Catalytic synthesis method of chiral isoxazole-5-ketone and derivative thereof

Abstract

The invention discloses a catalytic synthesis method of chiral isoxazole-5-ketone and derivatives thereof, and belongs to the field of organic synthesis. The preparation method comprises the following steps: by taking 3, 4-dihydro-b-carboline oxide and oxazolone as reactants, adding a halogenated hydrocarbon solvent for dissolving, then adding chiral phosphoric acid as a catalyst, and reacting at 25-60 DEG C for 5-24 hours to obtain the chiral isoxazole-5-ketone compound as shown in the formula (I), and adding zinc powder into the isoxazole-5-ketone as a reactant shown in the formula (I), and reacting in a mixed solvent of acetic acid, tetrahydrofuran and water at 25-40 DEG C for 1-12 hours to obtain the chiral alpha, beta-amino acid as shown in the formula (II). According to the present invention, the synthesis of the fused heterocyclic compound simultaneously having the tetrahydro-b-carboline and the isoxazole-5-ketone skeleton is achieved for the first time, and the method has advantages of simple operation, high yield, excellent enantioselectivity and excellent diastereoselectivity; the synthesized isoxazole-5-ketone compound can be converted into alpha, beta-amino acid, and structural diversity synthesis of non-natural amino acid is achieved. # imgabs0 #

Description

Technical Field

[0001] The invention relates to a synthesis method of chiral isoxazol-5-one and its derivatives, and belongs to the field of organic synthesis. Background Art

[0002] Isoxazol-5-one is an important building block that not only has multiple physiological activities but can also be used as a precursor for the synthesis of unnatural amino acids, such as α-quaternary amino acids or α,β-amino acids. Therefore, it is very important to develop methods for the synthesis of chiral isoxazol-5-one.

[0003] In 2000, Sibi's group (Sibi, MP; Narayanasamy, P.; Ghorpade, SG; Jasperse, CP Enantioselective Synthesis of α, β-Disubstituted-β-amino Acids. J. Am. Chem. Soc. 2003, 125, 11796-11797) reported the Lewis acid-catalyzed cyclization reaction of N-benzylhydroxylamine with α, β-unsaturated amide compounds to obtain isoxazol-5(4H)-one derivatives with moderate yields and excellent enantioselectivity.

[0004]

[0005] In 2016, the Brière research group (Cadart, T.; Berthonneau, C.; Levacher, V.; Perrio, S.; Brière, J.-F. Enantioselective Phase-Transfer Catalyzedα-Sulfanylation of Isoxazolidin-5-ones: An Entry toβ 2,2 -Amino Acid Derivatives.Chem.Eur.J.2016,22,15261-15264) reported an asymmetric substitution reaction involving racemic isoxazol-5(4H)-one, achieving the enantioselective synthesis of disubstituted chiral isoxazol-5-one. Under the action of Cs2CO3 and chiral phase transfer catalyst, the α position of the substrate carbonyl attacked the NS bond, and the phthalimide left to obtain a product with a medium ee value. Cutting the NO bond of the product can further obtain α-quaternary carbon amino acids.

[0006]

[0007] The [3+2] cycloaddition reaction of nitrones and oxazolones can also synthesize isoxazol-5-ones, which can be used as precursors of α,β-amino acids. In 2016, Liu Xiaohua's group (Xie, L.; Li, Y.; Dong, S.; Feng, X.; Liu, X. Catalyticasymmetric formal [3+2] cycloaddition of isatogens with azlactones to constructindolin-3-one derivatives. Chem. Commun. 2021, 57, 239-242) developed a chiral guanidine-catalyzed asymmetric [3+2] cycloaddition reaction of oxazolones and nitrones to obtain an isoxazol-5-one skeleton containing two consecutive quaternary carbon chiral centers. The chiral guanidine simultaneously activates the two substrates through hydrogen bond interactions, allowing the two substrates to undergo addition reactions in the form of Re-Si, and the resulting products have excellent diastereoselectivity and low to excellent enantioselectivity.

[0008]

[0009] The tetrahydro-β-carboline skeleton is widely present in natural products and active molecules and has a variety of biological activities. As two important nitrogen-containing heterocyclic compounds, the currently developed synthesis methods cannot achieve the synthesis of fused heterocyclic compounds with both tetrahydro-β-carboline and isoxazol-5-one skeletons. Therefore, in order to obtain more novel and diverse chiral isoxazol-5-ones and their derivatives, it is of great significance to develop other types of cyclization reactions of nitrones and oxazolones. Summary of the invention

[0010] In view of the above problems existing in the prior art, the purpose of the present invention is to provide a method for synthesizing chiral isoxazol-5-one and its derivatives (α, β-amino acids) by a [3+2] cyclization reaction involving oxazolone and nitrone, which method is simple to operate, has a high yield, and has excellent enantioselectivity and diastereoselectivity.

[0011] In order to achieve the above-mentioned object of the invention, the technical solution adopted by the present invention is:

[0012] A catalytic synthesis method of chiral isoxazol-5-one comprises the following steps: using 3,4-dihydro-β-carboline oxide and oxazolone as reactants, adding a halogenated hydrocarbon solvent to dissolve, adding chiral phosphoric acid as a catalyst, reacting at 25-60° C. for 5-24 hours, and obtaining a chiral isoxazol-5-one compound represented by formula (I):

[0013]

[0014] The above reaction process is as follows:

[0015]

[0016] In terms of molar amount, the amount of the chiral phosphoric acid is 5-20% of the 3,4-dihydro-β-carboline oxide; the amount of the oxazolone is 1-2 times of the 3,4-dihydro-β-carboline oxide.

[0017] The halogenated alkane solvent includes, but is not limited to, dichloromethane, 1,2-dichloroethane or chloroform.

[0018] The chemical structural formula of the 3,4-dihydro-β-carboline oxide is Where R 1 It is selected from the group consisting of hydrogen, 5-fluoro, 5-chloro, 5-bromo, 5-methyl, 6-fluoro, 6-chloro, 6-bromo, 6-methyl, 6-methoxy, 7-fluoro, 7-chloro, 7-bromo, 7-methoxycarbonyl, 7-methyl, 8-fluoro, 8-bromo, 8-methyl, 8-methoxy or 6,7-dichloro.

[0019] The chemical structural formula of the oxazolone is Where R 2 is selected from phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 4-methylphenyl, 4-tert-butylphenyl, 3-methylphenyl, 2-fluorophenyl, 2-naphthyl or 2-thienyl; R 3 Selected from methyl, ethyl, n-propyl or isobutyl.

[0020] In the preferred technical solution, the reaction temperature is 25°C.

[0021] In the preferred technical solution, the reaction time is 5 hours.

[0022] In a preferred technical solution, the amount of the chiral phosphoric acid used is 10% of the 3,4-dihydro-β-carboline oxide in terms of molar amount.

[0023] In a preferred technical solution, the amount of oxazolone used is 1.5 times that of 3,4-dihydro-β-carboline oxide on a molar basis.

[0024] In the preferred technical solution, the chemical structure of the chiral phosphoric acid AF includes but is not limited to:

[0025]

[0026] In the above technical solution, after the reaction is completed, the product can be separated by simple column chromatography (the eluent is preferably petroleum ether: ethyl acetate = 30:1 to 20:1) to obtain the target product.

[0027] A method for synthesizing an oxazolone derivative (α, β-amino acid) using the chiral isoxazol-5-one, comprising the following steps: using the isoxazol-5-one represented by formula (I) as a reactant, adding zinc powder, reacting in a mixed solvent of acetic acid, tetrahydrofuran and water at 25-40° C. for 1-12 hours to obtain a chiral α, β-amino acid represented by formula (II):

[0028]

[0029] The above reaction process is as follows:

[0030]

[0031] The amount of the zinc powder used is 10-15 times that of isoxazol-5-one in terms of molar amount.

[0032] In the preferred technical solution, the reaction temperature is 25°C.

[0033] In the preferred technical solution, the reaction time is 1 h.

[0034] In a preferred technical solution, the amount of the zinc powder used is 15 times that of isoxazol-5-one in terms of molar amount.

[0035] In the above technical solution, after the reaction is completed, the product can be separated by simple column chromatography (the eluent is preferably dichloromethane: methanol = 20:1) to obtain the target product.

[0036] Due to the application of the above technical solution, the present invention has the following advantages compared with the prior art:

[0037] 1. The present invention realizes the synthesis of chiral isoxazol-5-one compounds by using 3,4-dihydro-β-carboline oxide and oxazolone as reactants and catalyzing them with chiral phosphoric acid, and for the first time realizes the synthesis of fused heterocyclic compounds having both tetrahydro-β-carboline and isoxazol-5-one skeletons. The method is simple to operate, has high yield, and has excellent enantioselectivity and diastereoselectivity.

[0038] 2. The isoxazol-5-one compound synthesized by the present invention can be converted into α, β-amino acids, thereby realizing the structural diversity synthesis of non-natural amino acids. DETAILED DESCRIPTION

[0039] The present invention will be further described below in conjunction with specific embodiments.

[0040] Embodiment 1:

[0041]

[0042] 3,4-dihydro-β-carboline oxide 1a (18.6 mg, 0.1 mmol) and oxazolone 2a (28.4 mg, 0.15 mmol) were added to the reaction flask in sequence, CHCl3 (1.0 mL) was added, and finally chiral phosphoric acid catalyst A (7.5 mg, 0.01 mmol) was added, and the reaction was carried out at 25°C for 5 hours. After the reaction, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate = 30:1-20:1) to obtain the target product 3a (31 mg), with a yield of 82%, dr>19 / 1, and ee = 97%. The product 3a was analyzed, and the results were as follows: the melting point was 93.4-93.9°C; 1 H NMR (400MHz, CDCl3): δ10.88(s,1H),7.93-7.90(m,2H),7.65(t,J=7.4Hz,1H),7.56-7.50(m,4H),7.27(t,J=7.8Hz,1H),7.17(t,J=7.1Hz,1H), 6.95(s,1H),5.52(s,1H),3.96-3.80(m,1H),3.59-3.41(m,1H),3.10-3 .07(m,2H),2.47-2.42(m,1H),1.78-1.73(m,1H),1.02(t,J=7.4Hz,3H); 13 C NMR (101MHz, CDCl3): δ177.1,167.7,136.6,133.1,132.6,129.0,127.1,126.3,125.8,122.4,119.3,118.2, 111.8,109.8,68.2,63.6,53.0,26.9,20.2,7.4;IR(neat):ν3883,1715,1667,1562,1445,1327,1164,740cm –1 ; HRMS (ESI): m / z [M+H] + calcd.for C 22 H 22 N3O3:376.1656; found:376.1656; [α] D 23 = +126.6 (c = 0.60, DCM); the ee value of the product was determined by high performance liquid chromatography (HPLC), the separation conditions were: the chromatographic column was Chiracel IC, the mobile phase was i PrOH / Hexane=10 / 90, mobile phase is 1.0mL / min, retention time and peak area are t R1 =19.16min,98.4%,t R2=22.59min,1.6%.

[0043] Embodiment 2:

[0044]

[0045] 3,4-dihydro-β-carboline oxide 1b (20 mg, 0.1 mmol) and oxazolone 2a (28.4 mg, 0.15 mmol) were added to the reaction flask in sequence, CHCl3 (1.0 mL) was added, and finally chiral phosphoric acid catalyst E (7.5 mg, 0.01 mmol) was added, and the reaction was carried out at 40°C for 5 hours. After the reaction, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate = 30:1-20:1) to obtain the target product 3b (25 mg), with a yield of 64%, dr>19 / 1, and ee = 95%. The product 3b was analyzed, and the results were as follows: the melting point was 96.9-97.2°C; 1 H NMR (400MHz, CDCl3): δ11.04(s,1H),7.90-7.88(m,2H),7.64(t,J=7.4Hz,1H) ,7.56-7.52(m,2H),7.26(d,J=8.0Hz,1H),7.13-7.08(m,1H),6.94(s,1H),6.7 7(dd,J=10.7,7.8Hz,1H),5.48(s,1H),3.94-3.77(m,1H),3.57-3.45(m,1H),3 .30-3.20(m,2H),2.47-2.39(m,1H),1.86-1.74(m,1H),1.02(t,J=7.4Hz,3H); 13 CNMR (101MHz, CDCl3): δ176.8,167.8,158.2(d,J C-F =246.8Hz),139.2(d,J C-F =11.9Hz),133.0,132.8,129.0,127.1,126.2,122.9(d,J C-F =7.6Hz),115.1(d,J C-F =20.8Hz),108.2,107.9(d,J C-F =3.5Hz),104.3(d,J C-F =18.7Hz),67.9,63.7,53.1,27.2,21.6,7.4; IR(neat):ν3863,1776,1657,1562,1510,1460,1440,1387,740cm –1 ; HRMS (ESI): m / z [M+H]+ calcd.for C 22 H 21 FN3O3:394.1561; found:394.1564; [α] D 23 = +189.6 (c = 0.39, DCM); the ee value of the product was determined by high performance liquid chromatography (HPLC), the separation conditions were: the chromatographic column was Chiracel IC, the mobile phase was i PrOH / Hexane=10 / 90, mobile phase is 1.0mL / min, retention time and peak area are t R1 =11.16min,2.7%,t R2 =12.53min,97.3%.

[0046] Embodiment 3:

[0047]

[0048] 3,4-dihydro-β-carboline oxide 1c (22 mg, 0.1 mmol) and oxazolone 2a (28.4 mg, 0.15 mmol) were added to the reaction flask in sequence, CHCl3 (1.0 mL) was added, and finally chiral phosphoric acid catalyst E (7.5 mg, 0.01 mmol) was added, and the reaction was carried out at 60°C for 5 hours. After the reaction, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate = 30:1-20:1) to obtain the target product 3c (22 mg), with a yield of 76%, dr>19 / 1, and ee=95%. The product 3c was analyzed, and the results were as follows: the melting point was 88.0-88.7°C; 1 H NMR (400MHz, CDCl3): δ11.13(s,1H),7.90-7.88(m,2H),7.64(t,J=7.4Hz,1H),7.56-7.52(m,2H),7.38(dd,J=7.8,0.7Hz,1H),7.12-7. 04(m,2H),6.95(s,1H),5.52(s,1H),3.97-3.78(m,1H),3.57-3.31(m,3H),2.45-2.39(m,1H),1.86-1.74(m,1H),1.02(t,J=7.4Hz,3H); 13C NMR (101MHz, CDCl3): δ176.5,167.8,137.7,133.0,132.8,129.0,127.2,127.1,126.0,123.4,122.9,119.8,11 0.5,110.0,67.7,63.4,53.2,27.2,22.2,7.4;IR(neat):ν3830,1769,1644,1532,1327,1218,1164,805,699cm –1 ; HRMS (ESI): m / z [M+H] + calcd.for C 22 H 21 ClN3O3:410.1266; found:410.1268; [α] D 23 = +193.3 (c = 0.13, DCM); the ee value of the product was determined by high performance liquid chromatography (HPLC), the separation conditions were: the chromatographic column was Chiracel IC, the mobile phase was i PrOH / Hexane=2 / 98, mobile phase is 1.0mL / min, retention time and peak area are t R1 =25.90min,97.5%,t R2 =28.97min,2.5%.

[0049] Embodiment 4:

[0050]

[0051] 3,4-dihydro-β-carboline oxide 1d (20 mg, 0.1 mmol) and oxazolone 2a (37.8 mg, 0.20 mmol) were added to the reaction flask in sequence, CHCl3 (1.0 mL) was added, and finally chiral phosphoric acid catalyst E (7.5 mg, 0.01 mmol) was added, and the reaction was carried out at 25°C for 5 hours. After the reaction, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate = 30:1-20:1) to obtain the target product 3d (27 mg), with a yield of 69%, dr>19 / 1, and ee = 98%. The product 3d was analyzed, and the results were as follows: the melting point was 90.2-90.6°C; 1H NMR (400MHz, CDCl3): δ10.89 (s, 1H), 7.91-7.89 (m, 2H), 7.65 (t, J = 7.4Hz, 1 H),7.56-7.52(m,2H),7.34(d,J=8.2Hz,1H),7.12(t,J=7.4Hz,1H),6.93(s, 1H),6.85(d,J=7.1Hz,1H),5.53(s,1H),3.96-3.81(m,1H),3.54-3.32(m,3H ),2.69(s,3H),2.53-2.43(m,1H),1.86-1.77(m,1H),1.02(t,J=7.4Hz,3H); 13 C NMR (101MHz, CDCl3): δ177.3,167.7,136.7,133.1,132.7,130.4,129.0,127.1,125.7,124.9,122.5,120.5,110. 2,109.6,68.1,63.6,53.3,27.3,22.8,19.7,7.4;IR(neat):ν3831,1768,1643,1529,1453,1318,1159,800,669cm –1 ; HRMS (ESI): m / z [M+H] + calcd.forC 23 H 24 N3O3:390.1812; found:390.1806; [α] D 23 = +148.0 (c = 1.35, DCM); the ee value of the product was determined by high performance liquid chromatography (HPLC), the separation conditions were: the chromatographic column was Chiracel IC, the mobile phase was i PrOH / Hexane=20 / 80, mobile phase is 1.0mL / min, retention time and peak area are t R1 =15.60min,1.1%,t R2 =18.62min,98.9%.

[0052] Embodiment 5:

[0053]

[0054] 3,4-dihydro-β-carboline oxide 1e (22 mg, 0.1 mmol) and oxazolone 2a (18.9 mg, 0.10 mmol) were added to the reaction flask in sequence, CHCl3 (1.0 mL) was added, and finally chiral phosphoric acid catalyst E (7.5 mg, 0.01 mmol) was added, and the reaction was carried out at 25°C for 5 hours. After the reaction, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate = 30:1-20:1) to obtain the target product 3e (31 mg), with a yield of 77%, dr>19 / 1, and ee = 98%. The product 3e was analyzed, and the results were as follows: the melting point was 91.2-91.7°C; 1 H NMR (400MHz, CDCl3): δ11.00(s,1H),7.90-7.88(m,2H),7.64(t,J=7.4Hz,1H),7.56-7.49(m,3H),7.41(d,J=8.6Hz,1H),7.19(dd,J=8.6,2.0Hz,1H ),6.94(s,1H),5.46(s,1H),3.92-3.78(m,1H),3.60-3.42(m,1H),3.04- 3.01(m,2H),2.43-2.38(m,1H),1.82-1.74(m,1H),1.01(t,J=7.5Hz,3H); 13 C NMR (101MHz, CDCl3): δ176.8,167.7,134.9,133.0,132.8,129.0,127.8,127.1,126.9,125.0,122.7,117.8,112. 8,109.6,69.1,63.5,52.9,26.3,20.2,7.4;IR(neat):ν3863,1715,1704,1657,1561,1510,1469,1314,955,699cm –1 ; HRMS (ESI): m / z [M+H] + calcd.for C 22 H 21 ClN3O3:410.1266; found:410.1268; [α] D 23 = +121.8 (c = 1.55, DCM); the ee value of the product was determined by high performance liquid chromatography (HPLC), the separation conditions were: the chromatographic column was Chiracel IC, the mobile phase was i PrOH / Hexane=20 / 80, mobile phase is 1.0mL / min, retention time and peak area are t R1 =10.16min,1.2%,tR2 =11.11min,98.8%.

[0055] Embodiment 6:

[0056]

[0057] 3,4-dihydro-β-carboline oxide 1f (26 mg, 0.1 mmol) and oxazolone 2a (28.4 mg, 0.15 mmol) were added to the reaction flask in sequence, CHCl3 (1.0 mL) was added, and finally chiral phosphoric acid catalyst E (7.5 mg, 0.01 mmol) was added, and the reaction was carried out at 25°C for 24 hours. After the reaction, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate = 30:1-20:1) to obtain the target product 3f (36 mg), with a yield of 79%, dr>19 / 1, and ee = 98%. The product 3f was analyzed, and the results were as follows: the melting point was 96.4-97.2°C; 1 H NMR (400MHz, CDCl3): δ11.01(s,1H),7.89-7.87(m,2H),7.65-7.61(m,2H),7.56(t,J=7.8Hz,2H),7.37(d,J=8.6Hz,1H),7.30(dd,J=8.6,1.8Hz,1H ),6.93(s,1H),5.48(s,1H),3.91-3.79(m,1H),3.56-3.43(m,1H),3.03- 3.01(m,2H),2.42-2.37(m,1H),1.81-1.72(m,1H),1.00(t,J=7.5Hz,3H); 13 C NMR (101MHz, CDCl3): δ177.0,167.7,135.2,133.0,132.8,129.0,127.7,127.6,127.1,125.2,120.9,113.3,11 2.5,109.4,68.3,63.7,52.9,27.0,20.2,7.4;IR(neat):ν3659,1767,1640,1545,1461,1324,1109,805,638cm –1 ; HRMS (ESI): m / z [M+H] + calcd.for C 22 H 21 BrN3O3:454.0761; found:454.0766; [α] D 23= +133.1 (c = 0.65, DCM); the ee value of the product was determined by high performance liquid chromatography (HPLC), the separation conditions were: the chromatographic column was Chiracel IC, the mobile phase was i PrOH / Hexane=20 / 80, mobile phase is 1.0mL / min, retention time and peak area are t R1 =10.26min,1.2%,t R2 =11.50min,98.8%.

[0058] Embodiment 7:

[0059]

[0060] 1g (22mg, 0.1mmol) of 3,4-dihydro-β-carboline oxide and 2a (28.4mg, 0.15mmol) of oxazolone were added to the reaction flask, CHCl3 (1.0mL) was added, and finally chiral phosphoric acid catalyst A (6.0mg, 0.01mmol) was added. The reaction was carried out at 25°C for 5 hours. After the reaction, the product was purified by simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate = 30:1-20:1) to obtain the target product 3g (25mg), with a yield of 62%, dr>19 / 1, and ee = 97%. The product 3g was analyzed, and the results were as follows: the melting point was 87.6-88.6°C; 1 H NMR (400MHz, CDCl3): δ10.76(s,1H),7.90-7.88(m,2H),7.64(t,J=7.4Hz,1H),7.55(t,J=7.8Hz,2H),7.38(d,J=8.8Hz,1H),6.97-6.89(m ,3H),5.50(s,1H),3.87-3.75(m,4H),3.58-3.42(m,1H),3.06-3.03(m,2H),2.46-2.41(m,1H),1.80-1.71(m,1H),1.00(t,J=7.4Hz,3H); 13 C NMR (101MHz, CDCl3): δ176.7,167.7,153.9,133.1,132.7,131.8,129.0,127.1,126.9,126.1,112.59,112.55,109. 5,100.1,69.0,63.6,55.9,53.1,27.2,20.3,7.4;IR(neat):ν3895,1767,1640,1526,1492,1461,1220,1159,699cm –1 ; HRMS (ESI): m / z [M+H]+ calcd.for C 23 H 24 N3O4:406.1761; found:406.1762; [α] D 23 = +112.5 (c = 1.00, DCM); the ee value of the product was determined by high performance liquid chromatography (HPLC), the separation conditions were: the chromatographic column was Chiracel IC, the mobile phase was i PrOH / Hexane=20 / 80, mobile phase is 1.0mL / min, retention time and peak area are t R1 =20.72min,1.6%,t R2 =25.25min,98.4%.

[0061] Embodiment 8:

[0062]

[0063] 3,4-dihydro-β-carboline oxide 1h (20 mg, 0.1 mmol) and oxazolone 2a (28.4 mg, 0.15 mmol) were added to the reaction flask in sequence, CHCl3 (1.0 mL) was added, and finally chiral phosphoric acid catalyst B (7.0 mg, 0.01 mmol) was added, and the reaction was carried out at 25°C for 5 hours. After the reaction, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate = 30:1-20:1) to obtain the target product 3h (23 mg), with a yield of 59%, dr>19 / 1, and ee = 95%. The product 3h was analyzed, and the results were as follows: the melting point was 102.3-102.8°C; 1 H NMR (400MHz, CDCl3): δ10.92(s,1H),7.90-7.88(m,2H),7.64(t,J=7.4Hz,1H ),7.56-7.52(m,2H),7.44(dd,J=8.6,5.3Hz,1H),7.19(dd,J=9.8,2.2Hz,1H ),6.93-6.87(m,2H),5.47(s,1H),3.93-3.80(m,1H),3.57-3.43(m,1H),3.0 6-3.03(m,2H),2.44-2.39(m,1H),1.82-1.72(m,1H),1.01(t,J=7.4Hz,3H); 13 C NMR (101MHz, CDCl3): δ177.0,167.7,161.4(d,J C-F =238.8Hz),136.7(d,J C-F=12.9Hz),133.0,132.7,129.0,127.1,126.6(d,J C-F =14.0Hz),122.5,119.0(d,J C-F =10.3Hz),110.0,108.2(d,J C-F =24.7Hz),98.2(d,J C-F =26.2Hz),68.5,63.6,52.9,26.8,20.2,7.4; IR(neat):ν3835,1768,1640,1526,1492,1328,1141,805,670cm –1 ; HRMS (ESI): m / z [M+H] + calcd.forC 22 H 21 FN3O3:394.1561; found:394.1564; [α] D 23 = +147.1 (c = 1.15, DCM); the ee value of the product was determined by high performance liquid chromatography (HPLC), the separation conditions were: the chromatographic column was Chiracel IC, the mobile phase was i PrOH / Hexane=10 / 90, mobile phase is 1.0mL / min, retention time and peak area are t R1 =16.34min,2.4%,t R2 =17.66min,97.6%.

[0064] Embodiment 9:

[0065]

[0066] 3,4-dihydro-β-carboline oxide 1i (24 mg, 0.1 mmol) and oxazolone 2a (28.4 mg, 0.15 mmol) were added to the reaction flask in sequence, CHCl3 (1.0 mL) was added, and finally chiral phosphoric acid catalyst C (6.1 mg, 0.01 mmol) was added, and the reaction was carried out at 25°C for 5 hours. After the reaction, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate = 30:1-20:1) to obtain the target product 3i (31 mg), with a yield of 72%, dr>19 / 1, and ee=96%. The product 3i was analyzed, and the results were as follows: the melting point was 105.6-106.3°C; 1H NMR (400MHz, CDCl3): δ11.24(s,1H),8.25(s,1H),7.91-7.89(m,2H),7.83(dd,J=8.3,1.4Hz,1H),7.64(t,J=7.4Hz,1H),7.56-7.52(m,3H),6. 96(s,1H),5.47(s,1H),3.94-3.79(m,4H),3.57-3.47(m,1H),3.09-3. 07(m,2H),2.44-2.39(m,1H),1.83-1.74(m,1H),1.00(t,J=7.4Hz,3H); 13 C NMR (101MHz, CDCl3): δ176.7,168.0,167.7,135.8,132.9,132.8,130.0,129.2,129.0,127.1,124.0,120.4,117.8,114. 2,110.1,68.9,63.5,52.9,51.9,27.2,20.2,7.4;IR(neat):ν3863,1775,1704,1657,1562,1544,1510,1460,1214,719cm –1 ; HRMS (ESI): m / z [M+H] + calcd.for C 24 H 24 N3O5:434.1710; found:434.1704; [α] D 23 = +175.8 (c = 1.55, DCM); the ee value of the product was determined by high performance liquid chromatography (HPLC), the separation conditions were: the chromatographic column was Chiracel IC, the mobile phase was i PrOH / Hexane=50 / 50, mobile phase is 1.0mL / min, retention time and peak area are t R1 =15.35min,2.0%,t R2 =28.98min,98.0%.

[0067] Embodiment 10:

[0068]

[0069] 3,4-dihydro-β-carboline oxide 1j (20 mg, 0.1 mmol) and oxazolone 2a (28.4 mg, 0.15 mmol) were added to the reaction flask in sequence, CHCl3 (1.0 mL) was added, and finally chiral phosphoric acid catalyst D (5.6 mg, 0.01 mmol) was added, and the reaction was carried out at 25°C for 5 hours. After the reaction, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate = 30:1-20:1) to obtain the target product 3j (29 mg), with a yield of 62%, dr>19 / 1, and ee=95%. The product 3j was analyzed, and the results were as follows: the melting point was 104.8-105.4°C; 1 H NMR (400MHz, CDCl3): δ10.72(s,1H),7.91-7.89(m,2H),7.64(t,J=7.4Hz,1H ),7.56-7.52(m,2H),7.43(d,J=8.0Hz,1H),7.31(s,1H),6.98(dd,J=8.0,0. 6Hz,1H),6.92(s,1H),5.49(s,1H),3.90-3.81(m,1H),3.53-3.43(m,1H),3. 07-3.04(m,2H),2.49-2.40(m,4H),1.81-1.73(s,1H),1.00(t,J=7.3Hz,3H); 13 C NMR (101MHz, CDCl3): δ177.2,167.6,137.1,133.2,132.6,132.2,128.9,127.2,125.6,123.7,121.0,117.9,11 1.7,109.6,68.0,63.5,53.1,26.9,21.8,20.3,7.4;IR(neat):ν3846,1713,1614,1445,1348,1097,999,699cm –1 ; HRMS (ESI): m / z [M+H] + calcd.for C 23 H 24 N3O3:390.1812; found:390.1806; [α] D 23 = +114.1 (c = 1.20, DCM); the ee value of the product was determined by high performance liquid chromatography (HPLC), the separation conditions were: the chromatographic column was Chiracel IC, the mobile phase was i PrOH / Hexane=10 / 90, mobile phase is 1.0mL / min, retention time and peak area are t R1 =17.93min,97.7%,tR2 =23.2min,2.3%.

[0070] Embodiment 11:

[0071]

[0072] 3,4-dihydro-β-carboline oxide 1k (20 mg, 0.1 mmol) and oxazolone 2a (28.4 mg, 0.15 mmol) were added to the reaction flask in sequence, CHCl3 (1.0 mL) was added, and finally chiral phosphoric acid catalyst F (9.9 mg, 0.01 mmol) was added, and the reaction was carried out at 25°C for 5 hours. After the reaction, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate = 30:1-20:1) to obtain the target product 3k (32 mg), with a yield of 81%, dr>19 / 1, and ee = 97%. The product 3k was analyzed, and the results were as follows: the melting point was 126.4-126.6°C; 1 H NMR (400MHz, CDCl3): δ11.16(s,1H),7.92-7.90(m,2H),7.64(t,J=7.4Hz,1H),7.55-7.51(m,2H),7.31(d,J=7.8Hz,1H),7.06-7.01(m,1H),6.98 -6.93(m,2H),5.51(s,1H),3.93-3.79(m,1H),3.58-3.43(m,1H),3.08-3 .05(m,2H),2.47-2.41(m,1H),1.83-1.73(m,1H),1.02(t,J=7.4Hz,3H); 13 C NMR (101MHz, CDCl3): δ176.7,167.5,150.9(d,J C-F =246.0Hz),132.9,132.7,129.5(d,J C-F =5.3Hz),128.9,127.20,127.17,125.0(d,J C-F =12.9Hz),119.6(d,J C-F =6.2Hz),114.0(d,J C-F =3.5Hz),110.5,107.4(d,J C-F =16.4Hz),68.4,63.5,52.9,26.9,20.3,7.4; IR(neat):ν3881,1777,1640,1581,1544,1461,1329,1158,781,669cm –1 ; HRMS (ESI): m / z [M+H]+ calcd.forC 22 H 21 FN3O3:394.1561; found:394.1564; [α] D 23 = +152.3 (c = 1.60, DCM); the ee value of the product was determined by high performance liquid chromatography (HPLC), the separation conditions were: the chromatographic column was Chiracel IC, the mobile phase was i PrOH / Hexane=20 / 80, mobile phase is 1.0mL / min, retention time and peak area are t R1 =13.15min,1.5%,t R2 =15.74min,98.5%.

[0073] Embodiment 12:

[0074]

[0075] 3,4-dihydro-β-carboline oxide 1l (20 mg, 0.1 mmol) and oxazolone 2a (28.4 mg, 0.15 mmol) were added to the reaction flask in sequence, CHCl3 (1.0 mL) was added, and finally chiral phosphoric acid catalyst E (15 mg, 0.2 mmol) was added, and the reaction was carried out at 25°C for 5 hours. After the reaction, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate = 30:1-20:1) to obtain the target product 3l (24 mg), with a yield of 62%, dr>19 / 1, and ee = 97%. The product 3l was analyzed, and the results were as follows: the melting point was 89.3-89.7°C; 1 H NMR (400MHz, CDCl3): δ10.99 (s, 1H), 7.93-7.91 (m, 2H), 7.64 (t, J = 7.4Hz, 1 H),7.56-7.52(m,2H),7.41(dd,J=6.6,2.0Hz,1H),7.09-7.04(m,2H),6.94( s,1H),5.52(s,1H),3.94-3.83(m,1H),3.61-3.45(m,1H),3.09-3.06(m,2H ),2.62(s,3H),2.49-2.44(m,1H),1.82-1.75(m,1H),1.01(t,J=7.4Hz,3H); 13C NMR (101MHz, CDCl3): δ177.2,167.7,136.4,133.2,132.6,129.0,127.2,126.0,125.4,122.8,121.1,119.5,115.9,1 10.2,68.7,63.7,53.1,27.2,20.4,16.6,7.4;IR(neat):ν3867,1767,1640,1563,1525,1461,1326,1218,800,699cm –1 ; HRMS (ESI): m / z [M+H] + calcd.for C 23 H 24 N3O3:390.1812; found:390.1806; [α] D 23 = +123.2 (c = 1.20, DCM); the ee value of the product was determined by high performance liquid chromatography (HPLC), the separation conditions were: the chromatographic column was Chiracel IC, the mobile phase was i PrOH / Hexane=20 / 80, mobile phase is 1.0mL / min, retention time and peak area are t R1 =8.37min,98.3%,t R2 =9.86min,1.7%.

[0076] Embodiment 13:

[0077]

[0078] 3,4-dihydro-β-carboline oxide 1a (19 mg, 0.1 mmol) and oxazolone 2b (31 mg, 0.15 mmol) were added to the reaction flask in sequence, DCM (1.0 mL) was added, and finally chiral phosphoric acid catalyst E (7.5 mg, 0.01 mmol) was added, and the reaction was carried out at 25°C for 5 hours. After the reaction, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate = 30:1-20:1) to obtain the target product 3m (23 mg), with a yield of 58%, dr>19 / 1, and ee = 97%. The product 3m was analyzed, and the results were as follows: the melting point was 99.2-99.8°C; 1H NMR (400MHz, CDCl3): δ10.81(s,1H),7.94-7.91(m,2H),7.55(d,J=7.8Hz,1H),7.50(d,J=8.1Hz,1H)7.26-7.12(m,3H),7.16(t,J=7.8 Hz,1H),6.87(s,1H),5.49(s,1H),3.95-3.42(m,2H),3.09-3.07(m,2H),2.45-2.39(m,1H),1.83-1.71(m,1H),1.00(t,J=7.4Hz,3H); 13 C NMR (101MHz, CDCl3): δ177.2,166.6(d,J C-F =255.0Hz),166.5,136.6,129.7(d,J C-F =9.3Hz),129.3(d,J C-F =3.0Hz),126.2,125.8,122.5,119.3,118.3,116.2(d,J C-F =22.1Hz),111.8,109.9,69.0,63.8,53.1,26.6,20.3,7.4; IR(neat):ν3754,1766,1650,1562,1544,1460,1327,1163,858,739cm –1 ; HRMS (ESI): m / z [M+H] + calcd.forC 22 H 21 FN3O3:394.1561; found:394.1564; [α] D 23 = +142.0 (c = 1.15, DCM); the ee value of the product was determined by high performance liquid chromatography (HPLC), the separation conditions were: the chromatographic column was Chiracel IC, the mobile phase was i PrOH / Hexane=10 / 90, mobile phase is 1.0mL / min, retention time and peak area are t R1 =17.15min,98.7%,t R2 =20.27min,1.3%.

[0079] Embodiment 14:

[0080]

[0081] 3,4-dihydro-β-carboline oxide 1a (19 mg, 0.1 mmol) and oxazolone 2c (34 mg, 0.15 mmol) were added to the reaction flask in sequence, DCE (1.0 mL) was added, and finally chiral phosphoric acid catalyst E (7.5 mg, 0.01 mmol) was added, and the reaction was carried out at 25°C for 5 hours. After the reaction, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate = 30:1-20:1) to obtain the target product 3n (29 mg), with a yield of 71%, dr>19 / 1, and ee=97%. The product 3n was analyzed, and the results were as follows: the melting point was 110.1-110.5°C; 1 H NMR (400MHz, CDCl3): δ10.78(s,1H),7.85(d,J=8.5Hz,2H),7.55-7.48(m,4H),7.26-7.23(m,1H),7.16(t,J=7.2Hz,1H),6.88(s,1H) ,5.49(s,1H),3.93-3.80(m,1H),3.58-3.43(m,1H),3.09-3.06(m,2H),2.44-2.39(m,1H),1.84-1.71(m,1H),0.99(t,J=7.4Hz,3H); 13 C NMR (101MHz, CDCl3): δ176.8,166.6,139.1,136.6,131.4,129.3,128.6,126.1,125.8,122.5,119.3,118.3, 111.8,109.9,68.3,63.7,53.1,27.2,20.3,7.4;IR(neat):ν3865,1776,1651,1460,1321,1201,1001,699cm –1 ; HRMS (ESI): m / z [M+H] + calcd.for C 22 H 21 ClN3O3:410.1266; found:410.1268; [α] D 23 = +147.2 (c = 1.60, DCM); the ee value of the product was determined by high performance liquid chromatography (HPLC), the separation conditions were: the chromatographic column was Chiracel IC, the mobile phase was i PrOH / Hexane=10 / 90, mobile phase is 1.0mL / min, retention time and peak area are t R1 =17.85min,98.4%,t R2 =22.57min,1.6%.

[0082] Embodiment 15:

[0083]

[0084] 3,4-dihydro-β-carboline oxide 1a (19 mg, 0.1 mmol) and oxazolone 2d (39 mg, 0.15 mmol) were added to the reaction flask in sequence, CHCl3 (1.0 mL) was added, and finally chiral phosphoric acid catalyst E (7.5 mg, 0.01 mmol) was added, and the reaction was carried out at 25°C for 5 hours. After the reaction, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate = 30:1-20:1) to obtain the target product 3o (29 mg), with a yield of 65%, dr>19 / 1, and ee=95%. The product 3o was analyzed, and the results were as follows: the melting point was 107.6-108.2°C; 1 H NMR (400MHz, CDCl3): δ10.72(s,1H),8.03(d,J=8.1Hz,2H),7.82(d,J=8.2Hz, 2H),7.55(d,J=7.8Hz,1H),7.51(d,J=8.2Hz,1H),7.26-7.23(m,1H),7.16(t,J =7.2Hz,1H),6.96(s,1H),5.51(s,1H),3.94-3.80(m,1H),3.61-3.44(m,1H),3 .10-3.07(m,2H),2.45-2.40(m,1H),1.85-1.74(m,1H),1.00(t,J=7.4Hz,3H); 13 CNMR (101MHz, CDCl3): δ177.0,164.5,134.8,134.5,133.0(q,J C-F =33.3Hz),125.8,125.3(q,J C-F =244.0Hz),124.3(q,J C-F =3.6Hz),124.1,124.0,120.7,117.6,116.4,109.9,108.2,66.7,62.1,51.2,25.2 ,18.4,5.6;IR(neat):ν3848,1764,1658,1544,1461,1330,1133,1070,1019,737cm –1 ; HRMS (ESI): m / z [M+H] + calcd.for C 23 H 21 F3N3O3:444.1530; found:444.1526; [α] D23 = +114.7 (c = 0.90, DCM); the ee value of the product was determined by high performance liquid chromatography (HPLC), the separation conditions were: the chromatographic column was Chiracel IC, the mobile phase was i PrOH / Hexane=20 / 80, mobile phase is 1.0mL / min, retention time and peak area are t R1 =8.20min,97.3%,t R2 =9.27min,2.7%.

[0085] Embodiment 16:

[0086]

[0087] 3,4-dihydro-β-carboline oxide 1a (19 mg, 0.1 mmol) and oxazolone 2e (33 mg, 0.15 mmol) were added to the reaction flask in sequence, CHCl3 (1.0 mL) was added, and finally chiral phosphoric acid catalyst E (7.5 mg, 0.01 mmol) was added, and the reaction was carried out at 25°C for 5 hours. After the reaction, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate = 30:1-20:1) to obtain the target product 3p (25 mg), with a yield of 58%, dr>19 / 1, and ee=95%. The product 3p was analyzed, and the results were as follows: the melting point was 104.6-105.3°C; 1 H NMR (400MHz, CDCl3): δ10.92 (s, 1H), 7.81 (d, J = 8.2Hz, 2H), 7.55 (d, J = 7.8Hz, 1H),7.51(d,J=8.2Hz,1H),7.34(d,J=8.0Hz,2H),7.26-7.22(m,1H),7.16(t,J =7.8Hz,1H),6.90(s,1H),5.51(s,1H),3.95-3.77(m,1H),3.57-3.41(m,1H),3 .09-3.06(s,2H),2.46-2.42(m,4H),1.84-1.70(m,1H),1.00(t,J=7.4Hz,3H); 13 CNMR (101MHz, CDCl3): δ177.2,167.6,143.4,136.6,130.2,129.6,127.1,126.4,125.8,122.4,119.2,118.2,111. 8,109.7,68.4,63.5,53.1,27.0,21.5,20.3,7.4;IR(neat):ν3841,1753,1704,1657,1511,1460,1323,999,743cm–1 ; HRMS (ESI): m / z [M+H] + calcd.forC 23 H 24 N3O3:390.1812; found:390.1806; [α] D 23 = +209.9 (c = 1.10, DCM); the ee value of the product was determined by high performance liquid chromatography (HPLC), the separation conditions were: the chromatographic column was Chiracel IC, the mobile phase was i PrOH / Hexane=5 / 95, mobile phase is 1.0mL / min, retention time and peak area are t R1 =32.30min,99.6%,t R2 =37.36min,0.4%.

[0088] Embodiment 17:

[0089]

[0090] 3,4-dihydro-β-carboline oxide 1a (19 mg, 0.1 mmol) and oxazolone 2f (37 mg, 0.15 mmol) were added to the reaction flask in sequence, CHCl3 (1.0 mL) was added, and finally chiral phosphoric acid catalyst E (7.5 mg, 0.01 mmol) was added, and the reaction was carried out at 25°C for 5 hours. After the reaction, the product was purified by simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate = 30:1-20:1) to obtain the target product 3q (25 mg), with a yield of 58%, dr>19 / 1, and ee = 95%. The product 3q was analyzed, and the results were as follows: the melting point was 158.9-159.5°C; 1 H NMR (400MHz, CDCl3): δ10.93(s,1H),7.85(d,J=8.5Hz,2H),7.56-7.50(m,4H),7.27-7.23(m,1H),7.16(t,J=7.8Hz,1H),6.92(s,1H),5.52 (s,1H),3.93-3.78(m,1H),3.62-3.41(m,1H),3.10-3.07(m,2H),2.46-2.41(m,1H),1.83-1.68(m,1H),1.38(s,9H),1.00(t,J=7.4Hz,3H); 13C NMR (101MHz, CDCl3): δ177.2,167.6,156.4,136.6,130.2,127.0,126.4,125.9,125.8,122.4,119.2,118.2,111.8,109. 7,68.5,63.7,53.1,35.1,31.1,26.9,20.3,7.4;IR(neat):ν3885,1768,1643,1533,1504,1464,1329,1157,1020,669cm –1 ; HRMS (ESI): m / z [M+H] + calcd.for C 26 H 30 N3O3:432.2282; found:432.2276; [α] D 23 = +176.3 (c = 1.50, DCM); the ee value of the product was determined by high performance liquid chromatography (HPLC), the separation conditions were: the chromatographic column was Chiracel IC, the mobile phase was i PrOH / Hexane=10 / 90, mobile phase is 1.0mL / min, retention time and peak area are t R1 =17.24min,97.5%,t R2 =21.05min,2.5%.

[0091] Embodiment 18:

[0092]

[0093] 3,4-dihydro-β-carboline oxide 1a (19 mg, 0.1 mmol) and 2 g of oxazolone (30 mg, 0.15 mmol) were added to the reaction flask in sequence, CHCl3 (1.0 mL) was added, and finally chiral phosphoric acid catalyst E (7.5 mg, 0.01 mmol) was added, and the reaction was carried out at 25°C for 5 hours. After the reaction, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate = 30:1-20:1) to obtain the target product 3r (30 mg), with a yield of 77%, dr>19 / 1, and ee = 96%. The product 3r was analyzed, and the results were as follows: the melting point was 97.8-98.3°C; 1H NMR (400MHz, CDCl3): δ10.89 (s, 1H), 7.72-7.68 (m, 2H), 7.56 (d, J = 7.9Hz, 1H ),7.52(d,J=8.1Hz,1H),7.43-7.40(m,2H),7.27-7.23(m,1H),7.16(t,J=7. 8Hz,1H),6.92(s,1H),5.53(s,1H),3.97-3.75(m,1H),3.61-3.44(m,1H),3. 09-3.07(m,2H),2.47-2.41(m,4H),1.82-1.72(m,1H),1.01(t,J=7.4Hz,3H); 13 C NMR (101MHz, CDCl3): δ177.2,167.9,139.0,136.6,133.4,133.1,128.9,127.7,126.3,125.8,124.1,122.4,119.3,11 8.2,111.8,109.8,68.4,63.7,53.1,26.5,21.3,20.3,7.4;IR(neat):ν3847,1642,1513,1501,1349,1147,1002,745cm –1 ; HRMS (ESI): m / z [M+H] + calcd.forC 23 H 24 N3O3:390.1812; found:390.1806; [α] D 23 = +142.4 (c = 1.50, DCM); the ee value of the product was determined by high performance liquid chromatography (HPLC), the separation conditions were: the chromatographic column was Chiracel IC, the mobile phase was i PrOH / Hexane=10 / 90, mobile phase is 1.0mL / min, retention time and peak area are t R1 =18.12min,98.2%,t R2 =22.87min,1.8%.

[0094] Embodiment 19:

[0095]

[0096] 3,4-dihydro-β-carboline oxide 1a (19 mg, 0.1 mmol) and oxazolone 2h (36 mg, 0.15 mmol) were added to the reaction flask in sequence, CHCl3 (1.0 mL) was added, and finally chiral phosphoric acid catalyst E (7.5 mg, 0.01 mmol) was added, and the reaction was carried out at 25°C for 5 hours. After the reaction, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate = 30:1-20:1) to obtain the target product 3s (28 mg), with a yield of 65%, dr>19 / 1, and ee=95%. The product 3s was analyzed, and the results were as follows: the melting point was 106.4-106.9°C; 1 H NMR (400MHz, CDCl3): δ10.94(s,1H),8.43(s,1H),8.02-7.99(m,2H),7.95-7. 92(m,2H),7.67-7.60(m,2H),7.57-7.52(m,2H),7.28-7.24(m,1H),7.17(t,J= 7.8Hz,1H),7.09(s,1H),5.58(s,1H),4.00-3.79(m,1H),3.66-3.43(m,1H),3 .10-3.08(m,2H),2.51-2.46(m,1H),1.88-1.74(m,1H),1.05(t,J=7.4Hz,3H); 13 C NMR (101MHz, CDCl3): δ177.1,167.7,136.6,135.2,132.5,130.2,129.1,129.0,128.4,128.0,127.8,127.2,126.3,125.9,123.1,12 2.4,119.3,118.2,111.8,109.8,68.6,63.8,53.1,26.9,20.3,7.5;IR(neat):ν3438,1776,1640,1567,1510,1461,1326,1158,800cm –1 ; HRMS (ESI): m / z [M+H] + calcd.for C 26 H 24 N3O3:426.1812; found:426.1808; [α] D 23 = +141.0 (c = 1.40, DCM); the ee value of the product was determined by high performance liquid chromatography (HPLC), the separation conditions were: the chromatographic column was Chiracel IC, the mobile phase was iPrOH / Hexane=10 / 90, mobile phase is 1.0mL / min, retention time and peak area are t R1 =26.14min,97.5%,t R2 =39.08min,2.5%.

[0097] Embodiment 20:

[0098]

[0099] 3,4-dihydro-β-carboline oxide 1a (19 mg, 0.1 mmol) and oxazolone 2i (36 mg, 0.15 mmol) were added to the reaction flask in sequence, CHCl3 (1.0 mL) was added, and finally a chiral phosphoric acid catalyst (7.5 mg, 0.01 mmol) was added, and the reaction was carried out at 25°C for 5 hours. After the reaction, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate = 30:1-20:1) to obtain the target product 3t (20 mg), with a yield of 52%, dr>19 / 1, and ee = 97%. The product 3t was analyzed, and the results were as follows: the melting point was 97.8-98.7°C; 1 H NMR (400MHz, CDCl3): δ10.71(s,1H),7.66-7.62(m,2H),7.54-7.48(m,2H),7.25-7.22(m,1H),7.18-7.11(m,2H),6.77(s,1H),5. 50(s,1H),3.92-3.80(m,1H),3.58-3.42(m,1H),3.08-3.06(m,2H),2.43-2.37(m,1H),1.82-1.72(m,1H),1.00(t,J=7.4Hz,3H); 13 C NMR (101MHz, CDCl3): δ176.7,162.1,137.4,136.6,131.9,129.3,128.1,126.1,125.8,122.4,119.3,118.2,11 1.9,109.9,68.5,63.7,53.1,27.2,20.3,7.4;IR(neat):ν3575,1776,1657,1562,1544,1510,1460,1324,699cm –1 ; HRMS (ESI): m / z [M+H] + calcd.for C 20 H 20 N3O3S:382.1220; found:382.1223; [α] D 23= +152.1 (c = 0.80, DCM); the ee value of the product was determined by high performance liquid chromatography (HPLC), the separation conditions were: the chromatographic column was Chiracel IC, the mobile phase was i PrOH / Hexane=20 / 80, mobile phase is 1.0mL / min, retention time and peak area are t R1 =15.86min,98.7%,t R2 =17.94min,1.3%.

[0100] Embodiment 21:

[0101]

[0102] 3,4-dihydro-β-carboline oxide 1a (19 mg, 0.1 mmol) and oxazolone 2j (26 mg, 0.15 mmol) were added to the reaction flask in sequence, CHCl3 (1.0 mL) was added, and finally a chiral phosphoric acid catalyst (7.5 mg, 0.01 mmol) was added, and the reaction was carried out at 25°C for 5 hours. After the reaction, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate = 30:1-20:1) to obtain the target product 3u (24 mg), with a yield of 66%, dr>19 / 1, and ee = 94%. The product 3u was analyzed, and the results were as follows: the melting point was 105.5-105.9°C; 1 H NMR (400MHz, CDCl3): δ10.77(s,1H),7.89-7.86(m,2H),7.63(t,J=7.4Hz,1H),7.56-7.50(m,4H),7.27-7.25(m,1H),7 .16(t,J=7.8Hz,1H),6.94(s,1H),5.53(s,1H),3.92-3.83(m,1H),3.47-3.37(m,1H),3.09-3.06(m,2H),1.65(s,3H); 13 CNMR (101MHz, CDCl3): δ178.8,167.5,136.7,133.2,132.7,129.0,127.1,126.8,125.8,122.5,119.3,118.3, 111.8,109.8,67.5,61.3,53.1,21.6,20.1;IR(neat):ν3863,1776,1657,1562,1544,1460,1321,1260,699cm –1 ; HRMS (ESI): m / z [M+H] + calcd.for C 21 H 20N3O3:362.1499; found:362.1494; [α] D 23 = +161.8 (c = 0.55, DCM); the ee value of the product was determined by high performance liquid chromatography (HPLC), the separation conditions were: the chromatographic column was Chiracel IC, the mobile phase was i PrOH / Hexane=20 / 80, mobile phase is 1.0mL / min, retention time and peak area are t R1 =30.68min,3.0%,t R2 =36.23min,97.0%.

[0103] Embodiment 22:

[0104]

[0105] 3,4-dihydro-β-carboline oxide 1a (19 mg, 0.1 mmol) and oxazolone 2k (30 mg, 0.15 mmol) were added to the reaction flask in sequence, CHCl3 (1.0 mL) was added, and finally a chiral phosphoric acid catalyst (7.5 mg, 0.01 mmol) was added, and the reaction was carried out at 25°C for 5 hours. After the reaction, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate = 30:1-20:1) to obtain the target product 3v (21 mg), with a yield of 54%, dr>19 / 1, and ee = 94%. The product 3v was analyzed, and the results were as follows: the melting point was 96.8-97.3°C; 1 H NMR (400MHz, CDCl3): δ10.90 (s, 1H), 7.91-7.88 (m, 2H), 7.64 (t, J = 7.4Hz, 1 H),7.56-7.51(m,4H),7.28-7.24(m,1H),7.17(t,J=7.7Hz,1H),6.96(s,1H) ,5.49(s,1H),3.97-3.77(m,1H),3.60-3.43(m,1H),3.10-3.08(m,2H),2.3 7-2.34(m,1H),1.69-1.57(m,2H),1.43-1.34(m,1H),0.82(t,J=7.3Hz,3H); 13C NMR (101MHz, CDCl3): δ177.2,167.6,136.6,133.1,132.7,129.0,127.1,126.3,125.9,122.4,119.3,118.2,111 .9,109.8,68.3,63.5,53.1,35.7,20.3,16.5,13.9;IR(neat):ν3863,1717,1657,1460,1323,1118,1094,732cm –1 ; HRMS (ESI): m / z [M+H] + calcd.for C 23 H 24 N3O3:390.1812; found:390.1804; [α] D 23 = +136.1 (c = 0.9, DCM); the ee value of the product was determined by high performance liquid chromatography (HPLC), the separation conditions were: the chromatographic column was Chiracel IC, the mobile phase was i PrOH / Hexane=10 / 90, mobile phase is 1.0mL / min, retention time and peak area are t R1 =15.53min,97.0%,t R2 =22.04min,3.0%.

[0106] Embodiment 23:

[0107]

[0108] 3a (19 mg, 0.05 mmol) was dissolved in a mixed solvent of THF (0.5 mL), AcOH (0.5 mL) and H2O (0.17 mL), and Zn powder (49 mg, 0.75 mmol) was added. After reacting at 25°C for 1 h, the mixture was filtered and the filtrate was dried by spin drying. The product 4a (19 mg) was obtained by column chromatography (DCM: MeOH = 20: 1) with a yield of 99% and ee = 97%. The product 4a was analyzed and the results were as follows: the melting point was 216.2-216.9°C; 1H NMR (400MHz, CDCl3:CD3OD,5:1): δ7.54-7.51(m,2H),7.40-7.36(m,1H),7.30-7.25(m,4H),7.09-7.05(m,1H),6.98-6.85(m,1H),5.38( s,1H),3.83(dd,J=11.8,3.8Hz,1H),3.22-3.15(m,1H),3.02-2.85(m,2H),2.44-2.36(m,1H),2.16-2.07(m,1H),0.95(t,J=7.1Hz,3H); 13 C NMR (101MHz, CDCl3:CD3OD,5:1): δ172.6,169.3,136.4,132.3,132.3,128.5,126.9,125.5,125.3,122.7,119.5,1 17.8,111.6,108.6,67.8,59.7,42.7,23.5,18.4,8.6;IR(neat):ν3430,1781,1634,1544,1328,1211,1150,699cm –1 ; HRMS (ESI): m / z [M+H] + calcd.for C 22 H 24 N3O3:378.1812; found:378.1813; [α] D 23 =-23.18 (c = 0.65, MeOH); the ee value of the product was determined by high performance liquid chromatography (HPLC), the separation conditions were: the chromatographic column was Chiracel IC, the mobile phase was i PrOH / Hexane=40 / 60, mobile phase is 1.0mL / min, retention time and peak area are t R1 =9.09min,98.6%,t R2 =14.53min,1.4%.

[0109] Embodiment 24:

[0110]

[0111] 3d (19.5 mg, 0.05 mmol) was dissolved in a mixed solvent of THF (0.5 mL), AcOH (0.5 mL) and H2O (0.17 mL), and Zn powder (32.5 mg, 0.50 mmol) was added. After reacting at 25°C for 1 h, the mixture was filtered and the filtrate was dried by spin chromatography (DCM: MeOH = 20: 1) to obtain product 4b (13 mg) with a yield of 99%. The product 4b was analyzed and the results were as follows: the melting point was 143.8-144.7°C; 1 H NMR (400MHz, CDCl3): δ11.94(s,1H),10.71(s,1H),9.00(s,1H),8.53(s,1H),7.6 4(d,J=7.6Hz,2H),7.46(t,J=7.3Hz,1H),7.35(t,J=7.4Hz,2H),7.19-7.17(m,1H) ,7.00-6.95(m,1H),6.73(d,J=6.8Hz,1H),5.62(s,1H),3.98(s,1H),3.28-3.19(m ,2H),2.63-2.56(m,1H),2.51-2.39(m,4H),2.14-2.10(m,1H),1.00-0.97(m,3H); 13 C NMR (101MHz, CDCl3): δ173.9,169.0,136.7,132.9,132.2,130.1,128.6,127.1,126.1,124.8,122.5,120.9,109. 5,68.2,59.4,42.7,29.7,24.1,20.9,19.6,8.8;IR(neat):ν3353,1658,1640,1512,1485,1461,1378,1098,699cm –1 ; HRMS (ESI): m / z [M+H] + calcd.for C 23 H 26 N3O3:392.1969; found:392.1964; [α] D 23 = -21.0 (c = 0.85, DCM).

[0112] Embodiment 25:

[0113]

[0114] 3f (23 mg, 0.05 mmol) was dissolved in a mixed solvent of THF (0.5 mL), AcOH (0.5 mL) and H2O (0.17 mL), and Zn powder (49 mg, 0.75 mmol) was added. After reacting at 25°C for 1 h, the mixture was filtered and the filtrate was dried by spin chromatography (DCM: MeOH = 20: 1) to obtain product 4c (17 mg) with a yield of 75%. The product 4c was analyzed and the results were as follows: the melting point was 172.1-173.0°C; 1 HNMR (400MHz, CDCl3): δ12.27(s,1H),10.68(s,1H),9.02(s,1H),8.45(s,1H ),7.60(d,J=7.4Hz,2H),7.48-7.44(m,2H),7.36-7.32(m,2H),7.17-7.12(m ,2H),5.69(s,1H),3.92-3.89(m,1H),3.32-3.22(m,1H),3.02-2.96(m,1H), 2.87-2.84(m,1H),2.59-2.55(m,1H),2.43-2.39(m,1H),0.88-0.84(m,3H); 13 C NMR (101MHz, CDCl3): δ174.0,169.3,135.2,132.7,132.3,128.7,128.2,127.4,127.1,125.4,120.8,113.2,11 2.9,108.8,68.2,59.2,42.3,24.0,18.5,8.9;IR(neat):ν3463,1656,1639,1511,1481,1264,1094,801,691cm –1 ; HRMS (ESI): m / z [M+H] + calcd.for C 22 H 23 BrN3O3:456.0917; found:456.0908; [α] D 23 = -21.0 (c = 0.85, DCM).

[0115] Embodiment 26:

[0116]

[0117] 3n (21 mg, 0.05 mmol) was dissolved in a mixed solvent of THF (0.5 mL), AcOH (0.5 mL) and H2O (0.17 mL), and Zn powder (49 mg, 0.75 mmol) was added. After reacting at 25°C for 1 h, the mixture was filtered and the filtrate was dried by spin chromatography (DCM: MeOH = 20: 1) to obtain product 4d (13 mg) with a yield of 65%. The product 4d was analyzed and the results were as follows: the melting point was 208.5-209.4°C; 1 HNMR (400MHz, CDCl3): δ7.52-7.48(m,2H),7.36-7.28(m,4H),7.15-7.11(m,1H),7.05-7.01(m,1H),5.40(s,1H), 3.71-3.65(m,1H),3.26-3.20(m,1H),3.06-2.93(m,2H),2.43-2.36(m,1H),2.13-2.07(m,1H),0.98-0.95(m,3H); 13 C NMR (101MHz, CDCl3): δ172.3,168.2,138.6,136.4,130.7,130.6,128.7,128.3,125.2,122.7,119.6,117.8,111. 5,108.5,67.8,59.7,42.7,23.5,18.4,8.5;IR(neat):ν3383,1704,1658,1563,1511,1461,1327,1020,799,670cm –1 ; HRMS (ESI): m / z [M+H] + calcd.for C 22 H 23 ClN3O3:412.1422; found:412.1415; [α] D 23 =-55.6 (c=0.60, DCM).

[0118] Embodiment 27:

[0119]

[0120] 3v (19.5 mg, 0.05 mmol) was dissolved in a mixed solvent of THF (0.5 mL), AcOH (0.5 mL) and H2O (0.17 mL), and Zn powder (49 mg, 0.75 mmol) was added. After reacting at 25°C for 1 h, the mixture was filtered and the filtrate was dried by spin drying. The product 4e (12 mg) was obtained by column chromatography (DCM: MeOH = 20: 1) with a yield of 63%. The product 4e was analyzed and the results were as follows: the melting point was 197.6-198.2°C; 1 H NMR (400MHz, CDCl3+CD3OD): δ7.52-7.48(m,2H),7.37(t,J=7.5Hz,1H),7.28-7.21(m,4H),7.06(t,J=7.6Hz,1H),6.96-6.92(m,1H) ,5.29(s,1H),3.18-3.11(m,1H),3.00-2.84(m,2H),2.27-2.20(m,1H),1.98-1.91(m,1H),1.42-1.19(m,3H),0.87(t,J=7.3Hz,3H); 13 CNMR (101MHz, CDCl3+CD3OD): δ172.5,169.3,136.4,132.3,132.2,128.5,126.9,125.3,125.2,122.7,119.5,117.7,111. 5,108.5,67.2,59.8,42.7,32.6,18.3,17.6,13.7;IR(neat):ν3459,1703,1656,1561,1510,1460,1439,1314,955,699cm –1 ; HRMS (ESI): m / z [M+H] + calcd.for C 23 H 26 N3O3:392.1969; found:392.1962; [α] D 23 =-59.6 (c=0.30, DCM).

[0121] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A catalytic synthesis method of chiral isoxazol-5-one, characterized in that: The method comprises the following steps: using 3,4-dihydro-β-carboline oxide and oxazolone as reactants, adding a halogenated hydrocarbon solvent to dissolve, adding chiral phosphoric acid as a catalyst, reacting at 25-60° C. for 5-24 hours, and obtaining a chiral isoxazol-5-one compound represented by formula (I):

2. The catalytic synthesis method of chiral isoxazol-5-one according to claim 1, characterized in that: In terms of molar amount, the amount of the chiral phosphoric acid is 5-20% of the 3,4-dihydro-β-carboline oxide; the amount of the oxazolone is 1-2 times of the 3,4-dihydro-β-carboline oxide.

3. The catalytic synthesis method of chiral isoxazol-5-one according to claim 1, characterized in that: The halogenated alkane solvent is dichloromethane, 1,2-dichloroethane or chloroform.

4. The catalytic synthesis method of chiral isoxazol-5-one according to claim 1, characterized in that: The chemical structural formula of the 3,4-dihydro-β-carboline oxide is Where R 1 It is selected from the group consisting of hydrogen, 5-fluoro, 5-chloro, 5-bromo, 5-methyl, 6-fluoro, 6-chloro, 6-bromo, 6-methyl, 6-methoxy, 7-fluoro, 7-chloro, 7-bromo, 7-methoxycarbonyl, 7-methyl, 8-fluoro, 8-bromo, 8-methyl, 8-methoxy or 6,7-dichloro.

5. The catalytic synthesis method of chiral isoxazol-5-one according to claim 1, characterized in that: The chemical structural formula of the oxazolone is Where R 2 is selected from phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 4-methylphenyl, 4-tert-butylphenyl, 3-methylphenyl, 2-fluorophenyl, 2-naphthyl or 2-thienyl; R 3 Selected from methyl, ethyl, n-propyl or isobutyl.

6. The catalytic synthesis method of chiral isoxazol-5-one according to claim 1, characterized in that: The chiral phosphoric acid is one of the following AF:

7. The catalytic synthesis method of chiral isoxazol-5-one according to claim 1, characterized in that: After the reaction is completed, the method further comprises the step of separation and purification by column chromatography.

8. A method for synthesizing α,β-amino acids using the chiral isoxazol-5-one of claim 1, characterized in that: The following steps are involved: The isoxazol-5-one represented by formula (I) is used as a reactant, zinc powder is added, and the reaction is carried out in a mixed solvent of acetic acid, tetrahydrofuran and water at 25-40° C. for 1-12 hours to obtain a chiral α, β-amino acid represented by formula (II):

9. The method for synthesizing a chiral isoxazol-5-one derivative according to claim 8, wherein the amount of the zinc powder used is 10-15 times that of the isoxazol-5-one in terms of molar amount.

10. The method for synthesizing a chiral isoxazol-5-one derivative according to claim 8, characterized in that: After the reaction is completed, the method further comprises the step of separation and purification by column chromatography.

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