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Cyclopiane tetracyclic diterpene analogue, method for synthesizing same and application of cyclopiane tetracyclic diterpene analogue

A technology of a tetracyclic diterpenoid and a synthesis method, applied in the field of medicine and medicine, can solve the problems of less content and no chemical synthesis method and the like

Active Publication Date: 2015-12-16
LANZHOU UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] Although cyclopiane tetracyclic diterpenes can be isolated from the fermentation product of Penicillium, but the content is too small (for example, 0.64 mg conidiogenone was isolated from 300 liters of Penicillium fermentation broth), and there is no chemical synthesis method to prepare such compounds
In addition, cyclopiane tetracyclic diterpenes have a novel 6 / 5 / 5 / 5 fused tetracyclic structure, multiple consecutive chiral centers and four all-carbon quaternary carbon centers, which pose great challenges to their total synthesis

Method used

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  • Cyclopiane tetracyclic diterpene analogue, method for synthesizing same and application of cyclopiane tetracyclic diterpene analogue
  • Cyclopiane tetracyclic diterpene analogue, method for synthesizing same and application of cyclopiane tetracyclic diterpene analogue
  • Cyclopiane tetracyclic diterpene analogue, method for synthesizing same and application of cyclopiane tetracyclic diterpene analogue

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Experimental program
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Effect test

Embodiment 1

[0113] Preparation of compound (2)

[0114] Compound (1) (1.26 g, 10.0 mmol) was dissolved in 17 mL of tetrahydrofuran, under ice methanol bath, cuprous chloride (99 mg, 1.0 mmol) and freshly prepared 1 mol / L 3-methyl-3-butenyl were added successively A solution of magnesium bromide in tetrahydrofuran (14.0 mL, 14.0 mmol) was stirred for 3 hours, water was added to quench the reaction, the reaction solution was extracted with ether, the organic phase was washed with saturated aqueous sodium bicarbonate solution and saturated brine, and the organic phase was then washed with anhydrous sulfuric acid Dry over magnesium, filter, and concentrate the filtrate to obtain crude product. The crude product was dissolved in 20 mL of 2 mol / L aqueous sodium hydroxide solution, stirred at 100 degrees Celsius for 4 hours, extracted with ether, acidified by adding 6 mol / L hydrochloric acid to the aqueous phase until the pH value was 1-2, extracted with dichloromethane, and the organic phase of...

Embodiment 2

[0119] Preparation of compound (3)

[0120] Compound (2) (1.07 g, 0.64 mmol) was dissolved in 10 mL of dichloromethane, oxalyl chloride (0.80 mL, 0.96 mmol) was added, heated to reflux for 2 hours, cooled to room temperature, and the dichloromethane and excess were removed under reduced pressure. Oxalyl chloride. The prepared acid chloride was dissolved in 10 mL of toluene, and a solution of triethylamine (1.32 mL, 0.95 mmol) in 10 mL of toluene was added dropwise under reflux. After the addition was completed, it was cooled to room temperature, ether was added to dilute the system, the reaction was quenched with saturated aqueous ammonium chloride solution, the reaction solution was extracted with ether, the organic phase was washed with saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate, After filtration, the filtrate was concentrated and subjected to column chromatography to obtain a colorless oil (0.58 g, yield 60...

Embodiment 3

[0125] Compound (4) (Substituent R 4 for the preparation of phenylthio)

[0126] Dissolve diisopropylamine (0.22mL, 1.6mmol) in 7mL of tetrahydrofuran, add 2.5mol / L n-butyllithium in n-hexane solution (0.56mL, 1.4mmol) dropwise at minus 78 degrees Celsius, stir halfway under ice-water bath After 1 hour, it was lowered to minus 78 degrees Celsius, and a solution of compound (3) (0.15g, 1.0 mmol) in 1 mL of tetrahydrofuran was added dropwise. After stirring at room temperature for 1 hour, the temperature was reduced to minus 78 degrees Celsius again, and diphenyl disulfide (0.26 g, 1.2 mmol) in 1 mL of hexamethylphosphoric triamide solution, warmed to room temperature and stirred for 10 hours, diluted with diethyl ether, quenched with water, the reaction solution was extracted with diethyl ether, the organic phase was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated and subjected to column chromat...

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Abstract

The invention discloses a cyclopiane tetracyclic diterpene analogue, a method for synthesizing the same and cyclopiane tetracyclic diterpene natural products synthesized on the basis of the cyclopiane tetracyclic diterpene analogue. A structural formula of the cyclopiane tetracyclic diterpene analogue is shown. The method for synthesizing the cyclopiane tetracyclic diterpene analogue includes synthesizing intermediates (7) with conjugated enones and cyclobutanol structures from known conjugated ester (1) at first; carrying out rearrangement reaction under the effect of acid; constructing tricyclic framework structures of tetracyclic diterpene; structurally modifying the tricyclic framework structures and carrying out cyclization reaction under the effect of acid; constructing tetracyclic framework structures of the tetracyclic diterpene so as to obtain the cyclopiane tetracyclic diterpene analogue. The cyclopiane tetracyclic diterpene analogue, the method and the cyclopiane tetracyclic diterpene natural products have the advantages that the cyclopiane tetracyclic diterpene natural products conidiogenone B, conidiogenone and conidiogenol are synthesized from tetracyclic diterpene frameworks via multi-step chemical conversion for the first time, and the tetracyclic diterpene frameworks are used as key intermediates; the method can be used for quickly synthesizing a series of cyclopiane tetracyclic diterpene analogues.

Description

technical field [0001] The invention belongs to the field of medicine and medicine, and in particular relates to a cyclopiane tetracyclic diterpene analog, a synthesis method thereof, and its application in synthesizing a cyclopiane tetracyclic diterpene natural product. Background technique [0002] Natural products are one of the main sources of drug discovery. Cyclopane tetracyclic diterpenes are a class of natural products with a unique 6 / 5 / 5 / 5 fused tetracyclic skeleton, multiple continuous chiral centers and important biological activities. Among the cyclic diterpenes, some compounds showed important antibacterial, antitumor and conidia-inducing biological activities. The conidiogenone and conidiogenol involved in the present invention were firstly isolated from the fermentation broth of Penicillium cyclopium by the Olov Sterner group of Lund University in Sweden in 2002, and found that they have good selective inducing activity of Penicillium conidia (Tetrahedron Let...

Claims

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Application Information

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IPC IPC(8): C07C319/20C07C323/22C07C49/513C07C49/423C07C45/65C07C45/66C07C45/62C07C49/653C07F7/18C07D303/32C07D301/12C07D301/14C07C45/64
CPCY02P20/55
Inventor 涂永强侯四化葸超超
Owner LANZHOU UNIVERSITY
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