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Synthetic method for Dtena modified fragment of apratoxin marine natural product

A natural product and synthetic method technology, applied in the direction of organic chemistry, can solve the problems of long reaction steps and unsuitability for industrial production, and achieve the effects of fewer reaction steps, high total yield and good product selectivity

Inactive Publication Date: 2016-04-13
HARBIN INST OF TECH AT WEIHAI
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The synthesis of Dtena-modified fragments of this apratoxin-like marine natural product is currently only one report (J.Med.Chem.2014, 57, 3011), the reaction steps are long, and it is not suitable for industrial production

Method used

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  • Synthetic method for Dtena modified fragment of apratoxin marine natural product

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Embodiment 1: the synthesis of beta-hydroxy ketone (9, see accompanying drawing)

[0019] Add 20 ml of anhydrous diethyl ether to the reaction flask, cool to -78°C, add enol boroether 7 (see attached drawing, prepared according to the reference document Synthesis, 1998,639, 10 mmol) and aldehyde 8 (see attached drawing, according to Reference Org. Lett., 2003, 5, 3503 preparation, 10mmol) was added into the reaction flask, naturally raised to -20°C, stirred at -20°C for 16 hours, TLC detected the end of the esterification reaction. Add 20 ml of water to quench, shake and separate the liquids, extract the aqueous phase with ethyl acetate (20mLx3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography to obtain beta-hydroxyketone (9, See accompanying drawing), yield is 51%.

Embodiment 2

[0020] Embodiment 2: the synthesis of O-Troc alcohol (10, see accompanying drawing)

[0021] Beta-hydroxyketone (10, 10.0 mmol) and 20 ml of dichloromethane were added to the reaction flask, and TrocCl (12.0 mmol) and DMAP (13.0 mmol) were added at room temperature, stirred at room temperature, and detected by TLC. After the reaction (about 6 hours), add 20 ml of water to quench, shake and separate the liquids, extract the aqueous phase with dichloromethane (20mLx3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain beta-OTroc Ketones (90%). Take the beta-OTroc ketone (5.0mmol) and dissolve it in 10ml of H 2 In O / DCM / MeOH (1:1:1) mixed solvent, acetic acid (AcOH, 5.5 mmol) was added at zero temperature, stirred at room temperature, and detected by TLC. After the reaction (about 8 hours), add 20 ml of water to quench, shake and separate the liquids, extract the aqueous phase with dichloromethane (20mLx3), combine the organic phas...

Embodiment 3

[0022] Example 3: Synthesis of o-O-Bz-based ketones (12, see accompanying drawing) containing proline structural units

[0023] N-Fmoc proline (11, see attached figure, 2.0 mmol) with 2,4,6-trichlorobenzoyl chloride (2.0 mmol) and Et 3 N (2.0 mmol) was dissolved in 10 ml of toluene (PhMe), and stirred at room temperature for 2 hours to generate mixed anhydride. O-Troc alcohol (10, see figure, 2.0 mmol) was added to the mixed acid anhydride reaction system, and the reaction was stirred for 6 hours at a reaction temperature of 90°C. TLC detected the end of the reaction, quenched by adding 20 ml of saturated aqueous sodium bicarbonate solution, separated after shaking, and extracted the aqueous phase with dichloromethane (20mLx3), combined the organic phases, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography , and the o-O-Bz-based ketone (12, see attached figure) containing the proline structural unit was obtained with a yield of ...

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Abstract

The invention relates to a synthetic method for a Dtena modified fragment of an apratoxin marine natural product, which belongs to the field of chemical synthesis. The synthetic method comprises the following steps: subjecting boryl enol ether and aldehyde to adol reaction so as to prepare beta-hydroxyl ketone; preparing O-Troc alcohol through the Troc protection reaction of the hydroxyl group of beta-hydroxyl ketone and silyl ether deprotection reaction; subjecting the O-Troc alcohol and N-Fmoc proline to a coupling reaction to prepare o-O-Bz-yl ketone containing a proline constitutional unit; and carrying out O-Bz deprotection reaction of the o-O-Bz-yl ketone and oxidation reaction of newly generated o-hydroxyl ketone so as to prepare the Dtena modified fragment (as in a figure in the specification) of the apratoxin marine natural product. The synthetic method has the characteristics of a few reaction steps, high overall yield, good product selectivity, suitability for industrial production, etc.

Description

technical field [0001] The invention relates to a method for synthesizing a modified fragment of apratoxin-like marine natural product Dtena. Background technique [0002] Apratoxin-like marine natural product is a unique new anti-cancer drug, which can stop the cell division of cancer cells at the G1 stage and rapidly apoptosis, and can prevent the migration (diffusion) of secreted proteins of cancer cells, but cannot prevent the secreted proteins of normal human cells migration. Researchers from the National Cancer Research Center of the United States (http: / / dtp.nci.nih.gov / index.html) found that the marine natural drug apratoxin has a special mechanism of action on the biological activity of 60 cancer cells, which is different from the existing Anticancer drugs have different mechanisms of action and are a new class of anticancer drugs (Nat. Rev. Cancer, 2006, 6, 813). Studies have found that the active conformation of this type of marine natural product is its cis con...

Claims

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Application Information

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IPC IPC(8): C07D207/16
CPCC07D207/16
Inventor 李惠静王龙飞吴彦超
Owner HARBIN INST OF TECH AT WEIHAI
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