Method for constructing tetracyclic skeleton of abietane lactone-type euphorbia diterpenoid, and organic compound

Abstract

The present application relates to the field of organic chemistry technology, and in particular to a method for constructing a tetracyclic skeleton of abietane lactone-type euphorbia diterpene and an organic compound. The preparation method of the present application comprises the following steps: oxidizing the alcohol hydroxyl group of the compound shown in formula II to obtain an aldehyde group, and then adding a Grignard reagent R 4 (C≡H)MgX 1 Addition is performed, and then the alcoholic hydroxyl group of the obtained compound represented by formula III is protected with a benzyl group, and then the protecting group M is removed, and then the alcoholic hydroxyl group of the obtained compound represented by formula IV is oxidized to obtain an aldehyde group, and then it is intramolecularly cyclized with an alkynylene group, and then the protecting group Bn in the obtained compound represented by formula V is removed, and then intramolecular elimination is performed to obtain a compound represented by formula I, R 1 , R 2 , R 3 and R 4 are independently selected from C 1～3 The alkyl group, M refers to C 1～3 Alkyl substituted silicon group, X 1 Refers to halogen.

Description

Technical Field

[0001] The present application relates to the technical field of organic chemistry, and in particular to a method for constructing a tetracyclic skeleton of abietane lactone-type euphorbia diterpene and an organic compound. Background Art

[0002] Terpenoids are compounds derived from mevalonic acid and whose molecular skeletons are based on isoprene units (C5 units) and their derivatives. These oxygen-containing derivatives can be alcohols, aldehydes, ketones, carboxylic acids, esters, etc. They can be divided into monoterpenes (C10), sesquiterpenes (C15), diterpenes (C20) and triterpenes (C30) according to the number of isoprene units.

[0003] In recent years, abietolactone diterpenes have gradually attracted people's attention due to their unique chemical structure. Abietolactone diterpenes were first discovered in Euphorbia plants and have a special 6 / 6 / 6 / 5 tetracyclic ring system, specifically a 6 / 6 all-carbon ring structure and an α,β-unsaturated γ-lactone structure connected to a six-membered ring.

[0004]

[0005] The currently known structures of abietane lactone-type diterpenoid natural products include

[0006] etc. Their substituent groups on the B and C rings represent the main structural derivative categories of abietane lactone-type natural products.

[0007] The unique molecular structure of abietane lactone diterpenes is an important supplement to the current clinical research on drugs regulating multidrug resistance mechanisms, and has high research and development value. However, due to its low content in natural plants, in-depth research on the active mechanism of this type of natural products is limited. Therefore, the development of the total synthesis of abietane lactone natural products, especially large-scale, clustered asymmetric total synthesis, has extremely far-reaching significance for the research of this type of natural products in biology and even medicine. Summary of the invention

[0008] Based on this, the purpose of this application includes providing a method for constructing a tetracyclic skeleton of abietane lactone-type euphorbia diterpenoid and an organic compound. The preparation method can be used for the large-scale, clustered synthesis of natural products with this type of skeleton and their derivatives.

[0009] The specific technical solutions are described below:

[0010] A method for constructing a tetracyclic skeleton of abietane lactone-type euphorbia diterpene, comprising the following steps:

[0011]

[0012] S100: Oxidation of the alcoholic hydroxyl group of the compound represented by formula II to obtain an aldehyde group, and then addition of a Grignard reagent R 4 (C≡C)MgX 1 Carry out addition reaction to obtain the compound represented by formula III,

[0013] S200: protecting the hydroxyl group of the compound represented by formula III with a benzyl group, and then removing the protecting group M in the compound represented by formula III to obtain a compound represented by formula IV,

[0014] S300: oxidizing the alcoholic hydroxyl group of the compound represented by formula IV to obtain an aldehyde group, and then subjecting the obtained aldehyde group to an intramolecular cyclization reaction with the alkynylene group in the compound represented by formula IV to obtain a compound represented by formula V;

[0015] S400: removing the benzyl protecting group in the compound represented by formula V to obtain a hydroxyl group, and then subjecting the obtained hydroxyl group to an intramolecular elimination reaction to obtain a compound represented by formula I;

[0016] in,

[0017] R 1 , R 2 , R 3 and R 4 are independently selected from C 1～3 The alkyl group

[0018] X 1 Refers to halogen,

[0019] M refers to C 1～3 Alkyl substituted silicon group,

[0020] Each occurrence is independently selected from or

[0021] An organic compound whose structure is selected from:

[0022]

[0023] in,

[0024] R 1 , R 2 , R 3 and R 4 are independently selected from C 1～3 The alkyl group

[0025] X 1 Refers to halogen,

[0026] M refers to C 1～3 Alkyl substituted silicon group,

[0027] Each occurrence is independently selected from or

[0028] The technical method of the present application also solves the problem that it is difficult to carry out large-scale chemical synthesis of abietane lactone-type euphorbia diterpenoid natural products or their derivatives at the optical purity level. The method can be used to prepare abietane lactone-type euphorbia diterpenoid natural products of the desired configuration, such as (-)-jolkinolide E, (+)-jolkinolide E, C 12 -epi-(-)-jolkinolide E、C 12 -epi-(+)-jolkinolide E, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] In order to more clearly illustrate the specific implementation methods of the present application or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0030] Figure 1 The compound (-)-jolkinolide E and compound C prepared in Example 1 of the present application 12 -epi-(-)-jolkinolide E and compound 14b, and schematic diagrams of their corresponding single crystal structures. DETAILED DESCRIPTION

[0031] The preparation method, organic compound and application of the present application are further described in detail below in conjunction with the embodiments, examples and accompanying drawings. The present application can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the disclosure of the present application more thoroughly understood.

[0032] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which the present application belongs. The terms used in the specification in this application herein are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0033] the term

[0034] Unless otherwise specified or incompatible herewith, the terms and phrases used herein shall have the following meanings:

[0035] The terms "and / or", "or / and", and "and / or" used in this article include any one of two or more related listed items, and also include any and all combinations of related listed items, and the arbitrary and all combinations include any two related listed items, any more related listed items, or a combination of all related listed items. It should be noted that when at least three items are connected by at least two conjunctions selected from "and / or", "or / and", and "and / or", it should be understood that in this application, the technical solution undoubtedly includes technical solutions that are all connected by "logical and", and undoubtedly includes technical solutions that are all connected by "logical or". For example, "A and / or B" includes three parallel solutions of A, B and A+B. For example, the technical solution of "A, and / or, B, and / or, C, and / or, D" includes any one of A, B, C, and D (that is, the technical solution that is all connected by "logical OR"), and also includes any and all combinations of A, B, C, and D, that is, the combination of any two or any three of A, B, C, and D, and also includes the combination of four of A, B, C, and D (that is, the technical solution that is all connected by "logical AND").

[0036] Herein, "further", "further", "particularly" and the like are used for descriptive purposes to indicate differences in content, but should not be construed as limiting the scope of protection of this application.

[0037] Herein, "preferred", "preferable", "better", etc. are only used to describe implementation methods or examples with better effects. It should be understood that they do not constitute limitations on the scope of protection of this application.

[0038] In this article, the technical features described in an open manner include closed technical solutions composed of the listed features, and also include open technical solutions containing the listed features.

[0039] Herein, when it comes to numerical intervals (i.e., numerical ranges), unless otherwise specified, the optional numerical distribution is considered continuous within the above numerical interval, and includes the two numerical endpoints (i.e., the minimum and maximum values) of the numerical range, and each numerical value between the two numerical endpoints. Unless otherwise specified, when the numerical interval only refers to integers within the numerical interval, it includes the two endpoint integers of the numerical range, and each integer between the two endpoints. In addition, when multiple ranges are provided to describe features or characteristics, these ranges can be combined. In other words, unless otherwise specified, the ranges disclosed herein should be understood to include any and all subranges included therein.

[0040] The temperature parameters herein, if not specifically limited, are allowed to be either constant temperature treatment or to vary within a certain temperature range. It should be understood that the constant temperature treatment allows the temperature to fluctuate within the precision range controlled by the instrument. Fluctuations within the range of ±5°C, ±2°C, ±1°C, ±0.5°C, ±0.4°C, ±0.3°C, ±0.2°C, and ±0.1°C are allowed.

[0041] In the present application, Bn refers to benzyl, and TBDPS refers to tert-butyldiphenylsilyl.

[0042] In this application, PCC oxidant refers to pyridinium chlorochromate, which has the structure Dess-Martin oxidants are compounds Swern's oxidant is an oxidative system formed by mixing dimethyl sulfoxide and oxalyl chloride.

[0043] In the present application, "alkyl" refers to a saturated hydrocarbon containing primary (normal) carbon atoms, or secondary carbon atoms, or tertiary carbon atoms, or quaternary carbon atoms, or a combination thereof. Phrases containing this term, such as "C 1 ~ 3 "Alkyl" refers to an alkyl group containing 1 to 3 carbon atoms, each occurrence of which can be independently C 1 Alkyl, C 2 Alkyl, C 3 Suitable examples include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, i-propyl, -CH (CH 3 ) 2 ).

[0044] The term "halogen" or "halo" as used herein refers to F, Cl, Br or I.

[0045] The term "alkynylene" as used herein refers to a hydrocarbon group having two monovalent radical centers derived from an alkynyl group by removing a hydrogen atom, which may be an unsaturated branched hydrocarbon group or an unsaturated straight hydrocarbon group. Suitable examples include, but are not limited to, ethynylene (-C≡C-), propargyl (-CH 2 C≡C-) and 4-pentynyl (-CH 2 CH 2 CH 2 C≡C-). For example, compound R 4 (C≡H)MgX 1 The structural formula is R 4-C≡C-MgX 1 .

[0046] In one aspect of the present application, a method for constructing a tetracyclic skeleton of abietane lactone-type euphorbia diterpene is provided, which comprises the following steps:

[0047]

[0048] S100: Oxidation of the alcoholic hydroxyl group of the compound represented by formula II to obtain an aldehyde group, and then addition of a Grignard reagent R 4 (C≡C)MgX 1 Carry out addition reaction to obtain the compound represented by formula III,

[0049] S200: Protecting the hydroxyl group of the compound represented by formula III with a benzyl group, and then removing the protecting group M in the compound represented by formula III to obtain a compound represented by formula IV,

[0050] S300: oxidizing the alcoholic hydroxyl group of the compound represented by formula IV to obtain an aldehyde group, and then subjecting the obtained aldehyde group to an intramolecular cyclization reaction with the alkynylene group in the compound represented by formula IV to obtain a compound represented by formula V;

[0051] S400: removing the protecting group Bn in the compound represented by formula V to obtain a hydroxyl group, and then subjecting the obtained hydroxyl group to an intramolecular elimination reaction to obtain a compound represented by formula I;

[0052] in,

[0053] R 1 , R 2 , R 3 and R 4 are independently selected from C 1～3 The alkyl group

[0054] X 1 Refers to halogen,

[0055] M refers to C 1～3 Alkyl substituted silicon group,

[0056] Each occurrence is independently selected from or

[0057] M is the residue after the reaction of the silyl ether type hydroxyl protecting agent and the hydroxyl group. For example, M can be selected from trimethylsilyl tert-Butyldiphenylsilyl tert-Butyldimethylsilyl Triisopropylsilyl wait.

[0058] In one embodiment, the preparation method of the compound represented by formula II comprises the following steps:

[0059]

[0060] Take the compound shown in formula i, carry out elimination reaction in the presence of dichlorothionyl and triethylamine, and then carry out Brownian hydroboration-oxidation reaction on the obtained product.

[0061] The method for preparing the compound represented by formula II from the compound represented by formula I can also be found in the following documents: [Stéphane Poigny, Samia Nouri, Angèle Chiaroni, Michèle Guyot, and Mohammad Samadi. Total Synthesis and Determination of the Absolute Configuration of Coscinosulfate. A New Selective Inhibitor of Cdc25 Protein Phosphatase. J. Org. Chem., 2001, 66 (22): 7263-7269.], [Yu Sun, Ruofan Li, Wenhao Zhang, Prof. Dr. Ang Li. Total Synthesis of Indotertine A and Drimentines A, F, and G. Angew. Chem. Int. Ed. 2013, 52, 9201-9204.], [María C. de la Torre Dr., Isabel García Dr., Miguel A. Sierra Prof. Diversity Oriented Synthesis of Hispanane-like Terpene Derivatives from (R)-(+)-Sclareolide. Chem. Eur. J. 2005, 11, 3659–3667.].

[0062] In one embodiment, the compound represented by formula II is prepared by the following preparation steps:

[0063]

[0064] Take the compound shown in formula ii and carry out oxidation reaction in the presence of boric acid and base. The compound shown in formula ii in the present application can be purchased or prepared according to known schemes. The specific preparation method can be found in the following document: [Tetrahedron 58 (21) (2002) 4299-4309.].

[0065] The method for preparing the compound of formula II from the compound of formula II can also be found in the following documents: [Tetrahedron 58 (21) (2002) 4299-4309.], [Synthesis of some naturally occurring drimane and dinorlabdane derivatives, Liebigs Annalen 1995 (7) (1995) 1389-1392.].

[0066] Preferably, the compound represented by formula II is selected from: This configuration can avoid intramolecular cyclization before step S300.

[0067] In one embodiment, the compound represented by formula II is selected from

[0068] Further, the compound represented by formula III includes

[0069] Further, the compound represented by formula IV includes

[0070] Further, the compound represented by formula V includes

[0071] In one embodiment, the compound represented by formula II is selected from Further, the compound represented by formula III includes Further, the compound represented by formula IV includes Furthermore, the compound represented by formula V includes

[0072] In one embodiment, the compound represented by formula II is selected from The compound represented by formula III includes

[0073] Optionally, the compound represented by formula III is selected from The compound represented by formula IV is selected from The compounds represented by formula V include or

[0074] The compound represented by formula III is selected from The compound represented by formula IV is selected from The compounds represented by formula V include

[0075] Further optionally, the compound represented by formula V is selected from The compound represented by formula I is selected from or

[0076] The compound represented by formula V is selected from The compound represented by formula I is selected from

[0077] In one embodiment, the compound represented by formula II is selected from The compound represented by formula III includes

[0078] Optionally, the compound represented by formula III is selected from The compound represented by formula IV is selected from The compounds represented by formula V include or

[0079] The compound represented by formula III is selected from The compound represented by formula IV is selected from The compounds represented by formula V include

[0080] Further optionally, the compound represented by formula V is selected from The compound represented by formula I is selected from or

[0081] The compound represented by formula V is selected from The compound represented by formula I is selected from

[0082] In the method for constructing the tetracyclic skeleton of abietolactone-type euphorbia diterpene of the present application, the oxidation in step S100 and step S300 is to oxidize the methanol group in the structural formula to an aldehyde group, and to prevent the obtained aldehyde group from being further oxidized to a carboxyl group.

[0083] In one embodiment, the oxidation conditions in step S100 include at least one of the following technical features:

[0084] (1) The oxidant comprises at least one of a PCC oxidant, a Dess-Martin oxidant and a Swern oxidant, and the molar ratio of the oxidant to the compound represented by formula II is (1.2-1.5):1;

[0085] (2) The reaction temperature is 20°C to 30°C.

[0086] In one embodiment, the oxidation conditions in step S300 include at least one of the following technical features:

[0087] (1) The oxidant includes at least one of a PCC oxidant, a Dess-Martin oxidant, and a Swern oxidant, and the molar ratio of the oxidant to the compound II is (2.3-2.5):1,

[0088] (2) The reaction temperature is 20°C to 35°C.

[0089] In one embodiment, the conditions for the addition reaction in step S100 include at least one of the following technical features:

[0090] (1) The molar ratio of the Grignard reagent to the compound represented by formula II is (1.9-2.1):1;

[0091] (2) The reaction temperature is -5°C to 0°C.

[0092] Furthermore, step S100 has the characteristics of the oxidation conditions in step S100 and the characteristics of the addition reaction conditions in step S100 described in any of the above technical solutions.

[0093] In one embodiment, the step of protecting with benzyl in step S200 comprises: taking the compound represented by formula III, adding compound BnX in the presence of a base 2 Reaction, X 2 is a halogen group, further, the compound BnX 2 The molar ratio of the compound represented by formula III is (1.2-1.5):1.

[0094] In one embodiment, the step of removing the protecting group M in step S200 includes: taking the reactant protected by benzyl, adding tetrabutylammonium fluoride to react, and further, the molar ratio of tetrabutylammonium fluoride to the compound represented by formula III is (3.9-4.5):1.

[0095] Furthermore, step S200 has the characteristics of the step of protecting with benzyl group in step S200 and the characteristics of the step of removing the protecting group M in step S200 described in any of the above technical solutions.

[0096] In one embodiment, the conditions for the intramolecular cyclization reaction in step S300 include at least one of the following technical features:

[0097] (1) in the presence of molybdenum hexacarbonyl in a carbon monoxide atmosphere, wherein the molar ratio of molybdenum hexacarbonyl to compound IV is (2.4-2.6):1,

[0098] (2) The reaction temperature is 140°C to 160°C.

[0099] In one embodiment, the step of removing the protecting group Bn in step S400 includes: taking the compound represented by formula V, adding a dichloromethane solution of boron trichloride to react, and further, the molar ratio of boron trichloride to the compound represented by formula V is (5-6):1.

[0100] In one embodiment, the conditions of the intramolecular elimination reaction in step S400 include at least one of the following technical features:

[0101] (1) in the presence of thionyl chloride and an organic base, wherein the molar ratio of thionyl chloride, the organic base and the compound V is (12-15):(5-10):1,

[0102] (2) The reaction temperature is -5°C to 0°C.

[0103] Furthermore, step S400 has the characteristics of the step of removing the protecting group Bn in step S400 described in any of the above technical solutions and the characteristics of the conditions for the intramolecular elimination reaction in step S400.

[0104] It can be understood that in steps S100, S200, S300, and S400, preliminary purification of the intermediates is allowed so that the subsequent reaction can obtain better yield and purity. Considering that the above steps contain substances that are easily chemically transformed in an oxygen-containing environment, such as aldehyde groups, benzyl groups, hydroxyl groups, etc., the placement time and operation procedures should be reduced as much as possible during the processing, and protective gas can also be used for protection.

[0105] It can be understood that the preferences for steps S100, S200, S300, and S400 are all for the purpose of better constructing the abietane lactone-type euphorbia diterpene tetracyclic skeleton of the present application, and any combination of the above-mentioned preferred technical features is allowed and is regarded as a more optimal preparation scheme.

[0106] The present application also relates to an organic compound, the structure of which is selected from:

[0107]

[0108] in,

[0109] R 1 , R 2 , R 3 and R 4 are independently selected from C 1～3 The alkyl group

[0110] X 1 Refers to halogen,

[0111] M refers to C 1～3 Alkyl substituted silicon group,

[0112] Each occurrence is independently selected from or

[0113] The following are some specific embodiments.

[0114] The reagents or raw materials used in the following examples can be purchased or prepared by methods known in the art.

[0115] Example 1

[0116] 1. Providing compound 10i (compound represented by formula II)

[0117]

[0118] Compound 9 was prepared from compound 7 (+)-sclareolide (cas: 564-20-5, purchased from Beijing Inokai Technology Co., Ltd.) according to reference 1 (Stéphane Poigny, Samia Nouri, Angèle Chiaroni, Michèle Guyot, Mohammad Samadi, Total Synthesis and Determination of the Absolute Configuration of Coscinosulfate. A New Selective Inhibitor of Cdc25 Protein Phosphatase, J. Org. Chem. 2001, 66, 7263-7269.).

[0119] Compound 9 (2.2 g, 4.6 mmol) was dissolved in 11 mL of ultra-dry dichloromethane, and triethylamine (1.9 mL, 13.8 mmol) and thionyl chloride (0.54 mL, 7.4 mmol) were added and mixed under stirring at -80 °C, and the temperature was maintained and stirred for 10 min, and then quenched with 10 mL of saturated sodium bicarbonate aqueous solution. The mixture was slowly restored to room temperature, and then extracted with ethyl acetate (3×15 mL), and then the obtained organic phase was washed with 10 mL of water and 10 mL of saturated brine, and then dried over anhydrous sodium sulfate, filtered, concentrated, and separated with a silica gel column (petroleum ether / ethyl acetate, 50:1) to obtain a light yellow oil. The light yellow oil was taken for identification, and the results are as follows:

[0120] Thin layer chromatography: the raw material disappears, new spots appear, R f =0.78 (petroleum ether / EtOAc, 10:1), UV254nm fluorescence; phosphomolybdic acid color development; mass spectrometry identification: 475.3391 (M+H peak).

[0121] The obtained oil was dissolved in 20 mL of ultra-dry tetrahydrofuran, and a tetrahydrofuran solution of borane (9.2 mL, 9.2 mmol, 1 M) was added dropwise at -10°C under stirring conditions. After the addition was completed, the room temperature was slowly restored and stirring was continued for 4.5 h. Then, an aqueous solution of hydrogen peroxide (15.3 mL, 30% v / v) and an aqueous solution of sodium hydroxide (15.3 mL, 3 M) were added dropwise at -40°C. After the addition was completed, stirring was continued at 0°C for 2 h. Then, sulfur was slowly added at -40°C. The mixture was quenched with an aqueous solution of sodium sulfate (100 mL, 0.5 M), slowly restored to room temperature, extracted with ethyl acetate (3×50 mL), and then the organic phase was washed with 30 mL of water and 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated on a silica gel column (petroleum ether / ethyl acetate, 15:1) to obtain a colorless oil, which was compound 10i, weighing 1.4 g. The yield of compound 10i prepared from compound 9 was calculated, v=63%.

[0122] The characterization data of compound 10i are as follows: R f =0.33(petroleum ether / EtOAc,6:1); (c=1.0in CHCl 3 ); IR(film):ν max =2958,2935,1601,1471,1427,1363,1155,1110,1085,773,700cm -1 ; 1 H NMR (400 MHz, CDCl 3 )δ7.69–7.66(m,4H),7.45–7.36(m,6H),3.74–3.63(m,2H),3.53–3.45(m,2H),1.96–1.91(m,1H),1.73–1.69(m,1H),1.63–1.60 (m,2H),1.54–1.41(m,4H),1.40–1.19(m,6H),1.14(dd,J=13.8,4.6Hz,1H),1.07(s,9H),0.84(s,3H),0.78(s,3H),0.65(s,3H); 13 C NMR (100 MHz, CDCl 3)δ135.57,135.55,133.95,133.90,129.51,127.55,63.36,61.63,56.43,49.36,41.99,40.69,38 .86,37.59,33.35,33.19,29.14,28.63,26.89,21.46,19.10,18.52,17.53,15.74.HRMS(ESI):m / z calcd forC 32 H 49 O 2 Si[M+H] + :493.3502,found:493.3498.

[0123] 2. Preparation of Compound 11a and Compound 11b (Compounds of Formula III)

[0124]

[0125] Compound 10i (4.1 g, 8.3 mmol) was dissolved in 80 mL of ultra-dry dichloromethane, and PCC oxidant (2.2 g, 10.2 mmol) was added and mixed. The mixture was reacted at room temperature for 2 h, and then filtered through a silica gel column and the silica gel column was rinsed with ethyl acetate to obtain an eluent. The obtained eluent was concentrated and then subjected to column chromatography on a silica gel column (petroleum ether / ethyl acetate, 10:1) to obtain a light yellow oil. The light yellow oil was identified, and the results were as follows:

[0126] Thin layer chromatography: the raw material disappears, new spots appear, R f =0.88 (petroleum ether / EtOAc, 6:1), UV254nm fluorescence; phosphomolybdic acid color development; mass spectrometry identification: 491.3340 (M+H peak); HPLC purity: 99.10%.

[0127] The obtained light yellow oil was dissolved in 80 mL of ultra-dry tetrahydrofuran, and a Grignard reagent (1-propynyl magnesium bromide tetrahydrofuran solution (33 mL, 0.5 M) was added under stirring at 0°C, the temperature was maintained for reaction for 1 h, quenched with 50 mL of water, extracted with ethyl acetate (3×50 mL), and then the obtained organic phase was washed with 30 mL of water and 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by a silica gel column (petroleum ether / ethyl acetate, 60:1-40:1). According to the elution order, the first colorless oil was obtained, namely compound 11a, weighing 1.8 g, and the yield of compound 11a prepared from compound 10i was calculated to be v=40%; and the second colorless oil was compound 11b, weighing 2.0 g, and the yield of compound 11b prepared from compound 10i was calculated to be v=46%.

[0128] The characterization data of compound 11a are as follows: R f =0.66(petroleum ether / EtOAc,10:1); (c=1.0in CHCl 3 ); IR(film):ν max =2957,2830,1608,1463,1427,1365,1155,1085,773cm -1 ; 1 H NMR (400 MHz, CDCl 3 )δ7.73–7.67(m,4H),7.45–7.37(m,6H),4.63(td,J=7.1,3.7Hz,1H),3.78(ddd,J=10.9,6.7,4.4H z,1H)),3.68(ddd,J=10.2,7.3,4.6Hz,1H)),3.04(d,J=7.5Hz,1H),2.22–2.17(m,1H),2.13–2.17( m,1H),2.06–2.00(m,1H),1.84(d,J=2.1Hz,3H),1.73–1.70(m,1H),1.59–1.56(m,1H),1.54–1.42 (m,2H),1.41–1.29(m,6H),1.10–1.06(m,1H),1.08(s,9H),0.97(s,3H),0.84(s,3H),0.81(s,3H); 13 C NMR (100 MHz, CDCl 3 )δ135.73,135.66,133.46,133.31,129.63,129.61,127.66,127.63,81.97,80.73,65.52,64.73,56.94,52.76,42.5 4,42.04,39.46,38.17,33.38,31.10,29.69,28.65,26.81,21.45,19.06,18.56,18.37,15.72,3.65.HRMS(ESI):m / z calcd forC 35 H 50 NaO 2 Si[M+Na] + :553.3478,found:553.3474.

[0129] The characterization data of compound 11b are as follows: R f =0.5(petroleum ether / EtOAc,10:1); (c=1.0in CHCl 3 ); IR(film):ν max =2960,2930,2830,1608,1469,1425,1365,1110,1087,775cm -1 ; 1 H NMR (400 MHz, CDCl 3 )δ7.72–7.69(m,4H),7.44–7.38(m,6H),4.47–4.44(m,1H),3.84–3.75(m, 2H),2.19–2.15(m,1H),2.09–2.01(m,1H),1.85–1.83(m,1H),1.77–1.73(m ,1H),1.77(d,J=2.2Hz,3H),1.60–1.48(m,5H),1.43–1.28(m,5H),1.16(d d,J=13.9,4.4Hz,1H),1.08(s,9H),0.90(s,3H),0.86(s,3H),0.81(s,3H); 13 C NMR (100 MHz, CDCl 3 )δ135.62,135.59,134.18,129.46,127.54,82.05,81.65,63.36,62.05,56.90,49.94,42.60,42.06,39 .25,37.83,33.38,33.32,29.02,28.85,26.91,21.45,19.19,18.64,18.46,15.76,3.59.HRMS(ESI):m / z calcd for C 35 H 50 NaO 2 Si[M+Na] + :553.3478,found:553.3475.

[0130] 3. Preparation of Compound 12 and Compound 15 (Compounds represented by Formula IV)

[0131]

[0132] Compound 11a (1.5 g, 2.8 mmol) was dissolved in 9 mL of ultra-dry N,N-dimethylformamide, and sodium hydride (226 mg, 5.6 mmol, 60%) was added and mixed under stirring conditions at 0°C, and the temperature was maintained and stirred for 20 min, and then benzyl bromide (0.43 mL, 3.6 mmol) was added and mixed, and stirring was continued at room temperature for 12 h, and then quenched with 10 mL of water, extracted with ethyl acetate (3×50 mL), and then the obtained organic phase was washed with water 6 times (10 mL each time), and then washed with 10 mL of saturated brine, and then dried with anhydrous sodium sulfate, filtered, concentrated, and separated with a silica gel column (petroleum ether / ethyl acetate, 70:1) to obtain a light yellow oil. The light yellow oil was taken for identification, and the results are as follows:

[0133] Thin layer chromatography: the raw material disappears, new spots appear, R f =0.68 (petroleum ether / EtOAc, 30:1), UV254nm fluorescence; phosphomolybdic acid color development; mass spectrometry identification: 621.4125 (M+H peak); HPLC purity: 98.30%.

[0134] The obtained oil was dissolved in 14 mL of tetrahydrofuran, and a tetrahydrofuran solution of tetrabutylammonium fluoride (11 mL, 11 mmol, 1 M) was added under stirring at 0°C. After the addition was completed, the mixture was returned to room temperature and stirred for 6 h. It was then quenched with 20 mL of water and extracted with ethyl acetate (3×50 mL). The obtained organic phase was then washed with 30 mL of water and 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated on a silica gel column (petroleum ether / ethyl acetate, 5:1) to obtain a colorless oil, namely compound 12, weighing 0.86 g. The yield of compound 12 prepared from compound 11a was calculated, v=80%.

[0135] The characterization data of compound 12 are as follows: f =0.21(petroleum ether / EtOAc,10:1); (c=1.0in CHCl 3 ); IR (film): νmax=2954,2830,1614,1592,1465,1364,1156,1052,773,696cm -1 ; 1 HNMR (400MHz, CDCl 3)δ7.37–7.28(m,5H),4.80(d,J=11.2Hz,1H),4.41–4.36(m,2H),3.65(td,J=6.3,4 .0Hz,2H),2.32–2.26(m,1H),2.18–2.14(m,1H),1.92(d,J=2.0Hz,3H),1.87–1.86 (m,1H),1.66–1.59(m,3H),1.58–1.43(m,3H),1.43–1.31(m,4H),1.13(td,J=13.5 ,4.2Hz,1H),0.89(dd,J=12.0,2.3Hz,1H),0.84(s,3H),0.81(s,3H),0.80(s,3H); 13 C NMR (100 MHz, CDCl 3 )δ137.74,128.33,128.27,127.66,83.25,77.87,72.07,70.64,62.69,56.67,51.36,41.94,40. 58,39.24,38.08,33.40,33.29,31.06,28.88,21.46,18.60,18.49,15.38,3.64.HRMS(ESI):m / z calcd for C 26 H 38 NaO 2 [M+Na] + :405.2770,found:405.2768.

[0136] Compound 11b (1.5 g, 2.8 mmol) was dissolved in 9 mL of ultra-dry N,N-dimethylformamide, and sodium hydride (226 mg, 5.8 mmol, 60%) was added and mixed under stirring at 0°C, and the temperature was maintained and stirred for 20 min, and then benzyl bromide (0.5 mL, 4.2 mmol) was added and mixed, and stirring was continued at room temperature for 12 h, and then quenched with 10 mL of water, extracted with ethyl acetate (3×50 mL), and then the obtained organic phase was washed with water 6 times (10 mL each time), and then washed with 10 mL of saturated brine, and then dried with anhydrous sodium sulfate, filtered, concentrated, and separated with a silica gel column (petroleum ether / ethyl acetate, 70:1) to obtain a light yellow oil. The light yellow oil was taken for identification, and the results are as follows:

[0137] Thin layer chromatography: the raw material disappears, new spots appear, R f =0.92 (petroleum ether / EtOAc, 10:1), UV254nm fluorescence; phosphomolybdic acid color development; mass spectrometry identification: 621.4120 (M+H peak); HPLC purity: 98.55%.

[0138] The obtained oil was dissolved in 14 mL of tetrahydrofuran, and a tetrahydrofuran solution of tetrabutylammonium fluoride (12 mL, 12 mmol, 1 M) was added under stirring at 0°C. After the addition was completed, the mixture was returned to room temperature and stirred for 6 h. It was then quenched with 20 mL of water and extracted with ethyl acetate (3×50 mL). The obtained organic phase was then washed with 20 mL of water and 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated on a silica gel column (petroleum ether / ethyl acetate, 5:1) to obtain a colorless oil, namely compound 15, weighing 0.89 g. The yield of compound 15 prepared from compound 11b was calculated, v=82%.

[0139] The characterization data of compound 15 are as follows: f =0.19(petroleum ether / EtOAc,10:1); (c=1.0in CHCl 3 ); IR(film):νmax=2946,2927,2832,1605,1454,1364,1157,1050,775,700cm -1 ; 1 H NMR (400 MHz, CDCl 3 )δ7.38–7.27(m,5H),4.80(d,J=11.5Hz,1H),4.44(d,J=11.6Hz,1H),4.17(dt,J=6.2,2.0Hz,1H) ,3.84(ddd,J=10.6,9.2,4.9Hz,1H),3.69(dt,J=10.2,7.4Hz,1H),2.25(dd,J=13.3,2.0Hz,1H), 2.11–2.01(m,2H),1.88(d,J=2.1Hz,3H),1.75–1.62(m,2H),1.56(dt,J=13.5,3.4Hz,1H),1.52– 1.31(m,5H),1.30–1.26(m,1H),1.16–1.08(m,2H),0.90–0.85(m,1H),0.81(s,6H),0.74(s,3H); 13 C NMR (101 MHz, CDCl 3)δ138.20,128.21,128.15,127.48,82.39,79.57,70.08,68.30,62.48,56.81,50.24,41.98,40. 56,39.39,37.88,33.38,33.29,29.26,29.02,21.35,18.65,18.42,15.65,3.67.HRMS(ESI):m / z calcd for C 26 H 38 NaO 2 [M+Na] + :405.2770,found:405.2765.

[0140] 4. Preparation of Compound 14a, Compound 14b, Compound 17a, and Compound 17b (Compounds of Formula V)

[0141]

[0142] Compound 12 (1.0 g, 2.6 mmol) was dissolved in 26 mL of dichloromethane, and PCC oxidant (1.3 g, 6.0 mmol) was added and mixed. The mixture was reacted at room temperature for 20 min, and then filtered through a silica gel column and rinsed with ethyl acetate to obtain an eluent. The solvent was removed by vacuum, and then column chromatography was performed on a silica gel column (petroleum ether / ethyl acetate, 15:1) to obtain a light yellow oil. The light yellow oil was identified, and the results were as follows:

[0143] Thin layer chromatography detection: the raw material disappears, new spots are generated, R f =0.52 (petroleum ether / EtOAc, 5:1); UV254 nM fluorescence; phosphomolybdic acid color development; mass spectrometry identification: 381.2790 (M+H peak); HPLC purity 98.91%.

[0144] The obtained light yellow oil was dissolved in a mixed solvent of 50 mL of toluene and 28 mL of N,N-dimethylformamide to obtain a mixed solution A; hexacarbonyl molybdenum (1.7 g, 6.4 mmol) was placed in a double-necked flask equipped with a reflux condenser, vacuumed and flushed with CO 10 times, then the mixed solution A was added through a syringe, reacted at 140°C for 2 h, cooled to room temperature, then filtered through a silica gel column and rinsed the silica gel column with ethyl acetate to obtain an eluent, the solvent was removed in vacuo, and then extracted with ethyl acetate (3×20 mL), and the obtained organic phase was then washed with water. The mixture was washed with water for 5 times (10 mL each time), then washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column (petroleum ether / ethyl acetate, 20:1-13:1). According to the elution order, a yellow oil was obtained, namely compound 14a, weighing 446 mg, and the yield of compound 14a prepared from compound 12 was calculated to be 42%; and a white solid, namely compound 11b, weighing 180 mg, and the yield of compound 14b prepared from compound 12 was calculated to be 17%.

[0145] The characterization data of compound 14a are as follows: R f =0.4(petroleum ether / EtOAc,6:1); (c=1.0in CHCl 3 ); IR (film): νmax=2959,2830,2931,1757,1685,1604,1362,1089,1024,775cm -1 . 1 H NMR (400 MHz, CDCl 3 )δ7.37–7.26(m,5H),5.13–5.08(m,1H),4.58(d,J=12.3Hz,1H),4.34(d,J=4.1 Hz,1H),4.30(d,J=12.4Hz,1H),2.68(dd,J=13.7,6.4Hz,1H),1.89–1.81(m,3H) ,1.81(d,J=1.8Hz,3H),1.73–1.61(m,4H),1.60–1.52(m,2H),1.48–1.39(m,2H ),1.34–1.26(m,2H),1.17(s,3H),1.15–1.10(m,1H),0.88(s,3H),0.85(s,3H); 13 C NMR (100 MHz, CDCl 3)δ174.30,160.68,137.64,128.33,127.73,127.51,122.91,77.30,75.30,71.18,55.49,48.45,41.9 9,41.43,39.46,37.55,33.96,33.39,33.16,30.92,21.86,20.48,18.90,16.59,8.57.HRMS(ESI):m / z calcd for C 27 H 37 O 3 [M+H] + :409.2743, found:409.2738. HPLC purity is 98.05%.

[0146] The characterization data of compound 14b are as follows: R f =0.2(petroleum ether / EtOAc,6:1).mp:149-151℃, (c=1.0in CHCl 3 ); IR (film): νmax=2956,2832,1745,1687,1602,1363,1153,1083,1070,775cm -1 . 1 H NMR (400 MHz, CDCl 3 )δ7.40–7.29(m,5H),4.67–4.60(m,2H),4.48–4.44(m,1H),4.34–4.22(m,1H) ,2.63(dtd,J=13.1,6.3,3.3Hz,1H),2.26(dt,J=12.5,5.2Hz,1H),1.98(s,3H ),1.84–1.78(m,1H),1.68–1.65(m,1H),1.59–1.51(m,2H),1.46–1.35(m,4H) ,1.33–1.24(m,3H),1.17–1.08(m,2H),0.89(s,3H),0.88(s,3H),0.85(s,3H); 13 C NMR (100 MHz, CDCl 3)δ174.85,159.97,137.78,128.48,127.76,127.19,120.48,79.11,78.27,71.78,46.55,43.82,4 3.16,42.23,38.29,36.81,34.01,33.37,22.42,19.23,19.01,17.70,15.81,8.85.HRMS(ESI):m / z calcd for C 27 H 37 O 3 [M+H] + :409.2743, found:409.2738. HPLC purity is 98.16%.

[0147]

[0148] Compound 15 (537 mg, 1.4 mmol) was dissolved in 13 mL of dichloromethane, and PCC oxidant (0.75 g, 3.5 mmol) was added and mixed. The mixture was reacted at room temperature for 20 min, and then filtered through a silica gel column and rinsed with ethyl acetate to obtain an eluent. The solvent was removed by vacuum, and then column chromatography was performed on a silica gel column (petroleum ether / ethyl acetate, 15:1) to obtain a light yellow oil. The light yellow oil was identified, and the results were as follows:

[0149] Thin layer chromatography detection: the raw material disappears, new spots are generated, R f =0.62 (petroleum ether / EtOAc, 5:1); UV254 nM fluorescence; phosphomolybdic acid color development; mass spectrometry identification: 381.2786 (M+H peak); HPLC purity: 98.52%.

[0150] The obtained light yellow oil was dissolved in a mixed solvent of 25 mL of toluene and 14 mL of N,N-dimethylformamide to obtain a mixed solution B; hexacarbonyl molybdenum (0.9 g, 3.4 mmol) was placed in a double-necked flask equipped with a reflux condenser, vacuumed and flushed with CO 10 times, and then the mixed solution A was added through a syringe, reacted at 140°C for 2h, cooled to room temperature, and then filtered through a silica gel column and the silica gel column was rinsed with ethyl acetate to obtain an eluent, the solvent was removed in vacuo, and then extracted with ethyl acetate (3×20 mL), and the obtained organic phase was then washed with water. The mixture was washed five times (10 mL each time), then washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by a silica gel column (petroleum ether / ethyl acetate, 20:1-13:1). According to the elution order, an irregular white solid was obtained, namely compound 17a, weighing 228 mg. The yield of compound 17a prepared from compound 15 was calculated to be 40%, and a light yellow oily substance was obtained, namely compound 17b, weighing 114 mg. The yield of compound 17b prepared from compound 15 was calculated to be 20%.

[0151] The characterization data of compound 17a are as follows: R f =0.36(petroleum ether / EtOAc,6:1); IR(film):νmax=2954,2830,1760,1685,1610,1369,1155,1085,1068,773cm -1 . (c=1.0in CHCl 3 ). 1 HNMR (400MHz, CDCl 3 )δ7.40–7.32(m,5H),4.98(dd,J=10.7,7.1Hz,1H),4.85(d,J=11.5Hz,1H),4.50–4.40(m, 2H),2.66(dd,J=13.8,6.6Hz,1H),2.31(dd,J=14.4Hz,1H),2.02(s,3H),1.92–1.82(m,2H ),1.72(t,J=6.5Hz,1H),1.70–1.57(m,1H),1.57–1.48(m,1H),1.48–1.34(m,4H),1.31–1 .25(m,1H),1.20–1.08(m,2H),0.92–0.87(m,1H),0.89(s,3H),0.84(s,3H),0.75(s,3H); 13 C NMR (100 MHz, CDCl 3)δ174.77,162.39,137.03,128.59,128.51,128.17,119.66,78.73,75.86,73.55,55.75,48.61,45.0 2,41.59,40.44,38.49,34.30,33.80,33.00,27.03,21.63,19.22,18.44,17.64,8.91.HRMS(ESI):m / z calcd for C 27 H 37 O 3 [M+H] + :409.2743, found:409.2738. HPLC purity is 98.17%.

[0152] The characterization data of compound 17b are as follows: R f =0.52(petroleum ether / EtOAc,6:1); IR(film):νmax=2945,2830,1754,1683,1601,1364,1153,1085,1070,775cm -1 . (c=1.0in CHCl 3 ). 1 HNMR (400MHz, CDCl 3 )δ7.37–7.27(m,5H),5.04(t,J=8.9Hz,1H),4.53(d,J=11.2Hz,1H),4.39(d,J=11.2Hz,1H),4.35( d,J=7.2Hz,1H),2.42(dt,J=13.6,8.1Hz,1H),2.33(q,J=6.4Hz,1H),1.91(d,J=1.6Hz,3H),1.89– 1.85(m,1H),1.78(tt,J=12.3,7.0Hz,1H),1.64–1.59(m,1H),1.55–1.46(m,2H),1.45–1.33(m,3H ),1.33–1.19(m,2H),1.16–1.08(m,2H),0.98–0.92(m,1H),0.87(s,3H),0.83(s,3H),0.67(s,3H); 13 C NMR (100 MHz, CDCl 3)δ174.81,160.43,137.70,128.63,128.07,127.80,124.71,78.23,73.58,70.96,51.74,44.35,42.1 1,40.54,38.84,37.51,33.66,33.28,31.43,24.84,22.10,18.57,18.52,15.87,9.35.HRMS(ESI):m / z calcd for C 27 H 37 O 3 [M+H] + :409.2743, found:409.2737. HPLC purity is 98.39%.

[0153] 5. Preparation of Compound (-)-Jolkinolide E and Compound C 12 -epi-(-)-Jolkinolide E (compound represented by formula Ⅰ)

[0154]

[0155] Synthesis of (-)-Jolkinolide E:

[0156] 1) Compound 14a (33 mg, 0.08 mmol) was dissolved in 1 mL of ultra-dry dichloromethane, and a dichloromethane solution of boron trichloride (0.4 mL, 0.4 mmol, 1 M) was added at 0°C and mixed, and reacted at room temperature for 23 h, then quenched with 5 mL of saturated sodium bicarbonate, extracted with dichloromethane (3×5 mL), and then the obtained organic phase was washed with 5 mL of water and 5 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated with a silica gel column (petroleum ether / ethyl acetate, 4:1) to obtain a white solid. The light yellow oil was taken for identification, and the results were as follows:

[0157] Thin layer chromatography: the raw material disappears, new spots appear, R f =0.47 (petroleum ether / EtOAc, 2:1), UV254nm fluorescence; phosphomolybdic acid color development; mass spectrometry identification: 319.2270 (M+H peak); HPLC purity: 98.15%.

[0158] The obtained white solid was dissolved in 1 mL of ultra-dry tetrahydrofuran, and organic base DBU (0.1 mL, 0.67 mmol) and thionyl chloride (0.1 mL, 1.1 mmol) were added and mixed at 0°C, and the temperature was maintained and stirred for 10 min, then quenched with 5 mL of water, extracted with ethyl acetate (3×5 mL), and then the obtained organic phase was washed with 5 mL of water and 5 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column (petroleum ether / ethyl acetate, 10:1) to obtain a white solid, which is compound (-)-Jolkinolide E, weighing 19 mg. The yield of compound (-)-Jolkinolide E prepared from compound 14a was calculated, v=80%.

[0159] 2) Compound 17a (40 mg, 0.1 mmol) was dissolved in 1.3 mL of ultra-dry dichloromethane, and a dichloromethane solution of boron trichloride (0.5 mL, 0.5 mmol, 1 M) was added at 0°C, reacted at room temperature for 23 h, then quenched with 5 mL of saturated sodium bicarbonate, extracted with dichloromethane (3×5 mL), and then the obtained organic phase was washed with 5 mL of water and 5 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated with a silica gel column (petroleum ether / ethyl acetate, 4:1) to obtain a white solid. The light yellow oil was identified, and the results are as follows:

[0160] Thin layer chromatography: the raw material disappears, new spots appear, R f =0.40 (petroleum ether / EtOAc, 2:1), UV254nm fluorescence; phosphomolybdic acid color development; mass spectrometry identification: 319.2272 (M+H peak); HPLC purity: 98.39%.

[0161] The obtained white solid was dissolved in 1 mL of ultra-dry tetrahydrofuran, and an organic base DBU (0.1 mL, 0.67 mmol) and thionyl chloride (0.1 mL, 1.1 mmol) were added at 0°C and mixed, and the temperature was maintained and stirred for 10 min. Then, the reaction was quenched with 5 mL of water, and extracted with ethyl acetate (3×5 mL). The obtained organic phase was then washed with 5 mL of water and 5 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by a silica gel column (petroleum ether / ethyl acetate, 10:1) to obtain a white solid, which is compound (-)-Jolkinolide E, weighing 23 mg of the compound. The yield of compound (-)-Jolkinolide E prepared from compound 17a was calculated, v=79%.

[0162] The characterization data of (-)-Jolkinolide E are as follows: f=0.56(petroleum ether / EtOAc,3:1).mp:182-183℃. (c=0.6,CHCl 3 ); IR (film): νmax=2958,1747,1668,1608,1367,1085,1022cm -1 . 1 H NMR (400 MHz, CDCl 3 )δ6.26(br s,1H),4.86(ddd,J=13.5,6.3,1.7Hz,1H),2.56(dd,J=13.5,6.2Hz,1H),2.50(ddd,J=13.5,4.2,2.4Hz,1H),2.24–2.16(m,2H),1.91(dq,J =12.9,3.0Hz,1H),1.85–1.80(m,1H),1.81(d,J=0.8Hz,3H),1.62–1.32(m,5H),1.23–1.07(m,3H),0.91(s,3H),0.90(s,3H),0.84(s,3H); 13 C NMR (100 MHz, CDCl 3 )δ175.33,156.24,152.27,116.12,113.86,75.98,55.21,51.83,41.87,41.57,39.59 ,37.12,33.82,33.51,27.47,23.83,21.73,19.02,16.77,8.22.HRMS(ESI):m / zcalcd for C 20 H 29 O 2 [M+H] + :301.2168, found:301.2162. HPLC purity is 98.41%.

[0163]

[0164] Synthesis of Compound C 12 -epi-(-)-Jolkinolide E:

[0165] 1) Compound 14b (92 mg, 0.22 mmol) was dissolved in 3.7 mL of ultra-dry dichloromethane, and a dichloromethane solution of boron trichloride (1.1 mL, 1.1 mmol, 1 M) was added at 0°C to mix, and reacted at room temperature for 6 h, then quenched with 5 mL of saturated sodium bicarbonate, extracted with dichloromethane (3×5 mL), and then the obtained organic phase was washed with 5 mL of water and 5 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated with a silica gel column (petroleum ether / ethyl acetate, 4:1) to obtain a white solid. The light yellow oil was identified, and the results were as follows:

[0166] Thin layer chromatography: the raw material disappears, new spots appear, R f =0.41 (petroleum ether / EtOAc, 2:1), UV254nm fluorescence; phosphomolybdic acid color development; mass spectrometry identification: 319.2271 (M+H peak); HPLC purity: 98.13%.

[0167] The obtained white solid was dissolved in 2.3 mL of ultra-dry tetrahydrofuran, and organic base DBU (0.2 mL, 1.3 mmol) and thionyl chloride (0.2 mL, 3.1 mmol) were added at 0°C and mixed, and the temperature was maintained and stirred for 10 min, and then quenched with 5 mL of water, extracted with ethyl acetate (3×5 mL), and then the obtained organic phase was washed with 5 mL of water and 5 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated with a silica gel column (petroleum ether / ethyl acetate, 10:1) to obtain a white solid, which is compound C. 12 -epi-(-)-Jolkinolide E, weighing 54 mg, was calculated to prepare compound C from compound 14b 12 Yield of -epi-(-)-Jolkinolide E, v = 80%.

[0168] 2) Compound 17b (98 mg, 0.24 mmol) was dissolved in 4 mL of ultra-dry dichloromethane, and a dichloromethane solution of boron trichloride (1.2 mL, 1.2 mmol, 1 M dichloromethane) was added at 0°C and mixed, reacted at room temperature for 6 h, then quenched with 5 mL of saturated sodium bicarbonate, extracted with dichloromethane (3×5 mL), and then the obtained organic phase was washed with 5 mL of water and 5 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated with a silica gel column (petroleum ether / ethyl acetate, 4:1) to obtain a white solid. The light yellow oil was taken for identification, and the results were as follows:

[0169] Thin layer chromatography: the raw material disappears, new spots appear, R f=0.43 (petroleum ether / EtOAc, 2:1), UV254nm fluorescence; phosphomolybdic acid color development; mass spectrometry identification: 319.2268 (M+H peak); HPLC purity: 98.61%.

[0170] The obtained white solid was dissolved in 2.3 mL of ultra-dry tetrahydrofuran, and organic base DBU (0.2 mL, 1.3 mmol) and thionyl chloride (0.2 mL, 3.1 mmol) were added at 0°C and mixed, and the temperature was maintained and stirred for 10 min, and then quenched with 5 mL of water, extracted with ethyl acetate (3×5 mL), and then the obtained organic phase was washed with 5 mL of water and 5 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated with a silica gel column (petroleum ether / ethyl acetate, 10:1) to obtain a white solid, which is compound C. 12 -epi-(-)-Jolkinolide E, weighing 58 mg, was calculated to prepare compound C from compound 14b 12 Yield of -epi-(-)-Jolkinolide E, v = 80%.

[0171] C 12 The characterization data of -epi-(-)-Jolkinolide E are as follows: f =0.64(petroleum ether / EtOAc,3:1).mp:176-177℃. (c=1.0in CHCl 3 ); IR (film): νmax=2927,1743,1664,1601,1365,1087,1025cm -1 ; 1 H NMR (400 MHz, CDCl 3 )δ6.22(br s,1H),4.65(d,J=18.0Hz,1H),2.59–2.47(m,1H),2.37(dt,J=11.7,5.7 Hz,1H),2.19(ddt,J=28.4,9.8,5.6Hz,2H),1.82(s,3H),1.75–1.68(m, 1H),1.62(d,J=12.7Hz,1H),1.52–1.37(m,4H),1.34–1.26(m,1H),1.22 –1.12(m,2H),1.10–0.99(m,1H),0.90(s,3H),0.85(s,3H),0.72(s,3H); 13 C NMR (100 MHz, CDCl 3)δ175.81,156.60,152.60,115.70,114.41,78.44,54.13,51.53,41.80,39.25,39 .06,35.75,33.64,33.50,27.57,22.19,22.11,18.78,14.95,8.40.HRMS(ESI):m / z calcd for C 20 H 29 O 2 [M+H] + :301.2168, found:301.2161. The purity of HPLC is 98.22%.

[0172] Example 2

[0173] This example provides compound 10ii (compound represented by formula II), and the specific preparation steps are as follows:

[0174]

[0175] 1. Provide compound 6

[0176] Compound 5 (390 mg, 1.7 mmol) was dissolved in 3 mL of DMF, imidazole (337 mg, 4.9 mmol) and TBDPSCl (1.3 mL, 4.9 mmol) were added and mixed, and stirred at 25 °C for 15 h. Then 20 mL of water was added and extracted with ethyl acetate (3×10 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column (petroleum ether / ethyl acetate: 50:1) to obtain a yellow oil (compound 6).

[0177] 2. Preparation of compound 10ii

[0178] Dissolve compound 6 in 8 mL of tetrahydrofuran and add BH 3 Sodium borohydride solution (3.4 mL, 3.4 mmol, 1 M) was stirred at room temperature for 4.5 h, and then H 2 O 2 The mixture was stirred at 0 °C for 2 h, and then NaOH (5.7 mL, 3 M) was added at -40 °C. 2 S 2 O 3 The mixture was slowly heated to room temperature with an aqueous solution (50 mL, 0.5 M), extracted with ethyl acetate (3×20 mL), and then the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated with a silica gel column (petroleum ether / ethyl acetate: 15:1) to obtain compound 10, weighing 552 mg. The yield of compound 10ii prepared from compound 5 was calculated to be v=66%.

[0179] The characterization parameters of compound 10ii are as follows: R f =0.33 (petroleum ether / ethyl acetate, 6:1). The NMR data of (±)-10 are completely consistent with those of optically pure 10. 1 H NMR (400 MHz, CDCl 3 )δ7.69–7.66(m,4H),7.45–7.36(m,6H),3.74–3.63(m,2H),3.53–3.45(m,2H),1.96–1.91(m,1H),1.73–1.69(m,1H),1.63–1.60 (m,2H),1.54–1.41(m,4H),1.40–1.19(m,6H),1.14(dd,J=13.8,4.6Hz,1H),1.07(s,9H),0.84(s,3H),0.78(s,3H),0.65(s,3H); 13 C NMR (100 MHz, CDCl 3 )δ135.57,135.55,133.95,133.90,129.51,127.55,63.36,61.63,56.43,49.36,41.99,40.69,38 .86,37.59,33.35,33.19,29.14,28.63,26.89,21.46,19.10,18.52,17.53,15.74.HRMS(ESI):m / z calcd forC 32 H 49 O 2 Si[M+H] + :493.3502,found:493.3498.

[0180] Single crystal diffraction data:

[0181] Compound 14b:

[0182] CCDC:2202771

[0183]

[0184]

[0185] Compound (-)-jolkinolide E:CCDC:2220106

[0186]

[0187]

[0188] Compound C 12 -epi-(-)-jolkinolide E:CCDC:2220107

[0189]

[0190]

[0191] All documents mentioned in this application are cited as references in this application, just as each document is cited as reference separately. Unless they conflict with the application purpose and / or technical solution of this application, the cited documents involved in this application are cited with all contents and all purposes. When the cited documents are involved in this application, the definitions of relevant technical features, terms, nouns, phrases, etc. in the cited documents are also cited. When the cited documents are involved in this application, the examples and preferred methods of the cited relevant technical features can also be incorporated into this application as references, but are limited to the implementation of this application. It should be understood that when the cited content conflicts with the description in this application, the present application shall prevail or be modified adaptively according to the description of this application.

[0192] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments 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.

[0193] The above-mentioned embodiments only express several implementation methods of the present application, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for those of ordinary skill in the art, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims, and the description and drawings may be used to interpret the contents of the claims.

Claims

1. A method for preparing abietane lactone-type euphorbia diterpene tetracyclic skeleton represented by formula I, characterized in that: The steps include: S100: Oxidizing the alcohol hydroxyl group of the compound represented by formula II to obtain an aldehyde group, and then adding a Grignard reagent R4(C≡C)MgX1 to carry out an addition reaction to obtain a compound represented by formula III. S200: protecting the hydroxyl group of the compound represented by formula III with a benzyl group, and then removing the protecting group M in the compound represented by formula III to obtain a compound represented by formula IV, S300: oxidizing the alcoholic hydroxyl group of the compound represented by formula IV to obtain an aldehyde group, and then subjecting the obtained aldehyde group to an intramolecular cyclization reaction with the alkynylene group in the compound represented by formula IV to obtain a compound represented by formula V; S400: removing the protecting group Bn in the compound represented by formula V to obtain a hydroxyl group, and then subjecting the obtained hydroxyl group to an intramolecular elimination reaction to obtain a compound represented by formula I; in, R1, R2, R3 and R4 are independently selected from C 1～3 The alkyl group X1 represents a halogen group, M refers to C 1～3 Alkyl substituted silicon group, Each occurrence is independently selected from 2. The preparation method according to claim 1, characterized in that: The preparation method of the compound represented by formula II comprises the following steps: Take the compound of formula i, carry out elimination reaction in the presence of thionyl chloride and triethylamine, and then carry out Brownian hydroboration-oxidation reaction on the obtained product; or Take the compound shown in formula ii and carry out oxidation reaction in the presence of boric acid and base.

3. The preparation method according to claim 1, characterized in that: The compound represented by formula II is selected from:

4. The preparation method according to claim 3, characterized in that: The compound represented by formula II is selected from The compound represented by formula III is selected from The compound represented by formula IV is selected from The compound represented by formula V is selected from 5. The preparation method according to claim 3, characterized in that: The compound represented by formula II is selected from The compound represented by formula III is selected from The compound represented by formula IV is selected from The compound represented by formula V is selected from 6. The preparation method according to any one of claims 1 to 5, characterized in that: In step S100: The oxidation conditions include at least one of the following technical features: (1) The oxidant comprises at least one of a PCC oxidant, a Dess-Martin oxidant, and a Swern oxidant, and the molar ratio of the oxidant to the compound represented by formula II is (1.2-1.5):1, (2) the reaction temperature is 20°C to 30°C; and / or The conditions of the addition reaction include at least one of the following technical features: (1) The molar ratio of the Grignard reagent to the compound represented by formula II is (1.9-2.1):1, (2) The reaction temperature is -5°C to 0°C.

7. The preparation method according to claim 6, characterized in that: In step S200: The step of protecting with benzyl group comprises: taking the compound represented by formula III, adding compound BnX2 to react in the presence of base, Bn is benzyl, X2 is halogen, and the molar ratio of compound BnX2 to the compound represented by formula III is (1.2-1.5):1; and / or The step of removing the protecting group TBDPS comprises: taking the reactant protected by the benzyl group, adding tetrabutylammonium fluoride to react.

8. The preparation method according to claim 7, characterized in that: The molar ratio of the tetrabutylammonium fluoride to the compound represented by formula III is (3.9-4.5):

1.

9. The preparation method according to claim 7 or 8, characterized in that: In step S300: The oxidation conditions include at least one of the following technical features: (1) The oxidant includes at least one of a PCC oxidant, a Dess-Martin oxidant, and a Swern oxidant, and the molar ratio of the oxidant to the compound II is (2.3-2.5):1, (2) the reaction temperature is 20°C to 35°C; and / or The conditions of the intramolecular cyclization reaction include at least one of the following technical features: (1) in the presence of molybdenum hexacarbonyl in a carbon monoxide atmosphere, wherein the molar ratio of the molybdenum hexacarbonyl to the compound IV is (2.4-2.6):1, (2) The reaction temperature is 140°C to 160°C.

10. The preparation method according to claim 9, characterized in that: In step S400: The step of removing the protecting group Bn comprises: taking the compound represented by formula V, adding a dichloromethane solution of boron trichloride to react; and / or The conditions of the intramolecular elimination reaction include at least one of the following technical features: (1) in the presence of thionyl chloride and an organic base, wherein the molar ratio of the thionyl chloride, the organic base and the compound V is (12-15):(5-10):1, (2) The reaction temperature is -5°C to 0°C.

11. The preparation method according to claim 10, characterized in that: The molar ratio of the boron trichloride to the compound represented by formula V is (5-6):1.

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