Method for synthesizing key intermediate of bryostatin compound and method for synthesizing bryostatin compound

Abstract

The present invention relates to the field of chemical synthesis. Disclosed are a method for synthesizing a key intermediate of a bryostatin compound and a method for synthesizing a bryostatin compound. The method for synthesizing a key intermediate comprises: dissolving a compound of formula (III) in a reaction solvent and then adding a Lewis acid for an intramolecular Prins cyclization reaction to obtain a compound of formula (IV). Iodination and carbonylation reactions are then carried out on an exocyclic double bond on a B ring to convert an olefin into an alkenoate compound; and after a key common intermediate is obtained, synthesis is enabled to separately obtain bryostatins 1, 7, and 9 and a bryostatin 9-N3 analogue, thereby achieving divergent synthesis of bryostatin analogues. The present invention realizes the specific selective construction of a cis-Z form of the B ring in bryostatin 1 by means of a ring-closing strategy of performing an esterification reaction on a C1 carboxyl group and a C25 hydroxyl group and simultaneously performing acetalization on a C15 aldehyde group and then constructing a macrocyclic lactone scaffold by means of gem-disilyl-mediated intramolecular stereoselective Prins cyclization.

Description

Synthesis of a key intermediate of bryostatin compounds and method for synthesizing bryostatin compounds TECHNICAL FIELD

[0001] The present application relates to the field of chemical synthesis, in particular to a kind of synthesis of bryostatin compounds and method for synthesizing bryostatin compounds. BACKGROUND

[0002] Bryostatins (also known as Bryopsis inhibitor), is extracted from marine bryozoa total grass bryostatins and obtained a class of marine macrolide compounds, has been confirmed to have anticancer, anti-AIDS and anti-Alzheimer's disease and other effects.

[0003] The skeleton structure of natural product bryostatin includes: three different oxidation state ABC polysubstituted tetrahydropyran ring (A ring, B ring and C ring, respectively), C16-C17 E-form double bond with large steric hindrance linking BC ring, C18 position geminal dimethyl (Bryostatins 1-20) or chiral monomethyl (Bryostatins 21) and C13\C17 position two acid-base unstable exocyclic unsaturated ester (except C9 and C19 of Bryostatins 16 and 17 are ketal structure).

[0004] So far, the number of members of this kind of natural product has been increased to 21 by extraction and separation research. The National Cancer Institute of the United States has only extracted 18 grams of bryostatin from 14 tons of total bryopsis worm, and the total efficiency is about 0.00014%. Due to the scarcity of resources, scientists have been exploring the method of chemical synthesis in order to mass-produce this substance. For example, CN 109923110 A discloses a 29-step total synthesis route, the total yield is 4.8%, the average yield of each step is more than 80%, and more than 2 grams of bryostatin 1 is successfully synthesized. The method reported in the patent application has at least the following disadvantages: (1) In the A ring synthesis route, the dr value of C5 position is only 2:1; and a large number of expensive chiral auxiliaries are used in the synthesis of key intermediates, which is high in cost and not easy for industrial production; the total route of A ring synthesis has 10 steps, but there are 7 steps of separation, and the yield is only 13%; (2) In the B ring synthesis, the Z:E of the exocyclic double bond of the B ring is 11.6:1, which cannot be constructed specifically, resulting in E isomer of the final product bryopsis worm 1, which is difficult to separate and purify later; (3) In the C ring synthesis route, the equivalent of expensive chiral auxiliaries needs to be used to construct the chiral center at C23 position, which is high in cost, and ozone needs to be used in the last few steps, which is easy to pollute the environment, and a large number of dangerous reagents such as tert-butyl lithium and diethyl zinc are needed to construct the C15-C16 structure fragment, which is not convenient for operation in scale-up reaction and is not conducive to industrialization; (4) In the method for synthesizing bryopsis worm analogs by removing the protecting group, the equivalent of pyridine hydrogen fluoride acid used is more than 1000 equivalents, which is dangerous in operation and difficult to be industrialized. Technical solutions

[0005] One of the purposes of the present application is to provide a method for synthesizing a key intermediate of bryopsis worm, to solve the above problems.

[0006] In order to achieve the above purpose, the technical scheme adopted by the present application is as follows: a method for synthesizing a key intermediate of bryopsis worm compound, the method is to dissolve the compound of formula (III) in a reaction solvent under the protection of inert gas, and then add Lewis acid to carry out intramolecular Prins cyclization reaction to obtain the compound of formula (IV), and the reaction formula is as follows:

[0007] ,

[0008] In the above formula, R 2 is selected from H, silicon group, alkyl group, substituted alkyl group, acyl group, substituted acyl group, aromatic group or aromatic group substituted by each heteroatom, and other chemical protection groups of each hydroxyl group, or one of its synthetic equivalents; R 4 , R 6 , R 7one selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, or aryl substituted with each heteroatom, R 5 one selected from alkyl or substituted alkyl, R 8 one selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, or aryl substituted with each heteroatom, R 9 one selected from H, alkyl, substituted alkyl, aryl, or aryl substituted with each heteroatom, R 10 , R 11 , P 2 one selected from H, alkyl, substituted alkyl, aryl, or aryl substituted with each heteroatom, P, P 1 , P 3 each independently selected from one of H, silyl, alkyl, substituted alkyl, phenyl, substituted phenyl.

[0009] As a preferred technical solution, the Lewis acid is selected from one of trimethylsilyl triflate, 4-methylbenzenesulfonic acid pyridine, magnesium bromide ether, boron trifluoride ether, titanium tetrachloride, tin tetrachloride, zinc dichloride, aluminum trichloride, bis (perfluorophenyl) (3, 4, 5-trifluoro-2-methylphenyl) borane, preferably trimethylsilyl triflate; the reaction solvent is selected from one or a mixture of two of diethyl ether, methyl tert-butyl ether, isopropyl ether, dichloromethane, methanol, tetrahydrofuran, toluene.

[0010] As a preferred technical solution, the molar ratio of the compound of formula (III) to the Lewis acid is 1:1-1:4; further preferably 1:2; the economy and operability of the reaction at this molar ratio are better.

[0011] The reaction system concentration is 0.005 mol / L-0.05 mol / L, further preferably 0.05 mol / L, the yield and cis-Z selectivity are higher at this concentration.

[0012] As a preferred technical solution, the reaction temperature is -45℃- -90℃; further preferably -78℃, the yield and cis-Z selectivity are higher at this temperature.

[0013] Under the conditions of determining the optimal reaction feed ratio, the molar ratio of the compound of formula (III) to the Lewis acid is 1:2, and the optimal reaction temperature is -78℃, the reaction concentration can be increased to 50 mmol / L, the yield is maintained at 82%, and the existing yamaguguchi cyclization concentration is generally 0.34-1 mmol / L.

[0014] The second object of the present application is to provide a method for synthesizing the Litomosoides sigmodontis compound, and the technical solution comprises the following steps:

[0015] (1) under the protection of inert gas, taking the A ring compound of formula (I) and the C ring compound of formula (II) as raw materials, esterification and acetalization are carried out to obtain the compound of formula (III);

[0016] ;

[0017] (2) under the protection of inert gas, the compound of formula (III) is dissolved in a reaction solvent, then a Lewis acid is added to react to obtain the compound of formula (IV);

[0018] ;

[0019] (3) under the protection of inert gas, the compound of formula (IV) is subjected to iodination and palladium-catalyzed carbonylation to obtain the common intermediate compound of formula (V)

[0020] ;

[0021] (4) taking the common intermediate compound of formula (V) as raw material, under the action of a Lewis acid and hydrofluoric acid, the halichondrin 7 is obtained; or after the deacetylation of the C20 hydroxyl group and the butyryl protection of the C20 hydroxyl group, under the action of a Lewis acid and hydrofluoric acid, the halichondrin 9 is obtained; or after the removal of the acetyl protection of the C20 hydroxyl group and the 4-azido butyryl reaction of the C20 hydroxyl group, under the action of a Lewis acid and hydrofluoric acid, the halichondrin 9-N3 analogue is obtained for the first time; or after the removal of the acetyl protection of the C20 hydroxyl group and the octadecene acid esterification reaction of the C20 hydroxyl group, under the action of a Lewis acid and hydrofluoric acid, the halichondrin 1 is obtained;

[0022] The present application realizes the divergent synthesis of halichondrin analogues.

[0023] As a preferred technical scheme, in step (1), the reaction concentration is 0.02 mol / L-0.1 mol / L, preferably 0.05 mol / L.

[0024] As a preferred technical scheme, in step (1), the feeding ratio of the substances is the A ring compound of formula (I) to the C ring compound of formula (II)=1:1-1:2, preferably 1:1 in terms of cost.

[0025] As a preferred technical scheme, in step (3), the temperature of the carbonylation reaction is 60-90 DEG C, preferably 85 DEG C.

[0026] As a preferred technical scheme, in step (3), the reaction concentration is 0.02 mol / L-0.05 mol / L, preferably 0.025 mol / L.

[0027] As a preferred technical solution, in step (4), the Lewis acid is selected from one of 5wt.% hydrochloric acid, p-toluenesulfonic acid, 4-methylbenzenesulfonic acid pyridine, trifluoroacetic acid, triethylsilyl trifluoromethanesulfonate, preferably lithium tetrafluoroborate. Advantages

[0028] The present application realizes the specific selective construction of the cis-Z type of the B ring exocyclic double bond in the halichondrin skeleton by the esterification of C1 carboxyl and C25 hydroxyl, the simultaneous acetalization of C15 aldehyde group, and the subsequent closed-loop strategy of constructing the macrolide skeleton by the applicant's research and development of geminal bisilicon-mediated intramolecular stereoselective Prins reaction, Z:E≥95:5. It should be noted that the intramolecular Prins reaction of the present application saves at least three steps compared to the intermolecular Prins reaction reported in the prior art. The reaction concentration needs to be controlled between 0.34-1 mmol / L in the closed-loop strategy of Yamaguchi macrolactone, while the concentration of the intramolecular Prins reaction developed by the applicant can reach 50 mmol / L. This greatly improves the reaction scale and saves a large amount of solvent required for the reaction, reduces the cost, and therefore the synthesis method of the present application is more efficient and more conducive to industrialization. The reaction conditions of the synthesis method of the present application are mild and can reach a scale of 5 grams or more, and the raw materials used are simple and easy to obtain. For example, the esterification of octadienoic acid at C20 position, the octadienoic acid used in the present application is commercially available and does not need to be self-made, making the synthesis method more practical. The longest linear step of the whole synthesis route of halichondrin 1 is 20 steps, and the total yield is 5.9%, which is higher than the reported yield of 4.8%, and is improved by 23%. After synthesizing the key intermediates, the synthesis route of the present application can divergently synthesize multiple analogs of halichondrin, and the synthesis is more efficient. BRIEF DESCRIPTION OF DRAWINGS

[0029] Fig. 1 and Fig. 2 are the hydrogen spectrum and carbon spectrum of compound 22 of embodiment 3 of the present application, respectively;

[0030] Fig. 3 and Fig. 4 are the hydrogen spectrum and carbon spectrum of halichondrin 7 of embodiment 4 of the present application, respectively;

[0031] Fig. 5 and Fig. 6 are the hydrogen spectrum and carbon spectrum of halichondrin 9 of embodiment 5 of the present application, respectively;

[0032] Fig. 7 and Fig. 8 are the hydrogen spectrum and carbon spectrum of halichondrin 9-N3 of embodiment 6 of the present application, respectively;

[0033] Fig. 9 and Fig. 10 are the hydrogen spectrum and carbon spectrum of halichondrin 1 of embodiment 7 of the present application, respectively. Best mode for carrying out the present application

[0034] Embodiment 1:

[0035] A method for synthesizing the C1-C14 fragment of the ring C of bryostatins A, the reaction formula of which is as follows:

[0036]

[0037] 1) -45 ℃, under argon protection, lithium perchlorate (10.67 g, 100 mmol, 1.0 equivalent.) was weighed into a 2 L round-bottom flask, 1 L of dichloromethane and 660 mL of diethyl ether were added as mixed solvents, 9-O-benzylquinine (4.16 g, 10.0 mmol, 10 mol%) and diisopropyl ethylamine (32.4 g, 250 mmol, 2.5 equivalents.) were sequentially added, (R)-3-((tert-butyldiphenylsilyl)oxy)-5-oxopentanoic acid ethyl ester (40 g, 100 mmol, 1.0 equivalent.) was dissolved in 200 mL and added to the system, after stirring for 10 minutes, a solution of acetyl chloride (14.2 mL, 200 mmol, 2.0 equivalents.) in 120 mL of dichloromethane was added dropwise to the reaction system at a rate of 15 mL / h, and the reaction was continued for 24 hours; after the reaction was completed as detected by TLC, salt water was added to quench the reaction, dichloromethane was extracted 3-4 times, the organic phase was washed once with salt water, dried over anhydrous sodium sulfate, concentrated to obtain a concentrate of the tetra-lactone compound 2, and a sample was taken for nuclear magnetic hydrogen spectrum, the results showed that dr ≥ 95:5, and it was used in the next step without purification;

[0038] ​Structure identification of compound 2: 1H NMR (400 MHz, CDC13) δ 7.75 - 7.63 (m, 4H), 7.48 - 7.35 (m, 6H), 4.57 - 4.47 (m, 1H), 4.37 - 4.26 (m, 1H), 4.02 (qd, J = 7.2, 2.4 Hz, 2H), 3.41 (dd, J = 16.0, 6.0 Hz, 1H), 2.88 (dd, J = 16.0, 4.4 Hz, 1H), 2.49 (dd, J = 14.8, 5.6 Hz, 1H), 2.42 (dd, J = 14.8, 6.8 Hz, 1H), 2.13 - 1.92 (m, 2H), 1.17 (t, J = 7.2 Hz, 3H), 1.04 (s, 9H);13C NMR (150 MHz, CDC13) δ 170.5, 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 C25H32O5Si (M+Na)+ 463.1911, found 463.1916; [a]D25= + 0.34 o (c = 1.0 in CHCl3);

[0039] 2) At -78 °C, under argon protection, hexamethylbis(silyl)aminopotassium (452 ​​mL, 452 mmol, 5.0 equivalent, 1 M in THF) was drawn into a round-bottom flask using a syringe, and 400 mL of anhydrous tetrahydrofuran was added and mixed thoroughly before cooling. Allyl isobutyrate (61.34 g, 478.6 mmol, 5.3 equivalent) was dissolved in 300 mL of tetrahydrofuran and added dropwise through a dropping funnel. After the addition was complete, stirring was continued for 1 hour. This reaction solution was then transferred to a tetrahydrofuran (800 mL) solution of magnesium bromide diethyl ether complex (141 g, 541.8 mmol, 6.0 equivalent) pre-cooled at -78 °C, and stirring was continued for 1 hour. Meanwhile, the tetra-lactone compound 2 (90.3 mmol, 1.0 equivalence) obtained in step 1) was dissolved in 200 mL of tetrahydrofuran in a 500 mL round-bottom flask. After pre-cooling at -78 °C for 30 minutes, the pre-cooled tetrahydrofuran solution of tetra-lactone compound 100 was rapidly transferred to the above reaction system, and the reaction was continued at -78 °C for 20 hours. After the reaction was completed, saturated ammonium chloride aqueous solution was added to quench the reaction, followed by extraction with diethyl ether, drying with anhydrous sodium sulfate, and concentration to obtain compound 3 concentrate, which can be used directly for asymmetric reduction without purification.

[0040] 3) At room temperature, under argon protection, tetramethylammonium triacetoxyborohydride (114 g, 433.3 mmol, 8.0 eq.) was weighed into a 1 L 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 (54.2 mmol, 1.0 eq.) obtained in step 2) was dissolved in 270 mL of acetonitrile, and the above prepared tetramethylammonium triacetoxyborohydride solution was transferred into it in an ice bath, and after stirring for half an hour, it was transferred 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 reduced product compound 4 (25.7 g); sampling for1H NMR showed that dr ≥ 95:5, thus, the three-step yield of steps 1)-3) was 45%;1H NMR (400 MHz, CDCl3) δ 7.68 – 7.59 (m, 4H), 7.49 – 7.34 (m, 6H), 6.01 – 5.79 (m, 1H), 5.31 (dd, J = 17.2, 1.6 Hz, 1H), 5.24 (dd, J = 10.4, 1.6 Hz, 1H), 4.59 (d, J = 5.2 Hz, 2H), 4.41 – 4.30 (m, 1H), 4.23 – 4.12 (m, 1H), 4.00 (d, J = 10.0 Hz, 1H), 2.78 (s, 1H), 2.66 (dd, J = 17.2, 6.0 Hz, 1H), 2.49 (dd, J = 17.2, 7.2 Hz, 1H), 2.15 – 2.02 (m, 1H), 1.83 – 1.65 (m, 2H), 1.49 (ddd, J = 14.4, 10.8, 2.4 Hz, 1H), 1.21 (s, 3H), 1.17 (s, 3H), 1.05 (s, 9H).13C NMR (100 MHz, CDCl3) δ 177.2, 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;.

[0041] HRMS (MALDI, m / z) calcd for C30H40O6Si (M+Na)+ 547.2492, found 547.2488.

[0042] 4) The compound 4 (25.36 g, 44.4 mmol, 1.0 eq.) obtained in step 3 was concentrated in a 250 mL round bottom flask, argon protection, 88 mL diethoxypropane was added, stirred to completely dissolved, added dextro-camphorsulfonic acid (1.03 g, 4.44 mmol, 0.1 eq.) in ice bath, moved to room temperature and continued to react for 12 hours; after the reaction was completed, 100 mL saturated aqueous sodium bicarbonate solution was added to quench, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated and column chromatography was used for simple purification (eluent: petroleum ether / ethyl acetate = 20:1) to obtain the intermediate product a (24.63 g), which was directly used in the next step;

[0043] 5) The palladium tetraphenylphosphine (2.32 g, 2.02 mmol, 5 mol%) was weighed in a glove box and transferred to a 500 mL round bottom flask, which was then argon protected. Propylidene-protected intermediate product a (24.63 g, 40.32 mmol, 1.0 eq.) was dissolved in 160 mL of tetrahydrofuran and transferred to the round bottom flask, and the remaining raw material was rinsed with 4x10 mL. After adding morpholine (7.05 mL, 80.64 mmol, 2.0 eq.), the reaction was continued at room temperature for 16 hours. 1 M hydrochloric acid was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain the intermediate product b concentrate, which was directly used in the next step without purification;

[0044] 6) Room temperature, argon protection, the intermediate product b concentrate (38.3 mmol, 1.0 equivalent.) 38 mL of toluene was dissolved in a 100 mL round-bottom flask, and then triphenylphosphine (12.05 g, 45.96 mmol, 1.2 equivalent.) and 2,2'-dithio-5,5'-dimethyl dipyridine (11.41 g, 45.96 mmol, 1.2 equivalent.) were added in sequence, and reacted in a 30°C oil bath for 24 hours; after the raw material was completely reacted, the toluene was directly removed by vacuum concentration, and then an appropriate amount of silica gel and dichloromethane were added, and the sample was mixed with silica gel by means of a rotary evaporator, and was used for dry loading and column chromatography purification (eluent: petroleum ether / ethyl acetate = 1000:66) to obtain the thioester compound 5 (25.63 g), and the three-step yield of steps 4) -6) was 86%;

[0045] The parallel synthesis of iodide 5B is as follows: (1) Grignard reagent preparation: magnesium turnings (15.4 g, 640 mmol, 2.4 eq) were placed in a 1000 mL three-necked round-bottom flask, vacuumed, baked for 10-15 min until evenly dispersed, argon was introduced for cooling, a stirring bar and 350 mL of freshly distilled tetrahydrofuran were added, about 0.5 mL of 1,2-dibromoethane and a small amount of bromide were added at room temperature, and an electric hair dryer was directly blown on the outer wall. When a large amount of foam appeared on the liquid surface, it indicated that the initiation was successful. It was moved into a 60 ℃ oil bath to reflux, and then the raw material (1-bromo vinyl) trimethylsilane (57.3 g, 320 mmol, 1.2 eq) and 50 mL of anhydrous tetrahydrofuran were mixed and added dropwise into the reaction system through a dropping funnel, first slowly and then quickly, keeping the solution in a slightly boiling state. After dropping, it was stirred for about 2 hours, and then it was left to cool for the next step. (2) Ring opening of oxygen: -45 ℃, under argon protection, the freshly prepared Grignard reagent in the previous step was added dropwise into a 500 mL tetrahydrofuran solution of (S)-2-(chloromethyl) oxirane (24.67 g, 267 mmol, 1.0 eq) and cuprous cyanide (2.39 g, 26.67 mmol, 0.1 eq). After the addition was completed, the stirring was continued. After the reaction was completed, saturated ammonium chloride solution was added to quench at this temperature, and it was stirred at room temperature for 30 min. It was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the reaction system was clean. Simple column chromatography purification (eluent polarity: petroleum ether / ethyl acetate = 20:1 → 10:1) gave the product (S)-1-chloro-4-(trimethylsilyl)pent-4-en-2-ol (47.35 g), yield: 92%. (3) At room temperature, under argon protection, sodium iodide (180 g, 1.2 mol, 5.0 eq) was added into a 2 L round-bottom flask, argon was introduced for 3 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 eq) was added. After refluxing at 80 ℃ for 48 h, the raw material was detected to be completely reacted, cooled to room temperature, and then moved into an ice bath. 600 mL of dichloromethane was added, followed by the addition of imidazole (32.68 g, 480 mmol, 2.0 eq) and triethylchlorosilane (48.3 mL, 288 mmol, 1.2 eq) into the reaction system. With the addition of triethylchlorosilane, the solution changed from colorless and clear to turbid. After the addition was completed, the stirring was continued. TLC detection showed that the reaction was completed. Ice water was added to quench, and dichloromethane was used for extraction. After drying over anhydrous sodium sulfate and concentrating, column chromatography purification (eluent polarity: petroleum ether / ethyl acetate = 1000:1 → 200:1) gave iodide 5B (87.03 g), two-step yield: 91%.1H NMR (400 MHz, CDCl3) δ 5.72 (dd, J = 2.8, 1.6 Hz, 1H), 5.47 (d, J = 2.8 Hz, 1H), 3.72 - 3.56 (m, 1H), 3.25 (dd, J = 10.0, 4.8 Hz, 1H), 3.15 (dd, J = 10.0, 4.8 Hz, 1H), 2.45 (ddd, J = 14.0, 7.6, 1.2 Hz, 1H), 2.38 (ddt, J = 14.0, 5.6, 1.2 Hz, 1H), 0.98 (t, J = 8.0 Hz, 9H), 0.63 (q, J = 8.0 Hz, 6H), 0.11 (s, 9H).13C NMR (150 MHz, CDCl3) δ 147.8, 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 for C14H31IOSi2 (M+Na)+: 421.0850, found 421.0849; [a]D25= + 0.99 o (c = 1.0 in CHCl3).

[0046] 7) At room temperature, under argon protection, sulfur ester compound 5 (12 g, 17.7 mmol, 1.0 eq.) and iodo compound 5B (8.46 g, 21.24 mmol, 1.2 eq.) were dissolved in 36 mL of 1,3-dimethyl-2-imidazolidinone 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. In the glove box, dichlorobis-zirconocene (15.52 g, 53.1 mmol, 3.0 eq.) and zinc powder (6.95 g, 106.2 mmol, 6.0 eq.) were weighed separately, and then NiBr2dtbbpy (2.59 g, 5.31 mmol, 30 mol%) was added in the glove box. After addition, the solution color changed from green to brown yellow. After 5-10 minutes, the glove box was removed to room temperature, and the argon was replaced for 2-3 times. The solution was stirred vigorously for 32 hours. The solution continued to darken, and turned into dark red brown to black. After the reaction was completed, 2 mL of saturated aqueous sodium bicarbonate solution was added to quench the reaction, and then a few milliliters of ethyl acetate were added. The salt generated after quenching was filtered out with diatomite, and the ethyl acetate was washed. The collected filtrate was supplemented with 20 mL of saturated aqueous sodium bicarbonate solution, and then extracted with ethyl acetate for 3-4 times. The organic phase was dried with anhydrous sodium sulfate, and then 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), yield: 76%;

[0047] 8) At room temperature, under argon protection, 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, and then 315 mL of trimethyl orthoformate was added. Under ice bath, pyridine p-toluenesulfonic acid (39.48 g, 0.157 mol, 5.0 eq.) was added in three batches, and then the solution was moved to a 30 °C oil bath for reaction for 24 hours. After TLC detection, the reaction was complete. Under ice bath, saturated aqueous sodium bicarbonate solution was added to quench, and then stirring was continued for half an hour until the quenching was complete. The water phase was extracted with petroleum ether / ethyl acetate (1:1) for 4-5 times. The organic phase was dried with anhydrous sodium sulfate, and then concentrated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 20:1→ 10:1) to obtain compound 7 (18.51 g), yield: 86%;

[0048] 9) Under argon protection, compound 7 (17.07 g, 24.92 mmol, 1.0 eq.) was dissolved in 250 mL of dichloromethane in a 1000 mL round bottom flask, which was placed in an ice bath. Triethylamine (4.16 mL, 29.9 mmol, 1.2 eq.) and tribromopyridine (9.56 g, 29.9 mmol, 1.2 eq.) were added successively. The reaction was completed by adding triethylamine and tribromopyridine. 250 mL of methanol and 1 N sodium hydroxide aqueous solution (250 mL) were added at room temperature. The reaction was continued in an 80 °C oil bath for 12 hours. After the starting material was completely converted, 1 M hydrochloric acid aqueous solution was added in an ice bath to acidify to pH 6-7. The organic phase was extracted with ethyl acetate and washed with saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain compound 8, which was directly used in the next step without purification;

[0049] 10) Under argon protection, compound 8 (21.93 mmol, 1.0 eq.) was dissolved in 220 mL of dichloromethane in a 500 mL round bottom flask, which was taken out of the oven. 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 successively in an ice bath for 10 minutes. The reaction was continued at this temperature for 0.5 hours. After the reaction was completed, imidazole (17.92 g, 263.16 mmol, 12.0 eq.) was added in an ice bath under argon protection. Triethylchlorosilane (22.08 mL, 131.58 mmol, 6.0 eq.) was added slowly. The reaction solution changed from clear to turbid. The reaction was continued at room temperature for 30 minutes. After the reaction was completed by TLC detection, 200 mL of saturated ammonium chloride aqueous solution was added to quench. After stirring for 5-10 minutes, the organic phase was extracted with dichloromethane for 3-4 times. The organic phase was dried over anhydrous sodium sulfate and concentrated. Compound 9 (12.87 g) was obtained by column chromatography purification (eluent: petroleum ether / ethyl acetate = 15:1→5:1) with a yield of 63%;

[0050] 11) Under argon, compound 9 (6.1 g, 7.44 mmol, 1.0 equiv.) and 1,3-bis(diphenylphosphinopropane)nickel dichloride (403 mg, 0.744 mmol, 10 mol%) from step 10) were dissolved in 298 mL of diethyl ether in a 500 mL round bottom flask, and freshly prepared (bis(trimethylsilyl)methyl)magnesium chloride (51 mL, 29.76 mmol, 4.0 equiv. at 0.59 M) was added slowly under ice bath. After addition, the flask was fitted with a spherical condenser and purged with argon for 2-3 times, and then moved to a 45 °C oil bath for 2 hours. After reaction, saturated ammonium chloride aqueous solution was added, and 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 give compound 10 (6.02 g) as a yellowish viscous liquid in 90% yield;1H NMR (600 MHz, CDCl3) δ 7.77 – 7.62 (m, 4H), 7.50 – 7.32 (m, 6H), 4.97 (dd, J = 11.4, 4.8 Hz, 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, 3.6 Hz, 1H), 2.52 (dd, J = 15.0, 7.2 Hz, 1H), 2.19 (dd, J = 16.2, 3.6 Hz, 1H), 2.05 (dd, J = 15.6, 7.2 Hz, 1H), 2.01 (s, 3H), 1.94 – 1.79 (m, 2H), 1.73 (dd, J = 15.6, 7.8 Hz, 1H), 1.55 (ddd, J = 13.8, 6.0, 3.6 Hz, 1H), 1.32 (ddd, J = 12.6, 4.8, 3.0 Hz, 1H), 1.02 (s, 9H), 0.99 – 0.85 (m, 16H), 0.79 (s, 1H), 0.57 (q, J = 7.9 Hz, 6H), 0.06 (s, 18H).13C NMR (150 MHz, CDCl3) δ 176.2, 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.

[0051] 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.

[0052] HRMS (MALDI, m / z) calcd for C48H82O8Si4 (M+Na)+ 921.4979, found 921.4977. [a]D25= + 25.04 o (c = 1.97 in CHCl3);

[0053] The overall yield of all the above steps was 14.3%. Example 2

[0054] Synthesis of C-ring fragment of C- ring bryostatins, the reaction formula is as follows:

[0055]

[0056] (1) room temperature, under argon protection, trifluoroacetate (1.67 g, 5.0 mmol, 5 mol %.), diphenyl-2-pyridine phosphine (5.26 g, 20 mmol, 20 mol %.) and trifluoroethanol 30 mL in 250 mL round bottom flask, then compound 11 (13.4 g, 100 mmol, 1.0 eq.) in 75 mL of anhydrous dichloroethane dilution after the round bottom flask at room temperature for 48 hours, 48 hours after the reaction, the reaction system slowly poured into ice hydrochloric acid (100 mL, 1 M / L) quenching, dichloromethane extraction anhydrous sodium sulfate drying, concentrated directly used in the next step reaction;

[0057] (2) At room temperature, sodium iodide (75 g, 500 mmol, 5.0 eq.) was weighed into a 2 L round bottom flask under argon, followed by the addition of the crude compound from the previous step in 800 mL of dry acetone, and the reaction was stirred at 75 °C for 36 h. After 36 h, the reaction was cooled to room temperature, and imidazole (17.0 g, 250 mmol, 2.5 eq.) was added to the reaction mixture, followed by the slow addition of triethylsilylchloride (16.6 g, 110 mmol, 1.1 eq.) in 500 mL of dry dichloromethane. The reaction was stirred at room temperature for an additional 12 h. After 12 h, the reaction was quenched with water, dried over anhydrous sodium sulfate, and concentrated. The compound was purified by column chromatography (eluent: petroleum ether) to give compound 12 (22.1 g) in 65% yield over two steps; E / Z > 95:5.

[0058] Structural identification data for compound 12: Rf = 0.5 (EA / Petroleum ether = 2%),

[0059] 1H NMR (400 MHz, CDCl3) δ 5.61-5.50 (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=5.6 Hz, 3H), 0.97 (t, J=8 Hz, 9H), 0.62 (q, J=8 Hz, 6H);13C NMR (150 MHz, CDCl3) δ 128.6, 126.1, 71.5, 40.1, 18.0, 13.5, 6.8, 4.9;IR (neat) cm-1 3019, 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 = -45.29 o (c = 12.1 in CHCl3);

[0060] Method for preparing compound 12b in parallel: 1) 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 under argon protection, 1 L of anhydrous dioxane was added as solvent, then p-methoxybenzyl alcohol (62.1 g, 450 mmol, 1.5 eq.) was added. After stirring at room temperature for 10 min, a solution of allyl bromide compound 110 (66 g, 300 mmol, 1.0 eq) in 500 mL of dioxane was slowly added to the reaction system within 30 min, and the reaction was continued for 2 h. After the reaction was completed by TLC detection, the dioxane was removed by concentration under reduced pressure, and the intermediate compound xxx (71.7 g) was obtained by simple purification by column chromatography (eluent: petroleum ether / ethyl acetate = 20:1) with a yield of 86%; 2) The intermediate compound obtained in step (1) (45 g, 162 mmol, 1.0 eq.) was diluted with 400 mL of anhydrous tetrahydrofuran and added to a 2 L round bottom flask under argon protection at -20 °C, then dimethylhydroxylamine hydrochloride (48 g, 486 mmol, 3.0 eq.) was added and cooled at -20 °C for 10 min. After 10 min, isopropyl magnesium chloride (502 mL, 1004 mmol, 6.2 eq. 2 M in THF) was added dropwise to the reaction system within 1 h. After 1 h, the dropwise addition was completed, and the reaction was continued at -20 °C for 4 h. After 4 h, the intermediate compound was completely converted by TLC detection, 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 h. After the reaction was completed, saturated ammonium chloride solution was added for quenching, and the ethyl acetate extract was dried over anhydrous sodium sulfate, concentrated, and then simply purified by column chromatography (eluent: petroleum ether / ethyl acetate = 30:1) to obtain compound 12b (33.7 g) with a yield of 76%;

[0061] Structural identification data of the obtained compound 12b: Rf = 0.6 (EA / Petroleum ether = 20%).

[0062] 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J=8 Hz, 2H), 6.87(d, J=8 Hz, 2H), 6.72 (dd, J=17.2, 10.4 Hz, 1H), 6.33 (d, J=17.2 Hz, 1H), 5.78 (d, J=16 Hz, 1H), 5.70 (dt, J=16, 5.2 Hz, 1H), 5.62 (d, J=10.4 Hz, 1H), 4.43 (s, 2H), 4.00 (d, J=5.2 Hz, 2H), 3.79 (s, 3H), 1.25 (s, 6H);13C NMR (150 MHz, CDCl3) δ 201.0, 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 C17H22O3 (M+Na) + 297.1461, found 297.1463;

[0063] (3) At room temperature, under argon protection, tris(2,2'-bipyridyl)dichlororuthenium (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.), 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 pumped into the flow reactor at a rate of 10 mL / h. The flow reactor was irradiated with a blue LED lamp (hv = 427~440 nm) at a distance of 1 cm at room temperature. After the product was collected, it was directly concentrated under reduced pressure to remove acetonitrile, and then an appropriate amount of silica gel and dichloromethane were added, and the sample was mixed with silica gel by a rotary evaporator to prepare a sample for dry loading. Column chromatography purification (eluent: petroleum ether / ethyl acetate = 50:1) can obtain coupled compound 13 (5.7 g) with a yield of 78%. A single cycle of flow chemistry can obtain 5.7 grams of coupled compound 13, and finally 200 grams of coupled compound 13 can be prepared through multiple cycles.

[0064] The structural identification data of the compound 13 are as follows: Rf = 0.5 (EA / Petroleum ether = 10%),

[0065] 1H NMR (400 MHz, CDCl3) δ 7.26 (d, J=8 Hz, 2H), 6.88 (d, J=8 Hz, 2H), 5.78 (d, J=15.6 Hz, 1H), 5.67 (dt, J=16, 5.6 Hz, 1H), 5.46 – 5.35 (m, 2H), 4.43 (s, 2H), 3.99 (d, J=5.6 Hz, 2H), 3.80 (s, 3H), 3.67 – 3.58 (m, 1H), 2.44 (t, J=7.2 Hz, 2H), 2.194 – 2.078 (m, 2H), 1.64 (d, J=5.6 Hz, 3H), 1.60 – 1.44 (m, 2H), 1.43 – 1.29 (m, 2H), 1.22 (s, 6H), 0.94 (t, J=8 Hz, 9H), 0.58 (q, J=8 Hz, 6H);13C NMR (150 MHz, CDCl3) δ 212.9, 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 C29H48O4Si (M+Na) + 511.3214, found 511.3210;[α]D19.9 = - 60 o (c = 5.9 in CHCl3);

[0066] (4) Compound 13 (27.0 g, 55.0 mmol, 1.0 eq.) was dissolved in 500 mL of anhydrous chloroform, and p-toluenesulfonic acid monohydrate (11.5 g, 60.8 mmol, 1.1 eq.) was added sequentially at room temperature for 1 hour. TLC monitoring showed that compound 13 had been completely converted after 1 hour. Then, 4AºMS (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, and TLC monitoring showed that it had been completely converted. The reaction system was cooled at 0°C for 10 minutes, and anhydrous methanol (275 mL), sodium bicarbonate (13.8 g, 165.0 mmol, 3.0 eq.), and magnesium monoperoxyphtalic acid hexahydrate (17.0 g, 27.5 mmol, 0.5 eq.) were added sequentially at 0°C for 30 minutes. TLC detection showed that the compound had been completely converted after 30 minutes. Water was added for quenching, and the reaction was extracted with ether. The product was dried over anhydrous sodium sulfate, concentrated, and used directly in the next step;

[0067] (5) Compound 14 (based on 55.0 mmol, 1.0 eq.) was dissolved in 1.1 L of dichloromethane and cooled at 0°C for 5 minutes. Sodium bicarbonate (46.2 g, 550.0 mmol, 10.0 eq.) and Dess-Martin oxidizing agent (35.0 g, 82.5 mmol, 1.5 eq.) were added sequentially at 0°C for 12 hours. The reaction was quenched by slowly adding water after 12 hours. The reaction was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The product was 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%;

[0068] (6) Compound 15 (14.0 g, 34.8 mmol, 1.0 eq.) was dissolved in 200 mL of anhydrous methanol, and 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 sequentially at room temperature for 3 hours. TLC monitoring showed that compound 15 had been completely converted after 3 hours. The reaction was quenched with saturated ammonium chloride solution, and the product was extracted with ether, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 25:1) to obtain product compound 16 (13.5 g) with a yield of 82%; E / Z≥95:5;

[0069] (7) Compound 16 (9.44 g, 20.0 mmol, 1.0 eq.) was dissolved in 250 mL of anhydrous methanol and cooled at -50 °C for 10 min. Then, cerium chloride heptahydrate (3.73 g, 10.0 mmol, 0.5 eq.) was added and stirred at -50 °C for 15 min. Then, sodium borohydride (1.52 g, 40.0 mmol, 2.0 eq.) was added and stirred at -50 °C for 1.5 h. TLC detection showed that compound 16 was completely converted. The reaction was quenched with saturated ammonium chloride and extracted with diethyl ether. The residue was used directly in the next step without further purification;

[0070] (8) The residue (20.0 mmol, 1.0 eq.) was dissolved in 1.0 L of dichloromethane and cooled at 0 °C for 5 min. Then, pyridine (32.3 mL, 400.0 mmol, 20.0 eq.), 4-dimethylaminopyridine (2.46 g, 20.0 mmol, 1.0 eq.) and acetic anhydride (10.2 g, 10.0 mmol, 5.0 eq.) were added successively and reacted at 0 °C for 2 h. TLC detection showed that compound 17b was completely converted. The reaction was quenched with saturated sodium bicarbonate and stirred at 0 °C for 10 min. The residue was extracted with dichloromethane, dried over anhydrous sodium sulfate and concentrated. The residue 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%;

[0071] (9) Compound 17b (12.0 g, 23.4 mmol, 1.0 eq.) was dissolved in 500 mL of anhydrous dichloromethane and cooled at 0 °C for 5 min. Then, pH = 7 phosphate buffer (50 mL) and 2,3-dichloro-5,6-dicyanobenzoquinone (10.64 g, 46.8 mmol, 2.0 eq.) were added successively and reacted at 0 °C for 12 h. TLC detection showed that compound 17b was completely converted. The reaction was quenched with saturated sodium bicarbonate and extracted with diethyl ether. The residue was filtered with diatomite and used directly in the next step without further purification;

[0072] (10) The concentrated solution (23.4 mmol, 1.0 eq.) was dissolved in 500 mL of anhydrous dichloromethane and cooled at 0 °C for 5 min. Then, sodium bicarbonate (19.6 g, 234.0 mmol, 10.0 eq.) and Dess-Martin Oxidizer (14.9 g, 35.1 mmol, 1.5 eq.) were added successively. The reaction was continued at 0 °C for 6 h. After the reaction was completed, the reaction was quenched with water and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 25:1) to give compound 18b (8.1 g) in 88% yield over two steps;

[0073] (11) Potassium osmate (72.55 mg, 0.23 mmol, 5 mol%) and potassium ferricyanide (9.20 g, 27.96 mmol, 3.0 eq.) were added successively to a 250 mL round-bottom flask. The flask was purged with argon three times. Then, 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- naphthalocyanine) diether (363.1 mg, 0.46 mmol, 5 mol%) were added successively. The flask was purged with argon three times. Then, tert-butanol (93 mL) and deionized water (93 mL) were added. The reaction was stirred at room temperature for 45 min. In another 250 mL round-bottom flask, compound 18b (3.90 g, 9.92 mmol, 1.0 eq.) was dissolved in 0 °C for 5 min. Then, the solution prepared in the previous step was added at once. The reaction was continued at 0 °C for 2 h. After the reaction was completed, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1:1) to give 4.04 g of the intermediate product (dr = 11:1) in 95% yield. The intermediate product was unstable and was used directly in the next step;

[0074] (12) Into a 100 mL round bottom flask, the intermediate product from step (11) (4.02 g, 9.40 mmol, 1.0 eq.) was dissolved in 45 mL of anhydrous N,N-dimethylformamide, and then cooled at 0 °C for 5 min. After 5 min, 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 successively. The reaction was carried out at 0 °C for 2 h. After 2 h, the reaction was completed, and then quenched with water. The product was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to give compound 19b (3.82 g) in 75% yield with a dr of 11:1.

[0075] The structural identification data of the compound 19b are as follows: Rf = 0.5 (EA / Petroleum ether = 30%),

[0076] 1H NMR (400 MHz, CDCl3) δ 9.56 (d, J=8 Hz, 1H), 7.32 (d, J=16 Hz, 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=16 Hz, 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=6 Hz, 3H), 1.19 (s, 3H), 1.15 (s, 3H), 0.91 (s, 9H), 0.107 (d, J=3.6 Hz, 6H);13C NMR (150 MHz, CDCl3) δ 194.7, 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-1 3538, 2952, 2858, 2173, 1751, 1721, 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 = - 13.09 o (c = 1.1 in CHCl3).

[0077] The overall yield of all the above steps of this example was 18.5%. Example 3

[0078] Synthesis of the common intermediate of bryostatins, the reaction steps are as follows:

[0079] ;

[0080] (1) Under argon protection, compound 10 (6.01 g, 6.68 mmol, 1.0 eq) obtained from Example 1 was dissolved in 134 mL of toluene (0.05 M) and pre-cooled in an ice bath for 10 minutes. Triethylamine (5.57 mL, 40.08 mmol, 6.0 eq) and 2, 4, 6-trichlorobenzoyl chloride (1.88 mL, 12.02 mmol, 1.8 eq) were added dropwise in sequence, and the reaction was allowed to react at room temperature for 2 hours. The reaction system was again pre-cooled in an ice bath, and compound 19b (3.63 g, 6.68 mmol, 1.0 eq) obtained from Example 2 and 4-dimethylaminopyridine (2.45 g, 20.04 mmol, 3.0 eq) were dissolved in 104 mL of toluene and stirred to complete dissolution. The clear solution was gradually thickened, and was washed with 10 mL of toluene three times. After the addition was completed, the reaction was allowed to react for 12 hours. After the reaction was completed as detected by TLC, ice water was slowly added under ice bath quenching, and extraction was performed with petroleum ether / ethyl acetate = 2:1 (50 mL x 4). The organic phase was dried over anhydrous sodium sulfate and concentrated for use in the next step. A 500 mL round-bottom flask was used to dissolve the concentrated material in 267 mL of methanol (0.025 M), and p-toluenesulfonic acid pyridine (8.39 g, 33.4 mmol, 5.0 eq) and trimethyl orthoformate (5.34 mL) were added under ice bath. The reaction was allowed to react at room temperature for 20 hours. After the reaction was completed as detected by TLC, 100 mL of saturated aqueous sodium bicarbonate solution was added under ice bath quenching, and the aqueous phase was extracted with petroleum ether / ethyl acetate = 2:1 (50 mL x 4). The organic phase was dried over anhydrous sodium sulfate and concentrated, and column chromatography was performed (eluent: petroleum ether / ethyl acetate = 25:1→ 18:1) to obtain compound 21 (7.7 g) as a white foamy substance, with a two-step yield of 85%;

[0081] (2) Argon protection, compound 21 (7.7 g, 5.68 mmol, 1.0 eq) obtained in step (1) was dissolved in 99 mL of anhydrous ether, and was placed in a 250 mL round-bottom flask and pre-cooled in a -78 ℃ cold bath for 10 minutes; purified trifluoromethanesulfonic acid trimethyl silicate (2.06 mL, 11.36 mmol, 2.0 eq) was dissolved in 15 mL of anhydrous ether, and was transferred to the ether solution of compound 21 by a syringe, and the reaction was carried out at the temperature for 2 hours, and the solution changed from colorless and clear to light yellow and slightly turbid; after TLC detection showed that the reaction was completed, 100 mL of saturated sodium bicarbonate aqueous solution was added for quenching, and the solution became colorless and clear again. The aqueous phase was extracted with petroleum ether / ethyl acetate = 2:1 for 3-4 times, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 30:1→20:1) to obtain compound 22 (4.99 g) (cis-Z ≥ 95:5) in the form of white foam, and the yield was 72%;

[0082] Compound 22 structure identification: 1H NMR (400 MHz, CDCl3) δ 7.73 - 7.58 (m, 4H), 7.42 - 7.32 (m, 6H), 6.15 (d, J = 15.6 Hz, 1H), 5.92 (d, J = 1.6 Hz, 1H), 5.36 - 5.26 (m, 3H), 5.18 (dd, J = 11.7, 4.8 Hz, 1H), 5.14 (s, 1H), 4.57 (tt, J = 10.4, 2.4 Hz, 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, 2.8 Hz, 1H), 3.03 (s, 3H), 2.71 (s, 3H), 2.52 (dd, J = 17.2, 3.2 Hz, 1H), 2.31 (dd, J = 13.6, 2.4 Hz, 1H), 2.17 (dd, J = 17.2, 10.0 Hz, 1H), 2.11 - 1.96 (m, 10H), 1.95 - 1.64 (m, 4H), 1.50 (d, J = 16.4 Hz, 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 = 5.2 Hz, 3H), 0.86 (s, 9H), 0.81 (s, 3H), 0.15 (s, 9H), 0.03 (s, 3H), 0.03 (s, 3H);13C NMR (150 MHz, CDCl3) δ 170.7, 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.

[0083] IR (neat) cm-1 2950, 2901, 2859, 1737, 1665, 1620, 1466, 1432, 1369, 1235, 1156, 1096, 1026, 976, 877, 837, 756, 706; HRMS (MALDI, m / z) calcd for C66H102O15Si3 (M+Na)+ 1241.6419, found 1241.6418; NMR spectra are shown in Figures 1 and 2;

[0084] (3) ice bath, under argon protection, compound 22 (4.99 g, 4.09 mmol, 1.0 eq) from step (2) was dissolved in 140 mL of anhydrous acetonitrile in a 500 mL round bottom flask, the outer wall was wrapped with tin foil paper, and the reaction was carried out in the dark; N-iodosuccinimide (2.25 g, 9.98 mmol, 2.0 eq) was dissolved in 70 mL of anhydrous acetonitrile, and slowly added to the reaction system; After 2 hours, TLC detection showed that there was no remaining raw material, 80 mL of saturated sodium thiosulfate aqueous solution and 100 mL of petroleum ether / ethyl acetate (1:1) were added, and the stirring was continued at room temperature for 30 minutes; The organic phase was separated and collected, and the aqueous phase was washed with petroleum ether / ethyl acetate (1:1) for 3-4 times, and the organic phase was combined and dried over anhydrous sodium sulfate. After concentration, fast column chromatography was used to remove the salt, and 400 mL of petroleum ether / ethyl acetate (4:1) was used as the eluent to quickly flush the column, and the concentrated was used for the next step; under argon protection at room temperature, dichlorobis(acetonitrile) palladium (106 mg, 0.409 mmol, 10 mol%) and 1,1'-bis(diphenylphosphino)ferrocene (682 mg, 1.23 mmol, 30 mol%) were weighed into an oven-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 concentrated was added to the prepared solution, and CO was exchanged three times under ice bath; After completion, it was moved to an 85 ℃ oil bath and continued to stir overnight under CO protection; After 12 hours, the raw material reaction was completed, the oil bath was removed, 80 mL of saline and 40 mL of petroleum ether / ethyl acetate (1:1) were added under ice bath to quench the reaction, and the aqueous phase was extracted with petroleum ether / ethyl acetate (1:1) for 3-4 times, 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 white foam (4.2 g), two-step yield: 85%, which was the common intermediate compound 23;

[0085] Compound 23 structural identification data: 1H NMR (600 MHz, CDCl3) δ 7.68 - 7.57 (m, 4H), 7.45 - 7.33 (m, 6H), 6.18 (d, J = 16.2 Hz, 1H), 5.92 (d, J = 2.4 Hz, 1H), 5.72 (t, J = 1.8 Hz, 1H), 5.35 - 5.26 (m, 2H), 5.18 (dd, J = 11.4, 4.8 Hz, 1H), 5.14 (s, 1H), 4.50 (tt, J = 10.2, 2.0 Hz, 1H), 3.93 (ddd, J = 11.4, 7.2, 2.4 Hz, 1H), 3.84 (tt, J = 12.0, 9.0, 2.4 Hz, 1H), 3.71 (s, 3H), 3.69 - 3.62 (m, 7H), 3.49 (tt, J = 11.4, 2.4 Hz, 1H), 3.00 (s, 3H), 2.73 (s, 3H), 2.51 (dd, J = 17.4, 3.0 Hz, 1H), 2.16 (dd, J = 17.4, 10.2 Hz, 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, 2.4 Hz, 1H), 1.68 - 1.65 (m, 1H), 1.52 (d, J = 16.2 Hz, 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 = 6.0 Hz, 3H), 0.87 (s, 9H), 0.81 (s, 3H), 0.02 (s, 3H), 0.02 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 170.7, 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"1 2948, 2897, 2859, 2160, 1727, 1655, 1466, 1434, 1371, 1235, 1156, 1101, 1027, 878, 831, 775, 706; HRMS (MALDI, m / z) calcd for C65H96O17Si2 (M+Na)+ 1227.6078, found 1227.6082. Example 4

[0086] Synthesis of Graptolite 7: Lithium tetrafluoroborate (149 mg, 1.59 mmol, 46 equiv) was weighed into a PP tube, 6.25 mL of acetonitrile and 0.25 mL of pure water were added, and the mixture was stirred until it became clear to obtain a 0.25 M solution of lithium tetrafluoroborate in acetonitrile / water. The common intermediate compound 23 (41.6 mg, 0.0345 mmol, 1.0 equiv) was added to the above solution and moved to a 86 °C oil bath for 2 hours; removed from the oil bath and cooled to room temperature, and then imidazole (893 mg, 13.12 mmol, 380 equiv) and 40% hydrofluoric acid aqueous solution (285 uL, 6.56 mmol, 190 equiv) were added in turn, and placed in a 40 °C oil bath for 24 hours; after the reaction was completed, ice water was added to quench at room temperature, and extracted with petroleum ether / ethyl acetate (1:1) for 3-4 times; the organic phase was washed with 1 M hydrochloric acid, saturated sodium bicarbonate aqueous solution, and then re-extracted with petroleum ether / ethyl acetate (1:1) to wash the aqueous phase of the organic phase twice, and the combined organic phase was dried over anhydrous sodium sulfate. After concentration, column chromatography purification (eluent: petroleum ether / ethyl acetate = 2:1→1:1) gave Graptolite 7 as 14.5 mg of white paste, yield: 51%.1H NMR (600 MHz, CDCl3) δ 5.97 (d, J = 2.4 Hz, 1H), 5.77 (d, J = 16.2 Hz, 1H), 5.68 (t, J = 1.8 Hz, 1H), 5.32 (dd, J = 15.6, 8.4 Hz, 1H), 5.18 (s, 1H), 5.19 – 5.14 (m, 1H), 5.15 (dd, J = 12.0, 4.8 Hz, 1H), 5.10 (s, 1H), 4.24 (d, J = 12.0 Hz, 1H), 4.20 (tt, J = 12.0, 3.0 Hz, 1H), 4.17 – 4.10 (m, 1H), 4.07 (ddd, J = 11.4, 8.4, 2.4 Hz, 1H), 4.00 (tt, J = 11.4, 2.4 Hz, 1H), 3.87 (ddd, J = 11.4, 7.2, 2.4 Hz, 1H), 3.77 (h, J = 6.6 Hz, 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 = 7.6 Hz, 1H), 2.21 (d, J = 12.7 Hz, 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, 3.0 Hz, 1H), 1.74 (ddd, J = 12.6, 4.8, 2.8 Hz, 1H), 1.68 – 1.64 (m, 1H), 1.57 (dt, J = 15.0, 3.6 Hz, 1H), 1.48 (q, J = 12.0 Hz, 1H), 1.23 (d, J = 6.4 Hz, 3H), 1.15 (s, 3H), 1.00 (s, 6H), 0.94 (s, 3H).13C NMR (150 MHz, CDCl3) δ 172.3, 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-1 3462, 3364, 2972, 2956, 2926, HRMS (MALDI, m / z) calcd For C41H60O17 (M+Na)+ 847.3723, 847.3721 was found; NMR spectra are shown in Figures 3 and 4. Example 5

[0087] Synthesis of Ulapualide 9: 1) The key intermediate product (42.7 mg, 0.354 mmol, 1.0 equiv) was dissolved in 3.5 mL of methanol in a 10 mL test tube under argon protection at room temperature, and 24.5 mg of potassium carbonate (0.177 mmol, 5.0 equiv) was added. The mixture was stirred at room temperature for 1 h. After TLC detection showed that the reaction was complete, 5 mL of saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with petroleum ether / ethyl acetate (1:1) for 3-4 times. The organic phase was dried over anhydrous sodium sulfate and concentrated for the next step; 2) The concentrated product from the previous step was dissolved in 1.2 mL of dichloromethane in a 10 mL test tube under argon protection and placed in an ice bath. 4-Dimethylaminopyridine (4.3 mg, 0.0354 mmol, 1.0 equiv) and pyridine (28.6 uL, 0.354 mmol, 10 equiv) were added in sequence, and butyric anhydride (29 uL, 0.177 mmol, 5 equiv) was added dropwise after the solid was completely dissolved. The mixture was removed from the ice bath and stirred at room temperature for 4 h. After TLC detection showed that 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. The organic phase was dried over anhydrous sodium sulfate and concentrated, and the product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 20:1) to give 32.4 mg of white foam, with a yield of 74%; 3) The product from the previous step (18.7 mg, 0.0152 mmol, 1.0 equiv) was used as the starting material, and the experimental operation was the same as that described in the synthesis of Ulapualide 7. The obtained concentrated product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to give Ulapualide 9 as 9.5 mg of white film, with a yield of 73%.1H NMR (600 MHz, CD3OD) δ 5.87 (d, J = 2.4 Hz, 1H), 5.87 (d, J = 15.6 Hz, 1H), 5.75 (t, J = 1.2 Hz, 1H), 5.33 (dd, J = 15.6, 8.4 Hz, 1H), 5.22 (dd, J = 11.4, 4.8 Hz, 1H), 5.21 (ddd, J = 12.6, 4.2, 3.0 Hz, 1H), 5.10 (s, 1H), 4.24 (tt, J = 12.0, 3.0 Hz, 1H), 4.14 – 4.06 (m, 2H), 4.01 – 3.93 (m, 2H), 3.83 (qd, J = 6.6, 2.4 Hz, 1H), 3.68 (s, 3H), 3.67 (s, 3H), 3.64 (dd, J = 7.2, 2.4 Hz, 1H), 3.62 (dd, J = 7.2, 2.4 Hz, 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, 2.4 Hz, 1H), 1.88 (ddd, J = 13.8, 11.4, 2.4 Hz, 1H), 1.85 – 1.76 (m, 2H), 1.74 – 1.66 (m, 3H), 1.65 (dd, J = 7.2, 3.0 Hz, 1H), 1.62 (dd, J = 7.2, 3.0 Hz, 1H), 1.46 (q, J = 12.0 Hz, 1H), 1.19 (s, 3H), 1.14 (d, J = 5.4 Hz, 3H), 1.01 (s, 6H), 0.92 (s, 3H), 0.92 (t, J = 7.2 Hz, 3H).13C NMR (150 MHz, CDCl3) δ 172.4, 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-1 3471, 3354, 2964, 2932, 2860, 1737, 1721, 1657, 1463, 1435, 1379, 1367, 1282, 1258, 1250, 1158, 1101, 1081, 1061, 1029, 1001, 985, 860, 800; HRMS (MALDI, m / z) calcd for C43H64O17 (M+Na)+ 875.4036, found 875.4037; NMR spectra are shown in Figures 5 and 6. Example 6

[0088] Synthesis of the analogue of bryostatins 9-N3: 1) The concentrate obtained after the removal of the hydroxyacetyl protecting group at C20 and the 4-azidobutyrylation reaction was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 22:1→12:1) to give a white foamy substance 63.1 mg, yield: 99%; 2) The product of the previous step (51 mg, 0.04 mmol, 1.0 eq.) was used as a starting material, the experimental procedure is described in detail for the synthesis of bryostatin 7. The concentrate obtained after purification by column chromatography gave bryostatin 9-N3 analogue as a white film 23.2 mg, yield 65%.1H NMR (600 MHz, CD3OD) δ 5.88 (d, J = 2.4 Hz, 1H), 5.87 (d, J = 15.6 Hz, 1H), 5.75 (d, J = 1.2 Hz, 1H), 5.33 (dd, J = 15.6, 8.4 Hz, 1H), 5.24 – 5.17 (m, 2H), 5.11 (s, 1H), 4.24 (tt, J = 12.0, 3.0 Hz, 1H), 4.14 – 4.06 (m, 2H), 4.01 – 3.92 (m, 2H), 3.83 (qd, J = 6.6, 2.4 Hz, 1H), 3.68 (s, 3H), 3.67 (s, 3H), 3.64 (dd, J = 9.0, 2.4 Hz, 1H), 3.62 (dd, J = 9.0, 2.4 Hz, 1H), 3.35 (td, J = 6.6, 1.2 Hz, 2H), 2.56 (d, J = 7.2 Hz, 2H), 2.48 – 2.39 (m, 2H), 2.18 (d, J = 6.0 Hz, 2H), 2.11 – 2.03 (m, 2H), 2.02 (s, 3H), 1.97 (ddd, J = 14.4, 12.0, 2.4 Hz, 1H), 1.91 – 1.85 (m, 3H), 1.84 – 1.78 (m, 2H), 1.75 – 1.65 (m, 3H), 1.46 (q, J = 12.0 Hz, 1H), 1.19 (s, 3H), 1.15 (d, J = 6.6 Hz, 3H), 1.02 (d, J = 4.5 Hz, 6H), 0.92 (s, 3H).13C NMR (150 MHz, CD3OD) δ 171.8, 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 C43H63N3O17 (M+Na)+ 916.4050, found 916.4050; NMR spectra are shown in Figures 7 and 8. Example 7

[0089] Synthesis of Buglossin 1: 1) The key intermediate product (3.74 g, 3.1 mmol, 1.0 equiv) was used as the starting material, and the specific experimental operation for removing the hydroxyacetyl protection at C20 was described in the synthesis of Buglossin 9 precursor compound. 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 equiv) was dissolved in 62 mL of toluene in a 250 mL round-bottom flask, and triethylamine (1.3 mL, 9.3 mmol, 3.0 equiv) and 2,4,6-trichlorobenzoyl chloride (1.45 mL, 9.3 mmol, 3.0 equiv) were sequentially added dropwise. After addition, it was moved to room temperature for 1 hour. Then it was pre-cooled in an ice bath, while the concentrate from the previous step and 4-dimethylaminopyridine (947 mg, 7.75 mmol, 2.5 equiv) were dissolved in 50 mL of toluene and transferred to the pre-cooled reaction system with the help of a syringe. Slowly add, the clear solution in the reaction system gradually became turbid, and rinse the remaining raw materials with 3x4 mL. After addition, it was moved to room temperature for 12 hours; after the reaction was completed, ice water was added under ice bath quenching, extracted with petroleum ether / ethyl acetate (1:1) for 3-4 times, 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 white foam, yield: 99%; 3) The product from the previous step (3.05 g, 2.37 mmol, 1.0 equiv) was used as the starting material, and the specific experimental operation was described in the synthesis of Buglossin 7. The obtained concentrate was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 3:1→2:1) to obtain Buglossin 1 as 1.5 g of white solid, yield: 70%.1H NMR (600 MHz, CDCl3) δ 7.27 (dd, J = 15.0, 10.2 Hz, 1H), 6.20 – 6.12 (m, 2H), 6.01 (d, J = 2.4 Hz, 1H), 5.80 (d, J = 15.3 Hz, 1H), 5.78 (d, J = 15.8 Hz, 1H), 5.67 (t, J = 1.8 Hz, 1H), 5.31 (dd, J = 16.2, 8.4 Hz, 1H), 5.18 (s, 1H), 5.20 – 5.14 (m, 2H), 5.17 (s, 1H), 4.24 (d, J = 11.4 Hz, 1H), 4.20 (tt, J = 11.4, 2.8 Hz, 1H), 4.18 – 4.10 (m, 1H), 4.07 (ddd, J = 11.4, 8.4, 2.4 Hz, 1H), 4.01 (tt, J = 11.4, 2.4 Hz, 1H), 3.90 (ddd, J = 10.8, 7.2, 2.4 Hz, 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 = 12.0 Hz, 1H), 2.44 (dd, J = 12.6, 2.4 Hz, 1H), 2.20 (t, J = 12.0 Hz, 1H), 2.17 – 2.12 (m, 2H), 2.11 – 1.93 (m, 5H), 2.05 (s, 3H), 1.89 (dd, J = 15.0, 10.2 Hz, 1H), 1.82 (ddd, J = 14.4, 11.4, 3.0 Hz, 1H), 1.73 (ddd, J = 12.6, 4.8, 2.4 Hz, 1H), 1.66 (d, J = 15.0 Hz, 1H), 1.57 (dt, J = 15.0, 3.0 Hz, 1H), 1.49 (q, J = 12.6 Hz, 1H), 1.45 (h, J = 7.2 Hz, 2H), 1.23 (d, J = 6.6 Hz, 3H), 1.15 (s, 3H), 1.00 (s, 6H), 0.94 (s, 3H), 0.91 (t, J = 7.2 Hz, 3H).13C NMR (150 MHz, CDCl3) δ 172.3, 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 C47H68O17 (M+Na)+ 927.4349, found 927.4347; NMR spectra are shown in Figures 9 and 10.

[0090] Examples 8-12:

[0091] Compared with Example 3, the concentration of the reaction system in step (1) was adjusted 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 Example 3 step (1), and the corresponding yields were 40%, 65%, 78%, 64%, and 44%, respectively.

[0092] Examples 13-15

[0093] Compared with Example 3, the material ratio of the A ring compound to the C ring compound in step (1) was adjusted to 1:1.2, 1:1.5, and 1:2, respectively, and the rest was the same as Example 3 step (1), and the corresponding yields were 84%, 85%, and 84%, respectively.

[0094] Examples 16-20:

[0095] Compared with Example 3, the material ratio of compound 21 to trimethylsilyl trifluoromethanesulfonate 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 Example 3 step (2), and the corresponding yields were 50%, 71%, 74%, 73%, and 73%, respectively, and the cis-Z ratio was ≥90:10, ≥95:5, ≥95:5, ≥95:5, and ≥95:5, respectively.

[0096] Examples 21-24:

[0097] Compared with Example 3, the concentration of the reaction system in step (2) is adjusted to 0.005 mol / L, 0.01 mol / L, 0.02 mol / L, 0.04 mol / L respectively, and the rest is the same as that in Example 3, step (2), and the corresponding yields are 40%, 50%, 56%, 65% respectively, and the cis-Z ratio is ≥95:5, ≥95:5, ≥95:5, ≥95:5 respectively.

[0098] Examples 25-30:

[0099] Compared with Example 3, the temperature of the reaction system in step (2) is adjusted to -45℃, -50℃, -60℃, -65℃, -80℃, -90℃ respectively, and the rest is the same as that in Example 3, step (2), and the corresponding yields are 50%, 55%, 56%, 62%, 70%, 71% respectively, and the cis-Z ratio is ≥85:15, ≥85:15, ≥90:10, ≥90:10, ≥95:5, ≥95:5 respectively.

[0100] Examples 31-35:

[0101] Compared with Example 3, the Lewis acid trimethylsilyl trifluoromethanesulfonate in step (2) is adjusted to 4-methylbenzenesulfonic acid pyridine, magnesium bromide etherate, boron trifluoride etherate, titanium tetrachloride, tin tetrachloride respectively, and the rest is the same as that in Example 3, step (2), and the corresponding yields are 5%, 5%, 5%, 3%, 3% respectively.

[0102] Examples 36-41:

[0103] Compared with Example 3, the solvent ethyl ether in step (2) is adjusted to methyl tert-butyl ether, isopropyl ether, dichloromethane, methanol, tetrahydrofuran, toluene respectively, and the rest is the same as that in Example 3, step (2), and the corresponding yields are 70%, 65%, 50%, 30%, 22%, 33% respectively.

[0104] Examples 42-46:

[0105] Compared with Example 3, the temperature of the reaction system in step (3) is adjusted to 60℃, 65℃, 70℃, 80℃, 90℃ respectively, and the rest is the same as that in Example 3, step (2), and the corresponding yields are 40%, 57%, 68%, 81%, 85% respectively.

[0106] Examples 47-50:

[0107] Compared with Example 3, the concentration of the reaction system in step (3) was adjusted to 0.02 mol / L, 0.03 mol / L, 0.04 mol / L, and 0.05 mol / L, respectively, and the rest was the same as step (2) of Example 3, and the corresponding yields were 63%, 71%, 63%, and 43%, respectively.

[0108] Examples 51-55:

[0109] Compared with Example 3, lithium tetrafluoroborate in step (4) was adjusted to 5 wt.% hydrochloric acid, p-toluenesulfonic acid, 4-methylbenzenesulfonic acid pyridine, trifluoroacetic acid, and triethylsilyl trifluoromethanesulfonate, and the rest was the same as step (4) of Example 3, and the corresponding yields were 50%, 55%, 61%, 73%, and 81%, respectively.

[0110] Examples 56-59:

[0111] Compared with Example 3, the reaction solvent acetonitrile / water in step (4) was adjusted to a single solvent acetonitrile, dichloromethane, tetrahydrofuran, and 1,4-dioxane, and the rest was the same as step (4) of Example 3, and the corresponding yields were 65%, 50%, 30%, and 27%, respectively.

[0112] Examples 60-63:

[0113] Compared with Example 3, the concentration of the reaction system in step (4) was adjusted 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, and the corresponding yields were 39%, 89%, 82%, and 48%, respectively.

[0114] Examples 64-68:

[0115] Compared with Example 3, the protecting group P in general formula (III) was adjusted to trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, isopropyldiethylsilyl, tert-butyldimethylsilyl, and triisopropylsilyl, and the rest was the same as step (2) of Example 3, and the corresponding yields were 37%, 39%, 59%, 69%, 80%, and 81%, respectively, and the cis-Z ratio was ≥95:5, ≥95:5, ≥95:5, ≥95:5, ≥95:5, and ≥95:5, respectively.

[0116] Examples 69-74:

[0117] Comparing with Example 3, the protecting group P1 in general formula (III) is changed from H to trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, isopropyldiethylsilyl, t-butyldimethylsilyl, triisopropylsilyl, and the rest is the same as Example 3 step (2), and the corresponding yields are 50%, 43%, 18%, 15%, 8%, 5% respectively, and the cis-Z ratio is ≥95:5, ≥95:5, ≥95:5, ≥95:5, ≥95:5, ≥95:5 respectively.

[0118] Examples 75-76:

[0119] Comparing with Example 3, the protecting group P2 in general formula (III) is changed from methyl to ethyl, acetyl, and the rest is the same as Example 3 step (2), and the corresponding yields are 75%, 71% respectively, and the cis-Z ratio is ≥95:5, ≥95:5 respectively.

[0120] Examples 77-82:

[0121] Comparing with Example 3, R2 in general formula (III) is changed from acetyl to benzoyl, benzyl, ethyl, trichloroethyl, 2-trimethylsilyl ethyl, 4-methoxybenzyl, and the rest is the same as Example 3 step (2), and the corresponding yields are 78%, 86%, 85%, 81%, 78%, 87% respectively, and the cis-Z ratio is ≥95:5, ≥95:5, ≥95:5, ≥95:5, ≥95:5, ≥95:5 respectively.

[0122] Examples 83-87:

[0123] Comparing with Example 3, R4 in general formula (III) is changed from methyl to ethyl and ethyl, ethyl and hexyl, ethyl and phenethyl, pentyl, fluorine and ethyl, and the rest is the same as Example 3 step (2), and the corresponding yields are 81%, 78%, 89%, 79%, 83% respectively, and the cis-Z ratio is ≥95:5, ≥95:5, ≥95:5, ≥95:5, ≥95:5 respectively.

[0124] Examples 88-89:

[0125] Comparing with Example 3, R8 in general formula (III) is changed from acetyl to benzoyl, 2-octynoyl, and the rest is the same as Example 3 step (2), and the corresponding yields are 84%, 82% respectively, and the cis-Z ratio is ≥95:5, ≥95:5 respectively.

[0126] Example 90:

[0127] Comparing with Example 3, R11 in general formula (III) is changed from methyl to ethyl, and the rest is the same as Example 3 step (2), and the corresponding yield is 88%, and the cis-Z ratio is ≥95:5.

Claims

1. A method of synthesizing a key intermediate of a bryostatin analogue compound, characterized in that, The method is that under the protection of inert gas, the compound of formula (III) is dissolved in a reaction solvent, then a Lewis acid is added to perform intramolecular Prins cyclization reaction to obtain the compound of formula (IV), and the reaction formula is as follows: ， in the above formula, R 2 a chemical protecting group for each type of hydroxyl group selected from H, silyl, alkyl, substituted alkyl, acyl, substituted acyl, aryl, or aryl substituted with each heteroatom, or a synthetic equivalent thereof; R 4 , R 6 , R 7 selected from H, alkyl, substituted alkyl, alkenyl, alkynyl, halogen, amino, phenyl, substituted phenyl; R 5 selected from alkyl or substituted alkyl, R 8 selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, or aryl substituted with each heteroatom, R 9 selected from H, alkyl, substituted alkyl, aryl, or aryl substituted with each heteroatom, R 10 , R 11 , P 2 selected from H, alkyl, substituted alkyl; P, P 1 P, P 3 each independently is selected from one of H, silicon group, alkyl group, substituted alkyl group, phenyl group, substituted phenyl group.

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

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

4. The method of claim 1, wherein, The reaction temperature is -45℃ to -90℃, and preferably -78℃.

5. A method for synthesizing bryophyte compounds, characterized in that, The method comprises the following steps: (1) under the protection of inert gas, an A ring compound of formula (I) and a C ring compound of formula (II) are used as raw materials to perform esterification reaction and acetalization to obtain the compound of formula (III); ； in the above formula, R 1 a chemical protecting group selected from H, a silyl group, an alkyl group, a substituted alkyl group, an acyl group, a substituted acyl group, an aromatic group, or an aromatic group substituted with each heteroatom, and the like, or one of its synthetic equivalents; (2) under the protection of inert gas, the compound of formula (III) is dissolved in a reaction solvent, then a Lewis acid is added to perform reaction to obtain the compound of formula (IV); ； (3) under the protection of inert gas, the compound of formula (IV) is subjected to iodination and palladium-catalyzed carbonylation reaction to obtain the common intermediate compound of formula (V); ； (4) the common intermediate compound of formula (V) is used as raw material to perform reaction under the action of a Lewis acid and hydrofluoric acid to obtain ulaplandin 7; or after deacetylation of the C20 hydroxyl group and butyrylation of the C20 hydroxyl group, the reaction is performed under the action of a Lewis acid and hydrofluoric acid to obtain ulaplandin 9; or after removal of acetyl protection of the C20 hydroxyl group and 4-azido butyrylation of the C20 hydroxyl group, the reaction is performed under the action of a Lewis acid and hydrofluoric acid to obtain ulaplandin 9-N3 analog for the first time; or after removal of acetyl protection of the C20 hydroxyl group and octadienoate esterification of the C20 hydroxyl group, the reaction is performed under the action of a Lewis acid and hydrofluoric acid to obtain ulaplandin 1.

6. The method of claim 5, wherein, In step (1), the reaction concentration is 0.02 mol / L-0.1 mol / L, and preferably 0.05 mol / L.

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

8. The method of claim 5, wherein, In step (3), the carbonylation reaction temperature is 60℃-90℃, and preferably 85℃.

9. The method of claim 5, wherein, In step (3), the reaction concentration is 0.02 mol / L-0.05 mol / L, and preferably 0.025 mol / L.

10. The method of claim 5, wherein, In step (4), the Lewis acid is selected from one of 5wt.% hydrochloric acid, p-toluenesulfonic acid, 4-methylbenzenesulfonic acid pyridine, trifluoroacetic acid, and triethylsilyl trifluoromethanesulfonate, and preferably lithium tetrafluoroborate.

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