A novel process for the preparation of polycyclic cembran diterpene rameswaralide intermediates

Abstract

The application discloses a new method for preparing a polycyclic cembranoid diterpene Rameswaralide intermediate, and specifically comprises the following steps: performing an alkylating reaction on a phenolic hydroxyl group of 2-bromo-3-hydroxy-4-methoxybenzaldehyde to obtain a compound I; performing a Baylis-Hillman reaction on the obtained compound I and a cyclohexenone raw material II to obtain a compound III; performing a Dess-Martin oxidation reaction to obtain a compound IV; and finally performing a photocatalytic cyclization reaction to obtain a tetracyclic intermediate compound V of the Rameswaralide molecule; the preparation method has the advantages of a green, catalytic and simple synthesis route, cheap and easily obtained reagents, high yield, favorability for industrial preparation of the intermediate, and strong popularization potential.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a new method for preparing the intermediate of the polycyclic cerebroside diterpene Rameswaralide. Background Technology

[0002] Cerealisine diterpenes are a class of natural products that have received considerable research and attention from scientists in recent years due to their unique and novel structures. For example, some structurally novel natural cerealisines, such as papyifurans AC, have been found to effectively prevent renal fibrosis both in vitro and in vivo. Chemical proteomics analysis revealed that EEF2 is a key target for papyifurans A's in vitro anti-renal fibrosis activity. Polycyclic cerealisine diterpenes are an important subtype of cerealisine diterpenes, containing a 5 / 5 / 7 / 6 or 5 / 5 / 6 / 7 tetracyclic skeleton, six or seven chiral centers, and varying degrees of oxidation. This family of compounds is widely distributed in marine soft corals, and modern pharmacology has shown that polycyclic cerealisine diterpenes possess good anti-inflammatory and anti-tumor activities. Since the first isolation of polycyclic cerealisine (Sarcophytin) by Anjaneyulu's group in 1998, several other polycyclic cerealisine diterpenes have been discovered. For example, Pavidolide B, discovered by Lin Wenhan's group, exhibits highly selective inhibitory activity against various human promyelocytic leukemia cell lines. In 1998, Professor Venkateswarlu's group and Professor Faulkner's group collaborated to study soft corals off the coast of Mandapam in the southern Indian Ocean. Sinularia dissecta For the first time, Rameswaralide, a polycyclic cerebroside-type diterpenoid with a 5 / 5 / 7 / 6 tetracyclic ring fusion system, was isolated from marine soft corals. This compound was found to be cytotoxic to human non-small cell lung cancer cells (A549), making it a valuable lead compound for pharmacological research. However, due to limitations in geographical location, environment, and climate, the amount of Rameswaralide isolated from marine soft corals is limited, with a yield of only 0.003%, far from sufficient for further bioactivity studies of this type of natural product.

[0003] In view of this, the present invention designs a new method for preparing the intermediate of polycyclic systolic diterpenoid Rameswaralide through a photocatalytic tandem cyclization reaction. This preparation method has a green, catalytic, simple synthetic route, uses inexpensive and readily available reagents, and has a high yield. It is very beneficial for the large-scale preparation of this intermediate of polycyclic systolic diterpenoid Rameswaralide, which facilitates further in-depth research on the bioactivity of this series of polyoxygenated and multichiral polycyclic systolic diterpenoid molecules. Summary of the Invention

[0004] This invention primarily overcomes the shortcomings of existing technologies by proposing a novel method for preparing the intermediate of the polycyclic systolic diterpene Rameswaralide. This method utilizes a skeletal construction method with Rameswaralide molecules as the primary component. Specifically, it includes: using 2-bromo-3-hydroxy-4-methoxybenzaldehyde and allyl bromide as raw materials, reacting them with potassium carbonate at room temperature to obtain compound I; reacting compound I and cyclohexenone raw material II with 1,8-diazabicyclo[5.4.0]undec-7-ene at room temperature to obtain compound III; oxidizing compound III with a Dys-Martin oxidant to obtain compound IV; and finally, subjecting compound IV to tandem cyclization under photocatalytic conditions to obtain compound V, which is the aforementioned intermediate of the polycyclic systolic diterpene Rameswaralide. This preparation method features a green, catalytic, and simple synthetic route, uses inexpensive and readily available reagents, and achieves high yields. It is highly beneficial for the large-scale preparation of the intermediate of the polycyclic systolic diterpene Rameswaralide, facilitating the mass production of the Rameswaralide series of molecules and enabling more in-depth research on their biological and pharmacological activities. Meanwhile, this convergent and tandem efficient chemical reaction method is suitable for industrial preparation and has great potential for widespread application.

[0005] To achieve the above-mentioned technical objectives, the technical solution adopted by the present invention is as follows: A novel method for preparing the polycyclic cerebroside diterpene Rameswaralide intermediate is described below: ; The synthesis method includes steps one through four: Specifically: Step 1: Using compound 2-bromo-3-hydroxy-4-methoxybenzaldehyde and allyl bromide as raw materials, react with potassium carbonate at room temperature to obtain compound I; Step 2: Compound I and cyclohexenone raw material II were reacted with 1,8-diazabicyclo[5.4.0]undec-7-ene at room temperature to obtain compound III; Step 3: Compound III was oxidized at 0 degrees Celsius with a Des Martin oxidant to give compound IV; Step 4: Compound IV undergoes cyclization under photocatalytic conditions with eosin Y as a photosensitizer, blue light as a light source, and triethylamine as a reducing agent to obtain compound V, which is the intermediate of the polycyclic cerebroside diterpene Rameswaralide.

[0006] Furthermore, the structural formulas of the compound 2-bromo-3-hydroxy-4-methoxybenzaldehyde and compounds I to V are shown below: .

[0007] Furthermore, the specific synthesis method in step one is as follows: Using 2-bromo-3-hydroxy-4-methoxybenzaldehyde and allyl bromide as raw materials, compound I is obtained by reacting potassium carbonate at room temperature, specifically including: At room temperature, 2-bromo-3-hydroxy-4-methoxybenzaldehyde, acetonitrile, allyl bromide, and potassium carbonate were added sequentially to a reaction flask. The mixture was stirred at room temperature for 10 hours under normal pressure. After the reaction was completed, the mixture was filtered through a Buchner funnel. The filtrate was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography with a petroleum ether:ethyl acetate volume ratio of 5:1 to obtain compound I. The molar ratio of 2-bromo-3-hydroxy-4-methoxybenzaldehyde, allyl bromide, and potassium carbonate is 100:150:150.

[0008] Furthermore, the specific synthesis method for step two is as follows: Compound I and cyclohexenone starting material II were reacted with 1,8-diazabicyclo[5.4.0]undec-7-ene at room temperature to give compound III, which specifically includes: In an argon atmosphere, compound I and cyclohexenone raw material II were added sequentially to a reaction flask at room temperature. Then, 1,8-diazabicyclo[5.4.0]undec-7-ene was added dropwise over 5 minutes using a syringe. The reaction was then carried out at room temperature for 4 hours under normal pressure. After the reaction was completed, ice water was added and stirred at 0 degrees Celsius to quench the reaction. The mixture was extracted with dichloromethane, washed with saturated brine, dried with anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography with a petroleum ether:ethyl acetate volume ratio of 2:1 to obtain compound III. The molar ratio of compound I, cyclohexenone raw material II, and 1,8-diazabicyclo[5.4.0]undec-7-ene is 175:315:193.

[0009] Furthermore, the specific synthesis method for step three is as follows: Compound III was oxidized at 0 degrees Celsius with a Des Martin oxidant to give compound IV, specifically including: Compound III and dichloromethane solvent were added to a reaction flask at room temperature. The reaction was then oxidized in four batches with Des Martin oxidant added at 0°C, with stirring for 5 minutes after each addition of Des Martin oxidant at 0°C under normal pressure. After the reaction was complete, saturated sodium bicarbonate solution was added to quench the reaction, followed by extraction with dichloromethane. The mixture was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography with an eluent volume ratio of petroleum ether:ethyl acetate = 3:1 to obtain compound IV. The molar ratio of compound III to the Des Martin oxidant is 76:114.

[0010] Furthermore, the specific synthesis method for step four is as follows: Compound IV undergoes cyclization under photocatalytic conditions using eosin Y as a photosensitizer, blue light as a light source, and triethylamine as a reducing agent to yield compound V, which is the intermediate of the polycyclic cerebroside diterpene Rameswaralide, specifically comprising: In an argon atmosphere, at room temperature, eosin Y, compound IV, triethylamine, and solvent acetonitrile were added to a reaction flask. A blue light source was turned on, and the reaction was carried out at room temperature for 5 hours under normal pressure. After the reaction was completed, water was added to quench the reaction. The mixture was extracted with ethyl acetate, washed with water and saturated brine, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography with a petroleum ether:ethyl acetate volume ratio of 3:1 to obtain compound V. The molar ratio of compound VI, eosin Y, and triethylamine is 8:0.4:12.

[0011] Beneficial effects Compared with the prior art, the present invention has the following advantages: This invention discloses a novel method for preparing intermediates of the polycyclic systoleane diterpenoid Rameswaralide. A synthetic method for constructing the tetracyclic skeleton of Rameswaralide via a Baylis-Hillman reaction and a photocatalytic tandem cyclization reaction is designed. This method is a skeleton construction method with Rameswaralide as the leading molecule. Specifically, it includes: alkylating the phenolic hydroxyl group of 2-bromo-3-hydroxy-4-methoxybenzaldehyde to obtain compound I; reacting compound I with cyclohexenone starting material II via a Baylis-Hillman reaction to obtain compound III; undergoing a Desmond-Martin oxidation reaction to obtain compound IV; and finally, undergoing a photocatalytic cyclization reaction to obtain the tetracyclic intermediate compound V of Rameswaralide. A convergent synthesis scheme is designed using Rameswaralide as the guiding chemical synthesis method. This preparation method is green, catalytic, and simple, using inexpensive and readily available reagents with high yields, which is highly beneficial for the industrial preparation of intermediates and facilitates further in-depth research on the bioactivity of the Rameswaralide series of polycyclic systoleane diterpenoids, possessing strong potential for widespread application. Attached Figure Description

[0012] Figure 1 This is a synthetic route diagram of a novel method for preparing the polycyclic cephalosporin diterpene Rameswaralide intermediate in an embodiment of the present invention; Figure 2 The structural formulas of compound 2-bromo-3-hydroxy-4-methoxybenzaldehyde and compounds I to V in the embodiments of the present invention are shown below; Figure 3This is the 1H NMR spectrum of compound V in an embodiment of the present invention. Detailed Implementation

[0013] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0014] according to Figure 1 The synthetic route diagram shown illustrates the synthesis of the compounds in the following examples, and the structural formulas of each compound involved are described. Figure 2 As shown.

[0015] Example 1: Step 1: Add a stir bar to a 500 ml dry double-necked flask, weigh potassium carbonate (20.73 g, 150 mmol, 1.5 eq) and add it to a round-bottom flask. Replace the flask with argon gas twice and insert an argon balloon for protection. Place the apparatus at room temperature, add the starting material 2-bromo-3-hydroxy-4-methoxybenzaldehyde (22.3 g, 100 mmol) dissolved in acetonitrile (30 ml), and then add acetonitrile (100 ml) as solvent. Finally, add allyl bromide (12.99 g, 150 mmol, 1.5 eq) dropwise over 10 minutes using a constant-pressure dropping funnel. After the addition is complete, allow the mixture to react at room temperature for 10 hours. After the reaction was completed, the mixture was filtered through a Buchner funnel. The filtrate was extracted with ethyl acetate (80 ml × 3), washed with saturated brine (30 ml × 3), dried with anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography with a petroleum ether:ethyl acetate volume ratio of 8:1. The resulting light brown oily substance was compound I (26.46 g, 98%). R f = 0.62 (petroleum ether: ethyl acetate = 5:1).

[0016] Step Two: Add a stir bar to a dry 200 ml round-bottom flask, and weigh out compound I (47.25 g, 175 mmol) and cyclohexenone starting material II (30.28 g, 315 mmol, 1.8 eq). Purge the mixture with argon gas twice and insert an argon gas balloon for protection. Then, using a syringe, add 1,8-diazabicyclo[5.4.0]undec-7-ene (29.38 g, 193 mmol, 1.1 eq) dropwise over 5 minutes to the reaction flask. After the addition is complete, allow the mixture to react at room temperature for 4 hours. After the reaction was completed, ice water (20 ml) was added under stirring at 0 degrees Celsius to quench the reaction, and the mixture was extracted with dichloromethane (100 ml × 3). After washing with saturated brine (40 ml × 3), the mixture was dried with anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography with a petroleum ether:ethyl acetate volume ratio of 2:1. The resulting light brown oily substance was compound III (48.68 g, 76%). R f = 0.43 (petroleum ether: ethyl acetate = 2:1).

[0017] Step 3: Add a stir bar to a 500 ml dry double-necked flask and weigh out compound III (27.82 g, 76 mmol). Place the apparatus at 0°C and add dichloromethane (165 ml) to dissolve the substrate. Then, add Dysmartin oxidant (48.35 g, 114 mmol, 1.5 eq) in four batches to the reaction flask, reacting for 5 minutes after each addition at 0°C. After the reaction is complete, quench with saturated sodium bicarbonate solution (50 ml), extract with dichloromethane (100 ml × 3), wash with saturated brine (60 ml × 3), dry with anhydrous magnesium sulfate, concentrate under reduced pressure, and purify by column chromatography with a petroleum ether:ethyl acetate volume ratio of 12:1. The resulting pale yellow foamy substance is compound IV (24.62 g, 89%). R f = 0.58 (petroleum ether: ethyl acetate = 3:1).

[0018] Step Four: A 100 ml dry single-necked reaction flask was filled with a stir bar. Eosin Y (277 mg, 0.4 mmol, 0.05 eq), compound IV (2.912 g, 8 mmol), and triethylamine (1.214 g, 12 mmol, 1.5 eq) were weighed into the flask sequentially. The mixture was purged with argon gas three times, protected with an argon gas balloon, and finally, acetonitrile (25 ml) was added as solvent. The reaction was carried out under blue light for 5 hours. After the reaction was complete, the mixture was quenched with water (5 ml), extracted with ethyl acetate (40 ml × 3), washed with saturated brine (15 ml × 3), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a pale yellow solid, compound V (1.853 g, 81%). R f = 0.48 (petroleum ether: ethyl acetate = 3:1).

[0019] like Figure 3 As shown, its structure was characterized by TLC (thin-layer chromatography) and NMR data. Details are as follows: 1 H NMR (400MHz, CDCl3) δ 7.45 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 4.93 (t, J = 8.8Hz, 1H), 4.13 (dd, J = 10.8, 2.4 Hz, 1H), 3.93 (s, 3H), 3.88 (d, J = 6.8 Hz, 1H), 3.83 (d, J = 10.4 Hz, 1H), 3.02 (ddd, J = 14.4, 13.2, 6.8 Hz, 1H), 2.59 – 2.53(m, 1H), 2.45 – 2.39 (m, 1H), 2.32 – 2.29 (m, 1H), 2.12 – 2.07 (m, 1H), 1.81– 1.77 (m, 1H), 1.69 – 1.65 (m, 1H), 1.53 – 1.42 (m, 2H) ppm; 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. The structural formulas of compound 2-bromo-3-hydroxy-4-methoxybenzaldehyde and compounds I to V described in this embodiment are as follows: Figure 2 As shown.

[0020] In summary, this invention discloses a novel method for preparing the polycyclic sissonide diterpene Rameswaralide intermediate. Specifically, it includes: alkylating the phenolic hydroxyl group of 2-bromo-3-hydroxy-4-methoxybenzaldehyde to obtain compound I; reacting compound I with cyclohexenone II via a Baylis-Hillman reaction to obtain compound III; undergoing a Desmond-Martin oxidation reaction to obtain compound IV; and finally, a photocatalytic cyclization reaction to obtain the tetracyclic intermediate compound V of the Rameswaralide molecule. This preparation method features a green, catalytic, and simple synthetic route, uses inexpensive and readily available reagents, and achieves high yields, making it beneficial for the industrial preparation of intermediates and possessing strong potential for widespread application. Furthermore, this efficient, convergent and tandem chemical reaction method is suitable for industrial preparation and has significant potential for wider application.

[0021] Finally, it should be noted that the terms “comprising,” “including,” or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such process, method, article, or apparatus.

[0022] Although preferred embodiments of the invention have been described, those skilled in the art, upon learning the basic inventive concept, can make other changes and modifications to these embodiments. Therefore, the appended claims are intended to be interpreted as including both the preferred embodiments and all changes and modifications falling within the scope of the invention.

[0023] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. Therefore, if these modifications and variations fall within the scope of the claims of this invention and their equivalents, this invention also intends to include these modifications and variations.

Claims

1. A novel method for preparing the intermediate of the polycyclic cephalosporin diterpene Rameswaralide, characterized in that, The reaction route of the method is as follows: ； The synthesis method includes steps one through nine: Specifically: Step 1: Using compound 2-bromo-3-hydroxy-4-methoxybenzaldehyde and allyl bromide as raw materials, react with potassium carbonate at room temperature to produce compound I; Step 2: Compound I and cyclohexenone raw material II were reacted with 1,8-diazabicyclo[5.4.0]undec-7-ene at room temperature to obtain compound III; Step 3: Compound III is oxidized with Desmond-Martin oxidant to give compound IV; Step 4: Compound IV undergoes cyclization under photocatalytic conditions to obtain compound V, which is the intermediate of the polycyclic cerebroside diterpene Rameswaralide.

2. A novel method for obtaining a polycyclic cephalosporin diterpene Rameswaralide intermediate as described in claim 1, characterized in that, The structural formulas of the compound 2-bromo-3-hydroxy-4-methoxybenzaldehyde and compounds I to V are shown below: 。 3. A novel method for preparing the polycyclic cephalosporin diterpene Rameswaralide intermediate as described in claim 1, characterized in that, The synthesis method in step one is as follows: Using 2-bromo-3-hydroxy-4-methoxybenzaldehyde and allyl bromide as raw materials, compound I is obtained by reacting potassium carbonate at room temperature, specifically including: Potassium carbonate, 2-bromo-3-hydroxy-4-methoxybenzaldehyde, acetonitrile, and allyl bromide were added sequentially to a reaction flask at room temperature. The mixture was stirred at room temperature for 10 hours under normal pressure. After the reaction was completed, the mixture was filtered through a Buchner funnel. The filtrate was extracted with ethyl acetate, washed with saturated brine, dried with anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography with a petroleum ether:ethyl acetate volume ratio of 5:1 to obtain compound I. The molar ratio of 2-bromo-3-hydroxy-4-methoxybenzaldehyde, allyl bromide, and potassium carbonate is 100:150:

150.

4. A novel method for preparing the polycyclic cephalosporin diterpene Rameswaralide intermediate as described in claim 1, characterized in that, The synthesis method in step two is as follows: Compound I and cyclohexenone starting material II were reacted with 1,8-diazabicyclo[5.4.0]undec-7-ene at room temperature to give compound III, which specifically includes: In an argon atmosphere, compound I and cyclohexenone raw material II were added sequentially to a reaction flask at room temperature. Then, 1,8-diazabicyclo[5.4.0]undec-7-ene was added dropwise over 5 minutes using a syringe. The reaction was then carried out at room temperature for 4 hours under normal pressure. After the reaction was completed, ice water was added and stirred at 0 degrees Celsius to quench the reaction. The mixture was extracted with dichloromethane, washed with saturated brine, dried with anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography with a petroleum ether:ethyl acetate volume ratio of 2:1 to obtain compound III. The molar ratio of compound I, cyclohexenone raw material II, and 1,8-diazabicyclo[5.4.0]undec-7-ene is 175:315:

193.

5. A novel method for preparing the polycyclic cephalosporin diterpene Rameswaralide intermediate as described in claim 1, characterized in that, The synthesis method in step three is as follows: Compound III was oxidized at 0 degrees Celsius with a Des Martin oxidant to give compound IV, specifically including: Compound III and dichloromethane solvent were added to a reaction flask at room temperature. The reaction was then oxidized in four batches with Des Martin oxidant added at 0°C, with stirring for 5 minutes after each addition of Des Martin oxidant at 0°C. The reaction was carried out under normal pressure. After the reaction was completed, saturated sodium bicarbonate solution was added to quench the reaction, followed by extraction with dichloromethane. The mixture was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography with an eluent volume ratio of petroleum ether:ethyl acetate = 12:1 to obtain compound IV. The molar ratio of compound III to the Des Martin oxidant is 76:

114.

6. A novel method for preparing the polycyclic cephalosporin diterpene Rameswaralide intermediate as described in claim 1, characterized in that, The synthesis method in step four is as follows: Compound IV underwent cyclization under photocatalytic conditions with eosin Y as a photosensitizer, blue light as a light source, and triethylamine as a reducing agent to yield compound V, which is the intermediate of the polycyclic cerebroside diterpene Rameswaralide; specifically including: In an argon atmosphere, at room temperature, eosin Y, compound IV, triethylamine, and solvent acetonitrile were added to a reaction flask. A blue light source was turned on, and the reaction was carried out at room temperature for 5 hours under normal pressure. After the reaction was completed, water was added to quench the reaction. The mixture was extracted with ethyl acetate, washed with water and saturated brine, dried with anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography with a petroleum ether:ethyl acetate volume ratio of 3:1 to obtain compound V. The molar ratio of compound VI, eosin Y, and triethylamine is 8:0.4:12.

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