CN113559926A - Asymmetric Aldol reaction catalyst and preparation method and application thereof - Google Patents

Asymmetric Aldol reaction catalyst and preparation method and application thereof Download PDF

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CN113559926A
CN113559926A CN202110568219.1A CN202110568219A CN113559926A CN 113559926 A CN113559926 A CN 113559926A CN 202110568219 A CN202110568219 A CN 202110568219A CN 113559926 A CN113559926 A CN 113559926A
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reaction
catalyst
dichloromethane
proline
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李舂龙
江志波
郭鑫
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North Minzu University
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    • B01J2231/341—1,2-additions, e.g. aldol or Knoevenagel condensations
    • B01J2231/342—Aldol type reactions, i.e. nucleophilic addition of C-H acidic compounds, their R3Si- or metal complex analogues, to aldehydes or ketones
    • B01J2231/343—Aldol type reactions, i.e. nucleophilic addition of C-H acidic compounds, their R3Si- or metal complex analogues, to aldehydes or ketones to prepare cyanhydrines, e.g. by adding HCN or TMSCN
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Abstract

The invention discloses an asymmetric Aldol reaction catalyst and a preparation method and application thereof, the catalyst is L-proline modified spiral polyisonitrile, the preparation method of the catalyst comprises the steps of preparing an L-proline isonitrile monomer, preparing an intermediate and synthesizing a finished product, and the catalyst can be effectively applied to asymmetric Aldol reaction in salt water. The polyisonitrile polymer provided by the invention has the advantages that the polyisonitrile polymer has stable properties and high catalytic activity, the side group of the polyisonitrile polymer contains an L-proline structural unit, the synthetic route is reasonable in design, the yield is high, the applicability is wide, and the polyisonitrile polymer can catalyze the water-phase asymmetric Aldol reaction of various substrates; the method has the advantages of excellent enantioselectivity in catalytic organic asymmetric synthesis reaction, high ee% value of the product, easy recovery and reuse.

Description

Asymmetric Aldol reaction catalyst and preparation method and application thereof
Technical Field
The invention relates to the technical field of catalytic organic synthesis, in particular to an asymmetric Aldol reaction catalyst and a preparation method and application thereof.
Background
The L-proline has the advantages of good catalytic activity, high enantioselectivity, low cost of raw materials and the like, and is widely applied to asymmetric Aldol reaction. However, the L-proline has the defects of large dosage, difficult separation, incapability of being reused and the like, and the large-scale industrial production of the L-proline is limited. Therefore, researchers can copolymerize L-proline with other molecules or immobilize the L-proline on an organic polymer carrier to solve the problem, the L-proline is immobilized on the helical polyisonitrile, and the helical polyisonitrile with a proper structure can provide a redundant chiral microenvironment for small molecules, so that the stereoselectivity of the Aldol reaction is regulated and controlled, and meanwhile, the helical main chain and the side group proline of the polyisonitrile can act synergistically, so that the stereoselectivity of the Aldol product is further improved, and the L-proline-immobilized organic polymer carrier becomes a research hotspot.
In the prior art, Chandrasekaran et al (journal of chemical sciences,2003, 115(5-6): 365-) -372) bond L-proline to mesoporous molecular sieve (MCM-41) through covalent bond to prepare a supported catalyst for catalyzing asymmetric Aldol reaction between aldehyde and acetone, in the system, heterogeneous reaction medium influences Aldol reaction catalysis efficiency, catalytic activity is reduced, and stereoselectivity is lower than that of a homogeneous catalyst. Silver dunghol [ journal of catalysis, 2013,298: 138-.
Disclosure of Invention
The invention aims to overcome the problems in the prior art and provides an asymmetric Aldol reaction catalyst and a preparation method and application thereof.
In order to achieve the technical purpose and achieve the technical effect, the invention is realized by the following technical scheme:
an asymmetric Aldol reaction catalyst, which is L-proline modified spiral polyisonitrile, and the structural formula of the catalyst is shown as follows:
Figure DEST_PATH_GDA0003277160570000021
wherein n is 10-250.
Further, in the above asymmetric Aldol reaction catalyst, n =10 to 150.
An intermediate of an asymmetric Aldol reaction catalyst, the intermediate having the following structural formula:
Figure DEST_PATH_GDA0003277160570000022
wherein n is 10-250.
Further, in the intermediate of the asymmetric Aldol reaction catalyst, n =10 to 150.
A preparation method of an asymmetric Aldol reaction catalyst comprises the following steps:
a. preparing an L-proline isonitrile monomer;
b. adding L-proline isonitrile monomer and palladium initiator in a container, replacing with nitrogen gas for 2-5 times under anhydrous and oxygen-free conditions, introducing N2Adding dry tetrahydrofuran, reacting at 50-60 deg.C for 10-20h, adding methanol to terminate the reaction, adding a large amount of hexane, separating out solid, centrifuging, and vacuum drying to constant weight to obtain intermediate;
c. adding the intermediate and dichloromethane into a container, slowly adding trifluoroacetic acid in an ice bath, stirring at room temperature for 10-20h, pouring into water, adjusting to be neutral by using ammonia water, extracting by using dichloromethane, concentrating, adding a large amount of methanol for dissolving, then adding diethyl ether, precipitating, centrifuging, and drying in vacuum to constant weight to obtain a finished product of the catalyst.
Further, in the preparation method of the asymmetric Aldol reaction catalyst, a palladium initiator is also added into the container, and the structural formula of the palladium initiator is as follows:
Figure RE-GDA0003277160570000031
further, the preparation step of the L-proline isonitrile monomer comprises the following steps:
1) l-proline was dissolved in dichloromethane and then a triethylamine mixture was added, cooled to 0 ℃ in ice bath and added dropwise (Boc) in ice bath2A solution of O in methylene chloride; after the dropwise addition, stirring the reaction solution at room temperature until the reaction is finished, and concentrating in vacuum; adjusting the solution pH =2 with 2N hydrochloric acid solution under ice bath; extracting the obtained solution with dichloromethane, washing the organic phase with water, saturated salt water, and anhydrous sodium sulfate, filtering, and concentrating; the crude product is crystallized by petroleum ether/ethyl acetate to obtain white solid;
2) adding dichloromethane into a container a, then adding the white solid obtained in the step 1) and EDC & HCl, cooling to 0 ℃, adding 4-nitroaniline solution, continuing stirring for 0.5h in ice bath, then stirring at room temperature, using a 2N hydrochloric acid pickling agent for the reaction solution, then using a saturated ammonium chloride solution for washing, and separating an organic phase; extracting the water phase with dichloromethane, mixing the organic phases, drying with anhydrous sodium sulfate, filtering, and concentrating; purifying the crude product by column chromatography to obtain a yellow solid;
3) dissolving the yellow solid obtained in the step 2) in a tetrahydrofuran solution, adding 10% Pd/C, replacing hydrogen, reacting under hydrogen pressure, filtering after the reaction is finished, and concentrating to obtain a gray solid;
4) adding acetic anhydride and formic acid into the container b, stirring at room temperature, and mixing the solution for later use; adding the gray solid obtained in the step 3 into a container c, then adding ethyl acetate, cooling to 0 ℃ in an ice bath, slowly dropwise adding the mixed solution for later use, and stirring the mixed solution at room temperature; pouring the mixed solution into ice water, extracting with ethyl acetate for three times, combining organic phases, washing with water for three times, washing with saturated sodium bicarbonate for one time, then washing with saturated salt solution for two times, and drying with anhydrous sodium sulfate; filtering, concentrating, and purifying the crude product by column chromatography to obtain white solid;
5) dissolving the solid obtained in the step 4 in dichloromethane, adding triethylamine, cooling the reaction liquid to 0 ℃, dropwise adding a dichloromethane solution of triphosgene, stirring the reaction liquid at a room temperature, then pouring the solution into water, and extracting the solution with the dichloromethane for three times; combining the organic phases, washing with water for three times, washing with saturated sodium bicarbonate solution, washing with saturated saline solution for two times, and drying with anhydrous sodium sulfate; filtering, concentrating, and purifying the crude product by column chromatography to obtain the L-proline isonitrile monomer.
Further, in the preparation method of the asymmetric Aldol reaction catalyst, the column chromatography purification is performed by eluting with a mixed eluent of petroleum ether and ethyl acetate, wherein the volume ratio of the petroleum ether to the ethyl acetate is 5: 1.
The invention also provides application of the asymmetric Aldol reaction catalyst in the asymmetric Aldol reaction in salt water.
In the application, the catalyst and the ketone are added into a reaction bottle, saturated salt solution is added, after the mixture is stirred for a certain time at room temperature, a certain amount of aldehyde is added, the mixture reacts for a certain time at minus 10 ℃, and the mixture is centrifuged, dried and recovered; extracting the filtrate with dichloromethane, concentrating, and purifying with column chromatography to obtain corresponding asymmetric Aldol product, which has the following reaction formula:
Figure RE-GDA0003277160570000041
wherein R is1Is one of phenyl, substituted phenyl, aryl, substituted aryl and alkyl; r2、R3Each is one of alkyl, phenyl, substituted phenyl, aryl and substituted aryl.
The invention has the beneficial effects that:
the polyisonitrile polymer provided by the invention has the advantages of stable property, high catalytic activity and side group containing an L-proline structural unit, reasonable design of a synthetic route, high yield and wide application, and can catalyze the water phase asymmetric Aldol reaction of various substrates. The method has excellent enantioselectivity in catalytic organic asymmetric synthesis reaction, and under the optimal reaction conditions, the enantiomeric excess (ee) and diastereomer ratio (dr) of the aldol reaction product respectively reach over 90% and 20/1. In addition, the helical polyisonitrile catalyst can be reused for 5 times in the aldol reaction while maintaining its activity and stereoselectivity.
Of course, it is not necessary for any one product that embodies the invention to achieve all of the above advantages simultaneously.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings used in the description of the embodiments will be briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art that other drawings can be obtained according to the drawings without creative efforts.
FIG. 1 shows the proline isonitrile monomer of the invention1HNMR（600MHz）；
FIG. 2 shows proline isonitrile monomers and polymer poly-1 of the invention150(iii) infrared spectrum (KBr pellet, 25 ℃);
FIG. 3 shows poly-1 of the present invention150And poly-2150(iii) infrared spectrum (KBr pellet, 25 ℃);
FIG. 4 shows poly-1 of the present invention150And poly-2150CD and UV-vis plots of (a);
FIG. 5 is an HPLC chart of 2- [ hydroxy (4-nitrophenyl) methyl ] cyclohexanone as a racemate in accordance with the present invention (chiral column AD-H; n-hexane/isopropanol =85/15(v/v); flow rate 0.50mL/min; 254nm;25 ℃);
FIG. 6 is an HPLC plot of chiral 2- [ hydroxy (4-nitrophenyl) methyl ] cyclohexanone of the present invention (chiral column AD-H; n-hexane/isopropanol =85/15(v/v); flow rate 0.50mL/min; 254nm;25 ℃);
FIG. 7 is an HPLC chart of 2- [ hydroxy (3-nitrophenyl) methyl ] cyclohexanone, a racemate, according to the present invention;
FIG. 8 is an HPLC plot of chiral 2- [ hydroxy (3-nitrophenyl) methyl ] cyclohexanone of the present invention (chiral column AD-H; n-hexane/isopropanol =85/15(v/v); 0.50mL/min; 254nm;25 ℃);
FIG. 9 is an HPLC chart of 2- [ hydroxy (4-cyanophenyl) methyl ] cyclohexanone as a racemate in accordance with the present invention (chiral column AD-H; n-hexane/isopropanol =85/15(v/v); 0.50mL/min; 230 nm;25 ℃);
FIG. 10 is an HPLC plot of an achiral 2- [ hydroxy (4-cyanophenyl) methyl ] cyclohexanone of the present invention (chiral column AD-H; n-hexane/isopropanol =85/15(v/v); 0.50mL/min; 230 nm;25 ℃);
FIG. 11 is an HPLC chart of 2- [ hydroxy (4-trifluoromethylphenyl) methyl ] cyclohexanone as a racemate of the present invention (chiral column AD-H; n-hexane/isopropanol = 95/5 (v/v); 0.80 mL/min; 210 nm;25 ℃);
FIG. 12 is an HPLC plot of chiral 2- [ hydroxy (4-trifluoromethylphenyl) methyl ] cyclohexanone of the present invention (chiral column AD-H; n-hexane/isopropanol = 95/5 (v/v); 0.80 mL/min; 210 nm;25 ℃).
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
The synthetic route of the L-proline isonitrile monomer is as follows:
Figure RE-GDA0003277160570000061
synthesis of Compound 2
L-proline (5.75g,0.05mol) was dissolved in 50mL of dichloromethane, then triethylamine (10.4mL,0.075mol) was added to the mixture and the mixture was cooled to 0 ℃ in ice bath and added dropwise (Boc) in ice bath2O (13.8mL,0.06mol,50mL of CH)2Cl2) The solution was over 0.5 hours. After the dropwise addition, stirring the reaction solution at room temperature for 12h to finish the reactionAnd (4) concentrating in vacuum. The pH of the solution was adjusted to 2 with 2N hydrochloric acid solution while cooling on ice. The extracted solution was extracted three times with dichloromethane, and the organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was crystallized pure from petroleum ether/ethyl acetate (6:1v/v) to give 2 as a white solid (9.28g, 96%).
Synthesis of Compound 3
In a 500mL three-necked flask, 300mL of dichloromethane was added, followed by solid 2(8.84g,41.1mmol) and EDC & HCl (9.44g,49.3mmol) cooled to 0 deg.C, a solution of 4-nitroaniline (5.95g,43.1mmol) was added, stirring was continued for 15 minutes in an ice bath, then the reaction was stirred at room temperature for 2h with 2N hydrochloric acid wash, then rinsed with saturated ammonium chloride solution and the organic phase separated. The aqueous phase was extracted with dichloromethane and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (petroleum ether/ethyl acetate =4:1) to give solid 3 as a yellow solid (7.99g, 58%).
Synthesis of Compound 4
Solid 3(4.45g,13.3mmol) was dissolved in 100mL tetrahydrofuran, 10% Pd/C (0.5g) was added to displace the hydrogen, and after reaction for 24h under hydrogen pressure, filtration and concentration gave 4 as a gray solid (3.52g, 87%).
1H NMR (600 MHz, DMSO- d 6，25℃): δ 9.53 (s, 1H, NH), 7.24 (d, J = 8.6 Hz, 2H, ArH), 6.53 (d, J = 8.6 Hz, 2H, ArH), 4.86 (s, 2H, NH2), 4.37-4.11 (m, 1H, CH), 3.33-3.43 (m, 1H, CH), 2.22-2.11 (m, 1H, CH), 1.75-1.96 (m, 3H, CH2CH), 1.43 (s, 3H, CH3), 1.32 (s, 6H, CH3).
13C NMR (150 MHz, DMSO- d 6，25℃): δ 170.90, 153.68, 145.16, 128.64, 121.46, 114.23, 78.79, 60.67, 46.98, 31.46, 28.41, 23.81.
FT-IR (KBr, 25℃): 3224, 2977, 2882, 1662, 1525, 1407 cm-1. Anal. Calcd (%) for C16H23N3O3: C, 62.93；H, 7.59；N, 13.76. Found: C, 62.67；H, 7.68；N, 13.59.
Synthesis of Compound 5
In a 25mL single-neck flask, 5.0mL of acetic anhydride and 10mL of formic acid are added and stirred at room temperature for 2h for standby. In a 100mL three-necked flask, gray solid 4(1.72g,5.6mmol) was added, then 50mL ethyl acetate was added, cooled to 0 ℃ in ice bath, 3mL of acetic anhydride-formic acid mixed solution to be used was slowly dropped, the mixed solution was stirred at room temperature for 2 hours, poured into ice water, extracted three times with ethyl acetate, the organic phases were combined, washed three times with water, washed once with saturated sodium bicarbonate, then washed twice with saturated brine, and dried over anhydrous sodium sulfate. Filtration, concentration and purification of the crude product by column chromatography (petroleum ether/ethyl acetate =5:1) gave solid 5 as a white solid (1.30g, 69%).
1H NMR (600 MHz, DMSO-d 6) δ 10.06 (s, 1H), 9.89 (s, 1H), 8.19 (s, 1H), 7.47-7.51 (m, 3H), 7.08-7.10 (m, 1H), 4.12-4.21 (m, 1H), 3.27-3.40 (m, 2H), 2.09-2.21 (m, 1H), 1.73- 1.91 (m, 3H), 1.36 (s, 3H), 1.24 (s, 6H).
13C NMR (150 MHz, DMSO-d 6): δ 171.71, 159.65, 153.60, 135.36, 134.08, 120.64, 119.90, 119.77, 78.84, 60.66, 46.99, 31.42, 28.37, 23.84.
FT-IR (KBr, 25℃): 3265, 3100，2976, 2871, 1665, 1603, 1616, 1521, 1411, 1366 cm -1. HRMS m/z: calcd for C17H24N3O4 [M+H]+: 334.1689；Found: 334.1182. Anal. Calcd (%) for C17H23N3O4: C, 61.25；H, 6.95；N, 12.60. Found: C, 61.47；H, 6.88；N, 12.53.
Synthesis of L-proline isonitrile monomer
Solid 5(0.92g,2.76mmol) was dissolved in 50mL of dichloromethane, then 1.53mL of triethylamine was added. The reaction was cooled to 0 ℃ and a solution of triphosgene (0.72g,2.43mmol) in dichloromethane (10mL) was added dropwise. The reaction solution was stirred at room temperature for 1h and then poured into water and extracted three times with dichloromethane solution. The organic phases were combined, washed three times with water, twice with saturated sodium bicarbonate solution and twice with saturated brine, and dried over anhydrous sodium sulfate. Filtration, concentration and purification of the crude product by column chromatography (petroleum ether/ethyl acetate =5:1) gave L-proline isonitrile monomer 1(0.80g, 92%).
1H NMR (600 MHz, CDCl3, 25℃): δ 9.89 (s, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 4.41-4.52(m, 1H, CH), 3.28-3.51 (m, 2H, CH2), 2.49-2.62 (m, 1H, CH), 1.81-2.04 (m, 3H, CH2CH), 1.50 (s, 9H, CH3).
13C NMR (150 MHz, CDCl3, 25℃): δ 171.00, 163.21, 156.23, 139.63, 126.82, 119.81, 81.11, 60.70, 47.46, 28.56, 24.69.
FT-IR (KBr, 25℃): 3283, 3199，2978, 2876, 2123，1694, 1663, 1600, 1544, 1509, 1477, 1410，1368 cm-1. HRMS m/z: calcd for C17H20N3O3 [M-H]+: 314.1583；Found: 314.1259. Anal. Calcd (%) for C17H21N3O3: C, 64.74；H, 6.71；N, 13.32. Found: C, 64.57；H, 6.70；N, 13.41.
Example 2
Intermediate poly-1ms polymerization process with poly-1150For example, the following steps are carried out:
in a 10mL polymerization flask, L-proline isonitrile monomer (189.1mg,0.60mmol), palladium initiator (2.03mg, 4.0. mu. mol) and N were added to replace2After three times, the reaction is carried out under the condition of N2To the reaction solution, 3.0mL ([1 ]) of dry tetrahydrofuran was added]0/[Pd]0=150,[1]0= 0.16M). And (3) placing the polymerization bottle in an oil bath kettle at 55 ℃, and stirring for reaction for 15 h. Cooling the reaction flask to room temperature, adding a large amount of hexane into the reaction mixture to obtain a large amount of red solid, centrifuging the mixture, and pumping out by an oil pump to obtain red solid poly-1150(154.8mg,85.0%)。
1H NMR (600 MHz, CDCl3, 25℃): δ 9.11 (br, 1H, NH), 6.50 (br, 2H, ArH), 5.60 (br, 2H, ArH), 4.23 (br, 1H, CH), 3.46 (br, 2H, CH2), 2.13 (br, 1H, CH), 1.84 (br, 3H, CH2 CH), 1.32 (br, 9H, (CH3)3). FT-IR (KBr, 25℃ cm-1): 2975 (νC-H), 1670 (νC=O), 1597 (νC=N).
Example 3
Catalyst poly-2ms polymerization process with poly-2150For example, the following steps are carried out:
the intermediate poly-1ms (0.20g) was dissolved in 8.0mL of dichloromethane, and 0.6mL of trifluoroacetic acid was slowly added thereto while cooling on ice, stirred at room temperature for 15 hours, poured into water, made neutral with aqueous ammonia, and extracted three times with dichloromethane. Concentrating, dissolving in methanol, adding diethyl ether, precipitating, centrifuging, and vacuum drying to obtain poly-2150As a red solid (105.0mg,77% yield).
FT-IR (KBr, 25℃ cm-1): 3407 (νN-H), 2952 (νC-H), 1678 (νC=O), 1602 (vC=N).
Example 4
Catalyst catalysis asymmetric Aldol reaction
Adding a catalyst (calculated by a polymer repeating unit) accounting for 20 mol% of the quantity of the substrate aromatic aldehyde, 4 equivalents of cyclohexanone and 1mL of solvent used for reaction into a 10mL single-neck bottle, stirring at room temperature for 1h, adding 1 equivalent of the substrate aromatic aldehyde, adding a large amount of diethyl ether into the reaction mixed solution after the thin-layer chromatography tracking reaction is finished, centrifuging the mixed solution after the polymer catalyst is separated out, concentrating the supernatant, and performing column chromatography separation to obtain the corresponding Aldol reaction product.
Example 5
Preparation of 2- [ hydroxy (4-nitrophenyl) methyl ] cyclohexanone:
a10 mL single vial was charged with the catalyst (8.55mg,0.04mmol, based on polymer repeat units), cyclohexanone (78.52mg,0.80mmol), 1mL of saturated saline solution, stirred at room temperature for 1h, then added with 4-nitrobenzaldehyde (30.22mg,0.20mmol), and stirred at-10 ℃ for 48 h. After the thin layer chromatography tracking reaction is finished, centrifuging, drying and recovering the catalyst. The filtrate is extracted by dichloromethane, concentrated and purified by column chromatography to obtain the 2- [ hydroxy (4-nitrophenyl) methyl ] cyclohexanone. The yield thereof was 65%, dr (anti: syn)78/22, ee (anti):84%.
High Performance Liquid Chromatography (HPLC) conditions: the chiral column is Chiralpak AD-H; n-hexane/isopropanol =85/15(v/v); flow rate of flow0.50mL/min; the wavelength is 254nm;25 ℃; t is tR1 (syn.) = 28.09 min, tR2 (syn.) = 30.66 min, tR1 (anti.) = 33.66 min, tR2 (anti.) = 43.78 min.
Preparation of 2- [ hydroxy (3-nitrophenyl) methyl ] cyclohexanone:
adding poly-2 into a 10mL single-mouth bottle150(8.55mg,0.04mmol, based on the polymer repeating unit), cyclohexanone (78.52mg,0.80mmol), 1mL of saturated saline solution was added thereto, and after stirring at room temperature for 1 hour, 3-nitrobenzaldehyde (30.22mg,0.20mmol) was further added thereto, and stirring was carried out at-10 ℃ for 48 hours. After the thin layer chromatography tracking reaction is finished, centrifuging, drying and recovering the catalyst. Extracting the filtrate with dichloromethane, concentrating, and purifying by column chromatography to obtain 2- [ hydroxy (4-nitrophenyl) methyl]Cyclohexanone. The yield thereof was 70%, dr (anti: syn)81/19, ee (anti):81%.
High Performance Liquid Chromatography (HPLC) conditions: the chiral column is Chiralpak AD-H, n-hexane/isopropanol =85/15(v/v), flow rate is 0.50mL/min, wavelength is 254nm, t is 25 DEG CR1(syn.)=37.75min, tR2 (syn.) = 41.45 min, tR1(anti.) = 46.96 min, tR2 (anti.) = 60.75 min.
Preparation of 2- [ hydroxy (4-cyanophenyl) methyl ] cyclohexanone:
adding poly-2 into a 10mL single-mouth bottle150(8.55mg,0.04mmol, based on the polymer repeating unit), cyclohexanone (78.52mg,0.80mmol), 1mL of saturated saline solution was added thereto, and after stirring at room temperature for 1 hour, 4-cyanobenzaldehyde (26.22 mg,0.20mmol) was further added thereto, and stirring was carried out at-10 ℃ for 48 hours. After the thin layer chromatography tracking reaction is finished, centrifuging, drying and recovering the catalyst. Extracting the filtrate with dichloromethane, concentrating, and purifying by column chromatography to obtain 2- [ hydroxy (2-nitrophenyl) methyl]Cyclohexanone. The yield is 60 percent; dr (anti: syn) 80/20, ee (anti):72%.
High Performance Liquid Chromatography (HPLC) conditions: the chiral column is Chiralpak AD-H; n-hexane/isopropanol = 95/5 (v/v); the flow rate is 0.80 mL/min; the wavelength is 230 nm;25 ℃; t is tR1 (syn.) = 24.50 min, tR2 (syn.) = 27.81 min, tR1 (anti.) = 30.99 min, tR2 (anti.) = 38.42 min.
Preparation of 2- [ hydroxy (4-trifluoromethylphenyl) methyl ] cyclohexanone:
adding poly-2 into a 10mL single-mouth bottle150(8.55mg,0.04mmol, based on the polymer repeating unit), cyclohexanone (78.52mg,0.80mmol), 1mL of saturated saline solution was added thereto, and after stirring at room temperature for 1 hour, 4-trifluoromethylbenzaldehyde (34.82 mg,0.20mmol) was further added thereto, and the mixture was stirred at-10 ℃ for 48 hours. After the thin layer chromatography tracking reaction is finished, centrifuging, drying and recovering the catalyst. Extracting the filtrate with dichloromethane, concentrating, and purifying by column chromatography to obtain 2- [ hydroxy (4-trifluoromethylphenyl) methyl]Cyclohexanone. The yield is 67%; dr (anti: syn) 73/27, ee (anti):72%.
High Performance Liquid Chromatography (HPLC) conditions: the chiral column is Chiralpak AD-H; n-hexane/isopropanol = 95/5 (v/v); the flow rate is 0.80 mL/min; the wavelength is 210 nm;25 ℃; t is tR1 (syn.) = 12.80 min, tR2 (syn.) = 15.18 min, tR1 (anti.) = 20.83 min, tR2 (anti.) = 26.66 min.
Preparation of 2- [ hydroxy (2-trifluoromethylphenyl) methyl ] cyclohexanone:
adding poly-2 into a 10mL single-mouth bottle150(8.55mg,0.04mmol, based on the polymer repeating unit), cyclohexanone (78.52mg,0.80mmol), 1mL of saturated saline solution was added thereto, and after stirring at room temperature for 1 hour, 2-trifluoromethylbenzaldehyde (34.82 mg,0.20mmol) was further added thereto, and the mixture was stirred at-10 ℃ for 48 hours. After the thin layer chromatography tracking reaction is finished, centrifuging, drying and recovering the catalyst. Extracting the filtrate with dichloromethane, concentrating, and purifying by column chromatography to obtain 2- [ hydroxy (2-trifluoromethylphenyl) methyl]Cyclohexanone. The yield is 56 percent; dr (anti: syn)>20/1，ee (anti):90%.
High Performance Liquid Chromatography (HPLC) conditions: the chiral column is Chiralpak AD-H; n-hexane/isopropanol = 90/10 (v/v); the flow rate is 0.50mL/min; the wavelength is 254nm;25 ℃; t is tR1 (anti.) = 23.14 min, tR2 (anti.) = 24.59 min.
Example 6
And (3) testing the recycling performance of the supported catalyst:
to support a catalyst poly-2150For example, the procedure was the same as in example 5, and after recovering the catalyst, a large amount of methanol was added to dissolve it, followed by addition of ether, precipitation, and centrifugationVacuum drying, and recycling the asymmetric Aldol reaction of the 4-nitrobenzaldehyde and the cyclohexanone in the saturated saline solution. The results are shown in Table 1:
TABLE 1
Number of cycles Yield (%) dr ee (%) Recovery (%)
1 65 78/22 84 94
2 64 75/25 83 93
3 63 80/20 83 93
4 61 79/21 81 92
5 59 77/23 80 90
From the above table, it can be seen that, after the supported catalyst is recycled for 5 times, neither the activity of the catalytic reaction nor the stereoselectivity of the product is significantly reduced.
The preferred embodiments of the invention disclosed above are intended to be illustrative only. The preferred embodiments are not intended to be exhaustive or to limit the invention to the precise embodiments disclosed. Obviously, many modifications and variations are possible in light of the above teaching. The embodiments were chosen and described in order to best explain the principles of the invention and the practical application, to thereby enable others skilled in the art to best utilize the invention. The invention is limited only by the claims and their full scope and equivalents.

Claims (10)

1. An asymmetric Aldol reaction catalyst characterized in that: the catalyst is L-proline modified spiral polyisonitrile, and the structural formula of the catalyst is shown as follows:
Figure RE-FDA0003266932020000011
wherein n is 10-250.
2. The asymmetric Aldol reaction catalyst according to claim 1, characterized in that: n = 10-150.
3. An intermediate of an asymmetric Aldol reaction catalyst, characterized in that: the structural formula of the intermediate is shown as follows:
Figure RE-FDA0003193939390000013
wherein n is 10-250.
4. The intermediate of the asymmetric Aldol reaction catalyst according to claim 3, characterized in that: n = 10-150.
5. A preparation method of an asymmetric Aldol reaction catalyst is characterized by comprising the following steps:
a. preparing an L-proline isonitrile monomer;
b. adding L-proline isonitrile monomer and palladium initiator in a container, replacing with nitrogen gas for 2-5 times under anhydrous and oxygen-free conditions, introducing N2Adding dried tetrahydrofuran, and reacting at 50-60 deg.CAdding methanol for 10-20h to stop the reaction, adding a large amount of hexane, separating out solid, centrifuging, and drying in vacuum to constant weight to obtain an intermediate;
c. adding the intermediate and dichloromethane into a container, slowly adding trifluoroacetic acid in an ice bath, stirring at room temperature for 10-20h, pouring into water, adjusting to be neutral by using ammonia water, extracting by using dichloromethane, concentrating, adding a large amount of methanol for dissolving, then adding diethyl ether, precipitating, centrifuging, drying in vacuum to constant weight, and obtaining a product, namely a catalyst finished product.
6. The method of preparing the asymmetric Aldol reaction catalyst according to claim 5, characterized in that: a palladium initiator is also added into the container, and the structural formula of the palladium initiator is as follows:
Figure RE-FDA0003266932020000021
7. the method of preparing an asymmetric Aldol reaction catalyst according to claim 5, wherein the L-proline isonitrile monomer is prepared by the steps of:
1) l-proline was dissolved in dichloromethane and then a triethylamine mixture was added, cooled to 0 ℃ in ice bath and added dropwise (Boc) in ice bath2A solution of O in methylene chloride; after the dropwise addition, stirring the reaction solution at room temperature until the reaction is finished, and concentrating in vacuum; adjusting the solution pH =2 with 2N hydrochloric acid solution under ice bath; extracting the obtained solution with dichloromethane, washing the organic phase with water, saturated salt water, and anhydrous sodium sulfate, filtering, and concentrating; the crude product is crystallized by petroleum ether/ethyl acetate to obtain white solid;
2) adding dichloromethane into a container a, then adding the white solid obtained in the step 1) and EDC & HCl, cooling to 0 ℃, adding 4-nitroaniline solution, continuing stirring for 0.5h in ice bath, then stirring at room temperature, using a 2N hydrochloric acid pickling agent for the reaction solution, then using a saturated ammonium chloride solution for washing, and separating an organic phase; extracting the water phase with dichloromethane, mixing the organic phases, drying with anhydrous sodium sulfate, filtering, and concentrating; purifying the crude product by column chromatography to obtain a yellow solid;
3) dissolving the yellow solid obtained in the step 2) in a tetrahydrofuran solution, adding 10% Pd/C, replacing hydrogen, reacting under hydrogen pressure, filtering after the reaction is finished, and concentrating to obtain a gray solid;
4) adding acetic anhydride and formic acid into the container b, stirring at room temperature, and mixing the solution for later use; adding the gray solid obtained in the step 3 into a container c, then adding ethyl acetate, cooling to 0 ℃ in an ice bath, slowly dropwise adding the mixed solution for later use, and stirring the mixed solution at room temperature; pouring the mixed solution into ice water, extracting with ethyl acetate for three times, combining organic phases, washing with water for three times, washing with saturated sodium bicarbonate for one time, then washing with saturated salt solution for two times, and drying with anhydrous sodium sulfate; filtering, concentrating, and purifying the crude product by column chromatography to obtain white solid;
5) dissolving the solid obtained in the step 4 in dichloromethane, adding triethylamine, cooling the reaction liquid to 0 ℃, dropwise adding a dichloromethane solution of triphosgene, stirring the reaction liquid at a room temperature, then pouring the solution into water, and extracting the solution with the dichloromethane for three times; combining the organic phases, washing with water for three times, washing with saturated sodium bicarbonate solution, washing with saturated saline solution for two times, and drying with anhydrous sodium sulfate; filtering, concentrating, and purifying the crude product by column chromatography to obtain the L-proline isonitrile monomer.
8. The method of preparing an asymmetric Aldol reaction catalyst according to claim 7, wherein the column chromatography purification is performed by eluting with a mixed eluent of petroleum ether and ethyl acetate, wherein the volume ratio of petroleum ether to ethyl acetate is 5: 1.
9. Use of the catalyst of claim 1 in an asymmetric Aldol reaction in brine.
10. Use according to claim 9, characterized in that: adding a catalyst and ketone into a reaction bottle, adding saturated salt solution, stirring at room temperature for a certain time, adding a certain amount of aldehyde, reacting at-10 ℃ for a certain time, centrifuging, drying, and recovering the catalyst; extracting the filtrate with dichloromethane, concentrating, and purifying with column chromatography to obtain corresponding asymmetric Aldol product, which has the following reaction formula:
Figure RE-FDA0003193939390000031
wherein R1 is one of phenyl, substituted phenyl, aryl, substituted aryl and alkyl; r2 and R3 are respectively one of alkyl, phenyl, substituted phenyl, aryl and substituted aryl.
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