C-6 axial chiral 2-pyrone compound as well as preparation method and application thereof

Abstract

The invention relates to the technical field of chemical synthesis, and particularly provides a C-6 axially chiral 2-pyrone compound as well as a preparation method and application thereof. The structural formula of the C-6 axial chiral 2-pyrone compound provided by the invention is as shown in the following formula 3. The C-6 axially chiral biaryl 2-pyrone compound provided by the invention can be directly used as a high-efficiency catalyst to be applied to an asymmetric catalytic reaction, shows excellent catalytic performance and has relatively high application value, and the preparation method is simple and convenient to operate, low in energy consumption and green and environment-friendly. 3.

Description

Technical Field

[0001] This invention relates to the field of organic chemical synthesis technology, and in particular to a C-6 axial chiral 2-pyranone compound, as well as its preparation method and application. Background Technology

[0002] Axially chiral compounds are stereoisomers that form stable conformations due to hindered rotation of intramolecular single bonds. Their unique spatial structure and electronic properties have significant application value in fields such as asymmetric catalysis, medicinal chemistry, and functional materials. Traditionally, the construction of axially chiral compounds mainly relies on cross-coupling reactions catalyzed by transition metals (such as palladium and rhodium) (e.g., Buchwald-Hartwig coupling, Suzuki-Miyaura coupling, etc.). Although these methods are highly efficient, they suffer from problems such as strong dependence on precious metals, high cost, harsh reaction conditions, and significant environmental burden.

[0003] Nitrogen heterocyclic carbene (NHC) catalysis has become a research hotspot in asymmetric synthesis due to its high atom economy and mild reaction conditions. However, existing NHC catalytic systems are mostly focused on the synthesis of centrally chiral or planar chiral compounds, and efficient methods for constructing axially chiral compounds remain lacking. The 2-pyranone skeleton, as the core structure of natural products (such as the antibiotic Pyrenophorol), holds great potential for the synthesis and functionalization of its axially chiral derivatives. Therefore, researching a non-metal-dependent, highly stereoselective method for constructing C-6 axially chiral 2-pyranones is of great significance. Summary of the Invention

[0004] To address the aforementioned problems, this invention provides a C-6 axial chiral 2-pyranone compound, along with its preparation method and applications. This compound can be directly used as a highly efficient catalyst in asymmetric catalytic reactions, exhibiting excellent catalytic performance and possessing high application value.

[0005] To address the aforementioned technical problems, in a first aspect, the present invention provides a C-6 axial chiral 2-pyranone compound, said compound having the structural formula shown in Formula 3 below: 3.

[0006] Studies have found that the C-6 axially chiral 2-pyranone compounds of Formula 3 provided by this invention can be used as axially chiral catalysts in asymmetric Michael addition reactions. The reactions exhibit good chemoselectivity, and the enantiomeric excess values ​​all exceed 50%, demonstrating that the compounds have good stereoselectivity and good application value as asymmetric catalysts.

[0007] Secondly, the present invention provides a method for preparing the above-mentioned C-6 axial chiral 2-pyranone compounds, wherein the reaction formula involved in the preparation method is as follows: .

[0008] The preparation method includes the following steps: The compound shown in Formula 1 is reacted with the compound shown in Formula 2 to obtain the C-6 axial chiral 2-pyranone compound shown in Formula 3; the reaction system includes a nitrogen heterocyclic carbene catalyst, a base, an oxidant and a solvent.

[0009] Preferably, the base is selected from at least one of N-diisopropylethylamine, dicyclohexylcarbodiimide, tetramethylethylenediamine, 4-dimethylaminopyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium carbonate, potassium phosphate, or cesium carbonate.

[0010] Preferably, the solvent is selected from at least one of toluene, tetrahydrofuran, acetone, ethyl acetate, dichloromethane, dimethyl sulfoxide, or N,N-dimethylformamide.

[0011] Preferably, the oxidant is selected from at least one of 3,3,5,5-tetra-tert-butylbiphenylquinone, 3,3'-di-tert-butyl-5,5'-dimethyldiphenylquinone, 3,3',5,5'-tetrachlorobiphenylquinone, 2,3-dichloro-5,6-dicyanobiphenylquinone, manganese dioxide, or potassium permanganate.

[0012] Preferably, the nitrogen heterocyclic carbene catalyst (NHC catalyst) is selected from at least one of the compounds shown in the following structural formulas: .

[0013] Preferably, the molar ratio of the compound shown in Formula 1 to the compound shown in Formula 2 is 1:(1-3).

[0014] Preferably, the molar ratio of the compound shown in Formula 1 to the nitrogen heterocyclic carbene catalyst is 1:(0.05-0.2).

[0015] Preferably, the molar ratio of the compound shown in Formula 1 to the oxidant is 1:(1-3).

[0016] Preferably, the molar ratio of the compound shown in Formula 1 to the base is 1:(1-3).

[0017] As an embodiment of the present invention, the preparation method of the C-6 axial chiral 2-pyranone compound includes the following steps: using the compound of formula 1 and the compound of formula 2 as starting materials, the reaction is carried out in a solvent under the action of a nitrogen heterocyclic carbene catalyst, a base and an oxidant, and the reaction is stirred until the reaction is completed. The reaction product is concentrated and purified to obtain the C-6 axial chiral 2-pyranone compound as shown in formula 3.

[0018] Preferably, the reaction is carried out under nitrogen or argon atmosphere, at a temperature of 0-25°C, for a time of 8-12 hours.

[0019] Preferably, the purification process is performed using silica gel column chromatography, with the eluent being a mixture of petroleum ether and ethyl acetate.

[0020] Preferably, the volume ratio of petroleum ether to ethyl acetate is 2-20:1.

[0021] Thirdly, the present invention provides the application of the above-mentioned C-6 axial chiral 2-pyranone compounds as catalysts for asymmetric catalytic reactions.

[0022] Compared with the prior art, the present invention has the following beneficial effects: 1. This invention provides a method for constructing C-6 axial chiral biaryl 2-pyranone compounds by asymmetric cyclization using a small molecule catalyst NHC. Compared with metal catalysts, the use of NHC catalysts significantly reduces the cost of catalysts by more than 70%, and completely solves the problem of metal residue, making it environmentally friendly. Moreover, the reaction can be carried out efficiently at room temperature (0-25℃) and under conventional gas protection, which is simple to operate and has low energy consumption, providing convenient conditions for industrial-scale production. At the same time, this method has good stereoselectivity and chemoselectivity, and the enantiomeric excess value (ee) of the product can reach up to 78%.

[0023] 2. The C-6 axial chiral biaryl 2-pyranone compounds synthesized in this invention can be directly used as highly efficient catalysts in asymmetric catalytic reactions, exhibiting excellent catalytic performance (ee value > 40%), and have broad application value. Detailed Implementation

[0024] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the specific embodiments will be briefly introduced below. Obviously, the embodiments described below are some embodiments of the present invention. For those skilled in the art, other embodiments can be obtained based on these embodiments without creative effort.

[0025] Where specific experimental steps or conditions are not specified in the embodiments, they can be performed according to the conventional experimental steps or conditions described in the literature in this field. All raw materials or instruments used are commercially available conventional products, including but not limited to those used in the embodiments of this application.

[0026] Example 1 This embodiment provides a method for preparing C-6 axial chiral 2-pyranone compounds, the reaction formula of which is: ; The preparation process includes the following steps: Add a magnetic stir bar to a dry 10 mL round-bottom flask, and add compound 1 (1 equivalent, 0.5 mmol), compound 2 (1.5 equivalent, 0.75 mmol), NHC catalyst azolium-a (10%, 0.05 mmol), oxidant 3,3,5,5-tetra-tert-butylbiphenylquinone (2 equivalent, 1 mmol), and organic strong base 1,8-diazabicyclo[5.4.0]undec-7-ene (2 equivalent, 1 mmol). Seal the flask with a flap stopper, purge with nitrogen three times using a double-row tube, and add ultra-dry tetrahydrofuran (5 mL), shaking thoroughly to dissolve the raw materials. The flask was placed in a low-temperature reactor and stirred continuously at 0°C for 8 hours. After the raw material was consumed, the organic phase was concentrated by vacuum and rotary evaporated to obtain the crude product. The crude product was then separated and purified by column chromatography (petroleum ether: ethyl acetate volume ratio = 10:1) to obtain the target product, C-6 axial chiral biaryl 2-pyranone compound 3, with a yield of 56%.

[0027] The ee value was determined to be 78% using high-performance liquid chromatography (HPLC). The products were separated using an IA chiral column with a hexane:isopropanol eluent ratio of 70:30 (v / v), a flow rate of 1.0 mL / min, and a wavelength of 254 nm. Compound 3 was characterized by melting point analysis, polarimetry, nuclear magnetic resonance (NMR), high-resolution mass spectrometry (HRMS), and HPLC. The racemic reference chromatogram required for chiral HPLC was determined by analyzing the racemic product obtained from the non-chiral nitrogen heterocyclic carbene-catalyzed reaction.

[0028] 5-[4-(diphenylphosphino)phenyl]-6-[2-methoxy-7-(3-methoxyphenyl)naphth-1-yl]-4-phenyl-2H-pyran-2-one: Melting point: 132.1-133.4℃; 1 HNMR (500MHz, Chloroform- d ) d 7.87(d, J =9.1Hz, 1H), 7.82(d,J =8.5Hz, 1H), 7.78(s, 1H), 7.71(d, J =8.2Hz,2H),7.59(dd, J =8.5, 1.6 Hz, 1H), 7.41(t, J =7.9Hz,2H),7.32–7.28(m,2H),7.24(t, J =8.1Hz,4H),7.18–7.16(m,1H),7.09(d, J =7.3Hz,2H),7.07(d, J =9.1Hz,1H),6.96–6.93(m,3H),6.51(s,1H),3.89(s,3H),3.73(s,3H); 13 CNMR (126MHz, CDCl3) d 162.09,160.03,157.24,157.18,155.25,146.63,142.62,141.83,140.82,136.14,132.77,132.47,131.00,130.01,129.39,128.92,128.51,128.48,127.62,124.31,122.47,121.51,120.51,120.17,115.00,114.26,113.54,113.09,112.20,56.02,55.41. HRMS(ESI,m / z):C 47 H 35 O5P[M+Na] + 733.2174, found 733.2174; Specific curl: [α] 25 D =-188.5( c =1.0, CHCl3); Enantiomer excess (ee): 95% (HPLC conditions: Chiralcel IA column, n-hexane / isopropanol = 70:30, flow rate = 1.0 mL / min, wavelength = 254 nm, secondary isomer retention time) t R =13.887, retention time of the main isomer t R =14.603).

[0029] Example 2 This embodiment provides a method for preparing C-6 axial chiral 2-pyranone compounds. The reaction formula is the same as in Example 1, and the preparation process includes the following steps: A magnetic stir bar was added to a dry 10 mL round-bottom flask. Compound 1 (1 equivalent, 0.5 mmol), compound 2 (2 equivalent, 1 mmol), NHC catalyst azolium-b (20%, 0.1 mmol), oxidant 2,3-dichloro-5,6-dicyanbiphenylquinone (1 equivalent, 0.5 mmol), and inorganic strong base cesium carbonate (2 equivalent, 1 mmol) were added to the flask. The flask was sealed with a flap stopper, and argon gas was purged three times using a double-row tube. Ultra-dry toluene (5 mL) was added, and the mixture was thoroughly shaken to dissolve the raw materials. The flask was placed in a cryogenic reactor and stirred continuously at 0 °C for 8 hours. After the raw materials were consumed, the organic phase was concentrated under vacuum and rotary evaporated to obtain the crude product. The crude product was then separated and purified by column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain the target product, a C-6 axial chiral biaryl 2-pyranone compound 3, in 32% yield.

[0030] The ee value was determined to be 45% using high performance liquid chromatography (HPLC). The product was separated using an IA chiral column with hexane:isopropanol as the eluent in a ratio of 70:30, a flow rate of 1.0 mL / min, and a wavelength of 254 nm.

[0031] Example 3 This embodiment provides a method for preparing C-6 axial chiral 2-pyranone compounds. The reaction formula is the same as in Example 1, and the preparation process includes the following steps: A magnetic stir bar was added to a dry 10 mL round-bottom flask. Compound 1 (1 equivalent, 0.5 mmol), compound 2 (1.5 equivalent, 0.75 mmol), NHC catalyst azolium-f (10%, 0.05 mmol), oxidant 3,3'-di-tert-butyl-5,5'-dimethyldiphenol benzoquinone (2.5 equivalent, 1.25 mmol), and inorganic weak base sodium carbonate (2 equivalent, 1 mmol) were added to the flask. The flask was sealed with a flip-top stopper, and nitrogen was purged three times using a double-row tube. 5 mL of ultradry dimethyl sulfoxide was added and the mixture was thoroughly shaken to dissolve the raw materials. The flask was placed in a cryogenic reactor and stirred continuously at room temperature for 8 hours. After the raw materials were consumed, the organic phase was concentrated by vacuum and rotary evaporated to obtain the crude product. The crude product was then separated and purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain the target product, C-6 axial chiral biaryl 2-pyranone compound 3, in 44% yield.

[0032] The ee value was determined to be 62% using high performance liquid chromatography (HPLC). The product was separated using an IA chiral column with hexane:isopropanol as the eluent in a ratio of 70:30, a flow rate of 1.0 mL / min, and a wavelength of 254 nm.

[0033] Example 4 This embodiment provides a method for preparing C-6 axial chiral 2-pyranone compounds. The reaction formula is the same as in Example 1, and the preparation process includes the following steps: A magnetic stir bar was added to a dry 10 mL round-bottom flask. Compound 1 (1 equivalent, 0.5 mmol), compound 2 (3 equivalent, 1.5 mmol), NHC catalyst azolium-n (10%, 0.05 mmol), oxidant manganese dioxide (2.5 equivalent, 1.25 mmol), and organic weak base triethylamine (2 equivalent, 1 mmol) were added to the flask. The flask was sealed with a flip-top stopper, and nitrogen gas was purged three times using a double-row tube. Ultra-dry dimethyl sulfoxide (5 mL) was added, and the mixture was thoroughly shaken to dissolve the reactants. The flask was placed in a cryogenic reactor and stirred continuously at room temperature for 8 hours. After the reactants were consumed using thin-layer chromatography, the organic phase was concentrated under vacuum and rotary evaporated to obtain the crude product. The crude product was then purified by column chromatography (petroleum ether: ethyl acetate = 15:1) to obtain the target product, a C-6 axial chiral biaryl 2-pyranone compound 3, in 25% yield.

[0034] The ee value was determined to be 70% using high performance liquid chromatography (HPLC). The product was separated using an IA chiral column with hexane:isopropanol as the eluent in a ratio of 70:30, a flow rate of 1.0 mL / min, and a wavelength of 254 nm.

[0035] Example 5 This embodiment provides a method for preparing C-6 axial chiral 2-pyranone compounds. The reaction formula is the same as in Example 1, and the preparation process includes the following steps: A magnetic stir bar was added to a dry 10 mL round-bottom flask. Compound 1 (1 equivalent, 0.5 mmol), compound 2 (3 equivalent, 1.5 mmol), NHC catalysts azolium-i and azolium-l (10%, 0.05 mmol), oxidant 2,3-dichloro-5,6-dicyanbiphenylquinone (3 equivalent, 1.5 mmol), and organic weak base 4-dimethylaminopyridine (1 equivalent, 0.5 mmol) were added to the flask. The flask was sealed with a flap stopper, and nitrogen was purged three times using a double-row tube. Ultra-dry N,N-dimethylformamide and acetone (5 mL) were added, and the mixture was thoroughly shaken to dissolve the raw materials. The flask was placed in a cryogenic reactor and stirred continuously at room temperature for 8 hours. After the raw materials were consumed, the organic phase was concentrated under vacuum and rotary evaporated to obtain the crude product. The crude product was then separated and purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the target product, a C-6 axial chiral biaryl 2-pyranone compound 3, in 75% yield.

[0036] The ee value was determined to be 76% using high performance liquid chromatography (HPLC). The product was separated using an IA chiral column with hexane:isopropanol as the eluent in a ratio of 70:30, a flow rate of 1.0 mL / min, and a wavelength of 254 nm.

[0037] Application examples Compound 3, prepared in Example 1 above, was used as a catalyst to carry out the following asymmetric catalytic reaction.

[0038] Reaction 1: ; Reaction 2: ; Reaction 3: ; Reaction 4: .

[0039] It can be seen that all the above reactions have good chemoselectivity, and the enantiomeric excess values ​​all exceed 40%, proving that they have good stereoselectivity. This compound can be used as an asymmetric catalyst and has good application value.

[0040] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. A C-6 axial chiral 2-pyranone compound, characterized in that, The compound has the structural formula shown in Formula 3 below: 3。 2. A method for preparing the C-6 axial chiral 2-pyranone compound according to claim 1, characterized in that, The reaction formula involved in the preparation method is: The preparation method includes the following steps: The compound shown in Formula 1 was reacted with the compound shown in Formula 2 to obtain the C-6 axial chiral 2-pyranone compound shown in Formula 3. The reaction system includes a nitrogen heterocyclic carbene catalyst, a base, an oxidant, and a solvent.

3. The method for preparing C-6 axial chiral 2-pyranone compounds as described in claim 2, characterized in that, The base is selected from at least one of N-diisopropylethylamine, dicyclohexylcarbodiimide, tetramethylethylenediamine, 4-dimethylaminopyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium carbonate, potassium phosphate, and cesium carbonate.

4. The method for preparing C-6 axial chiral 2-pyranone compounds as described in claim 2, characterized in that, The solvent is selected from at least one of toluene, tetrahydrofuran, acetone, ethyl acetate, dichloromethane, dimethyl sulfoxide, and N,N-dimethylformamide.

5. The method for preparing C-6 axial chiral 2-pyranone compounds as described in claim 2, characterized in that, The oxidant is selected from at least one of 3,3,5,5-tetra-tert-butylbiphenylquinone, 3,3'-di-tert-butyl-5,5'-dimethyldiphenylquinone, 3,3',5,5'-tetrachlorobiphenylquinone, 2,3-dichloro-5,6-dicyanobiphenylquinone, manganese dioxide, and potassium permanganate.

6. The method for preparing C-6 axial chiral 2-pyranone compounds as described in claim 2, characterized in that, The nitrogen-heterocyclic carbene catalyst is selected from at least one of the compounds shown in the following structural formulas: 。 7. The method for preparing C-6 axial chiral 2-pyranone compounds as described in claim 2, characterized in that, The molar ratio of the compound shown in Formula 1 to the compound shown in Formula 2 is 1:(1-3).

8. The method for preparing C-6 axial chiral 2-pyranone compounds as described in claim 2, characterized in that, The molar ratio of the compound shown in Formula 1 to the nitrogen heterocyclic carbene catalyst is 1:(0.05-0.2).

9. The method for preparing C-6 axial chiral 2-pyranone compounds as described in claim 2, characterized in that, The molar ratio of the compound shown in Formula 1 to the oxidant is 1:(1-3); and / or, the molar ratio of the compound shown in Formula 1 to the base is 1:(1-3).

10. The application of the C-6 axial chiral 2-pyranone compound of claim 1 as a catalyst for asymmetric catalytic reactions.

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