Chiral amino acid loaded polyisocyanide catalyst as well as preparation method and application thereof

Abstract

The invention relates to the technical field of catalysts, in particular to a chiral amino acid loaded polyisocyanide catalyst as well as a preparation method and application thereof. The preparation method comprises the following steps: synthesizing an isonitrile monomer with a side chain containing chiral amino acid by taking chiral amino acid as an initial raw material, then polymerizing into chiral amino acid loaded spiral polyisocyanide under the initiation of a palladium catalyst, and then performing deprotection to prepare the chiral amino acid loaded polyisocyanide catalyst. The chiral amino acid loaded polyisocyanide catalyst provided by the invention has high catalytic activity and stereoselectivity, and provides a thought for exploration of subsequent other reaction types.

Description

Technical Field

[0001] The present invention relates to the technical field of catalysts, and in particular to a chiral amino acid-supported polyisonitrile catalyst and a preparation method and application thereof. Background Art

[0002] Natural amino acids and their derivatives have been widely used in the medical field and asymmetric catalysis due to their special biological activity, species diversity, selective substrate binding function and flexible coordination ability. Natural L-amino acids and chiral primary amine catalysts derived from them have become one of the most valuable sources of organic catalysts due to their simple structure, low cost, easy availability, and more controllable sites. In recent years, they have been widely used in asymmetric Aldol reactions, Michael reactions, tandem reactions, etc. However, chiral amino acids have disadvantages such as good solubility, difficulty in separation and recovery, so researchers have solved this problem by immobilizing chiral amino acids on organic polymer carriers or copolymerizing them with other molecules. Polyisocyanates have a helical structure, and the chiral groups on the side chains can cooperate with the main chain to provide more chiral microenvironments, so that polyisocyanates can be used as carriers for many small molecule catalysts. This new type of supported catalyst with multiple catalytic sites can improve the stereoselectivity of the Aldol reaction and has become a hot topic for scientists.

[0003] In 2000, proline reported by List et al. [Journal of the American Chemical Society, 2000, 122: 2395-2396] became the first organic small molecule catalyst directly used in intermolecular asymmetric Aldol reactions, and can catalyze a variety of asymmetric reactions such as Mannich and Michael with high stereoselectivity. Many unmodified amino acids, such as alanine, valine, serine, threonine, histidine, phenylalanine and tryptophan, are used as catalysts for Aldol reactions [Angewandte Chemie, 2005, 117: 7190-7194]. New chiral proline amides containing 2-aminocyclohexanol were prepared and showed moderate catalytic activity, but their diastereomeric ratio was as high as 97:3 [Tetrahedron Letters, 2024, 140: 155042].

[0004] Therefore, researchers in this field are committed to developing chiral amino acid-supported catalysts that can be recycled and have high catalytic activity. Summary of the invention

[0005] The purpose of the present invention is to provide a chiral amino acid-supported polyisonitrile catalyst and a preparation method and application thereof.

[0006] In order to achieve the above-mentioned object of the invention, the technical solution adopted by the present invention is:

[0007] In a first aspect, a method for preparing a chiral amino acid-loaded polyisonitrile catalyst is provided, which comprises the following steps: using a chiral amino acid as a starting material to synthesize an isonitrile monomer containing a chiral amino acid in the side chain, then polymerizing it into a chiral amino acid-loaded helical polyisonitrile under the initiation of a palladium catalyst, and then deprotecting it to prepare a chiral amino acid-loaded polyisonitrile catalyst.

[0008] Furthermore, the method specifically includes the following steps:

[0009] a. Add amino acid isonitrile monomer and palladium initiator to a container, replace with nitrogen 2-5 times under anhydrous and oxygen-free conditions, add tetrahydrofuran under N2 flow, react at 50-60°C for 10-20h, add methanol to terminate the reaction, add a large amount of hexane, precipitate solid, centrifuge, and vacuum dry to constant weight to obtain an intermediate;

[0010] b. Add the intermediate and dichloromethane to a container, add trifluoroacetic acid under an ice bath, stir at room temperature for 10-20 hours, pour into water, adjust to neutrality with aqueous ammonia, extract with dichloromethane, concentrate, add a large amount of methanol to dissolve, then add ether, precipitate, centrifuge, and vacuum dry to constant weight to obtain the finished catalyst.

[0011] Furthermore, the chiral amino acids include L-leucine, valine, L-isoleucine, L-methionine, and L-phenylalanine.

[0012] Furthermore, when the chiral amino acid is valine, the preparation route of the amino acid isonitrile monomer is:

[0013]

[0014] Further, the route for preparing chiral amino acid supported polyisocyanate catalyst from amino acid isonitrile monomer is:

[0015]

[0016] Wherein, the structural formula of palladium catalyst is: Degree of polymerization m=10-250.

[0017] In a second aspect, a chiral amino acid-supported polyisonitrile catalyst prepared by the above method is provided.

[0018] In a third aspect, a chiral amino acid-supported polyisonitrile catalyst is provided for use in catalyzing an asymmetric Aldol reaction.

[0019] In a fourth aspect, a use of a chiral amino acid-supported polyisonitrile catalyst in catalyzing an asymmetric oxa-Michael-Aldol tandem reaction is provided.

[0020] The beneficial effects of the present invention are:

[0021] The chiral amino acid-supported polyisonitrile catalyst provided by the present invention has high catalytic activity and stereoselectivity, and provides ideas for subsequent exploration of other reaction types. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 Compound 1 prepared in Example 1 1 HNMR (400 MHz);

[0023] Figure 2 Compound 2 prepared in Example 1 1 HNMR (400 MHz);

[0024] Figure 3 Compound 3 prepared in Example 1 1 HNMR (400 MHz);

[0025] Figure 4 Compound 4 prepared in Example 1 1 HNMR (400 MHz);

[0026] Figure 5 Compound 5 prepared in Example 1 1 HNMR (400 MHz);

[0027] Figure 6 Compound 5 prepared in Example 1 13 CNMR (400MHz);

[0028] Figure 7 The infrared spectrum of compound 5 prepared in Example 1 (KBr pellet, 25°C);

[0029] Figure 8 The compound poly-1 in Example 2 200 Infrared spectrum (KBr pellet, 25℃);

[0030] Fig. 9 The HPLC chromatogram of racemic 2-(hydroxy(4-nitrophenyl)methyl)cyclohexane-1-one (Chiralpak AD-H; n-hexane:isopropanol=85 / 15 (v / v); flow rate 0.6 mL / min; 254 nm; 25° C.);

[0031] Fig.10HPLC chromatogram of chiral (S)-2-((R)-hydroxy(4-nitrophenyl)methyl)cyclohexane-1-one (10a) prepared in Experimental Example 2 (Chiralpak AD-H; n-hexane:isopropanol=85 / 15 (v / v); flow rate 0.6 mL / min; 254 nm; 25° C.);

[0032] Fig.11 The HPLC chromatogram of racemic 2-(hydroxy(3-nitrophenyl)methyl)cyclohexane-1-one (Chiralpak AD-H; n-hexane:isopropanol=95 / 5 (v / v); flow rate 0.45 mL / min; 210 nm; 25° C.);

[0033] Fig.12 HPLC chromatogram of chiral (S)-2-((R)-hydroxy(3-nitrophenyl)methyl)cyclohexane-1-one (10b) prepared in Experimental Example 2 (Chiralpak AD-H; n-hexane:isopropanol=95 / 5 (v / v); flow rate 0.45 mL / min; 210 nm; 25° C.);

[0034] Fig.13 The high performance liquid chromatogram of racemic 2-(hydroxy(4-(trifluoromethyl)phenyl)methyl)cyclohexan-1-one (Chiralpak AD-H; n-hexane:isopropanol=85 / 15 (v / v); flow rate 0.45 mL / min; 210 nm; 25° C.);

[0035] Fig.14 HPLC chromatogram of chiral (S)-2-((R)-hydroxy(4-(trifluoromethyl)phenyl)methyl)cyclohexan-1-one (10c) prepared in Experimental Example 2 (Chiralpak AD-H; n-hexane:isopropanol=85 / 15 (v / v); flow rate 0.45 mL / min; 210 nm; 25° C.);

[0036] Fig.15 The high performance liquid chromatogram of racemic 2-(hydroxy(2-(trifluoromethyl)phenyl)methyl)cyclohexan-1-one (Chiralpak AD-H; n-hexane:isopropanol=90 / 10 (v / v); flow rate 0.45 mL / min; 210 nm; 25° C.);

[0037] Fig.16 HPLC chromatogram of chiral (S)-2-((R)-hydroxy(2-(trifluoromethyl)phenyl)methyl)cyclohexan-1-one (10d) prepared in Experimental Example 2 (Chiralpak AD-H; n-hexane:isopropanol=90 / 10 (v / v); flow rate 0.45 mL / min; 210 nm; 25° C.);

[0038] Fig.17 The high performance liquid chromatogram of the racemic 4-(hydroxy(2-oxocyclohexyl)methyl)benzonitrile of the present invention (Chiralpak AD-H; n-hexane:isopropanol=85 / 15 (v / v); flow rate 0.45 mL / min; 230 nm; 25° C.);

[0039] Fig.18 HPLC chromatogram of chiral 4-((R)-hydroxy((S)-2-oxocyclohexyl)methyl)benzonitrile (10e) prepared in Experimental Example 2 (Chiralpak AD-H; n-hexane:isopropanol=85 / 15 (v / v); flow rate 0.45 mL / min; 230 nm; 25° C.);

[0040] Fig.19 The high performance liquid chromatogram of the racemic 2-(hydroxy(4-nitrophenyl)methyl)cyclopentan-1-one of the present invention (Chiralpak AD-H; n-hexane:isopropanol=85 / 15 (v / v); flow rate 0.60 mL / min; 254 nm; 25° C.);

[0041] Fig. 20 HPLC chromatogram of chiral (S)-2-((R)-hydroxy(4-nitrophenyl)methyl)cyclopentan-1-one (10f) prepared in Experimental Example 2 (Chiralpak AD-H; n-hexane:isopropanol=85 / 15 (v / v); flow rate 0.60 mL / min; 254 nm; 25° C.);

[0042] Fig.21 The high performance liquid chromatogram of the racemic 2-(hydroxy(2-(trifluoromethyl)phenyl)methyl)cyclopentan-1-one of the present invention (Chiralpak AD-H; n-hexane:isopropanol=85 / 15 (v / v); flow rate 0.45 mL / min; 254 nm; 25° C.);

[0043] Fig. 22 HPLC chromatogram of chiral (R)-2-((R)-hydroxy(2-(trifluoromethyl)phenyl)methyl)cyclopentan-1-one (10 l) prepared in Experimental Example 2 (Chiralpak AD-H; n-hexane:isopropanol=85 / 15 (v / v); flow rate 0.45 mL / min; 254 nm; 25° C.);

[0044] Fig.23 The high performance liquid chromatogram of the racemic 2-phenyl-2H-benzopyran-3-carboxaldehyde of the present invention (Chiralpak AD-H; n-hexane:isopropanol=96 / 4 (v / v); 0.5 mL / min; 254 nm; 25° C.);

[0045] Fig.24 HPLC chromatogram of (S)-2-phenyl-2H-benzopyran-3-carbaldehyde prepared in Experimental Example 4 (Chiralpak AD-H; n-hexane:isopropanol=96 / 4 (v / v); 0.5 mL / min; 254 nm; 25° C.). DETAILED DESCRIPTION

[0046] The specific implementation modes of the present invention are described below so that those skilled in the art can understand the present invention. However, it should be clear that the present invention is not limited to the scope of the specific implementation modes. For those of ordinary skill in the art, as long as various changes are within the spirit and scope of the present invention as defined and determined by the attached claims, these changes are obvious, and all inventions and creations utilizing the concept of the present invention are protected.

[0047] Example 1

[0048] In this example, valine was used as the starting material to synthesize a chiral amino acid isonitrile monomer (Compound 5), and its preparation route is as follows:

[0049]

[0050] Synthesis of compound 1:

[0051] Dissolve valine (10.00 g, 85.43 mmol) in 120 mL 1,4-dioxane: water (2:1) in a 500 mL two-necked bottle, add 80 mL of 1M NaOH solution at 0°C, then add NaHCO3 (7.18 g, 85.43 mmol) and Boc2O (27.97 g, 128.15 mmol) and stir at room temperature for 24 h. Concentrate the reaction solution under reduced pressure, dilute with ethyl acetate, adjust the pH to 2.5-3 with 1M KHSO4, separate the liquids, extract the aqueous phase with ethyl acetate (30 mL×4), combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate to obtain 18.50 g of crude colorless transparent oil. 1 H NMR (400MHz, CDCl3) δ9.52 (s, 1H), 5.04 (s, 1H), 4.28 (s, 1H), 2.20 (s, 1H), 1.44 (s, 9H), 0.97 (d, J = 28.5Hz, 6H).

[0052] Synthesis of compound 2:

[0053] Compound 1 (10.72 g, 49.34 mmol) was dissolved in 100 mL of pyridine and placed in a 500 mL two-necked bottle. 4-nitroaniline (5.68 g, 41.12 mmol) was added, and phosphorus oxychloride (7.5 mL, 82.24 mmol) was added dropwise at 0°C under argon atmosphere for 0.5 h. After the reaction, the reaction solution was poured into 200 mL of ice water to quench, and the pH was adjusted to neutral with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined and concentrated to obtain a yellow transparent oil. Column chromatography purification (petroleum ether: ethyl acetate = 15: 1) gave a white powder (8.76 g, yield: 60.2%). 1 H NMR (400MHz, CDCl3) δ9.45(s,1H),7.99(d,J=8.6Hz,2H),7.54(d,J=8.7Hz,2H),5.37(d,J =8.5Hz, 1H), 4.16 (d, J = 7.6Hz, 1H), 2.22-2.08 (m, 1H), 1.46 (s, 9H), 1.04 (d, J = 6.8Hz, 6H).

[0054] Synthesis of compound 3:

[0055] Compound 2 (4.13 g) was dissolved in 50 mL of tetrahydrofuran in a 500 mL two-necked bottle, and 0.42 g of Pd / C was added, and the mixture was reacted for 5 h under H2 environment. After the reaction, the mixture was filtered through a funnel covered with diatomaceous earth and concentrated to obtain a white solid (3.65 g, yield: 97.1%). 1 H NMR (400MHz, CDCl3) δ: 8.53 (s, 1H), 7.22 (d, J = 8.2Hz, 2H), 6.57 (d, J = 8.2Hz, 2H), 5.56 (s, 1H), 4.09 (s, 1H), 3.99 (s, 2H), 2.14 (d, J = 6.8Hz, 1H), 1.41 (s, 9H), 0.99 (t, J = 7.8Hz, 6H).

[0056] Synthesis of compound 4:

[0057] Stir 9 mL of formic acid and acetic anhydride (2:1) at room temperature for 2 h to prepare a mixed acid for use. Dissolve compound 3 (3.64 g, 11.84 mmol) in 60 mL of ethyl acetate and place in a 250 mL two-necked bottle. Add 9 mL of the mixed acid dropwise at 0 ° C under Ar environment. After the addition is complete, heat from 0 ° C to room temperature and react for 5 h. Remove the acid by vacuum distillation, dilute with ethyl acetate, adjust the pH to neutral with saturated sodium bicarbonate, extract the aqueous phase with ethyl acetate (50 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to obtain a white solid (3.26 g, yield 82.3%). 1H NMR(400MHz, CDCl3)δ:9.25(s,1H),8.45(s,2H),7.61-7.17(m,3H),6.92(s,1H),5.82(s,1H),4.19(s,1H),2.14(s,1H),1.40(s,9H),1.03(s,6H).

[0058] Synthesis of compound 5:

[0059] Compound 4 (2.00 g, 5.96 mmol) was dissolved in 30 mL of dichloromethane and placed in a 100 mL two-necked bottle. Triethylamine (3.22 mL, 23.84 mmol) was then added. Triphosgene (0.71 g, 2.39 mmol) was added dropwise at 0°C and Ar environment and reacted for 1 h. Dichloromethane was added to dilute, and the pH was adjusted to neutral with saturated sodium bicarbonate. The aqueous phase was extracted with dichloromethane (50 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain a brown solid. Column chromatography purification (petroleum ether: ethyl acetate = 10: 1) gave a white solid (1.61 g, yield: 85%) 1 H NMR (400MHz, CDCl3) δ: 8.93 (s, 1H), 7.45 (d, J = 8.3Hz, 2H), 7.19 (d, J = 8.4Hz, 2H), 5.27 (d, J = 8.4Hz, 1H), 4.08 (s, 1H), 1.45 (s, 9H), 1.10-0.93 (m, 6H). 13 CNMR(101MHz, CDCl3)δ:170.99,163.70,156.85,138.76,127.04,120.10,80.91,77.16,61.28,30.68,28.48,19.50,18.46.

[0060] Example 2

[0061] Chiral amino acid supported polyisocyanide catalyst poly-1 200 Synthesis of:

[0062] In a 10 mL polymerization bottle, add compound 5 (400 mg, 1.26 mmol) synthesized in Example 1 and methoxy palladium catalyst (3.21 mg, 6.30 μmol), add 4.5 mL tetrahydrofuran solvent, and react at 55°C for 18 hours. After the reaction is completed, add n-hexane, and a yellow flocculent precipitate is precipitated. After centrifugation, dissolve the precipitate in tetrahydrofuran, slowly add n-hexane, precipitate a yellow flocculent precipitate, centrifuge, separate the supernatant and the precipitate, and repeat this process at least three times. Dry in a vacuum oven for 2 hours to obtain the polymer poly-2 200 .

[0063] 0.50g poly-2 200 Dissolve in 10 mL of dichloromethane and place in a 50 mL single-mouth bottle. Add 0.9 mL of trifluoroacetic acid at 0°C and stir overnight at room temperature. Add ammonia water to adjust the pH value of the reaction solution to neutral, filter, and the filter cake is the product, which is vacuum dried. If there is residual product in the filtrate, first dry it with anhydrous sodium sulfate, concentrate it under reduced pressure, and then treat it the same as poly-2 200 The precipitation method is used, and finally the obtained products are combined to obtain poly-1 200 (0.29 g, yield: 75%).

[0064] Test Example 1

[0065] poly-1 200 Catalytic asymmetric Aldol reaction:

[0066] The catalyst poly-1 200 Add to different solvents at a specific temperature, then add cyclohexanone to the reaction solution. After stirring for a period of time, different aromatic aldehydes are also added to the above solution, and stirring is continued for a period of time. After the reaction is completed, n-hexane is added to precipitate the catalyst. The supernatant is concentrated and the product is purified by column chromatography.

[0067] This test example takes the Aldol reaction between cyclohexanone and p-nitrobenzaldehyde as an example.

[0068] The catalyst poly-1 200 (10 mg, 0.028 mmol) was added to a 10 mL reaction bottle, followed by cyclohexanone (56.18 mg, 0.57 mmol) and 1 mL of solvent. After stirring at room temperature for 1 hour, p-nitrobenzaldehyde (21.61 mg, 0.14 mmol) was added to the reaction solution, and stirring was continued at room temperature for 2 to 7 days. After the reaction was completed, n-hexane was added, centrifuged, and the supernatant was separated by column chromatography. The chiral column Chiralpak AD-H (n-hexane / i-PrOH=85 / 15 (v / v); 0.6 mL / min; 254 nm) was used for detection. The reaction process involving other Aldol reactions followed a similar procedure as above.

[0069] Solvent screening:

[0070] This experiment uses the asymmetric aldol reaction of p-nitrobenzaldehyde and cyclohexanone as a model to evaluate the performance of the catalyst poly-1 200The catalyst was reacted at room temperature, and 16 solvents including toluene, tetrahydrofuran, chloroform, water, ether, saturated sodium chloride, methanol, ethanol, dichloromethane, acetonitrile, N,N-dimethylamide, isopropanol, ethyl acetate, 1,4-dioxane, 1,2-dichloroethane, and dimethyl sulfoxide were tried. As shown in Table 1, the catalytic activity and enantioselectivity were the best when water was used as the solvent, and the ee value was as high as 63.1%.

[0071] Catalyzed Aldol reaction of p-nitrobenzaldehyde and cyclohexanone:

[0072]

[0073] Table 1 Effect of different solvents on catalytic Aldol reaction

[0074]

[0075] Further, the reaction was optimized by adding triethylamine, diethylamine, sodium bicarbonate, potassium carbonate, p-toluenesulfonic acid, benzoic acid, citric acid, and trifluoroacetic acid. As shown in Table 2, when the solvent was saturated saline, room temperature, and the reaction lasted for seven days, there was almost no ee value when a base was added, while the ee value decreased when an acid was added. When the solvent was water, the reaction time increased from five days to seven days, and the ee value increased from 74.6% to 76.5%. When the solvent was saturated saline, the reaction time increased from five days to seven days, and the ee value increased from 68.9% to 74.9%. The change in reaction time further determined that the optimal reaction solvent was water.

[0076] Table 2 Effect of co-catalyst on catalytic Aldol reaction when the solvent is water and saturated brine

[0077]

[0078] Test Example 2

[0079] Preparation of (S)-2-((R)-hydroxy(4-nitrophenyl)methyl)cyclohexane-1-one:

[0080] Add poly-1 to a 10 mL single-necked bottle. 200(10mg, 0.0286mmol), cyclohexanone (111.89mg, 1.14mmol), add 1mL of water, stir at room temperature for 1h, then add p-nitrobenzaldehyde (42.31mg, 0.28mmol), stir at 25℃ for 7 days. After the reaction is completed by thin layer chromatography tracking, n-hexane is added dropwise, the catalyst is precipitated, centrifuged, dried, and the catalyst is recovered. The supernatant is concentrated and purified by column chromatography to obtain (S)-2-((R)-hydroxy(4-nitrophenyl)methyl)cyclohexane-1-one with a yield of 83%, an ee value of 76.5%, and a dr value of 65 / 35. High performance liquid chromatography (HPLC) conditions: Chiral column is Chiralpak AD-H; n-hexane / isopropanol = 85 / 15 (v / v); flow rate is 0.6mL / min; wavelength is 254nm; 25℃; t R1 (syn.)=25.13min,t R2 (syn.)=26.99min,t R1 (anti.)=29.55min,t R2 (anti.)=37.57min.

[0081] Preparation of (S)-2-((R)-hydroxy(4-nitrophenyl)methyl)cyclopentane-1-one:

[0082] Add poly-1 to a 10 mL single-mouth bottle. 200 (10mg, 0.0286mmol), cyclopentanone (96.30mg, 1.14mmol), add 1mL of water, stir at room temperature for 1h, then add 4-nitrobenzaldehyde (43.24mg, 0.28mmol), stir at 10℃ for 7 days. Add n-hexane dropwise, the catalyst precipitates, centrifuge, dry, and recover the catalyst. Concentrate the supernatant and purify by column chromatography to obtain (S)-2-((R)-hydroxy(4-nitrophenyl)methyl)cyclopentane-1-one with a yield of 76%, ee value of 97%, and dr value of 42 / 58. High performance liquid chromatography (HPLC) conditions: Chiral column is Chiralpak AD-H; n-hexane / isopropanol = 85 / 15 (v / v); flow rate is 0.6mL / min; wavelength is 254nm; 25℃; t R1 (syn.)=16.85min,t R2 (syn.)=20.43min,t R1 (anti.)=25.86min,t R2 (anti.)=28.38min.

[0083] Expansion of catalytic substrates:

[0084] The Aldol reaction route of cyclic ketones and aromatic aldehydes catalyzed by the catalyst is:

[0085]

[0086] The reaction solvent was water, the reaction temperature was 10 °C, and the reaction time was 7 days. 200 The scope of substrate applicability of catalytic asymmetric Aldol reactions was investigated, and the asymmetric Aldol reactions of cyclic ketones and aromatic aldehydes were investigated.

[0087] When cyclohexanone reacts with p-nitrobenzaldehyde (9a), m-nitrobenzaldehyde (9b), 4-trifluoromethylbenzaldehyde (9c), 2-trifluoromethylbenzaldehyde (9d) and 4-methylbenzonitrile (9e), the ee values ​​of the corresponding aldol condensation products 10a, 10b, 10c, 10d and 10e are 80%, 60.3%, 62.4%, 92.5% and 64.4%, respectively. When cyclopentanone reacts with p-nitrobenzaldehyde (9a), 4-trifluoromethylbenzaldehyde (9c), 2-trifluoromethylbenzaldehyde (9d) and 4-methylbenzonitrile (9e), the ee values ​​of the corresponding aldol condensation products 10f, 10k, 101 and 10m are 97%, 33.6%, 96.8% and 24.5%, respectively.

[0088] Table 3 Catalysts for Aldol reactions of cyclic ketones and aromatic aldehydes

[0089]

[0090]

[0091] Test Example 3

[0092] Catalyst recovery and recycling performance test:

[0093] With catalyst poly-1 200 Take the Aldol reaction of cyclopentanone and p-nitrobenzaldehyde as an example. Weigh the catalyst poly-1 200 (30mg, 0.084mmol), add 1mL water, stir, cyclopentanone (288.9mg, 3.42mmol), p-nitrobenzaldehyde (129.7mg, 0.84mmol). After the reaction is completed, a large amount of n-hexane is added, the polymer catalyst is precipitated, centrifuged, and vacuum dried. The asymmetric Aldol reaction of the reaction of cyclopentanone and p-nitrobenzaldehyde in water is continued to be circulated, and the results are shown in Table 4. After the supported catalyst is recycled and reused 3 times, the activity of the catalytic reaction and the stereoselectivity of the product are not significantly reduced.

[0094] Table 4 Catalyst poly-2 200 Cycle of the Catalyzed Aldol Reaction of 4-Nitrobenzaldehyde and Cyclopentanone

[0095]

[0096]

[0097] Test Example 4

[0098] poly-1 m Catalyzes asymmetric oxa-Michael-Aldol tandem reactions

[0099] Poly-1 200 (8 mg, 0.022 mmol) cinnamaldehyde (15.12 mg, 0.11 mmol) and 1 mL of solvent were added to a 10 mL reaction bottle and stirred at room temperature for 1 hour, followed by the addition of salicylaldehyde (20.97 mg, 0.17 mmol) and 4A MS molecular sieves, and finally the solution was stirred at room temperature for 2 days. The reaction solution was filtered, concentrated under reduced pressure, and the product was separated by thin layer chromatography.

[0100] poly-1 200 Route to catalyze asymmetric oxa-Michael-Aldol tandem reactions:

[0101]

[0102] Table 5 Effect of different solvents on catalyst poly-1 200 Effect of Catalysis on the Reaction of Salicylaldehyde and Cinnamaldehyde

[0103]

[0104] From the results in Table 5, we can see that poly-1 200 In the process of catalyzing the reaction of cinnamaldehyde and salicylaldehyde, when the solvent is acetonitrile, isopropanol or ethyl acetate, the ee value is greater than 15%.

[0105] Table 6 Effect of cocatalyst on poly-1 200 Effect of Catalysis on the Reaction of Salicylaldehyde and Cinnamaldehyde

[0106]

[0107] From the results in Table 5, it can be seen that when isopropanol is used as solvent and different co-catalysts are added, the catalytic performance is significantly improved, especially when the co-catalyst is p-formylbenzoic acid, the ee value is as high as 87.2%. When the co-catalysts are diethylamine, benzoic acid, trifluoroacetic acid, p-aminobenzoic acid, 4-chlorobenzoic acid, and p-trifluoromethylbenzoic acid, the ee values ​​are 30% to 60%, which are also higher than the ee values ​​when no co-catalyst is added.

[0108] In summary, the present invention takes valine as an example, and the prepared valine-supported catalyst poly-1 200Catalyzes the aldol reaction of cyclopentanone and p-nitrobenzaldehyde in water, with an enantiomeric excess (ee) value of up to 97% and a diastereoisomer selectivity (dr) value of 42 / 58. Catalyst poly-1 200 It can also be used in oxa-Michael-Aldol reactions, catalyzing the asymmetric oxa-Michael-Aldol reaction between cinnamaldehyde and salicylaldehyde with an ee value of 87.2%. It shows high catalytic activity and stereoselectivity, providing ideas for the subsequent exploration of other reaction types.

[0109] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the present invention can be implemented in other specific forms without departing from the spirit or essential features of the present invention. Therefore, the embodiments should be considered exemplary and non-restrictive in all respects, and the scope of the present invention is defined by the appended claims rather than the above description, and it is intended that all changes falling within the meaning and scope of the equivalent elements of the claims be included in the present invention.

[0110] In addition, it should be understood that although the present specification is described according to implementation modes, not every implementation mode contains only one independent technical solution. This description of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment may also be appropriately combined to form other implementation modes that can be understood by those skilled in the art.

Claims

1. A method for preparing a chiral amino acid-supported polyisocyanide catalyst, characterized in that: The method comprises the following steps: using chiral amino acids as starting materials to synthesize isonitrile monomers containing chiral amino acids on the side chains, then polymerizing into chiral amino acid-loaded spiral polyisocyanides under the initiation of palladium catalysts, and then deprotecting to prepare chiral amino acid-loaded polyisocyanides catalysts.

2. The method for preparing a chiral amino acid-supported polyisocyanide catalyst according to claim 1, characterized in that: The specific steps include: a. Add amino acid isonitrile monomer and palladium initiator to a container, replace with nitrogen 2-5 times under anhydrous and oxygen-free conditions, add tetrahydrofuran under N2 flow, react at 50-60°C for 10-20h, add methanol to terminate the reaction, add a large amount of hexane, precipitate solid, centrifuge, and vacuum dry to constant weight to obtain an intermediate; b. Add the intermediate and dichloromethane to a container, add trifluoroacetic acid under an ice bath, stir at room temperature for 10-20 hours, pour into water, adjust to neutrality with aqueous ammonia, extract with dichloromethane, concentrate, add a large amount of methanol to dissolve, then add ether, precipitate, centrifuge, and vacuum dry to constant weight to obtain the finished catalyst.

3. The method for preparing a chiral amino acid-supported polyisocyanide catalyst according to claim 1, characterized in that: Chiral amino acids include L-leucine, valine, L-isoleucine, L-methionine, and L-phenylalanine.

4. The method for preparing a chiral amino acid-supported polyisonitrile catalyst according to claim 3, characterized in that: When the chiral amino acid is valine, the preparation route of the amino acid isonitrile monomer is:

5. The method for preparing a chiral amino acid-supported polyisonitrile catalyst according to claim 4, characterized in that: The route for preparing chiral amino acid supported polyisocyanate catalyst from amino acid isonitrile monomer is as follows: Wherein, the structural formula of palladium catalyst is: Degree of polymerization m=10-250.

6. A chiral amino acid-supported polyisonitrile catalyst prepared by the method according to any one of claims 1 to 5.

7. Use of the chiral amino acid supported polyisonitrile catalyst according to claim 6 in catalyzing asymmetric Aldol reactions.

8. Use of the chiral amino acid-supported polyisonitrile catalyst according to claim 6 in catalyzing an asymmetric oxa-Michael-Aldol tandem reaction.

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