6 mg·kg-1) in the humanized P. falciparum mouse model of malaria (Pf/SCID model). Representative compounds displayed a moderate to fast killing profile that is comparable to that of chloroquine. This series demonstrates no cross-resistance against a panel of Pf strains with mutations to known antimalarial drugs, thereby suggesting a novel mechanism of action for this chemical class.
Asymmetric transfer hydrogenation over Ru-TsDPEN catalysts supported on siliceous mesocellular foam
Huang, Xiaohua,Ying, Jackie Y.
, p. 1825 - 1827 (2007)
A siliceous mesocellular foam-immobilized Ru-TsDPEN complex exhibited excellent catalytic reactivity, enantioselectivity and reusability in the asymmetric transfer hydrogenation of an imine and ketones. The Royal Society of Chemistry.
Enhancing cofactor regeneration of cyanobacteria for the light-powered synthesis of chiral alcohols
Fan, Jianhua,Zhang, Yinghui,Wu, Ping,Zhang, Xiaoyan,Bai, Yunpeng
, (2021/11/24)
Cyanobacteria Synechocystis sp. PCC 6803 was exploited as green cell factory for light-powered asymmetric synthesis of aromatic chiral alcohols. The effect of temperature, light, substrate and cell concentration on substrate conversions were investigated. Under the optimal condition, a series of chiral alcohols were synthesized with conversions up to 95% and enantiomer excess (ee) > 99%. We found that the addition of Na2S2O3 and Angeli's Salt increased the NADPH content by 20% and 25%, respectively. As a result, the time to reach 95% substrate conversion was shortened by 12 h, which demonstrated that the NADPH regeneration and hence the reaction rates can be regulated in cyanobacteria. This blue-green algae based biocatalysis showed its potential for chiral compounds production in future.
Biocatalytic preparation of a key intermediate of antifungal drugs using an alcohol dehydrogenase with high organic tolerance
Yan, Jinrong,Wang, Xiaojing,Li, Fangling,Yang, Lei,Shi, Guixiang,Sun, Weihang,Shao, Lei,Huang, Junhai,Wu, Kai
supporting information, (2021/10/20)
In this study, an alcohol dehydrogenase derived from Lactobacillus kefir (LkADH) was engineered and a simple and practical bioreduction system was developed for the preparation of (R)-2-chloro-1-(2, 4-dichlorophenyl) ethanol ((R)-CDPO), a key intermediate for the synthesis of antifungal drugs. Through active pocket iterative saturation mutagenesis, mutant LkADH-D18 (Y190C/V196L/M206H/D150H) was obtained with high stereoselectivity (99% ee, R vs 87% ee, S) and increased activity (0.44 μmol·min?1·mg?1). LkADH-D18 demonstrated NAD(P)H regeneration capability using a high concentration of isopropanol (IPA) as a co-substrate. Using 40% IPA (v/v), 400 mM of (R)-CDPO (90.1 g·L-1) was obtained via complete substrate conversion using 40 mg·mL?1 LkADH-D18 wet cells. The biocatalytic process catalyzed at constant pH with the cheap co-solvent IPA contributed to improved isolated yield of (R)-CDPO (97%), lower reaction cost, and simpler downstream purification, indicating the potential utility of LkADH-D18 in future industrial applications.
Efficient Biocatalytic Synthesis of (R)-2-Chloro-1-(3,4-difluorophenyl)ethanol by the Short-Chain Dehydrogenase PpKR8 from Paraburkholderia phymatum STM815
He, Ling,Liu, Qinghai,Wang, Hualei,Wei, Dongzhi,Xie, Youyu,Ye, Wenjie
, (2022/02/01)
Bioreductions catalyzed by ketoreductases play an important role in the synthesis of chiral alcohols. However, the synthesis of (R)-2-chloro-1-(3,4-difluorophenyl)ethanol (24b), an important chiral intermediate for the synthesis of the anticoagulant ticagrelor, poses significant challenges in terms of high substrate concentration requirements that limit its production. In this study, a novel NADH-dependent, short-chain dehydrogenase, PpKR8, from Paraburkholderia phymatum STM815, exhibited excellent enantioselectivity and high activity for the production of (R)-CFPL (24b) through the reduction of 2-chloro-1-(3,4-difluorophenyl)ethanone (24a). The coexpression of PpKR8 and glucose dehydrogenase from Bacillus subtilis in Escherichia coli allowed up to 300 g/L (1.57 M) CFPO (24a) to be completely converted into 24b with 99.9% enantiomeric excess and a high space-time yield (728 g/(L day)). Substrate specificity assays demonstrated a broad substrate spectrum for PpKR8, which included 35 α/β-ketoesters, aromatic ketones, and heterocyclic ketones. Moreover, three additional optically pure chiral alcohols that are used as important drug intermediates were synthesized at high substrate concentrations (150-330 g/L), demonstrating the excellent industrial potential of PpKR8-mediated bioreductions.
Deep Eutectic Solvents as Media in Alcohol Dehydrogenase-Catalyzed Reductions of Halogenated Ketones
Ibn Majdoub Hassani, Fatima Zohra,Amzazi, Saaid,Kreit, Joseph,Lavandera, Iván
, p. 832 - 836 (2019/12/24)
The application of deep eutectic solvents (DESs) in biotechnological processes has gained an outstanding relevance, as they can be used as greener media to obtain higher productivities and selectivities. In the present contribution, an eutectic mixture composed of choline chloride (ChCl): glycerol (1 : 2 mol/mol) has been used as a reaction medium in combination with Tris?SO4 50 mM buffer pH 7.5, applied to the alcohol dehydrogenase (ADH)-catalyzed reduction of various carbonyl precursors of chiral halohydrins. These alcohols are key intermediates of biologically active compounds, and hence they are of industrial interest. In the presence of up to 50 % v/v of DES, these biotransformations were achieved up to 300–400 mM of the α-halogenated ketone substrate, getting access to the final compounds with excellent conversions (usually >90 %) and enantiomeric excess (ee >99 %). Among the different ADHs tested, two stereocomplementary enzymes (Lactobacillus brevis ADH and Rhodococcus ruber ADH) afforded the best results, so both alcohol enantiomers could be obtained in all the studied examples. Selected bioreductions were scaled up to 250 mg and 1 g, demonstrating the potential that DESs can offer as media in redox processes for substrates with low solubility in water.
Lipase mediated enzymatic kinetic resolution of phenylethyl halohydrins acetates: A case of study and rationalization
Fonseca, Thiago de Sousa,Vega, Kimberly Benedetti,da Silva, Marcos Reinaldo,de Oliveira, Maria da Concei??o Ferreira,de Lemos, Telma Leda Gomes,Contente, Martina Letizia,Molinari, Francesco,Cespugli, Marco,Fortuna, Sara,Gardossi, Lucia,de Mattos, Marcos Carlos
, (2020/02/18)
Racemic phenylethyl halohydrins acetates containing several groups attached to the aromatic ring were resolved via hydrolysis reaction in the presence of lipase B from Candida antarctica (Novozym 435). In all cases, the kinetic resolution was highly selective (E > 200) leading to the corresponding (S)-β-halohydrin with ee > 99 %. However, the time required for an ideal 50 % conversion ranged from 15 min for 2,4-dichlorophenyl chlorohydrin acetate to 216 h for 2-chlorophenyl bromohydrin acetate. Six chlorohydrins and five bromohydrins were evaluated, the latter being less reactive. For the β-brominated substrates, steric hindrance on the aromatic ring played a crucial role, which was not observed for the β-chlorinated derivatives. To shed light on the different reaction rates, docking studies were carried out with all the substrates using MD simulations. The computational data obtained for the β-brominated substrates, based on the parameters analysed such as NAC (near attack conformation), distance between Ser-O and carbonyl-C and oxyanion site stabilization were in agreement with the experimental results. On the other hand, the data obtained for β-chlorinated substrates suggested that physical aspects such as high hydrophobicity or induced change in the conformation of the enzymatic active site are more relevant aspects when compared to steric hindrance effects.
