CN112110951B

CN112110951B - Carex C-ring framework compound, and synthesis method and application thereof

Info

Publication number: CN112110951B
Application number: CN202011031767.2A
Authority: CN
Inventors: 宋振雷; 高璐; 褚志文; 童瑞棋; 杨宇帆; 宋宣毅; 胡天宝; 范昱
Original assignee: Sichuan University
Current assignee: Sichuan University
Priority date: 2020-09-27
Filing date: 2020-09-27
Publication date: 2021-05-18
Anticipated expiration: 2040-09-27
Also published as: CN112110951A

Abstract

The invention discloses a bryodin C-ring framework compound, a synthetic method and application thereof, belonging to the technical field of chemical synthesis of natural products. In the invention, the ketene compound and the iodo-hydrocarbon compound are subjected to water-phase free radical coupling reaction to obtain a C-ring precursor compound, namely the bryodin C-ring skeleton compound; the known compound of the bryostatin C ring precursor is obtained by ring closing, epoxy opening, oxidation and Aldol reaction under acidic conditions, and the analogue of the bryostatin C compound is obtained by combining the prior art (such as Luche reduction butyrylation, TABF desilication, DMP oxidation, Sharpless asymmetric dihydroxylation reaction and the like) and is used as an important synthon compound library for drug screening to promote the drug development and clinical research of the Bryostatin family. The synthesis process has high synthesis efficiency, and compared with the existing synthesis route, the synthesis process has the advantages of reducing the operation steps and shortening the whole synthesis period.

Description

Carex C-ring framework compound, and synthesis method and application thereof

Technical Field

The invention relates to a bryodin C-ring framework compound, a synthetic method and application thereof, belonging to the technical field of chemical synthesis of natural products.

Background

Bryostatin (1968) is a marine macrolide compound extracted from Haematococcus sp, and has anticancer, AIDS resisting, and Alzheimer disease resisting effects. Since the Pettit group identified the compound as Bryostatin 1 in 1982 with the aid of single crystal and spectroscopic techniques, extraction and separation studies have been carried out to increase the number of members of this natural product to 21, wherein the anticancer activity of Bryostatin 1 was first discovered starting from the detection of its ability to inhibit the proliferation of murine P388 lymphoid leukemia cells, and then it was discovered that this natural product has significant antitumor activity against a range of cancer cells in vitro and in vivo, including homohl-60 human promyelocytic leukemia cells, P388 lymphoid leukemia, B16 melanoma, and M5076 reticulocyte malignancies. In view of the above good experimental results, scientists have conducted several anticancer clinical studies on Bryostatin 1, and Bryostatin 1 alone or in combination with other chemotherapeutic agents has been applied to over 80 clinical trials.

The Bryostatin family is a 20-membered macrolide natural product with complex structure, multiple chiral centers, high oxidation state and high functionalization, belongs to polyketides in terms of biogenesis, and has a framework structure comprising: three ABC polysubstituted tetrahydropyrane rings in different oxidation states, C16-C17E-type double bonds with larger steric hindrance linking the BC rings, gem-dimethyl (Bryostatins 1-20) or chiral monomethyl (Bryostatin 21) at C18 position and two acid-base unstable exocyclic unsaturated bonds at C13\ C17 positionEsters (C9 and C19 except Bryostatin 16 and 17 are ketal structures). The 21 molecular structures in the Bryostatin family differ slightly, for example: the structural differences of 15 family molecules such as Bryostatin 1, 2, 4-15 and 18 are only reflected in the change of acyloxy substitution at C7 on A ring and C20 on C ring, and common substituents include OAc and O₂C（CH₂）₂Me、O₂C（CH）₄（CH₂）₂Me, OPiv, etc. Research reports that C20 substituent groups in separated Bryostatin family molecules extracted from bryozoan groups grown in different depth sea areas and symbiotic bacteria are varied to obtain Bryostatin molecules with different contents. In addition, the Bryostatin 16 and 17 contain a special C19-C20 electron-rich double bond structure and are generally considered as biogenic molecules of the Bryostatin family: the C19-C20 electron-rich double bond in Bryostatin 17 can be converted into Bryostatin 18 through hydration; the double bond at C19-C20 position in Bryostatin 16 is oxidized, hydrated or reacted with oxidized C22 position to convert Bryostatin 1-15, 19 or 20 molecules.

Because the natural product bryostatin family molecules have a challenging unique structural framework, and high bioactivity shown in vitro and in vivo, and the extraction and separation yield from the nature is extremely low, the total synthesis of the natural product bryostatin family molecules is an urgent problem to be solved, wherein the key of the total synthesis efficiency is as follows: how to efficiently construct three polysubstituted pyran rings of Bryostatin A and B, C, especially the construction of a ring A and a ring C which are in a high oxidation state and polysubstituted, determines the specific molecular species of the Bryostatin synthesized and the length and efficiency of the synthetic route. At present, on the basis of synthesis of A, B, C three ring frameworks, according to different methods for splicing ABC three rings and constructing 26-membered macrolide core frameworks, a main total synthesis route comprises the following steps:

firstly, an Aldol or alkylation reaction is carried out to splice an AB ring, Julia olefination is connected with a BC ring, and Yamaguchi large ring lactonization is connected with an AC ring;

secondly, Julia olefination is connected with a BC ring, an AB ring is spliced through alkylation reaction, and Yamaguchi large ring lactonization is connected with an AC ring;

thirdly, Au-catalyzed alkene-alkyne coupling and Michael addition are carried out to construct an AB ring, Yamaguchi large ring internal esterification is carried out to construct an AC ring segment, and Au-catalyzed alkene-alkyne coupling and 6-endo-dig cyclization are connected to construct a C ring;

and fourthly, constructing a B ring by means of Prins cyclization and simultaneously connecting a BC ring, and performing macrocyclic lactonization of Yamaguchi to connect an AC ring.

In addition, the C-loop in the Bryostatin family molecules is a pharmacodynamic recognition domain (which is proposed in researches on Bryostatin analogues by groups such as Wender, Paul A group, Keck, Gary E group, Krische, Michael J group and the like), i.e. the efficient synthesis of the C-loop in the Bryostatin family is important in the whole synthesis research of the Bryostatin family molecules and the synthesis research of the Bryostatin family analogue molecules. Currently, the C-ring synthetic route involves the following major difficulties:

i, construction of C16-C17E-double bond: Julia-Lythgoe olefination and HWE olefination are commonly used;

II, C20 and C23 chiral hydroxyl synthesis: reducing by using C20 hydroxyl Luche, and reacting by using C23 hydroxyl Aldol;

III, constructing alpha, beta-unsaturated ester outside the pyran ring: the Aldol reaction is commonly used, alkenylsilicon iodocarbonyl.

Disclosure of Invention

Based on the current research situation, the inventor provides a brand-new synthesis route of C-ring framework molecules in the bryodin, obtains a class of bryodin C-ring framework compounds, then obtains a series of known compounds of bryodin C-ring precursors based on a brand-new synthesis process route, and finally combines the existing mature technologies, such as: through Luche reduction and butyrylation, TABF desilication, DMP oxidation, Sharpless asymmetric dihydroxylation reaction and the like (Total Synthesis of Bryostatin 8 Using an organic silane-Based Strategy, 2018) (Bryostatin 8 is completely synthesized Based on an Organosilane Strategy), the Bryostatin C ring compound or the analogue thereof is obtained and is used as an important synthon compound library for drug screening, and the drug development and clinical research of Bryostatin families are effectively promoted.

In order to achieve the technical purpose, the following technical scheme is proposed:

the technical scheme provides a bryodin C-ring framework compound which is a key intermediate for preparing a pharmaceutical composition containing bryodin or analogues thereof and is represented by the following structural general formula (I):

（Ⅰ）

in the general structural formula (I), R₁The representative group is straight-chain alkyl, cyclic alkyl, alkenyl, alkynyl, hydroxyl, ether, ester group, cyano, halogen, amino, aryl or alkyl substituted by each heteroatom;

R₂the representative group is straight-chain alkyl, cyclic alkyl, alkenyl, alkynyl, hydroxyl, ether, ester group, cyano, halogen, amino, aryl or alkyl substituted by each heteroatom;

R₃the representative group is straight-chain alkyl, cyclic alkyl, alkenyl, alkynyl, ether, halogen, aryl or alkyl substituted by each heteroatom.

Further, the bryodin C-ring framework compound is obtained by modifying an E-type double bond at the C25-26 position, and comprises the following structural formula:

。

further, the bryozoacin C-ring framework compound is obtained by modifying side chains at a geminal dimethyl alpha position and a C17 position, and comprises the following structural formula:

。

further, the bryodin C-ring framework compound is obtained by modifying a symmetrical gem-dimethyl group at the C18 position, and comprises the following structural formula:

。

further, the bryodin C-ring framework compound is obtained by modifying C25-26 site, C17 site side chain and C18 site, and comprises the following structural formula:

the technical scheme provides a method for synthesizing a bryodin C-ring framework compound, which comprises the steps of carrying out aqueous phase free radical coupling reaction on an ketene compound and an iodohydrocarbon compound to obtain a bryodin C-ring framework compound, namely a bryodin C-ring precursor compound; wherein, the ketene compound is represented by the following general formula (II), and the iodohydrocarbon compound is represented by the following general formula (III):

（Ⅱ）（Ⅲ）。

further, the method for synthesizing the bryodin C-ring framework compound comprises the following specific steps:

respectively adding an ketene compound, an iodo hydrocarbon compound, zinc powder, cuprous iodide, absolute ethyl alcohol and TPGS aqueous solution into a reaction device, and stirring and reacting for 8-24h at the temperature of 0-40 ℃; adding equal amount of zinc powder, cuprous iodide, anhydrous ethanol and TPGS aqueous solution (such as TPGS-750-M, purchased directly) into the reaction tube, stirring at 0-40 deg.C for 8-24 hr, adding water into the reaction device, and quenching; then, extracting with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, and concentrating under reduced pressure; purifying with silica gel column chromatography to obtain bryodin C ring skeleton compound as light yellow liquid. The reaction process is as follows:

（Ⅱ）（Ⅲ）（Ⅰ）

further, the zinc powder can also be replaced by zinc particles, but the zinc powder is preferably selected to effectively ensure the yield of the product.

Further, the cuprous iodide purity is > 90%.

Furthermore, before feeding materials into the reaction device, the ketene compound and the iodo-hydrocarbon compound are prepared into corresponding ethanol solutions by using absolute ethanol, so that the materials are fully contacted in the reaction process, and the influence on the reaction quality and efficiency due to overlarge local concentration is avoided; wherein, in the preparation process of the corresponding ethanol solution of the ketene compound and the iodo-hydrocarbon compound, the total ethanol amount entering the reaction device is ensured to be constant.

Further, in the TPGS aqueous solution, the mass fraction of TPGS is 1-5%, preferably 2%.

Furthermore, the stirring speed is 400-2400 r/min, so that the contact among all the substances is effectively ensured to be more sufficient, and the reaction quality and efficiency are improved.

Further, the mass ratio of the ketene compound to the iodohydrocarbon compound is 2: 1-1:6, the mass ratio of the ketene compound to the zinc is 1:1-1:8, and the mass ratio of the ketene compound to the cuprous iodide is 1: 0.2-1: 3.6.

Furthermore, the weight ratio of the ketene compound, the iodohydrocarbon compound, the zinc and the copper iodide is 1.0: 3.0: 5.0: 1.2.

further, the preparation method of the ketene compound comprises the following steps:

x1: under the protection of argon and at the temperature of-78 ℃ (a low-temperature anhydrous oxygen-free reaction environment is created), adding a diisopropylamine lithium-n-hexane solution into a reaction device filled with tetrahydrofuran, slowly adding isobutyric acid, stirring and reacting at the temperature of-78 ℃ for 1.5 h, and then heating to the temperature of-40 ℃ for reacting for 1 h; adding a tetrahydrofuran solution of 3-bromopropylene at the temperature of minus 40 ℃, and then heating to room temperature for reaction for 10 hours; then, adding an ammonium chloride aqueous solution for quenching, extracting by using ethyl acetate, combining organic phases, drying by using anhydrous sodium sulfate, and concentrating under reduced pressure; purifying with silica gel column chromatography to obtain intermediate product X1 as light yellow liquid;

x2: adding the obtained intermediate product X1 into a reaction device filled with carbon tetrachloride, adding N-bromosuccinimide and dibenzoyl peroxide, vacuumizing, introducing argon, and stirring and reacting for 1h at 105 ℃; then, cooling to room temperature, standing, adding water for quenching, extracting with dichloromethane, combining organic phases, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and spin-drying to obtain an intermediate product X2 which is a colorless liquid;

x3: adding 2, 6-di-tert-butyl-4-methylpyridine into dichloromethane at 0 ℃, cooling for 5min, and then sequentially adding silver trifluoromethanesulfonate and TBDSOH; stirring and reacting for 5min at the temperature of 0 ℃, slowly adding a dichloromethane solution of an intermediate product X2, and continuously stirring and reacting for 45min at the temperature of 0 ℃; then adding water for quenching, extracting by using dichloromethane, combining organic phases, drying by using anhydrous sodium sulfate, and concentrating under reduced pressure; purifying with silica gel column chromatography to obtain intermediate product X3 as colorless liquid;

x4: under the protection of argon, adding the intermediate product X3 into a reaction device filled with tetrahydrofuran, cooling for 10min at the temperature of minus 20 ℃, adding N, O-dimethylhydroxylamine hydrochloride, reacting for 10min under stirring, slowly adding N-hexane solution of i-PrMgCl, controlling the dropping speed to be 45min after dropping, and then heating to the temperature of minus 10 ℃ for reaction for 1 h; then, adding water to quench at room temperature, extracting with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, and concentrating under reduced pressure; purifying with silica gel column chromatography to obtain intermediate product X4 as light yellow liquid;

x5: under the protection of argon and at the temperature of 0 ℃, adding the intermediate product X4 into tetrahydrofuran, cooling for 10min, slowly adding a normal hexane solution of vinyl magnesium bromide, and reacting for 3h at the temperature of 0 ℃; then, adding an ammonium chloride aqueous solution for quenching, extracting by using ethyl acetate, combining organic phases, drying by using anhydrous sodium sulfate, and concentrating under reduced pressure; and purifying by a chromatographic silica gel column to obtain a product X5 (namely the ketene compound product) which is light yellow liquid.

Further, in the lithium diisopropylamide-n-hexane solution, the mass fraction of lithium diisopropylamide is 10.7%.

Further, in step X1, the ratio of the amounts of the lithium diisopropylamine-n-hexane solution, isobutyric acid and 3-bromopropene tetrahydrofuran solution is 1.1: 1.0: 1.0.

further, in the step X2, the mass ratio of the intermediate product X1, N-bromosuccinimide and dibenzoyl peroxide is 1: 1.3: 0.02.

further, in the step X3, the ratio of the amounts of the 2, 6-di-tert-butyl-4-methylpyridine, the silver N-bromosuccinimide trifluoromethanesulfonate, the TBDSOH and the intermediate product X2 is 1.5: 1.2: 1.0: 1.0.

furthermore, in the n-hexane solution of the i-PrMgCl, the mass fraction of the i-PrMgCl is 1.1%.

Further, in the step X4, the mass ratio of the intermediate product X3, N, O-dimethylhydroxylamine hydrochloride, and the N-hexane solution of i-PrMgCl is 1.0: 5.0: 10.2.

furthermore, in the n-hexane solution of the vinyl magnesium bromide, the mass fraction of the vinyl magnesium bromide is 1.4%.

Further, in the step X5, the mass ratio of the intermediate product X4 to the n-hexane solution of vinyl magnesium bromide is 1.0: 5.0.

further, the preparation method of the iodo-hydrocarbon compound comprises the following steps:

y1: under the protection of argon and at the temperature of-78 ℃, adding a propyne-tetrahydrofuran solution into ethylene glycol dimethyl ether, cooling for 5min, slowly adding an n-butyllithium-tetrahydrofuran solution, stirring for reaction for 10min, heating to-40 ℃, reacting for 30min, and cooling to-78 ℃; then adding a (R) -benzyloxymethyl oxirane-tetrahydrofuran solution, adding a boron trifluoride-diethyl ether solution after 5min, reacting for 15 min, heating to 0 ℃, and reacting for 1h at 0 ℃; then, reacting for 10min at room temperature, adding ammonium chloride aqueous solution for quenching, extracting with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, and concentrating under reduced pressure; purifying with silica gel column chromatography to obtain intermediate Y1 as light yellow liquid;

y2: adding the intermediate product Y1 into an ultra-dry solvent dimethyl ether at the temperature of 10 ℃, adding lithium aluminum hydride powder, heating to 100 ℃, and carrying out reflux reaction for 8 hours at the temperature of 100 ℃; then, cooling to 15 ℃, and adding ice blocks for quenching; slowly adding 2 mol/L hydrochloric acid under stirring until no air bubbles emerge, extracting with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, and concentrating under reduced pressure; purifying with silica gel column chromatography to obtain intermediate Y2 as colorless liquid;

y3: adding lithium particles and naphthalene into tetrahydrofuran at room temperature, and reacting for 45min under stirring until a dark green lithium naphthalene solution is formed; adding the intermediate product Y2 into a dark green lithium naphthalene solution at the temperature of minus 20 ℃, and stirring for reaction for 30 min; then, slowly adding an ammonium chloride aqueous solution at room temperature for quenching, extracting by using ethyl acetate, combining organic phases, drying by using anhydrous sodium sulfate, and concentrating under reduced pressure; purifying with silica gel column chromatography to obtain intermediate product C as colorless liquid;

y4: adding the intermediate product Y3 into dichloromethane at room temperature under the protection of argon, and then sequentially adding triethylamine and Bu₂SnO, stirring and reacting for 5min, then adding p-toluenesulfonyl chloride, and stirring and reacting for 2 h; then adding water for quenching, extracting by using dichloromethane, combining organic phases, drying by using anhydrous sodium sulfate, and concentrating under reduced pressure to obtain an intermediate product Y4 which is a light yellow liquid crude product;

y5: adding the intermediate product Y4 and sodium iodide into acetone at room temperature, and carrying out reflux reaction for 12 h under the protection of argon; then, sodium thiosulfate is added for quenching, ethyl acetate is used for extraction, organic phases are combined and dried by anhydrous sodium sulfate, and the mixture is decompressed and concentrated; and then purified by a column chromatography silica gel to obtain the product Y5 (i.e. iodo hydrocarbon compound) as a light yellow liquid.

Further, the mass fraction of propyne in the tetrahydrofuran solution of propyne is 7.31%.

Furthermore, in the tetrahydrofuran solution of the n-butyllithium, the mass fraction of the n-butyllithium is 1.168 percent

Further, in step Y1, the ratio of the propyne-tetrahydrofuran solution, the n-butyllithium-tetrahydrofuran solution, the 8-tetrahydrofuran solution, and the boron trifluoride-diethyl ether solution is 2.0: 2.0: 1.0: 2.0.

further, in step Y2, the material ratio of the intermediate product Y1 to the lithium aluminum hydride powder is 1.0: 5.4.

further, in step Y3, the ratio of the lithium particles, the naphthalene and the intermediate product Y2 is 8.0: 8.0: 1.0.

further, in the step Y4, the intermediate product Y3, triethylamine and Bu₂The mass ratio of SnO to p-toluenesulfonyl chloride is 1.0: 1.0: 0.02: 1.0.

further, in step Y5, the mass ratio of the intermediate product Y4 to sodium iodide is 1: 5.0.

further, in the purification of the chromatographic silica gel column, a petroleum ether-ethyl acetate system is adopted as a developing agent.

Further, in the quenching, the ammonium chloride is a saturated aqueous ammonium chloride solution.

Further, in the quenching, the sodium thiosulfate is a saturated aqueous sodium thiosulfate solution.

Based on the obtained bryodin C ring skeleton compound, the technical scheme also provides a bryodin C ring compound or an analogue thereof, and the bryodin C ring skeleton compound is prepared from the bryodin C ring skeleton compound.

The technical scheme also provides a preparation method of the bryodin C ring compound or the analogue thereof, which comprises the steps of carrying out ring closing, epoxy opening, oxidation and Aldol reaction on the bryodin C ring skeleton compound under an acidic condition to obtain a known compound of a bryodin C ring precursor; and then carrying out Luche reduction and butyrylation, TABF desilication, DMP oxidation and Sharpless asymmetric dihydroxylation reaction to obtain the bryodin C ring compound or the analogue thereof.

Further, the method for synthesizing the bryodin C-ring compound or the analogue thereof comprises the following specific steps:

A. adding a dichloromethane solution of the bryodin C-ring framework compound into a high-temperature-resistant reaction device, adding a 4A molecular sieve and hydrated p-toluenesulfonic acid, reacting at 60-100 ℃ for 8-24h, cooling to room temperature, filtering the molecular sieve, and concentrating under reduced pressure to obtain an intermediate product A which is a crude product;

B. to the intermediate A obtained, sodium bicarbonate, methanol and MMPP.6H were added₂O, reacting for 2-4h at the temperature of-15-0 ℃; then adding water for quenching, extracting by using ethyl acetate, and concentrating under reduced pressure to obtain an intermediate product B which is a crude product;

C. adding the obtained intermediate product B and a 4A molecular sieve into a dichloromethane solution, adding TPAP and NMO, and reacting at normal temperature for 0.5-3 h; then adding water for quenching, extracting by using dichloromethane, and concentrating under reduced pressure; purifying with silica gel column chromatography to obtain intermediate C as light yellow crude product;

D. adding the intermediate product C into tetrahydrofuran for dissolving, then adding potassium carbonate, methyl glyoxylate and methanol into the dissolved solution, and reacting for 0.5-3h at normal temperature; adding water for quenching, extracting with ethyl acetate, and concentrating under reduced pressure; purifying with silica gel column chromatography to obtain known compound of bryodin C ring precursor as light yellow crude product;

E. subjecting the obtained known compound of the C-ring precursor of the bryostatin to Luche reduction and butyrylation, TABF desilication, DMP oxidation and Sharpless asymmetric dihydroxylation reaction to obtain the bryostatin C-ring compound or the analogue thereof.

Further, in the dichloromethane solution of the bryozoacin C ring skeleton compound in the step A, the concentration of the bryocin C ring skeleton compound is 0.1-0.5 mol/L.

Further, in the step A, the amount ratio of the bryodin C ring skeleton compound to the substance of the hydrated p-toluenesulfonic acid is 1.0: 0.01-0.2, preferably 1.0: 0.1.

further, in step B, the sodium bicarbonate is mixed with MMPP.6H₂The mass ratio of O is 2.0: 0.5.

further, in step C, after the obtained intermediate product B and the 4 a molecular sieve are added to a dichloromethane solution, the concentration of the intermediate product B is 0.1-1.0 mol/L.

Further, in the step C, the amount ratio of the TPAP to the NMO is 0.1: 3.0.

further, in the step D, after the obtained intermediate product C is added into tetrahydrofuran to be dissolved, the concentration of the intermediate product C is 0.1-1.0 mol/L.

Further, in the step D, the mass ratio of the potassium carbonate to the methyl glyoxylate is 5.5: 2.0.

based on the obtained Bryostatin C ring compound analog, the technical scheme also provides a class of Bryostatin analogs, which are prepared by taking the Bryostatin C ring compound analog as a raw material and adopting the existing mature technology (for example, Total Synthesis of Bryostatin 8 Using an organic silane-Based strand, 2018 (completely synthesizing Bryostatin 8, 2018) Based on an Organosilane Strategy).

The technical scheme also provides an application of the bryodin C ring skeleton compound, which comprises the steps of using the bryodin C ring skeleton compound to prepare a bryodin C ring compound or an analogue thereof, using the obtained bryodin C ring compound to prepare bryodin, and using the obtained bryodin C ring compound analogue to prepare a bryodin analogue; finally, a method for preparing a product containing bryodin or its analogues is achieved.

The technical scheme also provides an application of the bryodin C-ring compound analogue, which comprises the application of preparing a product containing the bryodin analogue.

Further, the product is used for treating cancer, AIDS and Alzheimer.

The technical scheme also provides a pharmaceutical composition which takes the bryodin C-ring skeleton compound or the pharmaceutically available salt thereof as an active ingredient and pharmaceutically acceptable carriers, diluents and excipients.

The technical scheme also provides a pharmaceutical composition which is composed of the bryodin C ring compound analogue or the pharmaceutically available salt thereof as an active ingredient, and pharmaceutically acceptable carriers, diluents and excipients.

The technical scheme also provides a pharmaceutical composition which is composed of the bryozoacin analogue or the pharmaceutically available salt thereof as an active ingredient, and pharmaceutically acceptable carriers, diluents and excipients.

In the technical scheme, the term "rapidly adding" specifically means: under the permission of operating conditions, the feeding mode that the long-time placing of the reducing substance is oxidized to cause bad influence on the subsequent operation and the result is avoided, and the method is the conventional operation in the chemical technical field.

In the technical scheme, the slow addition refers to dropwise addition, and the dropwise addition is completed within 45min-2h according to the dosage of the reagent.

In the technical scheme, the quenching by adding water, the quenching by adding ammonium chloride and the quenching by adding sodium thiosulfate comprise the following steps according to the principle: the termination reaction is achieved by adding water/ammonium chloride/sodium thiosulfate, which decomposes the excess organic reagent; in addition, "quenching by adding ice blocks" is to counteract the heat released by the quenching reaction, so as to avoid boiling the reaction solvent, further effectively control the reaction, avoid the generation of impurities, realize the protection of the target object, i.e., effectively improve the controllability and stability of the synthetic process route.

In the technical scheme, the 'purification by a chromatographic silica gel column' adopts rapid column passing, so that the phenomenon that the stability of a product is influenced because the generated product is too long in a weak acid silica gel column is avoided. Where "fast" is the normal operation allowed under the operating conditions.

In the technical scheme, the related TBDSOH represents: tert-butyl diphenylsilanols; i-PrMgCl represents: isopropyl magnesium chloride; bu₂SnO represents: di-tert-butyl tin oxide; TABF denotes: tetrabutylammonium fluoride; DMP represents: dess-martin oxidizer; MMPP 6H₂O represents: magnesium di (monoperoxyphthalic acid) hexahydrate; TPAP represents: tetrapropyl ammonium homoruthenate; NMO denotes: 4-methylmorpholine-N-oxide; TPGS-750-M denotes:

by adopting the technical scheme, the beneficial technical effects brought are as follows:

1) in the synthetic process route of the invention, the related raw materials are easy to obtain, the cost is low, and the actual requirements can be met; a convergent synthesis mode is adopted, so that the use of protecting groups is reduced, and a target group is effectively ensured; meanwhile, strong carcinogenicity, irritation and toxic solvents are not used in the synthesis process, and the used solvent is small in dosage, so that the waste liquid discharge can be reduced for industrial scale-up production, and the environmental protection pressure is relieved; in addition, the synthesis efficiency is high, compared with the existing synthesis route, the operation steps are reduced, and the whole period is greatly shortened;

2) the invention is a diversity synthesis, R1, R2 and R3 groups related in the bryodin C ring framework compound are variable, a series of analogs (at present, 27 bryodin C ring framework compound libraries are prepared) can be prepared by the same synthetic route, and in subsequent analog design synthesis and activity research, countless new analog structures with rich structures are provided;

3) in the invention, the intermediate product can be directly used in the next process without purification process in the steps A-D, Y4, etc., which not only saves the time of reaction steps, but also effectively avoids the risk of deterioration of the compound in the purification process, thereby ensuring the stability of the synthesis process of the bryodin C-ring framework compound.

Detailed Description

In the following, the technical solutions in the embodiments of the present invention are clearly and completely described, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

In the following embodiments, reference is made to an apparatus comprising: bruker AC-E400 nuclear magnetic resonance apparatus, 600 MHz agilent nuclear magnetic resonance apparatus, determination of infrared spectra with VECTOR22 infrared spectrometer, determination of high resolution mass spectra with Finnigan LCQDECA mass spectrometer, 85-2 type constant temperature magnetic stirrer (shanghai serle instruments factory), 2ZX-2 type rotary vane vacuum pump (zhejiang huangji refining vacuum pump factory), AL204 type 1/10000 balance (shanghai mettler-toledo instruments ltd), SHB-III type circulating water pump (zheng changchengchi department industry & trade ltd.), RE-2000 type rotary evaporator (shanghai asia rong biochemical instruments factory), and HSGF 254 high efficiency thin layer silica gel plate (cigarette platform huiyou silica gel development ltd).

The related real reagent comprises:

diethyl ether, THF and redistilled over Na/benzophenone reflux;

DCM、MeCN、Et₃refluxing and redistilling N by calcium hydride;

MeOH via I₂Refluxing and redistilling in an Mg system;

n-butyllithium (2.5M in hexane, Warre chemical Co., Ltd.);

tert-butyllithium (1.3M in pentane, Warre chemical Co., Ltd.);

column chromatography is carried out by 200-300 mesh or 300-400 silica gel (Qingdao ocean factory);

TLC color development: 365 nm/254 nm UV; anisaldehyde, KMnO₄Phosphomolybdic acid, sulfuric acid/ethanol color development;

other solvents and reagents are all commercially available analytically pure and used directly, unless otherwise specified;

the anhydrous and anaerobic operation is carried out by using a Schlenk technology under the protection of inert gas Ar by using a double-row pipe, the required reaction containers are dried, an alcohol lamp burns under vacuum to remove water vapor, and the reaction containers are cooled under argon.

Example 1

The invention provides a method for synthesizing a bryodin C-ring framework compound by respectively taking isobutyric acid and (R) -benzyloxymethyl ethylene oxide as initial raw materials, which is further described and specifically comprises the following steps:

firstly, synthesizing ketene compounds

X1 preparation of intermediate X1

Under the protection of argon and at the temperature of-78 ℃ (a low-temperature anhydrous oxygen-free reaction environment is created), adding a lithium diisopropylamine-n-hexane solution (107 mL of lithium diisopropylamine in a 1.0M lithium diisopropylamine-n-hexane solution) into a reaction device which is filled with 300 mL of cooled tetrahydrofuran in advance, slowly adding 20.0 g of isobutyric acid, stirring and reacting at the temperature of-78 ℃ for 1.5 h, and heating to-40 ℃ for reaction for 1 h; adding 23.7 g of tetrahydrofuran solution of 3-bromopropylene at the temperature of-40 ℃, and heating to room temperature for reaction for 10 hours; then, 30mL of saturated aqueous ammonium chloride solution was added and quenched, extracted with ethyl acetate (3X 60 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure; purification was then carried out with a column chromatography silica gel (petroleum ether: ethyl acetate = 50: 1) to obtain 22.3g of intermediate product X1 as a pale yellow liquid with a yield of 81%;

x2 preparation of intermediate product X2

Adding 10g of the obtained intermediate product X1 (70.4 mmol) into a reaction device filled with 200mL of carbon tetrachloride, then adding 16g N-bromosuccinimide and 340mg of dibenzoyl peroxide, vacuumizing, introducing argon, and stirring and reacting for 1h at 105 ℃; then, cooled to room temperature, left to stand, quenched with 20mL of water, extracted with dichloromethane (3 × 60 mL), the organic phases combined and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried by spinning to give 14.2g of intermediate X2 as a colorless liquid with a yield of 92%;

wherein, for the intermediate product X2,¹H NMR (400 MHz, CDCl₃) δ 5.95 (d, J = 15.6 Hz, 1H), 5.72 (dt, J ₁ = 15.6 Hz, J ₂ = 7.6 Hz, 1H), 3.95 (d, J = 7.6 Hz, 2H), 3.67 (s, 3H), 1.30 (s, 6H); IR (liquid film) cm^-12928w, 1739w, 1733m, 2916m, 1462w, 1258w, 1221w, 1115m; HRMS (ESI-TOF, m/z) calcd forC₁₉H₂₇F₃O₃Si(M+Na)⁺: 242.9991, found 242.9987；

x3 preparation of intermediate product X3

Adding 7.0g of 2, 6-di-tert-butyl-4-methylpyridine into 200mL of dichloromethane at the temperature of 0 ℃, cooling for 5min, and then sequentially adding 7.0g of silver trifluoromethanesulfonate and 5.00g of TBDSOH; stirring and reacting for 5min at the temperature of 0 ℃, slowly adding a dichloromethane solution of the obtained 5.00g of intermediate product X2, and continuously stirring and reacting for 45min at the temperature of 0 ℃; then, 20mL of water was added for quenching, extraction was performed with dichloromethane (3X 60 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure; purification was then carried out with a column chromatography silica gel (petroleum ether: ethyl acetate = 20: 1) to obtain 8.10g of intermediate product X3 as a colorless liquid, with a yield of 90%;

wherein, for the intermediate product X3,¹H NMR (400 MHz, CDCl₃) δ 7.68 (dd, J ₁ = 8.0 Hz, J ₂ = 1.6 Hz, 4H), 7.34-7.46 (m, 6H), 5.87 (d, J = 15.6 Hz, 1H), 5.58 (dt, J ₁ = 15.6 Hz, J ₂ = 4.8 Hz, 1H), 4.21 (dd, J ₁ = 4.8 Hz, J ₂ = 1.6 Hz, 2H), 3.66 (s, 3H), 1.28 (s, 6H), 1.06 (s, 9H); ¹³C NMR (101 MHz, CDCl₃) δ 177.0, 135.6, 134.7, 133.8, 129.6, 127.6, 127.3, 64.4, 52.0, 43.9, 26.8, 25.0, 19.3; IR (liquid film) cm^-12931w, 2857w, 1731w, 1108m, 1140w, 699s, 740w, 608m; HRMS (ESI-TOF, m/z) calcd forC₁₉H₂₇F₃O₃Si(M+Na)⁺: 419.2013, found 419.2009；

x4 preparation of intermediate product X4

Under the protection of argon, adding 1.7g of the obtained intermediate product X3 into a reaction device filled with 100mL of tetrahydrofuran, cooling for 10min at the temperature of minus 20 ℃, adding 2.1g of N, O-dimethylhydroxylamine hydrochloride, reacting for 10min under stirring, slowly adding an N-hexane solution of i-PrMgCl (in an N-hexane solution of 2.0M of i-PrMgCl, 22.0M of Li-PrMgCl), controlling the dropping speed to be 45min, after dropping, heating to the temperature of minus 10 ℃ and reacting for 1 h; then, at room temperature, adding 20mL of water to quench, extracting with ethyl acetate (3X 30 mL), combining organic phases, drying with anhydrous sodium sulfate, and concentrating under reduced pressure; purification was then carried out with a column chromatography silica gel (petroleum ether: ethyl acetate =5: 1) to obtain 1.55g of intermediate product X4 as a pale yellow liquid with a yield of 85%;

wherein, for the intermediate product X4,¹H NMR (400 MHz, CDCl₃) δ 7.68 (dd, J ₁ = 8.0 Hz, 1.6 Hz, 4H), 7.34-7.46 (m, 6H), 5.91 (d, J = 15.6 Hz, 1H), 5.57 (dt, J ₁ = 15.6 Hz, J ₂ = 4.8 Hz, 1H), 4.22 (dd, J ₁ = 4.8 Hz, J ₂ = 1.2 Hz, 2H), 3.54 (s, 3H), 3.16 (s, 3H), 1.30 (s, 6H), 1.05 (s, 9H); ¹³C NMR (101 MHz, CDCl₃) δ 177.1, 135.6, 135.5, 133.7, 129.6, 127.6, 126.4, 64.5, 60.6, 44.0, 33.7, 26.8, 25.5, 19.2; IR (liquid film) cm^-13354s, 2953w, 1606m, 1469w, 1257w, 853w; HRMS (ESI-TOF, m/z) calcd forC₁₉H₂₇F₃O₃Si(M+Na)⁺: 448.2278, found 448.2292；

x5 preparation of intermediate product X5

Under the protection of argon, adding 1.2 g of the intermediate product X4 into 40mL of tetrahydrofuran at the temperature of 0 ℃, cooling for 10min, slowly adding an n-hexane solution of vinyl magnesium bromide (14.0 mL of vinyl magnesium bromide in 1.0M of the n-hexane solution of the vinyl magnesium bromide), and reacting for 3h at the temperature of 0 ℃; then, 20mL of saturated aqueous ammonium chloride solution was added and quenched, extracted with ethyl acetate (3X 20 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure; purification was then carried out with a column of silica gel (petroleum ether: ethyl acetate = 20: 1) to obtain 1.05 g of product X5 (i.e. an alkenone compound) as a pale yellow liquid in a yield of 95%;

wherein, for the product X5,¹H NMR (400 MHz, CDCl₃) δ 7.69 (dd, J ₁ = 7.6 Hz, J ₂ = 1.2 Hz, 4H), 7.35-7.47 (m, 6H), 6.68 (dd, J ₁ = 16.8 Hz, J ₂ = 10.4 Hz, 1H), 6.35 (dd, J ₁ = 17.2 Hz, J ₂ = 1.6 Hz), 5.78 (dd, J ₁ = 15.6 Hz, J ₂ = 1.2 Hz, 1H), 5.67 (dt, J ₁ = 15.6 Hz, J ₂ = 4.4 Hz, 1H), 5.62 (dd, J ₁ = 10.4 Hz, J ₂ = 1.6 Hz, 1H), 4.25 (dd, J ₁ = 4.4 Hz, J ₂ = 1.2 Hz, 2H), 1.24 (s, 6H), 1.08 (s, 9H); ¹³C NMR (151 MHz, CDCl₃) δ 201.3, 135.5, 133.8, 133.6, 131.7, 129.6, 129.4, 128.0, 127.6, 64.3, 48.6, 26.8, 23.57, 19.2; IR (liquid film) cm^-12961w, 2931w, 2857w, 1729w, 1697w, 1427w, 1464w,1107m,973w,822w,700s,611w;HRMS(ESI-TOF,m/z)calcd forC₁₉H₂₇F₃O₃Si(M+Na)⁺:415.2064, found 415.2068；

di, synthesizing iodo hydrocarbon compound

Y1 preparation of intermediate Y1

Adding a propyne-tetrahydrofuran solution (73.1 mL of propyne in a 1.0M propyne-tetrahydrofuran solution) into 600 mL of glycol dimethyl ether under the protection of argon at-78 ℃, cooling for 5min, slowly adding an n-butyllithium-tetrahydrofuran solution (29.2 mL of n-butyllithium in a 2.5M n-butyllithium-tetrahydrofuran solution), stirring for 10min, heating to-40 ℃, reacting for 30min, and cooling to-78 ℃; then adding (R) -benzyloxymethyl oxirane-tetrahydrofuran solution (5.6 mL, 36.7 mmol), adding 10.37g of boron trifluoride-diethyl ether solution after 5min, reacting for 15 min, heating to 0 ℃, and reacting for 1h at 0 ℃; then, the reaction was carried out at room temperature for 10min, and then 300 mL of a saturated aqueous solution of ammonium chloride was added thereto, followed by quenching, extraction with ethyl acetate (3X 80 mL), combination of organic phases, drying over anhydrous sodium sulfate, and concentration under reduced pressure; purification was then carried out with a column chromatography silica gel (petroleum ether: ethyl acetate =5: 1) to obtain 7.33g of intermediate Y1 as a pale yellow liquid with a yield of 98%;

wherein, for the intermediate product Y1,¹H NMR (400 MHz, CDCl₃) δ 7.27-7.39 (m, 5H), 4.57 (s, 2H), 3.88-3.96 (m, 1H), 3.59 (dd, J ₁ = 9.5 Hz, J ₂ = 3.9 Hz, 1H), 3.49 (dd, J ₁ = 9.5 Hz, J ₂ = 6.7 Hz, 1H), 2.54 (d, J = 3.8 Hz, 1H), 2.36-2.42 (m, 2H), 1.78 (t, J = 2.5 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 137.9, 128.4, 127.7, 78.0, 74.6, 73.3, 73.0, 69.1, 23.8, 3.5; IR (liquid film) cm^-13423m, 2918m, 1453w, 1114s, 698m; HRMS (ESI-TOF, m/z) calcd forC₁₉H₂₇F₃O₃Si(M+Na)⁺: 227.1043, found 227.1039；

y2 preparation of intermediate Y2

Adding 7.0g of the intermediate product Y1 into 300 mL of ultra-dry solvent dimethyl ether at 10 ℃, adding 7.0g of lithium aluminum hydride powder, heating to 100 ℃, and carrying out reflux reaction at 100 ℃ for 8 h; then, cooling to 15 ℃, and adding ice blocks for quenching; slowly adding 12 mL of 2 mol/L hydrochloric acid under stirring until no air bubbles emerge, extracting with ethyl acetate (3X 80 mL), combining organic phases, drying with anhydrous sodium sulfate, and concentrating under reduced pressure; purification was then carried out with a column chromatography silica gel (petroleum ether: ethyl acetate =5: 1) to obtain 7.0g of intermediate Y2 as a colorless liquid in a yield of 99%;

wherein, for the intermediate product Y2,¹H NMR (400 MHz, CDCl₃) δ 7.27-7.40 (m, 5H), 5.38-5.60 (m, 2H), 4.56 (s, 2H), 3.79-3.88 (m, 1H), 2.51 (dd, J ₁ = 9.5Hz, J ₁ = 3.4 Hz, 1H), 2.37 (dd, J ₁ = 9.4 Hz, J ₁ = 7.5 Hz, 1H), 2.41 (br s, 1H), 2.20 (t, J= 6.3 Hz, 2H), 1.68 (d, J = 6.1Hz, 2H); ¹³C NMR (151 MHz, CDCl₃) δ 138.0, 128.4, 127.7, 126.5, 74.0, 73.3, 70.0, 36.7, 18.0; IR (liquid film) cm^-13432w, 3028w, 2855m, 2916m, 1452m, 1088s, 967s, 736s; HRMS (ESI-TOF, m/z) calcd forC₁₉H₂₇F₃O₃Si(M+Na)⁺: 229.1199, found 229.1196；

y3 preparation of intermediate Y3

Adding 1.6g of lithium particles and 28.6 g of naphthalene into 100mL of tetrahydrofuran at room temperature, and reacting for 45min under stirring until a greenish black lithium naphthalene solution is formed; adding 5.8g of intermediate product Y2 into a dark green lithium naphthalene solution at the temperature of minus 20 ℃, and stirring for reaction for 30 min; then, at room temperature, slowly adding 20mL of saturated aqueous ammonium chloride solution for quenching, extracting with ethyl acetate (3X 30 mL), combining organic phases, drying with anhydrous sodium sulfate, and concentrating under reduced pressure; purification by column chromatography on silica gel (petroleum ether: ethyl acetate = 1: 1) gave 3.0g of intermediate Y3 as a colorless liquid in 92% yield;

wherein, for the intermediate product Y3,¹H NMR (400 MHz, CDCl₃) δ 5.34-5.60 (m, 2H), 3.65-3.73 (m, 1H), 3.63 (dd, J ₁ = 11.2 Hz, J ₂ = 3.2 Hz, 1H), 3.43 (dd, J ₁ = 11.2 Hz, J ₂ = 7.2 Hz, 1H), 2.87 (br s, 2H), 2.05-2.21 (m, 2H), 1.67 (dd, J ₁ = 6.4 Hz, J ₂ = 0.8 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 128.9, 126.3, 71.7, 66.2, 36.7, 18.0; IR (liquid film) cm^-13380s, 2921m, 1439m, 1074m, 968m, 750s; HRMS (ESI-TOF, m/z) calcd forC₁₉H₂₇F₃O₃Si(M+Na)⁺: 139.0730, found 139.0732；

y4 preparation of intermediate Y4

2.30 g of intermediate Y3 are added to 100mL of dichloromethane at room temperature under argon, followed by triethylamine (19.8 mmol) and 10.0 mg of Bu₂SnO is stirred and reacts for 5min, then 377.8 mg of paratoluensulfonyl chloride is added, and stirring and reacting are carried out for 2 h; then, 20mL of water was added for quenching, dichloromethane (3X 20 mL) was used for extraction, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain an intermediate product Y4 which is a light yellow liquid crude product;

y5 preparation of intermediate Y5

Adding the intermediate product Y4 and 14.8 g of sodium iodide into 50 mL of acetone at room temperature, and carrying out reflux reaction for 12 h under the protection of argon; then, 20mL of sodium thiosulfate was added for quenching, extraction was performed with ethyl acetate (3X 30 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure; purification was then carried out with a column of silica gel (petroleum ether: ethyl acetate =5: 1) to obtain 3.8 g of product Y5 (i.e., iodohydrocarbon compound) as a pale yellow liquid, with a yield of 86%;

wherein, for the product Y5,¹H NMR (400 MHz, CDCl₃) δ 5.53-5.65 (m, 1H), 5.35-5.45 (m, 1H), 3.50-3.59 (m, 1H), 3.35 (dd, J ₁ = 10.1 Hz, J ₂ = 4.0 Hz, 1H), 3.23 (dd, J ₁ = 10.1 Hz, J ₂ = 4.0 Hz, 1H), 2.20-2.34 (m, 2H), 2.11 (br s, 1H), 1.68 (dd, J ₁ = 6.3 Hz, J ₂ = 0.8 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 130.0, 125.5, 70.4, 39.7, 18.0, 14.9; IR (liquid film) cm^-13367w, 2918m, 2853w, 1435w, 1260w, 1011m, 967s, 750m；

thirdly, synthesizing the bryodin C-ring framework compound

Adding 500.0 mg of the obtained ketene compound, 861.1 mg of the obtained iodohydrocarbon compound, 406.4 mg of zinc powder, 294.5 mg of cuprous iodide, 1.4 mL of ethanol and 0.6 mL of TPGS aqueous solution (the mass fraction of TPGS is 2%, and the TPGS aqueous solution is commercially available as TPGS-750-M) into a reaction device, and reacting for 8-24h at the temperature of 0-40 ℃; adding 406.4 mg of zinc powder, 294.5 mg of copper iodide, 1.4 mL of ethanol and 0.6 mL of TPGS aqueous solution (the mass fraction of TPGS is 2 percent, and TPGS-750-M is sold in the market) into a reaction device, reacting for 8-24h at the temperature of 0-40 ℃, and adding 10mL of water into the reaction device for quenching; then, extraction was performed with ethyl acetate (5 × 20 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure; purifying with silica gel column chromatography (petroleum ether: ethyl acetate =5: 1) to obtain 443.6 mg of bryodin C ring skeleton compound (numbered as bryodin C ring skeleton compound 0) as light yellow liquid, with yield of 71%;

wherein, for the bryodin C ring skeleton compound 0,¹H NMR (400 MHz, CDCl₃) δ 7.64-7.73 (m, 4H), 7.34-7.46 (m, 6H), 5.78 (d, J = 15.6 Hz, 1H), 5.63 (dt, J ₁ = 15.6 Hz, J ₂ = 4.6 Hz, 1H), 5.33-5.59 (m, 2H), 4.23 (d, J = 4.4 Hz, 2H), 3.50-3.60 (m, 1H), 2.46 (t, J =7.1 Hz, 2H), 2.15-2.25 (m, 1H), 2.00-2.12 (m, 1H), 1.90 (br s, 1H), 1.68 (d, J = 6.0 Hz, 3H), 1.51-1.67 (m, 2H), 1.34-1.45 (m, 2H), 1.20 (s, 6H), 1.07 (s, 9H); ¹³C NMR (101 MHz, CDCl₃) δ 213.3, 135.5, 134.4, 133.6, 129.6, 128.8, 128.6, 127.6, 127.0, 70.6, 64.3, 49.6, 40.6, 37.2, 36.1, 26.8, 23.9, 20.0, 19.2, 18.0; IR (liquid film) cm^-13371m, 3078w, 2956w, 2910w, 1641w, 1426m, 1040s, 920s, 632m; HRMS (ESI-TOF, m/z) calcd forC₁₉H₂₇F₃O₃Si(M+Na)⁺:515.2952, found 515.295。

example 2

Based on the synthesis method of example 1, this example also proposes various bryodin C-ring framework compounds, which are specifically as follows:

wherein the yield in the serial numbers of the bryodin C ring framework compounds of 0-9, 17-29 and 31-37 is the separation yield and is the yield obtained by silica gel purification treatment; the yield in the serial numbers of the bryodin C ring skeleton compounds of 10-16, 30 and 38-40 is the nuclear magnetic yield which is obtained by nuclear magnetic treatment;

in addition, the bryodin C-ring skeleton compound 0 is a precursor compound of a known natural product (bryodin), and the bryodin C-ring skeleton compounds 1 to 40 are analogues of the precursor compound of the known natural product, and herein, the bryodin C-ring skeleton compounds 0 to 40 are collectively referred to as the bryodin C-ring skeleton compounds.

Example 3

Based on examples 1-2, this example also proposes a preparation method of various bryodin C-ring framework compounds, which specifically comprises the following steps:

1) preparation of bryodin C-ring framework Compound 1

By adopting the preparation method of the bryozoacin C ring skeleton compound 0 in the example 1, 52.3mg of the bryocin C ring skeleton compound 1 which is a light yellow liquid is prepared, and the yield is 50%;

wherein,for bryodin C ring backbone compound 1, [ alpha ]]_D ²⁵ = -2.1° (c = 1.0 in CHCl₃)；¹H NMR (400 MHz, CDCl₃) δ 7.59-7.74 (m, 4H), 7.30-7.49 (m, 6H), 5.71-5.89 (m, 2H), 5.62 (dt, J ₁ = 15.6 Hz, J ₂ = 4.8 Hz, 1H), 5.00-5.18 (m, 2H), 4.22 (dd, J ₁= 4.8 Hz, J ₂ = 1.6 Hz, 2H), 3.51-3.69 (m, 1H), 2.46 (t, J = 7.2 Hz, 2H), 2.22-2.33 (m, 1H), 2.08-2.20 (m, 1H), 1.51-1.72 (m, 2H), 1.34-1.46 (m, 2H), 1.20 (s, 6H), 1.06 (s, 9H); ¹³C NMR (151 MHz, CDCl₃) δ 213.3, 135.5, 134.8, 134.4, 133.6, 129.7, 128.7, 127.6, 118.0, 70.3, 64.3, 49.7, 41.8, 37.2, 36.2, 26.8, 23.9, 19.9, 19.2; IR (liquid film) cm^-13433.41w, 2928m, 2856w, 1427w, 1108s, 1056m, 978w; HRMS (ESI-TOF, m/z) calcd forC₁₉H₂₇F₃O₃Si(M+Na)⁺:501.2795, found 501.2795；

The structural formula of the bryodin C ring skeleton compound 1 is as follows:

2) preparation of bryodin C-ring framework Compound 2

By adopting the preparation method of the bryozoacin C ring skeleton compound 0 in the embodiment 1, 39.7mg of the bryocin C ring skeleton compound 2 which is a light yellow liquid is prepared, and the yield is 42%;

wherein [ alpha ] for bryodin C-ring skeleton compound 2]_D ²⁵ = +0.35° (c = 1.0 in CHCl₃)；¹H NMR (400 MHz, CDCl₃) δ 7.62-7.72 (m, 4H), 7.33-7.47 (m, 6H), 5.76 (dt, J ₁ = 15.6 Hz, J ₂ = 1.6 Hz, 1H), 5.62 (dt, J ₁ = 15.6 Hz, J ₂ = 4.8 Hz, 1H), 4.22 (dd, J ₁ = 4.8 Hz, J ₂ = 1.6 Hz, 2H), 3.49-3.59 (m, 1H), 2.45 (t, J = 7.2 Hz, 2H), 1.54-1.67 (m, 4H), 1.34-1.45 (m, 4H), 1.16 (s, 6H), 1.06 (s, 9H), 0.91 (t, J = 6.8 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 213.5, 135.5, 135.5, 134.4, 133.6, 129.7, 128.7, 127.7, 127.6, 71.2, 64.3, 49.7, 39.5, 37.2, 36.9, 26.8, 23.9, 19.8, 19.2, 18.8, 14.1; IR (liquid film) cm^-12927m, 2856s, 1708w, 1428w, 1111m, 977w, 823w, 702w; HRMS (ESI-TOF, m/z) calcd forC₁₉H₂₇F₃O₃Si(M+Na)⁺:503.2952, found 503.2950；

The structural formula of the bryodin C ring skeleton compound 2 is as follows:

3) preparation of bryodin C-ring framework Compound 3

By adopting the preparation method of the bryozoacin C ring skeleton compound 0 in the embodiment 1, 32.4mg of the bryocin C ring skeleton compound 3 which is a light yellow liquid is prepared, and the yield is 41%;

wherein, for the C-ring skeleton compound 3 of the bryozoacin, [ alpha ]]_D ²⁵ = +2.1° (c = 1.0 in CHCl₃)；¹H NMR (400 MHz, CDCl₃) δ 7.62-7.71 (m, 4H), 7.33-7.46 (m, 6H), 5.76 (dt, J ₁ = 15.6 Hz, J ₂ = 1.6 Hz, 1H), 5.62 (dt, J ₁ = 15.6 Hz, J ₂ = 4.8 Hz, 1H), 4.22 (dd, J ₁ = 4.8 Hz, J ₂ = 1.6 Hz, 2H), 3.55-3.67 (m, 1H), 2.45 (t, J = 6.8 Hz, 2H), 1.70-1.81 (m, 1H), 1.55-1.68 (m, 4H), 1.31-1.39 (m, 2H), 1.19 (s, 6H), 1.06 (s, 9H), 0.89 (t, J = 6.4 Hz, 6H); ¹³C NMR (101 MHz, CDCl₃) δ 213.5, 135.5, 134.4, 133.6, 129.7, 128.7, 127.7, 69.5, 64.3, 49.7, 46.6, 37.5, 37.3, 26.8, 24.6, 23.9, 23.5, 22.0, 19.7, 19.2; IR (liquid film) cm^-13362w, 2927m, 2856w, 1707w, 1466w, 1109s, 1054w, 701s; HRMS (ESI-TOF, m/z) calcd forC₁₉H₂₇F₃O₃Si(M+Na)⁺:517.3108, found 517.3109；

The structural formula of the bryodin C ring skeleton compound 3 is as follows:

4) preparation of bryodin C-ring framework Compound 4

By adopting the preparation method of the bryozoacin C ring skeleton compound 0 in the example 1, 21.4mg of the bryocin C ring skeleton compound 4 which is a light yellow liquid is prepared, and the yield is 30%;

wherein, for the C-ring skeleton compound 4 of the bryozoacin, [ alpha ]]_D ²⁵ = +0.59° (c = 1.0 in CHCl₃)；¹H NMR (400 MHz, CDCl₃) δ 7.61-7.75 (m, 4H), 7.33-7.47 (m, 6H), 5.77 (dt, J ₁ = 15.6 Hz, J ₂ = 1.6 Hz, 1H), 5.62 (dt, J ₁ = 15.6 Hz, J ₂ = 4.8 Hz, 1H), 4.22 (dd, J ₁ = 4.8 Hz, J ₂ = 1.6Hz, 2H), 3.60-3.72 (m, 1H), 2.46 (t, J = 6.8 Hz, 2H), 1.55-1.74 (m, 2H), 1.31-1.53 (m, 4H), 1.20 (s, 6H), 1.06 (s, 9H), 0.65-0.79 (m, 1H), 0.33-0.54 (m, 2H), -0.04-0.15 (m, 2H); ¹³C NMR (101 MHz, CDCl₃) δ 213.4, 135.5, 134.4, 133.6, 129.7, 128.7, 127.6, 72.1, 64.3, 49.7, 42.2, 37.3, 36.5, 26.8, 23.9, 19.9, 19.2, 7.4, 4.5, 3.7; IR (liquid film) cm^-13360w, 3072w, 2854m, 2925s, 1707w, 1427w, 1109s, 1055w, 702s, 505m; HRMS (ESI-TOF, m/z) calcd forC₁₉H₂₇F₃O₃Si(M+Na)⁺:515.2952, found 515.2957；

The structural formula of the bryodin C ring skeleton compound 4 is as follows:

5) preparation of bryodin C-ring framework Compound 5

By adopting the preparation method of the bryozoacin C-ring skeleton compound 0 in the example 1, 59.7mg of the bryocin C-ring skeleton compound 5 which is a light yellow liquid is prepared, and the yield is 66%;

wherein, for the C-ring skeleton compound 5 of the bryozoacin, [ alpha ]]_D ²⁵ = +6.3° (c = 1.0 in CHCl₃)；¹H NMR (400 MHz, CDCl₃) δ 7.66 (d, J = 6.7 Hz, 4H), 7.32-7.47 (m, 6H), 5.76 (d, J = 15.7 Hz, 1H), 5.61 (dt, J ₁ = 15.6 Hz, J ₂ = 4.6 Hz, 1H), 4.22 (d, J = 3.8 Hz, 2H), 4.16 (q, J = 7.1 Hz, 2H), 3.90-4.01 (m, 1H), 3.01 (br s, 1H), 2.45 (t, J = 7.1 Hz, 2H), 2.38 (dd, J ₁ = 16.5Hz, J ₂ = 9.0 Hz, 2H), 1.53-1.71 (m, 2H), 1.36-1.47 (m, 2H), 1.26 (t, J = 7.1Hz, 3H), 1.19 (s, 6H), 1.06 (s, 9H); ¹³C NMR (101 MHz, CDCl₃) δ 213.1, 173.0, 135.5, 134.4, 133.6, 129.7, 128.7, 127.6, 67.7, 64.3, 60.7, 49.7, 41.2, 37.0, 35.8, 26.8, 23.9, 19.8, 19.2, 14.2; IR (liquid film) cm^-13481w, 2928m, 2856w, 1708m, 1463w, 1427w, 1108m, 739m, 701s; HRMS (ESI-TOF, m/z) calcd forC₁₉H₂₇F₃O₃Si(M+Na)⁺:547.2850, found 547.2846；

The structural formula of the bryodin C ring skeleton compound 5 is as follows:

6) preparation of bryodin C-ring framework compound 6

By adopting the preparation method of the bryozoacin C ring skeleton compound 0 in the embodiment 1, 66.3mg of the bryocin C ring skeleton compound 6 which is a light yellow liquid is prepared, and the yield is 45%;

wherein, for the bryodin C ring skeleton compound 6, aα]_D ²⁵ = -2.7° (c = 1.0 in CHCl₃) ；¹H NMR (400 MHz, CDCl₃) δ 7.67 (d, J = 6.7 Hz, 4H), 7.30-7.49 (m, 6H), 5.76 (d, J = 15.6 Hz, 1H), 5.63 (dt, J ₁ = 15.6 Hz, J ₂ = 4.3 Hz, 1H), 4.24 (d, J = 3.6 Hz, 2H), 3.78-3.94 (m, 1H), 2.95 (br s, 1H), 2.36-2.60 (m, 4H), 1.56-1.74 (m, 2H), 1.46-1.55 (m, 2H), 1.20 (s, 6H), 1.07 (s, 9H); ¹³C NMR (101 MHz, CDCl₃) δ 213.6, 135.5, 134.1, 133.5, 129.7, 128.9, 127.6, 117.6, 67.2, 64.2, 49.6, 36.7, 35.8, 26.8, 25.9, 23.9, 19.3, 19.2；IR (liquid film) cm^-13468w, 2930w, 2856w, 2251w, 1704w, 1427m, 979w, 702s; HRMS (ESI-TOF, m/z) calcd forC₁₉H₂₇F₃O₃Si(M+Na)⁺:500.2591, found 500.2587；

The structural formula of the bryodin C ring skeleton compound 6 is as follows:

7) preparation of bryodin C-ring framework compound 7

56.1 mg of the bryodin C-ring skeleton compound 7 as a pale yellow liquid was prepared by the method for preparing the bryodin C-ring skeleton compound 0 in example 1, with a yield of 47%;

wherein, for bryodin C ring skeleton compound 7, [ alpha ]]_D ²⁵ = -1.9° (c = 1.0 in CHCl₃)；¹H NMR (400 MHz, CDCl₃) δ 7.62-7.73 (m, 4H), 7.32-7.48 (m, 6H), 5.78 (d, J = 15.7 Hz, 1H), 5.63 (dt, J ₁ = 15.7 Hz, J ₂ = 4.6 Hz, 1H), 4.87 (s, 1H), 4.78 (s, 1H), 4.23 (d, J = 4.0 Hz, 2H), 3.63-3.76 (m, 1H), 2.47 (t, J = 7.1 Hz, 2H), 2.18 (dd, J ₁ = 13.7Hz, J ₂ = 3.2Hz, 1H), 2.03-2.13 (m, 1H), 1.74 (s, 3H), 1.56-1.72 (m, 2H), 1.37-1.46 (m, 2H), 1.20 (s, 6H), 1.07 (s, 9H); ¹³C NMR (151 MHz, CDCl₃) δ 213.3, 142.7, 135.5, 134.4, 133.6, 129.6, 128.6, 127.6, 113.4, 68.4, 64.3, 49.7, 46.0, 37.2, 36.4, 26.8, 23.9, 22.4, 20.0, 19.2; IR (liquid film) cm^-13455w, 3071w, 2960w, 2929w, 2856w, 1705w, 1261w, 1106m, 701s; HRMS (ESI-TOF, m/z) calcd forC₁₉H₂₇F₃O₃Si(M+Na)⁺:515.2952, found 515.2956；

The structural formula of the bryodin C ring skeleton compound 7 is as follows:

8) preparation of bryodin C-ring framework compound 8

By adopting the preparation method of the bryozoacin C ring skeleton compound 0 in the example 1, 43.6mg of the bryocin C ring skeleton compound 8 which is a light yellow liquid is prepared, and the yield is 46%;

wherein, for the C-ring skeleton compound 8 of the bryozoacin, [ alpha ]]_D ²⁵ = +7.6° (c = 1.0 in CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.67 (dd, J = 7.9, 1.5 Hz, 4H), 7.34-7.43 (m, 6H), 7.30 (t, J = 7.2 Hz, 2H), 7.16-7.25 (m, 3H), 5.76 (dt, J ₁ = 15.7 Hz, J ₂ = 1.5 Hz, 1H), 5.61 (dt, J ₁ = 15.7 Hz, J ₂ = 4.7 Hz, 1H), 4.22 (dd, J ₁ = 4.7 Hz, J ₂ = 1.5 Hz, 2H), 3.71-3.80 (m, 1H), 2.80 (dd, J ₁ = 13.5 Hz, J ₂ = 4.4 Hz, 1H), 2.64 (dd, J ₁ = 13.5 Hz, J ₂ = 8.3 Hz, 1H), 2.45 (t, J = 7.1 Hz, 2H), 1.66-1.74 (m, 2H), 1.41-1.50 (m, 2H), 1.19 (s, 6H), 1.06 (s, 9H); ¹³C NMR (101 MHz, CDCl₃) δ 213.4, 138.5, 135.5, 134.4, 133.6, 129.7, 129.4, 128.7, 128.5, 127.7, 126.4, 72.3, 64.3, 49.7, 44.0, 37.2, 36.2, 26.8, 23.9, 20.0, 19.2; IR (liquid film) cm^-12926m, 2854w, 1707w, 1462w, 1110m, 701m, 504w; HRMS (ESI-TOF, m/z) calcd for C₃₄H₄₄O₃Si (M+Na)⁺:551.2952, found 551.2953；

The structural formula of the bryodin C ring skeleton compound 8 is as follows:

9) preparation of bryodin C-ring framework compound 9

By adopting the preparation method of the bryozoacin C ring skeleton compound 0 in the embodiment 1, 31.7 mg of the bryocin C ring skeleton compound 9 which is a light yellow liquid is prepared, and the yield is 48%;

wherein, for the C-ring skeleton compound 9 of the bryozoacin,¹H NMR (400 MHz, CDCl₃) δ 7.66 (d, J = 6.5 Hz, 4H), 7.57 (m, 3H), 7.39 (m, 8H), 5.72 (d, J = 15.7 Hz, 1H), 5.59 (dt, J ₁ = 15.7 Hz, J ₁ = 4.7 Hz, 1H), 5.26-5.43 (m, 2H), 4.20 (d, J = 4.5 Hz, 2H), 3.56-3.67 (m, 1H), 2.33 (t, J = 7.2 Hz, 2H), 2.08 (t, J = 5.5 Hz, 2H), 1.50-1.69 (m, 7H), 1.16 (s, 6H), 1.05 (s, 9H), 0.36 (s, 6H); ¹³C NMR (101 MHz, CDCl₃) δ 213.1, 138.3, 135.5, 134.5, 133.7, 133.6, 129.7, 129.4, 128.5, 127.7, 127.6, 127.5, 127.4, 72.8, 64.4, 49.6, 40.6, 37.5, 36.2, 26.8, 23.9, 20.1, 19.2, 18.0, -1.0, -1.1；

the structural formula of the bryodin C ring skeleton compound 9 is as follows:

10) preparation of bryodin C-ring framework Compound 10

By adopting the preparation method of the bryozoacin C-ring skeleton compound 0 in the example 1, the bryocin C-ring skeleton compound 10 is prepared, and the yield is 25%;

wherein, for the bryodin C ring skeleton compound 10, IR (film) cm^-13417w, 3071w, 2927m, 2655w, 1989w, 1707w, 1462w, 1427w, 1109s, 1055m, 823w, 737w, 702s, 612w；

The structural formula of the bryodin C-ring framework compound 10 is as follows:

11) preparation of bryodin C-ring framework compound 11

By adopting the preparation method of the bryozoacin C ring skeleton compound 0 in the embodiment 1, the bryocin C ring skeleton compound 11 is prepared, and the yield is 48%;

the structural formula of the bryodin C-ring skeleton compound 11 is as follows:

12) preparation of bryodin C-ring framework Compound 12

By adopting the preparation method of the bryozoacin C-ring skeleton compound 0 in the embodiment 1, the bryocin C-ring skeleton compound 12 is prepared, and the yield is 31%;

wherein, for the C-ring skeleton compound 12 of the bryozoacin, IR (film) cm^-1 3442w, 3071w, 2929w, 2857w, 1704w, 1461w, 1427w, 1108m, 1055w, 822w, 736m, 701s, 612w; HRMS (ESI-TOF, m/z) calcd for C₃₂H₄₆O₃Si (M+Na)⁺:529.3018, found 529.3093；

The structural formula of the bryodin C ring skeleton compound 12 is as follows:

13) preparation of bryodin C-ring framework compound 13

By adopting the preparation method of the bryozoacin C-ring framework compound 0 in the embodiment 1, the bryocin C-ring framework compound 13 is prepared, and the yield is 26%;

wherein, for the bryodin C ring skeleton compound 13, IR (film) cm^-1 3368w, 2960m, 2931w, 2862w, 1705w, 1460w, 1363w, 1108m, 1077w, 823w, 807w, 702s, 612w; HRMS (ESI-TOF, m/z) calcd for C₃₈H₅₂O₃Si(M+Na)⁺:607.3578, found 607.3567；

The structural formula of the bryodin C ring skeleton compound 13 is as follows:

14) preparation of bryodin C-ring framework compound 14

By adopting the preparation method of the bryozoacin C-ring skeleton compound 0 in the embodiment 1, the bryocin C-ring skeleton compound 14 is prepared, and the yield is 26%;

wherein, for the bryodin C ring skeleton compound 14, IR (film) cm^-1 3373w, 3071w, 2920s, 2851m, 1703w, 1447w, 1427w, 1109m, 1047w, 822w, 734m, 701s, 612w; HRMS (ESI-TOF, m/z) calcd for C₃₄H₅₀O₃Si (M+Na)⁺:557.3421, found 557.3429；

The structural formula of the bryodin C ring skeleton compound 14 is as follows:

15) preparation of bryodin C-ring framework compound 15

By adopting the preparation method of the bryozoacin C-ring skeleton compound 0 in the embodiment 1, the bryocin C-ring skeleton compound 15 is prepared, and the yield is 40%;

wherein, for the bryodin C ring skeleton compound 15, IR (film) cm^-1 2930m, 2857w, 1706w, 1462w, 1427w, 1109m, 1057w, 917w, 822w, 702s, 612w；

The structural formula of the bryodin C ring skeleton compound 15 is as follows:

16) preparation of bryodin C-ring framework Compound 16

By adopting the preparation method of the bryozoacin C-ring skeleton compound 0 in the embodiment 1, the bryocin C-ring skeleton compound 16 is prepared, and the yield is 38%;

wherein, for the bryodin C ring skeleton compound 16, IR (film) cm^-13416w, 2960w, 2928w, 2856w, 1704w, 1492m, 1461m, 1428w, 1241s, 1110s, 823w, 751m, 734m, 702s, 611w；

The structural formula of the bryodin C ring skeleton compound 16 is as follows:

17) preparation of bryodin C-ring framework compound 17

By adopting the preparation method of the bryozoacin C-ring skeleton compound 0 in example 1, 61.6mg of the bryocin C-ring skeleton compound 17 as a pale yellow liquid was prepared, with a yield of 56%;

wherein [ alpha ] for bryodin C-ring skeleton compound 17]_D ²⁵ = +4.0° (c = 1.0 in CHCl₃)；¹H NMR (400 MHz, CDCl₃) δ 5.71-5.90 (m, 1H), 5.02-5.21 (m, 2H), 3.51-3.70 (m, 1H), 2.47 (t, J = 6.8 Hz, 2H), 2.28-2.38 (m, 1H), 2.22-2.31 (m, 1H), 2.08-2.20 (m, 1H), 1.10-1.52, 1.56-1.87 (m, 14H); ¹³C NMR (151 MHz, CDCl₃) δ 214.3, 134.8, 118.1, 70.3, 50.8, 41.9, 40.3, 36.3, 28.5, 25.8, 25.7, 19.5; IR (liquid film) cm^-13456w, 2928m, 1702w, 995w; HRMS (ESI-TOF, m/z) calcd for C₁₉H₂₇F₃O₃Si(M+Na)⁺:247.1669, found 247.1673；

The structural formula of the bryodin C ring skeleton compound 17 is as follows:

18) preparation of bryodin C-ring framework compound 18

By adopting the preparation method of the bryozoacin C ring skeleton compound 0 in the embodiment 1, 64.2mg of the bryocin C ring skeleton compound 18 which is a light yellow liquid is prepared, and the yield is 65%;

wherein [ alpha ] for bryodin C-ring skeleton compound 18]_D ²⁵ = +4.1° (c = 1.0 in CHCl₃)；¹H NMR (400 MHz, CDCl₃) δ 7.56-7.68 (m, 4H), 7.31-7.49 (m, 6H), 5.71-5.95 (m, 1H), 5.05-5.18 (m, 2H), 3.64 (s, 2H), 3.56-3.65 (m, 1H), 2.57 (t, J = 6.4 Hz, 2H), 2.20-2.34 (m, 1H), 2.08-2.20 (m, 1H), 1.60-1.76 (m, 2H), 1.36-1.52 (m, 2H), 1.12 (s, 6H), 1.04 (s, 9H); ¹³C NMR (101 MHz, CDCl₃) δ 214.8, 135.6, 134.8, 133.2, 129.7, 127.7, 118.0, 70.8, 70.3, 49.6, 41.8, 37.7, 36.3, 26.8, 21.7, 19.4, 19.3; IR (liquid film) cm^-13451w, 3072w, 2924m, 2854w, 1704w, 1462w, 1108m, 701s; HRMS (ESI-TOF, m/z) calcd forC₁₉H₂₇F₃O₃Si(M+Na)⁺:475.2639, found 475.2637；

Bryodin C-ring framework compound 18 has the following structural formula:

19) preparation of bryodin C-ring framework compound 19

49.6mg of the bryodin C-ring skeleton compound 19 as a pale yellow liquid was prepared by the method for preparing the bryodin C-ring skeleton compound 0 in example 1, with a yield of 52%;

wherein [ alpha ] for bryodin C-ring skeleton compound 19]_D ²⁵ = +5.5° (c = 1.0 in CHCl₃)；¹H NMR (400 MHz, CDCl₃) δ 5.71-5.91 (m, 1H), 5.06-5.19 (m, 2H), 3.55-3.68 (m, 1H), 3.56 (s, 2H), 2.70 (td, J ₁ = 6.8 Hz, J ₂ = 2.4 Hz, 2H), 2.22-2.34 (m, 1H), 2.07-2.21 (m, 1H), 1.88 (br s, 1H), 1.57-1.72 (m, 2H), 1.36-1.51 (m, 2H), 1.08 (s, 6H), 0.86 (s, 9H), 0.02 (s, 6H); ¹³C NMR (101 MHz, CDCl₃) δ 215.1, 134.9, 118.0, 70.3, 70.3, 49.4, 41.8, 37.8, 36.3, 25.8, 21.6, 19.3, 18.2, -5.7; IR (liquid film) cm^-13441w, 2927s, 2856m, 1705w, 1468w, 1364w, 1097m, 837s, 779w; HRMS (ESI-TOF, m/z) calcd forC₁₉H₂₇F₃O₃Si(M+Na)⁺:351.2326, found 351.2322；

Bryodin C-ring framework compound 19 has the following structural formula:

20) preparation of bryodin C-ring framework Compound 20

By adopting the preparation method of the bryozoacin C ring skeleton compound 0 in the embodiment 1, 21.6mg of the bryocin C ring skeleton compound 20 which is a light yellow liquid is prepared, and the yield is 26%;

wherein, for the C-ring skeleton compound 20 of bryodin, [ alpha ]]_D ²⁵ = -6.6° (c = 1.0 in CHCl₃)；¹H NMR (400 MHz, CDCl₃) δ 7.64 (d, J = 4.8 Hz, 4H), 7.34-7.46 (m, 6H), 5.75-5.87 (m, 1H), 5.05-5.19 (m, 2H), 3.61 (t, J = 4.4 Hz, 2H), 3.54-3.63 (m, 1H), 2.41-2.52 (m, 2H), 2.23-2.30 (m, 1H), 2.09-2.17 (m, 1H), 1.84 (t, J = 4.4 Hz, 2H), 1.53-1.63 (m, 2H), 1.33-1.43 (m, 2H), 1.09 (s, 6H), 1.02 (s, 9H); ¹³C NMR (151 MHz, CDCl₃) δ 215.0, 135.6, 134.8, 133.6, 129.6, 127.7, 118.0, 70.4, 60.7, 46.1, 41.9, 41.8, 36.4, 36.2, 26.8, 24.7, 19.7, 19.1; IR (liquid film) cm^-13432w, 3072w, 2926m, 2855w, 1702w, 1465w, 1108w, 703w, 504w; HRMS (ESI-TOF, m/z) calcd forC₁₉H₂₇F₃O₃Si(M+Na)⁺:489.2795, found 489.2803；

The structural formula of the bryodin C ring skeleton compound 20 is as follows:

21) preparation of bryodin C-ring framework compound 21

By adopting the preparation method of the bryozoacin C-ring skeleton compound 0 in the example 1, 57.8mg of the bryocin C-ring skeleton compound 21 which is a pale yellow liquid is prepared, and the yield is 62%;

wherein [ alpha ] for bryodin C-ring skeleton compound 21]_D ²⁵ = -6.6° (c = 1.0 in CHCl₃)；¹H NMR (400 MHz, CDCl₃) δ 7.60-7.68 (m, 4H), 7.34-7.45 (m, 6H), 5.72-5.90 (m, 1H), 5.05-5.18 (m, 2H), 3.62 (t, J = 6.4 Hz, 2H), 3.57-3.65 (m, 1H), 2.48 (td, J ₁ = 6.8 Hz, J ₂ = 0.8 Hz, 2H), 2.23-2.32 (m, 1H), 2.09-2.19 (m, 1H), 1.53-1.69 (m, 4H), 1.35-1.46 (m, 4H), 1.09 (s, 6H), 1.04 (s, 9H); ¹³C NMR (101 MHz, CDCl₃) δ 215.8, 135.5, 134.8, 133.9, 129.6, 127.6, 118.1, 70.4, 64.0, 47.2, 41.8, 36.4, 36.3, 36.1, 27.9, 26.9, 24.3, 19.7, 19.2; IR (liquid film) cm^-12929m, 2857m, 1701w, 1427w, 1092s, 1020m,799m, 702s; HRMS (ESI-TOF, m/z) calcd forC₁₉H₂₇F₃O₃Si(M+Na)⁺:503.2952, found 503.2948.；

The structural formula of the bryodin C-ring framework compound 21 is as follows:

22) preparation of bryodin C-ring framework Compound 22

By adopting the preparation method of the bryozoacin C ring skeleton compound 0 in the embodiment 1, 36.8mg of the bryocin C ring skeleton compound 22 which is a light yellow liquid is prepared, and the yield is 41%;

wherein the C-ring of bryozoacin is skeletonizedCompound 22, [ alpha ]]_D ²⁵ = -2.7° (c = 1.0 in CHCl₃)；¹H NMR (400 MHz, CDCl₃) δ 7.14 (t, J = 7.2 Hz, 1H), 7.01 (d, J = 7.6 Hz, 1H), 6.87 (d, J = 8.0 Hz, 2H), 5.70-5.94 (m, 1H), 5.00-5.21 (m, 2H), 3.53-5.67 (m, 1H), 2.76 (s, 2H), 2.42 (t, J = 6.4 Hz, 2H), 2.31 (s, 3H), 2.23-2.32 (m, 1H), 2.10-2.20 (m, 1H), 1.54-1.73 (m, 2H), 1.34-1.49 (m, 2H), 1.12 (s, 6H); ¹³C NMR (101 MHz, CDCl₃) δ 215.8, 137.7, 137.4, 134.8, 131.0, 127.8, 127.2, 127.0, 117.9, 70.3, 48.2, 45.5, 41.8, 37.8, 36.1, 24.3, 21.3, 19.5; IR (liquid film) cm^-13437w, 2923m, 1698s, 1364w, 994m, 913m, 790m, 702m; HRMS (ESI-TOF, m/z) calcd forC₁₉H₂₇F₃O₃Si(M+Na)⁺:311.1982, found 311.1978；

The structural formula of the bryodin C-ring framework compound 22 is as follows:

23) preparation of bryodin C-ring framework compound 23

By adopting the preparation method of the bryozoacin C ring skeleton compound 0 in the embodiment 1, 100.3mg of the bryocin C ring skeleton compound 23 which is a light yellow liquid is prepared, and the yield is 91%;

wherein, for bryodin C ring skeleton compound 23, [ alpha ]]_D ²⁵ = -1.3° (c = 1.0 in CHCl₃)；¹H NMR (400 MHz, CDCl₃) δ 7.55-7.68 (m, 4H), 7.31-7.47 (m, 6H), 5.71-5.90 (m, 1H), 5.04-5.18 (m, 2H), 3.67 (s, 2H), 3.55-3.65 (m, 1H), 2.38-2.54 (m, 2H), 2.21-2.33 (m, 1H), 2.08-2.19 (m, 1H), 1.66-1.76 (m, 2H), 1.59-1.67 (m, 2H), 1.50-1.60 (m, 2H), 1.35-1.47 (m, 2H), 1.04 (s, 9H), 0.65 (t, J = 7.6Hz, 6H); ¹³C NMR (151 MHz, CDCl₃) δ 214.7, 135.7, 134.8, 133.3, 129.7, 127.7, 118.0, 70.4, 64.1, 56.7, 41.8, 37.9, 36.4, 26.9, 23.7, 19.3, 19.3, 8.0; IR (liquid film) cm^-12931m, 1699w, 1427w, 1261w, 1110s, 748s, 703m; HRMS (ESI-TOF, m/z) calcd forC₁₉H₂₇F₃O₃Si(M+Na)⁺:503.2952, found 503.2945；

The structural formula of the bryodin C ring skeleton compound 23 is as follows:

24) preparation of bryodin C-ring framework compound 24

By adopting the preparation method of the bryozoacin C ring skeleton compound 0 in the embodiment 1, 40.9mg of the bryocin C ring skeleton compound 24 which is a light yellow liquid is prepared, and the yield is 49%;

wherein, for the C-ring skeleton compound 24 of the bryozoacin, [ alpha ]]_D ²⁵ = -1.1° (c = 1.0 in CHCl₃)；¹H NMR (400 MHz, CDCl₃) δ 7.56-7.67 (m, 4H), 7.35-7.50 (m, 6H), 5.72-5.88 (m, 1H), 5.06-5.17 (m, 2H), 3.84 (s, 2H), 3.68-3.80 (m, 4H), 5.57-3.67 (m, 1H), 2.45-2.63 (m, 2H), 2.23-2.32 (m, 1H), 2.07-2.18 (m, 1H), 1.63-1.79 (m, 2H), 1.36-1.51 (m, 2H), 1.04 (s, 9H); ¹³C NMR (101 MHz, CDCl₃) δ 207.6, 135.6, 134.6, 132.2, 130.1, 127.9, 118.2, 70.3, 64.3, 57.9, 41.9, 39.2, 35.9, 33.3, 26.8, 19.3, 19.1; IR (liquid film) cm^-13410w, 3072w, 2855w, 2928w, 1713w, 1427w, 1110s, 702m; HRMS (ESI-TOF, m/z) calcd for C₂₈H₃₈Br₂O₃Si (M+Na)⁺:633.0829, found 633.0823；

The structural formula of the bryodin C-ring skeleton compound 24 is as follows:

25) preparation of bryodin C-ring framework Compound 25

By using the preparation method of the bryozoacin C-ring skeleton compound 0 in example 1, a bryocin C-ring skeleton compound 25 (29.7 mg as a pale yellow liquid) was prepared with a yield of 27%;

wherein, for bryodin C ring skeleton compound 25, [ alpha ]]_D ²⁵ = -2.0° (c = 1.0 in CHCl₃)； ¹H NMR (400 MHz, CDCl₃) δ 7.57-7.65 (m, 4H), 7.34-7.46 (m, 6H), 5.72-5.90 (m, 1H), 5.47-5.63 (m, 2H), 4.89-5.22 (m, 6H), 3.70 (s, 2H), 3.55-3.63 (m, 1H), 2.40-2.50 (m, 2H), 2.29-2.42 (m, 4H), 2.20-2.29 (m, 1H), 2.07-2.18 (m, 1H), 1.54-1.70 (m, 2H), 1.34-1.46 (m, 2H), 1.06 (s, 9H); ¹³C NMR (101 MHz, CDCl₃) δ 213.0, 135.7, 134.8, 133.1, 133.0, 129.8, 127.7, 118.4, 118.0, 70.4, 65.5, 56.2, 41.8, 38.5, 36.2, 35.7, 26.9, 19.3, 19.1; IR (film) cm^-13443w, 3072w, 2929w, 2857w, 1702w, 1469w, 1427w, 1106m, 1087m, 916w, 737w, 700s, 612w; HRMS (ESI-TOF, m/z) calcd for C₃₂H₄₄O₃Si (M+Na)⁺:527.2952, found 527.2932；

Bryodin C-ring framework compound 25 has the following structural formula:

26) preparation of bryodin C-ring framework compound 26

By adopting the preparation method of the bryozoacin C-ring skeleton compound 0 in example 1, 42.3mg of the bryocin C-ring skeleton compound 26 as a pale yellow liquid was prepared with a yield of 46%;

wherein, for bryodin C ring skeleton compound 26, [ alpha ]]_D ²⁵ = +1.4° (c = 1.0 in CHCl₃)；¹H NMR (400 MHz, CDCl₃) δ 7.58-7.70 (m, 4H), 7.33-7.49 (m, 6H), 5.72-5.89 (m, 1H), 5.02-5.20 (m, 2H), 3.85 (s, 2H), 3.55-3.66 (m, 1H), 2.70 (t, J = 7.2 Hz, 2H), 2.23-2.33 (m, 1H), 2.09-2.20 (m, 1H), 1.64-1.74 (m, 2H), 1.39-1.49 (m, 2H), 1.12-1.19 (m, 2H), 1.05 (s, 9H), 0.68-0.76 (m, 2H); ¹³C NMR (101 MHz, CDCl₃) δ 210.7, 135.6, 134.8, 133.2, 129.8, 127.7, 118.0, 70.2, 65.8, 41.8, 38.8, 36.3, 32.9, 26.9, 19.5, 19.3, 15.2, 15.1; IR (liquid film) cm^-13434w, 3072w, 2856w, 2927m, 1687w, 1427w, 1108s, 702s; HRMS (ESI-TOF, m/z) calcd forC₁₉H₂₇F₃O₃Si(M+Na)⁺:473.2482, found 473.2487；

The structural formula of the bryodin C-ring framework compound 26 is as follows:

27) preparation of bryodin C-ring framework compound 27

By adopting the preparation method of the bryozoacin C ring skeleton compound 0 in the example 1, 39.6 mg of the bryocin C ring skeleton compound 27 which is a light yellow liquid is prepared, and the yield is 37%;

wherein, for bryodin C ring skeleton compound 27, [ alpha ]]_D ²⁵ = +2.4° (c = 1.0 in CHCl₃)；¹H NMR (400 MHz, CDCl₃) δ 7.63 (d, J = 6.6 Hz, 4H), 7.34-7.48 (m, 6H), 5.67-5.95 (m, 1H), 5.12 (d, J = 12.6 Hz, 2H), 3.88 (s, 2H), 3.55-3.66 (m, 1H), 2.50 (t, J = 6.6 Hz, 2H), 2.22-2.39 (m, 3H), 2.09-2.21 (m, 1H), 1.81-1.91 (m, 2H), 1.62-1.78 (m, 4H), 1.36-1.50 (m, 2H), 1.04 (s, 9H); ¹³C NMR (101 MHz, CDCl₃) δ 213.2, 135.7, 134.8, 133.2, 129.8, 127.7, 117.9, 70.4, 68.3, 55.0, 41.8, 37.2, 36.4, 26.8, 26.3, 19.4, 19.3, 15.1; IR (film) cm^-1 3441w, 3071w, 2930m, 2857w, 1701w, 1427w, 1108m, 1085m, 741w, 702s, 614w; HRMS (ESI-TOF, m/z) calcd for C₂₉H₄₀O₃Si (M+Na)⁺:487.2639, found 487.2654；

The structural formula of the bryodin C ring skeleton compound 27 is as follows:

28) preparation of bryodin C-ring framework Compound 28

By adopting the preparation method of the bryozoadin C ring skeleton compound 0 in the embodiment 1, 28 mg of the bryodin C ring skeleton compound 28 which is a light yellow liquid is prepared, and the yield is 50%;

wherein, for bryodin C ring skeleton compound 28, [ alpha ]]_D ²⁵ = +2.0° (c = 1.0 in CHCl₃);¹H NMR (400 MHz, CDCl₃) δ 7.60 (d, J = 6.8 Hz, 4H), 7.32-7.48 (m, 6H), 5.72-5.91 (m, 1H), 5.11 (d, J = 12.6 Hz, 2H), 3.62 (s, 2H), 3.56-3.69 (m, 1H), 2.58 (td, J ₁= 6.6 Hz, J ₂= 1.5 Hz, 2H), 2.23-2.33 (m, 1H), 2.08-2.19 (m, 1H), 1.94-2.03 (m, 2H), 1.62-1.74 (m, 2H), 1.37-1.49 (m, 4H), 1.26-1.36 (m, 4H), 1.03 (s, 9H); ¹³C NMR (101 MHz, CDCl₃) δ 213.6, 135.7, 134.8, 133.2, 129.7, 127.7, 117.9, 70.4, 68.9, 61.7, 41.8, 38.4, 36.4, 31.8, 26.9, 25.1, 19.7, 19.3; IR (film) cm^-13340w, 3072w, 2929w, 2858w, 1701w, 1427w, 1107m, 908m, 823w, 734m, 701s, 613w.; HRMS (ESI-TOF, m/z) calcd for C₃₀H₄₂O₃Si (M+Na)⁺:501.2795, found 501.2810；

Bryodin C-ring framework compound 28 has the following structural formula:

29) preparation of bryodin C-ring framework compound 29

By adopting the preparation method of the bryozoacin C ring skeleton compound 0 in the embodiment 1, 42.1 mg of the bryocin C ring skeleton compound 29 which is a light yellow liquid is prepared, and the yield is 51%;

wherein [ alpha ] for bryodin C-ring skeleton compound 29]_D ²⁵ = -0.78° (c = 1.0 in CHCl₃)；¹H NMR (400 MHz, CDCl₃) δ 7.62 (d, J = 6.6 Hz, 4H), 7.33-7.47 (m, 6H), 5.72-5.92 (m, 1H), 5.04-5.23 (m, 2H), 3.69 (s, 2H), 3.54-3.65 (m, 1H), 2.57 (t, J = 6.5 Hz, 2H), 2.22-2.32 (m, 1H), 2.07-2.19 (m, 1H), 1.88-1.98 (m, 2H), 1.36-1.77 (m, 12H), 1.03 (s, 9H); ¹³C NMR (101 MHz, CDCl₃) δ 214.2, 135.7, 134.9, 133.2, 129.7, 127.7, 117.9, 70.5, 70.1, 53.6, 41.8, 38.0, 36.4, 30.4, 26.9, 26.0, 22.7, 19.5, 19.3; IR (film) cm^-1 3433w, 3071w, 2928m, 2856m, 1701w, 1427w, 1110s, 822w, 702s, 609w; HRMS (ESI-TOF, m/z) calcd for C₃₁H₄₄O₃Si (M+Na)⁺:515.2952, found 515.2963；

The structural formula of the bryodin C ring skeleton compound 29 is as follows:

30) preparation of bryodin C-ring framework Compound 30

By adopting the preparation method of the bryozoacin C ring skeleton compound 0 in the embodiment 1, the bryocin C ring skeleton compound 30 is prepared, and the yield is less than 10%;

the structural formula of the bryodin C ring skeleton compound 30 is as follows:

31) preparation of bryodin C-ring framework compound 31

By adopting the preparation method of the bryozoacin C ring skeleton compound 0 in the embodiment 1, 51.7mg of the bryocin C ring skeleton compound 31 which is a light yellow liquid is prepared, and the yield is 48%;

wherein [ alpha ] for bryodin C-ring skeleton compound 31]_D ²⁵ = +16.9° (c = 1.0 in CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.59-7.64 (m, 4H), 7.34-7.45 (m, 6H), 7.11 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 3.79 (s, 3H), 3.68-3.76 (m, 1H), 3.63 (s, 2H), 2.75 (dd, J ₁ = 13.7 Hz, J ₂ = 4.4 Hz, 1H), 2.52-2.63 (m, 3H), 1.67-1.74 (m, 2H), 1.42-1.52 (m, 2H), 1.11 (s, 6H), 1.03 (s, 9H); ¹³C NMR (101 MHz, CDCl₃) δ 214.7, 158.2, 135.6, 133.2, 130.7, 130.4, 129.7, 127.7, 114.0, 72.5, 70.8, 55.2, 49.6, 43.0, 37.7, 36.2, 26.8, 21.7, 19.6, 19.3; IR (film) cm^-13373w, 2961w, 2930w, 2857w, 1701w, 1612w, 1501s, 1461w, 1244s, 1177w, 1081m, 1034m, 806w, 703w; HRMS (ESI-TOF, m/z) calcd for C₃₃H₄₄O₄Si (M+Na)⁺:555.2901, found 555.2913；

The structural formula of the bryodin C-ring skeleton compound 31 is as follows:

32) preparation of bryodin C-ring framework compound 32

By adopting the preparation method of the bryozoadin C ring skeleton compound 0 in the embodiment 1, 47.5mg of the bryodin C ring skeleton compound 32 which is a light yellow liquid is prepared, and the yield is 49%;

wherein [ alpha ] for bryodin C-ring skeleton compound 32]_D ²⁵ = +2.8° (c = 1.0 in CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.11 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H), 3.78 (s, 3H), 3.69-3.77 (m, 1H), 3.56 (s, 2H), 2.75 (dd, J ₁ = 13.7 Hz, J ₂ = 4.5 Hz, 1H), 2.50-2.63 (m, 3H), 1.60-1.75 (m, 2H), 1.38-1.54 (m, 2H), 1.08 (s, 6H), 0.86 (s, 9H), 0.02 (s, 6H); ¹³C NMR (101 MHz, CDCl₃) δ 214.9, 158.2, 130.3, 113.9, 113.3, 72.4, 70.2, 55.2, 49.3, 43.0, 37.8, 36.2, 25.8, 25.7, 21.5, 19.5, -5.7；IR (liquid film) cm^-13436w, 2927s, 2855m, 1512m, 1464w, 1246m, 1097w, 837m; HRMS (ESI-TOF, m/z) calcd for C₂₃H₄₀O₄Si (M+Na)⁺:431.2588, found 431.2590；

The structural formula of the bryodin C ring skeleton compound 32 is as follows:

33) preparation of bryodin C-ring framework compound 33

By adopting the preparation method of the bryozoacin C ring skeleton compound 0 in the embodiment 1, 50.0mg of the bryocin C ring skeleton compound 33 which is a light yellow liquid is prepared, and the yield is 41%;

wherein [ alpha ] for bryodin C-ring skeleton compound 33]_D ²⁵ = -2.4° (c = 1.0 in CHCl₃)； ¹H NMR (400 MHz, CDCl₃) δ 7.61 (d, J = 7.6 Hz, 4H), 7.34-7.48 (m, 6H), 3.80-3.90 (m, 1H), 3.64 (s, 2H), 2.92 (br s, 1H), 2.53-2.69 (m, 2H), 2.47 (t, J = 5.4 Hz, 2H), 1.60-1.75 (m, 2H), 1.48-1.58 (m, 2H), 1.12 (s, 6H), 1.04 (s, 9H); ¹³C NMR (101 MHz, CDCl₃) δ 215.3, 135.6, 133.1, 129.8, 127.7, 117.6, 70.9, 67.2, 49.6, 37.3, 36.0, 26.8, 25.9, 21.7, 19.3, 18.7; IR (film) cm^-13431w, 3071w, 2929w, 2857w, 1701w, 1427w, 1106m, 1088m, 806w, 736w, 701s; HRMS (ESI-TOF, m/z) calcd for C₂₇H₃₇NO₃Si(M+K)⁺:490.2174, found 490.2170；

The structural formula of the bryodin C ring skeleton compound 33 is as follows:

34) preparation of bryodin C-ring framework compound 34

By adopting the preparation method of the bryozoacin C ring skeleton compound 0 in the embodiment 1, 48.8mg of the bryocin C ring skeleton compound 34 which is a light yellow liquid is prepared, and the yield is 40%;

wherein for bryodin C-ring backbone compound 34, [ α ] D25 = +4.7 ° (C = 1.0 in CHCl 3); 1H NMR (400 MHz, CDCl3) delta 7.63 (d, J = 6.8 Hz, 4H), 7.37-7.44 (m, 6H), 4.87 (s, 1H), 4.79 (s, 1H), 3.67-3.74 (m, 1H), 3.64 (s, 2H), 2.57 (t, J = 6.9 Hz, 2H), 2.17-2.22 (dd, J1 = 9.0Hz, J2 = 2.0 Hz, 1H), 2.06-2.12 (dd, J1 = 9.0Hz, J2 = 6.2 Hz, 1H), 1.75 (s, 3H), 1.65-1.73 (m, 2H), 1.39-1.49 (m, 2H), 1.12 (s, 6H), 1.04 (s, 9H), 13C (151, 36 Cl 214.7) NMR, 142.8, 135.6, 133.2, 129.7, 127.7, 113.4, 70.8, 68.5, 49.6, 46.0, 37.8, 36.6, 26.8, 22.4, 21.7, 19.6, 19.3, IR (film) cm-13441 w, 3072w, 2930M, 2857w, 1703w, 1427w, 1107M, 1087M, 822w, 807w, 701s, 613w, HRMS (ESI-TOF, M/z) calcd for C29H42O3Si (M + Na) +:489.2795, found 489.2802;

bryodin C-ring framework compound 34 has the following structural formula:

35) preparation of bryodin C-ring framework compound 35

By adopting the preparation method of the bryozoacin C-ring framework compound 0 in the embodiment 1, the bryocin C-ring framework compound 35 is prepared, and the yield is 41%;

wherein, for the C-ring skeleton compound 35 of the careubin, IR (film) cm-13444 w, 3071M, 2958w, 2930w, 1731M, 1708w, 1471w, 1427w, 1106M, 1088M, 822w, 808w, 702s, 612w, HRMS (ESI-TOF, M/z) calcd for C29H42O5Si (M + Na) +:521.2694, found 521.2707;

the structural formula of the bryodin C ring skeleton compound 35 is as follows:

36) preparation of bryodin C-ring framework Compound 36

By adopting the preparation method of the bryozoacin C ring skeleton compound 0 in the embodiment 1, 23.3mg of the bryocin C ring skeleton compound 36 which is a light yellow liquid is prepared, and the yield is 39%;

wherein [ alpha ] for bryodin C-ring skeleton compound 36]_D ²⁵ = -1.4° (c = 1.0 in CHCl₃)；¹H NMR (400 MHz, CDCl₃) δ 7.57-7.64 (m, 4H), 7.33-7.44 (m, 6H), 4.87 (s, 1H), 4.78 (s, 1H), 3.68-3.74 (m, 1H), 3.68 (s, 2H), 2.43-2.51 (m, 2H), 2.18 (dd, J ₁ = 13.6 Hz, J ₂ = 3.3 Hz, 1H), 2.08 (dd, J ₁ = 13.6 Hz, J ₂ = 9.2 Hz, 1H), 1.74 (s, 3H), 1.63-1.73 (m, 4H), 1.53-1.60 (m, 2H), 1.38-1.47 (m, 2H), 1.05 (s, 9H), 0.65 (t, J = 7.4 Hz, 6H); ¹³C NMR (151 MHz, CDCl₃) δ 214.6, 142.8, 135.7, 133.3, 129.7, 127.6, 113.4, 68.5, 64.1, 56.7, 46.0, 37.9, 36.6, 26.9, 23.7, 22.4, 19.5, 19.3, 8.0; IR (film) cm^-13425w, 3071w, 2961w, 2930m, 2857w, 1699w, 1427w, 1107s, 1088s, 823w, 702s, 608w; HRMS (ESI-TOF, m/z) calcd for C₃₁H₄₆O₃Si (M+Na)⁺:517.3108, found 517.3117；

Bryodin C-ring framework compound 36 has the following structural formula:

37) preparation of bryodin C-ring framework Compound 37

By adopting the preparation method of the bryozoacin C-ring skeleton compound 0 in the example 1, 81.2mg of the bryocin C-ring skeleton compound 37 which is a light yellow liquid is prepared, and the yield is 78%;

wherein [ alpha ] for bryodin C-ring skeleton compound 37]_D ²⁵ = +1.2° (c = 1.0 in CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.53-7.70 (m, 4H), 7.31-7.48 (m, 6H), 5.53-5.63 (m, 2H), 3.68 (s, 2H), 3.50-3.61 (m, 1H), 2.37-2.56 (m, 2H), 2.13-2.27 (m, 1H), 1.98-2.12 (m, 1H), 1.51-1.78 (m, 9H), 1.34-1.47 (m, 2H), 1.05 (s, 9H), 0.65 (t, J = 7.6 Hz, 6H); ¹³C NMR (101 MHz, CDCl₃) δ 214.7, 135.7, 133.3, 129.7, 128.8, 127.6, 127.1, 70.7, 64.1, 56.7, 40.6, 37.8, 36.2, 26.9, 23.7, 19.4, 19.3, 18.0, 8.0; IR (liquid film) cm^-13439w, 2961w, 2929w, 2856w, 1698w, 1459w, 1106m, 735m, 700.85; HRMS (ESI-TOF, m/z) calcd for C₃₁H₄₆O₃Si (M+Na)⁺:517.3108, found 517.3114；

The structural formula of the bryodin C-ring skeleton compound 37 is as follows:

38) preparation of bryodin C-ring framework compound 38

By adopting the preparation method of the bryozoacin C-ring skeleton compound 0 in the embodiment 1, the bryocin C-ring skeleton compound 38 is prepared, and the yield is 34%;

wherein, for the bryodin C ring skeleton compound 38, IR (film) cm^-1 2930m, 1731m, 1373w, 1184m, 1110w, 704w;

The structural formula of the bryodin C-ring skeleton compound 38 is as follows:

39) preparation of bryodin C-ring framework compound 39

By adopting the preparation method of the bryozoacin C ring skeleton compound 0 in the embodiment 1, the bryocin C ring skeleton compound 39 is prepared, and the yield is 45%;

wherein, for the bryodin C ring skeleton compound 39, IR (film) cm^-1 2927m, 1699w, 1427w, 1109m, 824w, 703w;

The structural formula of the bryodin C-ring skeleton compound 39 is as follows:

40) preparation of bryodin C-ring framework Compound 40

By adopting the preparation method of the bryozoacin C-ring skeleton compound 0 in the embodiment 1, the bryocin C-ring skeleton compound 40 is prepared, and the yield is 10%;

wherein, for the bryodin C ring skeleton compound 40, the molecular formula is as follows: c₂₈H₄₀O₄Si，M+Na: 491.2588，found491.2590。

The structural formula of the bryodin C ring skeleton compound 40 is as follows:

the polarity of the bryodin C-ring framework compounds 10-16, 30 and 38-40 is almost the same as that of a iodocarbon reduction by-product, and the bryodin C-ring framework compounds are difficult to obtain by purification, so the given yield is nuclear magnetic yield; the yield of the bryodin C-ring skeleton compounds in 0-9, 17-29 and 31-37 is the separation yield and is the yield obtained by silica gel purification treatment.

Example 4

Taking the bryozoacin C-ring framework compound 0 obtained in the example 1 as a raw material, the invention provides a method for synthesizing the bryozoacin C-ring compound, which is further described and specifically comprises the following steps:

z1 preparation of intermediate Z1

Adding 500 mg of the obtained bryodin C-ring framework compound into a sealed tube, adding 1.20 g of 4A molecular sieve and 19.3 mg of hydrated p-toluenesulfonic acid, reacting at 80 ℃ for 16 h, cooling to room temperature, filtering the molecular sieve, and concentrating under reduced pressure to obtain an intermediate product Z1 which is a crude product;

z2 preparation of intermediate Z2

Cooling the intermediate product Z1 at 0 ℃ for 10min, adding 170.7 mg of sodium bicarbonate, 10mL of methanol and 314.7mg of magnesium di (monoperoxyphthalic acid) hexahydrate, and reacting at 0 ℃ for 3 h; then, water was added for quenching, and extraction was performed with ethyl acetate (5 × 20 mL), followed by concentration under reduced pressure to obtain intermediate Z2 as a crude product;

wherein, for the intermediate product Z2,¹H NMR (400 MHz, CDCl₃) δ 7.64-7.73 (m, 4H), 7.33-7.45 (m, 6H), 6.12 (d, J = 15.9 Hz, 1H), 5.49-5.59 (m, 1H), 5.31-5.50 (m, 2H), 4.21 (d, J = 4.9 Hz, 2H), 3.60-3.78 (m, 1H), 3.33-3.41 (m, 1H), 3.32 (s, 3H), 2.01-2.22 (m, 2H), 1.72-1.92 (m, 2H), 1.62 (d, J = 3.6 Hz, 3H), 1.35-1.46 (m, 2H), 1.27-1.31 (m, 2H), 1.18 (s, 3H), 1.16 (s, 3H), 1.06 (s, 9H); ¹³C NMR (151 MHz, CDCl₃) δ 139.1, 135.6, 135.6, 134.8, 129.6, 129.5, 127.7, 127.6, 127.3, 124.8, 70.9, 69.9, 65.0, 50.8, 44.8, 38.8, 29.7, 26.8, 26.5, 24.6, 24.2, 19.2, 18.0.；

z3 preparation of intermediate Z3

The resulting intermediate Z2 and 100 mg of 4A molecular sieve were added to 10m LCH at room temperature₂Cl₂Adding 37.4 mg of TPAP and 355.0 mg of NMO, and sealing the tube at normal temperature for reaction for 1 hour; then, quench with 10mL of water, extract with dichloromethane (3X 10 mL), concentrate under reduced pressure; purification by column chromatography on silica gel (petroleum ether: ethyl acetate =10: 1) gave 396.2 mg of intermediate Z3 as a pale yellow crude product (total yield 75% for steps Z1-Z3);

wherein, for the intermediate product Z3,¹H NMR (400 MHz, CDCl₃) δ 7.64-7.73 (m, 4H), 7.30-7.38 (m, 6H), 6.05 (d, J = 15.9 Hz, 1H), 5.41-5.58 (m, 3H), 4.18 (dd, J ₁ = 5.0 Hz, J ₂ = 1.7 Hz, 2H), 3.74-3.85 (m, 1H), 3.27 (s, 3H), 2.43 (t, J = 7.2 Hz, 2H), 2.30-2.39 (m, 1H), 2.18-2.27 (m, 1H), 1.97-2.09 (m, 1H), 1.85-1.92 (m, 1H), 1.65 (d, J = 4.9 Hz, 3H), 1.07 (s, 6H), 1.06 (s, 9H)；

z4 preparation of known compounds of bryodin C-ring precursor

After 300.0 mg of the intermediate product Z3 was dissolved in 20mL of tetrahydrofuran at room temperature, 438.0 mg of potassium carbonate, 101.9 mg of methyl glyoxylate and 20mL of methanol were added to the solution and reacted at room temperature for 1 hour; then, 5mL of water was added to quench, extracted with ethyl acetate (3X 10 mL), and concentrated under reduced pressure; purifying with silica gel column chromatography (petroleum ether: ethyl acetate =10: 1) to obtain 289.0 mg of light yellow crude product, which is known compound of bryodin C ring precursor, with yield of 85%;

among them, compounds known for the C-ring precursor of bryodin,¹H NMR (400 MHz, CDCl₃) δ 7.61-7.71 (m, 4H), 7.33-7.45 (m, 6H), 6.48-6.56 (m, 1H), 5.91 (d, J = 15.9 Hz, 1H), 5.46-5.64 (m, 2H), 5.42 (dt, J ₁= 15.9 Hz, J ₂= 4.8 Hz, 1H), 4.08-4.15 (m, 2H), 3.81-3.92 (m, 1H), 3.70 (s, 3H), 3.29 (s, 3H), 3.21-3.26 (m, 1H), 2.79-2.94 (m, 1H), 2.26-2.44 (m, 2H), 1.66 (d, J = 5.6 Hz, 3H), 1.11 (s, 3H), 1.05 (s, 9H), 1.02 (s, 3H); ¹³C NMR (151 MHz, CDCl₃) δ 197.6, 166.1, 148.5, 135.5, 134.9, 133.8, 133.8, 129.6, 128.9, 127.7, 127.6, 125.7, 122.8, 104.4, 71.7, 64.6, 51.7, 51.6, 44.3, 38.4, 34.6, 26.8, 22.4, 22.2, 19.2, 18.0.；

z5 preparation of bryodin C ring compound

The obtained known compound of the Bryostatin C ring precursor is subjected to Luche reduction and butyrylation, TABF desilication, DMP oxidation, Sharpless asymmetric dihydroxylation reaction and the like ("Total Synthesis of Bryostatin 8 Using an organic silane-Based Strategy, 2018" (Bryostatin 8, 2018 is completely synthesized Based on an Organosilane Strategy), so as to obtain the Bryostatin C ring compound (specifically the C ring compound of Bryostatin 8, and the Bryostatin 8 can be obtained after the C ring compound is combined with the AB ring).

Example 5

Based on example 4, this example also proposes a preparation method of various intermediate Z1 analogues, which is specifically as follows:

1) preparation of intermediate Z1-1

By adopting the preparation method of the intermediate product Z1 in the embodiment 4, the corresponding crude product is prepared, and the intermediate product Z1-1 of 86.3 mg which is light yellow liquid is obtained after the purification of a rapid silica gel column, and the yield is 90 percent;

wherein, for intermediate product Z1-1, [ alpha ]]_D ²⁵ = +7.1° (c = 1.0 in CHCl₃); ¹H NMR (600 MHz, CDCl₃) δ 7.63-7.74 (m, 4H), 7.31-7.47 (m, 6H), 5.77 (d, J = 15.6 Hz, 1H), 5.39-5.58 (m, 3H), 4.50 (t, J = 3.6 Hz, 1H), 4.22 (d, J = 5.0 Hz, 2H), 3.66-3.75 (m, 1H), 2.26-2.36 (m, 1H), 2.13-2.21 (m, 1H), 1.91-2.05 (m, 2H), 1.73-1.80 (m, 1H), 1.65 (d, J = 4.7 Hz, 3H), 1.56-1.64 (m, 1H), 1.13 (s, 6H), 1.07 (s, 9H); ¹³C NMR (151 MHz, CDCl₃) δ 159.3, 138.5, 135.6, 134.0, 129.5, 127.5, 127.3, 127.1, 125.2, 92.7, 75.0, 65.0, 40.3, 38.1, 26.9, 26.7, 25.7, 25.6, 20.1, 19.2, 18.0; IR (liquid film) cm^-13071w, 3049w, 2958w, 2927w, 2855w, 1661w, 1462w, 1427w, 1107s, 1057m, 996w, 822w, 737w, 700s, 611w; HRMS (ESI-TOF, m/z) calcd for C₃₁H₄₂O₂Si (M+Na)⁺:497.2846, found 497.2840；

Intermediate Z1-1 has the following structural formula:

2) preparation of intermediate Z1-2

By adopting the preparation method of the intermediate product Z1 in the embodiment 4, the corresponding crude product is prepared, and is purified by a rapid silica gel column to obtain 31.8mg of the intermediate product Z1-2 which is light yellow liquid, wherein the yield is 90%;

wherein, for intermediate product Z1-2, [ alpha ]]_D ²⁵ = +11.3° (c = 1.0 in CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.63-7.76 (m, 4H), 7.32-7.47 (m, 6H), 5.76 (d, J =15.6 Hz, 1H), 5.53 (dt, J ₁ = 15.6Hz, J ₂ = 5.1Hz, 1H), 4.76 (d, J = 16.8 Hz, 2H), 4.52 (t, J= 3.7 Hz, 1H), 4.21 (d, J = 4.4 Hz, 2H), 3.83-3.93 (m, 1H), 2.35 (dd, J ₁ = 14.0 Hz, J ₂ = 7.2 Hz, 1H), 2.21 (dd, J ₁ = 14.0 Hz, J ₂ = 5.5 Hz, 1H), 1.94-2.11 (m, 2H), 1.76 (s, 3H), 1.38-1.53 (m, 2H), 1.13 (s, 6H), 1.07 (s, 9H); ¹³C NMR (101 MHz, CDCl₃) δ 159.5, 142.7, 138.5, 135.6, 134.1, 129.5, 127.6, 125.2, 112.3, 92.7, 73.8, 65.0, 43.3, 40.3, 27.1, 26.9, 25.6, 22.9, 20.3, 19.2; IR (film) cm^-13071w, 2927m, 2855w, 1709w, 1612w, 1461w, 1428w, 1106m, 1057m, 819m, 800m, 700s, 612w; HRMS (ESI-TOF, m/z) calcd for C₃₁H₄₂O₂Si (M+Na)⁺:497.2846, found 497.284；

Intermediate Z1-2 has the following structural formula:

3) preparation of intermediate Z1-3

By adopting the preparation method of the intermediate product Z1 in the embodiment 4, the corresponding crude product is prepared, and is purified by a rapid silica gel column to obtain 37.6 mg of the intermediate product Z1-3 which is light yellow liquid, and the yield is 95%;

wherein, for intermediate product Z1-3, [ alpha ]]_D ²⁵ = +10.5° (c = 1.0 in CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.67-7.72 (m, 4H), 7.35-7.46 (m, 6H), 5.73 (dt, J ₁ = 15.6 Hz, J ₂= 1.2Hz, 1H), 5.52 (dt, J ₁ = 15.6 Hz, J ₂ = 4.8 Hz, 1H), 4.59 (t, J = 3.6 Hz, 1H), 4.22 (dd, J ₁ = 4.8 Hz, J ₂ = 1.2 Hz, 2H), 3.99-4.07 (m, 1H), 2.52-2.65 (m, 2H), 1.97-2.17 (m, 2H), 1.84-1.96 (m, 1H), 1.57-1.71 (m, 1H), 1.14 (s, 6H), 1.07 (s, 9H); ¹³C NMR (101 MHz, CDCl₃) δ 158.7, 137.7, 135.6, 134.0, 129.6, 127.6, 125.8, 117.0, 93.5, 70.3, 64.8, 40.2, 26.9, 26.4, 25.6, 25.5, 23.4, 19.5, 19.3；IR (film) cm^-13071w, 2925m, 2854m, 1665w, 1462w, 1427w, 1105m, 1057m, 821w, 738w, 701s, 611w. HRMS (ESI-TOF, m/z) calcd for C₂₉H₃₇NO₂Si (M+Na)⁺:482.2486, found 482.2487；

Intermediate Z1-3 has the following structural formula:

4) preparation of intermediate Z1-4

By adopting the preparation method of the intermediate product Z1 in the embodiment 4, the corresponding crude product is prepared, and the intermediate product Z1-4 of 48.8mg which is light yellow liquid is obtained after the purification of a rapid silica gel column, and the yield is 95%;

wherein, for intermediate product Z1-4, [ alpha ]]_D ²⁵ = +10.4° (c = 1.0 in CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.66-7.74 (m, 4H), 7.32-7.49 (m, 6H), 5.75-5.91 (m, 1H), 4.97-5.18 (m, 2H), 4.40 (t, J = 3.6 Hz, 1H), 3.67-3.76 (m, 1H), 3.54 (s, 2H), 2.29-2.39 (m, 1H), 2.20-2.29 (m, 1H), 1.93-2.13 (m, 2H), 1.63-1.81 (m, 2H), 1.48 (q, J = 7.6 Hz, 4H), 1.07 (s, 9H), 0.73 (t, J = 7.2 Hz, 6H); ¹³C NMR (101 MHz, CDCl₃) δ 154.9, 135.7, 134.9, 134.1, 129.4, 127.5, 116.6, 96.0, 74.3, 63.7, 47.1, 39.8, 27.1, 26.9, 23.5, 20.5, 19.5, 7.9; IR (film) cm^-13071w, 2961m, 2931m, 2857w, 1700w, 1664w, 1461w, 1427w, 1109s, 1087s, 823w, 748s, 702s, 609w; HRMS (ESI-TOF, m/z) calcd for C₃₀H₄₂O₂Si (M+Na)⁺: 485.2846, found 485.2849；

Intermediate Z1-4 has the following structural formula:

5) preparation of intermediate Z1-5

By adopting the preparation method of the intermediate product Z1 in the embodiment 4, the corresponding crude product is prepared, and is purified by a rapid silica gel column to obtain 50.1mg of the intermediate product Z1-5 which is light yellow liquid, and the yield is 95%;

wherein, for intermediate product Z1-5, [ alpha ]]_D ²⁵ = +11.4° (c = 1.0 in CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.64-7.71 (m, 4H), 7.32-7.45 (m, 6H), 5.38-5.52 (m, 2H), 4.36 (t, J = 3.6 Hz, 1H), 3.60-3.69 (m, 1H), 3.53 (s, 2H), 2.21-2.30 (m, 1H), 2.10-2.19 (m, 1H), 1.95-2.06 (m, 2H), 1.70-1.78 (m, 2H), 1.64 (d, J = 4.8 Hz, 3H), 1.46 (q, J = 7.6 Hz, 4H), 1.05 (s, 9H), 0.71 (dd, J ₁ = 7.2 Hz, J ₂ = 1.2 Hz, 6H); ¹³C NMR (101 MHz, CDCl₃) δ 154.9, 135.7, 134.2, 129.4, 127.5, 127.2, 127.1, 95.9, 74.7, 63.7, 47.0, 38.5, 29.7, 26.9, 23.6, 20.5, 19.5, 18.0, 7.9; IR (film) cm^-13071w, 2957w, 2923m, 2854m, 1664w, 1460w, 1428w, 1108m, 1085m, 822w, 738w, 700s, 609w; HRMS (ESI-TOF, m/z) calcd for C₂₉H₄₀O₂Si (M+Na)⁺:499.3003, found 499.3004；

Intermediate Z1-5 has the following structural formula:

6) preparation of intermediate Z1-6

By adopting the preparation method of the intermediate product Z1 in the embodiment 4, the corresponding crude product is prepared, and is purified by a rapid silica gel column to obtain 25.1mg of the intermediate product Z1-6 which is light yellow liquid, wherein the yield is 85%;

wherein, for intermediate product Z1-6, [ alpha ]]_D ²⁵ = +11.0° (c = 1.0 in CHCl₃);¹H NMR (400 MHz, CDCl₃) δ 7.65 (d, J = 7.5 Hz, 4H), 7.32-7.47 (m, 6H), 4.62-4.69 (m, 1H), 3.86-3.96 (m, 1H), 3.55 (d, J = 9.2 Hz, 1H), 3.48 (d, J = 9.2 Hz, 1H), 2.47 (d, J = 6.2 Hz, 2H), 2.00-2.16 (m, 2H), 1.83-1.95 (m, 1H), 1.58-1.66 (m, 1H), 1.07 (s, 6H), 1.04 (s, 9H); ¹³C NMR (151 MHz, CDCl₃) δ 157.4, 135.7, 134.1, 129.5, 127.5, 117.0, 94.7, 70.2, 69.9, 40.8, 26.8, 26.5, 23.5, 22.7, 22.7, 19.6, 19.5; IR (film) cm^-12928m, 2855m, 1670w, 1427w, 1390w, 1289w, 1111s, 824w, 703m; HRMS (ESI-TOF, m/z) calcd for C₂₇H₃₅NO₂Si (M+Na)⁺:456.2329, found 456.2340；

Intermediate Z1-6 has the following structural formula:

7) preparation of intermediate Z1-7

By adopting the preparation method of the intermediate product Z1 in the embodiment 4, the corresponding crude product is prepared, and is purified by a rapid silica gel column to obtain 29.2mg of the intermediate product Z1-7 which is light yellow liquid, wherein the yield is 91%;

wherein, for intermediate product Z1-7, [ alpha ]]_D ²⁵ = +14.7° (c = 1.0 in CHCl₃);¹H NMR (400 MHz, CDCl₃) δ 7.66 (d, J = 7.0 Hz, 4H), 7.32-7.45 (m, 6H), 4.57-4.65 (m, 1H), 4.14-4.22 (m, 1H), 4.03-4.13 (m, 2H), 3.52 (d, J = 9.2 Hz, 1H), 3.46 (d, J = 9.2 Hz, 1H), 2.58 (dd, J ₁= 14.9 Hz, J ₂= 7.7 Hz, 1H), 2.44 (dd, J ₁ = 14.9 Hz, J ₂= 5.8 Hz, 1H), 2.06-2.18 (m, 1H), 1.94-2.04 (m, 1H), 1.78-1.89 (m, 1H), 1.47-1.55 (m, 1H), 1.21 (t, J = 7.1 Hz, 3H), 1.05 (s, 6H), 1.04 (s, 9H); ¹³C NMR (151 MHz, CDCl₃) δ 171.1, 157.7, 135.6, 134.1, 129.4, 127.5, 94.1, 71.6, 70.0, 60.4, 40.8, 40.4, 27.1, 26.8, 22.8, 22.7, 20.1, 19.5, 14.2; IR (film) cm^-12928m, 2855m, 1736s, 1427w, 1195w, 1111s, 824w, 703m, 611w; HRMS (ESI-TOF, m/z) calcd for C₂₉H₄₀O₄Si (M+Na)⁺:503.2588, found 503.2603；

Intermediate Z1-7 has the following structural formula:

。

the intermediate products Z1-1 to Z1-7 obtained in the method are respectively used as raw materials for preparing the bryodin C ring compound analogues.

Example 6

Based on the synthesis method in example 4, this example provides a synthesis method of a series of bryodin C-ring compound analogs (same as steps Z1-Z5 in example 4) using bryodin C-ring framework compounds 1-39 in example 3 as raw materials, respectively, to further describe the present invention.

Example 7

Based on the synthesis method in example 4, this example provides a synthesis method of a series of bryodin C-ring compound analogs (same as steps Z2-Z5 in example 4) using intermediate Z1-1 to intermediate Z1-7 in example 5 as raw materials, respectively, to further illustrate the present invention.

Example 8

Based on examples 1-2, the present example provides the use of a class of bryodin C-ring framework compounds, including using the bryodin C-ring framework compounds for preparing bryodin C-ring compounds or analogs thereof, using the obtained bryodin C-ring compounds for preparing bryodin, and using the obtained bryodin C-ring compound analogs for preparing bryodin analogs; finally, the use for the preparation of products containing bryodin or analogues thereof is achieved for further elucidation of the invention.

Example 9

Based on examples 4-7, this example provides the use of a class of bryodin C-ring compound analogs, including for the preparation of products containing bryodin analogs, to further illustrate the present invention.

Wherein the product is used for treating cancer, AIDS and Alzheimer.

Example 10

Based on example 4, this example provides a pharmaceutical composition comprising bryodin C-ring skeleton compound or its pharmaceutically acceptable salt as an active ingredient, and pharmaceutically acceptable carriers, diluents and excipients.

Example 11

Based on examples 4-7, this example proposes a pharmaceutical composition comprising an analog of the bryodin C-ring compound or a pharmaceutically acceptable salt thereof as an active ingredient, together with pharmaceutically acceptable carriers, diluents and excipients.

Example 12

Based on examples 8-9, this example proposes a pharmaceutical composition comprising a bryodin analog or a pharmaceutically acceptable salt thereof as an active ingredient, together with pharmaceutically acceptable carriers, diluents and excipients.

Example 13

For the method of synthesizing the bryodin C-ring skeleton compound in example 1, this example relates to the equivalent of the ketene compound, the equivalent of the iodohydrocarbon compound, the equivalent of the additive such as zinc powder, the kind and the equivalent of the acid-binding agent (TMEDA), the catalyst (TMEDA, AuCl) in the synthesis process₃) The influence factors of species and equivalent, solvent and reaction time were studied to further illustrate the present invention, and the results are shown in the following table 1:

as shown by numbers 1-3 in the above table: when the ketene compound is excessive, the reaction yield is lower no matter how much equivalent the additive (other substances except the ketene compound and the iodo hydrocarbon compound) is added, and when the iodo hydrocarbon compound is excessive, the yield is obviously improved;

as shown by numbers 3-7 in the above table: the equivalent of TMEDA (base) has no obvious influence on the reaction yield, the reaction yield is reduced when the equivalent of Cu (II) is too low, the reaction yield is improved when the reaction time is prolonged, but the yield is not greatly contributed when the reaction time is too long;

as shown by numbers 8-9 in the above table: when the used Cu (II) is replaced by Cu (I), the solvent is changed into an ethanol-water system, higher yield can be obtained without additional additives, and after the reaction is carried out for 8 to 12 hours, the same amount of zinc powder and Cu (I) are supplemented for continuous reaction, so that the reaction yield can be greatly improved, and the condition is used as the final optimal reaction condition.

Wherein Cu (I/II) is monovalent copper/divalent copper, i.e., CuI/Cu (OAc) in the corresponding table₂(ii) a The yields in the table refer to isolated yields, i.e. calculated after purification on silica gel; the proportion of ethanol and TPGS aqueous solution in the solvent does not need to be strictly controlled, and the influence on the reaction yield is not obvious.

Claims

1. A method for synthesizing a bryodin C-ring framework compound is characterized by comprising the following steps of carrying out water-phase free radical coupling reaction on an ketene compound and an iodohydrocarbon compound, wherein the bryodin C-ring framework compound is represented by the following structural general formula (I), the ketene compound is represented by the following structural general formula (II), and the iodohydrocarbon compound is represented by the following structural general formula (III);

the method specifically comprises the following steps:

respectively adding an ketene compound, an iodo hydrocarbon compound, zinc powder, cuprous iodide, absolute ethyl alcohol and TPGS aqueous solution into a reaction device, and stirring and reacting for 8-24h at the temperature of 0-40 ℃;

adding equal amount of zinc powder, cuprous iodide, absolute ethyl alcohol and TPGS aqueous solution into the reaction tube, stirring and reacting at 0-40 ℃ for 8-24h, and adding water into the reaction device for quenching;

then, extracting with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, and concentrating under reduced pressure; purifying with silica gel column chromatography to obtain bryodin C ring skeleton compound;

wherein the reaction process is as follows:

；

the bryodin C-ring framework compound is obtained by modifying an E-type double bond at the C25-26 position, and has a structural formula as follows:

；

the bryodin C-ring framework compound is modified by symmetrical gem-dimethyl at C18, and the structural formula is as follows:

；

wherein TBDPSO-represents tert-butyl diphenyl siloxy;

wherein TPGS in the TPGS aqueous solution is represented by the following structural formula:

。

2. the method for synthesizing the bryodin C-ring framework compound as claimed in claim 1, wherein the TPGS mass fraction in the TPGS aqueous solution is 1-5%.

3. The method for synthesizing the bryodin C-ring framework compound as claimed in claim 1, wherein the TPGS mass fraction in the TPGS aqueous solution is 2%.

4. The method for synthesizing the bryodin C-ring framework compound as claimed in claim 1, wherein the mass ratio of the ketene compound to the iodo-hydrocarbon compound is 2: 1-1:6, wherein the mass ratio of the ketene compound to the zinc powder is 1:1-1:8, and the mass ratio of the ketene compound to the cuprous iodide is 1: 0.2-1: 3.6.

5. The method for synthesizing the bryodin C-ring framework compound as claimed in claim 1, wherein the mass ratio of the ketene compound, the iodo hydrocarbon compound, the zinc powder and the cuprous iodide is 1.0: 3.0: 5.0: 1.2.