Catalytic asymmetric synthesis method of beta-substituted gamma-butyrolactone compound and application of beta-substituted gamma-butyrolactone compound in synthesis of podophyllotoxin drugs

Abstract

The invention discloses a catalytic asymmetric synthesis method of a beta-substituted gamma-butyrolactone compound, which comprises the following steps: under the action of palladium acetate, a chiral ligand, an acidic additive, an oxidant and a pro-oxidant, reacting an allyl alcohol compound with an alkenyl ether compound in an organic solvent to obtain the beta-substituted gamma-butyrolactone compound, the invention also provides podophyllotoxin, a homologue thereof and a synthesis method of a chiral intermediate compound in a synthesis process of the podophyllotoxin. According to the method, one-pot reaction / oxidation reaction is adopted, so that catalytic asymmetric synthesis of the beta-substituted-gamma-butyrolactone compound is economically and efficiently realized; the reaction substrates are two chemical raw materials and are good in universality, reaction conditions are mild, the process is simple and safe, and operation is easy and convenient.

Description

Technical Field

[0001] The present invention belongs to the technical field of asymmetric synthesis of flavors and fragrances, asymmetric synthesis of organic intermediates, asymmetric synthesis of drugs and asymmetric total synthesis of active natural products, and particularly relates to a catalytic asymmetric synthesis method of β-substituted γ-butyrolactone compounds and application thereof in the synthesis of podophyllotoxin drugs. Background Art

[0002] β-Substituted γ-butyrolactone and its derivatives are an important class of flavors and fragrances, as well as important structural units of active natural products, drug molecules and functional materials. They can also be used as key intermediates in the synthesis of natural products and drug molecules (such as podophyllotoxins).

[0003] Although chiral β-substituted γ-butyrolactone structural units can be obtained through asymmetric 1,4-addition reactions of furan derivatives (ACS Catal., 2019, 9, 11614.), asymmetric reduction reactions (J.Am.Chem.Soc., 2003, 125, 11253.), or asymmetric palladium halogenation reactions of 1,6-enynes (Chem.Eur.J.2022, 28, e202202528), these methods all require multiple transformations and have low synthesis efficiency. Therefore, it is necessary to develop a simpler, faster and more effective method for synthesizing such compounds, especially using commercially available chemical raw materials as reactants.

[0004] Podophyllotoxins and related aryl tetralins are natural products isolated from podophyllum plants. Their primary plant sources include Sinopodophyllum (S. hexandrum Ying) of the Berberidaceae family, D. versipellis, D. pleia-ntha, D. aurantiocaulis, D. tsayuensis of the Dysosma genus, and D. sinsnsis of the Diphylleia genus. Podophyllotoxins and their homologues possess numerous remarkable biological properties, including cytotoxic, insecticidal, antifungal, antiviral, anti-inflammatory, neurotoxic, immunosuppressive, antirheumatic, antioxidant, antispasmodic, and lipid-lowering activities. The structures of some podophyllotoxins and their homologues are shown below:

[0005]

[0006] Podophyllotoxin derivatives have been widely used in clinical cancer treatment since the 1970s. These derivatives are synthesized from podophyllotoxin, which is primarily extracted from plants. However, natural plant sources of podophyllotoxin (such as Psoralea corylifolia) are becoming increasingly scarce, necessitating the development of effective alternative methods to obtain podophyllotoxin.

[0007] In response to the two important technical problems mentioned above, the present invention first develops a completely new method for synthesizing β-substituted γ-butyrolactones, expands the substrate range and catalytic system, and opens up a new synthetic route for the catalytic asymmetric synthesis of β-substituted γ-butyrolactone flavors and fragrances; on this basis, a simple and efficient catalytic asymmetric synthesis method for podophyllotoxin and its homologues is provided, and specifically provides chiral intermediate compounds in the synthesis process and their synthesis methods. Summary of the Invention

[0008] The first purpose of the present invention is to solve the above problems and provide a new catalytic asymmetric synthesis method of chiral β-substituted γ-butyrolactone compounds.

[0009] The second object of the present invention is to provide a method for synthesizing podophyllotoxin, its homologues and chiral intermediate compounds in the synthesis process thereof.

[0010] The third object of the present invention is to provide podophyllotoxin, its homologues and chiral intermediate compounds in the synthesis process obtained by the above method.

[0011] The purpose of the present invention is specifically achieved through the following technical solutions:

[0012] A catalytic asymmetric synthesis method for β-substituted γ-butyrolactone compounds, wherein the structural formula of the β-substituted γ-butyrolactone compounds is shown in formula (I).

[0013]

[0014]

[0015] The synthesis method comprises the following steps: under the action of palladium acetate, a chiral ligand, an acidic additive, an oxidant and a co-oxidant, an allyl alcohol compound and an ether compound react in an organic solvent to obtain the β-substituted γ-butyrolactone compound;

[0016] In formula (I), R1 is an aryl group or a heteroaryl group, and R2 is a hydrogen atom, an aryl group or an alkoxy group.

[0017] Preferably, the organic solvent is benzene, toluene, chlorobenzene, dichloromethane, tetrahydrofuran, ethyl acetate, or ethylene glycol dimethyl ether;

[0018] The chiral ligand types include bisoxazolines, pyridine oxazoles, and phosphoramidites.

[0019] The acidic additives include: acetic acid, monochloroacetic acid, dichloroacetic acid, benzoic acid, 2-trifluoromethylbenzoic acid, 3-trifluoromethylbenzoic acid, 4-trifluoromethylbenzoic acid, 4-methoxybenzoic acid, 4-chlorobenzoic acid, 4-nitrobenzoic acid, 3,5-ditrifluoromethylbenzoic acid, and 3,5-dinitrobenzoic acid;

[0020] The oxidant includes p-Benzoquinone, oxygen, manganese dioxide, hydrogen peroxide, iodobenzene acetate, dibenzoyl peroxide, tert-butyl hydroperoxide, potassium peroxymonosulfonate;

[0021] The co-oxidants include: ferric chloride, ferric acetate, ferric trifluoromethanesulfonate, copper acetate, silver acetate, silver trifluoromethanesulfonate, manganese acetate, manganese acetate monohydrate, and manganese nitrate tetrahydrate;

[0022] The olefin ether compounds include vinyl ethyl ether, butyl vinyl ether, isobutyl vinyl ether, tert-butyl vinyl ether, cyclohexyl vinyl ether,

[0023] The allyl alcohol compounds include aryl allyl alcohol, heteroaryl allyl alcohol,

[0024] Further preferably, it is characterized in that the allyl alcohol compound comprises:

[0025]

[0026]

[0027] Further preferably, the β-substituted-γ-butyrolactone compounds include:

[0028]

[0029]

[0030]

[0031] Preferably, the molar ratio of the allyl alcohol compound to the olefinic ether compound, palladium acetate, chiral ligand, acidic additive, co-oxidant and oxidant is 1:4:0.075:0.15:0.15:0.075:1.2.

[0032] A method for synthesizing podophyllotoxin, its homologues and chiral intermediate compounds in their synthesis process, the method comprising the following steps:

[0033] (1) As the starting material, the compound in claim 4 is synthesized

[0034] (2) The intermediate compound 9 obtained in step (1) undergoes an intermolecular Aldol reaction with 3,4,5-trimethoxybenzaldehyde or an alkylation reaction with 3,4,5-trimethoxybenzyl bromide to produce the intermediate compound 10 or 12:

[0035]

[0036] (3) The intermediate compound 10 or 12 is subjected to a Friedel-Crafts reaction or an enzyme-catalyzed cyclization reaction to obtain the intermediate compound 11 or 13:

[0037]

[0038] (4) The intermediate compound 11 or 13 is subjected to ozonation reaction to obtain (+)-isopodophyllotoxin (1), (-)-isopodophyllotoxin (2), (+)-picropodophyllotoxin (3), (-)-podophyllotoxin (5), and (-)-podophyllotoxin (6):

[0039]

[0040] (5) (+)-picropodophyllotoxin (3) and (-)-podophyllotoxin (6) are selectively reduced to give (+)-picropodophyllotoxin (4) and (-)-deoxypodophyllotoxin (7), respectively:

[0041]

[0042] Furthermore, the method of step (1) is as follows:

[0043] ① First, 3,4-methylenedioxyacetophenone and triethyl phosphoacetate undergo Horner-Wadsworth-Emmons reaction under alkaline conditions, and then reduction is performed to obtain the intermediate compound pre-8. The reaction is as follows:

[0044]

[0045] ② The intermediate compound pre-8 and tert-butyl vinyl ether are reacted by Oshima-Utimoto reaction to obtain the intermediate compound 8, as follows:

[0046]

[0047] ③ Intermediate compound 8 is obtained by removing the tert-butyl group under acidic conditions and then PCC oxidation to obtain intermediate compound 9, the reaction is as follows:

[0048]

[0049] Preferably, the base used in step ① is sodium hydride, sodium hydroxide, potassium carbonate, cesium carbonate, potassium tert-butoxide, and the reducing agent is lithium aluminum hydride, sodium borohydride, or diisobutylaluminum hydride;

[0050] The acid used to remove the tert-butyl group under acidic conditions in step ③ is trifluoroacetic acid, hydrochloric acid, sulfuric acid, or p-toluenesulfonic acid;

[0051] The base used in the intermolecular Aldol reaction or alkylation reaction in step (2) is lithium diisopropylamide, lithium dicyclohexylamide, lithium diphenylamide, NaHMDS, LiHMDS, sodium hydroxide, sodium tert-butoxide, and the temperature is -78°C, -40°C, or 0°C;

[0052] The acid used in the Friedel-Crafts reaction in step (3) is ferric chloride, aluminum chloride, boron trifluoride etherate, iron trifluoromethanesulfonate, indium trifluoromethanesulfonate, scandium trifluoromethanesulfonate, tin trifluoromethanesulfonate, mercury trifluoromethanesulfonate, silver hexafluoroantimonate, or trifluoroacetic anhydride, and the reaction temperature is -20°C, -10°C, 0°C, or 20°C;

[0053] The enzyme used in the enzymatic cyclization reaction of step (3) is 2-ODD dioxygenase, P450 ATRCase1 , bifunctional catalase EasC;

[0054] The quenching agents used in the ozonation reaction in step (4) are triphenylphosphine, dimethyl sulfide, and sodium borohydride, and the reaction temperatures are -78°C, -40°C, and 0°C;

[0055] The selective reducing agent used in the selective reduction reaction of step (5) is lithium aluminum hydride, diisobutylaluminum hydride, lithium tri-sec-butylborohydride, red aluminum, lithium tri-tert-butoxyaluminum hydride, triethylsilylsilyl and phenylsilyl.

[0056] Podophyllotoxin and its homologues obtained by any of the above methods have the following structural formula:

[0057]

[0058] The structural formula of podophyllotoxin and its homologues is shown in formula (II):

[0059]

[0060] Wherein, R in formula (II) is OH, C=O or H.

[0061] The chiral intermediate compound of podophyllotoxin and its homologues obtained in the synthesis process according to any of the above methods has the following structural formula:

[0062]

[0063] Compared with the prior art, the present invention has the following advantages:

[0064] The present invention provides a method for synthesizing flavors and fragrances and organic intermediate β-substituted-γ-butyrolactone compounds. The method uses allyl alcohol and ether as reactants, adds an oxidant in an organic solvent and an acid solution, and can economically and efficiently achieve catalytic asymmetric synthesis of the organic intermediate β-substituted-γ-butyrolactone compounds. The method has good substrate universality, mild reaction conditions, a simple, safe and easy-to-operate process during the reaction process, and a high synthesis yield of the target compound. DETAILED DESCRIPTION

[0065] The preferred embodiments of the present invention are described below. It should be understood that the preferred embodiments described herein are only used to illustrate and explain the present invention, and are not used to limit the present invention.

[0066] Unless otherwise specified, the raw materials in the examples of the present invention were purchased from commercial sources.

[0067] Example 1

[0068] Using (E)-3-phenyl-2-butene-1-ol and tert-butyl vinyl ether as raw materials, the specific reaction is as follows:

[0069]

[0070] To a dry 10 mL reaction tube was added L17 (9.1 mg, 0.03 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), and A8 (15.5 mg, 0.03 mmol), followed by redistributed toluene (1.0 mL). The mixture was stirred at room temperature for 4 hours. (E)-3-phenyl-2-buten-1-ol (29.6 mg, 0.2 mmol), Mn(OAc)2 (2.6 mg, 0.015 mmol), MnO2 (20.8 mg, 0.24 mmol), tert-butyl vinyl ether (105.2 μL, 0.8 mmol), and additional redistributed toluene (1.0 mL) were then added. The tube was sealed with a glass stopper and stirred at 20°C for 7 days. After the reaction was complete, the solvent was evaporated, and acetone (1.0 mL) and Jones reagent (0.4 mL, 1 mol / L, 0.8 mmol) were added to the residue at 0°C. After the reaction was complete, the reaction was quenched by adding aqueous NaHCO₃ solution and extracted with dichloromethane (15 mL × 3). The combined organic phases were washed with water and brine, then dried over Na₂SO₄, filtered, and concentrated. Column chromatography (petroleum ether / ethyl acetate = 6:1) was performed. The product was finally obtained as a colorless oil (23.7 mg, 63% yield, 93% ee).

[0071] Product testing data are as follows:

[0072] 1 H NMR (400MHz, CDCl3): δ7.39-7.30 (m, 5H), 5.40 (s, 1H), 5.16 (d, J = 1.6Hz, 1H), 4.50 (dd, J = 9.2, 7.6Hz, 1H), 4.12(dd,J=8.8,7.6Hz,1H),3.81-3.73(m,1H),2.78(dd,J=17.6,8.4Hz,1H),2.57(dd,J=17.2,8.4Hz,1H); 13 C NMR (100MHz, CDCl3): δ176.4,147.0,140.2,128.8(2C),128.3,126.5(2C),113.3,72.4,40.0,34.0; HRMS(ESI)[M+Na] + calculated for C 12 H 12O2,211.0729,found 211.0733; IR(KBrplate):3437,2963,1776,1642,1563,1495,1438,1334,1261,1170,1102,1025,997,905,841,781,695,652,458cm -1 .

[0073] Example 2

[0074] Using (E)-3-(4-methylphenyl)but-2-ene-1-ol and tert-butyl vinyl ether as raw materials, the specific reaction is as follows:

[0075]

[0076] To a dry 10 mL reaction tube was added L17 (9.1 mg, 0.03 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), and A8 (15.5 mg, 0.03 mmol), followed by redistributed toluene (1.0 mL). The mixture was stirred at room temperature for 4 hours. (E)-3-(4-methylphenyl)but-2-en-1-ol (32.4 mg, 0.2 mmol), Mn(OAc)2 (2.6 mg, 0.015 mmol), MnO2 (20.8 mg, 0.24 mmol), tert-butyl vinyl ether (105.2 μL, 0.8 mmol), and additional redistributed toluene (1.0 mL). The tube was sealed with a glass stopper and stirred at 20°C for 7 days. After the reaction was complete, the solvent was evaporated, and acetone (1.0 mL) and Jones reagent (0.4 mL, 1 mol / L, 0.8 mmol) were added to the residue at 0°C. After the reaction was complete, the reaction was quenched by adding aqueous NaHCO₃ solution and extracted with dichloromethane (15 mL × 3). The combined organic phases were washed with water and brine, then dried over Na₂SO₄, filtered, and concentrated. Column chromatography (petroleum ether / ethyl acetate = 6:1) was performed. The product was finally obtained as a white solid (24.3 mg, 60% yield, 91% ee). The enantioselectivity was greater than 99% ee after recrystallization once from petroleum ether / dichloromethane = 5:1.

[0077] Product testing data are as follows:

[0078] mp:40.5-42.4℃; 1H NMR (400MHz, CDCl3): δ7.25-7.21(m,2H),7.17-7.15(m,2H),5.36(s,1H),5.10(s,1H),4.48(t,J=7.6Hz,1H),4. 09(t,J=7.6Hz,1H),3.78-3.72(m,1H),2.76(dd,J=17.2,8.4Hz,1H),2.55(dd,J=17.2,8.4Hz,1H),2.35(s,3H); 13 C NMR (100MHz, CDCl3): δ176.4,146.7,138.1,137.1,129.4(2C),126.3(2C),112.4,72.4,39.9,34.0,21.1; HRMS(ESI)[M+Na] + calculated for C 13 H 14 O2,225.0886,found 225.0889; IR(KBr plate):3089,2920,1780,1628,1513,1479,1418,1260,1169,1026,997,903,826,735,682,605cm-1.

[0079] Example 3

[0080] Using (E)-3-(4-tert-butylphenyl)but-2-en-1-ol and tert-butyl vinyl ether as raw materials, the specific reaction is as follows:

[0081]

[0082] To a dry 10 mL reaction tube was added L17 (9.1 mg, 0.03 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), and A8 (15.5 mg, 0.03 mmol), followed by redistributed toluene (1.0 mL). The mixture was stirred at room temperature for 4 hours. (E)-3-(4-tert-butylphenyl)but-2-en-1-ol (40.8 mg, 0.2 mmol), Mn(OAc)2 (2.6 mg, 0.015 mmol), MnO2 (20.8 mg, 0.24 mmol), tert-butyl vinyl ether (105.2 μL, 0.8 mmol), and additional redistributed toluene (1.0 mL). The tube was sealed with a glass stopper and stirred at 20°C for 7 days. After the reaction was complete, the solvent was evaporated, and acetone (1.0 mL) and Jones reagent (0.4 mL, 1 mol / L, 0.8 mmol) were added to the residue at 0°C. After the reaction was complete, the reaction was quenched by adding aqueous NaHCO₃ solution and extracted with dichloromethane (15 mL × 3). The combined organic phases were washed with water and brine, then dried over Na₂SO₄, filtered, and concentrated. Column chromatography (petroleum ether / ethyl acetate = 6:1) was performed. The product was finally obtained as a white solid (26.4 mg, 52% yield, 95% ee). The enantioselectivity was greater than 99% ee after recrystallization once from petroleum ether / dichloromethane = 5:1.

[0083] Product testing data are as follows:

[0084] mp:48.7-50.1℃; 1 H NMR (400MHz, CDCl3): δ7.39-7.37(m,2H),7.28-7.26(m,2H),5.39(s,1H),5.12(d,J=1.2Hz,1H),4.51(dd,J=9.2,7.6Hz,1H ),4.12(dd,J=8.8,7.6Hz,1H),3.80-3.72(m,1H),2.78(dd,J=17.2,8.4Hz,1H),2.58(dd,J=17.6,8.8Hz,1H),1.33(s,9H); 13 C NMR (100MHz, CDCl3): δ176.5,151.4,146.6,137.1,126.1(2C),125.7(2C),112.5,72.5,39.9,34.7,34.1,31.4(3C); HRMS(ESI)[M+Na] + calculated for C 16 H 20O2,267.1355,found 267.1357; IR(KBr plate):3089,2963,1783,1627,1514,1477,1364,1270,1170,1122,1027,998,904,842,608cm -1 .

[0085] Example 4

[0086] Using (E)-3-(4-methoxyphenyl)but-2-en-1-ol and tert-butyl vinyl ether as raw materials, the specific reaction is as follows:

[0087]

[0088] To a dry 10 mL reaction tube was added L17 (9.1 mg, 0.03 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), and A8 (15.5 mg, 0.03 mmol), followed by redistributed toluene (1.0 mL). The mixture was stirred at room temperature for 4 hours. (E)-3-(4-methoxyphenyl)but-2-en-1-ol (35.6 mg, 0.2 mmol), Mn(OAc)2 (2.6 mg, 0.015 mmol), MnO2 (20.8 mg, 0.24 mmol), tert-butyl vinyl ether (105.2 μL, 0.8 mmol), and additional redistributed toluene (1.0 mL). The tube was sealed with a glass stopper and stirred at 20°C for 7 days. After the reaction was complete, the solvent was evaporated, and acetone (1.0 mL) and Jones reagent (0.4 mL, 1 mol / L, 0.8 mmol) were added to the residue at 0°C. After the reaction was complete, the reaction was quenched by adding aqueous NaHCO₃ solution and extracted with dichloromethane (15 mL × 3). The combined organic phases were washed with water and brine, then dried over Na₂SO₄, filtered, and concentrated. Column chromatography (petroleum ether / ethyl acetate = 6:1) was performed. The product was finally obtained as a white solid (22.7 mg, 52% yield, 88% ee). The enantioselectivity was greater than 99% ee after recrystallization once from petroleum ether / dichloromethane = 5:1.

[0089] Product testing data are as follows:

[0090] mp:56.2-57.1℃; 1H NMR (400MHz, CDCl3): δ7.29-7.25(m,2H),6.91-6.87(m,2H),5.33(d,J=0.4Hz,1H),5.07(d,J=1.6Hz,1H),4.50(dd,J=8.8,7.2H z,1H),4.11(dd,J=9.2,7.6Hz,1H),3.83(s,3H),3.78-3.70(m,1H),2.77(dd,J=17.2,8.4Hz,1H),2.56(dd,J=17.2,8.4Hz,1H); 13 C NMR (100MHz, CDCl3): δ176.5,159.7,146.3,132.5,127.6(2C),114.2(2C),111.7,72.5,55.4,39.9,34.1; HRMS(ESI)[M+Na] + calculated for C 13 H 14 O3,241.0835,found 241.0833; IR(KBr plate):2839,1779,1608,1574,1512,1361,1296,1248,1180,1027,837,746,604cm -1 .

[0091] Example 5

[0092] Using (E)-3-(4-trifluoromethylphenyl)but-2-en-1-ol and tert-butyl vinyl ether as raw materials, the specific reaction is as follows:

[0093]

[0094] To a dry 10 mL reaction tube was added L17 (9.1 mg, 0.03 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), and A8 (15.5 mg, 0.03 mmol), followed by redissolved toluene (1.0 mL). The mixture was stirred at room temperature for 4 hours. (E)-3-(4-trifluoromethylphenyl)but-2-en-1-ol (43.2 mg, 0.2 mmol), Mn(OAc)2 (2.6 mg, 0.015 mmol), MnO2 (20.8 mg, 0.24 mmol), tert-butyl vinyl ether (105.2 μL, 0.8 mmol), and additional redissolved toluene (1.0 mL). The tube was sealed with a glass stopper and stirred at 20°C for 7 days. After the reaction was complete, the solvent was evaporated, and acetone (1.0 mL) and Jones reagent (0.4 mL, 1 mol / L, 0.8 mmol) were added to the residue at 0°C. After the reaction was complete, the reaction was quenched by adding aqueous NaHCO3 solution and extracted with dichloromethane (15 mL × 3). The combined organic phase was washed with water and brine, then dried over Na2SO4, filtered, and concentrated. Column chromatography (petroleum ether / ethyl acetate = 6:1) was performed. The product was finally obtained as a colorless oil (24.6 mg, 48% yield, 91% ee).

[0095] Product testing data are as follows:

[0096] 1 H NMR (400MHz, CDCl3): δ7.63(d,J=8.4Hz,2H),7.45(d,J=8.0Hz,2H),5.48(s,1H),5.27(d,J=1.6Hz,1H),4.51(dd,J=8.8 ,7.2Hz,1H),4.12(dd,J=9.2,7.2Hz,1H),3.81-3.73(m,1H),2.80(dd,J=17.2,8.4Hz,1H),2.56(dd,J=17.2,8.4Hz,1H); 13 C NMR (100MHz, CDCl3): δ175.9, 146.0, 143.7, 130.4 (q, J = 130Hz), 128.1, 126 .8(2C),125.8(q,J=15.6Hz),125.4,122.7,122.0,115.1,72.0,39.8,33.9; 19 FNMR (376MHz, CDCl3): δ-62.7; HRMS (ESI) [M+Na] + calculated for C 13 H 11F3O2,279.0603,found 279.0604;IR(KBr plate):3098,2918,1787,1617,1574,1481,1408,1328,1233,1168,1121,1065,1028,999,965,913,850,759,687,639,611,539,509cm -1 .

[0097] Example 6

[0098] Using (E)-3-([1,1'-biphenyl]-4-yl)but-2-en-1-ol and tert-butyl vinyl ether as raw materials, the specific reaction is as follows:

[0099]

[0100] To a dry 10 mL reaction tube, L17 (9.1 mg, 0.03 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), and A8 (15.5 mg, 0.03 mmol) were added, followed by redistributed toluene (1.0 mL). The mixture was stirred at room temperature for 4 hours. (E)-3-([1,1'-biphenyl]-4-yl)but-2-en-1-ol (44.8 mg, 0.2 mmol), MnO2 (20.8 mg, 0.24 mmol), tert-butyl vinyl ether (105.2 μL, 0.8 mmol), and additional redistributed toluene (1.0 mL) were then added. The tube was sealed with a glass stopper and stirred at 20°C for 7 days. After the reaction was complete, the solvent was evaporated, and acetone (1.0 mL) and Jones reagent (0.4 mL, 1 mol / L, 0.8 mmol) were added to the residue at 0°C. After the reaction was complete, the reaction was quenched by adding aqueous NaHCO₃ solution and extracted with dichloromethane (15 mL × 3). The combined organic phases were washed with water and brine, then dried over Na₂SO₄, filtered, and concentrated. Column chromatography (petroleum ether / ethyl acetate = 6:1) was performed. The product was finally obtained as a white solid (30.7 mg, 58% yield, 93% ee). The enantioselectivity was greater than 99% ee after recrystallization once from petroleum ether / dichloromethane = 5:1.

[0101] Product testing data are as follows:

[0102] mp:119.8-120.7℃; 1H NMR (400MHz, CDCl3): δ7.61-7.59(m,4H),7.47-7.35(m,5H),5.47(s,1H),5.19(d,J=1.6Hz,1H),4.54(dd,J=9.2,7. 6Hz,1H),4.15(dd,J=8.8,7.6Hz,1H),3.85-3.77(m,1H),2.81(dd,J=17.2,8.0Hz,1H),2.60(dd,J=17.2,8.4Hz,1H); 13 C NMR (100MHz, CDCl3): δ176.4,146.5,141.2,140.4,138.9,129.0(2C),127.7, 127.5(2C),127.1(2C),126.8(2C),113.2,72.4,39.9,34.1; HRMS(ESI)[M+Na] + calculated for C 18 H 16 O2,287.1043,found 287.1054;IR(KBr plate):3024,2993,2967,2907,2355,2310,1794,1768,1624,1488,1450,1403, 1464,1258,1208,1099,1068,1036,996,960,911,862,842,795,776,739,621cm -1 .

[0103] Example 7

[0104] Using (E)-3-(2-fluoromethylphenyl)but-2-en-1-ol and tert-butyl vinyl ether as raw materials, the specific reaction is as follows:

[0105]

[0106] To a dry 10 mL reaction tube was added L17 (9.1 mg, 0.03 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), and A8 (15.5 mg, 0.03 mmol), followed by redistributed toluene (1.0 mL). The mixture was stirred at room temperature for 4 hours. (E)-3-(2-fluoromethylphenyl)but-2-en-1-ol (33.2 mg, 0.2 mmol), Mn(OAc)2 (2.6 mg, 0.015 mmol), MnO2 (20.8 mg, 0.24 mmol), tert-butyl vinyl ether (105.2 μL, 0.8 mmol), and additional redistributed toluene (1.0 mL). The tube was sealed with a glass stopper and stirred at 20°C for 7 days. After the reaction was complete, the solvent was evaporated, and acetone (1.0 mL) and Jones reagent (0.4 mL, 1 mol / L, 0.8 mmol) were added to the residue at 0°C. After the reaction was complete, the reaction was quenched by adding aqueous NaHCO₃ solution and extracted with dichloromethane (15 mL × 3). The combined organic phases were washed with water and brine, then dried over Na₂SO₄, filtered, and concentrated. Column chromatography (petroleum ether / ethyl acetate = 6:1) was performed. The product was finally obtained as a colorless oil (9.1 mg, 22% yield, 87% ee).

[0107] Product testing data are as follows:

[0108] 1 H NMR (400MHz, CDCl3): δ7.35-7.29(m,1H),7.20(td,J=7.6,2.0Hz,1H),7.16-7.05(m,2H),5.33(d,J=0.8Hz,1H),5.32(s,1H) ,4.46(t,J=8.8Hz,1H),4.13(t,J=8.0Hz,1H),3.76-3.68(m,1H),2.74(dd,J=17.2,8.4Hz,1H),2.53(dd,J=17.2,8.8Hz,1H); 13 C NMR (100MHz, CDCl3): δ176.4, 159.6 (d, J = 245Hz), 143.4, 130.4 (d, J = 4.0Hz), 130.0 (d, J = 8.4Hz), 128.3 (d ,J=14.9Hz),124.6(d,J=3.6Hz),116.9,116.1(d,J=22.2Hz),72.2(d,J=1.3Hz),40.88(d,J=3.3Hz),34.0; 19 FNMR (376MHz, CDCl3): δ-115.0; HRMS (ESI) [M+Na]+ calculated for C 12 H 11 FO2,229.0635,found 229.0631;IR(KBr plate):2963,2922,2854,1779,1611,1577,1489,1450,1420,1372,1260,1213,1170,1027,999,916,845,801,765,683,617,560cm -1 .

[0109] Example 8

[0110] Using (E)-3-(3-fluoromethylphenyl)but-2-en-1-ol and tert-butyl vinyl ether as raw materials, the specific reaction is as follows:

[0111]

[0112] To a dry 10 mL reaction tube was added L17 (9.1 mg, 0.03 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), and A8 (15.5 mg, 0.03 mmol), followed by redistributed toluene (1.0 mL). The mixture was stirred at room temperature for 4 hours. (E)-3-(3-fluoromethylphenyl)but-2-en-1-ol (33.2 mg, 0.2 mmol), Mn(OAc)2 (2.6 mg, 0.015 mmol), MnO2 (20.8 mg, 0.24 mmol), tert-butyl vinyl ether (105.2 μL, 0.8 mmol), and additional redistributed toluene (1.0 mL). The tube was sealed with a glass stopper and stirred at 20°C for 7 days. After the reaction was complete, the solvent was evaporated, and acetone (1.0 mL) and Jones reagent (0.4 mL, 1 mol / L, 0.8 mmol) were added to the residue at 0°C. After the reaction was complete, the reaction was quenched by adding aqueous NaHCO₃ solution and extracted with dichloromethane (15 mL × 3). The combined organic phases were washed with water and brine, then dried over Na₂SO₄, filtered, and concentrated. Column chromatography (petroleum ether / ethyl acetate = 6:1) was performed. The product was finally obtained as a colorless oil (17.7 mg, 43% yield, 88% ee).

[0113] Product testing data are as follows:

[0114] 1H NMR (400MHz, CDCl3): δ7.36-7.31(m,1H),7.13-7.10(m,1H),7.05-7.00(m,2H),5.43(d,J=0.4Hz,1H),5.20(d,J=1.2Hz,1H),4.50 (dd,J=9.2,7.6Hz,1H),4.12(dd,J=8.8,7.2Hz,1H),3.77-3.71(m,1H),2.79(dd,J=17.2,8.4Hz,1H),2.55(dd,J=17.2,8.4Hz,1H); 13 C NMR (100MHz, CDCl3): δ176.1, 163.0 (d, J = 245Hz), 145.9 (d, J = 1.9Hz), 142.3 (d, J = 7.5Hz), 130.3 (d ,J=8.5Hz),122.1(d,J=2.8Hz),115.1(d,J=20.8Hz),114.1,113.5(d,J=21.7Hz),72.1,39.8,33.9; 19 F NMR (376MHz, CDCl3): δ-112.5; HRMS (ESI) [M+Na] + calculated for C 12 H 11 FO2,229.0635,found 229.0634;IR(KBrplate):3073,2995,2912,1780,1612,1581,1488,1435,1359,1 269,1226,1172,1027,998,966,923,877,838,791,732,684,649,628,598,521cm -1 .

[0115] Example 9

[0116] Using (E)-3-(4-fluoromethylphenyl)but-2-en-1-ol and tert-butyl vinyl ether as raw materials, the specific reaction is as follows:

[0117]

[0118] To a dry 10 mL reaction tube was added L17 (9.1 mg, 0.03 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), and A8 (15.5 mg, 0.03 mmol), followed by redistributed toluene (1.0 mL). The mixture was stirred at room temperature for 4 hours. (E)-3-(4-fluoromethylphenyl)but-2-en-1-ol (33.2 mg, 0.2 mmol), Mn(OAc)2 (2.6 mg, 0.015 mmol), MnO2 (20.8 mg, 0.24 mmol), tert-butyl vinyl ether (105.2 μL, 0.8 mmol), and additional redistributed toluene (1.0 mL). The tube was sealed with a glass stopper and stirred at 20°C for 7 days. After the reaction was complete, the solvent was evaporated, and acetone (1.0 mL) and Jones reagent (0.4 mL, 1 mol / L, 0.8 mmol) were added to the residue at 0°C. After the reaction was complete, the reaction was quenched by adding aqueous NaHCO3 solution and extracted with dichloromethane (15 mL × 3). The combined organic phase was washed with water and brine, then dried over Na2SO4, filtered, and concentrated. Column chromatography (petroleum ether / ethyl acetate = 6:1) was performed. The product was finally obtained as a colorless oil (18.4 mg, 44% yield, 91% ee).

[0119] Product testing data are as follows:

[0120] 1 H NMR (600MHz, CDCl3): δ7.31-7.29(m,2H),7.05(t,J=8.4Hz,2H),5.36(s,1H),5.15(d,J=1.2Hz,1H),4.87(dd,J=9.0,7 .8,Hz,1H),4.11(dd,J=9.0,7.2Hz,1H),3.75-3.70(m,1H),2.77(dd,J=17.4,8.4Hz,1H),2.56(dd,J=15.8,8.4Hz,1H); 13 C NMR (150MHz, CDCl3): δ176.2, 162.7 (d, J = 246Hz), 145.9, 136.2 (d, J = 2.7Hz), 128.1 (d, J = 8.0Hz), 115.7 (d, J = 21.2Hz), 113.3, 72.2, 40.0, 34.0; 19 F NMR (376MHz, CDCl3): δ-113.7; HRMS (ESI) [M+Na] + calculated for C 12 H 11FO2,229.0635,found229.0637; MS(EI)m / z(%):206(34),147(100),146(33),149(22),207(5); IR(KBr plate):3078,2919,2354,1780,1632,1602,1509,1417,1361,1229,1164,1026,997,907,842,740,681,621,602,555,504cm -1 .

[0121] Example 10

[0122] Using (E)-3-(4-chloromethylphenyl)but-2-en-1-ol and tert-butyl vinyl ether as raw materials, the specific reaction is as follows:

[0123]

[0124] To a dry 10 mL reaction tube was added L17 (9.1 mg, 0.03 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), and A8 (15.5 mg, 0.03 mmol), followed by redistributed toluene (1.0 mL). The mixture was stirred at room temperature for 4 hours. (E)-3-(4-chloromethylphenyl)but-2-en-1-ol (36.4 mg, 0.2 mmol), Mn(OAc)2 (2.6 mg, 0.015 mmol), MnO2 (20.8 mg, 0.24 mmol), tert-butyl vinyl ether (105.2 μL, 0.8 mmol), and additional redistributed toluene (1.0 mL). The tube was sealed with a glass stopper and stirred at 20°C for 7 days. After the reaction was complete, the solvent was evaporated, and acetone (1.0 mL) and Jones reagent (0.4 mL, 1 mol / L, 0.8 mmol) were added to the residue at 0°C. After the reaction was complete, the reaction was quenched by adding aqueous NaHCO3 solution and extracted with dichloromethane (15 mL × 3). The combined organic phases were washed with water and brine, then dried over Na2SO4, filtered, and concentrated. Column chromatography (petroleum ether / ethyl acetate = 6:1) was performed. The product was finally obtained as a colorless oil (22.3 mg, 50% yield, 90% ee).

[0125] Product testing data are as follows:

[0126] 1H NMR (600MHz, CDCl3): δ7.33(d,J=8.4Hz,2H),7.26(d,J=8.4Hz,2H),5.40(s,1H),5.18(s,1H),4.49(t,J=7.8, Hz,1H),4.10(t,J=7.8Hz,1H),3.75-3.69(m,1H),2.77(dd,J=17.4,8.4Hz,1H),2.54(dd,J=17.4,8.4Hz,1H); 13 CNMR (150MHz, CDCl3): δ176.1,145.8,138.5,134.2,129.0(2C),127.7(2C),113.8,72.1,39.8,33.9; HRMS(ESI)[M+Na] + calculated for C 12 H 11 ClO2, 245.0340, found 245.0343; MS (EI) m / z (%): 222 (19), 145 (18), 129 (100), 64 (14); IR (KBr plate):3098,2918,1787,1617,1574,1481,1408,1328,1233,1168,1121,1065,1028,999,965,913,850,759,687,639,611,539,509cm -1 .

[0127] Example 11

[0128] Using (E)-3-(4-bromomethylphenyl)but-2-en-1-ol and tert-butyl vinyl ether as raw materials, the specific reaction is as follows:

[0129]

[0130] To a dry 10 mL reaction tube was added L17 (9.1 mg, 0.03 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), and A8 (15.5 mg, 0.03 mmol), followed by redistributed toluene (1.0 mL). The mixture was stirred at room temperature for 4 hours. (E)-3-(4-bromomethylphenyl)but-2-en-1-ol (45.4 mg, 0.2 mmol), Mn(OAc)2 (2.6 mg, 0.015 mmol), MnO2 (20.8 mg, 0.24 mmol), tert-butyl vinyl ether (105.2 μL, 0.8 mmol), and additional redistributed toluene (1.0 mL). The tube was sealed with a glass stopper and stirred at 20°C for 7 days. After the reaction was complete, the solvent was evaporated, and acetone (1.0 mL) and Jones reagent (0.4 mL, 1 mol / L, 0.8 mmol) were added to the residue at 0°C. After the reaction was complete, the reaction was quenched by adding aqueous NaHCO3 solution and extracted with dichloromethane (15 mL × 3). The combined organic phases were washed with water and brine, then dried over Na2SO4, filtered, and concentrated. Column chromatography (petroleum ether / ethyl acetate = 6:1) was performed. The product was finally obtained as a light yellow oil (19.2 mg, 36% yield, 82% ee).

[0131] Product testing data are as follows:

[0132] 1 H NMR (400MHz, CDCl3): δ7.51-7.48(m,2H),7.22-7.18(m,2H),5.40(d,J=0.4Hz,1H),5.20(d,J=0.8Hz,1H),5.18(d,J=1.6Hz,1H),4.4 9(dd,J=9.2,7.6Hz,1H),4.10(dd,J=9.2,7.6Hz,1H),3.75-3.67(m,1H),2.77(dd,J=17.2,8.0Hz,1H),2.55(dd,J=17.6,8.4Hz,1H); 13 C NMR (100MHz, CDCl3): δ176.0,146.0,139.0,132.0(2C),128.1(2C),122.4,113.8,72.1,39.8,34.0; HRMS(ESI)[M+Na] + calculated for C 12 H 11BrO2,288.9835,found 288.9828; IR(KBr plate):3025,2919,2354,1780,1733,1602,1583,1487,1435,1167,1026,998,903,794,723,668,625cm -1 .

[0133] Example 12

[0134] Using (E)-3-(3-methyl-4-bromomethylphenyl)but-2-en-1-ol and tert-butyl vinyl ether as raw materials, the specific reaction is as follows:

[0135]

[0136] To a dry 10 mL reaction tube was added L17 (9.1 mg, 0.03 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), and A8 (15.5 mg, 0.03 mmol), followed by redistributed toluene (1.0 mL). The mixture was stirred at room temperature for 4 hours. (E)-3-(3-methyl-4-bromomethylphenyl)but-2-en-1-ol (48.2 mg, 0.2 mmol), Mn(OAc)2 (2.6 mg, 0.015 mmol), MnO2 (20.8 mg, 0.24 mmol), tert-butyl vinyl ether (105.2 μL, 0.8 mmol), and additional redistributed toluene (1.0 mL). The tube was sealed with a glass stopper and stirred at 20°C for 7 days. After the reaction was complete, the solvent was evaporated, and acetone (1.0 mL) and Jones reagent (0.4 mL, 1 mol / L, 0.8 mmol) were added to the residue at 0°C. After the reaction was complete, the reaction was quenched by adding aqueous NaHCO₃ solution and extracted with dichloromethane (15 mL × 3). The combined organic phases were washed with water and brine, then dried over Na₂SO₄, filtered, and concentrated. Column chromatography (petroleum ether / ethyl acetate = 6:1) was performed. The product was finally obtained as a yellow solid (26.4 mg, 47% yield, 88% ee). The enantioselectivity was greater than 99% ee after recrystallization once from petroleum ether / dichloromethane = 5:1.

[0137] Product testing data are as follows:

[0138] mp:56.5-57.8℃; 1H NMR (400MHz, CDCl3): δ7.51(d,J=8.0Hz,1H),7.19(s,1H),7.0(d,J=8.0Hz,1H),5.38(s,1H),5.16(s,1H),4.48(dd,J=8.8,7.6H z,1H),4.09(dd,J=8.8,7.6Hz,1H),3.75-3.67(m,1H),2.76(dd,J=17.2,8.4Hz,1H),2.54(dd,J=17.2,8.4Hz,1H),2.41(s,3H); 13 C NMR (100MHz, CDCl3): δ176.2,146.1,139.4,138.4,132.7,128.9,125.3,124.8,113.6,72.2,39.9,33.9,23.1; HRMS(ESI)[M+Na] + calculated for C 13 H 13 BrO2,302.9991,found 302.9986; IR(KBr plate):3108,2987,2911,1782,1628,1591,1478,1418,1378,1170,1027,998,906,825,730,685,641,550cm -1 .

[0139] Example 13

[0140] Using (E)-(3,4-methylenedioxyphenyl)but-2-en-1-ol and tert-butyl vinyl ether as raw materials, the specific reaction is as follows:

[0141]

[0142] To a dry 10 mL reaction tube was added L17 (9.1 mg, 0.03 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), and A8 (15.5 mg, 0.03 mmol), followed by redistributed toluene (1.0 mL). The mixture was stirred at room temperature for 4 hours. (E)-3-(3,4-methylenedioxyphenyl)but-2-en-1-ol (38.4 mg, 0.2 mmol), Mn(OAc)2 (2.6 mg, 0.015 mmol), MnO2 (20.8 mg, 0.24 mmol), tert-butyl vinyl ether (105.2 μL, 0.8 mmol), and additional redistributed toluene (1.0 mL) were then added. The tube was sealed with a glass stopper and stirred at 20°C for 7 days. After completion of the reaction, the crude product was filtered through celite, washed with CH2Cl2, and the filtrate was concentrated under reduced pressure. Then, the concentrated crude product was dissolved in CH2Cl2 (2.0 mL), TFA (4.0 mL, 0.2 mol / L CH2Cl2 solution) was added at 0°C, stirred for 3 minutes, and then TEA (0.1 mL, 0.8 mmol), Molecular sieves (107.8 mg) and PCC (107.8 mg, 0.5 mmol) were added, and the reaction mixture was warmed to room temperature and stirred until thin-layer chromatography showed the disappearance of the starting material. After completion of the reaction, aqueous NaHCO₃ was added to quench the reaction, and the mixture was extracted with dichloromethane (15 mL x 3). The combined organic phases were washed with water and brine, then dried over Na₂SO₄, filtered, and concentrated. Column chromatography was performed (petroleum ether / ethyl acetate = 6:1). The product was finally obtained as a white solid (25.1 mg, 54% yield, 87% ee). The enantioselectivity was greater than 99% ee after recrystallization once from petroleum ether / ethyl acetate = 5:1.

[0143] Product testing data are as follows:

[0144] mp:69.5-70.2℃; 1 H NMR (400MHz, CDCl3): δ6.82-6.79(m,3H),5.98(s,2H),5.32(s,1H),5.07(s,1H),4.49(t,J=8.4Hz,1H) ,4.10(t,J=8.0Hz,1H),3.73-3.65(m,1H),2.76(dd,J=17.2,8.4Hz,1H),2.55(dd,J=17.2,8.4Hz,1H); 13CNMR(100MHz, CDCl3): δ176.3,148.1,147.7,146.4,134.3,119.9,112.3,108.4,107.0,101.4,72.3,40.0,34.0; HRMS(ESI)[M+Na] + calculated for C 13 H 12 O4,255.0628,found255.0639; IR(KBr plate):3442,2991,2904,1776,1631,1605,1504,1490,1281,1172,966,867,656,645,559,522cm -1 .

[0145] Example 14

[0146] Using (E)-3-(1-(5-benzofuranyl))but-2-en-1-ol and tert-butyl vinyl ether as raw materials, the specific reaction is as follows:

[0147]

[0148] To a dry 10 mL reaction tube was added L17 (9.1 mg, 0.03 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), and A8 (15.5 mg, 0.03 mmol), followed by redistributed toluene (1.0 mL). The mixture was stirred at room temperature for 4 hours. (E)-3-(1-(5-benzofuranyl))but-2-en-1-ol (37.6 mg, 0.2 mmol), Mn(OAc)2 (2.6 mg, 0.015 mmol), MnO2 (20.8 mg, 0.24 mmol), tert-butyl vinyl ether (105.2 μL, 0.8 mmol), and additional redistributed toluene (1.0 mL). The tube was sealed with a glass stopper and stirred at 20°C for 7 days. After the reaction was complete, the solvent was evaporated, and acetone (1.0 mL) and Jones reagent (0.4 mL, 1 mol / L, 0.8 mmol) were added to the residue at 0°C. After the reaction was complete, the reaction was quenched by adding aqueous NaHCO3 solution and extracted with dichloromethane (15 mL × 3). The combined organic phase was washed with water and brine, then dried over Na2SO4, filtered, and concentrated. Column chromatography (petroleum ether / ethyl acetate = 6:1) was performed. The product was finally obtained as a colorless oil (22.8 mg, 50% yield, 92% ee).

[0149] Product testing data are as follows:

[0150] 1 H NMR (400MHz, CDCl3): δ7.66(d,J=2.4Hz,1H),7.54(d,J=1.6Hz,1H),7.49(d,J =8.8Hz,1H),7.26(dd,J=8.8,2.0Hz,1H),6.78(d,J=1.6Hz,1H),5.39(s,1H),5 .16(d,J=1.2Hz,1H), 4.50(dd,J=9.2,7.6Hz,1H), 4.13(dd,J=8.8,7.6Hz,1H), 3.86-3.78(m,1H),2.79(dd,J=17.2,8.0Hz,1H),2.60(dd,J=17.2,8.8Hz,1H); 13 C NMR (100MHz, CDCl3): δ176.5,154.8,147.1,146.0,135.3,127.9,123.1,119.2,113.1,111.6,106.8,72.4,40.6,34.1; HRMS(ESI)[M+H] + calculated for C 14 H 12 O3,229.0859,found 229.0852; IR(KBr plate):3299,2956,2917,2850,1776,1561,1443,1264,1170,1133,1112,1027,996,880,816,745,668,420cm -1 .

[0151] Example 15

[0152] Using (E)-3-(naphthalene-2-yl)but-2-en-1-ol and tert-butyl vinyl ether as raw materials, the specific reaction is as follows:

[0153]

[0154] To a dry 10 mL reaction tube was added L17 (9.1 mg, 0.03 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), and A8 (15.5 mg, 0.03 mmol), followed by redistributed toluene (1.0 mL). The mixture was stirred at room temperature for 4 hours. (E)-3-(naphthalen-2-yl)but-2-en-1-ol (39.6 mg, 0.2 mmol), Mn(OAc)2 (2.6 mg, 0.015 mmol), MnO2 (20.8 mg, 0.24 mmol), tert-butyl vinyl ether (105.2 μL, 0.8 mmol), and additional redistributed toluene (1.0 mL). The tube was sealed with a glass stopper and stirred at 20°C for 7 days. After the reaction was complete, the solvent was evaporated, and acetone (1.0 mL) and Jones reagent (0.4 mL, 1 mol / L, 0.8 mmol) were added to the residue at 0°C. After the reaction was complete, the reaction was quenched by adding aqueous NaHCO₃ solution and extracted with dichloromethane (15 mL × 3). The combined organic phases were washed with water and brine, then dried over Na₂SO₄, filtered, and concentrated. Column chromatography (petroleum ether / ethyl acetate = 6:1) was performed. The product was finally obtained as a white solid (23.8 mg, 50% yield, 91% ee). The enantioselectivity was greater than 99% ee after recrystallization once from petroleum ether / dichloromethane = 5:1.

[0155] Product testing data are as follows:

[0156] mp:55.3-56.2℃; 1 H NMR (400MHz, CDCl3): δ7.85-7.83(m,3H),7.76(s,1H),7.54-7.46(m,3H),5.54(s,1H),5.26(d,J=1.6Hz,1H),4.55(dd,J=8 .8,7.6Hz,1H),4.17(dd,J=9.2,7.6Hz,1H),3.95-3.87(m,1H),2.84(dd,J=17.2,8.4Hz,1H),2.63(dd,J=17.2,8.4Hz,1H); 13 C NMR (100MHz, CDCl3): δ176.3,146.9,137.4,133.4,133.1,128.6,128.2,127.8,126.8,126.6,125.3,124.6,113.7,72.5,40.0,34.1; HRMS(ESI)[M+Na] + calculated for C 16 H 14O2,261.0886,found 261.0894;IR(KBr plate):3056,2993,2916,1780,1626,1597,1505,1477,1418,1369,1274,1172,1026,997,900,862,823,754,682,621cm -1 .

[0157] Example 16

[0158] Using (E)-3-(thiophen-2-yl)but-2-en-1-ol and tert-butyl vinyl ether as raw materials, the specific reaction is as follows:

[0159]

[0160] To a dry 10 mL reaction tube was added L17 (9.1 mg, 0.03 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), and A8 (15.5 mg, 0.03 mmol), followed by redistributed toluene (1.0 mL). The mixture was stirred at room temperature for 4 hours. (E)-3-(thiophen-2-yl)but-2-en-1-ol (30.8 mg, 0.2 mmol), Mn(OAc)2 (2.6 mg, 0.015 mmol), MnO2 (20.8 mg, 0.24 mmol), tert-butyl vinyl ether (105.2 μL, 0.8 mmol), and additional redistributed toluene (1.0 mL). The tube was sealed with a glass stopper and stirred at 20°C for 7 days. After the reaction was complete, the solvent was evaporated, and acetone (1.0 mL) and Jones reagent (0.4 mL, 1 mol / L, 0.8 mmol) were added to the residue at 0°C. After completion of the reaction, the reaction was quenched by the addition of aqueous NaHCO₃ solution and extracted with dichloromethane (15 mL x 3). The combined organic phases were washed with water and brine, then dried over Na₂SO₄, filtered, and concentrated. Column chromatography (petroleum ether / ethyl acetate = 6:1) was performed. The product was obtained as a white solid (16.3 mg, 42% yield, 94% ee). The product was recrystallized once from petroleum ether / dichloromethane = 5:1, with an enantioselectivity greater than 99% ee.

[0161] Product testing data are as follows:

[0162] mp:64.8-65.2℃; 1H NMR (400MHz, CDCl3): δ7.34-7.32(m,1H),7.20-7.19(m,2H),5.50(s,1H),5.13(d,J=1.2Hz,1H),4.57(dd,J=8.8,7. 2Hz,1H),4.20(dd,J=9.2,6.8Hz,1H),3.74-3.66(m,1H),2.82(dd,J=17.2,8.4Hz,1H),2.61(dd,J=17.6,7.6Hz,1H); 13 C NMR(100MHz, CDCl3): δ176.4,141.3,141.1,126.5,125.9,121.0,111.5,72.4,39.8,34.0; HRMS(ESI)[M+H] + calculated for C 10 H 10 O2S,195.0475,found 195.0468; IR(KBr plate):3466,3401,2917,2851,1775,1678,1563,1448,1261,1166,1023,879,841,796,701cm -1 .

[0163] Example 17

[0164] Using (E)-3-(1-toluenesulfonyl-1-hydrogen-pyrrol-3-yl)but-2-en-1-ol and tert-butyl vinyl ether as raw materials, the specific reaction is as follows:

[0165]

[0166] To a dry 10 mL reaction tube was added L17 (9.1 mg, 0.03 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), and A8 (15.5 mg, 0.03 mmol), followed by redistributed toluene (1.0 mL). The mixture was stirred at room temperature for 4 hours. (E)-3-(1-tosyl-1-hydro-pyrrol-3-yl)but-2-en-1-ol (58.2 mg, 0.2 mmol), Mn(OAc)2 (2.6 mg, 0.015 mmol), MnO2 (20.8 mg, 0.24 mmol), tert-butyl vinyl ether (105.2 μL, 0.8 mmol), and additional redistributed toluene (1.0 mL). The tube was sealed with a glass stopper and stirred at 20°C for 7 days. After the reaction was complete, the solvent was evaporated, and acetone (1.0 mL) and Jones reagent (0.4 mL, 1 mol / L, 0.8 mmol) were added to the residue at 0°C. After the reaction was complete, the reaction was quenched by adding aqueous NaHCO3 solution and extracted with dichloromethane (15 mL × 3). The combined organic phases were washed with water and brine, then dried over Na2SO4, filtered, and concentrated. Column chromatography (petroleum ether / ethyl acetate = 6:1) was performed. The product was finally obtained as a colorless oil (34.5 mg, 52% yield, 91% ee).

[0167] Product testing data are as follows:

[0168] 1 H NMR (400MHz, CDCl3): δ7.76 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.14 (dd, J = 3. 2,2.4Hz,1H),7.11(t,J=2.0Hz,1H),6.40(dd,J=3.6,2.0Hz,1H),5.38(s,1H),5.03 (d, J=1.2Hz, 1H), 4.52 (dd, J=9.2, 7.6Hz, 1H), 4.18 (dd, J=8.8, 6.0Hz, 1H), 3.54-3. 47(m,1H),2.77(dd,J=17.2,8.4Hz,1H),2.54(dd,J=17.2,7.2Hz,1H),2.42(s,3H); 13 C NMR (100MHz, CDCl3): δ176.3,145.6,139.0,135.8,130.3(2C),128.5,127.0(2C),122.0,116.6,111.7,110.4,72.3,39.1,34.0,21.8HRMS(ESI)[M+H] + calculated for C17 H 17 NO4S,332.0951,found 332.0940;IR(KBr plate):3369,3135,2962,2925,2854,1776,1669,1626,1483,1449,1415,1 373,1261,1173,1143,1094,1068,1019,862,799,754,704,674,591,539cm -1 .

[0169] Example 18

[0170] Using (E)-3-(benzofuran-2-yl)but-2-en-1-ol and tert-butyl vinyl ether as raw materials, the specific reaction is as follows:

[0171]

[0172] To a dry 10 mL reaction tube was added L17 (9.1 mg, 0.03 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), and A8 (15.5 mg, 0.03 mmol), followed by redistributed toluene (1.0 mL). The mixture was stirred at room temperature for 4 hours. (E)-3-(Benzofuran-2-yl)but-2-en-1-ol (37.6 mg, 0.2 mmol), Mn(OAc)2 (2.6 mg, 0.015 mmol), MnO2 (20.8 mg, 0.24 mmol), tert-butyl vinyl ether (105.2 μL, 0.8 mmol), and additional redistributed toluene (1.0 mL). The tube was sealed with a glass stopper and stirred at 20°C for 7 days. After the reaction was complete, the solvent was evaporated, and acetone (1.0 mL) and Jones reagent (0.4 mL, 1 mol / L, 0.8 mmol) were added to the residue at 0°C. After the reaction was complete, the reaction was quenched by adding aqueous NaHCO₃ solution and extracted with dichloromethane (15 mL × 3). The combined organic phases were washed with water and brine, then dried over Na₂SO₄, filtered, and concentrated. Column chromatography (petroleum ether / ethyl acetate = 6:1) was performed. The product was finally obtained as a white solid (19.6 mg, 43% yield, 88% ee). The enantioselectivity was greater than 99% ee after recrystallization once from petroleum ether / dichloromethane = 5:1.

[0173] Product testing data are as follows:

[0174] mp:75.5-76.1℃; 1H NMR (400MHz, CDCl3): δ7.56(d,J=7.6Hz,1H),7.47(d,J=8.0Hz,1H),7.31(t,J=7.2Hz,1H),7.23(t,J=7.6Hz,1H),6.71(s,1H),5.99(s,1H),5 .32(s,1H),4.67(dd,J=9.2,7.6Hz,1H),4.32(dd,J=9.2,6.8Hz,1H),3.74(m,1H),2.89(dd,J=17.6,8.8Hz,1H),2.71(dd,J=17.6,7.6Hz,1H); 13 C NMR (100MHz, CDCl3): δ176.1,154.8,154.6,136.4,128.5,125.3,123.3,121.3,112.8,111.3,103.4,72.3,37.9,33.9; HRMS(ESI)[M+Na] + calculated for C 14 H 12 O3,251.0678,found251.0673;IR(KBr plate):3093,2917,1778,1681,1613,1554,1475,1452,1419,1369,1292,1179,1111,1068,1026,999,940,907,811,754,678cm -1 .

[0175] Example 19

[0176] Using (E)-3-(1-toluenesulfonyl-1-hydrogen-indol-3-yl)but-2-en-1-ol and tert-butyl vinyl ether as raw materials, the specific reaction is as follows:

[0177]

[0178] To a dry 10 mL reaction tube was added L17 (9.1 mg, 0.03 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), and A8 (15.5 mg, 0.03 mmol), followed by redistributed toluene (1.0 mL). The mixture was stirred at room temperature for 4 hours. (E)-3-(1-tosyl-1-hydrogen-indol-3-yl)but-2-en-1-ol (68.2 mg, 0.2 mmol), Mn(OAc)2 (2.6 mg, 0.015 mmol), MnO2 (20.8 mg, 0.24 mmol), tert-butyl vinyl ether (105.2 μL, 0.8 mmol), and additional redistributed toluene (1.0 mL). The tube was sealed with a glass stopper and stirred at 20°C for 7 days. After the reaction was complete, the solvent was evaporated and acetone (1.0 mL) and Jones reagent (0.4 mL, 1 mol / L, 0.8 mmol) were added to the residue at 0°C. After the reaction was complete, the reaction was quenched by adding aqueous NaHCO₃ solution and extracted with dichloromethane (15 mL × 3). The combined organic phases were washed with water and brine, then dried over Na₂SO₄, filtered, and concentrated. Column chromatography (petroleum ether / ethyl acetate = 6:1) was performed. The product was finally obtained as a white solid (34.3 mg, 45% yield, 94% ee). The enantioselectivity was greater than 99% ee after recrystallization once from petroleum ether / dichloromethane = 5:1.

[0179] Product testing data are as follows:

[0180] mp:79.8-80.7℃; 1 H NMR (400MHz, CDCl3): δ8.01(d,J=8.4Hz,1H),7.78(d,J=8.4Hz,2H),7.64(d,J= 8.0Hz,1H),7.53(s,1H),7.36(t,J=7.6Hz,1H),7.30-7.24(m,3H),5.56(s,1H) ,5.36(s,1H),4.51(t,J=8.0Hz,1H),4.16(dd,J=8.8,6.8Hz,1H),3.74-3.66(m ,1H),2.79(dd,J=17.2,8.4Hz,1H),2.57(dd,J=17.6,8.0Hz,1H),2.35(s,3H); 13C NMR (100MHz, CDCl3): δ176.1,145.5,138.8,135.4,135.0,130.2(2C),129.2,127.0(2C), 125.4,123.9,123.2,122.1,120.6,114.6,114.0,72.2,40.9,33.8,21.7; HRMS(ESI)[M+H] + calculated for C 21 H 19 NO4S,382.1108,found382.1098; IR(KBr plate):3468,3130,2925,1777,1668,1597,1477,1371,1279,1175,1141,1090,1022,961,814,717,575,537cm -1 .

[0181] Example 20

[0182] Using (E)-3,4-diphenylbut-2-en-1-ol and tert-butyl vinyl ether as raw materials, the specific reaction is as follows:

[0183]

[0184] To a dry 10 mL reaction tube, L17 (9.1 mg, 0.03 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), and A8 (15.5 mg, 0.03 mmol) were added, followed by redistributed toluene (1.0 mL). The mixture was stirred at room temperature for 4 hours. (E)-3,4-diphenylbut-2-en-1-ol (44.8 mg, 0.2 mmol), Mn(OAc)2 (2.6 mg, 0.015 mmol), MnO2 (20.8 mg, 0.24 mmol), tert-butyl vinyl ether (105.2 μL, 0.8 mmol), and additional redistributed toluene (1.0 mL) were then added. The tube was sealed with a glass stopper and stirred at 20°C for 7 days. After the reaction was complete, the solvent was evaporated, and acetone (1.0 mL) and Jones reagent (0.4 mL, 1 mol / L, 0.8 mmol) were added to the residue at 0°C. After the reaction was complete, the reaction was quenched by adding aqueous NaHCO3 solution and extracted with dichloromethane (15 mL × 3). The combined organic phases were washed with water and brine, then dried over Na2SO4, filtered, and concentrated. Column chromatography (petroleum ether / ethyl acetate = 8:1) was performed. The product E-formula was finally obtained as a white solid (10.6 mg, 20% yield, 90% ee), and the Z-formula was obtained as a white solid (15.9 mg, 30% yield, 97% ee). The enantioselectivity of the two configuration products was greater than 99% ee after recrystallization from petroleum ether / dichloromethane = 5:1.

[0185] Product testing data are as follows:

[0186] E-formula: mp:92.1-93.4℃; 1 H NMR (400MHz, CDCl3): δ7.42-7.40(m,6H),7.25-7.22(m,4H),6.70(s,1H),4.43 (t,J=8.8Hz,1H),4.22(t,J=8.8Hz,1H),4.10-4.01(m,1H),2.63-2.50(m,2H); 13 C NMR (100MHz, CDCl3): δ176.4,140.2,140.1,136.6,133.7,128.8(2C),128.74( 2C),128.68(2C),128.6(2C),127.9,127.7,71.5,37.2,33.6; HRMS(ESI)[M+Na] + calculated for C 18 H 16O2,287.1042,found 287.1037; IR(KBr plate):3055,3024,2916,1780,1561,1493,1445,1367,1229,1168,1019,930,879,842,779,760,698,656cm -1 .

[0187] Z-type: mp:84.2-85.3℃; 1 H NMR (400MHz, CDCl3): δ7.39-7.31(m,3H),7.11-7.08(m,5H),6.89-6.87(m,2H),6.51(s,1H),4.43(dd,J=8.8,8 .0Hz,1H),4.19(t,J=8.8Hz,1H),3.73-3.65(m,1H),2.71(dd,J=17.2,8.4Hz,1H),2.62(dd,J=17.2,9.6Hz,1H); 13 C NMR (100MHz, CDCl3): δ176.3,139.3,138.5,136.0,129.33(2C),129.31(2C),1 29.0(2C),128.5,128.2(2C),128.0,127.3,71.7,44.8,33.5; HRMS(ESI)[M+H] + calculated for C 18 H 16 O2,265.1223,found 265.1218; IR(KBr plate):3080,2913,2355,2320,1780,1598,1493,1446,1418,1233,1168,1113,1018,791,765,700,669cm -1 .

[0188] Example 21

[0189] Using (E)-4-(4-methoxyphenyl)3-phenylbut-2-ene-1-ol and tert-butyl vinyl ether as raw materials, the specific reaction is as follows:

[0190]

[0191] To a dry 10 mL reaction tube was added L17 (9.1 mg, 0.03 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), and A8 (15.5 mg, 0.03 mmol), followed by redistributed toluene (1.0 mL). The mixture was stirred at room temperature for 4 hours. (E)-4-(4-methoxyphenyl)-3-phenylbut-2-en-1-ol (50.8 mg, 0.2 mmol), Mn(OAc)2 (2.6 mg, 0.015 mmol), MnO2 (20.8 mg, 0.24 mmol), tert-butyl vinyl ether (105.2 μL, 0.8 mmol), and additional redistributed toluene (1.0 mL). The tube was sealed with a glass stopper and stirred at 20°C for 7 days. After the reaction was complete, the solvent was evaporated, and acetone (1.0 mL) and Jones reagent (0.4 mL, 1 mol / L, 0.8 mmol) were added to the residue at 0°C. After the reaction was complete, the reaction was quenched by adding aqueous NaHCO₃ solution and extracted with dichloromethane (15 mL × 3). The combined organic phases were washed with water and brine, then dried over Na₂SO₄, filtered, and concentrated. Column chromatography (petroleum ether / ethyl acetate = 6:1) was performed. The product E-formula was obtained as a white solid (12.7 mg, yield 22%, 87% ee), and the product Z-formula was obtained as a white solid (20.0 mg, yield 27%, 92% ee). The enantioselectivity of the two configurations was greater than 99% ee after recrystallization from petroleum ether / dichloromethane = 5:1.

[0192] Product testing data are as follows:

[0193] E-formula: mp:84.8-86.2℃; 1 H NMR (400MHz, CDCl3): δ7.41-7.34(m,3H),7.24-7.17(m,4H),6.95-6.92(m,2H),6.63(s,1H),4 .45(t,J=8.4Hz,1H),4.21(t,J=8.8Hz,1H),4.12-4.03(m,1H),3.84(s,3H),2.63-2.50(m,2H); 13 C NMR (100MHz, CDCl3): δ176.5,159.2,140.4,139.0,133.3,129.8(2C),129.0,128 .74(2C),128.72(2C),127.8,114.2(2C),71.6,55.5,37.2,33.7; HRMS(ESI)[M+H] + calculated for C 19 H 18O3,295.1329,found 295.1320;IR(KBr plate):2958,2922,2851,2376,2311,1780,1606,1510,1464,1249,1175,1110,1028,802,749,704,668,590,537cm -1 .

[0194] Z-type: mp:85.2-87.2℃; 1 H NMR (400MHz, CDCl3): δ7.41-7.31(m,3H),7.12-7.09(m,2H),6.82-6.78(m,2H),6.64-6.61(m,2H),6.44(s,1H),4.41(dd,J=8.8 ,7.6Hz,1H),4.18(t,J=8.8Hz,1H),3.72(s,3H),3.70-3.61(m,1H),2.68(dd,J=17.2,8.0Hz,1H),2.59(dd,J=17.2,9.6Hz,1H); 13 C NMR (100MHz, CDCl3): δ176.5,158.8,138.7,137.1,130.5(2C),129.4(2C),129. 1(2C),128.6,128.1,127.9,113.6(2C),71.8,55.3,44.9,33.5; HRMS(ESI)[M+H] + calculated for C 19 H 18 O3,295.1329,found295.1320; IR(KBr plate):3349,2928,1780,1607,1510,1448,1418,1252,1180,1142,1075,1009,974,862,830,741,705,668,533cm -1 .

[0195] Example 22

[0196] Using (E)-4-(4-trifluoromethylphenyl)3-phenylbut-2-ene-1-ol and tert-butyl vinyl ether as raw materials, the specific reaction is as follows:

[0197]

[0198] A dry 10 mL reaction tube was charged with L17 (9.1 mg, 0.03 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol) and A8 (15.5 mg, 0.03 mmol), followed by redistilled toluene (1.0 mL). The mixture was stirred at room temperature for 4 hours, followed by the addition of ((E)-4-(4-trifluoromethylphenyl)3-phenylbut-2-en-1-ol (58.4 mg, 0.2 mmol), Mn(OAc)2 (2.6 mg, 0.015 mmol), MnO2 (20.8 mg, 0.24 mmol), tert-butyl vinyl ether (105.2 μL, 0.8 mmol) and additional redistilled toluene (1.0 mL). The tube was sealed with a glass stopper and stirred at 20°C. Stir for 7 days. After the reaction was completed, the solvent was evaporated, and acetone (1.0 mL) and Jones reagent (0.4 mL, 1 mol / L, 0.8 mmol) were added to the residue at 0°C. After the reaction was completed, the reaction was quenched by adding aqueous NaHCO3 solution and extracted with dichloromethane (15 mL × 3). The combined organic phase was washed with water and brine, then dried over Na2SO4, filtered and concentrated. Column chromatography (petroleum ether / ethyl acetate = 8:1) was performed. The product E-formula was finally obtained as a white solid (10.0 mg, yield 15%, 91% ee) and the Z-formula was obtained as a white solid (19.3 mg, yield 29%, 96% ee). The enantioselectivity of the two configurations was greater than 99% ee after recrystallization from petroleum ether / dichloromethane = 5:1.

[0199] Product testing data are as follows:

[0200] E-formula: mp:54.3-55.8℃; 1 H NMR (400MHz, CDCl3): δ7.68(d,J=8.0Hz,2H),7.42-7.35(m,5H),7.26-7.23(m,2H),6.70( s,1H),4.43(t,J=8.8Hz,1H),4.23(t,J=8.8Hz,1H),4.02-3.96(m,1H),2.64-2.52(m,2H); 13 C NMR (100MHz, CDCl3): δ176.1,154.8,154.6,136.4,128.5,125.3,123.3,121.3,112.8,111.3,103.4,72.3,37.9,33.9; HRMS(ESI)[M+H] + calculated for C 19 H 15F3O2,333.1097,found333.1089; IR(KBr plate):2956,2918,2851,1781,1614,1445,1417,1325,1165,1118,1069,1016,887,862,830,706,669,600cm -1 .

[0201] Z-type: mp:51.8-52.3℃; 1 H NMR (400MHz, CDCl3): δ7.41-7.33(m,5H),7.10-7.08(m,2H),6.97(d,J=8.4Hz,2H),6.53(s,1H),4.44(dd,J=9.2, 8.0Hz,1H),4.21(t,J=8.4Hz,1H),3.76-3.67(m,1H),2.73(dd,J=17.2,8.0Hz,1H),2.63(dd,J=17.2,9.2Hz,1H); 13 C NMR (100MHz, CDCl3): δ176.1,142.1,139.6,137.8,129.5,129.4,129.2,128.8,128.7 ,128.4,127.1,125.5,125.1(q,J=14.4Hz),122.8,71.5,44.7,33.4; HRMS(ESI)[M+H] + calculated for C 19 H 15 F3O2,333.1097,found 333.1085; IR(KBrplate):3059,2923,2854,1782,1615,1494,1443,1417,1326,1166,1118,1069,1017,927,886,831,706,600,517cm -1 .

[0202] Example 23

[0203] Using (E)-3-phenyl-4-(thiophen-2-yl)but-2-en-1-ol and tert-butyl vinyl ether as raw materials, the specific reaction is as follows:

[0204]

[0205] To a dry 10 mL reaction tube was added L17 (9.1 mg, 0.03 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), and A8 (15.5 mg, 0.03 mmol), followed by redistributed toluene (1.0 mL). The mixture was stirred at room temperature for 4 hours. (E)-3-phenyl-4-(thiophen-2-yl)but-2-en-1-ol (46.0 mg, 0.2 mmol), Mn(OAc)2 (2.6 mg, 0.015 mmol), MnO2 (20.8 mg, 0.24 mmol), tert-butyl vinyl ether (105.2 μL, 0.8 mmol), and additional redistributed toluene (1.0 mL). The tube was sealed with a glass stopper and stirred at 20°C for 7 days. After the reaction was completed, the solvent was evaporated, and acetone (1.0 mL) and Jones reagent (0.4 mL, 1 mol / L, 0.8 mmol) were added to the residue at 0 ° C. After the reaction was completed, the reaction was quenched by adding aqueous NaHCO 3 solution and extracted with dichloromethane (15 mL × 3). The combined organic phase was washed with water and brine, then dried over Na 2 SO 4 , filtered and concentrated. Column chromatography (petroleum ether / ethyl acetate = 6:1) was performed. The product E-formula was finally obtained as a colorless oil (8.1 mg, yield 15%, 87% ee), and the Z-formula was obtained as a colorless oil (14.0 mg, yield 26%, 94% ee).

[0206] Product testing data are as follows:

[0207] E-formula: 1 H NMR (600MHz, CDCl3): δ7.40-7.34(m,4H),7.21-7.20(m,2H),7.08(dd,J=4.8,3.6Hz,1H),7.04(d,J=3.6Hz,1H),6.72(s,1H) ,4.64(t,J=8.4Hz,1H),4.43-4.37(m,1H),4.24(t,J=9.0Hz,1H),2.75(dd,J=17.4,9.0Hz,1H),2.56(dd,J=17.4,9.0Hz,1H); 13 C NMR (150MHz, CDCl3): δ176.5,140.2,138.4(2C),129.0,128.8(2C),128.5(2C),128.0,127.5,126.2,126.1,71.2,37.7,33.3; HRMS(ESI)[M+H] + calculated for C 16 H 14O2S,271.0788,found 271.0782; IR(KBr plate):2917,2851,1778,1560,1444,1261,1166,1017,879,865,801,703,668cm -1 .

[0208] Z-type: 1 H NMR (400MHz, CDCl3): δ7.50-7.45(m,3H),7.15-7.13(m,2H),7.02-7.00(m,1H),6.85-6.81(m,2H),6.74(s,1H),4.42(dd, J=8.8,8.0Hz,1H),4.18(t,J=8.8Hz,1H),3.68-3.59(m,1H),2.67(dd,J=17.2,8.4Hz,1H),2.58(dd,J=17.2,10.4Hz,1H); 13 C NMR (100MHz, CDCl3): δ176.2,139.6,137.2,136.6,129.8(2C),129.5(2C),128.84,128.76,126.7,126.3,122.9,71.3,44.9,33.2; HRMS(ESI)[M+H] + calculated for C 16 H 14 O2S,271.0788,found 271.0779; IR(KBr plate):2911,2376,2320,1779,1688,1491,1369,1229,1168,1016,795,668,513cm -1 .

[0209] Example 24

[0210] Using (Z)-4-((tert-butyldimethylsilyl)oxy))-3-phenylbut-2-ene-1-ol and tert-butyl vinyl ether as raw materials, the specific reaction is as follows:

[0211]

[0212] To a dry 10 mL reaction tube was added L17 (9.1 mg, 0.03 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), and A8 (15.5 mg, 0.03 mmol), followed by redissolved toluene (1.0 mL). The mixture was stirred at room temperature for 4 hours. (Z)-4-((tert-butyldimethylsilyl)oxy)-3-phenylbut-2-en-1-ol (55.6 mg, 0.2 mmol), Mn(OAc)2 (2.6 mg, 0.015 mmol), MnO2 (20.8 mg, 0.24 mmol), tert-butyl vinyl ether (105.2 μL, 0.8 mmol), and additional redissolved toluene (1.0 mL). The tube was sealed with a glass stopper and stirred at 20°C for 7 days. After the reaction was completed, the solvent was evaporated, and acetone (1.0 mL) and Jones reagent (0.4 mL, 1 mol / L, 0.8 mmol) were added to the residue at 0°C. After the reaction was completed, the reaction was quenched by adding aqueous NaHCO3 solution and extracted with dichloromethane (15 mL × 3). The combined organic phase was washed with water and brine, then dried over Na2SO4, filtered and concentrated. Column chromatography (petroleum ether / ethyl acetate = 15:1) was performed. The product E-formula was finally obtained as a colorless oil (13.4 mg, yield 21%, 86% ee), and the Z-formula was obtained as a colorless oil (20.4 mg, yield 32%, 84% ee).

[0213] Product testing data are as follows:

[0214] E-formula: 1 H NMR (400MHz, CDCl3): δ7.34-7.27(m,3H),7.16-7.14(m,2H),6.49(s,1H),4.55(t,J=8.4Hz,1H),4.33(t,J=8.8H z,1H),3.83-3.74(m,1H),2.78(dd,J=17.6,10.0Hz,1H),2.68(dd,J=17.6,9.6Hz,1H),0.96(s,9H),0.20(s,6H); 13 C NMR (100MHz, CDCl3): δ177.5,141.0,138.9,128.7,127.7,127.0,120.2,72.0,36.2,33.3,25.7,18.3,-5.2; HRMS(ESI)[M+Na] + calculated for C 18 H 26O3Si,341.1543,found 341.1534; IR(KBr plate):2955,2929,2857,1784,1735,1648,1561,1443,1256,1166,1019,837,786,753,700cm -1 .

[0215] Z-type: 1 H NMR (400MHz, CDCl3): δ7.33(t,J=8.0Hz,2H),7.23(d,J=7.6Hz,3H),6.38(s,1H),4.40(t,J=8.4Hz,1H),4.04(t,J=8 .8Hz,1H),3.59-3.51(m,1H),2.64(dd,J=17.2,8.0Hz,1H),2.48(dd,J=17.2,10.0Hz,1H),0.79(s,9H),0.08(s,6H); 13 C NMR (100MHz, CDCl3): δ176.7,137.8,135.9,129.2,128.3,127.1,119.0,72.5,39.1,33.7,25.5,18.2,-5.2; HRMS(ESI)[M+Na] + calculated for C 18 H 26 O3Si,341.1543,found 341.1532; IR(KBr plate):2955,2930,2858,1779,1686,1639,1597,1471,1447,1363,1256,1176,1010,930,836,787,754,702cm -1 .

[0216] Example 25

[0217] Using (Z)-3-phenyl-4-(trimethylsilyl)but-2-en-1-ol and tert-butyl vinyl ether as raw materials, the specific reaction is as follows:

[0218]

[0219] To a dry 10 mL reaction tube was added L17 (9.1 mg, 0.03 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), and A8 (15.5 mg, 0.03 mmol), followed by redissolved toluene (1.0 mL). The mixture was stirred at room temperature for 4 hours. (Z)-3-phenyl-4-(trimethylsilyl)but-2-en-1-ol (44.0 mg, 0.2 mmol), Mn(OAc)2 (2.6 mg, 0.015 mmol), MnO2 (20.8 mg, 0.24 mmol), tert-butyl vinyl ether (105.2 μL, 0.8 mmol), and additional redissolved toluene (1.0 mL) were then added. The tube was sealed with a glass stopper and stirred at 20°C for 7 days. After the reaction was complete, the solvent was evaporated, and acetone (1.0 mL) and Jones reagent (0.4 mL, 1 mol / L, 0.8 mmol) were added to the residue at 0°C. After the reaction was complete, the reaction was quenched by adding aqueous NaHCO3 solution and extracted with dichloromethane (15 mL × 3). The combined organic phases were washed with water and brine, then dried over Na2SO4, filtered, and concentrated. Column chromatography (petroleum ether / ethyl acetate = 15:1) was performed. The product Z-formula was finally obtained as a colorless oil (16.6 mg, 32% yield, 74% ee).

[0220] Product testing data are as follows:

[0221] Z-type: 1 H NMR (400MHz, CDCl3): δ7.35-7.33(m,3H),7.07(d,J=5.6Hz,2H),5.70(s,1H),4.34(t,J =8.8Hz,1H),4.11(t,J=8.8Hz,1H),3.59-3.51(m,1H),2.65-2.51(m,2H),-0.20(s,9H); 13 C NMR(100MHz, CDCl3): δ176.6,155.1,141.3,129.7,128.5,127.9,72.5,45.9,33.5,-0.09; HRMS(ESI)[M+Na] + calculated for C 15 H 20 O2Si,283.1125,found 283.1127; IR(KBr plate):2955,2930,2858,1779,1686,1639,1597,1471,1447,1363,1256,1176,1010,930,836,787,754,702cm -1 .

[0222] Example 26

[0223] Using (E)-2-(2,3-dihydro-1-hydro-indene-1-methylene)ethyl-1-ol and tert-butyl vinyl ether as raw materials, the specific reaction is as follows:

[0224]

[0225] To a dry 10 mL reaction tube was added L17 (9.1 mg, 0.03 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), and A8 (15.5 mg, 0.03 mmol), followed by redistributed toluene (1.0 mL). The mixture was stirred at room temperature for 4 hours. (E)-2-(2,3-dihydro-1-hydro-inden-1-methylene)ethyl-1-ol (32.0 mg, 0.2 mmol), Mn(OAc)2 (2.6 mg, 0.015 mmol), MnO2 (20.8 mg, 0.24 mmol), tert-butyl vinyl ether (105.2 μL, 0.8 mmol), and additional redistributed toluene (1.0 mL). The tube was sealed with a glass stopper and stirred at 20°C for 7 days. After the reaction was complete, the solvent was evaporated, and acetone (1.0 mL) and Jones reagent (0.4 mL, 1 mol / L, 0.8 mmol) were added to the residue at 0°C. After the reaction was complete, the reaction was quenched by adding aqueous NaHCO3 solution and extracted with dichloromethane (15 mL × 3). The combined organic phases were washed with water and brine, then dried over Na2SO4, filtered, and concentrated. Column chromatography (petroleum ether / ethyl acetate = 15:1) was performed. The product was finally obtained as a colorless oil (24.0 mg, 60% yield, 93% ee).

[0226] Product testing data are as follows:

[0227] 1 H NMR (400MHz, CDCl3): δ7.50 (d, J=7.2Hz, 1H), 7.35-7.24 (m, 3H), 6.36-6.35 (m, 1H), 4.71 (dd, J=9.2, 7.6Hz, 1H), 4.3 8(dd,J=8.8,6.4Hz,1H),3.86-3.78(m,1H),3.40(s,2H),2.94(dd,J=17.2,8.4Hz,1H),2.72(dd,J=17.6,7.6Hz,2H); 13C NMR(100MHz, CDCl3):176.6,144.7,143.4,142.6,128.6,126.5,125.6,124.4,118.9,72.1,38.0,34.6,33.8; HRMS(ESI)[M+Na] + calculated for C 13 H 12 O2,223.0729,found 223.0725; IR(KBr plate):2922,2851,1776,1621,1450,1419,1320,1261,1180,1176,1019,862,830,798,758,668,529cm -1 .

[0228] Example 27

[0229] Using (E)-2-(3,4-dihydronaphthalene-1(2H)-methylene)ethyl-1-ol and tert-butyl vinyl ether as raw materials, the specific reaction is as follows:

[0230]

[0231] To a dry 10 mL reaction tube was added L17 (9.1 mg, 0.03 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), and A8 (15.5 mg, 0.03 mmol), followed by redistributed toluene (1.0 mL). The mixture was stirred at room temperature for 4 hours. (E)-2-(3,4-dihydronaphthalen-1(2H)-methylene)ethyl-1-ol (34.8 mg, 0.2 mmol), Mn(OAc)2 (2.6 mg, 0.015 mmol), MnO2 (20.8 mg, 0.24 mmol), tert-butyl vinyl ether (105.2 μL, 0.8 mmol), and additional redistributed toluene (1.0 mL). The tube was sealed with a glass stopper and stirred at 20°C for 7 days. After the reaction was complete, the solvent was evaporated, and acetone (1.0 mL) and Jones reagent (0.4 mL, 1 mol / L, 0.8 mmol) were added to the residue at 0°C. After the reaction was complete, the reaction was quenched by adding aqueous NaHCO3 solution and extracted with dichloromethane (15 mL × 3). The combined organic phases were washed with water and brine, then dried over Na2SO4, filtered, and concentrated. Column chromatography (petroleum ether / ethyl acetate = 15:1) was performed. The product was finally obtained as a white solid (15.0 mg, 35% yield, 82% ee). The enantioselectivity was greater than 99% ee after recrystallization once from petroleum ether / dichloromethane = 5:1.

[0232] Product testing data are as follows:

[0233] mp:53.0-54.3℃; 1 H NMR (400MHz, CDCl3): δ7.25-7.17(m,3H),7.15-7.13(m,1H),5.98(td,J=4.4,0.8Hz,1H),4.63(dd,J=8.8,7.2Hz,1H),4.19(dd,J=8.8 ,6.4Hz,1H),3.83-3.75(m,1H),2.84(dd,J=17.2,8.4Hz,1H),2.74(t,J=8.0Hz,2H),2.61(dd,J=17.6,7.6Hz,1H),2.33-2.27(m,2H); 13 C NMR(150MHz, CDCl3):176.8,137.1,135.0,133.5,128.3,127.6,126.8,124.7,122.1,72.8,36.9,34.1,28.1,23.1; HRMS(ESI)[M+Na] + calculated for C 14 H 14 O2,237.0886,found 237.0887;IR(KBrplate):2932,2831,1778,1487,1419,1368,1172,1019,846,771,744,678cm -1 .

[0234] Example 28

[0235] Using (1-methyl-3,4-dihydronaphthalen-2-yl)methanol and tert-butyl vinyl ether as raw materials, the specific reaction is as follows:

[0236]

[0237] To a dry 10 mL reaction tube was added L17 (9.1 mg, 0.03 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), and A8 (15.5 mg, 0.03 mmol), followed by redissolved toluene (1.0 mL). The mixture was stirred at room temperature for 4 hours. (1-methyl-3,4-dihydronaphthalen-2-yl)methanol (34.8 mg, 0.2 mmol), Mn(OAc)2 (2.6 mg, 0.015 mmol), MnO2 (20.8 mg, 0.24 mmol), tert-butyl vinyl ether (105.2 μL, 0.8 mmol), and additional redissolved toluene (1.0 mL) were then added. The tube was sealed with a glass stopper and stirred at 20°C for 7 days. After the reaction was complete, the solvent was evaporated, and acetone (1.0 mL) and Jones reagent (0.4 mL, 1 mol / L, 0.8 mmol) were added to the residue at 0°C. After the reaction was complete, the reaction was quenched by adding aqueous NaHCO₃ solution and extracted with dichloromethane (15 mL × 3). The combined organic phases were washed with water and brine, then dried over Na₂SO₄, filtered, and concentrated. Column chromatography (petroleum ether / ethyl acetate = 15:1) was performed. The product was finally obtained as a white solid (21.9 mg, 51% yield, 94% ee). The enantioselectivity was greater than 99% ee after recrystallization once from petroleum ether / dichloromethane = 5:1.

[0238] Product testing data are as follows:

[0239] mp:53.0-54.3℃; 1 H NMR (400MHz, CDCl3): δ7.63-7.60(m,1H),7.25-7.19(m,2H),7.15-7.13(m,1H),5.67(s,1H),5.16(s,1H),4.39(d,J=9.2 Hz,1H),4.20(d,J=9.2Hz,1H),2.95(t,J=6.8Hz,2H),2.74(d,J=16.8Hz,1H),2.53(d,J=17.2Hz,1H),2.05-1.94(m,2H); 13 C NMR(100MHz, CDCl3):176.3,145.4,135.2,133.2,129.2,128.5,126.8,125.7,108.5,44.7,40.4,32.5,26.5; HRMS(ESI)[M+Na] + calculated for C 14 H 14O2,237.0886,found 237.0878;IR(KBr plate):3064,2925,2858,1780,1624,1486,1453,1372,1320,1270,1172,1012,975,903,861,845,778,737,668,512,423cm -1 .

[0240] Example 29

[0241] Using (Z)-3-phenyl-2-butene-1-ol and tert-butyl vinyl ether as raw materials, the specific reaction is as follows:

[0242]

[0243] To a dry 10 mL reaction tube was added L17 (9.1 mg, 0.03 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), and A8 (15.5 mg, 0.03 mmol), followed by redistributed toluene (1.0 mL). The mixture was stirred at room temperature for 4 hours. (Z)-3-phenyl-2-buten-1-ol (29.6 mg, 0.2 mmol), Mn(OAc)2 (2.6 mg, 0.015 mmol), MnO2 (20.8 mg, 0.24 mmol), tert-butyl vinyl ether (105.2 μL, 0.8 mmol), and additional redistributed toluene (1.0 mL) were then added. The tube was sealed with a glass stopper and stirred at 20°C for 7 days. After the reaction was complete, the solvent was evaporated, and acetone (1.0 mL) and Jones reagent (0.04 mL, 1 mol / L, 0.8 mmol) were added to the residue at 0°C. After the reaction was complete, the reaction was quenched by adding aqueous NaHCO3 solution and extracted with dichloromethane (15 mL × 3). The combined organic phase was washed with water and brine, then dried over Na2SO4, filtered, and concentrated. Column chromatography (petroleum ether / ethyl acetate = 6:1) was performed. The product was finally obtained as a colorless oil (20.3 mg, 54% yield, 91% ee).

[0244] Product testing data are as follows:

[0245] 1H NMR (400MHz, CDCl3): δ7.39-7.32(m,5H),5.40(s,1H),5.16(s,1H),4.50(t,J=8.0Hz,1H),4.12 (t,J=7.6Hz,1H),3.81-3.73(m,1H),2.78(dd,J=17.2,8.4Hz,1H),2.57(dd,J=17.2,8.4Hz,1H); 13 C NMR (100MHz, CDCl3): δ176.4,147.0,140.2,128.8(2C),128.3,126.5(2C),113.3,72.4,40.0,34.0; HRMS(ESI)[M+Na] + calculated for C 12 H 12 O2,211.0729,found 211.0724; IR(KBr plate):2917,2850,1777,1561,1442,1339,1261,1169,1113,1026,997,904,841,777,686,653,460cm -1 .

[0246] Example 30

[0247] Using (Z)-3-(4-tert-butylphenyl)but-2-en-1-ol and tert-butyl vinyl ether as raw materials, the specific reaction is as follows:

[0248]

[0249] To a dry 10 mL reaction tube was added L17 (9.1 mg, 0.03 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), and A8 (15.5 mg, 0.03 mmol), followed by redistributed toluene (1.0 mL). The mixture was stirred at room temperature for 4 hours. (Z)-3-(4-tert-butylphenyl)but-2-en-1-ol (40.8 mg, 0.2 mmol), Mn(OAc)2 (2.6 mg, 0.015 mmol), MnO2 (20.8 mg, 0.24 mmol), tert-butyl vinyl ether (105.2 μL, 0.8 mmol), and additional redistributed toluene (1.0 mL). The tube was sealed with a glass stopper and stirred at 20°C for 7 days. After the reaction was complete, the solvent was evaporated, and acetone (1.0 mL) and Jones reagent (0.4 mL, 1 mol / L, 0.8 mmol) were added to the residue at 0°C. After the reaction was complete, the reaction was quenched by adding aqueous NaHCO₃ solution and extracted with dichloromethane (15 mL × 3). The combined organic phases were washed with water and brine, then dried over Na₂SO₄, filtered, and concentrated. Column chromatography (petroleum ether / ethyl acetate = 6:1) was performed. The product was finally obtained as a white solid (23.4 mg, 48% yield, 91% ee). The enantioselectivity was greater than 99% ee after recrystallization once from petroleum ether / dichloromethane = 5:1.

[0250] Product testing data are as follows:

[0251] mp:44.2-45.6℃; 1 H NMR (400MHz, CDCl3): δ7.39-7.37(m,2H),7.28-7.25(m,2H),5.39(d,J=0.4Hz,1H),5.11(d,J=1.6Hz,1H),4.51(dd,J=9.2,7.6H z,1H),4.12(dd,J=9.2,7.6Hz,1H),3.80-3.72(m,1H),2.78(dd,J=17.2,8.4Hz,1H),2.57(dd,J=17.2,8.4Hz,1H),1.33(s,9H); 13 C NMR (100MHz, CDCl3): δ176.5,151.4,146.7,137.1,126.1(2C),125.7(2C),112.5,72.5,39.9,34.7,34.1,31.4(3C); HRMS(ESI)[M+Na] + calculated for C 12 H 12O2,267.1355,found 267.1341; IR(KBr plate):3439,2963,1779,1683,1603,1563,1477,1364,1269,1172,1111,1024,901,842,698,583cm -1 .

[0252] Example 31

[0253] Using (Z)-3-([1,1'-biphenyl]-4-yl)but-2-en-1-ol and tert-butyl vinyl ether as raw materials, the specific reaction is as follows:

[0254]

[0255] To a dry 10 mL reaction tube was added L17 (9.1 mg, 0.03 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), and A8 (15.5 mg, 0.03 mmol), followed by redissolved toluene (1.0 mL). The mixture was stirred at room temperature for 4 hours. (Z)-3-([1,1'-biphenyl]-4-yl)but-2-en-1-ol (44.8 mg, 0.2 mmol), Mn(OAc)2 (2.6 mg, 0.015 mmol), MnO2 (20.8 mg, 0.24 mmol), tert-butyl vinyl ether (105.2 μL, 0.8 mmol), and additional redissolved toluene (1.0 mL). The tube was sealed with a glass stopper and stirred at 20°C for 7 days. After the reaction was complete, the solvent was evaporated, and acetone (1.0 mL) and Jones reagent (0.4 mL, 1 mol / L, 0.8 mmol) were added to the residue at 0°C. After the reaction was complete, the reaction was quenched by adding aqueous NaHCO₃ solution and extracted with dichloromethane (15 mL × 3). The combined organic phases were washed with water and brine, then dried over Na₂SO₄, filtered, and concentrated. Column chromatography (petroleum ether / ethyl acetate = 6:1) was performed. The product was finally obtained as a white solid (28.5 mg, 54% yield, 87% ee). The enantioselectivity was greater than 99% ee after recrystallization once from petroleum ether / dichloromethane = 5:1.

[0256] Product testing data are as follows:

[0257] mp:112.1-113.9℃; 1H NMR (400MHz, CDCl3): δ7.59 (d, J = 8.0Hz, 4H), 7.47-7.34 (m, 5H), 5.46 (s, 1H), 5.17 (d, J = 0.8Hz, 1H), 4.53 (dd, J = 8. 8,8.0Hz,1H),4.14(t,J=7.6Hz,1H),3.83-3.76(m,1H),2.80(dd,J=17.2,8.4Hz,1H),2.59(dd,J=17.2,8.4Hz,1H); 13 C NMR (100MHz, CDCl3): δ176.3,146.5,141.2,140.4,138.9,129.0(2C),127.7,1 27.5(2C),127.1(2C),126.j8(2C),113.1,72.4,39.9,34.1; HRMS(ESI)[M+Na] + calculated for C 18 H 16 O2,287.1043,found 287.1054;IR(KBr plate):3299,2917[,2851,1794,1729,1625,1560,1448,1366,1260,1209,1159,1036,996,909,879,842,796,738,697,669cm -1 .

[0258] Example 32

[0259] Using (Z)-3-(naphthalene-2-yl)but-2-en-1-ol and tert-butyl vinyl ether as raw materials, the specific reaction is as follows:

[0260]

[0261] To a dry 10 mL reaction tube was added L17 (9.1 mg, 0.03 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), and A8 (15.5 mg, 0.03 mmol), followed by redistributed toluene (1.0 mL). The mixture was stirred at room temperature for 4 hours. (Z)-3-(naphthalen-2-yl)but-2-en-1-ol (39.6 mg, 0.2 mmol), Mn(OAc)2 (2.6 mg, 0.015 mmol), MnO2 (20.8 mg, 0.24 mmol), tert-butyl vinyl ether (105.2 μL, 0.8 mmol), and additional redistributed toluene (1.0 mL). The tube was sealed with a glass stopper and stirred at 20°C for 7 days. After the reaction was complete, the solvent was evaporated, and acetone (1.0 mL) and Jones reagent (0.4 mL, 1 mol / L, 0.8 mmol) were added to the residue at 0°C. After the reaction was complete, the reaction was quenched by adding aqueous NaHCO₃ solution and extracted with dichloromethane (15 mL × 3). The combined organic phases were washed with water and brine, then dried over Na₂SO₄, filtered, and concentrated. Column chromatography (petroleum ether / ethyl acetate = 6:1) was performed. The product was finally obtained as a white solid (23.8 mg, 50% yield, 89% ee). The enantioselectivity was greater than 99% ee after recrystallization once from petroleum ether / dichloromethane = 5:1.

[0262] Product testing data are as follows:

[0263] mp:52.9-54.7℃; 1 H NMR (400MHz, CDCl3): δ7.83(d,J=8.4Hz,3H),7.75(s,1H),7.52-7.45(m,3H),5.53(s,1H),5.23(s,1H),4.53(t,J =8.0Hz,1H),4.15(t,J=8.0Hz,1H),3.92-3.84(m,1H),2.81(dd,J=17.2,8.0Hz,1H),2.60(dd,J=17.2,8.4Hz,1H); 13 C NMR (100MHz, CDCl3): δ176.4,146.8,137.4,133.3,133.1,128.5,128.2,127.7,126.7,126.5,125.2,124.5,113.6,72.4,39.9,34.1; HRMS(ESI)[M+H] + calculated for C 16 H 14O2,239.1067,found 239.1059;IR(KBr plate):3301,3055,2958,2918,2851,1778,1626,1561,1445,1377,1261,1169,1097,1025,998,898,863,821,753,622,478cm -1 .

[0264] Example 33

[0265] Using (Z)-3-(1-toluenesulfonyl-1-hydrogen-pyrrol-3-yl)but-2-en-1-ol and tert-butyl vinyl ether as raw materials, the specific reaction is as follows:

[0266]

[0267] To a dry 10 mL reaction tube was added L17 (9.1 mg, 0.03 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), and A8 (15.5 mg, 0.03 mmol), followed by redistributed toluene (1.0 mL). The mixture was stirred at room temperature for 4 hours. (Z)-3-(1-tosyl-1-hydro-pyrrol-3-yl)but-2-en-1-ol (58.2 mg, 0.2 mmol), Mn(OAc)2 (2.6 mg, 0.015 mmol), MnO2 (20.8 mg, 0.24 mmol), tert-butyl vinyl ether (105.2 μL, 0.8 mmol), and additional redistributed toluene (1.0 mL). The tube was sealed with a glass stopper and stirred at 20°C for 7 days. After completion of the reaction, the solvent was evaporated under reduced pressure, and acetone (1.0 mL) and Jones reagent (0.4 mL, 1 mol / L, 0.8 mmol) were added to the residue at 0°C. After completion of the reaction, the reaction was quenched by adding aqueous NaHCO₃ solution and extracted with dichloromethane (15 mL x 3). The combined organic phases were washed with water and brine, then dried over Na₂SO₄, filtered, and concentrated. Column chromatography (petroleum ether / ethyl acetate = 6:1) was performed. The product was obtained as a colorless oil (28.5 mg, 43% yield, 88% ee).

[0268] Product testing data are as follows:

[0269] 1H NMR (400MHz, CDCl3): δ7.75 (d, J = 8.4Hz, 2H), 7.32 (d, J = 8.0Hz, 2H), 7.14 (dd, J = 3. 2,2.4Hz,1H),7.10(t,J=1.6Hz,1H),6.40(dd,J=3.2,1.6Hz,1H),5.38(s,1H),5.03 (d, J=1.2Hz, 1H), 4.52 (dd, J=9.6, 7.2Hz, 1H), 4.17 (dd, J=9.2, 6.4Hz, 1H), 3.54-3. 47(m,1H),2.77(dd,J=17.6,8.4Hz,1H),2.54(dd,J=17.2,7.2Hz,1H),2.42(s,3H); 13 C NMR (150MHz, CDCl3): δ176.3,145.6,139.1,135.8,130.3(2C),128.5,127. 1(2C),122.0,116.7,111.8,110.4,72.3,39.2,34.0,21.8; HRMS(ESI)[M+H] + calculated for C 17 H 17 NO4S,332.0951,found 332.0944;IR(KBr plate):3293,3135,2925,2855,1777,1627,1484,1450,1414,1372,1282,1261,1173,1143,1094,1068,1025,861,798,755,704,674,590,539cm -1 .

[0270] Example 34

[0271] Using (E)-3-phenyl-2-butene-1-ol and tert-butyl vinyl ether as raw materials, the specific reaction is as follows:

[0272]

[0273] To a dry 10 mL reaction tube was added ent-L17 (9.1 mg, 0.03 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), and A8 (15.5 mg, 0.03 mmol), followed by redistributed toluene (1.0 mL). The mixture was stirred at room temperature for 4 hours. (E)-3-phenyl-2-buten-1-ol (29.6 mg, 0.2 mmol), Mn(OAc)2 (2.6 mg, 0.015 mmol), MnO2 (20.8 mg, 0.24 mmol), tert-butyl vinyl ether (105.2 μL, 0.8 mmol), and additional redistributed toluene (1.0 mL) were then added. The tube was sealed with a glass stopper and stirred at 20°C for 7 days. After the reaction was complete, the solvent was evaporated, and acetone (1.0 mL) and Jones reagent (0.4 mL, 1 mol / L, 0.8 mmol) were added to the residue at 0°C. After the reaction was complete, the reaction was quenched by adding aqueous NaHCO3 solution and extracted with dichloromethane (15 mL × 3). The combined organic phases were washed with water and brine, then dried over Na2SO4, filtered, and concentrated. Column chromatography (petroleum ether / ethyl acetate = 6:1) was performed. The product was finally obtained as a colorless oil (21.8 mg, 58% yield, 91% ee).

[0274] Product testing data are as follows:

[0275] 7.39-7.30(m,5H),5.40(s,1H),5.16(d,J=1.6Hz,1H),4.50(dd,J=8.8,7.6Hz,1H),4.11(dd,J= 9.2,7.6Hz,1H),3.80-3.73(m,1H),2.78(dd,J=17.6,8.4Hz,1H),2.57(dd,J=17.2,8.4Hz,1H); 13 C NMR (100MHz, CDCl3): δ176.4,147.0,140.2,128.8(2C),128.3,126.5(2C),113.3,72.4,40.0,34.0; HRMS(ESI)[M+Na] + calculated for C 12 H 12 O2,211.0729,found 211.0724; IR(KBr plate):2917,2850,1777,1561,1442,1339,1261,1169,1113,1026,997,904,841,777,686,653,460cm -1 .

[0276] Example 35

[0277] Using (E)-3-(4-tert-butylphenyl)but-2-en-1-ol and tert-butyl vinyl ether as raw materials, the specific reaction is as follows:

[0278]

[0279] To a dry 10 mL reaction tube was added ent-L17 (9.1 mg, 0.03 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), and A8 (15.5 mg, 0.03 mmol), followed by redistributed toluene (1.0 mL). The mixture was stirred at room temperature for 4 hours. (E)-3-(4-tert-butylphenyl)but-2-en-1-ol (40.8 mg, 0.2 mmol), Mn(OAc)2 (2.6 mg, 0.015 mmol), MnO2 (20.8 mg, 0.24 mmol), tert-butyl vinyl ether (105.2 μL, 0.8 mmol), and additional redistributed toluene (1.0 mL). The tube was sealed with a glass stopper and stirred at 20°C for 7 days. After the reaction was complete, the solvent was evaporated, and acetone (1.0 mL) and Jones reagent (0.4 mL, 1 mol / L, 0.8 mmol) were added to the residue at 0°C. After the reaction was complete, the reaction was quenched by adding aqueous NaHCO₃ solution and extracted with dichloromethane (15 mL × 3). The combined organic phases were washed with water and brine, then dried over Na₂SO₄, filtered, and concentrated. Column chromatography (petroleum ether / ethyl acetate = 6:1) was performed. The product was finally obtained as a white solid (26.8 mg, 55% yield, 95% ee). The enantioselectivity was greater than 99% ee after recrystallization once from petroleum ether / dichloromethane = 5:1.

[0280] Product testing data are as follows:

[0281] mp:44.2-45.6℃; 1 H NMR (400MHz, CDCl3): δ7.39-7.37(m,2H),7.28-7.25(m,2H),5.39(d,J=0.4Hz,1H),5.11(d,J=1.6Hz,1H),4.51(dd,J=9.2,7.6H z,1H),4.12(dd,J=9.2,7.6Hz,1H),3.80-3.72(m,1H),2.78(dd,J=17.2,8.4Hz,1H),2.57(dd,J=17.2,8.4Hz,1H),1.33(s,9H); 13C NMR (100MHz, CDCl3): δ176.5,151.4,146.7,137.1,126.1(2C),125.7(2C),112.5,72.5,39.9,34.7,34.1,31.4(3C); HRMS(ESI)[M+Na] + calculated for C 12 H 12 O2,267.1355,found 267.1341; IR(KBr plate):3439,2963,1779,1683,1603,1563,1477,1364,1269,1172,1111,1024,901,842,698,583cm -1 .

[0282] Example 36

[0283] Using (E)-3-([1,1'-biphenyl]-4-yl)but-2-en-1-ol and tert-butyl vinyl ether as raw materials, the specific reaction is as follows:

[0284]

[0285] To a dry 10 mL reaction tube, ent-L17 (9.1 mg, 0.03 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), and A8 (15.5 mg, 0.03 mmol) were added, followed by redistributed toluene (1.0 mL). The mixture was stirred at room temperature for 4 hours. (E)-3-([1,1'-biphenyl]-4-yl)but-2-en-1-ol (44.8 mg, 0.2 mmol), Mn(OAc)2 (2.6 mg, 0.015 mmol), MnO2 (20.8 mg, 0.24 mmol), tert-butyl vinyl ether (105.2 μL, 0.8 mmol), and additional redistributed toluene (1.0 mL) were then added. The tube was sealed with a glass stopper and stirred at 20°C for 7 days. After the reaction was complete, the solvent was evaporated, and acetone (1.0 mL) and Jones reagent (0.4 mL, 1 mol / L, 0.8 mmol) were added to the residue at 0°C. After the reaction was complete, the reaction was quenched by adding aqueous NaHCO₃ solution and extracted with dichloromethane (15 mL × 3). The combined organic phases were washed with water and brine, then dried over Na₂SO₄, filtered, and concentrated. Column chromatography (petroleum ether / ethyl acetate = 6:1) was performed. The product was finally obtained as a white solid (29.0 mg, 55% yield, 90% ee). The enantioselectivity was greater than 99% ee after recrystallization once from petroleum ether / dichloromethane = 5:1.

[0286] Product testing data are as follows:

[0287] mp:112.1-113.9℃; 1 H NMR (400MHz, CDCl3): δ7.59 (d, J = 8.0Hz, 4H), 7.47-7.34 (m, 5H), 5.46 (s, 1H), 5.17 (d, J = 0.8Hz, 1H), 4.53 (dd, J = 8. 8,8.0Hz,1H),4.14(t,J=7.6Hz,1H),3.83-3.76(m,1H),2.80(dd,J=17.2,8.4Hz,1H),2.59(dd,J=17.2,8.4Hz,1H); 13 C NMR (100MHz, CDCl3): δ176.3,146.5,141.2,140.4,138.9,129.0(2C),127.7,1 27.5(2C),127.1(2C),126.j8(2C),113.1,72.4,39.9,34.1; HRMS(ESI)[M+Na] + calculated for C 18 H 16 O2,287.1043,found 287.1054;IR(KBr plate):3299,2917[,2851,1794,1729,1625,1560,1448,1366,1260,1209,1159,1036,996,909,879,842,796,738,697,669cm -1 .

[0288] The present invention not only realizes the catalytic asymmetric synthesis of chiral β-substituted-γ-butyrolactone compounds, but also utilizes this new synthesis method as one of the key synthesis steps to realize a new synthesis method of podophyllotoxin and its homologues and intermediate compounds for synthesizing such compounds. The technical scheme is as follows:

[0289] The primary purpose of the present invention is to provide synthetic podophyllotoxin and its homologues, the structural formula of the podophyllotoxin and its homologues are as follows:

[0290]

[0291] The structures of the chiral intermediate compounds for synthesizing podophyllotoxin and its homologues are as follows:

[0292]

[0293] The second part of the present invention is to provide a method for synthesizing podophyllotoxin, its homologues and chiral intermediate compounds in the synthesis process thereof, comprising the following steps:

[0294] (1) As starting materials, synthesize intermediate compounds

[0295] (2) The intermediate compound obtained in step (1) undergoes an intermolecular Aldol reaction with 3,4,5-trimethoxybenzaldehyde or an alkylation reaction with 3,4,5-trimethoxybenzyl bromide to produce intermediate compound 10 or 12:

[0296]

[0297] (3) The intermediate compound 10 or 12 is subjected to a Friedel-Crafts reaction or an enzyme-catalyzed cyclization reaction to obtain the intermediate compound 11 or 13:

[0298]

[0299] (4) The intermediate compound 11 or 13 is subjected to ozonation reaction to obtain (+)-isopodophyllotoxin (1), (-)-isopodophyllotoxin (2), (+)-picropodophyllotoxin (3), (-)-podophyllotoxin (5), and (-)-podophyllotoxin (6):

[0300]

[0301] (5) (+)-picropodophyllotoxin (3) and (-)-podophyllotoxin (6) are selectively reduced to give (+)-picropodophyllotoxin (4) and (-)-deoxypodophyllotoxin (7), respectively:

[0302]

[0303] Preferably, the method of step (1) is as follows:

[0304] ① First, 3,4-methylenedioxyacetophenone and triethyl phosphoacetate undergo Horner-Wadsworth-Emmons reaction under alkaline conditions, and then reduction is performed to obtain the intermediate compound pre-8. The reaction is as follows:

[0305]

[0306] ② The intermediate compound pre-8 and tert-butyl vinyl ether are reacted by Oshima-Utimoto-Larcock reaction to obtain the intermediate compound 8, as follows:

[0307]

[0308] ③ The intermediate compound 8 is de-tert-butylated and oxidized to PCC under acidic conditions to obtain the intermediate compound 9, as follows:

[0309]

[0310] Preferably, the base used in the Horner-Wadsworth-Emmons reaction under alkaline conditions in step ① is sodium hydride, and the reducing agent is lithium aluminum hydride.

[0311] Preferably, the acid used for de-tert-butylation under acidic conditions in step ③ is trifluoroacetic acid.

[0312] Preferably, the base used in the intermolecular Aldol reaction or alkylation reaction in step (2) is lithium diisopropylamide, and the reaction temperature is -78°C.

[0313] Preferably, the acid used in the Friedel-Crafts reaction in step (3) is trifluoroacetic anhydride, and the reaction temperature is 0°C.

[0314] Preferably, the enzyme used in the enzyme-catalyzed cyclization reaction in step (3) is 2-ODD dioxygenase.

[0315] Preferably, the quencher used in the ozonation reaction in step (4) is triphenylphosphine or sodium borohydride, and the temperature is -40°C.

[0316] Preferably, the selective reducing agent used in the selective reduction reaction in step (5) is lithium tri-tert-butoxyaluminum hydride or triethylsilyl hydride.

[0317] The present invention provides a method for catalytic asymmetric synthesis of podophyllotoxin and its homologues, and also provides a method for synthesizing intermediate compounds of podophyllotoxin and its homologues. By using readily available raw materials, a series of intermediate compounds for synthesizing podophyllotoxin and its homologues with novel structures are obtained through one-step or step-by-step reactions, and podophyllotoxin and its homologues are prepared. By using readily available chemical raw materials, catalytic asymmetric total synthesis of five natural products ((-)-podophyllotoxin, (-)-podophyllotoxin, (-)-deoxypodophyllotoxin, (-)-isopodophyllotoxin and (+)-picropodophyllotoxin) and two natural product enantiomers ((+)-isopodophyllotoxin and (+)-picropodophyllotoxin) can be achieved through 6-7 steps of reaction. The synthesis process of the present invention is simple, green, environmentally friendly, efficient, mild in conditions, and high in yield. The prepared podophyllotoxin and its homologues have biological activities such as antiviral, insecticidal, antifungal, anti-inflammatory, neurotoxic, immunosuppressive, anti-rheumatic, antioxidant, antispasmodic, lipid-lowering, anti-tumor, and microtubule assembly inhibition. Most importantly, the three compounds derived from podophyllotoxin can be used clinically for acute monocytic and acute myelomonocytic leukemia, acute myeloid leukemia, chronic eosinophilic leukemia, small cell lung cancer, non-Hodgkin's malignant lymphoma, testicular cancer, etc. In addition, more than ten compounds derived from podophyllotoxin are currently in phase II and phase III clinical studies and have broad application prospects.

[0318] The total synthesis reaction of the synthetic acetotoxin and its homologues and intermediate compounds of the present invention is as follows:

[0319]

[0320] Example 37

[0321] Preparation of compound pre-8

[0322] At 0°C, 60% pure sodium hydride (NaH) (1.6 g, 54.9 mmol) was dissolved in redistilled tetrahydrofuran (60 mL). Triethyl phosphoacetate (TEPA) (11.1 mL, 54.9 mmol) was added dropwise. Stir for 30 min until the solution became clear, then 3,4-methylenedioxyacetophenone (3 g, 18.3 mmol) was added. The mixture was refluxed in a 65°C oil bath for 24 h. The reaction was monitored by TLC. Upon completion, the temperature was lowered to 0°C and lithium aluminum hydride (2.08 g, 54.9 mmol) was added portionwise. Upon completion, saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by flash column chromatography using petroleum ether and ethyl acetate (6:1) as the mobile phase to obtain pre-8 (Z:E = 1:5, Z configuration as a clear liquid, E configuration as a white solid, 3.2 g, 75%).

[0323] Product testing data are as follows:

[0324] Spectral data (E-configuration):

[0325] 1 H NMR (600MHz, CDCl3, ppm): δ6.90 (s, 1H), 6.90-6.86 (m, 1H), 6.75 (d, J = 7.8Hz, 1H), 5.93 (s ,2H),5.87(td,J=6.6,1.2Hz,1H),4.31(t,J=5.4Hz,2H),2.17-2.08(m,1H),2.00(s,3H); 13 C NMR (150MHz, CDCl3, ppm): δ147.5,146.7,137.1,125.4,119.1,107.8,106.2,100.9,59.7,16.1; HRMS(ESI)m / z calculated for C 11 H 12 O3[MH2O + H] + :175.0754,found:175.0761;IR(KBr plate):3382,3073,2985,2890,2779,1711,1645,1607,1504,1487,1439,1382,135 3,1314,1277,1249,1231,1149,1113,1039,935,885,865,809,732,713,633,560cm -1 .

[0326] Spectral data of (Z-configuration):

[0327] 1 H NMR (600MHz, CDCl3, ppm): δ6.78(d,J=7.8Hz,1H),6.68(s,1H),6.63(d,J=8.4Hz,1H) ,5.95(s,2H),5.65(t,J=7.2Hz,1H),4.08(d,J=7.2Hz,2H),2.04(s,3H),1.55(s,1H); 13 C NMR (150MHz, CDCl3, ppm): δ147.4,146.6,139.6,134.6,126.0,121.1,108.2,107.9,100.9,60.2,25.4; HRMS (ESI) m / z calculated for C 11 H 12O3[MH2O + H] + :175.0754,found:175.0762;IR(KBr plate):2970,2937,2915,2888,1706,1605,1502,1489,1435,1376,1352,13 31,1238,1149,1110,1091,1040,997,936,899,865,811,729,706,648,619cm -1 .

[0328] Example 38

[0329] Preparation of compound 9

[0330] To a dry 10 mL reaction tube was added L17 (9.1 mg, 0.03 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), and A8 (15.5 mg, 0.03 mmol), followed by redistributed toluene (1.0 mL). The mixture was stirred at room temperature for 4 hours. (E)-3-(3,4-methylenedioxymethylphenyl)but-2-en-1-ol (38.4 mg, 0.2 mmol), Mn(OAc)2 (2.6 mg, 0.015 mmol), MnO2 (20.8 mg, 0.24 mmol), tert-butyl vinyl ether (105.2 μL, 0.8 mmol), and additional redistributed toluene (1.0 mL) were then added. The tube was sealed with a glass stopper and stirred at 20°C for 7 days. After completion of the reaction, the crude product was filtered through celite, washed with CH2Cl2, and the filtrate was concentrated under reduced pressure. Then, the concentrated crude product was dissolved in CH2Cl2 (2.0 mL), TFA (4.0 mL, 0.2 mol / L CH2Cl2 solution) was added at 0°C, stirred for 3 minutes, and then TEA (0.1 mL, 0.8 mmol), Molecular sieves (107.8 mg) and PCC (107.8 mg, 2.5 eq.) were added. The reaction mixture was warmed to room temperature and stirred until TLC indicated the disappearance of the starting material. After completion, aqueous NaHCO₃ was added to quench the reaction and extracted with dichloromethane (15 mL x 3). The combined organic phases were washed with water and brine, then dried over Na₂SO₄, filtered, and concentrated. Column chromatography was performed (petroleum ether / ethyl acetate = 6:1). The product was obtained as a white solid (25.1 mg, 54% yield, 87% ee). The enantioselectivity was greater than 99% ee after recrystallization once from petroleum ether / ethyl acetate = 5:1.

[0331] Product testing data are as follows:

[0332] mp:69.5-70.2℃; 1 H NMR (400MHz, CDCl3): δ6.82-6.79(m,3H),5.98(s,2H),5.32(s,1H),5.07(s,1H),4.49(t,J=8.4Hz,1H) ,4.10(t,J=8.0Hz,1H),3.73-3.65(m,1H),2.76(dd,J=17.2,8.4Hz,1H),2.55(dd,J=17.2,8.4Hz,1H); 13 CNMR(100MHz, CDCl3): δ176.3,148.1,147.7,146.4,134.3,119.9,112.3,108.4,107.0,101.4,72.3,40.0,34.0; HRMS(ESI)[M+Na] + calculated for C 13 H 12 O4,255.0628,found255.0639; IR(KBr plate):3442,2991,2904,1776,1631,1605,1504,1490,1281,1172,966,867,656,645,559,522cm -1 .

[0333] Example 39

[0334] Preparation of compound 10

[0335] At -78 ° C, lithium diisopropylamide (LDA) (17.4 mL, 6.6 mmol) was added dropwise to a solution of compound 9 (1.39 g, 6.0 mmol) in THF (60 mL) and stirred for 1 hour. Then, M6 (3,4,5-trimethoxybenzaldehyde) (1.41 g, 7.2 mmol) was dissolved in THF and added dropwise. After stirring for 30 minutes, the mixture was quenched with saturated NH4Cl and extracted with ethyl acetate (3×20 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (CH2Cl2:MeOH=100:1) to give the pure product 10 as a white solid in a 98% yield.

[0336] Product testing data are as follows:

[0337] mp:132.1-132.5℃; 1H NMR(600MHz,CDCl3,ppm):δ6.70(d,J=8.4Hz,1.2H),6.63(d,J=7.8Hz,1H),6.53-6.43(m,7.6H),6.39(d,J=1.8Hz,1H),5.95-5.93(m,4.3H),5.29(t,J=3.6Hz,1H),5.17(s,1.2H),5.12(s,1H),5.01(s,1.2H),4.95(s,1H),4.87(dd,J=7.2,1.8Hz,1.2H),4.56(t,J=9.0Hz,1H),4.41(t,J=8.4Hz,1.2H),4.15(dd,J=9.0,6.6Hz,1H),4.04(t,J=9.0Hz,1.2H),3.91(t,J=1.8Hz,1.2H),3.82(d,J=1.8Hz,6.5H),3.73(s,12H),3.61(dd,J=14.4,7.2Hz,1H),3.36(dd,J=17.4,8.4Hz,1.2H),3.12(brs,1H),3.07(dd,J=9.0,7.2Hz,1.2H),2.97(dd,J=7.2,2.4Hz,1H); 13 C NMR(150MHz,CDCl3,ppm):δ178.1,177.9,153.4,153.3,147.9,147.8,147.6,147.4,147.2,145.7,137.9,137.3,136.6,135.5,134.3,134.2,120.0,119.8,113.6,112.6,108.1,108.0,107.0,106.9,103.7,102.5,101.4,74.6,72.6,72.0,60.94,60.92,56.0,53.5,52.2,43.5,40.3;HRMS(ESI)m / z calculated for C 23 H 24 O8[M+Na] + :451.1363,found:451.1369;IR(KBr plate):3444,2979,2339,2840,1760,1705,1593,1505,1490,1463,1421,1384,1361,1328,1230,1236,1125,1085,1037,965,935,917,858,814,783,734,681,658cm -1 .

[0338] Example 40

[0339] Preparation of compound 11

[0340] To a solution of compound 10 (480 mg, 1.12 mmol) in CH2Cl2 (30 mL) at 0°C, TEA (0.93 mL, 6.72 mmol) and Tf2O (0.57 mL, 3.36 mmol) were added dropwise in sequence. The reaction was stirred at 0°C for 3 minutes, then quenched with aqueous NaHCO3 and extracted three times with CH2Cl2. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (CH2Cl2:Acetone = 120:1) to afford compound 11 in 82% yield.

[0341] Product testing data are as follows:

[0342] mp:251.5-253.2℃; 1 H NMR (600MHz, CDCl3, ppm): δ7.07 (s, 1H), 6.39 (s, 2H), 6.34 (s, 1H), 5.93 (s, 2H), 5.47 (d, J = 0.6Hz, 1H), 4.74 (d, J = 1.2Hz, 1H), 4.62 (dd, J = 7.8, 6.6Hz,1H),4.33(dd,J=10.2,9.0Hz,1H),4.13(d,J=11.4Hz,1H),3.85(s,3H),3.81(s,6H),3.17-3.12(m,1H),2.68(dd,J=14.4,12.0Hz,1H); 13 C NMR (150MHz, CDCl3, ppm): δ174.9,153.3,148.5,147.2,142.1,138.3,137.1,134.0,128 .4,110.0,106.6,104.5,104.0,101.5,68.8,61.0,56.3,49.1,47.5,44.7; HRMS(ESI)m / z calculated for C 23 H 22 O7[M+Na] +:433.1258,found:433.1265;IR(KBr plate):2965,2935,2848,1771,1700,1621,1591,1507,1486,1465,1424,1385,1367,1354,12 05,1184,1150,1128,931,902,876,855,783,758,732,702,676,634,619,596,588,542,530cm -1 .

[0343] Example 41

[0344] Preparation of (+)-Isopodophyllotoxin (1)

[0345] Compound 11 (20 mg, 0.048 mmol) was dissolved in DCM / MeOH (1.8 mL / 2 mL), Sudan Red III (0.2 mL, 0.0086 mg / mL in dichloromethane) was added, and the mixture was cooled to -40°C. Pyridine (20 μL, 0.24 mmol) was then added, and the ozone generation rate was controlled at 0.5 L / min. Ozone bubbles were slowly introduced. The reaction was stopped immediately when the system color changed from pink to colorless, and the remaining ozone gas was removed with argon. PPh3 (31.5 mg, 0.12 mmol) was then added and stirred at room temperature for 3 hours. After completion of the reaction, the solvent was concentrated under reduced pressure, and the residue was purified using a silica gel column (CH2Cl2:MeOH=200:1) to obtain (+)-isopodophyllotoxin (1) with a yield of 86%.

[0346] Product testing data are as follows:

[0347] mp:215.6-218.2℃; 1 H NMR (600MHz, CDCl3, ppm): δ7.45 (s, 1H), 6.40 (s, 3H), 6.03 (d, J = 4.2Hz, 2H), 4.65 (dd, J = 9.6, 7.2Hz, 1H), 4.44 (t, J =10.2Hz,1H),4.23(d,J=11.4Hz,1H),3.87(s,3H),3.83(s,6H),3.43-3.37(m,1H),3.08(dd,J=15.6,11.5Hz,1H); 13C NMR (150MHz, CDCl3, ppm): δ192.4,172.9,153.6,153.1,147.8,143.5,137.6,136 .1,128.1,109.7,105.6,102.4,66.4,61.0,56.3,49.8,48.2,47.4; HRMS(ESI)m / z calculated for C 22 H 20 O8[M+Na] + :435.1050,found:435.1058; IR(KBrplate):2985,2931,1782,1686,1621,1592,1511,1484,1465,1424, 1384,1362,1328,1259,1127,1090,1034,994,928,871,856,829,802,781,745,726,705,676,631,620cm -1 .

[0348] Example 42

[0349] Preparation of (-)-isopodophyllotoxin (2)

[0350] Compound 11 (20 mg, 0.048 mmol) was dissolved in DCM / MeOH (1.8 mL / 2 mL), Sudan Red III (0.2 mL, 0.0086 mg / mL in dichloromethane) was added, and the mixture was cooled to -40°C. Pyridine (20 μL, 0.24 mmol) was then added, and the ozone generation rate was controlled at 0.5 L / min. Ozone bubbles were slowly introduced. The reaction was stopped immediately when the system color changed from pink to colorless, and the remaining ozone gas was removed with argon. Sodium borohydride (4.5 mg, 0.12 mmol) was then added and stirred at -40°C for 4 hours. After completion of the reaction, the solvent was concentrated under reduced pressure, and the residue was purified using a silica gel column (CH2Cl2:MeOH=200:1) to obtain (+)-isopodophyllotoxin (2) with a yield of 84%.

[0351] Product testing data are as follows:

[0352] mp:271.4-273.1℃; 1H NMR (400MHz, CDCl3, ppm): δ7.11 (s, 1H), 6.37 (s, 2H), 6.32 (s, 1H), 5.94 (d, J = 3.2Hz, 2H), 4.91 (t, J = 9.6Hz, 1H), 4.68 (t, J = 7.6Hz, 1H) ,4.15(t,J=10.0Hz,1H),4.05(d,J=10.8Hz,1H),3.85(s,3H),3.81(s,6H),2.65(t,J=14.0Hz,1H),2.57-2.47(m,1H),2.03(brs,1H); 13 C NMR (100MHz, DMSO-d6, ppm): δ175.5,152.7,146.3,146.0,139.2,136.1,134.8,132.9 ,108.3,106.6,105.9,101.0,70.4,69.9,60.0,56.0,46.5,46.1,44.4; HRMS(ESI)m / z calculated for C22H 22 O8[M+Na] + :437.1207,found:437.1210;IR(KBr plate):2985,2937,1959,1743,1704,1621,1591,1507,1463,1417,1385,1319,1261,1204,1155,1124,1039,936,856,880,696cm -1 .

[0353] Example 43

[0354] Preparation of (+)-picropodophyllotoxin (3)

[0355] Compound 11 (20 mg, 0.048 mmol) was dissolved in DCM / MeOH (1.8 mL / 2 mL), Sudan III (0.2 mL, 0.0086 mg / mL in dichloromethane) was added, and the mixture was cooled to -40 °C. Pyridine (20 μL, 0.24 mmol) was then added, and the ozone generation rate was controlled at 0.5 L / min. Ozone bubbles were slowly introduced. The reaction was stopped immediately when the system color changed from pink to colorless, and the remaining ozone gas was removed with argon. Then PPh3 (31.5 mg, 0.12 mmol) was added and stirred at room temperature for 3 hours. After the reaction was completed, the solvent was concentrated under reduced pressure, and then the residue was dissolved in CHCl3 (1.0 mL), p-toluenesulfonic acid (16.5 mg, 0.096 mmol) was added, and refluxed at 80°C for 12 hours. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column (CH2Cl2:Acetone=30:1) to obtain (+)-picropodophyllin with a yield of 80%.

[0356] Product testing data are as follows:

[0357] mp:142.2-143.5℃; 1 H NMR (600MHz, CDCl3, ppm): δ7.50(s,1H),6.69(s,1H),6.24(s,2H),6.06(s,1H),6.05(s,1H),4.77(d, J=9.6Hz,1H),4.70(s,1H),4.36(dd,J=9.0,5.4Hz,1H),3.80(s,3H),3.76(s,6H),3.33-3.29(m,2H); 13 CNMR (150MHz, CDCl3, ppm): δ193.6,175.8,153.9,153.8,148.6,139.6,138.1,137.3, 127.3,109.5,106.1,104.6,102.4,70.7,60.9,56.3,46.8,43.5,43.4; HRMS(ESI)m / z calculatedfor C 22 H 20 O8[M+Na] +:435.1050,found:435.1058;IR(KBr plate):2959,5925,2872,2854,1772,1668,1615,1591,1505,1481,1464,1421,1404,134 1,1329,1258,1193,1127,1036,934,854,805,768,734,699,687,672,647,620,587,530cm -1 .

[0358] Example 44

[0359] Preparation of (+)-picropodophyllotoxin (4)

[0360] (+)-picropodophyllotoxin (20 mg, 0.048 mmol) was dissolved in dry tetrahydrofuran (2.0 mL) at room temperature, and then LiAlH(O t After completion of the reaction, the reaction was quenched by adding dilute aqueous hydrochloric acid and the mixture was extracted three times with CH2Cl2. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column (CH2Cl2:MeOH=120:1) to obtain (+)-picropodophyllotoxin in a yield of 93%.

[0361] Product testing data are as follows:

[0362] mp:227.3-228.1℃; 1 H NMR (600MHz, CDCl3, ppm): δ7.05 (s, 1H), 6.45 (s, 2H), 6.38 (s, 1H), 5.94 (d, J = 14.4Hz, 2H), 4.52-4.50 (m, 2H), 4.44 (dd, J = 9.6, 6. 6Hz,1H),4.12(d,J=5.4Hz,1H),3.86(s,3H),3.82(s,6H),3.24(dd,J=9.6,5.4Hz,1H),2.76-2.72(m,1H),2.19(d,J=7.8Hz,1H); 13C NMR (150MHz, CDCl3, ppm): δ178.0,153.7,147.5,147.2,139.4,137.2,132.1,130.7, 109.4,105.7,105.5,101.4,69.9,69.6,61.0,56.3,45.5,44.1,42.8; HRMS(ESI)m / z calculated for C 22 H 22 O8[M+Na] + :437.1207,found:437.1215;IR(KBr plate):2983,2939,2850,1959,1867,1770,1742,1705,1621,1592,1507,1477,1464,142 3,1385,1363,1336,1254,1156,1126,1092,1038,998,935,890,856,786,732,685,634cm -1 .

[0363] Example 45

[0364] Preparation of compound 12

[0365] At -78 ° C, lithium diisopropylamide (LDA) (17.4 mL, 6.6 mmol) was added dropwise to a solution of compound 9 (1.39 g, 6.0 mmol) in THF (60 mL) and stirred for 1 hour. Then, M9 (3,4,5-trimethoxybenzyl bromide) (1.88 g, 7.2 mmol) was dissolved in THF and added dropwise. After stirring for 2 hours, the mixture was quenched with saturated NH4Cl and extracted with ethyl acetate (3 × 20 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (CH2Cl2:MeOH=100:1) to give the pure product, compound 12, as a white solid, in an 84% yield.

[0366] Product testing data are as follows:

[0367] mp:112.3-113.5℃; 1H NMR (400MHz, CDCl3, ppm): δ6.73(d,J=8Hz,1H),6.64-6.61(m,2H),6.36(s,2H),5.96(s,2H),5.25(d,J=79.6Hz,2H) ,4.13(dt,J=167.6,8.4Hz,2H),3.84(s,3H),3.74(s,6H),3.31-3.24(m,1H),3.14-3.09(m,1H),3.00-2.93(m,1H); 13 C NMR (100MHz, CDCl3, ppm): δ177.7,153.1,147.9,147.5,145.3,136.6,134.1,132.8,119 .7,112.9,108.1,106.8,106.2,101.3,71.2,60.8,55.9,45.9,44.0,34.0; HRMS(ESI)m / z calculated for C 23 H 24 O7[M+Na] + :435.1414,found:435.1420;IR(KBr plate):2938,2839,1770,1704,1591,1506,1490,1460,1441,1423,1384,1351,1326,1239, 1185,1127,1073,1038,971,936,913,860,816,780,733,684,666,648,666,648,609,565cm -1 .

[0368] Example 46

[0369] Preparation of compound 13

[0370] A 250 ml Erlenmeyer flask was charged with a solution of 3-4L ((3R,4S)-4-(1-(benzo[d][1,3]dioxolyl)vinyl)-3-(3,4,5-trimethoxybenzyl)dihydrofuran-2(3H)-one) (32 mg, 0.0776 mmol) in 2.5 ml of DMSO, L-ascorbic acid (6.8 mg, 0.0388 mmol), and α-ketoglutaric acid (disodium salt, dihydrate, 44.0 mg, 0.194 mmol). 40 ml of 2-ODD-PH lysate (OD600 = 30) was added to the flask, followed by the addition of FeSO4·7H2O (2.2 mg, 0.00776 mmol). The reaction was stirred at 23°C, 200 rpm, and air-shaking for 20 hours. The mixture was then diluted with ethyl acetate (50 ml) and the resulting emulsion was filtered through celite to obtain a separable two-phase system. The mixture was extracted with ethyl acetate (400 mL x 3), concentrated in vacuo, and purified by column chromatography (petroleum ether / ethyl acetate = 2:1, P60 silica gel, caliber 40-63 μm, 230-400 mesh) to obtain white solid compound 13 with a yield of 75%.

[0371] Product testing data are as follows:

[0372] mp:111.5-113.2℃; 1 H NMR (400MHz, CDCl3, ppm): δ7.23(s,1H),6.56(s,1H),6.36(s,2H),5.99(d,J=10.0Hz,2H),5.55(s,1H),4.71(s,1H),4.66(d,J=4. 4Hz,1H),4.58(t,J=8.0Hz,1H),4.24(t,J=10.0Hz,1H),3.81(s,3H),3.75(s,6H),3.35-3.27(m,1H),2.88(dd,J=14.4,4.4Hz,1H); 13 C NMR (100MHz, CDCl3, ppm): δ174.7,152.7,148.7,147.7,141.5,137.2,135.1,132.4,128 .3,110.4,108.1,105.7,103.5,101.7,69.9,60.9,56.3,47.4,44.7,37.8; HRMS(ESI)m / z calculated for C 23 H 22 O7[M+H] +:411.1438,found:411.1427;IR(KBr plate):3322,2917,2851,2344,1780,1723,1587,1563,1504,1483,1452,14 20,1357,1329,1238,1188,1127,1072,1039,1008,935,878,800,752,668cm -1 .

[0373] Example 47

[0374] Preparation of (-)-podophyllotoxin (5)

[0375] Compound 13 (20 mg, 0.048 mmol) was dissolved in DCM / MeOH (1.8 mL / 2 mL), Sudan Red III (0.2 mL, 0.0086 mg / mL in dichloromethane) was added, and the mixture was cooled to -40°C. Pyridine (20 μL, 0.24 mmol) was then added, and ozone generation was controlled at a rate of 0.5 L / min. Ozone bubbles were slowly introduced. The reaction was stopped immediately when the system color changed from pink to colorless, and the ozone was purged with argon. PPh3 (31.5 mg, 0.12 mmol) was then added and stirred at room temperature for 3 hours. After completion of the reaction, the solvent was concentrated under reduced pressure, and the residue was purified using a silica gel column (PE:EA = 2:1) to obtain (-)-podophyllotoxin as a white solid with a yield of 86%.

[0376] Product testing data are as follows:

[0377] mp:189.5-190.8℃; 1 H NMR (400MHz, CDCl3, ppm): δ7.55(s,1H),6.71(s,1H),6.39(s,2H),6.10(d,J=6.4Hz,2H),4.85(d,J=4.4Hz,1H),4.56(d d,J=9.2,8.0Hz,1H),4.36(t,J=10.0Hz,1H),3.82(s,3H),3.75(s,6H),3.57-3.48(m,1H),3.29(dd,J=15.6,4.4Hz,1H); 13C NMR (100MHz, CDCl3, ppm): δ192.6,173.2,153.3,153.2,148.2,141.6,137.7,132.2, 128.3,109.8,107.7,106.2,102.5,67.1,60.9,56.4,46.8,44.8,43.6; HRMS(ESI)m / z calculated for C 22 H 20 O8[M+H] + :413.1231,found:413.1221;IR(KBr plate):3013,2914,2849,1784,1686,1617,1589,1504,1480,1420,1379,1327,1 248,1181,1127,1036,1009,933,887,861,831,797,751,705,668,616,529,420cm -1 .

[0378] Example 48

[0379] Preparation of (-)-podophyllotoxin (6)

[0380] Compound 13 (20 mg, 0.048 mmol) was dissolved in DCM / MeOH (1.8 mL / 2 mL), and Sudan Red III (0.2 mL, 0.0086 mg / mL in dichloromethane) was added. The mixture was cooled to -40°C, and pyridine (20 μL, 0.24 mmol) was then added. Ozone generation was controlled at a rate of 0.5 L / min and slowly introduced into the atmosphere. The reaction was stopped when the system color changed from pink to colorless, and the ozone was purged with argon. Sodium borohydride (4.5 mg, 0.12 mmol) was then added, and the mixture was stirred at -40°C for 4 hours. After completion of the reaction, the solvent was concentrated under reduced pressure, and the residue was purified on a silica gel column (PE:EA = 1:1) to obtain (-)-podophyllotoxin as a white solid in an 87% yield.

[0381] Product testing data are as follows:

[0382] mp:182.4-183.1℃; 1H NMR (400MHz, CDCl3, ppm): δ7.12(s,1H),6.51(s,1H),6.37(s,2H),5.98(d,J=8.0Hz,2H),4.77(t,J=8.8Hz,1H),4.63-4.59(m, 2H),4.09(t,J=10.0Hz,1H),3.81(s,3H),3.76(s,6H),2.85(dd,J=14.4,4.8Hz,1H),2.80-2.72(m,1H),2.19(d,J=8.4Hz,1H); 13 C NMR (100MHz, CDCl3, ppm): δ174.5,152.8,148.0,147.9,137.4,135.5,133.2,131.3, 110.0,108.5,106.4,101.6,73.0,71.5,60.9,56.4,45.5,42.2,40.9; HRMS(ESI)m / z calculated for C 22 H 22 O8[M+H] + :415.1387,found:415.1380;IR(KBr plate):3501,3440,3007,2925,2840,1775,1589,1505,1482,1421,1373,1330,1237,1187,1126,1079,1039,998,931,792,752,673cm -1 .

[0383] Example 49

[0384] Preparation of (-)-deoxypodophyllotoxin (7)

[0385] (-)-Podophyllotoxin (200 mg, 0.48 mmol) and triethylsilyl hydrochloride (116 μL, 0.72 mmol) were dissolved in DCM (10 mL) and cooled to 0°C. BF3·Et2O (65 μL) was then added dropwise. The mixture was stirred at room temperature for 2 hours, then diluted with water, washed with 5% NaHCO3 solution, dried over Na2SO4, and concentrated in vacuo to afford (-)-deoxypodophyllotoxin as a white solid in a 98% yield.

[0386] Product testing data are as follows:

[0387] mp:166.8-167.5℃; 1H NMR (400MHz, CDCl3, ppm): δ6.67(s,1H),6.52(s,1H),6.35(s,2H),5.94(d,J=9.2Hz,2H),4.61(s,1H),4.63-4 .46(dd,J=8.4,5.6Hz,1H),3.95-3.90(m,1H),3.81(s,3H),3.75(s,6H),3.12-3.04(m,1H),2.81-2.70(m,3H); 13 C NMR (100MHz, CDCl3, ppm): δ175.1,152.6,147.1,146.8,137.1,136.4,130.7,128.4, 110.6,108.6,108.3,101.3,72.2,60.9,56.3,47.6,43.8,33.2,32.8; HRMS(ESI)m / z calculated for C 22 H 22 O7[M+H] + :399.1438,found:399.1431;IR(KBr plate):2995,2916,2840,2251,1770,1588,1504,1484,1455,1379,1333,1289,122 6,1157,1127,1093,1038,998,958,943,929,866,799,769,731,682,647,558,426cm -1 .

[0388] The above embodiments of the present invention are used as examples to demonstrate a catalytic asymmetric synthesis method for a variety of β-substituted γ-butyrolactone compounds. This method uses allyl alcohol and an ether compound as reactants in an organic solvent, adds palladium acetate, a chiral ligand, an acidic additive, an oxidant, and a co-oxidant, and achieves the catalytic asymmetric synthesis of β-substituted γ-butyrolactone compounds. Furthermore, a catalytic asymmetric total synthesis method for active natural products such as podophyllotoxin and its homologues is provided. Using simple and readily available chemical raw materials, the catalytic asymmetric total synthesis of (+)-isopodophyllotoxin, (-)-isopodophyllotoxin, (+)-picropodophyllotoxin, (+)-picropodophyllotoxin, (-)-podophyllotoxin, (-)-podophyllotoxin, and (-)-deoxypodophyllotoxin can be achieved through 6 to 7 reaction steps.

[0389] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art will be able to modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein with equivalents. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the scope of protection of the present invention.

Claims

1. A catalytic asymmetric synthesis method of β-substituted γ-butyrolactone compounds, wherein the structural formula of the β-substituted γ-butyrolactone compounds is shown in formula (I). It is characterized in that The synthesis method comprises the following steps: under the action of palladium acetate, a chiral ligand, an acidic additive, an oxidant and a co-oxidant, an allyl alcohol compound and an ether compound react in an organic solvent to obtain the β-substituted γ-butyrolactone compound; In formula (I), R1 is an aryl group or a heteroaryl group, and R2 is a hydrogen atom, an aryl group or an alkoxy group.

2. The synthesis method according to claim 1, wherein The organic solvent is benzene, toluene, chlorobenzene, dichloromethane, tetrahydrofuran, ethyl acetate, ethylene glycol dimethyl ether; The chiral ligand types include bisoxazolines, pyridine oxazoles, and phosphoramidites; The acidic additives include: acetic acid, monochloroacetic acid, dichloroacetic acid, benzoic acid, 2-trifluoromethylbenzoic acid, 3-trifluoromethylbenzoic acid, 4-trifluoromethylbenzoic acid, 4-methoxybenzoic acid, 4-chlorobenzoic acid, 4-nitrobenzoic acid, 3,5-ditrifluoromethylbenzoic acid, and 3,5-dinitrobenzoic acid; The oxidant includes p-Benzoquinone, oxygen, manganese dioxide, hydrogen peroxide, iodobenzene acetate, dibenzoyl peroxide, tert-butyl hydroperoxide, potassium peroxymonosulfonate; The co-oxidants include: ferric chloride, ferric acetate, ferric trifluoromethanesulfonate, copper acetate, silver acetate, silver trifluoromethanesulfonate, manganese acetate, manganese acetate monohydrate, and manganese nitrate tetrahydrate; The olefin ether compounds include vinyl ethyl ether, butyl vinyl ether, isobutyl vinyl ether, tert-butyl vinyl ether, cyclohexyl vinyl ether, The allyl alcohol compounds include aryl allyl alcohol, heteroaryl allyl alcohol, 3. The synthesis method according to claim 2, wherein The allyl alcohol compounds include:

4. The synthesis method according to claim 3, wherein The β-substituted-γ-butyrolactone compounds include:

5. The synthesis method according to any one of claims 1 to 4, characterized in that The molar ratio of the allyl alcohol compound to the olefinic ether compound, palladium acetate, chiral ligand, acidic additive, co-oxidant and oxidant is 1:4:0.075:0.15:0.15:0.075:1.2。 6. A method for synthesizing podophyllotoxin, its homologues and chiral intermediate compounds in their synthesis, characterized in that: The synthetic method comprises the following steps: (1) As the starting material, the compound in claim 4 is synthesized (2) The intermediate compound 9 obtained in step (1) undergoes an intermolecular Aldol reaction with 3,4,5-trimethoxybenzaldehyde or an alkylation reaction with 3,4,5-trimethoxybenzyl bromide to produce the intermediate compound 10 or 12: (3) The intermediate compound 10 or 12 is subjected to a Friedel-Crafts reaction or an enzyme-catalyzed cyclization reaction to obtain the intermediate compound 11 or 13: (4) The intermediate compound 11 or 13 is subjected to ozonation reaction to obtain (+)-isopodophyllotoxin (1), (-)-isopodophyllotoxin (2), (+)-picropodophyllotoxin (3), (-)-podophyllotoxin (5), and (-)-podophyllotoxin (6): (5) (+)-picropodophyllotoxin (3) and (-)-podophyllotoxin (6) are selectively reduced to give (+)-picropodophyllotoxin (4) and (-)-deoxypodophyllotoxin (7), respectively:

7. The synthesis method according to claim 6, wherein The method of step (1) is as follows: ① First, 3,4-methylenedioxyacetophenone and triethyl phosphoacetate undergo Horner-Wadsworth-Emmons reaction under alkaline conditions, and then reduction is performed to obtain the intermediate compound pre-8. The reaction is as follows: ② The intermediate compound pre-8 and tert-butyl vinyl ether are reacted by Oshima-Utimoto-Larcock reaction to obtain the intermediate compound 8, as follows: ③ Intermediate compound 8 is obtained by removing the tert-butyl group under acidic conditions and then PCC oxidation to obtain intermediate compound 9, the reaction is as follows:

8. The synthesis method according to claim 7, wherein The base used in step ① is sodium hydride, sodium hydroxide, potassium carbonate, cesium carbonate, potassium tert-butoxide, and the reducing agent is lithium aluminum hydride, sodium borohydride, or diisobutylaluminum hydride; The acid used to remove the tert-butyl group under acidic conditions in step ③ is trifluoroacetic acid, hydrochloric acid, sulfuric acid, or p-toluenesulfonic acid; The base used in the intermolecular Aldol reaction or alkylation reaction in step (2) is lithium diisopropylamide, lithium dicyclohexylamide, lithium diphenylamide, NaHMDS, LiHMDS, sodium hydroxide, sodium tert-butoxide, and the temperature is -78°C, -40°C, or 0°C; The acid used in the Friedel-Crafts reaction in step (3) is ferric chloride, aluminum chloride, boron trifluoride etherate, iron trifluoromethanesulfonate, indium trifluoromethanesulfonate, scandium trifluoromethanesulfonate, tin trifluoromethanesulfonate, mercury trifluoromethanesulfonate, silver hexafluoroantimonate, or trifluoroacetic anhydride, and the reaction temperature is -20°C, -10°C, 0°C, or 20°C; The enzyme used in the enzymatic cyclization reaction of step (3) is 2-ODD dioxygenase, P450 ATRCase1 , bifunctional catalase EasC; The quenching agents used in the ozonation reaction in step (4) are triphenylphosphine, dimethyl sulfide, and sodium borohydride, and the reaction temperatures are -78°C, -40°C, and 0°C; The selective reducing agent used in the selective reduction reaction of step (5) is lithium aluminum hydride, diisobutylaluminum hydride, lithium tri-sec-butylborohydride, red aluminum, lithium tri-tert-butoxyaluminum hydride, triethylsilylsilyl and phenylsilyl.

9. Podophyllotoxin and its homologues obtained by the method according to any one of claims 6 to 8, characterized in that: The structural formula is as follows:

10. A chiral intermediate compound obtained in the synthesis process of podophyllotoxin and its homologues according to any one of claims 6 to 8, characterized in that: The structural formula is as follows:

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