Chiral covalent organic framework mimic enzyme catalyst as well as preparation method and application thereof

Abstract

The invention discloses a novel chiral covalent organic framework mimic enzyme catalyst and a preparation method and application thereof.The preparation method comprises the following steps that 1, 3, 5-tris (4-aminophenyl) benzene, 2, 5-bis (propyl-2-alkyne-1-yloxy) terephthalaldehyde and dialdehyde monomers with different functional groups are dissolved in an organic solvent, an acetic acid aqueous solution is added, a reaction is conducted for 2-4 h, and the chiral covalent organic framework mimic enzyme catalyst is obtained; the chiral covalent organic framework catalyst is prepared by the following steps of: reacting at the temperature of between 80 and 120 DEG C for 2 to 4 days to obtain three-component covalent organic framework materials with different properties, fixing a small molecular catalyst, namely a proline derivative, in a framework through click reaction, and washing, drying and deprotecting the framework to obtain the chiral covalent organic framework catalyst. The prepared chiral covalent organic framework material serves as a heterogeneous catalyst to be used for asymmetric aldol condensation reaction in a green solvent water phase, good catalytic effect and chiral selectivity are shown, separation and recovery of the catalyst can be achieved through simple centrifugation or filtration after the reaction, environmental pollution is effectively reduced, and the method is suitable for industrial production. Meanwhile, cost is reduced, and application prospects are good.

Description

Technical Field

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

[0002] The intensive development of chiral organic small molecule catalysts has also brought countless highly active catalysts to chemical synthesizers. However, in the process of product purification, separating a large amount of organic catalyst from the reaction mixture has become a headache and cumbersome problem. Therefore, the difficulty of catalyst recycling has seriously hindered its application in the asymmetric synthesis of optically active compounds, especially in pharmaceutical processes. Therefore, recovering valuable metal species or inhibiting metal leaching and chiral catalysts with more synthesis steps have become a timeless and important concept in environmentally friendly chemical reaction processes.

[0003] In organic reactions, most reaction substrates are incompatible with water, which greatly reduces the reaction efficiency of organic small molecule catalysts in aqueous media. Compared with some common catalyst carriers, covalent organic framework materials (COF) loaded catalysts have become the preferred choice 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 in 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 a preparation method and application thereof. The prepared chiral covalent organic framework material has good stability and can be used as a heterogeneous catalyst for an asymmetric aldol condensation reaction in an aqueous phase.

[0005] To achieve the above purpose, the specific technical solution is 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, hydroxyl 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 by 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 to a mixed solution of mesitylene, dioxane and dilute acetic acid in a certain proportion, ultrasonically mixed and then degassed with liquid nitrogen, reacted at 80-120°C for 72 hours, and after the reaction, washed repeatedly with tetrahydrofuran, methanol, ethanol and dichloromethane in turn, and vacuum dried to obtain a powder, namely the TADF-COF material, which is then modified by click reaction and acidic de-Boc treatment to obtain a 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 modification method after click reaction is: under nitrogen atmosphere, weigh appropriate amount of TADR-COF material and N-Boc-4-azido-L-proline and place them in a two-necked bottle, add catalytic amount of CuI and DIPEA, and add dichloromethane as solvent, react for 24 hours, wash with dichloromethane, methanol and acetonitrile for many times after the reaction, and vacuum dry 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: 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 turn, and vacuum dry to obtain a 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, weigh an appropriate amount of N-Boc-azidoproline methyl ester and place it in a two-necked flask, add lithium hydroxide, use THF / H2O as a solvent, and stir at room temperature for 12 hours. After the reaction is completed, add hydrochloric acid to the reaction system for acidification, separate the liquids, take the organic phase and extract it with ethyl acetate for multiple times, combine the organic layers and then rotary evaporate to obtain a yellow liquid crude product, purify the crude product by column chromatography (DCM / MeOH=10 / 1), and rotary evaporate and vacuum dry 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 with triphenylphosphine in dry THF, stirred in an ice-water bath under a nitrogen atmosphere, and when the mixture is clear, diethyl azodicarboxylate is added to the mixture. After 15 minutes, diphenylphosphoryl azide is slowly added to the reaction mixture, and the reaction is stirred at room temperature overnight. After completion, it 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 prior art, the present invention 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, and 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 asymmetric aldol condensation reaction, which is low in price, high in yield and purity, and easy to separate, thus avoiding the splitting and racemization in the synthetic route. No special, toxic or harmful reagents are used in the experimental process, and the reaction conditions are mild, thus 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 The present invention provides an X-ray diffraction spectrum of a novel chiral covalent organic framework catalyst.

[0029] Figure 3 The fourier transform infrared spectra of the novel chiral covalent organic framework catalyst prepared by the present invention at various stages.

[0030] Figure 4 The NMR and liquid chromatography 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 liquid chromatography 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 liquid chromatography 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 liquid chromatography 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 liquid chromatography 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] Fig. 9 The NMR and liquid chromatography 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 scheme of the present invention will be clearly and completely described below through embodiments and drawings of the specification, but the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field 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, hydroxyl 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 by a post-modification method. The reaction monomer structural formula is:

[0042]

[0043] The TADF-Pro-COF catalyst was prepared by the following method: monomers 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 tube, and mesitylene (1.5 mL) and dioxane (1.5 mL) were added as solvents, respectively, and ultrasonicated for 5 min, and then acetic acid solution (0.2 mL, 6 M) was added, and ultrasonicated for 5 minutes to obtain a suspension, and the suspension was subjected to liquid nitrogen freezing-vacuuming-degassing treatment 3 times, and then sealed and placed in an oven at 120 ° C for 3 days. After the reaction was completed, it was cooled to room temperature, the generated solid was filtered, and it was repeatedly washed with tetrahydrofuran, methanol, ethanol, and dichloromethane in turn, and vacuum dried to obtain TADF-COF material.

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

[0045] The TADD-Pro-COF catalyst was prepared by the following method: monomers TAPB (0.12 mmol), DDTP (0.09 mmol) and BPTA (0.09 mmol) were added to a 10 mL ampoule tube, and mesitylene (1.5 mL) and dioxane (1.5 mL) were added as solvents, and ultrasonicated for 5 min, and then acetic acid solution (0.2 mL, 6 M) was added, and ultrasonicated for 5 minutes to obtain a suspension, and the suspension was subjected to liquid nitrogen freezing-vacuuming-degassing treatment 3 times, and then sealed and placed in an oven at 120 ° C for 3 days. After the reaction was completed, it was cooled to room temperature, the generated solid was filtered, and it was repeatedly washed with tetrahydrofuran, methanol, ethanol, and dichloromethane in turn, and vacuum dried to obtain TADD-COF material.

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

[0047] The TADH-Pro-COF catalyst was prepared by the following method: monomers TAPB (0.12 mmol), DHTP (0.09 mmol) and BPTA (0.09 mmol) were added to a 10 mL ampoule tube, and mesitylene (1.5 mL) and dioxane (1.5 mL) were added as solvents, and ultrasonicated for 5 min, and then acetic acid solution (0.2 mL, 6 M) was added, and ultrasonicated for 5 minutes to obtain a suspension, and the suspension was subjected to liquid nitrogen freezing-vacuuming-degassing treatment 3 times, and then sealed and placed in an oven at 120 ° C for 3 days. After the reaction was completed, it was cooled to room temperature, the generated solid was filtered, and it was repeatedly washed with tetrahydrofuran, methanol, ethanol, and dichloromethane in turn, and vacuum dried to obtain TADH-COF material.

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

[0049] The TADM-Pro-COF catalyst was prepared by the following method: monomers TAPB (0.12 mmol), DMTP (0.09 mmol) and BPTA (0.09 mmol) were added to a 10 mL ampoule tube, and mesitylene (1.5 mL) and dioxane (1.5 mL) were added as solvents, and ultrasonicated for 5 min, and then acetic acid solution (0.2 mL, 6 M) was added, and ultrasonicated for 5 minutes to obtain a suspension, and the suspension was subjected to liquid nitrogen freezing-vacuuming-degassing treatment 3 times, and then sealed and placed in an oven at 120 ° C for 3 days. After the reaction was completed, it was cooled to room temperature, the generated solid was filtered, and it was repeatedly washed with tetrahydrofuran, methanol, ethanol, and dichloromethane in turn, and vacuum dried to obtain TADM-COF material.

[0050] TADM-COF (75 mg, containing 0.13 mmol alkynyl), N-Boc-4-azido-L-proline (66.6 mg, 2 eq.), cuprous iodide (7.5 mg, 0.3 eq.), DIPEA (15.6 mg, 1 eq.) were added to a two-necked flask, and 5 mL of dichloromethane was added as the reaction solvent. The mixture was reacted at room temperature for 24 h, filtered, and then washed with dichloromethane, methanol and acetonitrile in turn, and vacuum dried to obtain Boc-TADM-Pro-COF powder. Finally, the dried powder was transferred to a 10 mL glass bottle, and 1 mL of 4 M hydrochloric acid dioxane solution was added for every 30 mg of weight, and the Boc protecting group was removed by stirring at room temperature for 1 h. 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 finally obtain the desired TADM-Pro-COF catalyst.

[0051] The synthetic route of N-Boc-4-azido-L-proline is as follows, 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 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 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 for multiple times. After the organic layers are combined, the crude product is rotary evaporated to obtain a yellow liquid product, and the crude product is purified by column chromatography (DCM / MeOH=10 / 1), and a light yellow oil is obtained after rotary evaporation and vacuum drying.

[0054] The preparation method of N-Boc-4-azido-L-proline methyl ester is as follows: Boc-trans-4-hydroxyproline methyl ester (5.8 g, 23.7 mmol) was added to triphenylphosphine (7.8 g, 1.25 eq.) in dry THF (80 mL), and stirred in an ice-water bath under a nitrogen atmosphere. When the mixture was clear, diethyl azodicarboxylate (4.4 mL, 1.25 eq.) was added to the mixture. 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. After completion, it was purified by column chromatography (PE / EA=8 / 1) to obtain colorless liquid N-Boc-4-azido-L-proline methyl ester.

[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. It was then modified by a click reaction and it was found that the absorption peak of the alkynyl functional group disappeared and the absorption peak of the Boc functional group appeared, confirming the successful modification. It was then de-Boc protected and the absorption peak of the Boc functional group disappeared, indicating the successful preparation of the catalyst.

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

[0060] The following application examples take 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 the reaction tube, and then 2.3 μL of trifluoroacetic acid was added, and 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 reduced pressure 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 the reaction tube, and then 2.3 μL of trifluoroacetic acid was added, and 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 reduced pressure 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 87%, an ee value of 91% (measured by high performance liquid chromatography), and a dr value of 8:1 (measured by nuclear magnetic hydrogen spectrum).

[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 the reaction tube, and then 2.3 μL of trifluoroacetic acid was added, and 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 reduced pressure 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 86%, an ee value of 90% (measured by high performance liquid chromatography), and a dr value of 6:1 (measured by nuclear magnetic hydrogen spectrum).

[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 the reaction tube, and then 2.3 μL of trifluoroacetic acid was added, and 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 reduced pressure 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 88%, an ee value of 85% (measured by high performance liquid chromatography), and a dr value of 5:1 (measured by nuclear magnetic hydrogen spectrum).

[0070] Table 1 Yields and stereoselectivities of 5 cycles of catalytic reactions of 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 the reaction tube, and then 2.3 μL of trifluoroacetic acid was added, and 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 reduced pressure concentration, 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, such as Figure 6 As shown), the dr value is 2.5:1 (measured by nuclear magnetic hydrogen spectrum, such as 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 the reaction tube, and then 2.3 μL of trifluoroacetic acid was added, and 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 reduced pressure 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, such as Figure 5 As shown), the dr value is 5.3:1 (measured by nuclear magnetic hydrogen spectrum, such as 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 the reaction tube, and then 2.3 μL of trifluoroacetic acid was added, and 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 reduced pressure 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 Fig. 9 As shown), the dr value is 7.5:1 (measured by nuclear magnetic hydrogen spectrum, as Fig. 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 the reaction tube, and then 2.3 μL of trifluoroacetic acid was added, and 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 reduced pressure 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 78% and an ee value of 86% (measured by high performance liquid chromatography, as shown in FIG. 1 ). Figure 7 As shown), the dr value is 7.2:1 (measured by nuclear magnetic hydrogen spectrum, such 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 the reaction tube, and then 2.3 μL of trifluoroacetic acid was added, and 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 reduced pressure 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 42% and an ee value of 87% (measured by high performance liquid chromatography, as shown in FIG. 1 ). 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] With p-nitrobenzaldehyde and cyclohexanone as substrates, the reaction was tracked by a 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 to calculate the yield, and the ee value of the reaction product was determined by liquid chromatography analysis. The catalytic effect is shown in Table 2. It can be seen from Table 2 that after the catalyst was cycled twice, the yield and ee value of the product remained basically consistent. After five cycles, it only showed a slight downward trend, reflecting the excellent stability of the catalyst, which can be reused for more than five times, can significantly improve the utilization rate of the catalyst, and reduce the production cost.

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

[0090]

[0091] The invention provides a method for preparing TADR-Pro-COF. The prepared TADR-Pro-COF is used as a catalyst, which can be effectively used as a catalyst for an asymmetric aldol condensation reaction, and the yield and selectivity of the catalytic reaction are both high, heterogeneous catalysis is achieved, and the TADR-Pro-COF can be reused more than five times without changing the framework structure. After repeated use, the yield does not decrease significantly, 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 solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that they can still modify or replace the technical solution of the present invention with equivalents, and these modifications or equivalents cannot cause the modified technical solution to deviate from the spirit and scope of the technical solution of the present invention.

Claims

1. A chiral covalent organic framework mimic 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, hydroxyl 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 as claimed in 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: Specifically, the method comprises 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, mixing evenly by ultrasonication, degassing by freezing with liquid nitrogen, reacting at 80-120°C for 72 hours, washing repeatedly with tetrahydrofuran, methanol, ethanol and dichloromethane in sequence after the reaction, and drying in vacuo to obtain a powder, namely, a TADR-COF material, which is then modified by a 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 TADR-COF material and mix with N-Boc-4-azido-L-proline, add CuI, DIPEA, and add dichloromethane as solvent, react for 24 hours, and after the reaction, wash with dichloromethane, methanol, and acetonitrile in turn, 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 acidic de-Boc treatment are as follows: the obtained Boc-TADR-Pro-COF powder is subjected to de-Boc treatment using a 4M hydrochloric acid dioxane solution for 2 hours, and the mass ratio of the volume of the hydrochloric acid dioxane solution to the Boc-TADR-Pro-COF powder is 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 nitrogen atmosphere, weigh N-Boc-azidoproline methyl ester and lithium hydroxide, use THF / H2O as solvent, stir at room temperature for 12 hours, after the reaction is completed, add hydrochloric acid to the reaction system for acidification, separate the liquids, extract the organic phase with ethyl acetate, combine the organic layers and rotary evaporate to obtain a yellow liquid crude product, purify the crude product by column chromatography, and rotary evaporate and vacuum dry 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: add triphenylphosphine to Boc-trans-4-hydroxyproline methyl ester in dry THF, stir in an ice-water bath under a nitrogen atmosphere, and when the mixture is clarified, add diethyl azodicarboxylate to the mixture. After 15 minutes, slowly add diphenylphosphoryl azide 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 as claimed in claim 1 in catalyzing heterogeneous asymmetric reactions.

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