New method for preparing aryl abietane diterpene Plebein C intermediate

Abstract

The invention provides and discloses a novel method for preparing an aryl abietane diterpene Plebein C. The novel method specifically comprises the following steps: carrying out carbonyl alpha-site substitution on 4, 4-dimethyl-2-cyclohexene-1-ketone to obtain a compound I; performing TBS protection to obtain a compound II; carrying out Luche reduction reaction to obtain a compound III; 3-hydroxy-4-methoxybenzaldehyde is subjected to a 2-position iodination reaction, and a compound IV is obtained; carrying out Wittig reaction to obtain a compound V; carrying out a Mitsunobu reaction between the compound III and a compound V to obtain a compound VI; performing free radical cyclization reaction to obtain a compound VII; performing benzyl oxidation to obtain a compound VIII; finally, carrying out oxidation and ring closing to obtain a pentacyclic intermediate compound IX of the Plebein C molecule; the preparation method is simple in synthetic route, cheap and easily available in reagent, high in yield and beneficial to industrial preparation of intermediates, and has extremely high popularization potential.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and particularly relates to a new method for preparing an intermediate of aryl abietane diterpenoid Plebein C. Background Art

[0002] Aromatic abietane diterpenoids are a class of natural products that have been studied and attracted much attention by scientists in recent years. The abietane diterpenoids to which they belong contain a [6-6-6] tricyclic skeleton and have varying degrees of oxidation in the B ring and C ring. Among them, aromatic abietane diterpenoids are the largest category. This class of compounds is widely distributed in various terrestrial plants, and the characteristic aromatic C ring endows these aromatic abietane diterpenoids with diverse and significant biological activities. For example, the first aromatic abietane diterpenoid Dehydroabietic acid discovered in the 1950s has biological activities such as antibacterial, anti-inflammatory, anti-tumor, anti-ulcer, and improving diabetes and hyperlipidemia; another aromatic abietane diterpenoid Ferruginol discovered subsequently not only has antibacterial, anti-inflammatory, anti-tumor, and anti-ulcer activities but also has various biological activities such as antioxidant, anti-SARS, trypanocidal, and antimalarial and acaricidal activities. With the progress of technology, in recent years, natural products such as aromatic abietane diterpenoid compounds Isoabietenin A, Epoxyhinokiol, Plebein C, and Huperphlegmarin B with a rare epoxy bridge ring between the A ring and C ring have been discovered. In 2015, Epoxyhinokiol was first isolated from Chinese fir leaves and then again from Caryopteris incana (a medicinal plant used by Chinese folk to relieve cough and rheumatic pain), from which it was speculated that this rare epoxy bridge ring-containing aromatic abietane diterpenoid compound might be a class of very good compounds with potential drug activities. And, there is currently no research report on the pentacyclic aromatic abietane diterpenoid Plebein C.

[0003] In view of this, the present invention designs a new method for preparing an intermediate of aryl abietane diterpenoid Plebein C through a radical cascade cyclization reaction and an oxidative ring closure reaction. This preparation method has a simple synthetic route, inexpensive and easily available reagents, and a high yield, which is very conducive to the large-scale preparation of this aromatic abietane diterpenoid Plebein C intermediate and facilitates further in-depth research on the biological activities of this rare epoxy bridge ring-containing aromatic abietane diterpenoid series of molecules. Summary of the Invention

[0004] The present invention mainly overcomes the deficiencies in the prior art and provides a new method for preparing an intermediate of aryl abietane diterpenoid Plebein C. This method is a framework construction method led by the Plebein C molecule. Specifically, it includes: performing a substitution at the α-position of the carbonyl group on 4,4-dimethyl-2-cyclohexene-1-one to obtain compound I; obtaining compound II through TBS protection; obtaining compound III through Luche reduction reaction; performing an iodination reaction at the 2-position on 3-hydroxy-4-methoxybenzaldehyde to obtain compound IV; obtaining compound V through Wittig reaction; obtaining compound VI through the Mitsunobu reaction between compound III and compound V; obtaining compound VII through a key radical cyclization reaction; obtaining compound VIII through benzylic oxidation; and finally obtaining the pentacyclic intermediate compound IX of the Plebein C molecule through oxidation and ring closure. This preparation method has a concise synthetic route, inexpensive and easily available reagents, and a high yield, which is very conducive to the large-scale preparation of the intermediate of aryl abietane diterpenoid Plebein C, facilitating the large-scale production of Plebein C series molecules and more in-depth research on their biological activities. At the same time, this convergent and tandem high-efficiency chemical reaction method is applicable to industrial preparation and has great potential for popularization.

[0005] In order to achieve the above technical objectives, the technical solution adopted by the present invention is as follows:

[0006] A new method for preparing an intermediate of aryl abietane diterpenoid Plebein C, and the reaction process route is as follows:

[0007]

[0008] The said synthesis method includes steps one to nine:

[0009] Specifically: Step one: Using 4,4-dimethyl-2-cyclohexene-1-one as a raw material, reacting it with 4-dimethylaminopyridine and aqueous formaldehyde at room temperature to obtain compound I;

[0010] Step two: Reacting compound I with 4-dimethylaminopyridine, tert-butyldimethylchlorosilane and pyridine at room temperature to obtain compound II;

[0011] Step three: Performing a Luche reduction reaction on compound II and cerium trichloride heptahydrate with sodium borohydride to obtain compound III;

[0012] Step four: Using 3-hydroxy-4-methoxybenzaldehyde as a raw material, reacting it with iodine monochloride dissolved in pyridine and 1,4-dioxane under dark conditions at room temperature to obtain compound IV;

[0013] Step five: Reacting compound IV with methyltriphenylphosphonium bromide and sodium bis(trimethylsilyl)amide to perform a Wittig reaction to obtain V;

[0014] Step 6: Compound III and compound V undergo a Mitsunobu reaction with triphenylphosphine and diisopropyl azodicarboxylate to obtain VI;

[0015] Step 7: Compound VI is treated with tris(trimethylsilyl)silane and triethylborane in deoxytoluene to obtain compound VII;

[0016] Step 8: Compound VII undergoes a benzylic oxidation reaction with chromium trioxide and 3,5-dimethylpyrazole to obtain compound VIII;

[0017] Step 9: Compound VIII is oxidized with selenium dioxide and cyclized to obtain compound IX, which is the intermediate of the aryl abietane diterpenoid Plebein C.

[0018] Furthermore, the structural formulas of the compound 4,4-dimethyl-2-cyclohexen-1-one, 3-hydroxy-4-methoxybenzaldehyde, and compounds I - IX are shown as follows:

[0019]

[0020] Furthermore, the specific synthesis method of step 1 is as follows:

[0021] Using 4,4-dimethyl-2-cyclohexen-1-one as the raw material, reacting with 4-dimethylaminopyridine and aqueous formaldehyde at room temperature to obtain compound I, specifically including:

[0022] Add 4-dimethylaminopyridine to the reaction flask at room temperature, add the solvent tetrahydrofuran, the raw material 4,4-dimethyl-2-cyclohexen-1-one, and aqueous formaldehyde under an argon atmosphere, stir the reaction at room temperature for 24 hours, under normal pressure; after the reaction is completed, add 1N HCl for quenching with vigorous stirring at room temperature, extract with dichloromethane, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and then separate and purify by column chromatography. The volume ratio of the eluent is petroleum ether:ethyl acetate = 3:1 to obtain compound I;

[0023] The molar ratio of 4,4-dimethyl-2-cyclohexen-1-one, 4-dimethylaminopyridine, and aqueous formaldehyde is: 100:55:300.

[0024] Furthermore, the specific synthesis method of step 2 is as follows:

[0025] Compound I reacts with 4-dimethylaminopyridine, tert-butyldimethylchlorosilane, and pyridine at room temperature to obtain compound II, specifically including:

[0026] At room temperature, 4-dimethylaminopyridine and tert-butyldimethylchlorosilane were added to a reaction flask. Under an argon atmosphere at 0 °C, the solvent dichloromethane and pyridine were added. After stirring at 0 °C for 5 minutes, compound I dissolved in dichloromethane was added. After stirring at 0 °C for 30 minutes, the reaction was continued at room temperature for 2 hours under normal pressure. After the reaction was completed, the reaction was quenched by adding saturated ammonium chloride solution while stirring at 0 °C, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then separated and purified by column chromatography. The volume ratio of the eluent was petroleum ether:ethyl acetate = 20:1, and compound II could be obtained.

[0027] The molar ratio of compound I, 4-dimethylaminopyridine, tert-butyldimethylchlorosilane, and pyridine was: 82.7:24.8:165.3:206.6.

[0028] Furthermore, the specific synthesis method of step three was as follows:

[0029] Compound II and cerium(III) chloride heptahydrate underwent a Luche reduction reaction with sodium borohydride at 0 °C to obtain compound III, which specifically included:

[0030] At room temperature, compound II, cerium(III) chloride heptahydrate, and the solvent methanol were added to a reaction flask. Sodium borohydride was added in three portions at 0 °C. After each addition of sodium borohydride, the mixture was stirred for 10 minutes at 0 °C under normal pressure. After the reaction was completed, the reaction was quenched by adding ice water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then separated and purified by column chromatography. The volume ratio of the eluent was petroleum ether:ethyl acetate = 20:1, and compound III could be obtained.

[0031] The molar ratio of compound II, cerium(III) chloride heptahydrate, and sodium borohydride was: 41.8:41.8:25.

[0032] Furthermore, the specific synthesis method of step four was as follows:

[0033] Using 3-hydroxy-4-methoxybenzaldehyde as a raw material, it was reacted with iodine monochloride dissolved in pyridine and 1,4-dioxane at room temperature in the dark to obtain compound IV, which specifically included:

[0034] 3-Hydroxy-4-methoxybenzaldehyde was added to a reaction flask. Under an argon atmosphere at 0 °C, the solvent pyridine was added, and then iodine monochloride dissolved in 1,4-dioxane was added. The reaction was carried out at room temperature in the dark for 6 days under normal pressure. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and then water and HCl were added to adjust the pH to 1. It was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain compound IV.

[0035] The molar ratio of 3-hydroxy-4-methoxybenzaldehyde and iodine monochloride was: 120:156.

[0036] Furthermore, the specific synthesis method of Step 5 is as follows:

[0037] Compound IV undergoes a Wittig reaction with methyltriphenylphosphonium bromide and sodium bis(trimethylsilyl)amide to obtain V, which specifically includes:

[0038] At room temperature, methyltriphenylphosphonium bromide is added to a reaction flask, and the solvent tetrahydrofuran is added under an argon atmosphere. Sodium bis(trimethylsilyl)amide is added at 0 °C, and after stirring at 0 °C for 30 minutes, Compound IV dissolved in tetrahydrofuran is added, and the reaction is carried out at room temperature for 30 minutes under normal pressure; after the reaction is completed, the reaction is quenched with saturated ammonium chloride solution, extracted with ethyl acetate, washed with saturated brine, dried with anhydrous magnesium sulfate, concentrated under reduced pressure, and then separated and purified by column chromatography. The volume ratio of the eluent is petroleum ether:ethyl acetate = 5:1 to 3:1, and Compound V can be obtained;

[0039] The molar ratio of Compound IV, methyltriphenylphosphonium bromide, and sodium bis(trimethylsilyl)amide is: 72:172.8:158.4.

[0040] Furthermore, the specific synthesis method of Step 6 is as follows:

[0041] Compound III and Compound V undergo a Mitsunobu reaction with triphenylphosphine and diisopropyl azodicarboxylate to obtain VI, which specifically includes:

[0042] At room temperature, Compound III, Compound V, and triphenylphosphine are added to a reaction flask, and the solvent tetrahydrofuran is added under an argon atmosphere. After stirring at room temperature for 10 minutes, diisopropyl azodicarboxylate is added at 0 °C, and the reaction is carried out at room temperature for 3 hours under normal pressure; after the reaction is completed, the reaction is quenched with ice water, extracted with ethyl acetate, washed with saturated brine, dried with anhydrous magnesium sulfate, concentrated under reduced pressure, and then separated and purified by column chromatography. The volume ratio of the eluent is petroleum ether:ethyl acetate = 20:1 to 10:1, and Compound VI can be obtained;

[0043] The molar ratio of Compound III, Compound V, triphenylphosphine, and diisopropyl azodicarboxylate is: 51.2:56.3:58.8:58.8.

[0044] Furthermore, the specific synthesis method of Step 7 is as follows:

[0045] Compound VI is treated with tris(trimethylsilyl)silane and triethylborane in deoxygenated toluene to obtain Compound VII, which specifically includes:

[0046] At room temperature, add compound VI, tris(trimethylsilyl)silane and triethylboron into the reaction flask. Add the solvent deoxygenated toluene under an argon atmosphere, heat up to 85 °C and react for 5 hours under normal pressure; after the reaction is completed, concentrate under reduced pressure to remove toluene; extract with ethyl acetate, wash with water and saturated brine; dry with anhydrous sodium sulfate, concentrate under reduced pressure and then separate and purify by column chromatography. The volume ratio of the eluent is petroleum ether:ethyl acetate = 40:1 to 30:1, and compound VII can be obtained;

[0047] The molar ratio of the compound VI, tris(trimethylsilyl)silane and triethylboron is: 26:52:6.5;

[0048] The specific synthesis method of step eight is as follows:

[0049] Compound VII undergoes a benzylic oxidation reaction with chromium trioxide and 3,5-dimethylpyrazole at -15 °C to obtain compound VIII, specifically including:

[0050] At room temperature, add chromium trioxide and 3,5-dimethylpyrazole into the reaction flask. Add the solvent dichloromethane under an argon atmosphere at -15 °C, stir for 10 minutes at -15 °C, then add compound VII dissolved in dichloromethane at -10 °C, react at -10 °C for 5 minutes under normal pressure; after the reaction is completed, filter with diatomaceous earth using a suction funnel, concentrate under reduced pressure and then separate and purify by column chromatography; the volume ratio of the eluent is petroleum ether:ethyl acetate = 10:1 to 5:1, and compound VIII can be obtained;

[0051] The molar ratio of the compound VII, chromium trioxide and 3,5-dimethylpyrazole is: 5:40:40.

[0052] Furthermore, the specific synthesis method of step nine is as follows:

[0053] Compound VIII is treated in selenium dioxide to obtain compound IX:

[0054] Specifically including:

[0055] At room temperature, add compound VIII and selenium dioxide into the reaction flask. Add a mixed solvent of acetic acid and water at room temperature, react at 110 °C for 2 hours under normal pressure; after the reaction is completed, cool to room temperature, dilute with ethyl acetate, then add saturated sodium bicarbonate solution for quenching, extract with ethyl acetate, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate under reduced pressure and then separate and purify by column chromatography. The volume ratio of the eluent is petroleum ether:ethyl acetate = 5:1, and compound IX can be obtained;

[0056] The molar ratio of the compound VIII and selenium dioxide is: 0.2:1.

[0057] Beneficial effects

[0058] Compared with the prior art, the present invention has the following advantages:

[0059] The present invention discloses a new method for preparing an intermediate of arylabietane diterpenoid Plebein C, and designs a synthetic method for the pentacyclic skeleton of arylabietane diterpenoid Plebein C through radical tandem cyclization reaction and oxidative annulation. This method is a skeleton construction method led by the Plebein C molecule; specifically, it includes: performing carbonyl α-position substitution on 4,4-dimethyl-2-cyclohexene-1-one to obtain compound I; obtaining compound II through TBS protection; obtaining compound III through Luche reduction reaction; performing 2-position iodination reaction on 3-hydroxy-4-methoxybenzaldehyde to obtain compound IV; obtaining compound V through Wittig reaction; obtaining compound VI through Mitsunobu reaction between compound III and compound V; obtaining compound VII through a key radical cyclization reaction; obtaining compound VIII through benzylic oxidation; and finally obtaining the pentacyclic intermediate compound IX of the Plebein C molecule through oxidative ring closure. This preparation method has a concise synthetic route, inexpensive and easily available reagents, and high yield; guided by the Plebein C molecule, through chemical synthesis, a convergent synthesis scheme is designed, an aryl iodide precursor is constructed by Mitsunobu etherification reaction, and a radical tandem cyclization initiated by tris(trimethylsilyl)silane and triethylboron is used as the key reaction to quickly and efficiently construct the pentacyclic skeleton of arylabietane diterpenoid Plebein C, developing a new method for constructing this structural unit. This method is simple to operate, has inexpensive and easily available raw materials, and a concise synthetic route, laying a foundation for the synthesis of other types of aromatic abietane diterpenoid compounds in the future, reflecting the superiority of this method, having high practical value, being very conducive to the large-scale preparation of this intermediate of arylabietane diterpenoid Plebein C, facilitating the further study of the biological activities of this rare epoxy-bridged aromatic abietane diterpenoid series of molecules, being applicable to industrial preparation, and having extremely strong promotion potential. BRIEF DESCRIPTION OF THE DRAWINGS

[0060] Figure 1 It is a synthetic route diagram of a new method for preparing an intermediate of arylabietane diterpenoid Plebein C in an embodiment of the present invention;

[0061] Figure 2 It is the structural formulas of compound 4,4-dimethyl-2-cyclohexene-1-one, 3-hydroxy-4-methoxybenzaldehyde, and compounds I-IX in an embodiment of the present invention;

[0062] Figure 3 It is the 1H NMR spectrum diagram of compound IX in an embodiment of the present invention;

[0063] Figure 4 This is the carbon-13 NMR spectrum of compound IX in the embodiments of the present invention. Detailed implementation manners

[0064] In order to make the objectives, technical solutions and advantages of the present invention clearer, the present invention will be further described in detail below in conjunction with embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0065] According to Figure 1 the synthetic route diagram shown, the compounds in the following embodiments are synthesized, and the structural formulas of the respective compounds involved are Figure 2 shown as follows.

[0066] Example 1:

[0067] Step 1:

[0068] Take a 250 ml dry two-necked flask and add a magnetic stirrer. Weigh 4-dimethylaminopyridine (6.7 g, 55 mmol, 0.6 e.q) and add it to the reaction flask. Replace argon three times and protect with a balloon. Place the device at room temperature, add tetrahydrofuran (20 ml) to dissolve the substrate, and then add the raw materials 4,4-dimethyl-2-cyclohexen-1-one (13.1 ml, 100 mmol) and aqueous formaldehyde (37% - 40%, 29 ml, 300 mmol, 3.0 e.q) into the reaction flask. After dropping, place it at room temperature and react for 24 hours. After the reaction is completed, stir and add 1N HCl (15 ml) at room temperature to quench the reaction. Extract with dichloromethane (30 ml × 3), wash with saturated brine (20 ml × 3), dry with anhydrous sodium sulfate, concentrate under reduced pressure, and then purify by column chromatography. The volume ratio of the eluent is petroleum ether: ethyl acetate = 3:1, and a colorless oil compound I (11.7 g, 76%) is obtained. R f = 0.25 (petroleum ether: ethyl acetate = 3:1).

[0069] Step 2:

[0070] Add a magnetic stir bar to a 500 mL dry two-necked flask. Weigh 3 g (24.8 mmol, 0.3 eq) of 4-dimethylaminopyridine and 24.9 g (165.3 mmol, 2 eq) of tert-butyldimethylchlorosilane and add them to the reaction flask. Replace the argon three times and protect with a balloon. Place the apparatus at 0 °C, add 250 mL of dry dichloromethane to dissolve the substrate, then add 16.6 mL (206.6 mmol, 2.5 eq) of pyridine to the reaction flask. Stir at 0 °C for 5 minutes, then add 12.7 g (82.7 mmol) of Compound I to the reaction flask. Stir at 0 °C for 30 minutes, then allow the reaction to proceed at room temperature for 2 hours. After the reaction is complete, add 150 mL of saturated ammonium chloride solution to quench the reaction while stirring at 0 °C. Extract with ethyl acetate (150 mL × 3), wash with saturated brine (100 mL × 3), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography. The volume ratio of the eluent is petroleum ether:ethyl acetate = 20:1 to obtain 20 g (90%) of Compound II as a colorless oil. R f = 0.30 (petroleum ether:ethyl acetate = 20:1).

[0071] Step 3:

[0072] Add a magnetic stir bar to a 250 mL dry two-necked flask. Weigh 11.2 g (41.8 mmol) of Compound II and 15.6 g (41.8 mmol, 1.0 eq) of cerium(III) chloride heptahydrate and add them to the reaction flask. Place the apparatus at 0 °C, add 100 mL of methanol to dissolve the substrate, then add sodium borohydride (0.9 g, 25 mmol, 0.6 eq) in three portions to the reaction flask. React for 10 minutes at 0 °C after each addition of sodium borohydride. After the reaction is complete, quench with ice water (60 mL), extract with ethyl acetate (60 mL × 3), wash with saturated brine (50 mL × 3), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography. The volume ratio of the eluent is petroleum ether:ethyl acetate = 20:1 to obtain 10.5 g (93%) of Compound III as a colorless oil. R f = 0.25 (petroleum ether:ethyl acetate = 20:1).

[0073] Step 4:

[0074] Take a 500 ml dry two-necked reaction flask and add a magnetic stir bar. Weigh compound 3-hydroxy-4-methoxybenzaldehyde (18.2 g, 120 mmol) and add it to the reaction flask. Replace the argon three times and insert a balloon for protection. Place the apparatus at zero degrees Celsius, add pyridine (70 ml) to dissolve the substrate, and then add iodine monochloride (8 ml, 156 mmol, 1.3 e.q) dissolved in 1,4-dioxane (120 ml) into the reaction flask. React in the dark at room temperature for 6 days. After the reaction is completed, concentrate under reduced pressure to remove the solvent. Then add water (200 ml) and HCl to the reaction flask to adjust the pH to 1. Extract with ethyl acetate (120 ml × 3), wash with saturated brine (120 ml × 3), dry over anhydrous magnesium sulfate, and concentrate under reduced pressure to obtain a pale yellow solid as compound IV (31.1 g, 94%). R f = 0.45 (petroleum ether:ethyl acetate = 3:1).

[0075] Step Five:

[0076] Take a 250 ml dry two-necked reaction flask and add a magnetic stir bar. Weigh compound methyltriphenylphosphonium bromide (61.9 g, 172.8 mmol, 2.4 e.q) and add it to the reaction flask. Replace the argon three times and insert a balloon for protection. Place the apparatus at room temperature, add freshly distilled tetrahydrofuran (100 ml) to dissolve the substrate, and then add sodium bis(trimethylsilyl)amide (71.2 ml, 158.4 mmol, 2.2 e.q) to the reaction flask at zero degrees Celsius. Stir at zero degrees Celsius for 30 minutes, and then add compound IV (20 g, 72 mmol) dissolved in freshly distilled tetrahydrofuran (30 ml). React at room temperature for 30 minutes. After the reaction is completed, quench with saturated ammonium chloride solution (70 ml), extract with ethyl acetate (60 ml × 3), wash with saturated brine (60 ml × 3), dry over anhydrous magnesium sulfate, and concentrate under reduced pressure. Then purify by column chromatography with an eluent volume ratio of petroleum ether:ethyl acetate = 3:1. Obtain a pale yellow solid as compound V (16.7 g, 84%). R f = 0.40 (petroleum ether:ethyl acetate = 3:1).

[0077] Step Six:

[0078] Take a 500 ml dry two-necked reaction flask and add a magnetic stir bar. Weigh compound III (13.8 g, 51.2 mmol), compound V (15.5 g, 56.3 mmol, 1.1 eq), and triphenylphosphine (15.4 g, 58.8 mmol, 1.2 eq) and add them to the reaction flask. Replace the argon three times and insert a balloon for protection. Place the apparatus at room temperature, add freshly distilled tetrahydrofuran (200 ml) to dissolve the substrates, stir at room temperature for 10 minutes, then place the apparatus at 0 °C and add diisopropyl azodicarboxylate (9.9 ml, 58.8 mmol, 1.2 eq) to the reaction flask. React at room temperature for 3 hours. After the reaction is completed, quench the reaction with water (120 ml), extract with ethyl acetate (100 ml × 3), wash with saturated brine (100 ml × 3), dry over anhydrous magnesium sulfate, concentrate under reduced pressure, and then separate and purify by column chromatography. The volume ratio of the eluent is petroleum ether:ethyl acetate = 20:1. A colorless oil, compound VI (21 g, 78%), is obtained. R f = 0.40 (petroleum ether:ethyl acetate = 20:1).

[0079] Step 7:

[0080] Take a 500 ml dry two-necked reaction flask and add a magnetic stir bar. Weigh compound VI (13.7 g, 26 mmol) and add it to the reaction flask. After installing a condenser reflux device, replace the argon three times and insert a balloon for protection. Place the apparatus at room temperature, add water- and oxygen-free toluene (250 ml) to dissolve the substrate, then place the apparatus at 110 °C and slowly add tris(trimethylsilyl)silane (12.93 g, 52 mmol, 2.0 eq) and triethylborane (0.637 g, 6.5 mmol, 0.25 eq) to the reaction flask. React at 85 °C for 5 hours. After the reaction is completed, cool to room temperature, extract with ethyl acetate (100 ml × 2), wash with saturated brine (100 ml × 2), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and then separate and purify by column chromatography. The volume ratio of the eluent is petroleum ether:ethyl acetate = 40:1. A colorless oil, compound VII (4.2 g, 40%), is obtained. R f = 0.50 (petroleum ether:ethyl acetate = 40:1).

[0081] Step 8:

[0082] Add a magnetic stir bar to a 100 mL dry two-necked reaction flask. Weigh chromium(III) oxide (4 g, 40 mmol, 8 eq) and 3,5-dimethylpyrazole (3.8 g, 40 mmol, 8 eq) and add them to the reaction flask. Replace the argon three times and protect with a balloon. Place the apparatus in a bath at -15 °C and stir for 30 minutes. Then add freshly distilled dichloromethane (20 mL) to dissolve the substrate. Next, place the apparatus in a bath at -10 °C and add compound VII (2 g, 5 mmol) dissolved in dichloromethane (10 mL) to the reaction flask. Stir for 5 minutes to complete the reaction. Filter through a Buchner funnel with diatomaceous earth, concentrate under reduced pressure, and then separate and purify by column chromatography with an eluent volume ratio of petroleum ether:ethyl acetate = 10:1. Obtain a white solid, compound VIII (1.4 g, 68%). R f = 0.50 (petroleum ether:ethyl acetate = 10:1).

[0083] As Figure 3 shown, characterize its structure by TLC thin-layer chromatography and NMR data. Specifically as follows: 1 1H NMR (601 MHz, CDCl3) δ 7.40 (d, J = 8.5 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 4.97 (dd, J = 10.2, 7.7 Hz, 1H), 3.94 (s, 3H), 3.53 (q, J = 10.0 Hz, 2H), 2.81 (dd, J = 18.7, 7.0 Hz, 1H), 2.63 (d, J = 18.7 Hz, 1H), 2.46 (d, J = 6.9 Hz, 1H), 2.00 (ddt, J = 14.1, 7.3, 3.4 Hz, 1H), 1.50 (tdd, J = 13.8, 10.1, 3.3 Hz, 1H), 1.27 (dt, J = 13.8, 3.7 Hz, 1H), 1.14 (td, J = 14.3, 2.8 Hz, 1H), 0.95 (s, 3H), 0.89 (s, 9H), 0.46 (s, 3H), 0.01 (d, J = 13.6 Hz, 6H) ppm; 13 13C NMR (151 MHz, CDCl3) δ 196.1, 149.5, 144.4, 137.6, 124.2, 119.3, 113.1, 87.6, 65.4, 56.2, 47.8, 43.2, 36.5, 35.4, 32.7, 31.2, 25.8, 24.4, 21.1, 18.1, -5.5, -5.6 ppm.

[0084] Step 9:

[0085] Add a magnetic stir bar to a 50 mL dry two-necked flask. Weigh compound VIII (83 mg, 0.2 mmol) and selenium dioxide (111 mg, 1 mmol, 5 e.q) and add them to the reaction flask. At room temperature, add a mixed solvent of acetic acid (1.5 mL) and water (0.5 mL) to the reaction flask, and then place the apparatus in an oven at 110 °C for 2 h. After the reaction is completed, cool the apparatus to room temperature, add ethyl acetate (3 mL) for dilution, and then add saturated sodium bicarbonate solution (6 mL) to quench the reaction. Extract with ethyl acetate (10 mL × 3), wash with saturated brine (10 mL × 3), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography. The volume ratio of the eluent is petroleum ether:ethyl acetate = 5:1 to obtain a white solid, compound IX (55 mg, 70%). R f = 0.25 (petroleum ether:ethyl acetate = 5:1).

[0086] As Figure 4 shown, its structure was characterized by TLC and NMR data. The details are as follows: 1 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 8.5 Hz, 1H), 6.93 (d, J = 8.5 Hz, 1H), 4.58–4.51 (m, 2H), 3.98 (s, 3H), 3.68–3.64 (m, 2H), 3.31 (d, J = 1.4 Hz, 1H), 2.10 (ddd, J = 14.2, 7.6, 3.4 Hz, 1H), 1.63–1.51 (m, 1H), 1.42–1.36 (m, 2H), 0.96 (s, 3H), 0.48 (s, 3H) ppm; 13 13C NMR (101 MHz, CDCl3) δ 189.3, 150.9, 143.6, 136.4, 125.0, 120.1, 114.0, 86.1, 70.1, 66.1, 56.5, 45.3, 42.5, 35.1, 31.9, 29.7, 24.3, 22.1 ppm.

[0087] The structural formulas of the 4,4-dimethyl-2-cyclohexen-1-one, 3-hydroxy-4-methoxybenzaldehyde, and compounds I–IX described in this example are respectively as Figure 2 shown.

[0088] In summary, the present invention discloses a new method for preparing an intermediate of aryl abietane diterpenoid Plebein C. Specifically, it includes: subjecting 4,4-dimethyl-2-cyclohexene-1-one to α-substitution at the carbonyl group to obtain compound I; protecting it with TBS to obtain compound II; performing Luche reduction reaction to obtain compound III; subjecting 3-hydroxy-4-methoxybenzaldehyde to iodination at the 2-position to obtain compound IV; performing Wittig reaction to obtain compound V; performing Mitsunobu reaction between compound III and compound V to obtain compound VI; obtaining compound VII through a key radical cyclization reaction; obtaining compound VIII through benzylic oxidation; and obtaining the pentacyclic intermediate compound IX of the Plebein C molecule through oxidation and then closing the lactone ring. This preparation method has a concise synthetic route, inexpensive and readily available reagents, and high yield, which is very conducive to the large-scale preparation of the intermediate of aryl abietane diterpenoid Plebein C, facilitating the large-scale production of Plebein C series molecules and more in-depth research on their biological activities. At the same time, this convergent and tandem high-efficiency chemical reaction method is applicable to industrial preparation and has great potential for popularization.

[0089] Finally, it should also be noted that the term "comprising", "including" or any other variant thereof is intended to cover non-exclusive inclusion, so that a process, method, article or device comprising a series of elements not only includes those elements but also includes other elements not expressly listed, or also includes elements inherent to such process, method, article or device.

[0090] Although the preferred embodiments of the present invention have been described, those skilled in the art can make additional changes and modifications once they learn the basic creative concept. Therefore, the appended claims are intended to be construed as including the preferred embodiments as well as all changes and modifications falling within the scope of the present invention.

[0091] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalent technologies, the present invention is also intended to include these changes and modifications.

Claims

1. A new method for preparing an intermediate of aryl abietane diterpenoid Plebein C, characterized in that, The reaction process route of the described method is as follows: The described synthesis method includes steps one to nine: Specifically: Step one: Using 4,4-dimethyl-2-cyclohexen-1-one as the raw material, reacting it with 4-dimethylaminopyridine and aqueous formaldehyde at room temperature to obtain compound I; Step two: Reacting compound I with 4-dimethylaminopyridine, tert-butyldimethylchlorosilane and pyridine at room temperature to obtain compound II; Step three: Performing a Luche reduction reaction on compound II with cerium(III) chloride heptahydrate and sodium borohydride to obtain compound III; Step four: Using 3-hydroxy-4-methoxybenzaldehyde as the raw material, reacting it with iodine monochloride dissolved in pyridine and 1,4-dioxane under dark conditions at room temperature to obtain compound IV; Step five: Performing a Wittig reaction on compound IV with methyltriphenylphosphonium bromide and sodium bis(trimethylsilyl)amide to obtain V; Step six: Performing a Mitsunobu reaction on compound III and compound V with triphenylphosphine and diisopropyl azodicarboxylate to obtain VI; Step seven: Treating compound VI with tris(trimethylsilyl)silane and triethylboron in deoxygenated toluene to obtain compound VII; Step eight: Performing a benzylic oxidation reaction on compound VII with chromium(VI) oxide and 3,5-dimethylpyrazole to obtain compound VIII; Step nine: Oxidizing and cyclizing compound VIII with selenium dioxide to obtain compound IX, which is the intermediate of the arylabietane diterpenoid Plebein C.

2. A new method for preparing an intermediate of aryl abietane diterpenoid Plebein C as described in claim 1, characterized in that, The structural formulas of the described 4,4-dimethyl-2-cyclohexen-1-one, 3-hydroxy-4-methoxybenzaldehyde, and compounds I to IX are respectively as follows:

3. A novel method for preparing an intermediate of aryl abietane diterpenoid Plebein C as described in claim 1, characterized in that, The specific synthesis method of step one is: Using 4,4-dimethyl-2-cyclohexen-1-one as the raw material, reacting it with 4-dimethylaminopyridine and aqueous formaldehyde at room temperature to obtain compound I, specifically including: Adding 4-dimethylaminopyridine to the reaction flask at room temperature, adding the solvent tetrahydrofuran, the raw material 4,4-dimethyl-2-cyclohexen-1-one, and aqueous formaldehyde under an argon atmosphere, stirring the reaction at room temperature for 24 hours, at normal pressure; after the reaction is completed, adding 1N HCl for quenching with vigorous stirring at room temperature, extracting with dichloromethane, washing with saturated brine, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and then separating and purifying by column chromatography. The volume ratio of the eluent is petroleum ether:ethyl acetate = 3:1, and then compound I can be obtained; The molar ratio of the described 4,4-dimethyl-2-cyclohexen-1-one, 4-dimethylaminopyridine, and aqueous formaldehyde is: 100:55:

300.

4. A new method for preparing an intermediate of aryl abietane diterpenoid Plebein C as described in claim 1, characterized in that, The specific synthesis method of step two is: Reacting compound I with 4-dimethylaminopyridine, tert-butyldimethylchlorosilane and pyridine at room temperature to obtain compound II, specifically including: 4-Dimethylaminopyridine and tert-butyldimethylsilyl chloride were added to a reaction flask at room temperature. Under an argon atmosphere at 0 °C, the solvent dichloromethane and pyridine were added. After stirring at 0 °C for 5 minutes, compound I dissolved in dichloromethane was added. After stirring at 0 °C for 30 minutes, the reaction was carried out at room temperature for 2 hours under atmospheric pressure. After the reaction was completed, a saturated ammonium chloride solution was added with stirring at 0 °C for quenching. It was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then separated and purified by column chromatography. The volume ratio of the eluent was petroleum ether:ethyl acetate = 20:1, and compound II could be obtained. The molar ratio of the said compound I, 4-dimethylaminopyridine, tert-butyldimethylsilyl chloride, and pyridine was: 82.7:24.8:165.3:206.

6.

5. A new method for preparing an intermediate of aryl abietane diterpenoid Plebein C as described in claim 1, characterized in that, The specific synthesis method of the said step three was: Compound II and cerium(III) chloride heptahydrate underwent a Luche reduction reaction with sodium borohydride at 0 °C to obtain compound III, specifically including: Compound II, cerium(III) chloride heptahydrate and the solvent methanol were added to a reaction flask at room temperature. Sodium borohydride was added in three portions at 0 °C. After each addition of sodium borohydride, it was stirred at 0 °C for 10 minutes under atmospheric pressure. After the reaction was completed, ice water was added for quenching. It was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then separated and purified by column chromatography. The volume ratio of the eluent was petroleum ether:ethyl acetate = 20:1, and compound III could be obtained. The molar ratio of the said compound II, cerium(III) chloride heptahydrate, and sodium borohydride was: 41.8:41.8:

25.

6. A novel method for preparing an intermediate of aryl abietane diterpenoid Plebein C as described in claim 1, characterized in that, The specific synthesis method of the said step four was: Using 3-hydroxy-4-methoxybenzaldehyde as the raw material, it was reacted with iodine monochloride dissolved in pyridine and 1,4-dioxane at room temperature in the dark to obtain compound IV, specifically including: 3-Hydroxy-4-methoxybenzaldehyde was added to a reaction flask. Under an argon atmosphere at 0 °C, the solvent pyridine was added, and then iodine monochloride dissolved in 1,4-dioxane was added. The reaction was carried out at room temperature in the dark for 6 days under atmospheric pressure. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and then water and HCl were added to adjust the pH to 1. It was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain compound IV. The molar ratio of the said 3-hydroxy-4-methoxybenzaldehyde and iodine monochloride was: 120:

156.

7. A novel method for preparing an intermediate of aryl abietane diterpenoid Plebein C as described in claim 1, characterized in that, The specific synthesis method of the said step five was: Compound IV underwent a Wittig reaction with methyltriphenylphosphonium bromide and sodium bis(trimethylsilyl)amide to obtain V, specifically including: Methyltriphenylphosphonium bromide was added to a reaction flask at room temperature. Under an argon atmosphere, the solvent tetrahydrofuran was added. At 0 °C, sodium bis(trimethylsilyl)amide was added. After stirring at 0 °C for 30 minutes, compound IV dissolved in tetrahydrofuran was added. The reaction was carried out at room temperature for 30 minutes under atmospheric pressure. After the reaction was completed, a saturated ammonium chloride solution was added for quenching. It was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then separated and purified by column chromatography. The volume ratio of the eluent was petroleum ether:ethyl acetate = 5:1 - 3:1, and compound V could be obtained. The molar ratio of the compound IV, methyltriphenylphosphonium bromide, and sodium bis(trimethylsilyl)amide is: 72:172.8:158.

4.

8. A novel method for preparing an intermediate of aryl abietane diterpenoid Plebein C as described in claim 1, characterized in that, The specific synthesis method of Step 6 is as follows: Compound III and Compound V undergo a Mitsunobu reaction with triphenylphosphine and diisopropyl azodicarboxylate to obtain VI, specifically including: At room temperature, Compound III, Compound V, and triphenylphosphine are added to a reaction flask. Under an argon atmosphere, the solvent tetrahydrofuran is added. After stirring at room temperature for 10 minutes, diisopropyl azodicarboxylate is added at 0 °C, and the reaction proceeds at room temperature for 3 hours under normal pressure. After the reaction is completed, the reaction is quenched with ice water, extracted with ethyl acetate, washed with saturated brine, dried with anhydrous magnesium sulfate, concentrated under reduced pressure, and then separated and purified by column chromatography. The volume ratio of the eluent is petroleum ether:ethyl acetate = 20:1 to 10:1, and Compound VI can be obtained. The molar ratio of Compound III, Compound V, triphenylphosphine, and diisopropyl azodicarboxylate is: 51.2:56.3:58.8:58.

8.

9. A novel method for preparing an intermediate of aryl abietane diterpenoid Plebein C as described in claim 1, characterized in that, The specific synthesis method of Step 7 is as follows: Compound VI is treated with tris(trimethylsilyl)silane and triethylborane in deoxygenated toluene to obtain Compound VII, specifically including: At room temperature, Compound VI, tris(trimethylsilyl)silane, and triethylborane are added to a reaction flask. Under an argon atmosphere, the solvent deoxygenated toluene is added. The temperature is raised to 85 °C and the reaction proceeds for 5 hours under normal pressure. After the reaction is completed, toluene is removed by concentration under reduced pressure. Extracted with ethyl acetate, washed with water and saturated brine; dried with anhydrous sodium sulfate, concentrated under reduced pressure, and then separated and purified by column chromatography. The volume ratio of the eluent is petroleum ether:ethyl acetate = 40:1 to 30:1, and Compound VII can be obtained. The molar ratio of Compound VI, tris(trimethylsilyl)silane, and triethylborane is: 26:52:6.5; The specific synthesis method of Step 8 is as follows: Compound VII undergoes a benzylic oxidation reaction with chromium trioxide and 3,5-dimethylpyrazole at -15 °C to obtain Compound VIII, specifically including: At room temperature, chromium trioxide and 3,5-dimethylpyrazole are added to a reaction flask. Under an argon atmosphere at -15 °C, the solvent dichloromethane is added. After stirring at -15 °C for 10 minutes, Compound VII dissolved in dichloromethane is added at -10 °C, and the reaction proceeds at -10 °C for 5 minutes under normal pressure. After the reaction is completed, it is filtered through diatomaceous earth using a suction funnel, concentrated under reduced pressure, and then separated and purified by column chromatography; the volume ratio of the eluent is petroleum ether:ethyl acetate = 10:1 to 5:1, and Compound VIII can be obtained. The molar ratio of Compound VII, chromium trioxide, and 3,5-dimethylpyrazole is: 5:40:

40.

10. A novel method for preparing an intermediate of aryl abietane diterpenoid Plebein C as described in claim 1, characterized in that, The specific synthesis method of Step 9 is as follows: Compound VIII is treated in selenium dioxide to obtain Compound IX: Specifically including: Add compound VIII and selenium dioxide into a reaction flask at room temperature. Add a mixed solvent of acetic acid and water at room temperature, and react at 110 °C for 2 hours under normal pressure. After the reaction, cool to room temperature, dilute with ethyl acetate, then add saturated sodium bicarbonate solution for quenching, extract with ethyl acetate, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and then separate and purify by column chromatography. The volume ratio of the eluent is petroleum ether:ethyl acetate = 5:1 to obtain compound IX; The molar ratio of the said compound VIII to selenium dioxide is: 0.2:1.

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