Total synthesis method of rhododendron heteroterpenin Rhododaurines A-C

Abstract

The invention belongs to the technical field of organic synthesis and medicinal chemistry, and discloses a total synthesis method of rhododendron heteroterpenin Rhododaurines A-C. The total synthesis method comprises the following steps: carrying out allyl stereoselective addition on a compound 3 and a compound 5 in a toluene solvent under the conditions of catalysis of n-butyllithium and low temperature of-78 DEG C, and constructing a chiral center to obtain a compound 6; removing a methoxy methyl (MOM) protecting group from the compound 6 under an acidic condition, cyclizing, and reacting to generate rhododaurine C (7); the rhododaurine C (7) is subjected to intramolecular [4 + 2] cycloaddition and oxidation reaction in the illumination and oxygen atmosphere of 300-385 nm, and rhododaurine B (8) and an epoxy epimer epinedodaurine B (9) are obtained; and carrying out protonation and rearrangement on the epidodaurine B (9) by virtue of acid catalysis cyclic ether, so as to generate the rhododaurine A (10). The method can overcome the defects that the content of rhododendron miscellaneous terpenoids Rhododaurines A-C in nature is extremely low, and large-scale extraction is difficult.

Description

Technical Field

[0001] The present invention belongs to the technical fields of organic synthesis and medicinal chemistry, and more specifically, relates to a total synthesis method of rhododaurines A-C from Rhododendron dauricum. Background Art

[0002] Plants of the genus Rhododendron are rich in structurally diverse diterpenoids, and some of the components have been proven to have significant analgesic activity. However, diterpenoids from natural sources face major bottleneck problems: the content of the target component in plants is extremely low, and it is significantly affected by the growth environment and harvesting season, resulting in high extraction and separation costs.

[0003] The technology for extracting diterpenoids in our laboratory originally belongs to the field of natural medicinal chemistry. The plant used is the leaf of the medicinal plant Rhododendron dauricum L. of the family Ericaceae, 6.0 kg, collected from Tangyuan County, Jiamusi City, Heilongjiang Province (46.7°N, 129.9°E) in June 2018. The dried leaves of Rhododendron dauricum (6.0 kg) were crushed and soaked in 12 L of 95% ethanol at room temperature for 5 times, 3 days each time. The extraction solutions were combined and concentrated under reduced pressure to obtain a total extract (1.6 kg). The total extract was suspended in 1.6 L of water and then extracted with 1.6 L of petroleum ether 6 times. The petroleum ether layer was concentrated under reduced pressure to obtain the petroleum ether extraction fraction (460 g).

[0004] The research group where the inventors of the present invention are located previously developed a diterpenoid compound and its application for preparing analgesic drugs (see Chinese Patent Application No. 202311593051.5 for details). Through normal-phase, reverse-phase, liquid-phase and other chromatographic means, a series of structurally very novel rhododaurines A-C from Rhododendron dauricum were successfully isolated, and it was verified that they showed good analgesic activity in subsequent activity assays. The structural formulas of these rhododaurines A-C are as follows:

[0005]

[0006] However, the content of these diterpenoids in Rhododendron dauricum is too low to further study their activity mechanisms. The limited nature of natural medicinal resources makes overcollection and unreasonable utilization likely to lead to resource depletion, which in turn affects the balance of the entire ecosystem. In addition, extracting and separating such trace components requires a large amount of human and material resources for the mining, extraction and preparation of medicinal materials, resulting in high production costs. And there is currently no relevant report on the synthesis of rhododaurines A-C.

[0007] The above technical defects have severely restricted the large-scale supply of rhododaurines A–C from Rhododendron dauricum L. and the in-depth development of their pharmacodynamic studies. Therefore, developing a biomimetic total synthesis route with high yield and low cost has become the key to breaking through the limitations of natural sources and promoting the transformation of these components into drugs. Summary of the Invention

[0008] Aiming at the deficiencies still existing in the existing technology for extracting and separating rhododaurines A–C from the natural plant Rhododendron dauricum L., the object of the present invention is to provide a total synthesis method for rhododaurines A–C, which can overcome the disadvantages of extremely low content of rhododaurines A–C in nature and difficulty in large-scale extraction.

[0009] To achieve the above object, according to one aspect of the present invention, there is provided a total synthesis method for rhododaurines A–C, which is characterized by comprising the following steps:

[0010] Step 1: Compound 3 and compound 5 are subjected to allylic stereoselective addition in toluene solvent under the catalysis of n-butyllithium and at a low temperature of -78 °C to construct a chiral center to obtain compound 6;

[0011]

[0012] Step 2: Compound 6 is deprotected from the methoxymethyl (MOM) protecting group and cyclized under acidic conditions to react to form rhododaurine C (7);

[0013]

[0014] Step 3: Rhododaurine C (7) undergoes an intramolecular [4+2] cycloaddition and oxidation reaction under illumination at 300-385 nm and in an oxygen atmosphere to obtain rhododaurine B (8) and the epoxy epimer epirhododaurine B (9);

[0015]

[0016] Step 4: Epirhododaurine B (9) undergoes acid-catalyzed ring ether protonation rearrangement to form rhododaurine A (10);

[0017]

[0018] As a further preference of the present invention, in step one, the molar ratio of compound 3 to compound 5 is 1:1.1 - 1.4, and the dosage of n-butyllithium is 1.1 - 1.4 times the molar amount of compound 3.

[0019] As a further preference of the present invention, in step two, the reaction uses a hydrochloric acid / ethanol mixed solvent to provide an acidic condition;

[0020] Preferably, the hydrochloric acid / ethanol mixed solvent is obtained by mixing hydrochloric acid and ethanol at a volume ratio of 1:1, and the concentration of hydrochloric acid before mixing is 1.0 mol / L;

[0021] The dosage of hydrochloric acid is 1.0 - 2.0 times the molar amount of compound 6; the reaction time is 0.5 - 2 hours; the cyclization product is purified by column chromatography; more preferably, the column chromatography specifically uses petroleum ether / ethyl acetate column chromatography, and the volume ratio of petroleum ether to ethyl acetate in the petroleum ether / ethyl acetate is 10:1.

[0022] As a further preference of the present invention, in step three, the reaction is carried out in a methanol solvent, and the product is separated by gradient elution;

[0023] Preferably, the gradient elution specifically uses a petroleum ether / ethyl acetate eluent, and the volume ratio of petroleum ether to ethyl acetate in the petroleum ether / ethyl acetate eluent is 10:1.

[0024] As a further preference of the present invention, in step four, the acid catalysis uses a formic acid / acetone mixed solvent, the reaction temperature is 25 - 50 °C, and the reaction time is 2 - 5 hours;

[0025] Preferably, the formic acid / acetone mixed solvent is obtained by mixing formic acid and acetone at a volume ratio of 1:5, and the concentration of formic acid before mixing is 1 mol / L;

[0026] The dosage of formic acid is 1.5 - 2.5 times the molar amount of epirhododaurine B (9).

[0027] As a further preference of the present invention, compound 3 used in step one is prepared according to the following sub-steps:

[0028] S1: Using orcinol with the structural formula shown in formula 1 as a substrate, under the protection of a nitrogen atmosphere at 0 °C, a tetrahydrofuran solution of iodine is added dropwise to a tetrahydrofuran / aqueous solution of orcinol containing sodium bicarbonate. After reacting for 2 hours, compound 2 is formed;

[0029]

[0030] S2: Under the condition of 0 °C, dissolve compound 2 in DMF and stir it under nitrogen protection; subsequently, continue to add NaH dispersed in paraffin oil to the solution under nitrogen protection atmosphere. After 30 minutes, continue to dropwise add MOMBr to the reaction mixture at 0 °C; stir the reaction mixture for 3 hours to allow it to fully react at 23 °C, and the reaction produces compound 3.

[0031]

[0032] As a further preference of the present invention, compound 5 used in step one is prepared by the following preparation method:

[0033] Under the condition of 25 °C, dissolve compound 4 in dichloromethane and stir it under nitrogen protection; subsequently, continue to add MnO2 to the solution under nitrogen protection atmosphere, start to stir the reaction mixture for 10 hours to allow it to fully react at 25 °C, and obtain compound 5.

[0034]

[0035] Through the above technical solution conceived by the present invention, compared with the prior art, the following

[0036] beneficial effects can be achieved:

[0037] The present invention first uses a chemical synthesis method to obtain a series of natural product diterpenoid components rhododaurines A–C, and designs a mature reaction route. It can use compound 3 and compound 5 as starting materials (compound 3 and compound 5 can be purchased commercially), or use cheaper compound 1 and compound 4 as starting materials (also available commercially) to achieve the total synthesis of rhododaurines A–C from Rhododendron dauricum L. Taking compound 1 and compound 4 as starting materials as an example, starting from the easily available industrial raw materials orcinol and farnesal, and using photoinduced cyclization and oxidation reactions in the middle, the stereoselectivity of the reaction is improved. The reaction conditions are mild, the atom utilization rate is high, the reagents are cheap and easily available, and the reaction is green, safe and environmentally friendly.

[0038] The content of rhododaurines A–C from Rhododendron dauricum L. in nature is extremely low and it is difficult to extract on a large scale, while the total synthesis method of the present invention can provide a stable supply to meet the needs of research and application.

[0039] The present invention can especially use orcinol (i.e., compound 1) as the starting material, and through MOM protection, substitution with iodine, addition with farnesal (i.e., compound 4), deprotection, cyclization and then oxidation, rhododaurines A–C of Rhododendron dauricum L. are obtained. Using compound 1 and compound 4 as the starting materials, which are cheap and easily available, the natural product Rhododaurines A-C of Rhododendron dauricum L. is obtained through the artificial chemical synthesis route of the present invention, which can break through the limitation of synthesizing Rhododaurines A-C from natural sources.

[0040] In the prior art, due to the low extraction efficiency from plant sources and limited supply of the natural product rhododaurines A–C, using the method of the present invention, the total yields of rhododaurins A–C reach 5.0%, 16.6%, and 27.7% (calculated based on orcinol, w / w) respectively, which are significantly higher than the separation efficiency of the existing extraction process.

[0041] In summary, the new skeleton diterpene synthesis method in the present invention has high yield, mild reaction conditions and good selectivity, solves the problem of dependence on natural sources of rhododaurins A–C, provides a stable material basis for the analgesic activity research and drug development of rhododaurins A–C, and has practical application value. Brief Description of the Drawings

[0042] Figure 1 It is the total synthesis route diagram comprehensively obtained from Example 1 to Example 7 of the present invention.

[0043] Figure 2 It is the 1H NMR spectrum (400 MHz, CDCl3) of rhododaurine A (10) prepared in Example 7 of the present invention.

[0044] Figure 3 It is the 13C NMR spectrum (100 MHz, CDCl3) of rhododaurine A (10) prepared in Example 7 of the present invention.

[0045] Figure 4 It is the 1H NMR spectrum (400 MHz, CDCl3) of epirhododaurine B (9) prepared in Example 6 of the present invention.

[0046] Figure 5 It is the 13C NMR spectrum (100 MHz, CDCl3) of epirhododaurine B (9) prepared in Example 6 of the present invention.

[0047] Figure 61H NMR spectrum (400 MHz, CDCl3) of rhododaurine B (8) prepared in Example 6 of the present invention.

[0048] Figure 7 13C NMR spectrum (100 MHz, CDCl3) of rhododaurine B (8) prepared in Example 6 of the present invention.

[0049] Figure 8 1H NMR spectrum (400 MHz, CDCl3) of rhododaurine C (7) prepared in Example 5 of the present invention.

[0050] Figure 9 13C NMR spectrum (100 MHz, CDCl3) of rhododaurine C (7) prepared in Example 5 of the present invention.

[0051] Figure 10 1H NMR spectrum (400 MHz, CDCl3) of compound 6 prepared in Example 4 of the present invention.

[0052] Figure 11 13C NMR spectrum (100 MHz, CDCl3) of compound 6 prepared in Example 4 of the present invention.

[0053] Figure 12 1H NMR spectrum (400 MHz, CDCl3) of compound 3 prepared in Example 2 of the present invention.

[0054] Figure 13 13C NMR spectrum (100 MHz, CDCl3) of compound 3 prepared in Example 2 of the present invention.

[0055] Figure 14 1H NMR spectrum (400 MHz, CDCl3) of compound 2 prepared in Example 1 of the present invention.

[0056] Figure 15 13C NMR spectrum (100 MHz, CDCl3) of compound 2 prepared in Example 1 of the present invention. Detailed implementation manners

[0057] In order to make the objectives, technical solutions and advantages of the present invention more clear and understandable, the present invention will be further described in detail below with reference to the accompanying drawings and 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. In addition, the technical features involved in the various embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other.

[0058] Figure 1The synthetic route corresponding to the total synthesis method of the present invention for the rhododaurines A–C is shown below, which will be described in Examples 1 to 7. The key steps involved in this synthetic route are as follows:

[0059] (1) Electrophilic substitution reaction mediated by iodine; (2) Methoxymethyl (MOM) protection of the C-3 hydroxyl group of lichenol; (3) Stereoselective addition of the allylic group of farnesaldehyde; (4) Removal of the MOM protecting group and cyclization under acidic conditions; (5) Oxidation under light conditions to form a new carbon ring skeleton; (6) Ring-opening reaction of the cyclic ether under acidic conditions.

[0060] Of course, since both Compound 3 and Compound 5 are commercially available (Compound 5 is expensive), the total synthesis method of the present invention for the rhododaurines A–C can also be directly initiated from Compound 3 and Compound 5 as starting materials (in this case, Examples 1-3 can be ignored).

[0061] Example 1: Preparation of Compound 2

[0062] Based on commercially available orcinol (purchased from Aladdin, CAS No. 504-15-4), a solution of iodine (I2, 10.3 g, 40.4 mmol) in tetrahydrofuran (THF, 20 mL) was added dropwise at 0°C to a solution of orcinol (2.51 g, 20 mmol) in tetrahydrofuran / water (3:1, 44 mL) containing sodium bicarbonate (NaHCO3, 5.09 g, 61 mmol). After 2 hours of reaction, the reaction was quenched with an aqueous solution of sodium sulfite (Na2SO3, 5.03 g, 40 mmol) (20 mL) at 0°C. The mixture was stirred at 23°C for 30 min and then extracted with diethyl ether (Et2O, 3 x 50 mL). The combined organic phases were washed with saturated brine (2 x 50 mL) and dried over sodium sulfate (Na2SO4). The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate ratio of 10:1 by volume, all petroleum ether / ethyl acetate ratios mentioned herein refer to volume ratios) to obtain compound 2 (4.26 g, reaction yield 82%, liquid phase purity 96.61%) as a white solid. An analytical sample of compound 2 was obtained by recrystallization from n-hexane / chloroform (10:1 by volume) as colorless needles.

[0063]

[0064] Colorless needle-like solid, total yield 82%, 1 H NMR (400 MHz, CDCl3): δ H6.39(s, 2H), 5.18(s, 2H), 2.25(s, 3H). 13 C NMR (100 MHz, CDCl3): δ C 155.2, 155.2, 141.1, 108.2, 108.2, 73.5, 21.1.

[0065] For the compound 2, 1 the 1H NMR spectrum, 13 the 13C NMR spectrum are shown in Figure 14 and Figure 15 respectively.

[0066] Example 2: Preparation of Compound 3

[0067] Based on the compound 2 prepared by the method of Example 1, at 0 °C, the compound 2 (10.1 g, 40 mmol) was dissolved in 200 mL of DMF and stirred under nitrogen protection. Subsequently, a solution of NaH (4.03 g, 101 mmol) with a concentration of 60 wt% in paraffin oil was added to the solution. After 30 minutes, MOMBr (7.7 mL, 101 mmol) was added dropwise to the reaction mixture at 0 °C. The reaction mixture was stirred for 3 hours to allow it to react fully at 23 °C. After the reaction was completed, the reaction was quenched with 200 mL of water, and the reaction mixture was extracted with ethyl acetate (3 × 200 mL). The combined organic phases were washed with saturated brine (2 × 200 mL) and then dried over anhydrous sodium sulfate (Na2SO4). The mixture was concentrated under reduced pressure, and the residue obtained was purified by column chromatography (petroleum ether / ethyl acetate ratio of 10:1) to finally obtain compound 3 (10.5 g) as a white solid in a yield of 70%. Further recrystallization from n-hexane gave an analytical pure sample of compound 3, which was in the form of colorless granules with a liquid phase purity of 98.23%.

[0068]

[0069] Colorless granular solid, with a total yield of 70%, 1 1H NMR (400 MHz, CDCl3): δ H 6.60(s, 2H), 5.23(s, 4H), 3.52(s, 6H), 2.32(s, 3H). 13 13C NMR (100 MHz, CDCl3): δ C 157.0, 157.0, 140.3, 109.5, 109.5, 94.8, 94.8, 76.6, 56.4, 56.4, 21.7.

[0070] For the compound 31 The \(^1\)H NMR spectrum, 13 the \(^{13}\)C NMR spectrum is respectively as Figure 12 , Figure 13 shown.

[0071] Example 3: Preparation of Compound 5

[0072] Based on commercially available farnesol 4 (purchased from Aladdin, CAS No.: 4602 - 84 - 0), Compound 4 was oxidized by the oxidant manganese dioxide, and Compound 5 was obtained in a yield of 95%; specifically: at 25 °C, Compound 4 (10.1 g, 44.8 mmol) was dissolved in 400 mL of dichloromethane and stirred under nitrogen protection. Subsequently, MnO₂ (50.1 g, 600 mmol) was added to the solution, and the reaction mixture was stirred for 10 hours to allow it to react fully at 25 °C. After the reaction was completed, the reaction was quenched with 200 mL of water, and the reaction mixture was extracted with ethyl acetate (3 × 200 mL). The combined organic phases were washed with saturated brine (2 × 200 mL), then dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the residue obtained was purified by column chromatography (petroleum ether / ethyl acetate ratio of 50:1), and finally Compound 5 (9.6 g) was obtained as a colorless oily liquid in a yield of 95%.

[0073]

[0074] Colorless oily liquid, with a total yield of 95%, 1 \(^1\)H NMR (400 MHz, CDCl₃): δ H 5.11 (dt, J = 11.5, 6.2 Hz, 1H), 2.47 (t, J = 7.1 Hz, 1H), 2.13–2.03 (m, 3H), 1.95 (t, J = 7.0 Hz, 1H), 1.61 (d, J = 8.4 Hz, 4H). 13 \(^{13}\)C NMR (100 MHz, CDCl₃): δ C 191.4, 152.9, 135.4, 131.5, 128.5, 124.6, 123.8, 39.7, 39.2, 26.8, 26.1, 24.5, 19.1, 18.2, 16.1.

[0075] Example 4: Preparation of Compound 6

[0076] Compound 3 prepared by the method of Example 2 and compound 5 prepared by the method of Example 3. At -78 °C, n-butyllithium (7.0 mL, 1.5 M, 11.2 mmol) was added dropwise to a toluene (50 mL) solution of compound 3 (1.70 g, 8.0 mmol). Subsequently, the reaction solution was activated and stirred for 0.5 h. Then, a toluene solution (12 mL) containing compound 5 (2.46 g, 11.2 mmol) was added dropwise to the reaction mixture, and the reaction was continued to stir at -78 °C for 3 h. After the reaction was completed, the reaction was quenched with saturated NH4Cl solution (40 mL) and extracted with ether (3 × 50 mL). The combined ether organic phases were dried over MgSO4 and concentrated to give the crude product compound 6 (3.40 g). The mixture was concentrated under reduced pressure, and the residue obtained was purified by column chromatography (petroleum ether / ethyl acetate ratio of 5:1) to finally give compound 6 (2.5 g) as a colorless oily liquid in a yield of 68%.

[0077]

[0078] Colorless oily liquid, total yield 68%, 1 H NMR (400 MHz, CDCl3): δ H 6.59 (s, 2H), 6.77 (d, J = 16.8 Hz, 1H), 6.61 (d, J = 16.8 Hz, 1H), 5.16 (s, 6H), 5.15 (dd, J = 6.7, 6.7 Hz, 1H), 5.06 (dd, J = 6.7, 6.7 Hz, 1H), 3.46 (s, 6H), 2.28 (s, 3H), 2.10–1.90 (m, 7H), 1.65 (s, 3H), 1.57 (s, 3H), 1.53 (s, 3H), 1.36 (s, 3H). 13 C NMR: (100 MHz, CDCl3): δ C 155.9, 155.9, 152.8, 140.5, 143.9, 138.4, 135.6, 131.6, 124.6, 124.4, 117.5, 109.8, 109.8, 95.0, 95.0, 74.2, 56.4, 43.0, 40.0, 28.7, 27.0, 26.0, 23.2, 22.1, 16.2.

[0079] The 1 H NMR spectrum 13 and Figure 10 the Figure 11 C NMR spectrum of compound 6 are shown as follows

[0080] Example 5: Preparation of Compound 7

[0081] Compound 6 prepared by the method of Example 4. Compound 6 (2.16 g, 5.0 mmol) was dissolved in a mixture of hydrochloric acid and ethanol (10 / 10 mL; the concentration of hydrochloric acid before mixing was 1.0 mol / L, the same below). The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to dryness under reduced pressure. The reaction mixture was dissolved in ammonia water and methanol (4 / 16 mL; the concentration of ammonia water before mixing was 2.0 mol / L, the same below) and stirred at room temperature for 1 hour. It was extracted three times with ethyl acetate (3 × 50 mL). After liquid separation, the organic phase was washed with saturated sodium bicarbonate solution (30 mL) and saturated sodium chloride solution (30 mL). The organic phase was dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain 1.76 g of rhododaurine C(7) as a yellow oily liquid. The reaction yield was 71%, and the liquid phase purity was 98.53%.

[0082]

[0083] Rhododaurine C(7) is a yellow oily liquid with a total yield of 71%. [α] 20 D = 0 (c 0.1, MeOH), HRESIMSm / z 327.2323 [M+H] + (calcd for C 22 H 30 O2 327.2324). 1 HNMR(400MHz, CDCl3): δ H 6.21(s, 1H), 6.18(brs, 1H), 6.09(s, 1H), 5.01(t, J = 8.1Hz, 1H), 3.50(dd, J = 4.1, 4.1Hz, 1H), 2.15(s, 3H), 1.67(s, 3H), 1.61(s, 3H), 1.51(s, 3H), 1.34(s, 1H), 2.05–1.75(m, 8H). 13 CNMR(100MHz, CDCl3): δ C 155.0, 153.9, 137.5, 135.2, 131.8, 124.3, 122.1, 111.0, 109.8, 108.9, 78.3, 37.8, 37.3, 31.4, 30.0, 25.8, 23.9, 23.2, 22.5, 21.1, 20.6, 17.7.

[0084] The 1 1H NMR spectrum of rhododaurine C(7), 13The \(^{13}\)C NMR spectra are shown respectively as Figure 8 and Figure 9 shown.

[0085] Example 6: Preparation of Compounds 8 and 9

[0086] Based on rhododaurine C(7) prepared by the method of Example 5, rhododaurine C(7) (0.163 g, 0.5 mmol) was dissolved in methanol (25 mL). Under an oxygen atmosphere (i.e., oxygen was continuously introduced), the reaction was irradiated using a top-illumination light system with a wavelength of 365 nm (the light source power was 20 W, the same below), and the mixture was stirred at 30 °C for 4 hours until the reaction was complete. The reaction mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine (2 × 20 mL), and then dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the residue obtained was purified by column chromatography (the ratio of petroleum ether / ethyl acetate was 10:1), and finally rhododaurine B (8) (0.12 g) as a yellow solid was obtained in a yield of 60%, and epirhododaurine B (9) (0.06 g) as a white solid was obtained in a yield of 30%.

[0087]

[0088] Rhododaurine B (8) is a white solid with a total yield of 50%. [α] 23 D = 0 (c 0.1, MeOH), HRESIMSm / z 341.2110 [M + H] + (calcd for C 22 H 29 O3 341.2117). 1 \(^{1}\)HNMR (400 MHz, CDCl3): δ H 6.30 (brs, 2H), 3.65 (s, 1H), 2.51 (d, J = 5.9 Hz, 1H), 1.99 (ddd, J = 14.1, 3.0, 3.0 Hz, 1H), 1.64 (ddd, J = 14.4, 12.7, 4.6 Hz, 1H), 1.5–1.3 (m, 6H), 1.31 (dd, J = 11.8, 3.0 Hz, 1H), 2.22 (s, 3H), 1.58 (s, 3H), 1.36 (s, 3H), 1.31 (s, 3H), 0.92 (s, 3H). 13 \(^{13}\)C NMR (100 MHz, CDCl3): δ C157.4, 154.2, 137.9, 115.6, 112.4, 111.7, 85.3, 78.1, 62.9, 59.6, 51.2, 41.3, 36.1, 35.2, 33.7, 30.0, 26.1, 26.1, 23.2, 22.0, 21.9, 17.3.

[0089] The 1 1H NMR spectrum, 13 13C NMR spectrum of Rhododaurine B(8) are shown in Figure 6 and Figure 7 respectively.

[0090] Epirhododaurine B(9) is a white solid with an overall yield of 30%. [α] 23 D = 0 (c 0.1, MeOH), HRESIMSm / z 341.2113 [M+H] + 23 D (calcd for C 22 29 H 1 H 13 C O3 341.2117). + (calculated for C 22 H 29 O3 341.2117). 1 1H NMR (400 MHz, CDCl3): δ H H 6.33 (brs, 1H), 6.33 (brs, 1H), 3.79 (s, 1H), 2.41 (dd, J = 10.6, 5.9 Hz, 1H), 1.85 - 1.30 (m, 8H), 0.74 (dddd, J = 13.6, 13.6, 11.3, 6.0 Hz, 1H), 2.25 (s, 3H), 1.67 (s, 3H), 1.28 (s, 3H), 1.27 (s, 3H), 0.96 (s, 3H). 13 13C NMR (100 MHz, CDCl3): δ C C 156.6, 156.6, 138.3, 113.2, 112.6, 110.7, 85.1, 77.4, 63.1, 62.6, 49.2, 39.7, 38.9, 38.1, 31.3, 27.1, 26.0, 25.5, 23.5, 21.8, 20.4.

[0091] The 1 1H NMR spectrum, 13 13C NMR spectrum of Epirhododaurine B(9) are shown in Figure 4 and Figure 5 respectively.

[0092] Example 7: Preparation of Compound 10

[0093] Epirhododaurine B (9) prepared by the method of Example 6 (0.162 g, 0.5 mmol) was dissolved in a mixed solvent of formic acid and acetone (1 / 5 ml, v / v; the concentration of formic acid before mixing was 1 mol / L, the same below). The reaction mixture was stirred at 35 °C for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, dissolved in a mixed solvent of ammonia water and methanol (1 / 4 ml, v / v; the concentration of ammonia water before mixing was 1 mol / L, the same below), stirred at room temperature for 1 hour, and extracted three times with ethyl acetate (3 × 50 mL). After liquid separation, the organic phase was washed with saturated sodium bicarbonate solution (30 mL) and saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate 10:1) to finally obtain rhododaurine A (10) (0.09 g) as a white solid in a yield of 60%.

[0094]

[0095] Rhododaurine A (10) is a white solid with a total yield of 60%. [α] 23 D = 0 (c 0.1, MeOH), HRESIMSm / z 359.2218 [M+H] + (calcd for C 22 H 34 O4 359.2222). 1 HNMR (400 MHz, CDCl3): δ H 6.31 (brs, 1H), 6.25 (brs, 1H), 4.61 (d, J = 3.3 Hz, 1H), 2.65 (dd, J = 11.3, 6.0 Hz, 1H), 2.20 (s, 3H), 1.80 (m, 3H), 1.74 (ddd, J = 14.5, 6.0, 2.3 Hz, 1H), 1.50–1.20 (m, 3H), 0.69 (dddd, J = 13.6, 13.6, 11.3, 6.0 Hz, 1H), 1.64 (s, 3H), 1.29 (s, 3H), 1.18 (s, 3H), 0.88 (s, 3H). 13 C NMR (100 MHz, CDCl3): δ C 158.3, 157.3, 137.2, 111.1, 117.1, 113.0, 85.4, 77.7, 73.0, 72.9, 48.3, 42.5, 39.4, 38.8, 32.5, 31.6, 29.7, 26.7, 23.8, 21.9, 20.0.

[0096] The 1 1H NMR spectrum, 13 13C NMR spectrum of rhododaurine A(10) are respectively as Figure 2 and Figure 3 shown.

[0097] Based on the total synthesis routes obtained from Examples 1 to 7 of the present invention, the overall yields of rhododaurins A–C reach 5.0%, 16.6%, and 27.7% (calculated based on orcinol, w / w), respectively, which are significantly higher than the separation efficiency of the existing extraction process:

[0098] Overall yield of Rhododaurins A = Yield of Example 1 (82%) * Yield of Example 2 (70%) * Yield of Example 4 (68%) * Yield of Example 5 (71%) * Yield of Example 6 (30%) * Yield of Example 7 (60%) = 5.0%;

[0099] Overall yield of Rhododaurins B = Yield of Example 1 (82%) * Yield of Example 2 (70%) * Yield of Example 4 (68%) * Yield of Example 5 (71%) * Yield of Example 6 (60%) = 16.6%;

[0100] Overall yield of Rhododaurins C = Yield of Example 1 (82%) * Yield of Example 2 (70%) * Yield of Example 4 (68%) * Yield of Example 5 (71%) = 27.7%.

[0101] Example 8: Preparation of Compound 6

[0102] Based on Compound 3 prepared by the method of Example 2 and Compound 5 prepared by the method of Example 3, at -78 °C, n-butyllithium (5.5 mL, 1.5 M, 8.8 mmol) was added dropwise to a toluene (50 mL) solution of Compound 3 (1.70 g, 8.0 mmol). Subsequently, the reaction solution was activated and stirred for 0.5 hour. Then, a toluene solution (12 mL) containing Compound 5 (1.93 g, 8.8 mmol) was added dropwise to the reaction mixture, and the reaction was continued to stir at -78 °C for 3 hours. After the reaction was completed, the reaction was quenched with saturated NH4Cl solution (40 mL), and extracted with ether (3 × 50 mL). The combined ether organic phase was dried with MgSO4 and concentrated to obtain the crude product Compound 6 (2.68 g). The mixture was concentrated under reduced pressure, and the residue obtained was purified by column chromatography (petroleum ether / ethyl acetate ratio of 5:1) to finally obtain Compound 6 (1.9 g) with a yield of 52% as a colorless oily liquid.

[0103] Example 9: Preparation of Compound 7

[0104] Compound 6 prepared by the method of Example 4 (2.16 g, 5.0 mmol) was dissolved in a mixture of hydrochloric acid and ethanol (10 / 10 mL; the concentration of hydrochloric acid before mixing was 1.0 mol / L, the same below). The reaction mixture was stirred at room temperature for 0.5 h. The reaction solution was concentrated to dryness under reduced pressure, and the reaction mixture was dissolved in ammonia water and methanol (4 / 16 mL; the concentration of ammonia water before mixing was 2.0 mol / L, the same below), stirred at room temperature for 1 h, extracted three times with ethyl acetate (3×50 mL), separated, and the organic phase was washed with saturated sodium bicarbonate solution (30 mL) and saturated sodium chloride solution (30 mL). The organic phase was dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain 1.53 g of rhododaurine C(7) as a yellow oily liquid, and the reaction yield was 62%.

[0105] Example 10: Preparation of Compound 7

[0106] Compound 6 prepared by the method of Example 4 (2.16 g, 5.0 mmol) was dissolved in a mixture of hydrochloric acid and ethanol (5 / 5 mL; the concentration of hydrochloric acid before mixing was 1.0 mol / L, the same below). The reaction mixture was stirred at room temperature for 2 h. The reaction solution was concentrated to dryness under reduced pressure, and the reaction mixture was dissolved in ammonia water and methanol (2 / 8 mL; the concentration of ammonia water before mixing was 2.0 mol / L, the same below), stirred at room temperature for 1 h, extracted three times with ethyl acetate (3×50 mL), separated, and the organic phase was washed with saturated sodium bicarbonate solution (30 mL) and saturated sodium chloride solution (30 mL). The organic phase was dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain 1.36 g of rhododaurine C(7) as a yellow oily liquid, and the reaction yield was 55%.

[0107] Example 11: Preparation of Compounds 8 and 9

[0108] Rhododaurine C(7) prepared by the method of Example 5 was dissolved in methanol (25 mL). Under an oxygen atmosphere, the reaction was irradiated with a top-illumination light system at a wavelength of 300 nm, and the mixture was stirred at 30 °C for 4 hours until the reaction was complete. The reaction mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine (2 × 20 mL) and then dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the residue obtained was purified by column chromatography (petroleum ether / ethyl acetate ratio of 10:1) to finally obtain rhododaurine B (8) (0.09 g) as a yellow solid in a yield of 45%, and epirhododaurine B (9) (0.04 g) as a white solid in a yield of 22%.

[0109] Example 12: Preparation of Compounds 8 and 9

[0110] [[ID=,6]]Rhododaurine C(7) prepared by the method of Example 5 was dissolved in methanol (25 mL). Under an oxygen atmosphere, the reaction was irradiated with a top-illumination light system at a wavelength of 385 nm, and the mixture was stirred at 30 °C for 4 hours until the reaction was complete. The reaction mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine (2 × 20 mL) and then dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the residue obtained was purified by column chromatography (petroleum ether / ethyl acetate ratio of 10:1) to finally obtain rhododaurine B (8) (0.096 g) as a yellow solid in a yield of 48%, and epirhododaurine B (9) (0.048 g) as a white solid in a yield of 24%.

[0111] Example 13: Preparation of Compound 10

[0112] Epirhododaurine B (9) prepared by the method of Example 6 (0.162 g, 0.5 mmol) was dissolved in a mixed solvent of formic acid and acetone (1 / 5 ml, v / v; the concentration of formic acid before mixing was 1 mol / L, the same below). The reaction mixture was stirred at 25 °C for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, dissolved in a mixed solvent of ammonia water and methanol (1 / 4 ml, v / v; the concentration of ammonia water before mixing was 1 mol / L, the same below), stirred at room temperature for 1 hour, extracted three times with ethyl acetate (3 × 50 mL), separated, and the organic phase was washed with saturated sodium bicarbonate solution (30 mL) and saturated sodium chloride solution (30 mL). The organic phase was dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate 10:1) to finally obtain rhododaurine A (10) (0.06 g), a white solid, in a yield of 40%.

[0113] Example 14: Preparation of Compound 10

[0114] Epirhododaurine B (9) prepared by the method of Example 6 (0.162 g, 0.5 mmol) was dissolved in a mixed solvent of formic acid and acetone (1 / 5 ml, v / v; the concentration of formic acid before mixing was 1 mol / L, the same below). The reaction mixture was stirred at 50 °C for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, dissolved in a mixed solvent of ammonia water and methanol (1 / 4 ml, v / v; the concentration of ammonia water before mixing was 1 mol / L, the same below), stirred at room temperature for 1 hour, extracted three times with ethyl acetate (3 × 50 mL), separated, and the organic phase was washed with saturated sodium bicarbonate solution (30 mL) and saturated sodium chloride solution (30 mL). The organic phase was dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate 10:1) to finally obtain rhododaurine A (10) (0.05 g), a white solid, in a yield of 33%.

[0115] Example 15: Preparation of Compound 10

[0116] Epirhododaurine B (9) prepared by the method of Example 6 (0.162 g, 0.5 mmol) was dissolved in a mixed solvent of formic acid and acetone (1 / 5 ml, v / v; the concentration of formic acid before mixing was 1 mol / L, the same below), and the reaction mixture was stirred at 35 °C for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, dissolved in a mixed solvent of ammonia water and methanol (1 / 4 ml, v / v; the concentration of ammonia water before mixing was 1 mol / L, the same below), stirred at room temperature for 1 hour, extracted three times with ethyl acetate (3 × 50 mL), separated, the organic phase was washed with saturated sodium bicarbonate solution (30 mL) and saturated sodium chloride solution (30 mL), the organic phase was dried over anhydrous sodium sulfate, and then concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate 10:1), and finally rhododaurine A (10) (0.06 g), a white solid, was obtained in a yield of 46%.

[0117] Example 16: Preparation of Compound 10

[0118] Epirhododaurine B (9) prepared by the method of Example 6 (0.162 g, 0.5 mmol) was dissolved in a mixed solvent of formic acid and acetone (0.75 / 3.75 ml, v / v; the concentration of formic acid before mixing was 1 mol / L, the same below), and the reaction mixture was stirred at 35 °C for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, dissolved in a mixed solvent of ammonia water and methanol (0.75 / 3.75 ml, v / v; the concentration of ammonia water before mixing was 1 mol / L, the same below), stirred at room temperature for 1 hour, extracted three times with ethyl acetate (3 × 50 mL), separated, the organic phase was washed with saturated sodium bicarbonate solution (30 mL) and saturated sodium chloride solution (30 mL), the organic phase was dried over anhydrous sodium sulfate, and then concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate 10:1), and finally rhododaurine A (10) (0.07 g), a white solid, was obtained in a yield of 50%.

[0119] Example 17: Preparation of Compound 10

[0120] Epirhododaurine B (9) prepared by the method of Example 6 (0.162 g, 0.5 mmol) was dissolved in a mixed solvent of formic acid and acetone (1.25 / 5 ml, v / v; the concentration of formic acid before mixing was 1 mol / L, the same below). The reaction mixture was stirred at 35 °C for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, dissolved in a mixed solvent of ammonia water and methanol (1.25 / 5 ml, v / v; the concentration of ammonia water before mixing was 1 mol / L, the same below), stirred at room temperature for 1 hour, and extracted three times with ethyl acetate (3 × 50 mL). After liquid separation, the organic phase was washed with saturated sodium bicarbonate solution (30 mL) and saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate 10:1) to finally obtain rhododaurine A (10) (0.08 g), a white solid, in a yield of 55%.

[0121] Comparative Example 1: Preparation of Compound 6

[0122] Based on Compound 3 prepared by the method of Example 2 and Compound 5 prepared by the method of Example 3, at -60 °C, n-butyllithium (7.0 mL, 1.5 M, 11.2 mmol) was added dropwise to a toluene (50 mL) solution of Compound 3 (1.70 g, 8.0 mmol). Subsequently, the reaction solution was activated and stirred for 0.5 hour. Then, a toluene solution (12 mL) containing Compound 5 (2.46 g, 11.2 mmol) was added dropwise to the reaction mixture, and the reaction was continued to stir at -60 °C for 3 hours. After the reaction was completed, the reaction was quenched with saturated NH4Cl solution (40 mL) and extracted with ether (3 × 50 mL). The combined ether organic phase was dried over MgSO4 and concentrated to obtain the crude product Compound 6. The mixture was concentrated under reduced pressure, and the residue obtained was purified by column chromatography (petroleum ether / ethyl acetate ratio of 5:1) to finally obtain Compound 6 (1.4 g), a colorless oily liquid, in a yield of 39%.

[0123] Comparative Example 2: Preparation of Compound 6

[0124] Compound 3 prepared by the method of Example 2 and compound 5 prepared by the method of Example 3. At -40 °C, n-butyllithium (7.0 mL, 1.5 M, 11.2 mmol) was added dropwise to a toluene (50 mL) solution of compound 3 (1.70 g, 8.0 mmol). Subsequently, the reaction solution was activated and stirred for 0.5 h. Then, a toluene solution (12 mL) containing compound 5 (2.46 g, 11.2 mmol) was added dropwise to the reaction mixture, and the reaction was continued to stir at -40 °C for 3 h. After the reaction was completed, the reaction was quenched with saturated NH4Cl solution (40 mL), and extracted with ether (3 × 50 mL). The combined ether organic phases were dried over MgSO4 and concentrated to give the crude product compound 6. The mixture was concentrated under reduced pressure, and the residue obtained was purified by column chromatography (petroleum ether / ethyl acetate ratio of 5:1) to finally give compound 6 (0.3 g) as a colorless oily liquid in 8% yield.

[0125] Comparative Example 3: Preparation of Compound 6

[0126] Compound 3 prepared by the method of Example 2 and compound 5 prepared by the method of Example 3. At -20 °C, n-butyllithium (7.0 mL, 1.5 M, 11.2 mmol) was added dropwise to a toluene (50 mL) solution of compound 3 (1.70 g, 8.0 mmol). Subsequently, the reaction solution was activated and stirred for 0.5 h. Then, a toluene solution (12 mL) containing compound 5 (2.46 g, 11.2 mmol) was added dropwise to the reaction mixture, and the reaction was continued to stir at -20 °C for 3 h. After the reaction was completed, the reaction was quenched with saturated NH4Cl solution (40 mL), and extracted with ether (3 × 50 mL). The mixture was concentrated under reduced pressure, and the residue obtained was purified by column chromatography (petroleum ether / ethyl acetate ratio of 5:1), and finally compound 6 was not obtained.

[0127] Comparative Example 4: Preparation of Compound 6

[0128] Compound 3 prepared by the method of Example 2 and compound 5 prepared by the method of Example 3. At -78 °C, n-butyllithium (7.0 mL, 1.5 M, 11.2 mmol) was added dropwise to a solution of compound 3 (1.70 g, 8.0 mmol) in tetrahydrofuran (50 mL). Subsequently, the reaction solution was activated and stirred for 0.5 h. Then, a toluene solution (12 mL) containing compound 5 (2.46 g, 11.2 mmol) was added dropwise to the reaction mixture, and the reaction was continued to stir at -78 °C for 3 h. After the reaction was completed, the reaction was quenched with saturated NH4Cl solution (40 mL), and extracted with ether (3 × 50 mL). The combined ether organic phases were dried over MgSO4 and concentrated to give the crude product compound 6. The mixture was concentrated under reduced pressure, and the residue obtained was purified by column chromatography (petroleum ether / ethyl acetate ratio of 5:1), and finally compound 6 (0.8 g) was obtained in a yield of 23% as a colorless oily liquid.

[0129] Comparative Example 5: Preparation of Compounds 8 and 9

[0130] Based on rhododaurine C(7) prepared by the method of Example 5, rhododaurine C(7) (0.163 g, 0.5 mmol) was dissolved in methanol (25 mL). Under an oxygen atmosphere, the reaction was irradiated using a top-illumination light system with a wavelength of 445 nm, and the mixture was stirred at 30 °C for 4 h until the reaction was complete. The reaction mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine (2 × 20 mL), and then dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the residue obtained was purified by column chromatography (petroleum ether / ethyl acetate ratio of 10:1), and finally rhododaurine B(8) (0.016 g) was obtained in a yield of 8% as a yellow solid, and epirhododaurine B(9) (0.008 g) was obtained in a yield of 4% as a white solid.

[0131] Comparative Example 6: Preparation of Compounds 8 and 9

[0132] For rhododaurine C(7) prepared by the method of Example 5, rhododaurine C(7) (0.163 g, 0.5 mmol) was dissolved in methanol (25 mL). Under an oxygen atmosphere, the reaction was irradiated using a top-illumination light system with a wavelength of 405 nm, and the mixture was stirred at 30 °C for 4 hours until the reaction was complete. The reaction mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine (2 × 20 mL) and then dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the residue obtained was purified by column chromatography (petroleum ether / ethyl acetate ratio of 10:1) to finally obtain rhododaurine B(8) (0.056 g) as a yellow solid in a yield of 28% and epirhododaurine B(9) (0.028 g) as a white solid in a yield of 14%.

[0133] It is easy for those skilled in the art to understand that the above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principle of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for the total synthesis of rhododaurines A–C, diterpenoids from Rhododendron dauricum, characterized in that, It includes the following steps: Step 1: Allylic stereoselective addition of compound 3 and compound 5 is carried out in toluene solvent under the catalysis of n-butyllithium and at a low temperature of -78 °C to construct a chiral center to obtain compound 6; Step 2: The methoxymethyl (MOM) protecting group of compound 6 is removed and cyclized under acidic conditions, and the reaction generates rhododaurine C(7); Step 3: Intramolecular [4+2] cycloaddition and oxidation reaction of rhododaurine C(7) occur under light irradiation at 300-385 nm and in an oxygen atmosphere to obtain rhododaurine B(8) and epoxy epimer epirhododaurine B(9); Step 4: Epirhododaurine B(9) undergoes acid-catalyzed ring ether protonation rearrangement to generate rhododaurine A(10); 2. The total synthesis method according to claim 1, characterized in that, In Step 1, the molar ratio of compound 3 to compound 5 is 1:1.1-1.4, and the amount of n-butyllithium used is 1.1-1.4 times the molar amount of compound 3.

3. The total synthesis method according to claim 1, wherein In Step 2, the reaction uses a hydrochloric acid / ethanol mixed solvent to provide acidic conditions; Preferably, the hydrochloric acid / ethanol mixed solvent is obtained by mixing hydrochloric acid and ethanol at a volume ratio of 1:1, and the concentration of hydrochloric acid before mixing is 1.0 mol / L; The amount of hydrochloric acid used is 1.0-2.0 times the molar amount of compound 6; the reaction time is 0.5-2 hours; the cyclization product is purified by column chromatography; more preferably, the column chromatography is specifically carried out using petroleum ether / ethyl acetate column chromatography, and the volume ratio of petroleum ether to ethyl acetate in the petroleum ether / ethyl acetate is 10:

1.

4. The total synthesis method according to claim 1, characterized in that, In Step 3, the reaction is carried out in methanol solvent, and the product is separated by gradient elution; Preferably, the gradient elution is specifically carried out using a petroleum ether / ethyl acetate eluent, and the volume ratio of petroleum ether to ethyl acetate in the petroleum ether / ethyl acetate eluent is 10:

1.

5. The total synthesis method according to claim 1, wherein, In Step 4, the acid catalysis uses a formic acid / acetone mixed solvent, the reaction temperature is 25-50 °C, and the reaction time is 2-5 hours; Preferably, the formic acid / acetone mixed solvent is obtained by mixing formic acid and acetone at a volume ratio of 1:5, and the concentration of formic acid before mixing is 1 mol / L; The amount of formic acid used is 1.5-2.5 times the molar amount of epirhododaurine B(9).

6. The total synthesis method according to claim 1, characterized in that, Compound 3 used in Step 1 is prepared according to the following sub-steps: S1: Using orcinol with the structural formula shown in Formula 1 as the substrate, under the protection of a nitrogen atmosphere at 0 °C, a solution of iodine in tetrahydrofuran is added dropwise to the tetrahydrofuran / aqueous solution of orcinol containing sodium bicarbonate. After reacting for 2 hours, compound 2 is generated; S2: At 0 °C, compound 2 is dissolved in DMF and stirred under nitrogen protection; subsequently, under a nitrogen protection atmosphere, NaH dispersed in paraffin oil is added to the solution. After 30 minutes, MOMBr is added dropwise to the reaction mixture at 0 °C; the reaction mixture is stirred for 3 hours and allowed to react fully at 23 °C to generate compound 3; 7. The total synthesis method according to claim 1, characterized in that, Compound 5 used in Step 1 was prepared by the following preparation method: Under the condition of 25 °C, dissolve Compound 4 in dichloromethane and stir under nitrogen protection; subsequently, continue under a nitrogen protection atmosphere, add MnO2 to the solution, and start stirring the reaction mixture for 10 hours to allow it to react fully at 25 °C to obtain Compound 5;

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