- Chemical preparation method of 2-azabicyclo [2.2.1] hept-5-ene-3-one with optical activity
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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.
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- Stereo- and regiocontrolled synthesis of highly functionalized cyclopentanes with multiple chiral centers
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The synthesis of some highly substituted three-dimensional cyclopentanes with multiple chiral centers and with high regiochemical and stereochemical diversity has been accomplished starting from cyclopentadiene-derived aminocyclopentenecarboxylic acids. The small-molecular design consisted of stereo- and regiocontrolled functionalization of the starting cyclopentene β- and γ-amino acids through oxirane formation/oxirane opening and afforded regio- and diastereoisomers of orthogonally protected aminocyclopentanecarboxylates.
- Nonn, Melinda,Binder, Adrienn,Volk, Balázs,Kiss, Loránd
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p. 1199 - 1209
(2020/03/17)
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- Method for synthesizing (1R,4S)-1-amino-4-hydroxymethyl-2-cyclopentene hydrochloride
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The invention relates to a method for synthesizing (1R,4S)-1-amino-4-hydroxymethyl-2-cyclopentene hydrochloride. According to the method, the reaction conditions are mild, (1S,4R)-(-)-2-azabicyalo[2,2,1]hepta-5-alkene-3-ketone is directly used, (1R,4S)-1-amino-4-hydroxymethyl-2-cyclopentene hydrochloride is obtained through the reactions of hydrolysis and reducing, the yield is high, and the optical purity is high.
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Paragraph 0017; 0018
(2017/07/23)
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- Enhanced enzymatic synthesis of the enantiopure intermediate for the blockbuster drug intermediate abacavir through a two-step enzymatic cascade reaction
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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%.
- Galla, Zsolt,Forró, Enik?,Fül?p, Ferenc
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p. 729 - 731
(2016/08/01)
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- Catalytic Promiscuity of Ancestral Esterases and Hydroxynitrile Lyases
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Catalytic promiscuity is a useful, but accidental, enzyme property, so finding catalytically promiscuous enzymes in nature is inefficient. Some ancestral enzymes were branch points in the evolution of new enzymes and are hypothesized to have been promiscuous. To test the hypothesis that ancestral enzymes were more promiscuous than their modern descendants, we reconstructed ancestral enzymes at four branch points in the divergence hydroxynitrile lyases (HNL's) from esterases ～100 million years ago. Both enzyme types are α/β-hydrolase-fold enzymes and have the same catalytic triad, but differ in reaction type and mechanism. Esterases catalyze hydrolysis via an acyl enzyme intermediate, while lyases catalyze an elimination without an intermediate. Screening ancestral enzymes and their modern descendants with six esterase substrates and six lyase substrates found higher catalytic promiscuity among the ancestral enzymes (P 0.01). Ancestral esterases were more likely to catalyze a lyase reaction than modern esterases, and the ancestral HNL was more likely to catalyze ester hydrolysis than modern HNL's. One ancestral enzyme (HNL1) along the path from esterase to hydroxynitrile lyases was especially promiscuous and catalyzed both hydrolysis and lyase reactions with many substrates. A broader screen tested mechanistically related reactions that were not selected for by evolution: decarboxylation, Michael addition, γ-lactam hydrolysis and 1,5-diketone hydrolysis. The ancestral enzymes were more promiscuous than their modern descendants (P = 0.04). Thus, these reconstructed ancestral enzymes are catalytically promiscuous, but HNL1 is especially so.
- Devamani, Titu,Rauwerdink, Alissa M.,Lunzer, Mark,Jones, Bryan J.,Mooney, Joanna L.,Tan, Maxilmilien Alaric O.,Zhang, Zhi-Jun,Xu, Jian-He,Dean, Antony M.,Kazlauskas, Romas J.
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supporting information
p. 1046 - 1056
(2016/02/05)
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- Study on immobilization of (+) γ-lactamase using a new type of epoxy graphene oxide carrier
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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.
- Li, Wei,Wen, Huijiao,Shi, Qianqiao,Zheng, Guojun
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p. 270 - 276
(2016/02/05)
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- Enzymatic preparation of optically pure (+)-2-azabicyclo[2.2.1]hept-5-en-3-one by (-)-γ-lactamase from Bradyrhizobium japonicum USDA 6
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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.
- Zhu, Shaozhou,Ren, Lu,Yu, Songzhu,Gong, Cuiyu,Song, Dawei,Zheng, Guojun
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p. 4899 - 4902
(2015/02/19)
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- Identification and application of enantiocomplementary lactamases for Vince lactam derivatives
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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.
- Assaf, Zeinab,Eger, Elisabeth,Vitnik, Zeljko,Fabian, Walter M. F.,Ribitsch, Doris,Guebitz, Georg M.,Faber, Kurt,Hall, Mélanie
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p. 2517 - 2521
(2015/04/14)
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- Synthesis of regio-and stereoisomers of highly functionalized 1,2,3-triazole-substituted cyclopentanes
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Highly functionalized regio-and stereoisomers of 1,2,3-triazole-substituted cyclopentanes were prepared in six steps from either bicyclic β-lactam 7 or γ-lactam 23 by 1,3-dipolar cycloaddition of the azido cyclopentanol intermediates with acetylenes. The reactions of azido aminocyclopentanols with non-symmetric acetylenes resulted regioselectively in the corresponding 1,4-disubstitued triazole derivatives under both thermal and Cu(I)-catalysed conditions. These compounds can be regarded as highly functionalized 1,2,3-triazole-modified carbocyclic nucleoside analogues.
- Kiss, Lorand,Forro, Eniko,Fueloep, Ferenc
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scheme or table
p. 220 - 228
(2012/04/23)
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- Synthesis of highly functionalized cyclopentanes as precursors of hydroxylated azidocarbonucleosides
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Regio- and stereoisomers of functionalized azido amino alcohols with a cyclopentane skeleton were synthesized in enantiomerically pure forms. Enzymatic ring cleavage of racemic2-azabicyclo[2.2.1]hept-5-en-3-one gave the corresponding amino acid and one enantiomer of the lactam stereospecifically. These were protected by esterification and carbamoylation, and then epoxidized. The resulting oxiranes underwent cleavage by sodium azide with complementary stereoselectivities. The regioisomeric products were easily separated by crystallization or column chromatography.
- Kiss, Lorand,Forro, Enikoe,Sillanpaeae, Reijo,Fueloep, Ferenc
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scheme or table
p. 153 - 160
(2010/04/02)
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- Enzymatic method for the synthesis of blockbuster drug intermediates - Synthesis of five-membered cyclic γ-amino acid and γ-lactam enantiomers
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A very efficient enzymatic method was developed for the synthesis of cyclic γ-lactam and γ-amino acid enantiomers, intermediates for drugs with a prominent turnover (e.g., abacavir and carbovir), through the CAL-B-catalysed enantioselective (E > 200) hydrolysis of the corresponding N-Boc protected and unprotected racemic γ-lactams with H2O in iPr2O. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.
- Forro, Eniko,Fueloep, Ferenc
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scheme or table
p. 5263 - 5268
(2009/06/18)
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- Inhibition and substrate activity of conformationally rigid vigabatrin analogues with γ-aminobutyric acid aminotransferase
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Several cyclopentene GABA analogues were synthesized as conformationally rigid analogues of the epilepsy drug vigabatrin and tested as inhibitors and substrates of γ-aminobutyric acid aminotransferase (GABA-AT). None of these compounds produced time-dependent inhibition. (1R,4S)-(+)-4-Amino-2- cyclopentene-1-carboxylic acid ((+)-3), (4R)-(-)-4-amino-1-cyclopentene-1- carboxylic acid ((-)-4), and d,l-3-amino-1-cyclopentene-1-carboxylic acid (6) are good substrates. The K(m) and k(cat) values for the latter two compounds are very similar to those of GABA, suggesting that they bind in an orientation similar to that of GABA. The K(m) value for (+)-3 is 24 times lower than that for GABA, although its k(cat) value is only one-fourth that for GABA; nonetheless, it is a better substrate for GABA-AT than is GABA. All of these compounds, as well as the enantiomers of 3 and 4 and d,l-trans-4- amino-2-cyclopentene-1-carboxylic acid (5), are competitive inhibitors of GABA-AT. These results demonstrate the effects of the carboxylate group orientation and the stereochemistry of the amino and carboxylate groups on the substrate activity and inhibitor activity, and this should be important to the future design of inhibitors of GABA-AT.
- Qiu, Jian,Pingsterhaus, Joyce M.,Silverman, Richard B.
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p. 4725 - 4728
(2007/10/03)
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- An approach to a carbocyclic analogue of cyclic adenosine 5'-diphosphate ribose. The synthesis and bisphosphorylation of N1-[(1S,3R)-3-(hydroxymethyl)cyclopent-1-yl]inosine
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The synthesis of N1-[(1S,3R)-3-(hydroxymethyl)cyclopent-1-yl]inosine (11) via a cyclocondensation route is reported. Regioselective bisphosphorylation of the primary 5'-hydroxyl groups leads to a carbocyclic, inosine analogue of seco adenosine 5'-diphosphate ribose(3).
- Fortt, Simon M.,Potter, Barry V. L.
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p. 5371 - 5374
(2007/10/03)
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- Lipase-catalyzed resolution of 2-azabicyclo[2.2.1]hept-5-en-3-ones
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The lipase-catalyzed asymmetric resolution of 2-azabicyclo[2.2.1]hept-5-en-3-ones is reported; non-racemic chiral 2-azabicyclo[2.2.1]hept-5-en-3-ones were obtained conveniently by lipase-catalyzed enantioselective transesterification or hydrolysis of N-hydroxymethyl-2-azabicyclo[2.2.1]hept-5-en-3-one or N-acyloxymethyl-2-azabicyclo[2.2.1]hept-5-en-3-one.
- Nakano, Hiroto,Iwasa, Kazuto,Okuyama, Yuko,Hongo, Hiroshi
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p. 2381 - 2386
(2007/10/03)
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- Biocatalytical Transformations. IV. Enantioselective Enzymatic Hydrolyses of Building Blocks for the Synthesis of Carbocyclic Nucleosides
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Enantiomerically pure alkyl (1S,4R)- and (1R,4S)-4-acetamido-cyclopent-2-ene-carboxylates are obtained from their corresponding racemates by hydrolysis with PLE or the lipase from Candida cylindracea.
- Csuk, Rene,Doerr, Petra
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p. 269 - 276
(2007/10/02)
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- Development of the Biocatalytic Resolution of 2-azabicyclohept-5-en-3-one as an entry to Single-Enantiomer Carbocyclic Nucleosides
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For the resolution of the bicyclic lactam 2-azabicyclohept-5-en-3-one, efficient whole cell biocatalysts have been identified and from these, enzymes (lactamases) have been isolated.While the two enzymes obtained act on different enantiomers of the lactam, either can be used in scaleable processes to obtain synthons for carbocyclic nucleosides having the natural configuration.
- Taylor, Stephen J C,McCague, Raymond,Wisdom, Richard,Lee, Carol,Dickson, Karen,et al.
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p. 1117 - 1128
(2007/10/02)
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- Enzymatic asymmetric synthesis of cis-4-cyclopentene-1,3-dimethanol monoacetate
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Asymmetric synthesis of cis-4-cyclopentene-1,3-dimethanol monoacetate was performed via enzymatic hydrolysis of the diacetate or enzymatic acetylation of the diol precursor. Esterases and lipases were studied, and Candida cylindracea lipase was shown to afford the (-)-enantiomer with ee>97%.
- Mekrami,Sicsic
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p. 431 - 436
(2007/12/18)
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