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A kind of method for synthesizing eight-membered bridged ring compound by palladium-catalyzed asymmetric cycloaddition reaction

A compound and cycloaddition technology, which is applied to compounds of Group 5/15 elements of the periodic table, chemical instruments and methods, physical/chemical process catalysts, etc., to achieve the effects of low cost, cheap and easy-to-obtain reaction raw materials, and convenient operation

Active Publication Date: 2022-07-15
SHANDONG UNIV
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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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  • A kind of method for synthesizing eight-membered bridged ring compound by palladium-catalyzed asymmetric cycloaddition reaction
  • A kind of method for synthesizing eight-membered bridged ring compound by palladium-catalyzed asymmetric cycloaddition reaction
  • A kind of method for synthesizing eight-membered bridged ring compound by 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]azacycle Synthesis of Octene-5-carboxylate (Ⅲaa)

[0046] Under nitrogen atmosphere, to a 5 mL round bottom flask was added methyl 5-methylene-2-oxo-3-phenyltetrahydro-2H-pyran-3-carboxylate (Ia) (59 mg), 6-bromo Benzo[c]isoxazole (IIa) (39.4mg), palladium catalyst (Pd 2 (dba) 3 ·CHCl 3 ) (5.2mg), chiral ligand IV (11.5mg) and triethylboron (1mol / L triethylboron in THF solution, 40uL), then added p-xylene 0.6mL, then stirred at 10°C The reaction was carried out for 40h; the crude product after the reaction was directly separated and purified by column chromatography (the eluent was 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]azetioctene-5-carboxylate (IIIaa) 65mg, yield 82%, ee value 95%.

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

[0048]

[0049] ...

Embodiment 2

[0056] (1R,5S,6R)-3-methylene-5-phenyl-3,4,5,6-tetrahydro-2H-1,6-epoxybenzo[b]azetioctene-5 -Synthesis of Carboxylic Ester (IIIab)

[0057] Under nitrogen atmosphere, to a 5 mL round bottom flask was added methyl 5-methylene-2-oxo-3-phenyltetrahydro-2H-pyran-3-carboxylate (Ia) (59 mg), benzo[ c] Isoxazole (IIb) (24 mg), palladium catalyst (Pd 2 (dba) 3 ·CHCl 3 ) (5.2mg), chiral ligand IV (11.5mg) and triethylboron (1mol / L triethylboron in THF solution, 40uL), then added p-xylene 0.6mL, then stirred at 10°C The reaction was carried out for 40h; the crude product after the reaction was directly separated and purified by column chromatography (the eluent was 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]azepin-5-carboxylate (IIIab) 60mg , the yield is 80%, and the ee value is 93%.

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

[0059]

[0060] The c...

Embodiment 3

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

[0068] Under nitrogen atmosphere, add 3-(4-methoxyphenyl)-5-methylene-2-oxytetrahydro-2H-pyran-3-carboxylate methyl ester (i.e. Ib)( 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 (1mol / L triethylboron in THF solution, 40uL), then added p-xylene 0.6mL, then stirred at 10°C The reaction was carried out for 40h; the crude product after the reaction was directly separated and purified by column chromatography (the eluent was 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]azepin Methyl alkene-5-carboxylate (IIIba) 75 mg, yield 74%, ee value 94%.

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

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Abstract

The invention provides a method for synthesizing an eight-membered bridged ring compound through a palladium-catalyzed asymmetric cycloaddition reaction. -Valerolactone compound I and benzo[C]isoxazole compound II undergo a [4+4] cycloaddition reaction to obtain an eight-membered bridged ring compound III; the palladium catalyst system is composed of a palladium catalyst and a chiral ligand . The method of the invention can generate an eight-membered bridged ring compound with high stereoselectivity and regioselectivity, and can perform high-efficiency asymmetric synthesis of the eight-membered ring compound; The method of the eight-membered ring compound has the advantages of convenient operation, wide application range of substrates, cheap and readily available reaction raw materials, and the like.

Description

technical field [0001] The invention relates to a method for synthesizing an eight-membered bridged ring compound through a palladium-catalyzed asymmetric cycloaddition reaction, and belongs 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 Retamorelin (such as: Rong, Z.Q.; Yang, L.C.; Liu, S.; Yu, Z.Y.; Wang, Y.N.; Tan, Z.Y.; Huang, R.Z.; Lan, Y.; Zhao, Y.J.Am.Chem.Soc. ; Zuo, Z.J.Angew.Chem.Int.Ed.2020, 59,1243-1247; Hu, Y.J.; Li, L.X.; 5953.). However, the specificity of macrocyclic skeletons, coupled with various cross-ring interactions and unfavorable entropy and enthalpy effects, bring great challenges to the construction of macrocyclic compounds such as eight-membered rings with high stereoselec...

Claims

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Application Information

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Patent Type & Authority Patents(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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