Chiral 2-aryl-2'-aminobenzothiophene compounds, preparation methods and applications thereof

Abstract

The present invention discloses a class of chiral 2-aryl-2'-aminobenzothiophene compounds, belonging to the technical field of organic chemical synthesis. The compounds have a structure as shown in formula (I). A preparation method of the compounds is also disclosed, comprising dissolving a benzothiophene ketimine (II) and an arylamine (III) in an organic solvent, adding a chiral catalyst, stirring and reacting at 0°C to 25°C, and separating and purifying after completion of the reaction to obtain product I. The chiral 2-aryl-2'-aminobenzothiophene compounds provided by the present invention have a tetrasubstituted carbon atom center that is simultaneously connected to a nitrogen atom and a sulfur atom, and play a very important role in pharmaceutical chemical synthesis. In addition, the compounds of the present invention can be used to structurally modify clinical drug molecules, thereby further improving biological activity. The preparation method of the present invention has the advantages of being novel, simple, easy to operate, mild reaction conditions, high yield, and high stereoselectivity.

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, in particular to chiral 2-aryl-2'-aminobenzothiophene compounds, preparation methods and applications thereof. Background Art

[0002] Aniline and its derivatives have a wide range of applications in bioactive molecules, pharmaceuticals, and functional materials, and are also valuable synthetic intermediates. Due to their multiple reactive sites (NH, ortho-CH, meta-CH, and para-CH), controlling regioselectivity is a significant challenge. Due to the strong nucleophilic nature of the amino group, NH functionalization of aniline derivatives is the most common reaction mode. Although some progress has been made in the CH functionalization of anilines by introducing directing groups on the nitrogen atom, these methods suffer from poor atom economy, difficulty controlling ortho- / meta- / para-selectivity, and limitations in catalytic asymmetric formats. Furthermore, direct regioselective remote (para-) CH functionalization of anilines, particularly in catalytic asymmetric formats, remains a lagging stage and urgently needs to be addressed.

[0003] The catalytic enantioselective reaction of ketimines with aromatic reagents is an important method for constructing α-chiral arylamines, which are widely present in natural products and pharmaceutical molecules. In this field, the transition metal-catalyzed enantioselective reaction of ketimines with arylboronic acids is the most important method ( Chem. Commun. 2018, 54 , 10394-10404). In addition, some progress has been made in recent years by catalyzing the enantioselective aza-Friedel–Crafts reaction of electron-rich aromatic compounds and imines ( Chem. Commun. 2020, 56 , 10361-10364; Org. Chem. Front. 2022, 9 , 428-435). However, the catalytic asymmetric arylation of anilines and ketimines is rarely studied and faces many challenges, including chemoselectivity, site selectivity, and enantioselectivity. Summary of the Invention

[0004] One of the objectives of the present invention is to provide a new class of chiral 2-aryl-2'-aminobenzothiophene compounds to solve the above problems.

[0005] In order to achieve the above-mentioned object, the technical solution of the present invention is as follows: a new class of chiral 2-aryl-2'-aminobenzothiophene compounds having the structure shown in the following structural formula (I):

[0006]

[0007] In the above structural formula, R1 The group is a single or multiple substituent, and the substituent is selected from hydrogen, alkyl, alkoxy or halogen; R 2 The group is a single substituent or a multi-substituent, and the substituent is selected from hydrogen, alkyl, and alkoxy; Ar is an aryl group.

[0008] The benzothiophene structure is considered a dominant structure and is widely present in many natural products and drug molecules, and is widely used in drug design. Therefore, in the present invention, the inventors have achieved the asymmetric arylation reaction of benzothiophene imine and arylamine for the first time. Using chiral phosphoric acid as a catalyst, the reaction can react in the para position of the arylamine with very high regioselectivity, and a series of chiral 2-aryl-2'-aminobenzothiophene compounds can be obtained in high yield and high stereoselectivity. This class of compounds contains both arylamine and benzothiophene substructures with pharmacological functional groups, which can provide more candidate molecules for new drug development and drug screening.

[0009] The present invention discloses for the first time a new class of chiral 2-aryl-2'-aminobenzothiophene compounds, which simultaneously assemble two pharmacological functional groups: arylamine and benzothiophene substructures, and can provide more candidate molecules for the development of new drugs and drug screening.

[0010] As a preferred technical solution, the compound modified with the biologically active substance structure has the following structure.

[0011] ,

[0012] .

[0013] Vitamin E is a fat-soluble antioxidant that protects cell membranes from reactive oxygen species, and a vitamin E deficiency can lead to neurological diseases. Therefore, the inventors also structurally modified tocopherol (δ-tocopherol), the main component of vitamin E, and were able to obtain structurally modified product A with a yield of 76%. Antioxidant capacity tests also showed that the modified vitamin E had stronger antioxidant capacity. Furthermore, estrone is a weaker female steroidal sex hormone and one of the three main endogenous estrogens. It can be used to treat uterine hypoplasia, menstrual disorders, and menopausal disorders. Through this method, the inventors successfully performed late-stage structural modification on estrone, and were able to obtain estrone-modified product B with a high yield.

[0014] .

[0015] The second object of the present invention is to provide a method for preparing the above-mentioned chiral 2-aryl-2'-aminobenzothiophene compound, which adopts the following technical scheme: dissolving benzothiophenone imine (II) and arylamine (III) in an organic solvent, then adding a chiral catalyst, stirring and reacting at 0°C-25°C, and after the reaction is completed, separating and purifying to obtain product I; wherein,

[0016] The benzothiophenone imine (II) has the following structure:

[0017] ;

[0018] The arylamine (III) has the following structure:

[0019] ;

[0020] The synthetic route is:

[0021] .

[0022] The present invention adopts the above-mentioned synthesis method to synthesize a series of chiral 2-aryl-2'-aminobenzothiophene compounds with novel structures.

[0023] As a preferred technical solution: the reaction solvent is selected from one or a mixture of toluene, mesitylene, dichloromethane, chloroform, tetrahydrofuran, ether, acetonitrile, ethanol, methanol, 1,4-dioxane, and chlorobenzene.

[0024] As a further preferred technical solution: the reaction solvent is toluene, which has a higher yield and higher stereoselectivity.

[0025] As a preferred technical solution: the chiral phosphoric acid has the following structure:

[0026] .

[0027] As a further preferred technical solution: the catalyst is CPA-5, and the reaction yield and enantioselectivity are higher.

[0028] As a preferred technical solution: the reaction temperature is 0 ℃-25 ℃.

[0029] As a further preferred technical solution: the reaction temperature is 0°C, and the reaction yield and enantioselectivity are higher.

[0030] This invention uses benzothiophenone imine and arylamine as raw materials, using chiral phosphoric acid as a catalyst. The reaction is performed at the para position of the arylamine with very high regioselectivity, resulting in high yields and high stereoselectivity for a series of chiral 2-aryl-2'-aminobenzothiophene compounds. Notably, these compounds simultaneously incorporate two pharmacological functional groups: the benzothiophene and arylamine substructures. This technology not only provides new ideas and methods for the synthesis of these compounds, but also significantly enriches the variety of such compounds, providing more candidate molecules for new drug screening.

[0031] The third purpose of the present invention is to use the new compounds prepared by this method to modify the structures of biologically active molecules and drug molecules to improve their pharmacological properties.

[0032] Furthermore, the application value of the compounds of the present invention lies in the fact that many existing arylamine compounds and benzothiophene compounds have excellent biological activity, which makes it reasonable to predict that the new large class of compounds provided by the present invention will also have certain biological activity, thereby providing a sufficient source of compounds for screening drug activity. Furthermore, it can provide more candidate molecules for new drug development and drug screening, especially high-throughput screening, enriching the library of such compounds. Furthermore, the present invention provides a synthetic method that uses mild conditions, simple operation, and low catalyst usage to obtain a series of chiral 2-aryl-2'-aminobenzothiophene compounds.

[0033] Compared with the prior art, the advantages of the present invention are: using benzothiophenone imine and arylamine as raw materials, using chiral phosphoric acid as a catalyst, the present invention reacts in the para position of the arylamine with very high regioselectivity, and obtains a series of chiral 2-aryl-2'-aminobenzothiophene compounds in high yield and high stereoselectivity. These compounds are easy to functionalize, making it convenient to derive and synthesize other chiral compounds; and these compounds contain benzothiophene and arylamine substructures, which can provide more candidate molecules for new drug development and drug screening, especially high-throughput screening, enriching the library of such compounds; at the same time, this method can be used to structurally modify bioactive molecules and drug molecules to improve pharmacological properties. The method of the present invention has the advantages of mild reaction conditions, simple operation, high yield, and very good enantioselectivity. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 This is the hydrogen spectrum of In obtained in Example 1;

[0035] Figure 2 This is the carbon spectrum of In obtained in Example 1;

[0036] Figure 3 This is the single crystal structure of In prepared in Example 1. DETAILED DESCRIPTION

[0037] The present invention will be further described below with reference to the embodiments.

[0038] Example 1: Synthesis of Compound (I-a)

[0039]

[0040] A catalytic amount of chiral phosphoric acid CPA (0.01 mmol), benzothiophene imine (II-a) (0.12 mmol), arylamine (III-a) (0.1 mmol), and solvent (1 mL) were added sequentially to a dry reaction tube. The reaction mixture was then stirred at a specific temperature. After the reaction was complete, the crude product was separated and purified by column chromatography to obtain compound Ia, as follows:

[0041] ;

[0042] Table 1 Different reaction conditions

[0043]

[0044] As can be seen in Table 1, after examining various chiral phosphoric acids (CPAs), solvents, and temperatures, the preferred solution was 10 mol% CPA-5 as the catalyst, toluene as the solvent, and a reaction temperature of 0°C. Under the optimal solution, the yield, melting point, enantioselectivity, optical rotation, H-spectroscopy, C-spectroscopy, and mass spectrometry data for Ia are as follows: 78% yield, mp 139.4-140.1°C; 97% ee; [α] D 20 = -108.0 ( c 1.16, CH2Cl2). 1 H NMR (400 MHz, CDCl3) δ 7.64 – 7.48 (m, 3H), 7.37 (dd, J = 8.1, 1.9 Hz, 1H), 7.30 – 7.21 (m,3H), 7.08 – 7.00 (m, 2H), 6.99 – 6.89 (m, 3H), 5.80 (s, 1H), 5.70 (s, 1H),2.31 (s, 3H), 1.50 – 1.21 (m, 9H). 13C NMR (101 MHz, CDCl3) δ 197.5, 153.8,147.7, 144.2, 142.2, 137.5, 135.1, 129.4, 128.2, 128.0, 127.9, 127.8, 123.5,121.7, 118.7, 117.0, 81.1, 77.9, 28.2, 20.8. HRMS (ESI) m / z : Calcd. for [M+Na] + C 26 H 26 N2O3SNa 469.1556, found 469.1559. The ee was determined by HPLC:Chiralpak IA, EtOH / hexane = 30 / 70, flow rate = 1.0 mL / min, l = 254 nm, t R =20.9 min (minor), t R = 12.6 min (major).

[0045] Scale-up experiment: A catalytic amount of chiral phosphoric acid CPA-5 (0.125 mmol), benzothiophene imine (II-a) (3.0 mmol), arylamine (III-a) (2.5 mmol) and toluene (1 mL) were added to a dry reaction tube in sequence; the reaction mixture was then placed at 0 o The reaction was stirred at 400 °C. After the reaction was complete, the crude product was separated and purified by column chromatography to obtain compound Ia, 0.83 g, 74% yield, 96% ee.

[0046] Example 2: Synthesis of Compound (I-b)

[0047]

[0048] A catalytic amount of chiral phosphoric acid CPA-5 (0.01 mmol), benzothiophene imine (II-b) (0.12 mmol), arylamine (III-a) (0.1 mmol), and toluene (1 mL) were added sequentially to a dry reaction tube. The reaction mixture was then stirred at 0°C. After the reaction was complete, the crude product was separated and purified by column chromatography to obtain compound Ib.

[0049] The yield, melting point, enantioselectivity, optical rotation, hydrogen spectrum, carbon spectrum and mass spectrum data of the obtained Ib are as follows: 70% yield, mp 135.1-136.1 o C; 95% ee; [α] D 20 = -54.6 ( c 1.88, CH2Cl2). 1 H NMR (400MHz, CDCl3) δ 7.67 – 7.51 (m, 3H), 7.39 (dd, J = 8.1, 1.9 Hz, 1H), 7.31 –7.21 (m, 3H), 7.08 – 7.01 (m, 2H), 7.00 – 6.91 (m, 3H), 5.81 (s, 1H), 5.69(s, 1H), 2.61 (q, J = 7.6 Hz, 2H), 1.59 – 1.23 (m, 9H), 1.20 (t, J = 7.6 Hz,3H). 13 C NMR (101 MHz, CDCl3) δ 197.6, 153.8, 148.0, 144.2, 142.1, 141.5,136.6, 129.4, 128.2, 127.9, 127.8, 126.8, 123.6, 121.7, 118.7, 117.0, 81.2,77.9, 28.3, 28.2, 15.3. HRMS (ESI) m / z : Calcd. for [M+Na] + C 27 H 28 N2O3SNa483.1713, found 483.1709. The ee was determined by HPLC: Chiralpak IA, EtOH / hexane = 30 / 70, flow rate = 1.0 mL / min, l = 254 nm, t R = 13.1 min (minor), t R =10.4 min (major).

[0050] Example 3: Synthesis of Compound (I-c)

[0051]

[0052] A catalytic amount of chiral phosphoric acid CPA-5 (0.01 mmol), benzothiophene imine (II-c) (0.12 mmol), arylamine (III-a) (0.1 mmol), and toluene (1 mL) were added sequentially to a dry reaction tube. The reaction mixture was then stirred at 0°C. After the reaction was complete, the crude product was separated and purified by column chromatography to obtain compound Ic.

[0053] The yield, melting point, enantioselectivity, optical rotation, H-spectrum, C-spectrum and mass spectrometry data of compound Ic are as follows: 77% yield, mp 66.3-67.2 o C; 95% ee; [α] D 20 = -59.0 ( c 1.29, CH2Cl2). 1 H NMR (400MHz, CDCl3) δ 7.67 – 7.52 (m, 3H), 7.42 (dd, J = 8.3, 2.0 Hz, 1H), 7.33 –7.19 (m, 3H), 7.08 – 7.00 (m, 2H), 6.99 – 6.90 (m, 3H), 5.98 – 5.78 (m, 1H),5.69 (s, 1H), 3.03 – 2.77 (m, 1H), 1.48 – 1.29 (m, 9H), 1.22 (d, J = 2.5 Hz,3H), 1.20 (d, J = 2.5 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 197.7, 153.8, 148.1,146.2, 144.2, 142.1, 135.4, 129.4, 128.2, 127.9, 125.4, 123.6, 123.5, 121.8,118.7, 116.9, 81.1, 77.9, 33.6, 31.7, 29.7, 23.8. HRMS (ESI) m / z : Calcd. for[M+Na] + C 28 H 30N2O3SNa 497.1869, found 497.1868. The ee was determined by HPLC:Chiralpak IA, EtOH / hexane = 30 / 70, flow rate = 1.0 mL / min, l = 254 nm, t R =10.1 min (minor), t R = 8.6 min (major).

[0054] Example 4: Synthesis of Compound (I-d)

[0055]

[0056] A catalytic amount of chiral phosphoric acid CPA-5 (0.01 mmol), benzothiophene imine (II-d) (0.12 mmol), arylamine (III-a) (0.1 mmol), and toluene (1 mL) were added sequentially to a dry reaction tube. The reaction mixture was then stirred at 0°C. After the reaction was complete, the crude product was separated and purified by column chromatography to obtain compound Id.

[0057] The yield, melting point, enantioselectivity, optical rotation, hydrogen spectrum, carbon spectrum and mass spectrum data of the obtained compound Id are as follows: 74% yield, mp 139.4-140.1 o C; 95% ee; [α] D 20 = -49.9 ( c 1.64, CH2Cl2). 1 H NMR (400MHz, CDCl3) δ 7.73 (d, J = 2.1 Hz, 1H), 7.65 – 7.54 (m, 3H), 7.30 (d, J = 8.3Hz, 1H), 7.28 – 7.22 (m, 2H), 7.10 – 7.00 (m, 2H), 7.00 – 6.88 (m, 3H), 5.82(s, 1H), 5.68 (s, 1H), 1.53 – 1.30 (m, 9H), 1.28 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 197.7, 153.7, 148.6, 147.8, 144.2, 142.1, 134.2, 129.4, 128.2,127.9, 127.6, 124.5, 123.5, 123.4, 121.8, 118.7, 116.9, 81.2, 78.0, 34.6,31.2, 28.3. HRMS (ESI) m / z : Calcd. for [M+Na] + C 29 H 32 N2O3SNa 511.2026, found511.2027. The ee was determined by HPLC: Chiralpak IA, i PrOH / hexane = 30 / 70, flow rate = 1.0 mL / min, l = 254 nm, t R = 11.4 min (minor), t R = 8.9 min(major).

[0058] Example 5: Synthesis of Compound (I-e)

[0059]

[0060] A catalytic amount of chiral phosphoric acid CPA-5 (0.01 mmol), benzothiophene imine (II-e) (0.12 mmol), arylamine (III-a) (0.1 mmol), and toluene (1 mL) were added sequentially to a dry reaction tube. The reaction mixture was then stirred at 0°C. After the reaction was complete, the crude product was separated and purified by column chromatography to obtain compound Ie.

[0061] The yield, melting point, enantioselectivity, optical rotation, hydrogen spectrum, carbon spectrum and mass spectrum data of Ie obtained are as follows: 79% yield, mp 183.5-183.9 o C; 88% ee; [α] D 20 = -123.6 ( c 1.51, CH2Cl2). 1 H NMR (400MHz, CDCl3) δ 7.73 (dd, J= 8.6, 5.4 Hz, 1H), 7.56 (d, J = 8.6 Hz, 2H), 7.30– 7.22 (m, 2H), 7.05 (dd, J = 7.2, 1.8 Hz, 3H), 6.96 (dd, J = 8.3, 6.4 Hz,3H), 6.87 (td, J = 8.6, 2.3 Hz, 1H), 5.83 (s, 1H), 5.69 (s, 1H), 1.55 – 1.30 (m, 9H). 13 C NMR (101 MHz, CDCl3) δ 195.6, 167.8 (d, J = 260.3 Hz), 153.6 (d, J = 4.2 Hz), 153.5, 144.5, 142.0, 130.2 (d, J = 10.9 Hz), 129.4, 127.8,127.5, 124.4, 124.0, 121.9, 118.9, 116.8, 113.4 (d, J = 23.9 Hz), 81.4, 78.4,28.2. HRMS (ESI) m / z : Calcd. for [M+Na] + C 25 H 23 FN2O3SNa 473.1306, found473.1302. The ee was determined by HPLC: Chiralpak AD-H, EtOH / hexane = 30 / 70, flow rate = 1.0 mL / min, l = 220 nm, t R = 32.3 min (minor), t R = 20.7 min(major).

[0062] Example 6: Synthesis of Compound (I-f)

[0063]

[0064] A catalytic amount of chiral phosphoric acid CPA-5 (0.01 mmol), benzothiophene imine (II-f) (0.12 mmol), arylamine (III-a) (0.1 mmol), and toluene (1 mL) were added sequentially to a dry reaction tube. The reaction mixture was then stirred at 0°C. After the reaction was complete, the crude product was separated and purified by column chromatography to obtain compound If.

[0065] The yield, melting point, enantioselectivity, optical rotation, hydrogen spectrum, carbon spectrum and mass spectrum data of If obtained are as follows: 78% yield, mp 107.7-108.6 o C; 86% ee; [α] D 20 = -30.1 ( c 1.44, CH2Cl2). 1 H NMR (400MHz, CDCl3) δ 7.63 – 7.47 (m, 2H), 7.42 – 7.29 (m, 3H), 7.29 – 7.20 (m, 2H), 7.06 (d, J = 7.9 Hz, 2H), 6.95 (dd, J = 8.1, 5.9 Hz, 3H), 5.85 (s, 1H), 5.77(s, 1H), 1.52 – 1.22 (m, 9H). 13 C NMR (101 MHz, CDCl3) δ 194.9, 153.8, 153.7,144.4, 142.0, 135.9, 130.5, 129.4, 127.9, 127.5, 124.9, 123.8, 122.9, 121.9,118.9, 116.9, 81.2, 77.7, 28.2. HRMS (ESI) m / z : Calcd. for [M+Na] + C 25 H 23 BrN2O3SNa 533.0505, found 533.0504. The ee was determined by HPLC:Chiralpak IA, i PrOH / hexane = 30 / 70, flow rate = 1.0 mL / min, l = 254 nm, t R =29.5 min (minor),t R = 19.3 min (major).

[0066] Example 7: Synthesis of Compound (I-g)

[0067]

[0068] A catalytic amount of chiral phosphoric acid CPA-5 (0.01 mmol), benzothiophene imine (II-g) (0.12 mmol), arylamine (III-a) (0.1 mmol) and toluene (1 mL) were added sequentially to a dry reaction tube; the reaction mixture was then stirred at 0°C for reaction; after the reaction was complete, the crude product was separated and purified by column chromatography to obtain compound Ig.

[0069] The yield, melting point, enantioselectivity, optical rotation, hydrogen spectrum, carbon spectrum and mass spectrum data of the obtained Ig are as follows: 73% yield, mp 196.0-196.5 o C; 95% ee; [α] D 20 = -182.0 ( c 0.92, CH2Cl2). 1 H NMR (400MHz, CDCl3) δ 7.57 (dd, J = 12.4, 8.0 Hz, 3H), 7.37 (d, J = 7.3 Hz, 1H), 7.31– 7.19 (m, 2H), 7.11 (t, J = 7.5 Hz, 1H), 7.08 – 7.00 (m, 2H), 7.00 – 6.89 (m, 3H), 5.80 (s, 1H), 5.73 (s, 1H), 2.34 (s, 3H), 1.55 – 1.20 (m, 9H). 13 CNMR (101 MHz, CDCl3) δ 198.0, 153.8, 150.5, 144.2, 142.1, 136.4, 132.8,129.4, 128.2, 127.8, 127.7, 125.4, 125.3, 121.8, 118.7, 116.9, 81.1, 77.6,28.3, 18.9. HRMS (ESI) m / z : Calcd. for [M+Na] + C 26 H 26N2O3SNa 469.1556, found469.1550. The ee was determined by HPLC: Chiralpak IA, i PrOH / hexane = 30 / 70, flow rate = 1.0 mL / min, l = 254 nm, t R = 14.5 min (minor), t R = 20.9 min(major).

[0070] Example 8: Synthesis of Compound (I-h)

[0071]

[0072] A catalytic amount of chiral phosphoric acid CPA-5 (0.01 mmol), benzothiophene imine (II-h) (0.12 mmol), arylamine (III-a) (0.1 mmol), and toluene (1 mL) were added sequentially to a dry reaction tube. The reaction mixture was then stirred at 0°C. After the reaction was complete, the crude product was separated and purified by column chromatography to obtain compound Ih.

[0073] The yield, melting point, enantioselectivity, optical rotation, hydrogen spectrum, carbon spectrum and mass spectrum data of the obtained Ih are as follows: 79% yield, mp 92.1-92.8 o C; 96% ee; [α] D 20 = -154.7 ( c 1.25, CH2Cl2). 1 H NMR (400MHz, CDCl3) δ 7.46 (d, J = 8.2 Hz, 2H), 7.23 – 7.13 (m, 3H), 7.01 – 6.93 (m,2H), 6.93 – 6.82 (m, 3H), 6.79 (d, J = 7.5 Hz, 1H), 5.72 (s, 2H), 2.43 (s, 3H), 2.23 (s, 3H), 1.36 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 198.7, 154.0,151.3, 143.9, 142.2, 140.0, 135.5, 130.0, 129.4, 129.0, 127.7, 127.6, 124.8,121.6, 118.6, 117.0, 81.0, 77.5, 28.3, 18.7, 18.5. HRMS (ESI) m / z : Calcd. for[M+Na] + C 27 H 28 N2O3SNa 483.1713, found 483.1713. The ee was determined by HPLC:Chiralpak IA, EtOH / hexane = 30 / 70, flow rate = 1.0 mL / min, l = 254 nm, t R =19.0 min (minor), t R = 11.2 min (major).

[0074] Example 9: Synthesis of Compound (I-i)

[0075]

[0076] A catalytic amount of chiral phosphoric acid CPA-5 (0.01 mmol), benzothiophene imine (II-i) (0.12 mmol), arylamine (III-a) (0.1 mmol) and toluene (1 mL) were added sequentially to a dry reaction tube; the reaction mixture was then stirred at 0°C for reaction; after the reaction was complete, the crude product was separated and purified by column chromatography to obtain compound Ii.

[0077] The yield, melting point, enantioselectivity, optical rotation, hydrogen spectrum, carbon spectrum and mass spectrum data of the obtained Ii are as follows: 84% yield, mp 152.8-153.6 o C; 98% ee; [α] D 20 = -77.2 ( c 1.94, CH2Cl2). 1 H NMR (400MHz, CDCl3) δ 7.54 (d, J = 8.6 Hz, 2H), 7.39 (d,J = 1.8 Hz, 1H), 7.28 – 7.18(m, 3H), 7.07 – 7.01 (m, 2H), 6.98 – 6.89 (m, 3H), 5.81 (s, 1H), 5.74 (s,1H), 2.30 (s, 3H), 2.28 (s, 3H), 1.55 – 1.22 (m, 9H). 13 C NMR (101 MHz, CDCl3)δ 198.0, 153.8, 147.5, 144.1, 142.2, 137.8, 135.3, 132.5, 129.4, 128.5,127.7, 125.4, 121.7, 118.6, 117.0, 81.1, 77.8, 18.8. HRMS (ESI) m / z : Calcd.for [M+Na] + C 27 H 28 N2O3SNa 483.1713, found 483.1714. The ee was determined byHPLC: Chiralpak IA, EtOH / hexane = 30 / 70, flow rate = 1.0 mL / min, l = 254 nm, t R = 10.5 min (minor), t R = 12.3 min (major).

[0078] Example 10: Synthesis of Compound (I-j)

[0079]

[0080] A catalytic amount of chiral phosphoric acid CPA-5 (0.01 mmol), benzothiophene imine (II-j) (0.12 mmol), arylamine (III-a) (0.1 mmol) and toluene (1 mL) were added sequentially to a dry reaction tube; the reaction mixture was then stirred at 0°C for reaction; after the reaction was complete, the crude product was separated and purified by column chromatography to obtain compound Ij.

[0081] The yield, melting point, enantioselectivity, optical rotation, hydrogen spectrum, carbon spectrum and mass spectrum data of the obtained Ij are as follows: 89% yield, mp 160.3-160.9 oC; 95% ee; [α] D 20 = -74.7 ( c 1.56, CH2Cl2). 1 H NMR (400MHz, CDCl3) δ 7.72 (dd, J = 7.7, 1.3 Hz, 1H), 7.63 – 7.45 (m, 3H), 7.36 (d, J = 7.9 Hz, 1H), 7.30 – 7.20 (m, 2H), 7.20 – 7.11 (m, 1H), 7.08 – 7.00 (m, 2H),7.00 – 6.85 (m, 3H), 5.71 (s, 2H), 1.51 – 1.21 (m, 9H). 13 C NMR (101 MHz, CDCl3) δ 197.4, 153.7, 150.8, 144.3, 142.1, 136.2, 129.4, 128.0, 127.95,127.91, 127.8, 125.1, 123.8, 121.8, 118.7, 116.9, 81.2, 77.7, 28.1. HRMS(ESI) m / z : Calcd. for [M+Na] + C 25 H 24 N2O3SNa 455.1400, found 455.1399. The ee was determined by HPLC: Chiralpak IA, i PrOH / hexane = 30 / 70, flow rate = 1.0 mL / min, l = 254 nm, t R = 20.2 min (minor), t R = 24.2 min (major).

[0082] Example 11: Synthesis of Compound (I-k)

[0083]

[0084] A catalytic amount of chiral phosphoric acid CPA-5 (0.01 mmol), benzothiophene imine (II-a) (0.12 mmol), arylamine (III-b) (0.1 mmol), and toluene (1 mL) were added sequentially to a dry reaction tube. The reaction mixture was then stirred at 0°C. After the reaction was complete, the crude product was separated and purified by column chromatography to obtain compound Ik.

[0085] The yield, melting point, enantioselectivity, optical rotation, hydrogen spectrum, carbon spectrum and mass spectrum data of the obtained Ik are as follows: 83% yield, mp 93.4-93.8 o C; 98% ee; [α] D 20 = -93.7 ( c 1.82, CH2Cl2). 1 H NMR (400MHz, CDCl3) δ 7.66 – 7.43 (m, 3H), 7.35 (dd, J = 8.0, 1.9 Hz, 1H), 7.28 –7.21 (m, 1H), 7.10 – 7.02 (m, 2H), 7.00 – 6.92 (m, 2H), 6.92 – 6.83 (m, 2H),5.72 (s, 2H), 2.29 (d, J = 6.4 Hz, 6H), 1.53 – 1.16 (m, 9H). 13 C NMR (101 MHz, CDCl3) δ 197.6, 153.8, 147.7, 144.9, 139.3, 137.4, 135.1, 131.7, 129.9, 128.0, 128.0, 127.8, 127.5, 123.5, 119.7, 116.2, 81.1, 77.9, 28.2, 20.8,20.7. HRMS (ESI) m / z : Calcd. for [M+Na] + C 27 H 28 N2O3SNa 483.1713, found 483.1712.The ee was determined by HPLC: Chiralpak IA, i PrOH / hexane = 30 / 70, flow rate =1.0 mL / min, l = 254 nm, tR = 24.2 min (minor), t R = 21.1 min (major).

[0086] Example 12: Synthesis of Compound (I-1)

[0087]

[0088] A catalytic amount of chiral phosphoric acid CPA-5 (0.01 mmol), benzothiophene imine (II-a) (0.12 mmol), arylamine (III-c) (0.1 mmol) and toluene (1 mL) were added sequentially to a dry reaction tube; the reaction mixture was then stirred at 0°C for reaction; after the reaction was complete, the crude product was separated and purified by column chromatography to obtain compound Il.

[0089] The yield, melting point, enantioselectivity, optical rotation, hydrogen spectrum, carbon spectrum and mass spectrum data of the obtained I1 are as follows: 90% yield, mp 79.9-80.5 o C; 94% ee; [α] D 20 = -83.6 ( c 1.83, CH2Cl2). 1 H NMR (400MHz, CDCl3) δ 7.52 – 7.38 (m, 3H), 7.32 – 7.24 (m, 1H), 7.17 (d, J = 8.2 Hz,1H), 6.99 – 6.89 (m, 2H), 6.80 – 6.72 (m, 2H), 6.72 – 6.63 (m, 2H), 5.61 (s,1H), 5.54 (s, 1H), 3.70 (s, 3H), 2.23 (s, 3H), 1.53 – 1.13 (m, 9H). 13 C NMR(101 MHz, CDCl3) δ 197.6, 155.7, 153.7, 147.7, 146.1, 137.4, 135.0, 134.8,128.0, 127.8, 126.7, 123.5, 122.9, 115.1, 114.7, 81.0, 77.9, 55.6, 28.3,20.8. HRMS (ESI) m / z : Calcd. for [M+Na] + C 27 H 28N2O4SNa 499.1662, found 499.1665.The ee was determined by HPLC: Chiralpak IC, EtOH / hexane = 10 / 90, flow rate =1.0 mL / min, l = 254 nm, t R = 32.1 min (minor), t R = 23.1 min (major).

[0090] Example 13: Synthesis of Compound (I-m)

[0091]

[0092] A catalytic amount of chiral phosphoric acid CPA-5 (0.01 mmol), benzothiophene imine (II-a) (0.12 mmol), arylamine (III-d) (0.1 mmol) and toluene (1 mL) were added sequentially to a dry reaction tube; the reaction mixture was then stirred at 0°C for reaction; after the reaction was complete, the crude product was separated and purified by column chromatography to obtain compound Im.

[0093] The yield, melting point, enantioselectivity, optical rotation, hydrogen spectrum, carbon spectrum and mass spectrum data of the obtained Im are as follows: 92% yield, mp 67.3-68.2 o C; 94% ee; [α] D 20 = -69.4 ( c 2.00, CH2Cl2). 1 H NMR (400MHz, CDCl3) δ 7.72 – 7.52 (m, 5H), 7.52 – 7.45 (m, 2H), 7.45 – 7.34 (m, 3H), 7.34 – 7.23 (m, 2H), 7.15 – 7.06 (m, 2H), 7.04 – 6.91 (m, 2H), 5.89 (s, 1H), 5.72 (s, 1H), 2.31 (s, 3H), 1.55 – 1.16 (m, 9H). 13C NMR (101 MHz, CDCl3) δ197.5, 153.8, 147.8, 143.9, 141.6, 140.7, 137.5, 135.2, 134.4, 128.8, 128.5,128.04, 128.00, 127.9, 127.8, 126.7, 126.6, 123.5, 118.6, 117.3, 81.1, 77.8,28.3, 20.8. HRMS (ESI) m / z : Calcd. for [M+Na] + C 32 H 30 N2O3SNa 545.1869, found545.1868. The ee was determined by HPLC: Chiralpak IC, EtOH / hexane = 20 / 80, flow rate = 1.0 mL / min, l = 254 nm, t R = 7.5 min (minor), t R = 10.9 min(major).

[0094] Example 14: Synthesis of Compound (I-n)

[0095]

[0096] A catalytic amount of chiral phosphoric acid CPA-5 (0.01 mmol), benzothiophene imine (II-a) (0.12 mmol), arylamine (III-e) (0.1 mmol), and toluene (1 mL) were added sequentially to a dry reaction tube. The reaction mixture was then stirred at 0°C. After the reaction was complete, the crude product was separated and purified by column chromatography to obtain compound In.

[0097] The yield, melting point, enantioselectivity, optical rotation, hydrogen spectrum, carbon spectrum and mass spectrum data of the obtained In are as follows: 83% yield, mp 147.1-147.9 o C; 94% ee; [α] D 20 = -98.7 ( c 1.87, CH2Cl2). 1H NMR (400MHz, CDCl3) δ 7.63 – 7.43 (m, 3H), 7.41 – 7.30 (m, 1H), 7.24 (d, J = 8.1 Hz,1H), 7.09 – 6.88 (m, 4H), 6.88 – 6.74 (m, 2H), 5.76 (s, 1H), 5.72 (s, 1H), 2.29 (s, 3H), 1.59 – 1.20 (m, 9H). 13 C NMR (101 MHz, CDCl3) δ 197.6, 158.4 (d, J = 242.0 Hz), 153.8, 147.7, 145.0, 138.0 (d, J = 2.8 Hz), 137.5, 135.1,128.0, 127.9, 127.8, 123.5, 121.5 (d, J = 8.0 Hz), 116.1 115.9 (d, J = 18.2Hz), 81.1, 77.8, 28.2, 20.7. HRMS (ESI) m / z : Calcd. for [M+Na] + C 26 H 25 FN2O3SNa487.1462, found 487.1464. The ee was determined by HPLC: Chiralpak IA, i PrOH / hexane = 30 / 70, flow rate = 1.0 mL / min, l = 254 nm, t R = 17.8 min (minor), t R =15.2 min (major). See the hydrogen and carbon spectra for details. Figure 1 and Figure 2 .

[0098] Single crystal diffraction experiment:

[0099] Single crystal growth: The main component compound In (30 mg) obtained in Example 14 was dissolved in a mixture of 20 mL of dichloromethane and ethanol and allowed to stand at room temperature for 7 days. Single crystals precipitated and were collected for single crystal diffraction analysis.

[0100] The test parameters are shown in Table 2:

[0101]

[0102] The results of the test are as follows Figure 3 As shown, the structure of compound In was determined based on the above spectrum and data.

[0103] Example 15: Synthesis of Compound (I-o)

[0104]

[0105] A catalytic amount of chiral phosphoric acid CPA-5 (0.01 mmol), benzothiophene imine (II-a) (0.12 mmol), arylamine (III-f) (0.1 mmol), and toluene (1 mL) were added sequentially to a dry reaction tube. The reaction mixture was then stirred at 0°C. After the reaction was complete, the crude product was separated and purified by column chromatography to obtain compound Io.

[0106] The yield, melting point, enantioselectivity, optical rotation, hydrogen spectrum, carbon spectrum and mass spectrum data of the obtained Io are as follows: 70% yield, mp 77.6-78.1 o C; 69% ee; [α] D 20 = -72.1 ( c 1.45, CH2Cl2). 1 H NMR (400MHz, CDCl3) δ 7.68 – 7.55 (m, 2H), 7.53 (d, J = 1.9 Hz, 1H), 7.38 (dd, J =8.2, 1.9 Hz, 1H), 7.35 – 7.30 (m, 2H), 7.27 (d, J = 7.5 Hz, 1H), 6.98 – 6.86 (m, 4H), 5.79 (s, 1H), 5.71 (s, 1H), 2.32 (s, 3H), 1.55 – 1.29 (m, 9H). 13CNMR (101 MHz, CDCl3) δ 197.5, 153.8, 147.8, 143.5, 141.4, 137.6, 135.2,132.2, 129.0, 128.0, 127.9, 127.8, 123.5, 119.9, 117.4, 113.5, 81.3, 77.7,28.3, 20.8. HRMS (ESI) m / z : Calcd. for [M+Na] + C 26 H 25 BrN2O3SNa 547.0661, found547.0662. The ee was determined by HPLC: Chiralpak IC, EtOH / hexane = 20 / 80, flow rate = 1.0 mL / min, l = 254 nm, t R = 5.7 min (minor), t R = 6.6 min (major).

[0107] Example 16: Synthesis of Compound (I-p)

[0108]

[0109] A catalytic amount of chiral phosphoric acid CPA (0.01 mmol), benzothiophene imine (II-a) (0.12 mmol), arylamine (III-g) (0.1 mmol) and toluene (1 mL) were added sequentially to a dry reaction tube; the reaction mixture was then stirred at 0°C for reaction; after the reaction was complete, the crude product was separated and purified by column chromatography to obtain compound Ip.

[0110] The yield, melting point, enantioselectivity, optical rotation, hydrogen spectrum, carbon spectrum and mass spectrum data of the obtained Ip are as follows: 95% yield, mp 70.9-71.3 o C; 99% ee; [α] D 20 = -86.4 ( c 1.64, CH2Cl2). 1 H NMR (400MHz, CDCl3) δ 7.51 (d, J = 8.7 Hz, 3H), 7.35 (dd, J= 8.1, 1.9 Hz, 1H), 7.29– 7.23 (m, 1H), 7.06 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 2.1 Hz, 1H), 6.93 (dd, J = 8.1, 2.1 Hz, 1H), 6.77 – 6.66 (m, 2H), 5.67 (s, 1H), 5.37 (s, 1H), 2.30 (s, 3H), 2.28 (s, 3H), 2.15 (s, 3H), 1.53 – 1.21 (m, 9H). 13 C NMR (101 MHz, CDCl3) δ 197.6, 153.7, 147.7, 146.0, 137.4, 137.3, 135.0, 133.2, 131.7,130.8, 128.0, 127.9, 127.8, 127.3, 126.7, 123.5, 122.0, 115.5, 81.0, 77.9,28.3, 26.9, 20.8, 17.9. HRMS (ESI) m / z : Calcd. for [M+Na] + C 28 H 30 N2O3SNa497.1869, found 497.1868. The ee was determined by HPLC: Chiralpak IC, EtOH / hexane = 20 / 80, flow rate = 1.0 mL / min, l = 254 nm, t R = 6.3 min (minor), t R =8.0 min (major).

[0111] Example 17: Synthesis of Compound (I-q)

[0112]

[0113] A catalytic amount of chiral phosphoric acid CPA-5 (0.01 mmol), benzothiophene imine (II-a) (0.12 mmol), arylamine (III-h) (0.1 mmol), and toluene (1 mL) were added sequentially to a dry reaction tube. The reaction mixture was then stirred at 0°C. After the reaction was complete, the crude product was separated and purified by column chromatography to obtain compound Iq.

[0114] The yield, melting point, enantioselectivity, optical rotation, hydrogen spectrum, carbon spectrum and mass spectrum data of the obtained Iq are as follows: 96% yield, mp 76.5-77.4 o C; 98% ee; [α] D 20 = -80.8 ( c 2.03, CH2Cl2). 1 H NMR (400MHz, CDCl3) δ 7.52 – 7.35 (m, 3H), 7.27 (dd, J = 8.1, 1.9 Hz, 1H), 7.20 –7.13 (m, 1H), 6.98 (d, J = 8.6 Hz, 1H), 6.69 (d, J = 2.9 Hz, 1H), 6.61 (dd, J = 8.6, 3.0 Hz, 1H), 6.57 – 6.47 (m, 2H), 5.58 (s, 1H), 5.22 (s, 1H), 3.70 (s,3H), 2.23 (s, 3H), 2.08 (s, 3H), 1.48 – 1.20 (m, 9H). 13 C NMR (101 MHz, CDCl3)δ 197.6, 156.8, 153.7, 147.6, 147.2, 137.3, 135.0, 134.8, 132.6, 128.0,128.0, 127.8, 125.9, 123.5, 116.3, 114.4, 111.9, 81.0, 78.0, 55.4, 26.9,20.8, 18.2. HRMS (ESI) m / z : Calcd. for [M+Na] + C 28 H 30N2O4SNa 513.1818, found513.1819. The ee was determined by HPLC: Chiralpak IC, EtOH / hexane = 20 / 80, flow rate = 1.0 mL / min, l = 254 nm, t R = 8.1 min (minor), t R = 10.8 min(major).

[0115] Example 18: Synthesis of Compound (I-r)

[0116]

[0117] A catalytic amount of chiral phosphoric acid CPA-5 (0.01 mmol), benzothiophene imine (II-a) (0.12 mmol), arylamine (III-i) (0.1 mmol), and toluene (1 mL) were added sequentially to a dry reaction tube. The reaction mixture was then stirred at 0°C. After the reaction was complete, the crude product was separated and purified by column chromatography to obtain compound Ir.

[0118] The yield, melting point, enantioselectivity, optical rotation, hydrogen spectrum, carbon spectrum and mass spectrum data of the obtained Ir are as follows: 96% yield, mp 93.5-94.4 o C; 98% ee; [α] D 20 = -83.4 ( c 1.34, CH2Cl2). 1 H NMR (400MHz, CDCl3) δ 7.61 – 7.45 (m, 3H), 7.37 (dd, J = 8.2, 2.0 Hz, 1H), 7.25 (d, J = 2.5 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.94 – 6.85 (m, 3H), 6.81 (dd, J =7.9, 2.5 Hz, 1H), 5.65 (s, 2H), 2.32 (s, 3H), 2.20 (s, 6H), 1.52 – 1.26 (m,9H). 13C NMR (101 MHz, CDCl3) δ 197.5, 153.7, 147.7, 145.0, 139.6, 137.6,137.4, 135.1, 130.5, 130.4, 128.0, 127.9, 127.8, 127.4, 123.5, 121.1, 117.0,116.2, 81.0, 77.9, 28.1, 20.8, 19.9, 19.0. HRMS (ESI) m / z : Calcd. for [M+Na] + C 28 H 30 N2O3SNa 497.1869, found 497.1870. The ee was determined by HPLC:Chiralpak IC, EtOH / hexane = 20 / 80, flow rate = 1.0 mL / min, l = 254 nm, t R = 7.0min (minor), t R = 8.1 min (major).

[0119] Example 19: Synthesis of Compound (I-s)

[0120]

[0121] A catalytic amount of chiral phosphoric acid CPA-5 (0.01 mmol), benzothiophene imine (II-a) (0.12 mmol), arylamine (III-j) (0.1 mmol), and toluene (1 mL) were added sequentially to a dry reaction tube; the reaction mixture was then stirred at 0°C. After the reaction was complete, the crude product was separated and purified by column chromatography to obtain compound Is.

[0122] The yield, melting point, enantioselectivity, optical rotation, hydrogen spectrum, carbon spectrum and mass spectrum data of the obtained Is are as follows: 95% yield, mp 69.6-69.9 o C; 88% ee; [α] D 20 = -33.1 ( c 1.32, CH2Cl2). 1 H NMR (400MHz, CDCl3) δ 7.66 – 7.44 (m, 3H), 7.37 (dd,J = 8.2, 1.9 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 7.18 – 7.07 (m, 1H), 7.00 – 6.92 (m, 2H), 6.91 – 6.81 (m, 2H), 6.77 (d, J = 7.5 Hz, 1H), 5.74 (s, 1H), 5.69 (s, 1H), 2.32 (s, 3H), 2.29 (s,3H), 1.49 – 1.25 (m, 9H). 13 C NMR (101 MHz, CDCl3) δ 197.5, 153.8, 147.7,144.2, 142.1, 139.3, 137.5, 135.1, 129.2, 128.1, 128.0, 127.9, 127.8, 123.5,122.6, 119.3, 117.0, 115.8, 81.1, 77.8, 28.2, 21.5, 20.8. HRMS (ESI) m / z :Calcd. for [M+Na] + C 27 H 28 N2O3SNa 483.1713, found 483.1713. The ee was determined by HPLC: Chiralpak IC, EtOH / hexane = 10 / 90, flow rate = 1.0 mL / min, l = 254nm, t R = 11.0 min (minor), t R = 14.8 min (major).

[0123] Example 20: Synthesis of Compound (I-t)

[0124]

[0125] A catalytic amount of chiral phosphoric acid CPA-5 (0.01 mmol), benzothiophene imine (II-a) (0.12 mmol), arylamine (III-k) (0.1 mmol) and toluene (1 mL) were added sequentially to a dry reaction tube; the reaction mixture was then stirred at 0°C for reaction; after the reaction was complete, the crude product was separated and purified by column chromatography to obtain compound It.

[0126] The yield, melting point, enantioselectivity, optical rotation, hydrogen spectrum, carbon spectrum and mass spectrum data of It are as follows: 95% yield, mp 128.1-129.0 o C; 98% ee; [α] D 20 = -590.2 ( c 1.00, CH2Cl2). 1 H NMR (400MHz, CDCl3) δ 7.79 – 7.64 (m, 1H), 7.36 – 7.23 (m, 3H), 7.11 (d, J = 8.0 Hz,1H), 7.09 – 7.01 (m, 2H), 7.01 – 6.91 (m, 1H), 6.83 (d, J = 8.5 Hz, 1H), 6.64(d, J = 2.2 Hz, 1H), 6.44 (dd, J = 8.6, 2.2 Hz, 1H), 6.00 (s, 1H), 5.91 (s,1H), 3.89 (s, 3H), 2.32 (s, 3H), 1.47 – 1.24 (m, 9H). 13 C NMR (101 MHz, CDCl3)δ 198.4, 159.0, 153.5, 148.3, 145.4, 142.0, 137.3, 134.4, 129.6, 129.4,127.1, 126.6, 123.7, 121.9, 118.9, 118.2, 108.2, 100.8, 81.0, 75.7, 55.9,28.2, 20.8. HRMS (ESI) m / z : Calcd. for [M+Na] + C 27 H 28N2O4SNa 499.1662, found499.1662. The ee was determined by HPLC: Chiralpak IC, EtOH / hexane = 20 / 80, flow rate = 1.0 mL / min, l = 254 nm, t R = 9.2 min (minor), t R = 12.6 min(major).

[0127] Example 21: Synthesis of Compound (I-u)

[0128]

[0129] A catalytic amount of chiral phosphoric acid CPA (0.01 mmol), benzothiophene imine (II-a) (0.12 mmol), arylamine (III-l) (0.1 mmol) and toluene (1 mL) were added sequentially to a dry reaction tube; the reaction mixture was then stirred at 0°C for reaction; after the reaction was complete, the crude product was separated and purified by column chromatography to obtain compound Iu.

[0130] The yield, melting point, enantioselectivity, optical rotation, hydrogen spectrum, carbon spectrum and mass spectrum data of the obtained Iu are as follows: 89% yield, mp 73.3-73.9 o C; 98% ee; [α] D 20 = -91.7 ( c 1.37, CH2Cl2). 1 H NMR (400MHz, CDCl3) δ 7.55 (d, J = 8.8 Hz, 3H), 7.36 (dd, J = 8.1, 2.0 Hz, 1H), 7.26– 7.23 (m, 1H), 7.18 (dd, J = 7.7, 1.5 Hz, 2H), 7.15 – 7.07 (m, 1H), 6.98 –6.93 (m, 1H), 6.87 – 6.75 (m, 2H), 5.69 (s, 1H), 5.45 (s, 1H), 2.31 (s, 3H), 2.20 (s, 3H), 1.56 – 1.28 (m, 9H). 13C NMR (101 MHz, CDCl3) δ 197.6, 153.8,147.7, 145.2, 140.2, 137.4, 135.1, 131.0, 129.6, 129.4, 128.0, 127.9, 127.8,126.8, 123.5, 123.0, 120.3, 118.7, 116.5, 81.1, 77.9, 28.3, 20.8, 17.9. HRMS(ESI) m / z : Calcd. for [M+Na] + C 27 H 28 N2O3SNa 483.1713, found 483.1715. The ee was determined by HPLC: Chiralpak IA, i PrOH / hexane = 30 / 70, flow rate = 1.0 mL / min, l = 254 nm, t R = 13.7 min (minor), t R = 10.2 min (major).

[0131] Case Study 22: Synthesis of Vitamin E Structural Modification A

[0132]

[0133] A catalytic amount of chiral phosphoric acid CPA-5 (0.01 mmol), benzothiophene imine (II-a) (0.12 mmol), vitamin E-derived aniline (0.1 mmol), and toluene (1 mL) were added sequentially to a dry reaction tube. The reaction mixture was then stirred at 0°C. After the reaction was complete, the crude product was separated and purified by column chromatography to obtain estrone structure modification A.

[0134] The yield, optical rotation, hydrogen spectrum, carbon spectrum and mass spectrum data of the obtained A are as follows: 76% yield, [α] D 20 = -27.1( c 2.38, CH2Cl2). 1 H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 7.44 (d, J = 8.4 Hz,2H), 7.33 (dd, J= 8.1, 1.9 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 6.33 (d, J =8.3 Hz, 2H), 5.60 (s, 1H), 5.33 – 4.84 (m, 1H), 2.58 (t, J = 6.8 Hz, 2H),2.30 (s, 3H), 2.10 (s, 3H), 2.04 (s, 3H), 2.00 (s, 3H), 1.86 – 1.75 (m, 2H),1.66 – 1.48 (m, 4H), 1.45 – 1.38 (m, 9H), 1.31 – 1.20 (d, m, 12H), 1.17 –1.01 (m, 7H), 0.92 – 0.81 (m, 12H). 13 C NMR (101 MHz, CDCl3) δ 170.2, 153.6,142.3, 141.8, 141.7, 141.4, 140.7, 134.1, 133.9, 133.8, 129.5, 129.3, 128.3,127.7, 126.9, 124.2, 124.1, 122.2, 121.6, 120.3, 120.1, 117.4, 117.1, 115.8,115.4, 85.0, 84.1, 83.3, 79.8, 79.2, 59.4, 30.9, 30.4, 29.2, 28.7, 28.6,28.3, 27.2, 27.1, 23.1, 21.7, 20.1, 20.0, 13.2, 13.1. HRMS (ESI) m / z : Calcd.for [M+Na] + C 49 H 70 N2O4SNa 805.4949, found 805.4949.

[0135] Case Study 23: Synthesis of Estrone Structural Modification B

[0136]

[0137] A catalytic amount of chiral phosphoric acid CPA-5 (0.01 mmol), benzothiophene imine (II-a) (0.12 mmol), estrone-derived aniline (0.1 mmol), and toluene (1 mL) were added sequentially to a dry reaction tube. The reaction mixture was then stirred at 0°C. After the reaction was complete, the crude product was separated and purified by column chromatography to obtain estrone structural modification B.

[0138] The yield, melting point, optical rotation, hydrogen spectrum, carbon spectrum and mass spectrum data of B obtained are as follows: 70% yield, mp138.0-138.8 o C; [α] D 20 = -5.8 ( c 0.75, CH2Cl2). 1 H NMR (400 MHz, CDCl3) δ 7.59 –7.51 (m, 3H), 7.36 (dd, J = 8.1, 1.9 Hz, 1H), 7.24 (s, 1H), 7.16 (d, J = 8.4Hz, 1H), 6.95 – 6.89 (m, 2H), 6.87 – 6.78 (m, 2H), 5.67 (s, 2H), 2.88 – 2.78(m, 2H), 2.49 (dd, J = 18.8, 8.6 Hz, 1H), 2.36 (dd, J = 9.0, 4.2 Hz, 1H),2.30 (s, 3H), 2.27 – 2.19 (m, 1H), 2.18 – 2.09 (m, 1H), 2.06 – 1.90 (m, 3H),1.69 – 1.50 (m, 5H), 1.47 – 1.35 (m, 9H), 0.89 (s, 3H), 0.86 – 0.77 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 197.6, 153.8, 147.7, 144.5, 139.8, 137.7, 137.5,135.1, 133.5, 128.0, 127.9, 127.8, 126.3, 123.5, HRMS (ESI) m / z : Calcd. for [M+Na] + C 38 H 42 N2O4SNa 645.2757, found645.2756.

[0139] Example 24: Antioxidant Capacity (ORAC) Test Method

[0140] Prepare a 10 μM solution of hydrofluorescein (HFL), a 1 mM solution of hydrogen peroxide (H2O2), a 2 μg / mL solution of horseradish peroxidase (HRP), a 10 μM Trolox standard solution, and solutions of various concentrations of Vitamin E Modification A, such as 10 μM, 25 μM, 50 μM, and 100 μM. Add 100 μL of the hydrofluorescein (HFL) solution to each well of a 96-well plate. Add 10 μL of PBS to the control wells, 10 μL of Vitamin E Modification A sample solution (various concentrations) to the sample wells, 10 μL of a 10 μM Trolox standard solution to the Trolox standard wells, and 10 μL of PBS to the blank wells in place of the sample and Trolox. Next, add 10 μL of the HRP solution to each well, followed by 10 μL of the hydrogen peroxide (H2O2) solution. Incubate the 96-well plate in a 37°C incubator for 30 minutes. Fluorescence intensity was measured using a fluorescence plate reader at an emission wavelength of 520 nm and an excitation wavelength of 485 nm, and the ORAC value was calculated. The ORAC value of Vitamin E Modified A was 3100 µmol TE / mg, significantly greater than the ORAC value of vitamin E (2000 µmol TE / mg). This indicates that Vitamin E Modified A has significantly enhanced antioxidant capacity.

[0141] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A chiral 2-aryl-2'-aminobenzothiophene compound, characterized in that: It has the following structural formula: .

2. A method for preparing the chiral 2-aryl-2'-aminobenzothiophene compound according to claim 1, characterized in that: Dissolve benzothiophenone imine (II) and arylamine (III) in an organic solvent, then add a chiral catalyst, stir and react at 0°C-25°C, and after the reaction is completed, separate and purify to obtain product I; wherein, The benzothiophenone imine (II) has the following structure: ； The arylamine (III) has the following structure: ； The chiral catalyst is a chiral phosphoric acid catalyst, and the chiral phosphoric acid has the following structure: ， 。 3. The preparation method according to claim 2, characterized in that The organic solvent is selected from one or a mixture of toluene, mesitylene, dichloromethane, chloroform, tetrahydrofuran, ether, acetonitrile, ethanol, methanol, 1,4-dioxane, and chlorobenzene.

4. The preparation method according to claim 2, characterized in that The reaction temperature is 0°C.

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