Method for synthesizing C-ring fragment key intermediate of carex and method for synthesizing C-ring fragment

Abstract

The invention discloses a method for synthesizing a C-ring fragment key intermediate and a method for synthesizing the C-ring fragment, and belongs to the field of chemical synthesis.The method for synthesizing the C-ring fragment key intermediate of the grass moss comprises the steps that ketene compounds shown in the structural formula (I) and halogenated hydrocarbon compounds shown in the structural formula (II) are added into a solvent, a photosensitizer and an additive are added, and the ketene compounds shown in the structural formula (I) and the halogenated hydrocarbon compounds shown in the structural formula (II) are subjected to a reaction to obtain the C-ring fragment key intermediate of the grass moss. A free radical coupling reaction is carried out in a manner of combining visible light catalysis with continuous flow to obtain a key intermediate compound (III) for synthesizing the C-ring fragment of the carex, and the invention also discloses a method for synthesizing the C-ring fragment. According to the invention, a continuous flow chemistry technology is combined with visible light catalysis, the coupling reaction can be realized in only 1.5 hours, and a C-ring C15-C27 core all-carbon skeleton is finally prepared on the scale of 200g, so that the problem of difficulty in amplification of the traditional kettle reaction is avoided, the method can be realized under mild conditions due to introduction of continuous flow chemistry, and the method is suitable for industrial production. Meanwhile, the modularized synthesis of the C-ring fragment of the grass moss can be realized.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical synthesis, and in particular to a key intermediate for synthesizing a bruceastatin C-ring fragment and a method for synthesizing the C-ring fragment. Background Art

[0002] Bryostatins (1968) are a class of marine macrolide compounds extracted from the marine bryozoan bryozoan, which have been proven to have anti-cancer, anti-AIDS and anti-Alzheimer's effects. So far, the number of members of this class of natural products has increased to more than 20 through extraction and separation research.

[0003] The skeleton structure of the natural product bryostatin includes: three ABC polysubstituted tetrahydropyran rings with different oxidation states, a large sterically hindered C16-C17 E-double bond linking the BC ring, a geminal dimethyl group (Bryostatins 1-20) or a chiral monomethyl group (Bryostatins 21) at C18, and two acid-base unstable exocyclic unsaturated esters at C13\C17 (except for C9 and C19 of Bryostatins 16 and 17, which are ketal structures). Due to the challenging unique structural skeleton of this type of molecule, as well as their high biological activity in vitro and in vivo, and the extremely low yield of extraction and separation from nature, their total synthesis is an urgent problem to be solved. Among them, the key to the efficiency of the total synthesis lies in how to efficiently construct the three polysubstituted pyran rings of Bryostatins A, B, and C, especially the construction of the highly oxidized, polysubstituted A and C rings, which determines the specific type of Bryostatin molecules synthesized and the length and efficiency of the synthetic route.

[0004] Among them, the synthesis of its C ring fragment has been reported less. Among them, Chinese patent application CN 109923110A discloses a synthesis method, which has a total yield of about 16% through 13 steps of reaction. This synthesis method has at least the following problems: (1) There is room for further reduction of reaction steps and improvement of total yield, so as to facilitate further industrialization and reduce production costs; (2) This method requires the use of an equivalent amount of expensive chiral auxiliary when constructing the chiral center at the C23 position, which is costly and not conducive to industrialization; (3) This method requires the use of ozone in the last few steps, which has an adverse effect on the environment and is not conducive to industrialization; (4) 4) This method requires the use of a large amount of hazardous reagents such as tert-butyl lithium and diethyl zinc when constructing the C15-C16 structural fragment, which is inconvenient to operate when scaling up the reaction and is not conducive to industrialization; (5) When constructing the C19-C24 structural fragment, it requires the use of an equivalent amount of expensive chiral auxiliary agents that need to be prepared separately. At the same time, the other isomer obtained needs to be removed under reduced pressure for several days. At the same time, the maximum scale reported in the patent can only be prepared at a single batch level of 16.05g, which is costly and inefficient, and is not conducive to industrialization;

[0005] In addition, although a water-phase free radical coupling reaction is reported in Chinese patent application CN 112110951 A to achieve efficient construction of C19-C24 structural fragments, this method requires the use of equivalent zinc powder, cuprous iodide, and three equivalents of enone raw materials, resulting in a large amount of raw material waste. At the same time, the maximum scale of the reaction can only achieve 500 mg of preparation, and the reaction time requires 24 hours. At the same time, it is not environmentally friendly, has high cost, low efficiency, and is not conducive to industrialization. Summary of the invention

[0006] One of the purposes of the present invention is to provide a method for synthesizing a key intermediate of the C-ring fragment of bruceastatin to solve the above-mentioned problem.

[0007] In order to achieve the above-mentioned purpose, the technical solution adopted by the present invention is as follows: a method for synthesizing a key intermediate of the C-ring fragment of bruceascin, wherein the method comprises: adding a photosensitizer and an additive to a solvent under the protection of an inert gas, and performing a free radical coupling reaction in a manner of visible light catalysis combined with a continuous flow to obtain a key intermediate compound (III) for synthesizing the C-ring fragment of bruceascin, wherein the general structural formula of the enone compound of the structural formula (I) and the halogenated hydrocarbon compound of the structural formula (II) is as follows:

[0008]

[0009] In the above formula, R 1 , R 2is selected from the same or different alkyl or substituted alkyl groups; 1 One selected from H or a hydroxyl protecting group; P 2 is selected from one of H or a hydroxyl protecting group; and X is selected from one of chlorine, bromine and iodine.

[0010] Visible light catalysis has become an important means for the total synthesis of many natural products and the development of new drugs due to its advantages such as cleanliness, safety, low cost and easy availability. This method can achieve efficient free radical carbon-carbon bond coupling of complex fragments. However, this method has the problems of slow reaction rate and low yield when the reaction is scaled up. In the synthesis process of bruceastatin C ring, this application innovatively combines it with continuous flow chemistry for the first time, thereby solving the above problems and achieving 100-gram scale preparation.

[0011] As a preferred technical solution, the solvent is selected from at least one of anhydrous N,N-dimethylformamide, anhydrous dimethyl sulfoxide, anhydrous acetonitrile, water, anhydrous acetone, anhydrous dichloromethane, and anhydrous ethyl acetate;

[0012] Anhydrous acetonitrile is further preferred because a higher yield can be obtained; before adding the materials to the reaction device, the enone compound, the iodinated hydrocarbon compound, the photosensitizer, and the additive are first prepared into a corresponding mixed solution using anhydrous acetonitrile.

[0013] The photosensitizer is selected from one of tris(2,2'-bipyridyl)ruthenium di(perchlorate), tris(2,2'-bipyridyl)ruthenium di(tetrafluoroborate), tris(2,2'-bipyridyl)ruthenium(II) chloride hexahydrate, and tris(2,2'-bipyridyl)ruthenium chloride;

[0014] Tris(2,2'-bipyridyl)ruthenium chloride is further preferred because a higher yield can be obtained;

[0015] The additive is selected from one of trialkylamine or substituted alkylamine compounds, triethylenediamine, N,N-diisopropylethylamine, tribenzylamine, and dihydropyridine;

[0016] N,N-diisopropylethylamine is further preferred because a higher yield can be obtained.

[0017] As a preferred technical solution, the wavelength of the visible light catalysis is 390-450nm. A higher yield can be obtained by irradiating with a blue LED light near 440nm;

[0018] The continuous flow is carried out in a flow reactor, and the flow rate of the syringe pump is 0.5-10mL / h.

[0019] A flow rate of 10 mL / h is further preferred because a higher yield can be obtained.

[0020] As a preferred technical solution, the molar ratio of the ketene compound of structural formula (I) to the halogenated hydrocarbon compound of structural formula (II) is 2:1-1:6.

[0021] A molar ratio of 1.5:1 is further preferred because a higher yield can be obtained;

[0022] The reaction concentration is 0.1mol / L-1mol / L.

[0023] As a preferred technical solution, the molar ratio of the ketene compound of structural formula (I) to the halogenated hydrocarbon compound of structural formula (II), the photosensitizer and the additive is 1.5:1.0:0.05:3.0.

[0024] The second object of the present invention is to provide a method for synthesizing the C-ring fragment of bruceascin, the technical scheme adopted is comprising the following steps:

[0025] (1), the alkenyl halide represented by compound (Ⅰ) undergoes an isomerization reaction of the terminal double bond under the action of a catalyst to obtain a halogenated homoallyl alcohol compound (Ⅱ);

[0026] (2) the halogenated homoallyl alcohol compound (II) obtained in step (1) is iodinated and then protected in situ to prepare a halogenated hydrocarbon (III);

[0027] (3) The halogenated hydrocarbon compound (III) obtained in step (2) is coupled with the enone compound (IV) under the action of visible light catalysis combined with continuous flow chemistry to obtain the C15-C27 fragment (V) of the straight chain skeleton of the C ring of bruceastatin;

[0028] (4) under the catalytic action of p-toluenesulfonic acid monohydrate, the C15-C27 fragment (V) of the straight chain skeleton of bruceastatin C ring obtained in step (3) is deprotected and cyclized to form a cyclic product, and then epoxidation and ring opening and reoxidation are carried out in situ to obtain compound (VI);

[0029] (5) The cyclized product (VI) obtained in step (4) is subjected to an exocyclic aldol condensation reaction, asymmetric reduction, and protection of the C20 hydroxyl group to obtain compound (VII);

[0030] (6) Compound (VII) obtained in step (5) is subjected to deprotection oxidation, dihydroxylation and monoprotection to obtain the C15-C27 fragment of bruceastatin C ring of formula (VIII),

[0031] Wherein, the reaction formula of step (1) is:

[0032]

[0033] The reaction formula of step (3) is:

[0034]

[0035] The reaction formula of step (5) is:

[0036]

[0037] The reaction formula of step (6) is:

[0038]

[0039] Among them, R 1 , R 2 , R 3 is selected from the same or different alkyl or substituted alkyl groups; 1 One selected from H or a hydroxyl protecting group; P 2 is selected from one of H or a hydroxyl protecting group; and X is selected from one of chlorine, bromine and iodine.

[0040] As a preferred technical solution, in step (1), the catalyst is selected from at least one of palladium acetate, palladium trifluoroacetate, palladium chloride, palladium nitrate, and bis(dibenzylideneacetone)palladium, preferably palladium trifluoroacetate.

[0041] As a preferred technical solution, during the reaction of step (1), the solvent used is selected from one of dichloroethane, ether, tetrahydrofuran, dioxane, dichloromethane, chloroform and carbon tetrachloride, and the water content of the solvent is preferably less than 10 ppm.

[0042] As a preferred technical solution, during the reaction of step (1), the reaction temperature adopted is 0°C to 50°C, for example, it can be 0°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, etc., preferably 25°C.

[0043] Compared with the prior art, the advantages of the present invention are as follows: in the synthesis process of the C ring of bruceascin compounds, the present invention introduces the visible light catalysis mode for the first time, and can achieve efficient construction of the C19-C24 fragment under mild conditions in 12 hours, and only needs to use 5 mol% of a catalytic amount of a cheap commercial photosensitizer; however, when the visible light catalysis is prepared on a scale of grams or more, there are problems such as low reaction efficiency, the reaction time needs to be extended by double, and the raw material reaction is incomplete. The present invention combines the technology of continuous flow chemistry with visible light catalysis, and the coupling reaction can be achieved in only 1.5 hours, and finally the C ring C15-C27 core full carbon skeleton is prepared on a scale of 200g, which solves the problem of difficulty in scaling up traditional kettle reactions. The introduction of continuous flow chemistry enables the method to be implemented under mild conditions, and at the same time, the modular synthesis of the C ring fragment of bruceascin compounds can be achieved. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 is the hydrogen spectrum of compound 12 obtained in step (2) of Example 1 of the present invention;

[0045] Figure 2 The carbon spectrum of compound 12 obtained in step (2) of Example 1 of the present invention;

[0046] Figure 3 is the hydrogen spectrum of compound 13 obtained in step (3) of Example 1 of the present invention;

[0047] Figure 4 The carbon spectrum of compound 13 obtained in step (3) of Example 1 of the present invention;

[0048] Figure 5 is the hydrogen spectrum of compound 16 obtained in step (6) of Example 1 of the present invention;

[0049] Figure 6 The carbon spectrum of compound 16 obtained in step (6) of Example 1 of the present invention;

[0050] Figure 7 is the hydrogen spectrum of compound 17b obtained in step (8) of Example 1 of the present invention;

[0051] Figure 8 This is the carbon spectrum of compound 17b obtained in step (8) of Example 1 of the present invention;

[0052] Fig. 9 is the hydrogen spectrum of compound 19b obtained in step (12) of Example 1 of the present invention;

[0053] Fig.10 This is the carbon spectrum of compound 19b obtained in step (12) of Example 1 of the present invention. DETAILED DESCRIPTION

[0054] The present invention will be further described below in conjunction with the accompanying drawings.

[0055] It should be noted that the raw materials, reagents and equipment used in the following examples were all commercially available unless otherwise specified.

[0056] Among them, the flow reaction injection pumps are 4 LSP01-3A injection pumps of Lange Constant Flow Pump Co., Ltd., the visible light LED lamps are 4 sets of 440nm blue LED lamps of Kessil, and the flow reactor is 20 meters of FEP Teflon tube.

[0057] Embodiment 1:

[0058] A method for synthesizing the C-ring fragment of bruceascin, the reaction formula of which is as follows:

[0059]

[0060] The specific reaction steps are:

[0061] (1) At room temperature, under argon protection, palladium trifluoroacetate (1.67 g, 5.0 mmol, 5 mol%), diphenyl-2-pyridinylphosphine (5.26 g, 20 mmol, 20 mol%) and 30 mL of trifluoroethanol were weighed into a 250 mL round-bottom flask. Compound 11 (13.4 g, 100 mmol, 1.0 eq.) was then diluted with 75 mL of anhydrous dichloroethane and added to the round-bottom flask to react at room temperature for 48 hours. After 48 hours, the reaction was completed and the reaction system was slowly poured into glacial hydrochloric acid (100 mL, 1 M / L) to quench. The mixture was extracted with dichloromethane and dried over anhydrous sodium sulfate. After concentration, the mixture was directly used for the next step.

[0062] (2) At room temperature, under argon protection, sodium iodide (75 g, 500 mmol, 5.0 eq.) was weighed into a 2 L round-bottom flask. The crude compound obtained in the previous step was diluted with 800 mL of anhydrous acetone and added to the round-bottom flask. The reaction was carried out at 75° C. for 36 hours. After 36 hours, the reaction was completed. The reaction system was cooled to room temperature. Imidazole (17.0 g, 250 mmol, 2.5 eq.) was added to the reaction system. Triethylsilyl chloride (16.6 g, 110 mmol, 1.1 eq.) was diluted with 500 mL of anhydrous dichloromethane and slowly added to the reaction system. The mixture was stirred at room temperature for 12 hours. After 12 hours, the reaction was completed. Water was added to quench the mixture. The mixture was extracted with dichloromethane and dried over anhydrous sodium sulfate. After concentration, the mixture was purified by column chromatography (eluent: petroleum ether) to obtain compound 12 (22.1 g). The two-step yield was 65%. E / Z ≥ 95:5. Its H NMR spectrum and C NMR spectrum were as follows: Figure 1 and Figure 2 As shown;

[0063] The structural identification data of the obtained compound 12: Rf = 0.5 (EA / Petroleum ether = 2%), 1 H NMR (400MHz, CDCl3) δ5.61-5.50(m,1H),5.40-5.33(m,1H),3.67-3.57(m,1H),3.24-3.13 (m,2H),2.38-2.21(m,2H),1.66(d,J=5.6Hz,3H),0.97(t,J=8Hz,9H),0.62(q,J=8Hz,6H); 13 C NMR (150MHz, CDCl3) δ128.6,126.1,71.5,40.1,18.0,13.5,6.8,4.9; IR(neat)cm -13019,2955,2911,2879,1457,1416,1178,1057,1009,968,880,734; HRMS(MALDI,m / z)calcd forC 12 H 25 IOSi(M+H) + 341.0792, found 341.0790; [α] D 20 =-45.29°(c=12.1in CHCl3);

[0064] Parallel preparation method of compound 12b: 1) Under argon protection, silver trifluoromethanesulfonate (115.2 g, 450 mmol, 1.5 eq) and 2,6-di-tert-butyl-4-methylpyridine (92.7 g, 450 mmol, 1.5 eq) were weighed into a 2 L round-bottom flask, 1 L of anhydrous dioxane was added as a solvent, and then p-methoxybenzyl alcohol (62.1 g, 450 mmol, 1.5 eq.) was added and stirred at room temperature for 10 minutes, and then (E)-5-bromo-2,2-dimethylpent-3-enoic acid methyl ester (66 g, 300 mmol, 1.0 eq) in 500 mL of dioxane was slowly added to the reaction system over 30 minutes, and then the mixture was stirred for 10 minutes. The reaction was continued for 2 hours; after the reaction was completed as determined by TLC, the mixture was concentrated under reduced pressure to remove dioxane, and then purified by column chromatography (eluent: petroleum ether / ethyl acetate = 20:1) to obtain an intermediate compound (71.7 g) with a yield of 86%; 2) at -20°C, under argon protection, the intermediate compound (45 g, 162 mmol, 1.0 eq.) obtained in step (1) was diluted with 400 mL of anhydrous tetrahydrofuran and added to a 2 L round-bottom flask, followed by the addition of dimethylhydroxylamine hydrochloride (48 g, 486 mmol, 3.0 eq.) and cooled at -20°C for 10 minutes. After 10 minutes, isopropylmagnesium chloride (502 mL, 1004 mmol, 6.2 eq. 2M) was added. In THF) was added dropwise to the reaction system within 1 hour, and the addition was completed after 1 hour. The reaction was continued at -20°C for 4 hours. After 4 hours, TLC detected that the intermediate compound had been completely converted. Then, vinyl magnesium bromide (810 mL, 810 mmol, 5.0 eq. 1 M in THF) was slowly added to the reaction system, and the reaction was continued at -20°C for 1.5 hours. After the reaction was completed, saturated ammonium chloride solution was quenched, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After concentration, the mixture was simply purified by column chromatography (eluent: petroleum ether / ethyl acetate = 30:1) to obtain compound 12b (33.7 g) with a yield of 76%;

[0065] The structural identification data of the obtained compound 12b: Rf = 0.6 (EA / Petroleum ether = 20%). 1H NMR (400MHz, CDCl3) δ7.25(d,J=8Hz,2H),6.87(d,J=8Hz,2H),6.72(dd,J=17.2,10.4Hz,1H),6.33(d,J=17.2Hz,1H),5.78(d, J=16Hz,1H),5.70(dt,J=16,5.2Hz,1H),5.62(d,J=10.4Hz,1H),4.43(s,2H),4.00(d,J=5.2Hz,2H),3.79(s,3H),1.25(s,6H); 13 C NMR (150MHz, CDCl3) δ201.0,159.2,136.7,131.5,130.1,129.4,128.3,127.1,113.7,71.8,70.2,55.2,48.8,23.5; IR(neat)cm -1 2970,2846,1694,1611,1512,1300,1245,1175,1036,977,818; HRMS(MALDI,m / z)calcd for C 17 H 22 O3(M+Na) + 297.1461, found 297.1463;

[0066] (3) At room temperature and under argon protection, tris(2,2'-bipyridine)ruthenium dichloride (500 mg, 0.75 mmol, 5 mol%), compound 12b (6.16 g, 22.5 mmol, 1.5 eq.), compound 12 (5.1 g, 15 mmol, 1.0 eq.), and N,N-diisopropylethylamine (8 mL, 45 mmol, 3.0 eq.) were diluted with 40 mL of anhydrous acetonitrile and added to a 50 mL syringe, and then pumped into the flow reactor at a rate of 10 mL / h. At room temperature, a flow reactor was set at a distance of 1 c. m blue LED light (hv = 427 ~ 440nm) irradiated the flow reactor; after collecting the product, it was directly concentrated under reduced pressure to remove acetonitrile, and then an appropriate amount of silica gel and dichloromethane were added. The sample was mixed with silica gel by a rotary evaporator, and used for dry loading. Column chromatography purification (eluent: petroleum ether / ethyl acetate = 50:1) can obtain coupling compound 13 (5.7g), with a yield of 78%. 5.7g of coupling compound 13 can be obtained in a single cycle of flow chemistry. Finally, 200g of coupling compound 13 was finally prepared through multiple cycles; its H NMR spectrum and C NMR spectrum are shown as follows: Figure 3 and Figure 4 As shown;

[0067] The structural identification data of compound 13 are as follows: f=0.5(EA / Petroleum ether=10%),

[0068] 1 H NMR(400MHz,CDCl3)δ7.26(d,J=8Hz,2H),6.88(d,J=8Hz,2H),5.78(d,J=15.6Hz,1H),5.67(dt,J=16,5.6Hz,1H),5.46–5.35(m,2H),4.43(s,2H),3.99(d,J=5.6Hz,2H),3.80(s,3H),3.67–3.58(m,1H),2.44(t,J=7.2Hz,2H),2.194–2.078(m,2H),1.64(d,J=5.6Hz,3H),1.60–1.44(m,2H),1.43–1.29(m,2H),1.22(s,6H),0.94(t,J=8Hz,9H),0.58(q,J=8Hz,6H); 13 C NMR(150MHz,CDCl3)δ212.9,159.2,137.5,130.2,129.4,127.5,127.3,126.2,113.8,72.3,71.9,70.3,55.2,49.9,40.7,37.6,36.3,23.8,20.0,18.0,6.9,4.9;IR(neat)cm -1 2954,2877,1709,1613,1513,1461,1362,1247,1098,1011,974,821,737;HRMS(MALDI,m / z)calcd for C 29 H 48 O4Si(M+Na) + 511.3214,found 511.3210;[α] D 19.9 =-60°(c=5.9in CHCl3);

[0069] (4) At room temperature, under argon protection, compound 13 (27.0 g, 55.0 mmol, 1.0 eq.) was dissolved in 500 mL of anhydrous chloroform, and then p-toluenesulfonic acid monohydrate (11.5 g, 60.8 mmol, 1.1 eq.) was added in sequence and reacted at room temperature for 1 hour. After 1 hour, TLC monitored that compound 13 was completely converted. Subsequently, 4A°MS (160.0 g) was added and the reaction was continued at 80° C. for 20 hours. The reaction system was then cooled to room temperature. TLC monitored that compound 13 was completely converted. Complete conversion; after cooling the reaction system at 0°C for 10 minutes, anhydrous methanol (275 mL), sodium bicarbonate (13.8 g, 165.0 mmol, 3.0 eq.) and magnesium monoperoxyphthalate hexahydrate (17.0 g, 27.5 mmol, 0.5 eq.) were added in sequence and reacted at 0°C for 30 minutes. After 30 minutes, TLC detected that the compound had been completely converted, quenched with water, extracted with ether, dried over anhydrous sodium sulfate, and concentrated to obtain compound 14, which was directly used in the next step reaction;

[0070] (5) The concentrate of the previous step, compound 14 (55.0 mmol, 1.0 eq.), was dissolved in 1.1 L of dichloromethane and cooled at 0°C for 5 minutes. After 5 minutes, sodium bicarbonate (46.2 g, 550.0 mmol, 10.0 eq.) and Dess-Martin periodinane (35.0 g, 82.5 mmol, 1.5 eq.) were added in sequence and reacted at 0°C for 12 hours. After 12 hours, the reaction was completed, and water was slowly added to quench, and the mixture was extracted with dichloromethane and dried over anhydrous sodium sulfate. After concentration, the mixture was simply purified by column chromatography (eluent polarity: petroleum ether / ethyl acetate = 25:1) to obtain compound 15 (17.7 g), with a two-step yield of 80%;

[0071] (6) At room temperature, under argon protection, compound 15 (14.0 g, 34.8 mmol, 1.0 eq.) was dissolved in 200 mL of anhydrous methanol, and then anhydrous potassium carbonate (26.5 g, 191.5 mmol, 5.5 eq.) and methyl glyoxylate (64.0 mL, 174 mmol, 5.0 eq. 2.7 M in THF) were added successively and stirred vigorously at room temperature for 3 hours. After 3 hours, TLC monitoring showed that compound 15 was completely converted. The mixture was slowly quenched with saturated ammonium chloride solution, extracted with ether, dried over anhydrous sodium sulfate, concentrated, and simply purified by column chromatography (eluent: petroleum ether / ethyl acetate = 25:1) to obtain the product compound 16 (13.5 g) with a yield of 82%; E / Z ≥ 95:5; its H NMR spectrum and C NMR spectrum were as shown below: Figure 5 and Figure 6 As shown;

[0072] (7) At room temperature, under argon protection, compound 16 (9.44 g, 20.0 mol, 1.0 eq.) was dissolved in 250 mL of anhydrous methanol and cooled at -50°C for 10 minutes. Ce(III) chloride heptahydrate (3.73 g, 10.0 mol, 0.5 eq.) was added and stirred at -50°C for 15 minutes. Sodium borohydride (1.52 g, 40.0 mol, 2.0 eq.) was added and stirred at -50°C for 1.5 hours. After TLC detection, compound 16 was completely converted. The mixture was quenched with saturated ammonium chloride and extracted with ether. The mixture was concentrated and directly used in the next step.

[0073] (8) The concentrate from the previous step (20.0 mmol, 1.0 eq.) was dissolved in 1.0 L of dichloromethane and cooled at 0°C for 5 minutes. Pyridine (32.3 mL, 400.0 mol, 20.0 eq.), 4-dimethylaminopyridine (2.46 g, 20.0 mol, 1.0 eq.) and acetic anhydride (10.2 g, 10.0 mol, 5.0 eq.) were then added in sequence. After reacting at 0°C for 2 hours, TLC detected that the compound had been completely converted. Saturated sodium bicarbonate was slowly added to quench the mixture. After stirring at 0°C for 10 minutes, the mixture was extracted with dichloromethane and dried over anhydrous sodium sulfate. After concentration, the mixture was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 25:1) to give compound 17b (9.0 g) (dr>20:1), with a two-step yield of 88%. Its H NMR spectrum and C NMR spectrum were as shown below: Figure 7 and Figure 8 As shown;

[0074] (9) At room temperature, under argon protection, compound 17b (12.0 g, 23.4 mol, 1.0 eq.) was dissolved in 500 mL of anhydrous dimethane and cooled at 0°C for 5 minutes. After 5 minutes, pH = 7 phosphate buffer (50 mL) and 2,3-dichloro-5,6-dicyanobenzoquinone (10.64 g, 46.8 mmol, 2.0 eq.) were added in sequence and reacted at 0°C for 12 hours. After 12 hours, TLC monitored that compound 17b had been completely converted. The mixture was quenched with saturated sodium bicarbonate, extracted with ether, concentrated, and filtered through celite before being used directly in the next step.

[0075] (10) At room temperature, under argon protection, the concentrate of the previous step (23.4 mmol, 1.0 eq.) was dissolved in 500 mL of anhydrous dichloromethane and cooled at 0°C for 5 minutes. After 5 minutes, sodium bicarbonate (19.6 g, 234.0 mmol, 10.0 eq.) and Dess-Martin periodinane (14.9 g, 35.1 mmol, 1.5 eq.) were added in sequence and the reaction was continued at 0°C for 6 hours. After 6 hours, the reaction was completed, quenched with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent polarity: petroleum ether / ethyl acetate = 25:1) to obtain compound 18b (8.1 g), with a two-step yield of 88%;

[0076] (11) Potassium osmate dihydrate (72.55 mg, 0.23 mmol, 5 mol%), potassium ferrocyanide (9.20 g, 27.96 mmol, 3.0 eq.), anhydrous potassium carbonate (4.25 g, 27.96 mmol, 3.0 eq.), methanesulfonamide (888.0 mg, 9.33 mmol, 1.0 eq.) and hydroquinidine 1,4-(2,3-naphthyridine) diether (363.1 mg, 0.46 mmol, 5 mol%) were weighed into a 250 mL round-bottom flask at room temperature under argon protection. After evacuation three times, tert-butyl alcohol (93 mL) and deionized water were added. Deionized water (93 mL) was stirred vigorously at room temperature for 45 minutes; in another 250 mL round-bottom flask, dried compound 18b (3.90 g, 9.92 mmol, 1.0 eq.) was added, and cooled at 0°C for 5 minutes. After 5 minutes, the solution prepared in the previous step was poured in at once, and the reaction was continued at 0°C for 2 hours. After 2 hours, the reaction was completed, quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and simply purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1:1) to obtain 4.04 g (dr = 11:1) of the intermediate product with a yield of 95%. The intermediate product was easily unstable during storage and was directly used in the next step reaction;

[0077] (12) At room temperature, under argon protection, the intermediate product obtained in step (11) (4.02 g, 9.40 mmol, 1.0 eq.) was added to a 100 mL round-bottom flask and dissolved in 45 mL of anhydrous N,N-dimethylformamide. The mixture was cooled at 0°C for 5 minutes. After 5 minutes, imidazole (2.12 g, 30.94 mmol, 3.5 eq.) and tert-butyldimethylsilyl chloride (2.0 g, 13.26 mmol, 1.5 eq.) were added in sequence. The mixture was reacted at 0°C for 2 hours. After 2 hours, the reaction was completed, and the mixture was quenched with water. The mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After concentration, the mixture was simply purified by column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to obtain compound 19b (3.82 g). The yield was 75%, and dr = 11:1.

[0078] The structural identification diagram of compound 19b is shown in Fig. 9 and Fig.10 As shown, the data are as follows: R f =0.5(EA / Petroleum ether=30%),

[0079] 1 H NMR (400MHz, CDCl3) δ9.56(d,J=8Hz,1H),7.32(d,J=16Hz,1H),5.93(dd,J=16,8 Hz,1H),5.88(s,1H),5.43(s,1H),4.25-4.18(m,1H),3.73-3.66(m,5H),3.49(d, J=16Hz,1H),3.44(s,3H),2.39-2.31(m,2H),1.91(s,3H),1.70-1.62(m,3H),1. 22(d,J=6Hz,3H),1.19(s,3H),1.15(s,3H),0.91(s,9H),0.107(d,J=3.6Hz,6H); 13 C NMR (150MHz, CDCl3) δ194.7,168.7,167.2,166.4,151.5,126.6,117.7,102.3,71.99,71.61,71.4 7,68.6,51.4,51.2,47.4,40.3,32.7,25.8,23.9,21.6,21.2,20.3,18.0,-4.2,-4.8; IR(neat)cm -1 3538,2952,2858,2173,1751,1721,1687,1437,1372,1227,1153,1102,1077,884,836; HRMS(MALDI,m / z)calcd for C 27 H 46 O9Si(M+Na) + 565.2803, found 565.2804;[α] D 20.1 =-13.09° (c=1.1in CHCl3).

[0080] Embodiment 2-7:

[0081] Compared with Example 1, in step (5), the solvent anhydrous acetonitrile is replaced by anhydrous N,N-dimethylformamide, anhydrous dimethyl sulfoxide, water, anhydrous acetone, anhydrous dichloromethane, and anhydrous ethyl acetate, respectively, and the rest remain unchanged. The corresponding yields are: 10%, less than 5%, 10%, less than 5%, less than 5%, and less than 5%, respectively.

[0082] Embodiment 8-10:

[0083] Compared with Example 1, in step (5), the additive N,N-diisopropylethylamine is replaced by triethylamine, triethylenediamine, tribenzylamine, and dihydropyridine, respectively, and the rest remain unchanged. The corresponding yields are 40%, less than 5%, 20%, and less than 5%, respectively.

[0084] Examples 11-13

[0085] Compared with Example 1, in step (5), the photosensitizer tris(2,2'-bipyridyl)ruthenium chloride is replaced by tris(2,2'-bipyridyl)ruthenium di(perchlorate), tris(2,2'-bipyridyl)ruthenium di(tetrafluoroborate), and tris(2,2'-bipyridyl)ruthenium (II) chloride hexahydrate, respectively, and the rest remain unchanged. The corresponding yields are 45%, 30%, less than 5%, and 70%, respectively.

[0086] Examples 14-15

[0087] Compared with Example 1, in step (5), the flow rates of the injection pump in the flow reactor were replaced with 0.5 mL / h and 5 mL / h respectively, and the rest remained unchanged. The corresponding yields were 75% and 65% respectively.

[0088] Examples 16-17

[0089] Compared with Example 1, in step (5), the molar ratio of compound 12 to compound 12b was changed to 2:1 and 1:6, and the rest remained unchanged. The corresponding yields were 70% and 35%, respectively.

[0090] Embodiment 18

[0091] Compared with Example 1, in step (5), P in the general formula (I) of compound 12b is 1 The yields of tert-butyldimethylsilyl and tert-butyldiphenylsilyl were 70% and 60%, respectively. 2 The triethylsilyl group was replaced by hydrogen, and the yields of tert-butyldimethylsilyl group were 65% and 62% respectively.

[0092] Embodiment 19

[0093] Compared with Example 1, in step (1), P in compound 12 2 When H is replaced by triethylsilyl, tert-butyldiphenylsilyl, and tert-butyldimethylsilyl, the yields are 70%, 65%, and 60%, respectively.

[0094] Embodiment 20

[0095] Compared with Example 1, in step (1), X in compound 12 is replaced by chlorine with bromine and iodine, and the yields are 70% and 60%, respectively.

[0096] 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 principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for synthesizing a key intermediate of a bruceastatin C-ring fragment, characterized in that: The method comprises the following steps: in an inert gas atmosphere, a ketone compound of structural formula (I) and a halogenated hydrocarbon compound of structural formula (II) are placed in a solvent, a photosensitizer and an additive are added, and a free radical coupling reaction is carried out in a visible light catalytic combined with a continuous flow mode to obtain a key intermediate compound (III) for synthesizing the C-ring fragment of bruceastatin, wherein the general structural formula of the ketone compound of structural formula (I) and the halogenated hydrocarbon compound of structural formula (II) is as follows: In the above formula, R 1 , R 2 is selected from the same or different alkyl or substituted alkyl groups; 1 One selected from H or a hydroxyl protecting group; P 2 is selected from one of H or a hydroxyl protecting group; and X is selected from one of chlorine, bromine and iodine.

2. The method according to claim 1, characterized in that The solvent is selected from at least one of anhydrous N,N-dimethylformamide, anhydrous dimethyl sulfoxide, anhydrous acetonitrile, water, anhydrous acetone, anhydrous dichloromethane, and anhydrous ethyl acetate, preferably anhydrous acetonitrile; The photosensitizer is selected from one of tris(2,2'-bipyridyl)ruthenium di(perchlorate), tris(2,2'-bipyridyl)ruthenium di(tetrafluoroborate), tris(2,2'-bipyridyl)ruthenium(II) chloride hexahydrate, and tris(2,2'-bipyridyl)ruthenium chloride, preferably tris(2,2'-bipyridyl)ruthenium chloride; The additive is selected from one of trialkylamine or substituted alkylamine compounds, triethylenediamine, N,N-diisopropylethylamine, tribenzylamine, and dihydropyridine, preferably N,N-diisopropylethylamine.

3. The method according to claim 1, characterized in that The wavelength of the visible light catalysis is 390-450nm; The continuous flow is carried out in a flow reactor, and the flow rate of the syringe pump is 0.5-10 mL / h, preferably 10 mL / h.

4. The method according to claim 1, characterized in that: The molar ratio of the ketene compound of structural formula (I) to the halogenated hydrocarbon compound of structural formula (II) is 2:1-1:6, preferably 1.5:1, and the reaction concentration is 0.1 mol / L-1 mol / L.

5. The method according to claim 1, characterized in that The molar ratio of the ketene compound of structural formula (I) to the halogenated hydrocarbon compound of structural formula (II), the photosensitizer and the additive is 1.5:1.0:0.05:3.

0.

6. A method for synthesizing a bruceastatin C-ring fragment, characterized in that: The steps include: (1), the alkenyl halide represented by compound (Ⅰ) undergoes an isomerization reaction of the terminal double bond under the action of a catalyst to obtain a halogenated homoallyl alcohol compound (Ⅱ); (2) the halogenated homoallyl alcohol compound (II) obtained in step (1) is iodinated and then protected in situ to prepare a halogenated hydrocarbon (III); (3) The halogenated hydrocarbon compound (III) obtained in step (2) is coupled with the enone compound (IV) under the action of visible light catalysis combined with continuous flow chemistry to obtain the C15-C27 fragment (V) of the straight chain skeleton of the C ring of bruceastatin; (4) under the catalytic action of p-toluenesulfonic acid monohydrate, the C15-C27 fragment (V) of the straight chain skeleton of bruceastatin C ring obtained in step (3) is deprotected and cyclized to form a cyclic product, and then epoxidation and ring opening and reoxidation are carried out in situ to obtain compound (VI); (5) The cyclized product (VI) obtained in step (4) is subjected to an exocyclic aldol condensation reaction, asymmetric reduction, and protection of the C20 hydroxyl group to obtain compound (VII); (6) Compound (VII) obtained in step (5) is subjected to deprotection oxidation, dihydroxylation and monoprotection to obtain the C15-C27 fragment of bruceastatin C ring of formula (VIII), Wherein, the reaction formula of step (1) is: The reaction formula of step (3) is: The reaction formula of step (5) is: The reaction formula of step (6) is: Among them, R 1 , R 2 , R 3 is selected from the same or different alkyl or substituted alkyl groups; 1 One selected from H or a hydroxyl protecting group; P 2 is selected from one of H or a hydroxyl protecting group; and X is selected from one of chlorine, bromine and iodine.

7. The method according to claim 6, characterized in that In step (1), the catalyst is selected from at least one of palladium acetate, palladium trifluoroacetate, palladium chloride, palladium nitrate, and bis(dibenzylideneacetone)palladium, preferably palladium trifluoroacetate.

8. The method according to claim 6, characterized in that During the reaction of step (1), the solvent used is selected from one of dichloroethane, ether, tetrahydrofuran, dioxane, dichloromethane, chloroform and carbon tetrachloride, and the water content of the solvent is preferably less than 10 ppm.

9. The method according to claim 6, characterized in that During the reaction of step (1), the reaction temperature is 0°C to 50°C, preferably 25°C.

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