Synthetic method of 17-membered macrocyclic lipopeptide natural compound

A natural compound and synthetic method technology, applied in the field of organic synthesis, can solve problems such as low extraction efficiency and modified compound structure

Pending Publication Date: 2020-07-17
PEKING UNIV SHENZHEN GRADUATE SCHOOL +1
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  • Abstract
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  • Application Information

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Problems solved by technology

[0004] The purpose of the present invention is to provide a synthetic method of a seventeen-membered macrocyclic lipopeptide natural compound, aiming at solving the problem that the existing dysoxylactam A can only be separated and extracted from the bark of Sapia japonica, the extraction efficiency is low, and it is impossible to realize the synthesis of dysoxylactam A On the basis of further modification of the compound structure, exploring technical issues such as structure-activity relationship

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  • Synthetic method of 17-membered macrocyclic lipopeptide natural compound
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  • Synthetic method of 17-membered macrocyclic lipopeptide natural compound

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preparation example Construction

[0020] The embodiment of the present invention provides a synthetic method of a seventeen-membered macrocyclic lipopeptide natural compound, comprising the following steps:

[0021] S00. Obtain (R)-3-hydroxyisobutyrate methyl ester, and sequentially carry out reduction condensation reaction, lithiation-borylation reaction, migration reaction, lithium halide Exchange reaction and oxidation treatment to obtain compound 9;

[0022] S60. Performing an asymmetric Brownylation reaction on the compound 9 to obtain the compound 3;

[0023] S70. Esterifying the compound 3 with aminobenzyloxycarbonyl-protected L-valine to obtain compound 12;

[0024] S80. Catalyzing the hydrogenation reaction of the compound 12 and then reacting with 6-heptenoic acid to obtain the compound 14;

[0025] S90. Performing an allylation reaction on the compound 14 to obtain compound 2;

[0026] S11. Carrying out a ring-closing metathesis reaction on the compound 2 to obtain compound 15;

[0027] S12. Cat...

Embodiment 1

[0097] The steps for preparing compound 6 include: at -40 ° C ~ -80 ° C s BuLi (a solution in hexanes, 1.3M, 1.9mL, 2.48mmol, 2.0eq.) was slowly added dropwise to carbamate 5 (411mg, 1.24mmol, 1.0eq.) and TMEDA (0.41mL, 2.73mmol, 2.2eq .) in anhydrous diethyl ether (15mL, 0.08M). React at -40°C to -80°C for 5 to 8 hours and then slowly dropwise add HBpin (0.54mL, 3.72mmol, 3.0eq.) to a solution of ether (2mL). After reacting at -40°C to -80°C for one to three hours, remove the cold trap, and raise the temperature of the reaction solution to 30°C to 50°C to continue the reaction for 10 to 15 hours. After the reaction is over, cool the reaction solution to 0°C to 25°C and add KH to the system 2 PO 4 Aqueous solution (1M aq., 5 mL) was used to quench the reaction and stirring was continued for 10-30 minutes. The reaction solution was extracted with diethyl ether (3x 10 mL), and the combined organic phases were washed with water (15 mL) and saturated brine (20 mL) successively...

Embodiment 2

[0099] The steps for preparing compound 7 include: at -40 ° C ~ -80 ° C s BuLi (a solution in hexanes, 1.3M, 0.74mL, 0.96mmol, 3.0eq.) was slowly added dropwise to ethyl carbamate (166mg, 0.96mmol, 3.0eq.) and (+)-sparteine ​​(0.29mL, 1.28mmol, 4.0eq.) in anhydrous ether (10mL, 0.1M) solution. React at -40°C to -80°C for 3 to 5 hours and then slowly dropwise add compound 6 (100mg, 0.32mmol, 1.0eq.) to a solution of diethyl ether (5mL). After reacting at -40°C to -80°C for one to three hours, remove the cold trap, raise the temperature of the reaction solution to 30-50°C and continue the reaction for 10-15 hours. After the reaction is over, cool the reaction solution to 0°C to 25°C and add KH to the system 2 PO 4 The reaction was quenched with aqueous solution (1M aq., 5 mL) and stirring was continued for 10 minutes. The reaction solution was extracted with diethyl ether (3x 10 mL), and the combined organic phases were washed with water (15 mL) and saturated brine (20 mL) s...

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Abstract

The invention belongs to the technical field of organic synthesis, in particular to a synthetic method of 17-membered macrocyclic lipopeptide natural compounds. (R)-3-methyl hydroxyisobutyrate is usedas a raw material; the preparation method comprises the following steps in order: performing reductive condensation reactions; carrying out lithiation-boronation reaction, migration reaction, lithiumhalide exchange reaction, oxidation treatment and asymmetric Brown butene reaction, carrying out esterification reaction and catalytic hydrogenation reaction on levovaline protected by aminobenzoxycarbonyl, and then carrying out peptide connection reaction, allylation reaction, ring closing metathesis reaction and catalytic hydrogenation reaction with 6-heptenoic acid. The 17-membered macrocycliclipopeptide natural compound dysoxylactam A is obtained through synthesis, the synthesis yield is high, and the medicinal value of the product is high.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a synthesis method of a seventeen-membered macrocyclic lipopeptide natural compound. Background technique [0002] DysoxylactamA, a seventeen-membered macrocyclic lipopeptide natural product with the ability to reverse the multidrug resistance of tumor cells, was developed by the research group of Academician Yue Jianmin (Yue, J.M., et al. J. Am. Chem. Soc. 2019, 141, 6812. ) was isolated from the bark of Dysoxylum hongkongense in 2019. From the structural analysis, dysoxylactam A is a seventeen-membered macrocyclic desipeptide with six chiral centers, and the side chain is a unique fatty acid with five consecutive stereocenters. Preliminary biological activity studies have shown that dysoxylactam A can reverse the multidrug resistance of tumor cells. Through in vitro cell experiments, it was found that multidrug-resistant tumor cells induced by chemicals ...

Claims

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Application Information

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IPC IPC(8): C07D267/00
CPCC07D267/00
Inventor 叶涛郭益安杨明泽彭文泉
Owner PEKING UNIV SHENZHEN GRADUATE SCHOOL
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