A method for the catalytic synthesis of gamma-lactam derivatives using organophosphorus compounds

Abstract

The application discloses a method for catalytically synthesizing gamma-lactam derivatives by using organic phosphine, which uses oxetanone-derived MBH carbonate and aromatic aldehyde imine as raw materials, chloroform as a solvent, 4A molecular sieve and R 1 OH as additives, and is heated to 60 o C under the action of L-valine-derived organic phosphine catalyst to synthesize a target product in one step. The synthesis method is simple in operation, and raw materials and catalysts are simple and easy to obtain; the reaction time is short; the reaction substrate is suitable for a wide range; the target product has a high yield; the gamma-lactam can be asymmetrically synthesized; even a spiro ring structure can be introduced; and the industrial production prospect is wide.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis and relates to a method for synthesizing organophosphine-catalyzed γ-lactam derivatives. Background Technology

[0002] Gamma-lactams are crucial structural motifs in pharmaceuticals and natural products. Gamma-lactam structures are widely found in various natural secondary metabolites, particularly those derived from amino acid-derived metabolic pathways (such as proline and glutamate), antimicrobial or cytotoxic natural products from microorganisms, and nitrogen-containing heterocyclic molecules in marine natural products. In natural biosynthesis, γ-lactams are often formed through amino acid lactamation or oxidative cyclization. This structure possesses both metabolic stability and the ability to form specific hydrogen bond networks with proteins, thus exhibiting excellent adaptability in biological systems. From an evolutionary perspective, γ-lactams are "biocompatible structural units," and their frequency of occurrence reflects their advantage in biological recognition. In recent years, γ-lactam motifs have also found their place in many drugs. For example, etoricoxib (a COX-2 selective nonsteroidal anti-inflammatory drug), glimepiride (a hypoglycemic agent), piracetam (for improving brain metabolism), oxirasetam (for improving cognition), levetiracetam (for treating epilepsy), and brivaracetam (for treating epilepsy) are all commonly used drugs containing a γ-lactam skeleton. Similarly, γ-lactam structural motifs are frequently found in natural products. For example, alkaloids such as aspidospermidine and stemoamide, marine natural products such as batzelladine and salinosporamide, and microbial metabolites such as lactobacillus often exhibit important biological activities such as antitumor, antiviral, and antibacterial activity. This demonstrates the importance of the γ-lactam skeleton in medicinal chemistry and drug development; therefore, exploring the synthesis of γ-lactam skeletons is of great significance.

[0003] Currently, given the importance of γ-lactam compounds and the challenges of their synthesis, researchers have so far constructed γ-lactam derivatives through a series of cyclization reactions. However, these synthetic methods suffer from the following drawbacks:

[0004] (1) Expensive metal catalysts are required (see Sheng, T.; Zhang, T.; Zhuang, Z.; Yu, J. Nat. Synth., 2024, 3, 1550–1559.; Chan, H.; Lu, Y.; Yu, J. Nat.Synth., 2024, 3, 752–762.; Jia, K.; Tu, Y.; Low, K.; Luo, J.; Jiang, C. Adv.Synth. Catal., 2024, 366, 3297–3302.; Jung, H.; Schrader, M.; Kim, D.; Baik, M.; Park, Y.; Chang, SJ Am. Chem. Soc., 2019, 141, 15356–15366.)

[0005] (2) The substrate requires multi-step synthesis and final intramolecular cyclization (see Zhang, Y.; Shi, B.; Yu, JJAm. Chem. Soc., 2009, 131, 5072–5074.; Hong, S.; Park, Y.; Hwang, Y.; Kim, Y.; Baik, M.; Chang, S. Science, 2018, 359, 1016–1021.; Wang, H.; Park, Y.; Bai, Z.; Chang, S.; He, G.; Chen, GJ Am. Chem. Soc., 2019, 141, 7194–7201.).

[0006] (3) The reaction conditions are harsh and pose certain risks (see Png, Z.; Cabrera-Pardo, J.; PeiróCadahía, J.; Gaunt, M. Chem. Sci., 2018, 9, 7628–7633.; Zhang, J.; Chen, H.; Lin, C.; Liu, Z.; Wang, C.; Zhang, YJ Am. Chem. Soc., 2015, 137, 12990–12996.).

[0007] Therefore, the rapid construction of γ-lactam derivatives using simple and readily available starting materials remains challenging. Summary of the Invention

[0008] To address the shortcomings of current methods for synthesizing γ-lactam derivatives, we provide a method for synthesizing γ-lactam derivatives. This method uses readily available Morita-Baylis-Hillman carbonate and imine as raw materials to directly obtain γ-lactam derivatives under the action of an L-valine-derived organophosphorus catalyst.

[0009] The technical solution of the present invention is as follows:

[0010] A method for synthesizing γ-lactam derivatives via organophosphorus catalysis includes:

[0011] Using oxetine-derived MBH carbonate and aromatic aldehyde imine as raw materials, the reaction was catalyzed by an L-valine-derived organophosphorus catalyst, and a solvent was added and the mixture was heated to synthesize γ-lactam derivatives in one step.

[0012] The reaction formula is as follows:

[0013]

[0014] Among them, R 1 It is any one of C1-C4 alkyl and benzyl groups;

[0015] Ar is a substituted or unsubstituted C6~C12 aryl or a 5~12 membered ring heteroaryl, wherein the substituent on the C6~C12 aryl or the 5~12 membered ring heteroaryl is H, halogen, C1~C4 alkyl, C1~C4 alkoxy, NO2, or C1~C4 alkoxycarbonyl.

[0016] R 3 It is any one of 4-methylphenyl, 2,4,6-trimethylphenyl or 4-methoxyphenyl.

[0017] As a preferred option, R 1 It is any one of Me, Et, and Bn; Ar is any substituted phenyl or 2-furanyl, 1-naphthyl, 2-naphthyl, and 2-thiophenyl from F, Cl, Br, Me, OMe, NO2, CO2Et.

[0018] Preferably, the catalyst is an L-valine-derived organophosphorus, with the following structural formula:

[0019] .

[0020] Preferably, the amount of catalyst relative to the aromatic aldehyde imine is 10-30 mol.

[0021] Preferably, the solvent is chloroform.

[0022] Preferably, the reaction temperature is 50~70°C. o C.

[0023] Preferably, the molar ratio of the oxetane-derived MBH carbonate to the aromatic aldehyde imine is 1.1 to 1.3:1.

[0024] Preferably, the amount of the additive 4Å molecular sieve is 90-110 g·mol relative to the aromatic aldehyde imine. -1 R 1 The amount of OH used is 0.4~0.6 equivalents.

[0025] The optimal reaction conditions are an MBH carbonate to imine feed ratio of 1.2:1, a catalyst loading of 20 mol%, and a temperature of 60°C. o C, the reaction solvent is chloroform, and the additive is 100 g·mol⁻¹. -1 4Å molecular sieve and 0.5 equivalent R 1 OH.

[0026] Beneficial effects

[0027] Compared with existing methods for synthesizing γ-lactam derivatives, the method proposed in this application is simple to operate, does not require special reaction equipment, has a short reaction time, requires readily available raw materials and catalysts, and has low reaction costs. The target product has a high yield and a wide range of applicable substrates. It is environmentally friendly and can synthesize fully substituted γ-lactams asymmetrically. It can also introduce spirocyclic structures and even control the E / Z tautomer transition of olefins, making it a promising candidate for industrial production. Attached Figure Description

[0028] Figure 1 The 1H NMR spectrum of compound 3aa;

[0029] Figure 2 The carbon NMR spectrum of compound 3aa;

[0030] Figure 3 The HPLC chromatogram of the racemic product of compound 3aa;

[0031] Figure 4 The HPLC chromatogram of the chiral product of compound 3aa;

[0032] Figure 5 The 1H NMR spectrum of compound 3ba;

[0033] Figure 6 The carbon NMR spectrum of compound 3ba;

[0034] Figure 7 The HPLC chromatogram of the racemic product of compound 3ba is shown.

[0035] Figure 8 HPLC chromatogram of the chiral product of compound 3ba;

[0036] Figure 9 The 1H NMR spectrum of compound 3ca;

[0037] Figure 10 The carbon NMR spectrum of compound 3ca;

[0038] Figure 11 The HPLC chromatogram of the racemic product of compound 3ca is shown.

[0039] Figure 12 HPLC chromatogram of the chiral product of compound 3ca;

[0040] Figure 13 The 1H NMR spectrum of compound 3ab;

[0041] Figure 14 The carbon NMR spectrum of compound 3ab;

[0042] Figure 15 The HPLC chromatogram of the racemic product of compound 3ab is shown.

[0043] Figure 16 This is the HPLC chromatogram of the chiral product of compound 3ab. Detailed Implementation

[0044] The technical solution of the present invention will be described in detail below with reference to embodiments.

[0045] The raw material synthesis method is as follows:

[0046]

[0047] (1) Triethylenediamine DABCO (0.5 equivalents) was added to a mixture of oxetane (1 equivalent) and acrylate (3 equivalents) and reacted until the oxetane was completely reacted by TLC monitoring. The mixture was then purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain MBH alcohol.

[0048] (2) MBH alcohol (1 equivalent) and DMAP (0.1 equivalent) were added to dichloromethane, and (Boc)₂O (1.5 equivalent) was slowly added dropwise to the reaction mixture. The reaction was carried out at room temperature for 2 hours. The mixture was extracted with water and separated. The organic phase was dried over magnesium sulfate, filtered, and concentrated. The concentrate was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain MBH carbonate. (Montgomery, T.; Hassan, A.; Park, BJ Am. Chem. Soc., 2012, 134, 27, 11100–11103.)

[0049]

[0050] An aldehyde (1 equivalent), sulfonamide (1 equivalent), and tetraethyl orthosilicate (1.1 equivalent) were placed in a flask. The mixture was heated at 160°C for 5 hours under nitrogen protection. The reaction mixture was dissolved in warm ethyl acetate and cooled. The sample was treated with petroleum ether and stirred at room temperature for 1 hour. The solid was collected by filtration, washed with petroleum ether, and dried to give the product imine. (Yan, Z.; Wu, B.; Zhou, Y. Org. Lett., 2016, 18, 4, 692–695.)

[0051] Example 1:

[0052]

[0053] MBH carbonate 1a (31.0 mg, 0.12 mmol, 1.2 equiv.), imine 2a (25.9 mg, 0.1 mmol, 1.0 equiv.), 10 mg of 4Å molecular sieve, and methanol (2 μL, 0.05 mmol, 0.5 equiv.) were added to a sealing tube, followed by 1 mL of chloroform (0.1 M). The mixture was stirred at room temperature until completely dissolved. Subsequently, L-valine-derived organophosphorus (10.2 mg, 0.02 mmol, 0.2 equiv.) was added to the sealing tube, which was then sealed and heated to 60°C. o C, react for 12 hours. After the reaction is complete, the reaction solution is cooled to room temperature and then separated by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain product 3aa, a white solid, with a yield of 34.0 mg and a yield of 85%.

[0054] MP 81.1 – 81.7 o C

[0055] = -22.273 (c 0.66, CH2Cl2)

[0056] 11H NMR (400 MHz, CDCl3) δ 7.37 (d, J = 8.4 Hz, 2H), 7.34 – 7.31 (m,1H), 7.25 (t, J = 7.4 Hz, 2H), 7.09 – 7.02 (m, 5H), 5.47 (s, 1H), 5.02 (d, J= 5.8 Hz, 1H), 4.56 (d, J = 5.8 Hz, 1H), 4.19 (d, J = 7.4 Hz, 1H), 4.15 (d, J= 7.3 Hz, 1H), 4.03 (s, 3H), 2.35 (s, 3H).

[0057] 13 13C NMR (101 MHz, CDCl3) δ 163.5, 156.8, 144.4, 136.3, 135.3, 128.9,128.8, 128.5, 127.3, 111.2, 87.8, 68.6, 63.5, 46.9, 21.6.

[0058] HRMS (ESI): m / z calcd for [M+H] + = 400.1213, found = 400.1205

[0059] HPLC: Chiralpak IF, hexane : iPrOH 70:30, 1 ml / min, λ = 254 nm,fraction t r = 31.811 (major enantiomer) and 40.143 (minor enantiomer) er =92:8

[0060] Example 2:

[0061]

[0062] MBH carbonate 1b (32.7 mg, 0.12 mmol, 1.2 equiv.), imine 2a (25.9 mg, 0.1 mmol, 1.0 equiv.), 10 mg of 4Å molecular sieve, and methanol (2 μL, 0.05 mmol, 0.5 equiv.) were added to a sealing tube, followed by 1 mL of chloroform (0.1 M). The mixture was stirred at room temperature until completely dissolved. Subsequently, L-valine-derived organophosphorus (10.2 mg, 0.02 mmol, 0.2 equiv.) was added to the sealing tube, which was then sealed and heated to 60°C. o C, react for 12 hours. After the reaction is complete, the reaction solution is cooled to room temperature and then separated by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain product 3ba, a white solid, with a yield of 29.2 mg and a yield of 71%.

[0063] MP164.5 – 165.5 o C.

[0064] = -24.600 (c 0.50, CH2Cl2)

[0065] 1 H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 7.3Hz, 1H), 7.21 (t, J = 7.3 Hz, 2H), 7.08 (s, 1H), 7.04 (d, J = 7.6 Hz, 2H),7.00 (d, J = 8.1 Hz, 2H), 5.43 (s, 1H), 4.99 (d, J = 5.8 Hz, 1H), 4.52 (d, J= 5.8 Hz, 1H), 4.29 – 4.08 (m, 4H), 2.31 (s, 3H), 1.42 (t, J = 7.1 Hz, 3H).

[0066] 13 C NMR (101 MHz, CDCl3) δ 163.5, 155.7, 144.4, 136.4, 135.4, 128.9,128.8, 128.5, 127.3, 110.8, 88.0, 72.5, 68.6, 46.9, 21.6, 15.5.

[0067] HRMS (ESI): m / z calcd for [M+H] += 414.1370, found = 414.1366

[0068] HPLC: Chiralpak IF, hexane: iPrOH 80:20, 1 ml / min, λ = 254 nm, fraction t r = 44.483 (major enantiomer) and 59.771 (minor enantiomer) er =91:9

[0069] Example 3:

[0070]

[0071] MBH carbonate 1c (40.1 mg, 0.12 mmol, 1.2 equiv.), imine 2a (25.9 mg, 0.1 mmol, 1.0 equiv.), 10 mg of 4Å molecular sieve, and methanol (2 μL, 0.05 mmol, 0.5 equiv.) were added to a sealing tube, followed by 1 mL of chloroform (0.1 M). The mixture was stirred at room temperature until completely dissolved. Subsequently, L-valine-derived organophosphorus (10.2 mg, 0.02 mmol, 0.2 equiv.) was added to the sealing tube, which was then sealed and heated to 60°C. o C, react for 12 hours. After the reaction is complete, the reaction solution is cooled to room temperature and then separated by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain product 3ba, a colorless oily substance, with a yield of 26.2 mg and a yield of 55%.

[0072] = -66.176 (c 0.34, CH2Cl2)

[0073] 11H NMR (400 MHz, CDCl3) δ 7.41 – 7.31 (m, 7H), 7.32 – 7.24 (m, 1H), 7.19 (t, J = 7.5 Hz, 2H), 7.10 (s, 1H), 7.00 (d, J = 7.5 Hz, 4H), 5.42 (s, 1H), 5.22 (d, J = 12.7 Hz, 1H), 5.12 (d, J = 12.7 Hz, 1H), 4.93 (d, J = 5.8 Hz, 1H), 4.42 (d, J = 5.8 Hz, 1H), 4.09 (d, J = 7.4 Hz, 1H), 4.05 (d, J = 7.3 Hz, 1H), 2.31 (s, 3H).

[0074] 13 13C NMR (101 MHz, CDCl3) δ 163.3, 155.1, 144.4, 136.3, 135.5, 135.4, 128.9, 128.9, 128.8, 128.5, 127.6, 127.3, 111.9, 87.8, 68.7, 46.9, 21.6.

[0075] HRMS (ESI): m / z calcd for [M+H] + = 476.1526, found = 476.1522

[0076] HPLC: Chiralpak IA, hexane : iPrOH 90:10, 1 ml / min, λ = 254 nm, fraction t r = 29.779 (major enantiomer) and 36.050 (minor enantiomer) er = 91:9

[0077] Example 4:

[0078]

[0079] MBH carbonate 1a (31.0 mg, 0.12 mmol, 1.2 equiv.), imine 2b (27.5 mg, 0.1 mmol, 1.0 equiv.), 10 mg of 4Å molecular sieve, and methanol (2 μL, 0.05 mmol, 0.5 equiv.) were added to a sealing tube, followed by 1 mL of chloroform (0.1 M). The mixture was stirred at room temperature until completely dissolved. Subsequently, L-valine-derived organophosphorus (10.2 mg, 0.02 mmol, 0.2 equiv.) was added to the sealing tube, which was then sealed and heated to 60°C. o C, react for 12 hours. After the reaction is complete, the reaction solution is cooled to room temperature and then separated by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain product 3ab, a white solid, with a yield of 29.2 mg and a yield of 70%.

[0080] MP 196.7 – 197.7 o C

[0081] = -33.265 (c 0.68, CH2Cl2)

[0082] 1 H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 8.9 Hz, 2H), 7.28 (d, J = 6.7Hz, 1H), 7.21 (t, J = 7.5 Hz, 2H), 7.02 (d, J = 7.5 Hz, 2H), 6.99 (s, 1H), 6.65 (d, J = 8.7 Hz, 2H), 5.41 (s, 1H), 4.98 (d, J = 5.8 Hz, 1H), 4.51 (d, J = 5.8 Hz, 1H), 4.13 (q, J = 7.4 Hz, 2H), 3.98 (s, 3H), 3.77 (s, 3H).

[0083] 13 C NMR (101 MHz, CDCl3) δ 163.5, 156.8, 136.3, 130.8, 129.8, 128.9,128.9, 127.3, 113.5, 111.2, 87.8, 77.3, 68.6, 63.5, 55.6, 46.9.

[0084] HRMS (ESI): m / z calcd for [M+H] += 416.1162, found = 416.1162

[0085] HPLC: Chiralpak IB, hexane: iPrOH 70:30, 1 ml / min, λ = 254 nm, fraction t r = 23.656 (major enantiomer) and 41.392 (minor enantiomer) er =91:9

[0086] Example 5:

[0087]

[0088] MBH carbonate 1a (31.0 mg, 0.12 mmol, 1.2 equiv.), imine 2c (28.7 mg, 0.1 mmol, 1.0 equiv.), 10 mg of 4Å molecular sieve, and methanol (2 μL, 0.05 mmol, 0.5 equiv.) were added to a sealing tube, followed by 1 mL of chloroform (0.1 M). The mixture was stirred at room temperature until completely dissolved. Subsequently, L-valine-derived organophosphorus (10.2 mg, 0.02 mmol, 0.2 equiv.) was added to the sealing tube, which was then sealed and heated to 60°C. o C, react for 12 hours. After the reaction is complete, the reaction solution is cooled to room temperature and then separated by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain product 3ac, a white solid, with a yield of 28.3 mg and a yield of 66%.

[0089] MP 116.4 – 117.1 o C

[0090] = -8.529 (c 0.34, CH2Cl2)

[0091] 1H NMR (400 MHz, CDCl3) δ 7.42 – 7.31 (m, 5H), 6.95 (s, 1H), 6.91 (s,2H), 5.42 (s, 1H), 4.97 (d, J = 5.6 Hz, 1H), 4.50 (d, J = 5.5 Hz, 1H), 4.27(d, J = 7.4 Hz, 1H), 4.14 (d, J = 7.4 Hz, 1H), 3.96 (s, 3H), 2.60 (s, 6H), 2.26 (s, 3H).

[0092] 13 C NMR (101 MHz, CDCl3) δ 164.2, 156.6, 143.6, 140.9, 136.9, 132.7, 132.0, 129.0, 126.9, 110.6, 87.4, 77.0, 68.9, 63.4, 47.4, 22.7, 21.1.

[0093] HRMS (ESI): m / z calcd for [M+H] + = 428.1526, found = 428.1529

[0094] HPLC: Chiralpak IA, hexane: iPrOH 86:14, 0.5 ml / min, λ = 254 nm, fraction t r = 33.950 (major enantiomer) and 25.716 (minor enantiomer) er =83:17

[0095] Example 6:

[0096]

[0097] MBH carbonate 1a (31.0 mg, 0.12 mmol, 1.2 equiv.), imine 2d (27.3 mg, 0.1 mmol, 1.0 equiv.), 10 mg of 4Å molecular sieve, and methanol (2 μL, 0.05 mmol, 0.5 equiv.) were added to a sealing tube, followed by 1 mL of chloroform (0.1 M). The mixture was stirred at room temperature until completely dissolved. Subsequently, L-valine-derived organophosphorus (10.2 mg, 0.02 mmol, 0.2 equiv.) was added to the sealing tube, which was then sealed and heated to 60°C.o C, react for 12 hours. After the reaction is complete, the reaction solution is cooled to room temperature and then separated by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain product 3ad, a white solid, with a yield of 34.2 mg and a yield of 83%.

[0098] MPa 93.2 – 94.1 o C

[0099] = -14.808 (c 0.52, CH2Cl2)

[0100] 1 H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 8.2 Hz, 2H), 7.02 – 6.96 (m,5H), 6.90 (d, J = 7.9 Hz, 2H), 5.38 (s, 1H), 4.96 (d, J = 5.7 Hz, 1H), 4.50(d, J = 5.8 Hz, 1H), 4.16 (d, J = 7.4 Hz, 1H), 4.10 (d, J = 7.3 Hz, 1H), 3.97(s, 3H), 2.32 (s, 6H).

[0101] 13 C NMR (101 MHz, CDCl3) δ 163.5, 156.7, 144.4, 138.7, 135.4, 133.3,129.5, 128.8, 128.6, 127.2, 111.2, 87.7, 68.5, 63.4, 46.9, 21.6, 21.2.

[0102] HRMS (ESI): m / z calcd for [M+H] + = 414.1370, found = 414.1369

[0103] HPLC: Chiralpak IA, hexane: iPrOH 80:20, 0.5 ml / min, λ = 254 nm, fraction t r = 24.452 (major enantiomer) and 31.243 (minor enantiomer) er =93:7

[0104] Example 7:

[0105]

[0106] MBH carbonate 1a (31.0 mg, 0.12 mmol, 1.2 equiv.), imine 2e (27.3 mg, 0.1 mmol, 1.0 equiv.), 10 mg 4Å molecular sieve, and methanol (2 μL, 0.05 mmol, 0.5 equiv.) were added to a sealing tube, followed by 1 mL of chloroform (0.1 M). The mixture was stirred at room temperature until completely dissolved. Subsequently, L-valine-derived organophosphorus (10.2 mg, 0.02 mmol, 0.2 equiv.) was added to the sealing tube, which was then sealed and heated to 60°C. o C, react for 12 hours. After the reaction is complete, the reaction solution is cooled to room temperature and then separated by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain product 3ae, a yellow oily substance, with a yield of 32.3 mg and a yield of 78%.

[0107] = -27.361 (c 0.72, CH2Cl2)

[0108] 1 H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 8.4 Hz, 2H), 7.13 – 7.04 (m,2H), 7.00 (d, J = 8.9 Hz, 3H), 6.85 (d, J = 6.8 Hz, 1H), 6.67 (s, 1H), 5.38(s, 1H), 4.97 (d, J = 5.8 Hz, 1H), 4.51 (d, J = 5.8 Hz, 1H), 4.16 (d, J = 7.4Hz, 1H), 4.09 (d, J = 7.3 Hz, 1H), 3.99 (s, 3H), 2.32 (s, 3H), 2.13 (s, 3H).

[0109] 13 C NMR (101 MHz, CDCl3) δ 163.6, 156.9, 144.3, 138.7, 136.0, 135.4,129.5, 128.8, 128.8, 128.5, 127.4, 124.6, 111.2, 87.9, 68.8, 63.5, 46.8,21.6, 21.2.

[0110] HRMS (ESI): m / z calcd for [M+H] + = 414.1370, found = 414.1367

[0111] HPLC: Chiralpak IA, hexane: iPrOH 90:10, 0.5 ml / min, λ = 254 nm, fraction t r = 65.545 (major enantiomer) and 82.932 (minor enantiomer) er =95:5

[0112] Example 8:

[0113]

[0114] MBH carbonate 1a (31.0 mg, 0.12 mmol, 1.2 equiv.), imine 2f (27.3 mg, 0.1 mmol, 1.0 equiv.), 10 mg of 4Å molecular sieve, and methanol (2 μL, 0.05 mmol, 0.5 equiv.) were added to a sealing tube, followed by 1 mL of chloroform (0.1 M). The mixture was stirred at room temperature until completely dissolved. Subsequently, L-valine-derived organophosphorus (10.2 mg, 0.02 mmol, 0.2 equiv.) was added to the sealing tube, which was then sealed and heated to 60°C. o C, react for 12 hours. After the reaction is complete, the reaction solution is cooled to room temperature and then separated by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain product 3af, a white solid, with a yield of 29.2 mg and a yield of 71%.

[0115] MP 165.6 –166.5 o C

[0116] = -58.485 (c 0.66, CH2Cl2)

[0117] 11H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 7.6Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H), 7.01 (d, J = 8.1 Hz, 2H), 6.97 (s, 1H),6.76 (t, J = 7.6 Hz, 1H), 6.40 (d, J = 7.8 Hz, 1H), 5.81 (s, 1H), 4.97 (d, J= 5.9 Hz, 1H), 4.53 (d, J = 5.8 Hz, 1H), 4.09 (d, J = 7.4 Hz, 1H), 4.00 (d, J= 7.4 Hz, 1H), 3.97 (s, 3H), 2.65 (s, 3H), 2.32 (s, 3H).

[0118] 13 13C NMR (101 MHz, CDCl3) δ 163.8, 157.1, 144.5, 136.6, 135.3, 134.7,130.8, 128.9, 128.7, 128.3, 126.5, 124.8, 111.1, 88.0, 77.9, 63.6, 63.5,47.0, 21.6, 19.8.

[0119] HRMS (ESI): m / z calcd for [M+H] + = 414.1370, found = 414.1368

[0120] HPLC: Chiralpak IA, hexane : iPrOH 80:20, 0.5 ml / min, λ = 254 nm,fraction t r = 20.354 (major enantiomer) and 26.067 (minor enantiomer) er =97:3

[0121] Example 9:

[0122]

[0123] MBH carbonate 1a (31.0 mg, 0.12 mmol, 1.2 equiv.), imine 2 g (27.7 mg, 0.1 mmol, 1.0 equiv.), 10 mg 4Å molecular sieve, and methanol (2 μL, 0.05 mmol, 0.5 equiv.) were added to a sealing tube, followed by 1 mL of chloroform (0.1 M). The mixture was stirred at room temperature until completely dissolved. Subsequently, L-valine-derived organophosphorus (10.2 mg, 0.02 mmol, 0.2 equiv.) was added to the sealing tube, which was then sealed and heated to 60°C. o C, react for 12 hours. After the reaction is complete, the reaction solution is cooled to room temperature and then separated by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain 3 ag of product, a white solid, with a yield of 33.8 mg and a yield of 81%.

[0124] MP 91.1 – 91.8 o C

[0125] = -26.250 (c 0.40, CH2Cl2)

[0126] 1 H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 8.2 Hz, 2H), 7.05 (d, J = 8.5Hz, 2H), 7.04 – 6.98 (m, 3H), 6.91 (t, J = 8.5 Hz, 2H), 5.42 (s, 1H), 4.96(d, J = 5.8 Hz, 1H), 4.51 (d, J = 5.8 Hz, 1H), 4.13 (s, 2H), 3.99 (s, 3H), 2.33 (s, 3H).

[0127] 13 C NMR (101 MHz, CDCl3) δ 163.4, 162.8 (d, J = 248.7 Hz). 157.1,144.7, 135.3, 132.3, 129.0, 128.4, 116.0, 115.8, 110.7, 87.7, 67.8, 63.6,46.8, 21.7.

[0128] HRMS (ESI): m / z calcd for [M+H] + = 418.1119, found = 418.1114

[0129] HPLC: Chiralpak IA, hexane: iPrOH 80:20, 0.5 ml / min, λ = 254 nm, fraction t r = 30.942 (major enantiomer) and 41.702 (minor enantiomer) er =94:6

[0130] Example 10:

[0131]

[0132] MBH carbonate 1a (31.0 mg, 0.12 mmol, 1.2 equiv.), imine 2h (29.4 mg, 0.1 mmol, 1.0 equiv.), 10 mg 4Å molecular sieve, and methanol (2 μL, 0.05 mmol, 0.5 equiv.) were added to a sealing tube, followed by 1 mL of chloroform (0.1 M). The mixture was stirred at room temperature until completely dissolved. Subsequently, L-valine-derived organophosphorus (10.2 mg, 0.02 mmol, 0.2 equiv.) was added to the sealing tube, which was then sealed and heated to 60°C. o C, react for 12 hours. After the reaction is complete, the reaction solution is cooled to room temperature and then separated by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain product 3ah, a white solid, with a yield of 33.1 mg and a yield of 76%.

[0133] MP 151.2 – 152.1 o C

[0134] = 33.250 (c 0.40, CH2Cl2)

[0135] 1 H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4Hz, 2H), 7.09 (d, J = 8.1 Hz, 2H), 7.03 (d, J = 4.6 Hz, 2H), 7.00 (s, 1H), 5.44 (s, 1H), 4.99 (d, J = 5.9 Hz, 1H), 4.55 (d, J = 5.9 Hz, 1H), 4.17 (d, J= 1.6 Hz, 2H), 4.03 (s, 3H), 2.38 (s, 3H).

[0136] 13 C NMR (101 MHz, CDCl3) δ 163.3, 157.1, 144.8, 135.3, 135.0, 134.8,129.1, 129.0, 128.6, 128.4, 110.7, 87.7, 67.9, 63.5, 46.8, 21.6.

[0137] HRMS (ESI): m / z calcd for [M+H] + = 434.0824, found = 434.0822

[0138] HPLC: Chiralpak IA, hexane: iPrOH 70:30, 0.5 ml / min, λ = 254 nm, fraction t r = 18.695 (major enantiomer) and 23.675 (minor enantiomer) er =93:7

[0139] Example 11:

[0140]

[0141] MBH carbonate 1a (31.0 mg, 0.12 mmol, 1.2 equiv.), imine 2i (33.8 mg, 0.1 mmol, 1.0 equiv.), 10 mg 4Å molecular sieve, and methanol (2 μL, 0.05 mmol, 0.5 equiv.) were added to a sealing tube, followed by 1 mL of chloroform (0.1 M). The mixture was stirred at room temperature until completely dissolved. Subsequently, L-valine-derived organophosphorus (10.2 mg, 0.02 mmol, 0.2 equiv.) was added to the sealing tube, which was then sealed and heated to 60°C. o C, react for 12 hours. After the reaction is complete, the reaction solution is cooled to room temperature and then separated by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain product 3ai, an orange solid, with a yield of 36.2 mg and a yield of 76%.

[0142] MP 194.4 – 195.1 o C

[0143] = 2.833 (c 0.60, CH2Cl2)

[0144] 1 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 8.6Hz, 2H), 7.05 (d, J = 8.1 Hz, 2H), 6.90 (d, J = 8.5 Hz, 2H), 5.38 (s, 1H),4.95 (d, J = 5.9 Hz, 1H), 4.50 (d, J = 5.9 Hz, 1H), 4.17 – 4.08 (m, 2H), 3.99(s, 3H), 2.34 (s, 3H).

[0145] 13 13C NMR (101 MHz, CDCl3) δ 163.3, 157.2, 144.8, 135.4, 135.2, 132.0,129.1, 128.9, 128.4, 122.9, 110.6, 87.7, 67.9, 63.6, 46.7, 21.7.

[0146] HRMS (ESI): m / z calcd for [M+H] + = 478.0319, found = 478.0319

[0147] HPLC: Chiralpak IA, hexane : iPrOH 70:30, 0.5 ml / min, λ = 254 nm,fraction t r = 19.151 (major enantiomer) and 24.504 (minor enantiomer) er =88:12

[0148] Example 12:

[0149]

[0150] MBH carbonate 1a (31.0 mg, 0.12 mmol, 1.2 equiv.), imine 2j (28.9 mg, 0.1 mmol, 1.0 equiv.), 10 mg of 4Å molecular sieve, and methanol (2 μL, 0.05 mmol, 0.5 equiv.) were added to a sealing tube, followed by 1 mL of chloroform (0.1 M). The mixture was stirred at room temperature until completely dissolved. Subsequently, L-valine-derived organophosphorus (10.2 mg, 0.02 mmol, 0.2 equiv.) was added to the sealing tube, which was then sealed and heated to 60°C. o C, react for 12 hours. After the reaction is complete, the reaction solution is cooled to room temperature and then separated by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain product 3aj, a white solid, with a yield of 35.2 mg and a yield of 82%.

[0151] MPa 103.5 – 104.1 o C

[0152] = -11.364 (c 0.66, CH2Cl2)

[0153] 1 H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 8.2 Hz, 2H), 7.01 (d, J = 8.1Hz, 2H), 6.98 (s, 1H), 6.94 (d, J = 8.4 Hz, 2H), 6.71 (d, J = 8.4 Hz, 2H),5.38 (s, 1H), 4.96 (d, J = 5.8 Hz, 1H), 4.50 (d, J = 5.8 Hz, 1H), 4.17 (d, J= 7.3 Hz, 1H), 4.12 (d, J = 7.3 Hz, 1H), 3.98 (s, 3H), 3.79 (s, 3H), 2.31 (s, 3H).

[0154] 13 C NMR (101 MHz, CDCl3) δ 163.5, 159.9, 156.7, 144.4, 135.5, 128.9,128.6, 128.5, 128.4, 114.2, 111.2, 87.8, 68.3, 63.4, 55.4, 47.0, 21.6.

[0155] HRMS (ESI): m / z calcd for [M+H]+ = 430.1319, found = 430.1318

[0156] HPLC: Chiralpak IA, hexane: iPrOH 80:20, 0.5 ml / min, λ = 254 nm, fraction t r = 34.070 (major enantiomer) and 44.593 (minor enantiomer) er =93:7

[0157] Example 13:

[0158]

[0159] MBH carbonate 1a (31.0 mg, 0.12 mmol, 1.2 equiv.), imine 2k (30.4 mg, 0.1 mmol, 1.0 equiv.), 10 mg 4Å molecular sieve, and methanol (2 μL, 0.05 mmol, 0.5 equiv.) were added to a sealing tube, followed by 1 mL of chloroform (0.1 M). The mixture was stirred at room temperature until completely dissolved. Subsequently, L-valine-derived organophosphorus (10.2 mg, 0.02 mmol, 0.2 equiv.) was added to the sealing tube, which was then sealed and heated to 60°C. o C, react for 12 hours. After the reaction is complete, the reaction solution is cooled to room temperature and then separated by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain product 3ak, an orange solid, with a yield of 26.7 mg and a yield of 60%.

[0160] MP 125.6 – 126.4 o C

[0161] = 2.432 (c 0.37, CH2Cl2)

[0162] 11H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 8.6 Hz, 2H), 7.46 (d, J = 8.1Hz, 2H), 7.26 (d, J = 8.5 Hz, 2H), 7.07 (d, J = 8.1 Hz, 2H), 7.03 (s, 1H),5.53 (s, 1H), 4.97 (d, J = 5.9 Hz, 1H), 4.53 (d, J = 5.9 Hz, 1H), 4.13 (d, J= 7.4 Hz, 1H), 4.07 (d, J = 7.4 Hz, 1H), 4.02 (s, 3H), 2.34 (s, 3H).

[0163] 13 13C NMR (101 MHz, CDCl3) δ 163.2, 157.7, 148.1, 145.3, 143.7, 135.2,129.2, 128.4, 128.2, 124.1, 109.9, 87.6, 67.5, 63.8, 46.8, 29.7, 21.7.

[0164] HRMS (ESI): m / z calcd for [M+H] + = 445.1064, found = 445.1061

[0165] HPLC: Chiralpak IF, hexane : iPrOH 40:60, 0.5 ml / min, λ = 254 nm,fraction t r = 35.552 (major enantiomer) and 47.203 (minor enantiomer) er =66:34

[0166] Example 14:

[0167]

[0168] MBH carbonate 1a (31.0 mg, 0.12 mmol, 1.2 equiv.), imine 2l (33.1 mg, 0.1 mmol, 1.0 equiv.), 10 mg 4Å molecular sieve, and methanol (2 μL, 0.05 mmol, 0.5 equiv.) were added to a sealing tube, followed by 1 mL of chloroform (0.1 M). The mixture was stirred at room temperature until completely dissolved. Subsequently, L-valine-derived organophosphorus (10.2 mg, 0.02 mmol, 0.2 equiv.) was added to the sealing tube, which was then sealed and heated to 60°C. o C, react for 12 hours. After the reaction is complete, the reaction solution is cooled to room temperature and then separated by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain product 3al, a colorless oily substance, with a yield of 30.7 mg and a yield of 65%.

[0169] = 16.184 (c 0.38, CH2Cl2)

[0170] 1 H NMR (400 MHz, CDCl3) δ 7.99 (dd, J = 7.9, 1.4 Hz, 1H), 7.46 (dd, J= 8.3, 2.5 Hz, 2H), 7.37 – 7.28 (m, 1H), 7.15 (td, J = 7.7, 1.5 Hz, 1H), 4.45 (d, J = 5.3 Hz, 1H),4.29 (d, J = 6.8 Hz, 1H), 3.98 (s, 3H), 3.96 (d, J = 7.5 Hz, 1H), 2.34 (s,3H), 1.47 (t, J = 7.1 Hz, 2H).

[0171] 13C NMR (101 MHz, CDCl3) δ 167.0, 164.1, 157.1, 144.6, 138.5, 135.4,132.3, 130.8, 130.5, 129.0, 128.6, 128.1, 126.1, 111.9, 87.1, 78.5, 63.5,62.4, 61.8, 46.4, 21.7, 14.4.

[0172] HRMS (ESI): m / z calcd for [M+H] + = 472.1424, found = 472.1433

[0173] HPLC: Chiralpak IA, hexane: iPrOH 80:20, 0.5 ml / min, λ = 254 nm, fraction t r = 27.100 (major enantiomer) and 38.202 (minor enantiomer) er =87:13

[0174] Example 15:

[0175]

[0176] MBH carbonate 1a (31.0 mg, 0.12 mmol, 1.2 equiv.), imine 2m (30.9 mg, 0.1 mmol, 1.0 equiv.), 10 mg 4Å molecular sieve, and methanol (2 μL, 0.05 mmol, 0.5 equiv.) were added to a sealing tube, followed by 1 mL of chloroform (0.1 M). The mixture was stirred at room temperature until completely dissolved. Subsequently, L-valine-derived organophosphorus (10.2 mg, 0.02 mmol, 0.2 equiv.) was added to the sealing tube, which was then sealed and heated to 60°C. o C, react for 12 hours. After the reaction is complete, cool the reaction solution to room temperature, and then perform column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain product 3am, a white solid, with a yield of 33.7 mg and a yield of 75%.

[0177] MP 122.4 – 123.1 o C

[0178] = 12.105 (c 1.14, CH2Cl2)

[0179] 1 1H NMR (400 MHz, CDCl3) δ 7.81 – 7.77 (m, 1H), 7.68 – 7.64 (m, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.54 (d, J = 1.8 Hz, 1H), 7.52 – 7.48 (m, 2H), 7.27 (d, J = 8.4 Hz, 2H), 7.03 (s, 1H), 6.98 (dd, J = 8.5, 1.8 Hz, 1H), 6.77 (d, J = 8.1 Hz, 2H), 5.60 (s, 1H), 5.03 (d, J = 5.8 Hz, 1H), 4.55 (d, J = 5.8 Hz, 1H), 4.16 (d, J = 7.4 Hz, 1H), 4.11 (d, J = 7.4 Hz, 1H), 4.01 (s, 3H), 2.20 (s, 3H).

[0180] 13 13C NMR (101 MHz, CDCl3) δ 163.6, 157.1, 144.4, 135.3, 133.4, 133.3, 133.0, 128.9, 128.8, 128.4, 128.1, 127.6, 127.2, 126.8, 126.7, 123.8, 111.1, 87.9, 68.9, 63.5, 46.9, 21.5.

[0181] HRMS (ESI): m / z calcd for [M+H] + = 450.1370, found = 450.1369

[0182] HPLC: Chiralpak IA, hexane : iPrOH 93:07, 1 ml / min, λ = 254 nm, fraction t r = 67.734 (major enantiomer) and 82.549 (minor enantiomer) er = 92:8

[0183] Example 16:

[0184]

[0185] MBH carbonate 1a (31.0 mg, 0.12 mmol, 1.2 equiv.), imine 2n (30.9 mg, 0.1 mmol, 1.0 equiv.), 10 mg 4Å molecular sieve, and methanol (2 μL, 0.05 mmol, 0.5 equiv.) were added to a sealing tube, followed by 1 mL of chloroform (0.1 M). The mixture was stirred at room temperature until completely dissolved. Subsequently, L-valine-derived organophosphorus (10.2 mg, 0.02 mmol, 0.2 equiv.) was added to the sealing tube, which was then sealed and heated to 60°C. o C, react for 12 hours. After the reaction is complete, the reaction solution is cooled to room temperature and then separated by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain product 3an, a white solid, with a yield of 36.9 mg and a yield of 82%.

[0186] MP 108.3 – 108.8 o C

[0187] = -76.471 (c 0.44, CH2Cl2)

[0188] 1 H NMR (400 MHz, CDCl3) δ 8.41 (d, J = 8.6 Hz, 1H), 7.91 (dd, J = 8.2,1.3 Hz, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.70 (ddd, J = 8.5, 6.8, 1.3 Hz, 1H),7.61 – 7.55 (m, 1H), 7.39 (d, J = 8.3 Hz, 2H), 7.05 (dd, J = 11.5, 7.9 Hz,3H), 6.72 (dd, J = 7.3, 1.1 Hz, 1H), 6.47 (s, 1H), 5.14 (d, J = 5.9 Hz, 1H),4.59 (d, J = 5.8 Hz, 1H), 4.00 (d, J = 7.3 Hz, 1H), 3.97 (s, 3H), 3.93 (d, J= 7.4 Hz, 1H), 2.34 (s, 3H).

[0189] 13C NMR (101 MHz, CDCl3) δ 164.0, 157.3, 144.6, 135.3, 133.7, 132.4,131.6, 129.1, 129.0, 129.0, 128.8, 127.5, 126.3, 124.9, 123.2, 122.7, 110.8,87.6, 63.5, 62.8, 47.7, 29.7, 21.6.

[0190] HRMS (ESI): m / z calcd for [M+H] + = 450.1370, found = 450.1367

[0191] HPLC: Chiralpak IA, hexane: iPrOH 86:14, 0.5 ml / min, λ = 254 nm, fraction t r = 50.879 (major enantiomer) and 63.683 (minor enantiomer) er =96:4

[0192] Example 17:

[0193]

[0194] MBH carbonate 1a (31.0 mg, 0.12 mmol, 1.2 equiv.), imine 2o (24.9 mg, 0.1 mmol, 1.0 equiv.), 10 mg 4Å molecular sieve, and methanol (2 μL, 0.05 mmol, 0.5 equiv.) were added to a sealing tube, followed by 1 mL of chloroform (0.1 M). The mixture was stirred at room temperature until completely dissolved. Subsequently, L-valine-derived organophosphorus (10.2 mg, 0.02 mmol, 0.2 equiv.) was added to the sealing tube, which was then sealed and heated to 60°C. o C, react for 12 hours. After the reaction is complete, the reaction solution is cooled to room temperature and then separated by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain product 3ao, an orange oily substance, with a yield of 31.4 mg and a yield of 81%.

[0195] = -49.273 (c 0.69, CH2Cl2)

[0196] 11H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 8.3 Hz, 2H), 7.10 (d, J = 8.2Hz, 2H), 7.07 (d, J = 1.7 Hz, 1H), 6.97 (s, 1H), 6.54 – 6.51 (m, 1H), 6.32(dd, J = 3.3, 1.8 Hz, 1H), 5.54 (s, 1H), 4.94 (d, J = 6.0 Hz, 1H), 4.51 (d, J= 5.9 Hz, 1H), 4.30 (d, J = 7.3 Hz, 1H), 4.18 (d, J = 7.3 Hz, 1H), 3.96 (s,3H), 2.33 (s, 3H).

[0197] 13 13C NMR (101 MHz, CDCl3) δ 163.1, 156.6, 149.4, 144.5, 143.0, 135.1,129.1, 128.4, 111.4, 110.7, 110.3, 87.3, 77.5, 63.4, 61.8, 46.3, 21.6.

[0198] HRMS (ESI): m / z calcd for [M+H] + = 390.1006, found = 390.1005

[0199] HPLC: Chiralpak IF, hexane : iPrOH 70:30, 1 ml / min, λ = 254 nm,fraction t r = 30.323 (major enantiomer) and 40.401 (minor enantiomer) er =86:14

[0200] Example 18:

[0201]

[0202] MBH carbonate 1a (31.0 mg, 0.12 mmol, 1.2 equiv.), imine 2p (26.5 mg, 0.1 mmol, 1.0 equiv.), 10 mg 4Å molecular sieve, and methanol (2 μL, 0.05 mmol, 0.5 equiv.) were added to a sealing tube, followed by 1 mL of chloroform (0.1 M). The mixture was stirred at room temperature until completely dissolved. Subsequently, L-valine-derived organophosphorus (10.2 mg, 0.02 mmol, 0.2 equiv.) was added to the sealing tube, which was then sealed and heated to 60°C. o C, react for 12 hours. After the reaction is complete, the reaction solution is cooled to room temperature and then separated by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain product 3ap, a colorless oily substance, with a yield of 31.5 mg and a yield of 78%.

[0203] = -5.417 (c 0.72, CH2Cl2)

[0204] 1 H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 8.4 Hz, 2H), 7.13 (dt, J = 5.1,1.0 Hz, 1H), 7.09 (dd, J = 3.5, 1.3 Hz, 1H), 7.03 (d, J = 8.1 Hz, 2H), 6.97(s, 1H), 6.92 (dd, J = 5.1, 3.5 Hz, 1H), 5.79 (s, 1H), 4.96 (d, J = 5.9 Hz,1H), 4.51 (d, J = 5.9 Hz, 1H), 4.28 (s, 2H), 3.99 (s, 3H), 2.31 (s, 3H).

[0205] 13 C NMR (101 MHz, CDCl3) δ 162.6, 157.4, 144.4, 139.2, 135.3, 129.0,128.6, 128.3, 126.6, 126.4, 109.8, 86.9, 76.3, 64.5, 63.6, 47.4, 21.6.

[0206] HRMS (ESI): m / z calcd for [M+H] + = 406.0777, found = 406.0776

[0207] HPLC: Chiralpak IF, hexane : iPrOH 70:30, 1 ml / min, λ = 254 nm,fraction t r = 34.171 (major enantiomer) and 59.057 (minor enantiomer) er =85:15。

Claims

1. A method for synthesizing γ-lactam derivatives via organophosphorus catalysis, characterized in that, Using oxetine-derived MBH carbonate and aromatic aldehyde imine as raw materials, the reaction was catalyzed by an L-valine-derived organophosphorus catalyst, and a solvent was added and the mixture was heated to synthesize γ-lactam derivatives in one step. The reaction formula is as follows: ； Among them, R 1 It is any one of C1-C4 alkyl and benzyl groups; Ar is a substituted or unsubstituted C6~C12 aryl or a 5~12 membered ring heteroaryl, wherein the substituent on the C6~C12 aryl or the 5~12 membered ring heteroaryl is H, halogen, C1~C4 alkyl, C1~C4 alkoxy, NO2, or C1~C4 alkoxycarbonyl. R 3 It is any one of 4-methylphenyl, 2,4,6-trimethylphenyl or 4-methoxyphenyl.

2. The method for synthesizing γ-lactam derivatives according to claim 1, characterized in that, R 1 It is any one of Me, Et, and Bn; Ar is any substituted phenyl or 2-furanyl, 1-naphthyl, 2-naphthyl, and 2-thiophenyl from F, Cl, Br, Me, OMe, NO2, CO2Et.

3. The method for synthesizing γ-lactam derivatives according to claim 1, characterized in that, The catalyst is an L-valine-derived organophosphorus compound with the following structural formula: 。 4. The method for synthesizing γ-lactam derivatives according to claim 3, characterized in that, The amount of catalyst used relative to the aromatic aldehyde imine is 10-30 mol.

5. The method for synthesizing γ-lactam derivatives according to claim 1, characterized in that, The solvent is chloroform.

6. The method for synthesizing γ-lactam derivatives according to claim 1, characterized in that, The reaction temperature is 50~70°C. o C.

7. The method for synthesizing γ-lactam derivatives according to claim 1, characterized in that, The molar ratio of the oxetane-derived MBH carbonate and the aromatic aldehyde imine is 1.1~1.3 :

1.

8. The method for synthesizing γ-lactam derivatives according to claim 1, characterized in that, The amount of the additive 4Å molecular sieve is 90-110 g·mol relative to the aromatic aldehyde imine. -1 R 1 The amount of OH used is 0.4~0.6 equivalents.

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