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Functionalized unnatural amino acids with quaternary carbon centers and biocatalytic desymmetrization preparation method thereof

A compound and catalytic hydrolysis technology, applied in biochemical equipment and methods, microorganism-based methods, microorganisms, etc., can solve problems such as poor selectivity and harsh chemical transformation requirements

Inactive Publication Date: 2013-09-11
INST OF CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Amides are an important class of organic synthesis intermediates. The chemical transformation of amides requires harsh conditions and poor selectivity, while the biotransformation of amides has the advantages of mild conditions and high selectivity. At present, it has been possible to prepare from nitriles in industry Corresponding carboxylic acids and amide derivatives, and the preparation of carboxylic acids from amides, especially the preparation of chiral amide carboxylic acid compounds and their amino acid derivatives with quaternary carbon centers by biotransformation desymmetry method is still very rare. few

Method used

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  • Functionalized unnatural amino acids with quaternary carbon centers and biocatalytic desymmetrization preparation method thereof
  • Functionalized unnatural amino acids with quaternary carbon centers and biocatalytic desymmetrization preparation method thereof
  • Functionalized unnatural amino acids with quaternary carbon centers and biocatalytic desymmetrization preparation method thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0077]

[0078] Specific implementation method:

[0079] Get 2 grams of wet weight of Rhodococcus erythropolis AJ270 cells (Institute of Chemistry, Chinese Academy of Sciences), thaw at 30°C for 30 minutes, and use a buffer solution of dipotassium hydrogen phosphate and potassium dihydrogen phosphate (0.1M, pH7.0, 50ml) Wash the bacterium into an Erlenmeyer flat-bottomed flask with a threaded opening, disperse and shake well, and then put it in a shaker for activation at 30°C for 30 minutes, then add 2mmol (314mg) of the compound shown in formula VI-1 at one time, put The catalytic hydrolysis reaction was carried out in a shaker at 30° C. and 200 rpm. Whole reaction TLC monitors, stops reaction after reacting for 40 minutes, gained reaction solution removes thalline through one deck diatomite suction filtration, washes filter residue three times with 20 milliliters of water successively, obtains the compound shown in formula 1 provided by the invention (R 1 for -CH 2 CH=C...

Embodiment 2

[0083]

[0084] Specific implementation method:

[0085] Compound 1 (100mg) was added to DMF (5ml), K 2 CO 3 (1.5mmol), benzyl bromide (2mmol) and stirred at room temperature (25°C) overnight (12 hours) to complete the reaction. followed by H 2 O (25ml), extracted with ethyl acetate (3×25ml), anhydrous MgSO 4 Drying, remove solvent with rotary evaporator, dry loading, flash column chromatography obtains the compound described in formula I-2 provided by the invention (R 1 for -CH 2 CH=CH 2 , R 2 for-NH 2 , R 3 -Bn) 196 mg, yield: 91%, ee97.0%.

[0086] Compound 2 solid, mp145-146°C; [α] 25 D : +17.9° (c1.90, CHCl 3 ); ee=97.0% (chiral HPLC analysis); IR (KBr) v3437cm -1 , 1742cm -1 , 1689cm -1 , 1202cm -1 ; 1 H NMR (300MHz, CDCl 3 )7.32-7.19 (m, 10H), 7.08 (s, 1H), 5.80-5.66 (m, 2H), 5.29-5.13 (m, 4H), 3.61 (dd, J=26.7, 12.0Hz, 2H), 2.97 -2.84(m, 2H)2.31(s, 1H); 13 C NMR (75MHz, CDCl 3 ) 172.2, 170.7, 135.4, 131.5, 128.63, 128.58, 128.51, 128.47, 128.2, ...

Embodiment 3

[0089]

[0090] 1) Take two grams of wet weight of Rhodococcus erythropolis AJ270 cells (Institute of Chemistry, Chinese Academy of Sciences), thaw at 30°C for 30 minutes, and use a buffer solution of dipotassium hydrogen phosphate and potassium dihydrogen phosphate (0.1M, pH7.0, 50ml) and wash the bacterium into a 150ml Erlenmeyer flat-bottomed flask with a screw top, disperse and shake well, put it into a shaker and activate it at 30°C for 30 minutes, then add 2mmol (342mg) of the formula VI-2 at one time The compound was placed in a shaker at 30° C. and 200 rpm to carry out catalytic hydrolysis reaction. Whole reaction TLC monitors, stops reaction after reacting 50min, and gained reaction solution removes thalline through one layer of diatomaceous earth suction filtration, washes filter residue three times with 20 milliliters of water successively, obtains the compound shown in formula 3 provided by the invention (R 1 for -CH 2 CH=CHCH 3 , R 2 for-NH 2 ) 320 mg, the ...

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Abstract

The invention discloses a functionalized unnatural chiral amino acid compounds with quaternary carbon centers and a preparation method thereof. In the invention, a Rhodococcus erythropolis AJ270 microbial system is taken for catalytic hydrolysis of prochiral malonamide compounds with different substituent groups so as to obtain corresponding unnatural amino acids with an amide group. The dosage of the Rhodococcus erythropolis can be adjusted according to the dosage of a substrate. The reaction solvent is a common buffer solution with a pH value of 6.0-8.0, and the reaction is performed at 20-37DEG C for 0.1-120h. The Rhodococcus erythropolis microbial catalytic system has the characteristics of fermentable cultivation and convenient preservation. The method for preparing monoamide carboxylic acid and dicarboxylic acid through bioconversion has the characteristics of simple operation, high efficiency reaction, mild reaction conditions, high enantioselectivity, easy separation of products, and high product purity, and can be used for synthesis of other unnatural chiral amino acids with a quaternary carbon center.

Description

technical field [0001] The invention relates to a functionalized non-natural amino acid with a quaternary carbon center and a biocatalytic desymmetry preparation method thereof. Background technique [0002] Amino acid compounds are the most widely existing compounds in living organisms, and are important components of living organisms, which play a very important role in the process of life. Because of its similar structure to natural amino acids, unnatural amino acids can often be used as substitutes for natural amino acids to study the role of different amino acids in life processes. Unnatural amino acids have shown certain promise as synthetic raw materials for some growth factor receptor proteins. drug activity. Currently commercialized unnatural amino acids include 2-Amino-2-methyl-3-phenylpropanoic acid (sold by Pure Chemistry Scientific Inc, USA) and 2-Amino-2-methyl-4-pentenoic acid (sold by hexagon labs, USA) . [0003] Biocatalysis is by far the most efficient,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C237/16C07C237/20C07C237/06C07C229/30C07C229/22C07C215/24A61P35/00C12P13/04C12P13/02C12P13/00C12R1/01
Inventor 王梅祥王德先张立彬
Owner INST OF CHEM CHINESE ACAD OF SCI
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