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Synthesis method of chiral spiro[pyrrolidone-3,3'-oxindole] serial compounds and application of chiral spiro[pyrrolidone-3,3'-oxindole] serial compounds in synthesis of natural products

A technology of pyrrolidone and oxindole, which is applied in the synthesis of chiral spiro[pyrrolidone-3,3'-oxindole] ring system and the application field in the synthesis of natural products, which can solve the problem of limited scope of application of substrates and synthetic routes Excessive length, complex reaction conditions, etc., to achieve the effect of wide application range of substrates, high enantioselectivity, and easy availability of raw materials

Pending Publication Date: 2021-03-02
JINAN UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the construction methods for chiral spiro[pyrrolidone-3,3'-oxindole] compounds are still very scarce, and there are only a few cases reported: 2005 (J.Am.Chem.Soc.2005,127,11,3670) et al. obtained chiral spiro[pyrrolidone-3,3'-oxindone by chiral phase transfer catalyzed asymmetric aromatic nucleophilic substitution, reduction and cyclization Indole] compounds, but this reaction needs to be carried out under toluene / chloroform solvent and low temperature conditions, and expensive palladium catalyst is needed; prosthetic group, synthesized several chiral spiro[pyrrolidone-3,3'-oxindole] compounds, however, this synthetic route requires multi-step reactions, using toxic tetrahydrofuran, expensive palladium catalyst, and Substrate pretreatment and reaction need to be carried out under low temperature conditions, and the scope of application is limited; in 2012, Zhou (Cheminform, 2012, 43, 41, 3116) et al. disclosed a cuprous iodide-catalyzed lactam arylation, A method for constructing an oxindole skeleton and a spiro ring through a cyclization reaction. The reaction uses tetrahydrofuran as a solvent and must be carried out under strict anhydrous, oxygen-free and heating conditions.
[0005] In summary, in the existing synthetic methods, there are deficiencies such as complex reaction conditions, long synthetic routes, and limited scope of substrate application.

Method used

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  • Synthesis method of chiral spiro[pyrrolidone-3,3'-oxindole] serial compounds and application of chiral spiro[pyrrolidone-3,3'-oxindole] serial compounds in synthesis of natural products
  • Synthesis method of chiral spiro[pyrrolidone-3,3'-oxindole] serial compounds and application of chiral spiro[pyrrolidone-3,3'-oxindole] serial compounds in synthesis of natural products
  • Synthesis method of chiral spiro[pyrrolidone-3,3'-oxindole] serial compounds and application of chiral spiro[pyrrolidone-3,3'-oxindole] serial compounds in synthesis of natural products

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] The preparation of embodiment 1 compound formula (I)

[0044]The raw material compound formula (I) of the present invention is synthesized by the method reported in the literature (Alakesh B.et al.Org.Lett.2012,14,5864), by aromatic amine compound and 1-methyl-2-oxopyrrole Preparation by condensation of alkane-3-carboxylic acids. Concrete synthetic method is as follows: add 25mL dry dichloromethane and Dicyclohexylcarbodiimide (DCC) (5 mmol). The above reaction solution was stirred at 25° C. for 24 hours, then concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to obtain a white solid product formula (I) (yield rate was 74-80%). The synthesis reaction formula is as follows:

[0045]

[0046] Compounds 1a-1k were prepared from the aromatic amine compounds in Table 1 according to the above method.

[0047] Structural characterization data of compounds 1a~1k

[0048]

[0049]

[0050]

[0051] ...

Embodiment 2

[0054] The synthesis of embodiment 2 compound 2a

[0055] The synthetic reaction formula of compound 2a is as follows:

[0056]

[0057] Under a nitrogen atmosphere, 2 mL of dry acetonitrile and sodium hydride (7.2 mg, 0.3 mmol) were added sequentially to a reaction flask containing amide 1a (71.6 mg, 0.2 mmol) and cuprous iodide (3.8 mg, 0.02 mmol), respectively. and chiral diamine ligand (9.6mg, 0.04mmol). The above reaction solution was stirred at 25°C for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to obtain the white solid product 2a (38.2 mg, yield 83%, ee value 93%).

[0058] [α]20D=+14.2 (c=0.33, CHCl3); 1 H NMR (400MHz, CDCl3): δ7.29-7.24(m, 1H), 7.16-7.13(m, 1H), 7.08-7.05(m, 1H), 6.87-6.82(m, 1H), 3.81-3.74( m,1H), 4.10-3.99(m,2H),3.62-3.53(m,1H),3.19(s,3H),2.96(s,3H),2.69-2.62(m,1H), 2.40-2.33( m, 1H); 13C NMR (100MHz, CDCl3): δ173.7, 171.5, 143.5, 128.9, 128.0, 122.0, 121.8,...

Embodiment 3

[0064] The synthesis of embodiment 3 compound 2b

[0065] The synthetic reaction formula of compound 2b is as follows:

[0066]

[0067] Under a nitrogen atmosphere, add 2 mL of dry acetonitrile and sodium hydride (7.2 mg, 0.3 mmol) to a reaction flask containing amide 1b (74.4 mg, 0.2 mmol) and (3.8 mg, 0.02 mmol) of copper iodide, respectively. and chiral diamine ligand (9.6mg, 0.04mmol). The above reaction solution was stirred at 25°C for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to obtain a white solid 2b (35.3 mg, yield 72%, ee value 96%).

[0068] [α]20D=+23.6 (c=0.33, CHCl 3 ); 1 H NMR (400MHz, CDCl 3 ):δ7.12(d,J=8.0Hz,1H),6.99(s,1H),6.76(d,J=8.0Hz,1H),3.84-3.77(m,1H),3.63-3.57(m, 1H),3.22(s,3H),3.00(s,3H),2.72-2.68(m,1H),2.67-2.34(m,4H); 13 C NMR (100 MHz, CDCl 3 ): δ175.65, 170.71, 142.12, 132.64, 129.94, 129.24, 123.66, 108.29, 57.85, 47.24, 30.55, 29.53, 26.61, 21.11; HRM...

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Abstract

The invention discloses a preparation method of a chiral spiro[pyrrolidone-3,3'-oxoindole] derivative, and the method is effectively applied to synthesis of a natural product Horsfiline. According tothe invention, the chiral spiro[pyrrolidone-3,3'-oxoindole] derivatives are constructed by catalyzing an asymmetric intramolecular carbon-carbon coupling reaction of amide compounds through monovalentcopper. The method has the advantages of readily available raw materials, cheap and readily available catalyst, high catalytic efficiency, mild reaction conditions, high enantioselectivity, high yield and the like, and is suitable for mass production and application in the pharmaceutical industry.

Description

technical field [0001] The invention belongs to the technical field of chemical substances and their preparation. More specifically, it relates to the synthesis method of chiral spiro[pyrrolidone-3,3'-oxindole] ring system and its application in the synthesis of natural products. Background technique [0002] The chiral spiro[pyrrolidone-3,3'-oxindole] ring system is the core structural unit of many natural products and biologically active molecules, because it contains heteroatoms with strong electronegativity such as oxygen and nitrogen, and many Biomacromolecules have strong intermolecular forces and are a type of active compound with a special structure. They are known as "advantageous structures" in drug design and have attracted wide attention (Chem.Soc.Rev.2018, 47, 5946 ; Bioorg. Med. Chem. Lett. 2017, 27, 1105; Eur. J. Med. Chem. 2017, 126, 1701). As shown in the following structural formula, Horsfiline is a chiral spiro compound with oxindole and pyrrole units is...

Claims

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Application Information

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IPC IPC(8): C07D487/10
CPCC07D487/10
Inventor 周伟李麦占钟先强
Owner JINAN UNIVERSITY
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