Alpha-methylene-gamma-butyrolactone compound and asymmetric kinetic resolution synthesis method thereof

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to an alpha-methylene-gamma-butyrolactone compound and an asymmetric kinetic resolution synthesis method thereof. The compound provided by the invention is shown as a formula I. The invention provides a simple and efficient method for synthesizing the alpha-methylene-gamma-butyrolactone compound, and the prepared series of compounds have good anti-tumor activity and good application prospects. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical synthesis, and specifically relates to an alpha-methenyl-gamma-butyrolactone compound and an asymmetric kinetic resolution synthesis method thereof. Background Art

[0002] The α-methoxy-gamma-butyrolactone (AMGBL) skeleton is commonly found in many natural products and drugs. The Natural Products Database shows that more than 7,500 natural products have this skeleton structure, accounting for one-seventh of the unsaturated esters known in nature and 2% of all natural products. AMGBLs are highly reactive as Michael acceptors, enabling them to act as covalent inhibitors through conjugate addition to various proteins. Therefore, compounds containing AMGBL units show a wide range of biological activities. For example, parthenolide exhibits anti-inflammatory, anti-cancer and anti-viral properties, helenalin is anti-inflammatory, and eriolanin is anti-leukemic (structural formula below).

[0003]

[0004] In addition, the substituents and stereochemistry in AMGBL have a great influence on its biological activity, so it is very meaningful to establish its asymmetric synthesis method. In the past 20 years, a series of reliable methods have been established to synthesize AMGBL, including lactonization, halogenation lactonization, allylation / lactonization, olefin coupling cyclization, and ring strain-driven dyotropic rearrangement. Among them, the tandem allylation / lactonization reaction of (alkoxycarbonyl) allyl metal reagents with aldehydes or ketones is one of the most effective strategies. The reaction formula is as follows:

[0005]

[0006] Depending on the allylic reagent used, allylation / lactonization reactions can be roughly divided into two types: Barbier-type reactions and allylic boronation reactions. The catalytic asymmetric synthesis of β- or γ-monosubstituted AMGBLs has been achieved by Barbier-type reactions mediated by chiral metal catalysts or organocatalysts. In contrast, β,γ-disubstituted AMGBLs are easily synthesized by allylation / lactonization reactions of (alkoxycarbonyl)allyl borate esters with aldehydes catalyzed by Lewis acids or Bronsted acids. These reactions have been successfully applied to the synthesis of natural products containing AMGBLs, such as eupomatilones, chinensiolide B, xanthanolide, ovatodiolides, eupalinilide, etc. However, the asymmetric versions of such reactions mainly rely on the chiral induction of chiral auxiliary groups. Therefore, considering the synthetic efficiency and atom economy, it is of great significance to develop catalytic asymmetric allylation / lactonization reactions. Summary of the invention

[0007] In view of the problems of the prior art, the present invention provides an α-methenyl-γ-butyrolactone compound and an asymmetric kinetic resolution synthesis method thereof, aiming to realize the synthesis of AMGBL by catalyzing asymmetric allylation / lactonization reaction.

[0008] The compound represented by formula I, or its salt, or its crystal form, or its stereoisomer, the structural formula of the compound represented by formula I is as follows:

[0009]

[0010] in,

[0011] R 1 , R 2 are independently selected from H, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C2-C 10 Alkenyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-10 membered heterocycloalkyl, wherein the substituent is selected from halogen, cyano, hydroxyl, nitro, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C6-C 10 Aryl, C6-C 10 Arylthio, C1-C 10 Fluorinated alkyl, C1-C 10Ester group, C1-C 10 Sulfonyl, amino, C1-C 10 Amine group;

[0012] R 3 Selected from substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Alkenyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-10 membered heterocycloalkyl, wherein the substituent is selected from halogen, cyano, hydroxyl, nitro, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C6-C 10 Aryl, C6-C 10 Arylthio, C1-C 10 Fluorinated alkyl, C1-C 10 Ester group, C1-C 10 Sulfonyl, amino, C1-C 10 Amine group.

[0013] Preferably, R 1 , R 2 They are independently selected from H, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C2-C4 alkenyl, C5-C6 cycloalkyl, substituted or unsubstituted phenyl, and 5-membered heteroaryl, and the substituents are selected from halogen, phenylthio, phenyl, C1-C4 alkyl, methoxy, and trifluoromethyl.

[0014] Preferably, the compound has a structural formula as shown in any one of Formula II, Formula III, Formula IV or Formula V:

[0015]

[0016] in,

[0017] R 3 Selected from substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Alkenyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the substituent is selected from halogen, cyano, hydroxyl, nitro, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C10 Alkynyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C6-C 10 Aryl, C6-C 10 Arylthio, C1-C 10 Fluorinated alkyl, C1-C 10 Ester group, C1-C 10 Sulfonyl, amino, C1-C 10 Amine group.

[0018] Preferably, R 3 is selected from substituted or unsubstituted C1-C7 alkyl, C4 alkenyl, C5-C6 cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-9 membered heteroaryl, wherein the substituent is selected from halogen, cyano, nitro, hydroxyl, C1-C4 alkyl, ethynyl, amino, C2 amine, methoxy, methylthio, trifluoromethyl, C2 ester, and methylsulfonyl.

[0019] Preferably, R 3 Selected from

[0020] Preferably, the compound of formula I is selected from one of the following structural formulas:

[0021]

[0022]

[0023] The present invention also provides a method for preparing the above compound, or a salt thereof, or a crystal form thereof, or a stereoisomer thereof, comprising the following steps:

[0024]

[0025] Step 1, reacting raw material 1 and raw material 2 under the action of a catalyst to obtain product 3 and product 4;

[0026] The catalyst is obtained by combining a Lewis acid and a chiral nitrogen-oxygen ligand, wherein the chiral nitrogen-oxygen ligand is selected from L3-RaPr2 or its enantiomer ent-L3-RaPr2, and the structural formula of L3-RaPr2 is:

[0027]

[0028] Wherein, R4 is selected from C1-C 10 alkyl.

[0029] Preferably, the Lewis acid is selected from Al(OTf)3, In(OTf)3, Sc(OTf)3, Ga(OTf)3, Yb(OTf)3, Zn(OTf)2, Y(OTf)3, and other lanthanide metal trifluoromethanesulfonates Ln(OTf)3.

[0030] Preferably, in step 1, the reaction conditions are 30-90° C. for 24-120 hours; the reaction medium is toluene or dichloromethane or 1,2-dichloroethane; the Lewis acid and the chiral nitrogen oxide ligand are used in a molar ratio of 1:1 to 1:2; and the amount of the Lewis acid or the chiral nitrogen oxide ligand is 1-50 mol% of the raw material 1.

[0031] Preferably, the method further comprises the following steps:

[0032]

[0033] Step 2, product 4 is converted into product 5 through ester substitution reaction.

[0034] Preferably, in step 2, for the cis product 5, the ester substitution reaction is carried out under the action of a catalyst selected from p-toluenesulfonic acid, DBU, DABCO, sodium hydroxide, methanesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid; for the trans product 5, the reaction is carried out under 1-3 equivalents of triethylamine / methanesulfonyl chloride; the medium of the ester exchange reaction is toluene, dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, ether, ethyl acetate, methanol, acetonitrile, benzene; the conditions of the ester substitution reaction are 0-50°C for 1-24 hours. The present invention also provides the use of the above compound, or its salt, or its crystal form, or its stereoisomer in the preparation of anti-tumor drugs.

[0035] Preferably, the drug is used to treat liver cancer.

[0036] The present invention also provides an anti-tumor drug, which uses the above compound, or its salt, or its crystal form, or its stereoisomer as an active substance and adds a pharmaceutically acceptable salt.

[0037] Preferably, the drug is used to treat liver cancer.

[0038] The compounds and derivatives provided in the present invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0039] Definitions of terms used in the present invention: Unless otherwise stated, the initial definitions provided for groups or terms in this document apply to the groups or terms throughout the specification; for terms that are not specifically defined in this document, the meaning that a person skilled in the art can give them should be given based on the disclosure and context.

[0040] "Substitution" refers to the replacement of a hydrogen atom in a molecule by another different atom or molecule.

[0041] The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix C a -C b Alkyl refers to any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, "C1-C4 alkyl" refers to an alkyl group containing from 1 to 4 carbon atoms.

[0042] "Alkyl" refers to a saturated hydrocarbon chain with a specified number of member atoms. For example, C1-C6 alkyl refers to an alkyl group with 1 to 6 member atoms, such as 1 to 4 member atoms. The alkyl group can be straight or branched. Representative branched alkyl groups have one, two or three branches. The alkyl group may be optionally substituted with one or more substituents as defined herein. Alkyl includes methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) and hexyl. The alkyl group can also be part of other groups, such as C1 to C6 alkoxy.

[0043] "Cycloalkyl" refers to a saturated or partially saturated cyclic group having 3 to 14 carbon atoms and no ring heteroatoms and having a single ring or multiple rings (including fused, bridged and spiro ring systems). For polycyclic systems with aromatic and non-aromatic rings without ring heteroatoms, the term "cycloalkyl" is applicable when the point of attachment is at a non-aromatic carbon atom (e.g., 5,6,7,8,-tetrahydronaphthalene-5-yl). The term "cycloalkyl" includes cycloalkenyl groups such as cyclohexenyl. Examples of cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl and cyclohexenyl. Examples of cycloalkyl groups including polybicycloalkyl ring systems are bicyclohexyl, bicyclopentyl, bicyclooctyl, etc. The following are listed and named

[0044] Two such bicycloalkyl polycyclic structures: Biscyclohexyl and Bicyclohexyl. "Alkenyl" refers to a straight or branched chain hydrocarbon group having 2 to 10 carbon atoms, and in some embodiments 2 to 6 carbon atoms or 2 to 4 carbon atoms, and having at least 1 site of vinyl unsaturation (>C=C<). For example, (Ca-Cb)alkenyl refers to an alkenyl group having a to b carbon atoms and is intended to include, for example, vinyl, propenyl, isopropenyl, 1,3-butadienyl, and the like.

[0045] "Alkynyl" refers to a straight chain monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical containing at least one triple bond. The term "alkynyl" is also intended to include those hydrocarbon groups having one triple bond and one double bond. For example, (C2-C6)alkynyl is intended to include ethynyl, propynyl, and the like.

[0046] "Halogen" is fluorine, chlorine, bromine or iodine.

[0047] "Heterocycle" and "heterocycloalkyl" refer to a saturated ring or a non-aromatic unsaturated ring containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, or a sulfur atom;

[0048] "Aromatic heterocycle" refers to an aromatic unsaturated ring containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, or a sulfur atom;

[0049] "Stereoisomers" include enantiomers and diastereomers;

[0050] The term "pharmaceutically acceptable" means that a carrier, vehicle, diluent, excipient, and / or formed salt is generally chemically or physically compatible with the other ingredients that constitute a pharmaceutical dosage form and physiologically compatible with the receptor.

[0051] The terms "salt" and "pharmaceutically acceptable salt" refer to acidic and / or basic salts of the above-mentioned compounds or their stereoisomers, formed with inorganic and / or organic acids and bases, and also include zwitterionic salts (inner salts), and also include quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final separation and purification of the compound. It can also be obtained by mixing the above-mentioned compound, or its stereoisomer, with a certain amount of acid or base appropriately (e.g., equivalent). These salts may form a precipitate in the solution and be collected by filtering, or be recovered after solvent evaporation, or be obtained by freeze drying after reaction in an aqueous medium. The salt described in the present invention can be a hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate of the compound.

[0052] The present invention develops a method for achieving asymmetric allylation / lactonization using a chiral N,N'-dioxide / Al(III) complex. The method achieves enantioselectivity by asymmetric kinetic resolution of the allylation intermediate. Thus, various AMGBL and homoallylic alcohol compounds can be obtained with high diastereo- and enantioselectivity. Using chiral catalysts of different configurations and different lactonization methods, all four stereoisomers of AMGBL can be obtained from the same set of starting materials. The method can also be applied to the catalytic asymmetric total synthesis of natural products eupomatilones 2,5,6. Some chiral products synthesized by this method have a good inhibitory effect on hepatocellular carcinoma cells.

[0053] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

[0054] The following is a further detailed description of the above contents of the present invention through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies implemented based on the above contents of the present invention belong to the scope of the present invention. DETAILED DESCRIPTION

[0055] In the following embodiments and experimental examples, reagents and materials not specifically described are all commercially available.

[0056] Example 1: Standard reaction

[0057]

[0058] In a glove box, N,N'-dioxide L3-RaPr2 (14.0 mg, 0.02 mmol), Al(OTf)3 (9.4 mg, 0.02 mmol), MS. (30 mg) and 0.5 mL toluene. If benzaldehyde 2 (0.6 mmol) is solid, add a test tube in the glove box. After the above mixture is stirred at 35 ° C for 30 minutes, allyl borate ester 1 (0.2 mmol) and benzaldehyde (if liquid) are added to the tube by syringe. After stirring at 60 ° C for 45 hours, the reaction mixture is subjected to column chromatography on a silica gel column and eluted with petroleum ether / dichloromethane (1: 2, v / v) to obtain the corresponding product 3, and then with petroleum ether / ethyl acetate (2: 1, v / v) to obtain 4. If necessary, products 3 and 4 can be further purified by column chromatography (eluent: petroleum ether / diethyl ether = 4 / 1 to 1: 1, v / v). The diastereomeric ratio and enantiomeric excess are determined by HPLC analysis using a chiral stationary phase.

[0059] Some of the compounds prepared according to the above reaction, their yields and enantioselectivity data are as follows:

[0060]

[0061] In addition, the optional substrates for the standard reaction also include: Raw material 1 (where R 4 =Et or Me):

[0062]

[0063] Ingredients 2:

[0064]

[0065] Example 2: Synthesis of Compound Eupomatilones 2,5

[0066]

[0067] Pd2(dba)3 (0.004mmol, 4mmol%), SPhos (0.008mmol, 8mol%), 3aw (0.1mmol), arylboronic acid (0.25mmol) and K3PO4 (0.3mmol) were added to a dry test tube in a glove box. 3mL of toluene was added and the resulting mixture was stirred at 95°C for 48 hours. The reaction mixture was directly subjected to column chromatography on silica gel and eluted with petroleum ether / diethyl ether (1:1, v / v) to obtain the product. The dr and ee values ​​were determined by HPLC analysis.

[0068] Example 3: Synthesis of compound eupomatilones 2

[0069]

[0070] 1.0 mL MeOH and epi-5 (0.1 mmol) were added to a dry test tube. NaBH4 was added at 0°C and the mixture was stirred at 0°C for 30 minutes. TLC monitoring was performed on the silica gel column chromatography, and the mixture was eluted with petroleum ether / diethyl ether (1:1, v / v) to obtain the corresponding product epi-6. 2 Analyze and determine the dr and ee values.

[0071] Example 4: Conversion of Compound 4 under acid-base conditions

[0072]

[0073] Toluenesulfonic acid (p-TSA, 0.02 mmol, 3.4 mg) or DBU (0.02 mmol, 3.6 μL), 4aa (0.1 mmol, 23.4 mg) and 1 mL DCM were added to a dry test tube. The mixture was stirred at 35° C. for 12 hours. Column chromatography was performed on silica gel, eluted with petroleum ether / ethyl acetate (3 / 1, v / v) to obtain the product, and the dr and ee values ​​were determined by HPLC analysis.

[0074] Example 5: Conversion of Compound 4 into trans-α-methenyl-γ-butyrolactone

[0075]

[0076] Under the above standard reaction conditions, the forward and reverse configuration chiral ligands were used to obtain the forward and reverse configuration products 4, respectively, for the next step of transformation. Triethylamine (0.3 mmol), 4ad (0.1 mmol) and 0.2 mL DCM were added to a dry test tube. A solution of MsCl (0.2 mmol) in DCM (0.3 mL) was added to the test tube at 0°C. After stirring at 0°C for 1 hour, the mixture was moved to 35°C and stirred for another 24 hours. The products were separated by column chromatography (petroleum ether / ethyl acetate (3 / 1, v / v)) and the dr and ee values ​​were determined by HPLC analysis.

[0077] The technical solution of the present invention is further illustrated by experiments below.

[0078] Experimental Example 1 Determination of biological activity

[0079] 1. Experimental Methods

[0080] Cell characteristics:

[0081] Hepatoma cell lines HCCLM3 (obtained from Procell) and MHCC97 (obtained from Shanghai Zhongqiao Xinzhou Biotechnology Co., Ltd.) were cultured in Dulbecco's modified Eagle's medium (DMEM; Hyclone, Utah) supplemented with 10% (v / v) FBS (Gibco, New York), 1% (v / v) penicillin / streptomycin (Beyotime, Shanghai). All cells were cultured in an incubator at 37°C and 5% CO2.

[0082] Cell test method:

[0083] Cells were cultured in 96-well plates at a density of 2*104 per well. After overnight, cells with a density of 80% were treated with 1% DMSO (negative control) and the test compound at different concentrations for 24 hours. Each well was not added with FBSDMEM containing 10% (v / v) CCK-8 (Selleck, Houston) and cultured at 37°C for 1 hour. The absorbance was measured at 450nm to calculate the cell activity (%).

[0084] 2. Experimental Results

[0085] The results are shown in the table below:

[0086] HCCLM3 cell inhibition rate

[0087]

[0088]

[0089] Note: (R,S)-3ad, (S,R)-3ad, (S,S)-3ad, (R,R)-3ad represent the four stereoisomers of compound 3ad (the same below).

[0090] Half Inhibitory Concentration Test

[0091]

[0092]

[0093] The above experimental results show that the compound prepared by the present invention has a good inhibitory effect on liver cancer cells. Therefore, the compound of the present invention has the potential to be used in the preparation of anti-tumor drugs and has a good application prospect.

Claims

1. A compound of formula I, or a salt thereof, or a crystal form thereof, or a stereoisomer thereof, characterized in that: The structural formula of the compound shown in Formula I is as follows: in, R 1 , R 2 are independently selected from H, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C2-C 10 Alkenyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-10 membered heterocycloalkyl, wherein the substituent is selected from halogen, cyano, hydroxyl, nitro, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C6-C 10 Aryl, C6-C 10 Arylthio, C1-C 10 Fluorinated alkyl, C1-C 10 Ester group, C1-C 10 Sulfonyl, amino, C1-C 10 Amine group; R3 is selected from substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Alkenyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-10 membered heterocycloalkyl, wherein the substituent is selected from halogen, cyano, hydroxyl, nitro, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C6-C 10 Aryl, C6-C 10 Arylthio, C1-C 10 Fluorinated alkyl, C1-C 10 Ester group, C1-C 10 Sulfonyl, amino, C1-C 10 Amine group.

2. The compound according to claim 1, or its salt, or its crystal form, or its stereoisomer, characterized in that: R 1 , R 2 They are independently selected from H, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C2-C4 alkenyl, C5-C6 cycloalkyl, substituted or unsubstituted phenyl, and 5-membered heteroaryl, and the substituents are selected from halogen, phenylthio, phenyl, C1-C4 alkyl, methoxy, and trifluoromethyl.

3. The compound according to claim 1, or its salt, or its crystal form, or its stereoisomer, characterized in that: The structural formula of the compound is shown in any one of Formula II, Formula III, Formula IV or Formula V: in, R 3 Selected from substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Alkenyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the substituent is selected from halogen, cyano, hydroxyl, nitro, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C6-C 10 Aryl, C6-C 10 Arylthio, C1-C 10 Fluorinated alkyl, C1-C 10 Ester group, C1-C 10 Sulfonyl, amino, C1-C 10 Amine group.

4. The compound according to claim 1 or 3, or its salt, or its crystal form, or its stereoisomer, characterized in that: R 3 is selected from substituted or unsubstituted C1-C7 alkyl, C4 alkenyl, C5-C6 cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-9 membered heteroaryl, wherein the substituent is selected from halogen, cyano, nitro, hydroxyl, C1-C4 alkyl, ethynyl, amino, C2 amine, methoxy, methylthio, trifluoromethyl, C2 ester, and methylsulfonyl.

5. The compound according to claim 1, or its salt, or its crystal form, or its stereoisomer, characterized in that: The compound of formula I is selected from one of the following structural formulas:

6. A method for preparing the compound according to any one of claims 1 to 5, or a salt thereof, or a crystal form thereof, or a stereoisomer thereof, characterized in that: The steps include: Step 1, reacting raw material 1 and raw material 2 under the action of a catalyst to obtain product 3 and product 4; Step 2, product 4 is converted into product 5 through ester substitution reaction; The catalyst is obtained by combining a Lewis acid and a chiral nitrogen-oxygen ligand, wherein the chiral nitrogen-oxygen ligand is selected from L3-RaPr2 or its enantiomer ent-L3-RaPr2, and the structural formula of L3-RaPr2 is: Among them, R 1 , R 2 , R 3 As described in any one of claims 1 to 5, R 4 Selected from C1-C 10 alkyl.

7. The preparation method according to claim 6, characterized in that: The Lewis acid is selected from Al(OTf)3, In(OTf)3, Sc(OTf)3, Ga(OTf)3, Yb(OTf)3, Zn(OTf)2, Y(OTf)3, and lanthanide metal triflate Ln(OTf3; And / or, in step 1, the reaction conditions are 30-90° C. for 24-120 hours; the reaction medium is toluene or dichloromethane or 1,2-dichloroethane, the Lewis acid and the chiral nitrogen oxide ligand are used in a molar ratio of 1:1-1:2; the amount of the Lewis acid or the chiral nitrogen oxide ligand is 1-50 mol% of the raw material 1; And / or, in step 2, for the cis product 5, the ester substitution reaction is carried out under the action of a catalyst, and the catalyst is selected from p-toluenesulfonic acid, DBU, DABCO, sodium hydroxide, methanesulfonic acid, trifluoroacetic acid, and trifluoromethanesulfonic acid; for the trans product 5, the reaction is carried out under 1-3 equivalents of triethylamine / methanesulfonyl chloride; the medium of the ester exchange reaction is toluene, dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, ether, ethyl acetate, methanol, acetonitrile, and benzene; the conditions of the ester substitution reaction are 0-50° C. and 1-24 hours.

8. Use of the compound according to any one of claims 1 to 5, or its salt, or its crystal form, or its stereoisomer in the preparation of an anti-tumor drug.

9. The use according to claim 8, characterized in that: The medicine is used to treat liver cancer.

10. An anti-tumor drug, characterized in that: The invention uses the compound described in any one of claims 1 to 5, or its salt, or its crystal form, or its stereoisomer as an active substance, and adds a pharmaceutically acceptable salt.

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