A new method for the asymmetric synthesis of isomers of the natural product (‑)‑euscapholide

A technology of natural products and synthetic methods, applied in the production of bulk chemicals, organic chemistry, etc., can solve the problems of complex post-processing, long synthetic routes, and many side reactions, and achieve easy-to-obtain raw materials, few side reactions, and fast speed Effect

Inactive Publication Date: 2017-11-24
JIANGXI SCI & TECH NORMAL UNIV
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

Carefully analyze the reports of Hee-Yoon Lee et al. Their synthetic routes are relatively long, and the reagents they use are expensive (such as trimethylsilyl alkynyllithium) and highly toxic (such as mercuric sulfate used in the route), and some reactions exist more or less Slow speed, many side reactions, complex post-processing and other problems

Method used

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  • A new method for the asymmetric synthesis of isomers of the natural product (‑)‑euscapholide
  • A new method for the asymmetric synthesis of isomers of the natural product (‑)‑euscapholide
  • A new method for the asymmetric synthesis of isomers of the natural product (‑)‑euscapholide

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Embodiment 1

[0034] The synthesis of embodiment 1, formula 5 compounds

[0035] Before synthetic formula 5, at first synthetic formula 4 compound, carry out according to following process:

[0036] At 0°C and under the protection of nitrogen, sodium hydride powder (161.6 mg, 2 mmol) was slowly added to a solution of p-methoxybenzyl alcohol (2 mL, 8 mmol) in ether (6 mL), then warmed to room temperature, and The reaction was stirred for 30 minutes. Then the reaction mixture was cooled to 0°C again, and trichloroacetonitrile (1.6 mL, 8 mmol) was added at the same time, then the reaction mixture was warmed to room temperature, and after stirring for 2 hours, saturated sodium bicarbonate solution was added to quench the reaction. The obtained mixed system was extracted with dichloromethane (3×20mL) and the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate, then concentrated under reduced pressure to remove the organic solvent to obtain an orange...

Embodiment 2

[0038] The synthesis of embodiment 2, formula 6 compound

[0039] At -78°C, diisobutylaluminum hydride solution (22.44mL, 22.44mmol, 1M n-hexane solution) was slowly added dropwise to a solution of compound of formula 5 (4.45g, 18.70mmol) in dichloromethane (50mL), After completion of the dropwise addition, the reaction was carried out at this temperature for 2 hours. After the reaction was over, methanol (1 mL) was added to the reaction system at -78°C to quench the reaction, then warmed up to room temperature, and 10 mL of water was added to separate the layers. The aqueous phase was then extracted with dichloromethane (2×50 mL), and the combined The obtained organic phase was washed with saturated brine, and the obtained organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and the obtained crude product was subjected to flash column chromatography (ethyl acetate: petroleum Ether=1:15) separated and purifi...

Embodiment 3

[0040] Synthesis of embodiment 3, formula 8 compound

[0041] Before synthesizing the compound of formula 8, it is necessary to make enol silyl ether 7 by itself, and its preparation process is as follows:

[0042] Add triethylamine (43.5mL, 314.40mmol) into a solution of methyl acetoacetate (12.0g, 103.34mmol) in n-hexane (260mL), then slowly add trimethylchloromethane (18.2mL, 141.73mmol), after reacting at room temperature for 18 hours, filter out the solid in the reaction system and concentrate, and the concentrated solution is distilled under reduced pressure to obtain 3-trimethylsilyloxy-2-butenoic acid methyl ester (9.37g, 61%) for the following reaction. 1 H NMR (400MHz, CDCl 3 )δ:5.12(s,1H),3.65(s,3H),2.26(s,3H),0.26(s,9H).

[0043] Dissolve 3-trimethylsilyloxy-2-butenoic acid methyl ester (9g, 47.80mmol) in anhydrous tetrahydrofuran (40mL), cool down to -78°C, slowly add lithium diisopropylamide (35.8mL , 71.69mmol, 2M n-hexane solution), reacted at -78°C for 30 ...

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Abstract

The present invention relates to a novel method for asymmetrically synthesizing natural product (-)-Euscapholide isomers. Starting with (R)‑3‑hydroxybutyrate methyl ester, after p-methoxybenzyl protection, diisobutylaluminum hydride reduction, Mukaiyama aldol reaction, sodium borohydride reduction, acidic ring closure, hydroxyl Elimination, deprotection and other processes complete the asymmetric total synthesis of the target molecule 1. The synthetic route design is novel and reasonable, the raw materials are cheap and easy to obtain, the operation process is simple, the reaction conditions are mild, and the asymmetric total synthesis of one isomer of Euscapholide with two chiral centers is efficiently completed, and the product configuration is single.

Description

technical field [0001] The invention relates to an asymmetric synthesis method of a natural product (-)-Euscapholide isomer, belonging to the technical field of organic chemical synthesis. Background technique [0002] Many natural products with cis or trans 1,3-diol / 5,6-pyrone have shown good biological activity and have potential medicinal value. Such as, Kurzilactone, Tarchonanthuslactone, Cryptocarya diacetate, etc. In particular, tarchonanthuslactone, which has the effect of lowering blood sugar, is expected to be used in antidiabetic treatment. An important medicinal group of Tarchonanthuslactone is the structure of Formula 2, which is also a natural product named Euscapholide. Euscapholide is a kind of natural product with 1,3-diol / 5,6-pyrone, which was extracted and isolated from the leaves of Agvenia japonica plant by Takeda et al. in 1998. Dong Mei et al conducted biological tests on its analogues and found that Euscapholide and other compounds have strong anti-...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D309/32
CPCY02P20/55
Inventor 黄双平黄飞飞王晓季覃双林王高鹏张志滨林爽杰孙猛刘帅
Owner JIANGXI SCI & TECH NORMAL UNIV
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