Synthesis Method and Application of Chiral Tetrahydropyran Compounds

Abstract

The present invention relates to the fields of medicine, organic chemical industry and fine chemical industry, and particularly relates to a synthesis method and application of chiral tetrahydropyran compounds. The present invention uses enamine compounds and 1,4-dipole compounds as raw materials, under the catalysis of Pd2dba3 catalyst and (R)-BINAP chiral ligand, with tetrahydrofuran as the solvent, at -20 °C, and the product is synthesized after 96 hours. After simple post-treatment of the reaction, a series of chiral tetrahydropyran compounds can be obtained in high yield and high enantioselectivity. Enamine substrates substituted at different positions (para, ortho, meta) on the benzene ring, as well as enamine compounds containing naphthyl and thiophene groups can all be used as reaction substrates to obtain the corresponding chiral tetrahydropyran compounds. The chiral tetrahydrofuran compounds have an inhibitory effect on tumors and can be used to prepare anti-tumor drugs.

Description

Technical Field

[0001] The present invention relates to the fields of medicine, organic chemical industry and fine chemical industry, and particularly relates to a method for synthesizing chiral tetrahydropyran compounds. A method for obtaining chiral tetrahydropyran compounds by using enamine compounds and 1,4-dipole compounds as raw materials and reacting under the catalysis of Pd2dba3 catalyst and (R)-BINAP chiral ligand. Background Art

[0002] Enamine compounds are important C2 synthons or C4 synthons and are widely used in cycloaddition reactions. Among them, the cycloaddition reaction in which the double bond of enamine participates as a C2 synthon has received extensive attention in the synthesis of cyclic compounds. However, currently, the cycloaddition of the double bond of enamine with dipoles mainly occurs in the form of [3+2]. In 2016, the Chen Yingchun research group reported that using indigo-derived Morita-Baylis-Hillman carbonate as a 1,5-dipole, under the catalysis of a tertiary amine derived from cinchona alkaloid, it undergoes an enantioselective [3+2] cycloaddition reaction with an alkenyl-substituted 1,2-benzothiazole oxide or 1,2,3-benzoxazine oxide with an electron-withdrawing group to obtain a series of spiroindolinones (>19:1 dr, up to >99% ee). (See: K.-K. Wang, T. Jin, X. Huang, Q. Ouyang, W. Du, Y.-C. Chen, Org. Lett. 2016, 18, 872-875.)

[0003]

[0004] In 2021, the Wang Xingwang research group reported that based on vinyl carbonate as a 1,5-dipole precursor, it successfully undergoes a [3+2] cycloaddition reaction with the double bond of enamine under the catalysis of palladium metal, and a variety of chiral tetrahydrofuran derivatives are obtained with good diastereoselectivity and enantioselectivity, among which the diastereoselectivity is up to 20:1 and the enantioselectivity is up to 99%. (See: H.-P. Lv, X.-P. Yang, B.-L. Wang, H.-D. Yang, X.-W. Wang, Z. Wang, Org. Lett. 2021, 23, 4715-4720.)

[0005]

[0006] In 2022, the research group of Li Xiangji used vinyl ethylene carbonate as a precursor to achieve an enantioselective and diastereoselective dipolar [3+2] spirocyclization reaction with indole-modified alkenylimines under palladium catalysis, obtaining highly optically active furan spiroindole derivatives containing all-carbon quaternary chiral stereocenters, with a yield of up to 99%, an enantioselectivity of up to 99% ee, and a diastereoselectivity of up to 94:6. (See: H.J. Jeon, S.M. Park, Y.L. Lee, S. Lee, Org. Lett. 2022, 24, 9189-9193.)

[0007]

[0008] In 2022, the research group of Chen Fen'er reported an asymmetric [3+2] cycloaddition reaction of vinyl ethylene carbonate with alkenyl-substituted benz[d]isothiazole oxides through palladium catalysis, constructing tetrahydrofuran compounds with three chiral centers. It is worth mentioning that the structure also contains an α all-carbon quaternary chiral center. This reaction also has good enantioselectivity and diastereoselectivity. (See: M. Ke, B. Qiao, Y. Yu, X. Li, X. Xiao, S.-J. Li, Y. Lan, F. Chen, J. Org. Chem. 2022, 87, 8, 5166-5177.)

[0009]

[0010] As described above, 5-membered cyclic compounds can be effectively constructed through the cycloaddition reaction of alkenylimines. To further expand the reaction scope of alkenylimines with dipoles, the present invention successfully achieved an enantioselective [4+2] cycloaddition reaction of 1,4-dipoles with alkenylimines through palladium metal catalysis, obtaining a series of highly optically pure chiral tetrahydropyran derivatives in good yields. Although certain progress has been made in the methods for synthesizing the chiral tetrahydropyran compound skeleton, the limitation of substrates is still the main factor affecting the synthesis of such structures. Therefore, the present invention is very necessary for expanding the synthesis route and application of tetrahydropyran. Summary of the Invention

[0011] The present invention successfully used commercially available chiral ligands to achieve the [4+2] cycloaddition reaction of 1,4-dipoles with alkenylimines. Under the catalysis of Pd2dba3 catalyst and (R)-BINAP ligand, the 1,4-dipole selectively undergoes an enantioselective [4+2] cycloaddition reaction with the double bond, obtaining a series of chiral tetrahydropyran heterocycles in good yields, with an enantioselectivity of up to 94%. This is a new catalytic mode in the field of chiral tetrahydropyran heterocycles, and the corresponding chiral tetrahydropyran compounds are obtained. Chiral tetrahydrofuran compounds have an inhibitory effect on tumors and can be used to prepare anti-tumor drugs.

[0012] The present invention provides a method for synthesizing chiral tetrahydropyran heterocyclic compounds from alkenylimine compounds and 1,4-dipole compounds as raw materials, catalyzed by Pd2dba3 catalyst and (R)-BINAP chiral ligand, in an organic solvent at -20 °C for 96 hours. The specific process of this reaction is as follows:

[0013]

[0014] Furthermore, in the alkenylimine substrate (Formula I), R is selected from any one of hydrogen, ester group, nitro group, cyano group, aldehyde group, carbonyl group, amide group, phosphate group, alkyl group, aryl group, heteroaryl group, substituted aryl group, and substituted heteroaryl group;

[0015] The aryl group is selected from one of phenyl, naphthyl, phenanthryl, anthryl, acenaphthylenyl, acenaphthenyl, fluorenyl, pyrenyl, and fluoranthenyl;

[0016] The heteroaryl group is selected from one of pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzothienyl, benzofuryl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, and purinyl;

[0017] The substituents in the substituted aryl group and the substituted heteroaryl group are each independently selected from fluorine, chlorine, bromine, iodine, cyano group, hydroxyl group, amino group, carboxyl group, alkyl group, haloalkyl group, alkoxy group, alkylthio group, alkenyl group, alkynyl group, nitro group, mercapto group, hydroxyalkyl group, hydroxyalkoxy group, aminoalkoxy group, alkyl ester group, aryl group, arylalkyl group, heteroaryl group, heteroarylalkyl group, heterocyclic group, heterocyclicalkyl group, cycloalkyl group, aryloxy group, heteroaryloxy group, haloalkyloxy group, and cycloalkylalkyl group.

[0018] The structure of the compound of Formula I is preferably:

[0019]

[0020] Furthermore, in 5-methylene-1,3-dioxolan-2-one (1,4-dipole compound) (Formula II), R1 is selected from one of hydrogen, alkyl group, and aryl group; the alkyl group and the aryl group are selected to be the same as R.

[0021] The structure of the compound of Formula II is preferably:

[0022]

[0023] Furthermore, the external phosphine ligand is selected as triphenylphosphine, and the chiral phosphorus ligand is selected from the following, and its dosage is 10 - 20 mol% of the molar amount of the alkenylimine compound (Formula I) raw material, and further preferably 20 mol%.

[0024]

[0025] The palladium metal catalyst is Pd(PPh3)4 (tetrakis(triphenylphosphine)palladium), Pd2(dba)3 (tris(dibenzylideneacetone)dipalladium), Pd(dppf)Cl2 ([1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium), Pd(cod)Cl2 ((1,5-cyclooctadiene)dichloropalladium), PdCl2 or Pd(PPh3)2Cl2. Its dosage is 5-10 mol% of the molar amount of the enamine (Formula I) raw material, and further preferably 10 mol%.

[0026] Furthermore, the organic solvent is selected from chlorobenzene (PhCl), toluene, dichloromethane (DCM), 1,4-dioxane, tetrahydrofuran (THF), ethyl acetate (EA). Further preferably, tetrahydrofuran (THF) is the organic solvent.

[0027] Furthermore, the reaction temperature is preferably selected from 65°C to -20°C. Further preferably, -20°C is the reaction temperature.

[0028] Preferably, under the conditions of using Pd2(dba)3 as the catalyst and R-BINAP as the ligand, the reaction effect of the present invention is the best. The post-treatment of the reaction is simple. Only a simple column chromatography separation method is needed, and a pure compound can be obtained using a mixed solvent of petroleum ether and ethyl acetate as the eluent.

[0029] The structure of the chiral tetrahydropyran compound is:

[0030]

[0031] Among them, the above R is after optimization. The Pd2dba3 catalyst of this structural formula has the best effect. If the substituent changes, the enantioselectivity will become worse.

[0032] The molar ratio of the enamine compound used to the 1,4-dipole compound is 1:1;

[0033] Preferably, under the conditions of using Pd2(dba)3 as the catalyst and (R)-BINAP as the ligand, the reaction effect of the present invention is the best. And the experimental results show that under the catalysis of the Pd2dba3 catalyst and the (R)-BINAP chiral ligand, the 1,4-dipole selectively undergoes a [4+2] cycloaddition reaction with the olefin bond, and a product with a high yield and high enantioselectivity can be obtained. The post-treatment of the reaction is simple. Only a simple column chromatography separation method is needed, and a pure tetrahydropyran compound can be obtained using a mixed solvent of petroleum ether and ethyl acetate as the eluent.

[0034] Correspondingly, the prepared chiral tetrahydrofuran compound has an inhibitory effect on tumors and can be used to prepare anti-tumor drugs.

[0035] An anti-tumor agent, which comprises the anti-tumor chiral tetrahydrofuran compound prepared by the above method.

[0036] Preferably, the tumor includes one or more of the following: human cervical cancer cell line, breast tumor cell line, lung cancer cell line, ovarian cancer cell line.

[0037] Preferably, the anti-tumor agent further comprises at least one pharmaceutically acceptable excipient selected from glycerol, polysorbate, polyethylene glycol, high acyl gellan gum, xanthan gum, carrageenan, sodium alginate, sodium carboxymethyl cellulose, microcrystalline cellulose, hydroxypropyl methyl cellulose, crospovidone, polyacrylic resin polymers, safflower seed oil, lecithin and beeswax; and / or, the dosage form of the anti-tumor agent includes at least one pharmaceutically acceptable dosage form selected from oral liquid, capsule, tablet, ointment, powder, granule, pill, suppository, implantable preparation, targeted preparation, sustained release preparation and controlled release preparation.

[0038] Compared with the prior art, the beneficial effects of the present invention are as follows: An enantioselective [4+2] cycloaddition reaction for the synthesis of chiral tetrahydropyran heterocyclic compounds is developed. This method provides a way to synthesize various chiral tetrahydropyran heterocyclic skeletons with high enantioselectivity from simple starting materials, namely enamine compounds. The reaction conditions are simple and mild, and the yield is good. The substrate has good functional group tolerance, and groups such as naphthyl, halogen, alkoxy, etc. can be compatible. It has an inhibitory effect on tumors and can be used to prepare anti-tumor drugs. Detailed Embodiments

[0039] The present invention will be described in detail below with reference to the embodiments. The reactions of the embodiments of the present invention are as follows:

[0040] Example 1 3-((2S,3R)-5-Methylene-2-phenyltetrahydro-2H-pyran-3-yl)benzo[d]isothiazole-1,1-dioxide

[0041] 3-((2S,3R)-5-methylene-2-phenyltetrahydro-2H-pyran-3-yl)benzo[d]isothiazole-1,1-dioxide

[0042]

[0043]

[0044] At room temperature, in a nitrogen atmosphere, (Z)-3-styrylbenzisothiazole 1,1-dioxide (0.3 mmol, 1.0 equiv) and 1,4-dipole (0.3 mmol, 1.0 equiv) were added to a 10 mL vial, followed by Pd2(dba)3 (0.03 mmol, 10 mol%) and R-Binap (0.06 mmol, 20 mol%). Finally, 6 mL of tetrahydrofuran was added. The system was stirred at -20 °C for about 96 h. After determining the completion of the reaction by TLC, the reaction mixture was concentrated under reduced pressure, triturated, and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to obtain the corresponding cyclic compound. The yield was 74%, 91% ee. The compound was a white solid.

[0045] NMR data: 1 H NMR(400MHz,CDCl3)δ7.75(d,J=7.5Hz,1H),7.53(t,J=7.5Hz,1H),7.37(t,J=7.6Hz,1H),7.27(d,J=6.7Hz,2H),7.10(t,J=7.4Hz,2H),7.02(t,J=7.4Hz,2H),5.09(s,1H),5.00(s,1H),4.75(d,J=9.3Hz,1H),4.50(d,J=12.5Hz,1H),4.33(d,J=12.5Hz,1H),3.47-3.40(m,1H),3.10(t,J=13.4Hz,1H),2.76(dd,J1=3.2,J2=13.9Hz,1H),ppm. 13 C NMR(75MHz,CDCl3)δ176.4,140.3,139.2,139.1,133.3,133.2,130.7,128.6,128.5,126.4,123.7,122.4,112.2,83.5,72.8,47.1,36.2ppm. Mass spectrometry data HRMS(CI+)calculated for C 19 H 17 NO3S[M+H] + :339.1742,found:339.1741.

[0046] Comparative Example 1

[0047] Compared with Example 1, Pd2(dba)3 was not added in the reaction, and other operations were the same as those in Example 1.

[0048] At room temperature, under nitrogen protection, R-BINAP (0.02 mmol, 20 mol%) was added to a solution of (Z)-3-styrylbenzisothiazole 1,1-dioxide (0.1 mmol, 1.0 equivalent) and 1,4-dipole (0.1 mmol, 1.0 equivalent) in THF (2.0 mL). The reaction mixture was stirred at -20 °C for 96 hours. The target product could not be obtained in the reaction.

[0049] Comparative Example 2

[0050] Compared with Example 1, R-BINAP was not added in the reaction, and other operations were the same as those in Example 1.

[0051] At room temperature, under nitrogen protection, Pd2(dba)3 (0.01 mmol, 10 mol%) was added to a solution of (Z)-3-styrylbenzisothiazole 1,1-dioxide (0.1 mmol, 1.0 equivalent) and 1,4-dipole (0.1 mmol, 1.0 equivalent) in THF (2.0 mL). The reaction mixture was stirred at -20 °C for 96 hours. The target product could not be obtained in the reaction.

[0052] Comparative Example 3

[0053] Compared with Example 1, a Pd(PPh3)4 catalyst was added in the reaction, and other operations were the same as those in Example 1.

[0054] At room temperature, under nitrogen protection, Pd(PPh3)4 (0.01 mmol, 10 mol%) and R-BINAP (0.02 mmol, 20 mol%) were added to a solution of (Z)-3-styrylbenzisothiazole 1,1-dioxide (0.1 mmol, 1.0 equivalent) and 1,4-dipole (0.1 mmol, 1.0 equivalent) in THF (2.0 mL). The reaction mixture was stirred at -20 °C for 96 hours. The reaction mixture was diluted with ethyl acetate and concentrated, and then the residue was directly purified by silica gel column chromatography, with a yield of only 40%.

[0055] Comparative Example 4

[0056] Compared with Example 1, a Pd(dppf)Cl2 catalyst was added in the reaction, and other operations were the same as those in Example 1.

[0057] At room temperature, under nitrogen protection, Pd(dppf)Cl2 (0.01 mmol, 10 mol%) and R-BINAP (0.02 mmol, 20 mol%) were added to a solution of (Z)-3-styrylbenzisothiazole 1,1-dioxide (0.1 mmol, 1.0 equivalent) and 1,4-dipole (0.1 mmol, 1.0 equivalent) in THF (2.0 mL). The reaction mixture was stirred at room temperature for 96 hours. The target product could not be obtained in the reaction.

[0058] Comparative Example 5

[0059] Compared with Example 1, Pd(cod)Cl2 catalyst was added in the reaction, and other operations were the same as those in Example 1.

[0060] At room temperature, under nitrogen protection, Pd(cod)Cl2 (0.01 mmol, 10 mol%) and R-BINAP (0.02 mmol, 20 mol%) were added to a solution of (Z)-3-styrylbenzisothiazole 1,1-dioxide (0.1 mmol, 1.0 equivalent) and 1,4-dipole (0.1 mmol, 1.0 equivalent) in THF (2.0 mL). The reaction mixture was stirred at -20 °C for 96 hours. The target product could not be obtained in the reaction.

[0061] Comparative Example 6

[0062] Compared with Example 1, PdCl2 catalyst was added in the reaction, and other operations were the same as those in Example 1.

[0063] At room temperature, under nitrogen protection, PdCl2 (0.01 mmol, 10 mol%) and R-BINAP (0.02 mmol, 20 mol%) were added to a solution of (Z)-3-styrylbenzisothiazole 1,1-dioxide (0.1 mmol, 1.0 equivalent) and 1,4-dipole (0.1 mmol, 1.0 equivalent) in THF (2.0 mL). The reaction mixture was stirred at -20 °C for 96 hours. The target product could not be obtained in the reaction.

[0064] Comparative Example 7

[0065] Compared with Example 1, Pd(PPh3)2Cl2 catalyst was added in the reaction, and other operations were the same as those in Example 1.

[0066] At room temperature, under nitrogen protection, Pd(PPh3)2Cl2 (0.01 mmol, 10 mol%) and R-BINAP (0.02 mmol, 20 mol%) were added to a solution of (Z)-3-styrylbenzisothiazole 1,1-dioxide (0.1 mmol, 1.0 equiv) and 1,4-dipole (0.1 mmol, 1.0 equiv) in THF (2.0 mL). The reaction mixture was stirred at -20 °C for 96 h. The target product could not be obtained from the reaction.

[0067] Comparative Example 8

[0068] Compared with Example 1, phosphine ligand PPh3 was added to the reaction, and other operations were the same as those in Example 1.

[0069] At room temperature, under nitrogen protection, Pd2(dba)3 (0.01 mmol, 10 mol%) and phosphine ligand PPh3 (0.02 mmol, 20 mol%) were added to a solution of (Z)-3-styrylbenzisothiazole 1,1-dioxide (0.1 mmol, 1.0 equiv) and 1,4-dipole (0.1 mmol, 1.0 equiv) in THF (2.0 mL). The reaction mixture was stirred at -20 °C for 96 h. The reaction mixture was diluted with ethyl acetate and concentrated, and then the residue was directly purified by silica gel column chromatography. The NMR yield was 60%, but the product had no enantioselectivity.

[0070] Comparative Example 9

[0071] Compared with Example 1, chiral phosphine ligand L1 was added to the reaction, and other operations were the same as those in Example 1.

[0072] At room temperature, under nitrogen protection, Pd2(dba)3 (0.01 mmol, 10 mol%) and chiral phosphine ligand L1 (0.02 mmol, 20 mol%) were added to a solution of (Z)-3-styrylbenzisothiazole 1,1-dioxide (0.1 mmol, 1.0 equiv) and 1,4-dipole (0.1 mmol, 1.0 equiv) in THF (2.0 mL). The reaction mixture was stirred at -20 °C for 96 h. The reaction mixture was diluted with ethyl acetate and concentrated, and then the residue was directly purified by silica gel column chromatography. The NMR yield was 40%, and the ee value of the product was only 10%.

[0073] Comparative Example 10

[0074] Compared with Example 1, chiral phosphine ligand L2 was added to the reaction, and other operations were the same as those in Example 1.

[0075] At room temperature, under nitrogen protection, Pd2(dba)3 (0.01 mmol, 10 mol%) and chiral phosphorus ligand L2 (0.02 mmol, 20 mol%) were added to a solution of (Z)-3-styrylbenzisothiazole 1,1-dioxide (0.1 mmol, 1.0 equivalent) and 1,4-dipole (0.1 mmol, 1.0 equivalent) in THF (2.0 mL). The reaction mixture was stirred at -20 °C for 96 hours. The reaction mixture was diluted with ethyl acetate and concentrated, and then the residue was directly purified by silica gel column chromatography. The NMR yield was 78%, and the ee value of the product was only 24%.

[0076] Comparative Example 11

[0077] Compared with Example 1, chiral phosphorus ligand L3 was added to the reaction, and other operations were the same as those in Example 1.

[0078] At room temperature, under nitrogen protection, Pd2(dba)3 (0.01 mmol, 10 mol%) and chiral phosphorus ligand L3 (0.02 mmol, 20 mol%) were added to a solution of (Z)-3-styrylbenzisothiazole 1,1-dioxide (0.1 mmol, 1.0 equivalent) and 1,4-dipole (0.1 mmol, 1.0 equivalent) in THF (2.0 mL). The reaction mixture was stirred at -20 °C for 96 hours. The reaction mixture was diluted with ethyl acetate and concentrated, and then the residue was directly purified by silica gel column chromatography. The NMR yield was 92%, and the ee value of the product was only 14%.

[0079] Comparative Example 12

[0080] Compared with Example 1, chiral phosphorus ligand L4 was added to the reaction, and other operations were the same as those in Example 1.

[0081] At room temperature, under nitrogen protection, Pd2(dba)3 (0.01 mmol, 10 mol%) and chiral phosphorus ligand L4 (0.02 mmol, 20 mol%) were added to a solution of (Z)-3-styrylbenzisothiazole 1,1-dioxide (0.1 mmol, 1.0 equivalent) and 1,4-dipole (0.1 mmol, 1.0 equivalent) in THF (2.0 mL). The reaction mixture was stirred at -20 °C for 96 hours. The reaction mixture was diluted with ethyl acetate and concentrated, and then the residue was directly purified by silica gel column chromatography. The NMR yield was 55%, and the ee value of the product was only 73%.

[0082] Comparative Example 13

[0083] Compared with Example 1, chiral phosphorus ligand L5 was added to the reaction, and other operations were the same as those in Example 1.

[0084] At room temperature, under nitrogen protection, Pd2(dba)3 (0.01 mmol, 10 mol%) and chiral phosphorus ligand L5 (0.02 mmol, 20 mol%) were added to a solution of (Z)-3-styrylbenzisothiazole 1,1-dioxide (0.1 mmol, 1.0 equivalent) and 1,4-dipole (0.1 mmol, 1.0 equivalent) in THF (2.0 mL). The reaction mixture was stirred at -20 °C for 96 hours. The reaction mixture was diluted with ethyl acetate and concentrated, and then the residue was directly purified by silica gel column chromatography. The NMR yield was 78%, and the ee value of the product was only 24%.

[0085] Comparative Example 14

[0086] Compared with Example 1, chiral phosphorus ligand L7 was added to the reaction, and other operations were the same as those in Example 1.

[0087] At room temperature, under nitrogen protection, Pd2(dba)3 (0.01 mmol, 10 mol%) and chiral phosphorus ligand L7 (0.02 mmol, 20 mol%) were added to a solution of (Z)-3-styrylbenzisothiazole 1,1-dioxide (0.1 mmol, 1.0 equivalent) and 1,4-dipole (0.1 mmol, 1.0 equivalent) in THF (2.0 mL). The reaction mixture was stirred at -20 °C for 96 hours. The reaction mixture was diluted with ethyl acetate and concentrated, and then the residue was directly purified by silica gel column chromatography. The NMR yield was 50%, and the ee value of the product was only 74%.

[0088] Comparative Example 15

[0089] Compared with Example 1, chiral phosphorus ligand L8 was added to the reaction, and other operations were the same as those in Example 1.

[0090] At room temperature, under nitrogen protection, Pd2(dba)3 (0.01 mmol, 10 mol%) and chiral phosphorus ligand L8 (0.02 mmol, 20 mol%) were added to a solution of (Z)-3-styrylbenzisothiazole 1,1-dioxide (0.1 mmol, 1.0 equivalent) and 1,4-dipole (0.1 mmol, 1.0 equivalent) in THF (2.0 mL). The reaction mixture was stirred at -20 °C for 96 hours. The reaction mixture was diluted with ethyl acetate and concentrated, and then the residue was directly purified by silica gel column chromatography. The NMR yield was 50%, and the ee value of the product was only 61%.

[0091] Comparative Example 16

[0092] Compared with Example 1, chiral phosphorus ligand L9 was added to the reaction, and other operations were the same as those in Example 1.

[0093] At room temperature, under nitrogen protection, Pd2(dba)3 (0.01 mmol, 10 mol%) and chiral phosphorus ligand L9 (0.02 mmol, 20 mol%) were added to a solution of (Z)-3-styrylbenzisothiazole 1,1-dioxide (0.1 mmol, 1.0 equivalent) and 1,4-dipole (0.1 mmol, 1.0 equivalent) in THF (2.0 mL). The reaction mixture was stirred at -20 °C for 96 hours. The reaction mixture was diluted with ethyl acetate and concentrated, and then the residue was directly purified by silica gel column chromatography. The NMR yield was 70%, and the ee value of the product was only 33%.

[0094] Comparative Example 17

[0095] Compared with Example 1, chlorobenzene was selected as the reaction solvent, and other operations were the same as those in Example 1.

[0096] At room temperature, under nitrogen protection, Pd2(dba)3 (0.01 mmol, 10 mol%) and R-BINAP (0.02 mmol, 20 mol%) were added to a solution of (Z)-3-styrylbenzisothiazole 1,1-dioxide (0.1 mmol, 1.0 equivalent) and 1,4-dipole (0.1 mmol, 1.0 equivalent) in PhCl (2.0 mL). The reaction mixture was stirred at -20 °C for 96 hours. The reaction mixture was diluted with ethyl acetate and concentrated, and then the residue was directly purified by silica gel column chromatography. The NMR yield was 32%, and the ee value of the product was only 69%.

[0097] Comparative Example 18

[0098] Compared with Example 1, toluene was selected as the reaction solvent, and other operations were the same as those in Example 1.

[0099] At room temperature, under nitrogen protection, Pd2(dba)3 (0.01 mmol, 10 mol%) and R-BINAP (0.02 mmol, 20 mol%) were added to a solution of (Z)-3-styrylbenzisothiazole 1,1-dioxide (0.1 mmol, 1.0 equivalent) and 1,4-dipole (0.1 mmol, 1.0 equivalent) in toluene (2.0 mL). The reaction mixture was stirred at -20 °C for 96 hours. The reaction mixture was diluted with ethyl acetate and concentrated, and then the residue was directly purified by silica gel column chromatography. The NMR yield was 36%, and the ee value of the product was only 53%.

[0100] Comparative Example 19

[0101] Compared with Example 1, dichloromethane was selected as the reaction solvent, and other operations were the same as those in Example 1.

[0102] At room temperature, under nitrogen protection, Pd2(dba)3 (0.01 mmol, 10 mol%) and R-BINAP (0.02 mmol, 20 mol%) were added to a solution of (Z)-3-styrylbenzisothiazole 1,1-dioxide (0.1 mmol, 1.0 equivalent) and 1,4-dipole (0.1 mmol, 1.0 equivalent) in DCM (2.0 mL). The reaction mixture was stirred at -20 °C for 96 hours. The reaction mixture was diluted with ethyl acetate and concentrated, and then the residue was directly purified by silica gel column chromatography. The NMR yield was 24%, and the ee value of the product was only 68%.

[0103] Comparative Example 20

[0104] Compared with Example 1, the reaction solvent was selected as 1,4-dioxane, and other operations were the same as those in Example 1.

[0105] At room temperature, under nitrogen protection, Pd2(dba)3 (0.01 mmol, 10 mol%) and R-BINAP (0.02 mmol, 20 mol%) were added to a solution of (Z)-3-styrylbenzisothiazole 1,1-dioxide (0.1 mmol, 1.0 equivalent) and 1,4-dipole (0.1 mmol, 1.0 equivalent) in dioxane (2.0 mL). The reaction mixture was stirred at -20 °C for 96 hours. The reaction mixture was diluted with ethyl acetate and concentrated, and then the residue was directly purified by silica gel column chromatography. The NMR yield was 32%, and the ee value of the product was only 81%.

[0106] Comparative Example 21

[0107] Compared with Example 1, the reaction solvent was selected as ethyl acetate, and other operations were the same as those in Example 1.

[0108] At room temperature, under nitrogen protection, Pd2(dba)3 (0.01 mmol, 10 mol%) and R-BINAP (0.02 mmol, 20 mol%) were added to a solution of (Z)-3-styrylbenzisothiazole 1,1-dioxide (0.1 mmol, 1.0 equivalent) and 1,4-dipole (0.1 mmol, 1.0 equivalent) in EA (2.0 mL). The reaction mixture was stirred at -20 °C for 96 hours. The reaction mixture was diluted with ethyl acetate and concentrated, and then the residue was directly purified by silica gel column chromatography. The NMR yield was 28%, and the ee value of the product was only 82%.

[0109] Comparative Example 22

[0110] Compared with Example 1, the reaction temperature was selected as 65 °C, and other operations were the same as those in Example 1.

[0111] At room temperature, under nitrogen protection, Pd2(dba)3 (0.01 mmol, 10 mol%) and R-BINAP (0.02 mmol, 20 mol%) were added to a solution of (Z)-3-styrylbenzisothiazole 1,1-dioxide (0.1 mmol, 1.0 equivalent) and 1,4-dipole (0.1 mmol, 1.0 equivalent) in THF (2.0 mL). The reaction mixture was stirred at 65 °C for 96 h. The reaction mixture was diluted with ethyl acetate and concentrated, and then the residue was directly purified by silica gel column chromatography. The NMR yield was 86%, and the ee value of the product was only 72%.

[0112] Comparative Example 23

[0113] Compared with Example 1, the reaction temperature was selected as 55 °C, and other operations were the same as those in Example 1.

[0114] At room temperature, under nitrogen protection, Pd2(dba)3 (0.01 mmol, 10 mol%) and R-BINAP (0.02 mmol, 20 mol%) were added to a solution of (Z)-3-styrylbenzisothiazole 1,1-dioxide (0.1 mmol, 1.0 equivalent) and 1,4-dipole (0.1 mmol, 1.0 equivalent) in THF (2.0 mL). The reaction mixture was stirred at 55 °C for 96 h. The reaction mixture was diluted with ethyl acetate and concentrated, and then the residue was directly purified by silica gel column chromatography. The NMR yield was 74%, and the ee value of the product was only 75%.

[0115] Comparative Example 24

[0116] Compared with Example 1, the reaction temperature was selected as 40 °C, and other operations were the same as those in Example 1.

[0117] At room temperature, under nitrogen protection, Pd2(dba)3 (0.01 mmol, 10 mol%) and R-BINAP (0.02 mmol, 20 mol%) were added to a solution of (Z)-3-styrylbenzisothiazole 1,1-dioxide (0.1 mmol, 1.0 equivalent) and 1,4-dipole (0.1 mmol, 1.0 equivalent) in THF (2.0 mL). The reaction mixture was stirred at 40 °C for 96 h. The reaction mixture was diluted with ethyl acetate and concentrated, and then the residue was directly purified by silica gel column chromatography. The NMR yield was 71%, and the ee value of the product was only 80%.

[0118] Comparative Example 25

[0119] Compared with Example 1, the reaction temperature was selected as 0 °C, and other operations were the same as those in Example 1.

[0120] At room temperature, under nitrogen protection, Pd2(dba)3 (0.01 mmol, 10 mol%) and R-BINAP (0.02 mmol, 20 mol%) were added to a solution of (Z)-3-styrylbenzisothiazole 1,1-dioxide (0.1 mmol, 1.0 equiv) and 1,4-dipole (0.1 mmol, 1.0 equiv) in THF (2.0 mL). The reaction mixture was stirred at 0 °C for 96 h. The reaction mixture was diluted with ethyl acetate and concentrated, and then the residue was directly purified by silica gel column chromatography. The NMR yield was 70%, and the ee value of the product was only 87%.

[0121] Example 2 3-(2S,3R)-5-Methylene-2-(p-tolyl)tetrahydro-2H-pyran-3-yl)benzoisothiazole-1,1-dioxide

[0122] 3-((2S,3R)-5-methylene-2-(p-tolyl)tetrahydro-2H-pyran-3-yl)benzo[d]isothiazole-1,1-dioxide

[0123]

[0124] At room temperature, in a nitrogen atmosphere, (Z)3-(4-methylstyryl)benzoisothiazole 1,1-dioxide (0.3 mmol, 1.0 equiv) and 1,4-dipole (0.3 mmol, 1.0 equiv) were added to a 10 mL vial, followed by Pd2(dba)3 (0.03 mmol, 10 mol%) and R-Binap (0.06 mmol, 20 mol%). Finally, 6 mL of tetrahydrofuran was added. The system was stirred at -20 °C for about 96 h. After determining the end of the reaction by TLC, the reaction mixture was concentrated under reduced pressure, triturated, and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to obtain the corresponding cyclic compound. The yield was 77%, 91% ee. The compound was a white solid.

[0125] NMR data: 11H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 7.5 Hz, 1H), 7.55 (td, J1 = 0.8, J2 = 7.5 Hz, 1H), 7.38 (td, J1 = 0.9, J2 = 7.6 Hz, 1H), 7.15 (d, J = 8.1 Hz, 2H), 7.07 (t, J = 7.8 Hz, 1H), 6.90 (d, J = 7.8 Hz, 2H), 5.07 (d, J = 1.4 Hz, 1H), 4.99 (s, 1H), 4.72 (d, J = 9.3 Hz, 1H), 4.48 (dd, J1 = 1.6, J2 = 12.5 Hz, 1H), 4.32 (d, J = 12.6 Hz, 1H), 3.46 - 3.40 (m, 1H), 3.06 (t, J = 13.6 Hz, 1H), 2.76 - 2.72 (m, 1H), 2.12 (s, 3H) ppm.

[0126] 13 13C NMR (75 MHz, CDCl3) δ 176.5, 140.5, 139.2, 138.1, 136.1, 133.3, 133.2, 130.8, 129.2, 126.3, 123.9, 122.4, 112.1, 83.3, 72.9, 47.1, 36.3, 21.1 ppm. High resolution mass spectrometry data HRMS (CI+) calculated for C 20 H 19 NO3S [M + H] + : 353.2055, found: 353.2057.

[0127] Example 3: 3-((2S,3R)-2-(4-fluorophenyl)-5-methylenetetrahydro-2H-pyran-3-yl)benzo[d]isothiazole-1,1-dioxide

[0128] 3-((2S,3R)-2-(4-fluorophenyl)-5-methylenetetrahydro-2H-pyran-3-yl)benz o[d]isothiazole-1,1-dioxide

[0129]

[0130] At room temperature, in a nitrogen atmosphere, (Z)-3-(4-fluorostyryl)benzisothiazole 1,1-dioxide (0.3 mmol, 1.0 equiv) and 1,4-dipole (0.3 mmol, 1.0 equiv) were added to a 10 mL vial, followed by Pd2(dba)3 (0.03 mmol, 10 mol%) and R-Binap (0.06 mmol, 20 mol%). Finally, 6 mL of tetrahydrofuran was added. The system was stirred at -20 °C for about 96 h. After determining the completion of the reaction by TLC, the reaction mixture was concentrated under reduced pressure, triturated, and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to obtain the corresponding cyclic compound. The yield was 78%, 92% ee. The compound was a white solid.

[0131] NMR data: 1 H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 7.5 Hz, 1H), 7.59 (td, J1 = 0.7, J2 = 7.5 Hz, 1H), 7.45 (td, J1 = 0.8, J2 = 7.5 Hz, 1H), 7.45 (td, J1 = 0.9, J2 = 7.6 Hz, 1H), 7.29 - 7.25 (m, 2H), 7.11 (d, J = 7.7 Hz, 1H), 6.83 - 6.79 (m, 2H), 5.09 (d, J = 1.2 Hz, 1H), 5.01 (s, 1H), 4.76 (d, J = 9.3 Hz, 1H), 4.49 (dd, J1 = 1.5, J2 = 12.6 Hz, 1H), 4.32 (d, J = 13.4 Hz, 1H), 3.43 - 3.37 (m, 1H), 3.05 (t, J = 13.6 Hz, 1H), 2.79 - 2.74 (m, 1H) ppm. 13 C NMR (75 MHz, CDCl3) δ 176.2, 163.8, 161.3, 140.1, 139.4, 135.2, 135.1, 133.6, 130.6, 128.3, 128.2, 123.6, 122.6, 115.6, 115.4, 112.4, 82.6, 72.9, 47.1, 36.3 ppm. 19 F NMR (282 MHz, CDCl3) δ -113.3 ppm. HRMS data: HRMS (CI+) calculated for C 19 H 16 FNO3S [M + H] + : 357.2055, found: 357.2064.

[0132] Example 4: 3-((2S,3R)-5-methylene-2-(4-(trifluoromethyl)phenyl)tetrahydro-2H-pyran-3-yl)benzo[d]isothiazole-1,1-dioxide

[0133] 3-((2S,3R)-5-methylene-2-(4-(trifluoromethyl)phenyl)tetrahydro-2H-pyran-3-yl)benzo[d]isothiazole-1,1-dioxide

[0134]

[0135] At room temperature, under a nitrogen atmosphere, (Z)-3-(4-(trifluoromethyl)styryl)benzo[d]isothiazole 1,1-dioxide (0.3 mmol, 1.0 equivalent) and 1,4-dipole (0.3 mmol, 1.0 equivalent) were added to a 10 mL vial, followed by Pd2(dba)3 (0.03 mmol, 10 mol%) and R-Binap (0.06 mmol, 20 mol%). Finally, 6 mL of tetrahydrofuran was added. The system was stirred at -20 °C for about 96 h. After determining the completion of the reaction by TLC, the reaction mixture was concentrated under reduced pressure, triturated, and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to obtain the corresponding cyclic compound. The yield was 71%, 94% ee. The compound was a white solid.

[0136] NMR data: 1 H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 7.5 Hz, 1H), 7.57 (td, J1 = 0.8, J2 = 7.6 Hz, 1H), 7.43 - 7.36 (m, 5H), 7.03 (d, J = 7.7 Hz, 1H), 5.11 (d, J = 1.0 Hz, 1H), 5.03 (s, 1H), 4.84 (d, J = 9.3 Hz, 1H), 4.51 (dd, J1 = 1.3, J2 = 11.4 Hz, 1H), 4.33 (d, J = 12.6 Hz, 1H), 3.42 - 3.36 (m, 1H), 3.07 (t, J = 12.9 Hz, 1H), 2.81 - 2.76 (m, 1H) ppm. 1313C NMR (75 MHz, CDCl3) δ 175.8, 143.2, 139.8, 139.2, 133.6, 133.5, 130.8, 130.5, 127.0, 125.5, 125.4, 125.3, 125.1, 123.4, 122.7, 122.4, 82.6, 72.8, 47.0, 36.2 ppm. Mass spectrometry data: HRMS (CI+) calculated for C 20 H 16 F3NO3S [M + H] + : 407.2055, found: 407.2062.

[0137] Example 5: 3-((2S,3R)-2-(2-fluorophenyl)-5-methylenetetrahydro-2H-pyran-3-yl)benzo[d]isothiazole-1,1-dioxide

[0138] 3-((2S,3R)-2-(2-fluorophenyl)-5-methylenetetrahydro-2H-pyran-3-yl)benzo[d]isothiazole-1,1-dioxide

[0139]

[0140] At room temperature, under a nitrogen atmosphere, (Z)-3-(2-fluorostyryl)benzoisothiazole 1,1-dioxide (0.3 mmol, 1.0 equiv) and the 1,4-dipole (0.3 mmol, 1.0 equiv) were added to a 10 mL vial, followed by Pd2(dba)3 (0.03 mmol, 10 mol%) and R-Binap (0.06 mmol, 20 mol%). Finally, 6 mL of tetrahydrofuran was added. The system was stirred at -20 °C for about 96 h. After determining the completion of the reaction by TLC, the reaction mixture was concentrated under reduced pressure, triturated, and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to obtain the corresponding cyclic compound. The yield was 79%, 81% ee. The compound was a white solid.

[0141] Nuclear magnetic data: 11H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 7.5 Hz, 1H), 7.57 (t, J = 7.4 Hz, 1H), 7.49 - 7.40 (m, 2H), 7.16 (d, J = 7.7 Hz, 1H), 7.10 - 7.03 (m, 2H), 6.75 - 6.71 (m, 1H), 5.09 (s, 1H), 5.02 (t, J = 4.4 Hz, 2H), 4.49 (dd, J1 = 1.0, J2 = 12.5 Hz, 1H), 4.32 (d, J = 12.5 Hz, 1H), 3.70 - 3.63 (m, 1H), 3.11 (t, J = 13.2 Hz, 1H), 2.79 (dd, J1 = 2.4, J2 = 14.0 Hz, 1H), ppm. 13 13C NMR (282 MHz, CDCl3) δ 175.5, 161.0, 158.5, 140.1, 139.6, 133.4, 133.3, 130.6, 130.4, 130.3, 128.8, 128.7, 126.3, 126.1, 124.6, 123.7, 122.6, 115.9, 115.7, 112.3, 77.8, 73.0, 45.4, 36.2 ppm. 19 19F NMR (282 MHz, CDCl3) δ -115.8 ppm. HRMS (CI+) calculated for C 19 H 16 FNO3S [M + H] + : 357.1899, found: 357.1902.

[0142] Example 6: 3-((2S,3R)-5-methylene-2-(o-tolyl)tetrahydro-2H-pyran-3-yl)benzo[d]isothiazole 1,1-dioxide

[0143] 3-((2S,3R)-5-methylene-2-(o-tolyl)tetrahydro-2H-pyran-3-yl)benzo[d]isothiazo le1,1-dioxide

[0144]

[0145] At room temperature, in a nitrogen atmosphere, (Z)-3-(2-methylstyryl)benzisothiazole 1,1-dioxide (0.3 mmol, 1.0 equiv) and 1,4-dipole (0.3 mmol, 1.0 equiv) were added to a 10 mL vial, followed by Pd2(dba)3 (0.03 mmol, 10 mol%) and R-Binap (0.06 mmol, 20 mol%). Finally, 6 mL of tetrahydrofuran was added. The system was stirred at -20 °C for about 96 h. After determining the completion of the reaction by TLC, the reaction mixture was concentrated under reduced pressure, triturated, and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to obtain the corresponding cyclic compound. The yield was 68%, 52% ee. The compound was a white solid.

[0146] NMR data: 1 H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 7.5 Hz, 1H), 7.56 - 7.49 (m, 2H), 7.39 (td, J1 = 1.0, J2 = 7.6 Hz, 1H), 7.14 - 7.11 (m, 2H), 6.97 (td, J1 = 1.3, J2 = 7.5 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 5.08 (d, J = 1.4 Hz, 1H), 5.02 (d, J = 9.2 Hz, 2H), 4.77 (dd, J1 = 1.6, J2 = 12.5 Hz, 1H), 4.33 (d, J = 12.5 Hz, 1H), 3.63 - 3.57 (m, 1H), 3.13 (t, J = 13.6 Hz, 1H), 2.80 - 2.75 (m, 1H), 2.26 (s, 3H) ppm. 13 C NMR (282 MHz, CDCl3) δ 176.1, 140.5, 139.2, 137.4, 135.4, 133.3, 130.9, 130.5, 128.4, 126.6, 126.3, 124.1, 122.4, 112.1, 79.1, 72.9, 46.7, 36.5, 19.5 ppm. HRMS (CI+) calculated for C 20 H 19 NO3S [M + H] + : 353.1648, found: 353.1651.

[0147] Example 7: 3-(2S,3R)-5-Methylene-2-(m-tolyl)tetrahydro-2H-pyran-3-yl)benzisothiazole-1,1-dioxide

[0148] 3-((2S,3R)-5-Methylene-2-(m-tolyl)tetrahydro-2H-pyran-3-yl)benzo[d]isothiazole-1,1-dioxide

[0149]

[0150] At room temperature, under a nitrogen atmosphere, (Z)-3-(3-methylstyryl)benzoisothiazole 1,1-dioxide (0.3 mmol, 1.0 equiv) and the 1,4-dipole (0.3 mmol, 1.0 equiv) were added to a 10 mL vial, followed by Pd2(dba)3 (0.03 mmol, 10 mol%) and R-Binap (0.06 mmol, 20 mol%). Finally, 6 mL of tetrahydrofuran was added. The system was stirred at -20 °C for about 96 h. After determining the completion of the reaction by TLC, the reaction mixture was concentrated under reduced pressure, triturated, and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to obtain the corresponding cyclic compound. The yield was 71%, 89% ee. The compound was a white solid.

[0151] NMR data: 1 H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 7.5 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.08 - 6.96 (m, 4H), 6.81 (d, J = 7.4 Hz, 1H), 5.08 (s, 1H), 5.00 (s, 1H), 4.70 (d, J = 9.2 Hz, 1H), 4.50 (d, J = 12.4 Hz, 1H), 4.33 (d, J = 12.5 Hz, 1H), 3.44 - 3.38 (m, 1H), 3.09 (t, J = 13.2 Hz, 1H), 2.74 (dd, J1 = 2.3, J2 = 13.8 Hz, 1H), 2.11 (s, 3H) ppm. 13 C NMR (282 MHz, CDCl3) δ 176.5, 140.4, 139.2, 139.0, 138.3, 133.2, 130.9, 129.1, 128.5, 127.1, 123.6, 123.3, 122.2, 112.2, 83.6, 72.9, 47.1, 36.1, 21.2 ppm. Mass spectrometry data: HRMS (CI+) calculated for C 20 H 19 NO3S [M + H] + : 353.1648, found: 353.1651.

[0152] Example 8: 3-((2S,3R)-2-(3-chlorophenyl)-5-methylenetetrahydro-2H-pyran-3-yl)benzo[d]isothiazole-1,1-dioxide

[0153] 3-((2S,3R)-2-(3-chlorophenyl)-5-methylenetetrahydro-2H-pyran-3-yl)benzo[d]isothiazole-1,1-dioxide

[0154]

[0155]

[0156] At room temperature, under a nitrogen atmosphere, (Z)-3-(3-chlorostyryl)benzoisothiazole 1,1-dioxide (0.3 mmol, 1.0 equiv) and the 1,4-dipole (0.3 mmol, 1.0 equiv) were added to a 10 mL vial, followed by Pd2(dba)3 (0.03 mmol, 10 mol%) and R-Binap (0.06 mmol, 20 mol%). Finally, 6 mL of tetrahydrofuran was added. The system was stirred at -20 °C for about 96 h. After determining the completion of the reaction by TLC, the reaction mixture was concentrated under reduced pressure, triturated, and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to obtain the corresponding cyclic compound. The yield was 66%, 93% ee. The compound was a white solid.

[0157] NMR data: 1 H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 7.5 Hz, 1H), 7.58 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.4 Hz, 1H), 7.40 (s, 1H), 7.12 - 6.95 (m, 4H), 5.09 (s, 1H), 5.01 (s, 1H), 4.75 (d, J = 9.3 Hz, 1H), 4.49 (d, J = 12.6 Hz, 1H), 4.32 (d, J = 12.6 Hz, 1H), 3.42 - 3.36 (m, 1H), 3.04 (t, J = 13.2 Hz, 1H), 2.77 (dd, J1 = 2.4, J2 = 13.9 Hz, 1H) ppm. 1313C NMR(282MHz,CDCl3)δ175.9,141.2,139.9,139.4,134.7,133.6,133.5,130.6,129.7,128.6,126.4,125.1,123.6,122.6,112.5,82.6,72.8,46.9,36.3ppm.Mass spectrometry data:HRMS(CI+)calculated for C 19 H 16 ClNO3S[M + H] + :374.1648,found:374.1651.

[0158] Example 9: 3-((2S,3R)-5-methylene-2-(thiophen-2-yl)tetrahydro-2H-pyran-3-yl)benzo[d]isothiazole-1,1-dioxide

[0159] 3-((2S,3R)-5-methylene-2-(thiophen-2-yl)tetrahydro-2H-pyran-3-yl)benzo[d]isothiazole-1,1-dioxide

[0160]

[0161] At room temperature, under a nitrogen atmosphere, (Z)-3-(2-(thiophen-2-yl)vinyl)benzo[d]isothiazole 1,1-dioxide (0.3 mmol, 1.0 equiv) and a 1,4-dipole (0.3 mmol, 1.0 equiv) were added to a 10 mL vial, followed by Pd2(dba)3 (0.03 mmol, 10 mol%) and R-Binap (0.06 mmol, 20 mol%). Finally, 6 mL of tetrahydrofuran was added. The system was stirred at -20 °C for about 96 h. After determining the completion of the reaction by TLC, the reaction mixture was concentrated under reduced pressure, triturated, and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to obtain the corresponding cyclic compound. The yield was 79%, 63% ee. The compound was a white solid.

[0162] NMR data: 11H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 7.5 Hz, 1H), 7.62 (td, J1 = 0.6, J2 = 7.5 Hz, 1H), 7.51 (td, J1 = 0.8, J2 = 7.6 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 7.06 (dd, J1 = 0.8, J2 = 5.0 Hz, 1H), 6.79 (t, J = 3.0 Hz, 1H), 6.61 (q, J = 3.6 Hz, 1H), 5.12 (d, J = 9.4 Hz, 1H), 5.08 (d, J = 1.1 Hz, 1H), 5.01 (s, 1H), 4.49 (dd, J1 = 1.5, J2 = 12.6 Hz, 1H), 4.33 (d, J = 12.6 Hz, 1H), 3.54 - 3.48 (m, 1H), 3.01 (t, J = 12.8 Hz, 1H), 2.78 - 2.73 (m, 1H) ppm. 13 13C NMR (75 MHz, CDCl3) δ 176.4, 140.3, 139.2, 139.1, 133.3, 133.2, 130.7, 128.6, 128.5, 126.4, 123.7, 122.4, 112.2, 83.5, 72.8, 47.1, 36.2 ppm. Mass spectrum data: HRMS (CI+) calculated for C 17 H 15 NO3S2 [M + H] + : 345.2055, found: 345.2065.

[0163] Example 10: 3 - ((2S,3R)-5 - methylene - 2 - (naphthalen - 2 - yl)tetrahydro - 2H - pyran - 3 - yl)benzo[d]isothiazole 1,1 - dioxide

[0164] 3 - ((2S,3R)-5 - methylene - 2 - (naphthalen - 2 - yl)tetrahydro - 2H - pyran - 3 - yl)benzo[d]isothiazole 1,1 - dioxide

[0165]

[0166] At room temperature, under a nitrogen atmosphere, (Z)-3-(2-(naphthalen-2-yl)vinyl)benzo[d]isothiazole 1,1-dioxide (0.3 mmol, 1.0 equiv) and a 1,4-dipole (0.3 mmol, 1.0 equiv) were added to a 10 mL vial, followed by Pd2(dba)3 (0.03 mmol, 10 mol%) and R-Binap (0.06 mmol, 20 mol%). Finally, 6 mL of tetrahydrofuran was added. The system was stirred at -20 °C for about 96 h. After determining the completion of the reaction by TLC, the reaction mixture was concentrated under reduced pressure, triturated, and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to obtain the corresponding cyclic compound. The yield was 64%, with 92% ee. The compound was a white solid.

[0167] NMR data: 1 H NMR (400 MHz, CDCl3) δ 7.70 - 7.60 (m, 5H), 7.44 (dd, J1 = 1.6, J2 = 8.5 Hz, 1H), 7.36 - 7.31 (m, 3H), 7.10 (td, J1 = 0.8, J2 = 7.6 Hz, 1H), 6.95 (d, J = 7.7 Hz, 1H), 5.12 (d, J = 1.2 Hz, 1H), 5.03 (s, 1H), 4.94 (d, J = 9.3 Hz, 1H), 4.55 (dd, J1 = 1.5, J2 = 12.6 Hz, 1H), 4.39 (d, J = 12.6 Hz, 1H), 3.54 - 3.48 (m, 1H), 3.13 (t, J = 13.5 Hz, 1H), 2.81 - 2.76 (m, 1H) ppm. 13 C NMR (282 MHz, CDCl3) δ 176.4, 140.3, 139.1, 136.5, 133.1 (2C), 133.0, 132.9, 130.7, 128.5, 128.1, 127.4, 126.2, 126.1, 125.9, 123.8, 123.4, 122.2, 112.3, 83.5, 72.9, 47.1, 36.3, ppm. Mass spectrometry data: HRMS (CI+) calculated for C 23 H 19 NO3S [M + H] + : 389.1648, found: 389.1651.

[0168] Furthermore, in order to verify the progressiveness of the inhibitory effect of the bis(indolyl)methane prepared in the embodiments of the present invention on tumors, the compound prepared in the embodiments of the present invention was subjected to a tumor cell inhibition test.

[0169] In the embodiments of the present invention, the commercially available drug doxorubicin was used as the control group, and the compounds were used as the experimental group. Mouse mammary tumor cells (4T1), human cervical cancer cells (Hela), and lung cancer cells (A549) were used as tumor test objects. The MTT method was used to detect cell viability: Cells in the logarithmic growth phase were digested, counted, and inoculated into a 96-well culture plate. After 24 h of culture, different concentrations of the compound were co-incubated with tumor cells for 72 h. Then, the supernatant was removed, 100 μL of MTT solution (5 mg / mL) was added, and incubation was continued for 4 h. After removing the supernatant, 150 μL of DMSO was added to each well, and the mixture was shaken and mixed evenly. Then, the absorbance at 550 nm and 700 nm was measured using an enzyme-linked immunosorbent assay (ELISA) reader. The inhibition rate of the compound on tumor cells was calculated. The calculation formula is: Inhibition rate (%) = (Absorbance value of the control group - Absorbance value of the drug-administered group) / (Absorbance value of the control group - Absorbance value of the blank group) × 100%.

[0170] The IC 50 calculation software (China Pharmaceutical University) was used to calculate the half-maximal inhibitory concentration (IC 50 ). The half-maximal inhibitory concentrations (IC 50 ) of the compound against different tumor cells are shown in Table 1 below:

[0171] Table 1

[0172]

[0173] In Examples 1-8 of the present invention, the compounds 3a-3h were prepared, and their cytotoxicity in mouse mammary tumor cells (4T1), lung cancer cells (A549), human cervical cancer cells (Hela), and ovarian cancer cells (A2780) was screened. As shown in the table, on the one hand, these compounds all had good cytotoxicity against mouse mammary tumor cells (4T1), and all had half-maximal inhibitory concentration (IC 50 ) values in the low micromolar range, which were comparable to those of the drug doxorubicin. On the other hand, they also showed certain cytotoxicity in human lung cancer cells (A549), human cervical cancer cells (Hela), and ovarian cancer cells (A2780). Compared with the drug doxorubicin, they also showed very good cytotoxic activity. At the same time, the toxicity of 3a-3h to normal mouse epithelial cells L929 was also tested, and some compounds also showed activity similar to that of doxorubicin and did not show strong cytotoxic activity. The above cases fully demonstrate that the chiral tetrahydrofuran compounds synthesized in the present invention have the potential to become anti-tumor drugs.

[0174] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims

1. A method for synthesizing a chiral tetrahydropyran compound, characterized in that: The synthesis method is as follows: Using an alkenyl imine compound and a 1,4-dipole compound as raw materials, under the catalysis of a Pd2dba3 catalyst and an (R)-BINAP chiral ligand, a chiral tetrahydropyran compound is obtained through a reaction; The reaction conditions are as follows: The reaction is carried out at a temperature ranging from -20 °C to 65 °C, and the reaction time is 96 hours; the organic solvent in the reaction is selected from one of chlorobenzene, toluene, dichloromethane, 1,4-dioxane, tetrahydrofuran, and ethyl acetate; ; The structural formula of the alkenyl imine compound is as shown below: ; The structural formula of the 1,4-dipole compound is as follows: 。 2. The synthesis method of the chiral tetrahydropyran compound according to claim 1, wherein: The molar ratio of the alkenyl imine compound to the 1,4-dipole compound is 1:1; the dosage of the catalyst is 10% of the molar amount of the alkenyl imine compound raw material.

3. The synthesis method of the chiral tetrahydropyran compound according to claim 1, characterized in that: The dosage of the (R)-BINAP chiral ligand is 20% of the molar amount of the alkenyl imine compound raw material.

4. The synthesis method of the chiral tetrahydropyran compound according to claim 1, characterized in that: The organic solvent in the reaction is tetrahydrofuran, and the reaction temperature is -20 °C.

5. A tumor inhibitor, characterized in that, The tumor inhibitor contains a chiral tetrahydropyran compound prepared by the method according to any one of claims 1-4.

6. The tumor inhibitor according to claim 5, wherein The tumor is one or more of human cervical cancer, breast tumor, lung cancer, and ovarian cancer.

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