Key intermediate for synthesizing grass moss compound and method for synthesizing grass moss compound

Abstract

The invention discloses a key intermediate for synthesizing a bryochratoxin compound and a method for synthesizing the bryochratoxin compound, and belongs to the field of chemical synthesis.The synthesis method of the key intermediate comprises the steps that a compound shown in the formula (III) is dissolved in a reaction solvent, then Lewis acid is added for an intramolecular Prins cyclization reaction, and the compound shown in the formula (III) is obtained. Obtaining a compound as shown in a formula (IV); then carrying out iodination and carbonylation reactions of exocyclic double bonds of the B ring to convert the olefin into an olefine acid ester compound; after the key common intermediates are obtained, grass moss 1, 7 and 9 and grass moss 9-N3 analogues can be respectively synthesized, so that divergent synthesis of the grass moss analogues is realized; according to the invention, through an esterification reaction of C1 carboxyl and C25 hydroxyl, acetalation of C15 aldehyde group is carried out at the same time, and then through a closed-loop strategy of constructing a macrolide skeleton through gem-bisilicon-mediated intra-molecular stereoselective Prins cyclization, specific selective construction of the cis-Z type of the B ring in the carex 1 is 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 bryostatin compounds and a method for synthesizing bryostatin compounds. Background Art

[0002] Bryostatins (1968, also known as bryostatins) are a class of marine macrolide compounds extracted from the marine bryozoan bryozoan. They have been proven to have anti-cancer, anti-AIDS and anti-Alzheimer's effects.

[0003] The skeleton structure of the natural product bryostatin includes: three ABC polysubstituted tetrahydropyran rings in different oxidation states (A ring, B ring and C ring respectively), a large sterically hindered C16-C17 E-double bond connecting the BC ring, a geminal dimethyl group (Bryostatins 1-20) or a chiral monomethyl group (Bryostatins 21) at the C18 position, and two acid-base unstable extracyclic unsaturated esters at the C13\C17 positions (except for C9 and C19 of Bryostatin 16 and 17, which are ketal structures).

[0004] So far, the number of members of this class of natural products has been increased to 21 by extraction and separation research. The National Cancer Institute of the United States once extracted only 18 grams of bryostatin from 14 tons of total grass bryozoans, with a total efficiency of about 0.00014%. Due to the scarcity of resources, scientists have been exploring chemical synthesis methods in order to be able to mass-produce this substance. For example, CN109923110A discloses a 29-step total synthesis route with a total yield of 4.8% and an average yield of more than 80% per step. It successfully synthesized more than 2 grams of bryostatin 1. The method reported in this patent application has at least the following disadvantages: (1) In the A ring synthesis route, the dr value of the C5 position is only 2:1; and the large amount of equivalent expensive chiral auxiliary agents used in the synthesis of key intermediates is costly and not easy to industrialize; the entire A ring synthesis route has 10 steps, but there are 7 separation steps, and the yield is only 13%; (2) In the B ring synthesis, the Z:E of the double bond outside the B ring is 11.6:1, which cannot be achieved The specific construction results in the E-isomerization of the final product bryostatin 1, which is difficult to separate and purify in the later stage; (3) In the C-ring synthesis route, an equivalent amount of expensive chiral auxiliary is required to construct the chiral center at the C23 position, which is costly, and the last few steps require the use of ozone, which is easy to pollute the environment. A large amount of hazardous reagents such as tert-butyl lithium and diethyl zinc are required to construct the C15-C16 structural fragment, which is inconvenient to operate during the scale-up reaction and is not conducive to industrialization; (4) In the method of finally removing the protecting group to synthesize bryostatin analogs, the equivalent of the strong acid pyridine hydrofluoride used is more than 1000 equivalents, which is dangerous to operate and difficult to scale up industrially. Summary of the invention

[0005] One of the purposes of the present invention is to provide a method for synthesizing a key intermediate of bruceastatin to solve the above problems.

[0006] In order to achieve the above-mentioned object, the technical solution adopted by the present invention is as follows: a method for synthesizing a key intermediate of a bruceastatin compound, wherein the method comprises dissolving a compound of formula (III) in a reaction solvent under the protection of an inert gas, and then adding a Lewis acid to carry out an intramolecular Prins cyclization reaction to obtain a compound of formula (IV), wherein the reaction formula is:

[0007]

[0008] In the above formula, R 2 A chemical protecting group for hydroxyl selected from H, silicon, alkyl, substituted alkyl, acyl, substituted acyl, aromatic or aromatic substituted by heteroatoms, or one of the synthetic equivalents thereof; R 4 , R 6 , R 7 is selected from one of H, alkyl, substituted alkyl, alkenyl, alkynyl, halogen, amino, phenyl, and substituted phenyl; R 5 is selected from one of an alkyl group or a substituted alkyl group, R 8 is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aromatic, substituted aromatic or aromatic substituted by heteroatoms, R 9 is selected from H, alkyl, substituted alkyl, aromatic or aromatic substituted by heteroatoms, R 10 , R 11 , P 2 One selected from H, alkyl, substituted alkyl;

[0009] P, P 1 , P 3 Each is independently selected from one of H, silicon, alkyl, substituted alkyl, phenyl and substituted phenyl.

[0010] As a preferred technical solution, the Lewis acid is selected from one of trimethylsilyl trifluoromethanesulfonate, 4-methylbenzenesulfonate pyridinium, magnesium bromide ethyl ether, boron trifluoride ethyl ether, titanium tetrachloride, tin tetrachloride, zinc dichloride, aluminum trichloride, bis(perfluorophenyl)(3,4,5-trifluoro-2-methylphenyl)borane, preferably trimethylsilyl trifluoromethanesulfonate;

[0011] The reaction solvent is selected from one of diethyl ether, methyl tert-butyl ether, isopropyl ether, dichloromethane, methanol, tetrahydrofuran and toluene, or a mixture of two of them.

[0012] As a preferred technical solution, the molar ratio of the compound of formula (III) to the Lewis acid is 1:1 to 1:4;

[0013] A further preferred ratio is 1:2; this molar ratio has better economy and operability.

[0014] The concentration of the reaction system is 0.005mol / L~0.05mol / L,

[0015] A further preferred concentration is 0.05 mol / L, at which the yield and selectivity of cis-Z are higher.

[0016] As a preferred technical solution, the reaction temperature is -45°C to -90°C;

[0017] A further preferred temperature is -78°C, at which the yield and the selectivity of cis-Z are higher.

[0018] Under the conditions that the optimal feed ratio of the reaction is determined to be 1:2, and the optimal reaction temperature is -78°C, the reaction concentration can be increased to 50 mmol / L, and the yield is maintained at 82%, while the existing yamaguguchi cyclization concentration is generally 0.34 to 1 mmol / L.

[0019] The second object of the present invention is to provide a method for synthesizing bruceascin compounds, the technical scheme adopted is comprising the following steps:

[0020] (1) Under the protection of inert gas, using the A ring compound of formula (I) and the C ring compound of formula (II) as raw materials, and subjecting them to esterification and acetalization to obtain a compound of formula (III);

[0021]

[0022] (2) under the protection of an inert gas, dissolving the compound of formula (III) in a reaction solvent, and then adding a Lewis acid to react to obtain a compound of formula (IV);

[0023]

[0024] (3) Under the protection of an inert gas, the compound of formula (IV) is subjected to an iodine- and palladium-catalyzed carbonylation reaction to obtain a common intermediate compound of formula (V):

[0025]

[0026] (4) Using the common intermediate compound of formula (V) as a raw material, bryostatin 7 is obtained under the action of Lewis acid and hydrofluoric acid; or after deacetylation of the hydroxyl group at C20 and then hydroxybutyryl protection at C20, bryostatin 9 is obtained under the action of Lewis acid and hydrofluoric acid; or after removing the acetyl protection of the hydroxyl group at C20 and then 4-azidobutyryl reaction of the hydroxyl group at C20, bryostatin 9-N3 analogue is obtained for the first time under the action of Lewis acid and hydrofluoric acid; or after removing the acetyl protection of the hydroxyl group at C20 and then esterifying the hydroxyl group at C20 with octadecanoyl, bryostatin 1 is obtained under the action of Lewis acid and hydrofluoric acid;

[0027] The present invention realizes the divergent synthesis of bruceastatin analogs.

[0028] As a preferred technical solution, in step (1), the reaction concentration is 0.02 mol / L to 0.1 mol / L, preferably 0.05 mol / L.

[0029] As a preferred technical solution, in step (1), the feed ratio of the substances is A-ring compound of formula (I): C-ring compound of formula (II) = 1:1 to 1:2, preferably 1:1 considering the cost.

[0030] As a preferred technical solution, in step (3), the carbonylation reaction temperature is between 60°C and 90°C, preferably 85°C.

[0031] As a preferred technical solution, in step (3), the reaction concentration is between 0.02 mol / L and 0.05 mol / L, preferably 0.025 mol / L.

[0032] As a preferred technical solution, in step (4), the Lewis acid is selected from one of 5wt.% hydrochloric acid, p-toluenesulfonic acid, 4-methylbenzenesulfonate pyridine, trifluoroacetic acid, and triethylsilyl trifluoromethanesulfonate, preferably lithium tetrafluoroborate.

[0033] Compared with the prior art, the advantages of the present invention are as follows: the present invention simultaneously performs acetalization of the C15 aldehyde group through the esterification reaction of the C1 carboxyl group and the C25 hydroxyl group, and then constructs a macrolide skeleton ring-closing strategy through the geminal disilium-mediated stereoselective Prins reaction developed by the applicant, thereby realizing the cis-Z type of the exocyclic double bond of the B ring in the bryostatin skeleton, and Z:E≥95:5. It should be noted that the intramolecular Prins reaction of the present invention saves at least three steps compared with the intermolecular Prins reaction reported in the prior art, and the reaction concentration of the Yamaguchi macrolide reaction as the ring-closing strategy needs to be controlled between 0.34 and 1 mmol / L, while the concentration of the intramolecular Prins reaction developed by the applicant can reach 50 mmol / L. The reaction scale is greatly improved and a large amount of solvent required for the reaction is saved, and the cost is reduced. Therefore, the method of the present invention has higher synthesis efficiency and is more conducive to industrialization; and the reaction conditions of the synthesis method of the present application are mild and can reach a scale of 5 grams or higher. The raw materials used are simple and easy to obtain, such as the esterification of octadienoic acid at the C20 position. The octadienoic acid used in the present application is commercially available and does not need to be homemade, making our synthesis method more practical; the entire synthesis route, the longest linear step of brucestatin 1 is 20 steps, and the total yield is 5.9%, which exceeds the reported yield of 4.8%, an increase of 23%. And after synthesizing the key intermediates, our synthesis route can diverge to synthesize multiple analogs of brucestatin, and the synthesis is more efficient. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 and Figure 2 They are respectively the hydrogen spectrum and carbon spectrum of compound 22 of Example 3 of the present invention;

[0035] Figure 3 and Figure 4 They are respectively the hydrogen spectrum and carbon spectrum of bryocin 7 of Example 4 of the present invention;

[0036] Figure 5 and Figure 6 They are respectively the hydrogen spectrum and carbon spectrum of bryocin 9 of Example 5 of the present invention;

[0037] Figure 7 and Figure 8 They are respectively the hydrogen spectrum and carbon spectrum of bryocin 9-N3 of Example 6 of the present invention;

[0038] Fig. 9 and Fig.10 They are respectively the hydrogen spectrum and carbon spectrum of bryocin 1 of Example 7 of the present invention. DETAILED DESCRIPTION

[0039] The present invention will be further described below in conjunction with the accompanying drawings.

[0040] Embodiment 1:

[0041] The method for synthesizing the C1-C14 fragment of bruceastatin A ring has the following reaction formula:

[0042]

[0043] The specific synthesis steps are:

[0044] 1) At -45°C, under argon protection, lithium perchlorate (10.67 g, 100 mmol, 1.0 eq.) was weighed into a 2L round-bottom flask, 1L of dichloromethane and 660 mL of ether were added as a mixed solvent, and 9-O-benzylquinidine (4.16 g, 10.0 mmol, 10 mol%) and diisopropylethylamine (32.4 g, 250 mmol, 2.5 eq.), (R)-3-((tert-butyldiphenylsilyl)oxy)-5-oxopentanoic acid ethyl ester (40 g, 100 mmol, 1.0 eq.) were added in sequence. ) was dissolved in 200 mL and added to the system. After stirring for 10 minutes, 120 mL of dichloromethane solution of acetyl chloride (14.2 mL, 200 mmol, 2.0 equivalents) was added dropwise to the reaction system at 15 mL / h by means of a syringe pump, and the reaction was continued for 24 hours. After the reaction was completed by TLC detection, brine was added to quench, and dichloromethane was extracted 3-4 times. The organic phase was washed once with brine, dried over anhydrous sodium sulfate, and concentrated to obtain a concentrate of the quaternary lactone compound 2. A sample was taken for H NMR spectrum. The results showed that dr ≥ 95:5, and it was used for the next step without purification.

[0045] Structural identification of compound 2: 1 H NMR (400MHz, CDCl3) δ7.75–7.63(m,4H),7.48–7.35(m,6H),4.57–4.47(m,1 H),4.37–4.26(m,1H),4.02(qd,J=7.2,2.4Hz,2H),3.41(dd,J=16.0,6.0Hz ,1H),2.88(dd,J=16.0,4.4Hz,1H),2.49(dd,J=14.8,5.6Hz,1H),2.42(dd, J=14.8,6.8Hz,1H),2.13–1.92(m,2H),1.17(t,J=7.2Hz,3H),1.04(s,9H); 13 C NMR (150MHz, CDCl3) δ170.5,167.8,135.8,135.8,133.3,133.1,130.0,129.9, 127.8,127.7,68.0,67.5,60.5,43.4,42.3,42.2,26.8,19.3,14.0;IR(neat)cm-1 2963,2940,2863,1836,1733,1470,1113,1090,823,701; HRMS(MALDI,m / z)calcd for C 25 H 32 O5Si(M+Na) + 463.1911, found 463.1916; [α] D 25 =+0.34°(c=1.0in CHCl3);

[0046] 2) At -78°C, under argon protection, draw potassium hexamethyldisilazide (452mL, 452mmol, 5.0 equivalent. 1M in THF) into a round-bottom flask with a syringe, add 400mL of anhydrous tetrahydrofuran, mix and pre-cool; dissolve allyl isobutyrate (61.34g, 478.6mmol, 5.3 equivalent.) in 300mL of tetrahydrofuran, add dropwise through a dropping funnel, and continue stirring for 1 hour after the drop is complete. Then transfer the reaction solution to a tetrahydrofuran (800mL) solution of magnesium bromide ether complex (141g, 541.8mmol, 6.0 equivalent.) pre-cooled at -78°C, and continue stirring for 1 hour. At the same time, the quaternary lactone compound 2 obtained in step 1) (90.3 mmol, 1.0 equivalent) was dissolved in 200 mL of tetrahydrofuran in a 500 mL round-bottom flask, and after precooling at -78°C for 30 minutes, the precooled tetrahydrofuran solution of the quaternary lactone compound 2 was quickly transferred to the above reaction system, and the reaction was continued at -78°C for 20 hours; after the reaction was completed, a saturated aqueous solution of ammonium chloride was added to quench, extracted with ether, dried over anhydrous sodium sulfate, and concentrated to obtain a concentrate of compound 3, which was directly used for asymmetric reduction without purification;

[0047] 3) At room temperature, under argon protection, tetramethylammonium triacetoxyborohydride (114 g, 433.3 mmol, 8.0 eq.) was weighed into a 1L round-bottom flask, and 540 mL of acetonitrile and 540 mL of glacial acetic acid were added in sequence, and stirred until the solid was completely dissolved; the compound 3 concentrate obtained in step 2) (54.2 mmol, 1.0 eq.) was dissolved in 270 mL of acetonitrile, and the tetramethylammonium triacetoxyborohydride solution prepared above was transferred thereto in an ice bath, and after stirring for half an hour, the mixture was moved to room temperature and reacted for 12 hours to complete the reaction; saturated potassium sodium tartrate and sodium bicarbonate were added to quench, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 8:1→4:1) to obtain the reduction product compound 4 (25.7 g), and a sample was taken for nuclear magnetic hydrogen spectrum, and the results showed that dr ≥ 95:5. At this point, the yield of steps 1)-3) was 45%; 1H NMR(400MHz,CDCl3)δ7.68–7.59(m,4H),7.49–7.34(m,6H),6.01–5.79(m,1H),5.31(dd,J=17.2,1.6Hz,1H),5.24(dd,J=10.4,1.6Hz,1H),4.59(d,J=5.2Hz,2H),4.41–4.30(m,1H),4.23–4.12(m,1H),4.00(d,J=10.0Hz,1H),2.78(s,1H),2.66(dd,J=17.2,6.0Hz,1H),2.49(dd,J=17.2,7.2Hz,1H),2.15–2.02(m,1H),1.83–1.65(m,2H),1.49(ddd,J=14.4,10.8,2.4Hz,1H),1.21(s,3H),1.17(s,3H),1.05(s,9H). 13 C NMR(100MHz,CDCl3)δ177.2,170.6,135.6,135.6,133.3,133.1,131.8,130.0,129.9,127.8,127.8,118.5,73.5,71.7,65.3,65.2,46.6,39.7,38.8,37.6,26.8,22.6,19.8,19.0;IR(neat)cm -1 3448,2925,2855,2031,1729,1466,1426,1388,1256,1108,1084,1012,934,887,820,747,703;

[0048] HRMS(MALDI,m / z)calcd for C 30 H 40 O6Si(M+Na) + 547.2492,found 547.2488.

[0049] [α] D 25 =-63.70°(c=0.27in CHCl3);

[0050] 4) Compound 4 (25.36 g, 44.4 mmol, 1.0 eq.) obtained in step 3 was concentrated in a 250 mL round-bottom flask, and 88 mL of diethoxypropane was added under argon protection, and stirred until completely dissolved. D-camphorsulfonic acid (1.03 g, 4.44 mmol, 0.1 eq.) was added under an ice bath, and the mixture was moved to room temperature and continued to react for 12 hours; after the reaction was complete, 100 mL of saturated sodium bicarbonate aqueous solution was added to quench, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and simply purified by concentration column chromatography (eluent: petroleum ether / ethyl acetate = 20:1) to obtain intermediate a (24.63 g), which was directly used in the next step;

[0051] 5) In the glove box, weigh tetrakistriphenylphosphine palladium (2.32 g, 2.02 mmol, 5 mol%) into a 500 mL round-bottom flask, remove it and protect it with argon, dissolve the propylidene-protected intermediate product a (24.63 g, 40.32 mmol, 1.0 eq.) in 160 mL of tetrahydrofuran at room temperature and transfer it to the round-bottom flask, and rinse the remaining raw materials with 4×10 mL; add morpholine (7.05 mL, 80.64 mmol, 2.0 eq.), and continue to react at room temperature for 16 hours; add 1 M hydrochloric acid to quench, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to obtain the intermediate product b concentrate, which is directly used in the next step without purification;

[0052] 6) At room temperature, under argon protection, the concentrate of intermediate product b (38.3 mmol, 1.0 equivalent) was dissolved in 38 mL of toluene in a 100 mL round-bottom flask, and triphenylphosphine (12.05 g, 45.96 mmol, 1.2 equivalent) and 2,2'-disulfide-5,5'-dimethylbipyridine (11.41 g, 45.96 mmol, 1.2 equivalent) were added in sequence, and the mixture was reacted in an oil bath at 30°C for 24 hours; after the reaction of the raw materials was complete, the toluene was directly removed by vacuum concentration, and then appropriate amounts of silica gel and dichloromethane were added, and the sample was mixed with silica gel by a rotary evaporator, and used for dry loading, and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1000:66) to obtain thioester compound 5 (25.63 g), and the yield of steps 4)-6) was 86%;

[0053] The method for the parallel synthesis of iodine hydrocarbon 5B is as follows: (1) Preparation of Grignard reagent: Weigh magnesium chips (15.4 g, 640 mmol, 2.4 equivalents) into a 1000 mL three-necked round-bottom flask, evacuate, bake for 10-15 minutes until uniformly dispersed, replace with argon gas for cooling, add a stirrer and 350 mL of redistilled tetrahydrofuran, add about 0.5 mL of 1,2-dibromoethane and a small amount of bromine at room temperature, blow the outer wall with a hair dryer, and when a large amount of foam appears on the liquid surface, it indicates that the initiation is successful. Transfer to a 60°C oil bath and reflux, then mix the raw material (1-bromovinyl)trimethylsilane (57.3 g, 320 mmol, 1.2 equivalents) and 50 mL of anhydrous tetrahydrofuran, and then add dropwise through a dropping funnel, slowly at first and then quickly, keeping a slightly boiling state, stir for about 2 hours after the addition, let it stand and cool, and set aside for the next step. (2) Epoxy opening: At -45°C, under argon protection, the Grignard reagent prepared in the previous step was added dropwise to a 500 mL tetrahydrofuran solution of (S)-2-(chloromethyl)oxirane (24.67 g, 267 mmol, 1.0 equivalent) and cuprous cyanide (2.39 g, 26.67 mmol, 0.1 equivalent), and stirring was continued after the addition. After the reaction was completed, saturated ammonium chloride solution was added at this temperature to quench the reaction, and the mixture was moved to room temperature and stirred for 30 minutes, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The reaction system was clean and purified by simple column chromatography (eluent polarity: petroleum ether / ethyl acetate = 20:1→10:1) to obtain the product (S)-1-chloro-4-(trimethylsilyl)pent-4-en-2-ol (47.35 g) with a yield of 92%. (3) At room temperature, under argon protection, sodium iodide (180 g, 1.2 mol, 5.0 equivalents) was added to a 2 L round-bottom flask, and the argon was replaced three times. 250 mL of acetone was added to dissolve the sodium iodide, and then a 250 mL acetone solution of (S)-1-chloro-4-(trimethylsilyl)pent-4-en-2-ol (46.26 g, 240 mmol, 1.0 equivalent) was added. After reflux reaction at 80°C for 48 hours, the reaction of the raw materials was detected to be complete, and the mixture was cooled to room temperature. Then, 600 mL of dichloromethane was added to the mixture in an ice bath. Imidazole (32.68 g, 480 mmol, 2.0 equivalents) and triethylsilyl chloride (48.3 mL, 288 mmol, 1.2 equivalents) were added to the reaction system in sequence. With the addition of triethylsilyl chloride, the solution changed from colorless and clear to turbid. Stirring was continued after the addition was completed. After the reaction was completed by TLC detection, ice water was added for quenching, and the product was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent polarity: petroleum ether / ethyl acetate = 1000:1→200:1) to give iodoalkane 5B (87.03 g). The two-step yield was 91%. 1H NMR(400MHz,CDCl3)δ5.72(dd,J=2.8,1.6Hz,1H),5.47(d,J=2.8Hz,1H),3.72–3.56(m,1H),3.25(dd,J=10.0,4.8Hz,1H),3.15(dd,J=10.0,4.8Hz,1H),2.45(ddd,J=14.0,7.6,1.2Hz,1H),2.38(ddt,J=14.0,5.6,1.2Hz,1H),0.98(t,J=8.0Hz,9H),0.63(q,J=8.0Hz,6H),0.11(s,9H). 13 CNMR(150MHz,CDCl3)δ147.8,128.3,70.2,43.9,14.5,6.9,5.1,-1.3;IR(neat)cm -1 2954,2911,2878,1246,1091,1042,1005,934,834,729,690;HRMS(MALDI,m / z)calcd forC 14 H 31 IOSi2(M+Na) + :421.0850,found 421.0849;[α] D 25 =+0.99°(c=1.0in CHCl3);

[0054] 7) At room temperature, under argon protection, weigh the thioester compound 5 (12 g, 17.7 mmol, 1.0 eq.) and the iodide compound 5B (8.46 g, 21.24 mmol, 1.2 eq.) in 36 mL 1,3-Dimethyl-2-imidazolidinone was dissolved in a 500 mL round-bottom flask, and then 2,6-di-tert-butyl-4-methylpyridine (14.53 g, 70.8 mmol, 4.0 eq.) was added. Zirconocene dichloride (15.52 g, 53.1 mmol, 3.0 eq.) and zinc powder (6.95 g, 106.2 mmol, 6.0 eq.) were weighed in the glove box, and then NiBr2·dtbbpy (2.59 g, 5.31 mmol, 30 mol%) was added in the glove box. After the addition was completed, the color of the solution changed from green to brown after 5-10 minutes. The solution was removed from the glove box and cooled to room temperature. The argon gas was replaced 2-3 times, and the mixture was stirred vigorously for 32 hours. The solution was observed to continue to deepen and turn from dark red brown to black. After the reaction, 2 mL of saturated sodium bicarbonate aqueous solution was added to quench the reaction, and a few milliliters of ethyl acetate were added. The salt produced after quenching was simply filtered off through diatomaceous earth and rinsed with ethyl acetate. 20 mL of saturated sodium bicarbonate aqueous solution was added to the collected filtrate, and the mixture was extracted with ethyl acetate for 3-4 times, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 500:1→200:1→100:1) to obtain the coupling product compound 6 (11.10 g), with a yield of 76%.

[0055] 8) At room temperature, under argon protection, the compound 6 (25.93 g, 31.42 mmol, 1.0 eq.) obtained in step 7) was dissolved in 1260 mL of methanol in a 2 L round-bottom flask, 315 mL of trimethyl orthoformate was added, and pyridine p-toluenesulfonate (39.48 g, 0.157 mol, 5.0 eq.) was added in three batches under ice bath. After the addition, the mixture was moved to a 30°C oil bath for reaction for 24 hours. After TLC detection, the reaction was complete, and saturated sodium bicarbonate aqueous solution was added under ice bath for quenching. Stirring was continued for half an hour until the reaction was fully quenched. The aqueous phase was extracted 4-5 times with petroleum ether / ethyl acetate (1:1), and the organic phase was dried over anhydrous sodium sulfate. After concentration, the mixture was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 20:1→10:1) to obtain compound 7 (18.51 g), with a yield of 86%;

[0056] 9) Under argon protection, compound 7 (17.07 g, 24.92 mmol, 1.0 eq.) was weighed and dissolved in a dried 1000 mL round-bottom flask with 250 mL of dichloromethane. Triethylamine (4.16 mL, 29.9 mmol, 1.2 eq.) and pyridine tribromide (9.56 g, 29.9 mmol, 1.2 eq.) were added in turn in an ice bath. Triethylamine and pyridine tribromide were added until the reaction of the raw materials was complete. 250 mL of methanol and 1N sodium hydroxide aqueous solution (250 mL) were added at room temperature, and the mixture was moved into an 80°C oil bath and continued to react for 12 hours. After the raw materials were completely converted, 1M hydrochloric acid aqueous solution was added in an ice bath to acidify to pH 6-7, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to obtain compound 8, which was directly used in the next step without purification.

[0057] 10) Under argon protection, the concentrate of compound 8 obtained in step 9) (step 9) with a yield of 88%, 21.93 mmol, 1.0 eq.) was dissolved in 220 mL of dichloromethane in a 500 mL round-bottom flask taken out of the oven, ice-bathed for 10 minutes, and 4-dimethylaminopyridine (5.36 g, 43.86 mmol, 2.0 eq.) and acetic anhydride (2.47 mL, 26.32 mmol, 1.2 eq.) were added in sequence, and the reaction was continued at this temperature for 0.5 hours; after the reaction was complete, argon was still used for protection, and imidazole (17.92 g, 263.16 mmol, 12.0 eq.) was added under ice-bath, and triethylsilyl chloride (22.08 mL, 131.58 mmol, 6.0 eq.) was slowly added, and it can be seen that the reaction solution changed from clear to turbid. After the addition, the mixture was moved to room temperature and the reaction was continued for 30 minutes. After the reaction was complete as detected by TLC, 200 mL of saturated aqueous ammonium chloride solution was added to quench the mixture. After stirring for 5-10 minutes, the mixture was extracted with dichloromethane 3-4 times, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 15:1→5:1) to obtain compound 9 (12.87 g), with a yield of 63%;

[0058] 11) Under argon protection, the product compound 9 (6.1 g, 7.44 mmol, 1.0 eq.) of step 10) and 1,3-bis(diphenylphosphinopropane)nickel dichloride (403 mg, 0.744 mmol, 10 mol%) were dissolved in 298 mL of ether in a 500 mL round-bottom flask, and freshly prepared (bis(trimethylsilyl)methyl)magnesium chloride (51 mL, 29.76 mmol, 4.0 eq., based on a titration concentration of 0.59 M) was slowly added in an ice bath; after the addition, a spherical condenser was installed, argon was replaced 2-3 times, and the mixture was moved to a 45°C oil bath for reaction for 2 hours; after the reaction, a saturated aqueous ammonium chloride solution was added, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 15:1→6:1) to obtain a light yellow viscous liquid compound 10 (6.02 g), with a yield of 90%; 1 H NMR (600MHz, CDCl3) δ7.77–7.62(m,4H),7.50–7.32(m,6H),4.97(dd,J=11.4,4.8Hz,1H),4.66(s,1H),4.55(s,1H),4.29–4.21(m, 1H),4.18–4.10(m,1H),3.29–3.19(m,1H),2.96(s,3H),2.68(dd,J=15.0,3.6Hz,1H),2.52(dd,J=15.0,7.2Hz,1H),2.19(dd,J=16. 2,3.6Hz,1H),2.05(dd,J=15.6,7.2Hz,1H),2.01(s,3H),1.94–1.79(m,2H),1.73(dd,J=15.6,7.8Hz,1H),1.55(ddd,J=13.8,6.0, 3.6Hz,1H),1.32(ddd,J=12.6,4.8,3.0Hz,1H),1.02(s,9H),0.99–0.85(m,16H),0.79(s,1H),0.57(q,J=7.9Hz,6H),0.06(s,18H). 13 CNMR (150MHz, CDCl3) δ176.2,170.6,146.6,135.9,135.8,133.7,133.1,129.8,129.8,127.6,127.6,107.6,104.4,74 .0,68.8,67.4,65.5,50.8,48.2,43.3,42.5,41.7,39.9,32.5,29.7,26.8,21.2,20.8,19.2,17.2,7.1,5.5,0.5,0.3.

[0059] IR(neat)cm-1 3078,3051,2956,2877,2861,1744,1709,1618,1470,1428,1390,1367,1246,1105,1075,1025,968,865,839,740,702.

[0060] HRMS (MALDI, m / z) calculation for C 48 H 82 O8Si4(M+Na) + 921.4979, found 921.4977.

[0061] [α] D 25 =+25.04°(c=1.97in CHCl3);

[0062] The comprehensive yield of all the above steps is 14.3%.

[0063] Example 2

[0064] The C-ring fragment of bruceidin was synthesized by the following reaction formula:

[0065]

[0066] The specific reaction steps are:

[0067] (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.

[0068] (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, and then the crude compound obtained in the previous step was diluted with 800 mL of anhydrous acetone and added to the round-bottom flask, and reacted at 75° C. for 36 hours. After 36 hours, the reaction was completed, and the reaction system was cooled to room temperature, and then imidazole (17.0 g, 250 mmol, 2.5 eq.) was added to the reaction system, and then 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. Stirring was continued at room temperature for 12 hours. After 12 hours, the reaction was completed, and water was added to quench, and the mixture was extracted with dichloromethane and dried over anhydrous sodium sulfate. After concentration, simple purification by column chromatography (eluent: petroleum ether) was performed to obtain compound 12 (22.1 g), with a two-step yield of 65%; E / Z ≥ 95:5;

[0069] The structural identification data of the obtained compound 12: Rf = 0.5 (EA / Petroleum ether = 2%),

[0070] 1H 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); 13C NMR(150MHz, CDCl3)δ128.6,126.1,71.5,40.1,18.0,13.5,6.8,4.9; IR(neat)cm-1301 9,2955,2911,2879,1457,1416,1178,1057,1009,968,880,734; HRMS(MALDI,m / z)calcd for C12H25IOSi(M+H)+341.0792,found 341.0790;[α]D20=-45.29o(c=12.1in CHCl3);

[0071] 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%;

[0072] The structural identification data of the obtained compound 12b: Rf = 0.6 (EA / Petroleum ether = 20%).

[0073] 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); 13C 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-12970,2846,1694,1611,1512,1300,1245,1175,1036,977,818; HRMS(MALDI,m / z)calcd for C17H22O3(M+Na)+297.1461,found297.1463;

[0074] (3) At room temperature, 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, , irradiate the flow reactor with a blue LED light (hv=427-440nm) at a distance of 1cm; collect the product and directly concentrate it under reduced pressure to remove acetonitrile, then add appropriate amount of silica gel and dichloromethane, mix the sample with silica gel by means of a rotary evaporator, use it for dry loading, and purify it by column chromatography (eluent: petroleum ether / ethyl acetate=50:1) to obtain coupling compound 13 (5.7g), with a yield of 78%, and 5.7g of coupling compound 13 can be obtained in a single cycle of flow chemistry. Finally, 200g of coupling compound 13 is finally prepared through multiple cycles;

[0075] The structural identification data of the compound 13 are as follows: Rf = 0.5 (EA / Petroleum ether = 10%),

[0076] 1H 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 13C 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-12954,2877,1709,1613,1513,1461,1362,1247,1098,1011,974,821,737;HRMS(MALDI,m / z)calcd for C29H48O4Si(M+Na)+511.3214,found511.3210;[α]D19.9=-60o(c=5.9in CHCl3);

[0077] (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;

[0078] (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%;

[0079] (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. Saturated ammonium chloride solution was slowly quenched, extracted with ether, dried over anhydrous sodium sulfate, concentrated, and then 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;

[0080] (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.

[0081] (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 monitored that the compound had been completely converted. Saturated sodium bicarbonate was slowly added to quench the reaction. 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). The yield of the two steps was 88%.

[0082] (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.

[0083] (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%;

[0084] (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;

[0085] (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.

[0086] The structural identification data of the compound 19b are as follows: Rf = 0.5 (EA / Petroleum ether = 30%),

[0087] 1H NMR (400MHz, CDCl3) δ9.56(d,J=8Hz,1H),7.32(d,J=16Hz,1H),5.93(dd,J=16,8H z,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); 13C NMR (150MHz, CDCl3) δ194.7,168.7,167.2,166.4,151.5,126.6,117.7,102. 3,71.99,71.61,71.47,68.6,51.4,51.2,47.4,40.3,32.7,25.8,23.9,21.6, 21.2,20.3,18.0,-4.2,-4.8;IR(neat)cm-13538,2952,2858,2173,1751,172 1,1687,1437,1372,1227,1153,1102,1077,884,836; HRMS(MALDI,m / z)calcd for C27H46O9Si(M+Na)+565.2803, found 565.2804; [α]D20.1=-13.09o(c=1.1in CHCl3).

[0088] The comprehensive yield of all the above steps in this example is 18.5%.

[0089] Example 3

[0090] The common intermediate of bruceastatin is synthesized by the following reaction steps:

[0091]

[0092] (1) Under argon protection, compound 10 (6.01 g, 6.68 mmol, 1.0 equivalent) obtained in Example 1 was dissolved in 134 mL of toluene (0.05 M) and precooled in an ice bath for 10 minutes. Triethylamine (5.57 mL, 40.08 mmol, 6.0 equivalent) and 2,4,6-trichlorobenzoyl chloride (1.88 mL, 12.02 mmol, 1.8 equivalent) were then added dropwise. After the addition, the mixture was moved to room temperature for reaction for 2 hours. The reaction system was again precooled in an ice bath. Meanwhile, compound 19b (3.63 g, 6.68 mmol, 1.0 equivalent) obtained in Example 2 and 4-dimethylaminopyridine (2.45 g, 20.04 mmol, 3.0 equivalent) were dissolved in 104 mL of toluene and stirred until completely dissolved. The mixture was slowly added to the above reaction system through a syringe. The clear solution gradually became turbid and was rinsed with toluene 3 times, 10 mL each time. After the addition was completed, the reaction was allowed to proceed for 12 hours. After TLC detected that the reaction was complete, ice water was slowly added in an ice bath to quench the reaction. The mixture was extracted with petroleum ether / ethyl acetate = 2:1 (50 mL×4), dried over anhydrous sodium sulfate, and concentrated for the next step. Take a 500mL round-bottom flask, dissolve the concentrate in 267mL methanol (0.025M), add trimethyl orthoformate (5.34mL) and pyridine p-toluenesulfonate (8.39g, 33.4mmol, 5.0 equivalents) under ice bath, and react at room temperature for 20 hours. After TLC detection, add 100mL saturated sodium bicarbonate aqueous solution under ice bath to quench, extract the aqueous phase with petroleum ether / ethyl acetate = 2:1 (50mL×4), dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography (eluent: petroleum ether / ethyl acetate = 25:1→18:1) to obtain a white foamy substance, namely compound 21 (7.7g), with a two-step yield of 85%;

[0093] (2) Under argon protection, compound 21 (7.7 g, 5.68 mmol, 1.0 equivalent) obtained in step (1) was dissolved in 99 mL of anhydrous ether, placed in a 250 mL round-bottom flask, and precooled in a -78°C cold bath for 10 minutes; redistilled purified trimethylsilyl trifluoromethanesulfonate (2.06 mL, 11.36 mmol, 2.0 equivalent) was dissolved in 15 mL of anhydrous ether and transferred to the ether solution of compound 21 via a syringe. The mixture was reacted at this temperature for 2 hours, and the solution changed from colorless and clear to light yellow and slightly turbid; after the reaction was completed by TLC detection, 100 mL of saturated sodium bicarbonate aqueous solution was added to quench the reaction, and the solution became colorless and clear again. The aqueous phase was extracted 3-4 times with petroleum ether / ethyl acetate = 2:1, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 30:1→20:1) to obtain a white foamy product, namely compound 22 (4.99 g) (cis-Z ≥ 95:5), with a yield of 72%;

[0094] Structural identification of compound 22:1 H NMR(400MHz,CDCl3)δ7.73–7.58(m,4H),7.42–7.32(m,6H),6.15(d,J=15.6Hz,1H),5.92(d,J=1.6Hz,1H),5.36–5.26(m,3H),5.18(dd,J=11.7,4.8Hz,1H),5.14(s,1H),4.57(tt,J=10.4,2.4Hz,1H),3.95–3.85(m,1H),3.85–3.77(m,1H),3.72–3.57(m,6H),3.51(tt,J=10.8,2.8Hz,1H),3.03(s,3H),2.71(s,3H),2.52(dd,J=17.2,3.2Hz,1H),2.31(dd,J=13.6,2.4Hz,1H),2.17(dd,J=17.2,10.0Hz,1H),2.11–1.96(m,10H),1.95–1.64(m,4H),1.50(d,J=16.4Hz,1H),1.36–1.17(m,3H),1.08(s,3H),1.06(s,3H),1.03(s,9H),0.92(s,3H),0.89(d,J=5.2Hz,3H),0.86(s,9H),0.81(s,3H),0.15(s,9H),0.03(s,3H),0.03(s,3H); 13 C NMR(150MHz,CDCl3)δ170.7,169.7,169.1,166.8,154.7,151.5,138.6,135.8,135.7,134.7,133.7,129.7,129.6,127.7,127.6,127.2,122.3,119.1,102.9,102.9,79.1,73.9,73.7,73.1,71.1,67.7,67.4,66.8,64.6,53.1,51.1,47.9,45.5,45.2,44.6,42.8,41.4,40.7,40.0,34.2,33.9,30.8,26.9,26.0,25.7,21.4,21.3,20.6,20.2,19.2,17.9,17.7,17.4,0.4,-4.6,-4.8.

[0095] IR(neat)cm -12950,2901,2859,1737,1665,1620,1466,1432,1369,1235,1156,1096,1026,976,877,837,756,706; HRMS(MALDI,m / z)calcd for C 66 H 102 O 15 Si3(M+Na) + 1241.6419, found 1241.6418; NMR spectrum see Figure 1 and Figure 2 ;

[0096] (3) In an ice bath, under argon protection, compound 22 (4.99 g, 4.09 mmol, 1.0 equivalent) obtained in step (2) was dissolved in 140 mL of anhydrous acetonitrile and placed in a 500 mL round-bottom flask. The outer wall was wrapped with tin foil to protect the reaction from light; N-iodosuccinimide (2.25 g, 9.98 mmol, 2.0 equivalent) was prepared into a solution with 70 mL of anhydrous acetonitrile and slowly added to the reaction system; after 2 hours, after TLC detection of no residual raw materials, 80 mL of saturated sodium thiosulfate aqueous solution and 100 mL of petroleum ether / ethyl acetate (1:1) were added, and stirring was continued at room temperature for 30 minutes; the organic phase was separated and collected, and the aqueous phase was washed 3-4 times with petroleum ether / ethyl acetate (1:1), and the organic phases were combined and dried over anhydrous sodium sulfate. After concentration, the salt was filtered by rapid column chromatography, and 400 mL of petroleum ether / ethyl acetate (4:1) was used as the eluent to quickly flush the column and concentrate for the next step; at room temperature, under argon protection, bisacetonitrile palladium chloride (106 mg, 0.409 mmol, 10 mol%) and 1,1'-bis(diphenylphosphino)ferrocene (682 mg, 1.23 mmol, 30 mol%) were weighed and added to a dried 250 mL round-bottom flask, and 54 mL of N,N-dimethylformamide, 27 mL of methanol and 0.81 mL of triethylamine were added respectively, and stirred until the solid was completely dissolved; the above concentrate was added to the In the solution, CO was replaced three times under an ice bath; after completion, the mixture was moved to an 85°C oil bath and stirred overnight under a CO protection environment; after 12 hours, the reaction of the raw material was completed, the oil bath was removed, 80 mL of brine and 40 mL of petroleum ether / ethyl acetate (1:1) were added under an ice bath to quench the reaction, and the aqueous phase was extracted 3-4 times with petroleum ether / ethyl acetate (1:1), and the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 25:1→15:1) to obtain a white foam (4.2 g), with a two-step yield of 85%, that is, the common intermediate compound 23 was obtained;

[0097] Structural identification data of compound 23: 1H NMR(600MHz,CDCl3)δ7.68–7.57(m,4H),7.45–7.33(m,6H),6.18(d,J=16.2Hz,1H),5.92(d,J=2.4Hz,1H),5.72(t,J=1.8Hz,1H),5.35–5.26(m,2H),5.18(dd,J=11.4,4.8Hz,1H),5.14(s,1H),4.50(tt,J=10.2,2.0Hz,1H),3.93(ddd,J=11.4,7.2,2.4Hz,1H),3.84(tt,J=12.0,9.0,2.4Hz,1H),3.71(s,3H),3.69–3.62(m,7H),3.49(tt,J=11.4,2.4Hz,1H),3.00(s,3H),2.73(s,3H),2.51(dd,J=17.4,3.0Hz,1H),2.16(dd,J=17.4,10.2Hz,1H),2.11–2.04(m,4H),2.03(s,3H),2.02(s,3H),1.90–1.85(m,1H),1.85–1.79(m,1H),1.74(ddd,J=14.0,11.3,2.4Hz,1H),1.68–1.65(m,1H),1.52(d,J=16.2Hz,1H),1.31–1.19(m,3H),1.07(s,3H),1.05(s,3H),1.03(s,9H),0.92(s,3H),0.89(d,J=6.0Hz,3H),0.87(s,9H),0.81(s,3H),0.02(s,3H),0.02(s,3H); 13 C NMR(150MHz,CDCl3)δ170.7,169.9,169.1,166.8,166.7,158.3,151.5,139.2,135.8,135.7,134.6,133.7,129.7,129.7,127.7,127.6,126.6,119.1,114.1,102.8,102.8,78.5,73.8,73.5,72.5,71.4,67.9,67.5,66.8,64.7,52.9,51.1,50.9,47.7,45.2,44.6,42.5,42.4,41.4,39.8,36.4,34.2,33.8,30.7,26.9,26.2,25.7,21.4,21.2,20.6,20.2,19.2,18.0,17.8,17.3,-4.9;IR(neat)cm -12948,2897,2859,2160,1727,1655,1466,1434,1371,1235,1156,1101,1027,878,831,775,706; HRMS(MALDI,m / z)calcd for C 65 H 96 O 17 Si2(M+Na) + 1227.6078, found 1227.6082.

[0098] Example 4

[0099] Synthesis of bryostatin 7: Weigh lithium tetrafluoroborate (149 mg, 1.59 mmol, 46 equivalents) into a PP test tube, add 6.25 mL acetonitrile and 0.25 mL pure water, stir until clear, and a 0.25 M lithium tetrafluoroborate acetonitrile / water solution can be obtained. The common intermediate compound 23 (41.6 mg, 0.0345 mmol, 1.0 equivalent) was added to the above solution, and the mixture was moved to an 86°C oil bath for reaction for 2 hours; the mixture was removed from the oil bath and cooled to room temperature, and imidazole (893 mg, 13.12 mmol, 380 equivalent) and 40% hydrofluoric acid aqueous solution (285 uL, 6.56 mmol, 190 equivalent) were added in sequence, and the mixture was placed in an oil bath at 40°C for reaction for 24 hours; after the reaction, ice water was added at room temperature to quench the mixture, and petroleum ether / ethyl acetate (1:1) was used to extract the mixture 3-4 times; the organic phase was washed with 1M hydrochloric acid and saturated sodium bicarbonate aqueous solution in sequence, and the aqueous phase of the organic phase was extracted with petroleum ether / ethyl acetate (1:1) twice, and the organic phases were combined and dried over anhydrous sodium sulfate. After concentration, the mixture was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 2:1 → 1:1) to obtain 14.5 mg of bryostatin 7 as a white paste with a yield of 51%. 1HNMR(600MHz,CDCl3)δ5.97(d,J=2.4Hz,1H),5.77(d,J=16.2Hz,1H),5.68(t,J=1.8Hz,1H),5.32(dd,J=15.6,8.4Hz,1H),5.18(s,1H),5.19–5.14(m,1H),5.15(dd,J=12.0,4.8Hz,1H),5.10(s,1H),4.24(d,J=12.0Hz,1H),4.20(tt,J=12.0,3.0Hz,1H),4.17–4.10(m,1H),4.07(ddd,J=11.4,8.4,2.4Hz,1H),4.00(tt,J=11.4,2.4Hz,1H),3.87(ddd,J=11.4,7.2,2.4Hz,1H),3.77(h,J=6.6Hz,1H),3.70(s,3H),3.68(s,3H),3.69–3.63(m,2H),3.05(s,1H),2.53–2.42(m,2H),2.37(d,J=7.6Hz,1H),2.21(d,J=12.7Hz,1H),2.07(s,3H),2.05(s,3H),2.11–1.98(m,4H),1.98–1.93(m,1H),1.93–1.87(m,1H),1.82(ddd,J=14.4,11.4,3.0Hz,1H),1.74(ddd,J=12.6,4.8,2.8Hz,1H),1.68–1.64(m,1H),1.57(dt,J=15.0,3.6Hz,1H),1.48(q,J=12.0Hz,1H),1.23(d,J=6.4Hz,3H),1.15(s,3H),1.00(s,6H),0.94(s,3H). 13 C NMR(150MHz,CDCl3)δ172.3,171.0,169.3,167.0,166.7,156.7,151.6,139.0,129.6,119.7,114.3,101.8,98.8,79.1,74.4,73.7,72.8,71.5,70.2,68.4,65.7,64.7,51.1,51.1,44.8,44.1,42.2,41.9,41.0,39.8,36.4,35.9,33.3,31.2,24.6,21.5,21.2,21.1,19.8,19.8,16.8;IR(neat)cm -13462,3364,2972,2956,2926,2854,1740,1721,1652,1439,1412,1371,1276,1265, 1230,1162,1097,1082,1040,1033,987,861,762,751,703; HRMS(MALDI,m / z)calcd for C 41 H 60 O 17 (M+Na) + 847.3723, found 847.3721; NMR spectrum see Figure 3 and Figure 4 .

[0100] Example 5

[0101] Synthesis of bryostatin 9: 1) Under argon protection, at room temperature, weigh the key intermediate product (42.7 mg, 0.354 mmol, 1.0 equivalent) in a 10 mL test tube, dissolve it in 3.5 mL of methanol, add potassium carbonate (24.5 mg, 0.177 mmol, 5.0 equivalent), and continue stirring at room temperature for 1 hour. After TLC detection of the complete reaction of the raw material, add 5 mL of saturated aqueous ammonium chloride to quench the reaction, extract with petroleum ether / ethyl acetate (1:1) 3-4 times, dry with anhydrous sodium sulfate, and concentrate for the next step; 2) Under argon protection, dissolve the concentrate in the previous step in 10 mL test tube with 1.2 mL of dichloromethane and place it in an ice bath. 4-Dimethylaminopyridine (4.3 mg, 0.0354 mmol, 1.0 equivalent) and pyridine (28.6 uL, 0.354 mmol, 10 equivalent) were added in sequence. After the solid was completely dissolved, butyric anhydride (29 uL, 0.177 mmol, 5 equivalent) was added dropwise, and the mixture was moved to room temperature and continued to react for 4 hours. After TLC detection of the reaction was complete, 2 mL of saturated aqueous ammonium chloride solution was added to quench the reaction, and the aqueous phase was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 20:1) to obtain 32.4 mg of white foamy substance, with a yield of 74%. 3) The product of the previous step (18.7 mg, 0.0152 mmol, 1.0 equivalent) was used as a raw material. For specific experimental operations, see the synthesis of bryostatin 7. The concentrate was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to obtain 9.5 mg of bryostatin 9 as a white film, with a yield of 73%. 1HNMR(600MHz,CD3OD)δ5.87(d,J=2.4Hz,1H),5.87(d,J=15.6Hz,1H),5.75(t,J=1.2Hz,1H),5.33(dd,J=15.6,8.4Hz,1H),5.22(dd,J=11.4,4.8Hz,1H),5.21(ddd,J=12.6,4.2,3.0Hz,1H),5.10(s,1H),4.24(tt,J=12.0,3.0Hz,1H),4.14–4.06(m,2H),4.01–3.93(m,2H),3.83(qd,J=6.6,2.4Hz,1H),3.68(s,3H),3.67(s,3H),3.64(dd,J=7.2,2.4Hz,1H),3.62(dd,J=7.2,2.4Hz,1H),2.59–2.53(m,2H),2.39–2.25(m,2H),2.21–2.16(m,2H),2.09–2.03(m,2H),2.02(s,3H),1.97(ddd,J=13.8,12.6,2.4Hz,1H),1.88(ddd,J=13.8,11.4,2.4Hz,1H),1.85–1.76(m,2H),1.74–1.66(m,3H),1.65(dd,J=7.2,3.0Hz,1H),1.62(dd,J=7.2,3.0Hz,1H),1.46(q,J=12.0Hz,1H),1.19(s,3H),1.14(d,J=5.4Hz,3H),1.01(s,6H),0.92(s,3H),0.92(t,J=7.2Hz,3H). 13 C NMR(150MHz,CDCl3)δ172.4,172.0,171.0,167.0,166.8,156.9,151.8,139.1,129.6,119.6,114.2,101.8,98.9,79.1,74.2,73.7,72.9,71.5,70.2,68.4,65.7,64.7,51.1,51.1,44.8,44.1,42.2,41.9,41.0,39.8,36.5,36.4,35.9,33.3,31.2,24.6,21.1,21.1,19.8,19.8,18.2,16.8,13.6;IR(neat)cm -13471,3354,2964,2932,2860,1737,1721,1657,1463,1435,1379,1367,1282,125 8,1250,1158,1101,1081,1061,1029,1001,985,860,800; HRMS(MALDI,m / z)calcd for C 43 H 64 O 17 (M+Na) + 875.4036, found 875.4037; NMR spectrum see Figure 5 and Figure 6 .

[0102] Example 6

[0103] Synthesis of brucestatin 9-N3 analogs: 1) The concentrate obtained by removal of C20 hydroxyacetyl protection and 4-azidobutyrylation was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 22:1→12:1) to obtain 63.1 mg of white foamy substance, yield: 99%; 2) The product of the previous step (51 mg, 0.04 mmol, 1.0 eq.) was used as a raw material. For specific experimental operations, see the synthesis of brucestatin 7. The concentrate was purified by column chromatography to obtain 23.2 mg of a white film-like brucestatin 9-N3 analog, with a yield of 65%. 1HNMR(600MHz,CD3OD)δ5.88(d,J=2.4Hz,1H),5.87(d,J=15.6Hz,1H),5.75(d,J=1.2Hz,1H),5.33(dd,J=15.6,8.4Hz,1H),5.24–5.17(m,2H),5.11(s,1H),4.24(tt,J=12.0,3.0Hz,1H),4.14–4.06(m,2H),4.01–3.92(m,2H),3.83(qd,J=6.6,2.4Hz,1H),3.68(s,3H),3.67(s,3H),3.64(dd,J=9.0,2.4Hz,1H),3.62(dd,J=9.0,2.4Hz,1H),3.35(td,J=6.6,1.2Hz,2H),2.56(d,J=7.2Hz,2H),2.48–2.39(m,2H),2.18(d,J=6.0Hz,2H),2.11–2.03(m,2H),2.02(s,3H),1.97(ddd,J=14.4,12.0,2.4Hz,1H),1.91–1.85(m,3H),1.84–1.78(m,2H),1.75–1.65(m,3H),1.46(q,J=12.0Hz,1H),1.19(s,3H),1.15(d,J=6.6Hz,3H),1.02(d,J=4.5Hz,6H),0.92(s,3H). 13 C NMR(150MHz,CD3OD)δ171.8,171.4,171.1,167.0,166.6,157.5,151.5,139.1,129.3,119.2,113.5,101.2,98.8,79.2,74.3,73.0,72.3,72.3,68.8,67.9,65.3,64.9,50.3,50.2,50.0,44.4,43.6,41.5,41.4,41.1,40.0,36.1,34.7,33.2,31.0,31.0,23.8,23.7,19.9,19.6,18.7,17.4,15.8;IR(neat)cm - 1 3462,3348,2975,2953,2918,2858,2105,1717,1660,1439,1367,1245,1162,1093,1082,1059,1037,1002,987,858,812,736;HRMS(MALDI,m / z)calcd for C 43 H 63N3O 17 (M+Na) + 916.4050, found 916.4050; NMR spectrum Figure 7 and Figure 8 .

[0104] Example 7

[0105] Synthesis of brucestatin 1: 1) The key intermediate product (3.74 g, 3.1 mmol, 1.0 equivalent) was used as the raw material. The specific experimental operation of removing the hydroxyacetyl protection at the C20 position was detailed in the synthesis of the precursor compound of brucestatin 9. The obtained concentrate was directly used in the next step without purification; 2) Under argon protection, octadienoic acid (826 mg, 5.89 mmol, 1.9 equivalent) was dissolved in 62 mL of toluene in a 250 mL round-bottom flask. In an ice bath, triethylamine (1.3 mL, 9.3 mmol, 3.0 equivalent) and 2,4,6-trichlorobenzoyl chloride (1.45 mL, 9.3 mmol, 3.0 equivalent) were added dropwise in turn. After the addition, the mixture was moved to room temperature for reaction for 1 hour. Precool in an ice bath. Meanwhile, the concentrate from the previous step and 4-dimethylaminopyridine (947 mg, 7.75 mmol, 2.5 equivalents) were dissolved in 50 mL of toluene, transferred to the precooled reaction system with the aid of a syringe, and slowly added. The clear solution in the reaction system gradually became turbid, and the remaining raw materials were rinsed with 3×4 mL. After the addition, the mixture was moved to room temperature for reaction for 12 hours. After the reaction was complete, ice water was added to quench the mixture in an ice bath, and the mixture was extracted 3-4 times with petroleum ether / ethyl acetate (1:1). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 30:1→15:1) to obtain 3.95 g of a white foamy substance with a yield of 99%. 3) The product from the previous step (3.05 g, 2.37 mmol, 1.0 equivalent) was used as a raw material. For the specific experimental operation, see the synthesis of bryostatin 7. The concentrate was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 3:1→2:1) to obtain 1.5 g of bryostatin 1 as a white solid. The yield was 70%. 1H NMR(600MHz,CDCl3)δ7.27(dd,J=15.0,10.2Hz,1H),6.20–6.12(m,2H),6.01(d,J=2.4Hz,1H),5.80(d,J=15.3Hz,1H),5.78(d,J=15.8Hz,1H),5.67(t,J=1.8Hz,1H),5.31(dd,J=16.2,8.4Hz,1H),5.18(s,1H),5.20–5.14(m,2H),5.17(s,1H),4.24(d,J=11.4Hz,1H),4.20(tt,J=11.4,2.8Hz,1H),4.18–4.10(m,1H),4.07(ddd,J=11.4,8.4,2.4Hz,1H),4.01(tt,J=11.4,2.4Hz,1H),3.90(ddd,J=10.8,7.2,2.4Hz,1H),3.81–3.74(m,1H),3.70(s,3H),3.69–3.68(m,1H),3.66(s,3H),3.66–3.62(m,1H),3.26(s,1H),2.56(s,1H),2.50(t,J=12.0Hz,1H),2.44(dd,J=12.6,2.4Hz,1H),2.20(t,J=12.0Hz,1H),2.17–2.12(m,2H),2.11–1.93(m,5H),2.05(s,3H),1.89(dd,J=15.0,10.2Hz,1H),1.82(ddd,J=14.4,11.4,3.0Hz,1H),1.73(ddd,J=12.6,4.8,2.4Hz,1H),1.66(d,J=15.0Hz,1H),1.57(dt,J=15.0,3.0Hz,1H),1.49(q,J=12.6Hz,1H),1.45(h,J=7.2Hz,2H),1.23(d,J=6.6Hz,3H),1.15(s,3H),1.00(s,6H),0.94(s,3H),0.91(t,J=7.2Hz,3H). 13C NMR (150MHz, CDCl3) δ172.3,171.1,167.0,166.8,165.6,156.9,152.0,146.4,145 .5,139.1,129.5,128.4,119.6,118.6,114.2,101.8,99.0,79.1,74.1,73.7,72.9, 71.5,70.1,68.4,65.7,64.7,51.1,51.1,44.9,44.2,42.2,41.9,41.0,39.8,36.4, 35.9,35.0,33.3,31.3,24.6,21.8,21.1,21.1,19.8,19.7,16.8,13.7;IR(neat)cm -1 3475,3459,3281,3012,2960,2931,2860,1733,1721,1697,1649,1640,1612,1443,1439,1409,1384,1367,1349,1323,1289 ,1258,1159,1101,1093,1080,1063,1025,1009,987,969,939,926,876,868,796,768,751,755,711; HRMS(MALDI,m / z)calcd for C 47 H 68 O 17 (M+Na) + 927.4349, found 927.4347; NMR spectrum Fig. 9 and Fig.10 .

[0106] Embodiment 8-12:

[0107] Compared with Example 3, the concentration of the reaction system in step (1) was adjusted from 0.05 mol / L to 0.02 mol / L, 0.04 mol / L, 0.06 mol / L, 0.08 mol / L and 0.1 mol / L, respectively, and the rest was the same as step (1) of Example 3. The corresponding yields were 40%, 65%, 78%, 64% and 44%, respectively.

[0108] Examples 13-15

[0109] Compared with Example 3, the material feed ratio of A ring compound: C ring compound = 1:1 in step (1) was adjusted to 1:1.2, 1:1.5, and 1:2, respectively. The rest was the same as step (1) of Example 3, and the corresponding yields were 84%, 85%, and 84%, respectively.

[0110] Embodiment 16-20:

[0111] Compared with Example 3, the material feed ratio of compound 21: trimethylsilyl trifluoromethanesulfonate 1:2 in step (2) was adjusted to 1:1, 1:1.2, 1:1.5, 1:3, and 1:4, respectively, and the rest was the same as step (2) of Example 3. The corresponding yields were 50%, 71%, 74%, 73%, and 73%, respectively, and the cis-Z ratios were ≥90:10, ≥95:5, ≥95:5, ≥95:5, and ≥95:5, respectively.

[0112] Embodiment 21-24:

[0113] Compared with Example 3, the concentration of the reaction system in step (2) was adjusted from 0.05 mol / L to 0.005 mol / L, 0.01 mol / L, 0.02 mol / L, and 0.04 mol / L, respectively. The rest was the same as step (2) of Example 3. The corresponding yields were 40%, 50%, 56%, and 65%, respectively, and the cis-Z ratios were ≥95:5, ≥95:5, ≥95:5, and ≥95:5, respectively.

[0114] Embodiment 25-30:

[0115] Compared with Example 3, the reaction system temperature of -78°C in step (2) was adjusted to -45°C, -50°C, -60°C, -65°C, -80°C, and -90°C, respectively, and the rest was the same as step (2) of Example 3. The corresponding yields were 50%, 55%, 56%, 62%, 70%, and 71%, respectively, and the cis-Z ratios were ≥85:15, ≥85:15, ≥90:10, ≥90:10, ≥95:5, and ≥95:5, respectively.

[0116] Examples 31-35:

[0117] Compared with Example 3, the Lewis acid trimethylsilyl trifluoromethanesulfonate in step (2) was adjusted to 4-methylbenzenesulfonate pyridine, magnesium bromide ethyl ether, boron trifluoride ethyl ether, titanium tetrachloride, and tin tetrachloride, respectively. The rest was the same as step (2) of Example 3, and the corresponding yields were 5%, 5%, 5%, 3%, and 3%, respectively.

[0118] Examples 36-41:

[0119] Compared with Example 3, the solvent ether in step (2) was adjusted to methyl tert-butyl ether, isopropyl ether, dichloromethane, methanol, tetrahydrofuran, toluene, and the rest was the same as step (2) of Example 3. The corresponding yields were 70%, 65%, 50%, 30%, 22%, and 33%, respectively.

[0120] Embodiment 42-46:

[0121] Compared with Example 3, the reaction system temperature of 85°C in step (3) was adjusted to 60°C, 65°C, 70°C, 80°C, and 90°C, respectively. The rest was the same as step (2) of Example 3, and the corresponding yields were 40%, 57%, 68%, 81%, and 85%, respectively.

[0122] Embodiment 47-50:

[0123] Compared with Example 3, the concentration of the reaction system in step (3) was adjusted from 0.025 mol / L to 0.02 mol / L, 0.03 mol / L, 0.04 mol / L, and 0.05 mol / L, respectively. The rest was the same as step (2) of Example 3. The corresponding yields were 63%, 71%, 63%, and 43%, respectively.

[0124] Embodiment 51-55:

[0125] Compared with Example 3, the lithium tetrafluoroborate in step (4) is adjusted to 5 wt.% hydrochloric acid, p-toluenesulfonic acid, 4-methylbenzenesulfonate pyridine, trifluoroacetic acid, triethylsilyl trifluoromethanesulfonate, and the rest is the same as step (4) of Example 3. The corresponding yields are 50%, 55%, 61%, 73%, and 81%, respectively.

[0126] Embodiment 56-59:

[0127] Compared with Example 3, the reaction solvent acetonitrile / water in step (4) was adjusted to a single solvent of acetonitrile, dichloromethane, tetrahydrofuran, and 1,4-dioxane. The rest was the same as step (4) of Example 3. The corresponding yields were 65%, 50%, 30%, and 27%, respectively.

[0128] Embodiment 60-63:

[0129] Compared with Example 3, the concentration of the reaction system in step (4) was adjusted from 0.25 mol / L to 0.1 mol / L, 0.2 mol / L, 0.3 mol / L, and 0.5 mol / L, and the rest was the same as step (4) of Example 3. The corresponding yields were 39%, 89%, 82%, and 48%, respectively.

[0130]

[0131] Examples 64-68:

[0132] Compared with Example 3, the protecting group P in the general formula (III) is adjusted from tert-butyldiphenylsilyl (TBDPS) to trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, isopropyldiethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, and the rest is the same as step (2) of Example 3. The corresponding yields are 37%, 39%, 59%, 69%, 80%, and 81%, respectively, and the cis-Z ratios are ≥95:5, ≥95:5, ≥95:5, ≥95:5, ≥95:5, and ≥95:5, respectively.

[0133] Examples 69-74:

[0134] Compared with Example 3, the protecting group P in the general formula (III) is 1 H is adjusted to trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, isopropyldiethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, and the rest is the same as step (2) of Example 3. The corresponding yields are 50%, 43%, 18%, 15%, 8%, and 5%, respectively, and the cis-Z ratios are ≥95:5, ≥95:5, ≥95:5, ≥95:5, ≥95:5, and ≥95:5, respectively.

[0135] Embodiment 75-76:

[0136] Compared with Example 3, the protecting group P in the general formula (III) is 2 The methyl group was adjusted to ethyl group and acetyl group, and the rest was the same as step (2) of Example 3. The corresponding yields were 75% and 71%, and the cis-Z ratios were ≥95:5 and ≥95:5, respectively.

[0137] Examples 77-82:

[0138] Compared with Example 3, R 2 The acetyl group was adjusted to benzoyl, benzyl, ethyl, trichloroethyl, 2-trimethylsilylethyl, and 4-methoxybenzyl. The rest was the same as step (2) of Example 3. The corresponding yields were 78%, 86%, 85%, 81%, 78%, and 87%, respectively. The cis-Z ratios were ≥95:5, ≥95:5, ≥95:5, ≥95:5, ≥95:5, and ≥95:5, respectively.

[0139] Embodiment 83-87:

[0140] Compared with Example 3, R 4The methyl group was adjusted to ethyl and ethyl, ethyl and hexyl, ethyl and phenethyl, pentyl, fluorine and ethyl, and the rest was the same as step (2) of Example 3. The corresponding yields were 81%, 78%, 89%, 79%, and 83%, respectively, and the cis-Z ratios were ≥95:5, ≥95:5, ≥95:5, ≥95:5, and ≥95:5.

[0141] Embodiment 88-89:

[0142] Compared with Example 3, R 8 The acetyl group was adjusted to benzoyl and 2-octynoyl, and the rest was the same as step (2) of Example 3. The corresponding yields were 84% and 82%, and the cis-Z ratios were ≥95:5 and ≥95:5, respectively.

[0143] Embodiment 90:

[0144] Compared with Example 3, R 11 The methyl group was adjusted to an ethyl group, and the rest was the same as step (2) of Example 3. The corresponding yield was 88%, and the cis-Z ratio was ≥95:5.

[0145] 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 compound, characterized in that: The method comprises dissolving the compound of formula (III) in a reaction solvent under the protection of an inert gas, and then adding a Lewis acid to carry out an intramolecular Prins cyclization reaction to obtain a compound of formula (IV), wherein the reaction formula is: In the above formula, R 2 A chemical protecting group for hydroxyl selected from H, silicon, alkyl, substituted alkyl, acyl, substituted acyl, aromatic or aromatic substituted by heteroatoms, or one of the synthetic equivalents thereof; R 4 , R 6 , R 7 is selected from one of H, alkyl, substituted alkyl, alkenyl, alkynyl, halogen, amino, phenyl, and substituted phenyl; R 5 is selected from one of an alkyl group or a substituted alkyl group, R 8 is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aromatic, substituted aromatic or aromatic substituted by heteroatoms, R 9 is selected from H, alkyl, substituted alkyl, aromatic or aromatic substituted by heteroatoms, R 10 , R 11 , P 2 One selected from H, alkyl, substituted alkyl; P, P 1 , P 3 Each is independently selected from one of H, silicon, alkyl, substituted alkyl, phenyl and substituted phenyl.

2. The method according to claim 1, characterized in that The Lewis acid is selected from one of trimethylsilyl trifluoromethanesulfonate, 4-methylbenzenesulfonate pyridinium, magnesium bromide ethyl etherate, boron trifluoride ethyl etherate, titanium tetrachloride, tin tetrachloride, zinc dichloride, aluminum trichloride, and bis(perfluorophenyl)(3,4,5-trifluoro-2-methylphenyl)borane, preferably trimethylsilyl trifluoromethanesulfonate; The reaction solvent is selected from one of diethyl ether, methyl tert-butyl ether, isopropyl ether, dichloromethane, methanol, tetrahydrofuran and toluene, or a mixture of two of them.

3. The method according to claim 1, characterized in that The molar ratio of the compound of formula (III) to the Lewis acid is 1:1 to 1:4, preferably 1:2; the concentration of the reaction system is 5 mmol / L to 50 mmol / L, preferably 50 mmol / L.

4. The method according to claim 1, characterized in that: The reaction temperature is -45°C to -90°C, preferably -78°C.

5. A method for synthesizing bruceastatin compounds, characterized in that: The steps include: (1) Under the protection of inert gas, using the A ring compound of formula (I) and the C ring compound of formula (II) as raw materials, and subjecting them to esterification and acetalization to obtain a compound of formula (III); In the above formula, R 1 A chemical protecting group for a carboxyl group selected from various types of carboxyl groups such as H, silicon, alkyl, substituted alkyl, acyl, substituted acyl, aromatic or aromatic substituted by various heteroatoms, or one of their synthetic equivalents; (2) under the protection of an inert gas, dissolving the compound of formula (III) in a reaction solvent, and then adding a Lewis acid to react to obtain a compound of formula (IV); (3) Under the protection of an inert gas, the compound of formula (IV) is subjected to an iodine- and palladium-catalyzed carbonylation reaction to obtain a common intermediate compound of formula (V); (4) Using the common intermediate compound of formula (V) as a raw material, bryostatin 7 is obtained under the action of Lewis acid and hydrofluoric acid; or after deacetylation of the hydroxyl group at C20 and then hydroxybutyryl protection at C20, bryostatin 9 is obtained under the action of Lewis acid and hydrofluoric acid; or after removal of the acetyl protection of the hydroxyl group at C20 and then 4-azidobutyrylation of the hydroxyl group at C20, bryostatin 9-N3 analogue is obtained for the first time under the action of Lewis acid and hydrofluoric acid; or after removal of the acetyl protection of the hydroxyl group at C20 and then esterification of the hydroxyl group at C20, bryostatin 1 is obtained under the action of Lewis acid and hydrofluoric acid.

6. The method according to claim 5, characterized in that In step (1), the reaction concentration is 0.02 mol / L to 0.1 mol / L, preferably 0.05 mol / L.

7. The method according to claim 5, characterized in that In step (1), the feed ratio of the substances is A-ring compound of formula (I): C-ring compound of formula (II) = 1:1 to 1:2, preferably 1:1 considering the cost.

8. The method according to claim 5, characterized in that In step (3), the carbonylation reaction temperature is between 60°C and 90°C, preferably 85°C.

9. The method according to claim 5, characterized in that In step (3), the reaction concentration is 0.02 mol / L to 0.05 mol / L, preferably 0.025 mol / L.

10. The method according to claim 5, characterized in that In step (4), the Lewis acid is selected from one of 5wt.% hydrochloric acid, p-toluenesulfonic acid, 4-methylbenzenesulfonate pyridine, trifluoroacetic acid, triethylsilyl trifluoromethanesulfonate, preferably lithium tetrafluoroborate.

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