CN110756222B - Nucleoside triphosphate artificial metalloenzyme and preparation and application thereof - Google Patents

Nucleoside triphosphate artificial metalloenzyme and preparation and application thereof Download PDF

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CN110756222B
CN110756222B CN201911113376.2A CN201911113376A CN110756222B CN 110756222 B CN110756222 B CN 110756222B CN 201911113376 A CN201911113376 A CN 201911113376A CN 110756222 B CN110756222 B CN 110756222B
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nucleoside triphosphate
metalloenzyme
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artificial metalloenzyme
otf
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王长号
齐倩倩
陈亚芍
郝敏
吕舒婷
董星辰
顾由琨
邬佩哲
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Shaanxi Normal University
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Abstract

The invention discloses a nucleoside triphosphate artificial metalloenzyme, and preparation and application thereof. The structural formula of the metalloenzyme is shown as
Figure DDA0002273382060000011
In which n represents 1, 2 or 3 and A represents
Figure DDA0002273382060000012
Figure DDA0002273382060000013
Any one of B represents H or OH, C represents Cu (OTf) 2 、CuSO 4 、CuCl 2 、Cu(NO 3 ) 2 、
Figure DDA0002273382060000014
Any one of them. Nucleoside trisThe phosphoric acid is used as a main molecule and forms nucleoside triphosphate artificial metalloenzyme with metal ions or metal complexes through supermolecule self-assembly, the preparation method is simple and convenient, the structure is novel, the phosphoric acid is used for catalyzing asymmetric Diels-Alder reaction and asymmetric Michael reaction in a water phase, the catalytic activity is high, and higher enantioselectivity can be realized.

Description

Nucleoside triphosphate artificial metalloenzyme and preparation and application thereof
Technical Field
The invention relates to nucleoside triphosphate artificial metalloenzyme, a preparation method thereof and application of the nucleoside triphosphate artificial metalloenzyme as a chiral catalyst in asymmetric Diels-Alder reaction and asymmetric Michael reaction.
Technical Field
The artificial metalloenzyme combines the characteristics of homogeneous catalysis and biological catalysis, and the metal complex with catalytic performance is assembled into the skeleton of the biological macromolecule for expanding the type of homogeneous reaction and exploring the catalytic function of the biological macromolecule. The assembly of proteins as chiral scaffolds and metal complexes into artificial metalloproteinases has been extensively studied by researchers, and in recent years, nucleic acids with natural spatial structures have attracted great interest to researchers for the assembly of artificial nucleic acid metalloproteinases. Researchers use chiral skeletons of double helix DNA and achiral metal complexes to assemble artificial DNA metalloenzyme through supermolecular assembly or covalent interaction, and the artificial DNA metalloenzyme is successfully applied to a series of asymmetric catalytic reactions in water phase. In addition, there are a few studies reporting the assembly of artificial RNA metalloenzymes using RNA as a chiral backbone. So far, the nucleic acid fragments for assembling the artificial nucleic acid metalloenzyme are mostly in dozens to hundreds of nucleotide units, which causes difficulty in obtaining fine structure of the artificial nucleic acid metalloenzyme and chiral microenvironment information of the reaction, and limits the research on the reaction mechanism of the artificial nucleic acid metalloenzyme. Therefore, artificial metalloenzymes that attempt to assemble small fragment nucleic acids are critical to understanding the interaction of metal active species and nucleic acids. Adenosine Triphosphate (ATP), which is widely available in nature, is an unstable, high-energy compound that is an "energy currency" for organisms. ATP contains two high-energy phosphate bonds which can be broken to release energy for enzymes, primary active transport carriers and the like to supply energy for life activities. ATP can interact with metal ions to form a specific spatial configuration, which provides a precondition for constructing ATP-based nucleic acid metalloenzymes. To date, there has been no report of the assembly of artificial metalloenzymes using ATP as a chiral scaffold for asymmetric catalytic studies. Research on ATP artificial metalloenzyme not only can develop a practical type of biological hybrid catalyst, but also is helpful for researching the action mode between metal active center and nucleic acid.
Asymmetric Diels-Alder reactions and asymmetric Michael reactions are important types of carbon-carbon bond formation reactions in synthetic chemistry. Asymmetric Diels-Alder reaction can obtain one or more products of six-membered ring through intermolecular 4+2 cycloaddition reaction, wherein the products contain a plurality of potential chiral centers, and the method is an effective method for synthesizing natural organic compounds and substances with physiological activity. The asymmetric Michael reaction achieves the purpose of carbon chain extension by attacking an ketene substrate by a nucleophilic reagent, is one of important reactions in organic synthesis, and is also an important conversion reaction in the life process. The two types of asymmetric reactions have been extensively studied in organic synthesis, but most of the reactions are currently carried out in organic solvent media. The water used as a reaction medium has the characteristics of safety, low price, environmental friendliness and the like, and the development of asymmetric catalytic reaction in a water phase is beneficial to promoting green chemistry and reducing industrial cost.
Disclosure of Invention
The invention aims to provide a novel nucleoside triphosphate artificial metalloenzyme catalyst, and provides a preparation method and a new application thereof.
Aiming at the purposes, the structural formula of the nucleoside triphosphate artificial metalloenzyme adopted by the invention is shown as follows:
Figure BDA0002273382040000021
in which n represents 1, 2 or 3 and A represents
Figure BDA0002273382040000022
Any one of B represents H or OH, C represents Cu (OTf) 2 、CuSO 4 、CuCl 2 、Cu(NO 3 ) 2 、
Figure BDA0002273382040000023
Figure BDA0002273382040000024
Any one of them.
In the structural formula of the nucleoside triphosphate artificial metalloenzyme, n preferably represents 3, and A preferably represents
Figure BDA0002273382040000025
B represents H or OH, C represents Cu (OTf) 2 、Cu(NO 3 ) 2 、
Figure BDA0002273382040000026
Any one of them.
The preparation method of the nucleoside triphosphate artificial metalloenzyme comprises the following steps: adding nucleoside triphosphate shown in formula I and copper salt or copper complex into morpholine ethanesulfonic acid or morpholine propanesulfonic acid buffer solution with the pH value of 5.0-7.0 according to the molar ratio of 1: 1-20: 1, and stirring and reacting for 15-30 minutes at the temperature of 0-25 ℃ to obtain the nucleoside triphosphate artificial metalloenzyme.
Figure BDA0002273382040000031
The above copper salt is Cu (OTf) 2 、CuSO 4 、CuCl 2 、Cu(NO 3 ) 2 Any one of them, the copper complex is
Figure BDA0002273382040000032
Any one of them.
In the preparation method of the nucleoside triphosphate artificial metalloenzyme, preferably, the nucleoside triphosphate shown in the formula I and a copper salt or copper complex are added into a morpholine ethanesulfonic acid or morpholine propanesulfonic acid buffer solution with the pH value of 5.5-6.0 according to the molar ratio of 5: 1-10: 1, and the reaction is stirred at the temperature of 4-10 ℃ for 15-30 minutes to obtain the nucleoside triphosphate artificial metalloenzyme.
The invention relates to an application of nucleoside triphosphate artificial metalloenzyme catalysis asymmetric Diels-Alder reaction, which comprises the following steps: stirring the nucleoside triphosphate artificial metalloenzyme at 0-25 ℃ for 15-30 minutes, adding the azachalcone compound and cyclopentadiene, and continuously reacting at the temperature for 12-24 hours to obtain a Diels-Alder reaction product.
The molar ratio of the azachalcone compound to the cyclopentadiene and nucleoside triphosphate artificial metalloenzyme is 1: 50-300: 0.01-0.5, and the molar ratio of the azachalcone compound to the cyclopentadiene and nucleoside triphosphate artificial metalloenzyme is preferably 1: 150-200: 0.05-0.1.
The azachalcone compound is
Figure BDA0002273382040000033
In the formula, R represents phenyl and C 1 ～C 3 Alkyl-substituted phenyl, C 1 ～C 3 Any one of alkoxy substituted phenyl, nitro substituted phenyl, amino substituted phenyl, halogenated phenyl, pyridyl, furyl and thienyl.
The invention relates to an application of nucleoside triphosphate artificial metalloenzyme catalysis Michael reaction, which comprises the following steps: the method comprises the steps of stirring nucleoside triphosphate artificial metalloenzyme for 15-30 minutes at 0-25 ℃, adding a mixture of an imidazolone compound and a nucleophilic reagent, and continuing to react for 24-72 hours at the temperature to obtain a Michael addition reaction product.
The molar ratio of the imidazolenone compound to the nucleophilic reagent and the nucleoside triphosphate artificial metalloenzyme is 1: 20-250: 0.01-0.5, and the molar ratio of the imidazolenone compound to the nucleophilic reagent and the nucleoside triphosphate artificial metalloenzyme is preferably 1: 70-100: 0.05-0.1.
The above-mentioned imidarenone compounds are
Figure BDA0002273382040000041
In the formula R 1 Represents C 1 ～C 6 Alkyl, phenyl, C 1 ～C 3 Any one of alkoxy substituted phenyl and halogenated phenyl; the nucleophilic reagent is
Figure BDA0002273382040000042
Or R 3 NO 2 ，R 2 Represents C 1 ～C 3 Alkyl radical, R 3 Represents C 1 ～C 6 An alkyl group.
The invention has the following beneficial effects:
the invention combines the bioenergy molecule nucleoside triphosphate as a chiral main molecule with copper salt or copper complex for the first time, generates the nucleoside triphosphate artificial metalloenzyme by in-situ self-assembly, has simple preparation process and good stability in water and air, is used for catalyzing asymmetric Diels-Alder reaction and asymmetric Michael reaction in a water phase, and has higher catalytic activity, higher conversion rate and higher enantioselectivity. And the water used as a reaction medium has the characteristics of low price, safety and environmental friendliness.
Drawings
FIG. 1 shows ATP. Cu (OTf) in example 1 2 Middle ATP & Cu 2+ The structure of (1).
Detailed Description
The present invention is described in further detail below with reference to the drawings and examples, but the scope of the present invention is not limited to these examples.
Example 1
Preparation of adenine nucleoside triphosphate/copper triflate Artificial metalloenzyme (ATP. Cu (OTf)) 2 )
Figure BDA0002273382040000043
At 4 ℃ stripNext, to 1000. mu.L of 20mM morpholine ethanesulfonic acid buffer solution, pH5.5, 5. mu.L of 50mM Adenosine Triphosphate (ATP) aqueous solution was added, and 10. mu.L of 5mM Cu (OTf) was added 2 The aqueous solution was stirred for 30 minutes to obtain ATP. Cu (OTf) 2 . As can be seen from FIG. 1, Cu 2+ And N7 on adenine, phosphorus-oxygen bonds at the beta-and gamma-positions in ATP, and 6-NH on adenine 2 Form stable ATP. Cu by weak interaction 2+ An artificial metalloenzyme.
Example 2
Preparation of a guanine nucleoside triphosphate/copper triflate Artificial Metalloenzyme (GTP Cu (OTf)) 2 )
Figure BDA0002273382040000051
In this example, adenine nucleotide triphosphate (ATP) in example 1 was replaced with equimolar guanine nucleotide triphosphate (GTP) and the same procedure as in example 1 was repeated to obtain GTP Cu (OTf) 2 。
Example 3
Preparation of deoxyadenosine triphosphate/copper trifluoromethanesulfonate Artificial metalloenzyme (dATP. Cu (OTf)) 2 )
Figure BDA0002273382040000052
In this example, dATP. Cu (OTf) was obtained by replacing Adenosine Triphosphate (ATP) in example 1 with equimolar deoxyadenosine triphosphate (dATP), and the other steps were the same as in example 1 2 。
Example 4
Preparation of adenine nucleoside diphosphate/copper trifluoromethanesulfonate Artificial Metalloenzyme (ADP. Cu (OTf)) 2 )
Figure BDA0002273382040000053
In this example, Adenosine Triphosphate (ATP) in example 1 was replaced with equimolar Adenosine Diphosphate (ADP), and the procedure was otherwise the same as in example 1 to obtain ADP. Cu (OTf) 2 。
Example 5
Preparation of an adenine nucleoside triphosphate/copper nitrate Artificial Metalloenzyme (ATP. Cu (NO) 3 ) 2 )
Figure BDA0002273382040000061
In this example, equimolar amounts of copper nitrate (Cu (NO) were used 3 ) 2 ) Alternative copper trifluoromethanesulfonate in example 1 (Cu (OTf) 2 ) The other steps were carried out in the same manner as in example 1 to obtain ATP. Cu (NO) 3 ) 2 。
Example 6
Preparation of an adenine nucleoside triphosphate/copper tripyridylate nitrate Artificial Metalloenzyme (ATP. Cu (tpy)) (NO) 3 ) 2 )
Figure BDA0002273382040000062
In this example, equimolar amounts of copper terpyridyl nitrate (Cu (tpy)) (NO) were used 3 ) 2 ) Alternative copper trifluoromethanesulfonate in example 1 (Cu (OTf) 2 ) The other steps were carried out in the same manner as in example 1 to obtain ATP. Cu (tpy) (NO) 3 ) 2 。
Example 7
ATP. Cu (OTf) in example 1 2 Catalyzing asymmetric Diels-Alder reaction of (E) -3-phenyl-1- (pyridine-2-yl) prop-2-en-1-one and cyclopentadiene to generate (3-phenyl bicyclo [ 2.2.1)]The application of hept-5-ene-2-yl) (pyridine-2-yl) ketone comprises the following steps:
Figure BDA0002273382040000063
at 4 deg.C, to 100 deg.Cmu.L of 20mM morpholine ethanesulfonic acid buffer solution, pH5.5, 5. mu.L of 50mM Adenosine Triphosphate (ATP) aqueous solution, 10. mu.L of 5mM Cu (OTf) 2 The aqueous solution was stirred for 30 minutes to obtain ATP. Cu (OTf) 2 Then 0.21mg (1. mu. mol) of (E) -3-phenyl-1- (pyridin-2-yl) prop-2-en-1-one was dissolved in 10. mu.L of acetonitrile and added thereto, and 20. mu.L (200. mu. mol) of cyclopentadiene was added thereto, and the reaction was continued at 4 ℃ for 24 hours; after the reaction is finished, the mixture is extracted by anhydrous ether (2mL multiplied by 3), and the organic phase is taken and passed through a simple silica gel chromatographic column to remove residual water and trace Cu 2+ After rotary evaporation, concentration and drying, the crude product is analyzed by HPLC, the conversion rate of (E) -3-phenyl-1- (pyridine-2-yl) prop-2-ene-1-one is 94 percent, and the (3-phenyl bicyclo [2.2.1 ] is]Stereoselectivity of hept-5-en-2-yl) (pyridin-2-yl) methanone (endo: exo) is 90:10, with an enantioselectivity of 72% for the endo-type product and 80% for the exo-type product. The racemate product is characterized by a Bruker Avance type superconducting Fourier digital nuclear magnetic resonance spectrometer, and the characterization data is as follows: 1 H NMR(400MHz,CDCl 3 )δ8.78–8.59(m,1H),8.11–7.97(m,1H),7.79(td,J＝7.7,1.7Hz,1H),7.42(ddd,J＝7.6,4.8,1.3Hz,1H),7.30(ddd,J＝13.2,8.3,1.3Hz,4H),7.17(ddd,J＝8.5,2.6,1.3Hz,1H),6.51(dd,J＝5.6,3.2Hz,1H),5.85(dd,J＝5.6,2.8Hz,1H),4.56(dd,J＝5.2,3.4Hz,1H),3.64–3.43(m,2H),3.10(d,J＝1.4Hz,1H),2.09(d,J＝8.6Hz,1H),1.68–1.55(m,1H). 13 C NMR(100MHz,CDCl 3 ) δ 201.17(s),153.68(s),148.99(s),144.75(s),139.53(s),136.95(s),132.99(s),128.51(s),127.77(s),127.02(s),125.96(s),122.29(s),54.40(s),49.47(s),48.89(s),48.36(s),45.69(s) hrms (esi) theoretical value [ C(s) ] 19 H 17 NO]·Na + (M+Na) + : m/z 298.1202, found: 298.1199.
in this example, the GTP Cu (OTf) in example 2 was used in equimolar amounts 2 Alternative ATP. Cu (OTf) 2 The conversion of (E) -3-phenyl-1- (pyridin-2-yl) prop-2-en-1-one was 83%, (3-phenylbicyclo [2.2.1 ]]Stereoselectivity of hept-5-en-2-yl) (pyridin-2-yl) methanone (endo: exo) was 91:9, with an enantiomeric selectivity of 68% for the endo form and 77% for the exo form.
In this example, the same moles of dATP. Cu (OTf) as in example 3 were used 2 Alternative ATP. Cu (OTf) 2 The conversion of (E) -3-phenyl-1- (pyridin-2-yl) prop-2-en-1-one was 86%, (3-phenylbicyclo [2.2.1 ]]Stereoselectivity of hept-5-en-2-yl) (pyridin-2-yl) methanone (endo: exo) was 92:8, with an enantioselectivity of 50% for the endo-type product and 62% for the exo-type product.
In this example, ATP-Cu (NO) in example 5 was used in equimolar amounts 3 ) 2 Alternative ATP. Cu (OTf) 2 The conversion of (E) -3-phenyl-1- (pyridin-2-yl) prop-2-en-1-one was 90%, (3-phenylbicyclo [2.2.1 ]]Stereoselectivity of hept-5-en-2-yl) (pyridin-2-yl) methanone (endo: exo) was 91:9, with an enantiomeric selectivity of 64% for the endo form and 74% for the exo form.
Example 8
ATP. Cu (OTf) in example 1 2 Catalyzing asymmetric Diels-Alder reaction of (E) -3- (4-methoxyphenyl) -1- (pyridin-2-yl) prop-2-en-1-one and cyclopentadiene to generate (3- (4-methoxyphenyl) bicyclo [2.2.1]The application of hept-5-ene-2-yl) (pyridine-2-yl) ketone comprises the following steps:
Figure BDA0002273382040000081
in this example, (E) -3-phenyl-1- (pyridin-2-yl) prop-2-en-1-one in example 7 was replaced with equimolar (E) -3- (4-methoxyphenyl) -1- (pyridin-2-yl) prop-2-en-1-one, and the other steps were the same as in example 7, except that the conversion of (E) -3- (4-methoxyphenyl) -1- (pyridin-2-yl) prop-2-en-1-one was 85%, and (3- (4-methoxyphenyl) bicyclo [ 2.2.1-one]Stereoselectivity of hept-5-en-2-yl) (pyridin-2-yl) methanone (endo: exo) was 91:9, with an enantiomeric selectivity of 79% for the endo form and 62% for the exo form. Racemate characterization data are: 1 H NMR(400MHz,CDCl 3 )δ8.68(dd,J＝4.7,0.7Hz,1H),8.00(d,J＝7.8Hz,1H),7.81(td,J＝7.7,1.7Hz,1H),7.45(ddd,J＝7.5,4.8,1.2Hz,1H),7.24(d,J＝8.6Hz,2H),6.88–6.77(m,2H),6.48(dd,J＝5.5,3.2Hz,1H),5.82(dd,J＝5.6,2.7Hz,1H),4.49(dd,J＝5.1,3.4Hz,1H),3.76(d,J＝7.6Hz,3H),3.53(s,1H),3.38(d,J＝5.0Hz,1H),3.02(s,1H),2.06(d,J＝8.4Hz,1H),1.74–1.51(m,2H),1.26(s,1H). 13 C NMR(100MHz,CDCl 3 ) δ 201.21(s),157.77(s),153.65(s),148.85(s),139.45(s),136.76(d, J ═ 15.3Hz),132.74(s),128.55(s),126.85(s),122.18(s),113.79(s),55.28(s),54.30(s),49.68(s),48.69(s),48.17(s),44.93(s) hrms (esi) theoretical value [ C (C) 201.21(s),157.77(s),153.65(s), hrms (esi) ]theoretical value [ C(s) ], C(s), and C(s) 20 H 19 NO 2 ]·Na + (M+Na) + : m/z 328.1308, found: 328.1303.
example 9
ATP. Cu (OTf) in example 1 2 Catalyzing an asymmetric Diels-Alder reaction of (E) -3- (4-nitrophenyl) -1- (pyridin-2-yl) prop-2-en-1-one with cyclopentadiene to produce (3- (4-nitrophenyl) bicyclo [2.2.1]The application of hept-5-ene-2-yl) (pyridine-2-yl) ketone comprises the following steps:
Figure BDA0002273382040000082
in this example, (E) -3-phenyl-1- (pyridin-2-yl) prop-2-en-1-one in example 7 was replaced with equimolar (E) -3- (4-nitrophenyl) -1- (pyridin-2-yl) prop-2-en-1-one, and the other steps were the same as in example 7, except that the conversion of (E) -3- (4-nitrophenyl) -1- (pyridin-2-yl) prop-2-en-1-one was 85%, and (3- (4-nitrophenyl) bicyclo [ 2.2.1-one was]Stereoselectivity of hept-5-en-2-yl) (pyridin-2-yl) methanone (endo: exo) was 84:16, with an enantiomeric selectivity of 84% for the endo form and 78% for the exo form. Racemate characterization data: 1 H NMR(400MHz,CDCl 3 )δ8.69–8.63(m,1H),8.13(d,J＝8.6Hz,2H),8.01(d,J＝7.8Hz,1H),7.83(dd,J＝10.9,4.5Hz,1H),7.51–7.40(m,3H),6.48(dd,J＝5.4,3.3Hz,1H),5.87(dd,J＝5.5,2.7Hz,1H),4.53–4.41(m,1H),3.60(s,1H),3.53(d,J＝5.1Hz,1H),3.12(s,1H),2.00(d,J＝8.6Hz,1H),1.67(d,J＝8.4Hz,2H). 13 C NMR(100MHz,CDCl 3 )δ200.39(s),153.24(s),152.81(s),148.92(s),138.97(s),137.01(s),133.43(s),128.37(s),127.18(s),123.64(s),122.32(s)54.71(s),48.86(d, J ═ 19.0Hz),48.20(s),45.76(s), hrms (esi) theoretical values [ C 19 H 16 N 2 O 3 ]·Na + (M+Na) + : m/z 343.1053, found: 343.1044.
example 10
ATP. Cu (OTf) in example 1 2 Catalyzing an asymmetric Diels-Alder reaction of (E) -1, 3-bis (pyridin-2-yl) prop-2-en-1-one with cyclopentadiene to produce pyridin-2-yl (3- (pyridin-2-yl) bicyclo [2.2.1]The application of hept-5-ene-2-yl) ketone comprises the following steps:
Figure BDA0002273382040000091
in this example, (E) -3-phenyl-1- (pyridin-2-yl) prop-2-en-1-one in example 7 was replaced with equimolar (E) -1, 3-di (pyridin-2-yl) prop-2-en-1-one, and the other steps were the same as in example 7, except that the conversion of (E) -1, 3-di (pyridin-2-yl) prop-2-en-1-one was 99%, and that the pyridine-2-yl (3- (pyridin-2-yl) bicyclo [ 2.2.1-one was]Diastereoselective properties of hept-5-en-2-yl) methanone (endo: exo) is greater than 99:1, and the enantioselectivity endo of the endo-type product is 66%. Racemate characterization data are: 1 H NMR(400MHz,CDCl 3 )δ8.59(d,J＝4.4Hz,1H),8.48(d,J＝4.4Hz,1H),7.92(d,J＝7.8Hz,1H),7.81–7.66(m,1H),7.49(td,J＝7.7,1.6Hz,1H),7.36(dd,J＝6.7,5.1Hz,1H),7.17(d,J＝7.9Hz,1H),7.09–6.93(m,1H),6.40(dd,J＝5.3,3.1Hz,1H),5.83(dd,J＝5.5,2.7Hz,1H),4.97–4.80(m,1H),3.51(s,1H),3.44(d,J＝4.2Hz,1H),3.02(s,1H),2.23(d,J＝8.2Hz,1H),1.50–1.39(m,1H). 13 C NMR(100MHz,CDCl 3 ) δ 148.90(s),138.81(s),136.73(s),136.13(s),133.93(s),126.77(s),123.40(s),122.16(s),121.03(s),52.81(s),50.29(s),48.43(s),47.90(s),47.53(s), hrms (esi) theoretical value [ C(s) ] 18 H 16 N 2 O]·Na + (M+Na) + : m/z 299.1155, found: 299.1153.
example 11
ATP. Cu (OTf) in example 1 2 Catalysis of (E) -1- (1-methyl-1H-imidazol-2-yl) -3-phenylpropan-2-en-1-one with malonic acid bisThe application of the asymmetric Michael reaction of methyl ester to generate 2- (3- (1-methyl-1H-imidazole-2-yl) -3-oxo-1-phenylpropyl) malonic acid dimethyl ester comprises the following specific steps:
Figure BDA0002273382040000101
to 2000. mu.L of 20mM N-cyclohexyl-2-aminoethanesulfonic acid buffer solution, pH5.5, at 4 ℃ was added 10. mu.L of 50mM Adenosine Triphosphate (ATP) aqueous solution, and 20. mu.L of 5mM Cu (OTf) was added 2 The aqueous solution was stirred for 30 minutes to obtain ATP. Cu (OTf) 2 Then 0.21mg (1. mu. mol) of (E) -1- (1-methyl-1H-imidazol-2-yl) -3-phenylprop-2-en-1-one and 11.4. mu.L (100. mu. mol) of dimethyl malonate were dissolved in 12. mu.L of dimethyl sulfoxide, and then added to the system, and the reaction was continued at 4 ℃ for 72 hours; after the reaction is finished, extracting with ethyl acetate (2mL multiplied by 3), taking the organic phase, passing through a simple silica gel chromatographic column to remove residual water and trace Cu 2+ After rotary evaporation, concentration and drying, the crude product was analyzed by HPLC, and the conversion of (E) -1- (1-methyl-1H-imidazol-2-yl) -3-phenylprop-2-en-1-one was 95% and the enantioselectivity of dimethyl 2- (3- (1-methyl-1H-imidazol-2-yl) -3-oxo-1-phenylpropyl) malonate was 74%. The racemate product is characterized by a Bruker Avance type superconducting Fourier digital nuclear magnetic resonance spectrometer, and the characterization data is as follows: 1 H NMR(400MHz,CDCl 3 )δ7.31–7.27(m,2H),7.26–7.20(m,2H),7.17–7.12(m,1H),7.08(s,1H),6.95(s,1H),4.14(ddd,J＝7.9,7.2,2.8Hz,1H),3.90–3.77(m,5H),3.71(s,3H),3.49–3.41(m,4H). 13 C NMR(100MHz,CDCl 3 ) δ 189.61(s),168.63(s),168.18(s),142.78(s),140.49(s),128.91(s),128.41(d, J ═ 13.1Hz), 127.33-127.21 (m),127.08(d, J ═ 21.6Hz),57.70(s),52.82(s),52.47(s),42.89(s),40.33(s),36.22(s) · hrms (esi) theoretical value [ C (C) 898(s) ] 18 H 20 N 2 O 5 ]·Na + (M+Na) + : m/z 367.1264, found: 367.1263.
in this example, the equimolar amounts of GTP Cu (OTf) in example 2 were used 2 Alternative ATP. Cu (OTf) 2 (E) -1- (1-methyl-1H-imidazol-2-yl) -3-phenylprop-2-en-1-one conversionThe conversion was 58% and the enantioselectivity of dimethyl 2- (3- (1-methyl-1H-imidazol-2-yl) -3-oxo-1-phenylpropyl) malonate was 65%.
In this example, the same moles of dATP. Cu (OTf) as in example 3 were used 2 Alternative ATP. Cu (OTf) 2 The conversion of (E) -1- (1-methyl-1H-imidazol-2-yl) -3-phenylprop-2-en-1-one was 53% and the enantioselectivity of dimethyl 2- (3- (1-methyl-1H-imidazol-2-yl) -3-oxo-1-phenylpropyl) malonate was 43%.
In this example, ATP-Cu (NO) in example 5 was used in equimolar amounts 3 ) 2 Alternatives ATP. Cu (OTf) 2 The conversion of (E) -1- (1-methyl-1H-imidazol-2-yl) -3-phenylprop-2-en-1-one was 63% and the enantioselectivity of dimethyl 2- (3- (1-methyl-1H-imidazol-2-yl) -3-oxo-1-phenylpropyl) malonate was 75%.
Example 12
ATP. Cu (OTf) in example 1 2 The application of catalyzing asymmetric Michael reaction of (E) -3- (4-methoxyphenyl) -1- (1-methyl-1H-imidazole-2-yl) propan-2-ene-1-one and dimethyl malonate to generate dimethyl 2- (1- (4-methoxyphenyl) -3- (1-methyl-1H-imidazole-2-yl) -3-oxopropyl) malonate specifically comprises the following steps:
Figure BDA0002273382040000111
in this example, (E) -1- (1-methyl-1H-imidazol-2-yl) -3-phenylprop-2-en-1-one in example 11 was replaced with equimolar (E) -3- (4-methoxyphenyl) -1- (1-methyl-1H-imidazol-2-yl) propan-2-en-1-one, and the other steps were carried out in the same manner as in example 11, except that the conversion of (E) -3- (4-methoxyphenyl) -1- (1-methyl-1H-imidazol-2-yl) propan-2-en-1-one was 83%, and that 2- (1- (4-methoxyphenyl) -3- (1-methyl-1H-imidazol- 2-yl) -3-oxopropyl) malonic acid dimethyl ester with an enantioselectivity of 80%. Racemate characterization data are: 1 H NMR(400MHz,CDCl 3 )δ7.21–7.15(m,2H),7.04(d,J＝0.8Hz,1H),6.92(s,1H),6.77–6.71(m,2H),4.08(td,J＝10.0,4.3Hz,1H),3.82(d,J＝3.8Hz,3H),3.76(dd,J＝20.0,9.0Hz,2H),3.69(d,J＝6.9Hz,6H),3.44(s,3H),3.38(dd,J＝17.4,4.3Hz,1H). 13 C NMR(400MHz,CDCl 3 ) δ 189.83(s),168.65(s),168.21(s),158.49(s),142.95(s),132.47(s),129.35(s),128.99(s),126.95(s),113.76(s),57.85(s),55.17(s),52.69(s),52.40(s),42.94(s),39.68(s),36.09(s) hrms (esi) theoretical value [ C(s) ] 19 H 22 N 2 O 6 ]·Na + (M+Na) + : m/z 397.1370, found: 397.1363.
example 13
ATP. Cu (OTf) in example 1 2 The application of catalyzing asymmetric Michael reaction of (E) -3- (4-bromophenyl) -1- (1-methyl-1H-imidazol-2-yl) prop-2-en-1-one and dimethyl malonate to generate dimethyl 2- (1- (4-bromophenyl) -3- (1-methyl-1H-imidazol-2-yl) -3-oxopropyl) malonate comprises the following specific steps:
Figure BDA0002273382040000121
in this example, (E) -1- (1-methyl-1H-imidazol-2-yl) -3-phenylprop-2-en-1-one in example 11 was replaced with equimolar (E) -3- (4-bromophenyl) -1- (1-methyl-1H-imidazol-2-yl) propan-2-en-1-one, and the other steps were the same as in example 11, except that the conversion of (E) -3- (4-bromophenyl) -1- (1-methyl-1H-imidazol-2-yl) propan-2-en-1-one was 44% and the conversion of 2- (1- (4-bromophenyl) -3- (1-methyl-1H-imidazol-2-yl) propan-2-en-1-one was 44% ) The enantioselectivity of dimethyl (3-oxopropyl) malonate was 83%. Racemate characterization data are: 1 H NMR(400MHz,CDCl 3 )δ7.37–7.33(m,2H),7.20–7.15(m,2H),7.07(d,J＝0.7Hz,1H),6.96(s,1H),4.12(td,J＝10.3,4.1Hz,1H),3.86(s,3H),3.84–3.73(m,2H),3.71(d,J＝2.2Hz,3H),3.48(s,3H),3.45–3.36(m,1H). 13 C NMR(100MHz,CDCl 3 ) δ 189.38(s),168.36(s),167.96(s),139.63(s),131.56(s),130.18(s),129.08(s),127.11(s),121.08(s),57.33(s),52.84(s),52.55(s),42.63(s),39.85(s),36.15(s) 18 H 19 N 2 O 5 Br]·Na + (M+Na) + : m/z 445.0370, found: 445.0363.
example 14
ATP. Cu (OTf) in example 1 2 The application of catalyzing asymmetric Michael reaction of (E) -3- (furan-2-yl) -1- (1-methyl-1H-imidazole-2-yl) propane-2-ene-1-ketone and dimethyl malonate to generate dimethyl 2- (1- (furan-2-yl) -3- (1-methyl-1H-imidazole-2-yl) -3-oxopropyl) malonate comprises the following specific steps:
Figure BDA0002273382040000122
in this example, (E) -1- (1-methyl-1H-imidazol-2-yl) -3-phenylprop-2-en-1-one in example 11 was replaced with equimolar (E) -3- (furan-2-yl) -1- (1-methyl-1H-imidazol-2-yl) propan-2-en-1-one, and the other steps were the same as in example 11, except that the conversion of (E) -3- (furan-2-yl) -1- (1-methyl-1H-imidazol-2-yl) propan-2-en-1-one was 85% and the conversion of 2- (1- (furan-2-yl) -3- (1-methyl-1H-imid-ol Oxazol-2-yl) -3-oxopropyl) malonic acid dimethyl ester with an enantioselectivity of 58%. Racemate characterization data are: 1 H NMR(400MHz,CDCl 3 )δ7.26–7.22(m,1H),7.09(d,J＝0.8Hz,1H),6.98(s,1H),6.19(dd,J＝3.2,1.9Hz,1H),6.11(d,J＝3.3Hz,1H),4.26(td,J＝9.2,4.4Hz,1H),3.91(s,3H),3.88–3.78(m,2H),3.69(s,3H),3.59(s,3H),3.47–3.39(m,1H). 13 C NMR(100MHz,CDCl 3 ) δ 189.49(s),168.25(d, J ═ 7.6Hz),153.62(s),142.73(s),141.78(s),129.12(s),127.07(s),110.25(s),107.00(s),55.27(s),52.70(d, J ═ 8.5Hz),40.35(s),36.18(s),34.01(s), hrms (esi) theoretical value [ C (C), 18(s) ] 16 H 18 N 2 O 6 ]·Na + (M+Na) + : m/z 357.1057, found: 357.1055.
example 15
ATP. Cu (OTf) in example 1 2 The application of catalyzing asymmetric Michael reaction of (E) -1- (1-methyl-1H-imidazole-2-yl) -3-phenylpropan-2-en-1-one and diethyl malonate to generate diethyl 2- (3- (1-methyl-1H-imidazole-2-yl) -3-oxo-1-phenylpropyl) malonate comprises the following specific steps:
Figure BDA0002273382040000131
in this example, the dimethyl malonate in example 11 was replaced by an equimolar amount of diethyl malonate, and the conversion of (E) -1- (1-methyl-1H-imidazol-2-yl) -3-phenylprop-2-en-1-one was 98% and the enantioselectivity of diethyl 2- (3- (1-methyl-1H-imidazol-2-yl) -3-oxo-1-phenylpropyl) malonate was 77% in the same manner as in example 11. Racemate characterization data: 1 H NMR(400MHz,CDCl 3 )δ7.32–7.09(m,5H),7.06(d,J＝0.6Hz,1H),6.93(s,1H),4.21–4.10(m,3H),3.92–3.72(m,7H),3.44(dd,J＝17.4,4.1Hz,1H),1.22(t,J＝7.2Hz,3H),0.94(t,J＝7.1Hz,3H). 13 C NMR(100MHz,CDCl 3 ) δ 189.73(s),168.22(s),167.79(s),142.89(s),140.66(s),128.71(d, J ═ 33.0Hz),128.34(s),126.97(d, J ═ 18.4Hz),61.71(s),61.31(s),57.90(s),43.19(s),40.35(s),36.12(s),14.11(s),13.80(s), hrms (esi) theoretical value [ C (C), C(s) ]theoretical value(s) ("C(s)") 20 H 24 N 2 O 5 ]·Na + (M+Na) + : m/z 395.1577, found: 395.1571.
example 16
ATP. Cu (OTf) in example 1 2 The application of catalyzing asymmetric Michael reaction of (E) -1- (1-methyl-1H-imidazole-2-yl) -3-phenylpropan-2-ene-1-ketone and nitromethane to generate 1- (1-methyl-1H-imidazole-2-yl) -4-nitro-3-phenylbutan-1-ketone comprises the following specific steps:
Figure BDA0002273382040000141
in this example, the conversion of (E) -3- (4-methoxyphenyl) -1- (1-methyl-1H-imidazol-2-yl) propan-2-en-1-one was 90% and the enantioselectivity of 1- (1-methyl-1H-imidazol-2-yl) -4-nitro-3-phenylbut-1-one was 72% in the same procedure as in example 11, replacing the dimethyl malonate with equimolar nitromethane. Racemate characterization data are: 1 H NMR(400MHz,CDCl 3 )δ7.19(s,5H),7.06(s,1H),6.95(s,1H),4.63(ddd,J＝20.8,12.5,7.5Hz,2H),4.13(d,J＝7.2Hz,1H),3.88(s,3H),3.66(dd,J＝17.3,7.2Hz,1H),3.45(dd,J＝17.4,7.3Hz,1H). 13 C NMR(100MHz,CDCl 3 ) δ 189.14(s),139.03(s),129.29(s),128.96(s),127.77(s),127.68(d, J ═ 19.8Hz),79.91(s),41.90(s),39.33(s),36.12(s), hrms (esi) theoretical value [ C(s) ] 14 H 15 N 3 O 3 ]·Na + (M+Na) + : m/z 296.1006, found: 296.1001.

Claims (8)

1. the application of the nucleoside triphosphate artificial metalloenzyme catalysis asymmetric Diels-Alder reaction is characterized in that: stirring the nucleoside triphosphate artificial metalloenzyme at 0-25 ℃ for 15-30 minutes, adding the azachalcone compound and cyclopentadiene, and continuously reacting at the temperature for 12-24 hours to obtain a Diels-Alder addition product; wherein the molar ratio of the azachalcone compound to the cyclopentadiene-nucleoside triphosphate artificial metalloenzyme is 1: 50-300: 0.01-0.5;
the azachalcone compound is
Figure DEST_PATH_IMAGE001
In the formula, R represents phenyl and C 1 ～C 3 Alkyl-substituted phenyl, C 1 ～C 3 Any one of alkoxy substituted phenyl, nitro substituted phenyl, amino substituted phenyl, halogenated phenyl, pyridyl, furyl and thienyl;
the structural formula of the nucleoside triphosphate artificial metalloenzyme is shown as follows:
Figure 986079DEST_PATH_IMAGE002
in which n represents 1, 2 or 3 and A represents
Figure DEST_PATH_IMAGE003
、
Figure 465602DEST_PATH_IMAGE004
、
Figure DEST_PATH_IMAGE005
、
Figure 357859DEST_PATH_IMAGE006
Any one of B represents H or OH, C represents Cu (OTf) 2 、CuSO 4 、CuCl 2 、Cu(NO 3 ) 2 、
Figure DEST_PATH_IMAGE007
、
Figure 188412DEST_PATH_IMAGE008
、
Figure DEST_PATH_IMAGE009
、
Figure 368858DEST_PATH_IMAGE010
Any one of them.
2. Use of the nucleoside triphosphate artificial metalloenzyme to catalyze an asymmetric Diels-Alder reaction according to claim 1, characterized in that: the molar ratio of the azachalcone compound to the cyclopentadiene and nucleoside triphosphate artificial metalloenzyme is 1: 150-200: 0.05-0.1.
3. Use of the nucleoside triphosphate artificial metalloenzyme to catalyze an asymmetric Diels-Alder reaction according to claim 1, characterized in that: n represents 3, A represents
Figure 686575DEST_PATH_IMAGE003
B represents H or OH, C represents Cu (OTf) 2 、Cu(NO 3 ) 2 、
Figure 294274DEST_PATH_IMAGE010
Any one of them.
4. The use of the nucleoside triphosphate artificial metalloenzyme according to claim 1 to catalyze an asymmetric Diels-Alder reaction, characterized in that the nucleoside triphosphate artificial metalloenzyme is prepared by the method comprising: adding nucleoside triphosphate shown in a formula I and copper salt or copper complex into morpholine ethanesulfonic acid or morpholine propanesulfonic acid buffer solution with the pH value of 5.0-7.0 according to the molar ratio of 1: 1-20: 1, and stirring and reacting for 15-30 minutes at the temperature of 0-25 ℃ to obtain nucleoside triphosphate artificial metalloenzyme;
Figure DEST_PATH_IMAGE011
I
the copper salt is Cu (OTf) 2 、CuSO 4 、CuCl 2 、Cu(NO 3 ) 2 Any one of them, the copper complex is
Figure 346544DEST_PATH_IMAGE007
、
Figure 65101DEST_PATH_IMAGE008
、
Figure 315954DEST_PATH_IMAGE009
、
Figure 78242DEST_PATH_IMAGE010
Any one of them.
5. The use of the nucleoside triphosphate artificial metalloenzyme according to claim 4 to catalyze an asymmetric Diels-Alder reaction, characterized in that the nucleoside triphosphate artificial metalloenzyme is prepared by the method comprising: adding nucleoside triphosphate shown in formula I and copper salt or copper complex into morpholine ethanesulfonic acid or morpholine propanesulfonic acid buffer solution with the pH value of 5.5-6.0 according to the molar ratio of 5: 1-10: 1, and stirring and reacting for 15-30 minutes at the temperature of 4-10 ℃ to obtain the nucleoside triphosphate artificial metalloenzyme.
6. The application of the nucleoside triphosphate artificial metalloenzyme catalysis asymmetric Michael reaction is characterized in that: stirring nucleoside triphosphate artificial metalloenzyme and imidazole ketene compounds at 0-25 ℃ for 15-30 minutes, adding a nucleophilic reagent, and continuously reacting at the temperature for 24-72 hours to obtain a Michael reaction product; wherein the molar ratio of the imidazolone compound to the nucleophilic reagent to the nucleoside triphosphate artificial metalloenzyme is 1: 20-250: 0.01-0.5;
the above-mentioned imidarenone compounds are
Figure 414546DEST_PATH_IMAGE012
In the formula, R 1 Represents C 1 ～C 6 Alkyl, phenyl, C 1 ～C 3 Any one of alkoxy substituted phenyl and halogenated phenyl;
the above-mentioned nucleophilic reagent is
Figure DEST_PATH_IMAGE013
Or R 3 NO 2 ，R 2 Represents C 1 ～C 3 Alkyl radical, R 3 Represents C 1 ～C 6 An alkyl group;
the structural formula of the nucleoside triphosphate artificial metalloenzyme is shown as follows:
Figure 936794DEST_PATH_IMAGE002
in which n represents 1, 2 or 3 and A represents
Figure 245416DEST_PATH_IMAGE003
、
Figure 929338DEST_PATH_IMAGE004
、
Figure 487358DEST_PATH_IMAGE005
、
Figure 796986DEST_PATH_IMAGE006
Any one of B represents H or OH, C represents Cu (OTf) 2 、CuSO 4 、CuCl 2 、Cu(NO 3 ) 2 、
Figure 756851DEST_PATH_IMAGE007
、
Figure 611675DEST_PATH_IMAGE008
、
Figure 922571DEST_PATH_IMAGE009
、
Figure 521042DEST_PATH_IMAGE010
Any one of them.
7. Use of an artificial metalloenzyme-catalyzed asymmetric Michael reaction with nucleoside triphosphates according to claim 6, characterized in that: the molar ratio of the imidazolone compound to the nucleophilic reagent to the nucleoside triphosphate artificial metalloenzyme is 1: 70-100: 0.05-0.1.
8. Use of an artificial metalloenzyme with nucleoside triphosphates to catalyze an asymmetric Michael reaction according to claim 6, characterized in that: n represents 3, A represents
Figure 335414DEST_PATH_IMAGE003
B represents H or OH, C represents Cu (OTf) 2 、Cu(NO 3 ) 2 、
Figure 626718DEST_PATH_IMAGE010
Any one of them.
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