79200-56-9Relevant articles and documents
Chemical preparation method of 2-azabicyclo [2.2.1] hept-5-ene-3-one with optical activity
-
, (2020/05/08)
The invention discloses a chemical preparation method of 2-azabicyclo [2.2.1] hept-5-ene-3-one with optical activity. The chemical preparation method comprises the following steps: racemic 2-azabicyclo [2.2.1] hept-5-ene-3-one which is easily available on the market is used as a raw material and is subjected to chemical resolution to obtain (+/-) 4-aminocyclopent-2-ene-1-carboxylic acid methyl ester with optical activity, (+/-) 4-aminocyclopent-2-ene-1-carboxylic acid is prepared by hydrolysis, and the (+/-) 4-aminocyclopent-2-ene-1-carboxylic acid is subjected to intramolecular condensation to obtain the 2-azabicyclo [2.2.1] hept-5-ene-3-one with optical activity. The method has the advantages that the use of an enzyme fermentation method is avoided, the repeatability is good, and the yield is high.
Study on immobilization of (+) γ-lactamase using a new type of epoxy graphene oxide carrier
Li, Wei,Wen, Huijiao,Shi, Qianqiao,Zheng, Guojun
, p. 270 - 276 (2016/02/05)
In this article, a new type of graphene oxide material was obtained by modification with epoxy chloropropane, which was used for the (+) γ-lactamase immobilization research. The enzymatic properties of the immobilized (+) γ-lactamase were systematically tested and compared with those of the free enzyme. The free and immobilized enzymes have the same optimum temperature (80 °C) and pH (8.0), the range of pH tolerance increased from pH 8.0-9.0 to pH 4.0-10.0 after immobilization, and the immobilized enzyme is less tolerant to heat than the free enzyme. Kinetic experiments showed that the Km value of the immobilized enzyme was about 2.66 times higher than that of the free enzyme, whereas Vmax decreased 40%. Subsequently, the apparent activation energies (Ea) of the free and immobilized enzymes became 40.03 and 35.62 kJ/mol, respectively. Finally, a reusability assay demonstrated that 70% of the enzyme activity remained after 15 repeated batch experiments.
Green access to chiral Vince lactam in a buffer-free aqueous system using a newly identified substrate-tolerant (-)-γ-lactamase
Yin, Jin-Gang,Gong, Yi,Zhang, Xiao-Yan,Zheng, Gao-Wei,Xu, Jian-He
, p. 6305 - 6310 (2016/08/18)
A novel non-heme chloroperoxidase (SvGL) with promiscuous (-)-γ-lactamase activity towards Vince lactam was identified from Streptomyces viridochromogenes by genome data-mining. SvGL possesses high activity and excellent thermal stability and enantioselectivity. Furthermore, it is able to tolerate extremely high substrate concentrations (4.0 M, 436.5 g L-1). Using the newly discovered (-)-γ-lactamase as a biocatalyst, an efficient and environmentally benign process for the production of (+)-γ-lactam was developed. The process allowed an enantioselective resolution of 436.5 g L-1 racemic γ-lactam with only 0.2 g L-1 lyophilized cell-free extract, affording an extremely high substrate/catalyst ratio of 2183 (g g-1), a space-time yield of 458 g L-1 d-1, and a very low E factor (environmental factor) of 5.7 (kg waste per kg product) even when the process water is included.
Enhanced enzymatic synthesis of the enantiopure intermediate for the blockbuster drug intermediate abacavir through a two-step enzymatic cascade reaction
Galla, Zsolt,Forró, Enik?,Fül?p, Ferenc
, p. 729 - 731 (2016/08/01)
A very efficient enzymatic two-step cascade reaction was devised (E?>?200) for the resolution of activated γ-lactams (±)-1 and (±)-2. The N-hydroxymethyl group worked as a traceless activating group, when the reactions were performed with H2O (0.5?equiv) in the presence of benzylamine (1?equiv) in i-Pr2O at 60?°C. The ring-opened enantiomerically pure γ-amino acids (1S,4R)-6 (ee?=?99%, intermediate of abacavir) and (1S,3R)-8 (ee?=?99%) and unreacted lactams (1S,4R)-1 and (1R,4S)-2 (ee???96%) were obtained in good yields (?43%). Treatment of (1S,4R)-1 and (1R,4S)-2 with 18% HCl or NH4OH resulted in (1R,4S)-6·HCl and (1S,3R)-8·HCl or (1S,4R)-3 and (1R,4S)-4 quantitatively, with ee???96%.
HPLC enantioseparation on a homochiral MOF-silica composite as a novel chiral stationary phase
Tanaka, Koichi,Muraoka, Toshihide,Otubo, Yasuhiro,Takahashi, Hiroki,Ohnishi, Atsushi
, p. 21293 - 21301 (2016/03/08)
The last frontier in the development of chiral stationary phases for chromatographic enantioseparation involves homochiral metal-organic frameworks (MOFs). Using enantiopure (R)-2,2′-dihydroxy-1,1′-binaphthalene-6,6′-dicarboxylic acid as a starting material, we prepared three homochiral MOFs that were further used as chiral stationary phases for high-performance liquid chromatography to separate the enantiomers of various kinds of racemic sulfoxides, sec-alcohols, β-lactams, benzoins, flavanones and epoxides. The experimental results showed excellent performances for enantioseparation, and highlighted that enantioseparation on homochiral MOF columns is practical.
Efficient synthesis of the intermediate of abacavir and carbovir using a novel (+)-γ-lactamase as a catalyst
Gao, Shuaihua,Zhu, Shaozhou,Huang, Rong,Lu, Yingxiu,Zheng, Guojun
, p. 3878 - 3881 (2015/08/24)
Abstract The enantiomers of 2-azabicyclo[2.2.1]hept-5-en-3-one (γ-lactam) are key chiral synthons in the synthesis of antiviral drugs such as carbovir and abacavir. (+)-γ-Lactamase can be used as a catalyst in the enzymatic preparation of optically pure (-)-γ-lactam. Here, a (+)-γ-lactamase discovered from Bradyrhizobium japonicum USDA 6 by sequence-structure guided genome mining was cloned, purified and characterized. The enzyme possesses a significant catalytic activity towards γ-lactam. The active site of the (+)-γ-lactamase was studied by homologous modeling and molecular docking, and the accuracy of the prediction was confirmed by site-specific mutagenesis. The (+)-γ-lactamase reveals the great practical potential as an enzymatic method for the efficient production of carbocyclic nucleosides of pharmaceutical interest.
Identification and application of enantiocomplementary lactamases for Vince lactam derivatives
Assaf, Zeinab,Eger, Elisabeth,Vitnik, Zeljko,Fabian, Walter M. F.,Ribitsch, Doris,Guebitz, Georg M.,Faber, Kurt,Hall, Mélanie
, p. 2517 - 2521 (2015/04/14)
Four enzymes showing hydrolytic activity on derivatives of 2-azabicyclo[2.2.1]hept-5-en-3-one (Vince lactam) were successfully identified through analysis of protein crystal structure and amino acid sequence alignments. Enantiocomplementary activities were observed on Vince lactam and its saturated analog 2-azabicyclo[2.2.1]heptan-3-one with non-heme chloroperoxidase (CPO-T) from Streptomyces aureofaciens, cyclic imide hydrolase (CIH) from Pseudomonas putida, polyamidase (NfpolyA) from Nocardia farcinica, and amidase (AMI) from Rhodococcus globerulus, and perfect kinetic resolution was achieved (E>200). Computational analysis of amide bond resonance stabilization in lactams correlated well with the overall reactivity pattern of the lactams as a function of ring size and strain. The biocatalysts cloned and investigated in this study could be of interest for the synthesis of enantiopure carbocyclic nucleoside analogues.
Synthesis and Fungistatic Activity of Bicyclic Lactones and Lactams against Botrytis cinerea, Penicillium citrinum, and Aspergillus glaucus
Walczak, Paulina,Pannek, Jakub,Boratynski, Filip,Janik-Polanowicz, Agata,Olejniczak, Teresa
, p. 8571 - 8578 (2015/04/22)
Six analogues of natural trans-4-butyl-cis-3-oxabicyclo[4.3.0]nonan-2-one (3) and three derivatives, 11, 12, and 13, of Vince lactam (10) were synthesized and tested as fungistatic agents against Botrytis cinerea AM235, Penicillium citrinum AM354, and six strains of Aspergillus. Moreover, bioresolution carried out by means of whole cell microorganisms and commercially available enzymes afforded opposite enantiomerically enriched (a) and (+) isomers of Vince lactam (10), respectively. The effect of compound structures and stereogenic centers on biological activity has been discussed. The highest fungistatic activity was observed for four lactones: 3, 4, 7, and 8 (IC50 = 104.6-115.2 g/mL) toward B. cinerea AM235. cis-5,6-Epoxy-2-aza[2.2.1]heptan-3-one (13) indicated significant fungistatic activity (IC50 = 107.1 g/mL) against Aspergillus glaucus AM211. trans-4-Butyl-cis-3-oxabicyclo[4.3.0]nonan-2-one (3) and trans-4-butyl-cis-3-oxabicyclo[4.3.0]non-7-en-2-one (7) exhibited high fungistatic activity (IC50 = 143.2 and 110.2 g/mL, respectively) against P. citrinum AM354 as well.
Enzymatic preparation of optically pure (+)-2-azabicyclo[2.2.1]hept-5-en-3-one by (-)-γ-lactamase from Bradyrhizobium japonicum USDA 6
Zhu, Shaozhou,Ren, Lu,Yu, Songzhu,Gong, Cuiyu,Song, Dawei,Zheng, Guojun
, p. 4899 - 4902 (2015/02/19)
Whole cells of Bradyrhizobium japonicum USDA 6 showed both (+)-γ-lactamase activity and (-)-γ-lactamase activity. Insight into the genome of B. japonicum USDA 6 revealed two potential γ-lactamases: a type I (+)-γ-lactamase and a (-)-γ-lactamase, making it the first strain to contain two totally different enantioselective lactamases. Both recombinant enzymes could easily be used to prepare either optically pure (+)-γ-lactam ((+)-2-azabicyclo[2.2.1]hept-5-en-3-one) or optically pure (-)-γ-lactam ((-)-2-azabicyclo[2.2.1]hept-5-en-3-one), which are versatile synthetic building blocks for the synthesis of various carbocyclic nucleosides and carbocyclic sugar analogues. Bioinformatic analysis showed that the type I (+)-γ-lactamase belongs to the amidase signature family, with 504 amino acids; the (-)-γ-lactamase, which consists of 274 amino acids, belongs to the hydrolase family. Here, we report that B. japonicum USDA contains a (-)-γ-lactamase in addition to a (+)-γ-lactamase, and it is the (-)-γ-lactamase from this strain that is examined in detail in this Letter. Enzymatic synthesis of optically pure (+)-γ-lactam with nearly 50% isolated yield and >99% ee was achieved.
Asymmetric biocatalysis of S-3-amino-3-phenylpropionic acid with new isolated Methylobacterium Y1-6
Li, Yi,Wang, Wenfu,Huang, Yumian,Zou, Qianwen,Zheng, Guojun
, p. 1674 - 1678 (2013/11/19)
β-amino acids are widely used in drug research, and S-3-amino-3-phenylpropionic acid (S-APA) is an important pharmaceutical intermediate of S-dapoxetine, which has been approved for the treatment of premature ejaculation. Chiral catalysis is an excellent method for the preparation of enantiopure compounds. In this study, we used (±)-ethyl-3-amino-3-phenylpropanoate (EAP) as the sole carbon source. Three hundred thirty one microorganisms were isolated from 30 soil samples, and 17 strains could produce S-APA. After three rounds of cultivation and identification, the strain Y1-6 exhibiting the highest enantioselective activity of S-APA was identified as Methylobacterium oryzae. The optimal medium composition contained methanol (2.5 g/L), 1,2-propanediol (7.5 g/L), soluble starch (2.5 g/L), and peptone (10 g/L); it was shaken at 220 rpm for 4-5 days at 30 C. The optimum condition for biotransformation of EAP involved cultivation at 37 C for 48 h with 120 mg of wet cells and 0.64 mg of EAP in 1 ml of transfer solution. Under this condition, substrate ee was 92.1% and yield was 48.6%. We then attempted to use Methylobacterium Y1-6 to catalyze the hydrolytic reaction with substrates containing 3-amino-3-phenyl-propanoate ester, N-substituted-β-ethyl-3-amino-3-phenyl-propanoate, and γ-lactam. It was found that 5 compounds with ester bonds could be stereoselectively hydrolyzed to S-acid, and 2 compounds with γ-lactam bonds could be stereoselectively hydrolyzed to (-)-γ-lactam.
