阅读说明：本技术 十七元大环脂肽天然化合物的合成方法 (Synthetic method of seventeen-membered large cyclic lipopeptide natural compound ) 是由 叶涛 郭益安 杨明泽 彭文泉 于 2020-03-06 设计创作，主要内容包括：本发明属于有机合成技术领域,尤其涉及一种十七元大环脂肽天然化合物的合成方法,以(R)-3-羟基异丁酸甲酯为原料,依次经过还原缩合反应、锂化-硼基化反应、迁移反应、锂卤交换反应、氧化处理、不对称布朗丁烯基化反应、与氨基苄氧羰基保护的左旋缬氨酸通过酯化反应、催化氢化反应后与6-庚烯酸进行接肽反应、烯丙基化反应、关环复分解反应以及催化氢化反应,合成得到十七元大环脂肽天然化合物dysoxylactam A,合成产率高,产物药用价值高。(The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing a seventeen-membered large cyclic lipopeptide natural compound, wherein (R) -3-hydroxyisobutyric acid methyl ester is used as a raw material, and the synthesis method comprises the steps of carrying out reduction condensation reaction, lithiation-boronization reaction, migration reaction, lithium halide exchange reaction, oxidation treatment, asymmetric Brownian butene reaction, esterification reaction with aminobenzyloxycarbonyl protected levo valine, catalytic hydrogenation reaction, and then carrying out peptide grafting reaction, allylation reaction, ring closing metathesis reaction and catalytic hydrogenation reaction with 6-heptenoic acid to synthesize the seventeen-membered large cyclic lipopeptide natural compound dysaxylactam A.)

1. A method for synthesizing a heptadeca-macrocyclic lipopeptide natural compound, comprising the steps of:

obtaining (R) -3-hydroxyisobutyric acid methyl ester, and sequentially carrying out reduction condensation reaction, lithiation-boronization reaction, migration reaction, lithium halide exchange reaction and oxidation treatment on the (R) -3-hydroxyisobutyric acid methyl ester to obtain a compound 9;

carrying out asymmetric Brownian butene reaction on the compound 9 to obtain a compound 3;

carrying out esterification reaction on the compound 3 and the L-valine protected by aminobenzyloxycarbonyl to obtain a compound 12;

carrying out catalytic hydrogenation reaction on the compound 12, and then carrying out peptide grafting reaction on the compound 12 and 6-heptenoic acid to obtain a compound 14;

allylating said compound 14 to provide compound 2;

performing ring closing metathesis reaction on the compound 2 to obtain a compound 15;

carrying out catalytic hydrogenation reaction on the compound 15 to obtain dysxylactam A;

wherein said compound 9 is:the compound 3 is:the compound 12 is:the compound 14 is:the compound 2 is:the compound 15 is:wherein R is selected from: h or TMS; the dysxylactam A is:

2. the method for synthesizing a heptadeca-macrocyclic lipopeptide natural compound according to claim 1, wherein the step of subjecting the methyl (R) -3-hydroxyisobutyrate to a reductive condensation reaction, a lithiation-boronization reaction, a migration reaction, a lithium halide exchange reaction, and an oxidation treatment in this order comprises: obtaining methyl (R) -3-hydroxyisobutyrate, pThe (R) -3-hydroxyisobutyric acid methyl ester is subjected to reduction condensation reaction to obtain a compound 5,

carrying out lithiation-boronization reaction on the compound 5 to obtain a compound 6,

(ii) subjecting said compound 6 to a migration reaction to give a compound 7,

subjecting the compound 7 to a lithium halide exchange reaction to obtain a compound 8,

the compound 8 is subjected to oxidation treatment to obtain a compound 9.

3. The method of synthesizing a heptadecamacrocyclic lipopeptide natural compound of claim 2, wherein the step of subjecting the methyl (R) -3-hydroxyisobutyrate to a reductive condensation reaction comprises: after the hydroxyl of the (R) -3-hydroxyisobutyric acid methyl ester is protected by TBS, diisobutylaluminum hydride is sequentially added to carry out reduction reaction and condensation reaction of diisopropylmethylamine chloride at the temperature of 25-38 ℃, and a compound 5 is obtained by separation; and/or the presence of a gas in the gas,

the step of subjecting said compound 5 to lithiation-boration reaction comprises: under the condition that the temperature is-40 ℃ to-80 ℃, sec-butyl lithium is added into the mixed solution of the compound 5 and tetramethyl ethylene diamine to react for 5-8 hours, pinacolborane is added to react for 1-3 hours, then the temperature is increased to 30-50 ℃ to react for 10-15 hours, and the compound 6 is obtained through separation; and/or the presence of a gas in the gas,

the step of subjecting said compound 6 to a migration reaction comprises: under the condition that the temperature is-40 ℃ to-80 ℃, sec-butyl lithium is added into a mixed solution of ethyl carbamate and (+) -falcarina to react for 3-5 hours, a compound 6 is added to react for 1-3 hours, then the temperature is increased to 30-50 ℃ to react for 10-15 hours, and a compound 7 is obtained through separation; and/or the presence of a gas in the gas,

subjecting said compound 7 to a lithium halide exchange reaction: adding n-butyl lithium into the mixed solution of the compound 7 and iodochloromethane at the temperature of-40 to-80 ℃, heating to 25 to 38 ℃, reacting for 10 to 15 hours, and separating to obtain a compound 8; and/or the presence of a gas in the gas,

the step of subjecting the compound 8 to an oxidation treatment comprises: adding sodium bicarbonate, trichloroisocyanuric acid and tetramethylpiperidine oxynitride into the solution of the compound 8, reacting for 2-5 minutes at the temperature of 0-5 ℃, and separating to obtain a compound 9; and/or the presence of a gas in the gas,

the step of subjecting said compound 9 to an asymmetric brownian butene reaction comprises: under the anhydrous and oxygen-free environment with the temperature of-80 ℃ to-30 ℃, the compound 9 is mixed with potassium tert-butoxide, cis-2-butene, n-butyl lithium, (+) -Ipc₂And dissolving BOMe and boron trifluoride ethyl ether in the first organic solvent, reacting for 10-15 hours, and separating to obtain a compound 3.

4. The method for synthesizing a heptadecamacrocyclic lipopeptide natural compound of claim 3, wherein the molar ratio of the methyl (R) -3-hydroxyisobutyrate, the diisobutylaluminum hydride and the diisopropylmethylaminochloride is (0.5-1.5): (2.5-3.5): (3.5-4.5); and/or the presence of a gas in the gas,

the molar ratio of the sec-butyl lithium to the compound 5 to the tetramethylethylenediamine to the pinacolborane is (2-3): (1-12): (2.5-3.5): (3.5-4.5); and/or the presence of a gas in the gas,

the molar ratio of sec-butyl lithium, ethyl carbamate, (+) -falcon and the compound 6 is (1-2): (0.5-1.5): (1-2): (0.2 to 0.5); and/or the presence of a gas in the gas,

the molar ratio of the compound 7 to the iodochloromethane to the n-butyllithium is (0.2-0.5): (3-8): (1-2); and/or the presence of a gas in the gas,

the molar ratio of the compound 8, the sodium bicarbonate, the trichloroisocyanuric acid and the tetramethylpiperidine nitroxide is (0.3-1): (1.5-2.5): (0.5-1): (0.03-0.1); and/or the presence of a gas in the gas,

said compound 9, said potassium tert-butoxide, said cis-2-butene, said n-butyllithium, said (+) -Ipc₂The molar ratio of BOMe to boron trifluoride diethyl etherate is (1-1.5): (2.2-2.8): (6-6.5): (2.2-2.8): (3.5-4): (4.8-5.3); and/or the presence of a gas in the gas,

the solvent in the mixed solution of the compound 5 and the tetramethylethylenediamine is selected from the following solvents: at least one of anhydrous diethyl ether, tetrahydrofuran and methyl tert-butyl ether; and/or the presence of a gas in the gas,

the solvent in the mixed solution of ethyl carbamate and (+) -falcon is selected from the following solvents: at least one of anhydrous diethyl ether, tetrahydrofuran and methyl tert-butyl ether; and/or the presence of a gas in the gas,

the solvent in the mixed solution of the compound 7 and iodochloromethane is selected from: at least one of tetrahydrofuran, diethyl ether and methyl tert-butyl ether; and/or the presence of a gas in the gas,

the solvent in the solution of compound 8 is selected from: at least one of dichloromethane, toluene and acetonitrile; and/or the presence of a gas in the gas,

the first organic solvent is selected from: at least one of tetrahydrofuran, diethyl ether and methyl tert-butyl ether; and/or the presence of a gas in the gas,

the step of subjecting said compound 9 to an asymmetric brownian butene reaction comprises: dissolving the dry and oxygen-free potassium tert-butoxide in a first organic solution in an oxygen-free environment, cooling to-60 to-80 ℃, sequentially adding the cis-2-butene and the n-butyllithium, heating to-30 to-45 ℃, and reacting for 10 to 30 minutes; then cooling to-60 ℃ to-80 ℃, and adding the (+) -Ipc₂And reacting the BOMe for 10-30 minutes, sequentially adding the boron trifluoride diethyl etherate and the compound 9, and reacting for 10-15 hours at the temperature of-60-80 ℃.

5. The method for synthesizing a heptadeca-macrocyclic lipopeptide natural compound according to any one of claims 1 to 4, wherein the step of esterifying the compound 3 with aminobenzyloxycarbonyl-protected L-valine comprises: dissolving the compound 3 and the L-valine protected by aminobenzyloxycarbonyl in a second organic solvent, sequentially adding triethylamine and 2, 4, 6-trichlorobenzoyl chloride at the temperature of-5-0 ℃, and heating to the temperature of 25-38 ℃ for reaction for 10-30 minutes; then cooling to-5-0 ℃, adding 4-dimethylamino pyridine, heating to 25-38 ℃, reacting for 10-12 hours, and separating to obtain a compound 12; and/or the presence of a gas in the gas,

the step of subjecting said compound 12 to catalytic hydrogenation followed by peptide-grafting with 6-heptenoic acid comprises: dissolving the compound 12 and the first palladium catalyst in a third organic solvent in a protective gas atmosphere, and reacting for 3-5 hours in a reducing gas atmosphere to obtain an amino alcohol crude product; dissolving the coarse amino alcohol product and 6-heptenoic acid in a fourth organic solvent, sequentially adding N, N-diisopropylethylamine, 1-hydroxy-7-azobenzotriazol and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate at the temperature of-5-0 ℃, reacting for 8-10 hours at the temperature of 25-38 ℃, and separating to obtain a compound 14; and/or the presence of a gas in the gas,

the step of allylating said compound 14 comprises: and (2) dissolving the compound 14, an iridium catalyst, 4-chloro-3-nitrobenzoic acid and cesium carbonate in a mixed solution of tetrahydrofuran, water and allyl acetate in an oxygen-free environment, reacting for 48-72 hours at the temperature of 80-100 ℃, and separating to obtain a compound 2.

6. The method for synthesizing a heptadecamacrocyclic lipopeptide natural compound according to claim 5, wherein the molar ratio of the compound 3, the aminobenzyloxycarbonyl protected L-valine, the triethylamine, the 2, 4, 6-trichlorobenzoyl chloride and the 4-dimethylaminopyridine is (0.8-1.5): (1.8-2.5): (4-5): (3-4): (4-6); and/or the presence of a gas in the gas,

the second organic solvent is selected from: at least one of toluene, dichloromethane, nitrogen-nitrogen dimethylformamide and tetrahydrofuran; and/or the presence of a gas in the gas,

the compound 12, the first palladium catalyst, the 6-heptenoic acid, the N, N-diisopropylethylamine, the 1-hydroxy-7-azobenzotriazol and the 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate have a molar ratio of: (0.3-0.4): (0.1-0.2): (0.5-1): (3-4): (0.5-1): (1-2); and/or the presence of a gas in the gas,

the first palladium catalyst is at least one selected from palladium dichloride, palladium carbon and palladium hydroxide carbon; and/or the presence of a gas in the gas,

the third organic solvent is selected from: at least one of methanol, ethyl acetate, dichloromethane and chloroform; and/or the presence of a gas in the gas,

the fourth organic solvent is selected from: the volume ratio is (15-25): 1, a mixed solvent of dichloromethane and dimethylformamide; and/or the presence of a gas in the gas,

the protective gas is selected from: at least one of nitrogen, argon, helium; and/or the presence of a gas in the gas,

the reducing gas is selected from hydrogen; and/or the presence of a gas in the gas,

the molar ratio of the compound 14, the iridium catalyst, the 4-chloro-3-nitrobenzoic acid and the cesium carbonate is (1-2): (0.5-1): (1-2): (1.5-3); and/or the presence of a gas in the gas,

in the mixed solution, the volume ratio of the tetrahydrofuran to the water to the allyl acetate is (4-6) ml: (8-12) ul: (0.15-0.25) ml.

7. The method of synthesizing a heptadecamacrocyclic lipopeptide natural compound of claim 6, wherein the step of ring closing metathesis of compound 2 comprises: dissolving the compound 2 in a sixth organic solvent in an oxygen-free environment, adding a Grabbs second-generation catalyst, reacting for 20-25 hours at the temperature of 30-40 ℃, separating to obtain a compound 15a,alternatively, the first and second electrodes may be,

the step of subjecting the compound 2 to a ring closing metathesis reaction comprises: sequentially adding triethylamine and trimethylsilyl trifluoromethanesulfonate at-5-0 deg.CAdding the mixture into the solution of the compound 2, heating to 25-38 ℃, reacting for 3-5 hours, and separating to obtain a compound 2'; then, in an oxygen-free environment, dissolving the compound 2' in a seventh organic solvent, adding a Grabbs second-generation catalyst, reacting for 20-25 hours at the temperature of 30-40 ℃, separating to obtain a compound 15b,

8. the method for synthesizing a heptadecamacrocyclic lipopeptide natural compound according to claim 7, wherein the molar ratio of the compound 2, the triethylamine and the trimethylsilyl trifluoromethanesulfonate is (0.02-0.08): (1-1.5): (0.2-0.8); and/or the presence of a gas in the gas,

the molar ratio of the compound 2 or the compound 2' to the Grabbs second generation catalyst is (1-3): (0.1 to 0.3); and/or the presence of a gas in the gas,

the solvent in the solution of compound 2 is selected from: at least one of dichloromethane, toluene and acetonitrile; and/or the presence of a gas in the gas,

the sixth organic solvent and the seventh organic solvent are each independently selected from: at least one of dichloromethane, toluene and acetonitrile.

9. The method of synthesizing a heptadecamacrocyclic lipopeptide natural compound of claim 8, wherein the step of catalytically hydrogenating compound 15 comprises: and dissolving the compound 15 and the second palladium catalyst in an eighth organic solvent in a protective gas atmosphere, reacting for 3-4 hours in a reducing gas atmosphere, and separating to obtain the dysxylactam A.

10. The method of synthesizing a heptadecamacrocyclic lipopeptide natural compound of claim 9, wherein the compound 15 and the second palladium catalyst are present in a molar ratio of (1-3): (0.01-0.02); and/or the presence of a gas in the gas,

the second palladium catalyst is at least one selected from palladium dichloride, palladium carbon and palladium hydroxide carbon; and/or the presence of a gas in the gas,

the eighth organic solvent is selected from: at least one of methanol, ethyl acetate, dichloromethane and chloroform; and/or the presence of a gas in the gas,

the protective gas is selected from: at least one of nitrogen, argon, helium; and/or the presence of a gas in the gas,

the reducing gas is selected from: hydrogen gas.

11. The method of synthesizing a heptadecamacrocyclic lipopeptide natural compound of claim 10,

obtaining (R) -3-hydroxy methyl isobutyrate, protecting the hydroxyl of the (R) -3-hydroxy methyl isobutyrate by TBS, sequentially adding diisobutyl aluminum hydride for reduction reaction and diisopropyl methylamine acyl chloride for condensation reaction, and separating to obtain a compound 5;

adding sec-butyl lithium into the mixed solution of the compound 5 and tetramethylethylenediamine for reaction, adding pinacolborane for reaction, and separating to obtain a compound 6;

adding sec-butyl lithium into a mixed solution of ethyl carbamate and (+) -falcarinine for reaction, adding a compound 6 for reaction, and separating to obtain a compound 7;

adding n-butyllithium into the mixed solution of the compound 7 and iodochloromethane for reaction, and separating to obtain a compound 8;

adding sodium bicarbonate, trichloroisocyanuric acid and tetramethylpiperidine nitrogen oxide into the solution of the compound 8 for reaction, and separating to obtain a compound 9;

dissolving the compound 9, potassium tert-butoxide, cis-2-butene, n-butyllithium, (+) -Ipc2BOMe and boron trifluoride diethyl etherate in a first organic solvent for reaction, and separating to obtain a compound 3;

dissolving a compound 3 and the L-valine protected by aminobenzyloxycarbonyl in the second organic solvent, sequentially adding triethylamine and 2, 4, 6-trichlorobenzoyl chloride for reaction, adding 4-dimethylaminopyridine for reaction, and separating to obtain a compound 12;

dissolving the compound 12 and the first palladium catalyst in the third organic solvent for reaction to obtain an amino alcohol crude product; dissolving the coarse amino alcohol product and 6-heptenoic acid in the fourth organic solvent, sequentially adding N, N-diisopropylethylamine, 1-hydroxy-7-azobenzotriazol and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate, reacting, and separating to obtain a compound 14;

dissolving the compound 14, an iridium catalyst, 4-chloro-3-nitrobenzoic acid and cesium carbonate in a mixed solution of tetrahydrofuran, water and allyl acetate for reaction, and separating to obtain a compound 2;

sequentially adding triethylamine and trimethylsilyl trifluoromethanesulfonate into the solution of the compound 2 for reaction, and separating to obtain a compound 2'; then dissolving the compound 2' in the seventh organic solvent, adding a Grabbs second-generation catalyst for reaction, and separating to obtain a compound 15 b;

and dissolving the compound 15 and the second palladium catalyst in the eighth organic solvent for reaction, and separating to obtain the dysxylactam A.

Technical Field

The invention belongs to the technical field of organic synthesis, and particularly relates to a synthetic method of a seventeen-membered large cyclic lipopeptide natural compound.

Background

Seventeen-membered macrocyclic lipopeptides natural products dysoxyactam a with multidrug resistance reversing activity in tumor cells was isolated from the bark of cuminum hongkongense (dysoxylum hongkongense) in 2019 by yue founder academy group (Yue, j.m., et al.j.am.chem.soc.2019,141, 6812.). Structurally, dysxylactam a is a heptadeca-membered macrocyclic depsipeptide with 6 chiral centers, while the side chain is a unique fatty acid containing five consecutive stereocenters. Preliminary bioactivity studies indicate that dysxylactam a can reverse the multidrug resistance phenomenon of tumor cells. In vitro cell experiments show that multidrug-resistant tumor cells induced by such chemicals as adriamycin (adriamycin), vincristine (vincristine) and paclitaxel (paclitaxel) have a response improved by 28.4-1039.7 times after being treated with low-concentration dysxylactam A, and more importantly, dysxylactam A does not show any cytotoxicity at a concentration of 10 μ M. It was demonstrated that dysxylactam a significantly restored the sensitivity of P-gp (P-glycoprotein) substrate drugs (such as doxorubicin, vincristine and paclitaxel) to these drug-resistant cancer cells, and had no significant effect on the sensitivity of these drugs to parental counterpart cells. Inhibitors that reverse multidrug resistance in cancer cells generally act by two means: one is to inhibit the expression of P-gp to reduce its amount, thereby reducing the likelihood of the cancer cells releasing the anti-cancer drug; the other is direct binding with P-gp to reduce its transport function. The study on the tumor cells MCF7/ADR shows that dysoxylactam A does not obviously reduce the expression of P-gp, but inhibits the transport function of P-gp in the tumor cells.

In view of the excellent biological activity of dysoxylactam A in reversing the multidrug resistance phenomenon of tumor cells, dysoxylactam A is expected to be a breakthrough for treating multidrug resistance of cancers. On the basis of completing the synthesis of the active natural product dysoxylactam A, the structure of the natural product is further modified and optimized, the structure-activity relationship is explored, the action mode of the natural product and a target protein P-gp is searched, and the action mechanism of dysoxylactam A for reversing the multidrug resistance of tumor cells is tried to be clarified.

Disclosure of Invention

The invention aims to provide a method for synthesizing a seventeen-membered macrocyclic lipopeptide natural compound, and aims to solve the technical problems that the conventional dysxylactam A can only be separated and extracted from the bark of cuminum hongkongensis, the extraction efficiency is low, the structure of the compound cannot be further modified on the basis of the dysxylactam A, the structure-activity relationship cannot be explored, and the like.

In order to achieve the purpose of the invention, the technical scheme adopted by the invention is as follows:

a method for synthesizing a heptadeca-macrocyclic lipopeptide natural compound, comprising the steps of:

obtaining (R) -3-hydroxyisobutyric acid methyl ester, and sequentially carrying out reduction condensation reaction, lithiation-boronization reaction, migration reaction, lithium halide exchange reaction and oxidation treatment on the (R) -3-hydroxyisobutyric acid methyl ester to obtain a compound 9;

carrying out asymmetric Brownian butene reaction on the compound 9 to obtain a compound 3;

carrying out esterification reaction on the compound 3 and the L-valine protected by aminobenzyloxycarbonyl to obtain a compound 12;

carrying out catalytic hydrogenation reaction on the compound 12, and then carrying out peptide grafting reaction on the compound 12 and 6-heptenoic acid to obtain a compound 14;

allylating said compound 14 to provide compound 2;

performing ring closing metathesis reaction on the compound 2 to obtain a compound 15;

carrying out catalytic hydrogenation reaction on the compound 15 to obtain dysxylactam A;

wherein said compound 9 is:the compound 3 is:the compound 12 is:the compound 14 is:the compound 2 is:the compound 15 is:wherein R is selected from: h or TMS; the dysxylactam A is:

the present invention provides a method for synthesizing a heptadecatomic macrocyclic lipopeptide natural compound, wherein the retrosynthetic route is designed by analyzing the structure of a target product Dysoxylactam A, specifically, ester bonds and amide bonds contained in the structure of Dysoxylactam A are common cyclization sites of macrocyclic compounds, but certain steric hindrance exists, the present application intends to realize the construction of macrocycles by adopting olefin metathesis Reaction (RCM), the cutting of C6-C7 carbon-carbon bond can be reversely pushed to a precursor compound 2. the linear cyclization precursor compound 2 can be introduced into required 6-heptenoic acid and L-valine respectively by amidation (amidation) and esterification reaction (Yamaguchi esterification), the chiral hydroxyl at C9 can be introduced into required 6-heptenoic acid and L-valine respectively by Krischelylation (Krische allylation) high stereoselectivity, the thus, the complex precursor compound 2 can be simplified to a diol compound 3 which is singly protected by the above strategies, the chiral hydroxyl at C13 can be introduced into Brownotch allylation reaction (Krisphe allylation reaction) by the Browney-carbonyl group reaction catalyzed by the above-carbonyl group-N reaction, the reaction can be synthesized into a diol compound 3 which is synthesized by the transesterification reaction, the esterification reaction, the high-carbonyl group-isobutyrate reaction, the product can be synthesized by the high-carbonyl group conversion reaction, and the esterification reaction, the high-carbonyl group conversion reaction can be synthesized by the high-carbonyl group conversion reaction, the high-carbonyl group.

Drawings

FIG. 1 is a schematic diagram of the synthetic route of dysoxylactam A provided in the embodiment of the present invention.

Detailed Description

In order to make the purpose, technical solution and technical effect of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention is clearly and completely described, and it is obvious that the described embodiments are a part of the embodiments of the present invention, but not all embodiments. All other embodiments obtained by a person of ordinary skill in the art without any inventive step in connection with the embodiments of the present invention shall fall within the scope of protection of the present invention.

In the description of the present invention, it is to be understood that the terms "first", "second" and the like are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implying any number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of the present invention, "a plurality" means two or more unless specifically defined otherwise.

The weight of the related components mentioned in the description of the embodiments of the present invention may not only refer to the specific content of each component, but also represent the proportional relationship of the weight among the components, and therefore, the content of the related components is scaled up or down within the scope disclosed in the description of the embodiments of the present invention as long as it is in accordance with the description of the embodiments of the present invention. Specifically, the weight described in the description of the embodiment of the present invention may be a unit of mass known in the chemical industry field, such as μ g, mg, g, and kg.

The embodiment of the invention provides a method for synthesizing a seventeen-membered large cyclic lipopeptide natural compound, which comprises the following steps:

s00, obtaining (R) -3-hydroxyisobutyric acid methyl ester, and sequentially carrying out reduction condensation reaction, lithiation-boronization reaction, migration reaction, lithium halide exchange reaction and oxidation treatment on the (R) -3-hydroxyisobutyric acid methyl ester to obtain a compound 9;

s60, carrying out asymmetric Brownian butene reaction on the compound 9 to obtain a compound 3;

s70, carrying out esterification reaction on the compound 3 and the L-valine protected by aminobenzyloxycarbonyl to obtain a compound 12;

s80, carrying out catalytic hydrogenation reaction on the compound 12, and then carrying out peptide grafting reaction on the compound 12 and 6-heptenoic acid to obtain a compound 14;

s90, carrying out allylation reaction on the compound 14 to obtain a compound 2;

s11, carrying out ring closing metathesis reaction on the compound 2 to obtain a compound 15;

s12, carrying out catalytic hydrogenation reaction on the compound 15 to obtain dysxylactam A;

wherein said compound 9 is:the compound 3 is:the compound 12 is:the compound 14 is:the compound 2 is:the compound 15 is:wherein R is selected from: h or TMS; the dysxylactam A is:

the present invention provides a method for synthesizing a seventeen-membered large lipopeptide natural compound, wherein the above retrosynthetic route is designed by analyzing the structure of a target product Dysoxylactam A, specifically, ester bonds and amide bonds contained in the structure of Dysoxylactam A are common cyclization sites of a large ring compound, but certain steric hindrance exists, the present application intends to realize the large ring construction by adopting olefin metathesis Reaction (RCM), the cutting of carbon-carbon bonds of C6-C7 can reversely push to a precursor compound 2. the linear cyclization precursor compound 2 can respectively introduce the required 6-heptenoic acid and L-valine through the Yamaguchi esterification reaction (Yamaguchi esterification) and the high stereoselectivity construction of the esterification reaction (Krisallosylation reaction) catalyzed by a chiral Ir catalyst, thus, the complex precursor compound 2 can be simplified to a mono-protected diol compound 3 through the above strategies, the chiral hydroxyl group at C2 can be synthesized by using Brownotam (Krische allylation reaction) catalyzed by a high stereoselectivity reaction, dywayl group reduction reaction (R-carbonyl group) to obtain a high yield of a high-carbonyl group synthesized product, which can be synthesized by carrying out the subsequent conversion reaction, the synthesis of a high-carbonyl group synthesis reaction, and the synthesis of a high-carbonyl group synthesis reaction by using a Brownicbya high-carbonyl group substitution reaction (R-carbonyl group substitution reaction, a high-carbonyl group conversion reaction (R-carbonyl group conversion reaction, a high-carbonyl group conversion reaction shown in the synthesis reaction shown in the present invention, a high-carbonyl group conversion reaction (R-carbonyl group conversion reaction shown in the present invention, a high-carbonyl group conversion reaction, a high-carbonyl.

Specifically, the step of obtaining methyl (R) -3-hydroxyisobutyrate in step S00, and sequentially performing a reductive condensation reaction, a lithiation-boronization reaction, a transfer reaction, a lithium halide exchange reaction, and an oxidation treatment on the methyl (R) -3-hydroxyisobutyrate includes:

s10, obtaining (R) -3-hydroxy methyl isobutyrate, and reacting the (R) -3-The reduction condensation reaction of the methyl hydroxyisobutyrate is carried out to obtain a compound 5,

s20, carrying out lithiation-boronization reaction on the compound 5 to obtain a compound 6,

s30, carrying out migration reaction on the compound 6 to obtain a compound 7,

s40, carrying out lithium halide exchange reaction on the compound 7 to obtain a compound 8,

s50, carrying out oxidation treatment on the compound 8 to obtain a compound 9.

In the process of preparing compound 3 from methyl (R) -3-hydroxyisobutyrate, first, the commercially known procedure of preparing compound 3 from methyl (R) -3-hydroxyisobutyrate was followed by protecting the primary hydroxyl group with TBS under the action of triethylamine and tert-butyldimethylchlorosilane (TBSCl), then, at room temperature, the methyl ester in the molecule was reduced to a hydroxyl group using diisobutylaluminum hydride, followed by ester condensation with diisopropylmethylaminochloride (CbCl) to give the known compound 5. then, the OCb group was removed by lithiation-boronization reaction to introduce Bpin group (pinacol borate) to form organoboron reagent compound 6. then, hydrogen at position α of the carbonate was removed by sec-butyllithium to form a chiral lithium reagent under complexation with d-gold paw base, compound 6 formed a boron salt, compound 7 was then prepared by 1, 2-migration with good stereoselectivity by the formation of chiral methyl group, compound 7 was then, compound 3 was prepared by halogen exchange with n-butyllithium halide followed by the preparation of a highly selective reaction of a chiral methyl hydroxide solution with 2-bis (tris-bromopyridine) and subsequent oxidation of the compound 3, which was prepared by the following successive oxidation of the procedure of the reaction of the highly asymmetric pyridine hydroxide, and the reaction of the chiral pyridine hydroxide, which was carried out the reaction to give the following procedure of the formation of the reaction of the formation of a chiral methyl ester 3-bromopyridine compound 3, which was carried out the reaction to give the formation of a highly selective oxidation of a chiral methyl chloride:

specifically, in the step S10, the step of subjecting the methyl (R) -3-hydroxyisobutyrate to a reductive condensation reaction includes: and (2) after the hydroxyl of the (R) -3-hydroxyisobutyric acid methyl ester is protected by TBS, sequentially adding diisobutylaluminum hydride to perform a reduction reaction and a condensation reaction of diisopropylmethylamine chloride at the temperature of 25-38 ℃, and separating to obtain a compound 5. In some embodiments, the molar ratio of the methyl (R) -3-hydroxyisobutyrate, the diisobutylaluminum hydride, and the diisopropylmethylaminochloride is (0.5-1.5): (2.5-3.5): (3.5-4.5). According to the invention, through the raw material components proportioned in the embodiment, methyl (R) -3-hydroxyisobutyrate is taken as a starting material, and primary hydroxyl is protected by TBS under the action of triethylamine and tert-butyldimethylsilyl chloride; and then, reducing methyl ester in molecules into hydroxyl by diisobutylaluminum hydride at room temperature of 25-38 ℃, and then carrying out ester condensation with CbCl to obtain the compound 5, wherein the mixture ratio of the raw material components effectively ensures that the raw material substances react fully, the generation of byproducts is reduced, and the compound 5 has high yield and good purity.

Specifically, in step S20, the step of performing the lithiation-boronation reaction on the compound 5 includes: under the condition that the temperature is-40 ℃ to-80 ℃, sec-butyl lithium is added into the mixed solution of the compound 5 and tetramethyl ethylene diamine for reaction for 5-8 hours, pinacolborane is added for reaction for 1-3 hours, then the temperature is increased to 30-50 ℃ for reaction for 10-15 hours, and the compound 6 is obtained by separation. In some embodiments, the molar ratio of the sec-butyllithium, the compound 5, the tetramethylethylenediamine, and the pinacol borane is (2-3): (1-12): (2.5-3.5): (3.5-4.5). In the embodiment of the invention, under the condition of the material proportion, OCb groups are separated through lithiation-boronization reaction, and pinacol borate (Bpin group) is introduced to obtain the organoboron reagent compound 6, and the proportion of the raw material components effectively ensures that the raw material materials react fully, thereby reducing the generation of byproducts.

In some embodiments, the solvent in the mixed solution of compound 5 and tetramethylethylenediamine is selected from: at least one of anhydrous ether, tetrahydrofuran and methyl tert-butyl ether, and the solvents have better solubility for substance components such as compound 5, tetramethylethylenediamine, pinacolborane and the like.

In some embodiments, the temperature will be between-40 ℃ and-80 ℃^sBu L i is slowly dripped into anhydrous ether solution of carbamate compound 5 and TMEDA, the mixture reacts for 5 to 8 hours at minus 40 ℃ to minus 80 ℃, then the ether solution of HBpin is slowly dripped into the anhydrous ether solution of HBPin, the cold trap is removed after the mixture reacts for 1 to 3 hours at minus 40 ℃ to minus 80 ℃, the temperature of the reaction solution is increased to 30 ℃ to 50 ℃, the reaction solution continues to react for 10 to 15 hours, after the reaction is finished, the reaction solution is cooled to 0 ℃ to 25 ℃, and KH is added into the system₂PO₄And (5) quenching the aqueous solution for reaction, and continuously stirring for 10-30 minutes. The reaction solution was extracted with ether, and the combined organic phases were washed with water and then with saturated brine, and then dried with anhydrous sodium sulfate as a solid. After filtration, the filtrate is decompressed and concentrated by a vacuum water pump, and the obtained crude product is chromatographically separated by a silica gel column, thus obtaining the colorless oily organic boron reagent compound 6.

Specifically, in the step S30, the step of performing a migration reaction on the compound 6 includes adding sec-butyl lithium to a mixed solution of ethyl carbamate and (+) -falcarinine for reaction for 3 to 5 hours at a temperature of-40 ℃ to-80 ℃, heating to 30 to 50 ℃ for reaction for 10 to 15 hours after adding the compound 6 for reaction for 1 to 3 hours, and separating to obtain the compound 7. in some embodiments, the molar ratio of the sec-butyl lithium, the ethyl carbamate, the (+) -falcarinine and the compound 6 is (1 to 2): (0.5 to 1.5): (1 to 2): (0.2 to 0.5). in the embodiments of the present invention, after hydrogen at α position of carbonate is removed by sec-butyl lithium, a chiral lithium reagent is formed under the complexation of right falcarinine, and then boron salt is formed with the compound 6, and then the construction of a chiral methyl group is completed through 1, 2-migration in a good stereoselectivity manner, so as to obtain the compound 7.

In some embodiments, the solvent in the mixed solution of ethyl carbamate and (+) -falcon is selected from: at least one of anhydrous diethyl ether, tetrahydrofuran and methyl tert-butyl ether.

In some embodiments, the temperature will be between-40 ℃ and-80 ℃^sBu L i (sec-butyl lithium) is slowly dripped into anhydrous ether solution of ethyl carbamate and (+) -chloranthine ((+) -sparteine), the mixture reacts for 3 to 5 hours at the temperature of between 40 ℃ below zero and 80 ℃ below zero, then the ether solution of the compound 6 is slowly dripped into the mixture, the cold trap is removed after the mixture reacts for 1 to 3 hours at the temperature of between 40 ℃ below zero and 80 ℃ below zero, the reaction solution is heated to 30 to 50 ℃ and continuously reacts for 10 to 15 hours, and after the reaction is finished, the reaction solution is cooled to 0 to 25 ℃, and KH is added into the system₂PO₄The reaction was quenched with aqueous solution and stirred for 10 minutes. The reaction solution was extracted with ether, and the combined organic phases were washed with water and then with saturated brine, and then dried with anhydrous sodium sulfate as a solid. After filtration, the filtrate is decompressed and concentrated by a vacuum water pump, and the obtained crude product is chromatographically separated by a silica gel column to obtain the colorless oily organic borate compound 7.

Specifically, in step S40, the compound 7 is subjected to a lithium halide exchange reaction: adding n-butyllithium into the mixed solution of the compound 7 and iodochloromethane at the temperature of-40 to-80 ℃, heating to 25 to 38 ℃, reacting for 10 to 15 hours, and separating to obtain a compound 8. In some embodiments, the compound 7, the iodochloromethane, and n-butyllithium are in a molar ratio of (0.2 to 0.5): (3-8): (1-2). According to the embodiment of the invention, the molar ratio of the compound 7 to the iodochloromethane to the n-butyllithium is (0.2-0.5): (3-8): (1-2), extending a carbon chain of the compound 7 through lithium halide exchange under the conditions of chloroiodomethane and n-butyllithium, and directly treating a reaction solution with a sodium hydroxide solution and a hydrogen peroxide solution to obtain a hydroxyl compound 8. The proportion of each raw material component effectively ensures the full reaction among the raw material substances and reduces the generation of byproducts.

In some embodiments, the solvent in the mixed solution of compound 7 and iodochloromethane is selected from: at least one of tetrahydrofuran, diethyl ether and methyl tert-butyl ether.

In some embodiments, compound 7 and iodochloromethane are dissolved in extremely dry THF, and the n-butyllithium solution is slowly added dropwise at-40 deg.C to-80 deg.C (if the addition rate is too fast, the solution becomes yellow, and a large amount of by-product is produced). Then, the reaction system is heated to room temperature and continuously stirred for 10-15 hours. After the reaction is finished, cooling the reaction liquid to 0-25 ℃, and adding 2N NaOH/30 wt% H into the system₂O₂And quenching the aqueous solution for reaction, and continuously stirring for 30-50 minutes. The reaction solution was extracted with diethyl ether, and the combined organic phases were washed successively with water and saturated brine, and then dried with anhydrous sodium sulfate solid. After filtration, the filtrate is decompressed and concentrated by a vacuum pump to obtain a crude product, and the crude product is subjected to silica gel column chromatography separation to obtain the colorless oily alcohol compound 8.

In other examples, compound 7 and iodochloromethane were dissolved in extremely dry THF and n-butyllithium solution was slowly added dropwise at-40 ℃ to-80 ℃ followed by warming the reaction to room temperature and stirring for 10-15 hours. After the reaction is finished, cooling the reaction liquid to 0-25 ℃, and adding KH into the system₂PO₄And quenching the aqueous solution for reaction, and continuously stirring for 30-50 minutes. The reaction solution was extracted with ether, and the combined organic phases were washed with water and then with saturated brine, and then dried with anhydrous sodium sulfate as a solid. Filtering, concentrating the filtrate under reduced pressure with vacuum pump to obtain crude product, separating with silica gel column chromatography to obtain colorless oily compound S1 intermediate,

specifically, in step S50, the step of subjecting the compound 8 to oxidation treatment includes: adding sodium bicarbonate, trichloroisocyanuric acid and tetramethylpiperidine oxynitride into the solution of the compound 8, reacting for 2-5 minutes at the temperature of 0-5 ℃, and separating to obtain a compound 9. In some embodiments, the molar ratio of compound 8, the sodium bicarbonate, the trichloroisocyanuric acid, and the tetramethylpiperidine nitroxide is (0.3-1): (1.5-2.5): (0.5-1): (0.03-0.1). The compound 8 of the example of the present invention undergoes a TEMPO oxidation reaction in the presence of sodium bicarbonate to form the aldehyde compound 9. The proportion of each raw material component effectively ensures the full reaction among the raw material substances and reduces the generation of byproducts.

In some embodiments, the solvent in the solution of compound 8 is selected from: at least one of dichloromethane, toluene and acetonitrile.

In some embodiments, compound 8 is dissolved in dichloromethane, cooled to 0 ℃ to 5 ℃ and then sequentially added with NaHCO₃TCCA (trichloroisocyanuric acid) and TEMPO (tetramethylpiperidine nitroxide). Stirring the reaction system for 2-5 minutes at the temperature of 0-5 ℃, filtering the reaction solution by using kieselguhr, and then using Na₂S₂O₃The reaction was quenched with aqueous solution. The reaction was extracted with DCM (dichloromethane) and the combined organic phases were washed with saturated NaHCO₃The aqueous solution was dried over anhydrous sodium sulfate solid. After filtration, the filtrate is decompressed and concentrated by a vacuum pump, and the obtained crude product is separated by silica gel column chromatography, thus obtaining the colorless oily compound 9.

Specifically, in the step S60, the step of performing the asymmetric brownian butene reaction on the compound 9 includes: under the anhydrous and oxygen-free environment with the temperature of-80 ℃ to-30 ℃, the compound 9 is mixed with potassium tert-butoxide, cis-2-butene, n-butyl lithium, (+) -Ipc₂And dissolving BOMe and boron trifluoride ethyl ether in the first organic solvent, reacting for 10-15 hours, and separating to obtain a compound 3. In some embodiments, the compound 9, the potassium tert-butoxide, the cis-2-butene, the n-butyllithium, the (+) -Ipc₂The molar ratio of BOMe to boron trifluoride diethyl etherate is (1-1.5): (2.2-2.8): (6-6.5): (2.2-2.8): (3.5-4): (4.8-5.3). Examples of the invention Compounds9 the construction of two consecutive chiral centers can be achieved with high stereoselectivity by asymmetric Browncrotation reaction (Browncrotation reaction), completing the preparation of the TBS mono-protected diol compound 3. The proportion of each raw material component effectively ensures the full reaction among the raw material substances and reduces the generation of byproducts.

In a further embodiment, the step of subjecting the compound 9 to an asymmetric brownian butene reaction comprises: dissolving the dry and oxygen-free potassium tert-butoxide in a first organic solution in an oxygen-free environment, cooling to-60 to-80 ℃, sequentially adding the cis-2-butene and the n-butyllithium, heating to-30 to-45 ℃, and reacting for 10 to 30 minutes; then cooling to-60 ℃ to-80 ℃, and adding the (+) -Ipc₂And reacting the BOMe for 10-30 minutes, sequentially adding the boron trifluoride diethyl etherate and the compound 9, and reacting for 10-15 hours at the temperature of-60-80 ℃.

In some embodiments, the first organic solvent is selected from: at least one of tetrahydrofuran, diethyl ether and methyl tert-butyl ether.

In some embodiments, t-BuOK (potassium tert-butoxide) is weighed in a flask, the flask is vacuumized at 80-100 ℃ overnight, THF is added to dissolve the t-BuOK at the temperature of-60 ℃ to-80 ℃, cis-2-butene is added, n-Bu L i is dropwise added, the reaction solution turns orange, the temperature is increased to-30 ℃ to-45 ℃, the reaction solution is reacted for 10-30 minutes and then is cooled to-60 ℃ to-80 ℃, and then (+) -Ipc is weighed in a glove box₂The BOMe was dissolved in THF and added dropwise while the reaction turned bright black. Dripping BF dropwise after 10-30 minutes₃·OEt₂(boron trifluoride ether), then dissolving the compound 9 in THF, dropwise adding the mixture, reacting for 10-15 hours at-60 to-80 ℃, monitoring by T L C (thin-layer chromatography) to confirm that the compound 9 is completely converted, quenching the reaction by NaOH, adding hydrogen peroxide, refluxing for 1-2 hours at 50-70 ℃, stirring until the mixture is clear, extracting by ether, combining organic phases, and then adding saturated NH₄Washed with Cl solution and dried over anhydrous sodium sulfate solid. Filtering, distilling under reduced pressure to remove the organic solvent, and separating by flash column chromatography to obtain colorless oily product compound 3.

Specifically, in step S70, the step of reacting compound 3 with aminobenzyloxycarbonyl-protected levovaline by esterification comprises: dissolving the compound 3 and the L-valine protected by aminobenzyloxycarbonyl in a second organic solvent, sequentially adding triethylamine and 2, 4, 6-trichlorobenzoyl chloride at the temperature of-5-0 ℃, and heating to the temperature of 25-38 ℃ for reaction for 10-30 minutes; then cooling to-5-0 ℃, adding 4-dimethylamino pyridine, heating to 25-38 ℃, reacting for 10-12 hours, and separating to obtain the compound 12. After the diol compound 3 mono-protected by TBS is prepared in the embodiment of the invention, the diol compound and the L-valine protected by aminobenzyloxycarbonyl are subjected to ester grafting reaction under the condition of Yamaguchi esterification, and then the compound 12 can be successfully obtained.

In addition, the embodiment of the invention also tries to use PdCl in ethyl acrylate solution₂And hydrogen atmosphere, carrying out catalytic hydrogenation reaction to reduce double bonds, trying to connect corresponding alcohol with acid compound 10 under Yamaguchi esterification condition,however, since the compound 10 is a peptide compound, a racemic product appears during the ester grafting process, which affects the preparation of the target product and is not beneficial to improving the yield and the purity of the product.

In some embodiments, the molar ratio of compound 3, the aminobenzyloxycarbonyl protected levovaline, the triethylamine, the 2, 4, 6-trichlorobenzoyl chloride and the 4-dimethylaminopyridine is (0.8-1.5): (1.8-2.5): (4-5): (3-4): (4-6), the mixture ratio effectively ensures that the raw materials react fully, reduces the generation of byproducts, and improves the purity of the target product.

In some embodiments, the second organic solvent is selected from: toluene, dichloromethane, nitrogen-nitrogen dimethylformamide and tetrahydrofuran.

In some embodiments, compound 3 and aminobenzyloxycarbonyl protected L-valine (dissolved in toluene, triethylamine and 2, 4, 6-trichlorobenzoyl chloride (TCBC) were added sequentially at zero degrees C), and the reaction was warmed to room temperatureContinuously stirring for 10-30 minutes at room temperature, adding 4-Dimethylaminopyridine (DMAP) under the condition of zero temperature, heating the reaction solution to room temperature, reacting for 10-12 hours, monitoring by T L C (thin layer chromatography) to confirm complete conversion, and using saturated NH₄The reaction was quenched with aqueous Cl, then the combined organic phases were extracted with ethyl acetate and washed with saturated aqueous brine, and the anhydrous sodium sulfate solid was dried. Filtering, distilling under reduced pressure to remove organic solvent, and separating by flash column chromatography to obtain colorless oily product compound 12.

Specifically, in step S80, the step of subjecting the compound 12 to catalytic hydrogenation and then to peptide-grafting reaction with 6-heptenoic acid comprises: dissolving the compound 12 and the first palladium catalyst in a third organic solvent under the atmosphere of protective gas such as nitrogen, argon, helium and the like, and reacting for 3-5 hours under the atmosphere of reducing gas (hydrogen) to obtain an amino alcohol crude product; and dissolving the coarse amino alcohol product and 6-heptenoic acid in a fourth organic solvent, sequentially adding N, N-diisopropylethylamine, 1-hydroxy-7-azobenzotriazol and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate at the temperature of-5-0 ℃, reacting for 8-10 hours at the temperature of 25-38 ℃, and separating to obtain a compound 14. Compound 12 solution in the inventive example in PdCl₂And in the hydrogen atmosphere, catalytic hydrogenation reaction can be carried out to reduce double bonds and remove a protecting group Cbz (benzyloxycarbonyl), and simultaneously, HCl generated by hydrogenation reaction changes the solution into a weak acid environment to remove a primary TBS protecting group, thereby obtaining an amino alcohol compound 13,the amino alcohol compound 13 and 6-heptenoic acid peptide, N, N-diisopropylethylamine, 1-hydroxy-7-azobenzotriazol and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate undergo a peptide grafting reaction to obtain a compound 14.

In some embodiments, the compound 12, the first palladium catalyst, the 6-heptenoic acid, the N, N-diisopropylethylamine, the 1-hydroxy-7-azobenzotriazol, and the 2- (7-azobenzotriazol) -N, N' -tetramethyluronium hexafluorophosphate are in a molar ratio of: (0.3-0.4): (0.1-0.2): (0.5-1): (3-4): (0.5-1): (1-2), the raw material components in the ratio effectively ensure full reaction among raw material substances, reduce byproduct generation and improve the purity of a target product.

In some embodiments, the first palladium catalyst is selected from at least one of palladium dichloride, palladium on carbon hydroxide. The palladium catalysts used in the examples of the present invention can reduce double bonds and remove the protecting group Cbz (benzyloxycarbonyl) in a reducing gas atmosphere.

In some embodiments, the third organic solvent is selected from: at least one of methanol, ethyl acetate, dichloromethane and chloroform.

In some embodiments, the fourth organic solvent is selected from: the volume ratio is (15-25): 1 of a mixed solvent of dichloromethane and dimethylformamide. The embodiment of the invention adopts the following components in volume ratio (15-25): the mixed solvent of dichloromethane and dimethylformamide of 1 is used as a fourth organic solvent, so that the condition of ester connection of hydroxyl is better avoided, the reaction efficiency is further improved, and the reaction purity is improved.

In some embodiments, the compound 12 is dissolved in a methanol solution, palladium dichloride is added under the protection of nitrogen at room temperature, then the nitrogen in the reaction system is replaced by hydrogen, the mixture is continuously stirred at room temperature for 3-5 hours (L C-MS detects that all protecting groups are removed and double bonds are all reduced), the reaction is filtered by diatomite, the filtrate is decompressed and concentrated by a rotary evaporator to obtain a yellow oily amino alcohol compound 13, the yellow oily amino alcohol compound is directly used for the next reaction without further purification, the crude product of amino alcohol and 6-heptenoic acid is dissolved in a mixed solution of DCM and DMF, then N, N-diisopropylethylamine, 1-hydroxy-7-azobenzotriazol and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate are sequentially added under the zero-temperature condition, the reaction liquid is heated to room temperature and continuously reacted for 8-10 hours, the reaction liquid is monitored by T L C to confirm that the conversion is complete, and then saturated NH is used₄Quenching the reaction with aqueous Cl, extracting the combined organic phases with DCM, drying the combined organic phases with anhydrous sodium sulfate, filtering, distilling off the organic solvent under reduced pressure, separating by flash column chromatographyThe product compound 14 was obtained as a colorless oil.

Specifically, in step S90, the step of allylating the compound 14 includes: and (2) dissolving the compound 14, an iridium catalyst, 4-chloro-3-nitrobenzoic acid and cesium carbonate in a mixed solution of tetrahydrofuran, water and allyl acetate in an oxygen-free environment, reacting for 48-72 hours at the temperature of 80-100 ℃, and separating to obtain a compound 2. In the embodiment of the invention, the first-order hydroxyl is firstly selected to be oxidized into aldehyde through Dess-Matin oxidation reaction (Dess-martin oxidation reaction), and then chiral hydroxyl is stereoselectively established through Brown alkylation, but the post treatment in the process of oxidizing alcohol into aldehyde is very careful, otherwise racemization is easy to occur. Furthermore, Brown alloylation is cumbersome and IpcOH generated by post-treatment is cumbersome to handle. Therefore, in the embodiment of the invention, Krische allylation is adopted to replace Brownallylation, and allylation reaction is carried out under the conditions of iridium catalyst and Krische, so as to obtain the compound 2.

In some embodiments, the compound 14, the iridium catalyst, the 4-chloro-3-nitrobenzoic acid, and the cesium carbonate are in a molar ratio of (1-2): (0.5-1): (1-2): (1.5-3), the raw material components in the ratio effectively ensure full reaction among raw material substances, reduce byproduct generation and improve the purity of a target product.

In some embodiments, the volume ratio of the tetrahydrofuran, the water, and the allyl acetate in the mixed solution is (4-6) ml: (8-12) ul: (0.15-0.25) ml, wherein water and the allyl acetate participate in the allylation reaction.

In some embodiments, under the protection of nitrogen, compound 14, an iridium catalyst, 4-chloro-3-nitrobenzoic acid and cesium carbonate are added into a sealed tube, then a tetrahydrofuran solvent is added through nitrogen displacement, distilled water and allyl acetate are added, the sealed tube is sealed to avoid air contact, then the sealed tube is heated to 80-100 ℃ for reaction for 48-72 hours, the temperature of the reaction system is reduced to room temperature after the completion of conversion is confirmed through T L C monitoring, then dichloromethane is used for dilution, solid substances are filtered through diatomite, organic solvents are removed through reduced pressure distillation of filtrate, yellow oily substances are obtained, and the yellow oily substances are adsorbed on silica gel and separated through flash column chromatography, so that compound 2 is obtained.

Wherein the structural formula of the iridium catalyst is shown in the specification

Specifically, in some embodiments, in the step S11, the step of performing a ring closing metathesis reaction on the compound 2 comprises: dissolving the compound 2 in a sixth organic solvent in an oxygen-free environment, adding a Grabbs second-generation catalyst, reacting for 20-25 hours at the temperature of 30-40 ℃, separating to obtain a compound 15a,

specifically, in other embodiments, in step S11, the step of performing a ring closing metathesis reaction on compound 2 comprises: sequentially adding triethylamine and trimethylsilyl trifluoromethanesulfonate into the solution of the compound 2 at the temperature of-5-0 ℃, heating to the temperature of 25-38 ℃, reacting for 3-5 hours, separating to obtain a compound 2',then, in an oxygen-free environment, dissolving the compound 2' in a seventh organic solvent, adding a Grabbs second-generation catalyst, reacting for 20-25 hours at the temperature of 30-40 ℃, separating to obtain a compound 15b,

in the embodiment of the invention, RCM (Richardson-Grubbs-Beckmann) ring closing is carried out after a ring closing precursor is taken, a substrate with hydroxyl exposed is selected at the beginning, and HG-II (mercury-mercury) catalyst and toluene subjected to exhaust treatment are used as solvents, so that raw materials are completely consumed, but the separation yield of a product compound 15a is only 13%. The solvent yield was slightly increased by 22% when the vent treated DCM was used, and 40% when the G-II catalyst (the grubbs second generation catalyst) was used, but the yield was still not ideal. When selecting the hydroxyl protecting group, considering that the removal of the hydroxyl protecting group and the hydrogenation reduction of the newly generated double bond can be carried out in one step so as to improve the route efficiency, a smaller protecting group TMS is selected to protect the hydroxyl, and then the natural product precursor compound 15b is obtained with a better yield of 70 percent under the action of a G-II catalyst.

In some embodiments, the molar ratio of compound 2, the triethylamine, and the trimethylsilyl trifluoromethanesulfonate is (0.02-0.08): (1-1.5): (0.2-0.8). In some embodiments, the compound 2 or the compound 2' and the granbus secondary catalyst are in a molar ratio of (1-3): (0.1-0.3). The raw material components proportioned in the embodiments of the invention effectively ensure full reaction among raw material substances, reduce the generation of byproducts and improve the purity of target products.

In some embodiments, the solvent in the solution of compound 2 is selected from: at least one of dichloromethane, toluene and acetonitrile.

In some embodiments, the sixth organic solvent and the seventh organic solvent are each independently selected from: at least one of dichloromethane, toluene and acetonitrile.

In some embodiments, compound 2 is dissolved in dichloromethane and triethylamine and TMSOTf are added dropwise in sequence under zero temperature condition, then the reaction solution is reacted for 3-5 hours under room temperature condition, after the complete conversion is confirmed by monitoring of T L C, the reaction system is quenched with saturated ammonium chloride solution, after the reaction solution is returned to room temperature, DCM is used for extraction and organic phase combination, the organic phase is dried with anhydrous sodium sulfate, filtration and reduced pressure distillation are carried out to remove low boiling point organic solvent components, the obtained crude product is chromatographed with silica gel column (ethyl acetate/n-hexane is 1:4) to obtain colorless oily compound 2'.

Specifically, in step S12, the step of subjecting the compound 15 to a catalytic hydrogenation reaction includes: and dissolving the compound 15 and the second palladium catalyst in an eighth organic solvent in a protective gas atmosphere, reacting for 3-4 hours in a reducing gas atmosphere, and separating to obtain the dysxylactam A. Examples of the invention macrocyclic Compound 15b was then treated with PdCl in methanol solution₂And hydrogen atmosphere, catalytic hydrogenation reaction can be carried out to reduce double bonds, HCl generated by the hydrogenation reaction can change the solution into a weak acid environment, and a secondary TMS protecting group can be removed, so that the final natural product dysoxylactam A can be obtained.

In some embodiments, the compound 15 and the second palladium catalyst are in a molar ratio of (1-3): (0.01-0.02). In some embodiments, the second palladium catalyst is selected from at least one of palladium dichloride, palladium on carbon hydroxide. In some embodiments, the eighth organic solvent is selected from: at least one of methanol, ethyl acetate, dichloromethane and chloroform. In some embodiments, the shielding gas is selected from: at least one of nitrogen, argon, helium. In some embodiments, the reducing gas is selected from: hydrogen gas. The raw material components adopted in the above embodiments of the present invention and the provided gas atmosphere effectively ensure the synthesis yield and purity of the natural product dysxylactam A.

In some embodiments, compound 15b is dissolved in a methanol solution, palladium dichloride is added under the protection of nitrogen at room temperature, then the nitrogen in the reaction system is replaced by hydrogen, stirring is continued for 3-4 hours at room temperature (L C-MS detects that TMS protecting group is removed and double bonds are all reduced), the reaction is filtered through diatomite, the filtrate is subjected to reduced pressure concentration through a rotary evaporator to obtain a crude product, and the crude product is adsorbed on column chromatography silica gel and purified through silica gel column chromatography (ethyl acetate/n-hexane is 1:2) to obtain a white solid natural product, namely dysoxyactam a.

In some embodiments, a method of synthesizing a seventeen-membered macrocyclic lipopeptide natural compound, comprising the steps of:

s11, obtaining methyl (R) -3-hydroxyisobutyrate, protecting hydroxyl of the methyl (R) -3-hydroxyisobutyrate by TBS, sequentially adding diisobutylaluminum hydride to perform a reduction reaction and perform a condensation reaction with diisopropylmethylaminochloride, and separating to obtain a compound 5;

s21, adding sec-butyl lithium into the mixed solution of the compound 5 and tetramethylethylenediamine for reaction, adding pinacol borane for reaction, and separating to obtain a compound 6;

s31, adding sec-butyl lithium into a mixed solution of ethyl carbamate and (+) -falcarinine for reaction, adding a compound 6 for reaction, and separating to obtain a compound 7;

s41, adding n-butyllithium into the mixed solution of the compound 7 and iodochloromethane for reaction, and separating to obtain a compound 8;

s51, adding sodium bicarbonate, trichloroisocyanuric acid and tetramethylpiperidine nitrogen oxide into the solution of the compound 8 for reaction, and separating to obtain a compound 9;

s61, dissolving the compound 9, potassium tert-butoxide, cis-2-butene, n-butyllithium, (+) -Ipc2BOMe and boron trifluoride diethyl etherate in a first organic solvent, reacting, and separating to obtain a compound 3;

s71, dissolving the compound 3 and the L-valine protected by aminobenzyloxycarbonyl in the second organic solvent, sequentially adding triethylamine and 2, 4, 6-trichlorobenzoyl chloride for reaction, adding 4-dimethylaminopyridine for reaction, and separating to obtain a compound 12;

s81, dissolving the compound 12 and the first palladium catalyst in the third organic solvent, and reacting to obtain an amino alcohol crude product; dissolving the coarse amino alcohol product and 6-heptenoic acid in the fourth organic solvent, sequentially adding N, N-diisopropylethylamine, 1-hydroxy-7-azobenzotriazol and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate, reacting, and separating to obtain a compound 14;

s91, dissolving the compound 14, an iridium catalyst, 4-chloro-3-nitrobenzoic acid and cesium carbonate in a mixed solution of tetrahydrofuran, water and allyl acetate for reaction, and separating to obtain a compound 2;

s111, sequentially adding triethylamine and trimethylsilyl trifluoromethanesulfonate into the solution of the compound 2 to react, and separating to obtain a compound 2'; then dissolving the compound 2' in the seventh organic solvent, adding a Grabbs second-generation catalyst for reaction, and separating to obtain a compound 15 b;

s121, dissolving the compound 15 and a second palladium catalyst in the eighth organic solvent, reacting, and separating to obtain dysxylactam A.

In order to make the details and operations of the above-mentioned embodiments of the present invention clearly understood by those skilled in the art and to make the progress of the method for synthesizing the seventeen-membered macrocyclic lipopeptide natural compound of the present invention obvious, examples 1 to 10 of the present invention prepare a seventeen-membered macrocyclic lipopeptide natural compound, dysaxylacam a, the synthetic scheme of which is shown in fig. 1.