Preparation method and application of oxoindole spiro indanone derivative with optical activity

Abstract

The invention relates to a preparation method and application of an oxoindole spiro indanone derivative with optical activity. The compound has a structural formula represented by a general formula I. The synthesis method comprises the following steps: in the presence of a Lewis acid catalyst magnesium trifluoromethanesulfonate and a ligand IV, in an acetonitrile solvent, carrying out Michael addition / cyclization cascade reaction on compounds represented by a general formula II and a general formula III to obtain the compound. Through one-step operation, the 3, 2 '-oxoindole spiro indanone derivative with optical activity can be efficiently synthesized with high stereoselectivity, the yield is 70-99%, dr: 13: 1-gt; 19: 1, ee: 52-99%. The 3, 2 '-pyrroline oxoindole spiro indanone derivative can be used for effectively inhibiting the activity of lung cancer NCI-H460 and colon cancer SW-620 cells, so that the 3, 2'-pyrroline oxoindole spiro indanone derivative can be used as a potential lead compound of a new antitumor drug.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, and in particular to a method for preparing and applying an optically active oxidized indolespirinone derivative. Background Technology

[0002] Heterocyclic compounds are ubiquitous in nature, possessing unique chemical structures, important properties, and wide applications. Among numerous nitrogen-containing heterocyclic compounds, chiral 3,2'-pyrrolinoline spirocyclic indole stands out due to its unique structure, and this skeleton is a common basic unit in many natural products and drug molecules. On the other hand, spironinone is also an important core skeleton, exhibiting significant physiological and pharmacological activities. The broad-spectrum biological activities of these two skeletons have attracted increasing research interest from chemists, and the organic combination of these two advantageous skeletons presents a certain challenge. Therefore, developing efficient and convenient synthetic methods for spironinone-based oxyindole compounds has become a research goal for many organic synthesizers.

[0003] Therefore, it is necessary to develop an optically active oxidized indolespirinone compound and its preparation method. Summary of the Invention

[0004] The present invention aims to provide a method for preparing an optically active oxidized indole-spironinone derivative. This method utilizes a Michael addition / cyclization tandem reaction catalyzed by a magnesium trifluoromethanesulfonate and chiral pyridine bisoxazoline ligand complex to oxidize indole with 3-isothiocyanate and 2-aryl-1,3-indanedione, enabling the efficient and stereoselective synthesis of an optically active 3,2'-pyrrolline oxidized indole-spironinone derivative.

[0005] This invention provides a class of optically active oxidized indolespirinone derivatives, characterized by having the structural formula represented by general formula I, wherein R in formula I... 1 For hydrogen, 6-methyl, 6-methoxy, 7-methoxy, 6-fluoro, 7-fluoro; R 2 It is benzyl or n-propyl; R 2 For methyl, benzyl, n-propyl; R 3 It is phenyl, p-methylphenyl, p-methoxyphenyl, m-methoxyphenyl, o-methoxyphenyl, 3,4-dimethoxyphenyl, p-fluorophenyl, p-chlorophenyl, o-chlorophenyl, 2,4-dichlorophenyl, p-bromophenyl, p-nitrophenyl, p-cyanophenyl, p-trifluoromethylphenyl, 3,5-bis(trifluoromethyl)phenyl, 1-naphthalene, 2-naphthalene, styryl, cyclohexyl, 2-furan, 2-thiophene.

[0006] The preparation method of the optically active oxidized indolespirinone derivative represented by general formula I comprises the following steps: In the presence of a Lewis acid catalyst (magnesium trifluoromethanesulfonate) and chiral ligand IV, the compounds represented by general formulas II and III undergo a Michael addition / cyclization tandem reaction in acetonitrile solvent to obtain the product. The synthetic route is shown in the appendix. Figure 2 As shown: In formula I, R 1 For hydrogen, 6-methyl, 6-methoxy, 7-methoxy, 6-fluoro, 7-fluoro; R 2 For methyl, benzyl, n-propyl; R 3 The following are listed: phenyl, p-methylphenyl, p-methoxyphenyl, m-methoxyphenyl, o-methoxyphenyl, 3,4-dimethoxyphenyl, p-fluorophenyl, p-chlorophenyl, o-chlorophenyl, 2,4-dichlorophenyl, p-bromophenyl, p-nitrophenyl, p-cyanophenyl, p-trifluoromethylphenyl, 3,5-bis(trifluoromethyl)phenyl, 1-naphthalene, 2-naphthalene, styryl, cyclohexyl, 2-furan, 2-thiophene; R in formulas II and III 1 R 2 R 3 The definition of R in Equation I 1 R 2 R 3 The definitions are the same, where Mg(OTf)2 is magnesium trifluoromethanesulfonate and CH3CN is acetonitrile.

[0007] According to the above scheme, the molar ratio of the compound represented by general formula II to the compound represented by general formula III is 1:1.

[0008] According to the above scheme, the amount of the Lewis acid catalyst magnesium trifluoromethanesulfonate is 10 mol of the compound represented by general formula II in molar ratio.

[0009] According to the above scheme, the molar ratio of ligand IV to the Lewis acid catalyst magnesium trifluoromethanesulfonate is 1:1.

[0010] According to the above scheme, the reaction time is 15-24 hours.

[0011] According to the above scheme, the synthesis method has a yield of 70-99%, a diastereomer ratio of dr 13:1 to 19:1, and an enantiomer excess of ee 52-99%.

[0012] The specific steps of the above scheme are as follows: at room temperature, magnesium trifluoromethanesulfonate catalyst and ligand IV are dissolved in acetonitrile and stirred under nitrogen protection. Then, after 30 min, the compound represented by general formula III is added and stirred for 20 min. Then, the compound represented by general formula II is added to the reaction system and the reaction continues until the reaction is complete as detected by TLC. The target product of formula I is directly obtained by column chromatography with V petroleum ether / V ethyl acetate = 20:1-4:1.

[0013] The beneficial effects of this invention are as follows: This invention utilizes a cycloaddition mechanism to synthesize an optically active 3,2'-pyrrolline-oxidized indole spironinone derivative via a Michael addition / cyclization tandem reaction of 3-isothiocyanate oxidized indole and 2-aryl-1,3-indanedione under the catalysis of magnesium trifluoromethanesulfonate and a chiral bispyridine oxazoline ligand. The yield is 70-99%, dr: 13:1 -> 19:1, ee: 52-99%.

[0014] This invention provides the use of the optically active oxidized indolespirinone derivative in the preparation of medicaments for the prevention or treatment of cancer.

[0015] Furthermore, the cancer specifically includes one of breast cancer, lung cancer, and colon cancer.

[0016] Furthermore, the drug used for the prevention or treatment of cancer inhibits the activity of human lung cancer cells NCI-H460 and colon cancer cells SW-620, exhibiting good cytotoxicity.

[0017] One or more technical solutions in the embodiments of the present invention have at least the following technical effects or advantages: 1. This invention provides a highly efficient and rapid method for preparing optically active oxidized indole spironindone derivatives, requiring only one room-temperature reaction step to obtain spirocyclic oxidized indole compounds: Under nitrogen protection, compounds shown in Formula II and Formula III are reacted in a solvent under the catalysis of a Lewis acid catalyst, magnesium trifluoromethanesulfonate, and ligand IV. After complete reaction, the target compound shown in Formula I is obtained through separation and purification. This invention is compatible with a variety of substrates and provides structurally diverse optically active oxidized indole spironindone derivatives under mild reaction conditions.

[0018] 2. The chiral oxidized indole-spironinone derivatives synthesized by the method of this invention have not been reported before. These compounds contain a novel oxidized indole-spironinone skeleton. Biological studies have shown that one of the [3,2']-pyrrolinoline oxidized indole-spironinone compounds exhibits good cytotoxicity against NCI-H460 human lung cancer cells and SW-620 colon cancer cells. These optically active [3,2']-pyrrolinoline oxidized indole-spironinone derivatives enrich the spirocyclic oxidized indole library and provide new opportunities for drug discovery. Attached Figure Description

[0019] Figure 1 This is a structural diagram of the present invention represented by general formula I; Figure 2 The diagrams of Michael addition / cyclization tandem reactions of the compounds represented by general formulas II and III of this invention are shown. Figure 3 This is a structural diagram of compound I-1 of the present invention; Figure 4 This is a structural diagram of compound I-2 of the present invention; Figure 5 This is a structural diagram of compound I-3 of the present invention; Figure 6 This is a structural diagram of compound I-4 of the present invention; Figure 7 This is a structural diagram of compound I-5 of the present invention; Figure 8 This is a structural diagram of compound I-6 of the present invention; Figure 9 This is a structural diagram of compound I-7 of the present invention; Figure 10 This is a structural diagram of compound I-8 of the present invention; Figure 11 This is a structural diagram of compound I-9 of the present invention; Figure 12 This is a structural diagram of compound I-10 of the present invention; Figure 13 This is a structural diagram of compound I-11 of the present invention; Figure 14 This is a structural diagram of compound I-12 of the present invention; Figure 15 This is a structural diagram of compound I-13 of the present invention; Figure 16 This is a structural diagram of compound I-14 of the present invention; Figure 17 This is a structural diagram of compound I-15 of the present invention; Figure 18 This is a structural diagram of compound I-16 of the present invention; Figure 19 This is a structural diagram of compound I-17 of the present invention; Figure 20 This is a structural diagram of compound I-18 of the present invention; Figure 21 This is a structural diagram of compound I-19 of the present invention; Figure 22 This is a structural diagram of compound I-20 of the present invention; Figure 23 This is a structural diagram of compound I-21 of the present invention; Figure 24 This is a structural diagram of compound I-22 of the present invention; Figure 25 This is a structural diagram of compound I-23 of the present invention; Figure 26 This is a structural diagram of compound I-24 of the present invention; Figure 27 This is a structural diagram of compound I-25 of the present invention; Figure 28 This is a structural diagram of compound I-26 of the present invention; Figure 29 This is a structural diagram of compound I-27 of the present invention; Figure 30 This is a structural diagram of compound I-28 of the present invention; Figure 31 The concentration of compounds added in this invention relates to cell survival rate. Detailed Implementation

[0020] The present invention will be described in detail below with reference to specific embodiments and examples, thereby making the advantages and various effects of the present invention more clearly apparent. Those skilled in the art should understand that these specific embodiments and examples are for illustrative purposes only and are not intended to limit the present invention.

[0021] Throughout this specification, unless otherwise specified, the terminology used herein should be understood as having the meaning commonly used in the art. Therefore, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In the event of any conflict, this specification shall prevail.

[0022] The preparation method and application of the compound in Formula I of this invention will be described in detail below through examples.

[0023] The stereoconfiguration of the compounds synthesized in the following examples was determined by X-ray single-crystal diffraction. The diastereomeric ratio dr of the products was determined by a 400 MHz nuclear magnetic resonance spectrometer. The enantiomeric excess ee value was determined by a chiral HPLC. HPLC analysis was performed using chiral AD-H, OD-H, and IA columns.

[0024] The intermediates mentioned in the following examples

[0025] The compounds shown as 3-isothiocyanate-oxidized indole II-1, 2, 3, 4, 5, 6, 7, and 8 are respectively the compounds in the middle R. 1 For hydrogen, R 2 Methyl; R 1 It is 6-methyl, R 2 Methyl; R 1 It is 6-methoxy, R 2 Methyl; R 1 It is 7-methoxy, R 2 Methyl; R 1 It is 6-fluorine, R 2Methyl; R 1 It is 7-fluorine, R 2 Methyl; R 1 For hydrogen, R 2 It is benzyl; R 1 For hydrogen, R 2 These are the compounds corresponding to n-propyl.

[0026]

[0027] The compounds shown as 2-aryl-1,3-indanedion III-1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20 are respectively from the R group. 3 Compounds corresponding to phenyl, p-methylphenyl, p-methoxyphenyl, m-methoxyphenyl, o-methoxyphenyl, 3,4-dimethoxyphenyl, p-fluorophenyl, p-chlorophenyl, o-chlorophenyl, 2,4-dichlorophenyl, p-bromophenyl, p-nitrophenyl, p-cyanophenyl, p-trifluoromethylphenyl, 3,5-bis(trifluoromethyl)phenyl, 1-naphthalene, 2-naphthalene, styryl, cyclohexyl, 2-furan, and 2-thiophene.

[0028] Example 1, as Figure 3 As shown: Preparation of compound I-1 At room temperature, magnesium trifluoromethanesulfonate (3.22 mg, 0.01 mmol) and ligand IV (5.22 mg, 0.01 mmol) were dissolved in acetonitrile and stirred under nitrogen protection. After 30 min, 2-phenyl-1,3-indanedion III-1 (23.43 mg, 0.10 mmol) was added and stirred for 20 min. Then, 3-isothiocyanate oxyindole II-1 (20.43 mg, 0.10 mmol) was added to the reaction system and the reaction was continued until the reaction was complete as detected by TLC. 40.6 mg of the target product of formula I-1 was directly obtained by column chromatography with V petroleum ether / V ethyl acetate = 20:1-4:1, with a yield of 93%.

[0029] 1H NMR (400 MHz, CDCl3): δ 8.67 – 8.61 (m, 1H), 8.08 – 8.01 (m, 2H), 7.99 (dd, J = 5.6, 2.8 Hz, 1H), 7.85 – 7.78 (m, 2H), 7.36 – 7.32 (m, 1H), 7.29 – 7.23 (m, 1H), 7.02 – 6.88 (m, 5H), 6.70 (d, J = 7.6 Hz, 1H), 5.13 (s,1H), 3.14 (s, 3H).

[0030] 13 C NMR (100 MHz, CDCl3): δ 199.3, 195.4, 194.8, 174.5, 143.7, 143.3(2C), 136.2, 136.0, 130.8, 130.7, 130.3, 128.3 (2C), 128.1, 125.5, 124.4,124.3, 123.3, 108.6, 77.3, 73.9, 57.7, 27.0.

[0031] IR: 3332, 1735, 1709, 1607, 1491, 1470, 1342, 1261, 1193, 748, 703,575, 530cm -1 .

[0032] High resolution: Calculated value: [M+Na] + : 461.0930, measured value: 461.0929.

[0033] [α]D 25 = -34.48 (C = 0.50, CHCl3).

[0034] Optical purity analysis: The product had an enantiomeric excess of 82% and a diastereomer ratio > 95:5. Chiral OD-H column (isopropanol:n-hexane 30:70, v:v), 10 mL / min, 254 nm, 25 o C, the retention time is t1 = 25.94 minutes, t2 = 34.19 minutes.

[0035] Example 2, as Figure 4 As shown: Preparation of compound I-2 At room temperature, magnesium trifluoromethanesulfonate (3.22 mg, 0.01 mmol) and ligand IV (5.22 mg, 0.01 mmol) were dissolved in acetonitrile and stirred under nitrogen protection. After 30 min, 2-phenyl-1,3-indanedion III-1 (23.43 mg, 0.10 mmol) was added and stirred for 20 min. Then, 3-isothiocyanate oxyindole II-2 (21.83 mg, 0.10 mmol) was added to the reaction system and the reaction was continued until the reaction was complete as detected by TLC. The target product of formula I-2 was directly obtained by column chromatography with V petroleum ether / V ethyl acetate = 20:1-4:1, with a yield of 92%.

[0036] 1 H NMR (400 MHz, CDCl3): δ 8.45 (s, 1H), 8.07 – 8.0 (m, 2H), 7.85 –7.80 (m, 3H), 7.15 (d, J = 7.9 Hz, 1H), 7.01 – 6.90 (m, 5H), 6.59 (d, J = 7.9Hz, 1H), 5.15 (s, 1H), .310 (s, 3H), 2.52 (s, 3H).

[0037] 13 C NMR (100 MHz, CDCl3): δ 199.3, 195.3, 194.8, 174.2, 143.7, 143.3,141.0, 136.2, 136.1, 133.0, 131.0, 130.8, 130.3, 128.9, 128.3, 128.1, 125.5,124.5, 124.3, 108.3, 74.0, 57.6, 26.9, 21.4.

[0038] IR: 3332, 1738, 1712, 1603, 1494, 1480, 1331, 1254, 1102, 810, 797,702, 588, 554 cm -1 .

[0039] High resolution: Calculated value: [M+Na] + : 475.1087, measured value: 475.1077.

[0040] [α]D 25 = -2.08 (C = 0.25, CHCl3).

[0041] Optical purity analysis: The product had an enantiomeric excess of 80% and a diastereomer ratio > 95:5. Chiral AD-H column (isopropanol:n-hexane 30:70, v:v), 1.0 mL / min, 254 nm, 25 o C, the retention time is t1 = 13.68 minutes, t2 = 15.47 minutes.

[0042] Example 3, as Figure 5 As shown: Preparation of compound I-3 At room temperature, magnesium trifluoromethanesulfonate (3.22 mg, 0.01 mmol) and ligand IV (5.22 mg, 0.01 mmol) were dissolved in acetonitrile and stirred under nitrogen protection. After 30 min, 2-phenyl-1,3-indanedion III-1 (23.43 mg, 0.10 mmol) was added, and the mixture was stirred for 20 min. Then, 3-isothiocyanate oxyindole II-3 (23.43 mg, 0.10 mmol) was added to the reaction system, and the reaction was continued until the reaction was complete as detected by TLC. 石油醚 / V 乙酸乙酯 = 20:1-4:1 column chromatography directly yielded 40.0 mg of the target product of formula I-3, with a yield of 85%.

[0043] 1 H NMR (400 MHz, DMSO- d 6): δ 11.50 (s, 1H), 8.18 (d, J = 2.3 Hz, 1H),8.16 – 8.11 (m, 2H), 8.08 – 8.02 (m, 2H), 7.05 – 6.91 (m, 5H), 6.80 (d, J =6.5 Hz, 2H), 4.93 (s, 1H), 3.87 (s, 3H), 3.11 (s, 3H).

[0044] 13 C NMR (100 MHz, DMSO- d 6): δ 195.8, 195.6, 173.6, 155.7, 142.7, 142.6, 137.5, 137.4, 136.8, 131.0, 129.0, 128.5, 128.3, 126.6, 124.4, 124.2, 115.1, 114.2, 109.8, 77.2, 73.9, 56.2, 55.7, 26.9.

[0045] IR: 3267, 1747, 1715, 1606, 1589, 1501, 1427, 1298, 1241, 1095, 1028,884, 825, 702, 692, 592, 551 cm -1 .

[0046] High resolution: Calculated value: [M+Na] + : 491.1036, measured value: 491.1026.

[0047] [α] D 25 = 8.56 (C = 0.25, CHCl3).

[0048] Optical purity analysis: The product had an enantiomeric excess of 99% and a diastereomer ratio > 95:5. Chiral AD-H column (isopropanol:n-hexane 30:70, v:v), 1.0 mL / min, 254 nm, 25 o C, the retention time is t1 = 17.29 minutes, t2 = 20.51 minutes.

[0049] Example 4, as Figure 6 As shown: Preparation of compound I-4 At room temperature, magnesium trifluoromethanesulfonate (3.22 mg, 0.01 mmol) and ligand IV (5.22 mg, 0.01 mmol) were dissolved in acetonitrile and stirred under nitrogen protection. After 30 min, 2-phenyl-1,3-indanedion III-1 (23.43 mg, 0.10 mmol) was added, and the mixture was stirred for 20 min. Then, 3-isothiocyanate oxyindole II-4 (23.43 mg, 0.10 mmol) was added to the reaction system, and the reaction was continued until the reaction was complete as detected by TLC. 石油醚 / V 乙酸乙酯 = 20:1-3:1 column chromatography directly yielded 44.1 mg of the target product of formula I-4, with a yield of 85%.

[0050] 1 H NMR (400 MHz, CDCl3): δ 8.53 (d, J = 8.4 Hz, 1H), 8.07 – 8.00 (m,2H), 7.97 (dd, J= 5.9, 2.3 Hz, 1H), 7.85 – 7.77 (m, 2H), 7.01 – 6.91 (m 5H), 6.74 (dd, J = 8.4, 2.2 Hz, 1H), 6.27 (d, J = 2.2 Hz, 1H), 5.10 (s, 1H), 3.84 (s, 3H), 3.11 (s, 3H).

[0051] 13 C NMR (100 MHz, CDCl3): δ 198.9, 195.5, 194.9, 174.9, 162.0, 144.8,143.7, 143.2, 136.2, 136.0, 130.9, 130.3, 129.3, 128.2 (2C), 124.4, 124.3,117.1, 107.1, 96.5, 73.7, 57.4, 55.6, 27.0.

[0052] IR: 2959, 2924, 1728, 1709, 1625, 1478, 1401, 1269, 1096, 989, 800,728, 607 cm -1 .

[0053] High resolution: Calculated value: [M+Na] + : 491.1036, measured value: 491.1030.

[0054] [α] D 25 = -75.80 (C = 0.1, CHCl3).

[0055] Optical purity analysis: The product had an enantiomeric excess of 72% and a diastereomer ratio > 95:5. Chiral AD-H column (isopropanol:n-hexane 30:70, v:v), 1.0 mL / min, 254 nm, 25 o C, the retention time is t1 = 20.91 minutes, t2 = 26.94 minutes.

[0056] Example 5, as Figure 7 As shown: Preparation of compound I-5 At room temperature, magnesium trifluoromethanesulfonate (3.22 mg, 0.01 mmol) and ligand IV (5.22 mg, 0.01 mmol) were dissolved in acetonitrile and stirred under nitrogen protection. After 30 min, 2-phenyl-1,3-indanedion III-1 (23.43 mg, 0.10 mmol) was added, and the mixture was stirred for 20 min. Then, 3-isothiocyanate oxyindole II-5 (22.22 mg, 0.10 mmol) was added to the reaction system, and the reaction was continued until the reaction was complete as detected by TLC. 石油醚 / V 乙酸乙酯 = 20:1-4:1 column chromatography directly yielded 36.2 mg of the target product of formula I-5, with a yield of 79%.

[0057] 1 H NMR (400 MHz, DMSO- d 6): δ 11.51 (s, 1H), 8.33 (d, J = 8.0 Hz, 1H), 8.14 (d, J = 14.2 Hz, 2H), 8.09 – 7.99 (m, 2H), 7.29 (t, J = 7.8 Hz, 1H),7.03 (s, 4H), 6.78 (d, J = 5.7 Hz, 2H), 4.93 (s, 1H), 3.14 (s, 3H).

[0058] 13 C NMR (100 MHz, DMSO- d 6): δ 197.1, 195.9, 195.3, 173.8, 159.7,157.3, 142.8, 142.5, 139.8, 137.7, 137.5, 130.7, 128.9, 128.6, 128.5, 127.2,127.1, 124.5, 124.3, 117.2, 116.9, 114.8, 114.5, 110.5 (2C), 77.0, 73.6,56.2, 27.0.

[0059] IR: 2973, 1741, 1721, 1703, 1622, 1508, 1460, 1355, 1264, 1101, 1048,873, 777, 704, 602, 661 cm -1 .

[0060] High resolution: Calculated value: [M+Na] + : 479.0836, measured value: 479.0831.

[0061] [α] D 25 = 1.88 (C = 1.0, CHCl3).

[0062] Optical purity analysis: The product had an enantiomeric excess of 64% and a diastereomer ratio of 17:1. Chiral AD-H column (isopropanol:n-hexane 30:70, v:v), 1.0 mL / min, 254 nm, 25 o C, the retention time is t1 = 14.59 minutes, t2 = 16.40 minutes.

[0063] Example 6, as Figure 8 Preparation of compound I-6 shown At room temperature, magnesium trifluoromethanesulfonate (3.22 mg, 0.01 mmol) and ligand IV (5.22 mg, 0.01 mmol) were dissolved in acetonitrile and stirred under nitrogen protection. After 30 min, 2-phenyl-1,3-indanedion III-1 (23.43 mg, 0.10 mmol) was added, and the mixture was stirred for 20 min. Then, 3-isothiocyanate oxyindole II-6 (22.22 mg, 0.10 mmol) was added to the reaction system, and the reaction was continued until TLC showed complete reaction. 石油醚 / V 乙酸乙酯 = 20:1-4:1 column chromatography directly yielded 40.1 mg of the target product of formula I-6, with a yield of 88%.

[0064] 1 H NMR (400 MHz, CDCl3): δ 8.62 (dd, J = 8.4, 5.4 Hz, 1H), 8.20 (s,1H), 8.05 (dd, J = 5.5, 2.8 Hz, 1H), 8.02 – 7.96 (m, 1H), 7.86 – 7.78 (m,2H), 7.03 – 6.98 (m, 1H), 6.97 – 6.92 (m, 5H), 6.44 (dd, J = 8.5, 2.3 Hz, 1H), 5.09 (s, 1H), 3.13 (s, 3H).

[0065] 13 C NMR (100 MHz, CDCl3): δ 199.2, 195.4, 194.7, 174.9, 165.7, 163.2, 145.1, 145.0, 143.7, 143.2, 136.3, 136.1, 130.5, 130.2, 129.9, 129.8, 128.4, 128.3, 124.5, 124.4, 120.9, 120.8, 109.7, 109.5, 97.7, 97.4, 73.6, 57.7, 27.1.

[0066] IR: 2972, 2925, 1719, 1721, 1716, 1396, 1292, 1101, 1070, 917, 790,617, 571 cm -1 .

[0067] High resolution: Calculated value: [M+Na] + : 479.0836, measured value: 479.0826.

[0068] [α] D 25 = 1.88 (C = 1.0, CHCl3).

[0069] Optical purity analysis: The product had an enantiomeric excess of 64% and a diastereomer ratio > 95:5. Chiral AI column (isopropanol:n-hexane 20:80, v:v), 1.0 mL / min, 254 nm, 25 o C, the retention time is t1 = 19.44 minutes, t2 = 23.18 minutes.

[0070] Example 7, as Figure 9 As shown: Preparation of compound I-7 At room temperature, magnesium trifluoromethanesulfonate (3.22 mg, 0.01 mmol) and ligand IV (5.22 mg, 0.01 mmol) were dissolved in acetonitrile and stirred under nitrogen protection. After 30 min, 2-phenyl-1,3-indanedion III-1 (23.43 mg, 0.10 mmol) was added, and the mixture was stirred for 20 min. Then, 3-isothiocyanate oxyindole II-7 (28.04 mg, 0.10 mmol) was added to the reaction system, and the reaction was continued until TLC showed complete reaction. 石油醚 / V 乙酸乙酯= 20:1-4:1 column chromatography directly yielded 48.3 mg of the target product of formula I-7, with a yield of 94%.

[0071] 1 H NMR (400 MHz, CDCl3): δ 8.66 – 8.60 (m, 1H), 8.19 (s, 1H), 8.07 –7.99 (m, 2H), 7.85 – 7.80 (m, 2H), 7.25 – 7.18 (m, 2H), 7.14 (t, J = 7.3 Hz,1H), 7.10 – 7.03 (m, 3H), 7.02 – 6.91 (m, 4H), 6.71 (d, J = 7.4 Hz, 2H), 6.50(d, J = 7.1 Hz, 1H), 5.23 (d, J = 16.1 Hz, 1H), 5.19 (s, 1H), 4.47 (d, J =16.1 Hz, 1H).

[0072] 13 C NMR (100 MHz, CDCl3): δ 199.5, 195.1, 194.7, 174.7, 143.7, 143.3,142.4, 136.3, 136.1, 134.3, 130.7, 130.4, 128.6, 128.5, 128.3 (2C), 127.4,126.5, 125.7, 124.5, 124.4, 123.3, 109.7, 74.2, 58.4, 44.1.

[0073] IR: 3201, 2974, 1710, 1611, 1487, 1383, 1326, 1262, 1044, 874, 752,738, 705, 585 cm -1 .

[0074] High resolution: Calculated value: [M+Na] + : 537.1243, measured value: 537.1241.

[0075] [α] D 25 = -17.34 (C = 1.0, CHCl3).

[0076] Optical purity analysis: The product had an enantiomeric excess of 71% and a diastereomer ratio > 95:5. Chiral AD-H column (isopropanol:n-hexane 30:70, v:v), 1.0 mL / min, 254 nm, 25 o C, the retention time is t1 = 15.76 minutes, t2 = 31.85 minutes.

[0077] Example 8, as Figure 10 As shown: Preparation of compound I-8 At room temperature, magnesium trifluoromethanesulfonate (3.22 mg, 0.01 mmol) and ligand IV (5.22 mg, 0.01 mmol) were dissolved in acetonitrile and stirred under nitrogen protection. After 30 min, 2-phenyl-1,3-indanedion III-1 (23.43 mg, 0.10 mmol) was added, and the mixture was stirred for 20 min. Then, 3-isothiocyanate oxyindole II-8 (23.23 mg, 0.10 mmol) was added to the reaction system, and the reaction was continued until TLC showed complete reaction. 石油醚 / V 乙酸乙酯 = 20:1-3:1 column chromatography directly yielded 46.5 mg of the target product of formula I-8, with a yield of 99%.

[0078] 1 H NMR (400 MHz, CDCl3): δ 8.61 (d, J = 7.5 Hz, 1H), 8.11 (s, 1H), 8.04 (dd, J = 5.4, 2.7 Hz, 1H), 8.00 – 7.96 (m, 1H), 7.84 – 7.78 (m, 2H), 7.36 – 7.29 (m, 1H), 7.28 – 7.21 (m, 1H), 7.01 – 6.87 (m, 5H), 6.69 (d, J =7.7 Hz, 1H), 5.12 (s, 1H), 3.80 (dt, J = 14.3, 7.3 Hz, 1H), 3.39 (dt, J =13.9, 6.9 Hz, 1H), 1.52 – 1.43 (m, 2H), 0.67 (t, J = 7.4 Hz, 3H).

[0079] 13C NMR (100 MHz, CDCl3): δ 199.4, 195.3, 194.7, 174.4, 143.7, 143.3,142.8, 136.2, 136.0, 130.6 (2C), 130.4, 128.3, 128.1, 125.7, 124.4, 124.3, 123.0, 108.7, 74.0, 58.1, 42.1, 20.4, 11.0.

[0080] IR: 2930, 1726, 1708, 1613, 1514, 1487, 1370, 1339, 1259, 1150, 1113,995, 799, 756, 724, 701, 575 cm -1 .

[0081] High resolution: Calculated value: [M+Na] + : 489.1243, measured value: 489.1242.

[0082] [α] D 25 = -23.14 (C = 1.0, CHCl3).

[0083] Optical purity analysis: The product had an enantiomeric excess of 71% and a diastereomer ratio > 95:5. Chiral AD-H column (isopropanol:n-hexane 30:70, v:v), 1.0 mL / min, 254 nm, 25 o C, the retention time is t1 = 14.71 minutes, t2 = 20.39 minutes.

[0084] Example 9, as Figure 11 As shown: Preparation of compound I-9 At room temperature, magnesium trifluoromethanesulfonate (3.22 mg, 0.01 mmol) and ligand IV (5.22 mg, 0.01 mmol) were dissolved in acetonitrile and stirred under nitrogen protection. After 30 min, 2-aryl-1,3-indanedion III-2 (24.83 mg, 0.10 mmol) was added, and the mixture was stirred for 20 min. Then, 3-isothiocyanate oxyindole II-1 (20.43 mg, 0.10 mmol) was added to the reaction system, and the reaction was continued until the reaction was complete as detected by TLC. 石油醚 / V 乙酸乙酯 = 20:1-4:1 column chromatography directly yielded 37.2 mg of the target product of formula I-9, with a yield of 82%.

[0085] 1 H NMR (400 MHz, CDCl3): δ 8.64 (d, J = 7.4 Hz, 1H), 8.15 – 7.96 (m,3H), 7.87 – 7.78 (m, 2H), 7.35 (t, J = 7.6 Hz, 1H), 7.28 (d, J = 7.5 Hz, 1H), 6.84 (d, J = 8.0 Hz, 2H), 6.71 (d, J = 7.2 Hz, 3H), 5.10 (s, 1H), 3.13 (s, 3H), 2.05 (s, 3H).

[0086] 13 C NMR (100 MHz, CDCl3): δ 199.4, 195.4, 194.9, 174.5, 143.7, 143.3(2C), 138.1, 136.2, 136.0, 130.7, 130.2, 128.9, 128.3, 127.5, 125.6, 124.4,124.3, 123.3, 108.6, 73.9, 57.5, 27.0, 20.8.

[0087] IR: 3231, 2973, 1714, 1702, 1603, 1485, 1474, 1257, 1111, 996, 940,771, 597, 562 cm -1 .

[0088] High resolution: Calculated value: [M+H] + : 453.1267, measured value: 453.1259.

[0089] [α] D 25 = -30.74 (C = 1.0, CHCl3).

[0090] Optical purity analysis: The product had an enantiomeric excess of 71% and a diastereomer ratio > 95:5. Chiral AD-H column (isopropanol:n-hexane 30:70, v:v), 1.0 mL / min, 254 nm, 25 o C, the retention time is t1 = 15.75 minutes, t2 = 18.86 minutes.

[0091] Example 10, as Figure 12 As shown: Preparation of compound I-10 At room temperature, magnesium trifluoromethanesulfonate (3.22 mg, 0.01 mmol) and ligand IV (5.22 mg, 0.01 mmol) were dissolved in acetonitrile and stirred under nitrogen protection. After 30 min, 2-aryl-1,3-indanedion III-3 (26.43 mg, 0.10 mmol) was added, and the mixture was stirred for 20 min. Then, 3-isothiocyanate oxyindole II-1 (20.43 mg, 0.10 mmol) was added to the reaction system, and the reaction was continued until the reaction was complete as detected by TLC. 石油醚 / V 乙酸乙酯 = 20:1-3:1 column chromatography directly yielded 46.5 mg of the target product of formula I-10, with a yield of 99%.

[0092] 1 H NMR (400 MHz, CDCl3): δ 8.67 – 8.63 (m, 1H), 8.08 – 8.03 (m, 1H), 8.02 – 7.97 (m, 1H), 7.86 – 7.80 (m, 2H), 7.78 (s, 1H), 7.38 – 7.34 (m, 1H), 7.30 (dd, J = 7.5, 0.9 Hz, 1H), 6.90 (d, J = 8.8 Hz, 2H), 6.70 (d, J = 7.6Hz, 1H), 6.43 (d, J = 8.8 Hz, 2H), 5.09 (s, 1H), 3.57 (s, 3H), 3.12 (s, 3H).

[0093] 13 C NMR (100 MHz, CDCl3): δ 199.5, 195.5, 194.9, 174.4, 159.4, 143.8, 143.4, 143.3, 136.2, 136.0, 131.6, 130.8, 128.3, 125.6, 124.4, 124.3, 123.3, 122.4, 113.5, 108.6, 73.9, 57.5, 54.9, 26.9.

[0094] IR: 3435, 1727, 1708, 1611, 1514, 1383, 1260, 1182, 1094, 1032, 897,758, 560 cm -1 .

[0095] High resolution: Calculated value: [M+Na] + : 491.1036, measured value: 491.1025.

[0096] [α] D 25 = -50.16 (C = 1.0, CHCl3).

[0097] Optical purity analysis: The product had an enantiomeric excess of 80% and a diastereomer ratio > 95:5. Chiral AD-H column (isopropanol:n-hexane 30:70, v:v), 1.0 mL / min, 254 nm, 25 o C, the retention time is t1 = 16.20 minutes, t2 = 28.24 minutes.

[0098] Example 11, as Figure 13 As shown: Preparation of compound I-11 At room temperature, magnesium trifluoromethanesulfonate (3.22 mg, 0.01 mmol) and ligand IV (5.22 mg, 0.01 mmol) were dissolved in acetonitrile and stirred under nitrogen protection. After 30 min, 2-aryl-1,3-indanedion III-4 (26.43 mg, 0.10 mmol) was added, and the mixture was stirred for 20 min. Then, 3-isothiocyanate oxyindole II-1 (20.43 mg, 0.10 mmol) was added to the reaction system, and the reaction was continued until TLC showed complete reaction. 石油醚 / V 乙酸乙酯 = 20:1-3:1 column chromatography directly yielded 39.8 mg of the target product of formula I-11, with a yield of 85%.

[0099] 1 H NMR (400 MHz, DMSO- d 6): δ 11.47 (s, 1H), 8.49 (d, J = 7.4 Hz, 1H),8.16 – 8.10 (m, 2H), 8.08 – 8.01 (m, 2H), 7.48 – 7.40 (m, 1H), 7.30 (t, J =7.5 Hz, 1H), 7.04 (d,J = 7.8 Hz, 1H), 6.90 (t, J = 8.2 Hz, 1H), 6.58 (dd, J = 8.2, 2.0 Hz, 1H), 6.37 – 6.30 (m, 2H), 4.92 (s, 1H), 3.40 (s, 3H), 3.15 (s, 3H).

[0100] 13 C NMR (100 MHz, DMSO- d 6): δ 196.8, 195.6 (2C), 174.0, 158.6, 143.5,142.7 (2C), 137.4 (2C), 132.4, 130.7, 129.5, 127.1, 125.5, 124.3, 124.2,122.8, 121.4, 114.4, 113.9, 109.4, 77.2, 73.5, 56.1, 54.6, 26.8.

[0101] IR: 3298, 1740, 1720, 1702, 1606, 1589, 1494, 1470, 1389, 1263, 1151,1042, 922, 761, 704, 565 cm -1 .

[0102] High resolution: Calculated value: [M+H] + : 469.1217, measured value: 469.1208.

[0103] [α] D 25 = -30.36 (C = 0.5, CHCl3).

[0104] Optical purity analysis: The product had an enantiomeric excess of 90% and a diastereomer ratio > 95:5. Chiral AD-H column (isopropanol:n-hexane 30:70, v:v), 1.0 mL / min, 254 nm, 25 o C, the retention time is t1 = 12.91 minutes, t2 = 20.85 minutes.

[0105] Example 12, as Figure 14 Preparation of compound I-12 shown At room temperature, magnesium trifluoromethanesulfonate (3.22 mg, 0.01 mmol) and ligand IV (5.22 mg, 0.01 mmol) were dissolved in acetonitrile and stirred under nitrogen protection. After 30 min, 2-aryl-1,3-indanedion III-4 (26.43 mg, 0.10 mmol) was added, and the mixture was stirred for 20 min. Then, 3-isothiocyanate oxyindole II-1 (20.43 mg, 0.10 mmol) was added to the reaction system, and the reaction was continued until TLC showed complete reaction. 石油醚 / V 乙酸乙酯 = 20:1-3:1 column chromatography directly yielded 46.5 mg of the target product of formula I-12, with a yield of 99%.

[0106] 1 H NMR (400 MHz, CDCl3): δ 8.37 (d, J = 7.4 Hz, 1H), 8.20 (s, 1H), 8.09 (d, J = 7.2 Hz, 1H), 7.97 (d, J = 6.9 Hz, 1H), 7.82 (d, J = 7.5 Hz, 2H), 7.32 (t, J = 7.5 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 6.92 (t, J = 7.5 Hz, 1H), 6.76 (dd, J = 23.5, 7.7 Hz, 2H), 6.48 (d, J = 8.2 Hz, 1H), 6.43 (d, J = 7.6Hz, 1H), 5.67 (s, 1H), 3.37 (s, 3H), 3.23 (s, 3H).

[0107] 13 C NMR (100 MHz, CDCl3): δ199.0, 195.6, 194.5, 174.2, 156.9, 143.6, 143.4, 142.8, 135.9, 135.6, 130.5, 129.4, 128.7, 127.8, 126.0, 124.1, 123.3, 120.4, 119.9, 110.1, 108.5, 73.1, 54.6, 48.1, 27.0.

[0108] IR: 2973, 1728, 1709, 1610, 1517, 1493, 1462, 1381, 1347, 1257, 1150,1090, 1048, 889, 758, 580 cm -1 .

[0109] High resolution: Calculated value: [M+Na] + : 491.1036, measured value: 491.1030.

[0110] [α] D 25 = -66.28 (C = 0.5, CHCl3).

[0111] Optical purity analysis: The product had an enantiomeric excess of 95% and a diastereomer ratio > 95:5. Chiral IA column (isopropanol:n-hexane 10:90, v:v), 1.0 mL / min, 254 nm, 25 o C, the retention time is t1 = 22.47 minutes, t2 = 31.28 minutes.

[0112] Example 13, as Figure 15 Preparation of compound I-13 shown At room temperature, magnesium trifluoromethanesulfonate (3.22 mg, 0.01 mmol) and ligand IV (5.22 mg, 0.01 mmol) were dissolved in acetonitrile and stirred under nitrogen protection. After 30 min, 2-aryl-1,3-indanedion III-5 (29.43 mg, 0.10 mmol) was added, and the mixture was stirred for 20 min. Then, 3-isothiocyanate oxyindole II-1 (20.43 mg, 0.10 mmol) was added to the reaction system, and the reaction was continued until TLC showed complete reaction. 石油醚 / V 乙酸乙酯 = 20:1-3:1 column chromatography directly yielded 36.9 mg of the target product of formula I-13, with a yield of 74%.

[0113] 1H NMR (400 MHz, CDCl3): δ 8.64 (d, J = 7.4 Hz, 1H), 8.27 (s, 1H), 8.08 – 7.93 (m, 2H), 7.87 – 7.77 (m, 2H), 7.39 – 7.31 (m, 1H), 7.30 – 7.25(m, 1H), 6.71 (d, J = 7.7 Hz, 1H), 6.55 – 6.46 (m, 2H), 6.40 (s, 1H), 5.02(s, 1H), 3.62 (s, 3H), 3.46 (s, 3H), 3.09 (d, J = 3.6 Hz, 3H).

[0114] 13 C NMR (100 MHz, CDCl3): δ 199.3, 195.5, 195.0, 174.6, 148.7, 147.9, 143.7, 143.5, 143.3, 136.2, 136.0, 130.7, 128.1, 126.0, 124.3, 124.2, 123.2, 123.0, 122.7, 112.9, 110.2, 108.8, 74.0, 57.7, 55.5, 55.4, 26.9.

[0115] IR: 3237, 1728, 1703, 1605, 1518, 1509, 1464, 1327, 1264, 1150, 1101,1043, 785, 606, 589 cm -1 .

[0116] High resolution: Calculated value: [M+Na] + : 521.1142, measured value: 521.1136.

[0117] [α] D 25 = -47.04 (C = 0.5, CHCl3).

[0118] Optical purity analysis: The product had an enantiomeric excess of 82% and a diastereomer ratio > 95:5. Chiral AD-H column (isopropanol:n-hexane 30:70, v:v), 1.0 mL / min, 254 nm, 25 oC, the retention time is t1 = 13.12 minutes, t2 = 34.44 minutes.

[0119] Example 14 Figure 16 Preparation of compound I-14 shown At room temperature, magnesium trifluoromethanesulfonate (3.22 mg, 0.01 mmol) and ligand IV (5.22 mg, 0.01 mmol) were dissolved in acetonitrile and stirred under nitrogen protection. After 30 min, 2-aryl-1,3-indanedion III-6 (25.22 mg, 0.10 mmol) was added, and the mixture was stirred for 20 min. Then, 3-isothiocyanate oxyindole II-1 (20.43 mg, 0.10 mmol) was added to the reaction system, and the reaction was continued until the reaction was complete as detected by TLC. 石油醚 / V 乙酸乙酯 = 20:1-4:1 column chromatography directly yielded 45.0 mg of the target product of formula I-14, with a yield of 99%.

[0120] 1 H NMR (400 MHz, CDCl3): δ 8.63 – 8.58 (m, 1H), 8.23 ​​(s, 1H), 8.07 –8.02 (m, 1H), 8.01 – 7.96 (m, 1H), 7.87 – 7.80 (m, 2H), 7.38 – 7.34 (m, 1H),7.31 – 7.24 (m, 1H), 6.96 (dd, J = 8.8, 5.3 Hz, 2H), 6.73 (d, J = 7.7 Hz, 1H), 6.60 (t, J = 8.7 Hz, 2H), 5.09 (s, 1H), 3.15 (s, 3H).

[0121] 13 C NMR (100 MHz, CDCl3): δ 199.0, 195.2, 194.7, 174.5, 163.7, 161.3,143.7, 143.3, 143.2, 136.4, 136.1, 132.2, 132.1, 130.9, 128.1, 126.4 (2C),125.4, 124.4, 124.3, 123.4, 115.3, 115.1, 108.7, 73.9, 56.9, 27.0.

[0122] IR: 3403, 1731, 1706, 1605, 1502, 1476, 1377, 1271, 1236, 1160, 1109,808, 760, 612, 522 cm -1 .

[0123] High resolution: Calculated value: [M+Na] + : 479.0836, measured value: 479.0831.

[0124] [α] D 25 = -46.46 (C = 1.0, CHCl3).

[0125] Optical purity analysis: The product had an enantiomeric excess of 74%, and a diastereomer ratio > 95:5. Chiral AD-H column (isopropanol:n-hexane 30:70, v:v), 1.0 mL / min, 254 nm, 25 o C, the retention time is t1 = 11.39 minutes, t2 = 18.74 minutes.

[0126] Example 15 Figure 17 Preparation of compound I-15 shown At room temperature, magnesium trifluoromethanesulfonate (3.22 mg, 0.01 mmol) and ligand IV (5.22 mg, 0.01 mmol) were dissolved in acetonitrile and stirred under nitrogen protection. After 30 min, 2-aryl-1,3-indanedion III-7 (26.87 mg, 0.10 mmol) was added, and the mixture was stirred for 20 min. Then, 3-isothiocyanate oxyindole II-1 (20.43 mg, 0.10 mmol) was added to the reaction system, and the reaction was continued until TLC showed complete reaction. 石油醚 / V 乙酸乙酯 = 20:1-4:1 column chromatography directly yielded 41.2 mg of the target product of formula I-15, with a yield of 87%.

[0127] 1 H NMR (400 MHz, CDCl3): δ 8.62 (d, J = 7.5 Hz, 1H), 8.08 – 8.00 (m,2H), 7.96 (s, 1H), 7.89 – 7.82 (m, 2H), 7.41 – 7.35 (m, 1H), 7.29 (t, J= 7.6Hz, 1H), 6.96 – 6.87 (m, 4H), 6.74 (d, J = 7.7 Hz, 1H), 5.10 (s, 1H), 3.14 (s, 3H).

[0128] 13 C NMR (100 MHz, CDCl3): δ 199.0, 195.1, 194.5, 174.3, 143.7, 143.3, 143.2, 136.5, 136.2, 134.6, 131.8, 131.0, 129.1, 128.4, 128.2, 125.2, 124.5, 124.4, 123.4, 108.8, 73.7, 56.9, 27.0.

[0129] IR: 3190, 1736, 1709, 1601, 1508, 1329, 1251, 1099, 792, 751, 602,541 cm -1 .

[0130] High resolution: Calculated value: [M+Na] + : 495.0541, measured value: 495.0530.

[0131] [α] D 25 = -42.62 (C = 1.0, CHCl3).

[0132] Optical purity analysis: The product had an enantiomeric excess of 73% and a diastereomer ratio > 95:5. Chiral AD-H column (isopropanol:n-hexane 30:70, v:v), 1.0 mL / min, 254 nm, 25 o C, the retention time is t1 = 12.95 minutes, t2 = 20.11 minutes.

[0133] Example 16 Figure 18 Preparation of compound I-16 shown At room temperature, magnesium trifluoromethanesulfonate (3.22 mg, 0.01 mmol) and ligand IV (5.22 mg, 0.01 mmol) were dissolved in acetonitrile and stirred under nitrogen protection. After 30 min, 2-aryl-1,3-indanedion III-8 (26.87 mg, 0.10 mmol) was added, and the mixture was stirred for 20 min. Then, 3-isothiocyanate oxyindole II-1 (20.43 mg, 0.10 mmol) was added to the reaction system, and the reaction was continued until TLC showed complete reaction. 石油醚 / V 乙酸乙酯 = 20:1-3:1 column chromatography directly yielded 47.0 mg of the target product of formula I-16, with a yield of 99%.

[0134] 1 H NMR (400 MHz, CDCl3): δ 8.55 (d, J = 7.3 Hz, 1H), 8.29 (s, 1H), 8.05 (dd, J = 6.2, 1.8 Hz, 1H), 7.97 (dd, J = 6.1, 1.9 Hz, 1H), 7.85 – 7.77(m, 2H), 7.34 – 7.28 (m, 1H), 7.25 – 7.20 (m, 2H), 7.12 – 7.08 (m, 1H), 6.90– 6.86 (m, 1H), 6.75 – 6.69 (m, 1H), 6.67 (d, J = 7.7 Hz, 1H), 6.03 (s, 1H), 3.15 (s, 3H).

[0135] 13 C NMR (100 MHz, CDCl3): δ 199.5, 195.8, 194.2, 174.5, 143.6, 143.4, 143.2, 136.4, 136.0, 135.6, 132.3, 130.8, 129.5, 129.2, 128.4, 128.0, 125.9, 125.2, 124.5, 124.3, 123.0, 108.6, 73.6, 51.4, 27.0.

[0136] IR: 2982, 1742, 1605, 1502, 1397, 1295, 1107, 780, 758, 611, 538 cm -1 .

[0137] High resolution: Calculated value: [M+Na] + : 495.0541, measured value: 495.0536.

[0138] [α] D 25 = -65.60 (C = 0.9, CHCl3).

[0139] Optical purity analysis: The product had an enantiomeric excess of 90% and a diastereomer ratio > 95:5. Chiral AD-H column (isopropanol:n-hexane 30:70, v:v), 1.0 mL / min, 254 nm, 25 o C, the retention time is t1 = 10.35 minutes, t2 = 16.40 minutes.

[0140] Example 17 Figure 19 Preparation of compound I-17 At room temperature, magnesium trifluoromethanesulfonate (3.22 mg, 0.01 mmol) and ligand IV (5.22 mg, 0.01 mmol) were dissolved in acetonitrile and stirred under nitrogen protection. After 30 min, 2-aryl-1,3-indanedion III-9 (30.31 mg, 0.10 mmol) was added, and the mixture was stirred for 20 min. Then, 3-isothiocyanate oxyindole II-1 (20.43 mg, 0.10 mmol) was added to the reaction system, and the reaction was continued until TLC showed complete reaction. 石油醚 / V 乙酸乙酯 = 20:1-4:1 column chromatography directly yielded 50.2 mg of the target product of formula I-17, with a yield of 99%.

[0141] 1 H NMR (400 MHz, CDCl3): δ 8.52 (d, J = 7.2 Hz, 1H), 8.32 (s, 1H), 8.09 – 8.04 (m, 1H), 8.01 – 7.96 (m, 1H), 7.89 – 7.80 (m, 2H), 7.34 (t, J =7.4 Hz, 1H), 7.28 – 7.22 (m, 1H), 7.18 (d, J= 8.7 Hz, 1H), 7.13 (d, J = 2.1Hz, 1H), 6.71 (d, J = 8.3 Hz, 2H), 5.97 (s, 1H), 3.16 (s, 3H).

[0142] 13 C NMR (100 MHz, CDCl3): δ 199.1, 195.6, 193.9, 174.4, 143.6, 143.4, 143.1, 136.5, 136.4, 136.2, 134.7, 133.1, 131.0, 129.3, 127.9, 127.1, 126.4, 125.0, 124.6, 124.4, 123.2, 108.8, 73.4, 50.6, 27.1.

[0143] IR: 3110, 2974, 1726, 1709, 1613, 1585, 1523, 1472, 1342, 1258, 1148,1093, 909, 787, 753, 601, 527 cm -1 .

[0144] High resolution: Calculated value: [M+Na] + : 529.0151, measured value: 529.0149.

[0145] [α] D 25 = -82.00 (C = 1.0, CHCl3).

[0146] Optical purity analysis: The product had an enantiomeric excess of 76% and a diastereomer ratio > 95:5. Chiral AD-H column (isopropanol:n-hexane 30:70, v:v), 1.0 mL / min, 254 nm, 25 o C, the retention time is t1 = 7.16 minutes, t2 = 11.33 minutes.

[0147] Example 18, as Figure 20 Preparation of compound I-18 shown At room temperature, magnesium trifluoromethanesulfonate (3.22 mg, 0.01 mmol) and ligand IV (5.22 mg, 0.01 mmol) were dissolved in acetonitrile and stirred under nitrogen protection. After 30 min, 2-aryl-1,3-indanedion III-10 (31.32 mg, 0.10 mmol) was added, and the mixture was stirred for 20 min. Then, 3-isothiocyanate oxyindole II-1 (20.43 mg, 0.10 mmol) was added to the reaction system, and the reaction was continued until the reaction was complete as detected by TLC. 石油醚 / V 乙酸乙酯 = 20:1-4:1 column chromatography directly yielded 51.2 mg of the target product of formula I-18, with a yield of 99%.

[0148] 1 H NMR (400 MHz, CDCl3): δ 8.61 (d, J = 7.5 Hz, 1H), 8.09 – 8.04 (m,1H), 8.03 – 7.98 (m, 2H), 7.89 – 7.81 (m, 2H), 7.40 – 7.36 (m, 1H), 7.32 –7.27 (m, 1H), 7.05 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 6.74 (d, J = 7.7 Hz, 1H), 5.08 (s, 1H), 3.14 (s, 3H).

[0149] 13 C NMR (100 MHz, CDCl3): δ 198.9, 195.1, 194.5, 174.3, 143.7, 143.3, 143.2, 136.5, 136.2, 132.1, 131.4, 131.0, 129.6, 128.2, 125.2, 124.5, 124.4, 123.4, 122.9, 108.8, 73.7, 56.9, 27.0.

[0150] IR: 3465, 2360, 1708, 1630, 1399, 1384, 1280, 747, 528 cm -1 .

[0151] High resolution: Calculated value: [M+Na] +: 539.0035, measured value: 539.0034.

[0152] [α] D 25 = -34.08 (C = 1.0, CHCl3).

[0153] Optical purity analysis: The product had an enantiomeric excess of 75% and a diastereomer ratio > 95:5. Chiral AD-H column (isopropanol:n-hexane 30:70, v:v), 1.0 mL / min, 254 nm, 25 o C, the retention time is t1 = 14.22 minutes, t2 = 21.88 minutes.

[0154] Example 19 Figure 21 Preparation of compound I-19 shown At room temperature, magnesium trifluoromethanesulfonate (3.22 mg, 0.01 mmol) and ligand IV (5.22 mg, 0.01 mmol) were dissolved in acetonitrile and stirred under nitrogen protection. After 30 min, 2-aryl-1,3-indanedion III-11 (27.93 mg, 0.10 mmol) was added, and the mixture was stirred for 20 min. Then, 3-isothiocyanate oxyindole II-1 (20.43 mg, 0.10 mmol) was added to the reaction system, and the reaction was continued until the reaction was complete as detected by TLC. 石油醚 / V 乙酸乙酯 = 20:1-4:1 column chromatography directly yielded 47.3 mg of the target product of formula I-19, with a yield of 98%.

[0155] 1 H NMR (400 MHz, CDCl3): δ 8.62 (d, J = 7.3 Hz, 1H), 8.09 (dd, J =5.8, 2.2 Hz, 1H), 8.02 (dd, J = 5.8, 2.3 Hz, 1H), 7.93 (s, 1H), 7.90 – 7.85(m, 2H), 7.79 (d, J = 8.8 Hz, 2H), 7.41 (t, J = 7.4 Hz, 1H), 7.32 (t, J = 7.5Hz, 1H), 7.19 (d, J = 8.8 Hz, 2H), 6.75 (d, J= 7.7 Hz, 1H), 5.26 (s, 1H), 3.16 (s, 3H).

[0156] 13 C NMR (100 MHz, CDCl3): δ 198.3, 194.6, 193.9, 174.0, 147.8, 143.6,143.3, 143.0, 138.1, 136.7, 136.4, 131.4 (2C), 128.2, 124.8, 124.7, 124.6,123.7, 123.3, 109.0, 73.4, 56.4, 27.1.

[0157] IR: 3369, 1725, 1702, 1602, 1518, 1470, 1341, 1357, 1150, 1114, 1073,844, 760, 755, 567 cm -1 .

[0158] High resolution: Calculated value: [M+Na] + : 506.0781, measured value: 506.0775.

[0159] [α] D 25 = -24.68 (C = 0.5, CHCl3).

[0160] Optical purity analysis: The product had an enantiomeric excess of 91% and a diastereomer ratio > 95:5. Chiral AD-H column (isopropanol:n-hexane 30:70, v:v), 1.0 mL / min, 254 nm, 25 o C, the retention times are t1 = 18.50 minutes and t2 = 29.32 minutes.

[0161] Example 20, as Figure 22 Preparation of compound I-20 shown At room temperature, magnesium trifluoromethanesulfonate (3.22 mg, 0.01 mmol) and ligand IV (5.22 mg, 0.01 mmol) were dissolved in acetonitrile and stirred under nitrogen protection. After 30 min, 2-aryl-1,3-indanedion III-12 (25.93 mg, 0.10 mmol) was added, and the mixture was stirred for 20 min. Then, 3-isothiocyanate oxyindole II-1 (20.43 mg, 0.10 mmol) was added to the reaction system, and the reaction was continued until the reaction was complete as detected by TLC. 石油醚 / V 乙酸乙酯 = 20:1-4:1 column chromatography directly yielded 35.7 mg of the target product of formula I-20, with a yield of 77%.

[0162] 1 H NMR (400 MHz, CDCl3): δ 8.59 (d, J = 7.4 Hz, 1H), 8.08 (dd, J =5.1, 2.3 Hz, 2H), 8.01 (dd, J = 5.7, 2.5 Hz, 1H), 7.92 – 7.83 (m, 2H), 7.40(t, J = 7.7 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.23 (d, J = 8.4 Hz, 2H), 7.11(d, J = 8.4 Hz, 2H), 6.75 (d, J = 7.7 Hz, 1H), 5.17 (s, 1H), 3.15 (d, J = 2.7Hz, 3H).

[0163] 13 C NMR (100 MHz, CDCl3): δ 198.3, 194.7, 194.0, 174.1, 143.6, 143.2, 143.0, 136.6, 136.4, 136.1, 131.9, 131.3, 131.1, 128.2, 124.9, 124.6, 124.5, 123.6, 118.0, 112.5, 108.9, 73.5, 56.7, 27.1.

[0164] IR: 3286, 2972, 2233, 1724, 1703, 1612, 1489, 1374, 1349, 1260, 1174,1161, 1103, 1064, 906, 832, 758, 701, 597, 563 cm -1 .

[0165] High resolution: Calculated value: [M+Na] + : 486.0883, measured value: 486.0874.

[0166] [α] D 25 = -34.00 (C = 1.0, CHCl3).

[0167] Optical purity analysis: The product had an enantiomeric excess of 71% and a diastereomer ratio > 95:5. Chiral AD-H column (isopropanol:n-hexane 30:70, v:v), 1.0 mL / min, 254 nm, 25 o C, the retention time is t1 = 16.98 minutes, t2 = 37.93 minutes.

[0168] Example 21, as Figure 23 Preparation of compound I-21 shown At room temperature, magnesium trifluoromethanesulfonate (3.22 mg, 0.01 mmol) and ligand IV (5.22 mg, 0.01 mmol) were dissolved in acetonitrile and stirred under nitrogen protection. After 30 min, 2-aryl-1,3-indanedion III-13 (30.23 mg, 0.10 mmol) was added, and the mixture was stirred for 20 min. Then, 3-isothiocyanate oxyindole II-1 (20.43 mg, 0.10 mmol) was added to the reaction system, and the reaction was continued until the reaction was complete as detected by TLC. 石油醚 / V 乙酸乙酯 = 20:1-4:1 column chromatography directly yielded 49.3 mg of the target product of formula I-21, with a yield of 97%.

[0169] 1 H NMR (400 MHz, CDCl3): δ 8.63 (d, J = 7.5 Hz, 1H), 8.08 (dd, J =5.8, 2.5 Hz, 1H), 8.05 – 7.97 (m, 2H), 7.90 – 7.82 (m, 2H), 7.39 (t, J = 7.6Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.19 (d, J = 8.3 Hz, 2H), 7.11 (d, J = 8.3Hz, 2H), 6.75 (d, J = 7.7 Hz, 1H), 5.20 (s, 1H), 3.16 (s, 3H).

[0170] 13C NMR (100 MHz, CDCl3): δ 198.6, 194.8, 194.2, 174.2, 174.1, 143.7,143.3, 143.1, 136.5, 136.3, 134.8, 131.2, 130.8, 130.6, 130.3, 128.2, 125.2, 125.1 (3C), 124.9, 124.6, 124.5, 123.5, 122.2, 108.9, 73.6, 56.7, 27.0.

[0171] IR: 2974, 1727, 1710, 1614, 1521, 1472, 1329, 1261, 1092, 1049, 891,777, 667, 611, 551 cm -1 .

[0172] High resolution: Calculated value: [M+Na] + : 529.0804, measured value: 529.0798.

[0173] [α] D 25 = -36.30 (C = 1.0, CHCl3).

[0174] Optical purity analysis: The product had an enantiomeric excess of 64% and a diastereomer ratio > 95:5. Chiral AD-H column (isopropanol:n-hexane 30:70, v:v), 1.0 mL / min, 254 nm, 25 o C, the retention time is t1 = 10.18 minutes, t2 = 15.62 minutes.

[0175] Example 22 Figure 24 Preparation of compound I-22 shown At room temperature, magnesium trifluoromethanesulfonate (3.22 mg, 0.01 mmol) and ligand IV (5.22 mg, 0.01 mmol) were dissolved in acetonitrile and stirred under nitrogen protection. After 30 min, 2-aryl-1,3-indanedion III-14 (37.03 mg, 0.10 mmol) was added, and the mixture was stirred for 20 min. Then, 3-isothiocyanate oxyindole II-1 (20.43 mg, 0.10 mmol) was added to the reaction system, and the reaction was continued until the reaction was complete as detected by TLC. 石油醚 / V 乙酸乙酯= 20:1-8:1 column chromatography directly yielded 41.8 mg of the target product of formula I-22, with a yield of 73%.

[0176] 1 H NMR (400 MHz, CDCl3): δ 8.56 (d, J = 7.3 Hz, 1H), 8.26 (s, 1H), 8.06 (dd, J = 22.2, 6.4 Hz, 2H), 7.91 – 7.85 (m, 2H), 7.52 (s, 1H), 7.47 (s,2H), 7.39 (t, J = 7.4 Hz, 1H), 7.35 – 7.29 (m, 1H), 6.74 (d, J = 7.7 Hz, 1H), 5.20 (s, 1H), 3.15 (s, 3H).

[0177] 13 C NMR (100 MHz, CDCl3): δ 198.1, 194.2, 193.8, 174.2, 143.6, 143.1,143.0, 136.7, 136.4, 133.5, 131.5, 131.4, 131.2, 130.7 (2C), 128.0, 124.7, 124.6, 124.0, 123.7, 122.4 (2C), 122.3, 121.3, 109.0, 73.5, 56.1, 27.0.

[0178] IR: 3112, 2968, 1731, 1710, 1522, 1491, 1473, 1349, 1279, 1183, 1135,1013, 902, 802, 749, 710, 676, 598, 552 cm -1 .

[0179] High resolution: Calculated value: [M+Na] + : 597.0678, measured value: 597.0673.

[0180] [α] D 25 = -39.40 (C = 0.8, CHCl3).

[0181] Optical purity analysis: The product had an enantiomeric excess of 52% and a diastereomer ratio > 95:5. Chiral AD-H column (isopropanol:n-hexane 10:90, v:v), 1.0 mL / min, 254 nm, 25 o C, the retention time is t1 = 7.04 minutes, t2 = 15.58 minutes.

[0182] Example 23 Figure 25 Preparation of compound I-23 shown At room temperature, magnesium trifluoromethanesulfonate (3.22 mg, 0.01 mmol) and ligand IV (5.22 mg, 0.01 mmol) were dissolved in acetonitrile and stirred under nitrogen protection. After 30 min, 2-aryl-1,3-indanedion III-15 (28.43 mg, 0.10 mmol) was added, and the mixture was stirred for 20 min. Then, 3-isothiocyanate oxyindole II-1 (20.43 mg, 0.10 mmol) was added to the reaction system, and the reaction was continued until the reaction was complete as detected by TLC. 石油醚 / V 乙酸乙酯 = 20:1-4:1 column chromatography directly yielded 48.4 mg of the target product of formula I-23, with a yield of 99%.

[0183] 1 H NMR (400 MHz, CDCl3): δ 8.76 – 8.70 (m, 1H), 8.34 (d, J = 8.8 Hz, 1H), 8.00 (dd, J = 5.9, 2.0 Hz, 1H), 7.94 (dd, J = 5.5, 1.8 Hz, 2H), 7.80 –7.72 (m, 2H), 7.62 (d, J = 8.1 Hz, 1H), 7.59 – 7.53 (m, 1H), 7.48 (d, J = 8.2Hz, 1H), 7.43 – 7.36 (m, 2H), 7.31 (dd, J = 5.6, 3.2 Hz, 2H), 6.95 (t, J =7.8 Hz, 1H), 6.59 – 6.54 (m, 1H), 6.34 (s, 1H), 2.90 (s, 3H).

[0184] 13C NMR (100 MHz, CDCl3): δ 199.9, 196.1, 194.9, 174.4, 143.5 (2C),143.3, 136.2, 136.0, 133.4, 132.5, 130.8, 129.5, 128.8, 128.5, 128.3, 127.3, 126.4, 125.7 (2C), 124.5, 124.3, 123.3, 122.6, 108.5, 74.0, 50.0, 26.8.

[0185] IR: 2959, 2923, 1726, 1706, 1605, 1477, 1386, 1247, 1091, 1055, 989,898, 761, 596, 523 cm -1 .

[0186] High resolution: Calculated value: [M+Na] + : 511.1087, measured value: 511.1081.

[0187] [α] D 25 = -96.72 (C = 0.5, CHCl3).

[0188] Optical purity analysis: The product had an enantiomeric excess of 92% and a diastereomer ratio > 95:5. Chiral AD-H column (isopropanol:n-hexane 30:70, v:v), 1.0 mL / min, 254 nm, 25 o C, the retention time is t1 = 12.43 minutes, t2 = 31.06 minutes.

[0189] Example 24 Figure 26 Preparation of compound I-24 shown At room temperature, magnesium trifluoromethanesulfonate (3.22 mg, 0.01 mmol) and ligand IV (5.22 mg, 0.01 mmol) were dissolved in acetonitrile and stirred under nitrogen protection. After 30 min, 2-aryl-1,3-indanedion III-16 (28.43 mg, 0.10 mmol) was added, and the mixture was stirred for 20 min. Then, 3-isothiocyanate oxyindole II-1 (20.43 mg, 0.10 mmol) was added to the reaction system, and the reaction was continued until the reaction was complete as detected by TLC. 石油醚 / V 乙酸乙酯= 20:1-4:1 column chromatography directly yielded 46.3 mg of the target product of formula I-24, with a yield of 95%.

[0190] 1 H NMR (400 MHz, CDCl3): δ 8.78 – 8.72 (m, 1H), 8.21 (s, 1H), 8.01(dd, J = 5.6, 2.3 Hz, 1H), 7.95 (dd, J = 5.8, 2.7 Hz, 1H), 7.80 – 7.71 (m,2H), 7.55 (dd, J = 6.2, 3.3 Hz, 2H), 7.48 (s, 1H), 7.38 – 7.29 (m, 5H), 7.11(d, J = 1.6 Hz, 1H), 6.69 – 6.63 (m, 1H), 5.29 (s, 1H), 3.11 (s, 3H).

[0191] 13 C NMR (100 MHz, CDCl3): δ 199.2, 195.4, 194.9, 174.6, 143.6, 143.3, 143.2, 136.2, 136.0, 132.7, 132.6, 130.8, 130.5, 128.4, 128.1, 128.0, 127.7, 127.3, 127.1, 126.4, 126.0, 125.6, 124.4, 124.3, 123.3, 108.7, 74.1, 58.0, 27.0.

[0192] IR: 3361, 2928, 1730, 1706, 1601, 1470, 1398, 1274, 1108, 806, 777,603, 528 cm -1 .

[0193] High resolution: Calculated value: [M+Na] + : 511.1087, measured value: 511.1078.

[0194] [α] D 25 = -60.64 (C = 0.5, CHCl3).

[0195] Optical purity analysis: The product had an enantiomeric excess of 84% and a diastereomer ratio > 95:5. Chiral AD-H column (isopropanol:n-hexane 30:70, v:v), 1.0 mL / min, 254 nm, 25 o C, the retention time is t1 = 16.73 minutes, t2 = 25.81 minutes.

[0196] Example 25 Figure 27 Preparation of compound I-25 shown At room temperature, magnesium trifluoromethanesulfonate (3.22 mg, 0.01 mmol) and ligand IV (5.22 mg, 0.01 mmol) were dissolved in acetonitrile and stirred under nitrogen protection. After 30 min, 2-aryl-1,3-indanedion III-17 (26.03 mg, 0.10 mmol) was added, and the mixture was stirred for 20 min. Then, 3-isothiocyanate oxyindole II-1 (20.43 mg, 0.10 mmol) was added to the reaction system, and the reaction was continued until the reaction was complete as detected by TLC. 石油醚 / V 乙酸乙酯 = 20:1-4:1 column chromatography directly yielded 40.6 mg of the target product of formula I-25, with a yield of 87%.

[0197] 1 H NMR (400 MHz, CDCl3): δ 8.46 (d, J = 7.3 Hz, 1H), 8.10 (dd, J =5.9, 2.0 Hz, 1H), 8.08 – 8.01 (m, 2H), 7.90 – 7.81 (m, 2H), 7.40 (t, J = 7.7Hz, 1H), 7.30 (t, J = 7.2 Hz, 1H), 7.14 – 7.07 (m, 3H), 6.92 (dd, J = 6.5, 2.8 Hz, 2H), 6.84 (d, J = 7.7 Hz, 1H), 6.28 (d, J = 15.7 Hz, 1H), 5.83 (dd, J = 15.7, 10.3 Hz, 1H), 4.59 (d, J = 10.3 Hz, 1H), 3.26 (s, 3H).

[0198] 13 C NMR (100 MHz, CDCl3): δ 198.6, 194.7, 194.5, 174.5, 144.1, 143.3, 143.1, 136.3, 136.1, 135.9, 135.4, 130.8, 128.4, 128.2, 127.6, 126.6, 125.0, 124.5, 124.4, 123.6, 119.8, 108.9, 73.0, 53.8, 27.1.

[0199] IR: 1729, 1707, 1608, 1490, 1399, 1271, 1175, 1107, 781, 702, 600 cm -1 .

[0200] High resolution: Calculated value: [M+Na] + : 487.1087, measured value: 487.1083.

[0201] [α] D 25 = -32.88 (C = 1.0, CHCl3).

[0202] Optical purity analysis: The product had an enantiomeric excess of 78% and a diastereomer ratio > 95:5. Chiral AD-H column (isopropanol:n-hexane 30:70, v:v), 1.0 mL / min, 254 nm, 25 o C, the retention time is t1 = 13.50 minutes, t2 = 18.90 minutes.

[0203] Example 26 Figure 28 Preparation of compound I-26 shown At room temperature, magnesium trifluoromethanesulfonate (3.22 mg, 0.01 mmol) and ligand IV (5.22 mg, 0.01 mmol) were dissolved in acetonitrile and stirred under nitrogen protection. After 30 min, 2-aryl-1,3-indanedion III-18 (24.03 mg, 0.10 mmol) was added, and the mixture was stirred for 20 min. Then, 3-isothiocyanate oxyindole II-1 (20.43 mg, 0.10 mmol) was added to the reaction system, and the reaction was continued until the reaction was complete as detected by TLC. 石油醚 / V 乙酸乙酯 = 20:1-4:1 column chromatography directly yielded 31.0 mg of the target product of formula I-26, with a yield of 70%.

[0204] 1 H NMR (400 MHz, CDCl3): δ 8.54 – 8.48 (m, 1H), 8.15 – 8.11 (m, 1H), 8.09 – 8.05 (m, 1H), 7.95 – 7.87 (m, 2H), 7.84 (s, 1H), 7.45 – 7.41 (m, 1H), 7.30 – 7.22 (m, 1H), 6.91 (d, J = 7.7 Hz, 1H), 3.84 (d, J = 11.8 Hz, 1H), 3.29 (s, 3H), 1.74 – 1.65 (m, 1H), 1.42 – 1.27 (m, 3H), 0.94 – 0.74 (m, 4H), 0.71 – 0.63 (m, 3H).

[0205] 13 C NMR (100 MHz, CDCl3): δ 197.4, 194.9, 194.8, 174.2, 143.6, 142.8, 142.7, 136.2, 135.8, 130.7, 127.8, 125.0, 124.7, 124.2, 123.8, 108.6, 75.7, 71.6, 54.6, 35.0, 31.9, 30.0, 27.1, 25.5, 25.4, 25.1.

[0206] IR: 2948, 2866, 1726, 1708, 1612, 1503, 1495, 1358, 1257, 1150, 1041,771, 765, 598, 517 cm -1 .

[0207] High resolution: Calculated value: [M+Na] + : 467.1400, measured value: 467.1395.

[0208] [α] D 25 = -40.48 (C = 0.5, CHCl3).

[0209] Optical purity analysis: The product had an enantiomeric excess of 64% and a diastereomer ratio > 95:5. Chiral AD-H column (isopropanol:n-hexane 10:90, v:v), 1.0 mL / min, 254 nm, 25 o C, the retention time is t1 = 43.16 minutes, t2 = 52.33 minutes.

[0210] Example 27 Figure 29 Preparation of compound I-27 shown At room temperature, magnesium trifluoromethanesulfonate (3.22 mg, 0.01 mmol) and ligand IV (5.22 mg, 0.01 mmol) were dissolved in acetonitrile and stirred under nitrogen protection. After 30 min, 2-aryl-1,3-indanedion III-19 (22.42 mg, 0.10 mmol) was added, and the mixture was stirred for 20 min. Then, 3-isothiocyanate oxyindole II-1 (20.43 mg, 0.10 mmol) was added to the reaction system, and the reaction was continued until the reaction was complete as detected by TLC. 石油醚 / V 乙酸乙酯 = 20:1-4:1 column chromatography directly yielded 41.3 mg of the target product of formula I-27, with a yield of 96%.

[0211] 1 H NMR (400 MHz, CDCl3): δ 8.46 (d, J = 7.6 Hz, 1H), 8.14 (dd, J =6.1, 1.8 Hz, 1H), 8.06 – 8.00 (m, 2H), 7.94 – 7.85 (m, 2H), 7.41 – 7.37 (m,1H), 7.20 (t, J = 7.6 Hz, 1H), 6.89 – 6.83 (m, 2H), 5.88 (dd, J = 3.2, 1.8Hz, 1H), 5.35 (d, J = 3.3 Hz, 1H), 5.30 (s, 1H), 5.25 (s, 1H), 3.29 (s, 3H).

[0212] 13 C NMR (100 MHz, CDCl3): δ198.1, 194.4, 194.1, 174.0, 145.7, 143.5, 143.4, 143.0, 142.0, 136.2, 136.1, 130.9, 128.4, 125.0, 124.6, 124.3, 123.6, 110.1, 108.8, 108.5, 75.3, 71.8, 49.7, 27.2.

[0213] IR: 2974, 1730, 1711, 1613, 1522, 1467, 1381, 1255, 1173, 1092, 1048,953, 801, 760, 599, 559 cm -1 .

[0214] High resolution: Calculated value: [M+Na] + : 451.0723, measured value: 451.0713.

[0215] [α] D 25 = -45.84 (C = 0.5, CHCl3).

[0216] Optical purity analysis: The product had an enantiomeric excess of 64% and a diastereomer ratio > 95:5. Chiral IA column (isopropanol:n-hexane 15:85, v:v), 1.0 mL / min, 254 nm, 25 o C, the retention time is t1 = 28.28 minutes, t2 = 40.88 minutes.

[0217] Example 28 Figure 30 Preparation of compound I-28 shown At room temperature, magnesium trifluoromethanesulfonate (3.22 mg, 0.01 mmol) and ligand IV (5.22 mg, 0.01 mmol) were dissolved in acetonitrile and stirred under nitrogen protection. After 30 min, 2-aryl-1,3-indanedion III-20 (24.03 mg, 0.10 mmol) was added, and the mixture was stirred for 20 min. Then, 3-isothiocyanate oxyindole II-1 (20.43 mg, 0.10 mmol) was added to the reaction system, and the reaction was continued until the reaction was complete as detected by TLC. 石油醚 / V 乙酸乙酯 = 20:1-4:1 column chromatography directly yielded 39.2 mg of the target product of formula I-28, with a yield of 88%.

[0218] 1H NMR (400 MHz, CDCl3): δ 8.61 (d, J = 7.5 Hz, 1H), 8.15 – 8.05 (m,2H), 7.99 (dd, J = 6.0, 1.5 Hz, 1H), 7.89 – 7.80 (m, 2H), 7.39 (t, J = 7.7Hz, 1H), 7.30 – 7.23 (m, 1H), 6.92 – 6.86 (m, 1H), 6.78 (d, J = 7.7 Hz, 1H), 6.56 (d, J = 4.7 Hz, 2H), 5.47 (s, 1H), 3.20 (s, 3H).

[0219] 13 C NMR (100 MHz, CDCl3): δ 198.4, 194.6, 194.5, 174.2, 143.8, 143.7,143.3, 136.3, 136.1, 131.9, 131.1, 129.0, 128.6, 126.6, 126.1, 125.2, 124.4(2C), 123.5, 108.6, 73.5, 52.6, 27.1.

[0220] IR: 3288, 1712, 1610, 1470, 1396, 1262, 1110, 786, 716, 602, 593 cm -1 .

[0221] High resolution: Calculated value: [M+Na] + : 467.0495, measured value: 467.0487.

[0222] [α] D 25 = -65.90 (C = 1.0, CHCl3).

[0223] Optical purity analysis: The product had an enantiomeric excess of 77% and a diastereomer ratio > 95:5. Chiral AD-H column (isopropanol:n-hexane 30:70, v:v), 1.0 mL / min, 254 nm, 25 o C, the retention time is t1 = 14.88 minutes, t2 = 17.78 minutes.

[0224] Example 29: Pharmaceutical performance tests were performed on all optically active [3,2']-pyrrolline-oxidized indolespirinone derivatives from the examples.

[0225] 1. The activity of all compounds in Compound I against MCF-7 breast cancer cells, NCI-460 lung cancer cells, and SW-620 colon cancer cells was detected using the MTT assay. Taking compound I-26 as an example, the specific test method is as follows: 1) 1) Divide the above cells into 5 × 10⁶ cells per well. 3 Cells were seeded at a density of 1,000 cells in 96-well plates, and cultured at 37°C with 5% CO2 in complete culture medium (DMEM + 10% fetal bovine serum) for 24 hours.

[0226] 2) Different concentrations of compound I-26 (0, 0.15625, 0.625, 1.25, 2.5, 10, 40, 100 μM) were added to fresh DMEM medium (100 μL), and blank DMEM was used as a control. The mixture was incubated for 48 hours.

[0227] 3) Add 20 μL of 5 Mm MTT stock solution to each well and incubate for 4 hours.

[0228] 4) Measure the absorbance at 492 nm using a SpectraMax® Plus384 microplate reader (molecular device), calculate the cell viability, and analyze the experimental results.

[0229] The results are as follows Figure 31 As shown, with increasing concentration of the added compound, cell survival gradually decreased, exhibiting a significant effect. The half-maximal inhibitory concentration (WMC) of compound I-26 was [value missing], and [value missing] of NCI-H460 lung cancer cells [value missing] (IC50 [value missing]). 50 = 21.16 μM), SW-620 colon cancer cells (IC50) 50 = 27.66 μM), meaning that after treating NCI-H460 and SW-620 cells at the above compound concentration for 48 hours, cell viability was inhibited by nearly 50%.

[0230] Finally, it should be noted that the terms “comprising,” “including,” or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such process, method, article, or apparatus.

[0231] Although preferred embodiments of the invention have been described, those skilled in the art, upon learning the basic inventive concept, can make other changes and modifications to these embodiments. Therefore, the appended claims are intended to be interpreted as including both the preferred embodiments and all changes and modifications falling within the scope of the invention.

[0232] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. Therefore, if these modifications and variations fall within the scope of the claims of this invention and their equivalents, this invention also intends to include these modifications and variations.

Claims

1. An optically active 3,2'-pyrrolline-oxidized indolespirinone derivative, characterized in that, It has the structural formula represented by general formula I. In Equation I, R 1 With R 2 Its R 1 With R 2 The combination method is as follows: 1) R 1 For hydrogen, R 2 It is methyl; 2) R 1 It is 6-methyl, R 2 It is methyl; 3) R 1 It is 6-methoxy, R 2 It is methyl; 4) R 1 It is 7-methoxy, R 2 It is methyl; 5) R 1 It is 6-fluorine, R 2 It is methyl; 6) R 1 It is 7-fluorine, R 2 It is methyl; 7) R 1 For hydrogen, R 2 It is benzyl; 8) R 1 For hydrogen, R 2 It is n-propyl; The above R 1 With R 2 The combination method with R 3 The corresponding number of compounds are generated from the structural formula of general formula I; R 3 It is phenyl, p-methylphenyl, p-methoxyphenyl, m-methoxyphenyl, o-methoxyphenyl, 3,4-dimethoxyphenyl, p-fluorophenyl, p-chlorophenyl, o-chlorophenyl, 2,4-dichlorophenyl, p-bromophenyl, p-nitrophenyl, p-cyanophenyl, p-trifluoromethylphenyl, 3,5-bis(trifluoromethyl)phenyl, 1-naphthalene, 2-naphthalene, styryl, cyclohexyl, 2-furan, 2-thiophene.

2. A method for preparing an optically active 3,2'-pyrrolidone-oxidized indolespirinone derivative, characterized in that: The steps are as follows: In the presence of a Lewis acid catalyst, magnesium trifluoromethanesulfonate, and chiral ligand IV, the compounds represented by general formula II and general formula III are subjected to a Michael addition / cyclization tandem reaction in acetonitrile solvent to obtain the product. The synthetic route is shown in Figure 2. In formula I, R 1 For example, hydrogen, 6-methyl, 6-methoxy, 7-methoxy, 6-fluoro, 7-fluoro; R 2 For methyl, benzyl, n-propyl; R 3 The compounds are phenyl, p-methylphenyl, p-methoxyphenyl, m-methoxyphenyl, o-methoxyphenyl, 3,4-dimethoxyphenyl, p-fluorophenyl, p-chlorophenyl, o-chlorophenyl, 2,4-dichlorophenyl, p-bromophenyl, p-nitrophenyl, p-cyanophenyl, p-trifluoromethylphenyl, 3,5-bis(trifluoromethyl)phenyl, 1-naphthalene, 2-naphthalene, styryl, cyclohexyl, 2-furan, and 2-thiophene. In formulas II and III, R 1 R 2 R 3 The definition of R in Equation I 1 R 2 R 3 The definitions are the same, where Mg(OTf)2 is magnesium trifluoromethanesulfonate and CH3CN is acetonitrile.

3. The preparation method according to claim 2, characterized in that: The molar ratio of the compound represented by general formula II to the compound represented by general formula III is 1:

1.

4. The preparation method according to claim 2, characterized in that: The amount of the Lewis acid catalyst magnesium trifluoromethanesulfonate is 10 mol of the compound represented by general formula II, expressed as a molar ratio.

5. The preparation method according to claim 2, characterized in that: The molar ratio of ligand IV to the Lewis acid catalyst magnesium trifluoromethanesulfonate is 1:

1.

6. The preparation method according to claim 2, characterized in that: The reaction time for the Michael addition / cyclization tandem reaction is 15-24 h.

7. The preparation method according to claim 2, characterized in that: In the presence of the Lewis acid catalyst magnesium trifluoromethanesulfonate and the chiral ligand IV, in the acetonitrile solvent, the synthesis of compounds represented by general formula II and general formula III via Michael addition / cyclization tandem reaction yielded 70-99%, with a diastereomeric ratio dr 13:1 to 19:1 and an enantiomeric excess ee 52-99%.

8. The preparation method according to claim 2, characterized in that: The specific steps are as follows: at room temperature, magnesium trifluoromethanesulfonate, a Lewis acid catalyst, and ligand IV are dissolved in acetonitrile and stirred under nitrogen protection. After 30 min, the compound represented by general formula III is added, and after stirring for 20 min, the compound represented by general formula II is added to the reaction system. The reaction continues until the reaction is complete as detected by TLC. The target product of formula I is obtained directly by column chromatography with V petroleum ether / V ethyl acetate = 20:1-4:

1.

9. The application of an optically active 3,2'-pyrrolidone-oxidized indolespirinone derivative, characterized in that, Optically active 3,2'-pyrrolidone-oxidized indolespirinone derivatives are used for the prevention or treatment of cancer.

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