A method for synthesizing chiral 1,3-disubstituted isoindolines by palladium-catalyzed asymmetric cascade reaction

Abstract

The application discloses a method for synthesizing chiral 1,3-disubstituted isoindoline through palladium-catalyzed asymmetric tandem reaction, which uses palladium trifluoroacetate, a chiral nitrogen-phosphorus ligand and a base as a catalytic system, and a sulfonamide derivative as a substrate to generate an asymmetric boronic acid addition reaction, a palladium amine and a beta-acetoxy elimination reaction in series, and obtain chiral cis-1,3-disubstituted isoindoline. Through the method, cis-1,3-disubstituted isoindoline with optical purity can be obtained at a high yield (the enantiomeric excess percentage can reach >99%). The application has high enantiomeric and diastereomeric selectivity, a wide substrate range, simple operation, mild reaction conditions, low energy consumption, environmental friendliness and good yield.

Description

Technical Field

[0001] This invention relates to a method for synthesizing chiral cis-1,3-disubstituted isoindoline by using a palladium-catalyzed asymmetric boric acid addition reaction of sulfonylimide followed by tandem amine palladiumization and β-acetoxy elimination reaction. Background Technology

[0002] Chiral isoindoline, as a common structural motif in a variety of natural products and pharmaceutical compounds, exhibits a wide range of biological activities, including anxiolytic, antipsychotic, antitumor, and multidrug resistance reversal activities (Reference 1: (a) Leonard, MSARKIVOC 2013, 1-65. (b) Moniot, JL; Hindenlang DM; Shamma, M. J. J. G. Chem. 1979, 44, 4347. (c) Kukkola, PJ; Bilci, NA; Ikler, T.; Savage, P.; Shetty, SS; Del Grande, D.; Jeng, AY; Bioorg. Med. Chem. Lett. 2001, 11, 1737. (d) Valencia, E.; Freyer, AJ; Shamma, M.; Fajardo, V.; Tetrahedron). Lett. 1984, 25, 599. (e) Portevin, B.; Tordjman, C.; Pastoureau, P.; Bonnet, J.; Nanteuil, GDJ; Med. Chem. 2000, 43, 4582. (f) Stuk, TL; Assink, BK; Bates, RC; Erdman, DT; Fedij, V.; Jennings, SM; Lassig, JA; Smith, R.J.; Smith, TL; Org. Process Res. Dev. 2003, 7, 851.). To date, several research groups have achieved various synthetic schemes for constructing heterocyclic systems; however, only a few methods can obtain disubstituted dihydroisoindolines with high enantiomeric and diastereoselectivity.(Reference 2: (a) Enders, D.; Narine, AA; Toulgoat, F.; Bisschops, T. Angew. Chem. Int. Ed. 2008, 47, 5661. (b) Shinobu, T.; Naohito, I.; Shuichi, H.; Sasai, H. Angew. Chem. Int. Ed. 2010, 49, 9725. (c) Shinobu, T.; Makoto, S.; Mohamed, AA; Kenta, K.; Wathsala, HDP; Shuichi, H.; Kenichi, M.; Hiromichi, F.; Sasai, H. Org. Lett. 2017, 19, 5426.) However, all these methods are limited by the need for large amounts of organic catalysts (≥10 mol%), resulting in low catalytic efficiency, and due to the characteristics of the reaction mechanism, the types of nucleophiles are strictly limited, leading to a limited range of substrates. In 2011, Jarvo's group published a method for synthesizing 1,3-disubstituted isoindolines using palladium-catalyzed tandem reactions, but the chiral product was difficult to obtain due to the limitations of the catalyst structure. (Reference 3: Williams, FJ; Jarvo, ER Angew. Chem., Int. Ed. 2011, 50, 4386.) Therefore, developing a simple, efficient, high-yield, and highly enantioselective method for synthesizing chiral 1,3-disubstituted isoindolines is a very promising research direction. Summary of the Invention

[0003] The purpose of this invention is to provide a method for synthesizing chiral cis-1,3-disubstituted isoindolines via a palladium-catalyzed asymmetric boronic acid addition reaction of sulfonylimide derivatives followed by tandem amine palladiumization and β-acetoxy elimination reaction. This method can achieve high yields of cis-1,3-disubstituted isoindolines with optical purity. This invention exhibits high enantiomeric and diastereoselectivity, a wide substrate range, simple and easy operation, mild reaction conditions, low energy consumption, environmental friendliness, and good yield.

[0004] To achieve the above objectives, the technical solution of the present invention is as follows:

[0005] A palladium-catalyzed method for synthesizing chiral cis-1,3-disubstituted isoindoline via an asymmetric boric acid addition reaction tandemly with an amine palladiumization and β-acetoxy elimination reaction of a sulfonylimide derivative is disclosed. The method comprises a palladium catalyst, a chiral nitrogen-phosphorus ligand, and a base as the catalytic system. Sulfonylimide derivative 1 and arylboronic acid 2 are used as substrates, and the asymmetric boric acid addition reaction tandemly with an amine palladiumization and β-acetoxy elimination reaction is carried out to obtain chiral cis-1,3-disubstituted isoindoline 3.

[0006] The reaction formula is as follows:

[0007]

[0008] In the formula:

[0009] R is selected from phenyl or substituted phenyl; the substituents of the substituted phenyl are selected from at least one of methyl, methoxy, and chlorine;

[0010] Ar 1 Selected from phenyl or substituted phenyl; the substituents of substituted phenyl are selected from at least one of methyl, methoxy, fluorine, and chlorine;

[0011] Ar 2 It is selected from phenyl, naphthyl, or substituted phenyl; the substituent of the substituted phenyl is selected from one of methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and benzyloxy.

[0012] In the chiral phosphine ligand, R' is independently selected from phenyl, C7-C8 substituted aryl (e.g., phenyl), and cyclohexyl; the substituent of the substituted aryl group is selected from methyl, methoxy, trifluoromethyl, and fluorine atoms; Ar 3 It is selected from phenyl, naphthyl, or substituted phenyl; the substituent of the substituted phenyl is selected from methyl or fluorine atoms.

[0013] The palladium catalyst is one of palladium trifluoroacetate, palladium acetate, and palladium chloride, preferably palladium trifluoroacetate.

[0014] The alkali is one or more of potassium phosphate, sodium phosphate, lithium phosphate, potassium carbonate, cesium carbonate, sodium carbonate, and lithium carbonate, preferably potassium phosphate or sodium carbonate.

[0015] Based on the above technical solution, further, the chiral cis-1,3-disubstituted isoindoline derivative is one of 3aa, 3ba, 3ca, 3da, 3ea, 3fa, 3ga, 3ha, 3ab, 3ac, 3ad, 3ae, 3af, 3ag, 3ah, 3ai, 3aj, 3ak, 3al, and 3am.

[0016]

[0017]

[0018] Based on the above technical solution, furthermore, the reaction temperature is 30-80℃, for example 30, 40, 50, 60, 70, 80℃; the reaction time is 8-144 hours, preferably 36-72 hours.

[0019] Based on the above technical solution, the steps of the method are further as follows:

[0020] Under nitrogen protection, palladium catalyst, chiral nitrogen-phosphorus ligand L, and acetone were added to a sealed tube. The mixture was stirred at room temperature for 1–3 hours. The solvent was removed under reduced pressure. The solvent was added in an oil bath at 30–80°C and stirred for 3–15 minutes. Then, sulfonamide derivative 1 and arylboronic acid 2 were added. The mixture was stirred at 30–80°C for 1–10 hours. Then, alkali was added. The mixture was stirred at 30–80°C for 8–144 hours. After the reaction, the target product was obtained by column chromatography.

[0021] Based on the above technical solution, the catalytic system further includes allyl acetate, and the steps of the method are as follows:

[0022] Under nitrogen protection, palladium catalyst, chiral nitrogen-phosphorus ligand L, and acetone were added to a sealed tube. The mixture was stirred at room temperature for 1–3 hours. The solvent was removed under reduced pressure. The solvent was added in an oil bath at 30–80°C and stirred for 3–15 minutes. Then, sulfonylimide derivative 1 and arylboronic acid 2 were added. The mixture was stirred at 30–80°C for 1–10 hours. Then, alkali and allyl acetate were added. The mixture was stirred at 30–80°C for 8–144 hours. The target product was obtained by column chromatography.

[0023] Based on the above technical solution, furthermore, the reaction solvent is one or more of trifluoroethanol, hexafluoroisopropanol, methanol, and ethanol, with trifluoroethanol being preferred.

[0024] Based on the above technical solution, further, the molar ratio of the palladium catalyst and the sulfonyl imide derivative 1 is 0.01:1 to 0.20:1, preferably 0.05:1 to 0.10:1.

[0025] Based on the above technical solution, furthermore, the chiral phosphine ligand is one of L1-L12, preferably L3.

[0026]

[0027] Based on the above technical solution, further, the molar ratio of the chiral phosphine ligand and the sulfonylimide derivative 1 is 0.012:1 to 0.24:1, preferably 0.06:1 to 0.12:1.

[0028] Based on the above technical solution, the molar ratio of arylboronic acid 2 and sulfonylimide derivative 1 is further 1:1 to 8:1, preferably 2:1 to 4:1.

[0029] Based on the above technical solution, further, the molar ratio of allyl acetate and sulfonylimide derivative 1 is 0.05:1 to 1:1, preferably 0.1:1 to 0.3:1, and more preferably 0.2:1.

[0030] Based on the above technical solution, further, the molar ratio of the base and sulfonylimide derivative 1 is 0.5:1 to 4.0:1, preferably 1.0:1 to 3.0:1, and more preferably 2.0:1.

[0031] Based on the above technical solution, further, the amount of solvent used is 0.5 to 5 ml of solvent per 0.2 mmol of sulfonylimide derivative 1, preferably 3 ml of solvent.

[0032] Based on the above technical solution, further, the reaction involves a palladium-catalyzed asymmetric borate addition reaction followed by a tandem amination palladiumization and β-acetoxy elimination reaction of the sulfonylimide derivative to obtain the corresponding chiral cis-1,3-disubstituted isoindoline derivative, with palladium trifluoroacetate as the palladium precursor; in the chiral phosphine ligand (6-12 mol%), R' is p-methylphenyl, and Ar... 3 The base is phenyl; the solvent is potassium phosphate or sodium carbonate; the solvent is trifluoroethanol; and the temperature is 30-70 degrees Celsius. The results are optimal, and the enantiomeric excess can reach >99%.

[0033] The present invention has the following advantages:

[0034] 1. It exhibits high reactivity and enantioselectivity, produces specific products, facilitates separation, and can yield high enantiomeric excess purity (enantiomeric excess can reach >99%).

[0035] 2. It has a wide substrate range, enabling the production of various types of chiral cis-1,3-disubstituted isoindoline derivatives.

[0036] 3. The catalyst is cheap and readily available, and the reaction operation is simple, practical, and easy to carry out.

[0037] 4. The reaction conditions are mild, and the reaction can be carried out at a maximum temperature of 70 degrees Celsius.

[0038] 5. The present invention has high enantiomeric selectivity (up to >20:1), low energy consumption, environmental friendliness and high yield (up to 96%). Detailed Implementation

[0039] The present invention is described in detail below through embodiments; however, the present invention is not limited to the embodiments described below.

[0040] The substrate sulfonamide derivative 1 used in the following examples was synthesized according to the method described in the literature (Williams, FJ; Jarvo, ER Angew. Chem., Int. Ed. 2011, 50, 4386.).

[0041] Example 1: Condition Optimization

[0042] Under nitrogen protection, palladium trifluoroacetate (5 mol%, 0.005 mmol), chiral nitrogen-phosphorus ligand L (12 mol%, 0.012 mmol), and 1 mL of acetone were added to a 10 mL sealed tube. The mixture was stirred at room temperature for 2 hours, and the solvent was removed under reduced pressure. 1.5 mL of trifluoroethanol was added in a 30°C oil bath. After 5 minutes, sulfonylimide 1a (0.1 mmol) and arylboronic acid 2a (0.2 mmol) were added. The mixture was stirred at 30°C for 3 hours (first stage). Potassium phosphate (0.2 mmol) was then added, and the mixture was stirred at 60°C for 24 hours (second stage). After the reaction was complete, the solvent was evaporated, and the internal standard trimethoxybenzene (0.1 mmol) was added. A 1H NMR spectrum was then measured.

[0043] The yields were NMR yields, and the enantiomeric excess of the products was determined by chiral liquid chromatography, as shown in Table 1.

[0044]

[0045] Table 1. Screening of chiral ligands [a]

[0046]

[0047]

[0048] [a] 1a (0.10mmol), 2a (0.20mmol), Pd(TFA)2 (10mol%), Chiral Ligand (12mol%), TFE (1.5mL), 30℃, 3h; then K3PO4 (0.20mmol), 60℃, 24h. b Determined by NMR using 1,3,5-trimethoxybenzene as the internal standard. c Determined by HPLC. d 72 hours for stage 2. [e] Pd(TFA)2(5mol%),Chiral Ligand(6mol%),Allyl Acetate(20mol%),36hfor stage 2.

[0049] Example 2: Synthesis of chiral cis-1,3-disubstituted isoindoline derivatives by tandem palladium-catalyzed asymmetric borate addition reaction of sulfonylimide with amine palladiumization and β-acetoxy elimination reaction.

[0050] Procedure A: Under nitrogen protection, palladium trifluoroacetate (5 mol%, 0.01 mmol), chiral nitrogen-phosphorus ligand L3 (6 mol%, 0.012 mmol), and 2 mL of acetone were added to a 10 mL sealed tube. The mixture was stirred at room temperature for 2 hours, and the solvent was removed under reduced pressure. 3.0 mL of trifluoroethanol was added in a 30°C oil bath. After 5 minutes, sulfonylimide 1 (0.2 mmol) and arylboronic acid 2 (0.4 mmol) were added. The mixture was stirred at 30°C for 3 hours, followed by the addition of potassium phosphate (0.4 mmol) and allyl acetate (0.04 mmol). The mixture was stirred at 60°C for 36 hours. After the reaction was complete, the solvent was evaporated, and the product was separated by column chromatography (eluent: petroleum ether and ethyl acetate, volume ratio 20:1) to obtain the pure product.

[0051] Procedure B: Under nitrogen protection, palladium trifluoroacetate (10 mol%, 0.02 mmol), chiral nitrogen-phosphorus ligand L3 (12 mol%, 0.024 mmol), and 2 mL of acetone were added to a 10 mL sealed tube. The mixture was stirred at room temperature for 2 hours, and the solvent was removed under reduced pressure. 3.0 mL of trifluoroethanol was added in a 60°C oil bath. After 5 minutes, sulfonylimide 1 (0.2 mmol) and arylboronic acid 2 (0.8 mmol) were added. The mixture was stirred at 60°C for 5 hours, and then sodium carbonate (0.4 mmol) and allyl acetate (0.04 mmol) were added. The mixture was stirred at 60°C for 72 hours. After the reaction was complete, the solvent was evaporated, and the product was separated by column chromatography (eluent: petroleum ether and ethyl acetate, volume ratio 20:1) to obtain the pure product.

[0052] The reaction formula is as follows:

[0053]

[0054] The yield was the separation yield, and the enantiomeric excess of the product was determined by chiral liquid chromatography.

[0055] This invention achieves high-yield, optically pure cis-1,3-disubstituted isoindolines via a palladium-catalyzed asymmetric borate addition reaction of sulfonylimide followed by amine palladiumization and β-acetoxy elimination. The invention exhibits high enantiomeric selectivity, a broad substrate range, simple and easy operation, mild reaction conditions, low energy consumption, environmental friendliness, and good yield.

[0056] (-)-1-(4-Methoxyphenyl)-2-tosyl-3-vinylisoindoline(3aa):

[0057] 76.4 mg, 94% yield, colorless oily liquid, known compound (racemic mixture has been reported), R f =0.60 (petroleum ether / ethyl acetate / dichloro) 117.3, 113.8, 69.1, 68.3, 55.3, 21.4. HPLC: Chiralpak AD-H column, 254 nm, 30 °C, n-hexane / isopropanol = 60 / 40, flow = 0.7 mL / min, retention time 22.9 min (major). HRMS calculated for C 24 H 24 NO3S[M+H] + 406.1471, found: 406.1469.

[0058] (-)-1-(4-Methoxyphenyl)-2-(phenylsulfonyl)-3-vinylisoindoline(3ba):

[0059] 46.6 mg, 60% yield, colorless oily liquid, new compound, R f =0.60 (petroleum ether / ethyl acetate / dichloromethane 10 / 1 / 2), >99% ee, 129.3, 128.5, 128.4, 128.0, 127.5, 123.6, 123.2, 117.5, 113.8, 69.1, 68.4, 55.3. HPLC: Chiralpak AD-H column, 254 nm, 30 °C, n-hexane / isopropanol = 60 / 40, flow = 0.7 mL / min, retention time 23.2 min (major). HRMS calculated for C 23 H 22 NO3S[M+H] + 391.1242, found: 391.1243.

[0060] (-)-1-(4-Methoxyphenyl)-2-((4-methoxyphenyl)sulfonyl)-3-vinylisoindoline(3ca):

[0061] 40.4 mg, 48% yield, yellow oily liquid, new compound, R f =0.40 (petroleum ether / ethyl acetate / dichloromethane 10 / 1 / 2), >99% ee, 128.4, 128.0, 123.6, 123.2, 117.3, 113.8, 113.7, 69.1, 68.3, 55.5, 55.3. HPLC: Chiralpak AD-H column, 254 nm, 30 °C, n-hexane / isopropanol = 60 / 40, flow = 0.7 mL / min, retention time 20.7 min (major). HRMS calculated for C 24 H 24 NO4S[M+H] + 422.1421, found: 422.1431.

[0062] (-)-2-((4-Chlorophenyl)sulfonyl)-1-(4-methoxyphenyl)-3-vinylisoindoline(3da):

[0063] 49.9 mg, 59% yield, colorless oily liquid, new compound, R f =0.60 (petroleum ether / ethyl acetate / dichloromethane 10 / 1 / 2), >99% ee, 129.5, 128.9, 128.6, 128.6, 128.2, 123.6, 123.2, 118.0, 113.9, 69.1, 68.4, 55.3. HPLC: Chiralpak AD-H column, 254 nm, 30 °C, n-hexane / isopropanol = 60 / 40, flow = 0.7 mL / min, retention time 13.7 min (major). HRMS calculated for C 23 H 21 ClNO3S[M+H] + 426.0925 ( 35 Cl)and 428.0903( 37 Cl), found: 426.0929 ( 35 Cl)and 428.0904( 37 Cl).

[0064] (-)-5-Fluoro-3-(4-methoxyphenyl)-2-tosyl-1-vinylisoindoline(3ea):

[0065] 76.2 mg, 90% yield, colorless oily liquid, new compound, R f=0.60 (petroleum ether / ethyl acetate / dichloromethane 10 / 1 / 2), >99% (d, 4 J F-C =2.7Hz), 127.6, 124.8 (d, 3 J F-C =8.9Hz), 117.6, 115.6 (d, 2 J F-C =23.1Hz), 113.9, 110.6(d, 2 J F-C =23.6Hz), 68.8(d, 4 J F-C =2.7Hz), 67.8, 55.3, 21.5. HPLC: Chiralpak AD-H column, 254nm, 30℃, n-hexane / isopropanol = 60 / 40, flow = 0.7mL / min, retention time 19.3min (major). HRMS Calculated for C 24 H 23 FNO3S[M+H] + 424.1377, found: 424.1380.

[0066] (-)-5-Chloro-3-(4-methoxyphenyl)-2-tosyl-1-vinylisoindoline(3fa):

[0067] 66.4 mg, 75% yield, colorless oily liquid, new compound, R f =0.60 (petroleum ether / ethyl acetate / dichloromethane 10 / 1 / 2), 97.7% 68.7, 67.9, 55.3, 21.5. HPLC: Chiralpak AD-H column, 254 nm, 30 °C, n-hexane / isopropanol = 60 / 40, flow = 0.7 mL / min, retention time 11.2 min and 18.1 min (major). HRMS calculated for C 24 H 23 ClNO3S[M+H] + 486.1136 ( 35 Cl)and 488.1116( 37 Cl), found: 486.1130 ( 35 Cl)and488.1127( 37 Cl).

[0068] (-)-3-(4-Methoxyphenyl)-5-methyl-2-tosyl-1-vinylisoindoline(3ga):

[0069] 66.7 mg, 79% yield, colorless oily liquid, new compound, R f =0.60 (petroleum ether / ethyl acetate / dichloromethane 10 / 1 / 2), >99% Column, 254 nm, 30 °C, hexane / isopropanol = 60 / 40, flow rate = 0.7 mL / min, retention time 19.6 min (major). HRMS calculated for C 25 H 26 NO3S[M+H] + 420.1628, found: 420.1623.

[0070] (-)-1-(4-Methoxyphenyl)-5-methyl-2-tosyl-3-vinylisoindoline(3ha):

[0071] 73.9 mg, 76% yield, colorless oily liquid, new compound, R f =0.60 (petroleum ether / ethyl acetate / dichloromethane 10 / 1 / 2), >99% AD-H column, 254 nm, 30 °C, n-hexane / isopropanol = 60 / 40, flow rate = 0.7 mL / min, retention time 16.8 min (major). The HRMS calculated for C 25 H 26 NO3S[M+H] + 420.1628, found: 420.1626.

[0072] (-)-1-(2-Methoxyphenyl)-2-tosyl-3-vinylisoindoline(3ab):

[0073] 69.8 mg, 86% yield, colorless oily liquid, new compound, R f =0.60 (petroleum ether / ethyl acetate / dichloromethane 10 / 1 / 2), >99% 137.2, 135.8, 130.6, 129.3, 129.0, 128.6, 128.3, 127.8, 127.6, 123.3, 123.2, 120.8, 117.2, 110.9, 68.5, 63.8, 55.5, 21.5. HPLC: Chiralpak AD-H, 254 nm, 30 °C, n-hexane / isopropanol = 60 / 40, flow = 0.7 mL / min, retention time 20.8 min (major). HRMS Calculated for C 24 H 24 NO3S[M+H] + 406.1471, found: 406.1477.

[0074] (-)-1-(4-Ethoxyphenyl)-2-tosyl-3-vinylisoindoline(3ac):

[0075] 80.9 mg, 96% yield, colorless oily liquid, new compound, R f =0.60 (petroleum ether / ethyl acetate / dichloromethane 10 / 1 / 2), >99% 128.0, 127.6, 123.6, 123.2, 117.3, 114.4, 69.1, 68.3, 63.5, 21.5, 14.9. HPLC: Chiralpak AD-H, 254 nm, 30 °C, n-hexane / isopropanol = 60 / 40, flow = 0.7 mL / min, retention time 19.5 min (major). HRMS calculated for C 25 H 26 NO3S[M+H] + 420.1628, found: 420.1634.

[0076] (-)-1-(4-Propoxyphenyl)-2-tosyl-3-vinylisoindoline(3ad):

[0077] 76.4 mg, 88% yield, colorless oily liquid, new compound, R f =0.60 (petroleum ether / ethyl acetate / dichloromethane 10 / 1 / 2), >99% 134.0, 129.3, 129.2, 128.4, 128.0, 127.6, 123.6, 123.2, 117.3, 114.4, 69.5, 69.1, 68.3, 22.6, 21.5, 10.6. HPLC: Chiralpak AD-H, 254 nm, 30 °C, n-hexane / isopropanol = 60 / 40, flow = 0.7 mL / min, retention time 16.4 min (major). The HRMS calculated for C 26 H 28 NO3S[M+H] + 434.1784, found: 434.1780.

[0078] (-)-1-(4-Isopropoxyphenyl)-2-tosyl-3-vinylisoindoline(3ae):

[0079] 77.6 mg, 90% yield, colorless oily liquid, new compound, R f =0.60 (petroleum ether / ethyl acetate / dichloromethane 10 / 1 / 2), >99% Chiralpak AD-H, 254 nm, 30 °C, n-hexane / isopropanol = 60 / 40, flow rate = 0.7 mL / min, retention time 12.6 min (major). The HRMS calculated for C 26 H 28 NO3S[M+H] + 434.1784, found: 434.1780.

[0080] (-)-1-(4-Butoxyphenyl)-2-tosyl-3-vinylisoindoline(3af):

[0081] 82.2 mg, 85% yield, colorless oily liquid, new compound, R f =0.60 (petroleum ether / ethyl acetate / dichloromethane 10 / 1 / 2), >99% 143.0, 140.2, 138.7, 137.7, 136.8, 134.0, 129.3, 129.2, 128.4, 128.0, 127.6, 123.7, 123.2, 117.3, 114.3, 69.1, 68.3, 67.7, 31.3, 21.5, 19.3, 13.9. HPLC: Chiralpak AD-H, 254 nm, 30 °C, n-hexane / isopropanol = 60 / 40, flow = 0.7 mL / min, retention time 15.5 min (major). HRMS Calculated for C 27 H 30 NO3S[M+H] + 468.1628, found: 468.1633.

[0082] (-)-1-(4-(Benzyloxy)phenyl)-2-tosyl-3-vinylisoindoline(3ag):

[0083] 77.6 mg, 82% yield, colorless oily liquid, known compound (racemic mixture has been reported), R f =0.60 (petroleum ether / ethyl acetate / dichloro) 123.7, 123.3, 117.4, 114.7, 70.0, 69.1, 68.3, 21.5. HPLC: Chiralpak AD-H, 254 nm, 30 °C, n-hexane / isopropanol = 60 / 40, flow = 0.7 mL / min, retention time 29.5 min (major). HRMS calculated for C 30 H 28 NO3S[M+H] + 468.1628, found: 468.1633.

[0084] (-)-1-Phenyl-2-tosyl-3-vinylisoindoline(3ah):

[0085] 66.1 mg, 88% yield, colorless oily liquid, known compound (racemic mixture has been reported), R f =0.50 (petroleum ether / ethyl acetate) 128.1, 128.0, 127.8, 127.6, 123.6, 123.3, 117.5, 69.6, 68.5, 21.5. HPLC: Chiralpak AD-H, 254 nm, 30 °C, n-hexane / isopropanol = 60 / 40, flow = 0.7 mL / min, retention time 18.0 min (major). HRMS calculated for C 23 H 22 NO2S[M+H] + 376.1366, found: 376.1362.

[0086] (-)-1-(p-Tolyl)-2-tosyl-3-vinylisoindoline(3ai):

[0087] 66.6 mg, 85% yield, colorless oily liquid, new compound, R f =0.50 (petroleum ether / ethyl acetate 8 / 1), >99% ee, >20:1 dr, 30℃, n-hexane / isopropanol = 60 / 40, flow rate = 0.7 mL / min, retention time 17.0 min (major). HRMS calculated for C 24 H 24 NO3S[M+H] + 390.1522, found: 390.1517.

[0088] (-)-1-(4-Ethylphenyl)-2-tosyl-3-vinylisoindoline(3aj):

[0089] 72.0 mg, 89% yield, colorless oily liquid, new compound, R f =0.50 (petroleum ether / ethyl acetate 8 / 1), >99% ee, >20:1 dr, 127.6, 123.6, 123.3, 117.4, 69.4, 68.4, 28.6, 21.5, 15.7. HPLC: Chiralpak AD-H, 254 nm, 30 °C, n-hexane / isopropanol = 60 / 40, flow = 0.7 mL / min, retention time 13.6 min (major). HRMS calculated for C 25 H 26 NO2S[M+H] +404.1679, found: 404.1680.

[0090] (-)-1-(4-propylphenyl)-2-tosyl-3-vinylisoindoline(3ak):

[0091] 71.8 mg, 86% yield, colorless oily liquid, new compound, R f =0.50 (petroleum ether / ethyl acetate 8 / 1), >99% ee, >20:1 dr, 128.4, 128.0, 127.9, 127.6, 123.6, 123.3, 117.4, 69.4, 68.4, 37.7, 24.6, 21.5, 13.9. HPLC: Chiralpak AD-H, 254 nm, 30 °C, n-hexane / isopropanol = 60 / 40, flow = 0.7 mL / min, retention time 12.4 min (major). HRMS calculated for C 26 H 28 NO2S[M+H] + 418.1835, found: 418.1829.

[0092] (-)-1-(4-Isopropylphenyl)-2-tosyl-3-vinylisoindoline(3al):

[0093] 58.4 mg, 70% yield, colorless oily liquid, new compound, R f =0.50 (petroleum ether / ethyl acetate 8 / 1), >99% ee, >20:1 dr, 123.7, 123.3, 117.5, 69.4, 68.4, 33.8, 24.1, 24.0, 21.5. HPLC: Chiralpak AD-H, 254 nm, 30 °C, n-hexane / isopropanol = 60 / 40, flow = 0.7 mL / min, retention time 10.7 min (major). HRMS calculated for C 26 H 28 NO2S[M+H] + 418.1835, found: 418.1828.

[0094] (-)-1-(4-Butylphenyl)-2-tosyl-3-vinylisoindoline(3am):

[0095] 72.5 mg, 84% yield, colorless oily liquid, new compound, R f =0.50 (petroleum ether / ethyl acetate 8 / 1), >99% ee, >20:1 dr, 136.9, 129.1, 128.4, 128.4, 127.9, 127.9, 127.6, 123.6, 123.2, 117.4, 69.4, 68.4, 35.3, 33.7, 22.4, 21.4, 14.0. HPLC: Chiralpak AD-H, 254 nm, 30 °C, n-hexane / isopropanol = 60 / 40, flow = 0.7 mL / min, retention time 12.4 min (major). HRMS calculated for C 27 H 30 NO2S[M+H] + 432.1992, found: 432.1988.

[0096] The core skeleton of the aforementioned chiral cis-1,3-disubstituted isoindoline is a chiral isoindoline structure, which is widely found in natural products and active pharmaceutical ingredients. For example, diaporisoindole A, isolated from the endophytic fungus Diaporthe sp. SYSUHQ3, exhibits inhibitory activity against Mycobacterium tuberculosis protein tyrosine phosphatase B; (S)-PD172938, known as a dopamine D4 ligand, has shown important pharmacological activity.

Claims

1. A method for synthesizing chiral cis-1,3-disubstituted isoindoline via a palladium-catalyzed asymmetric boronic acid addition reaction of an asymmetric sulfonyl imine derivative followed by a tandem amine palladiumization and β-acetoxy elimination reaction, characterized in that, Using palladium catalyst, chiral nitrogen-phosphorus ligand L and base as catalytic system, sulfonylimide derivative 1 and arylboronic acid 2 as substrates, an asymmetric boric acid addition reaction followed by amine palladiumization and β-acetoxy elimination reaction was carried out to synthesize chiral cis-1,3-disubstituted isoindoline 3. The reaction formula is as follows: In the formula: R is selected from phenyl or substituted phenyl; the substituents of the substituted phenyl are selected from at least one of methyl, methoxy, and chlorine; Ar 1 Selected from phenyl or substituted phenyl; the substituents of substituted phenyl are selected from at least one of methyl, methoxy, fluorine, and chlorine; Ar 2 It is selected from phenyl, naphthyl, or substituted phenyl; the substituent of the substituted phenyl is selected from one of methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and benzyloxy. R' is independently selected from phenyl, C7-C8 substituted aryl, and cyclohexyl; the substituent of the substituted aryl group is selected from methyl, methoxy, trifluoromethyl, and fluorine atoms; Ar 3 Selected from phenyl, naphthyl, or substituted phenyl groups; the substituents of substituted phenyl groups are selected from methyl or fluorine atoms; The palladium catalyst is one of palladium trifluoroacetate, palladium acetate, and palladium chloride; The alkali is one of potassium phosphate, sodium phosphate, lithium phosphate, potassium carbonate, cesium carbonate, sodium carbonate, and lithium carbonate.

2. The method as described in claim 1, characterized in that: The reaction temperature is 30–80℃; the reaction time is 8–144 hours.

3. The method as described in claim 1, characterized in that: The steps of the method are as follows: Under nitrogen protection, palladium catalyst, chiral nitrogen-phosphorus ligand L, and acetone were added to a sealed tube. The mixture was stirred at room temperature for 1–3 hours. The solvent was removed under reduced pressure. The solvent was added in an oil bath at 30–80°C. After stirring for 5 minutes, sulfonamide derivative 1 and arylboronic acid 2 were added. The mixture was stirred at 30–80°C until the reaction was complete. Then, alkali was added, and the mixture was stirred at 30–80°C for 8–144 hours to obtain the target product.

4. The method as described in claim 1 or 2, characterized in that: The reaction solvent is one or more of trifluoroethanol, hexafluoroisopropanol, methanol, and ethanol.

5. The method as described in claim 1 or 2, characterized in that: The molar ratio of the palladium catalyst to sulfonamide derivative 1 is 0.01:1 to 0.20:

1.

6. The method as described in claim 1 or 2, characterized in that: The molar ratio of the chiral phosphine ligand to the sulfonylimide derivative 1 is 0.012:1 to 0.24:

1.

7. The method as described in claim 1 or 2, characterized in that: The molar ratio of arylboronic acid 2 to sulfonamide derivative 1 is 1:1 to 8:

1.

8. The method as described in claim 1 or 2, characterized in that: The catalytic system further includes allyl acetate, and the molar ratio of allyl acetate to sulfonamide derivative 1 is 0.05:1 to 1:

1.

9. The method as described in claim 1 or 2, characterized in that: The molar ratio of the base to sulfonamide derivative 1 is 0.5:1 to 4.0:

1.

10. The method as described in claim 1 or 2, characterized in that: The amount of solvent used is 0.5 to 5 ml per 0.2 mmol of sulfonylimide derivative 1.

Images