Chiral [oxindole-pyrrolidine-beta-lactam] bis-spiro compounds containing trifluoromethyl groups, and methods of making and using the same

Abstract

This invention discloses a chiral [oxyindole-pyrrolidine-β-lactam] bispirocyclic compound containing trifluoromethyl groups, with the following structural formula: The preparation includes the following steps: 1. Sequentially adding a metal catalyst, a chiral ligand, a base, indigo-derived trifluoromethylimine ylide, and 3-methylene β-lactam, followed by the addition of an organic solvent to obtain a mixture. The mixture is stirred at a reaction temperature of 0℃ to 50℃. 2. After the reaction is complete, the chiral [oxyindole-pyrrolidine-β-lactam] bispirocyclic compound containing trifluoromethyl groups is obtained through post-processing. The chiral [oxyindole-pyrrolidine-β-lactam] bispirocyclic compound containing trifluoromethyl groups prepared in this application lays a material foundation for in-depth drug activity research based on new drug development.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of organic synthesis, and particularly relates to a chiral [oxindole-pyrrolidine-beta-lactam] double spiro compound containing a trifluoromethyl group and a preparation method and application thereof. BACKGROUND

[0002] Spiro[oxindole-pyrrolidine] and spiro[pyrrolidine-beta-lactam] are two very important heterocyclic building blocks, which are widely present in drug active molecules and natural products. These molecular structures usually have superior drug activities such as antibacterial and antitumor activities, and are important lead compounds for new drug research and development. Therefore, the synthesis of such compounds has attracted widespread attention from synthetic chemists. However, the existing technical routes mainly focus on the asymmetric synthesis of spiro[oxindole-pyrrolidine] skeleton. The asymmetric synthesis of spiro[pyrrolidine-beta-lactam] skeleton, especially the asymmetric synthesis of chiral [oxindole-pyrrolidine-beta-lactam] double spiro compound, is still blank and is a challenging work. SUMMARY

[0003] The present application aims to provide a chiral [oxindole-pyrrolidine-beta-lactam] double spiro compound containing a trifluoromethyl group, so as to enrich the molecular structure diversity of chiral spiro[pyrrolidine-beta-lactam] compounds and lay a material foundation for in-depth drug activity research based on new drug research and development.

[0004] The chiral [oxindole-pyrrolidine-beta-lactam] double spiro compound containing a trifluoromethyl group in the present application has the following general structure:

[0005]

[0006] In the formula, Ar 1 are each independently selected from phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 5-methylphenyl, 5-methoxyphenyl, 5-fluorophenyl, 5-chlorophenyl, 5-bromophenyl, 5-nitrophenyl, 6-methoxyphenyl, 6-fluorophenyl, 6-chlorophenyl, 6-bromophenyl, 7-methylphenyl, 7-fluorophenyl, 7-chlorophenyl, 7-bromophenyl, 7-trifluoromethylphenyl, 5,7-dimethylphenyl, 4-pyridyl, 7-pyridyl;

[0007] R are each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, allyl, benzyl, phenyl.

[0008] The preparation method of the chiral [oxindole-pyrrolidine-beta-lactam] double spiro compound containing a trifluoromethyl group comprises the following steps:

[0009] Step one, successively adding metal catalyst, chiral ligand, base, indigo derived trifluoromethyl imine ylide and 3-methylene β-lactam, then adding organic solvent to obtain a mixture, and stirring the mixture at a reaction temperature of 0-50℃;

[0010] Step two, after the reaction is completed, separating by post-treatment to obtain chiral [oxindole-pyrrolidine-β-lactam] double spiro compound containing trifluoromethyl;

[0011] The structure of the indigo derived trifluoromethyl imine ylide is as follows:

[0012]

[0013] In the structure of the indigo derived trifluoromethyl imine ylide: Ar 1 each independently selected from phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 5-methylphenyl, 5-methoxyphenyl, 5-fluorophenyl, 5-chlorophenyl, 5-bromophenyl, 5-nitrophenyl, 6-methoxyphenyl, 6-fluorophenyl, 6-chlorophenyl, 6-bromophenyl, 7-methylphenyl, 7-fluorophenyl, 7-chlorophenyl, 7-bromophenyl, 7-trifluoromethylphenyl, 5,7-dimethylphenyl, 4-pyridyl, 7-pyridyl; each R is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, allyl, benzyl, phenyl;

[0014] The structure of the 3-methylene β-lactam is as follows:

[0015]

[0016] In the structure of the 3-methylene β-lactam: Ar 2 each independently selected from 2-methylphenyl, 2-methoxyphenyl, 2-trifluoromethoxyphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-iodophenyl, 2-cyanophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-trifluoromethoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-iodophenyl, 3-cyanophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 4-cyanophenyl.

[0017] Further, the metal catalyst is copper salt or silver salt. The use thereof can obtain relatively high yield and stereoselectivity of the product.

[0018] Further, the copper salt is copper sulfate, basic copper carbonate, copper acetate, copper trifluoroacetate, cuprous chloride, cuprous bromide, copper chloride, copper bromide, copper cyanide, copper triflate, cuprous oxide or copper oxide.

[0019] Further, the silver salt is silver acetate, silver nitrate, silver trifluoroacetate, silver triflate, silver hexafluoroantimonate or silver benzoate.

[0020] Further, the chiral ligand is any one of the following structures, preferably L3.

[0021]

[0022] The chiral ligand of the above structure has relatively high stereoselectivity of the obtained product.

[0023] Further, the base is an organic base or an inorganic base. Preferably, the base is an inorganic base.

[0024] Further, the base is triethylamine, diisopropylethylamine, 1,8-diazabicycloundec-7-ene, sodium acetate, potassium acetate, sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, cesium pivalate, sodium methoxide, sodium tert-butoxide or potassium tert-butoxide. Preferably, the base is cesium carbonate. The base is selected to have relatively high yield and stereoselectivity of the obtained product.

[0025] Further, the organic solvent is a hydrocarbon, an ether, an ester, an amide, a nitrile, a sulfone or a sulfoxide, preferably a hydrocarbon. The hydrocarbon is preferably toluene. The use of the hydrocarbon has relatively high yield and stereoselectivity of the obtained product.

[0026] Further, the reaction temperature is 10°C. The use of the temperature has relatively high yield and stereoselectivity of the obtained product.

[0027] Further, the step one is performed in a closed container. This helps to prevent the evaporation of the organic solvent.

[0028] Further, the post-treatment method in the step two includes recrystallization and / or column chromatography. Preferably, the separation method is column chromatography. The use of the separation method has relatively high yield of the obtained product.

[0029] Under the preferred conditions, the optical purity of the chiral [oxindole-pyrrolidine-β-lactam] bis-spiro compound containing trifluoromethyl group is ≧90%.

[0030] The chiral [oxindole-pyrrolidine-beta-lactam] double spiro compound containing trifluoromethyl provided by the present application is prepared by dissolving a metal catalyst, a chiral ligand, a base, an isatin-derived trifluoromethyl imine ylide and 3-methylene beta-lactam in an organic solvent, under the catalysis of the metal / chiral ligand complex and the base, the isatin-derived trifluoromethyl imine ylide and 3-methylene beta-lactam undergo asymmetric [3+2] cyclization reaction to produce the chiral [oxindole-pyrrolidine-beta-lactam] double spiro compound containing trifluoromethyl with high optical purity (high dr and ee), the product is separated by simple column chromatography or recrystallization to obtain the chiral [oxindole-pyrrolidine-beta-lactam] double spiro compound containing trifluoromethyl, the method has the advantages of economical catalyst system, mild reaction conditions and convenient operation, and the prepared chiral compound has novel structure and high optical purity, which lays a material foundation for enriching the asymmetric synthesis technology and molecular structure diversity of chiral spiro [pyrrolidine-beta-lactam] compounds and in-depth development of drug activity research based on new drug research and development.

[0031] The metal / chiral ligand and the base catalyze the asymmetric [3+2] cyclization reaction of the isatin-derived trifluoromethyl imine ylide and the 3-methylene beta-lactam substrate by the following mode, which is illustrated by taking the cuprous chloride / L3 and cesium carbonate catalysis process as an example: first, the isatin-derived trifluoromethyl imine ylide is deprotonated by cesium carbonate to generate trifluoromethyl imine ylide anion. Then, the anion further forms coordination with the in-situ generated chiral metal complex, under the chiral induction, the Si face of the coordinated trifluoromethyl imine ylide anion attacks the Si face of the 3-methylene beta-lactam to complete the stereoselective [3+2] cyclization cascade reaction, and generate the chiral [oxindole-pyrrolidine-beta-lactam] double spiro compound containing trifluoromethyl. The principle process of the reaction is shown in the following formula:

[0032]

[0033] It is verified that the chiral [oxindole-pyrrolidine-beta-lactam] double spiro compound containing trifluoromethyl has certain antitumor (including breast cancer cell MDA-MB-231, liver cancer cell HepG2 and cervical cancer cell Hela) drug activity. Therefore, the present application also provides the application of the chiral [oxindole-pyrrolidine-beta-lactam] double spiro compound containing trifluoromethyl in the preparation of antitumor drugs; the tumor is breast cancer, liver cancer or cervical cancer. BRIEF DESCRIPTION OF DRAWINGS

[0034] Figure 1 The single crystal of the compound 3a prepared in Example 1 is shown in the following figure;

[0035] Figure 2 The single crystal of the compound 3a prepared in Example 1 is shown in the following figure;1 H NMR spectrum;

[0036] Figure 3 H NMR spectrum of compound 3a prepared in Example 1 13 C NMR spectrum;

[0037] Figure 4 H NMR spectrum of compound 3b prepared in Example 2 1 H NMR spectrum;

[0038] Figure 5 H NMR spectrum of compound 3b prepared in Example 2 13 C NMR spectrum;

[0039] Figure 6 H NMR spectrum of compound 3c prepared in Example 3 1 H NMR spectrum;

[0040] Figure 7 H NMR spectrum of compound 3c prepared in Example 3 13 C NMR spectrum. DETAILED DESCRIPTION

[0041] The following is further described in detail through specific embodiments:

[0042] The present application is a preparation method of a chiral [oxindole-pyrrolidine-β-lactam] double spiro compound containing a trifluoromethyl group, comprising the following steps:

[0043] Step one, sequentially add a metal catalyst, a chiral ligand, a base, an isatin-derived trifluoromethyl imine ylide and 3-methylene β-lactam into a reaction tube, and then add an organic solvent, and stir the mixture at a reaction temperature of 0-50°C; the amount ratio of trifluoromethyl imine ylide to 3-methylene β-lactam ranges from 1:0.5 to 1:3;

[0044] Step two, after the reaction is completed, separate the chiral [oxindole-pyrrolidine-β-lactam] double spiro compound containing a trifluoromethyl group through post-treatment.

[0045] For example: 0.01 mmol of CuCl, 0.015 mmol of chiral ligand L3, 0.02 mmol of Cs2CO3, 0.2 mmol of isatin-derived trifluoromethyl imine ylide, 0.3 mmol of 3-methylene β-lactam, dissolved in 2 mL of toluene, stirred at a reaction temperature of 10°C for a corresponding time; then, the reaction solution is directly separated by column chromatography to obtain the corresponding chiral [oxindole-pyrrolidine-β-lactam] double spiro compound 3 containing a trifluoromethyl group.

[0046] The preparation method of the chiral [oxindole-pyrrolidine-beta-lactam] double spiro compound containing trifluoromethyl of the present application uses trifluorimine ylide with different structures and 3-methylene beta-lactam to synthesize different compounds 3a~z, and the specific structural formula is as follows:

[0047]

[0048] In the present application, the diastereoselectivity, enantioselectivity and absolute configuration of the product are measured by nuclear magnetic resonance instrument, chiral high-phase liquid chromatograph and X-ray single crystal diffractometer respectively.

[0049] Example 1:

[0050]

[0051] In a 10 mL dry reaction bottle, 0.01 mmol CuCl, 0.015 mmol chiral ligand L3, 0.02 mmol Cs2CO3, 0.2 mmol indigo-derived trifluorimine ylide, and 0.3 mmol 3-methylene beta-lactam were dissolved in 2 mL of toluene, and the mixture was stirred at 10 DEG C under sealed conditions for 48 hours, and the reaction progress was monitored by thin layer chromatography. After the reaction was completed, the mixture was separated and purified by column chromatography to obtain the double spiro product 3a (yield 99%, ee 96%, dr value > 20:1).

[0052] Product 3a characterization data: White solid; 79.4 mg, 99% yield; >20:1 dr, 96% ee; [alpha] D 25 = 76.9 (c 0.50, CH2Cl2). The ee was determined by HPLC (Chiralpak OX-3, i-PrOH / hexane = 30 / 70, flow rate 1.0 mL / min, λ = 210 nm, major diastereomer: t minor = 14.6 min, t major = 15.7 min). 1H NMR (400 MHz, DMSO-d6): major diastereomer: δ 7.67 (d, J = 7.6 Hz, 1H), 7.33-7.26 (m, 3H), 7.17 (d, J = 8.0 Hz, 2H), 7.04 (dd, J = 16.0, 8.0 Hz, 2H), 6.95 (d, J = 8.0 Hz, 1H), 4.30-4.27 (m, 1H), 4.08 (d, J = 8.8 Hz, 1H), 3.85 (d, J = 6.8 Hz, 1H), 3.70 (d, J = 6.4 Hz, 1H), 3.19 (t, J = 10.8 Hz, 1H), 3.05 (s, 3H), 2.66 (q, J = 5.6 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6): major diastereomer: δ 175.6, 163.0, 144.3, 137.5, 130.1, 129.2, 125.7, 125.1, 123.9, 121.7, 116.1, 108.4, 69.6, 64.7, 57.2 (q, J = 31.3 Hz, 1C), 49.1, 31.0, 25.9. HRMS (ESI-TOF) calcd. for C 21 H 19 F3N3O2[M+H] + 402.1424; found: 402.1420.

[0053] The single crystal of product 3a is shown in the attached figure Figure 1 and its single crystal data is shown in the following table:

[0054]

[0055]

[0056] Example 2:

[0057]

[0058] In a 10 mL dry reaction flask, 0.01 mmol CuCl, 0.015 mmol chiral ligand L3, 0.02 mmol Cs2CO3, 0.2 mmol 4-chloro-indigo-derived trifluoromethaniminium ylide, 0.3 mmol 3-methylene β-lactam were dissolved in 2 mL toluene, the mixture was stirred at 10 °C under airtight condition for 48 hours, the reaction progress was monitored by thin layer chromatography. After the reaction was completed, the mixture was separated and purified by column chromatography to obtain the double spiro product 3b (yield 97%, ee 93%, dr value > 20: 1).

[0059] Product 3b characterization data: White solid; 84.5 mg, 97% yield; >20:1 dr, 93% ee; [a] D 25 = 47.6 (c 0.50, CH2Cl2). The ee was determined by HPLC (Chiralpak IA-3, i-PrOH / hexane = 15 / 85, flow rate 0.8 mL / min, λ = 214 nm, major diastereomer: t minor = 19.0 min, t major = 21.5 min). 1 H NMR (400 MHz, DMSO-d6): major diastereomer: δ 7.34 (t, J = 8.0 Hz, 1H), 7.29 (t, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 8.4 Hz, 1H), 7.05 (t, J = 7.2 Hz, 1H), 6.96 (d, J = 7.6 Hz, 1H), 4.35 - 4.20 (m, 1H), 3.89 (t, J = 6.0 Hz, 2H), 3.62 (d, J = 6.8 Hz, 1H), 3.05 (s, 3H), 2.86 (t, J = 11.6 Hz, 1H), 2.70 - 2.66 (m, 1H). 13 C NMR (101 MHz, DMSO-d6): major diastereomer: δ 175.4, 162.6, 146.1, 137.3, 131.7, 130.6, 129.3, 124.1, 123.2, 123.1, 116.3, 107.8, 70.0, 64.7, 57.9 (q, J = 31.3 Hz, 1C), 51.9, 32.9, 26.4. HRMS (ESI-TOF) calcd. for C 21 H 18 ClF3N3O2[M+H] + 436.1034; found: 436.1037.

[0060] Example 3:

[0061]

[0062] In a 10 mL dry reaction flask, 0.01 mmol CuCl, 0.015 mmol chiral ligand L3, 0.02 mmol Cs2CO3, 0.2 mmol 4-bromoindoine-derived trifluoromethanimine ylide, 0.3 mmol 3-methylene β-lactam were dissolved in 2 mL toluene, the mixture was stirred at 10 °C under airtight condition for 48 h, the reaction progress was monitored by thin layer chromatography. After the reaction was completed, the mixture was separated and purified by column chromatography to obtain the bis-spirocyclic product 3c (yield 40%, ee 93%, dr value > 20:1).

[0063] Product 3c characterization data: White solid; 38.0 mg, 40% yield; >20:1 dr, 93% ee; [a] D 25 = 28.8 (c 0.36, CH2Cl2). The ee was determined by HPLC (Chiralpak IA-3, i-PrOH / hexane = 15 / 85, flow rate 0.8 mL / min, λ = 254 nm, major diastereomer: t minor = 20.8 min, t major = 23.4 min). 1 H NMR (400 MHz, DMSO-d6): major diastereomer: δ 7.31-7.25 (m, 4H), 7.20-7.17 (m, 2H), 7.06 (t, J = 7.2 Hz, 1H), 7.00 (dd, J = 6.4, 2.4 Hz, 1H), 4.36-4.32 (m, 1H), 3.87 (d, J = 6.4 Hz, 1H), 3.81 (d, J = 6.0 Hz, 1H), 3.63 (d, J = 6.4 Hz, 1H), 3.04 (s, 3H), 2.82 (t, J = 11.6 Hz, 1H), 2.72-2.68 (m, 1H). 13 C NMR (101 MHz, DMSO-d6): major diastereomer: δ 175.6, 162.6, 146.4, 137.3, 131.9, 129.3, 126.3, 124.7, 124.1, 119.8, 116.3, 108.3, 70.6, 64.7, 58.2 (q, J = 30.3 Hz, 1C), 52.2, 26.3. HRMS (ESI-TOF) calcd. for C 21 H 18 BrF3N3O2[M+H] +480.0529; found: 480.0533.

[0064] Example 4:

[0065]

[0066] In a 10 mL dry reaction vial, 0.01 mmol CuCl, 0.015 mmol chiral ligand L3, 0.02 mmol Cs2CO3, 0.2 mmol 5-methyl isatin-derived trifluoromethanimine ylide, 0.3 mmol 3-methylene β-lactam were dissolved in 2 mL toluene, the mixture was stirred at 10 °C under sealed condition for 72 h, the reaction progress was monitored by TLC. After the reaction was completed, the mixture was separated and purified by column chromatography to obtain the bis-spiro product 3d (yield 73%, ee 96%, dr value > 20:1).

[0067] Product 3d characterization data: White solid; 60.6 mg, 73% yield; >20:1 dr, 96% ee; [a] D 25 = 6.1 (c 0.50, CH2Cl2); The ee was determined by HPLC (Chiralpak OX-3, i-PrOH / hexane = 20 / 80, flow rate 1.0 mL / min, λ = 254 nm, major diastereomer: t minor = 25.3 min, t major = 21.6 min). 1 H NMR (400 MHz, DMSO-d6): major diastereomer: δ 7.49 (s, 1H), 7.29 (t, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.0 Hz, 1H), 7.04 (t, J = 7.6 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 4.30-4.23 (m, 1H), 4.00 (d, J = 8.8 Hz, 1H), 3.83 (d, J = 6.4 Hz, 1H), 3.68 (d, J = 6.8 Hz, 1H), 3.16 (t, J = 11.6 Hz, 1H), 3.03 (s, 3H), 2.65 (dd, J = 12.0, 6.4 Hz, 1H), 2.29 (s, 3H). 13C NMR (101 MHz, DMSO-d6): major diastereomer: δ 175.5, 163.2, 141.9, 137.6, 130.7, 130.2, 129.2, 126.4, 125.4, 123.9, 116.1, 108.2, 69.6, 64.6, 57.1 (q, J = 31.3 Hz, 1C), 49.1, 31.2, 26.0, 20.8. HRMS (ESI-TOF) calcd. for C 22 H 21 F3N3O2[M+H] + 416.1580; found: 416.1588.

[0068] Example 5:

[0069]

[0070] In a 10 mL dry reaction flask, 0.01 mmol CuCl, 0.015 mmol chiral ligand L3, 0.02 mmol Cs2CO3, 0.2 mmol 5-methoxyisatin-derived trifluoromethanimine ylide, 0.3 mmol 3-methylene β-lactam were dissolved in 2 mL toluene, the mixture was stirred at 10 °C under closed condition for 48 h, the reaction progress was monitored by thin layer chromatography. After the reaction was completed, the mixture was separated and purified by column chromatography to obtain the bis-spirocyclic product 3e (yield 99%, ee 99%, dr value > 20:1).

[0071] Product 3e characterization data: White solid; 85.7 mg, 99% yield; >20:1 dr, 99% ee; [a] D 25 = -19.6 (c 0.41, CH2Cl2). The ee was determined by HPLC (Chiralpak OZ-3, i-PrOH / hexane = 12 / 88, flow rate 1.0 mL / min, λ = 254 nm, major diastereomer: t minor = 44.1 min, t major = 49.7 min). 1H NMR (400 MHz, DMSO-d6): major diastereomer: δ 7.34 (s, 1H), 7.29 (t, J = 8.0 Hz, 2H), 7.20-7.18 (m, 2H), 7.04 (t, J = 7.6 Hz, 1H), 6.86-6.86 (m, 2H), 4.30-4.25 (m, 1H), 4.00 (d, J = 8.8 Hz, 1H), 3.85 (d, J = 6.4 Hz, 1H), 3.73 (s, 3H), 3.68 (d, J = 6.4 Hz, 1H), 3.17 (t, J = 11.2 Hz, 1H), 3.01 (s, 3H), 2.64 (dd, J = 12.4, 6.8 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6): major diastereomer: δ 175.5, 163.2, 154.9, 137.6, 137.6, 129.4, 126.5, 124.1, 116.2, 114.4, 113.3, 109.0, 70.0, 64.9, 57.3 (q, J = 31.3 Hz, 1C), 55.7, 49.3, 31.2, 26.1. HRMS (ESI-TOF) calcd. for C 22 H 21 F3N3O3[M+H] + 432.1530; found: 432.1531.

[0072] Example 6:

[0073]

[0074] In a 10 mL dry reaction flask, 0.01 mmol CuCl, 0.015 mmol chiral ligand L3, 0.02 mmol Cs2CO3, 0.2 mmol 5-fluoroindigo-derived trifluoromethanimine ylide, 0.3 mmol 3-methylene β-lactam were dissolved in 2 mL of toluene, the mixture was stirred at 10 °C under airtight conditions for 48 hours, and the reaction progress was monitored by thin layer chromatography. After the reaction was completed, the mixture was separated and purified by column chromatography to obtain the double spiro product 3f (yield 79%, ee 98%, dr value > 20:1).

[0075] Product 3f characterization data: White solid; 66.2 mg, 79% yield; >20:1 dr, 98% ee; [a] D 25= 62.1 (c 0.50, CH2Cl2). The ee was determined by HPLC (Chiralpak IA-3, i-PrOH / hexane = 15 / 85, flow rate 0.8 mL / min, λ = 214 nm, major diastereomer: t minor = 29.6 min, t major = 22.8 min). 1 H NMR (400 MHz, DMSO-d6): major diastereomer: δ 7.69 (t, J = 6.4 Hz, 1H), 7.31-7.27 (m, 2H), 7.19-7.17 (m, 2H), 7.06-7.03 (m, 1H), 6.94 (d, J = 10.0, 1H), 6.85 (t, J = 9.6, 1H), 4.30-4.23 (m, 1H), 4.09 (d, J = 8.8 Hz, 1H), 3.82-3.70 (m, 2H), 3.15 (t, J = 11.6, 1H), 3.06 (s, 3H), 2.69-2.64 (m, 1H). 13 C NMR (101 MHz, DMSO-d6): major diastereomer: 13 C NMR (101 MHz, DMSO-d6) δ 175.9, 163.5 (d, J = 243.0 Hz, 1C), 162.9, 146.3 (d, J = 12.1 Hz, 1C), 137.5, 129.2, 127.3 (d, J = 10.1 Hz, 1C), 123.9, 120.8, 116.1, 107.6 (d, J = 23.2 Hz, 1C), 97.4 (d, J = 28.3 Hz, 1C), 69.3, 64.7, 57.1 (q, J = 31.3 Hz, 1C), 49.2, 30.9, 26.2. HRMS (ESI-TOF) calcd. for C 21 H 18 F4N3O2[M+H] + 420.1330; found: 420.1333.

[0076] Example 7:

[0077]

[0078] In a 10 mL dry reaction flask, 0.01 mmol CuCl, 0.015 mmol chiral ligand L3, 0.02 mmol Cs2CO3, 0.2 mmol 5-chloro-indigo-derived trifluoromethanimine ylide, 0.3 mmol 3-methylene β-lactam were dissolved in 2 mL toluene, the mixture was stirred at 10 °C under airtight condition for 48 h, the reaction progress was monitored by thin layer chromatography. After the reaction was completed, the mixture was separated and purified by column chromatography to obtain the bis-spirocyclic product 3g (yield 42%, ee > 99%, dr value > 20:1).

[0079] Product 3g characterization data: White solid; 36.5 mg, 42% yield; >20:1 dr, >99% ee; [a] D 25 = -21.0 (c 0.50, CH2Cl2). The ee was determined by HPLC (Chiralpak OX-3, i-PrOH / hexane = 30 / 70, flow rate 1.0 mL / min, λ = 254 nm, major diastereomer: t minor = 10.1 min, t major = 12.7 min). 1 H NMR (400 MHz, DMSO-d6): major diastereomer: δ 7.77 (s, 1H), 7.38 (dd, J = 8.4, 2.0 Hz, 1H), 7.30 (t, J = 7.6 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 7.05 (t, J = 7.2 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 4.28-4.26 (m, 1H), 4.14 (d, J = 8.8 Hz, 1H), 3.73 (dd, J = 19.2, 6.8 Hz 2H), 3.12-3.05 (m, 4H), 2.68 (dd, J = 12.4, 6.4 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6): major diastereomer: δ 175.3, 162.8, 143.1, 137.5, 129.9, 129.2, 127.6, 127.3, 125.8 (d, J = 5.1 Hz, 1C), 123.9, 116.2, 109.9, 69.7, 64.6, 57.2 (q, J = 31.3 Hz, 1C), 49.2, 31.0, 26.1. HRMS (ESI-TOF) calcd. for C 21 H 18ClF3N3O2[M+H] + 436.1034; found: 436.1038.

[0080] Example 8:

[0081]

[0082] In a 10 mL dry reaction vial, 0.01 mmol CuCl, 0.015 mmol chiral ligand L3, 0.02 mmol Cs2CO3, 0.2 mmol 5-iodo-Indigo-derived trifluoromethanimine ylide, 0.3 mmol 3-methylene β-lactam were dissolved in 2 mL toluene, the mixture was stirred at 10 °C under sealed condition for 48 h, the reaction progress was monitored by TLC. After the reaction was completed, the mixture was separated and purified by column chromatography to obtain the bis-spiro product 3h (yield 79%, ee 95%, dr value >20:1).

[0083] Product 3h characterization data: White solid; 83.3 mg, 79% yield; >20:1 dr, 95% ee; [a] D 25 = -44.1 (c 0.50, CH2Cl2). The ee was determined by HPLC (Chiralpak OX-3, i-PrOH / hexane = 20 / 80, flow rate 1.0 mL / min, λ = 254 nm, major diastereomer: t minor = 18.0 min, t major = 20.8 min). 1 H NMR (400 MHz, DMSO-d6): major diastereomer: δ 8.00 (s, 1H), 7.65 (dd, J = 8.4, 1.6 Hz, 1H), 7.32-7.28 (m, 2H), 7.21-7.18 (m, 2H), 7.05 (t, J = 7.2 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 4.30-4.24 (m, 1H), 4.12 (d, J = 8.4 Hz, 1H), 3.72 (s, 2H), 3.10 (t, J = 11.2 Hz, 1H), 3.03 (s, 3H), 2.67 (dd, J = 12.4, 6.4 Hz, 1H). 13C NMR (101 MHz, DMSO-d6): major diastereomer: δ 175.1, 162.9, 144.0, 138.6, 137.5, 133.9, 129.3, 127.8, 124.0, 116.2, 111.0, 84.7, 69.5, 64.7, 57.2 (q, J = 31.3 Hz, 1C), 49.3, 31.0, 26.1. HRMS (ESI-TOF) calcd. for C 21 H 18 F3IN3O2[M+H] + 528.0390; found: 528.0396.

[0084] Example 9:

[0085]

[0086] In a 10 mL dry reaction flask, 0.01 mmol CuCl, 0.015 mmol chiral ligand L3, 0.02 mmol Cs2CO3, 0.2 mmol 6-chloro-indigo-derived trifluoromethanimine ylide, 0.3 mmol 3-methylene β-lactam were dissolved in 2 mL toluene, the mixture was stirred at 10 °C under sealed condition for 72 h, the reaction progress was monitored by TLC. After the reaction was completed, the mixture was separated and purified by column chromatography to obtain the bis-spiro product 3i (yield 69%, ee 94%, dr value > 20:1).

[0087] Product 3i characterization data: White solid; 60.0 mg, 69% yield; >20:1 dr, 94% ee; [a] D 25 = 9.3 (c 0.50, CH2Cl2); The ee was determined by HPLC (Chiralpak OX-3, i-PrOH / hexane = 30 / 70, flow rate 1.0 mL / min, λ = 254 nm, major diastereomer: t minor = 13.3 min, t major = 19.2 min). 1H NMR (400 MHz, DMSO-d6): major diastereomer: δ 7.67 (d, J = 8.0 Hz, 1H), 7.29 (t, J = 8.0 Hz, 2H), 7.18 (d, J = 7.6 Hz, 2H), 7.11-7.08 (m, 2H), 7.05 (t, J = 7.2 Hz, 1H), 4.30-4.24 (m, 1H), 4.12 (d, J = 8.4 Hz, 1H), 3.74 (dd, J = 34.8, 6.8 Hz, 2H), 3.15-3.06 (m, 4H), 2.66 (dd, J = 12.4, 6.8 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6): major diastereomer: δ 175.6, 162.9, 145.8, 137.5, 134.7, 129.3, 127.1, 124.0, 121.3, 116.2, 109.0, 69.3, 64.7, 57.2 (q, J = 30.3 Hz, 1C), 49.1, 30.9, 26.2. HRMS (ESI-TOF) calcd. for C 21 H 18 ClF3N3O2[M+H] + 436.1034; found: 436.1046.

[0088] Example 10:

[0089]

[0090] In a 10 mL dry reaction flask, 0.01 mmol CuCl, 0.015 mmol chiral ligand L3, 0.02 mmol Cs2CO3, 0.2 mmol 6-bromo-isatin-derived trifluoromethanimine ylide, 0.3 mmol 3-methylene β-lactam were dissolved in 2 mL toluene, the mixture was stirred at 10 °C under sealed condition for 48 hours, the reaction progress was monitored by thin layer chromatography. After the reaction was completed, the mixture was separated and purified by column chromatography to obtain the bis-spirocyclic product 3j (yield 35%, ee 89%, dr value > 20: 1).

[0091] Product 3j characterization data: White solid; 33.5 mg, 35% yield; > 20: 1 dr, 89% ee; [a] D 25= 55.8 (c 0.50, CH2Cl2). The ee was determined by HPLC (Chiralpak OX-3, i-PrOH / hexane = 30 / 70, flow rate 1.0 mL / min, λ = 254 nm, major diastereomer: t minor = 14.7 min, t major = 23.8 min). 1 H NMR (400 MHz, DMSO-d6): major diastereomer: δ 7.60 (d, J = 8.4 Hz 1H), 7.29 (t, J = 8.0 Hz, 2H), 7.25-7.23 (m, 2H), 7.18 (d, J = 8.0 Hz, 2H), 7.05 (t, J = 7.6 Hz, 1H), 4.30-4.23 (m, 1H), 4.13 (d, J = 8.8 Hz, 1H), 3.74 (dd, J = 32.8, 6.8 Hz 2H), 3.15-3.09 (m, 1H), 3.06 (s, 3H), 2.67 (dd, J = 12.4, 6.4 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6): major diastereomer: δ 175.6, 162.9, 145.9, 137.5, 129.3, 127.5, 124.5, 124.3, 124.0, 123.2, 116.2, 111.8, 69.4, 64.6, 57.2 (q, J = 30.3 Hz, 1C), 49.1, 31.0, 26.2. HRMS (ESI-TOF) calcd. for C 21 H 18 BrF3N3O2[M+H] + 480.0529; found: 480.0523.

[0092] Example 11:

[0093]

[0094] In a 10 mL dry reaction flask, 0.01 mmol CuCl, 0.015 mmol chiral ligand L3, 0.02 mmol Cs2CO3, 0.2 mmol 7-methyl isatin-derived trifluoromethanimine ylide, 0.3 mmol 3-methylene β-lactam were dissolved in 2 mL toluene, the mixture was stirred at 10 °C under airtight condition for 48 h, the reaction progress was monitored by thin layer chromatography. After the reaction was completed, the mixture was separated and purified by column chromatography to obtain the bis-spirocyclic product 3k (yield 95%, ee 97%, dr value > 20:1).

[0095] Product 3k characterization data: White solid; 78.6 mg, 95% yield; >20:1 dr, 97% ee; 150.2 (c 0.50, CH2Cl2); The ee was determined by HPLC (Chiralpak OX-3, i-PrOH / hexane = 20 / 80, flow rate 1.0 mL / min, λ = 254 nm, major diastereomer: t minor = 29.6 min, t major = 24.6 min). 1 H NMR (400 MHz, DMSO-d6): major diastereomer: δ 7.50 (d, J = 7.6 Hz, 1H), 7.28 (t, J = 8.0 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 7.06-7.02 (m, 2H), 6.94 (t, J = 7.6 Hz, 1H), 4.31-4.27 (m, 1H), 3.93 (d, J = 8.8 Hz, 1H), 3.83 (d, J = 6.4 Hz, 1H), 3.67 (d, J = 6.4 Hz, 1H), 3.36 (s, 1H), 3.19 (t, J = 11.6 Hz, 1H), 2.65 (dd, J = 12.4, 6.4 Hz, 1H), 2.47 (s, 3H). 13 C NMR (101 MHz, DMSO-d6): major diastereomer: δ 176.2, 163.1, 141.9, 137.5, 133.7, 129.2, 125.8, 123.9, 123.7, 121.5, 119.6, 116.1, 68.9, 64.8, 57.2 (q, J = 30.3 Hz, 1C), 49.0, 31.3, 29.0, 18.5. HRMS (ESI-TOF) calcd. for C 22 H 21 F3N3O2[M+H] +416.1580; found: 416.1580.

[0096] Example 12:

[0097]

[0098] In a 10 mL dry reaction vial, 0.01 mmol CuCl, 0.015 mmol chiral ligand L3, 0.02 mmol Cs2CO3, 0.2 mmol 7-fluoro-Indigo-derived trifluoromethanimine ylide, 0.3 mmol 3-methylene-β-lactam were dissolved in 2 mL toluene, the mixture was stirred at 10 °C under airtight condition for 48 h, the reaction progress was monitored by TLC. After the reaction was completed, the mixture was separated and purified by column chromatography to obtain the bis-spirocyclic product 3l (yield 45%, ee 98%, dr value > 20: 1).

[0099] Product 3l characterization data: White solid; 37.7 mg, 45% yield; >20: 1 dr, 98% ee; [a] D 25 = 36.0 (c 0.50, CH2Cl2). The ee was determined by HPLC (Chiralpak OZ-3, i-PrOH / hexane = 5 / 95, flow rate 06 mL / min, λ = 214 nm, major diastereomer: t minor = 92.6 min, t major = 85.1 min). 1 H NMR (400 MHz, DMSO-d6): major diastereomer: δ 7.52 (d, J = 7.2 Hz, 1H), 7.29 (t, J = 7.6 Hz, 2H), 7.24-7.21 (m, 1H), 7.19-7.17 (m, 2H), 7.09-7.03 (m, 2H), 4.31-4.27 (m, 1H), 4.13 (d, J = 8.4 Hz, 1H), 3.78 (d, J = 6.8 Hz, 1H), 3.69 (d, J = 6.4 Hz, 1H), 3.23 (d, J = 2.8 Hz, 3H), 3.11 (t, J = 11.6 Hz 1H), 2.68 (dd, J = 12.4, 6.8 Hz 1H). 13C NMR (101 MHz, DMSO-d6) major diastereomer: 175.3, 162.8, 146.6 (d, J = 243.4 Hz, 1C), 137.4, 130.5 (d, J = 9.1 Hz, 1C), 129.2, 128.4 (d, J = 3.0 Hz, 1C), 123.9, 122.6 (d, J = 6.1 Hz, 1C), 122.0 (d, J = 3.0 Hz, 1C), 118.0 (d, J = 19.2 Hz, 1C), 116.1, 69.7 (d, J = 3.0 Hz, 1C), 64.8, 57.2 (q, J = 30.3 Hz, 1C), 49.0, 30.9, 28.3 (d, J = 5.1 Hz, 1C). HRMS (ESI-TOF) calcd. for C 21 H 18 F4N3O2[M+H] + 420.1330; found: 420.1334.

[0100] Example 13:

[0101]

[0102] In a 10 mL dry reaction flask, 0.01 mmol CuCl, 0.015 mmol chiral ligand L3, 0.02 mmol Cs2CO3, 0.2 mmol 7-chloro-indigo-derived trifluoromethanimine ylide, 0.3 mmol 3-methylene β-lactam were dissolved in 2 mL toluene, the mixture was stirred at 10 °C under sealed condition for 48 h, the reaction progress was monitored by thin layer chromatography. After the reaction was completed, the mixture was separated and purified by column chromatography to obtain the bis-spirocyclic product 3m (yield 99%, ee 98%, dr value > 20: 1).

[0103] Product 3m characterization data: White solid; 86.1 mg, 99% yield; > 20: 1 dr, 98% ee; [a] D 25 = 123.1 (c 0.50, CH2Cl2). The ee was determined by HPLC (Chiralpak OZ-3, i-PrOH / hexane = 9 / 91, flow rate 1.0 mL / min, λ = 254 nm, major diastereomer: t minor = 30.3 min, t major = 26.5 min). 1H NMR (400 MHz, DMSO-d6): major diastereomer: δ 7.66 (d, J = 7.2 Hz, 1H), 7.32-7.27 (m, 3H), 7.18 (d, J = 8.0 Hz, 2H), 7.06 (dd, J = 16.0, 8.0 Hz, 2H), 4.35-4.27 (m, 1H), 4.10 (d, J = 8.4 Hz, 1H), 3.76 (d, J = 6.8 Hz, 1H), 3.70 (d, J = 6.8 Hz, 1H), 3.39 (s, 3H), 3.14-3.08 (m, 1H), 2.69 (dd, J = 12.4, 6.4 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6): major diastereomer: δ 176.0, 162.8, 139.8, 137.4, 132.1, 129.3, 128.5, 124.9, 124.0, 123.0, 116.2, 114.1, 69.2, 64.8, 57.2 (q, J = 31.3 Hz, 1C), 49.0, 31.0, 29.2. HRMS (ESI-TOF) calcd. for C 21 H 18 ClF3N3O2[M+H] + 436.1034; found: 436.1033.

[0104] Example 14:

[0105]

[0106] In a 10 mL dry reaction flask, 0.01 mmol CuCl, 0.015 mmol chiral ligand L3, 0.02 mmol Cs2CO3, 0.2 mmol 5,7-dimethyl isatin-derived trifluoromethanimine ylide, 0.3 mmol 3-methylene β-lactam were dissolved in 2 mL toluene, the mixture was stirred at 10 °C under sealed condition for 48 hours, the reaction progress was monitored by thin layer chromatography. After the reaction was completed, the mixture was separated and purified by column chromatography to obtain the double spiro product 3n (yield 44%, ee 96%, dr value > 20:1).

[0107] Product 3n characterization data: White solid; 37.8 mg, 44% yield; >20:1 dr, 96% ee; [a] D 25= 39.7 (c 0.50, CH2Cl2). The ee was determined by HPLC (Chiralpak OX-3, i-PrOH / hexane = 20 / 80, flow rate 1.0 mL / min, λ = 254 nm, major diastereomer: t minor = 31.3 min, t major = 22.1 min). 1 H NMR (400 MHz, DMSO-d6): major diastereomer: δ 7.31 - 7.28 (m, 3H), 7.19 (d, J = 7.6 Hz, 2H), 7.04 (t, J = 7.6 Hz, 1H), 6.86 (s, 1H), 4.29 - 4.25 (m, 1H), 3.88 (d, J = 8.8 Hz, 1H), 3.81 (d, J = 6.4 Hz, 1H), 3.65 (d, J = 6.4 Hz, 1H), 3.29 (s, 3H), 3.15 (t, J = 11.2 Hz, 1H), 2.63 (dd, J = 12.4, 6.4 Hz, 1H), 2.43 (s, 3H), 2.23 (s, 3H). 13 C NMR (101 MHz, DMSO-d6): major diastereomer: δ 176.2, 163.2, 139.5, 137.6, 134.0, 130.5, 129.3, 126.1, 124.2, 123.9, 119.3, 116.2, 69.0, 64.8, 57.1 (q, J = 30.3 Hz, 1C), 55.0, 49.1, 31.4, 29.0, 20.5, 18.4. HRMS (ESI-TOF) calcd. for C 23 H 23 F3N3O2[M+H] + 430.1737; found: 430.1742.

[0108] Example 15:

[0109]

[0110] In a 10 mL dry reaction flask, 0.01 mmol CuCl, 0.015 mmol chiral ligand L3, 0.02 mmol Cs2CO3, 0.2 mmol N-benzylindigo-derived trifluoromethanimine ylide, 0.3 mmol 3-methylene β-lactam were dissolved in 2 mL toluene, the mixture was stirred at 10 °C under airtight condition for 48 h, the reaction progress was monitored by thin layer chromatography. After the reaction was completed, the mixture was separated and purified by column chromatography to obtain the bis-spirocyclic product 3o (yield 87%, ee 86%, dr value > 20:1).

[0111] Product 3o characterization data: White solid; 83.1 mg, 87% yield; >20:1 dr, 86% ee; [a] D 25 = 7.2 (c 0.50, CH2Cl2). The ee was determined by HPLC (Chiralpak OX-3, i-PrOH / hexane = 30 / 70, flow rate 1.0 mL / min, λ = 210 nm, major diastereomer: t minor = 17.9 min, t major = 27.6 min). 1 H NMR (400 MHz, DMSO-d6): major diastereomer: δ 7.69 (d, J = 7.2 Hz, 1H), 7.38-7.36 (m, 2H), 7.33-7.29 (m, 2H), 7.28-7.18 (m, 6H), 7.04 (dd, J = 16.0, 8.0 Hz, 2H), 6.73 (d, J = 8.0 Hz, 1H), 5.02 (d, J = 16.0 Hz, 1H), 4.64 (d, J = 15.6 Hz, 1H), 4.36-4.34 (m, 1H), 4.14 (d, J = 8.4 Hz, 1H), 3.80 (d, J = 6.8 Hz, 1H), 3.74 (d, J = 6.8 Hz, 1H), 3.19 (t, J = 11.2 Hz, 1H), 2.74 (dd, J = 12.4, 6.8 Hz, 1H). 13C NMR (101 MHz, DMSO-d6): major diastereomer: δ 175.7, 163.3, 143.2, 137.6, 136.2, 130.0, 129.3, 128.5, 127.5, 127.4, 126.0, 125.8, 124.0, 122.0, 116.2, 109.3, 69.8, 64.7, 57.2 (q, J = 31.3 Hz, 1C), 49.1, 42.8, 31.2. HRMS (ESI-TOF) calcd. for C 27 H 23 F3N3O2[M+H] + 478.1737; found: 478.1742.

[0112] Example 16:

[0113]

[0114] In a 10 mL dry reaction vial, 0.01 mmol CuCl, 0.015 mmol chiral ligand L3, 0.02 mmol Cs2CO3, 0.2 mmol indigo-derived trifluoromethanimine ylide, 0.3 mmol N-(2-methoxyphenyl)-3-methylene β-lactam were dissolved in 2 mL toluene, the mixture was stirred at 10 °C under sealed condition for 36 h, the reaction progress was monitored by TLC. After the reaction was completed, the mixture was separated and purified by column chromatography to give the bis-spiro product 3p (yield 90%, ee 96%, dr 12:1).

[0115] Product 3p characterization data: White solid; 77.6 mg, 90% yield; 12:1 dr, 96% ee; [a] D 25 = -119.0 (c 0.32, CH2Cl2). The ee was determined by HPLC (Chiralpak AD-3, i-PrOH / hexane = 30 / 70, flow rate 0.8 mL / min, λ = 214 nm, major diastereomer: t minor = 15.8 min, t major = 9.7 min). 1H NMR (400 MHz, DMSO-d6): major diastereomer: δ 7.65 (d, J = 7.2 Hz 1H), 7.50-7.48 (m, 1H), 7.33 (t, J = 7.2 Hz, 1H), 7.11-7.01 (m, 2H), 6.96 (d, J = 8.0 Hz, 2H), 6.82 (t, J = 7.2 Hz, 1H), 4.30-4.22 (m, 1H), 4.10 (d, J = 6.8 Hz, 1H), 3.98 (d, J = 8.8 Hz, 1H), 3.82 (d, J = 6.8 Hz, 1H), 3.68 (s, 3H), 3.16 (t, J = 11.6 Hz, 1H), 3.04 (s, 3H), 2.61 (q, J = 5.6 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6): major diastereomer: δ 175.8, 164.2, 150.0, 144.3, 130.0, 126.0, 125.6 (d, J = 4.0 Hz, 1C), 125.2, 121.5, 121.4, 120.6, 112.8, 108.3, 69.7, 66.3, 57.2 (q, J = 30.3 Hz, 1C), 55.9, 53.9, 30.9, 25.9. HRMS (ESI-TOF) calcd. for C 22 H 21 F3N3O3[M+H] + 432.1530; found: 432.1533.

[0116] Example 17:

[0117]

[0118] In a 10 mL dry reaction flask, 0.01 mmol CuCl, 0.015 mmol chiral ligand L3, 0.02 mmol Cs2CO3, 0.2 mmol indigo-derived trifluoromethanimine ylide, 0.3 mmol N-(2-iodophenyl)-3-methylene β-lactam were dissolved in 2 mL of toluene, the mixture was stirred at 10 °C under sealed conditions for 20 hours, the reaction progress was monitored by thin layer chromatography. After the reaction was completed, the mixture was separated and purified by column chromatography to obtain the double spiro product 3q (yield 77%, ee 95%, dr value 7:1).

[0119] Product 3q characterization data: White solid; 81.5 mg, 77% yield; 7:1 dr, 95% ee; [a] D 25= 87.8 (c 0.50, CH2Cl2). The ee was determined by HPLC (Chiralpak AD-3, i-PrOH / hexane = 30 / 70, flow rate 0.8 mL / min, λ = 214 nm, major diastereomer: t minor = 17.5 min, t major = 20.9 min). 1 H NMR (400 MHz, DMSO-d6): major diastereomer: δ 7.72 (d, J = 38.4 Hz, 2H), 7.34 (s, 2H), 7.13 (d, J = 30.0 Hz, 2H), 6.97 (s, 2H), 4.32 (s, 1H), 4.08 - 4.02 (m, 2H), 3.77 (s, 1H), 3.19 - 3.06 (m, 4H), 2.69 (s, 1H). 13 C NMR (101 MHz, DMSO-d6): major diastereomer: δ 175.7, 164.1, 144.4, 139.8, 138.9, 130.0, 129.0 (d, J = 6.1 Hz, 2C), 126.3, 125.7, 125.5, 121.9, 108.6, 92.5, 69.9, 65.7, 57.3 (q, J = 31.3 Hz, 1C), 53.0, 30.6, 26.0. HRMS (ESI-TOF) calcd. for C 21 H 18 F3IN3O2[M+H] + 528.0390; found: 528.0393.

[0120] Example 18:

[0121]

[0122] In a 10 mL dry reaction flask, 0.01 mmol CuCl, 0.015 mmol chiral ligand L3, 0.02 mmol Cs2CO3, 0.2 mmol indigo-derived trifluoromethanimine ylide, 0.3 mmol N-(3-methylphenyl)-3-methylene β-lactam were dissolved in 2 mL toluene, the mixture was stirred at 10 °C under sealed condition for 36 hours, the reaction progress was monitored by thin layer chromatography. After the reaction was completed, the mixture was separated and purified by column chromatography to obtain the double spiro product 3r (yield 98%, ee 96%, dr value > 20: 1).

[0123] Product 3r characterization data: White solid; 81.4 mg, 98% yield; >20:1 dr, 96% ee; [a] D 25 = 43.0 (c 0.50, CH2Cl2). The ee was determined by HPLC (Chiralpak OZ-3, i-PrOH / hexane = 20 / 80, flow rate 1.0 mL / min, λ = 214 nm, major diastereomer: t minor = 13.5 min, t major = 17.1 min). 1 H NMR (400 MHz, DMSO-d6): major diastereomer: δ 7.66 (d, J = 7.2 Hz, 1H), 7.33-7.29 (m, 1H), 7.15 (t, J = 8.0 Hz, 1H), 7.06 (t, J = 7.2 Hz, 1H), 7.01 (s, 1H), 6.98-6.94 (m, 2H), 6.85 (d, J = 7.6 Hz, 1H), 4.32-4.21 (m, 1H), 4.06 (d, J = 8.4 Hz, 1H), 3.83 (d, J = 6.8 Hz, 1H), 3.67 (d, J = 6.4 Hz, 1H), 3.17 (t, J = 11..6 Hz, 1H), 3.05 (s, 3H), 2.64 (q, J = 6.0 Hz, 1H), 2.22 (s, 3H). 13 C NMR (101 MHz, DMSO-d6): major diastereomer: δ 175.6, 163.0, 144.3, 138.7, 137.5, 130.1, 129.0, 125.7, 125.1, 124.6, 121.7, 116.5, 113.3, 108.4, 69.5, 64.6, 57.2 (q, J = 30.3 Hz, 1C), 49.1, 31.0, 25.9, 21.0. HRMS (ESI-TOF) calcd. for C 22 H 21 F3N3O2[M+H] + 416.1580; found: 416.1583.

[0124] Example 19:

[0125]

[0126] In a 10 mL dry reaction flask, 0.01 mmol CuCl, 0.015 mmol chiral ligand L3, 0.02 mmol Cs2CO3, 0.2 mmol indigo-derived trifluoromethanimine ylide, 0.3 mmol N-(3-chlorophenyl)-3-methylene β-lactam were dissolved in 2 mL toluene, the mixture was stirred at 10 °C under sealed condition for 11 h, the reaction progress was monitored by TLC. After the reaction was completed, the mixture was separated and purified by column chromatography to obtain the bis-spiro product 3s (yield 98%, ee 97%, dr value > 20:1).

[0127] Product 3s characterization data: White solid; 85.3 mg, 98% yield; >20:1 dr, 97% ee; [a] D 25 = -6.1 (c 0.45, CH2Cl2). The ee was determined by HPLC (Chiralpak OZ-3, i-PrOH / hexane = 20 / 80, flow rate 1.0 mL / min, λ = 214 nm, major diastereomer: t minor = 14.1 min, t major = 21.1 min). 1 H NMR (400 MHz, DMSO-d6): major diastereomer: δ 7.66 (d, J = 7.2 Hz, 1H), 7.31 (dd, J = 15.6, 7.6 Hz, 2H), 7.25 (s, 1H), 7.14 (d, J = 8.0 Hz, 1H), 7.10 - 7.04 (m, 2H), 6.96 (d, J = 7.6 Hz, 1H), 4.32 - 4.24 (m, 1H), 4.09 (d, J = 8.8 Hz, 1H), 3.86 (d, J = 6.4 Hz, 1H), 3.72 (d, J = 6.8 Hz, 1H), 3.16 (t, J = 11.2 Hz, 1H), 3.06 (s, 3H), 2.68 (q, J = 6.0 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6): major diastereomer: δ 175.4, 163.5, 144.2, 138.7, 133.6, 131.0, 130.1, 125.7, 125.1, 123.6, 121.8, 115.9, 114.7, 108.5, 69.6, 65.0, 57.2 (q, J = 30.3 Hz, 1C), 49.4, 31.0, 25.9. HRMS (ESI-TOF) calcd. for C 21 H18 ClF3N3O2[M+H] + 436.1034; found: 436.1034.

[0128] Example 20:

[0129]

[0130] In a 10 mL dry reaction flask, 0.01 mmol CuCl, 0.015 mmol chiral ligand L3, 0.02 mmol Cs2CO3, 0.2 mmol indigo-derived trifluoromethanimine ylide, 0.3 mmol N-(3-bromophenyl)-3-methylene β-lactam were dissolved in 2 mL toluene, the mixture was stirred at 10 °C under sealed condition for 36 h, the reaction progress was monitored by thin layer chromatography. After the reaction was completed, the mixture was separated and purified by column chromatography to obtain the bis-spirocyclic product 3t (yield 98%, ee 96%, dr value > 20:1).

[0131] Product 3t characterization data: White solid; 93.9 mg, 98% yield; >20:1 dr, 96% ee; [a] D 25 = 10.2 (c 0.50, CH2Cl2); The ee was determined by HPLC (Chiralpak OZ-3, i-PrOH / hexane = 20 / 80, flow rate 1.0 mL / min, λ = 254 nm, major diastereomer: t minor = 14.2 min, t major = 21.0 min). 1 H NMR (400 MHz, DMSO-d6): major diastereomer: δ 7.65 (d, J = 7.2 Hz, 1H), 7.39 (s, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.24-7.23 (m, 2H), 7.19-7.16 (m, 1H), 7.06 (t, J = 7.6 Hz, 1H), 6.96 (d, J = 7.6 Hz, 1H), 4.33-4.21 (m, 1H), 4.08 (d, J = 8.8 Hz, 1H), 3.86 (d, J = 6.8 Hz, 1H), 3.71 (d, J = 6.8 Hz, 1H), 3.15 (t, J = 11.2 Hz, 1H), 3.06 (s, 3H), 2.68 (q, J = 5.6 Hz, 1H). 13C NMR (101 MHz, DMSO-d6): major diastereomer: δ 175.4, 163.5, 144.2, 138.8, 131.3, 130.1, 126.5, 125.7, 125.1, 122.0, 121.8, 118.7, 115.1, 108.5, 69.6, 64.9, 57.2 (q, J = 30.3 Hz, 1C), 49.4, 31.0, 25.9. HRMS (ESI-TOF) calcd. for C 21 H 18 BrF3N3O2[M+H] + 480.0529; found: 480.0532.

[0132] Example 21:

[0133]

[0134] In a 10 mL dry reaction vial, 0.01 mmol CuCl, 0.015 mmol chiral ligand L3, 0.02 mmol Cs2CO3, 0.2 mmol indigo-derived trifluoromethanimine ylide, 0.3 mmol N-(4-methylphenyl)-3-methylene β-lactam were dissolved in 2 mL toluene, the mixture was stirred at 10 °C under closed condition for 36 h, the reaction progress was monitored by TLC. After the reaction was completed, the mixture was separated and purified by column chromatography to give the bis-spiro product 3u (yield 89%, ee 96%, dr value 8.4:1).

[0135] Product 3u characterization data: White solid; 73.9 mg, 89% yield; 8.4:1 dr, 96% ee; [a] D 25 = 70.8 (c 0.50, CH2Cl2). The ee was determined by HPLC (Chiralpak OZ-3, i-PrOH / hexane = 20 / 80, flow rate 0.9 mL / min, λ = 254 nm, major diastereomer: t minor = 20.8 min, t major= 23.4 min). 1H NMR (400 MHz, DMSO-d6): major diastereomer: δ 7.66 (d, J = 7.6 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.07-7.03 (m, 5H), 6.94 (d, J = 8.0 Hz, 1H), 4.30-4.23 (m, 1H), 4.05 (d, J = 8.8 Hz, 1H), 3.82 (d, J = 6.4 Hz, 1H), 3.66 (d, J = 6.4 Hz, 1H), 3.17 (t, J = 11.6 Hz, 1H), 3.05 (s, 3H), 2.64 (dd, J = 12.4, 6.4 Hz, 1H), 2.19 (s, 3H). 13 C NMR (101 MHz, DMSO-d6): major diastereomer: δ 175.6, 162.7, 144.3, 135.2, 133.0, 130.1, 129.5, 125.7, 125.1, 121.6, 116.0, 108.4, 69.6, 64.7, 57.2 (q, J = 31.3 Hz, 1C), 49.1, 31.0, 25.9, 20.4. HRMS (ESI-TOF) calcd. for C 22 H 21 F3N3O2[M+H] + 416.1580; found: 416.1584.

[0136] Example 22:

[0137]

[0138] In a 10 mL dry reaction flask, 0.01 mmol CuCl, 0.015 mmol chiral ligand L3, 0.02 mmol Cs2CO3, 0.2 mmol indigo-derived trifluoromethanimine ylide, 0.3 mmol N-(4- trifluoromethoxyphenyl)-3-methylene β-lactam were dissolved in 2 mL toluene, the mixture was stirred at 10 °C under sealed condition for 48 hours, the reaction progress was monitored by thin layer chromatography. After the reaction was completed, the mixture was separated and purified by column chromatography to obtain the bis-spirocyclic product 3v (yield 99%, ee 95%, dr value > 20:1).

[0139] Product 3v characterization data: White solid; 96.5 mg, 99% yield; >20:1 dr, 95% ee; [a] D 25= 56.1 (c 0.50, CH2Cl2). The ee was determined by HPLC (Chiralpak OX-3, i-PrOH / hexane = 20 / 80, flow rate 1.0 mL / min, λ = 210 nm, major diastereomer: t minor = 13.6 min, t major = 16.7 min). 1 H NMR (400 MHz, DMSO-d6): major diastereomer: δ 7.68 (d, J = 7.6 Hz, 1H), 7.33-7.28 (m, 5H), 7.06 (t, J = 7.6 Hz, 1H), 6.95 (d, J = 7.6 Hz, 1H), 4.35-4.25 (m, 1H), 4.10 (d, J = 8.8 Hz, 1H), 3.87 (d, J = 6.8 Hz, 1H), 3.73 (d, J = 6.8 Hz, 1H), 3.19 (t, J = 11.6 Hz, 1H), 3.06 (s, 3H), 2.69 (dd, J = 12.4, 6.4 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6): major diastereomer: δ 175.6, 163.3, 144.1 (d, J = 32.3 Hz, 1C), 136.6, 130.2, 125.4 (d, J = 54.5 Hz, 1C), 122.3, 121.8, 121.4, 118.8, 117.6, 108.5, 69.7, 65.1, 57.2 (q, J = 31.3 Hz, 1C), 49.4, 31.0, 26.0. HRMS (ESI-TOF) calcd. for C 22 H 18 F6N3O3[M+H] + 486.1247; found: 486.1252.

[0140] Example 23:

[0141]

[0142] In a 10 mL dry reaction flask, 0.01 mmol CuCl, 0.015 mmol chiral ligand L3, 0.02 mmol Cs2CO3, 0.2 mmol indigo-derived trifluoromethanimine ylide, 0.3 mmol N-(4-chlorophenyl)-3-methylene β-lactam were dissolved in 2 mL toluene, the mixture was stirred at 10 °C under sealed condition for 11 hours, the reaction progress was monitored by thin layer chromatography. After the reaction was completed, the mixture was separated and purified by column chromatography to obtain the bis-spirocyclic product 3w (yield 91%, ee 92%, dr value 7.4:1).

[0143] Product 3w characterization data: White solid; 79.2 mg, 91% yield; 7.4:1 dr, 92% ee; [a] D 25 = 72.8 (c 0.5, CH2Cl2). The ee was determined by HPLC (Chiralpak OX-3, i-PrOH / hexane = 20 / 80, flow rate 1.0 mL / min, λ = 210 nm, major diastereomer: t minor = 23.5 min, t major = 27.4 min). 1 H NMR (400 MHz, DMSO-d6): major diastereomer: δ 7.66 (d, J = 7.6 Hz, 1H), 7.34-7.29 (m, 3H), 7.19 (d, J = 8.4 Hz, 2H), 7.07-7.03 (m, 1H), 6.95 (d, J = 8.0 Hz, 1H), 4.31-4.24 (m, 1H), 4.08 (d, J = 8.8 Hz, 1H), 3.83 (d, J = 6.4 Hz, 1H), 3.70 (d, J = 6.4 Hz, 1H), 3.16 (t, J = 11.6 Hz, 1H), 3.05 (s, 3H), 2.67 (dd, J = 12.0, 6.0 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6): major diastereomer: δ 175.6, 163.3, 144.3, 136.3, 130.2, 129.2, 127.6, 125.7, 125.1, 121.8, 117.8, 108.6, 69.7, 65.1, 57.2 (q, J = 31.3 Hz, 1C), 49.3, 31.0, 26.0. HRMS (ESI-TOF) calcd. for C 21 H 18 ClF3N3O2[M+H]+ 436.1034; found: 436.1041.

[0144] Example 24:

[0145]

[0146] In a 10 mL dry reaction vial, 0.01 mmol CuCl, 0.015 mmol chiral ligand L3, 0.02 mmol Cs2CO3, 0.2 mmol indigo-derived trifluoromethanimine ylide, 0.3 mmol N-(4-bromophenyl)-3-methylene β-lactam were dissolved in 2 mL toluene, the mixture was stirred at 10 °C under sealed condition for 11 h, the reaction progress was monitored by TLC. After the reaction was completed, the mixture was separated and purified by column chromatography to obtain the bis-spiro product 3x (yield 94%, ee 96%, dr value 17:1).

[0147] Product 3x characterization data: White solid; 90.2 mg, 94% yield; 17:1 dr, 96% ee; [a] D 25 = 53.6 (c 0.50, CH2Cl2). The ee was determined by HPLC (Chiralpak OX-3, i-PrOH / hexane = 20 / 80, flow rate 1.0 mL / min, λ = 254 nm, major diastereomer: t minor = 25.7 min, t major = 30.1 min). 1 H NMR (400 MHz, DMSO-d6): major diastereomer: δ 7.66 (d, J = 7.6 Hz, 1H), 7.46 (d, J = 8.8 Hz, 2H), 7.31 (t, J = 7.6 Hz, 1H), 7.15-7.12 (m, 2H), 7.05 (t, J = 7.2 Hz, 1H), 6.95 (d, J = 7.6 Hz, 1H), 4.30-4.26 (m, 1H), 4.08 (d, J = 8.4 Hz, 1H), 3.83 (d, J = 6.8 Hz, 1H), 3.70 (d, J = 6.4 Hz, 1H), 3.16 (t, J = 11.6 Hz, 1H), 3.05 (s, 3H), 2.68 (dd, J = 12.0, 6.0 Hz, 1H). 13CNMR (101 MHz, DMSO-d6): major diastereomer: δ 175.5, 163.3, 144.2, 136.7, 132.1, 130.2, 125.7, 125.1, 121.7, 118.1, 115.5, 108.5, 69.6, 65.0, 57.2 (q, J = 31.3 Hz, 1C), 49.2, 31.0, 26.0 (d, J = 3.0 Hz, 1C). HRMS (ESI-TOF) calcd. for C 21 H 18 BrF3N3O2[M+H] + 480.0529; found: 480.0532.

[0148] Example 25:

[0149]

[0150] In a 10 mL dry reaction vial, 0.01 mmol CuCl, 0.015 mmol chiral ligand L3, 0.02 mmol Cs2CO3, 0.2 mmol indigo-derived trifluoromethanimine ylide, 0.3 mmol N-(4-iodophenyl)-3-methylene β-lactam were dissolved in 2 mL toluene, the mixture was stirred at 10 °C under sealed condition for 11 hours, the reaction progress was monitored by thin layer chromatography. After the reaction was completed, the mixture was separated and purified by column chromatography to obtain the bis-spirocyclic product 3y (yield 98%, ee 95%, dr value > 20: 1).

[0151] Product 3y characterization data: White solid; 103.3 mg, 98% yield; > 20: 1 dr, 95% ee; [a] D 25 = -46.5 (c 0.50, CH2Cl2). The ee was determined by HPLC (Chiralpak OX-3, i-PrOH / hexane = 30 / 70, flow rate 1.0 mL / min, λ = 254 nm, major diastereomer: t minor = 16.1 min, t major = 18.8 min). 1H NMR (400 MHz, DMSO-d6): major diastereomer: δ 7.66-7.60 (m, 3H), 7.31 (t, J = 7.6 Hz, 1H), 7.07-6.94 (m, 4H), 4.31-4.23 (m, 1H), 4.06 (d, J = 8.4 Hz, 1H), 3.81 (d, J = 6.8 Hz, 1H), 3.68 (d, J = 6.8 Hz, 1H), 3.15 (t, J = 11.6 Hz, 1H), 3.05 (s, 3H), 2.66 (q, J = 6.0 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6): major diastereomer: δ 175.5, 163.2, 144.2, 137.8, 137.1, 130.1, 125.6, 125.1, 121.7, 118.3, 108.5, 87.4, 69.6, 65.0, 57.2 (q, J = 31.3 Hz, 1C), 49.1, 30.9, 25.9. HRMS (ESI-TOF) calcd. for C 21 H 18 F3IN3O2[M+H] + 528.0390; found: 528.0392.

[0152] Example 26:

[0153]

[0154] In a 10 mL dry reaction flask, 0.01 mmol CuCl, 0.015 mmol chiral ligand L3, 0.02 mmol Cs2CO3, 0.2 mmol indigo-derived trifluoromethanimine ylide, 0.3 mmol N-(4-cyanophenyl)-3-methylene β-lactam were dissolved in 2 mL toluene, the mixture was stirred at 10 °C under sealed condition for 11 hours, the reaction progress was monitored by thin layer chromatography. After the reaction was completed, the mixture was separated and purified by column chromatography to obtain the double spiro product 3z (yield 97%, ee 97%, dr value > 20:1).

[0155] Product 3z characterization data: White solid; 82.7 mg, 97% yield; >20:1 dr, 97% ee; [a] D 25= 64.0 (c 0.50, CH2Cl2). The ee was determined by HPLC (Chiralpak OZ-3, i-PrOH / hexane = 30 / 70, flow rate 0.9 mL / min, λ = 254 nm, major diastereomer: t minor = 57.6 min, t major = 33.9 min). 1 H NMR (400 MHz, DMSO-d6): major diastereomer: δ 7.73 (d, J = 8.8 Hz, 2H), 7.67 (d, J = 7.6 Hz, 1H), 7.34 - 7.30 (m, 3H), 7.06 (t, J = 7.6 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H), 4.37 - 4.25 (m, 1H), 4.10 (d, J = 8.8 Hz, 1H), 3.88 (d, J = 6.8 Hz, 1H), 3.77 (d, J = 6.8 Hz, 1H), 3.17 (t, J = 11.6 Hz, 1H), 3.06 (s, 3H), 2.73 (q, J = 5.6 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6): major diastereomer: δ 175.3, 164.0, 144.1, 140.8, 133.7, 130.2, 125.6, 125.1, 121.8, 118.7, 116.7, 108.5, 105.6, 69.7, 65.2, 59.8, 57.2 (q, J = 31.3 Hz, 1C), 49.3, 31.0, 26.0, 20.8, 14.1. HRMS (ESI-TOF) calcd. for C 22 H 18 F3N4O2[M+H] + 427.1376; found: 427.1376.

[0156] Anti-tumor activity verification:

[0157] The chiral [oxindole-pyrrolidine-β-lactam] double spiro compound containing trifluoromethyl prepared in the examples was selected, and human hepatoma cell line (HepG2), human breast cancer cell line (MDA-MB-231) and human cervical cancer cell (Hela) were used as receptors to test its in vitro anti-tumor activity (MTT colorimetric method).

[0158] The compound 3a of Example 1 was taken as an example to illustrate the specific experimental operation as follows:

[0159] (1) Take logarithmic growth period human hepatocellular carcinoma cell line (HepG2), human breast cancer cell line (MDA-MB-231) and human cervical cancer cells (Hela), and adjust the cell density to 1x10 5 cells·mL -1 , inoculate in a 96-well plate, 100 μL / well, and culture in a 37℃, 5% CO2 incubator.

[0160] (2) After 24h of cell adhesion culture, replace the fresh culture solution without serum, and at the same time, perform drug treatment. The sample is set at a dose of 0.4 μmol / mL, 2 μmol / mL, 10 μmol / mL and 50 μmol / mL, and at the same time, a positive control group is set.

[0161] (3) After 48h of cell drug treatment, add MTT staining solution (10 μL, 0.5mg / mL) to the culture medium, and continue to culture the cells at 37℃ for 4 hours.

[0162] (4) Remove the culture medium, add 100 μL dimethyl sulfoxide for dissolving formazan crystals, and use an enzyme-labeled instrument (ELx800, Bio-Tek, Winooski, VT, USA) to measure the OD value at 570nm, and calculate the IC 50 value of the compound 3a of Example 1.

[0163] The tumor cell inhibition experiment of the chiral [oxindole-pyrrolidine-β-lactam] double spiro compound containing a trifluoromethyl prepared in other examples is operated according to the method similar to the above 1.

[0164] Table 1 is the inhibition effect of some compounds of the example on the proliferation of human hepatocellular carcinoma cell line (HepG2), human breast cancer cell line (MDA-MB-231) and human cervical cancer cells (Hela).

[0165]

[0166] The results show that the chiral [oxindole-pyrrolidine-β-lactam] double spiro compound containing a trifluoromethyl prepared by the application has a certain degree of inhibition effect on human hepatocellular carcinoma cells, human breast cancer cells and human cervical cancer cells.

[0167] Extract compounds 3a, 3b and 3c for nuclear magnetic resonance spectrum analysis, as shown in Figures 2 to 7 .

[0168] The above-mentioned are only embodiments of the present application, and the common knowledge of specific structures and characteristics in the scheme is not described too much. It should be pointed out that for those skilled in the art, without departing from the structure of the present application, a number of modifications and improvements can be made, which should also be considered as the protection scope of the present application, which will not affect the effect and practicality of the patent. The protection scope claimed in this application should be subject to the content of its claims, and the specific implementation mode and the like recorded in the specification can be used to explain the content of the claims.

Claims

1. A chiral [indole-pyrrolidine-β-lactam] bispirocyclic compound containing a trifluoromethyl group, characterized in that: Structural formula as shown in 3a, 3e, 3i, 3l, 3m, 3s, 3t or 3y: 。 2. The method for preparing the chiral [oxyindole-pyrrolidine-β-lactam] bispirocyclic compound containing trifluoromethyl according to claim 1, characterized in that: The method comprises the following steps: Step one, sequentially adding a metal catalyst, a chiral ligand, a base, an isatin-derived trifluoromethyl imine ylide and 3-methylene β-lactam, and then adding an organic solvent to obtain a mixture, and stirring the mixture at a reaction temperature of 0-50℃; Step two, after the reaction is completed, separating by post-treatment to obtain a chiral [oxindole-pyrrolidine-β-lactam] double spiro compound containing a trifluoromethyl group; The structural formula of the isatin-derived trifluoromethyl imine ylide is as follows: ， In the structural formula of the isatin-derived trifluoromethanimine ylide: Ar 1 each independently selected from the group consisting of phenyl, 5-methoxyphenyl, 6-chlorophenyl, 7-fluorophenyl, 7-chlorophenyl; R is methyl; The structural formula of the 3-methylene β-lactam is as follows: ， 3-methylene β-lactam: Ar 2 each independently selected from the group consisting of phenyl, 3-chlorophenyl, 3-bromophenyl, 4-iodophenyl; The metal catalyst is copper sulfate, basic copper carbonate, copper acetate, copper trifluoroacetate, cuprous chloride, cuprous bromide or copper triflate; The chiral ligand is any one of the following structures, ； The base is sodium acetate, potassium acetate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, cesium pivalate, sodium tert-butoxide or potassium tert-butoxide.

3. The process for the preparation of trifluoromethyl containing chiral [oxindole- pyrrolidine-β-lactam] bispidine compounds according to claim 2, characterized by: The organic solvent is toluene.

4. The process for the preparation of trifluoromethyl containing chiral [oxindole- pyrrolidine-β-lactam] bispidine compounds according to claim 3, characterized by: The post-treatment method in step two is column chromatography.

5. Use of the chiral [oxindole-pyrrolidine-β-lactam] double spiro compound containing a trifluoromethyl group in claim 1 in the preparation of an anti-breast cancer, liver cancer or cervical cancer drug.

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