Method for synthesizing chiral phthalide derivative through dynamic kinetic resolution

Abstract

The invention discloses a method for synthesizing chiral phthalide derivatives through dynamic kinetic resolution. A catalyst used in the method is a chiral diphosphine complex of palladium. According to the method, asymmetric allylation of the phthalide compound can be realized, and the high-optical-purity phthalide derivative containing continuous tertiary carbon and quaternary carbon three-dimensional centers can be obtained with excellent yield (the enantiomer excess can reach 99%, and the diastereomer proportion is up to gt; 20: 1). The method has the advantages of excellent chemical selectivity, enantioselectivity and diastereoselectivity, simple and easy operation, commercially available catalyst, mild reaction conditions, low energy consumption, environmental friendliness and high yield.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of asymmetric catalytic synthesis, and relates to a method for realizing dynamic kinetic resolution of phthalide compounds and providing a method for synthesizing phthalide derivatives containing continuous tertiary carbon and quaternary carbon stereogenic centers by means of reverse oxa-Michael addition reaction and palladium-catalyzed asymmetric allylic alkylation reaction. TECHNICAL BACKGROUND

[0002] Small molecule natural products have been one of the pillars of organic chemistry research since their discovery, and have played a crucial role in the discovery of new drugs. More than 60% of the marketed drugs are derived from natural products, either based on them or inspired by them. Among them, a new class of compounds is isobenzofuranones, commonly known as phthalides. Phthalides are widely found in plants (such as Angelica and Chuanxiong), fungi, etc., and exhibit biological activity, and are important intermediates in organic synthesis. Therefore, how to simply and efficiently synthesize phthalides, especially chiral phthalides, has attracted more and more attention from organic chemists. At present, more research is on the catalytic asymmetric construction of isobenzofuranone skeleton to synthesize chiral phthalides, mainly three kinds of catalytic systems: 1) metal catalysis; 2) organic catalysis; 3) biocatalysis. (Reference one: (a) Tanaka, K.; Nishida, G.; Wada, A.; Noguchi, K. Angew. Chem. Int. Ed. 2004, 43, 6510-6512. (b) Phan, D. H. T.; Kim, B.; Dong, V. M. J. Am. Chem. Soc. 2009, 131, 15608-15609. (c) Yang, J.; Yoshikai, N. J. Am. Chem. Soc. 2014, 136, 16748-16751. (d) Cabrera, J. M.; Tauber, J.; Krische, M. Angew. Chem. Int. Ed. 2018, 57, 1390-1393. (e) Youn, S. W.; Song, H. S.; Park, J. H. Org. Lett. 2014, 16, 1028-1031. (f) Zhang, H.; Zhang, S.; Liu, L.; Luo, G.; Duan, W.; Wang, W. J. Org. Chem. 2010, 75, 368-374. (g) Mangas-Sánchez, J.; Busto, E.; Gotor-Fernández, V.; Gotor, V. Org. Lett. 2012, 14, 1444-1447.)However, examples of enantioselective construction of phthalide compounds based on the presence of isobenzofuranone skeleton are relatively rare (Reference two: (a) Cheng, T.; Ye, Q.; Zhao, Q.; Liu, G. Org. Lett. 2015, 17, 4972-4975. (b) Zhong, F.; Luo, J.; Chen, G.-Y.; Dou, X.; Lu, Y. J. Am. Chem. Soc. 2012, 134, 10222-10227. (c) Pan, Y.-L.; Zheng, H.-L.; Wang, J.; Yang, C.; Li, X.; Cheng, J.-P. ACS Catal. 2020, 10, 8069-8076.).

[0003] It is well known that dynamic kinetic resolution is a powerful method in asymmetric synthesis. Therefore, it is an efficient strategy to construct enantiopure phthalide compounds through dynamic kinetic resolution. Liu group constructed a series of phthalide derivatives with high ee value through dynamic kinetic resolution-asymmetric transfer hydrogenation, but only moderate diastereoselectivity was achieved (Reference two: (a)). This report realized dynamic kinetic resolution based on the racemization process of retro-oxa-Michael addition. We have developed application examples based on the racemization process of retro-oxa-Michael addition (Reference three: (a) Liu, L.-X.; Huang, W.-J.; Xie, Q.-X.; Wu, B.; Yu, C.-B.; Zhou, Y.-G. ACS Catal. 2021, 11, 12859-12863. (b) Xie, Q.-X.; Liu, L.-X.; Zhu, Z.-H.; Yu, C.-B.; Zhou, Y.-G. J. Org. Chem. 2022, 87, 7521-7530. (c) Liu, L.-X.; Huang, W.-J.; Yu, C.-B.; Zhou, Y.-G. Org. Biomol. Chem., 2023, 21, 8516-8520.). Therefore, we envisaged that the retro-Michael addition process would be combined with palladium-catalyzed asymmetric allylic alkylation to achieve dynamic kinetic resolution of 3-substituted phthalide compounds and synthesize phthalide derivatives containing multiple chiral centers (including one quaternary carbon chiral center) with high enantiomeric and diastereomeric selectivity. SUMMARY

[0004] The purpose of the present application is to provide a method for synthesizing chiral phthalide derivatives through dynamic kinetic resolution, to achieve dynamic kinetic resolution of 3-substituted phthalide compounds through the combination of retro-oxa-Michael addition process and asymmetric allylic alkylation reaction, and to construct phthalide derivatives containing multiple chiral centers (including one quaternary carbon chiral center) with high optical purity.

[0005] The technical solution of the present invention is as follows:

[0006] This invention provides a method for synthesizing chiral phthalide derivatives via dynamic kinetic resolution. It is a dynamic kinetic resolution process for 3-substituted phthalide compounds and offers a novel route for synthesizing phthalide derivatives with high optical purity containing multiple chiral centers (including one quaternary carbon chiral center). The method uses a palladium chiral bisphosphine complex as a catalyst, a base as a promoter (or without a base promoter), and 3-substituted phthalide compounds and allyl carbonate compounds as substrates. Through a dynamic kinetic resolution process, it constructs phthalide derivatives with high optical purity containing multiple chiral centers (including one quaternary carbon chiral center). The reaction formula of the method is as follows:

[0007]

[0008] In the formula:

[0009] R 1 It can be methyl, ethyl, n-butyl, or phenyl;

[0010] R 2 It can be methyl, ethyl, phenyl, methoxy, ethoxy, tert-butoxy, benzyloxy, or dimethylamino;

[0011] Ar is a benzene ring, a naphthalene ring, or a benzene ring containing a substituent, wherein the substituent is one of methyl, fluorine, chlorine, bromine, or methoxy.

[0012] R 3 It is hydrogen, methyl, benzyl, phenyl or a phenyl containing a substituent, wherein the substituent on the benzene ring is one of methyl, methoxy, fluorine, chlorine or bromine;

[0013] R 4 It can be hydrogen or phenyl;

[0014] The chiral bisphosphine complex of palladium is a complex formed by a palladium precursor and a chiral bisphosphine ligand.

[0015] Based on the above technical solution, preferably, the method further includes an additive, wherein the additive is a molecular sieve, comprising... or The mass ratio of the molecular sieve to the 3-substituted phthalide compound in the reaction was 250 mg: 1 mmol–500 mg: 1 mmol.

[0016] Based on the above technical solution, preferably, the reaction solvent is an organic solvent, and the organic solvent is one of dichloromethane (DCM), ethyl acetate, tetrahydrofuran (THF), toluene, trifluorotoluene (PhCF3), and acetonitrile.

[0017] Preferably, the reaction temperature is -40-30°C, and the reaction time is 1-100 hours, preferably 1-80 hours.

[0018] Preferably, the molar ratio of the allyl carbonate compound to the 3-substituted phthalide compound in the reaction is 1.2:1-1.5:1, the molar ratio of the base to the 3-substituted phthalide compound in the reaction is 0:1-1.0:1, the molar ratio of the amount of the metal monomer palladium used to the 3-substituted phthalide compound in the reaction is 0.05:1-0.10:1, the molar ratio of the amount of the chiral bisphosphine ligand used to the 3-substituted phthalide compound in the reaction is 0.06:1-0.12:1, and the molar ratio of the mass of the molecular sieve to the 3-substituted phthalide compound in the reaction is 250mg:1mmol-500mg:1mmol.

[0019] Preferably, the amount of the organic solvent is 1 milliliter per 0.2 millimoles of the 3-substituted phthalide compound, and the organic solvent is added twice, once in the preparation of the catalyst and once in the synthesis of the product.

[0020] Preferably, the metal palladium precursor is allyl palladium (II) chloride dimer ([Pd(C3H5)Cl]2), tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), bis(dibenzylideneacetone)palladium (Pd(dba)2), palladium acetate (Pd(OAc)2), or tetrakis(triphenylphosphine)palladium (Pd(PPh3)4).

[0021] Preferably, the chiral bisphosphine ligand is (R,R,R)-Ph-SKP, (S,S,S)-Ph-SKP, (R,R,R)-Tol-SKP, (S,S,S)-Tol-SKP, (R,R,R)-Xyl-SKP, (S,S,S)-Xyl-SKP, (R,R)-DACH-Naphthyl Trost Ligand, (R)-MONOPhos, (R)-PHANEPHOS, or (S)-SDP.

[0022] Preferably, the base used in the reaction is 1,5-diazabicyclo[5.4.0]-5-undecene (DBU), triethylamine (Et3N), or no base is used.

[0023] Preferably, the preparation method of the catalyst is that the metal precursor of palladium and the chiral bisphosphine ligand are dissolved in an organic solvent under nitrogen protection, and stirred at room temperature for 30-60 minutes.

[0024] Based on the above technical scheme, preferably, the specific reaction steps of the method are:

[0025] Under nitrogen protection, a metal palladium precursor and a chiral bisphosphine ligand are added to a Schlenk tube, then an organic solvent is added, after stirring at room temperature for 30-60 min, 3-substituted phthalide compound, base (or no base), additive, allyl carbonate compound and organic solvent (twice the same kind of organic solvent) are added under nitrogen, after stirring at-40-30°C for 1-100 h, the solvent is extracted, and column chromatography is used to separate to obtain pure chiral phthalide derivative;

[0026] For example: under nitrogen protection, a metal palladium precursor (0.0025 mmol) and a chiral bisphosphine ligand (0.006 mmol) are added to a Schlenk tube, then an organic solvent (0.5 mL) is added, after stirring at room temperature for 30 min, 3-substituted phthalide compound (0.2 mmol), base (0.2 mmol or 0 mmol), additive (50 mg), allyl carbonate compound (0.3 mmol) and organic solvent (0.5 mL) are added under nitrogen, after stirring at-40-30°C for 1-100 h, the solvent is extracted, and column chromatography is used to separate to obtain pure chiral phthalide derivative

[0027] Based on the above technical scheme, preferably, R 1 is methyl, R 2 is methoxy, R 3 is benzyl, R 4 is hydrogen, the catalyst is a complex formed by tris(dibenzylideneacetone)dipalladium (Pd2(dba)3) and (R,R,R)-Ph-SKP, the organic solvent is toluene, the temperature is-40°C, no base is added, and the additive is molecular sieve, and the reaction time is 48 h, and the reaction result is optimal.

[0028] The method can realize asymmetric allyl alkylation of 3-substituted phthalide compound, and high-optical-purity phthalide derivative containing continuous tertiary carbon and quaternary carbon stereogenic center can be obtained in high yield (enantiomeric excess up to 99%, diastereomeric ratio up to > 20:1). The method has excellent chemical selectivity, high enantioselectivity and diastereoselectivity, is simple and practical to operate, raw materials are easy to obtain, a commercial catalyst is used, reaction conditions are mild, energy consumption is low, the environment is friendly, and the yield is good.

[0029] Advantages

[0030] 1. The raw materials are simple and easy to obtain, and the operation is simple.

[0031] 2. The reaction activity is high, the raw materials are completely converted, separation is convenient, and high-purity products can be obtained.

[0032] 3. Good stereoselectivity, high enantioselectivity and diastereoselectivity to obtain optically pure products.

[0033] 4. Mild reaction conditions, environmentally friendly and green. BRIEF DESCRIPTION OF DRAWINGS

[0034] Figure 1 The X-ray structure of compound (+)-3ra determines that the absolute configuration of (+)-3ra is (R, R). DETAILED DESCRIPTION

[0035] The present application is described in detail below by examples, but the present application is not limited to the following examples.

[0036] The synthesis of 3-substituted phthalide compounds in the following examples is described in reference Di Mola, A.; Croce, G.; More, V.; De Caprariis, P.; Filosa, R.; Massa, A. Tetrahedron 2012, 68, 6146-6151. The synthesis of allyl carbonate compounds in the following examples is described in reference Liu, L.-X.; Huang, W.-J.; Xie, Q.-X.; Wu, B.; Yu, C.-B.; Zhou, Y.-G. ACS Catal. 2021, 11, 12859-12863.

[0037] Examples 1-19

[0038] Optimization of conditions: change the type and amount of chiral ligand, the type of organic solvent, the type of base or no base, palladium precursor and temperature

[0039] Under nitrogen protection, a Schlenk tube was added with a metal palladium precursor (0.0025 mol) and a chiral bisphosphine ligand (0.0075 mmol), then an organic solvent (0.5 mL) was added, after stirring at room temperature for 30 min, 3-substituted phthalide compound 1a (0.1 mmol), base (1.0 eq.), allyl carbonate compound 2a (0.15 mmol) and organic solvent (0.5 mL) were added under nitrogen, and the reaction was stirred at T°C until completion. The solvent was removed by suction, and the pure chiral phthalide derivative was separated by column chromatography.

[0040] The type and amount of chiral ligand, the type of organic solvent, the type of base or no base, palladium precursor and temperature, and the specific results are shown in Table 1. ee is enantioselectivity, and dr is diastereoselectivity.

[0041]

[0042] Table 1. Optimization of dynamic kinetic resolution conditions for 3-substituted phthalides

[0043]

[0044]

[0045] Examples 20-48

[0046] Dynamic kinetic resolution of 3-substituted phthalides.

[0047] To a Schlenk tube was added Pd2(dba)3(0.005 mol) and chiral bisphosphine ligand L3(0.012 mmol) under nitrogen protection, then toluene (0.5 mL) was added, after stirring at room temperature for 30 min, 3-substituted phthalide 1 (0.2 mmol) was added under nitrogen, Molecular sieve (50 mg), allyl carbonate compound 2 (0.3 mmol) and toluene (0.5 mL) were stirred at -40 °C or -30 °C until the reaction was complete, then the solvent was removed by suction, and the pure chiral phthalide derivative was separated by column chromatography.

[0048] 3-Substituted phthalides were 1a, and 10 different chiral phthalide derivatives 3 were obtained by changing the substituents of allyl carbonate compounds 2 in the reaction, and the changes were as follows:

[0049]

[0050] The reaction temperature of 3aa-3ab and 3ad-3af was -40 °C, and the reaction time was 48 h; the reaction temperature of 3ac was -30 °C, and the reaction time was 72 h; the reaction temperature of 3ag-3aj was -30 °C, and the reaction time was 48 h.

[0051] Allyl carbonate compounds were 2a, and 10 different chiral phthalide derivatives 3 were obtained by changing the carbonyl substituents of 3-substituted phthalides 1 in the reaction, and the changes were as follows:

[0052]

[0053] The reaction temperature of 3ba, 3ca, 3ha, and 3ia was -40 °C, and the reaction time was 48 h; the reaction temperature of 3da was -40 °C, and the reaction time was 55 h; the reaction temperature of 3ea, 3fa, and 3ja was -30 °C, and the reaction time was 48 h; the reaction of 3ka was first reacted at -40 °C for 55 h, and then the temperature was raised to -20 °C for 40 h.

[0054] The allyl carbonate compound is 2a, and the 3-substituted phthalide compound in the reaction is changed to 1 to obtain nine different chiral phthalide derivatives 3, and the changed types are as follows:

[0055]

[0056] The reaction temperature of 3la-3na and 3sa-3ta is -40℃, and the reaction time is 48h; the reaction temperature of 3oa-3ra is -30℃, and the reaction time is 48h.

[0057]

[0058]

[0059]

[0060]

[0061]

[0062]

[0063]

[0064]

[0065]

[0066]

Claims

1. A method for the synthesis of chiral phthalide derivatives by dynamic kinetic resolution, characterized in that, The method uses a chiral diphosphine complex of palladium as a catalyst, an alkali as a promoter or without a promoter, a 3-substituted phthalide compound and an allyl carbonate compound as substrates to synthesize a chiral phthalide derivative. The reaction formula is as follows: In the formula, Ar is a benzene ring, a naphthalene ring or a benzene ring containing a substituent, and the substituent is one of a methyl group, fluorine, chlorine, bromine or a methoxy group; R 1 R is hydrogen, methyl, ethyl, n-butyl or phenyl; R 2 is methyl, ethyl, phenyl, methoxy, ethoxy, t-butoxy, benzyloxy or dimethylamino; The chiral diphosphine complex of palladium is a complex formed by a metal palladium precursor and a chiral diphosphine ligand. R 3 is hydrogen, methyl, benzyl, phenyl or substituted phenyl, the substituents on the phenyl ring being one of methyl, methoxy, fluorine, chlorine, bromine; R 4 is hydrogen or phenyl; The method further comprises an additive, and the additive is a molecular sieve, and the mass and the molar ratio of the molecular sieve to the 3-substituted phthalide compound in the reaction is 250 mg:1 mmol-500 mg:1 mmol.

2. The method of claim 1, wherein, The promoter comprises one of 1,5-diazabicyclo[5.4.0]-5-undecene and triethylamine.

3. The method of claim 1, wherein, The reaction solvent is an organic solvent, and the organic solvent is one of dichloromethane, ethyl acetate, tetrahydrofuran, toluene, trifluorotoluene and acetonitrile; the reaction temperature is -40-30 oC; and the reaction time is 1-100 hours.

4. The method of claim 1, wherein, In the reaction, the molar ratio of the allyl carbonate compound to the 3-substituted phthalide compound is 1.2:1-1.5:1, the molar ratio of the alkali to the 3-substituted phthalide compound in the reaction is 0:1-1.0:1, the molar ratio of the metal monomer palladium to the 3-substituted phthalide compound in the reaction is 0.05:1-0.10:1, and the molar ratio of the chiral diphosphine ligand to the 3-substituted phthalide compound in the reaction is 0.06:1-0.12:

1.

5. The method of claim 1, wherein: The metal palladium precursor is allyl palladium (II) chloride dimer, tris(dibenzylideneacetone)dipalladium, bis(dibenzylideneacetone)palladium, palladium acetate or tetrakis(triphenylphosphine)palladium; and the chiral diphosphine ligand is (R,R,R)-Ph-SKP, (S,S,S)-Ph-SKP, (R,R,R)-Tol-SKP, (S,S,S)-Tol-SKP, (R,R,R)-Xyl-SKP, (S,S,S)-Xyl-SKP, (R,R)-DACH-Naphthyl Trost Ligand, (R)-MONOPhos, (R)-PHANEPHOS or (S)-SDP.

6. The method of claim 1, wherein: The preparation method of the catalyst is: under the protection of nitrogen, the metal palladium precursor and the chiral diphosphine ligand are dissolved in an organic solvent, and stirring is performed at room temperature for 30-60 minutes.

7. The method of claim 1, wherein: The specific reaction steps of the method are as follows:

8. The method of claim 1, wherein, Under the protection of nitrogen, the metal palladium precursor and the chiral diphosphine ligand are added to a Schlenk tube, then the organic solvent is added, and after stirring at room temperature for 30-60 min, the 3-substituted phthalide compound, the promoter or without the promoter, the additive, the allyl carbonate compound and the organic solvent are added under nitrogen, and after stirring at -40-30 oC for 1-100 h, the solvent is dried, and column chromatography is performed to obtain a pure chiral phthalide derivative. The organic solvent is one of dichloromethane, ethyl acetate, tetrahydrofuran, toluene, trifluorotoluene and acetonitrile.

9. The method of claim 7, wherein: ​ 10. The method of claim 1, wherein: R 1 is methyl, R 2 is methoxy, R 3 is benzyl, R 4 is hydrogen, 1,5-diazabicyclo[5.4.0]-5-undecene is the promoter or no promoter is used, the catalyst is a complex of tris(dibenzylideneacetone)dipalladium and (R,R,R)-Ph-SKP, the organic solvent is toluene, the temperature is -40°C, and the additive is molecular sieves, reaction time 48 h.

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