A process for the synthesis of aza-heteroaromatic rings with a chiral center in the alpha-position, catalyzed by a chiral phosphoric acid in cooperation with a lewis acid

Abstract

The application discloses a method for synthesizing an alpha-position chiral nitrogen heteroaromatic ring under the synergistic catalysis of a chiral phosphoric acid and a Lewis acid, and the method comprises the following steps: taking a nitrogen heteroaromatic ring olefin I as an electrophilic reagent, taking an aryl alkyl boronic acid II as a carbon nucleophile, and under the synergistic catalysis of a Lewis acid catalyst and a chiral phosphoric acid catalyst, in the presence of an organic solvent, an additive and a proton source, performing a conjugate addition-asymmetric protonation reaction to generate an alpha-position chiral nitrogen heteroaromatic compound shown in formula V, and the reaction is shown as follows: The application provides a conjugate addition-asymmetric protonation strategy for a nitrogen heteroaromatic ring olefin, which is synergistically catalyzed by a chiral phosphoric acid and a Lewis acid (Fe(OTs)3) and involves an organic boron reagent, a series of alpha-position chiral nitrogen heteroaromatic compounds are successfully synthesized by using the catalytic system, the highest enantioselectivity reaches 98% ee, and good universality is shown for aryl, heterocyclic and polysubstituted substrates, and the bottleneck problem of low reactivity of 1,1-disubstituted substrates in a traditional method is effectively overcome.

Description

Technical Field

[0001] This invention belongs to the field of asymmetric organic synthesis chemistry, specifically relating to a method for efficiently constructing an α-chiral central nitrogen-containing aromatic ring via an asymmetric conjugated addition-protonation reaction under the synergistic catalysis of chiral phosphoric acid and Lewis acid. Background Technology

[0002] Nitrogen-containing heterocyclic compounds are widely found in natural products, and many natural active ingredients and clinical drugs belong to this category [Caron, S.]. Org. Pro. Res. Dev. 2020, 24 , 470−480.; Shimizu, M.; Hiyama, T. Angew. Chem. Int. Ed. 2005, 44 , 214–231.; Reymond, J.-L.; Awale, M. ACS. Chemical. Neuroscience. 2012, 3 [649-657.]. An analysis of the FDA-approved drug database by Vitaku et al. revealed that 59% of small molecule drugs contain nitrogen-containing heterocyclic structures. These compounds have significant applications in the pharmaceutical field, primarily in antitumor agents, kinase inhibitors, hypoglycemic drugs, anticonvulsants, anti-inflammatory drugs, antibacterial agents, and antidepressants [He, X.-H.; Ji, Y.-L; Cheng, P.; Han, B.]. Adv. Synth. Catal. 2019, 361, 1923–1957.; Wilson, RM; Danishefsky, SJ Angew Chem Int Ed. 2010, 49, 6032–6056.; Wan, Z.-K. et al. ACS. Med. Chem. Lett. 2013, 4, [118–123.]. Electron-rich nitrogen heterocycles, due to their unique electronic structure, can act as both proton donors and acceptors, and can form a variety of weak intermolecular interactions. These interactions include, but are not limited to, hydrogen bonds, dipole-dipole interactions, π-π interactions, hydrophobic effects, and van der Waals forces. Structure-activity relationship studies of nitrogen heterocyclic derivatives have shown that fused-ring systems such as pyrimidines and pyrazoles enhance target binding stability through π-π stacking. Of particular note is that the specific binding of these compounds to DNA base pairs via hydrogen bonds is an important molecular mechanism by which they exhibit significant anticancer activity [Zhu, J.-B.]. et al . Chem. Sci. 2023, 14[1606–1612.] With the continuous advancement of synthetic methods for nitrogen-containing compounds, the growth of nitrogen-containing heterocyclic drugs is expected to continue. In drug development, the configuration of chiral compounds has a decisive influence on their efficacy, but the complexity of their synthetic processes also presents challenges to the screening of candidate drugs. During large-scale preparation, metal-derived catalysts may contaminate pharmacologically oriented products with toxic heavy metals. For example, the toxicity of some drugs to specific populations urgently needs attention, which poses new research requirements for developing safer and more effective nitrogen-containing heterocyclic chiral compounds.

[0003] The precise construction of α-chiral centers is a core research direction in modern medicinal chemistry, as their stereochemical properties have a decisive influence on biological activity and pharmacokinetic behavior. The stereoselective recognition mechanisms of biomolecules (such as enzymes and receptors) allow the spatial configuration of α-chiral centers to directly regulate drug-target interactions [Kawai, H.; Tachi, K.; Tokunaga, E.]. Org. Lett. 2010, 12 [5104–5107.]. Market data confirms that 65% of the top 200 best-selling drugs globally in 2020 were chiral drugs, of which 80% contained a key α-chiral center. Systematically constructing α-chiral centers has become a key strategy for optimizing targeting, improving ADME properties, and reducing toxicity, and has important guiding value for innovative drug development [Yearick, K; Wolf, C.]. Org. Lett. 2008, 10 [3915–3918.]. To construct enantiomeric-enriched α-chiral-centered aza-aryl hydrocarbons, conjugated addition-asymmetric protonation is one of the most direct methods [Motoki, R.; Tomita, D.; Kanai, M.; Shibasaki, M.]. Tetrahedron Letters , 2006, 47 [8083–8086.] Currently, the catalytic systems for constructing α-chiral central nitrogen-containing aromatic hydrocarbons mainly cover the following four categories: transition metal catalysis [Lee, K]. et al . Nature Chem , 2016, 8 [768–777.], Biocatalysis [Thomson, CJ; Barber, DM; Dixon, DJ] Angew Chem Int Ed 2020, 59 [, 5359–5364.], Photocatalysis [Yin, Y.; Li, Y.; Gonçalves, TP] J. Am. Chem. Soc. 2020, 142[19451–19456.], Organic small molecule catalysis [Kong, M.; Tan, Y.; Zhao, X.] et al . J. Am. Chem. Soc. 2021, 143 [4024–4031.]. Asymmetric protonation of conjugate addition with chiral phosphoric acid as a catalyst has been developed into various nucleophilic types: asymmetric protonation with hydrogen insertion [Cao, Y.; Zhang, S.; Antilla, JC]. ACS Catal. 2020, 10 , 10914–10919. ], Asymmetric protonation of nitrogen insertion [Xu, C.; Muir, CW; Leach, AG] et al . Angew Chem Int Ed 2018, 57 , 11374–11377.], Asymmetric protonation of sulfur insertion [Li, Y.-P.; Zhu, S.-F.; Zhou, Q.-L.]. Org. Lett. 2019, 21 , 9391–9395.], Asymmetric protonation of carbon insertion [Li, Y.-P.] et al . ACS Catal. , 2019, 9 [6522-6529.] Compared to metal catalysis systems (which have limitations such as high environmental risk and high cost) and bioenzyme catalysis strategies (which are limited by strict substrate specificity), chiral phosphoric acid catalysis has shown significant advantages in the asymmetric protonation reaction of azaolefins. This strategy combines high efficiency, environmental friendliness, and ease of operation. Its characteristics include: low catalyst loading, no need for additional additives, and broad compatibility with substrates containing different functional groups, highlighting its unique advantages in the context of green synthetic chemistry.

[0004] Metal catalysis, as a traditional core technology, has established a mature system for constructing complex molecular frameworks, while the rise of organic small molecule catalysis has made up for the shortcomings in stereoselective control through unique non-metallic activation modes [Shao Z, Zhang H]. Chem. Soc. Rev. 2009, 38 [2745-2755.]. However, single catalytic systems have inherent limitations, prompting researchers to explore synergistic catalytic strategies. In recent years, innovative breakthroughs in synergistic catalytic strategies combining metal catalysis and organocatalysis have opened up new dimensions for reaction design [Akiyama, T.; Mori, K. Stronger]. Chem. Rev. 2015, 115[9277–9306.]. Since the strategy was proposed in the 1990s, Brønsted acid catalysis, with its universality in organic synthesis, has gradually developed into an important methodological system for constructing chiral molecular frameworks. The synergistic system of chiral Brønsted acids and metal catalysts exhibits unique advantages: BINOL-derived phosphate diesters, as bifunctional catalysts, can both participate in acidic activation as proton sources and achieve precise stereochemical control through the regulation of chiral anion structures, successfully expanding the transformation boundaries of substrates such as olefins and aromatics. Currently, cascade catalysis has been established in this field [Cai Q, Zhao ZA, You SL]. Angew Chem Int Ed , 2009, 48 , 7428-7431.]、Anion catalysis [Mukherjee S, List B.] J. Am. Chem. Soc. 2007, 129 , 11336-11337.], Metal phosphate catalysis [Hatano M, Ikeno T, Matsumura T.] Adv. Synth. Catal. 2008, 350 , 1776-1780.] and dicarboxylic acid catalysis [Yamamoto H, Futatsugi K.] Angew Chem Int Ed , 2005, 44 [1924-1942.] Four basic modes of operation.

[0005] However, existing research has certain limitations. First, regarding the substrate scope, the existing techniques for 1,1-disubstituted nitrogen-containing heterocyclic alkenes exhibit low reactivity, and the α-substituents are mainly limited to aryl groups, with a lack of research on alkyl substitutions. Second, regarding the type of nucleophile, research on carbon nucleophiles mainly focuses on pyrrole and indole compounds, while the application of aryl alkenylboronic acids as carbon nucleophiles in highly efficient asymmetric conjugated addition catalytic systems has not been reported. Based on these research gaps, this study proposes an innovative solution: for the first time, a chiral phosphoric acid and metal synergistic catalytic system is used to drive aryl alkenylboronic acids as nucleophiles for asymmetric conjugated addition, achieving the construction of the α-chiral center in nitrogen-containing heterocyclic alkenes. Through systematic condition optimization and substrate expansion, we successfully achieved the efficient construction of C-C bonds and expanded the range of α-substituents, accommodating multifunctional group substitutions, providing a new approach for the synthesis of chiral nitrogen-containing heterocyclic compounds. This research not only enriches the catalytic system for asymmetric protonation reactions but also provides an important tool for the synthesis of related bioactive molecules. Summary of the Invention

[0006] In view of the above-mentioned technical problems existing in the prior art, the purpose of the present invention is to provide a novel, efficient and highly selective method for constructing alkenyl nitrogen-containing heteroaromatic rings with α-chiral centers by using chiral phosphoric acid as a catalyst in synergistic catalysis with Lewis acids.

[0007] This invention employs a novel strategy for the synergistic catalysis of Lewis acids and chiral phosphoric acid, aiming to efficiently construct nitrogen-containing aromatic heterocycles with α-chiral centers through a conjugated addition-asymmetric protonation reaction involving organoboronic acid reagents. Using nitrogen-containing heteroaromatic olefin I as the electrophile and aryl alkenylboronic acid II as the carbon nucleophile, this strategy is based on a 1,4-Michael addition-initiated dearomatization process to form an enamine intermediate, followed by asymmetric protonation under the stereoregulation of the catalyst, ultimately generating an optically active product through aromatization. The catalytic system design integrates three key elements: Lewis acid site activation of the electrophile, base site stabilization of the nucleophile via hydrogen bonding, and a free proton source to accelerate proton transfer. These three elements synergistically act on a chiral platform to achieve high stereoinduction.

[0008] The technical solution adopted in this invention is as follows:

[0009] A method for synthesizing α-chiral nitrogen-containing heteroaromatic rings under the synergistic catalysis of chiral phosphoric acid and Lewis acid, using nitrogen-containing heteroaromatic olefin I as an electrophile and aryl alkenylboronic acid II as a carbon nucleophile, in the presence of an organic solvent, additives and a proton source, a conjugate addition-asymmetric protonation reaction is carried out to generate α-chiral nitrogen-containing heteroaromatic compounds under the synergistic effect of Lewis acid catalyst and chiral phosphoric acid catalyst.

[0010] The reaction process is shown in the following reaction equation:

[0011] ;

[0012] .

[0013] X is selected from one of the following: C, N;

[0014] R is selected from one of the following: C6~C10 aryl, C4~C8 heteroaryl containing 1-4 heteroatoms selected from N, O, S, or C1~C4 alkyl; the H on the aromatic ring of the C6~C10 aryl is either unsubstituted or substituted by one or more substituents independently selected from halogen, trifluoromethyl, or alkoxy.

[0015] Ar is selected from one of the following: C6-C12 aryl groups that may or may not be substituted, or C5-C8 heteroaryl groups containing 1-2 heteroatoms selected from S and O; the C6-C12 aryl group has one or more substituents on its aromatic ring, each of which is independently selected from halogen, nitro, phenyl, cyano, ester, or alkoxy.

[0016] Furthermore, the 1,1-disubstituted nitrogen-containing heterocyclic olefin compounds shown in Formula I include one of the following:

[0017] .

[0018] Furthermore, the alkenylboronic acid nucleophilic reagent represented by Formula II includes one of the following:

[0019] .

[0020] Furthermore, the asymmetric protonation reaction temperature is between 30°C and 50°C, preferably 40-45°C; the organic solvent is selected from one or more combinations of benzene, toluene, trifluorotoluene, chlorobenzene, o-xylene, m-xylene, p-xylene, dimethylformamide, chloroform, carbon tetrachloride, ethyl acetate, tetrahydrofuran, and n-hexane, preferably trifluorotoluene.

[0021] Furthermore, the chiral phosphoric acid catalyst is selected from one of the following:

[0022] .

[0023] The chiral phosphoric acid catalyst is preferably... S D2 compounds with the following configuration.

[0024] Furthermore, the additive is a molecular sieve, specifically a 3Å molecular sieve, a 4Å molecular sieve, or a 5Å molecular sieve, preferably a 4Å molecular sieve; the mass ratio of the molecular sieve to the molar amount of compound I is 1-2:1, preferably 1.2-1.6:1, with mass measured in g and molar amount in mmol.

[0025] Further, the Lewis acid is at least one of boron tribromide, boron trifluoride diethyl ether, indium tribromide, bismuth acetate, ferric chloride, copper trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate, silver trifluoromethanesulfonate, ferric trifluoromethanesulfonate, ferric p-toluenesulfonate, ferrous trifluoromethanesulfonate, lithium trifluoromethanesulfonate, cobalt trifluoromethanesulfonate, indium trifluoromethanesulfonate, and scandium trifluoromethanesulfonate, preferably ferric p-toluenesulfonate.

[0026] Furthermore, the molar ratio of the Lewis acid to compound I is 0.2-0.8:1, preferably 0.4-0.5:1.

[0027] Furthermore, the molar ratio of compound I to compound II is 1:1.5-3, preferably 1:2.

[0028] Furthermore, the molar ratio of the chiral phosphoric acid catalyst to compound I is 0.05-0.2:1, preferably 0.08-0.1:1.

[0029] Furthermore, the proton source is at least one selected from boric acid, phenylboronic acid, p-fluorophenylboronic acid, p-methoxyphenylboronic acid, water, and p-toluenesulfonic acid hydrate, preferably phenylboronic acid. The molar ratio of the proton source to compound I is 0.5-2:1, preferably 1:1.

[0030] Compared with the prior art, the present invention has the following significant advantages:

[0031] (1) This invention follows the principles of green chemistry and uses recyclable chiral organic small molecule catalysts, thus avoiding the environmental burden of precious metal catalysts. By innovatively integrating the synergistic activation mechanism of chiral phosphoric acid and Lewis acid, and combining it with a stereochemical control strategy, the precise construction of highly enantioselective chiral centers at the α site of the nitrogen-containing aromatic ring is achieved, providing a new methodological basis for the synthesis of chiral nitrogen-containing aromatic compounds.

[0032] (2) The present invention has a broad substrate scope. This method is applicable not only to various aryl and heteroaryl-substituted nitrogen-containing heterocyclic alkenes, but also successfully introduces stable organoboron reagents such as aryl alkenylboronic acids into the reaction system, expanding the range of nucleophiles. By developing an efficient method for the synthesis of aryl alkenylboronic acids, a library of structurally diverse nucleophiles has been successfully constructed, establishing a sound substrate basis for subsequent asymmetric catalytic reactions. This synthetic strategy shows potential application value in the synthesis of natural product analogs and pharmaceutical intermediates.

[0033] (3) The conjugate addition-asymmetric protonation reaction method involving organoboron reagents developed in this invention can efficiently construct the α-chiral center of a nitrogen-containing heteroaromatic ring, with excellent enantioselectivity of up to 98% ee. The entire synthetic process is simple, and the precise construction of a highly enantioselective chiral center at the α-site of the nitrogen-containing heteroaromatic ring is achieved, providing a new methodological basis for the synthesis of chiral nitrogen-containing aromatic compounds.

[0034] (4) The present invention has strong scalability, mild reaction conditions, and controllable catalyst dosage. The practical value of this method has been demonstrated by the successful conversion of the product into a derivative with potential application value, showing its reliability in synthetic practice and good prospects for industrial application. Detailed Implementation

[0035] The following is a description of specific embodiments of the present invention, which is intended to further clarify the technical solution of the present invention, but does not limit the scope of protection of the present invention.

[0036] Analytical instrument settings:

[0037] 1. Melting point determination: The melting point was determined using a HyNeng MP430 video melting point apparatus to ensure purity and consistency.

[0038] 2. Nuclear Magnetic Resonance Spectroscopy (NMR): ¹H NMR and ¹³C NMR spectra were recorded using a Bruker 400 MHz or 600 MHz instrument. All ¹³C NMR spectra were obtained using broadband proton decoupling techniques to improve resolution. ¹H NMR chemical shifts are expressed in ppm and corrected for residual signal relative to the solvent.

[0039] 3. Mass Spectrometry (MS): High-resolution mass spectrometry analysis was performed using an Agilent 6210 TOF LC / MS with an ESI or EI ion source to ensure accurate mass determination.

[0040] 4. Polarimetry: The optical rotation was measured using an AUTOPOL V automatic polarimeter to confirm the optical purity of the compound.

[0041] 5. High Performance Liquid Chromatography (HPLC): An Agilent 1100 HPLC system equipped with Daicel Chiralpak IA, IB, IC, ID, IE, IF, IG, and IJ columns was used to analyze enantiomeric excess values ​​(ee values) to ensure high-precision determination of enantioselectivity excess values.

[0042] Preparation and application of the catalyst of this invention: Besides chiral phosphoric acid catalysts ( S )-D2 is all catalysts used in this invention, except those prepared in this application. S )-A to ( S The catalysts 1-G are derived from existing technologies, and specific preparation methods and usage conditions can be found in references [1-9]. These references provide detailed catalyst preparation steps and application examples in different chemical reactions to facilitate understanding and implementation of the method of this invention.

[0043] Literature [1]: RI Storer, DE Carrera, Y. Ni, DWC MacMillan, Enantioselective Organocatalytic Reductive Amination [J]. J. Am. Chem. Soc. 2006, 128 , 84–86.

[0044] Literature[2]: SJ Chapman, WB Swords, CM Le, IA Guzei, FDToste, TP Yoon, Cooperative Stereoinduction in Asymmetric Photocatalysis[J]. J. Am. Chem. Soc. 2022,144 , 4206–4213.

[0045] Reference [3]: C. Xing, Y. Liao, Y. Zhang, D. Sabarova, M. Bassous, Q. Hu, Asymmetric Allylboration of Aldehydes with Pinacol Allylboronates Catalyzed by 1,1′‐SpirobIIndane‐7,7′‐diol (SPINOL) Based Phosphoric Acids [J]. Eur J Org Chem 2012, 2012 , 1115–1118.

[0046] Reference [4]: Y. Zhang, R. Zhao, R. L. Bao, L. Shi, Highly Enantioselective SPINOL‐Derived Phosphoric Acid Catalyzed Transfer Hydrogenation of Diverse C=N‐Containing Heterocycles [J]. Eur J Org Chem 2015, 2015 , 3344–3351.

[0047] Reference [5]: N. H. Nguyen, Q. H. Nguyen, S. Biswas, D. V. Patil, S. Shin, β-Oxidation of Ynamides into N , O- Acetals by m CPBA: Application in Enantioselective Intermolecular Transacetalization [J]. Org. Lett. 2019, 21 ,9009–9013.

[0048] Reference [6]: Jie Yang See., Hui Yang., Yu Zhao., Ming Wah Wong., et al Desymmetrizing

[0049] Enantio- and Diastereoselective Selenoetherification throughSupramolecular Catalysis [J]. ACS Catal 2018, 8 (2): 850–858.

[0050] Literature [7]: C.-H. J. Org. Chem. 2011, 76 , 4125–4131.

[0051] Literature [8]: Y. Li, J. Huang, Z. Han, H. Huang, B. Hong, J. Sun, Organocatalytic Enantioselective Nucleophilic Addition of Indole Imine 5-Methides [J]. Org. Lett 2024, 26 , 396–400.

[0052] Literature [9]: T. Li, S. Liu, Y. Sun, S. Deng, W. Tan, Y. Jiao, Y. Zhang, F. Shi, Regio‐ and Enantioselective (3+3) Cycloaddition of Nitrones with 2‐Indolylmethanols Enabled by Cooperative Organocatalysis [J]. Angew Chem Int Ed 2021, 60 , 2355–2363. Example

[0053] Chiral phosphoric acid catalyst ( S )-D2 is a self-made product of this application, and its synthetic route is as follows:

[0054] ;

[0055] Its preparation process is as follows:

[0056] ;

[0057] Under nitrogen protection, add ( ) to a 500 mL three-necked flask that has been dried with a hot air gun. S 5.0 g (19.8 mmol, 1.0 equiv.) of spirocyclonaphthol (4.5 g, 45.5 mmol, 2.3 equiv.) and 198.0 mL of ultra-dry dichloromethane were added to dissolve the spirocyclonaphthol. The reaction mixture was then cooled to -78°C and stirred in an ice machine at this temperature for 15 minutes. The purified white crystalline powder was then slowly added to the reaction flask in three batches. N 1-Bromosuccinimide (NBS) (8.1 g, 45.5 mmol, 2.3 equiv.) was stirred at -78°C for 7 hours and then slowly brought to room temperature. After confirming the completeness of the reaction by TLC, 2M hydrochloric acid (240 mL) was slowly added to the reaction system for quenching, followed by extraction with dichloromethane (50 mL x 3). The mixture was washed successively with saturated sodium bicarbonate aqueous solution and saturated brine. The collected organic phases were dried over anhydrous sodium sulfate, filtered through a long-necked funnel, and distilled under reduced pressure. Finally, the crude product was purified by rapid silica gel chromatography (petroleum ether / ethyl acetate = 25 / 1 (v / v)) to give compound D int1 as a white solid (5.6 g), with a separation yield of 69%.

[0058] .

[0059] Under nitrogen protection, the binaphthol intermediate D int1 (5.6 g, 13.6 mmol, 1.0 equiv.) was added to a dry 250 mL two-necked flask and dissolved in 1,4-dioxane / water (40 mL / 13 mL). The solvent was thoroughly purged with nitrogen for 40 minutes. Then, 1-pyrboronic acid (10.0 g, 40.9 mmol, 3.0 equiv.), SPhos (279.0 mg, 0.7 mmol, 5 mol%), and potassium phosphate (8.7 g, 40.9 mmol, 3.0 equiv.) were added sequentially to the reaction flask, and the mixture was stirred at 25 °C for 10 minutes. Subsequently, Pd2(dba)3 (622.0 mg, 0.7 mmol, 5 mol%) was added to the system under nitrogen purging, and the mixture was purged again for 10 minutes. The system temperature was then raised to 90 °C, and the reaction was allowed to proceed for 16 hours. After the reaction was monitored by TLC, 1,4-dioxane was removed by vacuum distillation, followed by extraction with dichloromethane (50 mL × 3), and the organic layer was washed with saturated brine (50 mL). The collected organic phase was dried over anhydrous sodium sulfate, then filtered and the solvent was removed by vacuum distillation. The crude product was purified by rapid silica gel chromatography (petroleum ether / ethyl acetate = 200 / 1-90 / 1 (v / v)) to give compound D int2 as a white solid (4.2 g), with a separation yield of 48%.

[0060] .

[0061] Under nitrogen protection, the binatol product D int2 (4.2 g, 6.4 mmol, 1.0 equiv.) was added to a dry 100 mL two-necked flask, followed by the addition of ultra-dry dichloromethane (30 mL). Triethylamine (3.5 mL, 25.6 mmol, 4.0 equiv.) was then added dropwise at 0 °C, and the mixture was stirred for 10 minutes. Phosphorus oxychloride (1.1 mL, 12.8 mmol, 2.0 equiv.) was then added dropwise at the same temperature. After the addition was complete, the mixture was stirred for 10 minutes, then heated to 25 °C and stirred for another 18 hours. After complete conversion of the feedstock as monitored by TLC, the crude product was filtered through diatomaceous earth. The filter cake was washed with dichloromethane (40 mL × 3) and concentrated under reduced pressure to obtain D int3. Prepare a 250 mL single-necked flask and dissolve D int3 in a pyridine / water mixture (70 mL / 70 mL (v / v)). Reflux the reaction flask at 105 °C for 4 hours. After complete conversion of the starting material as monitored by TLC, allow the mixture to cool to room temperature and then remove excess pyridine by vacuum distillation. Extract with dichloromethane (40 mL × 3), wash the organic layer with 50 mL of saturated sodium chloride solution, dehydrate the organic phase with anhydrous sodium sulfate, filter through a funnel, and concentrate under reduced pressure. The crude product is purified by silica gel column chromatography (dichloromethane / methanol = 75 / 1 (v / v)), acidified, and recrystallized: dissolve the preliminarily purified white solid powder in dichloromethane (40 mL), then slowly add 6 M hydrochloric acid (45 mL) solution at room temperature and stir for 1 hour. After stirring, the reaction solution was extracted with dichloromethane (30 mL × 3). The extracts were combined, and the organic phase was then dried with anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The evaporated phosphoric acid product was then slurried with analytical grade methanol at 45°C for 30 minutes, followed by filtration and drying to obtain the product. S )-D2, a white powdery solid, was obtained in a separation yield of 3.3 g, with a separation rate of 73%.

[0062] 1 H NMR (400 MHz, DMSO- d 6) δ 8.3 – 8.1 (m, 7H), 8.1 – 8.1 (m, 6H), 8.0(d, J = 7.6 Hz, 1H), 8.0 – 7.9 (m, 3H), 7.9 – 7.7 (m, 2H), 7.4 – 7.3 (m, 4H), 3.3 (qd, J = 9.7, 9.3, 4.3 Hz, 2H), 3.1 (dtd, J = 18.2, 10.0, 8.8, 5.3 Hz,2H), 2.6 – 2.5 (m, 2H), 2.3 (td, J = 17.8, 14.4, 8.9 Hz, 3H). 13 C NMR (101MHz, DMSO- d6) δ 145.7, 145.3, 143.6, 143.4, 143.3, 141.0, 140.2, 140.2,133.6, 133.3, 132.9, 132.8, 132.0, 131.4, 131.3, 130.7, 130.7, 130.6, 130.3,130.2, 130.2, 129.9, 129.9, 129.8, 129.4, 129.4, 128.9, 128.9, 127.8, 127.2,127.1, 127.0, 127.0, 126.2, 126.0, 125.9, 125.3, 125.1, 124.8, 124.7, 124.5, 124.3, 124.3, 123.8, 123.8, 123.7, 123.3, 123.3, 122.3, 121.2, 59.6, 59.5, 59.4, 48.6, 29.9. 31 P NMR (162 MHz, DMSO- d 6) δ -13.2.

[0063] Example 1: Synthesis of Product III-0

[0064] .

[0065] Reactants I-0 (23 mg, 0.1 mmol, 1.0 equiv.), phenylboronic acid II-0 (30 mg, 0.2 mmol, 2.0 equiv.), 4 Å molecular sieve (125 mg), phenylboronic acid PhB(OH)2 (12 mg, 0.1 mmol, 1.0 equiv.), iron p-toluenesulfonate Fe(OTs)3 (28 mg, 50 mol%, 0.5 equiv.), and a chiral phosphoric acid catalyst ( S )-D2 (7 mg, 10 mol%, 0.1 equiv.) was added sequentially to a dry vial containing 0.5 mL of ultra-dry trifluorotoluene. The reaction system was carried out at a constant temperature of 45 °C with a stirring rate of 800 rpm, and the reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was complete, the reaction mixture was filtered through a short diatomaceous earth filter and passed through a 4 Å molecular sieve. The reaction solution was concentrated to an appropriate volume under vacuum. Using petroleum ether / ethyl acetate as eluent, the product was purified by silica gel column chromatography to obtain the reaction product III-0 as a yellow oily liquid (23 mg). The reaction time was 12 h, the yield was 68%, and the ee value was 95%.

[0066] [α] D 20 = -29.4 ( c 1.0, CHCl3)。 1 H NMR (600 MHz, CDCl3) δ 8.20 (s, 1H),8.05 (d, J = 8.5 Hz, 1H), 7.78 (dd, J = 8.1, 1.4 Hz, 1H), 7.74 (ddd, J = 8.4,6.9, 1.5 Hz, 1H), 7.55 – 7.51 (m, 1H), 7.46 – 7.42 (m, 2H), 7.37 – 7.29 (m,3H), 7.29 (d, J = 3.0 Hz, 1H), 7.26 – 7.24 (m, 3H), 7.23 (dd, J = 7.5, 1.4Hz, 1H), 7.17 (tt, J = 5.7, 2.8 Hz, 1H), 6.48 (dt, J = 15.8, 1.4 Hz, 1H),6.25 (dt, J = 15.8, 7.1 Hz, 1H), 4.49 (s, 1H), 3.43 – 3.36 (m, 1H), 3.12(dtd, J = 14.6, 7.3, 1.4 Hz, 1H). 13 C NMR (151 MHz, CDCl3) δ 163.3, 143.1,137.8, 136.4, 131.7, 129.5, 128.9, 128.7, 128.5, 128.5, 128.5, 128.4, 127.6,127.0, 127.0, 126.8, 126.2, 126.1, 121.5, 54.6, 38.4. HRMS (ESI) m / z calcd.for C 25 H 22 N [M+H] + : 336.1747; found: 336.1745.

[0067] Blank Example 1: Following the asymmetric protonation experimental procedure described in Example 1 above, a large number of chiral phosphoric acid catalysts were screened using compound I-0 as the substrate. All other conditions remained unchanged, the only difference being that "the catalyst (… S "-D2 is replaced by an equal molar amount of other chiral catalysts", and the other chiral catalysts are selected from ( S )-A to ( S )-C、( S )-D1 to ( S )-D7 and ( S )-E to ( S The yields and ee values ​​of the target product III-0 corresponding to )-G are shown below:

[0068] .

[0069] Comparative Example 1: Synthesis of Product III-0

[0070] The conditions in Example 1 were changed to not add Lewis acid (Fe(OTs)3), and the remaining operation steps were the same as in Example 1, finally yielding the corresponding compound III-0.

[0071] The target compound III-0 is a yellow oily liquid. The reaction time is 48 hours, the yield is 63%, and the ee value is 76%.

[0072] Comparative Example 2: Synthesis of Product III-0

[0073] The Lewis acid (Fe(OTs)3) in the conditions of Example 1 was replaced with an equimolar amount of AgOTf, and the remaining operation steps were the same as in Example 1, finally yielding the corresponding compound III-0.

[0074] The target compound III-0 is a yellow oily liquid. The reaction time is 72 hours, the yield is 24%, and the ee value is 88%.

[0075] Comparative Example 3: Synthesis of Product III-0

[0076] The Lewis acid (Fe(OTs)3) in the conditions of Example 1 was replaced with an equimolar amount of Fe(OTf)3, and the remaining operating steps were the same as in Example 1, finally yielding the corresponding compound III-0.

[0077] The target compound III-0 is a yellow oily liquid. The reaction time was 72 hours, the yield was 37%, and the ee value was 90%.

[0078] Comparative Example 4: Synthesis of Product III-0

[0079] The Lewis acid (Fe(OTs)3) in the conditions of Example 1 was replaced with an equimolar amount of LiOTf, and the remaining operation steps were the same as in Example 1, finally yielding the corresponding compound III-0.

[0080] The target compound III-0 is a yellow oily liquid. The reaction time is 72 hours, the yield is 39%, and the ee value is 82%.

[0081] Comparative Example 5: Synthesis of Product III-0

[0082] The conditions in Example 1 were changed to not adding the proton source PhB(OH)2, and the remaining operation steps were the same as in Example 1, finally yielding the corresponding compound III-0.

[0083] The target compound III-0 is a yellow oily liquid. The reaction time is 48 hours, the yield is 48%, and the ee value is 90%.

[0084] Comparative Example 6: Synthesis of Product III-0

[0085] In Example 1, the proton source PhB(OH)2 was replaced with an equimolar amount of B(OH)3, and the remaining steps were the same as in Example 1, finally yielding the corresponding compound III-0.

[0086] The target compound III-0 is a yellow oily liquid. The reaction time is 24 hours, the yield is 67%, and the ee value is 82%.

[0087] Comparative Example 7: Synthesis of Product III-0

[0088] In Example 1, the proton source PhB(OH)2 was replaced with an equimolar amount of H2O, and the remaining operating steps were the same as in Example 1, finally yielding the corresponding compound III-0.

[0089] The target compound III-0 is a yellow oily liquid. The reaction time is 24 hours, the yield is 17%, and the ee value is 48%.

[0090] Comparative Example 8: Synthesis of Product III-0

[0091] In Example 1, the proton source PhB(OH)2 was replaced with an equimolar amount of 4-MeO-PhB(OH)2, and the remaining operating steps were the same as in Example 1, finally yielding the corresponding compound III-0.

[0092] The target compound III-0 is a yellow oily liquid. The reaction time is 24 hours, the yield is 63%, and the ee value is 83%.

[0093] Comparative Example 9: Synthesis of Product III-0

[0094] The conditions in Example 1 were changed to omit the Lewis acid (Fe(OTs)3) and proton source PhB(OH)2, while the remaining operation steps were the same as in Example 1, and the corresponding compound III-0 was finally obtained.

[0095] The target compound III-0 is a yellow oily liquid. The reaction time is 48 hours, the yield is 63%, and the ee value is 73%.

[0096] Comparative Example 10: Synthesis of Product III-0

[0097] The solvent PhCF3 in the conditions of Example 1 was replaced with an equal volume of PhCl, and the remaining operation steps were the same as in Example 1, finally yielding the corresponding compound III-0.

[0098] The target compound III-0 is a yellow oily liquid. The reaction time is 36 hours, the yield is 52%, and the ee value is 72%.

[0099] Comparative Example 11: Synthesis of Product III-0

[0100] The solvent PhCF3 in the conditions of Example 1 was replaced with an equal volume of CCl4, and the remaining operation steps were the same as in Example 1, finally yielding the corresponding compound III-0.

[0101] The target compound III-0 is a yellow oily liquid. The reaction time is 36 hours, the yield is 35%, and the ee value is 68%.

[0102] Example 2: Experimental steps for the preparation of product III-1:

[0103] The compound shown in Formula I-0 in Example 1 was replaced with an equal molar amount of the compound shown in Formula I-1, and the remaining operating steps were the same as in Example 1, finally yielding the corresponding compound product III-1.

[0104] .

[0105] Product III-1 was obtained as a yellow oily liquid. The reaction time was 36 h, the yield was 40%, and the ee value was 96%. [α] D 20 = -18.7 ( c 1.0, CHCl3). 1 H NMR (400 MHz, CDCl3) δ 8.11 (dd, J = 8.9, 4.8 Hz, 2H), 7.79 (dd, J = 8.2, 1.4 Hz, 1H), 7.70 (ddd, J= 8.5, 6.8, 1.5 Hz, 1H), 7.50(t, J = 7.5 Hz, 1H), 7.34 (d, J = 8.5 Hz, 1H), 7.31 – 7.23 (m, 4H), 7.21 –7.13 (m, 1H), 6.42 (d, J = 15.8 Hz, 1H), 6.20 (dt, J = 15.8, 7.2 Hz, 1H), 3.31 (q, J = 7.2 Hz, 1H), 2.80 (dtd, J = 13.7, 6.7, 1.5 Hz, 1H), 2.60 (dt, J = 14.6, 7.7 Hz, 1H), 1.44 (d, J = 7.0 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ166.1, 160.7, 137.6, 136.6, 131.6, 129.4, 128.9, 128.6, 128.4, 127.5, 127.0,127.0, 126.0, 125.9, 119.9, 42.9, 40.4, 20.2 HRMS (ESI) m / z calcd. for C 20 H 19 N[M+H] + : 274.1590; found: 274.1580.

[0106] Example 3: Experimental steps for the preparation of product III-2:

[0107] The compound shown in Formula I-0 in Example 1 was replaced with an equal molar amount of the compound shown in Formula I-2, and the remaining operating steps were the same as in Example 1, finally yielding the corresponding compound product III-2.

[0108] .

[0109] Product III-2 was obtained as a yellow oily liquid. The reaction time was 72 h, the yield was 43%, and the ee value was 98%. [α] D 20 = -26.8 ( c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) δ 8.09 (dd, J = 8.4, 6.2 Hz, 2H), 7.79 (dd, J = 8.1, 1.5 Hz, 1H), 7.70 (ddd, J = 8.5, 6.9, 1.5 Hz, 1H), 7.50(ddd, J = 8.1, 6.8, 1.2 Hz, 1H), 7.30 (d, J = 8.5 Hz, 1H), 7.28 – 7.21 (m,2H), 7.17 (tq, J = 5.3, 2.7 Hz, 1H), 6.46 – 6.29 (m, 1H), 6.16 (dt, J = 15.8,7.2 Hz, 1H), 3.23 – 3.04 (m, 1H), 2.86 – 2.71 (m, 1H), 2.71 – 2.58 (m, 1H),1.85 (q, J = 7.8, 7.3 Hz, 2H), 1.46 – 1.21 (m, 3H), 1.22 – 1.09 (m, 1H), 0.83(t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 165.4, 148.0, 137.7, 136.3,131.4, 129.3, 129.2, 128.8, 128.5, 127.6, 127.1, 127.0, 126.1, 125.8, 120.6,49.0, 39.3, 34.8, 29.9, 22.9, 14.2. HRMS (ESI) m / z calcd. for C 23 H 26 N [M+H] + :316.2060; found: 316.2057.

[0110] Example 4: Experimental steps for the preparation of product III-3:

[0111] The compound shown in Formula I-0 in Example 1 was replaced with an equal molar amount of the compound shown in Formula I-3, and the remaining operating steps were the same as in Example 1, finally yielding the corresponding compound product III-3.

[0112] .

[0113] Product III-3 was obtained as a yellow oily liquid. The reaction time was 12 h, the yield was 70%, and the ee value was 89%. [α] D 20 = -37.5 ( c 1.0, CHCl3). 1 H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 8.5 Hz, 1H), 8.06(d, J = 8.5 Hz, 1H), 7.83 – 7.68 (m, 2H), 7.54 (ddd, J = 8.1, 6.9, 1.2 Hz,1H), 7.47 – 7.35 (m, 2H), 7.28 (d, J = 7.2 Hz, 5H), 7.19 (ddd, J = 8.6, 5.0,3.9 Hz, 1H), 7.12 – 6.92 (m, 2H), 6.48 (dt, J = 15.8, 1.4 Hz, 1H), 6.21 (dt, J = 15.8, 7.1 Hz, 1H), 4.45 (t, J = 7.5 Hz, 1H), 3.37 (dtd, J = 14.4, 7.3,1.4 Hz, 1H), 3.09 (dtd, J = 14.3, 7.7, 7.2, 1.4 Hz, 1H). 13 C NMR (101 MHz, CDCl3) δ 163.1, 163.0, 160.5, 147.9, 138.8, 138.8, 137.7, 136.6, 131.9, 129.8(d, J = 7.8 Hz), 53.7 – 53.5 (m), 129.5 (d, J = 11.7 Hz), 128.6 (d, J = 4.5Hz), 127.6, 127.1 (d, J = 6.4 Hz), 126.2 (d, J= 7.3 Hz), 121.4, 115.6,115.4, 53.8, 38.6. 19 F NMR (376 MHz, CDCl3) δ -119.7. HRMS (ESI) m / z calcd.for C 25 H 21 FN [M+H] + : 354.1653; found: 354.1649.

[0114] Example 5: Experimental steps for the preparation of product III-4:

[0115] The compound shown in Formula I-0 in Example 1 was replaced with an equal molar amount of the compound shown in Formula I-4, and the remaining steps were the same as in Example 1, finally yielding the corresponding compound product III-4.

[0116] .

[0117] Product III-4 was obtained as a yellow oily liquid. The reaction time was 72 h, the yield was 54%, and the ee value was 94%. [α] D 20 = -16.8 ( c 1.0, CHCl3). 1 H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 8.5 Hz, 1H), 8.05(d, J = 8.5 Hz, 1H), 7.82 – 7.70 (m, 2H), 7.53 (ddd, J = 8.1, 6.9, 1.2 Hz,1H), 7.40 – 7.34 (m, 2H), 7.33 – 7.23 (m, 7H), 7.22 – 7.14 (m, 1H), 6.47 (dt, J = 15.7, 1.4 Hz, 1H), 6.20 (dt, J = 15.8, 7.0 Hz, 1H), 4.42 (t, J = 7.5 Hz, 1H), 3.35 (dtd, J = 14.5, 7.3, 1.4 Hz, 1H), 3.17 – 3.00 (m, 1H). 13C NMR (101MHz, CDCl3) δ 162.7, 148.0, 141.7, 137.7, 136.5, 132.5, 132.0, 129.8, 129.5,129.5, 128.8, 128.5, 128.5, 127.6, 127.1, 127.1, 126.2, 126.2, 121.4, 54.0,38.5. HRMS (ESI) m / z calcd. for C 25 H 21 ClN [M+H] + : 370.1357; found: 370.1361.

[0118] Example 6: Experimental steps for the preparation of product III-5:

[0119] The compound shown in Formula I-0 in Example 1 was replaced with an equal molar amount of the compound shown in Formula I-5, and the remaining operating steps were the same as in Example 1, finally yielding the corresponding compound product III-5.

[0120] .

[0121] Product III-5 was obtained as a yellow oily liquid. The reaction time was 12 h, the yield was 86%, and the ee value was 88%. [α] D 20 = -27.1 ( c 1.0, CHCl3). 1 H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 8.4 Hz, 1H), 8.06(d, J = 8.4 Hz, 1H), 7.85 – 7.65 (m, 2H), 7.62 – 7.46 (m, 5H), 7.26 (d, J =7.3 Hz, 3H), 7.22 – 7.14 (m, 1H), 6.59 – 6.37 (m, 1H), 6.19 (dt, J = 15.7, 7.0 Hz, 1H), 4.49 (t, J = 7.7 Hz, 1H), 3.40 (dtd, J = 14.5, 7.3, 1.4 Hz, 1H), 3.24 – 2.88 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 162.19, 147.52 (d, J = 81.7Hz), 137.49, 136.72, 135.20, 132.11, 129.68, 129.44, 129.10, 128.74, 128.56,128.10, 127.66, 127.21, 127.07, 126.37, 126.15, 125.60 (q, J = 3.7 Hz),124.59, 122.98, 121.39, 54.38, 38.45. 19 F NMR (376 MHz, CDCl3) δ -65.6. HRMS(ESI) m / z calcd. for C 26 H 20 F3N [M+Na] + : 426.1440; found: 426.1424.

[0122] Example 7: Experimental steps for the preparation of product III-6:

[0123] The compound shown in Formula I-0 in Example 1 was replaced with an equal molar amount of the compound shown in Formula I-6, and the remaining steps were the same as in Example 1, finally yielding the corresponding compound product III-6.

[0124] .

[0125] Product III-6 was obtained as a yellow oily liquid. The reaction time was 24 h, the yield was 82%, and the ee value was 95%. [α] D 20 = -7.8 ( c 1.0, CHCl3). 1 H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 8.4 Hz, 1H), 8.01(d, J = 8.5 Hz, 1H), 7.83 – 7.66 (m, 2H), 7.51 (ddd, J = 8.1, 6.9, 1.2 Hz,1H), 7.43 – 7.31 (m, 2H), 7.29 – 7.21 (m, 3H), 7.17 (dq, J= 5.6, 2.6 Hz,1H), 7.00 – 6.76 (m, 2H), 6.59 – 6.36 (m, 1H), 6.24 (dt, J = 15.8, 7.0 Hz, 1H), 4.40 (t, J = 7.7 Hz, 1H), 3.78 (s, 3H), 3.35 (dtd, J = 14.4, 7.3, 1.4Hz, 1H), 3.23 – 2.91 (m, 1H). 13 C NMR (101 MHz, CDCl3) δ 163.7, 158.3, 147.9,137.8, 136.3, 135.2, 131.5, 129.4, 129.4, 129.3, 129.0, 128.5, 127.6, 127.0,126.1, 126.0, 121.4, 114.0, 55.3, 53.7, 38.5. HRMS (ESI) m / z calcd. forC 26 H 24 NO [M+H] + : 366.1852; found: 366.1848.

[0126] Example 8: Experimental steps for the preparation of product III-7:

[0127] The compound shown in Formula I-0 in Example 1 was replaced with an equal molar amount of the compound shown in Formula I-7, and the remaining steps were the same as in Example 1, finally yielding the corresponding compound product III-7.

[0128] .

[0129] Product III-7 was obtained as a colorless oily liquid. The reaction time was 24 h, the yield was 72%, and the ee value was 96%. [α] D 20 = -18.4 ( c 1.0, CHCl3). 1 H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 8.5 Hz, 1H), 8.03(d, J = 8.5 Hz, 1H), 7.81 – 7.69 (m, 2H), 7.55 – 7.48 (m, 1H), 7.32 (d, J=7.8 Hz, 2H), 7.30 – 7.21 (m, 5H), 7.21 – 6.96 (m, 3H), 6.68 – 6.38 (m, 1H), 6.25 (dt, J = 15.9, 7.0 Hz, 1H), 4.45 (t, J = 7.7 Hz, 1H), 3.49 – 3.26 (m,1H), 3.19 – 3.00 (m, 1H), 2.33 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 163.6,147.9, 140.1, 137.8, 136.4, 136.3, 131.6, 129.4, 129.4, 129.0, 128.5, 128.2,127.6, 127.0, 127.0, 126.1, 126.0, 121.5, 54.2, 38.4, 21.2. HRMS (ESI) m / z calcd. for C 26 H 24 N [M+H] + : 350.1903; found: 350.1893.

[0130] Example 9: Experimental steps for the preparation of product III-8:

[0131] The compound shown in Formula I-0 in Example 1 was replaced with an equal molar amount of the compound shown in Formula I-8, and the remaining steps were the same as in Example 1, finally yielding the corresponding compound product III-8.

[0132] .

[0133] Product III-8 was obtained as a colorless oily liquid. The reaction time was 48 h, the yield was 40%, and the ee value was 90%. [α] D 20 = -18.9 ( c 1.0, CHCl3). 1 H NMR (400 MHz, CDCl3) δ 8.23 ​​– 8.13 (m, 1H), 7.99 (dd, J = 8.5, 0.7 Hz, 1H), 7.80 – 7.65 (m, 2H), 7.50 (ddd, J = 8.1, 6.9, 1.2 Hz,1H), 7.37 (dd, J= 7.6, 1.7 Hz, 1H), 7.33 – 7.26 (m, 3H), 7.26 – 7.21 (m,3H), 7.20 – 7.13 (m, 1H), 7.00 – 6.83 (m, 2H), 6.46 (dt, J = 15.9, 1.3 Hz, 1H), 6.30 (dt, J = 15.8, 6.9 Hz, 1H), 4.98 (t, J = 7.6 Hz, 1H), 3.84 (s, 3H), 3.41 (dddd, J = 14.4, 8.0, 6.7, 1.4 Hz, 1H), 3.05 (dtd, J = 14.4, 7.3, 1.3Hz, 1H). 13 C NMR (101 MHz, CDCl3) δ 163.6, 157.1, 147.9, 138.0, 136.0, 131.7,131.1, 129.6, 129.5, 129.2, 128.9, 128.4, 127.6, 127.5, 127.0, 126.8, 126.1,125.8, 122.1, 120.8, 110.7, 55.6, 46.3, 37.6. HRMS (ESI) m / z calcd. forC 26 H 24 NO [M+H] + : 366.1852; found: 366.1859.

[0134] Example 10: Experimental steps for the preparation of product III-9:

[0135] The compound shown in Formula I-0 in Example 1 was replaced with an equal molar amount of the compound shown in Formula I-9, and the remaining operating steps were the same as in Example 1, finally yielding the corresponding compound product III-9.

[0136] .

[0137] Product III-9 was obtained as a colorless oily liquid. The reaction time was 12 h, the yield was 69%, and the ee value was 80%. [α] D 20 = -13.7 ( c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 8.4 Hz, 1H), 8.04(d, J = 8.6 Hz, 1H), 7.83 – 7.64 (m, 2H), 7.52 (ddd, J = 8.2, 6.9, 1.2 Hz,1H), 7.29 – 7.22 (m, 5H), 7.21 – 7.15 (m, 1H), 7.14 – 7.07 (m, 3H), 6.48 (dt, J = 15.8, 1.4 Hz, 1H), 6.21 (dt, J = 15.8, 7.0 Hz, 1H), 4.41 (t, J = 7.7 Hz,1H), 3.34 (dtd, J = 14.5, 7.3, 1.4 Hz, 1H), 3.08 (dtd, J = 14.5, 7.2, 1.4 Hz,1H), 2.24 (d, J = 1.9 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 162.9, 162.7, 160.3,147.9, 142.8, 142.8, 137.7, 136.5, 131.8, 131.5 (d, J = 5.5 Hz), 129.5 (d, J = 6.0 Hz), 128.5 (d, J = 4.2 Hz), 127.6, 127.1 (d, J = 2.0 Hz), 126.2 (d, J =3.9 Hz), 123.8 (d, J = 3.2 Hz), 123.1, 123.0, 121.3, 114.8 (d, J = 22.5 Hz),54.0, 38.4, 14.4, 14.3. 19 F NMR (376 MHz, CDCl3) δ -120.5. HRMS (ESI) m / z calcd. for C 26 H 23 FN [M+H]+ : 368.1809; found: 368.1817.

[0138] Example 11: Experimental steps for the preparation of product III-10:

[0139] The compound shown in Formula I-0 in Example 1 was replaced with an equal molar amount of the compound shown in Formula I-10, and the remaining operating steps were the same as in Example 1, finally yielding the corresponding compound product III-10.

[0140] .

[0141] Product III-10 was obtained as a colorless oily liquid. The reaction time was 24 h, the yield was 72%, and the ee value was 92%. [α] D 20 = -35.7 ( c 1.0, CHCl3). 1 H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 8.4 Hz, 1H), 8.00(d, J = 8.5 Hz, 1H), 7.89 (d, J = 1.8 Hz, 1H), 7.88 – 7.78 (m, 3H), 7.75 (td, J = 7.8, 7.1, 1.6 Hz, 2H), 7.58 (dd, J = 8.5, 1.8 Hz, 1H), 7.55 – 7.40 (m,3H), 7.30 (d, J = 8.5 Hz, 1H), 7.29 – 7.21 (m, 4H), 7.21 – 7.11 (m, 1H), 6.54(d, J = 15.9 Hz, 1H), 6.30 (dt, J = 15.8, 7.0 Hz, 1H), 4.63 (t, J = 7.7 Hz, 1H), 3.50 (dtd, J = 14.5, 7.3, 1.4 Hz, 1H), 3.36 – 3.18 (m, 1H). 13C NMR (101MHz, CDCl3) δ 163.2, 147.9, 140.6, 137.7, 136.4, 133.6, 132.5, 131.7, 129.5,129.4, 128.8, 128.5, 128.4, 127.9, 127.7, 127.6, 127.0, 126.9, 126.8, 126.1,126.1, 125.7, 121.6, 54.7, 38.3. HRMS (ESI) m / z calcd. for C 29 H 24 N [M+H] + :386.1903; found: 386.1898.

[0142] Examples 12-16

[0143] This invention has broad substrate applicability. Under the reaction conditions in Example 1, many substrates can participate in the reaction, yielding nitrogen-containing heterocyclic compounds with an α-chiral center in high yield and with high stereoselectivity.

[0144] The experimental methods of Examples 12-16 were repeated in Example 1, except that "the compound shown as Formula I-0 in Example 1 was replaced with an equimolar amount of the alkenyl nitrogen-containing heteroaromatic ring compound shown as Formula I". The remaining steps were the same as in Example 1, and the corresponding nitrogen-containing heteroaromatic ring compound with an α-chiral center, as shown in Formula III, was finally obtained. The reaction formula is as follows:

[0145] ;

[0146] In the above reaction formulas, the substituent R in Formula III is the same as that in Formula I. The molecular structures of the alkenyl nitrogen-containing heteroaromatic ring substrates used in Examples 12-16 are shown in I-11 to I-15, respectively, and the reaction results are shown in Table 1.

[0147] Table 1

[0148] .

[0149] The following are the product data after modification according to the method proposed in Example 1, and the results are shown in Table 1.

[0150] Example: General experimental procedures for the preparation of substrate II-(1-14):

[0151] .

[0152] Taking the synthesis of substrate II-1 as an example, the experimental steps are as follows:

[0153] Step 1: Sonogashira cross-coupling reaction

[0154] Under nitrogen atmosphere, add dichlorobis(triphenylphosphine)palladium (220 mg, 0.36 mmol, 1 mol%), copper iodide (137 mg, 0.72 mmol, 2 mol%), and 3- to a dried 100 mL three-necked flask. After rigorously purging with nitrogen, add ultra-dry tetrahydrofuran solution (25 mL), piperidine (3.7 mL, 37.5 mmol, 3.0 equiv.), and 3- N , N Dimethylbromobenzene (2.5 g, 12.5 mmol, 1.0 equiv.) and trimethylsilylacetylene (9.0 mL, 62.5 mmol, 5.0 equiv.) were added sequentially to the flask, and nitrogen gas was purged through the flask with a long needle for 15 min. The mixture was then allowed to react at room temperature for 36 hours. After the reaction was completed by TLC monitoring, the reaction solution was filtered through diatomaceous earth and washed with dichloromethane (15 mL × 3). The crude product was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether = 100%) to give a colorless oily substance S-int1 (2.3 g, 85% yield).

[0155] Step 2: TMS protection

[0156] Prepare a 100 mL pear-shaped flask. Add S-int1 (2.3 g, 10.6 mmol, 1.0 equiv.) to the flask and dissolve it in methanol (53 mL). Slowly add potassium carbonate (2.9 g, 21.2 mmol, 2.0 equiv.) to the flask. Stir the reaction continuously at 25 °C for 5 hours. Confirm the completion of the reaction by thin-layer chromatography (TLC). Concentrate under reduced pressure, then partition the crude mixture between dichloromethane and water, extract, collect the organic phase, wash with 30 mL of saturated sodium chloride solution, and dehydrate with anhydrous sodium sulfate. After filtration, remove the solvent under reduced pressure. Purify the crude product by silica gel column chromatography (petroleum ether = 100%) to obtain a clear liquid alkyne S-int2 (1.5 g, 99% yield).

[0157] Step 3: Copper-mediated hydroboration reaction

[0158] Chlorinated ketone (107 mg, 1.08 mmol, 10 mol%), bis(2-diphenylphosphine) ether (581 mg, 1.08 mmol, 10 mol%), and sodium tert-butoxide (242 mg, 2.16 mmol, 0.2 equiv.) were sequentially added to a dry 100 mL three-necked flask, followed by the addition of tetrahydrofuran (29 mL) under nitrogen protection. After stirring at room temperature for 45 minutes, bis(pinacol)diboron (5.4 g, 21.6 mmol, 2.0 equiv.) dissolved in tetrahydrofuran (28 mL) was added dropwise to the reaction system at room temperature using a syringe, and the mixture was stirred for 30 minutes under nitrogen atmosphere. Then, a solution of alkyne S-int2 (1.5 g, 10.8 mmol, 1.0 equiv.) in tetrahydrofuran was slowly added dropwise, followed by the dropwise addition of methanol (1.3 mL, 32.4 mmol, 3.0 equiv.). Once the reaction was complete as monitored by TLC, the mixture was immediately filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate (30 mL × 3). After rotary evaporation and concentration, the crude product was purified by silica gel rapid chromatography (petroleum ether / ethyl acetate = 90 / 1 (v / v)) to give the yellow oily liquid borate compound S-int3 (2.3 g, 77% yield).

[0159] Step 4: Hydrolysis of borate esters

[0160] Prepare a 100 mL single-necked flask and dissolve borate ester S-int3 in a mixture of acetone / water (21 mL / 21 mL) and stir thoroughly. Then, add sodium periodate (8.9 g, 41.8 mmol, 5.0 equiv.) and ammonium acetate (3.2 g, 41.8 mmol, 5.0 equiv.) to the reaction flask and stir continuously at 25 °C for 5 hours. After thin-layer chromatography (TLC) confirms the completion of the reaction, filter with diatomaceous earth and wash the filter cake with ethyl acetate (40 mL × 3). After concentrating under reduced pressure to remove most of the acetone, wash the organic layer with saturated brine (50 mL) and extract with ethyl acetate (40 mL × 3). Dehydrate the organic phase with anhydrous sodium sulfate, filter, remove the solvent by reduced pressure distillation, and then pulverize the concentrated crude product with analytical grade petroleum ether (PE) at room temperature for 1 hour. After filtration through a 50 mL sintered glass funnel, the filter cake was washed with petroleum ether (30 mL × 3) to obtain crude boric acid. The crude product was further recrystallized with water and acetone to precipitate the final product as crystals, yielding powdered solid II-1 (387 mg, 30% yield).

[0161] mp: 172.3 - 180.5℃. 1H NMR (400 MHz, CDCl3) δ 6.88 (dt, J = 7.5, 1.3Hz, 1H), 6.82 (t, J = 2.1 Hz, 1H), 6.81 – 6.73 (m, 1H), 6.73 – 6.70 (m, 1H), 5.79 (dd, J = 17.5, 1.1 Hz, 1H), 5.27 (dd, J = 10.8, 1.1 Hz, 1H), 3.01 (s, 6H). 13 C NMR (101 MHz, CDCl3) δ 150.9, 138.5, 137.8, 129.3, 115.0, 113.5,112.6, 110.8, 40.9. HRMS (ESI) m / z calcd. for C 10 H 14 BNO2 [M+H] + : 192.1190; found: 192.1187.

[0162] Example 17: Synthesis of Product IV-1

[0163] .

[0164] The reactants I-0 (23 mg, 0.1 mmol, 1.0 equiv.), arylalenoboronic acid II-1 (30 mg, 0.2 mmol, 2.0 equiv.), 4 Å molecular sieve (125 mg), phenylboronic acid (12 mg, 0.1 mmol, 1.0 equiv.), ferric p-toluenesulfonate (28 mg, 50 mol%, 0.5 equiv.), and a chiral phosphoric acid catalyst ( S D2 (7 mg, 10 mol%, 0.1 equiv.) was added sequentially to a dry vial containing 0.5 mL of ultra-dry trifluorotoluene. The reaction system was carried out at a constant temperature of 45 °C with a stirring rate of 800 rpm, and the reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was complete, the reaction mixture was filtered through a short diatomaceous earth filter and passed through a 4 Å molecular sieve. The reaction solution was concentrated to an appropriate volume under vacuum. Using petroleum ether / ethyl acetate as eluent, the product IV-1 was purified by silica gel column chromatography to obtain a yellow oily substance (24 mg). The reaction time was 24 h, the yield was 62%, and the ee value was 91%.

[0165] [α] D D 20 = -20.1 ( c 1.0, CHCl3). 1 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J =8.5 Hz, 1H), 8.02 (d, J = 8.5 Hz, 1H), 7.79 – 7.67 (m, 2H), 7.50 (ddd, J =8.1, 6.9, 1.2 Hz, 1H), 7.45 – 7.39 (m, 2H), 7.29 (dd, J = 14.1, 6.7 Hz, 3H),7.24 – 7.17 (m, 1H), 7.11 (t, J = 7.8 Hz, 1H), 6.65 (d, J = 7.6 Hz, 1H), 6.63– 6.54 (m, 2H), 6.43 (d, J = 15.8 Hz, 1H), 6.19 (dt, J = 15.6, 7.0 Hz, 1H),4.51 – 4.41 (m, 1H), 3.40 – 3.27 (m, 1H), 3.14 – 3.00 (m, 1H), 2.90 (s, 6H). 13 13C NMR (101 MHz, CDCl3) δ 163.4, 150.9, 147.9, 143.2, 138.6, 136.4, 132.5,129.4, 129.1, 128.7, 128.4, 127.6, 127.1, 126.7, 126.1, 121.5, 114.8, 111.8,110.9, 54.6, 40.8, 38.5. HRMS (ESI) m / z calcd. for C 27 H 26 N2 [M+H] + : 379.2169;found: 379.2167.

[0166] Examples 18 - 30

[0167] This invention has broad substrate applicability. Under the reaction conditions in Example 17, many substrates can participate in the reaction to obtain nitrogen-containing heterocyclic compounds containing an α-chiral center in high yield and with high stereoselectivity.

[0168] The experimental methods of Examples 18-30 were repeated in Example 17, except that "the compound shown in Formula II-1 in Example 17 was replaced with an equimolar amount of the aryl alkenylboronic acid substrate shown in Formula II". The remaining procedures were the same as in Example 17, and the corresponding nitrogen-containing heteroaromatic ring compound with an α-chiral center, as shown in Formula IV, was finally obtained. The reaction formula is as follows:

[0169] .

[0170] In the above reaction formulas, the substituent Ar in Formula IV is the same as that in Formula II. The molecular structures of the aryl alkenylboronic acid substrates used in Examples 18-30 are shown as II-2 to II-14, respectively, and the reaction results are shown in Table 2.

[0171] Table 2

[0172] .

[0173] The following are the product data after modification according to the method proposed in Example 17, and the results are shown in Table 2.

[0174] Special Note: Example II-2 a II-6 a II-7 a In this process, the temperature of the asymmetric protonation reaction was reduced from 45°C to 35°C. Example II-14 b In this process, the temperature of the asymmetric protonation reaction is reduced from 45℃ to 0℃.

[0175] Example 31: Application of the product

[0176] ;

[0177] Example 31-a

[0178] ;

[0179] Experiment 31-a, Preparation steps of derivative 2:

[0180] Compound 1 (37 mg, 0.1 mmol) was dissolved in 8 mL of dichloromethane and 2.0 mL of 2.5 M sodium hydroxide methanol solution under anhydrous and oxygen-free conditions, and the reaction was carried out at -78 °C. Ozone was introduced during the reaction with continuous stirring. After 0.5 hours of reaction, the reaction solution changed from the initial yellow color to the characteristic blue color of ozone, and a yellow precipitate was formed. The reaction system was then slowly heated to room temperature and the reaction was continued for 1 hour. After the reaction was completed, the reaction system was diluted with ethyl acetate and water, and extracted with ethyl acetate (10 mL × 3). After combining the organic layers, the mixture was dehydrated with anhydrous sodium sulfate, and then the solvent was removed by vacuum evaporation. The crude product was separated by silica gel column chromatography with a gradient elution of petroleum ether / ethyl acetate (12 / 1-8 / 1 (v / v)) to finally obtain a colorless oily product 2 (16 mg), with a separation yield of 50% and an ee value of 93%.

[0181] [α] D 20 = –15.3 (c 1.0, CHCl3); 1 H NMR (400 MHz, CDCl3) δ 8.09 (d, J =7.3 Hz, 1H), 8.00 (d, J = 8.5 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.70 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.53 – 7.47 (m, 1H), 7.26 (q, J = 8.4 Hz, 4H), 7.19(d, J = 8.5 Hz, 1H), 4.80 (d, J = 7.9 Hz, 1H), 3.65 (dd, J = 16.5, 8.5 Hz,1H), 3.62 (s, 3H), 3.02 (dd, J = 16.4, 6.8 Hz, 1H). 13 C NMR (101 MHz, CDCl3) δ172.9, 161.4, 141.2, 136.5, 132.9, 129.8, 129.5, 129.0, 127.6, 127.1, 126.4,121.8, 51.8, 48.9, 39.4. HRMS (ESI) m / z calcd. for C19 H 16 ClNO2 [M+H] + :326.0942; found: 326.0965.

[0182] Example 31-b

[0183] ;

[0184] Experiment 31-b, Preparation steps of derivative 3:

[0185] Compound 2 (34 mg, 0.1 mmol, 1.0 equiv.) and a methanol / deionized water mixture (0.6 mL / 0.2 mL) were added to a 10 mL round-bottom flask, and a magnetic stir bar was placed inside. Lithium hydroxide monohydrate (3 mg, 0.15 mmol, 1.5 equiv.) was then added, and the reaction mixture was stirred at 25 °C for 12 hours. After the reaction was complete, the reaction mixture was acidified to pH 1-2 with 1 M hydrochloric acid aqueous solution, followed by extraction with dichloromethane (10 mL × 3). All organic layers were combined, dehydrated using anhydrous sodium sulfate, filtered, concentrated by vacuum distillation, and finally dried under high vacuum to obtain a white solid, target product 3 (26 mg), with a separation yield of 83% and an ee value of 90%.

[0186] [α] D 20 = –16.8 (c 1.0, CHCl3); 1 H NMR (400 MHz, DMSO- d 6) δ 12.15 (s, 1H), 8.24 (d, J = 8.5 Hz, 1H), 7.99 (dd, J = 8.5, 1.1 Hz, 1H), 7.91 (dd, J =8.2, 1.4 Hz, 1H), 7.74 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H), 7.56 (ddd, J = 8.1,6.8, 1.2 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.42 – 7.37 (m, 2H), 7.33 (d, J =8.5 Hz, 2H), 4.77 (dd, J= 8.8, 6.5 Hz, 1H), 3.47 (dd, J = 16.5, 8.9 Hz, 1H), 2.97 (dd, J = 16.4, 6.6 Hz, 1H). 13 C NMR (101 MHz, DMSO- d 6) δ 172.8, 162.1,146.9, 141.7, 136.7, 131.3, 129.9, 129.6, 128.7, 128.5, 127.8, 126.7, 126.2,121.9, 48.0, 38.6. HRMS (ESI) m / z calcd. for C 18 H 14 ClNO2 [M+H] + : 312.0786;found: 312.0786.

[0187] Example 31-c

[0188] ;

[0189] Experiment 31-c, Preparation steps of derivative 4:

[0190] Under anhydrous and oxygen-free conditions, compound 1 (1.0 g, 2.7 mmol, 1.0 equiv.) was dissolved in 18 mL of an ultra-dry dichloromethane / methanol (1 / 1 (v / v)) mixture and added to a 50 mL Schlenk flask pre-dried by a flame and fitted with a stir bar. The solution was cooled to -78 °C and stirred for 10 min. Ozone was continuously bubbled into the reaction solution until the blue color persisted for 10 min. Nitrogen was then bubbled through for 15 min to remove excess ozone. The reaction was terminated by adding sodium borohydride (511 mg, 13.5 mmol, 5.0 equiv.) in portions at -78 °C. The reaction system was slowly heated to room temperature and stirred for 60 min. After the reaction was complete, 30 mL of deionized water was added to quench the reaction, and the mixture was extracted multiple times with dichloromethane (50 mL × 3). After merging the organic layers, the product was washed sequentially with 20 mL of saturated sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Finally, it was separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1 (v / v)) to give a yellow oily product 4 (466 mg), with a separation yield of 58% and an ee value of 91%.

[0191] [α] D 20= –29.0 (c 1.0, CHCl3); 1 H NMR (400 MHz, CDCl3) δ 8.08 (dt, J =8.5, 1.0 Hz, 1H), 8.00 (dd, J = 8.6, 0.8 Hz, 1H), 7.75 (dd, J = 8.1, 1.5 Hz, 1H), 7.69 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.50 (ddd, J = 8.1, 6.9, 1.2 Hz,1H), 7.28 – 7.19 (m, 4H), 7.16 (d, J = 8.5 Hz, 1H), 4.56 (dd, J = 8.5, 5.4Hz, 1H), 3.75 – 3.60 (m, 2H), 2.58 – 2.36 (m, 2H). 13 C NMR (400 MHz, CDCl3) δ163.0, 147.0, 141.5, 137.0, 132.5, 129.8, 129.8, 128.8, 128.7, 127.6, 126.9,126.5, 121.7, 60.2, 50.9, 37.2. HRMS (ESI) m / z calcd. for C 19 H 16 ClNO [M+H] + :310.0993; found: 310.1016.

[0192] Example 31-d

[0193] ;

[0194] Experimental steps for the preparation of derivatives 5 and 6 in Experiment 31-d:

[0195] Prepare a 25 mL Schlenk flask. Under anhydrous, oxygen-free, and nitrogen-purged conditions, dissolve the starting material, primary alcohol compound 4 (89 mg, 0.26 mmol, 1.0 equiv.), in anhydrous tetrahydrofuran (2.7 mL). Cool to 0°C in an ice bath. At this temperature, sequentially add o-nitrophenyl selenocyanate (136 mg, 0.5 mmol, 2.0 equiv.) and tri-n-butylphosphine (121 mg, 0.5 mmol, 2.0 equiv.). The reaction mixture is heated to room temperature and stirred continuously for 120 minutes. After the reaction is complete, slowly add m-chloroperoxybenzoic acid (…) at -40°C. m CPBA (85% purity, 41 mg) was added, and after reacting for 10 minutes, 2,4,6-trimethylpyridine (29 mg, 0.24 mmol) was added. The reaction temperature was slowly increased to 0°C under programmed control to continue the reaction. After the reaction was monitored to completion by thin-layer chromatography, 15 mL of saturated sodium thiosulfate solution was added under ice bath conditions to terminate the reaction. After separation, the aqueous layer was extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed successively with 30 mL of saturated sodium chloride solution, dehydrated with anhydrous sodium sulfate, and finally concentrated by vacuum evaporation. The crude product was separated by gradient elution using silica gel column chromatography (petroleum ether / ethyl acetate = 80 / 1-50 / 1 (v / v)) to finally obtain colorless oily olefin product 5 (11 mg, 31% yield, 73% ee) and colorless oily olefin product 6 (17 mg, 50% yield).

[0196] [α] D 20 = –21.1 (c 1.0, CHCl3); 1 H NMR (400 MHz, DMSO- d 6) δ 8.30 (d, J =8.5 Hz, 1H), 7.98 (d, J = 8.5 Hz, 1H), 7.93 (dd, J = 8.1, 1.5 Hz, 1H), 7.74(ddd, J = 8.5, 6.9, 1.5 Hz, 1H), 7.57 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 7.45(d, J = 8.5 Hz, 1H), 7.40 – 7.28 (m, 4H), 6.61 (ddd, J = 16.9, 10.1, 8.1 Hz,1H), 5.24 (d,J = 10.2 Hz, 1H), 5.19 – 5.09 (m, 2H). 13 C NMR (101 MHz, DMSO- d 6) δ 162.2, 147.2, 141.4, 139.5, 136.9, 131.2, 130.0, 129.7, 128.6, 128.5,127.8, 126.6, 126.3, 121.4, 116.7, 56.5. HRMS (ESI) m / z calcd. for C 18 H 14 ClN[M+H] + : 280.0888; found: 280.0888.

[0197] 1 H NMR (400 MHz, CDCl3) δ 8.1 (d, J = 8.5 Hz, 1H), 8.0 (d, J = 8.6 Hz,1H), 7.8 (dd, J = 8.2, 1.5 Hz, 1H), 7.7 (ddd, J = 8.5, 6.9, 1.5 Hz, 1H), 7.5(ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.4 – 7.4 (m, 2H), 7.2 – 7.2 (m, 2H), 7.1(dd, J = 15.4, 7.9 Hz, 2H), 1.9 (d, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, CDCl3)δ 158.73, 147.90, 141.13, 137.17, 136.31, 133.30, 131.72, 130.93, 129.80,129.56, 128.84, 127.52, 127.22, 126.26, 120.67, 15.92.

[0198] Through this series of embodiments, the present invention demonstrates its high efficiency and broad applicability to various structural substrates while maintaining high yield and high stereoselectivity. Finally, it should be noted that the above examples are merely specific embodiments of the present invention. Obviously, the present invention is not limited to the above embodiments and many variations are possible. All variations that can be directly derived from or conceived by those skilled in the art from the disclosure of this invention should be considered within the scope of protection of this invention.

Claims

1. A process for the synthesis of aza-heteroaromatic rings with a chiral center in the α-position, catalyzed by a chiral phosphoric acid in cooperation with a Lewis acid, characterized in that A conjugate addition-asymmetric protonation reaction is carried out in the presence of a Lewis acid catalyst, a chiral phosphoric acid catalyst, an organic solvent, an additive and a proton source, using a nitrogen-containing heteroaromatic ring olefin I as an electrophile and an arylalkyl boronic acid II as a carbon nucleophile, to produce an α-chiral nitrogen-containing heteroaromatic compound shown as formula V; the reaction process is shown in the following reaction formula: ； X is selected from one of C, N; R is selected from one of C6-C10 aryl, C4-C8 heteroaryl containing 1-4 heteroatoms selected from N, O, S, C1-C4 alkyl; the aromatic ring of the C6-C10 aryl is unsubstituted or substituted with one or more substituents independently selected from halogen, trifluoromethyl, alkoxy; or the structure of the nitrogen-containing heteroaromatic ring olefin I is shown as formula I-7, I-9, I-11 or I-12; 、 、 、 ； Ar is selected from one of C6-C12 aryl which can be substituted or unsubstituted, C5-C8 heteroaryl containing 1-2 heteroatoms selected from S and O; the substituents on the aromatic ring of the C6-C12 aryl are one or more, and each substituent is independently selected from halogen, nitro, phenyl, cyano, ester or alkoxy; or the structure of the arylalkyl boronic acid II is shown as formula II-1, II-6 or II-11; 、 、 ； The organic solvent is selected from one or a combination of several of trifluorotoluene, chlorobenzene, carbon tetrachloride; The chiral phosphoric acid catalyst is selected from one of the following: 、 ； ； The additive is a molecular sieve, and the type is 3Å molecular sieve, 4Å molecular sieve or 5Å molecular sieve; The Lewis acid is at least one of silver triflate, iron triflate, iron p-toluene sulfonate, lithium triflate; The proton source is at least one of boric acid, phenylboric acid, p-methoxyphenylboric acid; the molar ratio of the proton source to compound I is 0.5-2:

1.

2. A process for the synthesis of α-chiral center bearing nitrogen heteroaromatic ring catalyzed by a chiral phosphoric acid in cooperation with a Lewis acid according to claim 1, characterized in that 1,1-disubstituted nitrogen-containing heteroaromatic ring olefin compounds represented by Formula I include one of the following: .

3. A process for the synthesis of α-chiral center bearing nitrogen heteroaromatic ring catalyzed by a chiral phosphoric acid in cooperation with a Lewis acid according to claim 1, characterized in that The alkenyl boronic acid nucleophile shown as formula II includes one of the following: 。 4. A process for the synthesis of α-chiral center bearing nitrogen heteroaromatic ring catalyzed by a chiral phosphoric acid in cooperation with a Lewis acid according to claim 1, characterized by The asymmetric protonation reaction temperature is between 30°C and 50°C.

5. A process for the synthesis of α-chiral center bearing nitrogen heteroaromatic ring catalyzed by a chiral phosphoric acid in cooperation with a Lewis acid according to claim 1, characterized by The mass of the molecular sieve to the amount of substance of the compound shown as formula I is 1-2:1, the unit of mass is g, and the unit of amount of substance is mmol.

6. The method for synthesizing an α-chiral central nitrogen-containing aromatic ring under the co-catalysis of chiral phosphoric acid and Lewis acid as described in claim 1, characterized in that, The molar ratio of the Lewis acid to compound I is 0.2-0.8:

1.

7. The method for synthesizing an α-chiral central nitrogen-containing aromatic ring under the co-catalysis of chiral phosphoric acid and a Lewis acid as described in claim 1, characterized in that, The molar ratio of compound I to compound II is 1:1.5-3.

8. The method for synthesizing an α-chiral-centered nitrogen-containing aromatic ring under the co-catalysis of chiral phosphoric acid and a Lewis acid as described in claim 1, characterized in that, The amount of substance of the chiral phosphoric acid catalyst to compound I is 0.05-0.2:1.

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