A method for synthesizing chiral flavanol compounds by dynamic kinetic resolution

Abstract

The present invention discloses a method for asymmetric transfer hydrogenation synthesis of chiral flavanol compounds by dynamic kinetic resolution, and the catalyst used is a chiral ruthenium diamine complex. Through this method, asymmetric transfer hydrogenation of flavanone derivatives can be realized, and optically pure flavanol compounds containing three consecutive chiral centers can be obtained in high yield (the enantiomeric excess can reach 99%, and the diastereomeric ratio can reach >20:1). The present invention has high enantioselectivity and diastereoselectivity, is simple and easy to operate, the catalyst is commercially available, the reaction conditions are mild, the energy consumption is low, it is environmentally friendly and has good yield, and gram-scale experiments can be realized without loss of activity and enantioselectivity.

Description

Technical Field

[0001] The present invention belongs to the field of asymmetric catalytic synthesis, and relates to a method for realizing the dynamic kinetic resolution of flavan derivatives and providing a method for synthesizing flavanol derivatives containing three consecutive chiral centers through an alkali-promoted retro-oxa-Michael addition reaction and a ruthenium-catalyzed asymmetric transfer hydrogenation reaction. Technical Background

[0002] In recent years, the preparation of enantiomerically enriched compounds with multiple stereocenters from relatively simple starting materials has been an ideal goal for chemists. Kinetic resolution has become one of the important solutions for chiral compounds, including classical kinetic resolution (KR) and dynamic kinetic resolution (DKR). Due to the maximum theoretical yield of 100%, dynamic kinetic resolution has attracted continuous research attention and has become an effective means for synthesizing complex chiral molecules, which can start from easily available racemic starting materials and be converted into compounds containing multiple stereocenters in a single transformation. Currently, the dynamic kinetic resolution reduction of α-substituted ketones undergoes a rapid racemization process of the enolized chiral center. However, examples of the dynamic kinetic resolution reduction of β-substituted ketones are relatively rare. Chiral flavanol derivatives constitute a large class of important molecules with various useful biological activities, such as antiviral, antibacterial, and antifungal effects. Despite significant progress in the synthesis of chiral flavanols, the synthesis of functionalized flavanols with three chiral centers remains a challenge in organic synthetic chemistry. Summary of the Invention

[0003] The object of the present invention is to provide a method for synthesizing chiral flavanol derivatives through dynamic kinetic resolution, realizing the dynamic kinetic resolution of 2,3-disubstituted flavone compounds through a retro-oxa-Michael addition process combined with an asymmetric transfer hydrogenation reaction, and constructing flavanol derivatives containing three consecutive chiral centers with high optical purity, thereby constructing the basic skeletons of chiral flavanol natural products with biological activities such as Sideroxylonal B and Cordigol.

[0004] The technical solution of the present invention is as follows:

[0005] The present invention provides a method for synthesizing chiral flavanol derivatives through dynamic kinetic resolution. The dynamic kinetic resolution of 2,3-disubstituted flavone compounds is achieved through an inverse oxa-Michael addition process combined with an asymmetric transfer hydrogenation reaction, and chiral flavanol derivatives containing three consecutive chiral centers with high optical purity are constructed. The method uses a ruthenium chiral diamine complex as a catalyst, a 2,3-disubstituted flavone compound as a substrate, and a formic acid-triethylamine azeotrope as a hydrogen source. Under alkaline conditions, rapid racemization is achieved through the inverse Michael addition pathway, and chiral flavanol compounds containing three consecutive chiral centers are constructed in a dynamic kinetic resolution manner. The reaction formula of the method is as follows:

[0006]

[0007] In the formula:

[0008] R is one of methyl, ethyl, cyclohexyl, isopropyl, benzyl, and allyl;

[0009] R ’ is one of phenyl, naphthyl, cyclohexyl, isopropyl, or a phenyl with substituents. The substituents on the benzene ring of the phenyl are one of methyl, methoxy, fluorine atom, chlorine atom, and bromine atom;

[0010] Ar is a benzene ring or a benzene ring with substituents. The substituents are one of methyl, methoxy, and bromine atom;

[0011] The molar ratio of the formic acid / triethylamine azeotrope is 5:2.

[0012] The catalyst is a metal ruthenium diamine chiral complex.

[0013] Based on the above technical solutions, preferably, the reaction solvent is an organic solvent, which is one of ethyl acetate, isopropanol, dichloromethane, toluene, tetrahydrofuran, and N,N-dimethylformamide.

[0014] Based on the above technical solutions, preferably, the reaction temperature is 30-50 °C, preferably 40 °C; the reaction time is 17-60 hours.

[0015] Based on the above technical solutions, preferably, the molar ratio of the formic acid / triethylamine azeotrope and the 2,3-disubstituted flavanone compound in the reaction is 5:1-30:1, and the molar ratio of the metal ruthenium diamine chiral catalyst and the 2,3-disubstituted flavanone compound in the reaction is 0.01:1-0.05:1.

[0016] Based on the above technical solutions, the preferred metal ruthenium diamine chiral catalysts are (R,R)-3a, (R,R)-3b, (R,R)-3c, and (R,R)-3d.

[0017] Based on the above technical solutions, preferably, the specific reaction steps of the method are as follows:

[0018] Under nitrogen protection, add 2,3-disubstituted flavanone compounds, triethylamine formate azeotrope, ruthenium diamine catalyst and organic solvent into a Schlenk tube. After stirring and reacting at 40 °C for 17 - 60 h, evaporate the solvent to dryness, and separate by column chromatography to obtain pure chiral flavanol compounds.

[0019] Based on the above technical solutions, preferably, R is methyl, R’ is phenyl, Ar is a benzene ring, the catalyst is a ruthenium diamine chiral catalyst (R,R)-3, the organic solvent is N,N-dimethylformamide, the temperature is 40 °C, and the reaction time is 24 h. The reaction result is the best.

[0020] Through this method, the asymmetric transfer hydrogenation of flavanone derivatives can be realized, and optically pure flavanol compounds containing three consecutive chiral centers can be obtained in high yield (the enantiomeric excess can reach 99%, and the diastereomeric ratio can reach >20:1). The present invention has high enantioselectivity and diastereoselectivity, is easy to operate, the catalyst is commercially available, the reaction conditions are mild, the energy consumption is low, it is environmentally friendly and has good yield, and gram-scale experiments can be realized without loss of activity and enantioselectivity. It provides a new idea for the asymmetric synthesis of chiral flavanol drug molecules such as Sideroxylonal B and Cordigol.

[0021] Beneficial effects

[0022] 1. The raw materials are simple and easy to obtain, and the operation is simple.

[0023] 2. The reaction activity is high, the raw materials are completely converted, the separation is convenient, and high-purity products can be obtained.

[0024] 3. The stereoselectivity is good, and a single diastereoisomer can be obtained with high enantioselectivity.

[0025] 4. The reaction conditions are mild, and it is environmentally friendly and green.

[0026] 5. Gram-scale experiments can be realized without loss of activity and enantioselectivity. Description of the drawings

[0027] Figure 1 It is the single crystal structure diagram of 2a. Specific embodiments

[0028] The present invention will be described in detail below through examples, but the present invention is not limited to the following examples.

[0029] In the following examples, the references for the synthesis of 2,3-disubstituted flavonoids are: (a) Li, G.; Zhuang, C.; Wang, D.; Zhang, W.; Jia, R.; Sun, F.; Zhang, Y.; Du, Y. Construction of Trisubstituted Chromone Skeletons Carrying Electron-withdrawing Groups via PhIO-mediated Dehydrogenation and Its Application to the Synthesis of Frutinone A. Beilstein J. Org. Chem. 2019, 15, 2958 - 2965. (b) Zhu, Z.-H.; Ding, Y.-X.; Wu, B.; Zhou, Y.-G. Chem. Sci. 2020, 11, 10220 - 10224.

[0030] The catalysts used in the examples were all purchased from TCI.

[0031] Examples 1 - 13

[0032] Condition optimization: changing the type of organic solvent, the type and content of chiral catalyst, and the amount of formic acid / triethylamine

[0033] Under nitrogen protection, add racemic flavonoid 1a (0.2 mmol), formic acid / triethylamine (5:2) azeotrope (y eq.), chiral ruthenium diamine catalyst (x mol%), and organic solvent (2.0 mL) to a Schlenk tube. After stirring the reaction completely at 40 °C for 24 h, evaporate the solvent under reduced pressure, and separate by column chromatography to obtain pure chiral flavanol derivatives.

[0034] The type of organic solvent, the type and content of chiral catalyst, and the amount of formic acid / triethylamine, the specific results are shown in Table 1; ee is enantioselectivity, and dr is diastereoselectivity.

[0035]

[0036] Table 1. Optimization of Transfer Hydrogenation Conditions for 2,3-Disubstituted Flavonoids

[0037]

[0038] Examples 14 - 33

[0039] Dynamic kinetic resolution of 2,3-disubstituted flavonoids.

[0040] Under nitrogen protection, the racemic flavonoid compound 1 (0.2 mmol), formic acid / triethylamine (5:2) azeotrope (5 eq.), chiral ruthenium diamine catalyst (2 mol%), and organic solvent (2.0 mL) were added to a Schlenk tube. After stirring the reaction completely at 40 °C (17 - 48 h), the solvent was evaporated, and the pure chiral flavanol derivatives were obtained by column chromatography separation.

[0041] Twenty examples of different flavanol derivatives 3 were obtained by changing the type of flavonoid compound 1 in the reaction. The specific types changed are as follows:

[0042]

[0043] Among them, the structure of 2a was confirmed by single crystal, and its single crystal structure Figure 1 is shown.

[0044]

[0045]

[0046]

[0047]

[0048]

[0049]

Claims

1. A method for synthesizing chiral flavanol derivatives by dynamic kinetic resolution, characterized in that, the method uses a chiral diazine complex of ruthenium metal as a catalyst, a 2,3-disubstituted flavanone compound as a substrate, and a triethylamine formate azeotrope as a hydrogen source to synthesize a flavanol derivative with three consecutive chiral centers; The reaction formula is as follows: In the formula: R is one of methyl, ethyl, cyclohexyl, isopropyl, benzyl, allyl; R' is one of phenyl, naphthyl, cyclohexyl, isopropyl or a phenyl with substituents, and the substituent on the benzene ring of the phenyl is one of methyl, methoxy, fluorine atom, chlorine atom, bromine atom; Ar is a benzene ring or a benzene ring with substituents, and the substituents are one of methyl, methoxy, bromine atom; The catalyst is a chiral diazine complex of ruthenium metal, and its structural formula is as follows: The reaction solvent is an organic solvent.

2. The method according to claim 1, characterized in that: The organic solvent is one of ethyl acetate, isopropanol, dichloromethane, toluene, tetrahydrofuran, N,N-dimethylformamide; reaction temperature: 30-50 °C; reaction time: 17-60 hours.

3. The method according to claim 1, characterized in that: In the reaction, the molar ratio of the triethylamine formate azeotrope to the 2,3-disubstituted flavanone compound is 5:1-30:1, and the molar ratio of the chiral diazine complex catalyst of ruthenium metal to the 2,3-disubstituted flavanone compound in the reaction is 0.01:1-0.05:

1.

4. The method according to claim 1 or 2, characterized in that, The specific reaction steps of the method are as follows: Under nitrogen protection, add a 2,3-disubstituted flavanone compound, a triethylamine formate azeotrope, a chiral diazine complex catalyst of ruthenium metal and an organic solvent to a Schlenk tube, stir and react at 30-50 °C for 17-60 h, then evaporate the solvent to dryness, and separate by column chromatography to obtain a pure chiral flavanol derivative.

5. The method according to claim 1, characterized in that: R is methyl, R' is phenyl, Ar is a benzene ring, and the catalyst is a chiral diazine complex catalyst (R,R)-3a of ruthenium metal, the organic solvent is N,N-dimethylformamide, the temperature is 40 °C, and the reaction time is 24 h.

6. The method according to claim 1, characterized in that: The molar ratio of the triethylamine formate azeotrope is 5:2.

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