A synthetic method of Cochlearol B

Abstract

This invention discloses a synthetic method for Cochlearol B, belonging to the field of natural product technology. The method uses commercially available 2-bromo-3-methoxy-4-hydroxyacetophenone and 2,5-dihydroxyphenylboronic acid as raw materials. After protection with tert-butyldimethylchlorosilane, Wittig olefination, and Suzuki cross-coupling, a biphenyl compound is obtained. Following a Wacker-type cross-coupling tandem reaction, the substrate is protected with methoxymethylene bromide, and the tert-butyldimethylsilyl group is removed with a fluorine reagent. Then, under high-valent iodine reagent conditions, phenol is dearomatized in the next step. After reduction, a [2+2] cycloaddition reaction occurs under light to obtain a highly substituted cyclobutane product. Finally, through reduction, Wittig olefination, epoxidation, and epoxide ring-opening rearrangement, the chemical synthesis of Cochlearol B can be achieved. This synthetic route has the advantages of being simple, efficient, easy to operate, and low-cost, making it suitable for the large-scale synthesis of Cochlearol B and providing an important material basis for the evaluation of the bioactivity of the natural product Cochlearol B.

Description

Technical Field

[0001] This invention belongs to the field of natural product technology, and specifically relates to a method for synthesizing Cochlearol B. Background Technology

[0002] Reishi mushrooms are a type of woody, degradable mushroom widely distributed in tropical regions with hard fruiting bodies. As a traditional Chinese medicine, they are widely used in the treatment of diseases such as cancer, hypertension, nephritis, and diabetes. Due to the extensive biological activity of Reishi fungi, these substances have been extensively studied by phytochemists and biochemists. To date, more than 450 secondary metabolites have been isolated from the fruiting bodies of Reishi, with sugars and terpenoids being the main components and exhibiting good biological activity. This provides a sufficient material basis for screening bioactive lead compounds from Reishi fungi.

[0003] In 2014, Cheng Yongxian's research group isolated a class of structurally complex phenolic quinone-type diterpenoid natural products from the fruiting bodies of Ganoderma lucidum cochlea. Cochlearol B, as a representative molecule, has a 4 / 5 / 6 / 6 / 6 pentacyclic fused-ring skeleton and four fully substituted quaternary carbon centers. Particularly noteworthy is the presence of a highly substituted strained cyclobutane structure, which is extremely rare in other natural products. These structural features have attracted considerable attention from organic synthetic chemists, and only four total synthesis studies have been reported to date. Summary of the Invention

[0004] The purpose of this section is to outline some aspects of embodiments of the present invention and to briefly describe some preferred embodiments. Simplifications or omissions may be made in this section, as well as in the abstract and title of this application, to avoid obscuring the purpose of these documents; however, such simplifications or omissions should not be construed as limiting the scope of the invention.

[0005] In view of the problems existing in the above and / or prior art, the present invention is proposed.

[0006] Therefore, the purpose of this invention is to overcome the shortcomings of the prior art and provide a method for synthesizing Cochlearol B. To solve the above technical problems, this invention provides the following technical solution: 2-bromo-3-methoxy-4-hydroxyacetophenone is protected with tert-butyldimethylchlorosilane and undergoes a Wittig olefination reaction with methylenetriphenylphosphine to obtain the compound shown in formula (1);

[0007]

[0008] The compound shown in formula (1) was reacted with 2,5-dihydroxyphenylboronic acid under the conditions of a divalent palladium catalyst, a corresponding base and a solvent via a Suzuki cross-coupling reaction to obtain the compound shown in formula (2);

[0009]

[0010] The compound shown in formula (2) reacts with 1,1-dimethyl-2-propenyl acetate under the conditions of a divalent palladium catalyst, a corresponding base and a solvent in a Wacker-type cross-coupling tandem reaction to obtain the compound shown in formula (3).

[0011]

[0012] The compound shown in formula (3) was protected with bromomethyl methyl ether to obtain the compound shown in formula (4). The compound shown in formula (4) was deprotected by tert-butyldimethylsilyl protecting group under the action of fluorine reagent. The resulting phenol compound was not separated and under the condition of high-valent iodine reagent underwent an oxidative dearomatization reaction to obtain the compound shown in formula (5).

[0013]

[0014] The compound shown in formula (5) undergoes a 1,4-reduction reaction under reducing agent conditions to obtain the compound shown in formula (6). The compound shown in formula (6) can undergo a [2+2] cycloaddition reaction under ultraviolet light irradiation in the corresponding solvent to obtain the compound shown in formula (7).

[0015]

[0016] The compound shown in formula (7) was reduced under the conditions of a single-electron reducing reagent to obtain the compound shown in formula (8). The compound shown in formula (8) underwent a Wittig olefination reaction with methylenetriphenylphosphine prepared in situ to obtain the compound shown in formula (9).

[0017]

[0018] The compound shown in formula (9) undergoes epoxidation under peroxide conditions. After the reaction is complete, a reducing agent is added to remove excess peroxide. The resulting epoxy intermediate undergoes rearrangement reaction and removal of MOM protecting group directly under acidic conditions without separation, yielding the natural product Cochlearol B with the structural formula shown in formula (10).

[0019]

[0020] In a preferred embodiment of the synthesis method of Cochlearol B described in this invention, the divalent palladium catalyst in the Suzuki cross-coupling reaction includes one of bis(triphenylphosphine) palladium dichloride, tetra(triphenylphosphine) palladium, and acetonitrile palladium dichloride.

[0021] The alkali includes one of sodium carbonate, cesium carbonate, potassium phosphate, and potassium carbonate;

[0022] The solvent includes one of tetrahydrofuran, ethylene glycol dimethyl ether, and toluene;

[0023] The molar ratio of palladium source to base is 0.05–0.2:2.0–4.0.

[0024] In a preferred embodiment of the synthesis method of Cochlearol B described in this invention, the divalent palladium catalyst in the Wacker-type cross-coupling tandem reaction includes one of palladium hexafluoroacetylacetonate, palladium trifluoroacetate, palladium acetate, palladium dichloride, and palladium acetylacetonate.

[0025] The alkali includes one of sodium bicarbonate, sodium carbonate, potassium fluoride, cesium fluoride, potassium phosphate, and sodium acetate, or no alkali is added;

[0026] The solvent includes one of toluene, benzene, trifluorotoluene, mesitylene, xylene, monofluorobenzene, hexafluorobenzene, and monochlorobenzene;

[0027] The molar ratio of palladium source to base is 0.05:0 to 3.0.

[0028] In a preferred embodiment of the synthesis method of Cochlearol B described in this invention, the fluorine reagent includes one of potassium fluoride, cesium fluoride, and tetrabutylammonium fluoride.

[0029] In a preferred embodiment of the synthesis method of Cochlearol B described in this invention, the high-valent iodine reagent includes one of iodophenyl diacetic acid and bis(trifluoroacetyl)iodophenyl.

[0030] In a preferred embodiment of the synthesis method of Cochlearol B described in this invention, the reducing agent in the 1,4-reduction reaction includes one of lithium trisec-butylborohydride, rhodium chloride triphenylphosphine / hydrogen, platinum dioxide / hydrogen, and Raney nickel / hydrogen.

[0031] In a preferred embodiment of the method for synthesizing Cochlearol B according to the present invention, the ultraviolet lamp has a wavelength of 254–365 nm and a power of 50–100 W.

[0032] In a preferred embodiment of the synthesis method of Cochlearol B described in this invention, the single-electron reducing agent includes one of lithium (4,4′-bis-tert-butylbiphenyl) and samarium diiodide.

[0033] In a preferred embodiment of the synthesis method of Cochlearol B described in this invention, the peroxide includes one of m-chloroperoxybenzoic acid and dimethyldioxane; the reducing agent includes one of dimethyl sulfide and triphenylphosphine.

[0034] In a preferred embodiment of the synthesis method of Cochlearol B according to the present invention, the acid in the acidic conditions includes any one of methanesulfonic acid, p-toluenesulfonic acid, boron trifluoride ether, and diethylaluminum chloride.

[0035] Beneficial effects of this invention:

[0036] This invention uses commercially available 2-bromo-3-methoxy-4-hydroxyacetophenone and 2,5-dihydroxyphenylboronic acid as raw materials. The process involves protecting the phenolic hydroxyl group with tert-butyldimethylchlorosilane, Wittig olefination, and Suzuki cross-coupling to obtain a biphenyl compound. This is followed by a palladium-catalyzed Wacker-type cross-coupling tandem reaction to yield a 7-position quaternary carbon-substituted biphenylpyran compound. Further protection of the phenolic hydroxyl group in the substrate with methoxymethylene bromide and removal of the tert-butyldimethylsilyl group with potassium fluoride are then carried out in a phthalic acid ion exchange reaction. The next step, using an acid as an oxidant, is to dearomatize phenol to obtain a dearomatized enone compound. This dearomatized enone compound is then selectively reduced by lithium tri-sec-butylborohydride, and the resulting product undergoes a [2+2] cycloaddition reaction under light irradiation to yield a highly substituted cyclobutane product. Finally, through lithium (4,4′-di-tert-butylbiphenyl) reduction, Wittig olefination, epoxidation with m-chloroperoxybenzoic acid, and a methanesulfonic acid-promoted epoxide ring-opening rearrangement, the chemical synthesis of Cochlearol B can be achieved.

[0037] The synthetic route of this invention has the advantages of being simple, efficient, easy to operate, and low in cost. It is suitable for the large-scale synthesis of Cochlearol B and provides an important material basis for the evaluation of the bioactivity of the natural product Cochlearol B. Attached Figure Description

[0038] To more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings used in the description of the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort. Wherein:

[0039] Figure 1This is a synthesis route diagram for Embodiment 1 of the present invention. Detailed Implementation

[0040] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, the specific embodiments of the present invention will be described in detail below with reference to the examples in the specification.

[0041] Many specific details are set forth in the following description in order to provide a full understanding of the invention. However, the invention may also be practiced in other ways different from those described herein, and those skilled in the art can make similar extensions without departing from the spirit of the invention. Therefore, the invention is not limited to the specific embodiments disclosed below.

[0042] Secondly, the term "one embodiment" or "embodiment" as used herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The phrase "in one embodiment" appearing in different places in this specification does not necessarily refer to the same embodiment, nor is it a single or selective embodiment that is mutually exclusive with other embodiments.

[0043] Unless otherwise specified, all raw materials used in this invention are commercially available in the field.

[0044] Example 1

[0045] This embodiment provides a method for synthesizing Cochlearol B, the synthetic route of which is shown in the attached figure. Figure 1 As shown, specifically:

[0046] 1) 2-Bromo-3-methoxy-4-hydroxyacetophenone 1 (2 g, 8.03 mmol, 1.0 equiv) was dissolved in 30 mL of dichloromethane, and imidazole 710 mg (10.44 mmol, 1.3 equiv) and tert-butyldimethylchlorosilane 1.81 g (12.04 mmol, 1.5 equiv) were added. The mixture was stirred at 25 °C for 1 h, and then 30 mL of water was added to quench the reaction. The mixture was extracted twice with 50 mL of dichloromethane. The organic phases were combined and washed with saturated brine. The organic phase was collected, dried over sodium sulfate, and evaporated to dryness to obtain the crude product.

[0047] 6.95 g (19.48 mmol, 2.5 equiv) of PPh3MeBr was dissolved in 50 mL of toluene, and 2.01 g (17.92 mmol, 2.3 equiv) of potassium tert-butoxide was added. The mixture was stirred at 25 °C for 1 h. The crude product was added to the system and stirring was continued for 4 h. The reaction was then quenched with 30 mL of water. The mixture was extracted twice with 30 mL of ethyl acetate. The combined organic phases were washed with saturated brine, collected, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (using petroleum ether and ethyl acetate as eluents) to give target product 2 (2.65 g, 7.42 mmol). The two-step yield was 91%. The reaction equation is as follows:

[0048]

[0049] The target product 2 was characterized.

[0050] 1 H NMR (600MHz, CDCl3) δ (ppm): 6.82 (d, J = 8.2 Hz, 1H), 6.76 (d, J = 8.2 Hz, 1H), 5 .18(s,1H),4.91(s,1H),3.31(s,3H),2.07(s,3H),1.02(s,9H),0.2(s,6H); 13 C NMR (151MHz, CDCl3) δ (ppm): 148.7, 148.5, 145.9, 139.3, 124.5, 120.0, 117.5, 115.9, 60.2, 25.8 (three carbons), 23.9, 18.4, -4.5 (two carbons); IR (KBr, cm -1 ):3420,2933,2857,1480,1284,782; HRMS(ESI)m / z:[M+Na] + Calcd for C 16 H 25 BrO2SiNa 379.0699; Found379.0713.

[0051] 2) Add 500 mg (1.40 mmol, 1.0 equiv) of target product 2, 2,5-dihydroxyphenylboronic acid 3 (431 mg, 2.80 mmol, 2.0 equiv), 445 mg (4.2 mmol, 3.0 equiv) of sodium carbonate, and 20 mL of degassed tetrahydrofuran / water mixed solvent (tetrahydrofuran to water volume ratio 3:1) to a round-bottom flask. After stirring evenly, add 98 mg (0.14 mmol, 0.1 equiv) of bis(triphenylphosphine)palladium dichloride. Then heat the system to reflux and maintain this temperature with stirring for 8 hours. After the starting material is completely converted, cool the reaction system to room temperature and extract three times with 20 mL of ethyl acetate. Combine the organic phases, wash with saturated brine, collect the organic phase, dry it with sodium sulfate, concentrate it, and purify it by silica gel column chromatography (petroleum ether and ethyl acetate as eluents) to obtain target product 4 (259 mg, 0.67 mmol), with a yield of 48%. The reaction equation is as follows:

[0052]

[0053] The target product 4 was characterized.

[0054] 1 H NMR (600MHz, CDCl3) δ (ppm): 6.99 (d, J = 8.3Hz, 1H), 6.88-6.85 (m, 2H), 6.74 (d, J = 8.3Hz 1H),6.68(d,J=2.3Hz,1H),5.50-5.48(m,1H),4.95(s,1H),4.89(s,1H),3.52(s,3H),1.56(s,3H),1.02(s,9H),0.24(s,3H),0.22(s,3H); 13 C NMR (151MHz, CDCl3) δ (ppm): 149.7, 148.7, 148.6, 147.7, 146.4, 139.1, 129.7, 126.3, 126.1, 121.2, 118.5, 118.4, 116.6, 116.3, 61.3, 26.3 (three carbons),23.7,18.6,-3.9,-4.0; IR(KBr,cm -1 ):3672,3295,1693,1513,739,554; HRMS(ESI)m / z:[M+Na] + Calcd for C 22 H 30 O4SiNa409.1806; Found 409.1807.

[0055] 3) At room temperature, target product 4 (500 mg, 1.29 mmol, 1.0 equiv) and 10 ml of toluene were added to a dry reaction flask. After stirring, 1,1-dimethyl-2-propenyl acetate 5 (496 mg, 3.87 mmol, 3.0 equiv) and palladium hexafluoroacetylacetone 34 mg (0.06 mmol, 0.05 equiv) were added sequentially. The reaction system was then placed in an oil bath at 60 °C and stirred for 24 hours. After the starting material was completely converted, the reaction system was cooled to room temperature, concentrated directly, and purified by silica gel column chromatography (petroleum ether and ethyl acetate as eluents) to obtain target product 6 (498 mg, 1.10 mmol), with a yield of 85%. The reaction equation is as follows:

[0056]

[0057] The target product 6 was characterized.

[0058] 1 H NMR (600MHz, CDCl3) δ (ppm): 8.02 (d, J = 2.8Hz, 1H), 6.84 (d, J = 8.6Hz, 1H), 6.82 (d, J = 8.3Hz, 1H), 6.79 (d, J = 8.3Hz, 1H), 6.72 (dd, J = 8.6Hz and 2.9Hz,1H),5.00(t,J=7.0Hz,1H),3.70(s,3H),2.07-1.97(m,2H),1.84-1.79(m,1H),1.63- 1.61(m,1H),1.61(s,3H),1.60(s,3H),1.49(s,3H),1.04(s,9H),0.24(s,3H),0.21(s,3H); 13 C NMR (151MHz, CDCl3) δ (ppm): 150.0,148.9,148.8,148.7,147.0,134.9,131.7, 124.1,123.0,122.6,119.6,118.6,116.0,114.2,79.1,59.6,39.2,25.9(three carbons),25.8,25.0,22.9,18.5,17.6,-4.4,-4.5; IR(KBr,cm -1 ):3649,3177,1706,1512,832,546; HRMS(ESI)m / z:[M+Na] + Calcd for C 27 H 38 O4SiNa 477.2432; Found 477.2441.

[0059] 4) Target product 6 (500 mg, 1.10 mmol, 1.0 equiv) was dissolved in 15 mL of dry tetrahydrofuran. After stirring the system thoroughly, it was cooled to 0 °C. Then, 81 mg of NaH (2.20 mmol, 2.0 equiv) was added to the system, and the mixture was stirred for 5 minutes. Then, 1 mL of bromomethyl ether was slowly added to quench the reaction with 1 mL of water. The mixture was extracted three times with 20 mL of ethyl acetate. The organic phases were combined and washed with saturated brine. The organic phase was collected, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether and ethyl acetate were used as eluents) to obtain target product 7 (532 mg, 1.07 mmol), with a yield of 97%. The reaction equation is as follows:

[0060]

[0061] The target product 7 was characterized.

[0062] 1 H NMR (600MHz, CDCl3) δ (ppm): 8.02 (d, J = 2.7Hz, 1H), 6.92 (d, J = 8.7Hz and2.8Hz,1H),6.87(d,J=8.7Hz,1H),6.82(d,J=8.4Hz,1H),6.79(d,J=8.3Hz,1H),5.18-5.16(m,2H),5.00(t,J=6.8Hz,1H),3.72(s,3H),3.53 (s,3H),2.06-1.98(m,2H),1.87-1.81(m,1H),1.67-1.63(m,1H),1.62( s,3H),1.61(s,3H),1.50(s,3H),1.04(s,9H),0.24(s,3H),0.22(s,3H); 13 C NMR (151MHz, CDCl3) δ (ppm): 151.8,148.8,148.7,148.1,134.7,131.7,124.2,123.0 ,122.5,120.3,119.5,118.3,117.6,116.2,95.6,79.1,59.5,56.0,39.3,25.9(three carbons),25.8,25.2,22.9,18.5,17.6,-4.3,-4.4; IR(KBr,cm -1 ):3650,3282,1694,1515,833,546; HRMS(ESI)m / z:[M+Na] + Calcd for C 29 H 42O5SiNa 521.2694; Found 521.2684.

[0063] 5) At room temperature, 174 mg of potassium fluoride (3.0 mmol, 3.0 equiv) was added to 20 mL of methanol solution containing target product 7 (500 mg, 1.0 mmol, 1.0 equiv). After stirring at this temperature for 3 hours, 386 mg of iodophenyl diacetic acid (1.2 mmol, 1.2 equiv) was added to the system. After stirring for another half hour, the reactants were completely converted. Then, 10 mL of saturated sodium bicarbonate aqueous solution was added to quench the reaction. The mixture was extracted three times with 20 mL of ethyl acetate. The combined organic phases were washed with 20 mL of saturated brine. The organic phase was collected, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether and ethyl acetate were used as eluents) to obtain target product 8 (389 mg, 0.94 mmol) in 94% yield. The reaction equation is as follows:

[0064]

[0065] The target product 8 was characterized.

[0066] 1 H NMR (600MHz, CDCl3) δ (ppm): 7.69 (d, J = 2.8Hz, 1H), 6.94 (d, J = 8.8Hz and2.9Hz,1H),6.91(d,J=10.1Hz,1H),6.75(d,J=8.8Hz,1H),6.14(d,J=10.1Hz,1H),5.10(s,2H),5.00(t,J=7.0Hz,1H),3.49(s,3H),3.2 4(s,3H),3.22(s,3H),2.18-2.12(m,1H),2.05-1.99(m,1H),1.89-1. 82(m,1H),1.78-1.71(m,1H),1.63(s,3H),1.53(s,3H),1.49(s,3H); 13 C NMR (151MHz, CDCl3) δ (ppm): 195.7, 151.4, 148.6, 139.5, 135.3, 133.4, 132.4, 125.2, 123.5, 119.6 ,119.4,117.3,116.0,95.7,94.2,79.0,56.0,50.9,50.8,38.8,25.7,24.7,22.7,17.7; IR(KBr,cm -1 ):3649,3525,3177,1677,1548,548; HRMS(ESI)m / z:[M+Na] +Calcd for C 24 H 30 O6Na 437.1935; Found 437.1937.

[0067] 6) Target product 8 (300 mg, 0.72 mmol, 1.0 equiv) was dissolved in 15 mL of dry tetrahydrofuran. The system was cooled to -78 °C, and then 0.86 mL of tri-sec-butylborohydride (1.0 min THF, 1.3 equiv) was added. The mixture was stirred for 2 minutes while maintaining this temperature. After the starting material was completely converted, 5 mL of saturated ammonium chloride aqueous solution was added to quench the reaction. The mixture was extracted three times with 15 mL of ethyl acetate. The combined organic phases were washed with 20 mL of saturated brine. The organic phase was collected, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether and ethyl acetate were used as eluents) to obtain target product 9 (270 mg, 0.65 mmol), with a yield of 90%. The reaction equation is as follows:

[0068]

[0069] The target product 9 was characterized.

[0070] 1 H NMR (600MHz, CDCl3) δ (ppm): 7.57 (d, J = 2.9Hz, 1H), 6.87 (d, J = 8.7Hz and2.9Hz,1H),6.73(d,J=8.7Hz,1H),5.10(s,2H),5.00(t,J=7.1Hz,1H),3.49(s,3H),3.22(s,3H),3.18(s,3H),2.78-2.73(m,2H),2 .62-2.52(m,2H),2.17-2.11(m,1H),2.04-2.01(m,1H),1.75-1.80(m,1H),1.64(s,3H),1.60-1.62(m,1H),1.54(s,3H),1.41(s,3H); 13 CNMR(151MHz, CDCl3)δ(ppm):203.2,151.3,147.6,142.6,132.2,126.6,123.7,120.3,117.3,116 .9,115.2,97.7,95.8,79.6,56.0,51.5,51.4,37.1,36.3,26.8,25.8,22.9,22.4,17.7; IR(KBr,cm -1 ):3558,3416,2931,1736,1082,624; HRMS(ESI)m / z:[M+Na] +Calcdfor C 24 H 32 O6Na439.2091; Found 439.2091.

[0071] 7) Target product 9 (270 mg, 0.65 mol) was dissolved in 50 mL of methanol and degassed with nitrogen under ultrasonic conditions for half an hour. Subsequently, the system was irradiated with a UV lamp (365 nm, 100 W) and stirred at room temperature for 2 hours. After complete conversion of the starting material, the reaction system was directly concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether and ethyl acetate as eluents) to obtain target product 10 (192 mg, 0.46 mmol), with a yield of 71%. The reaction equation is as follows:

[0072]

[0073] The target product 10 was characterized.

[0074] 1 H NMR (600MHz, CDCl3) δ (ppm): 7.12 (d, J = 2.4Hz, 1H), 6.82 (dd, J = 8.6Hz and2.3Hz,1H),6.70(d,J=8.7Hz,1H),5.10(d,J=6.5Hz,1H),5.07(d,J=6.6Hz,1H),3 .49(s,3H),3.47(s,3H),2.93(s,3H),2.77-2.65(m,2H),2.26(ddd,J=13.5Hz,13.5Hz and5.9Hz,1H),2.13-2.11(m,1H),2.08-2.03(m,1H),1.68-1.59(m,2H),1.50-1.42(m,2H),1.35(s,3H),1.17(s,3H),0.81(s,3H); 13 C NMR (151MHz, CDCl3) δ (ppm): 209.0,150.5,150.1,126.1,121.1,118.1,116.6,101.7, 95.6,86.4,55.8,53.7,53.6,53.0,48.2,47.8,38.8,37.4,36.6,28.8,24.6,24.1(two carbons),23.6;IR(KBr,cm -1 ):3650,3441,3175,1740,1515,549; HRMS(ESI)m / z:[M+Na] + Calcd for C 24 H 32O6Na439.2091; Found 439.2086.

[0075] 8) Target product 10 (190 mg, 0.46 mmol, 1.0 equiv) was dissolved in 15 mL of dry and degassed tetrahydrofuran. The system was cooled to -78 °C, and then 4.6 mL of freshly prepared lithium (4,4′-bis-tert-butylbiphenyl) solution (1.84 mmol, 0.4 min THF, 4.0 equiv) was added. The mixture was stirred at this temperature for half an hour. After complete conversion of the starting material, 5 mL of saturated sodium potassium tartrate aqueous solution was added to quench the reaction. The mixture was extracted three times with 20 mL of ethyl acetate. The combined organic phases were washed with 20 mL of saturated brine. The organic phase was collected, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether and ethyl acetate as eluents) to obtain target product 11 (155 mg, 0.40 mmol), with a yield of 87%. The reaction equation is as follows:

[0076]

[0077] The target product 11 was characterized.

[0078] 1 H NMR (600MHz, CDCl3) δ (ppm): 7.18 (d, J = 2.0Hz, 1H), 6.84 (dd, J = 8.5Hz and 2.0Hz, 1H), 6.75 (d, J = 8.7Hz, 1H), 5.09 (q, J = 10.9Hz and 6.5Hz,2H),3.46(s,3H),3.30(s,3H),3.26(s,1H),2.83-2.73(m,2H),2.20(d,J=7.2Hz,1H),2.12-2.03(m,1H),2 .08-2.03(m,1H),1.74-1.72(m,1H),1.68-1.64(m,1H),1.56-1.46(m,2H),1.34(s,3H),1.17(s,3H),0.86(s,3H); 13 C NMR (151MHz, CDCl3) δ (ppm): 211.5, 150.6, 147.7, 128.1, 119.7, 118.6, 116.6, 95.5, 89.6, 86.0, 61.5, 55.8, 48.6 (two carbons),47.6,40.7,37.1,36.9,28.4,24.4(two carbons),23.9,22.6; IR(KBr,cm -1 ):3649,3525,2953,1722,1486,1023; HRMS(ESI)m / z:[M+Na]+ Calcd for C 23 H 30 O5Na409.1985; Found 409.1984.

[0079] 9) 72 mg of PPh3CH3Br3 (1.04 mmol, 4.0 equiv) was dissolved in 5 mL of toluene. The system was cooled to 0 °C, and 0.78 mL of KHMDS (1 min THF, 3.0 equiv) was added. The mixture was stirred at this temperature for half an hour. Then, target product 11 (0.26 mL, 0.26 mmol, 1.0 equiv, 1.0 min PhMe) was added to the system. The mixture was then brought to room temperature and stirred for one day. After complete conversion of the starting material, 2 mL of water was added to quench the reaction. The mixture was extracted twice with 10 mL of ethyl acetate. The combined organic phases were washed with 5 mL of saturated brine. The organic phase was collected, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether and ethyl acetate as eluents) to obtain target product 12 (62 mg, 0.16 mmol), with a yield of 62%. The reaction equation is as follows:

[0080]

[0081] The target product 12 was characterized.

[0082] 1 H NMR (600MHz, CDCl3) δ (ppm): 6.84 (d, J = 2.2 Hz, 1H), 6.67 (dd, J = 8.6 Hz and2.2Hz,1H),6.65(d,J=8.6Hz,1H),5.10(s,2H),4.74(s,1H),4.51(s,1H),4.29(s,1H),3.48(s,3H),3.14(s,3H),2.56-2. 51(m,2H),2.08-2.01(m,2H),1.89-1.86(m,2H),1.61-1.57(m,1H),1.53-1.41(m,2H),1.37(s,3H),1.31(s,3H),0.81(s,3H); 13 C NMR (151MHz, CDCl3) δ (ppm): 150.0 (two carbons),142.0,127.1,119.5,117.5,115.5,109.8,95.8,85.4,82.8,56.0,55.9, 51.3,47.8,47.2,39.2,38.5,29.1,27.4,25.7,24.0(twocarbons),23.4; IR(KBr,cm -1):3649,3299,1693,1490,1016,547; HRMS(ESI)m / z:[M+Na] + Calcd for C 24 H 32 O4Na407.2193;Found 407.2186.

[0083] 10) At room temperature, 36 mg (0.18 mmol, 3.0 equiv) of m-chloroperoxybenzoic acid was added to an acetonitrile solution containing target product 12 (23 mg, 0.06 mmol, 1.0 equiv). After stirring at this temperature for 8 hours, 11 mg (0.18 mmol, 3.0 equiv) of dimethyl sulfide was added to the system and the reaction continued for 5 hours. Then, the system was cooled to 0°C and 0.6 mL (1.0 min CH3CN, 10.0 equiv) of methanesulfonic acid was added. The mixture was stirred at 0°C for 9 hours until the starting material was completely converted. The reaction was quenched by adding 1 ml of saturated sodium bicarbonate aqueous solution to the system. The mixture was extracted three times with 5 ml of ethyl acetate. The combined organic phases were washed with 2 ml of saturated brine. The organic phase was collected, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (using petroleum ether and ethyl acetate as eluents) to give a colorless oily natural product, Cochlearol B(1) (11.3 mg, 0.035 mmol), in 58% yield. The reaction equation is as follows:

[0084]

[0085] The natural product Cochlearol B(1) was characterized.

[0086] 1 H NMR (600MHz, Acetone-d6) δ (ppm): 9.54 (s, 1H), 7.90 (s, 1H), 7.06 (d, J = 2.2Hz, 1H), 6.78 (d, J = 1.8Hz, 1H), 6.67-6.64 (m, 2H), 2.64 (ddd, J = 16.6Hz, 4.5Hz and 4.2Hz,1H),2.15-2.14(m,1H),2.05-2.04(m,1H),1.98-2.02(m,1H),1.75-1.71 (m,1H),1.69-1.58(m,3H),.1.37(m,1H),1.28(s,3H),0.99(s,3H),0.88(s,3H); 13C NMR (151MHz, Acetone-d6) δ (ppm): 193.4, 156.4, 152.3, 147.3, 142.1, 129.1, 119.9, 115.3, 115. 2,115.1,87.2,50.3,48.1,46.1,45.1,39.0,29.1,24.6,23.8,21.8,19.5; HRMS(ESI)m / z:[M+Na] + Calcd forC 21 H 24 O3Na 347.1618; Found 347.1626.

[0087] Example 2

[0088] The difference between this embodiment and Example 1 is that the sodium carbonate used in step 2) is replaced with potassium carbonate, while the rest of the synthesis conditions are the same as in Example 1. The yield of the target product 4 is only 40%, so the next reaction is not carried out.

[0089] Example 3

[0090] The difference between this embodiment and Example 1 is that the palladium hexafluoroacetylacetone used in step 3) is replaced with palladium trifluoroacetate. The rest of the synthesis conditions are the same as in Example 1. The yield of the target product 6 is only 40%, so the next reaction is not carried out.

[0091] Example 4

[0092] The difference between this embodiment and Example 1 is that sodium bicarbonate was added to the reaction system in step 3), while the rest of the synthesis conditions were the same as in Example 1. The yield of the target product 6 was only 60%, so the next reaction was not carried out.

[0093] Example 5

[0094] The difference between this embodiment and Example 1 is that the trisec-butylborohydride used in step 6) is replaced with triphenylphosphine rhodium chloride / hydrogen. The rest of the synthesis conditions are the same as in Example 1. The yield of the target product 9 is only 50%, so the next reaction is not carried out.

[0095] Example 6

[0096] The difference between this embodiment and Example 1 is that the three ultraviolet lamps (365nm, 100W) used in step 7) are adjusted to ultraviolet lamps (365nm, 50W). The other synthesis conditions are the same as in Example 1. The yield of the target product 10 remains unchanged, but the reaction time is extended from 2h to 6h. Therefore, the next step of the reaction is not carried out.

[0097] Example 7

[0098] The difference between this embodiment and Example 1 is that the methanol used in step 7) is replaced with benzene, while the rest of the synthesis conditions are the same as in Example 1. The yield of the target product 10 is only 60%, so the next reaction is not carried out.

[0099] Example 8

[0100] The difference between this embodiment and Example 1 is that lithium (4,4′-bis-tert-butylbiphenyl) used in step 8) was replaced with samarium diiodide, and 2-[N, bis(trifluoromethanesulfonyl)amino]-5-chloropyridine was added as an additive. The rest of the synthesis conditions were the same as in Example 1. The yield of the target product 11 was only 70%, so the next reaction was not carried out.

[0101] Example 9

[0102] The difference between this embodiment and Example 1 is that the methanesulfonic acid used in step 10) is replaced with p-toluenesulfonic acid, while the rest of the synthesis conditions are the same as in Example 1. The yield of the colorless oily natural product Cochlearol is still 58%, so no further reaction is carried out.

[0103] Through comparison, this invention successfully synthesized Cochlearol B, which was identified as consistent with the Cochlearol B isolated from the fruiting body of Ganoderma lucidum cochlea by Cheng Yongxian's research group in 2014. This invention achieves the chemical synthesis of Cochlearol B. The synthetic route of this invention has the advantages of being simple, efficient, easy to operate, and low in cost, and is suitable for the large-scale synthesis of Cochlearol B. It provides an important material basis for the evaluation of the bioactivity of the natural product Cochlearol B.

[0104] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the spirit and scope of the technical solutions of the present invention, which should all be included in the scope of the claims of the present invention.

Claims

1. A method for synthesizing Cochlearol B, characterized in that: include, 2-Bromo-3-methoxy-4-hydroxyacetophenone was protected with tert-butyldimethylchlorosilane and then reacted with methylenetriphenylphosphine via a Wittig olefination reaction to give the compound shown in formula (1); The compound shown in formula (1) was reacted with 2,5-dihydroxyphenylboronic acid under the conditions of a divalent palladium catalyst, a corresponding base and a solvent via a Suzuki cross-coupling reaction to obtain the compound shown in formula (2); The compound shown in formula (2) reacts with 1,1-dimethyl-2-propenyl acetate under the conditions of a divalent palladium catalyst, a corresponding base and a solvent in a Wacker-type cross-coupling tandem reaction to obtain the compound shown in formula (3). The compound shown in formula (3) was protected with bromomethyl methyl ether to obtain the compound shown in formula (4). The compound shown in formula (4) was deprotected by tert-butyldimethylsilyl protecting group under the action of fluorine reagent. The resulting phenol compound was not separated and under the condition of high-valent iodine reagent underwent an oxidative dearomatization reaction to obtain the compound shown in formula (5). The compound shown in formula (5) undergoes a 1,4-reduction reaction under reducing agent conditions to obtain the compound shown in formula (6). The compound shown in formula (6) undergoes a [2+2] cycloaddition reaction under ultraviolet light irradiation in the corresponding solvent to obtain the compound shown in formula (7). The compound shown in formula (7) was reduced under the conditions of a single-electron reducing reagent to obtain the compound shown in formula (8). The compound shown in formula (8) underwent a Wittig olefination reaction with methylenetriphenylphosphine prepared in situ to obtain the compound shown in formula (9). The compound shown in formula (9) undergoes epoxidation under peroxide conditions. After the reaction is complete, a reducing agent is added to remove excess peroxide. The resulting epoxy intermediate undergoes rearrangement reaction and removal of MOM protecting group directly under acidic conditions without separation, yielding the natural product Cochlearol B with the structural formula shown in formula (10).

2. The method for synthesizing Cochlearol B as described in claim 1, characterized in that: In the Suzuki cross-coupling reaction, the divalent palladium catalyst includes one of bis(triphenylphosphine) palladium dichloride, tetra(triphenylphosphine) palladium, and acetonitrile palladium dichloride; The alkali includes one of sodium carbonate, cesium carbonate, potassium phosphate, and potassium carbonate; The solvent includes one of tetrahydrofuran, ethylene glycol dimethyl ether, and toluene; The molar ratio of divalent palladium catalyst to base is 0.05–0.2:2.0–4.

0.

3. The method for synthesizing Cochlearol B as described in claim 1, characterized in that: In the Wacker-type cross-coupled tandem reaction, the divalent palladium catalyst includes one of palladium hexafluoroacetylacetonate, palladium trifluoroacetate, palladium acetate, palladium dichloride, and palladium acetylacetonate. The alkali includes one of sodium bicarbonate, sodium carbonate, potassium fluoride, cesium fluoride, potassium phosphate, and sodium acetate, or no alkali is added; The solvent includes one of toluene, benzene, trifluorotoluene, mesitylene, xylene, monofluorobenzene, hexafluorobenzene, and monochlorobenzene; The molar ratio of divalent palladium catalyst to base is 0.05:0 to 3.

0.

4. The method for synthesizing Cochlearol B as described in claim 1, characterized in that: The fluorine reagent includes one of potassium fluoride, cesium fluoride, and tetrabutylammonium fluoride.

5. The method for synthesizing Cochlearol B as described in claim 1, characterized in that: The high-valent iodine reagent includes one of iodophenyl diacetic acid and bis(trifluoroacetyl)iodophenyl.

6. The method for synthesizing Cochlearol B as described in claim 1, characterized in that: In the 1,4-reduction reaction, the reducing agent includes one of the following: lithium trisec-butylborohydride, rhodium chloride triphenylphosphine / hydrogen, platinum dioxide / hydrogen, and Raney nickel / hydrogen.

7. The method for synthesizing Cochlearol B as described in claim 1, characterized in that: The ultraviolet lamp has a wavelength of 254–365 nm and a power of 50–100 W.

8. The method for synthesizing Cochlearol B as described in claim 1, characterized in that: The single-electron reducing agent includes one of lithium (4,4′-bis-tert-butylbiphenyl) and samarium diiodide.

9. The method for synthesizing Cochlearol B as described in claim 1, characterized in that: The peroxide includes one of m-chloroperoxybenzoic acid and dimethyldioxane; the reducing agent includes one of dimethyl sulfide and triphenylphosphine.

10. The method for synthesizing Cochlearol B as described in claim 1, characterized in that: In the acidic conditions, the acid includes any one of methanesulfonic acid, p-toluenesulfonic acid, boron trifluoride ethyl ether, and diethylaluminum chloride.

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