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Enzymatic synthesis of chiral amino alcohol compounds

A technology of amino acid and biocatalysis, which is applied in the preparation of amino hydroxyl compounds, the preparation of organic compounds, methods based on microorganisms, etc. It can solve the problems of low yield, many by-products, and the maximum can only reach 50%. The effect of high conversion rate, less by-products and good catalytic activity

Active Publication Date: 2022-04-22
TIANJIN INST OF IND BIOTECH CHINESE ACADEMY OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Lipase and acylase are used to catalyze the synthesis of optically pure chiral o-amino alcohols through kinetic resolution, but the product yield can only reach 50%; ω-transaminase is also reported to catalyze the synthesis of chiral o-amino Alcohol, but there are problems such as low yield and many by-products; ω-transaminase, decarboxylase, transketolase cascade reaction can also obtain chiral aminoalcohol compounds; Arnold research team reported the use of cytochrome c to convert alkenes into amino groups Alcohol compounds; recently, Xu Jianhe's research group developed a new method for the synthesis of chiral o-amino alcohols using amine dehydrogenase, and synthesized a series of amino alcohol compounds

Method used

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  • Enzymatic synthesis of chiral amino alcohol compounds
  • Enzymatic synthesis of chiral amino alcohol compounds
  • Enzymatic synthesis of chiral amino alcohol compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Example 1: Construction and induced expression of imine reductase genetically engineered bacteria

[0025] The imine reductase gene was synthesized by General Biosystems (Anhui) Co., Ltd., connected to the pET28a vector, and then transformed into Escherichia coli BL21 (DE3) competent cells, and single clones were picked to obtain recombinant bacteria. Select a single colony on the plate and inoculate it into 20mL LB medium containing the corresponding antibiotic, cultivate it for about 12 hours as a seed solution, inoculate it into 700mL LB medium containing the corresponding antibiotic according to the inoculation amount of 1%, and inoculate it on a shaker at 37°C and 200rpm Grow to OD 600 =0.6-0.8, add IPTG with a final concentration of 0.1 mmol / L and induce at 25°C for 12 hours. The bacterial cells were collected by centrifuging the culture medium at 6000rpm.

Embodiment 2

[0026] Example 2: Synthesis of α-hydroxyketone substrates

[0027] 200mL of absolute ethanol was used as a solvent, added to a 500mL flask, and 2.8mL of triethylamine (20mmol / L), 3.6g of paraformaldehyde (600mmol / L), 2.88g of n-butyraldehyde (200mmol / L) or 3.44g isovaleraldehyde (200mmol / L) or 4.8g phenylacetaldehyde (200mmol / L) or 5.36g phenylpropionaldehyde (200mmol / L) or 3.96g p-bromophenylacetaldehyde (100mmol / L) or 4.24g p-bromine Phenylpropionaldehyde (100mmol / L), under the catalysis of 2.88g thiazole salt (20mmol / L), heated and refluxed at 60°C for 96h, during the reaction, N 2 Protection, to obtain α-hydroxy ketone compound 1-hydroxy-2-pentanone or 1-hydroxy-4-methyl-2-pentanone or 1-hydroxy-3-phenyl-2-propanone or 1-hydroxy-4- Phenyl-2-butanone or 1-hydroxy-3-(4-bromophenyl)-2-propanone or 1-hydroxy-4-(4-bromophenyl)-2-butanone. The solvent in the system after the reaction is removed, the target compound is obtained through column chromatography separation, the targ...

Embodiment 3

[0028] Example 3: Whole cells of imine reductase genetically engineered bacteria catalyze the reductive amination reaction of 1-hydroxy-3-phenyl-2-propanone and cyclopropylamine.

[0029]Weigh 0.05 g of imine reductase genetic engineering bacteria IR-27, IR-30, IR-36, IR-38, IR-40, IR-44, IR-51, IR-54, IR-56, IR -57, dissolved in 900 μL pH 8.0 K 2 HPO 4 -KH 2 PO 4 To the buffer, add 1.5 mg 1-hydroxy-3-phenyl-2-propanone (10 mmol / L) and dissolve it in 100 μL of anhydrous methanol, add 10 times equivalent of prepared cyclopropylamine (pH 8.0), 0.5 mg NADP + , 3U GDH enzyme powder, 7.2mg glucose (40mmol / L), after mixing evenly, react at 200rpm, 25℃ for 24h. After the reaction, the reaction system was treated with 1mol / L Na 2 CO 3 Adjust base and then extract with ethyl acetate, and detect by HPLC after the solvent is evaporated to dryness. The test results are: IR-27 catalyzes the reaction to obtain the S configuration product, the ee value is 99%, IR-36, IR-38, IR-40, IR...

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Abstract

The invention discloses a method for generating an optical pure chiral amino alcohol compound by catalyzing a reaction between alpha-hydroxy ketone and small molecule amine through a biocatalyst. More specifically, the invention provides a method for generating chiral amino alcohol by catalyzing reductive amination reaction of different types of alpha-hydroxy ketones and small molecular amine through imine reductase. The method has the remarkable characteristics of mild reaction conditions, good stereoselectivity, no pollution and the like.

Description

technical field [0001] The invention belongs to the field of biocatalysis and relates to the use of biocatalyst imine reductase to catalyze the reaction of α-hydroxy ketone and small molecule amine to generate optically pure chiral amino alcohol compound. Background technique [0002] Chiral aminoalcohol compounds are a class of compounds with a wide range of applications. In recent years, with the in-depth research on chiral compounds, more research has been done on the application of chiral amino alcohol compounds. As chiral auxiliary agents or chiral ligands, chiral amino alcohols play an important role in various asymmetric synthesis. In addition, chiral amino alcohols often exist in secondary metabolites and active pharmaceutical ingredients. Many natural products with chiral o-amino alcohol structures have certain physiological activities, such as ephedrine extracted from Macao, mainly It is used as cold medicine and cough medicine; Bestatin is a compound with dipept...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N9/06C12N1/21C12N15/70C12N15/53C12P13/00C07C213/10C07C215/28C07C215/24C12R1/19
CPCC12N9/0028C12P13/001C12N15/70C07C213/10C07C2601/02C07B2200/07C07C215/28C07C215/24
Inventor 姚培圆胡娜徐泽菲冯进辉吴洽庆朱敦明马延和
Owner TIANJIN INST OF IND BIOTECH CHINESE ACADEMY OF SCI
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