Chiral cis-hydrobenzofuran compounds and methods for their preparation

Abstract

The application discloses a chiral cis-hydrobenzofuran compound and a preparation method thereof. A mixture containing a compound shown in a formula I, a compound shown in a formula II, an oxidant and a catalyst is subjected to asymmetric acyloxylation cyclization reaction to obtain a chiral cis-hydrobenzofuran shown in a formula III. Through the method, the cis-hydrobenzofuran with optical purity (the enantiomer ratio can reach 98:2) can be obtained at a high yield. The application has high enantioselectivity, a wide substrate range, simple operation, mild reaction conditions, low energy consumption, environmental friendliness and good yield.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of asymmetric catalytic synthesis, and relates to a kind of asymmetric acyloxylation cyclization reaction of alkynyl cyclohexadienone by palladium catalysis, and a kind of chiral cis-hydrobenzofuran compound and its preparation method are provided. BACKGROUND

[0002] Chiral cis-hydrobenzofuran is a structural unit commonly present in natural products and biologically active molecules.Transition metal-catalyzed asymmetric cascade reaction of alkynyl cyclohexadienone is an effective way to obtain chiral cis-hydrobenzofuran.In 2013, Harned group reported that asymmetric acetoxylation cyclization reaction of alkynyl cyclohexadienone was realized based on pinene-derived chiral bipyridine ligand.The reaction can synthesize chiral cis-hydrobenzofuran compounds with excellent yield, and such compounds can be used as inhibitors of NF-κB signaling.However, there are limitations in the reaction as follows:(1) the enantioselectivity of the product is difficult to control;(2) acetic acid is used as both a reactant and a solvent in the reaction.(Reference One: Tello-Aburto, R.;Kalstabakken, K.A.;Harned, A.M.Org. Biomol. Chem.2013, 11, 5596-5604.)

[0003] Therefore, it is an extremely attractive research direction to develop a simple, effective, high-yield and high-enantioselectivity method for synthesizing chiral cis-hydrobenzofuran. SUMMARY

[0004] The purpose of the present application is to provide a method for synthesizing chiral cis-hydrobenzofuran by palladium-catalyzed asymmetric acyloxylation cyclization of alkynyl cyclohexadienone.

[0005] In one aspect, the present application provides a method for preparing chiral cis-hydrobenzofuran, which comprises mixing a compound shown in formula I, a compound shown in formula II, an oxidizing agent and a catalyst, and then performing asymmetric acyloxylation cyclization reaction to obtain chiral cis-hydrobenzofuran shown in formula III.

[0006]

[0007] In formula I, formula II and formula III:

[0008] R is selected from one of benzyl, phenyl or C1-C 20 alkyl, tert-butyldimethylsiloxy;

[0009] R' is selected from methyl, phenyl, substituted phenyl Ph1, heteroaryl or substituted heteroaryl; the heteroaryl is a five-membered heterocyclic group with a heteroatom S in its skeleton; the substituents of substituted phenyl Ph1 and substituted heteroaryl are independently selected from at least one of methyl, methoxy, acetyl, fluorine, chlorine and bromine;

[0010] R” is selected from methyl, ethyl, isopropyl, phenyl or substituted phenyl Ph2; the substituent of substituted phenyl Ph2 is selected from methyl, acetoxy, sulfonamide;

[0011] X is an O or p-toluenesulfonamide group.

[0012] Optionally, the heteroaryl group is a thienyl group.

[0013] Optionally, the catalyst is a chiral dinitrogen complex of palladium.

[0014] Optionally, the molar ratio of the compound shown in Formula I to the compound shown in Formula II is 1:10 to 1:85, the molar ratio of the compound shown in Formula I to the oxidant is 1:0.1 to 1:0.6, and the molar ratio of the compound shown in Formula I to the chiral dinitrogen complex of palladium is 1:0.02 to 1:0.1.

[0015] Optionally, the oxidant is selected from metal oxidants or non-metal oxidants.

[0016] Optionally, the oxidant is selected from benzoquinone, silver acetate, or oxygen.

[0017] Optionally, when the oxidant is not oxygen, the reaction atmosphere is an inactive atmosphere, preferably nitrogen.

[0018] Alternatively, when oxygen is used as the oxidant, the mixture is first stirred under a nitrogen atmosphere, and then the nitrogen is replaced with oxygen to carry out the reaction.

[0019] Optionally, the solvent Y1 in the reaction is selected from at least one of 1,2-dichloroethane, ethyl acetate, toluene, tetrahydrofuran, and methyl tert-butyl ether.

[0020] Optionally, the reaction temperature is 60°C to 80°C.

[0021] Optionally, the reaction time is 20 to 48 hours.

[0022] On the other hand, the present invention provides a class of chiral cis-hydrobenzofuran compounds having the structure shown in Formula III;

[0023]

[0024] In Formula III:

[0025] R is selected from benzyl, phenyl, or C1-C. 20One of alkyl or tert-butyldimethylsiloxy;

[0026] R' is selected from methyl, phenyl, substituted phenyl Ph1, heteroaryl, or substituted heteroaryl; the heteroaryl is a five-membered heterocyclic group with a heteroatom S in its skeleton; the substituents of substituted phenyl Ph1 and substituted heteroaryl are independently selected from at least one of methyl, methoxy, acetyl, fluorine, chlorine, and bromine; the heteroaryl is preferably thiophene.

[0027] R” is selected from methyl, ethyl, isopropyl, phenyl or substituted phenyl Ph2; the substituent of substituted phenyl Ph2 is selected from methyl, acetoxy, sulfonamide;

[0028] X is an O or p-toluenesulfonamide group.

[0029] Optionally, the chiral cis-hydrobenzofuran compound is selected from any one of the structures shown in 3aa, 3ba, 3ca, 3da, 3ea, 3fa, 3ga, 3ha, 3ia, 3ja, 3ka, 3la, 3ma, 3na, 3oa, 3pa, 3qa, 3ra, 3sa, 3ta, 3ua, 3va, 3wa, 3xa, 3tb, 3tc, 3td, 3te, 3tf, and 3tg.

[0030]

[0031]

[0032] As one preferred embodiment, the specific reaction steps of the method are as follows: under nitrogen protection, palladium acetate, a chiral dinitrogen ligand and the compound shown in Formula II are added to a sealed tube, followed by the addition of solvent Y1. After stirring at room temperature for 120 min, the compound shown in Formula I and an oxidant are added under nitrogen. After stirring at 60 °C for 20-48 h, the solvent Y1 is evaporated, and pure chiral cis-hydrobenzofuran is obtained by column chromatography.

[0033] The term "C1~C" used in this article 20 "alkyl" refers to a straight-chain or branched alkyl group having 1-20 carbon atoms; preferably "C1-C2". 20 "alkyl" includes methyl, ethyl, n-propyl, isopropyl, etc.

[0034] The term “heteroaryl” as used herein is selected from 5-membered ring heteroaryl, which refers to a 5-membered monocyclic aromatic heterocycle containing one or more (e.g., 1 to 3) sulfur atoms in addition to carbon atoms, such as thienyl, etc. Examples include 2thienyl, etc.

[0035] The aforementioned chiral dinitrogen complex of palladium refers to a mixture containing a palladium precursor and a planar chiral dinitrogen compound, which coordinate to form the chiral dinitrogen complex of palladium.

[0036] Optionally, the palladium precursor is selected from palladium acetate or palladium trifluoroacetate.

[0037] Optionally, the molar ratio of the palladium precursor to the planar chiral bis-nitrogen compound is 1:1.1-1:2.

[0038] Optionally, the mixture further comprises a solvent Y1 selected from at least one of 1,2-dichloroethane, ethyl acetate, toluene, tetrahydrofuran, methyl tert-butyl ether.

[0039] The molar concentration of the palladium precursor in the solvent Y1 is 0.002-0.01 mol / L.

[0040] The planar chiral bis-nitrogen compound has a structure shown in Formula I,

[0041]

[0042] In Formula 1:

[0043] The ring A is a heteroaryl containing at least one heteroatom;

[0044] The heteroatom is selected from N;

[0045] R0 is selected from one of H, C1-C3 alkyl, C1-C3 alkoxy, C2-C4 alkoxy carbonyl.

[0046] As an optional technical solution, the ring A is a heteroaryl containing 1-3 heteroatoms.

[0047] Further optionally, the ring A is a heteroaryl containing 1 N atom.

[0048] As an optional technical solution, the heteroaryl is a monocyclic heteroaryl; the monocyclic heteroaryl is a 6-membered ring heteroaryl.

[0049] Further optionally, the monocyclic heteroaryl is a pyridyl.

[0050] As an optional technical solution, the heteroaryl is a fused ring heteroaryl; the fused ring heteroaryl is a 10-membered fused bicyclic heteroaryl.

[0051] Optionally, the fused ring heteroaryl is selected from isoquinolyl.

[0052] As an optional technical solution, the C1-C3 alkyl is selected from methyl.

[0053] As an optional technical solution, the C1-C3 alkoxy is selected from methoxy.

[0054] As an optional technical solution, the C2-C4 alkoxy carbonyl group is selected from -CO-OCH3.

[0055] Further optionally, the planar chiral bisazide compound is selected from one of L1, L2, L3, L4, L5, L6, L7, and L8.

[0056]

[0057] Optionally, the planar chiral bisazide compound is in the R configuration.

[0058] The preparation method of any one of the above planar chiral bisazide compounds, one embodiment of which is prepared by method one;

[0059] The method one is a mixture solution a containing a compound shown in formula 2, a compound shown in formula a1, and a solvent Y2, which undergoes a condensation reaction a in an inactive atmosphere to obtain a planar chiral bisazide compound shown in formula 1.

[0060]

[0061] As an optional technical solution, in the method one:

[0062] The molar ratio of the compound shown in formula 2 to the compound shown in formula a1 is 1:1.1-1:1.5.

[0063] The molar concentration of the compound shown in formula 2 in the solvent Y2 is 0.2-0.5 mol / L.

[0064] Optionally, the reaction conditions of the condensation reaction a are a temperature of 40-60°C and a reaction time of 24-72 hours; optionally, the temperature of the condensation reaction a is selected from any value or any value between any two points of 40°C, 50°C, and 60°C; optionally, the reaction time of the condensation reaction a is selected from any value or any value between any two points of 24 hours, 48 hours, and 72 hours.

[0065] Optionally, the inactive atmosphere in the condensation reaction a is selected from at least one of nitrogen and argon.

[0066] Optionally, the solvent Y2 is selected from at least one of methanol, tetrahydrofuran, diethyl ether, and dioxane.

[0067] The preparation method of any one of the above planar chiral bisazide compounds, another embodiment of which is prepared by method two, the method two including a condensation reaction b and a cyclization reaction.

[0068]

[0069] The mixed solution b containing the compound shown in formula 2, the compound shown in formula b1, a base, a condensing agent and a solvent Y3 is subjected to a condensation reaction b in an inactive atmosphere to obtain a compound shown in formula b2;

[0070]

[0071] The mixed solution c containing the compound shown in formula b2, an acid and a solvent Y4 is subjected to a cyclization reaction in an inactive atmosphere to obtain the planar chiral bisazide compound shown in formula 1.

[0072] As an optional technical solution, in the method two:

[0073] The molar ratio of the compound shown in formula 2 to the compound shown in formula b1 is 1:1.1-1:1.5;

[0074] The molar ratio of the compound shown in formula b1 to the base is 1:1.5-1:3;

[0075] The molar ratio of the compound shown in formula b1 to the condensing agent is 1:1-1:1.2;

[0076] The molar concentration of the compound shown in formula 2 in the solvent Y3 is 0.1-0.3 mol / L.

[0077] Optionally, the reaction condition of the condensation reaction b is 0-25℃, and the reaction time is 5-10 hours; optionally, the temperature of the condensation reaction b is selected from any value or any value between any two points of 0℃, 5℃, 10℃, 15℃, 20℃ and 25℃; and the reaction time of the condensation reaction b is selected from any value or any value between any two points of 5 hours, 6 hours, 8 hours and 10 hours.

[0078] Optionally, the compound shown in formula 2, the compound shown in formula b1 and the base are mixed with the solvent, then cooled to 0℃ due to the heat released by the reaction, and then the condensing agent is added. Optionally, the inactive atmosphere in the condensation reaction b is selected from at least one of nitrogen and argon.

[0079] Optionally, the base is selected from at least one of N,N-diisopropylethylamine, diisopropylamine and triethylamine.

[0080] Optionally, the condensing agent is selected from at least one of N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate, benzotriazol-N,N,N',N'-tetramethyl urea hexafluorophosphate, diisopropyl carbodiimide and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide.

[0081] Optionally, the solvent Y3 is selected from at least one of N,N-dimethylformamide, N,N-dimethylacetamide and acetonitrile.

[0082] Optionally, the molar ratio of the compound of formula b2 to the acid is 1:1.2-1:1.5.

[0083] The molar concentration of the compound of formula b2 in the solvent Z is 0.05-0.1 mol / L.

[0084] Optionally, the condition of the cyclization reaction is 120-150℃, and the reaction time is 10-20 hours; optionally, the temperature of the cyclization reaction is selected from any value or any value between any two points of 120℃, 130℃, 140℃, 150℃; the reaction time of the cyclization reaction is selected from any value or any value between any two points of 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours.

[0085] Optionally, the non-reactive atmosphere in the cyclization reaction is selected from at least one of nitrogen, argon.

[0086] Optionally, the acid is selected from at least one of p-toluenesulfonic acid monohydrate, methanesulfonic acid, acetic acid.

[0087] Optionally, the solvent Y4 is selected from at least one of p-xylene, m-xylene, toluene.

[0088] The term "C1-C3 alkyl" as used herein refers to straight-chain or branched-chain alkyl groups having 1-3 carbon atoms; preferred "C1-C3 alkyl" groups include methyl, ethyl, n-propyl, i-propyl, and the like.

[0089] The term "C1-C3 alkoxy" as used herein refers to an alkoxy group in which the alkyl moiety is as defined above for "C1-C3 alkyl"; preferred "C1-C3 alkoxy" groups include methoxy, ethoxy, n-propoxy, i-propoxy.

[0090] The term "C2-C4 alkoxycarbonyl" as used herein refers to the group -CO-OR', wherein OR' is an alkoxy group as defined above for "C1-C3 alkoxy"; preferred "C2-C4 alkoxycarbonyl" groups include methoxycarbonyl, ethoxycarbonyl, and the like.

[0091] The term "Ring A" as used herein can be a 6-membered ring heteroaryl. A "6-membered ring heteroaryl" refers to a 6-membered monocyclic aromatic heterocycle containing one or more (e.g., 1-3) nitrogen atoms, oxygen atoms, or sulfur atoms in addition to carbon atoms, such as pyridine, pyridazine, pyrimidine, pyrazine, triazine, and the like. Examples of "6-membered ring heteroaryl" groups include: pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl (e.g., 3-pyridazinyl), pyrimidinyl (e.g., 5-pyrimidinyl), pyrazinyl (e.g., 2-pyrazinyl), and the like.

[0092] The term "ring A" used herein can be further fused to form an optionally substituted fused ring heteroaryl. "Further fused" means that the aromatic ring is further fused at a position in ring A that is capable of being fused. For example, when ring A is a "6-membered ring heteroaryl", a 10-membered fused bicyclic heteroaryl is formed in which the 6-membered ring heteroaryl is fused to a phenyl group.

[0093] Examples of the group of the 10-membered fused bicyclic heteroaryl include quinolinyl, isoquinolinyl, and the like.

[0094] The term "alkoxycarbonyl" used herein means an alkoxy group attached to the parent molecular moiety through a carbonyl group.

[0095] The term "alkoxycarbonylalkyl" used herein means an alkyl group substituted with 1, 2, or 3 alkoxycarbonyl groups.

[0096] The term "lower alkoxycarbonyl" means the group -CO-OR', wherein R' is lower alkyl and the term "lower alkyl" has the previously given meaning. Preferred lower alkoxycarbonyl groups include -CO-OCH3(methoxycarbonyl), and the like.

[0097] Beneficial effects: The asymmetric acyloxy-cyclization reaction of palladium-catalyzed alkynyl cyclohexadienone can be realized by the method of the present application, and cis-hydrobenzofuran with high optical purity can be obtained in high yield, with an enantiomeric ratio of 98:2. The present application has high enantioselectivity, a wide substrate range, simple and practical operation, readily available raw materials, high catalytic activity, complete conversion of raw materials, easy separation, and high-purity products; the product has good stereoselectivity, and cis-hydrobenzofuran can be obtained with high enantioselectivity; the reaction conditions are mild, energy consumption is low, the environment is friendly, and the yield is good. BRIEF DESCRIPTION OF DRAWINGS

[0098] Figure 1 X-ray single crystal diffraction test chart of compound 3ga of the present application. DETAILED DESCRIPTION

[0099] The present application is described in detail below by way of examples, but the present application is not limited to the following examples.

[0100] The synthesis of the raw material acetylenyl cyclohexadienone compound in the following examples is described in the references (a) Gollapelli, K. K.; Donikela, S.; Manjula, N.; Chegondi, R. ACS Catal. 2018, 8, 1440-1447. (b) Xu, D.; Zhao, Y.; Song, D.; Zhong, Z.; Feng, S.; Xie, X.; Wang, X.; She, X. Org. Lett. 2017, 19, 3600-3603. (c) Banfield, S. C.; Kerr, M. A. Can. J. Chem. 2004, 82, 131-138. (d) Tello-Aburto, R.; Kalstabakken, K. A.; Harned, A. M. Org. Biomol. Chem. 2013, 11, 5596-5604. (e) Wu, W.; Chen, T.; Chen, J.; Han, X. J. Org. Chem. 2018, 83, 1033-1040.

[0101] The present application synthesizes chiral cis-hydrobenzofuran by palladium-catalyzed asymmetric acyloxychlorination of acetylenyl cyclohexadienone, uses a chiral bidentate nitrogen complex of palladium as a catalyst, and uses acetylenyl cyclohexadienone and a carboxylic acid compound as substrates to construct cis-hydrobenzofuran with high optical purity. The reaction formula of the method is as follows:

[0102]

[0103] In the reaction formula:

[0104] The oxidizing agent is a metal oxidizing agent or a non-metal oxidizing agent.

[0105] The catalyst is a complex of palladium acetate and a bidentate nitrogen ligand.

[0106] R is at least one of a tert-butyldimethylsiloxy group, a benzyl group, a phenyl group, or a C1-C4 alkyl group; preferably a methyl group, an ethyl group, a n-propyl group, or an isopropyl group; 20 R' is a methyl group, a phenyl group, a substituted phenyl group Ph1, a heteroaryl group, or a substituted heteroaryl group; the heteroaryl group is a five-membered heterocyclic group containing a heteroatom S in the skeleton; the substituents of the substituted phenyl group Ph1 and the substituted heteroaryl group are independently selected from at least one of a methyl group, a methoxy group, an acetyl group, fluorine, chlorine, and bromine;

[0107] R" is a methyl group, an ethyl group, an isopropyl group, a phenyl group, or a substituted phenyl group Ph2; the substituents of the benzene ring of the substituted phenyl group Ph2 are selected from one of a methyl group, an acetoxy group, and a sulfonamide group;

[0108] R" is a methyl group, an ethyl group, an isopropyl group, a phenyl group, or a substituted phenyl group Ph2; the substituents of the benzene ring of the substituted phenyl group Ph2 are selected from one of a methyl group, an acetoxy group, and a sulfonamide group;

[0109] X is oxygen or p-toluenesulfonamide.

[0110] As an embodiment, the molar ratio of the alkyne cyclohexadienone compound and the carboxylic acid compound in the reaction is 1:10-1:85, the molar ratio of the oxidant and the alkyne cyclohexadienone compound in the reaction is 0.3:1, the molar ratio of the palladium acetate and the alkyne cyclohexadienone compound in the reaction is 0.04:1, and the molar ratio of the chiral bis-nitrogen ligand and the alkyne cyclohexadienone compound in the reaction is 0.044:1.

[0111] As an embodiment, the catalyst is a planar chiral oxazapiridine ligand based on a cycloaromatic skeleton. Preferably, the catalyst is prepared by dissolving palladium acetate and a chiral bis-nitrogen ligand in a solvent Y1 under nitrogen protection, and stirring at room temperature for 120 minutes in a nitrogen atmosphere, and the solvent Y1 is selected from at least one of 1,2-dichloroethane, ethyl acetate, toluene, tetrahydrofuran, and methyl tert-butyl ether.

[0112] As an embodiment, the specific reaction steps of the method are as follows:

[0113] Under nitrogen protection, palladium acetate, a chiral bis-nitrogen ligand, and a carboxylic acid compound are added to a sealed tube, then a solvent Y1 is added, and after stirring at room temperature for 120 minutes, an alkyne cyclohexadienone compound and an oxidant are added under nitrogen, and after continuing to stir at 60°C in a nitrogen atmosphere for 20-48 hours, the solvent is spun dry, and column chromatography is used to separate the pure chiral cis-hydrobenzofuran.

[0114] For example, under nitrogen protection, 10 mL of a sealed tube is added with palladium acetate (0.008 mmol), a chiral bis-nitrogen ligand (0.088 mmol), and a carboxylic acid compound (3.4 mmol or 2.0 mmol), then a solvent Y1 (1.8 mL or 2.0 mL) is added, and after stirring at room temperature for 120 minutes, an alkyne cyclohexadienone (0.2 mmol) and an oxidant (0.06 mmol) are added under nitrogen, and after continuing to stir at 60°C in a nitrogen atmosphere for 20-48 hours, the solvent Y1 is spun dry, and column chromatography is used to separate the pure chiral cis-hydrobenzofuran.

[0115] Based on the above technical solution, preferably, R is methyl, R' is phenyl, X is oxygen, R'' is methyl, the catalyst is a complex formed by palladium acetate (Pd(OAc)2) and a planar chiral oxazapiridine ligand based on a cycloaromatic skeleton, the organic solvent is a mixture of toluene and methyl tert-butyl ether, the temperature is 60°C, the oxidant is benzoquinone, and the reaction time is 22 hours, and the reaction results are optimal.

[0116] Preparation of the synthesis of the ligand L1

[0117]

[0118] To a 50 mL reaction flask was added optically pure compound 4 (1.215 g, 5.0 mmol), compound 5a (0.749 g, 5.5 mmol) and 15 mL of anhydrous methanol under nitrogen protection. The reaction was heated to 50 °C for 48 hours. The solvent was removed under reduced pressure, 10 mL of water was added, extracted with dichloromethane, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Column chromatography gave 1.207 g of compound L1 as a white solid with a yield of 74%.

[0119] Preparation 2 Synthesis of ligand L2

[0120]

[0121] To a 25 mL reaction flask was added optically pure compound 4 (0.372 g, 1.5 mmol), compound 5b (0.248 g, 1.65 mmol) and 4.5 mL of anhydrous methanol under nitrogen protection. The reaction was heated to 50 °C for 48 hours. The solvent was removed under reduced pressure, 5.0 mL of water was added, extracted with dichloromethane, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Column chromatography gave 0.430 g of compound L2 as a yellow solid with a yield of 84%.

[0122] Preparation 3 Synthesis of ligand L3

[0123]

[0124] To a 25 mL reaction flask was added optically pure compound 4 (0.363 g, 1.5 mmol), compound 5c (0.248 g, 1.65 mmol) and 4.5 mL of anhydrous methanol under nitrogen protection. The reaction was heated to 50 °C for 48 hours. The solvent was removed under reduced pressure, 5.0 mL of water was added, extracted with dichloromethane, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Column chromatography gave 0.349 g of compound L3 as a yellow solid with a yield of 68%.

[0125] Preparation 4 Synthesis of compound 7

[0126]

[0127] Under nitrogen protection, optically pure compound 4 (0.370 g, 1.5 mmol), compound 6 (0.226 g, 1.65 mmol), N,N-diisopropylethylamine (DIPEA, 0.50 mL, 3.0 mmol), and 7.5 mL of N,N-dimethylformamide were added to a 50 mL reaction flask. The mixture was cooled to 0 °C, and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (HATU, 0.627 g, 1.65 mmol) was added. The reaction was then brought to room temperature and allowed to proceed for 6 hours. The reaction was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Column chromatography yielded 0.433 g of a yellow solid, compound 7, in 80% yield.

[0128] Preparation Example 5: Synthesis of Ligand L4

[0129]

[0130] Under nitrogen protection, compound 7 (0.433 g, 1.2 mmol), p-benzenesulfonic acid monohydrate (0.342 g, 1.8 mmol), and 24 mL of p-xylene were added to a 50 mL reaction flask. The mixture was heated to 120 °C and reacted for 16 hours. After cooling to room temperature, the reaction was quenched with saturated sodium carbonate aqueous solution, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Column chromatography yielded 0.390 g of a pale yellow solid, compound L4, in 95% yield.

[0131] Preparation Example 6: Synthesis of Ligand L5

[0132]

[0133] Under nitrogen protection, optically pure compound 4 (0.370 g, 1.5 mmol), compound 5d (0.248 g, 1.65 mmol), and 4.5 mL of anhydrous methanol were added to a 25 mL reaction flask. The mixture was heated to 50 °C and reacted for 48 hours. The solvent was removed under reduced pressure, 5.0 mL of water was added, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Column chromatography yielded 0.435 g of a white solid, compound L5, in 85% yield.

[0134] Preparation Example 7: Synthesis of Ligand L6

[0135]

[0136] To a 25 mL reaction vial was added optically pure compound 4 (0.365 g, 1.5 mmol), compound 5f (0.320 g, 1.65 mmol), 4.5 mL anhydrous methanol under nitrogen protection. The reaction was heated to 50 °C for 48 hours. The solvent was removed under reduced pressure, 5.0 mL water was added, extracted with dichloromethane, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure and column chromatography gave 0.395 g of white solid as compound L7 with 68% yield.

[0137] Preparation example 8 synthesis of ligand L7

[0138]

[0139] To a 25 mL reaction vial was added optically pure compound 4 (0.365 g, 1.5 mmol), compound 5f (0.320 g, 1.65 mmol), 4.5 mL anhydrous methanol under nitrogen protection. The reaction was heated to 50 °C for 48 hours. The solvent was removed under reduced pressure, 5.0 mL water was added, extracted with dichloromethane, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure and column chromatography gave 0.395 g of white solid as compound L7 with 68% yield.

[0140] Preparation example 9 synthesis of ligand L8

[0141]

[0142] To a 25 mL reaction vial was added optically pure compound 4 (0.365 g, 1.5 mmol), compound 5f (0.320 g, 1.65 mmol), 4.5 mL anhydrous methanol under nitrogen protection. The reaction was heated to 50 °C for 48 hours. The solvent was removed under reduced pressure, 5.0 mL water was added, extracted with dichloromethane, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure and column chromatography gave 0.395 g of white solid as compound L7 with 68% yield.

[0143] Example 1 asymmetric acyloxy-cyclization reaction of alkynyl cyclohexadienone 1a

[0144] To a 10 mL sealed tube was added palladium acetate Pd(OAc)2(0.004 mmol), chiral bis-nitrogen ligand L1 (0.0044 mmol) and acetic acid 2a (17 eq.) under nitrogen protection, then toluene (0.9 mL) was added, after stirring at room temperature for 120 min, alkynyl cyclohexadienone 1a (0.1 mmol) was added under nitrogen, after the reaction was completed at 60 °C, the solvent was dried, the internal standard mesitylene (0.1 mmol) was added, and the hydrogen spectrum was measured, the nuclear magnetic yield was 70%, and the enantiomeric ratio was 95:5.

[0145] Example 2 asymmetric acyloxy-cyclization reaction of alkynyl cyclohexadienone 1a

[0146] To a 25 mL reaction tube was added palladium acetate Pd(OAc)2(0.004 mmol), chiral bis-nitrogen ligand L1(0.0044 mmol) and acetic acid 2a (17 eq.) under nitrogen protection, then toluene (0.9 mL) was added, after stirring the reaction at room temperature for 120 min, acetylenic cyclohexadienone 1a (0.1 mmol) was added under nitrogen, then an oxygen balloon was inserted into the reaction tube, and the reaction system was replaced with an oxygen atmosphere, after the reaction was completed at 60 °C, the solvent was dried, the internal standard mesitylene (0.1 mmol) was added, and the hydrogen spectrum was measured, the yield was 73%, and the enantiomeric ratio was 95:5.

[0147] Example 3 Asymmetric acyloxylation cyclization reaction of acetylenic cyclohexadienone 1a

[0148] To a 25 mL reaction tube was added palladium acetate Pd(OAc)2(0.004 mmol), chiral bis-nitrogen ligand L1(0.0044 mmol) and acetic acid 2a (17 eq.) under nitrogen protection, then toluene (0.9 mL) was added, after stirring the reaction at room temperature for 120 min, acetylenic cyclohexadienone 1a (0.1 mmol) and silver acetate (0.03 mmol) were added under nitrogen, then an oxygen balloon was inserted into the reaction tube, and the reaction system was replaced with an oxygen atmosphere, after the reaction was completed at 60 °C, the solvent was dried, the internal standard mesitylene (0.1 mmol) was added, and the hydrogen spectrum was measured, the yield was 58%, and the enantiomeric ratio was 92.5:7.5.

[0149] Example 4-18 Asymmetric acyloxylation cyclization reaction of acetylenic cyclohexadienone 1a

[0150] The same method as in Example 3 was used to prepare cis-hydrobenzofuran, only the type of oxidizing agent, the type of organic solvent, the amount of acetic acid, and the chiral ligand were changed, and the results are shown in Table 1.

[0151]

[0152] Table 1. Condition parameters and results of Examples 1-18

[0153]

[0154]

[0155] Example 19 Asymmetric acyloxylation cyclization reaction of acetylenic cyclohexadienone 1a

[0156] To a 10 mL sealed tube under nitrogen was added palladium acetate Pd(OAc)2(0.008 mmol), chiral bisphosphine ligand L3(0.0088 mmol) and acetic acid 2a (3.4 mmol), followed by toluene and methyl-tert-butyl ether (0.9 mL / 0.9 mL). After stirring at room temperature for 120 min, alkynyl cyclohexadienone la (0.2 mmol) and benzoquinone (0.06 mmol) were added under nitrogen. After stirring at 60 °C until the reaction was complete, the solvents were evaporated and the pure chiral cis-hydrobenzofuran 3aa was isolated by column chromatography in 84% yield with an enantiomeric ratio of 95.5:4.5.

[0157] Example 20 Asymmetric acyloxy-cyclization reaction of alkynyl cyclohexadienone lb

[0158] To a 10 mL sealed tube under nitrogen was added palladium acetate Pd(OAc)2(0.008 mmol), chiral bisphosphine ligand L3(0.0088 mmol) and acetic acid 2a (3.4 mmol), followed by toluene (1.8 mL). After stirring at room temperature for 120 min, alkynyl cyclohexadienone lb (0.2 mmol) and benzoquinone (0.06 mmol) were added under nitrogen. After stirring at 60 °C until the reaction was complete, the solvents were evaporated and the pure chiral cis-hydrobenzofuran 3ba was isolated by column chromatography in 84% yield with an enantiomeric ratio of 91.5:8.5.

[0159] Example 26 Asymmetric acyloxy-cyclization reaction of alkynyl cyclohexadienone lh

[0160] To a 10 mL sealed tube under nitrogen was added palladium acetate Pd(OAc)2(0.016 mmol), chiral bisphosphine ligand L3(0.0176 mmol) and acetic acid 2a (3.4 mmol), followed by toluene and methyl-tert-butyl ether (0.9 mL / 0.9 mL). After stirring at room temperature for 120 min, alkynyl cyclohexadienone lh (0.2 mmol) and benzoquinone (0.06 mmol) were added under nitrogen. After stirring at 60 °C until the reaction was complete, the solvents were evaporated and the pure chiral cis-hydrobenzofuran 3ha was isolated by column chromatography in 85% yield with an enantiomeric ratio of 94.5:5.5.

[0161] Example 27 Asymmetric acyloxy-cyclization reaction of alkynyl cyclohexadienone li

[0162] Into a 10 mL sealed tube were added palladium acetate Pd(OAc)2(0.016 mmol), chiral bis-nitrogen ligand L3(0.0176 mmol) and acetic acid 2a(3.4 mmol) under nitrogen protection, then added toluene and methyl tert-butyl ether (0.9 mL / 0.9 mL), after stirring the reaction at room temperature for 120 min, added alkynyl cyclohexadienone 1i(0.2 mmol) and benzoquinone (0.06 mmol) under nitrogen, after the reaction was completed at 60°C, the solvent was dried and separated by column chromatography to obtain pure chiral cis-hydrobenzofuran 3ia, yield 83%, enantiomeric ratio 94.5:5.5.

[0163] Example 33 Asymmetric acyloxy-cyclization reaction of alkynyl cyclohexadienone 1o

[0164] Into a 10 mL sealed tube were added palladium acetate Pd(OAc)2(0.016 mmol), chiral bis-nitrogen ligand L3(0.0176 mmol) and acetic acid 2a(3.4 mmol) under nitrogen protection, then added toluene and methyl tert-butyl ether (0.9 mL / 0.9 mL), after stirring the reaction at room temperature for 120 min, added alkynyl cyclohexadienone 1o(0.2 mmol) and benzoquinone (0.06 mmol) under nitrogen, after the reaction was completed at 60°C, the solvent was dried and separated by column chromatography to obtain pure chiral cis-hydrobenzofuran 3oa, yield 85%, enantiomeric ratio 94:6.

[0165] Examples 21-25, 28-32, 34-42 Asymmetric acyloxy-cyclization reaction of alkynyl cyclohexadienone 1

[0166] The same method and conditions as in Example 19 were used to prepare cis-hydrobenzofurans 3 of different structures, only the type of alkynyl cyclohexadienone 1 in the reaction was changed, and chiral cis-hydrobenzofurans 3ca, 3da, 3ea, 3fa, 3ga, 3ja, 3ka, 3la, 3ma, 3na, 3pa, 3qa, 3ra, 3sa, 3ta, 3ua, 3va, 3wa, 3xa were obtained in turn; the structures of alkynyl cyclohexadienones 1 are as follows.

[0167]

[0168]

[0169] After compound 3ga was tested by X-ray single crystal diffraction on a BRUKER D8 VENTURE diffractometer equipped with graphite monochromatic Mo-Ka radiation , the structure was analyzed by Olex2 1.2, and the single crystal structure was confirmed, and the single crystal structure of compound 3ga is as follows. Figure 1The crystal of the compound 3ga belongs to monoclinic system, space group P 21, and the cell parameters are a = 9. 01(3) A, b = 10. 01(3) A, c = 19. 01(5) A, a = 90°, b = 92. 59(3)°, g = 90°, V = 1 705. 7(9) A3, Z = 4, F(000) = 748, R = 0. 0421, wR = 0. 0937. b = 107. 4660(10)°, Z = 2.

[0170] Example 43 Asymmetric acyloxy-cyclization reaction of alkynyl cyclohexadienone 1t

[0171] Under nitrogen protection, a 10 mL sealed tube was charged with palladium acetate Pd(OAc)2(0.008 mmol), chiral bis-nitrogen ligand L3(0.0088 mmol) and carboxylic acid compound 2b(2.0 mmol), then toluene and methyl tert-butyl ether(1.0 mL / 1.0 mL) were added, after stirring at room temperature for 120 min, alkynyl cyclohexadienone 1t(0.2 mmol) and benzoquinone(0.06 mmol) were added under nitrogen, after the reaction was completed at 60 °C, the solvent was rotary evaporated, and column chromatography was used to separate to obtain pure chiral cis-hydrobenzofuran 3tb, with a yield of 80% and an enantiomeric ratio of 97.5:2.5.

[0172] Example 44-48 Asymmetric acyloxy-cyclization reaction of alkynyl cyclohexadienone 1t

[0173] The same method and conditions as in Example 43 were used to prepare cis-hydrobenzofuran 3 of different structures, only the type of carboxylic acid compound 2 in the reaction was changed, to obtain chiral cis-hydrobenzofuran 3tc, 3td, 3te, 3tf, 3tg, respectively; the structures of carboxylic acid compounds 2 are as follows.

[0174]

[0175] (+)-(R p )-2-(Pyridin-2-yl)[2.2]paracyclophano[4,5-d]oxazole(L1)

[0176] 1.207 g, 74% yield, white solid, melting range 191-192 °C, new compound, R f = 0.35 (petroleum ether / ethyl acetate / methylene chloride 6 / 1 / 1), [a] 20 D = +334.68 (c 0.51, CHCl3). 1 H NMR (400 MHz, CDCl3) d 8.97-8.85 (m, 1H), 8.47-8.37 (m,

[0177]

[0178] 131.6, 130.1, 127.3, 125.3, 125.2, 123.8, 123.4, 34.7, 34.1, 30.8, 30.0. HRMS: Calcd for C 22 H 19 N2O[M+H] + 327.1492, actual 327.1493. _____________________________________________________________________

[0179] (+)-(R p )-2-(6-Methylpyridin-2-yl)[2.2]paracyclophano[4,5-d]oxazole (L2)

[0180] 0.430 g, 84% yield, yellow solid, m.p. 155-156 °C, new compound, R f = 0.40 (petroleum ether / ethyl acetate 5 / 1), [a] 20 D

[0181]

[0182] (m, 6H), 2.76 (s, 3H). 13 C NMR (100 MHz, CDC13) δ 160.0, 159.7, 151.4, 146.3, 144.0, 138.8, 138.4, 137.2, 133.7, 132.7, 132.1, 131.5, 130.0, 127.3, 125.3, 125.2, 123.7, 120.8, 34.7, 34.1, 30.8, 30.1, 25.0. HRMS: Calcd for C 23 H 21 N2O[M+H] + 341.1648, actual 341.1648. _____________________________________________________________________

[0183] (+)-(R p )-2-(4-Methylpyridin-2-yl)[2.2]paracyclophano[4,5-d]oxazole (L3)

[0184] 0.349 g, 68% yield, yellowish solid, m.p. 154-156 °C, new compound, R f = 0.25 (petroleum ether / ethyl acetate 3 / 1),

[0185]

[0186] NMR (100 MHz, CDC13) δ 159.9, 151.4, 150.3, 148.5, 146.6, 143.8, 138.7, 138.4, 133.7, 132.7, 132.1, 131.5, 130.0, 127.3, 126.4, 125.2, 124.2, 123.8, 34.6, 34.0, 30.8, 29.9, 21.2. HRMS: Calcd for C 23 H 20 N2NaO [M + Na] + 363.1468, Found 363.1473. _____________________________________________________________________

[0187] (+)-(R p )-4-Hydroxy-5-N-((3-methylpyridin-2-yl)-formyl)[2.2]paracyclophane

[0188] 0.433 g, 80% yield, yellow solid, m.p. 211-213 °C, new compound, R f = 0.80 (petroleum ether / ethyl acetate 5 / 1), [a] 20 D

[0189]

[0190] 1H), 6.25 (d, J = 7.7 Hz, 1H), 3.58-3.48 (m, 1H), 3.39-3.31 (m, 1H), 3.27-3.12 (m, 2H), 3.11-3.01 (m, 2H), 2.94-2.79 (m, 4H), 2.69-2.58 (m, 1H). 13C NMR (100 MHz, CDC13) δ 164.2, 148.7, 145.9, 141.8, 139.9, 137.4, 136.8, 133.3, 132.9, 132.3, 131.7, 131.1, 128.6, 128.5, 126.6, 126.2, 125.6, 34.0, 33.6, 32.1, 30.7, 21.1. HRMS calcd for C 23 H 23 N2O2[M+H] + 359.1754, actual 359.1750. _____________________________________________________________________

[0191] (+)-(R p )-2-(3-Methylpyridin-2-yl)[2.2]paracyclophano[4,5-d]oxazole (L4)

[0192] 0.390 g, 95% yield, yellowish solid, m.p. 126-128 °C, new compound, R f = 0.25 (petroleum ether / ethyl acetate 5 / 1),

[0193]

[0194] 3.84-3.75 (m, 1H), 3.68-3.59 (m, 1H), 3.13-2.86 (m, 9H). 13 C NMR (100 MHz, CDC13) δ 159.8, 150.8, 147.7, 145.1, 143.9, 140.0, 138.7, 138.5, 135.1, 133.6, 132.7, 132.1, 131.5, 129.8, 127.0, 125.3, 124.7, 123.8, 34.7, 34.1, 30.8, 30.1, 21.5. HRMS calcd for C 23 H 21 N2O[M+H] + 341.1648, actual 341.1648. _____________________________________________________________________

[0195] (+)-(R p)-2-(5-Methylpyridin-2-yl)[2.2]paracyclophano[4,5-d]oxazole (L5)

[0196] 0.435 g, 85% yield, white solid, m.p. 224-226 °C, new compound, R f = 0.30 (petroleum ether / ethyl acetate 3 / 1), [α] 20 D

[0197]

[0198] (s, 3H). 13 C NMR (100 MHz, CDC13) δ 159.9, 151.3, 151.0, 144.1, 143.9, 138.7, 138.3, 137.5, 135.6, 133.6, 132.7, 132.0, 131.3, 130.0, 127.2, 125.1, 123.7, 123.0, 34.6, 34.0, 30.7, 29.9, 18.7. HRMS: calcd for C 23 H 21 N2O [M+H] + 341.1648, found 341.1656. _____________________________________________________________________

[0199] (+)-(R p )-2-(5-Methoxypyridin-2-yl)[2.2]paracyclophano[4,5-d]oxazole (L6)

[0200] 0.426 g, 80% yield, white solid, m.p. 174-175 °C, new compound, R f = 0.30 (petroleum ether / ethyl acetate 3 / 1), [α] 20 D

[0201]

[0202] 2.3 Hz, 3H), 3.85-3.73 (m, 1H), 3.68-3.52 (m, 1H), 3.10-2.84 (m, 6H). 13C NMR (100 MHz, CDC13) δ 159.8, 157.2, 151.3, 144.0, 139.3, 138.8, 138.7, 138.3, 133.5, 132.7, 132.1, 131.1, 129.9, 127.2, 125.2, 124.4, 123.6, 120.7, 56.0, 34.6, 34.1, 30.8, 30.0. HRMS: Calcd C 23 H 21 N2O2[M+H] + 357.1598, actual 357.1610. _____________________________________________________________________

[0203] (+)-(R p )-2-(5-Carbomethoxypyridin-2-yl)[2.2]paracyclophano[4,5-d]oxazole (L7)

[0204] 0.395 g, 68% yield, white solid, m.p. 210-211 °C, new compound, R f = 0.65 (petroleum ether / ethyl acetate 3 / 1), [α] 20 D

[0205]

[0206] 3.11-2.87 (m, 6H). 13 C NMR (100 MHz, CDC13) δ 165.3, 158.8, 151.7, 151.6, 149.8, 143.9, 138.8, 138.4, 138.3, 134.2, 132.8, 132.3, 132.2, 130.4, 127.3, 127.0, 125.1, 124.0, 122.8, 52.8, 34.7, 34.1, 30.8, 30.0. HRMS: Calcd C 24 H 21 N2O3[M+H] + 385.1547, actual 385.1554. _____________________________________________________________________

[0207] (+)-(Rp )-2-(Isoquinolin-3-yl)[2.2]paracyclophano[4,5-d]oxazole (L8)

[0208] 0.490 g, 88% yield, white solid, m.p. 246-248 °C, new compound, R f = 0.40 (petroleum ether / ethyl acetate 3 / 1), [α] 20 D

[0209]

[0210] J = 7.8, 1.7 Hz, 1H), 3.92-3.82 (m, 1H), 3.71-3.61 (m, 1H), 3.15-2.89 (m, 6H). 13 CNMR (100 MHz, CDC13) δ 160.4, 153.6, 151.5, 144.2, 140.5, 138.9, 138.4, 136.0, 133.7, 132.8, 132.1, 131.43, 131.37, 130.1, 129.4, 129.0, 128.1, 127.6, 127.4, 125.2, 123.7, 120.9, 34.7, 34.1, 30.8, 30.1. HRMS: Calcd for C 26 H 21 N2O [M+H] + 377.1648, Found 377.1647. _____________________________________________________________________

[0211] ((Z)-7a-Methyl-5-oxo-3a,4,5,7a-tetrahydrobenzofuran-3(2H)-ylidene)(phenyl)methyl acetate (3aa): 50.1 mg, 84% yield, colorless viscous oily liquid, known compound, R f = 0.38 (petroleum ether / ethyl acetate 3 / 1), 95.5:4.5 e.r., [α] 20 D

[0212]

[0213] 128.7, 128.2, 81.2, 68.6, 45.8, 36.2, 23.4, 20.8. HPLC: Chiralpak AS-H, 230 nm, 30 °C, n-hexane / isopropanol = 70 / 30, flow rate = 0.7 mL / min, retention time 19.6 min and 26.7 min (major). _____________________________________________________________________

[0214] ((Z)-7a-Methyl-5-oxo-3a,4,5,7a-tetrahydrobenzofuran-3(2H)-ylidene)(o-tolyl)methyl acetate (3ba): 52.2 mg, 84% yield, yellowish viscous oil, new compound, R f = 0.41 (petroleum ether / ethyl acetate 3 / 1), 91.5:8.5 e.r.,

[0215]

[0216] (100 MHz, CDC13) δ 196.5, 168.1, 150.4, 140.6, 137.6, 133.2, 131.2, 130.50, 130.47, 130.0, 129.6, 125.8, 81.1, 68.2, 45.9, 36.1, 23.1, 20.7, 19.6. HPLC: Chiralpak AS-H, 230 nm, 30 °C, n-hexane / isopropanol = 80 / 20, flow rate = 0.7 mL / min, retention time 12.3 min and 16.8 min (major). HRMS calcd for C 19 H 24 NO4 [M + NH4] + 330.1700, found 330.1699. ____________________________________________________________________

[0217] ((Z)-7a-Methyl-5-oxo-3a,4,5,7a-tetrahydrobenzofuran-3(2H)-ylidene)(m-tolyl)methyl acetate (3ca): 47.7 mg, 76% yield, colorless viscous oil, new compound, R f= 0.37 (petroleum ether / ethyl acetate 3 / 1), 96:4 e.r., [a] 20 D

[0218]

[0219] δ 196.6, 168.5, 150.2, 140.7, 138.4, 134.1, 130.3, 130.1, 130.0, 128.62, 128.58, 125.3, 81.2, 68.6, 45.7, 36.1, 23.4, 21.6, 20.9. HPLC: Chiralpak AS-H, 230 nm, 30 °C, n-hexane / isopropanol = 70 / 30, flow rate = 0.7 mL / min, retention time 11.9 min and 14.6 min (major). HRMS Calcd for C 19 H 24 NO4[M+NH4] + 330.1700, Found 330.1701. _____________________________________________________________________

[0220] ((Z)-7a-Methyl-5-oxo-3a,4,5,7a-tetrahydrobenzofuran-3(2H)-ylidene)(p-tolyl)methyl acetate (3da): 57.1 mg, 91% yield, yellowish viscous oil liquid, new compound, R f = 0.30 (petroleum ether / ethyl acetate 3 / 1), 95.5:4.5 e.r.,

[0221]

[0222] 36.1, 23.3, 21.5, 20.8. HPLC: Chiralpak AD-H, 230 nm, 30 °C, n-hexane / isopropanol = 90 / 10, flow rate = 0.7 mL / min, retention time 15.7 min and 22.7 min (major). HRMS Calcd for C 19 H 24 NO4[M+NH4] + 330.1700, Found 330.1702. _____________________________________________________________________

[0223] (Z)-(4-Methoxyphenyl)(7a-methyl-5-oxo-3a,4,5,7a-tetrahydrobenzofuran-3(2H)-ylidene)methyl acetate(3ea): 53.6 mg, 82% yield, yellowish viscous oil liquid, new compound, R f = 0.24 (petroleum ether / ethyl acetate 3 / 1),

[0224]

[0225] 130.0, 129.6, 129.1, 81.4, 68.6, 45.8, 36.2, 23.3, 20.8. HPLC: Chiralpak AD-H, 230 nm, 30 °C, n-hexane / isopropanol = 90 / 10, flow rate = 0.7 mL / min, retention time 18.1 min and 23.4 min (major). HRMS calcd for C 19 H 24 NO5 [M + NH4] + 346.1649, found 346.1646. _____________________________________________________________________

[0226] (Z)-(4-Chlorophenyl)(7a-methyl-5-oxo-3a,4,5,7a-tetrahydrobenzofuran-3(2H)-ylidene)methyl acetate (3fa): 53.1 mg, 80% yield, white solid, m.p. 130-131 °C, new compound, R f = 0.31 (petroleum ether / ethyl acetate 3 / 1),

[0227]

[0228] 130.0, 129.6, 129.1, 81.4, 68.6, 45.8, 36.2, 23.3, 20.8. HPLC: Chiralpak AD-H, 230 nm, 30 °C, n-hexane / isopropanol = 90 / 10, flow rate = 0.7 mL / min, retention time 18.1 min and 23.4 min (major). HRMS calcd for C 18 H 21 ClNO4 [M + NH4] + 350.115435 Cl) and 352.1131 ( 37 Cl), actual 350.1154 ( 35 Cl) and 352.1121 ( 37 Cl). _____________________________________________________________________

[0229] (3aR,7aR,Z)-(+)-(4-Bromophenyl)(7a-methyl-5-oxo-3a,4,5,7a-tetrahydrobenzofuran-3(2H)-ylidene)methyl acetate (3ga): 52.7 mg, 70% yield, yellowish solid, m.p. 156-157 °C, new compound, R f = 0.30 (sh

[0230]

[0231] 139.5, 133.1, 132.0, 131.4, 130.0, 129.8, 123.6, 81.4, 68.6, 45.8, 36.2, 23.3, 20.7. HPLC: Chiralpak AD-H, 230 nm, 30 °C, n-hexane / isopropanol = 90 / 10, flow rate = 0.7 mL / min, retention time 19.2 min and 25.0 min (major). HRMS calcd for C 18 H 21 BrNO4[M+NH4] + 394.0648 ( 79 Br) and 396.0630 ( 81 Br), actual 394.0655 ( 79 Br) and 396.0632 ( 81 Br). _____________________________________________________________________

[0232] (Z)-(4-Acetylphenyl)(7a-methyl-5-oxo-3a,4,5,7a-tetrahydrobenzofuran-3(2H)-ylidene)methyl acetate (3ha): 58.1 mg, 85% yield, colorless viscous oil liquid, new compound, R f = 0.15 (petroleum ether / acetone 5 / 1),

[0233]

[0234] 138.6, 137.2, 132.3, 129.9, 128.6, 128.1, 81.4, 68.6, 45.7, 36.2, 26.7, 23.2, 20.6. HPLC: Chiralpak AS-H, 230 nm, 30 °C, n-hexane / isopropanol = 70 / 30, flow rate = 0.6 mL / min, retention time 43.6 min and 53.9 min (major). HRMS calcd for C 20 H 24 NO5[M+NH4] + 358.1649, found 358.1651. _____________________________________________________________________

[0235] (Z)-(4-Fluorophenyl)(7a-methyl-5-oxo-3a,4,5,7a-tetrahydrobenzofuran-3(2H)-ylidene)methyl acetate (3ia): 52.4 mg, 83% yield, colorless viscous oil liquid, new compound, R f = 0.37 (petroleum ether / acetone 6 / 1),

[0236]

[0237] 130.8, 130.3 (d, 3 J F-C = 8.4 Hz), 130.0, 115.9 (d, 2 J F-C = 21.7 Hz), 81.3, 68.5, 45.8, 36.2, 23.2, 20.8. 19F NMR (376 MHz, CDC13) δ -110.93. HPLC: Chiralpak AD-H, 230 nm, 30 °C, n-hexane / isopropanol = 80 / 20, flow rate = 0.6 mL / min, retention time 12.9 min and 16.1 min (major). HRMS calcd for C 18 H 21 FNO4[M+NH4] + 334.1449, actual 334.1446. _____________________________________________________________________

[0238] (Z)-(3,5-Dimethylphenyl)(7a-methyl-5-oxo-3a,4,5,7a-tetrahydrobenzofuran-3(2H)-ylidene)methyl acetate(3ja): 56.9 mg, 87% yield, colorless viscous oil liquid, new compound, R f = 0.48 (petroleum ether / ethyl acetate 3 / 1),

[0239]

[0240] 36.1, 23.4, 21.4, 20.8. HPLC: Chiralpak AS-H, 230 nm, 30 °C, n-hexane / isopropanol = 85 / 15, flow rate = 0.7 mL / min, retention time 12.1 min and 19.9 min (major). HRMS calcd for C 20 H 26 NO4[M+NH4] + 344.1856, actual 344.1853. _____________________________________________________________________

[0241] ((Z)-7a-Methyl-5-oxo-3a,4,5,7a-tetrahydrobenzofuran-3(2H)-ylidene)(thiophen-2-yl)methyl acetate(3ka): 52.4 mg, 86% yield, yellowish viscous oil liquid, new compound, R f = 0.25 (petroleum ether / ethyl acetate 3 / 1),

[0242]

[0243] (100 MHz, CDCI3) δ 196.7, 168.2, 149.2, 135.6, 134.6, 131.9, 129.9, 127.5, 127.2, 127.0, 80.5, 68.4, 45.9, 36.1, 23.8, 20.6. HPLC: Chiralpak AS-H, 230 nm, 30 °C, n-hexane / isopropanol = 60 / 40, flow rate = 0.8 mL / min, retention time 16.7 min (major) and 29.4 min. HRMS Calcd for C 16 H 20 NO4S [M + NH4] + 322.1108, Actual 322.1107. _____________________________________________________________________

[0244] ((Z)-7a-Ethyl-5-oxo-3a,4,5,7a-tetrahydrobenzofuran-3(2H)-ylidene)(phenyl)methyl acetate (3la): 54.3 mg, 87% yield, colorless viscous oil liquid, new compound, R f = 0.31 (petroleum ether / ethyl acetate 5 / 1), 95:5 e.r., [a] 20 D

[0245]

[0246] 140.3, 134.1, 130.8, 130.7, 129.2, 128.6, 128.0, 83.5, 68.3, 43.2, 36.4, 29.8, 20.7, 8.1. HPLC: Chiralpak AS-H, 230 nm, 30 °C, n-hexane / isopropanol = 70 / 30, flow rate = 0.7 mL / min, retention time 26.5 min and 29.3 min (major). HRMS Calcd for C 19 H 24 NO4 [M + NH4] + 330.1700, Actual 330.1701. _____________________________________________________________________

[0247] ((Z)-5-Oxo-7a-propyl-3a,4,5,7a-tetrahydrobenzofuran-3(2H)-ylidene)(phenyl)methyl acetate (3ma): 58.8 mg, 90% yield, yellowish solid, m.p. 81-82 °C, new compound, R f = 0.42 (petroleum ether / ethyl acetate 5 / 1), 95:5

[0248]

[0249] MHz, CDCI3) δ 196.7, 168.4, 149.5, 140.4, 134.2, 130.8, 130.5, 129.3, 128.7, 128.1, 83.5, 68.5, 43.9, 39.4, 36.4, 20.8, 17.3, 14.7. HPLC: Chiralpak AS-H, 230 nm, 30 °C, n-hexane / isopropanol = 70 / 30, flow rate = 0.7 mL / min, retention time 18.2 min and 26.3 min (major). HRMS calcd for C 20 H 26 NO4[M+NH4] + 344.1856, found 344.1859. _____________________________________________________________________

[0250] ((Z)-7a-Isopropyl-5-oxo-3a,4,5,7a-tetrahydrobenzofuran-3(2H)-ylidene)(phenyl)methyl acetate (3na): 59.0 mg, 90% yield, colorless viscous oily liquid, new compound, R f = 0.37 (petroleum ether / ethyl acetate 5 / 1), 94:6 e.r.,

[0251]

[0252] 168.4, 148.1, 140.2, 134.3, 131.62, 131.56, 129.2, 128.8, 128.0, 85.6, 68.1, 41.4, 37.4, 34.8, 20.8, 17.5, 17.4. HPLC: Chiralcel OD-H, 230 nm, 30 °C, n-hexane / isopropanol = 90 / 10, flow rate = 0.8 mL / min, retention time 9.0 min (major) and 13.4 min. HRMS Calcd for C 20 H 26 NO4[M + NH4] + 344.1856, Actual 344.1857. _____________________________________________________________________

[0253] ((Z)-7a-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-5-oxo-3a,4,5,7a-tetrahydrobenzofuran-3(2H)-ylidene)(phenyl)methyl acetate (3oa): 74.9 mg, 85% yield, yellowish viscous oily liquid, new compound, R f = 0.38 (petroleum

[0254]

[0255] 2.23 (dd, J = 16.9, 3.6 Hz, 1H), 2.10 (s, 3H), 2.09-1.93 (m, 2H), 0.88 (s, 9H), 0.06 (s, 3H), 0.04 (s, 3H). 13 C NMR (100 MHz, CDC13) δ 197.1, 168.5, 149.6, 140.2, 134.2, 130.8, 130.4, 129.3, 128.7, 128.1, 82.9, 68.3, 58.4, 43.6, 39.6, 36.1, 26.0, 20.8, 18.2, -5.3, -5.4. HPLC: Chiralpak AD-H, 230 nm, 30 °C, n-hexane / isopropanol = 95 / 5, flow rate = 0.7 mL / min, retention time 10.0 min and 12.6 min (major). HRMS Calcd for C 25 H 38 NO5Si[M + NH4] +460.2514, actual 460.2514. _____________________________________________________________________

[0256] ((Z)-7a-Benzyl-5-oxo-3a,4,5,7a-tetrahydrobenzofuran-3(2H)-ylidene)(phenyl)methyl acetate (3pa): 70.7 mg, 94% yield, yellow viscous oily liquid, new compound, R f = 0.33 (petroleum ether / ethyl acetate 5 / 1), 94.5:5.5 e.r.,

[0257]

[0258] (100 MHz, CDC13) δ 196.5, 168.4, 148.9, 140.5, 135.3, 134.1, 130.8, 130.4, 129.3, 128.7, 128.5, 128.1, 127.2, 83.5, 68.5, 43.8, 43.5, 36.1, 20.8. HPLC: Chiralcel OD-H, 230 nm, 30 °C, n-hexane / isopropanol = 80 / 20, flow rate = 0.8 mL / min, retention time 12.7 min (major) and 19.0 min. HRMS calcd for C 24 H 26 NO4[M + NH4] + 392.1856, actual 392.1859. _____________________________________________________________________

[0259] ((Z)-5-Oxo-7a-phenyl-3a,4,5,7a-tetrahydrobenzofuran-3(2H)-ylidene)(phenyl)methyl acetate (3qa): 67.8 mg, 94% yield, pale yellow viscous oily liquid, new compound, R f = 0.47 (petroleum ether / ethyl acetate 3 / 1), 95.5:4.5 e.r.,

[0260]

[0261] CDCI3) δ 196.7, 168.5, 147.9, 140.4, 139.9, 134.0, 131.3, 130.1, 129.4, 129.0, 128.7, 128.6, 128.2, 125.5, 85.1, 69.1, 48.0, 35.5, 20.8. HPLC: Chiralpak AS-H, 230 nm, 30 °C, n-hexane / isopropanol = 70 / 30, flow rate = 0.7 mL / min, retention time 18.9 min and 30.0 min (major). HRMS Calcd for C 23 H 24 NO4[M+NH4] + 378.1700, Actual 378.1700. _____________________________________________________________________

[0262] ((Z)-5-Oxo-7a-phenyl-3a,4,5,7a-tetrahydrobenzofuran-3(2H)-ylidene)(m-tolyl)methyl acetate (3ra): 68.9 mg, 92% yield, colorless viscous oil liquid, new compound, R f = 0.37 (petroleum ether / ethyl acetate 5 / 1), 96:4 e.r., [a] 20 D

[0263]

[0264] (m, 5H), 2.13 (s, 3H). 13 C NMR (100 MHz, CDCI3) δ 196.7, 168.4, 147.9, 140.6, 139.9, 138.3, 133.9, 131.3, 130.2, 129.8, 129.0, 128.61, 128.59, 128.5, 125.5, 125.3, 85.1, 69.1, 48.0, 35.4, 21.5, 20.8. HPLC: Chiralpak AS-H, 230 nm, 30 °C, n-hexane / isopropanol = 80 / 20, flow rate = 0.7 mL / min, retention time 13.9 min and 23.8 min (major). HRMS Calcd for C 24 H 26 NO4[M+NH4] + 392.1856, Actual 392.1857. _____________________________________________________________________

[0265] ((Z)-5-Oxo-7a-phenyl-3a,4,5,7a-tetrahydrobenzofuran-3(2H)-ylidene)(p-tolyl)methyl acetate (3sa): 70.6 mg, 94% yield, colorless viscous oil liquid, new compound, R f = 0.40 (petroleum ether / ethyl acetate 5 / 1), 96:4 e.r., [a] 20 D

[0266]

[0267] 129.5, 129.4, 128.9, 128.6, 128.0, 125.4, 85.1, 69.1, 48.0, 35.4, 21.5, 20.8. HPLC: Chiralpak AS-H, 230 nm, 30 °C, n-hexane / isopropanol = 70 / 30, flow rate = 0.7 mL / min, retention time 13.3 min and 18.9 min (major). HRMS calcd for C 24 H 26 NO4[M + NH4] + 392.1856, found 392.1848. _____________________________________________________________________

[0268] (Z)-(3,5-Dimethylphenyl)(5-oxo-7a-phenyl-3a,4,5,7a-tetrahydrobenzofuran-3(2H)-ylidene)methyl acetate (3ta): 69.4 mg, 89% yield, yellowish viscous oil liquid, new compound, R f = 0.46 (petroleum ether / ethyl acetate 5 / 1),

[0269]

[0270] 2H), 2.27 (s, 6H), 2.13 (s, 3H). 13C NMR (100 MHz, CDC13) δ 196.8, 168.5, 148.0, 140.7, 140.0, 138.2, 133.8, 131.4, 131.2, 129.6, 129.0, 128.6, 125.8, 125.5, 85.2, 69.1, 48.0, 35.3, 21.4, 20.9. HPLC: Chiralpak AS-H, 230 nm, 30 °C, n-hexane / isopropanol = 70 / 30, flow rate = 0.7 mL / min, retention time 7.3 min and 15.8 min (major). HRMS calcd for C 25 H 28 NO4[M+NH4] + 406.2013, found 406.2011. _____________________________________________________________________

[0271] (Z)-(3,5-Dimethylphenyl)(5-oxo-7a-propyl-3a,4,5,7a-tetrahydrobenzofuran-3(2H)-ylidene)methyl acetate (3ua): 61.4 mg, 87% yield, yellowish solid, m.p. 113-114 °C, new compound, R f = 0.48 (petroleum ether / ethyl

[0272]

[0273] 1.56-1.44 (m, 2H), 0.98 (t, J = 7.3 Hz, 3H). 13 C NMR (100 MHz, CDC13) δ 196.9, 168.4, 149.7, 140.7, 138.2, 134.0, 131.0, 130.5, 130.3, 125.8, 83.4, 68.5, 43.9, 39.4, 36.2, 21.4, 20.8, 17.3, 14.7. HPLC: Chiralcel OD-H, 230 nm, 30 °C, n-hexane / isopropanol = 95 / 5, flow rate = 0.7 mL / min, retention time 9.1 min (major) and 12.2 min. HRMS calcd for C 22 H 30 NO4[M+NH4] + 372.2169, found 372.2168. _____________________________________________________________________

[0274] ((Z)-7a-Benzyl-5-oxo-3a,4,5,7a-tetrahydrobenzofuran-3(2H)-ylidene)(3,5-dimethylphenyl)methyl acetate(3va): 70.7 mg, 88% yield, yellow viscous oily liquid, new compound, R f = 0.39 (petroleum ether / ethyl acetate 5 / 1),

[0275]

[0276] 2.33-2.25 (m, 7H), 2.13-2.03 (m, 4H). 13 C NMR (100 MHz, CDC13) δ 196.7, 168.4, 148.9, 140.8, 138.1, 135.5, 133.9, 131.0, 130.7, 130.4, 129.9, 128.5, 127.2, 125.8, 83.4, 68.5, 43.9, 43.6, 36.1, 21.4, 20.8. HPLC: Chiralpak AS-H, 230 nm, 30 °C, n-hexane / isopropanol = 85 / 15, flow rate = 0.7 mL / min, retention time 12.6 min and 22.8 min (major). HRMS calcd for C 26 H 30 NO4[M + NH4] + 420.2169, found 420.2173. _____________________________________________________________________

[0277] (Z)-1-(5-Oxo-7a-phenyl-3a,4,5,7a-tetrahydrobenzofuran-3(2H)-ylidene)ethyl acetate(3wa):

[0278] 36.5 mg, 61% yield, colorless viscous oily liquid, known, R f = 0.28 (petroleum ether / ethyl acetate 5 / 1), 81.5: 18.5 e.r.

[0279]

[0280] 148.1, 140.6, 138.9, 130.5, 129.0, 128.5, 127.5, 125.5, 84.4, 68.4, 47.4, 37.7, 20.8, 17.2. HPLC: Chiralpak AS-H, 225 nm, 30 °C, n-hexane / isopropanol = 90 / 10, flow rate = 1.0 mL / min, retention time 19.6 min and 25.1 min (major). _____________________________________________________________________

[0281] ((Z)-7a-Methyl-5-oxo-1-tosyl-1,2,3a,4,5,7a-hexahydro-3H-indol-3- ylidene)(phenyl)methyl acetate (3xa): 68.7 mg, 76% yield, yellow viscous oily liquid, new compound, R f = 0.32 (petroleum ether / ethyl acetate 3 / 1), 77.5:22.5

[0282]

[0283] 128.75, 127.7, 127.0, 125.0, 64.1, 49.13, 49.10, 38.5, 25.7, 21.6, 20.8. HPLC: Chiralcel OD-3, 254 nm, 30 °C, n-hexane / isopropanol = 80 / 20, flow rate = 0.8 mL / min, retention time 11.1 min and 12.6 min (major). HRMS calcd for C 25 H 29 N2O5S [M+NH4] + 469.1792, found 469.1796. _____________________________________________________________________

[0284] (Z)-(3,5-Dimethylphenyl)(5-oxo-7a-phenyl-3a,4,5,7a-tetrahdrobenzofuran-3(2H)-ylidene)methyl propionate (3tb): 64.2 mg, 80% yield, yellow viscous oily liquid, new compound, R f = 0.53 (petroleum ether / ethyl acetate

[0285]

[0286] MHz, CDCI3) δ 196.8, 172.0, 148.0, 140.7, 140.0, 138.1, 133.9, 131.4, 131.1, 129.4, 129.0, 128.6, 125.7, 125.5, 85.2, 69.2, 48.0, 35.3, 27.6, 21.4, 9.2. HPLC: Chiralpak AS-H, 230 nm, 30 °C, n-hexane / isopropanol = 85 / 15, flow rate = 0.7 mL / min, retention time 8.4 min and 21.9 min (major). HRMS calcd for C 26 H 27 O4 [M+H] + 403.1904, found 403.1914. _____________________________________________________________________

[0287] (Z)-(3,5-Dimethylphenyl)(5-oxo-7a-phenyl-3a,4,5,7a-tetrahdrobenzofuran-3(2H)-ylidene)methyl isobutyrate (3tc): 53.6 mg, 64% yield, colorless viscous oily liquid, new compound, R f = 0.34 (petroleum ether / ethyl acetate

[0288]

[0289] Hz, 3H). 13C NMR (100 MHz, CDC13) δ 196.9, 174.6, 148.0, 140.7, 140.0, 138.1, 133.9, 131.4, 131.1, 129.2, 129.0, 128.6, 125.6, 125.5, 85.2, 69.1, 48.1, 35.2, 34.1, 21.4, 19.0, 18.9. HPLC: Chiralpak IC, 230 nm, 30 °C, n-hexane / isopropanol = 95 / 5, flow rate = 0.7 mL / min, retention time 14.0 min and 18.9 min (major). HRMS calcd for C 27 H 29 O4[M+H] + 417.2060, found 417.2061. _____________________________________________________________________

[0290] (Z)-(3,5-Dimethylphenyl)(5-oxo-7a-phenyl-3a,4,5,7a-tetrahdrobenzofuran-3(2H)-ylidene)methyl benzoate (3td): 76.2 mg, 85% yield, colorless viscous oil liquid, new compound, R f = 0.60 (petroleum ether / ethyl acetate 5 / 1),

[0291]

[0292] 148.1, 140.8, 140.0, 138.2, 133.8, 131.5, 131.2, 130.2, 129.8, 129.3, 129.0, 128.7, 128.6, 125.8, 125.5, 85.2, 69.3, 48.2, 35.3, 21.4. HPLC: Chiralpak AS-H, 230 nm, 30 °C, n-hexane / isopropanol = 70 / 30, flow rate = 0.7 mL / min, retention time 8.6 min and 14.9 min (major). HRMS calcd for C 30 H 27 O4[M+H] + 451.1904, found 451.1901. _____________________________________________________________________

[0293] (Z)-(3,5-Dimethylphenyl)(5-oxo-7a-phenyl-3a,4,5,7a-tetrahydrobenzofuran-3(2H)- ylidene)methyl 4-methylbenzoate (3te): 75.0 mg, 81% yield, yellow viscous oil liquid, new compound, R f = 0.67 (petroleum ether / acetic acid

[0294]

[0295] 1H), 4.55 (dd, J = 13.8, 2.4 Hz, 1H), 3.69-3.62 (m, 1H), 2.49-2.39 (m, 5H), 2.27 (s, 6H). 13 C NMR (100 MHz, CDC13) δ 196.9, 164.3, 148.1, 144.6, 140.8, 140.0, 138.1, 133.8, 131.4, 131.2, 130.3, 129.7, 129.4, 129.0, 128.6, 126.6, 125.7, 125.5, 85.2, 69.3, 48.1, 35.3, 21.8, 21.4. HPLC: Chiralpak IC, 230 nm, 30 °C, n-hexane / isopropanol = 85 / 15, flow rate = 0.7 mL / min, retention time 12.6 min and 17.2 min (major). HRMS calcd for C 31 H 29 O4 [M+H] + 465.2060, found 465.2073. _____________________________________________________________________

[0296] (Z)-(3,5-Dimethylphenyl)(5-oxo-7a-phenyl-3a,4,5,7a-tetrahydrobenzofuran-3(2H)- ylidene)methyl 4-methylbenzoate (3te): 75.0 mg, 81% yield, yellow viscous oil liquid, new compound, R f = 0.32 (petroleum ether / acetic acid

[0297]

[0298] 151.2, 148.1, 140.5, 139.9, 138.2, 134.7, 133.4, 132.3, 131.3, 130.2, 129.0, 128.6, 126.3, 125.7, 125.6, 124.2, 122.5, 85.2, 69.3, 48.2, 35.4, 21.4, 21.1. HPLC: Chiralpak AD-H, 230 nm, 30 °C, n-hexane / isopropanol = 90 / 10, flow rate = 0.7 mL / min, retention time 16.0 min (major) and 22.9 min. HRMS Calcd for C 32 H 29 O6[M+H] + 509.1959, actual 509.1953. _____________________________________________________________________

[0299] (Z)-(3,5-Dimethylphenyl)(5-oxo-7a-phenyl-3a,4,5,7a-tetrahydrobenzofuran-3(2H)- ylidene)methyl 4-(N,N-dipropylsulfamoyl)benzoate (3tg): 112.8 mg, 92% yield, yellowish viscous oil liquid, new compound, R f

[0300]

[0301] δ 196.7, 163.0, 148.0, 145.1, 140.7, 139.8, 138.3, 133.4, 132.5, 131.5, 131.4, 130.8, 130.3, 129.0, 128.7, 127.3, 125.8, 125.5, 85.2, 69.1, 50.1, 48.2, 35.3, 22.1, 21.4, 11.3. HPLC: Chiralpak IA, 230 nm, 30 °C, n-hexane / isopropanol = 80 / 20, flow rate = 0.7 mL / min, retention time 14.1 min (major) and 18.5 min. HRMS Calcd for C 36 H 40 NO6S[M+H] + 614.2571, actual 614.2569. _____________________________________________________________________

Claims

1. A method for preparing chiral cis-hydrobenzofuran, characterized in that, A mixture containing the compound shown in Formula I, the compound shown in Formula II, an oxidant, and a catalyst undergoes an asymmetric acylation cyclization reaction to obtain the chiral cis-hydrobenzofuran shown in Formula III; the catalyst is a chiral dinitrogen complex of palladium; the oxidant is selected from benzoquinone, silver acetate, or oxygen; ； ； ； Wherein: R is selected from benzyl, phenyl, or C1-C 20 One of alkyl or tert-butyldimethylsiloxy; R ’ The substituent is selected from methyl, phenyl, substituted phenyl Ph1, heteroaryl or substituted heteroaryl; the heteroaryl is a five-membered heterocyclic group with a heteroatom S in its skeleton; the substituents of substituted phenyl Ph1 and substituted heteroaryl are independently selected from at least one of methyl, methoxy, acetyl, fluorine, chlorine and bromine; R ’’ Selected from methyl, ethyl, isopropyl, phenyl, or substituted phenyl Ph2; the substituent of substituted phenyl Ph2 is selected from methyl, acetoxy, or sulfonamide. X is O or p-toluenesulfonamide group; The palladium chiral dinitrogen complex is formed by coordination of a palladium precursor and a planar chiral dinitrogen compound; The palladium precursor is selected from palladium acetate or palladium trifluoroacetate; The planar chiral dinitrogen compound is selected from one of L1, L2, L3, L4, L5, L6, L7, and L8: 。 2. The method according to claim 1, characterized in that, The heteroaryl group is a thiophene group.

3. The method according to claim 1, characterized in that, The molar ratio of the compound shown in Formula I to the compound shown in Formula II is 1:10 to 1:85, the molar ratio of the compound shown in Formula I to the oxidant is 1:0.1 to 1:0.6, and the molar ratio of the compound shown in Formula I to the chiral dinitrogen complex of palladium is 1:0.02 to 1:0.

1.

4. The method according to claim 1, characterized in that, When the oxidant is not oxygen, the reaction atmosphere is nitrogen; first stir the mixture under a nitrogen atmosphere, then add the oxidant to carry out the reaction.

5. The method according to claim 1, characterized in that, The mixture contains solvent Y1, which is selected from at least one of 1,2-dichloroethane, ethyl acetate, toluene, tetrahydrofuran, and methyl tert-butyl ether.

6. The method according to claim 1, characterized in that, The reaction temperature is 60°C. o C~80 o C.

7. The method according to claim 1, characterized in that, The reaction time is 20 to 48 hours.

8. The method according to claim 1, characterized in that, The chiral cis-hydrobenzofuran compound is characterized by having the structure shown in Formula III; Formula III; In Formula III: R is selected from benzyl, phenyl, or C1-C 20 One of alkyl or tert-butyldimethylsiloxy; R ’ The substituent is selected from methyl, phenyl, substituted phenyl Ph1, heteroaryl or substituted heteroaryl; the heteroaryl is a five-membered heterocyclic group with a heteroatom S in its skeleton; the substituents of substituted phenyl Ph1 and substituted heteroaryl are independently selected from at least one of methyl, methoxy, acetyl, fluorine, chlorine and bromine; R ’’ Selected from methyl, ethyl, isopropyl, phenyl, or substituted phenyl Ph2; the substituent of substituted phenyl Ph2 is selected from methyl, acetoxy, or sulfonamide. X is O or p-toluenesulfonamide group; The following structural formulas are excluded from Formula III: 。 9. The method according to claim 8, characterized in that, The heteroaryl group is a thiophene group.

10. The method according to claim 1, characterized in that, The chiral cis-hydrobenzofuran compound is selected from any one of the structures shown in 3aa, 3ba, 3ca, 3da, 3ea, 3fa, 3ga, 3ha, 3ia, 3ja, 3ka, 3la, 3ma, 3na, 3oa, 3pa, 3qa, 3ra, 3sa, 3ta, 3ua, 3va, 3wa, 3xa, 3tb, 3tc, 3td, 3te, 3tf, and 3tg. 。

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