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Method for synthesizing eight-membered bridged ring compound through palladium-catalyzed asymmetric cycloaddition reaction

A compound and cycloaddition technology, applied in the fields of compounds of Group 5/15 elements of the periodic table, chemical instruments and methods, catalysts for physical/chemical processes, etc., to achieve the effects of high efficiency, low price, and a wide range of substrates

Active Publication Date: 2021-06-11
SHANDONG UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, so far, the synthesis of eight-membered bridged ring compounds by asymmetric [4+4] cycloaddition reaction using γ-methylene-δ-valerolactone as substrate has not been reported.

Method used

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  • Method for synthesizing eight-membered bridged ring compound through palladium-catalyzed asymmetric cycloaddition reaction
  • Method for synthesizing eight-membered bridged ring compound through palladium-catalyzed asymmetric cycloaddition reaction
  • Method for synthesizing eight-membered bridged ring compound through palladium-catalyzed asymmetric cycloaddition reaction

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] (1R,5S,6R)-9-Bromo-3-methylene-5-phenyl-3,4,5,6-tetrahydro-2H-1,6-epoxybenzo[b]azacyclocycle Synthesis of Octene-5-carboxylate (Ⅲaa)

[0046] Under a nitrogen atmosphere, add 5-methylene-2-oxo-3-phenyltetrahydro-2H-pyran-3-carboxylic acid methyl ester (Ia) (59 mg) into a 5 mL round bottom flask, 6-bromo Benzo[c]isoxazole (IIa) (39.4 mg), palladium catalyst (Pd 2 (dba) 3 · CHCl 3 ) (5.2mg), chiral ligand IV (11.5mg) and triethylboron (THF solution of 1mol / L triethylboron, 40uL), then add p-xylene 0.6mL, then stir at 10°C Reacted for 40h; the reacted crude product was directly separated and purified by column chromatography (eluent: ethyl acetate:petroleum ether=1:10~1:30, v / v) to obtain a white solid (1R, 5S, 6R)- 9-Bromo-3-methylene-5-phenyl-3,4,5,6-tetrahydro-2H-1,6-epoxybenzo[b]azacycloctene-5-carboxylate (Ⅲaa) 65mg, yield 82%, ee value 95%.

[0047] The reaction scheme of the present embodiment is as follows:

[0048]

[0049] The characterization data of t...

Embodiment 2

[0056] (1R,5S,6R)-3-Methylene-5-phenyl-3,4,5,6-tetrahydro-2H-1,6-epoxybenzo[b]azacycloctene-5 -Synthesis of carboxylate (Ⅲab)

[0057] Under a nitrogen atmosphere, add 5-methylene-2-oxo-3-phenyltetrahydro-2H-pyran-3-carboxylic acid methyl ester (Ia) (59 mg) into a 5 mL round bottom flask, benzo[ c] isoxazole (Ⅱb) (24mg), palladium catalyst (Pd 2 (dba) 3 · CHCl 3 ) (5.2mg), chiral ligand IV (11.5mg) and triethylboron (THF solution of 1mol / L triethylboron, 40uL), then add p-xylene 0.6mL, then stir at 10°C Reacted for 40h; the reacted crude product was directly separated and purified by column chromatography (eluent: ethyl acetate:petroleum ether=1:10~1:30, v / v) to obtain a white solid (1R, 5S, 6R)- 3-Methylene-5-phenyl-3,4,5,6-tetrahydro-2H-1,6-epoxybenzo[b]azacycloctene-5-carboxylate (Ⅲab) 60mg , yield 80%, ee value 93%.

[0058] The reaction scheme of the present embodiment is as follows:

[0059]

[0060] The characterization data of the resulting product (Ⅲab) are ...

Embodiment 3

[0067] (1R,5S,6R)-9-Bromo-5-(4-methoxyphenyl)-3-methylene-3,4,5,6-tetrahydro-2H-1,6-epoxybenzene Synthesis of a[b]azacyclooctene-5-carboxylate methyl ester (Ⅲba)

[0068] Under a nitrogen atmosphere, add 3-(4-methoxyphenyl)-5-methylene-2-oxytetrahydro-2H-pyran-3-carboxylic acid methyl ester (i.e. Ib) into a 5mL round bottom flask ( 66mg), 6-bromobenzo[c]isoxazole (Ⅱa) (39.4mg), palladium catalyst (Pd 2 (dba) 3 · CHCl 3 ) (5.2mg), chiral ligand IV (11.5mg) and triethylboron (THF solution of 1mol / L triethylboron, 40uL), then add p-xylene 0.6mL, then stir at 10°C Reacted for 40h; the reacted crude product was directly separated and purified by column chromatography (eluent: ethyl acetate:petroleum ether=1:10~1:30, v / v) to obtain a white solid (1R, 5S, 6R)- 9-Bromo-5-(4-methoxyphenyl)-3-methylene-3,4,5,6-tetrahydro-2H-1,6-epoxybenzo[b]azepine Methyl ene-5-carboxylate (Ⅲba) 75 mg, yield 74%, ee value 94%.

[0069] The reaction scheme of the present embodiment is as follows: ...

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Abstract

The invention provides a method for synthesizing an eight-membered bridged ring compound by palladium-catalyzed asymmetric cycloaddition reaction. The method comprises the following steps: in an organic solvent, under catalysis of a palladium catalytic system and in the presence of an additive, carrying out [4 + 4] cycloaddition reaction on a gamma-methylene-delta-valerolactone compound I and a benzo [C] isoxazole compound II, thereby obtaining the eight-membered bridged ring compound III. The palladium catalysis system is composed of a palladium catalyst and a chiral ligand. According to the method disclosed by the invention, the eight-membered bridged ring compound can be generated with high stereoselectivity and regioselectivity, and the eight-membered ring compound is subjected to efficient asymmetric synthesis; and the method for preparing the eight-membered ring compound through the palladium-catalyzed [4 + 4] cycloaddition reaction has the advantages of being convenient to operate, wide in substrate application range, cheap and easily available in reaction raw materials and the like.

Description

technical field [0001] The invention relates to a method for synthesizing an eight-member bridged ring compound through palladium-catalyzed asymmetric cycloaddition reaction, belonging to the technical field of organic synthesis. Background technique [0002] The structure of the eight-membered ring is not only ubiquitous in many complex natural products and their derivatives, but also an important part of many clinical drug molecules, for example, the famous anticancer drug paclitaxel, antibacterial drug retapamulin (such as: Rong, Z.Q.; Yang, L.C.; Liu, S.; Yu, Z.Y.; Wang, Y.N.; Tan, Z.Y.; Huang, R.Z.; ; Zuo, Z.J.Angew.Chem.Int.Ed.2020,59,1243-1247; Hu,Y.J.; 5953.). However, the particularity of the macrocyclic skeleton, coupled with various cross-ring interactions and unfavorable entropy and enthalpy effects, brings great challenges to the construction of macrocyclic compounds such as eight-membered rings with high stereoselectivity. In recent years, researchers have d...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/18C07F9/6571B01J31/24
CPCC07D493/18C07F9/6571B01J31/2461B01J2531/824
Inventor 李孝训刘继田高灿王训华
Owner SHANDONG UNIV
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