A chiral covalent organic framework enzyme-mimicking catalyst and its preparation method and application

Abstract

The invention discloses a novel chiral covalent organic framework mimic enzyme catalyst and its preparation method and application, the preparation method comprises the following steps: 1,3,5-tris (4-aminophenyl) benzene, 2,5-bis (prop-2-yn-1-yloxy) terephthalaldehyde and dialdehyde monomers with different functional groups are dissolved in an organic solvent, an acetic acid aqueous solution is added, and the reaction is carried out at 80-120 DEG C for 2-4 days to obtain a three-component covalent organic framework material with different properties, and then a small molecule catalyst, i.e., a proline derivative, is fixed in the framework by a click reaction, and then washed, dried and deprotected to obtain a chiral covalent organic framework catalyst. The chiral covalent organic framework material prepared by the present invention is used as a heterogeneous catalyst for asymmetric aldol condensation reaction in a green solvent aqueous phase, showing good catalytic effect and chiral selectivity. After the reaction, the catalyst can be separated and recovered by simple centrifugation or filtration, effectively reducing environmental pollution, while reducing costs, and having good application prospects.

Description

Technical Field

[0001] The present invention belongs to the technical field of covalent organic framework materials, and in particular relates to a chiral covalent organic framework enzyme-mimicking catalyst, a preparation method thereof, and an application thereof. Background Art

[0002] The rapid development of chiral organic small molecule catalysts has brought countless highly active catalysts to chemists. However, separating the large amounts of organic catalysts from the reaction mixture during product purification has become a daunting and cumbersome task. Consequently, the difficulty of catalyst recycling has severely hampered their application in the asymmetric synthesis of optically active compounds, particularly in pharmaceutical processes. Therefore, recovering valuable metal species or suppressing metal leaching and the need for chiral catalysts with numerous synthesis steps have become enduring and crucial concepts in environmentally friendly chemical reactions.

[0003] In organic reactions, most reaction substrates are insoluble in water, which greatly reduces the reaction efficiency of organic small molecule catalysts in aqueous media. Compared with some common catalyst supports, covalent organic framework materials (COFs) have become the preferred catalyst carriers due to their advantages such as high specific surface area, controllable pore structure, and high crystallinity. The advantages include the following: 1) Insoluble polymers are easy to separate and recover; 2) The properties and structure of porous organic polymers are relatively stable compared to inorganic materials and are not easily destroyed; 3) The continuous and clear pore structure within COF provides a fast channel for mass transfer, increasing the chance of contact with the substrate. Compared with inorganic materials, it has better compatibility. On the one hand, it can be well dispersed in the reaction solvent to increase the exposure of active sites, and on the other hand, it can well adsorb substrate molecules, which is beneficial to increase the reaction rate in the aqueous phase. Summary of the Invention

[0004] The purpose of the present invention is to provide a chiral covalent organic framework enzyme-mimicking catalyst and its preparation method and application. The prepared chiral covalent organic framework material has good stability and can be used as a heterogeneous catalyst in an asymmetric aldol condensation reaction in an aqueous phase.

[0005] To achieve the above objectives, the specific technical solutions are as follows:

[0006] The present invention provides a chiral covalent organic framework mimicking enzyme catalyst, denoted as

[0007] TADR-Pro-COF catalyst, the structural formula of the TADR-Pro-COF catalyst is shown in formula (I)

[0008]

[0009] The substituent R in formula (1) 1 When it is hydrogen, the substituent R2 is methoxy, hydroxy or hydrogen; the substituent R 1 When fluorine, the substituent R 2 For fluorine.

[0010] The present invention also provides a method for preparing a chiral covalent organic framework enzyme-mimicking catalyst. The TADR-Pro-COF catalyst uses TAPB (1,3,5-tris(4-aminophenyl)benzene), BPTA (2,5-bis(prop-2-yn-1-yloxy)terephthalaldehyde) and DFTP or DDTP or DHTP or DMTP as reaction monomers to synthesize three-component TADR-COF (R is D, H, F, M, i.e., corresponding to different reaction monomers), and then synthesizes the TADR-Pro-COF catalyst through a post-modification method. The structural formula of the reaction monomer is:

[0011]

[0012] The specific preparation method is as follows: TAPB, BPTA and DFTP, DDTP, DHTP or DMTP are added in a certain proportion to a mixed solution of mesitylene, dioxane and dilute acetic acid, ultrasonically mixed and then degassed with liquid nitrogen, reacted at 80-120°C for 72 hours, and after the reaction is completed, repeatedly washed with tetrahydrofuran, methanol, ethanol and dichloromethane in sequence. After vacuum drying, the powder obtained is the TADF-COF material, which is then modified by click reaction and acidic Boc removal treatment to obtain the TADF-Pro-COF catalyst.

[0013] The molar mass ratio of TAPB, BPTA, DFTP, DDTP, DHTP or DMTP is 4:3:3, and the volume ratio of dioxane, mesitylene and dilute acetic acid is 15:15:2.

[0014] Preferably, the post-click modification method is as follows: under a nitrogen atmosphere, an appropriate amount of TADR-COF material and N-Boc-4-azido-L-proline are weighed and placed in a two-necked bottle, a catalytic amount of CuI and DIPEA are added, and dichloromethane is added as a solvent. The reaction is carried out for 24 hours. After the reaction is completed, the mixture is washed with dichloromethane, methanol, and acetonitrile several times, and vacuum dried to obtain Boc-TADR-Pro-COF powder.

[0015] The ratio of TADR-COF, N-Boc-4-azido-L-proline, CuI, DIPEA and dichloromethane is: 65 mg:66 mg:7.5 mg:15 mg:5 mL.

[0016] Preferably, the acidic Boc removal and post-modification method is as follows: under a nitrogen atmosphere, weigh an appropriate amount of Boc-TADR-Pro-COF powder, add 4M hydrochloric acid dioxane solution, react for 2 hours, wash with saturated NaHCO3, methanol, and ethanol in sequence, and vacuum dry to obtain the TADF-Pro-COF catalyst.

[0017] The mass volume ratio of Boc-TADR-Pro-COF powder and 4M dioxane hydrochloride solution is 30 mg:1 mL.

[0018] According to the above method, three other catalysts, TADD-Pro-COF, TADH-Pro-COF, and TADM-Pro-COF, with different hydrophilic and hydrophobic environments were obtained in the same manner.

[0019] Preferably, the preparation method of N-Boc-4-azido-L-proline is as follows: under the protection of a nitrogen atmosphere, an appropriate amount of N-Boc-azidoproline methyl ester is weighed and placed in a two-necked flask, lithium hydroxide is added, THF / H2O is used as a solvent, and the mixture is stirred at room temperature for 12 hours. After the reaction is completed, hydrochloric acid is added to the reaction system to acidify the mixture, the liquid is separated, and the organic phase is extracted with ethyl acetate multiple times. The organic layers are combined and rotary evaporated to obtain a yellow liquid crude product, the crude product is purified by column chromatography (DCM / MeOH=10 / 1), and rotary evaporated and vacuum dried to obtain a light yellow oil.

[0020] Among them, the mass volume ratio of N-Boc-4-azido-L-proline methyl ester, lithium hydroxide, and THF / H2O is: 272 mg:96 mg:10 mL:2 mL.

[0021] Preferably, the preparation method of N-Boc-4-azido-L-proline methyl ester is as follows: Boc-trans-4-hydroxyproline methyl ester is added to triphenylphosphine in dry THF, and the mixture is stirred in an ice-water bath under a nitrogen atmosphere. When the mixture becomes clear, diethyl azodicarboxylate is added to the mixture. After 15 minutes, diphenylphosphoryl azide is slowly added to the reaction mixture. The reaction is stirred at room temperature overnight. After completion, the mixture is purified by column chromatography (PE / EA = 8 / 1) to obtain colorless liquid N-Boc-4-azido-L-proline methyl ester.

[0022] The mass volume ratio of Boc-trans-4-hydroxyproline methyl ester, triphenylphosphine, diethyl azodicarboxylate, diphenylphosphoryl azide, and tetrahydrofuran is: 5.8 g: 7.8 g: 4.4 mL: 6.6 mL: 80 mL.

[0023] The present invention also provides an application of a TADR-Pro-COF catalyst in an asymmetric aldol condensation reaction.

[0024] Compared with the existing technology, it has the following beneficial effects:

[0025] (1) The TADR-Pro-COF prepared by the present invention can be used as a catalyst to effectively catalyze the asymmetric aldol condensation reaction of aromatic aldehydes and ketones, and the yield and stereoselectivity of the catalytic reaction are very high, achieving heterogeneous catalysis. At the same time, it can be reused more than five times, the catalyst is easy to recover, the utilization rate of the catalyst is improved, and the cost is reduced;

[0026] (2) The TADR-Pro-COF prepared in the present invention is used as a catalyst for the asymmetric aldol condensation reaction. It is low-priced, has high yield and purity, is easy to separate, and avoids the splitting and racemization in the synthetic route. No special, toxic or harmful reagents are used during the experiment, and the reaction conditions are mild, meeting the requirements of energy saving and environmental protection. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 This is a scanning electron microscope image of the novel chiral covalent organic framework catalyst prepared in the present invention.

[0028] Figure 2 This is the X-ray diffraction spectrum of the novel chiral covalent organic framework catalyst prepared in the present invention.

[0029] Figure 3 These are Fourier transform infrared spectra of the novel chiral covalent organic framework catalyst prepared in the present invention at various stages.

[0030] Figure 4 The NMR and LC spectra of the product obtained by using the novel chiral covalent organic framework catalyst prepared in Example 1 to catalyze the aldol condensation reaction of cyclohexanone and p-nitrobenzaldehyde.

[0031] Figure 5 The NMR and LC spectra of the product obtained by using the novel chiral covalent organic framework catalyst prepared in Example 6 to catalyze the aldol condensation reaction of cyclohexanone and o-nitrobenzaldehyde.

[0032] Figure 6 The NMR and LC spectra of the product obtained by using the novel chiral covalent organic framework catalyst prepared in Example 5 to catalyze the aldol condensation reaction of cyclohexanone and m-nitrobenzaldehyde.

[0033] Figure 7 The NMR and LC spectra of the product obtained by using the novel chiral covalent organic framework catalyst prepared in Example 8 to catalyze the aldol condensation reaction of cyclohexanone and p-cyanobenzaldehyde.

[0034] Figure 8 The NMR and LC spectra of the product obtained by using the novel chiral covalent organic framework catalyst prepared in Example 9 to catalyze the aldol condensation reaction of cyclohexanone and p-phenylbenzaldehyde.

[0035] Figure 9 The NMR and LC spectra of the product obtained by using the novel chiral covalent organic framework catalyst prepared in Example 7 to catalyze the aldol condensation reaction of cyclohexanone and p-bromobenzaldehyde. DETAILED DESCRIPTION

[0036] The technical solutions of the present invention are described clearly and completely below through the embodiments and drawings. However, the embodiments described are only some of the embodiments of the present invention, not all of them. All other embodiments obtained by persons of ordinary skill in the art based on the embodiments of the present invention without creative work are within the scope of protection of the present invention.

[0037] Example 1

[0038] The structural formula of TADR-Pro-COF catalyst is:

[0039]

[0040] The substituent R in formula (1) 1 When it is hydrogen, the substituent R 2 is methoxy, hydroxy or hydrogen; the substituent R 1 When fluorine, the substituent R 2 For fluorine.

[0041] The TADR-Pro-COF catalyst uses TAPB, BPTA and DFTP or DDTP or DHTP or DMTP as reaction monomers to synthesize three-component TADR-COF, and then synthesizes the TADR-Pro-COF catalyst through a post-modification method. The reaction monomer structural formula is:

[0042]

[0043] The TADF-Pro-COF catalyst was prepared using the following method: TAPB (42 mg, 0.12 mmol), DFTP (18.6 mg, 0.09 mmol), and BPTA (21.8 mg, 0.09 mmol) were added to a 10 mL ampoule. Mesitylene (1.5 mL) and dioxane (1.5 mL) were added as solvents, respectively. The mixture was sonicated for 5 minutes. Acetic acid solution (0.2 mL, 6 M) was then added and sonicated for 5 minutes to obtain a suspension. The suspension was then frozen in liquid nitrogen, vacuumed, and degassed three times. The mixture was sealed and placed in an oven at 120°C for 3 days. After the reaction, the mixture was cooled to room temperature, and the resulting solid was filtered and repeatedly washed with tetrahydrofuran, methanol, ethanol, and dichloromethane. The mixture was then dried under vacuum to obtain the TADF-COF material.

[0044] TADF-COF (65 mg, containing 0.13 mmol alkynyl groups), N-Boc-4-azido-L-proline (66.6 mg, 2 eq.), cuprous iodide (7.5 mg, 0.3 eq.), and DIPEA (15.6 mg, 1 eq.) were added to a two-necked flask. 5 mL of dichloromethane was added as the reaction solvent. The mixture was allowed to react at room temperature for 24 hours. The mixture was filtered and washed sequentially with dichloromethane, methanol, and acetonitrile. The powder was then dried under vacuum to obtain Boc-TADF-Pro-COF powder. The dried powder was transferred to a 10 mL glass vial. 1 mL of 4 M hydrochloric acid and dioxane solution was added per 30 mg of the powder. The mixture was stirred at room temperature for 1 hour to remove the Boc protecting group. After the reaction, the solid was filtered and washed with 6 mL of THF once, 6 mL of 2% triethylamine methanol solution twice, 6 mL of deionized water once, 6 mL of THF once, and finally washed with 6 mL of anhydrous ether once, and dried in a vacuum drying oven for 6 h to obtain the desired TADF-Pro-COF catalyst.

[0045] The TADD-Pro-COF catalyst was prepared using the following method: TAPB (0.12 mmol), DDTP (0.09 mmol), and BPTA (0.09 mmol) were added to a 10 mL ampoule. Mesitylene (1.5 mL) and dioxane (1.5 mL) were added as solvents, respectively. The mixture was sonicated for 5 minutes. Acetic acid solution (0.2 mL, 6 M) was then added and sonicated for 5 minutes to obtain a suspension. The suspension was then frozen in liquid nitrogen, vacuumed, and degassed three times. The resulting suspension was sealed and placed in an oven at 120°C for 3 days. After the reaction, the mixture was cooled to room temperature, and the resulting solid was filtered and repeatedly washed with tetrahydrofuran, methanol, ethanol, and dichloromethane. The mixture was then dried under vacuum to obtain the TADD-COF material.

[0046] TADD-COF (69 mg, containing 0.13 mmol alkynyl groups), N-Boc-4-azido-L-proline (66.6 mg, 2 eq.), cuprous iodide (7.5 mg, 0.3 eq.), and DIPEA (15.6 mg, 1 eq.) were added to a two-necked flask. 5 mL of dichloromethane was added as the reaction solvent. The mixture was allowed to react at room temperature for 24 hours. The mixture was filtered and washed sequentially with dichloromethane, methanol, and acetonitrile. The powder was then dried under vacuum to obtain Boc-TADD-Pro-COF powder. The dried powder was transferred to a 10 mL glass vial. 1 mL of 4 M hydrochloric acid and dioxane solution was added per 30 mg of the powder. The mixture was stirred at room temperature for 1 hour to remove the Boc protecting group. After the reaction, the solid was filtered and washed with 6 mL of THF once, 6 mL of 2% triethylamine methanol solution twice, 6 mL of deionized water once, 6 mL of THF once, and finally washed with 6 mL of anhydrous ether once, and dried in a vacuum drying oven for 6 h to obtain the desired TADD-Pro-COF catalyst.

[0047] The TADH-Pro-COF catalyst was prepared using the following method: TAPB (0.12 mmol), DHTP (0.09 mmol), and BPTA (0.09 mmol) were added to a 10 mL ampoule. Mesitylene (1.5 mL) and dioxane (1.5 mL) were added as solvents, respectively. The mixture was sonicated for 5 minutes. Acetic acid solution (0.2 mL, 6 M) was then added and sonicated for 5 minutes to obtain a suspension. The suspension was then frozen in liquid nitrogen, vacuumed, and degassed three times. The resulting suspension was sealed and placed in an oven at 120°C for 3 days. After the reaction, the mixture was cooled to room temperature, and the resulting solid was filtered and repeatedly washed with tetrahydrofuran, methanol, ethanol, and dichloromethane. The mixture was then dried under vacuum to obtain the TADH-COF material.

[0048] TADH-COF (73 mg, containing 0.13 mmol alkynyl groups), N-Boc-4-azido-L-proline (66.6 mg, 2 eq.), cuprous iodide (7.5 mg, 0.3 eq.), and DIPEA (15.6 mg, 1 eq.) were added to a two-necked flask. 5 mL of dichloromethane was added as the reaction solvent. The mixture was allowed to react at room temperature for 24 hours. The mixture was filtered and washed sequentially with dichloromethane, methanol, and acetonitrile. The powder was then dried under vacuum to obtain Boc-TADH-Pro-COF powder. The dried powder was transferred to a 10 mL glass vial. 1 mL of 4 M hydrochloric acid and dioxane solution was added per 30 mg of the powder. The mixture was stirred at room temperature for 1 hour to remove the Boc protecting group. After the reaction, the solid was filtered and washed with 6 mL of THF once, 6 mL of 2% triethylamine methanol solution twice, 6 mL of deionized water once, 6 mL of THF once, and finally washed with 6 mL of anhydrous ether once, and dried in a vacuum drying oven for 6 h to obtain the desired TADH-Pro-COF catalyst.

[0049] The TADM-Pro-COF catalyst was prepared using the following method: TAPB (0.12 mmol), DMTP (0.09 mmol), and BPTA (0.09 mmol) were added to a 10 mL ampoule. Mesitylene (1.5 mL) and dioxane (1.5 mL) were added as solvents, respectively. The mixture was sonicated for 5 minutes. Acetic acid solution (0.2 mL, 6 M) was then added and sonicated for 5 minutes to obtain a suspension. The suspension was then frozen in liquid nitrogen, vacuumed, and degassed three times. The resulting suspension was sealed and placed in an oven at 120°C for 3 days. After the reaction, the mixture was cooled to room temperature, and the resulting solid was filtered and repeatedly washed with tetrahydrofuran, methanol, ethanol, and dichloromethane. The mixture was then dried under vacuum to obtain the TADM-COF material.

[0050] TADM-COF (75 mg, containing 0.13 mmol alkynyl groups), N-Boc-4-azido-L-proline (66.6 mg, 2 eq.), cuprous iodide (7.5 mg, 0.3 eq.), and DIPEA (15.6 mg, 1 eq.) were added to a two-necked flask. 5 mL of dichloromethane was added as the reaction solvent. The mixture was allowed to react at room temperature for 24 hours. The mixture was filtered and washed sequentially with dichloromethane, methanol, and acetonitrile. The powder was then dried under vacuum to obtain Boc-TADM-Pro-COF powder. The dried powder was transferred to a 10 mL glass vial. 1 mL of 4 M hydrochloric acid and dioxane solution was added per 30 mg of the powder. The mixture was stirred at room temperature for 1 hour to remove the Boc protecting group. After the reaction, the solid was filtered and washed with 6 mL of THF once, 6 mL of 2% triethylamine methanol solution twice, 6 mL of deionized water once, 6 mL of THF once, and finally washed with 6 mL of anhydrous ether once, and dried in a vacuum drying oven for 6 h to obtain the desired TADM-Pro-COF catalyst.

[0051] The synthetic route of N-Boc-4-azido-L-proline is shown below, which specifically comprises the following steps:

[0052]

[0053] The preparation method of N-Boc-4-azido-L-proline is as follows: under the protection of a nitrogen atmosphere, N-Boc-azidoproline methyl ester (1 mmol, 272 mg) is weighed and placed in a two-necked flask, lithium hydroxide (96 mg, 4 eq.) is added, THF / H2O (10 mL / 2 mL) is used as a solvent, and the mixture is stirred at room temperature for 12 hours. After the reaction is completed, hydrochloric acid is added to the reaction system to acidify the mixture, the liquid is separated, and the organic phase is extracted with ethyl acetate multiple times. The organic layers are combined and rotary evaporated to obtain a yellow liquid crude product, which is purified by column chromatography (DCM / MeOH=10 / 1), rotary evaporated and vacuum dried to obtain a light yellow oil.

[0054] N-Boc-4-azido-L-proline methyl ester was prepared by dissolving Boc-trans-4-hydroxyproline methyl ester (5.8 g, 23.7 mmol) in dry THF (80 mL) and adding triphenylphosphine (7.8 g, 1.25 eq.). The mixture was stirred in an ice-water bath under a nitrogen atmosphere. Once the mixture became clear, diethyl azodicarboxylate (4.4 mL, 1.25 eq.) was added. After 15 minutes, diphenylphosphoryl azide (6.6 mL, 1.25 eq.) was slowly added to the reaction mixture. The reaction was stirred at room temperature overnight. Upon completion, the mixture was purified by column chromatography (PE / EA = 8 / 1) to yield N-Boc-4-azido-L-proline methyl ester as a colorless liquid.

[0055] Test result spectrum analysis

[0056] See also Figure 1 , which is a scanning electron microscope spectrum of the prepared chiral covalent organic framework material catalyst. It can be seen from the figure that the prepared chiral covalent organic framework material has a spherical morphology.

[0057] See also Figure 2 , which is the X-ray powder diffraction pattern of the prepared chiral covalent organic framework material catalyst. It can be seen from the figure that the prepared chiral covalent organic framework material has obvious X-ray diffraction peaks, indicating that the obtained material has a crystalline structure.

[0058] See also Figure 3 , which is the Fourier infrared spectrum of the prepared chiral covalent organic framework material catalyst. It can be seen from the figure that the original covalent organic framework material has an obvious absorption peak of the alkynyl functional group. After it is modified by click reaction, it is found that the absorption peak of the alkynyl functional group disappears and the absorption peak of the Boc functional group appears, confirming the successful modification. Then it is de-Boc protection treated and the absorption peak of the Boc functional group disappears, indicating the successful preparation of the catalyst.

[0059] The TADR-Pro-COF prepared by the invention is used as a catalyst for an asymmetric aldol condensation reaction.

[0060] The following application examples use the asymmetric aldol condensation reaction of cyclohexanone and p-nitrobenzaldehyde as an example to verify the catalytic activity and chiral selectivity of the four chiral covalent organic framework materials prepared in the present invention for the asymmetric aldol condensation reaction of aldehydes and ketones. The reaction equation in this example is as follows:

[0061]

[0062] Application Example 1

[0063] 25 mg of the prepared TADH-Pro-COF catalyst, 15.1 mg of p-nitrobenzaldehyde, 60 μL of cyclohexanone, 0.5 mL of water, and 0.5 mL of ethanol were added to a reaction tube, followed by 2.3 μL of trifluoroacetic acid. The reaction was stirred at room temperature for 3 days. After the reaction was completed, the liquid was collected by centrifugation or filtration and washing. After vacuum concentration, the residue was purified by column chromatography (ethyl acetate: n-hexane = 1:4, V / V) to obtain the target product, such as Figure 4 As shown, the yield is 94%, the ee value is 94% (determined by high performance liquid chromatography), and the dr value is greater than 20:1 (determined by nuclear magnetic hydrogen spectrum).

[0064] Application Example 2

[0065] 25 mg of the prepared TADF-Pro-COF catalyst, 15.1 mg of p-nitrobenzaldehyde, 60 μL of cyclohexanone, 0.5 mL of water, and 0.5 mL of ethanol were added to a reaction tube. Then, 2.3 μL of trifluoroacetic acid was added and the reaction was stirred at room temperature for 3 days. After the reaction, the liquid was collected by centrifugation or filtration and washing. After concentration under reduced pressure, the residue was purified by column chromatography (ethyl acetate:n-hexane = 1:4, v / v) to obtain the desired product with an 87% yield, an ee value of 91% (determined by HPLC), and a dr value of 8:1 (determined by H-NMR spectroscopy).

[0066] Application Example 3

[0067] 25 mg of the prepared TADD-Pro-COF catalyst, 15.1 mg of p-nitrobenzaldehyde, 60 μL of cyclohexanone, 0.5 mL of water, and 0.5 mL of ethanol were added to a reaction tube. Then, 2.3 μL of trifluoroacetic acid was added and the reaction was stirred at room temperature for 3 days. After the reaction, the liquid was collected by centrifugation or filtration and washing. After concentration under reduced pressure, the residue was purified by column chromatography (ethyl acetate:n-hexane = 1:4, v / v) to obtain the desired product with an 86% yield, an ee value of 90% (determined by HPLC), and a dr value of 6:1 (determined by H-NMR spectroscopy).

[0068] Application Example 4

[0069] 25 mg of the prepared TADM-Pro-COF catalyst, 15.1 mg of p-nitrobenzaldehyde, 60 μL of cyclohexanone, 0.5 mL of water, and 0.5 mL of ethanol were added to a reaction tube. Then, 2.3 μL of trifluoroacetic acid was added and the reaction was stirred at room temperature for 3 days. After the reaction, the liquid was collected by centrifugation or filtration and washing. After concentration under reduced pressure, the residue was purified by column chromatography (ethyl acetate:n-hexane = 1:4, v / v) to obtain the desired product with an 88% yield, an ee value of 85% (determined by HPLC), and a dr value of 5:1 (determined by H-NMR spectroscopy).

[0070] Table 1 Yields and stereoselectivities of 5 cycles of catalytic reactions using four catalysts

[0071] Entry cat solvent yield(%) ee(%) dr 1 TADF-Pro-COF <![CDATA[H2O / EtOH]]> 87 91 8:1 2 TADM-Pro-COF <![CDATA[H2O / EtOH]]> 88 85 5:1 3 TADD-Pro-COF <![CDATA[H2O / EtOH]]> 86 90 6:1 4 TADH-Pro-COF <![CDATA[H2O / EtOH]]> 94 94 >20:1

[0072] From the data in the above table, it can be found that TADH-Pro-COF catalyst has the best activity, so the substrate universality verification of TADH-Pro-COF catalyst was explored.

[0073]

[0074] Application Example 5

[0075] 25 mg of the prepared TADH-Pro-COF catalyst, 15.1 mg of m-nitrobenzaldehyde, 60 μL of cyclohexanone, 0.5 mL of water, and 0.5 mL of ethanol were added to a reaction tube, followed by the addition of 2.3 μL of trifluoroacetic acid. The reaction was stirred at room temperature for 3 days. After the reaction was completed, the liquid was collected by centrifugation or filtration and washing, and after concentration under reduced pressure, the residue was purified by column chromatography (ethyl acetate: n-hexane = 1:5, V / V) to obtain the target product with a yield of 96% and an ee value of 93% (measured by high performance liquid chromatography, as shown in FIG. 2 ). Figure 6 As shown), the dr value is 2.5:1 (measured by nuclear magnetic hydrogen spectrum, as shown Figure 6 shown).

[0076] Application Example 6

[0077] 25 mg of the prepared TADH-Pro-COF catalyst, 15.1 mg of o-nitrobenzaldehyde, 60 μL of cyclohexanone, 0.5 mL of water, and 0.5 mL of ethanol were added to a reaction tube, followed by the addition of 2.3 μL of trifluoroacetic acid. The reaction was stirred at room temperature for 3 days. After the reaction was completed, the liquid was collected by centrifugation or filtration and washing. After vacuum concentration, the residue was purified by column chromatography (ethyl acetate: n-hexane = 1:4, V / V) to obtain the target product with a yield of 95% and an ee value of 98% (measured by high performance liquid chromatography, as shown in FIG. 2 ). Figure 5 As shown), the dr value is 5.3:1 (measured by nuclear magnetic hydrogen spectrum, as shown Figure 5 shown).

[0078] Application Example 7

[0079] 25 mg of the prepared TADH-Pro-COF catalyst, 18.4 mg of p-bromobenzaldehyde, 60 μL of cyclohexanone, 0.5 mL of water, and 0.5 mL of ethanol were added to a reaction tube, followed by the addition of 2.3 μL of trifluoroacetic acid. The reaction was stirred at room temperature for 3 days. After the reaction was completed, the liquid was collected by centrifugation or filtration and washing. After vacuum concentration, the residue was purified by column chromatography (ethyl acetate: n-hexane = 1:6, V / V) to obtain the target product with a yield of 67% and an ee value of 93% (measured by high performance liquid chromatography, as shown in FIG. 2 ). Figure 9 As shown), the dr value is 7.5:1 (measured by nuclear magnetic hydrogen spectrum, as shown Figure 9 shown).

[0080] Application Example 8

[0081] 25 mg of the prepared TADH-Pro-COF catalyst, 13.1 mg of p-cyanobenzaldehyde, 60 μL of cyclohexanone, 0.5 mL of water, and 0.5 mL of ethanol were added to a reaction tube, followed by the addition of 2.3 μL of trifluoroacetic acid. The reaction was stirred at room temperature for 3 days. After the reaction was completed, the liquid was collected by centrifugation or filtration and washing. After concentration under reduced pressure, the residue was purified by column chromatography (ethyl acetate: n-hexane = 1:6, V / V) to obtain the target product with a yield of 78% and an ee value of 86% (measured by high performance liquid chromatography, as shown in FIG. 2 ). Figure 7 As shown), the dr value is 7.2:1 (measured by nuclear magnetic hydrogen spectrum, as Figure 7 shown).

[0082] Application Example 9

[0083] 25 mg of the prepared TADH-Pro-COF catalyst, 18.2 mg of p-phenylbenzaldehyde, 60 μL of cyclohexanone, 0.5 mL of water, and 0.5 mL of ethanol were added to a reaction tube, followed by the addition of 2.3 μL of trifluoroacetic acid. The reaction was stirred at room temperature for 3 days. After the reaction was completed, the liquid was collected by centrifugation or filtration and washing, and after concentration under reduced pressure, the residue was purified by column chromatography (ethyl acetate: n-hexane = 1:6, V / V) to obtain the target product with a yield of 42% and an ee value of 87% (measured by high performance liquid chromatography, as shown in FIG. 2 ). Figure 8 As shown), the dr value is greater than 20:1 (measured by nuclear magnetic hydrogen spectrum, such as Figure 8 shown).

[0084]

[0085] Table 2 Summary of substrate universality of TADH-Pro-COF catalyst

[0086]

[0087] Verification of the cyclic performance of TADH-Pro-COF catalyst

[0088] Using p-nitrobenzaldehyde and cyclohexanone as substrates, the reaction was tracked by spot plate. After the reaction was completed, the catalyst was recovered by centrifugation and directly put into the next cycle reaction. According to the above conditions, the catalyst was used for 5 cycles. The reaction liquid was separated and the yield was calculated. The ee value of the reaction product was determined by liquid chromatography analysis. The catalytic effect is shown in Table 2. As can be seen from Table 2, after two cycles of the catalyst, the yield and ee value of the product remained basically consistent. After five cycles, there was only a slight downward trend, reflecting the excellent stability of the catalyst. It can be reused for more than five times, which can significantly improve the utilization rate of the catalyst and reduce production costs.

[0089] Table 3 shows the yield and stereoselectivity of TADH-Pro-COF catalytic reaction for 5 cycles

[0090]

[0091] The present invention provides a method for preparing TADR-Pro-COF. The prepared TADR-Pro-COF can be used as a catalyst, which can effectively serve as a catalyst for an asymmetric aldol condensation reaction. The catalytic reaction has high yield and selectivity, achieving heterogeneous catalysis. The TADR-Pro-COF can be reused more than five times without changing the framework structure. After repeated use, the yield does not significantly decrease, and the TADR-Pro-COF has good stability and catalytic efficiency.

[0092] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit the same. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention can still be modified or replaced by equivalents, and these modifications or replacements cannot cause the modified technical solutions to deviate from the spirit and scope of the technical solutions of the present invention.

Claims

1. A chiral covalent organic framework mimicking enzyme catalyst, characterized in that: The structural formula of the catalyst is shown in formula (I) The substituent R in formula (1) 1 When it is hydrogen, the substituent R 2 is methoxy, hydroxy or hydrogen; the substituent R 1 When fluorine, the substituent R 2 For fluorine.

2. A method for preparing a chiral covalent organic framework enzyme-mimicking catalyst according to claim 1, characterized in that: The method comprises the following steps: using TAPB, BPTA and DFTP, DDTP, DHTP or DMTP as reaction monomers to synthesize three components, and then synthesizing a chiral covalent organic framework mimic enzyme catalyst by a post-modification method. The structural formula of the reaction monomer is as follows:

3. The method for preparing a chiral covalent organic framework enzyme-mimicking catalyst according to claim 2, characterized in that: The method specifically includes the following steps: adding TAPB, BPTA and three monomers, DFTP, DDTP, DHTP or DMTP, to a mixed solution of mesitylene, dioxane and dilute acetic acid, ultrasonically mixing the mixture evenly and then degassing the mixture with liquid nitrogen, reacting the mixture at 80-120°C for 72 hours, and repeatedly washing the mixture with tetrahydrofuran, methanol, ethanol and dichloromethane in sequence. After vacuum drying, the obtained powder is the TADR-COF material, which is then modified by click reaction and acidic de-Boc treatment to obtain a chiral covalent organic framework mimic enzyme catalyst.

4. The method for preparing a chiral covalent organic framework enzyme-mimicking catalyst according to claim 3, characterized in that: The molar mass ratio of the TAPB, BPTA and DFTP, DDTP, DHTP or DMTP is 4:3:3, and the volume ratio of mesitylene, dioxane and 6M dilute acetic acid is 15:15:

2.

5. The method for preparing a chiral covalent organic framework enzyme-mimicking catalyst according to claim 4, characterized in that: The specific steps of the click reaction are as follows: Under a nitrogen atmosphere, weigh the TADR-COF material and mix it with N-Boc-4-azido-L-proline, add CuI and DIPEA, and add dichloromethane as solvent. React for 24 hours. After the reaction, wash with dichloromethane, methanol, and acetonitrile in sequence, and vacuum dry to obtain Boc-TADR-Pro-COF powder.

6. The method for preparing a chiral covalent organic framework enzyme-mimicking catalyst according to claim 5, characterized in that: The specific steps of the acidic de-Boc treatment are as follows: the obtained Boc-TADR-Pro-COF powder is subjected to a de-Boc treatment using a 4M hydrochloric acid dioxane solution for 2 hours. The volume of the hydrochloric acid dioxane solution and the mass ratio of the Boc-TADR-Pro-COF powder are 1 mL: 20-40 mg.

7. The method for preparing a chiral covalent organic framework enzyme-mimicking catalyst according to claim 5, characterized in that: The preparation process of N-Boc-4-azido-L-proline is as follows: under the protection of a nitrogen atmosphere, N-Boc-azidoproline methyl ester and lithium hydroxide are weighed, THF / H2O is used as a solvent, and the mixture is stirred at room temperature for 12 hours. After the reaction is completed, hydrochloric acid is added to the reaction system for acidification, the liquid is separated, and the organic phase is extracted with ethyl acetate. The organic layers are combined and then rotary evaporated to obtain a yellow liquid crude product. The crude product is purified by column chromatography, and rotary evaporated and vacuum dried to obtain a light yellow oil, which is N-Boc-4-azido-L-proline.

8. The method for preparing a chiral covalent organic framework enzyme-mimicking catalyst according to claim 5, characterized in that: The preparation process of N-Boc-azidoproline methyl ester is as follows: Boc-trans-4-hydroxyproline methyl ester is added to triphenylphosphine in dry THF, and stirred in an ice-water bath under a nitrogen atmosphere. When the mixture is clear, diethyl azodicarboxylate is added to the mixture. After 15 minutes, diphenylphosphoryl azide is slowly added to the reaction mixture. The reaction is stirred at room temperature overnight. After completion, it is purified by column chromatography to obtain colorless liquid Boc-azidoproline methyl ester.

9. Use of the chiral covalent organic framework enzyme-mimicking catalyst according to claim 1 in catalyzing heterogeneous asymmetric reactions.

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