Method for totally synthesizing natural product (+/-)-rupestine G and resolving enantiomers

A technology for enantiomers, natural products, applied in the field of organic synthesis technology and separation

Active Publication Date: 2017-09-05
XINJIANG TECHN INST OF PHYSICS & CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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  • Method for totally synthesizing natural product (+/-)-rupestine G and resolving enantiomers
  • Method for totally synthesizing natural product (+/-)-rupestine G and resolving enantiomers
  • Method for totally synthesizing natural product (+/-)-rupestine G and resolving enantiomers

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Embodiment 1

[0053] a. Compound 1 was 2.0 g of 2-methyl-5-bromopyridine, (12 mmol) was dissolved in 30 ml of dichloromethane solution, and 2.9 g of m-chloroperoxybenzoic acid with a purity of 85% was added in batches under an ice bath, ( 13.9mmol) after naturally warming up to room temperature, stirring overnight reaction, after the reaction, the reaction solution was poured into saturated sodium sulfite solution to quench, after stirring for 1 hour, extract 3 times with dichloromethane 150ml, combine the organic phases, and use Dry over magnesium sulfate, remove the organic solvent to obtain the nitrogen oxidation product Compound 2 is 5-bromo-2-methyl-N-oxypyridine, the yield is 93%, 2.0g;

[0054] b. Under the protection of nitrogen, dissolve 1.0g (5.4mmol) of compound 2 as 5-bromo-2-methyl-N-oxypyridine in 20ml of acetonitrile solution, and then add 2.1g of trimethylsilyl cyanide, (21.6mmol ) and triethylamine 2.2ml, (16.2mmol), after reflux 12 hours, remove organic solvent, be COMBIFL...

Embodiment 2

[0075] Rupestine G (Rupestine G) and its three isomers Compound 13 is (5S,8R)-Rupestine G; Compound 14 is (5R,8S)-Rupestine G; Compound 15 is (5R, 8R)-one branch of artemisinine G was measured by the QstarElite quadrupole-time-of-flight hybrid high-resolution mass spectrometer of AB SCIEX, USA, its precise molecular weight was measured, the optical rotation value was measured by Rudolph RS Autopol VIautomatic polarimeter, and the EDC was measured experimentally by Chirascan circular dichroism spectrometer German COSMOlogic GmbH&Co.KG TmoleX 3.4 software calculates the ECD spectrum and compares it to determine its absolute configuration. For the high-resolution mass spectrum of Rupestine G (Rupestine G) and its isomers, see Figure 1-Figure 4 .

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Abstract

The invention relates to a method for totally synthesizing a natural product (+/-)-rupestine G and resolving enantiomers. The method comprises the following steps: oxidizing the raw material 2-methyl-5-bromopyridine (1) by m-chloroperoxybenzoic acid to obtain a nitrogen oxidation product compound 2, carrying out a Reissert-Henze reaction to perform cyano substitution so as to obtain a compound 3, carrying out a decarboxylation reaction on the compound 3 and potassium monoethyl malonate to obtain beta-ketoester 4, carrying out alkylation under the condition of sodium ethylate to obtain a compound 5, carrying out a coupling reaction to obtain a compound 6, carrying out an intramolecular olefin double replacement reaction on the compound 6 to obtain a key intermediate compound 7, carrying out reduction with sodium borohydride to obtain a compound 8, carrying out a reaction under the condition of pyridine/MsCl to obtain a compound 9, hydrolyzing the compound 9 under the action of lithium hydroxide, carrying out methyl esterification by using iodomethane to obtain a compound 10, carrying out palladium-carbon catalytic hydrogenation to obtain a pair of diastereoisomers 11 and 12, and carrying out resolution by a semi-preparative high performance liquid chromatograph to obtain the natural product rupestine G and three stereoisomers, namely a compound 13, a compound 14 and a compound 15.

Description

technical field [0001] The invention relates to the field of organic synthesis technology and separation technology, in particular to a total synthesis method and enantiomer resolution method of a natural product, Rupestine G. Background technique [0002] In 2008, the research group of Aji Aikebaier Aisa, Xinjiang Institute of Physical and Chemical Technology, Chinese Academy of Sciences, for the first time isolated five novel guaiacidin-type sesquiterpene alkaloids from Artemisia argyi. In 2012, He Fei and others in the research group isolated another eight compounds of this type from Artemisia argyi. Structurally, this type of compound has a pyridine ring, a saturated seven-membered ring, and two chiral centers. According to literature reports, guaiacol-like sesquiterpene alkaloids are toxic to liver cancer cells, while Artemisia argyi has anti-virus, liver-protecting and other effects. This has aroused the great interest of many synthetic chemists, biologists and patho...

Claims

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Application Information

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IPC IPC(8): C07D213/61C07D221/04C07B57/00C07D213/84
CPCC07B57/00C07B2200/07C07D213/61C07D213/84C07D221/04
Inventor 阿吉艾克拜尔·艾萨阿卜杜拉·玉苏普黄国正赵江瑜
Owner XINJIANG TECHN INST OF PHYSICS & CHEM CHINESE ACAD OF SCI
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