Chiral pyrylium compounds, methods for their synthesis and use

Abstract

This invention discloses a chiral pyran ring compound, its synthesis method, and its application. Using thioyl ylide (I) and vinyl-containing carbonate compounds (II) as reactants, molecular sieves are added under the action of a catalyst and chiral phosphoric acid, and the reaction is carried out in an organic solvent. Post-reaction processing yields a chiral pyran ring compound as shown in formula (III). The reaction formula is as follows: Wherein, when substituted, R is selected from a benzene ring, a substituted phenyl group, furan, thiophene, or a naphthalene ring; the substituent for the substituted phenyl group is tert-butyl, halogen, or trifluoromethyl; when substituted, R... 1 The reactants are selected from benzene rings, substituted phenyl groups, or thiophene, where the substituents of the substituted phenyl groups are methyl, methoxy, halogen, or trifluoromethyl. This invention features high yield and high selectivity; mild reaction conditions; readily available and stable reactants with no irritating odor, making it environmentally friendly.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a chiral pyran ring compound, its synthesis method, and its application. Background Technology

[0002] Dihydropyrans are widely found in many biologically significant natural products and drug molecules. Their olefinic functional groups facilitate structural changes, and they can also serve as common starting materials for many other important six-membered oxygen-containing heterocyclic compounds (such as tetrahydropyrans and pyranones). Due to their synthetic and pharmaceutical value, their preparation methods have been actively sought after. Drugs with chiral pyran rings are as follows:

[0003]

[0004] Currently, methods for asymmetric construction of chiral pyran rings can be mainly divided into two categories. The first is the [4+2] heterodiels-Alder reaction of carbonyl compounds with 1,3-dienes, and the second is the [5+1] Prince-type cyclization reaction of carbonyl compounds with 4-hydroxyvinylsilanes. However, both of these methods usually require the use of active aldehydes, glyoxylates, or ketoates as substrates, which substantially limits the scope of the reaction. Therefore, it is necessary to develop a more general cyclization strategy to facilitate the synthesis of such oxygen-containing heterocyclic compounds. Summary of the Invention

[0005] To address the above problems, the present invention aims to provide a chiral pyran ring compound, its synthesis method, and its applications.

[0006] To achieve the above objectives, the following technical solution is proposed:

[0007] A chiral pyran ring compound, the structure of which is shown in formula (Ⅲ),

[0008]

[0009] In the formula, when substituted, R is selected from a benzene ring, a substituted phenyl group, a furan, a thiophene, or a naphthalene ring, and the substituent of the substituted phenyl group is tert-butyl, halogen, or trifluoromethyl; when substituted, R 1 It is selected from benzene rings, substituted phenyl groups or thiophene, wherein the substituents of substituted phenyl groups are methyl, methoxy, halogen or trifluoromethyl.

[0010] A method for synthesizing a chiral pyran ring compound, using a thioyl ylide as shown in formula (I) and a vinyl-containing carbonate compound as shown in formula (II) as reactants, adding a molecular sieve, and reacting in an organic solvent at room temperature for 18-36 h in the presence of a catalyst and chiral phosphoric acid. After the reaction is completed, the chiral pyran ring compound as shown in formula (III) is obtained by silica gel column chromatography. The reaction formula is shown below:

[0011]

[0012] In the formula, when substituted, R is selected from a benzene ring, a substituted phenyl group, a furan, a thiophene, or a naphthalene ring, and the substituent of the substituted phenyl group is tert-butyl, halogen, or trifluoromethyl; when substituted, R 1 It is selected from benzene rings, substituted phenyl groups or thiophene, wherein the substituents of substituted phenyl groups are methyl, methoxy, halogen or trifluoromethyl.

[0013] Furthermore, the catalyst used is Pd(PPh3)4, and the amount used is 1-5 mol% of the amount of the compound shown in formula (I).

[0014] Furthermore, the chiral phosphoric acid is (S)-(+)-binaphthol phosphate, (R)-3,3'-bis(2,4,6-trimethylphenyl)-1,1'-binaphthol phosphate, (R)-3,3'-bis(1-naphthyl)-5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthol phosphate, and (R)-3,3'-bis(3,5-diphenylphenyl)-5,5',6,6' ,7,7',8,8'-octahydro-1,1'-binaphthol phosphate, (11bS)-2,6-di-9-anthrayl-8,9,10,11,12,13,14,15-octahydro-4-hydroxy-4-oxo-binaphthol[2,1-d:1',2'-f][1,3,2]dioxane, (R)-spirocyclic diphenol phosphonate or (R)-6,6'-di(9-anthrayl)spirocyclic diphenol phosphate.

[0015] Furthermore, molecular sieves are Molecular sieves Molecular sieve or Molecular sieve.

[0016] Furthermore, the organic solvent is dichloromethane, 1,2-dichloroethane, isopropanol, ethanol, carbon tetrachloride, chloroform, chlorobenzene, toluene, dimethylacetamide, or tetrahydrofuran.

[0017] Furthermore, the molar ratio of the compound shown in formula (I) to the compound shown in formula (II) is 1.0:1.0-1.0:2.0.

[0018] Furthermore, after the reaction is completed, the specific operation process of separation and purification by silica gel column chromatography is as follows: after the reaction is completed, the reaction solution is concentrated and column chromatography is performed. A mixture of petroleum ether and ethyl acetate is used as the eluent. The eluent containing the target compound is collected, concentrated, distilled and dried to obtain the compound shown in formula (Ⅲ). The volume ratio of the petroleum ether to ethyl acetate mixture is 10:1-20:1.

[0019] Preferably, the catalyst is Pd(PPh3)4, used in an amount of 3 mol% of the compound shown in formula (I), the chiral phosphoric acid is (R)-6,6'-bis(9-anthrayl)spirocyclic diphenol phosphate, and the molecular sieve is... Molecular sieve, organic solvent is 1,2-dichloroethane, and the molar ratio of the compound shown in formula (I) to the compound shown in formula (II) is 1.0:1.5.

[0020] Application of a chiral pyran ring compound in the preparation of anti-inflammatory drugs.

[0021] The beneficial effects of this invention are as follows:

[0022] This invention offers high yield and selectivity; the reaction conditions are mild; the reaction raw materials are simple, readily available, stable, odorless, and environmentally friendly. Furthermore, the chiral pyran ring compounds prepared have potential applications in organic synthesis, pharmaceuticals, and materials science. Bio-anti-inflammatory activity experiments were conducted on some of the obtained compounds, all of which exhibited good anti-inflammatory activity. Therefore, this invention has great potential in the preparation of anti-inflammatory drugs. Attached Figure Description

[0023] Figure 1 The effects of different concentrations of compounds on nitric oxide (NO) in lipopolysaccharide (LPS)-induced RAW264.7 macrophages;

[0024] Figure 2 The effects of different concentrations of compounds on reactive oxygen species (ROS) in lipopolysaccharide (LPS)-induced RAW264.7 macrophages were investigated. Detailed Implementation

[0025] The present invention will be further described in detail below with reference to specific embodiments. However, the scope of protection of the present invention is not limited to these embodiments. All variations and advantages that can be conceived by those skilled in the art without departing from the spirit and scope of the inventive concept are included in the present invention and are protected by the appended claims. The processes, conditions, reagents, experimental methods, etc., for implementing the present invention, except as specifically mentioned below, are all common knowledge and general knowledge in the art, and the present invention does not have any particular limitations. The data given in the following embodiments include specific operations and reaction conditions and products; the purity of the products was determined by NMR.

[0026] Example 1

[0027] Synthesis of compound 3aa:

[0028]

[0029] Under a nitrogen atmosphere, 1a (0.1 mmol, 30.4 mg, 1.0 equiv.), 2a (0.15 mmol, 28.8 mg, 1.5 equiv.), Pd(PPh3)4 (0.003 mmol, 3.5 mg, 3 mol%), and (R)-6,6'-bis(9-anthrayl)spirocyclodiphenol phosphate (0.01 mmol, 6.6 mg, 10 mol%) were added to the reaction tube. Molecular sieve (100 mg) and 1,2-dichloroethane (1.0 mL). The reaction system was reacted at room temperature for 18 h, and the reaction was monitored by TLC. After the reaction was completed, the product 3aa was directly purified by column chromatography (yield 80%, enantioselectivity 92%). (Eluent polarity: petroleum ether / ethyl acetate 10:1). 1 H NMR (400MHz, CDCl3) δ8.08-8.01(m,2H),7.60(t,J=7.4Hz,1H),7.50(t,J=7.6Hz,2H),7.39-7.27(m,5H),6.29-

[0030] 6.21(m,1H),5.01(dd,J=9.9,4.0Hz,1H),4.83-4.65(m,2H),2.75-2.61(m,1H),2.56-2.46(m,1H). 13 C NMR (101MHz, CDCl3) δ197.8,137.8,135.9,135.1,133.6,129.1,128.8,128.7,127.9,125.0,120.3,75.5,67.4,28.0.

[0031] Example 2

[0032] Synthesis of compound 3ab:

[0033]

[0034] Under a nitrogen atmosphere, 1a (0.1 mmol, 30.4 mg, 1.0 equiv.), 2b (0.15 mmol, 30.6 mg, 1.5 equiv.), Pd(PPh3)4 (0.003 mmol, 3.5 mg, 3 mol%), and (R)-6,6'-bis(9-anthrayl)spirocyclodiol phosphate (0.01 mmol, 6.6 mg, 10 mol%) were added to the reaction tube. Molecular sieve (100 mg) and 1,2-dichloroethane (1.0 mL). The reaction system was reacted at room temperature for 18 h, and the reaction was monitored by TLC. After the reaction was completed, the product 3ab was directly purified by column chromatography (yield 50%, enantioselectivity 90%). (Eluent polarity: petroleum ether / ethyl acetate 10:1). 1 H NMR (400MHz, CDCl3) δ8.04(d,J=7.2Hz,2H),7.59(t,J=7.4Hz,1H),7.49(t,J=7.6Hz,2H),7.22(d,J=8.2Hz,2H),7.15(d,J=8.1 Hz,2H),6.27-6.14(m,1H),4.98(dd,J=9.9,4.0Hz,1H),4.83-4.56(m,2H),2.79-2.59(m,1H),2.57-2.42(m,1H),2.35(s,3H). 13 C NMR (101MHz, CDCl3) δ197.9,137.7,135.7,135.2,134.9,133.6,129.4,129.1,128.8,124.9,119.4,75.6,67.4,27.9,21.3.

[0035] Example 3

[0036] Synthesis of compound 3ac:

[0037]

[0038] Under a nitrogen atmosphere, 1a (0.1 mmol, 30.4 mg, 1.0 equiv.), 2c (0.15 mmol, 33.0 mg, 1.5 equiv.), Pd(PPh3)4 (0.003 mmol, 3.5 mg, 3 mol%), and (R)-6,6'-bis(9-anthrayl)spirocyclodiol phosphate (0.01 mmol, 6.6 mg, 10 mol%) were added to the reaction tube. Molecular sieve (100 mg) and 1,2-dichloroethane (1.0 mL). The reaction system was reacted at room temperature for 18 h, and the reaction was monitored by TLC. After the reaction was completed, the product 3ac was directly purified by column chromatography (yield 43%, enantioselectivity 89%). (Eluent polarity: petroleum ether / ethyl acetate 10:1). 1H NMR (400MHz, CDCl3) δ8.04(d,J=7.4Hz,2H),7.59(t,J=7.4Hz,1H),7.48(t,J=7.7Hz,2H),7.33-7.20(m,2H),6.88(d,J=8.8H z,2H),6.22-6.07(m,1H),4.97(dd,J=9.9,4.0Hz,1H),4.79-4.58(m,2H),3.81(s,3H),2.74-2.59(m,1H),2.53-2.42(m,1H). 13 C NMR (101MHz, CDCl3) δ197.9,159.4,135.3,135.2,133.6,130.4,129.1,128.8,126.1,118.6,114.1,75.7,67.4,55.4,27.9.

[0039] Example 4

[0040] Synthesis of compound 3ad:

[0041]

[0042] Under a nitrogen atmosphere, 1a (0.1 mmol, 30.4 mg, 1.0 equiv.), 2d (0.15 mmol, 31.2 mg, 1.5 equiv.), Pd(PPh3)4 (0.003 mmol, 3.5 mg, 3 mol%), and (R)-6,6'-bis(9-anthrayl)spirocyclodiphenol phosphate (0.01 mmol, 6.6 mg, 10 mol%) were added to the reaction tube. Molecular sieve (100 mg) and 1,2-dichloroethane (1.0 mL). The reaction system was reacted at room temperature for 18 h, and the reaction was monitored by TLC. After the reaction was completed, the product 3ad was directly purified by column chromatography (60% yield, 92% enantioselectivity). (Eluent polarity: petroleum ether / ethyl acetate 10:1). 1 H NMR (400MHz, CDCl3) δ8.01(d,J=7.4Hz,2H),7.57(t,J=7.4Hz,1H),7.47(t,J=7.7Hz,2H),7.26(dd,J=8.5,5.4Hz,2H),7.01 (t,J=8.7Hz,2H),6.21-6.11(m,1H),4.96(dd,J=9.7,4.0Hz,1H),4.75-4.57(m,2H),2.71-2.60(m,1H),2.53-2.43(m,1H). 13C NMR (101MHz, CDCl3) δ197.5,162.2(d,J=263.3Hz),135.0,134.9,133.8(d,J=3.2Hz),1 33.5, 129.0, 128.7, 126.6 (d, J = 7.9Hz), 120.2, 115.5 (d, J = 21.5Hz), 75.3, 67.1, 27.7. 19 F NMR (376MHz, CDCl3) δ-114.44.

[0043] Example 5

[0044] Synthesis of compound 3ae:

[0045]

[0046] Under a nitrogen atmosphere, 1a (0.1 mmol, 30.4 mg, 1.0 equiv.), 2e (0.15 mmol, 33.6 mg, 1.5 equiv.), Pd(PPh3)4 (0.003 mmol, 3.5 mg, 3 mol%), and (R)-6,6'-bis(9-anthrayl)spirocyclodiol phosphate (0.01 mmol, 6.6 mg, 10 mol%) were added to the reaction tube. Molecular sieve (100 mg) and 1,2-dichloroethane (1.0 mL). The reaction system was reacted at room temperature for 18 h, and the reaction was monitored by TLC. After the reaction was completed, the product 3ae was directly purified by column chromatography (yield 76%, enantioselectivity 89%). (Eluent polarity: petroleum ether / ethyl acetate 10:1). 1 H NMR (400MHz, CDCl3) δ8.10-8.04(m,2H),7.66-7.60(m,1H),7.52(t,J=7.6Hz,2H),7.37-7.32(m, 2H),7.31-7.25(m,2H),6.34-6.20(m,1H),5.01(dd,J=9.7,4.1Hz,1H),4.80-4.60(m,2H),2.79-

[0047] 2.65 (m, 1H), 2.60-2.43 (m, 1H). 13 C NMR (101MHz, CDCl3) δ197.6,136.2,135.1,134.9,133.6,129.1,129.1,128.9,128.8,126.3,120.9,75.4,67.1,27.8.

[0048] Example 6

[0049] Synthesis of compound 3af:

[0050]

[0051] Under a nitrogen atmosphere, 1a (0.1 mmol, 30.4 mg, 1.0 equiv.), 2f (0.15 mmol, 40.2 mg, 1.5 equiv.), Pd(PPh3)4 (0.003 mmol, 3.5 mg, 3 mol%), and (R)-6,6'-bis(9-anthrayl)spirocyclodiol phosphate (0.01 mmol, 6.6 mg, 10 mol%) were added to the reaction tube. Molecular sieve (100 mg) and 1,2-dichloroethane (1.0 mL). The reaction system was reacted at room temperature for 18 h, and the reaction was monitored by TLC. After the reaction was completed, the product 3af was directly purified by column chromatography (62% yield, 90% enantioselectivity). (Eluent polarity: petroleum ether / ethyl acetate 10:1). 1 H NMR (400MHz, CDCl3) δ8.04(d,J=7.6Hz,2H),7.60(t,J=7.4Hz,1H),7.55-7.42(m,4H),7.18(d,J=8.5Hz,2H ),6.30-6.20(m,1H),4.98(dd,J=9.6,4.1Hz,1H),4.77-4.60(m,2H),2.76-2.59(m,1H),2.59-2.40(m,1H). 13 C NMR (101MHz, CDCl3) δ197.6,136.7,135.2,134.9,133.7,131.9,129.1,128.8,126.6,121.8,121.0,75.4,67.0,27.8.

[0052] Example 7

[0053] Synthesis of compound 3ag

[0054]

[0055] Under a nitrogen atmosphere, 1a (0.1 mmol, 30.4 mg, 1.0 equiv.), 2 g (0.15 mmol, 38.7 mg, 1.5 equiv.), Pd(PPh3)4 (0.003 mmol, 3.5 mg, 3 mol%), and (R)-6,6'-bis(9-anthrayl)spirocyclodiphenol phosphate (0.01 mmol, 6.6 mg, 10 mol%) were added to the reaction tube. Molecular sieve (100 mg) and 1,2-dichloroethane (1.0 mL). The reaction system was reacted at room temperature for 18 h, and the reaction was monitored by TLC. After the reaction was completed, the product was directly purified by column chromatography to obtain 3 ag of product (yield 74%, enantioselectivity 86%). (Eluent polarity: petroleum ether / ethyl acetate 10:1). 1 H NMR (400MHz, CDCl3) δ8.09-8.01(m,2H),7.61(dd,J=10.3,4.4Hz,3H),7.49(t,J=7.6Hz,2H),7.41(d,J=8.2Hz ,2H),6.39-6.32(m,1H),5.00(dd,J=9.5,4.1Hz,1H),4.79-4.64(m,2H),2.78-2.67(m,1H),2.60-2.50(m,1H). 13 C NMR (101MHz, CDCl3) δ197.5,141.3,135.1,134.9,133.7,129.8(q,J=32.6H z),129.1,128.8,125.9-125.4(m),125.2,122.9,122.6,75.3,67.0,27.7. 19 F NMR (376MHz, CDCl3) δ -62.6.

[0056] Example 8

[0057] Synthesis of compound 3ah:

[0058]

[0059] Under a nitrogen atmosphere, 1a (0.1 mmol, 30.4 mg, 1.0 equiv.), 2h (0.15 mmol, 29.4 mg, 1.5 equiv.), Pd(PPh3)4 (0.003 mmol, 3.5 mg, 3 mol%), and (R)-6,6'-bis(9-anthrayl)spirocyclic diphenol phosphate (0.01 mmol, 6.6 mg, 10 mol%) were added to the reaction tube. Molecular sieve (100 mg) and 1,2-dichloroethane (1.0 mL). The reaction system was reacted at room temperature for 18 h, and the reaction was monitored by TLC. After the reaction was completed, the product 3ah was directly purified by column chromatography (yield 80%, enantioselectivity 90%). (Eluent polarity: petroleum ether / ethyl acetate 10:1). 1H NMR (400MHz, CDCl3) δ8.15-7.94(m,2H),7.59(t,J=7.4Hz,1H),7.49(t,J=7.7Hz,2H),7.31(dd,J=5.1,2.9Hz,1H),7.21(dd,J=5.1,1.1 Hz,1H),7.06(d,J=1.7Hz,1H),6.33-6.17(m,1H),4.97(dd,J=9.7,4.0Hz,1H),4.81-4.55(m,2H),2.76-2.61(m,1H),2.56-2.41(m,1H). 13 C NMR (101MHz, CDCl3) δ197.7,138.8,135.2,133.6,131.4,129.1,128.8,126.1,124.6,119.3,118.7,75.7,67.0,27.6.

[0060] Example 9

[0061] Synthesis of compound 3ba:

[0062]

[0063] Under a nitrogen atmosphere, 1b (0.1 mmol, 36.0 mg, 1.0 equiv.), 2a (0.15 mmol, 28.8 mg, 1.5 equiv.), Pd(PPh3)4 (0.003 mmol, 3.5 mg, 3 mol%), and (R)-6,6'-bis(9-anthrayl)spirocyclodiphenol phosphate (0.01 mmol, 6.6 mg, 10 mol%) were added to the reaction tube. Molecular sieve (100 mg) and 1,2-dichloroethane (1.0 mL). The reaction system was reacted at room temperature for 18 h, and the reaction was monitored by TLC. After the reaction was complete, the product 3ba was directly purified by column chromatography (yield 80%, enantioselectivity 97%). (Eluent polarity: petroleum ether / ethyl acetate 10:1) 1 H NMR (400MHz, CDCl3) δ7.99(d,J=8.5Hz,2H),7.50(d,J=8.5Hz,2H),7.38-7.26(m,5H),6.30-6.19(m,1 H), 4.98 (dd, J = 9.9, 4.0Hz, 1H), 4.84-4.64 (m, 2H), 2.74-2.62 (m, 1H), 2.56-2.46 (m, 1H), 1.36 (s, 9H). 13C NMR (101MHz, CDCl3) δ196.3,156.4,136.9,134.9,131.5,128.0,127.7,126.8,124.7,124.0,119.4,74.5,66.4,34.3,30.2,27.0.

[0064] Example 10

[0065] Synthesis of compound 3ca:

[0066]

[0067] Under a nitrogen atmosphere, 1c (0.1 mmol, 32.2 mg, 1.0 equiv.), 2a (0.12 mmol, 23.0 mg, 1.2 equiv.), Pd(PPh3)4 (0.005 mmol, 5.8 mg, 5 mol%), and (R)-6,6'-bis(9-anthrayl)spirocyclodiphenol phosphate (0.01 mmol, 6.6 mg, 10 mol%) were added to the reaction tube. Molecular sieve (100 mg) and 1,2-dichloroethane (1.0 mL). The reaction system was reacted at room temperature for 36 h, and the reaction was monitored by TLC. After the reaction was complete, the product 3ca was directly purified by column chromatography (67% yield, 89% enantioselectivity). (Eluent polarity: petroleum ether / ethyl acetate 10:1) 1 H NMR (400MHz, CDCl3) δ8.10 (dd, J=8.4, 5.6Hz, 2H), 7.40-7.23 (m, 5H), 7.16 (t, J=8.5Hz, 2H), 6.29- 6.22(m,1H),4.92(dd,J=9.8,3.9Hz,1H),4.80-4.64(m,2H),2.76-2.64(m,1H),2.55-2.43(m,1H). 13 CNMR(101MHz, CDCl3)δ196.3,166.0(d,J=255.4Hz),137.7,135.8,131.9(d,J=9.3Hz), 131.5d, J=3.0Hz), 128.8, 127.9, 125.0, 120.2, 115.9 (d, J=21.9Hz), 75.7, 67.3, 27.7. 19 FNMR (376MHz, CDCl3) δ -104.29.

[0068] Example 11

[0069] Synthesis of compound 3da:

[0070]

[0071] Under a nitrogen atmosphere, 1d (0.1 mmol, 33.8 mg, 1.0 equiv.), 2a (0.12 mmol, 23.0 mg, 1.2 equiv.), Pd(PPh3)4 (0.005 mmol, 5.8 mg, 5 mol%), and (R)-6,6'-bis(9-anthrayl)spirocyclodiol phosphate (0.01 mmol, 6.6 mg, 10 mol%) were added to the reaction tube. Molecular sieve (100 mg) and 1,2-dichloroethane (1.0 mL). The reaction system was reacted at room temperature for 36 h, and the reaction was monitored by TLC. After the reaction was complete, the product 3da was directly purified by column chromatography (yield 40%, enantioselectivity 96%). (Eluent polarity: petroleum ether / ethyl acetate 10:1) 1 H NMR(400MHz, CDCl3)δ8.01(d,J=8.5Hz,2H),7.46(d,J=8.5Hz,2H),7.39-7.28(m,5H),6.35-6.1 6(m,1H),4.90(dd,J=9.7,4.0Hz,1H),4.79-4.62(m,2H),2.83-2.60(m,1H),2.57-2.42(m,1H). 13 C NMR (101MHz, CDCl3) δ196.7,140.0,137.7,135.8,133.5,130.7,129.08,128.8,127.9,125.0,120.2,75.8,67.3,27.6.

[0072] Example 12

[0073] Synthesis of compound 3ea:

[0074]

[0075] Under a nitrogen atmosphere, 1e (0.1 mmol, 38.4 mg, 1.0 equiv.), 2a (0.15 mmol, 28.8 mg, 1.5 equiv.), Pd(PPh3)4 (0.003 mmol, 3.5 mg, 3 mol%), and (R)-6,6'-bis(9-anthrayl)spirocyclodiol phosphate (0.01 mmol, 6.6 mg, 10 mol%) were added to the reaction tube. Molecular sieve (100 mg) and 1,2-dichloroethane (1.0 mL). The reaction system was reacted at room temperature for 18 h, and the reaction was monitored by TLC. After the reaction was complete, the product 3ea was directly purified by column chromatography (yield 36%, enantioselectivity 96%). (Eluent polarity: petroleum ether / ethyl acetate 10:1)1 H NMR (400MHz, CDCl3) δ7.93(d,J=8.4Hz,2H),7.63(d,J=8.4Hz,2H),7.43-7.28(m,5H),6.33-6.1 4(m,1H),4.90(dd,J=9.6,4.0Hz,1H),4.79-4.61(m,2H),2.80-2.62(m,1H),2.55-2.33(m,1H). 13 C NMR (101MHz, CDCl3) δ196.9,137.7,135.8,133.9,132.1,130.7,128.8,128.8,127.9,125.0,120.1,75.8,67.3,27.6.

[0076] Example 13

[0077] Synthesis of compound 3fa:

[0078]

[0079] Under a nitrogen atmosphere, 1f (0.1 mmol, 43.0 mg, 1.0 equiv.), 2a (0.15 mmol, 28.8 mg, 1.5 equiv.), Pd(PPh3)4 (0.003 mmol, 3.5 mg, 3 mol%), and (R)-6,6'-bis(9-anthrayl)spirocyclodiol phosphate (0.01 mmol, 6.6 mg, 10 mol%) were added to the reaction tube. Molecular sieve (100 mg) and 1,2-dichloroethane (1.0 mL). The reaction system was reacted at room temperature for 18 h, and the reaction was monitored by TLC. After the reaction was complete, the product 3fa was directly purified by column chromatography (yield 24%, enantioselectivity 92%). (Eluent polarity: petroleum ether / ethyl acetate 10:1) 1 H NMR(400MHz, CDCl3)δ7.86(d,J=8.2Hz,2H),7.76(d,J=8.2Hz,2H),7.39-7.27(m,5H),6.27-6.2 1(m,1H),4.89(dd,J=9.6,3.9Hz,1H),4.79-4.62(m,2H),2.75-2.63(m,1H),2.55-2.43(m,1H). 13 C NMR (101MHz, CDCl3) δ197.1,137.9,137.6,135.7,134.3,130.4,128.61,127.8,124.9,120.0,101.5,75.6,67.2,27.5.

[0080] Example 14

[0081] Synthesis of compound 3ga:

[0082]

[0083] Under a nitrogen atmosphere, 1 g (0.1 mmol, 37.2 mg, 1.0 equiv.), 2a (0.15 mmol, 28.8 mg, 1.5 equiv.), Pd(PPh3)4 (0.003 mmol, 3.5 mg, 3 mol%), and (R)-6,6'-bis(9-anthrayl)spirocyclodiphenol phosphate (0.01 mmol, 6.6 mg, 10 mol%) were added to the reaction tube. Molecular sieve (100 mg) and 1,2-dichloroethane (1.0 mL). The reaction system was reacted at room temperature for 18 h, and the reaction was monitored by TLC. After the reaction was complete, the product 3ga was directly purified by column chromatography (yield 36%, enantioselectivity 96%). (Eluent polarity: petroleum ether / ethyl acetate 10:1) 1 H NMR (400MHz, CDCl3) δ8.16(d,J=8.3Hz,2H),7.75(d,J=8.3Hz,2H),7.38-7.29(m,5H),6.35-6.1 6(m,1H),4.94(dd,J=9.6,4.1Hz,1H),4.79-4.60(m,2H),2.81-2.61(m,1H),2.60-2.38(m,1H). 13 C NMR(101MHz,CDCl3)δ197.0,137.8,137.5,135.7,134.4(dd,J=50.4,17.6Hz ),129.4,128.6,127.8,125.6(q,J=3.7Hz),124.9,119.9,75.83,67.2,27.2. 19 F NMR(376MHz, CDCl3)δ-63.20(s).

[0084] Example 15

[0085] Synthesis of compound 3ha:

[0086]

[0087] Under a nitrogen atmosphere, 1h (0.1 mmol, 35.4 mg, 1.0 equiv.), 2a (0.12 mmol, 23.0 mg, 1.2 equiv.), Pd(PPh3)4 (0.005 mmol, 5.8 mg, 5 mol%), and (R)-6,6'-bis(9-anthrayl)spirocyclodiphenol phosphate (0.01 mmol, 6.6 mg, 10 mol%) were added to the reaction tube. Molecular sieve (100 mg) and 1,2-dichloroethane (1.0 mL). The reaction system was reacted at room temperature for 36 h, and the reaction was monitored by TLC. After the reaction was complete, the product 3 ha was directly purified by column chromatography (yield 54%, enantioselectivity 91%). (Eluent polarity: petroleum ether / ethyl acetate 10:1) 1 H NMR(400MHz, CDCl3)δ8.60(s,1H),8.08(dd,J=8.6,1.5Hz,1H),7.99(d,J=8.0Hz,1H),7.95-7.86(m,2H),7.65-7.54(m,2H), 7.41-7.27(m,5H),6.35-6.21(m,1H),5.15(dd,J=9.7,4.0Hz,1H),4.90-4.65(m,2H),2.83-2.67(m,1H),2.64-2.48(m,1H). 13 C NMR (101MHz, CDCl3) δ197.8,137.8,135.9,132.6,132.5,130.9,129.8,128. 8,128.7,128.6,127.9,127.8,127.0,125.0,124.6,120.3,75.6,67.4,28.1.

[0088] Example 16

[0089] Synthesis of compound 3ia:

[0090]

[0091] Under a nitrogen atmosphere, 1i (0.1 mmol, 29.4 mg, 1.0 equiv.), 2a (0.12 mmol, 23.0 mg, 1.2 equiv.), Pd(PPh3)4 (0.005 mmol, 5.8 mg, 5 mol%), and (R)-6,6'-bis(9-anthrayl)spirocyclodiphenol phosphate (0.01 mmol, 6.6 mg, 10 mol%) were added to the reaction tube. Molecular sieve (100 mg) and 1,2-dichloroethane (1.0 mL). The reaction system was reacted at room temperature for 36 h, and the reaction was monitored by TLC. After the reaction was complete, the product 3ia was directly purified by column chromatography (yield 51%, enantioselectivity 79%). (Eluent polarity: petroleum ether / ethyl acetate 10:1) 1 H NMR (400MHz, CDCl3) δ7.65(s,1H),7.48(d,J=3.5Hz,1H),7.39-7.27(m,5H),6.58(d,J= 2.0Hz,1H),6.27-6.19(m,1H),4.83-4.73(m,2H),4.69-4.61(m,1H),2.72-2.50(m,2H). 13 C NMR (101MHz, CDCl3) δ185.7,149.8,146.1,136.8,134.9,127.7,126.9,124.0,119.1,119.0,111.5,75.2,66.4,27.1.

[0092] Example 17

[0093] Synthesis of compound 3ja:

[0094]

[0095] Under a nitrogen atmosphere, 1j (0.1 mmol, 31.0 mg, 1.0 equiv.), 2a (0.15 mmol, 28.8 mg, 1.5 equiv.), Pd(PPh3)4 (0.003 mmol, 3.5 mg, 3 mol%), and (R)-6,6'-bis(9-anthrayl)spirocyclodiol phosphate (0.01 mmol, 6.6 mg, 10 mol%) were added to the reaction tube. Molecular sieve (100 mg) and 1,2-dichloroethane (1.0 mL). The reaction system was reacted at room temperature for 18 h, and the reaction was monitored by TLC. After the reaction was complete, the product 3ja was directly purified by column chromatography (72% yield, 82% enantioselectivity). (Eluent polarity: petroleum ether / ethyl acetate 10:1) 1 H NMR (400MHz, CDCl3) δ8.05(d,J=3.6Hz,1H),7.69(d,J=4.8Hz,1H),7.52-7.28(m,5H),7.17(t,J=4.2Hz,1H),6.36-

[0096] 6.18(m,1H),4.92-4.61(m,3H),2.77-2.62(m,1H),2.62-2.47(m,1H). 13C NMR (101MHz, CDCl3) δ191.1,141.0,137.8,135.8,134.7,134.1,128.7,128.2,127.9,125.0,120.3,77.3,67.3,28.2.

[0097] Example 18

[0098] Synthesis of compound 4ba:

[0099]

[0100] Under a nitrogen atmosphere, 3ba (0.1 mmol, 36.0 mg, 1.0 equiv.) and ultradry methanol were added to a reaction tube. NaBH4 (0.15 mmol, 5.7 mg, 1.5 equiv.) was added at -40 °C, and the reaction was carried out at this temperature for 8 h. The reaction was monitored by TLC. After the reaction was complete, the product 4ba was directly purified by column chromatography (99% yield, 96% enantioselectivity, 2.5:1 diastereoselectivity ratio). (Eluent polarity: petroleum ether / ethyl acetate 10:1). 1 H NMR (400MHz, CDCl3) δ7.46-7.26(m,9H),6.31-6.01(m,1H),5.01(d,J=3.5Hz,1H),4.87-4.46(m,2 H),3.84(dt,J=10.5,3.5Hz,1H),2.59(s,1H),2.57-2.46(m,1H),2.03-1.80(m,1H),1.36(s,9H). 13 C NMR (101MHz, CDCl3) δ150.5,138.1,137.0,135.3,128.5,127.4,126.1,125.2,124.8,121.4,76.7,74.9,67.7,34.5,31.4,24.2.

[0101] Example 19

[0102] Synthesis of compound 5ao:

[0103]

[0104] Under a nitrogen atmosphere, 3ba (0.1 mmol, 36.0 mg, 1.0 equiv.) and ultra-dry tetrahydrofuran (1 mL) were added to a reaction tube. A 0.5 mol / L acetylenyl magnesium bromide tetrahydrofuran solution (0.3 mmol, 0.6 mL, 3 equiv.) was added dropwise at 0 °C. The reaction system was maintained at 0 °C for 12 h, and the reaction was monitored by TLC. After the reaction was complete, the product 5ba was directly purified by column chromatography (90% yield, 96% enantioselectivity, >20:1 diastereoselectivity). (Eluent polarity: petroleum ether / ethyl acetate 10:1). 1 H NMR (400MHz, CDCl3) δ7.51 (d, J = 8.2Hz, 2H), 7.34 (d, J = 8.2Hz, 2H), 7.28-7.15 (m, 5H), 6.01 (d, J = 4.2Hz, 1H), 4.80-4. 35(m,2H),3.82(dd,J=10.6,2.8Hz,1H),3.12(s,1H),2.58(s,1H),2.37-2.21(m,1H),1.88-1.63(m,1H),1.27(s,9H). 13 C NMR (101MHz, CDCl3) δ151.1,137.9,137.2,135.3,128.6,127.6,125.8,125.2,124.9,121.2,86.3,79.6,73.7,73.0,68.4,34.6,31.4,25.0.

[0105] Example 20

[0106] Synthesis of compound 5ao:

[0107]

[0108] Under a nitrogen atmosphere, 3ba (0.1 mmol, 36.0 mg, 1.0 equiv.) and ultra-dry tetrahydrofuran (1 mL) were added to a reaction tube. A 1.0 mol / L vinyl magnesium bromide tetrahydrofuran solution (0.3 mmol, 0.3 mL, 3 equiv.) was added dropwise at -78 °C, and the reaction was carried out at -78 °C for 12 h. The reaction was monitored by TLC. After the reaction was complete, the product 6ba was directly purified by column chromatography (99% yield, 96% enantioselectivity, >20:1 diastereoselectivity). (Eluent polarity: petroleum ether / ethyl acetate 10:1). 1H NMR (400MHz, CDCl3) δ7.43-7.33(m,4H),7.33-7.20(m,5H),6.37(dd,J=17.2,10.7Hz,1H),6.17-6.00(m,1H),5.34(dd,J=69.7 ,13.9Hz,2H),4.82-4.49(m,2H),3.94(dd,J=10.7,3.2Hz,1H),2.76(s,1H),2.53-2.29(m,1H),1.77-1.58(m,1H),1.31(s,9H). 13 C NMR (101MHz, CDCl3) δ149.9,143.1,139.2,138.1,135.09,128.7,127.5,125.3,125.2,124.9,121.9,113.8,78.0,77.5,68.1,34.6,31.5,25.1.

[0109] Example 21

[0110] Anti-inflammatory test:

[0111] Anti-inflammatory assays were performed on compounds 3ba, 3ag, 3ga, 3ea, and 3fa from the above examples. The levels of inflammatory factors in RAW264.7 cells were monitored when evaluating the anti-inflammatory activity of the synthesized compounds. The concentrations of nitric oxide (NO) and reactive oxygen species (ROS), two key pro-inflammatory mediators, play a crucial role in the organism's response to inflammatory stimuli. Studies have shown that elevated NO and ROS levels significantly affect the pathogenesis of various inflammatory diseases. Therefore, the concentrations of these two key pro-inflammatory mediators were detected in RAW264.7 cells. Figure 1 and Figure 2 The effects of different concentrations of the compounds on nitric oxide (NO) and reactive oxygen species (ROS) production induced by lipopolysaccharide (LPS) in RAW264.7 macrophages were shown. Con. represented the negative control group (blank experiment) without induced inflammation. The figures show that compounds 3ba, 3ag, 3ga, 3ea, and 3fa exhibited some inhibitory effects on NO, especially at a concentration of 30 μM. Compound 3ba at 30 μM was comparable in effect to 10 μM dexamethasone (DEX.), while compounds 3ga and 3fa showed weak inhibitory effects on ROS secretion at 30 μM, with effects comparable to 10 μM DEX.

Claims

1. A chiral pyran ring compound, characterized in that, Its structure is shown in equation (Ⅲ). ， In the formula, R is selected from a benzene ring, a substituted phenyl ring, or a naphthalene ring, and the substituent of the substituted phenyl ring is tert-butyl, halogen, or trifluoromethyl; R 1 It is selected from benzene rings or substituted phenyl groups, wherein the substituents of the substituted phenyl groups are methyl, methoxy, halogen or trifluoromethyl.

2. A method for synthesizing the chiral pyran ring compound as described in claim 1, characterized in that, Using thioyl ylides as shown in formula (I) and vinyl carbonate compounds as shown in formula (II) as reactants, molecular sieves were added, and the reaction was carried out in an organic solvent at room temperature for 18-36 h in the presence of a catalyst and chiral phosphoric acid. After the reaction was completed, the chiral pyran ring compound as shown in formula (III) was obtained by silica gel column chromatography. The reaction formula is shown below: ， In the formula, R is selected from a benzene ring, a substituted phenyl ring, or a naphthalene ring, and the substituent of the substituted phenyl ring is tert-butyl, halogen, or trifluoromethyl; R 1 Selected from benzene rings or substituted phenyl groups, wherein the substituents of the substituted phenyl groups are methyl, methoxy, halogen, or trifluoromethyl; The chiral phosphoric acid is (R)-6,6'-bis(9-anthrayl)spirocyclic diphenol phosphate, and the catalyst is Pd(PPh3). 4。 3. The synthesis method as described in claim 2, characterized in that, The amount of catalyst used is 1 to 5 mol of the compound shown in formula (Ⅰ).

4. The synthesis method according to claim 2, characterized in that, The molecular sieve is a 3Å molecular sieve, a 4Å molecular sieve, or a 5Å molecular sieve.

5. The synthesis method as described in claim 2, characterized in that, The organic solvent is dichloromethane, 1,2-dichloroethane, isopropanol, ethanol, carbon tetrachloride, chloroform, chlorobenzene, toluene, dimethylacetamide, or tetrahydrofuran.

6. The synthesis method according to claim 2, characterized in that, The molar ratio of the compound shown in formula (I) to the compound shown in formula (II) is 1.0:1.0-1.0:2.

0.

7. The synthesis method according to claim 2, characterized in that, After the reaction, the specific procedure for separation and purification by silica gel column chromatography is as follows: After the reaction, the reaction solution is concentrated and subjected to column chromatography. A mixture of petroleum ether and ethyl acetate is used as the eluent. The eluent containing the target compound is collected, concentrated, distilled and dried to obtain the compound shown in formula (Ⅲ). The volume ratio of the petroleum ether to ethyl acetate mixture is 10:1-20:

1.

8. The synthesis method according to claim 2, characterized in that, The catalyst was Pd(PPh3)4, used in an amount of 3 mol% of the amount of the compound shown in formula (I). The chiral phosphoric acid was (R)-6,6'-bis(9-anthrayl)spirocyclic diphenol phosphate. The molecular sieve was a 5 Å molecular sieve. The organic solvent was 1,2-dichloroethane. The molar ratio of the compound shown in formula (I) to the compound shown in formula (II) was 1.0:1.

5.

9. The use of a chiral pyran ring compound as described in claim 1 in the preparation of an anti-inflammatory drug.

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