Chiral spiro lactam and synthesis method thereof

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to chiral spiro lactam and a synthesis method thereof. According to the method, by switching a metal catalyst and a chiral ligand system, high-stereoselectivity synthesis of chiral spiro lactam with spiro quaternary carbon centers, namely chiral spiro gamma-lactam and chiral delta-lactam, is realized for the first time starting from a beta-ketoamide precursor connected with the same alkynyl group, and large-scale preparation can be realized. Compared with the prior art, the method disclosed by the invention is mild in condition, simple, efficient, easy to operate and good in repeatability, and has excellent regioselectivity and stereoselectivity.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a chiral spirocyclic lactam and its synthesis method. Background Technology

[0002] Spirocyclic γ-lactams and δ-lactams are important structural units widely found in drug molecules and natural products, exhibiting excellent biological activity and stereoselectivity. Their rigid helical chiral structure enables precise three-dimensional arrangement of pharmacophores, often translating into enhanced target selectivity and metabolic stability. Despite continued interest in these structural units within the chemical community, the asymmetric synthesis of spirocyclic compounds remains highly challenging, primarily due to the difficulty in constructing chiral tetrasubstituted spirocarbon centers. Traditional synthetic methods typically require multi-step reactions, demanding conditions, and struggle with stereoselectivity control, while also failing to achieve regioselectivity switching.

[0003] Over the past decade, a series of innovative asymmetric catalytic methods have provided a practical platform for constructing chiral spirocyclic skeletons. In particular, catalytic asymmetric intramolecular alkyne nucleophilic addition reactions have become a crucial and atom-economical method for constructing chiral pure skeletons in modern synthesis. However, achieving high enantioselectivity in synthesis while selectively switching between 5-exo-dig and 6-endo-dig cyclization modes remains an unsolved challenge.

[0004] While current reports on the synthesis of chiral spirocyclic compounds via the 5-exo-dig cyclization mode exhibit good stereoselectivity, they all fail to control the regioselectivity of alkynes. In 2021, the teams of Longwu Ye from Xiamen University and Xin Hong from Zhejiang University developed a strategy for the direct activation of alkyne amides by chiral Brønsted acids. This strategy achieved highly enantioselective dearomatization spirocyclic reactions of naphthol, phenol, and pyrrolithamides, efficiently constructing chiral spirocyclic enones and 2H-pyrrole skeletons with high enantioselectivity, overcoming the limitations of traditional chiral acid catalysis (Zhang, Y.-Q.; Chen, Y.-B.; Liu, J.-R.; Wu, S.-Q.; Fan, X.-Y.; Zhang, Z.-X.; Hong, X.; Ye, L.-W. Nat. Chem. 2021, 13, 1093-1100). In 2021, the team of Ye Jinxing, Liu Zhen, and Cheng Ruihua at East China University of Science and Technology developed a double silver / double amine complex catalytic system to achieve the asymmetric vinyl conia-ene reaction of alkynylcyclohexenone, efficiently constructing chiral all-carbon spirocyclic compounds (Zou, C.; Yang, L.; Zhang, L.; Liu, C.; Ma, Y.; Song, G.; Liu, Z.; Cheng, R.; Ye, J. ACS Catal. 2021, 11, 6865-6871). In 2022, the team of Zhang Liming at the University of California, Santa Barbara, and You Shuli at the Shanghai Institute of Organic Chemistry developed an asymmetric gold-catalyzed dearomatization-cyclization method based on a metal-chiral ligand synergistic strategy. By designing and synthesizing novel bifunctional axially chiral phosphine ligands, highly enantioselective spirocyclic reactions of naphthol and phenol derivatives were achieved, efficiently constructing chiral spiro[5,5]trienone skeletons (Zhao, K.; Kohnke, P.; Yang, Z.-G.; Cheng, X.-P.; You, S.-L.; Zhang, L.-M. Angew. Chem., Int. Ed.2022, 61, No. e202207518). In 2025, Eric N. Jacobsen's team at Harvard University developed a co-catalytic system of chiral proton donors and gold(I) to achieve highly enantioselective dearomatization spirocyclic reactions of naphthol, efficiently constructing spirocyclic compounds containing quaternary carbon chiral centers (Adrianov, T.; Jacobsen, ENJ Am. Chem. Soc. 2025,147, 41229-41236).

[0005] In stark contrast, to date, only a few examples of constructing spirocyclic δ-lactams via the 6-endo-dig cyclization mode have been reported, and all of them are racemic reactions. In 2023, the team of Luo Mujia and Xiao Qiang at Jiangxi University of Science and Technology developed a catalyst-free and chemical oxidant-free electrochemical method to generate aromatic free radical cations through anodic oxidation, which promotes the spirocyclization reaction of diaryl acetylacetonates with alcohols, efficiently synthesizing alkoxylated spiro[5,5]trienones (Zhou, W.; Li, Z.-Q.; Cheng, C.; Lu, L.; Yang, R.; Song, X.-R.; Luo, M.-J.; Xiao, Q. Org. Lett. 2023, 25, 9158-9163). In 2025, the teams of Liang Renxiao from Zhejiang University of Technology and Jia Yixia from Tianjin University of Technology developed a palladium-catalyzed 1,6-enyne cyclization isomerization reaction linking benzofuran and indole to an alkyne group, efficiently constructing spirocyclic dihydrobenzofuran and indoline compounds via 6-endo-dig cyclization (Lu, J.-B. Wang, Y.-F.; Xu, X.-T. Wang, B.-X.; Liang, R.-X.; Jia, Y.-X. Chem. Commun. 2025, 61, 7616-7619). Industrially, the synthesis of such spirocyclic lactams still largely employs traditional methods, such as intramolecular cyclization, rearrangement reactions, or multicomponent reactions, which generally suffer from lengthy steps, poor regioselectivity, difficulty in stereocontrol, and low atom economy. Especially when constructing spirocyclic lactams containing quaternary carbon chiral centers, existing methods often require chiral auxiliary groups, stoichiometric chiral reagents, or complex ligands, resulting in high costs and difficulty in scaling up.

[0006] Chinese patent CN120887876A discloses a method for synthesizing spiro[4.5]trienone compounds containing difluoroγ-lactams via photocatalytic reaction under an argon atmosphere and blue light irradiation. This method uses N-(4-methoxyphenyl)-N-methyl-3-phenylpropionamide and N-allyl-2,2-difluoro-2-bromo-N-arylacetamide as raw materials, reacting them in acetonitrile in the presence of an iridium catalyst and potassium carbonate to prepare γ-lactam compounds in a one-pot reaction. This method is simple to operate and has a wide substrate applicability, but all reactions are racemic. Chinese patent CN120349325A discloses a palladium-catalyzed method for synthesizing six-membered azaspirocyclic dihydrobenzofuran compounds. This method uses C2-acetylsyl benzofuran derivatives as raw materials, and in the presence of a palladium catalyst, ligands, and acetic anhydride, heats in an organic solvent to construct a δ-lactam skeleton in one step via an intramolecular [3+2] cycloaddition reaction. This method is simple to operate, has mild conditions, and is applicable to a wide range of substrates, but it cannot control the regioselectivity of alkynes, and all reactions are racemic. Summary of the Invention

[0007] The purpose of this invention is to overcome the defects of the prior art and provide a chiral spirocyclic lactam and its synthesis method. The method is to achieve regioselective asymmetric synthesis of chiral spirocyclic γ-lactam and chiral spirocyclic δ-lactam through catalyst regulation.

[0008] This invention aims to achieve highly regioselective and stereoselective synthesis of chiral spirocyclic lactams with different ring systems by switching catalytic systems, starting from the same precursor. Specifically, the overall inventive concept is as follows: by designing and identifying specific combinations of metal catalysts and chiral ligands, and utilizing the differences in activation modes of alkyne precursors by different metals (such as Cu and Ni) and their matching chiral ligands, the intramolecular cyclization reaction is precisely controlled to selectively follow the 5-exo-dig or 6-endo-dig pathway, thereby achieving diverse and highly enantioselective synthesis of chiral spirocyclic γ-lactams and chiral spirocyclic δ-lactams using a common β-ketoamide precursor as a starting material.

[0009] The objective of this invention can be achieved through the following technical solutions: A method for synthesizing a chiral spirocyclic lactam, comprising: Using β-ketoamide compounds as substrates, intramolecular cyclization reactions were carried out in the presence of a catalyst system to obtain chiral spirocyclic lactams; The structural formula of the β-ketoamide compound is shown in Formula 1 below: (Equation 1) In Formula 1, R is independently selected from hydrogen, aryl, aliphatic hydrocarbon, halogen, or ether group; R 1 It is alkyl or aryl.

[0010] Preferably, the aryl group is selected from phenyl, monosubstituted phenyl, disubstituted phenyl, trisubstituted phenyl or naphthyl; the alkyl group is selected from methyl, tert-butyl, methoxy or trifluoromethyl.

[0011] In this invention, β-ketoamide compounds undergo asymmetric cyclization reactions, where the substituents on the benzene ring can be unsaturated aliphatic hydrocarbon groups, saturated aliphatic hydrocarbon groups, halogens, ether groups, or aryl groups, etc. Different types of substituents (electron-donating and electron-withdrawing groups) have different effects on the cyclization reaction, but this effect is mainly reflected in the yield, with little impact on the regioselectivity and stereoselectivity of the reaction. Furthermore, when the benzene ring is disubstituted or trisubstituted, the effect on the cyclization reaction is minimal, and excellent regioselectivity and stereoselectivity can be obtained in both cases. At the same time, this reaction can be scaled up to gram scales, and the yield, regioselectivity, and stereoselectivity of the product remain essentially unchanged after scale-up.

[0012] Furthermore, the catalyst system is either a first catalytic system or a second catalytic system; The first catalytic system comprises a copper salt and a chiral pyrazine-bisoxazoline ligand; the molar ratio of the copper salt to the β-ketoamide compound is 0.1:1 to 0.2:1, and the molar ratio of the chiral bisoxazoline ligand to the β-ketoamide compound is 0.1:1 to 0.15:1; preferably, the molar ratio of the copper salt to the β-ketoamide compound is 0.15:1, and the molar ratio of the chiral bisoxazoline ligand to the β-ketoamide compound is 0.18:1. The second catalytic system comprises a nickel salt and a chiral bisoxazoline ligand; the molar ratio of the nickel salt to the β-ketoamide compound is 0.05:1 to 0.15:1; the molar ratio of the chiral bisoxazoline ligand to the β-ketoamide compound is 0.1:1 to 0.15:1; preferably, the molar ratio of the nickel salt to the β-ketoamide compound is 0.1:1; and the molar ratio of the chiral bisoxazoline ligand to the β-ketoamide compound is 0.12:1.

[0013] Furthermore, the β-ketoamide compound undergoes an intramolecular cyclization (5-exo-dig cyclization) reaction under the catalysis of the first catalytic system to obtain a chiral spirocyclic γ-lactam compound, the structural formula of which is shown in Formula 2. (Equation 2) In Formula 2, R is independently selected from hydrogen, aryl, aliphatic hydrocarbon, halogen, or ether group; R 1 It is alkyl or aryl; Preferably, the aryl group is selected from phenyl, monosubstituted phenyl, disubstituted phenyl, trisubstituted phenyl, or naphthyl; the alkyl group is selected from methyl, tert-butyl, methoxy, or trifluoromethyl. The above reaction is carried out in a haloalkane solvent.

[0014] Furthermore, the copper salt is selected from at least one of copper tetrafluoroborate tetraacetonitrile (Cu(MeCN)4BF4), copper tetraacetonitrile hexafluorophosphate (Cu(MeCN)4PF6), cuprous trifluoromethanesulfonate (CuOTf), and copper acetate (Cu(OAc)2).

[0015] Furthermore, the haloalkane solvent includes dichloromethane (DCM), 1,2-dichloroethane (DCE), or chloroform (CHCl3).

[0016] Furthermore, the reaction for synthesizing the chiral spirocyclic γ-lactam compound is carried out under a nitrogen atmosphere, with the reaction temperature controlled at 30-50 °C and the reaction time at 13-23 hours; preferably, the reaction temperature is controlled at 40 °C and the reaction time at 18 hours.

[0017] Furthermore, the β-ketoamide compound undergoes an intramolecular cyclization (6-endo-dig cyclization) reaction under the catalysis of the second catalytic system to obtain a chiral spirocyclic δ-lactam compound, the structural formula of which is shown in Formula 3. (Equation 3) In Formula 3, R is independently selected from hydrogen, aryl, aliphatic hydrocarbon, halogen, or ether group; R 1 It is alkyl or aryl; Preferably, the aryl group is selected from phenyl, monosubstituted phenyl, disubstituted phenyl, trisubstituted phenyl, or naphthyl; the alkyl group is selected from methyl, tert-butyl, methoxy, or trifluoromethyl. The above reaction is carried out in an ester solvent.

[0018] Furthermore, the nickel salt is selected from at least one of nickel tetrafluoroborate hexahydrate, nickel perchlorate hexahydrate, nickel trifluoromethanesulfonate, and nickel acetate.

[0019] Furthermore, the ester solvent includes ethyl acetate (EtOAc), butyl acetate, isopropyl acetate, or tert-butyl acetate.

[0020] Furthermore, the reaction to synthesize the chiral spirocyclic δ-lactam compound is carried out under a nitrogen atmosphere, with the reaction temperature controlled at 70-90 °C and the reaction time at 60-84 hours; preferably, the reaction temperature is controlled at 80 °C and the reaction time at 72 hours.

[0021] Furthermore, the intramolecular cyclization reaction is carried out in the presence of a base; The molar ratio of the base to the β-ketoamide compound is from 1.0:1 to 1.5:1; The base is selected from at least one of triethylamine (Et3N), N,N-diisopropylethylamine (DIPEA), triethylenediamine (DABCO), potassium carbonate (K2CO3), potassium hydroxide (KOH), or lithium hydroxide (LiOH).

[0022] Preferably, when synthesizing chiral spirocyclic γ-lactam compounds, the molar ratio of the base to the β-ketoamide compound is 1.5:1, and the base is DABCO; when synthesizing chiral spirocyclic δ-lactam compounds, the molar ratio of the base to the β-ketoamide compound is 1.0:1, and the base is Et3N, while a small amount of water is added to promote the reaction.

[0023] The present invention also provides a chiral spirocyclic lactam compound prepared by any of the methods described above, wherein the chiral spirocyclic lactam compound is a chiral spirocyclic γ-lactam compound or a chiral spirocyclic δ-lactam compound.

[0024] Preferably, in the reaction for synthesizing chiral spirocyclic γ-lactam compounds, the substrate β-ketoamide compound is selected from: ; The corresponding chiral spirocyclic γ-lactam compound generated is: .

[0025] Preferably, in the reaction for synthesizing chiral spirocyclic δ-lactam compounds, the substrate β-ketoamide compound is selected from: ; The corresponding chiral spirocyclic δ-lactam compound generated is: .

[0026] Compared with the prior art, the present invention has the following beneficial effects: (1) This invention is the first to use alkynyl-linked β-ketoamides as a single substrate. By simply switching the combination system of metal catalysts (copper salts / nickel salts) and chiral ligands (chiral pyrazine-bisoxazoline ligands / chiral bisoxazoline ligands), the intramolecular cyclization reaction pathway can be precisely controlled. In the synthesis of chiral spirocyclic γ-lactams, copper (Cu) adopts a tetrahedral coordination mode, and the triple bond and carbanion of the substrate are coordinated with Cu. Then, bonding occurs through a reductive elimination-like process. The chiral selectivity of the reaction comes from the steric hindrance effect between the ethyl group on the ligand and the carbonyl group in the substrate. However, nickel (Ni) requires planar square coordination. Therefore, under this coordination mode, the benzene ring and five-membered ring on the substrate will generate significant steric hindrance with the ligand, and the target product cannot be obtained. In the synthesis of chiral spirocyclic δ-lactams, Ni tends to form planar square coordination. The O and triple bonds of the substrate simultaneously coordinate with Ni. Due to steric hindrance, there is a 50° angle between the N-Ni-N plane of the ligand and the O-Ni-C plane of the substrate. When the terminal atom of the triple bond approaches the five-membered ring, the steric hindrance decreases due to the contraction of the substrate group. In the transition state, the angle between the N-Ni-N plane and the O-Ni-C plane of the substrate decreases to 30°, further favoring the planar square coordination with Ni. In other words, the planar square coordination of Ni promotes the formation of the transition state. The chiral selectivity stems from the steric hindrance effect of the fused ring on the substrate and the benzene ring perpendicular to the ligand plane on the ligand. If a Cu salt is used to coordinate with this ligand, although there is no significant steric hindrance, the C atom at the terminal of the triple bond and the C atom on the five-membered ring are located at opposite ends of the ligand plane. If they attempt to approach and form a bond, they will be blocked by the atoms on the ligand plane, preventing the reaction from proceeding. Therefore, metal catalysts ensure high regioselectivity (>20:1) in obtaining the target product, while chiral ligands regulate the stereoselectivity of the reaction. Based on this regulatory system, 5-exo-dig and 6-endo-dig cyclizations can be achieved, respectively, to synthesize chiral spirocyclic γ-lactams and chiral spirocyclic δ-lactams with high regioselectivity and high stereoselectivity. Both types of products exhibit regioselectivity >20:1 and excellent stereoselectivity, completely solving the core technical problem of simultaneously controlling regioselectivity and stereoselectivity in existing technologies, and providing a new technical route for the precise synthesis of these two types of chiral spirocyclic lactams.

[0027] (2) The copper salts (copper tetraethyl cyanophosphate, copper tetraethyl cyanophosphate, etc.), nickel salts (nickel tetrafluoroborate hexahydrate, nickel perchlorate hexahydrate, etc.) and chiral ligands used in this invention are all commercially available general chemical raw materials, without the need to design and synthesize complex ligands or use expensive special reagents; at the same time, the bases (such as DABCO, Et3N) and solvents (such as dichloromethane, ethyl acetate) used are also conventional and inexpensive chemicals, which greatly reduces the cost of raw material procurement and preparation, and has a greater economic advantage than existing synthesis methods that rely on chiral auxiliary groups and stoichiometric chiral reagents.

[0028] All reactions in this invention are carried out under a mild nitrogen atmosphere. The optimal temperature for synthesizing γ-lactam is 40°C and the optimal reaction time is 18 hours. The optimal temperature for synthesizing δ-lactam is 80°C and the optimal reaction time is 72 hours. No harsh high temperature and high pressure, strong oxidation / reduction or special light conditions are required, and the requirements for reaction equipment are low. Moreover, the reaction system has simple components, clear proportions, and simple operation steps, which facilitates process scale-up and industrial production control.

[0029] Compared with existing technologies, the raw materials are cheap and readily available, and the reaction conditions are mild, which greatly reduces production costs, simplifies the production process, and is beneficial to industrial production. It is more economical and cheaper than existing processes for synthesizing chiral spirocyclic γ-lactams and δ-lactams.

[0030] (3) The reaction of the present invention not only has a high yield, but can also be successfully scaled up to the gram level or above. At the same time, the separation and purification of the target product is simple and does not require a complicated separation process. It effectively solves the industry pain points of traditional synthesis methods, such as long steps, low atom economy and difficulty in large-scale production, and has significant prospects for industrial application.

[0031] (4) The technical solution of the present invention has broad substrate applicability and good compatibility with β-ketoamide substrates modified with different substituents. Regardless of whether the benzene ring has electron-donating or electron-withdrawing groups, or monosubstituted, disubstituted, or trisubstituted structures, it can participate in the reaction smoothly and obtain excellent regio and stereoselectivity. At the same time, based on the same type of substrate, chiral spirocyclic γ-lactams and chiral spirocyclic δ-lactams can be synthesized by switching the catalytic system. There is no need to design specific synthetic routes for different substrates, which greatly improves the versatility and flexibility of the synthetic process.

[0032] (5) This invention achieves efficient conversion of the same β-ketoamide precursor into two different cyclic systems (γ-lactam and δ-lactam) chiral spirocyclic compounds through differentiated regulation of the catalytic system, providing a flexible and convenient route for the diverse synthesis of chiral spirocyclic lactam compounds. The prepared products all possess chiral quaternary carbon centers and rigid spirocyclic structures, and have high synthetic purity. These structural units are widely found in drug molecules and natural products, and have important potential application value in drug development, natural product synthesis, and other fields. Detailed Implementation

[0033] The present invention will now be described in detail with reference to specific embodiments. These embodiments are based on the technical solution of the present invention and provide detailed implementation methods and specific operating procedures. However, the scope of protection of the present invention is not limited to the following embodiments.

[0034] Unless otherwise specified, all raw materials and equipment used in this invention are commercially available products.

[0035] All target compounds were obtained through1 1H NMR (H NMR) and 13 Characterized by C10 NMR (carbon nuclear magnetic resonance) spectral data.

[0036] Unless otherwise specified, all reactions were carried out in 25 mL Shrek tubes.

[0037] In the examples below, the yields of the target products are all separation yields; the regioselectivity of the reaction (5-exo-dig and 6-endo-dig pathway selectivity) is greater than 20:1.

[0038] Example 1 A chiral spirocyclic γ-lactam reacts according to the following reaction equation: The specific preparation method is as follows: Under anhydrous and oxygen-free conditions, Cu(MeCN)4BF4 (0.015 mmol, 15 mol% relative to substrate S1), chiral ligand L1 (0.018 mmol, 18 mol% relative to substrate S1), and 1 mL of redistilled DCM were added to a 25 mL Shrek tube, and the mixture was stirred at 25 °C for 1.5 h. Subsequently, under a nitrogen atmosphere, substrate S1 (0.1 mmol, 1.0 equiv.) and DABCO (0.15 mmol, 1.5 equiv. relative to substrate S1) were added, along with 1 mL of DCM. The mixture was heated to 40 °C and stirred for another 18 h. Thin-layer chromatography (TLC) was used to monitor complete substrate consumption. The product, chiral spirocyclic γ-lactam, was purified by column chromatography using a petroleum ether / ethyl acetate mixture as eluent.

[0039] In this embodiment, the β-ketoamide compound used has the structural formula shown in Formula S1: (Formula S1); The target product is: (C 20 H 16 BrNO2); White solid (melting point: 107-108℃); yield: 92%; enantiomeric excess (ee value): 94%; 1 ¹H NMR (400 MHz, deuterated chloroform CDCl₃ as solvent): δ 7.74 (s, 1H), 7.64–7.52 (m, 2H), 7.42–7.27 (m, 5H), 5.03 (s, 1H), 4.87 (s, 1H), 4.75 (d, 1H). J=15.2Hz, 1H), 4.52 (d, J =14.8Hz, 1H), 4.24(dt, J =13.6, 2.4Hz, 1H), 3.88-3.79(m, 2H), 3.17(d, J =17.6Hz, 1H); 13 C NMR (101 MHz, CDCl3): δ 199.9, 171.4, 155.5, 142.4, 135.6, 132.8, 131.8, 131.2, 129.8, 128.9, 128.2, 127.9, 126.5, 108.3, 64.3, 51.0, 46.9, 36.5.

[0040] Examples 2-22 below all reacted according to the following reaction equations to generate spirochetal γ-lactams: , Specifically as follows: Example 2 A chiral spirocyclic γ-lactam was prepared using a method essentially the same as in Example 1, except that the substrate used was a β-ketoamide compound represented by formula S2. (Formula S2); The target product is: (C 20 H 16 BrNO2); White solid (melting point: 167-168℃); yield: 90%; ee: 80%; 1 H NMR (400 MHz, CDCl3): δ 7.81 (d, J =7.6Hz, 1H), 7.70 (d, J =7.6Hz, 1H), 7.45-7.27(m, 6H), 5.05(s, 1H), 4.89(s, 1H), 4.75(d, J =15.2Hz, 1H), 4.55 (d, J =14.8Hz, 1H), 4.26(dt, J =13.6, 2.4Hz, 1H), 3.86(dt, J =13.6, 2.0Hz, 1H), 3.78(d, J =18.0Hz, 1H), 3.15(d, J =18.0Hz, 1H); 13C NMR (101 MHz, CDCl3): δ 200.4, 171.3, 153.7, 142.3, 138.3, 135.9, 135.6, 129.9, 128.9, 128.1, 127.9, 124.2, 121.9, 108.5, 64.2, 51.0, 46.9, 38.0.

[0041] Example 3 A chiral spirocyclic γ-lactam was prepared using a method essentially the same as in Example 1, except that the substrate used was a β-ketoamide compound represented by formula S3. (Formula S3); The target product is: (C 20 H 16 BrNO2); White solid (melting point: 71-72℃); yield: 82%; ee: 89%; 1 H NMR (400 MHz, CDCl3): δ 7.86 (s, 1H), 7.74 (dd, J =8.4, 2.0Hz, 1H), 7.48-7.27(m, 6H), 5.03(s, 1H), 4.87(s, 1H), 4.74(d, J =14.8Hz, 1H), 4.52 (d, J =14.8Hz, 1H), 4.24(dt, J =13.6, 2.4Hz, 1H), 3.88-3.73(m, 2H), 3.13(d, J =17.6Hz, 1H); 13 C NMR (101 MHz, CDCl3): δ 199.7, 171.3, 152.6, 142.4, 138.3, 135.8, 135.6, 128.9, 128.18, 128.17, 127.93, 127.89, 122.2, 108.4, 64.6, 50.9, 46.9, 36.5.

[0042] Example 4 A chiral spirocyclic γ-lactam was prepared using a method essentially the same as in Example 1, except that the substrate used was a β-ketoamide compound represented by formula S4. (Formula S4); The target product is: (C 20 H 16 BrNO2); White solid (melting point: 156-157℃); yield: 68%; ee: 90%; 1 H NMR (400 MHz, CDCl3): δ 7.57 (d, J =7.6Hz, 1H), 7.53-7.42(m, 2H), 7.42-7.28(m, 5H), 5.03(s, 1H), 4.87(s, 1H), 4.75(d, J =14.8Hz, 1H), 4.53 (d, J =14.8Hz, 1H), 4.26(dt, J =13.6, 2.4Hz, 1H), 3.86-3.77(m, 2H), 3.14(d, J =17.4Hz, 1H); 13 C NMR (101 MHz, CDCl3): δ 198.3, 171.4, 156.8, 142.4, 135.9, 135.5, 133.2, 131.3, 128.9, 128.2, 127.8, 125.4, 121.2, 108.4, 64.8, 51.0, 47.0, 35.8.

[0043] Example 5 A chiral spirocyclic γ-lactam was prepared using a method essentially the same as in Example 1, except that the substrate used was a β-ketoamide compound represented by Formula S5. (Formula S5); The target product is: (C 20 H 16 ClNO2); White solid (melting point: 100-101℃); yield: 75%; ee: 92%; 1 H NMR (400 MHz, CDCl3): δ 7.67 (d, J =8.0Hz, 1H), 7.55(s, 1H), 7.45-7.28(m, 6H), 5.03(s, 1H), 4.87(s, 1H), 4.75(d, J =14.8Hz, 1H), 4.52 (d, J =14.8Hz, 1H), 4.25(dt, J =13.6, 2.4Hz, 1H), 3.88-3.78(m, 2H), 3.16(d, J =17.6Hz, 1H); 13C NMR (101 MHz, CDCl3): δ 199.7, 171.4, 155.4, 142.5, 142.3, 135.6, 132.4, 129.0, 128.9, 128.2, 127.9, 126.7, 126.4, 108.3, 64.3, 51.0, 46.9, 36.5.

[0044] Example 6 A chiral spirocyclic γ-lactam was prepared using a method essentially the same as in Example 1, except that the substrate used was a β-ketoamide compound represented by formula S6. (Formula S6); The target product is: (C 21 H 19 NO2); White solid (melting point: 56-57℃); yield: 46%; ee: 94%; 1 H NMR (400 MHz, CDCl3): δ 7.64 (d, J =7.6Hz, 1H), 7.42-7.28(m, 6H), 7.22(d, J =7.6Hz, 1H), 5.00(s, 1H), 4.86(s, 1H), 4.77(d, J =14.8Hz, 1H), 4.53 (d, J =14.8Hz, 1H), 4.25(dt, J =13.6, 2.4Hz, 1H), 3.87-3.76(m, 2H), 3.14(d, J =17.2Hz, 1H), 2.46 (s, 3H); 13 C NMR (101 MHz, CDCl3): δ 200.6, 172.1, 154.6, 146.9, 143.1, 135.8, 131.6, 129.4, 128.9, 128.2, 127.8, 126.8, 125.3, 107.8, 64.4, 51.0, 46.9, 36.8, 22.3.

[0045] Example 7 A chiral spirocyclic γ-lactam was prepared using a method essentially the same as in Example 1, except that the substrate used was a β-ketoamide compound represented by Formula S7. (Formula S7); The target product is: (C 21 H 19 NO2); Yellow oily substance; Yield: 35%; ee: 92%; 1 H NMR (400 MHz, CDCl3): δ 7.54 (s, 1H), 7.50-7.27 (m, 7H), 5.00 (s, 1H), 4.86 (s, 1H), 4.76 (d, J =14.8Hz, 1H), 4.53 (d, J =14.8Hz, 1H), 4.25(dt, J =13.6, 2.4Hz, 1H), 3.87-3.75(m, 2H), 3.14(d, J =17.2Hz, 1H), 2.40 (s, 3H); 13 C NMR (101 MHz, CDCl3): δ 201.2, 172.0, 151.5, 143.0, 138.1, 136.8, 135.8, 134.1, 128.9, 128.2, 127.8, 126.1, 125.3, 107.9, 64.6, 51.0, 46.9, 36.6, 21.2.

[0046] Example 8 A chiral spirocyclic γ-lactam was prepared using a method essentially the same as in Example 1, except that the substrate used was a β-ketoamide compound represented by formula S8. (Formula S8); The target product is: (C 21 H 19 NO3); Yellow oily substance; Yield: 69%; ee: 88%; 1 H NMR (400 MHz, CDCl3): δ 7.42-7.27 (m, 7H), 7.08 (d, J =7.6Hz, 1H), 5.01(s, 1H), 4.89(s, 1H), 4.77(d, J =14.8Hz, 1H), 4.52 (d, J =14.8Hz, 1H), 4.25(dt, J =13.6, 2.8Hz, 1H), 3.93(s, 3H), 3.84(dt, J =13.6, 1.6Hz, 1H), 3.73(d, J =17.6Hz, 1H), 3.12(d, J =18.0Hz, 1H); 13 C NMR (101 MHz, CDCl3): δ 201.4, 171.9, 156.8, 143.0, 142.8, 135.8, 135.3, 129.7, 128.9, 128.2, 127.8, 116.8, 115.7, 108.0, 64.1, 55.7, 51.0, 46.9, 33.9.

[0047] Example 9 A chiral spirocyclic γ-lactam was prepared using a method essentially the same as in Example 1, except that the substrate used was a β-ketoamide compound represented by formula S9. (Formula S9); The target product is: (C 21 H 19 NO3); Yellow oily substance; Yield: 51%; ee: 94%; 1 H NMR (400 MHz, CDCl3): δ 7.44 (d, J =8.4Hz, 1H), 7.41-7.29(m, 5H), 7.28-7.21(m, 1H), 7.17(d, J =2.4Hz, 1H), 5.01(s, 1H), 4.88(s, 1H), 4.77(d, J =15.2Hz, 1H), 4.52 (d, J =15.2Hz, 1H), 4.25(dt, J =13.6, 2.8Hz, 1H), 3.90-3.80 (m, 4H), 3.76 (d, J =16.8Hz, 1H), 3.11(d, J =16.8Hz, 1H); 13 C NMR (101 MHz, CDCl3): δ 201.2, 171.9, 160.0, 147.1, 142.9, 135.8, 135.1, 128.9, 128.2, 127.8, 127.1, 125.1, 108.0, 106.4, 65.0, 55.8, 51.0, 46.9, 36.4.

[0048] Example 10 A chiral spirocyclic γ-lactam was prepared using a method essentially the same as in Example 1, except that the substrate used was a β-ketoamide compound represented by formula S10. (Formula S10); The target product is: (C 20 H 17 NO2); White solid (melting point: 98-99℃); yield: 78%; ee: 96%; 1 H NMR (400 MHz, CDCl3): δ 7.76 (d, J =7.6Hz, 1H), 7.69-7.61(m, 1H), 7.56(d, J =7.6Hz, 1H), 7.46-7.27(m, 6H), 5.01(s, 1H), 4.87(s, 1H), 4.78(d, J =14.8Hz, 1H), 4.53 (d, J =14.8Hz, 1H), 4.26(dt, J =13.6, 2.4Hz, 1H), 3.90-3.79(m, 2H), 3.20(d, J =17.3Hz, 1H); 13 C NMR (101 MHz, CDCl3): δ 201.1, 171.9, 154.1, 142.9, 135.8, 135.6, 133.9, 129.0, 128.2, 128.1, 127.9, 126.5, 125.5, 108.0, 64.3, 51.1, 46.9, 37.0.

[0049] Example 11 A chiral spirocyclic γ-lactam was prepared using a method essentially the same as in Example 1, except that the substrate used was a β-ketoamide compound represented by formula S11. (Formula S11); The target product is: (C 24 H 19 NO2); White solid (melting point: 112-113℃); yield: 70%; ee: 90%; 1 H NMR (400 MHz, CDCl3): δ 8.34 (s, 1H), 7.97 (d, J =11.6Hz, 2H), 7.89 (d, J=8.4Hz, 1H), 7.66-7.57(m, 1H), 7.55-7.47(m, 1H), 7.45-7.36(m, 4H), 7.35-7.28(m, 1H), 5.01(s, 1H), 4.87(s, 1H), 4.80(d, J =14.8Hz, 1H), 4.57 (d, J =14.8Hz, 1H), 4.28(dt, J =13.6, 2.4Hz, 1H), 4.05(d, J =17.2Hz, 1H), 3.86(dt, J =13.6, 2.4Hz, 1H), 3.37(d, J =17.6Hz, 1H); 13 C NMR (101 MHz, CDCl3): δ 201.3, 172.0, 146.0, 143.2, 137.6, 135.8, 132.8, 131.7, 130.5, 129.3, 128. 9, 128.2, 128.0, 127.8, 126.7, 126.4, 124.6, 108.2, 65.0, 51.0, 46.9, 36.4.

[0050] Example 12 A chiral spirocyclic γ-lactam was prepared using a method essentially the same as in Example 1, except that the substrate used was a β-ketoamide compound represented by formula S12. (Formula S12); The target product is: (C 19 H 16 N2O2); White solid (melting point: 69-70℃); yield: 91%; ee: 84%; 1 H NMR (400 MHz, CDCl3): δ 8.86 (s, 1H), 8.01 (dd, J =7.6, 1.6Hz, 1H), 7.42-7.24(m, 6H), 5.06(s, 1H), 4.92(s, 1H), 4.76(d, J =14.8Hz, 1H), 4.52 (d, J =15.2Hz, 1H), 4.25(dt, J =13.6, 2.4Hz, 1H), 3.96(d, J =18.0Hz, 1H), 3.86(dt, J=13.6, 1.6Hz, 1H), 3.33(d, J =18.0Hz, 1H); 13 C NMR (101 MHz, CDCl3): δ 199.7, 173.4, 171.2, 156.5, 142.2, 135.5, 133.5, 128.9, 128.2, 127.9, 123.3, 108.7, 64.0, 51.1, 46.9, 39.4.

[0051] Example 13 A chiral spirocyclic γ-lactam was prepared using a method essentially the same as in Example 1, except that the substrate used was a β-ketoamide compound represented by formula S13. (Formula S13); The target product is: (C 14 H 12 BrNO2); White solid (melting point: 164-165℃); yield: 89%; ee: 94%; 1 H NMR (400 MHz, CDCl3): δ 7.72 (s, 1H), 7.62-7.50 (m, 2H), 5.09 (s, 1H), 4.88 (s, 1H), 4.36 (dt, J =13.6, 2.4Hz, 1H), 3.97(dt, J =13.6, 2.0Hz, 1H), 3.76(d, J =17.6Hz, 1H), 3.13(d, J =17.6Hz, 1H), 3.02(s, 3H); 13 C NMR (101 MHz, CDCl3): δ 200.1, 171.3, 155.6, 142.7, 132.8, 131.8, 131.1, 129.8, 126.5, 108.2, 64.1, 53.7, 36.6, 30.0.

[0052] Example 14 A chiral spirocyclic γ-lactam was prepared using a method essentially the same as in Example 1, except that the substrate used was a β-ketoamide compound represented by formula S14. (Formula S14); The target product is: (C 15 H 14 BrNO2); White solid (melting point: 96-97℃); yield: 72%; ee: 96%; 1 H NMR (400 MHz, CDCl3): δ 7.72 (s, 1H), 7.61-7.50 (m, 2H), 5.10 (s, 1H), 4.88 (s, 1H), 4.37 (dt, J =13.6, 2.8Hz, 1H), 3.97(dt, J =13.6, 2.0Hz, 1H), 3.76(d, J =17.2Hz, 1H), 3.62-3.38(m, 2H), 3.13(d, J =17.6Hz, 1H), 1.22(t, J =7.2Hz, 3H); 13 C NMR (101 MHz, CDCl3): δ 200.1, 170.9, 155.6, 142.8, 132.8, 131.8, 131.1, 129.8, 126.5, 108.1, 64.5, 50.9, 37.7, 36.4, 12.6.

[0053] Example 15 A chiral spirocyclic γ-lactam was prepared using a method essentially the same as in Example 1, except that the substrate used was a β-ketoamide compound represented by formula S15. (Formula S15); The target product is: (C 16 H 16 BrNO2); White solid (melting point: 71-72℃); yield: 94%; ee: 94%; 1 H NMR (400 MHz, CDCl3): δ 7.71 (s, 1H), 7.61-7.47 (m, 2H), 5.08 (s, 1H), 4.87 (s, 1H), 4.36 (d, J =13.6Hz, 1H), 3.93(d, J =13.4Hz, 1H), 3.76 (d, J =17.6Hz, 1H), 3.57-3.46(m, 1H), 3.33-3.22(m, 1H), 3.12(d, J =17.6Hz, 1H), 1.72-1.56(m, 2H), 0.96(t, J =7.2Hz, 3H); 13 C NMR (101 MHz, CDCl3): δ 200.0, 171.2, 155.6, 142.9, 132.8, 131.7, 131.0, 129.8, 126.4, 107.9, 64.5, 51.4, 44.6, 36.3, 20.6, 11.2.

[0054] Example 16 A chiral spirocyclic γ-lactam was prepared using a method essentially the same as in Example 1, except that the substrate used was a β-ketoamide compound represented by formula S16. (Formula S16); The target product is: (C 16 H 16 BrNO2); White solid (melting point: 91-92℃); yield: 97%; ee: 95%; 1 H NMR (400 MHz, CDCl3): δ 7.71 (s, 1H), 7.60-7.46 (m, 2H), 5.09 (s, 1H), 4.87 (s, 1H), 4.53-4.38 (m, 1H), 4.28 (d, J =13.2Hz, 1H), 3.94 (d, J =13.2Hz, 1H), 3.75(d, J =17.6Hz, 1H), 3.11(d, J =17.6Hz, 1H), 1.26 (d, J =6.8Hz, 3H), 1.20(d, J =6.8Hz, 3H); 13 C NMR (101 MHz, CDCl3): δ 199.9, 170.5, 155.6, 142.8, 132.8, 131.7, 131.0, 129.8, 126.4, 107.9, 64.8, 46.5, 43.4, 36.0, 20.1, 19.8.

[0055] Example 17 A chiral spirocyclic γ-lactam was prepared using a method essentially the same as in Example 1, except that the substrate used was a β-ketoamide compound represented by formula S17. (Formula S17); The target product is: (C 18 H 21 NO3); White solid (melting point: 96-97℃); yield: 67%; ee: 91%; 1 H NMR (400 MHz, CDCl3): δ 7.62 (d, J =8.4Hz, 1H), 6.97-6.87(m, 2H), 5.02(s, 1H), 4.84(s, 1H), 4.43(dt, J =13.2, 2.8Hz, 1H), 4.06(dt, J =13.2, 2.0Hz, 1H), 3.89(s, 3H), 3.67(d, J =17.2Hz, 1H), 3.06 (d, J =17.6Hz, 1H), 1.47(s, 9H); 13 C NMR (101 MHz, CDCl3): δ 199.6, 165.9, 157.2, 143.3, 127.0, 126.9, 116.1, 109.5, 106.7, 66.1, 55.9, 54.8, 50.5, 36.2, 27.9.

[0056] Example 18 A chiral spirocyclic γ-lactam was prepared using a method essentially the same as in Example 1, except that the substrate used was a β-ketoamide compound represented by formula S18. (Formula S18); The target product is: (C 18 H 21 NO2); White solid (melting point: 94-95℃); yield: 89%; ee: 92%; 1 H NMR (400 MHz, CDCl3): δ 7.64 (d, J =8.0Hz, 1H), 7.51(s, 1H), 7.43(d, J =8.0Hz, 1H), 5.06(s, 1H), 4.89(s, 1H), 4.36(d, J =13.2Hz, 1H), 3.95(d, J =13.2Hz, 1H), 3.74 (d, J =17.2Hz, 1H), 3.12(d, J =17.2Hz, 1H), 3.01(s, 3H), 1.35(s, 9H); 13C NMR (101 MHz, CDCl3): δ 200.9, 172.0, 159.9, 154.4, 143.4, 131.6, 125.9, 125.0, 123.0, 107.7, 64.2, 53.8, 37.2, 35.7, 31.3, 30.0.

[0057] Example 19 A chiral spirocyclic γ-lactam was prepared using a method essentially the same as in Example 1, except that the substrate used was a β-ketoamide compound represented by formula S19. (Formula S19); The target product is: (C 17 H 17 NO3); White solid (melting point: 70-71℃); yield: 95%; ee: 92%; 1 H NMR (400 MHz, CDCl3): δ 7.63 (d, J =8.4Hz, 1H), 6.97-6.89(m, 2H), 6.11-5.97(m, 1H), 5.42(d, J =17.6Hz, 1H), 5.32 (d, J =10.4Hz, 1H), 5.05(s, 1H), 4.87(s, 1H), 4.62(d, J =5.2Hz, 2H), 4.35 (d, J =13.6Hz, 1H), 3.94 (d, J =13.6Hz, 1H), 3.70(d, J =13.6Hz, 1H), 3.07 (d, J =17.6Hz, 1H), 3.00 (s, 3H); 13 C NMR (101 MHz, CDCl3): δ 199.4, 172.0, 165.0, 157.0, 143.5, 132.3, 127.1, 127.0, 118.5, 116.7, 110.5, 107.5, 69.3, 64.2, 53.7, 37.0, 29.9.

[0058] Example 20 A chiral spirocyclic γ-lactam was prepared using a method essentially the same as in Example 1, except that the substrate used was a β-ketoamide compound represented by formula S20. (Formula S20); The target product is: (C 20 H 17 NO2); White solid (melting point: 156-157℃); yield: 88%; ee: 84%; 1 H NMR (400 MHz, CDCl3): δ 7.79 (d, J =8.0Hz, 1H), 7.72(s, 1H), 7.67-7.59(m, 3H), 7.52-7.44(m, 2H), 7.46-7.38(m, 1H), 5.10(s, 1H), 4.93(s, 1H), 4.39(d, J =13.6Hz, 1H), 3.98 (d, J =13.6Hz, 1H), 3.83(d, J =17.2Hz, 1H), 3.20(d, J =17.2Hz, 1H), 3.04(s, 3H); 13 C NMR (101 MHz, CDCl3): δ 200.8, 171.8, 154.8, 148.6, 143.3, 140.1, 132.8, 129.1, 128.6, 127.7, 127.6, 125.7, 124.9, 107.9, 64.4, 53.8, 37.1, 30.0.

[0059] Example 21 A chiral spirocyclic γ-lactam was prepared using a method essentially the same as in Example 1, except that the substrate used was a β-ketoamide compound represented by formula S21. (Formula S21); The target product is: (C 16 H 15 NO3); White solid (melting point: 152-153℃); yield: 81%; ee: 87%; 1 H NMR (400 MHz, CDCl3): δ 7.27 (d, J =8.8Hz, 1H), 7.06 (d, J =8.0Hz, 1H), 5.10(s, 1H), 4.93(s, 1H), 4.65(t, J =8.8Hz, 2H), 4.36 (d, J =13.6Hz, 1H), 3.98 (d, J=13.6Hz, 1H), 3.71(d, J =16.8Hz, 1H), 3.52-3.33(m, 2H), 3.10(d, J =16.8Hz, 1H), 3.03 (s, 3H); 13 C NMR (101 MHz, CDCl3): δ 201.6, 171.9, 161.0, 146.0, 143.3, 130.6, 125.5, 125.4, 116.5, 107.8, 72.5, 64.8, 53.7, 36.6, 29.9, 28.5.

[0060] Example 22 A chiral spirocyclic γ-lactam was prepared using a method essentially the same as in Example 1, except that the substrate used was a β-ketoamide compound represented by formula S22. (Formula S22); The target product is: (C 15 H 13 NO4); White solid (melting point: 167-168℃); yield: 82%; ee: 94%; 1 H NMR (400 MHz, CDCl3): δ 7.03 (s, 1H), 6.88 (s, 1H), 6.06 (s, 2H), 5.06 (s, 1H), 4.88 (s, 1H), 4.34 (d, J =13.6Hz, 1H), 3.94 (d, J =13.6Hz, 1H), 3.62 (d, J =17.2Hz, 1H), 3.05-2.96 (m, 4H); 13 C NMR (101 MHz, CDCl3): δ 199.2, 171.8, 155.1, 152.0, 148.9, 143.3, 128.3, 107.6, 105.6, 103.5, 102.6, 64.5, 53.7, 37.0, 30.0.

[0061] Example 23 A chiral spirocyclic δ-lactam reacts according to the following reaction equation: The specific preparation method is as follows: Under anhydrous and oxygen-free conditions, Ni(BF4)2·6H2O (0.010 mmol, 10 mol% relative to substrate S18), chiral ligand L2 (0.012 mmol, 12 mol% relative to substrate S18), and 1 mL of redistilled EtOAc were added to a 25 mL Shrek tube, and the mixture was stirred at 25 °C for 1.5 h. Subsequently, under a nitrogen atmosphere, substrate S18 (0.1 mmol, 1 equiv.) and Et3N (0.10 mmol, 1.0 equiv. relative to substrate S18) were added to the system, along with 1 mL of EtOAc and 5 μL of H2O. The mixture was then heated to 80 °C and stirred for another 3 days. After the substrate was completely consumed by thin-layer chromatography (TLC), the target product, chiral spirocyclic δ-lactam, was obtained by column chromatography separation and purification using a petroleum ether / ethyl acetate mixed solvent as the eluent.

[0062] In this embodiment, the β-ketoamide compound used has the structural formula shown in Formula S23: (Formula S23); The target product is: (C 14 H 12 BrNO2); White solid (melting point: 162-163℃); yield: 88%; ee: 90%; 1 H NMR (400 MHz, CDCl3): δ 7.68 (s, 1H), 7.58 (d, J =8.0Hz, 1H), 7.51(d, J =8.4Hz, 1H), 6.05-5.96(m, 1H), 5.59-5.51(m, 1H), 4.32(dt, J =18.4, 2.4Hz, 1H), 3.99-3.89(m, 2H), 3.04(s, 3H), 2.99(d, J =17.4Hz, 1H); 13 C NMR (101 MHz, CDCl3): δ 202.1, 166.7, 156.1, 133.3, 131.5, 131.1, 129.9, 126.8, 126.3, 123.7, 58.9, 51.5, 39.2, 34.9.

[0063] Examples 24-42 below all reacted according to the following reaction equations to generate spirochetal δ-lactams: Specifically as follows: Example 24 A chiral spirocyclic δ-lactam was prepared using a method essentially the same as in Example 23, except that the substrate used was a β-ketoamide compound represented by formula S24. (Formula S24); The target product is: (C 14 H 12 BrNO2); White solid (melting point: 188-189℃); yield: 85%; ee: 85%; 1 H NMR (400 MHz, CDCl3): δ 7.78 (d, J =7.6Hz, 1H), 7.68 (d, J =7.2Hz, 1H), 7.30-7.24(m, 1H), 6.05-5.98(m, 1H), 5.56(d, J =10.0Hz, 1H), 4.32(d, J =17.2Hz, 1H), 4.01-3.83(m, 2H), 3.06(s, 3H), 2.96(d, J =17.6Hz, 1H); 13 C NMR (101 MHz, CDCl3): δ 202.7, 166.7, 154.1, 138.3, 136.5, 129.6, 126.7, 124.0, 123.7, 122.0, 58.7, 51.5, 40.7, 34.9.

[0064] Example 25 A chiral spirocyclic δ-lactam was prepared using a method essentially the same as in Example 23, except that the substrate used was a β-ketoamide compound represented by formula S25. (Formula S25); The target product is: (C 14 H 12 BrNO2); White solid (melting point: 176-177℃); yield: 75%; ee: 93%; 1 H NMR (400 MHz, CDCl3): δ 7.84 (s, 1H), 7.70 (d, J =8.4Hz, 1H), 7.38 (d, J=8.0Hz, 1H), 6.04-5.97(m, 1H), 5.55(d, J =9.6Hz, 1H), 4.31(d, J =18.0Hz, 1H), 4.00-3.85(m, 2H), 3.04(s, 3H), 2.95(d, J =17.2Hz, 1H); 13 C NMR (101 MHz, CDCl3): δ 201.8, 166.7, 153.1, 138.2, 136.3, 128.1, 127.9, 126.7, 123.7, 121.9, 59.2, 51.5, 39.2, 34.9.

[0065] Example 26 A chiral spirocyclic δ-lactam was prepared using a method essentially the same as in Example 23, except that the substrate used was a β-ketoamide compound represented by formula S26. (Formula S26); The target product is: (C 14 H 12 ClNO2); White solid (melting point: 172-173℃); yield: 84%; ee: 91%; 1 H NMR (400 MHz, CDCl3): δ 7.65 (d, J =8.4Hz, 1H), 7.49(s, 1H), 7.35(d, J =8.0Hz, 1H), 6.05-5.96(m, 1H), 5.59-5.52(m, 1H), 4.31(dt, J =18.0, 2.4Hz, 1H), 3.99-3.88(m, 2H), 3.04(s, 3H), 2.98(d, J =17.2Hz, 1H); 13 C NMR (101 MHz, CDCl3): δ 201.8, 166.7, 155.9, 142.2, 132.9, 128.6, 126.8, 126.2, 123.7, 58.9, 51.5, 39.2, 34.9.

[0066] Example 27 A chiral spirocyclic δ-lactam was prepared using a method essentially the same as in Example 23, except that the substrate used was a β-ketoamide compound represented by formula S27. (Formula S27); The target product is: (C 14 H 12 ClNO2); White solid (melting point: 158-159℃); yield: 59%; ee: 93%; 1 H NMR (400 MHz, CDCl3): δ 7.69 (s, 1H), 7.57 (d, J =7.6Hz, 1H), 7.44 (d, J =8.0Hz, 1H), 6.05-5.97(m, 1H), 5.56(d, J =10.0Hz, 1H), 4.32(d, J =18.4Hz, 1H), 3.93(d, J =17.2Hz, 2H), 3.05(s, 3H), 2.98(d, J =17.2Hz, 1H); 13 C NMR (101 MHz, CDCl3): δ 202.0, 166.7, 152.6, 136.0, 135.5, 134.2, 127.7, 126.8, 124.8, 123.7, 59.4, 51.5, 39.2, 34.9.

[0067] Example 28 A chiral spirocyclic δ-lactam was prepared using a method essentially the same as in Example 23, except that the substrate used was a β-ketoamide compound represented by formula S28. (Formula S28); The target product is: (C 15 H 12 N2O2); White solid (melting point: 172-173℃); yield: 36%; ee: 90%; 1 H NMR (400 MHz, CDCl3): δ 8.00 (s, 1H), 7.85 (d, J =8.0Hz, 1H), 7.63(d, J =7.6Hz, 1H), 6.09-6.02(m, 1H), 5.56(d, J =10.4Hz, 1H), 4.33(d, J =18.4Hz, 1H), 4.03 (d, J=18.0Hz, 1H), 4.00-3.90 (m, 1H), 3.13-2.99 (m, 4H); 13 C NMR (101 MHz, CDCl3): δ 201.4, 166.2, 158.5, 137.9, 135.3, 129.3, 127.7, 126.1, 124.3, 118.0, 112.2, 59.0, 51.5, 39.9, 34.9.

[0068] Example 29 A chiral spirocyclic δ-lactam was prepared using a method essentially the same as in Example 23, except that the substrate used was a β-ketoamide compound represented by formula S29. (Formula S29); The target product is: (C 14 H 11 Cl2NO2); White solid (melting point: 166-167℃); yield: 46%; ee: 92%; 1 H NMR (400 MHz, CDCl3): δ 7.79 (s, 1H), 7.62 (s, 1H), 6.07-5.98 (m, 1H), 5.55 (d, J =10.0Hz, 1H), 4.31(d, J =18.4Hz, 1H), 3.99-3.87(m, 2H), 3.04(s, 3H), 2.96(d, J =17.2Hz, 1H); 13 C NMR (101 MHz, CDCl3): δ 200.9, 166.4, 153.2, 140.2, 134.1, 133.0, 128.4, 126.4, 126.4, 124.0, 59.3, 51.5, 38.9, 34.9.

[0069] Example 30 A chiral spirocyclic δ-lactam was prepared using a method essentially the same as in Example 23, except that the substrate used was a β-ketoamide compound represented by formula S30. (Formula S30); The target product is: (C 15 H 15 NO2); White solid (melting point: 179-180℃); yield: 61%; ee: 88%; 1 H NMR (400 MHz, CDCl3): δ 7.62 (d, J =8.0Hz, 1H), 7.29(s, 1H), 7.18(d, J =8.0Hz, 1H), 6.02-5.93(m, 1H), 5.56(dt, J =10.0, 2.0Hz, 1H), 4.32(dt, J =18.0, 2.4Hz, 1H), 3.97-3.88(m, 2H), 3.05(s, 3H), 2.96(d, J =16.8Hz, 1H), 2.44(s, 3H); 13 C NMR (101 MHz, CDCl3): δ 202.7, 167.3, 155.0, 146.9, 132.2, 129.1, 127.4, 126.9, 125.0, 123.2, 59.0, 51.5, 39.4, 34.9, 22.3.

[0070] Example 31 A chiral spirocyclic δ-lactam was prepared using a method essentially the same as in Example 23, except that the substrate used was a β-ketoamide compound represented by formula S31. (Formula S31); The target product is: (C 15 H 15 NO2); White solid (melting point: 138-139℃); yield: 24%; ee: 78%; 1 H NMR (400 MHz, CDCl3): δ 7.58 (d, J =7.6Hz, 1H), 7.42 (d, J =7.2Hz, 1H), 7.33-7.25(m, 1H), 6.03-5.96(m, 1H), 5.57(d, J =8.8Hz, 1H), 4.35 (d, J =17.6Hz, 1H), 4.00-3.83(m, 2H), 3.06(s, 3H), 2.90(d, J =17.2Hz, 1H), 2.36(s, 3H); 13C NMR (101 MHz, CDCl3): δ 203.6, 167.3, 153.5, 136.0, 135.8, 134.3, 128.1, 127.5, 123.2, 122.6, 58.7, 51.6, 38.6, 34.9, 17.9.

[0071] Example 32 A chiral spirocyclic δ-lactam was prepared using a method essentially the same as in Example 23, except that the substrate used was a β-ketoamide compound represented by formula S32. (Formula S32); The target product is: (C 15 H 15 NO2); White solid (melting point: 151-152℃); yield: 41%; ee: 86%; 1 H NMR (400 MHz, CDCl3): δ 7.53 (s, 1H), 7.43 (d, J =7.6Hz, 1H), 7.37 (d, J =8.0Hz, 1H), 6.02-5.94(m, 1H), 5.56(d, J =9.6Hz, 1H), 4.33 (d, J =18.0Hz, 1H), 3.99-3.88(m, 2H), 3.05(s, 3H), 2.96(d, J =16.8Hz, 1H), 2.39 (s, 3H); 13 C NMR (101 MHz, CDCl3): δ 203.3, 167.3, 152.0, 137.8, 136.8, 134.7, 127.6, 126.2, 125.1, 123.2, 59.2, 51.6, 39.3, 34.9, 21.2.

[0072] Example 33 A chiral spirocyclic δ-lactam was prepared using a method essentially the same as in Example 23, except that the substrate used was a β-ketoamide compound represented by formula S33. (Formula S33); The target product is: (C 15 H 15 NO3); White solid (melting point: 132-133℃); yield: 91%; ee: 86%; 1H NMR (400 MHz, CDCl3): δ 7.37 (d, J =8.4Hz, 1H), 7.20 (dd, J =8.4, 2.4Hz, 1H), 7.14 (s, 1H), 6.02-5.93 (m, 1H), 5.56 (d, J =10.0Hz, 1H), 4.31(d, J =18.0Hz, 1H), 4.01-3.83(m, 2H), 3.81(s, 3H), 3.05(s, 3H), 2.93(d, J =16.4Hz, 1H); 13 C NMR (101 MHz, CDCl3): δ 203.2, 167.2, 159.7, 147.5, 135.6, 127.3, 127.2, 125.0, 123.1, 106.1, 59.5, 55.8, 51.5, 39.0, 34.8.

[0073] Example 34 A chiral spirocyclic δ-lactam was prepared using a method essentially the same as in Example 23, except that the substrate used was a β-ketoamide compound represented by formula S34. (Formula S34); The target product is: (C 14 H 13 NO2); White solid (melting point: 128-129℃); yield: 84%; ee: 89%; 1 H NMR (400 MHz, CDCl3): δ 7.73 (d, J =8.0Hz, 1H), 7.65-7.57(m, 1H), 7.49(d, J =8.0Hz, 1H), 7.41-7.33(m, 1H), 6.03-5.95(m, 1H), 5.56(dt, J =9.6, 2.0Hz, 1H), 4.33(dt, J =18.0, 2.4Hz, 1H), 4.03-3.89(m, 2H), 3.05(s, 3H), 3.02(d, J =16.8Hz, 1H); 13C NMR (101 MHz, CDCl3): δ 203.2, 167.2, 154.5, 135.5, 134.4, 127.8, 127.3, 126.6, 125.2, 123.3, 58.8, 51.5, 39.6, 34.9.

[0074] Example 35 A chiral spirocyclic δ-lactam was prepared using a method essentially the same as in Example 23, except that the substrate used was a β-ketoamide compound represented by formula S35. (Formula S35); The target product is: (C 18 H 15 NO2); White solid (melting point: 202-203℃); yield: 55%; ee: 88%; 1 H NMR (400 MHz, CDCl3): δ 8.32 (s, 1H), 7.96 (d, J =8.4Hz, 1H), 7.92-7.82(m, 2H), 7.63-7.54(m, 1H), 7.53-7.44(m, 1H), 6.06-5.97(m, 1H), 5.63(dt, J =9.6, 2.0Hz, 1H), 4.35(dt, J =18.0, 2.4Hz, 1H), 4.16(d, J =16.8Hz, 1H), 4.02-3.91(m, 1H), 3.20(d, J =16.8Hz, 1H), 3.07(s, 3H); 13 C NMR (101 MHz, CDCl3): δ 203.5, 167.3, 146.6, 137.8, 132.7, 132.3, 130.5, 129.1, 128.0, 127.4, 126.3, 124.7, 123.4, 59.6, 51.6, 39.1, 34.9.

[0075] Example 36 A chiral spirocyclic δ-lactam was prepared using a method essentially the same as in Example 23, except that the substrate used was a β-ketoamide compound represented by formula S36. (Formula S36); The target product is: (C 15 H 14 BrNO2); White solid (melting point: 113-114℃); yield: 84%; ee: 89%; 1 H NMR (400 MHz, CDCl3): δ 7.68 (s, 1H), 7.57 (d, J =8.0Hz, 1H), 7.53-7.48(m, 1H), 6.08-6.00(m, 1H), 5.59-5.51(m, 1H), 4.33(dt, J =18.0, 2.4Hz, 1H), 4.01-3.87(m, 2H), 3.63-3.38(m, 2H), 2.98(d, J =17.2Hz, 1H), 1.17(t, J =7.2Hz, 3H).

[0076] 13 C NMR (101 MHz, CDCl3): δ 202.1, 166.1, 156.1, 133.3, 131.4, 131.0, 129.8, 126.7, 126.2, 124.0, 59.1, 48.8, 42.4, 39.1, 12.1.

[0077] Example 37 A chiral spirocyclic δ-lactam was prepared using a method essentially the same as in Example 23, except that the substrate used was a β-ketoamide compound represented by formula S19. (Formula S19); The target product is: (C 17 H 17 NO3); White solid (melting point: 86-87℃); yield: 92%; ee: 87%; 1 H NMR (400 MHz, CDCl3): δ 7.65 (d, J =9.2Hz, 1H), 6.94-6.88(m, 2H), 6.11-5.93(m, 2H), 5.61-5.52(m, 1H), 5.42(d, J =17.2Hz, 1H), 5.32 (d, J =10.8Hz, 1H), 4.65-4.59(m, 2H), 4.40-4.24(m, 1H), 3.92(d, J =17.2Hz, 2H), 3.04(s, 3H), 2.94(d, J =17.2Hz, 1H); 13C NMR (101 MHz, CDCl3): δ 201.1, 167.4, 165.0, 157.5, 132.4, 127.7, 127.6, 126.9, 123.1, 118.4, 116.5, 110.4, 69.3, 59.1, 51.6, 39.5, 34.9.

[0078] Example 38 A chiral spirocyclic δ-lactam was prepared using a method essentially the same as in Example 23, except that the substrate used was a β-ketoamide compound represented by formula S20. (Formula S20); The target product is: (C 20 H 17 NO2); White solid (melting point: 154-155℃); yield: 61%; ee: 90%; 1 H NMR (400 MHz, CDCl3): δ 7.80 (d, J =8.0Hz, 1H), 7.68(s, 1H), 7.66-7.57(m, 3H), 7.51-7.37(m, 3H), 6.06-5.97(m, 1H), 5.61(d, J =10.4Hz, 1H), 4.35 (d, J =18.4Hz, 1H), 4.04 (d, J =16.8Hz, 1H), 3.95 (dd, J =18.0, 4.0Hz, 1H), 3.13-3.02 (m, 4H); 13 C NMR (101 MHz, CDCl3): δ 202.8, 167.2, 155.2, 148.7, 140.3, 133.3, 129.1, 128.6, 127.7, 127.4, 127.3, 125.5, 125.0, 123.3, 59.1, 51.6, 39.6, 34.9.

[0079] Example 39 A chiral spirocyclic δ-lactam was prepared using a method essentially the same as in Example 23, except that the substrate used was a β-ketoamide compound of formula S21. (Formula S21); The target product is: (C 16 H 15 NO3); White solid (melting point: 217-218℃); yield: 67%; ee: 90%; 1 H NMR (400 MHz, CDCl3): δ 7.21 (d, J =8.4Hz, 1H), 7.03 (d, J =8.0Hz, 1H), 6.03-5.94(m, 1H), 5.58(d, J =10.0Hz, 1H), 4.63(t, J =8.8Hz, 2H), 4.31(d, J =18.0Hz, 1H), 3.98-3.85(m, 2H), 3.50-3.32(m, 2H), 3.05(s, 3H), 2.94(d, J =16.8Hz, 1H); 13 C NMR (101 MHz, CDCl3): δ 203.6, 167.3, 160.8, 146.5, 131.0, 127.5, 125.5, 125.2, 123.1, 116.6, 72.5, 59.5, 51.6, 39.2, 34.9, 28.5.

[0080] Example 40 A chiral spirocyclic δ-lactam was prepared using a method essentially the same as in Example 23, except that the substrate used was a β-ketoamide compound represented by formula S22. (Formula S22); The target product is: (C 15 H 13 NO4); White solid (melting point: 208-209℃); yield: 89%; ee: 91%; 1 H NMR (400 MHz, CDCl3): δ 7.04 (s, 1H), 6.84 (s, 1H), 6.05 (d, J =4.4Hz, 2H), 6.01-5.92(m, 1H), 5.55(d, J =9.6Hz, 1H), 4.31(d, J =18.0Hz, 1H), 3.91(dd, J =18.0, 4.0Hz, 1H), 3.83(d, J =17.2Hz, 1H), 3.04(s, 3H), 2.87(d, J =17.2Hz, 1H); 13 C NMR (101 MHz, CDCl3): δ 200.9, 167.2, 155.1, 152.5, 148.7, 128.9, 127.5, 123.2, 105.7, 103.4, 102.5, 59.3, 51.5, 39.4, 34.9.

[0081] Example 41 A chiral spirocyclic δ-lactam was prepared using a method essentially the same as in Example 23, except that the substrate used was a β-ketoamide compound represented by Formula S1. (Formula S1); The target product is: (C 20 H 16 BrNO2); White solid (melting point: 132-133℃); yield: 75%; ee: 88%; 1 H NMR (400 MHz, CDCl3): δ 7.70 (s, 1H), 7.61 (d, J =8.0Hz, 1H), 7.53(d, J =8.4Hz, 1H), 7.39-7.24(m, 5H), 6.03-5.94(m, 1H), 5.56(d, J =9.6Hz, 1H), 4.79 (d, J =14.8Hz, 1H), 4.61(d, J =14.8Hz, 1H), 4.22(d, J =18.0Hz, 1H), 4.05(d, J =17.2Hz, 1H), 3.85 (dd, J =18.4, 4.4Hz, 1H), 3.04(d, J =17.2Hz, 1H); 13 C NMR (101 MHz, CDCl3): δ 202.0, 166.9, 156.1, 136.4, 133.3, 131.5, 131.2, 129.9, 128.9, 128.0, 127.7, 126.5, 126.3, 124.0, 59.2, 50.5, 48.9, 39.3.

[0082] Example 42 A chiral spirocyclic δ-lactam was prepared using a method essentially the same as in Example 23, except that the substrate used was a β-ketoamide compound represented by formula S18. (Formula S18); The target product is: (C 18 H 21 NO2); Yellow oily substance; Yield: 43%; ee: 80%; 1 H NMR (400 MHz, CDCl3): δ 7.66 (d, J =8.4Hz, 1H), 7.49(s, 1H), 7.42(d, J =8.4Hz, 1H), 6.03-5.93(m, 1H), 5.58(d, J =9.6Hz, 1H), 4.34 (d, J =18.0Hz, 1H), 4.00-3.89(m, 2H), 3.06(s, 3H), 2.99(d, J =17.2Hz, 1H), 1.36 (s, 9H); 13 C NMR (101 MHz, CDCl3): δ 202.8, 167.4, 159.9, 154.9, 132.1, 127.6, 125.7, 124.8, 123.14, 123.13, 59.1, 51.6, 39.7, 35.7, 34.9, 31.3.

[0083] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for synthesizing a chiral spirolactam, characterized in that, include: Using β-ketoamide compounds as substrates, intramolecular cyclization reactions were carried out in the presence of a catalyst system to obtain chiral spirocyclic lactams; The structural formula of the β-ketoamide compound is shown in Formula 1 below: (Equation 1) In Formula 1, R is independently selected from hydrogen, aryl, aliphatic hydrocarbon, halogen, or ether group; R 1 It is alkyl or aryl.

2. The method for synthesizing a chiral spirolactam according to claim 1, characterized in that, The catalyst system is either a first catalytic system or a second catalytic system; The first catalytic system includes a copper salt and a chiral pyrazine-bisoxazoline ligand; the molar ratio of the copper salt to the β-ketoamide compound is 0.1:1 to 0.2:1, and the molar ratio of the chiral bisoxazoline ligand to the β-ketoamide compound is 0.1:1 to 0.15:

1. The second catalytic system includes a nickel salt and a chiral bisoxazoline ligand; the molar ratio of the nickel salt to the β-ketoamide compound is 0.05:1 to 0.15:1; the molar ratio of the chiral bisoxazoline ligand to the β-ketoamide compound is 0.1:1 to 0.15:

1.

3. The method for synthesizing a chiral spirolactam according to claim 2, characterized in that, Under the catalysis of the first catalytic system, the β-ketoamide compound undergoes an intramolecular cyclization reaction to obtain a chiral spirocyclic γ-lactam compound, the structural formula of which is shown in Formula 2. (Equation 2) In Formula 2, R is independently selected from hydrogen, aryl, aliphatic hydrocarbon, halogen, or ether group; R 1 It is alkyl or aryl; The above reaction is carried out in a haloalkane solvent.

4. The method for synthesizing a chiral spirolactam according to claim 3, characterized in that, The copper salt is selected from at least one of copper tetrafluoroborate tetraacetonitrile, copper hexafluorophosphate tetraacetonitrile, cuprous trifluoromethanesulfonate, and copper acetate.

5. The method for synthesizing a chiral spirolactam according to claim 3, characterized in that, The haloalkane solvent includes dichloromethane, 1,2-dichloroethane, or chloroform.

6. The method for synthesizing a chiral spirolactam according to claim 2, characterized in that, Under the catalysis of the second catalytic system, the β-ketoamide compound undergoes an intramolecular cyclization reaction to obtain a chiral spirocyclic δ-lactam compound, the structural formula of which is shown in Formula 3. (Equation 3) In Formula 3, R is independently selected from hydrogen, aryl, aliphatic hydrocarbon, halogen, or ether group; R 1 The group is alkyl or aryl; the above reaction is carried out in an ester solvent.

7. The method for synthesizing a chiral spirolactam according to claim 6, characterized in that, The nickel salt is selected from at least one of nickel tetrafluoroborate hexahydrate, nickel perchlorate hexahydrate, nickel trifluoromethanesulfonate, and nickel acetate.

8. The method for synthesizing a chiral spirolactam according to claim 6, characterized in that, The ester solvents include ethyl acetate, butyl acetate, isopropyl acetate, or tert-butyl acetate.

9. The method for synthesizing a chiral spirolactam according to claim 1, characterized in that, The intramolecular cyclization reaction is carried out in the presence of a base; The molar ratio of the base to the β-ketoamide compound is from 1.0:1 to 1.5:1; The base is selected from at least one of triethylamine, N,N-diisopropylethylamine, triethylenediamine, potassium carbonate, potassium hydroxide, or lithium hydroxide.

10. A chiral spirocyclic lactam compound prepared by the method according to any one of claims 1-9, characterized in that, The chiral spirocyclic lactam compound is a chiral spirocyclic γ-lactam compound or a chiral spirocyclic δ-lactam compound.

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