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Method for synthesizing chiral tetrahydrobenzoxepine compound through asymmetric cycloaddition reaction catalyzed by gold

A technology of benzoxazepines and compounds, applied in the field of organic synthesis, to achieve the effects of convenient and simple operation, mild reaction conditions, and a wide range of substrates

Active Publication Date: 2022-05-06
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

It is worth noting that there are only 3 reports on gold-catalyzed asymmetric [3+4] cycloaddition reactions involving 2-(1-alkynyl)-2-alken-1-ones

Method used

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  • Method for synthesizing chiral tetrahydrobenzoxepine compound through asymmetric cycloaddition reaction catalyzed by gold
  • Method for synthesizing chiral tetrahydrobenzoxepine compound through asymmetric cycloaddition reaction catalyzed by gold
  • Method for synthesizing chiral tetrahydrobenzoxepine compound through asymmetric cycloaddition reaction catalyzed by gold

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Experimental program
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preparation example Construction

[0046] The preparation method of chiral ligand used in the embodiment is as follows:

[0047] At 0-5°C, slowly add 5.8 mL of triethylamine dropwise to 50 mL of 0.2 mol / L phosphorus trichloride in dichloromethane for 5 minutes, and then add VI (10 mmol, 2.25 g) 20 mL of dichloromethane solution was added dropwise to the reaction solution. After the dropwise addition was completed, it was warmed up to room temperature and continued to stir at room temperature for 2 h. Then, compound VII (10 mmol, 2.94 g) was added and stirred at room temperature overnight. After the reaction was completed, the solvent was removed in vacuo. EA / PE=0.02-0.04:1, v / v), the target product IV was obtained (71% yield, 99% ee).

[0048] The reaction scheme is as follows:

[0049]

Embodiment 1

[0051] (6R,10S)-7-Methyl-6,9-diphenyl-10-((E)-styryl)-6H,10H-[1,3]dioxacyclo[4',5' : Synthesis of 4,5]benzo[1,2-b]furo[3,4-E]oxazepine(IIIaa)

[0052] The reaction scheme is as follows:

[0053]

[0054] The operation steps are as follows:

[0055] Under nitrogen protection, chiral ligand (7.5 μmol, 4.1 mg), Me 2 SAuCl (5 μmol, 1.5 mg) and 0.5 mL of dichloroethane were stirred at room temperature for 2 hours, and the solvent was removed in vacuo. Next the AgNTf 2 (5.5μmol, 2.2mg) and 1.0mL dichloroethane were added to the reaction flask respectively, after the mixture was stirred at room temperature for 15 minutes, the precipitate was removed by filtration, and the filtrate was transferred to a container containing substrate Ia (0.1mmol, 24.6mg), substrate Ⅱa (0.13mmol, 32.8mg) and 300mg Molecular sieve reaction flask. Then stirred at room temperature for 3 hours, TLC detection, the raw material Ia disappeared; after that, the solvent was removed by concentration und...

Embodiment 2

[0062] (6R,10S)-7-(4-fluorophenyl)-6,9-diphenyl-10-((E)-styryl)-6H,10H-[1,3]dioxane[ Synthesis of 4',5':4,5]benzo[1,2-b]furo[3,4-E]oxazepine(Ⅲba)

[0063] The reaction scheme is as follows:

[0064]

[0065] The operation steps are as follows:

[0066] Under nitrogen protection, chiral ligand (7.5 μmol, 4.1 mg), Me 2 SAuCl (5 μmol, 1.5 mg) and 0.5 mL of dichloroethane were stirred at room temperature for 2 hours, and the solvent was removed in vacuo. Next the AgNTf 2 (5.5μmol, 2.2mg) and 1.0mL dichloroethane were added to the reaction flask respectively, and after the mixture was stirred at room temperature for 15 minutes, the precipitate was removed by filtration, and the filtrate was transferred to a solution containing substrate Ib (0.1mmol, 26.4mg), substrate IIa (0.13mmol, 32.8mg) and 300mg Molecular sieve reaction flask. Then stirred at room temperature for 3 hours, TLC detection, the raw material Ib disappeared; after that, the solvent was removed by concentra...

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Abstract

The invention provides a method for synthesizing a chiral tetrahydrobenzoxepine compound through asymmetric cycloaddition reaction catalyzed by gold, which comprises the following steps: in a solvent A, under the catalysis of a gold catalysis system, performing asymmetric [3 + 4] cycloaddition reaction on an alkyne ketene compound I and an o-methylene benzoquinone compound II to obtain the chiral tetrahydrobenzoxepine compound. A chiral tetrahydrobenzoxazepine compound III is obtained; the gold catalysis system is composed of a gold catalyst, a chiral ligand and a silver salt, and the chiral ligand has a structure as shown in a formula IV. The tetrahydrobenzoxepine compound is constructed through the asymmetric cycloaddition reaction catalyzed by gold, and the method has the advantages that the operation is convenient and simple, the yield is high, the reaction raw materials are low in price and easy to obtain, the catalyst cost is low, the substrate application range is wide, the diastereoselectivity is good, the para-selectivity is high and the like.

Description

technical field [0001] The invention relates to a method for synthesizing chiral tetrahydrobenzoxazepine compounds through a gold-catalyzed asymmetric cycloaddition reaction, belonging to the technical field of organic synthesis. Background technique [0002] Chiral tetrahydrobenzoxazepine structures widely exist in active natural products and drug molecules, such as Callophycoic acid C with anti-tuberculosis effect, Tolvaptan with anti-diuretic effect, and Doxepin, an antidepressant drug widely used in clinical practice. However, such compounds are difficult to obtain only through natural isolation or biosynthesis, and have the disadvantages of low content and high cost. Therefore, obtaining such natural products through total synthesis is a very promising approach. In recent decades, the cycloaddition of dipolar ions catalyzed by transition metals can generate multiple carbon-carbon or carbon-heteroatom bonds in one step, which has the advantages of high atom economy and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/14C07D493/04C07F9/6571
CPCC07D493/14C07D493/04C07F9/6571
Inventor 李孝训王训华
Owner SHANDONG UNIV
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