Axial chiral aryl pyrrole derivative as well as preparation method and application thereof

Abstract

The invention discloses an axially chiral aryl pyrrole derivative, a preparation method thereof and application of the axially chiral aryl pyrrole derivative as a chiral catalyst, and relates to the technical field of organic matter synthesis. According to the invention, substituted primary amine and enyne are taken as raw materials and react in the presence or absence of an additive in the presence of a copper salt and a PyBOX ligand to obtain a novel axially chiral aryl pyrrole derivative, and a method for forming an aryl pyrrole rotation-hindered isomer through [1 + 4] cyclization of the primary amine and electron-deficient enyne under the catalysis of metal is developed. According to the present invention, the used catalyst is easily available, the preparation cost is low, the synthesis method is suitable for a variety of substrates, a variety of axially chiral aryl pyrrole compounds with novel structures can be constructed, and the obtained aryl pyrrole compound has characteristics of high yield and excellent enantioselectivity. The synthesis route of the aryl pyrrole compound is expanded, and a foundation is laid for further exploration and application of the compounds in asymmetric catalysis, drug development and other chemical fields.

Description

Technical Field

[0001] The present invention relates to the technical field of organic compound synthesis, and in particular to a class of axially chiral aryl pyrrole derivatives and a preparation method and application thereof. Background Art

[0002] As a typical representative of three-dimensional spatial configuration regulation, axially chiral aryl pyrrole derivatives have a unique rigid-flexible coupling molecular configuration that plays an irreplaceable role in the construction of drug active centers (such as anti-tumor drugs PD-1 / PD-L1 inhibitors), total synthesis of natural products (such as indole alkaloid compounds) and asymmetric catalysis (CH bond activation reaction). It is especially valuable in the fields of drug development, natural product synthesis and asymmetric catalysis. In recent years, its asymmetric synthesis strategy and application research have made significant progress, but it still faces challenges such as limitations of synthetic methods and stability. According to the 2023 annual report of the Catalysis Division of the American Chemical Society, the proportion of axial chiral compounds in the global chiral drug market has exceeded 38%, and the average annual growth rate of aryl pyrrole derivatives is as high as 21%. However, existing synthesis technology is still limited by two core bottlenecks: one is the balance problem between stereoselective control and the coordinated construction of multiple chiral centers; the other is the contradiction between thermodynamic stability and the universality of the catalytic system.

[0003] The light-driven asymmetric synthesis system reported by Lu Yixin's team at the National University of Singapore in J.Am.Chem.Soc.2022,144,21018-21032 innovatively combines UV-excited [2+2] cycloaddition (quantum yield Φ=0.42) with chiral phosphonic acid-catalyzed dynamic kinetic resolution (ee value>99%). This system achieves a photocatalytic reaction by precisely controlling the generation rate of the p-quinone methide (p-QM) intermediate (kobs=3.8×10 -3 s -1 ), successfully achieved the stereodivergent construction of tetrasubstituted pyrrole ring. Of particular note is that the chiral transfer strategy developed by it utilizes Pb(OAc)4-mediated oxidative cyclization reaction (conversion rate 92%) to convert the central chiral intermediate into The energy barrier difference is effectively converted into the configurational stability of the axial chiral product. Although this technology has been successfully applied to the gram-scale preparation of ixacillinone (IC50 = 0.32nM), substrate adaptability studies have shown that when a strong electron-withdrawing group (such as -NO2) is present at the ortho position of the aromatic ring, the diastereoselectivity will drop from 98:2 to 83:17 (J.Med.Chem.2023, 66, 11245-11258). In the scale-up experiment (>10mmol), the light source penetration depth limitation causes the reaction efficiency to drop by 30%-40%. In addition, this scheme also relies on chiral phosphonic acid, and the synthesis of chiral phosphonic acid ligands requires six steps of reaction (total yield <15%), which seriously restricts industrial application.

[0004] In the development of new catalytic systems, the [4+1] cycloaddition strategy proposed by Chen Xiao's research group at Central China Normal University (Master's thesis "Study on the Asymmetric Cycloaddition of Enyne Esters and Primary Amines to Construct Axially Chiral Compounds" 2023) is significantly innovative. The bifunctional chiral thiourea catalyst they designed is characterized by the NH···O=C double hydrogen bond (binding constant Ka=1.2×10 3 M -1 ), successfully achieved stereoselective attack on the β-site of the enyne ester (dr value>20:1). This single-step construction method increased the total yield of the traditional multi-step synthesis from 32% to 68%, and X-ray single crystal diffraction confirmed the rotation energy barrier of the CC axis of the product. The EE value of the product has been shown to drop sharply to <15% in compatibility experiments with aliphatic amines (such as n-butylamine), indicating a significant π-π stacking dependence on the substrate recognition mechanism.

[0005] Therefore, current technological development faces the following challenges: ① The catalytic system's dependence on precious metals / special ligands (e.g., PtCl₂ dosages up to 5 mol%); ② The steric hindrance of polycyclic fused systems (e.g., benzopyrrole) results in reaction yields generally below 40%. Therefore, developing novel synthetic strategies with broad substrate compatibility, mild operating conditions, and the ability to achieve long-term stability of axial configurations has become a key technical challenge urgently needed to be addressed in the chiral drug industry. Summary of the Invention

[0006] The present invention provides a new preparation scheme for a class of axially chiral arylpyrrole derivatives. Using substituted primary amines and enynes as raw materials, a new class of axially chiral arylpyrrole derivatives is obtained by reaction in the presence or absence of copper salts and PyBOX ligands, expanding the synthetic route of arylpyrrole compounds and laying the foundation for further exploration and application of these compounds in asymmetric catalysis, drug development and other chemical fields.

[0007] The technical solution adopted in the present invention is as follows:

[0008] One of the objectives of the present invention is to provide a class of axial chiral aryl pyrrole derivatives, the structure of which is

[0009] The structure shown in Formula 1 or its stereoisomers:

[0010]

[0011] in,

[0012] R 1 、R2 、R 3 Each of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted 4-10 membered cycloalkyl, substituted or unsubstituted 4-10 membered heterocycloalkyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl; the substituents of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted 6-10 membered aryl, halogen, -NR 7 R 8 ; R 7 、R 8 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl; the substituents of the alkyl and alkoxy groups are independently selected from C1-C6 alkyl, C1-C6 alkoxy, and halogen;

[0013] R 4 、R 5 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, halogen, -NR 9 R 10 、-O(CH2) n OR 11 、-OC(O)R 11 ; or, R 4 and R 5 connected to form a substituted or unsubstituted 4- to 10-membered cycloalkyl, a substituted or unsubstituted 4- to 10-membered heterocycloalkyl, a substituted or unsubstituted 6- to 10-membered aryl, or a substituted or unsubstituted 5- to 10-membered heteroaryl; n is an integer from 1 to 6; R 9 、R 10 、R 11 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl;

[0014] R 6 Selected from -NO2, -COOR 12 , -CN, -CF3; R 12 Selected from hydrogen, substituted or unsubstituted C1-C6 alkyl.

[0015] The second object of the present invention is to provide a method for preparing a novel axially chiral arylpyrrole derivative, the synthesis reaction formula of which is shown in Formula 2:

[0016]

[0017] Wherein, the ligand shown in Formula 2 is a PyBOX ligand.

[0018] The goal of this invention is to develop a method for forming atropisomers of arylpyrroles via the metal-catalyzed [1+4] cyclization of primary amines with electron-deficient enynes. The primary challenge of this method is achieving the desired reactivity, regioselectivity, and stereocontrol during the cyclization process. To obtain the desired atropisomer with a stable configuration (ΔGrotation > 30 kcal / mol), steric hindrance must be introduced at two ortho positions around the axial chirality of the aryl ring. Therefore, selecting an appropriate catalytic system is crucial to ensuring reactivity, regioselectivity, and precise stereochemical recognition.

[0019] Furthermore, the molar ratio of substrate 1, substrate 2, additive, copper salt and ligand shown in Formula 2 is 1:(1-5):(1-5):(0.01-0.1):(0.01-0.2); the molar volume ratio of substrate 1 and solvent is (0.05-0.2) mmol:1 ml.

[0020] Furthermore, the additive is DABCO, the molar ratio of substrate 1, substrate 2, DABCO, copper salt and ligand is 1:1.2:1:0.1:0.12; the molar volume ratio of substrate 1 and organic solvent is 0.1mmol:1ml.

[0021] Furthermore, the copper salt shown in Formula 2 is selected from one or more of Cu(CH3CN)4PF6, Cu(OTf)2 and Cu(CH3CN)4BF4.

[0022] Furthermore, the copper salt is Cu(OTf)2.

[0023] Furthermore, the solvent shown in Formula 2 is selected from one or more of dichloromethane, 1,2-dichloroethane, chloroform, toluene, acetonitrile, and tetrahydrofuran.

[0024] Furthermore, the solvent is 1,2-dichloroethane.

[0025] Furthermore, the PyBOX ligand is selected from one or more of L1 to L22 shown below:

[0026]

[0027] Furthermore, the PyBOX ligand is L21.

[0028] The third object of the present invention is to protect the application of the axially chiral aryl pyrrole derivative as a drug development or chiral catalyst or chiral catalyst development intermediate.

[0029] The compounds and derivatives provided herein can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0030] Definitions of terms used in the present invention: Unless otherwise stated, the initial definitions provided for groups or terms in this document apply to the groups or terms throughout the specification; for terms that are not specifically defined herein, they should be given the meaning that a person skilled in the art would give them based on the disclosure and context.

[0031] "Substitution" refers to the replacement of a hydrogen atom in a molecule by another different atom or molecule.

[0032] The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix C a ~C b Alkyl refers to any alkyl group containing "a" to "b" carbon atoms. Thus, for example, "C1-C6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms, specifically C1, C2, C3, C4, C5, and C6 alkyl; "C1-C6 alkoxy" refers to an alkoxy group containing 1 to 6 carbon atoms, specifically C1, C2, C3, C4, C5, and C6 alkoxy.

[0033] "Alkyl" refers to a saturated hydrocarbon chain having a specified number of carbon atoms. For example, C1-C6 alkyl refers to an alkyl group having from 1 to 6 carbon atoms, i.e., 1, 2, 3, 4, 5, or 6 carbon atoms. Alkyl groups can be straight or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and tert-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl, among others.

[0034] "Halogen" is fluorine, chlorine, bromine or iodine.

[0035] "Cycloalkyl" refers to a saturated or unsaturated all-carbon monocyclic or polycyclic ring (including fused, spiro or bridged rings) without a conjugated π electron system, including but not limited to:

[0036] wait.

[0037] "Heterocycloalkyl" refers to a cycloalkyl group in which at least one carbon atom is replaced by a heteroatom, wherein the heteroatom is O, N or S, and is a saturated or unsaturated monocyclic or polycyclic ring (including fused rings, spiro rings or bridged rings) without a conjugated π electron system, including but not limited to:

[0038]

[0039] wait.

[0040] "Aryl" refers to an all-carbon monocyclic or polycyclic ring (including fused, spiro, or bridged rings) with a conjugated π electron system, including, but not limited to, phenyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl, and indenyl. The aromatic ring may be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as O, N, or S. The point of attachment to the parent group must be on a carbon atom on the ring with a conjugated π electron system, including, but not limited to:

[0041] wait.

[0042] "Heteroaryl" refers to an aromatic group in which at least one carbon atom of the conjugated π-electron system is replaced by a heteroatom, wherein the heteroatom is O, N or S, such as but not limited to thienyl, furyl, isothiazolyl, etc.

[0043] In summary, compared with the prior art, the present invention has the following advantages and beneficial effects:

[0044] 1. The present invention provides a method for synthesizing atropisomers of arylpyrroles using copper catalysis. The catalyst used in the present invention is easily available and has a low preparation cost. The synthesis method is applicable to a variety of substrates and can construct a variety of arylpyrrole compounds with novel structures. The obtained arylpyrrole compounds have high yields and excellent enantioselectivity.

[0045] 2. This invention expands the synthetic route of arylpyrrole compounds and lays the foundation for further exploration and application of these compounds in asymmetric catalysis, drug development and other chemical fields. DETAILED DESCRIPTION

[0046] The present invention will be described in detail below in conjunction with specific embodiments, and the advantages and various effects of the present invention will be more clearly presented. It should be understood by those skilled in the art that these specific embodiments and examples are for illustrating the present invention, rather than limiting the present invention.

[0047] Throughout this specification, unless otherwise specified, the terms used herein should be understood as having the same meaning as 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 belongs. In the event of any conflict, the present specification shall take precedence.

[0048] Unless otherwise specified, various raw materials, reagents, instruments and equipment used in the present invention can be purchased from the market or prepared by existing methods.

[0049] The present application will be described in detail below with reference to specific embodiments and experimental data.

[0050] Example 1

[0051] This example is limited to substrate 1a, and the reactions of various alkane-substituted primary amines with substrate 1a are studied. The specific reaction formula is shown in Formula 3:

[0052]

[0053] Reaction conditions: 1 (0.1 mmol), 2 (0.12 mmol), Cu(OTf)2 (10 mol%), chiral ligand L21 (12 mol%), and DABCO (1.2 equivalents) were dissolved in 1 mL of 1,2-dichloroethane and reacted at -35°C for 48 hours. Product 3 was purified by silica gel column chromatography. The isolated yield (yield) of the product was calculated; the enantiomeric ratio (er) was determined by chiral high-performance liquid chromatography (HPLC). The molar amounts of Cu(OTf)2 and chiral ligand L21 were 10 mol% and 12 mol%, respectively, of 1 mol.

[0054] Referring to the above reaction conditions, compounds 3a-3u were prepared by using different alkanes to replace the primary amine. The structures, yields, and enantiomeric ratios of compounds 3a-3u are as follows:

[0055]

[0056] The relevant spectral data of compounds 3a~3u are as follows:

[0057] Compound 3a: 44.5 mg, 94% yield, light yellow solid, melting point 94.6–96.1°C; HPLC (Dacelid chiral column OD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =7.08min(major),t R =5.83min(minor); enantiomer ratio er=98:2, specific rotation [α] D 20 =+276.857 (c=0.14, ethyl acetate). 1 H NMR (600MHz, Chloroform-d) δ (ppm): 7.92-7.89 (m, 2H), 7.79 (d, J = 7.8Hz, 1H), 7.597.54 (m, 2H), 7.33 (d, J = 8.4Hz, 1H), 7.23-7.18 (m, 4H),7.17-7.11(m,3H),7.02(t,J=7.2Hz,1H),6.96-6.94(m,2H),6.88-6.86(m,2H),6,82-6.79(m,2H),628(brs,1H),5.90(brs,1H).13 CNMR (150MHz, Chloroform-d) δ (ppm): 140.5, 140.3, 138.2, 136.1, 134.5, 133.8, 132.9, 132.2, 130.8, 1301, 129.2, 1 28.6,1285,128.2,128.1,128.0,1279,1277,127.63,127.60,127.2,126.2,125.2.105.7.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 31 H 28 N2NaO2 + 489.1574; Found 489.1577.

[0058] Compound 3b: 36.0 mg, 77% yield, light yellow solid, melting point 164.2–167.5°C; HPLC (Dacelid chiral column OD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =5.09min(major),t R =5.64min(minor); enantiomer ratio er=99:1, specific rotation [α] D 20 =+110.462 (c=0.13, ethyl acetate). 1 HNMR(600MHz,Chloroform-d)δ(ppm):8.06(d,J=8.4Hz,1H),7.92(dd,J=7.2,2.4Hz,2H),7.67(d,J=9.0Hz,1H),7.53–7.49(m,2H),7.37–7.3 5(m,3H),7.33–7.29(m,3H),7.23–7.22(m,2H),6.94(s,1H),6.86–6.8 4(m,2H),3.30(d,J=14.4Hz,1H),3.16(d,J=14.4Hz,1H),0.15(s,9H). 13C NMR(150MHz,Chloroform-d)δ(ppm):141.3,140.0,137.5,135.8,133.1,132.9,132.7,130.5,129.5,128.9,128.53,1 28.46,128.3,128.0,127.6,127.18,127.18,126.4,126.3,125.9,107.0,55.3,33.2,28.3.HRMS(ESI-TOF)m / z:[M+Na] + Calcdfor C 31 H 28 N2NaO2 + 483.2043; Found 483.2050.

[0059] Compound 3c: 45 mg, 73% yield, light yellow solid, melting point 148.3–150.2°C; HPLC (Dacelid chiral column OD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =7.81min(major),t R =8.86min(minor); enantiomer ratio er=93:7, specific rotation [α] D 20 =+369.538 (c=0.13, ethyl acetate). 1 H NMR (600MHz, Chloroform-d) δ (ppm): 7.8.06 (d, J = 8.4Hz, 1H), 7.95 (d, J = 7.8Hz, 1H), 7.75 (d, J = 8.4Hz, 1H), 7.67 (d, J = 8.4Hz, 1H), 7.55–7.52 (m 1H),7.50–7.48(m,1H),7.37–7.32(m,6H),7.28–7.26(m,2H),6.97–6.96(m,2H),6.91(s,1H),3.09(dd,J=14 .4,7.8Hz,1H),2.97(dd,J=13.8,7.8Hz,1H),1.06–0.99(m,1H),0.26(d,J=6.6Hz,3H),0.17(d,J=6.6Hz,3H). 13CNMR(150MHz,Chloroform-d)δ(ppm):141.1,140.1,137.1,134.9,132.8,132.7,132.1,131.9,130.4,129.2,128.8,128.6, 128.39,128.36,128.3,127.6,127.4,127.3,126.4,125.6,125.4,106.0,52.7,28.3,19.6,19.4.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 30 H 26 N2NaO2 + 469.1887; Found 469.1898.

[0060] Compound 3d: 35 mg, 77% yield, light yellow solid, melting point 70.8–72.6°C; HPLC (Dacelido chiral column AD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =7.81min(major),t R =8.86min (minor); enantiomer ratio er = 93:7, specific rotation [α] D 20 =+166.133 (c=0.15, ethyl acetate). 1 H NMR(600MHz,Chloroform-d)δ(ppm):7.07(d,J=8.4Hz,1H),7.95(d,J=7.8Hz,1 H),7.67(d,J=9.0Hz,1H),7.64(d,J=8.4Hz,1H),7.55–7.52(m,1H),7.51–7.48 (m,1H),7.38–7.31(m,6H),7.31–7.27(m,2H),7.10–7.08(m,2H),6.90(s,1H), 3.32–3.20(m,2H),0.85–0.73(m,2H),0.68–0.59(m,2H),0.27(t,J=7.2Hz,3H). 13C NMR(150MHz,Chloroform-d)δ(ppm):140.9,140.2,137.0,134.3,133.0,132.7,132.0,131.6,130.3,129.3,128.7,128.6, 128.4,128.36,128.3,127.7,127.5,127.3,126.4,125.7,125.2,105.8,45.0,31.8,19.2,12.9.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 30 H 26 N2NaO2 + 469.1887; Found 469.1897.

[0061] Compound 3e: 36 mg, 76% yield, light yellow solid, melting point 122.4–124.7°C; HPLC (Dacelid chiral column OD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =5.14min(major),t R =5.98min(minor); enantiomer ratio er=90:10, specific rotation [α] D 20 =+237.000 (c=0.14, ethyl acetate). 1 HNMR(600MHz,Chloroform-d)δ(ppm):78.07(d,J=8.4Hz,1H),7.95(d,J=7.8Hz,1H) ,7.67(d,J=9.0Hz,1H),7.64(d,J=7.8Hz,1H),7.55–7.52(m,1H),7.50–7.48(m,1H), 7.37–7.31(m,6H),7.29–7.28(m,2H),7.10–7.08(m,2H),6.90(s,1H),3.31–7.26(m, 1H),3.23–7.18(m,1H),0.88–0.77(m,2H),0.70–0.52(m,4H),0.42(t,J=7.2Hz,3H). 13C NMR(150MHz,Chloroform-d)δ(ppm):140.9,140.2,137.0,134.3,132.9,132.7,132.0,131.6,130.3,129.2,128.7,128.6,128 .39128.36,128.3,127.6,127.5,127.3,126.4,125.7,125.3,105.9,45.3,29.4,28.1,21.4,13.3.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 31 H 28 N2NaO2 + 483.2043; Found 483.2045.

[0062] Compound 3f: 40 mg, 82% yield, light yellow solid, melting point 97.1–99.5°C; HPLC (Dacelid chiral column IE-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =8.98min(major),t R =8.35min (minor); enantiomer ratio er = 94:6, specific rotation [α] D 20 =+53.750 (c=0.24, ethyl acetate). 1 H NMR(600MHz,Chloroform-d)δ(ppm):7.95–7.92(m,1H),7.77–7.74(m,1H),7.59–7.56(m,1H),7.36–7.161(m,11H),6.92– 6.86(m,3H),6.75–6.73(m,1H),6.66–6.64(m,2H),6.10(d,J=7.8Hz,2H),4.40(d,J=15.6Hz,1H),4.25(d,J=15.6Hz,1H). 13 C NMR(150MHz,Chloroform-d)δ(ppm):141.0,140.1,137.4,135.6,134.9,132.61,132.55,132.3,131.3,130.5,129.6,128.9,1 28.6,128.5,128.1,127.9,127.43,127.39,127.2,127.1,126.8,126.1,125.5,125.2,105.9,49.0.HRMS(ESI-TOF)m / z:[M+Na]+ Calcd for C 33 H 24 N2NaO2 + 503.1730; Found 503.1734.

[0063] Compound 3g: 30 mg, 69% yield, light yellow solid, melting point 168.6–170.3°C; HPLC (Dacelid chiral column IE-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =8.54min(major),t R =7.94min(minor); enantiomer ratio er=92:8, specific rotation [α] D 20 =+136.600 (c=0.10, ethyl acetate). 1 HNMR(600MHz,Chloroform-d)δ(ppm):8.07(d,J=8.4Hz,1H),7.96(d,J=7.8Hz,1H),7.70(d,J=8.4Hz,1H),7.64(d,J=8.4Hz,1H),7.55–7.52(m,1H),7.50 –7.47(m,1H),7.38–7.30(m,8H),7.10(dd,J=7.8,2.4Hz,2H),6.92(s,1H),2 .30–2.06(m,1H),0.28–0.23(m,1H),0.10–0.02(m,2H),-0.06–-0.11(m,1H). 13 C NMR(150MHz,Chloroform-d)δ(ppm):141.4,140.5,136.6,135.9,134.2,132.6,132.4,131.7,130.2,128.8,128.6,12 8.5,128.5,128.3,127.9,127.7,127.5,127.4,126.3,126.2,124.9,105.0,28.4,8.9,8.8.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 29 H 22 N2NaO2 + 453.1574; Found 453.1578.

[0064] Compound 3h: 49 mg, 93% yield, light yellow solid, melting point 185.4–188.1°C; HPLC (Dacelid chiral column OD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =4.85min(major),t R =6.17min(minor); enantiomer ratio er=90:10, specific rotation [α] D 20 =+65.778 (c=0.18, ethyl acetate). 1 HNMR(600MHz,Chloroform-d)δ(ppm):7.94(d,J=8.4Hz,1H),7.85–7.83(m,1H),7.59–7.58(m,1H),7.52(d,J=8.4Hz,1H),7.46–7.42(m,2H),7.33–7.2 5(m,6H),7.19–7.18(m,4H),6.72(s,1H),1.69(d,J=10.8Hz,3H),1.54(s,3 H), 1.39 (d, J = 11.4Hz, 3H), 1.19 (d, J = 12.0Hz, 3H), 1.00 (d, J = 11.4Hz, 3H). 13 C NMR(150MHz,Chloroform-d)δ(ppm):141.7,139.4,137.0,136.5,136.0,134.0,132.4,132.0,131.7,130.2,129.7,129.1,1 28.3,128.29,128.2,127.8,127.5,127.34,127.25,126.1,125.5,110.9,65.9,42.3,35.1,29.8.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 36 H 32 N2NaO2 + 547.2356; Found 547.2360.

[0065] Compound 3i: 32 mg, 73% yield, light yellow solid, melting point 214.7–216.1°C; HPLC (Dacelido chiral column AD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =4.73min(major),t R =5.47min(minor); enantiomer ratio er=94:6, specific rotation [α]D 20 =+101.250 (c=0.16, ethyl acetate). 1 H NMR(600MHz,Chloroform-d)δ(ppm):8.09(d,J=8.4Hz,1H),7.96(d,J=7.8Hz,1H),7.66(d,J=8.4Hz,1H),7.58(d,J=8.4Hz,1H),7.55–7.53(m,1H), 7.50–7.47(m,1H),7.43–7.38(m,3H),7.36–7.35(m,2H),7.30–7.28(m,5H ), 6.93 (s, 1H), 4.10 (d, J = 2.4Hz, 2H), 1.84 (t, J = 2.4Hz, 1H), 1.26 (s, 1H). 13 C NMR(150MHz,Chloroform-d)δ(ppm):140.8,140.6,137.0,134.3,132.9,132.7,132.2,130.7,130.6,12 9.3,128.8,128.7,128.68,128.3,128.28,127.8,127.5,127.4,126.4,125.5,124.8,105.8,73.9,35.1. 19 F NMR(564MHz,Chloroform-d)δ(ppm):-75.67(d,J=5.6Hz,1F).HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 28 H 21 FN2NaO2 + 459.1480; Found 459.1489.

[0066] Compound 3j: 41 mg, 89% yield, light yellow solid, melting point 172.5–175.1°C; HPLC (Dacelido chiral column AD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =4.04min(major),t R =5.28min(minor); enantiomer ratio er=99:1, specific rotation [α] D 20 =+137.000 (c=0.12, ethyl acetate). 1H NMR(600MHz,Chloroform-d)δ(ppm):8.11(d,J=8.4Hz,1H),7.97(d,J=7.2Hz,1H),7.69–7.66(m,2H),7.59–7.52(m,2H),7.3 9–7.35(m,6H),7.28–7.26(m,2H),7.05–7.02(m,2H),6.95(s,1H),5.04–4.84(m,1H),3.70–3.63(m,1H),3.58–3.50(m,1H). 13 C NMR(150MHz,Chloroform-d)δ(ppm):140.5,140.1,137.9,135.1,132.82,132.76,131.9,131.0,1 30.4,129.6,129.0,128.9,128.6,128.5,128.0,127.64,127.56,126.7,124.9,124.5,112.1(t,J CF =224.1Hz),106.4,46.68(t,J CF =30.0Hz). 19 F NMR(564MHz,Chloroform-d)δ(ppm):-121.11–-122.54(m,2F).HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 28 H 20 F2N2NaO2 + 477.1386; Found 477.1389.

[0067] Compound 3k: 41 mg, 85% yield, light yellow solid, melting point 82.1–85.8°C; HPLC (Dacelido chiral column AD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =3.66min(major),t R =4.25min (minor); enantiomer ratio er = 98:2, specific rotation [α] D 20 =+312.000 (c=0.15, ethyl acetate). 1H NMR(600MHz,DMSO-d6)δ(ppm):8.32(d,J=8.4Hz,1H),8.16(d,J=7.8Hz,1H),7.79(d,J=8.4Hz,1H),7.70–7.62(m,3 H),7.51–7.7.45(m,6H),7.34–7.32(m,2H),7.11(s,1H),7.05–7.03(m,2H),4.34–4.27(m,1H),4.16–7.09(m,1H). 13 C NMR(150MHz,DMSO-d6)δ(ppm):140.4,137.9,135.9,133.1,132.7,132.6,131.3,130.2,1 29.42,129.38,129.0,128.8,128.7,128.1,128.0,128.0,127.0,125.4,124.2,123.8(q,J CF =279.8Hz),106.9,45.3(q,J CF =34.5Hz). 19 FNMR(564MHz,DMSO-d6)δ(ppm):-68.29(t,J=8.5Hz,3F).HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 28 H 19 F3N2NaO2 + 495.1291; Found 495.1292.

[0068] Compound 31: 32 mg, 67% yield, light yellow solid, melting point 99.5–102.4°C; HPLC (Dacelid chiral column OD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =8.25min(major),t R =9.11min (minor); enantiomer ratio er = 98:2, specific rotation [α] D 20 =+125.867 (c=0.15, ethyl acetate). 1H NMR(600MHz,Chloroform-d)δ(ppm):8.08(d,J=8.4Hz,1H),7.96(d,J=7.8Hz,1H), 7.68(d,J=8.4Hz,1H),7.60(d,J=7.8Hz,1H),7.55(t,J=7.2Hz,1H),7.50(t,J=7.2 Hz,1H),7.39–7.37(m,3H),7.35–7.32(m,3H),7.31–7.30(m,2H),7.10(dd,J=7.2, 3.6Hz,2H),6.92(s,1H),3.50–7.40(m,2H),2.87–2.80(m,2H),1.32–1.20(m,2H). 13 C NMR(150MHz,Chloroform-d)δ(ppm):140.8,140.3,137.3,134.3,132.9,132.8,131.9,131.1,130.5,129.3,128.8,128. 7,128.7,128.6,128.4,127.74,127.72,127.5,126.5,125.2,124.8,106.1,42.8,41.1,32.4.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 29 H 23 ClN2NaO2 + 489.1341; Found 489.1340.

[0069] Compound 3m: 41 mg, 92% yield, light yellow solid, melting point 85.9–86.2°C; HPLC (Dacelid chiral column OD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =6.18min(major),t R =5.31min(minor); enantiomeric ratio er=98:2, specific rotation [α] D 20 =+109.692 (c=0.13, ethyl acetate). 1H NMR(600MHz,Chloroform-d)δ(ppm):8.09(d,J=8.4Hz,1H),7.96(d,J=7.8Hz,1H),7.68–7.66(m,2H),7.57–7.50(m,2H),7.3 9–7.34(m,6H),7.29–7.28(m,2H),7.08–7.07(m,2H),6.93(s,1H),3.63–3.53(m,2H),2.78–2.74(m,1H),2.71–2.66(m,1H). 13 C NMR(150MHz,Chloroform-d)δ(ppm):140.7,140.2,137.6,134.6,132.8,132.7,131.9,130.9,130.7,129.3,128.9 ,128.8,128.7,128.5,127.8,127.63,127.55,126.7,125.0,124.9,106.2,46.2,41.0.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 28 H 21 ClN2NaO2 + 475.1184; Found 475.1199.

[0070] Compound 3n: 39 mg, 79% yield, light yellow solid, melting point 89.7–91.5°C; HPLC (Dacelid chiral column OD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =8.77min(major),t R =7.68min(minor); enantiomer ratio er=97:3, specific rotation [α] D 20 =+112.769 (c=0.13, ethyl acetate). 1H NMR(600MHz,Chloroform-d)δ(ppm):8.00(d,J=8.4Hz,1H),7.88(d,J=7.8Hz,1H),7.61(t,J=7.2Hz,2H),7.48–7.40(m,2H),7.28–7.19(m,8H),6.88 –6.83(m,3H),3.42(dd,J=53.4,8.4Hz,2H),3.13–3.97(m,2H),2.63–2.53 (m,2H),0.83(d,J=11.4Hz,2H),0.66(d,J=12.6Hz,1H),0.49–0.37(m,2H). 13 C NMR(150MHz,Chloroform-d)δ(ppm):140.9,140.1,137.3,135.0,132.8,132.7,132.0,131.5,130.5,129.3,128.8,128.75,12 8.6,128.5,128.4,127.6,127.5,127.4,126.5,125.4,125.0,105.8,66.9,50.8,35.1,30.0,29.8.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 32 H 28 N2NaO3 + 511.1993; Found 511.1994.

[0071] Compound 3o: 39 mg, 93% yield, light yellow solid, melting point 135.4–137.1°C; HPLC (Dacelido chiral column OD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =6.69min(major),t R =9.27min(minor); enantiomer ratio er=93:7, specific rotation [α] D 20 =+357.333 (c=0.15, ethyl acetate). 1H NMR(600MHz,Chloroform-d)δ(ppm):8.07(d,J=8.4Hz,1H),7.95(d,J=7.8Hz,1H),7.6 5(d,J=9.0Hz,1H),7.62(d,J=8.4Hz,1H),7.53–7.50(m,1H),7.41–7.38(m,1H),7.35– 7.30(m,6H),7.27–7.26(m,2H),7.23–7.20(m,3H),7.07–7.05(m,2H),6.90(s,1H),6. 85–6.84(m,2H),3.84(s,2H),3.59–3.54(m,1H),3.46–3.41(m,1H),2.85–2.76(m,2H). 13 C NMR(150MHz,Chloroform-d)δ(ppm):140.8,140.1,137.4,137.2,134.9,133.0,132.7,132.2,131.3,130.4,129.5,128.7,128.6,12 8.4,128.34,128.31,128.27,127.6,127.6,127.5,127.4,127.3,126.4,125.5,125.4,72.4,67.6,44.7.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 28 H 28 N2NaO3 + 547.1993; Found 547.1995.

[0072] Compound 3p: 47 mg, 84% yield, light yellow solid, melting point 104.6–107.5°C; HPLC (Dacelid chiral column IC-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =12.14min(major),t R =13.48min(minor); enantiomeric ratio er=97:3, specific rotation [α] D 20 =+157.467 (c=0.15, ethyl acetate). 1HNMR(600MHz,Chloroform-d)δ(ppm):8.00(d,J=8.4Hz,1H),7.88–7.87(m,1H),7. 74–7.73(m,1H),7.58(d,J=8.4Hz,1H),7.50–7.47(m,2H),7.32–7.30(m,3H),7.27 –7.25(m,3H),7.20–7.18(m,2H),6.88–6.86(m,3H),4.00–3.95(m,1H),3.19(dd,J =9.6,7.2Hz,1H),3.05(dd,J=16.8,7.8Hz,2H),2.90(t,J=8.4Hz,1H),1.09(s,9H). 13 C NMR(150MHz,Chloroform-d)δ(ppm):155.1,140.7,140.3,137.1,134.2,132.6,132.5,131.6,131.11,131.08,128.82,128.8,12 8.71,128.68,128.65,128.2,127.6,127.3,126.7,125.0,124.9,106.7,79.9,55.3,54.7,47.0,28.1.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 34 H 31 N3NaO4 + 568.2207; Found 568.2209.

[0073] Compound 3q: 53 mg, 87% yield, light yellow solid, melting point 115.1–117.4°C; HPLC (Dacelido chiral column IC-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =12.14min(major),t R =7.01min(minor); enantiomer ratio er=95:5, specific rotation [α] D 20 =+387.412 (c=0.17, ethyl acetate). 1HNMR(600MHz,Chloroform-d)δ(ppm):8.06(d,J=8.4Hz,1H),7.94(d,J=7.8Hz,1H),7.67–7.65(m,2H),7.55–7.48(m,2H),7.38–7.31(m,6H),7.29–7.26 (m,2H),7.13–7.12(m,2H),6.90(s,1H),3.56–3.52(m,1H),3.46–3.39(m,3H ),3.16–3.08(m,2H),2.90–2.77(m,4H),2.34(t,J=6.6Hz,2H),1.40(s,9H). 13 C NMR(150MHz,Chloroform-d)δ(ppm):170.7,140.8,140.1,137.1,134.8,133.0,132.7,132.0,131.3,130.4,129.5,128.7,128.6,128.5,1 28.4,128.3,127.7,127.5,127.4,126.4,125.5,125.3,105.9,80.5,69.8,69.7,68.9,66.7,44.5,36.1,28.1.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 37 H 38 N2NaO6 + 629.2623; Found 629.2629.

[0074] Compound 3r: 37 mg, 85% yield, light yellow solid, melting point 134.8–136.2°C; HPLC (Dacelido chiral column AD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =4.80min(major),t R =5.38min(minor); enantiomer ratio er=95:5, specific rotation [α] D 20 =+63.333 (c=0.18 ethyl acetate). 1H NMR(600MHz,Chloroform-d)δ(ppm):8.09(d,J=8.4Hz,1H),7.96(d,J=7.8Hz,1H),7.66(d,J=8.4Hz,1H),7.58(d,J=8.4Hz,1H),7.55– 7.53(m,1H),7.50–7.47(m,1H),7.43–7.39(m,3H),7.36–7.34(m,2H),7.31–7.28(m,5H),4.11(d,J=2.4Hz,2H),1.84(t,J=2.4Hz,1H). 13 CNMR(150MHz,Chloroform-d3)δ(ppm):140.8,140.6,137.0,134.3,132.9,132.7,132.2,130.7,130.6,129.3,128.8,1 28.7,128.67,128.3,128.28,127.8,127.5,127.4,126.4,125.5,124.8,105.8,73.9,35.1.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 29 H 20 N2NaO2 + 451.1417; Found 451.1422.

[0075] Compound 3s: 50 mg, 74% yield, light yellow solid, melting point 70.7–72.3°C; HPLC (Dacelido chiral column AD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =16.95min(major),t R =13.09min(minor); enantiomer ratio er=93:7, specific rotation [α] D 20 =+473.846 (c=0.13 ethyl acetate). 1H NMR(600MHz,Chloroform-d)δ(ppm):8.05(d,J=8.4Hz,1H),7.94–7.92(m,1H),7.65(d,J=8.4Hz,1H) ,7.60–7.59(m,1H),7.53–7.48(m,2H),7.38–7.30(m,11H),7.27(d,J=2.4Hz,2H),7.06–7.05(m,2H) ,6.89(s,1H),5.05(s,2H),4.90(d,J=8.4Hz,1H),3.97(q,J=7.8Hz,1H),3.62(s,3H),3.31–3.26(m, 1H),3.22–3.17(m,1H),1.14–1.08(m,1H),0.97–0.87(m,1H),0.85–0.76(m,2H),0.68–0.52(m,2H). 13 C NMR(150MHz,Chloroform-d)δ(ppm):172.4,155.6,140.8,140.3,137.1,136 .1,134.3,132.9,132.7,131.7,131.4,130.4,129.2,128.7,128.7,128.6,12 8.5,128.43,128.36,128.3,128.2,127.7,127.6,127.4,126.5,125.5,125. 1,105.9,67.0,53.3,52.3,44.8,31.7,29.3,21.9.HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 41 H 37 N3O6 + 668.2756; Found 668.2754.

[0076] Compound 3t: 50 mg, 54% yield, light yellow solid, melting point 84.4–86.5°C; HPLC (Dacelid chiral column OD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =17.99min(major),t R =21.98min(minor); enantiomer ratio er=93:7, specific rotation [α] D 20 =+497.600 (c=0.10 ethyl acetate). 1H NMR(600MHz,Chloroform-d)δ(ppm):8.05(d,J=8.4Hz,1H),7.95–7.93(m,1H),7.65(t,J=8.4Hz,1H),7.58(d,J =8.4Hz,1H),7.56–7.49(m,2H),7.36–7.30(m,6H),7.27–7.25(m,3H),7.11(t,J=7.8Hz,2H),7.03–7302(m,2H), 6.88(s,1H),6.84–6.79(m,2H),6.58(d,J=7.8Hz,2H),4.24–4.21(m,1H),3.73(d,J=3.6Hz,2H),3.57(s,3H),3. 25–3.20(m,1H),3.18–3.12(m,1H),1.11–1.05(m,1H),0.95–0.84(m,2H),0.78–0.71(m,2H),0.58–0.46(m,2H). 13 C NMR(150MHz,Chloroform-d)δ(ppm):172.0,169.7,140.8,140.3,137.1,13 4.3,132.9,132.7,131.8,131.4,130.3,129.4,129.2,128.73,128.68,128. 51,128.46,128.4,127.7,127.6,127.4,126.4,125.4,125.0,120.1,114.0 ,106.0,52.3,51.4,49.1,44.8,31.1,29.3,21.9.HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 41 H 39 N4O5 + 667.2915; Found 667.2916.

[0077] Compound 3u: 47 mg, 88% yield, light yellow solid, melting point 85.9–87.5°C; HPLC (Dacelid chiral column OD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =34.40min(major),t R =30.47min (minor); enantiomer ratio er = 98:2, specific rotation [α] D 20 =+154.667 (c=0.17, ethyl acetate). 1H NMR(600MHz,Chloroform-d)δ(ppm):8.02(d,J=8.4Hz,1H),7.92–7.90(m,1H),7.76(t,J=8.4Hz,2 H),7.65–7.62(m,2H),7.55–7.51(m,4H),7.40–7.26(m,12H),7.05(dd,J=7.8,2.4Hz,2H),6.88(s, 1H),5.92(s,1H),4.85(d,J=8.4Hz,1H),4.31–4.35(m,2H),4.16(t,J=6.6Hz,1H),3.79(s,2H),3.6 9–3.67(m,1H),3.32–3.27(m,1H),3.22–3.17(m,1H),1.46(s,9H),0.86–0.80(m,4H),0.61(s,2H). 13 C NMR(150MHz,Chloroform-d)δ(ppm):171.0,168.5,155.9,143.7,143.7,141.4,140.8,140.3 ,137.1,134.2,132.9,132.7,131.8,131.4,130.3,129.2,128.8,128.7,128.5,128.41,128.3 7,127.79,127.77,127.7,127.4,127.11,127.07,126.5,125.6,125.2,125.0,124.9,120.1, 106.0,82.5,66.8,54.3,47.2,44.8,41.9,29.7,29.6,28.1,22.1.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 53 H 50 N4O7 + 877.3572; Found 877.3575.

[0078] Example 2

[0079] In this example, 3 in Example 1 is defined as 3a. The reaction process is consistent with that in Example 1. The reaction is investigated with different additives, different chiral ligands, different combinations of copper sources and additives, and different solvents and temperatures. Multiple groups of experiments are set up. After purification by silica gel column, the yield and enantiomeric ratio of the experimental product 3a corresponding to each group of chiral ligands are shown in Table 1:

[0080] Table 1 Yields and enantiomeric ratios of different experimental groups

[0081]

[0082]

[0083]

[0084] Among them, C1 to C12 in Table 1 are as follows:

[0085]

[0086] D1 to D10 in Table 1 are as follows:

[0087]

[0088] The results of this example show that the reaction conditions of the present invention are relatively wide and have excellent reaction results under specific conditions.

[0089] Example 3

[0090] This example is limited to substrate 1a, and the reactions of various aromatic substituted primary amines with substrate 1a are studied. The specific reaction formula is shown in Formula 4:

[0091]

[0092] Reaction conditions: 1 (0.1 mmol), 2 (0.12 mmol), Cu(OTf)2 (10 mol%), chiral ligand L21 (12 mol%), and DABCO (1.2 equivalents) were dissolved in 1 mL of 1,2-dichloroethane and reacted at -35°C for 48 hours. Product 4 was purified by silica gel column chromatography. The isolated yield (yield) of the product was calculated; the enantiomeric ratio (er) was determined by chiral high-performance liquid chromatography (HPLC). The molar amounts of Cu(OTf)2 and chiral ligand L21 were 10 mol% and 12 mol%, respectively, of 1 mol.

[0093] Referring to the above reaction conditions, compounds 4a-4t were prepared by using different aryl-substituted primary amines. The structures, yields, and enantiomeric ratios of compounds 4a-4t are as follows:

[0094]

[0095] The relevant spectral data of compounds 4a to 4t are as follows:

[0096] Compound 4a: 45 mg, 92% yield, light yellow solid, melting point 228.7–230.2°C; HPLC (Dacelid chiral column IC-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R=7.66min(major),t R =9.07min(minor); enantiomer ratio er=97:3, specific rotation [α] D 20 =+448.00 (c=0.16, ethyl acetate). 1 H NMR(600MHz,Chloroform-d)δ(ppm):7.94–7.92(m,2H),7.-7.77(m,1H),7.59–7.55(m,2H),7.37(d,J=8.4Hz,1H),7.23 –7.21(m,3H),7.19(s,1H),7.18–7.14(m,3H),6.96–6.94(m,2H),6.92–6.89(m,2H),6.51–6.49(m,2H),5.63(brs,2H). 13 C NMR(150MHz,Chloroform-d)δ(ppm):161.7(d,J CF =247.5Hz)140.4,140.2,138.3,134.5,133.7,132.9,132.3,132.1(d,J CF =3.2Hz),130.6,130.3,129.2,128.7,128.6,128.3,128.1,127.81,127.79,127.6,127.4,126.3,125.0,124.9(d,J CF =11.3Hz),115.1(d,J CF =22.8Hz),105.8. 19 F NMR(564MHz,Chloroform-d)δ(ppm):-112.44–-112.48(m,1F).HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 32 H 21 FN2NaO2 + 507.1480; Found 507.1486.

[0097] Compound 4b: 45 mg, 89% yield, light yellow solid, melting point 215.3–217.4°C; HPLC (Dacelid chiral column IC-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =7.63min(major),t R=8.95min (minor); enantiomer ratio er = 97:3, specific rotation [α] D 20 =+328.400 (c=0.10, ethyl acetate). 1 H NMR(600MHz,Chloroform-d)δ(ppm):7.93(d,J=9.0Hz,2H),7.78–7.797(m,1H),7.60–7.55(m,2H),7.37(d,J=8.4Hz,1H),7. 22–7.20(m,3H),7.18(s,1H),7.18–7.15(m,3H),6.96–6.94(m,2H),6.90–6.88(m,2H),6.78(d,J=8.4Hz,2H),5.96(brs,2H). 13 C NMR(150MHz,Chloroform-d)δ(ppm):140.4,140.3,138.4,134.6,134.4,133.9,133.6,132.8,132.3,130.5,130.3,1 29.2,128.7,128.6,128.4,128.3,128.1,127.9127.7,127.4,126.3,125.0,124.8,106.0.HRMS(ESI–TOF)m / z:[M+Na] + Calcd for C 32 H 21 ClN2NaO2 + 523.1184; Found 523.1189.

[0098] Compound 4c: 49 mg, 88% yield, light yellow solid, melting point 99.3–101.5°C; HPLC (Dacelid chiral column IC-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =7.82min(major),t R =9.19min(minor); enantiomer ratio er=98:2, specific rotation [α] D 20 =+541.500 (c=0.12, ethyl acetate). 1H NMR(600MHz,Chloroform-d)δ(ppm):7.94–7.93(m,2H),7.78–7.77(m,1H),7.60–7.55(m,2H),7.37(d,J =9.0Hz,1H),7.22–7.20(m,3H),7.19–7.15(m,4H),6.96–6.92(m,4H),6.89–6.87(m,2H),5.90(brs,2H). 13 C NMR(150MHz,Chloroform-d)δ(ppm):140.4,140.3,138.4,135.1,134.4,133.6,132.7,132.3,131.3,130.5,130.4,12 9.2,128.7,128.6,128.4,128.1,127.9,127.7,127.4,126.3,124.9,124.7,122.0,106.0.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 32 H 21 BrN2NaO2 + 567.0679; Found 567.0680.

[0099] Compound 4d: 37 mg, 69% yield, light yellow solid, melting point 103.5–105.1°C; HPLC (Dacelid chiral column OD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =6.51min(major),t R =7.90min(minor); enantiomer ratio er=96:4, specific rotation [α] D 20 =+222.000 (c=0.15, ethyl acetate). 1 H NMR(600MHz,Chloroform-d)δ(ppm):7.96–7.94(m,2H),7.83–7.81(m,1H),7.62–7.57(m,2H),7.35(d,J=8 .4Hz,1H),7.23–7.15(m,7H),7.06(d,J=8.4Hz,2H),6.95–6.94(m,2H),6.80–6.79(m,2H),6.15(brs,2H). 13C NMR(150MHz,Chloroform-d)δ(ppm):140.2,139.1,138.6,134.4,133.6,132.7,132.3,130.6,130.3,129.8(q,J CF =32.7Hz),129.0,128.68,128.66,128.4,128.1,128.01,128.99,127.6,127.4,126.4,125.2(q,J CF =3.45Hz),124.9,124.5,123.4(q,J CF =270.9Hz),106.3. 19 F NMR(564MHz,Chloroform-d)δ(ppm):-62.7(s,3F).HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 33 H 21 F3N2NaO2 + 557.1448; Found 557.1453.

[0100] Compound 4e: 41 mg, 84% yield, light yellow solid, melting point 92.6–95.2°C; HPLC (Dacelid chiral column IC-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =8.29min(major),t R =9.39min(minor); enantiomer ratio er=95:5, specific rotation [α] D 20 =+547.500 (c=0.12, ethyl acetate). 1 H NMR (600MHz, Chloroform-d) δ (ppm): 7.83 (s, 2H), 7.70 (d, J = 6.6 Hz, 1H), 7.48 (s, 2H), 7.27 (d, J = 8. 4Hz,1H),7.19–7.05(m,7H),6.89–6.83(m,4H),6.52(d,J=7.2Hz,2H),5.87(brs,2H),2.06(s,3H). 13CNMR(150MHz,Chloroform-d)δ(ppm):140.6,140.3,138.1,137.9,134.5,133.8,133.5,133.0,132.2,130.9,123.0,129.2,1 28.7,128.6,128.4,128.1,127.9,127.7,127.6,127.5,127.2,126.1,125.3,125.2,105.6,21.0.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 33 H 24 N2NaO2 + 503.1730; Found 503.1735.

[0101] Compound 4f: 41 mg, 77% yield, light yellow solid, melting point 134.3–138.1°C; HPLC (Dacelido chiral column IC-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =4.91min(major),t R =8.67min(minor); enantiomer ratio er=93:7, specific rotation [α] D 20 =+572.909 (c=0.11, ethyl acetate). 1 H NMR(600MHz,Chloroform–d)δ(ppm):7.94–7.90(m,2H),7.80–7.78(m,1H),7.58–7.54(m,2H),7.33(d,J=8.4Hz,1H ),7.26–7.11(m,7H),6.98–6.96(m,2H),6.81(d,J=7.2Hz,2H),6.78(d,J=8.4Hz,2H),5,86(brs,2H),1.16(s,9H). 13 C NMR(150MHz,Chloroform-d)δ(ppm):151.0,140.6,140.2,138.1,134.4,133.8,133.4,133.0,132.3,131.0,130.0,129.1,1 28.5,128.4,128.1,127.9,127.6,127.5,127.1,126.1,125.3,125.2,124.9,105.7,34.5,31.1.HRMS(ESI-TOF)m / z:[M+Na] +Calcd for C 36 H 30 N2NaO2 + 545.2200; Found 545.2202.

[0102] Compound 4g: 41 mg, 80% yield, light yellow solid, melting point 97.8–100.9°C; HPLC (Dacelid chiral column OD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =6.52min(major),t R =9.44min(minor); enantiomer ratio er=94:6, specific rotation [α] D 20 =+492.923 (c=0.13, ethyl acetate). 1 H NMR(600MHz,Chloroform-d)δ(ppm):8.01–7.98(m,2H),7.86–7.85(m,1H),7.67–7.62(m,2H),7.45(d,J=9.0Hz,1H),7.32 –7.30(m,3H),7.26(s,1H),7.25–7.21(m,3H),7.07–7.01(m,4H)6.40(dd,J=7.8,1.8Hz,2H),5.79(brs,2H),3.71(s,3H). 13 C NMR(150MHz,Chloroform-d)δ(ppm):158.9,140.6,140.3,138.0,134.6,133.7,133.1,132.3,130.9,130.0,129.3,129.0,1 28.6,128.4,128.2,128.0,127.7,127.6,127.5,127.2,126.2,125.3,125.2,113.2,105.5,55.2.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 33 H 24 N2NaO3 + 519.1680; Found 519.1684.

[0103] Compound 4h: 36 mg, 73% yield, light yellow solid, melting point 127.1–130.5°C; HPLC (Dacelid chiral column OD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R=16.25min(major),t R =12.23min(minor); enantiomer ratio er=90:10, specific rotation [α] D 20 =+318.667 (c=0.15, ethyl acetate). 1 H NMR(600MHz,Chloroform-d)δ(ppm):7.97–7.95(m,2H),7.82–7.81(m,1H),7.62–7.58(m,2H),7.36(d,J=8 .4Hz,1H),7.34–7.16(m,6H),7.08(d,J=9.0Hz,2H),6.93–6.91(m,2H),6.81–6.80(m,2H),6.12(brs,3H). 13 C NMR(150MHz,Chloroform-d)δ(ppm):140.2,1401,139.9,138.8,134.4,133.5,132.5,132.0,130.7,130.1,129.0,128. 74,128.7,128.5,128.2,128.1,127.54,127.52,126.5,124.8,124.2,117.7,111.7,106.5.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 33 H 21 N3NaO2 + 514.1524; Found 514.1524.

[0104] Compound 4i: 41 mg, 78% yield, light yellow solid, melting point 90.5–92.6°C; HPLC (Dacelid chiral column OD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =8.61min(major),t R =9.71min (minor); enantiomer ratio er = 97:3, specific rotation [α] D 20 =+483.333 (c=0.12, ethyl acetate). 1H NMR(600MHz,Chloroform-d)δ(ppm):7.94–7.91(m,2H),7.82–7.80(m,1H),7.61–7.58(m,2H),7.48(d,J=9.0Hz,2H),7.33 (d,J=8.4Hz,1H),7.23–7.18(m,4H),7.17–7.12(m,3H),6.94–6.92(m,2H),6.84–6.82(m,2H),6.13(brs,2H),3.82(s,3H). 13 C NMR(150MHz,Chloroform-d)δ(ppm):166.0,140.34140.26,140.0,138.5,134.4,133.6,132.7,132.3,130.42,130.39,129.43, 129.41,129.1,128.64,128.6,128.4,128.1,127.9,127.6,127.4,126.4,125.0,124.7,106.2,52.3.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 34 H 24 N2NaO4 + 547.1629; Found 547.1634.

[0105] Compound 4j: 41 mg, 80% yield, light yellow solid, melting point 95.1–97.2°C; HPLC (Dacelid chiral column OD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =6.28min(major),t R =8.12min (minor); enantiomer ratio er = 92:8, specific rotation [α] D 20 =+414.500 (c=0.12, ethyl acetate). 1H NMR(600MHz,Chloroform-d)δ(ppm):7.93–7.92(m,2H),7.76(d,J=7.8Hz,1H),7.60–7.55(m,2H),7.37(d,J=8.4Hz,1H),7.26–7.25(m, 3H),7.19–7.15(m,4H),7.02–7.01(m,1H),6.97–6.96(m,2H),6.91–6.89(m,2H),6.74(t,J=7.8Hz,1H),6.18(brs,1H),5.62(brs,1H). 13 CNMR(150MHz,Chloroform-d)δ(ppm):140.3,138.4,137.1,134.4,133.6,132.9,132.3,130.4,130.3,129.0,129.0,12 8.58,128.56,128.4,128.3,128.2,127.9,127.8,127.6,127.4,126.3,124.9,124.8,105.9.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 32 H 21 ClN2NaO2 + 523.1184; Found 523.1188.

[0106] Compound 4k: 42 mg, 77% yield, light yellow solid, melting point 76.5–78.8°C; HPLC (Dacelid chiral column OD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =5.93min(major),t R =7.34min(minor); enantiomer ratio er=93:7, specific rotation [α] D 20 =+163.091 (c=0.11, ethyl acetate). 1 H NMR(600MHz,Chloroform-d)δ(ppm):7.95–7.92(m,2H),7.81(d,J=7.8Hz,1H),7.62–7.56(m,2H),7.33(d,J=8.4Hz, 1H),7.28(d,J=7.8Hz,1H),7.26–7.14(m,7H),6.95–6.92(m,3H),6.83–6.82(m,2H),6.42(brs,1H),6.08(brs,1H). 13C NMR(150MHz,Chloroform-d)δ(ppm):140.4,140.2,138.5,136.5,134.5,133.6,132.7,132.3,130.7,130.6(q,J CF =27.2Hz),130.4,130.23,130.20,128.9,128.8,128.7,128.6,128.4,128.3,128. 2,128.1,128.0,127.49,127.45,126.4,124.9,124.63,124.61,124.59,122.8(q,J CF =270.9Hz),106.0. 19 FNMR(564MHz,Chloroform-d)δ(ppm):-163.2(s,3F).HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 33 H 21 F3N2NaO2 + 557.1448; Found 557.1453.

[0107] Compound 41: 38 mg, 75% yield, light yellow solid, melting point 85.7–88.2°C; HPLC (Dacelid chiral column OD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =5.34min(major),t R =7.33min (minor); enantiomer ratio er = 88:12, specific rotation [α] D 20 =+227.385 (c=0.13, ethyl acetate). 1 H NMR(600MHz,Chloroform-d)δ(ppm):7.91–7.88(m,2H),7.77(d,J=8.4Hz,1H),7.58–7.53(m,2H),7.34(d,J=8.4Hz,1H),7.23–7.22(m,3H),7.19(s,1 H),7.15–7.11(m,3H),6.98–6.96(m,2H),6.91–6.89(m,2H),6.82(d,J=7.2 Hz,1H),6.69(t,J=7.8Hz,1H),6.20(brs,1H),5.52(brs,1H),1.88(s,3H). 13C NMR(150MHz,Chloroform-d)δ(ppm):140.6,140.2,138.1,138.0,136.0,134.4,133.8,133.0,132.2,130.9,130.6,130.0,129.21,129.18,1 28.7,128.5,128.4,128.1,128.0,127.9,127.8,127.61,127.59,127.5,127.1,126.1,125.3,125.2,105.6,20.9.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 33 H 24 N2NaO2 + 503.1730; Found 503.1727.

[0108] Compound 4m: 37 mg, 74% yield, light yellow solid, melting point 85.4–88.6°C; HPLC (Dacelid chiral column OD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =6.02min(major),t R =7.94min(minor); enantiomer ratio er=91:9, specific rotation [α] D 20 =+144.909 (c=0.22, ethyl acetate). 1 H NMR(600MHz,Chloroform-d)δ(ppm):7.91(t,J=6.6Hz,2H),7.82(d,J=7.8Hz,1H),7.59–7.53(m,2H),7.35(d,J=7.8Hz,1H),7.21–7 .14(m,8H),6.99(d,J=7.2Hz,2H),6.88(d,J=6.6Hz,1H),6.70(t,J=7.8Hz,1H),6.56(d,J=7.8Hz,1H),5.69(brs,2H),3.08(s,3H). 13CNMR(150MHz,Chloroform-d)δ(ppm):158.9,140.5,140.4,138.2,136.9,134.4,133.9,132.9,132.3,130.8,130.0,129.2,128.7, 128.53,128.46,128.2,127.9,127.74,127.69,127.65,127.2,126.2,125.3,125.2,115.1,105.6,54.8.HRMS(ESI-TOF)m / z:[M+Na] + Calcdfor C 33 H 24 N2NaO3 + 519.1680; Found 519.1683.

[0109] Compound 4n: 39 mg, 82% yield, light yellow solid, melting point 81.6–83.3°C; HPLC (Dacelid chiral column OD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =10.51min(major),t R =13.75min (minor); enantiomeric ratio er = 91:9, specific rotation [α] D 20 =+293.538 (c=0.13 ethyl acetate). 1 H NMR(600MHz,Chloroform-d)δ(ppm):8.18(d,J=4.2Hz,1H),7.86(d,J=8.4Hz,2H),7.73(d,J=7.8Hz,1H),7.54–7.48(m,2H) ,7.27(d,J=8.4Hz,1H),7.18–7.07(m,8H),6.87–6.85(m,2H),6.77-6.76(m,2H),6.70(dd,J=8.4,4.8Hz,1H),6.30(s,1H). 13 C NMR(150MHz,Chloroform-d)δ(ppm):148.5,140.3,140.2,138.7,134.6,133.6,133.0,132.7,132.4,130.7,130.0,12 8.9,128.7,128.5,128.3,128.1,128.0,127.6,127.5,126.5,124.8,124.3,122.7,106.2.HRMS(ESI-TOF)m / z:[M+Na]+ Calcd for C 31 H 21 N3NaO2 + 490.1526; Found 490.1531.

[0110] Compound 4o: 41 mg, 80% yield, light yellow solid, melting point 106.5–108.2°C; HPLC (Dacelid chiral column OD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =5.25min(major),t R =17.30min(minor); enantiomeric ratio er=98:2,>20:1dr, specific rotation [α] D 20 =+101.000 (c=0.16 ethyl acetate). 1 HNMR(600MHz,Chloroform-d)δ(ppm):7.81(d,J=8.4Hz,1H),7.78–7.76(m,2H) ,7.72–7.70(m,1H),7.44–7.39(m,3H),7.32–7.28(m,3H),7.21–7.19(m,3H),7. 07–7.00(m,4H),6.91–6.89(m,2H),6.78(dd,J=7.8,1.2Hz,1H),5.64(dd,J=7. 8,1.2Hz,1H),2.41–2.36(m,1H),0.44(d,J=7.2Hz,3H),-0.17(d,J=6.6Hz,3H). 13 C NMR(150MHz,Chloroform-d)δ(ppm):146.0,141.4,140.0,138.8,135.7,133.6,133.4,133.2,132.5,130.9,130.3,130.2,129.9,129.3,12 8.4,128.3,128.12,128.06,127.62,127.56,127.5,126.1,126.0,125.2,125.1,124.6,105.5,27.3,23.7,22.9.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 35 H 28 N2NaO2 + 531.2043;Found531.2046.

[0111] Compound 4p: 42 mg, 83% yield, light yellow solid, melting point 236.8–238.3°C; HPLC (Dacelid chiral column OD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =5.79min(major),t R =8.04min(minor); enantiomeric ratio er=98:2,>20:1dr, specific rotation [α] D 20 =+84.041 (c=0.49 ethyl acetate). 1 HNMR (600MHz, Chloroform-d) δ (ppm): 7.79 (d, J = 8.4Hz, 1H), 7.75–7.73 (m, 1H), 7.67–7.64 (m, 1H), 7.39–7.35 (m, 3H), 7.29–7.23 (m, 3H), 7.20–7. 15(m,3H),7.07–7.01(m,3H),6.93(t,J=7.2Hz,1H),6.88–6.86(m,2H),6 .74(d,J=7.2Hz,1H),6.67(t,J=7.2Hz,1H),5.75(d,J1=8.4Hz,J2=1.2Hz 1H),1.95–1.89(m,1H),1.83–1.77(m,1H),0.31(t,J=7.2Hz,3H). 13 CNMR(150MHz,Chloroform-d)δ(ppm):141.3,141.0,140.2,138.7,135.6,134.7,133.4,133.0,132.4,130.9,130.1,129.8,129.6,128.9,1 28.4,128.29,128.27,128.1,128.0,127.8,127.7,127.5,127.0,126.0,125.4,125.3,124.6,105.2,22.9,12.8.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 34 H 26 N2NaO2 + 517.1887; Found 517.1887.

[0112] Compound 4q: 35 mg, 72% yield, light yellow solid, melting point 107.7–109.3°C; HPLC (Dacelid chiral column OD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): tR =6.06min(major),t R =9.31min(minor); enantiomeric ratio er=96:4,>20:1dr, specific rotation [α] D 20 =+229.643 (c=0.28, ethyl acetate). 1 HNMR(600MHz,Chloroform-d)δ(ppm):7.86(d,J=8.4Hz,1H),7.82–7.81(m,1H),7.74(d,J=7.8Hz,1H),7.46–7.42(m,3H),7.35–7.30(m,3H) ,7.26–7.23(m,3H),7.14–7.08(m,3H),6.94–6.92(m,3H),6.71(d,J=7.8Hz,1H),6.67(t,J=7.8Hz,1H),5.80(d,J=7.8Hz,1H),1.59(s,3H). 13 C NMR(150MHz,Chloroform-d)δ(ppm):141.2,140.2,138.7,135.6,135.41,135.36,133.3,132.9,132.3,130.9,130.2,130.1,129.8, 129.7,128.7,128.4,128.3,128.2,128.0,127.7,127.5,126.9,126.1,125.6,125.6,124.6,105.4,18.1.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 33 H 24 N2NaO2 + 503.1730; Found 503.1736.

[0113] Compound 4r: 33 mg, 63% yield, light yellow solid, melting point 90.5–93.6°C; HPLC (Dacelid chiral column OD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =6.49min(major),t R =8.39min(minor); enantiomeric ratio er=96:4,>20:1dr, specific rotation [α] D 20 =+134.182 (c=0.11, ethyl acetate). 1HNMR(600MHz,Chloroform-d)δ(ppm):7.90–7.88(m,2H),7.82-7.81(m,1H),7.48–7.42(m,3H),7.36–7.31(m,3H),7 .24(s,1H),7.22–7.20(m,2H),7.17–7.11(m,3H),7.01–6.93(m,4H),6.76–6.73(m,1H),5.87(dd,J=7.8,1.2Hz,1H). 13 C NMR(150MHz,Chloroform-)δ(ppm):141.2,139.8,138.8,135.7,134.2,133.4,133.1,132.8,132.3,131.2,130.7,130.4,129.9,1 29.7,129.6,128.44,128.43,128.2,127.9,127.7,127.6,126.7,126.5,126.45,126.2,124.3,105.6.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 32 H 21 ClN2NaO2 + 523.1184; Found 523.1186.

[0114] Compound 4s: 45 mg, 87% yield, light yellow solid, melting point 245.4–247.1°C; HPLC (Dacelido chiral column AD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =11.39min(major),t R =15.39min(minor); enantiomeric ratio er=98:2, >20:1dr, specific rotation [α] D 20 =+218.133 (c=0.15, ethyl acetate). 1HNMR(600MHz,DMSO-d6)δ(ppm):8.07–8.05(m,2H),8.01–7.98(m,2H),7.69(t,J=7.2Hz,1H),7.63(t,J=7.2Hz,1H),7.56(s,1H),7.43(d,J =9.0Hz,1H),7.37–7.35(m,3H),7.33–7.31(m,3H),7.20–7.18(m,2H),6.91–6.90(m,2H),6.43(d,J=5.4Hz,1H),6.15(s,1H),1.97(s,6H). 13 C NMR(150MHz,DMSO-d6)δ(ppm):153.4,150.8,149.9,140.2,139.6,138.7,133.9,133.6,132.8,132.0,130.7,130.1,129.2,129.1, 128.91,128.86,128.64,128.59,128.0,127.5,127.0,126.4,125.7,124.3,122.0,112.7,106.7,60.2.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 33 H 26 N4NaO2 + 533.1948; Found 533.1953.

[0115] Compound 4t: 23 mg, 43% yield, light yellow solid, melting point 132.2–134.4°C; HPLC (Dacelido chiral column AD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =15.47min(major),t R =17.23min (minor); enantiomeric ratio er>99:1, >20:1dr, specific rotation [α] D 20 =+166.250 (c=0.08, ethyl acetate). 1HNMR(600MHz,Chloroform-d)δ(ppm):8.01–7.98(m,2H),7.91–7.89(m,1H),7.83( d,J=6.0Hz,1H),7.59–7.55(m,2H),7.49(s,1H),7.43(d,J=9.0Hz,1H),7.36–7.31 (m,3H),7.28–7.21(m,5H),7.00–6.99(m,2H),6.31(s,1H),6.19(d,J=6.0Hz,1H), 2.78(q,J=7.8Hz,2H),2.27(t,J=7.8Hz,2H),1.58–1.54(m,2H),1.15–1.11(m,2H). 13 C NMR(150MHz,Chloroform-d))δ(ppm):149.3,147.9,147.4,138.4,138.1,136.7,133.2,132.7,130.6,130.2,128.9,128.6,127 .5,127.1,127.0,126.8,126.6,126.2,126.0,125.3,124.5,123.4,121.9,108.2,104.3,46.3,22.4.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 35 H 28 N4NaO2 + 559.2105; Found 559.2102.

[0116] Example 4

[0117] This example discusses the reactions of various aromatic substituted primary amines with various substrates 1. The specific reaction formula is shown in Formula 5:

[0118]

[0119] Reaction conditions: 1 (0.1 mmol), 2 (0.12 mmol), Cu(OTf)2 (10 mol%), chiral ligand L21 (12 mol%), and DABCO (1.2 equivalents) were dissolved in 1 mL of 1,2-dichloroethane and reacted at -35°C for 48 hours. Product 3 was purified by silica gel column chromatography. The isolated yield (yield) of the product was calculated; the enantiomeric ratio (er) was determined by chiral high-performance liquid chromatography (HPLC). The molar amounts of Cu(OTf)2 and chiral ligand L21 were 10 mol% and 12 mol%, respectively, of 1 mol.

[0120] Referring to the above reaction conditions, various aryl-substituted primary amines were reacted with various substrates 1 to prepare compounds 5a-5t, respectively. The structures, yields, and enantiomeric ratios of compounds 5a-5t are as follows:

[0121]

[0122] The relevant spectral data of compounds 5a to 5t are as follows:

[0123] Compound 5a 32 mg, 65% yield, light yellow solid, melting point 95.8–97.4°C; HPLC (Dacelid chiral column OD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =5.36min(major),t R =6.54min(minor); enantiomer ratio er=98:2, specific rotation [α] D 20 =+430.143 (c=0.14, ethyl acetate). 1 H NMR(600MHz,Chloroform-d)δ(ppm):7.92–7.89(m,2H),7.78(d,J=7.8Hz,1H),7.59–7.54(m,2H),7.33(d,J=8.4Hz,1H),7.26–7.19 (m,3H),7.16(s,1H),7.03(t,J=7.2Hz,1H),6.94–6.91(m,2H),6.88–6.87(m,2H),6.84–6.80(m,4H),6.34(brs,1H),5.79(brs,1H). 13 C NMR(150MHz,Chloroform-d)δ(ppm):162.1(d,J CF =246.9Hz),140.5,140.3,138.1,135.9,133.7,133.4,132.9,132.2,130.5(d,J CF =8.1Hz),130.1,129.2,128.5,128.2,128.1,128.0,127.8,127.6,127.3,126.9(d,J CF =3.5Hz),126.2,125.1,125.0,115.3(d,J CF =21.6Hz),105.7. 19FNMR(564MHz,Chloroform-d)δ-113.45–-113.50(m,1F).HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 32 H 21 N2NaO2 + 507.1480; Found 507.1482.

[0124] Compound 5b 34 mg, 71% yield, light yellow solid, melting point 136.7–139.5°C; HPLC (Dacelid chiral column OD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =5.27min(major),t R =6.24min(minor); enantiomer ratio er=91:9, specific rotation [α] D 20 =+111.167 (c=0.12, ethyl acetate). 1 H NMR(600MHz,Chloroform-d)δ(ppm):7.92–7.89(m,2H),7.80(d,J=8.4Hz,1H),7.59–7.54(m,,2H),7.33(d,J=8.4Hz,1H),7.23–7.18(m,3H),7.1 6(s,1H),7.02(t,J=7.8Hz,1H),6.93(d,J=7.8Hz,2H),6.89–6.87(m,2H ),6.84(d,J=8.4Hz,2H),6.82–6.79(m,2H),6.08(brs,2H),2.24(s,3H). 13 C NMR (150MHz, Chloroform-d) δ (ppm): 140.5, 140.3, 138.1, 137.5, 136.2, 134.6, 133.8, 132.7, 132.2, 130.0, 129.2, 128.9, 128. 5,128.4,128.1,127.95,127.91,127.88,127.64,127.6,2127.2,126.2,125.3,125.2,105.3,21.1.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 33 H 24 N2NaO2 + 503.1730; Found 503.1734.

[0125] Compound 5c 42 mg, 79% yield, light yellow solid, melting point 200.8–202.5°C; HPLC (Dacelid chiral column OD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =4.71min(major),t R =7.31min(minor); enantiomer ratio er=98:2, specific rotation [α] D 20 =+169.091 (c=0.22, ethyl acetate). 1 H NMR(600MHz,Chloroform-d)δ(ppm):7.92–7.88(m,2H),7.79(d,J=8.4Hz,1H),7.59–7.53(m,2H),7.33(d,J=8.4Hz,1H),7.2 2–7.18(m,4H),7.15–7.13(m,2H),7.03(t,J=7.2Hz,1H),6.89–6.87(m,4H),6.83–6.80(m,2H),6.13(brs,2H),1.22(s,9H). 13 C NMR (150MHz, Chloroform-d) δ (ppm): 150.7, 140.5, 140.3, 138.2, 136.2, 134.5, 133.8, 132.8, 132.2, 130.0, 129.3, 128. 4,128.1,128.0,127.9,127.8,127.6,127.2,126.2,125.3,125.2,125.1,105.4,34.5,31.1.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 36 H 30 N2NaO2 + 545.2200; Found 545.2202.

[0126] Compound 5d 32 mg, 64% yield, light yellow solid, melting point 97.3–99.1°C; HPLC (Dacelid chiral column OD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =5.54min(major),t R =6.81min(minor); enantiomer ratio er=97:3, specific rotation [α] D 20=+418.182 (c=0.11, ethyl acetate). 1 H NMR(600MHz,Chloroform-d)δ(ppm):7.93–7.90(m,2H),7.77–7.76(m,1H),7.60–7.54(m,2H),7.34(d,J=8.4Hz,1H),7.26 –7.19(m,4H),7.11–7.04(m,2H),6.88–6.82(m,5H),6.75–6.73(m,1H),6.65–6.62(m,1H),6.40(brs,1H),5.80(brs,1H). 13 C NMR(150MHz,Chloroform-d)δ(ppm):162.3(d,J CF =244.8Hz),140.4,140.3,138.2,135.8,133.7,133.3,133.02,133.0,132.8(d,J CF =8.4Hz),132.2,130.2,129.7(d,J CF =8.4Hz),129.2,128.5,128.3128.2,128.0,127.7,127.6,127.3,126.2,125.0,124.9,124.2(d,J CF =2.9Hz),115.4(d,J CF =22.8Hz),114.6(d,J CF =20.9Hz),106.3. 19 F NMR(564MHz,Chloroform-d)δ(ppm):-112.63–-112.67(m,1F).HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 32 H 21 FN2NaO2 + 507.1480; Found 507.1484.

[0127] Compound 5e 36 mg, 71% yield, light yellow solid, melting point 103.1–105.3°C; HPLC (Dacelid chiral column OD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =5.80min(major),t R =7.06min(minor); enantiomer ratio er=96:4, specific rotation [α] D20 =+246.636 (c=0.22, ethyl acetate). 1 H NMR(600MHz,Chloroform-d)δ(ppm):7.93–7.90(m,2H),7.77–7.75(m,1H),7.59–7.54(m,2H),7.33(d,J=8.4Hz,1H),7.2– -7.19(m,4H),7.13–7.11(m,1H),7.07–7.00(m,3H),6.87–6.82(m,4H),6.76–6.74(m,1H),6.37(brs,1H),5.80(brs,1H). 13 C NMR(150MHz,Chloroform-d)δ(ppm):140.42,140.36,138.2,135.7,134.1,133.7,133.4,132.8,132.5,132.2,130.2,129.4,129.2,1 28.51,128.49,128.27,128.25,128.0,127.74,127.67,127.6,127.3,126.6,126.2,125.0,124.9,106.3.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 32 H 21 ClN2NaO2 + 523.1184; Found 523.1183.

[0128] Compound 5f43 mg, 87% yield, light yellow solid, melting point 89.5–92.2°C; HPLC (Dacelid chiral column OD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =5.12min(major),t R =6.43min(minor); enantiomer ratio er=97:3, specific rotation [α] D 20 =+259.000 (c=0.10, ethyl acetate). 1H NMR(600MHz,Chloroform-d)δ(ppm):7.92–7.89(m,2H),7.80–7.79(m,1H),7.59–7.54(m,2H),7.33(d,J=9.0Hz,1H),7.24–7.18(m,4H) ,7.04–7.01(m,1H),7.00–6.95(m,2H),6.89–6.87(m,2H),6.84(s,1H),6.81(m,2H),6.67(d,J=7.2Hz,1H),6.07(brs,2H),2.17(s,3H). 13 CNMR(150MHz,Chloroform-d)δ(ppm):140.5,140.3,138.1,137.9,136.2,134.6,133.8,132.8,132.2,130.7,130.0,129.3,129.2,128. 4,128.3,128.0,127.95,127.93,127.89,127.63,127.63,127.2,126.2,125.6,125.2,125.2,105.6,21.27.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 33 H 24 N2NaO2 + 503.1730; Found 503.1725.

[0129] Compound 5g 40 mg, 80% yield, light yellow solid, melting point 134.3–136.1°C; HPLC (Dacelid chiral column OD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =6.51min(major),t R =7.21min(minor); enantiomer ratio er=97:3, specific rotation [α] D 20 =+212.000 (c=0.12, ethyl acetate). 1H NMR (600MHz, Chloroform-d) δ (ppm): 7.91 (t, J = 9.0Hz, 2H), 7.86 (d, J = 7.8Hz, 1H), 7.61–7.54 (m, 2H), 7.35 (d, J = 8.4Hz, 1H), 7.27–7.21 (m, 4H),7.16–7.13(m,2H),7.07–7.04(m,1H),7.03–7.01(m,1H),6.92(t,J=7.8Hz,1H),6.88–6.87(m,2H),6.72–7.00(m,2H),6.05(brs,2H). 13 C NMR(150MHz,Chloroform-d)δ(ppm):140.4,140.2,137.7,135.6,134.8,133.7,132.8,132.3,132.2,131.1,130.3,130.1,123.0,129.5 ,129.2,128.5,128.0,127.73,127.73,127.68,127.56,127.2,127.1,126.3,126.2,125.11,125.06,107.4.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 32 H 21 ClN2NaO2 + 523.1184; Found 523.1187

[0130] Compound 5h 36 mg, 75% yield, light yellow solid, melting point 92.1–95.7° C.; HPLC (Dacelid chiral column OD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =7.14min(major),t R =6.43min(minor); enantiomer ratio er=98:2, specific rotation [α] D 20 =+306.545 (c=0.11, ethyl acetate). 1H NMR (600MHz, Chloroform-d) δ (ppm): 7.85–7.84 (m, 1H), 7.82 (d, J = 8.4Hz, 2H), 7.5 4–7.52(m,1H),7.50–7.48(m,1H),7.25(d,J=8.4Hz,1H),7.18–7.16(m,1H),7.15–7 .12(m,2H),7.04–7.01(m,1H),6.97(d,J=7.8Hz,2H),6.87(t,J=7.2Hz,1H),6.82( t,J=7.2Hz,1H),6.78–6.77(m,3H),6.62–6.60(m,2H),5.88(brs,2H),1.95(s,3H). 13 C NMR(150MHz,Chloroform-d)δ(ppm):140.6,140.2,137.8,137.7,135.7,133.7,133.5,132.3,131.7,131.4,130.6,130.0,129.9,129.3 ,128.6,128.5,127.9,127.73,127.67,127.6,127.5,127.1,127.0,126.2,125.4,125.3,125.1,106.5,20.2.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 33 H 24 N2NaO2 + 503.1730; Found 503.1733.

[0131] Compound 5i 42 mg, 89% yield, light yellow solid, melting point 135.5–138.3°C; HPLC (Dacelido chiral column AD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =5.68min(major),t R =8.49min(minor); enantiomeric ratio er=95:5, specific rotation [α] D 20 =+115.231 (c=0.13, ethyl acetate). 1H NMR(600MHz,Chloroform-d)δ(ppm):7.90–7.87(m,2H),7.72–7.71(m,1H),7.57–7.52(m,2H),7.34(d,J=9.0Hz,1H),7.25–7.22(m, 4H),7.12–7.10(m,2H),6.96–6.95(m,2H),6.90(t,J=6.6Hz,2H),6.75(dd,J=5.4,1.2Hz,1H),6.47(d,J=1.8Hz,1H),5.92(brs,2H). 13 C NMR(150MHz,Chloroform-d)δ(ppm):140.6,140.3,138.0,136.2,133.7,132.8,132.2,131.1,130.1,129.9,129.3,12 8.6,128.4,128.3,128.1,127.7,127.4,127.2,126.2,125.3,125.1,124.9,122.2,104.9.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 30 H 20 N2NaO2S + 495.1138; Found 495.1144.

[0132] Compound 5j 51 mg, 80% yield, light yellow solid, melting point 215.8–217.4°C; HPLC (Dacelido chiral column AD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =11.53min(major),t R =17.60min(minor); enantiomeric ratio er=98:2, specific rotation [α] D 20 =+148.267 (c=0.15 ethyl acetate). 1H NMR(600MHz,Chloroform-d)δ(ppm):7.92–7.88(m,2H),7.79(t,J=7.2Hz,1H),7.59–7.53(m,2H),7.33(dd,J=8.4,3.0Hz,1 H),7.21–7.18(m,3H),7.17(d,J=3.0Hz,1H),6.05–6.98(m,2H),6.89–6.86(m,2H),6.84–6.81(m,2H),6.78–6.73(m,1H),6. 65–6.58(m,1H),5.84(brs,2H),2.77–2.60(m,2H),2.48(dd,J=19.2,8.4Hz,1H),2.30–2.27(m,1H),2.21–2.17(m,1H),2.1 5–2.09(m,1H),2.05–2.00(m,1H),1.97–1.90(m,2H),1.65–1.55(m,2H),1.53–1.42(m,3H),1.40–1.33(m,1H),0.87(s,3H). 13 C NMR(150MHz,Chloroform-d)δ(ppm):220.7,140.5,140.3,139.2,138.1,136.41,13 6.35,136.2,134.4,133.8,132.8,132.2,130.0,129.3,129.0,128.4,128.2,128.0 ,127.94,127.89,127.6,127.2,126.2,125.7,125.2,125.1,125.0,105.3,50.5,47 .9,44.2,37.9,35.8,31.5,29.2,26.3,25.6,21.6,13.8.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 44 H 38 N2NaO3 + 665.2775; Found 665.2778.

[0133] Compound 5k42 mg, 90% yield, light yellow solid, melting point 163.5–165.1°C; HPLC (Dacelid chiral column IE-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =6.40min(major),t R=75.96min(minor); enantiomeric ratio er=99:1,>20:1dr, specific rotation [α] D 20 =+136.667 (c=0.15 ethyl acetate). 1 HNMR(600MHz,Chloroform-d)δ(ppm):δ7.39–7.31(m,5H),7.28–7.25(m,2H),7 .20–7.19(m,2H),7.17–7.14(m,1H),7.13(s,1H),7.12–7.08(m,3H),7.01(dd,J =7.8,1.2Hz,1H),6.97–6.95(m,2H),6.79(td,J=7.8,1.2Hz,1H),5.97(dd,J=7 .8,1.2Hz,1H),2.39–2.35(m,1H),0.88(d,J=6.6Hz,3H),0.54(d,J=6.6Hz,3H). 13 C NMR (150MHz, CDCl3) δ (ppm): 146.0, 141.9, 140.8, 136.3, 135.9, 134.8, 133.8, 132.4, 130.8, 130.2, 129.8, 129.7, 129.2 ,128.36,128.35,128.1,127.8,127.6,127.5,126.8,126.3,125.4,105.3,27.5,23.6,23.5.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 31 H 26 N2NaO2 + 481.1887; Found 481.1890.

[0134] Compound 51 33 mg, 71% yield, light yellow solid, melting point 143.4–145.2°C; HPLC (Dacelido chiral column AD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =10.18min(major),t R =13.67min(minor); enantiomer ratio er=97:3, specific rotation [α] D 20 =+130.833 (c=0.12, ethyl acetate). 1H NMR (600MHz, Chloroform-d) δ (ppm): 7.84–7.83 (m, 2H), 7.72–7.70 (m, 1H), 7.56 (d, J = 9.0Hz, 1H), 7.54–7.48 (m, 2H), 7.29 (s, 1H),7.28(dd,J=4.8,2.4Hz,1H),7.20–7.16(m,3H),7.10–7.08(m,2H),7.01–6.96(m,2H),6.83–6.81(m,3H),6.32(brs,2H). 13 C NMR(150MHz,Chloroform-d)δ(ppm):142.5,138.3,136.3,135.5,133.8,133.2,132.2,132.1,130.8,130.1,128.6,128.3 ,128.26,128.2,128.1,127.7,127.6,127.2,127.0,126.7,126.6,126.3,125.4,124.0,105.9.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 30 H 20 N2NaO2S + 495.1138; Found 495.1140.

[0135] Compound 5m 33 mg, 77% yield, light yellow solid, melting point 107.0–110.2°C; HPLC (Dacelid chiral column OD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =6.07min(major),t R =5.59min(minor); enantiomer ratio er=97:3, specific rotation [α] D 20 =+186.750 (c=0.16, ethyl acetate). 1H NMR (600MHz, Chloroform-d) δ (ppm): 7.83 (d, J = 9.0Hz, 1H), 7.75 (d, J = 7.8Hz, 1H), 7.47 (d, J = 8.4Hz, 1H), 7.41 (t, J = 7.2Hz, 1H), 7.32 (t, J =7.2Hz,1H),7.24(s,1H),7.22–7.21(m,3H),7.15–7.14(m,2H),7.11(d,J=9.0Hz,1H),7.06(t,J=7.2Hz,1H),6.96(brs,4H),3.70(s,3H). 13 C NMR(150MHz,Chloroform-d)δ(ppm):155.7,137.1,136.1,134.6,134.0,131.7,131.1,131.0,128.6,128.5 ,128.3,128.21,128.16,127.6,127.4,123.9,123.8,112.6,112.5,106.0,56.1.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 27 H 20 N2NaO3 + 443.1367; Found 443.1371.

[0136] Compound 5n 37 mg, 87% yield, light yellow solid, melting point 111.3–113.2°C; HPLC (Dacelid chiral column OD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =5.45min(major),t R =9.21min (minor); enantiomeric ratio er>99:1, specific rotation [α] D 20 =+343.867 (c=0.15, ethyl acetate). 1 H NMR(600MHz,Chloroform-d)δ(ppm):7.57(dd,J=7.2,2.4Hz,1H),7.45–7.40(m,2H),7.27–7.24( m,1H),7.20–7.09(m,8H),7.06(s,1H),6.94(d,J=7.2Hz,4H),6.82(d,J=7.8Hz,2H),5.83(s,1H). 13C NMR(150MHz,Chloroform-d))δ(ppm):142.1,140.1,136.1,134.0,135.1,134.0,132.7,130.8,129.84,129.8 1,128.7,128.6,128.2,128.1,128.01,128.00,127.7,127.6,127.1,127.0,105.8.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 28 H 20 N2NaO2 + 439.1417; Found 439.1435.

[0137] Compound 5o 42 mg, 80% yield, light yellow solid, melting point 206.4–208.1°C; HPLC (Dacelid chiral column OD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =4.92min(major),t R =7.04min (minor); enantiomer ratio er = 97.5:2.5, specific rotation [α] D 20 =+50.692 (c=0.26 ethyl acetate). 1 H NMR(600MHz,Chloroform-d)δ(ppm):7.99(d,J=8.4Hz,1H),7.96–7.94(m,1H),7.90–7.88(m,1H) ,7.62–7.57(m,3H),7.49–7.45(m,3H),7.43(s,1H),7.36(dd,J=9.6,2.4Hz,2H),7.19(t,J=8.4H z,1H),7.07(dt,J=15.0,7.8Hz,2H),6.97(d,J=7.8Hz,1H),6.94(s,1H),6.83–6.79(m,2H),5.80 (d,J=7.8Hz,1H),2.60–2.53(m,1H),2.26(s,3H),0.64(d,J=6.6Hz,3H),-0.01(d,J=6.6Hz,3H). 13C NMR (150MHz, CDCl3) δ (ppm): 146.0,141.4,140.0,138.7,137.7,135.8,133 .7,133.32,133.27,132.5,130.8,130.3,130.1,129.9,129.23,129.18,12 8.4,128.31,128.30,128.1,127.9,127.5,127.4,126.1,126.0,125.4,125 .2,125.1,124.6,105.3,27.3,23.7,22.9,21.2.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 36 H 30 N2NaO2 + 545.2200; Found 545.2207.

[0138] Compound 5p 42 mg, 78% yield, light yellow solid, melting point 197.7–199.2°C; HPLC (Dacelid chiral column OD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =5.85min(major),t R =7.69min(minor); enantiomer ratio er=96:4, specific rotation [α] D 20 =+165.500 (c=0.16, ethyl acetate). 1 H NMR(600MHz,Chloroform-d)δ(ppm):8.01(d,J=8.4Hz,1H),7.98–7.95(m,1H),7.90–7.87(m,1H),7 .63–7.58(m,3H),7.50–7.46(m,4H),7.36–7.34(m,2H),7.25–7.22(m,2H),7.14(t,J=7.8Hz,1H),7. 09(t,J=1.8Hz,1H),7.01(dd,J=7.8,1.2Hz,1H),6.93(dt,J=7.8,1.8Hz,1H),6.83(td,J=7.8,1.8Hz ,1H),5.77(dd,J=7.8,1.2Hz,1H),2.59–2.53(m,1H),0.69(d,J=6.6Hz,3H),-0.01(d,J=6.6Hz,3H). 13C NMR (150MHz, CDCl3) δ (ppm): 146.0, 141.3, 140.1, 138.8, 134.1, 134.0, 133.9, 133.3, 133.2, 132.6, 132.5, 130.3, 130.2, 129.9, 129.5, 129.3, 1 28.44,128.38,128.36,128.0,127.63,127.60,127.5,126.3,126.1,12 5.43,124.9,124.2,106.1,27.3,23.8,22.8.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 35 H 27 N2NaO2 + 565.1654;Found565.1654.

[0139] Compound 5q 47.5 mg, 93% yield, light yellow solid, melting point 214.3–216.1°C; HPLC (Dacelid chiral column OD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =5.17min(major),t R =8.97min(minor); enantiomer ratio er=96:4, specific rotation [α] D 20 =+191.250 (c=0.16 ethyl acetate). 1 HNMR(600MHz,Chloroform-d)δ(ppm):7.97(d,J=8.4Hz,1H),7.94–7.93(m,1H),7.88–7.87(m,1H ),7.59–7.56(m,3H),7.47–7.42(m,4H),7.36–7.34(m,2H),7.28(t,J=7.8Hz,1H),7.22(dd,J=5. 4,3.0Hz,1H),7.03(d,J=7.8Hz,1H),7.00(d,J=4.8Hz,1H),6.88(t,J=7.8Hz,1H),6.18(d,J=2.4 Hz,1H),5.77(d,J=8.4Hz,1H),2.57–2.51(m,1H),0.65(d,J=7.2Hz,3H),-0.01(d,J=7.2Hz,3H). 13C NMR (150MHz, CDCl3) δ (ppm): 144.5, 139.3, 138.0, 136.6, 131.9, 131.10, 131.06, 130.5, 129.1, 128.9, 128.3, 128.2, 128.1, 127.8, 126.41, 126.35,126.0,125.6,125.4,125.2,124.3,124.0,123.6,123.2,123.1,122.4,119.3,102.6,25.5,21.9,20.4.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 33 H 26 N2NaO2S + 537.1608; Found 537.1615.

[0140] Compound 5r 49 mg, 87% yield, light yellow solid, melting point 246.1–247.8°C; HPLC (Dacelid chiral column OD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =4.08min(major),t R =5.14min(minor); enantiomer ratio er=97:3, specific rotation [α] D 20 =+120.286 (c=0.14 ethyl acetate). 1 H NMR (600MHz, Chloroform-d) δ (ppm): δ7.96 (d, J = 8.4 Hz, 1H), 7.92 (dd, J = 7.2, 2.4 Hz, 1H),7.88–7.86(m,1H),7.58–7.54(m,3H),7.45–7.40(m,4H),7.34–7.33(m,2H),7.2 1–7.17(m,3H),6.97–6.94(m,3H),6.79(td,J=7.8,1.2Hz,1H),5.79(dd,J=7.8,1.2H z,1H),2.58–2.51(m,1H),1.30(s,9H),0.59(d,J=6.6Hz,3H),-0.01(d,J=6.6Hz,3H). 13C NMR (150MHz, CDCl3) δ (ppm): 150.7, 146.0, 141.4, 140.0, 138.8, 135.6, 133.8, 133.3, 132.5, 130.3, 130.1, 129.9, 129.2, 128.4, 128.3, 128 .0,127.9,127.8,127.5,127.4,126.1,126.0,125.3,125.1,125.0,124.6,105.1,34.5,31.1,27.4,23.7,22.8.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 39 H 36 N2NaO2 + 587.2669; Found 587.2673.

[0141] Compound 5s 39 mg, 70% yield, light yellow solid, melting point 140.6–142.3°C; HPLC (Dacelid chiral column OD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =5.13min(major),t R =5.71min(minor); enantiomeric ratio er=99.5:0.5,>20:1dr, specific rotation [α] D 20 =+136.769 (c=0.13, ethyl acetate). 1 H NMR(600MHz,Chloroform-d)δ(ppm): δ7.92–7.88(m,2H),7.79(d,J=7.8Hz,1H),7.59–7.53(m,2H),7.33(d,J=8.4Hz,1H),7.21–7.1 8(m,3H),7.17(s,1H),7.15–7.12(m,2H),7.03(t,J=7.8Hz,1H),6.89–6.86(m,4H),6.83–6.80(m,2H),6.00(brs,1H),1.22(s,9H). 13C NMR (150MHz, CDCl3) δ (ppm): 150.7, 140.5, 140.3, 138.2, 136.2, 134.4, 133.8, 132.8, 132.2, 130.0, 129.3, 128.4, 12 8.1,127.94,127.92,127.8,127.6,127.2,126.2,125.3,125.2,125.1,105.4,34.5,31.2.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 36 H 29 ClN2NaO2 + 579.1810; Found 579.1809.

[0142] Compound 5t 47 mg, 83% yield, light yellow solid, melting point 271.4–273.2°C; HPLC (Dacelido chiral column AD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =4.23min(major),t R =7.82min(minor); enantiomeric ratio er=99:1,>20:1dr, specific rotation [α] D 20 =+193.077 (c=0.13 ethyl acetate). 1 HNMR (600MHz, Chloroform-d) δ (ppm): δ7.99 (d, J=6.0Hz, 1H), 7.94–7.92 (m, 3H), 7.59–7.51 (m, 4H), 7.44–7.40 (m, 2H), 7.3 3(s,1H),7.28(d,J=8.4Hz,2H),6.98(dd,J=12.6,7.2Hz,4H),6.35(d,J=6.0Hz,1H),6.05(s,1H),2.27(s,6H),1.26(s,9H). 13C NMR (150MHz, CDCl3) δ (ppm): 154.6, 151.5, 140.3, 139.9, 139.0, 133.7, 133.1, 132.6, 132.0, 130.4, 130.4, 129.1, 128.8, 128.5, 128. 1,128.1,127.6,126.7,126.5,125.9,125.8,125.6,125.3,123.8,122.0,111.5,106.4,40.2,34.6,31.1.HRMS(ESI-TOF)m / z:[M+Na] + Calcdfor C 37 H 34 N4NaO2 + 589.2574; Found 589.2580.

[0143] It is not difficult to see from Examples 1, 3, and 4 that the synthesis method provided by the present invention is applicable to a variety of substrates, can construct a variety of novel structural aryl pyrrole compounds, and the obtained aryl pyrrole compounds have high yields and excellent enantioselectivity.

[0144] Example 5

[0145] In this example, compound 4s obtained in Example 3 was used to prepare a chiral PPY-N-oxide catalyst (named OC-5 during the experiment), and the reaction formula is as follows:

[0146]

[0147] The specific reaction process was as follows: 4s (50.0 mg, 0.1 mmol) was dissolved in 5 mL of DCM, followed by the addition of m-CPBA (69.0 mg, 0.4 mmol). The reaction was stirred at room temperature for 12 h, diluted with 20 mL of DCM, washed with 1N NaOH (15 mL), and the organic layer dried over MgSO4, filtered, and the solvent removed under reduced pressure. OC-5 was purified by automated silica gel chromatography using a 0-7% MeOH gradient in DCM to yield a pale yellow solid.

[0148] Compound CO-5 was obtained in a yield of 96% as a white solid with a melting point of 151.9–153.4° C.; HPLC (Dacelid chiral column IB-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =5.74min(major),t R =10.25min (minor); enantiomeric ratio er = 98:2, specific rotation [α] D 20=+88.532 (c=0.20, ethyl acetate). 1 HNMR(600MHz,DMSO-d6)δ(ppm):8.07(d,J=8.4Hz,1H),8.03(d,J=8.4Hz,1H),7.91 (d,J=7.8Hz,1H),7.80(dd,J=7.2Hz,1.8Hz,1H),7.64(t,J=7.2Hz,1H),7.59(t,J=7 .8Hz,1H),7.53(s,1H),7.45(d,J=8.4Hz,1H),7.38–7.24(m,7H),7.18–7.17(m,1H ), 6.90 (d, J = 7.2Hz, 2H), 6.49 (d, J = 7.2Hz, 1H), 5.45 (d, J = 1.8Hz, 1H), 1.84 (s, 6H). 13 C NMR(150MHz,DMSO-d6)δ(ppm):145.5,140.3,139.6,139.3,138.9,133.4,133.2,132.7,132.0,131.0,129.9,129.43,129.36,129.3,129 .0,128.95,128.8,128.7,128.3,128.1,127.8,127.5,127.3,126.5,125.6,124.1,123.6,115.5,107.1,60.2.HRMS(ESI-TOF)m / z:[M+H] + Calcdfor C 33 H 27 N4O3 + 527.2078; Found 527.2090.

[0149] Example 6

[0150] In this example, compound 4s obtained in Example 3 was used as a catalyst for the asymmetric reaction. The reaction formula is as follows:

[0151]

[0152] Reaction conditions: Under argon, substituted enynone 7 (0.1 mmol, 1.0 equiv), oxidized indole MBH carbonate 8 (0.15 mmol, 1.2 equiv), axially chiral DMAP4s (20 mol%, 0.1 equiv), and PPh3AuCl (10 mol%, 0.2 equiv) were dissolved in 2 ml of toluene, heated to 40°C, and reacted for 48 h. The product 9 was purified on a silica gel column and the isolated yield (yield) of the product was calculated. The enantiomeric ratio (er) was determined by chiral high performance liquid chromatography (HPLC) analysis.

[0153] Referring to the above reaction conditions, this example used three R groups to obtain 9a, 9b, and 9c, with the following structures:

[0154]

[0155] The relevant chromatographic data of 9a, 9b, and 9c are as follows:

[0156] Compound 9a, 19.5 mg, 45% yield, light yellow solid, melting point 186–188°C; HPLC (Dacelid chiral column IG-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =30.32min(major),t R =56.45min (minor); enantiomer ratio er = 7:93, specific rotation [α] D 20 =-85.474 (c = 0.12, ethyl acetate). 1 HNMR(600MHz,Chloroform-d)δ(ppm):7.56(s,1H),7.30–7.26(m,1H),7.21–7. 15(m,3H),7.05–7.01(m,3H),6.97(t,J=7.8Hz,1H),6.89(d,J=7.8,1H),6.80( d,J=7.8Hz,1H),5.77–5.74(m,1H),5.55–5.52(m,1H),3.56(s,3H),3.20(s,3H) ),2.17–2.13(m,1H),2.02–1.95(m,1H),1.93–1.87(m,1H),1.53–1.48(m,1H). 13 C NMR(150MHz,Chloroform-d)δ(ppm):206.6,174.1,162.4,149.2,145.1,143.5,134.9,134.2,131.6,128.4,128.3,127 .8,127.1,126.6,126.63,126.55,124.9,121.7,106.9,67.5,63.6,50.7,37.2,25.7,24.0.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 27 H 23 NNaO4 + 448.1520; Found 448.1527.

[0157] Compound 9b, 16 mg, 37% yield, light yellow solid, melting point 193–195°C; HPLC (Dacelid chiral column IG-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =24.72min(major),t R =30.56min (minor); enantiomer ratio er = 8:92, specific rotation [α] D 20 =-65.133 (c = 0.30, ethyl acetate). 1 HNMR(600MHz,Chloroform-d)δ(ppm):7.53(s,1H),7.30–7.27(m,1H),7.03–7.00(m,2H),7.00(s,1H),6.96(dd,J=7.8,1.2Hz,1H),6.90–6.87(m,3 H),6.80(d,J=7.8Hz,1H),5.77–5.75(m,1H),5.59–5.57(m,1H),3.56(s,3 H),3.21(s,3H),2.14–2.10(m,1H),2.00–1.90(m,2H),1.54–1.48(m,1H). 13 C NMR(150MHz,Chloroform-d)δ(ppm):207.4,175.0,163.4,162.4(d,J CF =246.6Hz),149.9,146.3,144.5,135.4,132.1(d,J CF =3.3Hz),131.4,130.6(d,J CF =8.1Hz),129.6,129.4,128.2,126.9,125.9,122.7,114.7(d,J CF =22.7Hz),108.0,68.5,64.6,51.8,38.2,26.8,25.1. 19 F NMR(564MHz,Chloroform-d)δ(ppm):-113.6.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 27 H 22 FNNaO4 + 466.1426; Found 466.1431.

[0158] Compound 9c, 23.0 mg, 52% yield, light yellow solid, melting point 155–157° C.; HPLC (Dacelid chiral column IG-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =25.03min(major),t R =36.55min (minor); enantiomer ratio er = 13:87, specific rotation [α] D 20 =-169.714 (c = 0.14, ethyl acetate). 1 H NMR (600MHz, Chloroform-d) δ (ppm): 7.54 (s, 1H), 7.29–7.26 (m, 1H), 7.02 (t, J = 8.4Hz ,3H),6.98–6.95(m,3H),6.89(dd,J=7.8,1.2Hz,1H),6.80(d,J=7.8Hz,1H),5.81–5.79 (m,1H),5.62–5.59(m,1H),3.56(s,3H),3.21(s,3H),2.58(q,J=7.8Hz,2H),2.19–2.14 (m,1H),2.10–2.03(m,1H),1.98–1.92(m,1H)1.56–1.51(m,1H),1.18(t,J=7.8Hz,3H). 13 CNMR(150MHz,Chloroform-d)δ(ppm):207.1,175.2,163.5,150.6,145.2,144.5,144.0,134.6,133.03,132.95,129.7,12 9.3,129.1,127.9,127.2,126.0,122.7,107.9,68.7,64.8,51.7,38.2,28.6,26.8,25.1,15.4.HRMS(ESI-TOF)m / z:[M+Na] + Calcd for C 29 H 27 NNaO4 + 476.1833; Found 476.1837.

[0159] It is not difficult to see from Examples 5 and 6 that the axially chiral arylpyrrole derivatives prepared by the present invention have obvious advantages in preparing catalysts for asymmetric reactions.

[0160] Finally, it should be noted that the terms "comprises," "comprising," or any other variations thereof are intended to encompass non-exclusive inclusion, such that a process, method, article, or apparatus comprising 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. Although preferred embodiments of the present invention have been described, additional changes and modifications may be made to these embodiments by those skilled in the art once the basic inventive concepts are known. Therefore, the appended claims are intended to be interpreted as including the preferred embodiments and all changes and modifications that fall within the scope of the invention.

[0161] The above-described embodiments merely represent specific implementation methods of the present application. While the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of protection of the present application. It should be noted that a person skilled in the art would be able to make numerous variations and improvements without departing from the technical concept of the present application, and all such variations and improvements fall within the scope of protection of the present application.

Claims

1. A class of axially chiral arylpyrrole derivatives, characterized in that: The structure of the pyrrole derivative is the structure shown in Formula 1 or its stereoisomers: in, R 1 、R 2 、R 3 Each of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted 4-10 membered cycloalkyl, substituted or unsubstituted 4-10 membered heterocycloalkyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl; the substituents of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted 6-10 membered aryl, halogen, -NR 7 R 8 ; R 7 、R 8 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl; the substituents of the alkyl and alkoxy groups are independently selected from C1-C6 alkyl, C1-C6 alkoxy, and halogen; R 4 、R 5 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, halogen, -NR 9 R 10 、-O(CH2) n OR 11 、-OC(O)R 11 ; or, R 4 and R 5 connected to form a substituted or unsubstituted 4- to 10-membered cycloalkyl, a substituted or unsubstituted 4- to 10-membered heterocycloalkyl, a substituted or unsubstituted 6- to 10-membered aryl, or a substituted or unsubstituted 5- to 10-membered heteroaryl; n is an integer from 1 to 6; R 9 、R 10 、R 11 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl; R 6 Selected from -NO2, -COOR 12 , -CN, -CF3; R 12 Selected from hydrogen, substituted or unsubstituted C1-C6 alkyl.

2. The method for preparing an axially chiral arylpyrrole derivative according to claim 1, wherein Its synthesis reaction formula is shown in Formula 2: Wherein, the ligand shown in Formula 2 is a PyBOX ligand.

3. The method for preparing an axially chiral arylpyrrole derivative according to claim 2, wherein: The molar ratio of substrate 1, substrate 2, additive, copper salt and ligand shown in formula 2 is 1:(1-5):(1-5):(0.01-0.1):(0.01-0.2); the molar volume ratio of substrate 1 and solvent is (0.05-0.2) mmol:1 ml.

4. The method for preparing an axially chiral arylpyrrole derivative according to claim 3, wherein: The additive is DABCO, and the molar ratio of the substrate 1, substrate 2, DABCO, copper salt and ligand is 1:1.2:1:0.1:0.12; the molar volume ratio of the substrate 1 and the organic solvent is 0.1 mmol:1 ml.

5. The method for preparing an axially chiral arylpyrrole derivative according to claim 2, wherein: The copper salt shown in Formula 2 is selected from one or more of Cu(CH3CN)4PF6, Cu(OTf)2 and Cu(CH3CN)4BF4.

6. The method for preparing an axially chiral arylpyrrole derivative according to claim 5, wherein: The copper salt is Cu(OTf)2.

7. The method for preparing an axially chiral arylpyrrole derivative according to claim 2, wherein: The solvent shown in Formula 2 is selected from one or more of dichloromethane, 1,2-dichloroethane, chloroform, toluene, acetonitrile, and tetrahydrofuran.

8. The method for preparing an axially chiral arylpyrrole derivative according to claim 2, wherein: The PyBOX ligand is selected from one or more of L1 to L22 shown below:

9. The method for preparing an axially chiral arylpyrrole derivative according to claim 8, wherein: The PyBOX ligand is L21.

10. Use of the axially chiral aryl pyrrole derivative according to claim 1 as a drug development or chiral catalyst or chiral catalyst development intermediate.

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