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

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to an alpha-methenyl-gamma-butyrolactone compound and an asymmetric kinetic resolution synthesis method thereof. The compound provided by the application is shown as formula I. The application provides a simple, efficient and alpha-methenyl-gamma-butyrolactone compound synthesis method. The series of compounds prepared have good antitumor activity and good application prospect.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medical synthesis, and particularly relates to an alpha-methylenyl-gamma-butyrolactone compound and an asymmetric kinetic resolution synthesis method thereof. BACKGROUND

[0002] Alpha-methylenyl-gamma-butyrolactone (AMGBL) skeletons are ubiquitous in numerous natural products and drugs. Natural product databases show that more than 7500 natural products have this skeleton structure, accounting for one seventh of all known unsaturated esters in nature, and 2% of all natural products. AMGBL as a Michael acceptor has high reactivity, enabling them to act as covalent inhibitors by conjugate addition with various proteins. Therefore, compounds containing AMGBL units show a wide range of biological activities. For example, parthenolide exhibits anti-inflammatory, anticancer and antiviral properties, helenalin is anti-inflammatory, and eriolanin is anti-leukemia (structural formula as follows).

[0003]

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

[0005]

[0006] Depending on the allyl reagent used, allylation / lactonization reactions are roughly divided into two types: Barbier-type reactions and allyl boronate reactions. The catalytic asymmetric synthesis of β- or γ-mono-substituted AMGBLs has been achieved by Barbier-type reactions mediated by chiral metal catalysts or organocatalysts. In contrast, β,γ-disubstituted AMGBLs are readily synthesized by allylation / lactonization reactions of (alkoxycarbonyl)allyl boronates 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 auxiliaries. Therefore, it is very meaningful to develop catalytic asymmetric allylation / lactonization reactions in terms of synthetic efficiency and atom economy. SUMMARY

[0007] In view of the problems of the prior art, the present application provides an α-methylene-γ-butyrolactone compound and an asymmetric kinetic resolution synthesis method thereof, aiming to achieve the synthesis of AMGBLs through catalytic asymmetric allylation / lactonization reactions.

[0008] The compound shown in formula I, or a salt thereof, or a crystal form thereof, or a stereoisomer thereof, the structural formula of the compound shown in formula I is as follows:

[0009]

[0010] wherein,

[0011] R 1 , R 2 are each 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, the substituents being 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 fluoroalkyl, C1-C 10ester, 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, the substituents being selected from halogen, cyano, hydroxy, 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 fluoroalkyl, C1-C 10 ester, C1-C 10 sulfonyl, amino, C1-C 10 amine group.

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

[0014] Preferably, the compound has a structure according to any one of formula II, formula III, formula IV or formula V:

[0015]

[0016] wherein,

[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, the substituents being selected from halogen, cyano, hydroxy, 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 fluoroalkyl, C1-C 10 ester, C1-C 10 sulfonyl, amino, C1-C 10 amine.

[0018] Preferably, R 3 selected from substituted or unsubstituted C1-C7alkyl, C4alkenyl, C5-C6cycloalkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-9 membered heteroaryl, the substituents being selected from halogen, cyano, nitro, hydroxyl, C1-C4alkyl, ethynyl, amino, C2amine, methoxy, methylthio, trifluoromethyl, C2ester, 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 application also provides a preparation method of the above-mentioned 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 after the coordination of a Lewis acid and a chiral nitrogen oxygen ligand, and the chiral nitrogen oxygen ligand is selected from L3-RaPr2or its enantiomer ent-L3-RaPr2, and the structural formula of L3-RaPr2is:

[0027]

[0028] wherein R4is selected from C1-C 10 alkyl.

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

[0030] Preferably, in step 1, the reaction is carried out at 30-90°C for 24-120 hours; the reaction medium is toluene or dichloromethane or 1,2-dichloroethane; the ratio of the Lewis acid and the chiral nitroxide ligand is 1:1 to 1:2 by mole; the amount of the Lewis acid or the chiral nitroxide ligand is 1-50 mol% of the starting material 1.

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

[0032]

[0033] In step 2, the product 4 is converted into product 5 through an ester substitution reaction.

[0034] Preferably, in step 2, for the cis product 5, the ester substitution reaction is carried out in the presence of a catalyst selected from the group consisting of p-toluenesulfonic acid, DBU, DABCO, sodium hydroxide, methanesulfonic acid, trifluoroacetic acid, and trifluoromethanesulfonic acid; for the trans product 5, the reaction is carried out in the presence of 1-3 equivalents of triethylamine / methanesulfonyl chloride; the medium for the ester exchange reaction is toluene, dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, diethyl ether, ethyl acetate, methanol, acetonitrile, and benzene; the reaction conditions for the ester substitution reaction are 0-50°C for 1-24 hours.

[0035] Preferably, the medicament is used for treating liver cancer.

[0036] The present application also provides an anti-tumor medicament, which is a medicament containing the above compound, or a salt thereof, or a crystal form thereof, or a stereoisomer thereof as an active substance.

[0037] Preferably, the medicament is used for treating liver cancer.

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

[0039] Definitions of terms used in connection with the present invention: Unless otherwise indicated, the initial definition of a group or term provided herein is intended to apply throughout the description in this document to that group or term; to the extent a term is not specifically defined herein, it should be given its art-recognized meaning by those of ordinary skill in the art based on the disclosure and context.

[0040] "Substituted" means that a hydrogen atom in a molecule is replaced with a different atom or molecule.

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

[0042] "Alkyl" means a saturated hydrocarbon chain having the indicated number of members. For example, C1-C6 alkyl means an alkyl group having from 1 to 6 members, e.g., from 1 to 4 members. The alkyl group can be straight or branched. Representative branched alkyl groups have one, two, or three branches. The alkyl group can be optionally substituted with one or more substituents as defined herein. Alkyl includes methyl, ethyl, propyl (n-propyl and i-propyl), butyl (n-butyl, i-butyl, and t-butyl), pentyl (n-pentyl, i-pentyl, and neopentyl), and hexyl. The alkyl group can also be part of other groups, e.g., C1-C6 alkoxy.

[0043] "Cycloalkyl" means a saturated or partially saturated cyclic group having from 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 multiple ring systems having both aromatic and non-aromatic rings with no ring heteroatoms, the term "cycloalkyl" applies when the point of attachment is to a non-aromatic carbon atom (e.g., 5,6,7,8,- tetrahydronaphthalen-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 that include polycycloalkyl ring systems are bicyclohexyl, bicyclopentyl, bicyclooctyl, and the like. The following are exemplified and named

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

[0045] "Alkynyl" refers to a straight chain monovalent hydrocarbyl radical or branched monovalent hydrocarbyl radical containing at least one triple bond. The term "alkynyl" is also intended to include those hydrocarbyl radicals 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," "heterocycloalkyl" refers 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, a sulfur atom;

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

[0049] "Stereoisomers" include enantiomers and diastereomers;

[0050] The term "pharmaceutically acceptable" means that which is generally compatible with the other ingredients of a pharmaceutical dosage form and / or the recipient of the pharmaceutical dosage form, chemically or physiologically, and generally non-toxic to the recipient at the levels used.

[0051] The terms "salt" and "pharmaceutically acceptable salt" refer to the acid and / or base salts of the compounds described above, or stereoisomers thereof, with inorganic and / or organic acids and bases, also including zwitterions, and also including quaternary ammonium salts, such as alkyl ammonium salts. These salts can be prepared in the final isolation and purification of the compounds. They can also be prepared by admixing the compounds described above, or stereoisomers thereof, with a stoichiometric amount (for example, equivalent) of an acid or a base, in a medium which is a solvent or a mixture of solvents, for example, water, or an organic solvent, or a mixture thereof. These salts can be formed in solution or in solid recovered from a solution, for example, by filtration, or by evaporation of the solvent, or by cold freezing of the solution. The salts of the present application can be hydrochloric, sulfuric, citric, benzenesulfonic, hydrobromic, hydrofluoric, phosphoric, acetic, propionic, succinic, oxalic, malic, succinic, fumaric, maleic, tartaric, or trifluoroacetic acid salts of the compounds.

[0052] This invention develops a method for asymmetric allylation / lactoneation using chiral N,N'-dioxide / Al(III) complexes. This method achieves enantioselectivity through asymmetric kinetic resolution of the allylation intermediate. Consequently, various AMGBL and high-allyl compounds can be obtained with high diastereoselectivity and enantioselectivity. Using chiral catalysts with different configurations and different lactoneation methods, all four stereoisomers of AMGBL can be obtained from the same set of starting materials. This 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 exhibit good inhibitory effects on hepatocellular carcinoma cells.

[0053] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions, or alterations can be made without departing from the basic technical concept of the present invention.

[0054] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Detailed Implementation

[0055] Unless otherwise specified, all reagents and materials used in the following examples and experimental cases are commercially available products.

[0056] Example 1: Standard Reaction

[0057]

[0058] In a glove box, add N,N'-dioxide L3-RaPr2 (14.0 mg, 0.02 mmol), Al(OTf)3 (9.4 mg, 0.02 mmol), and other substances to a dry test tube. MS (30 mg) and 0.5 mL toluene. If benzaldehyde 2 (0.6 mmol) is solid, add it to a test tube in a glove box. After stirring the above mixture at 35 °C for 30 min, add allyl borate 1 (0.2 mmol) and benzaldehyde (if liquid) to the tube using a syringe. After stirring at 60 °C for 45 h, the reaction mixture is subjected to column chromatography on a silica gel column, eluted with petroleum ether / dichloromethane (1:2, v / v) to give the corresponding product 3, and then with petroleum ether / ethyl acetate (2:1, v / v) to give 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] The partial compounds prepared according to the above reaction, their yields and enantioselectivity data are as follows:

[0060]

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

[0062]

[0063] Starting material 2:

[0064]

[0065] Example 2: Synthesis of compounds eupomatilones 2, 5

[0066]

[0067] In a dry test tube in a glove box were added Pd2(dba)3(0.004 mmol, 4 mol%), SPhos (0.008 mmol, 8 mol%), 3a w (0.1 mmol), arylboronic acid (0.25 mmol) and K3PO4(0.3 mmol). 3 mL of toluene were added and the resulting mixture was stirred at 95 °C for 48 h. The reaction mixture was directly submitted to column chromatography on silica gel eluting 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] In a dry test tube were added 1.0 mL of MeOH and epi-5 (0.1 mmol). NaBH4was added at 0 °C and the mixture was stirred at 0 °C for 30 min. TLC monitoring and the mixture was directly submitted to column chromatography on silica gel eluting with petroleum ether / diethyl ether (1 : 1, v / v) to obtain the corresponding product epi-6. The dr and ee values were determined by UPC 2 analysis.

[0071] Example 4: Transformation of compound 4 under acidic and basic conditions

[0072]

[0073] In a dry test tube, 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. The mixture was stirred at 35 °C for 12 h. Column chromatography on silica gel eluted with petroleum ether / ethyl acetate (3 / 1, v / v) gave the product and dr and ee values were determined by HPLC analysis.

[0074] Example 5: Conversion of compound 4 to trans α-methylenyl-γ-butyrolactone

[0075]

[0076] The above standard reaction conditions, by positive and negative configuration chiral ligand respectively obtained positive and negative configuration product 4, to do the next step conversion. In a dry test tube, triethylamine (0.3 mmol), 4ad (0.1 mmol) and 0.2 mL DCM were added. To the test tube was added a solution of MsCl (0.2 mmol) in DCM (0.3 mL) at 0 °C. After stirring at 0 °C for 1 h, the mixture was moved to 35 °C and stirred for another 24 h. The product was isolated by column chromatography (petroleum ether / ethyl acetate (3 / 1, v / v)) and dr and ee values were determined by HPLC analysis.

[0077] The technical solutions of the present application are further illustrated by experiments.

[0078] Experimental Example 1 Determination of biological activity

[0079] I. Experimental methods

[0080] Cell characteristics:

[0081] Hepatoma cell lines HCCLM3 (obtained from Procell) and MHCC97 (obtained from Shanghai Zhijiao Xin Zhou Biotechnology Co., Ltd.) were cultured with 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 a 37 °C, 5% CO2 incubator.

[0082] Cell testing method:

[0083] Cells were cultured in 96-well plates at a density of 2*104 per well. After overnight culture, the cells at 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 FBS DMEM containing 10% (v / v) CCK-8 (Selleck, Houston), and was cultured at 37°C for 1 hour. The absorbance was measured at 450 nm to calculate the cell activity (%).

[0084] II. Experimental results

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

[0086] Inhibition rate of HCCLM3 cells

[0087]

[0088]

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

[0090] Half-inhibitory concentration test

[0091]

[0092]

[0093] The above experimental results show that the compound prepared in the application has a good inhibitory effect on liver cancer cells, and therefore the compound of the application has the potential to be used for preparing an antitumor drug and has a good application prospect.

Claims

1. A process for the preparation of a compound of formula I ###0001### or a salt thereof, characterized in that comprising the following steps: or Step 1, reacting raw material 1 and raw material 2 under the action of a catalyst to obtain product 3 and product 4; the Lewis acid is selected from Al(OTf)3; or Step 2, converting product 4 into product 5 by an ester substitution reaction to obtain the compound shown in formula I; The catalyst is obtained by combining a Lewis acid and a chiral nitroxide ligand, and the chiral nitroxide ligand is selected from L3-RaPr2 or its enantiomer ent-L3-RaPr2, and the structural formula of L3-RaPr2 is as follows: ； wherein R 4 selected from C1-C 10 alkyl; The structural formula of the compound shown in formula I is as follows: Formula I Among them, R 1 , R 2 are each 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, the substituents being selected from halogen, cyano, hydroxy, 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 fluoroalkyl, C1-C 10 ester, C1-C 10 sulfonyl, amino, C1-C 10 amino; R3is 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, the substituents being selected from halogen, cyano, hydroxy, 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 fluoroalkyl, C1-C 10 ester, C1-C 10 sulfonyl, amino, C1-C 10 amine.

2. The preparation method according to claim 1, characterized in that: R 1 , R 2 are each independently selected from the group consisting of H, substituted or unsubstituted C1-C5alkyl, substituted or unsubstituted C2-C4alkenyl, C5-C6cycloalkyl, substituted or unsubstituted phenyl, 5-membered heteroaryl, the substituents being selected from the group consisting of halogen, phenylthio, phenyl, C1-C4alkyl, methoxy, trifluoromethyl.

3. The method of claim 1, wherein: The structural formula of the compound is shown in any one of formula II, formula III, formula IV or formula V: Formula II Formula III Formula IV Formula V Among them, R 3 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, said substituents being selected from the group consisting of halogen, cyano, hydroxy, 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 fluoroalkyl, C1-C 10 ester, C1-C 10 sulfonyl, amino, C1-C 10 amine.

4. The preparation method according to claim 1 or 3, characterized in that: R 3 Selected from substituted or unsubstituted C1-C7 alkyl, C4 alkenyl, C5-C6 cycloalkyl, substituted or unsubstituted C6-C 10 The aryl, substituted or unsubstituted 5-9 membered heteroaryl groups, wherein the substituents are selected from halogen, cyano, nitro, hydroxyl, C1-C4 alkyl, ethynyl, amino, C2 amino, methoxy, methylthio, trifluoromethyl, C2 ester, and methanesulfonyl.

5. The method of claim 1, wherein: The compound shown in formula I is selected from one of the following structural formulas: 。 6. The method of claim 1, wherein: In step 1, the reaction conditions are 30-90 ℃ for 24-120 hours; the reaction medium is toluene or dichloromethane or 1,2-dichloroethane, and the amount ratio of the Lewis acid and the chiral nitroxide ligand is 1:1-1:2; the amount of the Lewis acid or the chiral nitroxide ligand is 1-50 mol% of 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 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 the condition of 1-3 equivalents of triethylamine / methanesulfonyl chloride; the medium of the ester substitution reaction is toluene, dichloromethane, trichloromethane, 1,2-dichloroethane, tetrahydrofuran, diethyl ether, ethyl acetate, methanol, acetonitrile, benzene; the condition of the ester substitution reaction is 0-50 ℃ for 1-24 hours.

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