3-nitro-2-aryl pyrrole rotation-resistant isomer as well as preparation method and application of 3-nitro-2-aryl pyrrole rotation-resistant isomer

Abstract

The invention discloses a 3-nitro-2-aryl pyrrole rotation inhibitor as well as a preparation method and application thereof, and relates to the technical field of organic matter synthesis. The invention provides the 3-nitryl 2-aryl pyrrole rotation inhibitor and a preparation method of the pyrrole rotation inhibitor, the preparation method is excellent in yield and selectivity, and the prepared pyrrole rotation inhibitor has a plurality of reaction sites and can be continuously expanded to obtain a plurality of derivatives, so that the 3-nitryl 2-aryl pyrrole rotation inhibitor is suitable for industrial production. The nitryl-containing pyrrole rotation inhibitor is an excellent intermediate for drug development or catalyst development, a plurality of organic catalysts for catalyzing asymmetric reactions are prepared on the basis of the nitryl-containing pyrrole rotation inhibitor, and the prepared catalysts have excellent catalytic performance.

Description

Technical Field

[0001] The present invention relates to the technical field of organic compound synthesis, and in particular to a class of 3-nitro-2-arylpyrrole atropisomers 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 high yield by precisely controlling the generation rate of the p-quinone methide (p-QM) intermediate (kobs=3.8×10 -3 s -1 ), successfully achieved the stereo divergent 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 class of 3-nitro-2-arylpyrrole atropisomers, which are typical axially chiral arylpyrrole derivatives. The pyrrole atropisomers are prepared by reacting an aryl primary amine and a nitro-substituted enyne as raw materials in the presence of a copper salt, a specific PyBOX ligand, and an additive DABCO. The introduced nitro group increases the reaction sites and further broadens the substrate adaptability.

[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 3-nitro-2-arylpyrrole atropisomers, wherein the structure of the pyrrole atropisomer is as shown in Formula 1 or a stereoisomer thereof:

[0009]

[0010] in,

[0011] R 1 、R 2 、R 3Each 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 6 R 7 ; R 6 、R 7 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;

[0012] R 4 、R 5 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, halogen, -NR 8 R 9 、-O(CH2) n OR 10 、-OC(O)R 10 ; 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 8 、R 9 、R 10 Each is independently selected from hydrogen, and a substituted or unsubstituted C1-C6 alkyl group.

[0013] The second object of the present invention is to provide a method for preparing the pyrrole atropisomer, and the synthesis reaction formula thereof is shown in Formula 2:

[0014]

[0015] Wherein, the ligand represented by Formula 2 is a PyBOX ligand, and the PyBOX ligand is selected from one or more of the structures represented by the following L1 to L22 or their stereoisomers:

[0016]

[0017] The molar ratio of compound 1, compound 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 compound 1 and solvent is (0.05-0.2)mmol:1ml; the copper salt shown in Formula 2 is selected from one or more of Cu(CH3CN)4PF6, Cu(OTf)2 and Cu(CH3CN)4BF4; the solvent shown in Formula 2 is selected from one or more of dichloromethane, 1,2-dichloroethane, chloroform, toluene, acetonitrile and tetrahydrofuran.

[0018] Furthermore, the additive is DABCO, the molar ratio of compound 1, compound 2, DABCO, copper salt and ligand is 1:1.2:1:0.1:0.12; the molar volume ratio of compound 1 and organic solvent is 0.1mmol:1ml; the PyBOX ligand is L21; the copper salt is Cu(OTf)2; and the solvent is 1,2-dichloroethane.

[0019] The third object of the present invention is to provide the application of the pyrrole atropisomer as an intermediate in drug development or catalyst development.

[0020] A fourth object of the present invention is to further provide a hydrogen bonding catalyst prepared using pyrrole atropisomers, including OC-1 and OC-2, wherein the structures of OC-1 and OC-2 are as shown in Formula 3 or their stereoisomers:

[0021]

[0022] Among them, R 11 It is a substituted or unsubstituted 6- to 10-membered aryl group, or a substituted or unsubstituted 5- to 10-membered heteroaryl group.

[0023] The fifth object of the present invention is to further define the preparation method of the hydrogen bonding catalyst. The preparation process of OC-1 and OC-2 is shown in Formula 4:

[0024]

[0025] The sixth object of the present invention is to further limit the application of hydrogen bond catalysts as asymmetric reaction catalysts.

[0026] A seventh object of the present invention is to further define the tertiary amine bifunctional catalyst prepared using pyrrole atropisomers, including OC-3 and OC-4, wherein the structures of OC-3 and OC-4 are as shown in Formula 5 or their stereoisomers:

[0027]

[0028] Among them, R12 、R 13 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, halogen, -NR 8 R 9 、-O(CH2) n OR 10 、-OC(O)R 10 ; or, R 12 and R 13 connected to form a substituted or unsubstituted 3-10 membered cycloalkyl, a substituted or unsubstituted 3-10 membered heterocycloalkyl, a substituted or unsubstituted 6-10 membered aryl, or a substituted or unsubstituted 5-10 membered heteroaryl; n is an integer from 1 to 6; R 8 、R 9 、R 10 Each is independently selected from hydrogen, and a substituted or unsubstituted C1-C6 alkyl group.

[0029] The eighth object of the present invention is to further define the preparation method of the tertiary amine bifunctional catalyst. The preparation process of OC-3 and OC-4 is shown in Formula 6:

[0030]

[0031] A ninth object of the present invention is to further limit the application of tertiary amine bifunctional catalysts as asymmetric reaction catalysts.

[0032] In summary, compared with the prior art, the present invention has the following advantages and beneficial effects:

[0033] 1. The present invention provides a class of 3-nitro-2-arylpyrrole atropisomers. The pyrrole atropisomers have multiple reaction sites and can be further expanded to obtain various derivatives. They are excellent intermediates for drug development or catalyst development.

[0034] 2. The preparation method provided by the present invention has excellent yield and selectivity for the target product.

[0035] 3. The present invention prepares catalysts for multiple asymmetric reactions based on specific 3-nitro-2-arylpyrrole atropisomers, which have excellent catalytic performance. DETAILED DESCRIPTION

[0036] 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.

[0037] 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.

[0038] 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.

[0039] The present application will be described in detail below with reference to specific embodiments and experimental data.

[0040] Example 1

[0041] In this example, a 3-nitro-2-arylpyrrole atropisomer (Compound 3a) was prepared according to the following reaction formula:

[0042]

[0043] Reaction conditions: 1a (0.1 mmol), 2a (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. Purification on a silica gel column afforded 44.5 mg of compound 3a in a 94% yield. 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.

[0044] Compound 3a is a light yellow solid with a melting point of 94.6–96.1°C. Its relevant chromatographic data are as follows:

[0045] HPLC (Dacelido 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).

[0046] 1H 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 C NMR (150MHz, Chloroform-d) δ (ppm): 140.5, 140.3, 138.2, 136.1, 134.5, 133.8, 132.9, 132.2, 130.8, 1 301,129.2,128.6,1285,128.2,128.1,128.0,1279,1277,127.63,127.60,127.2,126.2,125.2.105.7.

[0047] HRMS (ESI-TOF) m / z: [M+Na] + Calcd for C 31 H 28 N2NaO2 + 489.1574; Found 489.1577.

[0048] A large-scale reaction was carried out under standard conditions, increasing the amount of 1a from 0.1 mmol to 1.0 mmol (a ten-fold increase) to obtain 438 mg of the product with a product yield of 84%. The enantiomeric ratio remained at 98:2, indicating that compound 3a prepared according to the specific reaction process of the present invention has a simple reaction process, a relatively high yield and er value, and good results in the scaled-up reaction.

[0049] Example 2

[0050] This example explores the effects of different additives on the reaction. Based on Example 1, only the additive DABCO is replaced with C1 to C12 as shown below, and multiple groups of experiments are set up:

[0051]

[0052] After purification by silica gel column, the yield and enantiomeric ratio of each group of additives corresponding to the experiment are shown in Table 1:

[0053] Table 1 Yield and enantiomeric ratio of different additives in experimental groups

[0054] Experimental group Chiral ligands additive copper salts Reaction time (h) Product yield (%) Enantiomeric ratio 1 L21 C1 <![CDATA[Cu(OTf)2]]> 3 92 74:26 2 L21 C2 <![CDATA[Cu(OTf)2]]> 5 88 50:50 3 L21 C3 <![CDATA[Cu(OTf)2]]> 5 91 74:26 4 L21 C4 <![CDATA[Cu(OTf)2]]> 12 Target not obtained - 5 L21 C5 <![CDATA[Cu(OTf)2]]> 12 Target not obtained - 6 L21 C6 <![CDATA[Cu(OTf)2]]> 12 Target not obtained - 7 L21 C7 <![CDATA[Cu(OTf)2]]> 12 Target not obtained - 8 L21 C8 <![CDATA[Cu(OTf)2]]> 3 89 46:54 9 L21 C9 <![CDATA[Cu(OTf)2]]> 5 76 39:61 10 L21 C10 <![CDATA[Cu(OTf)2]]> 5 91 38:62 11 L21 C11 <![CDATA[Cu(OTf)2]]> 5 81 47:53 12 L21 C12 <![CDATA[Cu(OTf)2]]> 5 84 39:61

[0055] Example 3

[0056] This example explores the effect of different chiral ligands on the reaction. Based on Example 1, only the chiral ligand L21 is replaced with D1 to D10 as shown below, and multiple groups of experiments are set up:

[0057]

[0058] After purification by silica gel column, the yield and enantiomeric ratio of each group of chiral ligands corresponding to the experiment are shown in Table 2:

[0059] Table 2 Yields and enantiomeric ratios of experimental groups corresponding to different chiral ligands

[0060] Experimental group Chiral ligands additive copper salts Product yield (%) Enantiomeric ratio 1 D1 DABCO <![CDATA[Cu(OTf)2]]> 20 52:48 2 D2 DABCO <![CDATA[Cu(OTf)2]]> 17 41:59 3 D3 DABCO <![CDATA[Cu(OTf)2]]> 18 72:28 4 D4 DABCO <![CDATA[Cu(OTf)2]]> 23 35:65 5 D5 DABCO <![CDATA[Cu(OTf)2]]> <10 70:30 6 D6 DABCO <![CDATA[Cu(OTf)2]]> <10 56:44 7 D7 DABCO <![CDATA[Cu(OTf)2]]> Target not obtained - 8 D8 DABCO <![CDATA[Cu(OTf)2]]> <10 34:66 9 D9 DABCO <![CDATA[Cu(OTf)2]]> <10 26:73

[0061] Example 4

[0062] This example explores the effect of different copper sources and additives on the reaction. Based on Example 1, only the copper source was replaced and other additives were added. Multiple groups of experiments were set up. After purification by silica gel column, the yield and enantiomeric ratio of each group of experiments are shown in Table 3:

[0063] Table 3 Yields and enantiomeric ratios of experimental groups with different copper sources and additives

[0064]

[0065]

[0066] Example 5

[0067] This example explores the effects of different solvents and temperatures on the reaction. Based on Example 1, only the solvent and temperature were replaced, and multiple groups of experiments were set up. After purification by silica gel column, the yield and enantiomeric ratio of each group of experiments are shown in Table 4:

[0068] Table 4 Yields and enantiomeric ratios of experimental groups with different copper sources and additives

[0069] Experimental group solvent Reaction temperature Reaction time (h) Product yield (%) Enantiomeric ratio 1 DCM r.t. 3 93 93:7 2 <![CDATA[CHCl3]]> r.t. 6 90 91:9 3 toluene r.t. 8 87 70:30 4 1,4-dioxane r.t. 3 93 78:22 5 THF r.t. 4 82 85:15 6 <![CDATA[CH3CN]]> r.t. 4 90 94:6 7 EA r.t. 3 94 86:14 8 DCE 0 12 86 91.5:8.5 9 DCE -20 16 82 95:5 10 DCE -30 48 94 98:2

[0070] Example 6

[0071] In this example, the compound 3a prepared in Example 1 was further reacted as follows to explore the potential of compound 3a as an intermediate.

[0072] (1) Pyrrole halogenation

[0073]

[0074] NXS (0.12 mmol) was dissolved in 3a (47.0 mg, 0.10 mmol) and DMSO (1.5 mg, 10 mol%) in DCM (2.0 mL). The resulting mixture was stirred at 0°C for 12 h. Subsequently, the solvent was removed under reduced pressure to obtain a colorless oily residue. The product was purified by silica gel column chromatography (PE / EA = 20:1) to afford compound 4.

[0075] ① When X = Cl, compound 4a (47 mg, 94% yield) was obtained as a pale yellow solid with a melting point of 104.4–106.6°C.

[0076] HPLC (Dacelido chiral column AS-H, n-hexane / isopropanol=70:30, 1.0 mL / min, at 254 nm): t R =4.89min(major),t R =6.02min(minor); enantiomer ratio er=99:1, specific rotation [α] D 20 =+234.000 (c=0.15, ethyl acetate).

[0077] 1 H NMR(600MHz,Chloroform-d)δ(ppm):7.92–7.89(m,2H),7.85(d,J=7.8Hz,1H),7.63–7.60(m,1H),7.58–7.55(m,1H),7.32(d,J=8.4Hz, 1H),7.28–7.23(m,4H),7.21–7.16(m,3H),7.04–7.02(m,2H),6.96(t,J=7.2Hz,1H),6.91–6.89(m,2H),6.76–6.73(m,2H),6.00(s,1H).

[0078] 13 C NMR(150MHz,Chloroform-d)δ(ppm):140.4,140.36,135.4,134.5,133.7,132.3,132.2,131.7,130.6,130.3, 129.2,128.5,128.4,128.3,128.09,128.05,128.0,127.98,127.9,127.6,127.4,126.3,125.0,124.6,107.2.

[0079] HRMS (ESI-TOF) m / z: [M+Na] + Calcd for C 32H 21 ClN2NaO2 + 523.1184; Found 523.1193.

[0080] ② When X = Br, compound 4b (54 mg, 98% yield) was obtained as a pale yellow solid with a melting point of 198.8–201.2°C.

[0081] HPLC (Dacelido chiral column OD-H, n-hexane / isopropanol=70:30, 1.0 mL / min, at 254 nm): t R =4.88min(major),t R =5.86min(minor); enantiomer ratio er=99:1, specific rotation [α] D 20 =+160.833 (c=0.12, ethyl acetate).

[0082] 1 H NMR(600MHz,Chloroform-d)δ(ppm):7.83–7.80(m,2H),7.77(d,J=8.4Hz,1H),7.55–7.52(m,1H),7.48(t,J=7.8Hz,1H),7.25(d,J=8.4Hz,1H ),7.21–7.16(m,3H),7.13–7.08(m,3H),6.95(d,J=6.6Hz,2H),6.87(t,J=7.8Hz,1H),6.84–6.82(m,2H),6.65(t,J=7.8Hz,2H),5.84(s,2H).

[0083] 13 C NMR(150MHz,Chloroform-d)δ(ppm):140.4,140.3,135.9,135.6,133.7,133.6,133.0,132.2,130.9,130.3,129 .22,129.16,128.51,128.45,128.1,128.04,127.99,127.92,127.86,127.6,127.4,126.3,125.0,124.7,92.7.

[0084] HRMS (ESI-TOF) m / z: [M+Na] + Calcd for C 32 H 21 BrN2O2 + 567.0679; Found 567.0682.

[0085] (2) Nitro reduction

[0086]

[0087] Prepare a solution of 3a (47.0 mg, 0.1 mmol) stirred in a mixture of 6 mL of ethanol and water. Zinc powder (92.2 mg, 12 equiv.) and acetic acid (0.9 mL, 150 equiv.) were then added. The mixture was heated to 50°C for 12 hours, cooled to room temperature, and filtered through Celite. The filtrate was then concentrated in vacuo, and the residue was redissolved in ethyl acetate (20 mL). The resulting solution was then washed with sodium carbonate (30 mL). The aqueous layer was separated and extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with 20 mL of brine, then dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EtOAc=5:1) to give 5.

[0088] Compound 5 was obtained: 37 mg, 84% yield, light yellow solid, melting point 95.2–97.3°C;

[0089] HPLC (Dacelido chiral column IE-H, n-hexane / isopropanol=70:30, 1.0 mL / min, at 254 nm): t R =5.27min(major),t R =5.00min(minor); enantiomer ratio er=2:98, specific rotation [α] D 20 =+53.625 (c=0.16, ethyl acetate).

[0090] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 7.98–7.95 (m, 2H), 7.93 (d, J = 8.4Hz, 1H), 7.62–7.59 (m,1H),7.57–7.54(m,1H),7.41(d,J=8.4Hz,1H),7.21–7.20(m,3H),7.09(t,J=7.8 Hz,2H),7.03(t,J=7.8Hz,1H),7.00–6.98(m,2H),6.91(t,J=7.8Hz,1H),6.87(d,J= 7.2Hz,2H),6.78(t,J=8.4Hz,2H),6.15(s,1H),6.01(d,J=7.8Hz,2H),3.69(s,2H).

[0091] 13C NMR(150MHz,DMSO-d6)δ(ppm):141.6,141.0,138.8,134.5,134.1,133.6,132.8,132.0,129.5,129.1,128.5 ,128.4,128.3,128.1,128.0,127.8,127.5,127.4,127.3,127.0,126.97,126.4,126.2,126.1,115.5,102.7.

[0092] HRMS (ESI-TOF) m / z: [M+Na] + Calcd for C 32 H 24 N2Na + 459.1832; Found 459.1836.

[0093] (3) Chiral induction of compound 5

[0094]

[0095] To a drying tube was added 5 (44.0 mg, 0.1 mmol), methyl 2-acetyl-4-oxopentanoate (20.8 mg, 0.12 mmol), PA (20 mol%), NaSO (50.0 mg), and 2 ml of DCM. The tube was then sealed with a rubber stopper and stirred at room temperature for 5 h. Upon completion, the reaction mixture was purified by silica gel flash chromatography to yield product 6 as a white solid.

[0096] Compound 6 was obtained: 54 mg, 85% yield, light yellow solid, melting point 172.7–174.2°C;

[0097] HPLC (Dacelido chiral column OD-H, n-hexane / isopropanol=70:30, 1.0 mL / min, at 254 nm): t R =4.96min(major),t R =4.49min(minor); enantiomeric ratio er=98:2, 10:1dr, specific rotation [α] D 20 =+179.538 (c=0.13, ethyl acetate).

[0098] 1H NMR (600MHz, DMSO-d6) δ (ppm): 7.78 (d, J = 8.4Hz, 1H), 7.57 (d, J = 7.8Hz, 1H), 7.32–7.21 (m, 9H), 7.09–7.06 (m, 3H), 7. 01–6.95(m,6H),6.81–6.75(m,3H),6.60–6.57(m,3H),6.45(d,J=8.4Hz,1H),6.05(s,1H),3.68(s,3H),1.42(s,3H).

[0099] 13 C NMR(150MHz,DMSO-d6)δ(ppm):165.0,141.3,140.6,140.4,139.00,134. 4,134.0,133.1,132.9,132.6,131.6,129.8,129.6,129.2,128.9,128.8, 128.6,128.6,128.3,128.0,127.9,127.5,127.5,127.2,127.1,127.0,12 6.7,126.7,125.9,125.0,124.3,122.5,111.4,111.2,109.5,50.9,11.4.

[0100] HRMS (ESI-TOF) m / z: [M+Na] + Calcd for C 45 H 34 N2NaO2 + 657.2513; Found 657.2514.

[0101] (4) Condensation of compound 5 with the pharmacophore

[0102]

[0103] A mixture of TCFH (31.0 mg, 0.11 mmol), NMI (17.4 mg, 0.21 mmol), acid (0.12 mmol, 1.2 equiv.), 5 (44.0 mg, 0.1 mmol), and DCM (10 mL) was stirred at room temperature for 2 hours. The reaction mixture was then filtered through a pad of silica gel and washed with DCM (3 x 10 mL). The organic solution of the crude product was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (PE:EA = 7:1) to afford product 7 as a light yellow solid.

[0104] ① When the pharmacophore is Artesunate, compound 7a was obtained as a pale yellow solid (75 mg, 93% yield) with a melting point of 132.6–134.1°C. Specific rotation [α] D 20 =+179.538 (c=0.13, ethyl acetate).

[0105] 1 H NMR(600MHz, DMSO-d6)δ(ppm):9.18(s,1H),7.98(d,J=8.4Hz,2H),7.82–7.80(m,1H),7.57–7.53(m,2H),7.40(d,J=8.4Hz,1H),7.23–7.18 (m,3H),7.12–7.05(m,3H),6.98–6.94(m,4H),6.989–6.87(m,2H),6.81(t,J=7.8Hz,2H),5.99(brs,1H),5.65(d,J=9.6Hz,1H),5.55(s,1H) ,2.54(q,J=6.6Hz,2H),2.46(t,J=6.6Hz,1H),2.34–2.27(m,2H),2.21–2.15(m,1H),2.01–1.98(m,1H),1.82–1.80(m,1H),1.65–1.62(m,2H ),1.60–1.54(m,1H),1.49–1.40(m,2H),1.36–1.31(m,1H),1.20–1.15(m,1H),0.98–0.94(m,1H),0.89–0.85(m,7H),0.77(d,J=7.2Hz,3H).

[0106] 13 C NMR(150MHz,DMSO-d6)δ(ppm):171.6,169.8,141.4,141.3,138.0,134.3,133.1,132.7 ,132.0,129.7,129.6,128.5,128.4,128.3,128.2,128.1,128.0,127.6,127.4,127.1,1 26.9,126.6,126.5,126.4,126.0,125.5,121.0,106.3,104.0,92.1,91.1,80.4,51.6,45.1,36.4,36.4,34.2,32.1,31.4,30.3,29.5,26.0,24.7,22.5,21.5,20.6,14.4,12.2.

[0107] HRMS (ESI-TOF) m / z: [M+Na] + Calcd for C 51 H 50 N2NaO7 + 825.3511; Found 825.3517.

[0108] ② When the pharmacophore was Isoxepac, 64 mg of compound 7b was obtained in a 92% yield as a pale yellow solid with a melting point of 120.8–122.6°C; HPLC (Dacelid chiral column OD-H, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =9.29min(major),t R =11.85min (minor); enantiomer ratio er = 99:1, specific rotation [α] D 20 = +60.500 (c = 0.20, ethyl acetate). Specific rotation [α] D 20 =+60.500 (c=0.20, ethyl acetate).

[0109] 1 H NMR(600MHz,Chloroform-d)δ(ppm):7.83(d,J=8.4Hz,1H),7.77(d,J=2.4Hz,1H),7.75(dd,J=7.8,0.6Hz, 1H),7.67(d,J=7.8Hz,1H),7.63–7.60(m,2H),7.49–7.46(m,1H),7.42–7.39(m,2H),7.33–7.30(m,1H),7.2 1(s,1H),7.15–7.05(m,7H),7.00–6.98(m,2H),6.89(dd,J=8.4,2.4Hz,1H),6.87–6.85(m,1H),6.69–6.66( m,2H),6.64–6.63(m,2H),6.52(d,J=8.4Hz,1H),6.50(s,1H),5.98(s,2H),5.13–5.08(m,2H),3.53(s,2H).

[0110] 13C NMR(150MHz,Chloroform-d)δ(ppm):190.3,168.0,160.1,141.1,140.6,140 .4,137.6,135.5,135.4,133.0,132.8,132.5,132.3,129.6,129.3,129.2,1 28.9,128.3,128.3,128.1,127.9,127.9,127.8,127.7,127.5,127.0,126.7 ,126.1,125.9,125.5,124.9,124.4,124.3,121.3,119.1,103.7,73.5,43.1.

[0111] HRMS (ESI-TOF) m / z: [M+Na] + Calcd for C 48 H 34 N2NaO3 + 709.2462; Found 709.2472.

[0112] ③ When the pharmacophore was oxaprozin, compound 7c (66 mg, 92% yield) was obtained as a pale yellow solid with a melting point of 170.4–172.6°C; HPLC (Dacelid chiral column OD-3, n-hexane / isopropanol = 70:30, 1.0 mL / min, at 254 nm): t R =7.69min(major),t R =6.79min(minor); enantiomer ratio er=98:2, specific rotation [α] D 20 =+532.000 (c=0.17, ethyl acetate).

[0113] 1 H NMR(600MHz,Chloroform-d)δ(ppm):8.06(d,J=7.8Hz,1H),7.84(d,J=7.2Hz,1H),7 .80(d,J=8.4Hz,1H),7.56–7.50(m,4H),7.46–7.45(m,2H),7.34–7.29(m,4H),7.23 –7.19(m,5H),7.14–7.05(m,6H),7.02–7.00(m,2H),6.89(t,J=7.2Hz,1H),6.77–6. 76(m,2H),6.70(t,J=7.8Hz,2H),6.03(s,2H),3.16–3.05(m,2H),2.78–2.66(m,2H).

[0114] 13 C NMR(150MHz,Chloroform-d)δ(ppm):168.9,162.4,145.3,141.3,140.8,137.7, 134.7,133.4,133.0,132.9,132.7,132.0,129.4,129.0,128.8,128.6,128.5,12 8.40128.39,128.36,128.3,128.0,127.88,127.85,127.78,127.7,127.5,127.2,126.7,126.5,126.2,126.08,126.06,126.0,124.7,124.5,119.5,33.3,23.8.

[0115] HRMS (ESI-TOF) m / z: [M+Na] + Calcd for C 50 H 37 N3NaO2 + 734.2778; Found 734.2785.

[0116] (5) Compound 5 constructs tertiary amine 10

[0117]

[0118] On a dry Schlenk tube, 5 (44.0 mg, 0.1 mmol) was dissolved in absolute methanol (2.0 mL) under an inert atmosphere. Paraformaldehyde (18.2 mg, 0.6 mmol) was added and stirred at room temperature for 10 minutes. NaBH3CN (31.7 mg, 0.5 mmol) was then added, and the reaction mixture was stirred at room temperature for 5 hours. Saturated NaHCO3 solution was added and the layers were extracted (20 × 3). The combined organic layers were dried over MgSO4, concentrated under reduced pressure, and the product was purified by column chromatography using PE:EA = 3:1 to obtain the target compound 8.

[0119] Compound 8 was obtained: 39.5 mg, 84% yield, light yellow solid, melting point 118.5–121.3°C;

[0120] HPLC (Dacelido chiral column OD-H, n-hexane / isopropanol=70:30, 1.0 mL / min, at 254 nm): t R =4.33min(major),t R =3.66min(minor); enantiomer ratio er=98:2, specific rotation [α] D 20=+160.588 (c=0.17, ethyl acetate).

[0121] 1 H NMR(600MHz,Chloroform-d)δ(ppm):8.07(s,1H),7.84–7.83(m,2H),7.53–7.47(m,2H),7.41–7.40(m,1H) ,7.20–6.99(m,10H),6.85(t,J=7.8Hz,1H),6.70(t,J=10.8Hz,2H),6.38(s,1H),6.16(s,2H),2.57(s,6H).

[0122] 13 C NMR(150MHz,Chloroform-d)δ(ppm):141.6,140.5,138.5,134.9,133.4,132.5,129.5, 128.8,128.0,127.8,127.7,127.6,127.5,126.43,126.37,125.8,125.7,102.1,44.2.

[0123] HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 34 H 29 N2 + 465.2326; Found 465.2328.

[0124] The above experiments in this example illustrate that the 3-nitro-2-arylpyrrole atropisomer prepared by the present invention has multiple reaction sites and can be further expanded to obtain various derivatives, thereby being an excellent intermediate for drug development or catalyst development.

[0125] Example 7

[0126] In this example, compound 5 prepared in Example 6 was used to construct hydrogen bonding catalysts OC-1a and OC-2a. The reaction formula and steps are as follows:

[0127]

[0128] (1) Compound 5 (44.0 mg, 0.1 mmol) was dissolved in DCM (2 ml) and 1-isocyanate-3,5-bis(trifluoromethyl)benzene (31.0 mg, 0.12 mmol) was added. Then, trimethylamine (27 μL, 0.20 mmol) was added at 0°C and stirred at room temperature for 1 h. After TLC showed that the reaction was complete, the reaction mixture was purified by preparative thin layer chromatography on silica gel (PE / EA=3:1) to obtain pure product CO-1a: 65.0 mg, 94% yield, white solid, melting point 142.5–144.4°C;

[0129] HPLC (Dacelido chiral column IB-H, n-hexane / isopropanol=70:30, 1.0 mL / min, at 254 nm): t R =3.74min(major),t R =4.53min(minor); enantiomer ratio er=99:1, specific rotation [α] D 20 =+549.273 (c=0.11, ethyl acetate).

[0130] 1 H NMR(600MHz,Chloroform-d)δ(ppm):7.75–7.79(m,3H),7.67(s,2H),7.48–7.41(m,4H),7.18–7 .09(m,8H),6.97(t,J=7.2Hz,4H),6.85(t,J=7.8Hz,2H),6.69(s,1H),6.44(s,2H),5.69(s,1H).

[0131] 13 C NMR(150MHz,Chloroform-d)δ(ppm):152.8,141.4,141.0,140.0,137.9,134.3,133.7,132.6,130.0(q,J CF =31.5Hz),129.8,129.0,128.5,128.2,128.0,127.5,127.3,127.1,126.8,126.2,125.9,125.6,124.7,124.1(q,J CF =271.1Hz),120.5,118.7,116.0,105.9. 19 F NMR(564MHz,Chloroform-d)δ-63.0(s,6F).

[0132] HRMS (ESI-TOF) m / z: [M+Na] +Calcd for C 41 H 27 F6N3NaO + 714.1951; Found 714.1955.

[0133] (2) Compound 5 (44.0 mg, 0.1 mmol) was dissolved in THF (2 mL) and 1-isothiocyanate-3,5-bis(trifluoromethyl)benzene (27.3 mg, 0.1 mmol) was added. The mixture was stirred at 30°C for 1 h. After TLC indicated the reaction was complete, the reaction mixture was purified by preparative thin-layer chromatography on silica gel (PE / EA = 3:1) to give the pure product OC-2a: 69.0 mg, 97% yield, as a white solid with a melting point of 135.3–137.3°C.

[0134] HPLC (Dacelido chiral column IB-H, n-hexane / isopropanol=70:30, 1.0 mL / min, at 254 nm): t R =4.91min(major),t R =4.01min(minor); enantiomeric ratio er>99:1, specific rotation [α] D 20 =+92.364 (c=0.11, ethyl acetate).

[0135] 1 H NMR(600MHz,Chloroform-d)δ(ppm):7.92(d,J=8.4Hz,1H),7.83(d,J=7.8Hz,1H),7.76(s, 1H),7.72(s,2H),7.59(d,J=7.8Hz,2H),7.51(d,J=8.4Hz,1H),7.43–7.41(m,1H),7.38–7.3 6(m,1H),7.27–7.25(m,2H),7.23–7.20(m,4H),7.17(d,J=7.2Hz,2H),7.12–7.11(m,2H),7. 01(t,J=7.2Hz,1H),6.97(s,1H),6.93(t,J=7.8Hz,2H),6.69(d,J=7.2Hz,2H),6.50(s,1H).

[0136] 13 C NMR(150MHz,Chloroform-d)δ(ppm):179.2,141.8,141.1,139.8,137.8,135.1,133.3,132.6,131.8,131.5(q,J CF=33.6Hz)),130.2,129.0,128.6,128.48,128.45,128.32,128.25,128.1,127 .34,127.31,127.28,127.2,126.2,125.1,124.14,124.12,124.07,123.0(q,J CF =271.2Hz),118.8,118.74,118.71,106.2.

[0137] 19 FNMR(564MHz,Chloroform-d)δ-62.9(s,6F).

[0138] HRMS (ESI-TOF) m / z: [M+Na] + Calcd for C 41 H 27 F6N3NaS + 730.1723; Found 730.1721.

[0139] (3) Catalyst OC-2a is applied to asymmetric applications. The reaction formula and steps are as follows:

[0140]

[0141] ① When R=H, compound 9a (28.0 mg, 76% yield) was obtained as a white solid with a melting point of 177.2–179.4°C.

[0142] HPLC (Dacelido chiral column IC-H, n-hexane / isopropanol = 98:2, 1.0 mL / min, at 254 nm): t R =9.96min(major),t R =8.60min(minor); enantiomer ratio er=94:2, specific rotation [α] D 20 =+123.649 (c=0.12, ethyl acetate).

[0143] 1 H NMR (600MHz, Chloroform-d) δ (ppm): 7.25–7.16 (m, 5H), 6.22 (s, 1H), 5.71 (s, 1H), 5.57 (d, J = 9.0Hz, 1H), 5.24 (d, J = 8.4Hz, 1H), 1.39 (s, 9H), 1.24 (s, 9H).

[0144] 13C NMR (150MHz, Chloroform-d) δ (ppm): 165.0, 155.0, 141.7, 140.4, 128.5, 127.4, 126.7, 125.2, 81.4, 79.8, 56.1, 28.4, 27.8.

[0145] HRMS (ESI-TOF) m / z: [M+Na] + Calcd for C 19 H 27 NNaO4 + 356.1833; Found 356.1839.

[0146] ② When R=OMe, 33.0 mg of compound 9b was obtained in 91% yield as a white solid with a melting point of 128.3–130.1°C.

[0147] HPLC (Dacelido chiral column IC-H, n-hexane / isopropanol = 98:2, 1.0 mL / min, at 254 nm): t R =20.43min(major),t R =15.06min(minor); enantiomer ratio er=90:10, specific rotation [α] D 20 =+98.361 (c=0.11, ethyl acetate).

[0148] 1 H NMR(600MHz,Chloroform-d)δ(ppm):7.18(d,J=8.4Hz,1H),6.83(d,J=9.0Hz,1H),6.26(s,1H),5 .74(s,1H),5.57(d,J=8.4Hz,1H),5.24(d,J=8.4Hz,1H),3.78(s,3H),1.44(s,9H),1.32(s,9H).

[0149] 13 C NMR (150MHz, Chloroform-d) δ (ppm): 165.1, 158.9, 154.9, 142.0, 132.5, 128.0, 124.5, 113.9, 81.3, 79.7, 55.5, 55.3, 28.4, 27.9.

[0150] HRMS (ESI-TOF) m / z: [M+Na] + Calcd for C 20 H 29 N2NaO5 +386.1938; Found 386.1931.

[0151] ③ When R=CN, compound 9c (30.0 mg, 83% yield) was obtained as a white solid with a melting point of 153.1–155.5°C.

[0152] HPLC (Dacelido chiral column IG-H, n-hexane / isopropanol=70:30, 1.0 mL / min, at 254 nm): t R =7.02min(major),t R =6.18min(minor); enantiomer ratio er=90:10, specific rotation [α] D 20 =+11.426 (c=0.11, ethyl acetate).

[0153] 1 H NMR(600MHz,Chloroform-d)δ(ppm):7.60(d,J=7.8Hz,1H),7.39(d,J=7.8Hz,1H),6.31(s ,1H),5.82(s,1H),5.65(d,J=8.4Hz,1H),5.55(d,J=7.8Hz,1H),1.44(s,9H),1.33(s,9H).

[0154] 13 C NMR (150MHz, Chloroform-d) δ (ppm): 164.5, 155.0, 146.1, 140.4, 132.3, 127.1, 118.7, 111.2, 82.0, 80.2, 56.1, 28.3, 27.9.

[0155] HRMS (ESI-TOF) m / z: [M+Na] + Calcd for C 20 H 26 N2NaO4 + 381.1785; Found 381.1792.

[0156] Example 8

[0157] In this example, compound 5 prepared in Example 6 was used to construct hydrogen bonding catalysts OC-3a and OC-4a. The reaction formula and steps are as follows:

[0158]

[0159] (1) Add 5 (88.0 mg, 2.0 mmol) and MeOH (5 ml) to a round-bottom flask. Then add 3,4-dimethoxycyclobut-3-ene-1,2-dione (31.5 mg, 1.1 mmol) dropwise. Heat the reaction to 40°C and stir for 8 h. Then add (1S,2S)-(+)-N,N-dimethylcyclohexane-1,2-diamine (34.4 mg, 1.2 mmol) to the flask and stir in an oil bath (40°C) for 12 h. After the reaction is complete, purify the reaction mixture by silica gel flash column chromatography to obtain the product OC-3a: 58.0 mg, 87% yield, white solid, melting point 203.5–205.6°C; specific rotation [α] D 20 =+284.350 (c=0.40, ethyl acetate).

[0160] 1 H NMR(600MHz,Chloroform-d)δ(ppm):7.96(d,J=6.6Hz,1H),7.90–6.88(m,2H),7.5 6–7.51(m,2H),7.37(d,J=8.4Hz,1H),7.16–7.08(m,7H),7.00–6.98(m,2H),694(t, J=7.2Hz,1H),6.83(s,2H),6.75(t,J=7.8Hz,2H),6.12(s,2H),3.75(s,1H),2.45(s ,2H),2.09(s,5H),1.80(s,2H),1.69(s,1H),1.31–1.17(m,4H),0.89–0.74(m,1H).

[0161] 13 C NMR (150MHz, Chloroform-d) δ (ppm): 183.3, 141.6, 140.8, 137.4, 133.8, 133.6, 132.8, 132.4, 129.8, 129.0, 128.44, 128.36, 128. 03,127.95,127.9,127.5,127.2,126.8,126.6,126.5,126.1,125.9,124.5,104.3,67.3,54.8,39.7,35.0,29.7,24.8,24.3,21.7.

[0162] HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 44 H 41 N4O2 +657.3225; Found 657.3233.

[0163] (2) Pyridine (24.0 mg, 0.3 mmol), thiophosphine (27.8 mg, 0.24 mmol), and 5 (88.0 mg, 0.2 mmol) were added to DCM (2 ml). The reaction mixture was then stirred at 25 ° C for 1 h and evaporated in vacuo to remove excess thiophosphine. The resulting residue was dissolved in DCM (2 ml), (1S, 2S)-(+)-N, N-dimethylcyclohexane-1,2-diamine (43.0 mg, 0.3 mmol) was added, and the mixture was stirred at 25 ° C for 1 h. After the reaction was completed, thin layer chromatography was performed to purify the reaction mixture by flash column chromatography on silica gel using petroleum ether and ethyl acetate (PE / EA = 3:1) as the solvent system to obtain pure product OC-4a: 58.0 mg, 93% yield, white solid, melting point 255.3–258.4 ° C; specific rotation [α] D 20 =+333.182 (c=0.22, ethyl acetate).

[0164] 1 H NMR(600MHz,Chloroform-d)δ(ppm):7.84–7.78(m,3H),7.43–7.40(m,2H),7.30(d,J=9.0Hz, 1H),7.25–7.17(m,1H),7.09–7.00(m,7H),6.91(d,J=7.2Hz,2H),6.84(t,J=7.2Hz,1H),6.78. (d,J=3.6Hz,2H),6.67(t,J=7.2Hz,3H),6.08(s,2H),3.80(s,1H),2.58(s,1H),2.30(s,1H), 2.15(s,5H),1.78–1.71(m,2H),1.58(d,J=13.8Hz,1H),1.29–1.07(m,4H),0.83–0.85(m,1H).

[0165] 13C NMR(150MHz,Chloroform-d)δ(ppm):179.2,141.1,140.8,137.4,133.5,132.7,132.3,129.7,129.0,128.3,128.1,127.90,127.86,127.8 4,127.81,127.2,127.1,126.7,126.44,126.38,126.0,125.7,124.6 ,123.7,123.0,105.4,66.7,56.3,39.9,32.6,29.6,25.2,24.5,21.7.

[0166] HRMS (ESI-TOF) m / z: [M+Na] + Calcd for C 41 H 40 N4NaS + 643.2866; Found 643.2864.

[0167] Catalysts OC-3a and OC-4a were used in asymmetric reactions. The reaction formula is as follows. Under the catalytic action of catalysts OC-3a and OC-4a, compound 10 was obtained with different yields and selectivities. Although the catalytic performance of catalysts OC-3a and OC-4a differed, the performance was still relatively ideal:

[0168]

[0169] Spectral data of compound 10:

[0170] 1 H NMR(600MHz,Chloroform-d)δ(ppm):7.22–7.20(m,3H),7.12-7.11(m,2H),4.60– 4.53(m,2H),4.30(d,J=10.8Hz,1H),4.20–4.16(m,1H),2.22(s,3H),1.87(s,3H).

[0171] 13 C NMR (150MHz, Chloroform-d) δ (ppm): 201.8, 201.0, 136.0, 129.3, 128.6, 128.0, 78.2, 42.8, 30.4, 29.6.

[0172] HPLC (Daicel Chiralpak AS-H, n-hexane / 2-propanol=70:30, 1.0mL / min, at254nm): tR =

[0173] 10.86min(major),t R =14.15min(minor).

[0174] 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.

[0175] 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 type of 3-nitro-2-arylpyrrole atropisomer, characterized in that: The structure of the pyrrole atropisomer is as shown in Formula 1 or its stereoisomer: 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 6 R 7 ; R 6 、R 7 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 8 R 9 、-O(CH2) n OR 10 、-OC(O)R 10 ; 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 8 、R 9 、R 10 Each is independently selected from hydrogen, and a substituted or unsubstituted C1-C6 alkyl group.

2. The method for preparing atropisomers of pyrrole according to claim 1, wherein Its synthesis reaction formula is shown in Formula 2: Wherein, the ligand represented by Formula 2 is a PyBOX ligand, and the PyBOX ligand is selected from one or more of the structures represented by the following L1 to L22 or their stereoisomers: The molar ratio of compound 1, compound 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 compound 1 and solvent is (0.05-0.2)mmol:1ml; the copper salt shown in Formula 2 is selected from one or more of Cu(CH3CN)4PF6, Cu(OTf)2 and Cu(CH3CN)4BF4; the solvent shown in Formula 2 is selected from one or more of dichloromethane, 1,2-dichloroethane, chloroform, toluene, acetonitrile and tetrahydrofuran.

3. The method for preparing atropisomers of pyrrole according to claim 2, wherein: The additive is DABCO, the molar ratio of compound 1, compound 2, DABCO, copper salt and ligand is 1:1.2:1:0.1:0.12; the molar volume ratio of compound 1 and organic solvent is 0.1 mmol:1 ml; the PyBOX ligand is L21; the copper salt is Cu(OTf)2; and the solvent is 1,2-dichloroethane.

4. Use of the pyrrole atropisomer according to claim 1 as an intermediate in drug development or catalyst development.

5. A hydrogen bonding catalyst prepared based on the pyrrole atropisomer according to claim 1, characterized in that: Including OC-1 and OC-2, the structure of OC-1 and OC-2 is as shown in Formula 3 or its stereoisomers: Among them, R 11 It is a substituted or unsubstituted 6- to 10-membered aryl group, or a substituted or unsubstituted 5- to 10-membered heteroaryl group.

6. The method for preparing a hydrogen bonding catalyst according to claim 5, wherein: The preparation process of OC-1 and OC-2 is shown in Formula 4:

7. Use of the hydrogen bond catalyst as claimed in claim 5 as a catalyst in an asymmetric reaction.

8. A tertiary amine bifunctional catalyst prepared based on the pyrrole atropisomer according to claim 1, characterized in that: Including OC-3 and OC-4, the structure of OC-3 and OC-4 is as shown in Formula 5 or its stereoisomers: Among them, R 12 、R 13 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, halogen, -NR 8 R 9 、-O(CH2) n OR 10 、-OC(O)R 10 ; or, R 12 and R 13 connected to form a substituted or unsubstituted 3-10 membered cycloalkyl, a substituted or unsubstituted 3-10 membered heterocycloalkyl, a substituted or unsubstituted 6-10 membered aryl, or a substituted or unsubstituted 5-10 membered heteroaryl; n is an integer from 1 to 6; R 8 、R 9 、R 10 Each is independently selected from hydrogen, and a substituted or unsubstituted C1-C6 alkyl group.

9. The method for preparing a tertiary amine bifunctional catalyst according to claim 8, wherein: The preparation process of OC-3 and OC-4 is shown in Formula 6:

10. Use of the tertiary amine bifunctional catalyst according to claim 8 as a catalyst in an asymmetric reaction.

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