Method for asymmetrically semi-synthesizing parsnilolactone or ring-expanded derivative of parsnilolactone

Abstract

The invention relates to the technical field of organic synthesis, in particular to a method for asymmetrically and semi-synthesizing parsnip lactone or an expanded ring derivative of parsnip lactone. According to the method, through a series of chemical reactions, including a ring closing addition reaction (RCM), an asymmetric alkenyl substitution reaction (AAS) and a ring opening ring closing addition reaction (ROM / RCM), a natural and rich precursor compound costunolide is converted into parsnilolactone or an expanded ring derivative thereof. The method has the characteristics of high efficiency, good selectivity and large-scale production, can provide possibility for large-scale synthesis of the parsnip lactone and the ring-expanded derivative thereof, is widely applied to the fields of drug discovery and treatment, and particularly has important potential in development of antiviral and anticancer drugs.

Description

Technical Field

[0001] This application relates to the field of organic synthesis technology, and in particular to a method for the asymmetric semi-synthesis of saposhnikovia lactone or its ring-expanded derivatives. Background Technology

[0002] Ovatodiolide (OVA) is a class of 14-membered macrocyclic diterpenoids with an α-methylene-γ-lactone structure, first isolated from the plant *Anisomeles indica*. OVA and its derivatives possess significant antitumor, anti-inflammatory, antiviral, and antifibrotic activities, making them an important source of lead molecules for novel drugs.

[0003] Because the natural content of saposhnikovia lactone is extremely low (<0.005% w / w), traditional plant extraction methods are difficult to meet the needs of subsequent pharmacological research and industrialization. At present, the synthetic routes of saposhnikovia lactone have the disadvantages of many steps, insufficient enantioselectivity and high cost, which prevent large-scale preparation.

[0004] Therefore, there is an urgent need to develop a simple, efficient, and enantioselective method for synthesizing saposhnikovia lactone. Summary of the Invention

[0005] Based on this, one or more embodiments of this application provide a method for the asymmetric semi-synthesis of saposhnikovia lactone or its ring-expanded derivatives, which is simple in steps, highly efficient in production, and highly enantioselective.

[0006] The method for the asymmetric semi-synthetic synthesis of saposhnikovia lactone or its ring-expanded derivatives according to this application includes the following steps:

[0007] Ⅰ; II; III;

[0008] IV; V;

[0009] VI;

[0010] The compound shown in Formula I was subjected to a ring-opening and metathesis reaction with ethylene to obtain the compound shown in Formula II.

[0011] The compound represented by Formula II was subjected to an isomerization reaction to obtain the compound represented by Formula III;

[0012] The compound shown in Formula III was subjected to a cross-olefin metathesis reaction with cis-1,4-dihalo-2-butene to obtain the compound shown in Formula IV; X is the halogen introduced by the cis-1,4-dihalo-2-butene.

[0013] In the presence of a rhodium catalyst and a chiral phosphine ligand, the compound shown in Formula IV and cycloalkenyl-1-carboxylic acid were subjected to an asymmetric allyl substitution reaction to obtain the compound shown in Formula V; The cycloalkenyl group introduced into the cycloalkenyl-1-carboxylic acid; Y is an alkylene group;

[0014] The compound represented by Formula V was subjected to a ring-opening-ring-closing metathesis tandem reaction to obtain the saposhnikovia lactone or its ring-expanded derivative represented by Formula VI; Y is an alkylene group.

[0015] In some embodiments, the step of preparing the compound of formula II by subjecting the compound of formula I to ethylene via a ring-opening and metathesis reaction includes:

[0016] In the gaseous atmosphere of ethylene, the compound represented by Formula I, the first olefin metathesis catalyst and the first solvent are mixed and heated under reflux for 2 h-3 h (e.g. 2 h, 2.5 h, 3 h, etc.) to obtain the compound represented by Formula II;

[0017] The first solvent includes at least one of dichloromethane and toluene.

[0018] Further, the molar amount of the first olefin metathesis catalyst is 4%-6% (e.g., 4%, 5%, 6%, etc.) of the molar amount of the compound represented by Formula I; and / or,

[0019] The ethylene gas atmosphere is an ethylene gas pressure of 0.8 atm-1.2 atm (e.g., 0.8 atm, 0.9 atm, 1 atm, 1.1 atm, 1.2 atm, etc.); and / or,

[0020] The first olefin metathesis catalyst includes at least one of Grubbs II catalyst and Hoveyda-Grubbs II catalyst.

[0021] In some embodiments, the step of isomerizing the compound represented by Formula II to obtain the compound represented by Formula III includes:

[0022] In an inert gas atmosphere, the compound represented by Formula II, vinyloxytrimethylsilane, a second olefin metathesis catalyst, and a second solvent are mixed and heated under reflux for 3-12 hours (e.g., 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, etc.) to obtain the compound represented by Formula III.

[0023] The second solvent includes at least one of dichloromethane, toluene, tetrahydrofuran, and 1,2-dichloroethane.

[0024] Further, the molar amount of the second olefin metathesis catalyst is 4%-6% (e.g., 4%, 5%, 6%, etc.) of the molar amount of the compound represented by Formula II; and / or,

[0025] The molar ratio of the compound represented by Formula II to the vinyloxytrimethylsilane is 1:(1.1-1.5) (e.g., 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, etc.); and / or,

[0026] The second olefin metathesis catalyst includes at least one of Grubbs I catalyst and Grubbs II catalyst.

[0027] In some embodiments, the step of preparing the compound of formula IV by subjecting the compound of formula III to a cross-olefin metathesis reaction with cis-1,4-dihalo-2-butene includes:

[0028] In an inert gas atmosphere, the compound represented by Formula III, the cis-1,4-dihalo-2-butene, and the third olefin metathesis catalyst are mixed and stirred for 50 min-70 min (e.g., 50 min, 60 min, 70 min, etc.) to obtain the compound represented by Formula IV.

[0029] Further, the molar number of the third olefin metathesis catalyst is 4%-6% of the molar number of the compound represented by Formula III; and / or,

[0030] The molar ratio of the compound represented by Formula III to the cis-1,4-dihalo-2-butene is 1:(0.5-0.7) (e.g., 1:0.5, 1:0.6, 1:0.7, etc.); and / or,

[0031] The third olefin metathesis catalyst includes at least one of Grubbs I catalyst, Grubbs II catalyst, and Hoveyda-Grubbs II catalyst.

[0032] In some embodiments, the step of reacting the compound of formula IV with cycloalkenyl-1-carboxylic acid in the presence of a rhodium catalyst and a chiral phosphine ligand to prepare the compound of formula V via an asymmetric allyl substitution reaction includes:

[0033] Under an inert gas atmosphere, the cycloalkenyl-1-carboxylic acid, the rhodium catalyst, the chiral phosphine ligand, the organic base, and the third solvent are mixed and stirred for 8 min-12 min (e.g., 8 min, 9 min, 10 min, 11 min, 12 min, etc.). Then, the compound shown in Formula IV is added and mixed, and stirred for 1 h-3 h (e.g., 1 h, 2 h, 3 h, etc.) to obtain the compound shown in Formula V.

[0034] The third solvent includes at least one of cyclohexane, tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, and toluene.

[0035] Further, the molar ratio of the rhodium catalyst to the chiral phosphine ligand is 1:(2-2.2) (e.g., 1:2, 1:2.1, 1:2.2, etc.); and / or,

[0036] The molar amount of the rhodium catalyst is 1.8%-2.2% (e.g., 1.8%, 1.9%, 2%, 2.1%, 2.2%, etc.) of the compound represented by Formula IV; and / or,

[0037] The molar ratio of the cycloalkenyl-1-carboxylic acid to the organic base is 1:(1-1.2) (e.g., 1:1, 1:1.1, 1:1.2, etc.); and / or,

[0038] The molar ratio of the cycloalkenyl-1-carboxylic acid and the compound represented by Formula IV is (1-1.2):1 (e.g., 1:1, 1:1.1, 1:1.2, etc.); and / or,

[0039] The chiral phosphine ligand comprises at least one of the following compounds:

[0040] ;

[0041] The rhodium catalyst includes at least one of (1,5-cyclooctadiene) rhodium chloride (I) dimer and bis(ethylene) rhodium chloride (I) dimer.

[0042] In some embodiments, the step of performing a ring-opening-ring-closing metathesis tandem reaction on the compound represented by Formula V to obtain the saposhnikovia lactone or its ring-expanded derivative represented by Formula VI includes:

[0043] In an inert gas atmosphere, the compound represented by formula V, the fourth olefin metathesis catalyst, and the fourth solvent are mixed and heated under reflux for 2-4 hours to obtain the saposhnikovia lactone or its ring-expanded derivative represented by formula VI.

[0044] The fourth solvent includes at least one of toluene, m-xylene, and mesitylene;

[0045] Furthermore, the fourth olefin metathesis catalyst is a Hoveyda-Grubbs II catalyst, and its molar number is 8%-12% of the molar number of the compound shown in Formula V.

[0046] This application uses the natural chiral sesquiterpene lactone (+)-Costunolide (the compound shown in Formula I) as the starting material. Based on a strategy combining skeletal recombination and asymmetric allyl substitution reactions, the process proceeds sequentially through ring-opening metathesis (ROM), double bond isomerization, cross-olefin metathesis (CM), Rh-catalyzed asymmetric allyl substitution reaction (AAS), and ring-opening-closing metathesis tandem reaction (ROM / RCM). This achieves efficient expansion from a ten-membered ring structure to a fourteen-membered macrocycle structure, completing the semi-synthetic route for the natural configuration (+)-Ovatodiolide (saposhnikovia lactone) or its ring-expanded derivatives.

[0047] The synthetic method of saposhnikovia lactone or its ring-expanded derivatives of this application is simple, mild, highly selective, and has precise stereocontrol. It can effectively overcome the problems of low yield of natural extraction, difficult purification and complex total synthetic route, and provide sufficient samples and technical basis for subsequent structure optimization, SAR (structure-activity relationship) research and drug development.

[0048] The synthetic method of saposhnikovia lactone or its ring-expanded derivatives of this application can construct ring-expanded derivatives of different ring sizes (including 14 to 16-membered rings) by changing the cycloalkenyl carboxylic acid substrate used in the AAS reaction, providing space for structural optimization.

[0049] The prepared products of this application, saposhnikovia lactone or its ring-expanded derivatives, have significant potential in antiviral and antitumor activity tests, laying the foundation for the development of highly selective natural product drugs. Attached Figure Description

[0050] To more clearly illustrate the technical solutions in the specific embodiments of this application or the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of this application. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0051] Figure 1 This is the synthetic route for saposhnikovia lactone or its ring-expanded derivatives as described in Example 1 of this application.

[0052] Figure 2 The structures and numbering of the compounds involved in Examples 1-4 of this application are shown. Detailed Implementation

[0053] The present application is further described below with reference to embodiments and examples. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the application. Furthermore, it should be understood that after reading the teachings of this application, those skilled in the art can make various alterations or modifications to this application, and these equivalent forms also fall within the protection scope of the appended claims.

[0054] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application.

[0055] In this document, "alkylene" refers to a hydrocarbon group derived from an alkyl group by removing one hydrogen atom to form a group with two monovalent groups at its center. This group can be a saturated branched alkyl group or a saturated straight-chain alkyl group. Alkylenes with 1 to 9 carbon atoms are preferred. Suitable examples include, but are not limited to: methylene (-CH2-), 1,1-ethyl (-CH(CH3)-), 1,2-ethyl (-CH2CH2-), 1,1-propyl (-CH(CH2CH3)-), 1,2-propyl (-CH2CH(CH3)-), 1,3-propyl (-CH2CH2CH2-), and 1,4-butyl (-CH2CH2CH2CH2-), etc.

[0056] In this article, "halogen" or "halogen group" refers to F, Cl, Br or I.

[0057] In this document, "cycloalkenyl" refers to a monovalent monocyclic group containing a carbon-carbon double bond in a ring formed by carbon atoms and lacking aromaticity. Cycloalkenyl groups with 4 to 8 carbon atoms are preferred, and suitable examples include, but are not limited to: , , , wait.

[0058] The following are some specific examples.

[0059] For experimental parameters not specified in the following specific embodiments, please refer to the guidelines given in this application document first, or refer to experimental manuals or other experimental methods known in the art, or refer to the experimental conditions recommended by the manufacturer.

[0060] The raw materials and reagents involved in the following specific embodiments can be obtained commercially or prepared by those skilled in the art using known methods.

[0061] In the following examples, when the product is a mixture of two isomers, no separation is performed since it does not affect the next reaction step; when the stereoselectivity is high (e.g., >20:1), no further purification is performed since the byproducts are negligible; compounds used for structural verification are obtained by semi-preparative separation and other methods. For example, compounds 12 and 10 in Example 1 are a mixture of cis-trans isomers, and the starting material compound 8a used for the synthesis of the natural product (+)-Ovatodiolide and compound 1aa contains negligible byproduct 8a'. Examples 2-4 are the same as in Example 1.

[0062] Example 1

[0063] 1. Synthesis of Compound 12

[0064]

[0065] (-)-Costunolide (1 g, 4.31 mmol) was dissolved in dichloromethane (170 mL, 0.025 M), and Grubbs II catalyst (0.18 g, 0.22 mmol) was added to the solution. The mixture was degassed three times with ethylene, and then refluxed and stirred for 2 hours under an ethylene balloon (1 atm). After confirming complete consumption of the starting material by TLC, the reaction was cooled to room temperature and degassed three times with argon. Vinyloxytrimethylsilane (0.75 g, 6.47 mmol, 1.5 equivalents) was added, and the resulting mixture was refluxed and stirred for 8 hours. The solvent was removed under reduced pressure, and the crude product was purified by rapid silica gel chromatography (petroleum ether / ethyl acetate = 50:1) to give compound 12 (0.97 g, 3.73 mmol) as an orange oil, in 86% yield (E / Z = 3:1). The detection data for compound 12 are as follows:

[0066] R f = 0.43 (ethyl acetate / petroleum ether = 1 / 8);

[0067] 1H NMR (400 MHz, CDCl3) δ 6.25 (d, J = 2.9 Hz, 1H), 5.57 (d, J = 2.5Hz, 1H), 5.52 – 5.30 (m, 2H), 5.20 (dd, J = 9.1, 1.2 Hz, 1H), 4.83 (dd, J =9.2, 5.9 Hz, 1H), 4.75 (s, 1H), 4.67 (s, 1H), 2.75 – 2.70 (m, 1H), 2.69 (d, J= 6.7 Hz, 2H), 2.05 (t, J = 7.8 Hz, 2H), 1.88 – 1.78 (m, 2H), 1.74 (d, J =1.1 Hz, 3H), 1.71 (s, 3H), 1.66 (dd, J = 6.2, 1.1 Hz, 3H);

[0068] 13 C NMR (101 MHz, CDCl3) δ 17.1, 18.0, 22.5, 30.8, 34.4, 42.7, 45.4,80.2, 111.0, 121.4, 123.0, 127.7, 127.8, 139.6, 143.2, 144.5, 170.4;

[0069] HRMS (ESI): m / z calcd for C 13 H 22 O2Na [M+Na] + : 283.1669, found:283.1668.

[0070] 2. Synthesis of Compound 10

[0071]

[0072] Hoveyda-Grubbs II catalyst (30 mg, 0.05 mmol), cis-1,4-dichloro-2-butene (72 mg, 0.58 mmol), and compound 12 (250 mg, 0.96 mmol) were added sequentially to a dry 10 mL round-bottom flask. The reaction mixture was stirred at room temperature for 1 h under argon protection. Rapid silica gel chromatography (petroleum ether / ethyl acetate = 30:1 → 20:1) yielded compound 10 (195 mg, 0.66 mmol) as a pale yellow oil in 72% yield (E / Z = 8:1). The detection data for compound 10 are as follows:

[0073] R f = 0.56 (ethyl acetate / petroleum ether = 1 / 5);

[0074] = +43.0 (c = 1.0 in CHCl3);

[0075] 1 H NMR (400 MHz, CDCl3) δ 6.27 (d, J = 2.9 Hz, 1H), 5.77 – 5.65 (m,2H), 5.59 (d, J = 2.5 Hz, 1H), 5.23 (dd, J = 9.1, 1.2 Hz, 1H), 4.84 (dd, J =9.1, 5.8 Hz, 1H), 4.77 (s, 1H), 4.68 (s, 1H), 4.04 (d, J = 6.1 Hz, 2H), 2.79(d, J = 6.0 Hz, 2H), 2.77-2.69 (m, 1H), 2.07 (t, J = 7.8 Hz, 2H), 1.77 (d, J= 1.2 Hz, 2H), 1.72 (s, 3H), 1.89-1.65 (m, 2H);

[0076] 13 C NMR (126 MHz, CDCl3). δ 17.2, 22.5, 30.9, 34.5, 42.0, 44.9, 45.4,79.9, 111.1, 121.7, 124.1, 128.7, 132.0, 139.4, 141.7, 144.4, 170.3;

[0077] HRMS (ESI): m / z calcd for C 20 H 32 O3Na [M+Na] + : 317.1279, found:317.1279.

[0078] 3. Synthesis of compounds 8a and 8a'

[0079]

[0080] Under argon protection, carboxylic acid 9 (19 mg, 0.19 mmol), [Rh(cod)Cl]2 (1.7 mg, 0.0034 mmol), and (S)-DTBM-Segphos (8 mg, 0.0068 mmol) were added sequentially to a dry round-bottom flask containing cyclohexane (10 mL). After adding Et3N (26 μL, 0.19 mmol), the mixture was stirred at room temperature for 10 min. Compound 10 (50 mg, 0.17 mmol) was added in a single addition, and the mixture was stirred at room temperature for 2 h (monitored by TLC). The reaction was quenched with water (2 mL) and extracted with ethyl acetate (4 × 2 mL). The combined organic layers were washed with brine (2 mL), dried over Na2SO4, and concentrated under reduced pressure. Rapid silica gel chromatography (petroleum ether / ethyl acetate = 20:1) yielded products 8a and 8a' (52 mg, 0.15 mmol), which were pale yellow oils with a yield of 86%, dr > 20:1, and B / L > 20:1.

[0081] The detection data for compound 8a are as follows:

[0082] R f = 0.49 (ethyl acetate / petroleum ether = 1 / 5);

[0083] = +44.3 (c = 1.0 in CHCl3);

[0084] 1 H NMR (400 MHz, CDCl3) δ 6.78 (s, 1H), 6.26 (d, J = 2.8 Hz, 1H), 5.79 (ddd, J = 17.0, 10.5, 6.3 Hz, 1H), 5.58 (d, J = 2.5 Hz, 1H), 5.45 (dd, J =13.1, 6.6 Hz, 1H), 5.32-5.23 (m, 2H), 5.18 (d, J = 10.5 Hz, 1H), 4.82 (dd, J= 9.2, 5.7 Hz, 1H), 4.76 (s, 1H), 4.67 (s, 1H), 2.80-2.60 (m, 3H), 2.52-2.45(m, 2H), 2.39 (dt, J = 23.0, 6.7 Hz, 2H), 2.03 (t, J = 7.8 Hz, 2H), 1.82 (s,3H), 1.76 (dd, J = 14.5, 6.5 Hz, 1H), 1.73-1.64 (m, 4H);

[0085] 13 C NMR (101 MHz, CDCl3) δ 17.6, 22.5, 27.3, 29.2, 30.9, 34.5, 44.5,45.6, 72.3, 79.6, 111.0, 117.2, 121.7, 126.5, 136.0, 138.7, 138.8, 139.4,144.5, 147.1, 161.4, 170.3;

[0086] HRMS (ESI): m / z calcd for C20H28O4Na [M+Na]+: 379.1880, found:379.1878.

[0087] The detection data for compound 8a' are as follows:

[0088] R f = 0.49 (ethyl acetate / petroleum ether = 1 / 5);

[0089] = +40.0 (c = 0.1 in CHCl3);

[0090] 1 H NMR (400 MHz, CDCl3) δ 6.77 (s, 1H), 6.27 (d, J = 2.7 Hz, 1H), 5.81 (ddd, J = 16.9, 10.5, 6.0 Hz, 1H), 5.57 (d, J = 2.3 Hz, 1H), 5.48 (dd, J =13.2, 6.1 Hz, 1H), 5.34-5.21 (m, 2H), 5.18 (d, J = 10.5 Hz, 1H), 4.83 (dd, J= 9.1, 5.6 Hz, 1H), 4.76 (s, 1H), 4.68 (s, 1H), 2.78-2.61 (m, 3H), 2.50-2.39(m, 3H), 2.38-2.30 (m, 1H), 2.03 (t, J = 8.0 Hz, 2H), 1.82 (s, 3H), 1.80-1.74(m, 1H), 1.72 (s, 3H), 1.70-1.64 (m, 1H);

[0091] 13C NMR (101 MHz, CDCl3) δ 17.4, 22.5, 27.3, 29.3, 31.0, 34.4, 44.8,45.7, 71.9, 79.6, 111.0, 117.0, 121.8, 126.6, 135.9, 138.7, 138.8, 139.3,144.5, 147.0, 161.3, 170.4;

[0092] HRMS (ESI): m / z calcd for C 20 H 28 O4Na [M+Na] + : 379.1880, found:379.1878.

[0093] 4. Synthesis of natural product (+)-Ovatodiolide and compound 1aa

[0094]

[0095] Under argon protection, a solution of compound 8a (290 mg, 0.81 mmol, 1.0 equivalent) and Hoveyda-Grubbs II (44 mg, 0.08 mmol, 0.1 equivalent) was added to a flame-dried round-bottom flask. Anhydrous toluene was then added to prepare a 0.0015 M solution of compound 8a, which was degassed three times with argon. The reaction mixture was refluxed and stirred until complete (monitored by TLC). After completion, the mixture was cooled to room temperature and the solvent was removed under vacuum. The residue was purified by silica gel rapid chromatography (petroleum ether / ethyl acetate = 5:1 to 3:1) to give the corresponding light brown oily product. Recrystallization of the light brown oily product from the petroleum ether / ethyl acetate system yielded pure Ovatodiolide, and the byproducts were separated by supercritical fluid chromatography. The weight of pure Ovatodiolide was 31 mg, with a yield of 70%.

[0096] The detection data for the natural product (+) – Ovatodiolide are as follows:

[0097] R f = 0.51 (ethyl acetate / petroleum ether = 1 / 1);

[0098] = +22.2 (c = 1.0 in CHCl3);

[0099] 1H NMR (400 MHz, CDCl3) δ 7.00 (s, 1H), 6.22 (d, , J = 1.9 Hz , 1H), 5.60 (d, , J = 1.7 Hz 1H), 5.15 (d, J = 10.2 Hz, 1H), 5.10 (s, 1H), 4.88 (d,, J = 5.9 Hz, 1H), 4.84 (dd, , J = 10.2 Hz, J = 1.6 Hz, 1H), 2.88 (dd, J =14.3, 3.2 Hz, 1H), 2.85-2.78 (m, 1H), 2.59-2.50 (m, 1H), 2.50-2.45 (m, 1H), 2.45-2.37 (m, 1H), 2.28 (dd, J = 14.7, 3.5 Hz, 1H), 2.24-2.14 (m, 1H), 2.15-2.08 (m, 1H), 2.08-2.00 (m, 1H), 1.75 (s, 3H), 1.70-1.64 (m, 2H), 1.62 (s, 3H);

[0100] 13 C NMR (101 MHz, CDCl3). δ 15.3, 19.5, 23.9, 25.1, 33.4, 36.5, 40.5,42.9, 78.1, 78.9, 122.9, 125.1, 129.4, 131.4, 134.5, 134.8, 139.9, 147.4,170.5, 173.1;

[0101] HRMS (ESI): m / z calcd for C 20 H 32 O3Na [M+Na] + : 351.1567, found:351.1566.

[0102] The detection data for compound 1aa are as follows:

[0103] R f = 0.51 (ethyl acetate / petroleum ether = 1 / 1);

[0104] = +32.2 (c = 0.1 in CHCl3);

[0105] 1H NMR (400 MHz, CDCl3) δ 6.94 (s, 1H), 6.23 (d, , J = 2.1 Hz , 1H), 5.66 (d, , J = 1.9 Hz 1H), 5.15 (d, J = 10.3 Hz, 1H), 5.12-5.08 (m, 2H), 4.69(dd, , J = 10.0 Hz, J = 2.9 Hz, 1H), 2.85 (dd, J = 14.2, 3.5 Hz, 1H), 2.81-2.68 (m, 1H), 2.56-2.34 (m, 4H), 2.27 (dd, J = 14.1, 3.7 Hz, 1H), 2.16-2.02(m, 1H), 2.02-1.90 (m, 1H), 1.90 -1.77 (m, 1H), 1.74 (s, 3H), 1.67 (d, J =1.3 Hz, 3H), 1.66-1.62 (m, 1H);

[0106] 13 C NMR (101 MHz, CDCl3). δ19.5, 22.9, 26.0, 26.3, 30.5, 32.9, 40.6,46.1, 78.6, 79.7, 122.6, 127.5, 128.7, 133.4, 134.2, 135.5, 140.2, 146.7,170.4, 173.4;

[0107] HRMS (ESI): m / z calcd for C 20 H 32 O3Na [M+Na] + : 351.1567, found:351.1566.

[0108] Example 2

[0109] 1. Synthesis of compound 8b

[0110]

[0111] Under argon protection, carboxylic acid 9b (19 mg, 0.19 mmol), [Rh(cod)Cl]2 (1.7 mg, 0.0034 mmol), and (S)-DTBM-Segphos (8 mg, 0.0068 mmol) were added sequentially to a dry round-bottom flask containing cyclohexane (10 mL). After adding Et3N (26 μL, 0.19 mmol), the mixture was stirred at room temperature for 10 min. Compound 10 (50 mg, 0.17 mmol) was added in a single batch, and the mixture was stirred at room temperature for 2 h (monitored by TLC). The reaction was quenched with water (2 mL) and extracted with ethyl acetate (4 × 2 mL). The combined organic layers were washed with brine (2 mL), dried over Na2SO4, and concentrated under reduced pressure. The product 8b (52 mg, 0.15 mmol) was purified by silica gel rapid chromatography (petroleum ether / ethyl acetate = 20:1) as a pale yellow oil with a yield of 78%, dr > 20:1, and B / L > 20:1.

[0112] The detection data for compound 8b are as follows:

[0113] R f = 0.53 (ethyl acetate / petroleum ether = 1 / 5);

[0114] = +40.0 (c = 0.1 in CHCl3);

[0115] 1H NMR (500 MHz, CDCl3) δ 6.79 (t, J = 2.1 Hz, 1H), 6.26 (d, J = 2.9Hz, 1H), 5.80 (ddd, J = 17.0, 10.5, 6.2 Hz, 1H), 5.58 (d, J = 2.5 Hz, 1H),5.47 (dd, J = 13.7, 6.2 Hz, 1H), 5.31-5.22 (m, 2H), 5.17 (d, J = 10.5 Hz,1H), 4.82 (dd, J = 9.2, 5.7 Hz, 1H), 4.76 (s, 1H), 4.67 (s, 1H), 2.70 (ddd, J= 11.0, 5.7, 3.0 Hz, 1H), 2.60-2.47 (m, 4H), 2.40 (ddd, J = 19.7, 14.0, 7.1Hz, 2H), 2.07-1.91 (m, 4H), 1.82 (d, J = 1.3 Hz, 3H), 1.72 (s, 3H), 1.85-1.66(m, 2H);

[0116] 13 C NMR (101 MHz, CDCl3). δ 17.6, 22.5, 23.2, 31.0, 31.5, 33.5, 34.6,44.6, 45.7, 72.3, 79.6, 111.0, 117.0, 121.6, 126.5, 136.2, 136.7, 139.0,139.5, 144.4, 144.5, 164.6, 170.3;

[0117] HRMS (ESI): m / z calcd for C 20 H 32 O3Na [M+Na] + : 393.2036, found:393.2034.

[0118] 2. Synthesis of compound 1ba

[0119]

[0120] Under argon protection, a solution of compound 8b (290 mg, 0.81 mmol, 1.0 equivalent) and Hoveyda-Grubbs II (44 mg, 0.08 mmol, 0.1 equivalent) was added to a flame-dried round-bottom flask. Anhydrous toluene was then added to prepare a 0.0015 M solution of compound 8b, which was degassed three times with argon. The reaction mixture was refluxed and stirred until complete (monitored by TLC). After completion, the mixture was cooled to room temperature and the solvent was removed under vacuum. The residue was purified by silica gel rapid chromatography (petroleum ether / ethyl acetate = 5:1 to 3:1) to give the corresponding light brown oily product.

[0121] The detection data for compound 1ba are as follows:

[0122] R f = 0.59 (ethyl acetate / petroleum ether = 1 / 1);

[0123] = +9.8 (c = 1.0 in CHCl3);

[0124] 1 H NMR (400 MHz, CDCl3) δ 7.03 (s, 1H), 6.25 (d, J = 3.3 Hz, 1H), 5.54 (d, J = 3.0 Hz, 1H), 5.40 (d, J = 9.9 Hz, 1H), 5.16 (s, 1H), 5.08 (t, J = 7.5Hz, 1H), 4.74 (dd, J = 9.8, 8.1 Hz, 1H), 2.97 (dd, J = 14.2, 4.2 Hz, 1H), 2.70 (td, J = 8.0, 3.8 Hz, 1H), 2.44 (dd, J = 14.2, 3.8 Hz, 1H), 2.41-2.36(m, 1H), 2.23-2.13 (m, 1H), 1.99-1.93 (m, 1H), 1.92-1.83 (m, 4H), 1.82 (s,3H), 1.77 – 1.71 (m, 2H), 1.71 (s, 3H), 1.46-1.37 (m, 1H);

[0125] 13C NMR (101 MHz, CDCl3). δ19.5, 22.7, 23.0, 25.3, 26.0, 28.5, 29.7,41.1, 45.7, 79.2, 79.6, 121.0, 124.5, 129.3, 135.5, 135.7, 136.1, 139.0,145.9, 170.2, 173.8;

[0126] HRMS (ESI): m / z calcd for C 20 H 32 O3Na [M+Na] + : 365.1723, found:365.1723.

[0127] Example 3

[0128] 1. Synthesis of compound 8c

[0129]

[0130] Under argon protection, carboxylic acid 9c (19 mg, 0.19 mmol), [Rh(cod)Cl]2 (1.7 mg, 0.0034 mmol), and (S)-DTBM-Segphos (8 mg, 0.0068 mmol) were added sequentially to a dry round-bottom flask containing cyclohexane (10 mL). After adding Et3N (26 μL, 0.19 mmol), the mixture was stirred at room temperature for 10 min. Compound 10 (50 mg, 0.17 mmol) was added in a single batch, and the mixture was stirred at room temperature for 2 h (monitored by TLC). The reaction was quenched with water (2 mL) and extracted with ethyl acetate (4 × 2 mL). The combined organic layers were washed with brine (2 mL), dried over Na2SO4, and concentrated under reduced pressure. The product was purified by silica gel rapid chromatography (petroleum ether / ethyl acetate = 20:1) to give product 8c (52 mg, 0.15 mmol), which was a pale yellow oil with a yield of 77%, dr > 20:1, and B / L > 20:1.

[0131] The detection data for compound 8c are as follows:

[0132] R f = 0.58 (ethyl acetate / petroleum ether = 1 / 5);

[0133] = +48.0 (c = 0.5 in CHCl3);

[0134] 1H NMR (500 MHz, CDCl3) δ 7.01 – 6.97 (m, 1H), 6.26 (d, J = 2.8 Hz, 1H), 5.80 (ddd, J = 17.0, 10.5, 6.2 Hz, 1H), 5.58 (d, J = 2.5 Hz, 1H), 5.46(dd, J = 13.6, 6.2 Hz, 1H), 5.30-5.22 (m, 2H), 5.16 (d, J = 10.5 Hz, 1H), 4.81 (dd, J = 9.2, 5.7 Hz, 1H), 4.76 (s, 1H), 4.67 (s, 1H), 2.70 (ddd, J =8.3, 5.7, 3.0 Hz, 1H), 2.40 (ddd, J = 19.7, 13.7, 6.9 Hz, 2H), 2.27-2.16 (m,4H), 2.04 (t, J = 7.9 Hz, 2H), 1.82 (d, J = 1.1 Hz, 3H), 1.72 (s, 3H), 1.86 –1.56 (m, 6H);

[0135] 13 C NMR (101 MHz, CDCl3). δ 17.5, 21.6, 22.2, 22.5, 24.3, 26.0, 30.9,34.5, 44.6, 45.6, 72.3, 79.6, 111.0, 116.9, 121.6, 126.4, 130.4, 136.3,139.0, 139.4, 140.3, 144.5, 166.8, 170.3;

[0136] HRMS (ESI): m / z calcd for C 20 H 32 O3Na [M+Na] + : 407.2193, found:407.2190.

[0137] 2. Synthesis of compounds 1c and 1ca

[0138]

[0139] Under argon protection, a solution of compound 8c (290 mg, 0.81 mmol, 1.0 equivalent) and Hoveyda-Grubbs II (44 mg, 0.08 mmol, 0.1 equivalent) was added to a flame-dried round-bottom flask. Anhydrous toluene was then added to prepare a 0.0015 M solution of compound 8c, which was degassed three times with argon. The reaction mixture was refluxed and stirred until complete (monitored by TLC). After completion, the mixture was cooled to room temperature and the solvent was removed under vacuum. The residue was purified by silica gel rapid chromatography (petroleum ether / ethyl acetate = 5:1 to 3:1) to give the corresponding light brown oily product.

[0140] The detection data for compound 1c are as follows:

[0141] R f = 0.60 (ethyl acetate / petroleum ether = 2 / 3);

[0142] = +40.0 (c = 1.0 in CHCl3);

[0143] 1 H NMR (400 MHz, CDCl3) δ 6.94 (d, J = 1.4 Hz, 1H), 6.26 (d, J = 2.2Hz, 1H), 5.61 (d, J = 1.9 Hz, 1H), 5.29 (d, J = 8.5 Hz, 1H), 5.15-5.03 (m,2H), 4.81 (dd, J = 8.6, 3.7 Hz, 1H), 2.72 – 2.60 (m, 2H), 2.46 – 2.30 (m,2H), 2.27- 2.20 (m, 1H), 2.19-2.14 (m, 2H), 2.13-2.06 (m, 2H), 1.79 (s, 3H),1.77-1.66 (m, 2H), 1.63 (s, 3H), 1.57 -1.44 (m, 3H), 1.40-1.34 (m, 1H);

[0144] 13 C NMR (101 MHz, CDCl3). δ 16.3, 18.2, 24.4, 26.1, 26.9, 28.0, 31.4,35.3, 43.3, 44.4, 78.4, 79.5, 122.5, 126.8, 129.6, 133.9, 135.1, 135.4,139.2, 146.4, 170.3, 173.5;

[0145] HRMS (ESI): m / z calcd for C 20 H 32 O3Na [M+Na] + : 379.1880, found:379.1879.

[0146] The detection data for compound 1ca are as follows:

[0147] R f = 0.60 (ethyl acetate / petroleum ether = 2 / 3);

[0148] = -29.9 (c = 0.1 in CHCl3);

[0149] 1 H NMR (400 MHz, CDCl3) δ 6.97 (s, 1H), 6.30 (d, J = 3.2 Hz, 1H), 5.60 (d, J = 2.8 Hz, 1H), 5.34 (d, J = 9.4 Hz, 1H), 5.16-5.09 (m, 2H), 4.78 (dd, J = 9.3, 6.9 Hz, 1H), 2.78 (td, J = 6.2, 3.1 Hz, 1H), 2.69 (dd, J = 13.7, 6.7Hz, 1H), 2.58 (dd, J = 13.6, 3.8 Hz, 1H), 2.42-.32 (m, 1H), 2.26-2.16 (m, 1H), 2.13-1.91 (m, 4H), 1.80 (s, 3H), 1.70 (s, 3H), 1.67-1.61 (m, 2H), 1.53-1.39 (m, 2H), 1.37-1.32 (m, 2H);

[0150] 13 C NMR (101 MHz, CDCl3). δ 18.7, 23.5, 24.2, 26.9, 26.9, 27.1, 28.3,28.7, 30.0, 78.5, 78.5, 121.9, 126.0, 129.3, 134.5, 135.7, 136.2, 138.7,146.2, 170.2, 173.7;

[0151] HRMS (ESI): m / z calcd for C20 H 32 O3Na [M+Na] + : 379.1880, found:379.1880.

[0152] Example 4

[0153] 1. Synthesis of compound 8d

[0154]

[0155] Under argon protection, carboxylic acid 9d (19 mg, 0.19 mmol), [Rh(cod)Cl]2 (1.7 mg, 0.0034 mmol), and (S)-DTBM-Segphos (8 mg, 0.0068 mmol) were added sequentially to a dry round-bottom flask containing cyclohexane (10 mL). After adding Et3N (26 μL, 0.19 mmol), the mixture was stirred at room temperature for 10 min. Compound 10 (50 mg, 0.17 mmol) was added in a single addition, and the mixture was stirred at room temperature for 2 h (TLC monitoring). The reaction was quenched with water (2 mL) and extracted with ethyl acetate (4 × 2 mL). The combined organic layers were washed with brine (2 mL), dried over Na2SO4, and concentrated under reduced pressure. The product was purified by silica gel rapid chromatography (petroleum ether / ethyl acetate = 20:1) to give product 8d (52 mg, 0.15 mmol), which was a pale yellow oil with a yield of 86%, dr > 20:1, B / L > 20:1.

[0156] The detection data for compound 8d are as follows:

[0157] R f = 0.59 (ethyl acetate / petroleum ether = 1 / 5);

[0158] = +54.0 (c = 1.0 in CHCl3);

[0159] 1H NMR (500 MHz, CDCl3) δ 7.18 (t, J = 6.7 Hz, 1H), 6.26 (d, J = 2.8Hz, 1H), 5.80 (ddd, J = 17.0, 10.5, 6.3 Hz, 1H), 5.58 (d, J = 2.5 Hz, 1H),5.43 (dd, J = 13.7, 6.3 Hz, 1H), 5.29-5.22 (m, 2H), 5.16 (d, J = 10.5 Hz,1H), 4.81 (dd, J = 9.2, 5.7 Hz, 1H), 4.76 (s, 1H), 4.67 (s, 1H), 2.69 (ddd, J= 8.2, 5.7, 3.0 Hz, 1H), 2.53-2.48 (m, 2H), 2.40 (ddd, J = 19.9, 13.9, 7.0Hz, 2H), 2.29 (dd, J = 11.3, 6.5 Hz, 2H), 2.04 (t, J = 7.9 Hz, 2H), 1.81 (d,J = 1.2 Hz, 3H), 1.72 (s, 3H), 1.84-1.61 (m, 4H), 1.60-1.45 (m, 4H);

[0160] 13 C NMR (101 MHz, CDCl3). δ 17.5, 22.5, 25.9, 26.4, 27.6, 29.0, 30.9,32.1, 34.5, 44.6, 45.6, 72.7, 79.6, 111.0, 116.9, 121.7, 126.4, 136.3, 136.7,139.0, 139.4, 144.5, 144.9, 167.5, 170.3;

[0161] HRMS (ESI): m / z calcd for C 20 H 32 O3Na [M+Na] + : 421.2349, found:421.2353.

[0162] 2. Synthesis of compounds 1d and 1da

[0163]

[0164] Under argon protection, a solution of compound 8d (290 mg, 0.81 mmol, 1.0 equivalent) and Hoveyda-Grubbs II (44 mg, 0.08 mmol, 0.1 equivalent) was added to a flame-dried round-bottom flask. Anhydrous toluene was then added to prepare a 0.0015 M solution of compound 8b, which was degassed three times with argon. The reaction mixture was refluxed and stirred until complete (monitored by TLC). After completion, the mixture was cooled to room temperature, and the solvent was removed under vacuum. The residue was purified by silica gel rapid chromatography (petroleum ether / ethyl acetate = 5:1 to 3:1) to give the corresponding light brown oily product.

[0165] The detection data for compound 1d are as follows:

[0166] R f = 0.57 (ethyl acetate / petroleum ether = 2 / 3);

[0167] = 143.9 (c = 0.5 in CHCl3);

[0168] 1 H NMR (400 MHz, CDCl3) δ 6.94 (s, 1H), 6.25 (d, J = 2.0 Hz, 1H), 5.61 (d, J = 1.6 Hz, 1H), 5.28 (d, J = 8.6 Hz, 1H), 5.13-5.05 (m, 2H), 4.80 (dd, J= 8.5, 3.6 Hz, 1H), 2.71 – 2.60 (m, 2H), 2.40 (dd, J = 13.3, 8.4 Hz, 1H), 2.34 -2.21 (m, 2H), 2.18-2.13 (m, 2H), 2.12-2.07 (m, 2H), 1.79 (s, 3H), 1.77-1.65 (m, 3H), 1.63 (s, 3H), 1.59 -1.30 (m, 5H);

[0169] 13 C NMR (101 MHz, CDCl3). δ 16.3, 18.2, 24.4, 26.1, 26.9, 27.9, 31.4,35.3, 43.3, 44.4, 78.4, 79.5, 122.5, 126.8, 129.6, 133.9, 135.1, 135.4,139.1, 146.5, 170.3, 173.5;

[0170] HRMS (ESI): m / z calcd for C 20 H 32 O3Na [M+Na] + : 365.1723, found:365.1723.

[0171] The detection data for compound 1ca are as follows:

[0172] R f = 0.57 (ethyl acetate / petroleum ether = 2 / 3);

[0173] = -80.0 (c = 0.1 in CHCl3);

[0174] 1 H NMR (400 MHz, CDCl3) δ 6.97 (d, J = 1.3 Hz, 1H), 6.30 (d, J = 3.2Hz, 1H), 5.60 (d, J = 2.8 Hz, 1H), 5.34 (d, J = 9.6 Hz, 1H), 5.17-5.08 (m,2H), 4.78 (dd, J = 9.3, 6.9 Hz, 1H), 2.83-2.74 (m, 1H), 2.69 (dd, J = 13.7,6.7 Hz, 1H), 2.58 (dd, J = 13.5, 3.8 Hz, 1H), 2.43-2.32 (m, 1H), 2.25-2.16(m, 1H), 2.10-2.04 (m, 1H), 2.01- 1.92 (m, 2H), 1.80 (d, J = 1.0 Hz, 3H), 1.71 (s, 3H), 1.68-1.63 (m, 1H), 1.56-1.45 (m, 3H), 1.42-1.31 (m, 3H);

[0175] 13 C NMR (101 MHz, CDCl3). δ 18.7, 23.5, 24.2, 26.9, 27.0, 27.1, 28.3,28.8, 30.1, 42.6, 46.0, 78.5, 78.5, 121.9, 126.0, 129.3, 134.5, 135.7, 136.2,138.7, 146.2, 170.2, 173.7;

[0176] HRMS (ESI): m / z calcd for C 20 H 32 O3Na [M+Na] + : 365.1723, found:365.1724.

[0177] The technical features of the above-described embodiments and examples can be combined in any suitable manner. For the sake of brevity, not all possible combinations of the technical features in the above-described embodiments and examples are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0178] The embodiments described above merely illustrate several implementation methods of this application and should not be construed as limiting the scope of the patent application. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of this application, and these all fall within the protection scope of this application. Furthermore, it should be understood that after reading the above teachings, those skilled in the art can make various alterations or modifications to this application, and the equivalent forms obtained also fall within the protection scope of this application. It should also be understood that technical solutions obtained by those skilled in the art based on the technical solutions provided in this application through logical analysis, reasoning, or limited experimentation are all within the protection scope of the appended claims. Therefore, the protection scope of this patent application should be determined by the appended claims, and the specification can be used to interpret the content of the claims.

Claims

1. A process for the asymmetric semisynthesis of a glabrolide or a expanded ring derivative thereof, characterized in that, The method comprises the following steps: Ⅰ； Ⅱ； Ⅲ； Ⅳ； Ⅴ； Ⅵ； a compound shown in formula I and ethylene are subjected to ring-opening metathesis reaction to prepare a compound shown in formula II; the compound shown in formula II is subjected to isomerization reaction to prepare a compound shown in formula III; the compound shown in formula III and cis-1,4-dihalogen-2-butene are subjected to cross olefin metathesis reaction to prepare a compound shown in formula IV; X is halogen introduced by the cis-1,4-dihalogen-2-butene; The compound of formula V is prepared by asymmetric allylic substitution of the compound of formula IV with a cycloalkenyl-1-carboxylic acid in the presence of a rhodium catalyst and a chiral phosphine ligand; the cycloalkenyl group introduced for the cycloalkenyl-1-carboxylic acid; Y is alkylene; the compound shown in formula V is subjected to ring-opening-cyclization metathesis tandem reaction to prepare a silibinin or a ring-expanded derivative thereof shown in formula VI; Y is an alkylene group.

2. The method of asymmetric semi-synthesis of a serratenediolide or a expanded ring derivative thereof according to claim 1, characterized in that, The step of subjecting a compound shown in formula I and ethylene to ring-opening metathesis reaction to prepare a compound shown in formula II comprises the following steps: the compound shown in formula I, a first olefin metathesis catalyst and a first solvent are mixed under the gas atmosphere of the ethylene, and heated to reflux for 2-3 hours to prepare the compound shown in formula II; wherein the first solvent comprises at least one of dichloromethane and toluene.

3. The method of asymmetric semi-synthesis of serratenediolide or its expanded ring derivatives according to claim 2, characterized in that, The mole number of the first olefin metathesis catalyst is 4-6% of the mole number of the compound shown in formula I; and / or, The gas atmosphere of the ethylene is 0.8-1.2 atm ethylene gas pressure; and / or, The first olefin metathesis catalyst comprises at least one of Grubbs II catalyst and Hoveyda-Grubbs II catalyst.

4. The method of asymmetric semi-synthesis of sanguilutins or expanded ring derivatives thereof according to claim 1, characterized in that, The step of subjecting the compound shown in formula II to isomerization reaction to prepare a compound shown in formula III comprises the following steps: the compound shown in formula II, vinyl oxymethylsilane, a second olefin metathesis catalyst and a second solvent are mixed under the inert gas atmosphere, and heated to reflux for 3-12 hours to prepare the compound shown in formula III; wherein the second solvent comprises at least one of dichloromethane, toluene, tetrahydrofuran and 1,2-dichloroethane.

5. The method of asymmetric semi-synthesis of sanguilutins or expanded ring derivatives thereof according to claim 4, characterized in that, The mole number of the second olefin metathesis catalyst is 4-6% of the mole number of the compound shown in formula II; and / or, The mole ratio of the compound shown in formula II and the vinyl oxymethylsilane is 1:(1.1-1.5); and / or, The second olefin metathesis catalyst comprises at least one of Grubbs I catalyst and Grubbs II catalyst.

6. The method of asymmetric semi-synthesis of sanguilutins or expanded ring derivatives thereof according to claim 1, characterized in that, The step of subjecting the compound shown in formula III and cis-1,4-dihalogen-2-butene to cross olefin metathesis reaction to prepare a compound shown in formula IV comprises the following steps: the compound shown in formula III, the cis-1,4-dihalogen-2-butene and a third olefin metathesis catalyst are mixed under the inert gas atmosphere, and stirred for 50-70 minutes to prepare the compound shown in formula IV.

7. The method of asymmetric semi-synthesis of serratenediolide or its expanded ring derivatives according to claim 6, characterized in that, The mole number of the third olefin metathesis catalyst is 4-6% of the mole number of the compound shown in formula III; and / or, The mole ratio of the compound shown in formula III and the cis-1,4-dihalogen-2-butene is 1:(0.5-0.7); and / or, The third olefin metathesis catalyst comprises at least one of Grubbs I catalyst, Grubbs II catalyst and Hoveyda-Grubbs II catalyst.

8. The method of asymmetric semi-synthesis of sanguilutins or expanded ring derivatives thereof according to claim 1, characterized in that, The step of preparing the compound shown as the formula V by asymmetric allylic substitution reaction of the compound shown as the formula IV and the cycloalkenyl-1-carboxylic acid in the presence of a rhodium catalyst and a chiral phosphine ligand comprises: The compound shown as the formula V is prepared by mixing the cycloalkenyl-1-carboxylic acid, the rhodium catalyst, the chiral phosphine ligand, an organic base and a third solvent, stirring for 8 min-12 min, adding the compound shown as the formula IV, stirring for 1 h-3 h, under an inert gas atmosphere. The third solvent comprises at least one of cyclohexane, tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane and toluene.

9. The method of asymmetric semi-synthesis of sanguilutins or expanded ring derivatives thereof according to claim 8, characterized in that, The molar ratio of the rhodium catalyst to the chiral phosphine ligand is 1:(2-2.2); and / or, The molar number of the rhodium catalyst is 1.8%-2.2% of the molar number of the compound shown as the formula IV; and / or, The molar ratio of the cycloalkenyl-1-carboxylic acid to the organic base is 1:(1-1.2); and / or, The molar ratio of the cycloalkenyl-1-carboxylic acid to the compound shown as the formula IV is (1-1.2):1; and / or, The chiral phosphine ligand comprises at least one of the following compounds: ； The rhodium catalyst comprises at least one of (1,5-cyclooctadiene)chloro rhodium (I) dimer and chloro bis(ethylene) rhodium (I) dimer.

10. The process for the asymmetric semi-synthesis of a glabrol or expanded ring derivative thereof according to any one of claims 1 to 9, characterized in that, The step of preparing the silibinin or the expanded ring derivative thereof shown as the formula VI by ring-opening-cyclization metathesis tandem reaction of the compound shown as the formula V comprises: The silibinin or the expanded ring derivative thereof shown as the formula VI is prepared by mixing the compound shown as the formula V, a fourth olefin metathesis catalyst and a fourth solvent, heating to reflux for 2 h-4 h under an inert gas atmosphere; The fourth solvent comprises at least one of toluene, m-xylene and mesitylene; Further, the fourth olefin metathesis catalyst is Hoveyda-Grubbs II catalyst, and the molar number of the fourth olefin metathesis catalyst is 8%-12% of the molar number of the compound shown as the formula V.

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