Method for preparing chiral lactam by organic catalysis of desymmetry of prochiral cyclic ketone

Abstract

The invention discloses a method for preparing chiral lactam from prochiral ketone, and belongs to the technical field of chemical synthesis. According to the method, chlorobenzene or toluene or a chlorobenzene / diethyl ether mixed solution is used as a solvent, under the action of a chiral catalyst, prochiral cyclic ketone and sulfonyl hydroxylamine are subjected to a desymmetrical nitrogen atom insertion reaction at-78 DEG C to 25 DEG C, high-stereoselectivity chiral lactam is prepared in one step, and the reaction time is 2-8 h. The method has the advantages that the raw materials are low in price and easy to obtain, the chiral catalyst is commercially available and small in dosage, the product has excellent stereoselectivity, post-treatment is simple and convenient, and a novel green and economical way with wide industrial application prospects is provided for synthesis of chiral drugs and fine chemicals.

Description

Technical Field

[0001] This invention belongs to the field of asymmetric synthesis in organic chemistry, specifically relating to a method for preparing chiral lactams by desymmetricization of a pre-chiral cyclic ketone via organocatalysis. Background Technology

[0002] Chiral lactams are a vital class of nitrogen-containing heterocyclic compounds with significant applications in chiral pharmaceuticals, fine chemicals, pesticides, and materials science. Furthermore, chiral lactams can be diversely derivatized into highly valuable chiral compounds, making them among the most frequently occurring structures in drug molecules. However, current strategies require the use of noble metal catalysts or specific pre-defined functional groups, resulting in lengthy synthetic substrate steps, harsh reaction conditions, and substantial consumption of chiral reagent equivalences. Consequently, these methods have very limited practical value for large-scale production.

[0003] Therefore, developing new strategies for efficient and highly selective chiral lactams is of great significance for constructing structurally diverse chiral lactam derivatives. Summary of the Invention

[0004] To address the shortcomings of existing technologies, this invention proposes a method for preparing chiral lactams by desymmetricization of pre-chiral cyclic ketones via organocatalysis.

[0005] The technical solution of this invention is as follows: A method for preparing chiral lactams by desymmetricization of a prochiral cyclic ketone via organocatalysis includes the following steps: in the presence of a chiral catalyst, using chlorobenzene, toluene, or a chlorobenzene / diethyl ether mixture as a solvent, a prochiral cyclic ketone having the structure of Formula 1 and a sulfonyl hydroxylamine having the structure of Formula 2 are subjected to a desymmetric nitrogen atom insertion reaction at -78°C to 25°C to obtain a chiral lactam, wherein the reaction time is 2-8 h; Equation 1 is or One of them, where R 1 It is one of H, cyano, or alkoxy; R 2 It is one of the following: phenyl, a benzene ring containing a substituent, a benzofuran ring, a piperon ring, 1-naphthyl, 2-naphthyl, benzothiophene, thiophene, an imidazole ring containing a substituent, methyl, ethyl, isopropyl, tert-butyl, a substituted straight-chain alkyl, a substituted cycloalkyl, trifluoromethyl, halogen, benzoyl, ester, acyl, amide, and sulfonamide, wherein the substituent is at least one of alkyl, alkoxy, halogen, alkenyl, and alkynyl; R 3 It is aryl or methyl; n is 0 or 1; Equation 2 is , , , , One of them; The chiral catalyst is one of chiral phosphoric acid, chiral phosphoramide, or chiral phosphate.

[0006] Furthermore, the chiral catalyst is selected from... , , , One of them.

[0007] Furthermore, the molar ratio of the prochiral cyclic ketone to sulfonyl hydroxylamine is 1:(1.2 - 3.0).

[0008] Furthermore, the molar ratio of the chiral catalyst to the pre-chiral cyclic ketone is 5% - 20%.

[0009] Furthermore, when the solvent is a mixture of chlorobenzene and diethyl ether, the volume ratio of diethyl ether to chlorobenzene is 1:(1-4).

[0010] Further, the method for preparing chiral lactams by the desymmetricization of a prochiral cyclic ketone via organocatalysis is as follows: First, the organic solvent is divided into two parts; under stirring conditions, a chiral catalyst, as well as one of the prochiral cyclic ketone and the sulfonyl hydroxylamine, are added to the reaction vessel, followed by the addition of the first part of the organic solvent to prepare solution A, and cooled to the reaction temperature; the other of the prochiral cyclic ketone and the sulfonyl hydroxylamine is dissolved in the second part of the organic solvent to prepare solution B; while maintaining the reaction temperature, solution B is added dropwise to solution A in batches, with an interval of 5-10 minutes between each batch, and the chiral lactam is obtained after the reaction is completed.

[0011] Furthermore, the desymmetric nitrogen atom insertion reaction is carried out in the presence of a base, which is an inorganic base; the molar ratio of the base to the prochiral cyclic ketone is 0-3.0.

[0012] Furthermore, the inorganic base is sodium bicarbonate.

[0013] Furthermore, the molar ratio of the base to the prochiral cyclic ketone is 2.0.

[0014] Furthermore, the method also includes separating and purifying the crude product using silica gel column chromatography, wherein the eluent for the silica gel column is a mixture of dichloromethane and methanol, wherein the volume ratio of dichloromethane to methanol is between 50 and 100.

[0015] Compared with the prior art, the present invention has at least the following advantages: This invention relates to a method for the desymmetrization of pre-chiral cyclic ketones to prepare chiral lactams via organocatalysis. The method employs chiral phosphoric acid, chiral phosphoramide, or their salts as catalysts, achieving the desymmetrization nitrogen atom insertion reaction of four- to six-membered pre-chiral cyclic ketones under low-temperature to room-temperature conditions. This method can construct a chiral lactam skeleton with high optical purity in one step. It eliminates the need for transition metal catalysts, utilizes commercially available catalysts in small quantities, employs readily available reactants, simplifies post-processing, and exhibits excellent stereoselectivity of the product. It overcomes the limitations of traditional Beckmann rearrangement-type reactions in terms of substrate applicability, providing an economical synthetic method for the synthesis of chiral drugs or fine chemicals, and has broad application prospects. Attached Figure Description

[0016] To more clearly illustrate the specific embodiments of the present invention, the accompanying drawings used in the description of the specific embodiments or the prior art will be briefly introduced below.

[0017] Figure 1 The proton NMR spectrum of compound 3s prepared in Example 19; Figure 2 The carbon NMR spectrum of compound 3s prepared in Example 19; Figure 3 The proton NMR spectrum of compound 3t prepared in Example 20; Figure 4 The carbon NMR spectrum of compound 3t prepared in Example 20; Figure 5 The proton NMR spectrum of compound 3u prepared in Example 21; Figure 6 The carbon NMR spectrum of compound 3u prepared in Example 21; Figure 7 The nuclear magnetic resonance fluorine spectrum of compound 3u prepared in Example 21; Figure 8 The proton NMR spectrum of compound 3v prepared in Example 22; Figure 9 The carbon NMR spectrum of compound 3v prepared in Example 22; Figure 10 The proton NMR spectrum of compound 3w prepared in Example 23; Figure 11 The image shows the carbon NMR spectrum of compound 3w prepared in Example 23. Detailed Implementation

[0018] The present invention will now be described in further detail. It should be noted that the following specific embodiments are only used to further illustrate the present invention and should not be construed as limiting the scope of protection of the present invention. Those skilled in the art can make some non-essential improvements and adjustments to the present invention based on the above application content.

[0019] This invention provides a general and / or specific description of the materials and experimental methods used in the experiments. Unless otherwise specified, all experimental or testing methods are conventional methods; all reagents or instruments used, unless otherwise specified, are commercially available conventional products prepared or used using conventional methods.

[0020] In some instances, the synthetic process route is as follows: Where R 1 H, cyano, or alkoxy; R 2 The following are phenyl groups, including substituted benzene rings, benzofuran rings, piperine rings, 1-naphthyl, 2-naphthyl, benzothiophene, thiophene, substituted imidazole rings, methyl, ethyl, isopropyl, tert-butyl, substituted straight-chain alkyl groups, substituted cycloalkyl groups, trifluoromethyl, halogen, benzoyl, ester, acyl, amide, and sulfonamide, where the substituent is alkyl, alkoxy, halogen, alkenyl, or alkynyl; R 3 It is an aromatic phenyl or methyl group.

[0021] The present invention is further preferably wherein the chiral catalyst is selected from one of the following: In a further preferred embodiment of the present invention, the solvent is selected from a mixture of chlorobenzene, diethyl ether, or chlorophenylethyl ether, wherein the volume ratio of chlorobenzene to diethyl ether in the mixed solvent is 4:1 or 1:1.

[0022] In a further preferred embodiment of the present invention, the amount of chiral catalyst added is 5-20 mol%, and the molar ratio of prochiral cyclohexanone to sulfonyl hydroxylamine is 1:(1.2-1.5).

[0023] A further preferred embodiment of the present invention is that the reaction time is 8 hours.

[0024] The following will provide further explanation in conjunction with Examples 1-18.

[0025] Example 1 A method for preparing chiral lactam 3a, the reaction process is as follows: The specific steps are as follows: Take a 10 mL dry reaction tube, add a magnetic stir bar, and add 0.2 mmol (34.8 mg) of 4-phenylcyclohexanone 1a, 0.01 mmol (7.2 mg) of chiral catalyst, and 0.4 mmol (33.2 mg) of sodium bicarbonate, respectively. Then add 1.0 mL of chlorobenzene, stopper the tube with a rubber stopper, and cool to -40 °C. Dissolve 0.1 mmol (24.2 mg) of freshly prepared sulfonyl hydroxylamine 2a in 1.0 mL of chlorobenzene solution, and add it dropwise to the reaction mixture over 1 minute (repeat this operation twice after 5 minutes). After reacting at -40 °C for 8 h, purify the mixture by column chromatography (dichloromethane:methanol = 100:1, 100:1 is a volume ratio). After purification, 37.8 mg of chiral lactam 3a is obtained as a white solid with a yield >99% and 93% ee.

[0026] The structural characterization results and chiral optical detection results of product 3a are as follows: 1 H NMR (400 MHz, CDCl3) δ7.36 –7.27 (m, 2H), 7.25 – 7.13 (m, 3H), 6.76 (brs, 1H), 3.45 – 3.24 (m, 2H),2.82 – 2.71 (m, 1H), 2.70 – 2.51 (m, 2H), 2.06 – 1.96 (m, 2H), 1.87 – 1.67(m, 2H). 13 C NMR (101 MHz, CDCl3) δ 179.4, 142.3, 128.7, 126.7, 126.7, 48.6,43.2, 37.4, 35.9, 29.8. HRMS (ESI) m / z calcd. for C 12 H 16 NO [M+H] + 190.1226, found 190.1226. HPLC analysis (Chiralcel AD-H, hexane / i-PrOH = 80 / 20, flowrate = 1.0 mL / min, λ = 210 nm), t r (major) = 12.37 min, t r (minor) = 6.05 min;[α] D 20 = +46.8 (c = 0.20, in CHCl3); mp = 190–192 °C; R f= 0.2 (DCM / MeOH: 80 / 1).

[0027] Example 2 A method for preparing chiral lactam 3b, the reaction process is as follows: The specific steps are as follows: Take a 10 mL dry reaction tube, add a magnetic stir bar, and add 0.2 mmol (30.9 mg) of 4-tert-butylcyclohexanone 1b, 0.01 mmol (7.2 mg) of chiral catalyst, and 0.4 mmol (33.2 mg) of sodium bicarbonate, respectively. Then add 1.0 mL of chlorobenzene, stopper the tube with a rubber stopper, and cool to -40 °C. Dissolve 0.1 mmol (24.2 mg) of freshly prepared sulfonylhydroxylamine 2a in 1.0 mL of chlorobenzene solution, and add it dropwise to the reaction mixture over 1 minute (repeat this operation twice after 5 minutes). After reacting at -40 °C for 8 h, purify the mixture by column chromatography (dichloromethane:methanol = 100:1, 100:1 is a volume ratio). After purification, 23.7 mg of chiral lactam 3b is obtained as a white solid with a yield of 70% and an ee of 92%.

[0028] The structural characterization and chiral optical detection results of product 3b are as follows: 1 H NMR (400 MHz, CDCl3) δ6.97 (brs, 1H), 3.36 – 3.11 (m, 2H), 2.52 – 2.33 (m, 2H), 2.05 – 1.86 (m,2H), 1.34 – 1.14 (m, 3H), 0.88 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ 179.3,52.3, 42.2, 35.7, 33.3, 30.6, 27.6, 23.9. HPLC analysis (Chiralcel AD-H,hexane / i-PrOH = 80 / 20, flow rate = 1.0 mL / min, λ = 210 nm), t r (major) = 7.65min, t r (minor) = 8.29 min; [α] D 20 = +27.5 (c = 0.04, in CHCl3); mp = 151–153°C; R f = 0.2 (DCM / MeOH: 80 / 1).

[0029] Example 3 A method for preparing chiral lactam 3c, the reaction process is as follows: The specific steps are as follows: Take a 10 mL dry reaction tube, add a magnetic stir bar, and add 0.2 mmol (33.9 mg) of 4-cyano-4-phenylcyclohexanone 1c, 0.01 mmol (7.2 mg) of chiral catalyst, and 0.4 mmol (33.2 mg) of sodium bicarbonate, respectively. Then add 1.0 mL of mixed solvent (chlorobenzene: ether 4:1), stopper the tube with a rubber stopper, and cool to -40 °C. Dissolve 0.1 mmol (24.2 mg) of freshly prepared sulfonyl hydroxylamine 2a in 1.0 mL of the mixed solution, and add it dropwise to the reaction mixture over 1 minute (repeat this operation twice after 5 minutes). After reacting at -40 °C for 8 h, purify the mixture by column chromatography (dichloromethane: methanol = 100:1, 100:1 is a volume ratio). After purification, 31.7 mg of chiral lactam 3c, a pink solid, is obtained, with a yield of 74% and an ee of 91%.

[0030] The structural characterization results and chiral optical detection results of product 3c are as follows: 1 H NMR (400 MHz, CDCl3) δ7.52 – 7.46 (m, 2H), 7.46 – 7.39 (m, 2H), 7.39 – 7.33 (m, 1H), 7.08 (brs,1H), 3.83 – 3.71 (m, 1H), 3.42 – 3.29 (m, 1H), 3.12 – 3.00 (m, 1H), 2.60 (dd,J = 15.0, 7.0 Hz, 1H), 2.28 – 2.14 (m, 3H), 2.14 – 2.04 (m, 1H). 13 C NMR (101MHz, CDCl3) δ 177.4, 140.0, 129.3, 128.5, 125.4, 121.5, 48.6, 40.8, 38.9,33.9, 33.0. HRMS (ESI) m / z calcd. for C 13 H 15 N2O [M+H] +215.1179, found215.1175. HPLC analysis (Chiralcel AD-H, hexane / i-PrOH = 90 / 10, flow rate =1.0 mL / min, λ = 210 nm), t r (major) = 15.79 min, t r (minor) = 14.94 min; [α] D 20 = +57.9 (c = 0.25, in CHCl3); mp = 207–209 °C; R f = 0.2 (DCM / MeOH: 80 / 1).

[0031] Example 4 A method for preparing chiral lactam 3d, the reaction process is as follows: The specific steps are as follows: Take a 10 mL dry reaction tube, add a magnetic stir bar, and add 0.05 mmol (7.0 mg) of 4-ethyl-4-methylcyclohexanone 1d, 0.0025 mmol (1.8 mg) of chiral catalyst and 0.1 mmol (8.3 mg) of sodium bicarbonate, respectively. Then add 0.2 mL of mixed solvent (chlorobenzene: ether 4:1), stopper the tube with a rubber stopper and cool to -40 °C. Dissolve 0.025 mmol of freshly prepared sulfonyl hydroxylamine 2a (6.05 mg) in 0.3 mL of the mixed solution and add it dropwise to the reaction mixture over 1 minute (repeat this operation twice after 5 minutes). After reacting at -40 °C for 8 h, purify by column chromatography (dichloromethane: methanol = 100:1, 100:1 is a volume ratio). After purification, 7.0 mg of chiral lactam 3d is obtained as a yellow solid with a yield of 90% and an ee of 67%.

[0032] The 3D structural characterization results and chiral optical detection results of the product are as follows: 1 H NMR (400 MHz, CDCl3) δ6.25 (brs, 1H), 3.29 – 3.06 (m, 2H), 2.51 – 2.32 (m, 2H), 1.59 – 1.28 (m,6H), 0.92 (s, 3H), 0.83 (t, J = 7.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 178.9,40.1, 37.8, 35.1, 33.9, 33.6, 31.3, 24.5, 7.7. HRMS (ESI) m / z calcd. forC9H 18 NO [M+H] + 156.1383, found 156.1388. HPLC analysis (Chiralcel IC, hexane / i-PrOH = 90 / 10, flow rate = 1.0 mL / min, λ = 210 nm), t r (major) = 58.39 min,t r (minor) = 55.38 min; [α] D 20 = +74.6 (c = 0.07, in CHCl3); mp = 78–80 °C; R f = 0.2 (DCM / MeOH: 80 / 1).

[0033] Example 5 A method for preparing chiral lactam 3e, the reaction process is as follows: The specific steps are as follows: Take a 10 mL dry reaction tube, add a magnetic stir bar, and add 0.2 mmol (40.1 mg) of 2',3'-dihydrospiro[cyclohexane-1,1'-indene]-4-one 1e, 0.01 mmol (7.2 mg) of chiral catalyst, and 0.4 mmol (33.2 mg) of sodium bicarbonate, respectively. Then add 1.0 mL of chlorobenzene, stopper the tube with a rubber stopper, and cool to -40 °C. Dissolve 0.1 mmol of freshly prepared sulfonylhydroxylamine 2a (24.2 mg) in 1.0 mL of chlorobenzene solution, and add it dropwise to the reaction mixture over 1 minute (repeat this operation twice after 5 minutes). After reacting at -40 °C for 8 h, purify by column chromatography (dichloromethane:methanol = 100:1, 100:1 is a volume ratio). After purification, 43.0 mg of chiral lactam 3e is obtained as a white solid with a yield >99% and 80% ee.

[0034] The structural characterization and chiral optical detection results of product 3e are as follows: 1H NMR (400 MHz, CDCl3) δ7.24 – 7.14 (m, 3H), 7.14 – 7.10 (m, 1H), 7.04 (brs, 1H), 3.51 – 3.39 (m,1H), 3.25 – 3.13 (m, 1H), 3.00 – 2.86 (m, 2H), 2.75 – 2.64 (m, 1H), 2.42 (dd,J = 14.4, 7.8 Hz, 1H), 2.15 – 2.03 (m, 2H), 2.03 – 1.93 (m, 1H), 1.88 – 1.79(m, 1H), 1.77 – 1.65 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 179.0, 151.0, 142.4,127.1, 126.7, 124.8, 122.4, 50.8, 40.3, 39.1, 34.9, 34.0, 32.8, 29.6. HRMS(ESI) m / z calcd. for C 14 H 18 NO [M+H] + 216.1383, found 216.1380. HPLC analysis(Chiralcel AD-H, hexane / i-PrOH = 80 / 20, flow rate = 1.0 mL / min, λ = 210 nm),t r (major) = 6.69 min, t r (minor) = 6.00 min; [α] D 20 = +43.8 (c = 0.29, inCHCl3); mp = 209–211 °C; R f = 0.2 (DCM / MeOH: 80 / 1).

[0035] Example 6 A method for preparing a chiral lactam 3f, the reaction process of which is as follows: The specific steps are as follows: Take a 10 mL dry reaction tube, add a magnetic stir bar, and add 0.2 mmol (40.4 mg) of 3'H-spiro[cyclohexane-1,1'-isobenzofuran]-4-one 1f, 0.02 mmol (14.4 mg) of chiral catalyst, and 0.4 mmol (33.2 mg) of sodium bicarbonate, respectively. Then add 1.0 mL of chlorobenzene, stopper the tube with a rubber stopper, and cool to -40 °C. Dissolve 0.1 mmol of freshly prepared sulfonylhydroxylamine 2a (24.2 mg) in 1.0 mL of chlorobenzene solution, and add it dropwise to the reaction mixture over 1 minute (repeat this operation twice after 5 minutes). After reacting at -40 °C for 8 h, purify by column chromatography (dichloromethane:methanol = 100:1, 100:1 is a volume ratio). After purification, 42.1 mg of chiral lactam 3f is obtained as a white solid with a yield of 97% and an ee of 77%.

[0036] The structural characterization results and chiral optical detection results of product 3f are as follows: 1 H NMR (400 MHz, CDCl3) δ7.34 – 7.25 (m, 2H), 7.25 – 7.18 (m, 1H), 7.12 – 7.07 (m, 1H), 7.02 (brs,1H), 5.08 (s, 2H), 3.90 – 3.69 (m, 1H), 3.24 – 3.02 (m, 2H), 2.33 (dd, J =14.1, 6.5 Hz, 1H), 2.10 – 1.87 (m, 4H). 13 C NMR (101 MHz, CDCl3) δ 179.1,146.0, 138.3, 127.9, 127.6, 121.3, 120.5, 87.4, 70.9, 40.5, 37.5, 34.3, 30.9.HRMS (ESI) m / z calcd. for C 13 H 16 NO2 [M+H] + 218.1176, found 218.1172. HPLC analysis (Chiralcel AD-H, hexane / i-PrOH = 80 / 20, flow rate = 1.0 mL / min, λ =210 nm), t r (major) = 7.58 min, t r (minor) = 6.22 min; [α] D 20= +21.7 (c =0.31, in CHCl3); mp = 171–173 °C; R f = 0.2 (DCM / MeOH: 80 / 1).

[0037] Example 7 A method for preparing 3g of chiral lactam, the reaction process is as follows: The specific steps are as follows: Take a 10 mL dry reaction tube, add a magnetic stir bar, and add 0.2 mmol (25.2 mg) of cis-3,5-dimethylcyclohexanone 1 g, 0.02 mmol (15.2 mg) of chiral catalyst and 0.4 mmol (33.2 mg) of sodium bicarbonate, respectively. Then add 1.0 mL of chlorobenzene, stopper the tube with a rubber stopper and cool to -40 °C. Dissolve 0.1 mmol of freshly prepared sulfonylhydroxylamine 2a (24.2 mg) in 1.0 mL of chlorobenzene solution and add it dropwise to the reaction mixture over 1 minute (repeat this operation twice after 5 minutes). After reacting at -40 °C for 8 h, purify the mixture by column chromatography (dichloromethane:methanol = 100:1, 100:1 is a volume ratio). After purification, 27.4 mg of chiral lactam 3 g, white solid, yield 97%, 81% ee.

[0038] The structural characterization and chiral optical detection results of product 3g are as follows: 1 H NMR (400 MHz, CDCl3) δ6.38 (brs, 1H), 3.03 – 2.79 (m, 2H), 2.38 – 2.26 (m, 1H), 2.26 – 2.13 (m,1H), 1.94 – 1.68 (m, 3H), 1.68 – 1.57 (m, 1H), 0.94 (d, J = 6.5 Hz, 3H), 0.82 (d, J = 6.9 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 177.7, 49.2, 48.5, 44.3, 35.1,29.8, 24.6, 20.6. HRMS (ESI) m / z calcd. for C8H 16 NO [M+H] +142.1226, found142.1227. HPLC analysis (Chiralcel AD-H, hexane / i-PrOH = 90 / 10, flow rate =1.0 mL / min, λ = 210 nm), t r (major) = 7.35 min, t r (minor) = 6.42 min; [α] D 20 =+23.4 (c = 0.16, in CHCl3); mp = 104–106 °C; R f = 0.2 (DCM / MeOH: 80 / 1).

[0039] Example 8 A method for preparing chiral lactam 3h, the reaction process is as follows: The specific steps are as follows: Take a 10 mL dry reaction tube, add a magnetic stir bar, and add 0.2 mmol (50.1 mg) of cis-3,5-diphenylcyclohexanone for 1 h, 0.02 mmol (15.2 mg) of chiral catalyst, and 0.4 mmol (33.2 mg) of sodium bicarbonate, respectively. Then add 1.0 mL of chlorobenzene, stopper the tube with a rubber stopper, and cool to -40 °C. Dissolve 0.1 mmol of freshly prepared sulfonylhydroxylamine 2a (24.2 mg) in 1.0 mL of chlorobenzene solution, and add it dropwise to the reaction mixture over 1 minute (repeat this operation twice after 5 minutes). After reacting at -40 °C for 8 h, purify the mixture by column chromatography (dichloromethane:methanol = 100:1, 100:1 is a volume ratio). After purification, 47.2 mg of chiral lactam for 3 h is obtained as a white solid with a yield of 89% and an ee of 87%.

[0040] The structural characterization results and chiral optical detection results of the product after 3 hours are as follows: 1H NMR (400 MHz, CDCl3) δ7.32 – 7.25 (m, 4H), 7.23 – 7.12 (m, 6H), 7.12 – 6.94 (brs, 1H), 3.69 – 3.56(m, 1H), 3.29 (dd, J = 14.8, 7.7 Hz, 1H), 3.13 – 3.01 (m, 2H), 2.98 – 2.87(m, 1H), 2.74 – 2.61 (m, 1H), 2.25 (d, J = 14.3 Hz, 1H), 2.09 – 1.96 (m, 1H). 13 C NMR (101 MHz, CDCl3) δ 177.1, 146.6, 144.1, 128.8, 128.7, 126.8, 126.6,126.6, 126.3, 48.4, 47.7, 47.2, 43.5, 40.9. HRMS (ESI) m / z calcd. for C18H 20 NO[M+H] + 266.1539, found 266.1543. HPLC analysis (Chiralcel AD-H, hexane / i-PrOH= 80 / 20, flow rate = 1.0 mL / min, λ = 210 nm), t r (major) = 10.20 min, t r (minor) = 8.27 min; [α] D 20 = +14.4 (c = 0.46, in CHCl3); mp = 161–163 °C; R f = 0.2 (DCM / MeOH: 80 / 1).

[0041] Example 9 A method for preparing chiral lactam 3i, the reaction process is as follows: The specific steps are as follows: Take a 10 mL dry reaction tube, add a magnetic stir bar, and add 0.1 mmol (29.4 mg) (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 2-(4-oxocyclohexyl)acetate 1i, 0.01 mmol (7.2 mg) chiral catalyst and 0.2 mmol (16.8 mg) sodium bicarbonate respectively. Then add 0.5 mL chlorobenzene, stopper with a rubber stopper and cool to -40 °C. Freshly prepared 0.05 mmol sulfonylhydroxylamine 2a (12.1 mg) was dissolved in 0.5 mL chlorobenzene solution and added dropwise to the reaction mixture over 1 minute (this operation was repeated twice after 5 minutes). After reacting at -40 °C for 8 h, the mixture was purified by column chromatography (dichloromethane:methanol = 80:1, 80:1 is a volume ratio). The purified product was 31.0 mg chiral lactam 3i, a white solid with a yield >99%, 12:1 dr.

[0042] The structural characterization and chiral optical detection results of product 3i are as follows: 1 H NMR (400 MHz, CDCl3) δ6.47 (brs, 1H), 4.68 (td, J = 10.9, 4.4 Hz, 1H), 3.33 – 3.16 (m, 2H), 2.56 –2.43 (m, 2H), 2.31 – 2.20 (m, 2H), 2.16 – 2.04 (m, 1H), 2.00 – 1.94 (m, 1H), 1.91 – 1.79 (m, 3H), 1.75 – 1.64 (m, 2H), 1.56 – 1.43 (m, 1H), 1.42 – 1.21(m, 4H), 1.12 – 0.94 (m, 2H), 0.92 – 0.88 (m, 6H), 0.75 (d, J = 7.0 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 178.4, 171.9, 74.4, 47.0, 42.0, 41.4, 41.0, 38.6,35.6, 35.1, 34.2, 31.4, 29.0, 26.3, 23.4, 22.0, 20.7, 16.2. HRMS (ESI) m / zcalcd. for C 18 H 32 NO3 [M+H] +310.2377, found 310.2370. HPLC analysis (ChiralcelOD-H, hexane / i-PrOH = 80 / 20, flow rate = 1.0 mL / min, λ = 210 nm), t r (major) = 5.79 min, t r (minor) = 5.42 min; [α] D 20 = -30.7 (c = 0.15, in CHCl3); mp =113–115 °C; R f = 0.2 (DCM / MeOH: 60 / 1).

[0043] Example 10 A method for preparing a chiral lactam 3j, the reaction process is as follows: The specific steps are as follows: Take a 10 mL dry reaction tube, add a magnetic stir bar, and add 0.2 mmol (54.8 mg) (1S,2R,5S)-5-methyl-2-(prop-1-en-2-yl)cyclohexyl-2-(4-oxocyclohexyl)acetate, 0.02 mmol (14.4 mg) chiral catalyst and 0.4 mmol (33.2 mg) sodium bicarbonate respectively. Then add 1.0 mL chlorobenzene, stopper with a rubber stopper and cool to -40 °C. Freshly prepared 0.01 mmol sulfonylhydroxylamine 2a (24.2 mg) was dissolved in 1.0 mL of chlorobenzene solution and added dropwise to the reaction mixture over 1 minute (this operation was repeated twice after 5 minutes). After reacting at -40 °C for 8 h, the mixture was purified by column chromatography (dichloromethane:methanol = 80:1, 80:1 is a volume ratio). The purified product was 61.6 mg chiral lactam 3j, a white solid with a yield >99% and a dr ratio of 7.3:1.

[0044] The structural characterization and chiral optical detection results of product 3j are as follows: 1H NMR (400 MHz, CDCl3) δ6.70 (brs, 1H), 4.92 – 4.78 (m, 1H), 4.71 (s, 2H), 3.32 – 3.09 (m, 2H), 2.54– 2.37 (m, 2H), 2.28 – 2.15 (m, 2H), 2.15 – 1.94 (m, 3H), 1.88 – 1.78 (m,2H), 1.78 – 1.62 (m, 5H), 1.62 – 1.48 (m, 1H), 1.44 – 1.34 (m, 1H), 1.34 –1.18 (m, 2H), 1.09 – 0.87 (m, 5H). 13 C NMR (101 MHz, CDCl3) δ 178.4, 171.6,146.2, 111.8, 73.6, 50.7, 42.0, 41.4, 40.5, 38.6, 35.5, 35.1, 34.0, 31.4,30.4, 28.9, 22.0, 19.5. HRMS (ESI) m / z calcd. for C 18 H 30 NO3 [M+H] + 308.2220, found 308.2215. HPLC analysis (Chiralcel OD-H, hexane / i-PrOH = 80 / 20, flowrate = 1.0 mL / min, λ = 210 nm), t r (major) = 9.23 min, t r (minor) = 11.50 min;[α] D 20 = +40.5 (c = 0.06, in CHCl3); mp = 133–135 °C; R f = 0.2 (DCM / MeOH: 60 / 1).

[0045] Example 11 A method for preparing chiral lactam 3k, the reaction process is as follows: The specific steps are as follows: Take a 10 mL dry reaction tube, add a magnetic stir bar, and add 0.1 mmol (32.5 mg) (R)-1-tert-butyl-2-[(4-oxocyclohexyl)methyl]pyrrolidine-1,2-dicarboxylic acid ester 1k, 0.01 mmol (7.2 mg) chiral catalyst and 0.2 mmol (33.2 mg) sodium bicarbonate respectively. Then add 0.5 mL chlorobenzene, stopper with a rubber stopper and cool to -40 °C. Freshly prepared 0.05 mmol sulfonylhydroxylamine 2a (12.1 mg) was dissolved in 0.5 mL chlorobenzene solution and added dropwise to the reaction mixture over 1 minute (this operation was repeated twice after 5 minutes). After reacting at -40 °C for 8 h, the mixture was purified by column chromatography (dichloromethane:methanol = 60:1, 60:1 is the volume ratio). After purification, 32.4 mg of chiral lactam 3k was obtained as a colorless oil with a yield of 95% and a dr ratio of 17:1.

[0046] The structural characterization and chiral optical detection results of product 3k are as follows: 1 H NMR (400 MHz, CDCl3,mixture of rotamers) δ 6.86 – 6.55 (m, 1H), 4.37 – 4.17 (m, 1H), 4.10 – 3.87(m, 2H), 3.58 – 3.33 (m, 2H), 3.33 – 3.13 (m, 2H), 2.52 – 2.38 (m, 2H), 2.31 – 2.12 (m, 2H), 2.02 – 1.82 (m, 6H), 1.54 – 1.38 (m, 9H), 1.34 – 1.28 (m,1H). 13 C NMR (101 MHz, CDCl3, mixture of rotamers) δ 178.4, 178.3, 173.1,173.0, 154.4, 153.7, 79.9, 79.8, 69.0, 68.9, 59.1, 58.9, 46.5, 46.3, 41.2,41.1,41.1,34.8,34.7,32.5,32.4,31.0,30.0,28.4,28.3,25.8,25.8,24.4,23.6. 17 H 29 N₂O₅ [M+H] +341.2071, found 341.2064.HPLC analysis (Chiralcel OJ-H, hexane / i-PrOH = 80 / 20, flow rate = 1.0 mL / min, λ = 210 nm), t r (major) = 6.00 min, t r (minor) = 6.67 min; [α] D 20 = +99.0 (c = 0.2, in CHCl3); R f = 0.2 (DCM / MeOH: 40 / 1).

[0047] Example 12 A method for preparing chiral lactam 3l, the reaction process is as follows: The specific steps are as follows: Take a 10 mL dry reaction tube, add a magnetic stir bar, and add 0.1 mmol (39.8 mg) of (3aR,5R,6S,6aR)-5-((S)-2,2-dimethyl-1,3-dioxolane-4-yl)-2,2-dimethyltetrahydrofurano[2,3-d][1,3]dioxolane-6-yl 2-(4-oxocyclohexyl)acetate, 0.01 mmol (7.2 mg) of chiral catalyst, and 0.2 mmol (33.2 mg) of sodium bicarbonate. Then add 0.5 mL of chlorobenzene, stopper the tube with a rubber stopper, and cool it to -40°C. Freshly prepared 0.05 mmol sulfonylhydroxylamine 2a (12.1 mg) was dissolved in 0.5 mL chlorobenzene solution and added dropwise to the reaction mixture over 1 minute (this operation was repeated twice after 5 minutes). After reacting at -40 °C for 8 h, the mixture was purified by column chromatography (dichloromethane:methanol = 80:1, 80:1 is a volume ratio). The purified product was 21.5 mg chiral lactam 3l, a white solid with a yield of 52% and a dr ratio of 17:1.

[0048] The structural characterization results and chiral optical detection results of product 3l are as follows: 1H NMR (400 MHz, CDCl3) δ6.25 (brs, 1H), 5.87 (d, J = 3.6 Hz, 1H), 5.30 (d, J = 2.4 Hz, 1H), 4.46 (d,J = 3.7 Hz, 1H), 4.20 – 4.13 (m, 2H), 4.12 – 4.06 (m, 1H), 4.05 – 3.99 (m,1H), 3.28 – 3.07 (m, 2H), 2.49 – 2.37 (m, 2H), 2.36 – 2.23 (m, 2H), 2.14 –2.01 (m, 1H), 1.91 – 1.83 (m, 2H), 1.53 (s, 3H), 1.40 (s, 3H), 1.31 (s, 3H), 1.30 (s, 3H), 1.27 – 1.19 (m, 2H). 13 C NMR (101 MHz, CDCl3,) δ 178.1, 170.8,112.4, 109.4, 105.1, 83.4, 79.9, 76.1, 72.4, 67.5, 42.0, 41.4, 38.5, 35.5,34.9, 28.9, 26.9, 26.7, 26.2, 25.3. HRMS (ESI) m / z calcd. for C 20 H 32 NO8 [M+H] + 414.2122, found 414.2112. HPLC analysis (Chiralcel IA, hexane / i-PrOH = 90 / 10, flow rate = 1.0 mL / min, λ = 210 nm), t r (major) = 17.43 min, t r (minor) = 20.49 min; [α] D 20 = +23.8 (c = 0.06, in CHCl3); mp = 121–123 °C; R f = 0.2(DCM / MeOH: 60 / 1).

[0049] Example 13 A method for preparing a chiral lactam 3m, the reaction process is as follows: The specific steps are as follows: Take a 10 mL dry reaction tube, add a magnetic stir bar, and add 0.1 mmol (39.8 mg) of ((3aR,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-3aH-bis([1,3]dioxacyclopentene)[4,5-b:4',5'-d]pyran-3a-yl)methyl 2-(4-oxocyclohexyl)acetate 1 mL, 0.01 mmol (7.2 mg) of chiral catalyst and 0.2 mmol (33.2 mg) of sodium bicarbonate. Then add 0.5 mL of chlorobenzene, stopper with a rubber stopper and cool to -40 °C. Freshly prepared 0.05 mmol sulfonylhydroxylamine 2a (12.1 mg) was dissolved in 0.5 mL chlorobenzene solution and added dropwise to the reaction mixture over 1 minute (this operation was repeated twice after 5 minutes). After reacting at -40 °C for 8 h, the mixture was purified by column chromatography (dichloromethane:methanol = 80:1, 80:1 is a volume ratio). The purified product was 34.7 mg chiral lactam 3m, a white solid with a yield of 84% and a 5:1 dr.

[0050] The structural characterization results and chiral optical detection results of product 3m are as follows: 1 H NMR (400 MHz, CDCl3) δ6.78 (brs, 1H), 4.61 (dd, J = 7.9, 2.8 Hz, 1H), 4.42 (dd, J = 11.7, 4.8 Hz,1H), 4.27 (d, J = 2.6 Hz, 1H), 4.25 (d, J = 7.9 Hz, 1H), 4.04 (dd, J = 11.7,4.2 Hz, 1H), 3.90 (dd, J = 13.0, 1.9 Hz, 1H), 3.76 (d, J = 13.0 Hz, 1H), 3.28– 3.10 (m, 2H), 2.52 – 2.37 (m, 2H), 2.35 – 3.36 (m, 2H), 2.15 – 2.03 (m,1H), 1.91 – 1.80 (m, 2H), 1.51 (s, 3H), 1.48 (s, 3H), 1.39 (s, 3H), 1.34 (s,3H), 1.30 – 1.18 (m, 2H). 13C NMR (101 MHz, CDCl3,) δ 178.5, 171.5, 109.1,108.7, 101.4, 70.7, 70.6, 70.0, 67.0, 65.4, 61.2, 41.3, 38.2, 35.5, 35.0,29.0, 26.4, 25.9, 25.3, 24.0. HRMS (ESI) m / z calcd. for C 20 H 32 NO8 [M+H] + 414.2122, found 414.2115. HPLC analysis (Chiralcel IA, hexane / i-PrOH = 80 / 20, flow rate = 1.0 mL / min, λ = 210 nm), t r (major) = 11.65 min, t r (minor) = 10.58 min; [α] D 20 = +44.9 (c = 0.07, in CHCl3); mp = 123–125 °C; R f = 0.2(DCM / MeOH: 60 / 1).

[0051] Example 14 A method for preparing chiral lactam 3n, the reaction process is as follows: The specific steps are as follows: Take a 10 mL dry reaction tube, add a magnetic stir bar, and add 0.1 mmol (37.8 mg) of (4-oxocyclohexyl)methyl 2-(11-oxo-6,11-dihydrodibenzo[b,e]oxa-2-yl)acetate 1n, 0.005 mmol (3.6 mg) of chiral catalyst and 0.2 mmol (33.2 mg) of sodium bicarbonate respectively. Then add 0.5 mL of chlorobenzene, stopper the tube with a rubber stopper and cool it to -40 °C. Freshly prepared 0.05 mmol sulfonyl hydroxylamine 2a (12.1 mg) was dissolved in 0.5 mL chlorobenzene solution and added dropwise to the reaction mixture over 1 minute (this operation was repeated twice after 5 minutes). After reacting at -40 °C for 8 h, the mixture was purified by column chromatography (dichloromethane:methanol = 80:1, 80:1 is a volume ratio). After purification, 39.3 mg of chiral lactam 3n was obtained as a colorless oil with a yield >99% and 85% ee.

[0052] The structural characterization and chiral optical detection results of product 3n are as follows: 1 H NMR (400 MHz, CDCl3) δ8.15 – 8.05 (m, 1H), 7.91 – 7.82 (m, 1H), 7.59 – 7.51 (m, 1H), 7.49 – 7.43(m, 1H), 7.43 – 7.38 (m, 1H), 7.36 (dd, J = 8.2, 2.2 Hz, 1H), 7.02 (dd, J =8.4, 2.2 Hz, 1H), 6.80 – 6.70 (m, 1H), 5.18 (d, J = 2.6 Hz, 2H), 4.02 – 3.89(m, 2H), 3.64 (d, J = 1.8 Hz, 2H), 3.29 – 3.17 (m, 2H), 2.53 – 2.41 (m, 2H), 1.98 – 1.79 (m, 3H), 1.38 – 1.27 (m, 2H). 13 C NMR (101 MHz, CDCl3,) δ 190.8,178.4, 171.3, 160.5, 140.4, 136.3, 135.6, 132.9, 132.4, 129.5, 129.3, 127.9,127.7, 125.2, 121.1, 73.7, 69.0, 41.3, 41.1, 40.2, 34.7, 32.5, 25.8. HRMS(ESI) m / z calcd. for C 23 H 23 NNaO5 [M+Na] + 394.1649, found 394.1642. HPLC analysis (Chiralcel OD-H, hexane / i-PrOH = 70 / 30, flow rate = 1.0 mL / min, λ =210 nm), t r (major) = 25.84 min, t r (minor) = 28.52 min; [α] D 20 = +39.2 (c =0.11, in CHCl3); R f = 0.2 (DCM / MeOH: 60 / 1).

[0053] Example 15 A method for preparing chiral lactam 3o, the reaction process is as follows: The specific steps are as follows: Take a 10 mL dry reaction tube, add a magnetic stir bar, and add 0.1 mmol (36.0 mg) of (4-oxocyclohexyl)methyl 5-(2,5-dimethylphenoxy)-2,2-dimethylvalerate 1o, 0.005 mmol (3.6 mg) of chiral catalyst and 0.2 mmol (33.2 mg) of sodium bicarbonate respectively. Then add 0.5 mL of chlorobenzene, stopper with a rubber stopper and cool to -40 °C. Freshly prepared 0.05 mmol sulfonylhydroxylamine 2a (12.1 mg) was dissolved in 0.5 mL chlorobenzene solution and added dropwise to the reaction mixture over 1 minute (this operation was repeated twice after 5 minutes). After reacting at -40 °C for 8 h, the mixture was purified by column chromatography (dichloromethane:methanol = 80:1, 80:1 is a volume ratio). After purification, 25.1 mg of chiral lactam 3o was obtained as a colorless oil with a yield of 67% and an ee of 70%.

[0054] The structural characterization and chiral optical detection results of product 3o are as follows: 1 H NMR (400 MHz, CDCl3) δ7.00 (d, J = 7.6 Hz, 1H), 6.66 (d, J = 7.6 Hz, 1H), 6.59 (s, 1H), 6.29 (brs,1H), 4.00 – 3.87(m, 4H), 3.30 – 3.19 (m, 2H), 2.56 – 2.43 (m, 2H), 2.30 (s,3H), 2.17 (s, 3H), 1.95 – 1.85 (m, 3H), 1.75 – 1.69 (m, 4H), 1.43 – 1.30 (m,2H), 1.22 (s, 6H). 13 C NMR (101 MHz, CDCl3,) δ 178.3, 177.8, 157.0, 136.6,130.4, 123.6, 120.8, 112.1, 68.6, 67.9, 42.3, 41.4, 41.3, 37.2, 34.9, 32.8,26.1, 25.3, 25.3, 25.2, 21.5, 15.8. HRMS (ESI) m / z calcd. for C 22 H 34 NO4 [M+H] +376.2482, found 376.2478. HPLC analysis (Chiralcel OJ-H, hexane / i-PrOH = 70 / 30, flow rate = 1.0 mL / min, λ = 210 nm), t r (major) = 5.54 min, t r (minor) = 8.43 min; [α] D 20 = +20.0 (c = 0.14, in CHCl3); R f = 0.2 (DCM / MeOH: 60 / 1).

[0055] Example 16 A method for preparing a chiral lactam 3p, the reaction process is as follows: The specific steps are as follows: Take a 10 mL dry reaction tube, add a magnetic stir bar, and add 0.1 mmol (36.0 mg) of (4-oxocyclohexyl)methyl(S)-2-(6-methoxynaphthyl-2-yl)propionate 1p, 0.005 mmol (3.6 mg) of chiral catalyst and 0.2 mmol (33.2 mg) of sodium bicarbonate respectively. Then add 0.5 mL of chlorobenzene, stopper with a rubber stopper and cool to -40 °C. Freshly prepared 0.05 mmol sulfonylhydroxylamine 2a (12.1 mg) was dissolved in 0.5 mL chlorobenzene solution and added dropwise to the reaction mixture over 1 minute (this operation was repeated twice after 5 minutes). After reacting at -40 °C for 8 h, the mixture was purified by column chromatography (dichloromethane:methanol = 80:1, 80:1 is a volume ratio). The purified product was 35.5 mg chiral lactam 3p, a white solid with a yield >99% and a dr ratio of 8:1.

[0056] The structural characterization results and chiral optical detection results of product 3p are as follows: 1H NMR (400 MHz, CDCl3) δ7.72 – 7.66 (m, 2H), 7.65 (d, J = 1.8 Hz, 1H), 7.38 (dd, J = 8.5, 1.9 Hz,1H), 7.18 – 7.08 (m, 2H), 6.21 (brs, 1H), 4.05 – 3.80 (m, 6H), 3.22 – 3.04(m, 2H), 2.43 – 2.28 (m, 2H), 1.82 – 1.78 (m, 1H), 1.78 – 1.68 (m, 2H), 1.58(d, J = 7.1 Hz, 3H), 1.26 – 1.09 (m, 2H). 13 C NMR (101 MHz, CDCl3,) δ 178.3,174.5, 157.7, 135.5, 133.7, 129.2, 128.9, 127.2, 126.1, 125.9, 119.1, 105.6,68.7, 55.3, 45.5, 41.2, 41.1, 34.7, 32.4, 25.8, 18.3. HRMS (ESI) m / z calcd.for C 21 H 26 NO4 [M+H] + 356.1856, found 356.1851. HPLC analysis (Chiralcel IA,hexane / i-PrOH = 95 / 5, flow rate = 1.0 mL / min, λ = 210 nm), t r (major) = 68.77min, t r (minor) = 74.42 min; [α] D 20 = +85.2 (c = 0.99, in CHCl3); mp = 82–84°C; R f = 0.2 (DCM / MeOH: 60 / 1).

[0057] Example 17 A method for preparing a chiral lactam 3q, the reaction process is as follows: The specific steps are as follows: Take a 10 mL dry reaction tube, add a magnetic stir bar, and add 0.1 mmol (52.4 mg) of (3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-((R)-6-methylheptane-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentadien[a]phenanthrene-3-yl 2-(4-oxocyclohexyl)acetate 1q, 0.01 mmol (7.2 mg) of chiral catalyst and 0.2 mmol (33.2 mg) of sodium bicarbonate. Then add 0.5 mL of chlorobenzene, stopper with a rubber stopper and cool to -40 °C. Freshly prepared 0.05 mmol sulfonylhydroxylamine 2a (12.1 mg) was dissolved in 0.5 mL chlorobenzene solution and added dropwise to the reaction mixture over 1 minute (this operation was repeated twice after 5 minutes). After reacting at -40 °C for 8 h, the mixture was purified by column chromatography (dichloromethane:methanol = 80:1, 80:1 is a volume ratio). The purified product was 42.0 mg chiral lactam 3q, a white solid with a yield of 78% and a dr ratio of 16:1.

[0058] The structural characterization results and chiral optical detection results of product 3q are as follows: 1 H NMR (400 MHz, CDCl3) δ6.40 (brs, 1H), 5.31 (d, J = 5.0 Hz, 1H), 4.73 – 4.41 (m, 1H), 3.30 – 3.05(m, 2H), 2.48 – 2.34 (m, 2H), 2.30 – 2.12 (m, 4H), 2.08 – 1.86 (m, 4H), 1.84 – 1.77 (m, 3H), 1.57 – 1.32 (m, 8H), 1.32 – 1.12 (m, 7H), 1.12 – 1.00 (m, 6H), 1.00 – 0.89 (m, 6H), 0.89 – 0.73 (m, 9H), 0.61 (s, 3H). 13C NMR (101 MHz, CDCl3,) δ 178.4, 171.7, 139.5, 122.8, 74.1, 56.7, 56.1, 50.0, 42.3, 42.0,41.5, 39.7, 39.5, 38.6, 38.2, 37.0, 36.6, 36.2, 35.8, 35.6, 35.0, 31.9, 31.9,29.0, 28.2, 28.0, 27.8, 24.3, 23.8, 22.8, 22.6, 21.0, 19.3, 18.7, 11.9. HRMS(ESI) m / z calcd. for C 35 H 58 NO3 [M+H] + 540.4411, found 540.4408. HPLC analysis(Chiralcel OD-H, hexane / i-PrOH = 95 / 5, flow rate = 1.0 mL / min, λ = 210 nm),t r (major) = 22.29 min, t r (minor) = 20.58 min; [α] D 20 = -1.5 (c = 0.20, inCHCl3); mp = 212–214 °C; R f = 0.2 (DCM / MeOH: 60 / 1).

[0059] Example 18 A method for preparing a chiral lactam 3r, the reaction process of which is as follows: The specific steps are as follows: Take a 10 mL dry reaction tube, add a magnetic stir bar, and add 0.1 mmol (46.7 mg) 4-(2-((3S,4R)-3-((benzo[d][1,3]dioxacyclopenten-5-yloxo)methyl)-4-(4-fluorophenyl)piperidin-1-yl)-2-oxoethyl)cyclohexane-1-one 1r, 0.01 mmol (7.2 mg) chiral catalyst and 0.2 mmol (33.2 mg) sodium bicarbonate. Then add 0.5 mL chlorobenzene, stopper with a rubber stopper and cool to -40 °C. Freshly prepared 0.05 mmol sulfonyl hydroxylamine 2a (12.1 mg) was dissolved in 0.5 mL chlorobenzene solution and added dropwise to the reaction mixture over 1 minute (this operation was repeated twice after 5 minutes). After reacting at -40 °C for 8 h, the mixture was purified by column chromatography (dichloromethane:methanol = 50:1, 50:1 is a volume ratio). After purification, 47.2 mg of chiral lactam 3r was obtained as a colorless oil with a yield of 98% and a dr ratio of 7.7:1.

[0060] The structural characterization results and chiral optical detection results of product 3r are as follows: 1H NMR (400 MHz, CDCl3,mixture of rotamers) δ 7.18 – 7.09 (m, 2H), 7.06 – 6.95 (m, 2H), 6.70 – 6.60(m, 1H), 6.53 (brs, 1H), 6.39 – 6.31 (m, 1H), 6.14 (d, J = 8.4 Hz, 1H), 5.96– 5.84 (m, 2H), 4.95 (d, J = 13.2 Hz, 1H, minor rotamer), 4.79 (d, J = 13.2Hz, 1H, major rotamer), 4.18 (d, J = 13.2 Hz, 1H, major rotamer), 3.98 (d, J= 13.2 Hz, 1H, minor rotamer), 3.63 (d, J = 9.2 Hz, 1H), 3.54 – 3.45 (m, 1H),3.39 – 3.19 (m, 2H), 3.19 – 3.02 (m, 1H), 2.89 – 2.61 (m, 2H), 2.60 – 2.43(m, 2H), 2.40 – 2.28 (m, 2H), 2.28 – 2.17 (m, 1H), 2.04 – 1.86 (m, 4H), 1.75– 1.61 (m, 1H), 1.37 – 1.25 (m, 2H). 13C NMR (101 MHz, CDCl3, mixture of rotamers) δ 178.8, 178.7, 169.8, 169.8, 161.7 (d, J = 245.4 Hz), 161.6 (d, J= 245.4 Hz), 154.2, 153.8, 148.3, 148.2, 141.9, 141.7, 138.5 (d, J = 3.0 Hz), 138.4 (d, J = 3.0 Hz), 128.8 (d, J = 8.1 Hz), 128.7 (d, J = 8.1 Hz), 115.7(d, J = 22.2 Hz), 115.6 (d, J = 21.2 Hz), 107.9, 107.8, 105.6, 101.2, 101.1, 98.0, 97.9, 68.6, 49.1, 46.2, 45.1, 44.3, 43.8, 42.8, 42.4, 41.9, 41.6, 41.6, 40.1, 38.6, 36.1, 36.0, 35.3, 34.6, 33.7, 29.5. 19 F NMR (377 MHz, CDCl3,mixture of rotamers) δ -115.6, -115.8. HRMS (ESI) m / z calcd. for C 27 H 32 FN2O5 [M+H] + 483.2290, found 483.2283. HPLC analysis (Chiralcel OJ-H, hexane / i-PrOH =70 / 30, flow rate = 1.0 mL / min, λ = 210 nm), t r (major) = 21.81 min, t r (minor) = 42.19 min; [α] D 20 = +11.4 (c = 0.66, in CHCl3); R f = 0.4 (DCM / MeOH: 30 / 1).

[0061] In some instances, the synthetic process route is as follows: Where R 1It can be phenyl, a benzene ring containing a substituent, naphthyl, benzothiophene, cyclohexyl or isobutyl.

[0062] In a further preferred embodiment of the present invention, the chiral catalyst is: In a further preferred embodiment of the present invention, the solvent is toluene.

[0063] In a further preferred embodiment of the present invention, the amount of chiral catalyst added is 20 mol%, and the molar ratio of prochiral cyclohexanone to sulfonyl hydroxylamine is 1:2.0.

[0064] A further preferred embodiment of the present invention is that the reaction time is 8 hours.

[0065] The following will provide further explanation in conjunction with Examples 19-23.

[0066] Example 19 A method for preparing a chiral lactam 3s, the reaction process is as follows: The specific steps are as follows: Take a 10 mL dry reaction tube, add a magnetic stir bar, and add 0.04 mmol (28.0 mg) of chiral catalyst and freshly prepared 0.4 mmol of sulfonyl hydroxylamine 2b (120.0 mg), followed by 1.0 mL of toluene. Seal the tube with a rubber stopper and cool to -78 °C. Dissolve 3-phenylcyclobutanone 1s (9.73 mg, 0.33 equiv.) in 1.0 mL of toluene solution and add it dropwise to the reaction mixture over 1 minute (repeat this operation twice after 5 minutes). After reacting at -78 °C for 8 h, purify the mixture by column chromatography (dichloromethane:methanol = 100:1, 100:1 is a volume ratio). The purified product is 30.0 mg of chiral lactam 3s, a white solid, with a yield of 93% and an ee of 96%.

[0067] The structural characterization and chiral optical detection results of product 3s are as follows: 1 H NMR (400 MHz, CDCl3) δ7.40 – 7.30 (m, 2H), 7.30 – 7.18 (m, 3H), 6.99 (brs, 1H), 3.84 – 3.75 (m,1H), 3.74 – 3.64 (m, 1H), 3.43 (dd, J = 9.4, 7.2 Hz, 1H), 2.74 (dd, J = 16.9,8.9 Hz, 1H), 2.51 (dd, J = 16.9, 8.8 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ178.0, 142.2, 128.9, 127.1, 126.8, 49.6, 40.3, 38.1. HPLC analysis (ChiralcelAD-H, hexane / i-PrOH = 90 / 10, flow rate = 1.0 mL / min, λ = 210 nm), t r (major) = 8.19 min, t r (minor) = 9.78 min; [α] D 20 = -51.2 (c = 0.13, in CHCl3); mp =48–50 °C; R f = 0.2 (DCM / MeOH: 80 / 1).

[0068] Example 20 A method for preparing chiral lactam 3t, the reaction process is as follows: The specific steps are as follows: Take a 10 mL dry reaction tube, add a magnetic stir bar, add 0.04 mmol (28.0 mg) of chiral catalyst and freshly prepared 0.4 mmol of sulfonylhydroxylamine 2b (120.0 mg), then add 1.0 mL of toluene, stopper the tube with a rubber stopper, and cool to -78 °C. Dissolve 1 t (10.67 mg, 0.33 equiv.) of 3-(4-methylphenyl)cyclobutane-1-one in 1.0 mL of toluene solution, and add it dropwise to the reaction mixture over 1 minute (repeat this operation twice after 5 minutes). After reacting at -78 °C for 8 h, purify by column chromatography (dichloromethane:methanol = 100:1, 100:1 is a volume ratio). After purification, 32.9 mg of chiral lactam 3 t, white solid, yield 94%, 97% ee.

[0069] The structural characterization results and chiral optical detection results of product 3t are as follows: 1H NMR (400 MHz, CDCl3) δ7.18 – 7.06 (m, 4H), 6.85 (brs, 1H), 3.76 (t, J = 8.8 Hz, 1H), 3.70 – 3.60(m, 1H), 3.39 (dd, J = 9.4, 7.3 Hz, 1H), 2.71 (dd, J = 16.9, 8.9 Hz, 1H), 2.48 (dd, J = 16.8, 8.9 Hz, 1H), 2.33 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ178.0, 139.1, 136.7, 129.5, 126.7, 49.7, 40.0, 38.1, 21.0. HPLC analysis (Chiralcel AD-H, hexane / i-PrOH = 95 / 5, flow rate = 1.0 mL / min, λ = 210 nm),t r (major) = 12.69 min, t r (minor) = 13.85 min; [α] D 20 = -51.1 (c = 0.13, inCHCl3); mp = 101–103 °C; R f = 0.2 (DCM / MeOH: 80 / 1).

[0070] Example 21 A method for preparing chiral lactam 3u, the reaction process is as follows: The specific steps are as follows: Take a 10 mL dry reaction tube, add a magnetic stir bar, add 0.04 mmol (28.0 mg) of chiral catalyst and freshly prepared 0.4 mmol of sulfonylhydroxylamine 2b (120.0 mg), then add 1.0 mL of toluene, stopper the tube with a rubber stopper, and cool to -78 °C. Dissolve 1 u of 3-(4-fluorophenyl)cyclobutane-1-one (10.93 mg, 0.33 equiv.) in 1.0 mL of toluene solution, and add it dropwise to the reaction mixture over 1 minute (repeat this operation twice after 5 minutes). After reacting at -78 °C for 8 h, purify by column chromatography (dichloromethane:methanol = 100:1, 100:1 is a volume ratio). After purification, 31.2 mg of chiral lactam 3 u, white solid, yield 87%, 96% ee.

[0071] The structural characterization and chiral optical detection results of product 3u are as follows: 1 H NMR (400 MHz, CDCl3) δ7.27 – 7.13 (m, 3H), 7.07 – 6.97 (m, 2H), 3.82 – 3.74 (m, 1H), 3.72 – 3.62(m, 1H), 3.44 – 3.32 (m, 1H), 2.73 (dd, J = 16.9, 8.9 Hz, 1H), 2.46 (dd, J =16.8, 8.6 Hz, 1H). 13 C NMR (101 MHz, CDCl3) δ 177.9, 161.8 (d, J = 245.6 Hz), 138.0 (d, J = 3.3 Hz), 128.3 (d, J = 8.0 Hz), 115.7 (d, J = 21.4 Hz), 49.7, 39.6, 38.2. 19 F NMR (377 MHz, CDCl3) δ -115.6. HPLC analysis (Chiralcel AD-H,hexane / i-PrOH = 90 / 10, flow rate = 1.0 mL / min, λ = 210 nm), t r (major) = 8.24min, t r (minor) = 9.81 min; [α] D 20 = -38.5 (c = 0.22, in CHCl3); mp = 57–59 °C; R f = 0.2 (DCM / MeOH: 80 / 1).

[0072] Example 22 A method for preparing a chiral lactam 3V, the reaction process is as follows: The specific steps are as follows: Take a 10 mL dry reaction tube, add a magnetic stir bar, and add 0.04 mmol (28.0 mg) of chiral catalyst and freshly prepared 0.4 mmol of sulfonylhydroxylamine 2b (120.0 mg), followed by 1.0 mL of toluene. Seal the tube with a rubber stopper and cool to -78 °C. Dissolve 3-(4-chlorophenyl)cyclobutane-1-one 1v (12.03 mg, 0.33 equiv.) in 1.0 mL of toluene solution and add it dropwise to the reaction mixture over 1 minute (repeat this operation twice after 5 minutes). After reacting at -78 °C for 8 h, purify by column chromatography (dichloromethane:methanol = 100:1, 100:1 is a volume ratio). The purified product is 34.4 mg of chiral lactam 3v, a white solid with a yield of 88% and an ee of 97%.

[0073] The structural characterization results and chiral optical detection results of product 3v are as follows: 1 H NMR (400 MHz, CDCl3) δ7.37 – 7.28 (m, 2H), 7.24 – 7.14 (m, 2H), 6.90 (brs, 1H), 3.83 – 3.74 (m,1H), 3.73 – 3.62 (m, 1H), 3.38 (dd, J = 9.6, 7.0 Hz, 1H), 2.73 (dd, J = 16.9,8.9 Hz, 1H), 2.45 (dd, J = 16.9, 8.5 Hz, 1H). 13 C NMR (101 MHz, CDCl3) δ177.6, 140.7, 132.9, 129.0, 128.1, 49.5, 39.7, 38.0. HPLC analysis (ChiralcelAD-H, hexane / i-PrOH = 90 / 10, flow rate = 1.0 mL / min, λ = 210 nm), t r (major) = 8.48 min, t r (minor) = 9.82 min; [α] D 20 = -54.9 (c = 0.18, in CHCl3); mp =70–72 °C; R f = 0.2 (DCM / MeOH: 80 / 1).

[0074] Example 23 A method for preparing a chiral lactam 3w, the reaction process is as follows: The specific steps are as follows: Take a 10 mL dry reaction tube, add a magnetic stir bar, and add 0.04 mmol (28.0 mg) of chiral catalyst and freshly prepared 0.4 mmol of sulfonyl hydroxylamine 2b (120.0 mg), followed by 2.0 mL of toluene. Seal the tube with a rubber stopper and cool to -78 °C. Dissolve 1 w of 3-(2-methylpropyl)cyclobutanone (7.47 mg, 0.33 equiv.) in 2.0 mL of toluene solution and add it dropwise to the reaction mixture over 1 minute (repeat this operation twice after 5 minutes). After reacting at -78 °C for 8 h, purify the mixture by column chromatography (dichloromethane:methanol = 100:1, 100:1 is a volume ratio). The purified product is 23.7 mg of chiral lactam 3 w, a colorless oil with a yield of 84% and an ee of 72%.

[0075] The structural characterization and chiral optical detection results of product 3w are as follows: 1 H NMR (400 MHz, CDCl3) δ7.20 (brs, 1H), 3.56 – 3.44 (m, 1H), 2.99 (dd, J = 9.6, 7.0 Hz, 1H), 2.59 –2.47 (m, 1H), 2.41 (dd, J = 16.5, 8.6 Hz, 1H), 1.98 (dd, J = 16.5, 8.4 Hz,1H), 1.64 – 1.52 (m, 1H), 1.39 – 1.31 (m, 2H), 0.94 – 0.88 (m, 6H). 13 C NMR (101 MHz, CDCl3) δ 178.8, 48.3, 43.9, 37.1, 33.0, 26.2, 22.7, 22.5. HPLC analysis (Chiralcel IA hexane / i-PrOH = 95 / 5, flow rate = 1.0 mL / min, λ = 210nm), t r (major) = 12.10 min, t r (minor) = 13.20 min; [α] D 20 = -30.4 (c = 0.14,in CHCl3); R f = 0.2 (DCM / MeOH: 80 / 1).

[0076] In some instances, the synthetic process route is as follows: Where R 1 It can be a phenyl group, a benzene ring containing a substituent, or an alkyl group.

[0077] In a further preferred embodiment of the present invention, the chiral catalyst is: In a further preferred embodiment of the present invention, the solvent is toluene.

[0078] In a further preferred embodiment of the present invention, the amount of chiral catalyst added is 20 mol%, and the molar ratio of prochiral cyclohexanone to sulfonyl hydroxylamine is 1:(1.2-3.0).

[0079] A further preferred embodiment of the present invention is that the reaction time is 2 hours.

[0080] The following will provide further explanation in conjunction with Examples 24-25.

[0081] Example 24 A method for preparing chiral lactam 3x, the reaction process is as follows: The specific steps are as follows: Take a 10 mL dry reaction tube, add a magnetic stir bar, and add 0.2 mmol (47.2 mg) of cis-3,4-diphenylcyclopentanone 1x and 0.04 mmol (28.0 mg) of chiral catalyst, respectively. Then add 1.0 mL of toluene, stopper the tube with a rubber stopper, and cool to -15 °C. Dissolve 0.2 mmol of freshly prepared sulfonyl hydroxylamine 2a (48.4 mg) in 1.0 mL of toluene solution, and add it dropwise to the reaction mixture over 1 minute (repeat this operation twice after 5 minutes). After reacting at -15 °C for 2 h, purify the mixture by column chromatography (dichloromethane:methanol = 100:1, 100:1 is a volume ratio). After purification, 50.3 mg of chiral lactam 3x is obtained as a white solid with a yield >99% and 93% ee.

[0082] The structural characterization and chiral optical detection results of product 3x are as follows: 1H NMR (400 MHz, CDCl3) δ7.24 – 7.10 (m, 7H), 6.87 – 6.71 (m, 4H), 3.70 – 3.62 (m, 2H), 3.55 – 3.50(m, 1H), 3.49 – 3.42 (m, 1H), 2.85 (dd, J = 17.8, 5.9 Hz, 1H), 2.72 (dd, J =17.9, 6.1 Hz, 1H). 13 C NMR (101 MHz, CDCl3) δ 172.4, 139.6, 139.1, 128.4,128.2, 128.1, 128.0, 127.1, 127.0, 43.9, 43.3, 43.2, 35.3. HRMS (ESI) m / zcalcd. for C 17 H 18 NO [M+H] + 252.1383, found 252.1387. HPLC analysis (ChiralcelOD-H, hexane / i-PrOH = 80 / 20, flow rate = 1.0 mL / min, λ = 210 nm), t r (major) = 13.19 min, t r (minor) = 11.32 min; [α] D 20 = -22.4 (c = 0.05, in CHCl3); mp= 141–143 °C; R f = 0.2 (DCM / MeOH: 80 / 1).

[0083] Example 25 A method for preparing chiral lactam 3y, the reaction process is as follows: The specific steps are as follows: Take a 10 mL dry reaction tube, add a magnetic stir bar, and add 0.2 mmol (27.6 mg) of cis-bicyclo[3.3.0]octane-3,7-dione 3y and 0.04 mmol (28.0 mg) of chiral catalyst, respectively. Then add 1.0 mL of toluene, stopper the tube with a rubber stopper, and cool to -15 °C. Dissolve 0.08 mmol of freshly prepared sulfonylhydroxylamine 2a (19.2 mg) in 1.0 mL of toluene solution and add it dropwise to the reaction mixture over 1 minute (repeat this operation twice after 5 minutes). After reacting at -15 °C for 2 h, purify the mixture by column chromatography (dichloromethane:methanol = 100:1, 100:1 is a volume ratio). After purification, 18.2 mg of chiral lactam 3y is obtained as a white solid with a yield of 59% and an ee of 92%.

[0084] The structural characterization results and chiral optical detection results of product 3y are as follows: 1 H NMR (400 MHz, CDCl3) δ6.83 (brs, 1H), 3.60 – 3.45 (m, 1H), 3.29 – 3.12 (m, 1H), 2.87 – 2.59 (m,3H), 2.58 – 2.41 (m, 2H), 2.31 – 2.11 (m, 3H). 13 C NMR (101 MHz, CDCl3) δ 216.2, 172.4, 44.3, 43.5, 41.7, 34.4, 32.6, 32.0. The ee value was determined by HPLC analysis of the N-Boc protected derivative of product 3z. HPLC analysis (Chiralcel OD-H, hexane / i-PrOH = 80 / 20, flow rate = 1.0 mL / min, λ = 210 nm), t r (major) = 11.68 min, t r (minor) = 13.09 min; [α] D 20 = -46.9 (c = 0.03, in CHCl3); mp = 116–118 °C; R f = 0.2(DCM / MeOH: 40 / 1).

[0085] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention, and they should all be covered within the scope of the claims and specification of the present invention.

Claims

1. A method for preparing chiral lactams by organocatalytic desymmetry of pre-chiral cyclic ketones, characterized in that, The process includes the following steps: in the presence of a chiral catalyst, using chlorobenzene, toluene, or a mixture of chlorobenzene and diethyl ether as a solvent, a pre-chiral cyclic ketone having the structure of Formula 1 and a sulfonyl hydroxylamine having the structure of Formula 2 are subjected to a desymmetric nitrogen atom insertion reaction at -78°C to 25°C to obtain a chiral lactam, wherein the reaction time is 2-8 h. Equation 1 is or One of them, where R 1 It is one of H, cyano, or alkoxy; R 2 It is one of the following: phenyl, a benzene ring containing a substituent, a benzofuran ring, a piperon ring, 1-naphthyl, 2-naphthyl, benzothiophene, thiophene, an imidazole ring containing a substituent, methyl, ethyl, isopropyl, tert-butyl, a substituted straight-chain alkyl, a substituted cycloalkyl, trifluoromethyl, halogen, benzoyl, ester, acyl, amide, and sulfonamide, wherein the substituent is at least one of alkyl, alkoxy, halogen, alkenyl, and alkynyl; R 3 It is aryl or methyl; n is 0 or 1; Equation 2 is , , , , One of them; The chiral catalyst is one of chiral phosphoric acid, chiral phosphoramide, or chiral phosphate.

2. The method according to claim 1, characterized in that, The chiral catalyst is selected from... , , , One of them.

3. The method according to claim 1, characterized in that, The molar ratio of the prochiral cyclic ketone to sulfonyl hydroxylamine is 1:(1.2 - 3.0).

4. The method according to claim 1, characterized in that, The molar ratio of the chiral catalyst to the pre-chiral cyclic ketone is 5% - 20%.

5. The method according to claim 1, characterized in that, When the solvent is a mixture of chlorobenzene and diethyl ether, the volume ratio of diethyl ether to chlorobenzene is 1:(1-4).

6. The method according to claim 1, characterized in that, The method for preparing chiral lactams by desymmetricization of a prochiral cyclic ketone via organocatalysis is as follows: First, the organic solvent is divided into two parts; under stirring conditions, a chiral catalyst, as well as one of the prochiral cyclic ketone and the sulfonyl hydroxylamine, are added to the reaction vessel, followed by the addition of the first part of the organic solvent to prepare solution A, and cooled to the reaction temperature; the other of the prochiral cyclic ketone and the sulfonyl hydroxylamine is dissolved in the second part of the organic solvent to prepare solution B; while maintaining the reaction temperature, solution B is added dropwise to solution A in batches, with an interval of 5-10 minutes between each batch, and the chiral lactam is obtained after the reaction is completed.

7. The preparation method according to any one of claims 1-6, characterized in that, The desymmetric nitrogen atom insertion reaction is carried out in the presence of a base, which is an inorganic base; the molar ratio of the base to the prochiral cyclic ketone is 0-3.

0.

8. The method according to claim 7, characterized in that, The inorganic base is sodium bicarbonate.

9. The method according to claim 7, characterized in that, The molar ratio of the base to the prochiral cyclic ketone is 2.

0.

10. The method according to claim 9, characterized in that, It also includes the separation and purification of crude products by silica gel column chromatography, wherein the eluent of the silica gel column is a mixture of dichloromethane and methanol, wherein the volume ratio of dichloromethane to methanol is between 50 and 100.

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