Chiral polycyclic spiro compound as well as preparation method and application thereof

Abstract

The invention discloses a chiral polycyclic spiro compound, and belongs to the technical field of organic chemical synthesis, the chiral polycyclic spiro compound is a compound assembled with benzothiophene ketone, trifluoromethyl pyrrolidine and benzothiophene sulfone substructures; the preparation method comprises the following steps: dissolving ketimine (I) and benzothiophene sulfone (II) derived from trifluoroethyl benzo [b] thiophene-2, 3-diketone in an organic solvent, then adding alkali and a metal-ligand compound, and after the reaction is finished, separating and purifying to obtain a product (III); the compound provided by the invention has four continuous chiral centers, simultaneously contains benzothiophene ketone, trifluoromethyl pyrrolidine and benzothiophene sulfone substructures with pharmacodynamic functional groups, can provide more candidate molecules for research and development of new drugs and screening of drugs, and shows a better application prospect in the anti-tumor aspect; the preparation method has the advantages of novelty, simplicity, simplicity in operation, mild reaction conditions, high yield, high stereoselectivity and the like.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis, and more particularly to chiral polycyclic spirocyclic compounds, their preparation methods, and their applications. Background Technology

[0002] Chiral polycyclic spirocyclic compounds are widely found in both natural and non-natural biologically active molecules, and most of these molecules have been found to possess excellent biological activity, making them an important source for new drug development. From a drug design perspective, the organic combination of two or more pharmacodynamic functional groups into a single molecule can produce unexpected biological activities. Therefore, the successful assembly of benzothiophene ones, trifluoromethylpyrrolidine, and benzothiophene sulfone substructures into a single molecule to form chiral polycyclic spirocyclic compounds is of great significance and has not yet been reported.

[0003] The catalytic asymmetric 1,3-dipolar cycloaddition of methyleneamine ylides with active alkenes has proven to be an efficient strategy for constructing pyrrolidine ring systems, a type of structure widely found in natural products and pharmaceutical molecules. Traditionally, methyleneamine ylide precursors undergo conventional [3+2] cycloaddition reactions with active alkenes primarily via a Cα' nucleophilic attack mechanism. Given the unique configuration of the resulting 2-azaallyl anionic intermediate, a new avenue has been opened for development in this field by achieving regioselective reverse cycloaddition triggered by Cα nucleophilic attack through an imine polarity reversal strategy, as shown below. This method holds promise for providing innovative solutions for the synthesis of novel pyrrolidine derivatives, but current reports in this field remain limited (J. Am. Chem. Soc. 2009, 131, 13819-13825; J. Am. Chem. Soc. 2018, 140, 2272-2283; Angew. Chem., Int. Ed. 2018, 57, 5888-5892; Org. Lett. 2022, 24, 5629-5634). Despite some progress, the types of methyleneamine ylide precursors suitable for asymmetric reversal 1,3-dipolar cycloaddition reactions remain very limited, which restricts both the development of new synthetic methods and the diversity of product structures. Therefore, while further exploration of polarity reversal strategies for other types of methyleneamine ylides to achieve enantioselective construction of complex nitrogen heterocyclic compounds holds great promise, significant challenges remain. Summary of the Invention

[0004] One of the objectives of this invention is to provide a new class of chiral polycyclic spirocyclic compounds to solve the above-mentioned problems.

[0005] To achieve the above objectives, the technical solution of the present invention is as follows: a new type of chiral polycyclic spirocyclic compound having the structure shown in the following structural formula (Ⅲ):

[0006] ;

[0007] In the above structural formula, R 1 base and R 2 The radical is selected from hydrogen, alkyl, alkoxy, aryl, and halogen.

[0008] As a preferred technical solution: the R 1 The radical is selected from hydrogen, methyl, ethyl, isopropyl, and halogen, and is either monosubstituted or disubstituted; the R 2 The radical is selected from one of hydrogen, methyl, methoxy, and phenyl.

[0009] This invention discloses for the first time a new class of chiral polycyclic spirocyclic compounds that simultaneously assemble three pharmacodynamic functional groups: benzothiophenone, α-trifluoromethylpyrrolidine, and benzo[b]thiophene sulfone structural units, which can provide more candidate molecules for new drug development and drug screening.

[0010] The second objective of this invention is to provide a method for preparing the above-mentioned chiral polycyclic spirocyclic compound. The technical solution involves dissolving trifluoroethylbenzo[b]thiophene-2,3-dione-derived ketimine (Ⅰ) and benzothiophene sulfone (Ⅱ) in an organic solvent, then adding a base and a pre-complexed copper salt and chiral ligand complex. After the reaction is complete, the chiral polycyclic spirocyclic compound (Ⅲ) is obtained through separation and purification.

[0011] The trifluoroethylbenzo[b]thiophene-2,3-dione-derived ketoimine (I) has the following structure:

[0012] ;

[0013] Benzothiophene sulfone (II) has the following structure:

[0014] .

[0015] The synthetic route is as follows:

[0016] .

[0017] The present invention utilizes the above-described synthetic method to achieve an asymmetric reversal of the 1,3-dipolar cycloaddition reaction, thereby synthesizing a series of novel chiral polycyclic spirocyclic compounds.

[0018] In this invention, the inventors developed a copper-catalyzed polarity reversal strategy for the derivatization of trifluoroethylbenzo[b]thiophene-2,3-dione ketimines, achieving an enantioselective 1,3-dipolar cycloaddition reaction with benzo[b]thiophene sulfone. This enables the enantioselective synthesis of structurally diverse polycyclic spirocyclic compounds—compounds that simultaneously integrate benzothiophene ketone, α-trifluoromethylpyrrolidine, and benzo[b]thiophene sulfone structural units, as shown below:

[0019] .

[0020] As a preferred technical solution, the organic solvent is selected from one or a mixture of more than one of toluene, mesitylene, dichloromethane, chloroform, tetrahydrofuran, diethyl ether, acetonitrile, ethanol, methanol, 1,4-dioxane, and chlorobenzene.

[0021] As a further preferred technical solution, the reaction solvent is toluene, which has a higher yield and higher stereoselectivity.

[0022] As a preferred technical solution, the chiral ligand is a chiral ferrocene diphenylphosphine oxazoline ligand having a structure of the following formula: L1, L2, L3, or L4:

[0023] .

[0024] Further optimization of ligand L4 resulted in higher enantioselectivity.

[0025] As a preferred technical solution, the base used in the reaction is a variety of organic and inorganic bases, such as triethylamine, diisopropylethylamine, potassium carbonate, sodium carbonate, potassium phosphate, dipotassium hydrogen phosphate, etc.

[0026] As a further preferred technical solution, the base used in the reaction is potassium phosphate, which results in a higher yield.

[0027] As a preferred technical solution, the reaction temperature is 0℃ to room temperature (rt.).

[0028] As a further preferred technical solution, the reaction temperature is 0°C, at which temperature the stereoselectivity is higher.

[0029] This invention utilizes ketoimines derived from trifluoroethylbenzo[b]thiophene-2,3-dione and benzothiophene sulfone as starting materials, and initiates a reciprocated 1,3-dipolar cycloaddition reaction catalyzed by a copper(II) hexafluorophosphate tetraacetonitrile and a ferrocene diphenylphosphine oxazoline L4 complex to construct chiral polycyclic spirocyclic compounds with high stereoselectivity. Notably, these compounds simultaneously assemble three pharmacologically active functional groups: benzothiophene ketone, α-trifluoromethylpyrrolidine, and benzo[b]thiophene sulfone structural units. This technique not only provides new ideas and methods for the synthesis of such compounds but also significantly enriches the variety of these compounds, offering more candidate molecules for drug screening.

[0030] A third objective of this invention is to provide the application of the above-mentioned chiral polycyclic spirocyclic compounds in the preparation of anticancer drugs.

[0031] Furthermore, the compounds of this invention have the following application value: many existing benzothiophene ketones, α-trifluoromethylpyrrolidines, and benzo[b]thiophene sulfones possess excellent biological activity, thus it is reasonable to predict that the new class of compounds provided by this invention will also possess certain biological activity, thereby providing a sufficient source of compounds for drug activity screening; in addition, it can provide more candidate molecules for new drug development and drug screening, especially high-throughput screening, enriching this type of compound library. Furthermore, this invention provides a mild and simple synthetic method to obtain a series of polycyclic spirocyclic compounds.

[0032] The advantages of this invention are as follows: Using trifluoroethylbenzo[b]thiophene-2,3-dione-derived ketoimine and benzo[b]thiophene sulfone as raw materials, a series of structurally diverse chiral polycyclic spirocyclic compounds were prepared through a reversible 1,3-dipolar cycloaddition reaction catalyzed by a chiral copper complex. Importantly, these compounds simultaneously integrate benzo[b]thiophene ketone, α-trifluoromethylpyrrolidine, and benzo[b]thiophene sulfone structural units, providing more candidate molecules for new drug development and screening, especially high-throughput screening, thus enriching the compound library. Furthermore, cell experiments have shown that the synthesized chiral polycyclic spirocyclic compounds possess good anticancer activity. The method of this invention has advantages such as mild reaction conditions, readily available raw materials and catalysts, simple operation, and excellent stereoselectivity. Attached Figure Description

[0033] Figure 1 The hydrogen spectrum of Ⅲ-a obtained in Example 1;

[0034] Figure 2 The carbon spectrum of Ⅲ-a obtained in Example 1;

[0035] Figure 3 This is a single crystal image of Ⅲ-a obtained in Example 1. Detailed Implementation

[0036] The present invention will be further described below with reference to embodiments.

[0037] Example 1: Synthesis of compound (Ⅲ-a)

[0038]

[0039] In a dry reaction tube, a copper source (0.01 mmol) and a ligand (0.011 mmol) were added, and the mixture was stirred and complexed under solvent for half an hour. Then, a trifluoroethylbenzo[b]thiophene-2,3-dione-derived ketoimine (Ia) (0.11 mmol), benzothiophene sulfone (II-a) (0.10 mmol), and a base (0.02 mmol) were added sequentially. The reaction was stirred at a specific temperature. After the reaction was complete, the crude product was purified by column chromatography to obtain compound III-a, as follows:

[0040]

[0041] Table 1 Different reaction conditions

[0042]

[0043] As shown in Table 1, after investigating different ligands, bases, solvents, and temperatures, the preferred scheme was ultimately Cu(MeCN)4PF6 as the copper salt, ferrocene diphenylphosphine oxazoline L4 as the ligand, toluene as the solvent, and a reaction temperature of 0 °C. Under the above preferred scheme, the yield, melting point, stereoselectivity, optical rotation, 1H NMR, 1C NMR, and mass spectrometry data of Ⅲ-a are as follows: 88% yield, melting point 184.6–185.2 °C; >20:1 dr, 94% ee; [α] D 20 = -27.7 (c 2.00,CH2Cl2); HPLC: Chiralpak IA column (80 / 20 hexane / EtOH; flow rate: 1.0 mL / min; λ = 254 nm; t major = 15.11 min, t minor = 10.28 min); 1H NMR (400 MHz, CDCl3) δ7.67 (d, J = 7.9 Hz, 1H), 7.48 – 7.34 (m, 1H), 7.32 – 7.24 (m, 1H), 7.07 (d,J = 7.9 Hz, 1H), 6.98 – 6.87 (m, 2H), 6.85 (s, 1H), 5.04 – 4.88 (m, 1H), 4.80 (d, J = 9.9 Hz, 1H), 4.45 – 4.27 (m, 1H), 2.92 (d, J = 6.6 Hz, 1H), 2.00 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 206.2, 137.6, 137.1, 135.8, 134.1, 133.7,130.7, 130.5, 129.1, 126.9, 126.7, 124.4 (q, J = 281.8), 122.9, 121.4, 81.9,60.9 (q, J = 32.3 Hz), 64.4, 55.7, 20.8; 19 F NMR (376 MHz, CDCl3) δ -75.86.HR-MS(ESI-TOF) m / z: Calcd for C 19 H 15 F3NO3S2 [M+H] + 426.0440, found 426.0446. Proton and carbon spectra are as follows. Figure 1 , Figure 2 As shown.

[0044] Single crystal diffraction experiment:

[0045] Single crystal culture: The main component compound III-a (40 mg) obtained in Example 1 was dissolved in a mixture of 20 mL dichloromethane and ethanol and left to stand at room temperature for 7 days. Single crystals were precipitated and collected for single crystal diffraction testing.

[0046] The test parameters are shown in Table 2:

[0047] ;

[0048] The measurement results are as follows Figure 3 As shown, the structure of compound III-a was determined using the above spectra and data.

[0049] Example 2: Synthesis of compound (Ⅲ-b)

[0050]

[0051] Cu(MeCN)4PF6 (0.01 mmol) and ligand L4 (0.011 mmol) were added to a dry reaction tube and stirred under toluene for half an hour to complex the compounds. Then, trifluoroethylbenzo[b]thiophene-2,3-dione-derived ketoimine (Ib) (0.11 mmol), benzothiophene sulfone (II-a) (0.10 mmol), and potassium phosphate (0.02 mmol) were added sequentially. The reaction mixture was stirred at 0 °C. After the reaction was complete, the crude product was purified by column chromatography to give compound III-b.

[0052] The yield, melting point, stereoselectivity, optical rotation, 1H NMR, 1C NMR, and mass spectrometry data of the obtained Ⅲ-b are as follows: 81% yield, melting point 169.6–169.9 °C; >20:1 dr, 94% ee; [α] D 20 = -63.4 (c 1.47, CH2Cl2); HPLC: Chiralpak IA column (80 / 20 hexane / EtOH; flow rate: 1.0 mL / min; λ = 254nm; t major = 24.83 min, t minor = 14.69 min); 1 H NMR (400 MHz, CDCl3) δ 7.66 (d, J= 7.8 Hz, 1H), 7.45 – 7.35 (m, 1H), 7.33 – 7.27 (m, 1H), 7.02 (s, 1H), 6.89 (d, J = 8.1 Hz, 2H), 6.65 (d, J = 8.0 Hz, 1H), 4.97 – 4.86 (m, 1H), 4.81 (d,J = 10.0 Hz, 1H), 4.38 – 4.29 (m, 1H), 2.89 (d, J = 6.7 Hz, 1H), 2.19 (s,3H); 13 C NMR (101 MHz, CDCl3) δ 206.2, 140.6, 137.7, 134.3, 133.8, 133.1,132.7, 130.6, 127.9, 126.8, 126.1, 124.6 (q, J = 282.0 Hz), 123.9, 121.7,81.9, 64.6, 60.8 (q, J = 33.0 Hz), 55.6, 21.4;19 F NMR (376 MHz, CDCl3) δ -75.88. HR-MS(ESI-TOF) m / z: Calcd for C 19 H 15 F3NO3S2 [M+H] + 426.0440, found426.0446.

[0053] Example 3: Synthesis of compound (Ⅲ-c)

[0054]

[0055] Cu(MeCN)4PF6 (0.01 mmol) and ligand L4 (0.011 mmol) were added to a dry reaction tube and stirred under toluene for half an hour to complex the mixture. Then, trifluoroethylbenzo[b]thiophene-2,3-dione-derived ketoimine (Ic) (0.11 mmol), benzothiophene sulfone (II-a) (0.10 mmol), and potassium phosphate (0.02 mmol) were added sequentially. The reaction mixture was stirred at 0 °C. After the reaction was complete, the crude product was purified by column chromatography to give compound III-c.

[0056] The yield, melting point, stereoselectivity, optical rotation, 1H NMR, 1C NMR, and mass spectrometry data of the obtained Ⅲ-c are as follows: 89% yield, melting point 146.4–147.1°C; >20:1 dr, 94% ee; [α] D 20 = ‒ 16.7.6 (c 2.00, CH2Cl2); HPLC: Chiralpak IA column (80 / 20 hexane / EtOH; flow rate: 1.0 mL / min; λ = 254nm; t major = 15.20 min, t minor = 9.56 min); 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J= 7.9 Hz, 1H), 7.43 – 7.33 (m, 1H), 7.32 – 7.21 (m, 1H), 7.09 (d, J = 7.9 Hz,1H), 7.01 – 6.81 (m, 3H), 4.96 (d, J = 8.1 Hz, 1H), 4.81 (d, J = 9.9 Hz, 1H), 4.41 – 4.27 (m, 1H), 2.94 (d, J = 6.6 Hz, 1H), 2.44 – 2.17 (m, 2H), 0.87 (t,J = 7.6 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 206.3, 143.7, 137.6, 135.9, 134.1,133.8, 130.4, 129.8, 129.3, 126.7, 125.9, 124.4 (q, J= 281.9 Hz), 123.0,121.5, 81.9, 64.5, 60.8 (q, J = 33.0 Hz), 55.7, 28.3, 15.4; 19 F NMR (376 MHz, CDCl3) δ -75.88. HR-MS(ESI-TOF) m / z: Calcd for C 20 H 17 F3NO3S2 [M+H] + 440.0596, found 440.0600.

[0057] Example 4: Synthesis of compound (Ⅲ-d)

[0058]

[0059] Cu(MeCN)4PF6 (0.01 mmol) and ligand L4 (0.011 mmol) were added to a dry reaction tube and stirred under toluene for half an hour to complex the mixture. Then, trifluoroethylbenzo[b]thiophene-2,3-dione-derived ketoimine (Id) (0.11 mmol), benzothiophene sulfone (II-a) (0.10 mmol), and potassium phosphate (0.02 mmol) were added sequentially. The reaction mixture was stirred at 0 °C. After the reaction was complete, the crude product was purified by column chromatography to give compound III-d.

[0060] The yield, melting point, stereoselectivity, optical rotation, 1H NMR, 1C NMR, and mass spectrometry data of the obtained Ⅲ-d are as follows: 88% yield, melting point 154.7–155.4 °C, >20:1 dr, 95% ee; [α] D 20 = -31.3 (c 2.00, CH2Cl2). HPLC: Chiralpak IA column (80 / 20 hexane / EtOH; flow rate: 1.0 mL / min; λ = 254 nm;t major = 15.74 min, t minor = 8.98 min); 1 H NMR (400 MHz, CDCl3)) δ 7.65 (d, J =7.8 Hz, 1H), 7.40 – 7.33 (m, 1H), 7.30 – 7.22 (m, 1H), 7.10 (dd, J = 8.5, 1.7Hz, 1H), 6.95 (dd, J = 4.6, 2.1 Hz, 2H), 6.88 (d, J = 7.8 Hz, 1H), 5.03 –4.90 (m, 1H), 4.82 (d, J = 9.9 Hz, 1H), 4.42 – 4.28 (m, 1H), 2.94 (d, J = 6.6Hz, 1H), 2.66 – 2.48 (m, 1H), 0.96 (dd, J = 6.8, 1.8 Hz, 3H), 0.89 (dd, J =7.0, 1.7 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 206.3, 148.5, 137.6, 135.9,134.1, 133.8, 130.3, 129.4, 128.6, 126.7, 124.5 (q, J = 281.9 Hz), 124.2,123.0, 121.6, 81.9, 64.5,60.8 (q, J = 33.0 Hz), 55.7, 33.8, 23.9, 23.3; 19 FNMR (376 MHz, CDCl3) δ -75.89. HR-MS(ESI-TOF) m / z: Calcd for C 21 H 19 F3NO3S2 [M+H] + 454.0753, found 454.0751.

[0061] Example 5: Synthesis of compound (Ⅲ-e)

[0062]

[0063] Cu(MeCN)4PF6 (0.01 mmol) and ligand L4 (0.011 mmol) were added to a dry reaction tube and stirred under toluene for half an hour to complex the mixture. Then, trifluoroethylbenzo[b]thiophene-2,3-dione-derived ketoimine (Ie) (0.11 mmol), benzothiophene sulfone (II-a) (0.10 mmol), and potassium phosphate (0.02 mmol) were added sequentially. The reaction mixture was stirred at 0 °C. After the reaction was complete, the crude product was purified by column chromatography to give compound III-e.

[0064] The yield, melting point, stereoselectivity, optical rotation, 1H NMR, 1C NMR, and mass spectrometry data of the obtained Ⅲ-e are as follows: 59% yield, melting point 153.2–153.9 °C, >20:1 dr, 94% ee; [α] D 20 = - 63.1 (c 1.16, CH2Cl2). HPLC: Chiralpak IA column (80 / 20 hexane / EtOH; flow rate: 1.0 mL / min; λ = 254nm; t major = 12.69 min, t minor = 9.27 min); 1 H NMR (400 MHz, CDCl3) δ 7.68 (d, J= 7.8 Hz, 1H), 7.47 – 7.39 (m, 1H), 7.39 – 7.30 (m, 1H), 7.11 – 7.04 (m, 1H), 6.99 – 6.88 (m, 2H), 6.61 – 6.50 (m, 1H), 4.98 – 4.87 (m, 1H), 4.82 (d, J =9.8 Hz, 1H), 4.41 – 4.28 (m, 1H), 2.91 (d, J = 6.1 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 205.0, 162.9 (d, J = 253.3 Hz), 137.5, 134.8 (d, J = 9.8 Hz), 134.3,133.4, 131.6 (d, J = 3.5 Hz), 130.8, 128.1 (d, J = 9.0 Hz), 126.5, 124.4 (q,J = 282.3 Hz), 121.8, 114.1 (d, J = 22.2 Hz), 110.9 (d, J = 25.6 Hz), 81.5,64.4, 60.5 (q, J = 33.2 Hz), 55.6; 19 F NMR (376 MHz, CDCl3) δ -75.92, -108.44.HR-MS(ESI-TOF) m / z: Calcd for C 18 H 12 F4NO3S2 [M+H] + 430.0189, found 430.0191.

[0065] Example 6: Synthesis of compound (Ⅲ-f)

[0066]

[0067] Cu(MeCN)4PF6 (0.01 mmol) and ligand L4 (0.011 mmol) were added to a dry reaction tube and stirred under toluene for half an hour to complex the mixture. Then, trifluoroethylbenzo[b]thiophene-2,3-dione-derived ketoimine (If) (0.11 mmol), benzothiophene sulfone (II-a) (0.10 mmol), and potassium phosphate (0.02 mmol) were added sequentially. The reaction mixture was stirred at 0 °C. After the reaction was complete, the crude product was purified by column chromatography to give compound III-f.

[0068] The yield, melting point, stereoselectivity, optical rotation, 1H NMR, 1C NMR, and mass spectrometry data of the obtained Ⅲ-f are as follows: 70% yield, melting point 181.3–181.7 °C. o C, >20:1 dr, 94% ee; [α] D 20 = - 74.7 (c 1.23, CH2Cl2). HPLC: Chiralpak IA column (80 / 20 hexane / EtOH; flow rate: 1.0 mL / min; λ = 254nm; t major= 19.51 min, t minor = 15.34 min); 1 H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 7.9 Hz, 1H), 7.42 – 7.34 (m, 1H), 7.28 (d, J = 8.3 Hz, 1H), 7.21 (d, J =7.8 Hz, 1H), 7.15 – 7.08 (m, 1H), 7.04 (d, J = 7.8 Hz, 1H), 6.92 (d, J = 7.8Hz, 1H), 6.89 – 6.81 (m, 1H), 5.01 – 4.89 (m, 1H), 4.83 (d, J = 9.9 Hz, 1H), 4.41 – 4.28 (m, 1H), 2.94 (d, J = 6.5 Hz, 1H); 13 C NMR (101 MHz, CDCl3) δ205.8, 137.6, 136.0, 134.1, 133.6, 132.8, 130.5, 130.0, 127.0, 126.6, 126.2,124.4 (q, J = 282.2 Hz), 123.2, 121.7, 81.9, 64.4, 60.8 (q, J = 33.1 Hz), 55.7; 19 F NMR (376 MHz, CDCl3) δ -75.88. HR-MS(ESI-TOF) m / z: Calcd forC 18 H 13 F3NO3S2 [M+H] + 412.0283, found 412.0287.

[0069] Example 7: Synthesis of compound (Ⅲ-g)

[0070]

[0071] Cu(MeCN)4PF6 (0.01 mmol) and ligand L4 (0.011 mmol) were added to a dry reaction tube and stirred under toluene for half an hour to complex the mixture. Then, a trifluoroethylbenzo[b]thiophene-2,3-dione-derived ketoimine (Ig) (0.11 mmol), benzothiophene sulfone (II-a) (0.10 mmol), and potassium phosphate (0.02 mmol) were added sequentially. The reaction mixture was stirred at 0 °C. After the reaction was complete, the crude product was purified by column chromatography to give compound III-g.

[0072] The yield, melting point, stereoselectivity, optical rotation, 1H NMR, 1C NMR, and mass spectrometry data of the obtained Ⅲ-g are as follows: 84% yield, melting point 180.2–180.9 °C. o C, >20:1 dr, 94% ee; [α] D 20 = -36.8 (c 2.00, CH2Cl2). HPLC: Chiralpak IA column (80 / 20 hexane / EtOH; flow rate: 1.0 mL / min; λ = 254 nm;t major = 13.03 min, t minor = 10.24 min); 1 H NMR (400 MHz, CDCl3) δ 7.66 (d, J =7.9 Hz, 1H), 7.43 – 7.34 (m, 1H), 7.30 – 7.25 (m, 1H), 6.86 (d, J = 7.8 Hz,1H), 6.76 (s, 1H), 6.66 (s, 1H), 5.01 – 4.87 (m, 1H), 4.80 (d, J = 10.0 Hz,1H), 4.38 – 4.27 (m, 1H), 2.90 (d, J = 6.8 Hz, 1H), 2.21 (s, 3H), 1.97 (s,3H); 13 C NMR (101 MHz, CDCl3) δ 206.2, 137.7, 136.8, 135.8, 134.0, 133.8,132.0, 131.7, 130.4, 128.9, 126.6, 124.5 (d, J = 281.9 Hz), 124.1, 121.4,82.5, 64.4, 60.9 (q, J = 32.9 Hz), 55.6, 20.7, 20.2; 19F NMR (376 MHz, CDCl3)δ -75.84. HR-MS (ESI-TOF) m / z: Calcd for C 20 H 17 F3NO3S2 [M+H] + 440.0596, found440.0599.

[0073] Example 8: Synthesis of compound (Ⅲ-h)

[0074]

[0075] Cu(MeCN)4PF6 (0.01 mmol) and ligand L4 (0.011 mmol) were added to a dry reaction tube and stirred under toluene for half an hour to complex the mixture. Then, trifluoroethylbenzo[b]thiophene-2,3-dione-derived ketoimine (Ia) (0.11 mmol), benzothiophene sulfone (II-b) (0.10 mmol), and potassium phosphate (0.02 mmol) were added sequentially. The reaction mixture was stirred at 0 °C. After the reaction was complete, the crude product was purified by column chromatography to give compound III-h.

[0076] The yield, melting point, stereoselectivity, optical rotation, 1H NMR, 1C NMR, and mass spectrometry data of the obtained Ⅲ-h are as follows: 98% yield, melting point 149.5–150.3 °C. o C, >20:1 dr, 95% ee; [α] D 20 = +12.6 (c 2.00, CH2Cl2. HPLC: Chiralpak ID-H column (90 / 10 hexane / EtOH; flow rate: 1.0 mL / min; λ = 254 nm;t major = 30.59 min, t minor = 17.49 min); 1 H NMR (400 MHz, CDCl3) δ 7.54 (d, J =7.8 Hz, 1H), 7.51 – 7.39 (m, 1H), 7.13 (dd, J = 8.0, 1.9 Hz, 1H), 7.02 – 6.92(m, 2H), 6.76 (s, 1H), 4.99 (d, J = 10.2 Hz, 1H), 4.94 – 4.82 (m, 1H), 4.43 –4.35 (m, 1H), 2.89 (d, J = 6.9 Hz, 1H), 2.00 (s, 3H);13 C NMR (101 MHz, CDCl3)δ 205.5,158.9 (d, J = 257.1 Hz), 140.2 (d, J = 3.9 Hz), 136.8, 135.3, 133.1(d, J = 7.0 Hz), 131.0, 130.5, 126.8, 124.3 (q, J = 281.6 Hz), 123.0, 121.7 (d, J = 22.4 Hz), 120.2 (d, J = 19.7 Hz), 117.3 (d, J = 4.3 Hz), 80.7, 65.0,60.7 (q, J = 33.2 Hz), 51.3, 20.8; 19 F NMR (376 MHz, CDCl3) δ -75.64, -110.64.HR-MS (ESI-TOF) m / z: Calcd for C 19 H 14 F4NO3S2 [M+H] + 444.0346, found 444.0350.

[0077] Example 9: Synthesis of compound (Ⅲ-i)

[0078]

[0079] Cu(MeCN)4PF6 (0.01 mmol) and ligand L4 (0.011 mmol) were added to a dry reaction tube and stirred under toluene for half an hour to complex the mixture. Then, trifluoroethylbenzo[b]thiophene-2,3-dione-derived ketoimine (Ia) (0.11 mmol), benzothiophene sulfone (II-c) (0.10 mmol), and potassium phosphate (0.02 mmol) were added sequentially. The reaction mixture was stirred at 0 °C. After the reaction was complete, the crude product was purified by column chromatography to give compound III-i.

[0080] The yield, melting point, stereoselectivity, optical rotation, 1H NMR, 1C NMR, and mass spectrometry data of the obtained Ⅲ-i are as follows: 92% yield, melting point 232.1–232.9 °C. o C, >20:1 dr, 95% ee; [α] D 20= -14.7 (c 2.00, CH2Cl2). HPLC: Chiralpak IB column (80 / 20 hexane / EtOH; flow rate: 1.0 mL / min; λ = 254 nm; t major = 10.73 min, t minor = 9.10 min); 1 1H NMR (400 MHz, CDCl3) δ 7.74 – 7.59 (m, 1H), 7.17 – 7.04 (m, 2H), 6.97 (d, J = 8.0 Hz, 1H), 6.90 (s, 1H), 6.59 (dd, J = 8.1, 2.8 Hz, 1H), 4.93 (dd, J = 8.8, 5.3 Hz, 1H), 4.74 (d, J = 9.9 Hz, 1H), 4.44 – 4.30 (m, 1H), 2.94 (d, J = 6.5 Hz, 1H), 2.05 (d, J = 2.0 Hz, 3H); 13 13C NMR (101 MHz, CDCl3) δ 205.8, 165.8 (d, J = 258.3 Hz), 137.3, 137.0 (d, J = 9.8 Hz), 135.4, 133.7 (d, J = 2.8 Hz), 131.1, 129.1, 126.7, 124.3 (q, J = 282.0 Hz), 123.8 (d, J = 10.1 Hz), 123.2, 118.6 (d, J = 24.2 Hz), 113.4 (d, J = 23.8 Hz), 81.8, 64.9, 60.9 (q, J = 33.1 Hz), 55.1 (d, J = 1.8 Hz), 20.8; 19 19F NMR (376 MHz, CDCl3) δ -75.89, -102.26. HR-MS (ESI-TOF) m / z: Calcd for C 19 H 14 F4NO3S2 [M+H] + 444.0346, found 444.0350。

[0081] Example 10: Synthesis of compound (Ⅲ-j)

[0082]

[0083] Cu(MeCN)4PF6 (0.01 mmol) and ligand L4 (0.011 mmol) were added to a dry reaction tube and stirred under toluene for half an hour to complex. Then, trifluoroethylbenzo[b]thiophene-2,3-dione-derived ketoimine (Ia) (0.11 mmol), benzothiophene sulfone (II-d) (0.10 mmol), and potassium phosphate (0.02 mmol) were added sequentially. The reaction mixture was heated to 0°C. o The reaction was stirred at C. After the reaction was complete, the crude product was purified by column chromatography to obtain compound III-j;

[0084] The yield, melting point, stereoselectivity, optical rotation, 1H NMR, 1C NMR, and mass spectrometry data of the obtained Ⅲ-j are as follows: 98% yield, melting point 224.6–224.9 °C. o C, >20:1 dr, 96% ee; [α] D 20 = +42.2 (c 2.00, CH2Cl2). HPLC: Chiralpak IB column (80 / 20 hexane / EtOH; flow rate: 1.0 mL / min; λ = 254 nm;t major = 9.02 min, t minor = 8.45 min); 1 H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 7.8Hz, 1H), 7.52 – 7.41 (m, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.13 (d, J = 7.9 Hz,1H), 7.00 (d, J = 8.0 Hz, 1H), 6.61 (s, 1H), 5.09 (d, J = 10.0 Hz, 1H), 4.91– 4.73 (m, 1H), 4.50 – 4.35 (m, 1H), 2.92 (d, J = 7.6 Hz, 1H), 1.99 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 205.2, 140.2, 136.7, 135.0, 134.3, 134.1, 132.4,132.0, 131.2, 131.0, 127.0, 144.3 (q, J = 282.0 Hz), 123.0, 119.9, 80.4,66.0, 60.2 (q, J = 33.4 Hz), 53.3, 20.9; 19 F NMR (376 MHz, CDCl3) δ -75.4. HR-MS (ESI-TOF) m / z: Calcd for C 19 H 14 ClF3NO3S2 [M+H] + 460.0050, found 460.0056.

[0085] Example 11: Synthesis of compound (Ⅲ-k)

[0086]

[0087] Cu(MeCN)4PF6 (0.01 mmol) and ligand L4 (0.011 mmol) were added to a dry reaction tube and stirred under toluene for half an hour to complex the mixture. Then, trifluoroethylbenzo[b]thiophene-2,3-dione-derived ketoimine (Ia) (0.11 mmol), benzothiophene sulfone (II-e) (0.10 mmol), and potassium phosphate (0.02 mmol) were added sequentially. The reaction mixture was stirred at 0 °C. After the reaction was complete, the crude product was purified by column chromatography to give compound III-k.

[0088] The yield, melting point, stereoselectivity, optical rotation, 1H NMR, 1C NMR, and mass spectrometry data of III-k are as follows: 95% yield, melting point 214.6–215.2 °C. o C, >20:1 dr, 95% ee; [α] D 20 = +56.9 (c 2.00, CH2Cl2). HPLC: Chiralpak IB column (80 / 20 hexane / EtOH; flow rate: 1.0 mL / min; λ = 254 nm;t major = 10.59 min, t minor = 8.84 min); 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J =8.3 Hz, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.14 (d, J = 7.9 Hz, 1H), 6.97 (d, J =8.0 Hz, 1H), 6.87 (d, J = 4.5 Hz, 2H), 4.93 (dd, J = 8.7, 5.5 Hz, 1H), 4.71(d, J = 9.8 Hz, 1H), 4.41 – 4.28 (m, 1H), 2.94 (d, J = 6.5 Hz, 1H), 2.04 (s,3H); 13 C NMR (101 MHz, CDCl3) δ 205.8, 140.5, 137.2, 136.1, 135.7, 135.4,131.1, 131.0, 129.0, 126.7, 126.6, 124.3 (q, J = 282.0 Hz), 123.1, 122.5,81.9, 64.6, 61.0 (q, J = 33.2 Hz), 55.1, 20.8; 19 F NMR (376 MHz, CDCl3) δ -75.8. HR-MS (ESI-TOF) m / z: Calcd for C 19 H 14 ClF3NO3S2 [M+H] + 460.0050, found460.0056.

[0089] Example 12: Synthesis of compound (Ⅲ-l)

[0090]

[0091] Cu(MeCN)4PF6 (0.01 mmol) and ligand L4 (0.011 mmol) were added to a dry reaction tube and stirred under toluene for half an hour to complex the mixture. Then, trifluoroethylbenzo[b]thiophene-2,3-dione-derived ketoimine (Ia) (0.11 mmol), benzothiophene sulfone (II-f) (0.10 mmol), and potassium phosphate (0.02 mmol) were added sequentially. The reaction mixture was stirred at 0 °C. After the reaction was complete, the crude product was purified by column chromatography to give compound III-l.

[0092] The yield, melting point, stereoselectivity, optical rotation, 1H NMR, 1C NMR, and mass spectrometry data of the obtained Ⅲ-l are as follows: 92% yield, melting point 202.3–202.9 °C. o C, >20:1 dr, 92% ee; [α] D 20 = -113.7 (c 2.00, CH2Cl2). HPLC: Chiralpak IB column (80 / 20 hexane / EtOH; flow rate: 1.0 mL / min; λ = 254nm; t major = 12.86 min, t minor = 10.16 min); 1 H NMR (400 MHz, CDCl3) δ 7.30 (d, J= 7.9 Hz, 1H), 7.22 – 7.13 (m, 1H), 7.06 (d, J = 7.8 Hz, 1H), 6.93 (d, J =8.2 Hz, 2H), 6.82 (d, J = 7.7 Hz, 1H), 4.97 (t, J = 7.0 Hz, 1H), 4.76 (d, J =9.9 Hz, 1H), 4.41 – 4.28 (m, 1H), 2.93 (d, J = 6.9 Hz, 1H), 2.07 (s, 3H); 13 CNMR (101 MHz, CDCl3) δ 205.9, 137.4, 136.5, 135.6, 135.1, 134.9, 131.2,130.8, 129.4, 129.1, 126.9, 124.8, 124.3 (q, J = 282.1 Hz), 123.0, 82.1,65.4, 61.0 (q, J = 33.1 Hz), 54.8, 20.8; 19 F NMR (376 MHz, CDCl3) δ -75.8. HR-MS (ESI-TOF) m / z: Calcd for C 19 H 14 ClF3NO3S2 [M+H] + 460.0050, found 460.0053.

[0093] Example 13: Synthesis of compound (Ⅲ-m)

[0094]

[0095] Cu(MeCN)4PF6 (0.01 mmol) and ligand L4 (0.011 mmol) were added to a dry reaction tube and stirred under toluene for half an hour to complex the mixture. Then, trifluoroethylbenzo[b]thiophene-2,3-dione-derived ketoimine (Ia) (0.11 mmol), benzothiophene sulfone (II-g) (0.10 mmol), and potassium phosphate (0.02 mmol) were added sequentially. The reaction mixture was stirred at 0 °C. After the reaction was complete, the crude product was purified by column chromatography to give compound III-m.

[0096] The yield, melting point, stereoselectivity, optical rotation, 1H NMR, 1C NMR, and mass spectrometry data of the obtained Ⅲ-m are as follows: 90% yield, melting point 204.5–205.2 °C. o C, >20:1 dr, 96% ee; [α] D 20 = +52.2 (c 2.00, CH2Cl2). HPLC:Chiralpak IB column (85 / 15 hexane / EtOH; flow rate: 1.0 mL / min; λ = 254 nm;t major = 12.98 min, t minor = 11.59 min); 1 H NMR (400 MHz, CDCl3) δ 7.78 (d, J =7.7 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.44 – 7.35 (m, 1H), 7.13 (d, J = 7.9Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.53 (s, 1H), 5.08 (d, J = 9.9 Hz, 1H), 4.87 – 4.75 (m, 1H), 4.51 – 4.39 (m, 1H), 2.93 (d, J = 7.9 Hz, 1H), 1.97 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 205.1, 140.2, 137.4, 136.7, 134.8, 134.4,132.0, 131.5, 131.1, 127.1, 124.3 (q, J = 282.0 Hz), 124.0, 122.9, 120.5,80.4, 66.5, 60.0 (q, J = 33.5 Hz), 54.9, 20.9; 19F NMR (376 MHz, CDCl3) δ -75.27. HR-MS (ESI-TOF) m / z: Calcd for C 19 H 14 BrF3NO3S2 [M+H] + 503.9545, found503.9547.

[0097] Example 14: Synthesis of compound (Ⅲ-n)

[0098]

[0099] Cu(MeCN)4PF6 (0.01 mmol) and ligand L4 (0.011 mmol) were added to a dry reaction tube and stirred under toluene for half an hour to complex the compounds. Then, trifluoroethylbenzo[b]thiophene-2,3-dione-derived ketoimine (Ia) (0.11 mmol), benzothiophene sulfone (II-h) (0.10 mmol), and potassium phosphate (0.02 mmol) were added sequentially. The reaction mixture was stirred at 0 °C. After the reaction was complete, the crude product was purified by column chromatography to give compound III-n.

[0100] The yield, melting point, stereoselectivity, optical rotation, 1H NMR, 1C NMR, and mass spectrometry data of the obtained Ⅲ-n are as follows: 91% yield, melting point 208.6–209.5 °C. o C, >20:1 dr, 92% ee; [α] D 20 = -78.1 (c 2.00, CH2Cl2). HPLC:Chiralpak IB column (80 / 20 hexane / EtOH; flow rate: 1.0 mL / min; λ = 254 nm;t major = 15.62 min, t minor = 11.11 min); 1 H NMR (400 MHz, CDCl3) δ 7.48 (d, J =7.8 Hz, 1H), 7.12 – 7.00 (m, 2H), 6.92 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 7.7Hz, 1H), 5.04 – 4.88 (m, 1H), 4.73 (d, J = 9.8 Hz, 1H), 4.39 – 4.28 (m, 1H), 2.92 (d, J = 6.5 Hz, 1H), 2.06 (d, J = 2.0 Hz, 3H);13 C NMR (101 MHz, CDCl3) δ205.9, 137.4, 136.9, 136.8, 135.6, 134.8, 134.5, 130.8, 129.1, 126.9, 125.4,124.3 (q, J = 280.0 Hz), 122.9, 116.1, 82.1, 65.4, 61.1 (q, J = 33.1 Hz)54.5, 20.8; 19 F NMR (376 MHz, CDCl3) δ -75.8. HR-MS (ESI-TOF) m / z: Calcd forC 19 H 14 BrF3NO3S2 [M+H] + 503.9545, found 503.9545.

[0101] Example 15: Synthesis of compound (Ⅲ-o)

[0102]

[0103] Cu(MeCN)4PF6 (0.01 mmol) and ligand L4 (0.011 mmol) were added to a dry reaction tube and stirred under toluene for half an hour to complex the mixture. Then, trifluoroethylbenzo[b]thiophene-2,3-dione-derived ketoimine (Ia) (0.11 mmol), benzothiophene sulfone (II-i) (0.10 mmol), and potassium phosphate (0.02 mmol) were added sequentially. The reaction mixture was stirred at 0 °C. After the reaction was complete, the crude product was purified by column chromatography to give compound III-o.

[0104] The yield, melting point, stereoselectivity, optical rotation, 1H NMR, 1C NMR, and mass spectrometry data of the obtained Ⅲ-o are as follows: 62% yield, melting point 166.4–166.9 g / L. o C, >20:1 dr, 93% ee; [α] D 20 = -69.3 (c 2.00, CH2Cl2). HPLC:Chiralpak IB column (80 / 20 hexane / EtOH; flow rate: 1.0 mL / min; λ = 254 nm;t major = 12.58 min, t minor = 9.19 min); 1H NMR (400 MHz, CDCl3) δ 7.10 – 7.03 (m,2H), 6.93 (d, J = 8.0 Hz, 1H), 6.87 (s, 1H), 6.82 – 6.71 (m, 2H), 4.98 – 4.85(m, 1H), 4.71 (dd, J = 9.9, 1.9 Hz, 1H), 4.39 – 4.29 (m, 1H), 3.78 (s, 3H), 2.90 (d, J = 6.5 Hz, 1H), 2.04 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 206.3,161.3, 138.6, 137.1, 136.0, 130.7, 129.1, 127.5, 127.0, 125.4, 124.5 (q, J =282.0 Hz), 122.9, 122.8, 103.3, 81.9, 65.3, 60.7 (q, J = 32.9 Hz), 55.9,55.1, 20.9; 19 F NMR (376 MHz, CDCl3) δ -75.90. HR-MS (ESI-TOF) m / z: Calcd forC 20 H 17 F3NO4S2 [M+H] + 456.0546, found 456.0549.

[0105] Example 16: Synthesis of compound (Ⅲ-p)

[0106]

[0107] Cu(MeCN)4PF6 (0.01 mmol) and ligand L4 (0.011 mmol) were added to a dry reaction tube and stirred under toluene for half an hour to complex the mixture. Then, trifluoroethylbenzo[b]thiophene-2,3-dione-derived ketoimine (Ia) (0.11 mmol), benzothiophene sulfone (II-j) (0.10 mmol), and potassium phosphate (0.02 mmol) were added sequentially. The reaction mixture was stirred at 0 °C. After the reaction was complete, the crude product was purified by column chromatography to give compound III-p.

[0108] The yield, melting point, stereoselectivity, optical rotation, 1H NMR, 1C NMR, and mass spectrometry data of the obtained Ⅲ-p are as follows: 89% yield, melting point 232.4–232.8 °C. oC, >20:1 dr, 93% ee; [α] D 20 = +11.4 (c 2.00, CH2Cl2). HPLC:Chiralpak IA column (80 / 20 hexane / EtOH; flow rate: 1.0 mL / min; λ = 254 nm;t major = 8.43 min, t minor = 6.92 min); 1 H NMR (400 MHz, DMSO-d6) δ 7.65 (d, J =8.0 Hz, 1H), 7.36 – 7.19 (m, 2H), 6.97 (d, J = 8.0 Hz, 1H), 6.80 (s, 1H),6.69 (s, 1H), 4.97 (d, J = 6.2 Hz, 1H), 4.85 (d, J = 9.8 Hz, 2H), 4.74 – 4.65(m, 1H), 2.09 (s, 3H), 1.94 (s, 3H); 13 C NMR (101 MHz, DMSO-d6) δ 207.4,145.1, 136.7, 135.9, 135.1, 135.0, 131.6, 130.5, 128.7, 127.6, 127.2, 125.5(q, J = 282.6 Hz), 123.1, 121.2, 82.1, 64.5, 60.5 (q, J = 31.9 Hz), 21.3,20.9; 19 F NMR (376 MHz, DMSO-d6) δ -74.94. HR-MS (ESI-TOF) m / z: Calcd forC 20 H 17 F3NO3S2 [M+H] + 440.0596, found 440.0601.

[0109] Example 17: Synthesis of compound (Ⅲ-q)

[0110]

[0111] Cu(MeCN)4PF6 (0.01 mmol) and ligand L4 (0.011 mmol) were added to a dry reaction tube and stirred under toluene for half an hour to complex the mixture. Then, trifluoroethylbenzo[b]thiophene-2,3-dione-derived ketoimine (Ia) (0.11 mmol), benzothiophene sulfone (II-k) (0.10 mmol), and potassium phosphate (0.02 mmol) were added sequentially. The reaction mixture was stirred at 0 °C. After the reaction was complete, the crude product was purified by column chromatography to give compound III-q.

[0112] The yield, melting point, stereoselectivity, optical rotation, 1H NMR, 1C NMR, and mass spectrometry data of the obtained Ⅲ-q are as follows: 90% yield, melting point 209.6–209.9 g / cm³. o C, >20:1 dr, 91% ee; [α] D 20 = -66.4 (c 2.00, CH2Cl2). HPLC:Chiralpak IB column (80 / 20 hexane / EtOH; flow rate: 1.0 mL / min; λ = 254 nm;t major = 8.09 min, t minor = 7.54 min); 1 H NMR (400 MHz, CDCl3) δ 7.16 – 7.08 (m,2H), 7.04 (dd, J = 7.8, 1.8 Hz, 1H), 6.90 (d, J = 9.5 Hz, 2H), 6.70 (dd, J =5.7, 3.3 Hz, 1H), 4.94 (s, 1H), 4.75 (d, J = 9.9 Hz, 1H), 4.35 – 4.21 (m,1H), 2.89 (d, J = 6.3 Hz, 1H), 2.61 (s, 3H), 2.02 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 206.3, 137.0, 135.9, 135.8, 134.9, 134.0, 133.8, 131.8, 130.5,129.1, 127.0, 124.5 (q, J = 281.9 Hz), 123.8, 122.8, 82.1, 64.7, 60.9 (q, J =32.9 Hz), 55.3, 20.8, 16.7; 19F NMR (376 MHz, CDCl3) δ -75.84. HR-MS (ESI-TOF)m / z: Calcd for C 20 H 17 F3NO3S2 [M+H] + 440.0596, found 440.0605.

[0113] Example 18: Synthesis of compound (Ⅲ-r)

[0114]

[0115] Cu(MeCN)4PF6 (0.01 mmol) and ligand L4 (0.011 mmol) were added to a dry reaction tube and stirred under toluene for half an hour to complex the mixture. Then, trifluoroethylbenzo[b]thiophene-2,3-dione-derived ketoimine (Ia) (0.11 mmol), benzothiophene sulfone (II-l) (0.10 mmol), and potassium phosphate (0.02 mmol) were added sequentially. The reaction mixture was stirred at 0 °C. After the reaction was complete, the crude product was purified by column chromatography to give compound III-r.

[0116] The yield, melting point, stereoselectivity, optical rotation, 1H NMR, 1C NMR, and mass spectrometry data of the obtained Ⅲ-r are as follows: 93% yield, melting point 237.8–238.2 °C. o C, >20:1 dr, 94% ee; [α] D 20 = -66.4 (c 2.00, CH2Cl2). HPLC:Chiralpak IA column (80 / 20 hexane / EtOH; flow rate: 1.0 mL / min; λ = 254 nm;t major = 18.91 min, t minor = 14.41 min); 1H NMR (400 MHz, CDCl3) δ 7.70 (dd, J =8.3, 1.9 Hz, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.41 (d, J = 6.2 Hz, 3H), 7.24 –7.17 (m, 2H), 7.12 (dd, J = 7.9, 1.9 Hz, 1H), 7.04 (s, 1H), 6.94 – 6.85 (m,2H), 5.04 – 4.91 (m, 1H), 4.81 (d, J = 9.8 Hz, 1H), 4.42 – 4.31 (m, 1H), 2.94(d, J = 6.2 Hz, 1H), 2.01 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 206.1, 147.4,138.6, 137.2, 136.2, 135.9, 134.5, 130.9, 129.6, 129.1, 129.0, 128.9, 127.1,127.0, 125.0, 124.5 (q, J = 282.0 Hz), 122.7, 121.7, 82.1, 64.7, 61.0 (q, J =32.9 Hz), 55.7, 20.8; 19 F NMR (376 MHz, CDCl3) δ -75.82. HR-MS (ESI-TOF) m / z:Calcd for C 25 H 19 F3NO3S2 [M+H] + 502.0753, found 502.0759.

[0117] Example 19: Synthesis of compound (Ⅲ-s)

[0118]

[0119] Cu(MeCN)4PF6 (0.01 mmol) and ligand L4 (0.011 mmol) were added to a dry reaction tube and stirred under toluene for half an hour to complex the mixture. Then, trifluoroethylbenzo[b]thiophene-2,3-dione-derived ketoimine (Ia) (0.11 mmol), benzothiophene sulfone (II-m) (0.10 mmol), and potassium phosphate (0.02 mmol) were added sequentially. The reaction mixture was stirred at 0 °C. After the reaction was complete, the crude product was purified by column chromatography to give compound III-s.

[0120] The yield, melting point, stereoselectivity, optical rotation, 1H NMR, 1C NMR, and mass spectrometry data of the obtained Ⅲ-s are as follows: 98% yield, melting point 218.6–219.1 °C. o C, >20:1 dr, 94% ee; [α] D 20 = -66.4 (c 2.00, CH2Cl2). HPLC:Chiralpak IA column (80 / 20 hexane / EtOH; flow rate: 1.0 mL / min; λ = 254 nm;t major = 25.24 min, t minor = 18.58 min); 1 H NMR (400 MHz, DMSO-d6) δ 8.08 (s,1H), 7.72 – 7.59 (m, 3H), 7.52 – 7.38 (m, 3H), 7.29 (dd, J = 7.9, 1.9 Hz,1H), 6.96 (d, J = 8.1 Hz, 2H), 6.83 (s, 1H), 5.04 (d, J = 6.3 Hz, 1H), 4.98 (d, J = 9.8 Hz, 1H), 4.88 (t, J = 7.9 Hz, 1H), 4.84 – 4.76 (m, 1H), 1.91 (s,3H); 13 C NMR (101 MHz, DMSO-d6) δ 207.3, 142.9, 138.6, 138.0, 136.7, 136.0,133.9, 132.8, 130.6, 129.6, 129.0, 128.7, 127.8, 127.3, 125.5 (q, J = 282.3Hz), 123.4, 118.8, 82.2, 64.9, 60.5 (q, J = 31.9 Hz), 56.0, 20.8; 19 F NMR (376MHz, DMSO-d6) δ -74.85. HR-MS (ESI-TOF) m / z: Calcd for C 25 H 19 F3NO3S2 [M+H] + 502.0753, found 502.0761.

[0121] Example 20

[0122] Activity experiments of the compounds prepared in Examples 1-19

[0123] Specific experimental procedures: The anticancer activity of the synthesized polycyclic spirocyclic compounds was evaluated using the MTT assay with K562 leukemia cells. 5000 human K562 leukemia cells were seeded into 96-well cell culture plates and allowed to grow for 24 hours. Then, specific concentrations of the compounds synthesized in Examples 1-19 above were added, with the antitumor drug cisplatin as a control, and the treatment lasted for 48 hours. The mean 50% inhibitory concentration (IC50) of all compounds was then determined. 50 Each concentration was repeated at least 3 times, and all experiments were repeated 3 times. The average results are shown in Table 3.

[0124] Table 3: Results of Cell Viability Assay

[0125] ,

[0126] As can be seen from Table 1, the compounds in Examples 1-19 of this invention all exhibit different degrees of anti-K562 activity.

[0127] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A chiral polycyclic spirocyclic compound, characterized in that, It has the structure shown in the following structural formula (Ⅲ): ； In the above structural formula, R 1 base and R 2 The radical is independently selected from one of hydrogen, alkyl, alkoxy, aryl, or halogen.

2. The chiral polycyclic spirocyclic compound according to claim 1, characterized in that, The R 1 The radical is selected from hydrogen, methyl, ethyl, isopropyl, and halogen, and is either monosubstituted or disubstituted; the R 2 The radical is selected from one of hydrogen, methyl, methoxy, and phenyl.

3. The method for preparing the chiral polycyclic spirocyclic compound according to claim 1 or 2, characterized in that, A ketoimine (Ⅰ) derived from trifluoroethylbenzo[b]thiophene-2,3-dione and a benzothiophene sulfone (Ⅱ) were dissolved in an organic solvent. Then, a base and a pre-complexed copper salt and chiral ligand complex were added. After the reaction was complete, the chiral polycyclic spirocyclic compound (Ⅲ) was obtained by separation and purification. The trifluoroethylbenzo[b]thiophene-2,3-dione-derived ketoimine (I) has the following structure: ； Benzothiophene sulfone (II) has the following structure: 。 4. The method according to claim 3, characterized in that, The organic solvent is selected from one or a mixture of more than one of toluene, mesitylene, dichloromethane, chloroform, tetrahydrofuran, diethyl ether, acetonitrile, ethanol, methanol, 1,4-dioxane, and chlorobenzene.

5. The method according to claim 3, characterized in that, The chiral ligand is a chiral ferrocene diphenylphosphine oxazoline ligand having a structure of the following formula: L1, L2, L3, or L4: 。 6. The method according to claim 5, characterized in that, The chiral ligand has a structure as shown in formula L4.

7. The method according to claim 3, characterized in that, The base is selected from at least one of triethylamine, diisopropylethylamine, potassium carbonate, sodium carbonate, potassium phosphate, and dipotassium hydrogen phosphate.

8. The method according to claim 3, characterized in that, The reaction temperature is 0℃ to room temperature.

9. The method according to claim 3, characterized in that, The reaction temperature is 0℃.

10. The use of the chiral polycyclic spirocyclic compound of claim 1 in the preparation of anticancer drugs.

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